The chemistry of enamines Part 1
The chemistry of enamines Part 2
THE CHEMISTRY OF FUNCTIONAL GROUPS
A series of advanced treatises under the general editorship of
Professors Saul Patai and Zvi Rappoport The chemistry of alkenes (2 volumes) The chemistry of the carbonyl group (2 volumes) The chemistry of the ether linkage The chemistry of the amino group The chemistry of the nitro and nitroso groups (2 parts) The chemistry of carboxylic acids and esters The chemistry of the carbon-nitrogen double bond The chemistry of amides The chemistry of the cyano group The chemistry of the hydroxyl group ( 2 parts) The chemistry of the azido group The chemistry of acyl halides The chemistry of the carbon-halogen bond (2 pans) The chem~stryof the quinono~dcompounds (2 volumes, 4 parts) The chemistry of the thiol group (2 parts) The chemistry of the hydrazo, azo and azoxy groups (2 parts) The chemistry of amdines and irnidates (2 volumes) The chemistry of cyanates and their thio derivatives (2 parts) The chemistry of diazonium and diazo groups (2 parts) The chemistry of the carbon-carbon triple bond (2 parts) The chemistry of ketenes, allenes and related compounds (2 parts) The chemistry of the sulphonium group (2 parts) Supplement A: The chemistry of double-bonded functional groups (2 volumes. 4 parts) Supplement 6 : The chemistry of acid derivatives (2 volumes, 4 parts) Supplement C: The chemistry of triple bonded functional groups (2 parts) Supplement D: The chemistry of halides, pseudo-halides and azides (2 parts) Supplement E: The chemistry of ethers. crown ethers, hydroxyl groups and their sulphur analogues (2 volumes, 3 parts) Supplement F: The chemistry of amino. nitroso and nitro compounds and their derivatives (2 parts) The chemistry of the metal-carbon bond (5 volumes) The chemistrv of ~eroxides The chemistry of organic selenium and tellurium compounds (2 volumes) The chem~stryof the cyclopropyl group (2 parts) The chemistry of sulphones and sulphoxides The chemistry of organic silicon compounds (2 parts) The chemistry of enones (2 parts) The chemistrv of sulohinic acids. esters and their derivatives The chemistry of iulphenic aclds and their derivatives The chernistrv of enols Tne cnemistrv of organopnospnor,~ compoLnas ( 3 vol,mes) of s ~ l p n o nc acios esters and trier arr vatlves Ttie ctiem~srr~ Thechemistry of alkanes and cycloalkanes Supplement S: The chemistry of sulphur-containing functional groups The chemistry of organic arsenic, antimony and bismuth compounds The chemistry of enamines UPDATES The chemistry of a-haloketones. a-haloaldehydes and a-haloimines Nitrones, nitronates and nitroxides Crown ethers and analogs Cyclopropane-derived reactive intermediates Synthesis of carboxylic acids, esters and their derivatives The silicon-heteroatom bond Syntheses of lactones and lactams The syntheses of sulphones, sulphoxides and cyclic sulphides Patai's 1992 guide to the chemistry of functional groups-Saul
Patai
Copyright 01994 by John Wiley & Sons Ltd, Baffins Lane, Chichester, West Sussex PO19 IUD, England Telephone: National Chichester (0243) 779777 International +44 243 779777 All rights reserved. No part of this book may be reproduced by any means, or transmitted, or translated into a machine language without the written permission of the publisher. Other Wiley Editorial Ofices John Wiley & Sons, Inc., 605 Third Avenue, New York, NY 10158-0012, USA Jacaranda Wiley Ltd, 33 Park Road, Milton, Queensland 4064, Australia John Wiley & Sons (Canada) Ltd, 22 Worcester Road, Rexdale, Ontario M9W 1L1, Canada John Wiley & Sons (SEA) Pte Ltd, 37 Jalan Pemimpin #05-04, Block B, Union Industrial Building, Singapore 2057
British Library Cataluguing in Publication Data A catalogue record for this book is available from the British Library
ISBN 0 471 93339 2 Typeset in 9/10pt Times by Techset Composition, Salisbury, Wilts. Printed and bound in Great Britain by Biddles, Guildford, Surrey
To my good friend
Hiroshi Taniguchi
The chemistry of enamines Part 1
Edited by
Zvr RAPPOPORT The Hebrew University, Jerusalem
JOHN WILEY & SONS CHICHESTER-NEW
YORK-BRISBANE-TORONTO-SINGAPORE An Interscience" Publication
The chemistry of enamines Part 2
Edited by ZVI RAPPOPOKT
The Hebrew University, Jerusalem
JOHN WILEY & SONS CHICHESTER-NEW
YORK- BRISBANE-TORONTO-SINGAPORE An Interscience@ Publication
Contributing authors Zeev B. Alfassi Jan-E. Backvall Francisco Garcia Blanco Gerhard V. Boyd Javier Catalan Otakar Cervinka Jose Luis Chiara Rafael Chinchilla Antonio Gomez-Sanchez Gunter Hafelinger
P.W. Hickmott Zhi-Tang Huang Frank Jordan Marianna Kaliska James R. Keeffe
A. Jerry Kresge U w e Kucklander
Department of Nuclear Engineering, Ben Gurion University of the Negev, Beersheva 84105, Israel Department of Organic Chemistry, University of Uppsala, Box 531, S-751 21 Uppsala, Sweden Departamento de Quimica Fisica, Facultad de Farmacia, Ins. Pluridisciplinar, Universidad Complutense de Madrid, Madrid 28040, Spain Department of Organic Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel Departamento de Quimica Fisica Aplicada, Universidad Autonoma de Madrid, Cantoblanco, Madrid 28049, Spain Department of Organic Chemistry, Prague Institute of Chemical Technology, Technicki 5, 166 28 Prague 6, Czech Republic Instituto de Quimica Orghica, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain Department of Organic Chemistry, University of Alicante, Apdo. 99, E-3080 Alicante, Spain Departamento de Quimica Organics, Facultad de Quimica, Universidad de Sevilla, Apartado de Correos 553, 41071 Sevilla, Spain Institut fur Organische Chemie der Universitat Tiibingen, Auf der Morgenstelle 18, D-72076 Tubingen, Germany 7 Quentin Smythe Road, Kloof, Natal 3610, South Africa Institute of Chemistry, Academia Sinica, Beijing 100080, People's Republic of China Department of Chemistry, Rutgers, The State University of New Jersey, 73 Warren Street, Newark, New Jersey 07102, USA Department of Chemistry, Warsaw University, Pasteura str. 1, 02-083 Warsaw, Poland Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, Califotnia 94132, USA Department of Chemistry, University of Toronto, Toronto, Ontario M5S IAl, Canada Institut fiir Pharmazeutische Chemie der HeinrichHeine-Universitat Dusseldorf, Universitat str. 1, D-40225 Dusseldorf 1, Germany
...
Yln
Shekhar V. Kulkarni Rami Lidor Joel F. Liebman Pierre Longiavalle Serge M. Lukyanov Hans-Georg Mack Barbara J . Oleksyn H . Mark Perks Giuliana Pitacco Jan Sandstrom Shimon Shatzmiller Tatsuya Shono Miles G. Siegel Jan Sliwihski Katarzyna Stadnicka Ennio Valentin Mei-Xiang Wang Jeffrey D. Winkler Mieczystaw Zielinski
Contributing authors Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA The Beverly and Raymond Sackler Faculty of Exact Sciences, School of Chemistry, Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel Department of Chemistry and Biochemistry, University of Maryland, Baltimore County Campus, 5401 Wilkens Avenue, Baltimore, Maryland 21228-5398, USA lnstitut de Chimie des Substances Naturelles du Centre National de la Recherche Scientifique, 91190 Gif sur Yvette, France Institute of Physical and Organic Chemistry, Rostov State University, 344711 Rostov on Don, Russia lnstitut fiir Physikalische und Theoretische Chemie der Universitat Tiibingen, Auf der Morgenstelle 8, D-72076 Tiibingen, Germany Faculty of Chemistry, Jagiellonian University, ul-R. Ingardena 3, 30-060 Krakbw, Poland Department of Chemistry, The Johns Hopkins University, Charles and 34th Streets, Baltimore, Maryland 21218, USA Dipartimento di Scienze Chimiche, Universita degli Studi di Trieste, Via Licio Giorgieri 1, 34135 Trieste, Italy Division of Organic Chemistry 3, Chemical Center, University of Lund, P.O. Box 124, S-22100 Lund, Sweden The Beverly and Raymond Sackler Faculty of Exact Sciences, School of Chemistry, Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel Department of Synthetic Chemistry, Kyoto University, Kyoto 606-01, Japan Department of Chemistry, The University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Faculty of Chemistry, Jagiellonian University, ul. R. Ingardena 3, 30-060 Krakbw, Poland Faculty of Chemistry, Jagiellonian University, ul. R. Ingardena 3, 30-060 Krakow, Poland Dipartimento di Scienze Chimiche, Universita degli Studi di Trieste, Via Licio Giorgieri 1, 34135 Trieste, Italy Institute of Chemistry, Academia Sinica, Beijing 100080, People's Republic of China Department of Chemistry, The University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Isotope Laboratory, Faculty of Chemistry, Jagiellonian University, ul. lngardena 3, 30-060 Krakow, Poland
In recent years The Chemistry of Functional Groups series included two volumes on composite functional groups in which a C=C double bond was attached to a C=O or an OH group. The present volume now joins The Chemistry of Enones (edited by S . Patai and Z. Rappoport, 1989) and The Chemistry of Enols (edited by Z . Rappoport, 1990).The two functional groups involved, i.e. C=C and NR1R2 influence one another in such a way that the usual properties of these groups are modified and new types of behaviour are observed. The 26 chapters, written by experts from 14 countries, cover a wide spectrum of topics related to the chemistry of enamines, including theory, structural chemistry, spectral properties, formation, reactions and stereochemistry, acidities, rearrangements, oxidation and reduction, as well as other topics. In two chapters, the material related to enamines was meagre. Hence, the chapter on radiation chemistry also deals with compounds with non-conjugated C=C and amino groups, and the chapter on synthesis and uses of isotopically labelled enamines includes enamines in which the nitrogen is part of a heterocyclic system. The literature coverage is mostly up to 1992. 1 will be grateful to readers who will call my attention to mistakes or omissions in the present volume. Jerusalem February, 1994
The Chemistry of Functional Groups Preface to the series The series 'The Chemistry of Functional Groups' was originally planned to cover in each volume all aspects of the chemistry of one of the important functional groups in organic chemistry. The emphasis is laid on the preparation, properties and reactions of the functional group treated and on the effects which it exerts both in the immediate vicinity of the group in question and in the whole molecule. A voluntary restriction on the treatment of the various functional groups in these volumes is that material included is easily and generally available in secondary or tertiary sources, such as Chemical Reviews, Quarterly Reviews, Organic Reactions, various 'Advances' and 'Progress' series and in textbooks (i.e. in books which are usually found in the chemical libraries of most universities and research institutes), should not, as a rule, be repeated in detail, unless it is necessary for the balanced treatment of the topic. Therefore each of the authors is asked not to give an encyclopaedic coverage of his subject, but to concentrate on the most important recent developments and mainly on material that has not been adequately covered by reviews or other secondary sources by the time of writing of the chapter, and to address himself to a reader who is assumed to be at a fairly advanced postgraduate level. It is realized that no plan can be devised for a volume that would give a complete coverage of the field with no overlap between chapters, while at the same time preserving the readability of the text. The Editors set themselves the goal of attaining reasonable coverage with moderate overlap, with a minimum of cross-references between the chapters. In this manner, sufficient freedom is given to the authors to produce readable quasi-monographic chapters. The general plan of each volume includes the following main seclions. (a) An introductory chapter deals with the general and theoretical aspects of the group. (b) Chapters discuss the characterization and characteristics of the functional groups, i.e. qualitative and quantitative methods of determination including chemical and physical methods, MS, UV, IR, NMR, ESR and PES-as well as activating and directive effects exerted by the group, and its basicity, acidity and complex-forming ability. (c) One or more chapters deal with the formation of the functional group in question, either from other groups already present in the molecule or by introducing the new group directly or indirectly. This is usually followed by a description of the synthetic uses of the group, including its reactions, transformations and rearrangements. (d) Additional chapters deal with special topics such as electrochemistry, photochemistry, radiation chemistry, thermochemistry, syntheses and uses of isotopically
xii
Preface to the series
labelled compounds, as well as with biochemistry, pharmacology and toxicology. Whenever applicable, unique chapters relevant only to single functional groups are also included (e.g. 'Polyethers', 'Tetraaminoethylenes' or 'Siloxanes'). This plan entails that the breadth, depth and thought-provoking nature of each chapter will differ with the views and inclinations of the authors and the presentation will necessarily be somewhat uneven. Moreover, a serious problem is caused by authors who deliver their manuscript late or not at all. In order to overcome this problem at least to some extent, some volumes may be published without giving consideration to the originally planned logical order of the chapters. Since the beginning of the Series in 1964, two main developments have occurred. The first of these is the publication of supplementary volumes which contain material relating to several kindred functional groups (Supplements A, B, C, D, E and F). The second ramification is the publication of a series of 'Updates', which contain in each volume selected and related chapters, reprinted in the original form in which they were published, together with an extensive updating of the subjects, if possible, by the authors of the original chapters. A complete list of all above mentioned volumes published to date will be found on the page opposite the inner title page of this book. Advice or criticism regarding the plan and execution of this series will be welcomed by the Editors. The publication of this series would never have been started, let alone continued, without the support of many persons in Israel and overseas, including colleagues, friends and family. The efficient and patient co-operation of staff members of the publisher also rendered us invaluable aid. Our sincere thanks are due to all of them. The Hebrew University Jerusalem. Israel
SAUL PATAI ZVI RAPPOPORT
Contents 1.
Enamines: General and theoret~calaspects
Giinter Hafelinger and Hans-Georg Mack 2.
3.
Structural chemistry of enamines. A statistical approach Barbara J. Oleksyn, Katarzyna Stadnicka and Jan Sliwinski Configuration, conformation and chiroptical properties of enamines
Otakar eervinka
4. Thermochemistry of enamines Joel F. Liebman and H. Mark Perks 5. NMR spectra Jose Luis Chiara and Antonio Gomez-Sanchez 6 . Static and dynamic stereochemistry of acceptor-substituted enamines
Jan Sandstram 7. The reactivity of ionized enamines i n the gas phase Pierre Longiavalle
8. The electrochemistry of enamines Tatsuya Shono 9.
Preparation of enamines
Otakar cervinka
10. Enaminones as synthones Uwe Kucklander 1 1 . Photochemistry of enamines and enaminones Miles G. Siegel and Jeffrey D. Winkler 12. Radiation chemistry of enamines Zeev B. Alfassi
13. Acidity and basicity of enamines Javier Catalin and Francisco Garcia Blanco
xiv 14.
Contents Electrophilic and nucleophilic substitution and addition reactions of enamines
P. W. Hickmott 15. Radical reactions of enarnines
Shekhar V. Kulkarni
16. Rearrangements and tautomerization of enamines Zhi-Tang Huang and Mei-Xiang Wang 1 7 . Oxidation and reduction of enamines Giuliana Pitacco and Ennio Valentin 18. Cycloadditions t o enamines
Rafael Chinchilla and Jan-E. Backvall 19. Mechanisms of enamine hydrolysis
James R. Keeffe and A. Jerry Kresge
20. Syntheses and uses of isotopically labelled enamines Mieczygaw Zielinski and Marianna Kanska 21.
Biochemistry of enamines
Frank Jordan
22, 1.I -Enediamines Zhi-Tang Huang and Mei-Xiang Wang 23. Heterocyclic synthesis from enamines Gerhard V. Boyd 24. Synthesis of N-acylenarnines from carbonyl compounds and nitriles Serge M. Lukyanov 25.
Lithium enamides-lithium
salts of azomethine derivatives
Shimon Shatzmiller and Rami Lidor
26.
Reactions of dienamines
P. W. Hickmott Author index Subject index
List of abbreviations used Ac acac Ad AIBN All An Ar
acetyl (MeCO) acetylacetone adamantyl azobutyronitrile ally1 anisyl aryl benzoyl (C,H,CO) butyl (also r-Bu or But)
CD CI CIDNP CNDO CP
ci)
circular dichroism chemical ionization chemically induced dynamic nuclear polarization complete neglect of differential overlap q5-cyclopentadienyl ~5-pentamethylcyclopentadien~~
DABCO DBN DBU DlBAH DME DMF DMSO
1,4-diazabicyclo[2.2.2]octane 1,5diazabicyclo[4.3.0]non-Sene 1,s-diazabicyclo[5.4.0]undec-7-ene diisobutylaluminium hydride 13-dimethoxyethane N,N-dimethylformamide dimethyl sulphoxide
ee El ESCA ESR' Et eV
enantiomeric excess electron impact electron spectroscopy for chemical analysis electron spin resonance ethyl electron volt ferrocenyl field desorption field ionization Fourier transform furyl (OC,H,)
xvi
List of abbreviations used
GLC
gas-liquid chromatography
Hex c-Hex HMPA HPLC HOMO
h e x ~ l(C6H13) cyclohexyl (C,H, ,) hexamethylphosphortriamide high performance liquid chromatography highest occupied molecular orbital
ICR
is0 ionization potential infrared ion cyclotron reasonance
LAH LCAO LDA LUMO
lithium aluminium hydride linear combination of atomic orbitals lithium diisopropylamide lowest unoccupied molecular orbital
M M MCPBA Me MNDO MS
metal parent molecule mchloroperbenzoic acid methyl modified neglect of diatomic overlap mass spectrum
n Naph NBS NMR
normal naphthyl N-bromosuccinimide nuclear magnetic resonance
PC
phthalocyanine pentyl (CSH, 1) piperidyl (C,H,,N) phenyl parts per million propyl (also i-Pr or Pri) phase transfer catalysis or phase transfer conditions pyridyl (C5H4N)
Pen Pip Ph PPm Pr PTC P Y ~
any radical room temperature SET SOMO
secondary single electron transfer singly occupied molecular orbital
TCNE TFA THF Thi TLC
tertiary tetracyanoethylene trifluoroacetic acid tetrahydrofuran thienyl (SC4H3) thin layer chromatography
S-
List of abbreviations used TMEDA TMS Tol Tos Trityl
xvii
tetramethylethylene diamine trimethylsilyl or tetramethylsilane tolyl (MeC,H,) tosyl (ptoluenesulphonyl) triphenylmethyl (Ph,C)
In addition, entries in the 'List of Radical Names' in IUPAC Nomenclarure of Organic Chemistry, 1979 Edition, Pergamon Press, Oxford, 1979, p. 305-322, will also be used in their unabbreviated forms, both in the text and in formulae instead of explicitly drawn structures.
CHAPTER
1
Enamines: General and theoretical aspects lnstitute of Organic Chemistry. University of Tubingen. Auf der Morgenstelle 18. D-72076 Tubingen. Germany
and HANS-GEORG MACK
.
Institute of Physical and Theoretical Chemistry. University of Tubingen Auf der Morgenstelle 8. D-72076 Tubingen Germany
.
-
I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Basic Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Reviews . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Classifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Substitution at nitrogen . . . . . . . . . . . . . . . . . . . . . . . . . . a. Primary enamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . b. Secondary enamines . . . . . . . . . . . . . . . . . . . . . . . . . . . c. Tertiary enamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . d . Heterosubstitution on nitrogen . . . . . . . . . . . . . . . . . . . . 2. Substitution of the ene part . . . . . . . . . . . . . . . . . . . . . . . . a . Acyclic enamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . b . Endocyclic enamines . . . . . . . . . . . . . . . . . . . . . . . . . . c. Exocyclic enamines . . . . . . . . . . . . . . . . . . . . . . . . . . . d . Heterocyclic enamines . . . . . . . . . . . . . . . . . . . . . . . . . e. Bicyclic enamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I1. MOLECULAR GEOMETRIES . . . . . . . . . . . . . . . . . . . . . . . . . A. Experimental Determinations of Molecular Structures . . . . . . . . . . 1. N-Cyclic tertiary enamines . . . . . . . . . . . . . . . . . . . . . . . . . 2. /%Enaminones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. fi Substituted and miscellaneous enamines . . . . . . . . . . . . . . . 4. a-Substituted enamines . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Summary of experimentally observed variations in molecular structures of enamines . . . . . . . . . . . . . . . . . . . . . . . . . . .
~-
1 1 4
5 5 5 7 7
8 8
8 10 11 11 11 12 12 12 13 17 20 22 23
The Chemistry of Enamines. Edited by Zvi Rappoport Copyrighl 0 1994 John Wiley & Sons. Ltd . ISBN: 0-471-93339-2
G . Hafelinger and H.-G. Mack
2
B . Ab Initio Calculations of Molecular Structures
..............
1. Computational methods . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Notation for Gaussian-type basis functions . . . . . . . . . . . . . . . 3. Vinylamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . a . Ground state geometry . . . . . . . . . . . . . . . . . . . . . . . . . b. Torsion of the NH, group . . . . . . . . . . . . . . . . . . . . . . . c. Enamineimine tautomerism: 2- and E-acetaldehyde imine . . . d . N and C protonation . . . . . . . . . . . . . . . . . . . . . . . . . . 4. a-Substituted vinylamines . . . . . . . . . . . . . . . . . . . . . . . . . 5. E, Z-Isomerism of 8-substituted vinylamines . . . . . . . . . . . . . . 6. N-Substituted vinylamines . . . . . . . . . . . . . . . . . . . . . . . . . a. N-Methyl substituents . . . . . . . . . . . . . . . . . . . . . . . . . b. N-Fluoro substituents . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Citations of special calculations . . . . . . . . . . . . . . . . . . . . . . a. Use of semi-empirical methods . . . . . . . . . . . . . . . . . . . . b . Ab initio calculations . . . . . . . . . . . . . . . . . . . . . . . . . . 111. ENERGETIC RELATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Protonation Energies and Basicities of Enamines . . . . . . . . . . . . . B. Enthalpies of Formation and Hydrogenation . . . . . . . . . . . . . . . C. CC-Tautomerism (Regioisomers) . . . . . . . . . . . . . . . . . . . . . . . IV. ELECTRONIC STRUCTURE: PHOTOELECTRON SPECTROSCOPY AND MO DIAGRAMS . . . . . . . . . . . . . . . . . . A. Experimental Ionization Potentials . . . . . . . . . . . . . . . . . . . . . B. Ab Initio Calculations of Molecular Orbital Energies . . . . . . . . . . . V. DIPOLE MOMENTS AND CONJUGATION . . . . . . . . . . . . . . . VI . SPECTROSCOPIC PROPERTIES . . . . . . . . . . . . . . . . . . . . . . . A. Electron Spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Infrared Spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII . ACKNOWLEDGEMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . VIII. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24
24 24 25 25 29 32 33 39 39 43 43 46 46 46 48 48 48 55 55 58 58 59 62 63 63 69 76 76
.
I INTRODUCTION
.
A Basic Deflnltlons
Enamines of the general formula 1 are vinylogous amines which contain an amino group in the a-position to. and consequently in conjugation with. an olefinic carboncarbon double bond . The term 'enamine' was introduced by Wittig and Blumental' in 1927 in analogy to that of structurally related 'enols' (3). which have already been treated in a previous volume of Patai's series of functional groupsZ. If at least one subsiituent at the nitrogen is hydrogen. the enamines show tautomeric proton exchange to the corresponding imines (2). which are generally thennodynamically the more favoured isomers. as is known also in the case of the keto tautomers (4) of enols (3). Therefore. stable enamines usually
(1) enamine
(2) imine
(3) en01
(4) ketone
1. Enamines: General and theoretical aspects
3
require two non-hydrogen subsliluents on nitrogen. Such tertiary enamines are easily obtained by reaction of aldehydes or ketones with acyclic or cyclic secondary amines3. Some special enamines, such as ethyl /3-aminocrotonate and its alkylation and acetylation products, have already been known since the last century4. The general preparation of enamines was first reported by Mannich and Davidsen5in 1936. However, this class of compounds found widespread synthetic applications only in the fifties due to the pioneering work of Stork and his coworkers6-" and for a long period of time enamines have been studied mainly as synthetic intermediates and as tools for specific mono-substitution of ketones or aldehydes. Due to the n,n-conjugation of the amino group with the C=C double bond, the electron density is increased at the /?-carbon atom as shown below by the mesomeric formula lb. As a consequence enamines may be attacked by electrophiles (EtX-) under neutral and mild conditions either at the electronegative nitrogen (as shown by the mesomeric formula la) leadine often reversiblv,to ammonium salts (6)or at the electronrich /3-carbon (as indicated by the mesomeric formula lb) leading to iminium compounds (7). The second reaction sequence shows the important course of electrophilic substitution of enamines derived frim ketones (5) by selective mono-alkylation or -acylation. This leads to ketones (9)into which they are converted by hydrolysis of the intermediate iminium salt (7) or of the isolable substituted enamine (8) if R4 is hydrogen. These electrophilic substitutions of enamines are called the Stork reaction in honour of their inventorg. Electrophilic reagents, E'X-, may be protons (leading to hydrolysis), reactive alkyl halides (allyl, propargyl or benzyl halides, leading to alkyl derivatives), acyl halides or acid anhydrides (forming keto derivatives), Vilsmeyer reagentsL0 (leading to formyl derivatives), epoxideslL (forming 14-hydroxyketones), thallium triacetate12 or lead
-
R3
I E
R4-C
&\ N-R' 1 4 ~
I R5
I
R2 X-
(6) ammonium salt
\
R3 E I I ,C++ R4-C N-R'
I R5
I R~ X-
Hz0
,
E 0 I II ~4--c-C-R3 I R5
(7) iminium salt
I E-C
&.. I
N-R' I
G. Hafelinger and H.-G. Mack
4
tetraacetate13 (leading to acetoxy substitution) or various electron deficient olefins (leading to substitution or to four-membered rings). The course of the electrophilic substitution of enamines and the yield of products depend critically on the kind of substitution on nitrogen, which may be derived from acyclic or cyclic secondary amines, the ring size of the cyclic nitrogen substituents, the ring size of the ketone part, the substituents on the aldehyde or ketone moiety, the polarity of the solvent and the reaction temperature. It may be extended also to [2 + 23 cycloaddition reactions with electron-deficient olefins substituted by strongly electronattracting (Michael type) sub~tituents'~,with ketenesL5-l7 or with phenyl isocyan a t e ~ ' ~ leading * ' ~ in each case to four-membered rings. 1,3-Dipolar cycloaddition of enamines as dipolarophiles has also been investigatedz0. B. Reviews
Nine years after his first publication6 Stork quoted in his own review articles 90 publications devoted to enamines. Our computer search2' in the chemical abstract service (CAS) resulted in 4389 hits for enamines from 1967 to 1992 (up to Volume 117 of Chemical Abslracts) which indicate the importance, use and applications of enamines. A CAS search for reviews on enamines for the same period yielded 92 hits. However, many of these referred to difficultly accessible sources and have therefore been neglected. Only the 22 most important reviews on preparations, properties and synthetic uses of enamines are listed here2242, and their titles and lengths are given in the list of references.
\
C=C
/
R3
I
\
R'
I
N-C-H
I
I
Li Ph
Classes of variously substituted enamines which are treated in separate review^^^-^^
1. Enamines: General and theoretical aspects
5
Among these reviews, that of Szmuszkoviczz3in 1963 and those of Hickmott3' in 1982 are very extensive and of special value. Our list contains three monograph^^^+^^^.^^. Of these, the second edition of the book of Cook4' published in 1988 is the latest and most extensive available review on enamines. A set of Russian special reviews on enamines was edited in 1990 by A l e k ~ a n d r o vunder ~ ~ the title Enaminy Org. Sint. to which, however, we did not have access. Special classes of substituted enamines are treated in the following reviews: fi-en am in one^^^ (functional group: O=C-C=C-N), P-enaminothi~ketones~~ (S=C-C=C-N), fi-nitr~enarnines~~ (0,N-C=C-N), cyclic fi-enaminonitriles4' (111 (121. ~ ~ 1.2-dihvdroisoo~inolines~~ (101. heterocvclic B-enamino esters48..~ ,enamide~ (13): metallo;nam;nes5' (14). 3-mrtallatzd rnaminrsS2(15a:'l~'b),z-t;aloenat~;ir~s~' (16), keteniminium salts"(l7), tetraaminoethyleness4 (IS) and ynamines" (19)(see Scheme I) C. Classifications 1. Substitution at nitrogen
In analogy to the classification of organic amines, enamines are called primary (20), secondary (21) or tertiary (22) depending on the extent of substitution on nitrogen.
a. Primary enamines. Primary enamines (20) contain two hydrogens as substituents on nitrogen. They tautomerize easily to imines (23), which are generally thermodynamically more stable. The resulting imines may show cis-trans (syn-anti or E,Z) isomerization around the C=N double bond as shown by 23a and 23b (equation 1). Vinylamine (RL= R2 = R3 = H) is the simplest primary enamine. It was prepared by gas-phase pyrolysis of ethylamine and characterized by its microwave spectrum which led to a crude determination of its molecular geometrys6.The interesting question refers to the extent of planarity or tetrahedral geometry of the amino group and this is discussed in the section on calculations of molecular structures. Stable primary enamines have been observed in the case of a- or fi-substitution of enamines by carbonyl or ester groups. The reduction of ethyl 3-methyl-2-nitro-2butenoate (24) with aluminium amalgam5' afforded ethyl 2-amino-3-methyl-2-butenoate (25), the enamine form, whereas the treatment of ethyl 3-methyl-2-oxobutanoate (26) with triphenylphosphinimine yielded ethyl 2-imino-3-methylbutanoate (27), the imino form, both of which were characterized by their IR and 'H NMR spectra. These two isomers,
6
G. HZfeIinger and H.-G. Mack
25 and 27, did not tautomerize but they dimerized to 3,6-diisopropylidene-23-dioxopiperazine (28) (equation 2). P - E n a m i n o n e ~contain ~~ the push-pull conjugated system 29. These may be vinylogous amides (29a and b), vinylogous urethanes (2%) or vinylogous ureas (2W). The 3-aminoacroleins (2911) are easily converted into 3-substituted pyridines or pyrimidines5' and b-aminocrotonic acid esters are involved in the famous Hantzsch synthesis4sS9of substituted pyridines. R3
I R4\ C &c,N-H I I A/C+o.+ H
(a) A = H: (b) A = -1
n~
(c) A = 0-alkyl: (d) A = NR1R2:
3-aminoacroleins58 vinylogous 1 p-enamimkebnu4} : = {amides p-enamino esters59 = vinylogous urethanes penamino amides = vinylogous ureas
In the case of primary (and secondary6') p-keto enamines, the enamino keto form 30a or 31a is stabilized by its push-pull conjugated mesomeric form 30b or 31b and by an intramolecular hydrogen bridge which dominates over the tautomeric imino en01 form 30c or 31c (equation 3). Similar results are reported for P-thioketone enamines61.
(304 (31~)
(sob) (304 (31b) (314 (30) primary p-keto e n a m i n e ~ ~ ~A: = Pr, B = R = H (31) secondary p-keto enamines6': A = B = Me; R = Me, Et or CHpPh
1. Enamines: General and theoretical aspects
7
The primary enamino keto form 30a,b was separated from the more polar form 30c by continuous extraction with petroleum ether at -2S°C and evaporation of the solvent6z.
6. Secondary enamines. Secondary enamines (21) have one hydrogen and one alkyl or aryl substituent on nitrogen. As in the case of primary enamines they show tautomerism with preference for the more stable imino form (33) (equation 4) and E,Z isomerism at the C=N double bond of the imino form. Such imine-enamine tautomeric equilibria have been r e ~ i e w e d and ~ ~ .the ~ ~ influence of molecular structures and of aryl-ring substituents on tautomeric equilibrium constants was studied by the research groups of Savignac" and AhlbrechP5. The secondary 8-keto enamines (31) occur to more than 95% in the enamino keto form 31a and 31b, as was shown by 'H NMR spectroscopy60. Stable secondary enamines (21) may be prepared66 in aprotic media by partial methanolysis of organo-tin6' (32a), magnesium6' (32b) or lithium ( 3 2 ~ salts ) ~ ~of imines and can be transferred from the reaction mixture under reduced pressure and trapped at -80 "C. These compounds are characterized by their 'H NMR spectra and show a characteristic C=C double-bond vibration at 1670 to 1675 cm-' and a N-H vibration around 3360 cm-' in the IR spectrum66. R3 R2 \ 1 C=C \ R; N-R'
I M
(32) (a) M = SnR3 (b) M = MgX (c) M = Li
-
R3 R2 \ / C=C
R;
\
N-R'
-
I H
(21)
R3 I R4-C-c
HI
~2
/
(4)
\)+R~
(33)
c. Tertiary enamines. The vast majority of enamines are tertiary (22) containing two alkyl, or one alkyl and one aryl, or two aryl substituents, or an alicyclic or a heterocyclic ring substituent including nitrogen as shown in 22b-22f. As already mentioned, tertiary enamines are easily synthesized by reaction of secondary amines and aldehydes or ketones and removal of the formed water by azeotropic d i s t i l l a t i ~ nor~ ~by~ ~use of potassium carbonate5, calcium oxide5 or molecular sieves7'. Owing to a lack of protons on nitrogen, tertiary enamines show no tautomerism. In the case of two different nitrogen substituents R1 and R2 two positional isomers are expected.
n 0,R3 = H,
(d) NR1R2 = N\
/
R4 = R5 = CH3
8
G.Hafelinger and H.-G. Mack
The simplest possible tertiary enamine is N,Ndimethylaminoethene (22a).It was obtained for the first time in a low yield by thermal degradation of neurine or cholineyz. Other methods for its preparation are presented elsewherez9. Cyclic secondary amines lead to N-cyclized tertiary enamines which are of great synthetic use. The rates of hydrolysis and the pK, values for the dissociation of N-protonated enamines decrease in the case of N-cyclic 1-N-isobutenes in the sequence from pyrrolidino (22b)to piperidino (2212)to the morpholino (22d)derivativey3,i.e. the pyrrolidino enamines hydrolyse fastest. However, enamines of 3,3-dimethylazetidiney4 analogous to 22e and acyclic tertiary enamines react even faster8.
d. Heferosubstitufion on nifrogen. Some classes of enamines with heteroatom sub~~ stituents on nitrogen are known. If in 22 R1 = R-C=O, the class of e n a m i d e ~(12), which are important reactants in photochemical reactions, is obtained49. N-Nitroenamines have been studiedy5 (22, R1 =NO,) and if R1 = N=O one obtains N-nitrosoenminesy6,which are reactive towards nucleophilic reagents such as dialkylcopper lithium and enolate anions, as well as being active in electrophilic reactions such as ~ ~ in ~ .22 ~~ acid-catalysed additions. N-Metalloenmines (14)have been r e v i e ~ e d and R1 may be Li69.77,MgX6' or SnR367which lead to an increase in enamine reactivity d~~~~~ at the 6-carbon. The N-silvl derivatives (22. ~. R1 = Me&) " . have also been ~ r e o a r e bv thermal rearrangement of C-silylimines or by silylation of imines with trimethylsilyltriflates0. N,N-bis(trir~~ethylsilyl)ir~~irlcs (22,R 1 = R2 = SiMe,) have also been synthesized8' as p&mary & ~ ~ l a & n e s The ~ ~ . synthesis ' and reactions of N-oxidis of tertiary enamines (34) have been reporteds3. Oxygen is present in enamines derived from isoxazolidine and cyclic ketoned"' (35).
. .
2. Substitution of the ene part
The double bond of the enamine may be acyclic (22),endocyclic (%), exocyclic (37) or part of a heterocyclic system (38).
a. Acyclic enamines. Tertiary acyclic enamines (22)with R3 = H are derived from aldehydes, while R4 and R5 may be alkyl or aryl substituents. If R3 is alkyl or aryl, the enamines are obtained from acyclic ketones. If R4 and R5 are different, one may observe E,Z isomerism at the C=C double bonds5. Substituents R3 to R5, instead of being
1. Enamines: General and theoretical aspects
9
hydrogen, alkyl or aryl, may be various functional groups. Some of these have been already mentioned in the earlier section on reviews. Functional substituents R3 at a-carbon may be nitrogen3', leading to 1,l-enediamine.^^^*^' (39), also called ketene aminalsB8,halogen3', representing a-haloenaminess3 ( a ) , Hal = F, CI, Br or I, which may be transformed into a-metalated enaminesa9, cyanogen, leading to a-cyanoenaminesgO(41), oxygen39,leading to ketene-0,N-acetal~~~ (42) or a-acyloxy enaminess3 (43), sulphur, leading to ketene-S,N-acetalsS3(44), silicon in a-trimethylsilyl derivativesg2(45) or phosphorus in a-diethylphosphonates93-95(46). R~ Hal \ C=C ' \ R5 NMe2
R4 \
C ,-
'C=C \
R5
NRW
Functional substituents R4 at the /3-carbon of compounds 22 may be n-electron donating, leading to electron-rich olefins: nitrogenj9, forming 1,2-enediamine~~~.~' (R4 = NR2), oxygen, in /3-alkoxy enaminesg8 (R4 = 0-R), sulphur, leading to /?(alkylthio)enaminesg9(R4= S-R), selenium, representing 8-(phenylselenyl) enaminesloO (R4 = Se-Ph) or halogen, leading to /3-haloenamine~'~'lo5(R4 = C1, Br or I). They may also be n-electron attracting forming push-pull substituted conjugated systems: in /3-cyano e n a r n i n e ~(R4 ~ ~ = CN), in &nitro e n a m i n e ~ ~(R4 ~ ~=~NO2), " ~ in 8-nitroso (R4 = R-C=O), sulphur in enarnine~'~'(R4 = NO), carbonyl in /3-enarninone~~~.~" /3-(thioketo) enarnines108 (R4 = R-C=S), ~ u l p h e n i u r n ~[R4 ~ ~= - ~SC(Me)J, ~~ /3sulphoxide enamines"' (R4 = R-S=O), /3-sulphonyl (tosylate) enamines113 (R4 = SO,-Ar), selenium in Pselenoketo enamines114 (R4 = R-C=Se), phosphorus in (diethylphosphono) enamine~"~ [R4 = O=P(OEt)J or vinyl (R4 = RZC=CR) leading to d i e n a m i n e ~or~ ~ even polyenamines39.In /3-metalated tertiary enamlnes5', i.e. lithium116'117,magnesium or tin (R4 = Li, MgHal, SnR,), the nucleophilicity of the enamine /3-carbon is increased. /3-Triorganosilyl enamines118 (R4 = SiR3) and /3-perfluoroalkyl e n a m i n e ~ "(R4 ~ = C6F13)are also known.
10
G. Hafelinger and Ha-G. Mack
b. Endocyclic enamines. Enamines of the type 36 containing the C=C double bond as part of a ring and the nitrogen atom with its substituents as exocyclic part may be classified as endocyclic enamines. In a broad sense aniline may be considered as a primary endocyclic enamine (in the same sense as phenol is related to enols). Endocyclic tertiary enamines are easily obtainable by reaction of secondary amines with cyclic ketones3. The qualitative rates of formation of enamines of pyrrolidine with ketones decrease in the sequences: cyclopentanone (47), cyclohexanone (48) to cycloheptanone (49), 2-methyl substituted cyclohexanone (50) and acyclic acetone (51).
(47) (48) (49) (50a) (50b) (51) Deuterium exchange at the /%carbon yields, for a given secondary amine, the following reactivity for the ketone substrate120: cyclopentanone (47) > cycloheptanone (49) > cyclohexanone (48). Pyrrolidine enamines of cyclic ketones have been preparedlZ1from cyclobutanone to cyclononanone. In the reaction of unsymmetrical 2-methyl or 2-phenyl cyclohexanone with pyrrolidine, of the two regio isomers 50a and 50b the less substituted enamine (50a) is formed preferentiallya~'Z2.This is in contrast to the behaviour of en01 derivatives, where the most stable regio isomer is the more substituted onelZ2.The reason for the destabilization of 5Ob is the steric interference of the 2-substituent with a CH, group of the pyrrolidine ring in a coplanar cis arrangement at the C=C double bond. Secondary amines used for reactions with cyclic ketones may be aziridinelZ3(52), a ~ e t i d i n e ' ~(53), ~ ~p' y~ r~r ~ l i d i n e ~ (54), . ' ~ ~piperidine3.lZ6(55), hexamethylenimine (56), (58) and acyclic amines like dimethylamorpholine3 (57), N-methylpipera~ine'~~~~~~ mine1'' (59).The general order of electrophilic attack of enamines as dependent on the nature of the amine moiety decreases in the sequence8~124~126~129: pyrrolidine (54) > dimethylamine (59) > hexamethylenimine (56) > piperidine (55) azetidine (53)> morpholine (57). This sequence seems to parallel the magnitude of conjugative interaction between the amino group and the C=C double bond as indicated by the 'H NMR chemical shiftLz9of the hydrogen at the fi-carbon.
-
CH3 I
(52) (53) (54) (55) (56) (57) (58) (59) Endocyclic enamines may be combined with p-functional groups leadmg to cycl~c 3-(pyrrolidi8-phospholene sulphide enamines' 30 (60),cyclic ~-ketoenamine~'~~.'~~61), n-1-y1)-5,6-dihydro-4H-thiopyran 1 , l - d i o ~ i d e ' ~(62) ~ and 3-amino-5,6-dihydro-4H~ y r a n (63). '~~
1. Enamines: General and theoretical aspects
c. Exocyclic: enamines. Cyclic enamines of the type 37, in which nitrogen is part of a cycle and the C=C double bond is exocyclic, may be termed exocyclic enamines. A reported example'" is 64 (equation S), which may occur in prototropic equilibrium with the corresponding heterocyclic enamine135.136(65). The exocyclic structure is realized (66). in Plancher's 1,3-dimethyl-2-methylene-3-phenylindoline137
d. Hererocyclic enamines. Enamines, which contain as in formula 38 the nitrogen and the C=C double bond as part of one ring, shall be called heterocyclic. Examples are (34, A2-pyrrolines135.'3665 and 67, as well as N-methyl-A2-tetrahydropyridine1388139 R = Me. The heteroaromatic pyrrole (68) is usually not considered as an enamine, but indole 69 is formally and, in accordance with its reactions, a heterocyclic enamine. Further important examples are 1,2-dihydroisoquinolinesSO(13).
e. Bicyclic enamines. If the enamine is incorporated into a bicyclic system, as shown, for example, for 2-dehydroquinu~lidines~~~ (70), we have truly bicyclic enamines. Another possibility is found in enamines of the type 71'41,142 and 72143, which are obtained by reaction of bicyclic ketones with secondary amines.
G. Hafelinger and H.-G. Mack
D. Nomenclature
The term enamine is used mainly for classifications of the functional group as an ensemble, but individual compounds are termed with respect to the parent compound usually as amino substituted olefins, i.e. tertiary enamines as (N,N-dia1kylamino)alkenes. The correct IUPAC nomenclature for tertiary enamines is dialkylalkenylamines, i.e. the basic compound in this case is the amine not the alkene. The difference may be demonstrated for two examples: 73 is in the first notation 1-N-methylanilino-2-methylpropene and, in IUPAC notation, N-methyl-N-(2-methyl-1-propeny1)aniline. Correspondingly 74 is usually called 2-methyl-1-pyrrolidinopropenebut in IUPAC notation it is N-(2-methyl-I-propeny1)pyrrolidine.
"
Me Me\
I
f=c\H
Me
0 f="\
Me\
Me
I
H
Me\
=
,C=C \ HzN H
Me\
COOEt
,C=e\ H2N H
Functional groups in the fl-position may lead to priority in notation. For example, 75 is called p-aminocrotonic acid nitrile and 76 is ethyl /I-aminocrotonate. Further examples pertaining to the nomenclature of complex enamines may be found in the next section in Schemes 2 to 5.
11. MOLECULAR GEOMETRIES
A. Experimental Determinations of Molecular Structures Experimental determinations of molecular geometries of enamines are relatively rare. Electron diffractions in the gas phase could be performed for simple enamines but are missing with the exception of tetrakis(dimethylaminoethene). The microwave determination of the molecular structure of vinylamines6 with an assumed C=C distance of 1.335 A yields a C-N distance of 1.401 (40)A for a planar molecule and 1.397 (40) A for a more probable pyramidal amino group, which is in contrast to the expected longer bond-length resulting from less conjugation. The experimental NCC angle is 124.5(20)"for the planar and 125.2(20)"for the pyramidal NH, group. This MW determination is very inaccurate with an error of 0.04 and 2.0" and uses basic assumptions for several distances and angles. Most structural determinations are X-ray diffractions of single crystals which refer to the solid state. These geometries may be influenced by crystal packing forces and various disorders, and the atomic positions derived by X-ray diffraction analysis do not correspond to equilibrium positions but rather to centroids of distributions obtained by
1. Enamines: General and theoretical aspects
13
averaging the electron density over the intra- and intermolecular vibrations and often over alternative positions with variable occupancies as The enamines studied by X-ray diffraction show a relatively complex pattern of substituents or complicated molecular structures. The reported structure of la (2-p-bromophenylsulphonylethyl)-4a-methyl-2-morpholin ~ - A ~ - t r a n s - o c t a l iwith n ~ ~ ~standard deviations of 0.02A and an R value of 0.094 is too imprecise to draw relevant conclusions from its distances. For the X-ray determinations of four dienamines by Reinhoudt and coworkers146no C-N distances are given. These two papers are neglected in the following discussion. 1. N-Cyclic tertiary enamines
A very interesting comparative X-ray diffraction study of six N-cyclic endocyclic enamines 77147and 78 to 82 was performed by Dunitz and coworkers144. Structural formulae and nomenclature of'these enamines are presented in Scheme 2. In addition, 1,1,2-trim0rpholinoethene~~~ (83) is included. Relevant heavy atom distances of the enamino groups are givpn in Table 1 and angles in Table 2. These structures (77-83) cover enamines mainly of cyclohexene with pyrrolidino, piperidino and morpholino substituents. The experimental geometry of the enamine group varies from one molecule to another and there are even marked differences between the same molecule in different crystalline environments (e.g. 78 A and B; and 81 A and B). From the projection down the respective C-N bonds shown in Figure 1 it is obvious that the pyramidality at the nitrogen atom varies over the whole range from virtual planarity (sp3 hybridized N) in 79 to nearly complete pyramidalization (sp3 hybridized N) in 77 and 78 with various twist angles of the nitrogen lone pair towards the olefinic n-system. The percentage of pyramidality41 may be expressed quantitatively by equation 6. %pyramidality =
360 - C angles at N ,100 360 - 328.40
These values vary from 60% in 77 to 2.5% in 79 and 0% in 80. The largest value is observed for the nitrogen N3 of the morpholino group at CZof 83 which is strongly twisted out of the plane of the C=C double bond and which is, with a value of 83.8%, very close to fully tetrahedral. The pyramidality is greater for molecules where the N-atom is part of a six-membered ring (piperidine in 78 or morpholine in 77 and 83) and smaller for molecules where the N-atom is part of a five-membered ring (pyrrolidine in 79,80 and 81). This is reminiscent of the general property of cyclopentanoid systems, in contrast to cyclohexanoid systems, to accommodate an exocyclic double bond. These structural differences seem to be reflected in the well-known differences in chemical reactivity: pyrrolidine enamines are more prone to alkylation at the j-carbon atom than the corresponding piperidine or open-chain enamines, which tend to be alkylated at the nitrogen atom8. The pyrrolidine ring in 79 has an envelope conformation and the morpholino groups in 77 and 83 as well as the piperidino groups in 78 possess a chair conformation. The cyclohexene moieties in 77 to 82 exist in half-chair conformations. In 77, N has maintained an sp3 pyramidal configuration rather than an sp3 planar configuration. The morpholino group is rotated out of the plane of the double bond by about 33". In 83 the three morpholino groups are not equivalently bonded to the ethene moiety. The two C1-N distances with 1.398 and 1.415 A are significantly shorter than the C2-N3 distance of 1.442A. This indicates conjugative delocalization of
14
G. Hafelinger and H.-G. Mack
TABLE 1. Experimental X-ray CC and CN distances (A).
le
Standard deviations in parentheses refer to the last digit
C=C Compound
C-N
a
b
N-C
N-C
C-C
c
d
e
C-H: 1.110(4) " Oricntational dioordcr in the crystal. Results obtained by assumption of a disordered model. 'Assumed value in electron diffraction.
Reference
1. Enamines: General and theoretical aspects
TABLE 2. Experimental X-ray valence angles in enamines.
W1
W6
/c,w2
-C/~~*,N-
I
IW1
Standard deviations in parentheses refer to the last digit Compound
W1
W2
" %Pyramidalitydefined by equation 6. Orientational disorder. 'Angles at C1. "ngles at C2.
W3
W4
W5
W6
% Pyramidality"
G. Hafelinger a n d H.-G. Mack
Cowound %Pyramidality
(79) 2.5
(81 '3) 6.6
(82) 14.6
@In) 17.1
(78) A 46.8
(77) 59.5
B 43.0
FIGURE I. Newman projection of enamines (77) to (82) looking down the M-C (sp2)bond. The C=C double bond is maintained in the vertical position throughout. (Reproduced with permission from Reference 144) (77) 3-Cyanomethylsulphonyl-2-morpholinocyclohe~ene~~' (78) A, B (l-Piperidyl-4-catechola~etal)-l-cyclohexene~~~ (79) (I-Pyrrolidyl-4-catecholacetal)-l-cyclohe~ene'~ (80) (l-Pyrrolidy14benzoyloxy)-l-cyclohexene144 (81) A, racemic (1-Homoprolyl-N-methylanilide-4-methyleneketal)-lcyclohexene'U (82) raccmic (I-Prolyl-N-mcthy1anilidc)-l-cyclohex~ne~~~ (83) 1,1,2-Trim0r~holinoethene'~~ "Two independent molecules are located in the unit cell.
0
SCHEME 2 Structural formulae and nomenclature for experimental X-ray data of tertiary N-cyclic enamhes
1. Enamines: General and theoretical aspects
17
the two nitrogen lone pairs with the C' carbon p-orbital, although the percentage pyramidality is 37% and 40%. Thus the C-N distances of 1.442A in 83 and 1.420 A in 77 may be taken to indicate experimentally the range of C-N bonds of essentially zero n-overlap. However, the C=C double-bond length of 1.330A in 77 is still larger than the experimental X-ray value of an unperturbed double bond [in ethene, the C=C electron-diffraction r, distance'49 is 1.337 (2)A and the X-ray distance'50 is 1.313A]. Figure 1 shows the tendency for one cis C-N bond to eclipse the C=C double bond. The maximum deviation from coplanarity for this C-N bond, as observed in 82, is only 11". The near-equality of observed C=C and C-C distances in 80 is a strong indication that the cyclohexene ring of this molecule occupies two alternative orientations in the crystal in about equal proportions and therefore in the observed average structure the distinction between the single and double bond is lost. The observed bond lengths for 77 to 83 in Table 1 and the angles in Table 2 show quite large variations but indicate the following trends: With decreasing pyramidality at the nitrogen atom the enamine C-N bond length decreases from about 1.420 to 1.380 A, indicating more C-N double-bond character. The adjacent C-C single-bond length e at a-C decreases from 1.514 to 1.480 A and the C=C double-bond length varies in the range of 1.330 to 1.366 A. Of the angles at the central carbon atom the NCC angle W5 is, in the case of high pyramidality, close to 124.4" and, for low pyramidality, around 122". The angle W6 is small as in ethene, being between 115 and 116". The sum of angles at the nitrogen atom must change with the degree of pyramidality from 360" for the planar N-atom to 328.4" for a fully tetrahedral nitrogen. The smallest sum of N-angles observed is 333.6" for N3 of 83. The required decrease in angles with increasing pyramidality occurs mainly at the exocyclic angles W2 and W3 in the range of 125 to 116". The endocyclic angle W1 stays nearly constant at about 111".
2. p- Enaminones X-ray determinations of the molecular structures of thirteen B-enaminones 84 to % with the formal possibility of push-pull conjugation and the formulae shown in Scheme 3 cover the range of tertiary: 84 to 86; and 89 to 92, secondary: 87,88 and 93, and primary: 94 to 96 B-keto enamines. Relevant distances are given in Table 1 and angles in Table 2. The non-hydrogen molecular framework of 84 is virtually planar with a push-pull through conjugation as indicated by mesomeric formulae 97a and 97b leading to a long C=C bond of 1.380A and a short C-N bond of 1.348 A. 'H and I3C NMR spectra distinguish the CZand Cs positions at the pyrrolidine ring indicating that the rotation around the C-N bond is slow on the NMR time scale'51. The keto-enamine part is also planar in 85 and the same kind of conjugative interaction leads to lengthening of the C=C bond (1.380 A) but to a smaller shortening of the C-N bond (1.390 A) with an opening of the NCC angle W5 to 130.1". In 86 the nitrogen atom is coplanar with the three atoms bonded to it, with the C=C double bond and the trans-ester group. Consequently, due to through conjugation one observes an elongation of the C=C distance to 1.380(5)A, a shortening of the C-N bond to 1.337(4)A and an opening of the NCC angle W5 to 131.0". The cis-ester group is strongly twisted due to steric interactions from the molecular plane and both carbonyl ester groups give rise to two resolved IR stretching frequencies at 1729 (in KBr) or 1724 cm-' (in CCI,) for the twisted and at 1694 cm-' for the planar ester group. The C=C vibration is observed at 1614cm-' in solution and in the solid state'53. In 87 a nearly coplanar arrangement of the secondary enamine group now in an intermolecularly
18
G.Hafelinger and H.-G. Mack
(84) (E)4-N-Pyrrolidyl-3-penten-2-0ne~~'
(85)(~-3-Dimethylamin0-1,2-diphenyl-2-propen-l-one~~~ (86)Dimethyl (dimethylamin~methylene)malonate'~~ (87)a-(4,4-Dimethylpyrrolidine-2-ylidene)-4-a~etylpynnde~~~ (88) 3-(2-Imidaz0lidinylidene)-2,4-pentanedione~~
(89)3-(1,3-Dimethyl-2-imida~olidinylidene)-2,4-pentanedione trihydratel'' (90) 3-(1,3-Diisopropyl-2-imidazolidinylidene)2,4-pentanedione rnon~hydrate'~~ (91)1,3-Dibenzyl-2-(4,4-dimethyl-2,5-bisthioxocyclohexylidene)imidolidine157 (92)2-Benzoyl-3-dimethylamino-3-methylthio-2-pr0pen~ttile~~~
(93)(3,5-Dimethylisoxazoly4)-2,6-biscarboxymethyl-3-amino~nzyl-5-methylcyclohexadiene-2,41s9 (94)2-Amino-5-cyano-3-ethoxycarbonyl-4,6-diphenyl-4H-pytafi~6o (95) 3-Amin0-4-acetyl-S-methylene-A~-pyrrolin-2-one~~~
(96)2-Imino-3-amino-4-acctyl-5-mcthylcne-2,S-dihydtof~ran~~'
SCHEME 3 Structural formulae and nomenclature for X-ray determinations of tertiary, secondary and primary p-enaminones
1. Enamines: General and theoretical aspects
SCHEME 3 (continued)
0
R4-C
0
-
R3
\
C=C
R;
I
\
N-R'
0-
/
R4 -C
R3
\\
C-C \\ R5 N4-R1
'
I R2
I
R2
hydrogen-bonded cis-configuration as indicated in mesomeric formulae 31a and 31b is observed. As before, the C=C bond of 1.386 A is rather long and the C-N distance with 1.315 A is very short, close to the X-ray distance of 1.318A in nearly planar f~rmamide'~~. The NCC angles W5 for 84 to % in Table 2 show large variations between 121" and 131". As in enamines 77 to 83 the angle W1 at nitrogen is around 111" in 84 and 85 but about 121.5" in 89 and 91.
-C
/
\
/c=C
-C
I
NI
\
N\
I
-
-C -C
1 " O
\
I
N-
€4; /
"0
N-
I
-
-C -C
P
I
\\
I
/
\\
C-C
"0
-C
NCC
P-
I
-C
//O \
/ C -C\ \
0-
I
/y+N-
I
20
G. Hafelinger and H.-G. Mack
In 88 to 91 unusually long 'C=C distances' from 1.414 to 1.482 A and rather short C-N distances around 1.32 A are observed. These push-pull ethylenes derived by substitution of two nitrogens as electron donors on one end of the double bond and two electron-withdrawingsubstituents at the other end do not show the effect of through conjugation as indicated by formula 97b, but have a zwitterionic ground state with a positive charge delocalized at the amino end and a negative charge delocalized between the carbonyl groups as shown by mesomeric formulae 98a to 98d. The C=C bond order is markedly lowered by the electronic effect of charge separation and steric effects of substituents. The molecules show a tendency to twist around the formal double bond with the following observed twist angles: 4.9(3)" because of internal hydrogen bridge in nearly planar 88, 38.3(4)" in 92, 72.9(5)" in 89, 80.8(5)" in 91 and a maximum value of 84.2(2)" in 90. In the secondary enamine 88 both carbonyl groups are syn to the C=C bond and form strong intramolecular hydrogen bonds with the imino N-H bonds of the imidazolidine ring. This conformation is enforced by the ring structure for the thio derivative 91. But in 89 and 90 the two acetyl groups adopt an E,Z configuration. In the benzyl-substituted secondary enamine 93 the hydrogen-bridged nitrogen is planar showing an intermediate C-N distance of 1.357 A and a long C=C distance of 1.382 A. Both distances are close to corresponding values of tertiary enaminones 84 to 86. In the primary keto enamine 94, which is substituted in the a-position by oxygen and in the P-position by a carboxylic group, the pyran ring adopts a very flat boat conformation with deviation of 0' and C4 from the plane defined by atoms C2, C3, CS and C6.N deviates by 0.096(8)A from this plane. The ethoxy carbonyl group is nearly planar and forms a dihedral angle of only 3.9(3)" with the pyran plane. The amino group is involved in an intramolecular hydrogen bond with the carbonyl oxygen and an intermolecular hydrogen bond to a carbonyl oxygen and to a ring oxygen of a second and third molecule. The C=C distance of 1.339(9)A is closer to the range of normal enamines than to those of 8-enaminones hut the C-N bond length of 1.325(11)A is in the range observed in other /?-enaminones 86 to 90. The NCC angle W5 with 130.4(3)" is opened very wide. The molecular structures of primary B-enaminones 95 and 96 are very similar. Both molecules are strictly coplanar and show intramolecular hydrogen bonds between the amino group and the carbonyl oxygen as well as intermolecular hydrogen bonds. Due to through conjugation the C=C distance is elongated to 1.38 A and the C-N bond is strongly shortened to 1.33 A as in 84. The NCC angle W5 is again opened up to 131". 3. P-Substituted and miscellaneous enamines
Molecular formulae of P-substituted enamines with different kinds of substituents are shown in Scheme 4. Relevant distances are collected in Table 1 and angles in Table 2. The intramolecularly hydrogen bridged /3-sulphoxide substituted secondary enamine 99 shows an elongation of the C=C bond to 1.348(3)A, which is close to the value in normal enamines 77 to 82 and less than that observed in the B-enaminones 84 to 87. The C-N distance is shortened to a value of 1.349(3)A, similar to that in 84. The /3-nitroenamines 100 to 103 show, due to push-pull through conjugation analogous to 97b, an even more elongated C=C distance in the range of 1.345 to 1.405 A with rather short C-N bond lengths between 1.30 and 1.33 A. In the secondary a-keto enamine 104, which possesses a nearly planar thiolactone enamine ring, and in the N-acetyl enamine 105 the observed C=C distance refers to a nearly unperturbed double bond with 1.323 and 1.315 A.In 104 the molecules are linked into a three-dimensional network by chains of hydrogen bonds. In 105 the cyclohexene ring adopts a half-chair conformation with the nitrogen N1 in the plane of the CZC1C6C5fragment, but the planar
1. Enamines: General and theoretical aspects
(99) (-)N-[(S)-I-Phenylethyl]-2-(S)-ethylsulphinylpropenyl-l-amine'6" (100) l-MethylL2-(nitromethylidene)pyrr0lidine'~~ (101) 2-(Nitromethylidene)thiazolidinem (102) N,N-Dimethyl-2-~~itroethenamine'~~ (103) N.Methyl-2-nit1oethenamine'~~ (104) 2.5-Dihydro-2-0x0-3-pyridoxaminothiophen= Pyridoxal homocysteine thiolactone
enaminelb7 (105) N-Methyl-N-[6-(~-cyanoethyl)-l-~yclohexenyl]a~tamide~~~ (106) 1,3-Dimethyl-2-imida/olidinylidene)malon0trile'~~ (107) (1,3-Dimethyl-2-perhydropyrimidylidene)malon0nitle~~ (108) N,N~,N"'-Tetraphenylbis(l,3-imidaz0lin-2-ylidene)'~ (109) Tetrakis(dimethylamino)ethenem
SCHEME 4 Structural formulae and nomenclature for X-ray determination of tertiary and secondary P-substitutedand miscellaneous enamines
22
G. Hafelinger and H.-G. Mack
acctamide group is twisted by 68.0" from this plane and, consequently, by diminution of the enamine conjugation the C-N bond with 1.442(4)A is especially long. The compounds 106 and 107, which are vicinally disubstituted on one end with electron-releasing nitrogens and on the other end with electron-withdrawing cyanosubstituents, show, like in 88 to 92, a tendency to twist around the C=C bond [twist angles: 20.2(3)"for 106 and 31.5(6)"for 1071 and an elongation of this bond to 1.407 and 1.429 A, but again accompanied by a shortening of the C-N bonds to about 1.34 A. The bonding situation may be described better by the zwitterionic situation indicated by mesomeric formulae 98b to 98d than by assuming a push-pull through conjugation of the kind given in 97b. The electron-rich tetra-amino-substituted ethenes 108 and 109 show elongated C=C distances in the range of 1.350 to 1.372 A and rather long C-N bonds between 1.392 and 1.417 A. The molecule 108 has a non-planar geometry of approximate C2,pointgroup symmetry. The four nitrogens deviate oppositely by 9.4" from the C=C plane and small tetrahedral distortions at the nitrogens and olefinic carbon atoms are observed. The phenyl rings are twisted by about 26" with respect to the NCC plane. This allows the tendency to extend the z-system from the olefinic carbons over nitrogens to the phenyl rings. For the last molecule 109 a comparison between an X-ray-determined structure and an electron diffraction determination is reported1" which indicates no significant deviations. The molecule is twisted around the C=C double bond by 28" and the four nitrogens show a pyramidal distortion at all N centres with sums of angles around 351" and a dihedral angle of 55" for the methyl CN bond with respect to the C=C bond. 4. a -Substituted enarnines
a-Substituted compounds 110 to 114, which are defined in Scheme 5, have been studied ~omparatively"~leading to the geometric parameters summarized in Table 3. The
"Two independent molecules in the unit cell. SCHEME 5 Structural formulae and nomenclature for X-ray determinations of a-substituted enamines
1. Enamines: General and theoretical aspects
23
TABLE 3. Heavy atom distances (A) and angles (deg) of a-substituted enamines as determined by X-ray diff~action'~~
Compound No. Standard deviation (A) C1-C3 C2-C" ~4-XJ
c3=c4
C4-N6
N6-C7 N6-C8
c7-c~' C5-N5
(110)
(111A)
(11lB)
(112)
(113)
0.002
0.004
0.004
0.006
0.004
(114) 0.002
1.509 1.504 1.510 1.332 1.437 1.462 1.464 1.522
1.497 1.484 1.436 1.336 1.437 1.459 1.469 1.514 1.139
1.488 1.486 1.445 1.342 1.433 1.464 1.465 1.519 1.149
1.492 1.492 2.201 1.310 1.399 1.461 1.458 1.517
1.501 1.500 1.799 1.330 1.396 1.461 1.468 1.521
1.501 1.508 1.398 1.306 1.386 1.471 1.474 1.510
-
-
-
-
standard deviation C1C3C2
c1c3c4 CZC"4 C"4X5
CT4N6 X5C4N6 C4NhC7 C4N6CB C7N6Cn NhC7CR' N6C8C7' C4C5N5 enamine part is not strictly planar but close to planarity, and each of the molecules is centrosymmetric. The valence angles around the B-carbon C3 are relatively constant but the angles around the a-carbon C4 vary significantly depending on the substituent X. Especially sensitive is the angle C3C4N6,which varies by 10" from X = CH, to X = F. The opening of this angle seems to be linearly correlated to the shortening of both the C4-N6 and C3=C4 bond lengths in the range of 1.437 to 1.386 A and 1.332 to 1.306 A, respectively. The nitrogen atom of the piperazine part is pyramidal in all cases. The sum of angles at nitrogen is on the average 339", close to the theoretical value of 328.4" for a tetrahedron. The nitrogen electron pair is mainly oriented in the plane of the enamine fragment in trans-position to the substituent X. This angle in the range of 5" to 33" seems to be strongly affected by crystal packing forces. 5. Summary of experimentally observed variations in molecular structures of enamines
In tertiary cyclic enamines 77 to 83, observed distances of the enamine fragment depend on the extent of pyramidality or of twist at nitrogen: a C-N value between 1.410 and 1.420A is characteristic for a nearly tetrahedral sp3-nitrogen and a distance between 1.380 and 1.395 A is observed for a nearly coplanar sp2-nitrogen which both still allow conjugative interaction with the C=C n-system whose distances are in the range of 1.330 to 1.349 A in the case of high pyramidality (sp3-N) and about 1.366 A for co-planarity (spZ-N).For the twisted planar amido group in 105 the C=C distance
24
G. Hafelinger and H.-G. Mack
of 1.315 A corresponds to the unperturbed C=C distance observed with 1.313 A in ethene and the C-N distance is as observed for N3 in 83 at 1.442 A. In push-pull substituted fi-enaminones 84 to 87 due to through conjugation the C=C distance is elongated to about 1.380 A. In other push-pull systems 99 to 103 the C=C bond lengths are in the range of 1.348 to 1.405 A. In both classes the C-N distances vary between 1.303 and 1.390 A. In the case of doubly push-pull substituted enamines 88 to 92 and 106 to 107, instead of through conjugation a tendency to adopt a zwitterionic form is observed. This form is characterized by a very long C=C distance between 1.407 to 1.482A, very short C-N lengths of 1.312 to 1.352 A and shows various angles of twist around the C=C bond. 6. Ab lnitlo Calculations of Molecular Structuree
1. Computational methods
Molecular geometries may be calculated by means of quantum-chemical semiempirical valence electron theories, such as Dewar's MIND0/3173, MND0174 or AM117' procedures, or by classical molecular force-field methods, such as Allinger's ~ ~ 2 1 7 6 , 1 procedure. 77 Alternatively, ab initio Hartree-Fock SCF MO m e t h ~ d s ' ~ ~ - ' ~ ~ allow, by virtue of analytical gradient e v a l ~ a t i o n ' ~the ~ , determination of molecular geometries independent of experimentally adjusted integral values. Information about the background of ab initio calculations is given in several excellent m o n ~ g r a p h s " ~ - 'and ~ ~ the basic assumptions have been summarized in another volume of this serieslS4and will not be repeated here. Ab initio calculated geometrical parameters depend on the kind of applied basis sets (which is the main variable when using an ab initio computer programme like, for example, Pople's GAUSSIAN go1") and on the kind of calculational procedure: The so-called Hartree-Fock limit is the theoretically best result obtainable with a single determinant MO basis. Because of the different weighting of inter-electron repulsion between electron pairs of like and unlike spin, Hartree-Fock calculations are in error. They may be improved by the use of configuration interaction methods'a6 (CI) or by the use of perturbation theory, like the Msller-Plesset treatment1" of second, third or fourth order (MP2, MP3 or MP4). Ab inirio MO computer programmes use the quantum-chemical Hartree-Fock selfconsistent-field procedure in Roothaan's LCAO-MO formalism188and apply Gaussiantype basis functions instead of Slater-type atomic functions. To correct for the deficiencies of Gaussian functions, which are, for s-electrons, curved at the nucleus and fall off too fast with exp(-ur2), at least three different Gaussian functions are needed to approximate one atomic Slater s-function, which has a cusp at the nucleus and falls off with exp(-cr). But the evaluation of two-electron repulsion integrals between atomic functions located at one to four different centres is mathematically much simpler for Gaussian functions than for Slater functions. The quality of the applied basis set may be inferred from the calculated total energy. By means of the quantum-chemical variational prin~iple"~the true energy is a lower bound to the calculated total energy value, i.e. the lower the calculated (negative) total energy, the better the basis set applied. 2. Notation for Gaussian-type basis functions
The term STO-3G denotes a minimal Gaussian basis set in which each Slater-type atomic orbital (s, p or d) is approximated by a fixed block of three Gaussian functionsla9,
1. Enamines: General and theoretical aspects
25
which are varied linearly in the MO calculation. The notation 3-21G190, 4-31G19' or 6-31G19' refers to so-called split-valence basis sets. These are constructed by one block of 3, 4 or 6 Gaussian functions for the inner-shell core electrons (first number) and by two blocks for valence shell electrons, constructed from two and one Gaussians (-21) or three and one Gaussians (-31), which are varied linearly and independently. Consequently, 6-311G193is a triply-split valence basis set with 6 Gaussian core functions and three blocked and two separate valence shell Gaussians. Although the use of split-valence basis functions introduces larger flexibility, this may be further increased by the addition of so-called polarization functions, which consist of five or six 3d orbitals for elements of the second row of the periodic table and of three 2p orbitals for hydrogen. The first case is marked by the addition of one asterisk, i.e. 6-31G*lg4. Two asterisks, i.e. 6-31G**194or 6-311G** 193,indicate the additional presence of polarization 2p orbitals on hydrogens. Especially for negatively charged systems, diffuse s- or p-type functions of high quantum numbers may be necessary. These are marked by + signs, i.e. 3-21 + G or 6-31 G**. Optimizations of molecular geometries may be performed with a simpler basis set followed by a single-point Hartree-Fock (HF) calculation with a larger basis set for that derived geometry. This is indicated by double slashes, i.e. 6-31G**//3-21G.
+
3. Vinylamine
a. Ground state geometry. Vinylamine CHz=CHNHz (115) is the simplest prototype of aliphatic enamines and small enough to be studied by calculations of high precision. Of strong interest is the geometry of the amino group, which may be coplanar to the vinyl group (sp2-hybridized nitrogen) or adopt pyramidality (sp3-nitrogen) and may show additional rotational twist around the C-N bond. Semi-empirical calculation^^^^^^^^ and the crude microwave spectroscopic analysis56~199.2uo indicate non-planarity of the amino group. The six possible conformations 116121 are shown in Scheme 6. A complete geometry optimizationz0' for 115 using the semi-empirical approximate ab initio SCF MO method PRDDO (partial retention of diatomic differential overlapzoz) leads to the results presented in Figure 2. A pyramidal and rotated configuration of type 118 at nitrogen with average bond angles slightly larger than tetrahedral was obtained. The pyramidalization at the nitrogen atoms is coupled with a torsion of 18.7" around the C-N bond so that the N-H bond syn to the C=C double bond moves less out of the CCN plane than the other N-H bond. In that workZo1additional geometries and energies of coplanar and perpendicularly twisted configurations of the NH, group are reported and corresponding minima of electrostatic potentials with respect to a positive point charge have been evaluated. Full ab initio optimizations of molecular geometries of enamines (and of any other kind of molecules) depend strongly on the kind of applied basis sets: application of STO-3G195.2033-21G195,204,2053-21G**205 4-jlGZo3,6-31GZv5,6-31G*195and 631G**'05 basis sets leads to optimizations for the coplanar framework of all atoms of vinylamine, but it was not stated in these references whether coplanarity was assumed by input constraint or not. Contrary to that, the use of a double-zeta basis set with heavy atom polarization functionszo6 as well as 6-31 + G*207 based optimization yielded a non-planar amino group for 115. These discrepancies may be solved by our test calculations using Pople's G 90 program systemzo8: In agreement with optimizations of f ~ r m a m i d i n e '(cf ~ ~137) the minimal STO-3G basis set leads, as in the semi-empirical result201 of Figure 2, to a pyramidal configuration of the type 117 at nitrogen as an energetically more stable form, if
26
G. Hafelinger and H.-G. Mack
(116) coplanar NH, group, full conjugation of the spZ N lone pair with the vinylic n-system, the N lone pair is parallel to the C=C n-system (117) pyramidal NH, group, sp3 N lone pair twisted in the plane of the C=C n-system (118) pyramidal NH, group, sp3 N with asymmetrical rotation around the C-N bond (119) planar NH, group, 90" rotated, sp2 N lone pair is perpendicularly rotated with respect to the plane of the C=C n-system (120) pyramidal NH, group, - 90" rotation, 2 hydrogens inside the sp" lone pair outside the vinylic group (121) pyramidal NH, group, + 90" rotation, 2 hydrogens outside and the sp3 N lone pair inside the vinylic group
(119)
(120) (121) SCHEME 6 Newman projections along the N-C' bond showing the six conformations, 116 to 121, of vinylamine (115) whose total energies in various basis sets have been collected in Table 9. (0 denotes C1.) Values for substituted vinyl amines refer to the same type of the five conformations: 116. 117 and 119 to 121. coplanarity is not assumed by input constraint. In contrast, the split-valence basis sets 3-21G and 6-31G optimize, as in the case of amidinesla4, starting from an assumed pyramidal nitrogen to the coplanar form 116 of 115. inclusion of polarization functions either in the 6-31G* or in the 6-31G** basis set again leads to the pyramidal configuration a t N of the type 118 of Scheme 6 as the most stable configuration.
FIGURE 2. Calculated PRDDO geometry of vinylamine (115) type 118 shown in projection onto the CCN plane and dihedral angles shown along the N-C' and C1=C2 bonds (distances in A, angles in degrees). (Reproduced with permission from Reference 201)
1. Enamines: General and theoretical aspects
27
Our consecutive optimizations and findings have been based on applications of 3-21G, 6-31G and 6-31G** basis sets. These three basis sets have been selected for the following reasons: The 3-21G basis set is the most economical split-valence basis set which allows comparison to similar systems1s4~209, the 6-31G basis set was used because this was statistically the best basis set for calculations of CC distances196and the 6-31G** basis set was applied as a highly reliable and computationally still manageable basis set and because we found, in agreement with References 206 and 207, that polarization functions are needed to treat successfully the problem of pyramidality at nitrogen. The results of our calculations of molecular geometries of 115 are presented in Tables 4 and 5 and total energies are given in Table 9. These results are in full agreement with those reported by Saebe and Radomzlo, who used STO-3G, 3-21G and 6-31G* basis sets. As already mentioned, only the application of 3-21G and 6-31G split-valence basis sets leads to a coplanar NH, group (i.e. 116)as the most stable form. Use of the minimal STO-3G as well as the addltlon of polarization functions (six 3d-functions on carbon and nitrogen in 6-31G* and additionally three 2p-functions on hydrogen in the 6-31G** basis set) leads to a pyramidal sp3 nitrogen of the amino group with the nitrogen TABLE 4. Basis set dependence of calculated geometries of planar vinylamine (type 116)and related
molecules. Distances in A and angles in deg Parameter
STO-3Ga
Angles C2CLN H1C2C1 H2CT1 H~C~H'
H3CLC2 H3C1N H4NC1 H5NCL H4NH5
DWb wC(debye) ethane: C-Cd ethene: C=Cd C-H angle HCH methylamine C-No formaldimine C=N0 "Values taken from Reference 195. DW = dihedral angle H'C'NH4. 'Dipole moment. Values taken from Reference 196. 'Our own calculations by D. Kaiser.
'
3-21G
6-31G
6-31G'"
6-31G**
28
G. Hafelinger and H.-G. Mack
TABLE 5. Basis set dependence of calculated geometries of pyramidal vinylamine (115) of the type 117 and 118. Distance in A and angles in deg Type 118
Type 117 Parameter
STOJG
6-31G*
6-31G**
6-31G**
6-31 + G*'
PRDDOb
Distances C'=C' C1-N C2-HI CZ-HZ C2-H3 N-H4 N-H5 Angles C2C1N H1C2C1 H2C2C1 H~C~H'
H3C'C2
HVN H4NC1 H5NC' H4NH5 DW J !
(debye)
Values taken from Reference 207. Values taken from Reference 201. ' Dihedral angle H3C1NH4+.
lone-pair, adjusted by input constraint, parallel to the C=C plane as an energetically stable configuration 117. But the global minimum is represented by the pyramidally rotated form 118. The energy gain on pyramidalization from 116 t o 117 derived from values of Table 9 is 4.17 kcal m o l l for STO-3G which drops to 1.38 and 1.05 kcal mol-I for the 6-31G* and 6-31G** basis sets. The true minimum of the total energy is calculated in the 6-31G** basis for the asymmetrically twisted pyramidal form 118 as 0.16 kcal mol-' further stabilization with respect to 117. The additional calculation of vibrational frequencies indicates only positive force constants, which as second derivatives of the energy must all be positive for a minimum on the potential energy curve. The conjugation of the coplanar amino group of the type 116 in vinylamine (115) derived from distances of molecules, which are presented for comparison in Table 4, causes an elongation of the C=C double bond by 0.0085 A compared with the value of unsubstituted ethene. This is nearly independent of the basis sets applied, except for the 6-31G difference of 0.0072 A and the 6-31G* difference of 0.0079 A. This lengthening is about 3.7% of the calculated difference between the pure C-C single bond in ethane and the C=C double bond in ethene. It is longer than the conjugative elongation of the double bond in b ~ t a d i e n e 'which ~ ~ is about 0.0057 A,nearly independent of the basis set. The in-plane pyramidalization in 117 leads to an inhibition of conjugation which is shown in Table 5 by a shortening of the C=C bond by 0.0034, 0.0030 and 0.027 A in
1. Enamines: General and theoretical aspects
29
the STO-3G, 6-31G* and 6-31G** basis sets, respectively, from the values for type 116 of planar 115. In the 6-31G** minimum configuration of the type 118 the C=C double bond is with 1.3218A slightly shorter than the 6-31G* and 6-31G** values of 1.3220 and 1.3221 A for 117. The range of calculated C-N distances in 116 is 1.404for the minimal STO-3G basis set which is of lowest significance, and 1.371 to 1.378 A for our split-valence basis sets. This may be compared to 1.364 and 1.359 A for the 3-21G and 6-31G C-N distances in planar E - f ~ r m a m i d i n e(137) ' ~ ~ indicating a stronger conjugation in the amidines than in 116. For the pyramidal NH, group in 117 the 6-31G** C-N distance is 1.3889 A, elongated by 0.018 A compared to the corresponding coplanar distance. For type 118 this bond is with 1.3901 A even longer. Both types 117 and 118 clearly show the effect of reduced conjugative interaction of the pyramidal nitrogen lone pair with the C=C bond. Whereas all distances reported in the 6-31 + G* basis set calculation of Smith and RadomZo7are very close to our 6-31G* and 6-31G** values, the only significant deviation refers to the C-N distance which, with the reported 1.312 A, is far off the range of significance, so that this value must be regarded as a misprint. The value of that total energy is less (- 133.06884 Hartree) than our 6-31G** value (- 133.070492) listed in Table 9. Therefore the latter must be regarded as more reliable according to the variational principle. The shortening of the C-N single bond due to the change in hybridization of nitrogen and due to the conjugation with the C=C double bond in vinylamine varies strongly depending on the basis set applied, when it is related to the calculated C-N distance in methvlamine. On the averaze this amounts to 0.083 A. which is bv a factor of ten larger than the elongation of the C=C bond. Consequently, the shortening of the C-N bond is about 40% of the calculated d i k e n c e between the C-N bonds in methylamine and formaldimine and is more strongly affected by conjugation than the elongation of the C=C bond. Calculated C-H distances obtained by split-valence basis sets are in a rather narrow range of 1.070 to 1.078 A and increase for each basis set from the outside CZ-H1 bond length over the inside C2-Hz bond to the neighbouring Ci-H3 distance. The outside N-H4 distance is also shorter than the inside N-H5 distance (except in the case of pyramidal NH, in the 6-31G** basis). Split-valence N-H distances are in the range of 0.988 to 0.999 A. STO-3G distances to hydrogen are consistently larger by 0.005 to 0.020 A, as was also observed in the case of hydrocarbons2". The CZCIN angle is calculated in the range of 126 to 127" close to the experimental MW value56 of 125 f 2". But this is larger than the X-ray-determined experimental range of W5 from 120 to 125' collected in Table 2 for tertiary enamines 77 to 83. The elTect of pyramidalization, calculated in the 6-31G** basis, is a reduction of this angle from 127.09" in 116 to 126.62" in 117 and 126.73 in 118 in contrast to the reported experimental MW expansion from 124.5 to 125.2". The H1C2H3 angle is consistently calculated to be larger by about 1.5" than the corresponding angle in ethene. The H4NH5 angle around 118.0" for the planar NH, group is strongly reduced to 112.1"on pyramidali~alion.
b. Torsion of the NH, group. In addition to the in-plane pyramidalization of the NH2 group as indicated by type 117, the pyramidal amino group may be rotated towards the global minimum of type 118 or by f90" with respect to the vinylic C=C group as indicated by types 120 and 121. The resulting six possible conformations, 116 to 121, considered in our ab initio calculations also for various substituted derivatives, are shown
G. Hafelinger and H.-G. Mack
30
TABLE 6. Basis set dependence of calculated gcomctrics of vinylaminc (115)with (planar (119)and pyramoidal amino groups rotated out of the vinylic plane by +90" (120 and 121). Distances in A and angles in deg 90" twist, pyramidal NH,
90" twist, planar NH2
Parameter Type Distances cl=c2
C1-N C2-H' C2-HZ C1-H3 N-H4 N-H5
3-21G
6-31G
6-31G8*
119
119
119
1.3153 1.4214 1.0729 1.0727 1.0726 0.9945 0.9945
1.3220 1.4146 1.0735 1.0734 1.0788 0.9895 0.9895
1.3175 1.4077 1.0761 1.0759 1.0824 0.9894 0.9894
6-31Gt* 2H inside
6-31G** 2H outside
120
121
1.3171 1.4303 1.0754 1.0775 1.0782 1.0001 1.0001
1.3154 1.4264 1.0755 1.0752 1.0826 1.0015 1.0015
Angles C2C'N H~c2C1
H2C2C'
H5NC' H4NH5
DW" @bye)
123.58 121.27 121.17
123.89 121.17 121.45
123.96 120.87 121.37
126.03 120.85 122.00
121.99 121.04 120.81
120.73 118.54 90.0 0.502
121.00 117.99 90.0 0.433
120.96 118.07 90.0 0.522
111.25 107.83 119.88 1.371
110.73 106.88 59.19 1.515
Dihedral angle: H3C'NH4.
in Scheme 6 above. The torsion of the coplanar amino group by 90" from 116 into the perpendicular planar conformation 119 leads to a complete loss of conjugation in the 3-21G and 6-31G calculation. The C=C distances shown in Table 6 correspond, up to the first three digits, to the calculated C=C bond lengths of ethene collected in Table 4. For the 6-31G** calculation we still observe an elongation of that bond by 0.0012 A, indicating that the polarization functions still allow in the perpendicularly twisted conformation some hyperconjugative interactions of the two NH bonds with the n-system of the vinylic group. In the case of the k90" rotated p ramidal NH, group, 120 and 121, the C=C distance is elongated only by 0.0008 from ethene in 120 where the nitrogen lone pair is outside and shortened by 0.0008 A in 121 when the nitrogen lone pair is inside. The calculated C'-N distances in the range of 1.42 to 1.41 A correspond to pure unconjugated C,,I-N,,~ values for the twisted planar NH, group 119. These bond lengths are elongated by about 0.04 A from distances in coplanar vinylamine 116 in Table 4. The pyramidalization from rotated N,+ in 119 to N,,, in 120 leads to an additional elongation up to 1.430A. But this bond with 1.426 A is shorter for the more stable form 121 with the nitrogen lone pair inside. These calculations for pyramidally rotated C-N distances are in accord with the range of 1.42 to 1.44A observed experimentally for strongly twisted tertiary enamines represented in 77 to 83. The two bonds CZ-H1 and C2-Hz at b-carbon in Table 6 are now very similar, but shorter than those of ethene in the corresponding basis set except in the case of
1
1. Enamines: General and theoretical aspects
31
pyramidally rotated 6-31G** values of 120 and 121. The two N-H bonds are all equal in the twisted systems 119 to 121 and close to the arithmetic mean of the two distances in the coplanar vinylamine 116. The CZCINangle is about 123.8"for the rotated planar amino group of 119 and is increased to 126" for 120 and decreased to 122" for 121, which has the nitrogen lone pair inside. The H4NH5 angle is reduced from 118" to 107" on rotated pyramidalization (120 and 121) which is less than the value of 112" calculated for coplanar pyramidalization in 117. The differences in total energies derived from numerical values presented in Table 9 are shown graphically in Figure 3 for the 6-31G** basis set. The rotational barrier from the coplanar 116 to the perpendicular conformation (119) is 8.74 kcalmol-' in the 6-31G** basis set (8.82 for the 3-21G and 8.34 kcal mol-I for the 6-31G calculation). The stabilization due to the in-plane pyramidalization, 116 to 117, which may also be considered as an inversion barrier at nitrogen, is 1.05 kcal mol-' with an additional lowering by 0.16 kcal m o l l towards the global minimum (118). The higher rotational barrier from 118 to 120 by rotation of - 90"is 6.24 kcal mol-I, and the lower one from 118 to 121 by rotation of + 90" is 4.96 kcal m o l l . Experimentally, free enthalpies of activation (AG&) corresponding to rotational barriers around C-N bonds of variously substituted enamines have been obtained from a linear correlation, represented by equation 7. This was derived from a relation of the AG& (kcal mol-')
= - 0.19
[A6(N) (ppm)]
+ 2.9
(7) temperature dependence of the 13C signals for C1 in the amine moiety of enamines and the relative I5N chemical shift [A6(N)] between the enamine and the corresponding
FIGURE 3. Rotational barriers (in kcal mol-') of vinylamine calculated with use of the 6-31G** basis set from values presented in Table 9. 4 is the angle between the orientation of the electron lone pair on N and the vinylic rr-system
G. Hafelinger and H.-G. Mack
32
hydrogenated tertiary amine212. For various tertiary enamines these free enthalpies of activation, derived from "N chemical shifts and application of equation 7, are in the order of 3.7 to 6.7 kcal mol-', which are in very good agreement with our calculations which are related to gaseous molecules at 0 K, i.e. without any entropy contribution. Direct determinations of the n-barrier to rotation by dynamic NMR spectroscopy 5.95 kcal mol-I yielded less than 5.5 kcal mol-' for N,N-dimethylamino-l-propene213, for 1-diethylaminocyclohexene214and 6.3 to 8.3 kcal mol-' for four pyrrolidino cyclon-alkenes (n = 5,6,7 and 8)'15. Recently, a very extensive post-Hartree-Fock calculation of the type MP2/6-31 lG**// HF/6-31G* for barriers of inversion, and inside and outside rotation of 115,have been reported216. The derived value for inversion is 1.78 kcal mol-', the lower rotational barrier is 4.80 kcal mol-I and the higher rotational barrier is 6.44 kcal mol-', which are not too far from our values presented in bigure 3. Experimental far-IR determinations~17-2 19 of 115 yielded an inversion barrier of 2.0 f 0.3 kcal mol-I or, more precisely, 1.02 0.01 kcal mol-' and for the rotational barrier 6.9 0.6 kcal mol- 1 217
+
c. Enamine-imine tautomerism: Z- and E-acetaldehyde imine. As already mentioned, primary and secondary enamines tautomerize easily to the corresponding i m i n e ~ In ~~. the case of vinylamine (115)this is the acetaldehyde imine. This occurs either in the Z- or in the E-configuration 122a and 122b (Scheme 7), whose calculated molecular geometries are given in Table 7 and total energies in Table 9. For the STO-3G basis set the Z-isomer is calculated to be more stable by 0.3 kcal mol-', but from applications
TABLE 7. Basis set dependence of calculated geometries of E and Z-acetaldehyde imine 122b and 1274 the tautomers of vinylamine. Distances in A angles in deg E-congfiguration l22b Parameter
3-21G
6-31G
Distances C1=N C2-C1 C2-H' C2-HZ C2-H3 C1-H4 N-H5 Angles NCICZ H5NC1 H'C'C'
HVN H'C'C' H2C'C' H3C2C1 H ~ C ~ H ~ H~C~H" pb (debye)
" Taken from Reference 195. Dipole moments.
6-31G*'
Z-configuration 122a 6-31G8*
3-21G
6-31G
6-31G**
1. Enamines: General and theoretical aspects
33
of split-valence basis sets the E-isomer is calculated to be favoured by 0.24, 0.89 and 0.64 kcal mol-' for 3-21G, 6-31G and 6-31G** basis sets, respectively. The stabilization of the thermodynamically favoured E-acetaldehyde imine l22b with respect to the most stable form 118 of vinylamine (115) reported in Table 9 is 10.74, 2.16, 2.50, 7.16 and 5.84 kcal mol-' for STO-3G, 3-21G, 6-31G, 6-31G* and 6-31G** basis sets. We consider the last value to be most reliable. The C=N bond distances, in the range of 1.252 to 1.264 8,, are for each basis set slightly longer in the Z-configuration and both values are a little bit longer than those of unsubstituted formaldimine collected in Table 4. A very characteristic behaviour shows the CZCINangle, which is calculated around 127.7" in the E-configuration and about 121.8"in the Z-isomer. This is in contradiction to expectation and to the trends observed for vinyl amine conformations 120 and 121: now the N lone pair in l22b seems to need more space than the N-HS bond in 1ZZa. The most stable conformation of the methyl group is shown in the drawing of the formulae l22a and 122b. Rotations of the methyl group by different angles lead to increase of total energies with a maximum value given by a rotation of 180", i.e. the CZ-H1 bond is then cis to the C1-H4 bond. That difference for the 6-31G** basis set is 1.44 kcal m o l l for the Z-isomer and 1.68 kcal mol-I for the E-form. Corresponding values in the 3-21G basis are 1.14 and 1.59 kcal m o l l , and for the 6-31G basis 1.30 and 1.52 kcal mol-I. For each basis set the N lone pair and C-H1 interaction in 122b is more destabilizing than the HI---H5 interaction in 122a. d. Nand Cprotonation. Enamines show, as indicated by mesomeric formulae l a and
lb, two sites towards attack of protons: either at nitrogen, which leads reversibly to the ammonium salt (6), or at carbon, which yields the iminium salt (7). In the case of protonation of vinylamine (115) as N-protonation product, the vinyl ammonium cation (123) and, as C-protonation product, the methyl iminium cation (124) (Scheme 7) is obtained. These systems have also been studied experimentally and by ab initio double-zeta basis set calculationsZZuwith inclusion of polarization d-functions on C and on N. Our calculated molecular geometries of these molecules are presented in Table 8 and total energies in Table 9. The C-protonation product 124, which may be chemically also obtained by Nprotonation of the imines l22a and 122b, is lower in energy than 123, so that it is the thermodynamically favoured product. The calculated energy difference of 124 to the kinetically preferred 123 is 18.66 kcal mol-' in the 6-31G** basis. (The 6-31G value is 17.32 and the 3-21G value is 13.17 kcal mol-I, so that this difference clearly increases with improvement of basis sets.). The C-protonation energy of 115 of the type 118 in the 6-31G** basis set is -240.27 kcal mol-' and the N-protonation energy of 122b related to 123 is -215.78 kcal m o l l . Both values are smaller than the 6-31G calculated value of -250.55 kcal mol-' for E-f~rmarnidine'~~ (137). For comparison, the 6-31G calculated protonation energy of methylamine's4 is -228.20 kcal mol-I and that for ammonialS4 is 2 1 7 . 3 8 kcal mol-'. The 6-31G** calculated C=C bond length in N-protonated 123 is shorter by 0.0073 8, than that in unsubstituted ethene (see Table 4). The other split-valence differences are 0.0084A. But in 124 the 6-31G** calculated C=N+ distance is longer by 0.022 8, (6-31G: 0.019 and 3-21G: 0.018 8,) than the corresponding C=N bond lengths in formaldimine presented in Table 4. Parallel to that, the C1-N+ bond in 123 is also elongated by 0.027 A (6-31Gi*), 0.039 8, (6-31G) and 0.042 A (3-21G) from the corresponding calculated distance of methylamine (see Table 4). The C1-C2 distance in 124 around 1.480 8, is by about 0.03 8, shorter than the C1-C2 bond in neutral acetaldehyde imines 122a and 122b of Table 7. The H-N+ bonds are also elongated
G. Hafelinger a n d H.-G. Mack
34
TABLE 8. Basis set dependence of calculated geometries of protonated vinylamine. N protonation = vinyl ammonium cation (123); C protonation = methyl iminium cation (124). Distances in A and angles in deg -
N-Protonation (123) Parameter
3-21G
6-31G
C-Protonat~on(124)
6-31G**
3-21G
6-31G
6-31G**
Parameter
Distances C'=C2 C1-N N-H4 N-H5 N-H6 C2-H' C2-HZ C1-H3 Angles C2C1N H1C2C' H'C2CL H'CZHz H3C1C2 H3C'N H4NC1 HSNC1 H6NC1 H4NHS HSNH6 (115) Vinylamine (1221) Z-Acetaldehyde imine (123) Vinylammonium cation (N protonation) (125) ZAminopropene (127a) E-1-Aminopropene (128a) E-IAmino-2-fluoroethcne
(122b) E-Acetaldehyde imine (124) Methyliminium cation (C protonation) (126) 1-Amino-1 -fluoroethene
(122a) Z
(122b) E
SCHEME 7 Nomenclature and numbering of atoms in molecules used for calculations in Tables 5 to 14
1. Enamines: General and theoretical aspects
I 2+c\
F-C
I
HZ
35
N-H3
I
H4
H3
H3 H4
H9
SCHEME 7 (continued)
H1-c
2
I
11 +c, N-F
Hz
I H4
TABLE 9. Basis set dependence of total energies (in hartrees) of molecules 115 and 122 to 136 shown in Scheme 7 (1 hartree = 627.5095 kcal mol-' = 2625.50 kJ mol-') No.
Configuration NH, planar NH, pyram. pyram. asyrn. rot. planar 90" r o t pyram. -90' rot. pyram. +9O0 rot.
z
E cation: N protonated cation: C protonated planar NH, pyram NH, planar 90" rot. pyram. -90" rot pyram. f 9 0 " rot. a-F, planar NH, a-F, pyram. NH, planar 90" rot. pyram. -90" rot. pyram +90" rot. a-OH, planar NH, a-OH, pyram. NH, planar 90" r o t pyram. -90" rot. pyram. +9W rot. E, planar NH, E, pyram NH, planar 90" rot pyram. -90' rot. pyram. +90" rot. Z, planar NH, 2,pyram. NH,
Type
STO-3W
3-21G
6-3 1G
6-31G*"
6-31G**
planar 90" rot. pyram. -90" rot. pyram. +90" rot. EB-F, planar NH, EB-F, pyram. NH, planar 90" rot. pyram. -90" rot. pyram. +90" rot. Z-&F, planar NH, Z-&F, pyram. NH, planar 90" rot. pyram. -90' rot. pyram. +90" rot. E-NO,, planar NH, s-E, N-Me, planar N s-E, planar N, 90" r o t pyram. N, -90" rot. s-2, NCH,. planar N s-2, NCH,. pyram. N planar N, 90" rot. pyram. N, -90" rot. N,N-dimethyl, planar N pyram. N pyram. N, asymm. rot planar N, 90" rot. pyram. N, -90" r o t pyram. N, +90" rot. s-E, N-F, planar N pyram. N planar N, 90" rot. pyram. N, -90" rot. pyram. N, +90" ror s-2, N-F, planar N s-2, N-F, pyram. N planar N, 90" rot.
(continued)
TABLE 9. (continued) No.
Configuration
134b 134b 135 135 135 135 135
pyram. N, -90" rot. pyram. N, +90" rot. planar NF, pyram. NF, planar NF,, 90" rot. pyram. NF,, -90" rot. pyram. NF,, +90" rot.
Type 120 121 116 117 119 120 121
'Values taken from Reiermcz 195. 'Unstable. Optimizes to coplanar form of type 116. ' O w n calculations. ?&en from Reference 221. 'Taken from Reference 216.
STO-3W
3-21G
6-31G
-230.570932 -230.569818 -328.783997 -328.827039 - 328.771574 -328.823202 -328.828914
-231.758159 -231.756107 -330.471389 -330.512266 -330.461363 -330.509507 -330.515329
6-31G"
6-31G** - 231.844350
- 231.842145 - 330.580711
-330.625617 -330.565636 - 330.620917 - 330.628941
1. Enamines: General and theoretical aspects
39
by about 0.02A with respect to the neutral H-N bond in 115. Consequently, protonation of nitrogen atom in each case leads to elongation of all bonds to that nitrogen atom. This is also observed e~perimentally'~~ for quaternary ammonium salts. The CZCINangle in 123 is around 121.2" and, with 124.1°, larger in 124. 4. a-Substituted vinylamines
Several substituted vinyl amines (125-I%), shown in Scheme 7, were also calculated. For the a-substituted vinylamines 125, 126 and 136 molecular geometries have been calculated for the substituents CH,, F and OH. The results are presented in Table 10. The methyl group is inductively and hyperconjugatively electron-donating. The fluorine atom and the hydroxyl substituent are inductively electron-attracting but conjugatively stron y electron-donating. This leads in a-position to a kind of cross- or Y-conjugationZ 22z3 as observed in urea (138) or phosgene (139). 136 is the tautomeric form of acetamide 140, which is calculated in the 3-21G basis set195to be less stable by 24.60 kcal mol- I.
8'
Both the C=C and the C-N distances in 2-aminopropene (125) are elongated in each basis set with respect to corresponding values of vinylamine (115) of Table 4. The C1-C3 bond is also longer by about 0.004 A than that of propene listed in Table 10. The NC'CZ and CzC1C3angles of 125 are smaller than those of vinylamine (115) and of propene by up to 2".This also holds for the twisted conformations of the type 117 and 121. The conformation of the methyl group shown in formula 125 was calculated to be the most stable conformation. In the case of fluoro-substitution in 126 both the C=C and the C-N distances are shortened in each basis set with respect to those of 115. The NC1C2 angle opens up to 130", as was also observed e~perimentally"~. For the hydroxy substituted 136 the C=C bond is elongated and the C-N bond is shortened from the corresponding values of 115 for each basis set. This indicates more conjugation in the enamine part of 136. The NC'C2 opens slightly to about 127". The s-trans planar conformation of the OH group presented in the molecular formula of 136 in Scheme 7 was calculated as the energetically most favourable conformation. The 6-31G** energy of pyramidalization (change from type 116 to type 117) is, as in 115, close to 1.05kcal m o l l [or 125, 126 and 136. But the rotational barriers depend on the kind of a-substitution. 6-31G**-values for pyramidal sp3-nitrogen derived from data of Table 9 are for the lower rotational barrier (type 117 to 120 of a-CH, (125): 5.19 kcal mol-I, and 6.00 kcal m o l l for the higher barrier (type 117 to 121); for a-F 126 these values are 2.14 and 5.51 kcal mol-I and for a-OH 136, 3.93 and 7.66 kcal mol-'. The corresponding data for unsubstituted 115 are shown in Figure 3. 5. E,Z-Isomerism of p-substituted vinylamines
Calculated properties of a- and p-substituted N,N-dimethylvinylamines reported by Cook4' in his book are based on the semi-empirical MNDO pr~cedure"~,which cannot
40
G. Hafelinger and H.-G. Mack
TABLE 10. Basis set dcpendcnce of calculated heavy atom parameters of a-substituted vinylamines: 2-aminopropene (US),I-amino-I-fluoroethene (126)and I-amino-I-hydroxyethene (136).Distances in A and angles in deg
Parameter
NH, planar 116
117
6-31G
6-31G**
3-21G
6-31G**
NH, pyram. 121 3-21G
6-31G
6-31G**
Distances in 125
cl=cl C1-N C1-C3
1.3262 1.3817 1.5134
Angles in 125 NC1C2 NC'C" C2C1C3
r (debye)
124.36 113.53 122.11 1.758
Distances in propenelg6
C=C C-C
1.3158 1.5107
Angles in propene C2C1C3
124.64
Distances in 126
cl=cZ C1-N C1-F
1.3149 1.3620 1.3588
Anales in 126
NH, planar
Type Parameter
116 3-21G
Distances in 136
cl=c2 C1-N C1-0
1.3274 1.3621 1.3751
116 631G 1.3324 1.3638 1.3742
NH, pyram.
116 6-31G** 1.3311 1.3612 1.3466
117 120 6-31G*V321G 1.3221 1.3782 1.3458
1.3209 1.4008 1.3872
120 6-31G 1.3231 1.4136 1.3452
121 6-31G** 1.3186 1.4084 1.3560
Angles in 136 NCICZ NCIO
126.96 108.92
127.33 108.92
126.42 109.52
126.07 109.62
124.19 112.13
125.37 110.60
122.79 112.65
be compared in accuracy with our calculations presented here. A set of empirical substituent parameters for calculations of E/Z equilibrium constants was derived by KnorrZZ4. We treated only a P-methyl and p-fluoro substituent, 127 and 128, in both the E- and Z-constitution, with the resulting molecular heavy atom geometries presented in Table 11. Additional split-valence basis set optimizations with diffuse functions (3-21 + G) have been performed comparatively by Rivail and coworkers225for P-push-pull sub-
1. Enamines: General and theoretical aspects
41
TABLE 11. Basis set dependence of calculated heavy atom parameters of E and Z j-substituted vinylamines: E-1-aminopropene (127a), Z-1-aminopropene (127b), E-I-amino-2-fluoroethene(128a) and Z-1-amino-2-fluoro ethene (128b). Distances in A and angles in deg NH, pyram. V twist
NH, planar
TYW Parameter
116 3-21G
116 6-31G
116 6-31G8*
NH, pyram. 117 6-31G**
121 3-21G
121 6-31G
121 6-31Ga*
Distances in 127a c'=cZ 1.3224 C1-N 1.3835 C2-C3 1.5111 Angles in 127a NC'C2 126.93 C3C2C1 123.59 DW" 0.0 r (debye) 1.487 Distances in 127b cl=c2 1.3238 C1-N 1.3823 cz-c3 1.5112 Angles in 127b NC1C2 128.41 C3C2C1 126.08 DWa 0.0 r (debye) 1.455 Distances in 128a cl=cz 1.3126 C1-N 1.3793 C2-F 1.3778 Angles in 128a NCIC~ 126.53 FC2C1 119.88 DWb 0.0 r (debye) 3.398 Distances in 128b C'=C2 1.3132 C1-N 1.3749 C2-F 1.3823 Angles in 128b NC1C2 124.92 FC2C' 119.77 DWb 0.0 p (debye) 2.681 " DW = dihedral angle H'C'NH6. DW = dihedral angle 'HCLNH3.
stituted ethenes 129 to 131. The results are collected in Table 12. The degree of deviation due t o the additional diffuse functions may be seen by comparison to our 3-21G calculation of 129. The bond lengths are thereby increased by about 0.006 A. All three molecules are calculated to be planar. Surprisingly, for the fluoro-substituted 128 and for 129 to 131, the most stable isomer corresponds to the Z-configuration. This behaviour was also found in the case of fluoro-substituted forrnarnidinesZz6and refers to the same situation of greater stability
G. Hafelinger and H.-G. Mack TABLE 12. Calculated bond lengths in .& of a$ push-pull conjugated ethenes 120 to 131 Basis set Bonds
3-21
ckc2
+ GZZ5 C1-N'
3-21Gx1 cl=c2
Ground States 125 Z 129 E 130 Z 130 E 131 Z 131 E
1.352 1.341 1.356 1.345 1.340 1.338
1.335 1.348 1.344 1.356 1.366 1.366
C1-N1
-
-
1.3349
1.3425
Transition state structures for C1=C2 rotation 129 130 131
1.465 1.457 1.450
1.287 1.291 1.290
LTransition state structures for C1-N1 rotation 129
1.322
1.425
of 1,2-disubstituted haloetheneszZ7. The energy gain due to pyramidalization (from type 116 to 117) is around 1.5 kcal mol-I, slightly larger than for 115. The calculated gas-phase barriers to internal rotationzz5 around the C1=CZ bond decrease by 56.60, 47.01 and 41.59 kcal mol-' in the sequence: CN > CHO > NO,, which parallels the increase in electron-attracting power of these three substituents. The transition state of this rotation is best described by a zwitterionic rotated configuration of the type indicated in 98b to 98d. The barrier to internal rotation around the C1-N1 bond varies in the reversed order from 21.82, 17.56 to 12.77 kcal mol-' for 129, 130, and 131, respectively. Both trends are consistent with the variations of the electron-acceptor properties of the substituents which decrease in the sequence: NO, > CHO > CN. The rotational barriers of 8-CH, and P-F substituted vinylamines 127 and 128 are calculated in the 6-31G** basis set to be much lower: 3.13 kcal mol-I for the E-CH, substituent 127a, (in parentheses, the value for the higher barrier to type 120: 4.64 kcal m o l l ) , 2.80 (4.64 kcal mol-I) for Z-CH, (127b); for E-F: 0.33 (2.89 kcal mol-I), and for l28b a reversal of the two barriers. That barrier to type 121 is now 4.55 kcal mol-', and that to 12Qis 3.89 kcal m o l l . Experimental determinations of the rotational barriers around C=C and C-N bonds have been performed by several research g r o ~ p s ~ ~leading ~ . ~to~the ~ same - ~ magni~ ~ , tude of values. The influence of solvents was simulated in calculationsz", which leads to a strong reduction of barriers of rotation around the C=C bond and an increase in the values for the C-N rotation. The C=C bond lengths shown in Table 12 for the Z-isomers vary in the ground state from 1.352, 1.356 to 1.340 A. In the rotated dipolar transition state this shortening, 1.465, 1.457 and 1.450 A, depending upon the substituent, is more pronounced. These distances are lengthened and correspondingly weakened, the stronger the electronaccepting character of the substituent, thus leading to a gain in the push-pull throughconjugation indicated in formula 97b. For the Z-isomers the C1-NL distance in the ground state with 1.335, 1.344 and
43
1. Enamines: General and theoretical aspects
1.363 A is shorter (due to push-pull conjugation) compared to 115. In the C=C rotated state, due to zwitterionic conjugation shown in 98b to 98d, the C1-N1 bond of 1.287, 1.291 and 1.290 A is rather short. The shortening again depends on the electron-acceptor properties of the substituents. 6. N-Substituted vinylamines
a. N-Methyl subslituents. The heavy atom geometries of three N-methylated vinylamines, 132a, 132b and 133, are presented in Table 13 and total energies in Table 9. These molecules represent two secondary enamines 132 and the N,N-dimethylvinylamine (133), the simplest possible tertiary enamine. The C=C double bond is in each basis set longer than that of unsubstituted vinylamine (115). The lengthening increases in the series from s-E 132a over s-Z 132b to the N,N-dimethyl substituted 133. The C1-N bond is shortest for 132b. In the 6-31G1* basis the pyramidalization from type 116 to 117 leads to a shortening of the C=C bond and a lengthening of both C-N distances by about 0.01 A in all three molecules, which is again an indication of diminished conjugation. The energy TABLE 13. Basis set dependence of calculated heavy atom parameters of N-methylated vinylamines: s-E-N-methylvinylamine (132a), s-Z-N-methylvinylamine (132b) and N,N-dimethylvinylamine (133).Distances in A and angles in deg N planar
Type Parameter
116 3-21G
Distances in 132a: 1.3246
cl=c"
Angles in 132a NCIC~ 127.21 C1NC3 122.54 P (debye) 1.764 Distances in 132b CkCZ 1.3257 C1-N 1.3746 C3-N 1.4510 Angles in 132b NCICZ 127.21 C'NC3 122.22 P (debye) 1.807 Distances in 133 c 1=cz 1.3271 C1-N 1.3745 C3-N 1.4566 C4-N 1.4531 Angles in 133 NCICZ 127.56
116 6-31G
N pyram.
116 6-31G**
117 6-31G**
N pyram. 90" twist
121 3-21G
121 6-31G
121 6-31G**
G. Hafelinger and H.-G. Mack
FIGURE 4. Schakal plot of calculated conformations (of types 11lL121) of N,N-dimethylvinylamine (133)
1. Enamines: General and theoretical aspects
45
gain on pyramidalization (from type 116 to 117) is around 3.0 kcal mol-', by a factor of three higher than that of 115. Our optimized conformations of the two methyl substituents of 133 are shown graphically in Figure 4. The 6-31G** total energy curve depending on the angle of rotation for pyramidal nitrogen around the C1-N bond of 133 is shown graphically in Figure 5. (A similar curve was derived233by the semi-empirical MNDO pr~cedure"~.)Our global minimum (corresponding to type 118) is located at 4 = 14.7". The type 117 with the pyramidal sp3-nitrogen in the plane of the C=C x-bond (4 = 0.0") is only 0.6 kcal mol-' higher in energy. The perpendicularly rotated dimethylamino group with the nitrogen lone pair inside (type 121) corresponds to shallow minimum on the energy curve, but type 120 with the N lone pair outside is a maximum on that curve. For the points denoted by numbers in Figure 5 we performed additionally a calculation of vibration frequencies to determine the kind of extremal values. For 120, which corresponds to a local maximum of the energy curve or, more precisely, to a saddle point of the energy hypersurface, all but one force constants (as second derivatives of the total energy) are positive, which is the mathematical criterion for a saddle point'".
FIGURE 5. 6-31G** total energies of N,N-dimethylvilynamine (133) with pyramidal sp3-nitrogen as dependent on rotational angle 4 around the C-N bond. Critical points belong to the types 117, 118, 120 and 121. Calculated and geometry optimized points are encircled
46
G. Hafelinger and H.-G. Mack
For the other three critical points only positive force constants have been obtained, which is the criterion for energetical minima. Here we have to stress a warning: Point 117 does not correspond to an energetical minimum, nevertheless only positive force constants are obtained. The reason is that this point was derived by the assumption of a fixed torsional angle (4 = 0.0") and it is below the turning point of the energy curve and very close to the true minimum of the type 118. These three conditions explain that discrepancy. Between 118 and 121 we observe another saddle point. In the conformational behaviour of enamines a kind of demon seems to rule the extent of pyramidalization at nitrogen and of rotational twist around the C-N bond as shown graphically234in Figure 6.
FIGURE 6. Pyramidalization and rotational distortion around the C-N (Reproduced with permission lrom Reference 234)
bond of enamines.
b. N-Fluoro substituents. Results of optimizations of molecular structures of three N-fluoro-substituted vinylamines 134a, 134b and 135 of Scheme 7 are presented in Table 14 and total energies in Table 9. For these three molecules the total energy in each of our three applied basis sets is now lower for the in-plane pyramidal nitrogen of the type 117 than for planar 116. The same behaviour was observed for N-fluoro-substituted formamidines2". The 6-31G** energy gain due to pyramidalization is now very large: 9.27 kcal mol-' for 134a, 9.09 kcal mol-' for 134b and 28.18 kcal mol-' for 135. The C=C and C-N bond lengths are in each case and each basis set shorter than in unsubstituted 115 of Table 4. The N-F distances depend strongly on the type of hybridization at nitrogen: They are shorter in the planar N spZcase (type 116) than for pyramidal N sp3 of type 117 and of type 121.6-31G** N-F distances are significantly shorter, by more than 0.04 A, than the 3-21G and 6-31G values. The NCICZ angle is significantly shorter than that of unsubstituted 115 in the N,N-difluoro-substituted 135 and shows a strong narrowing to 118" on rotation to type 121. 7. Citations of special calculations
a. Use of semi-empiricalmethods. A Pariser, Parr and (PPP) type n-electron calculation for electronic spectra (UV) of dihydronicotinamides and related molecules was performed by E ~ l e t h ' ~The ~ . related class of dihydropyridines was treated237 by use of the MIND013 method173. The CNDOIS method238 was used to evaluate structural increments in UV spectra in a series of B-amino-a$-unsaturated carbonyl compounds239. The MIND013 procedure was applied to calculate HOMO-LUMO properties of simple and conjugated enaminesZ4O,partial optimization of the molecular geometry of
TABLE 14. Basis set dependence of calculated heavy atom parameters of N-fluoro-substituted vinylamines: s-E-Nfluorovinylamine(134a), s-Z-N-fluorovinylamine(134b) and N,Ndifluorovinylamine (135). Distances in A and angles in deg
N planar
TYPe
Parameter
116 3-21G
116 6-31G
N pyramidal 116 6-31G**
117 3-21G
117 6-31G
N pyram. 90' twist, F inside 117 6-31G**
Distances in 134a CkC2 1.3195 C1-N 1.3755 N-F 1.4106 Angles in 134a NC'C2 126.35 CINF 114.38 DWa 0.0 P (debye) 1.282 Distances in 134b C'=c2 1.3169 CL-N 1.3773 N-F 1.4092 Angles in 134b NC'C2 125.96 C~NF 115.79 DWb 0.0 P (debye) 2.593 Distances in 135 cl=cz 1.3140 C'-N 1.3872 N-F' 1.3838 N-F2 1.3829 Angles in 135 NCLC2 124.77 CINF1 122.91 C1NF2 124.14 F'NF2 112.95 DW' 0.0 P (debye) 1.936 ~
--
~-
~
-
~p
"Dihedral angle: FNC'H3. 'Dihedral angle: H4NC'H3.'Dihedral angle: F'NC'H3.
120 3-21G
120 6-31G
120 6-31G**
48
G. Hafelinger and H.-G. Mack
I-dimethylamino-1-phenyletheneZ4'and to simulate Diels-Alder reactions of u-dimethylaminostyrene with d i e n ~ p h i l e s ~Relative ~~'. basicities of amino-substituted conjugated ethenes were studied by the IND0242bprocedure and confirmed by some ab initio 3-21G calculations243. The MNDO p r ~ c e d u r e " ~has been used to calculate charges on C atoms of enamines of 2-methylcyclopentane-1,3-dione244which have been related linearly to 13C-NMR chemical shifts and, together with the AM1 m e t h ~ d " ~to , derive molecular geometries of nitro enamines with intramolecular hydrogen bonds245. The AM1 procedure has been used also to derive molecular structures and rotational barriers of primary and secondary p - e n a m i n o n e ~ ~ ~ ~ . b. Ab initio calculations. An ab initio SCF MO STO-3G and 4-31G basis set study of photo-oxidative cleavage reactions of nitrogen activated C=C double bonds of enamines, indoles and tryptamines has been performed by ~ a m a g u c h i ~ ~STO-3G '. calculations of the transition state structure of the concerted and stepwise enamine addition to carbonyl compounds have been reported by Sevin and coworkers248. A theoretical study of the P-lithiation of enamines at the 3-21G level was presented by the pioneer of enamine reactions, Stork and coworkers249. The enolimine-ketoenamine tautomerism of o-hydroxy-substituted benzalimines was studied by STO-3G and 3-21G optimizations250.For nitroenamines, vibrational spectra have been studied by STO-3G and 3-21G basis sets and the MNDO/H methods251. For the same class of molecules the influence of solvation on isomeric equilibria and rotational barriers has been calculated by use of the 3-21G basis set and the AM1 procedure2s2. The rhodium(1) catalysed isomerization of allylic amines to enamines was also studied by ab initio calculations253. Ill. ENERGETIC RELATIONS A. Protonation Energies and Basicities of Enamines
In the gas phase, the negative of the enthalpy of the reaction (equation 8) is defined experimentally as the proton affinity (PA) of B, indicated by equation 9. This quantity represents the intrinsic basicity of the base B in the absence of s o l ~ e n tExperi~ ~ ~ ~ ~ ~ ~ . mental techniques for determination of gas-phase proton affinities are ion cyclotron resonance256,high-pressure mass ~pectroscopy~~', the flowing afterglow technique258 and molecular beam experiment^^^^-^^^.
In calculations, the energy of the naked proton is zero, so that the corresponding protonation energy, PE, at 0 K in the gas phase for an isolated molecule is obtained by equation 10. From the total energies presented in Table 9, theoretical gas-phase protonation energies, PE, are derived and presented in Table 15. In accordance with our calculation it has been shown experimentally that, in the gas phase, C protonation occurs with enamines and a large substituent effect due to substitution by an a-methyl group was observed263.The intrinsic C-protonation basicity, PE, of vinylamine (115)is calculated to be larger by 18.7 kcal mol-' than its N-protonation basicity and by 6.8 kcal mol-' larger than that of ethylamine. The PE of N protonation of 115 is higher than that of
TABLE 15. Basis set dependence of calculated protonation energies (PE of equation 10, in kcal mol-') for isolated molecules at 0 K Site of protonation and kind of molecules treated
3-21G
N protonation of vinylamine (115): 123-117 N protonation of Z-acetaldehyde imine: 12%122a N protonation of E-acetaldehyde imine: 12S122b C protonation of vinylamine (115): 126117 Watert9' AmmoniaLg5
-224.78 -227.18
-226.94 -237.95 - 191.56 - 226.95
'Based on 6-31Gg* calculations of 115 for the elobal minimum of tvoe 118. *Our calculation by D. Kaiser
6-31G
6-31G**
Other types
50
G. Hafelinger and H.-G. Mack
water and ammonia, but much lower than that of mcthylamine or of formamidincs. Thc C-protonation PE is between that of methylamine and formamidine (137). From the data on enamines and their saturated analogues (141-169)shown in Scheme 8, the same general phenomenon is also observed in solution. This is seen by comparison of C-protonation pK, values of enamines (160and 163)with N-protonation pK, values of the corresponding saturated amines (159and 162)from data presented in Table 16.
(141) 2-Aminopropene (143) N,N-Dimethyl-1-pryopenylamine (145) N,N-2-Trimethyl-1-propenylamine (147) N,N-Dimethyl-2-butenylamine (149) 1-Propenylpyrrolidine (151) ZMethyl-1-propenylpyrrolidine (153) 2-Methyl-I-propenylpiperidine (155) 2-Methyl-1-propenylmorpholine (157) 1-Cyclopentenylpyrrolidine (159) 1.2-Dimethylpyrrolidine (161) 1,3,4-Trimethyl-A'-pyrroline (163) 1.2-Dimethyl-1,2,3,44etrahydropyridine (165) 1,4,4-Trimethylpiperidine (167) 1,4,4-Trimethyl-1,4-dihydropyridine (169) Dehydroquinuclidine (171) l-Azabicyclo[3.2.21non-3-ene
(I4')
(142) Dimethylethylamine (144) N,N-Dimethylpropylamine (146) N,N-Dimethylisobutylamine (148) N,N-Dimethyl-2-butylamine (150) 1-Propylpyrrolidine (152) 2-Methyl-1-propylpyrrolidine (154) 2-Methyl-I-propylpiperidine (156) 2-Methyl-1-propylmorpholine (158) Cyclopentylpyrrolidine (160) 1,2-Dimethyl-A2-pyrroline (162) 1PDimethylpiperidine (164) 1-Methyl-3,s-diethyl-1,2,3,44etrahydropy-
ridine (166) 1,4,4-Trimethyl-1.2.34-tetrahydropyridine
(168) Quinuclidine (170) 1-Azabicyclo[3.2.2]non-2-ene
SCHEME 8
(148)
Molecular formulae and nomenclature of enamines and corresponding saturated amines for which experimental determination of basicities are reported in Table 16.
1. Enamines: General and theoretical aspects
51
G. Hafelinger and H.-G. Mack
52
TABLE 16. Experimental basicities in the gas-phase [PA of equation 9 (kcal mol-')I dctennined by ICR, and pK, in solution in water at 2YC, of amines and enamines shown in Scheme 8
No.
Enamine~".~
PK,
PA"
PA
No.
Amines
Ref.
N-protonation
PK.
C-protonation
Ref.
'PA values are given relative to ammonia, which has an experimental PAzT9of 208.5 f 1.5 kcal mol" 'Values taken from Reference 263. ' Values taken from Reference 266. "stimated values. 'In 25% aqueous methanol at 28'C. 'In acetonitrile.
However, in the rare cases when N protonation occurs in solution (because of kinetic determination of pK,) as in 145 and 153, the pK, of the enamine (and hence its basicity) is less by about 2.0 pK, units (corresponding to 2.7 kcal mol-') than that of the corresponding saturated amines: 146 and 154. This result is due to the conjugative interaction of the nitrogen lone-pair electrons with the C=C double bond as indicated by mesomeric formula l b and due to the inductive and field effect of the alkene group as seen in the case of dehydroquinuclidine (169), where the conjugation between the nitrogen lone pair and the alkene n-system is sterically i m p ~ s s i b l e ~ ~ ~Here, , " ~ . both the gas-phase basicity (PA) and the solution basicity (pK,) decrease relatively to the saturated quinuclidine (168).But usually, due to C protonation, the PA of the enamine is greater than that of the structurally related saturated amine. Experimental determinations of the equilibrium constants of equation 8 in solutions lead to pK, values which are generally dependent on the kind of solvent and on
1. Enamines: General and theoretical aspects
53
temperature. For enamines, the basicities in solution may be affected by the site of protonation, the source of protons, by solvent effects with respect to the gas phase and molecular structure as, for example, a- or p-substitution. Some examples of experimental gas-phase PA and solution pK, values are given in Table 16 for molecules shown in Scheme 8. In solution, the nature of the protonation agent affects the site of protonation of e n a m i n e ~ ' ~ ~The - ~ hard ~ ~ . hydronium ion, such as is formed in 70% perchloric acid, initially leads at low temperature to the kinetically favoured N protonation, whereas the softer carboxylic acids, where the proton is situated on an uncharged oxygen, preferentially attack the softer base site, namely the p-carbon atom, leading to C protonation and hence to the thermodynamically favoured product.
The kinetically controlled N-protonation product (173) of 2-methyl-1-(p-methylstyry1)piperidine (172) was i ~ o l a t e d ~as~ colourless ~ . ~ ~ ' crystals by passing dry HCI into a solution of 172 in benzene below 0 "C. When the resulting enammonium salt 173 was warmed in methanol, it changed to the more stable iminium salt 174 (equation 11). Experimentally it was shown that this isomerization is not an intramolecular process33, which as a concerted [1,3] shift would not be symmetry-allowed according to the Woodward-Hoffmann rules282. Solvent effects may influence strongly differences between pK, values of amines and sometimes even reverse themz'6,2'7. A well-known example is the relative basicity of tertiary amines which, in water, are weaker bases than secondary amines, but in the gas phase this situation is r e ~ e r s e d ~ ' ~ . ~ ' ~ . ~ ' ~ . This kind of solvent effect is also observed in comparison of enamines with corresponding saturated amines. In solution the C-protonated enamine 166 shows an increased basicity of only 0.2 kcal mol-' (derived from the relation4' of 1.36 kcal mol-' per pK, unit) with respect to the related N-protonated amine 165, but in the gas phase the basicity of 165 is increased by 3.4 kcal mol-'. This observed type of levelling effect due to solvent is quite general, when gas- and solution-phase basicities are compared263*270. It is mainly caused by hydrogen bonding with the ~olvent''~.Probably, this is also the explanation that N-protonated enamines are found in solution but not in the gas phase. The N-protonated enammonium ion should be stabilized much more by hydrogen bonding than the C-protonated iminium ion, which should diminish the energetic differences, making the production of enammonium ions a viable option in solution4'. The effect of structure on basicities of enamines may be seen from examples in Table 16. a-Alkyl substituents have a pronounced base-strengthening effect on enamines, both in the gas phase (see 145 and 147) and in solution285 (see 160 and 161). /.LAlkyl substituents are decreasing the basicity in solution (see 160 and 161 or 163 and 164). but not in the gas phase (see 143 and 145). Attempts have been made to correlate experimental first ionization constants of amines and enamines to their protonation affinities in the gas phase or to the s-character ~ ~ .are ~ ~relations, ~. which may be expected of the nitrogen lone pair e l e c t r ~ n s ~These
54
G. Hafelinger and H.-G. Mack
if the protonation is governed by the HOMO frontier orbitals. The path of proton addition to vinylamine (115) was examined by means of electrostatic molecular potentials and the C versus N protonation by use of the semi-empirical PRDDO m e t h ~ d * ~ ' . A linear correlation was foundz8' between experimental proton affinities and innershell 1s electron binding energies calculated by the semi-empirical CND0/2 methodzs9 within a homologous series of amines.
SCHEME 9 are collected in Table 17 Structures and names of amines whose enthalpie~~*~
TABLE 17. Experimental enthalpies of lormation and hydrogenationzg' (in kcalmol-') of amines shown in Scheme 9
Compound No.
AH;
AH" hydrogenation
1. Enamines: General and theoretical aspects
55
Lewis and Brensted basicities of enamino ketones, which present thc possibility of 0 , C or N protonation, have been determined experimentally by Geribaldi and cow o r k e r ~and ~ ~additional ~ STO-3G calculations for 4-N,N-dimethylaminopent-3-en-2one and its protonated forms have been performed. 6. Enthalples of Formation and Hydrogenation
Only one experimental determination291 of enthalpies of formation of enamines obtained from heats of combustion is reported in the literature. Compounds 175 to 180 shown in Scheme 9 are selected in such a manner that they allow the calculation of corresponding enthalpies of hydrogenation. The values collected in Table 17 show that the energy gain due to conjugation in the enamines 175 with respect to the allylic systems 176, which are isomers containing isolated C=C double bonds, is about 5.0 kcal mol-'. The enthalpies of hydrogenation derivcd from these data are in the range of -22 to -25 kcal mol-I, less than the value of about -28 kcal mol-I for an isolated C=C double bond which is observed for 176. The isodesmic reaction (all necessary total energies are taken from the compilation195) indicated in equation 12 yields for the 6-31Ga basis set 7.05 kcal mol-' and, from equation 13, 4.10 kcal mol-' are derived for the stabilization of viuylamine due to conjugation, which are in good agreement with the experimental value. The 6-31Gt calculated hydrogenation energy of equation 14 yields, with -36.91 kcal mol-I, a value which is much too high, i.e. calculations of hydrogenation need considerations of correlation energies. The calculation of the enthalpy of hydrogenation in the same basis set for ethene yields -44.06 kcal mol-' and that of propene, -41.01 kcal mol-'. Both values are also too large, but their difference. with respect to vinylamine with 7.2 and 4.1 kcal mol-' is close to the above-mentioned experimental difference.
C. CC-Tautomerlsm (Reglolsomers)
The equilibration of allylamines like 176, which have an isolated C=C double bond, to conjugated enamines under basic conditions has been studied e x t e n ~ i v e l y ' ~ ~ ~ ~ ~ ~ - ~ ~ ' . With only one exceptionzg8,that of I-(indol-3-ylethy1)-3-pyrroline(181), which is only partially transformed into its enamine 182 (equation 15), the equilibrium generally lies far on the side of the enamine: 1-N,N-dimethylamino-2-propene (183) is i s o m e r i ~ e d ~ ~ ~ with potassium tert-butoxide in DMSO, first to the Z-enamine (184) and then to the thermodynamically more stable E-enamine293.294(185, see equation 16) as was shown by 'H-NMR spectroscopy. Similarly, the heterocyclic amine 186 is i s o m e r i ~ e d to ' ~ ~the heterocyclic enamine 187 (equation 17) with a AG of -4 kcal m o l l , which may be considered as the energy gain
56
Me\
N-CH2-CH=CH2 / Me
G. Hafelinger and H.-G. Mack H I
ot-BuOK ~ Me-Ns c~*C-H I
Me
I
CH3
-
H I Me-N
I
Me
c*C-CH3 I
(16)
H
due to conjugation. Doering and coworkersm9 studied the equilibration of 170 and 171 in which the n-system is perpendicular to the nitrogen lone pair and found an equilibrium constant of 1.0, i.e. the enamine 170 is not preferred with respect to 171. An enantioselective hydrogen migration of prochiral allylamines 188 and 190 to chiral enamincs 189 was realized by use of chiral cobalt catalystsM0 (equation 18).
In the base-catalysed equilibration of 191 and 192 (equation 19) one observesm1 a contest between the conjugativc ability of a phcnyl ring and a N-methylanilino group. The equilibrium lies again on the side of the enamine 192 to the extent of AG = -2.3(3) kcal mol-' determined for the dimethylamino
Hine and coworkers302 showed that the dimethylamino group is by far one of the best known double-bond stabilizing substituents. This may be evaluated quantitatively from experimental enthalpies of formation291 and of hydrogenation presented in Table 17 and may be seen from the value of Hammett's a,(NMez)-constant303 which, at -0.83, has one of the largest negative values observed. Both enthalpy values mentioned show a stabilization of the enamine due to conjugation by - 5 to - 6 kcal mol-' with respect to allylamines which may be correctedzg9 in relation to olefinic systems to about -2.5 kcal mol-I.
1. Enamines: General and theoretical aspects
57
Rearrangement of an enamine to an equilibrium mixture of isomeric enamines will occur under acid catalysis, but will not take place under neutral or basic conditions304. The reaction of non-symmetric ketones 193 with secondary enamines leads to a mixture of both possible enamines 194 and 195 (equation 20) as was shown by 'H-NMR spectrosc0py3O5. Concerted symmetry-allowed [3,3] sigmatropic rearrangements282of enamines have been rep~rted""~". One example is the Cope rearrangement 197 (obtained easily from the methyl vinyl ketone dimer 196 by reaction with pyrrolidine on heating to 250 "C) which leads to 2-pyrrolidino-4-acetylcyclohexene"0 198 (equation 21). Claisen309, a z a - C l a i ~ e n ~ ' ~and . ~ I aza-Cope308.313*314 ~ rearrangements have also been reported.
A [1,3] sigmatropic rearrangement (equation 22) of the enamine 199, which yielded 2-pyrrolidino-3-(2-furyl)-2-methyl-2-propenal (m), was observed3'* by heating to 80 "C
G. Hafelinger and H.-G. Mack
58
in an argon atmosphere. However, this is suprafacially not symmetry-allowed by the Woodward- Hoffmann rulesz82. Non-concerted rearrangements of N-alkylated enamines have also been o b s e r ~ e d ~ . ~ ' ~ . These rearrangements have been shown to take place through a reversal of a primary N-alkylation, followed by subsequent C-alkylation. This was observed for methyl, ethyl and benzyl But allylic groups rearrange intra-molecularly in a concerted way314. Transannular reactions of enamines with the amino group of one side of a medium-size ring and the C=C double bond on the other side of the ring, positioned so that it can interact with the amine nitrogen, have been observedf16. For example, protonation of 201 gives the transannular bonded product 202, but alkylation leads to the open product 203 (equation 23).
IV. ELECTRONIC STRUCTURE: PHOTOELECTRON SPECTROSCOPY AND MO DIAGRAMS A. Experimental ionization Potentials
Ultraviolet photoelectron s p e c t r o ~ c o p y ~(PE) ' ~ ~allows ~ ~ ~ the experimental determination of the first and higher ionization potentials (IP), which are of theoretical interest because, by applications of Koopmans' theorem319, these IP quantities may be equated approximately to Hartree-Fock molecular orbital (MO) energies. Some references234~z87*320-325 deal with determinations of ionization potentials of enamines. A laree collection of IP data of enamines are oresented in Cook's monoerauh4' so will not be repeated here. We selected only some ch'aracteristic values in ~ a b l e i i8n d Scheme 10. Generally, the PE spectra of enamines show two distinct bands at the lowest energy. The lowest band as the HOMO is attributed mainly to the nitrogen lone-pair electrons lowered by conjugation with the CC n-system and the next higher-energy band is mainly due to the C=C n-system, which often show vibrational splitting corresponding to the C=C double-bond stretching frequency of the corresponding radical cation321. The first ionization potential (IP1) of the alkenes shown in Table 18 depend on the pattern of alkyl substituents which fall in the range of 8.9 to 10.5eV. IP1 of methylsubstituted tertiary acyclic or cyclic aminesza6collected also in Table 18 are in the range of 7.82 to 8.41 eV. IP1 of secondary a m i n e ~ ~ ' ~are . ~higher, ~ " around 8.4 to 8.9 eV. In the first section of I P values of enamines in Table 18 the amine part is kept constant as the pyrrolidinyl residue and the ene part is varied. This ranges from 1-butenyl (208) over 1-isobutenyl (151) to I-cyclopentenyl (157) and 1-cyclohexenyl (204). The IP' of corresponding saturated amines are, as far as they are available, also presented in Table 18. In these enamines the first IP is lowered by 0.5 to 0.9eV from the value of corresponding amines. The splitting (A1P)between the first and second I P in enamines, which may be regarded as an indication of the extent of conjugation323,lies in the range of 1.9 to 2.8 eV. In the case of orthogonality of the n-system and the nitrogen lone pair as presented in 169, this splitting is only 0.97 eV. The first IP in this molecule is raised by ./'% #
L.-,
1. Enamines: General and theoretical aspects
59
TABLE 18. Experimcntal first and second ionization potentials (TP)(in eV) of enamines and related compounds - --
Enamines Compound -
IP'
IP2
Amines AIP
Ref.
Compound
Alkenes
IP1
IPL
AIPb
Ref.
-
~p
Ethene Propene Cyclohexene Me,NH
Me,N 206 207
"Experimental differences of first second ionization potentials of enamines. Differences between IP1 of the enamine and 1P' of the corresponding saturated amine. [ matching of the structure of the saturated amine. ' AIP related to 1P2,the CC n-MO, 01 the enamme.
1 denotes no exact
0.42 eV from the value of that of the saturated amine 168. Interestingly, the IPZof the alkene n-bond in 169 is also raised by 0.40 eV from that of the corresponding bicyclic hydrocarbon 211. In the second section of IP values of enamines in Table 18, the alkene part is kept constant as the cyclohexenyl group (with the exception of 212) and the tertiary amine part is varied from dimethylamino (180b) over aziridinyl(212), azetidinyl(214), pyrrolidinyl (204) to piperidinyl (178b) and morpholinyl (215). Again the lowering of IP1 from that of the correspondingly saturated amine is between 0.5 and 0.9 eV. The splitting of IP is more uniform in the range of 1.8 to 2.4 eV. A rather large splitting of 2.7 eV is observed for the heterocyclic enamine 166. Here again, in comparison to 169 the effect of non-coplanarity on ionization potentials is clearly seen.
B. Ab lnltio Calculations of Molecular Orbltal Energies
As already mentioned, by the use of Koopmans' theorem319 the negative of the Hartree-Fock M O energies may be equated to IP values. We present MO orbital
60
G. Hafelinger and H.-G. Mack
(204) Cyclohexen-I-ylpyrrolidine (206) N,N-Dimethylcyclopentylamine (208) I-Buten-I-ylpyrrolidine (210) Aziridine (212) I-Propen-I-ylaziridine (214) 1-Cyclohexen-bylazetidine (216) I-Cyclohdexylmorpholine
(205) Cyclohexylpyrrolidine (207) N,-N-Dimethylcyclohexylamine (209) N-Methylpyrrolidine (211) Bicyclo[2.2.2]octen-2 (213) Azetidine (215) ~yclohexen-1-ylmorpholine
SCHEME 10 Structural formulae and names of compounds for which ionization potentials are prcsentcd in Tablc 18
diagrams graphically for our best basis set 6-31G** in Figure 7 for different conformations of vinylamine (115) and related compounds. The n-HOMO of ethcnc lics at -0.379 hartrec (-10.32cV) and that of propene at -0.357 hartree (-9.71 eV), which are 0.2 to 0.3 eV less than the experimental values collected in Table 18. For planar NH, the lone-pair HOMO lies at -0.380 hartree, which is lowered by pyramidalization to -0.418 hartree (- 11.38 eV). The interaction of ethene with planar ammonia leads to the MOs of coplanar vinylaminc (115) in thc form 116. Thc HOMO n, (with N lonc-pair and C=C n-character) is now at -0.298 hartree (-8.10 eV) and the splitting between n, and n, has a maximum value of 5.20eV. On torsion of the planar amino group to the perpendicular conformation 119 this splitting decreases to 0.18 eV. All three values differ strongly from experimental data presented in Table 18, but they refer to variously substituted tertiary enamines, so that from calculations of 115we only may detect trends. For the pyramidal minimum energy conformation 118 the HOMO n, is at 8.51 eV and the splitting of n, and n, is 4.82eV. On rotation of the pyramidal NH, group to
1. Enamines: General and theoretical aspects
planar
vinylamine
(115)
pyramidal
FIGURE 7. HF-6-31G** calculated M O energies for vinylamine (115) in several conformations 116 to 121 and those of related molecules (in hartree -- 27.2117 eV) 120 and 121 the splitting decreases to 0.96 and 1.02 eV. Both values are (incidentally?) in good agreement with the experimental splitting observed in orthogonal 169. In the case of pyramidally planar N,N-dimethyl vinylamine 1 3 3 of type 117, the HOMO lies at - 8.01 eV and the calculated splitting between n, and n, is 3.76 eV. Both values still do not match the experimentally observed range of values presented in Table 18, but calculated tertiary vinylamine values are shifted towards the experimental values of tertiary enamines. Especially, the calculated value for the second IP from n, is calculated to be too high. For the rotated form of types 120 and 121 the calculated splitting is now 0.49 and 0.21 eV, less than in the case of 115 mentioned above.
62
G. Hafelinger and H.-G. Mack V. DIPOLE MOMENTS AND CONJUGATION
Only few experimental determinations of dipole moments of enamines may be found in the l i t e r a t ~ r e ~ The ~ ~ -experimental ~~~. dipole moments in benzene at 25 "C for the e n a m i n e ~ ~presented ~' below vary between 2.16 and 2.32 D, but smaller values are reported for data from other source^^^^.^".
Our calculated values have been included in Tables 4 to 14. These values show a strong dependence on basis sets and will not be discussed in detail. We concentrate on 6-31G** values and comment first on the conformations 116 to 121 for vinylamine (115) from Tables 4 and 5. The dipole moment for the minimum energy conformation 118 is 1.580 D. This value increases to 1.665 D for the in-plane pyramidal N conformation 117 and is at 1.706 D the largest for the co-planar form 116, which allows maximal conjugation. Consequently the perpendicularly rotated planar form 119 yields with 0.522 D the smallest calculated dipole moment, due to the complcte loss of conjugation. The pyramidally rotated forms present again larger values of 1.371 and 1.515 D for 1U) and 121, respectively, which are close to the value of 118. This indicates that on rotation of the ~ ~ r a m i dNH, a l group the dipole moment changes onlv slinhtlv. This is in sharn contrast to the calculated rotational behaviour of the planar amino group, comparing 116 and 119 from which a mesomeric dipole moment contribution of 1.18 D may be derived, which falls in the range of 0.9 to 1.5 D, that has been suggested from experimental data3". For a-substituted enamines of Table 10, the introduction of a methyl group in 125 increases the calculated dipole moment with 1.721 D slightly for types 117 (which we consider as a close approximation to the not determined minimum energy form of the type 118). A larger value of 2.231 D is calculated for the a-fluoro substituent in 126, which reduces strongly to 1.107 D for the a-hydroxy substituent in 136. On rotation to type 121 the value for the methyl-substituted 125 increases to 1.719 D and to 1.313 D for 136, but for the fluoro-substituted 126 it strongly decreases to 0.943 D. The N-methylated vinylamines of Table 13 show the following behaviour: for 13211 the pyramidal conformation has the same value of 1.410 D for the in-plane type 117 and the 90" rotated form 121. For 132b the dipole moments decrease from 1.544 D to 1.403 D for change from type 117 to 121. For the dimethylated 133 the dipole moment for the minimum energy conformation of type 118 is 1.298 D; for type 117 we calculate 1.457 D, which indicates stronger conjugation. Surprisingly, the calculated dipole moments decrease by methyl substitution on N in relation to those of unsubstituted vinylamine (115). For the rotated molecule 133 with pyramidal nitrogen of the type 121 the value drops to 0.850 D. For the planar form (type 117) we calculate 1.756 D, and
1. Enamines: General and theoretical aspects
63
only 0.102 D for the perpendicularly rotated planar dimethylamino group, which indicates now a larger mesomeric dipole moment of 1.654 D for the dimethylamino group, in agreement with its strong electron-donating property. E- and Z-methyl substitution at P-carbon presented in Table 11 in l27a and 127b only slightly influences the dipole moments: 1.505 and 1.472 D for type 117, which change to 1.310 and 1.238 D on rotation to type 121. Fluoro substitution in 128s and 12% again increases dipole moments to 2.652 and 2.419 D for type 117 and 2.014 and 0.733 D for rotated forms of type 121. P-Nitroenamines 129 show a large increase in experimental dipole momentsM1 (from 2.3 to 5.5-7.2 debye) due to push-pull conjugative interaction which depends strongly on the kind of the amino substituents. For pyrrolidino and piperidino substituents the dipole moment is much larger than for the morpholino group. This indicates that the pyrrolidino and the piperidino enamines are much better able to accommodate an electron-withdrawing group at the P-carbon via electron delocalization than are morpholino enamines. This is consistent with the observation that morpholine enamines are less reactive in electrophilic addition reactions in solution. VI. SPECTROSCOPIC PROPERTIES A. Electron Spectroscopy
Electron (or UV-VIS) spectroscopy is the oldest spectroscopic technique applied in chemistry"""'. In non-conjugated tertiary heterocyclic amines the n + a* UV absorption is observed33Raround 213 to 218 nm with an extinction coefficient (E,,,) at A,, of 1600 to 3100. Additional long-wavelength absorptions around 260nm have been reported339, but these bands are much weaker in intensity with em,, below 100. The n -r n* transition of alkenes between 163 and 197 nm is located in the vacuum-UV = 163 nm, E,,, = region which is experimentally difficult to measure (ethene3&O:A,, 15,000 and tetramethylethet~e~~~: A,, 197 nm, E,, 11,500). Combination of both chromophores in conjugated enamines leads to a bathochromic shift to the range of 220 to 235 nm. This absorption is even slightly longer than the UV e ~, ~ = ~ 217 nm, s, = 21,000) but the extinction coefficients absorption of b ~ t a d i e n (A, for UV spectra of enamines collected in Table 19 are lower, in the range of 3000 to 10,000. For the compound (219b) of Table 19 the bathochromic shift from ethene is 68 nm. The so-called W o o d ~ a r d ~ ~ ' - F i e srules333 e r ~ ~ ~state the following incrementsS4Ofor the bathochromic shift induced by a dialkylamino group: (a) in conjugation to a 1,3-diene: 60 nm, (b) in conjugation to a P-position of an enone: 95 nm and (c) in conjugation to the p-position of an aromatic carbonyl group: 85 nm, which shows the effectiveness of extension of the conjugated system by introduction of a dialkylamino group. A closer look at the data presented in Table 19 shows that in each class of enamines the pyrrolidino group yields the longest-wavelength absorption, followed by the diethylamino group and the piperidino group. In simple acyclic enamines of the type 219 or endocyclic enamines with the cyclopentenyl or cyclohexenyl rest of the kind 158 or 204, the absorptions of the pyrrolidino derivatives are in the range of 233 to 235 nm. The absorption of the piperidino derivatives cover the range of 222.5 to 228 nm. The shortest absorption is observed in each case for the morpholino derivative, which is in the range 220 to 225 nm. This variation seems to indicate a trend in pyramidalization and distortion of conjugation of the nitrogen lone pair with the C=C n-system and is consistent with the above-mentioned changes of dipole moments. The introduction of a phenyl substituent at the P-carbon in 219h lengthens the conjugated system and leads to two bands in the UV region at 225 and 295 nm.
-
-
m P
TABLE 19. Maxima of UV absorption bands OF enamines Substituents Compound
No.
A Pyrrolidino Pyrrolidino Ethyl-n-butylamino Diethylamino Diethylamino Piperidino Piperidino Piperidino Piperidino Piperidino Morpholino Piperidinium
Pyrrolidino ~iperidino Morpholino Pyrrolidino Ethyl-n-butylamino Piperidino Morpholino
R1
R2
1-1 (nm)
La.
Ref
22% 225b 22 k 225d
Pyrrolidino Diethylamino Piperidino Morpholino
2269 226b 226c 226d 226e
Amino Dimethylamino Dimethylamino Dimethylamino Ethylamino
227a 227b 227c
Amino Ethylamino Ethylamino
228s 228b
Pyrrolidino Morpholino
TABLE 19. (continuedl Substituents L
No. 229a 229b
Pyrrolidino Morpholino
230s 230b 230e
Pyrrolidino Pyrrolidino Pyrrolidino Dimethylamino Dimethylamino Dimethylamino
230d 230e 230f
" R'
R'
A
H H Me H H Me
= R2 are R4 = R5 in 22b. In Reference 3% a value of 222 nrn is given, which may be considered as a printing error. 'The value refers to a E: Z ratio of 15%.
R"
H Me Me H Me H
X
inm)
366 384 357 361 380 359
LX
29,000 24,500 27,200 24,900 19.000 25.800
Ref.
354 354 354 354 354 354
1. Enamines: General and theoretical aspects
FIGURE 8. UV absorption spectra of the enamine (a): 1-piperidino-2ethyl-1-butene (2190 in a t e d salt (b):~-r2-eth~lbut~lidenc]~ipcridinium hexanc and the c o r r e ~ ~ & d i n ~ ~ - ~ r o t o niminium chloride (220) in acetunitrile. (Keproduccd with permlsslon from Kelerence 343)
The heterocyclic enamines 222 to 224 of Table 19 show absorption maxima in the longer-wavelength range of 228 to 238 nm, close to that of piperidino enamines, and extinction coefficients between 2900 and 7200. On C-protonation, which leads to formation of an iminium salt (7), the UV absorption maxima are only slightly shifted hypsochromically to lower wavelengths343.However, the shape of the UV band changes drastically: the broad absorption band of the enamine n + n* transition is transformed into a sharp and narrow absorption band of the iminium salt which is shown by comparison of compounds 219 and 220 of Table 19 in Figure 8. (For an indication of the intensities, the extinction coefficient E,,, at A,, is only a crude measure. For an exact description the integrated intensity of the absorption band must be evaluated and may be compared to a theoretically evaluated oscillator ~trength"~.)Figure 8 shows that the integrated absorption of the UV band of the iminium salt (220) is much smaller than that of the corresponding enamine (2190.
If N-protonation of enamines would occur, their UV spectrum should be strongly shifted hypsochromically to an absorption close to that of the corresponding alkene. This may be inferred from the agreement of the UV absorption of styrene (232) (A,, = 248 nm, E,,, = 15,00C1)~~~ with that of o-styryltrimethylammoniumbromide344 = 247 nm, E,,, = 15,350). The UV absorption of the bicyclic orthogonal (233) (A,,
68
G. Hafelinger and H.-G. Mack
enaminez6' (234) (A,,. = 249 nm) is very close Lo that of styrene and practically does not change on N - q ~ a r t e r n a r i z a t i o nto~ ~235 ~ with A,, = 247 nm. The chemistry and physical properties of dienamines were treated specifically in a review article39.The chromophoric system of dienamines 225a to 225d collected in Table 19 shows a bathochromic shift by 50 nm from that of simple enamines into the range of 267 to 280nm, which clearly show the hypsochromic shift mentioned above with variation in the kind of substitution of the tertiary amino group from pyrrolidine to morpholine. Extinction coefficients in the range of 22,000 to 34,200 are now much higher. The Woodward-Fieser rules have been extended345 to predict quantitatively the influence of alkyl substitution at carbons in cc-, 8-, y- or &positions of dienamines. The experimental diflerence between the absorption of a morpholine and a pyrrolidine substituent in dienamines is 13 nm. &Protonation leading to conjugated eniminium salts causes a hypsochromic shifP6 in the range of 250 to 260 nm. j?-Substituted enamines of Table 19 show a strong dependence of UV absorption maxima on the kind of 8-substituents. The cis-trans isomerization of secondary enamino ~ ' spectral aldehydes and ketones 236 to 239 has been studied by UV s p e c t r ~ s c o p y ~and increments have been derived which complement the Woodward-Fieser rules and describe the spectroscopic influence of the isomerization processes from 236 to 237 and from 238 to 237. The form 239 was never observed spectroscopically. Tertiary enaminones 2261, to 226d occur only in the trans, s-trans (E,E) form (236) and absorb in the range of 272 to 290nm. For secondary enaminones a spontaneous trans-cis isomerization from 226e to Z27b takes place on dissolution of the crystalline compounds, which show the form 236, in non-polar solvents, and inter-conversion of spectra of both forms 226e and 2271, around 265 and 306 nm may be recorded. R4 \ RZ N-H \ I /c=C \ O=C R3 \ R1
--
(237) cis, s-cis (Z,Z)
(236) trans, s-trans (E ,E) R4 \ RZ N-H \ I /c=C \ RL-C R3
R2 R3 \ I /c=C \ R'-C N-R4 \\O....HI
/
/
R2 R3 \ I /C=C \ O=C N -R4 \
RL
(238) trans, s-cis (E,Z)
H/
(239) cis, s-trans (Z,E)
These UV determinations have been extended to 8-alkylamino and P-dialkylamino acrylamide~~ and ~ ' to a-substituted enaminones"', and CNDO/S calculations239have been reported. These give only fair agreement with the experimental data of Table 19, i.e. for p-aminoacrolein: 224.3 nm calculated vs 252 nm observed for the trans-form (226a) and 239.7 nm calculated vs 287 nm observed for the cis-form (227a). However, the differences of calculated transitions which are related to experimentally derived spectral increments could be predicted better than absolute transitions.
1. Enamines: General and theoretical aspects
69
The cyclic j-enaminones 228a and 2281, show a long-wavelength absorption at 298 to 305 nm and the P-sulphonyl enamines 229a and 229b absorb at shorter wavelengths of 251 and 250 nm with higher extinction for the former compounds and lower ones for the latter compounds. Again, the UV maximum for the pyrrolidino derivatives is at longer wavelength than that of the morpholino derivatives. The P-nitroenamines 230 and 231 show the longest-wavelength absorption around 350 to 384 nm of all compounds collected in Table 19, which is a strong indication of the importance of a push-pull through conjugation of the amino group with the nitro group either in the E- or in the 2-configuration. For secondary /I-nitro enamines (231) the 2-configuration is preferred due to formation of an intermolecular hydrogen bond. As already mentioned PPP-type235 for the n + n* transition of several enamines have been performed with the following results: vinylamine (115):
199 to 239 nm
1-amino-l,3-butadiene:
249 to 291 nm
8-aminoacrolein (226a):
236 to 277 nm
The calculated UV transitions depend on the selection of semi-empirical parameters of which several combinations have been applied, leading to the above-quoted range of transitions. The agreement with experimental data of Table 19 is not bad in the sense that the experimental values are in the range covered by calculations. In Figure 7 the calculated 6-31G** MO energies of various conformations of vinylamine are shown. We had been interested in the question as to whether the gap between the HOMO x2 and the LUMO n,* may be related to the corresponding experimental n + n* transition. However, inspection of several sets of numerical data shows that this is not the case. The calculated transition of 115 would occur at 84 nm, far off the experimental value. B. Infrared Spectroscopy
Before the victorious introduction of NMR spectroscopy, infrared (IR) spectros~ o p and~ the~complementary ~ ~ - Raman ~ ~spectroscopy356 ~ have been the most important methods for elucidation of organic molecular structures. The C=C doublebond stretching vibrations of alkenes are located in the range of 1620 to 1680 cm-' with variable and rather weak intensities. For symmetrically substituted alkenes this vibration is IR inactive and may be observed only in the Raman spectrum (ethene355: 1623 cm-'). In enamines, with examples collected in Table 20, the C=C double-bond vibration is shifted by about 20 cm- ' to shorter wave numbers relative to corresponding alkenes, and gains strongly in intensity. This is caused by an increase in dipole moments due to the conjugative interaction between the nitrogen lone pair and the C=C double bond. The C=C vibration of acyclic enamines (219) presented in Table 20 depends more on the kind of substitution on carbon atoms than on substituents on nitrogen. The vinylic enamines 219b and 240a show, with 1628 and 1615cm-', rather low C=C vibrations bands, which may be compared to the C=C vibration of p r ~ p e n eat~ ~ ~ 1647 c n - I . The enamines substituted in the P-position by a trans (E) alkyl substituent (219a,c,i, 240d,e and 175a, R1 = alkyl) show C=C vibrations between 1647 and 1660 c m l . The corresponding cis (2)isomers (240f,g, R2 = alkyl) absorb at higher wave numbers: 1680 to 1685cm-'. The enamines with two alkyl substituents in /3-position (22b, 219d,f,g and 240h, R1 and RZ = alkyl) show C=C double-bond vibrations between 1656 and 1672 cm-I.
" ,
m
m m m
m m m
E
m m
m l o o m t - o d - m m o o m ~ ~ m m \ ~ oN l oO W ~ O o m t - - m m c c m v l o m m v l o w m m ~ w m lnmm m mmmm mmm
zzz2zzzzzz2zzzz252zz z2zzz
Sm 2225552
243b 244 244
Morpholino Pyrrolidino Morpholino
24%
Pyrrolidino Morpholino N-Me-piperazino
246a 246b 246c
Pyrrolidino Morpholino N-Me-piperazino
24% 245b
R4 = R5 = R6 = H R4 = Me; R5 = R6 = H 222~ R4 = R6 = H; R5 = Me 222.j R4 = H; R5 = R6 = Me
22%
161
225a 22% 225e 225g 22511
Me Me Me
H Me Me
5-Me H H
Me Me
H H Me Me
H Me H H
Et Me
Pyrrolidino Morpholino Pyrrolidino Morpholino Morpholino (continued)
TABLE 20. Infrared C=C double-bond stretching vibrations (cm-') of enamines
Substituents Compound
No.
R1
A
226b 226f 226e
Dimethylamino Methylamino Ethylamino
227d 227b
Methylamino Ethylamino
248a 24Sb 24&
Dimethylamino Pyrrolidino Morpholino
H H H
R2 Me Me Me
R3 Me Me Me
"m."
(m-')
Ref.
1609 s; 1576 w 1625 s;--~ 1622 s; -d
349 349 349
Pyrrolidino Morpholino Pyrrolidino Morpholino Morpholino
X = C=O X = C=O X = SO, X SO,
-
X=O
Amino Methylamino Dimethylamino Dimethylamino Pyrrolidino Amino Methylamino Amino Methylamino "Notations for intensities: s = strong; m = medium; w = weak. R' = R2 are R4 = R5 in residue 22. 'Six variations for the R' from methyl up to n-hex)+*' ' yielded strong C=C vibrations for the E-form in the range of 166C1659 cm-'. An accompanying weak absorption in cyclohexane as solvent between 1685 and 1675 cm-' was assigned to the Z-isomer. Value not determined or not reported.
'
74
G. Hafelinger and H.-G. Mack
Introduction of a phenyl substituent in a-position (240b,e) leads to a lowering of the C=C vibration to 1593-1615 cm-', which is due to additional conjugation. Phenyl substitution at 8-position in 219h and 240i shows a lowering by about 30 cm-' from the value of the corresponding @-alkylsubstituted enamines up to 1625-1630 cn-'. Looking for the same alkyl substituent pattern 219a, c, 175s and 240e the change of substituents at nitrogen shows a small variation: pyrrolidino = 1647 cm-' < diethylamino = 1648 c m ' < piperidino = 1653 cm-' < morpholino = 1654 c m ' , in which we again find the sequence observed in UV spectra. Less conjugative interaction between the nitrogen lone pair and the C=C z-system leads to a small increase in C=C double-bond vibration frequency. The endocyclic cyclopentenyl enamines 1781,217 and 241a,b show C=C double-bond vibrations from 1622 to 1635 cm-I which are higher than the 1611 cm-' of cyclopentene"'. The endocyclic cyclohexenyl enamines (221) and following compounds up to 244b yield C=C vibrations between 1630 and 1670cm-' which are bracketing the C=C vibration of c y c l o h e ~ e n e 1646 ~ ~ ~c: m l . Again we notice for compounds unsubstituted at the double bond the now extended sequence with changes in N-substitution: dialkylamino = 1630 cm-' < piperidino = 1637 cm-' < morpholino = 1641 c m ' < N-methylpiperazino = 1645 c m ' < azetidino = 1660 c m ' . Alkyl substitution at the C2 carbon in 243a and 243b show at 1635 and 1640 c m ' no important change. But additional introduction of a methyl group at the C-6 carbon in 244a and 244b lead lo a strong shift to higher wave numbers at 1666 and 1670 cm-', which is a clear indication of steric inhibition of enamine conjugation in 26-dimethyl-substituted cyclohexene enamines. The seven-membered ring enamines (24Ja-c) show normal C=C vibrations between 1634 and 1645 c m L ,slightly lower than that of ~ y c l o h e p t e n eat~ 1651 ~ ~ cm-'. But the C=C vibration of 1-methylcycloheptene which is better suited for comparison is355,with 1673 cm-', again higher. The eight-membered endocyclic enamines (246 a-c) yield C=C vibrations between 1610 to 1649 cm-'. The five-membered heterocyclic enamines (222) of Table 20 show C=C vibrations in the narrow range of 1635 to 1648 cm-'. Of the six-membered N-alkyl substituted hcterocyclic enamines (247a-g) the compound 247a without substituent at the double bond yields a C=C vibration at 1642 cm- I , which is slightly shifted to 1645-1650 cm- with alkyl substitution in cc-position in 247b, c, d. Alkyl substitution at 8-position in 247e and f results in hypsochromic shifts to 1657-1673 cm-' and phenyl substitution in cc-position in 247g again lowers the C=C vibration to 1630 cm-'. In determinations of the structure of the protonation products of enamines IR spectroscopy is very helpful: N-protonation to the ammonium structure (6) should lead to N-H valence and N-H deformation vibrations which are both absent in the Consequently, ~~. these experimental IR spectrum of immonium salts of e n a m i n e ~ ~ C-protonation products (7) show strong C=N* vibration bands in the region of 1644 to 1691 cm-', which are shifted hypsochromically by 7-69cm-' from the C=C vibration of corresponding e n a m i n e ~ For ~ ~ ~example, . the perchlorate of protonated 247b shows a C=N vibration361 at 1686 cm-', which is 36 cm-' higher than that of the parent enamine. On the contrary, P,y-unsaturated allylamines show no shift of their C=C vibration on p r o t ~ n a t i o n ~ ~ ' . Linear acyclic d i e n a m i n e ~(225) ~~~ give rise to two double-bond stretching vibrations in the range of 163C~1652cm-' and of 1601-1625cm-', which are caused by anti-symmetric and symmetric combinations of C=C stretching vibrations. @-Enaminones226,227,229 and 248 show also two double-bond stretching vibrations caused by antisymmetric and symmetric combinations. However, in this case the higher one from 1595 to 1654 cm-' may be assigned to the C=O vibration and the lower one at 1546 to 1579 cm-' to the C=C vibration, which is lowered by additional push-pull
'
1. Enamines: General and theoretical aspects
75
through conjugation. In the case of acyclic j3-enaminones the equilibrium between the isomeric E,E forms 236 and the Z,Z forms 237 was studied extensively by Kania and coworkers349. They assigned the vibrations from 1609 to 1625 cm-' to the C=O vibration of the trans, s-trans form 236 together with the C=C vibration at 1576 cm-'. For the cis, s-cis form of secondary p-enaminones (237) the two vibrations occur at 1644 to 1654 cm-' and from 1572 to 1579 cm-'. In addition, the vibrations of the trans, s-cis isomer 238 are observed around 1670 and 1565 cm-I. In cyclic enaminones 248 and 228 the trans-form is fixed through the skeleton. In the five-membered ring compounds (248a-c) the C=O vibration occurs between 1635 to 1650cm-' and the C=C vibration at 1543 to 1575 cm-'. In the six-membered ring compounds 228a and b these vibrations are lower around 1595 and 1546 to 1560 cm-'. In the cyclic sulphoxyenamines (229) the C=C vibration is slightly higher at 1570 c m ' . However, in the cyclic vinyl ether (249) with the morpholino substituent in additional conjugation, the C=C vibration occurs at 1660~11-', which is a clear indication of an electron-rich C=C double bond without push-pull conjugation. In extension of that work IR spectra of P-aminoacrylamide~~~%nd of p-aminomethaand 2,2-diacylethenarnine~~~~ have been crylic esterssG4,P-aminometha~rylonitriles~~~ studied with results similar to those presented here. IR spectra and isomerism of p-nitro enamines 250 and 251 have been studied recently by Gomez-Sanchez and coworkers363in combination with dynamic and high-field NMR spectroscopy. The isomeric behaviour of these compounds is similar to that of penaminones. p-Nitroenamines with primary or secondary amino groups 250a,b and 251a,b exist as solvent-dependent equilibrium mixtures of the intramolecularly hydrogen-bonded cis-form 251 and the trans-form 250. The latter isomer can adopt an additional Z or E conformation around the C1-N single bond to the amino substituent when the substituents are different, as in 250b. The compounds with a tertiary amino group exist solely in the E-forms 250c-e. Vibrational couplings occur inside the mesomeric system leading to a strong IR 'enamine C=C' band between 1550 and 1650 cm-I, which is the result of the asymmetrical coupling of the C=C and C1-N stretching modes, and when A is NH, and R' is H, with additional contributions of the in-plane N-H and C1-H bending modes. These dependencies have been derived from vibrations of N-deuterated species. In p-nitroenamines 250a-c the 'C=C1 vibrations occur between 1622 and 1632 cm-' as well as in the trans-form, as in the cis-form ZSla,b. This band is strongly shifted on a-substitution to 1565 CIT-' in 250d and 250e, but is clearly higher in the cis-forms 251c and 251d with 1580 to 1598 cm-'. Similar studies have been performed with 3-amino-2-nitroacrylic esters366(252) and 3-amino-2-nitrocrotonic esters36' (253). Compounds 252 with primary or secondary amino groups crystallize in one of the three isomeric forms 252a, b or e, but in solution they exist as equilibrium mixtures of the three forms, in ratios strongly dependent on the polarity of the solvent. Each isomeric form has easily distinguishable IR absorptions. The Z-forms 252a and b show a C=C vibration around 1623 cm-' and the E-fonn 25% around 1585 cm-'. The s-cis isomer of the ester group 2521 and the s-trans isomer 0
\\
H C-OMe \ 1 /c=C \+ R-N N-0-
~ . . //. . b
\
Me0 \ H /C=0 \ ,C=c \+ R-N N-0\H....O //
H
\
,C=C
R-N
NO2 \
\H....O?-OMe
G. Hafelinger and H.-G. Mack
0 Me \ R-N
dC--0Me I
,C=c\+
N-CF
H....OI/
\
?\ Me \
\\
C-OMe
,C=c
R-N
I
\+
N-0-
H....O//
\
Me \
,C=c
R-N
NO2
1
\
\H....O//C-OMe
252b may be distinguished by their C = O double-bond vibration around 1692 and 1732 cm-'. The related compounds36' 253 with both primary and secondary amino groups exist in solutions as equilibrium mixtures of the two enantiomeric quasi-s-cis-(Z) isomers 253a and 253b and the planar and less polar s-cis-(@ isomer 253c, of which the ratio is strongly dependent on the polarity of the medium. The C=C vibration occurs in the former cases around 1595 cm-' and in the isomer 253c a t 1535 c m '. All three isomers are intramolecularly hydrogen bridged. VII. ACKNOWLEDGEMENT
We thank cordially D r Siegfried Ettel for CA searches, Dip1.-Chem. Dietmar Kaiser for additional ab initio calculations and Cand. Chem. Georgios Piperopoulos for plotting molecular formulae using the C-design program.
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1. Enamines: General a n d theoretical aspects R. Walder and J. L. Franklin, Int. J. Mass Spectrom. Ion Physics, 36, 85 (1980). C. H. DePuy and V. M. Bierbaum, Acc. Chem. Res., 14, 146 (1981). T. Y. Lee, Angew. Chem, 99,967 (1987); Angew. Chem., Int. Ed Engl., 26,939 (1987). D. R. Hershbach, Angew. Chem., 99,1251 (1987); Angew. Chem., Int. Ed. Engl., 26,1221 (1987). R. B. Bernstein, Chemical Dynamics via Molecular Beam and Laser Techniques, Oxford University Press, Oxford, 1982. 262. R. D. Levine and R. B. Bernstein, Molecular Reaction Dynamics and Chemical Reactivity, Oxford University Press, Oxford, 1987; Molekulare Reaktionsdynamik, Teubner, Stuttgart, 1991. 263. M. R. Ellenberger, D. A. Dixon and W. E. Farneth, J. Am. Chem. Soc., 103, 5377 (1981). 264. R. A. Eades, K. Scanton, M. R. Ellenberger, D. A. Dixon and D. S. Marynick, J. Phys. Chem., 84, 2840 (1980). 265. C. A. Grob, A. Kaiser and E. Renk, Chem. Ind (Lundun), 598 (1957); C. A. Grob, A. Kaiser and E. Renk, Helv. Chim. Acta, 40, 2170 (1957). 266. R. Houriet, J. Vogt and E. Haselbach, Chimia, 34, 277 (1980). 267. J. Elguero, R. Jacquier and G. Tarrago, Tetrahedron Lett., 4719 (1965); 1112 (1966). 268. L. Alais, R. Michelot and B. Tchoubar, Compt. Rend., 273, 261 (1971). 269. L. Nilsson, R. Carlson and C. Rappe, Acta Chem. Scand, B30, 271 (1976). 270. D. H. Aue, H. M. Webb and M. T. Bowers, J. Am. Chem. Soc., 98, 318 (1976). 271. P. Y. Sollenberger and R. B. Martin, J. Am. Chem. Soc., 92,4261 (1970). 272. J. Hanson, Suensk Kem. Tidskrift, 67, 256 (1955). 273. R. Adams and J. E Mahan, J. Am. Chem. Soc., 64, 2588 (1942). 274. E. J. Stamhuis, W. Maas and H. Wynberg, J. Org. Chem., 30, 2160 (1965). 275. N. J. Leonard and A. G. Cook, J. Am. Chem. Suc, 81, 5627 (1959). 276. Cited in Reference 41, p. 80 and in Reference 285, but both citations to original references are erroneous. 277. E. M. Kosower and T. S. Sorensen, J. Org. Chem., 27,3764 (1962). 278. C. A. Grob, Helt~.Chim. Acta, 68, 882 (1985). 279. S. G. Lias, D. M. Shold and P. Ausloos, J. Am. Chem. Sac., 102, 2540 (1980). 280. H. Matsushita, Y. Tsujino, M. Noguchi and S. Yoshikawa, Chem. Lett., 1087 (1976). 281. H. Matsushita, Y. Tsujino, M. Noguchi and S. Yoshikawa, Bull. Chem. Sac. Jpn., 50, 1513 (1977); H. Matsushita, Y. Tsujino, M. Noguchi, M. Saburi and S. Yoshikawa, Bull. Chem. Soc. Jpn., 51,201 (1978); H. Matsushita, Y. Tsujino, M. Noguchi, M. Saburi and S. Yoshikawa, Bull. Chem. Soc. Jpn., 51, 862 (1978). 282. R. B. Woodward and R. HofTmann, Angew. Chem., 81, 797 (1969); Angew. Chem., Int. Ed. Engb, 8, 781 (1969). 283. M. S. B. Munson, J. Am. Chem. Soc., 87,2332 (1965) 284. E. M. Arnett. J. Chem. Educ.. 62. 385 119651. , 24, 1'85 (1968). ' 285. R. L. ~ i n m a h Tetrahedron, 286. K.Yoshikawa, M. Hashimoto and I. Morishima, J. Am. Chem. Soc., 96, 288 (1974). 287. F. P. Colonna, G. Distefano, S. Pignataro, G. Pitacco and E. Valentin, J. Chem. Soc., Faraday Trans. 2, 1572 (1975). 288. D. W. Davis and J. W. Rabalais. J. Am. Chem. Soc., 96. 5305 (1974). 289. J. A. Pople and D. L. Beveridge, Approximate MO Theory, McGraw-Hill, New York, 1970. 290. M. Azzaro, J. F. Gal, SLGeribaldiand B. Videau, J. Chem. Soc., Perkin Trans. 2, 57 (1983). 291. M. Prochazka, V. Kiestanov4 M. PaleEek and K. Pecka, Collect. Czech. Chem. Commun., 35, 3813 (1970). 292. C. C. Price and W. H. Snyder, Tetrahedron Lett., 69 (1962). 293. J. Sauer and H. Prahl, Tetrahedron Lett., 2863 (1966); J. Sauer and H. Prahl, Chem. Ber., 102, 1917 (1969). 294. M. Riviere and A. Lattes, Bull. Soc. Chim. France, 2539 (1967); M. R i v i k and A. Lattes, Bull. Sac. Chim France, 4430 (1968); M. Riviere and A. Lattes, Bull. Soc. Chim. France, 730 (1972). 295. A. J. Hubert, J. Chem. Soc. ( C ) , 2048 (1968). 296. A. Hattori, H. Hattori and K. Tanabe, J. Catalysis., 65, 245 (1980). 297. D. A. Evans, C. H. Mitch, R. C. Thomas, D. M. Zimmermann and R. L. Robey, J. Am. Chem. SOC.,102, 5956 (1980). 298. W. R. Ashcroft, S. J. Martinez and J. A. Joule, Tetrahedron, 37, 3005 (1981). 257. 258. 259. 260. 261.
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J. Dabrowski and K. Kamienska-Trela, J. Am. Chem. Soc., 98,2826 (1976). J. Dabrowski, K. Kamiehska-Trela and L. Kania, Tetrahedron,32, 1025 (1976). L. Kania, K. Kamienska-Trela and M. Witanowski, J. Mol. Struct., 102, 1 (1983). G. Opitz, H. Hellmann and H,W. Schubert, Justus Liebigs Ann. Chem., 623, 112 (1959). P. Dupuis, C. Sandorfy and D. Vocelle, Photorhem. PhotobioL, 39, 391 (1984). R. Dulou, E. Elkik and A. Veillard, BUN. Soc. Chim. France, 967 (1960). F. A. van der Vlugt, J. W. Verhoeven and U. K. Pandit, Recl. Trau. Chim. Pays-Bas, 89, 1258 (1970). D. L. Ostercamp and P. J. Taylor, J. Chem. Sor., Perkin Trans. 2, 1021 (198.5). L. J. Bellamy, The Infra-red Spectra of Complex Organic Molecules, 2nd ed., Methuen, London, 1957; Ultrarot-Spektrum und chcmisrhc Konsritution, 2. Aufl., Steinkopff, Darmstadt, 1966. N. B. Colthup, L. H. Daly and S. E. Wiberley, Introduction to Infrared and Raman Spectroscopy, 2nd ed., Academic Press, New York, 1975. H. Giinzler and H. Bock, IR-Spektroskopie. Eine Einfiihrung, 2. Aufl., Verlag Chemie, Weinheim, 1983. W. L. F. Amarego, J. Chem. Soc. ( C ) , 986 (1969). D. E. Heitmeier, J. T. Hortenstine, Jr. and A. P. Gray, J. Org. Chem., 36, 1449 (1971). F. Johnson, L. G. Duquette, A. Whitehead and L. C. Dorman, Tetrahedron, 30, 3241 (1974). N. J. Leonard and V. W. Gash, J. Am. Chem. Soc., 76, 2781 (1954). F. Eiden and K. T. Wanner, Arch. Pharm., 317,958 (1984). J. L. Chiara, A. Gomez-SBnchez and J. Bellanato, J. Chem. Soc., Perkin Trans. 2,787 (1992). F. Texier and J. Bourgois, Bull. Soc. Chim. France, 487 (1976). A. Gomez-Shchez, de G. G. Martin, P. Borrachero and J. Bellanato, J. Chem. Soc., Perkin Truns. 2, 301 (1987). J. L. Chiara, A. Gbmez-Sanchez, F.-J.Hidalgo and J. Bellanato, J. Chem. Soc., Perkin Trans. 2, 1691 (1988). J. L. Chiara, A. G6mez-Sanchez, E. Sanchez Marcos and J. Bellanato, J. Chem. Soc., Perkin Trans. 2, 385 (1990).
CHAPTER
2
Structural chemistry of enamines: a statistical approach SLIWINSKI University. ul. R. lngardena 3. 30-060 Krakak6w. Poland
BARBARA J . OLEKSYN. KATARZYNA STADNICKA and JAN Faculty of Chemistry. Jagiellonian
I . INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I1. REMARKS ON STRUCTURAL INFORMATION. CLASSIFICATION AND METHODOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Definition of the Enamine Grouping . . . . . . . . . . . . . . . . . . . . B. Structural Data Retrieval . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Descriptive Statistical Analysis-Useful Definitions . . . . . . . . . . . . D. Multivariate Statistical Analysis-Principal Components Method . . . 111. DESCRIPTIVE STATISTICAL ANALYSIS O F ENAMINE FRAGMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Unrestricted Substituents . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Bond lengths . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Bond angles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Torsion angles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Distances from planes . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Specific Substituents: Carbon as the First Atom in R1-R5 . . . . . . . . C . Parameters Describing Distortion of Enamine Fragments from Planaritv . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I V . PRINCIPAL CVMPONEN.I.S ANALYSIS OF ENAMINE FRAGMENTS WITH UNRESTRICTED SUBSTITUENTS . . . . . . . A. Bond Lengths . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Bond Angles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Torsion Angles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V . CORRELATIONS BETWEEN SOME GEOMETRICAL PARAMETERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Bond-length Correlations . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Corrclations Involving Angular Dcformation Parameters . . . . . . . . VI. EVALUATION O F SUBSTITUENT EFFECTS ON THE GEOMETRY O F ENAMINE FRAGMENTS . . . . . . . . . . . . . . . . VII. CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
.
134 137 141 142 146 146 149 158 158
The Chemist~jof Enamines Edited by Zvi Rappoport Copyright 0 1994 John Wiley & Sons. I.td. ISBN: 0-471-93339-2
88
B. J. Oleksyn, K. Stadnicka and J. ~liwinski
VIII. ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 IX. APPENDIX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 X.REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210 I. INTRODUCTION
Although a great number of crystal structures of compounds containing enamine fragments were reported, a systematic survey of the geometry of the enamine group in the crystalline state has not been published so far. The most probable reason for the lack of a comprehensive review on these structures seems to be due to the fact that they are considered by crystallographers together with amines rather than treated as a discrete class of compounds. An important and interesting exception is the comparative study of seven crystal structures of enamines published by Dunitz and coworkers1. The nitrogen atom of the compounds described in their study is part of the pyrrolidine, piperidine and morpholine ring systems (for the molecular formulae and details of the geometry, see Chapter X in this volume2). The discussion of geometrical features of the enamine moiety, such as its conformalion, the pyramidality of the nitrogen and central carbon atoms as well as their variability with bond lengths and bond angles, is very valuable. Of special importance seems to be the observation that one of the N-C (sp3) bonds tends to adopt a syn-periplanar conformation with respect to the enamine C=C bond. Although the conclusions drawn by Dunitz and coworkers concern a limited group of very specific compounds, they may serve as a useful reference material in the studies of other types of enamines. Dunitz and coworkers introduced two angular parameters, X, and x,, shown in Figure 1; X, describes a distortion of the D2 bond from the plane defined by the bonds D l and D3, whilst xC is a measure of D5 bond distortion from the plane defined by D l and D4 bonds. These parameters are related to the pyramidalities of the nitrogen (Nl, sp3) and carbon (C2, sp2) atoms, respectively, and are linear combinations of pairs of the corresponding torsion angles and n:
+ + w4 + n (modulo 271) xc = w1 - m3 + n (modulo 2rc) = -mz + m4 + n (modulo 2n)
XN = w z - o3 n (modulo 2n) = -ol
In most cases X, and zc are opposite in sign to each other and the absolute value of zN is greater than that of x,. The third angular parameter used by Dunitz is the average twist angle, T = (w, w2)/2, where o, is the angle between the planes through Dl, D3 and Dl, D5, and w, is the angle between the planes containing bonds D l and D2 and bonds D l and D4. The scatter plot of X, and T values for 9 enamine units found in 7 crystal structures gave a correlation curve which was interpreted by Dunitz and coworkers, according to his structural correlation principle3 ('if a correlation can be found between two or more independent parameters describing the structure of a given structural fragment in various environments, then the correlation function maps a minimum energy path in the corresponding parameter space'), as the relationship modelling the reaction path of cis-rrans inversion at N1 atom:
+
2. Structural chemistry of enamines: a statistical approach
FIGURE 1. Bond scheme (a) and Newman projections of the enamine grouping down N1-C' (b) and C1-N1 (c) directions based on Brown et al.' The symbols are those used throughout this
chapter
A further development of the Dunitz approach was undertaken by Gilli and his coworkers4 who considered the inversion path not only for enamines, but also for other I where X either denotes 0 (in the compounds containing the fragment N-C=X, case of amides and carbamates), S (thioamides and thiocarbamates) and N (amidines) or is involved in an aromatic moiety (anilines and naphthylamines). The set of enamines within the total file of 90 fragments was, however, rather small and consisted of only 16 items. Gilli and coworkers claimed a linear correlation (with a regression coellicient R = 0.893) between the N ' - C ~ bond length (Dl) and x,. This correlation, shown in Figure 2, can be understood as a decrease of the n-bond order in the N1=C2 bond together with the rehybridization of the N1 atom from sp2 to sp3. The experimental evidence of the n-bond order decrease is the lengthening of the D l bond, while the rehybridization corresponds to an increase of x,. It was concluded by Gilli and coworkers from the very weak correlation observed between D l and T, that the partial double bond N1=C2 is weakened mainly by the pyramidalization of the nitrogen atom N1 and, to a lower extent, by the twist of the enamine grouping around this bond. for the molecular The parameters of the out-of-plane deformation, namely T and x,, fragment considered by Gilli and coworkers4 are mutually correlated in a similar manner as for the enamines described by Dunitz'. The correlation curve, shown in Figure 3a,
B. J. Oleksyn, K. Stadnicka and J. ~liwinski
FIGURE 2. Correlation between dc-, = D ~ ( A and ) X, according to reference 4 (by permission of the authors): A-anilines, B--naphthylamines, D-mamines, N-amidines, 0 or S-amides, carbamates, thioamides and dithiocarbamates
consists of two parts, I and 11. Part I corresponds to the molecular fragments in which the deformation from planarity is caused chiefly by a change of X, ('butterfly' deformation) with angle T being near zero. Part I1 corresponds to those fragments in which the deformation is of 'combined' character and is caused both by 'butterfly' motion and rotation around the N1-CZ bond. This suggests, according to Gilli and coworkers, that the first stage of the cis-trans isomerization of enamines and other Cragmenls consists in pyramidalization of the nitrogen atom. The pyramidalization process, when sufficiently advanced, is accompanied by a rotation around the N1-CZ bond in further stages of the isomerization. The hypothetical course of the isomerization reaction, reconstructed by Gilli and coworkers from the crystal structure data, is shown in Figure 3b. On the basis of the structure correlation principle Gilli postulated that the isomerization reaction path, which can be inferred from the X, vs T correlation, proceeds along the valley of the energy surface. The valley connects the reagents (here cis isomers) and the products (here trans isomers). In order to construct thc energy surface model .Gilli used the equation V(T',xN)= (CTIB + IB)(l - cos 2712 + QP(1 - cos r1),&/2 IN1 - cos T')(COS 3XN- 1)/4 Enb(T',xN)
+
+
where V = potential energy, T' = 27, CTIB = the cis-trans isomerization barrier, IB = the pyramidal inversion barrier of the sp3 nitrogen atom, Q P = the force constant for the out-of-plane bending of the sp2 nitrogen and En, = the energy of non-bonded van der Waals interactions.
91
2. Structural chemistry of enamines: a statistical approach
XN
\ TI
60
//"-"
II
8-
X
0-
P- *P+-,
- <-.
*a C-N. *A& &
45
C-N
/,
\
1
FIGURE 3. (a) Correlation between
(4
Ix,I and IT\ for molecular fragments N-C=X
of anilines
(A),naphthylamines (B), enamines (D) and amidines (N). (b) Hypothetical reaction path for cis-trans isomerization. The cis enamine fragment passes from an originally planar arrangements, via transition conformations with increasing pyramidality of N1, followed by increasing twist, towards the trans isomer. Only part of the path is shown, up to the highest r value observed in the crystalline state. Taken from Reference 4 by permission of the authors
92
B. J. Oleksyn, K. Stadnicka and J. ~liwinski
A three-dimensional diagram of V, calculated for a hypothetical molecule, intermediate among all fragments considered by Gilli and coworkers, as a function of T and xN is shown in Figure 4. Most of the points which correspond to fragments with experimentally determined geometries are situated within the valley of the calculated energy surface. The lowest energy conformations are, as expected, those with the planar structures stabilized by the contribution of the polar form in the ground state.
The conformers of the highest energy near the cis-trans isomerization barrier are those with x, of about 60" and T of about go*, most of them corresponding to the enamine fragments. It seems worthwhile to confront the above conclusions concernine the eeometrv of a small sample of the enamine population with a study of all enamine fragments accessible in the Cambridge Structural Database System (CSDSJ'. Such a study is the subject of
- -
FIGURE 4. Energy surface, V(r,x,), with points corresponding to aniline (A), naphthylamine (B), enamine ID) . , and amidine IN) . ,fraement eeometries determined in the crvstalline state. The diagram is taken from Reference 4 by permission of the authors
-
-
.
2. Structural chemistry of enamines: a statistical approach
93
this chapter, which also aims at answering the Dunitz question: 'Should this (enamine grouping) be planar, like the amide group, because the nitrogen lone pair can conjugate with the C=C bond, or should it be non-planar, with a pyramidal N atom, because the conjugation with C=C is so much weaker than with C=O that the energy stabilization attributable to conjugation is insufficient to outweigh the energy cost of bringing the three bonds at N into a common lane?'^.
II. REMARKS ON STRUCTURAL INFORMATION, CLASSIFICATION AND METHODOLOGY A. Definition of the Enamine Grouping
The enamine grouping can be formally derived from ammonia in which one of the hydrogen atoms is substituted by a vinyl group.
The chemical properties of compounds containing the enamine grouping depend on the extent of conjugation between the lone pair on the nitrogen atom and the rest of the system consisting of one single and one double bond. The crystal structures of the enamines are important in this respect that they consist of various intermediate degrees of conjugation between two extreme states:
which show different electron density distribution within the enamine core. It is therefore necessary to examine the structures of enamines carrying diRerent substituents, in different crystalline environments in order to determine the geometrical variability of the enamine fragment and to model reaction paths such as the change ofelectron density in terms of the two extreme states defined above, cis-trans isomerization at the nitrogen atom, etc. The chemical moiety for which the CSDS (version 4.6, 1992) search has been carried out was defined in structure 1 where each of R', RZ,R3, R4 and R5 is any substituent.
B. Structural Data Retrieval
In the first 'naive' attempt a search for structures of compounds containing N-C-C grouping without any constraints on bond types or number of substituents at N and C atoms gave a huge amount of 7481 structures. This result prompted us to eliminate such formally enamine-like compounds as porphyrines, phthalocyanines, tetraazamacrocyclic compounds, purine and pyrimidine derivatives, as well as to formulate more precise conditions for selection of proper enamine groupings. To this end a new structural data retrieval from CSDS was performed in four stages.
94
B. J. Oleksyn. K. Stadnicka and J. Sliwinski
At the first stage, a file (1) containing 11 139 entries* (found in 1403 crystal structures) was created using programs QUEST and GSTAT (version 3.8, 1991)5 under the condition that (i) every atom of the enamine grouping N1-CZ-C3 has exactly three substituents. At the second stage, from file (1) a suhfile (1.1) was extracted comprising 5576 entries which met either both or only the second of the two additional conditions: (ii) the hybridization of the C2 and C3 atoms is sp2, (iii) the discrepancy factor, R, for the structures containing these fragments is G0.075. Among all the 5576 entries the subfile (1.1) contained 2494 entries (894 structures) which satisfied all three conditions (iHiii). Of them only 402 (set 1) were manually screened out as proper enamines, by inspection of the molecular structure views and some geometrical parameters like bond lengths and bond angles for both the enamine grouping and adjacent atoms. This approach was the only way to discriminate between the proper enamines and aromatic cyclic systems, metal chelates, metalo-organic compounds, nitro compounds, etc., involving N-"C-"C groupings. The remaining 3082 entries of subfile (1.1) which did not fulfil condition (ii) were examined and gave additionally 17 enamine fragments (set 2). All structures containing these fragments had R < 0.075. Finally, in the remaining part of file (I), i.e. in the subfile (1.2) which contained 5563 entries (from 509 crystal structures), 55 enamine fragments (set 3) were selected manually from among 1013entrics belonging to 264 crystal structures which fulfilled condition (iii). The relations between the file, subfiles and the various sets of entries of the proper enamine fragments are illustrated by a scheme in Figure 5. The three selected sets (1-3) were merged to form one set, S, consisting of 474 proper enamine fragments. By 'proper enamine fragments' the grouping shown in 1 is understood which corresponds to the characteristics given by Hafelinger and Mackz. On a chemical and geometrical basis four main classes of enamine fragments can be distinguished in the final set S: (a) typical enamines, (b) indole derivatives, (c) 'push-pull'-like systems of alternate single and double bonds, (d) other fragments. Although it is a generally accepted classification of enamines as (i) primary, (ii) secondary and (iii) tertiary, it was not necessary to form separate sets comprising these types of enamines for two reasons. The first was that (i) contained only 7 and (ii) 18 entries, which are insufficient for statistical analysis in comparison with the tertiary enamines (iii: 449 entries). The second reason was a lack of special structural features which would justify such a separate treatment, as it was found that primary and secondary enamines contribute to all the four classes (a)-(d). The structures of the compounds in set S together with their reference codes (REFCOD's) ascribed to crystal structures in CSDS and the appropriate reference are given in the Appendix at the end of this chapter. It should be noted that the number of published crystal structures is less than the number of entries (enamine fragments), because more than one fragment may occur in a particular molecule. Figure 6 presents the frequency distribution of enamine fragments (number of entries considered in this chapter) published over the years in the period 1969-1991. For each fragment having its reference code (REFCOD) from CSDS, a full list of 32 descriptors was stored in a computer file. These descriptors comprise 8 chemical symbols and 24 geometrical parameters. The symbols, consisting of letters and numbers, were those ascribed in the original crystallographic papers to the 'core' atoms (N', CZ,
* 'Entry' is a term used in CSDS for a positive result of the search for a given group of atoms.
B. J. Oleksyn, K. Stadnicka and J. Sliwinski
Year FIGURE 6. Frequency histogram of enamine fragments (entries) found in crystal structures published yearly in the period 1969-1991 and comprised in CSDS C3) of the enamine fragment and to the first atoms of the substituents R'-RS.The geometrical parameters comprised seven bond lengths (Dl-D7), nine bond angles (AlLA9), eight torsion angles (TILTB) and eight distances of atoms from four best planes (PD1-PD8). All these parameters are defined in Figure 7. Before statistical studies for the fragments contained in set S were undertaken, substituents at the N1and C3 atoms had been defined in such a manner that the torsion angles T1 and T6 had values close to 0 while the angles T3 and T5 were close to 180 180 ". Thus, the symbols R1 and R5 correspond to the trans substituents with or respect to R3, whereas RZ and R4 are cis to R3. In some cases, when the torsion angles above were very different from 0 "), the substituents were arbitrarily classified as trans for T1 and T6 less than 90" (i.e. R1, R5) while for torsion angles T3 and T5 very different from 180 or - 180 " but greater than 90 " as cis (i.e. RZ,R4). The first treatment of the data, systematized as above, concerned the whole set S without dividing it into subsets according to the chemical nature of the first atoms of the substituents, the distribution of which is shown in Table 1. The most numerous are the substituents in which the first atom is carbon or nitrogen. Hydrogen, oxygen and sulphur are present in a much lower number of substituents. Among other elements, only chlorine and silicon are the most frequent. O,
-
C. Descriptive Statistical Analysis--Useful Definitions
The statistical analysis was carried out first for the enamine fragments stored in set S with unrestricted substituents, R1-R5, and subsequently for smaller subsets of S, with various restrictions concerning the chemical nature of the first atoms in these substituents. All geometrical parameters, i.e. bond lengths, bond angles, torsion angles and distances from planes, were considered and a full characterization of their distributions was performed using program STATGRAPHICS PLUS6. Such summary statistics as the average, variance, standard deviation, geometric mean, minimum, maximum and range of observed values of the variable, mode, median and quartiles, standard error, coefficient of standardized skewness and kurtosis were calculated for each parameter.
2. Structural chemistry of enamines: a statistical approach
R3
R4
N1
R3
R5 R2
Newman projections: view down N ' - c ~
view down c2-c3
FIGURE 7. Geometrical parameters stored for every enamine fragments: (a) bond lengths, (b) bond angles, (c) torsion angles, (d) distances from planes
B. J. Oleksyn, K. Stadnicka and J. Sliwiliski TABLE 1. Frequency of elements appearing as the first atom of the unrestricted substituents R1-R5 N'
R' trans R"
C" R3
C3
R2
R4
R5
cis R 3
cis R 3
trans R3
Also, frequency polygons and histograms as well as frequency tabulation were displayed for each variable. The definitions of the most important statistical used in the analysis of different sorts of data are given below. Awrage (mean): 2 = x)/n, where x is a variable, x is the sum of n observed values of the variable x and n is the number of the values of x or sample size (number of items in the sample). Mode is the value of x that occurs most frequently. C ( X - .q2 Variance: sz
(1
-
.. .
Sample standard deviation: s = (s')'.~ =
1
I
1(x - x)
[
".'
- 1 Standard deviation and range measure the spread or dispersion of the sample. Standard error of the mean: a/nO.', where a is the standard deviation of the population from which a random sample of size n was taken (usually a is estimated by s). The skewness coefficient: [nCy=, (x, - i)"/(n - l)(n - 2)s"~ a measure of the asymmetry of the data distribution. The direction of the skewness is on the side of the longer tail of this distribution. The kurtosis coefficient
is a measure of the flattening of the data distribution with respect to a Gaussian or normal distribution and it has zero value for the normal distribution. The standardized coefficients, both skewness and kurtosis, indicate significant deviations from the normal distribution. The data depart significantly from a normal distribution when the standardized coefficients are outside the range - 2.0 to 2.0.
+
2. Structural chemistry of enamines: a statistical approach
99
D. Multivariate Statistical Anaiysis--Prlnclpal Components Method
As can he seen from the previous section, one of the main aims of the descriptive statistical methods, applied to the data provided by crystallographic research, is the determination of the average values for geometrical descriptors of molecules or their fragments. These methods give also a full characteristic of the frequency distributions of the descriptors and may lead to conclusions concerning homogeneity of a data set and their possible differentiation into subsets. Multivariate statistical analysis is another approach to a large amount of data, which often allows one to discover ccrtain rules hidden in a mass of numbers. Following Massart and coworkers9, it can be said that the main task of this approach is to categorize the objects for which the data are collected. Among the multivariate methods the most important are: principal components analysis (PCA), factor analysis, cluster analysis and the pattern recognition method, from which only PCA will be briefly described bclow. PCA is used to find such a system of new variables, called principal components (PC), which explains the variation of a given data set in a more convenient way than the original system of variables, e.g. x , , . . . ,xj, . . .,x,. The greater convenience of PC consists mainly in a reduction of dimensions, m, in which the data were originally described, because the PC variables are chosen so that only two or three of them should be sufficient to characterize the variation of the data. The PC are linear combinations of the original variables, xj, used to characterize the set of objects, PC, = w , , x , + w,,x, + ... + W l j X j ". w,,x, PC, = w,,x, + w,,x, + ... + W Z j X i + " ' + w,,x, (1)
+ +
... ...
P C , = w,,x,
. ..
+ w i 2 x 2 + . . . + w i j x j + . . . +w,,x,
PC, = w,,x, + w,,x, + . . . + w,xj + ... + w,,x, where the coefficient wij is called the weight of a variable x j for a component PC,. The system of equations 1 may be also written in the matrix form P C 1 = CWICxl (2) where matrix [ W ] represents a rotation of vector [ x ] in the m-dimensional space to a new vector [ P C ] . Matrix [ W ] is orthogonal ( [ W ] [ W I T= [ I ] = identity matrix: T designates matrix W transposed). In order to reduce the number of dimensions, PC variables should satisfy the following conditions: (i) PC, should have a maximum variance (i.e, it should represent the direction of the greatest variation among the data while the variation around this direction should be very small), (ii) subsequent variables, P C , should be uncorrelated with PC,-, and have the maximum variance among all other PC variables uncorrelated with PC,- ,. The condition (i) can be expressed as Var(PC,) = maximum (3) [w,lT = [ w , , , w,,, . . . ,w,J is the first row of matrix [ W ] , the so-called eigenvector of [ W ] ; [Cx] is the variancecovariance matrix of variables xj,
r
S :
C O V (2) ~,
. ..
COV(~, m)l
100
B. J. Oleksyn, K. Stadnicka and J. Sliwinski
where sj2 is the variance of the variable xi, and
i is the observation number (or the number of the object in which xj is observed), Zj is the mean value of the variable j over n observations (or n objects), xij is the value of the variable j given in the observation i (or measured in the object i) whilst A,
is the largest eigenvalue corresponding to the eigenvector [w,], which is the first solution of the equation
with [w] being eigenvectors and A being eigenvalues of matrix [Cx]. The variancecovariance matrix, [Cx], is often replaced by the matrix of the correlation coefficients: ri, = cov(ij)/(sisj); it is equivalent to the use of the standardized values of x.] The condition (ii) requires that Var(PC,) = maximum and that PC, is not correlated with PC,. By analogy to equation 3a we have
where [w,] is the eigenvector corresponding to A,, which is the second largest eigenvalue of [Cx]. The lack of correlation hetween PC, and PC, results from the properties of Cw,l and CwJ. The next, PC, are then obtained in the same way by successively finding the eigenvectors and eigenvalues with i = 3,4,. . . ,m and employing the equations Var[PCi]
=
[wilTICx][wi] = Ai = max
(6)
From equations 3a, 5 and 6 and from conditions (i) and (ii) it can be derived that the total variation of all PC variables is given by the sum A,, while the relative contribution of PC, in the total variation is A,/Cy= 5 .The first p principal components, where p is usually 2 or 3, should explain more than 80% of the total variation of the A, r 0.8. However, the nature of the observations and data set, thus variables does not always present such a convenient situation. The results of PCA can be displayed in the form of tables and two types of diagrams. The tables list the percentage of the total sample variation, which is explained by P C , and the weights of the original variables, xh for each PC,. In the first diagram type one point is ascribed to each variable, xj, in such a way that the abscissa of this point is the weight of x, for PC, while its ordinate is the weight of x, for PC,. The points which are situated close to each other on this diagram illustrate the variables, xj, which provide similar information. On the other hand, the position of a particular point shows the contribution of a given variable to PC, and PC,. A small distance between points with a large contribution to one of the PC's illustrates a strong positive correlation between the variables xi represented by these points. The diagrams of the second type are scatter plots consisting of points on the plane defined by PC, and PC,. These points represent objects for which given PCi-values (scores) were calculated. This kind of scatter plot shows the relationship between the objects and may make it possible to divide the studied sample of objects into classes according to their PC-values. The principal components analysis of the considered sample consisting of 474 objects (set S) was performed for the original variables: DlLD7, A1-A9, TI-T4, TS-T8 and PDlM-PD6M, using the program STATGRAPHICS PLUS6.
,
E,, L,/zr-,
x;=,
2. Structural chemistry of enamines: a statistical approach
101
Ill. DESCRIPTIVE STATISTICAL ANALYSIS OF ENAMINE FRAGMENTS
A. Unrestricted Substltuents
The values of selected statistics for the parameters of the fragments belonging to set S are listed in Table 2. It is obvious from this table that only few parameters can be treated as having approximately normal distributions. Among them are Dl, D4, Al, A2, A3, A4, A5 and A8, TI, T2, T3 and T4, PDIM, PD4M and PDSM.
1. Bond lengths
The frequency histograms of the bond lengths are shown in Figure 8a-g while Figure 9 displays the enamine fragment with the average values of interatomic distances ascribed to the corresponding bonds. The values of D l and D4, in contrast to the other bond lengths, are distributed quasi-normally with relatively low standardized skewness and kurtosis, and with unimodal histograms. This special behaviour of Dl and D4 is understandable, because both these bonds form links between the core atoms of the enamine grouping and are in a certain sense 'preselcctcd' according to thc eritcria givcn in Section 1I.A. Their standard deviations are comparable to the experimental error (3 x e.s.d.'s should not exceed 0.03 A), while for remaining bond lengths enlarged standard deviations seem to be the effect of structural variation due to chemical and crystallographic effectsi0. Still, the standard deviations of D l and D4 are almost one order of magnitude greater than the most often encountered values of e.s.d.'s for the bond lengths determined by the typical X-ray crystal structure analysis. The minimum values of Dl and D4 corresporld to the double N-C and C-C bonds, respectively, while their maximum values are typical for significantly shortened appropriate single bonds, which suggests a possible shift of electrons within the core of the enamine fragment. Inspection of Table 2 shows that the distributions of the remaining bond lengths are far from being normal. They have high standardized skewness and kurtosis and quite a large dispersion which results from diversity of the first atoms of the substituents R1-R5. This is also reflected by the occurrence of three distinct areas in the histograms for D2, D3, D5, D6 and D7 (Figure 8b-q e-g). The three areas (iHiii) located at about (i) 0.&1.1 A, (ii) 1.4 A and (iii) 1.7-2.0 A correspond, in succession, to (i) N-H (for R1 and RZ) and C-H (for R3 and R5) bond lengths, (ii) overlapping of similar bond lengths C-N, N-N, C-0 and N-0, and (iii) bond lengths between N or C and such atoms as S, P, Si, Br and CI. Only in the case of (ii) is a well-shaped frequency maximum observed since the prevailing first atoms of the substituents arc carbon, nitrogen and oxygen atoms. It is of some interest that the separation of the maximum (ii) from the maximum (iii) in the histograms for D6 and D7 is better than in those for D2 and D3. A possible explanation might be the involvement of the free electron pair of N1 in the bonding systems of the substituents R1 and RZ, leading to intermediate bond lengths which are not observed for R4 and R5. The high contribution of carbon and nitrogen elements as the first atoms of R1-R5 substituents leads to average interatomic distances D2, D3, D5, D6 and D7 which are close to the values of almost single N-C and/or C-C bond lengths. However, any evaluation of the substituent effects on the bond lengths can be carried out only after division of the set S into subsets with restrictions concerning the first atoms of R1-R5 substituents.
B. J. Oleksyn, K. Stadnicka a n d J. ~ l i w i n s k i
102
TABLE 2. Selected structural and statistical data for enamine fragments (sample size: 474) with unrestricted substituents R1, R2, R3, R4 and R 5 (a) Bond Lengths (A)
Standard deviation Standard error
Geometrical parameter
Average
Mode
Variance x lo3
D2 = N1-R1
1.418
1.388
9.934
0.100 0.005
D3 = N1-R2
1.424
1.456
16.760
0.129 0.006
D4 = C"C3
1.358
1.342
0.927
0.030 0.001
D5 = C1-R3
1.469
1.497
18.530
0.136 0.006
D6 = C3-R4
1.468
1.496
19.937
0.141 0.007
D7
1.478
1.444
9.512
0.098 0.005
= C3-R5
(b) Bond Angles (deg) Geometrical parameter
Variance Average
Mode
Standard deviation Standard error
Minimum maximum range
0.169 0.807 1.700 0.893 0.71 1 1.753 1.042 1.293 1.475 0.182 0.874 2.201 1.327 0.836 1.972 1.136 0.959 1.886 0.927
Minimum maximum range
Standardized skewness
kurtosis
- 29.031
76.690
- 23.136
49.749
10.236
8.750
- 11.191
36.388
-11.313
27.142
7.557
28.932
Standardized skewness
kurtosis
2. Structural chemistry of enarnines: a statistical approach
Standard deviation Minimum Variance Standard maximum Average Mode error range
103
(c) Torsion Angles (degFmodulo 2n
Geometrical parameter
Standardized skewness kurtosis
(12) Atom Deviation from Plane (A) Geometrical parameter
Standard deviation Minimum Variance Standard maximum Average Mode x lo3 error range
Standardized skewness kurtosis
8
0
R
0 0 L O
7S O-
0
FIGURE 8. Frequency histogram (a) N1-C2 bond lengths: Dl, (b) N1-R' bond lengths: D2, (c)N'-R2 D4, (e) C2-R3 bond lengths: D5, (fj C3-R4 bond lengths: D6, (g) C3-R5 band lengths: D7
bond lengths: D3, (d) C2-C3 bond lengths:
-E
B. J. Oleksyn, K.Stadnicka and J. Sliwitiski
R~
FIGURE 9. The enamine fragment with the average values of interatomic distances ascribed to the corresponding bonds with standard errors in parentheses
2. Bond angles
The frequency histograms for the bond angles are shown in Figure 1Oa-i, while the averagc values of thc corresponding angles are displayed in Figure 11. According to Murray-Rust and Bland1' the standard deviations for bond angles should be about 5W100 e.s.d.3 of C-C bond estimated in the course of the crystal structure refinement. Thus, in the examined set of enamine fragments the standard deviations can be attributed to the structural variation rather than to the experimental errors Most of the bond angle distributions have relatively small values of standardized skewness and kurtosis, which suggests their approximately normal character. However, the distributions of Al, A2 and A4 are bimodal with frequency maxima at about 109 and 120 ". The occurrence of angles less than 120 " can be explained for A1 and A2 by various degrees of N1 pyramidalization, while for A4 they are ascribed to the contribution of indole derivatives in which the atoms N1, C2 and C3 belong to the five-membered ring system having the typical endocyclic angle of 108 ". In spite of the high dispersion of the bond angles, two interesting observations can be made concerning their average values shown in Figure 11. (i) The sum of the angles around C2 and C3 atoms are 360 " in accordance with their sp2 hybridization, while the sum of the angles around N1 is 354 ", which confirms a certain pyramidality of the nitrogen atoms in numerous enamine fragments. (ii) The values of the angles Al, A4 and A8 on the side of the molecule opposite to the direction of bond C2-R3 are less than 120 ", while the angles A2, A6 and A7 on the slde of R3 are higher than 120 " (Figure 11). This asymmetry seems to be a result of thc steric repulsion between the substituent R3 and each of substituents R2 and R4. As the first atoms of both the R3 and R4 substituents are in most cases coplanar with CZ and C3, the A6 angle increases at the cost of A5, so that the distance between R3 and R4 increases, whereas the R3...R2 distance may be retained by the out-of-plane displacement of the first atom of R2. 3. Torsion angles
Taking into account the problems which can complicate the statistical analysis of torsion angles, as discussed by Murray-Rust and Motherwell", these angles were treated in a special way. In the case of TI, T4, T6 and T7 a value of 2n was added to the observed torsion angles, resulting in the main maximum near 360 " instead of 0 ",whereas for T2, T3, T5 and T8 a value of 2n was added only to torsion angles from - 180 " to
FIGURE 10. Frequency histogram (a) R'-N'-C~ bond angles: A l , (b) R ~ - N ' - C ~ bond angles: A2, ( c ) R'-N'-R' bond angles: A3, (d) NL-C2-C3 bond angles: A4, (e) N'-C2-R3 bond angles: A5, (0 R3-c2-C3 bond angles: A6, (g) c~-c'-R~ bond angles: A7, (h) C2-C3-R5 bond angles: A8, (i) R4-C3-R5 bond angles: A9
-
3
2. Structural chemistry of enamines: a statistical approach
(0
FIGURE 11. The enamine fragment with the average values of bond angles with standard errors in parentheses 0 ", so that the main maximum appeared near 180 ". Moreover, the extremes of the torsion angle ranges were chosen so that they do not overlap with modes. Low values of both the standardized skewness and kurtosis are observed only for T3 and T4, while for T I and T2 skcwncss is very small and kurtosis relatively small (Table 2). IIowever, only the distributions of TI and T2 can be considered as approximately normal, because in the T3 and T4 histograms two maxima of relativcly lower frequency can be clearly discerned on both sides of the main maximum (Figure 12c,d). Thus, these two distributions may be regarded as trimodal while all others are unimodal (Figure 12a,b,e-h). Thc variation rangcs of all thc torsion angles are wry widc: from 145 " for T5-T8, through 172 "-180 " for T3. T4 up to 225 "-228 " for T2 and T1. This means that individual enamine fragments may adopt, in respect of particular torsion angles, any conformation from syn-clinal through syn-periplanar to anti-clinal, obviously, some of thcsc conformations are observcd more frequently than others. All values of the standard deviation are high, which shows that the torsion angle variance is of structural origin rather than due to experimental errorsL0.It is interesting that thc group of angles 1'1-T4 differs in the standard deviations from thc othcr group,
112
B. J. Oleksyn, K. Stadnicka and J. ~liwinski
TSST8, where the values arc about three times lower. This differentiation can bc better understood with the help of Figure 13, which depicts Newman projections along the N1-C2 and C2-C3 bonds. The average values of angles TILT4 and TSST8 (Figure 13a,d) show that the average overall conformation of the enamine fragments can be described as planar. In this conformation the following pairs of bonds are mutually eclipsed: N1-R1, C2-C3; N 1-R2 CZ-R~. CZ-Nl C3-R5. CZ-R3, C3-R4, where the letter R designates the first atom of the substituent with the relevant numbers. However, the existence of the satellite frequency maxima in the distributions of T3 and T4 suggests that, besides the planar atom arrangements which have a prevalent contribution to the average structure of the enamine fragments, some other important conformations also occur. The frequency of appcarance of these conformations is about live times lower in comparison to that of the average conformalion. They differ from the latter in the orientation of the Rz-N1 bond, because only this bond is involved in the trimodal distributions. As shown in Figure 13b,c, there are two groups of these conformations with T3 changing in the ranges of about 35 ". Thcsc T3 variation ranges correspond t o those forming the bases of the satellite frequency maxima (Figure 12c,d). In both groups of conformations, 'b' and 'c', the bonds N1-RZ and CZ-R3 are mutually staggered, while the bonds N1-R' and C"C3 remain, on average, eclipsed. The syn-periplanarity of one of the N-C (sp3) bonds to the enamine C=C bond is in
FIGURE 13. Newman projection down the bonds N1-CZ (a, b, c) and C2-C3 (d). For TI, T2 and TST8 only average values are presented in the projections. For T3 and T4 values corresponding to satellite frequency maxima are also given in (b) and (c)
2. Structural chemistry of enamines: a statistical approach
113
agrccmcnt with the important observation made by Dunitz and coworkers1. Conformations 'c' are approximately the mirror images of conformations 'b' in the mirror plane, which is the plane through N1, C2, C3. The conformations 'b' and 'c' result from pyramidalization of the nitrogen atom N1 and are modified by the substituents R2 and possibly by steric repulsion between R2 and R3. Pyramidality of the C2 and C3 atoms is negligible since their hybridization was assumed to be spZ, and this explains the unimodality and relatively low dispersion of the distribution for TST8. 4. Distances from planes
The frequency histograms for the absolute values of the distances (PDM) from the best planes (for the definition of the best planes, see Figure 7) are depicted in Figure 14a-h. The standardized skewness and kurtosis (Table 2) indicate that only three of these distances, PDlM, PD4M and PDSM, have approximately normal distributions. The dispersion for all PDM values is high; their standard deviations are comparable to the averages. As could be expected, the variation ranges of the PDM values for the core atoms and the first atom of R3 are much narrower than for the first atoms of R1, R2, R4 and R5. Among the histograms, all J-shaped, two types can be discerned. Type (i) is characterized by one frequency maximum, while in type (ii) one or two small additional maxima are present. The distances with distributions belonging to type (i), i.e. PD2M, PD3M, PD6M, PD7M and PD8M, correspond to the atoms C2,C3 and the first atoms of their substituents, R3-R5, which have a tendency to remain relatively coplanar. Type (ii) comprises the distances PDIM, PD4M and PDSM of the atom N1 and the first atoms of its substituents, R1 and R2, which in numerous enamine fragments form a flat pyramid, with N1 at the apex. The origin of the additional maxima will be explained later when examining the substituent effects. These observations are in agreement with the average PDM values for the atoms of the enamine fragments shown in Figure 15. They increase, together with the corresponding maximum values, from the lowest values for C2,C3 and the first atom of R3, through the medium N1 and the first atoms of RS and R4, to the highest values for the first atoms of R' and R2. B. Speclllc Substituents: Carbon a s the First Atom In R'-R6
In order to examine to what extent the statistical parameters obtained for the sample with unrestricted substituents are influenced by the chemical nature of the first atom of the substituent, the descriptive statistical analysis was performed for a sample of 178 enamine fragments in which carbon was the first atom of all R1-R5 substituents. Only in this case was the sample size sufficient for the statistical treatment. The selected results of the analysis are given in Table 3. The average values of all thc structural parameters within the enamine core (Dl, D4, A4, T1-T8 and PDIM-PD3M) remain almost unchanged while the other parameters oscillate in the ranges of the corresponding standard deviations. Most of the distributions for the structural parameters become closer to a normal distribution, as shown by decreasing standardized skewness and kurtosis. However, some of the frequency histograms, displayed in Figures 16-19, reveal the multimodal character hidden in the diagrams for unrestricted R1-R5 substituents (compare with Figures 8, 10, 12 and 14, respectively). A typical bimodal character of the distribution appears for bond lengths D2, D3 and D7 (Figure 16b,c,g). In the case of D2 and D3 the two frequency maxima at about 1.39 A and 1.46-1.47 A correspond to N-C bond lengths for the sp2 and sp3 nitrogen atom hybridization, respectively. The bimodal D7 distribution shows frequency maxima at
PD5M
(A)
PD6M
(s)
-0.1
0.2
0.5 0.8 PD7M (A)
(A)
(h)
1.1
1.4
-0.1
0.2
0.5 0.8 PD8M (A)
1.I
1.4
FIGURE 14. Frequency histograms for the absolute values of atom deviations (A) from the plane defined through the appropriate neighbouring atoms: (a) N l from (R1, R2, C2): PDlM, (6)C2 from (N1,C3, R3): PD2M. (c) C3 from (C2,R4, RS): PD3M, (d) R' from (NL,CZ,C3): PD4M, (e) RZ from (N1,C2,C3): PDSM, (0 R3 from (N1,C2,C3): PD6M, (g) R4 from (N1,C 2 ,C3):PD'IM, (h) R' from (N', c2,C3): PD8M
B. J. Oleksyn, K. Stadnicka and J. Sliwinski
PDM
FIGURE 15. The maximrun and average ahsolute values of the atom deviations (PDM) from
planes defined above (Table 2, Figure 13). R1-RS unrestricted
TABLE 3. Selected structural and statistical data for enamine fragments (sample size: 178) with carhon as the first atom of the substituents R', R2.R3,R4 and R5
(a) Bond Lengths (A) Cieometrical parameter
Standard deviation Minimum Variance Standard maximum Average Mode x lo3 error range
Sta"dardi7ed skewness kurtosis
(continued)
2. Structural chemistry of enamines: a statistical approach
117
(b) Bond Angles (deg)
Geometrical parameter
Standard deviation Minimum Standard maximum Average Mode Variance error range
Standardized skewness kurtosis
(c) Torsion Anales (.d e",o k m o d u l o 271 "
Geometrical parameter
Standard dkviation Minimum Variance Standard maximum Average Mode error range
%x-dardized skewness kurtosis
(continued)
B. J. Oleksyn, K. Stadnicka and J. Sliwinski
118 TABLE 3. (confinurd)
(c) Torsion Angles (deg+nodulo 2n
Geometrical parameter
Standard deviation Minimum Variance Standard maximum Average Mode error range
(d) Atom Deviation from Plane
skewness kurtosis
(A) Standard
deviation
Geometrical parameter
Standardized
~
i
Variance Standard maximum x lo3 error range Average Mode
Standardized ~ i skewness kurtosis
PDlM = N'-(C2, R ' , R2)
PD2M
=
Cz-(N1, C3, R3)
PD3M
=
C 3 4 C Z ,R4, Rs)
PD4M =
R I ~ N Ic2, , c3)
PD5M =
c2,c3)
R ~ ~ N I ,
PD6M = R 3 4 N 1 ,C Z ,C 3 )
PD7M = R4-(N', C z , C 3 )
PD8M = R 5 - ( N 1 ,C 2 ,C 3 )
about 1.45 and 1.51 A. The latter value is typical for single C-C bond lengths, while the former value seems to be shortened, probably by the 'push-pull' through-conjugation effect. This effect is observed mainly for D7, since the bulky electron-withdrawing groups would rather adopt the trans orientation in respect to R3. Among the bond angle distributions, the most spectacular change is that shown by A3 (Figure 17c) revealing a trimodal character. The frequency maxima at about 95 ", 110" and 122 " can be ascribed to the presence of the N' atom in a four-membered
~
~
FIGURE 16. Frequency histogram of (a) N1-C2 bond lengths: Dl, (b) N1-R1 bond lengths: D2, (c) N1-R2 bond lengths: D3, (d) C2-C3 bond lengths: D4, (e) C2-R3 bond lengths: D5,(f) C3-R4 bond lengths: D6, (g) C3-R5 bond lengths: D7, for carbon as the first atom in each of the substituents R'-R5
*
rr! 7
FIGURE 17. Frequency histogram of (a) R1-NL-C' bond angles: A l , (b) R2-NL-c2 bond angles: A2, (c) R1-N1-RZ bond angles: A3, (dl N'-C2-C3 bond angles: A4, (e) N'-C2-R3 bond angles: A5, (Q R3-c2-c3 bond angles: A6, (g) C2-C3-R4 bond angles: A7, (h) C2-C3-RS bond angles: AS, (i) R4-C3-RS bond angles: A9, for carbon as the first atom in each of the substituents R'-Rs
--
M
2. Structural chemistry of enamines: a statistical approach
100
110
120 A9 W g )
130
123
140
FIGURE 17. (continued)
ring, five-membered ring (including indole derivatives) and in unconstrained almost planar surrounding. The frequency distribution of A9 has also a trimodal character (Figure 17i) with frequency maxima at about 116 ", 123 " and 130 ". The reason for the last, comparatively high, value may be the involvement of the C k C J bond in the four- or five-membered rings with a consequent tendency of this part of the enamine system to retain planarity (the sums of the average values of the bond angles at C2 and C3 are 359.86 " and 359.82 ",respectively). The shape of frequency histograms for the torsion angles (Figure 18a-h) remains almost the same whereas the variation ranges become narrower, especially for T5 and T6. This is understandable, because this sample is free from first atoms of the substituents RL-R5 which give rise to a steric hindrance. Both sets of atom deviations from planes, i.c. PDlM-PD3M, and PD4M-PD8M bchavc similarly to those for the sample with unrestricted substituenis (compare Figure 19 with Figure 14). This leads to the conclusion that the geometry of the enamine fragment is dominated by the enamine core being almost independent of the type of first atom of the substituents. However, it should be stressed that carbon atoms prevailed also in the original sample containing 474 enamine fragments.
C. Parameters Describing Distortion of Enamlne Fragments from Planarity
The distortion of the enamine fragments from planarity can be described not only by atom distances (PD) from selected planes, but also by the coefficient of pyramidality, P, and angular parameters x and T. The definition of P is given in Chapter 1 of this book2, while the formulae for x and T are given in Section I and in Figure 1. Besides IX, and rNtPc2, used by Dimitz and coworkers1, it is convenient to introduce Tc2-~3 which is an average twist angle around the D4 bond in the case when it has partial single-bond character. Consideration of sci=,3 is justified by PCA for torsion angles T5-T8 (see Section 1V.C). It is easy to show, using elementary trigonometry, that the pyramidality coefficient of a given atom is a function of its distance, PD, from the plane defined by three substituents attached to this atoms. A simplified form of such a function may be derived subject to the assumption that the bond lengths, D, between the considcrcd atom and
T I , (b) R ~ - N ~ - c ~ - R ? T2, (c) R2-N1-C2-C3: T3, (dl FIGURE 18. Frequency histograms of torsion angles:l-cz-C"--~S: (a) R1-N1-c2-c3: T6, p) R3-c2-c'-RJ: T7, (h) R ~ - C ~ - C ' - R ~ : T8, for carbon as the R ~ - N ~ - c ~ - R ~ :T4, (e) N ' - C ~ - C ~ - R ~ : T5, (0 N first atom in each of the substituents R1-R5
-
g
-0.02 0.03
0.08 0.13 0.18 PD6M (A)
0.23
0.28
0.9
1.1
(h)
-0.04
0.1 6
0.36 PD7M (A)
0.56
0.76
-0.1
0.1
0.3
0.5 0.7 PD8M (A)
FIGURE 19. Frequency histograms for the absolute values of atom deviations (A)from the plane defined through the appropriate neighbouring atoms: (a) N L from (R1, R2, C2]: PDlM, (b) CZ from (N1,C3, R3): PD2M.(c) C3 from (C2,R 4 RS): PD3M, (d) R1 from (NL;C2,C3): PD4M, (e) R2 from (N1,C2, C3):PD5M. If) R3 from (N', C2, C3): PD6M, (g) R4 from (N1,C2, C3): PD7M, (h) R5 from (N', C2, C3): PDSM, for carbon as the first atom in each of the substituents RL-R5.
P..
3
128
B. J. Oleksyn, K. Stadnicka and J. Sliwiliski
these substituents as well as three appropriate bond angles are approximately equal. Then P is expressed in the form
P = 100[360" - 6 arcsin[;(l - PDM)2/D2]0.5/(360"- 324.8')-I
(7)
For the nitrogen atom, N L ,of the enamine fragment and D equal to the average value of the bond lengths of the N1 in the set S (1.41 A), P,I = lOO(11.39 - 0.19 arcsin[0.75 - 0.38 (PD1M)2]0.5}
0
0.1
0.2
0.3
0.4
0.5
(8)
0.6
PDlM (A) FIGURE 20. Scatter plot of pyramidality coefficientP,,% versus the absolute value of PD1 for the sample of 474 enamine fragments
129
2. Structural chemistry of enamines: a statistical approach
A parabolic relationship between P,, and I,, of a very similar shape, although with a greater dispersion of points, is also followed by most of the fragments (Figure 21). Some outliers form a well-separated branch on the right-hand side of the main curve. The points belonging to this branch represent enamine fragments involved in a relatively rigid system of rings, often fused, with N 1 as a junction atom. Following P,,, from low to high values, it can be seen that the N 1position is changing from a position in which it lies between a four-membered ring and either an S- or 0-containing six-membered ring, through fused four- and five-membered, to 3 five-membered fused rings. These two correlations (P,, versus PDlM and P,, versus I X , , ~ ) lead to a third correlation, which is displayed in Figure 22. The relationship between the values of I X , , ~ and PDlM has a linear character and can be expressed by a linear regression (equation 9) with a
0
10
20
30
40
I
50
60
70
80
I (d%I
FIGURE 21. Scatter plot of pyramidality coefficient P,,% versus the angular out-of-plane deformation parameter 1x1 for the sample of 474 enamine fragments
B. J. Oleksyn, K. Stadnicka and J. Sliwinski
FIGURE 22. Scatter plot of angular parameter IX,,~ versus the absolute value of PD1 for the sample of 474 enamine fragments showing linear dependence
correlation coefficient of 0.989 and with RZ = 97.86% at the confidence limit of 95%: xNl(deg)= 0.57(deg)
+ 137.69 (deg/A). PDIM (A)
(9)
The standard errors for the empirically determined intercept and slope values in equation 9 are 0.17 and 0.94, respectively. Because of the linear dependence between x and PDM values, these two parameters may be used alternatively. This is convenient as the geometrical sense of PD is more obvious for an average reader than that of x. Inspection of Figure 22 shows that the greatest distortion from planarity of the N 1 surrounding, i.e. the highest values of X,I and PDI, are observed for molecules in which N1serves as a common link of the fused four- and five-membered rings. These values decrease when N' belongs either only to one ring or to two rings, but with the exception of the pair mentioned above. Such behaviour seems to result from the pyramidalization effect imposed on N1by its involvement in the ring systems and will be also considered in the next section. ? z , ~ ~ l - C ~P,t, , Pd and PC, Selected statistical data for the parameters X,I, Z ~ I - ~ and are listed in Table 4, while their histograms are shown in Figures 23a-f and 24a-f. Figure 23 displays histograms for the fragments with unrestricted substituents. In Figure 24, similar histograms are given under the restriction that the first atoms in the substituents are carbons. The values of the out-of-plane deformation parameter, X,I, for the enamine fragments with unrestricted substituents vary in a wide range (0 "-77.5 ")and have a high dispersion around the average value of 19.10 ". The frequency distribution of X,I is not normal. Its maximum corresponds to 0 I xN1I 18 (64% of all considered fragments) and, for a high percentage of the sample (about 32%), x,, is comprised in the range 18 "55" forming a continuous broad 'wing' on the right-hand side of the J-shaped histogram. When the first atoms of all five substituents are carbon atoms, the distribution parameters do not change significantly but the wing on the histogram is replaced by O
2. Structural chemistry of enamines: a statistical approach
131
TABLE 4. Selected statistical data for the absolute values of angular out-of-planc paramctcr, x,, (deg), and twist parameters, I N I - C ~ and EX-C, (deg), together with pyramidality coefficientsP (%) for the N', CZand C3 atoms of the enamine grouping both for a sample containing enamines with unrestricted substituents (size 474) and with carbon as the first atom in each of the R1-Rs substituents (sample size 178)
Parameter
Sample size
Average
Standardized Standard Standard Minimum Variance deviation error maximum skewness kurtosis
two low-frequency maxima at 30 " 4 0 " and at 50 "-55 ". Most probably these correspond to the fragments for which N1is involved in a system of two five-membered rings and/or one five-membered and one four-membered ring. The pyramidality values for CZand C3 atoms have J-shaped histograms due to the great majority of fragments having P,i and Pc3 near zero, with very high standardized skewness and kurtosis. The range of the pyramidality variance for C3 is slightly wider than that for C2;their average values (about 0.5%) are comparable within the standard errors. The change in the distribution parameters introduced by the restriction of the first atoms of the R1-R' substituents to carbon atom is more conspicuous for C2 than for C3 and consists mainly in a decrease of the dispersion. The average pyramidality value for N1(15% in the case of unrestricted substituents) is much higher than for C2 and C3,which is in agreement with the significant contribution of sp3-hybridized N' atoms in the studied sample of the enamine population. The N1 pyramidality varies over a very wide range, 0 IP,i 1 133.7%, in which the values exceeding 100% correspond to the enamine fragments with N 1belonging to strained five- and four-membered rings. The restriction of the first atoms of the N1 substituents, R1 and R2, to carbons diminishes the average value of P,,. Although this might suggest that non-carbon
B. J. Oleksyn, K. Stadnicka and J. Sliwinski
FIGURE 23. Frequency histograms (R1-R5 unrestricted) for the absolute values of the angular parameters I x , ~ I (a), 1 ~ ~ 1 (b) ~ and ~ 2 I 1r , ~ ~ , (0 l as well as for pyramidality coefficients: P,, (c),PC2 (d) and PC,(e)
B. J. Oleksyn, K. Stadnicka and J. Sliwinski
-10
10
30
50
70
90
110
l r c 2 =c3 I (deg) FIGURE 23. (continued)
substituents at N1 favour its pyramidal bond arrangement, this conclusion should be treated with caution since the respective average values, for both unrestricted and restricted substituents (15.9% and 13.5%), are comparable within the standard errors. The shape of the frequcncy histograms is almost independent of the nature of the first atom in the substituent. The value of the 'average twist', r,,-,,, also varies over a wide range from O " to 94 " with an average of 23.35" slightly higher for the set of enamine fragments with unrestricted substituents. The most frequent, however, are conformations with small twist as shown by almost 60% of fragments with .r < 17 ". The average value and variance of zc2=,, are, of course, much smaller than those for T,,-,~, but its distribution is far from normal (high standardized skewness and kurtosis). The restriction of the first atom of R'-R' substituents to carbon significantly reduces the variance and the range of this parameter and makes the distribution closer to normal. IV. PRINCIPAL COMPONENTS ANALYSIS OF ENAMINE FRAGMENTS WITH UNRESTRICTED PARAMETERS
The results of the principal components analysis (PCA), discussed below for each group of geometrical descriptors (original variables), comprise: (i) A correlation matrix, the calculation of which is the first stage of PCA (this matrix lists correlation coefficients together with their significance level for each pair of the original variables; the significance level is the probability that a given correlation may occur by chance). (ii) A table listing the percentage of variance for a given descriptor group explained by each principal component and weights of the original variables for PC,.
2. Structural chemistry of enamines: a statistical approach
FIGURE 24. Frequency histograms for the absolute values of the angular parameters l,yNll (a), IrNt-,21 (b) and Irc2=,,l (0as well as for pyramidality coefficients:P,I (c), PC2,(d) and PC,(e) in the case when carbon is the first atom of each R1-R5 substituent (sample size 178)
B. J. Oleksyn, K. Stadnicka nnd J. Sliwi~iski
2. Structural chemistry of enamines: a statistical approach
-3
7
17
27
37
47
I t C 2 =ZC3 I We@ FIGURE 24. (continued)
(iii) A diagram presenting weights of the original variables for PC, and PC,. (iv) A scatter plot of PC, and PC, for the objects, i.e. for 474 enamine fragments. As the corrclation matrix calculated for a11 thc geomctrical descriptors (D, A, T and PDM) did not contain any significant correlation for the 'mixed' pairs (D,A; D,T; D,PDM; A,T; A,PDM and T,PDM),PCA was carried out separately for each type of variable. A. Bond Lengths
In the bond-length correlation matrix (Table 5) only one strong negative correlation (correlation coefficient - 0.7428) can be noted between D l and D4. This correlation is understandable in view of the conjugation observed for the bond pair N1-CZ and CZ=C3. For thc othcr bond lcngths thc correlation coefficients arc less than 0.5. As can be seen from Table 6, PC, together with PC, explain only 49% of the total variation and the contribution of the remaining PC's to this variation is comparatively high. This is a natural consequence of a rather weak intercorrelation of the bond lengths in the enamine fragments. The weights for PC's (Table 7) are distributed among the original variables, Dl-D7, in such a way that only in PC, does one of the descriptors (D7) havc a significant predominance. The graphic representation of the two first columns of Table 6 is given in Figure 25. The symmetrical positions of points corresponding to D l and D4, in relation to the origin of the coordinate system, show their negative correlation, while the proximity of D5 and D6 suggests that these two bond lengths provide similar information (at least for PC, and PC,) dcspitc thcir wcak intercorrelation. In order to check whether the distribution of PC, and PC, values reflect the chemical diversity of the enamine fragments, the scatter plot depicted in Figure 26 can be examined. The major part of the points is clustered in the area defined by
B. J. Oleksyn, K. Stadnicka and J. Sliwinski
138
TABLE 5. Correlation matrix for the bond lengths (with significance levels in parentheses) Dl
D2
D3
D4
D5
TABLE6 Percentage of the sample variance explained by the principal components for bond lengths Component number
Percentage of variance
Cumulative percentage
TABLE 7. Weights of bond lengths for the principal components
D6
D7
2. Structural chemistry of enamines: a statistical approach
139
1;
q . .
I
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
PC1 FIGURE 25. Weights of bond lengths for the first two principal components
-6.9
-4.9
-2.9
-0.9
1.1
PC1 FIGURE 26. Principal-components scatter plot for bond lengths
3.1
TABLE 8. Correlation matrix for the bond angles (with significance levels in parentheses) Al
A2
A3
A4
A5
A6
A7
A8
A9
141
2. Structural chemistry of enamines: a statistical approach
- 1.0 s PC, s 1.5, - 1.0 s PC, s 1.0. A scattered surrounding of this area can be divided into 'flocks' (Fl-F4) of points, according to the specific features of the enamine fragments. The fragments prevailing in each of the flocks (marked in Figure 26 by dashed lines) can be characterized as follows: F1-primary enamines, F2--secondary enamines, F3-namines with oxygen or sulphur atoms in the vicinity of N1,e.g. at a carbon atom in position a, p or y with respect to N1, F k n a m i n e s with 'push-pull' through-conjugation eRect. Except for F1, the flocks are not well separated from each other; however, the tendency of similar enamines to assemble in the PC,, PC, scatter plot suggests that the PCA is a good categorizing tool. Moreover, the separation of F3 is an interesting example of how a certain class of objects can he revealed by this method. The chemical justification of such a finding should be, of course, carefully checked.
8. Bond Angles
The correlation matrix (Table 8) reveals two very strong positive correlations for two pairs of angles, A4,A8 and A6,A7, which can be explained by a steric repulsion between the pairs of bulky substituents R1,R5and R3,R4, respectively. The first of these interactions seems to be responsible also for slightly weaker positive correlations within pairs Al,A8 and Al,A4. The negative correlations for the pairs of angles A4,A6 and A7,AX are a consequence of the approximate sp2 character of the majority of CZ and C3 atoms, which requires the sums of angles around these two atoms to be equal to 360 ". The graphic representation of the above relationships is shown in Figure 27 by means of weights of bond angles for the first two principal components. The figure also reveals a certain similarity of the information provided by the angles within pairs A2,A3
-.!.A6........ - 7;
:...:. . :
. . .;..
!.-
:......;.....~ ..............
...; .............................
....................................>.. .............:.................................. :.-
-.:
Ali 0
-
- ............................................................................................ A8 iA4
- .i . . . . . . .p ; ............................................................................
-
k3
-.. .................. ,........................ .
'
Ago A5
;
-.: ...........o..... (.................. :... .............. ;.................................... .,..
.
-0.33
.
.
.
.
-0.13
.
.
.
.
0.07
.
.
.
.
0.27
.
.
.
.
0.47
.
.
.
0.67
PC1 FIGURE 27. Weights of bond angles lor the first two principal components
B. J. Oleksyn, K. Stadnicka and J. ~liwinski TABLE9. Percentage of thc sample variance explained by the principal components for bond angles
Component Number
Percentage of Variance
Cumulative Percentage
PC, PC2
44.62063 24.62140
44.62063 69.24203
PC,
2.29276 1.88760 0.01111 0.00442
99.98447 99.99558 100.00000
PC,
PC. PC9
98.09687
and A5,A9. The two negative correlations within the pairs A4,A7 and A6,A8 seem to result from those described above. The existence of a higher number of correlations for the bond angles than for the bond lengths leads to a better explanation of variance by PC, and PC, (Table 9). The data listed in Table 10 indicate that each of PC's is a linear combination of at least five bond angles with weights greater than 0.3, thus each PC should provide information based on several original variables. As can be seen in Figure 28, such information enclosed in the PC, versus PC, scatter plot resolves itself in an isolation of seven 'flocks' (subsets) from the considered set of 474 enamine fragments. The enamine types most representative for each of the flocks, ordered according to an increasing number of points, are as follows: F1-fragments in which N1 belongs to a four-membered ring and the double bond C2=C3 is exocyclic, F2-fragments in which the N1 atom forms a junction between two or three fivemembered rings, F3-fragments with N' forming a junction between the five-membered ring and the five-, six- or seven-membered ring, FGfragments with exocyclic double bond in four-membered ring and exocyclic N', FS-fragments in which an oxygen and/or sulphur atom occurs at C in position a, P or y with respect to N1, F b a big cluster containing fragments with N1 involved in a five-membered ring which often belongs to an indole system, F7-a cluster containing a significant number of the remaining enamine fragments of various types. It is of interest that the flocks, in the PC, versus PC, scatter plot, for bond angles are better separated than in the case of bond lengths. Neither the number of flocks nor the types of enamines (except for those represented by F5 for A's and F3 for D's) revealed in these two cases, coincide. Therefore, PCA for bond lengths and for bond angles are complementary. C. Torsion Angles
As the correlation coefficients between torsion angles around two different bonds were found to be less than 0.25, the PCA was carried out separately for two sets of angles, TI-T4 and TST8. The correlation coefficients for all pairs of torsion angles around the N1-C2 bond (TI-T4) and around the formally double C2=C3 bond (T5-T8)
OSS89E'O OOLESPU ILIILE'O POI LPP'O EEE SPE'O PPL8WO LO1 E W O 8PZPWO6S8IWO-
LL9619'0 IPZS6Z'OLW9SZ'OSIPOOZ'O 659S1P'OSLESZI'O 8ZEZSP'OOOL100'06EZELI'O
168161'0 19PSZI'O990PP0'0ZPZ LOT'O OOSLLZ'O6ZPIOI'O 810P99'0 W6829'0S!NIOI'O-
L9CS9PDELLZOOU OOSE9PD SOLSLP'O LPE60SDE68P80D6Z8ZLl DEW960DPIZ161'0
U99PZ'OP19L9P'O 688EZE'O PSZIZE'O880102'06Z6ZLP'O OELEZI'O8LOPEZ'O9112ZPU
P3d)~
('3db
(E3d)~
('3db'
('3d)M
144
B. J. Oleksyn, K. Stadnicka and J. ~liwinski
are all positive and very high, as shown by the relevant correlation matrices (Table 11). Consequently, the two first principal components (PC, and PC,) explain together almost 100% of the variance for TI-T4, while only one principal component (PC1) is sufficient for the explanation of 93% of the variance for T5-T8 (Table 12). It is worth mentioning that, according to the weights of TI-T4 for PC, and PC, (Table 13a),these two principal components are equal to 2rNl-,, and -I,,, respectively. This shows that the angular deformation parameters intuitively chosen by Dunitz have the statistical sense of two uncorrelated variables, optimally explaining the variance of the considered sample of the enamine fragments. On the other hand, PC, for T5-T8 (see the weights of T5-T8 in Table 13b) is equal to T,?=C~,an average twist angle around the formally C2=C3 double bond. T@=,I seems to be sufficient for a description of the angular deformation of the more planar part of the enamine fragment. The relationships between the PC's and the parameters x and T suggest that the scatter plot PC, versus PC, for TI-T4 could be easily transformed to the plot of Ix, I I as a function of 1~,1-,-1, presented in Figure 35 (Section V.B). Examination of Figure 29a shows that this is indeed the case, remembering that PC's are given in standard units (see the note within square brackets between equations 3 and 4 in section 1I.D). The corresponding scatter plot for T5-T8 (Figure 29b) is less informative since the great majority of the enamine fragments has rc,c close to zero, as expected, and since PC, alone explains as much as 93% of the sample variance. V. CORRELATIONS BETWEEN SOME GEOMETRICAL PARAMETERS
As mentioned earlier, it seems especially interesting to study two processes which occur in the enamine fragments. One of them is the distribution of electrons in the N-C-C system and the other is cis-trans isomerization.
2. Structural chemistry of enamines: a statistical approach TABLE 1 1 . Correlation matrix for the torsion angles around (a) N1-C2 and (b) C2=C3 bonds (with significance levels in parentheses) T1
(a)
T2
T3
T4
TABLE 12. Percentage of the sample variance explained the principal components for torsion angles around (a) N1-Ca (TI-T4) and (b) C2=C3 (T5-T8) bonds (a)
Component number
Percentage of variance
Cumulative percentage
(b)
Component number
Percentage of variance
Cumulative percentage
145
146
B. J. Oleksyn, K. Stadnicka and J. Qiwinski TABLE 13. Weights of torsion angles around (a) N'-C2 and (b) C2=CQonds for principal components
A. Bond-length Correlations
As the starting point of the first phenomenon mentioned above, the one of the two extreme states with the double bond localized between CZ and C3 atoms can be considered, while the other hybrid is a polar form in which electrons are shifted in such a way that the double bond is localized between the N 1 and C2 atoms, with excess of positive and negative charges at the N1 and C3 atoms, respectively. In order to model this "formal reaction path", a scatter plot of bond length D4 versus D l for all enamine fragments (sample of size 474) was obtained. As shown in Figure 30, this scatter plot gives a structural correlation which reminds one of those discussed by Dunitz for the systems X-X...X and X...Y...X 3. Taking into account Pauling's relati~nship".~ Ad
= d(1) - d(n) = - c
log n
(10)
where d(1) is the interatomic distance for bond number n = 1, d(n) is an interatomic distance for bond number n # 1, n is the bond number, 0 s n s 3 and c is a constant value for a given pair of atoms), it was possible to explain the variation of Dl and D4 bond lengths. For the enamine system, it can be assumed that n, + n4 = 3 where n, and n, are bond numbers for the N1-CZ and CZ-C3 bonds, respectively. Expressing the change of Dl bond length with the bond number, n,, as AD1 = Dl(n,) - Dl(1) (here, A values have sign opposite to that used by Pauling, but are more convenient since then AD1 > 0 and AD4 > 0) and the change of D4 bond length as AD4 = D4(n4) - D4(1), we obtain from the Pauling rule 10ADlla + 10AD41- - 3 (1 1) -
which leads to The values of c, and c, were calculated from the least-squares fitting of the curve described by equation 12 to the experimental correlation of AD4 versus AD1. The expressions (AD4,,, - AD4,,,J2 and (ADl,, - AD1,,,JZwere minimized simultaneously. The results of the fitting are shown in Figure 31. The obtained values c, = 0.5695
2. Structural chemistry of enamines: a statistical approach
147
(4
-9
-5
-1
3
7
11
PC1 FIGURE 29. Principal-components scatter plot for torsion angles: (a) TI-T4,(b) T5-T8
15
B. J. Oleksyn, K.Stadnicka and J. Sliwiliski
I
I
I
-
T
I
I
I
I
I
I
FIGURE 30. Scatter plot of D4 versus Dl bond lengths for a sample of 474 enamine fragments (R1-R' unrestricted)
and c, = 0.5653 are not far from those found by Pauling for C-C bonds (c = 0.71)12. On the basis of Dunitz's correlation principle, it can be suggested that the equation
AD4 = 0.5653 log (3 - lPD"0.5695 1
(13) bond
maps the minimum energy path of the electron shift in the enamine N-C-C system in the parameter space AD1 and AD4. In the case of a carbon atom as the first atom in all the substituents R1-R5 (sample size 178) a relation similar to equation 13 is also valid, but with parameters c, = 0.6042 and c, = 0.5426. The scatter plot AD4 versus AD1 together with the fitted curve is shown in Figure 32. In contrast to the strong negative correlation between Dl and D4, for which the correlation coefficient was - 0.7428, at a significance level <0.001 the other bond lengths can be treated as uncorrelated ones (see Table 5). Nevertheless, the relevant scatter plots, shown in Figure 33, provide some information about the effect of
2. Structural chemistry of enamines: a statistical approach
149
FIGURE 31. Scatter plot of AD4 versus AD1 (RL-R%nrestricted, sample size 474) and the curve corresponding to equation 12 with minimized values of parameters: c, = 0.5695 and c, = 0.5653 substituents on the bond lengths. In each of them three main areas can be distinguished according to the ranges of values observed for the bond lengths between the enamine core atoms and the first atoms of the substituents: (i) the area occupied by points corresponding to the lowest values (0.70-1.20 A) comprises N1-H, CZ-H and C3-H bonds, (ii) the areadensely occupied contains bonds N'-N, N1-C, N L - 0 , C2-C, C2-N, C2-0, C2-F, and C3-C, C3-N, C3-0, (iii) the area with a few points in the range of 1.60-2.20 A is characteristic for bond lengths either between a nitrogen atom and atoms such as P, S, Si (D2, D3) or between carbon atoms and atoms such as As, B, Br, CI, I, P, S, Se, Si (D5, D6, D7). 6. Correlations Involving Angular Deformation Parameters
In order to examine a possible correlation between the N1-C2 bond length, Dl. and the out-of-plane deformation parameter X, (defined in Section I), the scatter plot shown in Figure 34 was analysed.
I50
B. J. Oleksyn, K. Stadnicka and J. Sliwihski
FIGURE 32. Scatter plot of AD4 versus AD1 for the sample of size 178 (carbon is the first atom for each of the R1-Rs substituents) and the curve corresponding to equation 12 with minimized values of parameters: c, = 0.6043 and c, = 0.5426
The points representing the enamine fragments on this scatter plot are spread out on the surface of a triangle, the sides of which are formed by three lines:
( ~ ~ '=1 0,Dl
= 1.46, Dl = 1.28 + 0.00151~~1( (line 1,)
An intriguing feature of the point distribution in this plot is the occurrence of single, double and intermediate N1-C2 bonds for the low values of x,, and of only single N1-CZ bonds for high values of x,,. This behaviour may be schematically represented by the simplified graph shown below, in which arrows symbolize observed logic relations. single Nt-CZ bond double N'=C~ bond
-
2\
pyramidal surrounding of N1 planar surrounding of N'
2. Structural chemistry of enamines: a statistical approach
151
FIGURE 33. Scatter plot of bond lengths (in A): (a) D2 and D3 versus Dl, (b) D5 versus Dl and D4, respectively, (c) D6 and D7 versus D4, for a sample of 474 enamine fragments (RL-Rs
unrestricted) These relations suggest that the existence of the single bond. N1-CZ. is a necessarv condition for the occurrence of the pyramidal surrounhing of N'. The pyramidality df N1 is only a sufficient condition for the appearance of the single N1-C2 bond, because the planar arrangement (i.e., non-pyramidality) may be observed for both a single and a double bond between N1 and CZ. The detailed analysis of the various areas of the scatter plot of Figure 34 explains the reason for its specific character discussed above. For x , ~FZ 0 and for a short N-C
152
B. J. Oleksyn, K. Stadnicka and J. ~liwinski
FIGURE 33. (continued)
bond, the system can be described by the hybrid
with N1-CZ bond lengths within the range of 1.261.38 A, which overlaps that related by Dunitz3 for N-C double bonds. Lines 1, and I,, parallel to that found by Gilli and coworkers4 for enamines and other compounds (Figure 3a) and drawn through
2. Structural chemistry of enamines: a statistical approach
(c)
FIGURE 33. (continued)
the ends of this range, form the limits of the area comprising most of the cxpcrimcntal data which belong to the set S of the enamine fragments. For xN values approaching 90 ",only single N1-C2 bonds occur, in agreement with Gilli's correlation4. The most interesting cases, with relatively long N1-C2 bonds and xN E 0, are enclosed in the triangle area within the limits: 1.38 I N1-C2 I 1.47 A, 0 " IIxN,I5 3.0 " and the line 1,. These cases result from the following situations: (i) Atom N1, together with its three bonds, is engaged in a rigid system of condensed rings like that in indole derivatives.
154
B. J. Oleksyn, K. Stadnicka and J. Aliwinski
FIGURE 34. Scatter plot of Dl versus the absolute value of the out-of-plane deformation parameter, XN, for a sample of 474 enamine fragments (R1-RS unrestricted)
(ii) One of the
' substituents is either of the type \/C=X
or of the type -CEX,
where X is an electron-withdrawing group and forces the involvement of the nitrogen lone pair in the alternating single- and double-bond system.
enamine core
enamine core
This results in a planar arrangement of the bonds formed by N1, although the N1-C2 bond within the enamine fragment remains approximately a single bond. Thus Gilli's plot4, consisting of only a small group of enamine fragments, may be treated as a representative of this part of the enamine population in which none of the cases (i) and (ii) is present. The scatter plot Ix,II versus I T ~ , - ~ I I , where I T , I - ~ ~ is the average twist angle at N1-C2 bond (Dl), is shown in Figure 35. Its features can be better. understood by comparison with the corresponding plot published by Gilli4 (Figure 3) for enamines and other compounds. The points, which represent enamine fragments and belong to set S, can be divided into two, partially overlapping, groups. The points of the first group (i)
2. Structural chemistry of enamines: a statistical approach
155
FIGURE 35. Scatter plot of IX,,I versus the absolute value of the average twist parameter T,OL,~ for a sample of 474 enamine fragments (R1-Rs unrestricted)
are scattered along the line 1 ~ = 2~ ( ~~ ~ #1 -within ~ i [ the area enclosed between the - ~35l " and IxNLI= 2 l ~ ~ n --~35 I The points of the following lines: IxN,I= 2 l ~ ~ l + second group (ii) occupy the area defined by the h e s : IxN;I = 0 " . 1 ~ ~ =1 21 1 ~ ~ 1 - ~-2 1 3 5 " and the horizontal part of the curve which, accordmg to Gilh4, describes the O.
\
I
'combined' deformation of ihe,:N-C=X fragment. Group (i) comprises such fragments, the double bond of which, D4, is involved in a ring system, while the situation of N1 changes together with increase in IT^ and 1x1. The greater the values of 1x1, the higher the degree of the engagement of the N1 atom in the ring systems of increasing rigidity. Thus, for a XN, value close to 0 ", N1 is exocyclic, while for higher IxN1I values this atom appears in six- or five-membered rings, most often forming a junction between two or three of them. Finally, for very high IxN,I values N1 occurs as a link between five- and four-membered ring systems. The changes mentioned above of N' involvement in the rings are accompanied by a decrease in the sum of bond angles, = A1 + A2 + A3, from 360 to 318 ". This is, of course, a consequence of the increase in N1 pyrarnidality which, for C, 2 328.41 ",exceeds 100%.
xA
B. J. Oleksyn, K. Stadnicka and J. Sliwinski Especially interesting are the cases not observed by Gilli which extend the line = 40 ". In these cases the endocyclic IxN'I = 2 1 ~ , , - ~ lup to Ix, I = 80 and position of N1 in the rigid systems enforces on it a very high pyramidality. Thus it could be said that the line IxN,I = 21~,,-,~l does not separate the mostly 'butterfly' from the mostly 'combined' enamine conformations as suggested by Gilli and coworkers4, but represents a structural correlation function. This interpretation is confirmed by the results of PCA (Section 1V.C) for torsion angles, since the parameters 2 ~ , , - and ~ - x,, appeared as PC1 and PC2, respectively, and by definition should not be statistically correlated. Consequently, this correlation might be interpreted, according t~ Dunitz's principle3, as mapping a minimum energy path from planar to folded systems for a specific group of enamines (i). The characteristic feature of this group, besides those mentioned above, is the occurrence of 'push-pull' interactions in systems containing carbonyl C=O, thiocarbonyl, C=S or sulphoxide S=O groups as electron acceptors. Group (ii) consists of enamine fragments corresponding to points scattered in the area which is enclosed between the lines
IX,I I = ~ [ T , L , Z ~
- 35",
(X,I
I = 0' and I ~ , I I = 55'
In view of the fact that in Gilli's plot (Figure 3) only 15 such enamine fragments can be found, it is interesting to examine the changes of the N1 and D4 situation with the change of 1 ~ ~ and ~ 1 ~~ ~ 12 1For . 1 small 1 ~ ~ values, 1 1 irrespective of IT,,-^^^, either both N' and D4 are exocyclic or N1is a part of a flexible, six-membered saturated ring with < 60 ",N1 belongs to one or two D4 being outside it. For I , y N 1 l > 35 " and I T , I - ~ [ fused rings containing also D4, while for ~ T , , - ~ Z ~> 60 " either N1 or D4 is exocyclic. A decrease in the bond angle sum, accompanying the above changes amounts to ~ ~ 24 " and is independent of the I T , I ~ values. The discussion above leads to the conclusion that the horizontal part of the line drawn by Gilli and coworkers4 is not a correlation curve, but rather a limit of maximum I,y,,I values available for the enamine fragments outside the area enclosed between the lines
x,,
IxNj[=
+ 35'
and
IxN,I= 21rN,-,21 - 35"
Another, more important conclusion concerns the general condition for the planarity of the enamine system. The scatter plot of IX,,~ versus IT,,-^^^ suggests that the planar arrangement of the enarnine core atoms is most probable when N1 and/or the double bond CZ=C3 are exocyclic. It is instructive to investigate the correlations between bond lengths in the enamine core (Dl, D4) and the corresponding average twist angles ( T , ~ - ~ Z and T@=@)which are revealed by the scatter plots in Figure 36. (Figure 36a) is limited from the top by the The scatter plot Dl versus horizontal line D l = 1.46 A (a length typical of the single N-C bond) along which 7 seems to be independent of the conjugation between D l and D4. Its magnitude is determined by the flexibility of the molecule containing the enamine fragment. For example, those fragments which are parts of indole moieties have a low T angle despite high D l bond lengths. The curve which is a bottom limit of the scatter plot shows a decrease in the T angle with decreasing Dl, i.e. with an increase in the conjugation between D l and D4 caused mainly by a 'push-pull' effect. The points with minimum D l values and small T correspond to the N1-C2 bond order close to 2 or even to a zwitterionic form of the enamine fragment. The scatter plot D4 versus 17C2=C31(Figure 36b) shows a dense cluster of points with a centroid at a C2=C3 bond length of 1.35 A and an average twist angle T = 0. Together with the increasing conjugation between CZ=C%nd C2-N1 bonds, which is accompanied by the increase in D4, there appears a possibility of a twist at the formally
2. Structural chemistry of enamines: a statistical approach
157
FIGURE 36. Relation between bond length and the corresponding average twist parameter for N1-C2 (a)and formally double C2=C3 (b) bonds as found for a sample of474 enamine fragments
158
B. J. Oleksyn, K. Stadnicka and J. ~liwinski
double C2=C3 bond and the twist angle irl can achieve high values, as much as 84 " (zwitterionic form stabilized by a doubled 'push-pull' effect). However, when the enamine fragment is a part of a rigid moiety, the elongation of D4 is not followed by any increase of the r-angle, which can be seen for the small group of points with 1.39 5 D4 s 1.45 A and r value close to zero. VI. EVALUATION OF SUBSTITUENT EFFECTS ON THE GEOMETRY OF ENAMINE
FRAGMENTS The effect of the substituents R' on the enamine geometry can be traced by comparing the statistical parameters of the structural descriptors for various types of atom in each substituent. The other substituents (Rj # R') remain unrestricted, so that only changes introduced by one atom type in one of the substituents can be studied at a time. Within this approach two groups of descriptors were selected: (i) parameters describing the geometry of the enamine core such as Dl, D4, A4A6, (ii) parameters specific for a given substituent Di, Ai, Aj and PDiM. Hence, it was possible to follow the influence of the first atom of Ri on both the geometry of the enamine core and the Ri vicinity. The statistical parameters found for the chosen descriptors are listed in Table 14. Considering substituents (R1, RZ)at N1 it is seen that C and N atoms have a similar influence on the Dl and D4 bond lengths, leaving D l > D4. However, a certain conjugation in the enamine core system is conspicuous. S and Si atoms seem to counteract the tendency to conjugation, whereas the H atom favours a conjugation state close to the zwitterionic form. The characteristic feature of this state is the increase in the A4 angle accompanied by decrease in A6, which usually has the greatest value among angles A4, A5 and A6. Relatively high PD4M and PDSM values for S and Si are a natural consequence of their size and the single N'-C2 retention connected with a high pyramidality of N1. In the case of R3 no influence on bond lengths (Dl, D4) in the enamine core is observed except that of the N atom (Dl E D4) which, together with the 0 atom, increases the A4 angle according to the electron-withdrawing properties of these atoms. It seems that the type of the first atom in the R4 and RS substituents does not significantly modify the D l and D4 bond lengths, since the relation D l > D4 is always preserved, as well as the A4 bond angle. Nevertheless, they may contribute to a x-conjugated pathway in 'push-pull'-like systems as suggested by a certain shortening of the Dl and lengthening of the D4 bonds. The relatively high PD7M and PDXM values, which occur for S (R4) or S and N (R5), may be explained by the involvement of these atoms in the rigid ring systems. In the case of the C atom the outstanding PD7M and PDXM values are due to anomalous upper limits of their ranges rather than to a systematic tendency to a twist deformation around the formally double CZ=C3 bond. Table 14 may also be used as a source of information about the average values of bond lengths and bond angles formed by the enamine core atoms (N', C2 and C3) and various atoms of the substituents. VII. CONCLUSIONS The final conclusions of the present work are as follows: (1) The descriptive statistical analysis carried out for the sample comprising 474 items provided an average geometry of the enamine fragment. (2) Principal component analysis appears to be a good tool for finding strong correlations between geometrical descriptors, such as the correlation between N-C and C=C bond lengths in the enamine core, which is significant for the description of a
TABLE 14. Effect of the first atom from the R' substituent (unrestricted R' statistical parameters"
= R3 on
selected structural descriptors of enamine grouping expressed by
Enamine core R': first atom type (sample size)
Statistical parameters
D4
(A)
A4
(deg)
Substituent
A5 (ded
A6
PDiM ( 4
Ai (deg)
Aj
(deg)
S
min max
R': H (12)
.
X
S(X). S
min max -
X
SCf) S
min max
R': 0 (2) R': S (9)
.f
min max .
5
S(f) s min max (continued)
TABLE 14. (continued) Enamine core
R': first atom type (sample size)
Statistical parameters
R2:C
X
(421)
S(*)
.
S
min max
S
min max
-
R': 0
X
(2)
min max
Dl
(4
D4
(A)
A4 (deg)
Substituent A5 (deg)
A6 (deg)
PDiM
(4
Ai
(W
Aj (deg)
S
min max
5
min max X
S(f) S
min max
x min max X
min max
S
min max
P
(continued)
c2
TABLE 14. kontinuedl Enamine core
Substituent
R': first atom type (sample sue)
(13)
D4
A4 (deg)
A5 (deg)
A6 ( W
PDiM
(4
(A)
Di
Ai (deg)
AJ (deg)
Dl
D4
A4
A5
A6
PD4M
D2
A1
A3
1.389 0.002 0.036 1.298 1.462
1.361 0.002 0.03 1 1.340 1.376
1.410 0.004 0.019 1.375 1.440
1.325 0.004 0.018 1.297 1.380
Statistical parameters
(4
s(*) S
min max
R3: S (19)
.
X
sw S
min max
R4: C (363)
x
S(i) s
min max .
R4:H
x
(25)
s(2) s
min max
X
min max
min max .
X
S(3 S
min max
min max X
min max .
X
S(9 S
min max
X
S(3 S
min max (continued)
TABLE 14. Effect of the first atom from the R' substituent (unrestricted R' = R') on selected structural descriptors of enamine grouping expressed by statistical parameters" Enamine core
Substituent
R': first atom type (sample size)
Statistical parameters
Dl
(4
D4
(4
A4 (deg)
A5 (ded
A6 Wed
PDiM
(4
Di
(-4
Ai (deg)
Aj (deg)
.
X
min max
-
X
min max .
X
sf3 S
min max
-
X
S(2) S
min max -
X
min max -
X
S(.t) S
min rnax " PDiM-absolute value of the distance of the R"s first atom from NLC2C3plane; D i d i s t a n s of the R'h first atom from the nearest core atom; Ai, Aj--angles in which Di is involved (i <,I; .?-average (mean): S(itstandard error of the mean; s--standard deviation; min, max--minimum, maximum values
5
2. Structural chemistry of enamines: a statistical approach
165
chemical reaction path. It can also be used to define statistically uncorrelated variables which can reveal relationships of the chemical origin, e.g. those between the angular deformation parameters x and T. (3) It was found that the enamine group N-C=C follows the Pauling-type relationship (for C-C=C) which maps the minimum energy path of thc electron shift within the enamine core, according to Dunitz's correlation principle. ~ 4found to be more important than (4) The linear relationship lxNl = 2 1 ~ was suggested by Gilli. It represents a structural correlation which might be interpreted as mapping a minimum energy path from planar to folded systems of a specific group of enamines. (5) A 'push-pull' through-conjugation effect on some of the enamine geometrical parameters was detected. (6) From the survey given in this chapter the fundamental Dunitz question, quoted in the Introduction (Section I), can be tentatively answered as follows: The enamine group should be planar when the surrounding of the enamine fragment allows a relatively free conformational change and it cannot be planar when the N atom and/or the C=C group are part of a rigid moiety. VIII. ACKNOWLEDGEMENTS
We thank Mr Wojciech Nitek for his help in CSDS searches and in the preparation of the drawings, and Ms Zuzanna Brozek for correcting the manuscript. IX. APPENDIX
Structures of primary (P), secondary (S) and tertiary (T) enamines used for the analysis (set S), together with their CSDSS codes and the appropriate reference
B. J. Oleksyn, K. Stadnicka and J. Sliwifiski
*second molecule, equivalent atoms
2. Structural chemistry of enamines: a statistical approach
167
168
B. J. Oleksyn, K. Stadnicka and J. ~liwinski
2. Structural chemistry of enamines: a statistical approach
COOH
0
I
'yN\\ N] =N9
AdN
C3 = C23 C2 = C22
169
170
B. J. Oleksyn, K. Stadnicka and J. Sliwinski
2. Structural chemistry of enamines: a statistical approach
C107
NlOl OH
M
Ph Ph \ NIO-N'
N-N Ph'
\
Ph
171
B. J. Oleksyn, K. Stadnicka and J. ~liwinski
172
9,
CHO
/
2. Structural chemistry of enamines: a statistical approach
173
B. J. Oleksyn, K. Stadnicka and J. Sliwiliski
2. Structural chemistry of enamines: a statistical approach
175
176
B. J. Oleksyn, K. Stadnicka and J. ~liwinski
2. Structural chemistry of enamines: a statistical approach
177
B. J. Oleksyn, K. Stadnicka and J. aiwinski
S,T CPSAIA" N1-C8=C7 N2-C7=C8
T C U G X I L ~N3-C3=C4 ~
2. Structural chemistry of enamines: a statistical approach
179
180
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195. N. Farfan, J. M. Hernandez, P.Joseph-Nathan and R. Contreras, J. Heterocycl. Chem., 27, 1745 (1990). 196. N. Hirayama, M. Kohno, E. Shimizu and M. Kasai, Acta Crystallogr., C47, 680 (1991). 197. D. Seebach, T. Maetzke, W. Petter, B. Klotzer and D. A. Plattner, J. Am. Chem. Soc., 113, 1781 (1991). 198. B. Abarca, R. Ballesteros, F. Mojarrad, M. R. Metni, S. Garcia-Granda, E. Permcarreno and G. Jones, Tetrahedron,47, 5277 (1991). 199. M. Ishikura, M. Terashima, K. Okamura and T. Date, J. Chem. Soc., Chem. Commun., 1219 (1991). 200. S. Polanc, M.-C. Labille, Z. Janousek, R. Merenyi, M. Vermander, H. G. Viehe, B. Tinant, J. Piret-Meunier and J.-P. Declercq, New J. Chem. (Nouv. J. Chim.), 15, 79 (1991). 201. H. Rudler, A. Parlier, R. Yefsah, B. Denise, J. C. Daran, J. Vaissermann and C. Knohler, J. Organomel. Chem., 358,245 (1988). 202. P. Dubois, R. Ceolin and N. Rodier, Acta Crystallogr., C45,430 (1989). 203. A. G. Brook, A. K. Saxena and J. F. Sawyer, Organomelailics, 8,850 (1989). 204. P. Magnus, B. Mugrage, M. DeLuca and G. A. Cain, J. Am. Chem. Soc., 111, 786 (1989). 205. P. Magnus, B. Mugrage, M. R. DeLuca andG. A. Cain, J. Am. Chem. Soc., 112,5220(1990). 206. Whanchul Shin and Jungwon Choi, Acta Crystallogr., C45, 1186 (1989). 207. Lin-Hua Zhang, M. L. Trudell, S. P. Hollinshead and J. M. Cook, J. Am. Chem. Soc., 111, 8263 (1989). 208. K . Eger, G. Folkem, M. Frey, W. Zimmermann and G. KoopKirfel, Synthesis, 632 (1988). 209. F. G. Fang, M. E. Maier, S. J. Danishefsky and G. Shulte, J Org. Chem., 55, 831 (1990). 210. C. H. Heathcock, M. H. Norman and D. A. Dickman, J. Org. Chem., 55, 798 (1990). 211. B. Tinant, J.-P. Declercq, M. Vermander, Z. Janousek and H. G. Viehe, Acta Crystallogr., C46, 1145 (1990). 212. P. Briard and J. C. Rossi, Acta Crystaliogr., C46, 1033 (1990). 213. D. H. Hua, S. N. Bharathi, A. Tsujimoto and P. D. Robinson, Acta Crystallogr., C46, 1306 (1990). 214. K. Yonemoto, I. Shibuya and K. Honda, Bull. Chem. Soc. Jpn., 62,1086 (1989). 21 5. R. Destro, U. Cosentino, G. Moro, E. Ortoleva and T. Pilati, J. Mol. Struct., 212,97 (1989). 216. Kyong Pae Park and Jong Hwa Jeong, Acra Crystallogr., C46, 1659 (1990). 217. 2. V. Todres, A. Yu. Kosnikov, K. I. Dyusengaliev, D. S. Ermekov, S. V. Lindeman and Yu. T. Struchkov, Izu. Akad. Nauk SSSR, Ser. Khim., 791 (1990). 218. N. Hirayama, Acta Cry.yslailogr.,C46, 1962 (1 990). 219. V. K. Brel, E. V. Abramkin, A. N. Chekhlov and I. V. Martynov, Dokl Akad Nauk SSSR, 312, 619 (1990). 220. R. Weiss, R. Roth, R. H. Lowack and M. Bremer, Angew. Chem.,Int. Ed. Engl., 29,1132 (1990). 221. E. Kobal, L. Colic and M. Japelj, Vestn. Slou. Kem. Drus., 37, 43 (1990). 222. P. K. Mogensen and 0. Simonsen, Acra Crptalloyr., C47, 1854 (1991). 223. Yu. E. Ovchinnikov, V. N. Panov, I. A. Zamaev, V. A. Igonin, V. E. Shklover, Yu. T. Struchkov, 0. L. Lazareva, V. I. Suskika and A. B. Shapiro, Kristallografiya, 36, 86 (1991). 224. 1. Lukac, J. H. Bieri, and H. Heimgartner, Helv. Chim. Acta, 60, 1657 (1977). 225. 1. Galloy, J. P. Declercq and M. van Meerssche, Cryst. Struct. Commun., 8, 981 (1979). 226. G. A. P. Dalgaard, and R. G. Hazell, Acta Crystallogr., 834, 3099 (1978). 227. S. Abrahamsson, G. Rehnberg, T. Liljefors and J. Sandstrom, Acta Chem. Scand., BU), 1109 (1974). 228. A. avid son, I.E. P. Murray, P. N. Preston and T. J. King, J Chem. Soc, Perkin Trans. 1, 1239 (1979). 229. E. F. Paulus, Acta Crystallogr., B30, 2915 (1974). 230. L. A. Simonyan, Z. V. Safronova, N. P. Gambaryan, M. Yu. Antipin and Yu. T. Struchkov, Im.Akad. Nauk SSSR, Ser. Khim., 358 (1980). 231. G. Argay, A. Kalman, B. Ribar, S. Vladimirov and D. Zivanov-Stakic, Cryst. Struct. Commun., 9,917 (1980). 232. P. J. Abbott, R. M. Acheson, U. Eisner, D. J. Watkin and J. R. Carruthers, J. Chem. Soc., Perkin Trans. 1, 1269 (1976). 233. A. Horvath, I. Hermecz, L. Vasvari-Debreczy, K. Simon, M. Pongor-Csakvari and Z. Meszaros, J. Chem. Soc., Perkin Trans. 1, 369 (1983).
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(1941\ *,
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218 313. 314. 315. 316. 317.
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CHAPTER
3
Configuration. conformation and chiroptical properties of enamines OTAKAR ~ E R V I N K A Department of Organic Chemistry, lnst~fureof Chemical Technology. 7 6628 Prague 6. Czech Republic . -
~~p
-~.......
~~p
p~
.
.
I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 I1. CONFIGURATION O F ENAMINES . . . . . . . . . . . . . . . . . . . . . 220 A. 2-and E-Isomers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 B. NMR Spectra of Z- and E-Isomers . . . . . . . . . . . . . . . . . . . . . 222 111. GEOMETRICAL PARAMETERS O F ENAMINES . . . . . . . . . . . . 224 IV. CRYSTAL STRUCTURES O F ENAMINES . . . . . . . . . . . . . . . . . 226 V . CONFORMATION O F ENAMINES . . . . . . . . . . . . . . . . . . . . . 230 A . Internal Rotation about the C-C and C-N Bond in Enamines . . . 231 B. Enamines with High Barrier to Rotation . . . . . . . . . . . . . . . . . . 233 C . Enamines of Cyclic Ketones . . . . . . . . . . . . . . . . . . . . . . . . . 234 1. 2-Substituted cyclohexanones . . . . . . . . . . . . . . . . . . . . . . . 234 2. 3-Substituted cyclohexanones . . . . :. . . . . . . . . . . . . . . . . . 236 VI . CONFIGURATION AND CONFORMATION O F 'PUSH-PULL' ENAMINES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .236 A . Enaminoketones and Enaminoesters . . . . . . . . . . . . . . . . . . . . . 237 B. Nitroenamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 1. Effect of solvents on configuration of nitroenamines . . . . . . . . . . 244 VII . STEREOCHEMISTRY O F METALLOENAMINES . . . . . . . . . . . . 245 VIII. STEREOCHEMISTRY O F THE CARBON-NITROGEN DOUBLE BOND IN ENAMINES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246 IX . IMPORTANCE O F ENAMINES IN ASYMMETRIC SYNTHESIS AND THEIR CHIROPTICAL PROPERTIES . . . . . . . . . . . . . . . . 248 A. Optically Active Enamines . . . . . . . . . . . . . . . . . . . . . . . . . . 248 B. Chiroptical Properties of Enarnines . . . . . . . . . . . . . . . . . . . . . 249 X.REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
Thc Cl~ernirtryof Enmnincs . Edited by Zvi Rappoport Copyright O 1994 John Wiley & Sons. Ltd . ISBN: 0-471-93339-2
219
I. INTRODUCTION
Enamines are very reactive compounds, easily accessible and of great importance in organic chemistry. The regiochemistry and stereochemistry of enamine preparation and the reactivity of the produced enamines depends strongly on structure, stereochemistry and electronic considerations which are of particular importance. Consequently, it is sometimes found that the product distribution in an enamine reaction depends not only on the relative stability of various enamine isomers but also on their relative reactivity. The recorded reports of the synthesis of enamines which can exist as geometric isomers are generally characterized by the absence of discussion of the stereochemical constitution of the products. It is likely that, where possible, mixtures of stereoisomers are obtained when employing the general procedures, whose composition is the result of thermodynamic control. II. CONFIGURATION OF ENAMINES
The general procedures for the preparation of enamines, such as condensation of an open-chain aldehyde with a secondary amine in the presence of potassium carbonate or azeotropic removal of water from a solution of a ketone and secondary amine in benzene (frequently in the presence of an acid catalyst), fail to incorporate the desirable feature of stereospecificity. The spectra of a series of enamines prepared from both aldehydes and ketones indicated that the E-isomer predominated, but not to the total exclusion of the Z-isomer. When enamines are produced by the titanium tetrachloride method of White and Weingarten1s2,the kinetically controlled product is formed. A. 2- and E-Isomers
Enamines from aldehydes and acyclic ketones can form E-(1) and Z ( 2 ) stereoisomers. The stereoisomer distribution of several of these enamines are shown in Table 1. The principal factor responsible for this distribution is a A"v3' strain. RZ
R3
\
I
'C=C \
RI
X
(1)
E (R2 > R1; X > R3)
R1
R3
\
I
'
\
C=C
X (2) Z (R2 > R'; X > R3) R2
When the enamine is formed from an unsymmetrical methyl ketone, a choice of structural isomers having terminal double bond or a more fully substituted internal double bond is possible6'. Spectra and vpc analysis indicate that only one geometric isomer is obtained by Stork's procedure applied for the synthesis of the propiophenone enamines". When molecular models of the two possible geometrical isomers are examined, keeping the phenyl group and the double bond in different planes, it appears that the steric requirement of the phenyl group is lower than that of the amine. This steric consideration suggests that the isomer with the methyl and phenyl groups on the same side of the double bond is has been the preferred geometrical isomer. Z-1-(4-Morpho1ino)-l,2-diphenylethylene reported to be thermodynamically more stable than the corresponding E-isomer". The tendency of the E-enamine to isomerize to the Z-enamine was readily observed on numerous--sometimes inconvenient-occasions under unexpectedly mild conditions. It necessitated not only great care in handling, but the establishment of configurational
221
3. Configuration, conformation and chiroptical properties of enamines TABLE 1. Stereoisomer distribution of enamines 1 and 2 of aldehydes and acyclic ketones % Composition
R1
RZ
H H H
Me Me
Me Me Ph Ph Ph Ph i-Pr i-Pr
H
H Me Et i-Pr H H
X
E
Z
Ref.
Et Et Et
Diethylamino N-Methyl-o-toluidino
Ph
Morpholino Morpholino Morpholino Morpholino Morpholino Morpholino Pyrrolidino
86 83 20 98 88 85 60 20 72 97
14 17 80 2 I2 15 40 80 28 3
3 4 3 5 7 9 5
R3
N-Methylanilino
Ph
H H H H H
5 9 10
homogeneity just prior to use, by analysis of the ultraviolet or N M R spectrum. Similar difficulties in handling were not encountered with the Z-enamine. solvent^'^.'^ may have large effects on isomerization rates. Moreover, traces of acids or water in the solvents catalyse the isomerization of enamines (equation 1).
R~
I N-
\
1
/
\
C=C
R
'
H
R' +H+
'
I+ NI/
\
-
H RZ ,f
C-C
R1
I
R'
N+//
+H+
\
-H+
H
\
I
N
C=C \ R2 H
-
(1)
I
Johnson and c o w ~ r k e r s and ' ~ Danishefsky and Feldman16 believe that the so-called thermal equilibration of enamines does not exist and that, when equilibration does occur, it is due to the presence of adventitious traces of acid and proceeds via an immonium salt intermediate. The 'H-NMR spectra of 2-(nitromethy1idene)pyrrolidine(3),1-methyl-2-(nitromethylidene)imidazolidine (6) and 3-(nitromethylidene)tetrahydrothiazine (5) in CDCI, and (CD3),S0 indicate that these compounds have the intramolecularly H-bonded structures 2-3, E-6 and 2-5, while the N-methyl derivative 4 of 3 have an E-configuration in both solvents. 2-(Nitromethylidene)thiazolidine (7)has the E-configuration in CDCI,, but exists in (CD,),SO as a mixture of Z- and E-isomers with the former predominating. The N-methyl derivative 8 of 7 is Z-configurated in (CD,),SO. Comparison of the olefinic proton shifts of 2-7and 2-8 with those of analogues and also of 1,l-bis(methy1thio)-2nitroethylene (9) shows decreased conjugation of the lone pair of electrons of the ring N-atom in 2-7and Z-8. This is also supported by 13C-NMR studies and has been confirmed by X-ray studies. Plausible explanations for this phenomenon are oflered by postulating that the ring N-atoms are pyramidal in 2-7and 2-8and planar in other cases or, alternatively, that the conjugated nitroenamine system becomes twisted due to steric interaction between the NO,-group and the ring S-atom. Single-crystal X-ray studies of 7 and 4 show that, in the solid, the former exists in the 2-configuration and the latter in the E-configuration; the ring N-atom in the former has slightly more pyramidal character than in the latter".
At present, the enamines can be obtained fairly easily either in pure Z- or in pure E-isomeric form and enamines derived from a series of stcrically hindered amines have been prepared18 A consideration of the design of a stereospecific synthesis of enamines suggested that at least two requirements must be met. First, if the introduction of the double bond was to be the final step, it must be stereospecific in character and, second, the enamine, once formed, must retain its stereochemical integrity under the conditions employed in the double-bond-forming step. Munk and Kim" described a new approach to the synthesis of stereoisomeric enamines of known configuration which takes advantage of the well-documented facility and stereospecificity of the bimolecular p-elimination reaction. B. NMR Spectra of Z- and E-Isomers
NMR spectra of the E- and Z-isomers of enamines (Tables 2 and 3) show a high degree of differential shielding of their ethylenic protons. This may be explained on the basis of the enamine mesomerism A trB (equation 2) where the R2 substituent of the Z-isomer prevents the amine residue from taking up a conformation favourable to p-R overlap. Accordingly, a Z-configuration was assigned to the isomers having the ethylenic proton signal at a lower field. Conversely, in the E-isomer, steric inhibition being absent, there is greater shielding of the olefinic proton and the signal is at a higher fieldz3-z7.
However, the differences in the chemical shifts of the olefinic protons are generally not very large. Moreover, an overlap of the ranges is often observed. Dahumel and coworkersz4examined a number of enamines and were able to differentiate the E- and Z-isomers by the 'H nuclear Overhauser effect (NOE); see Figures 1 and 2. 13C-NMR spectroscopy can be used to distinguish between the E and Z-isomersz8. The 13C chemical shifts values are generally widely different, the ranges never overlapping. Table 2 shows that in the enamines derived from ketones the p-olefinic carbon
3. Configuration, conformation a n d chiroptical properties of enamines
Ph
\
223
1
F=F
8 1.93Me
uH"'" 28% NOE
FIGURE 1. NOE effect of enamines derived from aldehydes Ph
*
\
M e 8 1.51
/c=C
\
H784.% 23% NOE
FIGURE 2. NOE effect of enamines derived from ketones
TABLE 2. "C-NMR shifts (6 ppm downfield from TMS) of the relevant carbon atoms of the Eand Z-isomers of enamines derived from ketones'
R1
R2N
R'
Configurationb
c.
E 98% Z 2% E 95% Z 5% E 90% Z 10% E 86% Z 14% E 96% Z 4% E 88% Z 12% E 95% Z 5% E 97% Z 3%
154.2 c 151.3
Morpholino
Ph
Me
Pigeridino
Ph
Me
Diethylamino
Ph
Me
Diethylamino
Et
Me
Morpholino
2-Thi
Me
Morpholino
Ph
Ph
Morpholino
PhCH2
Ph
Morpholino
Me
Ph
c
147.7 c
148.9 c
143.9 c
150.9 149.6 147.2 143.1 146.2 c
C0
103.4 114.5 99.4 109.8 100.0 113.1 98.4 115.4 102.9 112.3 106.1 112.1 106.0 112.3 104.7 111.3
Ref.
25 31
23
-13
32 33 33
'All the enamines are mixtures of the E- and Z-isomers, the molecular ratio of which have been determined by 'H-NMR spectroscopy. ' E / Z ratios were measured from 'H NMR at 39°C in CDCI,, 'Too small to be detectable.
TABLE 3. 13C-NMRshifts (6 ppm downfield from TMS) of the relevant carbon atoms of the Eand 2-isomers of enamines derived from aldehydes
RzN
R1
RZ
R3
Morpholino
H
Morpholino
H
Morpholino
Me
Configuration"
c.
c#
C,
Ref.
E pure Z pure E 85% z 15% 2 60% E 40%
Morpholino Piperidono Pyrrolidino Pyrrolidino *The E/Z ratios were measured from the IH-NMR spectra of an equilibrium mixture at 39°C in CHCI, for all enamines, except for the first case, where the two isomers were independently prepared.
atoms of the Z-isomers always resonate at a lower field compared with those for the corresponding E-isomers. The enamines derived from aldehydes (Table 3) can be divided into two types. First, for those compounds where a hydrogen atom is bound to the 8-carbon atom the spectroscopic behaviour parallels that for the enamines derived from ketones. When the P-carbon atom bears two substituents, its chemical shift increases. In addition to the chemical shift difference, for the allylic and P-carbon atoms differences were noted for the coupling constants between the or-hydrogen and the allylic carbon atoms. The magnitude of the vicinal 13C-'H coupling constant changes with configuration and can be used to distinguish the Z-form from the E - f ~ r m ' ~ . ~ ~ . Ill. GEOMETRICAL PARAMETERS OF ENAMINES
An application of the resonance formalism to enamines illustrates that the properties of an enamine are largely a function of the extent to which the lone-pair electrons on the nitrogen atom are delocalized into the n-system of the a-carbon-carbon double bond (equation 2). The resonance hybrid B is very important in push-pull enamines, which have a strong electron-donating group on C , of the alkene and a strong electronwithdrawing group at Co. Normally, an amine has a pyramidal geometry with bond angles of 109.5 " around the nitrogen. The two unsaturated carbons and their four substituent atoms in an alkene describe a plane. In order to achieve full delocalization of the lone-pair of nitrogen electrons into the alkene n-system in the amine ground state, the plane formed by the
3. Configuration, conformation and chiroptical properties of enamines
225
nitrogen and its two substituents must be coplanar with the two carbons and four substituents of the alkene. Such coplanarity requ~ressp2-hybridization for the nitrogen atom. von Doering and coworkers35 have shown experimentally that conjugative interaction in enamines does require the nitrogen lone-pair orbital and the alkene n-system orbitals to be parallel in order to maximize the overlap. Calculations of the simple primary enamine, vinylamine, have shown it to be n ~ n - p l a n a r ~This ~ - ~conclusion ~. has been extended to tertiary enamines as well, based on the shape of bands in the photoelectron spectra4', on quantum-chemical calculat i o n ~ ~ ' - 'and ~ on X-ray diffraction studies of crystalline enamines4-' (cf Chapter 1). There are two geometrical parameters that describe how closely the orbital carrying the unpaired electrons on nitrogen parallels the p-orbitals in the alkene n-system. (a) The pyramidality around the nitrogen atom; when the enamine is planar, the nitrogen atom is sp2-hybridizedwith an orthogonal p-orbital for the lone-pair electrons; when the enamine geometry is pyramidal, the nitrogen atom is sp3-hybridized with the lone-pair orbital at 109.5 " (Figure 3). When the nitrogen atom is planar (completely non-pyramidal), the sum of the three bond angles around it is 3 x 120" = 360 ". When the nitrogen atom is completely pyramidal, the sum of the three bond angles is 3 x 109.5 " = 328.5 ". Consequently, the percentage pyramidality of a nitrogen atom is defined in equation 3: 360 -
three N-bond angles -- - ,100 360 - 328.5
(3)
Bond distances are a good index for determining the conjugative interaction in enamines. It is generally accepted that linear relationships exist between the bond lengths and the n-bond orders. As the s-character of a bond increases, the bond becomes shorter4'. In terms of enamine n-n interaction, as the amount of interaction increases, the s-character of the nitrogen atom a-bonds increases, i.e., they approach sp2-hybridization. Hence the C-N bond distances shorten. The relative importance of hybrid B becomes more important and of hybrid A less important as the n-n interaction increases. This means a higher double-bond character to the C-N bond (and shorter bond distance) and a lower double-bond character to the C=C bond (and a longer bond distance).
FIGURE 3. Enamine nitrogen pyramidality. fJ is L RNR, w is the angle between the extended bond and L RNR bisector. (Reprinted from Ref. 6, p. 16 by courtesy of Marcel Dekker, Inc.).
C-N
FIGURE 4. Torsional twist around an enamine carbon-nitrogen bond. The points RNR represent a projection of these atoms on a plane orthogonal to the C-N bond. 4 is the angle of torsional twist about the C-N bond as described by the angle of intersection of line W (which intersects both R groups) and the NCX plane. The bisector of the RNR obtuse angle is the lone-pair orbital geometry. So 4 can also be described as the torsional angle between the lone-pair orbital and the lobe of the alkene porbital (orthogonal to the NCX plane) which gives the smallest angle. (Reprinted from Ref. 6, p. 17 by courtesy of Marcel Dekker, Inc.).
This parallel between the bond distance and the n-n interaction (using decreasing pyramidality at the nitrogen atom as a measure of n-n interaction) was observed in the X-ray crystallographic studies of several crystalline enamines4=. There is a pronounced shortening of the enamine C-N bond distance as the n-n interaction increases from about 0.142 to about 0.138 cm nrn. The C=C distance remains almost constant, showing only a slight lengthening with increased n-n interaction. (b) The torsional twist around the C-N bond (Figure 4). IV. CRYSTAL STRUCTURES OF ENAMINES
The crystal structures of a large number of push-pull enamines (1616) have been determined, and C=C bond lengths between 133.0 and 141.2 pm have been observed4' (Table 4). The fundamental information about the geometry of the enamine moiety has TABLE 4. Bond lengths K (in pm) from X-ray crystallography of enamines 1046 Compound
R(C=C)
R(C-N)
Reference
3. Configuration, conformation and chiroptical properties of enamines
OHC H
NMe2
&cHzfi
227
gN,CH2C&Cl~-2,6
been obtained from X-ray analyses of simple crystalline enamines (17-23; see Tables 5-7). Some of the symbols used in these Tables are defined in Figure 5.
TABLE 5. Geometry of crystalline enamines 17-23 from X-ray crystallography
e
Compound
% Pyramidalityb
R (C-N)
(degl''
R (C=C)
(nm)
(nm)
1
Reprinted from Rct 6, p. 21 by courtesy of Marcel Decker, Inc. OAbsolute value, taking the smallest angle with respect to the Defined in equation 3. 'Two crystallographically independent molecules.
Reference
N-
\
/-.
C=C \
/
plane
TABLE 6. Torsion angles and out-of-plane parameters or crystalline 17-23'
17
- 63
18 19b
-61.4 -48.2 -46.0 -27.3 - 17.0 - 20.0
19b 20b 21
2tlb 22 23
- 6.0
-22.0
-3 -7.0 -1.1 0.8 6.5 11.4 3.0 6.8 -2.5
119 123.2 134.5 138.3 157.9 165.0 165.1 175.9 179.6
170 168.4 176.1 176.6 -178.6 - 170.6 177.8 175.1 175.9
0.0402 0.0370 0.0325 0.0311 0.0196 0.0178 0.0120 0.0072 0.0013
53 49.8 44.4 42.5 28.6 26.4 17.9 10.9 -2.1
- 35
-1 -4.6 -2.7 -4.3 -5.2 -2.0 -5.1 1.9 -1.6
- 34.2 -24.7 -22.6 - 10.4 -2.8 - 3.5 0.4 -2.2
Reproduced with permission from Ref. 46. 'For definition of symbols see Figure 5. LTwocrystallographically independent molecules.
TABLE 7. Bond lengths and angles for crystalline enamines 17-23' Enamine
a (nm)
b (nm)
c (nm)
d (nm)
e (nm)
17 18 19 19
0.154 0.1514 0.1503 0.1511 0.1495 0.15M) 0.1483 0.1480 (0.1427)
0.135 0.1334 0.1342 0.1337 0.1334 0.1349 0.1348 0.1366 (0.1412)
0.142 0.1426 0.1410 0.1412 0.1395 0.1393 0.1385 0.1380 0.1381
0.149 0.1476 0.1456 0.1450 0.1490 0.1439 0.1509 0.1451 0.1435
0.152 0.1461 0.1464 0.1449 0.1450 0.1458 0.1463 0.1457 0.1435
20b 21 20b 22
23
Reproduced with permission from Ref. 46. 'For definition of symbols see Figure 5. bTwo crystallograph~callyindependent molecules.
ab (deg)
ac (deg)
122 114 120.1 115.0 120.4 115.1 120.5 115.3 121.6 116.3 121.0 116.1 121.0 116.4 121.9 116.5 121.9 (118.8)
bc cd ce de (deg) (deg) (deg) (deg) 124 124.8 124.4 124.1 121.9 122.8 122.4 121.6 119.3
113 116.3 117.0 117.3 123.1 124.1 124.8 126.0 124.7
117 115.7 116.9 117.2 120.7 120.4 122.1 121.4 123.5
103 109.2 111.3 111.9 110.7 110.9 111.0 111.8 111.8
3. Configuration, conformation and chiroptical properties of enamines
229
w l = wabc) 02 = w(bce) Q = w(bcd) 0 4 = O(ace) FIGURE 5. Explanation of some of the symbols used in Tables 6 and 7. The angle r (twist angle) is the mean of w , and w,. Reproduced with permission from Ref. 46. Figure 6, which displays the projections down the respective C-N bonds, demonstrates that the pyramidality at the nitrogen atom varies over the whole range from virtually complete tetrahedralization to virtual planarity (sp2-hybridized N). The pyramidality is greater for molecules where the N-atom is part of a six-membered ring (piperidine or morpholine, structures 17, 18 and 19) and smaller for molecules where the N-atom is part of a five-membered ring (pyrrolidine). N-Vinylaziridine and all the other aziridine enamines are found to exist as equilibrium mixtures of variable compositions, with gauche conformation 24 as the major and a trans-bisected form 25 as the minor components4.
A second feature that is apparent from Figure 6 is the tendency for one of the bonds emanating from'the N-atom to eclipse the C=C bond; the maximum value of the torsion angle w2 (C-N-C=C) observed in any of the structures is only 11 " (structure 21, see Table 6). Figure 6 also shows that although the pyramidality at the central carbon atom of the enamine group is small, it is consistently in the opposite direction to that of the nitrogen atom. The observed bond lengths and angles in the enamine moiety also
FIGURE 6. Newman's projection of enamines 17-23 looking down the N-S(sp2) bond. The C=C bond is maintained in the vertical position throughout. Reproduced with permission from Ref. 46.
show quite large variations. With decreasing pyramidality at the nitrogen atom, the enamine N-C bond distance decreased from about 0.142 nm to about 0.138 nm. The adjacent C-C single-bond distance decreases from about 0.151 nm to about 0.148 nm, while the C=C double-bond distance remains practically constant at about 0.134 nm (Table 7). An important result is the finding that one of the N-C(sp3) bonds tends to be syn-periplanar to the enamine C=C bond. V. CONFORMATION OF ENAMINES
Isomerization around a double bond may be regarded as a torsional process involving rotation around the a-bond axis in this system. Activation energies for thermal isomerization of alkenes are 104-270 k J m ~ l - ' ~ The ~ , ~delocalization ~. of the Relectrons of the double bond in the ground state of the molecule is expected to lower the activation energy for this process. In enamines, a simple resonance structure provides one way for a qualitative description of such a situation. In push-pull enamines the groups X1 and X2 are capable of stabilizing a negative charge, while the nitrogen atom, on the second trigonal carbon, bears a positive charge. The structure of 27 clearly implies reduction of the bond order of the formally localized double bond in 26 and a concomitant increase in the orders of the C-N and the C-Xi and C-X2 bonds. H H
- p;
R1-N
\
R2
X2
Rl-fi
x2 \
RZ (26) (27) The activation energy for a torsional process around a covalent bond depends, among other factors, on the r-electron density associated with this bond. It is of interest to investigate whether the energy barrier for rotation around a carbon+arbon double bond can be sufficiently reduced to allow the establishment of the dynamic equilibrium between the isomers 26 and 28 in the ground state of the system. The complete equilibrium must also include the transformations 26 P 29 and 28 P 30, which are associated with restricted rotation around the C-N bond (Scheme 1).
3. Configuration, conformation and chiroptical properties of enamines
231
An additional type of equilibrium, which may exist, involves the inversion of the pyramidal nitrogen atom. A. Internal Rotation about the C-C
and C-N
Bond In Enamlnes
Resonance structures 26 and 27 must be considered for the ground state of enamines. Hindrance of free rotation about the C-N bond is dependent upon the contribution of 27. The kinetics of this process have been studied by dynamic NMR spectroscopy. With the aim of simplifying the equilibrium system, many investigators have studied the compounds where X1 = X2 and R1 = R2. For such a case, the two types of equilibria, 26 # 28 and 29 F? 30, involve equivalent structures. In any of the equivalent conformers, the two constitutionally equivalent X groups are diastereomerically related in the minimum energy conformation (Emin) of the molecule (vide injra). They should therefore, in principle, exhibit two signals with different chemical shifts in the NMR spectrum. Similar analysis applies to the two R groups. The most striking feature in the NMR spectrum of such compounds is the reversible temperature dependence of the shape of the X and R signals. The general behaviour clearly indicates that the two X groups and also the two R groups are involved in a kinetic process whereby they exchange their identities. The free energy of activation for the observed process at the temperature of coalescence (T,) was calculated from the chemical shift separation of the two equal intensity signals (A6) at temperatures where the exchange is slow and from T,using the Eyring equation. The NMR results reauire that in the Em,.conformation of the two interchanging species 26 and 27, the two x groups should be"diastereomerically related. This can be realized either in a planar structure or, if steric interactions prevail, in a twisted conformation where the X-C-X plane makes an angle of any value, except 90 ", with the C=C-H plane. The 90 "C twisted form where the X group is enantiomerically related is probably the conformation of maximum energy required for the interchange of the two X groups. Similar symmetry analysis can be invoked to describe the conformations associated with the two interchanging R groups, as has been observed in the NMR. Certain qualitative correlations between AG' values, for the two rotational processes, and the electronic nature of the double bond substituents should be predictable. By a resonance argument, enhancement of the capacity of the X groups to stabilize a negative charge should decrease AG' for rotation around the C=C bond and increase AG' for rotation around the C-N bond. An inverted trend is predicted for R groups which are capable of interacting competitively with the nitrogen lone-pair. The rotational barrier about the C-N bond in vinylamine has been determined theoreticallys7 and experimentally5R-60.The barrier seems to be of the order of 18-25 kJ mol-I. Enamines are expected to show high barriers to rotation about their C-N bonds, especially when X' and X2 are electronegative groups, leading to stabilization of resonance hybrid 27. Molecular orbital calculations of rotation barriers around the carbon-nitrogen bond in thioamides, amidinium salts, amidines and enamines have been described by Sandstrom6'. 'sN-chemical shifts of enamines and closely related amines have been determined using lSN of natural abundance62. In order to eliminate substituent effects, differential chemical shifts A6(N) are defined as 6,(amine)-6,(enamine). This parameter is shown to correlate well with the free energy of activation AG for restricted rotation about the N-C bond of enamines with extended conjugation. The experimental results suggest that the differential lSNshifts are a useful probe to study n-n interactions in enamines.
TABLE 8. Barriers to rotation about the C-N bond of enamines Compound
T.("a
Solvent acetone-d, CHCl.
33
CDB~;
34
CDBr, CDBr, acetone-d, pyr~dlne/CHCl, acetone-d, cyclohexanone cyclohexanone Ph20 acetone acetone CHBr, CHBr, CHBr, acetone acetone acetone acetone
35 36 37
38 39 40 41 42 43 44 (R=OMe)
(R=H) (R=N02)
45 46 (R=Me)
(R=CH,Ph) (R=Ph)
+ 52
+ 52.5 +60 -55.5 +7 - 16.5 48.5 106 160 100 -50 77 90 137 - 76 -81 -71 5
+ +
+
+ + +
+
AG:
References
(kJ mol-')
69.0 72.3 75.2 43.5 61.4 56.0 71.1 84.4 89.9 82.1 47.8 77.5 81.3 92.6 41.9 41.1 41.9 57.4
63 63 63 63 63 63 63 63 63 64,65 64,65 64,65 M,65 64,65 64,65 64.65 64.65 64,65
The kinetics of the rotation about the C-N bond in hindered systems have been studied by Mannschreck and Klle63. AGf values evaluated from the 'H-NMR methyl signals (see Table 8) indicate that the rate of rotation in enamines 31-35 depends upon the electron-attracting properties of the substituents. In 36 and 37 the benzo ring reduces the rotational barriers by 9.7-12.5 kJ mol-' as compared to 38 and 39. A formyl group raises the free energies of activation by 13.3-17.9 kJ mol-', as can be seen in the table by comparing 36 to 37,38 to 39 and 39 to 40. If one of the N-methyl groups is replaced by another substiluent, rotational isomers are possible. It will be difficult to separate such isomers in systems like 40 or 41, since the AG'; values for the isomerization are expected to be only 84.4 or 89.9 kJ mol+ In the cyanine dyes Me,N(CH=CH),CH=NMe, the activation free energy decreases from 71 to 42 to 29 kJ mol-' as n increases from 1 to 2 to 366.
'.
3. Configuration, conformation and chiroptical properties of enamines
Me
233
Me
")(hw, Mex"
COOMe
COOMe
MeOOC
COOMe
B. Enamines with High Barrier to Rotation
Mannschreck and Klle6' examined various systems in which the dipolar structure was stabilized by delocalization of the negative charge to the other end of the enamines. A high barrier to rotation of 105 kJ mol-' at 185 "C was estimated with 2,3-diformyl6-dimethylaminofulvene (40), and for 4-(dimethylaminomethylene)-1,2-diphenyldiazolidine-3,5-dione (47) the barrier was 90 kJ mol-' at 160 "C. In 1969 Mannschreck and Klle were able to isolate atropisomers of 4-(N-benzyl-N-methy1aminomethylene)-1,2diphenyl-1,2-diazolidine-3,s-dione(48). The E-isomer was isolated in a pure form and the 2-isomer was 93% pure. An equilibrium mixture in CDCI, solution at 28.5 "C contained 40% 2-48 and 60% E-48. To distinguish the barriers to rotation about the C=C and C-N bonds, the barriers were obtained with a compound carrying an N-methyl group instead of one of the phenyls on the nitrogens in the ring. The barrier to rotation about the C-N bond was 89.2 kJ mol-'. and that about the C=C bond
,Ph
Ph,
Ph 0 I
I
was 80.4 kJ mol-'. Mannschreck and coworkers6' were able to isolate a series of compounds 49 and 50 in the crystalline atropisomeric form.
(50) R' = ~ h R2 , = Me R' = Ph, R2 = CH2Ph R' = Me, R~ = CHZPh
C. Enamines of Cyclic Ketones
The enamines derived from five, six- and seven-membered ring ketones have been extensively studied, especially those of the six-membered ringh9.Mixtures of structurally isomeric enamines are usually obtained; the isomer distribution varies with the amine used (Tables 9 and 10).These differences can be attributed to different conjugating ability and steric requirements of the amine moiety. In the ground state these steric interactions can be reduced by rotation about the N-C(spZ) bond; however, this will reduce the nitrogen lone-pair interaction with the double bond. A('.Z) and A(183)strain will help determine which is the most abundant conformer at equilibrium, and can be a factor in determining the direction from which a reagent attacks the carbon-carbon double bond. The strain, involving a substituent on the alkene-carbon of cyclohexane ring (NR,) and a pseudoequatorial substituent on the adjacent alkane carbon (R1), is called A(lsz' strain (strain between groups on adjacent or 1- and 2-carbons of an allylic system). If NRz'and R1 are large, they will interfere with each other sterically to such an extent that a conformer 51 having an axial substituent will be the favoured form. The second
type of strain ( A l s 3strain) involves groups syn to one another on the C, and C , positions of an allylic system. 1. 2-Substltuted cyclohexanones
Enamines derived from Zsubstituted cyclohexanones can and do exist as a mixture of the more (52) and less (53) substituted double-bond isomers. The isomer ratio is determined by various steric and electronic factors which affect the overlap between the nitrogen lone-pair and the double bond of the enamine. In general, the greater the overlap, the greater the proportion of less substituted double-bond i~omer'~. The large steric interactions between the groups on nitrogen (R1 and Rz) and the substituent on the cyclohexane ring as in 52a precludes both their coplanarity and a
3. Configuration, conformation and chiroptical properties of enamines
235
TABLE 9. Isomer distribution of ena~ninesof 2-methylcyclohexanone -
Amine precursor
Trisubstituted isomer (%)
Dimethylamine Diethylamine Pyrrolidine Piperidine Morpholine 2,6-Dimethylpyrrolidine N-Methylaniline
60 25 90
-
Tetrasubstituted isomer (%)
Reference
46
52 10 0
high degree of overlap. Consequently, the groups twist out of coplanarity, thereby relieving the steric interactions, but overlap stabilization is lost as shown by 52b.
Isomer 53 with the R group axial is free of this steric interaction and so it can maintain the coplanarity and a high degree of overlap. It has, however, gained a 1,3-axial R-H steric interaction. Loss of the overlap stabilization makes 52 a higher energy form than 53 and so 53 should predominate. When the amount of overlap in either form is low, 'normal' double-bond stabilities should prevail and the more substituted doublc-bond isomer 52 should predominate. Furthermore, since the amount of overlap is the amount of double-bond character exo to the amine ring, it should be related to the exo double-bond stabilities of five- and six-membered rings. In the same series (in this case, the enamines of 2-methylcyclohexanone) one would expect dialkylamines to be intermediate between five- and six-membered ring mines, since in the five-membered ring overlap is favoured because of the increase in exu double-bond character, while in a six-membered ring overlap is disfavoured because of the resistance to increase in the exo double-bond character; with a dialkylamine, neither of these factors are operative (Table 9). Pyrrolidine enamines of 2,4-disubstituted cyclohexanone~'~ exist principally in the isomeric form 54 that has the 2-alkyl group quasiaxially oriented.
In the pyrrolidine enamine of 2-methyl-4-t-butylcyclohexanone the methyl group is largely axial1'. The morpholine enamine of 2-methyl-4-1-butylcyclohexanoneexists as an isomeric equilibrium mixture ofX54% trisubstituted enamines 55 and 56 and 46% tetrasubstituted enamine 57. The distribution between quasiequatorial and quasiaxial trisubstituted isomers is 1:1 (i.e. the mixture contains 27% of each)''.
The pyrrolidine or N-methylpiperazine enamines of 2-alkylcyclopentanones exist principally in the trisubstituted form7". 2. 3-Substituted cyclohexanones
The preponderance of the A6 isomer in an equilibrium mixture of the pyrrolidine enamine of 3-methylcyclohexanone can be attributed to A".z' strain (2.M.3 kJ mol-') between the quasiequatorial methyl group and the vinylic hydrogen atom in the A' i ~ o m e r ~ ~Equilibrium -~'. between the A' and A6 isomers of 3-substituted enamines takes place very readily at low temperature^'^-^^. When conjugation of the enamine with a 3-substituted aromatic ring is made possible, the A' isomer is the predominant isomcr81-89
Rotational barriers in simple enamines of cyclohexanone have not been systematically studied. It is only known that 1-diethylaminocyclohexene adopts a near-coplanar conformation at the N-C(spZ) bond with a 24.9 kJ mol-' n-barrier to rotation through an orthogonal conformation with the lone-pair in the x-plane. In contrast, l-diethylamino-2-methylcyclohexene adopts a non-planar conformation with the lone-pair to the n-plane and a steric barrier of the diethylamino group through the plane, of 33.9 kJ m ~ l - " ~ .The balance between the factors favouring the more and the less substituted enamines is clearly a delicate one, though from a practical point of view it must be kept in mind that the ultimate product ratio from a reaction is determined by a combination of starting material composition and the relative reactivity of the two enamines. As a general rule, the more substituted the enamine, the slower it undergoes ~eaction~~.~~. VI. CONFIGURATION AND CONFORMATION OF 'PUSH-PULL' ENAMINES
The spectral properties of enamines having one or two electron-withdrawing groups, usually acyl, phenyl, nitro, cyano or ester substituents, so called 'push-pull' ena m i n e ~ ~ ' -have ~ ~ , been extensively investigated due to the information they provide on the electronic distribution in such mesomeric systems, and on their static and dynamic conformational properties95 NMR spectroscopy has been the most popular technique for these studies.
3. Configuration, conformation and chiroptical properties of enamines
237
A. Enamlnoketones and Enamlnoesters
Enaminoketones and enaminoesters of formula 58a,b are planar, or nearly planar, mesomeric systems which can exist in several configurational and conformational isomeric forms due to restrictions to rotation around the C=C double bond and the C-N and C-C=O single bonds (cf equation 4).
Simple N,N-disubstituted enaminoketones seem to exist in solution predominantly in the E-form (59) with respect to the double bond. The situation is different with N-monosubstituted or with unsubstituted enaminoketones, in which the Z-form (60) is
- ' ~ 'Filleux-Blanchard stabilized by hydrogen bonding. Dabrowski and c ~ w o r k e r s ~ ~and and coworker^^^^^^^^ have found that the E-form with respect to the Cl=C, bond dominates when R1 = H, but that the Z-form gradually gains when the size of R1 increases. The E + Z barrier decreases in the same series, indicating increasing groundstate strain and nonplanarity of the E-form. The rotation of the amino group is hindered'8t'04~L0s and the barrier has been shown to diminish with increasing size of R', that is, with increasing deviation of the acyl group in the E-form from the plane (Tables 10 and 11). The E e Z isomerization in several such compounds has been studied in different solventsLo6.The rate of N H proton exchange was followed simultaneously using the N-Me doublet. The two processes were found to have very similar free-energy barriers (ca 84 kJ mol-') which indicates that the E + Z isomerization may not be a true double-bond rotation, but may proceed via one of the possible tautomeric forms with a C,-C, single bond, a mechanism proposed earlier by I-luisgen and coworkers107for 8-aminoacrylates. For these compounds a lower limit to the barrier to uncatalysed rotation was found to be 110 kJ mol-', but significantly lower barriers were observed in the presence of traces of acid, True double-bond rotation with low barriers1'' has been proposed for compounds 61 (AG' 47 kJ mol- ') and 62 (AGt 58 kJ mol- I).
TABLE 10. Barriers to rotation about the C,-C2 bonds in enamines AGz (c3
+
R
Solvent
c2)
E +Z
T("C)
AGt (C,-N)
T ("C)
P$
Reference
"p, is the fractional population.
In diacylenamines several authors have observed fast thermal isomerization at the double bond, using the DNMR technique. The IR, Raman and 'H-NMR spectra and the X-ray crystallographic study of 2,2-diacetylethenamines (63)and 2-aminomethylene-5,5-dimethylcyclohexane-1,3-diones (64)show that these substances exist exclusively in the chelated enamino-diketone form, and that the conjugated system contained in them is essentially planar. The open-chain enamino-diketones 63, exist either in the solid state or in solution in the (E,Z,E) conformation (65).A similar conjugated core, having the fixed (Z,Z,E)conformation (66).
TABLE 11. Barriers to rotation about the C-N
Me Me Me Me Me Me Me Me Me
Me Me D-MeOHC,H. -~ "--., Ph p-02NC6H, Me pMeOC,H, Ph p-OINC6H, ~
and C-C
bonds of 'push-pull' enamines
X1
X2
AScps
T,("C)
AGt (kJmol-')
COOEt COOMe COOMe -~ COOMe COOMe COMe COMe COMe COMe
COOEt COOMe COOMe COOM~ COOMe COMe COMe COMe COMe
3.4 5.0 8.2 7.2 5.5
22.0 18.5 76.5 90.0 137.0 < -40 - 30 -6.5 42.5
66.9 65.2 77.3 81.0 92.3 < 50.2 54.3 58.1 70.6
~
~
5 6.2 4.8
Agcps
K , "C
AGi kJ mol-'
Solvent
21.7 22.8
- 13.5
54.3
CH,CI,
53.9
CHB~: CHB~; CH,Cl, CH2CI, CH2CI, CH2C12
33.9
-11.0
contained in 5-aminomethylene-2,2-dimethyl-1,3-dioxane-4,6-diones is most probably planar or near-planar. The (E,Z,E) and (Z,Z,E) alignments of the enamino-diketones can be distinguished by their spectral properties and, particularly, by their vibrational spectra'Og. The X-ray structure a n a l y ~ i s l of ' ~ 64 shows that the (Z,Z,E)-enaminodione moiety is strictly planar, and that the cyclohexane-l,3-dione ring adopts a half-boat conformation, with C,-C4 and C , in the plane and C, above it. N-Substituted 3-aminocrotonic esters (67) tend to adopt a planar or near-planar structure. As a consequence of their push-pull nature these molecules show an increased facility for 2-67-E-67 isornerization around the C=C double bond as well as restricted rotation around the C-N and C-COORZ single bonds. The IR and 'H-NMR spectra of simple 3-(alkylamino)crotonicesters have shown that these substances exist either in the liquid state or in solution as equilibrium mixtures of the Z and E configurations, respectively. The position of the equilibrium is solvent-dependent, and the energy difference between the isomers varies from ca 7.3 kJ mol-I in non-polar solvents to ca 0.8 kJ mol-' in dimethyl sulphoxide, the intramolecularly bonded 2-form 68 or 69 being the most stable'"-'13.
Ethyl 3-(ben~ylamino)crotonate(67) R' = CH,Ph, R2 = Et) can be obtained in two crystalline forms114, which on the basis of their spectra and other physical evidence were shown to be the Z- and E-isomers. On the other hand, 3-aminocrotonic esters with primary amino groups exist in the liquid state and in solution almost exclusively as the isomers with the chelated 68 Z (R1 = H) c~nfiguration"~. Thus, the introduction of an alkyl substituent on the nitrogen destabilizes the Z-form, and this effect was considered to be due to the steric compression arising between the N-alkyl group and the =CMe group that can compromise the chelation energy. On the other hand, the data existing on 3-aminocrotonates bearing an electron-withdrawing substituent on the nitrogen indicate that the chelated Z-form is again much more stable than the E-form116 'I8; apparently the very strong hydrogen bond existing in these compounds overcomes all other unfavourable factors. Spectra of 3-(dialkylamino)crotonates 70 indicate that these substances exist as the isomer with the E-configuration. The low-temperature 'H-NMR spectra reveal the existence of barriers to rotationu9 around the C-N bond which amount to ca 4&58 kJ mol-'. The NMR spectra of N-mono (71, R' = H; RZ = alkyl,aryl) and disubstituted (71, R1 = RZ= alkyl, aryl) 3-amino-2-cyano acrylic esters indicate that these substances exist
3. Configuration, conformation and chiroptical properties of enamines
241
in the solid state or in solution either in the E- or the 2-71 geometric forms or as a mixture of them. Interconversion of the isomers was observed in some cases, the intramolecularly bonded 2-72 form being the most favoured in the case of the N-aryl derivatives. The variable-temperature NMR spectra of the N-dialkyl dcrivativcs show hindered rotation around the C-N singkbond, with an energy barrier of approximately 71-75 kJ mol-' at the coalescence temperatures (65-85 "C)51.'20. H COOEt \ / F'C \ RIRZN CN (71) E
H \ /c=C R'R2N
CN H \ 1 ,C=C
CN
/
\
COOEt
\
Ri-N \
H-0
(71) Z
IFoEt
(72)
The spectra of 2-alkoxycarbonyl-3-aminoacrylic esters (73, R1 = H, alkyl, aryl) show that these substances exist in the enamino-ester form with a strong intramolecular Z, E) and hydrogen bond between the amino and COOR2 groups. Conformers 73a (Z, 73b (E,Z,E)predominate in non-polar media; conformation 73b is also probably present in polar solvents and is preferred in the solid statelog. (The symbols indicate, in the order shown, the alignments of the free C=O, the bonded C=O and the R1 group with respect lo the carbon-carbon double bond.)
0
\C
H -0R2 \ I ,C=C \ R'N C-OR2 \ // H-0
(73a)
R20 \ H /C=0 \
F=C R'N
\
oC -OR' \
H-0
(73W
Several compounds of the type 74 and 75 with aliphatic and aromatic N-substituents show double-bond rotation with barriers in the range of 80 to 38 kJ mol-', while NMez torsional barriers are f ~ u n d ' ~ ~in' ~ the ' range of 73.7 to 38 kJ mol-'. When R = Me, all barriers are lower than when R = H. When R1 (R2) is aromatic, a decrease in the C-N and an increase in the C=C barrier is observed.
8. Nitroenamines
Nitroenamines are useful intermediates in synthetic organic chemistry1zz. They are typical push-pull ethylenesg5 and the E-Z isomerization is generally characterized by low-energy barriers. Nitroenamines containing a primary or a secondary amino group lead to more complicated systems than the tertiary derivatives since intramolecular hydrogen bonding between the amino and nitro groups may be formed, the Z-isomer being favoured in these cases. An additional proton-accepting group on the carbon substituted by the nitro group leads to molecules in which both configurational isomers have hydrogen-bonding interactions, and prediction of the isomer ratio is more difficult. 1-Amino-2-nitroethenes(76, R1 = H) and 1-amino-2-nitroprop-l-enes (76, R1 = Me) can exist in the four isomeric forms ( Z ) 76a,b and (E) 76c,d (equation 5).
(76~)
(76d)
The simplest nitroenamine, i.e. 1-amino-2-nitroethene (76, R1 = RZ = R" = H), exists as a solvent-dependent equilibrium mixture of the Z- and E- formslZ3,the proportion of the latter increasing with the polarity of the s o l ~ e n t ' .~M~ethylation ~ ' ~ ~ of C, causes an increase in the stability of the Z-form, while alkylation or arylation at the amino nitrogen stabilizes the E-form. In polar solvents, the proportion of the E-form in the compounds with secondary amino group increases with the hydrogen-bond donor capacity of the amino function. This isomer can exist in the Z- and/or the Econformation around the Cl-N single bond, the proportion of the rotamers being dependent on the steric requirement of the RZNH group. The energy of the intramolecular hydrogen bond of the Z-form of these compounds with primary or secondary amino groups increases in the order NH, < MeNH < PhNH, and on methyl substitution at C,. The energy barrier to rotation around the C=C bond decreases by increasing the n-donor capacity of the substituent at the amino function and by the introduction of the C,-Me group; comparison of these barriers with the AG' values for the exchange of the amino proton indicates that, in l-methylamino-2-nitroprop-lene, the Z # E isomerization takes place by a thermal mechanism via a dipolar transition state (equation 6), while in the more acidic I-amino-2-nitroethene and its N-methyl derivative both the thermal mechanism and an anionic mechanism (equation 7) contribute to the isomerization process. Compounds with a tertiary amino group exist exclusively in the E-form. In these compounds, the energy barrier to rotation around the C,-N bond decreases with the increased polarity of the solvent.
3. Configuration, conformation and chiroptical properties of enamines
243
(6) MeNH
N@
MeNH
MeNH
H
\\
xH x"@ H
H H-N
NO2
\
H
A-@
dl
H-N
\
H
H
Calculations of Gate and coworkers126 suggest that the intramolecularly bonded Z-isomer of N-methylamino-2-nitroethene is the most stable isomer. In compounds 77 (R = H, Me) with a second electron-withdrawing group, four planar isomers 77a (EE), 77b (EZ),77c (ZE) and 77d (ZZ) are theoretically possible. However 77a, which a priori is expected to be less stable, has never been d e t e ~ t e d * ~ ' . 'The ~~. presence of the other three isomers, with strong intramolecular hydrogen bonds, has been demonstrated for compound 77, R = H (equation 8). In compound 77, R = Me,
the steric hindrance introduced by the methyl group at C, precludes the existence of a planar structure in the Z-configuration and it has been proposed that this compound exists in solution as a mixture of the planar (EZ) and a non-planar (Z, quasi-s-cis) isomers 78.
Mex-OMe '
H-N
N-O-
H-0
//
1. Effect of solvents on configuration of nitroenamines
The effect of solvents on the configuration and conformation of structurally related nitroenamines 79-82 have been studied129. Compounds 76 exclusively adopt the Z configuration when dissolved in chloroform, but the Z / E ratio decreases when the solvent polarity increases, being 3: 1 in MeOH and 2: 1 in DMSOIZS.Compound 79, R' = RZ = H, R3 = OMe, as well as its N-methyl derivative 79, R1 = H, R2 = Me, R3 = OMe, give a 1:l ratio of the configurational isomers in chloroform, but in more polar solvents, such as dimethyl sulphoxide, the equilibrium is shifted towards the Z-forms, especially favouring the Z E - i s o m e r ~ ' ~ ~ . ~ ~ ~ . Compounds 79, R1 = R~ = H,R3 = OMe, and 8U R' = RZ = Me, R3 = OMe, adopt only one in each of the Z- and E- configurations. The former, having the ester group non-coplanar with the rest of the conjugated system, predominates in non-polar solvents. The N-alkyl derivatives of 81, R1 = H, R2 = Me, R3 = Me, and 82, R1 = RZ = Me, R3 = Me, exist preferentially in the EZ-form in chloroform solution134,I35 The Z F+ E isomerization of enamines with primary or secondary amino groups may proceed either through a thermal mechanism or by a proton-exchange reaction involving the anion13'. The calculati~nsperformed favour the thermal isomcrization, therefore
Rko KR3 0
R' RZ-N
\\
N-O-
H '
o/
R2-N
N-0-
H '
dl
(W
3. Configuration, conformation and chiroptical properties of enamines
245
the results should be comparcd with the experimental information concerning this found for compound 79 (R' = RZ = H, mechanism. In acetonitrile, the R3 = OMe) is greater than 87.8 kJ mol-', and for compound 79 (R1 = H, R2 = Me, R3 = OMe) it is 75.2 kJ mol-'. For the N-methyl derivative of 81 the barrier in o-dichlorobcnzcne is 79.4 kJ mol-'. Qualitative estimations for compounds 79 (R' = R2 = H, R3 = OMe) and 80 indicate barriers close to 42-46 kJ mol-' and 33.4-37.6 kJ mol-', respectively, in chloroform. VII. STEREOCHEMISTRY OF METALLOENAMINES'~~
The pioneering work of Stork and coworkersi39 and Wittig and coworkersi40 on the metallation of ketimines, and their subsequent reaction with a variety of electrophiles, has proven extremely useful for controlled aldol condensation and also for regioselective functionalization of ketonesi4'. Recently, reactions of chiral lithiated ketimines and aldimines have been established as an important method of asymmetric synthesis, producing chiral ketones in optical yields as high as 95%i42-i45. Various names have been used to describe the anions derived from imines including rnetalloenarnine~'~~, metallated Schiff bases14", or imine anion^'^'.'^". In the last ten years the stereo- and regiochemistry of formation of imine anions has been extensively investigated. A problem of interest is the question of the hybridization at nitrogen, whether it is sp2 as in enamines, with lone-pair-n-system overlapI4' (83), or sp3 with metal (e.g. lithiumtnitrogen-a-pair-rr system overlap'42 (84).
A theoretical study of dimeric ion-pair aggregates of isomeric lithioa~etaldimines'~~ and an ah initio study of the potential energy surfaces of isolated aldimine anions, their monomeric lithium and sodium ion-pairs and mechanistic consequencesis0 have been described. Knorr and L0w15' demonstrated that metallation occurs rapidly and quantitatively, that protonation of the imine (85) is a kinetically controlled process favouring the formation of the E-isomer about the C=C bond (86), that the anion is configurationally stable under the conditions generally used for its formation and that the E-anion
could be isomerized slowly but quantitatively to the thermodynamically more stable Z-anion (87) at 60 OC in the presence of additional free imine, acting as an acid catalyst. The kinetically controlled N-protonation of these lithium derivatives leads almost quantitatively and stereospecifically to secondary enamines 88 and 89 of considerable stability with retention of the isomer ratio (equation 9). Fraser and coworkers'52 examined the lithiation and alkylation of aliphatic ketimines of cyclohexanone 90 and found that the reaction proceeded to give >99% syn and axial isomer 91. Although some anti-axial (92) and anti-equatorial (93) alkylation products were also isolated, this was attributed to isomerization of the syn-axial product. Similar results were obtained on alkylation of aliphatic aldimines which have been shown to give syn and anti products in a 96:4 ratio'53. The electronic factor responsible for the preferential stabilization of the syn, or destabilization of the anti, lithiated aldimine was estimated to have a magnitude of at least 18 kJ mol-I.
In contrast to acyclic or exocyclic ketimines, it was shown that endocyclic ketimines give exclusively anti alkylation via the anions shown in equation 10'54.This reversal of stereochemical preference was attributed to the very large CCN bond angle (113 ") calculated for the syn anion. Constraint of this angle to 120" was calculated to result in a 28 kJ mol-' increase of energy. In anions derived from an endocyclic imine, the ring would constrain the CCN angle to 120 " or less, thus resulting in appreciable angle strain in the syn anion and destabilization relative to the anti anion, which consequently becomcs thermodynamically favoured.
With oximes and 0-methylated oximes, deprotonation has been shown to occur exclusively syn to the oxygen'55. Deprotonation of unsymmetrical imines occurs with at least as high, and the same sense of regioselectivity as observed with ketones, i.e, the least substituted carbon is deprotona~ed'~~. VIII. STEREOCHEMISTRY OF THE CARBON-NITROGEN DOUBLE BOND IN ENAMINES
Z-E Isomerism is to be expected for structures with an immonium double bond
I
(equation 11). The immonium &N+ I I
II
bonds in many compounds have a 'partial'
double-bond character. As a result of numerous NMR investigations, partial C=N double bonds in amidines, imidates and related compounds are among the most extensively studied types of bond^'^^^'^^. The rotational barriers in amides'5'.160 with a double-bond order of about 40% amount to 71-101 kJ mol-', depending on the nature of the substituents. The double-bond order in guanidinium ~ a l t s ' ~ ' is , ' expected ~~ to be less than about 33%. and rotational barriers of 42-84 kJ mol-' have been
3. Configuration, conformation and chiroptical properties of enamines
determined for these compounds. Extrapolation to the 'pure' -C=NI
+ I
247
double bond
leads to a barrier of the order of 190kJ mol-I or higher. his 'is in agreement with the findings of DNMR studies of C,C-dialkylimmonium salts in which no rotation salts (94), which are rclativcly about the double bond was f o ~ n d ' ~ ~, Im . ' ~monium ' stable, have been detected in solution by NMR16"'0, and in some cases the structure of the solid has been elucidated by X-ray analysis'69. Single-crystal X-ray diffraction studies1" have been carried out on N,N-dimethylisopropylidenimoniumperchlorate (95).
The tetragonal crystal showed a,planar imrnonium ion with
I distance of &f3 nm DK I I
and C-Me and N-Me distances of 0.151 nm. The C-C-c and Me-N-Me angles are both 125.4 ",and both Me-N-C angles are 117.3 ". The crystal structures of N-phenyl-3-@-ch1orophenyl)-2-propenimine (96) and Nmethyl-N-phenyl-3-@-chlorophenyl)-2-propenimmonium perchlorate (97) have been determined by single-crystal X-ray techniques. Both compounds exist as monoclinic crystals, space group P2&, with four molecules per unit cell172.The I3C-NMR spectrum of imminium perchlorate (97) was also obtained in the solid state by using the cross-polarization magic-angle spinning (CPMAS) technique. The overall conformations of 96 and 97 are similar despite the quite different crystal-packing arrangements in these rnolccules. It is the first opportunity to compare the structure of an imine and its immonium salt directly. N-Acylimmonium ions are becoming important intermediates in synthetic organic ~ h e r n i s t r ~ " ~ -The ~ ~ ~differential . NOE spectra of 98-100 (X = M,Me,OMe) were obtained at - 55 "C in CDCI,"% The more easily rotating immonium salts 101-103 have been prepared163,177.
xqH N+
~ e /'COOMe
IX. IMPORTANCE OF ENAMINES IN ASYMMETRIC SYNTHESIS AND THEIR CHIROPTICAL PROPERTIES A. Optically Active Enamines
There are numerous reactions in which enamines and enamine derivatives, such as metalloenamines, are used for the synthesis of enantiomerically pure compounds (EPC synthesis)"8~i79.In principle, such EPC synthesis could involve a chiral amine component of the enamine reacting with an achiral clcctrophilc or an achiral enamine reacting with a chiral electrophile. The cyclohexenamines seem to be the preferred test objects for this kind of reaction; enamines of open-chain ketones and aldehydes have been investigated only rarely. Examples are chiral enamines from substituted pyrrolidine 104'"0-' (R = CH20Me, CH20SiMe3,COOMe), 105i78.'84-186(R = Me,CH,OMe), (R = Me,CH,OMe) and phenylethylamine 107. piperidine
The process of enamine alkylation has found widespread application in natural product synthesisi8*. Since the overall sequence involves the reaction of a nitrogen moiety with a ketone to form a reactive intermediate, modification of the process through the use of chiral enamine seemed ideal for asymmetric induction. Previous attempts to obtain stereochemical control were for a long time unsuccessful, because proper attention had not been directed to the involvement of two reactive conformations, interconvertible
3. Configuration, conformation and chiroptical properties of enamines
249
by rotation about the CN bond'sg. A simple solution to this problem involved the use of a chiral amine with a local C, symmetry element present about the nitrogencontaining portion of the enamine. Indeed, the trans-2,5-dimethylpyrrolidineenamine of cyclohexanone (105, R = Me) underwent alkylation with quite satisfactory levels (ca 90%, e.e.) of asymmctric i n d u c t i ~ n ' ~ ~ . In a related approach, Whitesell and White~ell'~'and others'92 have examined the alkylation of the analogous imine anions (108) where bulky ligands about the metal are in a chelated form. Enantioselective reactions have also been reported for the hydrolysis of enamines containing a chiral amine moiety via protonation or of prochiral enamines by the use of a chiral acid. Other asymmetric reactions are summarized in an excellent review by Seebach and ~ o w o r k e r s " ~ and by Oare and Heathcock'"'.
6. Chiroptical Properties of Enamines
The R-&OR
as well as R-4-NR2 I
(R
=
alkyl) chromophores absorb only in
the low-wa:elength UV region of the spectrum: the former absorbs much below 190 nm, and the latter between 19@200 nm. The absorption maxima are associated with the lone-pair of electrons on the oxygen or the nitrogen atoms, the latter being more readily excited from their ground state to the antibonding orbital; When oxygen or nitrogen atoms are linked to a doubly bound carbon atom, the resulting unsaturated chromophores possess a high-wavelength UV absorption band. The en01 ethers absorb at ea 190 nm and the enamines at ca 21Cb230 n ~ n ' ~the~ 8, values of the two being between 5000-10,000. The absorption bands of enamines were assigned to a n-n* transition as in the corresponding alkenes, a resonance effect with the heteroatom being mainly responsible for the red shift.
200
250
300
350
400
A
(nm) FIGURE 7
There is only little information about ORD or CD of simple enamines. The ORD curves of (3N-pyrrolidyl)-Su-androst-2-en-17~-ol acetate (109) and of 4-methyl-4-azaandrost-5-en-17p-01acetate (110) were also investigatedLq5.The enamine 109 shows a high 228 nm, with e 8000 (cyclohexane). The absorption band in the UV spectrum at A,, 221 nm, E 8500 in cyclohexane; cyclic enamine 110 possesses a similar UV spectrum (A, , I , , :219 nm, e 8700 in ethanol). On the othcr hand, only the cyclic cnaminc 110 shows a h ~ g hCotton effect (Figure 7). The shape of this ORD curve indicates that the tint Cotton effect is negative, and is then followed by a second positive effect. The remarkable difference in the ORD curves of two enamines 109 and 110, despite their similar U V spectra, may be traced to the differences in steric repulsion of the p, orbital of the nitrogen atom, and the n-orbital of the double bond. Since free rotation along the C-N bonds in the cnamine 109 is possible, the N-C=Csystem becomes planar and the
.....
,
FIGURE 8
3. Configuration, conformation and chiroptical properties of enamines
251
transition is devoid of a magnetic moment. However, in enamine 110 the nitrogen is fixed in a ring, the relevant orbitals are non-planar (Figure 8) and the chromophore becomes inherently asymmetric. X. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
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3. Configuration, conformation a n d chiroptical properties of enamines
253
1. Dabrowski and L. J. Kozcrski, Org. Mayn. Rrsorr.. 4. 137 (1972). L. J. Kozerski and J. Dabrowski, Org. Magn. Heson., 4, 253 (1972). J. Dabrowski and K. Kamienska-Trela. Ora. Muon. Reson.. 4. 421 119721. ' L. Kozerski and J. Daborwski, Org. ~ = q n . - ~ e s o n5,. , 459 (1973). J. Dabrowski and L. Kozerski, Org. Magn. Reson., 5, 469 (1973). M. L. Filleux-Blanchard, F. Clesse, J. Blanchard and G. Martin, Tetrahedron Lett., 981 (1969). M. L. Filleux-Blanchard, H. Durand and G. J. Martin, Orq. Maqn. Reson., 2, 539 (1970). M. L. Filleux-Blanchard, F. Mabon and G. J. Martin, Tetrahedron Lett., 3907 (1974). E. C. Taylor and J. Bartulin, Tetrahedron Lett., 3259 (1967). E. Czerwinska, L. Kozerski and J. Roksa, Org. Magn. Reson., 8, 345 (1976). K. Herbig, R. Huisgen and H. Huber, Chem. Ber., 99,2546 (1966). D. Smith and P. 1. Taylor, Spectrochim. Acta, 32A, 1489 (1976). A. Gomez-Snncher E. Sempere and J. Bellanato, J. Chem. Soc., Perkin Trans. 2,561 (1981). M. J. Dianez, A. Lopez Castro and R. Marques, Actn Crystallogr., Sect. C, 41, 149 (1985). A. Gomu-Sanchez and A. M. Valle, J. Chem. Soc ( B ) , 2329 (1971). G. 0.Dudek and G. P. Volpp, J. Am. Chem. Soc., 85,2697 (1963). A. Gomez-Sanchez, M. T. Aldave and U. Scheidegger, J. Chem. Soc. ( C ) , 2570 (1968). R. Mohlau, Chem. Ber., 27, 3376 (1894). A. Gomez-Sanchez and A. M. Valle, J. Chem. Soc., Perkin Trans. 2, 15 (1973). G. de Stevens, B. Smolinski and L. Dorfman, J. Orq. Chem., 29, 1115 (1964). W. Werner, Tetrahedron, 27, 1755 (1971). A. Gomez-Sanchez, M. T. Aldave and U. Scheidegger, Carhohydr. Res., 9, 355 (1969). A. Gomez-Sanchez and J. Bellanato, J Chem. Soc, Perkin Trans. 2, 1975 (1975). A. Gomez-Sanchez and P. Borrachero, An. Quim., 70,.1186 (1974). Y. Shvo and H. Shanan-Atidi, J. Am. Chem. Soc., 91,6683, (1969). S. Rajappa, Tetrahedron, 37, 1453 (1981). J. L. Chiara, A. Gbmez-Sanchez and J. Bellanato, J. Chem Soc., Perkin Trans. 2, 1 (1992). A. I. Fetell and H. Feuer, J. Org. Chem., 43, 497 (1978). A. Krowczynski and L. Kozerski, Synthesis, 489 (1983). E. N. Gate, M. A. Meek, C. H. Schwalbe, M. F. G. Stevens and M. D. Threadgill, . J. Chem. Sot., Perkin Trans. 2, 251 (1985). 127. 1. L. Chiara, A. Gomez-Sanchez, F. J. Hidalgo and J. Bellanato, J. Chem. Soc., Perkin Trans.
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2. 1691 (1988). 128. J: L. ~h:lara,A. Gbmez-Sanchez, E. Sanchez-Marcos and J. Bellanato, J. Chem. Soc, Perkin Trans. 2, 385 (1990). 129. E. S. Marcos, J. J. Maraver, J. L. Chiara and A. Gomez-Sanchez, J. Chem. Soc, Perkin Trans. 2, 2059 (1988). 130. V. I.Bakhmutov and E. I. Fedin, Bull. Magn. Reson., 6, 142 (1984). 131. Y. A. Borisov, K. K. Babicvski, V. I. Bakhmutov, Y. T. Struchkov and E. I. Fedin, Iza. Acad Nauk SSSR, Ser. Khim., 123 (1982). Engl. Transl.: Bull. Acad. Sci. USSR, Div. Chem. Sci., 31, 115 (1982). 132. J. L. Chaira, A. Gomez-Sanchez and F. J. Hidalgo, J. Chem. Soc., Perkin Trans. 2,1691 (1988). 133. J. L. Chiara. A. Gomez-Sanchez. E. S. Marcos and J. Bellanato. J. Chem. Soc.. Perkin Trans. 2, 385 (1990). 134. T. Tokumitsu and T. Hayashi, Nippon Kagaku Kaishi, 88 (1983); Chem. Abstr., 98, 197557q 119831. --,~ 135. J. Bellanato, A. Gomez-Sanchez and J. L. Chiara, Publicado en la Reoista, Fisicas y Naturalis, de Madrid. 81(2) 383 (19871: Chem. Ahstr.. 110. 7491i (1989). 136. V. I. ~akhmuio; and‘^. *~urmistrov, org ~ a ~ n . . ~ e s o12, n , 185 (1979). 137. V. I.Bakhmutov, K. K. Babievskii, V. A. Burmistrov, E. I. Fedin and V. M. Belikov, Izu. Akad. Nauk SSSR, Ser. Khim., 2719 (1978); Engl. Trans.: Bull. Acad. Sci. USSR, Div. Chem. Sci., 27, 2426 (1982). 138. J. K. Whitesell and M. A. Whitesell, Synthesis, 517 (1983). 139. G. Stork and S. R. Dowd, J. Am. Chem. Soc., 85, 2178 (1963). 140. G. Wittig, H. D. Frommeld and P. Suchanek, Angew. Chem., 75,978 (1963); Angew. Chem., mt. ~ d Eng/., . 2, 683 (1963). 141. P. A. Wender and J. M. Scahus. J. Ora. Chem.. 43. 782 (19781. , , 142. A. I.Meyers, D. R. Williams and M. 6rueling& j Am. Chem. Soc., 98, 3032 (1976). 143. J. K. Whitesell and M. A. Whitesell, J. Org. Chem., 42, 377 (1977). 144. D. Mea-Jacheet and A. Horeau, BUN. Soc. Chim. Fr., 4571 (1968). 145. S. Hashimoto and K. Koga, Tetrahedron Lett., 573 (1978). \
-
~
146. 147. 148. 149. 150. 151. 152. 153. 154.
G. Stork and J. Benaim, J. Am. Chem. Soc., 93,5938 (1971). D. A. Evans, J. Am. Chem. Soc., 92,7593 (1970). H. Ahlbrecht, Chimia, 31, 391 (1977). R. Glaser and A. Streitwieser, J. Org. Chem., 56, 6612 (1991). R. Glaser, Ch. M. Hadag, K. B. Wiberg and A. Streitwieser, J. Org. Chem., 56,6625 (1991). P. Knorr and P. Low, J. Am. Chem. Sac., 102, 3241 (1980). R. Fraser, J. Banville and K. Dbawan, J. Am. Chem. Sac., 100, 7999 (1978). R. Fraser and I. Banville, Chem. Commun., 47 (1979). K. N. Houk, R. W. Strozier, N. G. Rondan, R. Fraser and M. Chuaqui-Offermanns, J. Am. Chem. Soc., 102, 1426 (1980). 155. W. G. Kofron and M. K. Yeh, J. Org. Chem., 41,439 (1976). 156. J. Smith, D. Berghreiter and M. Newcomb, J. Org. Chem., 46, 3157 (1981). 157. G. Haflinger and K. H. Kuske, in The Chemistry of Amidines and Imidates, Vol. 2 (Eds. S. Patai and 2.Rappoport), Wiley, New York, 1991, p. 1. 158. C. L. Perrin, in The Chemistry of Amidines and lmidntes, Vol. 2 (Eds. S. Pntni nnd Z. Rappoport), Wiley, New York, 1991, p. 147. 159. W. E. Stewart and T. H. Siddall, Chem. Rev., 70, 517 (1970). 160. C. A. Grob, Chimia, 25, 87 (1971). 161. H. Kessler and D. Leibfritz, Tetrahedron Lett., 427 (1969); Tetrahedron, 25, 5127 (1969). 162. H. Kessler and D. Leibfritz, Chem. Ber., 104, 2158 (1971). 163. A. Krebs and J. Breckwoldt. Tetrahedron Lett.. 3797 11969). 164. N. J. Leonard and J. V. ~a"kstelis,J. Org. ~h'em.,28: 302i (1963). 165. M. G. Reinecke and L. R. Kray, J. Org. Chem., 31,4215 (1966). 166. G. A. Olah and P. Kreienhuhl, J. Am. Chem. Sac., 89, 4756 (1967). 167. M. Pankratz and R. F. Childs, J. Org. Chem., 50, 4553 (1985). 168. B. Honig, U. Dinur, K. Nakanisbi and M. Motto, J. Am. Chem. Sac., 101, 7084 (1979). 169. K. L. Sorgi, C. A. Maryanoff, D. F. McComsey, D. W. Graden and B. E. Maryanoff, J. Am. Chem. Soc., 112, 3567 (1990). 170. A. Parkinen, J. Mattinen, H. Lonnberg and K. Pihlaja, J. Chem. Soc., Perkin Trans. 2, 827 (1988). 171. L. M. Trefonas, R. L. Flurry Jr., E. A. Meyers and R. F. Copeland, J. Am. Chem. Soc., 88, 2145 (1966). 172. R. F. Childs, G. S. Shaw and C. J. L. Lock, J. Am. Chem. Sac., 111, 5424 (1989). 173. W. N. Speckamp and H. Hiemstra, Tetrahedron, 41, 4367 (1985). 174. T. Shono, Tetrahedron, 40, 811 (1984). 175. H. E. Zaugg. Synthesis. 181 (1984). 176. Y. Yamamoto, T. Nakada and H. Nemoto, J. A m Chem. Soc., 114, 121 (1992). 177. A. Krebs, Tetrahedron Lett., 1901 (1971). 178. J. K. Whitesell, Acc. Chem. Res., 18, 280 (1985). 179. D. Seebach, R. lmwinkelried and T. Weber, in Modern Synthetic Methods 1986, Vol. 4 (Ed. R. Scheffold),Springer-Verlag, Berlin, Heidelberg, 1986, p. 217. 180. S. 1. Blaser, W. B. Schweizer and D. Seebach, Helu. Chim. Acta, 65, 1637 (1982). 181. S. J. Blaser and D. Seebach, Chem. Ber., 116, 2250 (1983). 182. Y. Ito and N. Ihikawa, J. Am. Chem. Soc., 107, 5303 (1985). 183. M. Kimamoto, K. Hiroi, S. Tarashima and S. Yamada, Chem. Pharm. BUN.,22,459 (1974). 184. J. K. Whitesell and S. W. Felman, J. Org. Chem., 42, 1663 (1977). 185. M. Yamaguchi, Tetrahedron Lett., 857 (1984). 186. D. Enders and H. Kipphardt, Nachr. Chem. Tech. Lab., 33, 882 (1985). 187. H. Matsnshita, Y. Tsnjino, M. Noguchi and S. Yoshikawa, Bull Chem. Soc. Jpn, 49, 3629 (1976). 188. D. Seebach, R. Imwinkelried and T. Weber, Modern Synthetic Methods (Ed. R. Scheffold), Vol. 4, Springer Verlag, Berlin, Heidelberg, 1986. 189. S. Yamada, K. Hiroi and K. Achiwa, Tetrahedron Lett., 4233 (1969). 190. J. K. Whitesell and S. W. Felman, J. Org. Chem., 45, 755 (1980). 191. J. K. Whitesell and M. A. Whitesell, J. Org. Chem., 42, 377 (1977). 192. D. 1. Valentine and J. W. Scott, Synthesis, 329 (1978). 193. D. A. Oare and C. H. Heathcock, Top. Stereochem., 20 (Eds. E. L. Eliel and S. H. Wilen), Wiley, New York, 1991. 194. N. J. Leonard and D. Locke, J. Am. Chem. Sac., 77, 437 (1955). 195. A. Yogev and Y. Mazur, Tetrahedron, 22, 1317 (1966).
CHAPTER
4
Thermochemistry of enamines JOEL F. LIEBMAN Department of Chemistry and Biochemistry, University of Maryland, Baltimore County campus. 5401 Wilkens Avenue, Baltimore. Maryland 21228-5398. USA
and H. MARK PERKS Depanment of Chemistry. The Johns Hopkins University. Charles and 34th Streets. Balt.'more. Maryland 2 12 18, USA
I. INTRODUCTION: WHAT FEW THERMOCHEMICAL 'DATA THEREARE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Properties and Units . , . . . . . . . . . . . . . . . . . . . . . . . B. What Compounds Will Appear in This Chapter? . . . . . . . . . . . . . C. Choicc of Phasc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. COMPARISON O F ENAMINES AND RELATED SPECIES: 'SIMPLE' ENAMINES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .A. Definition of 'Simple' . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Resonance Stabilization of Simple Enamines . . . . . . . . . . . . . . . . C. Cycloalkcnylpiperidincs . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Buried Enamines: Aniline vs Vinylamine . . . . . . . . . . . . . . . . . . E. Buried Enamines: Alkylated Anilines and Vinylamines . . . . . . . . . . 111. COMPARISON O F ENAMINES AND RELATED SPECIES: 'COMPLEX' ENAMINES . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Extended Conjugated Systems: Vinylogous Amidcs and Amidincs . . . B. Are 2-Aminotropone and 2-Aminotroponimine Buried, Nonbenzenoid, Enamines? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Dihydropyridines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Enamides (N-Acylenamines) . . . . . . . . . . . . . . . . . . . . . . . . . . E. Indigotin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. 'ANTI-BREDT' ENAMINES . . . . . . . . . . . . . . . . . . . . . . . . . . . V. ACKNOWLEDGMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VI. REFERENCES AND COMMENTARY . . . . . . . . . . . . . . . . . . . .
. . . .
.
. 256 256 256 259 259 259 259 261
262 263 263 263 264 266 267 267 269 270 270 -
~
The CIirmistn of Enamincs. Editcd by Zvi Rappoport Copyright t 3 1994 John Wiley & Sons, Ltd. ISBN: 0-471-93339-2
255
Joel F. Liebman and H. Mark Perks I. INTRODUCTION: WHAT FEW THERMOCHEMICAL DATA THERE ARE A. Properties and Units
As evidenced by diverse chapters in the current volume and other reviews, interest in enarnines has been dominated by the convenience and versatility of their numerous synthetic applications1. As such, numerous enamines have been prepared and their reaction chemistry studied and enjoyed. Regrettably, by contrast, enamines have not particularly attracted the attention of the thermochemical community: few enthalpies (heats) of formation (AH,) have been reported for enamines2, and essentially no other thermochemical properties such as entropies (either S" or AS,), heat capacities (C,) and phase change enthalpies have been reported3. In this chapter we will concern ourselves primarily with enthalpies of formation, and thus the derived concepts of resonance and strain energies. Only occasionally will we employ the long known Gibbs free energy (AG), two accompanying identities (equations 1 and 2) and a commonly employed approximation (equation 3) for its use.
-
AG = - RT In K,, = -2.303RT log K,,
(1)
AG = AH - TAS
(2) (3)
SAG
SAH
That is, from measured equilibrium constants, K,,, one can directly derive Gibbs free energy changes, and one can often approximate these changes and enthalpy changes. We acknowledge the rich rearrangement (conjugation/deconjugation and Z vs E isomerization) chemistry of enamines chronicled in References 4. However, we are not particularly confident of our neglecting entropy for species that have comparatively low energy (and high entropy) distortion modes-for enamines, there is C,,z-N bond , ' rotation and amine (-N,) pyramidalization/planarization.As such, use of the comparatively few insights from Cibbs free energy considerations must be considered somewhat precarious. Furthermore, experimental thermochemical data, however few, dominate this chapter. This is not to say calculational theory has been mute. For example, we recall the symbiotic study5 of gas phase ion experiment and ab initio calculational theory that interrelated imines and enamines. Yet, use of this study is seriously restricted because the enthalpy of formation of imines remains problematic6.The use of calculational theory naturally brings up the question of energy units for the current study. While energies are generally reported in the organic chemical literature in kJ mol-' and kcal mol-I, other units such as eV and Hartrees are more dominant in the theoretical and physical chemical literature. In this chapter, we will follow the 'orthodox' practice of thermochemists: all enthalpies will be in kJ mol-I with conversion factors of 1 kcal mol-' = 4.184 kJ mol-I; 1 kJ mol- = 0.2390 kcal mol-I. B. What Compounds Will Appear in This Chapter?
We have decided to restrict the scope of discussion in this chapter to those compounds in which the enamine functional group is not subsumed or 'buried' as part of a larger functional grouping. This larger grouping is most commonly an aromatic n system that so strongly affects the energetics of the molecule, and thus its enthalpy of formation, as to conceal the identity of the enamine. This criterion eliminates from consideration the parent and therefore derivatives of the aromatic, nitrogenous, 5-membered ring, heterocycles: pyrrole (I), pyrazole (Za),imidazole (2b) and 1,2,3-triazole(3).Likewise, numerous
4. Thermochemistry of enamines
257
N N'
N 'CH
L&,
CH
'CH
N'
\\N-CHI1
N-CH
derivatives of nitrogenous, 6-membered ring, heterocycles are ignored. Such consciously forgotten classes of compounds include the 0x0-derivatives of pyridine and pyrimidine such as 2- and Cpyridone (4a and 4b) and the nucleic acid bases7 uracil (5a) and thymine (Sb). Relatedly, treatment of aniline (6) and its substituted derivatives is all but omitted in the current text. 0
N H
H
H
H
Quite clearly then, multiring analogs of the above 1-ring species are likewise not discussed-and thus species such as derivatives of indole (7), purine (8) (such as adenine, species 9) and porphin (10)(cf. porphyrins) do not appear in our study. It is to he admitted
(9a)
(9b)
H Me2N(CH=CH),CH0 (11) (a) n = 1 (b) n = 2 (c) n = 3
258
Joel F. Liebman and H. Mark Perks
TABLE 1. Enthalpies of formation of enamines (in kJ mol-') Formula
AH, (s, h )
AH, (g)
- 175.0 (f3.3)'
- 103.4 (f4.9)d
Name" vinylamine 3-dimethylaminopropenal (lq, l l a ) (ON: trimethinemerocyanine) 5-dimethylamino-2,4-pentadienal(s, l l b ) (ON: pentamethinemerocyanine) 1-(l-propeny1)piperidine(Iq, 12) 7-dimethylamino-2,4,6-heptatrienal (s, l l c ) ( O N : hedtamethinemerocianine) l-(l-huteny1)piperidine ( I i 13) 1,6-imino[lO]annulene (lq. 14) ( O N : I l-azabicvclol4A.1lundeca-1.3.5.7.9. .... pentaene) l-(l-cyclopenten-l-y1)piperidine(Iq, 15) 1-(ldyclohexen-l-yl)piperidine(Iq, 16)
-128.1 ( f 1.3)' - 57.4 (+ 3.2)# - 109.6 (+ 6.3)'
-83.7 (t8.2)' 307.93( +'6.3Y
31
(f17)h
-29.1 ( k l . 6 Y
21.6 (+6.4Ih
367.2 (+7.0Y
>
1.4-dihydro-2,4,6-trimethylpyridine-3,5-
- 48.9 ( f 2.6)# - 99.8 (t5.6)v - 793'
dicarboxylic acid dimethyl ester ( O N : dimethyl dihydrocollidinedicarboxylate)(s, 17)
N-phenyl-3-(pheny1amino)-propenalimine
174'
(ON: malonaldehyde dianil) (s, 18a)
2.2'-bis(3-ketoindolidene)
- 133.9'
(ON: indigotin) (s, 19) a-benzamidocinnamic acid (ON: henzalhippuric acid)(s, 20)
- 429.3'
N-phenyl-5-(pheny1amino)-2,4-
23Sk
pentadienalimine (ON: glutacondialdehyde dianil) (s, 18b) 'We give what we trust is a generally intelligible semisystematic name and ofien accompany it with another name, prefaced by 'ON' that has been used elsewhere, often by the original authors of the original calorimetric study and/or the thermochemlcal archive from where we obtained the cited enthalpy of formation. See References 5. 'This value is derived from Reference 13 by accepting the suggested enthalpy of formation for the gas phase species and subtracting from that number the suggested enthalpy of vaporization at 298 K. dThis is the value suggested by the authors of Reference 13. However, we believe their suggested temperature correclion of 6.9 kJ mul-' for T,,,, = 41.4 "C = 314.6 K is too large. More precisely, if we assume the universality of the 'new' Sidgwick correction14 AHJT me,n)
- AH,(298 K) z 0.06(Tm,. - 298)
we derive AH& lla) = - 109.9 kJ mol-'. "This value is derived from Reference 13 by accepting the suggested enrhalpy of formation for the gas phase species and subtracting from that number the suggested enthalpy of sublimation at 298 K. f This is lhe value suggested by the aulhvrs ul Refercncc 13. However, we believe lheir suggested temperature correction of 6.2 kJ mol-' for T ,. = 39.9 'C = 313.1 K is too large. More precisely, if we assume the universality of the alternative correction" AHJT
'.
- AH,(298 K) = 2R(T,,,, - 298)
we derive AH,(g, llb) = -35.1 kJ m o l 'This value is taken from the archive by Pedley, Naylor and Kirby.' Varalleling our analysis in footnote f, we believe the original authors' suggested temperature correction of = 75.9 "C = 349.1 K is too large. We derive AH&, Ilc) = 1.2 W mol-'. 17.1 k J m o l ' for T., 'This value is taken from the archive by Pedley, Naylor and Kirby.' However, as will be discussed in some length in Section ILB, we note the original authors" had doubts about the quality of their measurement. We share these doubts and so the reader is advised to use this value with due care. 'This numher was denved from the reported thermochemicnl values in Referenct 17. 'This number wns der~vedfrom the rrporled lhrrmochrmicnl valurs in Rrfcrrncc 18. ' Wc ~ c u p l c dthc IlKbyrar-old wluc rllnl hy lhc archlv~lRrlrrcncr IV.
4. Thermochemistry of enamines
259
that had we included all of these 'buried' species, this chapter would have been far longer than it is now. For example, we are aware of dozens of anilines, pyrroles and porphyrins for which enthalpies of formation have been reported. We have asked ourselves and others: 'Does it really benefit the understanding of the enamines to learn that the solid phase enthalpies of formation of the isomeric 2,7,12,17-tetraethyl-3,8,13,18tetramethyl and 2,8,12,18-tetraethyl-3,7,13,18-tetramethylporphyrinsdiffer by 26.8 25.5 kJ mol-I?' Assuming the reader shares (or at least accepts) our prejudice what to include and what to omit in this chapter, we now present Table 1 that lists the available enthalpies of formation of 'classical' enamines. Somehow we feel we have gone from too much data to too little, but we do not know of any other self-consistent approach 10 combine coherence and conciseness of text. We wish to emphasize that there are so few thermochemical data for 'classical' (as opposed to 'buried') enamines that few generalizing principles exist to interrelate these species with any other class of molecules. As such, paralleling our review8 of another class of substituted doubly bonded systems (the enones) we plead 'insufficient data' and will omit Benson-like group increment analysisg~lO. Instead we will use enthalpies of formation of 'related' species" to provide comparison1z with the entries in Table 1.
+
C. Choice of Phase
Gas-phase species are the simplest to analyze and to understand because they obviate the difficulty of quantitatively deriving intermolecular interactions in a quantitative discussion". Surprisingly, liquid phase data are often almost as good. These data reflect an influence of no more than a 'few' kJ mol-' due to intermolecular interactions. More precisely, the enthalpy of vaporization of (a monosubstituted, singly functionalized compound) RX depends 'only' on the group X, and the total number and type (quaternary and nonquaternary) of carbons, with seeming indifference to the degree of unsaturationzl. Data for species in their solid phase are much less useful, and will be used only as a 'last resort" via the judicious use of 'macroincrementation reaction^'^^. II. COMPARISON OF ENAMINES AND RELATED SPECIES: 'SIMPLE' ENAMINES A. Definition of 'Simple'
Simple is clearly a subjective concept. Recall that we earlier mentioned considerations of resonance stabilization for enamines. More precisely, in the classical 'arrow-pushing' description of organic molecules, much of the reaction chemistry and the thermochemistry of enamines is describable in terms of contributions from the covalent and dipolar resonance structures
..<
>C=~-~J
-
\c--~=~+'
/
\
(4)
We therefore define here enamines to be simple when there is neither additional strain nor additional resonance to complicate interpretation of measured enthalpies of formation. 6. Resonance Stabilization of Slmple Enamines
As both the textbook and research literature amply document, resonance energy (RE) (and therefore stabilization) has multiple definitions. For 'simple enamines', we accept a customary model in which RE is the difference of enthalpies of formation of (otherwise analogous) conjugated and unconjugated species. There are but two pairs of compounds
260
Joel F. Liebman and H. Mark Perks
for which such measurements have been reported. The first set of data is for 1(1-propenyl) and 1-(2-propeny1)piperidine(species 12 and 21, respectively), for which the differenceof(liquid phase) enthalpies is -57.4 (k3.2) - [-36.4 (f1.111 = -21.0 (L3.4)
(18) (a) n = 1 (b) n = 2
4. Thermochemistry of enamines
+
kJ mol-'. We may immediately accept this cu -21 3 kJ m o l l difference and suggest the enamine resonance stabilization is thus some 18-24 kJ mol-'. The second set is for 1-(1-butenyl) and I-(2-butenyl)piperidine, species 13 and 22, respectively. The corresponding enthalpy of formation difference is the comparable -22 kJ mol-', but this quantity is clouded by impurities in enamine 13. (This was acknowledged by the original authors who estimated the necessary correctionsz4 from which the data given in Table 1 appear.) It would appear that the two sets of results are consonantz5. But are they? In the propenyl case (12 and 21), we are comparing 'internal' and 'terminal' ('external') olefins; in the butenyl case (13 and 22), we are comparing two internal olefins. We note the ca 10 kJ mol-' dikrence between the enthalpies of formation of 1- and 2-butene, and between 1- and 2-pentene, pairs of internal and terminal olefins with the same carbon skeleton. This suggests we have ignored a difference between the conjugated and unconjugated amines regardless of conjugation. Hydrogenation enthalpies provide us with numerous other examples of thermochemical results for internal and terminal olefinsz6. What do hydrogenation enthalpies tell us about enamines? Because the two propenylpiperidines hydrogenate to the same product, 1-propylpiperidine, and if the enthalpies of solvation of the three amines are the same, Hess' law tells us that the difference of their enthalpies of hydrogenation is numerically identical to the difference of their enthalpies of formation, namely 6AHf = 6AHH,
(5)
However, identical numbers do not necessarily convey the identical information content. More precisely, consider the - 111.6 3.5 kJ mol-' hydrogenation enthalpy of species 21, the unconjugated 1-(2-propenyl)piperidinez7.There is no conjugation between the double bond and the nitrogen, nor is there any steric repulsion. Therefore, one would expect the hydrogenation enthalpy to be the same as found in other terminal olefins. In fact, this enthalpy is nearly 15 kJ m o l l less negative than, say, 1-octene or 4-, 5- or 6-methyl-1-hepteneZ5.Relatedly, the -89.6 4.6 kJ mol-' hydrogenation enthalpy of the conjugated 12, 1-(1-propenyl)piperidine, is some 30 kJ mol-I less than those of (a-2-, 3- or 4-octenez5, three other internal olefins. It would appear that neither propenylpiperidine is a 'simple' olefin. These disparities in hydrogenation enthalpies undermine our confidence in any simple derivation of the resonance energy of any 'simple' enaminez8, although the value of ca 25 kJ mol-' is plausible and generally a c ~ e p t e d ~ ~ . ~ ~ .
+
+
C. Cycloalkenylplperidines
An interesting comparison is that of 1-(1-cyclohexen-yl)and 1-(1-cyclopenten-y1)piperidine, 16 and 15. The difference of enthalpies of formation of these species, again as liquids, is - 50.9 6.2 kJ mol- '. With such a large error bar, this value can be equated
+
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Joel F. Liebman and H. Mark Perks
with the difference of enthalpies of formation of the parent cycloalkenes, SAH,(lq) = [-38.5 (+0.6)] - r4.4 (*0.8)] = -42.9 1.0 kJ mol-', and their other I-(R-substituted) derivatives: R = Me, -44.8 & 1.0; R = Et, -48.4 + 1.4, R = OMe, -43.0 f 3.0 kJ mol-'. However, by analogy to hydrocarbon energetics3', one can alternatively ascribe the - 50.9 - (ca - 45) - 6 kJ mol- ' difference to greater inter-ring hydrogenhydrogen repulsion in the cyclopentene enamine than in the cyclohexene enamine. As with the acyclic alkenyl derivatives of piperidine, analysis of enthalpies of hydrogenation attempts to educate but results in confusion. The enthalpy of hydrogenation of 1-(1-cyclohexen-1-y1)piperidineis -84.7 f 5.8 kJ m o l l ; that of 1-methylcyclohexene is - 108.9 1.3 kJ mol-'. This suggests a resonance energy of the cyclic enamine of ca 24 6 kJ mol-l, and is compatible with our previous knowledge. From the preceding paragraph, we might expect there is less resonance stabilization for I-(I-cyclopenten-yl) piperidine than for the cyclohexenyl compound. The enthalpy of hydrogenation of 1-(1-cyclopenten-yl)piperidineis - 101.4 3.7 kJ mol-'; by contrast, that of l-methylcyclopentene is - 101.5 & 1.0 kJ m o l L .This suggests a zero resonance energy of the cyclic enamine. Our expectation is fulfilled, but we are astonished-the total loss of resonance stabilization is incomprehensible. We thus admit our disappointment that there are seemingly no corresponding studies for 1-(1-cyclohexen-y1)-and 1-(1-cyclopenten-yl)-pyrrolidine.Ring-size effects seem quite perilous for understanding the energetics of enamines. At the risk of mixing AH and AG results (cf thermodynamics and kinetics), we recall' that conjugated (5-membered nitrogenous ring) pyrrolines are seemingly less stable than their unconjugated isomers, while the reverse is found for (6-membered nitrogenous ring) piperidines. We conclude that simple understanding of ring-size effects seems perilous given the difference in enthalpies of formation of conjugated and nonconjugated cyclic ole fin^^^, even without additional complications of the planar vs pyramidal tricoordinated nitrogen that defines enamines.
+
+
+
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D. Buried Enamlnes: Aniline v s Vinylamine
One of the seemingly few interrelations between 'classical' and 'buried' enamines arises from the near-constant 30 kJ mol-' for the difference of enthalpies of formation found for most gas phase phenyl and vinyl-X derivativesj3. For the most relevant case of X = NH,, the difference for the experimental enthalpies of formation of aniline and vinylamine5 is -87.1 (+ 1.0)-31 (f 17) E 56 (f 17) kJ m o l l . Something seems seriously awry. The enthalpy of formation of aniline in its gas phase was derived from 'classical' combustion calorimetry and phase change techniques34and is expected to be trustworthy. The enthalpy of formation of gaseous vinylamine, however, comes from a composite of measurements and assumptions: (a) from appearance potentials3' to derive AH&, MeCH=NH2+), (b) from proton transfer equilibria35.36to derive AH, (g, MeCH=NH), (c) despite our earlier disclaimer about the use of theory, from the authors' ab initio quantum chemical calculations3' to derive 6AHf (g, CH,=CHNH,, MeCH=NH). Each of these can be in error. We wish to suggest that one 'correctable' source of discrepancy is the experimentally determined enthalpy of formation of acetalimine, 9 f 17 kJ mol-'. This value is disappointingly disparate from the 41 kJ mol-' state-ofthe-art G2 theoretical result38. Although we normally prefer experimental values over theoretical, we acceptJ9the G2 result for MeCH=NH, and thus for CH,=CHNH, as well. The G2 suggested value of AHdg, CH,=CHNH,) is 55 kJ mol-' ,and is in superb agreement with that predicted by assuming a nearly constant difference for the enthalpies of formation of phenyl and vinyl derivatives.
4. Thermochemistry of enamines
263
E. Burled Enamines: Alkylated Anillnes and Vlnylamlnes
Despite the adequate accuracy ( + 6 kJ mol-') for the calorimetrically derived enthalpies of formation of the isomeric N-ethyl and N,N-dimethylanilines, we disappointedly acknowledge the absence of thermochemical data for the corresponding N-ethyl and N,N-dimethyl vinylamines. Indeed, we would have thought that enthalpy of formation data on the latter should be available from reaction calorimetry (cf References 34 and 40). More precisely, there is apparently no published account of the thermochemical analysis of the seemingly simple hydrolysis reaction CH2=CHNMez t dil HX
-
CH,CHO
+ Me,NHz+X-
(6)
nor of any alkylation study, such as
In fact, we know of no analogous reaction calorimetric study of the hydrolysis or alkylation of any enamine, although this would appear to be a satisfactorily accurate and direct method of deriving enthalpies of formation of such species. One might also have thought that ion chemistry would have provided the enthalpy of formation of an N,N-dialkylated enamine. However, we know of no measured appearance potential of any immonium ion41 [R1RzC=NR3R4]+ for which there is also a measured deprotonation enthalpy that must result in an enamine. That is, R3 and R4 cannot be H, and at most one of R1 and RZmay be. The simplest cation that could qualify is [MeCH=NMeZlt for which a deprotonation enthalpy is known5, but we know of no appearance potential of this ion from Me2CHNMe, or from any other source. That is, what is the energy of the simple fragmentation process
This value would accompany the already reported experimental deprotonation energy measurement to give us an enthalpy of formation of N,N-dimethylvinylamine without any imine complications. Ill. COMPARISON OF ENAMINES AND RELATED SPECIES: 'COMPLEX' ENAMINES
A. Extended Conjugated Systems: Vlnylogous Amldes and Amldlnes
The first class of compounds we will discuss comprises species 11, the homologous series of the so-called 'merocyanines' or conjugated aminocnals, Me,N(CH=CH).CHO for n = 1, 2 and 3. From the data in the original paper, it is seen that the gasphase enthalpy of formation increases from n = 1 to n = 2 by 74.90 kJ m o l l and from n = 2 to n = 3 by 50.7 kJ m o l l . For calibration, the only other series of R1(CH=CH),RZ for which we know the gas phase enthalpies for n = 1, 2 and 3 has R' = R2 = HZ and results in corresponding enthalpy of formation increases of 57.5 f 1.2 kJ mol-I and 57.8 1.9 kJ mol-'. Given the atypical nature of R1 = RZ = H and of R1 = MezN, R" CHO 43,the + 17 and - 8 kJ mol-I difference between the enthalpy of formation increments for the two series is not implausible, although we would have thought that the difference would always be positive44.
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Joel F. Liebman and H. Mark Perks
We now turn to condensed phase enthalpies of formation for the merocyanines. We lack knowledge of the enthalpy of formation of solid Me,NCH=CHCHO. However, since the enthalpy of fusion is never negative, i.e. the enthalpy of formation of an arbitrary solid is always more negative than that of the corresponding liquid, we can be confident that the desired quantity must be somewhat less than - 175.0 kJ mol-I. As such, the solid phase incremental differences are >46.9 and 18.3 kJ mol-'. For calibration, the only other series of R'(CH=CH),RZ for which we know the solid phase enthalpies for n = 1, 2 and 3 has R' = R 2 = Ph45 for which the corresponding enthalpy of formation increases are 41.9 and 32.5 kJ mol-', respectively. Givcn thc earlicr cnunciatcd anomalics of MczN and CHO s u b ~ t i t u t i o nagain ~ ~ , thc two sets of results are not particularly discordant. Indeed, from the data in Table 1, we derive the difference of enthalpies of formation for R' = PhNH and R~ = CH=NPh with n = 1 and 2[6AH& laa, lab)] to be 64 kJ m o l l . Given the additional complication of intra- and intermolecular hydrogen bonding46 occurring in these vinylogous amidines, it would seem that all of these results are plausible4'. We now present one last calibration of these results. This compares one of the aminopolyenals to other well-characterized compounds for which the enthalpy of formation is known or easily derived. From Table 1 and our archive respectively, we find the difference of the enthalpies of formation of solid 5-(N,N-dimethy1amino)penta2,4-dienal and 1,4-diphenyl-1,3-butadieneis 288.6 kJ mol-'. Let us 'stitch' together the terminal carbons of the diene fragment with a -CH=CHgroup, is. formally synthesize p-dimethylaminobenzaldehyde and p-terphenyl. The enthalpy of formation of the former is known from experiment. The latter is surprisingly not. However, its gas phase value can be reliably estimated from Benson increments9, or as the difference [2AH,-(g, PhPh) -AHdg, PhH)], namely 280 kJ mol-'. From a major (unevaluated) archive of sublimation enthalpies15, we find three values for p-terphenyl which we casually average to obtain ca 115 5 kJ mol-'. The desired value of AH&s,p-C,H4Phz) is ca 165 kJ mol-'. Alternatively, one can use the recently developed Benson-like groups for solid hydrocarbons48 to derive the value of 160 kJ m o l l . Thus there is a some 300 kJ mol-I difference49 of enthalpies of formation of the stitched products. Consistency is once again obtained between the aminopolyenals and other classes of compounds. Nonetheless, given the novelty of these structures and of most of the calibrating reference species, new calorimetric investigations of these compounds and/or other examples of vinylogous amides and amidines seem advisable.
+
6. Are 2-Aminotropone and 2-Amlnotroponimine Buried, Nonbenzenoid, Enarnines?
It is well-recognized that tiopone has considerable resonance stabilizationsv befitting its occasional description as a nonbenzenoid aromatic compound. As such, its 2-amino derivative (23a) qualifies as a buried, albeit nonbenzenoid, enamine much as toluene is a benzenoid aromatic compound and its 2-amino derivative (2-toluidine) qualifies as a buried, benzenoid, enamine5'. On the other hand, the resonance stabilization of tropone is so much less than either benzene or cyclopropenone" that one may argue that its 2-amino derivative is an enamine which is qualitatively no different than any of the still thermochemically uncharacterized aminocycloheptatrienes. Leaving semantics aside, what can be said about the energetics of 2-aminotropone? The gas phase enthalpy of 4.3 kJ mol-', while formation difference of tropone and its 2-amino derivative is -4.4 that of benzene and its amino derivative is 4.5 + 1.2 kJ mol-I. Tropone and benzene are not so different when one considers the energetics consequences of amination. However, that is less informative than it might be, because if the difference of enthalpies
+
4. Thermochemistry of enamines
265
of formation of phenyl-X and vinyl-X is 'really' a constant (cf Section ILD) the same difference would be found for ethylene, and for its amino derivative as wells3. Somewhat more informative is to take the difference of the enthalpies of formation of monosubstituted tropones and benzeness4. For 2-aminotropone (23a) and aniline, the difference is 48.4 2.8 kJ mol-'; for tropolone (23b, 2-hydroxytropone) and phenol, it is 59.0 1.7 kJ mol-'. We lack enthalpy of formation data for any alkylated tropone. However,
+
+
+
for the parent tropone and benzene, the difference is 38.7 3.5 kJ mol-'. By analogy to amides and esterss5, one may use these differences to define the resonance energies (more correctly, stabilization energies) for the substituted species. More precisely, the increased resonance energy of 2-amino and 2-hydroxytropone over tropone, SRE, is quite naturally defined by SRE(X) = [AH& tropone) - AH,.(g, C6H6] - [AH,.(g, 2-X-tropone) - AH,.(g, PhX)]
(10)
We thus conclude that tropolone has a greater degree of stabilization than 2-aminotropone, a rather surprising conclusion perhaps, until it is realized that esters (and thus presumably carboxylic acids) have higher resonance energies than amides5'. (24) to be compared with? ThermoWith what is N,K-dimethyl-2-aminotroponimine chemical data on amidines are all but nonexistents6, and the reader should recall the earlier enunciated ambiguity (cf Reference 6) with regards to the parent benzalimine and troponimine. Nonetheless, we will attempt to gain some understanding by making assumptions that are quite plausible in the gas phase and admittedly precarious in the condensed phase. To begin with, let us compare N,N-dimethyl-2-aminotroponimine with its acyclic analogs7 N-methyl-5-(methylamino)-2,4-pentadienaline (25), and 2(N,N-diamethylamino)troponewith llb, the corresponding species, 5-(N,N-dimethylamino)-2,4-pentadienal. Admittedly, no thermochemical data are available from the literature for 25. Let us approximate its (solid phase) enthalpy of formation by assuming the
-
following 'mixed-phase' (solid, liquid) methyl/phenyl exchange reaction is thermoneutral : PhN=CHCH=CHCH=CHNHPh(s) + 2MeNH,(lq) MeN=CHCH=CHCH=CHNHMe(s)
+ 2PhNH,(lq)
(11)
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Joel F. Liebman and H. Mark Perks
This gives us AH&, 25) = 82 kJ mol-', and a resulting difference of this quantity and AH&, 24) of some 80 kJ mol-'. Likewise, we know of no thermochemical data for dimethylaminotropone. However, let us obtain a plausible value by assuming the 'mixed phase' transmethylation reaction (equation 12) is thermoneutral: This gives us an enthalpy offormation of - 18 kJ mol-I and thus 6AHf(s, 25, llb) equals ca 110 kJ mol-'. The differences of the two tropone derivatives and their acyclic counterparts are not that close, 80 and 110 kJ mol-'. However, whether to ascribe the difference to the wiles of aromaticity of nonbenzenoid species and of intra- vs intermolecular hydrogen bonding, or to errors in our models or in the original measurements, remains moot. C. Dihydropyridines
For all of the interest in dihydropyridines in the bioenergetics community5' (cf NADH and NADPH), it is surprising, as well as disappointing, that the only dihydropyridine for which we know the enthalpy of formation is compound 17, 1,4-dihydro-2,4,6trimethylpyridine-3,s-dicarboxylicacid dimethyl ester, found in its solid phase. Certainly this species is an enamine. It is also clearly a 'complex' enamine as well: after all, it is a divinyl amine with /I-carbomethoxy groups formally able to conjugate with the nitrogen lone pair. However, in the same (100-year-old) study, the enthalpy of formation of the corresponding solid phase pyridine (26) was also reported. The derived dehydrogenation reaction that converts the enamine into the pyridine is endothermic by 47 kJ moll-by contrast, the formally simpler dehydrogenation reaction of 1,4-cyclohexadiene to benzene is exothermicsg by some 17 kJmol-'. Is this difference of 47 - (- 17) = 64 kJ mol-' plausible?
Recall the ca 20 kJ mol-' suggested resonance energy for simple enamines. The 'push-pull' logic suggests that the two carbomethoxy groups P to. the amine should result in enhanced resonance stabilization for the dihydropyridine. That there are two double bonds trying to conjugate with the same nitrogen lone pair suggests that the resonance energy should be less than twice the resonance energy for one conjugating group. Forgetting about both 'new' effects suggests stabilization of the dihydropyridine by 2(20) = 40 kJ mol-'. We recall simple assumptions about phase changes that correctly suggest benzene should have nearly the same enthalpy of vaporization as 1,4-cyclohexadienebO.However, nothing tells us about an arbitrary pyridine and the corresponding dihydropyridine because the nitrogens in pyridine and secondary amines correspond to different functional groups by the analysis given in References 21b and 21c. It is not obvious what comparison to make here, but that of a monomethylated pyridine and 2,5-dimethylpyrrole seems plausible since they have the same number of carbons and are both aromatic. The difference is some 13 kJmol-'. The negative oxygens of the carbomethoxy group and the positive proton attached to nitrogen should
4. Thermochemistry of enamines
267
increase the enthalpy of vaporization/sublimation, a number only amplified by the presence of any additional push-pull resonance. Now that we have convinced ourselves that the formal dehydrogenation enthalpy of species 17 is plausible, we are ready to discuss its enthalpy of formation. More precisely, we ask if the enthalpy of formation of the derived pyridine (26) is plausible, and an affirmative answer to this will corroborate the value for the enamine of direct interest in this chapter. To estimate the pyridine, we will start with the parent heterocycle and affix the necessary substituents. Monomethylation and dimethylation of liquid phase pyridine result in ca 40 kJ mol-' drops in enthalpy of formation per methyl groupthere is no reason to suspect trimethylation will not do the same. As such, 2,4,6-trimethylpyridine is expected to have an enthalpy of formation of some6' 100 + 3(-40) = -20 kJ mol-'. To determine the enthalpic consequences of the affixed carbomethoxy groups, one can make use of the thermochemical data from pyridine-3carboxylic acid, and then conceptually esterify it, or from the preformed methyl benzoate. The biggest debit of the former is that we will have to estimate the effect of the ignored N-H-0 hydrogen bond. It is easier to add twice 6AHf (Iq, PhCOOMe, C6H6),namely 2(-343.5 - 49.0) = -785 kJ mol-I. From all of this, we predict AH&, 26) is some - 805 kJ mol- '. The discrepancy is some 60 kJ mol- '. It is worsened with the realization that we have not used a 'mixed-phase' reaction, but rather one that involves only liquids. It is not obvious where the error is6'. D. Enamides (N-Acylenamines)
If we ignore 'buried' species, the only enamine for which we have thermochemical data is cc-benzamidocinnamic acid. To estimate its enthalpy of formation, let us assume the following reaction is thermoneutral:
Making use of the enthalpy of formation of a-methylcinnamic acidz4' and of solid toluene38 we predict a value of -436 kJ mol-'. We recognize that the hydrogenation product of cc-benzamidocinnamic acid is N-benzoylphenylalanine. If we assume that vinyl-N conjugation in enamines is then the hydrogenation enthalpy of the compound of interest would equal that of cinnamic acid itself. Equivalently, the reaction
is assumed to be actually thermoneutral. Using the enthalpy of formation of the saturated amino acid1' and of hydrocinnamic acid34' we would predict a value of -452 kJ mol-l. The two values are reasonably consonant with each other as well as with the -429 kJ mol-' value64 in the archival literature19. E. lndigotin
Turning now to indigotin (19), we recognize the presence of a bis(indany1idene) (27), and the 1,2-ene-dione and 1,Zene-diamine functionalities, for each of which there is scant thermochemical precedent. There is also the explicit possibility of two hydrogen bonds. We opt to derive the enthalpy for the gas phase and then consider the enthalpy of sublimation, thereby making the greatest use of thermochemically well-defined numbers. To generate the first structural features and thus its energetics, one can stitch
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Joel F. Liebman and H. Mark Perks
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together two indanes using tetramethylethylene (equation 15); 2 indane + Me,C=CMe,
2,2'-bis(indany1idene)
+ 2(Me,CH,)
(15)
where a few kJ mol-' of additional strain may be expected as suggested in Reference 31. We opt to ignore this added contribution as errors of a 'few' kJmol-' will be tolerated for this highly functionalized, simultaneously rather commonplace and strange6', organic component. Our estimate of AHdg, 27) is thus 262 kJ mol-'.
Let us introduce the ene-dione and ene-diamine functionalities with the simple assumption that they are 'merely' enones and enamines with no additional destabilization. After all, indigotin has also two aminoenal functionalities that provide stabilization which we will likewise ignore. But as said earlier (cf. Reference 8), little is thermochemically known about enones and we trust the reader shares our judgment that seemingly litile is thermochemically known about enamines. It thus seems appropriate to use the earlier enunciated ~henvl-vinyle a ~ i v a l e n c eMore ~ ~ . vrecisely, all four C=C-X-C=C substructures (twdapiice wiih x'= CO and NH) will be mimicked by Ph,X, and twice [AHdg, Ph,X) - AHdg, Ph,CH,)]66 will be added to the 262 kJ m o l l for AHdg, 2 2 bis(indany1idene). The final result is 189 kJ mol-'. What sublimation enthalpy is predicted? For the experimental result for the enthalpy of formation of solid phase indigotin to be correct, we need the sublimation enthalpy to be 189 - (- 133.9) = ca 325 kJ mol-I. Is this number reasonable? We recognize 27 to be a long, thin molecule. Naphthacene (28) is likewise long and thin and has the same number of ring atoms. But it lacks the hydrogen bonding and additional polarity effects that intuitively characterize indigotin. To approximately correct for this, we add in twice the differences of sublimation enthalpies of 4-pyridone (4b) and benzene6'. The resulting predicted sublimation enthalpy is ca 290 kJ mol-I and so the enthalpy of formation of solid indigotin is predicted to be - 100 kJ mol-'. Prediction and experiment differ by ca 35 kJ mol-l.
Is the experiment wrong? What have we neglected? Let us return to the assumption of no destabilization due to the ene-dione and ene-diamine, and no stabilization due to the two aminoenal groups. The sole ene-dione (other than quinones) for which there are enthalpy of formation data is (solid) 1,2-dibenzoylethylene. Fortunately for us, there are also data on its solid, saturated, analog. More precisely, one can take the difference of the enthalpy of hydrogenation of the ene-dione (141 kJ mol- ') and that of other internal olefins (ca 120 kJ mot-') and equate this 21 kJ mol-' with the desired ene-dione destabilization. This value is the 30 kJ mol-' destabilization of 1,2-dicyanoalkene interactions as found from the enthalpies of formation of fumaronitrile, acrylonitrile and ethylene (equation 16).
4. Thermochemistry of enamines
269
The sole ene-diamine of any type for which we have thermochemical data is solid o-phenylenediamine. This species shows some 10 kJ mol-' stabilization from a 'mixedphase' reaction (equation 17). This is of a surprising sign, but small and so neglectable. But what about the stabilization of aminoenals? The exothermicity of the macroincrementation reaction would provide the desired number. In the absence of trusted values for the enthalpies of formation of either compound on the left side of the reaction, we will estimate them as the difference of (the thermochemically well-characterized) PhNMe, and PhCHO and twice the phenyl-vinyl correction. Some 57 kJ mol-' extra stabilization is found in the aminoenal. If we count this stabilization only o n d B though there are two such groups, we find there is some 37 kJ mol-' worth of stabilization in which case theory and experiment are almost identical. Counting it twice results in a predicted enthalpy of formation of solid indigotin of - 194 kJ mol-'. Should we do so, there is some 60 kJ m o l ' destabilization that is as yet unaccounted for. This ambiguity, as well as the seeming necessity of numerous approximations, suggests that a reinvestigation of the thermochemistry of this interesting, multifunctionalized molecule is strongly encouraged.
IV. 'ANTI-BREDT' ENAMINES
It is expected that conjugative interaction between an olefinic n-bond and the unshared pair of electrons of nitrogen would be prohibited in enamines structurally fixed so that the double bond and lone pair are orthogonal. That is, in order to have any contribution from the dipolar resonance structure (cf equation 4), Bredt's rule has to be violated6'. Therefore, paralleling both suitable bicyclic alkenes6' and amides7q such orthogonal enamines are expected to show considerable destabilization accompanying the loss of C-N double-bond character. Corroboration for enamines is shownz9by the essentially zero free energy change accompanying the catalyzed interconversion of the anti-Bredt enamine 1-azabicyclo[3.2.2]non-2-ene (29a) and its 3-isomer (29b), a fancy (but otherwise
rather normal) ally1 amine. Additionally, the structural rigidity helps enforce the approximate equality of free energy and enthalpy changes since entropy changes are expected to be minimal. Should one ask for direct enthalpy of formation investigations on anti-Bredt enamines, such studies are currently limited to I,6-imino[lO]annulene (14) with its gas phase enthalpy of formation of 367.2 7.0 kJ mol-'. How do we affirm the decrease in resonance energy accompanying its geometric constraints? There are no enthalpy of hydrogenation measurements for this compound, nor for any other 1 1-azabicyclo[4A.l]undecane (30) derivative7'. However, we do know the gas phase enthalpy of formation
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Joel F. Liebman and H. Mark Perks
\
of 1,6-methano[lO]annulene (31), 315.0 5.8 kJ mol-', and so the enthalpy of,NH, \ ,CH, exchange reactions is expected to be educational. For example, consider equation 19, involving pyrrole and cyclopentadiene. This reaction is 78.2 9.2 kJ mol-' exothermic. However, we recognize pyrrole is aromatic so this drives the reaction regardless. Alternatively, consider equation 20 that involves unconjugated isopropyl species since they locally mimic the saturated bicyclo[4.4.1] species. This reaction is endothermic by 5.5 9.2 kJ mol-'. Dare we conclude all enamine resonance energy in 1,6-imino[10] annulene is lost? Dare we conclude that we have lost the coherence we sought7'?
+
V. ACKNOWLEDGMENTS
The authors would like to thank Eugene S. Domalski, Ramachandra S. Hosmane and John A. Joule for numerous discussions about the structure and energetics of organic nitrogen compounds. JFL also thanks the Chemical Science and Technology Laboratory, National Institute of Standards and Technology, for partial support of his research. VI. REFERENCES AND COMMENTARY 1. See, for example:
(a) P. W. Hickmott, Tetrahedron, 38,1975 (1982); 40, 2989 (1984). (b) J. K. Whitesell and M. A. Whitesell, Synthesis, 517 (1983). (c) N. de Kimpe and N. Schamp, Org. Prep. Proc Int., 15, 71 (1983). (d) G. Gadamasetti and M. E. Kuehne, in Enamincs, Synthesis, Structure and Reactions, 2nd ed. (Ed. A. G. Cook), Marcel Dekkcr, Ncw York, 1988. 2. To simplify use of our review by the reader, we have opted to take the thennochemical data from archival sources wherever we can. This lessens the number of references to be accessed and provides a comparatively uniform bias in the obtaining and subsequent utilization of the data. Indeed, all unreferenced enthalpies of formation have been taken from the single compendium I. B. Pedley, R. D. Naylor and S. P. Kirby, Thermochemical Data of Organic Compounds, 2nd ed., Chapman & Hall, London, 1986. However, in that so much of the data used here come from other sources shows how criteria for meaningfulness and reliability of thermochemical data differ from archivist to archivist. It also documents the difficulties incumbent in attempts to provide completeness in the archiving ofany type of scientificdata.
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20. This is strictly true only for the ideal gas thermochemical reference state for which, by definition, there are no intermolecular interactions. In the absence of hydrogen bonding, complications and therefore corrections for nonideality are expected to be small. 21. We note the following papers that chronicle a hierarchy of methods for estimating enthalpies of vaporization: (a) For unsubstituted hydrocarbons; I. S. Chickos, A. S. Hyman, L. H. Ladon and J. F. Liebman, J. Org. Chem., 46,4294 (1981). (b) For monosubstituted hydrocarbons; J. S. Chickos, D. G. Hesse, 1. F. Liebman and S. Y. Panshin, J. Org. Chem., 53, 3424 (1988). And, admitting some additional complexities and nonadditivity effects; (c) For multiply substituted species; J. S. Chickos, D. G. Hesse and J. F. Liebman, J. Org. Chern., 54, 5250 (1989). 22. Progress in estimating enthalpies of sublimation is being made. See, for example, I. S. Chickos, D. 0.Hesse and J. F. Liebman, in Energetics of Organometallic Species (Ed. J. A. Martinho Simaes), NATO AS1 Series C, Vol. 367, Kluewer Academic Publishers, Dordrecht, 1992. The additivity methods presented in this paper apply only to hydrocarbons, and so are at the conceptual level of the 1981 study; see Reference lla. However, we know of no simple and general method to allow the data for solid phase enamines discussed in the current chapter to be corrected, modified or supplemented so as to apply to the gas phase. Regardless, it is clear that knowledge of groups alone cannot give the enthalpy of sublimation: it is well-established that the enthalpy of sublimation of racemates and their component pure enantiomers not uncommonly differ by ca 10 kJ mol-' (see the discussion in Reference 17). 23. ' Macroincrementation reactions' is a relatively new term and admittedly not such a new concept [J. F. Licbman, in Molecular Structure and Energetics: Studies of Organic Molecules (Vol. 3) (Eds. J. F. Liebman and A. Greenberg), VCH, Deerfield Beach, 19861. These reactions are simply defined: 'given two sets of molecules, if the net numbers and types of atoms, bonds, groups (e.g. CH,-, -CH,-) and more general structural features (e.g. cyclopropane and benzene rings) are the same, it is postulated that the resulting values from adding and subtracting the heats of formation (or any other property of interest) for the two sets are the same.' These reactions are definitionally thermoneutral if we have properly accounted for all of the structural features, an assumption that may be doubted for the gas phase and certainly is suspect for the solids discussed here. Yet how wrong can we be? For the current study, discrepancies between experiment and prediction of, say, *20 kJ mol-' will be tolerated. It is tempting to suggest that larger deviations are a sign that some key intra- and/or inter-molecular interaction (e.g. some ignored destabilizing strain or stabilizing conjugation or hydrogen bonding) has bcen omittcd in our reasoning. Howcvcr, it is also likely that the experimental measurement is in error since many of the measurements reported here predate modern calorimetric practice. In either case, a more thorough investigation of the species is in order. 24. These original authors (Reference 16) estimated an enthalpy of hydrogenation and 'worked backwards' to obtain an enthalpy of formation for 1-(1-buteny1)piperidine. 25. Alternatively, we could attempt to re-estimate the enthalpy of formation of 1,ldipiperidinobutane, the purported contaminant in 1-(1-buteny1)piperidine.However, since this gemdiamine is present in a thermochemically ill-defined amount (4-6%) and the only other gem diamines for which there are chronicled enthalpies of formation are his(dimethylamino)methane, hexamethylenetetramine (1,3,5,7-tetraazaadamantane) and the fluorinated CF.(NF,),-. (n = 0, 1 and 2), this re-estimation hardly seems advisable. Our prejudice is thus to disregard the enthalpy of formation data for 141-buteny1)piperidinealtogether. 26. See D. D. Rogers, K. Dejroongraung, S. D. Samuel, W. Fang and Y. Zhao, J. Chenr. Thermodyn., 24, 561 (1992) and references cited therein. 27. In fact, the hydrogenation enthalpies we cite were obtained by taking the difference of the archival enthalpies of formation of liquid phase unsaturated and saturated species, rather than by direct measurements (cf Reference 16). 2& We can further amplify our 'tale of woe' by deriving (from the thermochemical numbers in our archive) the enthalpy of hydrogenation of the cyclic, unconjugated, 1,2,3,64etrahydropyridine which is almost identical to its corresponding hydrocarbon, cyclohexene, 119.9 f 2.4 and 117.9 1.0 kJ mol-', respectively. And, as if to add insult to injury, while the enthalpy of reaction of dimethylamine with allyl chloride to give 3-(N,N-dimethylamino)propene has been measured [C. Beldie, A. Nicholae, A. Onu and G. Nemtoi, Rev. Chim. (Bucharest), 33, 917
*
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(1982)], we know of no calorimetrically determined enthalpy of formation of allyl chloride from which to derive that for the a m i n e h a d these authors only used allyl bromide or iodide. J. Am. Chem. Soc., 107, 29. W. v. E. Doerine L. Birladeanu, D. W. Andrews and M. Pagnotta, 428 (1985). A. R. Katritzky, M. Karelson and N. Malhorta, Heterocycles, 32, 127 (1991). In the simplest picture of optimum resonance-derived stabilization, the two carbons of the double bond, the amine nitrogen and all five atoms ffixed to these three enamine atoms lie in a common plane. Much the same demand for planarity exists for the exocyclic isopropylidenecycloalkanes. For these hydrocarbons, one finds the rearrangement of 1-isopropylcyclohexene to isopropylidenecyclohexaneis exothermic by 3.1 f 0.6 kJ mol-' but that of l-isopropylcyclopentene to isopropylidenecyclopentaneis endothermic by 4.3 0.3 kJ mol-I [D. B. Bigley and R. W. May, I. Chem. Soc. ( B ) , 1761 (1970)l. If one ignores error bars, the 3 1 - (-4.3) z 7 kJ mol-' net destabilization for the exocyclic double bond in the cyclopentene vs cyclohexene hydrocarbon case is essentially identical to the 51 - 45 2 6 kJ mol-' for the cyclopentenyl and c~clobexenylenamines. J. L. Jensen, Prog. Phys. Org. Chem., 12, 189 (1976). We note that if all the data are correct, ring size effects are also large for substituted saturated species. In particular, let us return to the saturated cyclopentyl and cyclohexylpiperidines. The archivally derived difference in liquid phase enthalpies of formation is 34.1 f 3.0 kJ mol-', while the corresponding differences for other cyclohexyl and cyclopentyl derivatives are: alcohol, 48.1 2.6; thiol, 51.2 k 1.1; hydrogen (parent hydrocarbon), 51.3 1.1; methyl, 52.2 1.3; amine, 52.6 f 1.5 kJ mol-I. It is tempting to say that the value reported for the enthalpy of formation of 1-cyclopentylpiperidineis too high by some 15-20 kJ mol-' in which case the resonance energy for 1-(I
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Joel F. Liebman a n d H. M a r k Perks
dialkylated immonium ion these authors studied was [CH,=NMe,]+, having investigated immonium ion these authors studied was [CH2=NMe2]', having investigated only immonium ions with no more than three carbons. 42. W. Fang and D. W. Rogers, J. Org. Chem., 57,2294 (1992). This is for the (ehexatriene case since we are implicitly assuming that all of the double bonds in the merocyanines have (a-stereochemistry. We now admit that we know the enthalpies of formation for the series cyclo-(CH=CH),CHz but suspect few readers will fault us for not considering cyclopropene, cyclopentadiene and cycloheptatriene as being truly homologous. Should we content ourselves with just the n = 1 and 2 cases, more examples become apparent. For example, we may consider the R1 = Et and R2 = H case for which the transformation from 1-butene to (E)-1,3-bexadiene results in an enthalpy increase of 54.3 2.0 kJ mol-'. By comparison, the alternative modes of introduction of a -CH=CHgroup into 1-butene to result in (E)-1,4- and 1,s-hexadiene lcad to enthalpy increases of 74.1 t 2.0 and 84.4 f 2.0 kJ mol-I, documenting the energetics consequences of diene conjugation and (again) internal vs terminal olefins. 43. We refer Lo these two sets of &xed groups as atypical because: (a) For R1 = R" H, one need only recall the size, polarizability, (hyper)conjugating, electron (withdrawing accepting) power of hydrogen compared to anything else, (b) For R' = MezN and R2 = CHO substituents taken together, there is a possibility of extended 'push-pull' conjugation MezN-(CH=CH),-CH=O Me2N = CH-(CH=CH).-044. More precisely, as the polyene chain becomes infinite in length, the end groups [R', RZ] should have a decreasing effect and so the presence of a new -CH=CHgroup for either R1-(CH=CH).-R2 series should result in the same enthalpy of formation change. One might think that the correct comparison for Me2N-(CH=CH),-CHO is the species with n + 1 double bonds, i.e. CH, = CH(CH=CH).-ICH=CHz. The 74.9 kJ mol-' for the first aminocnal difference is then compared with the 57.8 value, while there are no experimental data on the enthalpy of formation of 1,3,5,7-octatetraene with which to compare the second aminoenal difference of 50.7 kJ mol-'. This octatetraene number, however, can be obtained simply by linear extrapolation of the ethylene, butadiene, hexatriene enthalpies of formation. Alternatively, we note that the reaction RICH=CH, + R2CH=CH, R'CH=CHCH=CHR2 + H, is generally endothermic by ca 5 kJ mol-' [cf J. F. Liebman, Sfruct. Chem., 3,449 (199211 and thus with R' = R2 = CzH,, the desired enthalpy is ca 225 kJ mol-', the 57-58 kJ mol-' difference prevails. Regardless, we would think that there should always be more resonance stabilization in the aminopolyenal than in the polyene. 45. The enthalpies of formation of solid (E)-stilbene and (E,E)-1,4diphenyl-l,3-butadienewere taken from Reference 2 and that for (presumably) (E,,E,E)-1,6-diphenyl-1,3,5-hexatrienewas taken from Reference 34a. 46. We use the term 'probably' and admittedly hedge a little, because what we take to be aminopolyenalimines can also be bis-anils, i.e. we lack definitive proof that the compounds are not PhN=CHCH,CH=NPh and PhN=CHCH=CHCH,CH=NPh. These alternative structures we doubt. However, it is not unreasonable that the n = 2 species has aH of the framework carbon-carbon and carbon-nitrogen bonds trans or s-trans, while the n = 1 species is curled into a &membered 'aromatic' ring reminiscent of acetylacetone. This we do not know, nor if it is so, how to 'correct' for this alternative geometry. 47. The reader will note that we avoided mention of the n = 0 species and the difference of their enthalpies of formation and those with n = 1. For the gas phase Me,N(CH=CH).CHO series, the difference is 87.7 kJ mol-' whiie for the H(CH=CH),H series it is 52.5 kJ mol-'. For the liquid phase Me,N(CH=CH),CHO series, the difference is 64.3 kJ mol-', while for the solid phase Ph(CH=CH).Ph and PhN=CH(CH=CH),,NHPh series, they are now 8 and 37.5 kJ mol-'. A pattern is not particularly obvious-then again we have included 'real' amides and amidines, biphenyl that 'wants' to be twisted and diatomic hydrogen. Perhaps we have taken chemical homology and analogy too far. 48. E. S. Domalski and E. D. Hearing, J. Phys. Chem. Ref: Data, 17, 1637 (1988). 49. This analysis suggests that the enthalpies of formation of solid m- and p-terphenyl are the same
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within 2 kJ mol-'. Given their very different shape and conjugation patterns, somehow we doubt this near equality with admittedly no real data supporting our prejudice. 50. W. Jackson, T. S. Hung and H. P. Hopkins, Jr., J . Chem. 7hermodyn., 3, 347 (1971). 51. The authors doubt many readers would dispute that assertion. Yet, from a rigorous thermochemical point of view, it is particularly justified. More precisely, we acknowledge that Pedley, Naylor and Kirby (see Reference 2) do not cite any enthalpy of formation of a-toluidine, while Stull, Westrum and Sinke3" cite yet an earlier archive [M. S. Kharasch, J . Res. Bur. Stand., 2, 359 (1929)l in which a 100-year-old paper [P.Petit, Ann. Chim. Phys. [6], 18, 145 (1889)l is finally uncovered as the primary source. Should a-toluidine he added to our 'wishlist' of compounds for which the enthalpy of formation should be measured? Yes, but the authors doubt that many readers would place it particularly near the top. Certainly, the authors do not. 52. (a) A. Greenberg, R. P. T. Tomkins, M. Dobrovolny and J. F. Liebman, J. Am. Chem. Sac., 105, 6855 (19831, (b) W. V. Skele, B. E. Gammon, N. K. Smith, J. S. Chickos, A. Greenberg and I. F. Liebmar, J . Chem. 7hmmodyn., 17, 505 (1985). 53. This follows from application of simple algebra. If [AH,(& C6H5NH2)- AH&, CH2=CHNH2)]
= [AH&,
C6H6) - AH,(& C,HJI,
then [AH&, C6HsNHz) - AH&!, CeHs) = [AH& CHz=CHNHJ
- AH&, C,H31.
The reader may protest a little, remembering all of the atypical features of hydrogen (cf Section I1I.A). On the other hand, [AH,(& C,H,R) - AH,(& CH2=CHR)] equals 30.1 k 0.8, 30.4 f 1.0, 29.8 f 1.5, 31.6 f 1.3 and 37.9 f 1.8 kJmol-' for R = H, Me, Et, i-Pr and t-Bu, suggesting that H is not unlike a hydrocarbon that is lacking carbon. Consequently, if one takes the difference of the G2 value for the enthalpy of formation of vinylamine (cf footnote 27) and ethylene, the difference is 3 kJ mol-' corroborating our assertions. 54. It is only the 2-substituted tropones for which there is information about their enthalpies of formation. We have blithely ignored the effects of intramolecular hydrogen bonding since it is expected to be small because of the grossly nonlinear 0-H-0 angle. Nonetheless, a thermochemical comparison of 2-, 3- and Csubstituted tropones would prove informative. 55. See, for example, I. F. Liebman and A. Greenberg, Biophys. Chem., 1,222 (1974) and P. George, C. W. Bock and M. Trachtman, in Reference 33b. We admittedly bypass the question of the relative 0-H-0 and N-H-0 bond strengths in 2-hydroxy- and 2-aminotropolone because both are expected to be rather small. 56. Again, we ignore 'buried' amidines such as imidazoles and purines, and note the only such 'unburied' amidine for which the enthalpy of formation is known to the authors is the above N,N'-diphenylformamidine.(There are some guanidine derivatives for which the enthalpies of formation are known, but these seem inappropriate to use, much as carbonates and carbamates are not usually considered 'normal' carboxylates.) 57. Strictly speaking, we are lacking one -CH=CHgroup in the acyclic species. While this could have been 'corrected' for by using the experimentally measured 7-(N,N-dimethylamino)2,4,6-heptatrienal and devising a plausible value for the enthalpy of formation of solid N-phenyl-7-(phenylamino)-2,4,6-heptatrienimine, and hence its methylated analog, this would have been one more step involving hypothetical species. So why bother? 58. S. L. Miller and D. Smith-Magowen, J. Phys. Chem. Ref: Data, 19, 1049 (1990). We also note that the flavins also qualify as enamines, but we consider them too 'buried' to be particularly intelligible in the current context. 59. The enthalpy of formation of 1.4-cyclohexadiene has only recently been determined by combustion calorimetry: V. A. Luk'yanova, L. P. Timofeeva, M. P. Kozina, V. N. Kirin and A. V. Tarakanova, Russ. J . Phys. Chem., 65,439 (1991). This comparison is most educationally useful. Earlier equilibration studies showed that N-methyl-1,4dihydropyridinehad a 9.6 kJ mol-' lower Gibbs free energy than the corresponding 1.2- isomer [E. F. Johnson, J . Am. Chem. Sac., 93, 4016 (197111. This was compared to the ca 1 kJ mol-' difference in the enthalpies of formation of the corresponding (isoelectronic though desmethylated) bydrocarbons, 1.3- and 1,4-cyclohexadienes. However, this last result arose from a comparison of
Joel F. Liebman a n d H. Mark Perks
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the enthalpies of hydrogenation of these two dienes (see Reference 32). While the reaction products are the same, this hydrogenation study was done in glacial acetic acid, a solvent known to have significant interactions with solutes, especially the unsaturated starting materials. Indeed, if one uses the enthalpy of gas phase hydrogenation of 1,3-cyclohexadiene to derive that isomer's gas phase enthalpy of formation, and compares that number with the results of Luk'yanova and her coworkers, one finds the difference of enthalpies of formation of the two gaseous cyclohexadienes to be 7.1 3.4 kJ mol-'. The effect of the nitrogen is smaller than we had been earlier told. 60. Recall Section 1.C and the results of Chickos and his coworker^^^". This is in fact correct: the literature value for the enthalpy of vaporization of 1,4cyclohexadiene is 33.7 kJ mol-' 49 while the archival value for benzene is 33.8 kJ mol-I. 61. We can, in fact, do somewhat better than this by looking at the drop in enthalpy of formation of liquid 2-, 3- and 4-methylation of pyridine separately. For example, it is seen that 2-methylation of pyridine results in a 43.5 kJ mol-' drop and 2,6-dimethylation in the nearly identical 43.7 kJ mol-I per methyl. By contrast, 3-methylation results in a drop of only 38.3 kJ m o l L .Simple additivity would suggest that the 2,3- and 2,s-dimethylpyridines would have the same enthalpy of formation, some 43.5 38.3 = 81.8 kJ mol-' lower than pyridine. The experimental results are 80.8 and 81.5 kJ mol-'. This analysis results in a prediction of the enthalpy of formation of 2,4,6-trimethylpyridine of -27.8 kJ mol-I. There is a seemingly discrepancy of nearly 8 kJ mol-l. This is disconcertingly large, but when considered as ca 3 kJ m ~ l per - ~methyl, the discrepancy is more reasonable, and hesides, the three methyls are in the most stabilizing positions they can be on the pyridine ring. 62. It is possible that the abutting methyl groups force the carbomethoxy groups out of conjugation with the ring. This would destabilize the pyridine (26). However, it would also destabilize the dihydropyridine (17) in that the 'push-pull' stabilizing mechanism would become inoperative. Alternatively, the reason why theory and experiment do not coincide is because the experiment is wrong. 63. We extrapolate from the general nonadditivity of conjugative stabilization, and that barring cyclic conjugation (cf aromaticity), the whole is less than the sum of its parts. For example, it is generally assumed that imides have lower resonance energies (per carbonyl) than amides and carboxylic acid anhydrides have lower resonance energies (per carbonyl) than esters. 64. We acknowledge that there is some steric repulsion between the various groups on the olefinic carbons that lessens both resonance stabilization and intermolecular hydrogen bonding. The former is documented by the ca 16 kJ mol- differencein the enthalpies of formation of gaseous (Eb and (Zbstilbene. 65. We recognize indigotin as a long-known blue dye. That it is blue is rather strange. After all, fcw organic compounds are bluc, certainly thc other dioncs and diamincs known to thc authors are not. This suggests atypical interactions in either the ground and/or excited state of the molecule, the former being a recipe for errors in estimating enthalpies of formation. In addition, indigotin is not a 'buried' enamine in the same way that indole is. lndole is recognized as n-isoelectronic with naphthalene, a totally aromatic species. On the other hand, indigotin is n-isoelectronic with dibenzorc.c'lfulvalene in which the two benzene rings have been irrevocablv -. transformed into o-quinodimethanes. We suspect the benzene rings are largely left intact in the indigotin and thus this species is more like a 42-diacylene-1,2-diamine,and hence not a 'buried' enamine. 66. The enthalpy of formation of gaseous diphenylmethane was obtained by using the archival value of the liquid from Pedley and his coworkersz and the new value of enthalpy of fusion (Iq s) and sublimation (s + g) from I. S. Chickos, R. Annunziata, L. H. Ladon, A. S. Hyman and J. F.Licbman, J. Org. Chem., 51, 4311 (1986). 67. The enthalpy of sublimation of naphthacene was taken as the difference of the archival enthalpies of formation of solid and gas recommended by Pedley and his coworkers2; of 4-pyridone from M. A. V. Ribeiro da Silva, M. A. R. Matos, Y. Meng-Yan and G. Pilcher, 3. Chem. 7hermodyn., 24,107 (1992); and of benzene as the difference of the recommended values for the enthalpies of formation of the solid and gas from Domalski and Hearing48. 68. Besides desiring agreement between experiment and theory, we also note that one cannot draw any resonance structure in which both amino and both keto groups are totally conjugated with each other in a 'push-pull' manner. 69. P. M. Warner, Chem. Reu., 89, 1067 (1989).
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70. (a) A. Greenberg, in Structure and Reactivity (?3Js. J . F. Liebman and A. Greenberg), VCH, New York, 1988. (b) A. Greenberg, Y.-Y. Chiu, J. L. Johnson and J. F. Liebman, Struct. Chem., 2, 117 (1991). 71. Experimental measurements on the enthalpy of formation are also lacking for the saturated parent bicyclic hydrocarbon, as well as for any other substituted and/or hetero derivative, save the equally conceptually complicated 1,6-oxido[lO]annulene. 72. The original study of the enthalpy of formation of the 1,6-imino[lO]annulene [W. Bremser, R. Hagen, E. Heilbronner and E. Vogel, Helv. Chim. Acta, 52, 418 (196911 presented other, and somewhat more rigorous, argumentation as to the seeming ambiguities of apportioning the strain energy, resonance energy, enamine conjugation and intra-annulene aromaticity of this spccies. Fortunatcly, thcrc does not sccm to he any additional complication of equilibrium with the propellane derivative, 11-azatricyclo[4.4.1]uadeca-1,3,6,8-tetra This is fortunate if for no other reason than that the most recent thermochemical survey of compounds with three-membered rings [J. F. Liebman and A. Greenberg, Chem. Rev., 89, 1225 (1989)l listed the enthalpy of formation of but one aziridine. This was the parent aziridine for which (if one can extrapolate from the energetics of the related heterocycles oxirane and thirane) systematics as to the effects of substitution on these rings are still poorly understood.
CHAPTER
5
NMR spectra JOSE LUIS CHIARA lnstituto de Ouimica Organica. C.S.I.C., Juan de la Cierva. 3. 28006 Madrid. Spain
and
ANTONIO G ~ EZ-SANCHEZ M Departamento de Quimica OrgAnica, Facultad de Ouimica. Universidad de Sevilla. Apartado de Correos 553, 41077 Sevilla. Spain
. .. . . . . . .
.
. . . . . . . ...... . ...... . . . ................. ..... . ..... . . . A. Carbon-13 Spectra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Nitrogen-15 Spectra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Proton Spectra . . . .. . . . ..... . ...... . . . . ... . .
I. INTRODUCTION
11. SIMPLE ENAMINES
...
..
...
111. ENAMINES WITH ELECTRON-WITHDRAWING SUBSTITUENTS ATC(2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Enaminones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. 2-Acylenamines (Enaminoketones) . . . . . . . . . . . . . . . . . . . . . a. Carbon-13 and proton spectra . . . . . . . . . . . . . . . . . . . . . . b. Nitrogen-15 spectra . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. 2-Alkoxycarbonylenamines (Enaminoesters) . . . . . . . . . . . . . . . 3. 2,2-Diacylenamines . . . . . .. . . . . .... .. ... . . . . ... . . . . . B. Enamlnon~tnles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Nitroenamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. 1-Amino-2-nitroalkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. 2-Acyl-2-nitroenamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. 2,2-Dinitroenamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. DEUTERIUM ISOTOPE EFFECTS AND HYDROGEN BONDING . . V. ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . ... . . . . . . . . . VI.REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The Chemist~jof Enamines. Edited by Zvi Rappoport Copyright 0 1994 John Wiley & Sons, I.td. ISBN: 0-471-93339-2
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280
J. L. Chiara and A. G6mez-Sanchez I. INTRODUCTION
Nuclear magnetic resonance spectroscopy has been of paramount importance in investigating the structure and reactivity of enamines. First of all, this technique enables a rapid recognition of the structural features of the enamine system and provides a simple procedure for the study of the different isomeric forms and, in some cases, tautomeric form(s) that it can adopt. Secondly, due to the mesomerism inherent to this electrondelocalized system, as expressed by la-b, there is an increase of the C(1)-N bond order, a decrease of the bond order of the C(1)-C(2) formal double bond and a tendency-of the enamine skeleton to attain planarity. This results in an increase of the energy barrier to rotation around the C(1)-N bond and a decrease in the energy barrier to rotation around the C(1)-C(2) bond which are amenable, in many cases, to investigation by dynamic NMR. The results of a HF 6-31G* ab initio calculation of the charge distribution for the simplest enamine, aminoethene (2), in the N-pyramidal non-planar conformation of minimum energy, appear in Scheme 1. The polarization of the atoms of the enamine framework, and the attached substituents, is reflected in the NMR spectral parameters, thus providing insight into the electronic distribution of the delocalized system. The extent of the alternating polarity, N-61)-~(2), of the enamine skeleton is thus straightforwardly revealed, and consequently allows for a qualitative prediction of the reactivity at the three centres.
Important classes of enamines are those having electron-withdrawing substituents, Ra and/or R3, at C(2), particularly when the substituent(s) act(s) .~ by . a +R effect, as in aminoenones and nitroenamines. The stronger and more extensive electron delocalization and the concomitant changes in bond orders of the resulting push-pull systems is well reflected in the NMR spectra and have been extensively investigated in this way.
SCHEME 1. Calculated (HF 6-31G*) charge distribution for aminoethene (2)
Intramolecular hydrogen bonding can occur when the enarnine contains a primary or secondary amino group and R2 and/or R3 are hydrogen-bond acceptors. The strength of this hydrogen bond can be readily estimated by various NMR techniques. The NMR spectra of enamines with special reference to the proton spectra have been the subject of reviews containing references up to 1986'. This chapter will therefore mainly deal with progress made since then, with emphasis on the resonances of 13Cand lSN. Being the core of the enamine framework, the spectral parameters of these nuclei reflect structural changes in the molecule better than the parameters of the attached
5. NMR spectra
281
protons or nuclei present in substituents R1-R'. This is particularly true for the chemical shifts of nitrogen atoms possessing a lone pair of electrons available for conjugation which are more sensitive to structural changes in remote parts of a molecule, especially in n,n-conjugated systems. The spectra of the different classes of enamines will be discussed in order of increased complexity, and the spectral data mainly reported in the form of tables. Spectra of compounds discussed in previous reviews will be considered and tabulated in order to present an integrated view of the subject. The dynamic NMR spectra are dealt with in a different chapter. 11. SIMPLE ENAMINES
In the following discussion the expression 'simple enamine' is used to designate enamines where the only substituents R1-R3 on the double bond are H or alkyl, irrespective of their molecular complexity. Thc spectra of such 'conjugated' compounds as those where R2 and/or R3 are aryl groups, or those containing the N-C=C-C=C (dienamines), C=C(N)-C=C (2-amino-1,3-butadienes) and Aryl-C(N)=C (I-arylenamines) systems, will also be included in this section. The greatest simplicity occurs in tertiary enamines (1, R4 = R5 # H) where tautomerism is excluded and the only isomerism possible is the E, Z isomerism around the c a r b o n ~ a r b o ndouble bond. A. Carbon-13 Spectra
The magnetic symmetry of ethylene [SC(1,2) 123.5 ppm12" is broken down upon substitution by the amino function. Thus, aminoethene (vinylamine, 2) shows the signals due to C(1) and C(2) at 6 139.14 and 84.33 ppm, respectively3. The 13C NMR spectra of a number of tertiary acyclic enamines are summarized in Table 1. For comparative purposes, data of the spectra of the less hindered primary enamines have been included in the Table. The C(l) olefinic carbon of tertiary enamines resonates in the range 13+157 ppm (downficld from TMS) and thc C(2) carbon in the range 79-132 ppm. In contrast with that observed in the chemical shifts of the H(1) and H(2) olefinic protons (see Section II.C), the shifts of C(1) and C(2) are widely different and their ranges do not overlap. The shift between the two olefinic carbons is qualitatively accounted for by the mesomerism l a - lb, to which other effects, such as the inductive and steric effects of thc amino and R1-R3 groups, and changes in bond length and excitation energies, can be superimposed. Inspection of Table 1 shows that for R1-R3 being the same as, for instance, in the sterically unconstrained propenylamines 5 9 , the chemical shift of C(2), SC(2), increases in the order pyrrolidino < NAlkyl, < piperidino < morpholino, which reflects the decreasing ability of these groups to donate electrons by conjugation. The values found for compounds 28 and 29 suggest that the azetidino group has only a slightly smaller n,n interaction than the pyrrolidino group. For a given NR;, the 6C(2) value is altered by the steric interaction between the groups R1-R3 around the C=C bond which prevent the NR; from taking up a conformation favourable to the n,n overlap. Thus, for E, Z pairs of compounds with R2 or R3 = H, as in 14 and 15, the C(2) atom of the 2-isomer always resonates at lower field than that of the E-isomer [6C(2), > 6C(2),]. This is due to the reduced n,n overlap as a consequence of the steric hindrance exercised by the substituent R 2 or R3 other than H in the Z-isomer. This rule does not hold for (4-10 and (3-1-aminopropene (11) probably because of the low steric requirements of the NH, groupflb. When R 2 and R3 # H, the chemical shift of C(2) increases as a result both of the double substitution and the reduced degree of n.n overlap. This decreased delocalization exists in the E- and 2-isomers, both having a cis-substituent to the NR; group, and SC(2), is usually larger than SC(2),. However, in the case of 'conjugated' enamines where R 2 or R 3 = Ph, as in the pair of E,Z isomers
A
\P
48.6; 67.7
neat
-
-
-
13.3; 45.4
ncat
-
9
-
49.8: 66.4
neat
-
7
-
19
12.9
-
49.7: 67.0
-
22.5
15.0
-
114.75
-
22.9
18.0
25.4: 53.8
135.9
123.5
-
22.1
17.2
148.9
98.4
-
-
-
-
115.4
-
-
-
150.4
90.7
13.4; 195
12.3
147.4
90.5
13.3;22.1
150.9
97.7
13.4.21.1
Et
H
H
N
156.8
85.6
(Etl-DiethylaminoI-butene (19)
H
Et
H
NEt,
136.9
99.6
-
16.9; 24.8
(a-I-Morpholino-I-buteec
H
Et
139.5
"uO
103.5
-
15% U . 7
H
bPr
H
N(SiMe,),
133.7
121.0
-
(E)-2-Morpholino2-butene (12)
Me
Me
H
"wO
1449
97.6
14.7
I-Amino-2-methylpropene (23)
H
Me
Me
NH,
124.7
105.5
2-Methyl-I-piperidino propene (24)
H
Me
Me
135.0
2-Mcthyll-morpholino pro.me 05)
H
Mc
Me
N
(El-3- Diethylamino-2pcntene (26) (Zl-3-Diethylamino-2pcntenc (27)
El
Me
H
NEt,
Et
H
Me
NEt>
(E)-3-htidino-2pentem (28)
Et
Me
H
(E)-3-PyrroIidin+2pcnrene (29)
Et
Me
H
(0-3-Morpholino-2pentcne (30)
Et
Me
H
(20)
(E)-I-[N,N-Bis(trimethy1silyl)amino]-I-pentene (21)
n n
N3 n
P
0 n
"uO
13.4; 266
-
2-Marpholino-I-butene (18)
-
CDCI,
-
4
neat
-
7
CDCI,
223
3
nest
-
7
53.4: 66.7
nut
-
7
-
C&
303
8
-
CeDe
303
8
-
16.5: 51 2
C,H,
-
10
12.5
-
25.0; 480
nest
-
7
126
-
49.9;67.15
neat
-
-
136, 23.6: 32.4
N
(continued)
00 W
TABLE 1. (continued)
N
m
a "C chemical shifts
Enamine
(El-4-Morpholinc-3heptenc (32)
I-Dimethylamino-lphenylethene (34) (0-l-Diethylamino-lphenylpropene (35) (Ztl-Dicthylamino-lphenylpropene (36)
(0-l-Morpholina-lphenylpropene (39) (Ztl-Morpholino-lphenylpropene (40) (EJ-2-Morpholino-lphenylpropene (41)
R'
R2
R3
NR:
c(1)
42)
R1
R2
R'
R4
Solvent
Temp. (K)
Ref.
TABLE 1. (continued)
N QJ
u.
"C chemical shifts
R'
(2)-2-Morphohno-1.2diphenylprapene (55)
R'
R'
NR:
R'
Solvent
Et
-
neat
Et
51.5; 67.5
Enamine
c(I)
C(2)
R1
R'
R'
PhCH,
2-Thi
2-Thi
(0-l-Morpholinol,2. diphmylethene (59)
Ph
Ph
I-Morpholino-2.2diphenyl-
H
ethene (61)
i-Pr
26.1:
neat CDCI, neat
51.95 i-R
51.8; 67.7 -
Ph
-
neat CDCI, CsD,
Temp. (K)
Ref.
5. NMR spectra
287
45-46, 6C(2), < SC(2),, probably due to a difference in the steric hindrance in both isomers8. In the Z-isomer ( a ) , the phenyl group is twisted out of the plane of the N-C=C group, and the delocalization of the nitrogen lone-pair on the aromatic ring is inhibited. This limitation is absent in the E-isomer (45), and the more extended delocalization decreases the electron density at C(2) which, accordingly, resonates at a lower field8. A situation similar to that of 46 is present in l-dimethylamino-l-phenylethene (39,a cross-conjugated system for which quantum-chemical calculations and spectral data indicate a structure with the MezNC=CH2 group almost planar and strongly conjugated, and the phenyl ring twisted ca 55 " out of this plane and non-conj~gated'~. The large shielding (6 89.9 ppm) observed for C(2) of this compound supports this view. Thc morc hindered tetrasubstituted enamines (R', RZ and R3 # H; e.g. 64) show C(2) at a much lower field [6C(2) > 117 ppm] owing to pronounced twisting of the enamine system and the consequent reduced, or nil, n,rr overlapping (see below for further discussion). The difference between the chemical shifts of C(l) of the E and Z-isomer is smaller and can be either positive or negative. Therefore it has no diagnostic value.
rn
h
--\
Me (34) (45) (4) Inspection of Table 1 also shows that there is a large difference (6.5-8.2 ppm) between the chemical shifts on the allylic carbon [C(a) of R2 or R3] of the E,Z pairs (cf compounds 16 and 17), the upfield shifts being associated with the isomers where C(a) is cis-disposed to the NR: and consequently perturbed by a larger steric compression. Furthermore, the NR; group deshields the a-carbon atom of substituent R' by 1-3 pprn in comparison with the parent alkene, and deshields the a-carbon atom of a substituent R ~ the o extent of 0.5-1.5 ppm. This difference is sufficient to distinguish between substituents attached to C(l) and C(2) in the same enamine [viz compound 2 S(1-Me) 14.7; 6(2-Me) 12.9 ppm] or in different enamines [cf l8,6(1-CH,) 26.6 and 20,6(2-CH,) 23.7 pprn], the deshielding of the C(a) to C(l) being greater than that of C(a) to C(2). An alkyl substituent R' deshields C(l) by 3-1 1 pprn (cf 16 and 22), a substituent R2 deshields C(2) by 12-18 pprn (cf 3 and 12) and a substituent R3 deshields C(2) up to 28 ppm (cf 16 and 25). The large effect of R2 and R3 has been ascribed7 to changes in the electronic contribution of the NR; to the chemical shift of C(2), produced by the steric and electronic effects on introducing the substituents R2 and R3, as discussed below. The three-bond coupling constants, 3JC,,, between H(1) and the carbon a to C(2) for the E,Z pairs of trisubstituted enamines (viz 45-46) also allow the distinction between thc E and Zisomcrss. In linc with that obscrvedL3in vicinally disubstituted olefins, in the E-isomers, having the 2-Me and H(1) in trans-disposition, the coupling (J,,a,, 6.9-7.1 Hz) is always larger than in the Z-isomers with the 2-Me and H(l) cis (J,+ 5.8-6.0 Hz). The value Few data exist on the 'J,,, couplings over the double bond of enam~nes'~. (79.2 Hz) foundg for the coupling between C(l) and C(2) of (E)-1-diethylamino-1-butene (19), and its comparison with those observed14 for alkenes (ca 70 Hz), indicates that introduction of the AlkylzN group in the alkenic system increases 'J,, by about 10 Hz. Data on the 13C NMR spectra of representative cyclic enamines are listed in Table 2. The chemical shifts of the olefinic carbons depend on the size of the cycloalkene and
288
J. L. Chiara and A. Gbmez-Sanchez
TABLE 2. I3C NMR chemical shifts [a,-,, (ppm)] for cyclic enamines
R3 \
CH-(C\H2), CHR2 R4CH /
/
\
c(l)=Cp) / R ~ ~ N RI -
I3Cchemical shifts Enamine
n
R'
RZ
0
H
H
RJ
H
R4 NR;
C(1)
C(2) Solvent Ref.
H
148.8
93.9 CzC14
NEt,
15
CDCI, CZCL CzCL CZCL 3-Methyl-1-morpholinocyclopentene (72) 1-Diethylaminocyclohexene (73)
CDCI, CzCL
1
H
H
H
H
1
H
H
H
H
H
H
H
2-Methyl-1-pyrrolidinocyclohcxcne (78)
1 M e H
H
H
2-Mcthyl-1-piperidinocyclohexene (79)
1 M e H
H
H
2-Methyl-1-morpholinocyclohexene (SO)
1 Me H
H
H
3-Methyl-1-morpholinocyclohexene (81)
1 H
Me H
H
1 H
142.6
0 n u ~3 ~3 n 146.3
93.8 CzCI,
14
100.0 CzC14
15
145.8 100.1 C,C14
15
137.1 119.3 C,CI,
15
141.7
122.0 C,CI,
15
0
140.4
123.5 C,CI,
15
n 0 w
145.2
106.2 CDCI,
11
N
0
N
w
N
(continued)
289
5. NMR spectra TABLE 2. (continued)
I3Cchemical shifts Enamine
n
R L RZ
R3
R4
5-Methyl-I-pyrrolidinocyclohexene (82)
I
H
H
Me
H
5-tert-Butyl-I-pyrrolidino- 1 H cyclohexene (83)
H
t-Bu H
6-Methyl-1-pynolidino-
H
H
I
H
Me
cyclohexene (84)
NR:
aa dJ
C(1)
C(2)
Solvent Ref.
142.7
93.15 CDCII
16
142.96 93.6 CDC13
I6
147.5 147.5
15
95.0 C,CI, 94.9 neat
IS
7
6-Methyl-1-piperidinocyclohexene (85)
1
H
H
H
H
N C )
6-Methyl-1-morpholinocyclohexene (86)
I
H
H
H
Me
N
2,6-Dimethyl-I-morpholinocyclohexene (87)
1
Me H
H
Me
N
6-Isopropyl-3-methylI-morpholinocyclohexene (88)
1 H
Me H
i-Pr
N
I-Morpholinocycloheptene (89)
2 H
H
H
H
I-Morpholinocyclooctene (90)
3 H
H
H
H
n 0
u n O \
LI
151.7 101.4 CzC14
15
150.9 101.9 CzCI,
15
144.6 121.5 CDCI,
11
148.9
11
n 0
u
111.8 CDC13
n 0
154.6 106.4 CDCI,
11
0
149.1 103.3 CDC13
11
u n N
u
the heterocyclic moieties. For a given cycloalkene SC(2) decreases in the order pyrrolidino iEi,N ipiperidino imorpholino (e.g. 67-71) already noted in acyclic enamines. As described for the acyclic azetidino derivative (28) (Table I), the azetidino derivatives of cyclic ketones (68, 74) exhibit rather high levels of shielding intermediate between those of the Et,N and pyrrolidino groups. The explanation probably lies in the larger pyramidality of the nitrogen atom of the azetidino enamines relative to that of enamines with larger amino ring-size; this results in a diminished steric interaction between the nitrogen methylene groups and the alkene moiety, minimal torsion of the amine ring and, consequently, good alignment between the nitrogen lone pair and the olefin electrons favourable for the n,n overlap. This view is in accordance with quantumchemical structure calculations and photoelectron spectral data9. For a given NR:, the SC(2) for cyclopentene derivatives are always smaller than those of compounds with larger carbocyclic rings, the order being cyclopentenyl < cyclohexenyl < cyclooctenyl < cycloheptenyl. The larger shieldings observed for the enamines with a fivemembered ring either in the carbocyclic or in the heterocyclic moieties are consistent with the greater stability of a double bond exo to a five-membered ring when compared to a six- (or larger-) membered ring. This results in a greater stability of resonance form lb, a higher contribution of this form to the ground state of the molecule and a higher C(1)-N bond order. Accordingly, dynamic NMR measurements" show that the energy barrier to rotation around the C(1)-N bond of 1-pyrrolidinocyclopentene(69) is larger
290
J. L. Chiara and A. G6mez-Sanchez
(by ca 2.0 kcal mol-') than that of the analogous cyclohexene derivative (75); the difference in energy barrier can be attributed to a larger n,n interaction in the ground state in 69 than in 75 combined with a larger steric interaction (and distortion from planarity) in the ground state for 75 than for 69. The energy and rotation necessary to reach the transition state will thus be smaller for 75. The chemical shifts of C(l) do not show the same order as that of C(2); apparently the values of K(1) are more sensitive to influences other than the n,n overlap. The introduction of a methyl group at C(2) of aminocyclohexenes causes a large downfield shift ( + 22 to + 26 ppm) of the resonance of this carbon which can be explained by a large allylic 1,3-strain (A'.3) in the tetrasubstituted coplanar enamine. Theoretical c a l ~ u l a t i o n sas ' ~ well ~ ~ ~as the results of photoelectron spectros~opy'~ and X-ray crystal log rap hi^'^ studies indicate that in unhindered enamines with the nitrogen lone pair nearly orthogonal to the C=C plane, one of the substituents R4 of the flattened nitrogen eclipses the C=C bond. Accommodation of the 2-Me is achieved by a rotation of the N R h r o u p in such a way that in the ground state the lone-electron pair of the more pyramidal nitrogen lies near (or in) the C=C plane eclipsing the 2-Me, and strain substituents R4 are located at each side of this planez0, as shown in 91. The is relieved, but the n,n interaction decreases or vanishes. A picture similar to this explains the large values of 6C(2) of tetrasubstituted acyclic enamines (as 64): the ground state of these molecules is probably similar to 92 with the lone pair of the nitrogen in the C=C plane eclipsing R3. Further examples of the relationship between the 6C(2) values and the relative orientation of the unshared electron pair of the nitrogen and the C=C plane are provided by molecules where the enamine moiety is integrated in a ring. Thus, 1-methyl-1.2.3.4-tetrahydropyridine (93) has a geometry favourable to a strong n,n intcracrion and i t s I3C N M R spectrum, with rhe resonances ofC(S)and C(6)rcquivalcnt to C(2) and C(l) in the enamine numbering system used in this chapter] a t 6 97.3 and 137.6 ppm, respectively, are those of a typical sterically unhindered enamine2'. On the other hand, 1-azabicyclo-[3.2.2]non-2-ene (94,in which the nitrogen atom is constrained to remain pyramidal and has its unshared electron-pair nearly orthogonal to the C=C plane, shows the resonances of the olefinic carbons C(3) and C(2) [equivalent to the C(2) and C(l) in the numbering system used in this chapter] at 6 128.6 and 143.3 ppm, respectively".
The introduction of a methyl group at C(6) of aminocyclohexenes causes a downfield shift of the resonance of this carbon ( + 2.7 pprn for compound 84) and an upfield shift of C(4) ( - 4.6 pprn for 84). Comparison of these shifts with those corresponding to methyl-substituted cyclohexanes (equatorial a-Me group: + 5.96 ppm; axial &-Me: indicates that the 1.40 ppm; equatorial y-Me: + 0.05 ppm; axial y-Me: - 6.37 methyl group is in preference in the pseudoaxial disposition Ma, than in M e as shown below15.This conformation is free from allylic 1,2-strain and had been proposedz4 on the basis of reactivity studies. 2-Aryl-1-aminocyclohexenes(as 95) take up conformations with the aryl group out of the plane of, and not conjugated with, the N-C(I)=C(2) moiety (cf compound 46).
5. NMR spectra
C(2) then resonates at relatively high field [6C(2) 9 6 9 7 ppm]. The 2,4,6-trinitro derivatives (95, R = H, Me, t-Bu) show atropisomerisrn due to rotational barriers (AG' 12-18 kcal mol-I) around the C(2)-C(1') bond that separate the two magnetically non-equivalent conformations 95a and 95b16.
Attenuation of the n,n interaction, attributed to stereoelectronic effects, has been observed in some enamines derived from heterocyclic amines containing more than one heteroatomZ5.An illustrative example is provided by compound 96 which shows thc C(2) signal at 6 111.0 ppm, at lower field compared to the C(2) signal of the analogous morpholine enamine 17 (Table 1). This has been considered to be due, among other factors, to the conformation adopted preferentially by 96, with the N-substituent in axial disposition and the nitrogen lone pair orthogonal to the n-orbital of the double bond. This conformation minimizes adverse anomeric effects and is stabilized by interactions between the oxygen lone pairs and the propenyl residue2'.
In order to isolate the influence of the NR; group on the chemical shifts of the olefinic carbons, it is convenient to consider these shifts relative to those (experimental - SC(i),,,,,,] (i = 1 or 2)7311215. or calculated) of the parent alkene, AdC(1) = [6C(i),,,,,,, If the values of 6C(i),,,,,, are corrected7 for variation in the u- and p-effects of substituents R1-R3 with increasing substitution, the ASC(r] values obtained reflect better the contribution of the amino group to the olefinic chemical shifts. The ASC(i) values thus obtained for some acyclic morpholine enamines appear in Table 3. Inspection of the Table reveals that the magnitude of A6C(1) values remains fairly constant as could be anticipated if the @-effectof the NR; group were determined by its electronegativity. However, the magnitude of this effect is nearly half of that produced by the same NR; group in the nearest saturated amine, a relationship also observed when the similar ASC(1) of enol ethers are compared with the values corresponding to the nearest saturated ethersz6.
292
J. L. Chiara and A. G6mez-Sanchez
TABLE 3. Contribution, A6C(i), of the NR: group to thc olcfinic chemical shifts in acyclic morpholine enamines" R1 R2 \ / c(l)=C(2) / \ R3
Enamine
R'
Rz
R"
A6C(1)
AdC(2)
'Values (in ppm) taken from Reference 7.
The magnitude of ASC(1) is not sensitive to the configuration of the C=C bond and therefore has no diagnostic value. On the other hand, AK(2) varies widely and depends on the nature of the NR: group (it is larger, in absolute value, for pyrrolidino than for morpholino), the configuration of the C=C bond (larger, in absolute value, for E- than for Z-isomers and therefore diagnostic for configuration) and the number and bulk of substituents R1-R3 (it increases, in absolute value, with increasing substitution, being the largest when R', R2 and R3 it H). ASC(2) can be taken as a measure of the n,n inieraction and the twisting of the enamine: values between - 10 and 0 ppm can be associated with a geometry near 92 with very reduced, or nil, n,z interaction. An empirical equation has been developed" that enables one to calculate SC(i) (i = 1 or 2) of substituted morpholino enamines:
The basic values for C(1) and C(2) arc 147.15 and 84.12 ppm, respectively, to which are added the increments (Table 4) due to the carbon(s) contained in substituents RL-R3, and for cyclic enamines, the increments due to the ring. The results are better for C(1) than for C(2). The magnetic symmetry of 1,3-butadiene [6C(1,4) 116.6 ppm; SC(2,3) 137.2 ppmIzb is broken by the introduction of an amino function at C(l) or C(2). The MIND013 calculated27 charge distribution for I-dimethylamino- and 2-dimethylamino-1,3-butadiene in the s-cis ands-trans conformation appears in Table 5. The alternation of charge, typical of the enamine system, is maintained when the conjugation is extended, as is 97, the odd-numbered carbons bearing positive charge, and the nitrogen and even-numbered
5. N M R spectra
293
TABLE 4. I3C NMR increments for chemical shifts of morpholine enaminesa
Increments Substituents
Increments
c(2)
a )
Substituents
'3)
'32)
'Values taken from Reference 11. blncrrmentsfor a five-membered ring. 'Incrments for a six-membered ring.
TABLE 5. MIND013 calculated charge distribution for l-dimethylamino- and 2-dimethylamino1,3-butadienes"
H H s-cis (97)
flH
-0.1578
Me2N
H s-rmnc (97)
H ri
s-cis (98)
sValucs taken from Rekrencc 27
+0.1310
-0.1266
+0.0590
-0.0826
J. L. Chiara and A. Gbmez-Sanchez
294
carbons bearing negative charge. In the cross-conjugated isomer 98, thc largest nct negative charge goes to C(1), and only C(2) carries a positive charge. The NMR spectra of these compounds bear this out. Data for the 13C NMR spectrum1' of E-ldiethylamino-1,3-butadiene are shown in Scheme 2. The 'J,,, coupling constant (77.2 H z ) ~between C(l) and C(2) for this compound, and its comparison with that (79.2 Hz) for the alkenic carbons of (E)-1-diethylamino-1-butene(19) (see above), indicate that substitution of the vinyl group for the ethyl group at C(2) of an enamine slightly decreases this coupling. The 13C NMR data (Table 6) for some derivatives of 98 show that the chemical shifts of the carbon atoms are disposed in the order SC(1) < X(4) < K(3) SC(2) as anticipated.
C H ~ 'CH~
SCHEME 2.
13cNMR chemical shifts of the carbon chain of E-ldiethylamino-l,3-butadiene
8. Nitrogen-15 Spectra
15N-NMR spectroscopy is a particularly sensitive probe for the molecular structure and reactivity of enamines due to the usually excellent dispersion of the resonance lines in organic structures, even better than in 13C NMR, and the pronounced influence of the lone-pair electrons on the shielding of 15N nuclei. However, for I5N chemical shifts, a decrease in electron density at a particular atom does not necessarily result in a downfield shift, as is generally the case in IH and 13C NMR. This is specially so for spz-hybridized nitrogens carrying a lone pair due to the pronounced influence of the second-order paramagnetic effect associated with,the energy of the n -r n* transition3'. As a consequence, there is no general systematic correlation between the 15N chemical shifts and the n,n interaction of the nitrogen with the alkene. Besides, '% chemical shifts are particularly prone to medium effects, and therefore care should be taken when comparing data from different sources obtained under different conditions, i.e. solvent, concentration and temperature. Several reviews on enamines which include I5N-NMR data have already appearedlbd and compilations of 15N-NMR parameters of enamines have been also included in several reviews and monographs3' on 15N-NMR spectroscopy. Presuming that the variation in the nitrogen chemical shift is largely governed by delocalization effects in the electronic ground state, a decrease of the shielding constant is expected for the nitrogen nucleus with increasing electron delocalization. Accordingly, a general trend towards lower field is observed on going from the amines lo enamines. To our knowledge, no data exist in the literature on the I5N-NMR spectra of simple primary and secondary enamines, which exist largely in the imino form. Data for acyclic tertiary enamines, including 'conjugated' enamines, appear in Table 7, and data for some representative cyclic enamines are listed in Table 8. The enamine nitrogen is always less shielded ( - 301 to - 352 ppm, upfield from CH315NOz)than that of the analogous ~ expected, ~ . this deshielding effect is higher in tertiary m i n e ( - 312 to - 369 ~ p m )As 'conjugated' enamines where the olefin is of a diene or styrene type ( - 330 to - 301 ppm), than in 'non-conjugated' enamines ( - 350.8 to - 304.8 ppm). The shielding of the nitrogen is expected to be influenced by the substituent R1 at C(1), and especially by substituents R2 and R3 at C(2) as well as by the delocalization of the lone pair3'. In order to isolate the effect of the n,n delocalization, it is convenient to
5. NMR spectra
295
TABLE 6. 13CNMR chemical shifts [dTMs(pprn)] for 2-amino-1,3-butadienes in CDCI,'
R3
R4
/
\
H
?(3)=C\(4)
\
c(l)=c\(2) NRIRz
/
H
R5
Compound NO. NR'R"
R
I3Cchemical shifts R4
C(1)
R
C(2)
C(3)
C(4)
"Data from Reference 28, unless otherwise stated, ' D m from Reference 29.
consider the chemical shift of the enamine relative to that (experimental or calculated) of the corresponding tertiary amine, AS(N) = fi(N),,,,,,,. 6(N),,,i,,30.33. Values of AS(N) have been included in Tables 7 and 8. Large differential shifts, A6(N), indicate considerable n,x delocalization. The highest AS(N) values occur in 'conjugated' enamines ( + 26 to + 32 ppm as compared to - 0.3 to + 20 ppm in non-conjugated enamines). However, there are some inconsistencies when comparison is made with estimations of the degree of delocalization derived from 13C and 'H NMR. In general, cyclohexanone enamines show higher AS(N) values than the analogous enamines derived from cyclopentanone, indicating a higher n,n delocalization in the former case. This is contrary to expectation considering the higher stability of a double bond exo to a five-membered ring when compared to a six-membered ring, which predicts a higher contribution of the dipolar -
296
J. L. Chiara and A. Gbmez-Sanchez
TABLE 7. "N-NMR chemical shifts [SCI1315N0, (ppm)] for acyclic enamines in 80% v/v C6D6
R1 \
R2 /
w=cp
/
R ~ ~ N Enamine (a-I-Dimethylamino. propene (111) l-Dimethylamino-2methylpropene (112)
R1
R2
R3 R3
NR;
6I5N
NMe, NMe,
2-Methyl-1-pyrrolidinopropene (113)
2-Methyl-I-morpholinopropene (25)
~3 n N
\P
(E)-1-Dimethylamino-1,3-
NMe,
butadiene (97) (E)-I-Dimethylamino-2phenylethene (114)
NMe,
(E)-2-Phenyl-I-pyrrolidinoethene (115)
(a-2-Phenyl-1-piperidinoethene (116) (4-I-Morpholino-2phenylethene (117) l-Dimethylamino-2.2diphenylethene (118)
2.2-Diphenyl-I-pyrrolidinoethene (119) 2,2-Diphenyl- l-piperidinoethene (120) 1-Morpholino-2,2diphenylethene (61) 1-Dimethylamino-lphenylethene (34) I-Diethylamino-Iphenylethene (121) l-Dimethylamino-2-
'Neat.
~3 n
"uO
NMe,
a
0 n
"wO NMe,
NEt, NMe,
AS15N
Ref.
5. N M R spectra TABLE 8. 15N-NMR chemical shifts [6CH,"NO,
(ppm)] for cyclic enamines"
n
RzCH
\
(CHdn /
c(l)=c(2) / R42N RI Enamine
n
R1
R'
NR:
6"N
A6"N
Ref.
I-Dimethylaminocyclopentene (123) 1-Diethylaminocyclopentene (67) 1-Pyrrolidinocyclopentene (69)
1-Morpholinocyclopentene (71) I-(1'-Azacycloheptyl)cyclopentene (124) I-Dimethylaminocyclohexene (125) I-Diethylaminocyclohexene (73) 1-Azetidinocyclohexene (74) I-Pyrrolidinocyclohexene (75) I-Piperidinocyclohexene (76)
1-(1'-Azacyclohepty1)cyclohexene (126) 2-Methyl-I-pyrrolidinocyclohexene (78) 2-Methyl-I-piperidinocyclohexene (79) 6-Methyl-1-pyrrolidinocyclohexene (84) 6-Methyl-1-piperidinocyclohexene (85) (continued)
J. L. Chiara and A. Gomez-Shnchez
298 TABLE 8. (continued)
Enamine
n
R'
1-Pyrrolidinocycloheptene (127)
4
H
1-Piperidinocycloheptene (128)
4
H
1-Morpholinocycloheptene (89)
4
H
1-Pyrrolidinocyclooctene (129)
5
11
RZ
NR!
dl'N - 305.5
Adl'N
Ref.
14.0
30
304.8
19.3
30
u0- 309.4
19.3
30
- 307.4
10.3
30
~3 n
H
N'
'Data from References 30 and 33 have been measured in c-C,H,, (20% v/v) and C,D, (80% vlv), respectively.
resonance form l b in cyclopentanone enamines. The 13Cand 'H (as indicated in Sections 1I.A and ILC) data are in agreement with this notion. Also, pyrrolidine enamines are wrongly predicted to be less delocalized than the analogous piperidine enamines. A very small or negative A6(N) value, as found in enamines 78 and 79 (Table 8), is however an indication of the presence of a large steric hindrance to a coplanar conformation of the amino moiety and the double-bond system, and of a conformation similar to 92. 1-Dimethylamino-2-methyl-1-phenylpropene (122) is expected to take also a non-planar conformation close to 92. The lower 615N value observed for the sterically less hindered analogue 34 (Table 7) has been interpreted as an indication of the planarity of the Me,NC=CH, group, also evidenced by the I3C-NMR data (see Section II.A)9. Furthermore, the 'H-NMR spectra (see Section I1.C) and MIND013 calculations for 34 indicate that the phenyl ring is twisted out of the plane of the enamino group9. A reasonably linear correlation has been found33 between the A6(N) values and the free enthalpy of activation to restricted rotation around the N-C(1) bond as determined from variable-temperature 13C-NMRmeasurements in a series of enamines. In a similar approach, the shieldings in enamines and enaminones have been shown to fall into a linear correlation, together with those for amides, with the Arrhenius activation energies, E,, for internal rotation34. These correlations can be used for predicting barriers in molecules for which direct measurements have been either difficult or impossible to perform. However, these correlations should be considered as local, since they comprise only groups of structurally related molecules. Moreover, they are bound to fail if simple steric hindrance influences the height of the barrier considered3'. In any case, the goodness of the fit has been claimed to support the interpretation of the A6(N) values as a measure for n,n interaction. However, more recently it has been showd6 that the AG;,, values for rotation around the N-C(l) bond in a homogeneous series of enammones bear no linear relationship with several electronic parameters unless isosteric amino groups are compared. Thus, the degree of n,r delocalization is not necessarily a predominant factor in the variations of AG;,,, and non-bonded interactions can in fact be the main factor. n,n Delocalization has been studied in a similar manner in substituted anilinostyrenes (Table 9)33.The A6(N) values, calculated with respect to the nitrogen chemical shift of the corresponding aniline, show a good linear correlation with the Hammett 0 constants for a series of donor and acceptor substituents. Similarly, the 13C chemical shift of C(2) also exhibits a linear correlation with A6(N), since this nucleus is in a similar environment and no steric interactions with the substituents occur.
5. NMR spectra
299
TABLE 9. 13C-and I5N-NMR spectral dataa for substituted anilinostyrenes (130) in DMSO-d,
Me
Compound
R
615Nb
H
A615N'
' J N . ~
(T
6C(2)'
"Taken from Reference 33. 'In ppm from neat CH,I3NO,. 'In ppm. "n Hz. 'In ppm from TMS.
The one-bond and three-bond N,H coupling constants have been measured for a series of anilinostyrenes (Table 10). The 'J,,, values lie in the range typical for sp2-hybridized nitrogen. Although there is a general correlation between the amount of s character in the N-H bond and the magnitude of the corresponding spin-spin coupling39,no systematic variation with the change in the aromatic substituents can be coupling constant found for the compounds in Table 10. The.three-bond N-C=C-H show the expected dependence on the geometry of the double bond. C. Proton Spectra
Although proton chemical shifts are influenced significantly by factors other than electron density, they also reflect the polarization of the enamine framework and the degree of n,n interaction. Thus, the chemical shifts of the vinylic protons are modulated by the same factors discussed for the chemical shifts of the corresponding olefinic carbons, such as amine component, steric and electronic effects of the substituents and ring size effects. In particular, the chemical shift of the proton(s) at C(2) is lowered by increasing n,n interaction, in parallel with what has been observed for 6C(2). No general correlation exists between the chemical shifts of both nuclei probably as a consequence of their different sensitivity to steric, electronic and, particularly, anisotropic effects of the substituents. Nevertheless, for sets of structurally related compounds, reasonable linear correlations can be found between K(2) and SH(2) (see below). Since the 'H-NMR data available for enamines are more abundant than those for 13C and 15N, more complete structural information can be obtained for wider sets of compounds. The proton chemical shifts and coupling constants for a number of simple acyclic enamines are collected in Tables 11 and 12, respectively. Data collected in previous reviews that will be useful when discussing more complex enamines have been included.
J. L. Chiara and A. Gbmez-Sanchez
300
TABLE 10. Coupling constants, J (in Hz), from "N-NMR spectra of simple acyclic enamines
Enamine
'JN,H
-90.5 (Z) C&NOz-4
Ph- N,
3 J ~ , ~
(E)
4.68 (Z) 1.94 (E)
- 89.6 (Z) -90.1 (E)
5.19 (Z) 2.50 (E)
- 89.9
Solvent
Reference
H (133)
Compared to ethylene [6(H) 5.28 ppm], aminoethene (2)3shows the signals of the olefinic protons at 6 6.08, 3.89 and 3.63 ppm (Table 11). These shifts follow the same trend as those of the corresponding carbons. Thus, H(l) appears always at lower field than the proton(s) at C(2) of the same compound, although their ranges overlap for the series of compounds included in Table 11: 5.3&6.62 ppm for H(1), 3.35-6.50 ppm for H(2). In all cases, the H(2) and H(l) protons are shifted, respectively, upfield and downfield relative to those of the corresponding alkene. In enamines with RZ = R3 = H,the vinyl proton cis to the amino group is shielded relative to the proton in trans, except when NR4R5 is a primary, secondary or an aziridino group. The same pattern is observed for the E,Z pairs of compounds with RZ or R3 = H. This is the trend found for the corresponding SC(2) (see Section II.A), attributed to inhibition of the n,n interaction due to A1.%train with the R3 substituent cis to the amino group. This strain is greatly relieved in
TABLE 11 ' H - N M R chemical shins ,a,[
(ppm)] for simple acyclic emminer
'H chemical shihs Enamine
R'
R1
R'
NR'R'
R'
R'
R3
NH
Solvent
Temp. (K)
Ref.
E
TABLE 11. (continued)
'H chemical shifls Enamine
R1
R'
R3
NR4R'
PhNH
R1
R'
R3
NH
Solvent THF-d,
CGD, CDCI,
2-Morpholina-33-d1methyI-I butene (147)
CJ',
CDCI,
CDCI, CDCI, DMSOd, DMSOd, DMSOd, DMSOd. NM~; NEt, NEt, n-Pr,N
neat neat neat neat neat neat neat neat CDCI, CDCI,
Temp. (K)
Ref
(continued)
9a93
SO'P
lea"
-
lea" lea"
PZ'S -
IeaU lea" lau lea" lea" 'P-~HL 'P-~HL
SE'P
'P-~HL
CO'S
'1363 3363
81'P
ba3
-
SZ'P E IP 8 0
zsI -
'133
50'0 'Vl
'133
SSP 0'1 P'I tO'Z
'133
TABLE I I. (continued) W
0
m
'H chemical shifts Enamine
R1
R'
R'
NR'R'
R'
R3
NH
Solvent
r-BoNH
-
CCI,
MeU(SiMe,)
-
DMSO-d,
EtN(SiMc,)
-
DMSO-d,
N(SiMe,),
-
CCI,
PhNH p r o w e (207) I-[N-(4-Chloraphenyl)amino]-
R1
7-2 -
DMSD-d, CDCI, DMSO-d,
4-MeC6H,NH
-
DMSO-d,
4-MeOC$H,NH
-
DMSOd,
3-O,NC.H,NH
-
4-O,NC,H,NH
-
DMSOd, CDcl, DMSOd,
PhN(Me)
-
CDCI,
4-CIC,H,NH
2-melhylprapcne (208)
I-[N-(r-Methylphenyl)amina]-2methylpropene (269) 1-[N-(Y-MethoxyphenyI)amino]2-methylpropcne (210) I-[N-(3-Nitrophenynaminol-2methylpropene (211)
I-[N-(4'-Nitrophenyl)amino]-2methvloroocne 1212)
PhN(SiMe,),
-
CDCI,
4-CIC,H.N(Me)
-
CDCI,
4-MeC,H,N(Me)
-
CDCI,
CMeOC,H,N(Me)
-
CDCI,
3-O,NC,H,N(Me)
-
CDCI,
CO,NC,H,N(Me)
-
CDCI,
-
CDCI,
Temp. (K)
Ref.
TABLE I I.(continued)
W 0
00
'H chemical shifts Enarnine
RL
R'
R3
NRARs
RL
PhNH
-
PhNH
NEt,
-
NEt,
-
R'
R3
NH
Solvent
Temp. (K)
Rel
S'9
O'L
5'9 8'9 E'9
O'Z 9'8 ('I 9'8 9'8
O'L
8'9 P'9
('05
E'I 8'8 r'l 01 5'1 0
0
0
0
0
0
0
0
a a
I'L P'9 L
5'9
0
0
0 0 0
5'8
0
8
0 0
8 8
a
neat neat
neat
neat
neat
neat
neat
neat
THF-d,
CDCI,
CJ's CCI. CCI, CJh CCI, CCI,
--
w (continued)
3 14
J. L. Chiara and A. G6mez-Sbnchez
compounds with R4 and/or R5 = H or with the small aziridino group. In enamines with a primary amino group, the introduction of an alkyl group at C(l) increases the shielding of H(2) (cf compounds 2 and 4, 10 and 176, 11 and 177). For larger amino groups, increasing deshielding is observed with increasing size of R1 (cf 9,144 and 147),indicating increasing torsion about the N-C(l) bond to relieve the A'.' strain with R1. This is especially the case of enamines derived from diisopropylamine, which show the largest deshielding of H(2) upon alkyl substitution at C(l) (cf 159, 160, 185 and 186). Alkyl substitution at C(2) produces always a deshielding of H(2) without much affecting the chemical shift of H(l) (cf 2 and 10). The effect of the amino group on SH(2) depends on the substitution pattern of the double bond. For sterically unconstrained acyclic Me), 6H(2) increases in the order pyrrolidino r enamines (R1 = R3 = H, R" N(Alkyl), > MeNH > piperidino > morpholino > t-BuNH > NH, > N(SiMe3), > aziridino. This is the order of decreasing n,n interaction as determined from photoelectron spectral studies1', and it is also similar to that found for 6C(2) (see Section 1I.A). When R1 = alkyl, RZ = R3 = H, the order found is NH, > pyrrolidino > NEt, > NMe, > piperidino > morpholino. The anomalous position of the NH, group is probably the result of its small A'.' strain with R1. In the compounds with a tertiary amino group, this A ' , , strain prevents an appropriate alignment for optimum n,n overlap. When R3 f H, the order found is pyrrolidino r NMe, = N(Pr-n), > piperidino > NH, > NEt, > aziridino z N(Pr-I), z morpholino > N(SiMe,),. The poor electrondonor properties of nitrogen when directly bonded to silicon is ascribed to competitive (pd),bonding and substituent electronegati~ity~~. The aziridino group has a low n-donor capacity due to a structurally and electronically enforced high pyramidality at nitrogen with concomitant stabilization of the lone electron pair4'. PES and quantummechanical calculations show that the simplest of these enamines, aziridinoethene (139), exists as an equilibrium mixture of the gauche form 139a and the trans-bisected form 139b with the former being the major c ~ m p o n e n t Azetidine ~~. enamines keep a good compromise between the amine ring being small enough to allow steric crowding, but not so small that it cannot have conjugative interaction with the alkenelO. n
H(1) is generally deshielded by increasing n,n interaction, although its chemical shift variations are less systematic than those observed for H(2). It has been shown4' recently that in 2-propenylenamines, the H(l) resonance of compounds 207-212 with a secondary amino group appears at about 0.354.45 ppm lower than that of the corresponding tertiary enamines 21S219. This downfield shift has been attributed to a greater contribution of structure l b in the former (i.e. greater n,n interaction). The same effect is indicated by the UV spectra, which show a bathochromic shift when going from the tertiary to the secondary enamines, and it could explain the higher rates of hydrolysis observed for the secondary enamines. However, it appears that even with secondary enamines the n,x interaction is not always maximized. Thus, H(l) of 200 (6 5.42 ppm) is at 0.66 ppm higher field than that of 150 (6 6.08 ppm) in which the methyl group cis to the nitrogen is replaced by a hydrogen. This shielding effect is larger than that due to methyl substitution as observed in the analogous alkenes, isobutene (6 4.63 ~ p m ) ~ ~ and propene (6 4.97 ~ p m ) ~ ' . The three-bond coupling between H(l) and H(2) (Table 12) shows the normal dependence on double-bond geometry and is of diagnostic value: 3Jc,= 7-10 Hz and 3J,,,,, = 13.&16.5 Hz. Both ranges fall below the corresponding values in ethene
5. NMR spectra
315
(jJ,,,= 11.6 Hz, 3J,,a,,= 19.1 HZ) as expected considering the lower C(l)=C(2) bond order in enamines. When RZ = R3 = H, the geminal zJR,z,,RO, coupling constant is always nil (cf - 2.5 Hz for ethene). Allylic coupling constants also decrease with increasing enamine conjugation, their values ranging from 0 to 2 Hz5'. The NH proton signal of primary and secondary enamines appears at 6 2.4-7.2 ppm, and shows the usual dependence on the substituents R4 and R5 at nitrogen and on the polarity of the solvent, the highest values being observed for arylamino derivatives in DMSO-d,. The coupling constants 3JNH,H,,1 in non-conjugated enamines fall in the range 8.5-9.8 Hz. This is similar to the value of Jo,,,,,, found for vinyl that suggests an HN-C(1)H dihedral angle close to 180 ". In enamines with extended conjugation (R2or R3 = aryl, e.g. 24&248,250,252), this coupling increases to 11-13.3 Hz, probably due to a higher planarity at nitrogen resulting from a more efficient electron delocalization. Data of the 'H-NMR spectra of representative simple cyclic enamines are collected in Table 13. When C(2) bears no substituents, the chemical shift of the vinylic proton H(2) show approximately the trends observed for SC(2). In fact, for tertiary enamines derived from cyclopentanone and cyclohexanone, a good linear correlation is obtained between dH(2) and 6C(2) (Figure I):
FIGURE 1. 613C US 6'H values for tertiary enamines of cyclopentanone and cyclohexanone (NR, = diethylamino, azetidino. pyrrolidino, piperidino, and morpholino).
316
J. L. Chiara and A. G6mez-Sgnchez
TABLE 13. 'H-NMR chemical shifts,,a,[
(ppm)] for cyclic cnamines R3 \
CH-(CH&
/
\
CHR~ R4CH / \ c(l)=C(2) \
R~R~N'
R
'
Enamine
n R'
RZ Ri R4
I-Dimethylaminocyclopentene (123) 1-Diethylarninocyclopentene (67)
0 H
H
H
H NMe,
4.16 CDCI,
0 H
H
H
H NEt,
4.08 C,Cl,
NRsR6
S(R1) Solvent
3.92 CCI, 3.98 C,CI, 4.00 CDCI,
4.38 C2C1, 4.37 CDCI, I-(4Methylpiperazino)cyclopentene (257)
4.40 CDCI,
1-(4-Phenylpiperazino)cyclopentene (558)
4.50 CDCI,
3-Methyl-1-morpholinocyclopentene (72) 1-N-(Pheny1amino)cyclohexene (259)
O H M e H
H
1 H
H PhNH
H
H
N
\P
4.29 CCI, 5.26 DMSO-d,
1-(4'-Ch1orophenylamino)-
5.22 DMSO-dti
cyclohexene (260) 1-(3'-Nitropheny1amino)cvclohexene (261)
5.55 DMSO-d6 5.63 DMSOd, 5.40 CDCI, 5.45 CDCI,
5.60 CDCI, 5.60 CDCI,
Ref.
5. NMR spectra
317
TABLE 13. (continued) Enamine 1-[N-(4'-Chloropheny1)N-trimethylsilylaminolcyclohexene (268) 1-Dimethylaminocyclohexene (125) 1-Diethylaminocyclohexene (73) l-Di-n-butylaminocyclohexene (MY)
n R'
R2 R3 R4
NR5R6
1 H
H
H
H NMe,
1 H
H
H
H NEt,
3
1 H
H
H
H
N
I
H
H
H
N
H
n
\P
b(R')
Solvent
4.46 4.37 4.43 4.43 4.45
CDCI, neat C2C14 neat CDCI,
4.13 4.18 4.27 4.33 4.17
CCI, C2C14 CDCI, C6D6 neat
4.53 4.57 4.53 4.67 4.62
CCI, C,CI, CDCI, C6D6 neat
4.57 4.58 4.57 4.60 4.55
CCI, C2C14 CDCI, C6D, neat
Ref.
<
l-(1'-Azacyc1oheptyl)cyclohexene (126)
l-(4'-Methylpiperazino). cyclohexene (270)
4.52 CDCI,
1-(4'-Pheny1piperazino)cyclohexene (271)
5.62 CDCI,
l-(3'-Ch1orophenyl)amino2-methylcyclohexene (272) 2-Methyl-l-[(4'-nitrophenyl)amino]cyclohexene (273) 1-(N-Methyl-N-phenyl)amino-2-methylcyclohexene (274) l-[N-(4'-Chloropheny1)N-methyl)amino]-2methylcyclohexene (275) l-[N-Methyl-N-(3'-nitrophenyl)amino]-2-methylcyclohexene (276)
1.52 CDCI,
1.53 CDCI,
(continued)
318
J. L. Chiara and A. Gbmez-Sanchez
TABLE 13. (continued) Enamine
n R'
R2 R3 R4
I-[N-Methyl-N-(4'-nitrophenyl)amino]-2-methylcyclohexene (277)
1 Me H
3-Methyl-1-morpholino1 H M e cyclohexene (81) l-Dimethylamino-61 H H methylcyclohexene (278) 1-Diethylamino-6-methyl- 1 H H cyclohexene (279) 6-Methyl-I-(N-methyl1 H H N-phenylamino)cyclohexene (280)
NR5R6
H
H 4-O,NC,H,N(Me)
H
b(R1)
Solvent
1.49 CDCI,
47
H N
4.45 CC1,
11
H Me NMe,
4.45 neat
68
H Me NEt,
4.55 neat
68
H Me PhN(Me)
5.32 CDCI,
68
4.10 CDCI,
69
n
u0
1 H
H
H M e N
6-Methyl-I-pyrrolidinocyclohexene (W)
1 H
H
H
6-Methyl-1-piperidinocyclohexene (85)
1 H
H
H MeN
4.62 neat
6-Methyl-1-morpholinocyclohexene (86)
1 H
H
H
4.60 neat
1 H
H
H Me N
1 H
H
H M e N
6-Methyl-144'-phenylpiperazino)cyclohexene (283) 1-Aziridinocycloheptene (284) 1-Pyrrolidinocycloheptene (127)
Ref.
M
M
3 3 n
~
N
~
N \P
A
NMe
u
n
4.18 neat
4.62 CDC1,
uN" 4.71
CDCI,
5.00 C6D6 4.37 CC1, 4.50 CDC1,
1-Pipcridinocycloheptene (128)
4.75 CCI,
1-Morpholinocycloheptene (89)
4.77 CCI,
I-(4'-Methy1piperazino)cycloheptene (285)
4.85 CDCI,
I-(4'-Pheny1piperazino)cycloheptene (286)
4.91 CDCI, 4.08 CCI, 4.18 CDCI,
5. NMR spectra
319
TABLE 13. (continued)
Enamine
n R1 R2 R3 R4
3 H
H
H
H
1-Pyrrolidinocyclododecene (288)
7 H
H
H
H
1-Piperidinocyclododecene (289)
7
H
H
H
H
NRW
n
6(R1) Solvent
Ret
4.50 CCI,
11
3.97 CCI,
67
4.30 CCI,
67
"uO
"3
Compounds with larger carbocyclic rings or with substituents on the ring fall out of this correlation. As already noted for 6C(2), the effect of the amine moiety on SH(2) depends on the size of the carbocycle and on steric interactions. For enamines derived from cyclopentanone, dH(2) increases in the order pyrrolidino < N(Alkyl), < azetidino < piperidino < morpholino Cmethylpiperazino < 4-phenylpiperazino. For cyclohexanone enamines, the azetidino derivative 74 has an even lower 6H(2) value than the pyrrolidino derivative 75". The lowest 6H(2) value found for the I-amino-6-methylcyclohexene with 3,3-dimethylazetidino group (281) indicates the very efficient n,n interaction that results from a small A l q 2strain between thc 6-Me and this amino group6'. AS noted for the acyclic enamines, the aziridino derivatives show very high 6H(2) values (i.e. 284, b 5.00 ppm) indicative of a low, although not nil (cfcycloheptene 6HVin,,= 5.71), n,n interaction. N-Aryl substituted enamines show the highest 6H(2) due to competitive conjugation with the aryl group as well as to the anisotropic effect of the aromatic ring (estimated7' as A6 = - 0.21 ppm for a cis H(2) proton). For a given amino group, 6H(2) varies with the size of the cycloalkene moiety increasing in the order cyclopentenyl
-
'
R' R2 R R2 \ I \ / /C=C /?-CH \ \ R4NH R3 R4N R3 Enamine form Imine form SCHEME 3 substituents R1-R4 and, in solution, solvent-dependent equilibria are set up which can be described by linear free-energy relationships. These equilibria can be readily investigated by NMR spectroscopy. The enamine tautomer is stabilized when RZor R3 is aryl or any group which increases the n,n interaction. When R2 = 4-XC6H4, the percentage of the enamine tautomer increases with increasing electron-withdrawing power of X and it can be correlated with the Hammett a value of X. The enamine tautomer is also favoured when R' and RZ are aryl. Polar solvents favour the enamine, the solvent effect being larger in the compounds existing largely in the enamine form than in the compounds having a high imine content. Similar observations have been made in aminocyclohexenes with an XC,H,NH group (compounds 25%262, Table 13): these
J. L. Chiara and A. Gomez-Sanchez
(A) SCHEME 4
enamines exist in solution in equilibrium with the imine form (Scheme 4, R = H); in DMSO-d, both tautomers coexist, while only the imine form (A) is observed in CDC1341. The percentage of the enamine tautomer increases with increasing electron-withdrawing power of X, and no enamine was detected when X = 4-Me or 4-OMe. Likewise, the related I-amino-2-methylcyclohexenes with an XC,H,NH group (as 272 and 273) exists in DMSO-d, solution as equilibrium mixtures of the imine form (A) and the tetrasubstituted enamine (B) (Scheme 4, R = Me). No vinyl signal was observed which could indicate the presence of the tautomeric trisubstituted enamine form C41. l-Amino-2methylcyclohexenes with a MeNAr group exist exclusively in the more substituted It seems that in these compounds the nitrogen conjugates enamine form similar to B47,68. predominantly, if not entirely, with the aryl ring rather than with the enamine double bond. As discussed for the acyclic series, secondary enamines (B) are thought to exist predominantly in a planar conformation as shown, while the similar tertiary enamines with a MeNAr moiety are in a non-planar conformation with the lone pair on nitrogen near to, or in the plane of, the molecule. The difference in the rates of hydrolysis between secondary and tertiary enamines of 2-methylcyclohexanone has been ascribed to this difference in c o n f ~ r m a t i o n ~ ~ . Conjugation of the enamine system with an aromatic substituent at C(2) (cf 3 and 234,s and 243) deshields the H(2) proton (A6 > + 1 ppm) as a result of the substitution, the electron-withdrawing character of the substituent and its anisotropic effect. Aryl substitution at C(l) causes a smaller low-field shift of the H(2) signal (A6 = 0.5 to + 0.7 ppm). This deshielding effect is generally larger for the protons at the cis position in relation to the aromatic ring for planar vinyl aromatic systems, whereas rotation of the magnetically anisotropic ring gives rise usually to inversion of chemical shifts (6Hci, < 6H,,,,,)12,13. A similar effect is observed in the ease of Me groups at C(2). In 1-dimethylamino-1-phenylethene(34,the signal of the vinyl proton cis to the phenyl ring appears at 0.14 ppm higher field than when the proton is in trans position1'. The assignment was based on the presence of a non-resolved long-range coupling constant with the NMe, protons. The same long-range coupling has been observed for the upfield vinyl proton signal in various aryl- and hcteroarylenaminesl'. Consequently, significant deviation of the aromatic ring from the plane of the double bond seems to be general for 1-arylenamines, in agreement with MIND013 ca~culations'~. Such deviation of the aromatic ring in 1-arylenamines from the plane casts doubt on the assignment of the signals of their vinyl protonsss. "C- and 15N-NMR data on 34 are in agreement with a planar structure for the dialkylaminovinyl moiety (see Sections 1I.A and 1I.B)". The proton chemical shifts of representative acyclic and cyclic dienamines" are collected in Tables 1416. Examination of the Tables show that alkenyl substitution at C(1) or C(2) of an enamine produces also deshielding of the olefinic protons, as seen by comparing the dH(2) values of compound 149 (6 3.75, 3.85 ppm; Table 11) with those of the analogous cross-conjugated dienamine 105 (6 3.85, 4.05 ppm; Table 14). The chemical shift of the vinylic protons of dienamines correlate only partially with the charge calculated for the corresponding olefinic carbonss0. In the linear conjugated
+
TABLE 14. 'H-NMR chemical shifts [& (ppm)] for simple acyclic dienamines in CDCI,
'H chemical shifts
Compound No.
R'
R2
R3
R4
R5
R6
RL
RZ
R"
R4
R5
R6
Ref.
~3 n
N
\P n "J n "uO NEt,
a n Nu0 n
"d
w
continued
E
TABLE 14. (continued) W
No.
R'
R2
R3
NMe,
N N
'H chemical shifts
Compound
R4
H
Rs
R"
R1
R'
R3
R4
R5
R6
Ref.
"Neat
J. L. Chiara a n d A. Gomez-SCmchez
324
TABLE 15. 'H-NMR chemical shifts [6,,,
(ppm)] for simple cyclic dienamines in CDCI,
(316) 315
No.
a
c
d
a NR,
~3 n
N
316
317
H(2)
H(4)
H(2)
H(4)
H(4')
H(1)
H(3)
Reference
4.34
4.63
4.97
4.45
4.26
-
-
79
4.75
4.80
5.32
4.63
4.54
5.62
4.37
79
4.75
4.85
5.32
4.58
4.47
5.62
4.37
79
4.82
5.32
4.42
4.52
-
-
80
u0 n N 4.73 urn
TABLE 16. 'H-NMR chemical shifts ,6[ octalone and ~~.~"-2-octalone"
318
No.
(317)
(ppm)] for simple cyclic dienamines from A1,8n-2-
319
320
321
NR,
H(2)
H(4)
H(2)
H(3)
H(4)
H(l)
H(4)
Reference
a
~3
4.88
5.13
4.23
6 1
5.48'
4.80'
5.8f
79
b
N
5.14
5.22
4.64
n
P
'In CDCI, solution. CCI, solution.
81
5. NMR spectra
325
H(2) is always shielded relative to H(3), as compounds [R,N-C(l)=C(2)-C(3)=C(4)], expected from the charge alternation of the system (Table 5). Likewise, in the C(4) monosubstituted compounds [having the same substitution pattern at C(2) and C(4)], H(2) is also shielded relative to H(4) because of the larger negative charge of C(2) as compared to C(4). Comparing linear cyclic dienamines with fixed s-trans or s-cis diene configuration (cf318 and 319, Table 16) it can be seen that H(2) of the s-cis dienamine is shielded with respect to H(2) of the s-trans dienamine by 0.5-0.6 This originates probably from a larger deviation from planarity of the s-cis diene and the consequent higher charge localization at C(2). In cross-conjugated dienamines [C(1)=C(2)(NR2)C(3)=C(4)], the chemical shifts of the olefinic protons are generally in the order 6H(1) < 6H(4) < 6H(3), i.c. the order of decreasing negative charge of the corresponding carbons irrespective of the diene conformation (Table 5). For linear acyclic dienamines with no substituents at C(2) and C(3), the 3~H,2,,H(,, coupling constants ( I S 1 1 Hz) indicate a predominant s-trans conformation for the diene74s75.The 'J,,,, and 3JH(1,,H(21 and "H(3,,Hc4, coupling constants for simple 1- and 2-aminobutadienes reflect also the degree of conjugation in the diene system. Thus, in 290, 'J, ,(', (13 Hz) is smaller than 3JH(3,,H(4 ,,_,,(16.5 Hz)74as a consequence of the smaller bond order of C(l)=C(2) compared to C(3)=C(4). The latter coupling constant 18.0 This is larger in the analogous cross-conjugated dienamine 302 (3JH,3,,H,4, value, still larger than the analogous coupling in 1,3-butadiene (3Jc,a,, 17.05)82,suggests a probable non-planarity of the diene system and non-conjugation of the C(3)=C(4) double bond with the rest of the enamine moiety. The values of 2JH(1,,H(l., (-0 Hz) and 2JH(4,,,(4., (2.7 Hz) support this view.
Ill. ENAMINES WITH ELECTRON-WITHDRAWING SUBSTITUENTS AT C(2)
A. Enamlnones
The term 'enaminones' is used in this section to designate enamines having at C(2) a carbonyl function conjugated with the carbon-carbon double bond. The two main groups of these compounds, 2-acylenamines (enaminoketones) and 2-alkoxycarbonylenamines (enaminoesters),are discussed in the following subsections. 1. 2-Acylenamines (Enaminoketones)
The introduction of the strongly electron-withdrawing acyl group at C(2) of enamines results in a more extended (and stable) delocalized system (322a-c). The restricted rotations around the formal C(1)-C(2) and C(3)-N single bonds, and the formal C(2)=C(3) double bond, of this planar, or nearly planar, push-pull system allow the existence of up to eight isomeric forms, reduced to four (A-D, Scheme 5) in the case where R4 = R5. In the compounds with R4 and/or R5 = H, the Z-isomer is stabilized in the s-cis conformation (E) by the formation of an intramolecular hydrogen bond, while in the compounds with a secondary amino group (R4 # H, Rs = H), each of the E configurational isomers can exist in two rotameric forms owing to the restricted
J. L. Chiara and A. Gomez-Sanchez
326
H
EEE
EEZ
ZEE
(F)
('3
(H) R1
I
I
H
H EZZ
EZE (J)
ZEZ (1)
(K)
SCHEME 5 Possible geometric foms of 2-acylenamines. For A-D, the symbols indicate, in this order, the conformation around C(1)--C(2)and the configuration around C(2)=C(3). For K L , the symbols indicate, in this order, the conformation around C(1)-C(Z), the configuration around C(2)=C(3), and the conformation around C(3)-N rotation around the C-NHR4 bond, thus resulting in four isomers (F-I). Isomers J-L, sterically overcrowded, have never been observed. The results of a H F 6-31* ab initio calculation of charge distribution for the simplest enaminone, 3-aminoacrolein (323), are and the shown in Scheme 6. The alternating polarity, N--C(3)+-C(2)--C(l)+-O-, alignments of the enaminone framework are reflected in the NMR parameters of the 4.3463
H H,
4,43,c
II
+0 4 . 5 8 6 0
4.1844~
H'
t0.2112
0
&4.3463 /
4.5371
p+0.4504
\N-0.8899
B
+0.3323c11
t0.1994
11
+0.3886
hH
4.1313~
H'
+0.2106
+0.3891
ZZ
H
H4,361Zc - - ' /
'~4.8762
H 4.3846
EE
SCHEME 6 Calculated (HF 6-31G') charge distribution for ZZ and EE 3-aminoacrolein(323)
5. NMR spectra
327
carbon and nitrogen nuclei, and in the nuclei of substituents R' -R5. Consideration of resonance forms (322a-c) and comparison of the charge distribution for 323 with that for aminoethene (2) (Section I, Scheme 1) allows one to predict downfield shifts for the C(2) and C(3) resonances in enaminones as compared with those of the equivalent nuclei in the nearest simple enamines. The proton chemical shifts, more sensitive to the anisotropic effect of the neighbouring C=O group, depend on both the charge at the vicinal carbon and the geometry of the molecule. 2-Acylenamines with a primary or secondary amino group can theoretically exist also in the tautomeric iminoenol form (324n-c) and oxoimino form (325). The former is also a mesomeric system to which ionic structures bearing a positive charge on the oxygen contribute, and is for this reason much less stable than 322ax. The non-conjugated oxoimino form (325) is the most unfavourable.
a. Carbon-13 and proton spectra. 3-Dimethylaminoacrolein (326), and its vinylogous 5-dimethylamino-2,4-pentadienal(327) and 7-dimethylamino-2,4,6-heptatrienal(328), have structures well-suited for theoretical and s~ectralstudies. and have been the obiect of extensive i n v e s t i g a t i o r ~ ~ ~3-Dirnethylarninoacrolein -~~. is known93.94 to exist in solution as an equilibrium mixture containing more than 95% of the EE-form (326) and the corresponding ZE-form. 327 and 328 are c o n ~ i d e r e d ' ~ -to ~ ~exist . ~ ~in the most extended 'all-E' structures shown. CND0/2 calculationss9 for the 'all-E' structures of 326328 indicated alternating valence- and n-charge distribution, being larger in the even- than in the odd-numbered carbon atoms. X-Ray crystallographic studies on some model c o m p o ~ n d showed s ~ ~ ~alternating ~~ bond lengths (ca 1.35 A for the formal C=C bonds; ca 1.41 A for the formal C-C bonds) and alternating CCC angles (ca 120 " when the central carbon is even-numbered; ca 126 " when it is odd-numbered). The '" and
H
oJ
H
H
H
H
N 'Me
, + & y L y , M e H
H
H
M
e
H
I Me
328
J. L. Chiara and A. Gbmez-Sbnchez
'H chemical shifts and coupling constants for these compounds, and for the analogous compounds (EE)-3-dimethylamino-3-methylacrolein (329) and (EE)-3-dimethylamino-3phenylacrolein (330), are given in Table 17. The alternate values of the chemical shifts reflect, as expected, the alternation of charge along the carbon chain. Plots of the I3C and 'H chemical shifts us charge density calculated for 326328 show almost linear relationship.^^^^^' and, accordingly, the 13C and 'H chemical shifts are related by the linear relationships8: S(13C)= 23.3 6('H)
-
16.5 ppm (r = 0.966)
These results imply that the influence of the anisotropic effect on the S('H) values is practically the same for all the protons and can be discarded. The 'J,(,,,;, couplings (with the exception of the terminal ones) also show alternating values, bemg larger for the even-numbered positions (with larger charge densities and smaller CCC angles) than for the odd-numbered positions (with lower charge densities and larger CCC angles). The dependence of this vicinal coupling constant on the bond angle, 0, is approximately given by the expressionss JC(tJH(t,
-
soo[~~t(ep)l~
.,,+,,,
Similarly, the vicinal coupling constants, 3JH, also take alternating values related to the x-bond order by a linear relationship8'6 . Both the 13C and 'H chemical shifts of 326328 are sensitive to the polarity of the s o l ~ e n t ~showing ~ . ~ ~ ,almost linear relationships with the solvent polarity parameter ET9'. Likewise, the difference between the vicinal coupling constants, A J = JZ,,- J,,, of 326 isalmost linearly related to E,, A J decreasing as E, increases. These results have been rationalized in terms of changes in the xelectron distribution in the mesomeric system: increasing solvent polarity favours the contributions of the charged mesomeric forms 322b and 322c to the ground state of the molecule, and tends to equalize the C(1)-C(2) and C(2)-C(3) bond orders, and the J,,, and J,,, value^^^,^'. The EE geometry of 326,329 and 330 was confirmedg7 by the shifts induced by the lanthanide reagent Eu(fod),: large shifts were observed for H(2) of compounds 326 and 330 as expected by assuming that the lanthanide complex interacts with a lone pair on the oxygen atom near H(2) in the EE isomer. Further confirmation of this conformation is coupling constant of 326330 and its comparison with those provided by the 3JH(1,H,,, observed (see below and Table 18) for N-monosubstituted 3-aminoacrolcins with the E- and Z-conformation about the C(2)-C(1)=0 bond. No isomeric changes induced by changes in the polarity of the solvent were observed for these compounds. 3-Aminoacroleins with a secondary amino group exist in solution as equilibrium mixtures of isomers, the composition of which depends on both the nature of the substituent at the nitrogen and the polarity of the solvent. Data of the "C- and 'H-NMR spectra for some representative examples (compounds 331-337) and for the parent 3-aminoacrolein (323) appear in Table 18. The spectra at high fields show that the compounds with secondary amino group exist in CDCI, as equilibrium mixtures containing the intramolecularly bonded ZZE-form (E, Scheme 5), and the EEE- (F)and EEZ-form (G), the proportion of the former increasing with increasing bulk, and decreasing polarity, of RZ. In polar media the EEE aqd EEZ isomers strongly predominate or are the only detected. The ZZE isomer can be readily distinguished by the typical set of J H H coupling constants, the rather large long-range 4JH!,,H(3, coupling (larger than the 5~H,1,H,2,), and the large S(NH) value indicative of the mtramolecular hydrogen bond. Isomers having different conformation around the C(1)-C(2) bond coupling (2.1-2.3 Hz for the Z-conformation; 8.5-9.6 Hz have very different 3JH(1,H(2, for the E-conformation). Isomers having different configuration around the C(2)=C(3) '
TABLE 17. 13C- a n d 'H-NMR chemical shifts
[ams (ppm)]
and, in brackets, coupling constants J (Hz) for compounds 326330 in CDCI,'
'H chemical shifts [3JH(0,H(i+I,]
I3C chemical shifts ['J,ts.HciJ Compound
C(1)
326
189.V.' (161)
1Ml.4c 161.1' (157) (154)
327
192.1 (162) 192.9 (168)
119.6 (156) 123.7 (157)
328
(32)
C(3)
156.7 (146) 155.8 (141)
C(4)
97.2 (155) 117.8 (161)
qS)
(36)
C(7)
152.6 (163) 147.3 98.7 149.9 (146) (151) (162)
H(2)
37.1' (139)" 9.03 45.2 (139) (8.1)
5.04 (12.9)'
7.16
40.9'
937 (8.5) 9.46 (8.1)
581 (14.6) 5.89 (15.0)
7.17 (11.7) 7.16 (11.4)
9.47 (8.0) 8.6 (8.3)
5.07
2.268
2.99
5.19
7.3'
2.83
40.6'
3296 3Md
190 (166)
103 168 (155.5)
40.3 (139)
H(3)
H(4)
H(5)
H(6)
H(7)
NMe,
H(1)
NMe,
2.9gd 5.24 (12.6) 6.06 (14.0)
6.85 6.72 (10.7)
5.13 (12.9)
6.64
'Values taken from Reference 88, unless otherwise stated. Values taken from Reference 86. 'Values measured at 198 K, taken Irom Reference 96. d V a l ~taken e ~ from Reference 97. 'A value of ca 12.8 Hz has ban assigned to the planar EE-form (12.81 Hz was the averaged measured vahe for the mixture EE + ZE containing less than 5% of the latter ~road'si~nal. '3-Me resonance. 'Centn of the C,H, pattern.
J. L. Chiara and A. Gbmez-Sanchez
(332) R' = H, R2 = C(lr)H2CH3 (333) R' = H, RZ = &HI1 (334) R' = H, RZ= t-Bu (335) R' = H, RZ= C(1')H2C02Me
I
NHAc
(339) R1 = Me, R2 = H (340) R' = Me, R2 = CH2C02Me CH20H
L n
bond also differ in the 3Jc,,,,,,,coupling constants: the ZZE isomer, with C(1) and H(3) larger (ca 9 Hz) than the EEE and EEZ forms in trans-disposition, has a 3Jc,1,H,,, (5.9-0 Hz), with C(l) and H(3)cis. Rotamers EEE and EEZ differ in the coupling constant between H(3) and the NH proton, the chemical shifts of C(l) and C(2) and, to a lesser extent, of H(1)-H(3), the isomer with a larger SH(2) and smaller SC(2) having been a s ~ i g n e d ~ ~ to . " 'the ~ EEZ geometry because of the large steric compression (similar to the y-effect) existing in this isomer between R2 and the C(2)H(2) group; the C(a) of RZ of the EEZ isomer also appears, probably by the same reason, at higher field than that of the EEE i ~ o m e r ~ ~Confirmation .'~~. of this awignment was obtained for 3-methylaminoacrolein (331) by measuring the coupling Vc,, between H(3) and the carbon of the NCH, group: the value found for the EEZ-form [with this carbon and H(3) in W disposition] was larger (7.6 Hz) than for the EEE-form (4.2 Hz)99.The EEZ:EEE ratios observed depended on substituent R2, being > 1 when RZ = Me, and approximately 3:4 for the sugar derivative 336. C(l), C(2) and C(3) of the ZZE isomer are shielded relative to the same carbons in the EEE and EEZ forms. The spectra (at 500 MHz) of 331-333 in CDCI, at room temperature show the signals due to the ZZE isomer and a second set of signals that is the averaged spectrum of the rapidly interconverting EEZ and EEE rotamers; in more polar media, the barrier to rotation around the C(3)-N bond increases (because of the increased contribution of polar forms 322b,c to the ground state of the molecule) and separate spectra for the rotamers are observedg9.The lysine derivative 338 shows (at 400 MHz) in D 2 0 the two sets of 'H resonances typical of the EEZ-EEE e q ~ i l i b r i u m ' ~the ~ , ratio EEZ:EEE being ca 2: 1. However, the two isomers were consideredlo6to be the EEE form in equilibrium with the corresponding iminoenol form (similar to 324). This interpretation is unlikely, because the acrolein moiety of the minor isomer of 338 (the iminoenol, according to Reference 106) has almost identical resonances as the major (and more stable) isomer (EEE) of 336. The latter isomer should then be an iminoenol, a view untenable on energy considerations. In the 60-MHz 'H s p e ~ t r u m ' ~of' 331, and in the spectra of 334 and 335 taken at low fields, averaged
TABLE 18. 13Gand 'H-NMR chemical shifts [6,,
(ppm)] and coupling constants J (Hz) for 3-aminoacroleins
I3C chemical shifts ['J
331'
CDCI,
ZZE (24) EEE (8)
EEE (18)
332"
CDCI,
ZZE (27) EEE (14)
EEZ 1591
C(ilH,iJ
'H chemical shifts [3J,,li1H(i+
Other couplings
TABLE 18. (continued) --
' C chemical shifts ['J clOHal
'H chemical ~hilts[3JH,tm,i+,J
Other couplings
w N
Compound
Solvent
Isomer
C(1)
C(2)
C(3)
187.5
101.4
161.1
C(1)
H(1Y
R'
H(3)
NH
R2
7.82
3.19
("0)
DMSOd,
DzO
CDCI,
DMSO-d,
CLx1,
CD,OD CDCL
EEE
42.5
8.87
5.04
7.26
2JClI,H,11
2JC12,HIIl
2JC,21H,31
2 J ~ , l l ~ , 3 12 J ~ l ~ l ~ , 1 Ref. 1
EEE (100)
EEE (57)
EEZ (43)
EEE (45)
EEZ (55)
EEE (100)
EEE EEE
" 'C-and 'H-NMR spectra recorded at 126 and MO MHz, respectively. Broad signal. Jwmw 'J.",,,,". 'Averaged signal for the E E Z and EEE conformations. r3Jq,~,,,1317.65 Hz. 'VCl 4.8 Hz. *3Jo 7.54 Hz. i 3 J ~ I . I W4.2 , I Hz. 3 J c u 7.4 ~ Hz ~ ~ ~ ~ ~ * "C- and 'H-NMR spectra recorded at 20 and 100 MHE, respectively. S(t-Bu). " "C- and 'H-NMR spectra recorded at 22.5 and 90 MHz, respectively. " 13C- and 'H-NMR spectra recorded at 5 0 2 and 200 MHz, respectively. " "C- and 'H-NMR spectra recorded at 20 and 80 M H z respectively. '2-CH, signal at 6(C) 6.05 ppm ('J, 128.1 Hz). '2-CH3 signal at 6(C)6.07 ppm. 'ZCH, signal at S(C) 7.3 ppm r 3
,.,.,,, ,.,.,,
' '
J. L. Chiara and A. G6mez-Sanchez
334
spectra for the EEE and EEZ rotamers are observed. The 'H and '" spectra99 of 3-aminoacrolein (323) in D,O and in DMSO-d, show only one set of signals, which on measured corresponds to the EE-isomerg9(the formulation of the basis of the 3JH(,,H(,, this compound with the chelated ZZ structure in D,O solution'04b is erroneous). On the other hand, the proton spectrum in CDCI, reveals the presence of both the EE and Z Z forms, the latter predominating. Introduction of an alkyl group at C(2), as in 339-341, seems to increase the rigidity, and decrease the planarity, of the enaminal system: these compounds exist in a single isomeric form, most probably having the EE or EEE geometry, irrespective of the solvent101~'02~'03~105.
Me
Me
ZE
'quasi' EE
(342) Steric interactions also occur when R1-R3 # H with consequences related to the isomerism and planarity, clearly reflected in the NMR spectra. In the alkyl dimethylaminovinyl ketones 342, equilibria are set up between a strainless, planar ZE isomer and a sterically constrained 'quasi'-EE form having the C=CNR; in a plane and the RICO group rotated out of the plane by an angle which increases with the bulkg4 of Rt. Rotation around the C(1)-(72) bond is slow enough below 223 K to enable the observation of sharp I3C-NMR signals (Table 19) of both conformersg6 which were identified owing to their unequal population established by the 'H-NMR spectra at low temperature (Table 20)94. Inspection of Table 19 indicates that C(1), C(2) and C(3) of rotamer ZE are more shielded than the same carbons of the 'quasi'-EE form, and this TABLE 19. I3C-NMR chemical shifts [S,
(ppm)] and coupling constants, J (Hz), for compounds
342O
"C chemical shifts Compound
" ln CHCI,F
R1
Isomer
C(l)
C(2)
at 202 K. Data taken from Reference 96. In acetone-d, a1 223 K. Data taken from Reference 108
C(3)
R'
NMe2
3Jc~,,~~,~~z~
TABLE 20. Data from the 'H-NMR spectra of compounds 342'
quasi-EE
&m(R1@~m)
'JHc2,.
ncs,Wz)
population Compound
R1
Solvent
342a
Me
342b
Et
342c
i-PI
CH2=CC12 CH2CI, (CD3)zCO CD30D CH2=CC12 CD,OD CH,=CCI,
(Oh)"
27 33 SO 64
15 46 25
"Values taken from Reference 94, unless otherwise stated Measured at 202 K in CH2=CC12. 'Barrier to rotation around the C(1)-C(2) bond. 'Barrier to rotation around the C(3)-N bond. 'Values taken from Reference 109.
s,6 quasi-EE
ZE
quasi-EE
ZE
(NMe2) (PP~)
AGfc
AGO
AG;*
quasi-EE
quasi-EE
quasi-EE
+ZE
*ZE (kcalmol-')
(kcal mol-')
(kcal mol- l )
*ZE
TABLE 21. 'Tand 'H-NMR chemical shifts [6,, (ppm)] and, in brackets, coupling constants J (Hz) for compounds RICO-CH=CH-NHR2 (343) as neat liquids at ambient temperaturea unless otherwise indicated b 'H chemical shifts (3JHcs,He+l))
13C chemical shifts ('JC(O.H,i)) Isomer Compound
R1
R2
(%)
343a
Me
H
343b
Me
Me
ZZE (100) ZZE (30)
343e
Me
Et
E', (70) ZZE (40) E,'
('a
34M
Me
CH2Ph
34%
Me
t-Bu
ZZE (100) ZZE (1W
c(1)
197.5 196.4 197.4 196.1
196.6
c(2)
c(3)
R1
R1
H(2)
H(3)
R'
R2
NH
343f
Et
H
ZZE (87)
203.3
343h
t-Bu
H
208.1
343i
Ph
Me
343jJ
Ph
CH,Ph
ZZE (100) ZZE (100) ZZE (100)
-
-
"Values taken from References 1I 1 and 113. In CDCL, at room temperature: under these conditions the ZZE isomer predominates or is the only one observed (values taken from Reference 114). r 3
JH,3,,,".
*J N W ~ .
'The symbol E,. means mixture of several rotamers having the E configuration around C(Z)=q3) in rapid equilibrium at ambient temperature, giving rise to averaged signals for all the rotamers. 'Data from reference 115.
338
J. L. Chiara and A. G6mez-Sinchez
has been rationalizedg6 in terms of differences in the electron delocalization and the sterically induced bond polarization occurring in each rotamer as a result of their having a different degree of planarity and steric hindrance. The 'quasi'-EE and ZE forms of 342a (R' = Me) also differ in the 3J coupling between the carbon of the Me group at C(l) and H(2): in the 'quasi'-EE rotamer these nuclei are approximately in trunsdisposition and the coupling is larger (3.1 Hz) than in the ZE rotamer (ca 0 Hz) where the two nuclei are cislo8.The data in Table 20 show that the equilibrium shifts gradually in all solvents towards the strainless ZE form when passing from RL= Me to Et, i-Pr and t-Bu and, on the other hand, that, for a given R', the population of the more polar 'quasi'-EE rotamer increases with the polarity of the solvent. The reason for the diminution of stability of the latter form with increasing bulk of R' lies in the loss of resonance energy caused by loss of planarity. As a consequence, the barrier to rotation (AG?q-.E,,,E) around the C(3)-N bond decreases in parallel to increasing steric hindrance, passing from 14.69 kcal mol-' for R' = H (i.e. the planar, unhindered compound 326) to 12.27 kcal mol-' for R' = i-Pr9". The two conformers also differ in the values of 3J,0,,,3, which are larger for the twisted 'quasi'-EE form than for the strainless ZE rotamer [and for the planar EE form of compound 326 (Table 17)]. Above are observed. the coalescence temperature, averaged values of 3JH,,,H(2, Enamino ketones 343 having a secondary amino group usually show in their 13C-and 'H-NMR ~ p e c t r a " ~ - " ~at room temperature the presence of two sets of signals, of unequal intensities, which on the basis of the 3JH,,,H(3, measured are assigned to the chelated ZZE form, and to several rotamers, in a rapid equilibrium, having the E configuration around the C(2)=C(3) bond (designated, for abbreviation, E,J (Table 21 and Scheme 7). In dilute solution of non-polar solvents the ZZE form predominates whereas the more polar E,, form is more stable in polar media or in the neat liquids.
EEE
EEZ (343) SCHEME 7
ZEE
5. NMR spectra
339
At lower temperatures, rotations around the single bonds slow down, and the signals of the E,, form are split into two subspectra corresponding to two rotamers, which have been considered"' to be the EEZ and ZEZ forms. Support for this assignment was based"' on the 15N-NMR spectra at low temperature and the relative intensities of the I5N resonances observed for the three isomers (see Section IILA.l.b), the signal assigned to the more hindered EEZ form being the one decreasing with increasing the size of R1. It should be noted, however, that this interpretation is at variance with that presented above for the similarly constituted 3-aminoacroleins with a secondary amino group (e.g. compound 331), according to which isomers having the E conformation around the C(3)-N bond could also participate in the equilibrium. By analogy, it seems reasonable to assume that compounds 343 exist in a more complex equilibrium, such as the one depicted in Scheme 7. The data in Table 21 indicate that C(2) is shielded, and C(3) is deshielded, in the Z-isomer relative to the E,,-isomer. It has been foundlL3that in compounds of general formula XCH=CHY, where X and Y are, respectively, an electron-withdrawing and an electron-donating group, the olefinic carbon chemical shifts of isomeric E,Z pairs are simply related by an equation 6, = 6, + A. For enamino ketones 343 (and other structurally related c~rnpounds"~),the relationship for C(2) is 2.90 PPm (r = 0.9932) The deshielding effect observed for C(3) in the Z-isomer is given by the expression &(z)(~-isomer)
= 0.97
6 ~ ( 3 ) ( ~ - i w m e r= )
0.98
~ c ( z ) ( E #J
6C(3)(Esv)
+
ppm (r = 0.8773)
The near-unity values of the slopes indicate that the steric and electronic effects of the substituents on 6,(,, (i = 2,3) are equally transmitted in both isomers113. 'Jcc coupling constants over the formal C=C bond have been measured for a few 2-acylenaminesg.The values found for 3diethylaminoacrolein and for diethylaminovinyl methyl ketone (344) are 71.8 and 70.9 Hz, respectively, which are ca 8 Hz lower than the value observed in simple enamines (77-79 Hz)9 (see Section 1I.A). This is the result expected considering the more extended conjugation in Zacylenamines (322a4) and the decrease of the s character of the olefinic double bond. Data of the 'H- and (for some of the compounds) 13C-NMR spectra of enamino ketones with secondary amino group of structure:
ZZE
'E' (several conformers?)
are set up in Table 22. Inspection of the Table, and comparison with Table 21, indicate that methyl substitution at C(2) in 343a (i.e. compound 345) alters the ZZE-E,, equilibrium to favour the E,, form. In its N-methyl derivative 346 the equilibrium is shifted back again to the ZZE isomer". When R3 # H, the equilibrium is completely shifted towards the ZZE isomer irrespective of the polarity of the medium (cf compound 350 in different media). This is probably due to the strong intramolecular hydrogen
TABLE 22. 13C and 'H chemical shifts [aTYS(ppm)] and (in brackets) coupling constants ' J (Hz) for compounds:
'H chemical shifts (,J)
I3C chemical shifts Isomer Compound R1 RZ R3 R4 Me Me H
Solvent
H
CDCI,
Me H
Me H
CDCI,
Me H
Me Me
CCI, CDC1,
Me H
Me Et
CCI,
Me H
Me CH,Ph
neat CCI, CDCI, C5H5N
%
C(1) C(2) C(3)
R1
Rz R3
R4
R1
R2
R3
R4
NH
Ref.
342
J. L. Chiara and A. Gbmez-Shchez
bond evidcnced by thc low S(NH) values; this bond is stronger when R3 = Me than when R3 = H (cf compound 343b in Table 21 with 348 in Table 22), and when R4 = aryl. For compounds with R4 = 4-XCsH4 (i.e. 352-355 and 359-3613, the strength of the hydrogen bond increases with the electron-withdrawing capacity of X, a good linear correlation between 6(NH) and the Hammett u constant of the substituent X having been obtained"'. Good linear correlations have also been found between 6(NH) and the infrared v(N-H) frequency, and between 6(NH) and the v(C=O) frequency of the chelated carbonyl g r ~ u p " ~ . The investigation of the enaminoneketoimine-iminoenol equilibrium:
was one of the early applications of 'H-NMR spectroscopy to organic hemi is try""'^^. The data gathered in Tables 21 and 22 show that this equilibrium is completely displaced in the direction of the enaminone, which has NMR parameters clearly distinct from those expected for the ketoimine and the iminoenol tautomers. Even in some compounds where the enaminone system is fused to an aromatic system, as in the Schiff bases of 2-hydroxy-1-naphthaldehydewith aliphatic amines, the equilibrium is shifted to the enaminone tautomer even though this involves the loss of resonance energy of one aromatic ~ i n g " ~ . ' ~However, '. in the similar compounds with R = aryl, both tautomers seem to exist in eq~ilibrium"~.
Iminoenol form
Enaminone form
The NMR spectra of tertiary enaminones having only one vinyl hydrogen, such as 4-dimethylamino-3-penten-2-one (362), are less informative concerning their stereochemistry. The Z E structure has been assigned to 362 on the basis of its UVlZ4and IR93spectra. 'H- and 13C-NMR spectral data for 362 appear in Scheme 8. The relatively low value of 6C(5) (15.3 ppm), indicative of a y-effect, and the 3Jcoupling between C(5) and H(3) (6.3 Hz) observed and its comparison with those of model compounds, are in accordance with the configuration assigned'''. Data of the "C- and 'H-NMR spectra of 3-amino-2-cycloalkenones appear in Table 23. The observations made for acyclic enarnines (see Sections 11.A and II.B, and Tables 1 and 11) and for 1-aminocycloalkenes (Tables 2 and 13) can also be applied to these compounds. For a given 3-amino-2-cycloalkenone, 6C(2) and 6H(2) decrease in the order pyrrolidino < Alkyl,N < pipcridino < morpholino (e.g. compounds 36%365; 369-373; 38>393), and the azetidino derivative 385 exhibits the highesl level of shielding of the series 383-393. Similarly, for a given NR3R4, the SC(2) and 6H(2) for 3-amino-2cyclopentenones are smaller than those for 3-amino-2-cyclohexenones (cf compounds 344-365 and 369-373). The greater delocalization of nitrogen lone-pair electrons into five- rather than six-membered rings is also shown by dynamic NMR measurements of rotational barriers about the C(3)-N bond; thus, the proton NMe, signals of 363 are separated at 240 K and coalescence occurs at 306 K (at 60 MHz), whereas in 383 the proton NMe, signals, separated at 223 K, coalesce at 264 K66.
5. NMR spectra
(362) "C NMR C&MS (P~m)l( J c ~ . H HZ) ~. C(1)
C(2)
C(3)
C(4)
C(5)
NCH,
Other couplings (Hz)
SCHEME 8 Compounds 366393 with fixed E configuration around C(2)=C(3) and fixed E conformation around C(1)-C(2) are well suited for studying the influence of substituent NR3R4 on the chemical shifts of C(1), C(2) and C(3), and to establish whether some of these chemical shifts are able to describe the degree of delocalization. The 13C-NMR spectra of 3-substituted-2-cyclohexenones of general formula 394, including compound 371, show wide variation in 6C(3) that correlale with Pauling's eleclronegalivity X, and even wider variation in bC(2) that correlate with Taft's resonance parameter a,", while C(l) is rather insensitive to structural variationL2'. As the y, and a," parameters for different NR3R4 groups vary very little, these correlations cannot be used to estimate ~ C ( I(i ) = 1 or 2). An approachlZ8to determine the I3C spectra of 3-dialkylamino-5,5dimethyl-2-cyclohexenones 383-393 makes use of a mathematical model (the principal component analy~is"~).The main conclusions were that a fair correlation (r = 0.945) exists between the shifts of the resonances of C(1) and C(2) induced by different NR3R4, while the shifts of C(1) and C(3) show quite different trends. The variation of the n,n delocalization is the most important effect on the shifts of C(2) and, consequently, of C(1). This delocalizalion depends mainly on the inductive effects of R3 and R 4 and the steric effect between the hydrogen(s) a to nitrogen and the hydrogens in position 2 and 4 which gives rise to a y-effect and alters the coplanarity of the whole conjugated system.
(394) X = H, Me, Ph, OEt, SEt, N(Bu-n),
TABLE 23. "C- and 'H-NMR chemical shifts [ams (ppm)] and (in brackets) coupling oonstants 3J (HZ) for 3-amino-2-cycloalkenones
~
~~-~
'H chenkzd shifts
"C chemical shifts Compound
n
R'
R'
O
H
H
O
H
H
O
H
H
I
H
H
NR'R4
C(1)
C(2)
C(3)
C(4)
C(S)
C(6) R',R1
NC.
H(3
H(4)
H
H
1 I
H H
H H
I
H
H
1
H
H
I
H
H
NH
a
CDCI,
n
"uO NHCH,Ph
Solvent CDCI,
NMe,
CDCI, 224. (5.50)
iw'
1
H(6)
(5.50) 234"
2.42'
6.32'
CDCI,
15.50) i3+ (5.50)
7.52'
DMSO~,
243'
5.86'
CDCI,
NMe, NEt,
a
NBu,
CDCI, CDCI, CDCI,
Ref.
n
1
H
H
N
I
Me Me Me Me Me Me Me Me Me Me Me
H H H H H H H H H H H
BuNH PhCH,NH PhNH 4MeC,H,NH 3-CIC,H,NH ~-M&C,H,NH NMePh NPhMe NMe, NEt,
1
I 1
1 1 1
1 1 1 1
\P MeNH
CDCI, 2.18 2.17 2.03
2.22 217 127
6.48
4.73 7
CDCI, CDCI, CDCI, CDCI; CDCI, CDC1, CDCI, CDCI, CDCI, CDCI, CDCI, CDCI, CDCI,
CDCI,
CDCI,
CDCI,
CDCI,
CDCI,
CDCI,
CDCI, "Triplet.
'381 and 382 are rotational isomen.
346
J. L. Chiara and A. Gomez-Sanchez
For the quantitative evaluation of the inductive effect of R3 and R4, the pK,,+ values of the conjugate acid of the enaminone, or the enthalpy of complex formation, AH,,,, of boron trifluoride with the carbonyl oxygen for different NR3R4 groups were proposed. The variation of SH(2) ~, was considered to be a measure of the steric interaction. The following correlations were found: SC(1) = 0.125 AH;,, + 2.794 SH(2) + 198.42 dC(1) = -0.806 pK,,, + 3.152 SH(2) + 182.42 SC(2) = 0.252 AH;,, + 6.945 SH(2) + 95.23 SC(2) = - 1.761 pK,,, + 7.535 6H(2) + 64.26
(r = 0.977) (r = 0.966) (r = 0.976) (r = 0.974)
A simple formula has been proposed7' to calculate SH(2) of enaminones in any of their four isomeric forms A-D (Scheme 5): d = 60 - Ad*,,", - Ah,,,
+ K(q - qo)
where 6 is the chemical shift of interest, So is the chemical shift of a standard, AS,,,,, is the anisotropic shift caused by deviations from standard geometry, Ad,, is the anisotropic shift of aryl groups substituted in the system of interest, K is a constant and q and q, are the electron density on the adjacent carbon atom of the system of interest and of the standard. The anisotropic effects were calculated by McConnell's equation130, the electron densities were calculated by the HMO method and K and So were derived by applying the formula to a series of compounds of fixed structures. The observed and calculated chemical shifts of compounds whose geometrical structures are fixed are in fair agreement (f0.06 ppm). Larger differences were found for some compounds containing either benzyl or phenethyl groups. For non-rigid compounds such as 4dialkylamino3-penten-2-ones (395), the formula was applied to the four possible (A-D) alignments in order to find the one fitting best the experimental value. The drawback of the procedure is that the method used to calculate the q values does not distinguish between NR3R4 groups having different electron-donating abilities. Thus, the SH(2) value calculated (5.09 ppm) for 4-diethylamino-3-penten-2-one (395a) in the EE form is identical to the observed value, whereas the closer value calculated (4.93 ppm) to the observed one (4.95 ppm) for 4-pyrrolidino-3-penten-2-one (395b) corresponds to the EZ geometry. Most likely, both compounds (as their analogous 362) are the Z E isomers. The larger deshielding effect (due to the electron-donating ability) of the pyrrolidino group relative to those of the Me and Et groups is not taken into account in this treatment. Compounds 322 with R1-RS other than hydrogen are sterically very constrained. Representative examples are the tertiary cyclic enaminoketones 3%a which exist in a tautomeric equilibrium with the trisubstituted enamines 396b. The steric hindrance present in the tetrasubstituted 396a is relieved by migration of the carbonsarbon double bond13'. The structures were established by IR and NMR spectroscopy, and the isomer percentages were determinated by integration of the proton vinyl signals of 3968. The equilibrium positions were found to depend mainly on the size of the amino ring, the proportion of form a decreasing in the order pyrrolidino r piperidino > morpholino, i.e. the order of decreasing ability of the amino moiety to form an exocyclic double bond and n,n donation. In the pyrrolidino derivatives, where the percentages of form a reach 90%, the efficient conjugation compensates for the large The second factor determining the equilibrium is the + R effect of R' (OMe > Me > Ph) which competes with the amino group in conjugating with C=O: the greater the + R, the lower the conjugation in 396a and the larger the proportion of 396b (i.e. the proportion of this isomer is in the order Ph > Me)131.
5. NMR spectra
b. Nitrogen-I5 spectra. The 15N-spectral data for some 2-acylenamines are collected in Table 24. The 15N resonance of the neutral compounds appears in the range - 247 to - 314 ppm, close to that for amidesgl ( 4 6 - 301 to - 352 ppm in simple enamines, see Section 1I.B). The differential chemical shifts, AS(N) (see Section II.B), are larger [AS(N) = + 38.5 to + 54.2 ppm]30.33 than those found in simple enamines [AS(N) = - 0.3 to + 32 ppm]. These two parameters reflect the more efficient n,n interaction in 2-acylenamines. The expected decrease in the n + n* transition energy and a possible higher planarity at nitrogen in 2-acylenamines could also contribute to this downfield shift. Solvent and temperature effects on the "N shieldings are important, as expected. 3-Dimethylaminoacrolein (326), and its vinylogous 327 and 328 are particularly wellstudied examples of solvent-induced 15N chemical shiftsg2.Large downfield shifts of up to ca 35 ppm were observed with increasing solvent polarity (see Table 24). These solvent-induced shifts correlate linearly with the solvent polarity parameter E, and with the free energy of activation to rotation of the MezN group around the C(3)-N bond9'. This has been rationalized in terms of the n-electron distribution along the C-N bond: increasing solvent polarity favours nitrogen lone-pair delocalization with concomitant downfield shift of the lSN resonance and higher AGL, values for rotation around the C(3)-N bondgz. The effect is augmented in the case of 0-protonation at the carbonyl group, which produces a considerable deshielding ( + 60 to + 76 ppm) of the nitrogen nucleus, as can be seen by comparing the 6I5N values of compounds 344,398,402 and 404 measured in CDCI, or acetone with those found in CF,COOD solution133. The data in Table 24 illustrate three important effects on N-shielding in enaminones, i.e. N-substitution, change of configuration or conformation and H-bonding. By comparing compounds 343f and 343g 399 and 400 and 34311 and 403 it can be seen that Me substitution at nitrogen in primary enaminones results in a slight deshielding in both
TABLE 24. 15N-NMR chemical shifts [Gm,irNo, Compound
w
(ppm)] and coupling constants J (Hz). for 2-acylenamines
Isomef EE
All-E All-E ZZE ZEeEE ZZE ZE EE Z E S EE ZEeEE Z E - H" EE - H"
zz
ZESEE ZZE ZESEE ZZE ZE EE ZEeEE ZESEE Z E - H" EE - HC'
zz
ZESEE
6-N
AS(Nr
'JNH
2J~w.=r,~
i2 3 J ~ ~ z ~Solvent . ~
Temp ( K )
Ref.
ZZE ZESEE ZZE ZE EE ZZE ZZE ZEeEE ZE -Hte EE - H + e
4.2'
THFd,
3.8
THFd, THFd, THFd, THFd. CDCI,
zz
ZESEE ZZE ZE ZEGEE ZE - H+C ZZE ZZE ZE ZEeEE ZEeEE ZEGEE ZZE ZZE ZZE
f2 continued
TABLE 24. (continued)
Compound
w
3 Isomerb ZZE
a'SN - 273.5
A6@y
'JNH
'JC(~PI.N
3 J ~ ( 2 ) 8 . ~ Solvent
91.5
CDCI,
Temp (K)
Ref.
352
J. L. Chiara and A. Gomez-Sanchez
+
+
isomers ( 1.5 to 5 ppm), while further Me substitution in secondary enaminones produces an effect twice as large and opposite ( - 5.8 to - 9.5ppm), in such a way that the 15Nresonance of tertiary enaminones is more shielded than that of the corresponding compounds with primary amino group. These changes have been explained in terms of solvent effects and intramolecular H-bonding, which dominate over the 'true' Mesubstitution effect that can be reasonably assumed to cause de~hielding'~~. The Z E isomerization results in ca 10 ppm shielding132and shows solvent dependen~e"~.The dominant shielding contribution in this case is assumed to be the breaking of the intramolecular H-bond in the Z-isomer, in parallel with that found in the 0-protonation studies133. Increasing bulk of the R1 substituent in the COR1 group also produces shielding due probably to reduced conjugation resulting from non-planarity of the double bonds. The effect is less pronounced in the Z-isomers where the intramolecular H-bond enforces a higher planarity of the conjugated system. The spectra of the secondary enaminones show, at low temperature, separate signals for some of the isomers depicted in Scheme 61L2.Whereas the lowfield signal remains narrow over the entire temperature range, and therefore has been assigned to the ZZE isomer, the other two lines exhibit dynamic behaviour at low temperature. The weak highfield signal was assigned to the non-planar EEZ-isomer since it increases in intensity with decreasing size of the R1 group (see, however, Section 1II.A.l.a). The higher shielding of the N atom of this isomer is in agreement with expectations on the basis of a lower planarity of the double bonds in this isomer. Alkyl substitution at C(2) leads also to shielding of the signal of the isomers with E configuration (there are, however, no data to evaluate this effect in the corresponding Z-isomers). This shielding is again due to non-planarity of the double bonds caused by steric repulsion between the substituent at C(2) and the COR' group, although out-of-plane torsion of the amino group to release the steric strain could also contribute. The 'J,, coupling constants in Table 24 span from 88 to 95 Hz, in the range observed for amides31. In primary enaminones, this coupling is identical for both NH protons, probably due to fast exchange132.For C(2) unsubstituted enaminones with secondary amino group, this coupling is smaller in the Z- than in the E-configurational isomer; the latter is thought to exist predominantly in the Z conformation around the C(3)-N bond in these compounds. Thus, the difference in coupling constants follows the general trend that the coupling to the proton cis-disposed to the double bond is always smaller than when it is in trans disposition. In contrast, for the corresponding C(2)-alkyl substituted compounds, 'J,, is smaller for the E than for the Z configuration despite the fact that both configurational isomers keep the same E conformation around the C(3)-N bond. This change has been ascribed to changes in bond angles at the N atom resulting from steric repulsion between the C(2) substituent and the NH. This one-bond coupling also decreases with increasing size of the N-alkyl substituent and with C(3)-alkyl substitution. The solvent and intramolecular H-bond do not ,influence the value of 1J,,132.This coupling has been used as a probe for measuring ketoenamine-iminoenol equilibria (see Section 1II.A.l.a) in "N-substituted 2 - a ~ ~ l e n a m i n e s ~ ~ ' ~ ' ~ ~ . coupling can be used for stereochemical assignment since it is usually The 3J,2,,N higher for the Z-isomer (13J,!2,,,""""13.8 to 4.2 Hz) than for the E-isomer (1 3J,(,4Ncis~0.9 to 1.8 Hz)'32. The introduct~onof an alkyl substituent at C(3) reduces the I J,,,,,,( constant (~3J,(,,~N,tr'"s~ 1.8 to 2.7 Hz) due probably to angle distortions. The lZJco,,,N( coupling changes m the range 0.6 to 5.2 Hz and shows a complex dependence on solvent and stereochemical properties of the substituents on C(2)132. coupling constants along the conjugated system have been meaThe "JL,, suredg2 in i5~-labelled32&328. From the values of the one-bond coupling (15.315.9 Hz), a 36% s-character has been estimated for the N atom, as expected for an sp2-hybridized nitrogen. The corresponding three-bond coupling constant is 3.7 Hz for 326 and 327, and 2.4 Hz for 328, whereas the two-bond coupling is zero for 326 and
-
5. NMR spectra
353
327, and only 1.8 Hz for 328. The relative values of these two coupling constants have been explained on the basis of the difference in the corresponding Fermi-contact terms along two and three bonds, which dominates the 13C-"N couplingsq2. 2. 2-Alkoxycarbonylenamines (Enaminoesters)
Enaminoesters (418) are a particular case of 322 (R1 = OAlkyl) and most of the considerations in Section III.A.l concerning the electron delocalization and stereo-
chemistry of those compounds apply here. The calculated (HMO) n-electron distribution for ethyl 3-dimethylaminoacrylate (419) (Scheme 9)s4 indicates a highly efficient n,n interaction, and its comparison with that of 3-dimethylaminoacrolein (326) allows one to predict similar, or slightly higher, levels of shielding of C(2) and the amino nitrogen for 418 than for 322.
,
Et 0 1.9008 1 0.7034
0 1.6026
0.7132 I I
5c H /
1.6564
1.1476
0.7304
H'
M,
'~:8042
o ~c1 ~ \ ~ ~ L ~ 0.7534
1
H'
Me (326)
,Me
\~l.8168
Me (419)
SCHEME 9 Calculateds4 (HMO) n-charge distribution for 3-dimethylaminoacrolein 326 and for ethyl 3dimethylaminoacrylate419 Rotamers around C(1)-C(2) in 418 are separated by very low energy barriers and are not distinguishable by NMR spectroscopy. Enaminoesters with R4 = RS can adopt either the E or the Z configuration (A and B; Scheme 10)around C(2)=C(3). Secondary enaminoesters (R4 H; R' = H) can exist in forms C-E and in the tautomeric imino form F. Isomers similar to J-L (Scheme 5) with R1 = OAlkyl, which are sterically very crowded, have not been observed. The imino form (F) exists when severe steric hindrance prevents planarity and conjugation of 418. The 13C-, 15N- and (mainly) 'H-NMR spectra of different classes of acyclic enaminoesters have been summarized in Table 25. These data can be used in assigning the correct stereochemistry to a particular compound or its isomer. When R2 = R3 = H, the configuration around C(2) = C(3) follows straightforwardly from the values of 3J,,2H,3, (compounds 42W27: Z Z E isomer, 8.0-8.3 Hz; E,, or EE isomer, 12.9-13.7 Hz) and 1J,,,,,,,, (ZZE-422 10.4 Hz: EE-422, 3.7 Hz). For compounds with R2 = H, C(2) and H(2) are always more shielded in the ZZE than in the E,, or EE isomer, as was observed in the similar 2-acylenamines (Section III.A.l). In 3-aminocrotonic esters 4iB-4f9,the C(3)-Me proton signal appears at about the same position in the spectrum of each isomer ( 6 , 1.8-1.9 ppm; 6, 2.2-2.6 ppm) which allows their distinction even in cases when only one of the forms 1s available; the deshielding effect observed in the E,, form [C(3)-Me cis to C02R1] is a consequence of the proximity of coplanar CO,R1 in p-position13'. Likewise, when R2 = H and R3 = C02R1 (44143), the alkoxycarbonyl group at C(3) deshields the cis H(2) in the ZZE isomer [SH(2) 5.h5.41; the
+
TABLE 25. 13C,"N and 'H chemical shifts [G,dl'C. 'H),GW,D~NO, (15N), ppm] and, in brackets, coupling constants J (Hz)" for enamino esters
Compound
R1
RZ
R3
NFRVsomer (yo)
C(1)
C(2)
q3)
NR4R5
6'"
R'
R2
R3
NR'RS
Solvent
("JNH)
H
NHBu
CDCI,
H
NHPr-i
CCI,
H
NHPh
CDCI,
H
NEI,
B
CDCI, CDCI, H
N(R-i),
CDCI,
H
NHMc
CDCI,
%
Ref.
NHMe
NH2
ca, CDCI, DMSOd,
NHMe
CDCI,
NH,
neat
CDCI,
DMSOd,
NHMe
neat
cm,
(continued)
TABLE 25.
(continued) 8°C CJcuw,d
Compound
R1
R2
R3
NR'R5
Isomer (%)
C(1)
C(2)
C(3)
8'H
NR3R'
615N (.JNH)
R1
R2
W Ln
LO
m
(3J~~~w(i+
R3
NR4RJ
Solvent
ZZE (58)
Me
NHCH,Ph
ZZE
neat
(loo)
CDCI,
C A N
Me
NHPh
ZZE
C A
ZZE
neat
( W CDCI, CDCI,
Ref.
437
Me
H
Me
438
Et
H
Me
3.28
4.38
2.37
3.25' (7.0)p
CHCI,
139
1.22' (7.2) 4.04"
4.51
2.41
288
CDC1,
137
1.22' (7.0) 3.57 3.70
4.41
2.42
CDCI,
139
5.27 5.50
3.71 3.81
327' (6.9) 6.6'* 6.3",*
CDC1,
135
3.68
5.03
3.68
8.1.'b
CDCI,
135
3.48
5.02
3.58
g2Wb (6.24)' 4.40 (6.24Y 7.19
CDCI,
142
Eav (50)
3.43
4.58
3.68
5.Wb (5.16Y 4.03 (5.16Y 7.10
NHPh
ZZE
3.68
5.40
3.73
9.7°.b
CDCI,
135
NMe,
(100) E,
3.60
4.53
3.89
2.87
CDCI,
135
E, E,
CCl. CCl,
136 136
CDCI, CCl, CJ4
135 136 33
E.
NMe,
(la')
Et
439
H
Me
~3
G (: )
440
Me
H
C0,Mc
NH,
ZZE
441
Me
H
C0,Mc
NHHex-c
EX" ZZE (100)
442
Me
H
C0,Me
NHCH,Ph
ZZE (50)
443
Me
444
Me
H H
C0,Mc C0,Me
445
Me
H
C0,Me
NEt,
446
Me
H
CO,Me
N
447
El
H
CH,CO,H
NMe,
3
" NH signal. Broad. E, means averaged spectrum of the EE and EZ forms. 3J",3,.~".
'd(0CHJ 'JWlC!31
49.9 ppm.
P u r e hquid plus 1W15% of acetone-d, Multiplet. Triplet.
'
'
4.40 4.45
4"
3.64
Z
-270.9
4.73 4.60
3.93
1.63; 3.16
j'JNH.
2 J ~ . ~ w ~ 3 J ~ , w w
'NH not located. "r Quartet l J ~ l ~ l . ~ 3 . 3 J ~ ~ . w corn ,'-'NH.M,.
'
"Data taken from Reference 134.
w VI 4
358
J. L. Chiara and A. G6mez-Sanchez
ZZE
(E)
(F)
SCHEME 10 Isomeric forms of an enaminoester. For A and B, the symbol indicates the configuration around C(2)=C(3). For C and D, the symbols indicate, in this order, the configuration around C(2)=C(3) and the conformation around C(3)-N. For E,the symbols indicate, in this order, the conformation around C(1)-C(2), the configuration around C(2)=C(3) and the conformation around C(3)-N
6HHo, values of the E,, isomer are more similar to those of the E,, form of 3aminocrotonic and 3-amlnoacrylic esters where this deshielding effect is absent. The chelated ZZE form can be associated with the downfield NH signal which appears in the range 6 6.6 7.8 ppm for the compounds with a primary amino group, 6 7.3-8.6 for NHAlkyl and 6 9.7-11 for NHAryl, thus reflecting the increasing strength of the hydrogen bond. The 15N chemical shifts of the hydrogen-bonded Z Z E form of 427 and 428 are smaller than those of the corresponding E,, form132. 3-Amibocrotonic esters with a primary amino group often give a single, very broad two-proton NH, signal which, by lowering the temperature or changing the solvent, can be split into the typical signals of the free and chelated form. The broadening has been attributedlJ8 to restricted rotation around the C(3)-N bond, together with quadrupole coupling with the 14N nucleus and proton exchange between neighbouring molecules. In a different i n t e r p r e t a t i ~ n ' ~based ~ , on the observation in the 'H-NMR spectrum of ethyl 3-aminocrotonate (431) in CDCI, of a single, broad two-proton signal, it is considered that this compound adopts the Z configuration around the C(2)=C(3) but that the amino function is free. In a like manner, cyclic enamino esters 448 and 449 with a primary amino group are considered to be unchelated, whereas their N-alkyl and N-aryl derivatives have the NH intramolecularly bonded to the ester
n=l,2 X = 0,NH,S R2,R3= H,Me, Ph (448)
n=l,2 R1 = H, Et, Bu, Hex, CHzPh, Ph (449)
5. NMR spectra
359
Compounds 418 with RZ, R3 # H and R5 = H are sterically very constrained and tend to relieve compression by adopting the non-planar imino form F. Thus, the trisubstituted enaminoester 450 exists in the solid state and in solution in the intramolecularly bonded ZZE-form (a), as shown by its UV and IR absorptions, and (in 12.0 Hz). On the other CDCI, solution) by the proton NH signal at 6 10.1 ppm (3JH,3,,H hand, the analogous tetrasubstituted compound 451 shows, in the solid state, IR bands attributable to the imino form (b); its freshly prepared CDC1, solution also shows the IR bands of the imino form, lacks the typical proton NH signal of chelated N-aryl enaminoesters and exhibits instead a multiplet at 6 4.40 ppm due to H(2), and at 6 1.58 ppm the singlet, due to C(3)-Me, of 45lb. On standing, the intensities of these IR and NMR absorptions in solulion decrease gradually, whereas (he IR bands and NMR signals anticipated for the enaminoester form 451a appear and grow until an equilibrium is reached in which the latter isomer predominate^'^^.
(a) (b) (450) R 1= Me, R2 = H, R3 = Ph (451) Rl = Et, R2 = Me, R3 = 4-MeO-C& When R3-R5 # H, relief of the steric hindrance can be attained by migration of the C=C bond. Examples are the cyclic enaminoesters 452a which exist in equilibrium with the tautomeric trisubstituted enamine 452b143b,145 (cf compounds 396, Section III.A.1). The percentages of form a, determined by 'H-NMR and IR spectroscopies, decrease in the order pyrrolidino > hexahydroazepino > piperidino for the amino ring, and in the order cyclopentene > cycloheptene z cyclohexene for the carbocycle. Within each ringsize combination, the effect of varying the ester alkyl group R1 is that a methyl ester shows a more conjugated form a than the corresponding ethyl or isopropyl esters which are about equalI4'. As for the related enaminoketones 396, these results were
n = 2, 3,4 n' = 4, 5,6
R1 =Me, Et, i-Et (452) r a t i o n a l i ~ e d lby ~ ~considering the high strain in form a which is only counterbalanced by the highly efficient electron-donating ability of the pyrrolidine ring. A second factor is the energy difference between exocyclic and endocyclic double bonds for each
J. L. Chiara and A. Gomez-SBnchez
360
of the rings in 452. The order of stability of the exocyclic double bonds found was five-membered ring > seven-membered ring > six-membered ring; thus, the 515 ringsize combination is the most favourable one for form a, and the 616 combination the most unfavourable. The destabilizing effect of R1 chains larger than Me was attributed to a loss of rotational freedom of OR1 in the more stable conformation of the ester function in form a when R1 is Et or i-Pr. 3. 2,2-Diacylenamines
22-Diacylenamines (453) with R1 = R2 exist in a single configuration around C(2)=C(3), but due to restricted rotations about C(1)-C(2), C(1')-C(2) and C(3)-N, the occurrence of eight rotational isomers is theoretically possible. The tautomeric imino form 454 can also exist for derivatives with a primary or secondary amino group.
0 II R1-C(1) R3 \ / C(2)=C\(3) / R2-C(1') NR~R~
6
0
II
~1-c
/
/
\\
CH-C
R2-C
R3
\
1:
NR4
(453) (454) Extensive dynamic NMR investigations (Chapter 6) have revealed enhanced energy barriers to rotation around the C(3)-N bond and, usually, a concomitant reduction of energy of rotation around the C(2)=C(3) bond. Combined X-ray crystallographic and 1R spectral studies of some 2,2-diacetylethenamines with secondary amino group (453, R1 = RZ = Me, R3-R4 = H) have shown that these compounds adopt the chelated EZE conformation (A, Scheme 11) with the (diacety1)vinylamino group essentially planar (except for the intramolecularly bonded acetyl which is tilted by up to 9 " with respect to the rest of the delocalized system) irrespective of the m e d i ~ m ' ~ ~ *2-Aminomethyle'~'. ne-5,5-dimethyl-1,3-cyclohexanediones with a primary or secondary amino group (455) have the fixed ZZE conformation (B) with the chelated enaminodiketone system essentially planar'46,'47. The NMR parameters of these two classes of compounds can be considered characteristic of the EZE and ZZE conformation of enaminodiketones. The IR and Raman spectra of 3-amino-2-alkoxycarbonylacrylic (aminomethylenemalonic) esters with a primary or secondary amino group (453, R1 = R2 = OAlkyl, ~ ~these ~ ssubstances ~ ~ ~ exist in solution in the inR3 = R4 = H) have s h o ~ n that tramolecularly bonded enaminodiester form as equilibrium mixtures of the EZE (C) and ZZE conformer (D); both rotamers have been considered to be planar149 or to have the chelated enaminoester moiety planar and the free alkoxycarbonyl group twisted out of this plane148.As the barriers to rotation about C(1)-C(2) in rotamers C and D are very low, averaged NMR spectra for the two forms are observed. The NMR parameters of 5-aminomethylene-2,2-dimethyl-1,3-dioxane-4,6-diones (456) with fixed ZZE conformation can be taken as characteristic for aminomethylenemalonic esters with this dimethylaminomethylenemalonate (457) has been shown'50 c ~ n f o r m a t i o n lDimethyl ~~. to take the 'quasi'-ZE conformation (F) with the trans-dimethylaminoacrylate moiety [C(1)-C(3) and N] in a plane, and the other MeOC(ll)=O group twisted out of the plane by 68 ". It seems reasonable to assume that the related enaminoketones 458 adopt a similar conformation (G) with the acyl group cis to the amino function twisted out of the plane of the rest of the molecule. The structures of 3-aminomethylenemalonic esters, as deduced from their spectral properties, have been the subject of a reviewlS1.
5. NMR spectra
OR'
O=C
/
R'O-C
H
\
/C=C
R1O-C
0
I
//
H
\
/
c=c\
/
\
R'O-C
N -RZ \\Om,HI
N-R2
\;a,,,d
EZE
ZZE (D)
(0 0
//
0
I
//
0-C H 6 \ 1 Me2C\2 5C=C 4 1 \ y-C N-R \&,,,,HI /
ZZE (E) (456)
MeO-C(1) H \ /C(2)=C\(3) N-Me 0z=C(l1)
L
P
/
Me
Me
'quasi'-ZE (F) (457)
0
R'-C
0::c
I /
\ /c=C
H \
N -R2
bR' R2' 'quasi'-ZE (G) (458)
SCHEME 11 For A-E, the symbols indicate, in this order, the alignments of the free C=O, the chelated C=O and the N-R group with respect to C(2)=C(3). For F and G, the symbols indicate, in this order, the alignment of C(1)=0 and C(1)=0 with respect to C(2)=C(3)
Data of the I3C-, 15N- and lH-NMR spectra of representative 2,2-diacylenamines 453 (R3 = H) have been collected in Table 26. It can be seen that secondary enaminodiketones with the EZE geometry ( 4 6 1 4 3 ) show well-separated (A6 0.114.22 ppm) singlets for the two non-equivalent COMe groups, while in the diketones with fixed Z Z E conformation (465467) the chemical shift differences between the two COCH, is much smaller (A6 W.07 ppm). This is attributable to the fact that in the former compounds the chelated COMe has the methyl group flanked by two carbonyls and is deshielded relative to the unchelated COMe; in the Z Z E conformation the two CH, groups are in a more similar environment. For the same reason, H(3) appears more deshielded for the Z Z E than for the EZE c ~ n f o r m a t i o n ' ~Similarly, ~. H(3) of cyclic secondary enaminodiesters with fixed Z Z E conformation (474476) appears at lower field than that of aminomethylenemalonic esters (47M73); the chemical shifts measured for the latter compounds are the averaged values corresponding to the EZE and Z Z E conformers being in rapid e q ~ i l i b r i u m ' ~ ~Other ~ ' ~ ~features . of the 'H-NMR spectra are similar to those of
TABLE 26. "C-,15N- a n d 'H-NMR
chemical shifts
[G,dL3C, 'H),d,,,5,,2('5N)
ppm] and, in brackets, coupling constants (J. Hz) for compounds
0 6'H
6I3C ('JcH)
("JH~)
6"N
Compound
4M)
461
R1(1), R'(1')
Me, Me
Me, Me
R2
R3
Isomer
.,
H
H
H
Me
EZ"
EZE'
462
Me, Me
H
n-Bu
EZE'
463
Me, Me
H
Ph
EZE'
C(1)
C(1')
C(2)
C(3)
Rz
R3
('JNH)
- 273.0 (92.8; 92.1) - 264.2 -260.8 (91.71
- 249.2
RL(l) R1(l')
H(3)
9.52 (0.8Y . .
7.64'
9.52
R2 3.43 K . A6Y .
R3
Solvent
Ref.
3.44 CDCI, (0.6Y . . CDCI,
152 132
CDCI,
153
DMSO-4 153 CDCI, 132 2.23f
2.44'
7.77 10.08' (14.03"
CDCI,
146
2.27'
2.48'
7.75 11.07' (13.43"
CDCI,
146
CDCI,
132
TABLE 26. (continued) 6'H ("J,,)
613C ('J,)
"
S l 5.L w
Compound
R1(1), R1(1')
R2
R)
Isomer
474
-0-CMe,-O-
H
Me
ZZE'
475
-0-CMe,-O-
H
t-Bn
ZZE'
476
-0-CMe,-O-
H
Ph
ZZEe
477
-0-CMe,-O-
Et
Et
ZZE'
C(1)
1638"'
163.3
C(1?
C(2)
1613" 104.1
163.3
102.8
C(3)
R2
155.1 -
157.9
R3
54.7; 26.4
('J,,)
R1(l) R1(I') H(3)
1.53
1.61
'8.02
*4J~1~(31.
j2J
CILW,'
'3Jcmwei. 'Chelated NH. " Unchelated NH. " Unchelated C=O. " Chelated C=O.
R3
8.20 9.50' (14.0)' 8.04 9.7" (15.2r 8.66 11.26'
"Thesymbols indicate, in this order, the alignment oiC(l)=O and q l ' ) = O with respect to C(2)=C(3). 'Broad. d*Jw~mms 'The symbols indicate, in this order, the alignments of the free C(1)=0, the chelated C(l')=O and the N-R 'Unchelated COMe. OChelated COMe. h3Jwsm~. "J,, (the coupling to the ortho-protons of the aromatic ring).
R1
group with respect to C(Z)=C(3)
1.28; 5.49 (7.2)
Solvent
Ref.
CDCI,
146
CDCI,
1%
CDCI,
146
1.15; CDCI, 3.84
156
(7.2)
5. NMR spectra
365
enaminones with a single carbonyl function. On the other hand, double substitution by carbonyl at C(2) results in a strong N-deshielding as seen by comparing the 15Nspectrum of 461 with that of 343b (Table 24)i32. Compounds 453 with R1 # R2 and R4 (and/or R5) = H can exist in the E and Z configuration around C(2)=C(3). When R' = Me, R2 = Ph and R3 = H, the chelated E isomer (478) is the only isomer observed irrespective of the substituent R at the nitrogen, as shown by the UV and IR spectra, as well as by the 6(NH) values and their comparison with those of enaminones having a single chelated COMe or COPh group157.In compounds 479 where a COMe or COPh competes with a C 0 2 R group for chelation, an equilibrium favouring the E isomer (479a) with the intramolecularly bonded COMe or COPh is establishedlS7. Thus, the hydrogen-bonding acceptor capabilities of the C=O group in these compounds are in the order COMe > COPh, COMe > CO,K and COPh > C02K157.The Z:E ratio varies with the substituent R3: substitution of Me or Ph for H decreases, in this order, the proportion of the E isomer157. Me 0 ' / O=C
phcu
Me-C
N-R \\ O,,,,H1
(Ph)Me-C
(Ph)MeCO
)4"' N-Aryl
MeO-C
\\
O,,,,H1
)4"' N-Aryl \$,,#H'
A spectroscopic study, including NMR, of various azinylmalonic esters 480 has shown that these compounds exist as a tautomeric equilibrium involving an imine-like formi5'
H.,,
4, OMe
0
The HF 6-31G* ab initio calculations of charge distribution for the simplest enaminonitrile, 3-aminoacrylonitrile (481) (Scheme 12), indicate an n,rr interaction almost as efficient as that of 3-aminoacrolein (323, Scheme 6) and therefore the NMR spectra of enaminonitriles, NC-CR1=CR2-NR%4 (482), have many features in common
SCHEME 12 Calculated (HF 6-31Gm)charge distribution for Z- and E-3-aminoacrylonitrile(481)
366
J. L. Chiara and A. 3omez-Sanchez
with those of enaminones. Furthermore, most of the enaminonitriles so far investigated have an additional electron-withdrawing group (R1 = CN, COMe, CO,R) at C(2); the latter two classes of compounds can be viewed as enaminones, and have isomerism and spectral properties similar to those of enaminoketones or enaminoesters. Enaminonitriles with a secondary amino group (482, R4 = H) could also exist in the tautomeric imino form NC-CHR1-C(RZ)=NR3. Data of the 'H-NMR spectra for the E- and Z-isomers of representative 3-substituted 3-aminoacrylonitriles (483)''' appear in Table 27. Nuclear Overhauser-effect measureTABLE 27. 'H-NMRchemical shifts [aTMJ (ppm)] and, in brackets, coupling constants, J (Hz), for
compounds 483"
'H chemical shifts Solvent
Compound
CDCI,
CDCI,
DMSO-d, DMSOd,
CDCI,
CDCI,
DMSOd,
'Data taken from Reference 159. Broad signal.
'
5. NMR spectra
367
mcnts allowcd one to distinguish the pair of isomers and established that H(2) is more shielded in the Z-isomer than in the E-isomer in accordance with the charge density at C(2) (Scheme 12) in each of the isomers. Consequently, the rule held for enamino-ketones and -esters seems to be general for all enamines having an electron-withdrawing group at C(2) (see also Section IILC.l). In compounds 483 with R' = Me and R3 = H, the long-range coupling constants 4JH,2,,,,3, and 4JH,,,,, are larger in the Z- than in the E - i ~ o m e r ' ~and ~ , the =C-Me protons are more deshielded in the E- than in the Z-isomer probably due to the proximity of the cis-CN group. Application of these rules to spectral assignments in solutions in which both isomers are present is then simple. When only one isomer is present, recourse can be made to 4J,,,,M,p,and 4.1H,,,N, which are larger in the Z-isomer (0.5 and 0.9 Hz, respectively) than in the E-isomer (both 483 with R1 = Me tend to adopt the E configuration, < 0 . 2 H ~ ) ' ~Compounds ~. whereas when R1 = Ph the Z isomer prevailslS9.
483c o r in DMSO-d, The 15N chemical shift (6,,,5No, - 264.7 ppm) m e a ~ u r e d ~ ~ V is indicative of the efficient n,n interaction in this class of compounds. The IR and 'H-NMR spectra of the sterically crowded tetrasubstituted enaminonitriles 484 (R = CH2Ph, Ph, cc-Naph, HOCH2CH2)have been i n v e ~ t i g a t e d 'in~ ~order to detect the corresponding imino form. Only one enamino-isomer with the E or Z configuration was detected when R was CH,Ph, Ph or HOCH2CH2, as revealed by the single =C-Me signal at S 2.05-2.10 ppm (in CDCI,) and a single NH signal; for the and compound with R = cc-Naph, the two signals, of unequal intensities, for =C-Me NH, indicated the presence of two enamino forms, the one prevailing (with =C-Me more deshielded due to the proximity of the cis CN group) being assigned the E configuration.
NC Et
NC
N-R
H'
H'
E
Z (484)
Data for the "C- and 'H-NMR spectra of some aminomethylenemalondinitriles are given in Table 28. The large shift between the signals of the two olefinic carbons, C(2) and C(3), of compound 485 is suggestive of a very high n,n interaction, and the 3J,,,,NH (14 Hz) indicates a trans-relationship between H(3) and the amino proton. These strongly conjugated compounds seem to exist in the more extended geometry with the E conformation around C(3)-N. Accordingly, the derivatives with tertiary amino groups, such as 487, have non-equivalent N-Me groups and very high barriers to rotation around C(3)-N (Chapter 6). Data for the I3C-, I5N- and 'H-NMR spectra of enaminonitriles bearing a CO,R1 at C(2) appear in Table 29. The spectral properties of these compounds have been
TABLE 28. I3C- and 'H-NMR chemical shifts,a[
(I3C, 'H) in ppm] and (in brackets) coupling constants 3J (Hz) for compounds
'H chemical shifts (3 J w 3 d
'C chemical shifts Compound
R'
485
H
486 487
H Me
488 489 490
RZ e-Hex
Ph Me -(CH2k -(cH2)5-(CHWWCHz)z-
Solvent
c(1)
CU')
c(2)
c(3)
CDC1, DMSOd, CDCI, CDCI, CDCI, CDCI,
116.3
113.9
52.0
H(3)
R'
7.42 (14.0)
7.12
7.20 7.26 7.04 7.04
3.22
R2
Ref. 161
155.5 3.35
155 162 161 161 161
5. NMR spectra
369
thoroughly investigated in order to distinguish the configurational isomers and to detect the possible enamineimine tautomerism. From the data in Table 29 it is clear that these compounds exist solely in the enamine form and that the configuration around C(2)=C(3) and the conformation around C(3)-N can be readily ascertained. When R3 and/or R4 = H, the Z-isomer is distinguished by the proton NH signal at a low field (6 8.5-9 ppm for the N-alkyl derivatives, 10.5-11.8 ppm for N-aryl derivatives in CDCI,) due to the intramolecular hydrogen bond between the NH and the C=O of the ester group; the NH signal of the E-isomer appears at much higher field. For compounds with R Z = H, this proton [H(3)] appears more deshielded in the E-isomer [with H(3) and CO,R1 in cis-disposition] than in the Z-isomer [H(3) and CN cis] due to the larger coupling constant, magnetic anisotropy of the ester group. Moreover, the 3JH,3,,H usually in the range 13.5-15 Hz, is suggestive of an E conformation of the HC(3)-NH fragment. Compounds with tertiary amino groups (R3 = R4 # H) adopt the E configuration as deduced164by application of additivity rules'66. The strong n,n interaction is evidenced by the low value of 6I5N measured153for methyl 3-anilino-2-cyanoacrylate (493) and the barriers to rotation around C(3)-N measured for compounds 501 (AG' 17.3kcal mol-' in pyridine-d, at 338 K) and 502 (AG' 17.95 kcal mol-' at 357 K).
C. Nltroenamines
2-Nitroenamines have been the object of previous reviews that include spectroscopic
proper tie^'^'.'^^
The nitro group is one of the strongest electron-withdrawing g r o ~ p s ' ~ and ~ . ' its ~~ introduction at C(2) of enamines leads to highly delocalized systems (509a-c) that show restricted rotation around the formal C(1)-N single bond and isomerism around the formal C(l)=C(2) double bond. Owing to the symmetry of the nitro group, the isomeric equilibria in 2-nitroenamines are simpler than in enaminones and, when R3 # R4, only four isomeric forms are possible (Scheme 13). The results of an HF 6-31G*ab initio
CDCI, 8.62
DMSOd,
9.06
DMSOd, CDCI,
CDCI,
3.38'
CDCI,
3.95".'
CDCI,
3.81','
CDCI,
(7.0)
5.73
CDCI, CDCI, CDCI, CDCI, CDCI,
J. L. Chiara and A. Gomez-Sinchez
SCHEME 13 calculation of the charge distribution for the simplest 2-nitroenamine, l-amino-2nitroethene (510), are shown in Scheme 14. The strong polarization shown by these calculations is confirmed by the experimental dipole moments of a series of tertiary 2-nitroenamines, which are much larger than the values expected from bond moment~'~'.
SCHEME 14 Calculated (HF 6-31G8) charge distribution for Z- and E-isomers of 1-amino-2-nitroethene(510) 2-Nitroenamines with a primary or secondary amino group can exist also in two tautomeric forms: the imino-nitro form (511) and the imino-nitronic acid form (512). Although the enamine form represents the thermodynamically more stable tautomer, the imino-nitro form has been observed when severe steric hindrance prevents planarity of the conjugated system'72.Compounds 513, derived from 2-nitrocycloalkanones, have been r e ~ o r t e d ' ~ to ~ . exist ' ~ ~ exclusively as the imino-nitronic acid tautomer, although the spectroscopic evidence presented is also c~nsistent"~with the enamine form. The 13C-, 15N- and 'H-NMR spectral data for a series of simple l-amino-2nitroalkenes are collected in Table 30. The greater electron-withdrawing character of the nitro group as compared with carbonyl results in downfield shifts of the resonances of C(2) ( + 10 to + 14 ppm), the enaminic nitrogen ( 23.2 to 27.4 ppm) and the 1.5 to = 1.8 ppm for H(2)I of olefinic protons [ + 0.8 to + 1.0ppm for H(1); 2-nitroenamines with respect to enaminones. This deshielding does not affect C(1), which has in fact a lower chemical shift ( - 5.5 to - 10.2 ppm) in 2-nitroenamines. The NMR spectra show that 2-nilroenamines with a primary or a secondary amino groups exist in solution as solvent-dependent equilibrium mixtures of E- and Z-isomers. The
+
+
+
5. NMR spectra
373
compounds with a tcrtiary amino group exist exclusively in the E configuration. The configuration of the formal C(I)=C(2) is easily assigned using the criteria discussed for enaminones. For compounds with R1 = R~ = H, 3JHf1,H!,, is 5.5-6.2 Hz for the Zisomers and 9.8-1 1.0 Hz for the E-isomers. The configuration of 526 and 531 has been unambiguously assigned on the basis of the ,J,,(,, coupling, which is 2.5 Hz for the Z-isomer and 3 . 9 4 2 Hz for the E-isomer. The chem~calshifts of the R1 proton@)(higher for the E-isomer), the amino proton (higher for the Z-isomer, due in both cases to the cis deshielding effect of the NO, the 613C values of C(l) and C(2) (higher for the E-isomer) and the 615N value of the enaminic nitrogen (higher for the E-isomer) are also useful when both isomers coexist. For the compounds with a primary or secondary amino group, the Z-isomer, with an intramolecular H bond is the most favoured (by AG" of at least 1.7 kcal m ~ l - ' ) ' ~ ~ in CDCI,, and is the only isomer observed by NMR in dilute solutions. In DMSO-d,, the Z-isomer also predominates, except in compounds with R1 = R2 = H (510 excluded). The relative stabilization of the Z-isomer produced by the introduction of R' or R2 substituents is ascribed mainly to two factors: (i) the strengthening of the intramolecular H bond of the 2-isomer by a buttressing effect, as can be deduced from the 0.3 to 1.3 ppm increase in the 6 values of the amino proton (cf 516, 528 and 539, Table 30); (ii) the steric interaction between R1 and the NO, group and/or R2 and the NR3R4 group in the E-isomer hinders planarity and destabilizes this isomer. The relative stabilization of the Z-isomer is higher when substitution is at C(1). The geometrical changes produced upon Me substitution at C(l) of 510, i.e. compound 525, calculated for both isomers by the semiempirical method AMl, support the above explanationH5. The proportion of the E-isomer increases with increasing solvent polarity, e.g. for 510 the E:Z ratio increases in the order CDCI, < CD,OD < (CD,),NCDO < DMSOd617'. This stabilization of the E-isomer is attributed to its larger dipole moment relative to that of the intramolecularly bonded Z-isomer. The solvent effect on the isomeric equilibria of 510 has been reasonably reproduced by ~ e m i e m p i r i c a l ' ~ ~ and . ' ~high-level ~ ab initio calculation^'^^-^^^ using the self-consistent reaction field approach. The calculations also show that the solvent has a considerable influence on the molecular geometry and electronic distribution that can be interpreted as an increase in the contribution of resonance hybrids 509b,c to the ground state upon increasing solvent polarity. This explains the 1.0-3.7ppm deshielding of the signal of C(l) and the 0.2-1.4 ppm shielding of C(2) observed when going from CDCI, to DMSO-d, solution (e.g. 525, 526, Table 30). The conformation around the formal C(1)-N single bond in secondary 2-nitroenaor 3JCH couplings across this bond. When mines can be assigned on the basis of the 3JHH R1 = H, 3JHfl,N,(trans)is 14.0-18.0 Hz and ,J (cis) is 4.9-8.8 Hz. There have been discrepancies concerning the isomeric equilibria of I-methylamino-2-nitroethene (514) in solution: while some author^'^^^'^^ only observed the Z-isomer in CDCI,, others177 found a 312 Z:E ratio under these conditions. In DMSO-d6, this compound showed the presence of the ZE, EE and EZ isomers (Scheme 13),the E configuration predominating. However, there is no agreement on which is the major conformer around the C(1)-N bond in the E-isomer. An X-ray crystallographic study116 showed that the compound exists in the solid state in the EZ form. That this is also the major isomer 176 in DMSO-d6 solution has been unambiguously demonstrated measuring the 3JHf,,N, and 3JH(1,,,,,,175couplings (see Table 30). I-Anilino-2-nitroethene (517) also exists as an equihbrium mixture of ZE, EZ and EE isomers in DMSO-d6 solution. In this case, the EE isomer predominates, as deduced from the 'H-NMR ~pectrum'~'.The EZ form is probably destabilized by the large steric interaction between the Ph group and H(2). The analogous compound 516, with a t-BuNH group, also exist as a mixture of configurational isomers in DMSO-d,, but only one conformer is observed179for the E-isomer, most probably assigned to the EE geometry for steric reasons. Secondary
,,,
TABLE 30. 13C, "N- and 'H-NMR chemical shifts [6,("CC,
'Hb 6,,,,,d1"N) in ppm] and, in brackets, coupling mnstants, J (HzYfor nitroamines
w -4
R1 I
P
R2
R3R41V-~(1)=&(2)N0~ 6CCJa)
dN("Jd
Isomd Compound R1
R'
NR3R4
(%)
Temp.
C(1)
C(2)
R1 R'
NR3R4 NO2 NR3R4 -
R'
R'
NR3R4
Solvent
(K)
Ref
6.83 (14.2)"
6.49
(6.0y
5.73',@ 8.441.'
CDCI,
293
175
6.48 (5.8Y 6.48
3.18; 9.06'.# (5.1)k 3.09: 9.4f.s
CDCI,
293
175
DMSDd,
-
176
(R Av
514
H
H
MeNH
ZE
-
(100)
-
6.75 (14.011 7.22
7.15 (34.6)' 8.16
6.41 (5.8)' 6.78
3.05; 9.40'4 (5.0y 2.71: 8.16'.'
8.2-8.5"
6.87 ' (9.8)' 6.47 (5.8)' 6.51 (5.8)' 6.45 (5.9)' 6.76
6.83 (14.0)' 7.07 (14.3)' 7.38 (- 8 8.16 -
-266.7°
-
-
P 7.81 (14.0)'
-
6.63 (5.6Y 6.66 (6.2)' -
DMSOd,
293
175
2.82 (4.8)' 9.11.'
CDCI,
293
175
9.47'.'
CDCI,
-
178
9.4'.'
DMSOd,
-
179
8.75',' 9.v.'
CDCI,
293
175
10.88',.
DMSO-d,
293
175
293
175
10.19',*
8.12
6.54 (10.7)(
-
CDCI,
8.20
6.75 (IlY
-
CDCI,
-
180
8.28
6.58 110.51' . .
-
CDCI,
-
181 W
-4
(continued)
TABLE 30. (continued) -
WJar) Compound R1
R2
NR3R4
lsornefl IsorneP q 1 )
/ 0
E wN (1W E PhNMe Ph.N
(1W E
6NCJm)
W"HH) Temp.
C(2)
R'
R2 NR3R4 NO,
NR3R'
R'
R2
NR3R4
Solvent
6.85 CDCI, (10.8)' CDCI, 6.60 (llY 6.66 CDCI, (llr 6.53 6.72*.'; 9.U1.@ CDCI, U.3Y 6.50 8.741,*;9.161,@ DMSOd, (0.8V ~~ ~, 6.59 3.11 (5.4)L; CDCI, 10.2014 6.62 3.01 (5.3)L; DMSOd, (lo.loy~ 2.68 (4.8Y.' 6.59
6.47
4.60 (6.6)' 10.441.8 4.65 (6.4)L 10.481.8 4.34 (6.2y 8.461.g 10.7*.'
CDCI,
6.60
10.7*,'
DMSOd,
6.67 -
CDCI, DMSOd,
(K)
Ref.
P hNH
1 1 .911.@
CDCI,
1 1.52~.#
DM SO-d6
9.701.9 3.08
Me,N
EN
CDCI, -
CDCI,
MeNH
6.63/.#;8.36/,' CDCll 8.36/,@ 3.21 (4.8P CDCI, 9.43'4 DMS0-d.
n-PrNH
9.S.9
NH2
-
CDCI, -
9.4j.O
CDCI,
c-C,H,,NH
9.5'.9
CDCI,
t-BuNH
9.75'4
CDCI,
9.7s.'
DMSO-d6
i-PrNH
i-BuNH
7.3'4
539 510
H H
Me
Me
PhNH 4-h4eC6H,NH
(30) ZE E ZE
138.9 138.6 139.1
118.8 117.6 118.2
E
138.9
117.5
15.8
-
-
- 11.2 - 15.7
-
-
11.7
-
-
-
-
- 247.3 (93.7)" 1.6 -259.9 (3.5)" (92.6)"
(-IT -
-
-
-
-
-
-
-
-
-
DMSOd,
-
177
DMSOd,
-
177 W
4 4
(continued)
W
4
m
TABLE 30.(continued)
W"JcJ
W"Jd
W"HH)
IsorneP Compound R1
R'
NR'R4
(%)
Temp.
C(1)
C(2)
R'
R2 NR"'
NO2
NR3R4
R'
R2
NR3R4
(K)
Ref.
CDCI,
-
117
CDCL,
-
177
CDCI,
-
177,178
DMSO-d,
-
177
CDCI,
-
183
CDCI,
-
184
CDQ,
-
182
Solvent
Absolute values, unless sign is explicitly indicated. 'The symbols indicate, in this order, the configuration around C(l)=C(Z) and the conformation around C ( I k N . r 3 3H1,,,N, coupling to NH syn to C(l)=C(Z). * J,,,,,,, coupling to NH anti to C(I)=C(2). * J",U "12! Broad signal. NH signal.
' 'JCH. "J,.
across C(I)=C(2).
2JNa.
'
33-*c",. 3 J x 1 ~ ~ . ~ ~ ~ , .
"Not assigned. .1
J N E ~
' Mulllplet. 'Hidden under the multiplet due to the aromatic protons. Ref. 33. '4Jx,2,,,, wupling to NH anii to C(l)=C(Z). *J C H ~ U I ~ ~ I ~ I ~ 'In DMSOd,. Q
J. L. Chiara and A. Gomez-Sanchez
380
2-nitrocnamincs with R1 and/or R2 = alkyl or aryl show also a singlc conformer for the E-isomer. This conformer is tentatively assigned the EZ geometry in those compounds with R1 = alkyl, aryl and R2 = H, and the EE geometry in those compounds with R1 = H and R2 = alkyl, aryl. The difference between the "C resonances of C(1) and C(2) is much smaller in 2-nitroenamines (9.1-53.3 ppm) than in enaminones (42.5-68.6 ppm, see Section IILA). As observed for the latter compounds, this difference increases with the electron-donor ability of the NR3R4 group and the polarity of the solvent, and is almost independent of the configuration. The effect of alkyl substitution on the chemical shifts of the olefinic carbons can be analysed by comparing the data for compounds 514,526 and 533 (Table 30) with a MeNH group. The introduction of a methyl group at the double bond in the Z-isomer produces a 10-ppm deshielding of the olefinic carbon hearing the substituent and a 0.2-1.9-ppm deshielding of the other olefinic carbon. Methyl substitution at C(1) in the E-isomer produces a 13.5-ppm deshielding of the signal of this carbon, and a 1.5-ppm shielding of C(2). When the substitution is at C(2), there is a small deshielding, 2.2 ppm, of its signal and a 4.1-ppm shielding of C(1). These results seem to indicate a torsion of the NO, group out of the plane of conjugation due to steric interaction with the methyl group, which is higher when the substitution is at C(2). already mentioned, There are few 15N-NMR spectral data for n i t r ~ e n a m i n e s ~ ~As. ' ~ ~. the enaminic nitrogen resonates at a lower field than in enaminones, and exhibits the same dependence on the double-bond configuration (see Section 1II.A). The 15N resonance of the nitro group appears at 0.6-3.3 ppm for the compounds included in the Table. 2-(Nitrornethylidene)thiazoline (550) has the E configuration in CDCI,, but it exists as a mixture of Z- and E-isomers in DMSO-d,, with the former predominating, as shown by 'H NMRL9'. The corresponding 15N-NMRspectrum in DMSO-d, + CDC1, shows two enaminic signals at - 264.1 and - 275.4 ppm and two NO, signals at - 11.7 and - 11.3 ppm. In DMSO-d, solution there is only one NH signal at - 271 ppm and one NO, signal at - 11.0 ppm, assigned to the 2-isomer, which predominates in this solvent. H#,,MO
\+
I
p
N
=
I;)--, H
O
=
E
Z
NO2
(550) The 'H-NMR spectrum of 510 in (CD,),NCDO at 218 K showed well-resolved signals for cach proton of both geometrical i~omers"~.The H(l) proton of each isomer is coupled to H(2) and to both protons of the NH, group. In the E-isotner there is a geminal coupling ( - 3.7 Hz) between the two amino protons, of the same order as that ob~erved'~'in primary amides ( - 2.2 to - 2.5 Hz), which indicates the sp2 character of the amino nitrogen of 2-nitroenamines. This geminal coupling is not observed in the Z-isomer. The signal of the amino proton of the Z-isomer of 2-nitroenamines appears at 8.4 to 11.9 ppm, in between those of aminoacroleins or enaminoketones (6," 9.4-13.4 ppm) and enaminoesters (6," 6 . 6 1 1.0 ppm), thus indicating the following order for increasing strength of the intramolecular H-bond according to the acceptor group: CO,R < NO, < COR c CHO. Chiral2-nitroenamines 551-553 has been shown by Nuclear Overhauser Effect experiments to preserve in solution the EE conformation found in the solid state (Scheme 15)192.
5. NMR spectra
381
2-Acyl-2-nitroenamines (554) with R' = R4 can exist in four planar isomeric forms (Scheme 16) due to restricted rotation around the C(l)=C(2) and C(2)-C(3) bonds. The combined use of IR and NMR spectroscopy provides a complete picture of the isomeric equilibria of these corn pound^^^^^'^^^^^^. Quantum-mechanical calculations of the structure, relative energies, ~ o l v a t i o n and ~ ~ vibrational ' ~ ~ ~ ~ spectralg5of a series of model 2-acyl-2-nitroenamines have confirmed the structural assignment of the isomers either in solution or in the pure state.
0
II 02N\ /C(3) 72) ' Rl/C(l)
R2
I
02N, ~ 2
~3
'N'
I
/C(3),\ 72)
R1/'(I)
~3
'N'
R4 EE
0
I
R4 EZ
(554) SCHEME 16 The symbols indicate, in the order shown, the configuration around the C(l)=C(2) bond and the conformation around the C(2)-C(3) bond The 13C- and 'H-NMR spectral data of a set of 2-acyl-2-nitroenamines are collected in Tables 31 and 32. The stereochemistry around C(I)=C(2) has been assigned by correlation with the NMR spectral properties of the corresponding enamines with a single electron-withdrawing group at C(2), or by comparison with compounds of fixed configuration, as those in Table 32. In the case of 3-amino-2-nitroacrylic esters (554,
TABLE 31. "C, and 'H-NMR data for some representative acyclic 2-acyl-2-nitroenamines
0
II
NO,
I
R2-C(3)-C(2)=C(I
MeNH
R'
I
)-NR3R4
CDCI,
DMSO-d,
EtNH
CP,
CDCI, CDUl n-BuNH
CDCJ,
c-C,H,,NH
CDCI, CDCI,
PhCH,NH
CDCI,
DMSOd,
Me
PhNH
CDQ,
Z
DMSOd,
Me
CDCI,
Me
CDCI,
Me
CDCI,
Me
CDCI, CDCI,
Me
CDCI,
Me
CDCI, CHCIF, + CHCI,F (1 :1)
OMe
CHCI,F (I: 1) CDCI,
293
DMSOd,
293
(continued)
TABLE 31. (continued)
P 3 C (J c d
6'H( JHH)
Isomer Compound
R1
Temp. (K)
Ref.
R2
NR~R*
OMe
MeNH
CDCI,
293
134
OMe
PhNH
CF,CO,H CDCI,
293
196 134
DMSO-d,
293
CDCI,
293
DMSO-d,
293
CDCI,
293
OMe
OMe
4-MeOC,H,NH
4-MeC,H+NH
(%)
C(l)
C(2)
C(3)
R1
R'
R'
Rz
NH
Solvent
134
134
OMe
4-CIC,H,NH
CDCI,
DMSOd,
OMe
2-MeC,H,NH
CDCI,
DMSO-d,
OMe
2,4-CI,C,H,NH
CDCI,
DMSOd,
OMe
AcNH
CH,CI,
OMe OMe
Me,N NH,
CH,CI, CDCI,
CDCI,
OMe
MeNH
CDCl, CHC1.F
+
(continued)
TABLE 31. (continued) SL3C( JCH)
S1H(J,,l
w
00
Isomer Compound 579
RL Me
Me
Me
Me
Me
Me
R2 OMe
OMe
OMe
OMe
OMe
OMe
NR3R4 4-MeOC,H,NH
4-MeC,H,NH
4-CIC,H,NH
2-MeC,H,NH
2-BrC,H,NH
J,,.
3JC0,H(L).
C(1)
C(2)
C(3)
R'
R2
R'
R2
NH
3.88"
10.88'
3.8X6.'
10.98'
3.87
-
3.80
-
3.776 3.88'."
11.54"' 11.95'
3.88*.'
11.04'
3.86
-
3.80
-
3.7791.55" 3.89 11.86' 3.84
10.98'
3.9W
11.86'
3.9W
10.97'
3.90
11.75'
3.86
10.93'
3.81'
-
Solvent
QI
Ref.
CDCI,
CD,CI,
DMSOd, CDCI,
CD,CI,
DMSO-d, CDCI,
CDCI,
CDCI,
Me,N
. a 1
("1
Temp. (K)
CDCI,
293
3JH(,,NH.Averaged signal for both configurational isomers. 'Broad singlet. Not found. ' 2Jc,,,,,,,,. Doublet. ' Fast Z/E equilibration. 'Not measured.
5. NMR spectra TABLE 32. "C- and 'H-NMR data [6,,
13C, lH (ppm)] for compounds
Me Me 6°C
6'H
-
Compound
R
c(1)
c(2)
'33)
NH
Solvent
Reference
586 587
Me
165.5 163.2
123.6 124.2
185.6 186.0
10.66 11.81
CDCI, CDCI,
194 194
Ph
R1 = H, R2 = OMe), the resonance signals in the 'H-NMR spectra were assigned tb each configurational isomer using lanthanide shift reagent^'^^.'^^. An alternative approach t o establish the configuration of these compounds is based on the observation of the broadening of the H(l) signal on heating the sample200.201.This broadening results from quadrupole relaxation, which is more pronounced in the Z configuration due to the trans relationship between the 'H and 14N nuclei. In compounds with R1 = H ( e g 555, 560, 568, 569), this assignment was confirmed by the values of the 3~H,,,,p, coupling: 1.42.6 Hz for the Z-isomers and 5.0-7.7 Hz for the E-isomers. The chemical shift of the R1 proton(s) is also of diagnostic value, being higher for the E-configurational isomers due to the larger cis-deshielding effect of the NO, as compared with the C 0 2 R and COR groups. The compounds with primary o r secondary amino group exist as chelates in both configurations, as deduced from the high values of the chemical shift of the amino proton, the high value of the 3JH,1,,H coupling and the low frequency of the NH stretching ~ i b r a t i o n ' ~ ~ . ' ~The ~ . 'relative ~ ~ . strength of the intramolecular H-bonds can be estimated from the S, values and the frequency of the NH stretching v i b r a t i ~ n ' ~ ~ . ~ ~ ~ . ~ ~ ~ . As a function of the acceptor group, this strength diminishes in the order: COMe > NO, > CO,Me, which is different from that found for intermolecular H-bonds: COMe > C 0 2 M e > NOZzo2.AS a function of the donor group, the order is the same found in other enamines: ArylNH > AlkylNH > NH,. The substitution of Me for H at C(l) produces, in most cases, a low-field shift of the NH proton signal indicating, as seen for other enamines, an increase in the strength of the intramolecular H-bond due to the buttressing erect introduced by the C(1)-Me group. This low-field shift is not observed in the compounds with ArylNH group, where the aromatic ring adopts, most probably, a non-planar disposition to release the strain produced by the C(1)-Me group. 2-Acyl-2-nitroenamines with primary or secondary amino group adopt, in non-polar solvents, preferentially the configuration with the strongest intramolecular H-bond, i.e. the E configuration when R2 = Me, and the Z configuration when R2 = OMe. The preference for the strongest chelate is higher when R1 = Me. The latter compounds have very low energy barriers to rotation around C(l)=C(2), and separate signals for each configurational isomer can only be observed in the NMR spectra at low temperature. Conformational isomerism around the C(2)-C(3) bond could not be observed by NMR due either to a low barrier to interconversion or to the existence of a single conformer. This isomerism has been studied in compounds 554 (R1 = H, Me; R2 = Me, OMe) by a combination of vibrational spectroscopy and quantum-mechanical calculat i o n ~ ~ ~ ~ , The ~ ~EE ~ isomer, , ' ~ predicted ~ . ~ ~ to~ be- the ~ ~less~ table'"^""^ . , has never
388
J. L. Chiara and A. G6mez-Sknchez
been ~ b s e r v e d ~ ~ .~The . ' ~presence ~ , . ' ~of~the other three isomers has been demonstrated only for the 3-amino-2-nitroacrylic esters (554, RL= H; R2 = OMe) with primary or secondary amino group, which have readily distinguishable IR spectra for the three isomers, although the corresponding 'H- and 13C-NMR spectra present a single set of signals for the rapidly interconverting Z Z and Z E isomers134.4-Amino-3-nitro-3-buten2-ones (554, R1 = H, RZ = Me) have been shown, by IR spectroscopyL94and theoretical calculationsL86,to exist as a mixture of the planar E Z and Z Z isomers, with the former predominating as deduced from the 'H-NMR spectra'94. When RL = Me, steric hindrance precludes the existence of planar structures with Z configuration. The IR spectra show that these compounds exist as a mixture of the planar E Z isomer and a single ~ ~ ~ ~ ~ ~ . calculation^'^"^^^ predict that in the latter isomer of Z c o n f i g ~ r a t i o n ' Theoretical isomer, the COR2 group is rotated out of the plane of the nitroenamine system, taking a 'quasi'-ZZ disposition, as shown in 588.
3-Amino-2-nitroacrylic and 3-amino-2-nitrocrotonic esters with a tertiary amino group are preferentially in a configuration having the best electron-withdrawing group trans to the amino function, i.e. the E configuration. The acceptor group cis to the amino group adopts most probably a non-planar disposition. This has been demonstrated for methyl 3-dimethylamino-2-nitroacrylate (576) by X-ray crystallographyzo3. The isomeric equilibria of 2-acyl-2-nitroenamines with primary or secondary amino group are strongly solvent-dependent, as already seen for other enamines. An increase in the polarity of the solvent increases the population of the isomer(s) with Zconfiguration, as deduced from the 'H-NMR s p e ~ t r a ' ~ ~ In . ' 3-amino-2-nitroacry~~,~~~. lic esters (567-574), the IR spectra show that an increase of solvent polarity increases ~ ~ ~ moment. the population of the Z E isomer134,which has the highest c a l ~ u l a t e ddipole The effect of solvent polarity on the isomeric equilibria of some model 2-acyl-2nitroenamines (554, R1 = H, Me; R2 = Me, OMe; R3 = R4 = H) has been qualitatively predicted by quantum-mechanical calculations using the self-consistent reaction field approa~h'~~.'~~. Comparing 2-acyl-2-nitroenamines with the analogous enamines with a single electron-withdrawing group at C(2), i.e. 2-nitro- and 2-acyl-enamines, it can be observed that the introduction of a second electron-withdrawing group at C(2) produces an increase of both 6C(1) and 6C(2). The value of A6 = 6C(1) - 6C(2) increases with solvent polarity, indicating an increase in the polarization of the molecule, i.e. an increase in the n,n interaction of the amino group. A good linear correlation (equation 1, Figure 2) exists between the hC(1) values of the Z - and E-configurational isomers of the series of 2-nitroenamines of formula RINH-CH=C(R2)N02 (R2 = H, COMe, C02Me)L94.The value of the slope, approximately 1, indicates that the etlects of the substituents are transmitted through the bonds c ~ C ( I=) ~0.996C(1)Z + 5.6 (r = 0.998, n
= 21)
(1) in the same way for both configurational isomers. A similar relationship has been found for a series of /3-substituted enoneslL3.The intercept marks the averaged difference in
5. NMR spectra
FIGURE 2. Linear dependence of 6C(1) values of the Z- and E-isomers of 2-nitroenamines 510, 514,555565 and 567-574 (data from Tables 30 and 32).
C(l) chemical shifts between both configurational isomers. There is also a good linear correlation for the corresponding bC(2) value of both configurational isomers (equation 2, Figure 3)'94. However, in this case the slope is not as close to 1. Parallel linear
correlations (equations 3-6) exist between the total charges (qT) and the n-electron populations (p") at C(l) and C(2) in both configurations, calculated by the semiempirical method AM1 (Table 33)'94. The best correlations are those for the n-electron populations (equations 4 and 6). The parallel between the experimental correlation 1 for bC(1)
and the theoretical correlation 4 for pn[C(l)], with very similar slopes, indicates that the changes in bC(1) produced by a change of configuration reflect mainly changes in the n-electron distribution. Comparing the intercepts for both equations, it can be concluded that the averaged difference in chemical shift for the C(1) signal of both configurational isomers, 5.6 ppm, corresponds to an averaged change in n-electron population of 0.059 e, i.e. the sensitivity of X ( 1 ) to variations in pn[C(l)] is 95 ppmle.
J. L. Chiara and A. Gbmez-Shnchez
FIGURE 3. Linear dependence of 6C(2) values of the Z- and E-isomers of Znitroenamines 510, 514.555558 and 567-574.
Likewise, the parallel between equations 2 and 6 suggests that the change in 6C(2) produced by a change of configuration is mainly governed by the change in n-electron population. However, the changes in chemical shift and electronic population of C(2) are not independent of the substituents, as deduced from the slope values which differ from unity for equations 2 and 6. The calculated n-electron populations at C(l) and C(2) are lower in the E configuration (Table 33), thus explaining the low-field shift of the 13C resonances of C(l) and C(2) produced by the Z + E isomerization.
In 2,2-dinitroenamines the only possible isomerism is that around the N-C(l) bond. Only a few compounds of this type have been d e ~ c r i b e d ' ~and ~ . ~their ~ ~ 13C- and 'H-NMR spectral data are included in Table 34. 1,l-Diamino-2,2-dinitroethylenes (592599) have been prepared very recently and their structures have been studied by X-ray c r y s t a l l ~ g r a p h yThese ~ ~ ~ . compounds have twisted double bonds, some with twist angles (see Table 34) greater than any previously reported value for twisted ethylenes, with concomitant C(l)=C(2) bond distance distortions. The only exception is compound 596, which is essentially planar. The large chemical-shift difference between the signals of C(l) and C(2) indicates a strong polarization of the formal carbon-carbon double bond.
391
5. NMR spectra
TABLE 33. Total atomic charges (qT)and n-electron population (p") calculated by the semiempirical method AM1 for the planar isomers of compounds
-
R'
R2
IsomeP
C(1)
-
C(2)
-
--
N(1)
Reference
H
H
C02Me
C0,Me
COMe
COMe
"Thesymbols indicate, in this order, the configuration around the C(I)=C(2) bond and the conformation around the C(2)-R2 bond.
TABLE 34. I3C- and 'H-NMR chemical shifts [6,,,
613C Compound
TWIST"
n-RNH n-RNH
No2
(593)
PhNH
gNo2
PhNH (594)
N q
W
(ppm)] and coupling constants, J (Hz), for 2,2-dinitroenamines
c(1)
6'H c(2)
H(1)
Vi
N
C"H,I,NH] NH
Solvent
Reference
11.0
CDCI,
204
11.25
DMSO-d,
204
CDCI,
205
(599)
"TWIST is definedz0' as the angle between the bisectors of the 1.1- and 22-substituent angles on a Newman diagram of the olefin. Singlet. 'In DMSOd,. *Not assigned. 'Two molecules in the asymmetric unit cell.
394
J. L. Chiara and A. Gomez-Sanchez IV. DEUTERIUM ISOTOPE EFFECTS AND HYDROGEN BONDING
Primary and secondary enamines substituted with appropriate electron-withdrawing groups can form strong intramolecular hydrogen bonds when these groups are cisoriented with respect to the amino function. The presence of the hydrogen bond can be readily detected by the low frequency of the IR v,, stretching vibration and the high value of G(NH). However, it is not easy to evaluate the strength of the hydrogen bond from these two parameters. The ,v stretching appears in solution as a weak, rather broad, complex absorption. On the other hand, the chemical shift of the N H proton is also affected by the magnetic anisotropy of the acceptor group and by the solvent. Hydrogen bonding can be more conveniently studied by means of deuterium isotope effects on nuclear shielding'34~'75~'93~'94~206-2'9 , defined as "AX' = G[Xi(H)] G[Xi(D)], where n is the number of intervening bonds between the deuterium and the observed nucleus, Xi. The most studied of these effects is the two-bond isotope effect on I3C chemical shifts, 2AC(XD), produced upon HID exchange at XH. This isotope effect has been correlated with 6(XH) and, when XH takes part in an intramolecular hydrogen bond, to the hydrogen-bond enthalpy213-z'7. The magnitude of 'AC(1XND) produced upon N-deuteration in primary and secondary 2-substituted enamines can give an estimation of the relative energies of the intramolecular hydrogen bonds'34~175~193~'94~2'5~2'9~220. Table 35 contains deuterium isotope effects "AX(ND) on I T - and I5N-NMR spectra of primary and secondary enamines with electron-withdrawing groups at C(2). Isotope effects included in the Table are all positive, i.e. N-deuteration produces shielding of the nuclei close to the site of isotopic exchange. The fact that "AX decreases with increasing n indicates that the observed isotope effects are 'intrinsic' in nature and not of the equilibrium type characteristic of tautomeric systems. Table 35 contains also the corresponding G(NH) values. A general tendency towards larger 'AC(l)(ND) values as G(NH) increases is observed (Figure 4). However, the scattering of the points indicates that, even in these closely related structures, the 6(NH) values are significantly influenced by factors other than hydrogen bonding. ,AC(lXND) is higher when the NH(D) group takes part in an intramolecular hydrogen bond [cf Z(z)- and E-isomers of compounds 411,422,428,432,510 and 514, in Table 351. The order of decreasing 2AC(l)(ND) values produced by N-deuteration is, for the acceptor groups: COR > NO, > C02R, and for the amino groups: ArylNH > AlkylNH > NH,. This is the same order of decreasing hydrogen-bond strength deduced from the G(NH) values. In addition, substitution of Me for H at C(l) increases 2AC(lXND)and the hydrogen-bond strength. Thus, the strongest hydrogen bond gives the largest two-bond isotope effects. However, the nitrogen a-alkyl carbon exhibits almost invariant isotope effects. The magnitude of ,AC(l)(ND) can also be used to assign the stereochemistry around the C(l)=C(2) bond. The significant difference between the 'AC(1XND) values measured for compounds 566 and 586 indicates different doublebond geometry in each case, i.e. compound 566 adopts in solution mainly the E configuration. Long-range 4AC0 are observed in enaminoketones and enaminoesters, but only for the isomer where the C=O group takes part in the intramolecular hydrogen bond. Thus, the isotope effects are confined to the nuclei of the six-membered chelate ring, which are also those in close conjugation. 'The one-bond isotope effects on nitrogen, 'AN, increase also considerably by hydrogen bonding, making this a useful parameter for the detection of hydrogen Isotope effects due to C(2) deuteration have also been s t ~ d i e d ~ ' ~ ~ ~ ~ ~ . Isotope effects are vibrational in rigi in^^^-^'^. It has been claimed2I3that the isotope shift must involve the in-plane C-N-H bending vibrations and the associated C-C-XH bond-angle distortions. This distortion can be regarded as a perturbation on the hybridization which, in conjugated systems, is likely to spread over the whole
TABLE 35. Deuterium isotope effects on
I3C and
- ~-
Compound
~~
Isomer
15N nuclear shieldings in secondary Zsubstituted enamines"
-
'AC(1)
'AC(2)
ACO
AC:
'AC8'
'AN
WH)
Solvent
Ref.
(CDJKO CDCI, CDCI, CDCI, CDCI, CDCI, CDCI, CDCI, CDCI, CDCI, CDCI, CDCI, CDCI, DMSQd, DMSO-d, CDCI, CDCI, CDCI, CDCI, Dioxane-d,
(continued)
%
TABLE 35. (continued)
QI
Compound
Isomer
2AC(l)
"C(2)
4
~
~ 'Act 0
3AC;
'AN
WII)
Solvent
Ref.
CDCI,
194
CDCI,
I94
CDCI,
194
CDCI,
194
CDCI,
I94
CDCI,
194
CDCI,
194
CDCI,
I94
CDCI,
194
CDCI,
194
CDCI,
194
CDCI,
194
CDCI,
194
-
- -
-
-
-
CDCI,
194
CDCI,
134
CDCI,
134
CDCI,
134
CDCI,
134
CDCI,
134
CDCI,
134
CDCI,
134
CDCI,
134
-
"Isotope effects produced'by N-deuteration, defined as "AX = 6[X(NH)] - 6D((ND)] (in ppm), n being the number of intervening bonds between the deuterium and the observed nucleus, X. bTwo-bond deuterium isotope effect of a-alkyl carbon. "Three-bond deuterium isotope effect on Balky1 carbon. moiety. %e symbols indicate, in this order, the configuration around the C(1) = C(2) bond and the conformation of the O=C-C(Z)=C(I) 'Averaged spectrum of several rotamers with E configuration in rapid equilibrium 'Total effect of deuteration at N and C(2) centers. PEffects at CO cis to the amino group. Effects at CO trans to the amino group. 'Broad signal. j Averaged spectrum of Z- and E-configurational (major) isomers in rapid equilibrium. "Averaged spectrum of Z-(major) and E-configurational isomers in rapid equilibrium.
J. L. Chiara and A. Gomez-Sanchez
FIGURE 4. Dependence between the two-bond deuterium isotope effects on C(l) of enamines in Table 35 and the corresponding 6(NH) values.
molecule, as observed in enamines. N-Deuteration should produce a decrease in the strength of the intramolecular hydrogen bond, as found for the OH(D) groupZZ1,due to the lower averaged N-D distance as compared to N-H. Thus, the positive value of 'AC(l)(ND) isotope effects, and its dependence on the strength of the hydrogen bond, can be interpreted in terms of isotopic perturbation of resonance as a decrease in the contribution of form 600b compared with 600a. This is a further indication of the RAHB (resonance assisted hydrogen b ~ n d ) " ~ - ' character ~~ of the intramolecular hydrogen bond in enamines with acceptor groups at C(2).
402
J. L. Chiara and A. Gomez-Sanchez
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hem:
.
. ..
404 203. 204. 205. 206. 207. 208. 209. 210. 211. 212. 213. 214. 215. 216. 217. 218. 219. 220. 221. 222. 223. 224.
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Static and dynamic stereochemistry of acceptorsubstituted enamines JAN SANDSTROM Division of Organic Chemistry 3, Chemical Center, University of Lund, P.O. Box 124, S-22700 Lund. Sweden I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. STEREOCHEMISTRY O F SIMPLE ENAMINES . . . . . . . . . . . . . . 111. SIMPLE ENAMINES WITH ONE OR TWO ELECTRON-ATTRACTING 2-SUBSTITUENTS. . . . . . . . . . . . . . . A. 2-Acylenamines and Their Thio Analogues . . . . . . . . . . . . . . . . . B. 2-Nitro- and 2-Cyano-enamines . . . . . . . . . . . . . . . . . . . . . . . C. Enamines with Two Acceptor Groups . . . . . . . . . . . . . . . . . . . . D. Enamines with Other Electron-attracting Groups in 2-Position . . . . IV. DERIVATIVES O F 1,l-DIAMINOETHENES AND OTHER ENAMINES WITH A SECOND DONOR GROUP O N C1 . . . . . . . . A. 1,l-Diaminoethenes with One or Two Acyl or Nitro Groups in .. Position 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. 1,l-Diamino-2,2-diacylethenesand Analogues with the Nitrogen Atoms in a Ring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. 1,l-Diaminoethenes and Analogues with Other Types of Acceptor Groups in Position 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. DI- AND POLYENAMINE DERIVATIVES . . . . . . . . . . . . . . . . . V1. POLYMETHINE DYES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII. THEORETICAL CALCULATIONS O F ELECTRONIC STRUCTURES, ROTATIONAL BARRIERS, INTERACTION WITH THE SOLVENT ANDBONDLENGTHS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Charge Distributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Rotational Barriers and Solvent Effects . . . . . . . . . . . . . . . . . . . C. Calculations of Geometries and Conformational Energies . . . . . . . . VII1,REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Tlze C l r e ~ n i s ~ ofr Ennnnzines. ~ Edited by Zvi Rappopon Copyright O 1994 John Wiley & Sons, Ltd. ISBN: 0-471-93339-2
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406
J. Sandstrom I. INTRODUCTION
The electronic structures of enamines, such as they are derived from theoretical calculations, physical properties and the regioselectivity of nucleophilic reactivity, are governed by donation of electron density from the nitrogen atom into the carbon~arbondouble bond. When the double bond is substituted in the 2-position by an electron-accepting group, the physical and chemical properties undergo profound changes. Among the more striking are a large increase of the dipole moment and strongly decreased nucleophilic reactivity, which can be ascribed to donation of electrons from the amino group to the acceptor group relayed through the double bond, leading among other things to a notable stabilization of the molecular system. 2-Acylenamines can be described as vinylogous amides, 2-nitroenamines as vinylogous nitramides, etc. The electron distributions in the donor and acceptor groups are similar to those of the same groups in the corresponding simple amides. These qualitative descriptions will be substantiated by a discussion of calculated electron distributions for suitable model structures in Section VILA. 2-Acylenamines and analogues belong to the class of push-pull ethylenes, i.e. ethylenes containing one or two donor groups on one carbon atom and one or two acceptor groups on the other one. In the last decades, push-pull ethylenes have been the subject of considerable interest as versatile synthetic intermediates. Recently, push-pull ethylenes and push-pull polyenes have also become of interest in the search for new material for molecular switches1 and electro-optical devicesz. Calculations on model push-pull polyenes by the CNDO/C13 and PPP4 methods have predicted very high hyperpolarizabilities, which make push-pull polyenes promising material for study of nonlinear optical properties. However, push-pull ethylenes and polyenes are also of interest from a stereochemical point of view due to the observation of hindered rotation of donor and acceptor groups with considerable barriers, and also of low barriers to rotation about the carbon~arbon double bond. It may be appropriate here to lay out briefly, with 3-dimethylaminoacrolein as an example, the principles on which a discussion of the C1-N, Cz-acceptor and C1=C2 barriers* may be based. The most primitive approach considers only the electron delocalization in the ground state. The electron distribution is described by superposition of two limiting structures, the nonpolar A and the dipolar B (Scheme 1).
In the superposition, structure B contributes double-bond character to the C1-N and CZ-C3 bonds and single-bond character to the C1-C2 bond. Although discussion of barriers in terms of ground-state properties alone is not in general advisable, Scheme 1 'Throughout this chapter, enamines will he numbered N-C1=C2, even when it is against the IUPAC rules.
6. Static and dynamic stereochemistry of acceptor-substituted enamines
407
may give a useful qualitative approach for the C1-N and C2-C3 barriers. At least for thioamides, a linear correlation has been found between rotational barriers and C-N bond orders5. For the C1=C2 barriers on the other hand, crystallographic data show that even in systems with barriers lower than 16 kcal mol-I (25% of the barrier for unsubstituted ethylene7), the bond length is 138 pma, much closer to the length of a C(sp2)-C(sp2) double bond (134 pm) than to that of a C(spZ)-C(sp2) single bond (150.5 pm). A more adequate discussion has to consider the transition state as well. For a general push-pull ethylene (Figure 1) this state is twisted ca 90" about the C1-C2 bond and can be considered as a carbanion (A1-C--A2) and a carbocation (Dl-C+-D2) connected by a single bond. The stabilization of the ground state increases with increasing donor and acceptor capacity of the groups interacting via the double bond, but the carbanion and carbocation in the transition state are more strongly stabilized, which leads to lowering of the barrier with increasing donor and/or acceptor capacity of the substituents. Further lowering of all three kinds of barriers is often caused by steric effects, which raise the energy of the ground state (ground-state strain). The push-pull ethylene field has been the subject of several reviewsg-", and in particular C-N rotations are treated in a general review on isomerization processes at N-X bonds12. The present review will treat the stereochemistry and related properties of enamines containing one or two acceptor groups on the B-carbon atom and possibly one more donor group on the a-carbon atom. The dynamics of these molecules will to a large extent be discussed in terms of energy barriers, which have been determined by NMR bandshape technique1). Although enthalpies of activation (AH") are the thermodynamic parameters most pertinent for discussions of this kind, the large majority of published barriers are the more readily available free energies of activation (AG"), and the discussion must be based on them. This is somewhat unfortunate, because in general the rotations about C=C bonds in push-pull ethylenes have considerably negative activation entropies, which makes the free energies temperature-dependent (vide infra, Section VII.B), but it is at present the only practicable route. II. STEREOCHEMISTRY OF SIMPLE ENAMINES
An extensive study of the crystal structures of enamines derived from pyrrolidine, piperidine and morpholine (1)14 led to the result that the amino group in unhindered enamines (R1 = R2 = H) assumes the shape of a rather flat pyramid with the nearest
XA2
A Dl
D2
FIGURE 1. Schematic picture of ground and transition states in the rotation about the C=C bond in a push-pull ethylene. A' and A 2 are acceptor groups, D1and D2are donors
J. Sandstrom
CH,-N bond nearly eclipsing the double bond. Increasing the size of R2 or a change from pyrrolidine to piperidine or morpholine derivatives leads to increased pyramidalization, but the syn CHz-N bond is still nearly eclipsing the double bond. Calculations for vinylamine with the PRDDO methodL5predict a pyramidal amino group with the syn NH bond closer to the double-bond plane than the anti NH bond, in agreement with the structures for 1. Similar conformations with more flattened amino N-vinylpyrrolidine and N-vinylgroups are predicted for N,N-dimethyl-N-vinylamine, piperidine, whereas a cis-2-substituent (R2)leads to a conformation with a ca 90" twisted amino groupL6.Microwave spectral7 clearly show that vinylamine has a flattened pyramidal amino group. Barriers to rotation of the amino group in relatively unhindered enamines have been measured by 13C NMR bandshape technique and found to fall in the range 6.0 to 8.3 kcalmol-I 18.19,in good agreement with predictions from calculations16. The dipole moment of vinylamine has been estimated to fall in the range 1.08 to 1.14 Dl7. Ill. SIMPLE ENAMINES WITH ONE OR TWO ELECTRON-ATTRACTING 2-SUBSTITUENTS A. 2-Acylenamlnes and Their Thlo Analogues
Sterically unencumbered 2-acylenamines like N,N-dimethylaminoacrolein(2a) have a strong predominance for the E configuration with respect to both the C1=Cz and CZ-C3 bonds. With increasing size of R2 and/or R3, the population of the Z form increases. The rotations of the amino and the acyl groups are considerably hindered, and the rates of rotation and the corresponding barriers for both can be measured by DNMR techniques (Table 1). The barrier to rotation of the acyl group is lowered with , which is ascribed to increased ground-state increasing size of RZ when R3 = strain and to twisting of the acyl group out of the enamine plane in both the Z and the E form. As a consequence of the diminished electron delocalization in the vinylogous amide system, the barrier to rotation of the amino group is also lowered with increasing size of RZ. This barrier has been shown to be higher in compounds restrained by cyclization in the s-trans (3)than in the s-cis (4) formz1, which indicates a more efficient electron delocalization in the former case. It is well known from studies of rotational barriers that a thioamide in general has a ca 2 kcal mol-' higher barrier than the analogous a ~ n i d eThis ~ ~ .has been rationalized by PMO argumentsz5 which should also be valid for the vinylogous compounds. This assumption is supported by the data in Table 1, which also show that the exchange of oxygen for sulfur increases the Z isomer population. The latter effect can be ascribed to the larger van der Waals radius of S than of 0.
6. Static and dynamic stereochemistry of acceptor-substituted enamines
409
TABLE 1. Free energy barriers (AG' in kcal mol-' at T K) to rotation about C1-N and C2-(thio)acyl bonds and E conformer population (p,) in simple 2-acyl- and 2-thioacylenamines
Compound
Solvent
AGiSpN
A G ~ ~ - ( t w a c y(~E
+
Z)
P;
Reference
CH,=CCI, CDCI, CH,=CCI, CH,=CC12 CH,=CCI, CH,=CCI, CH,=CCI, CH,Br, CDCI, CDCI, CH,Br, CH,=CCI, CH,=CCI, 'With respect to the C2-(thio)acyl bond
All the N,N-dimethylenarnines shown in Table 1 exist in solution entirely in the E forms with respect to the C1=C2 bond. However, Henning and coworkers2' could isomerize a number of N,N-disubstituted 2-benzoylenamines like 2g to the Z form by flash photolysis and follow their thermal reaction back to the E form by UV spectroscopy. The barrier to this reaction was highly solvent-dependent, being ca 18 kcal mol-' for 2g in cyclohexane and ca 11 kcal mol-I in ethanol. The barrier to thermal E -P Z isomerization is in each case higher by the energy difference between the Z and E forms in the respective solvent.
J. Sandstrom
410
The situation is different for primary and secondary acylenamines (5). Here the Z form is stabilized by an intramolecular hydrogen bond, and G Z equilibria have been observed. These compounds have two mechanisms available for E-Z exchange: (1) the
R3
0
purely thermal rotation about the double bond, and (2) a three-step mechanism, involving proton exchange or abstraction to give the en01 or enolate, rapid 180"rotation about the C1-CZ single bond and reversed proton exchange (Scheme 2). The proton exchange probably takes place by the intervention of an external acid or base, and consequently reactions by this mechanism are acid-base catalyzed. The proton-exchange processes are rate-determining, and their rates can be followed by observing the shape of the 'H N M R signal of the NH group, provided that this is split by coupling to another proton at slow exchange. If the N-H exchange rate is lower than the rate of E-Z exchange, the latter proceeds by mechanism (I), whereas a rate of hydrogen exchange equal to the rate of E-Z exchange indicates mechanism (2). In the absence of other catalysts, substrate molecules may catalyze the proton exchange. If this step is ratedetermining, the reaction will be second order with respect to substrate concentration. In a thorough study of several compounds of type 5 with R4 = Me, Kozerski and coworkersz8 followed the rate of C=C rotation simultaneously with the rate of intermolecular N-proton exchange and found very similar barriers (ca 20 kcal mol- ') for the two processes. This was interpreted as a catalyzed E-Z exchange proceeding by
'*R 1
R2$:
R'
I
R4
R4
R4
R2$o
yo-
N'
I
\
I
H\N
N
o
-
Z
R4
E
e I
R4
R1
I
N
I
' R'
R4 SCHEME 2
6. Static and dynamic stereochemistry of acceptor-substituted enamines
41 1
the second mechanism discussed above. A similar mechanism was proposed already in 1966 by Huisgen and coworkers2gfor the acid-catalyzed E-Z exchange in P-aminoacrylates. In these systems, the barrier for the uncatalyzed rotation was found to be > 26 kcal mol- '. Chiara and coworkers30have studied the E-Z equilibria in methyl n-butylamino- and phenylamino-acrylate in CDCI, and found the population of the Z form (p,) to be 0.82 for the former and 1.0 for the latter comoound. Recen~ly,Minkin and coworkers'' have reported on thermal and photoinitiated E-Z isomerizations in a series of bicyclic N-monosubstituted 2-acylenamines (6). The E Z equilibrium was found to be strongly dependent on the heteroatom X. While the indole derivative 6a exists only in the hydrogen-bonded E form both in solution and in the crystalline state, the benzofuran analogue 6b adopts the Z form in the crystal and in polar solvents. In chloroform and in hydrocarbon solvents, a slow transformation to the E form occurs, accelerated by heat and by catalytic amounts of acids and bases. The benzothiophene analogue 6c behaves similarly, and on irradiation a photostationary mixture of E and Z forms is established, which returns to the initial form in the dark.
Wph r
X
H
H
NMe2
MeCox H
OAc NMe2
X 6a NMe 6b 0 6c S 6d CH2
On rapid cooling of hot saturated solution of 6b and of the indane derivative 6d, crystals of the E (for 6b) and Z (for 6d) forms could be isolated. No rate data or barriers are given but a half-life of ca 2 h for 6d at ambient temperature in toluene can be inferred from one of the figures, corresponding to an approximate free energy barrier to E-Z isomerization of 23 kcal mol-'. However, in N,N-disubstituted 2-acylenamines, suitable C2-substituents can also destabilize the E form sufficiently to make the observation of the Z form possible. Thus, barriers to rotation about the C=C bond of 11.2 and 13.8 kcal mol-', respectively, have been reported for 7 and S3'. The low barriers compared to those reported above may be ascribed to ground-state strain, but it is not completely excluded that the observed exchange is due to acetyl group rotation. 8. %Nitro- and BCyano-enarnines
The nitro group, as a more strongly electron-attracting group than the formyl group [a,(CHO) = 0.49, ap(N02)= 0.82]33,interacts more efficiently with the enamine moiety than the formyl group. T h ~ sfollows from a comparison of the barriers to rotation of the dimethylamino groups in 2a (14.6 kcalmol-', Table 1) and in 9a (16.5 kcalmol-I)34, According to an X-ray crystallographic study, 9a is planar and has an E c~nfiguration~~. Primary and secondary nitroenamines (91t9e) have been studied by IR spectroscopy, and band doubling indicated them to be mixtures of E and hydrogen-bonded Z forms36.
J. Sandstrom
An X-ray crystallographic study by Gate and coworker^'^ shows l-methylamino-2nitroethylene (9e) to exist as the intermolecularly hydrogen-bonded EZ form (Scheme 3) in the crystal. The same authors observed only one form in CDCI, solution, assigned to the Z E configuration on the basis of the coupling constants. On the other hand, Kozerski and Krowczynski3' observed two forms in a population ratio 2:3 in CDCI,, ascribed to E and Z forms with respect to the C=C bond. In DMSO-d, solution, three forms were o b s e r ~ e d ~Gate ~ . ~and ~ . coworkers ascribed the EZ configuration to the dominant one3', whereas Kozerski and Krowczynski preferred the EE form39.
ZZ
ZE
EE
EZ
SCHEME 3
Chiara, Gomez-Sanchez and Bellanato4' have made an extensive NMR and IR study of compounds of type 9 with R1 = H, alkyl or aryl and RZ = H or Me. They observed only the Z (ZE) form for all compounds in CDCI, solution. In DMSO-d, or in DMF-d, solution, amounts of the E form were observed, which depended on R1, R2 and R3, (Table 2). The configuration assignment was based on the downfield shift of the NH proton in the Z form caused by the hydrogen bond and the deshielding effect of the nitro group, and on the 3JHH value for the double bond (5.5-6.0 Hz for Z,
TABLE 2. Free-energy barriers (kcal mol-' at T K) to C=C and C-N rotation and to NH exchange and conformer populations (p,) for compounds 940 Compound
Solvent
AGE,
"With respect to the C=C bond. AH' = 14.2 kcal mol-I, AS' = -7.8 eu. 'AH' = 16.3 kcal mol-', AS' = +11.5 eu.
P;
AGk
AGEpN
6. Static and dynamic stereochemistry of acceptor-substituted enamines
413
10.0-10.8 Hz for E). Qualitative confirmations of the above results were obtained from IR spectra. Free-energy barriers to Z-E interconversion, to amino group rotation and to NH proton exchange were determined by NMR bandshape analysis. For the nitropropenylamines 9d and 9e, the rate of NH proton exchange was distinctly lower than the rate of Z-E exchange, and the latter is most likely a purely thermal process with a dipolar transition state. For the nitrovinylamines 9b and 9c, on the other hand, NH proton exchange was much faster, and the Z-E barriers were ca 12 kcal mol-' lower than expected on the basis of comparison with data from analogues. In this case, Z-E exchange probably proceeds via an anionic intermediate. The C-N barrier for 9f is lower than for 9a, probably at least partly due to ground-stnte strain. Judging from its up value (0.69), the cyano group is a more efficient electron attractor than the formyl group but inferior to the nitro group. However, the barrier to amino group rotation in 3-dimethylaminoacrylonitrile is lower (12.9 kcal mol-' 4 L ) than for the formyl and nitro analogues. C. Enamines with Two Acceptor Groups
Introduction of a second acceptor group at the 2-position increases the electron donation from the amino group, but decreases the delocalization into the individual acceptors compared with the situation with only one acceptor. This leads to increased barriers to amino group rotation but to decreased barriers to rotation of the acceptor groups. Since the stabilization of the carbanionic part of the transition state to rotation about the C=C bond is much improved, the corresponding barrier is decreased. Dahlqvist4' has performed a complete bandshape study of the enamine lob. He observed different barriers to rotation of the dimethylamino group in the E and Z forms with respect to the double bond and a quite low barrier to rotation about the double bond (Table 3). Inspection of the data for lob and llb reveal the different effects of the
R lla H llb Me
12b 12c
MeCO COMe MeCO COMe
H H
Ph Me
J. Sandstrom
414
TABLE 3. Free-energy barriers (kcal mol-' at T K) to C=C and C-N rotations and E conformer populations @dfor compounds of the general type A'A2C=C(R)NR'R2 Compound
Solvent
AGLAE-Z)
10a lob
PhBr CD2C12
14.8 (295)
lla llb 1Za 12b 12c
CH2C12 CH2C12 PhBr CH,C12 CD2C12
15.6 (292) 19.1 (178) 18.3 (305) 13.9 (267) 10.2 (179)
-
AGk-, 17.6 (329) 10.8 (298)" 13.0 (298)b 13.3 (264) ca 8.7 (176)
PE
Reference
0.99 0.56
44
-
-
0.69
-
-
-
12.7 (260)
-
42 6 6 44
45 46
" Z conlomet.
'E conformer.
ester and cyano groups on the C=C and C-N barriers. The highest C-N barriers are found for lob and the lowest for l l b . On the other hand, lob has a much higher C=C barrier. The cyano group is a strong inductive, but fairly weak, mesomeric electron attractor, while the ester group has the opposite characteristics. Evidently, the inductive effect is more efficient than the mesomeric in raising C-N barriers, while the opposite is true for lowering C=C barriers. A study of ketene mercaptals with different acceptor substituents on CZ has shown that the C=C barriers correlate best with the a; constants43. A high C-N barrier (14 kcalmol-I), which may be ascribed primarily to an inductive effect, is shown by 1347.A mesomeric effect would require electron delocalization into the d-orbitals of the sulfur atoms, a mechanism that would per se be facilitated by the strongly electron-attracting CCI, groups. Compound 1 3 is chiral with an enantiomerization barrier within experimental error equal to the C-N barrier. Probably, the diethylamino group is rotated out of the plane by the bulky CC13S groups, and enantiomerization occurs on rotation of the amino group. The mesomeric effect of the ester groups in malonic ester derivatives like l l b is diminished by a steric effect, which forces the ester group cis to the amino group out of the plane7. This effect is absent in analogues derived from cyclic 1,3-dicarbonyl compounds (14-16), which display high C-N and low C=C barriers (Table 4).
ph\
N-N
R1 /
Me, Me
H
N
6. Static and dynamic stereochemistry of acceptor-substituted enamines
415
TABLE 4. Free-energy barriers (kcal mol-' at T K) to C=C and C-N rotations for compounds 141646
Compound
Solvent
AGEzc
14a 14b 14c 15
Quinoline Ph,O CD,Cl, CD,Cl, Ph,O Ph,O
17.8 (311)
-
-
21.5 (433)
19.0 (345) 12.2 (228)
-
16
AGE-,
22.1 (442) 20.5 (398)
-
-
The ethyl 2-benzoyl-3-aminocrotonate 17 with a primary amino group exists in E and Z forms, and the barrier to Z-E exchange in CDCl, solution was found to be 18.7 kcal m o l 48. Although no study of the rate of NH exchange was made, this barrier is reasonable for a thermal isomerization with an ester and a benzoyl group as acceptors. Ph
I
Ph
OEt *
I
I
OEt
I
2-Nitro-2-acylenamines with primary and secondary amino groups (18) have been and G 6 m e ~ - S a n c h e z ~ ~ ~ ~ ~ * ~ ~ studied by the groups of B a k h m u t ~ v ~(R~ -=~OMe) ~ (R = OMe and Me). These compounds exist in two strongly hydrogen-bonded forms 18E and 182, and the two mechanisms for the E-Z exchange discussed above have to be considered: purely thermal rotation about the double bond, and rotation in a tautomer with C1-C2 single bond. Bakhmutov and BurmistrovSOfound that methyl 2-nitroacrylate 18a undergoes Z-E exchange in nitrobenzene solution with a barrier of 20.4 kcalmol-', while the barrier to NH exchange was >27 kcal mol-'. The kinetic order in 18a was 1.0, all in agreement with a purely thermal process. In pyridine solution, on the other hand, the kinetic order in 18a was 1.6 for the Z-E exchange and 2.0 for the NH exchange. The activation entropy for the NH exchange was -33 eu, in agreement with what should be expected for a bimolecular reaction. The exchange rate increased with the acceptor capacity of X when R2 was p-XC6H4, also supporting the
O I I
R1
R
AN,H I
R2 Z
R2 E
R 18a OMe 18b OMe 18c OMe 18d OMe 18e OMe 18f OMe U p OMe 18h Me 18i Me
R'
R2
H
H
Me Me H Me Me p - M e O C a H p-MeOCa Me p-CIC& H ~-CIC& H Me Me Et
I. Sandstrom
416
TABLE 5. Free-energy barriers (kcal mol-' at T K) to C=C and C-N populations ( p , ) for compounds 18
Compound
Solvent
+ CHCIF,(l : 1) PhNO, CD,CI, PhNO, CD,CI, PhNO, ODC" CHCI,F + CHCIF,(l: 1) CHCI,F
A%&
+
11.8 (206) 20.4 (347) 14.1 (262) 23.9 (298.2) 15.1 (275) 27.0 (298) 19.0 (29Qb 10.2 (180)
rotations and conformer Pz
Reference
0.98 (156) 0.43 (293) 0.77 (230) 0.45 (293) 0.69 (232) 0.45 (293) 0.18 (298Y 0.02 (152)
52 51 52 51 52
51 53 53
" ODC = o-dichlorobenzene. AH'
=
13.3 kcal mol-', AS'
' In CDCI,, 0.27 in DMSO-$.
=
-19 eu.
view that a considerable part of the reaction followed a mechanism involving deprotonation-protonation in a bimolecular complex. Chiara and coworkers30could show by IR spectroscopy that the form 18Z of methyl 3-amino-2-nitroacrylates with a hydrogen bond to the nitro group exists in two conformations (B' and B") with different orientations of the ester group. 'H NMR spectra showed only two forms in ratios near 1:1, fairly insensitive to the solvent. Evidently the B'-B" exchange is rapid on the NMR time-scale in the explored temperature region. The barriers to thermal Z-E rotation in these compounds fall in the range 20-27 kcal mol- 5 ' . A similar study of methyl 3-amino-2-nitrocrotonates 18b, 18d and 18fS2gave conconsiderably lower barriers (1 1.8-15.1 kcal mol- ', Table 5) because of ground-state strain. The barriers increase with increasing electron attraction by the N-substituent R2. This may reflect an effect on the strength of the hydrogen bond, which is a component in the barrier. The authors favor a thermal process for the Z-E rotation, partly because the barriers are well reproduced by theoretical calculations by the AM1 method, including solvent molecules54(vide infra, Section V1I.B).As expected, the C=C barriers for the acetyl derivatives 18h and 18i are lower than for the corresponding ester derivatives 1% and 18b.
'
D. Enamines with Other Electron-alracting Groups In BPositlon
Cyclic compounds with an aminomethylene substituent and a conjugated 4n-circumference can show low barriers to rotation about the exocyclic double bond, because the transition state to this rotation acquires an aromatic electron structure by accepting the double-bond n electrons. Similarly, elevated barriers to rotation about the C-N bond are found because of increased weight of the polar limiting structure in the ground state. A typical example is 6-dimethylaminofulvene (19a), which has a C=C barrier of 22 kcal mol- and a C-N barrier of 13.5 kcal mol-' 34,55. Introduction of one formyl group in position 1 of the cyclopentadiene ring (19b) increases the C-N barrier to 17.0 kcalmol-', while two formyl groups in the 2 and 3 positions (19c) increase the C=N barrier to 20.2 kcalmol-' 34. Inclusion of the amino group in a simple 6aminofulvene in a ring (20) lowers the C=C barrier to 19.6 kcal mol-', probably by increasing the planarity and decreasing the ground-state strain56.
'
6. Static and dynamic stereochemistry of acceptor-substituted enamines
R' R~ R3 H 19a H H 19b CHO H H 19c H CHO CHO
417
(20)
Candy and Jones5' have studied a series of p-substituted 6-aryl-6-dimethylamino-laza-fulvenes (21). They observed hindered rotation of the dimethylamino group with barriers in the range 14.0 to 15.4 kcal mol-' with no clear relation to the properties of the para substituents. The corresponding barriers in the carbocyclic analogues are ca 12 kcalmol-' 55. The difference is in the expected direction in view of the larger electronegativity of nitrogen than of carbon. A similar mechanism operates in quinone methides with an amino substituent in the methide group. The p-quinone methide 22 has a C=C barrier of 14.5 kcal mol-' and a C-N barrier of 12.4 kcal mol-I 58. IV. DERIVATIVES OF 1,l-DIAMINOETHENES AND OTHER ENAMINES WITH A SECONDDONORGROUPONC~ A. 1,l-Diaminoethenes with One or Two Acyl or Nitro Groups in Posltlon 2
1,l-Enediamines, also called ketene aminals, are stronger nucleophiles than the corresponding enamines, and when they are substituted with acceptor groups on CZ, strongly polarized systems result. However, most of the systems studied have disubstituted amino groups, and this gives rise to complicating steric interactions. As a simple example, 1,l-bis(dimethy1amino)ethene (23) has a structure, which is similar to those of
Me,N
"1" Me
I
Me
(23)
N'
I
Me
Me,
A 1 y 2Me N
N'
Me
Me
A
MeS
I
I
'
A'xA2 &
HIN02
H
Me
N'
MeS
I
Me
A2
24a Ph CN 24b Ph COMe 24 NC CN 24d MeCO C02Me 24e MeCO COMe 24f H NO2
A'
(25)
A2
26a Ph CN 26b Ph COMe 26c NC CN 26d MeCO C02Me 26e MeCO COMe 26f H NO2
418
J. Sandstrom
tetramethylurea and -thiourea. Simple models show that the nonhydrogen atoms of the dimethylamino groups in these compounds cannot be coplanar, and electron-diffraction studies of these59 showed rotation of the dimethylamino groups in the same direction by 23" and 32", respectively, with slight pyramidality of the nitrogen atoms. Kamath and Venkatesan60 have determined the crystal structures of two 1,l-bis(dimethy1amino)ethenes with different acceptor groups (24b and 24d), and they report twist angles for the practically planar dimethylamino groups between 18" and 33", but also twist angles about the C'=C2 bond of 34.8" and 56.9", respectively. The C=C bond lengths are respectively 140.9 and 146.1 pm. Evidently, the steric effects influence not only the orientation of the dimethylamino groups, but thcy also work betwccn the donor and acceptor groups. Similar data for two molecules with less bulky acceptor groups have been reported by Ganazzoli and coworkers61. They have studied the crystal structures of a nitroketene-N,S-aminal (25) and the analogous 1,l-bis(dimethy1amino) compound (24f). While 25 is nearly planar, 24f is twisted ca 33" about the double bond, and the dimethylamino groups are twisted 28.6" and 23.2" in the same direction out of the plane. The C'=C2 distances are 137.5 and 140.6 pm, respectively. As expected, introduction of a second amino group on C1 in enamines with acceptors on C2 lowers the barriers to C=C rotation. This can be ascribed to a better stabilization of the transition state, in which the carbocationic part assumes the character of an amidinium ion. Some typical barriers for 1,l-bis(dimethylamino)ethylenes with acceptor groups in position 2 (24) are shown in Table 6. It is observed that, with a pair of good acceptors, the barriers become too low to be accessible with the NMR technique. With weaker acceptors, the order of the barriers follows the expected capacity of the acceptor groups to stabilize the carbanionic part of the transition state. K e s s l e ~has ~ ~measured the C=C barriers in a number of p-substituted 1,l-bis(dimethy1amino)-2-cyano-2phenylethenes (24a) and found that the logarithms of the estimated rate constants at 25 "C correlated well with the a; values63 for the para substituents. Similar correlations with opposite signs for p and lower sensitivity were found for the C-N and C-aryl rotations. TABLE 6. Free-energy barriers (kcal mol-' at T K) to rotation about C=C, C-N bonds, and E conformer populations @), for compounds 24 and 26
and C-X
Compound
References
Solvent
24a
ODC" PhF
26a 24b 26b
CHCI,F CDCI, + CS, (1: 1) CHCI,F
26e 24f 261
CHCI~F
..
CHCI,F + PhF CHCLF
" ODC = o-Dichlorobenzene. Major of four rotamers. EZ-ZE.
AGE=,
AGE-,
AGE-X
p,
6. Static and dynamic stereochemistry of acceptor-substituted enamines
419
However, it is to be expected that the rotation of the dimethylamino groups out of the plane should diminish their donor capacity. This is supported by the observation that the C=C barriers are lower in acceptor-substituted l-dimethylamino-l-methylthioethenes (ketene N,S-acetals, 26) than in the 1,l-bis(dimethy1amino)ethenes(24) with the same acceptor combination (Table 6), in spite of the fact that dimethylamino groups in general are much better donors than methylthio groupsj3. However, the situation is not quite simple, since in a crystallographic study the ketene N,S-acetal 26a was found to have the dimethylamino group twisted 25" out of the plane with a C1=C2 bond twist of ca 20°6'. B. 1,l-Diamino-2,2-diacyiethenes and Analogues with the Nitrogen Atoms in a Ring
One way to improve the donor capacity of the amino groups in an acceptorsubstituted 1,l-diaminoethene could be to enforce planarity by inclusion of the nitrogen atoms in a five- or six-membered ring. This leads to a remarkable lowering of the C=C barrier, e.g. from 20.6 kcal mol-I for 24a to 9.5 kcal mol-I for 27a and 7.4 kcal mol-' for 28a6', which however, to some extent, must be ascribed to ground-state strain. According to an X-ray crystallographic study, 27a is twisted 23" about the C1=C2 bond69. The steric effect and the concomitant twisting is larger if the donor atoms are included in a six-membered than in a five-membered ring, other things being equal. Examples are found in 27c and 2% with twist angles of 20" and 32", respe~tively'~; others will be discussed in the following.
27a 27b 27c 27d 27e
A' A? R Ph CN Me Ph CN CH2Ph CN CN Me PhCO COMe CH2Ph MeCO COMe Me
28s 28b 28c 28d 28e
A' AZ R Ph CN Me Ph CN CHzPh CN CN Me PhCO COMe CH2Ph MeCO COMe Me
(29)
The barrier hindering the torsion about the C1=C%ond can be schematically divided into two components, -the contributions of which vary with the twist angle 0'': (1) the n-electron contribution (E,), which has a maximum at Q = 90' and 270", and which decreases with increasing efficiency of the donor and/or acceptor groups; (2) the steric contribution (E,,,,), which has its highest values at O = 0 and 180". and which increases with increasing bulk of donor and acceptor groups. Inclusion of the donors and/or the acceptors in rings, six-membered being more efficient than five-membered, increases the steric contribution by making the donorJacceptor parts more rigid. The total energy of the system is the sum of En and E,,,,. Figures 2-4 show three typical combinations of the two contributions. Figure 2 represents a nearly planar push-pull ethylene with a high E, value at 90" and 270" (the x-barrier) and low E,,,, at all twist angles (Case I).
FIGURE 2. Schematic potential energy curve for a Case 1 push-pull ethylene. E, B E,,,,
0
90
180
270
360
@(degrees)
FIGURE 3. Schematic potential energy curve for a Case 2 push-pull ethylene. EnQ E,,,,
421
6. Static and dynamic stereochemistry of acceptor-substituted enamines
.: 4
0
90
180
270
360
tJ(degrees)
FIGURE 4. Schematic potential energy curve for a Case 3 push-pull ethylene. Ex + E,,.,
A high n-barrier implies relatively weak donors (Dl and D2) and/or acceptors (A1 and A'). In systems with D' # D2 and/or A' # A2, the barrier to rotation about the C=C bond can be determined by DNMR technique, if the rate corresponds to the NMR time scale within the accessible temperature range. If the barrier is higher than ca 23 kcal mol-' and Dl # D2 and A' #A2, it may be possible to separate diastereomers at ambient temperature (by chromatography or fractional crystallization) and follow the rotation by a thermal isomerization monitored by NMR or HPLC. Figure 3 represents an opposite situation, with large steric effects and a low n-barrier (Case 2). Here the ground state has a large twist angle, and O will approach 90" and 270" with decreasing n-barrier. When the molecules pass from the energy minima near O = 90" to those near O = 270°, they have to pass the steric barrier. If A' # A2 and/or D1 # D2, this proccss affects thc shape of the resonances of prochiral nuclei and can thus be followed by DNMR. It is obvious that the steric barriers at O = 0' and O = 270" may be different if D1 # DZ and A' # A'. An intermediate case (Case 3) with E, similar to E,,,, is shown by Figure 4. To obtain systems of this type with barriers that can be measured by DNMR, it is desirable that both energy contributions have high valucs. These three types of conformational behavior will now be discussed and exemplified: Case 1 systems are found in Tables 1-6. It should be noted that X-ray studies of a number of compounds of this group show considerable twist in the crystal. Case 2 systems are found when the donor nitrogen atoms are part of a ring and also carry substituents. Typical molecules are 27d with AG!,, = 16.5 kcal mol-I and 28d with AGf,,, = 22 kcal mol-' ", which illustrate that a six-membered donor ring gives a higher steric barrier than a five-membered one. The twist angle in 27e is 72.9°69,and it is probably even larger in 28e.
422
J. Sandstrom
The A'-C-AZ part in molecules like 27d and 28d have electronic structures close to those of 1,3-diketone anions. Crystal structures show the anionoid part to be nearly planar@, and the rotation of the acceptor groups must be considerably hindered. The stereochemistry of the acceptor groups in 27e and 28e and analogues has been studied by DNMR7Z.One symmetric and one unsymmetric conformation was observed, the former identified by solvent effects (ASIS)73as the EE form while the other was assigned to the EZ form (Scheme 4, only one limiting structure represented). The Z Z form was not observed, in agreement with the expected repulsion between the parallel C=O dipoles, also supported by CNDO calculation^^^. However, band shape analysis of the exchange-broadened acetyl methyl resonances showed that in some cases the EZ -t ZE exchange occurs with the ZZ form as a high-energy intermediate. With 29, the EZ -, ZE exchange took place to about 113 via the Z Z form and to 213 via the EE form (AGz = 14.2 and 13.7 kcal mol-', respectively).
SCHEME 4
The conformational situation for twisted 2,2-diacyl compounds of type 29 is quite different from that for sodium or lithium 1,3-diketone enolates. In the latter, the ZZ form is stabilized by complexation with thc cation75,and only in the presence of crown ethers is the EZ form observed76. The barrier to E Z - t ZE exchange in the free carbanion is 12.9 kcal mol-I, as expected quite close to that found for 29. The steric interaction between the donor and acceptor parts is enhanced if also the acceptors are built into a ring. An example is given by 30a, for which the geminal methyl 'H resonance remained a sharp doublet to 200 "C, corresponding to AG' 2 26.5 kcal mol-' 71. The dissymmetric analogue 30b could be resolved into diastereomers by chromatography, and by monitoring the thermal isomerization by HPLC a barrier of 27.9 kcal mol-' could be obtained77.
6. Static and dynamic stereochemistry of acceptor-substituted enamines
423
Case 2 enediamines with different donors and different acceptors are chiral, and if the barrier to passage through the planar state is sufficiently high, such compounds can in principle be resolved into enantiomers. This has been achieved in several instances by the versatile technique of liquid chromatography on microcrystalline triacetylcell~lose~~. As an example, 31a was partially resolved, and AGf to passage of the steric barrier was found by thermal racemization to be 25.6 kcalmol-' at 58 "C in ethanol and 22.8 kcal mol-' at 35 "C in d i ~ x a n eto ~ ~be, compared with 23.1 kcal mol-' at 139 "C determined by DNMR in o-dichl~robenzene~~.
30a 30b 30c 30d 30e 30f
X 0 0 0 0 S S
R3 n Y R' R~ Me i-Pr 3 0 Me i-Pr 3 0 H Ph 3 S Me Me i-Pr 0 Me Me CH2Ph 3 S Me Me CH2Ph 2 S Me Me CH2Ph 3
31a 31b 31c 31d
X 0 0 S S
Y 0 S S
0
R Ph Ph Ph Me
R n 32a i-Pr 2 32b i-PC 3 3 2 ~CH2Ph 3
As discussed above (Section III.A), thiocarbonyl groups are better acceptors than carbonyl groups, and they are also sterically more demanding. Therefore, exchange of acyl groups in 1,l-diamino-2,2-diacylethenes(Case 2 systems) for thioacyl groups will lower E, and raise E,,,,, and the total result should be an increase in the steric barrier. This expectation is borne out by compounds 30c, 31L31d, 32a and 32b, which were resolved by chiral chromatography and subjected to thermal racemization at 90 "C77.80(Table 7). Some compounds of this type (30d, 30e, 30f and 324 have been and the results (Table 7) are in subjected to X-ray crystallographic conformity with the previously observed effects of ring size and replacement of carbonyl by thiocarbonyl groups. The low twist angle in 3242 compared to 30e, which should have a rather similar E,,,,, can be ascribed to a higher E, in the former compound, in which the acceptor part is less efficient in stabilizing a negative charge than in 30e. The strongly twisted Case 2 molecules should rather be classified as zwitterionic compounds than as enamines. They are of interest as models for the transition states to C=C rotation in Case 1 molecules, and also as carbanions free from a chelating cation. Case 3 systems are much less common. The best studied is 284 for which both a steric barrier of 10.7 kcal mol-' and a n-barrier of 7.3 kcalmol-' could be measured by DNMR68,71.The barriers can be modified by introducing different para substituents. An amino group increases E,, and a n-barrier of 8.3 and a steric barrier of 9.7 kcal mol-' can be measured. A p-nitro group on the other hand lowers En, and only the steric barrier, 13.9 kcal mol-', can be measured. These results show that the steric barrier varies with variation of En, although E,,,, must be the same for all three compounds.
424
J. Sandstrom
TABLE 7. Free-energy barriers (kcal mol-' at T K) to rotation through the plane, and torsonial angles (0") and C=C bond lengths (rc,, pm) for compounds 30-36
Compound
Solvent
AG' (ster)
0"
rc=c
Reference
Ethanol Ethanol Ethanol Ethanol Ethanol Toluene Ethanol Ethanol -
"Two different molecules in the unit cell.
The expected importance of the N-alkyl groups in 28a for the nonplanarity is confirmed by an X-ray crystallographic study by Huang and coworkerss3. A number of N-unsubstituted analogues were found to be nearly planar with twist angles of 3.6", 8.8" and 18.1" and C'=C2 bond lengths of 138.0, 139.5 and 138.8 pm, respectively. A group of 1,l-diamino-2,2-dinitroethenes has recently been describeds4. In these, E. must be quite low, and consequently the conformation is largely determined by E,,,,. Crystal structures are reported for seven compounds with acyclic or cyclic donor part, and twist angles O between 0.6" and 89" are reported. Data for four typical molecules, 3 S 3 6 , are given in Table 7. The most striking difference is between 34 (O = 0.6 or 2.0) with a five-membered and 35 (O = 89") with a six-membered ring. The planarity of 34 is ascribed to the existence of two intramolecular hydrogen bonds, which are absent in 35. Crystal forces, including intermolecular hydrogen bonds, may also influence the twist, since twist angles of 74.5" and 85.1" are found for the same molecule in two different crystal forms. The nitro groups are coplanar in all structures. These molecules show quite long C=C distances: 143.0 pm for the planar 34, 143.4 to 147.5 pm for the twisted structurcs.
6. Static and dynamic stereochemistry of acceptor-substituted enamines
425
C. 1,l-Dlamlnoethenes and Analogues with Other Types of Acceptor Groups in Position 2
As for the monoaminoethenes (Section IILD), lowering of the C=C and raising of the C-N barriers is expected to occur when C2 of 1,l-diaminoethenes is included in a ring of conjugated atoms with 4n n-electrons. However, the results for 6,6-diaminofulvenes are not quite compatible with those for the monoamino analogues. 6,6Bis(dimethylamino)fulvene 37a shows a simple temperature-independent 'H NMR spectrum in the range +I50 to -60 "CE5,indicating a C-N barrier lower than 11 kcal mol-'. Introduction of two formyl groups (37b) fails to lower the C=C barrier to an accessible region, while the C-N barriers are raised to 13.9 (Z) and 18.4 (E) kcal mol-', respectively. That noncoplanarity of the amino groups plays an important role for the high C=C barrier of 37b follows from a comparison with 38a-38c, in which the nitrogen atoms are included in five- or six-membered ringss6. In these compounds, however, ground-state strain must contribute to the low C=C barriers, at least in 38b and 3&.
pRy
R
N ' ~
Me2N
NMe2
R 37a H 37b CHO
/(CHd, X R n S Me 2 38a Me 2 38b NPh 38c PhCH2N i-Pr 3
MeN .
uNe (39)
A molecule with 2,3-diazafulvene structure and the donor nitrogen atoms in a five-membered ring (39) has been studied by X-ray crystallography and found to be twisted about the C1-CZ bond by 8T8'. Steric complications arise when the acceptor together with C2 forms a nine-membered ring. Hafner and coworkerss8~89 have studied 10,lO-bis(dimethy1amino)methylene cyclononatetraene (40) and found that thc compound participates in a solvent-dependent equilibrium between a twisted form with low polarity (40a, A,, = 330 nm), favored by nonpolar solvents, and a nearly planar dipolar form (40b, A,, = 403 nm), favored by polar solvents and low temperature. The N-CH, 'H resonance splits into a doublet
426
J. Sandstrom
at -53 "C, corresponding to a C-N barrier of 11.2 kcal mol-'. This barrier must be the result of an exchange rate, which is a population-weighted mean of a low rate in 40a and a higher rate in 40b. Heptafulvenes assume a push-pull character when the exocyclic carbon atom (C8)is substituted by acceptor groupsg0. Daub and coworkersg1 have studied this type of compound with dimethylamino groups and other donor groups on Cs. 'H NMR spectra of the bis(dimethy1amino) compound 41a show that the compound is boat-shaped with alternating single and double bonds, and a barrier to rotation about the exocyclic C=C bond z 2 7 kcal mol-' is reported for the 8-dimethylamino-8-triethylsilyloxy compound 41b. No low-temperature spectra are reported, but the C-N barrier is likely to be low. V. Dl- AND POLYENAMINE DERIVATIVES
The earliest studies in this field were concerned with the effect of the number of double bonds on the barrier to C-N rotation in the series dimethylformamide, 3-dimethylaminoacrolein and 5-dimethylamino-2,4-pentadienal.The barrier was found to diminish from 20.8 to ca 15 to ca 13 kcalmol-' 92,93,and for each compound it increased with the polarity of the solventg2. Prokof'ev and coworkersg4 have reported free activation energies to C3=C4 and C-N rotation in a number of 1-dimethylamino- and 1-N-methylanilino-4,4-diacylbutadienes (42). The results (Table 8) follow the same trends as for the enamino derivatives: combinations of good acceptors give high C-N barriers (highest value 16.9 kcal mol-' for X = NO,, Y = C0,Me) and low C=C barriers (16.1 kcal mol-' for the same acceptor combination). Most spectra are recorded in CD,OD solution. Change to CDCI, increases the C=C barrier strongly but has little effect on the C-N barrier.
MeOCO,
42a 42b 42c 42d
X Y R MeOCO C02Me Me MeCO COqMe Me MeCO ~ 6 Me ~ 02N C02Mc Me
4,C02Me C
n
43a 0 43b 1 e
McNab and coworkersg5 have made 'H and I3C DNMR and X-ray crystallographic studies of a series of mono-, di- and trienamines based on dimethyl malonate (43a-43~) and on 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid; 44a&). As expected, the C-N barriers (Table 8) were found to decrease with increasing conjugation (except for 43a), and they were also found to be higher for the cyclic compounds than for the corresponding acyclic diesters, also in agreement with previously discussed results. In these compounds, there are several possibilities for C=C rotations, but it seems as if
6. Static and dynamic stereochemistry of acceptor-substituted enarnines TABLE 8. Free-energy barriers (kcal mol-' at T K) to C=C and C-N
427
rotations for compounds
4246
Compound
Solvent
AG$==
AG$-N
Reference
CD,OD CD,OD CD30D CDCI, CD,OD + CDCI, (1:9) CD30D (CDdzCO (CD&SO (CDJzCO (CDdzSO (CDJzCO CDCI, (CDdzSO (CDMO (CDdzSO (CD.3)2C0
CD2C12 CD2C12
-b
+
'AHt:20.5 kcal m o l ' , ASt: 17.5 eu. No solvent is reported for compounds 46.
the NMR spectrum is only affected by rotation about the double bond including the carbon atom carrying the acceptor groups, as was also found by Prokof'ev and coworkers. Probably, the other double bond(s) take up strongly preferred configurations. The C=C barriers are lower for the cyclic than for the acyclic enamines, but the orders of barriers are at first sight unexpected, increasing in the series ene < triene < diene. However, the authors point out that the first member in each series is subject to ground-state strain, which lowers the barrier, and that, if only electrqnic effects had been at work, the barriers would have decreased in the order ene > diene > triene. The crystal structures, which have been determined for the Meldrum's acid derivatives 44a44c, showed that the ground-state strain in 44a results in twisting by ca 30" about the double bond, while the other two compounds were essentially planar. For the malonic ester derivative 43a, Shvo and coworkers8 have earlier shown that the ester group cis to the dimethylamino group is rotated out of the plane. The C=C bond carrying the dimethylamino group showed a progressive lengthening with increasing number of double bonds, indicating an increasing delocalization. Dahlqvist and F ~ r s e nhave ~ ~ studied two I-N,N-dirnethylarninobutadieneswith two carbomethoxy (45a) or two cyano groups (45b) as acceptors and with C1, C2 and C3 included in a six-membered ring. No indication of rotation about the C3=C4 bond is reported, probably because the barrier is too high, but barriers to rotation about the C-N bond of respectively 11.4 and 15.3 kcal rnol- were found by careful band shape analysis at two different magnetic field strengths. The value for 4% seems low in comparison with that for the open-chain analogue: 14.694and 14.395kcal m o l l . An explanation may be found in the steric effect exerted by the ring CH, group bound to C'.
J. Sandstrom
A methyl group bound in the same position in the acyclic 4-acetyl-4-methoxycarbonyl analogue lowers the C-N barrier by 1.8 kcal mol-' 94.
Schoeni and Fleury9' have studied a number of 1-dimethylamino-, 1-morpholino- and 1-piperidino-3-azabutadienes(e.g. 4 6 a 4 d ) with different combinations of methoxycarbonyl and cyano groups as acceptors on C4. C-N barriers were found in the range 13.6 to > 19.0kcal mol-', generally higher than for the carbon analogues. This shows that a spZ nitrogen atom is at least as efficient as a spZ carbon atom in transmitting electron delocalization. Some of the compounds with different acceptors showed two sets of signals in CDCI, or benzene solution, but not in DMSO-d, or in the presence of trifluoroacetic acid. This indicates slow rotation about the N3=C4 bond, accelerated by acids or polar solvents, but no rate data are given.
VI. POLYMETHINE DYES
Simple polymethine (or cyanine) ions like 47 are, together with cyclic aromatic compounds, the prototypes of complete electron delocalization (linear 'particle in a box' modelsg8). One may therefore expect low barriers to rotation about the C-C bonds and high barriers to rotation about the C-N bonds. The former barriers are difficult to study by NMR because these compounds prefer an all-trans configurationg9, but flash-photolysis experimentsloO have given AG' ca 15 kcal mol-I for Z + E isomerizations of a number of pentamethinium ions. The reverse reactions should have at least 2 kcal mol-' higher barriers, corresponding to the greater stability of the E form. By suitable substitution on the nitrogen and/or carbon atoms, it is possible to increase the stability of one or more Z forms so that they can be observed and the rate of equilibration measured. Already in 1953, Zechmeister and Pinckardl0' observed that a heptamethinium dye terminated by benzothiazole units could be separated by chromatography into three isomers, each rapidly giving an equilibrium mixture of all three in solution. The observed lifetimes seem to correspond to barriers of the same order of
6. Static and dynamic stereochemistry of acceptor-substituted enamines
429
magnitude as those found by photoisomerization. NMR studies of rates and equilibria in such systems were long hampered by the low solubility of the dyes, but Heinrichs and G r o ~ s ' ~could ' obtain reasonably intense exchange-broadened 'H NMR spectra of a number of carbocyanine dyes of the type 48 (Scheme 5) by using the relatively soluble perfluorobutyrates in conjunction with pulse-Fourier transform technique. The spectra showed the presence of both cis and trans forms, the population of the former increasing with the steric requirement of the heteroatom X and of R. Two degenerate cis forms are apparent (Scheme 5), and the exchange between them may proceed via the all-trans form or via the nonobservable, high-energy cis,cis form. It follows from the band shapes that the exchange takes the former route with the oxa compound 48a but the latter with the thia and selena compounds 48b and 48c. With the 9-phenyl derivative 48d the population of the cis form is too low to permit a decision about the route. The barriers are given in Table 9. In the all-trans polymcthine dyes, hindcred rotation of thc dimethylamino groups is observed with quite high barriers. Dale and coworkers99 have determined this barrier
'all-trans'
\
SCHEME
5
J. Sandstrom TABLE 9. Free-energy barriers (kcal mol-I at T K) to cis -.rrans and cis, -.cis, exchange for compounds 48 as perRuorobutyrates in
(CD3),C0102 Compound
AGLrnns
AGL,
in 47a47c and found it to fall off with increasing chain length, to be insensitive to the counterion but to diminish with increasing polarity of the solvent (Table 10). Dale and coworkers103 have studied the Y-shaped dication 49 as its diperchlorate and found it to exist both in the solid state and in solution as a propeller-shaped entity with C , symmetry. The N-methyl doublet in the 'H NMR spectrum showed coalescence at 170 "C in DMSO-6, (300 MHz) corresponding to a barrier to C-N rotation of 22.5 kcal mol-'.
+
VII. THEORETICAL CALCULATIONS OF ELECTRONIC STRUCTURES, ROTATIONAL BARRIERS, INTERACTION WITH THE SOLVENT AND BOND LENGTHS A. Charge Distrlbutlons
The particular properties of acceptor-substituted enamines are related to the electron distribution, which has been of primary interest in the increasingly sophisticated theoretical calculations that have been applied to this group of compounds. The same TABLE 10. Free-energy barriers (kcal m o l ' at T
K) to C-N
rotation in the polymethinium ions
4799
Compound
Solvent
AG&-N
6. Static and dynamic stereochemistry of acceptor-substituted enamines
431
FIGURE 5. Total net charges and n-electron densities (in parenthesis) from CNDO/S calculations for vinylamine, acrolein and 3-dimethylaminoacrolein. Experimental dipole moments are from References 17, 105 and 106, respectively general trcnds are reproduced by all-valencc-clcctron and ab initio calculations, and they can be illustrated by the results from CNDO/S calculations on vinylamine, acrolein and 3-dimethylaminoacrolein (Figure 5)lo4.It appears that the amino group in vinylamine donates more electrons to the double bond than are withdrawn from this bond by the formyl group in acrolein. According to the calculations, the amino group in the aminoacrolein donates considerably more n-clectron density to the double bond than in the vinylamine, but in both molecules it withdraws more u-electrons from its neighbors by an inductive mechanism and ends up with a net negative charge. The C=C bond is polarized, but C2 gains more electron density than is lost by C1.In fact, the high negative charge on C2 is one of the most striking effects of the push-pull substitution. The oxygen atom in the carbonyl group is not much affected by the extended conjugation, but the carbonyl carbon atom has its positive charge considerably diminished by an increase in its u-electron density. In Figure 6, data showing similar trends are given for nitroethene and the cis form of 1-amino-2-nitroethene. The total charges for the aminonitroethene are from AM1 calculation^^^ and all n-electron densities are from ab initio c a l ~ u l a t i o n s ' ~The ~ . electron distributions calculated by the CNDO-type methods gain credibility by the fact that experimental dipole moments are reasonably well r e p r o d u ~ e d l ~The ~ . ~AM1 ~ ~ . and ab initio electron distributions are very similar to those obtained by CNDO/S calculations104. SQnchez Marcos and ~ o w o r k e r s ' ~ ~ have ~''~ reported on more refined analyses of the electron distributions in vinylamine, nitroethylcne and cis- and trans-l-amino-2nitroethene. The populations of ionic and spin alternant electron pairs are analyzed in
FIGURE 6. Total net charges (AM140) and a-electron charges (ab initioLO',in parenthesis) for cis-2-nitrovinylamineand n-electron charges (ah initiolo7)for nitroethylene
432
J. Sandstrom
terms of occupancy of localized orbitals, and the relative weight of ionic pairs is found to increase in the series ethene < nitroethene < vinylamine < 1-amino-2-nitroethenelo5. A second analysis is directed at the simultaneous existence of electron pairs and electron holes in different relative positions. The result is that positive and negative charges may exist with considerable weights on nonvicinal positions, in qualitative agreement with conventional resonance structures like B in Scheme 1l l O . B. Rotational Barriers and Solvent Effects
In view of the model for the rotation around the C=C bond discussed in the Introduction, with a moderately polar ground state and a transition state, which can be seen as a combination of an acceptor-stabilized carbanion and a donor-stabilized carbocation, it is natural that the rate of rotation is strongly dependent on solvent polarity. This has also been noted and exemplified by numerous workers in the field. Kessler and coworkersL" and Shvo and coworkers1l 2 found linear correlations between free activation energies to C=C rotation and the polarity indices E, and Z, respectively. C-N barriers were found to increase slightly with increasing solvent polarity1". It is therefore not surprising that theoretical calculations of rotational barriers, which have neglected solvent effects, give consistently too high C=C barriers113-116. A primitive approach to treating the solvent effect was made with 6,6-diheterosubstituted fulvene~'~ by calculating the gas-phase barriers with the CND0/2 method and the solvent stabilization of ground and transition states in the reaction field formalism with a spherical cavity. The result was found to be very sensitive to the cavity size and to the calculated ground-state and transition-state dipole moments, and no reliable numerical data could be obtained. The calculated gas-phase barriers were too high, although they fell in the correct order. Sinchez Marcos and Pappalardo have recently performed considerably more elaborate studies of the solvent influence on barriers and conformation equilibria of nit r ~ e n a m i n e s ~ ~ .The " ~ . solute cavity was modeled after the shape of the molecule, and the solvent was treated both as a continuums4 and as a supermolecule with 1-5 methanol molecules per solute mole~ule"~.The solute-solvent interaction energy was obtained from the potential of a suitably defined surface charge density and the electron distribution in the solute from AM1 calculations. The agreement between experimental and calculated free-energy barriers was excellent, whereas the Z-E equilibria were less well reproduced with AM1 calculations. This discrcpancy was diminishcd when conformation gas-phase energies from ab initio calculations were used. Wiberg and c o ~ o r k e r s ' ~have ' described a similar study of 9b based on ab initio calculations and the reaction field theory. The resulting C=C barriers (Z + E) were around 30 kcal mol-I, 9-10 kcal mol-' higher than the experimental values (Table 2, Reference 40), but the difference between the barriers in o-dichlorobenzene and in N,N-dimethylformamide was well reproduced. Two similar studies of 2-nitrovinylamine, 3-aminoacrolein and 3-aminoacetonitrile s ~ ~results ~ ~ ~ in ~ ~good qualitative and their anions based on ah initio c a l ~ u l a t i o n gave agreement with experiments for both the C=C and C-N barriers, while simultaneously giving a good picture of the nature of the solvent effects in ground and transition states. While activation entropies (AS?) for conformational processes in molecules of low polarity, even for amides, have in general been found to be close to zero, the corresponding data for C=C rotations in Case 1 push-pull ethylenes are often strongly negativelzO This can be ascribed to a higher degree of order of the solvent molecules in the strongly polarized transition state than in the less polarized ground state, a view which is supported by the observation that A$ becomes less negative with increasing polarity of the ground state. In Case 2 systems, on the other hand, the nearly planar transition
6. Static and dynamic stereochemistry of acceptor-substituted enamines
433
state to rotation is less polar than the twisted ground state, and consequently a positive A$ value is expected and also found experimentallylzl. It has been observed in several i n s t a n ~ e s ~ ~that , ~ ~C=C . ' ~ ~rotations in Case 1 systems are strongly catalyzed by traces of acid. This can often be explained by protonation of the acceptor groups, which increases their acceptor capacity. Since halogenohydrocarbon solvents often contain traces of acid, it is advisable to add a small amount of a sterically hindered base like 2,6-lutidine in order to obtain reproducible results. Kleinpeter and Pulstlzz have found that the barrier to C-N rotation in N,Ndimethyl-2-thiobenzoylenamine in nitrobenzene first decreases, and then increases on addition of trifluoroacetic acid. The effects, which are quite small, are interpreted as N-protonation at low and S-protonation at higher acid concentrations. C. Calculations of Geometries and Conformational Energies In the following a few recent molecular orbital calculations concerned with conformer energies and geometries of acceptor-substituted enamines will be discussed in conjunction with known crystal structures. Gate and coworkers3' have made an X-ray crystallographic study of l-methylamino2-nitroethene (Scheme 3) and found the intermolecularly hydrogen-bonded EZ form (E for CL=C2, Z for CL-N) to be stable in the crystal, while STO-3G calculations predicted the ZE form to be more stable than the EZ and EE forms by 2.4 and 2.6 kcal m o l l . The predicted energy of the ZZ form, 178 kcal mol-', is exorbitantly high, but no geometry optimization had been performed. Sanchez Marcos and coworkers123 havc reportcd the results of MNDO/H and AM1 calculations on 1-amino-2-nitroethene (9b) and its 2-acetyl, 2-methoxycarbonyl and 1-methyl-2-methoxycarbonylanalogues, e.g. 18a and 18b. The isomer distributions agree reasonably well with those found by experimentssz, and the AM1 calculations give acceptable agreement with geometric data for 1% from a crystallogranhic study lZ4, while the MNDOm calculations underestimate the effect of conjugation, as is shown by the noncoplanar ester groups. Ganazolli and coworkers6' have described charges and bond orders for 24f and 25 from CND0/2 calculations and geometries from INDO13 calculations for three analogues of 24f. All these compounds have two donor groups, and consequently the C1=CZ bonds are more polarized than in the compounds discussed above.
Emsley and coworkersL2*have made an X-ray crystallographic and empirical forcefield study of a simple non-hydrogen-bonded 2-acetvlenamine (50). The molecule has the EZ configuration in the crystal, 6ut the calculations (MM2 and M M P ~ predict ) the ZZ form to be more stable by 0.7 kcal mol- '. Ab initio calculations on 3-aminoacrolein also favor the ZZ form, but here the intramolecular hydrogen bond plays a decisive role.
J. Sandstrom VIII. REFERENCES 1. K. Tanaka, S. Yamanaka, T. Koike and Y. Yamabe, Phys. Rev., B32, 2731 (1985). 2. M. Blanchard-Desce, I. Ledoux. J.-M. Lehn, J. Malthete and J. Zvss. . . J. Chem. Soc.. Chem. Commun., 737 (1988). 3. J. 0. Morley, V. J. Docherty and D. Pugh, J. Chem. Soc., Perkin Trans. 2, 1351 (1987). 4. 1. D. L. Abert. P. K. Das and S. Ramasesha. Chem. Phvs. 119901 , Lett.. 168.454 - -,~ 5. J. ~ a n d s t r ~ m ,Phys. ' ~ . Chem., 71, 2318 (1967). 6. Y. Shvo and H. Shanan-Atidi, J. Am. Chem. Soc., 91,6683 (1969). 7. J. E. Douglas, B. S. Rabinowitch and F. S. Looney, J. Chem. Phys., 23, 315 (1955). 8. U. Shmueli, H. Shanan-Atidi, H. Horwitz and Y. Shvo, J. Chem. Soc., Perkin Trans. 2, 657 (1973). 9. H.-0. Kalinowski and H. Kessler, Top. Stereochem., 7, 303 (1973). 10. L. M. Jackman, in Dynamic Nuclear Magnetic Resonance Spectroscopy (Eds. L. M. Jackman and F. A. Cotton), Academic Press, London and New York, 1975, p. 303. 11. J. Sandstrom, Top. Stereochem., 14, 83 (1983). 12. M. L. Martin, X. Y. Sun and G. J. Martin, Ann. Rep. NMR Spectrosc., 16, 187 (1985). 13. J. Sandstrom, Dynamic NMR Spectroscopy, Academic Press, London and New York, 1982. 14. K. L. Brown, L. Damm, J. D. Dunitz, A. Eschenmoser, R. Hobi, and C. Kratky, Helv. Chim. Acra, 61, 3108 (1978). 15. K. Muller and L. D. Brown, Helv. Chim. Acta, 61, 1407 (1978). 16. K. Muller, F. Previdoli and H. Desilvestro, Helv. Chim. Acta, 64, 2497 (1981). 17. F. J. Lovas, F. 0. Clark and E. Tiemann, J. Chem. Phya, 62, 1926 (1975). 18. G. J. Martin and J.-P. Gouesnard, Tetrahedron Lett., 4251 (1975). 19. L. Lunazzi, D. Casarini and J. E. Anderson, Gazz. Chim. Ital., 120, 217 (1990). 20. J. Dabrowski and L. Kozerski, J. Chem. Soc. ( B ) , 345 (1971). 21. J. Dabrowski and L. Kozerski, Org. Magn. Reson., 4, 137 (1972). 22. M. L. Filleux-Blanchard, F. Mabon and G. J. Martin, Tetrahedron Lett., 3907 (1974). 23. M. L. Filleux-Blanchard, F. Clesse, J. Bignebat andG. J. Martin, Tetrahedron Lett., 981 (1969). 24. C. Piccinni-Leopardi, 0. Fabre, D. Zimmerman, J. Reisse, F. Cornea and C. Fulea, Can. J. Chem., 55, 2649 (1977). 25. J. Sandstrom, Tetrahedron Lett., 639 (1979). 26. J. Dabrowski and K. Kamienska-Trela. Ora. Maan. Reson.. 4. 421 11972) T~ , r a k t .hem:, 320,945 (1978). 27. H.-G. Henning, M. Bandlow, Y. ~ e d r ~ c h ' a n d~ke. k n ~ h o fJ: 28. E. Czerwinska, L., Kozerski and J. Boksa, Ory. Muyn. Resun., 8, 35 (1976). 29. K. Herbig, R. Huisgen and H. Huber, Chem. Ber., 99, 2546 (1966). 30. J. L. Chiara, A. G6mez-Sanchez, F.-J. Hidalgo and J. Bellanato, J. Chem. Soc., Perkin Trans. 2, 1691 (1988). 31. V. P. Rybalkin, L. M. Sitkina, Zh. V. Bren', V. A. Bren' and V. I. Minkin, Zh. Org. Khim., 26,2389 (1990); Engl. Transl. J. Org. Chem. USSR, 26, 2061 (1990). 32. J. Dabrowski and L. Kozerski, Org. Magn. Reson., 5, 469 (1973). 33. 0. Exner, in Adt~ancesin Linear Free Energy Relationships (Eds. N. B. Chapman and J. Shorter), Chap. 1, Plenum, London 1972, p. 21. 34. A. Mannschreck and U. Koelle, Tetrahedron Lett., 863 (1967). 35. A. Hazell and A. Mukhopadhyay, Acta Crystallogr., Sect. B, 36, 747 (1980). 36. D. L. Ostercamp and P. J. Taylor, J. Chem. Soc., Perkin Trans. 2, 1021 (1985). 37. E. N. Gate, M. A. Meek, C. H. Schwalbe and M. F. G. Stevens, J. Chem. Soc., Perkin Trans. 2, 251 (1985). 38. L. Kozerski and A. Krowczynski, Synthesis, 25, 489 (1983). 39. L. Kozerski and A. Krowczynski, Magn. Reson. Chem., 25, 46 (1987). 40. J. L. Chiara, A. Gomez-Sanchez and J. Bellanato, J. Chem. Soc., Perkin Trans. 2, 787 (1992). 41. R. F. Hobson and L. W. Reeves, J Phys. Chem., 77,419 (1973). 42. K.4. Dahlqvist, Acta Chem. Scand., 24, 1941 (1970). 43. C. Dreier, L. Henriksen, S. Karlsson and J. Sandstrom, Acta Chem. Scand., B32, 281 (1978). 44. Y. Sbvo and H. Shanan-Atidi, J. Am. Chem. Soc., 91, 6689 (1969). 45. Y. Shvo, E. C. Taylor and J. Bartulin, Tetrahedron Lett., 3259 (1967). 46. U. Koelle, B. Kolb and A. Mannschreck, Chem. Ber., 113, 2545 (1980). ~~~
.-~-.
\
-
~
6. Static a n d dynamic stereochemistry of acceptor-substituted enarnines
435
47. A. Senning and P. Kelly, Acta Chem. Scand., 26, 2877 (1972). 48. G. D. Fallon, B. M. Gatehouse, A. Pring, I. D. Rae and J. A. Weigold, Can. J. Chem., 58, 1821 (1980). 49. V. I. Bakhmutov, K. K. Babievski, V. A. Burmistrov, E. I. Fedin and V. M. Belikov, Izu. Akad Nauk SSSR, Ser. Khim., 2719 (1978); Engl. Trans1 Bull. Acad Sci. USSR, 22, 2726 (1978). 50. V. I. Bakhmutov and V. A. Burmistrov, Org. Magn. Reson., 12, 185 (1979). 51. V. I. Bakhmutov and E. I. Fedin, Bull. Magn. Reson., 6, 142 (1984). 52. J. L. Chiara, A. G6mez-Sanchez, E. Sanchez Marcos and J. Bellanato, J. Chem. Sac., Perkin Trans. 2, 385 (1990). 53. J. L. Chiara, Ph.D. Thesis Universidad de Sevilla, Spain, 1988. 54. R. R. Pappalardo and E. Sanchez Marcos, J. Chem. Res. ( S ) , 290 (1989). 55. A. P. Downing, W. D. Ollis and I. 0. Sutherland, J. Chem. Sac. ( B ) , I l l (1969). 56. J. H. Crabtree and D. Bertelli, J. Am. Chem. Sac., 89, 5387 (1967). 57. C. F. Candy and R. A. Jones, J. Chem. Sac. ( B ) , 1405 (1971). 58. A. Mannschreck and B. Kolb, Chem. Ber., 105,696 (1972). 59. L. Fernholt, S. Samdal and R. Seip, J. Mol. Struct., 72, 217 (1981). 60. N. U. Kamath and K. Venkatesan, Acta Crystallogr., Sect. C, 40, 559 (1984). 61. F. Ganazzoli, S. V. Meille and P. Gronchi, Acta Crystallogr., Sect. C, 42, 1385 (1986). 62. H. Kessler, Chem. Ber., 103, 973 (1970). 63. Reference 33, p. 29. 64. 1. Wennerbeck and J. Sandstrom, Org. Magn. Reson., 4, 783 (1972). 65. J. Sandstrom and I. Wennerbeck, Acta Chem. Scand., B32, 3305 (1978). 66. G . Isaksson and J. Sandstrom, Acta Chem. Scand., 27, 1183 (1973). 67. N. Sen and K. Venkatesan, Acta Crystallogr., Sect. C, 40, 1730 (1984). 68. J. Sandstrom, U. Sjostrand and I. Wennerbeck, J. Am. Chem. Sac., 99,4526 (1977). 69. D. Adhikesvalu, N. U. Kamath and K. Venkatesan, Proc. Indian Acad. Sci. (Chem. Sci,), 92, 449 (1983). 70. D. Adhikesvalu and K. Venkatesan, personal communication. 71. J. Sandstrom and U. Sjostrand, Tetrahedron, 34, 371 (1978). 72. U. Sjostrand and I. Sandstrom, Tetrahedron, 34, 3305 (1978). 73. P. Laszlo, Prog. Nucl. Magn. Reson., 3, 231 (1967). 74. F. P. Colonna, G. Distefano, J. Sandstrom and U. Sjostrand, J. Chem. Soc., Perkin Trans. 2, 279 (1978). 75. E. A. Noe and M. Raban, J. Chem. Sac., Chem. Commun., 165 (1976). 76. E. A. Noe and M. Raban, J. Am. Chem. Soc., 96, 6184 (1974); 98,641 (1976). 77. A. Z.-Q. Khan and J. Sandstrom, unpublished results. 78. A. Mannschreck, H. Koller and R. Wernicke, Kontakte (Darmstadt), 1, 40 (1985) and references cited therein. 79. U. Berg, R. Isaksson, J. Sandstrom, U. Sjostrand, A. Eiglsperger and A. Mannschreck, Tetrahedron Lett., 23, 4237 (1982). 80. A. Z.-Q. Khan, R. Isaksson and J. Sandstrom, J. Chem. Soc., Perkin Trans. 2, 491 (1987). 81. J. Sandstrom, K. Stenvall, N. Sen and K. Venkatesan, J Chem. Sac., Perkin Trans. 2, 1939 (1985). 82. A. Z.-Q. Khan, J. Sandstrom nnd S.-L. Wnng. Unpublished results. 83. Z.-T. Huang, W.-X. Gan and X.-J. Wang. J. prakt. Chem., 330, 724 (1988). 84. K. Baum, S. S. Bigelow, N. V. Nguyen, T. G. Archibald, R. Gilardi, J. L. Flippen-Anderson and C. George,J. Org. Chem., 57, 235 (1992). 85. K. Hartke and G. Salamon, Chem. Ber., 103, 147 (1970). 86. T. Olsson and J. Sandstrom, Acla Chem. Scand., 836, 23 (1982). 87. M. Henschmann, K.-P. Hartmann and K. Polborn, private communication. 88. K. Hafner and H. Tappe, Angew. Chem., Int. Ed. EngL, 8, 593 (1969). 89. S. Braun, K. Hafner and H.-J. Lindner, personal communication. 90. Reference 11, p. 117. 91. W. Bauer, I. Betz,J. Daub, L. Jacob, W. Pickl and K. M. Rapp, Chem. Ber., ll6,1154(1983). 92. R. Radeglia, Z. Phys. Chem., 235, 335 (1967). 93. M. L. Blanchard. A. Chevallier and G. 1. Martin. Tetrahedron Lert.. 5057 (1967). 94. E. P. Prokof'ev, 2. A. Krasnaya and V. F. ~ u c h e r o v ,Org. Magn. ~eson.,'6,240 (1974) and references cited therein.
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A. J. Blake, H. McNab and L. C. Monahan, J. Chem. Soc., Perkin Trans. 2, 2003 (1991). K.4. Dahlqvist and S. Forsen, Acta Chem. Scand., 24, 2075 (1970). J. P. Schoeni and I. P. Fleury, Tetrahedron, 31, 671 (1975). E. Heilbronner and H. Bock, Das HMO-Mode0 und Seine Anwendung, Verlag Chemie, Weinheim 1967, p. 2 ff. 99. J. Dale, R. G. Lichtenthaler and G. Teien, Acta Chem. Scand., B33, 141 (1979) and references cited therein. 100. F. Dorr, J. Kotschy and H. Kausen, Ber. Bunsenges. Phys. Chem., 69, 11 (1965). 101. L. Zechmeister and I. H. Pinckard, Experientia, 9, 16 (1953). 102. P. M. Heinrichs and S. Gross, J. Am. Chem. Soc., 98,7169 (1976). 103. 1. Dale, 0. I. Eriksen and P. Groth, Acta Chem. Scand., 841, 653 (1987). 104. J. Sandstrom, unpublished results. 105. R. Wagner, J. Fine, J. W. Simmons and J. H. Goldstein, J. Chem. Phys., 26, 634 (1957). 106. J. R. Hulett, J. A. Pegg and L. E. Sutton, J. Chem. Soc., 3901 (1955). 107. E. Sanchez Marcos, P. Karafiloglou and J. F. Sanz, J. Phys. Chem., 94, 2763 (1990). 108. E. Ericsson, T. Marnung, J. Sandstrom and I. Wennerbeck, J. Mol. Struct., 24, 373 (1975). 109. Reference 11, p. 146. 110. P. Karafiloglou and E. Sanchez Marcos, Int. J. Quantum Chem., 44, 337 (1992). 111. H. 0. Kalinowski, H. Kessler and A. Walter, Tetrahedron,30, 1137 (1974). 112. 1. Belsky, H. Dodiuk and Y. Shvo, J. Org. Chem., 42, 2734 (1977). 113. R. Osman, A. Zunger and Y. Shvo, Tetrahedron,34, 2315 (1978). 114. Yu. A. Borisov, K. K. Babievski, V. I. Bakbmutov, Yu. T. Struchkov and E. I. Fedin, Izv. Akad. Nauk SSSR, Ser. Khim., 123 (1982). Engl. Transl. Bull. Acad. Sci. USSR, 31,115 (1982). 115. G. Favini, A. Gamba and R. Todeschini, J. Chem. Soc., Perkin Trans. 2, 915 (1985). 116. A. Mehlhorn, J. Fabian and F. Dietz, Izu. Khim., 20, 569 (1987); Chem. Abstr., 110, 22298a (1989). 117. R. R. Pappalardo and E. Sanchez Marcos, . I . Chem. Soc., Faraday Trans., 87, 1719 (1991). 118. M. W. Wong, M. I. Frisch and K. B. Wiberg, J. Am. Chem. Soc., 113,4776 (1991). 119. R. R. Pappalardo, E. Sanchez Maicos, M. F. Ruiz-Lopez, D. Rinaldi and J.-L. Rivail, J. Phys. Org. Chem., 4, 141 (1991). 120. R. R. Pappalardo, E. Sanchez Marcos, M. F. Ruiz-Lopez, D. Rinaldi and J.-L. Rivail, J. Am Chern. Soc, 115,3722 (1993). 121. U. Berg and U. Sjostrand, Org. Magn. Reson., 11, 555 (1978) and further references therein. 122. E. Kleinpeter and M. Pulst, J. prakt. Chem., 319, 1003 (1977). 123. E. Sanchez Marcos, J. J. Maraver, J. L. Chiara and A. Gomez-Sanchez, J. Chem. Soc., Perkin Trans. 2, 2059 (1988). 124. V. G. Andrianov, Yu T. Struchkov and K. K. Babievsky, Cryst. Struct. Comrnun.,l l , 3 5 (1982). 125. J. Emsley, N. I. Freeman, R. J. Parker, R. Kuroda and R. E. Overill, J. Mol. Strucr., 159, 173 (1987). 95. 96. 97. 98.
CHAPTER
7
The reactivity of ionized enamines in the gas phase PIERRE LONGEVIALLE lnstitut de Chimie des Substances Naturelies du Centre National de la Recherche Scientifique 91 190 Gif sur Yvette France
.
.
I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437 I1. GENERAL CONSIDERATIONS . . . . . . . . . . . . . . . . . . . . . . . . . 438 111. REACTIVITY O F DIRECTLY IONIZED ENAMINES . . . . . . . . . . . 439 A. Simple Ruptures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439 1. Allylic cleavage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439 2. a-Cleavage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441 3. Vinylic cleavage of haloenamines . . . . . . . . . . . . . . . . . . . . . . 443 B. Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443 C . Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447 1. Retro-Diels-Alder (RDA) reactions . . . . . . . . . . . . . . . . . . . . . 447 2. Enamine-imine tautomerism . . . . . . . . . . . . . . . . . . . . . . . . 447 3. Dehydrogenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449 IV. IONIZED ENAMINES AS REACTION INTERMEDIATES . . . . . . . . 450 A. Rearrangement of Cycloalkylamines . . . . . . . . . . . . . . . . . . . . . . 450 B. Rearrangement of Imines . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456 v. ACKNOWLEDGEMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457 VI . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457
I. INTRODUCTION
Enamines are usually unstable compounds. especially primary ones. By contrast. enamine radical cations as produced by electron ionization (EI) in the source of a mass spectrometer have been found to be very stable by recent ab initio calculations'. Among isomeric nitrogen-containing hydrocarbon radical cations with one degree of unsaturation. [C.H2.+lN]+'. ionized enamines and cycloalkylamines are the most stable; these isomers lie usually in deep wells on the potential energy surface. and may also TI?? Cl?emrstn of Emmines . Edited hy Zvi Rappoport Copynght O 1994 John Wiley & Sons. Ltd . ISBN: 0-471-93339-2
438
Pierre Longevialle
intekonvert before decomposing. Consequently, the reactivity of ionized enamines cannot be separated from that of other isomers and may be studied either directly by electron ionization of the neutral enamines themselves when they are stable enough (tertiary enamines), or sometimes indirectly by ionization of the more stable neutral isomers (Scheme 1).For example, primary cycloalkylamines, which are stable as neutral molecules, may isomerize after ionization to primary enamines which cannot conveniently be prepared as neutrals. Decomposition products
t
t
Enamines
Isomers SCHEME 1
Following Section 11, which deals with general considerations, Sections I11 and IV describe examples relevant to these two different approaches.
II. GENERAL CONSIDERATIONS
Molecular radical cations produced by electron ionization of an organic compound generally have a wide range of internal energies. As predicted by the Quasi-Equilibrium Theory (QET)', the reactivity of ions depends directly on their internal energy content, and it is indeed very commonly observed that high- and low-energy parent ions present quite different reactivities. As a general rule, simple ruptures, having favourable entropy factors, usually dominate in the upper energy range, whereas rearrangements having lower critical energies due to bond breaking-bond making compensation are relatively more important in low-energy ion^^-^. These general principles are particularly well illustrated by the reactivity of ionized enamines: high-energy ones preferentially lose neutral radicals by simple bond cleavage (Scheme 2) whereas less energized ones often rearrange preferentially to distonic ions6 which may fragment further by less-energy-demanding pathways. These two different types of unimolecular reactions (simple ruptures and rearrangements) may easily be distinguished using a simple mass spectrometer: fragment ions formed in the ion source, i.e. at relatively short times, derive mainly from high-energy ions and are represented by 'normal', well-resolved signals in the standard mass spectrum. On the other hand, metastable parent ions, which fragment later during their flight towards the collector, are on average less energized and their products may sometimes be represented by low-intensity, characteristic signals (the so-called 'metastable peaks'). The reactivity of metastable ions is more conveniently studied, however, with a reverse-geometry two-sector instrument, by mass analysed ion kinetic energy (MIKE) spectrometry7; by this technique parent ions of a given m/z ratio are first selected by the magnet and their fragment ions produced in the second field-free region (FFR) are analysed in kinetic energy by the electrostatic analyser. The complete ensemble of the products from low-energy parent ions of a given m/z ratio is so obtained.
7. The reactivity of ionized enamines in the gas phase
439
+-/./,'", /.-/'v"N
t High energy Simple bond cleavage
/../'v"&// /..A
LA,,\
a-cleavage
i Low energy Rearrangement
Distonic irnmonium radical cation (DIRC)
Subsequent reactions SCHEME 2
Ill. REACTIVITY OF'DIRECTLY IONIZED ENAMINES A. Simple Ruptures
I . Allylic cleavage
Pyrrolidine, piperidine and morpholine enamines of aldehydes and ketones have been the subject of a pioneering work by D. H. Williams and collaborators8. The most abundant fragment ion is produced by the loss of an alkyl radical R' by allylic cleavage (Scheme 3). When R = H the loss of a H atom is more energy demanding and the
Pierre Longevialle
(5) SCHEME 3
[M - HI+ ion correspondingly less abundant. For this reason isomers 1 and 2 show different mass spectra: the main fragmentation of 1 is the loss of a methyl radical whereas 2 is more stable and loses a H atom with more difficulty. Isomers 3 and 4 are also easily distinguishable losing methyl and ethyl radicals, respectively. Both isomers 5 and 6, however, lose a methyl radical and have very similar mass spectra. The stability of the radical which is lost exerts a strong influence on the fragmentation: in the case of 7 (Scheme 4) the loss of a resonance-stabilized carbomethoxymethyl radical is favoured over the loss of CH!'. The same preference8 is observed in 8. Enamines prepared from b-d~ketonesand ethyl acetoacetates also lose a radical by allylic cleavage. When R = CH, or OCH, (Scheme S), 9, 10 and 11 lose preferentially CH,' or OCH,' radicals9, respectively. Enamines of alkyl-substituted cyclic ketones may lose alkyl substituents in a manner characteristic of their structures. For instance, 12 easily loses a methyl radical from C(,, as shown in Scheme 6. The ratio of isomers of 'enamines derived from 2-alkylcyclohexanones varies with the nature of the heterocyclic base employed' in their preparationi0. The reaction of morpholine with 2-propylcyclohexanone gives a mixture of 13 and 14 (Scheme 7) as shown by the electron ionization of the products leading to the formation of both [M-Et']+ and [M-propyl']' fragment ions8.
7. The reactivity of ionized enamines in the gas phase
441
SCHEME 4
SCHEME 5
SCHEME 6
The main decomposition products of substituted dihydropyridines 15 after El derive from the dominant [M - R']' fragment ions" (Scheme 8) and have a stable pyridinium structure. 2. a - Cleavage
A simple rupture may also take place by u-cleavage on the nitrogen side of the enamine function. This is observed in many cases where the substituents on N are aliphatic chains.
Pierre Longevialle
SCHEME 7
(15) SCHEME 8
The base peak in the mass spectrum of 16 (Scheme 9) represents the loss of an isropropyl radical9. It is followed by the loss of isobutene according to the well-known r eactivity of closed-shell immonium ions1'.
Such is the case also of 17 (Scheme 10)deriving from the reaction of the methyl ester of phenylalanine with acetylacetone. Characteristic fragment ions m/z 170 and m/z 202 of this derivative have been used for the determination of phenylalanine in blood by mass fragmentography* 3.
7. The reactivity of ionized enamines in the gas phase
443
(17)
SCHEME 10 3. Vinylic cleavage of haloenamines
Haloenamines of general structure 18 (Scheme 11) give an important resonancestabilized fragment ion by loss of their halogen atom. Most of the other fragment ions result from subsequent fragmentation of the [M - X]+ ionI4.
SCHEME 11
6. Rearrangements
The presence of longer alkyl chains or aromatic rings as substituents may provide the opportunity for rearrangements to take place. They are dominant at low energy and generally appear as metastable transitions in standard or MIKE spectra. Aliphatic enamine cation radical 19 loses both C,,H,,' and C,H; radicals15. The former loss results from &-cleavage in the parent Ion and produces the most abundant ion in the source, whereas the latter fragmentation largely dominates in the field free region. It has been interpreted by the displacement of the radical on the C,, aliphatic chain by H-transfer (Scheme 12; --- indicate that the number of carbons in this moiety is unknown) followed by reaction between the radical and the immonium ion leading to ring formation. The alicyclic amine formed, whose ring might be preferentially six-membered, readily loses an ethyl radical by &-cleavage.The homologue
Pierre Longevialle
\N+W(CH~)< High-energy ions
SCHEME 12
of 19 with one more CH, group in the enamine chain loses a propyl radical in the same process. Compounds 9 and 10 with R = OC,H, lose also a C,H,O, neutral in the metastable time frame and the resulting fragment ion loses in turn a methyl radical. This has been explaineds by the initial transfer of a H from the ethyl chain as shown in Scheme 13, followed by the loss of ethylene and CO,. The 5 D atoms incorporated in the star-labelled positions are all retained in the fragment ion m/z (71 + 5).
(10)
mlz 71 SCHEME 13
When R is a longer alkyl chain as in 20, it may be lost after a McLan'erty H-transfer16 as shown in Scheme 14. The resulting ion subsequently loses ketene. In the case of 21 the presence of an alkyl chain on the other side of the enamine group'6 induces a H rearrangement in low-energy ions with loss of propylene, again followed by the loss of ketene (Scheme 15).
445
7. The reactivity of ionized enamines in the gas phase
mlz 71 SCHEME 14
In some cases where the N is alkyl-substituted, an important [M - OH]+ ion has been observed8.The N-trideuterio methyl analogue of 22 loses OD and the mechanism in Scheme 16 has been proposed16.
(22) SCHEME 16
Interestingly, in linear and cross-conjugate dienamines vinylic tission at the terminal double bond has been found important in high- and low-energy ions1'. The origin of the propyl radical which is lost from 23 has been demonstrated by D-labelling. The mechanism which has been proposed implies ring formation (Scheme 17). A similar
\ SCHEME 17
Pierre Longevialle
mechanism explains the loss of an isopropyl radical from the linear dienamine 24 (Scheme 18). The acyclic linear conjugated dienamines are found more stable than the crossconjugated ones. This 'enhanced stability can be attributed to the fact that the steric interactions which cause the cross-conjugated dienamines to be non-planar are absent from the linear dienamine'". This planarity allows extensive delocalization of the charge in the ion (Scheme 19).
SCHEME 19 The molecular ion of the tricarbonyl (dienamine) iron complex 25 (cross-conjugated) is more abundant than that of 26 (linear) (Scheme 20) confirming their different relative stabilitie~'~. They fragment essentially by successive losses of 3 CO and CH, molecules leading to an abundant ion m/z 231 [Fe(C,,H,,N)]+'.
N+.
N +.
7. The reactivity of ionized enamines in the gas phase
447
C. Miscellaneous
1. Retro-Diels-Alder (RDA) reactions
Although ionized enamines of cyclohexanone 27 give an abundant [M - C,H,If' ion (Scheme 21)', it is not quite clear whether this fragmentation is indeed a specific RDA reaction1'. 'The enamine group generally does not show a tendency to induce RDA fragmentati~n"~.
(27) SCHEME 21
Compounds 28 and 29 decompose, however, into an abundant m/z 109 ion which may be viewedz0,at least formally, as resulting from RDA decomposition (Scheme 22).
SCHEME 22
2. Enamine-imine tautomerism Fragmentations have been interpreted as requiring initial enamine to imine tautomerization. The mass spectrum of 30, for example, shows a relatively intense m/z 118 signal8 interpreted as a simple cleavage of the imine tautomer (Scheme 23). Tertiary amines cannot isomerize to imines and therefore do not give this fragmentation.
448
Pierre Longevialle
SCHEME 23
The question about which of the imine or enamine forms dominates in the gas phase when both tautomers can equilibrate has been examined in a series of articles dealing with more complex nitrogen-containing aromatic compoundsZ1-25. For example, the homologue compounds 31 and 32 are shown to exist as enamine and imine structures, respectivelyz5 (Scheme 24), from their EI-induced fragmentation. H-bonding in 31 may contribute to ~ t a b i l i z a t i o n ~ ~ - ~ ~ . In a more recent paperz6 it is shown that the imine form of 33 loses ketene, whereas the enamine form loses preferentially CO (Scheme 25). Hence, the abundance ratio
q
H
H
N
\
I
H..
/
0
J
0
SCHEME 24
(33) imine
(33) enarnine SCHEME 25
0
J
0
7. The reactivity of ionized enamines in the gas phase
449
[M - ketene]+'/[M - CO]+' is taken to reflect the relative abundances of both tautomers, respectively. The increase of this ratio with temperature of the ion source is explained by the enamine structure being less stabilized by H-bonding at higher temperature. Conversely, in least-energized ions, a stronger participation of H-bonding makes the enamine tautomer relatively more stable, hence more abundant, as confirmed by the collisional activation spectrum of non-decomposing molecular ions. Recently, it has been shown' by molecular orbital calculations that the ionized vinylamine 34 (Scheme 26) is more stable than the ionized ethylideneimine isomer 35 by 122 kJ mol- '.The reverse is true for neutral compounds, the imine being more stable than enamine by 22 kJ mol-'. Moreover, the conversion of 34 to 35 by 1,3 H-transfer requires 265 kJ mol-' of critical energy.
SCHEME 26
3. Dehydrogenation
It has been ob~erved',~'that enamines of cycloalkanones can successively lose several H atoms. 'This tendency is greatly accentuated at higher temperature of the inlet system''. For example, 27 loses 2, 3,4 and up to 5 hydrogens with relative abundances of the corresponding ion-products 17, 17,40 and 51 %, respectively8. The most probable aromatized structure of the [M - 53 ion is represented in Scheme 27. This phenomenon is worthy of mention although it is not a 'simple EI phenomenon". +
(27) SCHEME 27
Pierre Longevialle IV. IONIZED ENAMINES AS REACTION INTERMEDIATES A. Rearrangement of Cycloalkylamines
As noted above, ionization of cycloalkylamines provides facile access to ionized enamines in the gas phase. This is especially valuable in the case of primary enamines which are unstable as neutrals. The reactivity of ionized cyclohexylamine 36 will be described first (Scheme 28). A sharp contrast exists between reactivities of high- and low-energy ions 36: the former (standard spectrum) decomposes essentially to C,H,N+ m/z 56 ions, whereas the latter (MIKE spectrum) give C,H,N+ m/z 70 ions as the most abundant fragment. Only recently the energy profile of these decompositions has been determinedz8. First, a 36 + 38 isomerization takes place by ring-opening, a-cleavage and 1,5 H-transfer. Ionized enamine 38, which has more than 134 kJ mol-' energy, may lose a propyl radical and produce the conjugated immonium fragment ion m/z 56. However, a less-energy-demanding pathway is opened to less-energized ions leading finally to fragment ions m/z 70 and a neutral ethyl radical through a succession of steps which indeed represent the most important reactions of ionized enamines and isomers, cycloalkylamines and immonium radical cations, in the gas phase. These reactions are: (i) Ring formation between radical and immonium cation and the reverse ring-opening by a-cleavage (36 + 37, 39 40, 40 + 41).
*
SCHEME 28
7. The reactivity of ionized enamines in the gas phase
45 1
(ii) Reversible H-transfers which transform ionized enamines to distonic immonium radical cations (DIRC) and vice versa (37 8 38, 38 8 39,41 P 42). Only ionized enamines are able to fragment by simple cleavage (fragmentation of DIRC would demand more energy). The cycloalkylamine 36 to enamine 38 isomerization (by ring-opening 36 -r 37 and H-transfer 37 + 38) is a very common reaction which has early been recognizedz9 in the EI-induced decomposition of nitrogen-containing alicyclic compounds (alkaloids). Formally, this reaction is the same as the loss of alkane from aliphatic amines, alcohols and ketones which have been described by Cooks and coworkers30 and later by Hammerum and coworkers3' and Audier and coworkersgz. For example, high-energy ionized 2-pentylamine 43 (Scheme 29) loses a propyl radical by a-cleavage, whereas low-energy 43 ions lose propane (35%) with a H-transfer3'. This 1,2-elimination of alkane, now regarded as ion-neutral complex mediated33-36,becomes an isomerization when occurring in a cycloalkylamine.
High energy
.
NHJ
NH2+' I
SCHEME 29
Ionized larger-ring cycloalkylamines give again preferentially m/z 56 ions at high energy and lose, at low energy, all other homologous alkyl radicals leading to more or less abundant fragment ions differing by 14 amu (CHz)37,38.For example, cyclohexadecylamine 44 rearranges first to long-chain enamine 46 by a specific H-transfer to the terminal carbon3' followed bv the interconversion between cvcloalkvlamines (48.52.54) . . . and enamines (5U,53,55) through distonic ~mmoniumradicai cations (UIKC) (47.49.51 etc.. . . ) Enamines occasionally lose alkyl radicals by allylic fission3" (Scheme 30). is not at all fortuitous. Since H-transfers The ring size of intermediate~~cloalk~lamines and ring formations are essentially governed by the ring size of corresponding transition states, consequently the sequence of intermediates represented in Scheme 30 involving only 1,5 H-transfers and six-membered ring formations is the most important, as confirmed by the predominance of the corresponding product ions in the MIKE spectrum. However, this six-membered ring sequence may be shifted along the chain by the incidental occurrence of less favoured five- or seven-membered ring intermediates. By this process, all the carbons may become involved, leading in turn to all other possible enamine isomers which decompose by losing the corresponding homologue alkyl radicals. Ionized enamines also play an important role in the El-induced decomposition of more comdex r~~~~ molecules. Formation of the most important fragment m/z 85 from the d4-labelled 3-dimethylamino steroids 56 involves the intermediacy of the enamine 57, as shown in Scheme 3129,39. However, along with the dominant miz 85 ion, a small fraction (10%) of non-labelled m/z 84 ions is also formed resulting from H-D exchange before fragmentation between the enamine group and other hydrogens of the molecular ion4'. ~-~ ~
~
~-~
~-~~~~
SCHEME 30
453
7. The reactivity of ionized enamines in the gas phase
mlz 84
mlz 85
10% SCHEME 3 1 When the intermediate enamine fragments easily, no exchange is observed. Such is the case of 58 (Scheme 32) in which H-D exchange cannot compete with the allylic C(,,-C(,,, bond cleavage (100% m/z 85)40.By contrast, a more difficult fragmentation step of the enamine may offer a large energy range in which H-D exchange may compete efficiently; in the case of 59 up to 36% of m/z 84 ion is formed along with m/z 85 due to the more energy demanding Co,-C., cleavage4'.
(59)
mlz 84
It
36%
DIRC H-D exchanges SCHEME 32
m / z 85
Pierre Longevialle
454
The 1-methylamino steroid 60 shows an important loss of propyl radical whose intensity considerably increases at low energy. Both hydrogens at C,? strongly participate in this fragmentation as shown by D-labelling, and the mechanism in Scheme 33 has been proposed in which enamines 61 and 62 play a key role as intermediates4'. Fragment ions m/z 70 are only formed in the source by allylic rupture of more energized enamines 61. Homologous primary and tertiary amines also lose a propyl radical with a lesser intensity. H-D exchange
(60)
.
' N H
I
Ithw
energy
SCHEME 33
7. The reactivity of ionized enamines in the gas phase
45 5
Ionized primary enamines of low energy may also be reaction intermediates in the loss of ammonia. Scheme 34 shows a mechanism proposed for the extensive loss of ammonia from low-energy ionized 3-amino steroids. Enamine 63 may lose ammonia after two successive 1,4 H-transfers. The participation of the H at Ct5, has been established by D-labelling4z. Only higher energy ions lead to m/z 82 fragment ions through the ionized dienamine 64,
Briefly, the whole reactivity of these ions may be regarded as a continuous interconversion of isomeric enamines and cycloalkylamines through the intermediacy of DIRC (Scheme 30). In fact, the molecular ions exiting from the source after about 1 p of lifetime are a complex mixture of all these isomeric structures. These interconversions are the least-energy-demanding reactions and therefore dominate in low-energy ions. In competition with these interconversions, enamines may fragment when the required energy happens to accumulate in their allylic C-C bond. Furthermore, starting from cyclohexylamine 36, for example (Scheme 28), the formation of ions m/z 70 requires less energy but more steps than that of m/z 56 ions. Therefore, high-energy ions decompose more readily to m/z 56 ions by a more direct, hence less entropically limited, pathway. The same reasoning also obtains in the case of larger-ring cycloalkylamines. The rearrangement of small-ring cycloalkylamines (3,4-membered) to enamines is more difficult because the H-transfer after ring-opening is more energy-demandingz8. Cyclobutylamine suffers essentially two decomposition processes (Scheme 35). Loss of
Pierre Longevialle
mlz 56
SCHEME 35
CH; after rearrangement to the enamine leads to m/z 56 fragment ions and cycloreversion leads to ionized vinylamine 34 and ethene. In fact, these decomposition processes have final states with very close standard enthalpies and they are found to compete in the metastable time frame. However, only the formation of 34 is observed in the experimental conditions of FTICR (long life time and deactivation with Ar) which analyses least-energized parent ions43.This shows the existence of an energy barrier in the formation of the m/z 56 ions attributable to the difficult 1,3 H-transfer required by the rearrangement to enamine. This cycloreversion reaction has been utilized to generate 34 and study its reactions 34 has been found to react with various olefins with olefins in a FTICR ~pectrometer~~. essentially along two competing channels: H atom abstraction leading to the immonium ion m/z 44 (Scheme 36) and regioselective cycloaddition~ycloreversion.The latter reaction opens up a new possible access to ionized primary enamines in the gas phase.
SCHEME 36
8. Rearrangement of lmines
Ionized i m i n e ~ may ~ ~ .rearrange ~~ to DIRC by intramolecular H-abstraction and subsequently lead to the reactions described above, i.e. ring formations and rearrangements to enamines. 65 does not rearrange to enamine after y H-transfer, but rather decomposes into ionized N-methyl vinylamine (Scheme 37).
7. The reactivity of ionized enamines in the gas phase
457
SCHEME 37
66 leads to the ionized enamine with mlz 71 after two successive y H-transfers. Loss of ethene from 67 leads to the enamine 68 which loses either a propyl radical (m/z 56) or, more easily, a methyl radical probably after pyrrolidine ring formation (cf 19 in Scheme 12) (Scheme 37). V. ACKNOWLEDGEMENT
The author gratelully acknowledges critical reading of the manuscript and communication of unpublished results by Prof. Guy Bouchoux (Ecole Polytechnique, Palaiseau). VL REFERENCES
1. 2. 3. 4.
M. T. Nguyen and G. Bouchoux, unpublished results. W. Forst, Theory of Unimolecular Reactions, Academic Press, New York, 1973. F. W. McLaKerty, Interpretation of Muss Spectra, University Science Books, Mill Valley, 1980. 1. Howe, D. H. Williams and R. D. Bowen, Mass Spectrometry. Principles and Applications, second edition, McGraw-Hill, New York, 1981. 5. P. Longevialle, Principes de la Spectromdtrie de masse des substances organiques, Masson, Paris, 19x1~ -. 6. S. Hammerum, Mass Spectrom. Rev., 7 , 123 (1988). 7. R. G. Cooks, J. H. Beynon, R. M. Caprioli and G. R. Lester, Metastable Ions, Elsevier, Amsterdam, 1973.
458
Pierre Longevialle
H. J. Jacobsen, S. 0. Lawesson, J. T. B. Marshall, G. Schroll and D. H. Williams, J. Chem. SOC.(B), 940 (1966). M. LeBlanc, G. Santini, J. Gallucci and J. G. Riess, Tetrahedron, 33, 1453 (1977). W. D. Gurowitz and M. A. Joseph, Tetrahedron Lett., 4433 (1965). G. Schroll, S. P. Nygaard, S. 0. Lawesson, A. M. Duffield and C. Djerassi, Arkivfor Kemi, 29: 525 (1968). R. D. Bowen, Mass Spectrom. Rev., 10,225 (1991). S. Tokuhisa, K. Saisu, H. Yoshikawa, T. Tsuda, T. Morishita and S. Baba, Ckem. Pkarm. Bull. (Japan), 26, 3647 (1978). S. J. Huang and M. V. Lessard, J. Am. Ckem. Sac., 90, 2432 (1968). B. Boukobbal, 0.Lefevre. P. Lonaevialle and G. Bouchoux.. Raoid . Commun. Mass Soectrom.. 5, 330 (1991). M. Vandewalle, N. Schamp and M. Francque, Org. Mass Spectrom., 2, 877 (1969). P. W. Hickmott and C. T. Yoxall, J. Ckem. Soc., Perkin Trans. 2, 890 (1972). M. G. Ahmed, P. W. Hickmott and M. Cais, J. Ckem. Soc., Dalton Trms., I557 (1977). F. Turecek and V. Hanus, Mass Spectrom. Rev., 3.85 (1984). K. G. R. Sundelin, R. A. Wiley, R. S. Givens and D. R. Rademacher, J. Med. Chem., 16, 235 (1973). J. Tamas, K. Ujszaszy, G. Bujtas and ZI Meszaros, Acta Pharm. Hung., 44, 7 (1974). T. Inagaki and Y. Iwanami, Org. Mass Spectrom., 12,222 (1977). Y. Iwanami, T. Inagaki and H. Sakata, Org. Mass Spectrom., 12, 302 (1977). T. Inagaki and Y. Iwanami, Mass Spectrom. (Japan) Skitsuryo Bunseki, 26,353 (1978); Ckem. Abstr., 93, 167065 g (1978). Y. Iwanami, Dev. Biochem., 4 4 3 (1979). K. P. Madhusudanan, N. Borthakur and M. Goswami, Indian J. Ckem., 29 B, 14 (1990). P. P. Lynch, Gazz. Chim. Ital., 99, 787 (1969). G. Bouchoux, C. Alcaraz and 0. Dutuit, Analusis, 20, 23s (1992). H. Budzikiewin, C. Djerassi and D. H. Williams, Structure Elucidation o/Natural Products by Mars Spectrometry, Vol. 11, Holden Day, San Francisco, 1964, p. 8. J. F. Litton, T. L. Kruger and R. G. Cooks, J. Am. Ckem. Soc., 98,2011 (1976). S. Hammerum. K. F. Donchi and P. J. Derrick. Int. J. Mass Soectrom. Ion Pkvs.. 47.347 (1983). G. Sozzi, H. E. Audier, J. P. Denhez and A. ~ i l l i e t Nouv. , j. Chim., 7, 73i(l983). T. H. Morton, Tetrahedron, 38, 3195 (1982). D. J. McAdoo, Mass Spectrom. Rev., 7, 363 (1988). R. D. Bowen, Acc. Chem. Res., 24, 364 (1991). P. Longevialle, Mass Spectrom. Rev., 11, 157 (1992). N. Mollova and P. Longevialle, J. Am. Sac. Mass Spectrom., 1, 238 (1990). 0. L e f h e , N. Mollova and P. Longevialle, Org. Mass Spectrom., 27, 589 (1992). Z. Pelah, M. A. Kielczewski, J. M. Wilson, M. Ohashi, H. Budzikiewin and C. Djerassi, J. Am. Chem. Sac., 85, 2470 (1963). P. Longevialle and C. Marazano, Org. Mass Spectrom., 11, 964 (1976). 0. Lefevre and P. Longevialle, Org. Mass Spectrom., 27, 765 (1992). N. Mollova, P. Longevialle and G. Bouchoux, Rapid Commun. Mass Spectrom., 4, 163 (1990). G. Bouchoux and F. Penaud-Bermyer, Org. Mass Spectrom., 28 271 (1993). M. Fischer and C. Djerassi, Ckem. Ber., 99, 1541 (1966). C. A. Zezza and M. B. Smith, Org. Mass Spectrom., 19, 645 (1984). ~
32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45.
The electrochemistry of enamines TATSUYA SHONO Departmer)t of Synthetic Chemistry. Kyoto University, Kyoto 606-01 Japan
I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459 11. ANODIC OXIDATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459 111. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
I. INTRODUCTION
Despite the large utility of enamines in organic synthesis, the study of the electrochemistry of enamines and especially the application to synthetic organic reactions has been a rather minor area in electroorganic chemistry, and only a few studies have been reported. In this review these works are summarized and electrochemical synthesis and some reactions of a,P-unsaturated urethanes (enecarbamates) are also described, since their chemical reactivity is considerably similar to that of the enamines.
II. ANODIC OXIDATION
The electrooxidative properties of some enamines derived from cyclic ketones and cyclic amines have been studied in detail1. It has been found that the electrooxidation is irreversible and the peak potentials (Table 1) are rather low, as expected on the basis of the chemical reactivity of the enamines. The peak potentials of the enamines depend on the ring size of the amine component and follows the order 5 < 7, 8 < 6 < 1-MP (1-methylpiperazine) < MO (morpholine). The morpholinoenamines are the most difficult to oxidize and their peak potentials are about 0.2 V more positive than those of pyrrolidinoenamines. Variation in the ring size of the ketone component causes only small differences in the peak potentials. In the electrooxidation, one electron is transferred from the enamine to the anode to form a cation radical intermediate which is very unstable, its lifetime being less than 0.2 ms. When the anodic oxidation is carried out in a nucleophilic solvent such as methanol, the intermediate reacts rapidly with the solvent2. The anodic oxidation of morpholinoenamines (la,b) in methanol, for instance, yields two types of enamine, TI?? Cl~emistnof Enaminex Edited hy Zvi Rappoport Copyright O 1994 John Wiley & Sons, Ltd. ISBN: 0-471-93339-2
459
Tatsuya Shono TABLE 1. Anodic peak potential (EJ of the enamineb
3
m
4
5
I-MI"
Mod
namely the methoxylated enamines at the vinylic (2a,b) and allylic (3a,b) positions of the precursor enamines (equation 1).
(1) (a) n = 2 (b) n = 3
(2) "=
n -"uO
The cation radical intermediates formed from the enamines may be trapped by nucleophiles other than the solvent when these nucleophiles are electrochemically less oxidizable than the enamines. Indeed, the cation radical intermediates formed from morpholino-, piperidino-and pyrrolidinoenamines are trapped by carbanions derived from active methylene compounds such as methyl acetoacetate, acetylacetone and dimethyl malonate with moderate yields (equation 2)3. The products are easily transformed to the corresponding a-substituted ketones by hydrolysis with dilute hydrochloric acid.
461
8. The electrochemistry of enamines
An enamine (4) prepared from aniline and an aromatic ketone yields indole-type compounds (5 and 6) upon anodic oxidation (equation 3)4.
,xPh
Ph
-c, 2.6-lutidine
ph
2.2 F mol-'
PhNH
Ph
Y
ph
PhNA Ph
PhNH
1-
Although the reactivity of enaminones is not always the same as that of typical enamines due to the additional conjugative interaction with the carbonyl group, the anodic oxidation of enaminones seems useful in organic synthesis since they yield dimerized or cyclized products upon anodic oxidation. In anodic oxidation of the enaminones or enaminoesters in methanol containing sodium perchlorate, for instance, derivatives of pyrrole are formed via initial dimerization (equation 4)5.
MeOH
CH3
H3C RNH NHR
X =NHR X' = COR'
H3c
-H+
CH3
RNH NHR
462
Tatsuya Shono
When N-benzyl- or fl-phenethylenaminones are anodically oxidized, cyclization reactions take place and compounds containing isoquinoline or benzazepine skeleton are formed (equation 5)6.
Bichromones are also formed by anodic dimerization of the enaminones in acetonitrile (equation 6)'.
-
-
Althoueh it is well known that the nitrogen atom of the enamine form is always tertiary and that secondary enamines generally exist in the imine form, secondary enamines can be prepared when the nitrogen atom is acylated. The synthesis of the N-acylated enamines, namely enamides and enecarbamates, is, however, rather difficult when usual chemical methods are employed. The synthesis of enecarbamates and enamides has been achieved by eliminating methanol from a-methoxy carbamates and a-methoxy amides which were synthesized by anodic methoxylation of the corresponding amine derivatives (equation 7). Heating a-methoxy carbamates in the presence of ammonium chloride as the acid catalyst results in formation of encarbamates whereas enamines are formed from the a-methoxylated amides by simple distillation or by heating in the presence of silica gel as the acid catalysts.
R '\
N
I
J~~
COR
LR '\ CH3OH
lR2 acid catalyst
N
I
OCH~
4H30H
COR R = OCH3, OCHzPh, CH3, Ph or H R',R' = Alkyl or R1R2 = -(CHO)"-
RL\
fR2
N I
COR
(7)
463
8. The electrochemistry of enamines
Although the nucleophilic reactivity is generally less than that of the enamine, one of the typical reactions of the enecarbamates and enamides is the reaction with electrophiles at the 1-position (equation 8). Since this review deals with electrochemistry, chemical reactions of enecarbamates and enamides are not included but some of them are summarized elsewhere9. The oxidation potentials of enecarbamates are more positive than those of enamines (E,,/V us SCE, 7 = 1.59 V; 8 = 1.37 V in CH,CN-O.lN LiClO,, 100 mV/s).
The anodic oxidation of carbamates of pyrrolidine and piperidine in a nucleophilic solvent such as acetic acid or methanol yields a$-disubstituted compounds in which the nature of the a- and P-substituents depends on the reaction conditions employed (equation 9)1°. This a$-disubstitution has been explained by the intermediary formation of the enecarbamate and its further anodic oxidation.
-
MeOH or AcOH
R
N
R
N
Y
X = OAc or C1 Y = OAc, OCH3 or OH Indeed, the anodic oxidation of enecarbamates in acetic acid in the presence of potassium or sodium acetate yields the corresponding a$-diacetoxycarbamates in reasonable yields (equation 10).
When ammonium chloride is used as the supporting electrolyte in the anodic oxidation of enecarbamates in acetonitrile or methanol, chlorination at the 8-position takes place. In the mechanism of this 1-chlorination, the electron transfer from the unsaturated bond of the enecarbamate may not be involved, but the chloride ion is anodically oxidized to a positively charged active species which subsequently adds to the 1-position of the
464
Tatsuya Shono
enecarbamate so that a cationic center is developed at the a-position of the enecarbamate. This a-cation is then trapped by an anionic nucleophile such as acetate, hydroxide or chloride (equation 11).
Y = C1, OAc, OCH3 or OH P-Bromination and iodination are also achievable in a similar way by using ammonium bromide or iodide as the supporting electrolyte. The cc-substituents in the cc,/3-disubstituted products are generally easily eliminated by reduction with sodium borohydride under acidic conditions. The formation of a carbon<arbon bond at the P-position of carbamates has been achieved when cc-methoxy-P-bromocarbamates were allowed to react with carbon nucleophiles such as dimethyl malonate or isopropenyl acetate (equation 12)".
(7 N
I C02Me
-2e. m B r
MeOHor BIT'N~OM~ MeOH
OMe
I
I
C02Me
C02Me
Nu = CH2(C02Me)2or isopropenyl acetate X = Y = C02Me X = H . Y =COMe
Ill. REFERENCES 1. 2. 3. 4. 5.
W. W. Schoeller and J. Niemann, J. Chem. Soc., Perkin Trans. 2, 369 (1988). T. Shono, Y. Matsumura and H. Hamaguchi, Bull. Chem. Soc. Jpn., 51,2179 (1978). T. Chiba, M. Okimoto, H. Nagai and Y. Tanaka, J. Org. Chem., 44, 3519 (1979). M. Cariou, R. Carlier and J. Simonet, Bull. Chim. Soc. France, 781 (1986). D. Koch and H. J. Schafer, Angew. Chem., 85,264 (1973).
8. The electrochemistry of enamines 6. W. Eilenberg and H. J. Schafer, Tetrahedron Lett., 25, 5023 (1984). 7. Z. Sanicanin and I. Tabakovic, Electrochim. Acta, 33, 1601 (1988). 8. T. Shono, Y. Matsumura, K. Tsubata, Y. Sugihara, S. Yamane, T. Kanazawa and T. Aoki, J. Am. Chem. Soc., 104,6697 (1982). 9. (a) T. Shono, Electroorganic Chemistry as a New Tool in Organic Synthesis, Springer-Verlag, Heidelberg, 1984. (b) T. Shono, Electroorganic Synthesis, Academic Press, London, 1990. LO. T. Shono, Y. Matusumura, 0. Onomura, M. Ogaki and T. Kanazawa, J. Org. Chem., 52, 536 (1987). 11. T. Shono, Y. Matusumura, M. Ogaki and 0 . Onomura, Chem. Lett., 1447 (1987).
CHAPTER
9
Preparation of enamines OTAKAR CERVINKA Department of Organic Chemistty. Institute of Chemical.Technology. 16628 Prague 6. Czech Republic
I . INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468 I1. PREPARATION O F ENAMINES . . . . . . . . . . . . . . . . . . . . . . . . 468 A. Enamines from Aldehydes and Ketones . . . . . . . . . . . . . . . . . . . 468 1. The Mannich-Davidsen procedure . . . . . . . . . . . . . . . . . . . . 468 2 . The Herr and Hey1 procedure . . . . . . . . . . . . . . . . . . . . . . . 469 3. The titanium tetrachloride method . . . . . . . . . . . . . . . . . . . . 470 a . The secondary amine . . . . . . . . . . . . . . . . . . . . . . . . . . . 470 b . The carbonyl group . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471 4. Aziridine, azetidine. cyclopropane and cyclobutane enamines . . . . . 472 5. Optically active enamines . . . . . . . . . . . . . . . . . . . . . . . . . . 474 6. Side reactions during the enamine formation . . . . . . . . . . . . . . 474 B. Enamines from Imines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475 C . Enamines from Alkenes, Alkynes and Allenes . . . . . . . . . . . . . . . . 477 D . Enamines by the Horner-Wittig Reaction . . . . . . . . . . . . . . . . . . 478 E. Enamines by Allylamine-Enamine Rearrangement . . . . . . . . . . . . . 479 1. Isomerization of aliphatic allylamines . . . . . . . . . . . . . . . . . . . 480 2. Isomerization of cyclic allylamines . . . . . . . . . . . . . . . . . . . . . 482 F . Enamines by Elimination Reactions . . . . . . . . . . . . . . . . . . . . . . 484 1. Mercuric acetate oxidation . . . . . . . . . . . . . . . . . . . . . . . . . 484 2. Other types of elimination reactions . . . . . . . . . . . . . . . . . . . . 486 G. Enamines by Reductioh Methods . . . . . . . . . . . . . . . . . . . . . . . 488 H . Enamines by Means of Organometallic Reagents . . . . . . . . . . . . . . 489 I . Enamines by Condensation Reactions . . . . . . . . . . . . . . . . . . . . 490 J . Silicon in the Synthesis of Enamines . . . . . . . . . . . . . . . . . . . . . 491 K . The Role of Phosphorus. Arsenic, Tin and Boron in the Synthesis of Enamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492 L. Miscellaneous Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492 111. PREPARATION O F DIENAMINES . . . . . . . . . . . . . . . . . . . . . . 496 IV. PREPARATION O F ENAMINE DERIVATIVES . . . . . . . . . . . . . . 499 A. Nitroenamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499 B. Synthesis of Enaminones . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500 Tl?c~Chemrstn of Enamines . Edited by Zvi Rappoport Copyright O 1994 John Wiley & Sons. Ltd . ISBN: 0-471-93339-2
467
C. Synthesis of Enamides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502 D. Synthesis of Dienamides . . . . . . . . . . . . . . . . . . . . . . . . . . . . 504 . . . . . . . . . . . . . . . . . . . . . . . . . . 506 E. Synthesis of Enaminonitriles . . 1. a-Enaminon~tnles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506 2. P-Enaminonitriles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506 V. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507
I. INTRODUCTION
Enamine chemistry, from the beginning of the 1960s to the present time, has become one of the principal new research areas in synthetic organic chemistry. Compounds not only with simply enamine grouping, but also substitution derivatives of enamines, or push-pull type compounds with an electron-donating amino group attached to one carbon of the double bond, and a strongly withdrawing group ( N 0 2 C 0 ,CN) to the other carbon, are considered as suitable starting materials for further synthetic manipulations. Synthesis of enamines up to 1988 has been well reviewed in the literature1-13. Preparation of enamines in the following years utilized common reactions elaborated in previous periods with simpler systems. In this review the synthetic approach is discussed as a practical guide for elaboration to more complicated systems.
II. PREPARATION OF ENAMINES A. Enamines from Aldehydes and Ketones
The most widely employed procedures for the preparation of enamines are condensations of an aldehyde or a ketone with a secondary amine in the presence of solid base and the water formed is removed by the following methods of potential general applicability: (a) by an azeotropic removal from a solution of the aldehyde or the ketone and the secondary amine in benzene, frequently in the presence of an acid catalyst, and (b) by the use of molecular sieves. A newer method involves titanium tetrachloride as a catalyst and water scavenger. 1. The Mannich-Davidsen procedure
The first general synthesis, which has been useful for the preparation of enamines derived from aldehydes, was discovered by Mannich and Davidsen14. According to this method aldehydes and secondary amines react in the cold in the presence of potassium carbonate to give aminals 1 (equation 1). In many cases the aminal becomes the major product15~16 by the use of two equivalents of the amine. Destructive distillation of the aminal then leads to the enamine. Aminals are thermally stable up to temperatures of about 170°C in the presence of base, and their decomposition to enamines at lower temperatures is acid-catalysed". r ~ Curphey ~ The aminal can be isolated in some case^'^-^^. Both Wittig and M e ~ e and and coworkersz4 have questioned the need for the initial formation of the aminal and have developed procedures for the preparation of aldehyde enamines by using equimolar amounts of amine and aldehyde. For enamines of straight-chain aldehydes or acyclic amines, the Mannich-Davidsen procedure may be modified by using ether as a solvent and one equivalent of amine. Experiments designed to clarify the situation were carried out by Wittig and Meyerz3,and evidence that a dynamic equilibrium exists between an
9. Preparation of enamines
enamine, N-hemiaminal and an aminal has been presented by Gaux and Henaffz5. Enamino sugars (2) (R = diethylamino, pyrrolidino, morpholino) have been prepared from the corresponding aldehyde via the aminalzb.In the case of ketones, calcium oxide was employed, higher temperatures were required and the reaction appeared to be more limited in scope. Thus, while cyclohexanone and phenylacetone gave the corresponding enamine with piperidine, the reaction is not successful with diethyl ketone, benzylacetone and acetophenone. This condensation has been used e x t e n s i ~ e l and y ~ ~was ~ ~modifiedz9 ~ to include the use of barium hydroxide.
2. The Herr and Hey1 procedure
Herr and Hey130-33 introduced in the early 1952 a most useful procedure for the preparation of enamines. A solution of the carbonyl compound and excess of a cyclic secondary amine in benzene, toluene or xylene34.35is refluxed and the water removed azeotropically by means of a water separator. Addition of a catalytic amount of p-toluenesulphonic acid accelerates the reaction3'j. to many ketones and a This method has been extended by Stork and his large number of applications may be found in the According to the procedure outlined by Stork, a ketone (1 equivalent), an amine (1.5-2 equivalents) and a catalytic amount of p-toluenesulphonic acid were refluxed in toluene under a DeanStark water trap. About 400 ml of solvent and 2 g of the catalysing acid were used per mole of ketone. The construction of a simple and inexpensive water separator for the preparation of the pyrrolidine enamine of cyclohexanone in the student organic laboratory was described4'j. The azeotropic procedure has also been employed using one equivalent of amine ~ i t hand ~ ~ . ~ solvent ~ to give the enamine directly. Various techniques in addition to azeotropic removal of water have been used to drive the enamine formation to completion, as well as to accelerate the rate of its formation. By far the most common dehydrating agents used today are molecular sieves, which have demonstrated catalytic activity for enamine f ~ r m a t i o n ~ ~A- ~ less * .common method
for water removal includes other absorption agent^'^-^^ (magnesium sulphates8,sodium sulphate, calcium chloride) as well as chemical dehydrating agents [calcium hydrides9, calcium carbide6', boron trifluoride etherate6', tris(dialkylamino)borane]. Montmorillonite and alumina were used as solid supports in synthesis of e n a m i n e ~ ~ ' . ~ ~ . 3. The titanium tetrachloride method
In 1967, White and W e i n g a r t e ~presented ~ ~ ~ a new enamine synthesis. In their method, titanium tetrachloride was used as a catalyst and also as a water scavenger. This made it possible to synthetize enamines from acyclic ketones, such as methyl ketone^^^-^^, which had previously been difficult to make by conventional methods. This method fails in the case of several branched acyclic ketones. An optimization of this procedure has been reported74. In this modified procedure the ketone is added to a preformed complex between the amine and titanium tetrachloride. The method permits the synthesis of enamines from sterically congested ketones, for which the original procedure has failed. A study on the scope of the reaction applied to different types of carbonyl compounds (aldehydes, cyclic ketones and some substituted alkyl aryl ketones75)has been published. Two different secondary amines (pyrrolidine, morpholine) were used. Titanium tetrachloride on various supports (e.g. A1,0,) acted as effective dehydrating agents for the preparation of enamines from hindered ketones and secondary a m i n e ~ ~ ~ . Mechanisms of the formation of enamines have been d e ~ c r i b e d ' ~ . ~ ~ . The rate of formation of an enamine depends upon several factors: (a) the basicity of amine, (b) the degree of steric hindrance in either the amine or the ketone, which affects the rate of formation of the carbinolamine 3, (c) the rate of loss of the hydroxyl group from 3 with formation of 4 (Scheme 1)and (d) the rate of loss of a proton from 4 (Scheme 1). An intermediary of an aminal in the course of formation of enamines from ketones and secondary amines is not usually proposed, but stable aminals and hemiaminals of ketones have been p r e ~ a r e d ~ ~ - ~ ~ . a. 7he secondary amine. The most commonly used amines have been the cyclic amines pyrrolidine, piperidine, morpholine, hexamethylene-imine, N-methyl and N-phenyl pip e r a ~ i n e ~ a~~- e~t~i d, i n e ~ 'a, ~ i~r,i d i n eand ~ ~ open-chain a m i n e ~such ~ ~as dimethylamine, diethylamine, dipropylamine and N-methylaniline. In general, the order of the three most commonly used amines for formation of enamines is: pyrrolidine > morpholine > piperidine. In the case of enamines derived from N-methylaniline, the method of Hoch9' can be
(4) SCHEME 1
47 1
9. Preparation of enamines
employed. It involves heating a mixture of the amine and diethyl acetal of the ketone at 14&240 "C, followed by distillation of the ethanol formed (equation 2). Me\
~h'
C(OEt)2 + PhNHMe
-
CH2=CN(Me)Ph
I
+
2 EtOH
(2)
Ph
b. 7he curbunyl group. The carbonyl compound may be an aldehyde or k e t ~ n e ~ ~ - ' " ~ , and the latter may be acyclic, cyclic or heterocyclic. Stork's method for synthesis of enamines from carbonyl compounds has been developed with aldehydes and cyclic ketones. However, when this method is applied to acyclic aliphatic ketones, it sometimes gives poor yields and/or undesired side reactions. Enamine synthesis with molecular sieves has given excellent results with aldehydes and cyclic ketones. Titanium tetrachloride has given good results with acyclic ketones. This technique can also be used to make enamines from ketones possessing various functional groups such as nitriles, esters or amideslO'. De Benneville and coworkersz7synthesizkd a number of enamines derived from both aliphatic and aromatic aldehydes and several secondary amines. Benzing used excess of aldehyde49,102.The enamines of aldehydes and dimethylamine can be formed under alicyclic enamines were prepared by the quite different c o n d i t i ~ n s ' ~.~Sub - ' ~stituted ~ condensation of an alicyclic enamine with aldehydes in an inert solvent'06s107. Synthesis of enamine derivatives of Zvinyl-4-pentenal has been described108. Enamines from aldehydes can be synthesized by an acid-catalysed transamination reaction involving a ketonic enamine and an aldehydelog.Another variation is the use of tris(dimethylamino)methane in place of the usual secondary aminello. Intramolecular cyclizations to enamines have also been observed" '-I1 . Enamines from a-fluoroaldehydes are more stable than the corresponding simple enamines114. If a molecule contains both aldehydic and ketonic functions, reaction with a secondary amine occurs at the f ~ r m e r ~ ~, A~cyloins - ~ " (a-hydroxyketones) condense with secondary amines to give a-aminoketones rather than enamines"". Most studies of enamine chemistry have involved the use of cyclohexanone, but some other cyclic119,h e t e r o c y c l i ~ ~and ~ ~open-chain -~~~ ketones have also been used. The rate of enamine formation is greatly reduced by increasing the degree of a-substitution to the carbonyl group of the precursor ketoneiz5. Enamines have been made from a bicyclic aldehyde (5)Iz6 from bicyclic ketones (6)127,128, (7)lZ9,(8)lZ9and (9)lZ9,from cyclic ketones fused to a benzene ring, such as a - t e t r a l ~ n e ' ~ ~and - ' ~ p~- t e t r a l ~ n e ' ~ ' . ' ~from ~.~~ ketones ~, with a seven-membered ring133.137,138 fused to the benzene ring, or with a five-membered ketonic ring130,139-143 fused to the benzene ring.
Enamines 10 (R,R1,R2= H,Me; X = O,S,NMe; X1 = morpholino, pyrrolidino, piperidino) were prepared by reaction of the appropriate heterocyclic ketones with the heterocyclic base144. The conditions for optimal synthesis of morpholine enamines from alkyl methyl ketones (alkyl = isopropyl, isobutyl, t-butyl) were studied by using molecular sieves or titanium tetrachloride as the water scavengerP.
Enamines derived from relatively reactive amines, such as pyrrolidine and sterically unhindered cyclic ketones, are formed rapidly either with or without acid ~ a t a l y s i s ~ ~ ~ ~ ' . In the case of 2-substituted cyclic ketones (2-methylcyclohexanone,l-tetralone),cycloheptanone and higher cyclic ketones on the one hand, and with weakly basic (e.g. morpholine) or hindered amines on the other, the use of toluene solvent and a catalytic amount of p-toluenesulphonic acid affords good yields and shortens the reaction time. The reaction of a secondary amine with an open-chain aldehyde or ketone gives a mixture of E- and Z-isomers. Most reports of the synthesis of enamines are generally characterized by the absence of a discussion of the stereochemical constitution of the products. It is likely that, where possible, mixtures of stereoisomers, whose composition is thermodynamically controlled, are obtained when employing the procedures described above. The 'H-NMR, infrared and Raman spectra indicated that the E-isomer predominated, but not to the total exclusion of the Z-isomer. Seebach and coworkers'45 have prepared E-4-propenylmorpholine (11, R' = H, R2 = Me) from propanal and morpholine according to Dulou and coworkersz9 and E-4-(pent-2-en-3-yl)morpholine(11, R1 = Et, RZ = Me), E-4-(hept-3-en-4-yl)morpholine (11, R1 = Pr, R2 = Et) and E-4-(1-phenyl-1-propenyl)morpholine (11, R' = Ph, RZ = Me) according to Carlson and coworkerss6. The 'H-NMR a n a l y ~ i s ' ~ ~in-- ' ~ ~ dicated z90% of the E-isomer. The effect of kinetic and thermodynamic control on the E versus Z configuration of the resulting enamine has been investigatedzz.
4. Aziridine, azetidine, cyclopropane and cyclobutane enamines
Aziridine enamines of cycloheptanone (12, n = 2) and cyclooctanone (12, n = 3) have been prepared7" by the titanium tetrachloride method, but cyclohexanone gave only compounds 13,14 and 15.
9. Preparation of enamines
473
It was shown that the rate of formation of the enamine of 3,3-dimethylaziridine is 5 to 10 times faster than that of pyrrolidine with 2-methylcyclohexanone and 1-tetralone, probably due to decreased steric hindrance. However, the yields of monomethylated products are significantly lower with the azetidine enamineg2. Aziridine enamines (16, R = Me, Ph) have been prepared by an aminomercuration4emercuration reaction149(equation 3).
1
NaBH* aq. NaOH
(3)
CH~=C(CH~R)N~
(16) Addition of aziridine to prop-2-ynyltriphenyl phosphonium bromide (17) give aziridine enamines (18)L50-L52.
Cyclopropyl ketones (19, R1 = Me, Et, cyclopentyl) have been converted to enamines (20 RiN = Me2N, Et2N, pyrrolidino, morpholino), but when R = aryl or cyclopropyl, ring opening occurs153.
Cyclopropane enamines of type 21, have not been isolated, and only their possible precursors, i.e. carbinolamines such as 22, were i ~ o l a b l e ' ~ ~ .
Enamines in which the double bond is in a four-membered ring, such as 1,l-difluoro2-piperidino-3-phenyl-2-cyclobutene (23)' 5 5 or 1,l-difluoro-2,4-dipiperidino-3-phenyl-2cyclobutene (24)156,and in which the nitrogen is a part of a three-membered ring (e.g. 25) have also been d e s ~ r i b e d ' ~ ' . ' ~An ~ . interesting heterocycle with the C4.4.11 ring system (26) with a double bond at a bridgehead position has been d e ~ c r i b e d ' ~ ~ . ' ~ ~ .
5. Optically active enamines
In the recent literature numerous reactions in which enamines are used for synthesis of enantiomerically pure compounds (EPC) can be foundl6l. Optically active enamines from substituted pyrrolidine (e.g. 27, R = CH20Me, CH20SiMe,, COOMe52.162-168 or 28, R = Me, CH20Me) , or from ~ i p e r i d i n e ' ~such ~ , as 29, (S)-phenylethylamine (30)"' and stanna-N,0-heterocyclic amine (31)17', are used. The cyclohexanenamines seem to be the preferred test compounds for this kind of reaction, whereas enamines of open-chain ketones and aldehydes have been investigated only rarely166.Enamines from carbonyl compounds and secondary amines are obtained with azeotropic removal of water or by the Weingarten64~"2 method with TiCl,. A titanium chloride-catalysed variation in which perfluorinated alkyl groups can be introduced is also known173.
6. Side reactions during the enamine formation
Side reactions have been observed when aldehydes or some methyl ketones react with secondary amines (equation 4).
Aldol condensation occurs to give the usual dehydrated dimer, together with its enamine. The low yield observed in the preparation of the enamine of acetaldehyde is
9. Preparation of enamines
475
most likely due to competitive condensation reactions and is typical of the results to be expected with reactive, sterically unhindered aldehydes. Enamines derived from simple aldehydes are often unstable, being easily hydrolysed, oxidized or polymerized. For example, the enamine of acetaldehyde is unstable and readily polymerizes in the presence of a trace of acid. Some anomaly in the enamine formation has been observed153,154,174-180 8. Enamines from lmines
The imine, prepared in the usual way from a carbonyl compound and a primary amine, can be converted into the tertiary enamine by direct N-alkylation to tertiary iminium salt, which can be converted into the corresponding enamine by base181-183 (equation 5). PhCH2N=CHPh
Me1
+
PhCH?N=CHPh I
base
PhCH=CHN(Me)CH2Ph
(5)
This method may be used in the case of aliphatic methyl ketones which give, under acidic conditions, the products of aldol condensation, while higher homologues require a very long time18*.185.N-Methylation of dihydroisoquinolines [32, R = H, Ph, R1 = R2 = Me; R = H,R1 = Me,R2 = Et; R1R2 = (CH,),] with methyl iodide gave enamines 33"'. The bicyclic enamine 34 has been prepared by alkylation of the imine 35 followed by treatment of the iminium salt with base18'. A variation of the alkylation of imines has been d e ~ e l o p e d ~ ~The ~ . 'imine ~ ~ . is first converted to the ambident ion by sodium hydride, sodium amide or lithium diisopropylamide and an alkylating agent is then added. Intramolecular alkylation of imines with cyclopropyl and cyclobutyl groups, such as 36, produces heterocyclic enamines 37190-192
Tertiary iminium salts have been prepared by reaction of substituted aliphatic nitriles with silver nitrate or with silver iodide'93 (equation 6).
The imine may be N-acylated, and the amide formed reduced by lithium aluminium hydride (equation 7). RCH2C=NRL
I
ACzO
Me
R1
RCH=CN
I
/
\
Li A l h
R'
RCH=CN
Me COMe
I
(7)
I '
Me Et
Another modification involves the reaction of the imine with a Grignard reagent (equation 8). Me2CHCH0
-
MgBr Me2CHCH=NCMe3
EtMgBr
Me2C=CHN
/
\
(8)
CMe3
Iminium salt (39) was readily obtained by treatment of aminal(38) with trimethylsilyl iodide194.
A very simple and effective method, developed by Leonard and P a u k s t e l i ~ 'and ~~ used by Newman and Fields196,involves heating a ketone with the secondary amine perchlorate (equation 9).
/
R2
/
R2
Decarboxylation of a-tertiary amino acids in phosphorus oxychloride results in iminium salt product^^^'.'^^. Using Polonovski reaction (treatment of the tertiary amine-N-oxide with trifluoracetic acid) various iminium salts have been made199-z04. Cycloaddition of keteniminium ions to olefins gives cyclobutyliminium salts205-207. Anodic ~ x i d a t i o n ~ and ~ ~ -oxidation ~'~ of trityl salts of tertiary amines to iminium salts215*216 has been described. It is very easy to release enamines from iminium salts by reaction with alkali. A new one-pot synthesis of enamines has been described. Acids RRICHCOOH (R = H, R1 = Zthienyl, Ph, mesityl, 1-adamantyl, Me3C, Me,CH; R = R1 = Me) were deprotonateg with LiN(CHMe2), and then treated with methoxymethyliminium salts MeOCH=NRi MeSO; [RZ = Me; R: = (CH,),] to give 89% of enamines RRIC= CHNRiZL7.Aryl substituted enamines were also prepared. For example, reaction of aromatic anils with aromatic ethers gave unsymmetrically substituted enamines. Treatment of N-~henvlbenzalimine with PhOCH,Ph and NaIDMF eave 73% of F ~ h ~ ~ , ~ ~ h , : w on h i treatment ;h with ~ - ~ h e n ~ l 6 e n z a l i maiindeM ~ , C ~ K / D Mgave 75% PhCH=C(Ph)NPh,Z'8.
9. Preparation of enamines
477
Condensation of RRINCHzPh (R = Ph, R1 = Ph, Et; RR1 = 2,2'-biphenylyl) with PhCH=NPh in DMF in the presence of Me,COK gave enamines RRINC(Ph)=CHPh in 67-81% yield219. Quaternizing 1-pyrrolines (40, R1 = H, R2 = Me; R' = Ph, Rz = H) with 4-R3C6H,CH2Br (R3 = 4-NO2, Br, CN, COOMe) gave 1-pyrrolinium salts, which were deprotonated with base to give the tertiary pyrrolidino enamines 4lZz0.
C. Enamines from Alkenes, Alkynes and Allenes
The addition of amines to electrophilic alkynes and allenes to give enamines is well known221.22z.It is possible to prepare the E-isomer in a pure state by a stereospecific addition of an amine to an alkyne (equation 10). Enamines have also been obtained by an aminomercuration-demercuration sequence involving addition of aromatic amines to the substituted carbon of unactivated terminal acetylenes 223-225 (equation 11).
Aminomercuration of CH=CCH2OCHR1C=CR2 (R1 = H, RZ = Me, SiMe,) with morpholine (R3 = morpholino) gave enamines RZC=CCHRIOCH = CMeRyZz6.Regiospecific synthesis of terminal oxyfunctionalized methyl ketone enamines via catalytic aminomercuration of prop-2-ynyl esters and ethers has been also describedz2'. Aliphatic amines add to the terminal carbon of perfluoroalkylacetylenes without a ~ a t a l y s t ' ' ~ ~(equation '~~ 12).
RzN = Et2N, i-Bu2N,(PhCH2),N, piperidino, pyrrolidino, morpholino Diethylamine adds to perfluoro-2-methylpent-2-ene (42) to give enamine 43 after rearrangement with expulsion of a fluoride ionz30.
2- or 3-chlorobicyclo[3.2.l]oct-2-enes 44 and 45 give enamines 46 and 47 with amines in the presence of a strong basez3'.
The addition of ynamines to unsaturated systems provides access to a variety of cyclic and acyclic enamine systemsz32-z34(equation 13).
D. Enamines by the Horner-Wittig Reaction
The Horner-Wittig reaction has been applied to the synthesis of both aldehyde and ketone enamines. The substituted lithio aminomethylphosphonates (48, R' = H, alkyl, aryl; R Z = Me, Et, Ph; RzN = MeNPh, morpholino) unite with aliphatic, aromatic and cc,/3-unsaturated aldehydes or ketones to furnish the corresponding e n a m i n e ~ ~ j ~ - ~ ~ ~
Preparation of each geometrical isomer of the N-methylaniline enamines is possible, since the intermediate diastereoisomeric adduct can be separated. It is a route to pure Z-isomers, which are very difficult to prepare by other means244(equations 14 and 15).
PhCHO
(Ph0)2P(O)CHzNR2 THF,OnC *
NR2 I KH THF (PhO)2P(0)CHCH(OH)Ph
Ph
NR2 ' F=C
\
\
H
H
(14)
9. Preparation of enamines
479
The Horner m o d i f i ~ a t i o n ~ ~ of ~ , the ~ " Wittig ~ - ~ ~ ~reaction uses substituted lithio(dialkylaminomethyl)diphenylphosphineoxide (49, R' = H, alkyl, aryl; R2 = Me, Et, Ph: NR, = morpholino).
Use of anions from iminoalkanephosphonic esters2*' leads to 2-aza-1,3-dienes (equation 16)., An attractive alternative to the direct prcparation of enamincs from mono.-substituted phosphonate reagents is the use ofdimcthyl diazomcthylphosphon3te (MeO),P(O)CH= N,. Treatment of this diazo compound with t-BUOK (or with LiOH or K2C0,), followed by various ketones in the presence of secondary amines, delivered the corresponding e n a m i n e ~ ~ (equation ~ l - ~ ~ ~17). In the presence of amines, (MeO),P(O)CH= N, and RCHO afforded the terminal acetylenes RCECH. ~~
~
~~
MeCOAr
(E10)2P(0)CH(Ph)N=CHPh NaH, THF, A
-
ArCH(Me)COPh
The Horner-Wittig reaction of a phosphonium ylide with trifluoracetamides lead to a Z/E mixture of enamineszs4.A convenient synthesis of chiral enamines is describedzss. Tetrahydrooxazines (SO, R = Me, Bz, PhCH,) reacted with Ph,PCI to give phosphine oxides Ph,P(O)CH,NR(CH,),CI, which cyclized on l i t h i a t i ~ n ,to ~ ~give substituted pyrrolidines (51, R = Me, Bz, PhCH,) in 80-90% yield. Pyrrolidines were lithiated and treated with R 2 C H 0 (R2 = Me, Ph, 4-MeOC6H4) at -70°C to give the labile pyrrolidine E-enamines 52, which were isolated as their perchlorate salts. Lithiated pyrrolidine (R = Bz) and R2CH0 (R2 = Et, Ph) gave the stable enamines (R2 = Et, Ph) at - 70 0Cz48. A reaction of tungsten Wittig reagents to give enamines has been describedz56.
E. Enamlnes by Allylamlne-Enamine Rearrangement Several s t ~ d i e s ~ have ~ ~ demonstrated ~ ~ ~ ' - ~that ~ ~allylamines are thermodynamically less stable than the corresponding enamines, and that equilibration can be achieved and favours the enamine over the allylamine. A stabilizing overlap between the nitrogen lone
pair and the double bond is possible in an enamine, but is impossible for its allylamine isomer. One would anticipate on this ground then that equilibrating conditions would allow allylamine-enamine isomerization (equation 18). The base-catalysed allylamineto-enamine rearrangement corresponds to a gain in stability of ca 21 kJ mol-', of which about 10.5 kJ m o l l is attributed to p z conjugation in the enaminez66.
Price and Snyderz5' were the first to show that the higher relative stability of enamine versus allylamine could be used preparatively for the equilibration of the latter into the former. 1. lsomerization of aliphatic allylamines
Using t-BuOK in DMSO at room temperature they isomerized allyldimethylamine (53) into dimethylpropenylamine (54), diallylmethylamine (55) into methyldipropenylamihe (56) and di~llylanifine(57) into diprbpeny~inihe(58). Russian workers'67 isomerized but-2-en-1-yl dimethylamine (59) into but-1-en-1-yl dimethylamine (60) with sodium at 110 "C.
Sauer and Prah1258showed that the main product from the base-catalysed transformation of allyldimethylamine and several other allylamines, including 1-allylpiperidine and I-allylpyrrolidine, is the Z-enamino isomer. Seebach and coworkers'45 isomerized 4-allylmorpholine with t-BuOK in DMSO to a mixture of Z- and E-4-(1-propeny1)morpholine in a 87: 13 ratio. The E-enamine which presumably arose by a subsequent isomerization of the (Z) isomers was shown t o be the thermodynamically stable isomer.
9. Preparation of enamines
481
Hubert259 demonstrated that the transformations into enamines could be conveniently carried out with KNH,-alumina in hexane at room temperature. Again Z-isomers were the predominant products. Rivire and LattesZ63.268used LiNH, and NaNH, in liquid ammonia at -70°C, in hexamethylphosphortriamide at room temperature or C-BuOKIHMPAat room temperature for allylamine + enamine isomerizations. An anion formed by deprotonation of the allylamine at C, was considered to be the intermediate species in the isomerization. Intramolecular transfer of hydrogen in the transition state of the isomerization was suggested to explain both the kinetic formation of the Z-enamine and the absence of exchange with deuteriated base during the isomerization. Quantum chemical calculat i o n showed ~ ~ ~ that ~ the Z-carbanion (61) is actually more stable than the E-carbanion (62).
The double-bond isomerization of 1-pyrrolidino-2-propene or of N,N-dimethyl-2propenylamine to give the corresponding enamines was examined at 40°C over MgO, CaO, BaO, La,O,, Tho,, ZrO, or ZnO catalysts270a. A series of rearrangements has been reported by Ollis and coworkers270b.The isomerization of R,NCH,CH=CRIMe to R,NCH=CHCHRIMe with Bu,BBBu, has been observed2' l . Fe(CO), catalysed the photochemical isomerization of CH,=CH(CH,),CH,N(SiMe,), (n = 0, 1,3) to give a mixture of E- and Z-enamines Me(CH,),CH=CHN(SiMe3)227Z. The corresponding rearrangement of propargylamines (63, R1 = Bu, Ph; RZ = H, D; R,N = morpholino, piperidino) gives allenic enamines (64)273(equation 19). a, BuLi, hexane
RICzCH2NR2
b, MeOH(Me0D)
-
R1 \
C=C=CHNR2
(19)
It is known that the Wilkinson complex PhCl(PPh,), is able to catalyse the migration of a double bond. A chiral rhodium complex should in principle bring about the asymmetric s y n t h e ~ i s ~ ~ "described ~'~ in equation 20, or to its analogue in a
nitrogen-containing system. A major challenge is to find a substrate~atalystpair such that the reaction is both highly enantioselective and irreversible (in order to avoid racemization of the product). Isomerization of N,N-diethylnerylamine (65) and N,N-diethylgeranylamine (66) with HCoH,(PPh,), gave racemic citronellal-E-enamine (67). ~, Otsuka and coworker^^"^^^^ have described the isomerization of prochiral allylamines into chiral enamines with a [Rh(BINAP)COD]+BF,- catalyst (COD = cyclooctadiene). The isomerization of 66 gave R-citronella1 enamine (68) and
+
( )-R-citronella1 (69). This isomerization is a crucial step in the synthesis of ( - )-menthol. Enantioselectivity in this isomerization exceeds 96%.
BINAP [(2,2'-diphenylphosphino)-1,l'-binaphthyl] is the best among the various chiral diphosphines which were tried. The same complex isomerizes N,Nneryldiethylamine to S-citronella1 enamine. Enamines RR1CHCR2=CR3NR4RS (R-R3 = H, alkyl, aryl; R4 = H, alkyl, cycloalkyl; R5 = alkyl, cycloalkyl; NR4R5 = heterocyclic amine) were prepared by isomerization of allylamines RR1C=CRZCHR3NR4R5in the presence of a cationic Rh complex (RhLL1)+C104- [L = norbornadiene, L1= R-( + )-BINAP]. was heated to 100°C, it gave 98% When E-HOCMe2(CHz),CMe=CHCH2NEt2 E-( - )-HOCMe2(CH2)3CHMeCH=CHNEt2279. The mechanism of the BINAP rhodium complexes catalysed isomerization of allylamines to enamines has been published280.The reaction course and its intermediates have been probed by ab initio calculations281. Asymmetric allylamine-to-enamine isomerizations can be readily applied to bifunctional C5-isoprenoid substrates, which contain an allylic dialkylamino function at the tail end and an allylic 0-function at the head end. Asymmetric inductions with cationic [Rhl(BIPHEMP)] complexes [(BIPHEMP = 6,6'-dimethylbiphenyI-2,2'-diyl)bis(diphenylphosphine)] give generally e.e. of over 90%282. 2. Isomerization of cyclic allylamines
Only few examples of preparative isomerizations of cyclic allylamine to cyclic enamine (70) was converted into have been reported. Thus, 1-methyl-1,2-dihydro-1-benzazocine enamine 71 by reaction with t-BuOK-DMSO at room temperature262, 1-methyl-1,2dihydroquinoline (72) was isomerized under the same conditions to enamine 73 and the indoloquinolizines 74 were isomerized with t-BuOK-DMSO at 100 "C to enamines 75204.265 N-Alkylpyridinium salts are easily prepared and reduced by borohydride in protic solvents to give tetrahydropyridines having the double bond at the 3,4-position, i.e. to cyclic allylaminesz83.If the latter could be isomerized to enamines, a very useful simple
9. Preparation of enamines
483
(74) (R = Et, CH2COOMe) route to enamines would be available. Beeken and FowlerZB4have observed that
N-methyl-1,2,3,4-tetrahydropyridine(77) can be prepared by a treatment of N-methyl-1,2,3,6-tetrahydropyridine(76) with t-BuOK in DMSO. However, Martinez and Joule266were unable to isolate the enamine and the main product they isolated was N,N-dimethyl-1,4,5,64etrahydroanabasine(78).
Eisner and SadeghiZs5 described the isomerization of dihydropyridine with RhCI,-Ph,P complex in benzene. lsomerization of 1-alkyl-4-acyl-1,2,5,6-tetrahydropyridines into l-alkyl-4-acyl-1,4,5,6-tetrahydropyridineshas been observed. to N-acylenamines Pd/C-catalysed rearrangement of N-acyl-1,2,3,6-tetrahydropyridines is describedzs6. Besselitvre, Beugelmans and H u s s ~ n ~reported ~' the photochemical isomerization of cyclic allylamine 79 to enamine 80. An equilibrium favouring 81 over 82 by 93:7 was established by treating 81 with t-BuOK-DMSO at 90°C.
These experiments clearly show that piperidin-2-enes are thermodynamically more stable than the piperidin-3-ene (allylamine) isomers and that they can be produced from them by equilibration.
F. Enamines by Elimination Reactions 1. Mercuric acetate oxidation
Leonard and coworker^^^^-^^^ have developed the mercuric acetate oxidation of cyclic tertiary amines into a general method for the synthesis of heterocyclic enamines. This method has been used by other author^^^'-^^'. A solution of the amine with a four-molar excess of mercuric acetate in 95% aqueous acetic acid was refluxed on a steam bath and, after 1.5 hours, the mercurous acetate had precipitated and the amine obtained in 6 0 4 0 % yield. It was assumed that 1,2-elimination, which requires an antiperiplanar arrangement of the nitrogen-electron pair and the eliminated hydrogen atom, took place, and that elimination of the hydrogen atom on the tertiary carbon atom is preferred. Overoxidation can be avoided by adding disodium ethylenediaminetetraacetate to the reaction mixture298. Bohlmann and c o w ~ r k e r s ~ ~observed ~ - " ~ that an infrared absorption band between 270G2800 cm- is characteristic of a piperidine derivative possessing at least two axial carbon-hydrogen bonds in anti-periplanar relationship to the lone pair on the nitrogen atom (equation 21). The possibility of forming an enamine by dehydrogenation can be determined by this probe305~306.Experiments conducted on the oxidation of quinolizidine-10-D showed that cleavage of the C-H bond occurs in the rate-limiting step, but proof of the necessity of a trans relationship of the C-H to the nitrogen-mercury complex was lacking. Conformational effects appear to be important in determining which tertiary a-hydrogen is r e m o ~ e d ~ ~ ' . ~ ~ ~ . AcO-
&\
AcOH
+
(21)
For example, yohimbine containing an a-oriented axial hydrogen at C , can be dehydrogenated by mercuric acetate, whereas reserpine or pseudoyohimbine with 1-oriented hydrogen does not react305.309-312.Sparteine (83) is oxidized to a mixture of isomers: Ass"-didehydrosparteine (84) and As-dehydrosparteine (85). The other two stereoisomers of sparteine, i.e. a-isosparteine (86) and P-isosparteine (87) dehydrogenate to 84290.313-315
9. Preparation of enamines
485
The piperidineS6 and quinolizidine3" enamines and enamines of 1-azabicyclo[4.3.0]nonane, 1-azabicyclo[5.3.0]decane, 1-azabicyclo[5.4.0]undecane and l-azabicyclo[5.5.0]dodecane have been prepared in this mannerzg1. The dehydrogenation of 4-arylquinolizidines is interesting since the double bond of the salts is formed in the A9*I0-positionand not in the expected A4~10-p~sition318. In several cases, hydroxylation takes place. Examples are the dehydrogenation of 1-methylquinolizidineand of cis- and rrans-l-methyldecahydroquinolines319.320 (equation 22).
It AcOH
OAc
OAc
Knabe and coworkers' s t ~ d i e s ~have ~ ~ been - ~ ~centred ~ on the oxidation of
2-alkyl-1,2,3,4-tetrahydroisoquinolines. The indolizidine skeleton can be dehydrogenated by mercuric acetate as well as by N-bromosuc~inimide~~~. Substituted pyrrolidines afford the corresponding pyrrolines very readily. The formation of dimers and oligomers is a frequent complication in the preparation of e n a m i n e ~ ~Dehydrogenation ~~.~~~. of 1-methylpyrrolidine gives a dimer in addition to a trimer. Dehydrogenation of 1-methyl-1-azacycloheptane,followed by treatment with hydrogen sulphide, gave only the trithiane derivative^^^'. These results give further evidence for the instability of enamines of medium-sized rings. Dehydrogenation of amino alcohols of type 88 affords cyclic compounds 89, the formation of which can be explained by an intramolecular nucleophilic attack of the hydroxyl group on the formed enamine salt328.329.Several and b i c y c l i ~ ~ ~ l enamines were prepared by mercuric acetate oxidation.
A'-Piperideine-N-oxides and A'-pyrroline-N-oxides were obtained together with dimeric products by oxidation of N-hydroxypiperidines and N-hydroxypyrrolidines332-335 Some other metal salts and other reagents which have been used to oxidize tertiary amines to enamines include palladium(I1) chloride336,copper(I1) chloride"', copper(1) chloride with oxygen338, iodine, iodine p e n t a f l ~ o r i d e ~ ~ chlorine ~ . ~ ~ ~dioxide341, , permanganate ion342, manganese N-bromo~uccinimide~~~, benzoyl perq u i n o n e ~ ~and ~ ~ a. z~~~d' i f o r m a t e ~ ~ ' , ~ ~ ~ . 2. Other types of elimination reactions
A versatile synthesis of e n a m i n e ~ ~and ~ ~ dienamines ,~~' has been developed from aldehydes via a-aminonitriles (equation 23). KCN, R2NH
-
lCN LDA
R ~ C H O N~HSOJ-RICH, NR2 -7Ch0c
'
R2 R ,CN R 2 R 3 C H X \CH-C I ,CN R~C, \ I NR2 Li R3 NR2
1
KOH or r-BuOK
(23)
R2 RI \ 1 CTC ' \ R~ NR2 R1 = alkyl, aryl; R~ = H, Me, CH=CH2; R~ = H, Me; RZR3= (CH2)4 R2N = Me2N, MePhN, morpholino n-Dimethylaminophenylacetonitrile (90)can be alkylated with benzyl chloride and the resulting compound can be dehydrocyanated to give enamine 91. Alkylation of 90 with benzhydryl chloride and a-phenylethyl chloride led to enamines 92 and 93, respectively352.
a-Elimination of mesylate has also been reported. Compound 94 gives, with K,C03 in DMSO at 115"C, a mixture of enamineP3 95 and 96. Alkaloid 97 with t ~ i e t h y l a r n i n eand ~ ~ ~1,5-azabicyclo[5.4.0]undecene-5 gives 98.
9. Preparation of enamines
An addition-elimination mechanism of enamine formation has been proposed in some elimination reaction^^^^.^^^ (e.g. equation 24).
Cl
N Mixtures of Z and E stereoisomers have been obtained in most syntheses. This undoubtedly holds in the presence of an acid catalyst. The tendency of the E-enamine to isomerize to the Z-enamine was readily observed on numerous occasions under unexpectedly mild conditions. Munk and Kim357summarized the requirements for the stereospecific synthesis of enamines. First, if the introduction of the double bond is to be the final step of the synthesis, it must be stereospecific in character. Second, once the enamine is formed it must retain its stereochemical integrity under the conditions employed in the double-bond-forming step. The base-induced bimolecular p-elimination reaction fulfills both these requirements. Indeed, treatment of the mesitoate esters of ( k )-threo- (99) and ( f)-erythro- (100) 1-(4-morpho1ino)-1,2-diphenylethanolwith
JOR
r
H
07 "N& , ph
Ph
H
H
H (99)
(loo)
potassium t-butoxide in dimethyl sulphoxide gave rise to Z- and E-1-(4-morpho1ino)1,2-diphenylethylene, 101 and 102, respectively.
The best procedure for the preparation of A'-pyrroline (103, n = 1) and A'-~iperideine (103, n = 2) consists of dehydrohalogenation of N-chloropyrrolidine and Nchloropiperidine, respectively, by means of potassium
G. Enamines by Reduction Methods
Reductions of pyridines, quinolines, isoquinolines and their quaternary salts is a useful approach for the preparation of heterocyclic enamines. The 1,2-dihydro derivative is formed by reduction of pyridine with LiAIH43S9. Analogous reduction with sodium in 95% ethanol affords the 1,4-dihydro derivative. Monomeric N-trimethylsilyl-1,2-dihydroand 1,Cdihydro derivatives of pyridine have been prepared by treatment of pyridine with trimethylsilane in the presence of palladium360.Pyridines with a carbonyl function in the 3-position can be hydrogenated to the corresponding 1,4,5,6-tetrahydropyridinederivatives in good yieldj6'. Reduction of quaternary pyridine salts with sodium amalgam afford the 1,2-dihydro whereas sodium hydrosulphite gives the 1,Cdihydro derivative, re~pectively~~'. From a preparative point of view, partial hydrogenation of quaternary pyridinium salts in alkaline media to give substituted 1-methyl-A2-piperideines is very i m p ~ r t a n t ~ ~ ~ . ~ ~ ~ . 1,2- and 1,4-dihydropyridinederivatives were also formed from 3,5-dicyanopyridinesby reduction with sodium b o r ~ h y d r i d e ~ ~ ~ . The reduction of quinoline with either lithium or sodium in liquid ammonia produces only 1,4-dihydroquinoline366.Formation of 1,2-dihydroisoquinolineswas observed in the reduction of quaternary isoquinoline salts with sodium h y d r ~ s u l p h i t e ~ lithium ~~, aluminium h ~ d r i d e ~ ~ ~NaBH4371, -j~O, dialkylalumin~hydrides~~~ or on treatment with a Grignard reagent373. 1,2-Dihydropyridinesare intermediates in the synthesis of pyridines from mixtures of aldehydes or ketones and ammonia in the liquid phase374. Formation of enamines was observed in the reduction of 1-methyl-2-piperidonewith sodium in ethanol375or with lithium aluminium hydride316. I-Styryl-2-pyrrolidone is reduced by LiAlH, to 1-styrylpyrrolidine. The lithium-propylamine reducing system has been found capable of reducing julolidine to a mixture of e n a m i n e ~ ~Selective ~~. reduction of lactams with
9. Preparation of enamines
489
diisobutylaluminium hydride affords e n a m i n e ~ ~ However, ~ ~ - ~ ~ it~ has . been reported that for some lactams, lithium aluminium hydride is a better reducing agent than DIBAL3". Many achiral or chiral s u b ~ t i t u t e d ~ and " ~ bridged 1,4-dihydropyridine~~"~ have been prepared by a reduction of quaternary pyridium salts with sodium hydrosulphite as NADH models for enantioselective reduction of some prochiral substrates. A lithium aluminium hydride reduction of N-acylenamines has also been observed38e386. H. Enamines by Means of Organometalllc Reagents
LukeS and coworker^^^'-^^^ developed a very simple and useful method for the preparation of heterocyclic enamines. N-Methyl lactams with five- and six-membered rings (104, n = 1,2)give, with Grignard reagents, 1-methyl-2-alkyl(ary1)-2-pyrrolines(105, n = 1) and I-methyl-2-alkyl(ary1)-2-piperideines (105, n = 2), respectively. 2,2-Dialkylated bases (106, n = 1,2) are by-products of this reaction. Aromatic Grignard reagents afford only the unsaturated bases, probably because of steric f a ~ t o r s ~ Some ~~-~~~. authors who repeated the reactions isolated only pyrrolines398.399or, in other cases, 2,2-dialkylated bases400.This can be ascribed to the use of unsuitable isolation technique by the authors. The reaction was also carried out with various s ~ b s t i t u t e d ~ and ~'-~~~ non-methylated lac tarn^^^^.
Lactams with larger rings, i.e. ~even-~O~.~O', eight-408, nine-409, eleven- and thirteen-membered4" lactams, yield only acyclic amino ketones (107, n = 5-7,9, 11) when treated with Grignard reagents. There are cases in which alkyllithium reagents are superior to Grignard reagents in reacting with lactarns4''. Treatment of a thirteen-membered lactam with 1-naphthylmagnesium bromide forms both a cyclic enamine and the amino ketone4". Imides of dicarboxylic acids produce with organometallic reagents cyclic enamino compounds such as 108 (n = 1, 2)413418.
A'-Pyrrolines (109, n = 3) and A'-piperideines (109, n
= 4) are
formed on treatment of
y- and 6-halogenonitriles, respectively, with Grignard reagents4194" (equation 25).
For synthesis of certain alkaloids, the requisite cyclopropylimines were prepared by bisalkylation of the appropriately substituted benzyl cyanide. Cyanides could be selectively reduced in high yield to the corresponding aldehydes by employing diisobutylaluminium hydride. Treatment of these aldehydes with a primary amine with acids afforded the completes the synthesis of the imines. Rearrangement191.432-435 2-pyrrolines in high yield (equation 26).
2-Alkyl-A'-piperideines were ~ b t a i n e d ~ ~on~ treatment .~~' of imino ethers with Grignard reagents (equation 27). Ar
/
/CI(CH2IC\
NMgBr
CI(CH2),CN
-- 4NAAr (CH2)n-2
+ ArMgBr
n = 3.4
\
.NMgBr .
R1,R2= Me, Et
Evans and D ~ m e i e r ' ~ ~ have + " ' ~described a general method for the synthesis of a variety of cyclic enamines from imine anions. An imine was added to a cooled ( - 30 "C) solution of lithium diisopropylamide in THF and, after 15 min, 1-chloro-Ziodoethane (or 1-chloro-3-iodopropane) was added in one portion (equation 28). This method was used by Bruno and coworkers439.
Reaction of Grignard reagents with N,N-dialkylformamides gives acyclic e n a m i n e ~ ~ ~ ~ . Sterically hindered enamines can be synthesized in this manner. I. Enamines by Condensation Reactions
A synthesis, which leads to enamines in the form of their iminium salts, involves the cyclization of N-P-arylethyl tertiary amides with phosphorus pentoxide or phosphorus oxychloride (Bischler-Napieralski reaction)441445.
49 1
9. Preparation of enamines
The reactivity of the methylene group adjacent to the lactam group affords a possibility for a Claisen condensation446452. Treatment of esters of aromatic acids with 1-alkyl-2-pyrrolidones and l-methyl-2piperidones is an useful method for the preparation of simple pyrrolines and piperidines, respectively. The 1-alkyl-3-aroyl-2-pyrrolidones(110, n = 1) and l-alkyl-3-aroyl-2piperidones (110, n = 2) thus formed are cleaved by the action of concentrated (111, n = 1) and 1-alkyl-2-arylhydrochloric acid to give l-methyl-2-aryl-2-pyrrolines453 2-piperidine~~'~ (111, n = 2), respectively. After blocking the secondary nitrogen atom in a lactam by means of acylation, one can prepare 2-aryl-1-pyrrolines (112, n = 1) and 2-aryl- l - p i p e r i d i n e ~ ~ " (112, ~ ' ~ n = 2).
1,2-Dialkyl-2-pyrrolines and piperideines are readily formed by cyclization of y- and
6-alkylaminoketones4584700 Phenol and phenol ethers can be acylated by y-alkylamino or 6-alkylamino acids in the presence of polyphosphoric acid to form l-alkyl-2-aryl-2pyrrolines or 2-piperideine~'~'.The preparation from anhydro-5-hydroxyoxazolinium hydroxides (113) is also important. By the reaction with styrene, 1-methyl-2,3,5-triphenyl2-pyrroline (114) is formed472.
J. Silicon in the Synthesis of Enamines
Enamines have been prepared by using the reaction of trimethylsilyl derivative of various secondary amines with aldehydes or ketones473,474(e.g., equation 29).
- /C\ Et
Me3SiNR2 + EtCOMe
OSiMe3
\ 1
Me
NR2
-
CHMe \\
(29) FNR2 Me
An interesting recent development is the synthesis of protectedprimary enamine~"~'.
N-Mono(trimethy1silyI)enamines have been prepared by trimethylsilylation of m e t a l l ~ e n a m i n e sThe ~ ~ ~stereoselective . synthesis of (E)-N,N-bis(trimethyIsily1)enamines PhCH,CH=CHN(SiMe,), has been described477. The ~ i l y l a t i o n ~of~N-trimethylsilylimine ' R1R2CHC(R)=NSiMe, with trimethylsilyl tritlate (TMSOTQ Me,SiOS02CF3 gave N,N-bis(trimethylsilyl)enamine R1R2C= C(R)N(SiMe,), [R1 = H, R = Ph, R2 = H, Pr; R = Me(CHZ),, R2 = HI. The silylation of ~t-arninonitriles~~~ R1NHC(CN)RZCH2R3(R1 = H, Me, Ph; RZ = R3 = H, Me, Et)
with TMSOTf gave 39-97% of N-silylenamine Me3SiNCR'R2=CHR3 and N,N-disilylenamine (Me3Si),NCR2=CHR3. Reductive ~ i l ~ l a t i of o na-siloxynitriles ~~~ RCR1(CN)OSiMe, [R = Me, Et; R' = Me, Et, Pr, Bu; RR1 = (CH,),, n = 3-63 by Me3SiC1/Li in THF at 0 "C gave E- and Z-enamines RR1C=C(SiMe3)N(SiMe,),. Deprotonation of silanes XCH,SiMe3 (X = 2- or Cpyridyl, COOCMe,, 3-methyl-5-isoxazoyl), followed by treatment with PhCN or 2-, 3- and 4-pyridyl cyanide, gave silyl enamines RCH=CHNHSiMe, (R = Ph, 2-, 3- and 4-pyridy1)481. Silyl enamines have been prepared from c y a n ~ h y d r i n sRR1C(OSiMe3)CN ~~~ by reductive silylation with Me3SiC1/Li. Photodesilylation by HC1 gas in dry diethyl ether or by trimethylchlorosilane in methanol gave, after neutralization, the enamines, RR1C=C(NHZ)SiMe3 which were surprisingly stable. Enamines RNHCF=C(CF,)COOMe (R = Me, SiMe,) and P-siloxy-N,N-bis-silylenamines Me3SiOCMe=CR1N(SiMe3), (R' = Me, Bu, Ph, CMe,) have been prepared483. The catalytic hydrosilylation of 1-aza- and 1,4-diaza-1,3-dienes RIN=CH-CH=CHR [R = Me, Ph; R' = MezCH, Me,C, (Me,CH),CH] and RIN=CH-CH=NR1 were performed with rhodium(1) complexes. Under mild conditions N-silylated enamines, such as RIN(SiR:)CH=CHCHzR or R1NCH=CHN(SiR:)R', were formed as the main K. The Role of Phosphorus, Arsenic, Tin and Boron in the Synthesis of Enamlnes
It has been reported by Burgada and coworker^^^^-^^^ that highly enolized ketones form enamines when they are treated with tris(dimethy1amino)phosphite. Enamines are formed by the reaction of cyclic ketones with hexamethylphosphorous triamide488. Both van H i r ~ h ~ 'and ~ " Weingarten and Whitelg have described the amination of aldehydes and ketones by tris(dimethylamino)arsine, tripiperidinoarsine or tripyrrolidinoarsine. Aminostannanes react with aldehydes and ketones to produce ena m i n e ~ ~ ~ ~ ~ ~ ' . Nelson and Pelter493prepared a pyrrolidine enamine from tris(pyrrolidinyl)borane, pyrrolidine and a ketone and a catalytic amount of p-toluenesulphonic acid. Bicyclic enamines were prepared using the bicyclic ketone, tris(dimethylamino)borane, dimethylamine and potassium carbonate in an autoclave heated to 95-105 0C494. The reaction of arylaldehydes with hexamethylphosphorous triamide gave RCH(NMe,)P(O)(NMe,), which was treated with butyllithium and RICHO (R' = Ph, 2-MeOC,H4) and then with water to give Me,NC(R)=CHR1 495. Phosphorylated enamines R2C=C(NR~)P(0)(OR2), (R = COOMe, COOEt, CN R', RZ = Me, Et) were prepared496. Phosphorus-containing enamines have been prepared by phosphorylation of N-vinyl substituted tertiary amides, lactams and cyclic imides with phosphorus p e n t a ~ h l o r i d e ~ ~ ~ . Addition of amines to diphosphoryl alkynes has been described. Addition of RR'NH [R = H, R' = Me, cyclohexyl, PhCH,; RR' = (CH,),] to (EtO),P(O)C=CP(O)(OEt,), in CH,CI, at 25°C gave 93-100% of (EtO)zP(0)C(NRR1)=CHP(O)(OEt,),498. Speziale and coworker^^^^.^^^ have studied the reactions of phosphorus compounds with trichloroacetamides. L. Mlscellaneous Methods
The simplest enamines, dialkylvinylamines CH,=CHNR,, are often difficult to prepare due to their tendency to hydrolyse, oxidize or p o l y m e r i ~ e ~The ~ ' ~reaction ~~~.
9. Preparation of enamines
493
of trialkyl phosphites with N,N-dialkyl-a-trichloroacetamidesaffords stable trichlorovinylamines C1zC=C(C1)NR,499~503 Seyferth and coworkers504 have also synthesized N,N-diethyltrichlorovinylamine from the reaction of triethylamine and phenyl(trichloromethyl)mercury. Primary enamines 115 have been obtained by flash thermolysis of adducts 116 at 600°C in vacua. A retro-Diels-Alder reaction occurs to give vinylamine (R = R1 = RZ = H). These primary enamines have been identified by their spectroscopic properties at - 80°C. At temperatures >8O0C isomerization to the imine occurs as well as self-condensation to various nitrogen heterocycles or acyclic azadienes.
Primary enamines are also postulated as intermediates in the conversion of vinyl azides into aldehydes or ketones505(equation 30).
N-Protonation of 1-azaallyl anionssn6, prepared by deprotonation of azomethines, leads almost quantitatively and stereospecifically to secondary enamines of considerable stability (equation 31). R2 RL,
I
CH;
C
LDA
"NR~
R1 \
RZ
,C=C \ H NR3 Li
H
----
RZ
\
I
C=C \ R1 NR3 Li
'
The dilithio derivative of an N,N-dihydroxyenamine RCH=CHN(OLi), ('superenamine') has been proposed. This species may be also considered as a reduced form of the nitro-alkene RCH=CHNOZSo7.Heating of secondary amines with ketals yields enamines95.508-511 (equation 32).
PhCMe(OEt)2
+ MeNHPh
-
Ph \ C, =CH2 PhNMe
(32)
The reaction of propargyl alcohols with an amide acetal affords enamine productsSL2. The preparation of enamines (E)-RCH=CHNMez (R = substituted pyridyl) by the reaction of suitable substituted picolines, lutidines and collidines with Me2N(CHOMe), was described513. Treatment of secondary amines RzNH (morpholine, pyrrolidine, piperidine) with S02Clz gave N,N,N',N'-tetraalkylsulphinyldiamines, which subsequently underwent dehydration in the presence of aldehydes and ketones to give enamines in good yieldsSl4. The use of a nitrimino group instead of a carbonyl group in the synthesis of enamines has been reported515 (equation 33).
Sterically hindered enamines can be synthesized from an a-chloroenamine by treating it with t-butyllithium at - 70°C and then adding water516(equation 34). N-Benzoylhep-
tamethylene imine, a transannular enamine, gave by microbial oxygenation the 5-0x0 derivative, which was converted by the Wittig reaction to the enamine 117517.
Synthesis of enamines from amino acids has been described518.Van Tamelen and have described a useful method for the preparation of enamines by the oxidative decarboxylation of N,N-dialkyl-a-amino acids with sodium hypochlorite. Synthesis of enamines by the Babyan rearrangement-cleavage reaction has been describedsz0.
9. Preparation of enamines
495
Distillation of w-carboxyalkyl lactams 118 (n = 3, m = 2, R = Me; n = 4, m = 2-4, R = H; n = 5, m = 2, R = H) from soda lime gives salts of bicyclic enamines 119 with loss of CO, and H2OSz1.
Pd(PPh,),-Catalysed reaction of perfluoroalkyl and polyfluoroalkyl iodides, e.g. CF,(CF,),CF,I and CI(CF,),CF,I, respectively, with R,NH (R = Et, Pr, Bu) gave 4&50% of enamines, e.g. CF,(CF,),CH=CHNR, and Cl(CF,),C(Me)=CHNR,, which on hydrolysis with 2 M HCl afforded 95% of enaminonesSz2. The relative catalytic activities of the Ni group metals in the reactions of perfluoroalkyl and polyfluoroalkyl iodides with amines to give enamines were compared, and the reactivity order Ni > Pd > Pt was foundsz3. A convenient synthesis of P-sulphonylenamines from a$-epoxysulphones has been describedsz4. E-2-Iodo-1-tosyl-1-alkenes are useful synthetic intermediates for the regio- and/or stereoselective preparation of P - t o ~ y l e n a m i n e sN-Tosylenamines ~~~. are available from a palladium(I1) catalysed reaction using iodoazabicyclooctenes26. An unexpected synthesis of enamines has been observed. Treatment of hexahydrobenzazocinium halides 120 (R = H, Me; R = Alkyl, R1 = Me, Et) with sodium in liquid (121)s27. ammonia gave 7&86% of E-4-aryl-1-(dialky1amino)-1-butenes
Enamines 123 are the thermal rearrangement products of 5R*,6R*-6-(dimethylamino)= 2) and [4,4]-nonene (122, n = 3)s28.
4-methylene-1-thiaspiro[4,5]-2-decene (122, n
Enamines 125 (R = H, 3-C1,4-C1,3-NO,, X = 0 ; R = 3-C1,3-NO,, X = CH,) are prepared by the reaction of 5-aryl-l-oxa-5-azaspiro[2,4]-heptane-4,6-diones124 with piperidineszg and morpholine.
The reaction of bromopropenoic acids 126 (X = 0 , S) with secondary amines at 4@180°C gave enamines of 5-nitro-2-furans (127, X = 0) or 5-nitro-2-thiophenes (127, X = S)530. R
I
NO2
NO2=CH=CHN
'
I
I Br R2 (126) (127) (R1R2N = Me,N, Et,N, morpholino, piperidino, pyrrolidino, PhNH)
2- and 4-(N,N-dimethylaminovinyl)-1-methyl pyridinium iodides were prepared by vinylation of pyridinium salts with Me,NCH(OMe), in tetrahydr~furan~~'. Various heterocycles, such as 4,5-dihydrooxazoles, 4,5-dihydro-4H-oxazines and tetrazoles, can be readily metallated and condensed with a variety of organic nitriles to afford heterocyclic enamines such as 128 and 129 (R = Me, Et, Pr, t-Bu, Ph)532.
Ill. PREPARATION OF DIENAMINES
The literature up to 1988 has been r e v i e ~ e d ~Dienamines ~ ~ , ~ ~ ~are . usually prepared from E,P-unsaturated aldehydes or ketones under conditions analogous to those used for preparation of the simple Reaction of secondary amines with a,/hnsaturated ketones in the presence of p-toluenesulphonic acid is slower than that with the corresponding saturated ketones. Pyrrolidine is more reactive than morpholine. In some cases, satisfactory yields may be obtained when the water formed is removed by azeotropic distillation using a solvent such as benzene or toluene, but better results are obtained when the condensate is passed over a molecular sieve. The pyrrolidine dienamines of certain A4-3-oxosteroids may be prepared by simply mixing the ketone with a secondary amine in hot methanol. Compounds with 17- or 20-0x0 group are unreactive3'. With acyclic a$-unsaturated ketones and some cyclic unsaturated ketones, the situation is sometimes complicated by conjugate addition of the amine to the carbon-
497
9. Preparation of enamines
carbon double b ~ n d ~ ' . 'In~ the ~ . case of a,D-unsaturated aldehydes, conjugate addition of the amine does not prevent dienamine formation, owing to the greater reactivity of the carbonyl function. The reaction is then best carried out with two equivalents of the amine at low temperatures ( - 10 "C) in the presence of anhydrous potassium carbonate. This gives the 1,3-diaminoalkene, which eliminates the p-amine moiety on heating to 1W130°C under partial v a ~ ~ u m ~ ~ ~ , ~ ~ ~ . Mixtures of linear (130a and 130b) and cross-conjugated (131a and 131b) dienamines have also been obtained from cyclic a,Sunsaturated ketoness39.s40(equation 35). A similar mixture is formed by dimerisation of enamines derived from methyl alkyl ketoness4' and ketals542~s43 (equation 36).
n 0 w
RCH2C(OEt)2 + HN
I
Me
-
R = Me, Et, Pr, Bu
CH2=C-N
A
CH2R
In contrast, morpholine enamines from higher alkyl ketones do not dimerise but undergo disproportionation to the reduced enamine and various oxidation products. Aldehyde enamines dimerise, but with more difficulty at higher temperatures544.Crossconjugateds45 and linear dienamines (e.g. 132)546have been prepared by condensation of amide acetals with alkynyl alcohols (equation 37). R1CH2
'c-CSH
RZ/~~
-
RICH2
+ MezNCH(0Et)z
'c-C~H
I
R2 OCHNMe2
I
OEt
R2
I
RICH=C-CH=CH-NMe2 (132)
+ HCOOEt
-
n HtfR1(37)
5,
E~O-CH-0-C-R2 I ~e&> 111
R1 = CH=CH2, R2 = Me; R1 = Me2C=CH, R2 = H; R1R2= --(CH2).-,
n =4 5
Cross-conjugated dienamines may also be obtained by base-catalysed isomerization of propargylic amines with potassium t-butoxide in dimethyl sulphoxideS4'. Condensation of aliphatic aldehydes with 1,3,3-trimethyl-2-methyleneindolinegives enamines 133548.549.Attempted preparation of cyclobutane enamines is reported550to yield dienamine 134.
Dienamines are prepared by the reaction of 1,3-butadiene, dialkylamine, CO and Hz in the presence of RhH(CO)(PPh,), and Ph,P catalyst in toluene at 110"CSs1. Rey and DreidinglS0 have isolated endo- (135) and exo- (136) bicyclic aminals. At a temperature of 140°C both aminals were converted into a 1: 1 mixture of syn- (137) and anti- (138) -4-(pyrrolidinomethylene)bicyclo[3.1.0]hex-2-ene. This is in contradiction to earlier reports by Cook and coworkers1s0b. Cyclic non-conjugated (139 and 140) or conjugated (141 and 142) dienamines may be . The preferred obtained by Birch reduction of the corresponding aromatic amine552~553 conditions involve the use of lithium and t-pentyl alcohol rather than ethanol, since the latter tends to give a considerably higher proportion of the further reduced tetrahydro derivative554.
9. Preparation of enamines
Among the heterocyclic dienamines dihydropyridines are a very important class of compounds. Dihydropyridines play an essential role in biochemistry and they have many applications in pharmacology. They are indispensable intermediates in the synthesis of natural products, mainly alkaloid^^^^-^^^. These aspects as well as the preparation of dihydropyridines were dealt with exhaustively in several recent r e v i e ~ s ~ ~ ~ - ~ ~ ~ . Synthetic ways to dihydropyridines can be classified into ring-forming processes and ring transformations. The first general approach is best represented by the versatile Hantzsch synthesis. This method conveniently affords 1,4-dihydro- or 3,4-dihydro-, but not 1,2-dihydro-pyridines.The second approach may be illustrated by partial reduction of pyridines or pyridinium salts and nucleophilic addition of organometallic reagents to pyridines and pyridinium salts leading to 1,2- or 1 , 4 - d i h y d r o p y r i d i n e ~ ~ ~ ~ ~ ~ ~ . IV. PREPARATION OF ENAMINE DERIVATIVES A. Nitroenamines
An important class of enamine derivatives are the nitroenamines, that have been considered as suitable starting materials for further synthetic manipulations. For some reviews see References 56C571. A reaction forming 'enamine adducts' between nitroalkenes and enamines takes place and enantioselectivity. Seebach and coworkwith excellent diastereo~electivity~~~.~~~ e r ~ have ~ ~proposed " ~ a topological ~ ~ rule for the carbon-carbon bond-forming process between prochiral centres in enamines and nitroalkenes. This reaction is very important in the synthesis of enantiomerically pure organic compounds.
Dimethylaminoallene reacts with alcohols, thiols and aliphatic secondary amines to give the adducts CH,=CH(Y)NR, (Y = OR, SR, NR,) under the influence of acids. The adducts rearrange to the enamines YCH,CH=CHNR,. If Y = SR or NR,, the enamines are obtained in good yields5". On heating CH,=C(OEt)CHO with Bu,NH, morpholine or piperidine in benzene, the corresponding R,NCH,C(OEt)=CHNR, is obtained579.The reaction of RICH= CR2CH0 (R' = H, Me, Et, Pr, Ph; R2 = H, Me) with Me3SiNR2 (R,N = morpholino, piperidino, NMe,) gave 7&98% of R2NC(R1)=C(R2)NR2580. 'Bisenamines', i.e. E,E-S02[C(COOR=CHNMe2]2 (R = Me, t-Bu) were prepared by a consecutive esterification of SO,(CH,COOH), and condensation with dimethylformamide dimethyl acetal. The configuration of the products was deduced from the X-ray crystal structure58'. B. Synthesis of Enamlnones
The term enaminone is used to indicate any compound containing the conjugated It may be a mono-enamine of 1.3-diketone or of a system N-C=C-C=0582,583. 3-keto ester. A general method for the preparation of enaminones involves reaction between ammonia or primary or secondary amine and a 1,3-diketone(3-chloro(bromo)2-alkenone) or a 3-ketoe~ter~~"~~O. An improved procedure employed ammonium and amine acetates591(equation 38). R=H, alkyl; R1=Me, Ph; RZ=Me; R3=H, alkyl; RIRZ=-(CH,),R(Cl)C=CHCOR1 (R1 = CF3CF2CF2,C3F7)reacted with ammonia in benzene to give 40-65% yields of the corresponding enaminones R C O C H = C R N H , ~ ~ ~ . A facile preparation of E-alkyl enaminones E-MeCOCH=CHNRR1 in 90% yield involves refluxing MeCOCH,CH(OMe), with amines RRINH (R = R1 = H, Me, Et; R = Me, R1 = Ph, PhCH, or RRIN = 1-pyrrolidino, piperidino, m ~ r p h o l i n o ) ~ ~ ~ . The addition of a base to an acetylenic ester or ketone provides another method of preparation of en am in one^^^^.^^^ . A convenient one-pot synthesis of enaminones from trimethylsilylethynyl ketones and amines was described596.The reaction of activated methylene compounds, such as cycloalkanones, MeCOPh and PhCH,COOMe, with amide acetals gave high yields of en am in one^^^' (equation 39). MeCOPh
+ MeC(OEt)2NMe2
-
PhCOCH=CNMe2 I
(39)
Pummerer's ketone and its 1,2-dihydro derivatives reacted with CH(OMe), to give enaminones 143 and
9. Preparation of enamines
501
Mannich reaction of CH(OEt),, a ketone MeCOR [R = Et, Me2CHCH2,Ph, oC6H4(CH2),,p-ClC,H4, p-anisyl, 2-thienyl, 2-pyridyl, 2-furyl] and RiNH (R' = Me, Et; NR: = piperidino, morpholino) gave 33-80% of enaminones RCOCH=CHNR: 599. Treatment of 8-aminoketones with bis(acetonitrile)dichloropalladium(I1) in the presence of Et,N afforded the corresponding enaminones regioselecti~ely~~~. Ring closure of enamines and acid chloride^'^, esters6'' or nitriles (equation 40) or intramolecular alkylation of e n a m i n ~ n e ~(equation ~ ~ , ~ ' ~41) are general methods for the preparation of cyclic enaminones.
Photocyclization of N-haloaryl enaminone has been employed in the synthesis of a variety of heterocyclic c o m p ~ u n d s ~ ' "(equation ~~~ 42).
Enaminones were obtained from lactam acetals by reaction with active methylene c~rnpounds~~'. Heterocyclic 8-enaminoesters are synthons in the preparation of condensed systems6". Acylated alkyl aminoisobutyrylmalonates (145) can be converted to 3-0x0-2-pyrrolines (146)6'2,613.
CO-CH(COOEt)2 Me, l C COPh ~ e ' ''
NI
0
M~D Me
I
Ph
Condensation of 2,2-dimethoxy-1-methyl pyrrolidine(piperidine) with 1-indanone, 1-tetralone, 4-thiochromanone, butyrolactone, phthalide and substituted 2-oxindoles gives the corresponding enaminoketones614. Rearrangement of enaminones has been described615. By treating RR'CH, with R3C(OMe), or RZC(OEt), and R3R"NH, P,p-diacylenamines RR1C=CRZNR3R" (R = CN, COOMe, COOEt, Ph, Bz, COCH,CI, CONHPh, Ac; R1 = NO,, CONH,, CONHPh, COOMe, COOEt, CN; RZ, R3 = H, Me; R4 = Ph, PhCHz, 1-adamantyl) werey prepared616. E and Z-RNHC(Me)=C(CI)CONHMe (R = Ph, substituted phenyl, phenylalkyl) were prepared in 60% yields by treating MeCOCH(C1)CONHMe with MeNHZ6". Treating RCOCHR1COOR2 [RR1 = -(CHZ),-, R2 = Me; R = R1 = Me, RZ = Et; R = Me, R1 = alkyl, R2 = Et] with (S):valine t-butyl ester gave chiral enamines618. Reaction of RCN (R = Ph, 4-MeC6H,) with MeCOOR1 (R1 = Et, CHMe,, CMe,) in diethyl ether-toluene containing Et,NMgBr gave 18-36% of enamine esters H2NCR= CHCOOR1 619. C. Synthesis of Enamides
Enamides R,C=CHNRCOR (N-acylated enamines) are thermally stable compounds under neutral or basic conditions. However, they show sensitivity to aqueous acid, hydrolysing to form aldehydes or ketones and amides. The photocyclization of enamides has been used to form a wide variety of natural products because it gave higher yields than the conventional thermal s y n t h e ~ e s ~ ~ ~ - ~ ~ ~ . The general method used for the preparation of enamides is the acylation of the imine624-6z7.The imine may be prepared by usual methods and also by chlorination of the amino group of an amine with N-chlorosuccinimide, and subsequent dehydrochlorination of the N - c h l o r ~ a m i n e (equation ~ ~ ~ . ~ ~43). ~
R = H, Me, Et n = 0,1,2 The preparation of the imine by heating of ketones with ammonia under pressure and subsequent acetylation gives, as a rule, lower yield. Acylation of heterocyclic compounds carrying an imine grouping has been studied630-632.Although E$Z isomerism is possible, the Z-isomer is usually formed e x c l ~ s i v e l yA~ variety ~ ~ ~ ~of~ other ~ . methods has been used to synthesize enamides. The conversion of steroidal ketoximes and the derived oxime acetates, benzoates and methyl and benzyl ethers into enamides was described by Barton and coworkers621~6zz. For example, the oxime of 5-a-cholestan-3-one (147) forms with acetic anhydride in pyridine the enamide 148 which, under the reaction conditions, is acetylated on nitrogen to form the enimide 149. Chromatography on alumina cleaves the enimide to the enamide. A reductive acylation of oximes was developed6". Acylated oximes in the presence of excess acetic anhydride in dimethylformamide are readily reduced to imines using
9. Preparation of enamines
HON aMe
-
H
HN
I
COMe
H
MeCON
I
COMe
H
salts of either chromium(I1) or t i t a n i ~ m ( I I I ) ~The ~ ~ . imines ~ ~ ~ . furnished aliphatic, alicyclic and stereoidal enamides in good yields, although generally the yields were lower than those obtained with the refluxing anhydridelpyridine method. The Beckmann rearrangement of a,B-unsaturated oximes to enamides has been described637. Two methods for the preparation of enamides from nitriles are generally used. Reaction of ethylmagnesium bromide with a variety of aromatic nitriles in refluxing ether and subsequent treatment of the suspension of the iminomagnesium bromide with acetyl or benzoyl chloride or with a variety of esters638-640yielded the enamides in 25-60% yield (equation 44). Another method employing nitriles for the synthesis of enamides starts from amino nitriles prepared by Strecker ~ y n t h e s i s ~An ~ ' . aminonitrile has been acylated to form the acylaminonitrile, and pyrolysis of the latter under reduced pressure over quartz at 45e650 "C yielded the enamide in approximately 95% yield (equation 45).
-
Ar
ArCN
+ EtMgBr
Et
R2
I
R'CH-COR3
HCN
R4NH2
\ C=NMgBr
/
-
Ar
RCOCl
\ C-NHCOR
//
MeCH
R2
R3
1
1 R1-CH-CNHR4 I CN
R5COCI
R2R3 CORS
I I / R~CHCN &J'R~
(44)
Amides would condense directly with aldehydes under acid catalysis, to yield directly the e n a ~ n i d (equation e ~ ~ ~ 46). Me2CHCH0
+ RCONH2
-
Me2C=CHNHCOR
(46)
R = Me, Ph Amidals with a single /?-substituent prepared from primary amides and aldehydes eliminated an equivalent of an amide upon heating to form the e n a m i d e ~ ~(equation ~' 47). R1CH2CH(NHCOR2)2
A
R1CH=CHNHCOR2
(47)
R1 = H, Me, Ph; R2 = Me, Ph Amides reacted with acetals of aldehydes and ketones to form N-(a-alkoxyalk~~. yl)amides, which upon pyrolysis over alumina at 29C300 "C yielded e n a m i d e ~It~ was found that it was possible to obtain the enamide directly from the acetal by refluxing it in the presence of an acid (equation 48).
Reppe and coworkers644 described the N-vinylation of amides and lactams by acetylene. The amide and one percent by weight of potassium were heated in an autoclave at 14&16OoC in an acetylene-nitrogen atmosphere. A method to produce selectively either the E- or the Z-isomers has been described645. Syntheses of enamides utilizing o x a ~ o l i d i n e(150) ~ ~ ~and t h i a z ~ l i d i n e(151) ~ ~ ~derivatives have been published (equation 49). CH2OAc
CH20Ac
-AcoQ
AcO N
NHCOMe
&
(150)
-
\ MeCO&
MeCON
I
(151)
Et
(49)
H
D. Synthesis of Dienamides Dienamides are formed by the acylation of an a,/?-unsaturated imine or by the acylation of an imine by an a,/?-unsaturated acid chloride. Linear E-dienamides were
9. Preparation of enamines
505
prepared by acylation of the anion derived from irnines'j4'. In this system exclusive acylation occurred at the nitrogen atom. It was reported that a,Sunsaturated imines did not react with anhydrides under standard conditions, although thc cro~ss-conjugated enamide 152 was easily prepared by acetylation of an a$-unsaturated i m i ~ ~ e ~ ~ ' .
A mixture of dienamides was prepared from the oxime of isophorone (equation SO). Metallated 2-propynyl alcohols react with trichloroacetonitrile to form dienamides after a (3,3)-sigmatropicrearrangement and suitable prototropic shifts649;thus the dienamides formed exist as a mixture of isomers (equation 51). NOH
Me Me
NHCOMe
Me
Me
CH2
NHCOMe
Me
Me
NHCOMe I
E. Synthesls
of Enaminonitriles
1. a-Enaminonitriles-54
The quaternary salts (153, R = CIC6H4, R i = morpholino; R = Ph, RfN = piperidino) were treated with KCN to give 154, and then underwent desulfurization on treatment with Me1 to give 155655. CN RCH2C~NR12 I: SMe X1 (153) +
I
RCHzCNRLz I SMe (154)
RCH=CNR'~ I CN (155)
Cyanating bromoimmonium bromides R,N+=CH(Br)R1R2 (R' = Me, Et; R2 = H, Me, R2N = morpholino, piperidino, pyrrolidino) with KCN in dimethylformamide gave R,NCH(CN)C(Br)R1R2, which was dehydrobrominated in various base-solvent systems to give E- and Z-a-cyanoenamines R,N(CN)=CR1R2 656. Catalytic two-phase synthesis of a-cyanoenamines has been described. Condensation of PhN(Me)CH,CN with RR'CO (R = H, R1 = Ph, p-MeOC6H4, Pr; R = Me, R1 = Me, Et, RRICO = cyclohexanone) gave 4 4 7 9 % of RR1C=C(CN)NMePh657. Alkylation of (EtO),P(O)CH(CN)NMe, with EtCHO in CH2C1,65\nder reflux for 1-3 h gave 50% of EtCH=C(CN)NMe,. Nucleophilic addition of t-butyl isocyanide to aldehyde acetals in the presence of TiCI, afforded P-alkoxycyanoenamines R20CR1= C(CN)NHCMe, (R1 = H, Me, Et, Pr, i-Pr, hexyl, Ph; R2 = Me, Et)659. a-Enaminonitriles PhNRIC(CN)=CHR (R = aryl, heteroaryl; R1 = alkyl) were prepared via silylation of PhNRICH,CN with Me,SiCI and condensation of PhNRICH(CN)SiMe, with RCH0660.
The base-catalysed intermolecular condensation of nitriles of the type RCH2CN is one of the oldest known methods for the preparation of p-enaminonitriles, and in the case of simple self-condensation it leads to aliphatic analogues of the cyclic p-enaminonitriles formed in the classical Thorpe-Ziegler cyclization. For example, the base-catalysed dimerization of acetonitrile with sodium gives 3-amino-cr~tononitrile~~'. Cross-condensation between acetonitrile and aromatic or higher aliphatic nitrileP5 leads to substituted p-enaminonitriles 156 (R = alkyl, aryl).
Dimethylaminomaleonitrile is readily formed in dilute aqueous solution of HCN at room temperature666. The base-catalysed dimerization of malononitrile gives the dimer 1,1,3-tricyano-2-aminopropene, which exists mainly in the enamine form667-670. The condensation of substituted acetonitriles XCH2CN (X = CN, COOR, COPh) with trichloroacetonitrile, using a base catalyst, gives the p-enaminonitriles in good yields . Spectroscopic studies of p-enaminonitriles also after only short reaction showed that the enamine tautomeric structure is preferred over the imino structUre673-679
An intramolecular hydrogen bond makes the Z-form 157 more stable than the E-isomer 158. In the case of p-aminocrotononitrile it has been established that isomeriza-
9. Preparation of enamines
tion either in solution or in the solid state takes place. A mixture of E- and 2-isomers is The Thorpe-Ziegler cyclization has been found applicable to the preparation of cyclic enaminonitriles varying from 5- to 33-membered rings. It has been used for the construction of nitrogen, phosphorus, arsenic and oxygen heterocyclic enaminonitriles, and constitutes the most generally applicable and versatile route to these compounds and their derivatives. The wide range of bases which has been utilized for the ThorpeZiegler cyclization includes sodium ethoxide, potassium sand in hydrocarbon solvents such as toluene and xylene, sodium or lithium ethyl or methylanilide (the original Ziegler catalyst), sodium or potassium t-butoxide, sodium amide, sodium hydride in toluene or dimethyl sulphoxide, diethylamine and sodium bis(trimethylsily1)amide NaN(SiMe,),, which is not air-sensitive. P-Cyanoenamines were prepared6', in 49-80% yield by condensation of ortho esters with NCCH,COOH and secondary amines (equation 52).
Reaction of 2-(P-cyanoethyl)cyclohexanonebenzylimide with carboxylic acid chlorides RCOCl (R = Me, Et, Pr, i-Pr, Bu, Me,CHCH,) in benzene containing pyridine gave 47-81% N-acylenamines with high regio~pecificity"~. Cyanoenamines 160 (R = CN, COOMe, COOCMe,, Br, NO,, PhSO,, 2-pyridyl) were prepared in 15-90% yields by the condensation of RCH,CN with thiolactam 159 in the presence of Ag,CO,. Amino acid enamine derivatives 162 (R = CN, COOEt) were prepared similarly from thioamide 161h85.
V. REFERENCES 1. I. Szmuszkovicz, in Advances in Organic Chemistry, Methods and Results, Vol. 4 (Eds. R. A. Raphael, E. C. Taylor and H. Wynberg),Interscience-Wiley, New York, 1963, p. 1. 2. W. I. Taylor, lndole Alkaloids, An introduction to the Enamine Chemistry ojNatura1 Products,
Pergamon Press, Oxford 1966. 3. K. Blaha and 0. cervinka, in Advances in Heterocyclic Chemistry, Vol. 6 (Eds. A. R. Katritzky and A. J. Boulton), Academic Press, New York and London, 1966, p. 147. 4. E. Wenkert, Acc Chem. Res., 1, 78 (1968). 5. S. Hiinig and H. Hoch, Fortschr. Chem. Forsch., 14, 235 (1970).
6. M. E. Kuehne, Synthesis, 510 (1970). 7. S. F. Dyke, in Advances in Heterocyclic Chemistry, Vol. 14 (Eds. A. R. Katritzky and A. J. Boulton), Academic Press, London, 1972, p. 279. 8. S. F. Dyke, The Chemistry of Enamines, Cambridge University Press, 1973. 9. P. W. Hickmott, Tetrahedron, 38, 1975, 3363 (1982); 40, 2989 (1984). 10. J. K. Whitesell and M. A. Whitesell, Synthesis, 517 (1983). 11. G. Kneen, Gen. Synth. Methods, 6, 193 (1983); Chem. Abstr., 100, 5339k (1984). 12. A. G. Cook (Ed.), Enamines: Synthesis, Structure and Reactions, Marcel Dekker, New York and Basel: 1st edn., 1969; 2nd edn.,, 1988. 13. S. G. Agbalyan, K. K. Lulukyan and G. V. Grigoryan, in Enamines in Organic Synthesis (Ed. B. R. Alexandrov), Akad. Nauk SSSR, Ural, Sverdlovsk, 1990; Chem. Abstr., 114, 1638812 (1991); 184495s (1991). 14. C. Mannich and H. Davidsen, Chem. Ber., 69, 2106 (1936). 15. H. Bohme. H. Ellenbere E. Herboth and N. Lehners. Chem. Ber.. 92., 1608 (1959). -, 0. ~, 16. G. Laban and R. Mayer, Z. Chem., 8, 165 (1968). 17. L. Duhamel and P. Siret, Bull. Sac. Chim. Fr., 908 (1975). 18. F. Danusso, P. Ferruti and G. Peruzzo, Atti Accad. Naz. Lincei, 39, 498 (1965). 19. H. Weingarten and W. A. White, J. Org. Chem., 31, 4041 (1966). 20. P. Ferruti, D. Pocar and G. Bianchetti, Gazz. Chim. Ira/., 97, 109 (1967). 21. P. Ferruti, A. Segre and A. Fere, J. Chem. Sac. ( C ) , 2721 (1968). 22. L. Duhamel, P. Duhamel and P. Siret, Tetrahedron Lett., 3607 (1972); see also Chapter 3 of
.
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521
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CHAPTER
10
Enaminones as synthones lnstitut fur Pharrnazeutische Chernie der He~nrich-Heine-Unrversitijr Dusseldorf. Universitatsstr . 1. 40225 Dusseldorf 1. Germany
I . INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525 I1. P-KETOENAMINES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525 A. a-Substituted /3-Ketoenamines (Enaminones) . . . . . . . . . . . . . . . . 525 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525 2. Reaction with electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . 526 a . Heterocumulenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 526 b. Ketones and aldehydes . . . . . . . . . . . . . . . . . . . . . . . . . 530 c. Carboxylic acids and derivatives . . . . . . . . . . . . . . . . . . . . 536 d . P-Dicarbonyl compounds and derivatives . . . . . . . . . . . . . . 539 e. a$-Unsaturated carbonyl compounds . . . . . . . . . , . . . . . . . 544 f. Alkynes and arynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 555 g. Quinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557 h. Bromine and nitronium ion . . . . . . . . . . . . . . . . . . . . . . . 564 i. Alkyl, aryl and acyl halides . . . . . . . . . . . . . . . . . . . . . . . 564 j . Metal complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568 k. Anodic oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569 3. Reaction with nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . 570 a . Aromatic amines, indoles and phenols . . . . . . . . . . . . . . . . . 570 b . Hydrazine and hydroxylamine . . . . . . . . . . . . . . . . . . . . . 574 c. Hydride and hydrogen . . . . . . . . . . . . . . . . . . . . . . . . . . 576 d . CH-acidic compounds . . . . . . . . . . . . . . . . . . . . . . . . . . 578 4. Reaction with radicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . 578 5. Cycloaddition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 580 6. Photochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 581 7. Aromatization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 582 B. a-Unsubstituted P-Ketoenamines (a-Aminomethylene Carbonyl Compounds) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584 2. Reaction with electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . 584 a . Quinones and quinone imines . . . . . . . . . . . . . . . . . . . . . 584 b. Ketones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 587 c. /3-Dicarbonyl compounds and derivatives . . . . . . . . . . . . . . . 589 d . Heterocumulenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 591 e. Bromine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 592 The Chemistn of Enumines . Edited hy Zvi Rappopon Copyright O 1994 John Wiley & Sons. Ltd . ISBN: 0-471-93339-2
523
U . Kucklander 592 3. Reaction with nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . a . CH-acidic compounds . . . . . . . . . . . . . . . . . . . . . . . . . . 592 b. Activated aromatic compounds . . . . . . . . . . . . . . . . . . . . . 594 c. Aliphatic and aromatic amines . . . . . . . . . . . . . . . . . . . . . 594 d . Nitroketene aminals . . . . . . . . . . . . . . . . . . . . . . . . . . . 596 e. Guanidine and amidines . . . . . . . . . . . . . . . . . . . . . . . . . 596 f. Hydroxylamine and hydrazines . . . . . . . . . . . . . . . . . . . . . 597 g. Hydride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599 4. Cycloaddition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 600 I11. b,P-DIKETOENAMINES (2-AMINOALKYLIDENE 1,3-DICARBONYLCOMPOUNDS . . . . . . . . . . . . . . . . . . . . . . 602 A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602 B. Reaction with Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . 602 1. Hydrazines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602 2. Hydroxylamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604 3. Guanidine and amidines . . . . . . . . . . . . . . . . . . . . . . . . . . 604 4. Aromatic amines, and indole and pyridine rings . . . . . . . . . . . . 606 5. CH-acidic compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609 6. Aqueous base . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609 C. Reaction with Electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . . 610 D . Reaction with Radicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 610 E. Cycloaddition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 610 F. Pyrolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611 G. Aromatization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611 IV. a-KETOENAMINES (ENAMINONES FROM 1,2-DICARBONYL COMPOUNDS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 612 A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 612 B. Reaction with Electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . . 612 1. Acetals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 612 2. Acyl chloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 612 3. Quinone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613 C. Reaction with Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . 613 1. CH-acidic compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615 2. Phenol ether . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 616 3. Organometallic compounds . . . . . . . . . . . . . . . . . . . . . . . . 616 4. Phenylhydrazine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 616 5. Aqueous base . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617 D . Cycloaddition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617 1. Diazenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617 2. Nitroalkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 618 3. Acetylquinone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621 621 4. Phenyl azide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E . Photochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621 F. Aromatization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625 V. HETEROFUNCTIONAL ENAMINONES . . . . . . . . . . . . . . . . . . 625 A. Nitroenamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625 B. Enamlnolmines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626 C. Enaminothiones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627 VI . ACKNOWLEDGEMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629 VII . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629
10. Enaminones as synthones
525
I. INTRODUCTION
The term enaminone is given and defined by Greenhill' as a monoenamine of a 1,3-diketone or 3-ketoester. Because of their special chemical properties enaminones represent 'a class of organic compounds in its own right'. In our opinion enamines from 3-ketonitriles exhibiting a similar reactivity may also be included in this definition. In order to define the scope, it seems useful to distinguish between P-ketoenamines (the term for enaminones resulting from 1,3-dicarbonyls, according to Greenhill) and a-ketoenamines (the term for the enamines derived from 1,2-dicarbonyls). P-ketoenamines are called 'push-pull olefines', whereas a-ketoenamines can be regarded as 'capto-dative olefins' according to the definition of Viehe and coworkers3. Though exhibiting both electrophilic and nucleophilic reactivity, ketoenamines usually react as ambident nucleophiles at their nitrogen or (and) C,, atom. Ambident electrophiles are therefore suitable partners for cyclization yielding heterocycles. Of importance are heterocycles of medicinal interest (e.g. 4-aminoquinolines as chloroquine and congeners as antimalaria drugs or the group of gyrase inhibitors derived from nalidixic acid and used as antibacterial agents) which are synthesized starting from enaminone precursors. The same is true for nifedipine, the first of an important group of 1,4-dihydropyridines known as Ca antagonists and acting as coronary therapeutics. Though the chemistry of enaminones is well established, it has not yet been reviewed except for Greenhill's 1979 article.16 Enaminones are useful and widely used synthons in organic synthesis of alicyclic, aromatic and heterocyclic compounds. Frequently, it is assumed that enaminones are formed as intermediates in the synthesis of heterocycles. However, when they are not isolated, they are not considered in this article. Moreover, there are many examples of formal analogues of enaminones (e.g. aromatic or quinonoid compounds) as well as heterosubstituted derivatives4 which are also not discussed in the present chapter.
A. cr-Substituted BKetoenamInes (Enamlnones)
1. Introduction
a-Substituted-P-ketoenamines are the most frequently used enaminones in organic synthesis. Their N- and P-position are their most reactive sites. Acting as bisnucleophiles these enaminones are suitable reagents for building heterocyclic compounds, such as pyridines, pyrroles, pyrimidines or isoxazoles. However, an a-methylene or a-methyl group in the enaminones also shows sometimes nucleophilic character. On the other hand, electrophilic properties of the a-carbon or the carbonyl group can also influence a cyclization reaction depending on the substrate. The reaction path is influenced by the conditions and its regioselectivity can be partly controlled. By suitable substitution the enaminones can often serve as precursors for heterocycles and preparation of indoles, carbazoles, quinolines, acridines and phenaNthridines can be achieved easily. However, this part of enaminone chemistry can lead to surprising and unexpected reactions if the multifunctional properties of the enaminones are ignored, e.g. ring contraction, ring expansion and other rearrangements are observed. In some cases P-ketoenamines react as the ene-component in cycloaddition. Enaminones are even suitable synthones for building aromatic rings.
526
U. Kucklander
2. Reaction with electrophiles a. Heterocumulenes. On addition of diphenylcarbodiimide to a-substituted enaminone
attack by the CB-atom rather than the nitrogen is observed5 (equation 1). However, the a-unsubstituted derivatives are attacked at nitrogen (Section II.B.2.e),clearly demonstrating the potential ambident reactivity of the enaminone structure, depending on the substitution pattern of enaminone. The resulting vinylogous amidine does not cyclize.
R = M e 36% R = OEt 25%
Reaction of tertiary enaminones with benzoyl isothiocyanate gives substituted 2pyridinethiones in moderate yields, indicating the reactivity of enaminones at a-methyl group6 (equation 2). Phenylisothiocyanate reacts simply at the /3-position7 (equation 3).
PhNCS 5 MA
Greenhill and coworkers have shown that the reaction of cyclic enaminones with isothiocyanates can be controlled regioselectively to attack the nitrogen or the /3-carbon according to the reaction conditionss. Surprisingly, a heterocyclic spiro-product formed by reaction with two isothiocyanate molecules is observed in one case (equation 4). (equation 4).
10. Enaminones as synthones
I
PhNCS, NaH dioxane. A R=Me, R 1 = H
bNH- Mebk S
1
RR
ZEN
R1
I
R=RI=H MeNCS NaHldioxane, A
(autoclave) R=Me
Me
NH I
R1 R 1= H 77% R 1=Me 37%
An interesting substitution by sulphur at the 8-position is performed in a special type of enaminone with thiocyanate anion (equation 5).
528
U. Kucklander
Reaction of a primary cyclic enaminoester with aryl isocyanates yield urea derivatives, which can be cyclized to fused ~ r a c i l s '(equation ~ 6). COOEt
pmco 1&20 h, A
NH2
+
dmEt NH-C-NH-Ph II
NaOH
I
IM)"C
The reaction of acyclic enaminones with phenyl isocyanate produces 1:2 adducts by attack of both the P-carbon and the a-methyl group on the isocyanate" (equation 7).
Similar to the reaction of the corresponding thiocyanates, attack of benzoyl isocyanates on enaminones occurs at the 8-position. The intermediate is isolated in benzene at room temperature in one case and then cyclized to the pyridone12 (equation 8). An interesting application of the isocyanate addition is a reaction which initially yielded carbodiimide that reacted with a simple enamine to give an intermediate leading in a hetero-Diels-Alder reaction to a phenanthridine derivativei3 (equation 9). N-aryl substituted enaminones react similarly with carbon disulphide with attack by the P-position, thus opening a way to acridine derivatives14.The use of excess CS, leads to a benzothiazine derivative. However, application of the reaction to o-aminophenylsubstituted enaminone affords 3-thioxo-3,5,6,7-tetrahydrobenzo[1,2]dithiol-4-one (equation 10). The ambident nucleophilic character of enaminones is again demonstrated by the reaction with keto carbenes, produced in situ from diazoketones. Acyclic enaminones react via the P-position to directly yield pyrroles (equation 11). Cyclic enaminones are shown to react at the nitrogen to give adducts which can be cyclized with KOH to
10. Enaminones as synthones
X=H I . CS2/< 10°C NaOH, DMSO 2. Me2S04, 25°C
H
H
U. Kucklander
indol-4-ones (equation 12). Diazoketones bearing different a- and P-substituents sometimes give mixtures instead of regioi~omers'~.
b. Ketones and aldehydes. Tertiary P-aminoketones can be condensed with primary enaminones easily to yield substituted pyridines16 (equation 13). Me,
,Me +N-H
0 II (13) Me
Ph
4-Aryl-1,4-dihydropyridines, which are easily convertible to 4-arylpyridines, are usually prepared according to the method of Hantzsch starting from arylaldehyde, 1,3dicarbonyl compound and ammonia in a one-step A variation of the Hantzsch synthesis uses enaminones instead of P-dicarbonyl derivatives (for another variant, see Section 1I.A.l.e). Here the method consists of a condensation of two enaminone molecules and one molecule of aromatic or aliphatic aldehyde to give 1,4-dihydropyridines (equation 14).Various dihydropyridines have been synthesized by this m e t h ~ d ~ Enaminonitriles ~-~~. can be cyclocondensed in the same mannerz"equation 15). The extension of the Hantzsch method to other systems with a less usual substitution pattern, using tricarbonyl compounds, leads similarly to 2-phenylethylidene 1,4-dihydropyridines in low yieldz4 (equation 16).
10. Enaminones as synthones
H 33-80%
R1 = H, CH3; R2 = Me, OEt; R3 = H, Me, Ph
R1 = H, 2-CF3,2-N02; R2 = H, CI, F, Me, NMez
In another variant the combination of benzaldehyde, ethyl aminocrotonate benzoic acid and ammonium acetate in EtOH at room temperature yields a tetrahydropyrimidinium ion, whereas heating leads to a tetrahydropyridinium acetate again through attack at the a-methyl group of the enaminoneZ5(equation 17).
25'C/2 h
0 II
Ph P~COOH.P ~ C H O m A c , EtOH
Me
PhCOOH H 65% '
(17)
NH2
PhCOOI
\
Ph
532
U. Kucklander
The normal Hantzsch variant can be extended to the synthesis of acridine derivatives by using cyclic en am in one^^^-^^ (equation 18). Similar, partly aromatic acridones are obtained in high yield from N-(0-hydroxymethy1phenyl)enaminonesderived from dimedonez9.
The reaction of dimedone enamines with aldehydes is complex and the products depend on the structure of the aldehyde and the conditions. Acetaldehyde leads to benzoxazine as was independently reported by GreenhillZ7 and Akhrem and coworkers3'. The same reaction proceeds according to Hammouda and coworkers with formaldehyde when the N-phenylenaminone of dimedone31 or indanedione3' is used.
: R
R'CHO, AcOH EtOWA
:
&-
(19)
R1
R R' = Me, R = H 30%=' R1= Me, R = H 5 ~ % ~ * R' = H, R = Ph 60%31
Condensation of primary dimedone enaminones with formaldehyde according to Greenhill and coworkersz6~z7 give, in neutral medium, methylenbisenaminones, whereas acidic conditions produce spirocompounds. Structure A is given by Greenhillz7for the spiro-product, but structure B (equation 20) also seems reasonable. Modern spectroscopic methods should be used to solve this problem. Similar products are obtained in the Mannich reaction of enaminones derived from indan-1,3-di0ne~~. The Mannich reaction of enaminones was examined intensively. Enamines derived from dimedone are aminoalkylated in the b-position in good yield if the nitrogen is unsubstituted or m o n o s ~ b s t i t u t e d ~Primary ~ . ~ ~ . amines and formaldehyde react with enaminones to yield tetra hydro pyrimidine^^^ (equation 21). A similar reaction is observed for acyclic enaminones. With primary amines and formaldehyde, tetrahydropyrimidines are formedj5 (equation 22). An intramolecular Mannich reaction is observed as well. In this way enaminones derived from o-phenylendiamine are condensed to indenodiazepineS6 (equation 23).
10. Enaminones as synthones
H ( A ) 79%
0 RzNH, HCHO C6H6. 30 min, A
1
50-90%
R l = Ph R3NH2. HCHO, AcOH. EtOH, A
46% RL=R2=Me RL= Ph, R2 = Me 35%
R1 = H, Me, Et, PhCH, R~ = Me, Et, -(CH2)44-
R1 = H, Me, CH2Ph, Ph 24-84% R2 = Me, -(CH2)44
U. Kucklander
AcOH HCHO, EtOH, A
*
(23)
0
0
According to a method of Miyano and Abe3' N-arylenaminones bearing an orthoamino-substituent can be cyclocondensed to pharmaceutically useful dibenzo-1,4-diazepine derivatives3'. The same enaminones with benzoyl chloride derivatives give first the benzoylated derivative which by intramolecular condensation gave the same ring system3' (equation 24). An extension of this reaction to heterocyclic enaminones derived from N-substituted piperidine-3,s-diones is also knownj9.
86%
1
R = i-R PhCHO. AcOH, HCVEtOH, r.t.112 h
A & ,) H 73%
The enaminones obtained by condensation of cyclohexane-1,3-diones with aminoacetaldehyde acetals can be cyclized with p-toluenesulphonic acid to 4-oxotetrahydroindoles, which are useful synthons for synthesis of the corresponding c a r b ~ l i n e s(equa~~ tion 25).
J 43s-0~~- # TsOH
R
C&,
R
I
R' R=H,Me
24h. A
(25)
R
R
I
R' R1 = PhCH2 61%
535
10. Enaminones as synthones
The same principle of intramolecular enaminone attack by aldehyde acetals has been used later for higher functionalized indoles4'. In an intramolecular reaction with N,N-diethylformamide or N,N-dimethylacetamide diethyl acetal, enaminones are known to react at the nitrogen to form amidines4'. The corresponding products from acetamide acetals can be converted to 2-aminoquinolines by condensation with DMF acetals or to 1,4-dihydroquinolines by cycloaddition with diethyl maleate (see Section II.A.5) (equation 26).
Me2NCR(OEt)~ toluene, A
RL R
'
-
R
AJ N
R1
COOEt
&Y
RI R
I H
I
Me
R = CH3
COOEt
N' Me
i
1. Me2NCH(OEt)2, DMF,A
2. HCI
&
R I R1
N 'Me
(26)
I
Me
R1 = H, Me, Ph; R = H, Me In a reaction similar to that given in equation 25 enaminones derived from 2-aminoD-glucose and cyclohexanediones were cyclized to give 2-substituted indol-Cones. The corresponding 1-aminofructose derivatives were transformed into 3-substituted indo lone^^^ (equations 27 and 28).
536
U. Kucklander
c. Carboxylic acids and derivatives. Enaminones derived from acetoacetic acid, acetylacetone and acetylacetonitrile can be acylated at the P-position by a-cyano carboxylic acids. The products are useful synthons for 2-amino-Cpyridones or 2-pyrid0nes~~ (equation 29).
COOH
R21 I
+ CH-R3 I NHR1 CN
Me
*
@X's"
Me
NHR1 15-83%
"YH, "'hR3 NaOEt, E toH, A
A
Eto/'i'rR3
Me
H 33-5296
0
Me
I
NH2
(29
'
R 89-98%
Reaction of enaminones and carboxylic acids is mainly interesting as a route for cyclization of suitable substituted enaminoketones to N- heterocycle^^^. In this way N-cyclohexenylglycines can cyclize to indoxyl derivatives (equation 30). By a similar intramolecular acylation at the P-carbon of enaminones, fused indoles or pyrrole derivatives are obtained4648.
Cyclic N-quinonylenaminones have been treated with trifluoroacetic acid/trifluoroacetic anhydride in order to obtain cyclization to carhazole derivatives. However, the result was a nucleophilic (!) attack by trifluoroacetate at the enaminone a-methylene group. Cyclization gave a phenoxazinone derivative49 (equation 31). By intramolecular acylation Cquinolones are also availables0 (equation 32). Quinolone ring closure to fused heterocycles is possible as shown in equation 33 for the formation of pyrazoloquinolones, which are potential pharmaceuticals5'. A modification of this kind of ring closure is the replacement of the carboxyl group by a nitrile leading to aminoquinoline derivatives5' (equation 33).
10. Enaminones as synthones
1
CH,Cl~/CF3COOH,(CF3COhO 1.t.. 30 min
a1 EtOOC COOMe
N
I
COOMe r-BuOWr-BuOH 1.5 h, 90°C *
COOMe
H
COOMe
I
H 90%
CHzPh PPE = Polyphosphoric esters
65%
538
U. Kucklander
The cyclocondensation of enaminones with an aromatic nitrile was previously used for the synthesis of 9-aminoacridine~~~ analogous to Tacrine, which is a pharmaceutical agent against Alzheimer's disease (equation 34). Similarly acyclic enaminones serve as useful precursors for synthesis of the quinoline ring system as shown in equation 3553.
A Vilsmeyer reaction of alkyl anilinobutenoates directly yields quinoline derivatives in a simple way and in a good yield (equation 36)54. It is reported that a bis(enaminoester) can be cyclocondensed with formamide to give a pyrimidoquinazoline (equation 37)55. R
'
COOR
DMF/POC13
R2
(36)
I R3 H R1,R2,R3= H, OMe R = Me, Et
R3 47-70%
COOEt HCONH2 1-180°C,
E~OOC
6h
HN
NH2
Acylations of enaminones is a well known process'. However, the reaction of trichloroacetyl chloride interestingly differs from the normal reaction of acyl halides in yielding pyrans by attack of the a-methyl group of enaminone (equation 38)56.This gives a new access to cyclic and acyclic compounds by using various transformations. Another example of an unexpected acylation reaction is the action of excess nicotinoyl chlorides on enaminones leading to fused pyridopyrimidines or to spiro compounds5'.
10. Enaminones as synthones
The reaction apparently proceeds with both 3- and Cnicotinoyl chlorides by an initial acylation of the 1-carbon of the enaminone. The reaction is followed by action of nucleophilic enaminone nitrogen on the 4-position of the pyridine ring to form spiro compounds or naphthyridones in moderate yield (equation 39). If the p-position is blocked as in the case of cyclic enaminones, the acylation proceeds on nitrogen. The corresponding amide is isolable, and the spirocyclization to 2-indolone derivatives can be later accomplished in good yield (equation 40). d. P-Dicarbonyl compounds and derivatives. Greenhill and coworkerss8 have studied the reaction of cyclic enaminones with 8-amino-a-methylacrolein and showed the concurrent formation of quinolinones and ac;idinediones.as products (equation 41). Formation of the acridines is accompanied by loss of a carbon as formic acid. Similar reaction is observed with aminoacrolein starting from cyclohexanediones itself (see equation 170) (equation 41). Cyclocondensation of acetylacetone or dibenzoylmethane (presumably acting in the en01 form) and an enaminone derived from 1,3-cyclohexanedione easily leads to q u i n o l i n o n e ~(equation ~ ~ . ~ ~ 42). In the same manner, by reaction of dibenzoylmethane and an enaminone derived from cyclopentanedione the 5-oxopyrindine derivative is obtained in 28% yield6'.
U. Kucklander
.
a:, --" 0 : 6
COOEt
I CH2
I Ph
I CH2
I
N'PhcQ
/N
10. Enaminones as synthones
R l = Ph, R2 =Me 45% Interestingly, the reaction of formylcyclohexanone with an enamine of 1,3-cyclohexanedione yields linear condensed acridones, whereas acetylcyclohexanone leads to an angular fused phenanthridine derivative6' (equation 43).
Enaminones can be simply condensed with malonic acid derivatives to yield pyri d i n e ~ ~ ' . ~Thus, * . 2,5-disubstituted pyridines are accessible by the reaction shown in equation 44.
Me M
NHz e
+
'"3
MeOOC
AczO ___) B~-,, 40 min,AT
RO
0
R = H, OMe
f i ~ u - n Me
OH
1
I. FOCI3 2. H2Pd-c
Me Condensation reaction of an enaminone with 2-aminopropene-l,1,3-tricarbonitrile leads to a low yield of 2-dicyanomethylene-3-cyano-dihydropyridinswhich are used as synthons for 1.6-naphthyridine~~~ (equation 45). Cyclic enaminones react similarly with malononitrile to give isoquinoline derivatives (equation 46).
R = Ph, CH2Ph Me
Me
0
0
H
CN
H
CONH2
543
10. Enaminones as synthones
Readion of dimedone enamines with a-ketoacids has recently been shown to lead mainly to indole-2,4-dione derivative^^^ (equation 47). Glyoxylic acid, however, reacts similarly to other aldehydes in a Hantzsch-type reaction yielding N-phenylacridinedione in 30% yield64.
R
R = Ph or substituted Ph, PhCH2, Bn Pyridines can be synthesized starting from a primary enaminoester and POCl,65. Likewise, primary enaminones derived from acetylacetone undergo, on treatment with HCI gas, self-condensation to pyridine derivatives in good yield66.The analogous tertiary enaminones, however, mainly yield N,N-dialkylaniline derivatives when exposed to acid66 (equation 48).
I
HCI R =alkyl
Interesting alternative biselectrophiles are P-ketoesters which react in the presence of molecular sieves with aminocrotonate esters to give pyridones67(equation 49).
lcooR mol. sieve, xylene
+
A. 2 h
R1
H2N
Me
R =Me, Et R' =Me, substituted Ph; R2 = H R'R2 = -(CH2)34-
-
R R1
I
~
(4% ~
T
544
U. Kucklander
Aminocrotonate ester or aminocrotonitriles are cyclocondensed with vinylogous amidinium salts or enaminone ketals to give pyridine-3-carboxylic acid derivatives via electrocyclic ring closure of an intermediate a d d ~ c t ~ ~(equation -~O 50).
R
'
R1 Pyr or EtOH
NaOMe, AT, 8 h
Me R' = COOEt, CN
I
N-Me I Me
R
Me
52-95%
RZ= H, Me, OMe, PhCH2, Ph; R3 = H; R2R3= -(CH2)3-5e. a,SUnsaturated carbonyl compounds. The enaminone modification of the Robinson annellation reaction to form carbocycles is known from the work of Coates and Shaw7'; the reaction was re-investigated by Telschow and Reusch7', showing that either of the isomeric enaminones shown in equation 51 afforded the same 5: 1 mixture of isomeric products.
The main interest in the reaction with unsaturated carbonyl compounds lies in the synthesis of heterocycles, mainly pyridines. Simple pyridines can be obtained starting with an alkyl aminocrotonate and a ~ r o l e i n an ~ ~ ,acetal-substituted en01 ether14 or benz~ylacrylonitriles~~ (equation 52). Pyrrolinones are obtained by SnC1,-catalysed ~~ 53). action of 3-ethoxycarbonylacrylonitriles on e n a m i n ~ e s t e r(equation Enaminones are condensed with in situ eno-tosylates from ethoxycarbonylmalonaIdehyde to give p y r i d i n e ~(equation ~~ 54). According to the work of Greenhill and Mohamed dimedone enamine is attacked by methyl vinyl ketone in propionic acid at the 8-position leading to quinoline ring closure.
10. Enaminones as synthones EtOOC Me
I
CHO
d
EtOOC
EtOOC
I. Pipendine, EtOH
b
2. HNO?
Me
NH2
Me
COOEt PhQMe
EtOoCl $N EtOOC
I. SnCId, Et3N * 2. C6H6.25'C
+
Me
NH
COOEt
Me
0
I
1. EtlN, TsCI, DMF,1.t. 2. Pyr. 70-SOT. 10-15 h
COOEt Me
(53)
546
U. Kucklander
Excess of the a.B-unsaturated ketone vields ~ r o d u c of t further reaction to ovranoauino,, line77. The reaction with alkyl acrylates proceeds regioselectively at nitrogen or the B-carbon depending on the condition^'^. Cyclohexenones are added to yield azatricyclo ~
<
~
THF,NaH. 15-cmwn-5
0
~~~=/e,t4aH
H&=CHCOOR. THF.NaH
0 11
P-Benzoylacrylonitrile and a cyclic enaminone simply react to give Zphenylquinolone in good yield. The cyano group is lost as a hydrogen cyanides0 (equation 56).
547
10. Enaminones as synthones
When diacylethenes react with 3-aminocyclohexenones, either 4-oxotetrahydroindole or 5-oxotetrahydroquinoline derivatives are obtained by selection of the reaction conditionss1 (equation 57).
By addition of carbocyclic, acyclic and heterocyclic enamino ester to nitroalkenes and subsequent expulsion of the nitro group, pyrrole ester and fused derivatives are accessiblesz (equation 58).
Ph
COOEt (58)
Me
NO2 MeNH
Me
Another type of cyclic enaminones was used for stereospecific synthesis of cyclohexanone derivatives by addition of a,Sunsaturated carbonyl compound^'^ (equation 59).
R',R2 = Me, OEt, t-BuO
548
U. Kucklander
N-Tosylated aminocyclohexenones react with methyl acrylate in the presence of base to give directly bicyclo~ctanones~~ (equation 60).
0
II
+ CH2=CH-C-OMe
I
N-Ts
I
Me
LDA, THF -78°C
+ 20°C
bN:: COOEt
I
N
+ NHR
II
E~OOC'
N
,COOEt Nz MeCN, 3 h, A
-
N
h EtO
EtO
Me
Me H 32-36%
H -10%
'
~
~
~ ~ 61)
t
10. Enaminones as synthones
549
Reaction of cyclic P-ketoenamines with diethyl diazene dicarboxylate is observed to yield Michael-type a d d ~ c t s (equation ~ ~ . ~ ~61).For aromatization of the products see Section II.A.5. In contrast, the corresponding a-ketoenamine reaction leads to heterocyclic Diels-Alder adducts (see Section IV). Another modification of the Hantzsch reaction for synthesis of 14-dihydropyridines starts from 2-benzylidene-1,3-dionesand alkyl aminocrotonatesS7or a P-aminopentena-oness (equation 62). The synthesis is simple and generally applicables9 though the yields are not very high and side products are observed. Especially in the case of enaminones bearing a substituent at the nitrogen, side reactionsg0 become predominant and open a method for synthesis of carbocyclic compounds, which can be aromatized to substituted diphenyl derivatives9'. An interesting azocine ring is produced in a side reactiong1 (equation 63).
Me&Me Me
R = Me, PhCHZ 0%
NHR
OH
R = PhCHZ - 100%
I
1. AcOH 2. Mn02
5 50
U. Kucklander
Application of the method to benzylidenemalonates and primary enaminones leads to 2-hydroxy-1,4-dihydropyridinesin high yield92 (equation 64). In a similar manner a P-cyanoenamine, produced by ultrasonic irradiation of acetonitrile in the presence of potassium t-butoxide, reacts with several benzylideneketones to give 3-cyanopyridine~~~ (equation 65).
If the aryl residue bears a free phenolic hydroxyl group, addition to the ene system of the intermediate produces dihydropyridine by a one-step r e a c t i ~ n ~ ~(equation .~"~~ 66).
According to Stankevich and coworkers9' an enamino ester and an enamin nitrile lead similarly to condensed dihydropyridines when reacted with a benzylidenecyclopentanetrione derivative. Dimedone enamines react analogously to give an annelated tricyclic system (equation 67).
551
10. Enaminones as synthones
Enaminones react9' with alkoxymethylene compounds derived from 1,3-dicarbonyl derivatives according to Bottorf and coworkersg9to give substituted pyridines as a result of Michael addition of the enaminone nitrogen (equation 68). Similarly, nitroolefines can be condensed with enaminone derivatives to give 3-nitropyridine derivatives1" (equation 69).
+ovMe COOEt
HzN
COOEt
A,.. EtOH
Me
NH2
M & eN *
OEt
Me
0-Na+
(68)
\
N
DNo2
EtOOC 1. TsCl
2. DMF.r.t., 2 h
Me
H
t
(6%
Me
61%
The reaction of an heterocyclic enaminoketone with dimethyl methoxymethylenemalonate shows the ambident nucleophilic character of the enaminone anion by yielding products resulting from both P-carbon and nitrogen attack1" (equation 70).
COOMe 46%
552
U. Kucklander
A special kind of cyclization is the reaction of enaminonitriles and tetracyanoethene, with evolution of HCN102 (equation 71). which give 2-amino-3,4,5-tricyanopyridines,
Another interesting reaction is the addition of an enaminoester to phenyl4-chromone sulphonate, leading to a mixture of fused heterocyclic products in nearly equimolar a m ~ u n t s ~ ~ ~ e q u a72). tion
5-Oxoindolizines are obtained by reaction of ethyl pyrrolidinylideneacetate with several acyclic a$-unsaturated carbonyl compounds by cyclization of the formed Michael adductslo4 (equation 73). When this reaction was modified by changing the ring size of the enaminoester, the substitution pattern of the enone structure and by varying the conditions, different products were isolatedlo5. N-acylation could be accomplished by reaction of acyl chlorides in the presence of pyridine. Bicyclic lactams are yielded by Michael addition of acrylic esters and NaH (equation 74). In contrast to earlier results, the adducts formed by condensation of maleimide and ethyl 3-aminocrotonate or 3-aminocrotononitrile are cyclized to pyrrolo(3,4-c)pyridines and not to pyrrol0(2,3-b)pyrroles'~~(equation 75). Simple tertiary enaminones derived from acetylacetone and benzoylacetone react with acryloyl chloride to yield carbocyclic derivatives. The reaction proceeds via an initial Michael addition of the enaminone P-carbon to the e n ~ n e ' ~(equation ' 76). Analogous behavior of cyclic enaminones leads, according to ring size, to tetrahydroindole, quinoline and benzazepine derivativeslo8 (equation 77).
10. Enaminones as synthones
% H
COOEt
or maleic acid anhydride
I
COOEt 60%
CI-C
$. 6
R3
Pyr. C d i ~ M e
H COOEt n=1,2,3
\ R ~ ,
c=c
or C6H,Me, 12h.A
7&100% R ~ ,= R H, ~ Me, Ph
U. Kucklander
/ \ A
I
Acetone, 2 h
R3 26-74% R' = H, Me, CH2Ph R2 = COOEt, CN R3 = H, Me, PhCH2
Dioxane. 4 12 h
10. Enaminones as synthones
0
J Alkynes and arynes. Simple and activated alkynes have been used for synthesis of pyridine derivatives starting from enaminones. Di-yne or alkoxy- and amino-substituted en-ynes react with enaminones to produce pyridines. However, the yields are low and 78). isomeric mixtures are ~ b t a i n e d ' ~ ~(equation ."~
EtOOC
-
- - INa or
Me
NH2
,Me N.
EtOO (78)
Me
Me I . AcOH. NH40Ac, 50-60PC 2. 100°C. 5 h
43%
Alkynes bearing electron-withdrawing substituents are more suitable for this reaction as was shown earlier by Bohlmann and Rahtz"'. Pyridines are formed from intermediate Michael adducts in the reaction of u-oxoalkynes having a P-hydrogen and several primary enaminones in high yield. If, however, P-substituted propargylaldehyde derivatives are used, a normal Hantzsch-type reaction without attack of the alkyne bond leads to 1,4-dihydropyridines(equation 79). This method was used later for converting cyclic enaminones to pyridine derivativeslzz, however in low yield, and to quinolines in a better yield1'3-115(equation 80). Similarly, quinoline-2,Sdione derivative was prepared in 44% yield by the action of methyl propiolate on 3-aminocycl~hexenone'~~.
R3
R2 4
R
Me
I H (R1 = Me)
Me
EtOH, A, 1 h CHO
=
NH
0 1. EtOH, 3 U ° C ~2. A. 12W130"C
R = H, Ph R1 = Me, Ph R2 = COOEt, COMe, CN
RI
80-90%
U. Kucklander
A cyclic enaminoester reacts with methyl propiolate to give a Michael adduct which serves as a precursor for indolizine derivatives. Dimethyl acetylenedicarboxylate leads to isomeric adducts with different EIZ configuration depending on conditions"' (equation 81).
7 C O
O M e
C6H6. A. 4 d
H
H
COOEt \
I
COOEt 60% A I h NaH. C6H6
COOMe
H
15 min Et,N, MeOH
COOEt MeOOC
54% (R=H) 100% (R = COOMe)
Amino-Claisen rearrangement of propargylamino-cyclohexenone and cyclopentenone is reported to proceed with ring closure to quinoline and pyridine derivatives (equation 82). The isomeric 2-propynylenaminone gave an indolone in good yield118(equation 83). An interesting new application of enaminone chemistry is ring closure involving benzyne intermediates. In this way an intramolecular arylation of enaminones is effected. The method is used for the synthesis of fused heterocyclic compounds and natural products119-121.Phenanthridone derivatives can be obtained in good yield"'.
10. Enaminones as synthones
A ring closure takes place by participation of the enaminone /3-position if N(0-bromophenylmethyl)enaminones are used119 (equation 84). The corresponding N-(0-bromophenylethyI)enaminones lead to indolines by reaction of the nitrogen as the nucleophilic center1'' (equation 85). In the latter case benzazepine formation via arylation of the /3-position was successful by using p h o t o l y ~ i s ' ~ ~ .
30 min, r.t.
-
LiNEt2. THF
g. Quinones. Since the first reaction of enaminones and p-benzoquinone in 1929 by Nenitzescu the reaction is called a 'Nenitzescu reaction' and is extensively used for synthesis of 5-hydroxyindoles substituted in positions 2 and 3 (equation 86).The yields, however, are generally below SO%, though the ring system is easily obtained. It was reported that the use of nitromethane as a solvent and methyl instead of ethyl
I
R' = H,akyl R' R2 = awl,aryl R3 = COOR,COMe,CN
aminocrotonates give much higher yields, sometimes up to 90%122.This reaction was the object of many r e ~ i e w s ' ~ ~and - ' ~thus ~ only new aspects and developments are reported here. As was earlier established by Nenitzescu himself and coworkers, ethyl 3-aminocinnamate and p-benzoquinone in refluxing acetic acid yielded the expected 5-hydroxyindole127.In n-butanol as a solvent, however, new kind of main products are surprisingly formed, as was shown recently by Nenitzescu's coworkers'28 (equation 87). A by-product was observed earlier in other caseslZ9, which seems to be a precursor which, by rearrangement under the influence of butanol, leads to the diazaheptalenedione.
noL~~~~ -
0
AcOH, reflux, 30 mio
+
H2N
Ph
H
O
::&
~I
cPh
~
E
t
1 Ph + p i&H n-BuOH
NH2
WEt
H-N
Ph Ph
COOEt 0
H
H 46%
559
10. Enaminones as synthones
The influence of the solvent and the substitution of the starting material was examined recently. It was found that a change from acetic acid to methanol at lower temperatures leads to Michael adducts in good yield130 (equation 88). The obtained hydroquinones were oxidable in excellent yield, though no further transformations were reported. Several attempts in the past have been made to use the Nenitzescu reaction for synthesis of 1,2-annulated indoles similar to the antitumor agent m i t o m y ~ i n ' ~ ~In~ ' ~ ~ . this area interesting reactions with cyclic enaminoester were recently developed by Parr and re is^'^^. They succeeded in the formation of the 'normal' 5-hydroxyindoles starting from naphtoquinone (equation 89). Simple benzoquinone, however, lead in good yield to quinonoid Michael adducts, which on an attempted cyclization in the absence of reducing agent did not give the corresponding normal indoles, but instead acetoxylated products are formed by attack of solvent and acyl migration (equation 90), a fact that had been observed and examined e a r l ~ e r ' ~ ~ ' ~ ' . 0
COOMe 0
HN
C COOMe
MeOH. AcOH 2S°C,10 h
0
Acyloxynaphthoquinones and secondary alkylaminocrotonates react to give 4-hydroxybenzo(g)indoles and benzov)indole-4,9-dione in a low yield138(equation 91). A similar reaction of tertiary alkyl aminocrotonates leads to a mixture of isomeric naphthofuran derivative^'^^ (equation 92).
560
U. Kucklander
R1 = PhCH2 9%
14-35% R1 = Me, CHzPh, substituted Ph R = Me, Et
OAc COOEt
0
Awr EtCOOH, r.t.. or EtOH, A
A
OMe
C
/ 30%
~
(92)
OAc 20%
The use of tertiary enaminones in the reaction with quinones to give benzofurans is a long known reaction'40. If acetylbenzoquinone is used as the starting material, the resulting ben~ofuran'~'(whose structure had to be corrected)14' (equation 93) can be transformed to furanobenzopyrans.
561
10. Enaminones as synthones
As is known from the work of Domschke and Oelmann143.144dimethyl 2-aminofumarate reacts with quinones to give aminocoumarins, whereas with BF, in ether the corresponding N-monosubstituted enaminones substitution pattern is changed and the normal Nenitzescu products are formed, from which 2,3-unsubstituted 5-hydroxyindoles are accessible (equation 94). This method is not well known in the literature, but it was recently used145.
BF,, Elher, 1.t.
I
R
I
R = H AcOtUr.1.
COOMe
I
COOMe
R R = alkyl, aryl 43-90%
COOMe
Several N-(quinonylalky1)enaminones have served as model compounds for an intramolecular Nenitzescu reaction demonstrating the ambident reactivity of both the enaminone and the quinone. The compounds cyclized unexpectedly, mainly to heterocyclic spiro-compounds146~'47.A phenanthridinium salt and benzofuranoazocine are also obtained, depending on the length of the chain connecting the quinone and the enaminone moieties (equation 95). It is observed that C-quinonylethylenaminones mainly give tricyclic heterocycles as products, which undergo ring opening to carbocyclic spiro compounds in solution148 (equation 96).
U. Kucklander
HO Toluene, A, l h n=l or AcOH. 24 h. 1.1.
Me 0
*
Me
0 n
or AcOH, r.1.
R = -CH2C(CH3)2CHr, X = AcO, OH R=Me
"=3
THF, HC104
\\
6165%
Me 0 R = Me, RR = CH2C(CH3)2CH2 R' = H, Me, PhCH2 n = 1 25-77% n = 2 50-70%
C104-
563
10. Enaminones as synthones
Similarly, secondary enaminones substituted in the B-position by a quinonylmethyl group easily cyclize to spiroheterocycles, demonstrating the nucleophilic potential of enaminone nitrogen. The corresponding primary quinonylmethylenaminones are suitable starting materials for the synthesis of 6-hydroxyquin~lines'~~ (equation 97).
/\
R=H
N
Me
Me
8-20
EtOH, 1.1.
R = Me, PhCH2, Tolyl
ry
Me
56%
0
M
(97)
R
0 R = Me, Bz 50% R = p-Toly l 80%
The use of quinone monoketals in the reaction with an exocyclic enaminoester is a new variation'50. It is not a typical Nenitzescu reaction since an enamine anion is used. Tricyclic intermediates are obtained, which nevertheless formally give typical Nenitzescu products in high yield and regioselectively (equation 58). In this way annelated indoles of mitomycin type become accessible.
OMe
Me
HN
OMe
__t
HCI
OM^
-(kHz),,
n = 1 94%
n = 2 59% (overall yield)
564
U. Kucklander
Other extensions of the Nenitzescu reaction are the use of a-ketoenamines (see equations 233-235) which mainly yield non-indolic compounds. Another extension is the application to b-substituted aminomethylene ketones leading to compounds with indole-2-one structure by rearrangement (see Section II.B, equations 158-160).
h. Bromine and nitronium ion. Different heterocyclic enaminoesters have been brominated. The reaction further proceeds to give ketones. This is reminiscent of the behaviour of the a-hydrogen substituted derivatives which give aldehydes. The same reaction takes place under initial attack of the nucleophilic /l-position. As a consequence endocyclic olefins suffer ring contraction (equation 99), whereas exocyclic alkenes undergo ring expansion (equation loo), opening interesting synthetic abilitie~'~'.
The reaction of a lithiated pyrrolidine enaminone with nitronium tetrafluoroborate leads to the fl-nitro derivative which is found to be a mixture of E/Z isomers'52 (equation 101).
"kPh I H
1. BuLi, THF, -40°C
-
2. N02+BF4-
i Alkyl, aryl and acyl halides. Alkylation and acylation of intact enaminones have been reviewed by Greenhill'. Later he and MotenlS3 reported in more detail on the reaction of alkyl halides after deprotonation, mainly by NaH. The reaction is complex due to possible reaction at the 0 , N, b-C and (or) the a-methyl(ene). Selective specific alkylations at the a-methylene group of enaminones are of interest because of their preparative value. The alkylation of cyclic enaminones involving deprotonation with n-butyllithium is called y - a l k y l a t i ~ n ' (equation ~~ 102). Similarly lithium diisopropylamide in THF (-78°C) can be also usedlS5. In a similar way interesting intramolecular alkylations leading to heterocycles can be accomplished in good yieldlS5(equation 103). On the other hand N-alkylation with the aid of butyllithium is reported in some casesIs6 (equation 104).
565
10. Enaminones as synthones
THF. -78°C
0
I . n-BuLi, THF, -78 'C 2. CHz=C-CH20S@Me I CH2SiMe3
(104)
NHCH2-C-CH2SiMe3
II
CH2 Specific alkylation or acylation at the nitrogen has been observed in the case of secondary pyrrolidine enaminones in the presence of potassium tert-butoxide. The configuration of the double bond was changed from Z to E in this reaction"'JS8 (equation 105).
2. Me2s*
1. I-BuOK. DMF,
2. MeCOCl
566
U. Kucklander
The copper(1) iodide promoted cyclization of N-(2-haloary1)-substituted enaminones is a good method to yield indoles and carbazoles. This type of intramolecular arylation is a reasonable alternative to the route via benzyne (see Section A.1.f) (equation 106). The method could be extended to N-(2-ha1oaryl)alkyl-substituted enaminones which give the expected dihydroisoquinolines whereas a nucleophilic attack of the nitrogen instead of the p-carbon give the undesired indoleslS9(equation 107).
R2
H
R1 = RZ= R~ = H, Me 80-97%
-
&JR R
4~*1R
I H
1. NaH 2. 1.5-2 eq. CuI, A, H M W
X=Br,I
R = Me, Ph RR = -OCH20-,
-CH~(CH~)~CHT
I
Me
R2 H R1 = R2 = H, Me; R4 = Me, Ph 3443%
R1 = Me; R2 = Me, Ph R = Me0 or RR = -0CH20-42-67%
567
10. Enaminones as synthones
A similar intramolecular nucleophilic aromatic substitution has been used for the synthesis of pyrrolo[1,2-alindoles in astonishing high yield from E-enaminonitriles (equation 108)160.
-
1 . Nan, DMP 2. CuBr, 1 h, 80PC
Me0
Me (108)
Me0
Cyclization is even successful with enaminoesters of Z c o n f i g ~ r a t i o n (equation '~~ 109).
According to this method p-carbolines are accessible in good yield (60-67%), starting from heterocyclic N-(0-br~maryl)enaminones~. Acylation of a side chain of enaminones is essential for some heterocyclic synthesis although the enaminone moiety is not involved directly in the reaction. The enaminone moiety is used as protecting group in Dane's ~ a l t ' ~ ' , 'which ~ ~ , is employed for synthesis of 3-amino-2-azetidinones according to a method by Bose and coworker^'^“ (equation 110).
3;
Me
N 'H I CH2COO-K+
CH2C12. 20°C, 12 h * 1 . ClCOOEt, NEt, 2. P ~ C H = N C H ~ P ~ 3. NEt3
M,
2;
0A
N I
H Ph
568
U. Kucklander
On activation of Dane's salt by an acyl halide to give a mixed anhydride, N-acylation is prevented by the enaminone moiety. The product of cyclocondensation can be hydrolysed, losing the enaminone group to yield a free aminoazetinone. Such p-lactam derivatives are of great interest due to the structural analogy to aminopenicillins and cephalosporins. The method of Bose and coworkers was used, for example, for synthesis of carbapenames and carbacephames (e.g. as in equation 11I), as potential antibiotics by condensation with cyclic i m i n e ~ ' ~Similar ~. azetidino benzodiazepines (cf equation 111) are accessible166by a similar approach.
R=
&
COOEt
j. Metal complexes. Another possibility of heterocyclization is by the use of Pd(OAc), and triphenylphosphine via metal complexes. Cyclic N-(2-bromary1)-enaminones are transformed in moderate yield to carbazole~'~'(equation 112).
NaHCO3, Pd(0Ac)dEYPh)j DMF, 120-130PC, 2&35 h
(112)
The use of enaminones without a halogen on the aromatic residue on the nitrogen seems to be more relevant to such a process. However, the yields are low and the method is expensive because 1-2 equivalents of Pd(OAc), are necessary16' (equation 113).
4-0x0-8-carbolines have been also synthesized in 21-31% yield by using arylpalladiurn complexes168. Ten years after the introduction of the method this palladiumcatalysed cyclization of cyclic and acyclic N-(2-iodopheny1)-substituted enaminones was
569
10. Enaminones as synthones
achieved in better yields (47-85%) by modification of the reaction conditions (Pd(OAc),/Et,N/DMF/120°C/sealed t ~ b e / 6 h ) ' ~ ~ . Another kind of enaminone arylation, making use of the nitrogen as the nucleophilic center, is the Pb(OAc),-promoted cyclization of P-(4-hydroxyaryl)enaminonesto indoles (equation 114). Although the reaction opens a new way to 6-hydroxyindoles, the yield is low and the reaction seems to be limited to N-aryl deri~atives"~.
dMe
HO
\
4 Me
Pb(OAc)d, CHCI3.- I O T
*
HO
&M~
(114)
0 Me
58% (crude) 16% (pure) A cyclic N-phenylenaminone could be cyclized with Pb(OAc), in acetic acid in good yield to a carbazole derivative"' (equation 115).
k. Anodic oxidation. Schafer and Eilenberg"' have shown that secondary N-phenylenaminones are electrochemically oxidized to yield carbazoles as the end-products. However, a 3,4-dimethoxy-substitutedaniline residue seems generally to be necessary for this anodic cyclization (equation 116). The same fact was demonstrated by electrochemical cyclization of N-arylalkylenaminones at the anode. Isoquinolines and benzazepines were obtained in acceptable yields"2 (equation 117).
570
" ' O \ n N & Me0 HI
U. Kucklander
-
0.1 graphite M HC1041MeOH anode 10°C
~~~n Me0
72% I
3. Reaction with nucleophiles
a. Aromatic amines, indoles and phenols. The electrophilic carbonyl group of enaminone derivatives often serves for cyclization with nucleophilic aromatic positions. One example is Combe's synthesis. The condensation of 1,3-diketones with primary aromatic amines gives anils, which undergo cyclodehydration with sulphuric acid to yield 2,4-substituted q~inolines"~.These anils are enaminones and are often used as starting material for the cyclization. They can be synthesized by other ways, too. The method of Combe, using polyphosphoric acid in the cyclization, was applied, e.g., for the synthesis of dimethoxy-quinolines in high yield'74 (equation 118). Recently, it was
10. Enaminones as synthones
571
shown that enaminones derived formally from unsymmetrical 1,3-diketones can rearrange under the cyclization conditions giving mixtures or products of regioselective rea~tion"~ (equation 119). The Combe synthesis was applied for the synthesis of pyrrolo[3,2-g]- and pyrrolo[2,3g]quinolines176 (equation 120). Even during the synthesis of an enaminone from a OMe
OMe Me
Me
N
Me
OMe H R=H,Me
R1 = R3 = H, R2 = C8H17 R' = Br, R2 = C6H13. R3 = H R' = H, R Z = ~ h ~, 3 = ~ R l = H, R2 = Ph, R3 = OMe
OMe 85-90%
55% 39% 1 73% 77%
R ' = R ~ = R ~ = 21% H
572
U. Kucklander
1,3-diketone and an aromatic amine in toluene, production of 2,4,6-trimethyl-3-(4hydroxypheny1)quinoline in a 17% yield was observed17". Similar to the Combe synthesis, primary aromatic mines condense with alkyl acetoacetates at lower temperatures to give p-anilinocrotonates, which can be used as precursors for cyclization to 4-hydroxyq~inolines~~' by action of hot sulphuric acid or hydrochloric acid in a Conrad-Limpach synthesis. Newer examples of this synthesis use high boiling s ~ l v e n t s " ~ or PPA'79 for performing the cyclocondensation (equation 121). Similarly, acid catalysed condensation of a tertiary enaminoester affords a 4 - q ~ i n o l o n e '(equation ~~ 122). Recently, a secondary 2-arylaminomaleic acid derivative was cyclized under similar conditions to methyl 4-oxo-2-quinolinecarboxylate181 (equation 123).
PPA
120°C, I h
COOMe NO2
H
N-Arylenaminoester with an o-amino group can be cyclized to the benzodiazepine ring system, as has been shown with a b i s e n a m i n ~ n e '(equation ~~ 124). However, the structure of the deep red product seems to be unclear since no 'H NMR spectrum was given. Similarly, simple 3-(2-aminoani1ino)-2-cyclohexenones undergo intramolecular attack of the primary amino group at the a-carbon of the enone and rearrangement under severe conditions yield substituted ben~imidazoles'"~(equation 125). 3-(2-aminocarbonylanilino)-2-cyclohexenonesreact in a similar way except for ring opening of the carbocyclic enaminone ring to yield quinazoline derivative^"^ (equation 126). A very fruitful development in the chemistry of enaminones is the use of the nucleophilic a-position for intramolecular reaction with an electrophilic indole-2-
10. Enaminones as synthones
COOEt
I
I
AcOH. 90°C, 30 min
TsOH A, 250-270°C, 20-30 min
I
H
Me
position. In this way the Michael addition simply yields P-carboline derivatives (equation 127). The new reaction was applied to a cyclic enaminoester leading to spirocyclic ~ a r b o l i n e s ' ~(equation ~ 128). The corresponding enaminones gave higher yields (51-82%).
574
U. Kucklander
An intermolecular attack of a phenolic oxygen in a similar Michael addition at the enaminone a-carbon is used for synthesis of 4 H - c h r o m e n e ~ '(equation ~~ 129).
~ 1 . =~ H,2
OMe; R = Me, Ph
b. Hydrazine and hydroxylamine. Heterocyclic enaminones with E configuration react with hydroxylamine and hydrazine according to Anand and coworkersls7 to give the corresponding 1,5-disubstituted 3-(o)-alkylaminoalkyltpyrazoles and 3-(o-alkylaminoalky1)-5-substituted isoxazoles (equation 130).
I
RZNHNH~
"H2)nNHR Ph
I R2 n = 3,4,5 R~=H,P~ 5690% R = Me, n-Bu, PHCh2
n = 3,4,5 R = Me, CH2Ph 4690%
575
10. Enaminones as synthones
Fused heterocyclic tertiary enaminones were later reported to similarly give the corresponding isoxazoles and pyra~oles"~(equation 131). The products of the Anand reaction would be the result of nucleophilic attack at the a-carbon of the enaminone followed by spirocyclization and ring opening. His observations are in clear contrast to the results of Dannhardt and coworkers who have recentlylg9 used the closely related
secondary pyrrolidine enaminones with Z configuration. They reported that, with hydroxylamine, transformation to 5-(3-aminopropyl)isoxazoleswas achieved. The corresponding spiro intermediates have been isolated and characterized. The reaction in this case starts by nucleophilic attack at the carbonyl carbon and leads to regioisomers (equation 132). According to Dannhardt and coworkers the same reaction is observed with hydrazine to give 5-(w-aminopropyl)pyra~oles'~~ (equation 132). Recently, it was shown that the reaction proceeds in a highly regioselective way via a 1,2-addition of hydroxylamine to NH- and N-methyl pyrrolidine enaminones,
3
NH20H, Ph = 6, 12 MeOH h, 1.t.
%
N H
.'
-
R3w RI
I 0-N H
R1
0
NH20H, MeOH, 5 h, A
H
R1 = Ph; R2 = H, Ph; R3 = H, Me 69-78%
R1 = Me, Ph, 3- or CPyridinyl, PhCH; R2=H,aryl; R3=H,Me 604.5%
576
U. Kucklander
whereas N-acetyl derivatives react via 1.4-addition. Thus substituted 5- or 3-aminopropylisoxazoles are yieldedigi (equation 133).
c. Hydride and hydrogen. For older literature on these reactions, Greenhill's review1 should be consulted. Enaminones can be reduced selectively at carbonyl with borohydride, if the nitrogen is first acylated. Subsequent hydrolysis and elimination of water produces 3-hexen-2-one (equation 134) or 3-hepten-2-one or 3,l 1-tetradecadien-2,13-dioneig2.
60-76% R = Me, Ph, OMe
The method of treating protonated tertiary enaminones with NaBH, in isopropan01 is also used to produce a,Sunsaturated ketonesig3(equation 135).
10. Enaminones as synthones
R1 = Ph, CHMe2 R2 = n-PC,isobutyl, neopentyl R3 = Et; R j = -(CH2)zO(CH2)2-
6&80%
Reduction by NaBH,/FeCl, leads to y-aminoalcohols, which after oxidation and desamination yield enones, toolg5 (equation 136). HO H 1. CrOs, acetone
R3,
(136)
2. HzsO,
N
I
R3-N
I H R3 45-100%
R2
R'
R3 R ' , R ~= Me, Ph, H R3 = Me R3R3= -(CH2)r. -(CH2)5-, -(CH2)20(CH2)~-
R1 = Ph, R2 = Me 90%
NaBH,CN has been used for similar reduction of ethyl 2,4-dioxoalkanoates via Michael addition of a hydride to give y-ox~acrylates'~~. An unexpected ring expansion during catalytic hydrogenation of a cotarnine derivative involving an enaminone structure to give benzazepine is reported196 (equation 137). Sodium amalgam reduction of the same molecule simply attacks the carbonyl to give a secondary alcohol.
1
AcOH, HJRaney Ni or Pt02
578
U. Kucklander
d. CH-acidic compoundr. Primary enaminoesters react with CH-acidic pyrazolones or isoxazolones via Michael addition and elimination to give suitable precursors for heter~cycles'~'(equation 138).
AcOH
0
I
I
Ph R = Me, Ph
Ph
COOEt
I
Ph
> 50% Intramolecular attack of the enamino carbonyl is possible too. Ethyl 3-hydroxypyrrolecarboxylate and 3-hydroxyindole-2-carboxylate derivatives can be synthesized by Dieckmann condensation of an enamino ester derived from glycine ester and a /I-ketoester. Transformation to the 2-pyrrolin-4-011 system is easy19' (equation 139). COOEt
G
NCHzCOOEt I
3.5 h. A NaOEt, EtOH
Ho J J ' (
COOEt
I
H
70%
I
6 N HCI
4. Reaction with radicals
Cyclic enaminones react with diacyl peroxides to yield products of monoacyloxylation, which subsequently give cycl~hexadienones'~~ (equation 140).
10. Enaminones as synthones
I
R R1= c-Hex, R2= OEt 17% RZ= c-Hex, R2= Ph 67% Simple enaminones can be attacked by dibenzoyl peroxide in the /%position to give a-benzoyloxy derivatives which, on reflux in acetic acid, undergo ring closure to oxazoles in good yieldszo0(equation 140a).
R = Me, OEt
R 82-84% overall yield
Acetamides of cyclic enaminones cyclized upon treatment with tributylstannane and AIBN to give spirocyclic compounds201(equation 141).
AIBN, BulSnH
&r,Ac
Ph-Se
/
.&A
-
&
580
U. Kucklander
5. Cycloaddition Huebner and coworkersZoZhad shown in an early work the utility of enaminones as synthons in cycloadditions. Ethyl anilinocrotonate as a secondary enaminone and dimethyl acetylenedicarboxylate undergo cycloaddition to give cyclobutene, the cleavage of which leads to enaminoester with a prolonged chain by insertion of two carbons (equation 142). Similarly a primary enaminone reacts to yield a pyrroline derivative after heating in water (equation 143). By the same principle a tertiary enaminone and dimethyl acetylenedicarboxylate in a brilliant reaction are cyclocondensed to give an aromatic compound (equation 144).
Ph good yield
Me MeOOC Me
COOMe
Me00CCSCCOOMe
THF
Me00CC32COOMe A, 15 min
MeOOC MeOOC good yield
10. Enaminones as synthones
581
In a recent publication, amidine derivatives of a cyclic enaminone are used as the heterodiene component in a Diels-Alder reaction with diethyl maleate to yield 5q u i n o l o n e ~(equation ~~~ 145).
R = H, Me, Ph
Me
6. Photochemistry
In some cases an intramolecular aryla60n (Section A.l.i, f, equations 85 and 107) is problematic. Cyclic N-(2-bromophenylethylenaminones instead of benzazepines with i i ~ ~yield t , indolines. ~ h o t o l ~ sseems i s to be a good alternative method. ~ b h o t o l ~ t i c reaction of the same reagents leads to the desired benzazepines in high yieldz0'"' (equation 146). Carbazoles and phenanthridines can also be obtained by photocyclization of brominated N-phenyl, N-benzyl derivatives of cyclic enaminones in yields similar to those in the base promoted cyclization (see equations 84, 106 and 107).
More interesting for the synthesis of carbazoles is the photochemical reaction of non-halogenated N-arylenaminones which stereospecifically leads to carbazoles in high yieldzo8(equation 147). The enaminone P-position may be alkylated as wellzog.
R = H, Me, CH2CH=CH2 R 1= Me, CHzPh
85-1008
N-Vinylenaminones are photochemically transformed to 3-acylpyrroles or indolones (equation 148). However, acyclic enaminones give low yield and cyclic enaminones yield mixtures of indoline and indole derivative^^'^.
U. Kucklander
H
H
Z&3 1% R' = H, Me; R2 = COOR; R3 = H, Me; R4 = OEt, Me 7. Aromatization . Aromatization of the enaminone moiety may sometimes be of interest as a method to yield an aromatic substitution pattern which i s n o t accessible starting with the aromatic compound. An example is the reaction of simple acyclic tertiary enaminones derived from acetylacetone which on treatment with gaseous HCl, are condensed to aniline derivatives"" (equation 149).
R = Me, Et, -CH2Similarly alkyl p-aminocrotonates lead to phenolic A method was also developed for the synthesis of phenols. Condensation of different cyclic and acyclic tertiary enaminones and 3-oxoglutarate affords substituted phenols, including condensed systemsz"c (equation 150).
R1Y+2 H
0
+ M~OOC 0 R' = H, Me, Ph, PhCH=CH RZ= H, Me RIRZ= -(CH2)4-
H AcOH. KF Dioxane, A, 12 h
-
(150) MeOOC *R
COOMe OH 3143%
A sequence of bromination4ehydrobromination of a cyclic bisenaminoester yielded the a r o m a t i c c o m p o ~ n d(equation ~~~ 151). On heating aminocyclohexenones with mercury(I1) acetate in acetonitrile, the corresponding m-aminophenols were formed. The yields depend on the N-substituentzl" (equation 152).
583
10. Enaminones as synthones EtOOC
(151)
Br2. 2 1"C
RHN
COOEt
RHN
R = Me, Et, i-Pr, allyl, n-(CH2)2-6CH3
54-90%
Hg(OAc)z. MeCN
(152)
NR 10-73% R l = H,Me; RZ = H, Me; R = H, n-Pr, PhCH2, MeOPh, -(CH2)4When a heterocyclic N-acylated enaminone was treated with PC&, the 6-chloroindoline was produced214 (equation 153).
I
OMe 72% Tertiary enaminones bearing a hydrazino-type substituent undergo side-chain cyclization and then aromatization (equation 154). Similarly, secondary enaminones yield phenolic benzimidazoles in low yield2" (equation 155). In a variant of the Hantzsch synthesis N-substituted enaminones gave aminocyclohexenone derivatives, which were convertible with MnO, to the corresponding substituted diphenyls (see Section I1.A.l.e and see equation 63). For an aromatic product resulting from cycloaddition, see Section II.A.4 (equation 144).
U.Kucklander
B ol-UnsubstitutedPKetoenamlnes (ol-AminomethyleneCarbonyl Compounds) 7. Introduction
Reaction of a-aminomethylene ketones with biselectrophiles is usually expected to occur at the /3-position and at the nitrogen of the enaminone under ring closure. However, enaminone chemistry, due to the multifunctional structure, is often characterized by surprising reactions such as rearrangements. Attack of nucleophiles at the a-position of the enaminone predominates, leading to Michael addition which mostly results in substituted, mainly cyclic end-products. Also observed are subsequent amine elimination and reactions at the carbonyl. Some initial reactions of nucleophilic reagents at the enaminone carbonyl carbon are known. Enaminones are often better starting materials for several reactions than the corresponding dicarbonyls. As a result, a-aminomethylene ketones act as 1,3-biselectrophiles. Due to their combined electrophilic and nucleophilic properties, enaminones act as 1,3bisnucleophiles as well. The assumed first step in the following reactions is the one used for classification of the reactions. In addition, enaminones are used as heterodienes in 4 + 2-cycloaddition mostly with electron-deficient dienophiles. 2. Reaction with electrophiles a. Quinones and quinone imines. Secondary and primary unsubstituted j-ketoenamines
are known to initially react in the /3-position with p-benzoquinone in the so-called Nenitzescu reaction giving indole-3-ones (see Section ILA.2.g). In 1979 Kozerski216 showed, however, that open-chain enaminones with a methyl group in the /3-position do not give indoles. It was reported that after refluxing the enaminone and pbenzoquinone in benzene, benzodioxepines were formed, and this was confirmed later by more examplesZl7.The benzodioxepine formation is the first example of enaminone reaction with an electrophilic quinone at the carbonyl oxygen of the enaminone. So far, only hard electrophiles such as a proton are known to attack the oxygen. However, in 1987 we showedz1' that the products obtained by Kozerski had indeed the 2-aminobenzofuran structure. Consequently, the reaction follows the normal course of attack at the j-position of the enaminone (equation 156). In this case subsequent cyclization, acyl migration and, at last, oxidation lead to the 2-aminobenzofuran derivative as the end product. Later. Kozerski and coworkers s h o ~ e that d ~in ~EtOH ~ ~the~same ~ ~enaminones react with 1,4-benzoquinone to give 1:2 adducts of the 2-aminobenzofuran type (equation 156). Similarly, the reaction of dichloroquinones and aminomethylenecyclohexanones does not lead to indoles but to dibenzofurans. However. this results from vrior oxidation of the enaminone by the dichloroquinone and subsequent reaction bf the postulated dienamine with the quinone derivative. Further oxidation of the end product can afford the fully aromatized dibenzofuranszzl (equation 157).
10. Enaminones as synthones
R' = Et, R2 = M e 50%
HO
N-C
I R2 R' = Et, i - h R2 = Et, Me 65%
\
R'
'Goqo
AcOH. c.t.*
+
R
'
RZ Rl=R3=C1; R z = H R4 = 4-MeOCgHq 10% R4 = 4-FC6Hq 13% R' = RZ = C1; R3 = H R4 = 4-MeC& 23% R4 = 4-MeOC6H4 35%
NHR4
w y
0
RZ NHR4 R1 = R3 = C1; R2 = H; R4 = 4-MeOCgb
1 '
1. DPQ, CH2C12,AcOH 2.50% AcOH
(157)
OH CHO
586
U. Kucklander
We have studied the reaction of similar cyclic P-substituted enaminones which yielded indolones when the reaction was carried out in acetic acid and the quinones had lower oxidation potential, thus preventing prior oxidation of the enaminones. Secondary aminomethylene derivatives of cyclopentanone, cyclohexanone and cycloheptanone reacted with the quinones to presumably form intermediate spiro compounds, as a consequence of normal enaminone chemistry. However, this was unexpectedly followed by rearrangement with ring expansion to indolones (equation 158). In this way carbazoles, cycloheptindoles and cyclooctindoles can be obtained by a simple entry to this class of indoles, although partially in low yieldsZz2-2z4.Due to their bifunctionality the produced indol-2-ones are versatile synthons for fused heterocycles (e.g. triazepino- and pyrazino-carbazoles) which become easily accessiblezz5~z26. O
n
o
+p:
(158)
RZ R NH I R
n = 1 34-53%222 = 2 5-24%222. 223
'
R' = Me, Ph, CH2Ph, CHzCN, CHzC1 R2 = H, Me
n = 3 3%224 R' = Me, PhCH2,Ph; R2 = H, Me
The reaction can be extended to benzo-condensed aminomethylenecycloh e x a n ~ n e ~and ~ ' . clopen ~ ~ ~ en tan one^^^ derivatives. N-arylcycloheptindolones, are accessible in a good yield. Enaminones in the indanone series react to give benzocarbazoles, which are readily oxidized in one step to benzocarbazolquinones (equation 159), the derivatives of which bear high cytostatic activityzz9.
R = Me, p-Tol, CHzPh
67-70s
10. Enaminones as synthones
587
The use of a quinone monoimine resulted in the isolation of a spirocyclic compound (equation 160), thus providing evidence for the postulated course of the reaction with the q u i n ~ n e ~ The ~ ' ~reaction ~ ~ ~ . is initiated by alkylation of the /I-position of the enaminone.
1
AcOH, r.t
Aminomethylene pyrrolidones are converted in a similar manner to /?-carbolines by reaction with a substituted phenylhydrazine (equation 161). The reaction involves hydrazinolysis of the enaminone followed by the Fischer reaction of the intermediate spiro-compounds230.
R = Me, n-Bu R1= H, Me, OMe R2 = H, Ph, CH2Ph
Me2N
6. Ketones. According to Breitmaier and BayerZ3' open-chain primary aminomethylenecarbonyl compounds can be condensed with cycloalkanones to give fused pyridines up to cyclooctanopyridine. In this method, which is widely used for the synthesis of pyridines (see below), the enaminone nitrogen is incorporated into the heterocyclus (equation 162). Aminoacrolein itself reacts as a primary enaminone with cyclic ketones under forced conditions to give higher polymethylene p y r i d i n e ~(equation ~~~ 163). Later, Thummel and coworker^^^^.^^^ extended the Friedlander cyclocondensation by using cyclic primary aminomethyleneketones instead of aminoacrolein. Thus with cyclic ketones bisannelated pyridines are obtained. However, instead of the expected merafused pyridines, the rearranged para-fused pyridines were obtained, though in low yield
U. Kucklander
(equation 164). The rearrangement may be explained by transamination between the ketone and enaminone and subsequent cyclization according to Curran'". However, isomerization or condensation of the enaminone with the ammonium catalyst to give another enaminone precursor is more likely. Apparently the linearly fused isomers are thermodynamically favoured.
Secondary and tertiary enaminones react with formaldehyde and secondary amines as well as with methylene iminium chloride in a Mannich-type reaction with reaction at the P-position (equation 165). The use of primary amines leads to pyrirnidine~.'~~
10. Enaminones as synthones
46-7 1%
R' = H, Me, Ph, PhCH2; R = Me, -(CHz)46c. /3-Dicarbonyl compounds and derivatives. Breitmaier and coworkers have extended this method to cyclocondensation of acyclic 1,3-dicarbonyls with open-chain and cyclic aminomethylene ketones which, after rearrangement, lead to cycloalkeno[b]pyridines (equation 166). In the same manner dihydronaphthopyridines are synthesizedz3' (equation 167).
(166)
n = 1-4.8
0 R = Me, OEt
5249%
Cyclocondensation of 3-aminoacroleins and 1,3-dicarbonyl compounds yield the corresponding substituted simple pyridines without rearrangement in satisfactory yield238.Z39(equation 168).
R1 = H, Me R2 = Me, OEt R3 = Me, Et, PI
590
U. Kucklander
Dihydroquinoline-5-ones are obtained by cyclocondensation of 3-aminoacroleins with cyclohexan-1,3-diones or 3-ethoxyacrylaldehydes and aminocyclohexenone. The coiresponding ketone (R' = Me) behaves analogously235(equation 169). The unexpected pattern of the quinoline substitution therefore can be reasonably ascribed to intermediate transamination between the 1,3-dicarbonyl components.
The same reaction was later carried out by Greenhill and coworkers240 using two equivalents of a cyclohexanedione derivative and 2-alkylaminoacroleins with the result of isolating unexpected acridinedione derivatives (equation 170). The reaction is explained by loss of the formyl group of aminoacrolein as a formic acid and is reminiscent of the Hantzsch synthesis of 19-dihydropyridines.
Under acidic conditions secondary a,/?-unsubstituted enaminones undergo self-condensation to give 3-acylpyridinium salts in high yieldz4' (equation 171). The /?protonated enaminone acts with the intact enaminone in the same manner as the CH-acidic 1,3-dicarbonyls.
HCI gas or CF3COOH MeCN. Et@
NH I
Me R = Me, Et, Ph
-
R
dR N I Me C1- or CF3COO> 90%
591
10. Enaminones as synthones
A similar cyclocondensation is reported starting from corresponding primary enaminones, which gave on heating 3 - a c y l p y r i d i n e ~(equation ~~~ 172).
d. Heterocumulenes. The use of diphenylcarbodiimide as an electrophilic reagent in the reaction with aminoacroleins results in the formation of pyrimidine imines by primary attack at the enaminone nitrogen243(equation 173).
I
R = Me, Et, Pr
Ph 3347%
With isocyanates and isothiocyanates, attack at the nitrogen is again observed. Phenyl isocyanate reacted with 2-alkyl-3-aminoacroleins to afford the N-carbamoyl derivatives which could not be cyclized to p y r i m i d i n o n e ~(equation ~~~ 174).
"p
Ph-N=C=OMeCN, A, 0.5 h
NH2 R = Me, Et, Pr, Bu, Pen
NHC-NHPh II
0 63-75%
In the case of phenyl isothiocyanate, however, the reaction directly leads to cyclic products; the corresponding pyrimidinethiones are obtained in satisfactory yields. Benzoyl isothiocyanate immediately gives mercaptopyrimidines by hydrolysis, caused by formation of water during the c y ~ l i z a t i o n(equation ~~~ 175).
R (175)
MeCN, A. 5 h
R = Me, Et, Ph
N
N
R' = ~h 30-5 1%
R1 = PhCO 4347%
592
U. Kucklander
e. Bromine. Acyclic enaminones are brominated at the reactive P-positionz (equation 176).
R = H, Me, OMe
An interesting feature is the ring contraction of cyclic enaminones. On bromination at the p-position with subsequent hydrolysis of the iminium ion formed, cyclization of the acyclic intermediate to the resulting pyrrolidine- or piperidine-2-carboxaldehydes proceeds in excellent yieldz4' (equation 177). The enaminone a-carbon is formally functionalized in this way to ag aldehyde group via reduction of the size of the ring.
3. Reaction with nucleophiles
a. CH-acidic compounds. An alicyclic ketone can be also used for construction of a pyridine ring, if a tertiary enaminone reacts with the nucleophilic carbanion derived from a ketone and ammonium acetate is used as the nitrogen source. As shown in equation 178 for the synthesis of terpyridine, an interesting tridentate ligand, the reaction is initiated by 1,4-addition of a carbanion to the enaminoneZd6.
Me,
N
,Me
1
r-BuOK, THF NH40Ac. ZO'C, 14 h
593
10. Enaminones as synthones
In special cases the reaction of the anions of carbon acids at the enaminone carbonyl group in a 1,2-addition can be forced by acetalization. For example, a tertiary aminomethylenelactone can thus be attacked by the anion derived from cyanoacetamide. Substitution of the tertiary amine in a second step yields tetrahydrofuropyridone in good yield. Reaction of thiourea or guanidine leads to fused pyrimidines"' (equation 179).
X=SH 43% X = NHCN 30%
I
CN
70%
Junek and coworkers reacted tertiary aminomethylene derivatives of cycloalkanones with malonodinitrile to yield cycloalkenopyridone derivative^^^^^^^^ (equation 180).The reaction of acyclic enaminones and cyanoacetamide was also studied249.
NCCH~CONH~, Pip, E~OH A. 0.54 h
(180) H
good yield
594
U. Kucklander
b. Activated aromatic comaounds.~3-Aminoacrolein and its 2-alkvl derivatives are useful synthons for formation of vinylogue aromatic and heteroaromatic aldehydes, when submitted to Vilsmeyer conditions. In this way 3-(2-pyrroly1)acroleins and 3. .. @-dimethylaminophenyl)ac~oleinsare synthesized in fairly good yik~hwhen dimethylaminoacroleins react as vinylogue formamide in the Vilsmeyer reactionz5' (equation 181).
MezN 2. 2 h, 60'C
I. r n 1 3
CHCI~
N-Me
I
Me
PhNMe2
R1 = H 42% R1=Me 61%
> / '
A
qJ R2
(181)
I
CHO
R2
RL,R2= H, Me 49-5 1% Intramolecular reaction with nucleophilic groups can also lead to heterocycles. For example, good yields of 3-acylbenzofurans result from cyclization caused by intramolecular substitution of the tertiary amino group by a phenol formed by cleavage of a phenol ether by boron tribromidez5' (equation 182). o-Hydroxybenzyl alcohols were used to obtain 4H-chromenes by their reaction with 4-morpholino-3-buten-2-one in acetic acid-acetic anhydride18'.
A similar reaction is observed25z when tertiary aminomethylene derivatives of o-hydroxyacetophenones are treated with acid. Chromones are formed in high yields according to a method of Fohli~ch"~(equation 183). c. Aliphatic and aromatic amines. Treatment of CH-acidic tertiary enaminones substituted in the /3-position with dimethylformamide dimethyl acetal leads to ketones with two aminomethylene moieties. The intermediates undergo ring closure to 4-pyridones by treatment with methylamine, with a loss of both tertiary amino g r o ~ ~ s ~ ~ ~ , ~ (equation 184).
10. Enaminones as synthones
R1 = H, Pip R2 = H, Me
RI,R2= H 98% R l = pip, R2 = H 83%
1. MeOH, A
ph+~
N-Et
(MeO)2CHNMq
I
Et R = 4-N02C&, CN, COOR1, 3-CF3, PhC&
-
phfi~ I .hph N-Et
I Et
N-Me I Me
2. MeNH2, A
N
(184)
I
Me overall yield 3 M 5 % Intramolecular reaction involving attack of an electrophilic ortho-position of aryl groups on the enaminone carbonyl is shown by the ring closure of anilinomethylenecyclohexanones to tetrahydro phenanthridines (equation 185). Including rearrangement, the reaction leads to acridines (equation 185). The course of the reaction depends on the conditions255b.
I
PhNH3+CIor lactic acid
596
U. Kucklander
d. Nitroketene aminals. Substituted nitroketene aminals are used as nucleophiles when reacting with enaminones which serve as 1,3-biselectrophiles to yield 2-amino-3-nitropyridines, suitable precursors for 3-deazapteridines, in good yield256.257(equation 186). The first step appears to be a 1,Caddition to the enaminone.
EtOH, AcOH
R
'
NRZ2
(186) R
NRZ2
R =Me, CHzPh, CHzCOOEt R1 = Me, Ph, H RZ= H, Me e. Guanidine and amidines. Simple tertiary aminomethyleneketones on treatment with guanidine carbonate lose the amine moiety and give pyrimidineszs8 (equation 187). In a similar way pyrimidine-4-aldehydes are accessible in good yield259(equation 188).
(H2N)f2=NH NaOEt. EtOH
NMe2
R = CH(OEt),; R' = H: 74% R = CHO: R1 = H: 47%
61
SMe
R = CH(OEt)2 63% 12% R = CHO Even heterocyclic fused aminomethyleneketones can be similarly cyclocondensed with amidines or guanidine to give fused pyrimidines, such as interesting d i a z a c a n n a b i n ~ l s ~ ~ ~ (equation 189). -
-
~
10. Enaminones as synthones
n
Me
\\
C-RZ
EtONa, H2NF/a H , A, 3 h*
\
R1 R=H,OH R1 =H, CsHll
1
HN
Me
MMe (189)
R1
O
Me
R2 = NH2, H, Me, Ph 70-95%
Acting as 1,3-biselectrophile in a combined substitution and condensation, different tertiary aminopropenones give the corresponding pyridopyrimidinesZ6' after treatment with aminouracil, diaminohydroxypyrimidine or aminothiouracil in acetic acid (equation 150). This is similar to the reaction of aminoacroleins with 1,3-dicarbonyls to give py ridines.
I
H 45100%
R1 = substituted Ph; X = 0,NH, S
A cyclization of enaminones to pyrimidopyrimidine~~~~ is shown in equation 191. EtOOC(CH2),
Y
COOEt I
COOEt 250'C
H
1: Hydroxylamine and hydrazines. Tertiary enaminones react as typical 1,3-biselectrophiles with hydroxylamine as a nucleophile to give high yields of 5-alkylisoxazoles after substitution and cyclization. The obtained isoxazoles are a source of 8-ketonitriles after cleavage of the isoxazole ring by EtONa263(equation 192).
EtONa
MeOH. 1.5 h. A
R = Me 59% R = Pr 89%
0 11 R-C-CH2CN
92% 91%
(192)
Substitution and cyclization of the tertiary amino group of aminomethyleneketones by hydrazine leads to 3-formylpyrazole in good yield264 (equation 193). In the same way 2-pyrazolylpyridine is accessible in high yield265 (equation 194). Even specially substituted 3-arylpyrazoles and Carylpyrimidines are thus accessible in good yieldzsz (equation 195).
R = CH(OEt)2 83% R = CHO 71%
Ph-C,
P
(
EtOH
599
10. Enaminones as synthones
Reaction of enaminones with phenylhydrazines gives a Fischer cyclization to indoles (see equation 161). Reaction of aminomethylene chroma none^^^^ has brought some insight into the regioselectivity of the cyclocondensation with hydroxylamine and substituted hydrazines. Treatment of pyrrolidinomethylene chromanone with hydroxylamine afforded an aldoxime indicating a 1,4-addition-eliminationprocess with the nitrogen of the hydro~ y l a m i n ewhich ~ ~ is the first step of the isoxazole ring synthesis as shown in equation 196 and explaining the exclusion of reaction leading to the isomeric isoxazole.
RNHNH2
82%
R,
'
N-N
N-N'
86%
R
0
The reaction of phenylhydrazine leads nearly quantitatively to l-phenylbenzopyranopyrazole whereas methylhydrazine yields a 3: 1 mixture of 1- and 2-methylbenzopyranopyrazole, reflecting the somewhat higher nucleophilic character of N1 of methylhydrazine (equation 196). Both reactions are in accordance with a 1,Caddition of nitrogen to the enaminone prior to the 1J-addition. g. Hydride. Acyclic tertiary aminomethyleneketones are reduced by NaBHJFeCl, to the corresponding y-aminoalcoholsz6' (equation 197). According to Martin and coworkers, tertiary aminomethyleneketones can be reduced by LiAIH, to b-aminoketones in good yield via a Michael addition of hydride"'. The reduction stops at the ketone stage due to formation of the enolate salt. The free aminoketone is further reducible in an extra step to the aminoalcohol (equation 198).
U. Kucklander
OH
I
NaBH4/FeC13
0
MeOH. 60% 16 h
a
PhC HCHZCHZN
(197)
4. Cycloaddition
Due to the amino group, enaminones are more electron-rich than 1-oxabutadiene and are well reactive in cycloadditions with electrophilic dienophiles as sulphene, ketene and electron-deficient alkenes. Theoretical interpretation and a brief review of literature concerning the chemistry of sulphene addition to open-chain, cyclic or heterocyclic enaminones have been given269. Schenone and coworkers have shown in a large number of papers that tertiary aminomethyleneketones react as heterodienes, e.g. with sulphene generated from aliphatic sulphonyl chlorides and triethylamine as a heterodienophile, to yield B-aminosultons in a Diels-Alder reaction. An early simple example is reported by Opitz270(equation 199).
+
The 4 2-cycloaddition of enaminones could be extended to many tertiary alicyclic derivatives and by using benzylsulphonyl chloridesz7' as sulphene precursors. The are a mixture of cis- and resulting 4-amino-3-phenyl-1,2-benzoxathiin-2.2-dioxides trans-isomers (equation 200).
10. Enaminones as synthones
Addition of ketene to diethyl aminomethylenecyclohexanone apparently gave unstable cycloadducts, which after elimination of the amine yielded tetrahydro~oumarin'~~ (equation 201).
The same reaction has been also carried out with heterocyclic aminomethyleneketone derivatives of, e.g., 4 - ~ ~ r a n o n echromanones s~~~, and derivatives and 4-piperidone~'~~ (equation 202). A useful dienophile is dichloroketene, produced from dichloroacetyl chloride and triethylamine. It enables the enaminone oxygen to be incorporated into the functional group of a lactone instead of a sultone (equation 202).
HIR' MeSQCl Nm3
*
X X = 0,NCHzPh Cl2C=C=0
1
xQ&o
X = O 79-80% R1 = R2 = Me, Et R'R2 = -(CHz)&5-,
0'
\\
0
-(CH2)20(CH2)2-
R ~ = R Z = P ~
R1 = Me, RZ= Ph 37-82% The use of fused heterocyclic enaminones in the reaction with dichloroketene leads to unstable furobenzopyranones which are dehydrochlorinated and aromatized to give 4-amino-3-chloroangelicinicacid and its 7-thioisoster in high (equation 203). The products exhibit interesting photobiological activity, similar to that of psoralenes. Another special example in the use of enaminones of the aminomethylene type as dienes in the Diels-Alder cycloaddition is the stereoselective reaction with several dienophiles to yield substituted c y c l o h e ~ e n e (equation s~~~ 204).
U. Kucklander
85%
1
1.
DBN
2. DDQ
+
HNP~
RL= H, CN, COOMe; R~ = CN, Ac, COOCH3, H
NHP~ 3143%
Ill. ~~DlKETOENAMlNES (2-AMINOALKYLIDENE-1,3-DICARBONYL COMPOUNDS) A. Introduction
Due to their two electron-withdrawing groups, P,B-diketoenamines are reactive towards nucleophilic reagents. Attack usually occurs at the a-carbon. With dinucleophiles, the substitution of the amino group is followed by ring closure to 5- or 6-membered heterocycles. However, due to the enaminedione structure, few successful reactions with electrophiles are known. Only if an electrophilic group is incorporated into the enaminone molecule is such intramolecular reaction observed. Enaminediones are also suitable heterodienes in 4 + 2-cycloaddition. Their electron-deficient character as heterodienes requires the use of electron-rich dienophiles. The result is a Diels-Alder reaction with inverse electron demand. 6. Reaction with Nucleophiles
I . Hydrazines
Open-chain cyclic and acyclic 1-methyl- or 1-phenyl-4-acyl-5-substitutedpyrazoles had been synthesized in high yields starting with fi,P-dicarb~nylenarnines~~~ (equation 205).
10. Enaminones as synthones
Cyclic enaminediones, which are easily accessible from cyclohexanedione and dimethylformamide dimethylacetal in nearly quantitative yield, gave indazolones when treated with hydrazine derivatives as din~cleophiles~~' (equation 206).
NMez
MeOH.RNHNH2
(206)
5 NNaOH, 90 min, A I
Enaminones derived from cyclopentanedione react similarly. However, an ene hydrazine intermediate is isolated and ring closure is achieved by applying forced conditions (equation 207).
C&Me.
p-TsOH. Toluene
1
15 h. A
By reaction of phenylhydrazine with enaminediones bearing an olefinic side-chain conjugated with the carbonyl, cyclization can be accomplished, depending on the solvent, to 3-vinylpyrazoles or to d i h y d r ~ p ~ r i d o n (equation e s ~ ~ ~ 208).
U. Kucklander
PhNHNH2 DME
R* 2 RI R3
I NHPh
2. Hydroxylamine
Reaction of open-chain and cyclic aminomethylenediones with hydroxylamine yields the correspondingly substituted 4-acylisoxazoles. Cyclopentanedione derivatives lead to simple non-cyclized product by substitution of the amine. The 3-unsubstituted isoxazoles easily isomerize to the corresponding 2-cyano-1,3-dionesza3(equation 209).
NH30HtCl-, MeOH 1 h.A
R = Me. i-Pr, t-Bu, Ph
R 27-94%
3. Guanidine and amidines
Dinucleophilic amidines and guanidines can be condensed with aminomethylenediones to give pyrimidines (equation 210). In the case of cyclic diketo derivatives quinazolinediones are obtainedza4. The aminomethylene component may be a part of a lactone as shown in the synthesis of functionalized pyrimidinesm5 (equation 211).
10. Enaminones as synthones
H~N'
28-100%
R = Me, i-Pr, t-Bu, Ph RR = -(CH2)r, -CH2C(CH3)2CH2R1= H, Me, Ph, NH2
- o$yNH2
0KoNMe2 (H~N)~c=~~H~HCO~
EtOH, Ba(OH)z, 15 h, A
(211)
0
0
Starting from 3-acetyl-2,6-dimethylpyroneand secondary amines, aminocyclohexenediones can be obtained, which are easily condensed with benzamidine or hydrazine derivatives to give in good yield benzoannelated pyrazoles or pyrimidines after oxidation of the tetrahydro products288(equation 212).
1
KOH, EtOH
I
KOH, EtOH
606
U. Kucklander
4. Aromatic amines, and indole and pyridine rings
Anilinomethylidene- and anilinoethylidene-cyclohexanediones can be cyclodehydrated to phenanthridones, which are useful precursors for 6-azasteroidal analogues, in high yield28',288(equation 213).
The enaminedione may be heterocyclic and its intramolecular condensation via Michael addition of an indole moiety is possible, as shown in a new, easy and simple route to the olivacine-type alkaloid ring system by cyclocondensing a substituted indolylethyl-aminomethylenepiperidine-2,-done followed by elimination of 'ethaneamine moietyT89(equation 214).
1
A@, AcOH (5:3), 48 h
0
A modification of the known Conrad-Limpach synthesis of quinolines, using anilinomethylenemalonates instead of B-anilinocrotonates, has long been k n ~ w n ~ ~ ~ ~ ' ~ ' . N-Aryl and N-heteroaryl derivatives of aminomethylene malonates are also very useful and fruitful synthons for formation of 4-aminoquinolines used as antimalarials and (equation 215), of the anticoccidial 6,7-dialkoxy-4-hydroxyquinoline-3-carboxylates of antibacterial nalidixic acid derivatives (equation 216). Each of these is an important group of pharmaceuticals, developed in the last twenty years. Because of its medicinal interest this route is widely used for synthesis of quinolines and pyridinofused heterocycles. The chemistry has been comprehensively reviewed in a recent monographz92. Hence, no further details are given here. For typical examples of 4-hydroxyquinoline synthesis see Riegel and coworkers293.
10. Enaminones as synthones
chloroquine
~t Nalidixic acid
A fused heterocyclic quinolone is similarly available by ring closure of an aminomethylene derivative with indoline structurezg4(equation 217). By reaction of anilinomethylene malonodinitriles under Friedel-Crafts conditions 4-aminoquinolines are available295.An example is given in equation 218.
608
U. Kucklander
In the same manner carbazolylaminomethylene malonates are cyclized to give fused 4-pyridoneszg6(equation 219). COOEt
COOEt
It is possible to cyclize N-anilinomethylene acetoacetic acid derivatives regioselectively to quinolones by intramolecular Friedel-Crafts acylation (equation 220), or to 3hydroxypyrroles (see equation 225) depending on reaction condition^^^'. On the other hand, the corresponding N-(2-pyridy1)aminomethylenediones gave pyridopyrimidines (equation 221).
Ethyl 3-(pyridy1amino)propenoates were treated with PPA to give hydrolysis and cyclization to pyrimidopyrimidines in good yield (equation 222), thus demonstrating that exchange of one ester group by a nitro group yields nitroheterocycles which can serve as precursors for the corresponding amino compounds after reductionz9'.
0 PPA
l2O6C,1.5 h
609
10. Enaminones as synthones 5. CH.acidic compounds
N-monosubstituted aminomethylene derivatives of 1,3-dicarbonyls are accessible from trialkyl orthoformates, aromatic amines and 1,3-diketones. They are useful synthons for formation of hexahvdroauinolinediones by treatment with KOH and m a l o n ~ d i n i t r i l e ~ ~ ~ . Depending on the substituents of the aniline derivative, replacement of the amine results from 1,4-addition~eliminationof malonodinitrile or alkyl cyanoacetate to the enaminedione and lead to q u i n o l ~ n e sThe ~ ~ ~yields . are not high but acceptable, since the starting materials are easily accessible (equation 223).
RL=Me, R2 = Ph 20%
R1 =Me, R2 = Ph* 27%
R'=H, R ~ = P ~ 70%
* A quinoline rather than an inoquinoline structure was later determined248. 6. Aqueous base
Aminomethylene derivatives of ketones and 1,3-dicarbonyls are used in order to incorporate a formyl group into CH-acidic heterocycles via initial reaction with ethyl orthoformate and aniline followed by hydrolytic cleavage, as is shown e.g. with barbituric acid301 (equation 224).
.Ao .AOH NHPh
NaOH. H20 *
H N 0~ N H
\
""K"" 0
* A quinoline rather than an isoquinoline structure was later determinedz4'.
610
U. Kucklander
C. Reaction with Electrophiles
Chloroacetyl enaminones cyclize under basic conditions (see equation 220) to 3hydroxypyrroles, thus demonstrating the nucleophilic character of the enaminedione nitrogen, which however can be used only for cyclization after its deprotonationZ9' (equation 225).
PNHP
CI
.oH,-.~c NaOAc, 70°C
NH
*
(225)
N
D. Reaction with Radicals
Radical reactions of enamines are the subject of another chapter in the present book. Acyloxylation of anilinomethylene dimedone to a-hydroxy derivatives of b-diketones is achieved by treating enaminediones with a diacyl peroxide. The aminomethylene group is lost in this process30z(equation 226).
E. Cycloaddition
Cycloaddition of enaminone carboxaldehyde (formylenaminone) with a vinyl ether leads to pyrans as hetero-Diels-Alder ad duct^^^'.^^^. The stereochemistry is dependent on the substituents of the N-acyl group and on the reaction temperature (equation 227). Photochemical cycloaddition of enaminones with olefines leads to 1,4-dihydronicotinic acids305(equation 228). With cycloalkenes, fused pyridines are available, too306.
10. Enaminones as synthones
0
0
II NH-C-R M
e
o
o
c
h
+
II
NH-C-R M e o o c h
OEt
'OEt
0
1 : 2 to 1 : 1.1 R = Me, t-Bu, Ph, COOMe, NHPh, 4-N02C6H4
yo - "W H
R1>
+
R2
OMe
2. I. CF3COOH. hv 20T
HN
I
R R = H, Me, t-Bu R1 = H, CN, COOMe R2 = H, Me, COOMe, Ph
N
(228)
I
R 82-90%
F. Pyrolysis
In some cases pyrolysis of N-alkyl-/?-enaminoesters yields pyridones in high yield307 (equation 228a).
G. Aromatlzation
Amin~c~clohexenones, easily accessible from 3-acetyl-2,6-dimethylpyroneand secondary amines, are converted in good yield to 2-amino-6-hydroxyacetophenone derivative~'~'(equation 229).
U.Kucklander
R
HO Me R1 = H, Ac
H+,* or KOH. ElOH
-
"e
Me
Me NR2
R~=H,R~=R~=M~ ~1 = H, R2 = ~3 = Et RL= R2 = H, R3 = CH2Ph RL= H, R2R3 = -(CH2)20(CH2)2R1 = H, RzR3 = -(CH2)6
41% 75% 73% 42% 65%
IV. a-KETOENAMINES (ENAMINONES FROM 1,BDICARBONYL COMPOUNDS) A. Introduction
Little is known so far about a-ketoenamines, probably because they are sometimes not directly accessible from the corresponding diketones. Nevertheless, they are useful synthones, especially for heterocyclic synthesis. Compared with j-ketoenamines, the chemical behaviour of the or-keto-derivatives is somewhat different. They react as enamines, as well as a,j-unsaturated ketones, which means that they act either as an electrophile or as a nucleophile in the P-position. For example, protonation usually occurs at the j-C atom with subsequent enolizati~n"~.Aminomethylation according to Mannich takes place in the j-position as The alkylation with alkyl halide, however, is reported to occur at nitrogen"'."'. In addition to electrophilic and nucleophilic chemistry, a-ketoenamines are useful synthons in photochemistry and electrocyclic reactions.
0. Reaction with Electrophiles
1. Acetals
In a typical enamine reaction, a-ketoenamines with suitable N-substitution are converted to indol-7-ones although in low yield312 (equation 230). Better methods starting from a-ketoenamines are known (equations 231 and 242). N,N-Dimethylformamide dimethyl acetal can be used to obtain N-benzyldihydroindole-7(6H)ones in good yield by reaction with a j-methyl derivative of a cyclic ketoenamine (equation 231). Apparently no other substitution in 1,2,3-position of indole is available by this method313.
10. Enaminones as synthones
2. Acyl chloride Dimethyl 2,4-dioxopentanedioate (as a monoenol) can be obtained by normal enamine B-acvlation of 2-aminopropenoic acid derivatives after hydrolysis of the resulting
2O'C
1
1 N HCI.EtzO
0
3. Quinone
The first step in the reaction of aminocycloalkenones with quinones is a normal Michael addition to yield hydroquinone adducts, as is known from the Nenitzescu reaction with P-ketoenamines. However, the consecutive cyclization is quite different, and the structure of the heterocycles formed depends on the substitution at the nitrogen and the size of the cycloalkane ring. N-alkyl-substituted ketoenamines in the aminocyclopentenone series react with pbenzoquinone to surprisingly yield benzocyclopentoxazepines by 'intramolecular oxidation', achieved by rearrangement of the quinone intermediate and a subsequent polar cyclizati~n"~(equation 233). Secondary and tertiary N-alkylamino-cyclohexenones and -cyclopentenones react quite differently with quinones. Partially reduced dibenzooxazinone can be obtained in low yield by reaction of 2,5-dichloro-1,4-benzoquinoneand a secondary ketoenamine as a consequence of [4 + 21-heterocyclization. Tertiary enaminones, however, yield hydroxy cyclohexa- and cyclohepta-benzofuranones by a polar reaction in good yield after splitting the amine moiety3l6 (equation 234).
U.Kucklander
AcOH, r.1.
I
AcOH 1.1
10. Enaminones as synthones
615
By reaction of secondary N-arylketoenamines in the aminocyclopentenone series and quinones, the cyclopent[b]indole skeleton and dibenzo[b,dlcyclopent~azepines are accessible. The reaction involves an oxidative cyclization of the Michael adduct by attack of either the nucleophilic nitrogen atom or of the aromatic o-position of the aniline moiety on the quinone317(equation 235).
0
AcOH, CHCb
C. Reaction with Nucleophiles 1. CH-acidic compounds
Nitroalkanes can be added to the enone moiety of enaminones to give, e.g., nitroalkylsubstituted cyclohexanone derivatives by a base-catalysed Michael additionJ18(equation 236). The reaction of enaminones and nitroalkenes in the absence of catalyst was studied intensively by Valentin and coworkersJ" and found to proceed mainly by electrocyclic
U. Kucklander
R1CHN02 EtONa. EIOH. 4 h
reaction in the case of cyclohexenone-type enaminones to form indolones (equations 242-245).
2. Phenol ether
A homoveratryl enaminone derived from cyclohexane-1,Zdione was cyclized through a 1,Caddition at the a$-unsaturated ketone moiety of the enaminone3I9 (equation 237). The spiro compound obtained, which is a useful intermediate in the synthesis of erythrina-alkaloids, demonstrates the special character of a-ketoenamines.
OMe OMe
3. Organometallic compounds
Ketoenamines derived from chiral cyclic amines were found to react with Grignard reagents or organolithium compounds by a 1,Zaddition. Subsequent hydrolysis gives R- (or (9-a-hydr~xycycloalkanonesin high enantiomeric excess. The stereochemical selectivity is caused by different structures of the intermediate formed by complexation of the different organometallic compounds320(equation 238).
4. Phenylhydrazine
With morpholinocyclohexenone, a normal Fischer indole synthesis is possible when the enaminone reacts as a ketone. The phenylhydrazone of 2-carbazolone is obtained in good yield"8 (equation 239).
10. Enaminones as synthones
OMe
R R = Me, Et, Ph
H
NNHPh
5. Aqueous base
The surprising rearrangement of an aminocycloheptenone to the aminoacylcyclopentenone skeleton3" is achieved by a nucleophilic attack of the hydroxide ion at the P-position of an enaminone, a special reaction known only for a-ketoenamines. This step is followed by a retro-aldol cleavage of the cycloheptanone ring and a subsequent aldol cyclization yields the cyclopentane derivative (equation 240).
D. Cycloaddltion 1. Diazenes
Secondary ketoenamines react with electrophilic diazenes to give products which undergo rearrangement to an adduct which affords benzimidazolinones after subsequent as unstable cycli~ation"~.In the case of tertiary a-enaminones, 1,3,4-oxadiazole-2-ones, intermediates of a [4 + 21-cycloaddition, can be obtainedw3 (equation 241).
U. Kucklander COOEt
I
NeN
+
Ax
COOEt
48-72 h O0C
X
0 X = Et, Ph, 4-02NC6H4
t HN-COOEt
COOEt
R1 = H, R2 = Ph, X = OEt 100%
I
90% R'R2 = -(CH2)20(CH2)~-. X = Ph 100% RL= H, RZ= Ph, X = OEt 90% R ~ = HR , ~ = x = P ~ 25%
I
R' = H; X = OEI KOH. ElOH, 30 min
COOEt I
NH
(241) N \
0
Ph
2. Nitroalkenes
According to Pitacco, Valentin and coworkers324 secondary ketoenamines react generally with nitroolefins to give alkyl- and aryl-substituted tetrahydroindole-7-ones under thermodynamic control in good yield without any catalyst, if the a-ketoenamine is an N-alkyl derivative. The course of the reaction depends on the substituents and the conditions which result in different cleavage or rearrangement reactions. In the case of a-nitrostilbene a Michael adduct is obtained in low yield. If, however, for example, 1-nitrocyclopentene is used in the reaction with N-t-butylenaminone under kinetic control, an unstable [4 2lcycloadduct can be isolated. The reaction clearly demonstrates the concurrence of Michael addition and subsequent cyclization to 7-indolones
+
619
10. Enaminones as synthones
+
with [4 + 21-cycloaddition to benzoxazin-N-oxide and [2 21-cycloaddition to bicyclo[4.2.0]octane as well as intramolecular aldoladdition of the Michael adduct and rearrangement with ring contraction to pentalenone, depending on the substitution pattern of the reactants (equation 242).
&
@
0
NHBu
diastereomeric mixture
0
13%
t
'Y
R 1 = R3 = Ph, R2 = Me, Ph R' = Ph, R2 = -(CH2)4R' = t-Bu, R2R3 = -(CH2)3-
78'C. 2 h EtOH
7040% 7040% 95%
R' = Bu, Ph R2 = H, Me, Ph R3 = Me, Ph R2R3 = -(CH2)3-46540%
Whereas cyclic secondary enaminones and nitroolefins mainly yield indoles in which the enamine nitrogen is incorporated into the heterocyclus (equati'on 242), linear tertiary a-ketoenamines are shown to react with nitroolefines at low temperature under kinetic control to give 1,2-oxazine N-oxides as [4 + 21-cycloadducts, followed by retro-DielsAlder reaction or rearrangement under thermodynamic control which leads diastereoselectively to aminocyclopentenes. The reaction is called [3 21-carbocyclization, apparently because the ketoenamine is reacting as a 1,3-dipole. The products are hydrolysable to polysubstituted nitrocyclopentanones with retained configuration3z5 (equation 243).
+
U. Kucklander
1
10%HCI, MeOH
RLRZ= -(CH2)20(CH2)T R3 = Et, Ph R4 = R5 = H,Me, Ph R6 = H, Me 62-96%
In the case of cyclic tertiary enaminones as dienophiles in the reaction with nitroalkenes as heterodienes, [4 21-cycloaddition yields tetrahydrobenzo[e][l,2]oxazin-8ones nearly quantitatively. Heating in aprotic solvents affords substituted diastereoisomeric pentalenones by ring contraction of the six-membered ring326(equation 244).
+
I
McCN A . U h
'Me
62 1
10. Enaminones as synthones
In a similar manner the reaction of tertiary enaminones and cyclic nitroolefins is used for the synthesis of a triquinan in high yield327(equation 245).
1
1. Reduction 2. -HzO
72% (overall)
3. Acetylquinone
Addition of secondary and tertiary enaminones derived from 1,2-cyclohexanediones
as dienophiles to acetylbenzoquinone leads in a hetero-Diels-Alder reaction to benzo[c]chromentriones. The Diels-Alder adducts are unstable and rearrange easily to condensed benzofurans. They can be converted by acids to a carbazolone derivative in low yield and to cyclopenta- and cyclohexa[c]isoquinolinium salts in fair yield328(equation 246).
4. Phenyl azide
In [3 + 21-cycloaddition reactions a-ketoenamines serve as synthons, reacting with phenyl azide as the 1,3-dipole component. The resulting tetrahydrophenylcyclopentatriazol-4-ones are interesting and easily accessible heterocycles32g(equation 247).
E. Photochemistry
Photochemical reaction of bifunctional ketoenamines in CCI, with maleic and fumaric acids and esters can be used for stereoselective synthesis of cis and trans alkyl 7-azabicyclo[2.2.l]heptanecarboxylates in good yield330(equation 248). Indolines, including spiro compounds, are synthesized in good yield by photoarylation of compounds having the N-aryl a-ketoenamine structure331(equations 249 and 250).
U. Kucklander
1
Toluene,- 15% IZh
n = 0, not isolated 62% n = 1, RL = H, R2 = p-To1 n = 1, RLR2= -(CH2)20(CH2)2- 40%
/\
A, Solvent
24 h, 6 N HCI. MeOH
623
10. Enaminones as synthones
HN COOMe
h.
==r
COOR t CCl4
COOMe
&,","" MeOOC cis
6548%
COOR
HN COOMe
q
OCOOR o
R
trans 74-94%
O\U N
COOMe
I
Me
7.5 h
I
COOMe
Me 87%
O\y +?@ I
H
COOEt
N
I
COOEt
H X = CH2 70% X = NCOOEt 87%
624
U. Kucklander
The photochemical behavior of aminocyclohexenones depends on the substituents on nitrogen. Cyclization of N-arylketoenamines to 2-carbazolones is achieved photochemically332 (equation 251). However N-benzyl-N-tosyl-a-ketoenamines yield stereospecifically on irradiation a-keto azetidinones. Branched N-alkyl substituents suffer desulphonation and intramolecular aryl migration to give 2-amino-3-aryl-2-cyclohexenones333 (equation 252).
Simple tertiary enamines derived from 1,2-cyclohexanedione can be also converted by photolysis to a-ketoazetines, but as isomeric mixture334(equation 253).
mixture 66% Photoirradiation of N-acylketoenamines gave spiro-8-lactams in moderate to good yield335.336(equation 254). Secondary ketoenamines on irradiation lead to spirocyclic ketoaziridines as a mixture of isomers337(equation 255).
10. Enaminones as synthones
mixture 40% F. Aromatizatlon
Ketoenamines derived from 1,2-cyclohexanedioneare oxidized by sulphur or selenium to aromatic compounds. In this way o-aminophenols are accessible in good vield3js (equation 256).
Some examples of other functional groups than carbonyl in the P-position of enamine, but resembling the character of a carbonyl moiety, are known. A. Nitroenamines P-Nitroenamines react similarly to tertiary aminocrotonate esters with quinones in yielding 3-nitrobenzof~rans"~(equation 257).
626
U. Kucklander
6. Enaminolmines
Formal substitution of the carbonyl group of enaminones by an imino group leads to enamino imines. In the reaction with isocyanates or isothiocyanates they result in urea or thiourea derivatives, which can be transformed to pyrimidines or pyrimidones depending on substitution340(equation 258). Treatment of similar enaminoimines with hydroxylamine gives regiospecifically isoxazoles by thermal cyclocondensation of the isolated o x i ~ n e s (equation ~~l 259).
M ~ ~ N - c - \N H ~ ~ X=O.S
Ph
NHR
Ph
NHR1
68-87% R1= Ph, C-C6HII;R2 = Ph; R3 = H, Me; R4 = Ph, C - C ~ H I I
63-96%
According to Barluenga and coworkers342 enaminoimines react with acetylenedicarboxylic esters regioselectively depending on the b-substitution of enaminone in a normal Michael addition, to give a 2-pyridone or a pyridine derivative. By reaction with an aromatic aldehyde both nitrogen atoms are incorporated into the heterocyclic product343(equation 260).
10. Enaminones as synthones
1
AICI, P~CHO.90°C. 12 h
0 R3 = Me, n-Pr, Ph 80-9 1%
R' = Ph, c-C6HI1 RZ= H, Me R3 = Et, Ph 70-9390 C. Enaminothiones
An interesting application of Lawesson's reagent to enaminone chemistry is the formation of thiazinethione as the main product together with an intermediate thioamide344 (equation 261). At room temperature in dimethoxyethane (1.5 h) successful enaminothione synthesis (70-90%) was reported by using Lawesson's reagentL5'.
At room temperature in dimethoxyethane (1.5 h) successful enaminothione synthesis (70-90%) was reported by using Lawesson's reagent.'57 The nucleophilic property of the thiocarbonyl group in enaminothiones give rise to a different manner of reaction with bifunctional groups. For example, a-bromoketones lead to thienoazepines with spiro-heterocycles as isolable intermediates. The reaction also takes place with benzo-fused heterocycles345(equation 262). Dialkylaminomethylene dithiomalonates have been recently condensed with hydrazines, hydroxylamine and amidine to yield pyrazoles, isothiazoles and pyrimidines, respectively346(equation 263).
628
U. Kucklander
RI
-dl R3
R2
R4
R L=Me, i-Pr, 1-Bu, Ph, PhCHz R2 = H, Ph R3,R4 = H, Me R5 = Ph, Me, COOEt 60-80%
(262)
10. Enaminones as synthones VI. ACKNOWLEDGEMENT
I a m indebted to Mr. A. Hilgeroth for his help with the literature search.
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10. Enaminones as synthones V. Kvita, H. Sauter and G. Rihs, Helu. Chim. Acta, 66, 2769 (1983). P. Schenone, L. Mosti and G. Menozzi, J. Heterocycl. Chem., 19, 1355 (1982). N. Peet and M. E. LeTourneau, Heterocycles, 32.41 (1991). S. Gelin and C. Deshayes, Synthesis, 566 (1983). G. Menozzi, P. Schenone and L. Mosti, J. Heterocycl. Chem., 20, 645 (1983). L. Mosti, G. Menozzi and P. Schenone, J. Heterocycl. Chem., 20, 649 (1983). K. B. Walter and H. H. Otto, Arch. Pharm. (Weinheim), 320,749 (1987). F. Eiden and G. Patzelt, Arch. Pharm. (Weinheim), 318, 328 (1985). A. Martani, A. Fravolini and G. Grandolini, J. Heterocycl. Chem., 11, 455 (1974). S. V. Sunthankar and S. D. Mehendale, Indian J. Chem., 14B,94 (1976). S. Takano, K. Yuta, S. Hatakeyama and K. Ogasawara, Tetrahedron Lett.,469 (1979). R. G. Gould and W. A. Jacobs, J. Am. Chem. Sac., 61,2890 (1939). C. C. Price and R. M. Roberts, J. Am. Chem. Sac., 68, 1204 (1946). J. Hermen, G. Kereszturi and L. Vasvari-Debreczy,Adv. Heterocycl. Chem.,54,1432 (1992). B. Riegel, G. R. Lappin, B. H. Adelson, R. I. Jackson, C. J. Albisetti, R. M. Dodson and R. H. Baker, J. Am. Chem. Sac., 68, 1264 (1946). 294. V. D. Parikh, A. H. Fray and E. F. Kleinman, J:Heterocycl. Chem., 25, 1567 (1988). 295. H. Schafer and K. Gewald, Monatsh. Chem., 109, 527 (1978). 296. F. Corelli, S. Massa, G. Stefancie, M. Artico and R. Silvestri, Farmaco, Ed. Sci., 42,641 (1987); Chem. Abstr., 108, 204524g (1988). 297. 0. S. Wolfbeis and H. Junek, Monatsh. Chem., 110, 1387 (1979). 298. J. F. Parric and H. K. Rami, J. Chem. Res. ( S ) , 308 (1990); ( M ) , 2411 (1990). 299. G. Zacharias, 0 . S. Wolfbeis and H. Junek, Monatsh. Chem., 105, 1283 (1974). 300. 0. S. Wolfbeis and E. Ziegler, Z. Naturforsch., 31b. 1519 (1976). 301. F. A. L'Eplattenier, I. Vuitel, H. Junek and 0. Wolfbeis, Synthesis, 543 (1974). 302. G. Bouillon and K. Schank, Chem. Ber., 112, 2332 (1979). 303. M. Buback, W. Trost, L. F. Tietze and E. Voss, Chem. Ber., 121, 781 (1988). 304. L. F. Tietze, K. Harms and G. M. Sheldrick, Tetrahedron Lett., 26, 5273 (1985). 305. L. F. Tietze, A. Bergmann and K. Bruggemann, Tetrahedron Lett., 24, 3579 (1983). 306. L. F. Tietze and K. Bruggemann, Angew. Chem., 91, 575 (1979). 307. F. Arya, J. Boquant and J. Chuche, Synthesis, 946 (1983). 308. U. Kucklander and B. Schneider, Arch. Pharm. (Weinheim), 326, 287 (1993). 309. M. Ohashi, T. Takahashi, S. lnoue and K. Sato, Bull. Chem. Sac. Jpn., 48, 1892 (1975). 310. V. N. Kovaleva, I. P. Stremok and N. S. Kozlov, J. Org. Chem. USSR (Engl. Transl.), 12,72 (1976). 311. K. Sato, S. Inoue, T. Kitagawa and T. Takahashi, J. Org. Chem., 38, 551 (1973). 312. S. Massa, G. Stefancich, M. Artico, F. Corelli and R. Silvestri, Farmaco, Ed. Sci., 42, 567 (1987); Chem. Abstr., 108, 112327s (1988). 313. B. Kasum, R. H. Prager and C. Tsopelas, Aust. J. Chem., 43, 355 (1990). 314. Z. Arnold, Synthesis, 39 (1990). 315. U. Kucklander and B. Schneider, Chem. Ber., 119, 3487 (1989). 316. U. Kucklander, K. Kuna and B. Schneider, Arch. Pharm. (Weinheim), 326,415 (1993). 317. U. Kucklander and B. Schneider, Chem. Ber., 121, 577 (1988). 318. G. I. Polozov and I. G. Tishchenko, Vestsi Akad. Nauuk BSSR, Ser. Khim. Navuk, 3, 62 (1978); Chem. Abstr., 89, 109284j (1978). 319. Y. Zhang, S. Takeda,T. Kitagawa and H. Irie, Heterocycles, 24, 2151 (1986). 320. T. Fujisawa, W. Watanabe and T. Sato, Chem. Lett., 2055 (1984). 321. E. S. Balenkova and M. A. Gorokhova, Zh. Org. Khim., 13,896 (1977); Engl. Transl.: J. Org. Chem. USSR, 13,819 (1977). 322. F. Benedetti, M. Forchiassin. G. Pispisa. . . P. Nitti, G. Pitacco, C. Rus'so and E. Valentin, Gazz. Chim. Ital., 120, 327 (1990). 323. M. Forchiassin, G. Pitacco, A. Risaliti, C. Russo and E. Valentin, J. Heterocycl. Chem., 20, 305 (1983). 324. F. Benedetti, F. Berti, P. Nitti, G. Pitacco and E. Valentin, Gazz. Chim. ItaL, 120, 25 (1990). 325. F. Felluga, P. Nitti, G. Pitacco and G. Valentin, J. Chem. Sac,, Perkin Trans. 1, 1645(1991). 326. G. Barbarella, S. Briickner, G. Pitacco and E. Valentin, Tetrahedron, 40, 2441 (1984). 327. M. M. Cooper and J. W. Huffman, J. Chem. Soc., Chem. Commun., 348 (1987). 328. U. Kucklander, K. Kuna, B. Schneider, A. Steigel and B. Mayer, J. Prakt. Chem., 335, 345 (1993). 279. 280. 281. 282. 283. 284. 285. 286. 287. 288. 289. 290. 291. 292. 293.
U. Kucklander 329. G. I. Polozov and G. I. Tishchenko, Vestnik Beloruss. Un-ta Gosudarstvennogo, 74 (1976); Chem. Abstr., 87, 135213~ (1977). 330. T. Zaima, C. Matsuno, Y. Matsunaga and K. Mitsuhashi, J. Heterocycl. Chem.,21,445 (1984). 331. A. G. Schultz and C.-K. Sha, Tetrahedron, 36, 1757 (1980). 332. 1. C. Arnould, J. Cossy and J. P. Pete, Tetrahedron, 36, 1585 (1980). 333. J. Cossy and J. P. Pete, Tetrahedron, 37, 2287 (1981). 334. J. C. Arnoud, J. Cossy and J. P. Pete, Tetrahedron, 37, 1921 (1981). 335. M. Ikeda, T. Uchino, H. Ishibashi, Y. Tamura and M. Kido, J. Chem. Soc., Chem. Commun., 758 (1984). 336. M. Ikeda, T. Uchino, M. Yamano, Y. Watanabe, H. Ishibashi and M. Kido, Chem. Pharm. Bull., 34, 4997 (1986). 337. J. Cossy and J. P. Pete, Tetrahedron Lett., 21, 2947 (1980). 338. G. I. Polozov and I. G. Tishchenko, Vestsi Akademii Navuk BSSR, Serya Khim. Nauuk, 6, 96 (1977); Chem. Abstr., 88, 120647e (1978). 339. V. M. Lyubchanskaya, G. S. Chernov and V. G. Granik, Khim. Geterotsikl. Soedin., 704 (1989); Engl. Transl.: Chem. Heterocycl. Compd., 25, 589 (1989). 340. J. Barluenga, V. Rubio and V. Gotor, J. Org. Chem., 45,2592 (1980). 341. J. Barluenga, J. Jardon, V. Rubio and V. Gotor, J. Org. Chem., 48, 1379 (1983). 342. J. Barluenga, M. Tomas, S. Fustero and V. Gotor, Synthesis, 345 (1979). 343. 1. Barluenga, M. Tomas, S. Fustero and V. Gotor, Synthesis, 346 (1979). 344. R. Shabana, J. B. Rasmussen and S. 0 . Lawesson, Bull. Soc. Chim. Belg., 90, 75 (1981). 345. G. Dannhardt, A. Grobe and R. Obergrusberger, Arch. Pharm. ( Weinheim), 320,582 (1987). 346. K. Hartke and A. Kraska, Arch. Pharm. (Weinheim), 326, 57 (1993).
CHAPTER
11
Photochemistry of enamines and enaminones MILES G. SIEGEL and JEFFREY D. WINKLER
.
Department of Chemistry. The University of Pennsylvania Philadelphia. Pennsylvania 19104. USA
I . INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637 I . CIStTRANS PHOTOISOMERIZATION . . . . . . . . . . . . . . . . . . . 638 I11. ENAMIDE PHOTOCYCLIZATION . . . . . . . . . . . . . . . . . . . . . 638 A. Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 638 B. Nature of the Photosubstrate . . . . . . . . . . . . . . . . . . . . . . . . 641 C. Control of Regiochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . 642 D . Miscellaneous Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . 643 IV. ENAMINE PHOTOCYCLOADDITION . . . . . . . . . . . . . . . . . . . 647 A. Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 647 B. Synthetic Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 648 V. THE PHOTOCHEMISTRY O F B-ENAMINONES AND fl-ENAMIDONES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 649 A. Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650 B. Vinylogous lmides or P-Enamidone Chromophores . . . . . . . . . . . 650 C . Vinylogous Amides or 8-Enaminones . . . . . . . . . . . . . . . . . . . . 654 . . 1. Cyclic chromophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . 654 2. Acyclic chromophores . . . . . . . . . . . . . . . . . . . . . . . . . . . 659 D . Migrations and Fragmentations ; . . . . . . . . . . . . . . . . . . . . . . 667 VI. THE PHOTOCHEMISTRY O F ENAMINONITRILES . . . . . . . . . . 672 A. Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675 VII . CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .677 VIII . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 677
.
I INTRODUCTION
The photochemical behavior of enamines and their derivatives has been the subject of extensive mechanistic and synthetic investigations. The goal of this chapter is to summarize the photochemistry of enamines as well as enamides. enaminones. enamidones and enaminonitriles. with particular emphasis on the application of the photochemistry of these chromophores in the synthesis of natural products. The Chemistn. of Enurninex Edited by Zvi Rappoport Copyright O 1994 John Wiley & Sons. Ltd . ISBN: 0-471-93339-2
637
638
Miles G. Siege1 and Jeffrey D. Winkler II. ClS/TRANS PHOTOISOMERIZATION
Enamines and their derivatives, upon excitation, can relax to the ground state by olefin isomerization' and will usually do so in the absence of a reactive alkene partner. Couchouron and coworkers recently examined the isomerization of l a (equation 1). Upon irradiation, enamine l a was converted to the isomer lb with the less stable intramolecular hydrogen bond. A thermal reversion to the more stable hydrogen bonded isomer l a could be observed. In this manner, Couchouronand coworkers could establish that the hydrogen-bonding acceptor abilities of carbonyl groups are in the decreasing order of MeCO >> MeOCO > p-XC,H4C0.
This photochemically mediated cisltrans isomerization of enamines has been used to synthetic advantage by Nakanishi and coworkers in a synthesis of the tunichromes Mml and Mn12~.These workers observed that the stereochemistry of the enamine formed by the Emmons reaction shown in Scheme 1 could be changed from E/Z = 811 to E/Z = 112 on irradiation. The undesired E isomer could then be separated and recycled. It should be noted, however, that cidtrans isomerization is more typically an undesired competitive relaxation pathway for most of the photochemical transformations described in this chapter.
Ill. ENAMIDE PHOTOCYCLIZATION
The most widely utilized photoreaction of enamine derivatives is undoubtedly the photocyclization of enamides. Since this subject has already been extensively reviewed3 only a brief discussion is presented here.
The course of the enamide photocycloaddition is outlined in Scheme 2. The enamide
2 undergoes a Woodward-Hoffman allowed six n-electron conrotatory electrocyclic ring closure via the resonance form 3 to produce an intermediate of type 4. The fate of this intermediate is dependent on reaction conditions. In the absence of oxygen or a reducing agent, species 4 undergoes a suprafacial 1,5-hydride shift to generate six-membered ring lactams such as 6. In the presence of oxygen, the fully oxidized system 5 is formed. In the presence of reducing agents such as metal hydrides, the saturated lactam 7 is generated. A chiral reducing agent leads to some asymmetry induction in the formation of the lactam product4. Photocyclization of the homochiral enamide 8 in Scheme 3 gives rise to products of high the cyclized product 9 in 73% yield, which - outical . uuritv. Irradiation of 8 produced xylopinine in 94.7% enantiomeric excess5. was converted to-the natural
11. Photochemistry of enamines and enaminones
Tme
WOW;
RZO
OR2
LDAlTkIF O
H
p OR^
C OR3
t-BOCNH
RZO
OR3 EIZ = 8/1
t-BOCNH
0
R20 OR2
EIZ = 112
SCHEME 1
Miles G. Siege1 and Jeffrey D. Winkler
&
Meo:xC" :,co;Me Me0
\
..
0
SCHEME 2
,,
Me0 M
COzMe e
O
T
(')
--
/
\
\
OMe
OMe
OMe
OMe
(9)
(8) Me0
SCHEME 3
Xylopinine 94.7%ee
OMe
641
11. Photochemistry of enamines and enaminones 8. Nature of the Photosubstrate
A variety of olefins undergo the enamide photocyclization. The reaction proceeds readily when either one or both of the olefins are part of an aromatic ring. In addition, olefins which are part of a heteroaromatic ring also participate in the reaction6.'. For example, Ninomiya and coworkers have shown that irradiation of enamidofuran 10 led to the formation of three new isomeric compounds 11,12 and 13, in yields of 53%, 21% and 6%, respectively (Scheme 4)6". The dihydrofuran products 11 and 12 were subsequently converted to the ergot alkaloids agroclavines, fumigaclavine B, and lysergene.
&+&+& /
H
N MBS'
/
/
H
'
N
'H
MBS'
MBS'
(11) 53%
N
(12) 21%
(13) 6%
SCHEME 4
Ninomiya and coworkers also reported the intramolecular photocycloaddition of a furan and a thioenol ether, as shown in equation 26b. When the enamine is terminally disubstituted, the photocyclization can lead to the formation of a spirocyclic ring system (equation 3)'s8. This spirocyclization proceeds in good yield both with substituted phenyl rings as well as with furan, thiophene, pyridine or indole heteroaromatic rings.
Miles G. Siege1 and Jeffrey D. Winkler
C. Control of Regiochemistry
The effect of aromatic substitution on the regiochemical outcome of the enamide photocyclization has been extensively ~ t u d i e d ~ "In , ~ .general, electron-withdrawing groups tend to retard the reaction, while electron-donating groups promote the cyclization. An ortho methoxy group generally promotes cyclization at that position, as shown in equation 4.
During the course of their recently reported syntheses of the alkaloids oxogambirtannine and nau~leficine'~ Naito and coworkers observed that this ortho methoxy directing effect could be overridden by other substituents on the aromatic ring (equation 5). Irradiation of 14 (R = H) leads to the exclusive formation of 15 in 80% yield. When R = OMe, the major product of the photocyclization is the expected lactam 16, accompanied by a substantial amount of 15 (R = OMe; 16/15 = 311). An amine in the ortho position leads to the opposite regiochemical outcome in the photocyclization reaction, a consequence of a hydrogen bond between the amine and the enamide carbonyl group (equation 6))'.
11. Photochemistry of enamines and enaminones
(16) (oxogambirtannine)
D. Miscellaneous Reactions
Couture and coworkers have reported that irradiation of enamide 17 in deoxygenated sodium methoxide/methanol solution leads to the formation of unsaturated lactam 2Oa, which is isomeric with the typical product of 1,5-hydrogen atom shift, i.e. 20b". The likely mechanism for the formation of ZOa is shown in Scheme 5. The initial zwitterionic photoproduct 18, instead of undergoing a 1,5-hydrogen atom shift, is deprotonated by methoxide to give enamine 19. A base-catalyzed isomerization. then produces the observed product, 2Oa. The reaction is reported to proceed in high yield with either electron-withdrawing or electron-donating aromatic substituents R. In the absence of base, the normal photoproducts, i.e. ZOb, were obtained. A completely different product outcome is observed with enamides derived from a-ketoester~'~.Benzoylation of the product obtained by condensation of methyl pyruvate with benzyl amine led to the formation of enamide 21 (Scheme 6). Irradiation of 21 in methanol produced only a 10% yield of the expected cyclization product 22,
Miles G. Siegel and Jeffrey D. Winkler
(17)
R = H, Me, OMe, C1, cq
SCHEME 5
together with a 20% yield of the novel compound 23 (R = H), the product of addition of one equivalent of methanol. The analogous products of ethanol and isopropanol addition could also be obtained in 50% and 49% yield, respectively. These compounds were readily converted to 2-amino-y-lactones such as 24, potentially useful starting materials for organic synthesis. The reaction of enamide 21 was also observed with THF to give ether 25 in 44% yield as a 1 : l mixture of diastereomers, as well as with the normally inert solvent cyclohexane to give compound 26 in 27% yield (equation 7). When the normal enamide photocyclization is disfavored, other reaction pathways can be observed13. For example, irradiation of enamide 27 leads to the formation of the expected cyclization product 28 (equation 8). Replacement of the phenyl ring of 27 with an alkene leads to different products as a function of alkene substitution (Scheme 7). The cyclization of 29 (R = Me) gives
11. Photochemistry of enamines and enaminones
NBn PhCO 1
645
Miles G. Siege1 and Jeffrey D. Winkler
the analogous cyclization product 31. However, irradiation of the unsubstituted alkene (R = H) leads to the exclusive formation of the rearranged product 30. Such 1,3-acyl migrations are common reactions of enamines14. These different reaction outcomes were rationalized as shown in Scheme 7. Cyclization should occur from the S-trans conformation, which is favored when R is large but disfavored when R is small. The enamide substrate cannot undergo cyclization from the S-cis conformation, so that 1,3-acyl migration is observed when R = H.
The intramolecular [2 + 23 photocycloaddition of an cc-carboxy enamide with an olefin has been elegantly exploited independently by Pirrung and by Clardy and coworkers in the synthesis of the toxic amino acid 2,4-methanoproline via irradiation of 32 (equation 9)15.
Ic~c02Me B~
(32)
benzene, hv acetophenone
\
Bz
87%
2.4-Methanoproline
11. Photochemistry of enamines and enaminones
647
IV. ENAMINE PHOTOCYCLOADDITION
Dienamines can undergo electrocyclic ring closure to form a new pyrrolidine ring. The first example of this type of cyclization was reported by Chapman and EianI6. Irradiation of N-phenylenamines 33 produced the corresponding dihydroindole 34 (equation 10). Since the initial electrocyclization is a conrotatory process1' the resulting ring fusion is predominantly trans, except for the case where n = 1, where only the cis-bicyclo[3.3.0] ring fusion stereochemistry is observed, presumably due to the strain associated with the trans stereochemistry. This reaction has also been observed for the corresponding en01 ethers and thioenol ethers1'.
(34)
-70% yield
The mechanistic details of this reaction have been examined by several workers. Absorption of a photon produces the enamine excited singlet statelEA*, which undergoes intersystem crossing to the excited triplet state 3EA*. Cyclization leads to an excited zwitterion 3ZW*, which relaxes to the zwitterionic ground state (Scheme 8)19. A suprafacial hydride shift produces the observed product. The presence of the zwitterionic intermediate has been detected by laser flash p h o t ~ l y s i s ~ In~ studies . on the related sulfide ring closure, the zwitterion was trapped by a dipola~ophile"'~.
SCHEME 8
Deuterium labeling experiments have been employed to determine the nature of the final hydride shift17.Two different pathways leading to the formation of the observed product are possible: a 1,Chydride shift or two successive 1,Zshifts. When enamine 35 was irradiated (Scheme 9), the resulting dihydroindole 36 contained deuterium at both C-2 and C-3, suggesting that both possible pathways occur.
Miles G. Siege1 and Jeffrey D. Winkler
SCHEME 9
0. Synthetic Applications
The enamine cyclization reaction has not been utilized in organic synthesis to the same extent as the corresponding enamide reaction. Schultz and Chiu have utilized this reaction in an approach to the synthesis of the aspidosperma alkaloids2'. Irradiation of compound 37 produces tetracyclic compound 38 in 71% yield (equation 11).
A similar route to these alkaloids has been employed by Gramain and coworkers22. Irradiation of compound 39 produced the tricyclic dihydroindole 40, which was converted in five steps to the tetracyclic aspidosperma skeleton 41 in 57% overall yield as outlined in Scheme 10. The cyclization proceeds with terminally disubstituted enamines as well. In a model study for the synthesis of the alkaloid gelsemine, Fleming and coworkers reported that irradiation of enamine 42 gave spirodihydroindole 43, albeit in a modest 34% yield (equation
11. Photochemistry of enamines and enaminones
LAH
t -
57% for 6 steps
V. THE PHOTOCHEMISTRY OF P-ENAMINONES AND P-ENAMIDONES
The utility of p-enaminones (vinylogous amides) and P-enamidones (vinylogous imides) has been successfully demonstrated in both inter- and intramolecular [2 21 photocycloaddition reactions. The vinylogous amide, which reacts as a P-heteroatom substituted enone, serves as the nitrogen analogue of the enol form of a P-diketone in the de Mayo reaction2".
+
650
Miles G. Siege1 and Jeffrey D. Winkler
A. Mechanism
The mechanism of enone-olefin [2 + 21 cycloaddition is still a subject of debate, but several generalizations can be made (Scheme 11). Initial excitation of the chromophore is probably an n-n* transition to give the excited singlet chromophore (S,), which undergoes intersystem crossing to either the n-n* or n-n* triplet state Typically, the enone olefin must be constrained in a five- or six-membered ring; otherwise relaxation via cis-trans isomerization competes with intersystem crossing26.The excited triplet enone may then interact with the olefin in some cases to form an exciplex2', which can either revert to ground state enone and olefin, or form a 14-biradical intermediate resulting from initial bond formation to either the or- or P-carbons of the enone alkene. Alternatively, the 1,4-biradical may form directly without the intermediacy of an exciplex2*. This diradical can then either revert to starting material or close to the cyclobutane product.
SCHEME 11 0. Vlnyiogous lmides or P-Enamidone Chromophores
+
Some of the earliest work on the [2 21 photocycloaddition chemistry of vinylogous imides was reported by Wiesner and coworkers, who described the isolation of the [2 + 21 photoaddition products resulting from the irradiation of cyclic vinylogous imides with ethyl acrylate and allene, respectively (Scheme l2)'*.
1 1. Photochemistry of enamines and enaminones
SCHEME 12 Similarly, Cantrell observed intermolecular photocycloaddition of vinylogous imide 44 with cyclopentene on irradiation through Pyrex to give cyclobutane 45 (equation 13)30.
A key step in the synthesis of 12-epi-lycopodine reported by Wiesner and coworkers is the intramolecular [2 21 photocycloaddition of a vinylogous imide and an allene. Irradiation of photosubstrate 46 produced a single cyclobutane 47, in which the allene added to the vinylogous imide anti to the methyl group (Scheme 13)31. Photoadduct 47 was converted to ketal-alcohol48 via a three-step sequence of ketalization, epoxidation and reduction. Hydrolysis of the ketal unmasked the P-hydroxy ketone functionality. Retro-aldol fragmentation followed by aldol closure gave hydroxyketone 49, which was readily converted to the polycyclic alkaloid 12-epi-lycopodine.
+
Miles G. Siege1 and Jeffrey D. Winkler
(49) R=OH
(a) hv, 70%; (b) ethylene glycol, acid; (c) perbenwic acid, CHC13, 100%. (d) L i H 4 , THP, 96%; (e) 1) 1% HCl, 47%; 2) 0.6% NaOH, 80% SCHEME 13 Schell and coworkers have reported the cyclization-fragmentation chemistry of related vinylogous imides as a function of tether length (Scheme 14)32. Irradiation of the vinylogous imide 50 produced the crossed photoadduct 51, in which the N-acetyl group
(a) hv, cyclohexane, 33%; (b) 1-BuOK, i-BuOH, d l u x , 30 (c) 10%KOWMeOH, reflux, 5 h, 76% SCHEME 14
11. Photochemistry of enamines and enaminones
653
precludes retro-Mannich fragmentation. The trans 6,4-ring junction of compound 51 was confirmed by X-ray structure analysis. Cyclobutane 51 was converted to cyclobutene 52 on treatment with potassium t-butoxide in t-butanol at reflux for 30 min. More vigorous basic conditions (10% potassium hydroxide/methanol) led to formation of the eight-membered ring diketone 53 in 76% yield. It was subsequently reported by Swindell and coworkers that, in addition to the formation of 51 (70% yield) on irradiation of 50, there was also obtained 54 and 55, in 8% and 13% yields, respectively (equation 14)33.The formation of a relatively large amount of the 'straight' photoadduct 55 is noteworthy; in general, the empirical 'rule of five' precludes the formation of this type of adducP4.
Irradiation of vinylogous imides 56 and 58 led to products derived from a different reaction pathway. None of the expected [2 + 23 adducts formed, but instead products 57 and 59 resulting from a photochemical ene-type reaction were isolated in good yield (Scheme 15)35.The authors proposed that hydrogen atom transfer from diradical 60 could lead to the formation of the observed product 57. The [2 + 23 photochemistry of vinylogous imides has been exploited by Swindell and coworkers in an elegant synthesis of a highly functionalized taxane skeleton". As shown in Scheme 16, the trichloroethoxycarbonyl protected vinylogous imide 61 was irradiated in benzene to give the [2 + 23 adduct 62 in analogy to Schell's earlier work. After Rubottom oxidation, p-face reduction of the resulting cc-silyloxyketone with K-selectride gave 63. Mesylation of 63 with mesyl chloride and deprotection of the carbamate with zinc led to imine 64 via Grob fragmentation. Hydrolysis of the imine and protection as the formamide yielded compound 65, which was subsequently converted in several steps to 66.
Miles G. Siege1 and Jeffrey D. Winkler
SCHEME 15
C. Vinylogous Amides or P-Enamlnones 1.
Cyclic chromophores
The utility of the vinylogous amide chromophore in inter- and intramolecular cycloadditions has been reported by several different groups. The photocycloaddition of vinylogous amides is particularly noteworthy for the facile retro-Mannich fragmentation of the photoadduct to give a ketoimine product, in analogy to the retro-Aldol fragmentation that is part of the de Mayo reaction. The first example of a vinylogous amide [2 + 21 cycloaddition-retro-Mannich fragmentation sequence was observed by Tamura and coworkers3'. As shown in Scheme 17, irradiation of vinylogous amide 67 through Pyrex, in aprotic solvents, leads to the formation of the crossed cycloadduct 68 in 5&60% yield. Photoadduct 68 was stable in refluxing toluene; however, exposure of 68 to protic solvent led to rapid retro-Mannich fragmentation. Tamura and coworkers
11. Photochemistry of enamines and enaminones
(a) hv, benzene, 715% @) TBDMSOTf, Et3N, (c) MCPBA, 79% 2 steps (90:lO); (d) K-selectride, 87% (946);(e) MsCl, Et3N; (f) Zn; (g) HOAc, HzO; (h) AdCHO, pyridine, 61% for 3 steps. SCHEME 16
Miles G. Siegel and Jeffrey D. Winkler
SCHEME 17 observed that refluxing 68 in water led to a 94% yield of an equilibrium mixture of compounds 69, 70 and 71, all derived via retro-Mannich fragmentation of the intermediate photoadduct. Tamura and coworkers also reported that irradiation of vinylogous amide 72, containing a trisubstituted alkene, led to the isolation of 74, the product of intramolecular hydrogen atom abstraction from the intermediate diradical 73 (equation 15)".
11. Photochemistry of enamines and enaminones
.~
657
-
A nhotoaddition-fragmentation seauence similar to that described in Scheme 17 was subsequently reported by Schell an'd Cook, who described the isolation of ketoimine 77 on irradiation ofsecondary vinylogous amide photosubstrate 75 in I-butanol (Scheme 18). The observed product was presumed to form via the intermediacy of cyclobutane 76". Exposure of 77 to Schotten-Bauman conditions produced the diketo-amide 78. ~
~
~
~~~
~
NHCOPh (78)
(77) 57%
(a) hv, t-butanol, 57%; (b) 10%KOH, BzCI, THF, 84% SCHEME 18
The same workers reported the application of this cyclization-fragmentation sequence to substrates 79 and 81, which led to the formation of retro-Mannich fragmentation products 80 and 82, respectively, in good yield (Scheme 19)40. Guerry and Neier have reported both the intra- and intermolecular photoaddition of a dihydropyridone, in which the vinylogous amide nitrogen is part of a six-membered ring. Irradiation of 83 in the presence of dimethyl maleate led to the formation of cyclobutane 84 in good yield (Scheme 20)41.The intramolecular version of this reaction was observed on irradiation of 85, which led to the formation of photoadduct 86 in good yield (n = 2 or 3). Winkler and coworkers have exploited the intramolecular photocycloaddition of vinylogous amides in the stereoselective synthesis of ( - )-perhydrohistrionicotoxin (Scheme 21)42.Photolysis of the L-glutamic acid-derived vinylogous amide 87 produced the cyclobutane photoadduct 88 as a single diastereomer in 95% yield. No stereoselectivity was observed on irradiation of the corresponding imide photosubstrate. Fragmentation of 88 by ketone reduction to 89 followed by base treatment led to the formation of ketolactone 90 in 60% overall yield from 87. Attempted fragmentation of dioxanone photoadduct 88 with acidic methanol to give the desired azaspiroundecane ring of histrionicotoxin led only to the formation of products derived from the
Miles G. Siege1 and Jeffrey D. Winkler
(80) R = H, 70% R = Me. 60%
(82) R = H, 75% R = Me, 80% SCHEME 19
11. Photochemistry of enamines and enaminones
(a) hv, Pyrex, CH3CN; (b) NaBH4, EtOH; (c) NaH, THF; 60% overall yield from 87
SCHEME 2 1 retro-Mannich product 91. Ketolactone 90 was subsequently elaborated in seven steps to ( - )-perhydrohistrionicotoxin. 2. Acyclic chromophores
The photocycloaddition of vinylogous amides is not limited to substrates in which the chromophore is constrained in a five- or six-membered ring, and several groups have recently described the photocycloaddition of acyclic vinylogous amides. Tietze and coworkers reported that irradiation of 92 gives the bicyclic product 95 in quantitativc yield (Scheme 22)43. The authors proposed that the observed product 95 could be the result of cycloaddition from the tautomeric form of the chromophore, followed by fragmentation of the resulting cycloadduct 93 to the imino-aldehyde 94, which condensed to the observed product. Tietze and Wiinsch have combined this methodology with a subsequent Lewis acid-mediated cyclization to produce a sequence that generates two new rings, as outlined in Scheme 2344. Cycloaddition of vinylogous amide 92 and diene 96, after fragmentation and cyclization, gave enamine 97, which on exposure to Lewis acid led to the formation of the fused ring system 98 as a single diastereomer in 40-50% yield for the entire sequence. Winkler and coworkers have coupled the photocycloaddition and retro-Mannich fragmentation of an acyclic vinylogous amide with a subsequent Mannich closure to produce perhydroindole structures as outlined in Scheme 2445. The acyclic secondary
Miles G. Siege1 and Jeffrey D. Winkler
(93) SCHEME 22
(98) SCHEME 23
11. Photochemistry of enamines and enaminones
(a) hv, Pyrex, CH3CN, 77%; (b) Me30+BF4-; (c) 20% HCI, 31% for 2 steps SCHEME 24
vinylogous amide chromophore, which can be stabilized by the internal hydrogen bond as shown in 99, undergoes intramolecular [2 + 21 reaction on irradiation through Pyrex to form the ketoimine 101, presumably via retro-Mannich fragmentation of cyclobutane 100. Treatment of this ketoimine with trimethyloxonium tetrafluoroborate yielded the ketoiminium salt 102, which underwent Mannich closure under either basic or acidic conditions to form the perhydroindole system 103. The application of this cycloaddition-retro-Mannich-Mannich sequence to a synthesis of the alkaloid mesembrine is outlined in Scheme 2545. Irradiation of 104 led to the formation of ketoimine 105 in 74% yield. Reaction of 105 with trimethyloxonium tetrafluoroborate then gave iminium ion 106, which on refluxing with 4-dimethylaminopyridine (DMAP) yielded mesembrine in 84% yield. The degree of asymmetric induction in the photocycloaddition reaction can be quite high with substrates containing a stereogenic center. Winkler, Scott and Williard have reported that irradiation of 1-tryptophan-derived vinylogous amide 107 led to the ~. to the isolation of ketoimine 108 in 91% yield as a single d i a ~ t e r e o m e r ~Closure tetracyclic portion of the aspidosperma ring system 109 was achieved in two steps by formation of the silyl en01 ether with LDA and r-butyl dimethylsilyl triflate followed by treatment with tetrabutylammonium fluoride (TBFA). Conversion of 109 to 110 with >97% optical purity was then achieved. As 110 is an intermediate in Biichi's synthesis of vindorosine4', the sequence outlined in Scheme 26 represents a formal total synthesis of vindorosine. The extension of this intramolecular photocycloaddition-retro-Mannich-Mannich sequence to B-substituted secondary vinylogous amides, the photochemistry of which had been originally reported by Schell and Cook (Scheme 18), was also examined
Miles G. Siege1 and Jeffrey D. Winkler
Mesembrine (a) hv, Pyrex, CH3CN, 74%; (b) Me30+BF4-; (c) DMAP, CH3CN, reflux, 84%
SCHEME 25
(Scheme 27)48. Irradiation of 111 led to the formation of 112, which was formed by a sequence involving photoaddition and retro-Mannich fragmentation to the intermediate ketoimine, followed by tautomerization of the imine to enamine, transannular closure and dehydration. The same sequence was observed with the acyclic analog 113, which led to the formation of 115, via ketoimine intermediate 114 (Scheme 28). Under no conditions could 114 be directly converted to the desired perhydroindole ring system. Efforts to form larger ring systems by increasing the length of the chromophore-olefin tether were not successful. Irradiation of 116 and 117, both of which would lead to the formation of six-membered rings in the photocycloaddition, yielded only recovered starting material, a result that is consistent with five-membered ring formation (for substrates 111 and 113 in Schemes 27 and 28, respectively) being faster than rotational deactivation of the triplet excited state via cisltrans alkene i~omerization~~. In contrast to the results reported by Guerry and Neier (Scheme 20), constraining the chromophore
11. Photochemistry of enamines and enaminones
CBz
0
CBz
663
0
(a) hv, 91%, single diastereomer; (b) 1) LDA, TBDMSOTf, 2) TBAF, 51% SCHEME 26
in a seven- or eight-membered ring, i.e. 117 (Scheme 29), does not promote the desired photocycloaddition at the expense of rotational deactivation of the chromophore. The use of acyclic tertiary vinylogous amides would exploit all of the valencics of nitrogen, thereby increasing the degree of substitution that would be possible in both substrates and products. Winkler, Haddad and Ogilvie have reported that, even though stabilization of the acyclic chromophore by internal hydrogen bonding is not possible with this system, the photocycloaddition competes effectively with cisltrans photoisomerization. Irradiation of 118 in either acetonitrile or benzene gave, after retroMannich fragmentation, the aminal product 119, resulting from 0-closure onto the intermediate iminium ion (Scheme 30)49. Exposure of the aminal to triethylamine hydrochloride in acetonitrile led to the formation of ketoiminium 120, which had been previously converted to perhydroindole products (Scheme 24)45b.Alternatively, irradiation of 118 in acetonitrile in the presence of triethylamine hydrochloride or other weak acids led directly to the formation of ketoiminium 120 in 80% yield.
Miles G. Siege1 and Jeffrey D. Winkler
(112) SCHEME 27 The effect of a stereogenic center on the stereochemical course of the photoreaction of tertiary vinylogous amides has been investigated by Siegelso. Irradiation of l2la at 0 "C led to the formation of a single aminal 123a, containing three new stereocenters with the relative stereochemistry shown in Scheme 31. Irradiation of 121b under identical conditions, however, produced a mixture of two compounds l22b and 123b in a ratio of 1:2. Irradiation of the epimeric alcohol 121c produced the two aminals in a 2.5:l
(115)
SCHEME 28
11. Photochemistry of enamines and enaminones
ratio, in which 122c predominated. At -78 "C, irradiation of an ethereal solution of 121c led to the exclusive formation of 122c. Exposure of 122c to triethylamine hydrochloride and 4-dimethylaminopyridine (DMAP) led to the formation of ketoamine 124, which embodies the tetracyclic core of the marine alkaloid manzamine A (36% overall yield from vinylogous amide 121c).
(a) hv, CH3CN. 82%; (b) Et3N*HCl,CH3CN, 75%; (c) hv, CH3CN, 1.3 eq. Et3N*HCl, RT 80%
SCHEME 30
666
Miles G. Siege1 and Jeffrey D. Winkler
hv, Pynx b CH,CN, O T
.
(a) X = H , R = M e (b) X = OH P, R = C02Me (c) X = OH a, R = C02Me
.
substrate l2la 121b 121c
1 . Et3N.HC1
P
2. DMAP
36% from lZlc
.OH
Manzamine A SCHEME 31
1221123 123only 1 :2 2.5 : 1
11. Photochemistry of enamines and enaminones
667
D. Migrations and Fragmentations
The photochemistry of vinylogous amides is not limited to [2 + 21 photoadditions. This section will describe some of the migration and fragmentation reactions observed on irradiation of vinylogous amides. Schell and coworkers have reported that irradiation of 125 leads to the formation of 126, the formal product of an aza-Claisen reaction, in 57% yield (equation 16)40.
The authors proposed that initial bond formation occurs from the less substituted olefin carbon to the a-carbon of the vinylogous amide to yield diradical intermediate 127 (Scheme 32, path A). This diradical can then undergo carbon-nitrogen bond homolysis to give the observed product, 126. However, the formation of 126 is also consistent with the formation of 128 by a 'straight'cycloaddition followed by cycloreversion as outlined in Scheme 32, path B.
(128) SCHEME 32
The formation of aza-Claisen products corresponding to 126 does not appear to be general for related substrates. Irradiation of 129 (Scheme 33) proceeded to give a 1:l mixture of photo-aza-Claisen product 130 and the straight cycloaddition-retro-Mannich fragmentation product 131, albeit in low yield. Irradiation of tertiary vinylogous amide photosubstrate 132 led to the formation of the crossed cycloadduct 134 as the major product, along with a small amount of the photo-aza-Claisen product 133. RetroMannich fragmentation of photoadduct 134 was not observed, presumably because the
Miles G. Siegel and Jeffrey D. Winkler
SCHEME 33
antiperiplanar relationship between the nitrogen lone pair and the cyclobutane a bond that is required for fragmentation to occur cannot be established. As described previously in Scheme 17, photocycloaddition of a vinylogous amide with an acyclic olefin led to the formation of the crossed cycloadduct in good yield, with none of the aza-Claisen product being f ~ r m e d ~ ' . ~ ' . A common feature of vinylogous imide photochemistry is 1,3-migration of the N-acyl group. Tamura and coworkers reported that irradiation of vinylogous imide 135 (R = H, Me or PhCH,) in either diethyl ether or methanol led to the formation of products, 136, resulting from 1,3-acyl migration as shown in equation 17. The authors suggest that product formation occurs either through cage recombination of a radical pair or through a concerted photochemical [1,3] sigmatropic shift5,.
Similar photo-Fries reactions have been reported by Schell and coworkers. Irradiation of vinylogous imide 50 led not only to the formation of the crossed photoadduct 51 (as outlined in Scheme 14) but also to the formation of 137, the product of acyl group migration (equation 18)32.
11. Photochemistry of enamines and enaminones
Acyl migration of N-acyl enamines was first observed by Eschenmoser and coworkers, and subsequently reported by Yang and Lenz as shown in Scheme 34 for 138 + 1393e.s3, in the transformation of 140 to 14lS4.
Yang and Lenz proposed two possible mechanistic explanations for this result (Scheme 35). Attack of the enamine on the amide carbonyl would lead to the formation of a four-membered ring iminium-alkoxide intermediate that could collapse to form the imine
SCHEME 35
670
Miles G. Siege1 and Jeffrey D. Winkler
tautomer of 141 (path A). Alternatively (path B), initial bond homolysis of the nitrogen-carbonyl carbon bond occurs, yielding two intermediate radicals which could recombine to form the imine tautomer of 141. The photochemistry of 2-acyl-vinylogous amides has also been investigated by Tamura and coworkers, who reported that irradiation of 142 (R1 = CH2R; R2 = H; R1 = RZ= CH,R) through a quartz filter in methylene chloride led to the formation of the dealkylated product 143, albeit in modest yield (equation 19), both in the case of
mono- and di-N-alkylated substrates. With dialkylated substrates, loss of both N-alkyl substituents was observed. However, in cases where the N-alkyl substituent did not contain a-hydrogen atoms (R1 = Ph or t-Bu), no reaction was observed. Irradiation of 144, in which a methyl group is substituted for the 2-acetyl group of 142, led to no dealkylation (equation 20)55.
hv, quartz
no dealkylation
I
Based on the observation that both the 2-acetyl group and the presence of an a-hydrogen atom in the N-alkyl group are required for the dealkylation to occur, the authors proposed the mechanism outlined in equation 21. The 2-acyl group in the excited state of 145 could abstract a 6-hydrogen atom from the N-alkyl group to give diradical 146. This diradical could then fragment to a carbene and 147, the en01 form of the dealkylated vinylogous amide. An unusual photochemical fragmentation reaction of a /3-keto vinylogous amide has recently been observed by Siegel5'. Irradiation of 148 in acetonitrile through a pyrex
67 1
11. Photochemistry of enamines and enaminones
+
filter led not to the expected aminal product 149 (the result of the [2 21 photocycloaddition as outlined in Scheme 31), but instead the fused pyrrole 150 was obtained in 25% yield (Scheme 36).
1
hv, pyrex CH3CN
SCHEME 36
The authors have proposed the mechanism illustrated in Scheme 37. The vinylogous amide chromophore can, upon excitation, undergo bond cleavage a: to the amine, generating diradical 151. This diradical can close to form the ten-membered ring ketoimine 152, which could undergo transannular condensation to form 150. The initial bond homolysis is facilitated by the presence of the ketone carbonyl, acting to stabilize the incipient radical. When the ketone is replaced by an alcohol, this pathway is not observed and vinylogous amide [2 + 21 photocycloaddition products are observed (Scheme 31). To determine the generality of this novel formation of pyrroles, the irradiation of a series of 8-keto vinylogous amides was examined, the results of which are outlined in Table 1. The size of the ring containing the ketone and the vinylogous amide nitrogen was varied from four to eight carbons. The highest yield was obtained with 153, producing the fused pyrrole product 159 in 29% yield. The analogous six-membered ring substrate, 156, underwent rapid decomposition on irradiation. It is interesting to note that the four-membered ring substrate 157 was inert to irradiation, presumably because in the constrained four-membered ring the ketone carbonyl cannot assume the geometry with the carbon-nitrogen bond that is required for fragmentation to occur. Irradiation of acyclic P-keto vinylogous amide 158 resulted in only a low yield of the pyrrole product 162.
Miles G. Siege1 and Jeffrey D. Winkler
672
SCHEME 37
VI. THE PHOTOCHEMISTRY OF ENAMINONITRILES
The unusual photochemical behavior of enaminonitriles (or P-cyanoenamines) has recently attracted a great deal of attention. Ferris and coworkers have reported that irradiation of diaminomaleonitrile leads to the very efficient formation ( z80% yield) of imidazole 163 (equation 22)56.It is interesting to note that 163 forms adenine on reaction with hydrogen cyanide in the dark and can also be readily converted to guanine, isoguanine, diaminopurine, hypoxanthone and ~ a n t h o n e ' ~Since ~ . diaminomaleonitrile is a major product in the oligomerization of hydrogen cyanide, the authors suggested that enaminonitrile photochemistry might be involved in the prebiotic synthesis of these biological bases5'. The scope of this methodology was established by forming imidazoles fused to five-, six- and seven-membered rings, 165, as outlined in Scheme 3856c,d. It was also found that while N-monosubstituted enaminonitriles such as 166 underwent photochemically mediated rearrangement to give imidazole 167, the reported conversion of 2-(dimethylamino)-1-cyclohexene-1-carbonitrile to 1,2-dimethyl-4,5,6,7-tetrahydrobenzimidazole could not be reproduced, i.e. no reaction was observed with N,N-disubstituted en-
am in on it rile^^^'.^. 5 8 .
1 1 . Photochemistry of enamines and enaminones
673
TABLE 1. Photolysis of 0-ketovinylogous amides Photosubstrate
Solvent
Reaction time (h)
Roduct
Yield
(%I
CH3CN
CH3CN
MeOH
CH3CN
CH3CN
decomposition
CH3CN
no reaction
CH3CN
88 (rec, SM)
674
Miles G. Siege1 and Jeffrey D. Winkler
(163)
Diaminomaleonitrile Diaminofumaronitrile
Adenine
.N
A
)
I
80-90% yield
'N H
@'
-
-50%
hv
N
NHR
R
(166) R = Me, t-Bu SCHEME 38
The same authors reported that irradiation of 168 (cc-anomer), prepared by condensation of the requisite amino sugar with a-cyanocyclohexanone, in acetonitrile led to the formation of imidazole 169 in 80% yield as a single anomer (equation 23)59.
Cyclization of 168 in methanol, however, led to the formation of the epimeric (P-anomer) product 172, as outlined in Scheme 39. Irradiation of 168 in methanol leads, via the triplet excited state of the enaminonitrile, to the formation of 170, the product of addition of methanol to the enamine double bond. On standing in the dark, 170 reverted to the starting enaminonitrile as a mixture of isomers 168 and 171 at the anomeric center, presumably via equilibration at the anomeric center prior to elimina-
11. Photochemistry of enamines and enaminones
tion of methanol to generate the p-anomer of 171. Subjection of 168 to five cycles of irradiation in methanol for 12 hours, followed by standing for 60 hours in the dark, led to a 70% yield of a 2.4: 1 mixture of 1721169. A. Mechanism
The mechanism of the enaminonitrile -+ imidazole conversion has been the subject of extensive study, although only a few mechanistic features are known with certainty. The nitrile and the amine must have a cis relationship in the starting material. In the case of diaminomaleonitrile, the initial step would therefore be a photoisomerization to diaminofumaronitrile, via the triplet excited state of the enaminonitrile (equation 22)'j0. The rearrangement to imidazole, however, is presumed to occur via the singlet excited state, since triplet sensitizers do not promote the reaction and triplet quenchers do not inhibit it56b. 59b
676
Miles G. Siege1 and Jeffrey D. Winkler
Since N,N-dialkylenaminonitriles do not undergo this rearrangement, Ferris and coworkers proposed that a hydrogen atom transfer from the enamine nitrogen may be involved as the first step in the photochemically mediated rearrangement reaction. The authors reported the irradiation of 173 (equation 24) at -196 "C and examination of the reaction products by IRs6'<59h. The observed absorption at 2000-2020~m-~, characteristic of the stretch for a keteneimine, led the authors to postulate intermediate 174 as the initially formed photoproduct, which would result from hydrogen atom transfer from the enamine nitrogen to the nitrile nitrogen. Upon warming, the keteneimine IR stretch disappeared as the keteneimine collapsed to the proposed azetine 175, which could undergo the previously reported thermal conversion of azetine to the product imidazole 17656h* 6 1 .
''*
Ab initio calculations performed by Bigot and Roux have led to an alternative mechanism involving two photochemical steps and the intermediacy of an azirine, as shown in Scheme 406'. Hydrogen atom transfer from the enamine nitrogen to the nitrile carbon of 173 would generate diradical intermediate 177, which would then collapse to the postulated azirine 178. In a second photochemical step, the azirine would then undergo carbon-rbon bond homolysis to 179 followed by reclosure to the imidazole 176. In support of this proposed second photochemical step, structurally similar azirines have been shown to undergo facile carbon-rbon bond p h o t o l y ~ i sThis ~ ~ . mechanism does not, however, explain the initial formation of a thermally unstable intermediate with the observed IR stretch, since azirines of this type are thermally stable at room ternperat~re~~.
SCHEME 40
11. Photochemistry of enamines a n d enaminones
677
VII. CONCLUSIONS While some of the mechanistic details for the examples described in this chapter have not yet been fully elucidated, it is clear from the scope of the examples discussed herein that the photochemistry of enaminones a n d enamidones is a fascinating research area. T h e novel sequence for the annelation of imidazole rings o n t o a preexisting structure, the synthesis of perhydroindoles via vinylogous amide [2 21 photocycloaddition chemistry a n d the enamide cyclization reactions all underscore the enormous utility of these chromophores in the development of new reactions a n d novel synthetic methods.
+
VIII. REFERENCES
1. B. Couchouron, J. LeSaint and P. Courtot, Bull. Soc. Chim. Fr., pt. 11, 66 (1983); see also References 19 and 53. 2. D. Kim, Y. Li, B. A. Horenstein and K. Nakanishi, Tetrahedron Lett., 31, 7119 (1990). 3. (a) I. Ninomiya and T. Naito, in The Alkaloids, Vol. 28 (Ed. A. Brossi), Academic Press, New ~ & k 1983, , dp. 189-279. (b) I. Ninomiya and T. Kiguchi, in The Alkaloids, Vol. 38 (Ed. A. Brossi), Academic Press, New York, 1990, pp. 1-156. (c) 1. Ninomiya and 0. Miyata, in Studies in Natural Products Chemistry, Vol. 3, Stereoselective Synthesis, Pt. B (Ed. Atta-ur-Rahman), Elsevier, New York, 1989, pp. 399416. (d) 1. Ninomiya, Heterocycles, 14, 1567 (1980). (e) G. R. Lenz, Synthesis, 489 (1978). (0 I. Ninomiya, Heterocycles, 2, 133 (1974). 4. (a) T. Naito, K. Katsumi, Y. Tada and 1. Ninomiya, Heterocycles, 20, 779 (1983). (b) T. Naito, Y. Tada and I. Ninomiya Heterocycles, 16, 1141 (1981). 5. T. Kametani, N. Takagi, T. Masahiro, T. Honda and K. Fukumoto, Heterocycles, 16,591 (1981). 6. (a) I. Ninomiya, T. Kiguchi, C. Hashimoto and T. Naito, Chem. Pharm. Bull., 39, 23 (1991). (b) T. Naito, 0.Miyata, N. Kida, K. Namoto and I. Ninomiya, Chem. Pharm. Bull. 38, 2419 (1990). (c) I. Ninomiya, T. Naito, 0.Miyata, T. Shinada, E. Winterfeldt, R. Freund and T. Ishida, Heterocycles, 30 (2, spec. issue), 1031 (1990). (d) T. Naito, N. Kojima, 0.Miyata, I. Ninomiya, M. lnoue and M. Doi, J. Chem. Soc., Perkin Trans. 1, 1271 (1990). 7. J. C. Gramain and Y. Troin, Tetrahedron, 47,7301 (1991). 8. J. C. Gramain, S. Mauel and Y. Troin, Tetrahedron, 47, 7287 (1991). 9. (a) I. Ninomiya, T. Kiguchi and T. Naito, J. Chem. Sac., Perkin Trans. 1, 81 (1974). (b) I. Ninomiya, T. Kiguchi, 0.Yamamoto and T. Naito, J. Chem. Sac., Perkin Trans. 1, 1723 (1979). 10. T. Naito, E. Kurodo, 0.Miyata and 1. Ninomiya, Chem. Pharm. Bull., 39,2216 (1991). 11. A. Couture, P. Grandclaudon and S. 0.Hooijer, J. Org. Chem., 56, 4977 (1991). 12. T. Naito and I. Ninomiya, Heterocycles, 27, 1325 (1988). 13. S. Eguchi, K. Asai, H. Takeuchi and T. Sasaki, J. Chem. Sac., Perkin Trans. 1, 1171 (1987). 14. See Reference 3e and references cited therein. 15. (a) M. C. Pirrung, Tetrahedron Lett., 21, 4577 (1980). (b) P. Hughes, M. Martin and J. Clardy, Tetrahedron Lett., 21, 4579 (1980). 16. (a) 0.L. Chapman and G . L. Eian, J. Am. Chem. Soc., 90, 5329 (1968). (b) A. Bloom and J. Clardy, J. Chem. Soc., Chem. Commun., 531 (1970). 17. 0. L. Chapman, G . L. Eian, A. Bloom and J. Clardy, J. Am. Chem. Soc., 93, 2918 (1971). 18. (a) A. G. Schultz and W. Y. Fu, J. Org. Chem., 41, 1483 (1976). (b) A. G. Schultz and M. B. DeTar, J. Am. Chem. Soc., 98, 3564 (1976). 19. T. Wolff and R. Waffenschmidt, J. Am. Chem. Sac., 102,6098 (1980). 20. K. H. Grel1man.W. Kuehnle and T. Wolfl, Z. Phys. Chem., 101,295 (1976). 21. A. G . Schultz and I. C. Chiu, J. Chem. Soc., Chem. Commun., 29 (1978).
Miles G. Siegel and Jeffrey D. Winkler 22. (a) I. C. Gramain, H. P. Husson and Y. Troin, J. Org. Chem., 30, 5517 (1985). (b) I. C. Gramain, H. P. Husson and Y. Troin, J. Am. Chem. Soc., 101, 6398 (1979). (c) J. C. Gramain, Y. Troin and H. P. Husson, J. Heterocycl Chem., 25, 201 (1988). (d) D. Gardette, I. C. Gramain, M. E. LePage and Y. Troin, Can. J. Chem., 67, 213 (1989). 23. 1. Fleming, R. S. Moses, M. Tercel and J. Ziv, J. Chem. Soc., Perkin Trans. 1,617 (1991). 24. P. de Mayo, H. Takeshita and A. B. M. A. Sattar, Proc. Chem. Sac. London, 119 (1962); P. de Mayo and H. Takeshita, Can. J. Chem., 41,440 (1963); P. de Mayo, Acc. Chem. Res., 4.41 (1971). 25. N. J. Turro, Modern Molecular Photochemistry, Benjamin Cummings, Menlo Park, 1978, p. 458. 26. H. Morrison and 0. Rodriguez, J. Photochem., 3, 471 (1974). 27. E. J. Corey, J. D. Bass, R. LeMahieu and R. B. Mitra, J. Am. Chem. Soc., 86, 5570 (1964). 28. D. I. Schuster, G. E. Heibel and P. B. Brown, J. Am. Chem. Soc., 110, 8261 (1988). 29. E. H. W. Bohme, Z. Valenta and K. Wiesner, Tetrahedron Lett., 2441 (1965); K. Wiesner, I. Jirkovsky, M. Fishman and C. A. J. Williams, Tetrahedron Lett., 1523 (1967). 30. T. Cantrell, Tetrahedron, 27, 1227 (1971). 31. K. Wiesner, V. Musil and K. I. Wiesner, Tetrahedron Lett., 5643 (1968). 32. F. M. Schell, P. M. Cook, S. W. Hawkinson, R. E. Cassady and W. E. Thiessen, J. Org. Chem., 44, 1380 (1979). 33. C. S. Swindell, S. J. deSolms and J. P. Springer, Tetrahedron Lett., 25, 3797 (1984). 34. For exceptions, see S. WollT and W. C. Agosta, J. Am. Chem. Soc., 105, 1292 (1983); S. WollT and W. C. Agosta, J. Am. Chem. Soc., 105,1299 (1983); H. Yoshioka, T. J. Mabry and A. Higo, J. Am. Chem. Sac., 92,923 (1970). 35. F. M. Schell and P. M. Cook, J. Org. Chem., 43,4420 (1978). 36. C. S. Swindell and S. J. deSolms, Tetrahedron Lett., 25, 3801 (1984); C. S. Swindell, B. P. Patel, S. I. deSolms and J. P. Svrin~er,J. Oru. - Chem., 52.2346 (1987): C. S. Swindell and B. P. Patel, J. Org. Chem., 55, 3 (1990). 37. Y. Tamura, Y. Kita, H. Ishibashi and M. Ikeda, Tetrahedron Lett., 1977 (1972); Y. Tamura, H. Ishibushi, M. Hirai, Y. Kita and M. Ikeda, J. Org. Chem., 40,2702 (1975). 38. Y. Tamura. H. Ishibashi and M. Ikeda. J. Ora. Chem.. 41. 1277 (1976). ~, 39. F. M. ~chelland P. M. Cook, J. Org. ~hem.,"49,4067(1984). 40. B. Vogler, R. Bayer, M. Meller, W. Kraus and F. M. Schell, J. Org. Chem., 54, 4165 (1989). 41. P. Guerry and R. Neier, Chimia, 41, 341 (1987). 42. I. D. Winkler and P. M. Hershberger, J. Am. Chem. Soc., 111, 4852 (1988); I. D. Winkler, P. M. Hershberger and J. P. Springer, Tetrahedron Lett., 43, 5177 (1986). 43. L. F. Tietze and K. Bruggemann, Angew. Chem., Inr. Ed. Engl,, 18, 540 (1979); L. F. Tietze, A. Bergmann and K. Bruggemann, Synthesis, 3, 190 (1986). 44. L. F. Tietze and J. R. Wunsch, Angew. Chem., Int. Ed. EngL, 30, 1697 (1991). 45. (a) J. D. Winkler, C. L. Muller and R. D, Scott, J. Am. Chem. Soc., 110, 4831 (1988). (b) C. L. Muller, PhD Dissertation, University of Chicago, 1990. 46. J. D. Winkler, R. D. Scott and P. G. Williard, J. Am. Chem. Soc., 112, 8971 (1990). 47. G. Buchi, K. Matsumoto and H. Hishimura, J. Am. Chem. Soc., 93,3299 (1971); M. Ando, G. Buchi and T. Ohnuma, J. Am. Chem. Soc., 97,6880 (1975). 48. R. D. Scott, PhD Dissertation, University of Chicago, 1990. 49. I. D. Winkler, N. Haddad and R. J. Ogilvie, Tetrahedron Lett., 30, 5703 (1989). 50. M. G. Siegel, PhD Dissertation, University of Chicago, 1992. 51. Y. Tamura, H. Ishibashi and M. Ikeda, J. Chem. Soc., Chem. Commun., 1167 (1971). 52. Y. Tamura, J. Uraoka, S. Fukumori and Y. Kita, Chem. Pharm. BUN.,21, 1372 (1973). 53. E. Bertele, H. Boos, I. D. Dunitz, F. Elsinger, A. Eschenmoser, I. Felner, H. P. Gribi, H. Gschwend, E. F. Meyer, M. Pesaro and R. Scheffold, Angew. Chem., Inr. Ed. Engl., 3, 490 (1964). Also see Reference 3e. 54. N. C. Yang and G. R. Lenz, Tetrahedron Lett., 4897 (1967). 55. Y. Tamura, S. Fukumori, A. Wada, S. Okuyama, J. Adachi and Y. Kita, Chem. Pharm. Bull., 30, 1692 (1982). 56. (a) I. P. Ferris and L. E. Orgel, J. Am. Chem. Soc., 88, 1074 (1966). (b) I. P. Ferris and J. E. Kuder, J. Am. Chem. Soc., 92, 2527 (1970). (c) J. P. Ferris and R. W. Trimmer, J. Org. Chem., 41, 19 (1976). (d) J. P. Ferris, R. S. Narang, T. A. Newton and V. R. Rao, J. Org. Chem., 44, 1273 (1979).
11. Photochemistry of enamines a n d enaminones
679
57. J. P. Ferris and W. J. Hagan, Jr., Tetrahedron, 40, 1093 (1984) and references cited therein; J. P. Ferris, P. C. Joshi, E. H. Edelson and J. G. Lawless J. Mol. Evol., 11,293 (1978) and references cited therein. 58. J. H. Hong, H. J. Pownall and R. S. Becker, Photochem. Photobiol., 24, 217 (1976). 59. (a) J. P. Ferris, R. S. Narang, T. A. Newton and V. R. Rao, J. Org. Chem., 44, 4378 (1979). (b) J. P. Ferris, V. R. Rao and T. A. Newton, J. Org. Chem., 44, 4381 (1979). 60. T. H. Koch and R. M. Rodehurst, J. Am. Chem. Sac., %, 6707 (1974). 61. L. deVries, J. Org. Chem., 39, 1707 (1974). 62. B. Bigot and D. Roux, J. Org. Chem., 46, 2872 (1981); see also H.Tanaka, Y. Osamura, T. Matsushita and K. Nishimoto, Bull. Chem. Sac. Jpn., 54, 1293 (1981). 63. A. Padwa, J. Smolanofl and A. Tremper, J. Am. Chem. Sac., 97,4682 (1975). 64. G. R. Harvey and K. W. Ratts, J. Org. Chem., 31, 3907 (1966).
CHAPTER
12
Radiation chemistry of enamines ZEEV B. ALFASSI Department of Nuclear Engineering, Ben Gurion University of the Negev, Beersheva 84105, Israel
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . THE FORMATION O F INITIAL SPECIES . . . . . . . . . . . . . . . . . . RADIOLYSIS O F AQUEOUS SOLUTIONS O F ENAMINES . . . . . . POLYMERIZATION O F ENAMINES BY RADIATION . . . . . . . . . . A. Allylamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. ZAminoethyl Vinyl Ether . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. N-Vinylcarbazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VI.REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I. 11. 111. IV.
I. INTRODUCTION
Radiation chemistry is the study of the chemical effects produced in a system by the absorption of ionizing radiation from radioactive sources, high-energy charged particles and short-wavelength (less than about 400 A)' electromagnetic radiation from accelerators. The principal characteristic of high-energy radiation is that it causes ionization in all materials. This makes a distinction between radiation chemistry and photo~ h e r n i s t r y ~Photochemistry ,~. deals with longer-wavelength radiations which have energy lower than about 30 eV. This relatively low energy frequently leads only to the excitation of the molecules and does not produce ions. Usually, the energy of the particles and photons applied in radiation chemistry is much higher. The whole energy is not absorbed by a single molecule, as in photochemistry, but rather distributed over several molecules, along the track of the ionizing particle or photon. The high-energy photons and particles are not selective and may ionize, excite or dissociate any molecule lying in their path. This is in contrast to photochemistry where only some compounds may interact with the radiation, in accordance with the energy of the photons. The high-energy photons or particles lose energy in successive events and produce ions and primary electrons, which in turn form several secondary electrons with lower energies4. The chemical effects of ionizing radiation occur almost exclusively through the secondary electrons, most of which have less than 100 eV. These electrons will ionize and excite the surrounding molecules and will lose energy until they reach thermal energies. In many solvents these thermal electrons polarize the solvent molecules and Tlze Clremisln oJEnamines. Edited hy Zvi Rappoport Copyright O 1994 John Wiley & Sons, Ltd. ISBN: 0-471-93339-2
68 1
682
Zeev B. Alfassi
are bound in a stable quantum state to them; these electrons are called solvatedelectrons. On the average half of the absorbed energy . . leads to ionization while the other half leads to excited molecules. The study of radiation chemistry might be divided into two parts. The first is the study of unstable intermediates which have short lifetimes and thus cannot be studied by usual chemical methods. The second part is the study of the final products of the radiolysis which are measured by common chemical techniques. One way to make the short-lived intermediates amenable to study is to increase their lifetime, usually by irradiation in the solid state and/or at very low temperatures. The intermediates can be then detected at the end of the irradiation by ESR or optical absorption spectroscopy. The ESR of radicals in the solid state is done on single crystals, polycrystalline samples or frozen aqueous solution. In the two latter cases the identification of the radicals from the ESR spectra is frequently difficult and for better identification the ESR should be done on irradiated single crystals. Later, the method of spin trapping, developed for the liquid phase5, was extended to polycrystalline solids. In this technique the polycrystalline solids are y-irradiated and subsequently dissolved in a solution containing the spin trap. Most commonly it is aqueous solution and several spin traps were used6. Another method of increasing the lifetime in the liquid phase is by adding compounds which, upon addition of radicals, produce long-lived radicals; this method is called spin trapping5.A diamagnetic spin-trap is used to convert radicals which are short-lived into long-lived radicals. For example, using nitroso compounds (as, e.g., t-nitrosobutane, t-NB) the short-lived radicals form long-lived nitroxide radicals (the spin-adduct) according to reaction 15.
More common in the liquid phase is pulse radiolysis7. In this technique, electron accelerators which can deliver intense pulses of electrons lasting a very short time (ns up to ps) are used. Each single pulse can produce intermediates with sufficiently high concentration to be studied by various methods, such as light absorption spectroscopy or electrical conductivity. The yields of radiolysis products are always expressed by the G value, which is defined as the number of particles (molecules, radicals, ions) produced or consumed per 100 eV of energy absorbed in the system. The units for the absorbed energy (dose) are the rad, defined by 1 rad =100erg g-' = 6.243 x loL3eV g-', and the Gray (Gy) defined by 1 Gy = 100 rad. When radiolysing a solution, the radiation interacts mainly with solvent molecules which are in large excess since the radiation interacts with the molecules unselectively. Consequently, the radiation chemistry of a solution is the combination of the production of initial intermediates from the solvent, which will be the same as in pure solvents, and the reactions of those intermediates with the solute. The most common solvent is water. The radiolysis of water produces hydrated electrons (e,,-', G = 2.9), hydrogen atoms (G = 0.55) and hydroxyl radicals (G = 2.8) which react with the solute molecules. In addition, the radiolysis of aqueous solutions leads to formation of molecular products H,O, (G = 0.75) and gaseous hydrogen (G = 0.45). Also produced are hydronium ions (H,O+, G = 2.9). In most cases the molecular products do not interfere with the reactions of the radicals. To study the reaction of one radical with the solute without interference from other radicals, scavengers for the other radicals should be added7-''.
12. Radiation chemistry of enamines
683
eqs-l can be eliminated and even converted to the other radicals OH and H, by the addltion of N,O or H + to the system (equations 2 and 3, respectively). Therefore, in aqueous N 2 0 saturated solutions, OH radicals are the predominant species (90%), while in acidic aqueous solution H and OH radicals exist, but not hydrated electrons. The small fraction (- 10%) of hydrogen atoms in NzO-saturated aqueous solution does not interfere significantly with the measurements of the reactions of OH radicals. Frequently, H atoms and OH radicals react with solutes in a similar manner, e.g. by addition to a double bond or by hydrogen atom abstraction. eeS- + NzO
H20
N,
+ OH- + OH
(k = 9 x lo9 M-I s-I )
(2)
The reaction of H atoms can be studied in acidic solution if the OH radicals are scavenged by t-butyl alcohol, in a very fast reaction, while hydrogen atoms react only very slowly with this alcohol (equations 4 and 5). The radical produced in reaction 4 is relatively unreactive and does not interfere with the study of the reaction of H atoms with the solute.
Hydrated electrons are obtained as predominant radicals by removing the OH radicals with t-butyl alcohol. The removal of both H and OH radicals is accomplished by isopropanol (equations 6 and 7).
II. THE FORMATION OF INITIAL SPECIES
Williams and coworkers" studied the ESR spectrum of the radicals produced by radiolysis of a solid solution (at low temperatures) of allylamine (prop-Zenylamine) in various freons. The radiolysis in freon matrices is usually called radiolytic oxidation, since in these media only the parent cation of the solute can be observed at lower temperatures. The electrons are reacting with the matrix material. They found for solid solution of allylamine in CF,CCl, irradiated at 77 K a well-resolved 22.7 G triplet of a 16.9 G triplet in the ESR spectrum measured at 95 K. Each triplet displays the 1:2:1 intensities ratios characteristic of the unpaired electron of the radical coupled to two equivalent hydrogens. The larger value of 22.7 G is typical of a-hydrogen atoms coupled to a carbon-centred radical. Thus, the radical must have a RCH,CH,' structure, different than the parent molecule CH,=CH-CHzNH,. Photoelectron spectroscopy showedLzthat the ground state-ion of allylamine is CH,=CHCH,NH,+', a novicecentred radical cation. Williams and coworkers" argued that the initially formed nitrogen-centred propen-2-enyl amine radical cation CH,=CHCH,NH,+' is isomerized to carbon-centred 3-iminopropyl radical cation by 1,2-hydrogen shift which leads to separation of the radical centre from the cation (equation 8).
Zeev B. Alfassi Williams and coworkers performed several other experiments to show that the observed radical is really a carbon-centred radical, and did not rely only on the typical splitting of 8-CH, group. They also radiolysed N-dideuterioallylamine in freon matrices, obtaining the same spectrum as in the all-hydrogen molecule. This indicates that the deuterium atoms are not bound to the radical centre, ruling out a nitrogen-centred radical. Another proof for the structure of the radical was found by comparison to the ESR spectrum of radiolysed solution of cyclopropylamine in freons13. In CF,CCl,, the spectrum was found to be identical with that found for allylamine in CF3CCI,. For the case of cyclopropylamine, it was-proved that the observed spectrum is due to the Identical spectra for cyclocarbon-centred radical cation" CH,CH,CH,=NH,+. propylamine and allylamine were also observed for matrices of CFCI, and CF,ClCCI,F, although the spectra are different in the various solvents, due to different line-broadening caused by the various freons. It is unlikely that this correlation is accidental, and it indicates that the radicals from cyclopropylamine and allylamine are identical. There are an additional two pieces of evidence that these two radicals are identical: (1) The magnitude of the 8-hydrogen coupling is the same for the two radicals (16.8-17.6 G depending on the temperature). Since a value of 16.9 G is quite atypical for p-hydrogen coupling in RCH,CH,' radicals, it is too fortuitous that two different radicals will have the same atypical value for the p-hydrogen coupling. (2) Warming solutions of both allylamine and cyclopropylamine in CF,CICCI,F to 110 K led in both cases to a change in the ESR spectrum and to the formation of an 80 G doublet. This doublet is attributed to the CH,CH,CH=N' radical, formed by ion-molecule reactions in the matrix. Holroyd and coworkers14 studied the properties of free electrons in liquid tetrakis (dimethy1amino)ethylene[(CH3)?N],C=C[N(CH3),1,. In the course of this study, they measured the free electron yield in X-ray radiolysis at various electric fields, and found by extrapolation that the free-ion yield at zero field is 0.20 & 0.02 ion pairJ100 eV. Initial ion pair formation has usually a G value of 4.0, which means that about 5% of the formed ions escaped geminate recombination. Ill. RADlOLYSlS OF AQUEOUS SOLUTIONS OF ENAMINES
Getoff and Schworter15 studied the rate constants for the reaction of the initial intermediates in water radiolysis, e,,- and OH, with various amines, including allylamine. For OH reaction with amines at pH 4.0 they found a correlation between the rate constant and the number of carbon atoms in the molecule. For aliphatic branched carbon skeletons the rate constants are slightly smaller than for straight-chain amines. Allylamine has an exceptionally high rate constant according to this correlation. Thus, while OH reacts with propylamine at pH = 4 with a rate constant of 4.0 x lo9 M-I s-', it reacts with allylamine with a rate constant of 2.2 x 10" M-Is-'. The high rate constant is probably due to a higher concentration of electrons on the NH, group, due to resonance forms with the olefinic double bond in the radical. Another possible explanation for the high rate constant for the reaction with allylamine is that, in the case of allylamine, there are two pathways of reactions; the OH can react by abstraction of a hydrogen atom or by addition to the double bond. For the reaction of e,,- with allylamine at pH 11 the rate constant is k = 1.2 x 10' M-Is-' , a value which is considerably higher than for other aliphatic amines except isobutylamine. For example, the rate constant for n-propylamine is almost an order of magnitude lower, being 1.33 x lo6 M-' s-'. The high rate constant for reaction with OH and the low rate constant for reaction with e,,- made the allylamine a good candidate for studying the two possible mechan-
12. Radiation chemistry of enamines
685
isms of positronium formation. Although the rate constants ratio is much higher for n-pentylamine, its lower solubility together with practically the same rate constant for the reaction with OH radicals increases the use of allylamine for the study of positronium formation. Positronium is an unstable species which consists of an oppositely-charged electron and positron, similar to the hydrogen atom consisting of an electron and a proton. The o-positronium (0-Ps) with anti-parallel spins has a half-life of 10-' s in vacuum, after which there is annihilation of the pair to two photons of 511 keV. In liquids, the half-life of o-Ps is considerably shorter and depends on the liquid and the solutes. Thus, e.g., its half-life in water is 1.86 ns and in benzene 3.2 ns. Not all the positrons form positronium, since some annih!late before they succeed in forming positronium. There is also formation of a p-Ps with parallel spins of the positron and electron with a ratio of 3: 1 due to the different degeneracies of the spin values. The ionization potential of o-Ps, i.e. the bond strength of the e-++ pair in o-Ps, is half the ionization potential of hydrogen atom (6.8 eV vs 13.6eV), due to the reduced mass of o-Ps which is half that of the H atom; this leads to a double radius for o-Ps compared with a hydrogen atom (1.06 8, compared to 0.53 8,).This ionization potential is lower than that of any molecule of the solvents or the solutes. Consequently, the formation of o-positronium by the reaction of equation 9 is highly endothermic and quite improbable. e++A
-
o-Ps+A+
(9)
Two mechanisms were suggested for the formation of o-Ps. The first one is the o r e gap model, which suggests that the positron undergoes reaction 9 while it still has high kinetic energy. The positron itself is formed by the decay of unstable nuclides which have an excess of protons, and in the decay the excess potential energy of the nucleus (above 1.022 MeV required for the formation of e+ and e-) is converted to kinetic energy of the positrons (usually hundreds and thousands of keV). The positron loses this high kinetic energy by interaction with the media (similarly to radiolysis, where electrons lose their energies), and along the track in which it loses this energy it can react via reaction 9, as long as it has sufficient energy. The other model, called the spur model, argues that the positronium is formed not via reaction 9, but by the reaction of the thermalized positrons with free electrons formed by the radiolysis of the liquid due to the high kinetic energy of the positrons. There is competition for the free electrons between the positrons and the holes (OH radicals in the case of water media). When OH competes for these free electrons the addition of OH scavengers is predicted to cause an increase in the yield of o-Ps, a phenomenon called 'enhancement'. On the other hand, addition of electron scavengers will reduce the yield of o-Ps, an effect known as 'inhibition'. The yield of o-Ps is usually denoted by I, (where I, and I, are the yields of free positrons and p-Ps, respectively, having a much shorter half-life than o-Ps). Duplatre and coworker^'^^'^ found that the yield of o-Ps in aqueous solution in the presence of concentration C of allylamine is given by equation 10. The enhancement factor 1 + /Kis due to the reaction of allylamine with OH radicals, while the 1 + ~Cinhibitionfactor is due to the reaction with aqueous or free electrons. The enhancement by amines is one of the main pieces of evidence for the existence of the 'spur mechanism'. Yet, it should be emphasized that it does not rule out the simultaneous existence of both mechanismsL8.Duplatre and coworkers16 found that the inhibition by a strong inhibitor such as N O , is the same in the presence or absence of allylamine.
Zeev B. Alfassi Talamoni and coworkers" found that in methanol, allylamine has no influence on the yield of o-Ps. Other amines, such as n-propylamine and triethylamine, increase the yield of the o-Ps. The authors ascribe this difference to the higher ionization potential of allylamine, making positive charge transfer from the solvent ions (the holes) ineffective. The ionization potential of allylamine (9.6 V) is considerably higher than that of other amines (n-propylamine 8.8 eV, triethylamine 7.8 eV, aniline 7.7 eV). They found a correlation between the ionization potentials and the enhancement factors. In water, allylamine also enhances the formation of o-Ps, due to the much higher ionization potential of water, 12.6 eV (while the value for methanol is only 10.8 eV). IV. POLYMERIZATION OF ENAMINES BY RADIATION A. Allylamlne
Dyachkovskii and coworker^'^ measured the radiation-induced gas-phase polymerization of allylamine and diallylamine on polyethylene. The purpose of this work was the formation of the amine functional group on developed surfaces of polymeric substrates. The gas and substrate mixture were irradiated either by 60 Co y-rays or by fast electrons (3-5 MeV) from electron accelerators. It was found that the amount of grafted amine is linear with the absorbed dose, at least up to grafted allylamine 1% of the polymer. The G value of the grafted amine is 10, independent of the dose rate over a wide range of dose rates (0.6 Mrad h- '-6.5 Mrad min- '). The independence of the dose rate indicates that there is a termination by combination of two radicals. These results are characteristic for all olefinic compounds, but the influence of the amine group is minor. For example, similar results were obtained for allyl alcohol, although the G values are different (2) for allyl alcohol vs 10 for allylamine). It can be assumed that the grafting is of short chains, as was found for grafting of several allylic monomersz0. In additional work, the same groupz1 extended the study of graft polymerization of allylamine and diallyl amine to surfaces of different polymers. They used polyethylene, polypropylene, ethylene-propylene copolymer and polybutadiene. The grafting of allylamine and diallylamine was performed in the gas phase, initiating the polymerization by 60Co irradiation. Grafted polymers with functional amine groups of about 1% of the total polymer were formed. Due to the low concentration of the functional groups it was difficult to study the structure of the polymers by the common methods of chemical analysis. The structure of the grafted polymers, mainly those of allylamine and diallylamine with polyethylene, was studied by the spin labelling method. This method enables one to clarify the topochemical features of the primary and secondary amino groups grafted to the surfaces of the carbon chain polymers. It consisted of reacting the functional cover of the polymer with stable radicals used as spin labels, based on the iminoxyl radical. The radical contains chlorine atoms, one of which reacts with the amino group (eliminating HC1) thus binding the spin label to it. In this method they could find the distances between the side chains of the grafted polymer, using the ESR spectrum of the spin-labelled polymer. The polymerization of pure allylamine in the liquid state was studiedz2 and it was found that the addition of protonic acids increases considerably the rate of polymerization, together with increasing the molecular weight of the product polyallylamine. These effects are maximal with phosphoric acidsz2.In order to be able to study the mechanism of the elementary steps of the polymerization, it was necessary to slow them. Kreindel and coworkersz3 irradiated a 1:3 mixture of allylamine and phosphoric acid at 77 K, and followed the post-irradiation chemical processes, when the mixture was slowly defrosted. The irradiation was done with 60Co irradiator with absorbed doses in the range 0.2-30 Mrad. They found that slow defrosting (at a rate below 2" per min) leads to the formation of a high-molecular-weight product, which is not formed in the case
12. Radiation chemistry of enamines
687
of pure allylamine with the same dose range. IR and NMR spectra and elemental analysis show that the product is polyallylamine. For a 2-Mrad irradiation, polymer with molecular weight of ca 100,000 was formed. Similar polymer was also found with rapid defrosting, but the yield was considerably less (< 3%) compared with > 80% for slow defrosting. This leads to the conclusion that practically all the polymer is formed during the post-irradiation warm-up, whereas the irradiation at 77 K merely leads to accumulation of the active centres in the system. Using slow defrosting, it was found that the polymer yield rises almost linearly with the dose up to about 2 Mrad. For 2-3 Mrad and larger doses, the yield is constant, being ca 80%. It was found that addition of benzoquinone to the system before irradiation prevents the formation of the polyallylamine, indicating that the polymerization proceeds by a radical mechanism. Calorimetric measurements of the warm-up-show an exothermic step, apparently due to the polymerization process. On increasing the absorbed dose in the sample, the onset of the exothermic process is shifted to lower temperatures. These data can be transformed to an Arrhenius plot for the polymerization reaction to give an activation energy of 13.8 + 3 kcal mol-'. The activation energies are slightly larger for larger doses. This activation energy is higher than that for usual chain propagation in the liquid'phase (3-7 kcal mol-'), but it is similar to values found for other chain-propagation postirradiation polymerization. The higher activation energies show that at low temperatures the reaction takes place in the diffusion range, while at higher temperatures the reaction occurs in the kinetic range. One difference between allylamine and a mixture of allylamine with H,PO, is that, at 77 K, the former is crystalline while that latter is vitreous. To check if the different polymerization is due to the different phase state, a mixture of allylamine with glycerin was also irradiated at 77 K and defrosted. Although a 2:5 v/v mixture of allylamine and glycerin vitrifies in the same temperature region as the allylamineH,PO, mixture, it was found that polymerization does not take place in the allylamine-glycerin mixture. ESR studies of the irradiated mixture (allylamine-H,P04) at 77 K show the spectrum of ally1 radical, as in pure allylamine, but, in contrast to irradiated pure allylamine, there are also components with higher hyperfine interactions which are detectable at the edges of the spectrum. For the case of pure allylamine, the radicals decay as the slow defrosting comes to an end at 128 K, where all the radicals disappear, while the irradiated material is still solid. The decay of radicals in the allylamine-H,P04 mixture is distinctively different. The decay of the radicals is much slower, and even at the glass transition temperature (ca 190 K) the decay is not complete. At 19C240 K, the concentration of radicals remaining in the system is practically constant and proportional to the absorbed dose. The ESR spectrum at 190K is a quartet with intensity ratio 1:3:3:1. Kreindel argued that this is the spectrum of radicals of the type R-CH,-CH-CH,-&H,, which is influenced by only two b hydrogen atoms. The other two b hydrogen atoms are undetectable in the ESR spectrum due to anisotropic interaction with the u hydrogen, caused by a conformation angle in the range 20-40". The size of the peaks in this spectrum is similar to those obtained as wings in the spectrum at 77 K, before the defrosting. Consequently, the authors concluded that individual acts of addition of primary radicals to monomer molecules take place at the irradiation at 77 K. However, effective polymerization starting above 210 K is the result of the involvement of the main bulk of the monomer in the reaction. The initial addition is not hindered by diffusion, while diffusion prevents further growth of the chain. For involvement of the main bulk of the monomer, softening of the matrix has to take place (devitrification temperature 190 K). The authors showed that the initial rate of 'rapid' polymerization is proportional to the number of initial radicals. Also, the larger the number of initial radicals, the smaller is the molecular weight of the final polymer. The phosphoric acid has two roles which lead to the formation of high-molecular-
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weight polymers; (1) it stabilizes the radicals, both at the stage of initiation and at the step of chain propagation, by binding them through hydrogen bond complexation; (2) protonation of the amino group leads to larger C-H bond strength in the a-CH, group of the monomer, which means prevention of chain transfer to monomers at low temperatures. B. 2-Aminoethyl Vinyl Ether (H2NCH2CH20CH=CH2)
Nurkeyava and coworkers2' studied the y-ray induced polymerization of 2-aminoethyl vmyl ether. They used this monomer as well as vinyl ethers of ethylene and diethylene glycols in order to synthesize water-soluble polymers. Homopolymers of these monomers cannot be obtained by other methods. In the presence of thermal radical initiators only low-molecular-weight oligomers were formed, whereas the use of acid catalysts leads to the formation of polyacetals25~26. The liquid 2-aminoethyl vinyl ether was polymerized by y-irradiation from a 60Co source. The polymer yield increases with radiation dose. The G value of the formation of the polymers decreases with dose rate and increases with temperature of the monomer while irradiated. The polymer obtained is a viscous, slightly yellowish material which is soluble in water, alcohols and dimethylformamide. A completely soluble product is obtained only up to 30% conversion. At a higher degree of conversion, partially insoluble and cross-linked polymers are formed. Up to 30% conversion there is quantitative maintenance of the amino groups, whereas at a higher degree of conversion there is a reduction in the number of amino groups, due to the incorporation of the amino groups in the cross-linking. The IR spectrum of the formed soluble polymer compared to that of the monomer shows the absence of frequencies characteristic of -C=C-(1620cm-') and =C-0-C (1205,1075 cm- ') bonds. The absorption spectrum of the amino group in the region 33W3400 cm-' remains also in the polymer. This fact, together with chemical analysis which shows that the content of the amino group in the polymer remains practically 95-100%, indicate that the polymerization is taking place only through the double bond. The G value obtained for 2-aminoethyl vinyl ether, ca 60 molecules per 100 Ev, is considerably less than that obtained for glycols-vinyl ether, probably due to the greater mobility of the hydrogen atom of the amino group, which leads to faster termination of the growing chains. The addition of small amounts of radical scavenger (such as benzoquinone and diphenylpicrylhydrazyl)led to the appearance of induction periods in the kinetic curves. The duration of the induction periods are proportional to the concentration of the radical scavenger. The presence of atmospheric oxygen slightly slowed the polymerization. These observations indicate that the polymerization proceeds by a radical mechanism. The radicals are formed from the y-radiolysis of the monomers. By comparison to the ESR spectrum of the radicals formed by thermal initiation with azobisisobutyronitrile in the presence of a spin trap, the radical formed is
-cH~-CH-O-CH,-CH~-NH~.
Tabata and coworkers studied extensively the radiation-induced polymerization of vinylcarbazole (VC) in various solvent^^^-^^. In one paperz7 they studied the initial species formed in the polymerization of VC in benzonitrile solutions. To identify the products, they used the optical spectrum obtained for glassy solutions of vinylcarbazole in butyl chloride and 2-methyltetrahydrofuran irradiated at 77 K with y-rays. Irradiation in butyl chloride matrix is known, similarly to that in other organic chlorides, to give
12. Radiation chemistry of enamines
CH=CH2
(VC) Vinylcarbazole rise to the radical cations of the solute, especially for aromatic compounds. Thus, the absorptions at 780,700. 620 and 510 nm observed for butyl chloride glassy solutions of VC are assigned to the cation radical of the VC. In a 2-methyltetrahydrofuran glassy solution of VC, irradiated at 77 K, they observed an optical spectrum with peaks at 720 and 660 nm, which they assigned to the anion radical of VC. Pulse radiolysis of a 3 mM benzonitrile solution of VC does not show any peaks. Addition of high concentration (0.5 M) of naphthalene or biphenyl to this solution leads, after pulse radiolysis, to an optical spectrum identical to that obtained at 77 K for an irradiated glassy butyl chloride solution of VC. Since pulse radiolysis of solutions of naphthalene or biphenyl in benzonitrile does not exhibit this optical spectrum, it is concluded that the optical spectrum observed in the pulse radiolysis of VC (3 mM) and naphthalene (0.5 M) in benzonitrile is due to the cation radical of VC. The radiation interacts mainly with the main component of the solution, i.e. the solvent, to form the benzonitrile cation radical. The half-life of the latter is short, and in dilute solution it will disappear prior to having a chance to transfer its charge to the solute. However, if an appropriate second solute, such as naphthalene or biphenyl, exists in large concentration, the benzonitrile radical cation will transfer its charge to this solute. The half-lives of the radical cations of naphthalene or biphenyl are considerably longer than that of the benzonitrile radical cation, and they can transfer their charge to the low-concentration solute before disappearing. This explanation indicates that in pulse radiolysis of high-concentration VC solution in benzonitrile, the optical spectrum of VC radical cation should be observed. Actually, pulse radiolysis of 0.2 M and 1 M VC solution in benzonitrile gives a very similar spectrum to that obtained from 3 mM with 0.5 M naphthalene, but it is slightly shifted to a shorter wavelength, mainly for 1 M solution. Oxygen, which is known to be an effective radical and anion scavenger, had no effect on the observed spectra, while cation scavengers such as triethylamine or N,N-dimethylaniline prevent the formation of this spectrum, indicating that it is due to a radical cation. The optical spectrum observed 1.6 $5 after the pulse is clearly different from that observed immediately after the pulse, when a sharp peak at 790 nm and broad peaks at 700, 640 and 510 nm are displayed. 1.6 ps after the pulse, the sharp peak becomes broader and the other peaks become obscure. This is probably due to polymerization, initiated by vinylcarbazole cation, taking place during this 1.6 ps. The authors suggest that the absorption spectrum of 1 M VC (with a peak at 770 nm, whereas for 0.2 M and 3 mM the peak is at 790 nm) is probably due to propagation cations, for which the absorption spectra and rate of decay are similar to one another regardless of different chain lengths. The G value for the VC cation radical can be assumed to be equal to that of the benzonitrile radical cation, from which it was formed. The G value of the benzonitrile cation has been found to be 0.8. In order to elucidate the detailed mechanism of the radiation-induced polymerization, both direct observation of the intermediates and analysis of the final products should be carried out, as was done in a later paperz8. The authors found that although the spectrum of the transient is unaffected by the presence of oxygen, the final product depends on the presence or absence of oxygen. De-aerated benzonitrile solution of VC
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yields, on y-irradiation, a white amorphous compound, while aerated solutions lead to the formation of a colourless needle-like crystal. The former product is of high molecular weight, whereas the latter product has molecular weight of only 386. The IR, UV and NMR spectra prove that the product of irradiation of de-aerated solution is polyvinylcarbazole, whereas in the presence of oxygen the crystalline dimer, frans-1,2dicarbazylcyclobutane, is formed. The G value for the formation of the cyclodimer was found to be linearly dependent on the concentration of VC, being about 300 for 1 M solution. The cyclodimerization was inhibited by cation scavengers such as triethylamine, aniline or N,N-dimethylaniline and was not inhibited by oxygen, a known radical and anion scavenger, indicating that the cyclodimerization proceeds by a cationic mechanism. Since the yield of the initial radical cation is 0.8, and the value of G for the cyclodimer in 1 M solution is 300, it means that the formation of the dimer is a chain reaction, with chain length of about 400. The authors suggested the mechanism shown in equations 11-14, S
-
S+', e+, other products
(11)
where S is the solvent (benzonitrile), M is the monomer (VC) and M 2is the cyclodimer. It was shown that the optical spectrum of the initial intermediate (the cation) is independent of the presence of oxygen, and the yields of the radical cation are the same for aerated and de-aerated solutions. The observation, that the absence of oxygen leads to the formation of the polymer rather than to the dimer, shows that oxygen plays an important role in the formation of the cyclodimer, after the production of the VC radical cation. Tabata and coworkers suggested that an oxygen molecule forms a complex with the monomer radical cation or dimer radical cation. This complexation may prevent the additional polymerization of the dimer and promotes the cyclization of a linear dimer cation to a cyclic dimer radical cation. The dimer cation reacts with 0,-in the reaction.
-
M2+ + 0 2 -
M 2+02
(15)
However, this mechanism does not explain the chain reaction. Tabata and coworkers measured the optical spectrum of the dimer cation radical, by pulse radiolysis of benzonitrile solution of the dimer immediately after the pulse. They found only a peak at 770 nm without other peaks, except for a possible small shoulder at 740 nm (which is within the limit of experimental error). Addition of cation scavengers leads to elimination of this spectrum, while oxygen does not remove it, suggesting that the spectrum is due to a cation. This 770-nm peak of the cation of the cyclodimer of VC reminds one of the 770-nin peak found 1.6 ps after the pulse in the case of 1 M VC solution. It should be noticed that while in this second paper the authors also mentioned this shift from 790 nm to 770 nm, the data in their figure show a peak at 790 nm both immediately and 1.6 ps after the pulse. Consequently, Tabata and coworkers suggested that the observed spectrum in pulse radiolysis of aerated solution of VC in benzonitrile is a composite of the spectrum of VC cation together with that of the cation of the cyclodimer of VC. The contribution of each intermediate to the observed spectrum depends on the concentration of VC and how long after the pulse the spectrum was taken. In a dilute solution, the dimer cation will be produced as time proceeds, but it is absent immediately after the pulse. In concentrated solutions, both cations coexist even immediately after a pulse.
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691
In a following paperz9Tabata and coworkers studied the radiation-induced polymerization of solutions of VC in several solvents. Irradiating both aerated and de-aerated solutions, they found that the solvents can be divided into two groups. The first group behaves similarly to benzonitrile, i.e. forming the crystalline cyclodimer trans-1,2dicarbazylcyclobutane on irradiation of aerated solution, whereas the irradiation of de-aerated solutions leads to the formation of amorphous poly-VC. Other solvents in this group, besides benzonitrile, are acetone, ethyl methyl ketone, diethyl ketone and acetophenone. Irradiation of solutions of VC in the solvents of the second group always leads to the formation of the white amorphous poly-VC, for both aerated and de-aerated solutions. The solvents that belong to this group are nitrobenzene, benzene, toluene and tetralin. Formation of both the crystalline cyclodimer and the amorphous polymer were inhibited by the presence of cation scavengers, while they were uninhibited by the anion and radical scavenger, oxygen. This indicates that in both cases the initiator of the chain reaction is a cationic species. Since the two groups differ in the behaviour of aerated solutions, Tabata and coworkers studied also the difference in the transient optical spectrum by pulse radiolysis of aerated solutions of VC in benzonitrile and in nitrobenzene. 2 ps after the pulse there is a distinct optical spectrum in aerated nitrobenzene solution, which is removed by cation scavengers. There is a difference between the spectra of 1 mM and 0.5 M VC. For 1mM aerated VC solution in nitrobenzene, there is an absorption spectrum with maxima at 790,720,640 and 500 nm, similar to that obtained in glassy butyl chloride matrix, and which is assigned to the cation radical of VC. However, for 0.5 M solution there is a flat peak between 750 and 780nm. The absorption at 750nm becomes more intense relative to that at longer wavelengths, as time proceeds. Pulse radiolysis of aerated benzonitrile solution of poly-VC shows immediately after the pulse an optical spectrum with a peak at 750 nm. It was ascribed to the radical cation of the polymer, since it can be eliminated by cation scavengers, while oxygen does not prevent its formation. Thus, the two groups of solvents can be distinguished both on the grounds of the final product in aerated solutions and on the observed transient optical spectrum. Both groups of solvents show the formation of the cation radical of VC, as can be seen from the spectrum of dilute solutions. Its spectrum changes to the spectrum of the dimer cation in the first group of solvents, whereas in the second group the change is to the polymer cation radical (although the difference between the spectra of the dimer cation and the polymer cation is not large). For concentrated solution a mixed spectra is obtained in pulse radiolysis studies. The observed spectrum consists of a mixture of monomer + cyclodimer cations in the case of the first group, while a mixture of monomer + polymer cations are observed for the second group of solvents. It should be mentioned that the spectrum after pulse radiolysis of aerated 1 M VC solution in benzonitrile immediately after the pulse is quite different in References 28 and 29. The authors did not mention this difference and did not give any indication why there are two different spectra for the same solution. However, since the spectrum given in Reference 29 is given also in a later article3', it can be assumed to be the correct one. In this later paper, Tabata explained the difference. between the two groups of solvents on the basis of a pulse spectrum of a representative from each group--benzonitrile and nitrobenzene, and the spectra obtained in various mixtures of the two solvents. Tabata found that, although the absorption of benzonitrile anion was observed in de-aerated benzonitrile, it was not observed in aerated solutions. In the case of nitrobenzene solutions, the spectrum of the anion of nitrobenzene is observed for both aerated and de-aerated solution. Therefore, the main negative species in aerated benzonitrile solution This different formation of is probably the anion radical of the oxygen molecule, 0,-'. solvent anion vs oxygen anion can be ascribed to a competitive capture of the electron
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Zeev B. Alfassi
by the solvent and oxygen molecules. The authors conclude that the difference between the two groups of solvents is due to the presence of the anion radical 0,-', which is responsible for the cyclization-neutralization of the linear dimer cation. Another difference between benzonitrile and nitrobenzene solutions is the different yield of the vinylcarbazole cation radical VC" (assuming that the molar absorption coefficient is the same in both solvents, since the observations can be explained also by assuming equal yields with different molar absorption coefficients). However, this cannot be the cause of the different behaviour of the solvents, as the initial yield can be changed by varying the dose rate, which has no influence on the final product. In mixtures of benzonitrile and nitrobenzene, the anion of nitrobenzene is observed as long as the concentration of nitrobenzene-is at least 5%. This agrees with the product analysis from irradiation of aerated VC solution in a mixture of the solvents. A cyclodimer is obtained only if the concentration of nitrobenzene does not exceed 5%, while polymers are obtained from solutions containing more than 5% nitrobenzene. Tabata suggested equation 16 as an explanation for the effects of 0,-'.
It should be noted that another molecule of the monomer must be a part of the cyclization process, in order to explain the chain character of the process. Tabata suggests that although the main catalyst for the cyclodimerization is 0,-', at high oxygen concentration an 0, molecule can also promote the formation of the biradical of the linear dimer and the following biradical cyclization. However, Tabata does not explain why this mechanism will not lead to cyclodimerization also in nitrobenzene or why polymerization of VC in nitrobenzene is inhibited by cation scavengers but not by DPPH (diphenylpycrilhydrazide-a radical scavenger) while dimerization and polymerization in benzonitrile were inhibited by both DPPH and cation scavengers. Another open question is: what is happening in a mixture of 5% nitrobenzene and 95% benzonitrile, where neither the cyclodimer nor the polymer are formed? Why, in this mixture, does the VC cation radical (whose yield is higher than that in pure benzonitrile) not react with other molecules of VC? Irradiation of either aerated or de-aerated nitrobenzene solution leads to formation of the polymer, poly-VC. The nature of the product is the same, but the yields and the molecular weights of the product depend on the presence or absence of oxygen. In aerated solution, higher yields and smaller molecular weights were observed than in de-aerated solution. In nitrobenzenebenzonitrile mixtures, both the rate of polymerization and the molecular weight decrease with decreasing fraction of nitrobenzene, for both aerated and de-aerated solutions. These findings lead to the conclusion that 0,promotes the chain transfer reaction in the higher-concentration region of nitrobenzene. The role of 0, as a chain-transfer agent in the polymerization was ascribed by Tabata to the scheme given in equations 17-21.
12. Radiation chemistry of enamines
69 3
Tabata and coworkers3' found that, at low temperatures, there are two types of dimer cation-a non-bonded n-n sandwich type and a bonded linear type. Cation scavengers were found to inhibit both the radiation-induced dimerization and polymerization. Tabata and coworkers3' studied the rate of VC+' disappearance with the cation scavengers triethylamine, diphenylamine and N,N-dimethylaniline in nitrobenzene solution, and found the rate constants to be 1.3 x lo9, 2.0 x lo9 and 3.0 x I O ~ M - s-' ' , respectively. The rate constants of charge transfer for the different scavengers correlate well with the ionization potential of the cation scavengers (7.12, 7.25 and 7.50eV, respectively) in the gas phase. Almost the same rate constants for charge transfer that were measured for the vinylcarbazole cation radical were found also for N-ethylcarbazole cation radical, indicating that a large portion of the positive charge in VC+' as well as in the ethylcarbazole radical cation is localized on the carbazole ring, and not on the olefinic double bond which does not exist in N-ethylcarbazole. V. ACKNOWLEDGEMENT
The help of Dr A.B. Ross from the Radiation Chemistry Data Center, Radiation Laboratory, University of Notre Dame, in the literature survey is very much appreciated. Vl. REFERENCES
1. J. H. O'Donnell and D. F. Sangster, Principles of Radiation Chemistry, Edward Arnold, London, 1970. 2. J. W. T. Spinks and R. J. Wood, An Introduction to Radiation Chemistry, 2nd edn., Wiley, Chichester, 1976. 3. A. J. Swallow, Radiation Chemistry--An Introduction, Longman, London, 1973. 4. A. Mozumder, Adv. Radiat. Chem., 1, 1 (1969). 5. E. G. Janzen, Acc. Chem. Res., 4, 31 (1971). 6. C. Lagercrantz and S. Forshult, Nature, 218, 1247 (1968). 7. P. K. Ludwig, Adv. Radiat. Chem., 3, 1 (1972). 8. J. H. Baxendale and F. Busi, The Study of Fast Processes and Transient Species by Electron Pulse Radiolysis, Reidel, Dordrecht, 1982. 9. V. Buxton, in Radiation Chemistry, Principles and Applications (Eds. Farhataziz and M. A. J. Roders), Verlag Chemie, Weinheim, 1987. 10. 1. D. Draganic and Z. D. Draganic, The Radiation Chemistry of Water, Academic Press, New York, 1971. 11. S. Dai, Q. X. Guo, J. T. Wang and F. Williams, J. Chem. Soc., Chem. Commun., 1069 (1988). 12. J. B. Peel and G. D. Willet, Atcrt. J. Chem., 30, 2571 (1977). 13. X. Z. Qin and F. Williams, J. Am. Chem. Soc., 109, 595 (1987). 14. R. A. Holroyd, S. Ehrenson and J. M. Preses, J. Phys. Chem., 89, 4244 (1985). 15. N. Getoff and F. Schworer, Int. J. Radial. Phys. Chem., 2, 81 (1970). 16. G. Duplatre, J. C. Abbe, J. Talamoni and A. G. Maddock, Chem. Phys. Lerr., 100,553 (1983). 17. J. Talamoni, J. C. Abbe and G. Duplatre, Radiat. Phys. Chem., 24, 449 (1984). 18. Z. B. Alfassi, Ber. Bunsen. Phys. Chem., 88, 453 (1984). 19. D. A. Kritskaya, A. D. Pomogailo, A. N. Ponomarev and F. S. Dyachkovskii, Polymer Sci. USSR, 21, 1214 (1979); J. Polymer Symp., MI, 23 (1980). 20. V. J. Volodina, A. P. Tarasov and S. S. Spasskii, Usp. Khim., 39, 276 (1970); Russ. Chem. Rev., 39, 140 (1970).
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21. N. M. Bravaya, A. D. Pomogailo and F. S . Dyachkovskii, Polymer Sci. USSR, 12,1964(1979). 22. M. N. Masterova, L. I. Andreyeva, V. P. Zubov, V. A. Kabanov and L. S. Polak, Polymer Sci. USSR, 18,2234 (1976). 23. M. Ya. Kreindel, L. I. Andreyeva, A. M. Kaplan, V. B. Golubev, M. N. Masterovo, V. P. Zubov, S. Polak and V. A. Kabanov, Polymer Sci. USSR, 18, 2553 (1976). 24. Z. S. Nurkeyava, Ye. M. Shaikhutdinov, A. Z. Seitov and S. Kh. Saikiyeva, Polymer Sci. USSR, 29, 1032 (1987). 25. R. M. Nowak, USA Patent 33282468, RZhKhim, 21,21S263P, 1968. 26. M. F. Shostakovskii, A. S. Atavin, B. A. Trofimov, V. I. Larov, R. D. Yakubov and M. A. Aleshin, USSR Pat. 172043, B.I. 12, 76, 1965. 27. S. Tagawa, S. Arai, A. Kira, M. Imamura, Y. Tabata and K. Oshima, Polymer Lett., 10, 295 (1972). 28. S. Tagawa, S. Arai, M. Imamura, Y. Tabata and K. Oshima, Macromolecules, 7, 262 (1974). 29. S. Tagawa, Y. Tabata, S. Arai and M. Imamura, J. Polymer Sci. B, 12, 545 (1974). 30. Y. Tabata, J. Polymer Sci., Symp. 56, 409 (1976). 31. S. Tagawa, M. Washio, A. Kira, Y. Tabata and M. Imamura, Proc. 26th Inr. Cong. Pure Appl. .. them:, 26, 1294 (1977). 32. M. Washio, S. Tagawa and Y. Tabata, J. Pkys. Ckem., 84, 2876 (1980).
CHAPTER
13
Acidity and basicity of enamines Departamento de Quimica FIsIca Aplicada, Universidad Autonoma de Madrid, Cantoblanco, Madrid 28049. Spain and
FRANCISCO GARCIA BLANCO
Departamento de Ouimica Fisica, Facultad de Farmacia, Ins. Pluridisciplinar Universidad Complutense de Madrid, Madrid 28040, Spain --
.. . ......... . . .. . . . ..... .. .. ..... .. . . .......... .............. ............................ 1. Protonation site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Hydrogen atom affinities . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Analogies with the basicity of saturated amines . . . . . . . . . . . . . 4. Ionization energies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Theoretical calculations . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Analysis of intrinsic effects . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Conjugation indicators . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Condensed-phase Basicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Protonation site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111. ACIDITY O F ENAMINES . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. HYDROGEN BONDING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Enamines with Primary Amino Group . . . . . . . . . . . . . . . . . . . . B. Other Types of Enamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Enamines with Secondary Amino Group . . . . . . . . . . . . . . . . . . . D. Solid State Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V.REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I. INTRODUCTION
11. BASICITY O F ENAMINES A. Gas-phase Basicity . . . .
I. INTRODUCTION
Enamines are classical reagents, most properties of which originate from their acidity or high basicity and their strong amphiprotic character. Their special molecular behaviour is a result of their being resonance hybrids of the two resonance structures 1 and 2. TIIFCheinistn ~fEnamincs. Edited by Zvi Rappoport Copyright 0 1994 John Wiley & Sons, Ltd. ISBN: 0-471-93339-2
695
J. Catalan and F. G. Blanco
Ever since the earliest attempt at accounting for the reactivity of enamines was reported by Stork and coworkers1, approaches to the subject led to a fascinating chemistry whereby a given electrophilic reagent can yield variable types of different products on attacking an enamine by slight changes in the reaction conditionsz" (e.g. temperature, solvent, presence or absence of a base) or by structural alterations (e.g. the size of the amine moiety). More remarkably, by introducing substituents into the alkene residue, which in principle have little or no effect on its properties, modification of the reaction products have been obtained. Every review on enamines published so far includes a section dealing, however briefly, with the acid-base properties of these compound^^,^. In our chapter we shall focus on the behaviour of enamines in protonation and deprotonation processes and try to systemize the available information on the subject, in order to shed some light on the active site involved in the processes concerned. In order to avoid any complications resulting from the well-known enamine ( 3 ) e i mine (4) equilibrium (equation I), we shall concentrate on the acid-base behaviour of tertiary enamines, even though we shall also consider pertinent available information on primary and secondary enamines. H \
\
..
N-
I
/"=%
-
\ H-C-C /
'N//
\
(1)
A number of subjects related to protonation or deprotonation (such as stereoselectivity, hydrolysis mechanisms or asymmetric induction) will be avoided, since they are dealt with in other chapters of this volume. II. BASICITY OF ENAMINES
Enamines are classical bidentate reagents that interact with electrophilic species via both their nitrogen and their jcarbon atoms. The simplest instance of such reaction (equation 2) is a proton attack which results in the formation of an iminium cation (5) and an
13. Acidity and basicity of enamines
697
enammonium cation (6). It is thus crucial to determine which site undergoes the attack and why the site attacked may be changed with the molecular conformation or the attacking agent. A. Gas-phase Basicity
The acidity and basicity concepts are among the most significant in chemistry4s5and have played major roles in the rationalization of this science. An intrinsic acid-base behaviour can be expressed5 by means of the hypothetical process of equation 3. BH&,#B&
' + Hi,
(3)
The standard free energy for this reaction, AGO, is a measure of the gas-phase acidity The standard enthalpy change for of BH (AG,",,) or the gas-phase basicity of B (AGH.+). this reaction, AH", is known as the proton affinlty (PA) of the base B (a neutral or anionic species, depending on whether v = 1 or v = 0, respectively). The significance of these values lies in the fact that they are intrinsic in nature, as they are free of solvation contributions6 from both neutral and charged species in a bulk condensed phase. In practice, experimental AG,",,, and AQH+ values are obtained from the pertinent gas-phase proton transfer equilibria, shown in equations 4 and 5. BH
+ B,;,t---
BH+
+ B,,-B:,H
B,,,H
+ B+B
(4) (5)
These two equilibria provide the relative strength of an acid and base, respectively, relative to a reference compound (B,,,H or B,!,) of known acidity or basicity. The reference with respect to which the gas-phase bas~cityscale was constructed is ammonia, which features AQH+ = 195.6 kcal mol-' and PA = 204 kcal mol-' 4. All the data given in this review are referred to these values; also, the standard states of the different species involved in equilibria 3-5 above-perfect gases-shall be assumed to have unit fugacity. Even though the experimental AG;, values for the equilibria of equations 4 and 5 are known to within 0.1 kcal mol-', it is often more useful to determine AHo for equation 3 by studying acid-base behaviours. For a given process such as equation 5, the unknown basicity of species B can be calculated from equation 6 provided the equilibrium constant for the process and the basicity of the reference compound are known: PA = PA,,,
+ 2.303RT log K - T A P
(6)
where K is the equilibrium constant for equation 5 and AS" is the corresponding entropy change. The entropic term in equation 6 can be determined experimentally by measuring equilibrium constants at various temperatures or, more commonly, by means of statistical corrections considering symmetry changes in the reaction concerned7. Gas-phase acid-base studies are usually performed by using one of the following techniques: high-pressure mass spectrometry (HPMS), chemical ionization mass spectroscopy (CIMS) with mass-analysed ion kinetic energy spectroscopy/collision induced dissociation (MIKESICID), flowing afterglow (FA) or ion cyclotron resonance (ICR) spectrometry. For a brief description of all methods, Reference 8 should be consulted. Enamine basicity has been investigated exclusively by the ICR technique, one of the most salient features of which is the low working pressures usually employed (between and torr). Drift-cell instruments allow the ion-molecule reaction to develop with thermalization of the species involved in the equilibrium in a few milliseconds at a pressure of ca torr. Trapped-ion cell instruments afford reaction times of up to
J. Catalan and F. G. Blanco
698
a few seconds. Trapping entails the simultaneous use of electric and magnetic fields and allows not only measurement of the overall equilibrium constant, but the rates for the forward and reverse reactions to be determined by means of double resonance experiments. Because of the high instability of enamines (particularly primary and secondary ones, which rearrange to their corresponding imines), they are handled with ICR, in its drift mode, and a bracketing technique in order to detect charged forms on altering the basicity of the reference base used, on the assumption that exothermic proton transfer processes will be observed whereas endothermic processes will not be observed. Since primary and secondary enamines are unstable, they cannot be used as such by the ICR technique, so that they have to be obtained in situ. Thus, Ellenberger and c o w ~ r k e r s ~obtained ~'~ a protonated form of the enamine at its /3 carbon (a), by elimination of a methyl group from isopropylamine (7) by electron bombardment fragmentation (equation 7). On reacting cation 8 with bases of increasing basicity, these CH3 H \ / FH-N \
cH3
+ e-
-
H
H H \ +I /C=N \
CH3
(7)
(7)
H (8)
author^^^'^ determined its acidity (or, similarly, the basicity of the neutral form obtained) from its deprotonation reaction. However, they showed that the results could not be directly assigned to the enamine concerned; in fact, in some elegant experiments involving various deuterated isopropylamines (9 and 10) as the precursors, they found that the most acidic proton in the cation was not one in the methyl group but a proton in the amino group, so that the deprotonation gave rise to the imine rather than to the enamine (equation 8). CD3 H / \ ,CH-N \ H CD3
+ e-
-
H
\
H
+/
C=N / \ CD3 H
+ BEf
-
+ BEfH+ + CD3CH=NH (8)
(9)
CH3
D
\
/
/
\
CH-N
CH3
+ e-
D
-
H
D
\
+/
/
\
C=N
CH3
+ BEf
-
+ BEfD+ + CH3CH=ND
D
(10) Ellenberger and c o w ~ r k e r s also ~~'~ estimated the basicity of some primary enamines by using the theoretically evaluated isomerization energy of the imine+namine (4+3) reaction. Consequently, their reported basicities for primary enamines are less accurate than those obtained directly by them from equation 5, as usual for tertiary enamines. Table 1 lists known intrinsic basicities for some enamines, the experimental sources of the data and the most likely protonation sites according to the discussion below. 1. Protonation site
Inasmuch as enamines are amphiprotic reagents, they can undergo electrophilic attacks on either the /3 carbon or the nitrogen atom. Gas-phase evidence has been
13. Acidity and basicity of enamines
699
commonly used to infer that these substances are preferentially protonated on their carbon atom. Thus, Ellenberger and coworkers1° claim that the aliphatic enamines they investigated (Table 1) are all carbon bases. On the other hand, Haselbach and cowo r k e r ~ assert '~ that the situation with cyclic enamines may vary depending on whether or not the molecular structure concerned hinders conjugation. Since correct assignment of the protonation site for the enamine systems is essential, we believe that careful evaluation of the evidence in this context is in order. For this purpose, we shall consider such data as hydrogen affinities, analogies with saturated amines, theoretical calculations and the analysis of structural effects by using the Taft-Topsom substituent model13. 2. Hydrogen atom affinities
The homolytic cleavage of the bond that links the basic site of the base to the proton in the cationic form gives rise to a hydrogen atom and the cation radical of the base according to equation 9. The enthalpy increment for this process is known as the hydrogen atom affinity (HA) and can be obtained from the thermodynamic cycle in equation 10 provided that PA and the ionization potential for the base B are known, by using equation 11,
PA(B:)\
/IP(B:)
B:
- IP(W
+ H+
HA(B+') = PA(B:) + IP(B:) - 313.6
(1 1) where IP (H') is assumed to be 313.6 kcal m o l l '. As shown by Aue and coworkers14, HA values remain roughly constant within a homologous series. The ionization potential of the lone electron pair at the nitrogen site of both amines and enamines is unambiguously assigned. It may therefore be of much use in order to determine whether the enamine is protonated at the same site as its corresponding saturated amine (i.e. whether or not it is protonated at the nitrogen atom) on the basis of HA values. Vinylamine (11) has a vertical ionization potential IP, = 199.5 kcal mol-' l 5 which, together with its PA ( = 219.1 kcal mol-'), results in 105 kcal mol-', i.e. a very different value from the 120.9 kcalmol-' for ethylamine (IP, = 217.4 kcal mol-I, PA = 217.0 kcal mol-I). Therefore, vinylamine is definitely not a nitrogen base. This is consistent with both theoretical data and the analysis of intrinsic effects, as shown below. N,N-dimethylvinylamine (13) is another important model compound in this context. Despite the fact that its IP, has not been determined experimentally, it can be estimated from relations between the IP, of some RNMe, derivatives and the a,, a, and a, values for the substituents13. On the basis of the data for compounds with R = H, Me, Et, Ph, c-Hex, CF,, CH,CF,, NH, and NMe, one obtains equation 12, IP, = (19.6 5 4 . 0 ) ~+~(67.5 5 7 . 2 ) + ~~ (16.5
4 . 5 )+ ~~ 204.6
(12) with n = 9, r = 0.98 and SD = 2.9 kcal mol-'. From this equation it follows that the
700
J. Catalan and F. G. Blanco
TABLE 1. Gas-phase basicity of enamines Enamine
Aq+
PA
H NH2 \ I /C=C \ H H
21 1.3
219.1
C[HA, Th, IP, TT]
220.0
227.8
N[An, IP, HA]
10
221.7
229.4
NAnl
10
221.7
229.5
N[HA, IP]
10
228.6
236.7
C[HA, IP, An]
10
228.6
236.7
C[HA, PA, An]
220.7
228.5
N[HA, IP]
MLPS"
Reference
9
(11)
13. Acidity and basicity of enamines TABLE 1. (continued)
Enamine
AGi+
MLPS"
PA
Reference
NHAI
C[HA, IP]
N[HA, IP]
CCHA, IP]
ClIPI
" MLPS =most likely protonation sites; An =analogy with saturated amines; HA =hydrogen affinities; Th = theoretical calculation; IP = ionization potential; 'IT = Taft-Thopson intrinsic
IP, of 13 is 196.3 kcal m o l l . From this value and PA = 227.8 kcal m o l l , one obtains HA = 110.5 kcal m o l l , which is very close to the value of 107.3 kcal mol-I for EtNMe, (PA = 227.5 kcal mol-l, IP, = 193.4 kcal mol-I). According to these results, this enamine seemingly behaves as a nitrogen base. This conclusion can also be reached on analysing data for Me,CH=CHNMe, (15), with PA = 229.5 kcal m o l t and IP, = 187.9 kcal mol-', which result in HA = 103.4 kcal mol-', similar to the 107.5 kcalmol-I for the corresponding saturated amine, Me2CHCH2NMe2(PA = 229.5 kcalmol-I, IP, = 191.6 kcalmol-I). Therefore, judging from HA values, not all the aliphatic enamines studied appear to be carbon bases, which contradicts the assertions of Ellenberger and coworkerslO. The situation for cyclic enamines as pictured by Haselbach and coworkers12 is quite clear: while rigid cyclic enamines, for which resonance structures as in 2, like dehydroquinuclidine (18) are unimportant, are protonated at their nitrogen atom, those for which resonance is possible, like 23, are protonated at their carbon atom. If the enamine
J. Catalin and F.G. Blanco
c
e
(18)
(25)
N: HA = 109.7 kcal mol-'
N: HA = 103.5 kcalmol-'
HA = 100.0 kcalmol-1
HA = 106.9 kcal mol-1
structure is not rigid (e.g. in 21), then protonation takes place at the carbon atom. On the other hand, compound 22 would be a model for protonation at the nitrogen atom. This is discussed in greater detail below. 3. Analogies with the basicity of saturated amines
Let us analyse the effect of alkyl substituents on the basicity of vinylamine and compare it with those of saturated amines bearing equivalent substituents. In principle, the alkyl substituents will exert their action through their polarizability effect, so that introducing them at roughly equivalent positions relative to the nitrogen atom should result in comparable effects if the nitrogen atoms were protonated. On analysing data (in kcal mol-') for the methylation of vinylamine, at the a position, it is clearly apparent that these compounds are protonated at their carbon atoms.
H
H
H N-H \ I ,C=C \ H H
= 211.3
H N-H \ I ,C=C \ H Me
AGO
= 218.5
7.2
208.5
H H H I I I H-C-C-N I I \H H Me
AGO
= 21 1.0
2.5
H H I I H-C-C-N I I H H
AGO
H I AGO=
' H
&AGO
\
\
The results for the dimethylation of vinylamine at the nitrogen atom again reveal that the dimethyl derivative obtained appears to be protonated at the nitrogen atom-otherwise the basicity would increase much more ostensibly. If this conclusion is correct, then
703
13. Acidity and basicity of enamines H
\
H N-H \ I /C=C \ H H H H I I H-C-C-N
I
H
I
H
AGO
=211.3
Me\ H N-Me \ I /C=C \ H H
AGO
\H
= 208.5
I
AGO
= 220.0
8.7
AGO
= 219.7
11.2
Me
H H
H
I
&AGO
I
/
H-C-C-N
h e
N,N-dimethylvinylamine derivatives with alkyl substituents at the carbon atoms should behave similarly to saturated amines, being protonated on nitrogen. The results of both monomethylation and dimethylation at the B carbon are consistent which such a behaviour, as shown by the SAG" values below. Consequently, they should be protonated at the nitrogen atom. On the other hand, the uJ3-dimethyl derivative appears to be protonated at a different site, so it could be a carbon base. Me\ H N -Me \ I ,C=C \ H H H I H-C-C-N
I
H H
I
I
H AGO
= 220.0
Me / AGO
= 219.7
\
I
I
AG0=221.7
Me H
I
I
AGO
= 220.4
0.7
AGO
= 221.7
2.0
h e
Me /
H-C-C-N
h e
1.7
Me /
H-C-C-N
Me
= 219.7
N -Me
/"="\H Me I H I Me
AGO
&AGO
I
h e
/
H-C-C-N
Me\
h e
From the reasoning above one could also expect the occurrence of alkyl derivatives of vinylamine which have very similar carbon and nitrogen basicities.
H H
I
I
H-C-C-N
Me I AGO
h e
= 219.7
H H I I H-C-C-N e
A
Me I AGO
h e
= 223.0
3.3
704
J. Catalan and F.G. Blanco
4. Ionization energies
Clearly, in the thermodynamic cycle above for the estimation of hydrogen affinities there must indeed exist, for a family of homologous compounds, a linear relationship between the basicity, defined as PA or as AG" (because the entropic correction would be constant within the family), and the IP, for the lone electron pair that undergoes the protonation. Because the lone pair at the nitrogen site is usually correctly assigned in both saturated amines and enamines, the linear correlation above could serve as a powerful predictive alternative16which might allow one to determine whether an enamine is a nitrogen base. Let us consider vinylamine, a model for primary enamines. Figure 1 shows the linear relationship between AG" and IP, for saturated primary amines. The value for vinylamine clearly deviates from such a relationship, so this compound cannot be a nitrogen base. On analysing the situation of saturated tertiary amines (Figure 2) it is seen that their AG"", and IP, values are linearly related. Including known data for tertiary enamines in this graph allows one to conclude that the enamine of quinuclidine, (CH,),NCH=CMe, and Me,C=CHNMe, behave as nitrogen bases, whereas those and cyclopentylpyrrolidine do not, confiof 1,4,4-trimethyl-1,2,3,4-tetrahydropyridine rming again that the latter two are carbon bases. It is interesting to note that on introducing the IP, value estimated above for CH,=CHNMe, in the graph, it is clearly seen that the compound behaves as a nitrogen base. Ever since Martin and Shirley" and Davis and RabalaislQemonstrated the analogy between the addition of a proton to a neutral molecule and the removal of a 1s electron from its protonation site, a number of linear relations between intrinsic basicity (APH+ or PA) values and measured or theoretically estimated 1s binding energies have been reportedIg for different families.
215
205 IP,
N
( k c a l rnol-')
FIGURE 1. AGH+of protonation for primary amines in the gas phase versus IP!
13. Acidity and basicity of enamines
FIGURE 2. AGH+of protonation for tertiary amines in the gas phase versus IP;
Inasmuch as binding energies can be unequivocally assigned to given atomic sites, such relations are seemingly very useful for determining the site for the proton attack. Thus, on the basis of calculated C,, energiesz0,we showed that both pyrrole and indole carbon atoms; however, are carbon bases, proton attack on which takes place at their /I the P-protonated pyrrole rearranges to its a-protonated isomer, which is thermodynamically more stable. Both compounds can be regarded as models for secondary enamines. 5. Theoretical calculations
Theoretical calculations of enamine basicities have to date been limited to investigation of the higher stability of the iminium cation relative to the enammonium cation of vinylamine. Thus, Elguero and coworkers", in their pioneering work involving CNDO/2 calculations and optimized geometries, calculated the iminium ion to be 32 kcal mol-I more stable. Later, Jordanzz obtained a difference of 17.3 and 16 kcalmol-I by using the STO-3G and 4-31G levels, respectively. Also, Miiller and Brownz3, who used PRDDO SCF MO, reported a value of 9.7 kcalmol-', while Eades and coworkersz4 using PRDDO optimized geometries observed that the values obtained are a function of the calculation base used, being 19.5 (PRDDO), 16.9 (STO-3G), 17.4 (DZ), 18.7 (DZD) and 18.3 kcal mol ' (DZP). Recently, Smith and Radomz5contributed the most sophisticated calculation on these cations reported to date. It was done at the MP4/6-311 + G** level by including ZPVE on HF/6-311 + G* geometries. According to their results, the iminium cation is more stable than its enammonium counterpart by 14.6 kcal mol-'. By using a binding energy
. I . Catalan and
! +
CH,= CH, t CH,NH,
F.G. Blanco
\
CH,= CHNH, t
FIGURE 3. Schematic representation of calculated relative energies including calculated gas-phase proton affinities (PA) for vinylamines and related systems (MP4/G-311 + G" together with zero-point vibrational corrections). Reprinted with permission from J. Am. Chem. Soc., 114, 36 (1992).Copyright (1992) American Chemical Society
707
13. Acidity and basicity of enamines
resolving technique, they accounted for the basicity of vinylamine and the fact that it is a carbon base. The results of their calculations are given in Figure 3. In conclusion, all of the calculations above show that vinylamine is a carbon base. 6. Analysis of intrinsic effects
While developing a simple model to describe the effect of substituents (X) on the properties of a molecular system (M) has been one of the most earnestly pursued goals by chemists ever since the Hammett equationz6 was reported, it was not accomplished until Taft and Topsom13 succeeded in providing a description for the SAG" values of gas-phase acid-base equilibria shown in equation 13, where v is either unity or zero. This was adapted by introducing the intrinsic contributions from the substituent, namely polarizability. (o,), fieldlinductive effect (a,) . . . and resonance effect (o,), via equation 14,,
6AG" = pea,
+ p,a, + p,aR + A
(14) where the products in the first three terms on the right-hand side of the equation denote the contributions of the polarizability (P), IieldJinductive effect (F) and resonance effect (R) of the substituent to SAGo. The reaction constants for these contributions provide some information on the type of molecular skeleton (M) on which the substituent and reaction site are supported. The results provided by this type of analysis are highly s a t i s f a c t ~ r y ' ~and ~ ~ 'have opened up a new approach for a rationalized treatment of the subject. In fact, it was recently applied to enaminesZ8as described below. While, as noted earlier, vinylamine is protonated preferentially at its carbon site, the reason why this is so remains unclear. The question therefore arises as to how an ethylene molecule (AG;, = 155.6 kcal m o l l 4, and an ammonia molecule (AGH+= 195.6 kcalmol-I 4, i.e. 40 kcalmol-' more basic than the former) contribute to making the P carbon the more basic site when incorporated into vinylamine. In order to provide an answer within the context of the Taft-Topsom model, let us consider the equilibrium of equation 15.
+
+ CHz=CH,
H3C-CHX
d CHZ=CHX
+
+ H3C-CHz
(15)
The reported theoretical data for this equilibriumz8 are consistent with the following expression (equation 16):
+
+
+
~ ~(44.9 1 . 5 ) + ~ (139.1 ~ 1 . 6 )+ ~ 0.2 ~ SAE = (27.9 1 . 9 ) + (16) with n = 8 (H, Me, F, Ph, OH, OMe, NH, and CN), r = 0.9996 and SD = 0.8. On the other hand, the experimental information available on the carbon protonation in the ethylene family7 is consistent with equation 17: SAG" = (24.4
+ 3 . 4 ) +~ ~(29.4 + 8 . 1 ) ~+ ~(108.2 + 6 . 1 ) ~-~0.6
(17) with n = 8 (H, Me, c-Pr, Ph, CH=CHz, F, OMe and NH,), r = 0.995 and SD = 2.3. Let us analyse the basicity of the vinylamine at its P-carbon atom. Based on fitting of the experimental data, an amino group would increase the basicity of ethylene by 57 kcalmol-', which is quite consistent with the experimental value of 56 kcal mol-l. What is the origin of the increased basicity? The polarizability would increase it by 3.9 kcalmol-', the fieldlinductive effect would decrease it by 4.1 kcal mol-I and the resonance effect would increase it by 56.2 kcalmol-'. Consequently, the significant
J. Catalan and F.G. Blanco
708
contribution from the resonance effect is the key to the markedly enhanced basicity. One should thus speak of a super-resonance effect, since a reaction constant of 108.2 kcal mol- is more than twice the highest reported value for any process involving cationic forms, namely 50.4 kcal mol-' for the X-C(O)CF, + H + SX-C(CF3)OH+ system13. In summary, the protonation of enamines at their carbon site is markedly dependent on such a dramatic resonance effect, so that slight structural alterations resulting in decreased conjugation are bound to markedly decrease the basicity of the carbon atom concerned and hence to favour protonation at the nitrogen site.
'
7. Conjugation indicators
All enamine systems involve a resonance interaction between the lone pair of the nitrogen atom and the n orbital of the ethylene system which is obviously influenced by the presence of substituents whose effect is especially marked if the structural alteration results in the loss of planarity of the enamine system. It would thus be of interest to develop a quantitative index for the strength of such interaction. One such index could be the difference between the ionization potentials assigned to the fragments, which will increase with the increase in the resonance between them. In principle, they could indeed be linearly related. Figure 4 shows a plot of one ionization potential against the other (experimental data were taken from References 12 and 29). It is noteworthy that MeCH=C(Et)NMe,, 1-N-pyrrolidino-1-cyclopentene(21) and 1,4,4-trimethyl-1,2,3,4-tetrahydropyridine(23), which are protonated at their carbon atoms, feature a strong interaction (AIP, > 2) and are grouped about a straight line. On the other hand, compounds such as N,N-
FIGURE 4. IPfJ versus IP: of enamines. The number at the side of the molecular structure of each compound is AJP, = JP; - JPY
709
13. Acidity and basicity of enamines
dimethylisobutyleneamine (15), 1-N-piperidino-l-isobutene(22) and 1-N-morpholinol-isobutene, which are protonated at their nitrogen atoms, gradually deviate from such a straight line in the range of smaller AZP, values ( < 1.4). One other possible index for the resonance interaction in these systems is the 15N chemical shift of the enamine, whether as such" or relative to that of the corresponding saturated amine30b. It is a measure of the activation energy for twist about the C-NR'RZ bond, but it is less generally applicable than the former index based on the ionization potentials, even though it can be measured in the condensed phase where the basicity is to be determined. 8. Condensed-phase Basicity
The basicity of dissolved enamines has been an exciting subject ever since it was approached over 50 years ago, since it is influenced not only by the amphiprotic character of the system and the site (N or C) being protonated, but also by certain parallel processes such as hydrations3' and oligornerization~"~~. In addition, it is highly sensitive to seemingly negligible changes such as the incorporation of a methyl group at the u carbon, which may increase the basicity of the compound concerned by as much as 3 pK units. The earliest work on this s ~ b j e c t ~dealt ~ " . with ~ ~ the basic behaviour of pyrrolines and tetrahydropyridines, and resulted in the development of a model according to which tertiary enamines would be more basic than their corresponding saturated amines. Later, Stamhuis and coworkers" questioned this hypothesis by claiming that N-isobutenylpyrrolidine, N-isobutenylpiperidine and N-isobutenylmorpholine were less basic than their corresponding saturated amines. Table 2 gathers the most significant data on tertiary amines in this respect. Table 3 gives similar data for secondary amines. 1. Protonation site
The controversy over whether enamines are more or less basic than their saturated amines was resolved by Elguero and coworkers3', according to whom enamines that TABLE 2. pK. values of tertiary enamines in water Enamine
I-N,N-Dimethylaminoisobutene N-Isobutenylmorpholine N-Isobutenylpiperidine N-Isobutenylpyrrolidine 9-Methyl-9-azabicyclo[3.3.l]non-l-ene Dehydroquinuclidine "In 66% of DMF.
PK,
Reference
J. Catalan and F.G. Blanco
TABLE 3. pK, values of secondary enamines in water" Compound
PK.
Reference
"The struclures are those of the imines rather than of the enamines
are less basic than their respective amines may be protonated at the nitrogen whereas those that are more basic than the amines may be protonated at carbon, so that the two types cannot be compared. For roughly 30 years, enamine protonation has been believed to proceed following equation 18, according to which a fast step involving nitrogen protonation (kinetic protonation) is followed by a subsequent rearrangement step to a supposedly more stable iminium cation (thermodynamic protonation).
Tesseyre and coworkersz1 used the CND0/2 method with optimized geometries to elucidate the protonation pathway for vinylamine and concluded that protonation occurred only by attack on the nitrogen atom; they could not envisage the attack on the carbon atom even by considering the solvation effect via Jano's modeP9. Consequently, they stated that conversion of the enammonium into the iminium form could not take place via an intramolecular process. Miiller and Brownz3 also studied the reactivity of vinylamine towards a proton on the basis of the electrostatic potentials provided by the PRDDO calculation method. Figure 5a shows the isopotential map corresponding to the optimized molecular geometry for vinylamine. The situation is quite clear: it is the nitrogen site which undergoes the proton attack on the lone pair. Figure 5b shows a similar map for a planar vinylamine molecule. The situation differs markedly from that of the equilibrium geometry: in the planar geometry, the attack on the nitrogen site is markedly deactivated, in such a way that the minimum potential changes from -65 to -25 kcalmol-'. On the other hand, a secondary minimum which appeared in the region of the ethylene double bond slightly increases in energy from -25 to -30 kcal mol-'. In conclusion, theoretical calculations suggest that, in the equilibrium non-planar geometry vinylamine features a single protonation pathway on the nitrogen; the situation can be changed only if the molecular geometry is adequately distorted, presumably by another molecule. Even though enammonium ions have been shown to be eventually transformed into iminium ions3840, the steps that determine the protonation of enamines are highly sensitive to the reaction conditions, so that they can be accelerated or decelerated in order to preferentially direct the attack at the carbon or the nitrogen site of the enamine.
711
13. Acidity and basicity of enamines
FIGURE 5. Electrostatic potentials of vinylamine with respect to a positive point charge. Equipotential curves through planes parallel to the CCN plane at a distance d = 1.220A for non-planar equilibrium configuration (a)and d = 1.292 A for the all planar structure (b). All energies in kcal mol-'. Reproduced by permission of Helveticu Chimica Actu from Reference 23 Thus, Alais and coworkers41, who studied the influence of the protonation agent on the protonation site of N,N-dimethylisobutylenamine,concluded the following: (a) the transformation of enammonium ion into iminium ion by concentrated perchloric acid is much slower than by hydrochloric acid, so that the process cannot be intramolecular, but it requires the presence of a base capable of transferring the proton from the nitrogen to the carbon; (b) if a carboxylic acid (such as CH,COOH or CF,COOH), whether neat or in solution, is used as the protonation agent, the product is the corresponding iminium ion. Nilsson and coworkers4z showed that addition of trifluoroacetic acid to enamines in dry pentane at 0 "C results initially in protonation at the /3 carbon and proposed that the proton is transferred to the nitrogen atom by a bifunctional catalysis according to equation 19. They also showed that appropriate exchange resins can be used to favour selective protonation of e n a m i n e ~ ~ ~ ' . The effect of introducing a methyl group at the a or /3 carbon of an enamine on its basicity was thoroughly discussed by H i n m a r ~ Kova ~ ~ . and B ~ j a d i e wdisrupted ~~ the conjugation between the lone pair of the nitrogen and the ethylene residue through steric hindrance, in polynitroarylenamines and verified that these compounds are protonated on nitrogen.
\
/ +N-
H'
-
\,c=c,
HI'
/ NI
O\
,H +
.c=0'
-
\/
C-C I \\ H +N-
/
+ ChCOOH
(19)
712
J. Catalan and F.G. Blanco
The pK, values of the secondary enamines given in Table 3 are ca 2 units lower than those of the corresponding tertiary enamines. This is largely due to the fact that these compounds have imine structures3", so we shall not deal with them here. In principle, a solvent may favour protonation at the N site over the C site through solvating effects; in fact, -NH: sites are known to be more readily solvated than SO that enammonium ions will also be easier to solvate than will -CHl iminium cations. Bearing in mind that many enamines are nitrogen bases in the gas phase, it is not very surprising that a number of enamines are initially protonated in solution at the nitrogen, not only by kinetic but also by thermodynamic control. Ill. ACIDITY OF ENAMINES
Some enamine carbanions have been used as reagents for generating carbon+arbon b o n d P , as well as in a-,' and 8-48 metallation processes. However, the lack of quantitative data for enamine acidity precludes rationalization. The acidity of the amino protons of vinylamine was recently investigated by Smith and Radomz5 using 6-31 G*//6-31 + G* calculations and correlation energy at the MP416-311 + G** level, and introducing zero-point energy corrections. They discussed the acidity of vinylamine in terms of a bond separation energy scheme on the basis of an isodesmic process involving neutral forms (equation 20),
+
HzC=CH-NH,
+ CH,
H,C=CHz
---t
+ CH,NHz (AE = 12 kcal mol-')
(20)
which involves a stabilizing interaction (ca 12 kcalmol-') between the amino and ethylene groups. On the other hand, the isodesmic process involving the anion forms (equation 21) HzC=CHNH-
+ CH,
-
H2C=CH2
+ CH,NH-
(AE = 41 kcal mol-l)
(21)
indicates that the interaction between the ethylene moiety and the NH- group in vinylamine anion is ca 3.4 times stronger than that of the amino group in the neutral form. As a result of the higher stability of the anionic form, vinylamine is 23 kcal mol-' more acidic than methylamine. H
\
H N-H \ I ,C=C \ H H H H I 1 H-C-C-N I I H H
&,id
= 376 kcal mol-'
H
I
MfoaCid = 399 kcd mol-'
\H
On comparing vinylamine and its homologue ethylamine, it is seen that the former is ca 23 kcal mol-' more acidic than the latter. Even though such a higher acidity can in principle be ascribed to a greater fieldlinductive effect (and also, partly, to the greater polarizability of the HzC=CH group compared with the CH,CHz group), there is a clear need for accurate acidlty values for substituted ethylenes in order to understand more quantitatively this increased acidity. Although the acidic protons of vinylamine should logically be those of its amino group, whose acidity increases by a charge transfer to the ethylene group, it would
13. Acidity and basicity of enamines
713
obviously be of great help to have quantitative information on the acidity of the u and p protons. The acidity of the u and /3 protons of ethylene can increase by the presence of electron-withdrawing substituents at the ethylene residue. By way of example, cyanoethylene (acrylonitrile, AHaci,= 371 kcal mol-' ') is intrinsically 5 kcal mol-' more acidic than vinylamine. At this point, it is interesting to mention the MIND013 results reported by Schmidt and coworkers49 on the acidity of 8-aminoacrylonitrile. The AH,,, values (kcal mol-') are:
We note that these values should be taken with reservation since the structure involves strong neighbouring-group electrostatic interactionss0. The anionic form usually obtained in using enamines as synthesis reagents is usually the ally1 form. Thus, Blomquist and M ~ r i c o n i showed ~ ~ " that, by reacting a solution of the pyrrolidine enamine of indan-Zone in tetrahydrofuran with n-butyl lithium in n-hexane at -65 "C (equation 22), the proton removal is complete in about 10 min.
Thompson and Huegi4"' used phenyl groups at appropriate positions in enamines to stabilize the anionic forms produced by strong bases. The latter were used to obtain alkyl derivatives in a high yield (equation 23).
ihlbrecht5' reported on the deprotonation of tertiary enamines at C, and that the ~lting1-aminoallyl anions were so highly nucleophilic that they yielded 'gamma' (y) #ductswith many electrophiles El (equation 24).
714
J. Catalan and F.G. Blanco
lnagaki and coworkers46h predicted that the 2-aminoallyl anion resulting from an enamine would be more stable than the corresponding 1-aminoallyl anion on the basis of orbital phase continuity-discontinuity arguments. In support of their hypothesis, deprotonation of the enamine of 1-morpholinocyclohexen-1-enewith n-BuLi-TMEDA took place at position 2 rather than at position 3 (equation 25). Their model is also supported by the results of Woodward and coworkers5' for 2-pyrrolidino-1,Cdihydronaphthalene, which is also deprotonated at the a position.
Stork and coworkers48 have shown that the deprotonation of chelating enamines yields B- rather than a-lithium enamines (equation 26). The fact that lithiation usually occurs in hydrocarbon solvents suggests that the enamine deprotonation will only occur if it undergoes a Lewis acid-base interaction forming a complex with the base used. This is consistent with the assertions of a number of authors that formation of a cyclic transition state is necessary to explain the regiochemistry of these reactionss3. In order to analyse the origin of regioselectivity in the lithiation of enamines in hydrocarbon solvents using alkyl lithium reagents, Stork and coworkers54 carried out a theoretical study at the 3-21G level of the lithiation of various vinylamines. According to this studys4, one model for studying the complex reactions of alkyl lithium compounds, involving aggregation and interactions with the solvent molecules, could be the reaction between vinylamine and LiH. The complex formed between lithium
715
13. Acidity and basicity of enamines
hydride and vinylamine is estimated to be stabilized by ca 28 kcal mol-' (at the 3-21G level). It is also noteworthy that, as a result, the rotational barrier for the C-N bond in vinylamine is decreased by 5 kcal mol- '. This reflects a marked decrease in conjugation between the lone pair of the nitrogen atom and the vinylic residue of vinylamine, and hence an increased acidity of the vinylic protons. Figure 6 shows the results obtained by these authors for various structures leading to the a- or P-lithiated form. As can be seen, the calculated activation barrier for a-lithiation is 46 kcalmol-' relative to the energy of the neutral precursor, whereas that for P-lithiation is 39.7 kcalmol- ', i.e. 6 kcal mol- lower than the former value. A similar difference (5.2 kcalmol-') was obtained from more elaborate calculations at the MP2/6-31G* level. Similarly, the final P-lithiated product is 11 kcal mol-' more stable than its a counterpart. In order to determine the effect of the presence of a methyl group at the a or fi position in an enamine on metallation, Stork and coworkerss4 studied the attack of LiH on E and Z MeCH=CHNH, and H,C=(Me)NH,. Figure 7 shows the results obtained. The calculated potential barrier rules out tram-y-lithiation as it features a 21.7 kcal mol-' higher activation energy than cis-y-lithiation. On comparing the results shown in Figures 6 and 7 one can also infer that P lithiation is more favourable than lithiation, so that a methyl group at the a carbon will not favour metallation in any way. In y-lithiation, the cis option is clearly more favourable, both kinetically and thermodynamically than is the trans option. However, rearrangement of the vinyl to the allyl compound is not always fast, notwithstanding the fact that the allyl species are normally more stables5. Knorr and Lattke5'j calculated the activation parameters for these rearrangements and found quite large and negative AS" values. No doubt an expression for the reorganization of the solvent sphere is required for such reaction. On the other hand, large, negative ASovalues are also typical for the formation of highly aggregated organolithium compounds5', a process which is governed by solvation energiess8. In order to elucidate the central role of complexation on regioselectivity and stereospecificity, Stork and coworkerss4 studied the attack by hydride anion on cis- and
'
1
+ 46.0 kcal mol--'
a-lithiation
FIGURE 6. Relative energies (kcal mol-') and the geometries of the complexes of vinylamine with LiH. Reprinted with permission from J. Am. Chem. Sac., 110, 8360 (1988). Copyright (1988) American Chemical Society
J. Catalan and F.G. Blanco
cis-y-lithiation
H3C
+
w2
-29.5 kcalmol-I
Li4
-
,LiH
H3C+N-
1
H2
56.0 kcal mnl-I
trans-y-lithiation FIGURE 7. The 3-21G energetics (kcalmol-I) for the reactions of methyl substituted enamines with LiH. Reprinted with permission from J. Am. Chem. Soc., 110, 8360 (1988). Copyright (1988) American Chemical Society
trans- MeCH=CHNH,. The results shown in Figure 8 suggest that the resulting anions have similar stability and energies, in clear contrast with the situation described above for cis- and trans-y-lithiated compounds. This, in turn, shows that the interaction between the lithium and the lone pair of the nitrogen atom of the enamine determines the regioselectivity and stereospecificity in the metallation of enamines.
13. Acidity and basicity of enamines
717
trans-y-deprotonation FIGURE 8. The 3-21G energetics (kcal mol-') for the reactions of E- and 2-I-aminopropenes with hydride anion. Reprinted with permission from J. Am. Chem. Soc., 110, 8360 (1988). Copyright (1988) American Chemical Society
IV. HYDROGEN BONDING
As noted earlier, the development of new alkylation and acylation methods for compounds bearing carbonyl groups has fostered the use of enamines as reaction intermediates. As also stated above, the unique properties of enamines essentially arise from the conjugation between the electrons of the double bond and the lone pair of the nitrogen, so that a given electrophilic attack on the N or C, of enamine 28 will depend on the
nature of R1-R5.In addition, the nature of R1,R2, R3, R4 and R5 will determine the ability of the enamine concerned to form inter- and/or intra-molecular hydrogen bonds. The occurrence of such bonds, in turn, determines whether the E or Z form of the compound predominates and accounts for the equilibrium constant for the equilibrium of equation 27.
13. Acidity and basicity of enamines
R3 = H; R4 = Bu, t-Bu) failed to conclusively demonstrate the occurrence of hydrogen bonds except, perhaps, in CDCI,, where the chemical shift of the NH resonance is low ~ "the . other hand, recently reported "0-NMR data seem to point to (ca 4 5 ~ p m ) ~On the presence of hydrogen bonds. However, the energy of these bonds must be much lower than for those of other enamines mentioned above64. A theoretical based on the semi-empirical AM1 method was carried out in order to account for the tautomeric equilibria of enaminones 35. The results obtained were consistent with previous X-ray o b s e r ~ a t i o n sand ~ ~ showed the enamine form of acyclic primary and secondary amines with a hydrogen bond between the N and 0 atoms to be ca 5 kcal mol-' more stable than its tautomer.
Nitroenamines (36) have also been the subject of much research. They have been studied both theoretically6' and e~perimentally~~ using such diverse techniques as IR, Raman, 'H-NMR and 13C-NMR spectroscopy, and two-bond deuterium isotopic H, tautomer Z effects. The results obtained show that, with R1 = Me and RZ or R" (stabilized by hydrogen bonding) is the major form. However, with R1 = H and R2 (R3) = H, the two forms are in equilibrium, whereas when R2 = R3 = H, the E isomer is the sole form present.
Factors discussed responsible for the increased stability of the Z form include the energy of twist about the C-N bond, the solvent used, the steric hindrance involved and the electron-releasing or electron-withdrawing character of R2 and R3. Primary and secondary a-amino-p-nitro stilbenes (37) have been shown69 to form an C6Hs PHs \ ,C=C \ R-N N-0 \ // H--0 (37)
720
J. Catalan and F.G. Blanco
intramolecular hydrogen bond. The evidence includes the absence of the characteristic band of the NH group at 3300 c m l in the IR spectrum and a 6 value of 11-12 ppm for the 'H-NMR spectrum. Some authors70 have developed a rather different approach for investigating the occurrence of hydrogen bonds and for determining their strength using isotopic effects on nuclear shielding. The model equation is equation 29, where n is the number of bonds between deuterium and the atom X. By using a value of 'C' (ND), i.e. the effects at C1 arising from deuteriation of the nitrogen atom, various nitroenamines, enamine esters and enaminones71 were shown to contain more of the Z than of the E form, which can be ascribed to the presence of hydrogen bonds in the former. In other words, when such bonds are present there are larger isotopic effects on C, in the Z form. Obtaining quantitative data for hydrogen bonding energies is still unfeasible; however, there is a clear relation between 'AC16(ND) and 'H6(NH) values which depends on the type of electron-withdrawing group and change in the following order: NO, > C=O > COOR [i.e. the most markedly electron-withdrawing group forms the strongest hydrogen bond and has the largest 'AC1 (ND) value].
C. Enamines with Secondary Amino Group
As a rule, investigations of different types of systems have shown the occurrence of conformational equilibria, some of which are displaced to a greater or lesser extent in one direction. The predominance of a given form is directly dependent on the occurrence of hydrogen bonds; however, no experimental data or systematic studies enabling quantification of the hydrogen bonding energy have been reported to date. Carbamoyl derivatives bearing a secondary nitrogen atom at the carbamoyl group have been shown to occur preferentially as the enamine form. The opposite holds true with tertiary nitrogen atoms7'. 9-Formyltetrahydro-4H-pyrido[l,2-a]pyrimidin-4-ones38, where R1 = H, 6-Me and R2 = C2HSCOZ,CH3, Ph, H, CHO, CN, CH3C0,, CONH', occur prefer en ti all^^^ as tautomer 39 (whereas tautomer 40 occasionally amounts to 15% as shown by J,,, coupling data). The equilibrium between 39 and 40 (equation 30) is seemingly not influenced by the nature of R2; however, R2 was reported to strongly influence the equilibria in 9-substituted tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-ones.
It is interesting to note that the equilibrium constant K, ( = 39/40) is an indirect measure of the hydrogen bonding energy, though this is not the sole factor affecting the equilibrium. Bond twisting resulting in loss of orientation of the groups that can form the hydrogen bond or lack of planarity can significantly alter the 39/40 equilibrium.
13. Acidity and basicity of enamines
721
Therefore, a comprehensive comparative study of hydrogen bond energies can only be made on the basis of previously determined structural data. This accounts for the lack of quantitative relevant information on this type of hydrogen bonding in enamines. 2-Ketomethylquinolines can exist as the two forms 41 and 42 (equation 31). An IR and NMR study of 19 compounds with various R1-R4 substituents in CDCI, and d i ~ x a n showed e ~ ~ that the 41/42 ratio is much larger than unity for all of them. As a rule, with the exception of simultaneous substitution at R' and R3, isomers 42 were found to be the minor isomers. Only with R' = Ph, R3 = R4 = H and R2 = Me was no 41 detected. Since the 41/42 ratio is related to the hydrogen bonding energy, any substituent that increases the acidity of the pyridine nitrogen (such as a Me group) and the basicity of the ketone oxygen (such as a phenyl ring) will also raise the hydrogen bond energy. R4
The occurrence of hydrogen bonds cannot be detected in 6-methylcarbamoyl-
tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-ones43 when R1 = H, Me, RZ = H, Me, C,H,, C,H,, CN, CO,C,H,, probably because of the lack of planarity in the O=C-C,=Cl,-NH system7'.
A study of aminomethylene derivatives of ketones, thiones and selenones including pyrrole, furan or pyrazole as the heterocyclic ring showed them to form intermolecular hydrogen bonds with D. Solid State Studies
Some enamines have been shown to form inter- and intra-molecular hydrogen bonds in the solid state77.Thus, a-tetrahydropyrrolidinylidene-2 (44) and ethyl a-hexahydroazepirylidene acetate (45) have been shown to occur as /I-enaminoesters of configuration Z in the solid state, i.e. the same configuration as they have in solution78. X-ray diffraction data also showed the occurrence of inter- and even intra-molecular -NH . . . 0 hydrogen bonds of lengths between 2.758 and 2.93 A.
J. Catalan and F.G. Blanco
The behaviour described above is rather different from that reported by Brugger and coworkers7' for triazinones, which occur in different forms in the solid state and in solution. 2-Guanidinobenzimidazole is a powerful chelating agent with biological activity. On the basis of theoretical calculations, Catalan and coworkerss0 inferred that the predominant form in the gas phase must be 46. However, this could not be confirmed by NMR datasO~sl. An X-ray diffraction study showed the occurrence of two structures in the solid state, where the compound acts as guest to crown ether hosts, with which it forms hydrogen bondss2. Very recently, the structure proposed by Catalan and coworkerssO was detected in the solid states3. Occurrence of hydrogen bonds in the solid state and resulting stabilization of the enamine concerned have also been reported for N-(2,2-diacetylviny1)-0-phenylenediaminean azomethine-P-diketones4.
The practical potential of hydrogen bonds in enamines has been investigated by several authorss5in relation to studies involving polymers. In some instances (such as polymers of 1,6-diethoxy-1,5-hexadiene-3,4-dione with aromatic and aliphatic amines), mixtures of enamino ketones and imines are obtaineds6. Traditionally, rigid polymers are obtained by inserting aromatic rings into the macromolecule concerned. However, if too many rings are introduced, the resulting polymer is infusible and scarcely or not at all soluble in common solvents. The presence in the polymer of a structure such as 47, which is the case with 48 [Ar = Ph; R = (CH,),, m-[Et-C,H,-Et], gives rise to phase transitions at much lower temperatures (a few tens of degrees), which enables easier processing and increases solubility. The predominance of enamino ketone forms has been demonstrated by IR and 'H-NMR spectroscopys7.
13. Acidity a n d basicity of enamines V. REFERENCES 1. (a) G . Stork, R. Terrel and J. Szmuszkovicz, J. Am. Chem. Soc., 76, 2029 (1954). (b) G. Stork and H. Landesman, J. Am. Chem. Soc., 78, 5128 (1956). (c) G. Stork and I. J. Borowitz, J. Am. Chem. Soc., 84, 313 (1962). (d) G. Stork and J. W. Schulemberg, J. Am. Chem. Sac., 84,284 (1962). (e) G. Stork, A. Brizzolara, H. Landesman, J. Smuszkovicz and R. Terrel, J. Am. Chem. Sac., 85, 207 (1963). (fJG. Stork and S. R. Dowd, J. Am. Chem. Soc., 85, 2178 (1963). (g) G . Stork and J. E. Dolfini, J. Am. Chem. Sac., 85,2872 (1963). (h) G. Stork, R. A. Kretchmer and R. H. Schlessinger, J. Am. Chem. Sac., 90, 1647 (1968). 2. (a) P. W. Hickmott, Tefrahedron,38, 1975 (1982). (b) P. W. Hickmott, Tetrahedron, 40, 2989 (1984). 3. (a) K. Blaha and 0. Cervinka, Adv. Heterocycl. Chem., 6, 147 (1966). (b) E. C. Taylor and A. Mckillop, Adv. Org. Chem., 7, 1 (1970). (c) M. Miller, Adv. Phys. Org. Chem., 11, 267 (1975). (d) H. Bohme and H. G. Viehe (Eds.), Iminium Salts in Organic Chemistry, John Wiley, New York (1976). (e) G . Pitacco and E. Valentin, in The Chemistry of Amino, Nitroso and Nitro Compounds and Their Derivatives (Ed. S. Patai), Part 1, Chap. 15, Wiley, New York, 1982. 4. (a) R. G. Pearson, Hard and Soft Acids and Bases, Dowden, Hutchinson and Ross, Strousburg, PA, 1973. (b) R. P. Bell, The Proton in Chemistry, Chapman & Hall, London, 1973. (c)W. B. Jensen, The Lewis Acid-Base Concepts. An Overview, Wiley, New York, 1980. (d) R. Stewart, The Proton: Applicafions lo Organic Chemistry, Academic Press, New York, 1985. 5. R. W. Taft, Prog. Phys. Org. Chem., 14, 248 (1983) and references cited therein. 6. E. M. Arnett, J. Chem. Educ., 62, 385 (1985) and references cited therein. 7. (a) S. G. Lias, J. F. Liebman and R. D. Levin, J. Phys. Chem. Ref: Data, 13, 695 (1984). (b) S. G. Lias, J. E. Bartmess, J. F. Liebmann, J. L. Holmes, R. D. Levin and W. G . Mallar, J. Phys. Chem. Ref: Data, 17, Suppl. 1 (1988). 8. J. Catalan, J. L. M. Abboud and J. Elguero, Adv. Heterocycl. Chem., 41, 187 (1987). 9. M. R. Ellenberger, R. A. Eades, M. W. Thomsen, W. E. Farneth and D. A. Dixon, J. Am. Chem. Sac., 101, 7151 (1979). 10. M. R. Ellenberger, D. A. Dixon and W. E. Farneth, J. Am. Chem. Sac., 103, 5377 (1981). I I. D. H. Aue and M. T. Bowers, in Gas Phase Ion Chemistry, Vol. 2 (Ed. M. T. Bowers), Academic Press, New York, 1979, p. 1. 12. R. M. Houriet, J. Vogt and E. Haselbach, Chimia, 34, 277 (1980). 13. R. W. Taft and R. D. Topsom, Prog. Phys. Org. Chem., 16, 1 (1987). 14. D. H. Aue, H. M. Webb and M. T. Bowers, J. Am. Chem. Sac., 98, 311 (1976). !5. B. Albrecht, M. Allan, E. Haselbach, L. Neuhaus and P. A. Carrupt, Helv. Chim. Arm, 67, 220 (1984). 16. (a) R. H. Staley and J. L. Beauchamp, J. Am. Chem. Soc., 96,6252 (1974). (b) 1. Koppel, V. Molder and R. Pikver, Org. React. (Engl. Transl.), 17, 457 (1980). (c) I. Koppel, V. Molder and R. Pikver, Org. React. (Engl. Transl.), 20, 45 (1983). (d) J. Catalan, 0 . Mo, P. Perez and M. Yaiiez, J. Am. Chem. Sac., 101, 6520 (1979). (e) J. Catalan and J. Elguero, J. Chem. Soc., Perkin Trans. 2, 1869 (1983). (0 J. Catalan, 0.Mo, J. L. G. Paz, P. Perez, M. Yaiiez and J. Elguero, J. Org. Chem., 49, 4379 (1984). 17. R. L. Martin and D. A. Shirley, J. Am. Chem. Soc., 96,5299 (1974). 18. D. W. Davis and J. W. Rabalais, J. Am. Chem. Soc., 96, 5306 (1974). 19. (a) R. S. Brown and A. Tse, J. Am. Chem. Soc., 102, 5222 (1980). (b) J. M. Buschek, F. S. Jorgensen and R. S. Brown, J. Am. Chem. Sac., 104, 5019 (1982). (c) J. Catalan, 0. Mo, P. Perez and M. Yaiiez, J. Chem. Sac., Perkin Trans. 2, 1409 (1982). (d) J. Catalan, J. L. G. Paz, M. Yatiez, F. Amat-Guerri, R. Houriet, E. Rolli, R. Zehringer, P. Oelhafen, R. W. Taft, F. Anvia and J. H. Quian, J. Am. Chem. Soc., 110, 2699 (1988). (e) M. Speranza, Adv. Heterocycl. Chem., 40, 25 (1986). 20. J. Catalan and M. Yaiiez, J. Am. Chem. Soc., 106, 421 (1984).
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43. 44. 45. 46.
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13. Acidity a n d basicity of enamines (g) H. Ahlbrecht and H. Simon, Synth. Cummun., 13, 58 (1983). (h) S. Inagaki, K. Iwase and N. Goto, J. Chem. Soc., Perkin Trans. 2, 2019 (1984). 47. (a) H. Gilman and J. W. Morton, Jr., Org. Reacr., 8, 258 (1954). (b) H. W. Gschwend and H. R. Rodriguez, Org. React., 26, 1 (1979). 48. (a) G. Stork, C. S. Shiner, C. W. Cheng and R. L. Polt, J. Am. Chem. Soc., 108, 304 (1986). (b) R. L. Polt, G. Stork, P. G. Williard and G. B. Carpenter, J. Am. Chem. Soc., 106,4276 (1984). 49. R. R. Schmidt, J. Talbiersky and P. Russegger, Tetrahedron Lett., 4273 (1979). 50. J. Catalan, J. L. G. Paz, J. Elguero, A. Martinez, R. W. Taft and F. Anvia, J. Mol. Srrucr. (Theochem)., 205, 367 (1990). 51. H. Ahlbrecht, Chimia, 31, 391 (1977). 52. R. B. Woodward, I. J. Pochter and M. L. Scheinbaum, J. Org. Chem., 36, 1137 (1971). 53. (a) M. Schlosser, Struktur und Reactiviralpolarer Organomeralle, Springer-Verlag. Berlin, 1973. (b) J. Hartmann and M. Schlosser, Helu. Chim. Actu, 59, 453 (1976). (c) P. Beak, J. E. Hunter and Y. M. Jun, J. Am. Chem. Soc., 105, 6350 (1983). 54. G. Stork, R. L. Polt, Y. Li and K. N. Houk, J. Am. Chem. Soc., 110, 8360 (1988). 55. (a) R. A. Finnegan, Tetrahedron Lett., 429 (1962). (b) D. H. Hunter and D. J. Cram, J. Am. Chem. Soc., 86, 5478 (1964). (c) W. E. Fristad, Y. K. Han and L. Paquette, J. Organomet. Chem., 174, 27 (1979). 56. R. Knorr and E. Lattke, Tetrahedron Lerr., 4655 (1977). 57. (a) R. P. Quirk, D. E. Kester and R. D. Delaney, J. Organomrt. Chem., 59, 45 (1973). (b) R. P. Quirk and D. E. Kester, J. Organomet. Chem., 72, C23 (1974). (c) J. Heinzer, J. F. 0 t h and D. Seebach, Helv. Chim. Acta, 68, 1848 (1985). 58. (a) M. A. Weiner and R. West, J. Am. Chem. Soc., 85,485 (1963). (b) J. L. Brown, Ace. Chem. Res., 1, 23 (1968). (c) L. D. McKeever and R. Waack, J. Chem. Soc., Chem. Commun., 750 (1969). (d) D. Seebach, R. Hassig and J. Gabriel, Helu. Chim. Acta, 66, 305 (1983). (e) G.Fraenkel, M. Henrichs, M. Hewitt and B. M. Su, J. Am. Chem. Soc., 106, 255 (1984). (0 J. F. Mffiarrity and C. A. Ogle, J. Am. Chem. Soc., 107, 1805 (1985). (g) J. F. McGarrity, C. A. Ogle, Z. Brich and H. R. Loosli, J. Am. Chem. Soc., 107,1810(1985). 59. S. D. Nikonovich and A. V. Rukosueva, Zh. Strukt. Khim., 13, 939 (1972). J. Struct. Chem. (Engl. Transl.), 13, 875 (1973). 60. R. A. Zadorozhnyi and I. K. Ishehenko, Optika i Spektr., 16,686 (1962). Opt. Spectrosc, (Engl. Transl.), 19, 306 (1965). 61. P. Courtot, R. Pichon and J. LeSaint, Tetrahedron Lett., 1591 (1979). 62. B. Couchouron, J. Le Saint and P. Courtot, Bull. Soc. Chim. Fr., 66 (1983). 63. (a) L. Kozerski, R. Kawecki nnd E. Bednarek, Magn. Reson. Chem., 25, 712 (1987). (b) M. Yokoyama and T. Takeshima, Tetrahedron Lett., 147 (1978). (c) R. Knorr, A. Weiss, P. Low and E. Rapple, Chem. Ber., 113, 2462 (1980). 64. L. Kozerski and R. Kawecki, Su[fur and Silicon, 59,201 (1991). 65. M. N. Eberlin, Y. Takahata and C. Kascheres, J. Mol. Struct. (Theochem), 207, 143 (1990). 66. J. P. Celerier and G. Lhommet, J. Heterocycl. Chem., 19, 481 (1982). 67. (a) F. Sanchez Marcos, J. P. Maraver, J. L. Chiara and A. Gomez Sanchez, J. Chem. Soc., Perkin Trans. 2, 2059 (1988). (b) E. N. Gate, M. A. Meek, C. H. Schwalbe, M. F. G. Stevens and M. D. Threadgill, J. Chem. Sac., Perkin Trans. 2, 251 (1985). (c) Yu. A. Borisov, K. K. Babievskii, V. I. Bakhmutov, Yu. T. Struchko and E. S. Fedin, Izv. Akad. Nauk SSSR. Ser. Khim.. 123 (19821. Chem. Abstr.. 96. 140264~119821. ' n . '142'(1984). 68. (a) V. I. ~akhumov'and E. I. Fedin, 'Bull.' ~ a ~Reson., (b) S. Wolfbeis, Chem. Ber., 110, 2480 (1977). (c) R. Huisgen, K. Herbig, A. Siegl and H. Huber, Chem. Ber., 99, 2526 (1966). (d) D. L. Oestercamp and P. J. Taylor, J. Chem. Soc., Perkin Trans. 2, 1021 (1985). (e) A. Gomez Sanchez, M. G. Garcia Martin, P. Borrachero and J. Bellanoba, J. Chem. Soc., Perkin Trans. 2, 301 (1987). (0 D. Smith and P. J. Taylor, J. Chem. Soc., Perkin Trans. 2, 1376 (1979). (g) L. Kozerski and A. Krownynski, Magn. Reson. Chem., 25, 46 (1987). (h) J. L. Chiara, A. Gomez Sanchez and J. Bellanoba, J. Chem. Soc., Perkin Trans. 2,787 (1992). (i) J. Sandstrom, Top. Stereochem., 14, 83 (1983). (j) K. I. Dahlquist, Acta Chem. Scand., 24, 1941 (1970). 69. I. Allade, P. Dubois, P. Levillain and C. Viel, Bull. Soc. Chim. Fr., 339 (1983).
J. Catalan a n d F.G. Blanco 70. (a) P. E. Hansen, Annu. Rep. NMR Spectrosc., C 15, 105 (1983). (b) J. Reuben, J. Am. Chem. Soc., 108, 1735 (1986). (c) P. E. Hansen, Magn. Reson. Chem., 24, 903 (1986). (d) P. E. Hansen, Acta Chem. Scand., B42, 423 (1988). (e) J. Reuben, J. Am. Chem. Soc., 109, 316 (1987). 71. P. E. Hansen, R. Kawecki, A. Krowczynski and L. Kozerski, Acta Chem. Scand., 44,826 (1990). 72. I. Bitter, I. Hermecz, G. Toth, P. Dvortsak, Z. Bende and Z. Meszaros, Tetrahedron Lett., 2557 (1979). 73. G. Toth, A. Szollosy, C. Szantay Jr., I. Hermecz, A. Horvath and Z. Meszaros, J. Chem. Soc, Perkin Trans. 2, 1153 (1983). 74. J. V. Greenhill, H. Loghman-Khovzani and D. J. Maitland, Telrahedron, 44, 3319 (1988). 75. G. Toth, C. De La Cruz, I. Bitter, I. Hermecz, B. Pete and Z. Meszaros, Org. Magn. Reson., 20, 229 (1982). 76. A. V. Elitsov, I. Ya. Kvitko, E. A. Panfilova and V. A. Amelichev Zh. Obshch. Khim., 48,2307 (1978). J. Gen. Chem. USSR (Engl. Transl.), 48, 2094 (1979). 77. J. P. Celerier and G. Lhommet, J. Hererocycl. Chem., 19, 481 (1982). 78. J. P. Celerier, E. Deloisy, G. Lhommet and P. Maitte, J. Org. Chem., 44, 3089 (1979). 79. M. Brugger, H. WamhoKand F. Korte, Ann. Chem., 757, 100 (1972). 80. C. Acerete, J. Catalan, F. Fabero, M. Sanchez Cabezudo, R. M. Claramunt and J. Elguero, Heterocycles, 26, 1581 (1987). 81. E. Grundemann, H. Graubaum, D. Martin and E. Schiewald, Magn. Reson. Chem., 24, 21 (1986). 82. (a) W. H. Watson, G. Galloy, D. A. Crossie, F. Vogtle and W. M. Muller, J. Org. Chem., 49, 347 (1984). (b) M. R. Caira, W. H. Watson, F. Vogtle and W. Muller, Acra Crystallogr., C40, 1047 (1984). 83. P. J. Steel, J. Heterocycl. Chem., 28, 1817 (1991). 84. C. Svensson, I. Ymen and B. Yom-Tov, Acta Chem. Scand., B36, 71 (1982). 85. (a) Y. Imai, M. Ueda and K. Otaira, J. Polym. Sci., Polym. Chem. Ed., 15, 1457 (1977). (b) F. Higashi, A. Tai and K. Adachi, J. Polym. Sci., Polym. Chem. Ed., 8, 2563 (1970). (c) S. J. Huang, B. C. Benicewicz, J. A. Pavlisko and E. Quiroga, Polymer Preprints, 1, 22 (1981). 86. J. A. Pavlisko, S. J. Huang and B. C. Benicewicz, J. Polym. Sci., Polym. Chem. Ed., 20, 3079 (1982). 87. J. Huang, B. Benicewicz and J. A. Pavlisko, ACS Symp. Ser., 195, 403 (1982).
CHAPTER
14
Electrophilic and nucleophilic substitution and addition reactions of enamines P. W . HICKMOTT* University of Natal. Durban. Natal. South Africa
I . INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I1. PROTONATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Regioselectivity .. ................................. B. Stereoselectiv~ty. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Asymmetric Induction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I11. ALKYLATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Reaction with Alkyl Halides . . . . . . . . . . . . . . . . . . . . . . . . . B. Reaction with Electrophilic Alkenes . . . . . . . . . . . . . . . . . . . . . C. Reaction with Electrophilic Alkynes . . . . . . . . . . . . . . . . . . . . . D . Arylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E. Reaction with Aldehydes and Ketones . . . . . . . . . . . . . . . . . . . F . Reaction with Iminium Ions . . . . . . . . . . . . . . . . . . . . . . . . . G . Miscellaneous Alkylating Agents . . . . . . . . . . . . . . . . . . . . . . H . Asymmetric Induction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. ACYLATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Reaction with Carboxylic Acid Chlorides, Anhydrides and Ketenes . . B. Reaction with Sulphonyl and Sulphenyl Derivatives . . . . . . . . . . . C. Reaction with Isocyanates and Isothiocyanates . . . . . . . . . . . . . . D . Miscellaneous Acylating Agents . . . . . . . . . . . . . . . . . . . . . . . V. HALOGENATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VI . CARBOCYCLIC SYNTHESIS . . . . . . . . . . . . . . . . . . . . . . . . . A. Three-membered Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Four-membered Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Five-membered Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D . Six-membered Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E . Seven-membered and Larger Rings . . . . . . . . . . . . . . . . . . . . . VII. MISCELLANEOUS REACTIONS . . . . . . . . . . . . . . . . . . . . . . . VIII . SECONDARY ENAMINES . . . . . . . . . . . . . . . . . . . . . . . . . . . IX. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
728 731 731 733 735 735 735 741 760 761 764 769 770 773 778 779 784 785 787 788 794 794 798 801 804 830 831 843 861
*Present address: 7 Quentin Smythe Rd. Kloof. Natal 3610. South Africa The C h e m i s q of Enarnines. Edited by Zvi Rappoport Copyright 0 1994 John Wiley & Sons. Ltd . ISBN: 0-471-93339-2
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P. W. Hickmott I. INTRODUCTION
Although enamine reactivity has been known since 1883', the generality and wide ranging applicability of the reaction of enamines with electrophilic reagents was not realized until the pioneering work of Gilbert Stork and coworkers in 19542,3,This review of what has consequently become known as the Stork reaction4 attempts to cover the period from 1954 to 1992. However, in view of the immense amount of work published on the Stork reaction the review is confined to those applications in which an aldehyde or ketone is converted into an enamine intermediate which then reacts with an electrophilic reagent E+ (Scheme 1). Further reaction may regenerate the carbonyl function, to give an u-substituted aldehyde or ketone (path b), or result in further electrophilic attack at the P- or /l'-positions of the regenerated enamine (paths d and e, respectively) or nucleophilic attack on the u-position of the iminium salt thus formed (path c). Although reaction at nitrogen (path a) is usually the unwanted process, and good electrophiles are those in which this is reversible, reaction at nitrogen can be useful if followed by a [1,3] or [3,3] N + C sigmatropic rearrangement (Sections III.A, 1V.A and VII). The diversity of possible synthetic applications of the Stork reaction is therefore immediately apparent. The course of the reaction is often critically dependent on the
SCHEME 1
14. Electrophilic and nucleophilic reactions of enamines
729
1
iii
Reagents: (i) R2NH, H+, & (ii) RNH2, H+ & (iii) hydrolysis SCHEME 2
amine moiety in the enamine and the type of electrophilic reagent used. Even with the same electrophilic reagent and the same enamine, completely different products may be obtained depending on the experimental conditions used. For example, relatively trivial changes in the solvent, temperature, presence or absence of base or catalyst, molar proportion of reagents, order of mixing the reagents, substituents present in the enamine or electrophile, etc., may change the course of the reaction as will become evident in the sections which follow. The situation is rendered even more complex when an unsymmetrical ketone is used as the enamine precursor, since then a mixture of enamines is formed. If the ketone is @-substituted,as with 2-alkylcyclohexanones, a mixture of the more substituted or tetrasubstituted (It) and the less-substituted (la) enamine isomers is usually obtained, in acid catalysed equilibrium (Scheme 2). Normally the less substituted double-bond isomer (la) is the more reactive since reaction at the more substituted position It engenders severe allylic interactions (A1,3-strain5)in the transition state. Further reaction therefore occurs preferentially to give the P,P-disubstituted enamine or iminium salt (3)and hence the a,@'-disubstituted ketone (5) on hydrolysis. However, there are exceptions to this (see Sections IKB, V and V1.D). A recent development uses the observation6 that such steric interactions do not apply to secondary enamines (Section VIII) since a conformation (2) can be adopted
P. W. Hickmott
+
R-N
c?,p R-N
I
SCHEME 3
in which allylic strain is eliminated in the ground state and in the transition state for subsequent reaction. Alkylation of secondary enamines with electrophilic alkenes therefore give access to a,a-disubstituted ketones (4) and is therefore complementary to the Stork alkylation of tertiary enamines. A further complication arises from the fact that in the less substituted isomer of a tertiary enamine derived from a 2-alkylcyclohexanone, the alkyl substituent may adopt a quasi-axial (la) or a quasi-equatorial (le) orientation. Subsequent reaction may then occur from an axial or 'equatorial' direction depending on the relative magnitude of the destabilizing steric effects and on whether the transition state is reactant-like or product-like (Scheme 3). In a product-like transition state axial attack on l e and i t is destabilized by developing A1,3-strain and equatorial attack on all three isomers is destabilized by developing non-bonded boat or twist interactions. Axial attack on isomer la, which only develops 1,3-diaxial interactions, is usually therefore the lowest energy process. However, if reaction with l a is reversible (Sections 1II.A and B), or if a reactant-like transition state is involved (Section II.B), such considerations do not apply. Returning to Scheme 1, if the two electrophilic reagents (E', in paths d and e) or the electrophilic and nucleophilic reagents (E+ and Nu- in path c) are part of the same attacking reagent, then clearly ring formation will occur. In the latter case annulation may occur by concerted or two-step cycloaddition and such reactions together with their subsequent rearrangement or ring expansion processes are dealt with in Chapter 18. Only annulation processes which necessitate a reorganization of atoms or groups in the enamine or electrophilic reagent before cyclization can occur (and therefore they cannot be regarded as cycloaddition processes in the generally accepted sense of the term), are dealt within this chapter. Such processes include, for example, annulations with acrolein, acryloyl chloride, methyl vinyl ketone, etc. A more liberal definition of cycloaddition which also includes these processes has been favoured by Chinchilla and Backvall in Chapter 18 thus resulting in some overlap. However, it seems beneficial to have a second perspective on the more important ring-forming reactions. Heterocyclic enamines7, in which both the nitrogen and the carbonxarbon double bond are part of the same ring, as in tetrahydropyridines, indoles, A'-p~rrolines, etc., and their exo-enamine tautomers, are outside the scope of this survey. In addition, conjugated enamines in which either the nitrogen or the double bond is further
14. Electrophilic and nucleophilic reactions of enamines
731
conjugated with an electron-withdrawing or electron-donating substituent have also been omitted from this chapter. Such systems include enaminoesters and enaminones', h a l ~ - ~and . ' ~cyano-enamines", enamideslZ,nitro-enamines", dienamines14 (Chapter 26), enediamines and triamines14 (Chapter 22). Nucleophilic reactions of preformed iminium salts15.16are also not considered. Other reviews or books published previously enaminesZ0, include ones dealing with the general chemistry of e n a m i n e ~ ~ , ' ,~aldehyde -'~ reactions with carbon disulphide and sulphur2', allylic strain5, chiral iminesz2, synthesis of natural p r o d u ~ t s ~acylationZ5, ~ . ~ ~ , enaminothioketones" and stereocontrolz7. II. PROTONATION A. Regloselectlvity
The factors affecting the propensity for N-protonation versus C-protonation, kinetic versus thermodynamic control, etc., are discussed in depth in Chapters 13 and 19. Apart from the protonation of dienamines (Chapter 26) further discussion of this question is therefore inappropriatez8. As regards C-P' versus C-P protonation of a mixture of unsymmetrical enamines such as that derived from 2-methylcyclohexanone, the products of C-protonation are the iminium salts 6 and 7 or 8 (E = H) (Scheme 3), respectively. Iminium salts 6 and 8 are destabilized by the A1.3-interactions shown and, in a reaction involving a product-like transition state, the activation energies leading to 6 and 8 will be increased by these developing steric interactions. However, since it has been shown2' that the protonation of cyclohexanone enamines occurs via a reactant-like transition state (Section 1I.B) such considerations should be irrelevant. It may therefore initially seem surprising that the rate of hydrolysis of 2-methylcyclohexanone enamine 9 (Scheme 4) is some 10'-lo6 slower than that for cyclohexanone enamine 10 in the pH range where the ratedetermining step is that for C - p r o t ~ n a t i o n However, ~~. as we have previously pointed out3', the allylic strain in the ground state of a tetrasubstituted enamine, such as i t or 9, can be minimized by rotation about the C,-N bond. This means that in the transition state for C-protonation less positive charge can be delocalized onto thc nitrogen with consequent increase in the activation energy, and this is the explanation favoured by Capon and Wu30. Evidence cited in support of this proposal is the report by Anderson and coworkers3' that whereas 1-N,N-diethylaminocyclohexene(11, Scheme 5) exists in a conformation in which the nitrogen lone-pair orbital is parallel to the n-orbital of the (12) exists in a conformation in double bond, 1-N,N-diethylamino-2-methylcyclohexene which the nitrogen lone-pair orbital is orthogonal to the n-orbital. Clearly in such a conformation the pn-conjugation and hence the reactivity of the enamine will be reduced.
P. W. Hickmott
SCHEME 5
Capon and Wu have shown that the rate of hydrolysis of secondary enamines of cyclohexanone (13 and 14) is decreased only slightly by the C(,, methyl group. They have therefore concluded that the methyl substituent has little effect on the ground state or the transition state conformations of secondary enamines3'. However, in this case there is no developing allylic strain whether the transition state is reactant-like or product-like (see also Section VIII) and pn-conjugation is uninhibited. The pn-conjugation in secondary P,P-disubstituted acyclic enamines (15) compared to the corresponding tertiary enamines (16) is also demonstrated by the UV and N M R evidence provided by Capon and Wu3". A practical application of the preference for C-fi rather than C-P' protonation is the separation of a mixture of structurally isomeric enamines into their individual components. For example, careful titration of the mixture of enamines (17 and 18) derived from 3-methyl-2-butanone, with trifluoroacetic acid in pentane at O" gave a precipitate of the iminium salt (19) derived exclusively from isomer 17. The less reactive isomer (18) remained in solution. InterestingTy the subsequent deprotonation of the iminium salt 19 regenerated the less substituted enamine 17 without even trace amounts of 18 being formed (Scheme 6). No interconversion 17 and 18 via 19 occurred under these condiexample, reflecting regioselective C-P-protonation during hydrolysis, t i o n ~ A~ similar ~. is the isolation of the more substituted enamine 21 from a mixture of 20 and 2134.This isomer (21) was stable indefinitely in the solid state at 5 "C, and was unchanged after seven days in benzene at ambient temperature, or in pyrrolidine at 80 "C. However, a trace of acid rapidly led to the equilibrium mixture of 20 and 21 via the iminium salt 2234 (Scheme 7). Similar studies were carried out with 2335.
14. Electrophilic and nucleophilic reactions of enamines
Reagents: (i) CF3C02H,pentane, 0°C; (ii) i-Pr2NH SCHEME 6
Reagents: (i) 0.1 M HCI, petroleum ether, 5 min at ambient temperature; (ii) aqueous layer neutralized with 0.1 M NaOH SCHEME 7
6. Stereoselectivity
Contrary to previous r e p o ~ t s ~ ~the - ~ stereoselectivity ' of deuteriation, and hence protonation, of enamines of cyclohexanone is lowz9. This means that the transition state is reactant-like since, if it were not, the transition state for 'equatorial' protonation (attack from the a-face) would be destabilized by the non-bonded interactions associated
P. W. Hickmott
SCHEME 8
with a developing boat or twist conformation (Scheme 8). The equatorial :axial ratios for deuterium incorporation are summarized in Table 1. The small but reproducible difference in stereoselectivity between the pyrrolidine and morpholine enamines [Expts. (i) and (ii)] suggests that the rehybridization of the b-carbon of the morpholine enamine is slightly more advanced than that of the pyrrolidine enamine in the transition state. Consequently, an orbital bias is created which slightly favours attack from an axial dircction cvcn in a rcactant-likc transition statcz9(Figure 1). In the case of the pyrrolidine enamine of 2-methylcyclohexanone, if allowance is made for the high proportion of D2 relative to D, isomers formedz9,the results [in parentheses, Expt. (iii)] indicate a slight preference for equatorial attack. This is to be expected since the quasi-axial methyl group would shield the B-face of the enamine to some extent even in a reactant-like transition state. The higher axial stereoselectivity of deuteriation of the enol cther [Expt. (iv)], although not as great as previously claimed3', is a reflection of the lower reactivity. The transition state is therefore more product-like compared with that for an enamine, and hence a greater degree of stereoselectivity results as a consequence of the thermodynamic factors which favour a developing chair over a developing boat or twist transition state". For tctrasubstitutcd cnaminc doublc bonds thc situation is less clear. The stereoselectivity depends to a very large extent on the nature of the Cz-substituent (R) and varies from being completely non-stereoselective (R = CH3)34 to completely axial stereoselective [R = N(C02Et)NHC02Et]"4'.
TABLE 1. Deuteriolysis of enamines and enol ethers
I
I R'
R' X
R
Deuterium incorporate R'
Axial
Equatorial
52 57 50 (45) 70
48 43
(i) Pyrrolidinyl (ii) Morpholinyl
H H
t-butyl 1-butyl
(iii) Pyrrolidinyl
Me
H
(iv) Ethoxy
H
t-butyl
50 (55) 30
14. Electrophilic and nucleophilic reactions of enamines
735
Axial @-face)
Equatorial (a-face) FIGURE 1.
C. Asymmetric lnductlon
Both chiral amines4' and chiral protonating agents43 have been used for the enantioselective deracemisation 0f.a-substituted aldehydes and ketones via the derived enamine. However, the enantiomeric excesses achieved were usually not very high and there have been no new developments reported in this area4'.
Ill. ALKYLATION A. Reaction with Alkyl Halides
In the words of Gilbert Stork44,'the alkylation of enamines with alkyl halides is not a very good reaction and in many cases leads to total disaster!'. Certainly mixtures of N-alkylated, P-alkylated (25) and P,p-dialkylated products may be formed from [he morpholine or pyrrolidine enamines 24 of cyclic ketones in protic and aprotic solvents. Hydrolysis of the N-alkylated enamine regenerates the starting ketone 28, but this may also arise from hydrolysis of the C-protonated iminium salt formed by proton exchange between the unalkylated enamine 24, and the C-alkylated iminium salt. The regenerated alkylated enamine 25 may then undergo further alkylation at the p-position. Nevertheless, the mixture of ketones 26, 27 and 28 thus produced (Scheme 9) may readily be separated, at least in the case of methylation (R = Me), by making use of their different rates of enamine formation (28 > 26 4 27) since the enamines (24 or 25) have appreciably higher boiling points than the ketones (26 and 27)45. The use of highly reactive alkylating agents, such as a-halogeno earbonyl compounds (ketones and esters), a-halogeno ethers, a-halogenonitriles, and allylic, benzylic and propargylic halides results in better yields of C-alkylated five-, six- and seven-membered rings. In these cases the enhanced reactivity of the alkylating agent facilitates the reversal of N-alkylation. Some typical examples taken from the early literature are summarized in Scheme 10, together with the yields obtained (in parentheses) after h y d r o l y s i ~ ~ ~ - ~ ~ . The more reactive pyrrolidine enamine has generally been found to be the most useful for alkylations with alkyl halides3. The problem of N- versus C-alkylation has been investigated by several groups53. In the majority of cases there was an increase in the C to N alkylation ratio on heating to 100 "C for 18 h, due to N to C alkyl transfer. The facility of N-alkylated enamines to act as carbon alkylating agents was found to vary with the amine, the ketone and the alkylating agent. Morpholine enamines were
P. W. Hickmott
(27)
(28)
Reagents: (i) R'I; (ii) enamine 24; (iii) hydrolysis SCHEME 9
particularly poor in this respect showing the least C + N transfer and reactive alkylating agents showed the most C -t N transfer on heating. The evidence available indicates that the C + N transfer occurs by dissociation back to the alkyl halide and subsequent C-alkylation rather than direct intramolecular or intermolecular N -+ C alkyl transfer. The exception to this is where N + C migration may occur via a [3,3]sigmatropic rearrangement as with ally1 or propargyl halides54s55. This is particularly the case with aldehyde enamines where simple alkyl halides give almost entirely the N-alkylated salt3 (Scheme 11). In the case of enamines of cyclic ketones the nature of the amine was found to profoundly affect the course of the reaction. The pyrrolidine enamine in Scheme 11 gave 7&90% direct C-alkylation while the piperidine and morpholine enamines gave 80-90% rearranged product via the N-alkylated e ~ ~ a m i nthe e ~ ratio ~ ; of C/N allylation was shown to reflect the ,!I-carbon and P-proton chemical shifts rather than the basicity constants of the amine components56. p,p-Dialkylation becomes the predominant process when an excess of allyl bromide is used in the presence of a strong base (ethyl dicyclohexylamine)" (Scheme 12). N-Allylenamines undergo the 3-aza-Cope rearrangement at high temperature^^^. Methylation of the n i t r ~ g e n ~, or ~ "N-methylation ~ ~ ~ . ~ ~ of an allylimine followed by addition of base6', or the presence of titanium tetrachloride58b,reduces the electron density on the nitrogen and allows [3,3]sigmatropic rearrangement at lower temperatures (Scheme 13). The temperature for the rearrangement may be reduced still further
14. Electrophilic and nucleophilic reactions of enamines
737
Reagents: (i) MeI, benzene, A, 18 h (37%)46; (ii) BuI, toluene, A, 19 h (57%)46; (iii) PhCH2CI,dioxane, A, 12 h (53%)47; (iv) CH2=CHCH2Br, CHFN, A, 13 h (67%)48; (v) CICH2CONEt2,MeOH, KI,A, 17 h (41%)49; (vi) CICH2CN, dioxanc, A, 3 h (53%)50; (vii) BrCH2COPh, toluene, A, 2 h, (55%)51; (viii) BrCH2COMe, toluene, A, 2 h (40%)5'; (ix) C1CH20Me, ether, 25°C. 12 h (33%)52; (x) BrCH2C02Et,MeOH, A, 2 h (58%)5L,52 SCHEME 10
by the use of aluminium reagents and subsequent reduction of the rearranged imine gives access to &&-unsaturatedamines6' (Scheme 14). Palladium(0) complexes also catalyse the low-temperature 3-aza-Cope rearrangement of N-allylenamines in the presence of trifluoroacetic acid as co-catalyst6' (Scheme 15). A significant improvement in the alkylation of ketone and aldehyde enamines involves the use of sterically hindered a m i n e ~ N-Alkylation ~~. is prevented with consequent increase in C-alkylation. For example, reaction of the n-butylisobutylamine enamine of cyclohexanone (29) with methyl iodide in boiling acetonitrile (Scheme 16), or trimethyloxonium tetrafluoroborate at room temperature gave 2-methylcyclohexanone in increased yields of 56% and 74%, re~pectively~~ (compare Scheme 10).
P. W. Hickmott
i, iii
(80%) Reagents: (i) CH3CH=CHCH2Br; (ii) CH=CH2Br;
(20%) (iii) hydrolysis
SCHEME 11
small-quantities of unchanged ketone and 2,6-dialkylated ketone are still formed, howcvcr, owing to proton interchange between 29 and 30 thus generating 31 and 32. Interestingly, not only does the use of hindered arnines prevent N-alkylation, but it also inhibits hydroxylation of the resulting iminium salts 30, 32, 33, which can withstand boiling aqueous acid virtually unchanged (Scheme 16). Only ally1 and benzyl halides give good yields of C-alkylated aldehydes unless hindered enamines are used64. Otherwise N-alkylation or aldocondensation are often the only reactions . H'~nderedaldehyde enamines may also be prepared
Reagents: (i) Excess CH2=CHCH2Br,EtN(C6HI,-c)z; (ii) hydrolysis SCHEME 12
14. Electrophilic and nucleophilic reactions of enamines
E
i
R
R
iii
Reagents: (i) Me1 or MeOTs or Tick; (ii) 2W250°C; (iii) 80°C; (iv) -TiC14; (v) H30t(-RMeNH) E = Me or TiCb SCHEME 13
Reagents: (i) Me2CHCHO; (ii) RCOCl, Et3N; (iii) LiAIH4; (iv) AIC13 or MeAIC12 or Me2AICI, toluene, 50°C, 24 h SCHEME 14
739
P. W. Hickmott
Reagents: (i) Pd(PPh3)4, CF3C02H, benzene, 50°C, 20 h (ii) aq. HCI, 25OC,4 h SCHEME 15
and alkylated in s i d 6 . The method has also been used to achieve direct C-alkylation of isobutyraldehyde with propargylic halides54e,thus circumventing the formation of allenic products normally arising by initial N-alkylation and N -,C sigmatropic rearrangement54c. Reaction of enamines with perfluoroalkyl iodides gives a-perfluoroalkyl ketones via a free radical m e ~ h a n i s m The ~ ~ . reaction is rapid and uncatalysed for many enamines in the absence of oxygen; only when the double bond of the enamine is not sufficiently The mechanism for electron rich is irradiation with ultraviolet light neces~ary"~. unassisted trifluoromethylation involves the formation of a charge transfer complex as a result of electron donation by the nitrogen, followed by the addition of trifluoromethyl (Scheme la), radicals to the double bond (Scheme 17). Difluor~dihalomethanes~~ trifluoromethyldibenzothiophenium triflate70and trifluoromethyl metal reagents71have also been used. The free radical chain reaction between PhCOCH,HgCI and 1-morpholinocyclohexene has been reported to involve addition of the acceptor radical PhCOCH,. to the j-position of the enamine followed by electron transfer to regenerate the attacking radical7* (Scheme 19). Photostimulated reactions of simple alkylmercury halides failed since an electrophilic radical is required. Photolysis of p-nitrobenzyl chloride in the presence of enamines gave the a-p-nitrobenzyl ketone on h y d r ~ l y s i sRadical ~~. mediated reductive alkylation of acyclieenamines has also been reported with radical precursors such as PhSCH,CN, PhSO,CH,CI and Me3CS0,CH,SePh74". Reductive alkylation also occurred with chloromethyl p-tolyl sulphone in the presence of tributyltin hydride and azobis(isobutyronitrile)(AIBN)74b(Scheme 20). In addition to alkylation of enamines with a-halocarbonyl c o m p o ~ n d s ~(Scheme ~,~~.~~ lo), 1,4-dicarbonyl compounds and derivatives may also be prepared by propenylation of enamines followed by o z o n ~ l y s i s propynylation ~~, followed by h y d r a t i ~ n ~and ~~,~' reaction with ketone thioacetal monoxide79, diethyl 3-bromopropene phosphonatesO and dichloroacetaldehyde oximesl (Scheme 21).
14. Electrophilic and nucleophilic reactions of enamines
Reagents: (i) RBr or RI, benzene or CH3CN, A; (ii) NaOAc-HOAc-H20, (iii) enamine 29
741
&
SCHEME 16
8. Reactlon with Electrophilic Alkenes
As pointed out by Stork and coworkers in their definitive 1963 paper3, the reaction with electrophilic alkenes is especially successful since reaction at nitrogen is reversible. Reaction at the /3-carbon is (usually) rendered irreversible by, in the case of cyclohexanone enamines, internal proton transfer of the axial C-B' proton to the anionic centre of the initially formed zwitterionic intermediate (34), under conditions of stereoelectronic control (Scheme 22). When this intramolecular proton transfer cannot occur in aprotic solvents, or when the product produced in protic solvents is a stronger carbon acid than adduct 35 (i.e. when Z = COR, NO2), then carbon alkylation is also reversible and surprising changes in the regioselectivity of reaction may be observed (vide infra; see also Section V1.D and Chapter 26). Cyclobutanes (36) and, in the case of a,j-unsaturated
P. W. Hickmott
Reagents: (i) CF31; (ii) 'CF,; (iii) H30+ SCHEME 17
Reagents: (i) CF2Br2; (ii) H30+; (iii) ( ~ - B U ) ~ N F . ~ H ~ O SCHEME 18
14. Electrophilic and nucleophilic reactions of enamines
Reagents: (i) PhCOCH2HgCl; (ii) -HgO. -C1SCHEME 19
Reagents: (i) p-MeC6H4S02CH2ClrBu3SnH (AIBN) SCHEME 20
Reagents: (i) BICH~CH=CHPO(OE~)~; (ii) H30+; (iii) Na2PdC14, t-BuOOH, 60°C, 24 h; (iv) CH2=C(SMe)S(O)Me, CH3CN, A; (v) HzO, & (vi) C12CHCH=NOH; (vii) HC104, aq. CH3CN SCHEME 2 1
743
P. W. Hickmott
Reagents: (i) CH2=CHZ (2= CN, C02Me) in benzene or dioxane, A, 12 h; (ii) H20, A, 1 h; (iii) CH2=CHZ, EtOH SCHEME 22
14. Electrophilic and nucleophilic reactions of enamines
745
- bMebMe 1 i, iii
ii, iii
(38) Reagents: (i) CH2=CHZ, MeOH, A, 3 h; (ii) CH2=CHZ, benzene or dioxane, A, 66 h; (iii) hydrolysis (Z = CN, C02Me) SCHEME 23
(38) Reagents: (i) CH2=CHZ, benzene or dioxane, A, 66 h SCHEME 24
746
P. W. Hickmott
ketones (2 = COR), dihydropyrans (Sections V1.B and IILB, respectively)may be formed initially at low temperatures. However, those cycloadducts derived from enamines of cyclic ketones are unstable and are readily ring opened on heating to generate the corresponding zwitterionic intermediate (34). The regenerated enamine (35) may be hydrolysed to the mono-alkylated ketone or undergo further alkylation to give the p,p-dialkylated enamine (37) and hence the up'-dialkylated ketone on hydrolysis3. The rate for the second alkylation step is considerably lower than that for the first, owing to developing IJdiaxial interactions for axial approach, developing non-bonded boat or twist interactions for equatorial approach, or developing A1.3-interactionsif the first substituent is equatorially orientated (cf Scheme 3). Consequently, by proper choice of experimental conditions either product may be isolated in high yield. Thus, a$unsaturated esters and nitriles give about 80% yield of monoalkylation products with the pyrrolidine enamine of cyclohexanone in benzene or dioxane and the morpholine enamine in alcoh01"~'. On the other hand, the pyrrolidine enamine in alcohol gives 70% yield of the a,&'-dialkylatedp r o d ~ ~ t 3 , 4 6 . Similarly, the enamine of a 2-substituted cyclohexanone is alkylated by electrophilic alkenes such as acrylonitrile or methyl acrylate at the C6-position in methanol or acetonitrile. However, prolonged reaction time (66 h) of the pyrrolidine enamine of 2-methylcyclohexanone with these reagents in dioxane or benzene under reflux gives a 1 :1 mixture of 2,2- and 2,6-disubstituted cyclohexanones (38 and 39)s2.s3(Scheme 23). Two explanations have been suggested for this anomalous r e s ~ l t ~Huffinan ~ . ~ ~ and . coworkers84 have proposed that the 2,2-disubstituted cyclohexanone (38) is derived directly from a 2,6-disubstituted enolate intermediate by simultaneous alkylation at C, and dealkylation at C,. This is in effect a S,2' mechanism for which there is no precedent in enamine chemistry (Scheme 24). The basis for this suggestion is the anomalous solvent-dependent annulation of 2-substituted cyclohexanone enamines with methyl vinyl ketone (MVK) and the assumption that direct C-alkylation of a tetrasubstituted enamine is 'improbable for it is known that there is considerably less overlap of the unshared electrons on nitrogen with the n system of the double bond in this isomer relative to the more stable trisubstituted isomer, thereby greatly decreasing the rate of alkylation'. The anomalous results obtained with MVK will be referred to later (Section V1.D). All we would point out at this stage is that the results of Huffman and coworkerss4 prove, without any doubt, that alkylation with MVK is reversible in a protic solvent even after protonation of the anionic centre has occurred. This can be attributed to the greater carbon acidity of a methylene alpha to a ketone carbonyl group relative to one alpha to an ester or nitrile group. With regard to the 'improbability' of direct alkylation of a tetrasubstituted enamine via a normal enamine mechanism (i.e. pn-conjugation between the nitrogen lone-pair electrons and the n-electrons of the double bond) one only has to consider the difference in energy between a 1,3-diaxial methyl-methyl interaction (3.7 kcal m ~ l - ' )and ~ ~an A'.3 methyl-methyl interaction (5-6 kcal m 0 1 - l ) ~(i.e. ~ the strain energy which has to be overcome in the reaction of a tetrasubstituted enamine) compared to the energy barrier to chair inversion of a cyclohexane ring (10 kcal m ~ l - ' ) ~ 'which , occurs at room temperature, to put this statement by Huffman into its proper perspective! The cyclobutane adduct 40, from which the enolate anion 41 is supposedly derived, is itself destabilized by eclipsed interactions between the methyl group and the pyrrolidine or cyclobutane rings. Fleming and Harley-Masonss" have shown that formation of 40 (Z = CN) is difficult and reversible, and that reversion occurs primarily to starting enamine rather than to a 2,6-disubstituted intermediatessb.We therefore regard the S,2' mechanism (Scheme 24) for an enamine reaction as improbable and, in the absence of
747
14. Electrophilic and nucleophilic reactions of enamines
-We)
I
SCHEME 25
more compelling evidence, see no reason to doubt the validity of our earlier explanations3, an abbreviated version of which is given in Scheme 25. In essence the argument is as follows. In an aprotic solvent of low dielectric constant at low concentration of reactants, the low energy alkylation of the less substituted enamine conformer la, with the C,-methyl quasi-axially orientated, is rendered reversible since internal proton transfer to the anionic centre of the zwitterion 41a or 41e, via a cyclic six-membered transition state, cannot occur. The reaction is therefore diverted through two higher energy paths (i) involving axial attack on conformer l e in which the C,-methyl is quasi-equatorially orientated and (ii) axial attack on the tetrasubstituted enamine (It). Both may be rendered irreversible by internal proton transfer and both engender the same developing A'.' interactions between the methyl group and the a-methylene of the pyrrolidine ring, thereby leading to equal amounts of 2,6- and 2,2-disubstitution. As the concentration of the reagents is increased, so the amount of 2,6-disubstitution increases (Table 2) owing to increased intermolecular protonation of the anionic centre of the zwitterions 41a or 41e formed by low energy attack on la. In polar solvents of high dielectric constant the lifetimes of zwitterions 41a and 41e will be increased sufficiently to allow intermolecular protonation, etc., to occur, and in methanol the anionic centre is protonated by solvent, thus resulting in virtually complete 2.6-disubstitution via the low energy route. However, it must be emphasized that this
748
P. W. Hickmott
TABLE 2. Regioselectivity of alkylation of the pyrrolidine enamine of 2-methylcyclohexanone Electrophilic alkene
Solvent
Reflux time (h)
Yield
Disubstituted cyclohexanone
(%)
2,2Methyl acrylate Methyl acrylate Methyl acrylate Methyl acrylate Methyl acrylate Methyl acrylate Methyl acrylate Acrylonitrile Acrylonitrile
2,6- (%)
Methanol CH,CN
Dioxane Dioxane Dioxane Benzene Mesitylene Methanol Dioxane
" [Enamine]
= 2.3 mol I-' [Enamine] = 0.1 1 mol I-'. ' [Enamine] = 36.5 mol I-'.
argument applies only to those reactions which are rendered irreversible by protonation of the anionic centre, and certainly not to a$-unsaturated ketones such as MVK, reaction of which is clearly not irreversible as we had previously assumedsg. The fact that Pandit and Huismango have demonstrated that intramolecular protonation occurs in preference to intermolecular deuteriation by deuteriomethanol (Scheme 26) clearly illustrates the possible overriding importance of this step in determining the course of an enamine
Reagents: (i) 1-pyrrolidinylcyclopentene,MeOH or MeOD, lS°C X=O,NR SCHEME 26
14. Electrophilic and nucleophilic reactions of enamines
749
Reagents: (i) 1-pyrrolidinylcyclohexene; (ii) 177'C; (iii) 110°C; (iv) hydrolysis SCHEME 27
alkylation with elcctrophilic alkenes. Further examples which illustrate the effects of reversible initial reaction by electrophilic alkenes on the regioselectivity of dienamine reactions are discussed in Sections 111 and VILC of chapter 26. Interestingly, enamines attack the terminal olefinic carbon of 1,l-bis(ethoxycarbonyl)2-vinylcyclopropane (42), with ring opening of the cyclopropane ring, in contrast to sodiomalonic ester which attacks the more substituted cyclopropane carbong1. With diethyl cyclopropylmethylidenemalonate (43) reaction occurs at the P-carbon and the cyclopropyl ring remains intactg2 (Scheme 27). Titanium tetrachloride catalyses the highly diastereoselective addition of enamines to 2.2-dimethoxyethyl crotonateg3. The reaction of enamines with acrylaldehyde and methyl vinyl ketone (MVK) is probably best known as a means of forming bridged and fused bicyclic rings (Section V1.D). However, at low temperatures the initially formed products are dihydropyrans94. (See also Chapter 18, Section III.D.l.) Although these are heterocyclic systems, it is appropriate to consider them here since ring opening readily occurs to give an equilibrium mixture of a zwitterion, cyclobutyl ketone and dihydropyranY4<; subsequent chemical reactions then proceed from any one of these intermediates (Scheme 28). The dihydropyran produced from I-pyrrolidinylcyclohexene and MVK at -35 "C was even more unstable and decomposed at room temperature to give a succession of intermediatesg5 and ultimately the dienamine of octalone3. Similarly dihydropyrans from cyclohexanone enamines and acrylaldehyde give bicyclo[3.3.l]nonan-9-ones on heaEvidence for the two-step nature of the dihydropyran formation follows from the observation that both cis- and trans-dibenzoylethene gave the same dihydropyrang6, under conditions where cis-trans isomerism of the electrophilic alkene did not occur. On heating, the dihydropyrans rearrange into a mixture of the corresponding alkylated enamines (44 and 45) (Scheme 29). This is kinetically rather than thermodynamically controlled, since the equilibrium composition was obtained only after treatment with acidg6, and can therefore be regarded as irreversible in an aprotic solvent (benzene) at 80°C.
P. W. Hickmott
iii
-t
CHO I
Ph
vii
L
Reagents: (i) MVK, 20°C; (ii) CH2=CHCH0, 20°C, 21 h; (iii) MeI, ether, 20°C. 21 d; (iv) H30+, 20°C 10 h; (v) Hz, Pt02, 20°C, 48 h; (vi) (NC)2C=C(CN)2,20°C, 16 h; (vii) PhLi, ether, O0C, 2 h
SCHEME 28
14. Electrophilic and nucleophilic reactions of enamines
751
Reagents: (i) cis or trans-PhCOCH=CHCOPh, dry ether 5-20 "C, 24 h; (ii) 80 "C; (iii) H30+ SCHEME 29
Reaction of 1-morpholino-4-f-butylcyclohex-1-ene and phenyl vinyl ketone (PVK) gave the cis-fused dihydropyran (46) and the trans ketone (46s) on mild hydrolysis, indicating initial attack from the axial direction. The cis isomer (46b) can be obtained by heating 46s with acid (Scheme 30). In view of the poor yield of 46 (20%) compared to the dihydropyran 47 (75%) obtained from 1-morpholinocyclohexene(Scheme 31), it was suggested that cis-ring closure to the dihydropyran is less favoured than trans96,since the latter can occur after ring inversion. However, the corresponding reaction of trans-decalin-2-one enamine again gave the cis-fused dihydropyran derivative derived by initial axial attack at C-397 (Scheme 32). The corresponding reaction with the 4a-methyl enamine resulted in equatorial attack at C-397. The preference for the formation of the cis-fused dihydropyran (49) was attributed to the bulky morpholine ring having to be axially orientated in the trans-fused dihydropyran (48)97.98(Scheme 33). Zwitterionic intermediates (50) have been isolated as stable products in the reaction of 2-oxoindolin-3-ylidene derivatives with enediamines and their structure confirmed by X-ray analysis99(Scheme 34). Considerable work has been carried out by Risaliti and coworkers on the regioselectivity and stereoselectivity of the alkylation of enamines with vinyl sulresult was observed in the reaction phones100-105and nitro a l k e n e ~ ' ~ ~ - A " ~surprising . of phenyl vinyl sulphone with 1-N-morpholinocyclohexene in that the more substituted mono-alkylated enamine (51)was the main product. Its isomer 52 was formed only in 25% yield (Scheme 35).
P. W. Hickmott
(4m
Reagents: (i) H30+, 20 "C; (ii) H@+, A NR2 = morpholino SCHEME 30
The authors assume this reflects the rotamer population of the zwitterionic intermediate and that 51 arises by abstraction of an equatorial proton (Scheme 36). However, this would be more likely to occur via a twist conformation which could arise, at least in part, from equatorial attack on the enamine. Interestingly the tetrasubstituted enamine (51) crystallized from the reaction mixture and was shown on heating in benzene, without added acid catalyst, to revert to the same mixture of 51 and 52. This presumably reflects the greater carbon acidity of a methylene alpha to a sulphone group which can therefore catalyse the interconversion or cause reversion to enamine followed by re-alkylati~n'~~. Equatorial attack occurs with the morpholine enamine of 4u-methyl-trans-decalin-2one to give a mixture of 1- and 3-P-arylsulphonylethyl derivative^'^' (Scheme 37). Methyl P-styryl sulphones react at both the a- and P-carbon with enamines'0'~'03-'05. Kuehne and Foley"' have shown that nitroethene reacts exothermically with 1-Nmorpholinocyclohexene in acetonitrile to give the less substituted alkylated enamine (54, whereas the cyclobutane (53)is produced in hydrocarbon solvent. This is attributed to the increased lifetime and selectivity of the intermediate zwitterion in polar solvents, which is expressed in the proton transfer, via a six-membered transition state, to the enamine product (54, Scheme 38).
14. Electrophilic and nucleophilic reactions of enamines
Reagent: (i) CH2=CHCOPh NR2 = morpholino SCHEME 3 1
753
P. W. Hickmott
Reagents: (i) PVK; (ii) H30+ SCHEME 33
SCHEME 34
14. Electrophilic and nucleophilic reactions of enamines
Reagent: (i) PhS02CH=CH2, r.t., 48 h or A 4 h SCHEME 35
SCHEME 3 6
Reagent: (i) p-BrC&14S02CH=CH2(ArS02CH=CH2), 100eC SCHEME 3 7
755
756
P. W. Hickmott
1
iii
Reagents: (i) CH2=CHN02; (ii) petroleum ether, -20°C; (iii) CH3CN, -20°C; (iv) H30+,-20°C. 12 h SCHEME 38
1
iii
Reagents: (i) CH2=C(Me)N02, ether, 0°C; (ii) 20°C; (iii) H30+ X = 0,CH2 SCHEME 39
14. Electrophilic and nucleophilic reactions of enamines
757
Similar results were obtained with enamines of acyclic ketones such as desoxybenzoin. Nitrostyrene gave only the less substituted mono-alkylated enamine and hence the /3-nitro-a-phenylethyl ketone on hydrolysis"'. Surprisingly 2-nitropropene gives mainly the tetrasubstituted cyclohexanone enamine106. A hexahydrobenzo-l,2-oxazine-N-oxide (55) was isolated at low temperatures (in 80% yield) which rearranged at room temperature to a mixture of alkylated enamine isorner~'~'(Scheme 39). Reaction of 3-substituted cyclohexanone enamines with /3-nitrostyrene gives, on hydrolysis, a mixture of 6- and 2-alkylated ketones (59 and 57; ratio 4:1, respectively). Since the 6-alkylated ketone (59) is formed in much greater amount than enamine (58)
i
iii
R
I
iii
Reagents: (i) PhCH=CHN02, ether, 5°C. 48 h; (ii) benzene-petroleum ether or dry MeOH, & (iii) H30+ R = Me, Ph, t-BuO SCHEME 40
P. W. Hickmott
SCHEME 41
is present in the 5 6 S 5 8 equilibrium, this result confirms the rapid equilibration of the two enamine isomer^'^^"^^ (Scheme 40). The preference for attack at the C,-position can clearly be attributed to developing gauche butane interactions with the R-substituent for axial attack at C,, thus necessitating equatorial attack at C, with consequent increase in the activation energy owing to developing non-bonded twist interactions in 60109 (Scheme 41). In contrast to pnitrostyrene, 1-nitropropene undergoes both axial and equatorial attack on both 3- and 4-substituted cyclohexanone enamines, except for reaction at C, of the 3-substituted enamine where only equatorial attack occurs110. The regioselectivity of reaction of 2-tetralone enamines depends on the amine moiety as well as the electrophilic reagent. For example, p-nitrostyrene reacts with the morpholine enamine mainly at C,, whereas the pyrrolidine enamine reacts exclusively at C3, in contrast to phenyl isocyanate which reacts with both enamines at C,"'. P-Nitrostyrene reacts with the morpholine enamine of trans-decalin-2-one at C, from an axial direction,
(61) Reagents: (i) PhCH=C(Me)N02; (ii) CDC13 X = 0 , CH2 SCHEME 42
(62)
14. Electrophilic and nucleophilic reactions of enamines
759
Reagents: (i) CH2=C(Ph)N02; (ii) MeOH, 20°C; (iii) H30', pH 5-6 SCHEME 43
but with the 4-methyl-trans-decalin-2-one enamine at C, from an equatorial direction112. 1-Phenyl-2-nitropropene reacts with cyclohexanone enamines to give the cyclic nitronic ester (61)which is in equilibrium with the open-chain form (62)' l 4 (Scheme 42). As expected, a-nitrostyrene shows lower stereoselectivity than p-nitrostyrene and gives the 1,2-oxazine N-oxide (63) as the initial product of kinetic contro1116 (Scheme 43).
Reagents: (i) CH2=C=CHS02Ph, -50°C; (ii) chromatography on silica gel SCHEME 44
760
P. W. Hickmott
Reactions of nitroalkenes and enamines take place not only in good chemical yields but also in excellent diastereomeric yields (>90%)'18. A topological rule has been formulated for carbon-carbon bond-forming processes between prochiral centres in enamines and nitroalkenes as well as other sy~tems"~. The reaction of enamines and imines with acrylamide results in a z a - a n n ~ l a t i o n ' ~ ~ ~ ' ~ ' . Other electrophilic alkenes which have been used to alkylate enamines and the products used in hetero- 'or carbocyclic synthesis include ethyl / ? - n i t r o a ~ r ~ l a t ewhere ' ~ ~ , reaction occurs beta to the nitro not the ester group, 2-(pheny1seleno)prop-2-enenitrile [CH, = C(SePh)CN]'23,'24, phenyl a-phenylselenovinyl sulphone [CH, = C(SePh)S02Ph]'24 and phenyl a-bromovinyl s u l p h ~ n e ' An ~ ~electrophilic . allene, phenylsulphonylpropadiene, has also been used to alkylate enamines12' (Scheme 44).
C. Reaction with Electrophiiic Aikynes
The reaction of enamines with acetylenic compounds has been the subject of intensive studies. In general, alkyl acetylenedicarboxylates and propiolates undergo initial cycloaddition (Chapter 18) to form cyclobutene derivatives. These cyclobutenes rearrange, in most cases spontaneously, to form products whose structures depend on the starting enamine and on the reaction c o n d i t i ~ n s ' ~ ~(Scheme - ' ~ ~ 45). Berchtold and Uhlig'" and Brannock and c ~ w o r k e r s ' ~have ~ ~ 'shown ~ ~ that enamines of cyclic ketones undergo ring expansion by two carbon atoms, again via a cyclobutene adduct. Huebner and coworkers'29 have isolated the cyclobutene adducts and showed that bond rearrangement with ring expansion takes place on heating, but hydrolysis with cold dilute acetic acid gives an unsaturated keto-ester corresponding to Michael addition (Scheme 46). Cyclohexanone enamines reacted with methyl propiblate to form an unexpected rearranged product (64)'" (Scheme 47). Non-activated terminal alkynes also add to aldehyde enamines in the presence of copper catalysts'30 (Scheme 48).
Reagents: (i) Me02CC=C02Me; (ii) CHSX02Me; (iii) H30+ SCHEME 45
761
14. Electrophilic and nucleophilic reactions of enamines
1
I
iii
iii
Reagents: (i) CH=C02Et, 0-5°C; (ii) A; (iii) aq. AcOH SCHEME 46
D. Arylation
A number of methods for the C-arylation of enamines have been reported, but most have serious limitations. Highly reactive aryl halides, such as 2,4-dinitrochlorobenzene, react with pyrrolidine enamines of cyclic ketones to give the a-arylated ketone on h y d r ~ l y s i s ' ~ ' - ' ~(Scheme ~ 49). The method fails with less reactive halides, such as
I
0-l- -mCozMe iii
CHO
;Me
[mc02~e
i,,
NRz (64)
Reagents: (i) HC=COzMe, 25-35"C, 50 minor r.t. overnight (ii) +RzNH (trace); (iii) -R2NH; (iv) H30+ SCHEME 47
NR2
P. W. Hickmott
Reagents: (i) Ph-H,
CuCI; (ii) H30+; (iii) HOSCHEME 48
Reagents: (i) 2,4-(N02)2Cd3CI,Et3N; (ii) H 3 0 + SCHEME 49
OMe
Reagents: (i) P-M~OC&P~(OAC)~, CHC13, 20°C, 5 min [-P~(OAC)~]; (ii) H30+ SCHEME 50
4-nitrochlorobenzene, which yield N-arylated products. Good yields are obtained from pyrrolidine enamines, poor yields from piperidine enamines, and morpholine enamines fail to react. The pyrrolidine enamine of 2-methylcyclohexanone is arylated at C,. Other activated halides which have been used successfully include 2-chloro-5-nitropyridine, 4-chloro-3-nitropyridine and 2-chlor0-4,5-dicarbethoxypyrimidine~~~. In another approach, diaryliodonium salts have been employed as the arylating agent, but yields of the u-aryl ketone by means of this method were generally low13'. The treatment of 1-N-morpholinocyclopentenewith p-methoxyphenyllead triacetate in chloroform at room temperature provides a simple high-yielding route to 2-p-
14. Electrophilic and nucleophilic reactions of enamines
Reagents: (i) C,@6. 80°C; (ii) H30+; (iii) A; (iv) chloranil, C6H6,A SCHEME 5 1
-
Reagents: (i) Br2, THF, Et3N, -7g°C; (ii) PhM, -23 25 "C, 3 h; M = Li, CuSMe2,Cu, PhCuLi; (iii) H30+ SCHEME 52
763
P. W. Hickmott
Reagents: (i) benzyne; (ii) p-quinone dibenzene sulphonimide; (iii) p-benzoquinone SCHEME 53
methoxyphenylcyclopentanonel" (Scheme 50). However, the reaction is very sensitive to steric effects and is thus a useful synthetic method in a relatively small number of cases. Acetoxylation is a major competing reaction with enamines which give a low to moderate yield of C-arylated product. Condensation of enamines with perfluoroarenes, such as perfluorobenzene, perfluorotoluene, bromopentafluorobenzene and perfluoropyridine, leads after hydrolysis to the formation of a-perfluoroaryl ketones13'. C-Arylation may be followed by intramolecular N-arylation thus leading to fluorinated tetrahydrocarbazoles (Scheme 51). The C-versusN initial arylation ratio is very dependent on the amine moiety and was best for diethylamine enamines. a-Phenylation of ketones has also been carried out by reaction of bromoenamines with phenyl copper reagents138(Scheme 52). Other methods of arylation include reaction with a r y n e ~ ' ~ ' . ' ~p-benzoquin~, 0 n e s ~ 4 0 - ~ 4 sand quinone dibenzenes~lphonimide'~~" (Scheme 53). E. Reaction with Aldehydes and Ketones
Good yields of 2-alkylidene or 2-benzylidene ketones are readily achieved by condensation of enamines of cyclic ketones with aldehydes146-148.Except for the reaction with ~ h l o r a 1 ' ~ where ~ ~ ' ~the ~ , intermediate carbinolamine (65) was isolated and hydrothe corresponding aldol intermediates formed in these lysed to the p-hydroxyketone (613, reactions could not be isolated (Scheme 54). However, it has recently been shown that in the presence of a slight excess of Lewis acid the reaction can be carried out under very mild conditions and high yields of the crossed aldol products can be obtained from
14. Electrophilic and nucleophilic reactions of enamines
765
Reagents: (i) RCHO (R = alkyl or aryl); (ii) hydrolysis; (iii) C13CCH0 (2 equiv.); (iv) C13CCH0(1 equiv.) SCHEME 54
both ketone and aldehyde enamine~'~' (Scheme 55). Best yields (%92%) were obtained using the morpholine enamine and boron trifluoride etherate as catalyst, but high yields were also obtained using titanium tetrachloride, aluminium chloride and stannic chloride. Use of the piperidine enamine gave much lower yields and the pyrrolidine enamine failed to react. The aldol products were isolated as mixtures of threo and erythro diastereomers the ratio of which varied with the Lewis acid, the molar ratio of Lewis acid and the enamine. The use of zinc chloride as catalyst gave only the threo isomer of 67 but in much lower yield (19%)'51. 2-Alkylidenecyclopentanones (68 and 69), formed by condensation of the morpholine enamine and the corresponding aldehyde with azeotropic removal of water, may be isomerized to the thermodynamically stable 2-alkyl-2-cyclopentenones by heating with hydrochloric acid in butan01'~~(Scheme 56). Condensation of glyoxylic esters with aldehyde enamines gives a mixture of (E)- and (Z)-3-alkyl-4-0~0-2-butenoicesters (70 and 71). The Z-isomers (71) cyclysed to the butenolide (72) under neutral conditions,
766
P. W. Hickmott
+ (I) L
1
vi
-+Lh CHO
ii, iv, v
Reagents: (i) Me2CHCHO; (ii) PhCHO, (iii) MeCH=CHCHO, (iv) BF3.0Et2,CH2C12,20°C, 0.5 h; (v) HzO, 20°C, 1 h; (vi) PhCH2CH2CH0 SCHEME 55
14. Electrophilic and nucleophilic reactions of enamines
767
I
1
iii
iii
Reagents: (i) R02CCH0, hexane, A, 24 h (R = n-C4H9); (ii) MeOzC(CH2)5CHO, hexane, A, 24 h; (iii) conc. HCI, butanol, 90°C. 5 h SCHEME 56
Reagents: (i) R02CCH0, C&, p-MeC6H4S03H,A, 1.5-3 h; (ii) HzO, 20°C, 1-20 h Y = OH, NC4Hs0 SCHEME 57
P. W. Hickmott
Reagents: (i) PhCHO, EtOH, A, 30 min; (ii) enamine SCHEME 58
leaving the E-isomer which can be isolated pure by flash ~ h r o m a t o g r a p h y '(Scheme ~~ 57). Condensation of 1-pyrrolidinylcyclohexene with benzaldehyde in boiling ethanol occurs twice and is followed by cycloaddition of enamine to give a xanthene derivative14' (Scheme 58). o-Hydroxyaromatic aldehydes also cyclize to xanthene~"~,which on oxidation give xanthones (Scheme 59). Enamines react with Schiff bases to give N-substituted 8-aminoketones on hydrolysis155. Although enamines readily undergo intramolecular condensation with ketones (Section V1.D) the only intermolecular reaction we are aware of is that with diethyl k e t ~ m a l o n a t e ' ~Whereas ~. cyclic ketone enamines gave the aldol product, with enamines of acyclic ketones only the morpholine enamine of pentan-3-one gave the aldol product (73). The more reactive pyrrolidine enamine cyclysed onto the ester group to give the
Reagents: (i) o-HOC6H4CHO; (ii) C a 3 , C5H5N SCHEME 59
14. Electrophilic and nucleophilic reactions of enamines
769
i ii iii L
1
i, ii, iii or iv
(74) Reagents: (i) (Et02C)2CO, C6H6. 0 +25% 2.5 h; (ii) NaOAeHOAc-H20, 25 "C, 2.5 h; (iii) R = Me; (iv) R = Ph R4N = C4H80N,C4H8N; n = 0.1 SCHEME 60
pyrrolidinylcyclopentenone (74). Condensation of diethyl ketomalonate with both enamines of 1,3-diphenylacetone also gave only the corresponding cyclopentenone (74; R,N = pyrrolidinyl, R = R = Me,Ph; R,N = morpholino, R = Ph; Scheme 60).
F. Reaction with lminium Ions
The reaction of enamines with iminium ions provides access to substituted fi-amino aldehydes and ketones15' (Scheme 61). In a similar manner the Mannich reaction gives access to a,&unsaturated aldehydes158 or fi-amino ketones159(Scheme 62). Enamines .'~~. of the undereo the Vilsmeier reaction to eive a-formvl k e t o n e ~ ' ~ ~ Solvolysis .~ Vilsmeier salt with aqueous or alcoholic sodium hydrogen sulphide produces an enamino ~hioaldehyde'~~. The use of N-dichloromethylene-N,N-dimethylammonium chloride gives tertiary fi-ketoamide~'~~ (Scheme 63). Iminoalkylation of enamines with nitrilium salts provides access to enamino ketones and f i - d i k e t o n e ~ (Scheme '~~ 64). ~
~
.,
-
770
P. W. Hickmott
a N , M e
I
-
a
R
NOM^ I
ii
Qd*LH, I
R
R
1
iii, iv
A+
0-N=CH2
*
R
Reagents: (i) anodic oxidation, MeOH; (ii) TiC14; (iii) 1-N-morpholinocyclohexene;(iv) H20; (v) 1-N-rn0rpholin0i~0b~tene SCHEME 61
+
Reagents: (i) CH20, Me2NH, H+; (ii) hydrolysis; (iii) Me2N=CH2 AlCbSCHEME 62
G. Miscellaneous Alkylating Agents
Carboxyethylation of enamines occurs on heating with /?-propiolactone. A bketocarboxylic acid amide is produced directly in high yield in the absence of waterIb5 (Scheme 65). The same product was obtained on replacing /?-propiolactone by acrylic acid, and saturated carboxylic acids gave cyclohexanone and the corresponding carboxylic acid amide.
,
Electrophilic and nucleophilic reactions of enamines
("I N
Reagents: (i) DMF, COC12, CHzC12, A; (ii) HzO;
+
(iii) aq. NaHS; (iv) CI2C=NMe2 C1SCHEME 63
+
Reagents: (i) RCa-R;
(ii) HOAc; (iii) 6 N HCI
SCHEME 64
772
P. W. Hickmott
Reagent: (i) P-propiolactone, 155°C. 6 h SCHEME 65
a-Phenylthiomethylation of aldehydes and ketones can be carried out by heating the corresponding enamine with a (phenylthio)methylamine in the presence of hydrogen (Scheme 66). Enamines react with acetals or trialkyl orthoformates in the presence of Lewis acids to give b-alkoxycarbonyl compounds on hydroly~is'~'(Scheme 67).
Reagents: (i) PhSCH2NMe2,EtOH, HC1, A; (ii) H30*, A SCHEME 66
Enamines of acyclic and cyclic ketones react with 2,2-dimethoxyethyl esters of a,b-unsaturated acids in the presence of titanium tetrachloride under very mild conditions to give the Michael adduct with high syn-selectivity. A reactive 1,3-dioxolan-2ylium salt is formed which reacts with the enamine via a chair-like transition state16'
14. Electrophilic and nucleophilic reactions of enamines
773
Reagents: (i) RCH(OR)2; (ii) BF3.0.Et2, CH2C12,20°C. 1 h; (iii) H20; (iv) CH(OEt)3 SCHEME 67
OMe I
R
d o T O M e \
R
23 +
\
I
OMe
ii, iii
Reagents: (i) TiCI4, CH2CI2,-45 "C, 3 h; (ii) 1-N-morpholinocyclohexene,CH2C12,-78°C. 24 h (iii) MeOH, O°C, 15 rnin SCHEME 68
(Scheme 68). A highly stereoselective synthesis of 2-C-glycosyl ketones has been carried out by Michael addition of enamines to hexenopyranuloses. 1-Pyrrolidinocyclohexene, for example, is converted to 2-(2,4,6-tri-0-acyl-8-D-ribohexopyranosy1)cyc l ~ h e x a n o n e ~Hexafluoroacetone ~~". azine reacts with enamines having a 8-hydrogen atom to give the corresponding C-alkylation product. Without the /3-hydrogen, [2 + 2lcycloaddition to the azetidine occurs169b. H. Asymmetric induction
In 1969 Yamada and coworkers reported the first in a series of investigations on the alkylation of chiral enamines, derived from L-proline esters, with methyl acrylate and a ~ r ~ l o n i t r i l eThe ' ~ ~enamines . were prepared under the usual azeotropic conditions but were not distilled since this resulted in cyclization, by nucleophilic attack of the enamine on the ester function, or partial r a ~ e m i z a t i o n ' ~Optical ~. yields were found to be
774
P. W. Hickmott
increased by the use of bulky ester groups (C0,Bu-t) and low temperatures, as would be expected, and to be best in non-polar solvents of low dielectric constant such as dioxane or benzene. Unfortunately, such solvents gave low chemical yields (8-9%). Although the best optical yields obtained were in the range 50-60%, more typical values fell in the range 10-30%. The optically active Zsubstituted cyclohexanones thus obtained were all shown to have the S-configuration. The methodology was extended to strongly electrophilic alkyl halides such as ally1 bromide, ethyl bromoacetate and benzyl bromide, but the best optical yield was only 30% and tetrahydrofuran was then the best solvent"'. As pointed out by Whitesell and Fel~nan"~,of the two enamine rotamers which maintain piwonjugation (75 and 76) the ester group would be expected to exert a significant steric interaction with an approaching electrophile only in 76. Consideration of the two half-chair conformations of 76 shows that a transition state resulting from axial attack on 76a would be destabilized relative to one resulting from attack on 76b. Both half-chair conformations of 75 (not shown) can undergo axial alkylation, thus leading to a mixture of R- and S-substituted cyclohexanones, and the
(S)
E+= CH2=CHCN, CH2=CHC02Me, CH2=CHCH2Br,Me02CCH2Br,PhCH2Br; R = Me, Et, r-Bu SCHEME 69
14. Electrophilic and nucleophilic reactions of enamines
775
predominance of the S-2-substituted cyclohexanones must therefore result from the kinetically controlled enantioselective alkylation of 76b (Scheme 69). Whitesell and Felman therefore concluded that an amine with a C, axis of symmetry was required in order to ensure that the same side of the cyclohexene ring was shielded from attack whichever conformation of the enamine underwent alkylation. The enantioselectivity was thereby considerably increased, but in the opposite chiral sense, by using the cyclohexanone enamine derived from (+)-trans-2,5-dimethylpyrrolidine.This was assumed to have the S,S-configuration based on the results of the alkylation (Scheme 70). Optical yields of 82-93% ee were obtained. Also noteworthy was the low level of dialkylation observed ( 4 7 % ) and the fact that formation of enamine 77 was at least ten times faster using type 3A molecular sieves compared to 4A molecular sieves. Similar methodology has been applied to the alkylation of Csubstituted cyclohexanone enamines to give mainly the less stable trans disubstituted ~yclohexanone"~.
Reagents: (i) RX, CH3CN, A; (ii) pentane, buffered aq. HOAc RX = MeI, n-PrI, CH2=CHCH2Br SCHEME 70
A new diastereoselective and enantioselective synthesis of a-amino-y-0x0 acid esters has been reported involving the alkylation of enamines with acyliminoacetates (78). The stereocontrol is attributed to formation of a Diels-Alder like transition state (79). Ring opening of the adduct leads to a zwitterion or alkylated enamine, hydrolysis of which gives the single diastereoisomer (80; de 3 96%)'74 (Scheme 71). The use of a chiral ester [R = (+)- or (-)-menthy1 or (-)-8-phenylmenthyl] converted this process into an enantioselective reaction (de and ee 2467%). Since the reaction proceeds with complete anti-diastereoselectivity the two stereoisomers, enantiomeric at the two new stereogenic centres, could readily be separated by fractional crystallization. The main isomer of 80 (X = CH,), obtained in 80% yield, was shown to have the (l'S, 2R)-~onfiguration'~~. The use of a chiral enamine (81) derived from (9-2-methoxymethylpyrrolidineand an achiral ester (78; R = Me) again resulted in complete anti-diastereoselectivity and an enantiomeric excess in favour of 80 (R = Me) of 85%. A chiral enamine moiety was hence shown to have a stronger influence on the asymmetric induction compared to a chiral ester group'74. TO obtain maximum effect the concept of double stereodifferentiat i ~ n ' 'was ~ employed. That is, the chiral enamine (81; X = CH,, S) was alkylated with a chiral ester [78; R = (+)-menthyl]. In this case the reaction proceeded with complete diastereoselectivity and complete enantioselectivity (de = ee 3 99.9%), and gave the pure products (l'S, 2R)-80 [R = ( - )-menthy], X = CH,] and (l'R*, 2R)-80 [R = (+)-menthyl, X = S] in quantitative yield'74.
* Stereochemical configuration changed owing to substituent priority.
P. W. Hickmott
NHCOPh
!
Reagents: (i) N-morpholinoenamine, THF, - 100'C. 6 h; (ii) aq. citric acid to pH 4-5, 2S°C, 4-5 hr, R = Me, Et, c S 6 H , , ; X = CH2, S SCHEME 7 1
Desulphurization of 82 [R = (+)-menthyl, X = S] gave the crystalline acyclic amino acid derivative (2R, 3s)-83 (de = ee > 98%)174(Scheme 72). The reaction of chiral enamine 81 (X = CH,) with 8-nitrostyrenes has also been investigated by Seebach and c~workers"~".Only one of the four possible enantiomerically pure diastereomers was formed and a-alkylated cyclohexanones were obtained in 90% or greater optical purity (Scheme 73). Their configuration was deduced as (l'R, 2 9 by chemical methods and X-ray analysis. The chiral enamine (84)has been shown to react with 8-nitrostyrenes to give a mixture of mainly the 3- together with some of the 1-alkylated tetralone on hydrolysis. The main product (85) was shown to be greater than 90% diasteromerically pure and of 75-99% optical purity, and to have the (l'R, 3$)-~onfiguration"~~ (Scheme 74). 2-Alkyloxazolidines are ring opened by trimethylchlorosilane to give chiral N-[2(trimethylsilyloxy)aIkyl] enamines which undergo enantioselective magnesium chloride promoted Michael reaction with methyl acrylate and methyl 1-(trimethylsilyl)vinyl ketone (53-95% ee)176(Scheme 75). The proline ally1 ester (86) has been shown to undergo intramolecular C-allylation in the presence of palladium catalysts to give after hydrolysis optically active 2-allylcyclohexanonein 47% yield and 100% optical (Scheme 76). Chiral titanium reagents have also been reported to induce good to moderate enantioselectivity in the reaction of enamines with methyl (E)-o~azolidin~lbutenoate~~~.
14. Electrophilic and nucleophilic reactions of enamines
1
iii
(83 Reagents: (i) (78) (R = menthyl), THF, - 100°C; (ii) H30+; (iii) Raney Ni, EtOH, pH 6.5,50°C X = CH2, S SCHEME 72
SCHEME 73
Reagents: (i) AICH=CHNO~,toluene, O°C, 3 4 d; (ii) aq. HCI, 80°C. 45 min SCHEME 74
777
P. W. Hickmott
-0SiMe3 iii, iv
Reagents: (i) Me3SiC1, i-Pr2NEt, C6H6,A, 1 h; (ii) CH2=CHC02Me, MgCI2, THF,20°C, 15 h; (iii) CH2=C(SiMe3)COMe,MgCI2, THF, 20°C, 15 h; (iv) H20, silica gel SCHEME 75
Reagents: (i) Pd(PPh3)4,Ph3P, CHC13, 61 OC, 21.5 h; (ii) NaOAc-HOAc-H20-C&, 2ooc SCHEME 76
IV. ACYLATION
In addition to the synthesis of 8-dicarbonyl c ~ m ~ o u n dthe s ~acylation ~ ~ ~ , of enamines also gives access to a wide variety of acyclic, carbocyclic and heterocyclic systems. The course of the reaction is often critically dependent upon the type of enamine used, on the substituents present in the two reagents, and on the experimental conditions, such as temperature, solvent, presence of added tertiary amine, etc. In contrast to alkylation, N-acylation is readily reversible. Since enamines are stronger bases than the C-acylated enamines, half an equivalent of the enamine is lost by salt formation in their reaction with acid chlorides. This can be avoided by addition of a tertiary a~nine"~,but this in
14. Electrophilic and nucleophilic reactions of enamines
779
turn can give rise to complications owing to ketene formation (vide infra). In general the less reactive morpholine enamines give better yields of C-acylated products than do the more reactive pyrrolidine enamines. A. Reaction wilh Carboxylic Acid Chlorides, Anhydrides and Ketenes
Aldehyde enamines may be readily acylated at low temperatures to give 8-ketoaldehvdes on mild hvdrolvsis. Subseauent acid-catalvsed deformvlation then provides a convenient method fo; the convkrsion of an aidehyde into- the corresponding ket o n e ~ 8 0 . ~ 8(Scheme ~ 77). Although N-acylation is reversible at low temperatures, at high temperatures (i.e. boiling benzene) C,-N heterolysis can occur to give the corresponding amide, sometimes in quite high yield, particularly with the morpholine enamines of aldehydes'a1. The use of hindered aldehyde enamines derived from diisopropylamine, for example, prevents this from happening.
R1CWHR2
iii
t R'COCR2CH0
Reagents: (i) R'COCI; (ii) H20; (iii) H30t
SCHEME 77 In the presence of triethylamine, acid chlorides having an a-hydrogen are converted into the corresponding ketenes which undergo cycloaddition to aldehyde and acyclic ketone enamines to give aminocyclobutanones. Provided there are no hydrogens alpha to the carbonyl group, the cyclobutanones are thermally stable and can be isolated; otherwise ring opening occurs on heating to give vinylogous amidesl" (Scheme 78). The corresponding cycloadducts from enamines of cyclic ketones may be isolated in some cases but in general they are unstable and, depending on the ring size, undergo ring opening to give the acylcyclanone or the ring-expanded dione on h y d r o l y ~ i s ' ~ ~ ~ ' ~ ~ . Treatment of the acylcyclanone with alkali causes cleavage either to the cyclanone (n = 7-8) or the keto acid (n = 5 6 ) . Alkaline cleavage of the ring-expanded 1,3-dione
Reagents: (i) Et3N; (ii) R2NCH=CHR1
SCHEME 78
780
P. W. Hickmott
0 -
ii
1
/
iv
iii
RCH2CO(CH2),-1C02H
viii
R(CHZL+ICOZH
Reagents: (i) RCH2COCI, Et3N; (ii) A, n 9; (iii) n = 5-8; (iv) H30+; (v) HO-, n = 7-8; (vi) HO-, n = 5-6; (vii) HO-; (viii) Wolff-Kishner reduction
$i,ii
SCHEME 79
()APA
-
iii, iv
Me(CH2)7CH(CH2)2C02H Me I R
Me
Me
v, vi, ii
Reagents: (i) Me(CH2)4COCI; (ii) H30+; (iii) HO-, (iv) Wolff-Kishner reduction; (v) SOzC12; (vi) 1-N-morpholinocyclohexene SCHEME 80
14. Electrophilic and nucleophilic reactions of enamines
781
1
iii. ii
Reagents: (i) ClCO(CH2).COCI, Et3N (n = 6 or 8); (ii) H30'; (iii) CICO(CH2)2COC1 SCHEME 81
also gives keto acids (Scheme 79). Since these can be converted, by Wolff-Kishner reduction, into the corresponding saturated acid this gives an excellent method for chain elongation of acids by fivelS5, or twelve1" carbon atoms (for best yields). Substituents can be introduced in a specific manner at all positions in the carbon chain1", with the exception of C,. The process is illustrated by the synthesis of tuberculostearic acidlSsb (Scheme 80). If a dicarboxylic acid chloride is used, chain elongation by ten, twelve or twenty-four carbon atoms can be achieved. However, intramolecular acylation may also o ~ c u r ' " ~ -(Scheme ~~' 81).
I
iii
Reagents: (i) RS02CI, C5H5N, (ii) enamine; (iii) H20; (iv) HO-; (v) Wolff-Kishner reduction SCHEME 82
P. W. Hickmott
Reagents: (i) Hz,Pt02; (ii) 200°C; R = Me, Ph, 0-C1C6H4; n = 5-6
SCHEME 83
Functionality at the terminal (o) position can be realized by starting with an o-unsaturated acid chloride and carrying out the Wolff-Kishner reduction under carefully controlled conditions in order to avoid reduction or migration of the double bond19'. The use of imin~tosylates'~~", obtained by Beckmann rearrangement, gives terminal amino acids'92b(Scheme 82). The enamino ketone 87 (Scheme 79) can of course be isolated. Hydrogenation of the double bond then gives a Mannich base which eliminates amine on heating or treatment with acid to give the a,/?-unsaturated ketone; further hydrogenation gives the corresponding saturated ketone in good yield193 (Scheme 83). When an excess of acid chloride is used further 0-acylation of the intermediate enaminoketone results. In the case of cyclohexanone enamines, mild hydrolysis then gives the exo- or endo-keto-en01 ester (89 and 90, respectively) depending upon the nature of the substituents (R); more vigorous hydrolysis then gives the 2-acylcyclohexanone. Further acylation of the intermediate enamino ketone may also occur at C6 to give 88194,'95(Scheme 84). N-Trimethylsilyl enamines undergo N-acylation on treatment with acid chlorides (replacement of the trimethylsilyl group) to give the amide and starting ketone on hydrolysis. However, in the presence of potassium fluoride and a catalytic amount of crown ether, C-acylation occurs to give the a-acylimine in high yield'96 (Scheme 85). The reaction of a,/?-unsaturated acid chlorides with ketone enamines provides a useful method of u,a'-annulation of ketones and is dealt with in Section V1.D. Anhydrides may also be employed instead of an acid chloride3. The mixed anhydride of acetic and formic acid reacts with 1-N-morpholinocyclohexene to give 2-hydroxymethylenecyclohexanone'97. Acylation of isobutyraldehyde enamines with trichloroacetic anhydride in tetrahydrofuran at room temperature gives the a-trichloromethyl/?-trichloroacetyl a d d ~ c t ' ~ 'This . occurs by initial /?-acylation to give the acyl iminium trichloroacetate, followed by decarboxylation and nucleophilic addition of the trichloromethyl anion to the iminium group. Trifluoroacetic anhydride under the same conditions just gave the /?-trifluoroacetyld e r i ~ a t i v e ' ~ ~ .
14. Electrophilic and nucleophilic reactions of enamines
783
(90)
Reagents: (i) RCOCI; (ii) H30+; (iii) H 2 0 SCHEME 84
Ph,N/SiMe3
Ph,
I ,SiMe3
N -
0
R' R
R
R
R
R
R
R
Reagents: (i) KF, crown ether, CH2CI2, 0-20°C, 20 m i n d h; (ii) R'COC1
SCHEME 85
784
P.W. Hickmott
B. Reaction with Sulphonyi and Sulphenyl Derivatives
Aliphatic sulphonyl chlorides containing an a-hydrogen undergo cycloaddition (Chapter 18) with aldehyde enamines to give the corresponding thietane-1,l-dioxide, via the intermediacy of s ~ l p h e n e s (Scheme ~ ~ ~ ~ 86). ~ ~ Ketone ' enamines behave in the same way to give thietane-1,l-dioxides, which ring open on prolonged heating or distillation to give the expected or rearranged b-keto sulphone on h y d r o l y ~ i s " ~ (Scheme , ~ ~ ~ 87). The presence of a second tertiary amine group can result in further complications owing to competition with the neighbouring enamine function for the electrophilic sulpheneZo4(Scheme 88). Aromatic sulphonyl chlorides cannot form sulphenes and hence give the acyclic s u l p h ~ n e ~ ~ (Scheme ~ - ~ ~89). ' Reaction of enamines with alkyl p-toluenethiosulphonates (p-CH,C,H,SO,SC,H,,) gives a-alkylmercapto ketones208, and reaction with p-toluenesulph~n~c acid in the
Reagents: (i) CH3S02CI,Et3N (i.e. CHz=S02)
SCHEME 86
Ph
1
iii
Reagents: (i) CH2=S@; (ii) A, (iii) H30i
SCHEME 87
14. Electrophilic and nucleophilic reactions of enamines
785
Reagent: (i) CH2=S02, - 15°C SCHEME 88
Reagents: (i) p-CH3C&SO2Cl;
(ii) H30t
presence of phenyl phosphorodichloridate gives b-keto sulphoxideszog,on hydrolysis. a-Arylsulphonyloxy ketones may be obtained by reaction of enamines with arylsulphonyl peroxides210,and b- ketosulphonamides are formed from alkyl sulphamoyl chlorides"" Reaction of 1-pyrrolidinylcyclohexenewith o-, m- or p-nitrobenzenesulphenyl chloride gives the corresponding 2- or 2,6-bis-nitrophenylsulphenylcyclohexanoneon hydrolysiszo6. C. Reaction with isocyanates and lsothiocyanates
As with other heterocumulenes, isocyanates undergo cycloaddition to enamines to give aminoazetidinones. Aldehyde enamines containing a j-hydrogen give the corresponding amide2'2-215. If there is no /&hydrogen, azetidinones can be isolated at low
P. W. Hickmott
-
NHR
I
1
iii
Reagents: (i) RN=C=O, 20°C. (ii) H30+; (iii) RN=C=O (2 equiv.), 12&140°C; (iv) Na2Crz@, H2S04, 20°C. 20 h
SCHEME 90
. At h'~ghertemperatures ring opening occurs and further reaction with isocyanate gives aminohydrouracils, which can be hydrolysed and then oxidized to the corresponding barbituric acid218(Scheme 90). Enamines of a c y ~ l i c " ~ ~and " ~ cyclic212~213~z21 ketones do not give azetidinones. The mono or dicarboxanilide is obtained on reaction with phenyl isocyanate (Scheme 91). Vinyl isocyanate reacts with enamines of cyclic ketones to give N-vinyl carboxamideszZ2. Isothiocyanates react similarly, to give the t h i ~ a m i d e ~ 'and ~ . ~have ~ ~ ,been utilized in heterocyclic synthesiszz4(Chapter 23).
Reagents: (i) PhN=C=O; (ii) H30+
SCHEME 91
14. Electrophilic and nucleophilic reactions of enamines
787
I
iii
Reagents: (i) CIC02Et, C6Hs, A, 10 h; (ii) H30+; (iii) LiAlH4 X = 0 , CH2 SCHEME 92
D. Miscellaneous Acylating Agents
8-Keto esters can be obtained by acylation of enamines of acyclic and cyclic ketones with ethyl chloroformate3. Surprisingly no j-keto ester was obtained when the reaction was carried out in the presence of triethylamine and an extra mole of enamine or a tertiary aromatic amine must therefore be used to neutralize the acid liberated. The intermediate enamino ester can be isolated and reduced by hydride donors225(Scheme 92). Acylation with phosgene occurs under very mild conditions to give enamino-acyl chlorides which undergo solvolysis to esters or amidesZz6 (Scheme 93). Cyanogen chloride reacts with enamines to give cyanoenamines and a-cyanoketones on hydrol y s i ~ ~Cyanogen ~'. bromide and iodide react differently; a 1 :1 adduct is formed which, on hydrolysis, leads to 2-haloketones (Scheme 94). Hexafluoropropene oxide reacts with enamines to give pentafluorinated 1,3-diketonesZz8.
Reagents: (i) COCI2, ether, Et3N, -20°C; (ii) ROH, Et3N, or R2NH (Z = OR, NR2) SCHEME 93
P. W. Hickmott
Reagents: (i) CICN, Et3N; (ii) H30+; (iii) BrCN SCHEME 94
V. HALOGENATION
The halogenation of enamines is extremely sensitive to the experimental conditions employed, such as the temperature, the solvent, the amine moiety, the duration of the reaction, the order of mixing the reagents, the molar proportions, etc. The majority of literature reports using elementary halogens are concerned primarily with bromination rather than chlorination, presumably owing to the greater convenience of handling. Carlson and Rappe229-232have studied the bromination of unsymmetrical acyclic enamines and a number of interesting facts have emerged. At -78°C the enamines are converted rapidly into the a-bromoiminium salts (92 and 97) which are stable towards further bromination; consequently the yields of dibromoketone are low at this temperature and hydrolysis gives a-bromoketones (94 and 100). At room temperature, or in the presence of added base (Me3N),dehydrobromination occurs to give bromoenamines (93 and 98) and, after further bromination, gives a,a- and a,a'-dibromoketones (95 and 102). The yield of 94 far exceeds the amount of the less substituted enamine (91a) present in the equilibrium mixture of enamines, and is even formed (to the extent of 14%) when a pure sample of the more substituted enamine (91b) is brominated. This result was explained, not by displacement of the enamine equilibrium (91ae91b), but by debromination of the bromoiminium salt (101). The resulting bromoenamine 99 is then protonated or brominated on the nitrogen, and thus prevented from undergoing further C-bromination. Reaction at nitrogen would be expected to be kinetically favoured over reaction at the p-carbon and, furthermore, the bromoenamine (99) would be thermodynamically favoured over its precursor (98). Consequently, under conditions of reverse addition virtually no a,a-dibromoketone 95 is formed because of preferential Nbromination of 93. If the bromine is added to the enamine, however, deprotonation of 92 occurs and a$-dibromination results. This can be made the exclusive product from isomer 91a by a bromination-trimethylamine dehydrobromination-bromination sequence (92 + 93 + % + 95). These brominations occur with great rapidity and the products are formed reversibly (Scheme 95).
789
14. Electrophilic and nucleophilic reactions of enamines
/ iii
RzN
6 Br
-f
i~~
R2N+ B r
&B~
iii
Br
Reagents: (i) Br2. CH2CI2. -7goC,1 min; (ii) Me3N, -20°C, 5 min; (iii) H20; (iv) Br2, 20°C R2N = C4HBON SCHEME 95
Bromination, chlorination and iodination of enamines of cyclic ketones also occurs at -78°C233. The P-haloiminium salt is formed and acid hydrolysis leads to the a-haloketone in good yield (Scheme 96). In principle the pyrrolidine enamine of 2-methylcyclohexanone,which exists primarily in the less substituted form (lo&), would be expected to give the 6-halogenoketone (103). In practice, several halogenation procedures (no experimental details given) were reported to give primarily 105 and only a little of 103234(Scheme 97).
P. W. Hickmott
0- & R2N
&B.
a
ii, iv
1
iii, iv
Reagents: (i) Brz, Et20, -78°C; (ii) C12, Et20, -78°C; (iii) 12, Et20, -7S°C, R2N = C4HBN; (iv) H30+; n = 5-7 SCHEME 96
However, bromination in acetic acid at 0-5°C did give mainly 103 which rearranged slowly at room temperature to 105235.The morpholine enamine of 2-methylcyclohexanone exists as a mixture of 52% less and 48% more substituted isomers (106a,b). The greater reactivity of the former has been utilized as a means of separating the brominated products. Thus, treatment of the mixture of enamines with 0.52 equivalents of bromine results in precipitation of the 6-bromoiminium salt (107), which can be filtered off and hydrolysed to the 2,6-disubstituted cyclohexanone (108). The less reactive isomer (106b) remains in solution and can then be brominated in the same way to give a precipitate of the 2-bromoiminium salt and hence the 2,2-disubstituted cyclohexanone (109) on hydrolysis236(Scheme 98). The stereoselectivity of bromination of 4-t-butylcyclohexanone enamines has been studied and the ratio of axia1:equatorial bromine incorporation shown to vary with the amine moiety (pyrrolidine 51 :49; piperidine 66 :34; morpholine 74 :26; N-methylaniline 52:48, di-isobutylamine 52:48)237.This variation in the axia1:equatorial selectivity has been rationalized in terms of the nature of the transition state. C-Bromination of the pyrrolidine, N-methylaniline and di-isobutylamine enamines must occur via an early reactant-like transition state thus resulting in low stereoselectivity (Scheme 99). The
79 1
14. Electrophilic and nucleophilic reactions of enamines
(1068)
+
48%
(107) precipitate
(106b) filtrate
i, ii, iii
Reagents: (i) Br2, (0.52 equiv.), Et20, -60°C; (ii) filter; (iii) H20 SCHEME 98
Br
1
iii
iii
0 Reagents: (i) Br2 axial attack; (ii) Br2 equatorial attack; (iii) H20 R2N = C&N, PhNMe, (i-Bu)2N SCHEME 99
792
P. W. Hickmott
R2N = C4H80N,CSHL$J SCHEME 100
Reagents: (i) Et3W, (ii) equatorial H+; (iii) H20 SCHEME 101
Reagents: (i) N-chlorosuccinimide (NCS), CH2C12, 0°C; (ii) 2 equiv. NCS SCHEME 102
14. Electrophilic and nucleophilic reactions of enamines
793
piperidine and morpholine enamines are believed to react, at least in part, via initial N-bromination and rearrangement to the C-bromoiminium salt via a product-like transition state and thus result in higher stereoselectivity (Scheme 100). However, equilibration of the bromoiminium salts with triethylamine prior to hydrolysis gives mainly the axially orientated trans-2-bromo-4-t-butylcyclohexanone on hydrolysisz3' (Scheme 101). Halogenation of enamines with N-chloro- and N-bromosuccinimide has been carried out in various solvents238.With cyclohexanone enamines this method suffers from the disadvantage that a mixture of mono-, di- and trichloroenamines is formedz3'. However, the use of two equivalents of N-chlorosuccinimide gives the dichloroenamine (110) in high yieldz3' (Scheme 102). A convenient method for the monochlorination of cyclohexanone enamines involves the use of hexachloroacetone. For example, the pyrrolidine enamine of 2-methylcyclohexanone (104a and 104b) gave a mixture of 90% of the 6-chloroketone 103 (Scheme 97) and 9% of the 2-chloroketone 105240.Similar treatment of the morpholine enamines of 3-methylcyclohexanone (llla,b) gave a mixture of 64% cis-6-chloro-3-methyl-, 15% cis-2-chloro-3-methyl-, 8% trans-2-chloro-3-methyl- and 13% trans-6-chloro-3-methylcyclohexanone240(Scheme 103). The reaction exhibits regioselectivity in favouring the formation of the cis-6-chloro-3-methyl isomer which was explained in terms of the strain between the C-3 methyl group and the C-2 proton which destabilizes the A' isomer of the morpholine enamine of 3-methylcyclohexanone. Prolonged standing showed that the kinetic mixture did not correspond to the equilibrium mixture, the cis-isomer being converted into the thermodynamically more stable trans-isomer via epimerization of the a-chlorocarbon by keto-enol t a u t ~ r n e r i s m ~ ~ ~ .
(llla)
64%
(lllb)
15%
13%
8%
Reagents: (i) CI3CCOCCl3,THF, O°C, 45 min; (ii) H30i SCHEME 103
794
P. W. Hickmott
The fluorination of enamines has been carried out with several reagents, such as perchloryl f l ~ o r i d e ~ ~trifluoromethyl ',~~~, hypofluorite243, d i f l u o r o d i a ~ e n eand ~~~ l-fluor0-2-p~ridone~~~ (Scheme 104). Reaction of bromotrichloromethane with 1-Npyrrolidinylcyclohexene generates a trichloromethyl anion which adds on to the a-halogenoiminium cation and gives a complex mixture of a-Bromocyclanones have also been formed in high yield by reaction of the corresponding enamine with bromodimethylsulphonium bromide247.
i or ii,
H
I
iv, i, iii
Reagents: (i) FC103, C6H6,30 rnin; (ii) F3COF, CFC13, -75°C; (iii) H30+; (iv) pyrrolidine; (v) N2F2,CH 2C12, pyridine, O0C SCHEME 104
VI. CARBOCYCLIC SYNTHESIS
A. Three-membered Rings
The most common method for preparing aminocyclopropanes is, of course, by cycloaddition of carbenes to enamines. Such cheletropic reactions and their nonconcerted analogues are dealt with in Chapter 18. All we would say here is that when the carbene carries a good leaving group, such as a chlorine substituent, the cycloadduct may ring-open to give an a,Sunsaturated compound. In the case of a bicyclic [n.l.O]adduct, depending on which bond of the three-membered ring is broken, this may lead to
14. Electrophilic and nucleophilic reactions of enamines
79 5
Reagents: (i) :CC12; (ii) n = 6; (iii) n = 5 SCHEME 105
the introduction of an endocyclic double bond with ring expansion or an exocyclic double bond with retention of ring size248(Scheme 105). When there is only one good leaving group in the carbene the ring opening depends on the stereochemistry of the substituent in the cycloadduct. For example, reaction of phenylchlorocarbene with 1-N-morpholinocyclohexene gives the bicyclic adduct as a
iii, i v
Reagents: (i) P ~ C C (ii) ~ ; CSH5N,A, 2 h; (iii) CSH5N,A, 45 h; (iv) hydrolysis SCHEME 106
P. W. Hickmott
iii
Reagents: (i) R'SCH2Cl, t-BuOK; (ii) KMn04; (iii) aq. HOAc SCHEME 107
mixture of stereoisomers. The endo-chloroadduct (1124 undergoes disrotatory ring opening in boiling pyridine to give the ring expanded product (113). Electrocyclic ring opening is sterically prohibited in ll2b which therefore reacts via a dipolar intermediate to give 114 and 115249(Scheme 106). However, the subsequent fate of the cycloadduct also depends on the nature of the amine moiety and the ketone from which the enamine was derived, in addition to the substituents present in the carbene. Cycloaddition of thiocarbenes gives access to mercaptocyclopropanes which undergo oxidative ring opening to fl-ketosulphones2" (Scheme 107).
Reagents: (i) C4HsN; (ii) H30+; (iii) NaBH4; (iv) Me2C0, H+; (v) NaN3, H+ SCHEME 108
14. Electrophilic and nucleophilic reactions of enamines
797
Reagent: (i) PhC(OMe)Cr(CO)5 SCHEME 109
Substituted bicyclo[n.l.O]alkanes may also be obtained by condensation of secondary amines with 2-haloketones. A variety of nucleophilic reactions can be carried out on the intermediate cyclopropaniminium salt 116zs1 (Scheme 108). Competing alkene scission and cyclopropanation occurs on reaction of enamines with pentacarbonylchromium carbene complexeszs2(Scheme 1 W). N-Silylated allylamines and their derived N-silylated enamines undergo rhodium or copper catalysed cyclopropanation by methyl d i a ~ o a c e t a t e '(Scheme ~~ 110). A versatile synthetic procedure has been developed by Vilsmaier and coworkers. The method involves treatment of an enamine with S,S-dimethyl-N-succinimidosulphonium fluorosulphonate to give an enaminosulphonium salt (117).The latter gives the cyclopropane derivative under the influence of a nucleophile and base254-259(Scheme 111). Cyclopropanes have also been obtained by reaction of enamines with a-chloro electrophilic alkenes. After Michael addition the chlorine undergoes nucleophilic displacement by the regenerated enamine or enolate anionz60,z61(Scheme 112). Bicyclo[l.l.O]butanes may be obtained by cycloaddition of trimethyl ethylenetricarboxylate followed by a base catalysed displacement of the amine moietyz6* (Scheme 113).
1
iii
Reagents: (i) Fe(CO)5, A or hv; (ii) N2CHC02Me,Cu(a~ac)~, 80°C; (iii) NzCHCOzMe, RhZ(OAc),, 20°C; (iv) HCI; (v) NaOH SCHEME 110
P. W. Hickmott
Reagents: (i) succinimide, NEt(i-Pr)2; (ii) %N; (iii) R2NH SCHEME 111
B. Four-membered Rings
Four-membered carbocyclic ring systems are commonly formed by cycloaddition of electrophilic alkenes, ketenes and arynes to enamines. Since cycloaddition reactions of enamines are dealt with in Chapter 18 these reactions will only be mentioned briefly here. Cycloaddition of electrophilic alkenes to enamines, at low temperatures and under aprotic conditions, is a well documented method for the formation of cyclobutanes from
R
CHO
\ /
Reagents: (i) CH2=C(Cl)CN; (ii) H30i SCHEME 112
14. Electrophilic and nucleophilic reactions of enamines
799
1
iii
Reagents: (i) Me02CCH=C(C02Me)2; (ii) MeS 03Me; (iii) NaH E = C02Me SCHEME 1 13 aldehyde e n a m i n e ~and ~ ~ ~bicyclo[4.2.0]alkanes from cyclohexanone enamineP4 (Scheme 114). The reaction has been clearly shown to be a two-step process and the intermediate zwitterion demonstrated to be formed under reversible conditions265.The same cycloadduct was obtained from diethyl maleate and diethyl fumarate under conditions where cis-trans isomerization of the two electrophilic alkenes did not occur. Hence, rotation about the carbon-carbon single bond in the intermediate zwitterion must occur prior to ~ y c l i z a t i o n ~ ~ ~ .
6 70~ - n& m n
i
/
lv
WCN i)-Reagents: (i) CH2=CHCN, pentane, 20°C, 1 h; (ii) 80°C; (iii) MeI, 20°C. 10 d; (iv) HO-, (v) H20, A SCHEME 114
P. W. Hickmott
Reagents: (i) CH2=CHCH=C=O; (ii) m-CIC6H4C03H SCHEME 115
Cyclobutanones are obtained from cycloaddition of ketenes to enamines (see Section 1V.A and Chapter Such cycloadditions may be concerted or step-wise depending upon the amine moiety and the experimental conditions. Vinylketenes are especially interesting since these may undergo [2 21 or [4 + 21 cycloadditions to give after oxidation a vinylcyclobutanone or a cyclohexenone, respe~tively267~268. Cycloaddition of arynes to enamines gives aminobenzocyclobutenes, which undergo amine elimination or ring expansion on thermolysis of the amine oxidez6' (Scheme 116).
+
Reagents: (i) C6H4(benzyne); (ii) RC03H; (iii) A, n = 6; (iv) A, n = 5 SCHEME 116
14. Electrophilic and nucleophilic reactions of enamines
I
iii
Reagents: (i) (NC)2C=C(CN)2; (ii) ( N C ) ~ ~ € ( C N ) ~ ; (iii) (NC)~CH-C(CN)~;(iv) -2H+, +2H+ SCHEME 117
The reaction between electrophilic alkynes and enamines gives cyclobutene interm e d i a t e ~ ~which, ' ~ on heating, give cyclic compounds resulting from a two-carbon ring expansion (see Chapter 18). C. Five-membered Rings
Tetracyanoethylene is unusual in that it reacts with cyclohexanone enamines to give a five-membered ring instead of a cyclobutane adduct. Reaction occurs at the y-position of the enamine and an initial one-electron transfer between the two reactants is
Reagents: (i) (MeCHBr)zCO, Fe2(C0)9 or CeCI3-SnCI2; (ii) H O ~ SCHEME 1 18
P. W. Hickmott
Reagents: (i) Pb(OAc),. BF3.OEt2, EtOH, C&, 20°C 30 h SCHEME 119
proposedzll (Scheme 117).Cyclopentenones can be obtained by cyclocondensation of up'-dibromo ketones with enamines in the presence of iron carbonyls272or CeC1,SnClZ2l3(Scheme 118). A Favorskii-type rearrangement occurs on boron trifluoride promoted lead tetraacetate oxidation of enamines214 (Scheme 119). Five-membered rings may also be constructed by a Michael addition-radical cyclization process275(Scheme 120). Activated cyclopropanes undergo nucleophilic ring opening with enamines at the less substituted Dosition. The . ~erhvdroindene thus obtained from cvclohexanone enamines . ring opens on heating and then undergoes recyclization to the corresponding spir0[4,5]decenone (118)276(Scheme 121). Reaction of enamines with diphenylcyclopropenone is complex and a variety of products arising from C,N- and C,C-insertion, condensation and addition can be i s ~ l a t e d ~ ' ~(Scheme -~ 122). The analogous reaction with diacylmethylenecyclopropene gave dihydrocyclopenta[b]furans282. Other fivemembered ring-forming reactions from enamines include condensation with cyclohepta[b]furanonez8" cycloaddition to 8-cyanoheptaful~ene~~~ and 1,3-dipolar cycloaddition of diphenylphosphorazidate to cholestanone and other cyclic ketone enamines which results in ring contraction via a labile triazolineZa5(Scheme 123).
Reagents: (i) CH2=C(X)Z; (ii) H20; (iii) RC=Li; X = PhSe, Br; Z = CN, SOzPh SCHEME 120
(iv) Ph3SnH-AIBN
14. Electrophilic and nucleophilic reactions of enamines
(118)
Reagents: (i) I-N-pyrrolidinylcyclohexene;(ii) EtOH, A, 19 h SCHEME 121
Reagent: (i)
A
Ph
SCHEME 122
ph
803
P. W. Hickmott
Reagents: (i) (Ph0)2P(0)N3, THF, 40°C; (ii) aq. HC1, MeOHIHCI SCHEME 123
D. Six-membered Rings
By far the most common annulation reactions of enamines lead to the formation of six-membered rings. Depending on the nature of the electrophilic reagent, the same enamine can act as either a two-carbon or a three-carbon component in the annulation p r 0 C e S S ~ . ~ . z 8 6 . 2 8 ~(Scheme 124). Furthermore, the same enamine and the same electrophilic reagent can give completely different products depending on the experimental conditions e m p l ~ y e d ~(Scheme ~ ' , ~ ~ 125). ~ A further thought to bear in mind is that an enamine reaction, particularly an annulation process involving a bidentate reagent, rarely gives a single pure product; mixtures are usually obtained and, hopefully, the desired product is the one in excess and/or can readily be separated from the rest. For example, in the reaction between methyl vinyl ketone (MVK) with 1-N-pyrrolidinylcyclohexeneto give A1.8a-2-octalone
Reagents: (i) CH2=CHCOMe(MVK); (ii) CH2=CHCOCI; (iii) NaOAc-HOAc-H20; (iv) H20 SCHEME 124
14. Electrophilic and nucleophilic reactions of enamines
805
+ MeCH=CHCOCl
Reagents: (i) 25°C; (ii) 8O0C; (iii) Et3N; (iv) hydrolysis SCHEME 125
(119) (Scheme 124) additional products 120-124 (Scheme 126) were also isolated288.The formation of cis- and trans-Sdecalone suggests that a disproportionation reaction had occurred between enols of 119 and 120 to give 122 and 123 together with the tetrahydro-P-naphthol (124); however, the latter was not identified in the reaction mixture. The formation of the 8a-hydroxy-2-decalone (121) is significant evidence for the mechanism of cyclization. A similar cycloadduct (126) has been isolated, together with the bridged-ring ketol (127). in the pyrrolidine catalysed cyclization of Michael adduct (125)289(Scheme 127). The formation of ketol (121) precludes a cyclization mechanism involving nucleophilic attack by an en01 or an enolate anion on an iminium group. This, together with the direct isolation of the pyrrolidine dienamine (128) from
P. W. Hickmott
the reaction mixture, suggest the mechanism given in Scheme 128 for A1.aa-2-octalone formation289.The trans-enamination (step ii) is catalysed by a trace of water either originally present or eliminated in the conversion of the ketol to the eniminium salt. This mechanism applies only to the pyrrolidine enamine; with morpholine and piperidine enamines the octalone, not the dienamine, is the product of the reaction. Stork's original mechanism must therefore apply to this annulation3 (Scheme 129). Any uncyclized diketone precursor to the octalone, formed by hydrolysis of the initial Michael alkylation product (129). may readily be cyclized by treatment with boiling ethanolic potassium hydroxide. The formation of dihydropyrans by cycloaddition of MVK to enamines at low temperature has been discussed in Section IILB. Incidentally, the dienamines obtained exist as a mixture of the linear exo and endo isomers (128a and 128b, respectively); contrary to even recent reviews18, the crossconjugated dienamine (12%) cannot be observed by spectroscopic methods290although it can participate in subsequent reactions with displacement of the dienamine equilibrium (Chapter 26). Application of this annulation reaction to substituted cyclohexanone enamines has led to the observation of some remarkable solvent-dependent regioselectivity effects. Thus, the pyrrolidine enamine of 2-methylcyclohexanone underwent annulation with MVK to give only the 'expected' A1.8"-2-octalone,derived from the more reactive less substituted enamine isomer, in both benzene and methanol as solvent^^.^^ (Scheme 130). However, the corresponding reaction with 2,s-disubstituted cyclohexanone enamines shows dramatic ~ o l v e n t ' ~and . ~ s~t o~ i ~ h i o m e t r yeffects. ~ ~ For example, the pyrrolidine enamine (130a) of 2-methyl-5 isopropenylcyclohexanone (dihydrocarvone) on reaction with one or two equivalents of MVK in benzene, or with one equivalent of MVK in methanol, gave the expected product (131) exclusively. However, with five equivalents of MVK in methanol the 'unexpected' product (132) derived from the less reactive more substituted enamine (130b) was obtained exclusively (Scheme 131). Similar results (Scheme 132) were obtained with the enamine (133a) of 2-methyl-Sisopropylcyclohexanone (carvomenthone) which gave both 134 and 135. The results are summarized in Table 3s4. These results clearly demonstrate that the reaction of MVK with an enamine in methanol, unlike the corresponding reaction of methyl acrylate or acrylonitrile (Section 1II.B). is reversible. Since the regioselectivity of the reaction changes in methanol with increasing molar proportion of MVK, Huffman and coworkersa4have suggested a mechanism whereby the unexpected octalone (135) can be derived form the more reactive enamine isomer (133a), rather than the less reactive isomer (133b) where the transition state would be stabilized by developing A1f3-strain(Scheme 133). Initial
14. Electrophilic and nucleophilic reactions of enamines
807
Reagents: (i) MVK, CsHs, k, (ii) trace HzOor C4H8N(trans-enamination): (iii) NaOAc-HOAc-Hz0 SCHEME 128
reaction occurs at C-p of the less substituted enamine isomer (133a) via a twist-like transition state according to Huffman and coworkerss4, in order to avoid the 'very energetically unfavourable' (ca 5-6 kcal mol-') or 1,3-diaxial (ca 3.7 kcal mol-') interactions (see Section 1II.B for comments on this reasoning). This leads to zwitterion (136)and, presumably intermolecular, protonation of the anionic centre and regeneration
P. W. Hickmott
a ("I 0
Reagents: (i) MVK, C&, A SCHEME 129 of the enamine gives 137 which is the precursor for octalone 134. However, in methanol an intramolecular proton transfer is supposed to occur to give 138, which then undergoes an SET reaction with a second equivalent of MVK thus leading to 139, 140 and octalone 135. (Full details of this proposed mechanism are given in Chapter 18, Section 1I.D). Apart from the fact that there is no precedent for an SET mechanism in enamine chemistry, there are several other aspects of Huffman's mechanism which are doubtful. TABLE 3. Reaction of MVK with enamine 133"
Equivalents of MVK
Solvent
Reaction time
Expected octalone (134)
C6H6 MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH C6H6 C6H6 "Relative % composition of product mixture obtained under reflux conditions. In the presence of 4-dimethylaminopyridine (2 equiv.).
Unexpected octalone (135)
14. Electrophilic and nucleophilic reactions of enamines
809
Reagents: (i) MVK, C,H, or MeOH, A; (ii) NaOAc-HOAc-H20 SCHEME 130
Firstly, bearing in mind that the twist form of methylenecyclohexane (a model for the twist form of 136) is 4.4 kcal mol-' more energetic than the chair conf~rmation~'~, this together with the gauche butane interaction between the incoming MVK moiety and the C,-isopropyl group (>O.9 k c a l m ~ l - ' ) means ~~ that there would not be much difference in the energetics of reaction of 133a or 133b (and 130a or 130b) if a twist conformation was involved. Secondly, the step 137 + 138 involves protonation of a weak basic centre by a weak carbon acid. A more likely event would be C-protonation and reversion to starting enamine (133a). Thirdly, the fact that Huffman and coworkers have shown that alkylation of 133 with two equivalents of MVK in benzene leads to dialkylated products means that reaction of MVK, unlike methyl acrylate, is irreversible in benzene. The lifetime of the initially formed zwitterion (136) is presumably being prolonged by dihydropyran formation until intermolecular protonation can occur. In
Reagents: (i) MVK (1 or 2 equiv.), C6H6.A, 24 h or MVK (1 equiv.), MeOH, A, 3 h; (ii) MVK (5 equiv.), MeOH, A, 3 h; (iii) hydrolysis SCHEME 131
P. W. Hickmott
SCHEME 132
methanol, the greater carbon acidity of a methylene alpha to a ketone carbonyl group, relative to one alpha to an ester carbonyl group as in methyl acrylate or a nitrile group in the case of acrylonitrile (Section III.B), means that the zwitterion could be regenerated and revert, under highly favourable conditions of stereoelectronic control, to starting enamine (133a). In a protic solvent the enamine interconversion ( 1 3 3 a e 133b) is rapid and the rate of the subsequent reaction of the less reactive isomer (133b) will be increased by increase in the concentration of MVK (rate = k[l33b][MVK]). The reaction rate of the other isomer will also be increased, of course, but if reaction of 133a is reversible and reaction of 133b is not, then the effect of increased molar ratio of MVK to enamine could be accounted for. In other words it is possible that in benzene the product of kinetic control is being obtained, but in methanol the reaction is under thermodynamic control. There is no doubt that the octalones 131 (Scheme 131) and 134 (Scheme 132) will be thermodynamically less stable than octalones 132 and 135 because of the steric interactions between the isopropenyl or isopropyl group with the nearby equatorial proton at C, in 131 and 134. Such effects would be present in the intermediates leading to the octalone at a stage where reversion to starting material could still occur (Scheme 134). Indeed, if reversion to starting material commenced after trans-enamination (stage ii, Scheme 128) had occurred, and if trans-enamination (is. 143 + 144) did not occur in the reverse process, then there is the intriguing possibility that formation of the 'unexpected' octalones 132 and 135could occur via an enolate anion (143 + 145 + 146 + 147 + 148) rather than the original enamine (133). However, whether the unexpected octalones 132 and 135 arise via an enamine (133b) or an enolate anion (148) mechanism, the sequence of events outlined in Scheme 134 would account for Huffman's observation that the presence of strong base decreases the amount of expected octalone (134) formed in benzene (last two entries in Table 3) by causing deprotonation of 141 to 142 to become possible in benzene. In the absence of the isopropyl or isopropenyl group there is nothing
14. Electrophilic and nucleophilic reactions of enamines
811
I
COMe
(14)
Reagent: (i) MVK R,N = C,H,N SCHEME 133
to be gained by reversion to starting enamine (or enolate anion equivalent) and reaction proceeds to give the normal product of enamine annulation. Clearly there is scope for further mechanistic investigation in this area. Returning to the unsubstituted cyclohexanone enamine, the use of ethanol as solvent instead of benzene favours 2,6-dialkylation. In addition to the octalone dienamines this has resulted in the isolation of the tricyclic dione 149293(Scheme 135). The same ring
f '
Reagents: (i) 133, MeOH or 4-Me2NC5H4N, C6H6; (ii) trans-enamination; (iii) 146 SCHEME 134
14. Electrophilic and nucleophilic reactions of enamines
(149) Reagents: (i) MVK (2 equiv.), EtOH, A, 3 h SCHEME 135
Reagents: (i) MVK, (ii) H20, A; (iii) CH2=C(Me)COMe; (iv) NaOAcHOAc-H20 SCHEME 136
813
P. W. Hickmott
Reagents: (i) 1-acetylcyclohexene; (ii) NaOAc-HOAc-H20 SCHEME 137
system as in 149 was isolated in two isomeric forms from the further reaction of the octalone dienamine with MVK (Structure 27; Scheme 21; Chapter 26), the two isomers differing in the stereochemistry at the ring junctions. Compound 149 was in fact identical with the minor isomer obtained from the dienamine reaction294. When a large flexible cycloalkanone enamine 150 is used, MVK gives fused and bridged annulation products295,and the relatively unreactive 3-quinuclidinone enamine 151 gives the quinolone 152 with methyl 2-propenyl ketone296(Scheme 136). The use of 1-acetylcyclohexene as an MVK equivalent gives tricyclic systems2" (Scheme 137).
Reagents: (i) MVK; (ii) H30+ SCHEME 138
Reagents: (i) CH2=CHCOCH20Me; (ii) MeMgI; (iii) P-MeC6H4S03H.C6H6.A R,R' = alkyl or ring residues SCHEME 139
14. Electrophilic and nucleophilic reactions of enamines
/ iii
Oco2*vii, viii
Reagents: (i) CH2=CHCH0, 10°C; (ii) H30t; (iii) 80°C; (iv) H+; (v) transenamination; (vi) Cr03; (vii) MeI; (viii) HO-
SCHEME 140
Reagents: (i) PhCH=CHCHO; (ii) MeI; (iii) alc. KOH, A
SCHEME 14 1
815
816
P. W. Hickmott
Application of the MVK annulation procedure to enamines of acyclic ketones and aldehydes gives cyclohexenones3. If the aldehyde carbonyl group is attached to a ring, the procedure provides a valuable stereoselective method for the spiroannulation of cyclic ketonesz98(Scheme 138). The use of 1-methoxybut-3-en-2-one in place of MVK provides a means for subsequent 1,2-transposition of a ketone carbonyl functionm9 (Scheme 139). Condensation of 2,2,2-trifluoroethyl vinyl ketone with enamines gives 2-trifluoromethylcyclohexenones300. a,SUnsaturated aldehydes react with aldehyde and ketone enamines at low temperatures to give d i h y d r ~ p y r a n s ~These ~. are readily hydrolysed to the corresponding glutaraldehyde in the case of an aldehyde enamine3O1 or to the 8-2-oxocyclohexylpropanal in the case of a cyclohexanone enamine302. At higher temperatures transenamination followed by annulation occurs3. In this way a variety of bicyclic and ring-expanded products have been ~ b t a i n e d ~ , ~However, ~ ' . ~ ~ ~the . reaction fails for some inexplicable reason with enamines of ~ y c l o h e p t - 4 - e n o n e(Scheme ~ ~ ~ 140). Cinnamaldehyde gives similar reactions3o5(Scheme 141). 2-Formylcyclohex-2-enones react with acyclic ketone enamines to give octalindiones in high yields and with high d i a s t e r e o s e l e c t i ~ i (Scheme t ~ ~ ~ ~ 142).
Reagents: (i) Me2CHC(=CH2)NC4He;(ii) CF3C02H SCHEME 142
Reagents: (i) CH2=CHCOCl, 80°C; (ii) Et3N; (iii) H30+ SCHEME 143
The reaction of a,p-unsaturated acid chlorides with enamines has become a useful method for the u,a'-annulation of ketone^"^.^^^. Acyclic ketones are converted into aminocyclohexenones in good yield and hydrolysis gives the corresponding cyclohexa1,3-dione307(Scheme 143). Application of the reaction to enamines of cyclohexanones The yields are greatly affected by the experigives bicyc10[3.3.l]nonane-2,9-diones~~~. mental conditions used and, in the presence of triethylamine, the course of the reaction is changed completely and tetrahydrochromanones are usually the main or only product308(Scheme 144).
14. Electrophilic and nucleophilic reactions of enamines
817
Reagents: (i) CH3CH=CHCOC1, 80°C; (ii) H20; (iii) CH3CH=CHCOCl, Et3N; (iv) H30+ SCHEME 144
The reason for the change in the course of the reaction is interesting. Since enamines are ambident nucleophiles, the reaction with electrophiles can occur at the nitrogen or the /I-carbon. Acylation at nitrogen, like protonation, is kinetically controlled but is reversible so that high yields of C-acylated products are normally obtained. Nevertheless, the propensity for N-acylation is reflected in the isolation of amides, formed by heterolysis of the enamine carbon-nitrogen bond, particularly at high temperatures309 (Scheme 145). However, in the case of a,/?-unsaturated acid chlorides the N-acylated enamine has an alternative reaction pathway available, namely a [3,3]sigmatropic rearrangement to give a ketene intermediate. Cyclization of the regenerated enamine system onto the ketene then gives an enolate anion, which is subsequently protonated to give a bicyclic iminium salt (Scheme 146). In the presence of triethylamine, a$unsaturated acid chlorides containing a y-hydrogen are converted into vinylketenes. N-Acylation is then reversible and cannot lead to bicyclic dione since the double bond is /I,y- rather than a,/?- to the carbonyl group in the N-acylated enamine. The reaction is therefore directed through the C-acylation pathway to give a vinylacetyl derivative. Hydrolysis and double-bond rearrangement then leads to the tetrahydrochromanoneZ6' (Scheme 147). The reaction between a,/3-unsaturated acid chlorides and enamines of medium to large ring cyclic ketones gives bicyclo[n.3.1] products, the nature of which is determined by the ability of the bridgehead position to accommodate a double bond in the 1-carbon bridge. When this is not possible, the product is an iminium salt which is readily hydrolysed to the bicyclic dione. With larger rings proton loss from the iminium salt becomes increasingly more favourable to give bicyclic enamino ketones, the lowest
Reagents: (i) RCOCI, 20°C; (ii) 80°C SCHEME 145
P. W. Hickmott
Reagents: (i) CH2=CHCOC1, 80°C; (ii) H20 SCHEME 146
member of this series which has been isolated being 11-morpholinobicyclo[5.3.l]undec7(11)-en-8-one. The increased torsional strain in the bridgehead double bond of this compound is reflected in the bathochromic shift of the ultraviolet absorption to longer wavelength310(Scheme 148). The reaction has been applied to the enamine of cyclohept4-enone, where other methods of annulation failed, as the key element in an approach to elemanolide s e s q ~ i t e r p e n e (Scheme s ~ ~ ~ 149). The stereochemical course of the annulation process has been determined by reaction of acryloyl chloride with the morpholine enamine of 4-t-butyl-2-methylcyclohexanone. The bicyclic dione was obtained in 76% yield as a 4:l mixture of two isomers (Scheme 150). X-ray analysis of the main isomer showed that reaction had occurred by axial attack from the same side as the C-2 methyl group. In order for regeneration of the enamine system to occur under conditions of stereoelectronic control, the intermediate ketene-iminium salt presumably adopts a twist conformation. Cyclization of the ketene
14. Electrophilic and nucleophilic reactions of enamines
Reagents: (i) R'CH2CH=CHCOCI, Et3N; (ii) H30+ SCHEME 147
Reagents: (i) CH2=CHCOC1, 80°C; (ii) H20 (n = 7,S); (iii) Et3N(n 8)
SCHEME 148
819
P. W. Hickmott
+
Reagents: (i) RCH=CHCOCl, 80°C; (ii) H20, (iii) PhNMe3Br3-; (iv) Li2C03,LiBr; (v) HOCH2CH20H,H+; (vi) L~CU(CH=CH~)~ R = H, Me, CH20Me, CH20CH2CH=CH2,CHzOPh SCHEME 149
onto the tetrasubstituted enamine double bond thus formed then occurs readily and in high yield despite the developing A1."strain"' (Scheme 150). An important consequence of the mechanism of the reaction of a.1-unsaturated acid chlorides with cyclohexanone enamines is that the enolate anion intermediate can be trapped by an axially oriented electrophilic group at C, to give a substituted adamantane312.Both crotonoyl and methacryloyl chloride, when added to a boiling solution of the pyrrolidine enamine (153)of 4,4-diethoxycarbonylcyclohexanone in benzene, gave a precipitate which was hydrolysed by cold water to give the corresponding ethyl 2,4,6-trioxoadamantane-1-carboxylate in moderate yield but in a high state of purity (Scheme 151). Interestingly acryloyl chloride, which is normally the best reagent for the @,a'-annulation of ketones, resisted all attemvts to form an adamantane with this enamine. The only product which could be isolied was 1-ethoxycarbonylbicyclo[3 3 11nonane-2,6-dione, formed by cyclization across the 2.4-positions of the cyclohexene ring, rather than across the 2,6-positions as normally obsemed3l3 (scheme 152). his difference in behaviour suggests that the presence of an a- or 1-alkyl substituent in the a$-unsaturated acid chloride produces a subtle conformational change. It appears that the 1,3-diaxial interactions between the ester group at C, and the ketene-methylene group at C, are significantly greater than the A1a3 interactions between the a-methylene
14. Electrophilic and nucleophilic reactions of enamines
821
Reagents: (i) CH2=CHCOCl, 80°C; (ii) H20 SCHEME 150
group of the pyrrolidine ring and an equatorially orientated ketene-methylene group. Possibly these interactions can be minimized by the iminium salt taking up a twist conformation of the cyclohexane ring. As a result the ketene group is prevented from reacting with the regenerated enamine system and remains in this predicament until the axial ethoxycarbonyl group is eliminated, when cyclization is then directed to the more reactive carbanionic centre at C, rather than the enamine centre at C,. In the case of crotonoyl and methacryloyl chlorides the extra a- or P-substituent presumably increases the A's3 interactions without affecting the 1,3-diaxial interactions since the methyl substituent can be orientated outside the ring, away from the bulky ester group (Scheme 153).
P. W. Hickmott
Reagents: (i) CH3CH=CHCOCl, C6H6,80°C; (ii) H20 E = C02Et SCHEME 151
Analogous results were obtained with enamines of 4,4-dimethylcyclohexanone. Both crotonoyl and methacryloyl chlorides cyclized to give 4,7,7- and 3,7,7-trimethylbicyclo[3.3.l]nonane-2,9-dione, respectively. In contrast, acryloyl chloride gave 3-(5,5dimethyl-2-oxocyc1ohexyl)propanoicacid (Scheme 154). Again this change in the course of the reaction is attributed to competing steric interactions, which determine the conformation of the reactive ketene intermediate. When the ketene moiety is axial (AL." 1,3-diaxial strain) cyclization to the bicyclic dione occurs; when it is equatorial (ALs3< 1,3-diaxial strain) hydrolysis to the acid occurs314.The corresponding reaction with the enamine of 4,4-diphenylcyclohexanonegave only the corresponding 3-(2-0x05,5-diphenylcyclohexyl)propanoicacids with all three acid chlorides. Clearly 1.3-diaxial strain exceeds A's3 strain in aN cases now, not just that of acryloyl chloride314. Surprisingly, when the axial C, substituent was changed, from methyl, phenyl or ethoxycarbonyl, to benzoyl, then acryloyl chloride gave the adamantane derivative, in
14. Electrophilic and nucleophilic reactions of enamines
823
Reagents: (i) CH2=CHCOCl, 80°C; (ii) -C2H4, -C02; (iii) H30+
SCHEME 152 better yields than crotonoyl or methacryloyl ~hlorides''~!(Scheme 155). This has been attributed to a stronger attractive interaction between the negative end of the ketene dipole (C)=C=Cd-) and the more electrophilic carbonyl carbon of a ketone relative to an ester316. Corresponding cyclizations to the adamantane derivatives occurred with enamines of 4-methyl-4-thien-2'-oylcyclohexanone and 4-cyano-4-phenylcyclohexanone31'. Conceptually similar a,@'-annulationsof ketone enamines have also been carried out with electrophilic alkenes containing a reactive allylic halogen, such as ethyl a-bromo(Scheme 156). An elegant onemethylacrylate or dimethyl y-bromomesa~onate~'~-~~~ pot synthesis of the adamantane ring system involving sequential double Stork and Dieckmann reactions has been developed by Stetter and Thomas3" (Scheme 157). Reaction of the bis-enamine 154 with ethyl a-bromomethylacrylate leads to the pentacyclic system 155322(Scheme 158).
SCHEME 153
P. W. Hickmott
i. iii
ii, iii
Reagents: (i) CH2=CHCOCI; (ii) CH3CH=CHCOCI or CH2=C(Me)COCI; (iii) H20 SCHEME 154
4
Me
COPh
Reagents: (i) RCH=C(R')COCl, 80 "C; (ii) H,O R, R' = H, Me SCHEME 155
Reagent: (i) Me02CCH=C(CH2Br)C02Me SCHEME 156
14. Electrophilic and nucleophilic reactions of enamines
COzEt
Reagents: (i) CH2=C(CHzBr)C02Et; (ii) H20 E = C02Et SCHEME 157
Reagents: (i) CH2=C(CH2Br)C02Et E = C02Et SCHEME 158
826
P. W. Hickmott
A, 3-8 h; Reagents: (i) -78°C to r.t, 15 h; r.t. 40-6O0C, (ii) aqueous tartaric acid R = -(CH2)4-, -(CH2)20(CH2)2-; R1= H, Me, C3H7; R2 = H, Me. CO2Et; = Me, t-C4H9 R3 =Me, C4H9; R4 = H, Me; R 3 , ~=4 -(CH2)3-;
SCHEME 159 Instead of a-bromomethylacrylates, a-acyloxymethyl-u-nitroalkenes (i.e. nitroallylic esters in which the ester replaces the bromine as the good leaving group, and nitro replaces ester as the electrophilic activating group) may be used as the annulating agenPZ3(Scheme 159). This process has been termed [3 + 3]carbocyclization and gives access to a wide range of mono- and bicyclic nitro ketones323(Scheme 160). a,a'-Annulation has also been achieved with some reactive 1,3-dichloropropanes. For example, annulation of cyclohexanone enamines with 2,2-bis(chloromethyl)acetophenone gives the corresponding 3-benzoylbicyclo[3.3.I]nonan-9-one. This has been used in an adamantane synthesis by carbene insertion into an adjacent methyl (Scheme 161). Condensation of 1-N-pyrrolidinylcyclopentenewith 1,3-dialkoxy-1,3dichloropropanes gives the corresponding 2,4-dialkoxybicyclo[3.2.l]octan-8-ones, which are synthons for 2-oxocyclopentane-l,3-dicarboxylicacid3z5"(Scheme 162). Cy2-Acetoxybiclohexanone enamines give 2,4-dimethoxybicyclo[3.3.1]nonan-9-ones325b. cyclo[3.3.l]non-9-one derivatives have also been prepared by palladium acetate catalysed annulation of cyclohexanone enamines with allylic 1,l-diol d i a ~ e t a t e s ~(Scheme '~ 163). Enamines undergo [4 2]cycloaddition with electrophilic alkenes such as ethyl orba ate^^', methyl 2,4-pentadien0ate~~'~,~~~, penta-2,4-dieno1329, hexa-3,5-dien-2-
+
14. Electrophilic and nucleophilic reactions of enamines
Reagents: (i) 3-N-morpholinopent-2-ene; (ii) Pymlidine enamine of 6-methoxy-2-tetralone or 6-methoxy-2-N-pyrrolidinyl-3,4-dihydronaphthalene; (iii) 1-N-pyrrolidinylcycylopentene; (iv) 1-N-pyrrolidinylcyclohexene; (v) 1-N-pyrrolidinylcycloheptene; (vi) H30+ SCHEME 160
Reagents: (i) PhCOCH(CH2C1)2 SCHEME 161
827
828
P.W. Hickmott
Reagents: (i) ROCH(CI)CH2CH(Cl)OR. (i-h)2NEt, CH3CN, A, 16 h; (ii) H20. SCHEME 162
Reagents: (i) CH2=CHCH(OAc)2, Pd(OAc)& (ii) Hz0 SCHEME 163
Reagents: (i) CH2=CHCH=CHC02R; (ii) 200°C (or MnOz) SCHEME 164
14. Electrophilic and nucleophilic reactions of enamines
829
Reagents: (i) RCH=C(CH2R)NR"'2 R = H, C02Et; R' = Me, Ph, p-ClC6H4,p-tolyl, y-pyridyl, a-furyl, a-thienyl; R" = Me, Ph, p - C I C a , a-thienyl; R"' = C6H,~.Me2CH, HOCH2CH2, -(CH2)4-. -(CH2)20(CH2)2SCHEME 165
one329 and 1,3-bis(phenylsulphonyl)butadienes330to give aminocyclohexenes. These readily lose the secondary amine moiety to give cyclohexadienes, which can be dehydrogenated to the aromatic system (Scheme 164). Aromatic ring systems have also been prepared by cycloaddition of pyrylium salts and a-pyrones to e n a m i n e ~ ~ ~ ' - "annula~, tion of acyclic ketone enamines with halogeno a,gunsaturated acid chlorideP4 and 1,3-dichloro-1,3-dimethoxypropane335, Although enamines do not normally undergo intermolecular reaction with ketone or ester carbonyl groups, condensation with isonitroso-/?-dicarbonylcompounds has been reported336(Scheme 165). Condensation of enamines with 4-trimethylsilyl-3-dialkylaminocrotonic esters under acid catalysed conditions gives aromatic compounds in which the enamine has acted as a two-carbon or three-carbon component in the annulation process337(Scheme 166).
Reagents: (i) MeCH=C(Et)NC4HsO; (ii) 1-N-morpholinocyclohexene SCHEME 166
830
P. W. Hickmott
E. Seven-membered and Larger Rings
The most general methods for preparing seven- or eight-membered rings from enamines are by ring expansion of the cyclobutene, cyclobutanone or chlorocyclopropane adducts formed by cycloaddition of acetylene carboxylates, ketenes or chlorocarbenes, respectively, to enamines of cyclopentanone or cyclohexanone. These are two-carbon or one-carbon ring expansions. Three-carbon ring expansions can also be carried out by cycloaddition of activated cyclopropenes or cyclopropenones. Palladium salt catalysed annulation with 1,4-diacetoxybut-2-ene provides a means of introducing a four-carbon bridge to give bicyclo[n.4.l]alkanones (path a) in moderate yield338'. However 1,Zaddition (path b) also occurs to give the corresponding bicyclo[n.2.l]alkanone (Scheme 167). Somewhat better yields and higher purity are realized by using 1,4-dichlorobut-2-ene with ethyldiisopropylamine and potassium iodide in dim e t h y l f ~ r m a r n i d eThe ~ ~ ~report ~. that annulation of 1-N-pyrrolidinylcyclopentenewith 1,4-diiodobutane gives bicycl0[4.2.l]nonan-9-one~ has been shown to be incorrect. The reaction was in fact shown to result in a,a-annulation rather than a,a'-annulation, and a mixture of spiro[4,4]nonan-1-one and dispiro[4,1,4,2]tridecan-6-one was ~btained"~~.
Reagents: (i) AcOCH2CH=CHCH20Ac; (ii) Pd(OAc)2, PPh3 SCHEME 167
14. Electrophilic and nucleophilic reactions of enamines
I
83 1
iii
Reagents: (i) B2H6.THF,20°C, 30 min; (ii) RC02H, 4 4 h; (iii) RC02H, 20°C, 18 h; (iv) H20 SCHEME 168
VII. MISCELLANEOUS REACTIONS
The reduction and oxidation of enamines is discussed in Chapter 17. The hydrogenolysis of enamines by a hydroboration-protonolysis procedure was first reported by Lewis and coworkers, who developed the reaction into a general synthesis of a l k e n e ~ ~ With ~'. ketone enamines electrophilic attack at the /3-carbon occurs to give a trans-/3-aminoorganoborane (156) by overall cis-addition to the double bond. Trans-elimination of the boron group and the amine function occurs on heating in the presence of a carboxylic acid such as propionic acid to give the alkene; at low temperatures a boronic acid (157) is formed (Scheme 168). Lewis and coworkers further showed that a-substituted cyclohexanone enamines gave only the 3-substituted cyclohexene, free of the 1-substituted isomer since hydroboration of the less reactive, more substituted form of the enamine did not occur (Scheme 169). Similarly, the pyrrolidine enamines of acyclic ketones gave high yields of the corresponding acyclic alkene. In contrast /3,P-disubstituted aldehyde enamines give a mixture of alkene and alkane, the latter arising from initial attack at the nitrogen, thus reversing the polarization of the double bond and giving rise to the a-aminoorganoborane (158)340 (Scheme 170). This methodology has recently been further investigated by Singaram, Brown and coworkers who showed that modification of the hydroboration procedure
P. W. Hickmott
Reagents: (i) B2H6; (ii) RC02H, A SCHEME 169
allowed the diastereospecific conversion of a single acyclic ketone enamine into either the (Z)- or the (E)-alkene341.342,as required (Scheme 171). Enamines of unsaturated aldehydes can be converted into the corresponding dienes; for example, citronellal, a chiral aldehyde, gives the chiral non-conjugated diene, p-citronellene, in 92% enantiomeric e x c e s ~ ~(Scheme ~ ' ~ ' ~172). ~ The combination of the Lewis hydroboration procedure with the thallium acetate a ~ e t o x y l a t i o nof~ enamines ~~ provides a means of converting enamines into acetoxycycloalkenes344(Scheme 173). The hydroboration-oxidation of enamines to give P-aminoalcohols was first reported by Borowitz and Williams345.Cis-13-addition of BH, occurs, to give the trans-P-aminocy-
Reagents: (i) B2H6; (ii) EtC02H. SCHEME 170
14. Electrophilic and nucleophilic reactions of enamines
Reagents: (i) H3B.Me2S (BMS); (ii) MeOH; (iii) H202, HO-; (iv) 9-borabicyclo[3.3.1]nonane (9-BBN) SCHEME 171
Reagents: (i) 9-BBN, (ii) MeOH SCHEME 172
Reagents: (i) TI(OAC)~;(ii) aq. Na2C03, 2 rnin; (iii) BzH,, 0 ° C ; (iv) HOAc, A, 12 h SCHEME 173
833
P. W. Hickmott
Reagents: (i) BH3.SMe2(BMS); (ii) MeOH; (iii) H202,HO-. SCHEME 174 cloalkylborane, and peroxide oxidation of the boronate ester gives the aminoalcohol (Scheme 174). The methodology has again been further investigated by Brown and coworkers346, who have shown that the use of trimethylamine N - o ~ i d e ~for ~ ' the oxidation of the aminoboronate esters greatly suppresses the side reactions, protonolysis and elimination, and thus greatly increases the yields of the B-dialkylamino alcohols346. Cope reaction of the derived N-oxide has been utilised for the 1,2-transposition of carbonyl g r o ~ p s(Scheme ~ ~ ~ 175). . ~ ~ ~ Diethyl azodicarboxylate (DAD) behaves like a reactive electrophilic alkene and attack on a substituted cyclohexanone enamine can occur from an axial or equatorial direction depending on the steric effects in the transition state. For example, DAD reacts with 159 to give 160 by equatorial attack, together with 161 (ratio 1 :9), whereas the
n i, ii, iii
Reagents: (i) C4HsNH; (ii) B2H6; (iii) HZ02,HO'; (iv) H202; (v) 160°C; (vi) Cr03; (vii) HZ, Pt02. SCHEME 175
14. Electrophilic and nucleophilic reactions of enamines
Reagents: (i) Et02CN=NC02Et (DAD), 5°C; (ii) H20 R = CH(Me)CH2N02;R' = N(C02Et)NHC02Et; RzN = morpholino SCHEME 176
835
836
P. W. Hickmott NHE
E
I
I
I
N-
E'
a'NHE
I
Reagents: (i) Et02CN=NC02Et (DAD), axial attack; (ii) DAD, equatorial attack. E = C02Et SCHEME 177
epimer (163) gives 164 by axial attack together with 165 (ratio 3:7)350"(Scheme 176). Enamines of acyclic dissymmetric ketones react also with DAD, first at the less substituted P-position and then at the more substituted p-position to give the a,a'bis(N,N-diethoxycarbonylhydrazino)ketone on hydrolysis350b.Interestingly, enamine 161 undergoes stereospecific axial protonation and hydrolysis to 162, whereas 165 undergoes stereospecific equatorial protonation to 16fi41(Scheme 176). The regioisomers 160 and 164 do not undergo hydrolysis under these conditions since protonation apparently occurs on nitrogen rather than on carbon. The morpholine enamine of trans-Zdecalone exists as a 1 :4 mixture of A'- and AZ-isomers;DAD reacts with the former by equatorial attack and the latter by axial attack351(Scheme 177). In contrast, less electrophilic alkenes, such as P-nitrostyrene and phenyl vinyl ketone, react only with the AZ-isomer at C-3 by axial attack (see Section III.B), unless sterically impeded. A further difference to electrophilic alkenes shown by DAD and other diimides is that tertiary amines, such as N-cyclohexylpyrrolidine (167), are dehydrogenated to the enamine. Further reaction then occurs to give the product of 2,6-disubstitution ( 1 1 5 8 ) ~ ~ ~ . Diacyl diimides, such as dibenzoyldiimide (DBD), are even more remarkable. The action of DBD on 167 at room temperature results in dehydrogenation of the pyrrolidine ring and reaction with a further two equivalents of DBD to give 169s53 (Scheme 178).
14. Electrophilic and nucleophilic reactions of enamines
837
Reagents: (i) DAD; (ii) H30+;(iii) DBD E = C02Et SCHEME 178
Reaction of DBD with 1-N-morpholino- or 1-N-piperidinocyclohexenegives the 1,3,4oxadiazine (170), hydrolysis of which gives the monosubstitution product (171) or cyclohexane-1,2-dione (172)354(Scheme 179). The analogous adduct to 170 from the pyrrolidine enamine could only be isolated by working with an excess of the enamine. Otherwise, further reaction occurred to give the products of 2,6-disubstitution (173 and 174) on hydrolysis; however, the main product was the oxadiazine (175) derived by 2,2-disubstitution and isolated in 5&80% yield! Such is the reactivity of DBD that simply heating with cyclohexanone gives 171353.With 2-methylcyclohexanone enamines the normal product 176 of 2,6-disubstitution is, however, formed354(Scheme 180). Mono-benzoyldiimides such as 177 behave in a relatively normal manner, reaction with the pyrrolidine enamine of cyclohexanone (or cyclopentanone) giving the oxadiazine 178355(Scheme 181). Reaction of dimethvl azodicarboxvlate with a-disubstituted aldehyde enamines is reported to give the 1,i-diazetidine l?9 and hence the aldehyde 180 on hydrolysis356a,dibenzoyldiimide gives the oxadiazine 181356b (Scheme 181). The ethoxycarbonyl aroyl diimide 182 reacts to give oxadiazine 183 exclusively357(Scheme 182). A remarkable reaction occurs between enamines and Chloramine-T in which the amine moiety migrates to the P-position of the enamine to give an u-dialkylaminoaldehyde on hydrolysis in high yield358(Scheme 183). Woodward and coworkers have shown that trimethylene dithiotosylate reacts with enamines in the presence of triethylamine to give d i t h i a n e ~(Scheme ~ ~ ~ 184). Since
838
P. W. Hickmott
COPh (170)
iii
Reagents: (i) PhCON=NCOPh (DBD), C6H6, 2 5 T , 24 h; (ii) H30+,25 O C . (iii) H30+, 100°C X = 0, CH2 SCHEME 179
q-?' NHCOPh
PhCON I NHCOPh
(173)
SCHEME 180
COPh
0
14. Electrophilic and nucleophilic reactions of enamines
839
Reagents: (i) 1-N-pyrrolidinylcyclohexene SCHEME 18 1
C&foAr
R2N
OY" o
~t
+ Et02C, NII
"K" o (182)
i
P;
,C02Et
R2N
O ~r y N
(183)
Reagents: (i) I-N-rnorpholino- or 1-N-pyrrolidinylcyclohexene SCHEME 182
P. W. Hickmott
R NR'2
\I
C-CHO
NR'2 OH
I
/
R2C-CH
\
NHTs
iii
R'
\+/
R'
N
/ \
R2C-CH-NHTs
Reagents: (i) RI2NH; (ii) Chloramine -T, 20°C, 20 h; (iii) HzO R = Me, Et, Ph; R'2N = piperidino, morpholino, pyrrolidino, dimethylamino; R = Me, Et, Ph; RR = -(CHZ)5-
SCHEME 183
dithianes are stable to acid and base, and can be converted back to methylene compounds by reduction, this reaction provides a means for protecting a reactive a-methylene or a-methyl group while chemical transformations are carried out at less reactive sites of a molecule. The method has been ingeniously utilized by van Tamelen and coworkers360 for descending a homologous series of aldehydes (Scheme 185). 1,3-Dithiane itself has been widely exploited as a formyl anion equivalent and 2-chloro1J-dithiane is a readily accessible synthetic equivalent to a formyl halide (i.e. a formyl cation equivalent). Reaction with aldehyde enamines gives half-protected malondialdehyde derivatives, and acyclic and cyclic ketone enamines can be a-formylated by this method361. Enamines react with ethoxycarbonylnitrene to give N-substituted a-amino ketones via an aziridine intermediate362a(Scheme 186). Using chiral enamines the a-amino ketone can be obtained in relatively high optical yield (77% ee) but low chemical yield (18%)362b. N,N-Bis(trimethylsilyl)enamines are weak nucleophilic reagents and fail to react with electrophiles at the P-carbon. However, under the influence of fluoride ion catalysis,
Reagents: (i) P-CH~C&SO~S(CH~)~SSO~C~H~CH~-P. Et3N, CH3CN, A, 1&24 h; (ii) H30+. SCHEME 184
14. Electrophilic and nucleophilic reactions of enamines
841
1
ii, iii
Reagents: (i) CsHI$JH; (ii) TSS(CH~)~STS, Et3N; (iii) H30+; (iv) NaOMe, Me2S0, H20; (v) MeI, CaCO,, H,O SCHEME 185
aldehydes and ketones react at the nitrogen to give 2-aza-1,3-butadienes and acid chlorides give the enamide363(Scheme 187). Trichlorosilane adds on to the enamine double bond in the absence of catalyst to give the 8-protonated a-trichlorosilyl adducP4. 1,2-Cyanoselenenylation of enamines occurs with phenyl ~elenocyanate"~. N-Morpholine arene selenides (ArSeNC4H,0) give 8-arylseleno enamines and aarylseleno ketones on hydrolysis366.In the presence of [RhCI(CO),], the reaction of enamines with a hydrosilane and carbon monoxide resulted in regioselective incorporation of CO into the a-carbon atom to give a-(siloxymethylene) amines, which are hydrolysed to a-doxy ketones"' (Scheme 188).
Reagents: (i) E~O~CN: SCHEME 186
842
P. W. Hickmott
+ NHCOPh
-N\~
\
+N\YPh
Ph
ii,lviii
SiMe3 I
rii, viii
-N'~iMe,
/
Ph
. iv, viii
Reagents: (i) PhCOCI, CsF, 2 h, 80°C; (ii) PhCHO, CsF, 2 h, 80°C; (iii) Ph2C0, CsF, 2 h, 80°C; (iv) Me2CHCH0, TBAF,1 h, 2S°C; (v) Et2C0, TBAF, 1 h, 25'C; (vi) PhCH=CHCHO, TBAF, 1 h, 2S°C; (vii) PhCH=CHCOPh, CsF, 2 h, 80°C; (viii) H20 SCHEME 187
iii
Reagents: (i) R2NH; (ii) [R~ICI(CO)~]~; HSiR3, CO, 50 atm, 140°C, 20 h; (iii) H30+ Rz = Me, Et, PhCH2,-(CH2)20(CH2)2-; R' = C4H9,PhCH2, Me2C=CH(CH2)2CH(Me); R" = Me, Et SCHEME 188
14. Electrophilic and nucleophilic reactions of enamines
843
VIII. SECONDARY ENAMINES
As in the previous sections, secondary enamines in which either the nitrogen or the double bond is further conjugated with an electron-withdrawing or electron-donating substituent are not reviewed. Metal derivatives of imines (metalloenamines) are discussed in Chapter 25. We are only concerned with secondary enamines, in equilibrium with their imine tautomer, formed by condensation of a primary amine with an aldehyde or ketone. Such condensations can readily be carried out using potassium hydroxide as catalyst368or by azeotropic distillation in the presence or absence of acid catalysts369 or, for more hindered or acid-sensitive ketones, titanium tetrachloride3" or dibutyltin dichloride3", respectively, may be used. Spectroscopic studies of imine-enamine tautomerism have shown that the equilibrium is almost completely in favour of the imine form for simple aldehydes and Nevertheless, some secondary enamines are sufficiently stable to exist in detectable amounts in equilibrium with the corresponding imines; for example, the t-butylamine imine of cyclohexanone shows signals due to the secondary enamine tautomer in the NMR spectrum (LC, 4.6)375.Studies of the imine-enamine equilibria have shown, as expected, that the enamine form is stabilized by methyl or aryl substituents at the B-position (Scheme 189).
R
'
-
7
N-R I
"g
R' H
N-R
R1,R2= Me, Ar SCHEME 189 The imine-enamine equilibria have also been clearly demonstrated in reactions which involve the enamine form reacting with a variety of electrophilic reagents at the a-position to the original carbonyl function (C-p of the e n a m i ~ ~ e ) ~ ~Despite ' ~ ~ ~ .their thermodynamic instability, methods have been developed for the generation of the secondary enamine quantitatively, or at concentrations- greater than those present at equilibrium, by methanolysis of their tin3'', . maanesium3'" or lithium3n' derivatives. or b; hydrolysis of their trim~thylsily130 derivatives. Primary enamines have been generated by flash thermolysis of their Diels-Alder adducts with anthracene3" and vinylamine has been generated in the gas phase by pyrolysis of e t h ~ l a m i n e ~ or' ~cyclob~tylarnine~~~. The reactions of secondary enamines differ from those of tertiary enamines in that (i) reaction at the nitrogen can be rendered, irreversible by proton loss from the nitrogen and (ii) reaction at the more substituted position of an unsymmetrical a-substituted ketone imine can occur without the generation of A1,3-strain (vide infra). This is also reflected in the different stereochemical consequences in the hydrolysis of imines compared to the corresponding tertiary enamine. In the pyrrolidine enamine of 2-methyl4-t-butylcyclohexanone the methyl group is quasi-axially orientated to avoid A1,2-strain in the ground state. Hydrolysis therefore leads to the trans ketone. In contrast, the methyl group is equatorially orientated in the corresponding imine and hydrolysis leads to the cis ketoneS (Scheme 190).
844
P. W. Hickmott
SCHEME 190
The reaction of imines with aliphatic and aromatic acylating agents has been reported to result in the formation of N - a ~ y l a t e d and ~ ' ~C~-~a ~ y l a t e d ~products. '~ It is difficult to give a rational explanation for these conflicting results. However, C-acylation appears to have been achieved in the absence of solvent, at high temperature using acetic anhydride (140-180°C) but at low temperature (545°C) using ketene or benzoyl chloride in the presence of pyridine (5&60"C)386. Surprisingly (vide infra), when an unsymmetrical imine was used acylation occurred at the less substituted /3-carbon (Scheme 191). N-Acylation has been achieved using solvents (benzene, chloroform, THF) at low temperature in the presence of pyridine or trieth~lamine'~~ or boiling benzene in the absence of triethylamineJsSc(Scheme 192). The enamides thus obtained could have been formed by acylation of the imino nitrogen followed by loss of an a-hydrogen or by acylation of the enamino nitrogen followed by loss of the nitrogen proton. What evidence there is suggests that both processes occur. Thus at low temperatures a,/?-unsaturated acid chlorides react with the benzylamine imine of cyclohexanone to give the enamide"sc.d, which could be cyclized to the hexahydro-a-quinolone by UV irradiationJssd
Reagents: (i) (MeCOhO, 140-180°C p = CH(Me)CH2CHMe2] or CH2=C=0, 5-10°C (R= Ph) or CH2=C=O, 40-50°C [R = CH(Me)CH2CHMe2]; (ii) H30+ SCHEME 191
14. Electrophilic and nucleophilic reactions of enamines
845
Reagents: (i) R'COCI, Et3N, 0-S0C SCHEME 192
(Scheme 193). On heating the mixture, preferably in the absence of triethylamine, the hexahydro-a-quinolone 185 was obtained directly, together with the enamide 184 and amide 186385c.Since the enamide could not be cyclized to the hexahydro-a-quinalone under thermal or acid-catalysed conditions, then clearly the enamide is not an intermediate in the formation of the heterocycle which must therefore arise by N-acylation of the enamine tautomer, followed by a [3,3]sigmatropic rearrangement and cyclization of the ketene intermediate385c(Scheme 194). Significantly (vide infra), when the imine of 2-methylcyclohexanonewas used, the rearrangement to the ketene occurred at the more substituted C, position. A similar dichotomy was observed in the acylation of imines with isocyanates and i s o t h i ~ c y a n a t e sIn ~ ~both ~ ~ . cases reaction occurred at nitrogen to give the cyclohexenyl urea or thiourea, but with arylisothiocyanates rearrangement to the C-acylated enamine (vinylogous urea) occurred on heating (Scheme 195). Bromination of imines has also been reported to occur at nitrogen and carbon3s7. With unsymmetrical a-substituted ketone imines bromination occurred at the more substituted a'-position and the less substituted a-position with the latter predominating at low temperature^"^^. It is suggested that an equilibrium is set up between 187, 188, 189 and 190 on warming (Scheme 196). Alkylation of imines with alkyl halides occurs at nitrogen to give the ternary iminium salt388.With imines having an a-hydrogen, deprotonation occurs in the presence of base to give the tertiary enamine60s389(Scheme 197). In a similar way silylation of imines gives access to N-silylenamines390(Scheme 198). A major breakthrough in the regioselectivity of enamine reactions followed from the observation by Pfau and Ughetto-M~nfrin~~' that the cyclohexylamine imine of acetone 191 underwent @,a-bis-alkylationto give 196, in addition to products 1% and 197 derived from self-condensation (Scheme 199). There was no evidence for the formation of the a,al-bis-alkylated product 194. Clearly, as we pointed out in 1982, this can be attributed
Reagents: (i) RCH=CHCOCI, Et3N, C6H6or CHC13, CLS 'C; (ii) hv SCHEME 193
P. W. Hickmott
1
iii
RNHCOCH=CH2 (186) Reagents: (i) CH2=CHCOC1, C6H6,& (ii) -HCI; (iii) -C6H7CH3 ? SCHEME 194
to the enamine taking up a conformation (i.e. 193)in which interactions are minimal in both the ground state and the transition state6. In other words the developing steric impediment to reaction at the more substituted position of a tertiary enamine is eliminated in a secondary enamine, thus allowing a change in the regioselectivity of reaction from a,a'- to a,a-dialkylation. Following on from this observation both we39z.393 and Pfau and coworkers394 have shown that alkylation of imines of 2methylcyclohexanone with electrophilic alkenes occurs at the more substituted position (Cz) of the derived secondary enamine tautomer (Scheme 200). This reaction therefore provides a mild and highly regioselective route to 2,2-disubstituted cyclohexanones, complementary to the 2,6-disubstituted cyclohexanones obtained by alkylation of the
14. Electrophilic and nucleophilic reactions of enamines
Reagents: (i) ArN=C=S, 20°C; (u) H30+; (iii) ArN=C=S, A; (iv) A. SCHEME 195
Reagents: (i) N-bromosucci~rnide(NBS),20°C. or 2,4,4,6-tetrabromo-2,5-cyclohexadienone, -46 to -20°C SCHEME 196
847
P. W. Hickmott
C4H9CH=C-N
I
-iii
Me
\ C5HllC=v
I
Me
y~
I-
Reagents: (i) C6HllNH2; (ii) Mel; (iii) EtzNH SCHEME 197
corresponding tertiary enamine of 2-methylcyclohexanone. By the use of chiral imines Pfau, d'Angelo and coworkers were able to convert this reaction into an extremely efficient enantioselective synthesis of quaternary carbon centres (9&98% ee) involving a 'deracemizing alkylation' p r o c e s ~ ~ ~ ~ . ' ~ ~ . However, secondary enamines suffer from the disadvantages that (i) reaction at carbon only occurs with electrophilic alkenes; alkyl halides and acylating agents undergo preferential reaction at nitrogen (vide supra); (ii) even reaction with electrophilic alkenes is extremely sensitive to steric effects and to the reactivity of the electrophilic alkene. Thus although acrylonitrile reacts with the benzylamine imine of 2-methylcyclohexanone (Scheme 200), reaction occurs only once with the unsubstituted cyclohexanone imine; under forcine conditions 2.6- rather than 2.2-disubstitution (Scheme 2011 , However, both phenyl viny'l sulphone and methyl acrylate react twice with'the cyclohexanone imine 198 to give the 2.2-dialkylated products 200 and 201, respectively, and methyl acrylate reacts further with the cyanoethylated enamine 199 to-give the 2-8cyanoethyl-2-~-(methoxycarbonylethyl)cyclohexanone202396.These differences clearly reflect the increased electrophilicity of methyl acrylate and phenyl vinyl sulphone relative to acrylonitrile. This greater reactivity means that the transition state will be more reactant-like in nature. In other words, the bonding interactions will begin at greater interatomic distances and the influence of a more bulky substituent at the reaction site will be less pronounced. Further evidence of these reactivity-steric sensitivity effects is evident in the alkylation of imines of medium-large ring ketones"' (Scheme 202). The larger rings are sign-
-
Reagents: (i) Me3Si03SCF3,Et3N Rt = H, Me, Et, Ph; R2, R3 = H, Me, Et; R2R3= SCHEME 198
14. Electrophilic and nucleophilic reactions of enamines
RNH.
+
yy &
R'
RNH
849
1wE
(195)
E
N R'
(1%)
Reagents: (i) CH2=CHC02Me; (ii) 191 R = cy clohexyl; E = C02Me
(197) SCHEME 199
Reagents: (i) CH2=CHZ; (ii) H20 Z = CN, COzMe, COMe SCHEME 200
P. W. Hickmott
(198) iii, ii
(19% iv, ii
Reagents: (i) CH2=CHCN, MeOH, A, 21 h; (ii) H20, A, 1 h; (iii) neat CH2=CHCN, 100-130°C; (iv) CH2=CHC02Me, MeOH, A, 4 h; (v) CH2=CHS02Ph, MeOH, A, 4 h SCHEME 201
ificantly more sterically hindered at C, and only the cycloheptanone imine could be bis-alkylated, and then only with methyl acrylate. Reducing the size of the C, substituent (i.e. CH,CH,CN -r Me) resulted in C, alkylation of the 2-methylcycloheptanone imine with both acrylonitrile and methyl acrylate (Scheme 203) but the 2-methylcyclododecanone imine gave mainly the 2J2-disubstituted product (204; Z = CN, C0,Me). So it would appear that the change CH,CH,Z -r Me has reduced the combined steric impediment of the C, substituent and the ring residue sufficiently to allow reaction at C, to take place but, in the case of the 12-membered ring, the rate of reaction is less than the rate of tautomeric interconversion into the less substituted secondary enamine tautomer 203, which then reacts more rapidly to give the 2,12-disubstituted ketone 204 The implications of this observation are referred to later. as the main
14. Electrophilic and nucleophilic reactions of enamines
Z = C02Me, CN, S02Ph Reagents: (i) CH2=CHS02Ph, MeOH, A,, (ii) CH2=CHC02Me, MeOH, A; (iii) CH2=CHZ, MeOH, A (Z = C02Me, CN, S02Ph); (iv) CH2=CHCN, MeOH, A ; (v) aq. AcOH, A . SCHEME 202
Reagents: (i) CH2=CHZ, MeOH, A (Z = CN, C02Me); (ii) aq. HOAc, A SCHEME 203
85 1
P. W. Hickmott
Z = CN, COzMe 50% Z = S02Ph 70%
Z = CN, COzMe 100% z = S02Ph 97%
50% 30%
95%
Reagents : (i) CH2=CHZ, MeOH, A (Z = C02Me, CN, S02Ph); (ii) aq. HOAc, r.t., R1 = R3 = H, R2 = Me, i-Pr; R1 = R 2 = Me; R3 = H; R1 = R3 = H,R2 = Me SCHEME 204
The alkylation of acyclic imines with electrophilic alkenes such as acrylonitrile, methyl acrylate or phenyl vinyl sulphone is also sensitive to steric effects and again, as a consequence, only mono-alkylation occurs398. The regioselectivity of the reaction in methanol varied from 100% attack at the more substituted a-position to 70% attack at the less substituted a'-position depending upon the steric inhibition manifested and the stabilization of the competing secondary enamine tautomers (vide infra) (Scheme 204). In contrast, the reaction of butanone and other methyl ketone imines with phenyl vinyl ketone occurs twice at the more substituted a-position but this is then followed by a double cyclization process (Scheme 205). Four carbon-carbon bonds are formed sequentially in this one-pot synthesis of the bicyclo[2.2.2]octanone 205 from acyclic pre~ursors~~~.~~~. The mechanism of the alkylation of imines with electrophilic alkenes has been discussed by D'Angelo and coworker^^^^^^^^, who conclude that reaction occurs via an aza-ene reaction-like transition state 206 involving concerted proton transfer from the nitrogen and carbon-carbon bond formation (Scheme 206). They further propose that the remarkable regiocontrol observed in these reactions originates from this crucial internal proton transfer which would not be possible in a conformation such as 207 of the less substituted enamine tautomer, since the N-H bond would be anti to the enamine double bond. However, although this seems probable, it is by no means proven. Inconsistencies in the argument and the evidence presented cast some doubt on the validity of these conclusions. For example: (i) Although conformation 208 of the less substituted enamine tautomer is destabilized by strain in the ground state and by developing A1.%train in the transition state for subsequent reaction, conformation 209 in which the methyl is quasi-axial (Scheme 206) is devoid of both these allylic interactions. One should therefore observe reaction
14. Electrophilic and nucleophilic reactions of enamines
853
1
iii
Reagents: (i) CH2=CHCOPh, MeOH, A ,4 h; (ii) - H20; (iii) H20, A , 1 h R = PhCH,, CH,CH,CH,; R' = Me, Ph, PhCH, SCHEME 205
at the less substituted 8'-position if this tautomer is present in the imine-enamine equilibrium mixture. (ii) The N-H bond is assumed to be in the plane of the double bond in 206, as it most certainly is in enamino-esters such as 210 which also undergo highly regioselective and stereoselective attack at the more substituted C, position under forcing conditions when a chiral imine is used (R = CHMePh). However, this is not the required geometry for a concerted ene reaction where, for continuous overlap of interacting orbitals, the N-H bond would have to be in the plane of the n-electrons of the double bond (parallel to the p-orbitals) as in 211 (Scheme 207). Since the N-H bond in 206 is orthogonal to
P.W. Hickmott
EWG = Electron-withdrawinggroup SCHEME 206
(211)
(212)
EWG = Electron-withdrawing group SCHEME 207
Reagents: (i) CH2=CHZ, 20°C. 1 h; (ii) CH2=CHZ, 80°C, 24 h Z = CN, C02Me, COMe; R = Me, Et, i - h SCHEME 208
14. Electrophilic and nucleophilic reactions of enamines
Reagents: (i) MeOD, 0.75 equivalents; (ii) CH2=CHCN, dry benzene, 20°C, 1 h. M = SnBu3,MgX SCHEME 209
SCHEME 210
855
P. W. Hickmott
Me02c H PhS > ~(
Me' +H Ph
Reagents: (i) THF,24 h, 20°C; (ii) aq. HOAc SCHEME 2 1 1
the n-orbital, the concerted electron transfer implicated in 206 is not feasible. A more realistic representation would therefore be that indicated in 212. The presence of substituents at C, and C,. of the amine moiety do seem to render the N-H in the plane of the double bond rather inaccessible, however. (iii) The investigations by De Jeso and P ~ m m i e r ~prove ' ~ that imine-secondary enamine interconversion is the rate-determining step, since it was shown that Michael addition to the isolated secondary enamine 213 is fast and exothermic whereas reaction of the corresponding imine 214 was slow or did not occur (Scheme 208). Although the formation of the u-deuteriated product 216 from the N-deuteriated enamine 215 (Scheme
SCHEME 212
14. Electrophilic and nucleophilic reactions of enamines
857
SCHEME 213
209) appears at first sight to be indicative of an internal deuterium transfer, closer examination of the experimental procedure reveals that the reaction was carried out in aprotic media. The deuteriated enamine was therefore the only source of deuterium, and the deuterium transfer could therefore be intra- or intermolecular and, as a consequence, could occur simultaneously with or after c a r b o n ~ a r b o nbond formation. (iv) Considerable importance is given to ab initio calculations, using ethenamine and propenal as prototype reagents, as evidence for a concerted rather than a step-wise mechanism involving a zwitterionic intermediate. Approach structures 217 (calculated energy 7.81 kcal mol-') and 218 (energy 8.79 kcal mol-') are considerably lower in energy than zwitterion 219 (energy 89.5 kcal mol-l) (Scheme 210). However, structures 217 and 218 (the latter being favoured from frontier orbital considerations) represent possible situations on the reaction co-ordinate before the transition state is reached, and could therefore occur at an early stage on the energy profile, whereas 219 represents a possible intermediate ajier the transition state has been passed. So this is not a valid comparison. A more likely intermediate than 219, certainly in aprotic media of low dielectric constant, would be the dihydropyran 220, formed by [4 + 2lcycloaddition to the enamine. Dihydropyrans have been shown to be the initially formed adducts in the reaction of methyl vinyl ketone and tertiary enamines (Section 1II.B). This possibility does not seem to have been considered. (v) The main evidence quoted by dlAngelo and coworkers395in favour of a concerted intramolecular proton transfer implicit in an ene reaction is the high stereocontrol observed at C,. (90% ee) in the adduct (S,S)-224 formed from the chiral imine 221 and methyl a-(pheny1thio)acrylate 222401.This is.presumed to arise via an ene reaction-like approach as depicted in structure 223 (Scheme 211). However, the objection to this is that it corresponds to a boat-like approach of the a$-unsaturated ester which has been calculated by Sevin and coworkers40z to be some 3.5 kcal mol-' higher in energy than the corresponding chair-like approach depicted in 218 for the ethenamine-propenal
858
P. W. Hickmott
system. The chair-like approach 225, corresponding to low energy approach 218, would lead to the R-configuration at C,, in 226 (Scheme 212). It is difficult to see how a phenylthio substituent at C,. could change the preferred approach from chair-like to a higher energy boat-like approach, and d'Angelo offers no explanation for this. (vi) The explanation by d'Angelo and coworkers for the regioselectivity of imine alkylations, namely that reaction occurs via an aza-ene mechanism and that this is only possible with the more substituted enamine in conformations such as 229 (Scheme 213), rests on the assumption that the observed regioselectivities do not reflect the ratio of enamine tautomers at equilibrium. However, this assumption is only justified if the rate of interconversion of the enamine tautomers, via the imine or iminium salt (Scheme 213), is fast and further reaction of the enamines is slow. However, the work of De Jesso and P ~ m m i e has r~~ shown ~ that this is not the case. The rate-determining step is in fact the imine-enamine interconversion. Since the more substituted enamine 229 is stabilized by the hyperconjugative interaction of the methyl group, without engendering a destabilizing allylic interaction, the transition state leading to it will also be stabilized by these developing hyperconjugative interactions. As a consequence the activation energy for the formation of the more substituted enamine 229 could be sufficiently lower than that leading to the less substituted isomer 227 to ensure that there is little, or even none, of the latter present in an aprotic medium. An energy profile similar to that represented schematically in Figure 2 could therefore be envisaged. In other words the enamine tautomers are clearly not in rapid equilibrium and, since further reaction of the low energy tautomer 229 is rapid and exothermic, the product ratio could well be a reflection of the isomer distribution. This does not mean that reaction does not occur via an aza-ene-like transition state, but merely that such a mechanism is not necessarily responsible for the observed regioselectivity of reaction. (vii) In protic solvents of high dielectric constant such as methanol, or in the presence of Lewis acid catalysts, solvent or Lewis acid assisted formation of the less substituted enamine tautomer is possible (viz 228 + 231 -+ 227a). Further reaction could then occur via conformations 227a or 227b, since in neither case is there any development of allylic strain. The activation energy for the formation of the more substituted enamine 229 will also of course be lowered by solvent or Lewis acid assistance. However the point is, if km (and kZB)becomes more comparable to k,,, (Figure 2), and since a P-substituent
FIGURE 2
859
14. Electrophilic and nucleophilic reactions of enamines
Reagents: (i) CH2=CHC02Me, 20°C. 7 days; (ii) HOAc, HzO, 20°C. 2 h; (iii) CH2=CHC02Me, MgBrz (2 equiv.), ether, 0°C. 5 rnin.
i, ii, iii
THF MeOH
25 1
Reagents: (i) CH2=CHCOMe, solvent; (ii) H30+; (iii) NaOH SCHEME 214
. .
lowers the reactivity of an enamine even without the introduction of allylic strain [i.e. > R,NC(Me)=CHMe > R,NCH=CHMel then k, > k, and R,NC(Mel=CH, , , < . , 2.k-disubstitutio~hecomesmore significant evin if the populkon of tautom&-227 is still considerably less than that of 229. Examples of the decreased regioselectivity thus expected in the presence of Lewis acids or protic solvents have been reported by d'Angelo and coworkers (Scheme 214)"'. However, the solvent effect is not always as drastic as that indicated in Scheme 214. For example, reaction of methyl acrylate with the benzylamine imine of 2-methylcyclohexanone gives an approximately 10:l mixture of 2,2- and 2,6-disubstituted cyclohexanones, respectively, in boiling methanol. This ratio
SCHEME 215
860
H
P. W. Hickmott
h
COzMe
-
,C02Me
iii, iv
C02Bu-t
90% ee
Reagents: (i) CH2=CHC02Me, 7 days, r.t. or 12 h, 60°C; (ii) MVK, ZnC12, EtzO, -7goC, 1-5 h; (iii) CH2=CHC02Bu-t, 7 days, r.t. or 12 h, 60°C (iv) aq. HOAc, r.t. SCHEME 216
14. Electrophilic and nucleophilic reactions of enamines
86 1
rises to approximately 27:l in benzene and 300:l in t e t r a h y d r ~ f u r a nHowever, ~~~. there is no doubt that the methodology developed by Pfau, d'Angelo and coworkers using an aprotic solvent such as THF, toluene, cyclohexane or ether does give a higher regioselectivity than that obtained using polar or protic solvents. The other factor which drastically reduces the regioselectivity of the reaction is steric inhibition at the reaction site. Thus, as we have mentioned earlier, increasing the size of the C, substituent [i.e. Me + CH,CH,CN (Schemes 201 and 204)], increasing the size of the ring of a cyclic imine (ie. 6 + 7,8 + 12) (Schemes 202, 203) or the presence of a fl-substituent on the electrophilic alkene, all serve to increase the amount of a,d-disubstitution sometimes to the extent that no a,&-disubstitution is observed or, in extreme cases, prevents any reaction from taking place at all. Finally, the remarkable stereoselectivity discovered by Pfau, d'Angelo and coworkers in the asymmetric Michael addition of electrophilic alkenes to chiral imines derived from (R)-or (9-1-phenylethylamine has provided a powerful and simple method for the enantioselective creation of carbon-carbon bonds. The reason for the high stereocontrol is clearly due to the more substituted enamine tautomer 232 being fixed in the conformation having the N-H bond syn and coplanar with the enamine double bond in order to avoid powerful A'.3-interadtions between the C, methyl group and the bulky 1-phenylethyl substituent. Furthermore, since the C,-N bond has partial double-bond character owing to pn-conjugation, the conformation is also confined along the CIS-N bond in order to avoid allylic interactions with the C-6 hydrogens. Since the conformations around the two single bonds between the chiral centre and the reacting prochiral C, carbon are therefore fixed, Michael addition occurs predominantly to the less hindered n-face opposite to the phenyl ring of the amine moiety. The suggestion that this effect is magnified by the formation of a compact chair-like activated complex 233 seems entirely plausible, but it remains to be seen whether further progress along the reaction co-ordinate proceeds via an aza-ene reaction or a dihydropyran intermediate, involving a concerted and possibly stereospecific intermolecular protonation and ring opening, in aprotic solvents, or a zwitterionic intermediate in polar protic solvents. Some applications of this enantioselective synthesis are summarized in Scheme 216395.
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CHAPTER
15
Radical reactions of enamines SHEKHAR V. KULKARNI Department of Chemistry, Purdue University, West Lafayette. IN 47907. USA
I. INTRODUCTION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. GENERAL BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . 111. RADICAL ADDITION T O T H E C=C BOND O F ENAMINES . . . . A. Radical Addition Followed by Loss of Electron . . . . . . . . . . . . . . B. Radical Addition Followed by Hydrogen Atom Abstraction . . . . . . IV. REACTIONS O F ENAMINES WITH ONE-ELECTRON OXIDANTS VLREFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
I. INTRODUCTION
In spite of the tremendous advances in free radical chemistry in recent years, the area of radical reactions of enamines has remained relatively unexplored. So far there have been very few reports of radical reactions of enamines which is reflected in the fact that none of the standard books on free radical chemistry1-3 or chemistry of e n a m i n e ~ ~ . ~ has dealt with this topic. However, in the last 5-6 years there has been an increase in the activity in this area as the usefulness of these reactions for mechanistic and synthetic purposes is becoming apparent. Enamines have so far been shown to undergo two types of radical reactions as shown by equations 1 and 2. The addition of a carbon-centered radical to the C=C bond of enamines (equation 1) leads to a nitrogen substituted radical which then either transfers an electron to a suitable electron acceptor to form an iminium ion or abstracts a hydrogen atom (reductive homolytic alkylation). The second type of the reaction involves the initial formation of an enamine radical cation by reaction with an oxidant (equation 2), which then leads to products by processes such as dimerization, etc. Since this is the first time the radical reactions of enamines are being reviewed, an attempt has been made to cover all the relevant literature. In Section I1 of this chapter, a brief discussion of the general principles of radical additions to alkenes with special emphasis on the modifying effect due to the presence of amino group (as is the case in enamines) is included. Section 111 deals with the reactions of enamines in which the radical addition takes place on the C=C bond of enamines while Section IV describes the reactions with one-electron oxidants such as metal ions and oxygen. The Chemisfiy of Ennmines. Edited by Zvi Rappopon Copyright O 1994 John Wiley & Sons, Ltd. ISBN: 0-471-93339-2
Shekhar V. Kulkarni
R'
-
R3 \ I C=C \ Ri m42
Iminium ion
R-C-C'
R' R3 I I
R-C-C-H
I I R~ N R ~ ~
Enamine radical cation
II. GENERAL BACKGROUND
In general the rate of addition of a radical to an alkene depends largely on the substituents at the radical center and the alkene. Since the transition states of these exothermic reactions occur very early on the reaction coordinate, the polar effect of the substituents on the reactivity and selectivity can be described using frontier orbital theory6. The interaction of the SOMO of the radical with the LUMO and/or H O M O of the carbon-carbon double bond plays a major role in determining the polar effect of the substituents. Carbon-centered radicals are nucleophilic or electrophilic species, depending upon the substituents at the radical center. Electron-donating substituents like alkyl or alkoxy groups increase the nucleophilicity6.' of the radicals whereas electron-withdrawing groups (EWG) like ester or nitrile groups increase their electrophilic In nucleophilic radical reactions SOMO-LUMO interaction dominates whereas electrophilic radical reactions are controlled by SOMO-HOMO interactions. Enamines are electron-rich alkenes with high-energy H O M O and are therefore energetically favored towards attack by electrophilic radicals due to the lowering of the SOMO-HOMO energy gap9. For example, kinetic experiments with substituted styrenes showed that the electrophilic malonyl radical [(EtO,C),C'] reacts 23 times faster with the enamine CH,=C(Ph)NMe, than with the ester-substituted alkene CH,=C(Ph)C02Et1'. Similarly, the pyrrolidine enamine of cyclohexanone reacts 20 times faster than the corresponding morpholine enamine with the electrophilic pTolSO,CH,' radical" since pyrrolidine enamines are easier to oxidize (have higherenergy HOMO) than morpholine enamines. The regiochemical outcome of a radical addition to substituted alkenes generally depends on a complex blend of bond strength, polarity and steric effect^^,'^. The more common result is the attack on the less substituted carbon. Recently Shaik and Canadell" used a state correlation diagram (SCD) model to derive the regiochemical trends in radical addition to substituted alkenes. Regiochemistry was discussed in terms of the relative spin density in the 'n,n* state of the alkene (which directs the radical
15. Radical reactions of enamines
875
attack towards the olefinic carbon which possesses the highest spin density) and the relative bond strength of the radical to the olefinic carbons (which directs the radical attack towards the olefinic terminus which forms the strongest bond with the radical). In the case of enamines, the radical attack at the olefinic carbon not attached to nitrogen (C,,,) is more exergonic, and this site also has a higher spin density in the triplet state14. Thus both effects operate in the same direction and there is a large regiochemical preference for radical attack at C(,, of the enamine, which is indeed observed experimentally. The addition of a radical to the C=C bond of enamines generates an cc-amino radical, stabilized via spin delocalization onto the nitrogen atom1'. The extent of this stabilization as compared to the unsubstituted methyl radical has been determined by theoretical cal~ulations'~ and experimental studies'' to be about 9-10 kcal mol-'. However, the contribution of this stability effect to the reactivity in radical addition to enamines is important only if the addition process has a late transition state, which is usually not the case for radical addition to alkenes. Theoretical calculations for the addition of n u ~ l e o p h i l i cas~ ~well as electr~philic'~ radicals t o alkenes point to an unsymmetrical transition state 1 in which the distances between the attacking radical and the two olefinic carbon atoms of the alkene are unequal. This unsymmetrical transition state readily explains the fact that alkyl groups R' exert a large rate-decreasing steric effect (a-effect) while alkyl groups R2 reduce the rate of addition only slightly (p-effect). Thus while enamines 2 and 3 undergo addition by p-TolS02CH2' radical readily, enamine 4 fails t o undergo the addition under the same conditions due to the steric hindrance by the two methyl substituents in the cc-position1l .
Ill. RADICAL ADDITION TO THE C=C BOND OF ENAMINES A. Radical Additlon Followed by Loss of Electron
The first reports of radical addition to enamines were those of the reaction of perhaloalkanes with enamines. Carbon tetrachloride was reported to undergo photochemical and thermal reactions with enamines giving x-dichloromethylene ketones" or aldehydes2' but no precise mechanism was proposed. Cantacuzene and Wakselman found that pyrrolidine enamines react readily with perhaloalkanes such as RF122.23or BrCF2XZ4(X = Br, CI, CF2Br) without irradiation or use of radical initiators, affording, after hydrolysis, the corresponding cc-perhaloalkyl aldehydes and ketones in moderate yields (equation 3). The yields are much higher if an additional tertiary amine is used to trap HI. In the reactions of perfluoroalkyl iodides with enamines in which the nitrogen lone pair is delocalized (R' or R2 = Ph or COR) use of irradiation is necessarvZ3 and the iields are not as hi& as in the case of R1 or R2 = alkyl or H. Some of the representative
Shekhar V. Kulkarni
u-perhaloalkyl aldehydes and ketones prepared according to equation 3 are given in Figure 1. The observations that these reactions are inhibited by nitrobenzene (a free radical inhibitor), no hydrogenated by-products are formed and that CF2BrCI gives only wCF2CI carbonyl compounds, led the authors to propose a radical chain mechanismz4 for these reactions (Scheme 1). The chain initiation step is the formation of XF2C' radical and enamine radical cation by electron transfer from the enamine to BrCF2X. The addition of this perhaloalkyl radical to the enamine generates a R,NC'R'Rr' type radical which is known to have an unusually low oxidation potential with E,,20x in the range of - 1 V (sce)". An electron transfer from this radical to another molecule of perhaloalkane then takes place to form the iminium salt and another perhaloalkyl radical which continues the chain. A similar mechanism operates in the case of RFZ3. A similar mechanism is thought to be involved in the formation of a-trifluoromethyl ketone 7 instead of expected amine 6 during the reaction of iminium salt 5 with CF,Br under Barbier conditions (equation 4)26. It was pioposed that pyridine probably transforms iminium ion 5 into the enamine (I-pyrro1idino)-1-cyclohexeneby elimination of HCI, which then undergoes a radical chain reaction with CF,Br as shown in Scheme 1 to give 7. This is supported by the observation that no condensation products are observed when iminium salts lacking removable a-hydrogens are used. Russell and Wang2' carried out detailed studies on the homolytic alkylation of various enamines by electrophilic radicals generated from p-nitrobenzyl chloride and 2,2dinitropropane. A free radical chain mechanism similar to that shown in Scheme 1 was
FIGURE I. Representative a-perfluoroalkyl ketones and aldehydes prepared according to equation 3 with their yields2'
15. Radical reactions of enamines
BrSCHEME 1
proposed for these reactions in which the electrophilic nitro-conjugated radicals add regioselectively to the enamine to yield an easily oxidizable aminoalkyl radical. Photolysis ofp-nitrobenzyl chloride in the presence of enamines 8-11 in DMSO, CH,CN or D M F at 35-40°C yields products 12-14 after hydrolysis of the intermediate iminium salts. The reaction of p-nitrobenzyl chloride with 8, 9a, or 9b also occurs slowly in the dark by a process inhibited by the free-radical scavenger (t-Bu),NOq (Table 1) which suggests the formation of free radicals by electron transfer between the enamine and p-nitrobenzyl chloride. Products 15 and 16 resulting from a slow ionic process are also observed, particularly in the absence of irradiation or in the presence of (t-Bu),NO'.
00
+
+
CFm
1 . 3 4 bar. pyridine 2,H30+
C1-
Reactions of PhCH,CI and m-O,NCpH,CH,CI with 9 and 10 failed to produce the a-alkylated ketones under similar reactlon conditions. The failure of a chain reaction with PhCH,CI reflects the increased reduction potential of the alkyl halide while, in the case of the latter, the radical anion formed by the facile reduction does not readily undergo the fragmentation step required to continue the chain process.
878
Shekhar V. Kulkarni TABLE 1. Reaction of p-O,NC,H,CH,CI
with enamines 8-11 at 35-40"Ca2'
Equivalents Enamine (equiv)
Et,N
(t-Bu),NO'
Conditionsh
Product
(%y
DMSO, D 2 h DMSO, D, 2 h DMSO, R, 30 rnin DMSO, R, 30 rnin DMF, s 1 h DMF, S, 20 min DMF. S. 20 min
12 (53) 12 not detected 12 (40) 12 (8) i3a'(i2) 13b (59) 13b not detected
CH,CN, s, i h CH,CN, S, 4 h CH,CN, D, 4 h DMF, S, 80 min DMF, S, 40 min
lk (75) lk not detected 14 (42)d 14 not detected
'0.5 M p-O,NC,H,CH,CI. b D=dark, R = 350-nm Rayonet Photoreactor, S = 275 W G.E. fluorescent sunlamp co 20 cm lrom
reaction vessel. 'Products analyzed by GC with an internal standard alter hydrolysis and extraction by CH,CI,. *Isolated yield.
15. Radical reactions of enamines
879
The relative reactivities of these enamines towards p-nitrobenzyl radical were found by carrying out competitive studies in the presence of the resonance stabilized anion Me,C=NO,-Li+, which is known to trap the p-nitrobenzyl radical to form p-0,NC,H,CH,CMe,NO, by an S,1 processz8. Enamine 9 is more reactive than 10 and 11, while 9a and 9c are slightly more reactive than 9b. The photostimulated reaction of MeZC(NO2), with enamine 8 in DMSO occurs readily to give the ionic product (isolated as a C10,- salt) Me,C=CHC(NMe,),+C 1 0 , resulting from the loss of HNO, from the initial electron-transfer product Me,C(N02)CH2C(NMez),+. No significant reaction occurs between Me,C(NO,), and enamines 9 or 10, although in competition with Me2C=NOzLi (with which it reacts by an SRN1process) the expected ketone is observed in the case of 9b. The electrophilic PhCOCH,' radical generated by photolysis of PhCOCH,HgCI in DMSO adds readily to enanline lob to form the substituted enamine 18,which upon hydrolysis gives the 1,4-diketone 19 in 60% overall yield29. In this free radical chain reaction (Scheme 2), the electron transfer from the easily oxidizable adduct radical 17 to PhCOCH,HgCI is facilitated by the fact that the irreversible half-wave reduction potentials of alkylmercury halides are typically more positive than - 0.6 V30. Silyl derivative 20 of an aci-nitroalkane reacts with morpholine enamine 2 in the presence of 2.5 equivalents of manganese(lI1) 2-pyridinecarboxylate [Mn(pic),] to give
(18)
-
CH2COPh
H3Oi
(19) SCHEME 2
Shekhar V. Kulkarni
a mixture of products 22-24 (equation 5)31. The reaction is thought to proceed via the initial formation of a radical cation 21 from 20 by reaction with Mn(pic),. Addition of this radical cation to the enamine 2 followed by loss of silyl group and further oxidation by another molecule of Mn(pic), then leads to the observed products. 6. Radical Addition Followed by Hydrogen Atom Abstraction
Renaud and coworkers have demonstrated that reductive alkylation of enamines by electrophilic radicals can lead to a product with high s t e r e ~ s e l e c t i v i t.yR~eaction ~~~~~~~ of cyclic enamines 25 with radical precursors XCH,EWG (X = CI, EWG = SO,Ph, S0,Tol-p; X = SPh, EWG = CO,Me, CN) in the presence of Bu,SnH and AIBN gives products 26 with a high degree of preference for the cis isomer (equation 6)11.32.
The reaction works well with a variety of cyclic enamines and in all cases the cis isomer is obtained as the major product. The diastereoselectivity is especially high in the case of cyclohexane derivatives (Table 2, entries 2-5) and somewhat lower for the cyclopentane derivative (entry 1). The reaction was reported to proceed via a radical chain process" in which the hydrogen atom abstraction occurs in a highly stereoselective manner. On the basis of competition experiments, the authors showed that the reaction of the radical generated from CICH,SO,Tol-p with 1-cyclohexenylpyrrolidine (9b) occurs with a rate constant similar to that found for hydrogen atom abstractions from Bu,SnH (lo6 L mol-I s-I). This rate constant is as high as the rate constant for addition of a primary alkyl radical to acrylonitrile, indicating that the rate of addition of sulfinylated and sulfonylated carbon-centered radicals to enamines is high enough to be synthetically useful in intra- and intermolecular reactions.
881
15. Radical reactions of enamines
TABLE 2. Reductive alkylation ofcyclicenamines 25 with XCH,EWG in the presence of Bu,SnH and AlBN (equation 6) Enamine Entry
-NR,
n
XCH,EWG
Product Yield"
%
cis: trans-eference
"Yield of the purified cis product. 'Determined by GC and NMR analysis of the crude products. 'After crystallization.
In order to explain the high stereoselectivity of these reactions, it was suggested that out of the two possible conformers 27 and 28 of the adduct radicals, only conformer 27 is involved in the transition state, as the reaction of conformer 28 would be less stereoselective. The absence of conformer 28 may be due to the steric repulsion between groups CH,EWG and NR, which destabilize 28. Alternatively, if 28 is the more stable conformer, the ring flip of the initially formed 27 may be slower than hydrogen atom abstraction from Bu,SnH.
The use of an enamine derived from a chiral C2-symmetric amine such as (2R, 5R)2,5-dimethylpyrrolidine leads to products 30 with high diastereoselectivity as well as high stereofacial selectivity (equation 7),'. In this case the radical addition is thought to take place from the relatively less hindered face of the enamine 29. The most remarkable feature of this method is that even acyclic enamines undergo reductive alkylation with good diastereoselectivity. The reaction of propiophenone enamines 31-33 with primary carbon-centered radicals substituted by different electron-
882
Shekhar V. Kulkarni
withdrawing groups gives products 34 with a syn relationship between the methyl and the amino groups in a highly diastereoselective manner, the relative topicity of the reaction being ul (equation 8)33.
(31) NR2 = pyrrolidino (33) NR2 = morpholino (34) NR2 = diethylamino
EWG (34) (major)
(35) (minor)
The yields of the products are in the range of 40-80% with the pyrrolidine enamine giving somewhat higher yields than the others. In the reactions of enamine 31 it was observed that the level of diastereoselectivity is dependent on the size of the EWG. Low stereoselectivities are obtained with C N and C 0 , M e in refluxing benzene (66 and 64% diastereoselectivity, respectively) while sterically more hindered phenylsulphonyl and t-butylsulphonyl groups give better selectivities (72 and 74% diastereoselectivity, respectively), which increase to 81 and 85% when the reaction is carried out at 10°C.Reductive alkylation of 31-33 with PhSO,CH,CI and I-BuSO,CH,SePh showed that morpholino and pyrrolidino enamines give similar diastereoselectivities, while lower diastereoselectivity is obtained in the case of noncyclic diethylamino enamine 33. In order to rationalize the stereochemical outcome of the reaction, the authors calculated the heat of formation of the radical intermediate generated from the reaction of PhSO,CH,CI with 31 using semiempirical methods and proposed that the most stable conformer 36 is responsible for the formation of the major diastereomer. The radical center in this conformer is planar and is stabilized by interaction with the adjacent nitrogen, while there is practically no delocalization onto the phenyl ring. The stereoselectivity of the hydrogen atom abstraction is governed by steric effects and occurs anti to the more bulky CH,SO,Ph group leading to the major product isomer. The pair of electrons on nitrogen is antiperiplanar to the bond being formed, allowing stabilization of the transition state by delocalization of this electron pair into the a* orbital in formation. Based on these results the authors proposed a general model 37 for the radical reductive
15. Radical reactions of enamines
883
alkylation of acyclic enamines. This model explains the low selectivities observed for small EWG which do not allow a good differentiation between large L ( = CH,EWG) and medium M ( = CH,) groups.
Radical reductive alkylation of enamines has also been utilized for the intramolecular cyclization reaction34. Enamine 38 bearing an exo-olefin moiety, on treatment with Bu,SnH in the presence of a radical initiator, generates an aryl radical 39 which undergoes exclusive 1,6-cyclization t o give the isoquinoline 40 as the sole product in 51.3% yield (equation 9).
Me0 Bu3SnH. AlBN
PhMe, reflux
Me0
oiO (38)
884
Shekhar V. Kulkarni IV. REACTIONS OF ENAMINES WITH ONE-ELECTRON OXIDANTS
Enamines have unusually low oxidation potentials and readily undergo one-electron oxidation to a radical cation in the presence of a suitable oxidant. For example, enamines 1-(N,N-dimethylamino)cyclohexene(41), 2,5-dimethyl-1-(N,N-dimethylamino)cyclohexene (42) and 1-(N,N-dimethylamino)-1-phenylethene(43) have oxidation potentials of
0.42,0.38 and 0.70 V (sce), r e ~ p e c t i v e l yComparison ~~. of these oxidation potentials with those of triethylamine (1.07 V), aniline (0.95 V) and 1,4-cyclohexadiene (1.85 V) demonstrates their relatively low values36.
SCHEME 3
(47)
885
15. Radical reactions of enamines
Formation of an enamine radical cation 45 was proposed as the chain initiation step in the autooxidation of enamines and Schiffs bases of a$-unsaturated ketones to give unsaturated 1,4-di0nes~~. Pyrrolidine enamine of 10-meth~l-A"~'-octaI-2-one(44) reacts with oxygen at room temperature to produce, after acid hydrolysis, 10-methyl-A1(9'octalin-2,8-dione (47) in 20% yield. Addition of a catalytic amount of FeCI,, Cu(OAc), or CuCI, causes a pronounced enhancement in the oxidation rate and increases the yield to 8&85% after 1 h. The proposed free radical chain mechanism for this reaction is given in Scheme 3. The striking catalytic effect of the metal ions such as C u Z +and Fe3+ is attributed t o their ability to accept an electron from the enamine in the chain initiation step. The autooxidation of the Schiffs bases of a,b-unsaturated ketones is thought to proceed similarly via the enamine form of the Schiffs bascs. Ledwith and coworkers have shown that certain aromatic enamines undergo cyclodimerization under the catalytic influence of suitable inorganic one-electron oxidants such as Fe3 and Ce4+38.Cyclodimerization of N-vinylcarbazole (48)in the presence of Fe3+ or Ce4+ salts in methanol leads to trans-1,2-di-carbazol-9-ylcyclobutane (50) and a small amount of 1,4-dicarbazol-9-yl-1,4-dimethoxybutane (51). The intermediacy of the radical species is indicated by the efficient free radical copolymerization of 48 with added methyl methacrylate. For given reaction conditions, +
OMe
I
OMe
I
Ar2NCHCH2CH2CHNAr2
MeOH
+
+
X-(Ar2NCHCH2CH2CHNAr2)X-+ 2FeX2
SCHEME 4
886
Shekhar V. Kulkarni
the rate of cyclodimerization of 48 is always six to seven times greater than concurrent formation of Fe(II), in line with a chain mechanism for the cyclodimerization. The reaction is believed to proceed via an initial formation of an enamine radical cation 49 which undergoes head-to-head addition with another molecule of 48 leading ultimately to the observed product (Scheme 4). N-Vinylcarbazole (48) also undergoes photosensitized cyclodimerization producing the same cyclobutane 50 as obtained in the metal catalyzed reaction39. In the presence of most sensitizers, cyclodimerization of 48 occurs only when oxygen is present in the system. Photosensitization in the absence of oxygen leads to slow polymerization. The complete absence of products containing oxygen and the lack of increase in the rate of dimerization when pure oxygen is used instead of air, points to a catalytic function of oxygen. Measurements of the quantum yields (4,) for photosensitized cyclodimerization of 48 for several sensitizers gave in all cases a value 4, >, 1, indicating a chain mechanism. On the basis of these observations, a radical cation chain mechanism was proposed for this 2 2 cycloaddition (Scheme 5).
+
(sens)O
(sens)* (singlet or triplet)
V. REFERENCES 1. J. K. Kochi, Free Radicals, Vols. I and 11, Wilev-Interscience. New York. 1973 2. D. C. Nonhebel and I. C. Walton, ~ r e e~ a d i c a lChemistr;, ~ a m b r i-d kUniversitv Press. Cambridge, 1974. 3. B. Giese, Radicals in Oryunic Synthesis: Formation of Carbon-Carbon Bonds, Pergamon Press, Oxford. 1986. 4. A. G. cook, Enamines: Synthesis, Structure and Reactions, 2nd ed., Marcel Dekker, New York, 1988.
15. Radical reactions of enamines S. F. Dyke, The Chemistry of Enamines, Cambridge University Press, Cambridge, 1973. B. Giese, Angew. Chem., Int. Ed. Engl., 22, 753 (1983). A. Citterio, F. Minisci, 0. Porta and G. Sesana, J. Am. Chem. Soc., 99, 7960 (1977). G. J. Gleicher, B. Mahiou and A. J. Aretakis, J. Org. Chem., 54, 308 (1989). B. Giese, J. He and W. Mehl, Chem. Ber., 121, 2063 (1988). B. Giese, H. Horler and M. Leising, Chem. Ber., 119, 444 (1986). P. Renaud and S. Schubert, Angew. Chem., Int. Ed. Engl., 29,433 (1990). J . M. Tedder and J. C. Walton, Adu. Phys. Org. Chem., 16, 51 (1978); J. M. Tedder and J. C. Walton, Tetrahedron, 36,701 (1980); J . M. Tedder, Angew. Chem., Int. Ed. Engl., 21,401 (1982); A. L. Beckwith, Tetrahedron, 37, 3073 (1981); K. Munger and H. Fischer, Int. J. Chem. Kinet., 17, 809 (1985).
S. S. Shaik and E. Canadell, J. Am. Chem. Soc., 112, 1446 (1990). F. Delhecq, D. Ilavsky, N. T. Anh and J. M. Lefour, J. Am. Chem. Soc., 107, 1623 (1985). S. F. Nielsen, in Free Radicals, Vol. 11 (Ed. J. K. Kochi), Wiley, New York, 1973, p. 527. D. J. Pasto, R. Krasnansky and C. Zercher, J. Org. Chem., 52, 3062 (1987) and references cited therein. F. G. Bordwell, X. Zhang and M. S. Alnajjar, J. Am. Chem. Soc., 114,7623 (1992) and references cited therein. K. N. Houk, M. N. Paddon-Row, D. C. Spellmeyer, N. G. Rondan and S. Nagase, J. Org. Chem., 51, 2874 (1986); C. Gonzalez, C. Sosa and H. B. Schlegel, J. Phvs. Chem., 93, 2435 (1989); C. Sosa and H. B. Schlegel, J . ' A ~ Chem. . Soc., 1UY,4193 (1987). . 19. H. Zipse, J. He, K. N. Houk and B. Giese, J. Am. Chem. Soc., 113,4234 (1991). 20. J. Wolinsky and D. Chan, J. Chem. Soc., Chem. Commun., 567 (1966). 21. E. Elkik and P. Vaudescal, Compt. Rend. Acad. Sci. Paris 264C, 1779 (1967). 22. D. Cantacuzene and R. Dorme, Tetrahedron Lett., 2031 (1975). 23. D. Cantacuzene, C. Wakselman and R. Dorme, J Chem. Soc., Perkin Trans. 1, 1365 (1977). 24. I.Rico, D. Cantacuzene and C. Wakselman, Tetrahedron Lett., 22, 3405 (1981). 25. J. A. Hawari, J. M. Kanabus-Kaminska, D. D. M. Wayner and D. Griller, NATO ASI Series C , 189, 91 (1986). 26. M. Tordeux, C. Francese and C. Wakselman, J. Chem. Soc., Perkin Trans. 1, 1951 (1990). 27. G. A. Russell and K. Wang, J. Org. Chem., 56, 3475 (1991). 28. G. A. Russell and W. C. Danen, J Am. Chem. Soc., 88,5663 (1966); N. Kornblum, R. E. Michel and R. C. Kerber, J. Am. Chem. Soc., 88, 5662 (1966). 29. G. A. Russell, S. V. Kulkarni and R. K. Khanna, J. Org. Chem., 55, 1080 (1990). 30. H. Kurosowa, H. Okada and T. Hattori, Tetrahedron Lett., 22, 4495 (1981). 31. K. Narasaka, K. Iwakura and T. Okauchi, Chem. Lett., 423 (1991). 32. P. Renaud and S. Schubert, Synlett, 624 (1990). 33. P. Renaud, P. Bjorup, P. Carrupt, K. Schenk and S. Schubert, Synlett, 211 (1992). 34. S. Takano, M. Suzuki, A. Kijima and K. Ogasawara, Tetrahedron Lett., 31, 2315 (1990). 35. J. M. Fritsch, H. Weingarten and J. D. Wilson, J. Am. Chem. Sor., 92, 4038 (1970). 36. C. K. Mann and K. K. Barnes, Electrochemical Reactions in Nonaqueous Systems, Marcel Dekker, New York, 1970. 37. S. K. Malhotra, J. J. Hostynek and A. F. Lundin, J. Am. Chem. Soc., 90, 6565 (1968). 38. F.A. Bell, R. A. Crellin, H. Fujii and A. Ledwith, J. Chem. Soc., Chem. Commun.,251 (1969). 39. R. A. Carruthers, R. A. Crellin and A. Ledwith, J. Chem. Soc., Chem. Commun., 252 (1969).
Rearrangements and tautomerizations of enamines ZHI-TANG HUANG and MEI-XIANG WANG Institute of Chemistry, Academia Sinica. Beuing 100080, People's Republic of China - --
-
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . TAUTOMERISM BETWEEN ENAMINES AND IMINES . . . . . . . . [1,3]-SIGMATROPIC REARRANGEMENTS . . . . . . . . . . . . . . . . CLAISEN AND COPE REARRANGEMENTS INVOLVING ENAMINES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. 3-AZA-COPE REARRANGEMENT O F N-ALLYLENAMINES . . . . . V1. MISCELLANEOUS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VILREFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I. 11. 111. IV.
I. INTRODUCTION
Since the first publication by Stork and coworkers' on alkylation and acylation of enamines in 1954, much progress has been achieved in many aspects of enamine c h e m i ~ t r y ~ -Rearrangement ~. reactions, however, have been largely ignored, and they are overshadowed by the overwhelming documents related to the electrophilic and nucleophilic6 reactions of enamines and iminium salts, respectively. Only one recent reviewz mentioned this subject briefly. However, several types of rearrangements have been reported and some are significant in organic synthesis. For example, N-allylenamines prepared readily from allylamines and aldehydes undergo 3-aza-Cope rearrangement to give imines which can be converted to useful synthetic materials such as y,s-unsaturated carbonyl compounds and 6,wunsaturated amines. In this chapter, we will discuss mainly the rearrangements of enamines starting with a general review of the enamine-imine tautomerism (Section 11). In analogy to enols, enamines derived from primary amines are capable of tautomerizing to their imine isomers. The preferential formation of the enamine or the imine tautomer is affected by many factors including the nature of the substituents, the media or solvent and so on. There are many reports related to this subject and several brief reviews4,' have also been published. We will review the tautomeric equilibrium between enamine and imine with emphasis on the factors which influence the position of the equilibrium. The Clzemistrl).ofEnamines. Edited by Zvi Rappoport Copyright O 1994 John Wiley & Sons, Ltd. ISBN: 0-471-93339.2
889
890
Zhi-Tang Huang and Mei-Xiang Wang
In Section 111, [1,3]-sigmatropic rcarrangcments of enamines will be presented. Aliphatic Claisen rearrangements and Cope rearrangements involving enamines will be discussed in Section IV. With amino-substituted allyl vinyl ethers and 1,5-hexadienes, these rearrangement reactions show some interesting results. The nitrogen analogue of the aliphatic Claisen rearrangement, named the 3-aza-Cope rearrangement, will be discussed in detail in Section V and other miscellaneous rearrangements will be shown briefly in Section VI. In this review the rearrangement of enamines, i.e. when enamines are the reactants, will be predominantly considered. Rearrangements which involve enamines as a final product, e.g. the preparation of enamines from the isomerization of allyl amines3, are not included. In addition, aromatic amino-Claisen rearrangement of N-allylaniliness is also excluded. The literature survey in this chapter is up to early 1992. II. TAUTOMERISM BETWEEN ENAMINES AND MINES
Prepared from the primary amines, enamines bearing one proton on the nitrogen (1) would tautomerize to imine isomers (1') (equation 1).
(1) enamine form
(1') imine form
Extensive studies have shown that the enamine-imine tautomeric equilibrium of equation 1 shifts almost completely to the enamine side when an unsaturated electronwithdrawing group including nitrile9, nitroL0, carbonyllL, t h i o ~ a r b o n ~ el 't~~ . ' ~ - ~IS 'O attached to the P-carbon. Reviews related to these enamines which include enaminonitriles 2, nitroenamines 3, enaminones 4 and the enaminothioketones 5, have appeared in the l i t e r a t ~ r e ~ - ~ ~ . H R'-N
I
\
C=C
R'
x
1
\
R~
(2) X = CN, (3) X = NOz (4) X = COR; (5) X = CSR
IR, UV and NMR spectra obtained so far are compatible with the structure of the secondary enamines. The tautomeric enamine structure of some enaminones in the solid state has also been established unambiguously by single-crystal X-ray diffraction analysesz1. In agreement with the experimental evidence, theoretical calculation^^^^^^ performed on enaminones 6 8 and nitroenamine 9 indicate that the enamine forms are
(6)
(7) R1,R2 = H, Me; R3 = Me (8) R',R' = H, Me; R = OEt
(9)
89 1
16. Rearrangements and tautomerizations of enamines
the most stable tautomers. Due to intramolecular hydrogen bond formation, the isomers with Z-configuration are more stable than the E-isomers. These enamines show some intriguing spectral and structural characteristics. In the infrared spectra, all the P-functionalized secondary enamines 2-5 exhibit an unusually large bathochromic shift of the stretching frequency assigned to the carbonxarbon double bond and especially of the frequency involving a double bond to the electronwithdrawing groups X. The C=C double bonds of enamines generally absorb at 156g1590 c m ' in enaminonitriles Z9, at 1 6 0 & 1 6 5 0 ~ m - in ~ nitroenamines 310.2"27 and at 154%1590cm1 in enaminones 411.13,28829 . Th e carbonyl stretching frequency of 4 shifts to as low as approximately 1 6 0 0 c m 1 ",13.28,29 and the nitrile stretching frequency of 2 appears at 2165-2190 cm-' 9. Similarly, the nitro group of 3 displays an . Such absorption band at lower frequency than in the saturated nitro d e r i ~ a t i v e ' ~ ~ ~~-~' enormous bathochromic effects result from the presence of a long conjugated system involving the clcctron-withdrawing group and the lonc-pair clcctrons of the nitrogen atom on both sides of the double bond. The ultraviolet spectra show a n-n* absorption band at a longer wavelength with higher intensity than the saturated analog^'^-^' which is also consistent with a highly conjugated system. NMR spectra9-12.24.32.33of these enamines display upfield signals corresponding to the P-carbons and to the protons bondcd to thcm, reflccting thc accumulation of clcctron density on P-carbons. Indeed, it is usually the P-carbon rather than secondary amino moiety that serves as the nucleophilic reaction center when enamines react with electr~philes'~-'~. It is therefore concluded that the stabilization of secondary enamines such as 2-5 by the unsaturated electron-withdrawing substituents at the P-carbon leads to the interesting spectral and chemical properties resulting from the formation of a long conjugated system. The electrons of the lone pair on nitrogen are delocalized into the double bond, giving rise to increased electron density on the P-carbon. Intramolecular hydrogen bonding between the amino hydrogen and the heteroatom on X further stabilizes the enamine tautomers. It is noteworthy that the stability resulting from conjugation and intramolecular hydrogen bonding is sufficient to destroy the aromatic structure of one of the naphthalene rings, since imine 10 rearranges completely to 11 (equation 2)34.
Although secondary enamines 2-5 are the predominant species, imine tautomers are suggested to he involved in the E-Z isomerization in some cases (equation 3)35.
H R-N
H
I
EWG
\
I
2-
-
R-N
EWG
'c-C!-H
/
R-N
I
/
\
\
EWG = electron-withdrawing gmup
(3)
E-
In contrast to the enamines discussed above, the species derived from primary amines and simple aldehydes and ketones exist predominantly in the imine form, based on
892
Zhi-Tang Huang and Mei-Xiang Wang
spectroscopic s t ~ d i e s ' ~Apparently, ,~~. the enamine-imine tautomeric equilibrium (equation l) lies far on the imine side under normal conditions. Nevertheless, chemical reactions between imines and electrophilic reagents have revealed that imine-enamine tautomerization exists and that the enamine tautomers are the reactive species which undergo the reaction^^',^^. For example, imines 12 prepared from aliphatic amines and a variety of ketones react with aryl azides to afford triazolines 14 in good yields. On heating or in the presence of catalytic amounts of an acid, triazolines 14 are converted to triazoles 15 in a process which may proceed via rearrangement and a deamination pathway (equation 4). Formation of 14 demonstrates clearly the existence of imine-enamine tautomerism during the reaction394'.
Pfau and ~ i b i e d have - ~ ~shown that the enamine tautomer 17 is involved in the reaction between N-isopropylideneisopropylamine (16) and dimethyl maleate (18).The C-alkylated product 19 and ketone 20 were obtained in high yields (equation 5). When
(19)
1
Hydrolysis 20"C
16. Rearrangements and tautomerizations of enamines
893
the imine of cyclohexanone 21 was employed, the C-alkylated intermediate 23, presumably formed via 22, underwent spontaneous tautomerization and cyclization to give lactam 25 (equation 6)42.44.In addition, 'H NMR spectra of 16 in deuteriomethanol showed the disappearance of the signals corresponding to the two magnetically nonequivalent methyl groups of the isopropylidene moiety (at 6 1.94 and 2.01 ppm). This was ascribed to a rapid deuterium exchange via 1743.
A detailed investigation by Pfau and Ughetto-Monfrin4' of the reaction of Nisopropylidenecyclohexylamine (26) with methyl acrylate (28) demonstrates convincingly the imine-enamine (27) tautomerism. All the products 29, 31-34 which were separated and characterized result from the enamine tautomer (Scheme 1). Hence, although the imine tautomer is the exclusive form based on spectroscopic observations, tautomerization between imine and enamine does exist and is sufficiently rapid to give products from the latter. Though the secondary enamines are thermodynamically unstable and often undetectable, except for those which are further conjugated by electron-withdrawing groups (vide supra), successful preparation and characterization of pure secondary enamines have been reported by methanolysis of tin46.47,m a g n e ~ i u mor ~~,~~ derivatives and hydrolysis of organosilicon compounds49. When organometallic enamines 35 and imines 36 prepared from iminesS0 are treated with an insufficient amount of methanol (75% of the theoretical amount), they give quantitatively enamines 37 as the kinetic-controlled products of the reaction. These enamines are stable in strictly aprotic media and can be distilled from the reaction
894
Zhi-Tang Huang and Mei-Xiang Wang
SCHEME 1
mixture under reduced pressure and trapped at -80 "C. Methanolysis using deuteriated methanol gives N-deuteriated enamines which are quite stable at -80 "C (imine content 25% after 18 h) and can be characterized at room temperature, where, however, complete isomerization to imines takes one hour. The secondary enamines 37 undergo a fast exothermic reaction at 0 "C with u,P-unsaturated compounds 38 to yield products 39 (Scheme 2). Either slow reaction (24 h at 80 "C) occurs or no reaction takes place when the corresponding imines are used in the same reactions. N-Deuteriated enamines afford adducts 39 having a deuterium atom at an u-position to the EWG, indicating that the proton shifts i n t r a m o l e ~ u l a r l yAn ~ ~ ene-addition ~~~. mechanism between 37 and 38 has been proposed4'.
16. Rearrangements and tautomerizations of enamines
EWG
R2 I EWG-CH~CH, -c-CH=NR~ I R3
(38)
\ H
~2
\
C=C
I
\
R3
NR' I
Rl = Me, i-Pr, i-Bu; R2,R3 =Me, Et, H; M = SnBu3, MgC1; EWG = CN, COMe, C02Et SCHEME 2
Recently, Capon and W U have ~ ~ reported the generation of secondary enamines from their N-trimethylsilyl derivatives through hydrolysis. In DMSO-d, (99% v / v t D 2 0 (1% v/v) solution, enamine 40 is converted to the N-deuteriated enamine 41 quantitatively in 5-10 min at room temperature. The solution obtained is stable for several hours, but over a period of 2-3 days 41 is oxidized to acetone and N-deuterio-N-phenylformamide. On adding 15% (v/v) D,O/DCI (0.1 M) to the solution, enamine 41 is completely hydrolyzed to 2-[2HJisobutyraldehyde and aniline without detection of any intermediates. Enamine 42 is formed by the acid-catalyzed hydrolysis of 40 (Scheme 3). Similar results are obtained with other N-aryl enamines. Me
\
H (CDdzSO (99%)-D20 (1%)
/"="I
Me
H
NPh I
Me2CDCH=NPh
/
I H
I
C
I
/"="\ NPh
Me
H
\
rl
/"="\ NPh
Me
Me \
Me
I
1
MeCOMe
+ PhN(D)CHO SCHEME 3
Me2CDCH0
+
PhNHz
Zhi-Tang Huang and Mei-Xiang Wang
896
N-Silylated enamines,43 can undergo similar acid-catalyzed hydrolysis under the conditions outlined in Scheme 3 to N-alkyl enamines 44, while 45 fail to hydrolyze, presumably due to their sensitivity to the conditions employed. However, by using tetrabutylammonium fluoride as a catalyst enamines 46 are formed4'. Me
\
H 1
F="\
Me
N-R
(43) L = SiMe3; R = Me, Et (44) L = H or D; R = Me, Et
H
N-R
(45) L = SiMe3; R = Me, t-Bu (46) L = H or D; R = Me, t-Bu
In general, the tautomeric equilibrium (equation 1) is completely on the enamine side when an unsaturated electron-accepting substituent substitutes the P-carbon of 1; otherwise, the equilibrium lies far on the side of imine 1'. However, apart from the two extreme cases above, some secondary enamines are sufficiently stable to exist in detectable amounts in equilibrium with the corresponding imines and thus it becomes possible to investigate the factors affecting the enamine-imine e q ~ i l i b r i u m ~ ' - ~ ~ . Clarke and Parker54 have reported a thermodynamic study of the tautomerization of 2-(N-cyclohexylimino)-1,3-diphenylpropane(47) to its Z- and E-enamine tautomers 48a and 48b in DMSO-d, solution (Scheme 4). The equilibriuin constants and the values of the thermodynamic parameters AH, AG and A S have been determined by variabletemperature NMR measurements. Polar solvents are found to favor enaminization, but have little effect on the E$Z isomerization of the enamine tautomers.
A study of the tautomerism between 49 and 5055, which are synthesized from the condensation of 3-aminopyridines and isobutyraldehyde, shows that the equilibrium position varies drastically according to the substituents and their position on the pyridine ring. With a nitro or an ethoxy group at position-2, the equilibrium lies well to the
16. Rearrangements and tautomerizations of enamines
897
enamine side with 86-100% of 49. The situation is the opposite whcn a bromo or an ethoxy group substitutes position-5 of the pyridine, when the percent of imine 50 is 92-100%. The condensation product from 3-aminopyridine N-oxide and isobutyraldehyde exists exclusively in the enamine form 51 (Scheme 5)55.
SCHEME 5
Ahlbrecht and coworker^^^-^^ have studied extensively the enamine-imine tautomerlc equilibrium between 52 and 53 having at least one aryl moiety (equation 7). The equilibrium is strongly amected by the nature of the substituents. Enamines derived from primary aromatic amines are more preferable than those derived from primary aliphatic amines. With the increase in the electron-withdrawing ability of the substituents R1, the percent of enamine 52 increases. An extreme case is the condensation reaction between p-nitroaniline and isobutyraldehyde which affords 100% of e ~ ~ a m i nSubstituents e~~. R3 and R4 at the /3-position also stabilize the enamine form. Particularly, with an aryl bearing an electron-withdrawing group, the equilibrium shifts to the enamine side. In addition, steric effects also play a role in determining the position of the equilibrium. The ratio of enamine to imine increases with the increased bulk of R in the order Me < Et < CH,Ph < t-Bu for the 54/55 pair (equation 8) which is prepared from cc-phenylpropanal and the corresponding a m i n e P . H
I
R'-N
R3
\
/
c=c\
R2
-
R3 ' C-C-H
R'-N
R4
\\ /
\
R2
(52)
R4 (53)
R',RZ,R~,R~ = alkyl, aryl, hydrogen Ph H \ I ,C=C \
H3c
N-R
I H (54)
-
Ph \ H-C-C /
H
I
\\
H3c
N-R (55)
(7)
898
Zhi-Tang Huang and Mei-Xiang Wang
The steric influence on the enamine-imine tautomerism has also been observed in the cyclic ketone derivatives. Cyclohexanone imines of n-propylamine, cyclohexylamine and 2-bornylamine show no signals ascribed to the enamine tautomer in their 'H NMR spectra, but the t - b ~ t ~ l a m i ndoes e ~ ~display signals of the enamine. In DMSO-d, it comprises 38% of enamine 56 at equilibrium. The proportion of the 3,3,5,5-tetramethylcyclohexanone and cyclopentanone enamines 57 and 58 is even higher, rising to 52% and 58%, respectively, in DMSO-d,63.
The enamine-imine tautomeric equilibrium is dependent on the solvents emp l ~ y e d ~Examination ~.~~. of different tautomeric compounds in solvents of different polarity shows that the polar solvents favor the enamine tautomer. The preference of enamine tautomers in polar solvents is not surprising in view of the expectation that the latter would have appreciably greater polar character than the inline tautotners and hence will be more efficiently stabilized by solvation in the more polar solvents. It may be noted in this connection that the tautomerization of N-isobutylideneanilines (59) to the corresponding enamines 60 in CCI, solution, which was earlier reporteds2, has recently been proved to be in error49. The ' H NMR spectra earlier assigned to the proposed enarnines is quite different from those of N-arylisobutenylamines (60) which have been independently prepared and characterized. Especially, the signal of the olefinic proton of the proposed enamine is at 6 ca 7.7 ppm, shifted > 1 pprn downfield from that in 60. In fact, a solution of 59 in CDCI, shows only the signals of the imine, but when 10% (v/v) CCI, is added, new signals at 6 1.61.7 ppm and 7.7 ppm are formed rapidly. When a solution of 59 in CCI, is left overnight, it turns red, indicating the compound is decomposing. Therefore, the new signals at 6 1.6-1.7 ppm and 7.7 ppm are due to the formation of decomposition products of the imine in CCI, rather than to the presence of the enamine tautomer.
H3C\ H-C-C /
H3C
H
/
\\
N-Ar
H3C\ f=C H3C
H (6 ca. 6.12)
/
\
N-Ar I H
The tautornerism between cyclohexanone enamines 61 and the corresponding imines 62 has been investigated recently49. Although 'H NMR spectra in CDC1, solution show only the presence of imines 62, the spectra recorded in DMSO-d, solution indicate the existence of both tautomers. In agreement with the prediction by Ahlbrecht and c o w ~ r k e r s ~ ' -the ~ ~ ,percent of the enamine tautomer 61 increases with the increase in the electron-withdrawing power of the substituent R, and the equilibria are completely on the imine side when R is p-methyl o r p-methoxy (equation 9).
16. Rearrangements and tautomerizations of enamines
Very recently, an enamine-imine tautomerism of ketene aminals has been reported by Huang and coworkers"-". Due to competition by increased aromaticity, very stable enaminone isomers 6 M 5 equilibrate to their imine isomers 63'45' (equation 10). It is
(63) Z = NMe (64) Z = S (65) Z = 0
(63') (64')
a R = C1
b
H
c Me
d OMe
(65')
striking that the isolation of the tautomers is strongly affected by the substituent at the benzoyl group. Only the enamine species 63a with R =p-C1 and imine 63'd with R = p - M e 0 were isolated. More interestingly, both pairs of tautomers 63b,c and 63'b,c were recrystallized from ethanol and they could be easily separated mechanicallyb7. In solution, enamines 6.M5 and imines 63'45' exist at equilibrium. Similarly, electronwithdrawing group R favors in general the enamine tautomers, and this is strongly supported by the exclusive isolation of 63a. The solvent effect on the equilibrium, however, is somewhat complicated. The ratio 63/63',' or 64/64'65increases in the polar solvent DMSO-d,. In contrast, the equilibrium for the oxygen-containing heterocycles 65 shifts in the direction of imine in DMSO-d665.The different preference of the enamine and imine tautomers of 6 M 5 in DMSO-d, is attributed to the influence of the heteroatom Z. The lower values of electronegativity of nitrogen and sulfur atoms compared to oxygen make the double bond of 63 and 64 more polarized due to the higher electron-donating power of these atoms. Therefore, the more highly polarized enamine forms of 63 and 64 are stabilized by the more polar solvents, such as dimethyl sulfoxide. However, for 65 having the more electronegative oxygen atom, the polarization of the double bond in the enamine isomer is alleviated, with a consequent decrease in the percent of the enamine form in polar solvents and increase in nonpolar solvents, particularly in CCI,. Ill. [1,3]-SIGMATROPIC REARRANGEMENTS
Several [1,3]-sigmatropic rearrangements of enamines are known. The enamine substrates are mainly N-functionalized enamines, and the rearrangements usually give the secondary enamines with a transferred functional group at &carbon.
900
Zhi-Tang Huang and Mei-Xiang Wang
Among the examples of [1,3]-sigmatropic rearrangements is the photoinduced [1,3]acyl shift of N-acylenamines, which has been investigated extensively and reviewed in 197868. Thus, the irradiation of N-acyl enamines, known as enamides, provides a facile synthesis of enaminones. A mixture of enaminones 67 is obtained in good yield from the photolysis of enamides 66 (equation ll)69. It is interesting to note that the photochemical equilibrium between the E and Z isomers of 67 is different from the thermodynamic equilibrium.
::
R-C-N
,--J \
H
I \
-
I1 O R-C
\
IN
Me
0
H\ / - J N
-
I
R-C
hV
F="\
H
Me
II
\
H
I
(11) Me
R
Ph
Me
OMe
Yield (%)
85
60
80
EIZ
15/85
50150
6W40
N-Acetylenamines 68a-dgenerated from 2-tetralone underwent [1,3]-acetyl migration to the enaminones 69a-d in moderate yields when irradiated with high-energy light light (equation 12). When N-benzoyl enamine analogue 70 was photolyzed under the same condition, however, only a small amount of [1,3]-benzoyl migration product 71 was obtained. This was attributed to a competition by a photoinduced cyclization which led to the fused heterocycle 72 (equation 13)".
Yield (%) 67
46
60
50
16. Rearrangements and tautomerizations of enamines
901
Photoinduced [1,3]-acyl shift has also been found for N-acylated i s o q u i n ~ l i n e s ~ ~ ~ ~ ~ and other enamine c ~ m p o u n d s ' ~ ~ ~ ~ . A detailed investigation of the photolysis mechanism of enamines has been conducted by Hoffmann and Eicken7'. The rearrangement proceeds through radical processes. When N-acylenamine 73 was irradiated at the wavelength corresponding to the n + n*transition of the amide at approximately 200 nm, the amide bond was cleaved to the radical pair. This radical pair could either recombine and revert back to the reactant or undergo a [1,3]-acyl shift to give the imine 74. In turn 74 underwent rapid tautomerization to the enaminone 75, which was in photochemical equilibrium with its isomer 75' (Scheme 6).
0 R-C
\
H 1
F="\ N-Me
Ph
SCHEME 6
When a mixture of the mono-deuteriated N-benzoylenamiaes 76a and 76b was irradiated, the product obtained contained approximately 8% of dideuteriated (R1 = RZ = D) enaminone (equation 14). It indicates that although the reaction mainly proceeds intramolecularly, at least some intermolecular reactions do take place. The radical mechanism was further corroborated by irradiating enamine 76 (R1 = R2 = H) in carbon tetrachloride. Benzoyl chloride (60%) rather than the enaminone was isolated, and this was ascribed to halogen abstraction from the solvent by the benzoyl radical. Thermal [1,3]-sigmatropic rearrangements of enamines have also been reported7'. Compound 78 obtained from the reaction of dihydroisoquinoline and phenyl isocyanate,
Zhi-Tang Huang and Mei-Xiang Wang
which is stable at room temperature, undergoes a rapid and irreversible rearrangement to give enaminone 79 when heated in toluene (equation 15)76. Thermolysis of N-nitroenamines 80a leads to a-nitroimines 81 by [1,3]-rearrangement, or while 80b is converted to the thermodynamically more stable nitroenamine isomer 82 (equation 16)77.
(80) (a) R1 = H, Me; RZ= n-Pr (b) R1 =Me; RZ= H
(81) R' = H,Me; RZ= n-Pr
(82) R' = Me; RZ= H
On successive treatment with trimethyloxonium tetrafluoroborate, triethylamine and aqueous acid, oxime acetate 83 prepared from cyclohexanone oxime and Ac,O yields a-acetoxy ketone 87 (Scheme 7). A similar result is obtained with other symmetric ketones including 4-heptanone, deoxybenzoin and dihenzyl ketone. 87 can also be formed by the reaction of cyclohexanone and 0-acetyl-N-methylhydroxylamine hydrochloride upon hydrolysis. If the reaction time is prolonged prior to hydrolysis, ketoamide 89 is isolated as the main product. The key step of the reaction is the [1,3]-acetoxy shift of N-acetoxyenamine 85 to the a-acetoxyimine 86. The formation of 89 provides support for the intermediacy of acetoxyimine 86 in the reaction sequence. The evidence available suggests that the [1,3]-acetoxy migration proceeds via a Claisen-type rearrangement (Scheme 7)".
16. Rearrangements and tautomerizations of enamines
SCHEME 7
In a recent study of the 3-aza-Cope reaction, Murahashi and coworker^'^^^^ have found that N-(2-buteny1)-enamines 90 undergo [1,3]-sigmatropic rearrangement rather than [3,3]-rearrangement in the presence of Pd(0) and CF,CO,H. Thus, y,&unsaturated aldehyde 92 is formed in 60% yield from 90 (R = Me, Ph) through rearrangement and hydrolysis reactions (equation 17).
Rh*Ph
U.31
RxN
/
v Pd
Me
ChCOzH
"30'
M~
\
Me
se OHC
\
(17)
Zhi-Tang Huang and Mei-Xiang Wang
904
IV. CLAISEN AND COPE REARRANGEMENTS INVOLVING ENAMINES
The Claisen and Cope rearrangements are of great importance in both theoretical and synthetic organic chemistry and d o not need an introductions1. When an amino group substitutes an allyl vinyl ether or a 1,5-hexadiene, the rearrangements lead to some interesting results. Four kinds of Claisen rearrangements involving enamines would be expected corresponding to the presence of an amino group at C C C,,, and C However, most investigators have focused on the rearrangement of 0-allylketene N,O-acetals 93, i.e. ally1 vinyl ethers having an amino moiety at C,,,, probably owing to their easy access and higher reactivity (equation 18). Several methods have been developed for the synthesis of 0-allylketene N,O-acetals. These include the reactions between an allylic alcohol and amide a c e t a l ~ ~ ~ketene . ~ ~ , N,O-acetalss4, a-haloenaminess4 and ynaminess5,s6. Relative to the parent allyl vinyl ether, 0-allylketene N,O-acetals undergo the rearrangement smoothly at moderate or even ambient temperature. Most conveniently, the rearrangement can be effected under the conditions of the preparation of the allylketene N,O-acetals.
,,,, ,,,,
,,.
By the exposure of an allylic alcohol to an amide acetal, a y,h-unsaturated amide is obtained. For example, 9787and 99" are produced from 95 and corresponding alcohols (equations 19 and 20). /CONMe2 OMe
I
Me-C-NMe2 I OMe
+
voH a
N I
(19)
N
I
16. Rearrangements and tautomerizations of endmines
905
In the presence of boron trifluoride catalyst, primary allylic alcohols 100 add to ynamines 101 at 30°C to afford ketene N,O-acetals 102 and the rearrangement products 103 in good yields (equation 21)85.
a-Haloenamine 104 reacts with 105 to give 106 quantitatively (equation 22)84.
0-Allylketene N,O-acetals usually rearrange with high stereoselectivity; this has been demonstrated by Sucrow and Richters9. By the ethoxy exchange of ketene N,O-acetal 108 with trans-allylic alcohols 107,O-allylketene N,O-acetal intermediates afford erythro products 109A. When cis-allylic alcohols 107 are used, thrra products 109B are obtained. These results indicate that the rearrangement proceeds via a chair-like transition state with a Z-geometry for the ketene N,O-acetal intermediates. The preference for the Z-configuration may be ascribed to the steric interaction between methyl group and a large dimethylamino substituent (Scheme 8). Sucrow and coworkers have used this procedure in the synthesis of natural product^.^" Bartlett and Hahne9' have achieved selective synthesis of the diastereomeric amides by the reaction of allylic alcohols and ynamine. When the reaction was carried out at ambient temperature in the presence of BF,, the ketene N,O-acetals have the thermodynamically favored Z-configuration. If the reaction was carried out by adding the alcohols slowly to a refluxing solution of an ynamine in xylene, the rearrangement proceeded via formation of a kinetically controlled intermediate with E-configuration. Thus alcohol 110 reacted with ynamine 111 using BF, at 25 "C to give 114 and 115 in the ratio of 1: 10. The product ratio was reversed (114/115 = 10: 1) when the reaction was conducted under conditions of kinetic control (Scheme 9). Only few investigations concerning the Claisen rearrangement of ally1 vinyl ether bearing an amino substituent on C,,,92-94, C,!)95.96 and C(6,97have been reported. While investigating catalytic aminomercuration of terminal acetylenes, Barluenga and coworker^^^.^^ have developed a facile synthesis of P-allyloxyenamines 117. These substrates readily undergo the Claisen rearrangement at a relatively low temperature to
906
Zhi-Tang Huang and Mei-Xiang Wang
trans-(107)
RHO
me2
+
MeCH=C
/
\
xylene
OEt
-
65-85% A
R
An% 9515
cis
Me Ph Me
cis
Ph
7/93
trans trans
9218 3/97
Z-
ESCHEME 8
16. Rearrangements and tautomerizations of enamines
907
give 2-aminopent-4-enals (118) almost quantitatively (equation 23). The rearrangement is highly stereoselective, proceeding through a transition state possessing a chair conformation with E-geometry of enamine and an equatorial R3 substituent.
On heating at 250 "C, enamine 120 (formed from 119 and pyrrolidine) is transformed to enamine 121 and then to 3-acetylcyclohexanone 122 after hydrolysis (equation 24). The transformation of 120 to 121 is via the Claisen rearrangement involving the enamine groupg5.
It can be seen from the examples displayed above that the Claisen rearrangement of allyl vinyl ethers with an amino substituent at C and C,z, proceeds much faster than that of allyl vinyl ether itself. Several model^^^'^)^" have been proposed in order to interpret the substituent effect on the rate of Claisen rearrangement. Both the acceleration of the rearrangements of P-allyloxyenamine and 0-allylketene N,O-acetals and deceleration of the reaction of cnamine 120 are in agreement with the prediction of the models. Cope rearrangement involving enamines has been found in the case of a-(3-buteny1)enamineslo1.Heterocyclic enamine 123 rearranges almost quantitatively to product 124, which tautomerizes rapidly to the isomer 125 at 22&245 "C (equation 25). On the other hand, only partial rearrangement of the five-membered analogue 1%-126b has been found (equation 26). The difference between 123 and 126 is attributed to the different
Zhi-Tang Huang and Mei-Xiang Wang
population of the 1,5-hexadiene isomers. Spectroscopic studies have shown that the position of the double bond (exocyclic or endocyclic) is dependent on the ring size; 1-Methyl-2-alkyl-2-pyrrolines equilibrate mainly to the 1-methyl-2-alkylidenepyrrolidines, and the ratio of 126aJ126b is approximately 1:9. However, enamines with endocyclic double bond are the exclusive isomers in the case of five-membered heterocycles. V. 3-AZA-COPE REARRANGEMENT OF N-ALLYLENAMINES
N-Alkyl-N-allyl enamines 128 (X = NR), like their carbon and oxygen counterparts 128 (X = CH,, O), can undergo [3,3]-sigmatropic rearrangement to form y,&unsaturated imines 129 (X = NR) (equation 27). This reaction has been defined as a 3-aza-Cope o r the aliphatic amino-Claisen rearrangements.
Although the Claisen-type rearrangement of N-ally1 enammonium salts had been demonstrated in 1961102.103,Hill and Gilman in 1967'04 communicated the first example of a [3,3]-sigmatropic rearrangement of N-alkyl-N-allylenamines. O n heating for one hour at 250 "C in a sealed ampule, N-allyl-N-methylisobutenylamine (130a), prepared from N-methyl-N-allylamine and isobutyraldehyde, was converted completely to N-methyl-2,2-dimethylpent-4-enimine 131b. Similarly, enamine 130b derived from a-phenylpropionaldehyde rearranged to the corresponding y,bunsaturated imine 131b at 205 "C. N-Phenyl-N-allylenamine rearranged at a lower temperature (170-175 "C). Hydrolysis of the imines gave y,6-unsaturated aldehydes 132 (equation 28).
(130) (a) R = Me ( b ) R = Ph
(131) (a) R = Me ( b ) R = Ph
'Me
(132)
16. Rearrangements and tautomerizations of enamines
909
In a later report by Hill and N e w k ~ m e ' ~N-allylenamines 134, prepared from 133, ~, are transformed to 2-butenylquinolines 135 in refluxing benzene (equation 29). The lower temperature required for the 3-aza-Cope rearrangement is due to the regain of aromaticity of the quinoline ring in the conversion of 134 to 135.
Although the 3-aza-Cope rearrangement reaction provides a useful approach to the synthesis of y,6-unsaturated imines or aldehydes upon hydrolysis and to G,&-unsaturated amines upon hydrogenation, it did not arouse any extensive synthetic interest due to the elevated temperatures required for this thermally induced [3,3]-sigmatropic rearrangement. An important paper solving this problem was published in 19781°6.Using TiCI, as a catalyst, Hill and Khatri found that the 3-aza-Cope rearrangement was effected in boiling benzene and even at room temperature, where it proceeds at a slow reaction rate. Most conveniently, the preparation and the rearrangement of N-allylenamines can be carried out in a single step, and hydrolytic workup gives the y,6-unsaturated aldehydes. Thus, aldehydes 136 react with N-allylamine 137 in the presence of 0.25 equivalent of TiCl, to afford imines 139, and aldehydes 140 upon hydrolysis (equation 30).
1""' CHO I R1-C-CH2CH=CHMe
I
R2
The 3-aza-Cope rearrangement proceeds in a concerted cyclic fashion under both catalytic and noncatalytic condition^'^^^'^^. On heating at 17G175 "C or with TiCI,, N-phenyl-N-(a-metha1lyl)-2-phenylpropenyamine(141) rearranges after hydrolysis to unsaturated aldehydes 144A and 144B formed in a roughly 9:l ratio. This result demonstrates that the rearrangements proceed via chair-like transition states 142A and
Zhi-Tang Huang and Mei-Xiang Wang
910
142B with a predominance of the former in which the methyl group is equatorial. A pericyclic reaction mechanism has been further corroborated by testing a chiral reactant 141, which gave optically active 144A and 144B with configurations in agreement with the predictions based on the steric interactions in the two transition states (Scheme 10).
(142A)
-
(143A)
+
Hydrolysis
+
+
(144A)
+ H3C
CH3
Ph
H3C 1
(144B)
ph%ph CH3
CH3
SCHEME 10
I
I. LiAIH4 2. aq. NaOH
(145) (a) R = i-Pr (b) R = %HI SCHEME 1 1
I
16. Rearrangements and tautomerizations of enamines
911
The method of using TiCI, as a catalyst has been extended to the asymmetric 3-aza-Cope rearrangement, and asymmetric induction as high as 90% for the substrate (R)-N-(a-methylbenzy1)-N-allylaminewas achieved'''. Recently, Stille and c ~ w o r k e r s ~have ~ ~ ~studied " ~ the 3-aza-Cope rearrangement in the presence of protic acids and Lewis acid reagents. N-Allylenamines 145 are synthesized in excellent yield through the route illustrated in Scheme 11. The [3,3]-sigmatropic rearrangement of enamines 145 forms imines 146,which give the corresponding amines 147 by in situ reduction with LiAIH, (equation 31). HCI and a variety of Lewis acids have been examined in the transformation of 145s and 14Sb to 146a and 146b.It has been found that 0.5 equivalent of HCI and Lewis acids, such as 0.1-0.2 equiv TiCI,, 0.5 equiv Et,0,BF3 and 1.0 equiv AIMe, are effective in accelerating the rearrangement. More acidic aluminum reagents, e.g. ClAlMe, and CI,AlMe, promote the 3-aza-Cope rearrangement at 50 "C. Remarkably, with the use of methylaluminum bis(2,6-diphenylphenoxide), the rearrangement of 145a to 146a is completed within 24 h at 25 "C, which represents a reduction in the reaction temperature of 200 "C compared with the thermal rearrangementlo4.
(a) R1 = i-Bu; R2 = H; R3 = R4 = Me (b) R' = c-C6H11CH2;RZ= H; R3 = R4 = Me (c) R1 = i-Bu; R2 = H; R3 = Ph; R4 = Me (d) R1 = i-Bu; R~ = R~ = H; R3 = Et
(e) R' = i-Bu; R2R3= -(CH2)4-. (f) R1 = i-Bu; R2R3= -(CH2),-,
R4 = H R4 = H
The rearrangement is highly dependent on both the properties and the substituent pattern of the enamines and reagents employed. By the treatment with HCI or TiCI,, enamines 145a and 145c derived from a-substituted aldehydes such as isobutyraldehyde and 2-phenylpropanal undergo the rearrangement and reduction to give amines 147a and 147c in good yields. However, the reaction of the enamine of butyraldehyde 145d leads to oligomeric products. More strikingly, the enamine of cyclohexanone 145e rearranges quantitatively with the use of HCI and TiCI,, and reduction of the intermediate imine results in the formation of amine 147e as a 9: 1 mixture of diastereomers while the enamine of cyclopentanone 145f gives low yields (3-10%) of unsaturated amine 147f.Using a stoichiometric amount of trimethylaluminum, the 3-aza-Cope rearrangement of all substrates 145a-f examined is successfully promoted, giving amines 147a-f in overall yields of 83-96% for both the rearrangement and reduction steps of the N-allylenamines (equation 31). The acceleration of the rearrangement by protic and Lewis acids (E-X) is attributed to activation by forming the enammonium complex 149, which undergoes [3,3]-. sigmatropic shift easily. These are examples of 'charge-induced' or 'charge-accelkrated' reactions (Scheme 12)108.109.Apparently, the formation of an enammonium cation is
912
Zhi-Tang Huang and Mei-Xiang Wang
necessary. The reason for the failure of 145d and 145f to rearrange in the presence of HCl is the occurrence of C-protonation rather than N-protonation of these enamines. Except for protic and Lewis acids, other electrophilic reagents can also promote the aliphatic 3-aza Cope rearrangement. In fact, the first example of a [3,3]-sigmatropic rearrangement of N-allylenammonium salt may date back to the early 1 9 6 0 ~ ' When ~~. enamine 152 reacted with crotyl bromide at 80 OC, it gave after hydrolysis 2,2,3-trimethyl4-pentenal (153) rather than 2,2-dimethyl-4-hexenal (equation 32).
That the rearrangement occurs with the enammonium salt has been confirmed by the fact that N-allyl-N-methylisobutenylamine (154), which is stable under the reaction conditions, affords aldehyde 155 by treatment with methyl tosylate followed by hydrolysis (equation 33)lo3. MeOTs acts as a promoting reagent which facilitates the rearrangement. Other electrophilic reagent^'^^-'^^ have also been employed to create a quaternary nitrogen center in order to accelerate the 3-aza-Cope rearrangement.
+ MeOTs
80 C
16. Rearrangements and tautomerizations of enamines
913
More recently, surprisingly mild conditions for the 3-aza-Cope rearrangement have been reported113. By treatment with methyl trifluoromethanesulfonate and 1,8-bis (dimethylamino)naphthalenein acetonitrile, both halogenated and nonhalogenated Nallylenamine 156 undergo the [3,3]-sigmatropic rearrangement at room temperature completely within two hours (equation 34). In addition, the reaction is highly stereoselective. All reactants yield exclusively isomers 160, with the single exception that enamine 161 derived from cc-fluorocyclohexanone gives products 162A and 162B in a ratio of 12: 1 (equation 35). Such high stereoselectivity in the rearrangement has been rationalized
X = H, Me, C1, F; RL=Me; RZ= H, Me; R I R ~ = -(CH2),-,
n = 2,3,4
as resulting from a selective deprotonation of imine salt 157 with a bulky base to form predominant N-allylenamines 158. When 1,l-dideuteriated allylimine 163 is tested, only 7,7-dideuterio-2-fluoro-6-hepten-3-one (164) is formed, suggesting that the rearrangement proceeds via a concerted mechanism (Scheme 13). The acceleration of the 3-aza-Cope rearrangement of N-allylenamines through formation of a cationic quaternary nitrogen center (enammonium salt) has obvious advantages. However. direct allvlation of enamines in order to form the enammonium ions is unsatisfactory, and h i c u l t . Moreover, the rearrangement-hydrolysis product is often contaminated by the C-allylated product when an unsymmetrical allyl halide is employed
Zhi-Tang Huang and Mei-Xiang Wang
SCHEME 13
in the allylation of the e n a m i n e ~ " ~ ~The " ~ . reactions of 165 and 167 with crotyl bromide give mainly the C-allylated products 166 and 1681169, respectively (equations 36 and 37).
d-1:
VN
+
MeCH=CHCH2Br
80 T
MeCN
16. Rearrangements and tautomerizations of enamines
915
In addition to the 'charge-accelerated' 3-aza-Cope rearrangement, another set of mild conditions for facilitating the rearrangement has been reported. N-methyl- or N-phenylN-allylenamines 170 undergo a [3,3]-sigmatropic rearrangement at 50 "C to 10O0C using 0.1 equivalent of Pd(PPh,), and 0.1 equivalent of CF,CO,H to afford the corresponding imines 171, and the carbonyl compounds 172 upon hydrolysis, in good to excellent yields (equation 38)79,s0. The rearrangement can also be achieved conveniently and with high efficiency by the direct reaction of allylamines and carbonyl compounds.
(170) (171) R' = Ph, Me; R2 = H; R3 = R4 = Me R2 = H; R3 = Ph; R4 = Me R2 = H; R3R4= -CH2CH=CHCHZCHZR2R3= -(CH2)4-; R4 = H R2R3= -(CH2)4-, R4 = Me
(172) 61-99%
The available evidence indicates a nonconcerted mechanism which is depicted in Scheme 14. Oxidation of a Pd(0) species by the carbon-nitrogen bond of the allylenammonium ion gives cleavage to the n-allylpalladium complex and an enamine. Nucleophilic reaction by the enamine on the Pd salt then forms resultant imines after a loss of a proton. The role of co-catalyst CF,CO,H is to form the N-allylenammonium ion, which reacts readily with the Pd(0) species.
SCHEME 14
916
Zhi-Tang Huang and Mei-Xiang Wang
A nonconcerted mechanism of the 3-aza-Cope rearrangement of the enammonium salts has also been proposed by Mariano and coworkers 116".b,although the chargeaccelerated rearrangements so far discussed proceed via the pericyclic route. The zwitterionic N-vinylisoquinuclidines formed from substrates 173 and a propiolate ester rearrange to fused heterocyclic compounds 174 through a stepwise pathway (Scheme 15)l16".
(174) SCHEME 15
In the presence of an acid, 175 is converted to the product 176 by a similar mechanism (Scheme 16)'16*. The rate of a Claisen rearrangement, as we know, is enhanced by introducing an electron-donating substituent such as an alkoxy group at C,,, of the allyl vinyl ethers. For the N-allylenamines, however, the acceleration effect by using the same manner is less obvious. Thermally induced [3,3]-sigmatropic rearrangements of N-allyl-N,Oacetals take place generally at 180 "C117. N-ally1 amide enolates rearrange at a somewhat reduced temperature1" with excellent yields and stereoselectivities. For example, amide enolates (177) having a chiral group at the nitrogen undergo the 3-aza-Cope rearrangement at 120-150 "C; both relatively high asymmetric induction and excellent internal
16. Rearrangements and tautomerizations of enamines
asymmetric induction have been achieved. The proportion of syn products is over 99% and the ratio of RSJSR is as high as 92:s (equation 39)'18,11'.
J
-
iq -R*
*
,, , ,
30 min
RR anh-
Based on the study of the thermal 3-aza-Cope rearrangement of N-allylketene N,O-a~etals~~', Kurth and c o w ~ r k e r s l ~ have ~ - developed ~~~ a similar methodology to the asymmetric synthesis of C(G()and C(P)-substituted-4-pentenoicacids by using a chiral auxiliary. Prepared from the alkylation of oxazolines 179 with tosylate esters 180, followed by neutralization with n-butyllithium in THF, N-allylketene N,O-acetals of 182 rearrange without isolation at 180 "C to 2-butenylisoxazolines (183) with 79-92% diastereoselectivity (d.e.). Enantiomeric excess (e.e.%) reaches as high as 98%. In
918
Zhi-Tang Huang and Mei-Xiang Wang
addition, the overall yields for this one-pot process are good, ranging from 73 to 87%. Hydrolysis of 183 furnishes Cpentenoic acids (184) with recovery of the chiron (Scheme 17).
1
A decalin
(183) 73-87% d.e. 79-92% SCHEME 17
There are several stereochemical factors, including the configuration of both the allyl derivative and enamine, the oxazoline face selectivity and the chairjboat selectivity, which play a role in the process. It is the combination of excellent face selectivity, excellent Z-enamine olefin selectivity and good chair selectivity that gives rise to the high asymmetric induction in the rearrangement1". Modifying N-allylenamines with dialkylamino substituent at C,,, causes a rateretarding effect. This is in contradiction to the Claisen rearrangement of 0-allylketene N,O-acetals and to the predictions made from theoretical considerations. The 3-azaCope rearrangement of N-allylketene aminall85 to 186 does not take place up to 280 "C (equation 40). However, substituted by an ethoxycarbonyl group at C(s,, the Nallylketene aminal 187 rearranges at room temperature to 188 (equation 41)lZ3.
16. Rearrangements and tautomerizations of enamines
VI. MISCELLANEOUS
Rearrangements of enamines which d o not fall into the classes mentioned above have been ~ e p o r t e d ' ~ " '.~Of ~ synthetic utility is the rearrangement of the enamines derived from Zacetylfuran. Distillation of 189 produces o-aminophenols 190 (equation 42)126J27.
VII. REFERENCES
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
G. Stork, R. Terrell and J. Szmuszkovicz, J. Am. Chem. Sac., 76, 2029 (1954). A. G. Cook, Enamines: Synthesis, Structure, and Reactions, Marcel Dekker, New York, 1988. P. W. Hickmott, Tetrahedron, 38, 1975 (1982). P. W. Hickmott, Tetrahedron, 38, 3363 (1982). P. W. Hickmott, Tetrahedron, 40, 2989 (1984). H. Bohme and H. G. Viehe, eds., Iminium Salts in Organic Chemislry, in Advances in Oraanic Chemistrv (Ed. E. C. Taylor), Vol. 9, Parts 1 and 2, Wiley-Interscience, New York, 19% and 1979. B. A. Shainyan and A. N. Mirskova, Russ. Chem. Rev., 48, 107 (1979) R. P. Lutz. Chem. Rev.., 84., 205 119841 E. C. ~ a ; l o r and A. ~ c ~ i l l b(~ds.), p The Chemistry of Cyclic Enaminonitriles and 0-Aminonitriles, in Advances in Organic Chemistry (Ed. E. C. Taylor), Vol. 7, Wiley-lnterscience, New York, 1970. S. Rajappa, Terrahedron, 37, 1453 (1981). J. V. Greenhill, Chem. Sac. Rev., 277 (1977). M. Pulst, D. Greif and E. Kleipeter, Z. Chem., 28, 345 (1988). B. Witkop, J. Am. Chem. Sac., 78, 2873 (1956).
16. Rearrangements a n d tautomerizations of enamines
114. 115. 116. 117. 118. 119. 120.
N. C. Yang and G. R. Lenz, Tetrahedron Lett., 4897 (1967). I. Ninomiya, T. Naito and T. Mori, J. Chem. Soc, Perkin Trans. 1, 505 (1973). R. W. Hoffmann and K. R. Eicken, Chem. Ber., 102, 2987 (1969). P. T. Izzo and A. S. Kende, Tetrahedron Lett., 5731 (1966). D. J. Anderson, A. Hassner and D. Y. Tang, J. Org. Chem., 39, 3076 (1974). E. Bertele, H. Boos, J. D. Dunitz, F. Elsinger, A. Eschenmoser, 1. Felner, H. P. Gribi, H. Gsohwend, E. F. Mever, M. Pesaro and R. Scheffold, Angew. Chem., 76, 393 (1964). M. D. Nair and S. R: Mehra, Indian J. Chem., 7, 684 (1969) R. Richter, Chem. Ber., 105, 82 (1972). G. Biichi and H. Wiiest. J. Ora. Chem.. 44. 4116 (19791. H. 0. House and F. A, k i c h e i Jr., J 0rg.'~hem.; 34, 1430 (1969). S:I. Murahashi and Y. Makabe, Tetrahedron Lett., 26, 5563 (1985). S:I. Murahashi, Y. M a k a k and K. Kunita, J. Ory. Chern., 53,4489 (1988). For recent reviews, see: Reference 8 and L. E. Overman, Angew. Chem., Int. Ed. Engl., 23, 579 (1984). A. E. Wick, D. Felix, K . Steen and A. Eschenmoser, Helu. Chim. Acta, 47, 2425 (1964). D. Felix, K. Steen, A. E. Wick and A. Eschenmoser, Helu. Chim. Acta, 52, 1030 (1969). J. Corbier, P. Cresson and P. Jelenc, C. R. Acad. Sci. Paris, 270, 1890 (1970). J. Ficini and C. Barbara, Tetrahedron Lett., 6425 (1966). 1. Ficini, Tetrahedron, 32, 1449 (1976). F E. Ziegler and G. B. Bennett, J. Am Chem Soc., 95, 7458 (1973). R. C. Costin, C. J. Morrow and H. Rapoport, J. Org. Chem., 41, 536 (1976). W. Sucrow and W. Richter, Chem. Ber., 104, 3679 (1971). W. Sucrow, P. P. Caldcira and M. Slopianala, Chem. Ber., 106, 2236 (1973). P. A. Bartlett and W. F. Hahne, J. Org. Chem., 44, 882 (1979). J. Barluenga, F. Aznar, R. Liz and M. Bayod, J. Chem. Soc., Chem. Commun., 1427 (1984). J. Barluenga, F. Aznar, R. Liz and M. Bayod, J. Org. Chem., 52, 5190 (1987). J. Barluenga, b'. Aznar, M. Hayod and J. M. Alvarez, Tetrahedron Lett., 30, 5912 (1989). B. P. Mundy and W. G . Bornmann, Tetrahedron Lett., 957 (1978). B. P. Mundy and W. G . Bornmann, Synth. Commun., 8, 227 (1978). K. A. Parker and R. W. Kosley, Jr., Tetrahedron Lett., 341 (1976). J. J, Gajewski and J. Emrani, J. Am. Chem. Soc., 106,5733 (1984) and references cited therein. C. J. Burrows and B. K. Carpenter, J Am. Chem. Soc., 103,6983, 6984 (1981). M. J. S. Dewar and E. F. Healy, J. Am. Chem. Soc., 106, 7127 (1984). 0 . Cervinka, A. Fabryova, J. Josef, V. Sermek and S. Smrckova, Collect. Czech. Chem. Commun., 48, 3407 (1983). G. Opitz, Ann. Chem., 650, 122 (1961). K. C. Brannock and R. D. Burpitt, J. Org. Chem., 26, 3576 (1961). R. K. Hill and N. W. Gilman, Tetrahedron Lett., 1421 (1967). R. K. Hill and G . R. Newkome, Tetrahedron Lett., 5059 (1968). R. K. Hill and H. N. Khatri, Tetrahedron Lett., 4337 (1978). P. D. Bailey and M. J. Harrison, Tetrahedron Lett., 30, 5431 (1989). G. R. Cook and J. R. Stille, J. Org. Chem., 56, 5578 (1991). G. R. Cook, N. S. Barta and J. R. Stille, J Org. Chem., 57, 461 (1992). P. M. McCurry, Jr. and R. K. Singh, Tetrahedron Lett., 3325 (1973). P. Houdewind and U. K. Pandit, Tetrahedron Lett., 2359 (1974). I. C. Gilbert and K. P. A. Senaratne, Tetrahedron Lett., 25, 2303 (1984). I. T. Welch, B. De Corte and N. De K i m ~ e J. Ora. Chem.. 55.4981 (1990). G . Opitz, H. Mildenberger and H. Sahr, i n n . C h e k , 649, 47 (1961). ' Reference 6, part 2, pp. 660-674. (a) P. S. Mariano, D. Dunaway-Mariano and P. L. Huesmann, J. Org. Chem.,44, 124 (1979). (b) F.-A. Kung, J.-M. Gu, S. Chao, Y. Chen and P. S. Mariano, J. Org. Chem.,48,4262 (1983). R. E. Ireland and A. K. Willard, J. Org. Chem., 39, 421 (1974). T. Tsunoda, 0 . Sasaki and S. Ito, Tetrahedron Lett., 31, 727 (1990). T. Tsunoda, M. Sakai, 0 . Sasaki, Y. Sako, Y. Hondo and S. Ito, Tetrahedron Lett., 33, 1651 (1992). M. J. Kurth,O. H. W. Decker, H. Hopeand M. D. Yanuck, J. Am. Chem. Soc., 107,443 (1985).
922
Zhi-Tang Huang and Mei-Xiang Wang
121. 122. 123. 124. 125. 126. 127.
M. J. Kurth and 0. H. W. Decker, J. Org. Chem., 50, 5769 (1985). M. J. Kurth and 0. H. W. Decker, J. Org. Chem., 51, 1377 (1986). R. Gompper and B. Kohl, Angew. Chem., Inf. Ed. Engl., 21, 198 (1982). F. H. M . Deckers, W. N. Speckamp and H. 0. Huisman, Chem. Commun., 1521 (1970). Z. Cekovic, J. Bosnjak and M. Cvekovic, Tetrahedron Lett., 21, 2675 (1980). L. Birkofer and G. Daum, Angew. Chem., 72, 707 (1960). L. Birkofer and G . Daum, Chem. Ber., 95, 183 (1962).
CHAPTER
17
Oxidation and reduction of enamines GlULlANA PITACCO and ENNlO VALENTIN
.
Dipartimento d i Scienze Chimiche. Universita degli Studi di Tiieste Via Licio Giorgieri 1.34 7 35 Triesre. Italy
I . INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 923 I1. OXIDATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 924 A. Photooxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 924 B. Autooxidation (Molecular Oxygen) . . . . . . . . . . . . . . . . . . . . . . 931 C. Ozonization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 933 D. Peroxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 935 E . Disproportionation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 942 F. Miscellaneous Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 943 G. Electrochemical Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . 953 1. Dimerization reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 954 2. Nucleophilic addition . . . . . . . . . . . . . . . . . . . . . . . . . . . . 957 3. Disproportionation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 958 111. REDUCTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 960 A. Hydrides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 960 B. Borane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 974 C . Catalytic Hydrogenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 975 D . Formic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 981 E. Amines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 983 F. Miscellaneous Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 984 IV. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 987
.
I INTRODUCTION
There are already a few reviews1. and a comprehensive book3 surveying the chemistry of enamines . This contribution aims at offering a view on the oxidation -and reduction of enamines. covering the widest possible literature on these subjects. We apologize for any unintentional omissions . The Chrmistry of Enamines . Edited by Zvi Rappoport
Copyright O 1994 John Wiley & Sons. Ltd . ISBN: 0-471-93339-2
G. Pitacco and E. Valentin 11. OXIDATIONS
A. Photooxldatlon
In the dye-sensitized photooxygenation of enamines, the carbonxarbon double bond is cleaved by singlet oxygen to give a ketone (or aldehyde) and an a ~ n i d e(Scheme ~.~ 1).
R1,R2= Me, Me; Ph, Ph; Ph, H; ZTP = Zinc tetraphenyl porphine SCHEME 1
Formation of a singlet oxygen is achieved by the use of sensitizers, which are usually dyes, and lamps whose intensity should be considered when mild conditions are needed. A proof for the formation of singlet oxygen is the decrease of the pseudo-first-order rate constant in the presence of '0, quenchers, whereas it is enhanced in CDCl, compared with CHCI,, as a consequence of a longer lifetime of the singlet oxygen. Furthermore, the rate was unaffected by radical scavengers and different sensitizer-solvent combinations gave the same products. Finally, the oxidation ceased when irradiation was stopped6. The mechanism involves attack by singlet oxygen on the carbon-carbon double bond, followed by a two-step cleavage of the 1,2-dioxetane intermediate. Formation of polar intermediates such as a 1,4-zwitterion (ZWI) has been proposed in order to account for the fact that radical inhibitors have no effect on the reaction rate, whereas the intermediates can be trapped by a l ~ o h o l s ~ ~ ~ - " . Semiempirical calculations based on analysis of the C N D 0 / 2 molecular orbital^'^,'^ indicated that the 13-ZWI is more stable than the 1,4-diradical (DR), owing to stabilization by the nitrogen. The same conclusions were obtained by M1ND0/314 as well as by I N D O RHF115 and by ab initio M O c a l ~ u l a t i o n s ~ ~ -M' ~O. calculations based on the ab inifio STO-3G and 4-31G bases and the semiempirical INDO method16 which were performed in order to evaluate the total energies of the DR and ZWI states of singlet oxygen plus substituted aminoethylenes gave a similar answer. Obviously, protic solvents highly stabilize the zwitterion intermediate by hydrogen bonding. The formation of the perepoxide intermediate (PE) has been excluded on the basis of semiempirical ~ a l c u l a t i o n s ' ~(Scheme ~'~ 2). The dioxetane intermediate was isolated independently by two groups. Foote and coworkers18 identified it with certainly and even determined its molecular weight, by
DR
ZWI SCHEME 2
PE
17. Oxidation and reduction of enamines
925
starting from enamines of linear ketones and carrying out the reaction at -78 "C, in CDCI,, with ZTP as sensitizer and using visible light. Isolation of the intermediate was also achieved from enamines of cyclic ketones. However, in this case an a-elimination involving a C-N bond cleavage was a successive steps (Scheme 3).
I
C-N bond cleavage
SCHEME 3
When the same reaction was carried out on linear enamines bearing @-hydrogenatoms it was less satisfactory. With linear enamines bearing no /$hydrogen atoms, @-elimination was no longer possible and a different route for the product formation (Scheme 4) had to he envisagedl0.
I
C-C bond cleavage
R2
X
-
+
cleavage
0
n n N-CHO + X
X
w
X = 0: R', R2, R3 =Me, H, Me; Et, H, Et; H, Et, Me; Me, i-PC,Me; H, PhCH2, Ph; Me, Ph, Me; H, Ph, Me X = CH2: R1, R2, R3 = Me, Ph, Me; H, Et, Me SCHEME 4
wNH
G. Pitacco and E. Valentin
926
A hiradical mechanism involving a DR intermediate seems preferable, especially when R ~ Ph. s The phenyl group is able to assist the oxygen-oxygen homolysis and in fact the C-N cleavage products are formed preferentially. However, formation of the dioxetane intermediate might be preceded by the formation of a peroxide intermediate, which could be trapped as an addition product with an alcohol or an amine (half-life of the peroxide (R = Me) is ca 20 min at 30 "C in CDC1,)19. As neither dioxetanes nor peroxiranes are known to react with nucleophiles, an initially formed peroxide zwitterion is probably the species intercepted by a nucleophile or competitively rearranges to a dioxetane (Scheme 5).
R = Me, Et SCHEME 5 Intermediacy of a zwitterionic peroxide was postulated also for the oxidation of 1-benzyl-3,4-dihydroisoquinolinesto the corresponding 1-benzoyl derivatives6 (Scheme 6).
X,Y = CI, NO2, OMe at positions 3', 4', 6, 7,one substituent at a time SCHEME 6
17. Oxidation and reduction of enamines
927
Of five possible mechanisms, the authors are in favour of the one proceeding through the initial rate-determining formation of a charge-transfer complex, followed by formation of a zwitterionic peroxide, prototropy and loss of water. This choice was made on the basis of the observed sign of the Hammett's p values for the substituents X and Y at the aromatic rings, as compared with the predicted effect of the substituents in each of the mechanisms considered. An interesting application to the synthesis of a-diketones, a-ketoesters and a-ketoamides, starting from ketones, esters and amides, was achieved by Wasserman and IveszO-". The method involves conversion of the starting carbonyl compound to the corresponding enamino carbonyl compound, followed by oxidative cleavage of the enamine double bond by singlet oxygen (Scheme 7).
a: X = CH2: ~ - B u O C H ( N M ~ 55-60°C ~)~, X = 0 : Me2NCH(NMe2)2, 60°C X = NR : LDA, -78°C; DMF,(Me0)2S02adduct, 50°C
7489% 78-92% 45%
SCHEME 7
In the case of lactams, the choice of the sensitizer which was Rose Bengal (v, 550 nm), with the use of a potassium dichromate filter to avoid decomposition of the products by the high-intensity UV and visible light was crucial. In the other cases BANT (Bisacenaphthenethiophene) was used. A slightly modified version of the same reaction allowed the synthesis of polyfunctionalized a-diketones from linear enamino ketonesz3 (Scheme 8).
R = Ph
7 '.
t-BuOOC
ph-
,
@
52-77.5%
H
R' = Me, i-Bu SCHEME 8
Particular cases are also reportedz4in which the enamine unit is part of more complex natural products. In that case, however, the mechanisms invoked to account for the products are quite different (Scheme 9). Singlet oxygen failed to produce cleavage of enamines bearing electron-withdrawing groupsg. In toluene heterocyclic enamines underwent photooxygenation in the usual manner to give double bond fragmentation products, whereas in methanol a n oxetanol derivative was formed as the main productz5 (Scheme 10).
G. Pitacco and E. Valentin
928
R R
R = OMe
37%
R SCHEME 9
R = Me RR = -(CH2),a
: 15% : 20%
25%
0%
23%
5%
02/Methylene blue, MeOH, 50°C 90 min 02/Methylene blue, toluene, 6 h SCHEME 10
Eosine-sensitized photooxidations have been carried out on heterocyclic N-arylenamines, resulting in the formation of the corresponding carbonyl compounds". With the analogous quinoline derivatives, oxidation at the /3-carbon atom was also observed (Scheme 11).
17. Oxidation and reduction of enamines
R2
~1
Oz/hv/25WW i-PrOH. 4 h, eosine
R1 = Me, (CH2)f2H0
=Me, RZ= H; R1R2= -(CH2)3-
13%.
21%
Photooxygenation of enamines by singlet oxygen has been proved to be particularly useful for the synthesis of natural products, for which mild reaction conditions must be usedz6. An example is given in Scheme 12.
25°C 18 h, Rose Bengal
62%
SCHEME 12
Similarly Masamune and coworkersz7 succeeded in preparation of a$- and p,yunsaturated ketones in the steroid series, by photooxygenation under irradiation with a fluorescent lamp (Scheme 13).
r
J
Odhu
. -
C6H6.1.1.. 7.5 h,
AcO
Rose Bengal
H
24% SCHEME 13
930
G. Pitacco and E. Valentin
In the second reaction a product of D ring contraction was also formed in 19% yield. When the solvent was benzene, the yield of this undesired product increased to 50%, thus demonstrating a solvent dependence of the oxidation reaction. Dehydrogenation of heterocyclic enamino diketones of the azasteroid series was also effected by means of oxygenz8 (Scheme 14).
6@80%
R1,R2 = H, H; H, Me; OMe, Me S C H E M E 14
Photooxygenations in the presence of Cu(1) were also applied with good yields in the chemistry of natural products. Under mild conditions a pyrrolidino dienamine derived from bile acids underwent cleavage at the y,S-double bond to give the corresponding 5P-pregnan-20-onez9 (Scheme 15).
S C H E M E 15
Similarly, application to the chemistry of isoquinoline alkaloids allowed the preparation of a 1-isoquinolone derivative in good yield from the corresponding enamine3' (Scheme 16).
17. Oxidation and reduction of enamines
An example is reported of photochemical insertion of oxygen into silylenamines, leading to silylperoxides3' (Scheme 17). R
Me-C=CH-N I Me
/
'
\
SiMe3
Ozlhv
Me
I I
Me3SiOO-C-CH=NR1 porphyrins
Me
R' =Me, Et, Me2CHCH2 SCHEME 17
B. Autooxidation (Molecular Oxygen)
Molecular oxygen reacted with enamines of cyclic ketones bearing a j-hydrogen atom, furnishing the corresponding or-amino k e t o n e P (Scheme 18). A similar reactivity was observed for piperidino enamines of linear ketones which gave or-amino ketones, derived by rearrangement of the epoxide intermediates, and products of carbon-carbon double-bond oxidative cleavage33. An oxidation
SCHEME 18
G. Pitacco and E. Valentin
SCHEME 19
In contrast, oximino enamines were obtained by a concurrent action of oxygen and nitrogen m o n o o ~ i d eas~ shown ~ in Scheme 20 for N-morpholinocyclohexene.
0 ("I
NO/Oz
hexane, 20°C. 3 h
0
-
("I 0
SCHEME 20
Chlorides and bromides of both oxidation states of copper, as well as cuprous cyanide, are active in promoting the oxidative cleavage of the enamine double bond (Scheme 21).
SCHEME 21
17. Oxidation and reduction of enamines
933
The reactions are clean and quantitative, particularly when the P-carbon atom is fully s ~ b s t i t u t e d Substances ~~. which may compete with oxygen for coordination with the copper inhibited the oxygenation. Radical scavengers had no effect on the reaction, neither had the presence or absence of light, thus excluding photogeneration of singlet oxygen. In the same manner bicyclic fully conjugated dienamines underwent autooxidation in air giving mainly the 6-keto products. Addition of a catalytic amount of cupric salts (as well as ferric salts) enhanced the oxidation rate and increased the yields37(Scheme 22).
SCHEME 22
The action of cupric halides on enamines has been extensively studied by Kaneda and coworkers38.A strong dependence of the product distribution on the type of substituent at the enamine P-carbon atom has been observed. Enamines with no P-vinylic hydrogen gave exclusively double-bond cleavage products, whereas enamines bearing a P-hydrogen afforded only non-cleavage products. This result is in favour of the existence of a common intermediate, identified as a 1,2-dioxetane derivative. Participation of singlet oxygen, however, could be ruled out since the reaction is unaffected by the presence of quenchers of singlet molecular oxygen. ESR spectra suggested that CuX, (no halide effect was observed) could act as a one-electron acceptor from enamines. These facts, together with the observations that the oxidation rates are correlated with the ionization potentials of the enamines and dependent on the oxygen pressure, induced the authors to postulate the reaction mechanism presented in Scheme 23. In this scheme the reaction of Cu(I1) with enamines gives an enamine-copper complex which is successively attacked by molecular oxygen to form a ternary copper-enamine-oxygen complex in which the transfer of one electron from enamine to oxygen takes place, followed by formation of Cu(l1) and a dioxetane intermediate.
C. Ozonization
Ozonization is a widely applicable method for scission of carbon-carbon double bonds.
G. Pitacco and E. Valentin
enamine -copper complex
ternary complex
t oxygenation products SCHEME 23
In fact steroidal enamines react with a mixture of ozone and oxygen to give the corresponding expected ketones, progesterone in the example of Scheme 243'.
7&84% SCHEME 24
In the same manner ozonolysis of enamides leads to the corresponding products of double-bond fission4' (Scheme 25).
17. Oxidation and reduction of enamines
CH2C12
0 I
I
COMe
COMe n = M , 10 R = Ph, p-MeC6H4 SCHEME 25
On the contrary, linear enamines having the E configuration and carbocyclic enamines underwent oxidation by ozone without fragmentation of the double bond4' (Scheme 26).
x"'
R1
H
03
0
CH2C12,py. -70°C
0
OH 3040%
Rl,R2 = Et, Me; i-Pr, Et; RlR2 = -(CH2)3-,
-(CH2)4-
SCHEME 26
D. Peroxidation
Peracids attack the carbon-carbon double bond to give the corresponding epoxides which, however, are not isolated in most cases. The epoxide is attacked by a second mole of peracid to give a perester intermediate, which undergoes fragmentation to two carbonyl derivatives (Scheme 27, route a). With secondary enamines, fission of the epoxide ring may be induced by the base itself (route b)42; the imine group can be further oxidized to an oxaziridine intermediate which then undergoes nucleophilic ring fission with fragmentation (route c ) ~ ~ . Enamines are oxidized by peracids to yield, after hydrolysis, the corresponding a-hydroxy ketones, as shown in Scheme 28 for a steroidal e t ~ a m i n e ~ ~ . An analogous reaction carried out on a heterocyclic enamide showed a more complex feature4'. In addition to the usual fragmentation a ring enlargement product was obtained (Scheme 29).
936
G. Pitacco and E. Valentin
SCHEME 27
30-50%
R = Ph, CHzPh SCHEME 28
Treatment of heterocyclic enamides with peracids resulted in the oxidative fission of the double bond, followed by Baeyer-Villiger reaction of the methoxylated benzaldehyde intermediate45 (Scheme 30). The peracid must be used in excess, as in another example (Scheme 31). When methanol was used as cosolvent to the methylene chloride the reaction took a different course, giving a product in which a regiospecific incorporation of methanol had occurred46 (Scheme 31).
17. Oxidation and reduction of enamines
1
n=1,2 AKOOOH = MCPBA R,R1 = H, H; H, Me; OMe, Me
ArComH
0
R
SCHEME 29
A particularly complicated reaction is reported to o ~ c u r ~with ~ . ~a steroidal ' enamine. Formation of the products can be explained in terms of the intermediacy of a n oxaziridinium salt. Perbenzoic acid oxidation followed by pyrolysis allowed the transformation of 1-acetyl-3-(S)-methyl-1,2,3,4-tetrahydropyridineinto the corresponding P - k e t ~ a m i n e ~ ~ (Scheme 32).
G. Pitacco and E. Valentin
938
SCHEME 30
ZMCPBA CH2Cll
MCPBA
l
0
o C
H
C
H
Mg
SCHEME 31
cH3
'0
2. 1. PBA pyrolysis
- cH3T)"0
NI SCHEME 32
NI
17. Oxidation and reduction of enamines
939
A regioselective peroxidation by m-chloroperbenzoic acid was accomplished during the multistep synthesis of alkaloids of pentacyclic Aspidosperma skeleton. By operating at low temperature, oxidation of the enamine double bond was effected more rapidly than that of the sulphoxide group and the epoxide intermediate was isolated49 (Scheme 33).
1 : 1 diastereoisomer mixture SCHEME 33
Acyloxylation reactions have been performed on a secondary enamine of dimedone with a series of diacyl peroxides. The isolated monoadducts could undergo further acyloxylation to yield products of acyl rearrangements0 (Scheme 34).
I
R NH R1 = c-C6HII 'R2 = Ph, 4-C1C6H4,4-N02C6H4 bR2= OEt, OCH2Ph SCHEME 34
Oxybenzoylation of enamines of cyclic ketones by benzoyl peroxide was performed in the early six tie^^'.^'. The corresponding 2-benzoyloxycycloalkanones were formed (Scheme 35). The asymmetric variant of a-oxybenzoylation makes use of lithioenamines. Lithioenamines formed with P-ketoesters and (S)-valine t-butyl ester were in fact easily oxidized with benzoyl peroxides3 with high enantioselectivity (78-92% e.e.) to give, after hydrolysis, the corresponding protected tertiary a-ketols having (R) configuration (Scheme 36). Cyclic, fully conjugated enaminones underwent mono- and bis-oxyacylation by diar o y l p e r ~ x i d e s(Scheme ~~ 37).
G. Pitacco and E. Valentin
I . (PhC00)2, dioxane, 50-70°C 3 h
("I
2. H20, reflux 12 h
Ph
0
X
25-30%
n=O,1; X = 0 , C H 2 SCHEME 35
HN
I. LDA. THF, -78°C 1 h 2. (PhC00)2, 72 h 3. 2NHCI
C02Me
OH*OcOph
* R1
&OzMe
R2
'Q"
OCOAr
I
("I X
(M00)2 McCN, 5&60"C 12-15 h
("I X
("I X
SCHEME 37
Arylsulphonyl peroxides were also efficient in the oxyacylation of a variety of linear and cyclic enamines, leading to a-arylsulphonoxy ketones (a-nosyl ketones), after h y d r ~ l y s i s (Scheme ~ ~ . ~ ~ 38). The latter products could be easily converted quantitatively either into the corresponding a-hydroxy ketones, by treatment with methanolic potassium carbonate and acidic workup, or into a-amino ketones, by treatment with a secondary base. Dimethyl dioxirane (DMD) also performs epoxidation of enamines. Since the epoxide intermediate is unstable, it dimerizes to give 1,4-dioxane derivative^^^. It can, however, be trapped by methanol at - 70 "C (Scheme 39). In their reaction with 3.3-dibenzyl dioxetanes, enamines of linear and cyclic ketones yielded, after hydrolysis, the corresponding P-keto-8'-hydroxy ethers5' (Scheme 40).
17. Oxidation and reduction of enamines
SCHEME 38
R = i-Pr, i-Bu; RR = -(CH2).+-, R1 = Me
-(CH2)5-,
-(CH&O--
SCHEME 39
c-1 HR3
R1
+
R2 CHzCh, -20°C
-,0°C
0.5 -t 3 h
1 N HCI
4 0 ~30rnin,
ho&;
R1
R2 R~
0-0
3864%
Ph R 1 = P h , R2=Me, R 3 = H , X = O R1 = Ph, R2R3= -(CH2)5-. X = CH2 R1R2= -(CH2)P, R3 = H, X = 0 SCHEME 40
G. Pitacco and E. Valentin
942
The reactions proceeded regioselectively, the less hindered oxygen being the site of nucleophilic attack by the enamine. With the morpholino enaminone derived from dimedone the oxidized enamine adduct shown in Scheme 41 could be isolated.
SCHEME 4 1
E. Disproportionation
A disproportionation reaction was proposed to occur when 4-substituted cyclohexanones are heated in hexamethylphosphoramide in order to account for the tricyclic products formed (R = H)59 (Scheme 42).
+ -+ -4.";) 215-220°C. HMn 40 min
0
215-220°C. 4 hr
NMe2
R = H, Me, i-Pr, t-Bu SCHEME 42
NMe2
Me'3I?$'*
17. Oxidation and reduction of enamines
943
A hydrogen transfer reaction takes place on heating N-morpholinocyclohexene in dioxane in the presence of 10% Pd. N-Cyclohexylmorpholine and N-phenylmorpholine are obtained in a 2: 1 ratio60 (Scheme 43).
0
10% Pd dioxane
("I 0
SCHEME 43
F. Miscellaneous Reactions
Potassium permanganate oxidizes a heterocyclic compound, acetoneberberine, containing an enamine-type subunith1 (Scheme 44). Different products were obtained, however, when the enamine P-carbon had a methyl group. Formation of enaminoesters from acetylated 1- and 2-amino sugars (N-Gluco- and N-Galacto-pyranosylamines)and successive oxidation by KMn0,-NaIO, allowed the
OMe
RO
i;
HoJ
+-
OMe
HO \
RO HO
OMe
R = Me; RR = -CHT SCHEME 44
OMe
944
G. Pitacco and E. Valentin
isolation of a-hydroxyamides, in particular when the enamine P-carbon was disubstituted (Scheme 45). Enaminoketones of the same sugars furnished N-formyl and N-acyl amino sugars6'.
SCHEME 45
Progesterone was synthesized from ergosterol through many steps including the oxidation of an enamine intermediate, which was effected in a sodium dichromatebenzene-acetic acid stern^^."^ (Scheme 46). The same system was also used for other steroid e n a m i n e ~ Yields ~ ~ . were usually high (>75%).
SCHEME 46
On the contrary, the pyridinium chlorochromate-iodine system which is a very effective oxidant of silylenol ethers failed with enamineP. When treated with lead tetraacetate (LTA) enamines (and also imines capable of imine%namine tautomerism) underwent either a- or p-elimination, depending on the nature of the substrate, furnishing 2-acetoxy ketones and 2-amino ketones as final products6' (Scheme 47). Oxidation promoted by LTA of dimethyl anilinofumarate led to the formation of an N-phenylpyrrole tetraester6', through the mechanism given in Scheme 48. Indeed, the 2-phenylamino intermediate was successively isolated by Vernon and
coworker^^^. A series of N-alkylamino fumarates have been oxidized by LTA in the presence of trifluoroacetic acid as a catalyst, leading to mixtures of pyrroles, pyridones and pyrrolo [3,2-blpyrroles given in Scheme 49". In some cases acyclic oxidative dimers were isolated. The enamine molecules in them are linked through their P-carbon atoms (Scheme 49). Similarly, B-aminocrotonates of Z configuration afforded the corresponding pyrroles7'. In contrast, with 8-aminocinnamates (R' = Ph) the yields of the corresponding
17. Oxidation and reduction of enamines
R,R1 = Ph, Me R,R1 = Ph, Ph RR1 = -(CH2)3-
945
: 48% : 43% : 10%
R,R1 = Ph, H; Ph, Me; Ph, Ph;
1
R = P ~ R~ =
R,R1 = Ph, Me R,RI = ~ h~h , RR1 = -(CH2)3-
: 38%
: 47% : 49%
OAc
R
PhN
N N
I I Ph Ph
R = COOMe
N
R
I
Ph SCHEME 48
-F'hNH2
R ~R
I Ph
NHPh
G. Pitacco and E. Valentin
E = C02Me R = Me, Et, i-Pr, c-C6Hllr Ph
E = C02Me R = Me, Et, i-Pr, c-C6HIl
E = C02Me R = Me, Et
SCHEME 49
pyrroles were very low, probably due to steric hindrance. The mechanism (Scheme 50) is likely to involve a two-electron oxidation of the enamine. Et02C LTA CH2CI2.r.1.. 3-7 h
R
C02Et
XR1 NI
R1
R 2 0 4 0 % (R1 = Me) 10-20% (R1 = Ph)
HxC02Et
-
H I ,
b RI
NR
I
RI
t t EtOzC COzEt
NHR
AHR
R1
NI R1 R
C~b(~~c)3
R = Me, i-Bu, CHzPh, C-C7H13.4-ClC6H4; R1 = Me R = Me, i-Pr, CH2Ph, 4-CIC6H4; R1 = Ph SCHEME 50
17. Oxidation and reduction of enamines
947
A version of this type of oxidation, which used a combination of lead tetraacetate and boron trifluoride etherate, allowed the transformation of enamines of cyclic ketones into esters of the corresponding contracted ring, as in the classical Favorskii rearrangement of u-haloketones under basic condition^^^ (Scheme 51). P~(OAC)~-BF~.E~~O EIOH, C6H6.1.t.. 30 min
I
I C02Et
NR2
n=l,2
72-78% SCHEME 5 1
Oxidation of tertiary amines PhNR, (R = Et, Bu, Pent, Hex) by LTA in a 1:2 ratio involved the initial formation of an enamine which was further oxidized to a diacetoxy deri~ative~~. A particular use of aryllead triacetate is reportedT4by which cycloalkanone enamines are arylated at the b-carbon atom, giving sometimes acetoxylated compounds as by-products, by a mechanism analogous to that proposed for thallium t r i a ~ e t a t e ~ ~ . Oxidation of enamines derived from cyclic and acyclic ketones with thallium triacetate in equivalent amount leads to the formation of the corresponding 2-acetoxy ketonesj5 (Scheme 52). The reactions are stereoselective (the antiparallel attack of the oxidizing agent is preferred over a parallel attack on 3- and 4-t-butylcyclohexanone enamines) and the attack occurs preferentially at the tetrasubstituted enamine double bond, when there is more than one possibility due to isomerism.
In fact, treatment of cycloalkanone enamines with thallium triacetate, followed by rapid treatment with sodium hydroxide afforded trans-a-acetoxy enamines (R f H) from which either the corresponding 2-acetoxycycloalkanones or 1-acetoxy-2-cycloalkenes can be obtained, under suitable conditions76 (Scheme 53). Oxidative dimerization of Fischer base (1,3,3-trimethylmethyleneindolenine)is reported77 to occur by means of potassium nitroso disulphonate (Scheme 54). Oxaziridines are highly strained and are therefore susceptible of attack by nucleophiles, particularly when the nitrogen atom is sulphonated. The use of N-sulphonyl oxaziridine allowed the isolation of either cc-hydroxy ketones, when the enamine was trisubstituted, or of cc-amino ketones, when the enamine was d i s u b s t i t ~ t e d(Scheme ~~ 55).
G. Pitacco and E. Valentin
948
AcOH
52-100%
R = H, Me, t-Bu
AcO
SCHEME 5 3
~e two isomers SCHEME 54
-
I NSOA. CDC13R%MeOH
NSOA, THF/2% MeOH
R3=H
R3 H
OH 0
5246%
75-79%
R1=Ph, R 2 = R 3 = M e R1R2= -CH2C6H4CH2-,
R1 = Ph, R2 = Me, Ph R'R2 = -(CH2)r
R3 = Me
0.
NSOA = C N - S O ~ A I SCHEME 55
Addition of 2% MeOH as cosolvent resulted in improved yields. The use of the optically active (camphorylsulphonyl)oxaziridine did not afford enantioselectivity. A possible explanation for this lack of stereocontrol lies in the mechanism proposed (Scheme 56). It involves formation of an cc-amino epoxide, its nucleophilic ring opening and either loss of a proton (route a) or hydrolysis (route b) (Scheme 56).
17. Oxidation and reduction of enamines
949
SCHEME 56
Enaminoketones are readily oxidized in aqueous solution by Ag(1) or Ce(1V) salts7'. The major product obtained is a dimer which incorporated an oxygen atom (Scheme 57). The mechanism proposed involves a radical-cation intermediate.
o."."
*
Ag(Il;2y
N
fi N
I R
I R
O
N
I R
30%
R = H, Me; X = OEt, Me, NH2 SCHEME 57
Ce(IV) is preferred over Ag(1) because the products can be isolated more easily from the reaction mixture. Non-conjugated dienediamines were oxidized by silver nitrate in acetonitrile to give diamidinium salts (isolated as hexafluorophosphate salts), as a result of a coupling reaction between two radical c a t i ~ n s (Scheme ~ ~ . ~ ~58).
2AgN03, MeCN
-
950
G. Pitacco and E. Valentin
The same type of dimerization was observed for simpler endiaminess2 (Scheme 59) although with CBr, (ether, -50 "C, 2 h), yields were much better (69-96%). With enamines, tetrabromomethane forms stable crystalline pentabromo carbonatess3.
NR2 = NMe2, 1-piperidinyl
13,21% isolated as 2C10i SCHEME 59
An analogous one-electron oxidative dimerization was observed by Hiinig and LinhartS4 for the Fischer base, by means of potassium ferricyanide (Scheme 60).
SCHEME 60
In the presence of sodium carbonate, the reaction followed a different course, furnishing an oxidized dimer in which a ring enlargement had occurred (Scheme 61).
SCHEME 61
95 1
17. Oxidation and reduction of enamines
A head-to-head cyclodimerization of N-vinyl carbazole by means of ferric or cerium(1V) salts takes place in the presence of 2,2'-bipyridyl in methanol, through the corresponding enamine radical-cation intermediates5 (Scheme 62). Fe+' or CeA 2.2'-bipyndyl. MeOH
I
SCHEME 62
Oxidative cleavage of an enamine double bond by RuO, (prepared from R u 0 2 and NaIO,) was first accomplished successfully by Desai and coworkerss6 in the steroids series (Scheme 63).
71% SCHEME 63
Tr = Trityl
Oxidation performed with potassium dichromate gives similar results. Oxidation with ruthenium tetroxide was also used on N-acyl and N-ethoxycarbonyl heterocyclic enamines8' (Scheme 64).
RuOdCCI4-H20 r.l., I0 h
I
0 I COMe
COMe SCHEME 64
91%
952
G. Pitacco and E. Valentin
Osmium tetroxide oxidizes olefins as well as enamines, furnishing the corresponding diol derivatives, as shown in an example (Scheme 65) concerning a Vinca alkaloid analogue88.
SCHEME 65 Nitric acid oxidation of enamines produces fission of the C-C double bond in preference over fission of the C-N bond and this preference increases on increasing the concentration of NO,, which was shown to be the reactive speciese9 (Scheme 66). Bu2N-CH=CH-Et
63%HNO,, Ac20 50°C. 30min
-
Bu2N-CHO 47%
+
Bu2N-NO 1.5%
+ MeCONBu2 21%
SCHEME 66 1,2-Diaminoethylenes were converted into a-diiminium salts by treatment with benzoquinone, instead of giving the usual cycloaddition productsg0 (Scheme 67).
SCHEME 67 Biochemical oxidation of a tertiary amine has been shown to proceed through the intermediacy of a heterocyclic enamine, formed upon two-electron oxidation at the level of microsomes9' (Scheme 68).
17. Oxidation and reduction of enamines
0
microsomes
30 min
NI
9 1 nmol
*021"J +N I
35 nmol
30 nmol
NI
1800 nmol
SCHEME 68
G. Electrochemical Oxidation
Both cyclic and acyclic enamines are oxidized very easily, at potentials smaller than that of N,N-dimethylaniline ( + 0.7 V os SCE). The ease of oxidation is affected by many factors, such as the length of the n system, the degree and nature of substitution at the enamine function (alkyl groups lower the potentials considerably, aryl group much less) and the steric interactions. Mainly, however, it depends on the number of amino groups linked to the double bondg2, and then on the electron-donating power of the aminocomponent. Pyrrolidino enamines are oxidized more easily than piperidino and morpholino ones93. The yields also depend on the oxidation potential, since they decrease with increasing ease of electrolytic oxidation93. Electrooxidation involves an initial step in which one electron is transferred to the anode from the N-C=C moiety with formation of a radical cation94. The occurrence of this step was confirmed by ESR studies, exhaustive c.p. voltammetry and cyclic polarograms. Compounds in which large delocalization is possible, and hence are capable of stabilizing two positive charges, exhibit two one-electron processes at relatively low potentials which may be reversible95 and i r r e ~ e r s i b l e Mono~ ~ . and dications are stable in the absence of oxygen and water. Formation of the radical cation is usually a reversible process and it is followed by an irreversible reaction (EC mechanism). The fate of the cation depends on the substrate and the conditions. The possible reactions it may undergo are (1) dimerization, which occurs at the /?-carbon atom, (2) nucleophilic addition of either the solvent or a stronger nucleophile, which again occurs at the /?-carbon, and (3) disproportionation.
G. Pitacco and E. Valentin
954 1. Dimerization reactions
Secondary enaminones and enaminoesters are dimerized at the anode to symmetrically substituted 3,4-diacylpyrroles, thus indicating that dimerization proceeds by combination of two radicals9'j (Scheme 69). H
R'OC -(C)
H
t
MeOH. NaCIO,
Me
Me
I
NH
I
R
Me
R
N NH I I R R
R = H, Me, CH2Ph,Ph R' = OMe, Me
RIOC
R'OC -RNHZ
Me
I
R
I
R
1245% SCHEME 69
Two successive anodic oxidations, the first one of the enaminone moiety and the second one of the aryl group, allowed intramolecular cyclization to occur in N-benzyl and N-P-phenethyl enaminones with formation of isoquinolines and benzazepines, respectively9' (Scheme 70).
SCHEME 70
17. Oxidation and reduction of enamines
955
Analogous behaviour was observed for the enamines derived from cyclopentanedione and methyl acetoacetate. An application of oxidative coupling of enamines to the synthesis of bichromones is also reported9' (Scheme 7 1).
R = H, OMe SCHEME 71
Kinetic data show that the intramolecular cyclization occurs before dimerization, in accordance with the mechanism shown above. An elegant work99 is reported concerning the oxidation of 2-alkyl and 2-benzylthiazolium salts, in the presence of a base, with the scope of finding a structural relationship for the thiamine-bound intermediate which intervene in the oxidative decarboxylation of a-ketoacids catalysed by thiamin diphosphate-dependent enzymes. 2-Alkyl and 2-benzylthiazolium salts, which are not electroactive, can be transformed into electroactive species by treatment with the base (trimethylsily1)amide. Subsequent anodic oxidation affords the corresponding symmetrical dimers, by an EC mechanism (Scheme 72). As expected, the stabilizing effect of the substituents RL,RZ at the a-carbon on the radical cation follows the order H < Me < OMe. When RZ is aryl, electron-donating p-substituents again enhance the enamine oxidation. An analogous reaction had already been observed for the benzothiazolium salts of the dicarbocyanine dye series, with the difference that the dimerization was reversible and an equilibrium was established with the monomers in acetonitrile solutionLo0 (Scheme 73). An oxidative dimerization product of (2-cyano-2-phenylvinyl)dimethylamine, in which coupling occurred between the p-carbon atom of one monomer and the p-position of the phenyl ring in another monomer is also reportedL0'(Scheme 74).
956
G. Pitacco and E. Valentin
RL,R2= H, H; H, Me; Me, Me; OMe, Me; H, Ph; o-pyranyl, ph; OMe, ph R1 = MeO, R2 = 4-XCsH4 (X = CF3, Br, CH3, OMe) SCHEME 72
SCHEME 73
17. Oxidation and reduction of enamines
Ph-C=CH-NMe2 I CN
-e(C) MeCN-NaC104, 1Fmol-I
-
957
CHO P h - I& o C= C H -I N M e 2 CN CN
SCHEME 74
2. Nucleophilic addition Cyclopentanone and cyclohexanone morpholino enamines underwent oxidation in methanol-sodium methoxide solution to yield 2-methoxycycloalkanones (Scheme 75). The enamine intermediates were also identifiedLoz.
SCHEME 75
80%
Particular cyclic enaminoesters derived from proline underwent a two-electron oxidation process, with loss of carbon dioxideLo3(Scheme 76).
SCHEME 76
G. Pitacco and E. Valentin
958
Electrolyses of a series of enamines have been carried out in the presence of carbanions generated from dimethyl malonate (DM), methyl acetoacetate (MA) and acetylacetone (AA)93(Scheme 77). In each case the corresponding enamine, alkylated at the P-position, was obtained.
X = 0 ; R',R2 = Me, Me; RlR2 = -(CH2)2-. -(CH2)3X = - ; R'RZ = -(CH2)2-, -(CH2)3R3 = R4 = C02Me, COMe R3,R4= C02Me, COMe SCHEME 77
15-70%
Secondary and tertiary triphenylated enamines underwent two-electron oxidation with formation of indole derivatives, by intramolecular cyclization through an ECEC mechanism'04 (Scheme 78). Ph -e(W
t
MeCN-LiC104, 26-lutidine R = H: 2.2 Fmol-' R = Me: 4.3Fmo1r1
SCHEME 78
Similarly, endiamines in E/Z configuration afforded an indole oxazolidine as a major product, after intervention of water (Scheme 79). Enaminoethers and enaminonitriles furnished dimers, and the latter also trimers. Ph \
Ar Ar
N
NMePh * ArxNPh
-2e(Pt) MeCN-LiC104, 4Fam-'
0
PhMeN
Ar
+
\
N\
AI
SCHEME 79
3. Disproportionation
cis-1-(4-Morpholiny1)-1,2-diphenylethene underwent anodic oxidation in a r-butanolwater system, with lithium perchlorate as supporting electrolyte. The products formed
17. Oxidation and reduction of enamines
959
were the result of a disproportionation reaction between two radical cations, followed by either addition of water or further o ~ i d a t i o n ' "(Scheme ~ 80). The mechanism was supported by experiments carried out on the deuteriated enamine.
SCHEME 80
Electrooxidations can also make use of m e d i a t ~ r s ' " ~In . this case they proceed at lower potentials and need milder conditionslo7. Enarnines derived from aldehydes and bearing a P-hydrogen atom were oxidized, using KI as a mediator, into the corresponding P-keto amines. In the mechanism proposed, an unknown active species, 'I' is assumed to be formed by oxidation of I - and to add to the double bond. The resulting iodohydrin cyclized into an a-amino epoxide and subsequently is ring opened into a P-ketoamine, by a 1,2-hydrogen shift (Scheme 81). !(OH) -el 'I' I R-CH=CH-NRIR~ R-CH-CH-NR~R~ (KI,H20-t-BuOH)
-
I
OWI)
17-60% R = Me(CH2)d-, Me2C=CH-(CH2)2-CH(Me)~, Rl,R2 = Me, Me; Bu, Bu; R1R2= P ( C H ~ ) -(CH&-, SCHEME 8 1
-(CH2)20--
G. Pitacco and E. Valentin Ill. REDUCTIONS A. Hydrides
The enamine group itself is resistant to reduction. However, rapid and reversible protonation of the /3-carbon atom generates a readily reducible iminium salttos (Scheme 82).
SCHEME 82
In fact, the morpholino enamine of cyclohexanone is not reduced by hydride reagents, whereas the enamine hydrochloride is easily and quantitatively reduced within 15 minutes. If the enamine is conjugated with the carbonyl group, reduction becomes more difficult and the pH must be decreased to 4. Enamines from /3-diketones are resistant to reduction. Reductive amination of aldehydes and ketones can also be accomplished in that way provided the pH is 6-8. 3- and Csubstituted cyclohexanone enamines have been reduced with several hydride reagentstog in order to establish the stereoselectivity of the reaction. Acidic medium is necessary to generate the iminium ion intermediate, which has been demonstrated to be the reactive species. Essential also is the sequence of addition of the reactants. The hydride reagent must be initially stirred with AcOH for sufficient time in order to ensure formation of the corresponding acetoxy borane hydride reagent and then the substrate is a d d e d t t o . t l (Scheme 83).
R = 4-I-Bu, 4-Me, 3-Me R'R2 = -(CH2)4-, -(CHZ)~SCHEME 83
Under these conditions the stereoselectivity is higher, as the attack of the reagent occurs equatorially, leading to axial amjnes (72-92%). A comparison with the results of reduction of 4-t-butylcyclohexanone shows a complete inversion of stereoselectivity (1627% of equatorial attack). Reductions of 2-alkylcyclohexanone enamines also proceed with high stereoselectivity, leading predominantly to the cis amines in the six-membered ring derivatives (6696%), and almost exclusively in the case of the five-membered enamines (95-98%) (Scheme 84). The At.3 strain1lZin fact would shift the conformational equilibrium towards the axial (or pseudoaxial) orientation of the substituent.
17. Oxidation and reduction of enamines
SCHEME 84
Equatorial attack on equatorial 2-alkyl conformers and axial attack on axial 2-alkyl conformers would eventually lead to the cis products. Steroidal dienamines of the conessine and cholestane series have been regio- and stereoselectively reduced by NaBH,, in the presence of acetic acid, on the u,P-double bond to give the corresponding 3P-amino d e r i ~ a t i v e " ~ . "(Scheme ~ 85).
44%
R = Me, RR = -(CH2)4SCHEME 85
Selective reduction of amino dienes, which may exist as various isomers, can be performed with NaBH,, as only the P,y-unsaturated amines were obtained1'* (Scheme 86). Other reducing agents were less selective.
HNR2 = N-methylpiperazine, N-phenylpiperazine, morpholine, pipendine SCHEME 86
G . Pitacco and E. Valentin
962
Of the three isomers of 1-methyl-3-cyanodihydropyridines only the 1,2-isomer underwent rapid and quantitative reduction by NaBH, in the presence of trimeth~xyborane"~ (Scheme 87). The role of BH, in generating the protonating species, in contrast to the was clearly evident. direct protonation by water suggested by other
SCHEME 87
Zinc-modified cyanoborohydride (the exact nature of the reagent is not clear), generated from Na(CN)BH, and zinc chloride in a 2: 1 ratio, is a selective reducing agent. In methanol, reduction of tertiary enamines proceeded smoothly and the corresponding amines could be isolated in good yie1ds""Scheme 88).
("I
Zn(ll) cyanobarohydride
MeOH, 1.1.. 1 h, pH 5
X
X = 0, CH2, n = 1,2
X
73-90% SCHEME 8 8
The reduction of enamine unit occurs much more rapidly than that of the carbonyl group. Therefore, this reagent can be used to perform reductive amination of aldehydes and ketones, by simply reacting the carbonyl compound with a fourfold excess of the amine. In a similar manner, reductive methylation of amines could be accomplished by addition of formaldehyde to the amine119. Secondary enamino sulphoxides were reduced through their imino forms, with L-selectride [lithium tri(s-buty1)borohydridel to give P-aminosulphoxides of R*,R* configuration with high s t e r e o s e l e ~ t i v i t y(Scheme ~~~ 89).
R =Me, R 1 = CH2Ph, (CH&OH SCHEME 8 9
Cyclic chiral 8-sulphinyl enamines have been reduced by a number of hydride reducing agents [Na(CN)BH,/AcOH, Na(CN)BH,/ZnC12, MeOH, Zn(BH,),/THF, NaBHJ MeOH]lZ1. Of these reagents, sodium borohydride in methanol afforded the best yield and selectivity. Four diastereoisomers were separated in a 4:4: 1: 1 ratio12' (Scheme 90).
17. Oxidation and reduction of enamines
963
81% SCHEME 90
In contrast, reduction of the corresponding enamide with Na(CN)BH, was much more selective giving a single enantiomer, derived by attack of the hydride from the opposite side of the bulky sulphinyl grouplZ2(Scheme 91).
* 3Na(CN)BH3 AcOH-CF5COOH catalysts, 2 5 T , 2 h; 50°C. 4 h 0
0
73% single stereoisomer SCHEME 91
Analogous reactions have been carried out on an optically active quinolizine ena ~ n i n e ' ~No ~ . stereocontrol by the sulphoxide centre was observed. Interestingly, however, reduction performed in the presence and absence of cerium salts resulted in an opposite configuration of the bridge atom in the respective major products (Scheme 92). ..
SCHEME 92
G. Pitacco and E. Valentin
FIGURE l A possible explanation is based on the formation of cerium borohydride which would complex with oxygen, delivering the hydride from the side of the molecule (Figure l), while NaBH, would attack preferably from the less hindered cr side. The resulting anions would be successively protonated by methanol preferably from the same side (P in the former case, a in the latter case), to give products in which the two hydrogens are in cis relationship. Other reducing agents, such as hexakis[hydrido(triphenylphosphine)copper(I)] in benzene, H,/Pd-C in ethanol, lithium triethylborohydride in THF, failed to give the desired product. Treatment of acylated chloroenamines with sodium borohydride in methanol resulted in the formation of bicyclic lac tarn^'^^ (Scheme 93). The final isomerization is the result of a proton catalyzed ring-opening-ring closure mechanism.
NaBH4
N H A ~ MeOH, [.I., 20 h
CI H%
NR2
0
-
Ar NI
R2N
Ar = Ph, Ts;
NR2 = 4-morpholinyl
:a",
pXoL
H
R2N
yAr
39%,34% SCHEME 93
In the synthesis of l ~ p i n i n e optically '~~ active quinolizidine esters have been reduced by sodium borohydride in methanol to the corresponding saturated systems, which furnished ( + ) and (- )-lupinine by treatment with lithium aluminum hydride (Scheme 94). The diastereoselectivity of the reduction with NaBH4 was very high as no trace of epi-lupinine (with trans H-1 and H-9a) was detected. In fact, hydride is delivered at the bridge carbon (as shown by deuteriation experiments) from the less hindered side of the molecule, which is defined by the isopropyl group of the menthoxy substituent. The resulting carbanion is then protonated from the same side. In contrast, the enantioselectivity was poor, the enantiomeric excess of the product being 10%. The same diastereoselectivity was observed for reduction with sodium borohydride of enamine functions present in natural products, both in the presence and absence of acetic acid as ~ a t a l ~ s t ' ~ ~ - ' ~ ~ .
17. Oxidation and reduction of enamines
1
LiAIH4 ether. l hr
(+)
I
LiAIH4 ether. 1 hr
(+)-lupinine SCHEME 94
In contrast, lack of stereoselectivity was found in the reduction of a heterocyclic enamine with NaBH, (and H,/PtO,), as four isomers were formed. Three of them were isolatedl3' (Scheme 95). Reduction of cathenamine with NaBD, in D,O resulted in the incorporation of two deuterium atoms in the reduced product, tetrahydroalstonine131 (Scheme 96). A case of a high stereoselective reduction is reported in which indolizidine derivatives were reduced predominantly to the corresponding cis isomers by catalytic hydrogenation and to the trans isomers by sodium ~ ~ a n o b o r o h ~ d r i (Scheme d e ' ~ ~ 97).
G. Pitacco and E. Valentin
SCHEME 95
SCHEME 96
SCHEME 97
17. Oxidation and reduction of enamines
967
Some particular thia-substituted heterocyclic enamides underwent both reduction and ring fission when treated with NaBH,l3' (Scheme 98).
SCHEME 98 Linear enaminones, protonated by CF3COOH, were successively reduced with sodium borohydride to give the corresponding a$-unsaturated ketones, by loss of the amino group134 (Scheme 99).
5% NaOH
~1-CH=CH-C-R~
II
R1, R2 = i-Bu, i-Pr; neo-Pent, i-Pr; neo-Pent, c-Hex; n-Pr, Ph; i-Bu, Ph; neo-Pent, Ph NR2 = 4-morpholinyl
SCHEME 99 Treatment of particular fully conjugated heterocyclic enaminediones with NaBH, resulted in a chemoselective reduction of the keto carbonyl group, followed by a stereoselective reduction of the carbon<arbon double bond13' (Scheme 100). Catalytic hydrogenation allowed a complete reduction of the second carbonyl group.
SCHEME 100
95%, 84%
G. Pitacco and E. Valentin
968
A steroidal ketoenamine was reduced by an excess of NaBH, to the corresponding 3P-amino-4P-01 d e r i ~ a t i v e ' ~ ~Other . reducing agents [LiAI(OBu-t),, B(NMe,),, HCOOH, Raney Nil were unsuccessful. Reduction with LiAIH, afforded mixtures of a-ketols (Scheme 101).
I
LiAIHc ether. 4 h
SCHEME 101
Easy access to y-oxoacrylates is possible by reduction ofenaminone esters with sodium ' 102). cyanoborohydride, followed by d e a m i n a t i ~ n ' ~(Scheme
1
I . (C0~Et)~iEt0Na 2. pymolidine, AcOH
Rl'YC02Et Na(CN)BH,
CH3COOH,r.t.
-Ryw Silica gel
C02Et
0
R = Ph, Me, Et, i-Bu, n-Pent, n-Hex, 2-furyl, 3-butenyl
20-30% (from methyl ketones)
SCHEME 102
A series of vinylogous formamidinium salts and formamidines were reduced at the enamine and iminium double bonds by NaBH, giving the corresponding 1,3-diam i n ~ p r o p a n e s ' ~ (Scheme ~ , ' ~ ~ 103). Enamines can be reduced to the corresponding amines in 6 6 8 2 % yield with the CoCI, or NiCI,/NaBH, system in methanol-THF, at - 10 "C, for 2 h140.
969
17. Oxidation and reduction of enamines R3
I
R2
I
R4
NaBH4 EtOWMeCN, - 1 5 T to -25°C. 30 min
R4
I
I
R2
R1= ~2 = ~3 = R4 = Me; ~ 1 = R3R4 ~ 2= -(CH2)r , -(CH2)5~ 1 = ~ 3 = M Re 2, = R 4 = P h R1R2= -(CH2)4-, -(CH2)20(CH2)2-r R3 = R4 = R-BU R1 = R2 = Me, R3 = 2-pyridyl, 4-morpholinyl, R4 = H R1 = R2 = c-Hex. R3 = 2-thiazolyl, R4 = H
R3
45-85%
R1 = R2 = Me, R3 = Ph, 4-C1C6H4 R1R2= -(CH2)4-, R3 = 4-N02CsH4, 2-thiazolyl, 4-OMe-pyridazyl R ' = R ~ = P ~R, ~ = H SCHEME 103
Mercuric acetate attacks the P-carbon of enamines to afford the corresponding iminium salts, which can be demercuriated and reduced in situ with NaBH, to give tertiary aminesl4l (Scheme 104).
R = Et, R ' R ~= -(CH2),-, n = 3 4 , R3 = H R = R 1 = E t , R?=Me, R ~ = H R = Me, R1R2= -(CH2)5-, R3 = H RR = R1R2= -(CH2)4-, ~3 = H RR = -(CH2)20(CH2)2-, R1 = H, R2 = R3 = Me SCHEME 104
The reaction of NaBH, involves an initial protonation by the solvent, followed by hydride attack. Since LiAIH, cannot be used in protic solvents, it does not react at all on simple e n a m i n e ~ ' ~ ~Mixtures . ' ~ ~ . of LiAIH, and AICI,, which are electrophilic in character, can be used to reduce enamines s u ~ c e s s f u l l y ' .~Sa ~ nsoulet ~ ' ~ ~ and W e l ~ a r t ' , ~ reacted a number of enamines with aluminium dichlorohydride and obtained the corresponding saturated amines. They showed that the adduct of the aluminium derivative was formed, as hydrolysis of the crude mixture with D,O resulted in incorporation of deuterium at the P-carbon atom of the product amine (Scheme 105).
G. Pitacco and E. Valentin
970
\ 1 N-C=C/
1
-\ AIHC12
I
1
N-CH-C-A1C12
I
/
- \I D2O
N-CH-CD
/
SCHEME 105
Bicyclic dienamines were reduced by AIH, at the @double bond',, (Scheme 106). The reductions of enamines by mixed hydrides are accompanied in most cases by hydrogenolysis leading to ole fin^'^^. The amount of this side reaction is greater for AIH, than for AICIH, and AICI,H. Attack of AIH, at the P-carbon is controlled not only by the electronic effect of the base, but also by the steric effects related to the degree of substitution at the P-carbon atom.
SCHEME 106
Hydrogenolysis of cyclic enamines to the corresponding alkenes was in fact performed using an equimolar mixture of LiAIH, and AIC1,146.'47. Similar results were also obtained with diborane, followed by acid treatment148. Reduction by lithium aluminium hydride is effective in reducing the double bond of enaminones, leaving the carbonyl group untouched, as it acts via 1 , 4 - a d d i t i 0 n ' ~ ~ ~ ' ~ ~ (Scheme 107). Ph
Ph LiAIH4
N
0
ether, lC-15T-
Me\
N
0
I
68%. 53%
R = Me, (CH2)20H SCHEME 107
17. Oxidation and reduction of enamines
97 1
In contrast, reduction with NaBH, in methanol, as well as hydrogenation on Pt or Pd, resulted in the fragmentation of the m o l e ~ u l e ' ~ ~ ~ ~ ~ ~ . Lithium aluminium hydride is also capable of reducing N-silyloxy e n a m i n e ~ ' ~ ~ . Active methylene compounds such as open-chain and cyclic ketones can be converted into the corresponding Mannich base through the intermediacy of enaminones, which are reduced by LiA1H,l5, (Scheme 108).
R
4 0
XYCHNMe;*
ll0"C
.,A
NMe2 LiAIH4
R1
ether. & S T
0
0
X,Y = NMe2, OBu-t; X = Y = OMe, NMe2 RR' = -(CH2),-, n = 3-5 R=OMe,R1=Ph; R=Ph, R 1 = H SCHEME
108
A similar reaction forming the Mannich base can be applied to steroids as in the example in Scheme 109 from the work of de Stevens and H a l a m a n d a r i ~ ' ~ ~ .
22% SCHEME 109
It is known that LiAIH, reduces esters to alcohols, and that under the mild conditions used the enamine function remains untouched. Indeed, in the steroid series Hogg and coworkers used the enamine function to protect a carbonyl group which had not to be reduced as demonstrated in Scheme 110156. The same was observed for steroidal dicnamines having a carbonyl group at C-1715' and for enamino esters which were reduced by LiAIH, at the keto and ester functions, respectively, leading in the latter case to saturated pyran and furan derivative^'^^^'^^ (Scheme 111). In contrast, reduction of enamino esters of cyclohexanone resulted in the formation of a series of fragmentation products, among which the a,P-unsaturated aldehyde is of interest16'. The ratio of the products depended on the amount of the reducing agent (Scheme 112). The same was observed for enamino amides, for which fragmentation products were also formed16'. In both cases reduction with NaBH, afforded the corresponding amino esters and amino amides.
G . Pitacco and E. Valentin
972
I
1 . LiAIHdether 2. alkali. MeOH-Hz0
SCHEME 1 10
LiAIh
C O ~ E ether, ~ 0-25T
3h
. 96100% SCHEME 1 1 1
1 LiAIHl
1
ether, &25"C, 2 h
SCHEME 1 12
17. Oxidation and reduction of enamines
973
In contrast, 3-(N,N-dia1kylaminovinyl)indoleshave been reduced either with NaBH, or with LiAIH,, thus demonstrating that the substrate is of paramount importance in determining the reactivity of the reducing agentsI6' (Scheme 113).
SCHEME 1 13
Enaminoesters of the isoquinoline series could be completely reduced by LiA1H,163 (Scheme 114).
SCHE ME 1 14
A case is reported16, (Scheme 115) in which a cyclic enamide was reduced at the carbonyl group by LiAIH, as it was for lactams and amides, leaving untouched the enamine function.
\
\
n-Pr
n-Pr SCHEME 1 15
Sodium bis[2-~nethoxyethoxy]alana(e is a selective reagent for reducing the enamine double bond of linear enaminoketones, leaving the carbonyl group untouched165 (Scheme 116).
Rl,R2 = H, Me; H, Ph; R ' R ~= -(CH2)4-,
-(CHZ)~-
SCHEME 1 16
10-55%
974
G. Pitacco and E. Valentin
8. Borane
Attack of diborane occurs at the P-carbon atom with the exception of enamines of acetaldehyde for which a-borane product is formed. When isomerism is possible, as in the case of a 2-methylcyclohexanone enamine, the less substituted isomer is the more reactive form, for steric reasons. Protonolysis with propionic acid in diglyme afforded alkenes, as a consequence of a trans elimination of the base and the borane A carbonyl transposition based on enamine hydroboration has been described by Gore and coworker^'^'-^^^ . The same reaction attempted on enamines of 5cc-3-ketosteroids resulted in an unusual reactivity of diborane, leading to reduction of the enamine double bond. The 3 a-derivative prevailed over the 3b-derivative as a consequence of the presence of the 19-methyl group, as demonstrated successively for the 19-nor- steroid^"^ (Scheme 117).
The intermediacy of diastereoisomeric P-aminoboranes is to be assumed. Actually, one of them was isolated from a different reaction and gave the 3P-amino derivative, when treated with methanol under reflux (Scheme 117). Differently from the secondary enamino sulphoxides, tertiary enamino sulphoxides cannot be reduced by L-selectride, but they are reduced by the borane-THF complex120 (Scheme 1 18).
R,RIRZ= Me, -(CHZ)~-; Et, -(CH2)5-; SCHEME 118
R, R1, R2 = n-Pr, Me, CH2Ph
17. Oxidation and reduction of enamines
975
Hydroboration-oxidation of enamines has been reported by Borowitz and Will i a m ~ ' ~to' furnish the corresponding trans amino alcohols (Scheme 119).
1. BzH6. THF, r.t., 12 h
2. H202/0H, EtOH, reflux, 2.5 h
NR2
NR2 SCHEME
119
The same reaction applied to bicyclic derivatives was shown to be both regioselective and ~tereoselective"~,as a single product was isolated (Scheme 120).
1. BZH6,THF. 1.t.. 8 h
NR2
2. 30% H2O2,0H ~ f l u x 1, h
-
+:" H OH
82-95% SCHEME 120
C. Catalytic Hydrogenation
Secondary enamines derived from 3-ethylaminopyridine and isobutanal have been treated with a series of reducing agents. Whereas LiAIH, and NaBH, had no effect, hydrogenation in the presence of Adams catalyst was e f f e ~ t i v e ' " ~ 'leading ~~ to mixtures of reduction and fragmentation products in ratios which were dependent on the reaction temperature. Loss of methoxy group was also observed, when present in the substrate (Scheme 121). Cyclic cis vicinal tertiary amines could be easily prepared in high yield by hydrogenation of amino enamines over Pd on carbon'75 (Scheme 122). Enaminones derived from cyclohexan-1,3-dione were treated with a variety of reducing agentsl"j, with the aim of obtaining amino alcohols. While metal hydrides were inefficient and hydrogenation over Pd produced fragmentation, Raney nickel furnished the desired products in fairly good yields (Scheme 123). A reductive cyclization was found by Greenhill and coworkers'77 to occur with a particular dienaminone derivative of dehydrated dimedone dimer (Scheme IL4). Heterocyclic p-enamino esters were stereospecifically hydrogenated in the presence of Raney Ni, under thermal control. By this method diastereoisomerically pure pyrrolizidines and quinolizidines could be prepared'" (Scheme 125). When enaminoketones were hydrogenated on PtO,, the corresponding a$-unsaturated ketones were formed with a loss of the amino group'79 (Scheme 126).
976
G. Pitacco and E. Valentin
H2/Adams catalysl/AcOH
20°C. 5 h
R
N
N
H R = H, OMe
75%, 70%
N
SCHEME 121
SCHEME 122 Raney Ni~OH-204bNaOH
H z 70DC.W atm
50-75% R',R2 = H, H: H, Me; Ph, CH,Me; R'R2 = - ( c H ~ ) ~ SCHEME 123
17. Oxidation and reduction of enamines
SCHEME 1 2 4
SCHEME 125
EiOH, up u, 20O0C
""* 0 n = 1; n =2;
- @Y1 0
79%
R' = Ph, o-CIC& = ~ ePh,
SCHEME 126
977
G. Pitacco and E. Valentin
978
eHeH
The stereochemical course of the hydrogenation of the enamine of 3-aryl bicyclo[2.2.2]octane carboxaldehyde was found to be dependent on the catalyst and the conditions usedlS0 (Scheme 127).
H &
CH2NMe2
HdPQ '-mH
H 39% (98% cis) Ar = 3.4-C12C6H3
H#% ELOH Pd-C-
CHNMe2
CH2NMe2 99% (100% trans)
SCHEME 127
Similarly, camphor enamines were hydrogenated to give preferentially the exo amineslsi. Reductive amination of keto-steroids, both of the 5u and 5p series, was accomplished by pyrrolidine over Pd/C, furnishing the 3p-amino derivatives, whereas the u,p-unsaturated analogues gave mixtures of 5u- and 5P- and 3u- and 3P-isomersis2. In the total svnthesis of biotin. Marx and coworkers had to reduce a t h i o ~ h e n e intermzd~atecon~ainlng;in endiamide function which &as par~icularlyrefractory to hyd~oge~iatiun. This was accomplished only by thc use of 20% Pd(OH), on ch;trcoal as a c&alystis3 (Scheme 128)
H2/20% Pd(OH)2/charcoal
C02CH3
MeOH. 60 psi. 20°C. 24 h
*
SCHEME 128
Asymmetric synthesis of p-amino acids was achieved by hydrogenation of secondary enaminoesters of (2)configuration over Pd(OH),/C, fol!owed by hydrolysis1s4. Interestingly, treatment with sodium cyanoborohydride gave the opposite configuration. Hydrogenation of heterocyclic enamines of the alkaloid series can be accomplished either in acetic acid using Adams catalystlS5 or, better, with amalgamated ZinclS6 (Scheme 129). Me0 Me0
Me0 a: I12/Adams catalyst/AcOll b: Zn(Hg), HCI-EtOH, 5@6lPC,
Me
t
20 min
R
R = H. OMe
R = H : 70%a, 86%b R = OMe : 92%b SCHEME 129
17. Oxidation and reduction of enamines
979
High diastereoselectivity was found in the hydrogenation of pyrrolizidine alkaloids on Pt0,187,188and on Pd on c a r b ~ n ' ~ ~ . ' ~ ~ . Particular bis-enamines, in which two enamine units are linked to a dinitroxylene, cyclized to the corresponding benzodipyrrole derivative, by catalytic hydrogenation which simultaneously reduced the nitro group^'^' (Scheme 130).
qNM H2/10% Pd-C
Me2N
AcOEt, IS.
N02
NO2
SCHEME 130
H
H
70%
Enamides can be hydrogenated in fairly high optical purity. The influence of the substrate on the steric course of the reaction is probably due to the coordination with the metal and it appears to be a general p h e n o m e n ~ n ' ~ ~ . A similar process occurred when the double bond bore a carboxylic function. Reduction of a-acylaminoacrylic acids with the catalytic system ( - )-(diop)-Rh(1) allowed an asymmetric hydrogenation with optical yields ranging from 70 to (Scheme 131).
R',R2 = H, H; H, Ph; H, 4-HOC6H4; H, i-Pr; Me, Me; R3 = Me, Ph diop = 2,3-O-isopropylidene-2,3-dihydroxy-l,4-bis(diphenylphosphino)butane SCHEME 131 Successively a rhodium chiral biphosphine catalyst ([Rh(l,5-C0D)bisphosphinel + B F i allowed better selectivity in reducing cc-acylaminoacrylic acids (95-96% e.e.)'93. Enamide substrates were reduced in high enantiomeric excess through the mediation of chiral norbornene d i p h ~ s p h i n e ' The ~ ~ . same results were obtained using the saturated congener ligand shown in Scheme 132. R
yNH COOH
R=H,Ph
H2/(renorphos)Rh(NED)C100 MeOH. I h, 1.6 atm
4
H COOH AcNH
97% (95% e.e.) renorphos = (+)- or (-)-(R,R)-2-exo-3-endo-bis(diphenylphosphino)bicyclo[2.2.llheptane NBD = norbornadiene SCHEME 132
9 80
G. Pitacco and E. Valentin
Other chiral catalysts, such as (binap)Ru(OAc), complexes, were efficient in catalyzing the reduction of Z-N-acylated-1-alkylidenetetrahydroisoquinoines, giving excellent chemical and optical yields (>96%)195(Scheme 133). The E-isomers were not reduced at all. o-Methoxy-substituted arylphosphines used as ligands in rhodium-catalysed asymmetric hydrogenation of enamides induce inversion of the chiral centre with respect t o the unsubstituted a r y l p h o ~ p h i n e s ' ~ ~ . Hydrogen telluride (H,Te), prepared in situ from aluminium telluride AI,Te, and water, reduces enamines to the corresponding amines. The presence of water, however,
OMe
A-W) BINAP = 2,2'-bis(diphenylphosphino)-1,l'-binaphthyl SCHEME 133
A-(S)
17. Oxidation and reduction of enamines
981
may cause partial hydrolysis of the enamines. The problem can be overcome if the carbonyl compound is condensed with the amine in the presence of AI,Te,, at -78 to 0 "C. The water formed generates hydrogen telluride which acts as reducing agent for the enamines. Yields are generally high197. Reductive alkylations of amines with carbonyl compounds can be also accomplished quantitatively by means of selenophenol (PhSeH) at room temperature in chloroform198 and by sodium hydrogen telluride (NaHTe) in ethanol at room temperature199.
D. Formic Acid
The mechanism of formic acid reduction has been investigated in the reactions of deuterium-labeled formic acid (DCOOH, HCOOD, DCOOD) with q u i n ~ l i z i d i n e ~ ~ ~ (Scheme 134).
SCHEME 134
The number of incorporated D atoms and their positions led to the conclusion that the proton of formic acid attacks the enamine P-carbon by a reversible process (which would explain incorporation of more than 1 D per molecule). Then the hydride derived from the formate becomes attached to the iminium carbon to give the saturated amine. Enamines of aliphatic aldehydes were reduced by the same procedurez0'. 2-Alkylcyclohexanone enamines were reduced by formic acid with a high degree of stereoselectivity, giving a ca 9 cidtrans ratio of the resulting aminesZo2(Scheme 135).
G. Pitacco and E. Valentin
982
Indeed, the iminium formate intermediates are approached by hydride from the more accessible side of the molecule. A similar result had been obtained by Noyce and Bachelorzo3 for the enamines of 2-methylcyclohexanone. The reduction of camphor enamines by the same method has been found to be highly selective, leading to the endo isomer as the predominant product (85-87%)'04 (Scheme 136). The lack of solvent effect and the incorporation of up to 3 deuterium atoms when using DCOOD, are in favour of a two-step mechanism. This would involve reversible protonation of the P-carbon atom with formation of the iminium ion, followed by irreversible transfer of hydride from the formate ion to this ion.
major isomer SCHEME 136
A great variety of tertiary enamines derived from aliphatic ketones, aryl alkyl ketones and functionalized ketones were reduced by formic acid, most of them in good yields, even in the presence of other functional groups, such as carhonyl, cyano and other carbon-carbon double bonds205 (Scheme 137).
35-88% SCHEME 137
Enamines of steroids formed in situ by condensation of the corresponding ketones with secondary amines, followed by treatment with formic acid, gave the 3P-saturated amine derivatives as the main productszo6. In a similar manner enamines of heterocyclic ketones were also reduced to the corresponding amineszn7(Scheme 138).
R2p R3
anh. HCOOH
NR4RS
NR4R5 41-92%
X = 0, S, NMe R',R2,R3 = H md Me; R4Rs = -(CH2)4-, -(CH2)5-. SCHEME 138
-(CH2)20(CH2)2-
17. Oxidation and reduction of enamines
983
Enamines are readily reduced by phosphorous acid, but with a lower degree of stereoselectivity than by formic acidzo8 (Scheme 139).
80%, 91%
n=O, 1 SCHEME 139
E. Amines
The reductive power of hexamethyleneimine has been demonstrated during the preparation of enamines from norbornanone and other bicyclic ketones. In fact, equal amounts of unsaturated and saturated amines were formedzo9 (Scheme 140).
R = H : 50% R R = -(CH2)3-
: 30%
50% 70%
SCHEME 140
The reduction is acid-catalysed and, when 2-methylhexamethyleneimine was used as the amine, the corresponding oxidation product, 2-methyl-1-azacycloheptene, was identified, thus allowing the mechanism to be clarifiedz1'. Other aliphatic amines, such as pyrrolidine, piperidine or tetrahydroisoquinoline, as well as aromatic amines are also capable of reducing action, whereas morpholine is n ~ t ~ ' ~ ~ ~ " .
G. Pitacco and E. Valentin
984
When piperidine was used for the formation of the enamine of 1-methyl-3-phospholanone 1-oxide, the saturated amine was obtained, thus confirming the reductive properties of secondary amines, morpholine excluded212 (Scheme 141).
Me
(",
qs0
,excess
benzene, reflux, 12 h
q5"+0- 0 Me
*
Me
p4
H
Me
I p'--o
OH
0
SCHEME 141
F. Miscellaneous Reactions
When reacting with trichlorosilaae, enamines added it in a regiospecific manner to give either the trichlorosilyl adduct or the saturated amine or both, depending on the enamine substrate213 (Scheme 142).
R ' , R ~= Et, Me; R'R2 = -(CH2)- , -(CH2)4-, R2N = 1-pyrrolidinyl, 1-piperidinyl
-(CH2)5-
SCHEME 142
Reductive alkylations via a radical pathway have been performed on enamines of ~ c ~and~ c ~ ~ketones. ~ . In~ both ~ cases ~ the diastereoselectivity was high, Reductive alkylations via a radical pathway have been performed on enamines of ~ y c l i c ~ and '~~~'~ ketones. In both cases the diastereoselectivity was high, leading to cis products preferentially in the case of the cyclic derivatives and to ul substituted amines in the case of linear systems (Scheme 143). The stereoselectivity depended on the size of the electron-withdrawing group in the radical precursor and on that of the amine component. Ionic hydrogenation of azasteroids containing an enamino diketone function is selective2". The reaction was carried out by treating a 1:40:8 mixture of the substrate, CF3COOH/Et3SiH with 3% BF, . OEt, in 1% aq. LiCIO, in CF3COOH. When a further double bond was present in the C ring, the selectivity was inverted219. Enamines of cyclic and linear ketones were reduced to the corresponding saturated amines by hydridotetracarbonylferrate under carbon monoxide220. Biomimetic reduction enamides by a model of NADH was also carried out in the presence of magnesium salts to afford the corresponding saturated compounds221 (Scheme 144). c
17. Oxidation and reduction of enamines
'
I
Bu3SnH. AIBN kvorA
EWG = CN, C02Me, S02Ph, S02Bu-t HNR2 = pyrrolidine, piperidine, diethylamine SCHEME 143
1
1. Mgt*, MeCN, 60°C, 3 d, dark 2. H 2 0
R = H 27% R = OMe 90% SCHEME 1 4 4
The same reaction attempted on similar non-cyclic enamides gave no results. The mechanism would involve a transition state in which Mg2+ is simultaneously linked to the ' N A D H model' and the substrate, through their respective carbonyl groups. Within this ternary complex an electron migrates from the ' N A D H model' to the substrate and this migration is successively followed by a proton transfer from the ' N A D H model' radical cation to the radical anion.
G. Pitacco and E. Valentin
986
Introduction of a chiral centre in the NADH model resulted in a low enantioselectivity of the final The Hantzsch ester can be used as reducing agent of enamines, since it is resistant to acidic conditionszz3 (Scheme 145).
X = 0,CH2 SCHEME 145
Steroidal enaminoZz4and dienaminoZz5perchlorates were reduced with the Hantzsch ester to the corresponding P-amines in the former case and to the 5P-H ketones in the latter. Reduction of an enamine double bond belonging to an alkaloid by NADPH was also performedzz6. However, in that case no diastereoselectivity was observed, as three isomers were formed. Reductive cyclization of aliphatic and aromatic bis-enaminoesters via electrochemical methods takes place on cathode to give heterocyclic derivative^^^' (Scheme 146).
SCHEME 146
Polarographic reductions of 2-methylenehexahydroazepines were (Scheme 147). The half-wave potentials are linearly related to the Xu, and Xu, Hammett substituent constants.
anh. DMFlHg
R
'
R1 = R2 = C02Me R1,R2= C02Me, Ph; C02Et, CN; CONH2, CN; H, NO2; CN, Ph SCHEME 147
17. Oxidation a n d reduction of enamines
987
Fully conjugated enaminoketones were reduced polarographically a t t h e carbonyl group, by two one-electron stepsz3' (Scheme 148). DMF1O.I 2.25 VM(vs Bu4NC10a SCE)
( @CH-:-F%
OH
0 Me SCHEME 148
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G. Pitacco a n d E. Valentin
131. P. Heinstein, J. Stoeckigt and M. H. Zenk, Tetrahedron Left.,21, 141 (1980). 132. T. Ohnuma, M. Tabe, K. Shiiya, Y. Ban and T. Date, Tetrahedron Lett., 24, 4249 (1983). 133. P. Neelakantan, N. Rao, U. T. Bhalerao and G. Thyagarajan, Indian J. Chem., 11,1051 (1973); Chem. Abstr., 80, 828722 (1974). 134. L. Nilsson, Acta Chem. Scand, B 33, 547 (1979). 135. V. N. Pshenichnyi, 0. F. Lakhvich, E. V. Borisov, N. V. Khripach and V. A. Khripach, Zh. Org. Khim., 27, 928 (1991); Chem. Abstr., 116, 6801x (1992). 136. C. H. Robinson, L. Milewich and K. Huber, J. Org. Chem., 36, 211 (1971). 137. S. Manfredini, D. Simoni, V. Zanirato and A. Casolari, Tetrahedron Lett., 29, 3997 (1988). 138. C. Jutz, A. F. Kirschner and R. M. Wagner, Chem. Ber., 110, 1259 (1977). 139. C. Jutz, R.-M. Wagner, A. Kraatz and H.-G. Lobering, Justus Liebigs Ann. Chem., 874 11975) ,-.. -,. 140. M. Periasamy, A. Devasagayaraj, N. Satyanarayana and C. Narayana, Synth. Commun., 19, 565 (1989). 141. R. D. Bach and D. K. Mitra, J. Chem. Sac. ( D ) , 1433 (1971). 142. J. Smuszkovics, in Advances in Organic Chemistry, Methods and Results, Vol. 4, (Eds. R. A. Raphael, E. C. Taylor and H. Wynberg), Interscience, New York, 1963, pp. 1-113. 143. K. Blaha and 0. Cervinka, in Advances in Heterocyclic Chemistry, Vol. 6, Academic Press, New York, 1966, pp. 147-227. 144. J. M. Coulter, J. W. Lewis and P. P. Lynch, Tetrahedron, 24, 4489 (1968). 145. 1. Sansoulet and Z. Welvart, BUN. Chim. Sac. Fr., 77 (1962). 146. J. W. Lewis and P. P. Lynch, Proc. Chem. Sac., 19 (1963). 147. L. Jaenicke and W. Boland, Justus Liebigs Ann. Chem., 1135 (1976). 148. J. W. Lewis and A. A. Pearce, Tetrahedron Lett., 2039 (1964). 149. J. C. Martin, K. R. Barton, P. G. Gott and R. H. Meen, J. Org. Chem., 31,943 (1966). 150. G. N. Walker, J Org. Chem., 27, 4227 (1962). 151. R. H. Baker and A. H. Schlesinger, J. Am. Chem. Sac., 68, 2009 (1946). 152. N. K. Kochetkov, Izv. Akad. Nauk SSSR, Otdel. Khim. Nauk, 47 (1954); Chem. Abstr., 49, 6090i (1955). 153. H. Feger and G. Simchen, Justus Liebigs Ann. Chem., 1456 (1986). 154. P. F. Schuda, C. B. Ebner and T. M. Morgan, Tetrahedron Lett., 27,2567 (1986). 155. G. de Stevens and A. Halamandaris, J. Org. Chem., 26, 1614 (1961). 156. G. B. Spero, J. L. Thompson, B. J. Magerlein, A. R. Hanze, H. C . Murray, 0. K. Sebek and J. A. Hogg, J. Am. Chem. Sac., 78, 6213 (1956). 157. F. W. Heyl and M. E. Herr, J. Am. Chem. Soc., 75, 1918 (1953). 158. S. Carlsson and S. 0 . Lawesson, Tetrahedron, 36, 3585 (1980). 159. S. Carlsson, A. El-Barbary and S. 0 . Lawesson, Bull. Sac. Chim. Belg., 89, 643 (1980). 160. S. Carlsson and S. 0. Lawesson, Tetrahedron, 38, 413 (1982). 161. A. B. A. G. Ghattas, K. A. Joergensen and S. 0. Lawesson, Acta Chem. Scand, B 36, 505 (1982). 162. 1. W. Daly and B. Witkop, J. Org. Chem., 27, 4104 (1962). 163. M. S. Gavrilov, V. S. Shklyaev and B. B. Aleksandrov, Khim. Geferotsikl. Saedin., 1089 (1987); Chem. Abstr., 109 3772311 (1988). 164. A. A. El-Barbary, S. Carlsson and S. 0. Lawesson, Tetrahedron, 38, 405 (1982). 165. W. W. Weselowsky and A. M. Moiseenkov, Synthesis, 58 (1974). 166. J. W. Lewis and A. A. Pearce, J. Chem. Sac. ( B ) , 863 (1969). 167. J. Gore, J. P. Drouet and J.-J. Barieux, Tetrahedron Lett., 9 (1969). 168. 1.-1. Barieux and J. Gore, Bull. Sac. Chim. Fr., 1649 (1971). 169. M. Montury and J. Gore, Tetrahedron, 33, 2819 (1977). 170. J. J. Barieux and J. Gore, Tetrahedron, 28, 1537 (1972). 171. I.J. Borowitz and G. J. Williams, J. Org. Chem., 32, 4157 (1967). 172. F. Bondavalli, P. Schenone, A. Ranise and S. Lanteri, J. Chem. Sac., Perkin Trans. 1, 2626 (1980). 173. A. Sauleau, Bull. Sac. Chim. Fr., 2832 (1973). 174. A. Sauleau, Bull. Soc. Chim. Fr., 2828 (1973). 175. G. Fraenkel, J. Gallucci and H. S. Rosenzweig, J. Org. Chem., 54, 677 (1989). 176. J. V. Greenhill, M. Ramli and T. Tomassini, J. Chem. Sac., Perkin Trans. 1, 588 (1975). 177. 1. Chaaban, J. V. Greenhill and M. Ramli, J. Chem. Soc., Perkin Trans. 1, 3120 (1981).
17. Oxidation a n d reduction of enamines
99 1
178. 1. P. Cklerier, M. Haddad, C. Saliou, G. Lhommet, H. Dhimane, J. C . Pommelet and J. Chuche, Tetrahedron, 45, 6161 (1989). 179. P. Zhang and L. Li, Synth. Commun., 16, 957 (1986). 180. D. C. Horwell and G . H. Timms, Synth. Commun., 9, 223 (1979). 181. F. Bondavalli, P. Schenone and A. Ranise, J. Chem. Res. ( S ) , 257 (1980). 182. J. Schmitt, J. J. Panouse, Cornu, H. Pluchet, A. Hallot and P. Comoy, BUN. Soc. Chem. Fr., 753 (1964). 183. M. Marx, F. Marti, J. ReisdorK, R. Sandmeier and S. Clark, J. Am. Chem. Soc., 99,6754 (1977). 184. M. Furukawa, T. Okawara, Y. Noguchi and Y. Terawaki, Chem. Pharm. Bull., 27,2223 (1979). 185. M. P. Cava, S. C. Havlicek, A. Lindert and R. J. Spangler, Tetrahedron Lett., 2937 (1966). 186. M. P. Cava, M. J. Mitchell, S. C . Havlicek, A. Lindert and R. J. Spangler, J. Org. Chem., 35, 175 (1970). 187. S. Miyano, S. Fujii, 0 . Yamashita, N. Toraishi and K. Sumoto, J. Org. Chem., 46, 1737 (1981). 188. W. Flitsch and P. Wernsmann, Tetrahedron Lett., 22, 719 (1981). 189. H. W. Pinnick and Y.-H. Chang, J. Org. Chenl., 43, 4662 (1978). 190. J. M. Muchowski and P. H. Nelson, Tetrahedron Lett., 21, 4585 (1980). 191. A. Berlin, S. Bradamante, R. Ferraccioli, G. A. Pagani and F. Sannicolo, J. Chem. Soc., Chem. Commun., 1176 (1987). 192. H. B. Kagan and T.-P. Dang, J. Am. Chem. Soc., 94, 6429 (1972). 193. B. D. Vineyard, W. S. Knowles, M. J. Sabacky, G. L. Bachman and D . J. Weinkauff, J. Am. Chem. Soc., 99, 5946 (1977) and references cited therein. 194. E. P. Kyba, R. E. Davis, P. N. Juri and K. R. Shirley, Inorg. Chem., 20, 3616 (1981). 195. R. Noyori, M. Ohta, Y. Hsiao, M. Kitamura, T. Ohta and H. Takaya, J. Am. Chem Soc., 108, 7117 (1986). 196. J. M. Brown and B. A. Murrer, Tetrahedron Lett., 21, 581 (1980). 197. N. Kambe, T. Inagaki, N. Miyoshi, A. Ogawa and N. Sonada, Chem. Lett., 1275 (1987). 198. K. Fujimori, H. Yoshimoto and S. Oae, Tetrahedron Lett., 21, 3385 (1980). 199. M. Yamashita, M. Kadokura and R. Sucmitsu, BUN Chem. Soc. Jpn., 57, 3359 (1984). 200. N. J. Leonard and R. R. Sauers, J. Am. Chem. Soc., 79, 6210 (1957). 201. P. L. de Benneville and J. H. Macartney, J. Am. Chem. Soc., 72, 3073 (1950). 202. J. 0 . Madsen and P. E. Iversen, Tetrahedron, 30, 3493 (1974). 203. D. S. Noyce and F. W. Bachelor, J. Am. Chem. Soc., 74, 4577 (1952). 204. R. Carlson and A. Nilsson, Acta Chem. Scand., B 39, 181 (1985). 205. A. Nilsson and R. Carlson, Acta Chem. Scand., B 39, 187 (1985). 206. R. R. Sauers, J. Am. Chem. Soc., 80,4721 (1958). 207. S. A. Vartanyan and E. A. Abgaryan, Arm. Khim. Zh., 37, 316 (1984); Chem. Abstr., 102, 2 4 4 3 5 ~(1985). 208. D. Redmore, J. Org. Chem., 43, 992 (1978). 209. A. G. Cook, W. C. Meyer, K. E. Ungrodt and R. H. Mueller, J. Org. Chem., 31, 14 (1966). 210. A. G. Cook and C. R. Schulz, J. Org. Chem., 32,473 (1967). 21 1. C. Kaiser, A. Burger, L. Zirngibl, C. S. Davis and C. L. Zirkle, J. Org. Chem., 27,768 (1962). 212. L. D. Quin and R. C. Stocks, J. Org. Chem., 39, 686 (1974). 213. D. C. Snyder, J Organomet. Chem., 301, 137 (1986). 214. D. C. Snyder, J. Organomet. Chem., 320, 163 (1987). 215. P. Renaud and S. Schubert, Angew. Chem., 102,416 (1990). 216. P. Renaud and S. Schubert, Synlell, 624 (1990). 217. P. Renaud, P. Bjoerup, P. A. Carrupt, K. Schenk and S. Schubert, Synletr, 211 (1992). 218. A. A. Akhrem, F. A. Lakhvich, L. G . Lis and Z. N. Parnes, I m Akad. Nmk SSSR, Ser. Khim., 1465 (1978); Chem. Ahstr., 89 215650k (1978). 219. A. A. Akhrem, F. A. Lakhvich, L. G. Lis, S. U. Sagaidak, N. I. Garbuz and V. Z. Kurbako, Zh. Org. Khim., 17, 1527 (1981); Chem. Abstr., 95, 204259n (1981). 220. T. Mitsudo, Y. Watanabe, M. Tanaka, K. Yamamoto and Y. Takegami, BUN. Chem. Soc. Jpn., 44, 302 (1971). 221. C. Leroy, V. Levacher, G. Dupas, J. Bourauignon and G. Oubauiner, Tetrahedron Lett., - . 33, 161<(1992). 222. V. Levacheur, R. Benoit, J. Duflos, G . Dupas, J. Bourguignon and G. Qukguiner, Tetrahedron, 47, 429 (1991). 223. S. Singh, V. K. Sharma, S. Gill and R. I. K. Sahota, J. Chem. Soc., Pcrkin Trans. 1,437 (1985).
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224. U. K . Pandit, R. A. Gase, F. R. Mas Cabrk and M. I. de Nie-Sarink, J. Chem. Soc., Chem. Commun., 21 1 (1975). 225. U. K. Pandit, F. R. Mas Cabre, R. A. Gase and M. J. de Nie-Sarink, J. Chem. Soc., Chem. Commun., 627 (1974). 226. J. Stockigt, H.-P. Husson, C. Kan-Fan and M. H. Zenk, J. Chem. Soc., Chem. Commun., 164 (1977). 227. B. Vieth and W. Jugelt, Z. Phys. Chem. (Leipzig), 265, 947 (1984). 228. M. K. Polietkov, A. B. Grigor'ev, V. G. Granik and R. G. Glushkov, Zh. Obshch. Khim., 43, 1162 (1973); Chem. Abstr., 79, 48635u (1973). 229. A. B. Grigor'ev, V. G. Granik, R. G. Glushkov and M. K. Polievktov, Tezisy Dokl. Vses. Soveshch. Elektrokhim. Org. Soedin., 8th, 132 (1973); Chem. Abstr., 82, 36473p (1975). 230. A. B. Grigor'ev, V. G. Granik and M. K. Polietkov, Zh. Obshch. Khim., 46,404 (1976); Chem. Abstr., 84, 157204b (1976). 231. A. B. Grigor'ev, V. E. Sarokhvostova, M. K. Polievktov and V. G. Granik, Soveshch. Polyarogr., 6th, 94 (1975); Chem. Abstr., 86 112960~(1977).
Cycloadditions to enamines RAFAEL CHlNCHlLLAt and J A N - E BACKVALL
.
.
.
Department of Organic Chemistry University of Uppsala. BOX531 S 751 21 UppsaI3 Sweden
I . INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. CARBOCYCLIZATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Three-membered Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Four-membered Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Five-membered Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Six-membered Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Alicyclic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 . Aromatic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E. Larger Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I11. HETEROCYCLIZATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . A . Three-membered Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Four-mcmhcrcd Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C . Five-membered Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. One hetero atom . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Two hetero atoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 . Three hetero atoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Six-membered Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. One hetero atom . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 . Two or more hetcro atoms . . . . . . . . . . . . . . . . . . . . . . . . . E . Larger Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. IMINES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V.REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
993 994 994 995 999 1001 1001 1012 1015 1016 1016 1016 1018 1018 1022 1024 1026 1026 1034 1040 1041 1431
.
I INTRODUCTION
The present chapter is dedicated to the cycloaddition reactions of enamines. which include transformations that. independently of the mechanism. create a new ring1. The cycloadditions may proceed via a concerted mechanism (following Woodward-Hoffmann rules) or a two-step mechanism which may involve zwitterionic or diradical intermediates . Due to their low ionization potentials and asymmetric molecular orbital
t Present address: Department of Organic Chemistry. University of Alicante. Apdo. 99. E-3080 Alicante. Spain
Tlic Cltemrstn of Ennnzines. Editcd hy Zvi Rappopon Copyright O 1994 John Wiley & Sons. Ltd. ISBN: 0-471-93339-2
993
994
Rafael Chinchilla and Jan-E. Backvall
coefficients2, enamines are good electron-releasing species, thus providing favorable conditions for the formation of a zwitterion. It is therefore not surprising that dipolar intermediates are very frequent in enamine cycloadditions. In concerted cyclizations the simultaneous formation of the new two u-bonds would allow a stereospecific reaction, whereas in a diradical o r zwitterionic pathway the stereospecificity will depend on the ratio of the rates of ring closure and rotation about single bonds in the intermediate3. sufficiently cover the developments in this field until the Since previous beginning of the 80s, thc intention with the present review is to focus principally on the recent synthetic methods for the preparation of cyclic compounds, although general and basic reactions of less recent origin will also be mentioned. The chapter has been divided into two sections describing methodologies leading to the synthesis of carbo- and heterocycloadducts of different size. Finally, a brief section has been dedicated to the use of imines in cyclization reactions which occur via their enamine tautomer. II. CARBOCYCLIZATIONS
This section will show different methods for the introduction of carbon atoms into the enamine system leading to the synthesis of an all-carbon ring. A. Three-membered Rings
The addition of carbenes to the enamine double bond gives aminocyclopropanes. These carbene species can be generated from CH,f2/Et2Zn7 or CH2N2/CuClR.If the carbene carries a good leaving group, as a halogen, l ~ k ein the case of phenylchloro-9,10, dichloro-9.11, bromo-lo or flu~rocarbenes'~~", the opening of the cycloadduct is possible. When the cyclopropane is part of a bicyclic compound, the opening leads to a$-unsaturated ketones with either an exocyclic double bond and conservation of the ring size, o r an endocyclic double bond and ring expansion. For example, when cycloadduct 1 or 2, prepared from addition of phenylchlorocarbene to the correspondmg enamine, were heated, unsaturated ketones 4 (obtained from disrotatory ring opening to 3 without participation of the nitrogen electron-pair and hydrolysis) or 8 (via dipolar intermediate 5) could be obtained after hydrolysis, depending on the stereochemistry of the cyclopropane ring (equation 1)". Also thiocarbenesl" m e t h o ~ ~ p h e n ~ l c a r b e n e ' ~ and e t h o ~ ~ c a r b o n ~ l c a r b e nhave e s ~ ~been ~ ~ ~ used in the synthesis of aminocyclopropanes. Photochemical Fe(CO),-induced rearrangement of silylated allyl amine 9 gave Nsilylated enamine lo1',which on subsequent Cu-catalyzed cyclopropanation by methyl diazoacetate afforded cyclopropane derivative 11. The use of an optically active catalyst gave an asymmetric induction of 56% ee for the cis isomer and 20% ee for the trans isomer. Further acid-induced ring cleavage afforded the P-formyl ester 12, whereas reduction and desilylation produced aminocyclopropane carboxylic acid 13 (equation 2). Bicyclic aminocyclopropane derivatives have been obtained using a methodology developed by Vilsmaier and coworkers involving reaction of enaminosulfonium s a l ~ s ' ~ or c h l o r ~ e n a m i n e s ~ ' -with ~ ~ nucleophiles. For example, benzoylation of enamine 14 afforded a mixture of isomers 15 and 16,'. Treatment of this mixture with Nchlorosuccinimide gave chloroenamine 17 which, under the influence of a nucleophile such as cyanide anion, eliminates chloride to give the endo-bicyclic nitrile 19, presumably via 18 (equation 3). Chloroenamines 21 and 22, obtained by reaction of the parent enamine 20 with one or two equivalents of N-chlorosuccinimide respectively, interact with cyanide in a diastereocomplementary way23.24.Whilst the monochloroenamine 21 leads t o pure endo-amino bicycloalkanenitrile 23, the presence of the second chlorine
18. Cycloadditions to enamines
995
atom in dichloroenamine 22 causes a reversal of the stereochemical result, producing the exo-compound 24 which can be dechlorinated to give exo-amino bicycloalkane nitrile 25 (equation 4). 6. Four-membered Rings
Enarnines 27 can react with electron-deficient olefins (26) to give cyclobutanes 30 and open-chain products 31 (after hydrolysis), the ratio being dependent on the nature of the enamine and the reaction conditions. The extensive investigations of Brannock and
Rafael Chinchilla and Jan-E. Backvall
0
%
&NaCN
COPh
(19)
18. Cycloadditions to enamines
EWG
EWG
1
EWG = electron-withdrawing group
H,Ot
coworkersZ5and Hall and Ykman26 support the initial formation of a 1,Czwitterionic intermediate (28) which explains the formation of both type of compounds (equation 5). This cycloaddition has also been achieved photochemically in the reaction of Nisobutcnyl pyrrolidine with dimethyl fumarate2'. The latter reaction procccds via a non-ionic process to give a product, which is the stereoisomer of the product of the corresponding thermal reaction. Examples of cyclobutane derivatives obtained via the thermal cycloaddition with electrophilic olefins are (i) compounds 32 and 33, from reaction of N-cyclohexenylmorpholine with (E)-P-cyanovinyl phenyl sulfoneZ8and 1-cyanocyclobutene in the presence of MgBrZ2', respectively, (ii) nitroketone 34 from a cross-conjugated enamino
m pH:0 H
Ph
0 NHPh
(33)
0
(34)
998
Rafael Chinchilla and Jan-E. Backvall
ketone and P-nitrostyreneso, (iii) aminoester 35, from N-isobutenyl morpholine and a crotonic acid ester3'. Cyclopropene esters give aminobicyclo[2.1.0]pentane derivatives, which can undergo ring-opening reactions to c y ~ l o p e n t e n e s ~ ~For - ~ ~example, . methyl 3,3-dimethylcyclopropene-1-carboxylate (37), obtained by photolysis of the corresponding pyrazolinic derivative, reacted with the diquinanic enamine 36 to give a mixture of the alkylation product 38 and the [2 + 21 cycloadduct 3934 which, on acid treatment, was transformed into the triquinanic cyclopentene alcohol 40 (equation 6).
Asymmetric induction in the [2 + 21 cycloaddition of enamines, e.g. 42, with methyl (E)-4-oxo-4-(2-oxo-1,3-oxazolidin-3-yl)-2-butenoate (41) has been reported (equation 7)35. The reaction is promoted by a chiral titanium reagent generated in situ from dichlorodiisopropoxytitanium and a tartrate-derived chiral 1,4-diol (43). In the presence of excess amounts of the titanium reagent, 77% ee of cycloadduct 44 was achieved together with 45. The reaction also works with only a catalytic amount of the chiral reagent. Enamines of cyclic ketones react with acetylenic esters in an apolar solvent via [2 + 21 cycloaddition leading to cyclobutenes, which normally undergo a sigmatropic ring opcning to a 1,3-diene at room temperature36*". Nevertheless, cycloadduc~shave been isolated, such as cyclobutenes 46 and 47, which are stable solids in inert solvents3', or cycloadduct 48 obtained by reaction of a p-nitro enamine with dimethyl acetylenedicarb~xylate'~. Vinylcyclobutanones (51) can be prepared by cycloaddition of vinylketenes such as 49 (generated in situ by elimination of hydrogen chloride with triethylamine from cc$-unsaturated acid chlorides) to P,P-dialkyl enamines such as 50 (equation Q40. This type of reaction was originally reported by Hickmott and coworkers4'. When a mixture of aminocycloheptatriazolones 52 and 53 (prepared by amination of 6H-cycloheptatriazol-6-one) was treated with lead tetraacetate in the presence of cyclic
18. Cycloadditions to enamines
<
b c/)0 2 M e
:eNxC
Me
S
MeHN
C02Me
morpholino enamines, 4,s-dehydrotropone (54) was generated and cyclized with the electron-rich species affording mainly the [2 + 21 cycloadduct 55 (equation 9)42.
C. Five-membered Rings
The reaction of cc,oc'-dibromoketones with enamines in the presence of some activating agents gives [3 + 21 cycloadducts. The reagents that have been used so far are
Rafael Chinchilla and Jan-E. Backvall
Fe2(C0),43 and CeC13-SnC1244; the latter present some advantages like lower toxicity, lower temperature and homogeneous reaction conditions. The first step in the reaction (equation 10) involves a single debrominaof u,d-dibromoketone 56 with CeCI,-SnCI, tion in analogy with a Reformatsky reaction to aRord a cerium a-bromo enolate 57. This intermediate suffers from further elimination of bromide via ionization to oxyallyl cation 58 which undergoes the [3 + 21 cycloaddition to the enamine. The aminocyclopentanone 59 obtained was easily deaminated to cyclopentenone 60. Reaction of oc-ketoenamines with a series of cyclic and acyclic nitroolefins gave aminocyclopentene derivatives with high diastereoselectivity, as products of kinetic control instead of the expected 1,2-oxazine N-oxides (see Section III.D.2)45~46.For example, ketoenamine 62 when reacted with cyclic nitroalkcnc 61 afforded 65 as a single diaslereoisonierAb, first through the dipolar interniediate 6 3 and later through the betaine-type intermediate 64. Hydrolysis of this enamine furnished the cyclopentanone derivative 66. also as a single diastcrcoisomcr kauation 11). Ester-substituted fulvencs of the type 67 (equation 12) werc found to undergo read) cycloadditions to ennmines"'. Nucleophilic additmn 01 68 to the electrophilk 6-position of the fulvene, and cyclization of the iesulting zwitterionic intermediate 69 with loss of diethylamine resulted in the formation of the tricyclic fulvene 70 (equation 12). By reaction of cycloheptafuranone 71 with the pyrrolidino enamine 72,2-(cyclohepta1,3,5-trieny1)azulene (73) was obtained (equation 13)48.
-
~.
18. Cycloadditions to enamines
OCeC12 Br
Br
Br
D. Six-membered Rings
The Stork reaction of methyl vinyl ketones and enamines (e.g. 74) is a complementary procedure to the Robinson annulation method (equation 14)49. With this procedure, products from attack of the most reactive less substituted form of the enamine to the
1002
Rafael Chinchilla and Jan-E. Backvall
18. Cycloadditjons to enamines
1003
electrophilic olefin are obtained. In the variation studied by Konst and coworkersso reaction of 3-alkyl- and 3,3-dialkyl-6-methyl-1-pyrrolidinocyclohexenes,e.g. 76, with methyl or ethyl vinyl ketone in methanol afforded 77 as well as octalones 78 and 79 which are products of a change in the regioselectivity of the reaction (equation 15). Apparently attack of the most substituted form of the enamine has occurred.
I
i CH2=CHCOMe ii. KOHfEtOH
On the basis of distribution of products obtained in these reactions with the change of solvents, temperature and molar ratio of reactants, a mechanism has been suggested for the anomalous annulation which does not involve an initial attack of the tetrasubstituted isomer of the enamine (equation 16)51.Alkylation of the more stable cis isomer of the enamine (80) with methyl vinyl ketone (MVK) would afford zwitterion 81 (attack by the other side of the enamine leads to strong steric interactions in thc transition state). Reaction of the thermodynamically less favorable trans isomer 83 gives rise to zwitterions 84 and 89 (both without axial-axial interactions), and ion 84 is sterically able to undergo intramolecular proton shift to afford enamine 85. Zwitterionic intermediates 81 and 89 can be stabilized by conversion to dihydropyrans 82 and 90, or protonated to immonium ions. The pair 81-82 will lead to enamine 85, while the pair 89-90 will afford enamine 91. Then, cyclization of 85 or 91 will afford the enone expected from the normal enamine version of the Robinson annulation. The anomalous products may be obtained hy conversion of enamines 85 and 91 to the corresponding enolates 86 and 92 due to the effect of external base or the tetrasubstituted enamine, followed by attack on a second molecule of methyl vinyl ketone affording isomeric enolates 87 and 93. Protonation of these enolates would afford precursors to enones 88 (cis alkyl groups) and 94 (trans alkyl groups). Asymmetric induction has been observed in some of these cycloaddition reactions with the use of chiral e n a m i n e ~ ~ ' -For ~ ~ .example, reaction of L-proline derived enamines (e.g. 95) with methyl vinyl ketone (equation 17) afforded, after hydrolysis, chiral cyclohexenones (e.g. 96) with optical yields up to 50%'=. Enamines from ketones can react with double Michael multicoupling reagents to give, after aqueous workup, mono- and bicyclic ketones, products of a , a ' - a n n u l a t i ~ n ~ ~ - ~ ~ .
Rafael Chinchilla and Jan-E. Backvall
18. Cycloadditions to enamines
Examples of such three-carbon synthons are 2-nitro-2-propen-I-yI acetates and pivalates, which have been developed by Seebach and coworker^^'^^^ as reagents for [3 33 cyclizations with cyclic and acyclic ketone enamines. After workup these reactions give 4-nitrocyclohexanones. With enamines from prolinol methyl ether and cyclic ketones, enantiomerically pure compounds were obtained5'. An example of such a [3 + 31 cyclization is the synthesis of bicyclic nitroketone 99 from nitroallylic ester 97 and enamine 98 (equation 18).
+
% I
OMe
The mechanism of this cyclization involves a conjugate addition of the enamine (100) to the nitroallyl ester (101) to give 102, which on elimination produced 103. The immonium salt 103 undergoes proton transfer to give enamino nitro olefin 104, which cyclizes to an etlamine (107) via 105 and 106. Hydrolysis of 107 produces the ketone (108). Depending on the reaction conditions and the structure of the enamine and nitroolefin components employed, intermediates can be isolated (equation 19). Similar cc,a'-annulations were achieved from reaction of cc,gunsaturated acid chlorides with cyclic ketone enamines which afforded bicycl0[3.3.1]nonane-2,9-diones~'~~~-~~ or bicycI0[4.3.l]decanones~~.In this reaction, N-acylation of the enamine 109 occurs as the first step giving 110, followed by a [3,3] sigmatropic rearrangement to a ketene intermediate (111). Ketene 111 subsequently cyclized via 112 to a bicyclic immonium salt (113) which after hydrolysis gave the corresponding dione 11463.If there is an axially oriented electrophilic substituent at C-4 of the enamine (for example, R = COPh) the enolate anion 115 may cyclize to an adamantane derivative 116 (equation 20). Hickmott and c o w o r k e r P have shown that the reaction of crotonoyl chloride with the pyrrolidino enamine of 4-benzoyl-4-methylcyclohexanone 117 gives a mixture of the three adamantane dione derivatives 118, 119 and 120 (equation 21). Surprisingly the main product obtained was the sterically most crowded 119, with the 6-phenyl and 9-methyl in mutually 1,3-diaxial position. This could be explainedif the [3,3] sigmatropic rearrangement of 121 to 122 occurs via a boat transition state conformation from the same face of the cyclohexene moiety as the benzoyl group (equation 22). Although a boat conformation (125 + 126) normally is preferred for this type of rearrangement,
1006
(loo) +
Rafael Chinchilla and Jan-E. Backvall
I
+
NR2
R3
R4
OCOR ? RZ '? NO? 'I+ -
+ R'
*
RCO? ~ R ZR3
R1
R2
NO2
which would give 120 (equation 23), an electrostatic attraction between the electrondeficient hydrogens of the crotonoyl group and the n-electrons of the benzene ring (cf. 121) was inferred to account for the preferred pathway. 2-Formyl-2-cyclohexenones (e.g. 129) react with 3-methyl-2-pyrrolidino-1-butene (130) to give, after hydrolysis, bicyclic ketols, e.g. 134, which on dehydration with trifluoroacetic acid gave octaline diones such as 135 (equation 24)67. This type of [3 + 31 carbocyclization requires a molar ratio enamine:enalone of 2:l for optimum results, which is explained by the exchange of the enamine 130 with hydroxymethylene ketone 131 to form pyrrolidinomethylene ketone 132 and 3-methyl-2-butanone.
18. Cycloadditions to enamines
(11 R = PhCO
1008
Rafael Chinchilla and Jan-E. Backvall
Palladium-catalyzed reaction of allylic 1,l-diol diacetate 136 with the pyrrolidino enamine of cyclohexanone (137) yields 2-acetoxybicyclo[3.3.1]nonan-9-one (138)68 (equation 25). Treatment of the enamine 139 with acrolein and then addition of dilute acid afforded bicyclic ketoalcohol 140 (equation 26)69. The inverse electron demand Diels-Alder reaction between enamines and electrondeficient dienes is a useful method for the synthesis of six-membered rings. The process ~ ~ ~ its ~ , rate (as in the other Diels-Alder is considered L U M O , , , , , - ~ o n t r o l l e d ~and
18. Cycloadditions to enamines
reactions) depends on the magnitude of the lowest HOMO-LUMO energy difference, This Dielsthat is HOMOdi,,,-LUMO,, ,,,,,i,, or LUMO,,,,,-HOMO,, ,,,, Alder reaction employs an electron-rich dienophile, as is the enamine (increasing HOMOdi,,,,,,,. energy), and an electron-deficient diene (decreasing LUMO,,,,, energy) leading to suitable reaction rates.
Rafael Chinchilla and Jan-E. Backvall
(13%
(140)
Examples of [4 + 21 cycloadducts obtained using this type of carbocyclization are given by compounds 14373(equation 27) and 14574,75 (equation 28) formed from 1- (141) and 2-substituted butadicnes ( l a ) , respectively.
g
-
M .-
P *
+
C02Me
High ;tsymmetric induction was rcported in thc cyclnadditivn of 2-sulfonyldienc~with chiritl cnarnines'".'-. For example". reaction of 2-phenvlsulfonvl-I,?-pentadiene(1461 with enamine 147 leads to adduct 148 as only one diastereoisomer (equation 29') fo; which the absolute stereochemistry was determined by X-ray dinraction.
1011
18. Cycloadditions to enamines
Dienamines are well documented, synthetically useful Diels-Alder dienes2. 78-"7. The main features of their reactions with dienophiles are high reactivity and the fact that the amino moiety controls the regiochemistry of the cycloaddition. For example, the reaction of an electron-deficient dienophile with 149 leads to the selective formation of cycloadduct 150, which on elimination of amine gives cyclohexadiene 151 (equation 30y5.
l:~:] -R2q r
R
R3
'
/
R4
CH2=CHEVfG~
NR2
7
,NR2
R3
\
R4
-R2NH
Rle R4
'
EWG (30)
R5
R4
Octalone dienamines, e.g. 152, have shown a remarkable solvent dependence in the reaction with methyl vinyl ketone (equation 31)86.In methanol, reaction occurs primarily at the less reactive 6-position of the dienamine and the mechanism probably involves a prototropic shift in the initially formed enolate anion to give 153, and subsequent cyclization onto C-8a of the enimmonium salt to give 154. In toluene, the change in regioselectivity is complete and the product obtained is 157, which must arise from 156, formed in turn from cycloaddition to cross-conjugated dienamine 155.
1012
Rafael Chinchilla and Jan-E. Backvall
2. Aromatic
Pyridazines (1,2-diazines) substituted with electron-withdrawing groups undergo inverse electron demand Diels-Alder reaction with e n a m i n e ~ ~ ~ -The ~ ' . cycloaddition occurs across C-3/C-6 of the diazine ring and with a predictable regiospecificity with respect to the substituents on the nucleus. Loss of nitrogen from the initial bicycloadduct followed by elimination of the amine residue afforded benzene rings. Some examples are the transformation of phthalazines 158 into naphthalenes 160 (equation 32)91, o r the synthesis of phthalazine derivatives 163 from condensed pyridazines 161 (equation 33)92,with addition of the enamine to the less hindered ring.
This cycloaddition has also been used in the regiospecific preparation of 3- or 4-substituted-2,6-dimethylbenzoates(167) by reaction of 4,6-dimethyl-2-0x0-2H-pyran5-carboxylic acid esters (164) and morpholino enamines (equation 34)y3.
18. Cycloadditions to enamines
1013
Biaryl-2-carbonitriles 172 can be ~ r e ~ a r by e d [4 + 21 cycloaddition of ylidenemalono168 to dienamines 16994., followed bv elimination of amine and HCN from the intermediates 170 and 171 (equation 35). nitriles ..-~ ~~~
- -
The acid-catalyzed reaction of enamines with the ester carbonyl group of Ctrimethylsilyl-3-dialkylaminocrotonate esters (173) leads to the formation of highly substituted aromatic rings as in 174 and 17595(equation 36). Different enamines react either as a 2C or as a 3C component depending on their structures; enamines from acyclic ketones give aromatic compounds by [3 + 31 annulation, whereas enamines derived from cyclic ketones afford [4 + 2) products. A probable mechanism involves displacement of the ester's alkoxide group by the enamine to give intermediate 178, which undergoes isomerization to 179 and then intramolecular Michael condensation leading to the
+
[3 33 product 180 (equation 37). The silyl group is protodesilylated under the reaction conditions. For cyclic enamines, isomerization of 178 to 181 by a 1,5-silyl shift intervenes, followed by Mannich reaction giving a [4 + 21 product 182. The reaction of electron-poor butadienes with enamines can afford the corresponding benzenes by treatment of the initial 1,3-cyclohexadiene derivatives with some oxidants or by heating96. An example is the preparation of sulfonyl benzenes 186 from disulfonyl dienes 183 and enamines 184 giving adduct 185, which then aromatizes (equation 38)97.98.The presence of an additional unsaturation like in trimethylsilyl
1014
Rafael Chinchilla and Jan-E. Backvall
18. Cycloadditions to enamines
S
T
,A ii. 5% HCI
COMe
*
Me3si COMe
vinylallenone 187 (equation 39) results in a spontaneous aromatization at room temperature to produce substituted arylsilanes 1 8 8 ~ ~ .
E. Larger Rings
Cycloadducts with more than six carbon atoms have been obtained by reaction of enamines of cyclic ketones (e.g. 14) with acetylenic esters such as 189 in apolar solvents. The reaction involves formation of the [ 2 + 21 cycloadduct 190 followed by thermal electrocyclic reaction of the cis-fused cyclobutene (see Section ILB)366,77. It has been demonstrated that the initial ring-opening product has the cis,trans configuration (191)37,indicating conrotatory opening of the cyclobutene ring. The cycloalkadiene 191 formed isomerizes via a [1,5] sigmatropic hydrogen shift to cis&-cycloalkadiene 192 and some of the latter isomerizes to 193 (equation 40).
1016
Rafael Chinchilla and Jan-E. Bickvall
Dienamines and enamines have been used in intermolecular [6 + 4I1O0 and inand [6 + 2]1°' cycloadditions to fulvenes, probably via a tramolecular [6 + 4]101. zwitterionic intermediatelo'. Example of a [6 + 43 cycloaddition is given in equation 41102. The initial product from reaction between 194 and 195 eliminates the amine to produce 196.
This section is concerned with methods for the ring formation of heterocyclic systems containing one, two or more hetero atoms, with the enamine nitrogen being included or not in the new heterocycle created. A. Three-membered Rings
Suitable enamines can react with (ethoxycarbonyl)nitrene, generated from ethyl N-(4-nitrophenylsulphoxy)carbamate, giving relatively unstable aziridineslo3. Diastereoselective attack of this nitrene on the double bond of chiral enamine 98 and opening of the intermediate aziridine (197) afforded enantiomerically enriched 2-ethoxycarbonylaminocyclohexanone 198104,105(equation 42).
8. Four-membered Rings
Sulfenes (RCH=SO,) (usually generated in situ from the corresponding sulfonyl chlorides in the presence of triethylamine) react with enamines to give [2 23 cycloadducts (thietane l , l - d i o ~ i d e s ) ' ~or~ open-chain -~~~ sulfones depending on the nature of R in RCH,SO,CI. Generally, cyclization occurs when R = H or Ar but not when R = Alkyl. The putative mechanism of this cyclization involves a two-step process via a zwitterionic intermediate 200 (equation 43)Io8. Both [2 + 23 and [4 + 23 cycloadditions have been observed in the reaction of dienamines with sulfenes. For example, reaction of cross-conjugated dienamine 202 with sulfene afforded a mixture of 203 and 204 (equation 44)'". Also, enamines of 1-tetralone (205,206) can react as enamines or as aminodienes with phenylsulphene giving 207-209 (equation 45)"'.
+
18. Cycloadditions to enamines
Sulfonyl imides (RN=SO,), generated from alkylsulfamoyl chloride (RNHS0,CI) and triethylamine, react with enamines in the same way as sulfenes do, to give four-membered heterocycloadducts such as 210"3. Phenyl isocyanate undergoes [2 21 cycloaddition with enamines affording azetidinonesl l 4 (211) whereas azetidinothiones (212) have been obtained from the reaction of isothiocyanates with enamines without b- hydrogen^"^. Azetidines (215) have been synthesized by high-pressure-promoted [2 23 cycloadditions between imines such as 213 and b,p-disubstituted enamines such as 5O1I6 in a weak polar solvent so that the dipolar intermediate 214 is neither stabilized nor intercepted (equation 46). The azetidines formed were unstable at a normal pressure and slowly decomposed into starting materials on standing.
+
+
Rafael Chinchilla and Jan-E. Backvall
1018
C. Five-membered Rings 1. One hetero atom
The synthesis of benzofuranols has been accomplished by reaction ofp-benzoquinones with enamines'10.117.For example, when silylenamine 217 was allowed to react with p-benzoquinone 216, a 1,3-cycloaddition took place to give dihydrofuranol 218, which after treatment with acid was transformed to benzofuranol 219'1° (equation 47).
SiMe3
HCI
f7
-HN
\P
(219) (218)
18. Cycloadditions lo enamines
1019
The reaction of 3-bromo-4-nitroquinoline 1-oxide (220) with 1-morpholinocyclohexene 14 gave furoquinoline 228 after treatment with base (equation 48)"'. It was demonstrated that the reaction proceeds via a multistep ionic process involving the initial formation of 225 via 221-224 followed by a base-catalyzed enolization to 226 and cyclization to 227 and 228. Apparently, the strong electron-withdrawing effect of the nitro group is essential for the reaction to occur, because similar compounds without the nitro group do not undergo this conversion.
1020
Rafael Chinchilla and Jan-E. Backvall
Aminofuran derivatives 229,230 and 231 were obtained by reaction of the corresponding enamines with styrene oxide1lY,2 - c h l o r o t r 0 ~ o n eor~ ~photochemically ~ with tris(2,4pentadionate)~obalt(III)~, respectively.
* COMe
Azirines with electron-withdrawing substituents at the imine function can be used in ring-transformation reactions with enamines to give pyrrole mono-'22 o r di-carboxylateslZ3.L'abbC. and coworkers'23 proposed a mechanism involving cycloaddition of the enamine 232 to the C=N bond of the azirine 233, to give the zwitterion 234, which cyclizes to 235. Ring expansion of 235 and elimination of the amine residue give a pyrrole 239, whereas Katritzky and coworkers1z2 have proposed that the bicycle 235 is converted into a mixture of 2,3-dihydropyrrole 237 and a 3,4-dihydropyrrole 238, before elimination of amine (equation 49).
(232)
(233) path A
A R4
R4
(237)
(236)
R2
R3
18. Cycloadditions to enamines
1021
Quaternary anilinium salts (240), obtained from reaction of (pyrrol-1-yl)methanol and the appropriate aniline with trioctylphosphine, react in polar solvents via the azoniafulvene ion (241) with enamines through a Mannich-type reaction followed by cyclization to give pyrrolizidines 242 and 243lZ4.The ratio between the pyrrolizidines formed varies considerably with ring size of the enamine employed (equation 50). Pyrrolizines have also been obtained by reaction of pyrrole with two equivalents of enaminelzS or condensation of some ketones with L-sodium or L-ethyl prolinate126.
(243) lndole derivatives have been prepared by reaction of 2-bromoanilines with enamines in the presence of palladium(I1) acetateI2', reductive cyclization onto a nitro group'2R, or by the same type of cycloaddition that allows the synthesis of benzofuranols (see above) but using p-quinone d i i m i d e ~ ' ~An ~ . example of an application of this latter method is the regioselective nucleophilic addition of 1-piperidino-1-propene (245) t o the selectively activated N4-(phenylsulfonyl)-p-quinone diimide 244 (equation 51)130. FurNS02Ph
b
+
yJ
- 04-77
NHsOzph
OCHzPh
NCOPh
PhOC
OCH2Ph
Rafael Chinchilla and Jan-E. Backvall
1022
ther acid-catalyzed elimination of piperidine from cycloadduct 246 produced the indol derivative 247, which is a key intermediate in the synthesis of the antitumor agent CC-1065. Hydroindole derivatives can be obtained by photocyclization of N-aryl enamines.13'. Nucleophilic attack by enamines, e.g. 248, on dichlorophenylphosphine gives an intermediate 249, which can react with a second mole of enamine to give 250. Further amine elimination from 250 and cyclization yield 2-amino-1-phenylphospholes251 (equation 52)13'.
(251)
2. Two hetero atoms
Five-membered rings containing two nitrogens or a nitrogen and an oxygen atom have been frequently obtained using dipolar reactants in a 1,3-dipolar cycloaddition reaction across the enaminic double bond'33. Some examples are: (i) the synthesis of indazole derivatives 255 by reaction of 2-indanone enamine 252 with diarylnitrilimines~34.135 via the stable zwitterionic nitrilimine-enamine cycloadduct 254 (equation 53)135;(ii) the preparation of isoxazole 257 from the heterocyclic enamine 256 using a nitrile oxide (equation 54)136.'37; and (iii) the formation of isoxazolidine 260 by cycloaddition of cnamine 259 to nitrone 258 (equation 55)'38. Enamines derived from 2,2-disubstituted aldehydes (e.g. 261) react with N-chloro-N'aryl- and N-chloro-N'- aroylamidines (262) according t o two different pathways atfording either imidazoline rings (264) or open-chain amidines (265)139 depending on the substituent at the enamine double bond and at the N' atom of the benzamidine (equation 56). N,N-bis-trimethylsilyl enamines (e.g. 269) obtained by sequential addition of methyllithium and acyl chlorides to acetyltrimethylsilane cyanohydrin 267, cyclize under thermolysis o r by trimethylsilyl trifluoromethanesulfonate treatment to give substituted oxazoles (e.g. 270) (equation 57)140.
18. Cycloadditions to enamines
Rafael Chinchilla and Jan-E. Backvall
1024
Me
N
-
OCOR A or
Me,siom
Me+~(si~e3)2 Me
3. Three hetero atoms
Five-membered rings with three hetero atoms have been obtained by 1,3-dipolar cycloaddition of azides (RN,) to enamines leading to 4,5-dihydro-1,2,3-triazoles.In general these [3 + 21 cycloaddition products are unstable and eliminate the amine to give stable triazoles or rearrange or undergo cycloreversion via different pathways'41. This cycloaddition is stereospecific and regiospecific with respect to the enamine, with the substituted nitrogen of the azide forming a bond to the carbon of the enamine bearing the amine. The mechanism is considered to be concerted and not synchronous because of charge separation in the transition state, as has been satisfactorily explained by MO perturbation treatment^'^^.'^^,'^^. Some recent examples of the use of this cycloaddition include reaction of aryl azides with: (i) enamine 271 to give diaminodihydrotriazoI272, which on deamination produces
18. Cycloadditions to enamines
1025
(ii) enamine 274 affording spiro-aminodihydrotriazol aminotriazol273 (equation 275 which rcarrangcs to aminotriazol 276 possibly because of relief of strain (equation 59)145.146;(iii)enamine 277 to give labile and not isolable 278, which loses diazomethane yielding product 279 (equation 60)147.Chiral proline-derived optically active enamines
Rafael Chinchilla and Jan-E. Backvall
1026
of cyclohexanone cyclized with azidoformate t o give the expected triazol, which after photolysis afforded an aziridine and then 2-(ethoxycarbonylamino)cyclohexanone with moderate ee values (3%-35%)lo5 (see Section 1II.A).
D. Six-membered Rings 1. One hetero atom
Heterocyclic azadienes like di- and triazines have been used in the synthesis of pyridine rings. In general terms the reaction involves a regiospecific inverse electron demand Diels-Alder cycloaddition between the heterocycle and the enamine 280 followed by elimination of HCN (diazines) o r N, (triazines) and an amine from the primary cycloadduct 281 or 283, respectively, to give pyridines 282 and 284 (equation 61). At least in one case the latter type of intermediate has been isolated and fully characterized14'.
1.3-Diazines (pyrimidines) bearing a strong electron-withdrawing substituent like NO, can undergo [4 21 cycloaddition reaction with enamines leading to pyridine derivatives~49.~so . Heterocyclic azadienes like 1 , 2 , 3 - t r i a ~ i n e s ' ~ ~and - l ~ ~principally 1,2,4t r i a ~ i n e s ' ~ ~h-ave ' ~ ~been used more extensively in this kind of cycloaddition to enamines. It is noteworthy to remark the pioneering work by Boger and coworkers155-158 on this type of cycloaddition reaction with 1,2,4-triazines. Via this methodology even 'catalytic' Diels-Alder reactionslS6 were developed with an in situ generation of the enamine, employing a catalytic amount of the amine (equation 62). 4-Nitro-3-phenylisoxazole-5-carboxylates (290) act as heterocyclic 1-azadiene components in [4 + 21 cycloaddition reaction with some enamines affording bicyclo derivatives 295 probably via a stepwise ionic cycloaddition involving the Michael adducts 292 as primary intermediates. Further intramolecular attack by the isoxazole nitrogen on the immonium carbon followed by elimination of the amine and aromatization of dihydropyridine 293 afforded 294, which was transformed into pyridine 295 by simple reduct i ~ n (equation ' ~ ~ 63). The pyridine ring system has also been obtained via the [4 + 21 cycloaddition reaction between enamines and acyclic azadienes like a$-unsaturated c a r b ~ d i i m i d e s ' ~ ~In .'~~. this way, compounds like 297 (obtained from the vinyliminotriphenylphosphorane 296
+
18. Cycloadditions to enarnines
using an aza-Wittig reaction) led to the intermediate 298 which underwent hydrogen migration and subsequent deamination to give pyridine 299 with high regiospecificity (equation 64)'". 2-Aza-1,3-butadienes have been used for the synthesis of the pyridine ~ k e l e t o n ' ~ ' - ' ~ ~ o r substituted piperidines16! If the azadiene is not activated by an electron-withdrawing group, high temperatures16' or the use of BF,16' is required in order to achieve the Diels-Alder reaction.
Rafael Chinchilla and Jan-E. Backvall
C)
g: NPh
Ring-fused pyridines of type 300 and 301 have been prepared by condensation of enamines with immonium salts"0, and by reaction of morpholino enamines derived from a-pyridyl ketones with aromatic aldehydes and further treatment with ammonium a ~ e t a t e ' ~ ' . 'respectively. ~~,
2-Pyridinone derivatives such as 305 are obtained from the reaction of enamines with substituted vinyl isocyanates 303 as azadiene equivalents. These isocyanates can be prepared directly from the corresponding E,/J'-unsaturated acids by using one of several modified Curtius procedures'73 employing diphenylphosphorazidate (DPPA) as the azide transfer reagent. The isocyanates thus obtained are not isolated but are immediately exposed to a nucleophilic dienophilic partner such as an enamine to give 2-pyridinones 305 (equation 65)'7"'76. Compounds with skeleton 306 can be readily transformed to highly substituted pyridines by reaction with POCI, and subsequent hydrogenation of the chloropyridine 307 formed to give 308 (equation 66)176. With simple unsubstituted vinyl isocyanate the N-vinyl carboxamides obtained do not cyclize readily 177. 2-Pyridinones have been obtained by reaction of malononitrile with some enamines of 1-tetral~ne"~,and 2-pyridinones 313 were obtained by 1,4-dipolar cycloaddition
18. Cycloadditions to enamines
reaction between enamines and the oxazinium species 311, obtained from (chlorocarbony1)phenylketene (309) and amides, followed by thermolysis (equation 67)179. The Stork's aza-annulation method with a ~ r ~ l a m i d e ' ~has ~ . ' been ~ ' used frequently for the synthesis of six-membered nitrogen-containing heterocycles. Recently, this reaction was applied to the synthesis of 315 and 316 from protected enamine 314 (equation 68)18'. Compound 315 is a key intermediate in the synthesis of the alkaloid Huperzine A and its analogues. Enamine carbaldehydes (317) have been used in the synthesis of 1,4-dihydropyridines (318) via photochemical cycloaddition with a l k e n e ~ ' ~ ~ , " ' ~ . Cross-conjugated enamines like 2-morpholinobutadienes (319) react with benzylideneaniline (320) in the presence of ZnC1, to give tetrahydropyridine (322) with a high degree of stereo~electivity'~~. The high stereoselectivity was explained by assuming that the reaction takes place in a concerted manner via coordination of diene and dienophile to the Lewis acid (equation 69). Tetrahydroquinoline derivatives can be obtained by cycloaddition of aromatic imines or immonium salts with enamines having an ~ - h ~ d r o ~ e n ' ~ Anodic ~ . ' ~ ' . oxidation of N,N-dimethylaniline 323 in methanol to cc-methoxylated compound 324 and subsequent
Rafael Chinchilla and Jan-E. Backvall
treatment with a Lewis acid in the presence of aldehyde enamines afforded tetrahydroquinolines such as 326, most likely via an immonium ion (325) (equation 70)"'. Dihydropyrans (330) have been found to be the first formed product in the reaction of u,P-unsaturated carbonyl compounds 327 with enamines 328 and their stability is highly dependent on the enamine and heterodiene structures. The formation of these dihydropyrans could occur via a concerted [4 + 21 cycloaddition reaction or via a two-step process involving a zwitterionic immonium enolate intermediate 329 (equation 7 1). There is evidence strongly supporting the two-step mechanism. For example, the zwitterionic intermediate1" has been trapped, and, furthermore, cis- and trans-isomeric electrophilic olefins give the same p r o d u ~ t " ~ ~The ' ~ ~reaction . has been applied to many different conjugated systems and its regio- and stereoselectivity has been extensively s t ~ d i e d ' ~. So ~ .me ' ~ examples ~ of this heterocycloaddition include the preparation of 1,Cdihydropyran derivative 331lY3,332194 and 333195by intermolecular reaction. In another example 336 was obtained by intramolecular enamine-enal cycloaddition from
18. Cycloadditions to enamines
i. CH2=CHCONH2 ii. H 2 0
*
1031
1032
Rafael Chinchilla and Jan-E. Backvall
the 2,7-substituted oct-2-ene-13-dial 334196,'97(equation 72). In the latter case, the use of a chiral secondary amine afforded a cycloadduct 336 as two diastereoisomers in a ratio of 17:1198. Dihydropyran derivatives (339) have also been obtained by the hetero Diels-Alder reaction between electron-rich olefins such as en01 ethers 338 and amino ketones 337 bearing electron-withdrawing groups such as methoxycarbonyl, trifluoromethyl or
18. Cycloadditions to enamines
/
OHC
-
EWG
(337)
EWG
(338)
11 at ~osition2 or 3 of the oxabuta,diene moiety (equation 73)1yy~200 . W'~ t h a methyl substituent in the 2-position the oxabutadiene is not reactive enough in hetero DielsAlder reactions, but a phenylthio group in the 3-position leads to a facile cycloaddition reaction. In the latter Case further hydrogenation leads to the desulfurized dihydropyranZ0'. Chromenes (342) were prepared, via o-quinone methides, from o-phenolic Mannich bases and enaminesZo2,but have also been obtained by reaction of functionalized enamines like 340, with an electron-withdrawing substituent in the P-position, and substituted o-hydroxybenzyl alcohols 341 in boiling acetic acid203(equation 74).
Formation of the xanthane skeleton (347) by condensation of a cyclohexanone enamine (343) with o-hydroxybenzaldehyde (344) (equation 75) was reported by PaquetteZo4.Since then, many related heterocycles have been synthesized using appropriately functionalized ~ a l i c ~ l a l d e h ~ dThis e s ~condensation ~~. involves initial bimolecular combination, wherein the aldehydic carbon is attacked by the P-carbon of the enamine, resulting in the formation of a dipolar species 345 which, on proton transfer, gives 346. Subsequent ring closure of the latter intermediate produces 347. Interestingly, the condensation of 5-chlorosalicylaldehyde with an enamine derived from the ethoxymethylenemalonyl urethane has been reported to afford the coumarin 34S206 instead of the expected hydroxyxanthane.
Rafael Chinchilla and Jan-E. Backvall
Xanthone derivatives can be obtained by oxidation of the hydroxyxanthanes prepared by the Paquette method or by employing the same method on derivatives of salicylic acidZo7or ~ - k e t ~ e s t e rWith s ~ ~ ~the . latter procedure compounds 349 and 350, respectively, were prepared.
OMe
Six-membered sulfur heterocycles such as 352 and 353 have been synthesized by 14 23 cycloaddition of enaminothiones (351) to electrophilic olefins and acetyl, I.ike acrylonitrile and dimethyl acetylenedicarboxylate (equation 76)'OY. eneszo9-z~~ have been used in the preparaThioacylketene t h i o a c e t a l ~ or ~ ' ~1,2-dithiole-3-thione~~'~ tion of thiopyranthiones.
+
2. Two or more hetero atoms
Regiospecific inverse electron demand Diels-Alder reactions of enamines with 1,3diazines or 1,2,3- and 1,2,4-triazines (see Section III.D.l), which on elimination of HCN or N,, respectively, produce a pyridine ring, can be used with 1,3,5-triazines and 1,2,4,5-tetrazines as a useful method for the synthesis of pyrimidinesz16216 (1,3-diazines) and pyridazines217-219(1,2-diazines). Examples of the use of this methodology are the preparation of the pyrimidine substituted benzomorphane 356 (equation 77)'" and the pyridazine 359 (equation 78), intermediate in the total synthesis of cis- and transtrikentrin A216.
18. Cycloadditions to enamines
SMe
MeS
The 1,3-diazines have also been prepared by a reaction of enamines and S,S-dimethyl-
N-(N-arylbenzimidoyl)sulfimides360 in boiling tetraline220.221. The mechanism of the ring formation probably involves a thermal cleavage of the imidoylsulfimides 360 into imidoylnitrenes 361 and dimethyl sulfide. The nitrene can then react with the enamine to give an aziridine intermediate 362 which rearranges to a 3,4-dihydroquinazoline 363. Subsequent elimination of amine yields the quinazoline 364'". When cc-bromoacetophenone semicarbazone (366) is allowed to react with enamines of cyclic ketones or aldehydes, such as 365 in the presence of triethylamine, substituted
1036
Rafael Chinchilla and Jan-E. Backvall
6-amino-1,4,5,6-tetrahydropyridazines (367) are (equation 80). These compounds were transformed, after loss of the aminic residue, into the corresponding dihydropyrazine derivatives (368) and, by subsequent aromatization, into pyridazines (369). When the reaction was performed with the morpholinoenamines of ketones, pyridazines, 6-hydroxy-1,4,6-tetrahydropyridazinesand open-chain compounds were obtainedzz2. 1,3-Diazadienes 370 and 371, formed in situ from the corresponding silyl imine and phenylisocyanate, readily undergo [4 21 cycloadditions with enamines derived from butyraldehyde and cyclohexanone leading, after deamination, to pyrimidone 372 and pyrimidothione 373, respectivelyzz4. Alkylation of enamines with phenacyl bromide oxime (374) affords dihydro-1,2oxazines 376 after base-catalyzed cyclization of the intermediate immonium salt under
+
18. Cycloadditions to enamines
anhydrous conditionszz5. Treatment of oxime 374 with a base such as potassium carbonate generates a vinylnitroso compound (375) in situ, which participates as a 4rr component in a [4 + 21 cycloaddition to the enamine226-22y(equation 81)229. The presence of an electron-withdrawing substituent on the vinylnitroso system enhances their r e a ~ t i v i t y The ~ ~ ~dihydro-1,2-oxazines ~~~~. obtained have been used for the preparation of pyrroles2", pyrrolidi~~eszZy and pyridineszz8.
Enamines (e.g. 377) have been shown to react with conjugated nitroolefins 378 to give mainly dihydro-1,2-oxazine N-oxide derivatives 379 as products of kinetic control (sometimes a cyclobutane ring is formed in these reactions; see Section 1I.B). The stability of these heterocycles is largely dependent on the parent enamine and the type of substitucnt uscd on the nitro olcfin as has bccn extcnsively studied by Valentin and coworker^^^'-^^^ . U sually they open into the corresponding nitroalkylated e n a m i n e ~ ~ ~ ~ 380 (equation 82), in particular in a solution of methanol or deuteriated chloroform231,232,235, and often an equilibrium between the two forms is established. Stable 1,2-oxazine N-oxides have been obtained in the reaction of 2-nitro-1,3-dienes with cyclic enamine~~~'. The reaction, usually considered as a two-step process2", gives a high degree of diastereoselectivity affording normally a single heterocyclic compound although three new stereocenters can be created, and with a cis junction between rings when cyclic
Rafael Chinchilla and Jan-E. Bickvall
1038
enamines are used. Examples are 1,2-oxazine N-oxides 381234and 382238,with asymmetric carbons with a relative configuration resulting from the Re-Re approach of the reagents. When a chiral enamine derived from (3-2-(methoxymethyl)pyrrolidine was used, heterocycloadduct 383 was obtained in a very high diastereomeric excess239. Oxazine N-oxides 386 obtained from cross-conjugated keto enamines 384, and 1nitrocyclohexene 385 d o not ring open to nitroalkylated enamines, but undergo ring ~ ~ . ~ ~ ~ . ring fission fission and rearrangement to five-membered c a r b o c y c l e ~ ~Nucleophilic of 386 to the intermediate 387 followcd by recyclization gave the hexahydroindene
(83) 'OH
HO
NR2
0-
18. Cycloadditions to enamines
1039
derivative 389, which isomerized into its diastereoisomer 391 when left in a protic solvent. Acidic hydrolysis of diastereomeric enamines 390 and 391 afforded cyclopentanones 392 and 393, respectively (equation 83). When 3-nitro-2,4-hexadiene (394) was allowed to react with the pyrrolidino enamine 137 (equation 84) the oxazine 395 was detected, but the latter immediately opened and closed again forming a new C-C bond, affording the Diels-Alder-type carbocycloadduct 397. With the use of a chiral enamine, this adduct was obtained in 71% de2j9.
Dihydro-1,3-oxazines (398) are cyclic intermediates in the synthesis of a-amino-y-0x0 acid esters by reaction of acyliminoacetates with enamines derived from six-membered ketones240.Sulfur-containing heterocycloadducts 399 and 400 have been prepared by [4 + 21 cycloaddition of enamines to heterocumulenes like thioacyl isocyanates and acyl isothi~cyanates~~'.
("I
("I
N
phyD N
$"hp
N
' H
0
1040
Rafael Chinchilla and Jan-E. Backvall
When pyrocatechols are oxidized using cerium(1V) sulfate, the corresponding labile 1,2-benzoquinones are obtained which can be trapped by enamines affording aminobenzodioxins (401)242.The reaction probably proceeds via an ionic mechanism including a zwitterionic intermediate such as 402 formed via a charge-transfer complex.
Cyclopentanone (403) and cyclohexanone enamines react with symmetric and nonsymmetric diimides of type EtO,CN=NAr, ArCON=NCOAr and ArN=NCOAr' (404) to give 1,3,4-oxadiazine derivatives 405 or open-chain Michael-type compounds 406 (equation 85)243-245.The formation of the former products seems to be favored by the presence of acceptor substituents on the aromatic ring of the diazene, and their stability is highly dependent on the ring size of the enamine employed.
E. Larger Rings
The two-carbon ring expansion which involves the [2 + 21 cycloaddition of enamines of cyclic ketones with electron-deficient acetylenes followed by thermal rearrangement of the resulting fused cyclobutenes (see Section 1I.E) has been successfully used in the synthesis of medium-size heterocycles. Examples include the preparation of compounds 407246,40V4' and 409248.
18. Cycloadditions to enamines
IV. MINES
It has been demonstrated that imines 410 are in tautomeric equilibrium with their secondary enamine forms 4111.249(equation 86). Except where the enamine tautomer is stabilized by further c ~ n j u ~ a t i o n ~the ~ equilibrium ~ . ~ ~ ' , is almost completely in favor of the imine form.
The present section is briefly devoted to cyclization reactions to imines (in fact, to their secondary enarnine tautomers), and will show some recent examples of the synthetic use of these 'hidden' enamines in annulation reactions. Chiral imines have proved to be useful reagents in the synthesis of cyclic systems. For example, imines derived from (S)-( - )- and (R)-( + )-1-phenylethylarnine 412 have been used in the preparation of optically pure polysubstituted cyclopentanone derivatives 414 (equation 87)252and in enantioselective steroid synthesis (equation 88)253. When ketone 419 and an ammonia saturated solution of methyl propiolate in methanol were heated in a Parr reactor, 2-pyridone 424 was obtained254.Presumably, the reaction course involves initial condensation of ammonia with the ketone to imine 420, which reacts via its enamine tautomer 421 in a Michael fashion with the methyl
Rafael Chinchilla and Jan-E. Backvall
Me
8 OMe
Me;FH
N'
I
0
OMe 0
OMe
i. CH2=CHCOMe
ii. HOAc iii. MeONaJMeOH
HN I Me' * b H Ph (417)
propiolate 422. Subsequent attack of nitrogen on the ester carbonyl group of 423 gives the pyridone (equation 89). When acrylate derivatives reacted with N-alkylirnines, subsequent cyclization via their enarnine tautorner to pyridones occurredz55.
OMe
Lo
/
1044
Rafael Chinchilla a n d Jan-E. Backvall
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~
~
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1046
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~
\
~
~
,
-
~. ~
~
18. Cycloadditions to enamines
1047
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1048
Rafael Chinchilla a n d Jan-E. Backvall
B. Lamm and C.-J. Aurell, Acta Chem. Scand., Ser. B, 35, 197 (1981). M.-S. Lin and V. Snieckus, J. Org. Chem., 36, 645 (1971). G. Markl and H. Baier, Tetrahedron Lett., 4439 (1972). J. d'Angelo, D. Desmaele, F. Dumas and A. Guingant, Tetrahedron: Asymmelry, 3,459 (1992). A. Guingant and H. Hammami, Tetrahedron: Asymmetry, 2,411 (1991). T. Volpe, G. Revial, M. Pfau and J. d'Angelo, Tetrahedron Lett., 28, 2367 (1987). F. Felluga, P. Nitti, G. Pitacco and E. Valentin, J. Chem. Res. ( S ) , 86 (1992); J. Chem. Res. ( M ) 709 (1992). 253. J. d'Angelo, G. Revial, T. Volpe and M. Pfau, Tetrahedron Lett., 29, 4427 (1988). 254. A. P. Kozikowski, E. R. Reddy and C. P. Miller, J. Chem. Soc., Perkin Trans. 1, 195 (1990). 255. K. Paulvannan and J. R. Stille, J. Org. Chem., 57, 5319 (1992). 246. 247. 248. 249. 250. 251. 252.
CHAPTER
19
Mechanisms of enamine hydrolysis J A M E S R . KEEFFE Department of Chemistry and Biochemistry. San Francisco State University. San Francisco. CA 94 132. USA
and A . JERRY KRESGE
.
Department of Chemistry. University of Toronto. Toronto. Ontario M5S 7 A l Canada
I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I1. PROTONATION O F ENAMINES . . . . . . . . . . . . . . . . . . . . . . . . A. Equilibrium Basicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. General features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Effects of amino group structure on basicity . . . . . . . . . . . . . . . 3. ElTects of alkene group structure on basicity . . . . . . . . . . . . . . . 4. Gas-phase basicity of enamines . . . . . . . . . . . . . . . . . . . . . . . I11. HYDROLYSIS MECHANISMS . . . . . . . . . . . . . . . . . . . . . . . . . A . N-Alkylenamines of Isobutyraldehyde . . . . . . . . . . . . . . . . . . . . 1. The higher pH region . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. The middle pH region . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. The lower pH and H, region . . . . . . . . . . . . . . . . . . . . . . . . B. N-Alkylenamines of Propiophenone . . . . . . . . . . . . . . . . . . . . . . 1. The higher pH region . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. The middle pH region . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. The lower pH and H, region . . . . . . . . . . . . . . . . . . . . . . . . C . fi-Cyanoenamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D . /3-Carboethoxyenamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E . N-Arylenamines of Isobutyraldehyde, Cyclohexanone and 2-Methylcyclohexanone . . . . . . . . . . . . . . . . . . . . . . . . . . F. Miscellaneous Enamines and Some Related Compounds . . . . . . . . . 1. Two b-arylenamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Some enaminones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
TIIFCheinistn ~fEnarnines. Edited by Zvi Rappoport Copyright 0 1994 John Wiley & Sons. Ltd . ISBN: 0-471-93339-2
1049
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James R. Keeffe and A. Jerry Kresge
3. Two 1,4-dihydropyridines . . . . . . . . . . . . . . . . . . 4. Modified enamines: aminoarenes, enamides and pyrroles G . A Brief Summary of Section 111 . . . . . . . . . . . . . . . . IV. COMPARISONS AMONG NUCLEOPHILIC ALKENES . A. Equilibrium Basicities of X-C=C Compounds . . . . . . B. Kinetic Basicities of X-C=C Compounds . . . . . . . . . C. Enamine vs En01 Pathways in Amine-catalyzed Reactions . V. REFERENCES AND NOTES . . . . . . . . . . . . . . . . . . .
I. INTRODUCTION
Although the term 'enamine' was coined in 1927 (to emphasize the structural analogy with enols)', it wasn't until 1936 that a general synthesis for enamines was published, namely the condensation between aldehydes and secondary amines developed by Mannich and Davidsen2. That method was improved in the early 1950s by Herr and Hey1 who employed the azeotropic removal of water t o facilitate formation of a wider variety of enamines than had been available3. As described by Haynes, many other preparations were subsequently devised4. The modern era of enamine chemistry is considered to have begun with Stork and coworkers in 19545. Stork and others initiated programs in which the controlled P-carbon nucleophilicity of the vinylamine functional group was exploited. Reviews of this work and of other aspects of enamine structure and function were not long in c~ming~'~~. The reaction of electrophiles with tertiary enamines can be formulated as having several stages and is illustrated by equation 1. The fact that C-substitution can be forced, even when initial reaction occurs at the enamine nitrogen, is one of the synthetic virtues of the Stork enamine synthesis7.
(enammonium ion)
(iminium ion)
\
mostly
Perhaps the simplest example of this reaction sequence is the hydrolysis of enamines, shown in equation 2. It is the purpose of this chapter to consider in detail the mechanism(s) of enamine hydrolysis. Comparison between enamines and other nucleophilic alkenes, among them enolates, enols and en01 ethers, will also be made.
19. Mechanisms of enamine hydrolysis II. PROTONATION OF ENAMINES
A. Equilibrium Basicity
1. General features
The overall bonding changes which occur upon hydrolysis of enamines are shown by equation 2. Experimental studies on the protonation of enamines revealed that enamine salts are formed prior to attachment of a nucleophilic moiety. That is, protonation of enamines occurs before attack by water or any other n u ~ l e o p h i l e ~As , ~is . the case for alkylation7 and acylation5"~',protonation can occur either on nitrogen or on the b-carbon (equation 3).
Subsequent studies by Opitz and Griesingerl' and by Stamhuis and his coworkers" showed that, while protonation at nitrogen is faster, the C-protonated iminium ion is the more stable conjugate acid. Similar conclusions were reached on the basis of a 'H NMR study carried out by Elguero, Jacquier and Tarrayo". Table 1 shows the results of Opitz and Griesinger on protonation studies carried out in diethyl ether at -70 OC vs room temperature''. Stamhuis, Maas and Wynberg were able to deduce from kinetic studies that the N-protonated conjugate acids of compounds 1-3 have the pK, values ( H 2 0 , 25 "C, 1 = 0.10 M) shown with the structure^"^. Titrimetric and spectroscopic determinations were in good agreement"'. Sollenberger and Martin have reported a value for 4 and an approximate one for 5 (X = H), both at 25 "C in H,O (p = 0.20 M)13. The p@H' of compound 6 was determined by spectrophotometric titration (H,O, 2 5 T ,
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James R. Keeffe and A. Jerry Kresge
TABLE 1. C a r b o n versus nitrogen basicity of enamines1° % Protonation, - 70°C"
Enamine
at C
at N
% Protonation, r o o m tempb at C
at N
'The amine was treated at -70 "C with ethereal HCI. The precip~tatedsalt was then treated with ethereal lithium aluminum hydride at - 70 "C and the evolved H, was measured. Very similar results were obtained by use of ethereal diazomethane instead of LiAIH,. These numbers were obtained by allowing the salt to be at room temperature for a period of time prior to treatment with LiAIH,.
p = 0.10 M)l4. The N-basicity of enamines 1 4 is less than that of the corresponding saturated tertiary amines by about 35200 That of 5 (X = H) is probably reduced by a similar amount, while enamine 6 is weaker by lo5 or more. For compounds related to 1-5 (X = H) two factors are generally invoked to explain this decrease: stabilization of the enamine base by resonance, and destabilization of the N-protonated conjugate acid by the polar electron-withdrawing effect of the alkene. Grab and coworkers' measurement of the pK, values of quinuclidine, 7, and 2,3-dehydroquinuclidine, 8, establish that both effects are importantth, as they are in explaining the much
1053
19. Mechanisms of enamine hydrolysis
weaker basicity of aniline compared with cyclohexylaminel'. The weakened basicity of the bridgehead enamine, 9-methyl-9-azabicyclo[3.3.l]non-1-ene(9), relative to its saturated analogue reinforces this interpretationls. Base weakening of compound 6 is exaggerated owing to additional stabilization of this enamine by conjugation of nitrogen's lone pair, through the double bond, with the b-phenyl group. In Table 2 a number of relevant aqueous solution values are listed. values has been reported for the secondary enamine series, An additional set of 10, and the primary enamine series, 11, by Coward and Bruicezo. In both series the enamine is stabilized by a cyano group at Cg;both N-basicity and C-basicity should be greatly reduced. The N-basicities for both series are given in Table 3. These data show clearly the electronic effects of variously placed substituents on N-basicity. For series 10, the Hammett p value is + 2.8, essentially the same as the p value of + 2.77 (H,O, 25 "C)for the acid ionization of substituted anilinium ions themselvesz3. Coward and Bruice use this correspondence to argue that the preferred conformation of these enamines (though not best suited for C-protonation) is one in which the aromatic n-system and the lone pair on nitrogen are not well conjugated with the C=C bond. For series 11 the p value of + 0.84 (calculated without the value for X = COz-) is much smaller. It appears that the net result here is stabilization of the enammonium ion by the polar effect of electron-donating substituents, countered in part by stabilization of the enamine itself by the same substituents.
peH'
NC
Carbon-protonated enamines can be prepared in moderately concentrated aqueous and can be precipitated from organic solvent^^.'^. It is mineral acid difficult to measure values for these species in aqueous solution, however, for simple iminium ions would be in equilibrium with their enamines only at alkaline pH values, and under these conditions the iminium species are rapidly destroyed by h y d r o l y s i ~ ' ~There , ~ ~ . are favorable cases, however, in which this equilibrium occurs prior to the rate-determining step for overall hydrolysis, and values for can be estimated from kinetic data (see discussion in Section 111)". For example, in their study of hydrolysis kinetics, Sollenberger and Martin report a biphasic reaction course (below pH 10) for compounds 5, 12 and 1313; the initial, faster phase produces an intermediate species which, they argue, is the iminium ion. Consistent with this argument are the
eH'
en'
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James R. KeelTe and A. Jerry Kresge
TABLE 2. Nitrogen and carbon basicities of some enamines and related amines according to equation 3 (H,O, 25 "C)"
Enamine
p~rH*
~KP+
PK, of corresponding saturated tertiary amine
PK, of corresponding saturated secondary amineb
Reference
19. Mechanisms of enamine hydrolysis
1055
TABLE 2. (continued)
Enamine
pK.NH'
pKCH+
PK, of corresponding saturated tertiary amine
PK, of corresponding saturated secondary amineb
Reference
'Basicities of some heterocyclic enamines have been reported by Adams and Mahan"' and Leonard and coworkersnb.' and are listed by HinmanZ2.There remains uncertainty about the site of protonation, however. This column refers to the amine product of hydrolysis. ' Reference 15. N-Basicity of substituted piperidines averages ca lo2.' greater than that of the corresponding morpholines. ' Reference I l b,c. 'This entry is for cyclohexylamine.
TABLE 3. Nitrogen basicities of P-cyano enamines (H,O, 30 "C)20
some
pK,NH* Substituent X
H
co; CI
" Extra~olatedvalues.
Series 10
Series 11
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James R. Keeffe and A. Jerry Kresge
observations that the rate of phase one increases as the pH is lowered and is subject to general acid catalysis, and that the UV maximum of the intermediate formed from 12 (X = H), occurs at 270 nm, which is the same wavelength as the maximum observed when 12 is dissolved in 5.0 M H2S04. Moreover, the 'H NMR spectrum of 12 in 5.0 M H,S04, taken as quickly as possible after dissolution, shows two species, the more abundant of which has the peaks expected for the iminium ion while the minor component appears to be the enammonium ion. The latter quickly disappears in favor of the former, and after several days both species are replaced by propiophenone. Sollenberger and Martin's estimates for the p c H ' values of compounds 12 (X = H), 13 and 14 are included in Table 2.
2. Effects of amino group structure on basicity
Tables 2 and 3 show that the N-basicity order for enamines parallels very well that expected from the relative basicities of the corresponding parent amines. Structural effects on the C-basicity of enamines are, however, more complex. Because of the paucity of values for p c H ' , we shall anticipate our discussion of the kinetics of C-protonation (see Section 111) so that some of the information presented there can be incorporated into the present section. The justification for doing so is that many of the effects that influence the stability of the iminium ion are expected to be operational in the transition state. In particular, the coplanarity of the atoms about the C=N bond in the iminium ion (already preferred for some enamines, but only when geometrically possible24)should be maintained or improved in the transition state in order to maximize p n overlap (equation 4)25. This means that, besides the ability of the amino nitrogen to bear a positive charge, other factors such as formation of the C=N double bond (with attendant rehybridization at nitrogen), and steric interactions between groups attached to the alkene and amine moieties will be important both in the transition state and in the iminium ion product.
(H- -A moiety above the paper) Table 4 collects rate constants for P-carbon protonation of some tertiary enamines studied by Stamhuis and coworkers" and by Sollenberger and MartinI3. These enamines comprise two sets, in each of which the amino group is varied, but the other substituents on the vinyl group remain the same. For the propiophenone-based enamines the data in Tables 2 and 4, though limited, indicate that the C-basicity order is the same whether measured by p c H ' or the rate of protonation, namely morpholine ipiperidine << dimethylamine < pyrrolidine. We expect the same order to hold for other enamine sets provided they are based on a given carbonyl precursor. The C-basicity order is roughly the same as the N-basicity order of the corresponding saturated amines, except that the dimethylamine and pyrrolidine enamines are more reactive toward C-protonation than predicted from the basicities of the parent amines. The enhanced C-basicity of a pyrrolidine enamine compared with its piperidine analogue probably has its source in the greater ease of the hybridization change,
19. Mechanisms of enamine hydrolysis
1057
TABLE 4. Rate constants for carbon protonation of some enamines (H,O, 25 "C)"
Enamine
k,+ (lo5 M - ' S - I )
k,,,,(10~2s-1)
Reference
14
30
too fast
-
" Tidwell and coworkers have estimated from structure-reactivity relationships that the P,P-dimethylenatnines are slower by a factor of 30 than if the fl-methyl groups were absent. Similarly, the single P-methyl group on the propiophenone derwatives is expected to reduce k,+ by a factor of 3.4"'.
1058
James R. Keeffe and A. Jerry Kresge
sp3 +sp2, for an atom in a five-membered ring compared with an atom in a sixmembered ring. (Alternatively, and for the same reasons, the nitrogen of a pyrrolidine enamine is likely, in general, to be already sp2-like and well conjugated with the double bond24".) A variety of examples support these statements: Solvolysis of l-chloro-lmethylcyclopentane is faster than that of l-chloro-l-methylcyclohexane26. The elimination of HCN from cyanohydrins has equilibrium constants in the order, cyclopentanone>> ~ ~ c l o h e x a n o n e 'Heats ~. of dehydrogenation to the exocyclic alkene take the order, methylcyclopentane << methylcy~lohexane~~. Similarly, the endoergic heats of oxidation of alcohols to ketones are in the order, cyclopentanol < c y c l ~ h e x a n o lIt~ ~is. argued that whereas the sp3 + sp2 change relieves some torsional strain in a fivemembered ring, in a six-membered ring some torsional strain is generated by this ~hange'~.~~. The sp3 -. spZ hybridization change is shown by similar examples to be more facile for a dimethylamino nitrogen than for a piperidino nitrogen. Thus, the poorer N-basicity of compound 4 relative to 2 is apparently more than balanced by a relative lack of conformational problems upon rehybridization. Insight into the effects of amino group structure on the carbon basicity of enamines is also available from data on the protonation of indoles3' and p y r r o l e ~ ~Although ~.~~. the absolute basicities of these compounds are a good deal less than those of simple aliphatic enamines, the effects of N-alkylation should be transferable to ordinary enamines. Alkylation at nitrogen (that is, conversion of a secondary to a tertiary indole or pyrrole) enhances C-basicity by 0.fG2.0pK units, the increment depending on othcr structural details. Predictably, N-phenyl-2,5-dimethylpyrroleis less basic (by 1.3 pK units) than 2,s-dimethylpyrrole itself3'.
3. Effects of alkene group structure on basicity
Structural changes in the alkene portion of an enamine can also affect its basicity. Table 2 (equilibrium) and Table 4 (kinetics) contain a few examples, but these few data do not show the results of systematic variation of structure. A better view is possible through the analysis of HinmanZ2of the protonation behavior o l alkylated indoles (equation 5)31. Pertinent p g H ' values are given in Table 5. As
mentioned above, indoles are considerably less basic than simple enamines. Nevertheless, the effects of alkylation on basicity should show the same pattern for the two types of enamine. Hinman's conclusions can be simply stated: alkylation at position 2 (the cc-position) significantly increases C-basicity; alkylation at position 3 (the P-position) decreases C-basicity, though somewhat less strongly. Bulky alkyl groups can perturb these rules, but not by much. As applied to simple enamines, this analysis (combined with the discussion given above on amino group structure) suggests that the most basic of the simple enamines should be the pyrrolidine derivatives of acetone (15), cyclopenta-
19. Mechanisms of enamine hydrolysis TABLE 5. Alkyl substituent effects on t h e carbon basicity of indoles (cf equation 5; H,O, 25 "C)"
'Reference 31. Protonation occurs at position 3. N-Ethylated indoles have similar p e n ' values. Results in H,SO,/H,O and HCIO,/H,O were very similar. *Based on the H, acidity scale". However, indole itself does not conform to the H, function, and a value of = -3.2 f 0.1 is obtained for this substance by noting the additivity of substituent effects upon ten indoles which are H, indicators. A similar treatment predicts &"' z -3.6 for 1.3dimethylindole". Still another estimate gives = -2.38 for indole and -4.49 for 3-methylindole, the latter quite close to the value quoted here: see R. Stewart, The Proton: Applications to Organic Chemistry, Academic Press, Orlando, 1985, p. 126.
pe'
none (16) and, perhaps, acetophenone (17), especially if the last has electron-donating groups on the aromatic ring.
It is also useful, if one is careful, to compare the ambident basicity of enamines with that of enolates (equation 6). A wide range of structural effects on enolate basicity is now available; relevant data for some simple enolates are listed in Table 6. In making these comparisons we will keep two caveats in mind: the charge type of equations 6 is 0-
P
a
faster
OH
KaE
- 4
+ H + -
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James R. Keeffe and A. Jerry Kresge
TABLE 6. Selected rate and equilibrium constants for protonation of cnolates according to equation 6 (H,O, 25 "C, p = 0.10 M)"
Enolate
PK,E
~K,K
p ~ ,
kH+( I O ~ M -s-' ' )
kH2, (lo2s - ')
Reference
'These and other data pertaining to equation 6 are listed and discussed in References 35 and 44 Uncorrected for symmetry.
different from that in equations 3, and the NR, group of an enamine has variable steric requirements both internally and toward other parts of the enamine and iminium molecules. Our discussion will not include enamines derived from cyclic ketones. T o anticipate: the analysis which follows agrees with, but expands upon, that of HinmanZ2. The data in Table 6 show that an alkyl group at the cr-carbon stabilizes the carbonyl isomer much more than either the en01 or the enolate. That is, aldehydes are both more acidic and more highly enolized than otherwise similar ketones. This inhibitions of en01 and enolate formation on the part of ketones can be somewhat countered by a P-aryl group, especially if coplanarity of the entire x-electron system is enforced (see the last
19. Mechanisms of enamine hydrolysis
1061
two entries in Table 6)45. The effect of an a-phenyl group is seen to be similar to that of an a-alkyl group. Although a-alkyl and a-aryl groups are known to stabilize carbon-carbon double bonds46, their stabilizing effects on the polar carbonyl groups are even greater37,44.We anticipate parallel effects on the stabilities of enamines, iminium ions and enammonium ions. That is, both a-alkyl and a-aryl groups will stabilize the iminium ion much more than they will the enamine o r enammonium ion, hence the equilibrium preference for protonation at Cpwill be greater for ketone enamines than for aldehyde enamines. The enhancement of K, = (CH'/F$"') caused by a-substitution (see equation 3) might be somewhat attenuated if the group at C, is large enough to interfere with the other groups on the C=N bond in the iminium ion. However, even this point is a complex one. A look at equation 4 shows that a n a-substituted enamine is subject to some cis-strain (R3 vs R5 and RLR% vs R4) as well as 1,2-allylic strain (R1 or R2 vs R3) and 1,3-allylic strain (R' or R2 vs R4)47. Protonation at Cp exchanges cis-strain about the C=C bond for cis-strain about the C=N bond. Since the C=N bond is slightly shorter4*, the potential for increased strain from an a-alkyl or a-aryl group (R3) is present. But the net result clearly also depends on the relative sizes of R1, R2, R4 and R5. Of the two types of allylic strain, only the 1,2 variety is influenced by a-substitution. In the enamine this involves repulsion between R1 (or R2) and R3. In the iminium ion the interaction is between R3 and the R4R5CH moiety. T o the extent which the enamine nitrogen is already flat and sp2-like, protonation at Cpwill actually relieve this type of strain. Obviously it is difficult to generalize about the steric effects of a-substitution, and the data of Tables 2 and 4 are neither numerous nor systematic enough to provide a n answer. Table 6 also shows that alkylation at the P-carbon has a pronounced stabilizing effect on the en01 form relative to its keto tautomer. Analogy with the conjugate acids of enamines therefore predicts stabilization of the enammonium ion, but not much effect on the iminium ion. Thus we expect that P-alkylation will reduce Ki (equation 3). It seems clear from the work of Stamhuis and on compounds 1-3 that even a combination of two P-alkyl groups and no a-alkyl group is insufficient to invert the basicity order in favor of N-protonation. However, there remain some difficulties with this conclusion, a point we will return to in Section III.A.2. The steric erects of P-alkylation upon carbon protonation are, like the effect of a-alkylation, expected to be complex. This time, however, a prediction is permitted. Consider again the reactant enamine and product iminium ion in equation 4. An increase in the size of R4 or R5 increases cis-strain in the enamine and also increases 1,2-allylic strain (between R4R5CH and R3) in the iminium ion. The dominant factor, however, may well be 1,3-allylic strain. This factor (more important than its 1,2 counterpart4') encompasses repulsion between R1 (or R2) and R4 in the enamine. Upon protonation the repulsion is between R1 (or R2) and the R4R5CH unit. The latter group will adopt the preferred equilibrium conformation shown below as structure 18 in order to minimize 1,3-allylic train^^^.^. The net result of this model is that alkylation at CB,might enhance equilibrium protonation at the P-carbon, by a little or a lot, depend~ngon how much 1,3-allylic
1062
James R. Keeffe and A. Jerry Kresge
strain is thereby relieved. Unfortunately, the available p e H ' data for acyclic enamines (Table 2) do not address this point. An aryl group at the P-carbon strongly stabilizes an enolate ion, and (a little less strongly) an en01 as ~ e 1 1 ~. Th' ~ 1s- effect ~ ~ is. not ~ ~due entirely to conjugation of the aryl group with the C=C bond. Hydroxyl groupssoad, alkoxyl groups4'j and amino groupss0' also stabilize carbon-carbon double bonds. Moreover, the conjugation of a donor (RO, R,N) with an acceptor (e.g. aryl) through the double bond provides enhanced stabilization, geometry permitting46. The stabilization of P-aryl enols and enolates takes place through interaction of a pair of electrons on the enolic oxygen with the attached rc system. Enammonium ions do not possess a lone pair on nitrogen, hence the analogy between enols and enammonium ions is not a close one when it comes to anticipating the effect of a P-aryl group on the basicity of enamines. We expect that both N-basicity and C-basicity will be reduced by P-aryl substitution (see Table 2, compound 6 ) but that the difference between the two will not be greatly affected. Although this chapter will not emphasize complex enamines (that is, enamines in which another functional group is conjugated with the double bond), it is of interest in the present context to survey briefly the protonation behavior of a few examples. Conjugated dienamines (19) have three basic sites: nitrogen, C,, and C,. Each can be protonated under the proper set of conditions. As with simple enamines the kinetically favored site is nitrogen, but at equilibrium the eniminium ions, 20 and 21 (equation 7),
are dominant5'. Although it is likely that the conjugated eniminium ion, 21, is more stable than its unconjugated tautomer, both can be produced efficiently. For example, the protonation of the pyrrolidine enamine of A4-3-cholestenone (22) by the strong acids HC1 or HBr takes place at C, to produce the conjugated eniminium ion (23), as shown by UV spectroscopy (equation 8)52.The same enamine can also be protonated at C,
19. Mechanisms of enamine hydrolysis
1063
by acetic acid, as shown by reduction of the product to give 2453. Equation 9 is not an isolated example of protonation at Cp.Reaction 10, for which the type of mechanism shown was proposed by K a t r i t ~ k ywas ~ ~ ,observed by Anderson and Lyle5'. It appears that weaker acids are more apt to protonate the beta-carbon while stronger acids give predominantly the conjugated eniminium ion by protonation at C,. In this respect the competition resembles the protonation of dienolate anions by water in which the nonconjugated enone forms fa~ter'~.". However, this competition is influenced by a number of steric and electronic factors5'. The same is true for the protonation of dienols and dienol ethers5', and one should not expect a simple rule to govern the C,/C, protonation rate ratio for all dienamines. The reader can consult the chapter on electrophilic and nucleophilic reactions of this volume for further discussion.
A special class of dienamines is the pyrroles. Since pyrroles are somewhat aromatic (and their conjugate acids are not), they are not as basic as ordinary enamines. However, the effects of substitution on the pyrrole nucleus should offer clues toward understanding and predicting substituent effects on the basicities of nonaromatic dienamines. Whipple, Chiang and Hinman have made a systematic study of the effects of methyl substitution on the p c H ' of pyrroles (equation 11)32.33. Their results are listed in Table 7.
James R. Keeffe and A. Jerry Kresge TABLE 7. Carbon basicity of some methylated pyrroles (H,O, 25 "Cpb
" References 32, 33. Values quoted are for a-protonation, i.e. at C-2 or C-5. Protonation at C-3 or C-4 is disfavored by a variable amount: zero to ca 6 p K units, depending an the substitution pattern. E -5.9"; for protonation at nitrogen, 'For protonation at C-3, PC"' the p c H ' is estimated at ca - 10. Protonation occurs at C-5. 'Protonation occurs at C-2.
Protonation occurs predominantly on one of the a-carbons (C-2 or C-5), less so at a p-carbon (C-3 or C-4), and very much less so on the nitrogen (see footnote c of Table 7). Note that all C-protonated pyrroles are conjugated eniminium ions. The degree of preference for cc-protonation is, however, sensitive to the precise pattern of methylation. Chiang and Whipple tabulate incremental ApK values by which p e n * for any of the 19 methylated pyrroles can be estimated, apparently to within 0.2 pK unit or so33. Qualitatively the results may be expressed as follows: The best site for protonation is that which maximizes the number of methyl groups attached to sp2 atoms in the eniminium ion. A corollary is that protonation at a methyl-bearing carbon is generally avoided. Further, therc is a pronounced tendency in the eniminium ion for nitrogcn to be one of the termini of the conjugated diene system (a-protonation), and a smaller tendency for the carbon terminus to carry a methyl group. The rules set forth earlier for the protonation of alkylated indoles (Table 5) may be considered a simplified special example of these considerations. Finally, we note that conjugated enaminoketones ('enaminones') are virtually always protonated on oxygen59.Reaction 12, observed both by UV60 and NMR spectroscopy6', is an example. It is possible, however, for the preferred site of protonation to be carbon, as reaction 13 illustrate^^^.
(mixture of isomers)
19. Mechanisms of enamine hydrolysis Greenhill reports in his review59 that a number of enaminones have the range 2.8-3.1. Stable salts of enaminones can be prepared.
1065 values in
4. Gas-phase basicity of enamines
Although the hydrolysis of enamines is not a gas-phase reaction, useful information about the protonation of enamines, applicable to the aqueous phase, may be obtained from gas-phase basicities, provided that the comparisons made are between species of similar size and shapeb3. Thus, it is interesting that the gas-phase basicities [AG" (g)] for N,N-dimethylethylamine and N,N-dimethylvinylamine are only 0.3 kcal mol-I apart, the enamine being slightly the more basic64. It is well established that a nearby vinyl group weakens N-basicity both in s ~ l u t i o n ' ~and ~ ' in ~ the gas phaseh5,hence it follows that N,N-dimethylvinylamine is protonated on carbon in the gas phase to form a n iminium ion. We argue that these results are qualitatively transferable to aqueous solution. The saturated ammonium ion has one N-H bond and the iminium ion none; this difference allows different hydrogen-bonding solvation of the two cations. However, at room temperature this difference is expected to produce opposite effects of similar magnitude on A H and - TASo for acid ionization in wateP3". Thus, although the comparison is indirect, the gas-phase data support the contention that the carbon hasicity of enamines is similar to or greater than the nitrogen hasicity of their saturated
analogue^'^,^'. Ill. HYDROLYSIS MECHANISMS
Historically, the first quantitative work on the kinetics of enamine hydrolysis was that done by Stamhuis and coworkers on several tertiary enamines of isobutyraldehyde: compounds 1-3". Stamhuis summarized this work in his 1969 review67. The overall mechanism proposed by Stamhuis is in very good agreement with the conclusions of Sollenberger and Martin, who investigated the hydrolysis of several tertiary enamines derived from propiophenone: compounds 5, 12-1413. At about the same time, Coward and Bruice reported their study of the secondary and primary enamine series, 10 and 1lZ0, and shortly thereafter Guthrie and Jordanb8published their work on the hydrolysis of two stabilized secondary enamines, 25 and 26, one of which (26) had previously been examined by Coward and BruiceZ0. Recently, Capon and Wu have reported a study of the hydrolysis of three series of tertiary enamines, and the corresponding set of secondary enamines, 27-2969. The latter, ordinarily in unfavorable equilibrium with their imine tautomers, could be generated as stable solutions in 99% DMSO/l% D,O by the rapid desilylation of N-trimethylsilyl precursors. Such solutions could then be rapidly diluted into the hydrolytic medium and the rates of hydrolysis thereupon be monitored. For convenience, all the substrates or series referred to above are shown in groups below. In the last part of Section 111 a miscellaneous group of enamines will be discussed. The main elements of the mechanism proposed by StamhuiP7 and verified by Sollenberger and Martin" have stood up very well. For this reason, and because their work covers the largest p H range (thereby revealing the variety of rate-determining steps possible for the reaction), the hydrolysis of the tertiary enamines 1-3 and 5, 12-15 will be discussed first.
1066
James R. Keeffe and A. Jerry Kresge
Reference 20
Reference 68
L
L
Reference 69
A. UAlkylenamines of lsobutyraldehyde
Figure 1 shows the pH-rate profiles obtained by Stamhuis and coworkers for 1, 2 and 3, all enamines derived from isobutyraldehyde11d67. The points refer to rate constants for solvent-related species only, buffer contributions having been subtracted, and the lines drawn through the points are derived from the mechanistic model to be discussed. We present this model first, as Scheme 1 (comprising equations 1419), then rationalize it in terms of the pH-rate profiles and auxiliary information. 1. The higher pH region
Following Stamhuis6' we begin at the high pH end of Figure 1. For all three compounds the plateau at the alkaline side of the scale is attributed to rate-controlling protonation of the free enamine by water (equation 15, substitute H,O for H+). This
19. Mechanisms of enamine hydrolysis
1067
FIGURE 1. pH-rate profile for the hydrolysis of three isobutyraldehyde enamines at 24.84 "C: 0, morpholine (1); A, piperidine (2); 0, pyrrolidine (3). Reprinted with permission from Maas rt al., J . Org. Chem., 32, 111. Copyright (1967) American Chemical Societylld
region of uncatalyzed hydrolysis, in which kls-' = kH20/sC1,can extend to lower pH values only while the enamine is predominantly in the unprotonated condition and while the protonating agent in equation 15 is water itself. As the acidity of the medium is increased two things begin to happen. First, when the enamine is still mostly unprotonated (see pKzH' values for equation 14 in Table 2), carbon protonation by H,O+ begins to appear. This event is signalled by an increase in k/s-I with decreasing pH. This increase occurs at relatively high pH (greater than p H = 10) for compounds 2 and 3, but the p H range over which it takes place, hence the amplitude of the rise in k/s-', is very small. Continued increase in medium acidity for these two compounds results in a second plateau. In this region (extending down to p H % 7 for 3) the enamine is predominantly in the N-protonated form. The lack of dependence of k s ' on p H is then a consequence of the necessity of deprotonating the unreactive enammonium ion (equation 14, inhibited by acid) prior to C-protonation of the free enamine by H,O+ in the rate-controlling step. Compound 1 displays the same behavior, but more dramatically. Because the morpholine moiety in 1 is a considerably weaker base than the amine functions in 2 and 3, the enamine remains largely in the free form over a pH range (approximately 8-6) where C-protonation is dominated by H,O+ rather than water.'For compound 1 the second plateau extends down to pH x 1. All the behavior in the p H ranges mentioned so far is attributed to rate-controlling C-protonation (equation 15). Taking N-protonation into account, the rate law for this mechanism is equation 20. The factor involving represents the fraction of enamine in the free, unprotonated form. The first plateau (alkaline region) and the rise > >> [H+], hence in ksC1 with decreasing pH occur in pH ranges where k/sC1= kH20+ kH+[H+]. At the second plateau [H+] >> KrH', the enamine is rapidly
eH en'
James R. Keeffe and A. Jerry Kresge
R4 \ +NR'R2 // CH-C / \ R3 R5
/
/
KIT
R3
/
R4 +NHRIR2 \ / CH-C\-OH R5
KIX
R3
\
R5
(17)
R3
R4 +NHRIR~ \ I CH-C-0 + Hf /
\
R5
R3
/
\
R4 +NHR1R2 \ / CH-C-OH
\
R5
R4 N R ~ R ~ / \ CH-C-OH + H+ R5
R4 NR~RZ \ / CH-C-OH
hp + k,,-lo"-]) +..............
(18)
R3 (Z9
R4 +NHRIRZ \ / CH-C-0/
\
R5
k19
R4 0 \ // R ~ R ~ N+H CH-c /
R3
(z*)
R5
\
(19)
R3
SCHEME I
and overwhelmingly N-protonated, kH+[H+]>> kHz,, and equation 20 reduces to k/s-' = e H ' k H + . Stamhuis and coworkers have provided solid confirmation of this mechanism in the following way: General acid catalysis of the hydrolysis of 1 was demonstrated over the pH range 4.1-7.3L'b.70.Likewise, compounds 2 and 3 showed general acid catalysis in the pH = 8 . s 9 . 5 region. Second, the hydrolysis of compound 1 in acetate buffers is accompanied by kinetic solvent isotope effects: (kH+/k,+)= 2.5 0.7 and (kHoA,/ kmAJ = 9 1, both at 25 "C. The combination of general acid catalysis and normal, primary solvent isotope effects is strong evidence for rate-controlling proton transfer, that is, equation 20 with terms added for general acids, HA. The specific rate constants, kH+and k,,,, are given for 1-3 in Table 4. Figure 1 and Tables 2 and 4 reveal some interesting aspects of structure-reactivity behavior. Clearly, the rate at which the free enamine is protonated decreases in the order
+
+
19. Mechanisms of enamine hydrolysis
1069
3 > 2 >> 1. This fact was discussed above in Section 11. Nevertheless, from approximately pH = 5 on downward compound 1 is hydrolyzed fastest with 2 slightly faster than 3. For the pyrrolidino compound (3) a change in rate-controlling step is responsible for the diminution (see below), but for compounds 1 and 2 in the pH region 5-3 (i.e. the 'second plateau'), rate-controlling proton transfer still prevails. The reason that 1 is faster than 2 in this domain is simply that both enamines are mostly protonated in this region and [H'] >> This causes equation 20 to become k/s-' = e H ' k H + . Although the catalytic coefficient, kH+,is larger for 2 than for 1 by a factor of 450, the N-basicity of 1 is poorer than that of 2 by an even larger factor: 760.
eH'
2. The middle pH region
In Figure 1, the regions in which C-protonation of the enamine is rate-controlling are indicated by a solid line. For compounds 1, 2 and 3 this region ends at pH E 1, 3 and 7, respectively. At greater medium acidities the rates become smaller; the points are linked by the dashed lines. Stamhuis and coworker^^^^.^' have proposed a change in rate-determining step to explain the observations: at the indicated pH values, nucleophilic attack on the iminium ion (equation 16) begins to control the rate of hydrolysis. Their study of compound 3, the pyrrolidino enamine, revealed the most information. When reaction 16 is rate-controlling the rate law becomes equation 21 (neglecting contributions from buffer components). In equations 21 and 22, kNindicates nucleophilic attack. If we assume, as discussed previously, that C-basicity exceeds N-basicity (see Section I1 and Table 2), then EH' i< and equation 21 becomes equation 22''. For compound 3 in the pH range 7 4 , the declining value of kls-' is attributable to the decreasing
cH*
hydroxide ion concentration; in other words, nucleophilic attack on iminium ion by O H - is an important or dominant aspect of equation 16. From about pH E 4 down to 2, the decline in k/s-' is arrested and the rate becomes virtually pH-independent. This result is explicable in terms of equation 22 by stating that ki,, [H+] >> kgH-Kwund that [H+]/EH' >> 1. Now, nucleophilic attack by water has taken over from attack by extremely dilute hydroxide ions and equation 22 reduces to equation 23. The entire picture is
strengthened by the observation that hydrolysis of 3 at pH = 4.4 and 4.9 (acetate bulks) is subject to general base, not general acid catalysis11d.Rather than nucleophilic attack by acetate on the iminium ion, the authors envision a general-base-assisted nucleophilic attack by water. Rate constants for equation 16 (compound 3) are given in Table 8. A puzzle remains. If equation 16, nucleophilic hydration, is fully rate-controlling, then equations 14 and 15 must be at equilibrium. At the pH values in question, namely pH z 2-7, the dominant form of the enamine in equilibria 14 and 15 should be the iminium ion (30).That is, 30 should not be a steady-state intermediate. In this judgement we are assuming, as before, that the C-basicity of 3 exceeds the N-basicity; for the latter, = 8.84 (see Table 2). Yet no buildup of iminium ion is reported under hydrolytic
James R. Keeffe and A. Jerry Kresge
1070
TABLE 8. Rate constants for hydrolysis of some tertiary iminium ions"
Iminium
k:2,(103
s l )
kgH. ( l o 3 M - ' s 1)
k
o (
Ms
)
References
ion
'See equation 16 in Scheme I . H,O, 24.84 "C, p = 0.100 M (NaCI). 'H,O, 25.0 "C, p = 0.20 M (KCI). Buffer catalysis of this step was not observed for these compounds.
'
conditions. In terms of Scheme 1 such a negative observation may mean that for these particular enamines, having two P-alkyl groups and no substituent at C,, the N-basicity is greater than the C-basicity. In that case iminium ion 30 can be a steady-state intermediate, equations 22 and 23 are altered to 22a and 23a, respectively, and the rate constants for hydrolysis of iminium ion 30 given in Table 8 are incorrect by the factor ( K ~ ' / ~ " ' AS ) . discussed in Section II.A.3., the two alkyl groups at Cg and the lack of substitution at C, is just the combination most likely to invert the N-basicity vs C-basicity order.
Another rationalization for a lack of buildup of iminium ion is that both reactions which destroy it, namely hydration (equation 16) and deprotonation (reverse of equations
19. Mechanisms of enamine hydrolysis
15), are fast. To accommodate the change in catalytic behavior observed for 3 in the pH = 7-2 region one must argue further that deprotonation is faster than hydration, but that true equilibrium for equations 14 and 15 is never quite established because of the rapidity of equation 16. A consequence of this interpretation is that equation 15, protonation of the enamine at Cp,is still partly rate-controlling in this pH region. If so, its share of the control must be small enough that general acid catalysis is not manifested. For compounds 1 and 2, a break in the pH-rate profile analogous to that observed for 3 between pH 4 and 2 is not observed. This fact does not require a gross mechanistic switch; rather, it can be explained more simply by noting that the iminium ions derived from 1 and 2 should be much more reactive toward nucleophilic hydration than the iminium ion from 3, and equation 16 does not become rate-determining in the case of 1 and 2. These ions are shown as structures 3&32. The same features which enhance formation of 30 relative to 32, namely the greater ease of creating a double bond exocyclic to a five-membered ring than to a six-membered ring (discussed in Section II), serve to stabilize 30 toward nucleophilic attack. Iminium ion 31, owing to the polar effect of the oxygen, will be most reactive of all. In sum, nucleophilic attack (equation 16) on 31 and 32 is never slow enough to be rate-controlling.
3. The lower pH and H, region
The hydrolysis rate of all three enamines (1-3) undergoes a sharp decline as the pH drops below 1 (for 2 and 3) or 0 (for 1). This result signifies that equation 23 (or 23a) is no longer the rate law and that another change in rate-controlling step has occurred. The last stage of Scheme 1 is the breakdown of the carbinolamine, equations 17-19. At the acidities in question (pH < I), equations 14-17 are in equilibrium, that is, the enamine is fully protonated ([EH+] = [NH+] + [CH'], see Table 2) as is the hydration product, the c a r b i n ~ l a m i n e Equation ~~. 24 describes the situation. The observed inverse
relation of kls-' with acidity then indicates that deprotonation to the neutral carbinolamine or to the zwitterion, Z' (equation 18) must occur during or prior to the rate-controlling step. Since the only base present is water, and since the activity of water changes only by a factor of two over the acidity range under c ~ n s i d e r a t i o n ~the ~,
James R. Keeffe and A. Jerry Kresge
1072
pronounced decline in k/sC1 cannot be attributed to a decreasing rate of N-deprotonation of carbinolamine H + . For the same reasons a concerted, bimolecular, base-assisted fragmentation of carbinolamine . H + (equation 25) is unlikely. This leaves unimolecular fragmentation of the neutral carbinolamine or of the zwitterion as the rate-determining
.
step in the breakdown of the carbinolamine. Several lines of evidence favor the zwitterion pathway. For one thing it has been established that nucleophilic attack by amines upon the carbonyl group of aldehydes is not acid-catalyzed when the more strongly basic amines are used, e.g. hydroxylamine and aliphatic a m i n e ~Since ~ ~ . such attack produces the zwitterion, Z*, the principle of microscopic reversibility allows that the decomposition of carbinolamines to amines plus aldehydes and ketones passes through the same intermediate. The same argument has been used to rationalize the rates of hydrolysis of a number of Schiff bases of aliphatic amines, reactions which also occur via a carbinolamine and which are also retarded in low-pH media74b. Another argument concerns the basic hydrolysis of tertiary amides vs ''0 exchange of those same amides. As the base strength of the departing amine is increased, the hydrolysis/exchange ratio increases. Brown and coworker^'^ argue that hydrolysis is completed by expulsion of an amine from an N-protonated tetrahedral intermediate, 33 or 34. The more basic the
amine, the greater is the proportion of the tetrahedral intermediate in an N-protonated form, and the greater is the fraction of tetrahedral intermediates which complete hydrolysis rather than return to the exchanged amide. The analogy of species 3 3 a n d 34 with Z* (equation 19) is clear. Finally, we record an argument which, although a priori, is strong. As noted above, the dominant form of the carbinolamine at the acidities in question is the N-protonated form. Surely this form will fragment much faster than the carbinolamine itself, since the leaving group is so much better. But fragmentation via the carbinolamine- H + has already been ruled out by the sharpness of the decline in k/s-' (see above and equation 25). If the superior intermediate is not involved, then the inferior one cannot be competent either. Apparently the strong intramolecular push by a fully negative oxygen is necessary to expel these sluggishly nucleofugic amineS11d.67.74b
A final point concerns the relative reactivities of 1-3 in the low-pH regime. The least basic substrate (I), much the slowest in alkaline solution, has become very much faster than 2, which is somewhat faster than 3. When breakdown of the tetrahedral intermediate becomes rate-controlling, 1 has everything going for it. It is more strongly hydrated (owing to the relative instability of its iminium ion), hence equilibria 14-17 are favored. Formation of Z* (equation 18) will also be improved, because the positive charge on the nitrogen is less well dispersed by the morpholino moiety and will provide better electrostatic stabilization of the negative oxygen. Lastly, morpholine is a much better leaving group (equation 19) than are piperidine and pyrrolidine. Compounds 2 and 3 contain amine functions which are of comparable N-basicity and nucleofugality. The
19. Mechanisms of enamine hydrolysis
1073
difference between the two may lie in the fact that the iminium ion from 2 is the less stable (see above) and is therefore more strongly hydrated11d.67. B. N-Alkylenamines of Propiophenone
Another set of tertiary enamines, compounds 5, 12-14, was given a thorough kinetic study by Sollenberger and Martin13. Here too the amine functions are aliphatic, but the carbonyl precursor is a ketone, propiophenone, rather than an aldehyde. For two of the series. 5 and 12, several para-substituted derivatives were also examined, allowing Hammett p values to be determined. As we shall see, the mechanistic conclusions reached by Sollenberger and Martin are the same as those of Stamhuis6', but there are differences in detail made possible by the presence of an aryl group on C, rather than a hydrogen. The pH-rate profiles, obtained by Sollenberger and Martin for compounds 5 (X = H), 12 (X = H), 13 and 14, are shown in Figure 2. Buffer contributions to k/sC1 have been subtracted for this figure. 1. The higher pH region
As in Figure 1, Figure 2 shows that at alkaline pH values there is a pH-independent plateau. Only compound 14, the pyrrolidino enamine, does not show this feature, and this is probably because the rates of hydrolysis had become too fast ( t , , , < 1 s) for observation above pH = 10. In this region all members of series 5, 12 and 13 showed general-acid catalysis (bicarbonate buffers). The [buffer]-independent rate constants for series 5 at pH 10.38 give a good Hammett correlation, with p = - 1.29. showing that
FIGURE 2. pH-rate profile for the hydrolysis of several propiophenone enamines at 25 "C: A, morpholine (5); 0, dimethylamine (13); @, piperidine (12); A, pyrrolidine (14). Reprinted with permission from Sollenberger and Martin, J. Am. Chem. Soc., 92,4261. Copyright (1970) American Chemical Society from Reference 13
1074
James R. Keeffe and A. Jerry Kresge
electron donors significantly accelerate hydrolysis. All these results are accommodated simply by rate-controlling protonation of the enamine (in the free state above pH = 10, see Table 2) by water or by a buffer acid (equation 15, substitute H,O or HA for H+). In this region the reaction rates for the parent compounds of each series are in the expected order of C-basicity: 14 > 13 > 12 (X = H) >> 5 (X = H). This order is entirely consistent with the C-protonation rates of 1-3 (see Table 4). As pH drops below 8, the k/s-I values for compound 5 (X = H) begin to rise. This compound is still largely unprotonated down to pH % 5.5 ( p e n ' s 5.0), hence the increasing rates of hydrolysis are due to rate-controlling protonation of enamine by H,O+ (equation 15). In confirmation, Sollenberger and Martin observed catalysis by buffer acids at pH 7.5-6.2; general-acid catalysis could be found at still lower pH values. but only if the buffer acid concentration was kept low. Below pH 5, however, the general-acid catalysis disappeared. The onset of the second plateau at about pH 5, and the fading of general-acid catalysis signify a change in rate-controlling step and will be discussed below in Section III.B.2. The rate law governing the hydrolysis of 5 (X = H), in the pH region discussed so far is equation 26, which is just a version of
-
k / s l = kH,,
+ kH+[H+]+
kHA[HA]
(26)
equation 20, modified to include general-acid catalysis and to acknowledge that the enamine is almost entirely in the unprotonated state. In addition to acid catalysis by H3Ot and H,O, Sollenberger and Martin showed catalysis by four buffer acids: two zwitterionic substances [N-tris(hydroxymethyI)methyl-2-aminoethanesulfonic acid (TES) and 2-(morpholino)ethanesulfonic acid (MES)], dihydrogen phosphate and hydrogen carbonate. A Brsnsted correlation was constructed from the catalytic coefficients for H,Of, MES, TES and H,O (cc = 0.50). Although the ApK, range is enormous, and points for H,O catalysis and H 3 0 + catalysis frequently do not fit Brsnsted correlat i o n ~it~ is~ noteworthy , that the two negatively charged acids, H,PO,- and HC0,-, lie above the Brmsted line (i.e. they are more effective catalysts than predicted) by 1.5 to 2.1 log units. Electrostatic effects are known to influence catalytic effecti~eness'~-~~. It is reasonable, therefore, to ascribe a role to such an effect in the protonation of an enamine: as a proton is transferred from a negatively charged general acid, the developing conjugate base residue acquires more than a unit negative charge at the transition state enabling a superior electrostatic attraction with the partial positive charge on the enamine moiety. 2. The middle pH region
Already at pH z 10 and continuing down to pH E 6, compounds 12 (X = H), 13 and 14 show a sharp decrease in k/s-'. Reaction is not buffer-catalyzed in this region, hence this is not due to rate-controlling protonation, by water, of a minority of enamine in equilibrium with its enammonium ion (equations 14 and 15). Nor can C-protonation by H 3 0 + be rate-controlling since one would observe either an upward slope in the pH-rate profile (when [El > [NH']) or a plateau (when [NH+] > [El). Although such characteristics in the rate profile were observed for compounds 1-3, they were not observed for the propiophenone enamines. Rather, a switch to rate-controlling nucleophilic attack on the iminium ion is indicated (equation 16) for which rate-law equation 22 is appropriate. The high pH end of this region, where the switch in rate control from equation 15 to equation 16 is occurring, has some interesting catalytic features which argue strongly for the interpretation given. At pH = 10.36 compound 12 (X = H) shows general-acid
19. Mechanisms of enamine hydrolysis
1075
catalysis at low buffer concentration, but at higher [buffer], saturation occurs and buffer catalysis vanishes. Sollenberger and Martin ascribe this observation to rate-controlling C-protonation at low [buffer], but as buffer concentration is increased, equation 15 becomes fast enough (in both directions) that partitioning of the iminium ion in the forward direction (equation 16) becomes rate-determining. Exactly the same kind of buffer saturation is seen for the morpholino derivative (5) X = CI) except that its occurrence is at lower pH. In fact, some very nice fine tuning could be demonstrated: at pH = 4.67,s (X = CI) shows buffer saturation curvature, hut at the same pH the more strongly basic 5 (X = H) and 5 (X = C H ) d o not. In the latter two cases equations 14 and 15 have reached equilihrium rapid$enough, even at low [buffer], that nucleophilic attack by water is rate-controlling. Thepara-substituent effects on series 5 agree well with this interpretation. At pH = 4.67 the non-buffer-catalyzed rate constants generate a Hammett p value of + 1.4. Hydrolysis is accelerated by electron-withdrawing groups. The value is similar to that obtained by Cordes and Jencks, p = 1.7, for the attack of water upon the iminium ions derived from Schiff bases (equation 27)74b.
+
The rates of hydrolysis of compounds 12 (X = H), 13 and 14 are independent of pH from about pH 6 to 1, and buffer catalysis is not seen. The interpretation of these results is the same as it is for series 5, namely rate-controlling attack by water on the iminium ion. At these pH values the enamine is present in a protonated form and equation 23 is the rate law. As is clear from Figure 2, the morpholine-derived iminium ion is by far the most electrophilic, while the pyrrolidino iminium ion is least reactive. This order is exactly the same as for compounds 1-3; the reasons were discussed in Section III.A.2. Rate constants for nucleophilic attack upon the iminium ions are given in Table 8. Two other kinds of observation verify the general picture described here. One has to d o with substituent effects. We have already seen that rate-controlling C-protonation produces a substantial negative Hammett p value. On the other hand, at the upper end of the pH range wherein equation 16 controls the rate, different behavior can be found: for series 12 at pH = 10.36, p is very small ( ~ 0 . 2 ) The . authors interpret this result according to equation 28, a simplification of equation 22 for the situation where O H is the dominant nucleophile. At this pH, [ H + ] / e ' < 1, so substituent effects on both k g , and l / c H ' are important. These will affect the two terms in an opposite way, because a substituent which stabilizes the iminium ion also reduces its reactivity toward nucleophiles. The result is a tiny p value. The other observation just referred to is that Sollenberger and Martin were able to see a buildup of the iminium ion under certain conditions. This result was discussed in detail in Section II.A.1. Recall that Stamhuis and coworkers did not report seeing iminium ion under hydrolytic conditions6'. Two possible explanations were advanced in Section III.A.2. One of these is expanded upon here using arguments in which the expected behavior of iminium ions derived from aldehyde enamines is contrasted with that expected for iminium ions related to ketones. An iminium ion is destroyed by two processes according to Scheme 1: nucleophilic attack in equation 16 and deprotonation at Cp, the reverse of equation 15. By analogy with the chemistry of aldehydes and ketones, and from the data in Table 8, we infer that reaction 16 is faster for Stamhuis' aldehyde enamines (R3 = H) than it is for the propiophenone derivatives (R3 = Ph). Continuing the analogy, it is well known44 that aldehydes are deprotonated at CDfaster than are ketones. It is likely that the same is
1076
James R. Keeffe and A. Jerry Kresge
true for the corresponding iminium ions. Thus both paths which consume iminium ions should be considerably faster for compounds 1-3 than for 5,12 (X = H), 13 and 14 and a measurable concentration of 'aldo-iminium' ions does not develop.
A related argument accounts for another difference between aldehyde enamines (1-3) and the keto analogues studied by Sollenberger and Martin. For the former group a 'second plateau', above thejrst, is clearly seen in Figure 1 for compound 1 and is faintly evident for 2 and 3. As described in Section III.A.1, this was shown by Stamhuis and coworkers to be caused by rate-controlling C-protonation occurring in a pH region where the N-protonated conjugate acid is dominant. Compounds 12 (X = H), 13 and 14 show no higher 'second plateau'. And although compound 5 (X = H) does (Figure 2, pH % 5-I), Sollenberger and Martin have shown clearly that it is due to ratecontrolling attack of water on iminium ion, that is, equation 23 (a simplification of 22) is the rate law. The en01 isomers of ketones are protonated at Cg faster than are the enols of aldehydes44. By analogy, the propiophenone enamines are more rapidly protonated than are those derived from aldehydes (see Table 4). As already mentioned, 'keto-iminium' ions are attacked by water more slowly than those derived from aldehydes. Thus, the iminium ion concentration can actually build up, and it is left to a slower step (equation 16) to be rate-controlling. 3. The lower pH and
H, region
Below pH 2 1, all compounds in series 5 and 12 (X = H), 13 and 14 are hydrolyzed at rates which decrease markedly with acidity. The interpretation of this behavior is the same as for Stamhuis' compounds (1-3). That is, another change in rate-controlling step has occurred: equations 1 6 1 8 are at equilibrium and decomposition of the carbinolamine, via its zwitterionic tautomer (Z*), is rate-controlling (equation 19). The argument for this assignment was given above in Section III.A.3. However, Sollenberger and Martin provide some extra information which marks the change in rate-controlling step. Recall that the Hammett p value for attack of water on the series 5 iminium ions is p = + 1.4. At greater acidities, namely Ho = -2.3 and -3.3, p has changed to approximately + 2.2. If there were no change in p, no mechanistic statement could be made, but since a change does occur, it is reasonable to infer that some mechanistic detail has been altered.
Coward and Bruice examined the kinetics of hydrolysis of two series of enamines, 10 and 11, both stabilized by a cyano group at Cpwhich is in formal conjugation with the amine functionz0. Series 10 are secondary keto-enamines in which an N-aryl group allows the electron-donating ability of the nitrogen to be varied. In series 11 the aryl group is attached to C.. The pH-rate profiles were established over the range pH E 6 down to zero. They are linear over virtually the entire range with slope = -1. This result indicates acid catalysis by H,O+, and consistent with this interpretation is the general-acid catalysis found for all the enamines at pH values ranging from 3-7. The Brarnsted slopes for all the compounds are very similar: c~E 0.65. These results indicate rate-controlling protonation of Cp down to pH = 1 or below. It is evident that P-cyanoenamines are much less basic than the simpler enamines studied by Stamhuis and coworkers" and by Sollenberger and Martin". Below pH = 1, the
19. Mechanisms of enamine hydrolysis
1077
pH-rate profile appears to level out. This result could indicate either that carbon protonation by H 3 0 + is still rate-controlling, but that most of the enamine has been rapidly N-protonated (equations 14 and IS), or that the nucleophilic attack by water is rate-controlling, but that most of the enamine has been rapidly protonated (on N or C or both). We'll return to this point later. Over the large-pH range where C-protonation is rate-controlling, several structurereactivity relationships in addition to the Brsnsted correlation mentioned above were established. Table 3 contains pK, values for members of both series (assuming that N-protonation was measured). The p,* value for series 10 is + 2.80, almost exactly the same as that for substituted anilinium ions2'. For series 11, pKa= t0.84. Rate constants for reaction 15 are shown in Table 9. For series 10, p,,, is -0.61, and for 11, P k H + = -0.49. Additionally, k,+ for compound 26 was measured and found to be at least 43 times greater than for 10 (X = H); the carbethoxy group is not as deactivating as a cyano group. Finally, replacement of the a-methyl group of 10 (X = H) by phenyl causes a 90-fold reduction ink,,. Substitution of phenyl for methyl at an sp2-hybridized carbon is known to have a variable effect on the rate of C-protonation. For example, alkene hydration, a comparatively slow reaction, is accelerated by phenyl: k(styrene)/k(propene) = 1008'. On the other hand, the ketonization of enols (which are of more similar reactivity to series 10) is slightly retarded by phenyl: k(acetophenone enol)/k(acetone enol) = 0.2336. It seems likely that for 10, an a-phenyl group cannot achieve good conjugation with the developing positive charge without encountering torsional strain. The YO-fold rate reduction is then mainly a consequence of the electron-withdrawing polar effect of phenyl. In series 10, Coward and Bruice contrast the small value of p,,, with the substantial size of p,*. An argument is made that optimal substituent influence on k,+ is possible only when the p orbitals comprising the n system of the ring, the double bond and the nitrogen lone pair are all parallel. Such a conformation in which optimal conjugation occurs is, however, strained. The most important alignment for C-protonation is that in which the nitrogen lone pair and the alkene moiety are well conjugated in the transition state. To achieve this conformation the aryl group rotates out of conjugation and only a remote, polar substituent effect on k,, remains. On the other hand, equilibrium protonation at nitrogen may, as described in Section 11, involve preferred reactant-state conformations in which rotation about Cm-N has occurred: the lone pair on nitrogen is, in that case, not well conjugated with the C=C n bond, but it can interact with the aromatic ring much as with ordinary anilines for which p,#, is very similarz3. For series 11 substituent effects are small. N-protonation cannot ~nvolvemore than the polar influence of the para-substituent, but the small effect of substituents on the rate of C-protonation, p,,,, = -0.49, is perhaps surprising in view of the larger (though not large) value found for series 5, p = - 1.2913. There are, however, important differences between the two reactions, one of which is that Coward and Bruice's value
1078
James R. Keeffe and A. Jerry Kresge TABLE 9. Rate constants for carbon protonation of some conjugated enamines (H,O, 30 "C) Enamine
X
kH+(10' M - ' sC1)
Reference
19. Mechanisms of enamine hydrolysis
Enamine
X
k,, (10' M - ' s C ' )
Reference
" A t 37°C. A t 25 T.
for 11 refers to protonation by H,O+, while the p value for 5 refers to protonation by water. In series 5, C-protonation by water is endoergic by perhaps 1&12 kcal mol-I, while for 11, C-protonation by H 3 0 f may actually be exoergic. Thus, it is likely that in series 5 the transition state is later (more like the iminium ion) than in 11 and therefore permits larger substituent effects. It remains to comment on a seeming contradiction for series 10: pkH, is small (-0.61), but the Brmsted oc is 0.65. The Brmsted coefficient suggests that the proton is more than half transferred from the general acid to Cg in reaction 15. To assess the significance of the kinetic p value, we need an idea of what p would be if the proton were completely transferred. As previously seen, N-protonation ( p e n ' ) produces p~~ = 2.80, hence the value of p expected for establishing a full positive charge on nitrogen in reaction 15 is perhaps in the neighborhood of -2.5 to -3.0. If so, then the observed kinetic value, p,,, = -0.61, is much less than half the expected equilibrium value. It is probable that the two different probes, cc and p,,,, measure different aspects of transition state structure, and that the protonation of enamines represents another case of 'transition state i m b a l a n ~ e ~ Coward ' ~ ~ ~ . and Bruice's interpretation, given above, is that proton transfer from HA to Cg is well advanced. The buildup of positive charge on nitrogen keeps pace through overlap of nitrogen's lone pair with the alkenyl n system, but relay of this information to the para-substituent is inhibited because the ring has rotated out of conjugation with nitrogen. Alternatively, it is conceivable that although proton transfer is well advanced, conjugation of the nitrogen lone pair with the alkene carbons has lagged owing to conformational restraints, and the buildup of positive charge on nitrogen has therefore not kept pace with proton transfer. Whatever the explanation, it
+
James R. Keeffe and A. Jerry Kresge
1080
appears that the small value of p,,,, for series 10 has something to do with the p-cyano function. For series 27-29, N-arylenamines without electron-withdrawing groups at Cp, the p,,, values (-2.4 to -3.7) are much larger69. We will return to series 27-29 in Section IILE. We return now to a point raised above regarding the levelling-off of the pH-rate profiles, which occurs below pH 1, for series 10 and 11. Mechanistically this plateau is ambiguous. In fact we have already seen that such a plateau could be due to ratecontrolling C-protonation (in a pH domain where the enammonium ion is dominant), or it could represent rate-controlling nucleophilic attack by water (equation 16, enammonium and/or iminium ions predominant in the reactant mixture). Compounds 1-3 exhibited the first type of behavior (at higher pH) while 5 (X = H) and 12 (X = H), 13 and 14 showed the second. If C-protonation is rate-controlling, the rate law, a simplification of equation 20, is equation 29. If nucleophilic attack by water controls the rate, then the rate law is equation 30, a modification of equation 21 for the case where N-basicity and C-basicity are both importantn4.Coward and Bruice report values of k,, and which combine to produce the observed kls-'
eH'
value at the plateau. This seems to imply equation 29. However, elsewhere in their article they argue for equation 30. If the plateau is in fact due to rate-controlling hydration, then equilibria 14 and 15 must be fully established prior to equation 16, and either NH' or C H + , or both, must dominate the equilibrium with free enamine. Both conjugate acids should have unique U V spectra; however, the initial spectra of reacting solutions at plateau acidities are not reported. Although simple enamines are more basic at Cp than at N, we cannot assume this to be so for 10 and 11. Moreover, we cannot rule out protonation at the cyano nitrogen (equation 31). As discussed above (see equation 12), virtually all enaminones are preferentially protonated on oxygen59.
Should the dominant species at pH < 1 turn out to be iminium ion, then its formation cannot be rate-controlling and the plateau represents a switch to rate-controlling hydration. If the pK, values reported by Coward and Bruice, given here in Table 3, are taken at face value as N-protonation constants, then the implication is either that the iminium ion equilibrium is not established (the rate law is equation 29), or that it is established but N-basicity exceeds C-basicity (equation 30, EH+ >> The choice is not obvious.
eH*).
The carboethoxy stabilized secondary enamines, 25 and 26, were studied by Guthrie and Jordan68. In the absence of buffer, and at pH E 5 to 6, acid catalysis is evident and a solvent kinetic isotope effect, (k,+/k,+) = 2.3, is found for 25. These results clearly support rate-controlling C-protonation of the enamine; the catalytic constants are included in Table 9. Both 25 and 26 show general-acid catalysis of hydrolysis in the pH
19. Mechanisms of enamine hydrolysis
1081
range 4 6 . However, the general-acid catalysis is seen only at low buffer concentration and becomes saturated at higher [buffer]. This result recalls that of Sollenberger and Martin for enamines 5 (X = C1) and 12 (X = H)I3. The disappearance of general catalysis is, however, accompanied by a switch to specific hydronium ion catalysis and a concomitant inverse solvent kinetic isotope effect, (k,+/k,+) = 0.45. All these data are accommodated by Scheme 1 starting at equation 15. At zero or low [buffer], Cprotonation is slow. At higher [buffer], equation 15 is at equilibrium Vaooring the free enamine), and the subsequent hydration step, with water the dominant nucleophile, is rate-controlling. The only possible perturbation of Scheme 1 is that, at the highest pH values used by Guthrie and Jordan, a portion of the iminium ion, once formed, might be present as its alternative conjugate base, the i n ~ i n e ' ~ ~ . ~ ~ . E. KArylenamines of lsobutyraldehyde, Cyclohexanone and Z-Methylcyclo-
hexanone
Capon and Wu have prepared several series of secondary enamines (27-29) and compared the kinetics of hydrolysis of these compounds with their tertiary, N-methyl analogues69. All six sets of compounds have an aryl group attached to nitrogen, that is, all are derivatives of substituted anilines or N-methylanilines. Substituents on the aromatic ring were varied in each set, providing a Hammett p value for every series. One other set discussed in this chapter, compounds 10, also gives a p value for N-aryl substitutionz0. Enamines 27 are derived from isobutyraldehyde; thus some comparisons with compounds 1-3, studied by Stamhuis and coworkers", are possible. Compounds 28 and 29 are derived from cyclohexanone and 2-methylcyclohexanone, respectively. As will be seen, the P-methyl group in series 29 has a significant effect on the rates of hydrolysis for the secondary series, and a dramatic effect on the tertiary series.
The pH-rate profiles obtained by Capon and Wu consist of a pH-independent region at higher pH, becoming proportional to [Hi] at lower pH. For example, in series 27 (Ar = Ph, L = H) the break occurs between pH 7 and 6, while for the tertiary analogue (Ar = Ph, L = CH,) the change occurs ca 2 pH units slower. No downward curvature or plateau at still lower pH is readily observable in Capon and Wu's Figure (not a log-log plot). However, they do report that at lower pH values there are downward deviations, that is, the experimental rate constants are smaller than expected for a first-order dependence on [Hi]. Nevertheless, at sufficiently high pH the results are correlated by equation 32, and rate constants based on adherence to this equation are listed in Table 10. Other pertinent mechanistic evidence is provided as well. The authors report no observation of any intermediates. A control experiment showed that the iminium ion derived by C-protonation of 27 (Ar = Ph, L = H) and/or its conjugate base imine would,
TABLE 10.
Substituent
Rate constants for carbon protonation by H,Ot of some N-arylenarnines (H,O, 25 "CI"
NHAr
\
NHAr
NHAr
" k , , / M - I s ' , Reference 69. The isobutenyl compounds were measured at 1 = 1.00 M (KCI), while for the other series 1 = 0.10 M (KCI), 'The a- constant was used for the p-nitro substituent.
\
19. Mechanisms of enamine hydrolysis
1083
if generated, be itself hydrolyzed over 5000 times faster than the enamine. General-acid catalysis by acetic acid was demonstrated for 27, Ar = m-nitrophenyl, L = H and CH,, and normal solvent deuterium isotope effects, (k,+/k,+) = 2.8-3.8, were found for six of the members of series 27, including both secondary and tertiary enamines. No evidence for base catalysis was obtained for any of the secondary enamines even at pH as high as 12.1. This important result rules out a rate-determining step in which base deprotonates nitrogen while an acid protonates Cg (equation 33). Although this mechanism, or
its stepwise variant, might have been imagined (by analogy with base-catalyzed ketonization of e n o l ~ ~Capon ~ ) , and Wu argue that it is not chemically reasonable. For one thing, the acidity of a secondary enamine is expected to be much less than that of an enoI8'. Second, the iminium ion is not as unstable an intermediate as is a protonated aldehyde or ketone, and therefore there is no need for a mechanism which avoids it. T o this argument we add that there is considerable evidence that acid-catalyzed ketonization passes through a protonated carbonyl intermediate44, and that if this intermediate is not avoided, neither will an iminium ion be avoided. Using different arguments, Coward and Bruice also ruled out a concerted mechanism for compounds 10 and 11. In terms of Scheme 1, the best interpretation of these results is rate-controlling protonation of the enamine a t Cg:by water in the pH-independent part of the pH-rate profile, by H 3 0 4 in the lower-pH regon and by general acids as well in buffer solutions. The small negative deviations from equation 32 at low pH reported by Capon and Wu would then be due to the onset of a change in rate-controlling step as described in previous sections. It remains to discuss the structure-reactivity results obtained by Capon and Wu; this will be done in the context of equation 15: rate-controlling C-protonation by H 3 0 + . One noteworthy result (see Table 10) is that, for the cyclohexenyl series 28, the change from a secondary to a tertiary enamine has very little effect on k,,. By contrast, for series 27, the N-methylenamines are hydrolyzed at rates ranging from 20-800 times slower than the secondary analogues, while for series 29 the N-methylenamines are slower than their secondary counterparts by a factor of 15,000 to more than 400,000. For 27, L = CH, and 29, L = CH, it is apparently difficult to achieve the desired coplanarity of the amino and alkenyl moieties in the transition state (cf equation 4) which permits the conjugative donor properties of the amino group to be fully exploited. In agreement with this interpretation is the fact that for series 28, where the rates of hydrolysis of secondary and tertiary members are very similar, the p values for hydrolysis are also very similar: p,,, = -3.45 and -3.26, respectively. For series 27 and more so for 29, the p,,,, values are smaller in absolute magnitude (see Table 10) for the tertiary series, which indicates that in those cases the aryl substituents are less responsive in the transition state, a predictable result if the amino lone pair is hindered from optimal conjugative interaction with Cg. For all three series the secondary enamines produce p,,,, values which are identical within experimental error. By this criterion, transition state conjugation between the N-arylamino group and the alkenyl part of the molecule is not restricted, at least in the transition state. These values can therefore be taken as representative of N-aryl substituent effects on the rates of hydration of simple secondary enamines. It is noteworthy in this context that even when steric hindrance is strongly implicated, as in the tertiary series (29, L = CH,), the p,,,, value is -2.38, a much larger value than the
1084
James R. Keeffe and A. Jerry Kresge
Px.+ = -0.61 found for series loz0. It is clear that for 10 the cyano group strongly affects the difference in the N-aryl substituents' responsiveness toward reactant and transition state demands. Alkyl substitution at the or and P carbons of the alkene portion of Capon and Wu's enamines exerts effects that can be rationalized according to principles already discussed in this chapter. Thus, for the secondary series we see that or-alkylation, as in the keto-enamines (28 and 29), produces rate accelerations relative to the aldo-enamines (27). Only when steric hindrance becomes too great, as for the tertiary series (29, L = CH,), do compounds 27 react faster. A further insight is possible by comparing some of Stamhuis' compounds with members of series 27. The k,, values for the three tertiary enamines are in the order of basicity of the parent amines (although 1 is only about three times faster than 27). But secondary enamine 27 (L = H) is 50 times faster than 1 despite the (presumed) weaker basicity of the former. This result suggests that C-protonation of 1 and 2 is somewhat retarded by steric hindrance to conjugation, and allows a prediction that the enamines formed from isobutyraldehyde and ammonia or primary aliphatic amines will be found to be C-protonated significantly faster than compounds 1, 2 and possibly even 3.
Alkylation at Cp retards protonation at that site as it does for e n o l and ~ ~ enolates ~ (see also Table 6). The effect is a modest one when steric hindrance to conjugation in the transition state is not too great: the secondary enamines of series 29 are hydrolyzed but 4 to 7 times slower than those in series 28. Huge differences, factors of ca lo6,exist between some of the tertiary members of 28 and 29, however. As discussed above, these differences are dominated by the inability of 29 (L =. CH,) to take full advantage of conjugative stabilization in the transition slate. It is worth pointing out, as do Capon and WuG9,HickmottGf and many others, that structural effects on the reactivity of enamines toward electrophiles are anticipated by a variety of physical properties of the enamines, including UV absorption frequencies, IR stretching frequencies, NMR chemical shifts and first ionization potentials. These properties in turn are influenced by the ability of the formal lone pair on the nitrogen to conjugate with the formal double bond, an ability which is modulated by both steric and electronic effects.
F. Miscellaneous Enamines and Some Related Compounds
1. Two P-arylenamines
The hydrolysis of compounds 6 and 35, the only P-arylenamines addressed in this chapters9, was studied in Kresge's laboratory in 197214. Compound 6 was examined in unbuffered H,O and D,O, and in tris and ammonia buffers, all at 25 "C. Hydrolysis (to phenylacetaldehyde and morpholine) was faster in H 2 0 by a factor of about five.
19. Mechanisms of enamine hydrolysis
The buffer studies showed general-acid catalysis with no curvature of the buffer plots up to a buffer base concentration of 0.10 M. These results indicate the usual ratecontrolling C-protonation mechanism to be operative under these conditions. From the intercepts of the buffer plots a rough value, kH+E 3 x lo5 M 1 s- , could be estimated (see Table 4). This value is surprisingly high-about lo3 greater than kH+for compound 1, the morpholine enamine of isobutyraldehyde~speciallyin light of the fact that the N-basicity of 6 is much less than that of 1 (see Table 2). If accurate, this result is difficult to explain except by postulating a transition state for protonation of 6 in which conjugation between the morpholino and phenyl moieties is preserved or even enhanced! In alkaline solution (pH = 11.612.0) the rate of hydrolysis was independent of pH and s-'. This provided a value for the rate of protonation of 6 by H,O, kHz, ,= 4.8 x number is just slightly smaller than that for compound 1. The kmetics in dilute sodium hydroxide solution were actually found to be biphasic; k,,, was obtained from the initial 1.5-2.0 half-lives. After this period, the aldol condensation between two molecules of phenylacetaldehyde perturbs the first-order time course, as was demonstrated by control experiments. The hydrolysis of compound 35 in acidic and in buffer solutions is, by and large, similar to that of 6. In dilute aqueous perchloric acid (0.005-0.07 M), hydrolysis was found to be accurately first-order in lyonium ion and yielded kH+= 4.80 x lo3 M - ' s-I and (kH+/k,+) = 3.53 0.02. General-acid catalysis in four carboxylic acid buffers was observed with no curvature of the buffer plots at high [buffer] evident. A Brernsted coefficient, a = 0.60 0.03, was obtained. Buffer acid catalysis in a series of substituted pyridine buffers was also found. For the more basic of these pyridines, at high [buffer], there was slight apparent curvature. Moreover, the kH+values calculated from the acid concentrations of these solutions and the buffer plot intercepts are too high relative to the constant obtained by direct measurement in HCIO,/H,O solutions; this is also consistent with the onset of buffer saturation at high [buffer]. Such results could signal the beginning of a change in rate-determining step from C-protonation to a subsequent step, perhaps nucleophilic attack upon the iminium ion by water (Scheme 1, equation 16),as proposed by Sollenberger and Martin in their study13 and by Guthrie and Jordan in theirs.68 The most unusual feature in the study of compound 35 was found for hydrolysis in dilute sodium hydroxide solutions (0.02-0.10 M). No complications arising from aldol condensation of p-nitrophenylacetaldehyde were evident, presumably because in these solutions this aldehyde is completely in the enolate formg0. However, the rate of hydrolysis was first-order in hydroxide concentration, k,, = (2.26 k 0.06) x W 4 M-' s-'. This result, together with the structure of 35, suggests a new mechanism for the hydrolysis of this enamine in alkaline solution, namely nucleophilic vinylic substitution (equation 34). We believe this suggestion to be a reasonable one in view of the known ability of nucleophiles to add to p-nitrostyrene via the p-nitrophenyl-stabilized benzylic aniong2.
James R. KeelTe and A. Jerry Kresge
2. Some enaminones
In 1974, Dixon and Greenhill reported a study of the hydrolysis of 14 enaminones at 37 "C over the pH range 2-11". Although the study was not as detailed as some of those reported above, a number of interesting observations were made. To anticipate: their results (though indicative of complexity) seem to fit well the general mechanistic picture of Scheme 1, but with some twists caused by the peculiarities of enaminone structure. Two sets of enaminones, 36 and 37, were studied. Their hydrolysis reactions are shown as equations 35 and 36. For compounds 36, groups R 1 and R 2 were combinations of H and small alkyl groups (CH,, C,H,, [CH,],), while R3 was H except for one compound for which R3 = CH,. Group R4 was usually CH3 with one instance each of R4 = Ph and OEt (an enaminoester). The R group in series 37 was varied from H to
19. Mechanisms of enamine hydrolysis
CH, to Br to NO,. The product fi-diketones (largely enolic) were susceptible to hydrolytic retroaldol cleavage, a result which affected the UV spectrum of the reacting solutions. Only when this process occurred at a rate similar to that of the enamine hydrolysis, was the first-order behavior of the time course compromised, and in these cases correction for loss of dione was made. Although buffers were used by Dixon and Greenhill to control the pH of their reaction solutions, the concentration of buffer components was very low (total [buffer] E M) and, perhaps for this reason, catalysis by buffers was not detected. Nor were experiments carried out in D,O. Therefore two of the major criteria for rate-controlling proton transfer, general-acid catalysis and a primary kinetic solvent isotope effect were not demonstrated. Nevertheless the pH-rate profiles are indicative, for the most part, of a mechanism much like Scheme 1. Five of the enaminones (all those with primary amino groups plus 37, R = CH,) give linear plots of k/s-' vs [H+]. These plots were extended to as low as pH = 4 only in one instance, ending at pH = 5, 6 or 7 in other cases owing to the rapidity of the reactions. In these cases second-order k,, values could be easily obtained and are listed in Table 9. The simplest interpretation of this behavior is rate-controlling C-protonation (Scheme 1, equation 15). However, since enaminones are preferentially protonated on oxygen, with pK, values generally below 359, it is also possible that protonation is reversible and in Scheme 2 (equations 3740) attack of water (equation 38) is ratecontrolling. Four other compounds gave nonlinear plots with a shallow or flat pH dependence at a higher pH, yielding to a steeper, acid-catalyzed region at lower pH before k/s-I passed through a clear maximum and declined with further increase in acidity. Three of the remaining ketones gave similar curvature at a higher pH, but rates became too fast at lower pH for a rate maximum to be reached. These seven compounds are either N-alkylated members of series 36, or those members of series 37 for which R = H, that is, with no extra P-alkyl group. As such, they are among the more reactive of the compounds studied. In terms of Scheme 2, the shallow region of the pH-rate profile could reflect a situation in which enaminone is essentially unprotonated and its conjugate acid is attacked in the rate-controlling step by both OH- and H,O, the hydroxide ion contribution fading away at lower pH in favor of attack by water. At still lower pH (but still where pH > p e H ' ) the decrease in k/s-' must represent a change in rate-determining step to decomposition of the carbinolamine/enol intermediate to the ultimate products (equation 40). At the pH values for which the fall of k/s-' was demonstrated, the dominant form of the carbinolamine/enol is its N-conjugated acid, compound 38". The remaining question then is: which path in equation 40, a, b, or c, is preferred? Dixon and Greenhill consider 40a and 40c. On the basis of our previous discussion (see Section III.A.3) we prefer 40h over 40a. A choice between formation and decomposition of the two different zwitterions, path 40b vs 40c, is not simple. Both OH groups in 38 are acidified by the positive pole. Enols are intrinsically more acidic than alcohols, and the enolate can be further stabilized by an intramolecular hydrogen bond. On the other hand, the positive nitrogen is proximate to the alcohol OH group, little or no restriction of rotational freedom being needed to exert its full stabilizing effect on the alcoholate. Moreover, fewer bonding changes accompany the breakdown of the alcoholate zwitterion than is the case for the enolate zwitterion and step b' might well be much faster than c' (the principle of least motion)93. The preferred path for the decomposition of 38 is not clear. The interpretation of the results given so far, namely Scheme 2, is a reasonable one, but should be taken with some caution for two reasons. One is that the experiments which would allow or exclude a mechanism more exactly like that of Scheme 1 (C-protonation), that is, a thorough search for buffer catalysis and kinetic determinations
James R. Keeffe and A. Jerry Kresge
1088
R3
R3
/'
I
R3
(or tautomer)
R2 NH- - -0-
R1\ +
/
R3 SCHEME 2
19. Mechanisms of enarnine hydrolysis
1089
in D,O, were not done. Second, a C-protonation pathway cannot be dismissed out of hand just because 0-protonation is more facile. As evidence, we remind the reader of Guthrie and Jordan's study of compounds 25 and 26, two enaminoesters which might have been expected t o react by 0-protonation, but which apparently d o not6'. Additionally, in the next section we will encounter another pair of /-carbonyl substituted enamines, both of which also react via C-protonation (Scheme 1)". In acidic media (below pH = 6 ) the two most sluggish enamines examined by Dixon and Greenhill were the members of series 37, R = Br and NO,. Both showed pH-rate profiles which were concave upward, i.e. the pH plots passed through minima. On the low-pH side of the minima the observed acid catalysis is likely due either to ratecontrolling hydration (Scheme 2, equation 38) o r rate-controlling protonation (Scheme 1, equation 15). The increase in rate on the high-pH side of the minimum is more interesting. We can dismiss the variant of Schemes I and 2 in which fully protonated substrate must lose a proton prior to reacting; enaminones, especially those with electron-withdrawing groups attached, are not basic enough to be protonated at the pH values in question, a fact directly demonstrated by Dixon and Gree~~hill'~. Therefore, a mechanism in which the substrate reacts with hydroxide ions is implied. The mechanism proposed by Dixon and Greenhill, conjugate nucleophilic addition of O H followed by expulsion of the amine (equation 41), is analogous to that proposed in Section III.F.1 for enamine 35. At sufficiently high pH, the base-catalyzed mechanism for enaminones might prove to be general for enamines with electron-withdrawing groups at Cp
3. Two 1,4-dihydropyridines Several groups have studied the acid-catalyzed hydration of dihydropyridine derivatives related to NADHS0.94-9s. W e present in this section the results of Bunton, Rivera and Sepulvedaso, who studied the hydration of the N-benzyl compounds, 39 and 40. The reactions (equation 42) are not, strictly speaking, hydrolyses, yet the overall result is the same as in Scheme 1 (or Scheme 2) up to the carbinolamine stage.
1090
James R. Keeffe and A. Jerry Kresge
Hydration was studied in aqueous HC1 solution (approximately 3 x M up to greater than 1 M) and, in carboxylic acid buffer solutions, all at 25 "C. General-acid catalysis was demonstrated (a = 0.6, a value very similar to that found by other^'".'^.^^ ), and primary kinetic isotope effects were found: (kH+/kD+) = 3.2 for 39 and 3.7 for 40, while (k H,2, /k , ), was 5.3 for 39 and 6.2 for 40. At the higher acid concentrations (above ca 0.1 M) the first-order dependence of kls-' on [H'] was found to curve downward, levelling off for 40 near [H'] = 1.0 M. At much higher [HCI], k/s-' actually fell slightly for 40 (reaction of compound 39 had become too fast for the plateau to be reached). All these data were rationalized by the mechanism of equation 43, which leads to rate equation 44. This equation fits the experimental data well, except above [HCl] = 1.0 M where electrolyte effects are likely to alter the apparent value of kH+and where the decline in the activity of water might cause the hydration step to become partly rate-controlling. The kH+values for 39 and 40, evaluated in dilute HC1, are included in Table 9. From the data in the region of curvature, values for p e n ' could be extracted. These turned out to be 0.62 for 39 and 0.87 for 40, not inconsistent with expectations for /J'-acylated enaminesS9.
Equation 44 is essentially the same as equation 20 except that, in equation 20, the equilibrium constant factor, c H i , refers to the unreactive enammonium ion of a simple enamine. In equation 44 the unreactive protonated form is proposed to be the 0protonated conjugate acid. This conjugate acid is, of course, potentially reactive toward nucleophilic water, but such a reaction (equation 45, corresponding to equations 38 and 39 of Scheme 2) destroys the conjugated enaminone n system, while the observed reaction (equation 43) leaves it intact. It is quite possible that all or part of reaction 45 occurs, and represents an unproductive, but rapidly established, equilibrium. If this were correct, in equation 44 would refer to then the equilibrium constant identified as equilibrium between the starting enamine and all three of the species in equation 45.
cH'
19. Mechanisms of enamine hydrolysis
Bunton and coworkerss0 also investigated salt and micellar effects on the hydration of 39 and 40 in aqueous HCI. In dilute HCI ten different added salts produced positive, but relatively modest, effects on reaction rate. These almost nonspecific effects were attributed to the typical ability of strong electrolytes to increase medium acidity. At 1 M HCL, however, the effects were very small or slightly negative for 40. Since this is the region in which k/sC1 reaches a plateau, the result can be attributed to enhancement of the unproductive equilibrium discussed above. Micellar effects were found to be variable and dependent on the type of micelle employed. Cationic micelles, such as cetyltrimethylammonium bromide, inhibited hydration. Anionic micelles formed from sodium lauryl sulfate (NaLS) produced a small amount of catalysis at low concentration, k,,, actually passing through a maximum at P a L S ] < the critical micelle concentration (cmc). O n the other hand, micelles formed from monopotassium n-dodecyl phosphate in unbuffered water give impressive catalysis relative to water itself. Detailed discussion of these effects is given in Reference 80.
4. Modified enamines: aminoarenes, enamides and pyrroles
Several reactions have been examined in which the substrates, though not enamines in the strict sense, are nonetheless related to enamines in their reliance on the powerful p n donor ability of nitrogen to activate an unsaturated carbon toward electrophilic attack. Rate constants, and in some cases equilibrium constants, for C-protonation of these 'modified enamines' are known. The substrates include p-amino- andp-dimethylaminostyrene (41, 42)99, seven 1,3,5-triaminobenzenes (4M9)L00-102,six enamides (Nvinyl- or N-styrylamides; 5&55)'03 and three trialkylated/pyrroles (56'04, and 57 and 5S107).
(42) (43) (44) (45) (46) (47) (48) (49)
NR2 = NH2; R1 = H NR2 = pyrrolidino; R1 = H NR2 = pyrrolidino; R1 = Me NR2 = pyrrolidino; R1 = Et NR2 = pyrrolidino; R' = i-Pr NR2 = m o ~ o l i n n ;R' = H NR2 = piperidino; R1 = H
James R. Keeffe and A. Jerry Kresge
The reactions of the aminostyrenes and of the acetamidostyrenes was hydration; that of the four other enamides, 52-55, was hydrolysis of the enamine moiety to acetamide plus the carbonyl compound. These reactions were shown to take place by ratecontrolling C-protonation of the neutral substrate according to the usual criteria: primary solvent kinetic isotope effects; acceleration of the rate by methyl and phenyl substitution at C,; general-acid catalysis for compound 53 (which was reactive enough to be studied in acetic acid buffers at 25 "C), and for 41 and 42 at 80 "C; and analogy with closely related reactions such as the hydrations of other substituted styreneslo6 and the hydrolyses of ordinary enamines",13." . Th e reactions of the triaminobenzenes were protonation-deprotonations in which C-protonation competes with N-protonation to an extent which depends upon structure and (somewhat) upon temperature. These reactions were characterized by spectroscopic (UV, NMR) and kinetic (stoppedflow, tJump, p-Jump) techniques over a wide range of pH. In several cases a second C-protonation product containing the cyanine chromophore, (R2N-C-C-C-NR,)', could be observed at low pH. General-acid catalysis was demonstrated for protonation of compound 441°". For the pyrroles the reaction studied was either direct protonation4eprotonation (compound 56, a stopped-flow study)'04 or pr~tiodetritiation'"~. The reaction of 56 was characterized by observation of general-acid catalysis (a = 0.54 for six carboxylic acids plus H,PO,-), and a solvent isotope effect on the rate of C-protonation, (k,+/k,+) = 2.77'04. The reactions of 57 and 58 also displayed generalacid catalysis105. Rate constants for C-protonation (k,,, kHz,) and equilibrium constants ( p e n ' and p e H ' , as they are known) are listed in Table 11 for all the compounds shown in this section. The most prominent result is that the reactivity of an alkene moiety toward protonation becomes greatly attenuated as the amine moiety with which it is conjugated is moved from being directly attached (as in ordinary enamines, see Table 4) to being either conjugated through an aromatic ring or being cross-conjugated (as in enamides). The relative reactivities (k,,) of an aminoethylene, ap-aminostyrene, acetamidoethylene and 2 x a range andp-acetamidostyrene are, respectively, ca lo7, lo-', 5 x
19. Mechanisms of enamine hydrolysis
1093
TABLE 11. Rate and equilibrium constants for C-protonation of some modified enamines: aminoarenes, enamides and pyrroles (H20,25 "C) Compound
pK$'
Aminostyrenes and Enamides 41 42 50 51
52 53 54 55
-
-
-
pK,NH*
kH+( M - '
3.68" 4.36' ca - 1.6( cu -1.6'
5.0 x 0.25b 2.06 x 8.9 x 5.0 x 10.8 0.32b 0.18b
-
-
-
-
-
-
-
SKI)
k ~ 2 0( s l )
-
-
-
Reference 99, 103 99, 103 103 103 103 103 103 103
Triaminobenzenes 43 44 4Sd 46d 47d 48 49
Pyrroles 56 57
58
5.44 9.62 12.75 14.70 > 15 2.45 4.64 3.75 1.4' -0.24'
-
6.12 -
3.40 6.30 -
-
-
3.2 x lo7 ca 3 x lo5 ra 7 x lo6
-
0.62 5.7 10" 0.13 -
3.1 x 10' 7.0 x lo2 5.69 x lo' 3.6 x IO3j 3.8 x loJf
-
-
-
100,101 102b 102b 102b 102b 102b 102b 104 105 105
'H,O, 80 "C, p = 0.10 M. Wbtained by extrapolation of linear plot of log kls-' vs H, to H, = 0. 'These values may refer to 0-protonation. dThe 2-alkyl-1,3,5-tripyrrolidinobenzenesare protonated on C-2102. 'Estimated according to the additivity procedure of Chiang and Whipple". 'Calculated by Terrier and coworkers'04 from data of Alexander and Bu~ler'~'by assuming a kinetic isotope effect, (kJkT) = 18, for dehydrogenation of the pyrrole conjugate acids. N o statistical correction is made here.
of almost 1013. This falloff in the rate of protonation is not surprising, but its magnitude is impressive. The C-protonation of triaminobenzenes requires disruption of a benzenoid sextet of rr electrons, but here activation is provided by three amino groups, not just one. High reactivity, both kinetic and thermodynamic, is shown by the tripyrrolidinobenzenes, 4 4 4 7 . As discussed in Section ILA.2, a pyrrolidino group is expected to be a more powerful activator than piperidino or morpholino. It is surprising, however, that the difference in kH+between the latter two amounts only to a factor of two when the equilibrium basicities (for C- as well as for N-protonation) differ by factors of 102.2-102.9. (4547) is highly favorRing protonation of the 2-alkyl-1,3,5-tripyrrolidinobenzenes able, even in somewhat alkaline solutions, and occurs regiospecifically at C-2. This result, and the fact that basicity increases in the order R 1 = H < Me < Et < i-Pr seems to require an explanation based on steric effects. For the neutral bases R1 doubtless interferes with the pyrrolidino group to either side: this interaction could cause torsional or van der Waals strain, and could also cause loss of p n resonance stabilization of the base. All this can be relieved, at least in part, by protonation and rehybridization at C-2. The alkyl group in the conjugate acid is thought to occupy a 'quasi-axial position"02d. The explanation just given might be too simplistic, however. Equation 46,
James R. Keeffe and A. Jerry Kresge
(Py = pyrrolidino)
(45)
which has K,, = 1.3 x lo3, is completely controlled by entropic considerations; AH = 0 f 1 kcal mot-' while AS" = 14 5 cal deg-I mol-' '02". In an additional exercise, Knoche and coworkers'02 combined their results with data from other work on the protonation ofactivated arenes to update a Brffnsted correlation originally based on a group of alkoxybenzenes and azulenes"". of log kH+vs This correlation, edited to exclude the alkylated triaminobenzenes, 4547, which fit poorly, and to include recent data on phenol'09 and 1,3,5-trihydroxybenzenem, is shown in Figure 3 and displayed in equation 47.
+ +
log(kH+/q') = (0.56 _f 0.03). (pK,CH- log q) + (1.90 f 0.21) r = 0.969
FIGURE 3. Correlation of log (k,+/q') with p(qK,) for the protonation of activated arenes; see equation 47 in text as well as Table 12
1095
19. Mechanisms of enamine hydrolysis
TABLE 12. Rate and equilibrium constants for the protonation ofactivated arenes (H,O, 25 "C)" Activated arene
pK,CH
Iog(kH./M
sl)
Reference
Methoxybenzene 2,6-Dimethoxytoluene 2,6-Dihydroxytoluene 1,3-Dimethoxybenzene 1,3,5-Trimethoxybenzene 1,3,5-Triethuxybenzene 1,3,5-Trihydroxybenzene Phenoxide ion 3.5-Dihydroxyphenoxide ion Azulene 4,6,8-Trimethylazulene
1,4-Dimethyl-7-(i-propyl)-azulene 1,4-Dimethyl-7-(i-propyl)-azulene-2-sulfoae ion 1,3,5-Trimorpholinobenzene(48) 1.3,s-Tripiperidinobenzene (49) 1,3,5-Tripyrrolidinobenzene(44) 1,2,5-Trimethylpyrrole (58) 1,3,4-Trimethylpyrrole (57)
2,4-Dimethyl-3-ethylpyrrole(56) "Statistical factors taking into account multiple protonation sites were applied to these data in constructing the correlation of Figure 3 and equation 47. Specific rate ofprotodetritiation; this was converted to rate of protonation of protio substrate by applying the isotope erect kJk, = 18, as recommended by Reference 104. 'Specific rate of protodedeuteriation; this was converted to rate of protonation of protio substrate by applying the isotope effect kJk, = ( kJkJk,)'1'-442= (18)'1"42 = 7.4. *Estimated using the correlation of Reference 33.
In this equation q is a statistical factor denoting the number of equivalent basic sites involved in the equilibrium protonation and q' is a statistical factor denoting the number of basic sites involved in the kinetic process; q' is not necessarily the same as q when the kinetic process is monitored by an isotopic tracer originally present in the arene substrate. The data upon which equation 47 is based are listed in Table 12. The correlation extends over 25 log units in p e H and is quite good, considering its extent. Figure 3 shows a hint of curvature, and the data are fitted slightly better by a quadratic rather than a linear equation, but the difference is hardly significant. The correlation provides a practical means of estimating one of the two reactivity parameters from the other, providing steric effects are not dominant. G. A Brief Summary of Section Ill
The vast majority of enamine hydrolyses which have been investigated from the mechanistic point of view fit comfortably the mechanism given in Scheme 1. The sometimes convoluted pH-rate profiles are caused by changes in rate-controlling step from protonation at Cp,to nucleophilic hydration of the intermediate iminium ion, to breakdown of the carbinolamine addition product, probably via a zwitterion. The pH values at which changes in rate-controlling step occur are determined by a combination of structural features of the enamine and, in some cases, by the concentrations of buffer species which might be present; these issues are discussed in the text.
1096
James R. Keeffe and A. Jerry Kresge
Rate-controlling C-protonation is dominant for many of the enamines over most or all of the pH range surveyed. As a class, simple enamines are among the most reactive of all alkenes toward electrophiles. We can estimate (following Tidwell and coworkers103) that the k,, values for 1-pyrrolidinoethene and I-phenyl-I-pyrrolidinoetheneare greater than los M - ' s - ' . That is, simple enamines are protonated on carbon faster than all the common classes of nucleophilic olefins except for the simple enolates (see Tables 4 and 6). However, the carbon basicity of enamines, in both the thermodynamic and kinetic senses, is quite sensitive to aspects of amine moiety structure, of alkene moiety structure, and of interactions (both electronic and steric) between the two. Although the basicity of the parent amine determines, in a rough way, the reactivity of the enamine toward electrophiles, it is noteworthy that pyrrolidine enamines are consistently more reactive than other enamines. A relative lack of steric problems allows good p n overlap between the nitrogen's formal lone pair and the alkene n system for pyrrolidine enamines. The ability of this nitrogen to assume spZ hybridization, with concomitant optimization of n overlap, is especially important in the transition state for protonation at Cg. Features of enamine structure which interfere with the desired transition state geometry reduce the rate of protonation. Alkylation at Cp lowers the kinetic reactivity of an enamine by a combination of reactant state electronic stabilizan system in the transition tion and steric hindrance affecting coplanarity of the C=C-N state. Arylation at Cpshould also retard protonation, although the single example, i.e. compound 6, seems surprisingly fast. Attachment of conjugating electron-withdrawing groups, e.g. cyano or carbonyl, to Cggreatly reduces the kinetic and thermodynamic basicity of an enamine by reactant state stabilization. Alkylation and arylation at C, turn an aldo-enamine into a keto-enamine. Notwithstanding the potential for steric inhibition of coplanarity (see above), it appears that electronic effects prevail and keto-enamines as a class are more reactive than aldo-enamines. The effects of substitution on the alkene moiety cited in this paragraph all have parallels in keto-enol-enolate chemistry. It is possible that conjugated enamines such as enaminones hydrolyze by the mechanism shown in Scheme 2, a variation of Scheme 1 in which nucleophilic hydration occurs on an 0-protonated enamine rather than on the C-protonated (iminium) ion. This mechanism has been proposed for the acidic hydrolysis of compounds 36 and 37. This mechanism cannot be considered established, however, as the experiments that would rule out C-protonation were not done. It is highly pertinent that hydrolyses of other conjugated enamines, 10,11,25,26,39and 40, all obey the expectations of Scheme 1, equation 15, namely they exhibit general-acid catalysis and (for 25, 26, 39 and 40) primary kinetic solvent isotope effects. Enamines with good n-acceptor substituents at Cp,including conjugated enamines of the type just described, can hydrolyze by a base-catalyzed mechanism: probably stepwise nucleophilic vinylic substitution at C, (see equations 34 and 41). The generality of this mechanism has yet to be demonstrated, but it is strongly implied for compounds 35 and 37 (R = NO,), and less dramatically for 37 (R = Br). Compounds in which the donor nitrogen is separated from the carbon-protonation site by an intervening aromatic ring (aminostyrenes, aminoarenes), or in which conjugation between nitrogen and the alkene moiety is diverted by cross-conjugation (enamides), are protonated much more slowly and to a far smaller extent than are simple enamines. IV. COMPARISONS AMONG NUCLEOPHILIC ALKENES
The high reactivity of enamines demonstrates the ability of trivalent nitrogen, directly attached to a multiple bond, to activate that bond toward electrophilic attack. In this section we will document the order of reactivity of a number of nucleophilic alkenes
19. Mechanisms of enamine hydrolysis
1097
toward protonation. First we compare equilibrium basicities of these species, and second, their rates of protonation. A. Equilibrium Basicities of X-C=C
Compounds
In the gas phase the free energy of protonation of N,N-dimethylvinylamine (equation 48) is -220.0 kcal mol-' 64. AS discussed in Section II.A.4, protonation occurs at Cg, as s h ~ w n ~ ~ ' ~ ' ~ The ' ~ free " ~ .energies of protonation of methyl vinyl ether and methyl vinyl sulfide are - 198.8 and - 198.6 kcal mol-', respectively; these substances also are protonated at C6'14.Far more basic than any of these is the enolate of acetaldehyde (vinyloxide-) for which C-protonation is accompanied by AG"(g) = -359 kcal mol-' l 1 5 . Thus, the gas-phase reactivity order is enolates >>> enamines >> enolethers % enols vinyl sulfides. (For the present purpose, we ignore the real, but smaller, differences in reactivity between enols, their ethers and vinyl sulfides.)
=
Taft, Topsom and coworkers have carefully analyzed substituent effects on gas-phase proton transfer equilibriaH6. From that analysis we can conclude that the superior activating effect of dimethylamino over methoxy is due to a superior response by all three modes of electron release: resonance, polar (field/inductive) and polarizability. The largest effect, however, is the resonance effect. Between dimethylamino and methylthio, the resonance effect is even more dominant in favor of the amino function, but electron release via polarization of the sulfur function is actually better than that of the amino function. The equal basicities of methyl vinyl ether and methyl vinyl sulfide turn out to result from cancellation between the better resonance response of C H 3 0 and the greater polarizability of CH3S with the polar effects of these two having no difference. One should also keep in mind, especially for the comparison between CH,OCH=CH, and CH,SCH=CH,, that the oxygen and sulfur substituents may stabilize the neutral reactants to different extents. A second warning, issued by &apay and c ~ w o r k e r s " ~ , is that the preferred (relaxed) geometry of the cationic conjugate acids produced in the experimental gas-phase work may not be fully reflected by the AG" measurements. Basicity differences in solution tend to be compressed relative to those in the gas phase. Moreover, the polarizability response of a substituent is largely masked by solvation. Nevertheless, especially for comparisons between oxygen and nitrogen, there are plentiful data with which the base-strengthening effects of substituents attached by these atoms can be quantitatively judged. Selected aqueous-phase pK, values are shown in Tnble 13; these are qualitatively in line with the gas-phase effects discussed above. The basicity order is RNLC=C >> OLC=C >> RN-C=C >> RO-C=C, and appears to be preserved (though attenuated) when the site of protonation is oxygen rather than carbon. This order is sensible, of course, but the range of basicities (greater than 30 pK units) is impressively large for a group of substances all of which are regarded as activated toward protonation. Also shown in Table 13 are an ynamine and an ynol, both as their conjugate bases. The triple bond has a remarkable acid-strengthening effect on a n attached O H or N H Similarly, the carbon basicities of ynolates and ynamine anions are a good deal less than those of enolates and enamine anions, respectively. Despite the fact that the p c H values for the triple bond compounds are but estimates, it is clear that the negatively charged nitrogen is still a much more powerful base-strengthener than is negative oxygen.
1098
James R. Keeffe and A. Jerry Kresge
T A B L E 13. C o m p a r i s o n of the base-strengthening effects of nitrogen a n d oxygen a t o m s attached t o multiple b o n d s (H,O, 25 " C p b Base N-compound
Base,
PK,'
Reference
O-compound
>>20 (est.)
87, 88, 117
I =/ 0-
PK,'
Reference
'The site of protonation is indicated by an arrow. 'For further comparison one can estimate a value for isobutylene, as follows: Eberz and Lucas"' give Kc, = 7.5 x lo3 for the hydrat~onof ~sobutyleneto r-butyl alcohol; Arnett and H o f e l i ~ h " interpolate ~ pK,, z -14.7 for t-hutyl alcohol. Combination of these results yields pK, - 11 for protonation ofisobutylene. 'pK, of conjugate acid formed by protonation of base at site indicated.
1099
19. Mechanisms of enamine hydrolysis B. Kinetic Basicities of X-C=C
Compounds
Tidwell and coworkers studied extensively the rates of protonation of alkenes (equation 49)103.'26.The rates for over one-hundred 1,l-disubstituted ethylenes, ranging from ethylene (and other simple alkenes) to 1,l-diethoxyethylene, were well correlated by equation 50. Improvements in the correlation coefficient could be obtained by use of selected data points, but neither the slope nor the intercept was significantly affected.
log k,,
= - 10.5
up+- 8.92, r
= 0.938
(50)
As might be expected, if one culls examples which are structurally homogeneous, o r almost so, even further improvements in the correlation can be made while still covering very large reactivity ranges. Tidwell, then Capon and Wu6', have done this for 1-substituted cyclohexenes (equation 51) to which we now add the hydroxyl substituent (that is, the enol of cyclohexanone). The data, covering over 14 powers of ten in k,,, are listed in Table 14. The correlation is shown as Figure 4 and equation 52. It is noteworthy that inclusion of i~obutylene'~'in the correlation actually improves it slightly: 1-methylcyclohexene and isobutylene have very similar reactivity.
1u,'
= 0,'
T A B L E 14. R a t e constants (k,,) for protonation o f of a;(X), H,O, 25 "C X
k,, ( M i s ~ ' )
0-
> I x lo9 6.78 x lo6 575 80.0 42.3 0.18lc 3.05 lo-4c 4.41 x
NHPh OH OEt
OMe NHAc Me H
' Most of the a'
oxas
X) + u,' (CH,)
a,t(X)+a,t(CH,)"
a function
Reference
2.61 - 1.71 - 1.23 - 1.14 - 1.09
-0.96 -0.62 -0.31
values were taken from 0.Exner, in Correlarion Analysis in Chemistry (Eds. N. B. Chapman and 1. Shorter), Plenum Press, New York, 1978. The value for CH, is -0.31. For the present purpose we sum the a+ values of X and the alkyl attachment at C-I, approximating that attachment as a methyl group. qk,, for most keto-enolates exceeds lo9 M ' s 1 36. The o,i value for 0-is considered to be relatively unreliable; see Reference 46a, page 72. 'These k.. values were obtained by extrapolation to H, = 0.
James R. Keeffe and A. Jerry Kresge
FIGURE 4. Linear free-energy plot of log k,, vs 1 c,+ for the protonation of I-substituted cyclohexenes; see equations 51 and 52 in tcxt, as well as Tablc 14. Cap' is taken as c,*(X) + apt(CH3)
There is another series, the 1-X-1-phenylethylenes (equation 49, R2 = Ph), which also gives a very good correlation between protonation rates and o+.The compounds contributing to this correlation are listed in Table 15, and the correlation itself is given in Figure 5 and equation 53. The compounds in this series log k,,
= (-
8.060 f 0.54)
r
=
o;
- (7.13 f 0.59)
(53)
0.985
range from styrene to a-pyrrolidinostyrene and span 15 powers of ten in kH+.The correlation is not at all harmed by inclusion of data for i s o b ~ t ~ l e n eand '~~ (CH,0)zC=CH2133; logk,, = (-8.2 k 0.5) xu: - (7.36 k 0.56), r = 0.969. In fact a composite correlation of the data from Tables 14 and 15 is a good one, as seen in equation 54. log kH+= ( - 8.53 f 0.48)
u;
- (7.92 f 0.52)
(54)
In both series [reactions 49 (R2 = Ph) and 511 the enamines are the most reactive of the neutral compounds included in the correlations. Enolate anions are protonated on carbon even faster, hut these data points fall below the least-squares lines, in all likelihood because the rates are approaching the diffusion limit. In addition to the correlations between rate constants and substituent constants, it is desirable to attempt a Brsnsted correlation between rate and equilibrium constants, just as Knoche did for activated arenes (see equation 47)'02. Unfortunately there are not as many examples of alkenes for which both k,, and p e H are known, as is the case for the arenes; many k H +values have been determinedlz6, hut p e H values are known
19. Mechanisms of enamine hydrolysis TABLE 15. Rate constants ( k , , ) for protonation of PhC(R)=CH2 as a function of a;(R), H,O, 25 " R
k,+ (M-I s-l)
NMeZc OH OEt OMe Me 02P(OW2 0Ac H'
ca 1.0 x lo7 1.25 x 103 118 53.3 9.67 x 1.11 x lo-56 9.8 x lo-'* 2.04 x lo-'
a,'(R)
+ a;(Php
Reference
" Most of the o,' values are taken from 0. Exner, in Correlorion Ann1ysi.s in Chemisrry (Eds. N . B . Chapman and J. Shorter), Plenum Press, New York, 1978. The value for Ph is -0.18. The :a for 0 is considered to be relatively unreliable; see Reference 46a, p. 72. 'The k,, values for Lhe currespunding propiuphenone enamines" were mulliplied by 3.4, as recommended by Tidwell and coworker^'"^. For the pyrrolidino enamine, k , is reckoned to be faster than the piperidino enamine by the same factor (60,see Table 4) found for the corresponding cnamines of isohutyraldchyde. The a; value for NMe, is that rccommended by Tidwell and coworker^'^'; that for pyrrolidino is estimated t o be even more negative on the basis of its consistently greater donor ability. These k,. values were obtained by extrapolation to H, = 0. T h e k,, value quoted here is that obtained by extrapolation to X, = 0, where X, is the 'excess acidity function' recommended for HCIO,/H,O s ~ l u t i o n s ' ~ ' .
10;
FIGURE 5. Linear free-energy plot of log k,+ vs for the protonation of 1-substituted I-phenylethylenes, PhC(R1)=CH2; see equations 49 (R2 = Ph) and 53 in text, as well as Table 15.10,' = a,' (R') + a,' (Ph)
1I02
James R. Keeffe and A. Jerry Kresge
or can be estimated only for such highly activated alkenes as several enolates, a few enamines and three enols (equation 55). We have listed rate and equilibrium constants for these alkenes in Table 16. The correlation is shown in Figure 6. The eight terminal alkenes, RC(X)=CH,, produce a curved relationship which is very well fit by the quadratic equation 56. Predictably, 8-alkyl or 8-aryl groups inhibit protonation and appear to affect kH+more than pKaCH:these compounds fall below the correlation line in Figure 6.
log kH+= -(0.89 f 0.32) + (1.015 f 0.068)-pK2H-(0.024 f 0 . 0 0 3 ) . ( p ~ y ) 2(56) Local Brsnsted slopes for Figure 6 may be calculated from equation 56. These range from u = 0.05 at p e H = 20 all the way to u 2 0.8 at p e H = 4.0. A variable Brsnsted coefficient is perhaps not surprising for a reaction set covering such a wide reactivity range: almost 10' in kH+and about 15 pK, units. In this light thc almost constant slope of Knoche's correlation (equation 47 and Figure 3) is surprising and impressive. We must emphasize that the principal uses to which equations 47 and 56 be put are empirical, and that the use of the equations to make empirical estimates should be intcrpolativc rather than extrapolative. For example, therc is a hint in Figure 3 that at the low-reactivity end of the correlation, the slope is increasing. Departure from linearity is very pronounced if one adds the data for b e n ~ e n e ' ~ ' " . to '~~ the plot. Similarly, if one uses equation 56 to estimate the basicity of isobutylene from its k,, value, one obtains
FIGURE 6. Extended Br~nstedplot of log k,+ vs p c Hfor the protonation of some highly activated alkenes: RC(X)=CH,, R = H, CH,, Ph; see equations 55 and 56 in text, as well as Table 16. The squares represent alkenes with 0-substituents; these were not included in the correlation
TABLE 16. Rates of p r o t o n a t i o n (k,,) a n d equilibrium constants ( p c H ) for highly activated alkenes, RC(X)=CH, (R = H, CH,, P h ) ; H,O, 25 " C k,+ (M-'sC1)
Compound
PK?'
Reference
"Rate constants listed here are those measured for the propiophenone enamines" multiplied by 3.4'03. The equilibrium constants are taken to be those measured for the propiophenone enamines"; the latter may, however, be less basic. See discussion in Section II.A.3. = pKE p c H * . Ketone basicities were taken from Reference 118.
+
1103
1104
James R. Keeffe and A. Jerry Kresge
E -2.4, a value some ninc powers of ten more basic than an estimate made earlier (see Table 13, footnote b). Similar caution is recommended on the use of Tidwell's equation (equation 50) and its daughters (equations 52, 53 and 54). Such interpolative use is itself valuable, but further interpretation, especially of the Brernsted slopes in equations 47 and 56, must be highly qualified.
C. Enamine vs Enol Pathways in Aminetatalyzed Reactions
In his 1982 review on enolization, Toullec drew attention to a number of reactions of aldehydes and ketones which are catalyzed by primary amines, and for which enamine or iminium ion intermediates are i m p l i ~ a t e d ' ~These ~ . reactions include isotopic hydrogen exchange, halogenation and several enzyme-catalyzed reactions in which a lysine residue provides the amino function. It is appropriate here to record Toullec's explanation of why the enamine pathway is competitive with or superior to an ordinary amine-catalyzed enolization pathway. He notes that in at least some of these processes (isotopic hydrogen exchange and aldolase catalyzed reactions), enamine formation is not rate-controlling o r is only partly rate-controlling. Thus, comparison of the enamine path with the enol path requires two factors to be considered: the relative amounts of enamine and en01 at equilibrium with the carbonyl compound, and the relative nucleophilicities/basicities of enamine and enol. Data on ketone/enamine equilibria are relatively scarcc; however, reaction 57 has been determined to have Kq,ir 6 x lO-'M-l 136. Recall (Table 6) that the enolization constant lor acetone is K , = 4.7 x Therefore, even at amine concentrations less than 0.1 M, the equilibrium enamine concentration in reaction 57 is greater than the equilibrium en01 concentration of acetone. Couple this fact with the ca lo4 kinetic superiority of N-alkylenamines over enols (see Table 16) and it becomes clear why the amine-catalyzed enamine path is preferred, especially when p H is low enough that an enolate anion pathway is unimportant.
V. REFERENCES AND NOTES 1. G. Wittig and H. Blumenthal, Chem. Ber., 60, 1085 (1927). 2. C. Mannich and H. Davidsen, Chem. Ber., B 69, 2106 (1936). 3. M. E. Herr and F. W. Heyl, J. Am. Chem. Soc., 74, 3627 (1952); F. W. Hey1 and M. E. Herr, J. Am. Chem. Snc., 75, 1918 (1953); M. E. Herr and F. W. Heyl, J Am. Chem. Soc., 75, 5927 (1953). 4. L. W. Haynes, in Enamines: Synthesis, Structure, and Reactions (Ed. A. G . Cook), Marcel Dekker, New York, 1969. 5. (a) G. Stork, R. Terrell and I. Szmuszkovicz, J. Am. Chem. Sac., 76, 2029 (1954). (b) G . Stork and H. K. Landesman, J. Am. Chem. Sac., 78, 5128, 5129 (1956). (c) G. Stork, A. Brizzolara, H. Landesman, J. Szmuszkovicz and R. Terrell, J. Am. Chem. Sac., 85, 207 (1963). 6. (a) J. Szmuszkovicz, Adv. Org. C h e m . Merhods and Results, 4, 1 (1963). (b) K. Blaha and 0. Cervinka, Adv. Heterocycl. Chem., 6, 147 (1966). (c) A. G. Cook (Ed.), Enamines: Synthesis, Structure, and Reactions, Marcel Dekker, New York, 1969.
19. Mechanisms of enamine hydrolysis
1105
(d) M. E. Kuchne, Synrhesis, 510 (1970). (e) S. Hiinig and H. Hoch, Fortschr. Chem. Forsch., 14, 235 (1970). (0 P. W. Hickmott and H. Suchitzky, Chem. Ind. (London), 1188 (1970); P. W. Hickmott, Chem. Ind (London), 731 (1974); P. W. Hickmott, Tetrahedron, 38, 1975, 3363 (1982). (g) J. K. Whitesells and M. A. Whitesells, Synthesis, 517 (1983). (h) G. Pitacco and E. Valentin, in The Chemistry of Functional Groups, Supplement F, Part I (Ed. S. Patai), Chap. 15, Wiley, Chichester, 1982. 7. (a) E. Elkik, Bull. Soc. Chim. Fr., 972 (1960). (b) K. C. Brannock and R. D. Burpitt, J. Org. Chem., 26, 3576 (1961). (c) E. Elkik, Bull. Soc. Chim. Fr., 903 (1969). (d) M. E. Kuehne and T. Garbacik, J. Org. Chem., 35, 1555 (1970). 8. N. J. Leonard and V. W. Gash, J. Am. Chem. Sac., 76, 2781 (1954). 9. G. Opitz, H. Hellman and H. W. Schubert, Ann. Chem., 623, 117 (1959). 10. G. Opitz and A. Griesinger, Ann. Chem., 665, 101 (1963). 11. (a) E. J. Stamhuis and W. Maas, Recl. Trav. Chim. Pays-Bas, 82, 1155 (1963). (b) E. J. Stamhuis and W. Maas, J Org. Chem., 30, 2156 (1965). (c) E. J. Stamhuis, W. Maas and H. Wynberg, J. Org. Chem., 30, 2160 (1965). (d) W. Maas, M. J. Janssen, E. J. Stamhuis and H. Wynberg, J. Org. Chem., 32, 1111 (1967). 12. J. Elguero, R. Jacquier and G. Tarrago, Tetrahedron Lett., 4719 (1965). 13. P. Y. Sollenberger and R. B. Martin, J. Am. Chem. Soc., 92, 4261 (1970). 14. H. J. Chen, Y. Chiang and A. J. Kresge, unpublished results. 15. H. K. Hall, Jr., J. Am. Chem. Soc., 79, 5441 (1957). 16. C. A. Grob, A. Kaiser and E. Renk, Chem. Ind. (london), 598 (1957). 17. B. M. Wepster, Recl. Trav. Chim. Pays-Bas, 71, 1171 (1952). 18. Y. Chiang, A. J. Krcsgc and P. A. Walsh, J. Org. Chem., 55, 1309 (1990). 19. A. I. Biggs and R. A. Robinson, J. Chem. Soc., 388 (1961). 20. J. K. Coward and T. C. Bruice, J. Am. Chem. Soc., 91, 5329 (1969). 21. (a) R. Adams and J. E. Mahan, J Am. Chem. Soc., 64, 2588 (1942). (b) N. J. Leonard, A. S. Hay, R. W. Fulmer and V. W. Gash, J. Am. Chem. Soc., 77,439 (1955). (c) N. J. Leonard and F. P. Hauck, Jr., J. Am. Chem. Soc., 79, 5279 (1957). 22. R. L. Hinman, Tetrahedron, 24, 185 (1968). 23. See H. H. Jaffe, Chem. Rev., 53, 191 (1953) and references cited therein. 24. (a) Hickmott, in his 1982 review6/, gives an account of the various kinds of evidence, experimental and theoretical, which bear on this issue. (b) J. E. Anderson, D. Casarini and L. Lunazzi, Terrahedron Lett., 29, 3141 (1988). 25. The hydrolysis of 2,3-dehydroquinuclidinc (scc Tablc 2) is extremely slow: C. A. Grob, A. Kaiser and E. Renk, IIelv. Chbn. Acta, 40, 2170 (1957). The same is true for compound 918. 26. H. C. Brown, J. Chem. Suc., 1248 (1956). 27. V. Prelog and M. Kobelt, Helv. Chim. Acra, 32, 1187 (1949). 28. J. B. Pedley, R. D. Naylor and S. P. Kirby, Thermochemical Data of Organic Compoundr, 2nd ed., Chapman and Hall, London, 1986. 29. K. B. Wiberg, L. S. Crocker and K. M. Morgan, J. Am. Chem. Soc., 113, 3447 (1991). 30. (a) E. L. Eliel, Stereochemistry o f Carbon Compounds, McGraw-Hill, New York, 1962, pp. 266267 and references cited therein. (b) K. Mullet, F. Previdolt and H. Desilvestro, Helv. Chim. Acta, 64, 2497 (1981). 31. R. L. Hinman and J. Lang, J Am. Chem. Soc., 86, 3796 (1964). 32. E. B. Whipple, Y. Chiang and R. L. Hinman, J. Am. Chem. Soc., 85, 26 (1963). 33. Y. Chiang and E. B. Whipple, J. Am. Chem. Soc., 85, 2763 (1963). 34. Y. Chiang, M. Hojatti, J. R. Keeffe, A. J. Krcsge, N. P. Schcpp and J. Wirz, J. Am. Chem. SOC.,109, 4000 (1987). 35. (a) Y. Chiang, A. J. Kresge, Y. S. Tang and J. Wirz, J. Am. Chem. Soc., 106, 460 (1984). (b) Y. Chiang, A. J. Kresge and N. P. Schepp, J. Am. Chem. Soc., 111, 3977 (1989). 36. Y. Chiang, A. J. Kresge, J. A. Santaballa Lopez and J. Wirz, J. Am. Chem. Soc., 110, 5506 (1988). 37. J. R. Keeffe, A. J. Kresge and N. P. Schepp, J. Am. Chem. Soc., 110, 1993 (1988); J. Am. Chem. Soc., 112, 4862 (1990). 38. (a) Y. Chiang, A. J. Kresge and J. Wirz, J. Am. Chem. Soc., 106, 6392 (1984). (b) J. R. Keeffe, A. J. Kresge and J. Toullec, Can. J. Chem., 64, 1224 (1986).
1106
James R. Keeffe and A. Jerry Kresge
39. Y. Chiang, A. J. Kresge and P. A. Walsh, J. Am. Chenl. Sac., 104, 6122 (1982); J. Ant. Chern. Sac., 108~6314(1986). 40. P. Pruszynski, Y. Chiang, A. J. Kresge, N. P. Schepp and P. A. Walsh, J. Phys. Chem., 90, 3760 (19861. 41. Y. ~ h i a n g ,J.~ Kresge, . P. A. Walsh and Y. Yin, J. Chem. Sac., Chem. Commun., 869 (1989). 42. J. R. Keeffe, A. J. Kresge and Y. Yin, J. Am. Chem. Sac., 110, 1982, 8201 (1988). 43. (a) A. M. Ross, D. L. Whalen, S. Eldin and R. M. Pollack, J. Am. Chem. Sac., 110, 1981 (1988). (b) S. Eldin, R. M. Pollack and D. L. Whalen, J. Am. Chem. Sac., 113, 1344 (1991). 44. J. R. Keeffe and A. J. Kresge, in The Chemistry of Enols (Ed. Z . Rappoport), Chap. 7, Wiley, Chichester, 1990. 45. Coplanarity is optimal for the Zindanone s y s t e ~ n ~Enolization ~ . ~ ~ . of 1-phenyl-2-propanone is inhibited by lack of enforced ~ o p l a n a r i t y ~It~has . been estimated that for l-phenyl-2propanone p c 2 16.2 and pK, z 6 . 4 4 2 . 46. (a) J. Hine, Structural Effects on Equilibria in Orga~licChemistry, Wiley, New York, 1975, pp 265-276. (b) J. Hine and M. J. Skoglund, J. Org. Chem., 47,4766 (1982). 47. (a) F. Johnson and S. K. Malhotra, J. Am. Chem. Sac., 87, 5492 (1965). (b) F. Johnson, Chem. Rev.., 68, 375 (1968). (c) Allylic strain about heteroatomic double bonds has been reviewed: R. W. Hoffmann, Chem. Rev., 89, 1841 (1989). (d) Ab initio and molecular mechanics calculations on allylic strain have recently been performed: J. L. Broeker, R. W. Hoffmann and K. N. Houk, .I. Am. Chem. Soc., 113, 5006 (1991). 48. L. M. Trefonas, R. L. Flurry, Jr., R. Majeste, E. A. Mayers and R. F. Copeland, J. Am. Chem. Sac., 88, 2145 (1966). 49. Y. Chiang, A. J. Kresge and E. T. Krogh, J. Am. Chen~.Sac., 110, 2600 (1988). 50. (a) F. Turetek and Z. Havlas, J. Org. Chem., 51, 4066 (1986) and references cited therein. (b) F. TureEek, L. Brabek and J. Korvola, J. Am. Chem. Sac., 110, 7984 (1988). (c) J. P. Guthrie, in The Chemistry of Enols (Ed. Z . Rappoport), Chap. 2, Wiley, Chichester, 1990. (d) J. R. Keeffe and A. J. Kresge, J. Phys. Org. Chem., 5, 575 (1992). (e) R. A. Eades, D. A. Weil, M. R. Ellenberger, W. E. Farneth, D. A. Dixon and C. H. Douglass, Jr., J. Am. Chem. Sac., 103, 5372 (1981). 51. G. Opitz and W. Merz, Ann. Chem., 652, 139, 163 (1962). 52. J. L. Johnson, M. E. Herr, J. E. Babcock, A. Fonken, J. E. Stafford and F. W. Heyl, J. Am. Chem. Sac., 78, 430 (1956). 53. J. A. Marshall and W. S. Johnson, J. Org. Chem., 28, 421 (1963). 54. A. R. Katritzky, J. Chem. Sac.., 2586 (1955). 55. P. S. Anderson and R. E. Lyle, Tetrahedron Lett., 153 (1964). See also the review by R. E. Lyle and P. S. Anderson, Adv. Heterocycl. Chem., 6, 45 (1966). 56. D. L. Whalen, I. F. Weimaster, A. M. Ross and R. Radhe, J. Am. Chem. Soc., 98,7319 (1976). 57. T. Okuyama, A. Kitada and T. Fueno, Bull. Chem. Sac. Jpn., 50, 2358 (1977). 58. See the review by R. M. Pollack, P. L. Bounds and C. L. Bevins, in The Chemistry of Enones (Eds. S. Patai and Z. Rappoport), Chap. 13, Wiley, Chichester, 1989. 59. J. V. Greenhill, Chem. Sac. Rev., 6, 277 (1977). 60. G. H. Alt and A. J. Speziale, J. Org. Chem., 30, 1407 (1965). 61. (a) H. E. A. Kramer and R. Gompper, Terrnhedron Lerr., 969 (1963). (b) H. E. A. Kramer and R. Gompper, Z. Physik. Chem., 43, 350 (1964). (c) H. E. A. Kramer, Ann. Chem., 696,15 (1966). 62. A. S. Boyley, M. H. Vandrevla and J. V. Greenhill, Tetrahedron Lett., 4407 (1979). 63. (a) E. M. Arnett, F. M. Jones, Ill, M. Taagepera, W. G. Henderson, J. L. Beauchamp, D. Holtz and R. W. Taft, J. Am. Chem. Soc., 94, 4724 (1972). See also the chapters by E. M. Arnett and R. W. Taft, in Proton Transfer Reactions (Eds. E. F. Caldin and V. Gold), Chapman and Hall, London, 1975. (b) D. H. Aue, H. M. Webb and M. T. Bowers, J. Am. Chem. Sac., 94,4726 (1972). 64. S. G. Lias, J. F. Liebman and R. D. Levin, J. Phys. Chem. Ref: Data, 13, 695 (1984). 65. Allylamine is about 1.5 kcal mol-' weaker as a base than n-propylamine: see References 63 and 66.
1108
James R. Keefle and A. Jerry Kresge
98. S. L. Johnson and P. T. Tuazon, Biochemistry, 16, 1175 (1977). 99. W. M. Schubert and I. L. Jensen, J. Am. Chem. Soc., 94, 566 (1972). 100. H. Kohler and H. Scheibe, Z. Anorg. Allg. Chem., 285, 221 (1956). 101. T. Yamaoka, H. Hosoya and S. Nakagura, Tetrahedron, 26,4125 (1970). 102. (a) W. Knoche, W. W. Scholler, R. Schomacker and S. Vogel, J Am. Chem. Soc., 110, 7484 (1988) and references cited therein. (b) W. Sachs, W. Knoche and C. Herrmann, J. Chem. Soc., Perkin Trans. 2, 701 (1991). (c) M. Lohrie and W. Knoche, J Am. Chem. Soc., 115, 919 (1993). (d) F. EtTenberger, F. Reisinger, K. H. Schonwalden, P. Baurle, J. I. Stezowski, H. H. Jagun, K. Schollkopf and W.-D. Stohrer, J. Am. Chem. Soc., 109, 882 (1987). 103. V. M. Csizmadia, K. M. Koshy, K. C. M. Lau, R. A. McClclland, V. J. Nowland and T. T. Tidwell, J. Am. Chem. Soc., 101, 974 (1979). 104. F. G. Terrier, F. L. Debleds, I. R. Verchere and A. P. Chartrousse, J. Am. Chem. Soc., 107, 307 (1985). 105. R. S. Alexander and A. R. Butler, J. Chem. Soc., Perkin Trans. 2, 110 (1980). 106. (a) W. M. Schubert, B. Lamm and J. R. Keeffe, J. Am. Chem. Soc., 86,4727 (1964). (b) W. M. Schubert and J. R. KeetTe, J. Am. Chem. Soc., 94, 559 (1972). (c) N. C. Deno, F. A. Kish and H. J. Peterson, J. Am. Chem. Soc., 87, 2157 (1965). (d)J.-C. Simandoux, B. Torck, M. Hellin and F. Coussemant, Bull. Soc. Chim. Fr., 4402 (1972). 107. (a)A. J. Kresge, S. G. Mylonakis,Y. Satoand V. P. Vitullo, J. Am. Chem. Soc.,93,6181(1971). (b) A. I. Kresge, in Proton Transfer Reactions (Eds. E. F. Caldin and V. Gold), Chap. 7, Chapman and Hall, London, 1975. 108. A. I. Kresge, H. I. Chen, L. E. Hakka and J. E. Kouba, J. Am. Chem. Soc., 93, 6174 (1971). 109. (a) M. Capponi, I. Gut and J. Wirz, Angew. Chenr., III!.Ed. Engl., 25, 344 (1986). 110. (a) M. T. Reagan, J. Am. Chem. Sac., 91, 5506 (1969). (b) L. C. Gruen and F. A. Long, J. Am. Chem. Soc., 89, 1287 (1967). I l l . J. L. Longridge and F. A. Long, J. Am. Chem. Soc., 89, 1292 (1967). 112. R. Houriet, I. Vogt and E. Haselbach, Chimia, 34, 277 (1980). 113. M. R. Ellenberger, D. A. Dixon and W. E. Farneth, J. Am. Chem. Soc., 103, 5377 (1981). These works provide further evidence for C-protonation. 114. K. Osapay, I. Delhalle, K. M. Nsunda, E. Rolli, R. Houriet and L. Hevesi, J. Am. Chem. Soc., 111, 5028 (1989). 115. S. J. Lias, I. E. Bartmes, I. F. Liebman, R. D. Levin, I. L. Holmes and W. G . Mallard, J. Phys. Chem. Ref: Data, Suppl. 1, 17 (1988). 116. (a) R. W. Taft and R. D. Topsom, Prog. Phys. Org. Chem., 16, 1 (1987). (b) R. W. Taft, J. L. M. Abboud, F. Anvia, M. Berthelot, M. Fujio, 1.-F. Gal, A. D. Headley, W. G. Henderson, I. Koppel, J. H. Qian, M. Mishima, M. Taagepera and S. Veji, J. Am. Chem. Soc., 110, 1797 (1988). 117. Protonation on nitrogen gives the secondary enamine; the pK, for this process was argued to be well in excess of 20. Protonation,on carbon produces the imine which is more stable than its enamine tautomer, hence its pK, is larger yet. 118. A. Bagno, V. Lucchini and G. Scorrano, unpublished results cited in A. Bagno, G. Scorrano and R. A. More O'Ferrall, Rev. Chrm. Intrrmed., 7, 313 (1987). These authors list p c H ' (acidity constants of carbonyl-oxygen-protonated conjugate acids) values for acetone, acetophenone, pinacolone and methyl benzoate. For the first three, the values were combined with keto-enol equilibrium constants to give the pK values shown in the Table. 119. (a) A. R. Katritzky, Handbook of Heterocyclic Chemistry, Pergamon Press, Oxford, 1985, p. 250. (b) Ibid., p. 302. 120. R. A. Cox, L. M. Druet, A. E. Klausner, T. A. Modro, P. Wan and K. Yates, Can. J. Chem., 59, 1568 (1981). 121. The pK, of phenyl(amino)acetylene (PhC=CNH,) is <18". Since kQenimines are more stable than their aminoacetylene t a u t o m e r ~ ' ~the ~ , pK, of phenylketenimine (PhCH= C=NH) must be somewhat greater. 122. C. Wentrup, H. Riehl, P. LorenEak, V. I. Vogelbacher, H:W. Winter, A. Maquestiau and R. Flammang, J. Am. Chem. Soc., 110, 1337 (1988) and references cited therein. 123. Y. Chiang, A. I. Kresge, R. Hochstrasser and J. Wirz, J Am. Chem. Soc., 111, 2355 (1989).
19. Mechanisms of enamine hydrolysis
1109
In this paper the pK, of phenylhydroxyacetylene (PhCFCOH) is reported to be c2.8. Since the tautomeric phenylketene (PhCH=C=O) is more stable than the ynol, pK, for the ketene is greater. 124. W. F. Eberz and H. J. Lucas, J. Am. Chem. Sac.,56, 1230 (1934). 125. E. M. Arnett and T. C. Hofelich, J. Am. Chem. Sac.,105, 2889 (1983). 126. (a) V. J. Nowlan and T. T. Tidwell, Acc. Chem. Res., 10,252 (1977)and references cited therein. (b) W. K. Chwang, V. J. Nowlan and T. T. Tidwell, J. Am. Chem. Sac.,99, 7233 (1977). (c) K. M. Koshy, D. Roy and T. T. Tidwell, J Am. Chem. Sac.,101, 357 (1979). 127. (a) F. G . Ciapetta and M. Kilpatrick, J Am. Chem. Sac.,70, 639 (1948). (b) V. Gold and M. A. Kessick, J. Chem. Sac.,6718 (1965). Combination of the data from these two sources yields k,+ = (3.56 f 0.08) x M - I s - ' for hydration of isobutylene (HCIO,/H,O, 25 "C). 128. A. J. Kresge, D. S. Sagatys and H. L. Chen, J. Am. Chem. Sac.,99, 7228 (1977). 129. Y. Chiang, W. K. Chwang, A. J. Kresge, L. H. Robinson, U. S. Sagatys and C. I. Young, Can. J. Chem., 56, 456 (1978). 130. R. D. Frampton, T. T. Tidwell and V. A. Young, J. Am. Chem. Sac.,94, 1271 (1972). 131. D. S. Noyce and R. M. Pollack, J. Am. Chem. Sac.,91, 119 (1969). 132. (a) R. A. Cox and K. Yates, Can. J. Chem., 59,2116 (1981). (b) A. J. Kresge, H. J. Chen, G. L. Capon and M. F. Powell, Can. J Chem., 61, 249 (1983). 133. A. J. Kresge and M. Leibovitch, J. Am. Chem. Soc.,114, 3099 (1992). 134. D. P. N. Satchell, J. Chem. Sac.,3911 (1956). Equation 47 predicts protonation of benzene to be too fast by about lo3. 135. J. Toullec, Ado. Phys. Org. Chem., 18, 1 (1982). 136. J. Toullec and C. Verny-Doussin, unpublished work cited by T o u l l e ~ ' ~ ~ .
CHAPTER
20
Syntheses and uses of isotopically labelled enamines MIECZYSCAW ZIELINSKI isotope Laboratory. Faculty of Chemtstry. Jagtellon~anUniversity. Cracow. Poland
and
MARIANNA KANSKA Department of Chemistry. University of Warsaw. Poland
I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I1. SYNTHESIS AND USES O F ENAMINES AND RELATED COMPOUNDS LABELLED WITH STABLE ISOTOPES . . . . . . . . . A . Deuterium Labelled Compounds . . . . . . . . . . . . . . . . . . . . . . . . 1. Deuterium isotope effects on I3Cand I5N nuclear shielding in enamine . . denvat~ves. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Synthesis of ["Iarecoline ......................... 3. Synthesis of [I-CDJtheophylline and [3-CDJtheophylline . . . . . 4. Synthesis of deuterium labelled 1,3-dimethyluric acid . . . . . . . . . 5. Synthesis of (S)-N'-[DJmethylhistidine ................. 6. Synthesis of 4.4.dimethyl.l.{2.3.dideuterio.4~[4.(2.pyrimidinyl ). l.piperazinyl]butyl).2. 6.piperidinedione . . . . . . . . . . . . . . . . . 7. Synthesis of [5'-2H]-3'-O-acetylthymidine . . . . . . . . . . . . . . . . 8. Synthesis of trideuteriomethyl-3(5) pyrazoles . . . . . . . . . . . . . . 9. Introduction of deuterium-labelled methyl groups into aromatic amlnes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10. Synthesis of deuterium labelled lorazepam . . . . . . . . . . . . . . . . 11. Synthesis of c10mipramine.d~ . . . . . . . . . . . . . . . . . . . . . . . 12. Synthesis of [methyl-'HI-labelled ajmalicine. yohimbine. tabersonine and catharanthine . . . . . . . . . . . . . . . . . . . . . . . 13. Synthesis of dideuteriated thioridazine . . . . . . . . . . . . . . . . . . 14. Synthesis of 'H and 3H isotopomers of RSU-1069 and Ro-03-8799 (Pimonidazole) . . . . . . . . . . . . . . . . . . . . . . . . . 15. Synthesis of 'H and 'H isotopomers of etanidazole (SR 2508) . . . . 16. Synthesis of the 'H.. 3H- and 14C-isotopomers of 2'-deoxy2'.2'.difluorocytidine hydrochloride . . . . . . . . . . . . . . . . . . . . 17. Synthesis of deuteriated methylpyridines . . . . . . . . . . . . . . . . . Tire Ciienzistn of Enmnines. Edited hy Zvi Rappoport Copyright O 1994 John Wiley & Sons. Ltd . ISBN: 0-471-93339-2
1112
Mieczyslaw Zielihski and Marianna Kaliska
B. Carbon-13 Labelled Compounds . . . . . . . . . . . . . . . . . . 1. Synthesis of "C-bucindolol hydrochloride . . . . . . . . . . 2. Synthesis of multi-13C-labelled 5-substituted methyl N-(1H-benzimidazol-2-yl)carbamates . . . . . . . . . . . . . 3. Synthesis of 6-aminolevulinic acid (ALA) regioselectively labelled with ''C . . . . . . . . . . . . . . . . . . . . . . . . . 4 . Synthesis of 13C-labelled uracil, 6. 7.dimethyllumazine and lumichrome . . . . . . . . . . . . . . . . . . . . . . . . . 5 . Stereoselective synthesis of L-[13C]carnitine . . . . . . . . 6. Synthesis of optically pure I3C-labelled propionate from alanine by asymmetric hydrolysis . . . . . . . . . . . . . . . 7. Synthesis of "C- and 14C-labelled pirmenol hydrochloride 8. Synthesis of tetrazole-'T and 1,2.4-triazole-1,2.'"N, . . . 9. Stereoselective biosynthesis of 'H.. 13C- and 15N-labelled L-sennes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10. Synthesis of triple [13C,. N15]. single [14C] and double [14C2] labelled trimetrexate . . . . . . . . . . . . . . . . . . C. Nitrogen-15 and Oxygen-18 Labelled Compounds . . . . . . . 1. Svnthesis of ' 5N. 5N-imidaz~lea~eti~ acid . . . . . . . . . . 2. sinthesis of methotrexate-1-I5N and methotrexate-4-l5NH2 . . . . and their derivatives . 3. Synthesis of inda~ole.l.'~N, inda~ole-2-'~N 4. Synthesis of 1.([180,].2.nitro.1.imidazolyl).3.methox y. 2-propanol (C1W2]-misonidazole) . . . . . . . . . . . . . . . . . . . 111. SYNTHESIS AND USES O F ENAMINES AND RELATED COMPOUNDS LABELLED WITH RADIOACTIVE ISOTOPES . . . A. Tritium Labelled Compounds . . . . . . . . . . . . . . . . . . . . . . . 1. Synthesis of 3H-labelled rifamycin L 105 . . . . . . . . . . . . . . . 2. Synthesis of N-phenyl-N-{I-12-(4-isothiocyanatophenyl3,5.3H2).ethyl]. 4.piperidinyl)propanamide and 2-(4-ethoxybenzy1)1.diethylaminoethyl.5.isothiocyanatobenzimidazole.4, 6 ... 3. Synthesis of tritiated (6R) and (6s) 5,10.dideaza.5,6,7, 8. tetrahydrofolate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 . Synthesis of ['HI-prazosin . . . . . . . . . . . . . . . . . . . . . . . 5 . Synthesis of [8-3H]pentostatin . . . . . . . . . . . . . . . . . . . . . 6. Synthesis of tritium labelled zomepirac . . . . . . . . . . . . . . . . 7. Synthesis of 5-['HI-indole-3-carbinol . . . . . . . . . . . . . . . . . 8. Synthesis of tritium labelled (5.HT, ) receptors . . . . . . . . . . . 9. Synthesis of 5,6.dihydr0.7.(lH.[G.~H]imidazo I. 1-yl-naphthalene-2-carboxylicacid . . . . . . . . . . . . . . . . . . 10. Synthesis of nicardipine [4',6'.3H] . . . . . . . . . . . . . . . . . . . 11. Enzymatic synthesis of 3H-labelled P-ureidoisobutyric acid and P-aminoisobutyric acid from [3H]thymidine . . . . . . . . . . . . 12. Synthesis . . of mitomycin C monotritiated at the C,,,. methyl posltlon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13. Synthesis of tritiated (S)-10-bromoacetamidomethylcamptothecin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14. Catalytic synthesis of 'H-labelled imidazoles . . . . . . . . . . . . 15. Synthesis of tritium-labelled simple seven-membered ring compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16. Nuclear Overhauser effects in tritium NMR . . . . . . . . . . . . . B. Carbon-14 Labelled Compounds . . . . . . . . . . . . . . . . . . . . . . 1. Synthesis of E-~-[2-14C]indol-3-ylacrylicacid . . . . . . . . . . . .
20. Syntheses and uses of isotopically labelled enamines
1113
2. Synthesis of {[2-14C]pyrimidyl)sulphometuron methyl and {[2-'4C]-triazinyl)metsulphuron methyl . . . . . . . . . . . . . . 1171 3. Synthesis of [14C]labelled pyrano[3. 441 and thiopyrano[3. 4.bIindoles . . . . . . . . . . . . . . . . . . . . . . . . . . 1172 4. Svnthesis of carbon-14 labelled cis.2.amino.1,9.dihydr o.
9.[4.(hydroxymethyl).2.cyclopenten.l.yl].6~.purin~d~one, [8-14C]carbovir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Synthesis of 14C-labelled leukotriene inhibitor Sch 37224 . . . . . . . 6. Synthesis of carbon-14 labelled LTD, antagonist MK-571 . . . . . . 7. Synthesis of 3,4.dihydro.4.oxo.3.{[(5.(trifluoromethyl ).
2-'4C-benzothiazolyl]methyl)-l-phthalazineacetic acid . . . . . . . . 8. Synthesis of [2-14C]-2'-deoxycytidine-3N-cyanoborane . . . . . . . . 9. Synthesis of carbon-14 labelled CI-926 and CI-927 . . . . . . . . . . . 10. Synthesis of 4-(2-hydroxy-3-isopropylaminopropoxy)-2methyl-[2-'4C]indole sulphate . . . . . . . . . . . . . . . . . . . . . . . 11. Synthesis of 3.benzylamino.8,9.dimethoxy.5,6.dihydro[5,l.a 1. i~oquinoline[5-'~C]hydrochloride . . . . . . . . . . . . . . . . . . . . 12. Synthesis of [2-14C]tetramethyluric acids . . . . . . . . . . . . . . . . 13. Synthesis of the muscle relaxant [14C]L.637, 510 . . . . . . . . . . . . 14. Synthesis of 14C-labelled pyrimidoxime . . . . . . . . . . . . . . . . . 15. Synthesis of 3.amin0.l.meth~l.9H.[4.'~C]p~rido[3, 4.blindole . . . . 16. Synthesis of S-(2-carboxyethyl)-N-(2-t-butyl-5-methoxybenzthiaz01-6-~l)-[~~C]dithiocarbamate [CGP 20376 (CGl16483)l . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17. Synthesis of carbon-14 labelled 6-(4-fluoropheny1)-5(4.pyridyl).2,3.dihydroimidazol[2, 1.blthiazole (SK&F 86002) . . . . . 18. Synthesis of 14C-labelled perlinone . . . . . . . . . . . . . . . . . . . . 19. Synthesis of 2-(difluoromethyl)-4-(2-methylpropy1)-5[(methylthio)carbonyI]-6-(trifluoromethyl)-3-pyridine[4-'4C]-carboxylic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . 20. Synthesis of [2-14C]penem antibacterials (FCE 22101 and FCE 22891) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21. Synthesis of 7-[a-(2-aminothiazol-4-yl)-a-(Z)-methoximinoacetamido]-3-(l-[14C]methylpyrrolidino)methyl3-cephem-4-carboxylate sulphate . . . . . . . . . . . . . . . . . . . . . 22. Synthesis of 5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline2,3.14C, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23. Synthesis of carbon-14 labelled spiro-piperidyl-rifamycins (LM 118) and rifabutin (LM 427) . . . . . . . . . . . . . . . . . . . . . 24. Synthesis of 3-cyan0-4-meth~l-5[~~C]meth~l-2-[5-'~C] pyrrolyloxamic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25. Synthesis of 2-hydroxymethyl-l-methyl-4-nitro-5imidazolcarbonitrile.4, 5 . W . . . . . . . . . . . . . . . . . . . . . . . . 26. Synthesis of 1.{4.[3(N.methyl.N.2'-13,4.dimethox y. phenyl]ethyl)[3-14C]propoxy]benzosulphonyl}-2-isopropyl .. indohzine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1192 27. Synthesis of 5.(3,3.di[14C]methyl.l.triazeno)imidazo I. 4.carboxamide, DTIC . . . . . . . . . . . . . . . . . . . . . . . . . . . .1195 28. Synthesis of [14C]flupitrine maleate labelled in the pyridine ring . . 1196 29. Synthesis of [14C]stanozolol . . . . . . . . . . . . . . . . . . . . . . . . 1197 C . Carbon-11 Labelled Compounds . . . . . . . . . . . . . . . . . . . . . . . . 1197 1. Synthesis of carbon-11 labelled 1,4.dihydropyridines . . . . . . . . . . 1197
1114
Mieczysiaw Zielinski and Marianna Kanska
2. Synthesis of "C-pindolol . . . . . . . . . . . . . . . . . . . . . . . . . . 1198 3. Synthesis of "C-labelled 5-hydroxytryptamine . . . . . . . . . . . . . 1199 4. Radiosynthesis of 1-[11C]-methyl-9-[(2-hydroxyethoxy)methyl] guanine ([llC].N.methylacyclovir, MAC) . . . . . . . . . . . . . . . . 1199 5. Synthesis of 1-["C]alprazolam . . . . . . . . . . . . . . . . . . . . . . 1200 6. Synthesis of [llC]Ro 15-1788 (flumazenil) . . . . . . . . . . . . . . . . 1200 7. Synthesis of 9.["C]methyIamino.l,2,3. 4.tetrahydroacridine . . . . . 1201 8. Synthesis of 2-[11C]cyanoisonicotinic acid hydrazide . . . . . . . . . 1201 9. Synthesis of ["Clbuprenorphine (BPN) . . . . . . . . . . . . . . . . . 1202 10. Synthesis of [llC]-labelled N-methylketanserin . . . . . . . . . . . . . 1203 11. Synthesis of 2-ethyl-8["C]methyl 2.8-diazaspiro[4,5 1. decane.1. 3-dione ([llC]RS 86) . . . . . . . . . . . . . . . . . . . . . . . 1204 12. Synthesis of "C-labelled N-methylparoxetine . . . . . . . . . . . . . . 1204 13. Synthesis of llC-labelled prazosin . . . . . . . . . . . . . . . . . . . . . 1205 14. Synthesis of ["Clclebopride . . . . . . . . . . . . . . . . . . . . . . . . 1206 15. Synthesis of ["C]sodium thiocyanate and [isopropyl"Clnimodipine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1206 16. Synthesis of "C-labelled 4-dimethylaminoantipyrine . . . . . . . . . 1206 . . . 1206 17. Synthesis of racemic. (+)- and (-)-N-(methyl-"C)nom~fensine 18. Synthesis of "C-labelled radiopharmaceuticals in N-alkylation reaction with "C-methyl iodide . . . . . . . . . . . . . . 1207 19. Synthesis of ["Clmesulergin . . . . . . . . . . . . . . . . . . . . . . . . 1208 20. Synthesis of [llC]-benzodiazepine (BDZ) ligands . . . . . . . . . . . 1209 21. Synthesis of "C-labelled indolealkylamines . . . . . . . . . . . . . . . 1209 22. Sonification as a method of methylation . . . . . . . . . . . . . . . . . 1209 D. Synthesis of Nitrogen-13 Labelled Compounds . . . . . . . . . . . . . . . 1210 1. Synthesis of 13N-labelled adenosine and nicotinamide by . ammonolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1211 2. Svnthesis of 'w-labelled amines bv reduction of 13N-labelled amides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1212 3. Synthesis of 13N-/3-phenethylamine. . . . . . . . . . . . . . . . . . . . . 1212 4. The synthetic precursor for 13N-labelling . . . . . . . . . . . . . . . . . 1213 ~ etracers s . . . . . . . . . . . . . . . . . . 1213 5. ~valuzitionof i 3 ~ - a m i ~ as E. Fluorine-18 Labelled Compounds . . . . . . . . . . . . . . . . . . . . . . . 1214 1. Synthesis of [18F]fluoroalkylated analogues of neuroleptics YM-09151-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1215 2. Synthesis of 18F-labelled fluoromelatonins and 5-hydroxyfluorotryptophans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1216 3 . Syntheses of spirone containing aliphatic halogens {[18F] fluoroethyl spiperone} . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1216 4. Synthesis of [18F]4-fluorobenzyl iodide and alkylation of spiperone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1217 5. Radiosynthesis of [18F]PK 14105 . . . . . . . . . . . . . . . . . . . . . 1217 6. Microwave-facilitated synthesis of [18F]spiperone . . . . . . . . . . . 1217 7. Synthesis of 1-{4-[18F]fluoromethyl-I-(2-thienyl)cyclohexy1)piperidine (FTCP) . . . . . . . . . . . . . . . . . . . . . . . . . . 1218 8. Synthesis of [18F]-p-fluorophenylhydrazineand synthesis of radiolabelled glucocorticoid ["F] WIN 44577 . . . . . . . . . . . . 1222 9. Synthesis of no-carrier-added 3-[18F]-fluoro-l-(2-nitro1-imidazolyl)-2-propanol . . . . . . . . . . . . . . . . . . . . . . . . . . 1222 10. Automated synthesis of 5-[18F]fluoro-2'-deoxyuridine . . . . . . . . . 1222
20. Syntheses and uses of isotopically labelled enamines
F. Compounds Labelled with Radioisotopes of Iodine . . . . . . . . . . . . 1. Synthesis of 3,3'-dimethylthiacarbocyanine-[1251] . . . . . . . . . . . . 2. Synthesis of 5-amino-I-P-D-rybofuranosylimidazole4-{N-(p-1251]iodophenyl)}carhoxamide . . . . . . . . . . . . . . . . . . and 3. Synthesis of [2-14C]3'-deoxythymidin-2'-ene(d4T) [5-1251]3'-azido-2',3'-dideoxy-5-iodouridine. . . . . . . . . . . . . . . . 4. Synthesis of lZ3Iand lZ5Ilabelled iodobenzodiazepines (ethyl 7-iodo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[l,5-a][1,4]benzodiazepine-3-carboxylate) . . . . . . . . . . . . . . . . . . . . . 5. Synthesis of 1251-labelled[1,3-Hlimidazole . . . . . . . . . . . . . . . . 6. Synthesis of 4-[82Br]bromoantipyrine and 4-[1311]iodoantipyrine . . G. Multilabelled Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Synthesis of tritium and carbon-14 labelled N(3-dimethylaminopropyl)-N-(ethylaminocarbonyl)-6(2-propen-1-yl)ergoline-8P-carhoxamide (cabergoline) . . . . . . . . . . 2. Synthesis of 3H-donetidine trihydrochloride, 14C-donetidine and I4C2-donetidine trihydrochloride . . . . . . . . . . . . . . . . . . . . . . 3. Synthesis of radioactively labelled indole-3-acetaldehyde, indole-3-acetaldoxime and indole-3-acetonitrile . . . . . . . . . . . . . 4. Synthesis of 6,7-dimethoxy-%-chlorbenzyl)[3-D]isoquinoline and 6,7-dimethoxy-4[p-chlorobenzyl(methylene-14C)]isoquinoline. . . 5. Synthesis of 14C- or 3H-labelled indometacine farnesil (E-0710) . . . . 6. Synthesis of series of pergolide and lysergol analogues radiolabelled with lZ5Ior 75Seat 17-position or at C(,, of the indole moiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Iodine-125 cytotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . H. Svntheses of Comoounds Labelled with 6 2 , 6 7 C 99mTc. ~. Io3Ru and 'I9"Sn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Synthesis of [ 6 2 C ~and ] [67Cu]copper(II) his(thiosemicarbazone) derivatives . . . . . . . . . . . . . . . . . . . . . 2. ~ ~ n t h e sand i s application of 99"Tc labelled compounds . . . . . . . . 3. Synthesis and application of lo3Ru-labelled ruthenocene compounds 4. Synthesis of [119mSn]-mesoporphyrinIX dichloride . . . . . . . . . . . IV. ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1115 1223 1213 1225 1225 1226 1226 1227 1227 1227 1229 1230 1232 1232 1233 1236 1237 1237 1238 1240 1241 1242 1242
I. INTRODUCTION
Thc synthetic applications of enamines, the nucleophilic carbon species possessing carbon-carbon double bonds bearing amino substituents, are described in general organic chemistry books. They are produced by heating secondary amines with ketones in the presence of an acidic catalyst (e.g. titanium tetrachloride) or more recently by employing the organosilicon reagents. The amino substituent increases the nucleophilicity of the P-carbon due to the electrondonating power of the nitrogen and makes it useful in alkylation reaction^^^^.^^^. Isotopically labelled enamines have been utilized to study the conjugation of the double bond with nitrogen in these and related compounds by investigating the deuterium isotope effects on 13C and I5N nuclear shielding in enamine derivatives. Mechanistic
1116
Mieczyslaw Zielinski and Marianna Kanska
kinetic applications of isotopically labelled enamines are very rare. Numerous syntheses of isotopically labelled enamines, especially cyclic ones containing the double bond attached to a tertiary nitrogen atom, have been carried out chiefly because of their physiological activity and important medical applications. This chapter illustrates the richness of the different synthetic approaches used in the past and the present decades for preparation of pharmaceuticals labelled with stable and radioactive isotopes containing the enamine moiety, almost always in a heterocyclic system.
II. SYNTHESIS AND USES OF ENAMINES AND RELATED COMPOUNDS LABELLED WITH STABLE ISOTOPES A. Deuterium Labelled Compounds
1. Deuterium isotope effects on I3C and I5N nuclear shielding in enamine derivatives
Deuterium isotope effects on 13C and I5N nuclear shielding in enaminones, enamine esters and nitroenamines which often exist in solution as a mixture of E (1) and Z (2) isomers have been recently investigated1. When labelled with deuterium E and Z isotopomers are obtained
The NH and Co,H protons of enamines of general structures 3 have been deuteriated' by dissolution of compounds 4 2 3 in excess of Me'OD, followed by evaporation after some time and repetition of the (HID) exchange procedure until the required degree of deuteriation is achieved. Many of these compounds exist in solution also as the E isomers as shown below.
The compounds can be sub-divided according to the atom X and Y as shown below: X = C; Y = C, compounds 4 1 1 X = C, Y = 0, compounds 12-14 X = C; Y = N, compound 15 X = N; Y = 0, compounds 1 6 1 9 X = S; Y = C, compounds 2&23
20. Syntheses and uses of isotopically labelled enamines Enaminones 4 1 1 MeCOC,,,H=C(,,HNHCa(Mea),, 4 (Z) Me,CHCOCH=CHNHCMe,, 5 (Z) Me,CHCOCH=CHNHC,H, 6 (Z) Me,CCOCH=CHNHMe, 7 (Z, E) MeCH,COC(Me)=CHNHCH,CH,, 8 (Z, E) MeCOCH=C(Me)NHCHMe,, 9 (Z) MeCOC(COMe)=CHNHC,H,, 10 (Z, E) C,H,COCH=CHNMe,, 11 (E) Enamino esters 12-14 and amide 15 EtOCOCi2,(Me)=Ci,,NHMe, 12 (Z, E) EtOCOCH=C(Me)NHMe, 13 (Z, E) EtOCOCH=C(Me)NHCH,C,H,, 14 (Z) Me,CNHCOC,2,H=C(,,HNMe,, 15 ( E ) 2-Nitroenamines and their derivatives
0,NC,2,(Me)=C,,,HNH(2'-C5H4N), 16 (Z, E) 0,NCi2,(Me)=Cil,HNH(2'-C4H,N,), 17 (Z, E) HONC(,,(Me)=C,,,ONH(2'-C5H4N), 18 (2) HONC(,,(Me)=C(,,ONH[2'-(6'-CH3C5H3N)], 19 (2) /I-Sulphinyl enamines 2&23 EtSOC(Me)=CHNHCMe,, 20 ( Z ) C,H,SOC(Me)=CHNHCMe,, 21 (2) p-EtC,H,SOC(Me)=CHNHCH(Me)C,H,, 22 (2) EtSOC(Me)=CHNHCH(Me)C,H,, 23 ( Z ) Deuterium substitution at nitrogen leads to large two-bond isotope effects at C,,, and to one-bond isotope effects at nitrogen in the Z isomer. ZAC,,,(ND),the low-frequency shift of a given resonance upon deuteriation, is always larger for the Z isomer than for the Eisomer. For the latter, the change in 2AC(ND)is linked to a change in the C(,,-N bond order. The larger isotope effect for the Z isomer is caused predominantly by hydrogen bonding. In the Z isomer a six-membered hydrogen-bonded ring is formed (2). The strongest acceptor groups give the strongest hydrogen bonds and the largest two-bond isotope effects which decrease in the order NO, C = 0 > COOR. In the Z isomer, isotope effects are observed at the carbonyl carbon which is located in the six-membered ring formed by hydrogen bonding. The positive one-bond isotope effects on nitrogen are larger for the Z isomer than for the E isomer, also due to intramolecular hydrogen bonding. A linear relationship has been found between 'AC(ND) and 6 , of NH for both E and Z isomers. The Z isomers show the narrower I5N resonances (line-widths) also as a result of hydrogen bonding. Deuteriation at Ci2,made it possible to observe an isotope effect, ,AN(CD), over three bonds, analogously to the large values of long-range isotope effects on nitrogen studied in the case of o-hydroxy azo compounds2.
-
2. Synthesis of fHlarecoline
Deuterium labelled arecoline, methyl l-[ZH,]methyl-l,2,5,6-[2,6-2H,]tetrahydropyridine-3-carboxylate 24, the cholinergic agonist, readily crossing the blood-brain barrier, enhancing memory in normal healthy subject3 and used in treating Alzheimer's patients4,
1118
Mieczyslaw Zielinski and Marianna Kahska
has been synthesized5 (equation 1) for use as internal standard in GC-MS assays of the concentrations at picogram levels of this principal alkaloid of Areca catechu in plasma and cerebrospinal fluid of treated patients.
NaB2H4,MeOH
1
RT, IS min
I
C2H3 (24) colourless oil, 36%
k 2 ~ 3
(24) pale yellow oil, 38% GC-MS analysis of the deuteriated product 24 obtained by sodium borodeuteride reduction procedure was a mixture containing ['HJ (SO%), C2H4] (18%) and C2H3] (1.4%)isotopic species. Similar analysis showed that the product 24 of sodium cyanoborodeuteride reduction of 25 contains 96% of ['H,] and 4% of C2H4] analogs. Sodium cyanoborodeuteride is therefore a preferred reducing agent to label arecoline and 1,2,5,6-tetrahydroxypyridines in general. It has been suggested5 that the enamine
20. Syntheses and uses of isotopically labelled enamines
1119
1,2-dihydropyridine 26 is an obligatory intermediate in the reaction leading to the formation of 1,2,5,6-tetrahydropyridines641 (equation 2). Enamines are readily converted to more stable immonium ions 27 in acidic medium". 3. Synthesis of [1-CDJtheophylline and [3-CDJtheophylline
The title theophylline isotopomers 28 and 29, 2,6-dihydro-1,3-dimethylpurines,are alkaloids known for their diuretic, cardiotonic and coronary-dilating properties, and are used at present in therapeutics as a bronchodilators in all kinds of asthma1'. They have
been synthesizedI3, respectively, from I-methyl and 3-methyl xanthine in three steps (equation 3) which involve the protection of the N,,, position by chloromethyl pivalate, deuteriomethylation of the protected monomethyl xanthines and alkaline hydrolysis of the N-[(pivaloyloxy)methyl] bonds in the labelled xanthines. 7-CD,-para-xanthine 30, a side product in the synthesis of 29, has been also isolated in 2% yield. The isotopomer 29 has been synthesized similarly in 27% yield starting from 1-methylxanthine. The deuteriated theophillines 28, 29 and 7-CD, paraxanthine 30 are used as tracers in pharmacological studies and in deuterium isotope effect studies13.
0 II HXN/ C \
I
0
II
C-
N'
11
I
H
Me3CCOOCHzCI Na2C03, DMF
/
HXN
1
C \ C-
N I
II
0
,CH200CCMe3
I
I
1
h C I , NazCO3 RT, 48 h, work-up
II D3C\N/C\
II C--N'
I 11 I O+ C \ N /C\N+CH
H
2 N NaOH
95-100°C. 2 h, reflux
D3C\N/C\ I
xc 0,' \ N
c-N/
II I /CXNI/CH
CH200CCMe3 (3)
1120
Mieczyslaw Zielihski and Marianna Kanska
4. Synthesis of deuterium labelled 1.3-dimethyluric acid
1,3-di(trideuteriomethy1)uric acid (DMU-d,, 31), a major metabolite of theophilline, has been labelled at N(,, and N(,, position^'"'^ by treatment of 4-amino-5-carboethoxyuracil 32 with bis(trideuteriomethy1) sulphate followed by cyclization of the dimethylated intermediate (33) by heating (equation 4). DMU-D, of 99.4% D, isotopic purity
0 II
0
D3C\
N
II /C\
I
C-N'
II
/C O/ \N
I
H
I
/c\ N /c+ 0
A, 160°C + 240°C
*
under N2, 2 h
CD3 (31) 70%
D3C ,N,C,
I
/c
O/\N
I
c ,NHCOOEt II /c.. NH2
(4)
CD3 (33) 74%
has been applied1' as an analytical internal standard for the GC-MS-SIM (Gas chromatography-mass spectrometry-selected ion monitoring) of 1,3-dimethyluric acid in biological fluids (human blood and urine). Derivatization of DMU for the GC-MIS analysis has been carried out using EtI and tetramethylammonium hydroxide. The mass spectra of diethyl derivatives of DMU-D, and DMU have been presented and discussed. The results confirmed that six deuterium atoms were incorporated into the N,,, and N,,, methyl groups of DMU.
5. Synthesis of (S)-W-[DJmethylhistidine
This amino acid which is synthesized by muscle and excreted into urine without recycling1' has been methylated19 with [DJ-methyl iodide exclusively at Nr site and applied as tracer in vivo and as an isotopic dilution standard in uitroZ0,by protecting the Nu and N" positions in a cyclic urea derivative 34. The latter was obtained by treating the (9-histidine methyl ester 35 with carbonyl diimidazole and hydrolysing the product 36 in boiling dilute hydrochloric acid to give isomerically and isotopically pure title compound 37 retaining at least 95% of its optical rotation (equation 5). 37 has been applied in clinical research.
20. Syntheses and uses of isotopically labelled enamines
HC=C
I
HN,C+N
, c',,COOMe I
4c,,
NH;?H
HC=CH +
I
N+
H
HC-
I
CH
I
I
N C NyN\C+ H H /
free base (35)
I
MeOH, 1 h work-up
CD3L
HC=C
I
85 "C.24 h. sealed DMF pressure glass vessel
/
Hz C\
I
COOMe / C. I 'H NH
fN+ /Ii\ c' D7C C
HC=C/
I
Hz C
'c,/
I
4
N
D3C/N'C/' H
COOH
NH;?'H
2z=-24.5"
(37) 82%. [a]
6. Synthesis of 4,4-dimethyl-1-{2,3-dideuterio-4[4-(2-pyrimidinyl)-I-piperazinyl]butyl)-2,6-piperidinedione
The title compound, MJ-13805, gepirone 38, possessing pharmacological properties indicative of auxiolytic activity in man, distinct from the activities of classical benzodiazepine a u x i ~ l y t i c s ~ 'has . ~ ~ been , deuterium labelledz3 according to a general synthetic route, illustrated by equation 6. It permits one to obtain in a similar manner the W H ,
1122
Mieczysiaw Zielinski and Marianna Kanska
species by direct reduction of alkyne 39 with tritium, or to prepare 14C-labelled compounds of this type by substitution of labelled formaldehyde in the Mannich step followed by catalytic reduction.
RNH
1
R'NH
1
H2/PdlC, EtOAc quinoline
RNCH2CH=CH*CH2N'R
(38) 79%. colourless crystals X = H or D; *C = 14C label
The pharmacological auxiolytic agent (38) has been used to study the receptor binding properties of compounds of this type and the mechanism of their action.
7. Synthesis of [5'-2H]-3'-O-acetylthymidine
The labelled compound 40, needed for the solid-state deuterium NMR analysis of specifically 'H-labelled DNA sequences, has been prepared in 68% overall yield from unlabelled 40 by using a modified Swern o ~ i d a t i o n ~followed ~,'~ by borodeuteride reduction (equation 7).
20. Syntheses and uses of isotopically labelled enamines
Me\
H O , ~
"CH
C II
0 II C\ /
0 II /C
Me\
NH
I
II
N .0\1 CH
I I ,CH-CH2 AcO
..NH
C
o* C, I . DMSO, (COCI)2,NEtj, C H ~ C-78°C I~ 2. CF$OOH, -78°C
t
H AcO
I
P\I CH I
CH
I
,CH-CH2
I
~ a ~ ~ Hat.% ~ (D). 9 25°C 8
I AcO
I
,CH-CH2
(40) > 95% isotopic purity 8. Synthesis of trideuteriomethyl-3(5) pyrazoles
3,s-bis(trideuteriomethy1)pyrazole (41) has been synthesized for spectroscopic purposes by the reaction of perdeuteriated acetylacetone with perdeuteriated hydrazine h ~ d r a t e ~(equation ~ - ~ ~ 8). The heptadeuteriated 3,s-dimethylpyrazole 42 has been obtained when the reaction of equation 8 has been carried out in 75% EtOH. Direct exchange between 3,5-dimethylpyrazole 43 and D,0/K2C0, yielded only the product 44, since methyl groups on pyrazole are much less acidic than methyl groups alpha to the carbonyl groups in 2,4-pentanedione (equation 9).
D
H
(41) 98% yield
(42)
Mieczystaw Zielinski and Marianna Kanska
H 3 C \ C C H II II KN/C\
I
K2COfl20
CH3
H
H3C
\
c-c' II
D (91%)
II
NtN/C\
I
' 3 3
D (72%D)
Deuteriation at the N!,, position is achieved easily by exchange with D 2 0 at room temperature; deuteriation at C(,, proceeds at 200 "C in a sealed tube26. The method outlined in equation 8 is simpler than the one described in the literaturez9. 9. Introduction of deuterium-labelled methyl groups into aromatic amines
The N-permethylation reaction of amines3' has been extended3' to aromatic amines with strong electron-withdrawing substituents in the o- and p-positions which reduce the basicity of the nitrogen centre. N-Permethyl derivatives of amines of type N(CH,_,D,), have been synthesized by using formaldehyde, dideuterioformaldehyde, sodium borodeuteride and sodium borohydride (equation 10). The final step in the reaction presented in equation 10 involves H- (or D - ) transfer from the reducing agent to a reactive species (equation 11). The electron-impact-induced fragmentations of aromatic N-methylamines have been investigated. The MS of the obtained deuteriated compounds revealed an extensive label exchange in the ionization chamber. 37% aqueous CH20 + BD4THF, 3 M H,SO,
1
CD20 + BD4temperature control of the exothermic rapid reaction
* AWCHzDh
* ANCD3h
2-, 3- and 4-nitroanilines, methyl 2- and 4-aminobenzoates and 2- and 4-phenylazoanilines have been N-permethylated smoothly and cleanly in nearly quantitative yield. For instance, 2-nitro-N,N-di(trideuteriomethyl)aniline has been obtained in 97% yield by the method illustrated in equation 10. A new homogeneous procedure has been worked out for a larger-scale N-permethylation which involves slow addition of the solution of the aniline and sodium borohydride
20. Syntheses and uses of isotopically labelled enamines
1125
in ethylene glycol monomethyl ether to a solution of 37% aqueous formaldehyde and 3 M aqueous sulphuric acid at &20 "C and addition of sodium hydroxide to the postreaction mixture till the pH become strongly basic. The N,N-dimethylaniline formed has been extracted from the aqueous phase with ether in 100% yield. 10. Synthesis of deuterium labelled lorazepam
'H3-Loraze~am, 3-hydroxy-1,4-benzodiazepine,45, a sedative hypnotic and antianxiety agent, has been synthesized32 in a seven-step procedure presented in equation 12 for use as an internal standard in GC-MS-NICI-SIM (NICI-SIM = negative ion chemical ionization-selective ion monitoring) quantitative analysis of this drug in complex matrices encountered in forensic work" and for study of its complex kinetics34. The procedure involved selective trideuteriation, protection of the amino group and
D2SOdCD&OOD * IM)"C, 5 days
1
(i) Pyrlreflux
(iij m-CIC6HdCOOOH
(iii) AczO
Cbz = Carbobenzyloxy
1126
Mieczysiaw Zielinski and Marianna Kanska
reduction, ring closure of the diamine formed with pyridine, MCPBA oxidation, N-oxide product rearrangement and hydrolysis. GS-MS and 'H NMR analysis of the selectively deuteriated intermediate product 2-amino-5,2'-dichloro-3,4',6'-trideuteriobenzophenone, 46, have shown that in the first acid-catalysed key exchange reaction one deuterium has been incorporated into the triply substituted 'A' ring and two deuterium atoms into the doubly substituted aromatic ring 'B'. Hydrogens 'a', 'b' and 'c' have been deuteriated in 99%, 98% and 92%, respectively. 11. Synthesis of clomipramine-d,
The hydrochloride salt of 3-chloro-5-(3-dimethylaminopropyl)-l0,ll-dihydro-5H-dibenz[bflazepine, the antidepressant drug (47), containing six deuterium atoms at the methylenic positions of the dimethylaminopropyl side chain and two deuterium atoms
LiAIDa THF
t
37% aqueous H2CO. 95% HCOOH
Me2NCD2CD2CD20H '
D2NCD2CD2CD20D 80%
60%
t CICD2CD2CD2NMe2.HCI
base (6 N NaOH)
* CICD2CD2CD2NMe2 (50) oil D D \
1
toluene. 8032090°C
D \
CI
D
D D \ I HC-CH
I
I
CD2CD2CD2NMe2 HCI (47) 51%
C1
I
20. Syntheses and uses of isotopically labelled enamines
1127
at the 10 and 11 positions, has been s y n t h e ~ i z e din ~ ~order to study the relative bioavailability of different formulations. 1,1,2,2,3,3-Hexadeuterio-3-dimethylaminopropyl chloride was first prepared (equation 13) and then condensed in the presence of 48 strong base with 5,10,11-trideuterio-3-chloro-l0,11-dihydr0-5H-dibenz[bazepine prepared by catalytic reduction of the 10,ll-double bond of 3-chloro-5H-dibenz[hfjazepine 49 after exchanging the NH proton with deuterium (equation 14). The mass spectrum of 47 showed a fragment ion at m/z = 258, which is higher by four mass units than ion 51 derived from unlabelled c l ~ m i p r a r n i n e ~ ~ .
12. Synthesis of [methyl-2H]-labelled ajmalicine, yohimbine, tabersonine and catharanthine
These compounds 52, 53, 54 and 55 have been deuterium-labelled3' in 33%, SO%, 8 1% and 70% yield, respectively, starting from the corresponding unlabelled compounds by direct transesterification with perdeuteriated methanol containing 0.1 M NaOH (equation 15).The 'H-labelled methyl esters 52-55 have been used as internal standards for thermospray HPLC mass spectrometric determination of alkaloids produced by Catharanthus roseus, many of which are medicinally important3'.
1128
Mieczyslaw Zielinski and Marianna Kanska
(54) obtained in 4 h
(53)
(55) 99% transmethylation in 20 h 13. Synthesis of dideuteriated thioridazine
6,6-ZH,-labelled thioridazine 56 (the phenothiazine-type antipsychotic agent) has been obtained recently39for metabolic and pharmacokinetic studies by a new route (equation 16) from 2-(2-hydroxyethy1)piperidine 57. The key steps in this sequence of reactions involve ruthenium tetroxide oxidation of the N,O-diacetylated starting material 58 and subsequent lithium aluminium deuteride reduction of the 2-(2-acetoxyethy1)-6-piperidinone (59, R = Ac). Treatment of 60 with thionyl chloride produced 2-(2-chloroethy1)1-methyl[6,6-2H,]piperidine which, on N(,,,-alkylation of 2-methylthio-lOH-phenothiazine, yielded 56. For each of the seven steps in the conversion of 57 to 56 the yield has been at least 76%40. 14. Synthesis of "H and (Pirnonidazole)
3H isotoporners of RSU-1069 and Ro-03-8799
RSU-1069, 6141A3, and pomonizadole (Ro-03-8799), 6244,45, are electron-affinic radiosensitizers less toxic than misonidazole 63. The aziridine 61 exhibits also greater selective toxicity towards hypoxic cells than 6346-48. 61 and 62 have been deuterium- and
(61) R = aziridin-1-yl (62) R = piperidin-1-yl (63) R = OMe
20. Syntheses and uses of isotopically labelled enamines
Hz$/
Hz C
HzC\
I
AQO, ~ y r
/CH I
Hz C Hz?/ \CHZ
-
HZ
\CH~CH~OH
37% HCHO. 98% HCOOH
DZC\~/CH \CH~CH~OH I H
Hz C HZ$/ \CHZ I HzC\~/CH \CH~CH~OAC I
Hz C HZ? \CHZ
'
I
DzC ,,CH
I
'CH~CH~OH
Me
(60)
1129
Mieczyslaw Zielinski and Marianna Kanska
1130
tritium-labelled49 in a reaction sequence shown in equation 17 in order to extend the previous pharmacokinetic and metabolism studies using unlabelled materials0 and to establish the nature and location of these chemical and metabolic processes involving covalent binding to biological macromolecules in vitro in hypoxia and in the presence of oxygen. CH=CH
I
N
CrOgacetone/HzSOa 3 days
I
-
I *C/~'CH~CH(OH)CH~C~
CH=CH I I 0 N * cI / ~ \ c H ~ CIIC H ~ C I
1
1. NAB2H4 (99 atom%), abs. EtOH or
NaB3H4 (220 mCi), abs. EtOH. acetone
2. 10%aq. NaOH
(66) X = 2H (76%) X = % (86% radiochemical yield) 189 mCi aziridine, EtOH, NEt3 15 min reflux
CH=CH
I
I
N+C/N,
I
\
X OH \
CH2CCH2N, I CHZ
NO2
excess piperidhe, EtOH
CH=CH I I NQC/N
I NO2
(61) (a) . . X = 2H. 94% (b) X = 3H, 100%, 118 mCi, radiochemical purity > 96%. specific activity 200 mCimmol-I
X OH \ /
,N,$c &c. H2 HZ
HZ
\
CH2
(62) (a) X = 2H, 99 % (b) X = 3H, 35 mCi, (100% yield), radiochemical purity > 96%, specific activity 200 mCi mmol-I
A fractionation of deuterium has been observed when a nearly 1:1 mixture of NaB1H4 and NaBZH4 has been used in the second reduction step of equation 17 and the cumulative amounts of sodium boroC2H + 'Hlhydride and ketone 64 used in the test reaction were equal to 1.963 mmoles and 2.0mmoles, respectively. After complete reduction of ketone 64 and of the cyclization of chlorohydrin 65 to epoxide 66, the integration of the multiplet centred at S 3.44 in the 'H NMR spectrum of the obtained mixture of the ['HI- and ['HI-epoxides, corresponding to the 2-H of the side chain, showed that this mixture contained 61% of ['HI-epoxide and 39% ['HI-epoxide. Neglecting the fractionation of deuterium between Co,-H and 0-H bonds the observed (61%/39% = 1.564) ratio (at hydride conversion equal to about 0.5) leads to kf,,/k&, 1.9. Therefore, to minimize the losses of 3H the excess of 64 has been treated wlth NaBC3H14, followed after a short period by addition of excess of NaB1H4 to
-
20. Syntheses and uses of isotopically labelled enamines
1131
complete the reduction. No deuterium and tritium isotope effect study of the mechanism of reaction 17 has been presented and the degree of deuterium enrichment of unreacted mixture of NaBIH, and NaB2H, has not been determined. 15. Synthesis of
'H and 3H isotopomers of etanidazole (SR 2508)
Etanidazole (SR 2508), 67, designed for the sensitization of hypoxic tumour cells to r a d i a t i ~ n ~ ' . ~which " is less neurotoxic than misonidazole, has been labelled with deuterium and tritium5) by reduction of the corresponding aldehyde with isotopically labelled sodium borohydrides (equation 18), to assess selective uptake and covalent retention of 67 in hypoxic and oxic regions of tumours and in normal tissues, including brain.
1
anh CF3COOH stining 16 h
CH=CH
I
DCCD, NH2CH2CH(OMe)2
I
NbC/ NCH2CNHCH2CH(OMe)2 II I 0 NO2 'modest yield'
THF, stirring 3 days
CH=CH I I N+C'NCH2C00H
I
NO2 100%
I
Dowex 50x4 (Hf form) THF/H20, boiling. I h
L A 1 - L . L
EtOH, acetone
Dowex 50x4,H+ form)
- 1
Ln=c.n
N
I
OH +'\C/~'CH~CNHCH~CH I 11 \ /
0
NO2
X
(67) (a) X = 2H, 74% (b) X = 3H, 87% chemical yield;
80% radiochemical yield radiochemical purity > 97%, specific activity 4.5 mcimrnol-I
1
A q 0 . Pyr
1132
Mieczysiaw Zielinski and Marianna Kanska
Treatment of the intermediate aldehyde 69 with 2,4-dinitrophenylhydrazinein ethanol for 5 min yielded, after recrystallization from water bright yellow-orange crystals of N-(2-oxoethy1)-2-(2-nitroimidazol-1-yl)acetamde2,4-dinitrophenylhydrazone,70, for identification by NMR.
A deuterium fractionation has been observed when 69 has been reduced with an excess of an equimolar mixture of NaB1H4 and NaB2H4 (98 atom%). NMR analysis of the derivative 68 (obtained by complete acetylation of the isotopomeric mixture of 67a), based on integration of signals at 6 3.45 (CONCIH,) and the triplet centred at 6 4.10 (C'HZHOAc + C1H20Ac), showed that the mixture of isotopomers of 68 contained 65% of the 'H-compound and 35% of the ZH-compound.No information concerning the 'excess' of sodium borohydride + sodium borodeuteride equimolar mixture used in the reduction step was given and it is impossible to calculate the amount of unreacted [NaBIH, + NaB2H,] enriched in deuterium content, necessary to evaluate correctly the primary deuterium isotope effect for this process5,. Therefore the assessed value ktlH,/k(+,,= 1.5 given by the authors cannot be used to draw conclusions concerning the transition state structure for the reduction of 69 with sodium borohydride. Nevertheless, it enabled one to avoid large losses of tritium in the reduction step, caused by the
- F nF
HO'
,CH-
c, I C
N+X I II ,,C,N/CH HOCH2 0 \cH'O\ c. I I 'H .CHF F HO' F
I
20. Syntheses and uses of isotopically labelled endmines
1133
competitive reaction of [NaB3H4 + NaB1H3H3f NaB'H,3H2 + NaB'H,3H] isotopic species by a proper design of the tritium reduction of 69 with sodium borotritide. 16. Synthesis of the 'H-, 3H- and '4C-isotoporners of 2'-deoxy-2',2'-difluorocytidine hydrochloride
This agent, gemcitabine hydrochloride, 71a, of potential use in humans, showing promising activity in tissue culture against a variety of DNA and RNA virus strainsss and having also in vioo anti-tumour activity against solid tumourssb, has been deuteriumand tritium-labelleds7 by treating 71a with iodic acid/I, in a mixture of AcOH and CC14 and hydrogenolysis of 72 with deuterium or tritium gas in 50:50 dioxane/D20 in the presence of 5% Pd/CaSO, (equation 19) at atmospheric pressure, giving 34.5% 2'-deoxy2',2'-difluorocytosine-[5-2H], 73a. The radiochemical purity of 5-'H-isotopomer 73b following the purification by radio-HPLC was >99%; the specific activity was 100 mCi mggl (26.5 Ci mmol- '). The '4C-isotopomer of 2'-deoxy-2'2'-difluorocytidine hydrochloride has been synthesized in two radiochemical steps starting with reaction of ~ytosine[2-'~C],74, with 3,5-bis-O-benzoyl-l-O-methanesulphonyl-2-deoxy-2,2-difluororibose 75 (equation 20).
(74) 250 mCi, specific activity 54 mCi m m o l
I
(75)
II
,C* ,CH BzOCH2 O' N 'm
,o
.
48 h reflux
.
*
I
BzU
C* = 14c HMDS = Hexamethyldisilazane
XH-
I 'H
+a
F F F
(71b) 63% specific activity 178.4 pCi mg-' (53.3 mCi mmol-')
anomer
Mieczyslaw Zielinski and Marianna Kanska
1134
The mixture of anomers of 3',5'-dibenzyl-2'-deoxy-2',2'-difluorocytidine 76 obtained has been separated by crystallization from ethyl acetate. Deprotection with methanolic ammonia yielded 71b containing, after radio-HPLC, 99.8% of the desired /I-isomer of >99.4% radiochemical purity. The overall radiochemical yield was 10.2%. 17. Synthesis of deuteriated methylpyridines
Picolines and 2,6-lutidines partially or fully deuteriated in the methyl group of high isotopic purity have been prepared recently by Lautie and Leygue5' for spectroscopic studies. a. Monodeuteriation o f the methyl aroua has been achieved either bv deuteriolvsis of lithiated derivatives or by reduction of the CH,X group with BU&D (equation-21). I . HBr
HOH2C
N
CH20H
b. Dideuteriomethyl compounds have been synthesized by reduction of the corresponding esters with LAID,, and conversion of the alcohol to chloromethyl or bromomethyl derivatives which have then been reduced by zinc in AcOH or with LiAIH, (equation 22) or AcOH/Zn for ClCH, derivative.
1
LiAIH4 or AcOHiZn for CICH2 derivative
CD2H
I
The y-picoline-2H, containing one 'H in the methyl group has been obtained by hydrolysis of the lithium derivative of the perdeuteriated molecules. c. 2-Methyl-6-trideuteriomethylpyridine has been prepared according to reaction schemes of equation 23a or 23b. 2,6-bis(trideuteriomethy1)pyridine was synthesized earlier59. d. Kinetic deuterium isotope effects in proton transfer reactions from C-acids to enamines have been studied by G r e l l ~ n a n nby ~ ~Jarczewski303 ~, and c o ~ o r k e r s ~ ~ ~ - ~ ~ ' .
20. Syntheses and uses of isotopically labelled enamines
nLiAID4
H3C
N
COOR
H3C ~
c
I . HCI
D
2
0
H
1
2. SOCI2
or I . Neutralization
H3C
I I
H CI-
8. Carbon-13 Labelled Compounds
1. Synthesis of '3C-bucindolol hydrochloride
[Cyano-13C]bucindolol hydrochloride 77.HC1, required in order to study the metaholic fate of bucindolol, a novel antihypertensive agent currently under clinical investig a t i ~ n ~ ~has , ~been ' , synthesizedhZfrom 2-hydroxybenzo11itrile-[cyano-~~ as shown in equation 24.
lo'
cxccss CICH CH-CHI
H2NCMe2CH2
2. heating 2 hat 95-100°C after removal of acetone
-w +
NaOH, THF (diluted)
OCH2CH-CH2 100% H
94% yield (in last step)
93% I3C enrichment
Mieczysiaw Zielihski and Marianna Kahska
1136
2. Synthesis of multi-'3C-labelled 5-substituted methyl N-(1H-benzimidazol-2-yl) carbamates
Eight methyl N-(1H-benzimidazol-2-y1)carbamates78 with various 5-substituents have been labelled with 13C at carbon-2, and at the carbonyl and methoxy carbons according to the synthetic scheme of equation 25 using commercially available 13Cenriched (91-92 atom%) carbon tetrachloride, methanol and thiourea63. The three labelled positions indicated with asterisks are at or near the site involved in binding to tubulin (which performs a variety of vital functions in the cell). A correlation has been found between anthelmintic potency of the benzilnidazole carbamate group of anthelrnintic drugs widely used to control nematode parasites in sheep and their ability to bind tubulin.
*
H2N-C-NH2 II
*
CC14
*
-
HN=C-NH2 I
*
v
CI-C-CI
?H~OH
CI-C-OCH3 * *
(78) R = PhCO, n-PrO, n-PrS, PhS, n-Bu, PhCH(OH), PhSO, n-PrSO
3. Synthesis of 6-aminolevulinic acid (ALA) regioselectively labelled with 13C 6-Aminolevulinic acid (ALA), labelled with 13C at C(I).C(2,,C(3!, C(4)and C,,,, has been synthesized64from 13C-labelled KCN, glycine, Meldrum's acld or bromoacetate, prepared in turn from 13C-sodium acetate or 13C-acetic acid (equations 26 and 27). It was used for direct observation of the enzymatic transformation of ALA to porphobilinogen (PBG) by 13C-high-field FT-NMR spectroscopy without chemical degradation of the intermediate and the compounds.
20. Syntheses and uses of isotopically labelled enamines
KC*N
CuS04
->yCUC*N
Na2S03 0.5 N NaOH
Et00CCH2CH2COCI
ZnJAcOH, Ac20 ultrasonication, 40°C. I0 min
6 N DCI
HOOCCH~CD~CO~D~NH~.HCI
(5-13C)ALA (79)
E~OOCCH~CH~~N
*
I
*
EtOOCCH2CH2COCH2NHAc
(26)
overall 90%
C = 13C (90% enriched 13C)
COOEt
* I* *
~!H~CCHCH~COOE~
1138
Mieczyskaw Zielinski and Marianna Kanska
Following the synthetic method illustrated by equation 27 and starting from (1-13C)or (2-13C)-acetate or (1-13C)- or (2-13C)-glycine, all the '3C-labelled isotopomers of aminoluvelinic acid [I-13C]-, [2-13C]-, [3-13C]-, [4-13C]- and [5-13-CIALA have been obtained. 13C-NMR spectra of the enzymatic reaction ALA -t PBG (equations 28a and 28b) have been measured in sodium phosphate buffer (pH 6.8) in a 5-mm NMR tube using a JNM-GX-400 spectrometer at 100.4 MHz. COOH
I I
COOH
CH2 CHz
I c=o I
COOH
I
(human peripheral blood) ALA-D
HzC
*
35.5 ppm
C*H2
I2
NHz 47.8 ppm
HN'H~
*
HZ$'
, c-c
C/
II C
'N'
,CH2
II *CH
H
2117.8 ppm
PBG
(5-I3C)ALA
(3-I3C)ALA ALA (79), known as an intermediate in the hiosynthesis of heme, vitamin B,, and chlorophyl, has also been reported as a herbicide65. 4. Synthesis of '3Clabelled uracil, 6,7-dimethyllumazine and lumichrome
82, Uracil(6-13C), 80, 6,7-dimethyllumazine(8a-q), 81, and lumi~hrome(lOa-~~C), have been s y n t h e s i ~ e din~ ~ reaction sequences shown in equations 29a and 29b which 83, stable for storage. involve the common isolable intermediate ~yanoacet~lurea(6-'~C), Increased intensities of the I3C-NMR signal of carbon-8a in 81 and of carbon-l0a in 82 indicate the presence of the label, as well as its positions in 81 and 82, respectively. Compounds 80, 81 and 82 have been used to assign correctly the 13C-NMR spectra of the covalent adducts which result from nucleophilic attack of bisulphite anion on them66. Previously, uracil labelled with 13C at C(,, has been applied6' to study its incorporation into transfer ribonucleic acid (tRNA) by taking the 13C NMR spectra of 13C-enriched tRNA. The fluidity of the fatty acids within biological membranes has been investigated6' by feeding 13C-labelled acetate. 5. Stereoselective synthesis of L-[-'3C]carnitine L-Carnitine, [(3R)-3-hydroxy-4-(trimethylammonio)butanoicacid], 84, transporting fatty acids from the cytosol across the mitochondria1 m e ~ n b r a n e ~ ~and - l ' used in the
20. Syntheses and uses of isotopically labelled enamines
*
KCN + C1CH2COOH
Na2C03
c
NCCH2COOH
-NC*CH~CONHCONH~
1139
NH2CONH2
(83)
1
PhNHICl Raney NiM2
1
NaOH
n
treatment of a wide variety of diseases72,has been 13C-labelledin a five-step synthesis79 presented in equation 30. L-Carnitine (84) has been produced in 30% overall yield from 3-deoxy-~-[l-'~C]glucose (86). It serves as substrate for carnitine a~etyltransferase'~. The synthetic route of equation 30 leads to D-carnitine if 3-deoxy-o-mannose is used as a starting compound.
1140
Mieczystaw Zielihki and Marianna Kanska
CH2 I HCOH I HCOH
1. K"CN (99.2% I3C)
2. Hz
I
HOCH 1 HCH I HCOH
H~OH +
I
HCOH
I
CH20H
I
HCH
I
HCOH
HCOH
1
Chromatographic separation of 85 and 86
I HCH I
NaBH3CN, 3 M NaOH (pH 9.0)
*
RT , 9 days
I HCH
*
I
I . MezNH.HCI
2. pH 9.0, RT, 3 h
86
HCOH I HCOH
NMe2
I
*CH2
I
HCOH
I
B r~
*&H2
I
HCOH
excess Me1
*b Hz I
HCOH I
HCH
I
n
6. Synthesis of optically pure '3C-labelledpropionate from alanine by asymmetric hydrolysis
Sodium (R)-[2-2H,3-13C]propionate89, sodium (S)-[2-2H,3-13C]propionate90, sodium (R)-[3-13C]-2-fluoropropionate91 and sodium (S)-[3-113C]-2-fluoropropionate92 have been synthe~ized'~ from ~[(S)]-[3-'~C]alanine,87, and L[(R)]-3-I3C]alanine, 88, which had been obtained by asymmetric hydrolysis with the use of acylase from porcine kidney (equations 31-35). All compounds 87-92 have been obtained in high optical purity (100% ee).
20. Syntheses and uses of isotopically labelled enamines
13CH31
AcNHCH(COOEt)2 EtOH, Na
* 13CH3C(COOEt)2 I NHAc
conc. HCI
H
13CH3-A-COOH
I
NH2 62%
H 13CH3-6-COOH
I
NH2 L (R) (88) 38%
H
I
I3CH3-C-COOH
I
H
NHAc
7
13CH3---C-COOH
98%
I
I
NHAc
NH2 D ( S ) (87) 32% H 13CH3-c-COOH
I
NH2 L (R) (88)
NaN02, KBr
2.5 N HzSOd
H,
* 1
3
~
.Br C'
'cooH ~ /
~
60% (> 98% ee) I
81% (> 98% ee)
1
1. LiBEt3D 2. work up. Na2C03 solution
H, 13cH3/
.D
c'
COON^
( S ) (89) (> 98% ee)
Mieczyslaw Zielinski and Marianna Kanska
H
1
13CH3---C-COOH
I
,F
CsHsN (HF), NaNOz
13cH3/
NH2
,H C.
COON^
(S) (92) 95% (> 97% ee)
D (S) (87)
[2-2H]propionates derived from DL-, D- and L-alanine have been esterified with (R)-methyl mandelate using 4-dimethylaminopyridine (DMAP) and dicyclohexylcarbodiimide (DCCD) in 47% yield (equation 36) and their 'H-NMR spectra determined.
v
PhCHCOOMe DMAP, DCCD
-
X4c,J
CH~'
\
COO
I
"C-labelled propionates double-labelled with deuterium or fluorine have been needed to study the stereochemistry of the chain elongation steps in the biosynthesis of polyether antibodiesT5. NMR spectroscopy allows one to identify the stable isotope-labelled positions in these compounds, thus avoiding a chemical degradationT6. 7. Synthesis of 13C- and 14C-labelledpirmenol hydrochloride
This new orally active, long-lasting antiarrhythmic drug 93, used for acute and chronic has been "C- and 14C-labelledT9for metabolism and bioavailability studies by reacting labelled benzoyl chloride with 2-trimethylsilylpyridinesO, treatment of the formed 2-benzoylpyridine with cis-1-(3-ch1oropropyI)-2,6-dimethylpiperdineand converting the obtained pirmenol-free base 93 to its HC1 salt (93.HCI) (equation 37). 8. Synthesis of tetra~ole-'~C and 1,2,4-triaz0le-1,2-'~N,
Tetrazole-I3C has been obtained in 70% yield by heating K13CN, NaN,, isopropyl alcohol and acetic acid in a sealed pyrex ignition tube for 96 h at 110 "Cs1,82. 1,2,4-tria~oIe-l,2-'~N,(94) has been synthesized in 35% yield by refluxing for 18 h a mixture of 1,3,5-triazine, ethanol and hydrazine-15N, sulphate (98.6 atom% 15N, commercially available); see equation 38. Hydrazine monohydrochloride reacting with 1,3,5-triazine in refluxing ethanol yields 1,2,4-triazole in near-quantitative yieldsz. The H2SO, produced in reaction 38 degrades the product 94 during the prolonged reaction time required. The location of 15N in the 1 and 2 positions of 94 has been assigned by the 15N-NMR spectra. Tetrazole-13Cand 1,2,4-tria~ole-l,2-'~N~ were found to be good inhibitors of carbonic anhydrases3.
20. Syntheses and uses of isotopically labelled enamines
1. Na, NH3. THF 2. Cis-CI(CHd3N
Me 3. Hi, H 2 0
1
(93aHCl) specific activity 11.1 mCi mmolkl; 82% step yield; radiochemical purity > 99% by TLC and HPLC (93b.HCI) 74% step yield; purity > 99%; I3C isotopic abundance of 94.5%
9. Stereoselective biosynthesis of
%-, '
3
and ~ '5N-labelled L-serines
Different 'H-, 13C- and/or 15N isotopomers of L-serine, [(S)-2-amino-3-hydroxypropanoic acid], 95, required for studies of aminoacid metabolism and for studies of peptide and protein structure and dynamics. have been biosynthesized stereoselectively" using the serine-type methylotrophic bacterium, Methy/obacteri extorquens AMI, which contains'' large amounts of the enzymes methanol dehydrogenase and hydroxymethyltransferase (equation 39). Stationary cultures of M. extorquens AM1 incubated at pH = 8.0 in the presence of glycine and methanol accumulate serine in their culture mediuma6, but under these conditions most of the methanol has been oxidized to carbon dioxide and dilution of the label from [13C]methanol 99.7% 13C)when incorporated into C(3,of serine (85-92% 13C) has been observed. These pitfalls have been partially overcome by adding boric
Mieczyslaw Zielinski and Marianna Kanska
methylenetetrahydrofolate
acid to the culture medium containing the glycine. Borate inhibits formate dehydrogenase by slowing the oxidation of formate to carbon dioxide and inhibits also the expression of glycine decarboxylase. Stationary culture of M. exlorquens AM1 maintained at 20°C in alkaline culture medium (pH = 8) containin glycine, [13C]methanol and borate produced ~-[3-'~C]serine. The 13C-label from ["Clmethanol has been incorporated into the C,,, of serine without significant dilution. Using [13C]methanol (99.2% "C) and ['H,, 13C]methanol ('H, 98%; 13C, 99.2%) as starting materials, the [3-13C]-, [2,3-13C2] and [3-'Hz, 13C]-isotopomers of serine have been produced in 31%, 29% and 32% isotope yield, respectively. Starting with [2-13C]glycine, the [2-'"1and [2,3-13C2] isotopomers of serine have been obtained in 47% and 44% isotopic yields, respectively. Incubating the methylotrophic bacterium AM1 in a medium containing [1-15N]glycine the [1-"C] and [15N] isotopomers of serine have been isolated in 45% and 44% isotopic yields. The isotopic purity of all listed isotopomers of serine was in the range 97-99%, as determined by NMR. The total recovery of isotope (i.e. the sum of the labelled products and labelled starting materials recovered) was in the range 75-91%. 13C-labelled glycines have been prepareds4 from the corresponding bromoacetic acids8', used in the synthesis of the 2',3',5'-tri-0-benzoyl[4-L3C]uridine and regiospecific introduction of isotopic carbon or nitrogen into one or more positions of the pyrimidine ring8'. [15N]glycine has been prepared from potassium [15N]phthalimide8s. ~
-
10. Synthesis of triple ['3C2,15N], single [14C] and double ['4C,]labelled trimetrexate
Trimetrexate, CI-898, 96,showing antineoplastic activity in breast, head and neck cancer, and found to be active in treatment of Pneumocysris carinii pneumonia in AIDS patientss9, has been 13C-, 15N- and 14C-labelledgoto facilitate the human and
20. Syntheses and uses of isotopically labelled enamines
1145
pharmacokinetic and metabolism studies of this drug, since it accumulates at high levels in certain organs and administration of 14C-labelled CI-898 at the specific activity required for good detection limits causes unacceptable radiation doses to these organs. a. Triple ['3C,15N/-labelled rrimetrexate, 5-methyl-6-{[(3,4,5-trimethoxypheny1)amin0][~~C]methyl-[l-'~N,4-~~C]}-2,4-quinazolinediamine, [13C,,15N]CI-898, 96, has been synthesized by the method outlined in equation 40. CH3
-
2. I. HCI. Ran- MezCHOH N i H& z;HT
6 ~ HC1 2 I. NH40H 2. Cu*CN, Pyr
'LAO i
I Me
CH3
I
Raney Ni, H2, AcOH. HzO (3.4.5-MeO),C6H2NH2
*
N = 15N label *C = I3C label
1
b. Sin le 14C-labelled CI-898, 97, was synthesized originally according to equation 41. Dou le carbon-14 labelled synthesis providing higher specific activity of drug 96, starting from 1.5 Ci of potassium [14C]cyanide, has been carried out similarly as indicate in equation 40. The purity of the 2-hydroxyethanesulphonate salt formed by
Mieczysiaw Zielinski and Marianna Kanska K ~ (100 N m~i+ ) NazSO3 + CuS04.5H20
1 . NaN02, HBr
H2N
%byNH2 Me
NH2
2 CUBE,HBr
Br
-
*
CuCN
pq)~~~ Me
NH2.HBr
1. aq. NaOH
2 Cu*CN, 0 1
I Me
1
Raney Ni, HZ.AcOH, HzO (3,4,J-MeO)3C6H2NH2
OMe
(97) *C = '4C
treating 96 with HOCH,CH,SO,H/MeOH was higher than 99%. 98.1 atom% excess of three labels has been found in 98. [14C]CI-898 had specific activity of 282 pCi mg-I (104 mCi m m o l ' ) and a radiochemical purity of 98.9%.
C. Nitrogen-15 and Oxygen-18 Labelled Compounds
1. Synthesis of '5N,'5N-imidazoleaceticacid
1 5 N , 1 5 N - i m i d a ~ ~ l e aacid ~ e t(IAA, i ~ 99),a metabolite of histidine 100, and histamineg1, found in brain and cerebrospinal f l ~ i d ~has ~ , been ~ ~ , synthesizedg4 by oxidizing 15N,15N-~~-histidine with sodium hypochlorite, subsequent acid hydrolysis of the formed 15N,1SN-imida~~leacetonitrile 101 and separation of the product 99 on an anion exchange column with 0.1 N acetic acid (equation 42). The 15N,15N-IAAobtained served as an internal standard for GC-MS analysis of physiological fluids.
20. Syntheses and uses of isotopically labelled enamines
CH=C
I
[~NH.
I 1
c5
,CH2CH \COOH
5
,CH2CN CH=C
HCI. excess NaOCl
-COz
~
c5
H
I
H
1
6 N HCI reflux
CH=C
,CH2COOH
,CH2CONH2 CH=C I I5NH N : 'C H
HCI
4, . c N~I
I
water
H (99) 33% total yield
2. Synthesis of methotrexate-I-15N and methotre~ate-4-'~NH,
These compounds, needed to measure NMR spectral shifts between methotrexate and its complex with the dihydrofolate reductase enzyme, have been synthesized9' following the method described by Taylor and coworkersg6 for preparation of 2,4-diaminopteridines substituted at C(,!, which allows the insertion of 15Nlabels at the 2-NH, or 3-CN functional group (equat~on43). The synthetic procedure leading to production of lO8a and 108b, illustrated by equation 43, involves oximination of ethyl cyanoacetate-"N followed by reduction to give ethyl 2-aminocyanoacetate-CI5N, 102 (as the tosylate). Condensation of 102 with 3-bromopyruvaldoxime and 4-methylaminobenzoic acid afforded the N-oxide 103a. Treatment of 103 with ammonium hydroxide at room temperature gave the 3-carboxamide 104a. Reduction of the N-oxide with PCI,, esterification and dehydration of the
I5NC -CH2COOEt
HNO,
15NC-CCOO~t
Al-amalgam
II
-
15NC-CHCOOEl
I
NOH
NH2.TsOH
Me
4-MeNHC6H4COOH
I
E
~
H215N
O N
I
0
O
C
~
C
H COOH
~
N
~
Mieczyslaw ZieliAski and Marianna Kanska
1. NaOH/MeOCH2CH20WH20. RT, 3 days 2. CICOOBu-i-EtOOCCH(NHI).HCI I
J&6)cH2Na COOR I
H215N
I5N
N
CONHCH I
(107) R = Et (108a) R = H, 1-I5N (108b) R = H, 4-I5NH2
1
1. 0.1 N NaOH, THF.4 h 2. I N HCI
(yH2)2 COOR
20. Syntheses and uses of isotopically labelled enamines
1149
amide with phosphoryl chloride produced the 2-amino-3-cyanopyrazine benzoate ester 105. Ring closure with guanidine followed by hydrolysis of the benzoate ester 106, glutamate coupling and hydrolysis of the glutamate diethyl ester 107 yielded methotrexate-1-ISN, 108a. Amination of the unlabelled 2-amino-3-carbethoxypyrazine intermediate 103b with 15N NH40H gave the lSN-carboxamide 104b which, after the chemical reactions described for production of 108a, afforded methotre~ate-4-'~NH,, 108b.
3. Synthesis of indazole-l-'5N, inda~ole-2-'~N and their derivatives
a. Indazole-l-15N, 109, has been prepared9' starting from 2-nitrotoluene-'%, 110 (equation 44), in 51% yield. A four-step synthetic method based on anthranilic acid-I5N, 111, yields 109 in 53% total yield9', but 110 is cheaper than 111. b. Indaz0le-2-'~N,112, has been ~ b t a i n e d ~in' ,the ~ ~reaction sequence of equation 45.
CH N* H
1. NaN02, HCI
2. H3P02
H
c. The N-methyl derivatives 114 and 115 of 109. These were obtained by methylation with dimethyl sulphate. 112 and 113 have been also produced and isolated (equation 46). The 'SN-labelling has been performed in order to study the ISN-NMR spectra of indazole in solutions in relation to previous 13C-NMRinvestigations of these systemsLo0.
1150
Mieczyslaw Zielinski and Marianna Kahska
4. Synthesis of 1-(['80,]-2-nitro-l-imidazolyl)-3-methoxy-2-propanol (['80,]-rnisonidazole)
The imidazoles, extremely important drugs used in chemotherapy, showing antiparasitic and anticancer activity and used for the treatment of human trichomoniasis and as hypoxic cell radiosensitizers in radiotherapy, have been extensively studied in terms of chemical synthesis, biosynthesis and biochemical modes of a c t i ~ n ' ~ ." ~ ~ [lsO,]Misonidazole 116 has been synthesizedlo5, as indicated in equations 47a-c in order to investigate further the proposed earlier mechanism of DNA strand breakagelo6 presented in the scheme of equation 48. It involves a nucleophilic attack of the oxygen atom of the nitro group of misonidazole 116 on the C-.5' radical of the sugar of the thymidylate residue 118 and production of formate or formyltris (N-tris(hydroxymethyl)methylformamide) 119 in which the carbonyl oxygen atom is derived from the oxygen atoms of misonidazole 116 and cleavage of the C-5'-C-4' bond of the sugar moiety.
NaN02
Dowex-50W (HI) H2I80 (98 at%), 0°C. RT,24 h
85% (82 atom%) and 88% (recovery of H2I80) [70.6% of NaNI8O2,24.1% of NaN180160, 5.3% of ~ a I i ' 6 0 ~ by~FAB-MS] 0 CIH2CCH(OH)CH20Me
NaOH E,zO, RT,
-
H2C-CHCH20Me \ / 0 70%
20. Syntheses and uses of isotopically labelled enamines DNA
DNA
m
m
I
I
HO-P=O
HO-P=O
I 0 I
Activated
H-C-H
I
CH
NCS-Chrom
,O\
I
/Th CH
I
CH-
H-C'
I ,o\
CH
/Th CH
CH-
CH2
I
CH2
I I
I 0 I
I
I I
0
0
HO-P=O
0
HO-P=
I
I
m
DNA
1
116 ('RNOz*') anaerobic car~ditiar~
DNA m
DNA
m
I
RNO*
-
I
+
I
HO-P=O
HO-P=O
0
I
H-C-0*'
I 0
0*'
I
H-C-0*-N-R
-I
I DNA
DNA
HO-P=O
HO-P=O
I
I
0-
I
CHI I
0
I
HO-P=O
I
I
+
NH
I
H-C=O*
(119)
cr
(117)
'CH
C(CHzOH)3
Nu.
H-C=O*
+ ,o\
I
/Th CH
H'O
I HO-P=O
OH
+
I
HC=O*
I
m
I
CH2
DNA
-
0HO-;=O
I
m
JVIIVVV.
DNA
DNA
+ thymine +
sugar fragments
(48)
Mieczysiaw Zielinski and Marianna Kanska
1152
NCS-Chrom = the non-protein chromophore of the antitumor antibiotic neocarzinostatin, associated with the generation of a reactive form of formate 117 from C-5' of deoxyribose of the thymidylate residues. Nu: = amino-containing nucleophile, such as tris(hydroxymethyl)aminomethane (Tris).
I HO-P=O
= phosphate-ended DNA
I Th = thymidine residue (cf 143). Ill. SYNTHESIS AND USES OF ENAMINES AND RELATED COMPOUNDS LABELLED WITH RADIOACTIVE ISOTOPES A. Tritium Labelled Compounds 1. Synthesis of 3H-labelled rifamycin L 105
Rifamycin SV (120) and rifampicin (121), very active antibiotics on Gram-positive bacteria and on mycobacteria through the inhibition of the bacterial enzyme DNAdenendent RNA . n ~ l v m e r a s e ' ~ .~are - ' ~used ~ in theranv n o w a d a v ~ ' ~A~new . rifamvcin potential intestinal disinfectant (antibacterial agent) named rifamycin L 105 (122) has been tritium-labelled for radiopharmacological studies by condensing 3-bromorifamycin S (123) with 3~-2-amino-4-me~hylpyridin~(124) synthesized according to the ~ i l t z b a c h method (exposure of unlabelled 124 to 260 Ci of tritium gas during 21 days followed by purification"0; sec cquation 49). The specific activity of 122 was 33.79 Ci mg-'. 0.33% of the original tritium activity (8.72 f 3% mCi) was found in the final product. A.
d
MeOCO,
CH
/
CH
,CH
tcH
I
,CH XCH I
,CH
(120) Rifamycin SV R = H (121) Rifampicin R
H2 H2 C-C \ = C H = ~ NMe I
20. Syntheses and uses of isotopically labelled enamines
OH
L
OH
00
ascorbic acid
N-CH
H
N-CH
Me
Me
(122)
2. Synthesis of N-phenyl-N-{1-[2-(4-isothiocyanatophenyl-3,5-3H2)-ethyl]-4piperidininy1)propanamide (125)and 2-(4-ethoxybenzy1)-l-diethylaminoethyl-5isothiocyanatobenzimidazole-4,6-3H, (126) The tritium-labelled &specific opioid alkylating ligand 125 and the tritium-labelled p-specific opioid alkylating ligand111.112126 have been synthesized113 by catalytic reduction of dibrominated amino intermediates 125a and 126a with carrier-free tritium gas (25 Ci) over 10% Pd/C followed by conversion of the amine functions of 125b and 126b to isocyanates.
Mieczyslaw Zielinski and Marianna Kanska
(126) R1 = NCS; R2 = 'H (126a) RL= NH2; R2 = Br (12121)R' = NH2; R2 = 3H (126c) RL= NH2; R2 = H The dibromo derivatives 125a and 126a have been prepared by reaction of the unsubstituted amine 12% and the methanesulphonate salt of 126c with excess bromine in acetic acid. Amines 125b and 126b have been converted to the isothiocyanates 125 and 126 by reaction with thiophosgene in a biphasic chloroform-bicarbonate system. The radiochemical purity and the specific radioactivity of the isothiocyanate 125 were 99.9% and 27.4 Ci mmol- ', respectively. The benzimidazole isothiocyanate 126 has been prepared with 2 9 5 % radiochemical purity and with specificaclivily of16.3 Ci mmol-'. 3. Synthesis of tritiated (613) and (6s) 5,fO-dideaza-5,6,7,8-tetrahydrofolate
Two diastereomers of 5,lO-dideaza-5,6,7,&tetrahydrofolic acid, DDATHF, 127, both potent inhibitors of folate m e t a b ~ l i s m " ~ and de novo purine synthesis115, have been synthesized116 by catalytic reduction of the unsaturated intermediate diethyl 2-acetyl5,lO-dideaza-9,lO-didehydrofolatewith Adams catalyst and carrier-free tritium gas in AcOH and 3H,0 solution. Each of the separated (6R)and (6s)diastereomers had specific activity 11.2 Ci mmol-' and contained tritium almost exclusively at the metabolically stable positions C(5,,C(6,,C(,,. C(9),C(IO)and the phenyl ring of DDATHF.
The relatively low 12% overall yields for each diastereomer is attributed to a lower average pressure than 722 torr of 3H, inside the reaction vessel and to no-ideal concentration of tritium on the catalyst. 4. Synthesis of pH]-prazosin
[3H]-prazosin, 128, which is an a,-adreno-radioligand, has been prepared"' in a four-step synthesis starting from furoic acid and involving reductive catalysed debromination with tritium gas (equation 50).The specific activity and radiochemical purity of the product 128 were 22.6 Ci mmol-I and 98%, respectively.
1155
20. Syntheses and uses of isotopically labelled enamines Chloroform
+
Br2
I?
384hrenux-
c, Br
Br
Hz Hz C-C \ NH.6Hz0 HN\ C-C Hz Hz I
,
C-c,
0
1
HN
\
Br
I
C-C Hz Hz
'Hz (400 Ci canier-free) (660 mm Hg pressure) 5% Pd/BaSOs, 4 h, DMF, 15-20°C
Hz 9 C-C / \ ,C N \ '
HCI (501 3H
Me0 (128)
The labile tritium has been removed by repeated exchange with EtOH and evaporation. N o radiative decomposition of the product 128 has been observed in the course of the tritiation step. 5. Synthesis of [8-3H]pentostatin
Pentostatin, a nucleoside of structure 129a, isolatedlL8from the fermentation beers of Streptomyces antibioticus NRRL 3238, and obtained by a total synthe~is"~, is effective as co-drug for enhancing the antivirallZ0 and a n t i t u m ~ r efficacy '~~ of various adenine
1156
Mieczystaw Zielinski and Marianna Kadska
nucleosides, and also desirable in the treatment of lymphoid m a l i g n a n ~ i e s 'and ~ ~ in immunosuppression'23. It has been tritiatedlZ4at Clq,via C3H]NaBH, reduction (1.5 Ci, sp.activity 2.88 Ci mmol-') of ketonucleoside 129c wlth less than a theoretical amount of [3H]sodium borohydride over a long reaction period in order to achieve the maximum incorporation of tritium and to minimize possible tritium loss due to a n isotope effect. The R isomer, 129b, has been isolated in ca 24% overall chemical yield from the R and S isomers, 129b and l29d respectively, by preparative reverse-phase chromatography employing an octadecylsilyl-derivatized silica gel stationary support'25. The specific activity of the purified 129b was as high as 227 mCi mmol-', the chemical purity was >98% and the radiochemical purity >98%. 129a has been also tritium-labelled by a tritium exchange methodlZ6.
R!
f2
'c-17)
N. /(n C\H2 1 '~)NH (s,) H C p HO-CH~ N,$\!=CH I o
1 /',I C-H
HCw)
,,.,CH-CH
I
OH
(5)
4'"'
I
R3
(129) (a) R1 = OH; R2 = R3 = H (b) R' = OH; R2 = 3H; R3 = H (c) R'R2 = 0; R3 = H (d) R' = 3H; R2 =OH; R3 = H 6. Synthesis of tritium labelled zomepirac
The metabolism and p h a r m a c o l ~ g ~of' ~sodium ~ ~ ' ~ zomepirac ~ 130, a non-narcotic analgesic drug used in the treatment of mild to moderately severe pain, as well as the synthesis of deuterium labelled 130 in the chlorobenzoyl grouplZ9,have been described previously.
',
Tritium labelled 130 with specific activity of 85 Ci mmol- required for use in receptor site studies, has been preparedl3' by selective alkylation of the N-desmethyl zomepirac 131 with methyl i ~ d i d e - ~ H(equation , 51). A solution of 50-mCi portions of [3H3]-130 in 9:l EtOH/H,O mixture have been stored at - 20 "C at a radioactive concentration of 4.5 mCi ml-' and the radiochemical purity of the sample was 95-96% after one year. No labile tritium was found after refluxing a portion of the sample for 1 h in a methanolic solution of NaOH. The intermediate 131, 5-(4-chlorobenzoyl)-4-methyl-1H-pyrrole-2-acetic acid, has been obtained in a n eight-step synthesis starting with terr-butyl acetoacetate (equation 52).
20. Syntheses and uses of isotopically labelled enamines
1
1. 2 eq. n-BuLi. THF,under Na -78 "C 2. 3Hf21 (10 Ci, 85 Ci mmol-I), 12-crown-4, 100°C. 8 h in sealed flask
k3H3 [3~3]-130, 4 Ci, radiochemical purity > 98%. 1&20°/0 purified chemical yield
COOCH, NaOH
TS0H.A
1
EtOH HCl
H
7. Synthesis of 5-pH]-indole-3-carbinol
Indole-3-carbinol (I3C) 132, a natural anticarcinogen, found in cabbage, cauliflower and broccoli, inhibiting tumorogenesis in rodents exposed to polycyclicaromatic hydroc a r b o n ~ and ' ~ ~ inhibiting cc-toxin B1 (AFB1)-induced hepatocarcinogenesis in rainbow and rat, has been tritium-labelled at C(,,position starting from 5-bromoindole according to the synthetic route presented in equation 53'33.'34.
1158
Mieczyslaw Zielinski and Marianna Kaliska
The 5-C3H]-13C product, found to be >99% radiochemically pure, was stable when stored under N, in 95% EtOH at - 20 "C protected from light, but gradually turned orange if left at RT or if exposed to air. The mechanism of anti-carcinogenesis by this dietary inhibitor is under current study133.
lo%
1
T2 (10 Ci)&
gas (12-15 psi) RT,60 min
5-[3H]-13C, (132), 85-90%, specific activity 21.14 Ci m m ~ l - ~ (73% of the molecules labelled exclusively at C(5)).
8. Synthesis of tritium labelled (5-HT,$ receptors
a. Synthesis of 3-(1,2,5,6-tetrahydropyridyl)-2-tritiopyrrolo[3,2-b]pyrid-5-one, C3H]CP-93,129. [3H]-CP-Y3,12Y, 133, a potent radioligand for the serotonin 5-HT,, re~ e p t o r ' ~ ~has . ' ~been ~ , synthesized13' in five steps, as shown in equation 54, for the study of the location and function of serotonin receptors, particularly of 5-HT,, receptors. The product 133, of >99% radiochemical purity, had specific activity of 19 Ci mmol- I . In the course of the synthesis of L3H]-133, 2-deuterio-5-t-butoxy-1-phenylsulphonylpyrrolo[3,2-blpyridine 134 has been obtained (equation 55). b. Synthesis of 5-(2,3-ditritiopropoxy)-3-(1,2,5,6-tetrahydropyrid-4-yl)indole ([3H]CP96,501).[3H]CP-Y6,501, 135, a selective radioligand for the neurotransmitter serotonin
20. Syntheses and uses of isotopically labelled enamines CH
N ~ HPhS02CI. , RT
CH
under N ~stir , 12 h, THF, 0°C under NI
'1
_
t-BuO
I
H
S02Ph 69%
t-BuO
t-BuO
I
I . t-BuLi 2. l2 in THF. -78°C
10% P d C , EtlN, C H S N 'Hz (14 Ci, 0.172 mmoles). RT,2 h
I
I
I
SOzPh
S02Ph
-
I
61%
NaOMelMeOH, reflux under argon. 5 h
COOBu-t -
-
I
Hz?'
N \CH~
I
I
H2C\C// CH
H I . Me3SiUMeCN, 50°C. 2 h r 2. Exuaction, workup purification
' 3 ~
1.6 Ci
CH CH
II
I
II
H I C yC X N / C 3.H
(54)
H H [3H]CP-93,129 (133). 1.51 c i
H
t-BuO
O+ ,N\ C C-C
I. r-BuLi 2, 2H20, THF. -78°C I
(5-HTIB)receptor13', has been synthesized also in four steps, presented in equation 56, starting with 5-hydroxyindole'39. Product 135, which has been stored under argon at - 70 "C in MeOH at concentration of 1 mCiml-' with 1% (wt/vol) ascorbic acid for stability, underwent 30% decomposition after 5 weeks.
Mieczyslaw Zielinski and Marianna Kanska
I-
CH2=CHCH21, NaH, acetone. RT. I h under Nz
1
'Hz (1 1.2 Ci). RT. AcOEt RT @-di-r-butylcatechol)
HzC, C 3HC1H2-~3~L~~'~20
'CHZ I ,,CH
w
/
MqSiI, MeCN 1 h under argon in the dark
(135) specific activity 50.5 Cimmol-I radiochemical purity > 98% 9. Synthesis of 5,6-dihydro-7-(1H-[G-3H]imidazol-l-yl)-naphthalene-2-carboxylic acid
C3H]FCE 22178, 136, inhibitor of thromboxane A,(TXA,) synthetase140, exerting appreciable stimulation of prostacyclin (PGI,) synthesis14', has been obtained in three steps14' (equation 57) avoiding the undesired reduction of the 7,8-double bond by tritium. The product 136 was 98% radiochemically pure and had a specific radioactivity 9.15 GBq mmol-', which allowed its use for pharmacokinetic and metabolism studies.
20. Syntheses and uses of isotopically labelled enamines
N-CH*
3H2 (370 CBq),
II
10%Pd/C, MeOH, KOH
H *HC\N+
t
H2S04. 96% 96% 1. IOO0C, H2S04. 3 hglacial glacial AcOH AcOH
(3H),
HOOcQf*z;
*
c'
N-CH N-CH 11 V II
1. IOO0C,3 h
2. 0°C. work-up
H2 (136) n = 2-3 . -.-.. 180.45 MBq (48% Loverall radiochemical yield)
II 11
(57)
ZNSH \ \
(3H)n (3H)n
H* = [3H]-label
n = 2-3 268 MBq G = the labelling position unknown
10. Synthesis of nicardipine [ ~ ' , c Y - ~ H ]
The synthesis of this tritium-labelled dihydropyridine derivative, 137, a powerful antihypertensive agent attenuating smooth muscle and cardiac muscle contractions by blocking the influx of calcium ions into vascular smooth muscle cells'43, has been carried by preparing initially the 3-nitroben~aldeh~de[4,6-~H] 138 of high specific activity in the four steps shown in equation 58. It was then used in the Hantzsch
CHlOH specific activity 51 Ci rnmo1-l
1
MCPBA CH2C12
3~
m-0dCaH4COOH 3H CHO
CH20H
(138) MCPBA = mCPBA 5 m-dichloroperbenzoic acid
1162
Mieczystaw Zielinski and Marianna Kanska
c o n d e n ~ a t i o n ' ~with ~ ~ methyl ' ~ ~ fl-aminocrotonate 139 and the acetoacetate 140 to give 137 in 26% yield (equation 59).The specific activity of the nicardipine-3H, 137, was 51 Ci mmol-I. 138 + MeOOCCH=CMe + MeCCH2COO(CH2)2N(Me)CH2Ph I
I1
1
I. i-PIOH. 8 0 T 28 h 2. HCI
3H I
(137) 23 mCi, specific activity 51 Ci mmol-I, purity > 99% 11. Enzymatic synthesis of 3H-labelled 8-ureidoisobutyric acid and fl-aminoisobutyric acid from fH]thymidine
3-Amin0-2-[~H]methylpropanoic acid 141 and 3-[(aminocarbonyl)amino]-2-L3H]methylpropanoic acid 142 have been synthesized (equation 60) by in~ubating'~'the
*
il HN
/C\C/CH3
I
II
/C /CH O/ \N HOCH2 C 'H
I
37T
75 min
II HN /C\C/CH3
I II O+C\N/ CH
,oJ
* -
H CH
Thymine
I
Thymidine (143).100 pCi
(141) P-aminoisobutyric acid 59.3 pCi, radiochemical purity > 99%
(142) P-ureidoisobutyric acid 18.8 pCi, radiochemical purity > 99%
20. Syntheses and uses of isotopically labelled enamines
1163
dialysed supernatant of homogenized dog liver with [3H]thymidine (specific activity 41 Ci mmol-') in the presence of NADPH and P-ureidopropanol acid (a competitive enzymatic inhibitor increasing the yield of P-ureidoisobutyric acid relative to fi-aminoisobutyric acid). The synthesis of 14C-labelledP-ureidoisobutyric acid and P-aminoisobutyric acid from thymine using purified enzymes has been carried out earlier148. 12. Synthesis of mitomycin C monotritiated at the C,,-methyl position
Mitomycin C, 144, used in cancer chemotherapy against a variety of solid tumors149, has been m ~ n o t r i t i a t e d 'in ~ ~a four-step synthesis presented in equation 61.
I
N a B 3 h (25 mCi. EtOH specific activity 500 mCi mmol-I)
= tritium labelled
15% yield based on 145, 13% 3H incorporation, 98.8% radiochemical purity, specific activity 16.2 mCi mmol-' The product 144 has 98.8% radiochemical purity after chromatography and recrystallization. No kinetic tritium isotope effect and tritium exchange with the solvent in the last two syntheses has been studied.
Mieczyslaw Zielinski and Marianna Kanska
1164
13. Synthesis of tritiated (S)-10-bromoacetamidomethylcamptothecin
The derivative 147 of camptothecin 146, naturally occurring antineoplastic agent15', stabilizing the enzyme-mediated DNA cleavage, has been tritium-labelled at C,,, position by a three-step sequence starting from (S)-10-hydroxycamptothecin'52 in order to investigate whether the presence of a peripheral electrophilic substituent in 147 renders the reversible binding of 146 with DNA-topoisomerase I covalent complex irreversiblelS2. 7
HO-C, ,O "CH~ 0 I9c~3
E
(146) R = H (147) R = B1CH2CONHCH2 (148) (S)- l0-~romoacetamidometh~lcamptothecin-5-~H 110 mCi, specific activity 19.9mCimmol-I, radiochemical purity ca 98% (after HPLC) The key step in the synthesis of L3H]SK&F S106470, 148, consisted of a palladiumcatalvsed direct tritium exchange - with the intermediate 149, (9-aminomethylcamptothecin (equation 62), and coupling the bromoacetic acid with the tritiatedintermediate product 150. ~
~~
Raney Ni, HOAc H2.100 psi
H2NCH2
1
Q Q g ~- ~ o
3H2(10 Ci, caniec-free), DMF. 10% RT. PdK 24 h
II HC\
C
I +C,
(149) 61% CH2
I
HO-C,
I
,O
d ~ 2E
0 CH3 (150) 443 mCi I
Excess BrCHzCOOH
1
DCCD. DMF
148 25% radiochemical yield
20. Syntheses and uses of isotopically labelled enamines
1165
3H NMR spectroscopy indicated that the tritium label in 148 is located exclusively at the C,,, position and the 3H,:3H, :3H2species are in a 44:44:12 ratio, in agreement with the FAB-MS measurement. In a previous deuteriation of camptothecin 146 the label has been found at both the CIS,and Cl,, siteslS3. Apparent reduction with D, of the B-ring was observed153,and the product was then oxidized with air or oxygen to regenerate camptothecin. This resulted in deuterium incorporation at Cl,, in addition to the initial benzylic exchange at C(,, (equation 63).
The postexchange mixture in the tritium-labelling experiment has not been subjected to oxidation, and if the tritiated (saturated) B-ring product had been formed, it probably would not have undergone reoxidation; and its bromoacetylated derivative has been separated from 148 in the course of its HPLC purification.
14. Catalytic synthesis of 3H-labelled imidazoles
Imidazoles are the most widely used epoxy curing agents producing resins with good high-temperature properties. Several imidazoles 151-160 and epoxides important for the study of the mechanism of epoxy resin cure have therefore been tritiated by one-step catalytic procedures (HTO 3-10 PI, platinum oxide PtO, 1&50 mg, prereduced with NaBH,, temperature interval of tritiation 10&165 "C, reaction times 12-48 h). The positions and the extent of labelling have been determined in these compounds by tritium nuclear magnetic resonance s p e c t r o s c ~ p y ' ~ ~ . The following imidazoles have been tritiated by base-catalysed hydrogen isotope exchange routes at the specified positions. imidazole (151)
I -methylimidazole (152)
N-CH
II
II HLN/CH
N-CH
II
II
CH WN/ I
specific activity 130 mCi mrnolkL C(Z,('H) - 100%
specific activity 3 mCi mmol-' C(z)(H)- 65% N(L)-CH~- 35%
Mieczyskaw Zielinski and Marianna Kanska
1166
2-methylimidazole (154)
N -CH II II C ,CH H ~ C / 'N H
specific activity 80 mCi mmol-I C(2)-CH3 - 38% c ,s)(H) - 62%
N-CH
specific activity 53 mCi mmol-I N-CH3 - 10% C(2)-CH3 - 60% C(4)(H)- 15% C(5)(H)- 15%
1,2-dimethylimidazole (155)
(aC II ~
3
II
/CH \yll c
~
CH3 I-benzyl, 2-methylimidazole (156)
N---CH
cII
specific activity 60 mCi mmol-I C(2)-CH3 - 7% c ,s)(H) - 93%
II CH
H ~ C / \N/
I
CH2Ph 2-ethyl, 4-methylimidazole
,CH3 N II C i II4 ) /C\ /CH
(157)
N(~)
GH5
2-(p-dimethy1aminophenyl)4,s-dimethylimidazole (158) P - ( C H ~ ) ~ N-C6H4 (~)
H
,CH3 N-C II
,c,
II x, $11
specific activity 46 mCimmo1-I C(2)-C2H5 - 56% C(4)-CH3 - 36% C(s)(H) - 8% specific activity 9 mCi mmol-' N(3)-CH3 - 100%
CH3
(6)
I-dodecyl-2-methyl3-benzylimidazolium chloride (160)
PbCHz -CI \ N-CH + II II C ,CH HF/ 'N I C12~25
specific activity 21 mCi mmol-I C(6)(H2)- 100%
20. Syntheses and uses of isotopically labelled enamines
1167
A large part (65%) of the label located at the C,,,(H) position in 152 is probably due to base-catalysed hydrogen isotope exchange still operating even in the presence of prereduced PtO,. The specific activities of the tritium-labelled epoxides by the same procedure are lower than for the imidazoles. The specific activities of the tritiated imidazoles can be improved by using tritiated water of higher specific activity. The use of tritiated imidazoles and epoxides provide more precise information concerning the mechanism of resin synthesis and related problems than traditional methods used, such as scanning c a l ~ r i m e t r y 'and ~ ~ Fourier-transform infrared spectro~copy'~~. 15. Synthesis of tritium-labelled simple seven-membered ring compounds Many biologically active substances and neuroleptic drugs have in common a seven-membered ring in their structure. They have been triti~m-labelled'~'-'~~ bY multistep radiosynthesis, by catalytic isotope exchange with tritium or by tritiodebromination of precursors in alkaline medium in the presence of PdO with tritium gas. Buchman and coworkers'57 obtained 14-tritium-labelled tricyclic antidepressant including different derivatives of iminobibenzyl by the in situ prereduced PdO-catalysed simple hydrogen-tritium/deuterium exchange catalysed by prereduced PdO by gaseous tritium, since in the in situ labelling a prereduced PtO, acted as a milder and slower catalyst.
X
=
H; R
= (CH,),NHCH,,
specific activity 14.7-18.4 Ci mmol-'
X = H; R = (CH,),N(CHJ,, specific activity 12.8-20.4 Ci mmol-' X = H ; R = CH,CH(CH,)CH,N(CH,),, specific activity 10.2 Ci mmol-' X = CI; R = (CH,),NHCH,, specific activity 6.2 Ci mmol-' X = C1; K = (CH,),NH,, specific activity 6.7 Ci mmol-' The exchange occurred mainly and preferentially at the benzylic positions. In derivatives having nitrogen as the central atom, the activity of the benzylic positions is lowered and only partial isotopic exchange is taking place. But even such a lowered exchange provided tritiated derivatives with specific activity sufficient for research purposes. In 161a, R = X = H, tritium and deuterium were*located mainly in benzylic groups and partly at the central nitrogen 'NH' roup. In compound 161a, X = H, R = (CH,),N(CH,), the hydrogens of the ‘EH, H,' top benzylic grou and the hydrogens of the first ' t ~ , - m e t h ~ l e n egroup ' attached to nitrogen 'N H,' have been labelled. Benzodiazepines with reasonably high specific activity have been also tritium-laare fast and belled16' using adsorbed tritium or actiuated tritium. These do not require one to synthesize the precursors. In the ACT (activated tritium) method the substrate to be labelled, spread on different catalyst supports (such as silica-alumina 980-25 containing 0.5% Ru, 1% Ni or 1% V; alumina catalyst Al-3945, 1% Ni, 1% Pd or 5% Pd; silica, 1% Ni and carbon, 4.6% Pd; the metal catalysts were activated by heating to 60&700 "C in hydrogen or on untreated silica-alumina), has been reacted
*CH,EH;
&
8
1168
Mieczystaw Zielinski and Marianna Kanska
with gaseous tritium plasma (tritium pressure 2.7 to 5.2 torr) activated by a microwave generator. In the AdT (adsorbed tritium) method, the supported metal pellets were exposed to a tritium plasma (tritium pressure 3.9 to 7.0 torr). After exposure and removal of tritium gas, the 'tritium charged' pellets were dropped into approximately 100 p1 of the ligand to be labelled, mixed and left for the tritium exchange reaction. In tritium labelling of solid substrates, the tritium-charged pellets mixed with solid substrate were heated slightly above the melting point of the compound to be labelled (HTI-high-temperature tritium ion method). The Pd-on-alumina support gives higher specific activity and less radioimpurities than other supports. Fourteen seven-membered ring compounds have been tritium-labelled by ACT, AdT or HTI methods'65 including: (+)3,3,5-trimethylhexahydroazepine-162, 2-oxohexamethyleneimine (caprolactamtl63, 1-aza-2-methoxy-1-cycloheptenel64,1,4-diazacycloheptane (homopiperazinetl65, 1,8-diazabicyclo-[5.4.0]undec-7-ene-166, 5Hdibenzo[bAazepine (iminostilbenetl67, 8-chloro-1 I-(4-methyl-1-piperaziny1)SHdibenzo[b,e][1,4]diazepine (clozepinetl68.
.
0 Hz /C ch HZ?
\
NH
/
Hz [3H]-(162) (ACTmethod) crude yield - 72 mCi purified yield - 2.4 mCi specific activity 16 mCi mmol-I HZ H25
/c-c'
A!H2 H2 [3H]-(163) (HTI)* crude yield - 369 mCi purified yield - 166 mCi specific activity 107 mCi mmol-I
OMe \\N
H2 [3H]-(164) (HTI)* crude yield - 322 mCi purified yield - 299 mCi specific activity 428 mCi mmol-I
H2 [3H]-(165) (HTI)* crude yield - 219 mCi purified yield - 3 1 mCi specific activity 48 mCi mmol-I
H2 [3H]-(166) (HTI)* crude yield - 175 mCi ourified vield - 101 mCi specific activity 151 mCi mmol-I
[3H]-(167) (HTI)* crude yield - 491 mCi ourified vield - 117 mCi specific activity 238 mCi mmol-'
20. Syntheses and uses of isotopically labelled enamines
[3H]-(168) labelled with activated tritium with substrate dispersed on multipore filter crude yield - 23 mCi purified yield - 2 mCi specific activity 562 mCi mmol-I
Compound 162 dispersed on 1% Ni on silica-alumina (980-25) labelled with activated tritium had almost the entire label bound to nitrogen. Tritium in this position is very labile and undergoes back-exchange, resulting in low 'purified yield'. The labelled products can be rigorously purified and lyophilized to constant specific activity. Hydrogens at the a-position to the keto group are also labile and can back-exchange at room temperature. Tritium labels at stable positions exchange only at high temperatures. Tritium NMR spectroscopy has been used to directly determine the tritium distribution in labelled molecules without need for chemical m a n i p ~ l a t i o n s ' ~ ~ .
16. Nuclear Overhauser effects in tritium NMR
3H NMR spectra, used for the quantification of the tritium distribution, are generally recorded using 'H broad-band decoupling which simplifies the 3H signals and enhances their intensity. This enhancement, named the 'nuclear Overhauser effect' (NOE)16' depends on the different sites and/or number of 3H atoms and therefore introduces errors in the quantification of the 3H distribution. These errors can be avoided by suppressing the NOE170, but 'inverse-gated' 'H decoupling experiments (under NOEsuppressed conditions) providing more accurate information, concerning the tritium distribution within labelled molecules require longer recording times. The differential NOES have been determinedL7' for [10-3H]-0rg 3770 (mepirzepine) 169 with specific activities of about 1 Ci mmol-' and for a mixture of monolditritiated [pyrrolidine-3H] (bepridil-170). In the case of compounds 169 and 170 the differential NOEs were found to be unimportant. The ratio of NMR signals of 169 obtained at 3.38 ppm C3H (eq)] and 4.50 ppm C3H (ax)] without decoupling was 6.87, and was changed to 6.74 only in the case of an 'H-coupled spectrum. For 170 the ratios [mon0-3-~H]/[cis-3,4-~H,1 determined under NOE and NOE-suppressed conditions were 1.19 and 1.21, respectively. However, in the 3H NMR spectra of other tritiated materials substantial differential NOEs have been measured. Examples are [16-3H]desogestrol 171 and [1,2-3H]-rimexolone 172. In the case of 172, in the NOE spectrum the 3H11,/3H12, ratio was 1.83, while in the NOE-suppressed spectrum a ratio of 1.56 was found'".
Mieczystaw Zielinski and Marianna Kanska
0. Carbon-14 Labelled Compounds
1. Synthesis of E-P-[2-'4C]indol-3-y/acry/icacid
Indol-3-ylacrylic acid, a tryptophane metabolite found in animals and in plant^"^, has been 14C-labelledat the 2-position of the indole nucleus179in order to investigate the possibility of its light-initiated covalent binding to DNA and its capability of photoinactivating phage174. [2-'4C]Indole 175 has been formylated at the 3-position with phosphorous ~ x ~ c h l o r i d e / D M Fand ~ ' ~the aldehyde 174 obtained was condensed with malonic acid in pyridine/piperidine176(equation 64) yielding the title compound 173. 173 labelled with 14C in the a-position is obtained using 14C-labelledmalonic acid and non-labelled 174. It has been found that 173-[14C] binds photolytically to DNA"~.
20. Syntheses and uses of isotopically labelled enamines
(175) specific activity 49 mCi t n t n ~ l - ~
(174) chemical purity 97% radiochemical yield 76.7% radiochemical purity > 99%
I
Pyr, 40T.48 h
H (173) chemical purity 96% radiochemical yield 43% radiochemical purity > 99%
2 Synthesis of {[2-'4C]pyrimidyl}sulphometuron methyl 176 and ([2-'4C]-triazinyl)mehu/phuron methyl 177
These two herbicides have been prepared'77 by condensation of 14C-labelled heterocycles 179 and 180 with methyl 2-(sulphonylisocyanate)benzoate 178 (equations 65 and 66). [2-14C]2-Amino-4,6-dimethyl pyrimidine 179 has been obtained from [14C]guaniCOOMe
OMe
/
d-
*/
+ H2N-C
SO2-N=C=O
N-C
\
N=C
(178)
\\
N
/
\
Me
COOMe
/
(177) l I%, 173 MBq mmol-'
OMe
I
Mieczyslaw Zielinski and Marianna Kanska Me
COOMe
/
178 +
* H2N-C\
N-C
N-Y SO2-NHCONH- *C\ %H / N=C,
\kH L7h_
N=C\
Me /
/
(66)
(176) 1 1.4MBq specific activity 346 MBq mmol-'
Me
/
NH2
HN--C,,
/
+ CH3COCH2COCH3
N-C
,,
,,)
HzOLNa2CO3
12
* '1 HzN-C \
NH~CI-
N=C
\LH /
(67)
\
Me
(17%
*
N-CN
NH; CI-
CH3-C
//
\
OEt
+ NH~;N
EtOH
//
CH~C \
+ 'NH~CI
OEt
OMe
/
dine as shown in equation 67. [2-14C]2-amino-4-methoxy-6methyl-l,3,5-triazine 180 has been obtained from [14C]cyanamide (equation 68). 3. Synthesis of f4C]labelled pyrano[3,4-b] and thiopyrano[3,4-b] indoles
a. The title compounds, tetrahydropyranoindole 181a or tetrahydrothiopyranoindole 181b, exhibiting antiinflamatory a ~ t i v i t y " ~ when Y = O , R1=alkyl and R2 = CH2COOH or having antidepressant proper tie^"^.^^^ when Y = 0 , R1 = alkyl and R2 = N,N-dimethylaminoethyl, have been labelled with 14C by the reaction seq u e n c e ~ ' ~presented ' in equations 69 and 70.
20. Syntheses and uses of isotopically labelled enamines
(181) (a) X = NH; Y = 0 (b) X=NH; Y = S
"&/!;'"c'. /
H Z = NMe2 Z = +NMe3CH3S0c
N H
mc/
I I CH3
N/'$N H
6 N NaOH reflux
*
,CH2CH20H
anh THF
H
R/jH H
I
RCOCHf202Et C6Hb.reflux BFYEt2O
R & H 2
* I. KOH/H20, BHT. MeOH, antioxidant reflux
(69)
2. 6 N H C I , O 0 C
c, C ,o
d \CH~COOE~
P r '
\CH~COOH (181a) specific activity 1.56 mCimmolkl
*
C = I4C label BHT = ~ , ~ - ( ~ - B U ) ~ - ~ - M ~ C ~ H ~ O H [3-14C]Prodolic acid, 181a, 99% radiochemically pure, has been obtained in 26% overall yield. In a similar manner etodolic acid, 181a', with specific activity of 3.03 mCi mmol-' and with 99% radiochemical purity, has been obtainedlS1.
1174
Mieczyslaw Zielinski and Marianna Kanska
I
CH3COCH2CH2NMe2 anh C&Me
lo%, specific activity 2.15 m~immol-' 99%radiochemical purity
H&OE~)~~/M~~OWCI,
2 h reflux under argon
CH
CH
I
CH-CH
I
(186)
1
1. 13&L4OoC. 15 min under argon
NaOH 2. Work-up
HN I H7N
/C*
K C-N N
II ,C,
II*
N
,CH
(184)
34% overall radiochemical yield, specific activity 19.6 m~immol-'
(71)
1175
20. Syntheses and uses of isotopically labelled enamines
b. [3 - 14C] - 9 - Ethyl - 1,3,4,9- tetrahydro - N,N- dimethylthiopyrano[3,4 - blindole1-ethanamine (tandamine hydrochloride) 181b has been obtained1'' by reacting thiosulphate 182 with (1-N,N-dimethy1amino)butan-3-onein anhydrous toluene in the presence of BF,+therate (equation 70). 181b has been obtained in 3% overall yield from the tryptophol 183 as shown above. 4. Synthesis of carbon-14 labelled cis-2-amino-1,9-dihydro-9-[4-(hydroxymethyl)2-cyclopenten- 1-yll-6H-purine-6-one, [8-'4C]carbovir
The title compound, 18-14C]carbovir, 184, a promising anti-AIDS drug182,inhibiting the infectivity and replication of HIV virus at concentrations of approximately 200-400fold below its toxic concentrations, has been labelled with 14C by treatinglU3a solution of triethyl[14C]orthoformate in dry chloroform with cis-{[4-(2,5-diamino-6-chloro-4pyrimidinyl)amino]-2-cyclopentyl} carbinol 185 and hydrolysis of the crude 186 with 2 N sodium hydroxide (equation 71). Triethyl ['4C]orthoformate has been prepared as shown in equation 72 by modifying an earlier m e t h ~ d ' ' ~ . NH.HC1
OEt
98.9 mCi 5 mmol 5. Synthesis of "C-labelled leukotriene inhibitor Sch 37224
Sch 37224,187, an efficient leukotriene release inhibitorlS5,has been radiolabelled in three steps giving 97% radiochemical purity and 27.3% radiochemical yieldlS6 starting from U-['4C]-aniline as outlined in equation 73. 187 has been required to study the drug's absorption, distribution, metabolism and excretion.
[U-14C]6H5NH2HC1 + 50 mCi
ac
C6HsNMq 130°C. 2.5 hat inert atmosphere
C1WMe
N
orcooH N
60% radiochemical yield, 97% radiochemical purity
DMFs Cs2C03.
-
I. xylene, NaH. 138°C under Nz
3
2. EtOOCCH2N
u-[l4C1
r-BuOH, xylene, 3 h reflux 3. Work-up
(187) specific activity 3.13 mCi mmol-'
NHC6H5[U-14C]
Me2S04
1
a. RT, I h. b, CH~CI* extraction
(73) N NHC6HS[U-14C] a C O O M e 25.7 mCi (93% yield)
Mieczyskaw Zielinski and Marianna Kanska
1176
6. Synthesis of carbon-14 labelled LTD, antagonist MK-571
The title compound, ['4C]MK-571, 188, a promising antiasthmatic has been ~ y n t h e s i z e d ' ~from ~ . ' ~ [14C]cyanide ~ in five steps as presented in equation 74. *
H2caBr + NaCN
CuCN (279 mCi) DMF, reflux, 5 h
*
AqO, Xylene
1
HSCH2CH2CONMe2, (Me6i)zNH. 1. Imidazole, RT, 18 h 2. HSCH2CH2COOMe.BFxEt20, -30°C
SCH2CH2COOMe
I
1 II
HcxY'N
201 mCi, 71% radiochemical yield
' v S C H $ H 2 C O N M e 2 20 mCi, 64% radiochemical yield
1
I. LiOH. THF/H20, 0°C. 6 h 2. H* (pH 4)
(188) 14%overall radiochemical yield The labelled drug 188 possesses limited stability with respect to light and temperature (ca 10% decrease in purity after 24 h in RT) and therefore had to be stored at - 55 "C,
protected from light. 7. Synthesis of 3,4-dihydro-4-oxo-3-([5-(trifluoromethyl)-2-'4C-benzothiazo/yl]methyl)-I-phthalazineacetic acid
This title compound, aldose reductase inhibitor CP-73,850 (zopolrestat) 189, has been 14C-labelled191(equation 75) for use in metabolism and pharmacokinetic studies, since
20. Syntheses and uses of isotopically labelled enamines
CH2COOEt
NHTHCI
190c or 190d
II Hz 0 (191) (a) R = CF3, *C = I3C (b) R = CF3, *C = 14C (c) R = F, *C = I4C
I
EIOWTHF, 5% aq. KOH RT, l h
CH2COOH I
(189a. b, c) as in 191 189b 75% (last two steps), 99.3%radiochemical purity, specific activity 22.5 ~ C i m g ' 18% 98% radiochemical purity, specific activity 25.1 pCi mg-'
it has been suggested'92 that complications found in long-term diabetes which include neuropathy, retinopathy and cataracts are caused by intracellular accumulation of sorbitol mediated by NADPH-dependent enzyme, aldose reductase metabolizing glucose to s ~ r b i t o l ' ~ ~ , ' ~ ~ . 8. Synthesis of [2-'4C]-2'-deoxycytidine-3N-cyanoborane
The dual-mechanism of cytotoxic activity of amine-boranes, possessing significant antineoplastic activity and useful also in boron neutron capture therapy (BNCT), initiated the search during recent years for therapeutic compounds of this class which accumulate preferentially in the tumor t i ~ s u e ' ~ ~The . ' ~title ~ . compound 192, one of the
Mieczysiaw Zielinski and Marianna Kanska
1178
more active boronated nucleosides possessing significant activity against several leukemias and several lines of carcinomas, has been 14C-labelled in the 2-position of the pyrimidine ring'96, for tissue distribution and elimination studies in rodents, by the three-step synthetic pathway1'' shown in equation 76. This includes protection of 3'- and 5'-hydroxy groups with the triisopropylsilyl group, transfer of the cyanoborane group from triphenylphosphine onto the more basic ring nitrogen and finally the deprotection of the 3'- and 5'-hydroxyl groups by fluoride.
A
N' CH I II CH o;cC\N/ HOCH2 \cgO\IH
I
HO-CH-CH2
N'
(i-Pr)$icl * imidazole, DMF,22 h under N2
II *I O+C\N/ CH (i-Pr)giOCH2 C 'H
I
A CH
I
/'\IH
(i-h)3Si0 -CH-CH2
(193)
I
51%
1
Ph3PBH2CN. dry THF,N2 2.5 h, reflux
A ' ;c\
NCBN
CH II CH
I
0
Bu4NF
NCBN
THF, RT, 0.5 h
A '
CH 11 CH
(76)
'N
(192) 81% specific activity 1.67 mCimmol-'
70%
Commercially available [2-'4C]-2'-deoxycytidine, 193, having specific activity of 20 mCi mmol-' was diluted with unlabelled 193 to specific activity of 1.67 mCi mmol-'.
9. Synthesis of carbon-14 labelled Cl-926 and CI-927
The new antihypertensive agents 194 and 195, which function in part through interaction with a-and re no receptor^'^^, have been '4C-labelled'99 in three steps starting from ethylene-14C, oxide (equation 77). The overall radiochemical yields for 194 and 195 were 69% and 62%, respectively, and the specific activities of both compounds before final dilutions were initialy 22.6 mCi mmol- '. The unlabelled primary amines 196 and 197 have been prepared according to equations 78 and 79.
20. Syntheses and uses of isotopically labelled enamines
*/0\ *
+
R1
1179
A
Heating-
H2C-CH2
NHCH2CH20H
R1
H2 0
(194) R1 = Me; R2 = - ( c H ~ ) ~ -N
9
0
94% radiochemical yield radiochemical purity > 98%
0 II
ACHI CH II
(195) R1 = OEt; R2 = -(CH2)4NH-C,n,C,-Me
I
radiochemical yield C* = 14C-label
1
I . Raney cobalt, H2 ( 1 50 psi)/DMA 2. HCI, 100°C. 17 h
Mieczyskaw Zielinski and Marianna Kanska
10. Synthesis of 4-(2-hydroxy-3-isopropylaminopropoxy)-2-methyl-[2-14C]indole sulphate (798)
The title compound, mapindolol 198, a potent P-adrenoceptor blocking (antihypertensive) agent, has been synthesizedZo0by the Madelungs method of indole synthesis using [1-14C]acetyl chloride as starting material (equation 80).
& -& OCH3
OCH3
*+o
CH~&CI
NH2
N
/c,
H
NaNH2 215°C. under l hN2
-
/
CH3
H
\
CH3
+
NaOHiBu4NH S04.RT, I h
OH I OCH2CH-CH2NHCH(CH3h I
/O\ OCH2CH-CH2
I
(198) 69%, radiochemical purity > 97.9% spccific activity 2.06 GBq (55.8 mCi mmol-I)
The final product 198, which has been stored in EtOH at - 20 "C, had shown a 15% decomposition (14.36 mCi ml- ') after three months. 11. Synthesis of 3-benzylamino-8,9-dimethoxy-5,6-dihydro[5,l-a] isoq~ino/ine[5-'~C] hydrochloride 199
This antiarrhithmic and hypotensive agentz0' has been synthesizedzo2in eight steps (equation 81) in 5.3% total radiochemical yield.
1181
20. Syntheses and uses of isotopically labelled enamines
The drug 199 labelled with 14C at C(2,position of the imidazole ring (199a) has been obtained also202 but the metabolic invest~gationsshowed that the imidazole ring opens and radiocarbon had to be incorporated into the isoquinoline ring according to equation 81.
I ""mC:2 NH20H.HCI NaHC03, ELOH, 22 11 mflun
H2
H2
7&80"C, AczO 3 h
yH
Me0
//NOH
CH2C\ NH2
* M e 0e 0 ~ ~ ;II ~ c I I / N H 2 HC-N PhCHO, n-BuOH
1
120-125°C, 45 min
MeO)g;ec, -MeO)Q(cie Hz
Hz
& H ~ C H ~ P Pdm2 ~
Me0
C II
II
Cl-
HC-N (199) 73% step yield, total activity 14.7 mCi, specific activity 4.74 mCi mmol-'
Me0
C II
HC-
C I I /N=CWh
N
1182
Mieczyslaw Zielinski and Marianna Kanska
12. Synthesis of [2-'4C]tetramethyluric acids
Tetramethyluric acids 200,201 and 202 14C-labelled at C,2, have been synthesizedzo3 by methylation of [2-14C]uric acid (specific activity 5 1 mCi mmol-') with dimethyl sulphate at pH 9 (during 22 h), in 44.9%, 4.4% and 6.3% yields, respectively, in order to study their mode of action on the genetic materia1204and to elucidate their metabolic fate in caffeine-containing plants205,206 or in mammals.
13. Synthesis of the muscle relaxant ['4C]L-637,510
This potential muscle relaxant 203 has been labelled with 14C in the 3-position of the N,N-dimethylamino-1-propylside chain in eight steps shown in equation 82 starting from [14C]cyanide, with an overall radiochemical yield207of 4.8%. HOCH2CH2Cl
N~CN
*
HOCHzCH2CN
HCI
*
CICH2CH2COOH
-
I . HCI * ----Me2NCH2CH2CH20H 2. S0Cl2
Me2NH
1 *
C1CH2CH2CH20H
1. Me2CHCH2MgBr (for neutralization) 2. Mg. 2 h reflux
7
*
Me2NCH2CH2CH2MgCI
JVVVVVVV.
(204)-E 63% from 205
preparative silica HPLC
\c/ *I I
H-CCH2CH2NMe2
JVVVVVVV.
+
\c/ Me2NCH2CH2C-H II*
20. Syntheses and uses of isotopically labelled enamines
II* Me2NCH2CH2-C-H.H
H \
,C=C
HOOC
H
1
\
COOH
(203) [14C]L-637.5 10 63% step yield, 4.8% yield for eight steps
c* =14c
14. Synthesis of '4C-labelled pyrimidoxime
This drug 206 used for detoxification and regeneration of active acetylcholinesterase sites of enzyme, after poisoning with toxic organophosphoric compounds208, has been '4C-labelled209 in 50% yield as shown in equation 83.
CH-N/ II I CH /,CH 'N
Me Br(CHz)@ AcOEt, 25 "C
-
CH-N' II I CH +,CH
'y"
Me Br
CH3CN, 50PC, l week
(45 mCi)
(206) specific activity 9 mCi mrnol-' (333 MBq mmol-I * c = '4C
Pyridine['4C]-aldoxime-4, 207, has been synthesized starting from [14C]sodium formate (equation 84).
Mieczyslaw Zielinski and Marianna Kanska
-0.' CH3
H ~ O O N+~ D N H C H 3
\*
CHO
NH20H.HCI
(84)
K2C03,EtOH, overnight
(207) 90% step yield
80% step yield
Quaternary salts H16 (208), TMB-4 (209) and R665 (210) labelled with 14C in the hydroxylimino group have also been prepared2'' by formylating the pyridinium lithiated intermediates with N-methyl '4C-formanilide.
15. Synthesis of 3-amin0-l-methyl-9H-[4-'~C]pyrido[3,4-b]indole The title compound, 3-amino[4-'"Clharman, 211, found to have synergistic and co-mutagenic effects in bacterial mutation2", has been synthesized2" in seven steps starting from DL-[methylene-'4C]tryptophan, 212, and acetaldehyde (equation 85).
16. Synthesis of S-(2-carboxyethyl)-N-(2-t-buty1-5-methoxybenzthiazo1-6-y/)['4C]dithiocarbamate [CGP 20376 (CGI 16483)] This compound, 213, exhibiting potent micro- and macrofilaricidal activityzL3in rodent, cattle and man, has been L4C-labelledat the dithiocarbamoyl carbon in the side chain at 6-position of the benzthiazolyl ring system214 in four steps starting with potassium [L4C]thiocyanate (equation 86) in an overall radiochemical yield of 45%. The stability of 213 in different solvents has been investigated. It is unstable in solvents
1185
20. Syntheses and uses of isotopically labelled enamines
1
MeOH conc. H2S01. 12 h reflux
Hz sulphur, dry xylene 160°C. 6 h
AH::: ,=
""'-
,COOMe CH
CH
I
H
Me
Me
1 1
1 . H2NNH2 n-pentanol, EtOH, H20, 5 h reflux
2. NaN02, conc. HCI ODC,30 min
-0
NHCOOC+Il I
xylene, n-pentanol
O
N H
Me
130°C. 30 min
O
N
Me
I
KOH, BuOH, H20 3 h reflux
(211) 17.7% starting from 212, specific activity 0.93 mCi mmol-', radiochemical purity ca 92%
Mieczyslaw Zielinski and Marianna Kanska
1186
Me0
SC*N
Me0 /
Bu-t
-
xylene, reflux
CGP 20308
A
H~NC*NH II
Bu-t
S
+
byproducts
I
HSCH2CH2COOH, DMF under N2, RT, overnight
(213) [14C]CGP20376lCGI 16483 specific activity 6.13 pCi mg-I
such as DMF, MeOH, acetone or MeCN. The 14C-dithiocarbamate 213 has been used for pharmacokinetic and metabolism studies in laboratory animals. 17. Synthesis of carbon-14 labelled 6-(4-fluoropheny1)-5-(4-pyridy1)-2,Sdihydroimidazo[2,1-blthiazole (SK&F 86002)
SK&F 86002, 214, is a non-steroidal anti-inflammatory agent used for treatment of rheumatoid arthritis and acting also as immunomodulatory agent215.2'6.It has been labelled2" with 14C at C(', or at C,,,,, using either [14C]thiourea or 1,2-dibromo[14C]ethane, according to a synthetic route which involves condensation of an asymmetric benzoin with [I4C]thiourea followed by alkylation and chromatographic separation of two structural isomers 214 and 215 (equation 87). The use of 1,2-dibromo[14C,]ethane as the labelling reagent in the final step of the synthesis, providing greater overall radiochemical vield. is refera able. . , Flash chromatography and recrystallization gave the desired SK&F 214 in 17% final purified radiochemical yield with a specific activity of 16 mCi mmol- and radiochemical and chemical purities >YY%. No change of radiopurity was found in a solid sample of 214 stored under argon at - 25 "C during 6 months. -- ~
~- -
-
~~~~
----
~~~~
,
L
'
18. Synthesis of '4C-labelled perlinone
Perlinone 216, a potent inotropic agent selected for clinical development2", has been labelled219 with carbon-14 as shown in equation 88 in an overall combined yield of 15.6% from [14C]sodium cyanide, at specific activity 66.2+ 1.5 pCi m g and 98.8% radiochemical purity.
'
20. Syntheses and uses of isotopically labelled enamines CHO
1187
PhCOO-CHCN
R' = =O or PhCOO R2 = PhCOO or =O
R1 = (=O) or PhCOO R2 = PhCOO or (=O)
ClCH2COOH
Na*CN
*
NCCH2COOH
II
NH II CH3CNH2.HCI
*
II
c /c\ H ~ C / 'N H
*
NCCH2COOEt
1. CS2, KOH
n N
EtOH
SMe
2. DMS,dimethyl sulphate
I MeS
\
;N
,c=c1
MeS
\
COOEt
Mieczyslaw Zielihski and Marianna Kanska
1188
19. Synthesis of 2-(difluoromethyl)-4-(2-methy/propyl)-5-[(methylthio)carbonyl]6-(tr~fluoromethyl)-3-pyr~dine-[4-14C]-carboxylic acid 218
Dithiopyr 217, an experimental herbicidal candidatezz0, is metabolized to several acidic metabolites including the title compound, the monoacid 218 (equation 89), which has been synthesized in four steps (equation 90), in order to complete the metabolism studies required for dithiopyr registration.
0
CHz-Pr-i I MeSCXQfSMe II
II
0
cF3
CHz-Pr-i I
0
II MeSC
KOH EtOWH20
CF2H
CF3
20. Synthesis of [Z-14C]penem antibacterials (FCE 22101 and FCE 22891)
Penem[2-14C] FCE 22101, 219, a p-lactam antibioticzz2,has been synthesized223in eight steps in overall radiochemical yield of 21 %, 98% radiochemical purity and specific activity of 641 MBq m m o l l (17.3 mCi mmol-') using sodium salt of [l-14C]glycolic acid as the starting labelled material (equation 91). The acetoxymethyl ester FCE 22891 220 has been prepared in 41% yield by condensing 219 with bromomethyl acetate.
0
II
MeSC
CH2-Pr-i I CSMe
0
II
CIC
CHz-Pr-i
I
0
RT
CF3 MeSH ( I equiv.) EtlN
0
CH2-Pr-i
0
II
CIC
(218) 43% overall yield, specific activity 29.2 mCi mmol-'
CH2-Pr-i
I
20. Syntheses and uses of isotopically labelled enamines OH
I I
CH2
Me-CH
8 steps +-++-+++
0
C*OONa
N-C-COONa
(21%
21. Synthesis of 7-[ac-(2-aminothiazoI-4-yl)-oc-(Z)-methoximinoacetamido]-3(l-['4C]methylpyrrolidino)methyl-3-cephem-4-carboxylate sulphate 221
The sulphate salt of the title quaternary compound, cephalosporin, 221, showing high antipseudomonal activity, has been ~ ~ n t h e s i z e in d six ~ ~steps ~ . ~for ~ ~metabolism and pharmacokinetic studies (equation 92).
*
(100 mCi) HCOONa
+ CIOCCH3
N-C II
-n
*
HC-0-C-CH3 II II O O N - OMe II ,C-C-NH II II 0
Ph3CNH ,C,S/CH
NI
*CHO 80% 225
0
II
'CH-CH 4CH2
I 05C-N
I
I
'c+ C'CH~I I c=o I OCH Phz
(222)
I-
N
3-CH~ 'ZH~,
LiAIHl
1
n N
*CH3 I
Mieczyslaw Zielinski and Marianna Kanska 1. HCOOH 12. HCI
N-C
II
H~N'
C
,C-C-NH II II 0 CH
'S'
'CH-CH /S\ CH2 I I I C O+C-N, C+ CH2
-.
I
I
*
(221) 97% radiochemical purity specific activity 21.7 pCimg-'
22. Synthesis of 5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline-2,3-i4C2 This compound, 223, a potent and selective cc,-adrenoceptor agonistZz6used also in studies of v a s o c ~ n s t r i c t i o ,n has ~ ~ ~been ~ ~ ~obtainedz2' ~ according to the reaction sequence of equation 93. This involves oxidation of high-specific-activity paraldehydeI4C, with selenous acid to ethanedial-1,2-'4C, which was condensed directly with 1,2,4in 56% yield, bromibenzenetriamine dihydrochloride to 6-quino~alin-2,3-'~C~-amine nation of 224 and conversion of 225 to its isocyanate 226 by reaction with thiophosgene, and finally the reaction of 226 with ethylenediamine in refluxing 1: 1 methanol-toluene. The overall radiochemical yield of 223 was 11% starting from paraldehyde-14C,. The radiochemical purity of the tartrate 227 was 98.2%, specific activity 101.5 mCi mmol- I .
23. Synthesis of carbon-14 labelled spiro-piperidyl-rifamycins (LM 118) and rifabutin (LM 427) These two rifamycins S antibiotics 228 and 229 showing a promising activity against atypical Mycobacterium tuberculosis strains230 have been 14C-labelled in five steps (equations 94) and in three steps (equation 95), re~pectively~'~. The radiochemical purity of [14C]LM 118 was 98%, the overall radiochemical yield from *CH,I was 19.8% and the specific activity 440 MBq m m o l ' (11.9 mCi mmol-I). The radiochemical yield of 229 from 231 was about 38% (13.35 mCi, 493.9 MBq), the radiochemical purity 97% and the specific activity 34.32 mCi mmol-I (1.27 GBq m m o l 'I.
24. Synthesis of 3-cyan0-4-methyl-5['~C]methyl-2-[5-'~C]pyrrolyloxamicacid 232
Compound 232 has been obtainedz3' in 19.7% overall yield from uniformly labelled 14C-L-alanineaccording to the reaction scheme of equation 96. The acid 232 had specific activity of 66.7 pCi mmol-I and radiochemical purity of 98% as determined by radio-
20. Syntheses and uses of isotopically labelled enamines
*
0\ *
H$,c~/
I
0
C' H'
* lCH3
CH I 0
+
HzSeo3
70°C. 18 h stirring dioxane, 50% aq. HOAC*
I
*CH~ (42.8 mCi, specific activity 324 mCi mmol-')
'
* *
OHC-CHO 3 1.9 mCi, 74% radiochemical yield
10% aq. NazCO,, 2 H c l H 2 N ~ N H ;9 o 0 19 h
Brz, AcOH
N
N
(225) 14.8 mCi, 82% radiochemical yield CIzC=S, NaHCO,
1
H20/CHCl3, RT. 14 h under argon
HzNCHzCHzNHz 1:1 tolueneMeOH, 7 5 T , 18 h, under AI
(226) 9 mCi, 61% radiochemical yield
. (223) 4.7 mCi, 52% step radiochemical yield, 1 1 % overall yield
/
HOOCCH(OH)CH(OH)COOH MeOH, RT, 18 h
(227) 48% radiochemical yield
chromatographic scanning of TLC plates. Compound 232 was found to possess antlallergic activity233. The aminoketone (233) has been prepared by the method of Wiley and B o r ~ m and '~~ the amine-substituted pyrrole 234 according to the method of G e ~ a l d ~ ~ ~ .
Mieczystaw ZieliAski and Marianna Kanska
I
I
I
,CH
AcOCH
I
I
I
OH
MeCH
,CH
II CH
OH
\
/
HCOMe
CH II ,C\
H N,
C II 0
Me
Me
(228) R = &e (LM 118) * (229) R = -CH2CHMez (rifabutin) Me
I
,CH,CH,CH AcOCH I I OH MeCH
Me
Me
I
I
,CH 'CHI
OH
\CH
II
CH
25. Synthesis of 2-hydroxymethyl-l-methyl-4-nitro-5-imidazolcarbonitrile-45-
14C This compound, 235, has been synthesized236in 10 steps in 17% overall radiochemical yield starting from 0xalic-l,2-'~C acid (equation 97) for investigation of new substances controlling coccidiosis. 26. Synthesis of l-{4-[3(N-methyl-N-2-[3,4-dimethoxypheny/]ethyl)[3-'4C]propoxy]benzosulphonyl)-2-isopropyl indolizine Drug SR33557 236, possessing calcium channel blocking a c t i ~ i t y ~ and ~ ' . ~of~ ~ interest in the treatment of cardiovascular pathologies, has been prepared239in a six-step synthesis in an overall 3.8% yield starting from sodium [14C]cyanide (equation 98).
20. Syntheses and uses of isotopically labelled enamines
LiAIQ
~ - O ~ N - ~ N - P o C H M e ~ CH2-0
1193
r-"~ *
N-CH2CHMe2
CH2-0
(231) 35 mCi, 0.42 mmol
230
229
* *
* *
;H~CHCOOH
I
NH2 specific activity
A C ~ OP, ~ I
9&1W°C, 8 h stir
CH6HCOCH3 I NHCOCH, (233)
*
OCN-CHzCHMe2
(95)
-H~C*H3c'JCH*CN~
N H
NH2
H3CnCN H3cn ~~z 2. I . 5% 2 N NaOH HC1
N H
NHCOCOOH
H~?
N H
(96) NHCOCOOEt
1194
Mieczyskaw Zielinski and Marianna Kanska
* Me CIC-N' I 11 * /c, ,c OzN N' 'CHZOH
AC~O
HOAc
* Me CIC-N' I II * 0 2 /C\N'C\CH20Ac ~
1
KCN DMSO
NC,
*
Me
c-N '
II I c * /C 0 2 N / \ N / \CHZOH
anh NH, MeOH
+ NaI4CN 40 mCi
Me C-N' II I C* / C O ~ N / \N/ \CH~OA~
(97)
*
(235) radiochemical purity > 99%
H2C-CH2 \ / 0
*
. NC,
C = I4C label
-
HOCH2CH2I4CN
HCI
C1CH2CH214COOH
1
S0Cl2
I
CICH2CH214COC1
20. Syntheses and uses of isotopically labelled enamines
S02C6H40H-p I HC+C,C+C,C/C"Me2 DMSO,K2C03, RT, stir, 72 h I I II HC, ,N-CH 'C H
H
t
OMe
H
(236) 15 mCi (555 Mbq), 98% radiochemical purity
(237) DTIC
27. Synthesis of 5-(3,3-di['4C]methyl-7 - t r i a z e n o J i m i d a z o l DTIC
This compound, DTIC, 237,has been preparedz4' on micro-scale in 67% yield starting with 5-180 pmol of di[14C]methylamine of high specific activity and with an excess of the diazo precursor (equation 99) employing a vacuum technique. The 14C-labelled DTIC has been used to investigate the decomposition mechanism and the biochemical fate of 237, which possesses an anti-tumor activityZ4l. 5.5 pmol of pure DTIC of 10.8 MBq total activity has been obtained, if dimethylamine of specific activity 2.15 GBq mmol-I is used.
1196
Mieczystaw Zielihski and Marianna Kanska
28. Synthesis of ['4C]flupitrine maleate labelled in the pyridine ring
This centrally acting analgesic agent242, ethyl 2-amino 6{[(4-fluoropheny1)methyll amin0}-3-p~ridin~l-2,6-'~C carbamate maleate, 238, has been '4C-labelled243 in nine steps starting with potassium ~yanide['~C]and 1,3-dibromopropane (equation 100).
*
BrCH2CH2CH2Br
KCN
*
*
NCCH2CH2CH2CN
AcOH, H+
H~C;/ ,c*
0'
CHCOOH II CHCOOH
(238) 6.3%overall yield (5.4 mCi), radiochemic& purity 99.8%
H2 C 'CH~ I*
'N
,C*
I
0
20. Syntheses and uses of isotopically labelled enamines
1197
29. Synthesis of ['4C]stano~olol
Stan~zolol~ 239, ~ ~ used , in treatment of lipodermato-sclerosis and other disorders, has been labelled with 14C in the pyrazole ring in overall 62% yield245 by reaction of 17a-methylandrostanolone 240 with ethyl[14C]formate, which gave intermediate 241, and on treatment with hydrazine hydrate gave the product 239 (equation 101).
C. Carbon-11 Labelled Compounds 1. Synthesis of carbon-1 1 labelled 1,Cdihydropyridines
Carbon-1 1 labelled calcium channel antagonists IIC-nifedipine, "C-nisoldipine, IICnitrendipine and "C-CF,-nifedipine possessing vasodilating and hypotensive -properties have been synthesizedz4' using a modified ~antzsch-typecyclicondensation proced ~ r e ' ~ ~ , 'Condensation ~'. of aldehydes 242, 243 and 244 with 3-aminocrotonic acid esters 245,246, 247 and with acetoacetic ester 248 produced in 'one pot' after 12 hours reflux in dry ethanol the methyl sulphonylethyl protected dihydropyridines 249-252. Deprotection of the carboxylic acids by alkaline hydrolysis followed by conversion into the dihydropyridine monocarboxylic acids 25S256 gave potassium salts in situ, and subsequent methylation with "CHJ produced the corresponding labelled title compounds 257-260 (equation 102). The precursor 2-(methylsulphonylethyl)acetoacetate 248 has been prepared in the reaction sequence of equation 103.
Mieczydaw Zielinski and Marianna Kahska
1198
Q a:" CHO
1
0
MeOCCH=CCH3 0 II NH2 I
(242)
(244)
(243)
(245)
NH2 I i-PrCH20CCH=CCH3
EtOCCH=CCH3
0 II II MeSCH2CH20CCH2COMe 0 II
(246)
(247)
(248)
0
0
II
C6H4R1 I "CH300CxCHxCOOR2
0
NH2
I
II
-
"CH$
C6H4R1 I K O O C ~ C H ~ C O O R ~ (102)
phase transfer conditions
Me
(257) (258) (259) (260)
N Me H R1 = o-NO2, R2 = Me R1 = o-NO2, R2 = CH2F'r-i R1 = m-NO2, R2 = Et R1 = o-CF, R2 = Me
Me
N H
Me
2. Synthesis of "C-pindolol
100 mCi of pindolol (4-[2-hydroxy-3-(isopropylamino)-propoxy] indole)261 has been obtained248 from 1.5 Ci of llCO, in 30 minutes after the end of bombardment of N, with 20-MeV protons during 30 minutes in the reaction sequence of equation 104, which involves the preparation of ["Clacetone followed by its reaction with DL-2-hydroxy-
20. Syntheses and uses of isotopically labelled enamines
14N(p,a)I1C
0 2 (present in target)
llCOZ
-
'
-
Me OLi Hz0 11C / \ . Me OLI
MeLi
Me. \ 1lC=O / Me
OH
Me O C H ~ C H C H ~ N\ H L ~ ~ Me
I
&,E
* NaBH3CN
H
(261) specific activity 60CL1000 mCi pmol-I
3(4-indoly1oxy)propylamine and reduction of the imine 262 with c y a n o b o r ~ h y d r i d e ~ ~ ~ to give DL-pindolol261. Pindolol was found convenient for PET studies because of its high affinity for the /3-adrenergic receptor and the lower liposolubility compared with p r o p r a n o l 0 1 ~ ~ ~ ~ ~ ~ ~ . 3. Synthesis of "C-labelled 5-hydroxytryptamine
The title compound, 3-/3-aminoethyl-5-hydroxyindole (HT), 263, "C-labelled in the P-position of the ethyl group, has been synthesized252in three steps (equation 105) involving the reaction of ["Clcyanide with 5-methoxygrarnine methylsulphate 264 to give [11C]-5-methoxy-3-indoleacetonitrile265, cleavage of the methoxy group with boron tribromide and reduction of the obtained intermediate product 266 to give ["C]5-HT, 263, in 13% overall radiochemical yield. After a 78-min procedure, 410 MBq of 263 with specific activity of 5.1 GBq pmol-' and radiochemical purity >99% were ready for injection and use for external non-invasive measurements of uptake of amines by the lungs damaged in patients with Adult Respiratory Distress S y n d r o ~ n e ' ~ ~ . ~ ~ ~ .
4. Radiosynthesis of I-["CI-methyl-9-[(2-hydroxyethoxy)methyl]guanine (["C]-N-methylacyclovir, MAC)
This selective and potent analogue 267 of the anti-herpes drug acyclovir 268 inhibiting HSV-1 and HSV-2 herpes simplex virusesZS5has been "C-labelledzS6 for the noninvasive detection of HSV encewhalistic wine wositron emission tomoerawhv, . (PET). 1-Methyl-9-[12-hydroxyethohy)methyl]guandine267, has been prepared by methylation with ["Cliodomcthane, the conjugate base of xyclovir 268. generated at - 70 'C in D M F ~ i t h ~ t e t r a b ~ t ~ l a m m o nhydroxide ium~ (equation 106). The average isolated radiochemical yield of 267 was 20% based on ["Cliodomethane, average specific activity 955 mCi pmol-' at the end of synthesis and radiochemical purity >98%.
.
-
8
- .
Mieczyslaw Zielinski and Marianna Kanska
1ZOO
Me0
+ ,CH2NMe3
Me0 Me2S04 THF, < IOT
*
H
m
/
:
H 11
-0S0,Me
H
5. Synthesis of 1-["C]alprazolam Alprazolam, 269, a popular sedative/hypnotic agent and benzodiazepine receptor agonist, has been labelled2s7with "C in metabolically stable position in reaction of the amidrazone, 7-chloro-5-phenyl-3H-1,4-benzodiazepine-2-yl hydrazone, 270, with 1["Clacetyl chloride followed by pyrolysis of the resulting 1-acetylhydrazone 271. Compound 269 has been obtained in 43-65% yield during 40-55 min at specific activity 0.93-218 Ci pmol- ', and used for metabolism and tissue distribution studies2s7(equation 107). 6. Synthesis of ["C]Ro 15-1788(flumazenil)
The antagonist [methyl-llC]Ro 15-1788, an imidazodiazepine 272, high-affinity and high-specificity ligand for the central benzodiazepine receptor used in PET2", has been synthesizedzs9 by reaction of ["Clrnethyl iodide with the desmethyl precursor2" and
20. Syntheses and uses of isotopically labelled enamines
;02
MeMgBr
*
MeCOzMgBr
phthaloyl dichloride DMP, THF, B4..C
M~?OCI
I
appliedz59 for the determination of the percentage of unchanged 272 with respect to total radioactivity in blood radioactivity decrease determinations in PET studies. A conclusion has been reached that only ["C]Ro 15-1788, 272, and its acid metabolite [llC]Ro 15-3890,273 (equation log), and no other radioactive compounds, are present in blood at detectable concentrations.
7. Synthesis of 9-["C]methylamino-1,2,3,4-tetrahydroacridine
This potent acetylcholineesterase inhibitorZ6l 274 has been obtainedz6' by methylation of tetrahydroacridine with ["Clmethyl iodide after deprotonation by sodium hydride in DMSO at 100 "C in 45 min total synthesis time from end of bombardment (EOB) (equation 109). 8. Synthesis of 2-["C]cyanoisonicotinic acid hydrazide
Isonicotinic acid hydrazide (isoniazid 275), a drug used in treating tuberculosisz69, has been 11C-labelled264by introduction of a ["Clcyano group at the 2-position of the pyridine ring of I-methoxy-4-methoxcarbonylpyridinium methyl sulphate and subsequent treatment of the "C-labelled methyl ester 276 with hydrazine hydrate. The reaction has been carried out on a solid support (silica gel) to yield methyl 2["C]cyanoisonicotinate in 32.4k 12% (EOB) yield. 275 was obtained in 10% (EOB), radiochemical
Mieczyslaw Zielinski and Marianna Kanska
I
llCH31 DMSOIDMF,100DC, 10 mirl
HNlLCH3
(274) specific activity 35 GBq pmol-'
COOMe
& J N
-6 -& COOMe
COOMe
I
llCN (276)
0
1
NH>NHz, H20 EtOH
CONHNH2
I
(275) 100% radiochemical purity
yield during approximately 35 min (equation 110) and used to differentiate between glioma (tumor) and tuberculoma (infection) by computer tomography (CT).
9. Synthesis of ["C]buprenorphine (BPN) BPN, a potent opioid partial a g o n i ~ t ' ~277, ~ , has been labelled with carbon-1 1 at the 6-methoxy position, ["C PPN], using a precursor 278 synthesized in high yield (89%) from BPN 277 in two stem (equation l l l a ) and employing ["Cliodomethane as the * . radiolabelling reagent266(equation 1lb). The ["cIBPN is ready for use in cerebral opioid receptor studies by PET within 24 minutes from EOB, including radiosynthesis, purifications, formulation for in vivo injection and specific-activity determinati~n'~~. ~~
20. Syntheses and uses of isotopically labelled enamines
H O - ~ ~ C M ~ ~ Me BPN (277) t-BuMe2SiO
CH-CH2
I
I1CH3I
HCI (aq.)
NaWDMF
HPLC
HO
(Illb)
(277) ["CIBPN 97% radiochemical purity, specific activity 41 GBq ymol-' (1 120 mCi ymol-', 10% radioactivity yield at the end of synthesis
10. Synthesis of ["CI-labelled N-methylketanserin
"C-N-Methylketanserin 279, the analogue of serotonin-2 receptor antagonist, ketanserin 280, has been synthesizedz6' for studying these receptors in vivo using PET by alkylation of ketanserin in DMF solution in the presence of small amount of aqueous tetrabutylammonium hydroxide at 80 "C for 2 minutes followed by chromatographic purification during 22 minutes total synthesis time from EOB, with 10% radiochemical yield calculated at the end of synthesis (EOS). The specific activity of 279 was 1835 mCi p m o l ' (3670 mCi pmol-' at EOB). In vivo rodent studies showed that 279 accumulates selectively in the cerebral cortex rich in serotonin-2 receptors, which may play an important role in neurode generative disorders.
Mieczystaw Zielinski and Marianna Kanska
I I . Synthesis of 2-ethyl-8["C]methyl2,8-diazaspiro[4,5]decane-1,3-dione (["CIRS 86)
["CIRS 86,281, a muscarinic acetylcholine receptor agonist, has been synthesizedz6' from nor-RS 86 (R1 = H, R2 = Et) and ["CICHJ in 5-7% yield with specific activity 15S170 mCi m m o l ' . The biodistribution of 281 in rats has been studied and a 1.1% uptake of injected dose of 281 per organ at 5 min has been observed, which decreased to 0.62 at 30 min.
0
//
RI-N
nr f \
0 R2 (281) RS 86 R' = "CH3, R2 = Et radiochemical purity > 98%
12. Synthesis of "C-labelled N-methylparoxetine
This potential radioligand 282b for studying serotonin uptake sites using PET has been prepared by 'lC-N-methylation" of paroxetine 282a in D M F at 80 "C for 2 minutes.
bhF-p (282a) R = H (282b) R = " C H ~ specific activity 1300 mCi pmol-I at the end of synthesis 3800 mCi pmol-' EOB overall radiochemical yield 15%
20. Syntheses and uses of isotopically labelled enamines
1205
13. Synthesis of llC-labelled prazosin
The antihypertensive drug prazosin 283 has been labelled270 with "C by reacting "C-labelled methyl iodide with desmethylated compound 284 prepared from 283 .HCI by stirring it with 1.1 equivalent of BBr, in CH2C12under N2 (equation 112). The specific activity of 283 10 min after the end of a 25 min synthesis was 3500 Ci mmol-'.
NH~HI "C-(283) 99.9% radiochemical purity 0
OMe
(287) 2. "CH31. 140°C, 7 min
0
(285) 40% radiochemical yield, 98% radiochemical purity, specific activity 200 mCi mmol-I
1206
Mieczyskaw Zielinski and Marianna Kanska
14. Synthesis of ["C]clebopride
This selective D, receptor antagonistZ7' 285 has been s y n t h e s i ~ e d ~by' ~O-demethylation of clebopride 286 with boron tribromide in CHZC12 at RT, and subsequent methylation of the norclebopride 287 with [llC]methyl iodide (equation 113). Tissue distribution of 285 in rats after intravenous administration of ["Clclebopride with low specific activity of 200 mCi mmol- ' confirmed the brain activity uptake.
15. Synthesis of ["C]sodium thiocyanate and [isopropyl-"C]nimodipine 288 These compounds have been s y n t h e s i ~ e d ~to' ~ study in vivo the kinetics of C a Z + , Na ', K t and C1- ion flow by ion channels through lipid environment of the membrane, and the physiological control of the opening and closing of C a Z + and C1- channels. [llC]SCN- has been radiolabelled (equation 114) in order to study C1- transport into brain cells274by the PET method. NaLICN
S,H z 0
-
100°C, 10 min
NaS1ICN
Nimodipine 288 has been labelled with "C in order to study the density of the L-type calcium channels and the dihydropyridine binding275"~275b sites (equation 115) with the PET techniqueZ7".
HOOC,
c
C6H4NO2-m I ,CH, R
II
Me/C'N/
c"
II C
-.Me
MezllCHOOC, Mezl'CHI
c
c6H4No2-m I ,CH R
'c'
II II (115) C C ~ e /'N' ' ~ e H (288) 40%
DMFIDMSOrnP (80120)
H R = -00C(CH2)20Me TMP = 2,2,6,6-tetramethylpipendine 16. Synthesis of 17C-labelled4-dimethylaminoantipyrine
The title compound 289, used in clinical investigations on liver function2", has been 11C-labelled278~279 in order to observe the liver transplants by PET (equation 116).
I O+C/N,N/CH3
I I1CH3I (800 mCi)
1.0.4M NaOH, 70°C, 30 min CH3NH
CH3
17. Synthesis of racemic, (
2. chromatography
+ )- and ( -
0+C/N,N/CH3
*
(116) 1'CH3N
CH3 \CH~ (289) 98% purity 120 mCi at 50 min after EOB
)-N-(methyl-"C)nomifensine
Compound 290 needed for evaluation of monoamine re-uptake sites by PET, and a promising marker for evaluation of the pre-synaptic nerve terminal, has been synthe-
20. Syntheses and uses of isotopically labelled enamines
1207
sizedzg0 by N-alkylation of the corresponding N-desmethylnomifensine 291 using "CHJ (equation 117).
78. Synthesis of "C-labelled radiopharmaceuticals in N-alkylation reaction with "C-methyl iodide
Several "C-labelled radiopharmaceuticals have been preparedz8' by Lingstrom and coworkers by N-alkylation reactions with "C-methyl iodide, carried out in DMF as demonstrated in equation 118.
They include N-["Clmethyl-4-phenyltetrahydropyridine (MPTP, 292), apomorphine 293, clozapin 294, mepivakain 295, hydromorfon 296, and zimelidine 297 in S&80% yields with respect to "C-methyl iodide and with better than 98% radiochemical purity. N-["C]methylketanserin 298 and N-[llC]methyldexetimide 299 have also been synthesized by this method.
The LC-purification of 299 has been simplified by addition of n-heptyl iodide, CH,(CHz),I, to the post-reaction mixture in order to decrease the amount of the unreacted precursor.
Mieczystaw Zieliliski and Marianna Kanska
19. Synthesis of ["C]rnesulergin
Mesulergin 300, a selective ligand for the serotonin-2 receptor282(related to a number of neurological diseases), has been labelledz83 with "C in N(,, by reaction of N,,,desmethyl-300 with "CHJ. The yield (decay corrected) was 4&50% after a synthesis time of 30 min. Up to 12 mCi of 300 have been prepared at specific activity lOCi mmol- '.
20. Syntheses and uses of isotopically labelled enamines
1209
20. Synthesis of [iiC]-benzodiazepine (BDZ) ligands
Flumtra~epam[~'C]301, RO 15 1788-["C] 302 and PK 11 195["C] 303 have been synthesized by methylation of their nor-derivatives using [llC]CH,I precursor284. A total time of 30 minutes has been required to obtain compounds 301-303 (from the EOB of nitrogen with 20-MeV protons to yield 185 mCi of l l C with a mean specific activity of 1.9 Ci pmol-') ready for administration into a baboon Papio for PET studies of central and periferal receptors.
21. Synthesis of "C-labelled indolealkylamines
Indolealkylamines, [llC]-dimethyltryptamine ("C-DMT, 304), [llC]-5-methoxyN,N-dimethyltryptamine ([llC]-5-OMe DMT, 305) and ["CI-bufetenine 306, known to have hallucigenic properties285and expected to serve as potential serotonin-1 receptor mapping radiopharmaceuticals, have been synthesized286(equation 119) in 46%, 18% and 8.9% overall radiochemical yields, respectively, with average specific activity of 63 Ci mmol-I at the time of use. Tissue distribution of these ["Clradioalkylamines has been studiedZa6and it has been found particularly that 304 (["CI-DMT) has the highest brain uptake, while ["Clbufotenine 306 has the lowest since the 5-hydroxylation of indolelalkylamine inhibits the transport through the blood-brain barrier. 22. Sonification as a method of methylation
The use of sonification in reactions 12LL123 involving short-lived carbon-1 1 increased markedly the yield and reduced the reaction time^^^'.'^^.
Mieczyslaw Zielihski and Marianna Kahska
"CH,I
1
I . acetone, 60°C 2. HPLC
H (304) R = H (305) R = OMe (306) R = OH
~ ~ C H + NaN02 ~ I
UMF a, IOOoC,
or
b. ultrasonic Branson 450 W
-
11CH3NO~
(120)
a. 35% b. 80%
I
KOH, Kryptofix 222 THF-10% HMF'T a. 60°C, I5 mi0 b. ultrasound RT. 15 min
Ranitidine a. 0% b. 15%
,
+
cH31
Toluene, KOH-Kryptofix 222 b. 80°C, a. ultrasound, slining RT,I010 mi" min *
H
l1LH3
HMPT = [Me2N13P
D. Synthesis of Nitrogen-13 Labelled Compounds
The positron emitter nitrogen-13 (half-life 9.965 min, Em,,= 1.20 MeV, no y, ( P ' ) = 491 keV, specific activity 1.451.109 Ci g-') has been produced in the following nuclear reactions289: l:B(a, n)':N, ':C(d, n ) ' : ~ ,
n)N1: and l:O(p, a)':N,
20. Syntheses and uses of isotopically labelled enamines
I
Toluene. KOH. Kriptofix 222 a. 80DC.10 min b. ultrasound, RT, 10 min
Usually aqueous [13N]ammonia is obtained by reducing an aqueous solution of 13N-labelled oxides of nitrogen, produced via the 160(p,a)13N nuclear reaction with 18-MeV protons in water, with Devarda's alloy (50% Cu, 45% Al, 5% Zn) and sodium hydroxide in a glass flaskzg0.The [13N] ammonia (about 200 mCi),.distilled in a stream of nitrogen and collected in a volume of about 5 ml, did not contain radiocontaminants such as 18F(j+,TlI2= 1.8295 h), I1C(j+, TI,, = 20.39 min) and ;!V(jl+, T,,, = 15.976 days) as confirmed by Ge(Li) pray spectroscopy detector. 1. Synthesis of '3N-labelled adenosine and nicotinarnide by amrnonolysis
These physiologically active natural compounds 307 and 308 have been labelled with 13N in a simple and rapid one-step ammonolysis reaction (equations 124 and 125) in sealed glass vials. They were used for studies of biological function and in nuclearmedical studies. [13N]nicotinamide (NAM) has been found to be a useful tracer for studying the utilization of the vitamin, nicotinamideZ9'. A comparison of the distribution of [ 1 3 ~ ] ~ Awith M that of [llC]NAM has been carried o ~ t ~ ~ ~ , ~ ~
.
HCI
~
.
1212
Mieczyslaw Zielihski and Marianna Kahska
2. Synthesis of 13N-labelledamines by reduction of '3N-labelled amides
13N-P-Phenethylamine (309) and 13N-n-octylamine (310) have been synthesized, respectively2y3,by LiAIH, reduction of 13N-phenylacetamide and 13N-octamide prepared by 13N-ammonolysis in ether (equation 126) in a 25-min total synthesis time. 75% yields of 309 and 310 have been reached after a 20-min reduction time. The radiochemical purities of the isolated amines were >90%. Both 13N-amines 309 and 310 in vivo administered to male CSH mice rapidly transferred to brain, lung and heart, but long-term retention of the radioactivity has been observed only in the brain and in the heartzy3.The uptakes of 13N-310 in these organs have been higher than uptakes of "N-309. It has been suggested that "N-310 is oxidized by monoamine oxidase to octanoic acid and 13NH3which is converted into 13N-glutamineand other amino acids and trapped in the tissue. 13N-309 has been synthesized previously294 in aqueous solution by the Hoffman rearrangement but with a low (5%) labelling yield. LiAlHfither
I3NH3
RCOC'
EtzO. powdered Na2C03. RT. 1 mi" stir
RC013NH2 5-20
min reflux*
RCH213NH2
3. Synthesis of I3N-P-phenethylamine
Nitrogen-13 labelled j-phenethylamine [13N]-309 has been synthesized2y4by Hoffman rearrangement of ['3N]phenylpropionamide, prepared in turn from phenylpropionyl chloride and aqueous [13N]ammonia solution (equation 127). PhCH2CH2COC1 ,
aq. I3NH3, NaOH , stirring 30 secD
P~CH~CH~CO~'NH~ (311)
1
NaOBr a. 5 min heating a1 100°C b, exlri~clion,preparative TLC
71% yield of 311 has been obtained by increasing the concentration of NaOH from 10 to 2000 pmol. An optimum 50% TLC yield of 309 has been obtained by increasing the [NaOBr] from 5 to 100 pmol. The organ distribution of the neuromodulator 309 in mice has been studied and high accumulation and long-term retention of the radioactivity in the brain and heart It has been suggested that trapping of the [I3N]-309 proceeds according to the mechanism outlined in equation 128.
-
TISSUE
PhCH2CH213NH2
MA0
PhCH2COOH
+
I3NH3
GS
I3N-Gln
CELL MEMBRANE
c
BLOOD
PhCH2CH213NH2
MA0
4'
- Monoamine
oxidase, GS - Glutamine synthetase, Gln - Glutamine
(128)
20. Syntheses and uses of isotopically labelled enamines
1213
4. The synthetic precursor for '3N-labelling
[13N]Ammonia in organic solvents has been foundzg5 to be a potent synthetic precursor for 'W-labelling. The improvement in the yields of "N derivatives, such as [13N]adenine or [13N]nicotinamide, and the feasibility of labelling compounds containing functional groups unstable in aqueous solution, such as [13N]-p-nitrophenyl carbamate ([l3N]NPC) or [13N]glutamine, are advantages of 13N-ammonolysis in organic media. [13N]NPC is a potential metabolic trapping tracer for estimation of cholineesterase activity in vivo295.296,but it is very easily hydrolysed even in a weak alkaline solution (as shown in equation 129). Consequently, its labelling must be carried out under strictly anhydrous conditions.
The higher yields of amides achieved by using organic solution of [13N]amnionia as a precursor are due to the higher stability and higher reactivity of the acid chlorides in organic solvents compared with water and because ammonia in water is hydrated and is less reactive. 5. Evaluation of '3N-amines as tracers
Amines labelled with positron-emitting nuclides ("C, 13N, 18F) combined with PET are useful for external measurement of the rate of transport, metabolism and excretion of a number of substances in humans and animals, and were used for various aims. After a detailed studv of the orean distribution and the metabolic fate of the 13N-amines. l'N-(l-phenclh)lamlnc, 13N-n-oct)lamine and '.IN-3,4-tlimc~hoxyphenethylaminc, a general tronsformalion path of amines in 19ic.o has been formulatedzyz(equalion 130).
-
BLOOD
RCH213NH2
MEMBRANE CELL
4
rapid
I
RCH2I3NH2
MA0
I
tI
RCOOH
-
4
P-oxidation, COz
+
I3NH3
(130)
13N-Gln etc.
non-spec. binding The administered 13N-amines are rapidly transferred to the tissues and oxidized by M A 0 to 13N-ammonia and an aldehyde which is rapidly oxidized to an acid. Some of the acids undergo further metabolism, such as p-oxidation, which can be traced by using "C-fatty acidsz9', or are excreted as suchzg8. 13N-ammonia produced by M A 0 from
1214
Mieczyskaw Zielinski and Marianna Kanska
'3N-amines299 is converted very rapidly by enzymes (mainly glutamine synthetase) into 13N-amino acids ('non-volatile metabolites')300 and trapped in the tissue (the biological half-life of '%ammonia in the rat brain is four seconds). In the brain and in the heart the 13N-amino acids synthesized from ammonia are utilized and trapped; in the lung they are excreted rapidly. The radioactivity trapped metabolically in the heart opens a possibility of determining myocardial M A 0 activity. Very high uptake of "N-amines by the lung3'', especially of amines with a long carbon chain, makes them candidates for lung imaging tracers. E. Fluorine-18 Labelled Compounds
The preparation of 18F-labelled radiopharmaceuticals carried out before April 1976 has been critically reviewed by Palmer and coauthors302. "C, 13N and 150are ideal for labelling of radiopharmaceuticals since no 'foreign' atom is introduced into the organic molecule but, due to their very short half-lives, fluorine-18 has been considered in the past as an ideal label from the radiochemical point of view. Consequently about 80 papers have been devoted to nuclear and radiochemical production of fluorine-18 labelled precursors and to methods of 18F labelling of organic compounds via the Balz-Schiemann reaction (equation 131) or to tnethods employing nucleophilic displacement of good leaving groups such as bromide, iodide, tosylate and a n ammonium ion. C6H4XY
~tration
02NC6H3XY
reduction
H2NC6H3XY
*
*
FC6H3XY
F-labelling
+
+
diazatization
BFr N2C6H3XY
(131)
X and Y denote different protected or unprotected groups The anions are unsolvated in aprotic solvents such as DMA, DMSO o r HMPA, whereas large cations ( K + , Rb+, Cs+, TI+ and Bu,N+) are highly solvated in these solvents. However, fluoride ion is essentially 'naked', and the rate of reaction is thus increased. Crown ethers and phase transfer catalysts such as cetyl tributyl phosphonium bromide have also been used to increase cation solvation. Ion exchange resin (Dowex-1) [CH,NMe;F-I, was labelled with fluoride-18, and has been also used as the fluorinating agent. Other fluorinating agents such as silver fluorides, antimony and bismuth fluorides, perchloryl fluoride (FCIO,), fluoroxytrifluoromethane (CF,OF) and molecular fluorinegoghave been used as a source of electrophilic fluorine (equation 132). It was concluded that the methods applied are 'a long way' from regular utilization. In this section, examples of recent achievements in preparing 18F-labelled radiopharmaceuticals are presented.
II
II
HNxC\CH
1. [18F]F2
5
2. Sublimation 3. Ion exchange
I
0
N H
yCH
HN
*
I
II
05C\N/CH
H
20. Syntheses and uses of isotopically labelled enamines 1. Synthesis of ['sF]fluoroalkylated analogues of neuroleptics YM-09151-2(-313
a n d -314) Continuing previous isotopic studies related t o synthesis and PET applications of dopamine antagonists YM-09151-2 (312a, 312b)304, the NCA[18F]-labelled analogues of YM-09151-2 (313 and 314) have been s y n t h e s i ~ e d ~by~ the ' nucleophilic substitutions of N-methanesulphonoxyalkyl derivatives of nor-YM-09151-2 with [18F]- (equation 133). OMe
I
I . NaH, THPO(CHz).BrlDMSO. RT. I h 2. lU% HCIIMeOH, RT, I h
3. MsCI, Et3N/CH2Cl2,RT, 30 min
OMe I
[18~1-,KZC03,Kryprofix 222
1
MeCN, 60°C under N2, 20 min
OMe
&
RNH
J& :
THP = Tetrahydropyranyl Preliminary biodistribution studies3'' dopamine receptor measurements.
in vivo have shown that 314 is potent for
1216
Mieczyskaw Zielinski and Marianna Kanska
2. Synthesis of "F-labelled fluoromelatonins and 5-hydroxy-fluorotryptophans
Both these 5-hydroxyindoles are natural compounds, playing an important role in the brain. 5-hydroxytryptophan (5-HTP) 315 is the metabolic precursor for the neurotransmitter serotonin; melatonin 316 is a neurohormone involved in the regulation of chronobiological rhythms such as sleep and fertility306. They have been labelled with F-18, for in viuo metabolic imaging with PET, in reaction of dilute [18F]fluorine gas with melatonin or with 5-hydroxytryptophan in hydrogen fluoride3'' at - 70°C (equation 134).
(315) . . R' = R3 = H. R2 = COOH. R3 = H. 9% (316) R1 = Me, R2 = H, R3 = Ac, 19%
+
byproducts
(134)
(315') R1 = R3 = H, R2 = COOH, 6.5% (316') R' = Me, R2 = H, R3 = Ac, 8% 'H- and lgF-NMR data for both the isomers 4- and 6-fluoro-5-HTP, for 5-HTP, 4-F-melatonin, 6-F-melatonin and melatonin were obtained3''. The preferential electrophilic attack of fluorine at position 4 to give 315 and 316 parallels the larger extent of deuterium exchange at position C,,, rather than at position C(6, of the deuteriated acid3''. The specific activity of 235 mCi mmol-' was found insufficient for quantitation of the melatonin receptors. Synthesis of 315 and 316 with specific activity > 100 Ci mmol-' is in progress. 3. Syntheses of spirone containing aliphatic halogens {['aF]fluoroethyl spiperone)
The 3-N-haloethyl spiperones 317 displaying high affinity for dopamine receptor in = 110 min) in the final synthetic step which virro have been labelled309 with 18F involves displacement of the mesylate group of 318 by C1'F]fluoride ion (equation 135). The precursor 318 has been prepared in the four steps outlined in equation 136. N-(["F]Fluoroalkyl)spiperone derivatives have also been prepared310 by N-alkylation of spiperone with 2-['8F]fluoroethyl bromide, 3-[1sF]fluoropropyl bromide and 4[18F]fluorobutyl bromide (equation 137), which were prepared in turn by ["%]fluoride ion displacement of the corresponding triflates. The 2-[1'F]fluoroethyl, 3-["Flfluoro-
20. Syntheses and uses of isotopically labelled enamines
~h' (317) 2@28% radiochemical yield of isolated product
propyl and 4-[18F]fluorobutyl spiperone derivatives have been prepared and purified within 40 min in yields of 3 W 0 % (at the end of synthesis, EOS). 4. Synthesis of ['BF]4-fluorobenzyl iodide and alkylation of spiperone
The title compound, 319, has been prepared"' in three steps starting with nucleophilic displacement of the nitro group of 4-nitrobenzaldehyde 321 with [18F]CsF, followed by reduction of the [18F]4-fluorobenzaldebyde 322 with LiAlH, and treatment of crude alcohol with 47% HI. 320 has been obtained in the reaction of 319 with spiperone (equation 138). The in vitro studies have shown that N-(4-fluorobenzy1)spiperone 320 has high affinity for the dopamine D, receptor and low affinity for the serotonin 5-HT, receptor3". [18F]-319 can be used for incorporating 18Finto a pharmacologically active molecule possessing an N atom with a certain degree of bulk-tolerance. 5. Radiosynthesis of [18F]PK
14105
N-Methyl-N-(l-methylpropyl)-1(2-fluoro-5-nitrophenyl)isoquinoline-3-carboxamide, 323, possessing high affinity and selectivity for PBBS (peripheral-type benzodiazepine binding sites)312in living man, has been labelled313 with n.c.a. fluorine-18, obtained via "O(p, n)lsF nuclear reaction, by an aromatic nucleophilic substitution process (equation 139). (n.c.a. = no carrier added) The radiosynthesis of 323 in ca 15% radiochemical yield (decay-corrected) required 210 min from EOB. 6. Microwave-facilitated synthesis of ["F]spiperone
Application of microwave heating to the synthesis of the positron-labelled dopamine receptor active ligand, [18F]-SP 324, carried out recently314 in the three steps outlined in equation 140, resulted in a decrease315 of the total synthesis time from 2 h needed for conventional heating to 6 7 0 min when microwave heating was used. The radio-
Mieczysiaw Zielinski and Marianna Kanska
chemical yields of 324 based on ['8F]-fluoride are 3.5-7% using this new synthetic method315. 7. Synthesis of l-{4-['8F]fluoromethyl-l-(2-thieny/)cyclohexyl)piperidine (FTCP)
The radiosynthesis of cis-325a and trans-325b isomers of FTCP, the potent N-methyl~-aSpartatereceptor channel blocker, has been acc~mplished"~by displacement on
20. Syntheses and uses of isotopically labelled enamines
~ h / spiperone
sulphonate ester 326a with [18F]fluoride ion. The total preparation time was 60 rnin including the two-step HPLC purification. The trans isomer of the 18F-labelled FTPC has been obtained in 1.2-4.4% yields, and the cis-isomer in 3.2-15.4% yield at end of synthesis with 98% radiochemical purities. The range of specific activities was in the order of 222C2960 GBq mmol- (6@80 Ci rnmol-') at the end of synthesis.
'
1
EqNOWMcCNIspipcrone RT,5 min
Mieczystaw Zielinski and Marianna Kanska
I8F,DMSO, Rb2CO3
I
140°C, 20 min
Me
20. Syntheses and uses of isotopically labelled enamines
(325a) R = I8F (326s) R = OTs
H C l . H # N H e 1 8 F
4
(325b) R = 18F (326b) R = OTs
b. a. Na[BH,(CN)] rapid decomposition
of the excess reagent
I
18F (328) specific activity > 1 Ci kmol-I at EOS 10%(for last 3 steps)
1222
Mieczystaw Zielinski and Marianna Kanska
8. Synthesis of [lBF]-p-fluorophenylhydrazine 327 and synthesis of radiolabelled glucocorticoid ["FIWIN 44577, 328
Both title compounds labelled with [18F], 327 and 328, have been prepared3" according to the reaction scheme outlined in equation 141. The "F-containing steroid 328 exhibits high in uitro GR (glucocorticoid receptor) binding affinity318. 9. Synthesis of no-carrier-added 3-[18F]-fluoro-l-(2-nitro-l-imidazolyl)-2-propano/, 330
[18F]-330, suggested as a potential in vivo marker of hypoxic t i s s ~ e by~ PET, ~ ~ . ~ ~ ~ has been prepared3" in the reaction of epoxide 331 with [18F]-tetrabutylammonium fluoride ([18F]TBAF) (equation 142a) in 1-2% radiochemical yield and in the reaction of epifluorohydrin 332 with 2-nitroimidazole 333 (equation 142b) in 3 U 0 % yield in an overall synthesis time of 2 h starting with 200 mCi of fluorine-18 in H Z L 8 0 . 0 NO2 I / +C, ,CH2CH \ N N CH~ I I HC-CH
1
+ ("-Bu)~N'~F
*
NO2 OH I I ,cH~CHCH~~~F N+ C N
-.
1HC-CH
I
(142a)
1330) specific activity 400 Ci mmol-I
Preliminary in isolated perfused rabbits hearts following 15 minutes of infusion of [18F]-330 showed greater accumulation of [18F]-330 in ischemic (62 f 7%) or hypoxic hearts (61 f 11%) when compared to control hearts (25 f 5%). 330 is therefore a promising tracer for delineation of ischemic but viable myocardium. 10. Automated synthesis of 5-['BF]fluoro-2-deoxyuridine
5-[18F]fluoro-2'-deoxyuridine, [18F]FdUrd, 334, used in tumor chemotherapy and detection of tumors in human brain and lung, is produced for routine clinical use in a microcomputer-controlled process consisting of addition of l8FZto 3',5'-di-0-acetyl-2'deoxyuridine 335, hydrolysis and elimination of AcOH from the "F-triacetate 336 and chromatographic purification of [18F]FdUrd in tandem columns of ion retardation resin and alumina (equation 143)322.(The mechanism of elimation of AcOH from the 18F-adduct 336 has not been studied.) Portions of about 30 mCi of 334 in a sterile and pyrogen-free aqueous solution with radiochemical yield of 20% within 60 min after the 60-min 15.7-MeV deuteron irradiation of a 'ONe target were obtained.
20. Syntheses and uses of isotopically labelled enamines 0
0
II
II
HNyC\cH I II C CH oG \ N ' AcOCH2,
,o
CH
I
AcO
C 'H
,CH-CH2
1
I
,]SF
HN%H I I o//C\N/ CH
-
,o
AcOCH2,
1 8 ~ , / ~ ~ ~ ~ CH RT
I
C 'H
1
, OAc
I
,CHCH2 AcO
I I
EtONa EtOH, 80°C. 10 min
1. AG1 IAB(Bio-Rad) columns 2. Alumina
0
(334) radiochemical purity > 98% Polymer-supported nucleophilic radiolabelling reactions with [18F]fluoride and ["Clcyanide ions on the surface of quaternary ammonium resins (337,338) have been found313 valuable in radiopharmaceutical syntheses where fast, simvle and easilv automated chemical operations are necessary. 3-[18F]-diazepam has been obtained in 30% yield by this method3z3.
(337) Y = piperidino (338) Y = dimethylamino F. Compounds Labelled with Radioisotopes of Iodine 1. Synthesis of 3,3'-dirnethylthiacarbocyanine~251]
This lipophilic cationic cyanine dye, 339, a tumor specific localizing tracer, labelled with lZ5Iin the 5,5'-positions, has been ~ynthesized"~as outlined in equation 144. Compounds of this class may have promise as specific radiopharmaceuticals for diagnosis and therapy of some tumors.
1224
Mieczyslaw Zielihski and Marianna Kanska
HC(OEt), Pyr, 1 LOT, 1 h
~ a l 2 5 1 CuS04, , SnS04
LOOT, ascorbic acid
2. Synthesis of 5-amino-l-~-~-rybofuranoxylimidazole-4~N-([p-'~~/]iodopheny1)fcarboxamide
The para-iodophenyl analogue 340 of naturally occurring imida~oleribonucleoside 341 has been prepared325by coupling p-[1251]iodoaniline with 342. Deacetylation of the intermediate compound 343 gave 340 (equation 145), which in 2.9-pCi portions has
I
AcO
I
OAc
20. Syntheses and uses of isotopically labelled enamines
been administered intravenously into nude mice implanted with human colorectal carcinoma for biodistribution studies. Compound 340 accumulates preferentially in the proliferating tissues such as tumor and bone marrow3225and can serve as the metabolic marker and indicator of tumor growth. 3. Synthesis of [2-'4C]3'-deoxyfhyrnidin-2'-ene(d4T), 344, and [5-'251]3'-azido2',3'-dideoxy-5-iodouridine, 345
These potent inhibitors of human immunodeficiency virus (HIV-1) have been synthesized326as shown in equations 146 and 147.
(344) specific activity 16.5 Ci mol-' 99% radiochemical purity
* '4C c=
Mieczyslaw Zielinski and Marianna Kanska 0
I HOCH2
,
x0
II
I
CH 'CH I I (147) , C H CH2 N3 (345) 11.3% 98% purity after semipreparative chromatography
CF3COOAg.'2512/12, dioxane
I . 0% 2. RT.5 h
4. Synthesis of lZ31a n d lZ61labelled lodobenzodiazepines ethyl 7-iodo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[l,5-a](l,4]benzodiazepine-
3-carboxylate Radiolabelled benzodiazepine antagonists 346 useful for the in vivo imaging and quantitation of benzodiazepine-GABA receptor sites in the human brain327.328have been synthesized in 5670% radiochemical yield and >98% purity by a one-step Pd-catalysed reactionsz9 between bis(tributyltin) and Ro 16-0154,347, followed by electrophilic iodination of the tributyltin compound 348 with no-carrier-added '''I and lZ3I(equation 148).
Iodogen = 1,3,4,6-Tetrachloro-3aa6a-diphenylglycauril, Ref.: P.J.Fraker and J.C.Speck, Biochem. Biophys. Res. Commun,,80,849(1978) 5. Synthesis of 1251-label/edp.3-H]imidazole
2-n-Butyl-4(5)-[12'I]iodo-5(4)-hydroxymethylene imidazole 349 has been prepared330 by treatment of 350 with chloramine T in the presence of [1251]sodium iodide (equation 149).The product 349 isolated by HPLC is obtained in chemical and radiochemical yields of 70% at specific activity equal to 2200 Ci mmol-'.
20. Syntheses and uses of isotopically labelled enamines
1227
~ - f ~ ~ ~dioxane a ' ~ chioramhe % ol MeOCH2CH20H , T or NCS
n-C4Hg
IGH~ CI-
//
n-C4H9C
\
OEt
n-C4H9
or M~O-o
H
+ 0*cI ,CHzOH CH20H
N H (liquid) ~
90°C. I6 h
-
H
J-$~ (150) ~ ~ n-C4H9
H Unlabelled 349 has been synthesized by treatment of ethyl valerimidate hydrochloride with 1,3-dihydroxyacetone in arnmonia3j1 (equation 150). 6. Synthesis of 4-[BZBrIbromoantipyrine and 4-['3'l]iodoantipyrine
4-[82Br]bromoantipyrine 351 has been synthesized332 by the melt method in about 90% yield; 352 has also been synthesized with high radiochemical yield.
G. Multilabelled Compounds 1. Synthesis of tritium and carbon-14 labelled N-(3-dimethylaminopropy1)-N(ethylaminocarbonyl)-6-(2-propen-l-yl)ergoline-8~-carboxamide(cabergoline)
The title compound, alkaloid 353, cabergoline o r FCE 21336, useful as an antiParkinson and prolactin lowering now under extensive clinical evalua-
1228
Mieczystaw Zielinski and Marianna Kaliska
t,on334,335
, ha s been 3H- and 14C-labelled for pharmacokinetic and biotransformation
~tudies"~. Tritiated cabergoline ([3H]cabergoline), 354, has been obtained by catalytic reduction with tritium gas of the 6-propargyl derivative 355 employing 10% Pd/C, poisoned with 16% quinoline in dioxane, as catalyst (equation 151)in order to minimize the production of the fully saturated 6-propyl derivative 356. FOOMe R \ CH2CECH
-
HZN(CH2)3NMe2
-
CONH(CH2)3NMe2
1
EtNCO
R
\
0, ,CONHEt R,CNx(CH2)3N~e2
/: ; 1
\CH~CECH (355)
CH2CECH
(354) [3H]cabergoline 23% radiochemical yield specific activity 1.06 TBq mmol-'
3H2. PUC, quinoline
TCH
H~C
R'CN\(CH2)3N~e2
'CH~
'
,CONHEt
0,
1
pflquinoline
(15 1)
(61
\CHZ
= @ ~ ; $ ~ C H . CCH? H=CH.
\
C3H2-CH3H2
(356) HN-CH
The specific activity of 356 was up to 4.03 TBq mmol-'. [3H]dihydrocabergoline 356 (FCE 3241 1) has been used as labelled hapten in cabergoline radioimmunological assays in order to determine very low levels of the drug in biological fluids of humans. ['4C]cabergoline 357 has been prepared similarly according to the method outlined in equation 152337. RCOOMe
NH2NH2.H20 MeOH,
RCONHNH2
NaN02. HCL Hz0
-
RNH2
1
NaNO2, HCI. SnC12
R14C00H
1
NaOH H ~ Oreflux ,
RI4CN
-
NaI4CN (925 MBq) (EtoH)
ROH
+ RCI
EDPC DMF.TEA
R14CON(CH2)3NMe2 RI4CONEt + I I CONHEt CONH(CH2)3NMe2 (357) [L4C]cabergoline EDPC = N-ethyl-N-(3-dimethylamino)propylcarbodiimide The specific activity of 357 was 2.09 GBq mmol-' and the radiochemical purity >97%. The overall radiochemical yield from potassium [14C]cyanide was 16% (150.5 MBq). The NMR spectra of intermediate compounds indicated that the reactions of equation 152 yielding 357 proceeded with complete retention of configuration at the chiral centre at C,,,. In the reaction of RCI with Na14CN, the S,2 displacement occurred with an overall retention of configuration due to participation of the nitrogen ring336.33R.
20. Syntheses and uses of isotopically labelled enamines 2. Synthesis of 3H-donetidine trihydrochloride, 14C-donetidineand '4C,-donetidine trihydrochloride
a. Donetidine trihydrochloride 358, inhibitor of histamine-stimulated acid secretion in animals339 and man340, has been tritium-labelled340 in the methylene of the furanylmethylthio moiety in five steps starting from sodium b~ro[~H]-hydridewith 1 % overall radiochemical yield at a specific activity of 33.7 mCi mmol-' for pharmacokinetic and drug metabolism studies (equation 153). HC-CH
II
II
+
NaB3H4 (750 mCi.
HC\O/C,CHO
MeOH
HC-CH
11
II
HC, 0yC, CH3HOH
272 hcimm&l)
1
CH2[NMe2I2 glacial AcOH
-
HCCH II II ,C\o/C, CH3HSCH2CH2NH2 Me2NCH2 (359)
HSCH2CH2NH2.HCI
cone. HCI
HC-CH
II II /'LO/ C \CH~HOH Me2NCH2 (360)
NOzNH OMe
HCl gas
0
II
HC-CH
II
C '0' Me2NCH2 /
II C
Hz
H
C / C\C / C\C / C+ N
II II ,C, ,CH 'CH~HSCH~CH~NH N H
II HC,
H I ,NH.3HCI
C II 0
(358) 7.77 mCi, radiochemical purity 98.3%
b. 14C-donetidine labelled with 14C at CIZ,,positionof the pyrimidone ring 362 has been obtained340in five-stage synthesis (equat~on154) starting from barium [14C]cyanamide, with 9% overall radiochemical yield at specific activity 57.8 mCi mmol-'.
Mieczyskaw Zielinski and Marianna Kanska
*
BaNCN (500 mci, 58 mcimmol-I
*
Ba(OH)2.8H20 H2S
* S=C
NHz
I
\
NH2
0
CH3LEtOH NaOWH20
HS'
unlabelled 359
II
II
*C
'N
,CH
H
OMe
1
1. Pyr., 24 h reflux 2. l N HCUMeOH
1
HC1 gas
[14C]-(362) 99% radiochemical purity, 45.1 mCi
362 has been synthesized for pharmacokinetic studies in healthy human volunteers. c. 14C,,-donetidinetrihydrochloride 363 labelled in the p-methylene groups of the aminoethylthlo moiety has been obtained in three-step synthesis starting from [l,2-14C,]cystearnine hydrochloride with 17.4% overall radiochemical yield at a specific activity of 15.4 mCi mmol- (equation 155). 363 has been prepared for pharmacological and drug metabolism studies. 3. Synthesis of radioactively labelled indole-3-acetaldehyde, indole-3-acetaldoxime and indole-3-acetonitrile
All these compounds are intermediates in indole-3-acetic acid (auxin) biosynthesis of plants. They have been prepared on r n i c r ~ s c a l ewith ~ ~ reasonably ~ high yield, high purity
20. Syntheses and uses of isotopically labelled enamines
+
360
H S E H ~ ~ H ~HCIN H ~
(unlabelled) 40 mCi, 17.3 mCi mmol-I
1
conc. HCI
0
II
HC-
II
CH
II
C / \O/C\CH2S6H2C*H2NH Me2NCHz
N
/
C\
II
,C,
N H
/
C II ,CH
\
H2 CA
*
C II HC,
H C
CH
I
,NH,3HC1
(155)
C II 0
(363) 6.97 mCi, radiochemical purity 97.3% (>99%) and high specific radioactivity from tryptophan 364, which is available in different radiolabelled versions. Equation 156 illustrates two-phase synthesis of these compounds using DL-(side chain-3-14C)-tryptophan. The yields and radiochemical purities of the end products obtained from 364 were found to be, respectively: 365 (75%, 94%), 366 (95%, 99%), 367 (95%, 94%) and 368 (ca 65%, 98%). All products have been stored in benzene at 4 OC for more than three months without decrease in purity.
Mieczysiaw Zieliliski and Marianna Kaliska
1232
4. Synthesis of 6,7-dimethoxy-4(p-chlorobenzyl)[3-D]isoquin01ine 369 and 6.7dimethoxy-4[p-chlorobenzyl(methylene-'4C)]isoqu~nol~ne 370
These two compounds possessing antispasmodic and vasodilatation properties342 have been ~ r e p a r e d " ~by the condensation of a-deuterioveratrylaminoacetaldehyde diethyl acetal 371 with p-chlorobenzaldehyde (equation 157) and in the reaction of p-chlorobenzaldehyde (carbonyl-14C) 372 with veratrylaminoacetaldehyde diethyl acetal (equation 158). Mass spectrometric determinations of the specific activity of 370 gave 55 mCi mmol-'. Product 370 has been isolated as methanesulphonate salt by reaction with CH3S03H.
34 mCi specific activity 54 mCi mmol-I
1. conc. HCI 2. unlabelled 371 EtOH, 30 min reflux
C
4
C
H
0 (158)
(370) 10 mCi, purity > 99% specific activity 54 mCi mmol-' 5. Synthesis of '4C-or 3H-labelled indometacin farnesil (E-0710)
The drug E-0710(IMF), a farnesyl ester of indomethacin, 373a and 373b, showing anti-inflammatory activity with diminished gastro-intestinal irritation, has been 14C-and 3H-lahelled for oharmacokinetic 14C-Labelled indomethacin and 3H-inr - ~ ~ ~ domethacin 374 are commercially available. 14C-IMF(373a) has therefore been prepared according to eauation 159 by esterification of 6E-3,7,11-trimethyl-2,6,10-dodecatrienol ~
-
-
~~
~
20. Syntheses and uses of isotopically labelled enamines
1
PBr31Pyr 0°C.hexane
$ -CH2Br
(374) (a) X = OH (b) X = CI
I
(373a) 7 1% from 374a. specific activity 52.4 pCi m g l , radiochemical purity > 98% ['4C]-F-IMF, 373b, with the '4C-labelled farnesyl moiety has been synthesized as shown in equation 160. The 7.3 (2E:22) isomeric mixture of 6E-3,7,1 l-trimethyl-2,6,1O-d0decatrien~l[G-~H]l(p-chlorobenzyl)-5-methoxy-2-methyl-1H-indoe-3-acetateL3H-IMF] has been obtained from [G-3H]indomethacin (20 mCi) and 375 similarly, as shown in equation 1603,, 6. Synthesis of series of pergolide, 377, and lysergol, 378, analogues radiolabelled with lZ51 or 75Seat 17-position or at C,2, of the indole moiety
A series of analogues of pergolide 377 (a-d) and lysergol 378(a-e) have been radiolabelled with lZ5Ior 15Se and evaluated as to their ability to cross the blood brain barrier (BBB) of rats for potential use as radiopharmaceuticals for imaging the brain345. ergoline 377e and Two pergolide analogues, 8~-(methyl-75Se-seleno)-methyl-6-propyl 8~-[1251]-iodomethyl-6-propylergoline 377a showed the highest uptake in the brain, adrenal and heart with good organ-to-blood ratios and have been found therefore t o be clinically useful brain-imaging radiopharmaceuticals. Compound 377a has been obtained in 91% yield by refluxing 379 with NalZ5I in ethanol under nitrogen atmosphere for 40 minutes (equation 161). Compound 377e has been prepared as shown in equation 162 by treating unlabelled 377a with sodium hydrogen ~ e l e n i d e - ~ ~prepared Se, from selenious acid-?%e, exposing the selenol380 to air t o form the diselenide 381, reduction with NaBH, and subsequent addition of methyl iodide giving compound 377e with specific activity 400 mCi mmol-'.
Mieczyslaw Zielinski and Marianna Kanska
1
(Et 0)2P(O)CH2COOEt NaOEt
Me Me I I* CH3(C=CHCH2CH2)2C=CHCOOEt
d = I4C
I
unlabelled 374b Et3N
pergolide (377) (a) R' = I25I, R2 = H (b) R1 = 2-'251C6H4CH2Se (c) RI = SMe, R2 = lZ5I (d) R1 = OS02Me, R2 = Iz5I (e) R' = 7 5 S e ~ eR2 , =H
lysergol (378) (a) R' = Iz5I, R2 = H (b) R' = 4-'251C6H4S03, R2 = H (c) RL= 4-L251CgHqS,R2 = H (d) R' = 2-'251C6H4C02, R2 = H (e) RL= OH, R2 = lZ5I
20. Syntheses and uses of isotopically labelled enamines
This method avoids the direct use of methylselenide-75Se, which is highly volatile and dangerous. Compounds 378(a-e) have been radiolabelled according to the scheme outlined in equation 163. Pergolide derivatives gave a higher brain and adrenal uptake than lysergol derivatives, probably due to the longer alkyl chain attached to No,, i.e., n-propyl us methyl. The biodistribution of compound 377e, a true Se for S analogue of pergolide, a new346 dopamine agonist, has been studied extensively345. Statistically significant uptake of 377e has been found in these parts of the brain which are known t o contain higher amounts of dopamine receptor^^^^.^^^.
unlabelled (377a)
(380)
Io2
H CH275SeMe ', I C \ CH2 I
~~7'
I . N&H4 2. Me1
Pr-n
5 min stir under argon
HN-CH (377e) 74% (2 mCi) specific activity 400 mCi mmol-'
I
N
(162)
Pr-n
Mieczyshw Zieliliski and Marianna Katiska
II
I
NMe
7. Iodine-125 cytotoxicity
The chemical consequences of the '''I (half-life = 60.14 d) nuclear decay by capturing an inner-shell electron are the production of stable "'Te and 35.5-keV excess energy, observed in the case of 12'IUdR (iododeoxyuridine, equation 164a) decomposition which differs significantly from the products of external radiolysis of 14C IUdR (equation 164b), which gives simple dehalogenation. A study347 of the reEptor binding affinities of carrier-free '251-labelled nonsteroidal tamoxifen (I2'I TAM, sex hormone) ( [ a - l l p dimethylaminoethoxyphenyl]-1,2-diphenyl-l-butene), which is translocated to the cell nucleus and can be synthesized by a chloramine-T reaction using a tri-n-butyltin tamoxifen inte~mediate"',"~, demonstrated that differential subcellular accumulation of radionuclide lZ51results in marked cytotoxicity of iodine-125, which has t o be taken into account in the a priori estimations of radiation risks and in design and development of radiopharmaceuticals for therapy. Highly localized ionizatjons from Auger and conversion electrons are the principal modes of action creating the molecular and biological damage. There is at least an order of magnitude increase in energy deposition within the small volume of the DNA helix. Average microdosimetric calculations may underestimate the biological toxicity of radionuclides like lz5I if a 'quality factor' is not introduced properly to account for
20. Syntheses and uses of isotopically labelled enamines
0
0
II
HN'
I
c \ c/ I II
II
aq. e(external radiolysis)
O%NA H I
-1-
HN
AC.
I
II C\H
o!2c,N/ I
specific subcellular localization of radionuclide. Nearly every lZ5Idecay produces a double strand break in coliphage DNA and no detectable repair of DNA single strand breaks was noted. Dose response curves of 'ZSIUdR and 13'IUdR therapy of mouse ascite tumor cells demonstrated that 13'IUdR no antineoplastic activity while lZ51UdRreduce tumor cell survival to lo-'. lZ51TAM is differentially cytotoxic to cells containing estrogen receptors348.
H. Syntheses of Compounds Labelled with "'"Cu, 99mT~, '03Ru and ""Sn
Generator-produced (equation 165) [6zCu]copper(ll) bis (N4-methylthiosemicarbazone)CuPTSM and CuPTSM, have been suggested351as a Cu-62 radiopharmaceutical for evaluation of cerebral and myocardial blood flow by PET3". Complexes 282-387 of copper-67, a convenient radiolabel which has a half-life of 2.58 days (equation 166), have been prepared in >95% radiochemical yield35Zby addition of NaOH solution of the ligand to an acetate-buffered ethanol solution of the ionic radiocopper [Cu(II) in 2N HCI, specific activity 5 x lo5 Ci mol-I). The biodistribution of each C6'Cu] bis(thiosemicarbazone) complex has been determined. Methylation of the terminal amino groups was found to be essential for good cerebral uptake of tracer352.
Mieczyslaw Zielihski and Marianna Kanska
1238 62
10Zn
Pt (0.66 MeV) 9.3 h
*
%
Pt(z2.91 MeV, < B t > = 1.28 MeV), K 9.37 min (half-life) *
EN^
(stabil.)
(165)
(382) CuPPS, R1 = Me, R2 = R3 = H, log P = 0.75 (383) CuPTSM, R1 = R2 = Me, R3 = H, log P = 1.97 (384) CuPTSM2, RI = R2 = R3 =Me, log P = 2.7 (385) CuETS, RL= Et, R2 = R3 = H, log P = 1.36 (386) CuETSM, RL= Et, R2 =Me, R3 = H, log P = 2.7 (387) CuETSM2, R' = Et, R2 = R3 = Me, log P = 3.3 P = measure octanoYwater partition coefficient 2. Synthesis and application of 99mTclabelled compounds
a. Synthesis and application of 99mTc-p-butylIDA complex, a hepatobiliary agent. The p-butylacetanilide iminodiacetic acid, 'p-butyl-IDA, 388', useful for application to patients with biliary atresia, has been synthesized353according to equation 167 and used in 'instant' form for labelling with 9 9 m T ~ 3by 5 3treating 388 with SnC1, .2 H 2 0 , followed by reaction with pertechnetate. The 99mTc-p-butyl-IDA complex preparations have been administered t o normal and to adults and diseased patients. A conclusion has been reached on the basis of the chemical and biological investigations of the properties of 99mTc-p-butyl-IDA preparates that this radiopharmaceutical has very good hepatobiliary properties (high accumulation in liver and low urinary excretion) which can be used in studies of liver function of patients even with raised bilirubin levels.
20. Syntheses and uses of isotopically labelled enamines
1239
b. Synthesis of "'"Tc-labelled N-pyridoxal-5-methyltryptophan (5-PMT). This hepatoma imaging agent, ""Tc-5-PMT 389354,has been synthesized recently355 by using sodium borohydride for reduction of the Schifl base derived from pyridoxal and 5-methyltryptophan (equation 168). The 99mTc-5-PMT preparations have been carried out by adding 15 mCi (2-6 ml) of 99mTc0,- solution to freshly thawed kits containing 5 mg of 5-PMT, 0.3 mg of SnCI, .2H,O and 0.12 mg of L-( + )-ascorbic acid in 2 ml of final solution (lyophylized and stored at - 25 "C) and heating the mixture at 100 "C for 10 min. 99mTc-5-PMThave been obtained in 96% radiochemical purity. The usefulness of 99mTc-5-PMTfor the detection of hepatic and metastatic tumors has been established by studying 18 patients with histologically proven hepatoma. 61% of them showed positive images at 2-5 h after in vivo injection. Tumors as small as 2 cm in diameter with a tumor/liver ratio of 4 could be identified by visualization of regions with increased uptake of radioactivity.
1
KOH,MeOH RT.5 min
NaBH4
1
RT. 1 h
1240
Mieczyslaw Zielinski and Marianna Kanska
3. Synthesis and application of '03Ru-labelled ruthenocene compounds
The 103Ru-labelledruthenocene derivatives 390 and 391 have been synthesized356 by heating lo3RuC13 in MeOH or in EtOH with ferrocene derivatives obtained by the reaction of ferrocenecarboxaldehyde with quinuclidin-2-one, followed by reduction of the keto group to corresponding alcohol. During the exchange reaction in MeOH or EtOH the H O group of the quinuclidine moiety has been partly transformed to a methoxy or an ethoxy group3". The tissue distribution studies have shown that lo3Ru-labelled diethers 391 concentrate preferentially in myocardium in a very high heartlblood ratio of 60: 1 (for R = OEt) or a heartlliver ratio of 2.72: 1 (for R = OEt). These values are much higher than the corresponding ratios found for complexes of 99Tc with t-butisonitrile (TBI) which are 7.6 and 0.92, respectively. The half-life of 9 5 R ~ is 1.64 11, making this positron emitter suitable for nuclear medicine applications (PET).
(390)
/ R = OH, OMe, OEt or R-CH
\
= O=C
/ \
(391) R = OH, OMe, OEt or R-CH
/ \
= O=C
/ \
20. Syntheses and uses of isotopically labelled enamines
1241
4. Synthesis of ["gmSn]-mesoporphyrin IX dichloride
[119mSn]-MPCI,, 392, has been synthesized358for drug metabolism and disposition studies in 60% radiochemical yield by metalation of the porphyrin nucleus of mesoporphyrin IX dihydrochloride 393 with tin(I1)-119m acetate (equation 169). 392, a potent competitive inhibitor of heme o x y g e n a ~ eeffectively ~~~, decreases plasma bilirubin levels in adult and neonatal animals and humans and is under current evaluation for treatment of neonatal hyperbiliruh~nemia (infantile ia~ndicz)'"~.'"'.The metas~lihleisomer of tin-119, '19m~n;isa gamma emitter possessing a half-life of 293.0 dayszw9,suitable for biotransformation studies (usually, the value To,,, = 250 days is cited in previous publications for "9mSn). -
I
C
~
I
H
\C//C\C/
C
+CHEt 1 \\ I -NH N-C .2 HCI \bH HC / \ /C=N HN-C \ I \\ C, ,C+ Me' qC/ \C C I H I CH2 CH2
MeLC// \
I
I
1. L 19mSn(ll)/Ac20. NaOAc, AcOH 70DC(30 mi") -t lOO0C(2.5 h) under Nz 2. 6 M HCI
a.
60°C 20 min
b. RT overnight
\
CH~ I COOH
CH~ I COOH
(392) specific activity 43.4 mCi mmol-I radiochemical purity of 99%
1242
Mieczyslaw Zielinski a n d Marianna Kanska
IV. ACKNOWLEDGEMENTS The work o n this chapter has been supported by the Faculty of Chemistry of Jagiellonian University a n d by the Department of Chemistry of the University of Warsaw. W e gratefully acknowledge the typing of the chapter by Dr. R. Kanski. Mgr. Halina Papiernik-Zielinska's keen interest in numerous bio-pharmaceutical applications of isotopically labelled enamine derivatives is recognized. M.Z. thanks also Gregory Czarnota for his careful final examination of all references a n d for some help in the preparation of the manuscript.
V. REFERENCES
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CHAPTER
21
Biochemistry of enamines FRANK JORDAN Department of Chemistry. Rutgers. the State University of New Jersey. Newark . New Jersey
I . INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1254 I1. ENAMINES IN THIAMIN DIPHOSPHATE-DEPENDENT REACTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1254 A. Chemical Models of Enamine Reactivity . . . . . . . . . . . . . . . . . . 1255 Structure in solution . . . . . . . . . . . . . . . . . . . . . . . . . . . .1257 Acidity of enamine precursor 2-alkylthiazolium salts at C2a in DMSO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1257 Acidity of enamine precursor 2-alkylthiazolium salts at C2a in water 1257 Kinetics of proton transfer to and from C2a in 2-alkylthiazolium salts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1258 Redox chemistry of the enamine . . . . . . . . . . . . . . . . . . . . . 1259 a. Indirect evidence for oxidative enamine t r a o ~ i n e. . . . . . . . . . 1259 b . Direct electrochemical oxidation behavior of enamines . . . . . . 1261 Condensation reactions of the enamines at C2a . . . . . . . . . . . . 1263 B. Enzymatic Reactions of Thiamin-bound Enamines in Decarboxylases . 1266 1. Generation and identification of enamines bound to pyruvate decarboxylase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1268 2. Visible spectroscopic properties of enzyme-bound enamines . . . . . 1271 3. Redox properties of enzyme-bound enamines . . . . . . . . . . . . . . 1272 a . Evidence for 2-acylthiamin diphosphate intermediates on a-keto acid dehydrogenases . . . . . . . . . . . . . . . . . . . . . . . . . . 1272 b . Oxidation of the thiamin-bound enamines on pyruvate decarboxylase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1274 . c. Redox reactions resulting from enamines derived from halopyruvate analogs . . . . . . . . . . . . . . . . . . . . . . . . . . 1275 d . Trapping the enzyme-bound enamines by flavins . . . . . . . . . . 1276 e. Adventitious enamine oxidation by dioxygen . . . . . . . . . . . . 1278 4. Kinetic competence of enzyme-bound enamines . . . . . . . . . . . . 1279 5. Stereochemical behavior of enzyme-bound enamines . . . . . . . . . 1279 6. Are enamine mimics general transition-state analogs for thiamin diphosphate-dependent enzymes? . . . . . . . . . . . . . . . . . . . . . 1280 7. Possible role of thiamin diphosphate-dependent enzymes in enamine stabilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1281 C. The Reaction of Transketolase . . . . . . . . . . . . . . . . . . . . . . . . 1281
.
The Chpmistn of Enarninrs. Edited by Zvi Rappoport Copyright O 1994 John Wiley & Sons. Ltd . ISBN: 0-471-93339-2
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F. Jordan
111. ENAMINES I N SCHIFF BASE ENZYMES . . . . . . . . . . . . . . . . . 1283 A. Lysine-dependent 'Schiff base' Enzymes . . . . . . . . . . . . . . . . . . 1283 1. Acetoacetate decarboxylation . . . . . . . . . . . . . . . . . . . . . . . 1283 2. Class I aldolases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1285 B. Pyridoxal-dependent Enzymes . . . . . . . . . . . . . . . . . . . . . . . .1286 C. Pyruvyl-dependent Decarboxylations . . . . . . . . . . . . . . . . . . . . 1288 IV. ENAMINES IN OXIDATION-REDUCTION COFACTORS . . . . . . 1291 A. Flavin Cofactors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1291 B. Nicotinamide Cofactors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1292 C. Biopterin Cofactors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1293 V. ENAMlNES IN TRYPTOPHAN METABOLISM . . . . . . . . . . . . . 1293 VI. RECENT APPLICATIONS O F BIOCHEMICAL ENAMINES . . . . . 1294 A. Enamines as Mechanism-based Enzyme Inhibitors . . . . . . . . . . . . 1295 B. Chiral Synthesis with Enzymes that Utilize Enamines Intermediates. . 1295 VII. ACKNOWLEDGMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . 1299 . VIII. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1299
I. INTRODUCTION
Enamines have been recognized in organic chemistry as useful synthetic reagents since the early reports from Stork's laboratory1. At almost the same time similar chemical moieties were being implicated in biochemical systems. Because of their intrinsic instability in water, the biochemical enamines exist primarily as intermediates, although, some well-known coenzymes that participate in oxidation-reduction reactions also incorporate enamine structures in one of their oxidation states. The electronic structure of enamines involves two extreme resonance contributions as shown in equation 1.
neutral
dipolar (zvitterionic)
While the ability of enamines to be alkylated at carbon is their synthetically most useful attribute, the oxidation-reduction chemistry of such systems is also well documented. It is the purpose of this review to discuss some of the better known biological enamines. Due t o the preoccupation of the author with thiamin chemistry and enzymology, many of the properties of enamines will be exemplified by a variety of results obtained on this particular system. Enamines are, however, present in a number of other biochemical processes as well, where their remarkably rich chemistry is reauired. In most of these ieactions the enamines are only present as intermediates; that are the result of covalent catalysis, in which the substrate of the enzymatic reaction forms a covalent bond with either a protein side chain o r a required coenzyme. II. ENAMINES IN THIAMIN DIPHOSPHATE-DEPENDENT REACTIONS
There are two carbanions that dictate the important biological activity of thiamin diphosphate (ThDP, the vitamin B, coenzyme): the C2-carbanion or ylide, and the
21. Biochemistry of enamines
1255
C2a-carbanion or enamine as suggested 35 years ago by Breslowz. After considerable research by many the true structure of the former is still unknown, as its existence is too fleeting for direct detection. Suffice it to say that more recent kinetic studies suggest that it is formed with a pK near 17-197 and its behavior is consistent with a localized carbanion structure similar to that of cyanide ion. While there were some reports favoring a carbene8-lo, rather than nucleophilic2 reactivity for the C2-carbanion vis-a-vis electrophiles, more recently there was evidence presented reconfirming that the reactivity of this C2-carbanion is best reflected by nucleophilic pathways, and the mechanistic probes developed provided evidence inconsistent with carbene insertion into C-H single bonds or addition across C=C double bonds". Although the reactivity of the C2-carbanion is crucial to initiating the reaction, the chemistry of the second C2a-carbanionlenamine is much richer in biochemical systems, as there are known three distinct enzymatic pathways that emanate from the enamine: prdtonationlz, oxidation"-'5 and condensation16, each known to occur both on enzymes and in appropriate model reactions. a-Keto acids appear to be nearly universally decarboxylated with the intervention of ThDP. The reactions are of importance in sugar metabolism, as well as in the biosynthesis of some essential amino acids in plants. The electron sink required to facilitate such reactions by electrophilic catalysis involves covalent bond formation between the 2-keto carbon and the thiazolium nucleus, in a manner analogous to catalysis by cyanide. The simplest example of such reactions is the decarboxylation of pyruvate. Both model and enzyme studies have shown the intermediacy of covalent complexes formed between the cofactor and the substrate. Kluger and coworkers have studied extensively the chemical and enzymatic behavior of the pyruvate and acetaldehyde complexes of ThDP As (2-lactyl or LThDP, and 2-hydroxyethylThDP or HEThDP, re~pectively)'~.'~. Scheme 1 indicates, the coenzyme catalyzes both nonoxidative and oxidative pathways of pyruvate decarboxylation. The latter reactions are of immense consequence in human physiology. While the oxidation is a complex process, requiring an oxidizing agent (lipoic acid in the a-keto acid dehydrogenases13, or flavin adenine dinucleotide14, FAD or nicotinamide adenine dinu~leotide'~, NAD' in the a-keto acid oxidases and Fe,S4 in the pyruvate-ferredoxin oxid~reductase'~) in addition to ThDP, it is generally accepted that the enamine is the substrate for the oxidation reactions.
A. Chemical Models of Enamine Reactivity
In 1979 it was reportedZothat by converting the 2-a-hydroxy group of 2-a-hydroxyethyl-3,4-dimethylthiazoliumsalts to an ether, the enamine could be generated, as deduced from its product with the oxidizing agent diphenyl disulfide, generating a tetrahedral intermediate at the C2a position by sulfenylation (equation 2). This would be consistent with nucleophilic and/or redox reactivity of the enamine at the C2a position. Based on this report, an attempt was made to generate the enamine quantitatively from 2-alkyl and 2-a-alkoxyalkyl-3,4-dimethylthiazolium salts (1) in aprotic solvents employing nonnucleophilic bases, according to equation 3. In fact, this could be achieved in either pyridine or DMSOZ1. In typical experiments performed in an NMR tube t-BuOK or (TMS),NNa were added to the salts, the spectrum being recorded before and after addition of the base. As a control, after each set of NMR experiments, acid quench was performed in deuterated solvent and it was thus demonstrated that D was specifically incorporated at the C2a position. The properties of the enamines so generated follow.
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F. Jordan
Ylide
ThDP
LThDP
Enamine or 2-a-curbanion
HEThDP
thiazolium cation radical
.Itk.
1
1
one electron
gx-
AH
CH2R1
+ Wide
or
0
R = C H ~ C H ~ O P O R1 ~; = Me
JY N
NH2
4-Amino-2-methyl-5-pyrimidyl
SCHEME 1
CoAS
a
+
Ylide
21. Biochemistry of enamines
Thiazolium salt
Zwitterion
Enamine
(2) Examples of R1 and R2 employed are given in Table 1, R3 = H or Me
(1)
1. Structure in solution
The structure of the enamines 2 was investigated by multinuclear NMR and shown to be consistent with slow rotation around the C2-C2a bond, in that two sets of resonances were observed for a varietv of R1 and R2 erouvs. P e r h a ~ sthe most strikine confirmation of such E and Z configurations is the finding that even in the enamine generated from the 2-methylthiazolium salt (2, R'=R2=H) there are two well-separated proton resonances for the C2aH2". Such results had been observed before for enamines derived from 2,3-dimethylbenzothiazoliumsalts". The 13C chemical shift for the C2a atom in the enamine indicated significant carbanion character. The fact that two sets of resonances persisted for 2 to at least 100 "C in DMSO suggested a barrier of at least 20 kcal m o l l for rotation around the C2-C2a bond, a barrier that was present in pyridine as wellz1. The conjugation in structures such as 2 is supported by their UV-visible spectra with A,, ranging from ca 290 nm for R = Me to 400 nm for R = C,H,, and 4 3 W 4 0 nm for R = C,H,CH=CH-, compared to 250 nm for the thiazolium salt precursors.
- .
-
2. Acidity of enamine precursor Palkylthiazolium salts at C2a in DMSO
This was investigated for a variety of R1 and R2 groups using the visible spectroscopic indicators developed by Bordwell and coworkers. It was found that a phenyl group acidified the C2aH by ca 2 pK units, compared to a Me groupz3. Little difference was found among H, OMe or Me substituents in their acid-weakening character. In DMSO the pK leading to enamine was 14 for the 2-a-alkoxyalkyl-3,4-dimethylthiazolium salts and ca 12 for the 2-a-alkoxybenzyl-3,4-dimethylthiazolium salts. 3. Acidity of enamine precursor 2-alkylthiazolium salts at C2a in water
The acidity at the C2a position had been estimated before based on the loss of deuterium o r tritium to solvent as a measure of deprotonation rates, and assuming diffusion-controlled rate constants for the reprotonation by Sable and coworker^^^,^^
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and Zoltewicz and a s s o ~ i a t e s ~ ~In- ~the ' . latter studies the rates of H-D exchange were measured at the C2a position in C2-substituted benzothiazolium salts. General base catalysis by formate was detected at pD 3.2. Based on diminished rates in C2-ahydroxyethyl vs C2-a-hydroxymethyl substituted benzothiazolium salts, steric inhibition to resonance in going to a planar transition state was suggested. The kinetic behavior of the C2aH of 2-a-hydroxyethylthiazolium salts, including thiamin, was extensively reinvestigated in water28~29 by Stivers and Washabaugh using triiodide trapping rates of the enamine as a measure of the deprotonation rate constant. Based on the magnitude of the Bronsted constant, a diffusion-controlled reprotonation rate constant by water of 3 x lo9 sK1M K 1was estimated, along with a C2aH pK, of 21.8 for 2-a-hydroxyethyl-3,4-diamethylthiazolium28 and 19.8 for 2-a-hydroxyethylthiaminZ9. The acidity at C2aH was also reconsidered recently using an entirely different approach. Based on the ability to directly observe the enamine when generated from C2-a-alkoxyalkyl- and C2-a-alkoxybenzylthiazolium salts in nonaqueous media, the enamine was next generated on a stopped-flow instrument by rapid mixing of hydroxide ion with C2-a-methoxybenzyl-3,4-dimethylthiazolium salts in water. The transient enamine was detected by monitoring the rapid rise and subsequent slower depletion of the absorbance corresponding to it at 400 nm (see above), as the thiazolium salt suffers concomitant ring opening according to equation 4. Rigorous kinetic analysis was rewarding in that both the deprotonation and reprotonation rate constants for equation 3 and the relevant pK values C15.3 for 2-(1-methoxy-p-trimethylammoniophenylmethy1)3,4-dimethylthiazolium ion (3, R = Me, X = Me,Nt)30 and ca 16 for 2-(1-methoxyphenylmethy1)-3,4-dimethylthiazoliumion (3, R = Me, X = H)31] could be extracted. 4. Kinetics of proton transfer to and from C2a in 2-alkylthiazolium salts
The kinetics of deprotonation leading to the enamine had been investigated by several groups using isotope exchange kinetic^^"^', as well as triiodide trapping of the
(3) X = NMe3+,CF-,, Br, Me, H R = Me or tetrahydropyranyl
ring-opened form
X,,,
enamine = ca 400 nm
21. Biochemistry of enamines
1259
enamine28,29.Stopped-flow methods offer the advantage of enabling us to study both enamine formation and reprotonation rates directly. For 3, X = Me3Nt, R = Me the rate constant for reprotonation of the enamine by water3' is only 500 s-' M-', orders of magnitude below the diffusion-controlled limit. This was attributed to a high barrier to protonation of the highly planar enarninelcarbani~n~~. The primary hydrogen kinetic isotope effects were estimated between 4 6 for the deprotonation rate constant k , for 3, X = Me3Nt, R = Me3', affirming that a proton transfer is rate-limiting and supporting the mechanism assumed in equation 4 above. Recent preliminary evidence indicates that even for alkyl substituents attached to the enamine, the reprotonation rate constant may be very much below diffusion-controlled. This conclusion is based on the ability to observe the enamine 2 (in equation 3) derived from compounds with R1 = OMe, R2 = n-pentyl, in partially aqueous solutions and only in the presence of cyclodextrins of appropriate cavity to accommodate the alkyl chaing3. 5. Redox chemistry of the enamine
While there has been ample evidence for in situ oxidative trapping of the enamine intermediate, direct evidence of its redox properties has only recently become available.
a. Indirect evidence for oxidative enamine trapping. Shinkai and coworkers developed flavin (see below) as a trap for carbanions, and bleaching of the oxidized isoalloxazine absorbance near 443 nm was employed as indicator of carbanionic reactivities, and implicating the transient presence of carbanionic intermediates in a variety of enzymic reactions and in corresponding chemical models. In one report N-hexadecylthiazolium bromide was found to be effective in decarboxylating 4-chlorobenzoylformic acid 4
(X = CI), as expected, to 4,4'-dichlorobenzoin and 4$-dichlorobenzil via the enamine. The latter compound resulted from subsequent air oxidation of the benzoin. On addition of the flavin analog 3-methyltetra-0-acetylriboflavin(MeFI), the thiazolium compound converted 4-chlorobenzaldehyde and 4-chlorobenzoylformic acid t o 4-chlorobenzoic acidj4. The 2-hydroxybenzylidenethiazolium complex (the enamine) was suggested to be the intermediate in order to explain all of the observations, wherein the MeFl intercepted the enamine, oxidizing it from the aldehyde to the acyl oxidation state (as in Scheme 1). An interesting synthetic application of such a mechanism is the thiazolium-MeFI catalyzed conversion of aldehydes to esters by oxidative trapping of the enamine followed by transfer of the acyl group to methanol35. Shinkai and coworkers also reported the synthesis of some isoalloxazine-thiazolium bis-coenzyme conjugates of the type 5 and found a significant intramolecular kinetic advantage over the intermolecular models above36. Hilvert and Breslow reported synthesis and catalytic properties of the B-cyclodextrinthiazolium conjugate 637.The conjugate provided a 40-fold rate acceleration for the ferricyanide assisted oxidation of p-t-butylbenzaldehyde compared to thiazolium ring per se. There was additional evidence presented to suggest that the conjugate 6 bound the benzaldehyde, since the thiazolium catalyzed exchange of tritium from the C7 position of [3H-C7]-benzaldehyde (presumably by the steps k - , , then k-, leading t o
F. Jordan
enamine in Scheme 1, followed by reprotonation, then release of ['H-C71-benzaldehyde) was also accelerated by the P-cyclodextrin-thiazolium conjugate compared to the thiazolium ring per se. Yano and coworker^'^ synthesized the 18-crown-6-thiazolium conjugate 7. It was found that the conjugate accelerated the flavin-dependent oxidative trapping of the enamine produced from pyruvate decarboxylation in the presence of alkali metal cations such as K + and Na', but not Li+, indicating the specificity of the particular crown ether for the larger cations. The authors suggested that the pyruvate anion is held by the crown-ether-bound metal ion in the proximity of the thiazolium ion, thereby accelerating the nucleophilic attack. In a different example, the thiazolium ring was incorporated in a bipyridine scaffold 8 that was capable of chelating metal i o d 9 . It was found that in the presence of the bipyridine-bearing thiazolium ring only, metal ions would catalyze the decarboxylation of pyruvate, as monitored by the bleaching of the isoalloxazine absorbance at 443 nm in ethanol in the presence of DBU. It was suggested that the metal ion may play a
21. Biochemistry of enamines
1261
catalytic role in the enzymatic reactions [note that all ThDP-dependent enzymes require Mg(I1) in addition to thiamin diphosphate]. These electrostatic effects in the last two examples are interesting. However, in the two ThDP-dependent enzymes for which there are now published 3D structures4042, the metal ion is quite far from the thiazolium ring, and is unlikely to have much influence since its charge is neutralized by both a negatively charged side chain of the protein (one incidentally conserved in all ThDP-dependent enzymes4345) and the diphosphate side chain. On the other hand, perhaps these metal-coordinating models are appropriate mimics for substrate binding and/or alignment towards nucleophilic attack by the ylide. In yet another study the thiazolium ring was attached to a macrotricyclic quaternary ammonium ion 9, bearing several positive charges to determine if rate accelerations of pyruvate decarboxylation could be observed46. Such rate accelerations could indeed be observed, especially for phenylpyruvic acid as a substrate. In addition, lumiflavin-3-acetic acid as a potential oxidant of the intermediate (see the oxidative decarboxylation pathway in Scheme 1) was shown to be reduced by the pyruvic acid analog in the presence of DBU in ethanol and the macrotricyclic quaternary ammonium salt.
Diederich's group has reported some bis-coenzyme models in which the thiazolium ring was a pendant on a macrocyclic system, that in the presence of MeFl in methanol converted aliphatic and aromatic aldehydes to the corresponding methyl esters4'. According to the mechanism in Scheme 1, the aldehyde is added to the ylide via k - , to produce HEThDP-type compounds, then is deprotonated ( k , ) to the enamine, that is oxidized to 2-acylThDP, that in turn is deacylated using methanol and resulting in the methyl ester. The principal novelty of the report is the ability to electrochemically recycle the reduced MeFIH-. The yield of aromatic methyl esters, especially with electron-withdrawingpara substituents, was much superior to that of the aliphatic esters of valeric and cyclohexanecarboxylic acids. b. Direct electrochemical oxidation behavior of enamines. Recently, the enamine generated from C2a-alkoxyalkyl and C2a-alkoxybenzylthiazolium salts by the addition of (Me,Si),NNa in DMSO according to equation 3 was subjected to electrochemical
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oxidation to determine whether the oxidation followed a one- or two-electron pathway. Both cyclic voltammetry and controlled potential (bulk) electrolysis indicated that, on deprotonation at C2a, all compounds studied underwent one-electron oxidation, presumably via a cation radical4'. These conclusions were given further credence by the isolation of two dimeric structures, that must have resulted from dimerization of the oxidized enamine at its C2a position. These electrochemical studies also provided the first oxidation potentials for such intermediates. 1
BFi
\
1,
BFi
Electrochemical oxidation
(5)
BFT
Table 1 lists the electrochemical results obtained for enamines derived from 2,3,4trimethylthiazolium salts 1 (according t o equation 5), where R' and R Z are the substituents on C2-methyl carbon and R3 = H. Two important conclusions can be drawn about the particular redox model: the occurrence of a one-electron pathway, and the predominance of the free electron spin TABLE 1. Summary of electrochemical data"
R1
R2
Peak potential (mV) vs Ferroceneb
Za Zh
2c Zd Ze
Zf
zg Zh Zi
3
Zk
H H CH3 OCH, H 0-Pyran OCH, OCH, OCH, OCH, OCH,
H CH3 CH3 CH3 Ph Ph Ph P-CF~C~H, p-BrC6H, p-CH,C,H, p-CH,OC,H,
-270 - 336 -450 -583 340 -447 - 426 - 320 - 392 -
vs SCE' 144 78 - 36 169 74 -33 - 12
-
Number of electrons transferredd
1.12
1.03 0.98 0.92
94
22
-447
-33
-461
- 47
" Counterion is BF;. Counter electrode: Pt wire; reference electrode: Ag/AgNO, (0.1 M) in CH,CN; working electrode: Pt disk; scan rate: 100 mV/s; solvent: Me,SO; supporting electrolyte: Me,NfBF,-. Ferrocene was used as an internal standard. Totentials obtained by adding 414 mV to column b. Counter electrode: Pt mesh separated from bulk solution; reference electrode: Ag/AgNO, (0.1 M) in CH,CN; working electrode: Pt mesh; supporting electrolyte: KNO,; solvent: Me,SO.
21. Biochemistry of enamines
1263
at the C2a position. These studies demonstrate that there is at least a possibility for the intermediacy of a thiazolium cation radical intermediate in the enzymatic pathways, only shown to date on the Fe4S4-dependent pyruvate-ferredoxin oxidoredu~tase'~.A possible caveat that needs to be raised about the electrochemical experiment is that the methoxy group in place of the biochemically relevant free hydroxy would indeed favor the one-electron process, and with the unprotected hydroxy group two-electron oxidation may be preferred. There is no evidence along these lines yet. 6. Condensation reactions of the enamines at C2u
It had been reported in the early fifties that thiamin was capable of producing acetoin from either pyruvate or acetaldehyde4'. Metzler's group also showed the production of acetolactate, and its thermal P-decarboxylation to acetoin. Presumably, the acetolactate was a result of the reaction of the enamine with pyruvate5". Later the C2a-hydroxyethylthiamin, HETh, was prepared and shown to be stable in acidic medium. It was also shown that both HETh and 2-methylthiazolium as well as 2-methylthiamin can condense with aldehydes in the presence of base, suggesting for the first time that the carbon acidity at C2a is not significantly altered by the OH-substituentS1. Thiazolium salts, presumably via their C2 ionized ylide, can act as catalysts in benzoin condensation (Scheme 2), in a reaction reminiscent of the reactivity of cyanide ionS2. Treatment of vroduces no thiazolium salts (inchdine. thiamin) with aaueous base and vvruvate .. detectable acetaldehyde, only acetolactate and its P-decarboxylated derivative acetoin. This suggests the preference of the enamine to condense with a good electrophile, rather than react with water protons to yield the ~2u-h~drox~eth~lthi&olium ion (reminiscent
-
SCHEME 2
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1264
of HEThDP). Also, Breslow and McNelis synthesized a series of C2a-hydroxyethylthiazolium salts, including the thiamin analog, then measured the acetoin produced on addition of acetaldehyde, thereby confirming the intermediacy of the HEThDP-type intermediates in benzoin condensationss3. In benzoin condensations using benzaldehyde as starting material, the initial adduct, i.e. the C2m-hydroxybenzylthiazolium (HBT) compound o r its alkoxide form, is readily tautomerized to the enol, o r enolate, that then condenses with a second benzaldehyde molecule. In a series of reports it was suggested that this is the result ofcarbene insertion behavior of the ylide"", rather than the result of nucleophilic additioni4. In aprotic media several mechanistic probes tended to disprove this thesiss5. The need for a protic solvent t o complete the condensation reaction (since compounds such as HBT are rather stable in D M s O ~ ~prompted ) the suggestion of the intermediacy of the charged species
HBT +
HBT 0-I+
(+ enol-amine resonance)
a-carbaniodenolate amine
HBT C-I+ a-carbaniodenolate amine
PhCHO
PhCHO
Ph
I
spontaneous
Benzoin, or Benzoin hemiacetal
+ Thiazolium ylide SCHEME 3
I
hase catalyzed or S N ~ (with OH- or MeO-)
21. Biochemistry of enamines
1265
shown in Scheme 3 in benzoin condensations, all of which would be better supported by protic solvents. In an aprotic medium, such as DMSO, a C2a-hydroxybenzylthiazolium salt is formed by nucleophilic additions5. There have appeared suggestions that in nonaqueous media, the 'double enamine' or syn-anti symmetrical dimer formed between two thiazolium salts on addition of base is the template for benzoin condensations (Scheme 4)s6. The
unsymmetrical dimer
"Double enamine" or "symm etrical" syn-anti dimer
'Double enamine'
+
OH
SCHEME 4
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X-ray evidence on ThDP enzymes of course rules out the possibility of two thiamin molecules being near enough to make such a pathway plausible on the e n ~ ~ m e s ~ ~ , ~ ' . More recent evidence from our laboratory indicates that when the thiazolium salt is first converted totally to the unsymmetrical and symmetrical syn-anti dimers (13C NMR indicated the presence of both configurations), addition of benzaldehyde to this solution cannot form HBT, whereas addition of benzaldehyde to a mixture that still contains monomeric thiazolium salts indeed forms this HBT adducP7. Such experiments tend to confirm that it is the enamine rather than the 'double enamine'(the benzaldehyde adduct of the syn-anti dimers) that participates in thiazolium salt catalyzed benzoin condensations. A further complicating feature in these reactions is the finding that HETh and its thiazolium and benzothiazolium analogs can, in the presence of a base such as Me,N or DBU, be tautomerized to the rather stable 2-benz0~lthiazolines~~~~. This reaction apparently requires a aprotic medium. Further, Chen s h o ~ e dthat ~ ~for , ~a number ~ of aromatic aldehydes, when the reaction is performed in methanol, the principal product is not HBT but rather the dimethoxyacetal of the precursor aldehyde. Thiazolium salts appear to catalyze conversion of some aromatic aldehydes to their acetals in reasonable yields. This appears to be a rare example of acetal formation under alkaline conditions. These various reactions of aldehydes and thiazolium salts, additional to the benzoin condensations, are outlined in Scheme 5. It may also be noted that in water, many of these reactions would give 'virtual' products that would not be distinguishable. While the epoxide has not been detected yet (in fact, it was suggested to the author by a kind referee), it offers a plausible explanation for the observations. The 2-benzoylthiazoline may be the thermodynamically favored product, as it is usually formed at reflux especially from benzothiazolium analogs, or with an electron-withdrawing group at the thiazolium C5 position. In the author's lab it was never observed in working with 3,4,5-trimethylthiazolium salts. Evidence for the intermediacy of the enamine has also been confirmed in some examples involving synthetic utilization of thiazolium salts, for example in the catalysis by thiazolium salts of Michael reactions between aldehydes and a,P-unsaturated compoundss8 (equation 6). In a different application, the reactivity of the condensing decarboxylase acetolactate synthetase was modeled (equation 7). C2a-hydroxyethylbenzothiazolewas converted to its silyl ether, that on treatment with BuLi and methylpyruvate afforded the acetolactyl adduct, whose desilylation, followed by N-alkylation, then treatment with Et,N in MeOH gave the methyl ester of acetolactate, along with some 2-acetylbenzothiazoline side product59.
6. Enzymatic Reactions of Thiamin-bound Enamines in Decarboxylases
That there is an enamine-like intermediate in all thiamin diphosphate-dependent enzymatic pathways has been suggested for many years, although the issue is still sometimes clouded by the observation that the C2a-protonated form, the C2a-hydroxyethylThDP when added to oxidases such as pyruvate oxidase (POX) and the pyruvate dehydrogenase multienzyme complex (PDHc), will undergo oxidation. In the early eighties the author's group undertook an effort to detect such an enamine on the enzymes, especially pyruvate decarboxylase (PDC, E.C. 4.1.1.1) (see Scheme 6 for reaction mechanism), as produced from conjugated substrate analogs.
21. Biochemistry of enamines
base
HBT +
HBT 0 - I t
-It
It
HBT 2-I+
(+ enol-amine
resonance')
HBT C-I+
OMe
r;-"..
+ Thiazolium ion
2-a-Methoxybenzylthiazolium ion
Benzaldehyde dimethylacetal SCHEME 5
F. Jordan
>A4H75 R3
S
OI
CH-CH=C-X R4
v H O S i M e 2 B u - t
S
(6)
R-CH-CH-C-X 0 II
R3
R4
*
I. BuLi
2. MeCOCOOMe
Me
*
MeOH. Et3N
4
COOMe
OH
Acetolactate Methyl Ester 1. Generation and identification of enamines bound to pyruvate decarboxylase
The substrates used to generate the enamines to date include both benzylidenepyruvic acids 10 and benzoylformic acids 4. In 1983 it was reported that (E)-4-p-chlorophenyl2-0x0-3-butenoic acid (CPB, 20, X =p-CI) acts as a mechanism-based inactivator of PDC60, and on decarboxylation it generates a new absorbance on the enzyme with A,, near 440 nm6'.
21. Biochemistry of enamines XC6H4CH=CHCOCOOH
XC6H4COCOOH
Py=4-amino-2-methyl-5-pyrimidyl ThDP
LThDP k C O 2
$5
RLCH2
/
OH-
R
'- CH3CH0 + -(J , S
R
HO Ylide
HEThDP
SCHEME 6
Subsequently, such enamines were detected on PDC derived from a number of other compounds related to 1062,63.Some years later Chung synthesized an appropriate thiazolium salt analog, treatment of which with (Me,Si),NNa in DMSO produced a n absorbance with the same A,,,64. AS discussed below, enamines derived from compounds 10 possess two potential protonation sites that are allylic with respect to each other. Zeng has shown that virtually all such compounds give two products on turnover (Scheme 7): the cinnamaldehyde, resulting from C2a protonation-the normal turnover product, and dihydrocinnamic acid, resulting from C2y protonation, followed by tautomerization to the 2-acylThDP and its hydrolysis64.65.The ratio of cinnamaldehyde to dihydrocinnamic acid decreases substantially with the electron-withdrawing power
F. Jordan
Y = H. F. CI. 61 ThDP
/
\
Protonallon.
climinslian. Hdide followed by slow regain 01 activity
ky
Inactive enzyme
Turnover
1
0 p-Methyl (or halomethyl) cinnamaldehyde
+
OH Quinone methide. k,,.,
Active P D C
+
h,,,
near 580 n m
1
Tautamerizatian
0
,,,,X,
0 2-Acyl T h D P
= 382 nm
1
khyd Hydrolysis
+
H 0
SCHEME 7
active P m
+ active P D C
0
21. Biochemistry of enamines
1271
of the phenyl substituent and is 1:40 for 10, X = FCH,. Interestingly, the ratio of the two protonation products is also under allosteric control in that addition of the substrate surrogate pyruvamide to PDC can increase the cinnamaldehyde:dihydrocinnamic acid ratio dramatically, thus the allosteric regulation affectsthe relative C2c(:C2y protonation rateP. 2. Visible spectroscopic properties of enzyme-bound enamines
To date enzyme-bound enamines have been detected from two different conjugated pyruvate analogs: 4 and 10, where X is a para or meta substituent. For compounds 10, for a variety of X groups, ranging from m- or p-, C1, Br, F, OMe, Me as well as for I , , is,4 3 M 4 0 nm, but for the p-NO, it is 585 nm. For 4, X = p-NO,, the m-NO,, the , A,, is 550 nmb6. The very large red shifts observed for the para nitro compounds serve as particularly strong confirmation of the assignments, and suggest that for 4 and 10, X =p-NO,, (i.e., 11 and 12) the quinoidal resonance structures on the left are quite prominent in providing this long-wavelength absorbance:
other resonance smcmes
1272
F. Jordan
The electronic spectroscopic data collected both on the model enamines and on the PDC-bound ones leave little doubt that all of these enamines are planar, highly conjugated structures. Therefore, invoking a pyramidal C2a atom in the enamine intermediates no longer offers a valid hypothesis, at least on PDC, and likely not on other ThDP-dependent enzymes either. 3. Redox properties of enzyme-bound enamines
a. Evidence for 2-acylthiamin diphosphate intermediates on a-keto acid dehydrogenases. In these multienzyme complexes the first enzyme E l carries the decarboxylating ThDP that forms the enamine on decarboxylation. The second enzyme E2 performs oxidative transfer of an acyl group from E l to coenzyme A. In a seminal contribution, Reed identified lipoic acid covalently bound to the E2 enzyme as the oxidizing agent responsible for this function in a-keto acid dehydrogenases6'. Finally, the third enzyme E3 is responsible for reoxidation of the reduced E2, using flavin adenine dinucleotide (FAD) and, ultimately, nicotinamide adenine dinucleotide (NAD'). The sequence of these reactions, as catalyzed by the pyruvate dehydrogenase multienzyme complex isolated from E. coli, is summarized in Scheme 8. The lipoic acids (there appear to be
ThDP-El
+
CH3COCOOH
ThDP=C(OH)CH3-E I
-i-
CO2
ThDP=C(OH)CH3-El
+
Lipoamid-E2
CH3CO-DihydrolipoyLE2 DihydrolipoyLE2
+
+
FADH2-E3
CoASH FAD-E3
+
NAD+
-
enamine
ThDP-El
+ CH3CO-DihydrolipoylLE2
DihydrolipoylLE2 Lipoamide-E2 FAD-E3
+ AcetylCoA
+ FADH2-E3
+ NADH
SCHEME 8
two or three present on E2, depending on the complex) are covalently attached via an amide linkage to the second protein chain E2. Rastetter and coworkers showed that the thiazolium-bound enamine could be sulfenylated by linear disulfides, although lipoic acid (admittedly a weaker oxidizing agent) could not accomplish this in an intermolecular reactionz0. Assuming that such a tetrahedral complex does result in the reaction (i.e. electron and group transfers are coupled, as discussed by Frey6'), one could still envision two distinct mechanisms for the reductive acylation of lipoamide-E2 by the ThDP-bound enamine on El as drawn in Scheme 9. Formation of a tetrahedral intermediate is assumed, but this may collapse to 2-acylThDP-El and dihydrolipoyLE2, followed by acyl transfer (upper pathway, Scheme 9). Alternatively, the lower pathway is followed and direct collapse of the tetrahedral intermediate to ThDP-El and acyldihydrolipoyl-E2 may result. Frey and coworkers were able to demonstrate three facts: (a) the presence of a small amount of 2-acylThDP in the reaction mixtures; (b) that 2-acetylThDP-El is chemically competent to acetylate dihydrolipoamide, unlike in model systems; and (c) the PDHc reaction is likely reversible all the way to 2a ~ e t ~ l T h DThus, P ~ ~ while . there is the suggestion of a stepwise redox process, in which the enamine is first oxidized to 2-acylThDP-El and dihydrolipoamide-E2, followed by transfer of the acyl group from the ThDP to dihydrolipoamide on E2, this is difficult
21. Biochemistry of enamines Enamine-El
-
Enamine-El
SCHEME 9
to differentiate unequivocally from the case where there is a small equilibrium concentration of 2-acylThDP. That is, the arrow pointing to formation of 2-acylThDP may be reversible. In addition, Frey's group could also demonstrate the regiospecificity of the reaction, i.e. the S8 of the lipoic acid is the initial recipient of the acyl group'j9. Perham and coworker^'^ overexpressed the lipoyl domain of the E2 protein from E. coli. They reported that the ThDP-El-bound enamine had a ca 10,000 larger k,,,/K, for the reductive acetylation of lipoamide covalently attached to this lipoyl domain than for the reductive acetylation of lipoamideper se. Apparently, there is recognition between certain protein segments of E l and the lipoyl domain of E2 that enhances the interaction and facilitates the reaction.
1274
F. Jordan
It is also relevant that the oxidation of the enamine to 2-acylThDP (Scheme 9) generates what appears to be a high-energy bond between the C2 of the thiazolium ring and the C2u carbon atoms. At least in enzymatic reactions, the 2-acylThDP can transfer a n acetyl group to a thiol, generating another high-energy bond, and thence to coenzyme A, generating acylCoA, yet another high-energy compound. In fact, 2-acylThDP can also acylate inorganic orthophosphate and form acetylphosphate, yet another highenergy compound7'. In model systems the transfer of the 2-acyl group from 2-acylThDP to a variety of nucleophilic acceptors, including thiols, was found to be exceedingly s l ~ g g i s h ~ ' - ~ ~ . The oxidation of the enamine on E l in PDHc by nonlipoic acid acceptors has also been explored for many years. For example, ferricyanide reduction monitored by visible spectroscopy has become a standard test to assay El activity, notwithstanding the attendant problems, including the instability of the thiazolium ring to such conditions. 2,6-Dichlorophenolindophenol (DCPIP) has also been used as an alternative electron acceptor in mechanistic studies of PDHcs7=. More recently, McNally developed an alternative chromophoric assay for the E l component of PDHc in either the multienzyme complex or the isolated E l ~ u b e n z y m e ~ ~ . This assay is predicated on the earlier finding that the linear disulfide 4,4'-dithiodipyridine is capable of trapping the enzyme-bound enamine (equation 8) on PDC, generating a chromophore at 380 nm77. 4,4'-Dithiodipyridine was indeed also effective in trapping the enamine on PDHc isolated from E. coli K-12 cells, as well as in the purified E l subenzyme, resulting in the formation of the A,,,. Therefore, at least using this linear disulfide it would appear that there is formed a 2-acetylThDP intermediate on E l during the oxidation process. This new assay of the E l activity in the intact PDHc turned out to be a very effective monitor of induced conformational changes. When exposed to a variety of inhibitory monoclonal antibodies elicited to either the holo-PDHc or the E l , the assay sensed antibody-induced conformational changes76.
Enamine
b. Oxidation of the thiamin-bound enamines onpyruvate decarboxylase. It was reported by Christen in 1973 that a number of enzymes that proceed via transient carbanionic intermediates could be inactivated in a 'paracatalytic' f a s h i ~ n by ~ ~oxidation .~~ of the carbanion in situ using ferricyanide ion o r tetranitromethane. Some of the enzymes discussed in this review, including PDC and the SchiK-base class of aldolases, were
21. Biochemistry of enamines
1275
among those tested. The oxidative trapping led to inactivation, whose mechanism is still not clear. A variation on this theme was exploited by Hiibner and colleaguesso and Atanassovasl who used 2,6-dichlorophenolindophenolto oxidatively trap the enamine derived from compounds with the structure of 4 on PDC. Interestingly, it was found that the turnover number kc,, and the efficiency for such substrates was unaltered in the oxidative decarboxylation reaction, compared to the normal turnover. This was interpreted to mean that the oxidative and nonoxidative decarboxylation pathways shared a common rate-limiting step, enamine formation (i.e. decarboxylation), and that the oxidation took place subsequently. This finding is not unexpected. The author's group took an alternative approach. Having succeeded in observing the PDC-bound enamine at 440nm derived from compounds 10, it was of interest to determine whether it could he oxidized on the enzyme by disulfides, mimicking the lipoamide reaction on PDH. Two experiments were useful in this regard. On the one hand, on mixing PDC-ThDP with CPB, 4,4'-dithiopyridine was added after the formation of the enamine at 440 nm. This resulted in the gradual reduction of the absorbance at 440 nm and a concomitant increase at 380 nm, with a rather good isobestic point. In a different experiment, pyruvate or CPB were mixed with PDC-ThDP and 4,4'dithiodipyridine all at once, leading to the formation of a new absorbance at 380 nm, irrespective of the nature of the While the origin of this new absorbance was puzzling initially, it was eventually clearly shown that it pertained to the N-acyl-4-thiopyridone, rather than to the thiol esters2. This information suggested that, at least on PDC, the oxidation of the enamine by the linear disulfide takes place via a stepwise mechanism, forming a 2-acylThDP, that is deacylated by the nitrogen end of the ambident nucleophile, 4-pyridinethiol. c. Redox reactions resulting from enamines derived from halopyruvate analogs. When the conjugated enamine has a Cp-leaving group, whose elimination would produce a n system in direct conjugation with the rearomatized thiazolium ring, such elimination will often take precedence over the normal turnover, as exemplified with the fate of P-fluoropyruvate.
\+ ThDP
+ FCH2COCOOH CH3COOH
co2
0 Tautomerization
Enamine It was reported that P-fluoropyruvate is an eRective inhibitor of P D H C ' ~ .that ~~ eliminated fluoride ion in an enzyme concentration-dependent manner. Presumably, this resulted from initial formation of the enamine from decarboxylation, followed by elimination of fluoride leading to 2-(1-hydroxyethenyl)ThDP, that on ketonization gave
1276
F. Jordan
2-acylThDP (equation 9). The acyl group could then suffer a variety of fates. It may be transferred to water, resulting in the formation of acetic acid. Alternatively, if there is a cysteine thiol group nearby on the enzyme, the 2-acetylThDP may acetylate this thiol. The S-acetylcysteine so formed would be hydrolyzed slowly near physiological pH. Were the cysteine being acetylated, essential for enzymatic activity, its acetylation would lead to inactivation of the enzymes3. Both Hiibners5 and Kluger's groups6 reported that fluoropyruvate was a substrate for PDC, that also eliminated fluoride ion producing acetate, without inactivating the enzyme. In extending this idea to other potentially inhibitory and mechanistically informative molecules, Kozarich and his associates synthesized p-halomethylbenzoylformic acids 4 (X = p-haloCH, and found that the bromomethyl and chloromethyl analogs eliminated halide ion during the decarboxylation by the enzyme benzoylformate decarboxylase. It was suggested that the reaction proceeded by halide elimination from the central enamine, leading to a quinone methide, that on tautomerization yielded 2-benzoylThDP, whose hydrolysis led to the benzoic acids8'. Based on these precedents, the author's group synthesized the series ofp-halomethyl analogs of 10, including the BrCH,, CICH, and FCH, compounds. Interestingly, the p-bromomethyl compound indeed eliminated bromide ion quantitatively in a PDC . ThDP-dependent reaction. Formation of 2-acylThDP was confirmed by: (a) UV measurements of the time course of the formation of thep-methylcinnamic acid, and (b) trapping of the 2-p-methylcinnamoylThDP with 4-thiopyridine, resulting in the characteristic 380-nm absorbance (as shown in equation 8)". The enamine in this case underwent halide elimination leading to the quinone methide, that was later identified at 580 nm, and its rate of formation was shown to be under allosteric The enamine formed from thep-CICH, compound was partitioned between chloride elimination and turnover, while thep-FCH, compound undergoes turnover only66(Scheme 7). These examples provide enough precedents to allow some generalizations. Apparently, when the terminal carbon atom of the conjugated enamine system is endowed with any respectable leaving group, this will lead to elimination of the leaving group. This reactivity is totally consistent with the propensity of the enamine for oxidation, as formally the elimination is equivalent to oxidation of the C2o( site. Formation of the quinone methide (only observed directly on PDC so far66) is a particularly powerful indication of the presence of the enamine preceding it. This observation could be very useful for both synthetic and mechanistic purposes, as the quinone methide produced on PDC has already been shown to he trapped by both electrophiles (H') and nucleophiles ( t h i ~ p h e n o l ) ~ ~ . This idea of elimination from the C-terminus of conjugated enamines gains further support from the preliminary observations that when 4 (X = p-NO,), is added to PDC, 4 gives rise to a species with a blue color near 550 nm, and that blue-colored species is slowly converted to a green-colored one. According to accepted mechanistic criteria both highly chromophoric species are enzyme-bound. A possible explanation of these observations is the equilibration between the enzyme-bound nitro and nitroso compounds, since the latter are among the few organic functionalities with green colorss9 (equation 10). d. Trapping the enzyme-boundenaminesbyflauins. It has been known that the enamine pyruvate oxidase (POX), a membrane-activated ThDP-dependent bacterial oxidative pyruvate decarhoxylase, oxidizes the enamine using first flavin (FAD) then ubiquinone as the electron acceptor. It has been shown that decarboxylation/enamine formation is the rate-limiting step in the reaction of the activated POX, rather than oxidationg0. A still somewhat puzzling observation is that POX appears to be able to generate the
21. Biochemistry of enamines
f s \
fls
Y
H0
"$_
t )
0-N
+ I
+ I
O=N
0-
0-
& Il
Tautornerization
&nax
enarnine = 550
I
&L /
(10)
t
<-N
O=N
I 0-
I OH
II
H20
2-a-carbanion
Ht,-H20
"i, flS\ O=N
? Green, I-,,,,, = 675 nm
acetic acid either from HEThDP or from ThDP and pyruvate with comparable rates. Based on the cumulative evidence in favor of the enamine, rather than HEThDP, being the substrate for oxidation, it is likely that the active center environment can ionize the HEThDP to the enamine, prior to oxidation. That P D C possesses the ability to ionize the HEThDP to the enamine gains support from its ability to catalyze the synthesis of acetoin from acetaldehydeg1. Interestingly, POX has a genetically closely related cousin acetolactate ~ y n t h a s e ~ ~ (ALS) that still has a bound FAD. Instead of oxidizing the enamine, ALS employs the enamine in nucleophilic addition to a second pyruvate producing acetolactate, an important anabolic intermediate in the biosynthesis of the 'essential' aliphatic amino acids in plants. ALS is a major target for herbicidesgz. ALS may be using the FAD to protect the enamine from being protonated, prior to condensation. In an attempt to mimic the function of these enzymes, P D C was derivatized with the flavin analogs 8-bromoacetyl- and 6-bromoacetyl-10-methylisoalloxazine (the heterocyclic core of flavin cofactors shown in equation 20 below). The former led to total
1278
F. Jordan
inactivation of PDC vis-a-vis pyruvate decarboxylation, the latter to ca 80% inactivation. Interestingly, the former could indeed produce acetate in a rather inefficient process93. Presumably, the production of acetate was the result of oxidative interception of the enamine by the covalently attached isoalloxazine. The exact nature of this oxidation process is somewhat obscured by the likelihood that the covalent attachment of isoalloxazine may be as far as 20 A from the ThDP binding ~ i t e ~ ' . ~ ~ . e. Adventitious enamine oxidation by dioxygen. In a survey of ThDP-dependent decarboxylases, including acetolactate synthase, along with some other enzymes believed to operate by carbanionic intermediates, Abell and Schloss reported that these reactions are always accompanied by some oxidative side-product. These side-products result from a dioxygen-dependent 'oxygenase' side reaction, and point once again to the propensity of the enamine to facile oxidation95. This type of oxidative trapping of carbanionic intermediates was mentioned above under 'paracatalytic' i n a c t i v a t i ~ n ~In ~ . ~the ~. presence of dioxygen, acetolactate was found to be converted to pyruvate and acetate by ALS, and isotopic labeling studies showed that the acetate molecule incorporated one oxygen atom from the added dioxygen, prompting the authors to propose the mechanism of equation 11.
Acetolactate
coo-
enamine I
In fact, a closer examination of the products of decarboxylation from compound 4 and 10 led Zeng to conclude that, unless dioxygen is rigorously excluded, there is always perhaps 1&15% carboxylic acid product formed (along with the 'normal' turnover products as discussed in Scheme 7) that can best be explained as resulting from dioxygen oxidation of the intermediate enamine in each case66, similar to the proposal by Abell and Schloss. It is also noteworthy that, in the presence of ThDP and pyruvate only, some PDHcs have been reported to undergo slow i n a ~ t i v a t i o nThis ~ ~ . inactivation could be explained using a combination of now known facts. If on decarboxylation of pyruvate the enamine undergoes slow air-oxidation concomitant with turnover, the resulting 2-acetylThDP can periodically transfer its acetyl group to a CysSH on the enzyme, rather than to water. This would lead to inactivation, according to the model for fluoropyruvateinduced inactivation discussed in equation 9.
21. Biochemistry of enamines
1279
4. Kinetic competence of enzyme-bound enamines
In order to demonstrate that the enamine formed from compounds 10 is kinetically competent to be on the turnover pathway, stopped-flow experiments were performed at 440 nm by mixing P D C with compounds 10, X = p-CI, m-CF, and m-N0297.In each case studied, the rate of formation of the enamine was very significantly enhanced by the addition of the allosteric activator pyruvamide (a nondecarboxylatable substrate surrogate98, and there was evidence that the rate of enamine formation on P D C from the latter two compounds was nearly the same as the turnover rate constant per subunit for pyruvate under similar condition^^^. Furthermore, and interestingly, the formation of the enamine by a variety of different pyruvate decarboxylating enzymes, as well as turnover of 4 by benzoylformic acid decarboxylase, proceed with similar turnover numbers (within the limits imposed by the required estimations). This led to the speculation that the environments on such enzymes have been optimized for ThDPcatalyzed decarboxylations, essentially reaching the highest attainable value97. The kinetic results suggest that enamine intermediates are kinetically competent on all such enzymatic pathways. The rate-limiting steps were examined in both model and PDC-catalyzed decarboxylation reactions using the k12/k13 kinetic isotope effect (KIE) on the scission of the C-C bond, by measuring 45C02/44C0, ratios in an isotope ratio mass spectrometer. An excellent model system for the unimolecular decarboxylation of LThDP to the enamine provided an intrinsic KIE for the decarboxylation step per se of 1.0519'. The model reaction for the enzyme-catalyzed process, the decarboxylation of pyruvate with thiamin, yielded a k12/k13 KIE of 0.992 that varied with solvent c o m p o s i t i ~ n ' ~The ~ . k12/k13 KIE for the pyruvate decarboxylase-catalyzed reaction at pH 6.2 has been measured by four g r o ~ p s ~ and ~ - l can ~ ~ be safely placed between 1.006 and 1.008. In both the thiamin-catalyzed model reaction and in the enzyme-catalyzed nonoxidative reaction, C-C bond scission (enamine formation) was only partly rate-limiting. O n the enzyme the partitioning ratio for LThDP, i.e. k ,/k, (Scheme 1) is ca 0.2. Since such 'competitive' methods measure KIEs on V,, JK,, they are not incormative concerning decarboxylation vs product release. More extensive KIEs using a variety of methods were performed by Schowen and colleagues on the PDC-catalyzed reactions of both substrates and some i n a c t i v a t ~ r s ' ~ enabling ~ ~ ' ~ ~ , a description of the relative rates of the various steps on the pathway, including the effects of substrate activation.
5. Stereochemical behavior of enzyme-bound enamines
While the substrate and products of the decarboxylases are achiral (e.g. pyruvate and acetaldehyde or acetate), LThDP and HEThDP are chiral, and knowledge of the stereochemical behavior of these intermediates would provide significant insight to the mechanism. For example, are both enantiomers of LThDP decarboxylated to the enamine, is the enamine converted to only one or both enantiomers of HEThDP and can the enzyme convert only one or both enantiomers of HEThDP to acetaldehyde and ThDP? It had been reported that HEThDP isolated from reaction mixtures of PDHc is optically active, suggesting that the enamine is in a chiral environment on the enzyme and protonation is favored from one side1O6.This is a significant finding, yet protonation is only an undesirable side reaction for PDHc. Kluger and coworkers have expended considerable effort on the resolution of racemic HETh into its enantiomers and, with the help of X-ray crystallography, could assign the absolute configuration to each optically pure enantiomer. These pure enantiomers were next converted to the ( + ) and (-)HEThDP. When added to the apo-wheat germ
1280
F. Jordan
PDC (devoid of its ThDP), both enantiomers of HEThDP were converted to acetaldehyde with a modest preference of PDC for one enantiomerlo7. As pointed out by the authors, this is not as surprising as may appear at first glance, since the expulsion of acetaldehyde may be induced by -OH deprotonation of HEThDP, and may not be subject to as stringent a steric requirement as reactions at the C2m atom itself, the chiral center. That the enamine is in a chiral environment on PDC could also be deduced from an examination of the partial reaction of the enzyme in the reverse direction (see Scheme 1). One can add acetaldehyde to the enzyme, presumably creating HEThDP (k-,), followed by C2mH ionization to form the enamine (k-,), then react the enamine with a second acetaldehyde molecule and release the acetoin from the enzyme. Chen and Jordan showed that the acetoin so formed is optically active9', clearly indicating that addition of acetaldehyde to the enamine has a definite 'sidedness', i.e. there is a preferred approach of acetaldehyde for reaction with the enamine. 6. Are enamine mimics general transition-state analogs for thiamin diphosphate-dependent enzymes?
If the formation of the enamine in ThDP-dependent reactions is via a high-energy transition state, then according to the Pauling 'transition state' hypothesis, the enzyme active centers performing such reactions should have evolved to be complementary to these high-energy transition states. In other words, by preferentially binding the transition state of such reactions, rather than the ground state, the enzymes could achieve their maximal rate accelerations. In 1976 Gutowski and Lienhard reported that the 2-thiothiazoline and 2-thiazolinone derivatives of ThDP (14,15) are potent slow-binding inhibitors of PDHclo8 from E. coli and suggested that this inhibition was due to the resemblance of the compounds to the transition state of the decarboxylation step, i.e. the transition state is enamine-like. It was later found that neither PDC from brewers'
ThDP-bound enamine
(13)
21. Biochemistry of enamines
1281
yeast log or wheat germ1lo, nor other ThDP-dependent enzymes such as transketolasel " and pyruvate oxidase112 had a significantly higher affinity for these compounds than for ThDP itself. Apparently these structures are not universal 'transition state analogs' for ThDP-dependent enzymes. One may also speculate that, perhaps on PDHcs only, there may be a side chain near the ThDP site that can reversibly form a transient covalent bond with the 2-S or 2 - 0 substituents of the 'transition state' analogs. 7. Possible role of thiamin diphosphate-dependent enzymes in enamine stabilization
Starting with the work of Lienhard and his coworker^^^^^^'^ there have been several contributions in the literature that indicate that the thiazolium catalyzed decarboxylation is significantly accelerated by the use of a low dielectric medium, leading to the suggestion that a major source of rate acceleration in enzymes that perform this reaction is provided by a medium effect. As estimated recently by Alvarez and coworkers105,the enzyme accelerates the overall pyruvate decarboxylation reaction by a factor of over and above the corresponding thiamin catalyzed rate. It was also estimatedlo5 that the enzyme accelerates the decarboxylation step by a factor of 10'. Based on available evidence concerning the ability to generate the enzyme-bound enamine from a variety of ThDP-dependent enzymes near pH 7, stabilization of the enamine in the enzyme active centers could overcome at least some of this barrier. For example, the pK for ionization of C2a-hydroxybenzylThDP to generate the corresponding enamine appears to be near 15-1630-32, yet the enzyme benzoylformate decarboxylase functions near pH 7. Also, PDC is capable of synthesizing acetoin from acetaldehyde at pH 6, even though there is a claim that the pK for ionizing HEThDP at C2aH is near 2OZ9.Three rate constants in Scheme 1 have relevance to the enamine's stability: k,, k, and k , , the ratio k_,/k3 determines the pK here referred to. For benzoylformate decarboxylase, the model suggests that k, is within a factor of 5&100 compared to the turnover This step may require only modest rate acceleration. The models clearly indicate that the rate constants k, and k-, must be greatly accelerated. Both steps (denoted by k, and k-,) proceed with considerable charge neutralization in going to the transition state, given that LThDP and HEThDP are ionic and the enamine is neutral overall. Therefore, lowering of the effective dielectric constant could benefit both rates. A measure of the pK for the ionization leading to the enamine on the enzyme would be valuable in assessing the ability of the enzymes to lower the pK and the pertinent rate constants, and is nearly at hand with the use of chromophoric substrates. Since each unit of pK lowering would gain 1.4 kcal mol-I, it is not impossible that the relevant enzymes could gain much of the 10 kcal mol-I rate acceleration simply by suppressing the pK discussed. Recently, the molecular structure of the first member of this large class of enzymes, PDC, has been determined to 2.4 A resolution and an excellent R f a c t ~ r ~ It' ?is~already ~. quite obvious that in the ThDP vicinity, especially near the thiazolium ring, there is a considerable number of hydrophobic side chains, perhaps creating a lowered 'effective dielectric constant'. The tools of molecular genetics in combination with kinetics will shed further light on the ability of each of these amino acids to accelerate the individual steps involved with enamine turnover. C. The Reaction of Transketolase
A second class of ThDP-dependent enzymes, that perform the biological equivalent of the benzoin condensation reaction, interconvert sugar phosphates of different chain lengths. In the pentose shunt transketolase catalyzes the reaction shown in Scheme 10,
F.Jordan
Glyceraldehyde-3-phosphate
2-(1,2-Dihydroxyethy1idene)-ThDP the C2a enamine
BH+ OH OH OH
emf-
+
+ ThDP
-
Ribose-5-phosphate
OH OH OH
0~05Sedoheptulose-7-phosphate SCHEME 10
21. Biochemistry of enamines
1283
in which the enamine intermediate again plays a central role (although never directly detected). In this case the enamine is used to react with the aldehyde of a sugar phosphate, and the single most important difference between such reactions and the decarboxylases is the nature of the binding sites: one would surmise that the active center of transketolase should be more charged than that of PDC to enable binding of the phosphates. A cursory look at their active centers does not give any obvious insight to this i ~ s u e ~ ~ . ~ ' , since the ThDP binding sites are very similar, except that in transketolase there appear to be more positively charged side chains4' near the diphosphate of ThDP.
Ill. ENAMINES IN SCHIFF BASE ENZYMES
There are several enzymes that form a Schiff base between their substrates and either a lysine &-amino group from the protein, the aldehyde electrophile of pyridoxal-5phosphate or the keto group of a covalently bound pyruvyl moiety. The 'electron sink' under all these conditions is either the imine or its protonated iminium form, that in many cases leads to the formation of an enamine by the variety of pathways outlined below. A. Lysine-dependent 'Schlff base' Enzymes
1. Acetoacetate decarboxylation
Acetoacetic acid and related b-keto acids undergo a 'spontaneous' thermal decarboxylation, according to which the unionized form of the acid is decarboxylated 30-100 times faster than the ionized one (depending on the a n a l ~ g ) ' ' ~ . " ~The . unionized form is believed to undergo concerted proton transfer and C-C scission resulting in the enol of acetone, 16 whose existence is well-established from halogen trapping experiments. The decarboxylation has also long been known to be catalyzed by primary amines117. According to this pathway, the keto group forms a covalent complex (SchilT base) with the primary amine. The imine formed, or its iminium form is decarboxylated to an enamine, that in turn is hydrolyzed to the ketone (Scheme 11). It was established by Westheimer and coworkers that the enzyme acetoacetate decarboxylase isolated from Clostridium acetobutylicum follows this scheme as well, the E-amino group of a lysine serving the primary amino group f~nction"~. The mechanism was put on a firm basis by using the in situ trapping of the ketimine with BH4- ions, a mechanistic tool first used by Fischer, Krebs and coworker^"^ to demonstrate that pyridoxal phosphate is covalently bound to phosphorylase A by such an aldimine linkage. Addition of borohydride to acetoacetate decarboxylase and [2-l4C]-acetoacetate, on acid hydrolysis, gave labeled N"-isopropylaminolysinem, presumably formed by reductive amination of the acetone-imine product resulting from decarboxylation. This catalytic lysine E-amino group in acetoacetate decarboxylase was shown to have a pK of 5.912', significantly lower than the pK near 10 observed for this group in water. This dramatic pK lowering would impart nucleophilicity to this group at pH 6-7. In model systems it was found that amines, such as cyanomethylamine and 2,2,2-trifluoroethylamine (with pK values near 6), could act as excellent mimics of the enzymatic r e a ~ t i o n s l ~ " ~ In ~ . the amine catalyzed decarboxylation reaction, the bell-shaped rate-pH profile indicated that the mechanism changed from rate-limiting nucleophilic addition of the amine to the carbonyl at low pH, to rate-limiting decarboxylation at higher pH. Evidence was obtained for the presence of the imino complex on mixing
F. Jordan
Acetoacetic acid
L
Acetoacetate ion
Enolate
Acetone
Schiff base SCHEME 11
acetoacetic acid with such amines at pH 6, since it tautomerized to a conjugated intermediate whose formation and disappearance could be detected by UV spectroscopy at 280 nm. This same absorbance could also be produced by reacting ethyl acetoacetate with the same amines. It is believed that in both cases the enamine intermediate CH3C(NHR)=CHCOORf (or H) is formed. In addition, the imino complex was subject to trapping by NaBH3CN. The electronwithdrawing power of the imine or its N-protonated form are superior to the ketone in providing as much as a millionfold rate acceleration compared to the 'spontaneous' reaction. The KIEs for scission of the C-C bond to form the enamine (by measuring 45C02/44COzratios) of both the model amine and the acetoacetate decarboxylase catalyzed reactions were studied by O'Leary and B a ~ g h n " ~In . the primary amine catalyzed reaction the KIE exhibited pH-dependence consistent with the kinetic data above. In the enzyme catalyzed reaction a pH independent k12/k" KIE of 1.018 was reported, consistent with the idea that a nucleophilic attack by the lysine amino group and decarboxylation are both partially rate-limiting. The stereochemistry of the acetoacetate decarboxylase catalyzed reaction was also investigated. It was first demonstrated that the enzyme selectively exchanged one of two methylene protons of butanone with deuteronslZ6. Subsequently, it was shown using substrates 17 and 18 that the reaction proceeds with retention of configuration giving 19 and 20127.128(equation 12), as appears to be the case in the pyridoxal catalyzed decarboxylations as well (see below). Both experiments suggest that the enamine is protected from one side, and departure of carboxy group and protonation of the enamine take place from the same side.
21. Biochemistry of enamines Acetoacetate ~ecarboxylase)
R
H
R ~CHR NH-Enzyme
1285
D20
R
t 1
(-)-(17) R = -(CH2)4(+)-(IS) R = methyl
RCOCH2R . + Aceto acetate Decarboxylase
H
(-)-(19) R = -(CH2)4 (+)-(20) R = methyl
2. Class I aldolases
It was reported by Horecker and coworkers that one class of aldolases (called Class I to distinguish it from the Class I1 aldolase that is metal ion-dependent) could be inhibited by the addition of borohydride reducing agent to reaction mixtures containing both enzyme and s u b ~ t r a t e ' ~ ~It. 'was ~ ~ then . shown for the fructose-1,6-bis-phosphate aldolase that the inhibition resulted from reduction of the SchitT base formed between the dihydroxyacetone phosphate substrate and the &-aminogroup of a lysine side chain, thereby compromising the ability of the lysine to participate in subsequent turnover. The reaction of the glycolytic enzyme fructose-1,6-bis-phosphatealdolase, perhaps the best-known class I aldolase, is believed to proceed according to the mechanism shown in Scheme 12131.
F0
+
NH2Lys-E
CH20H Dihydroxyacetone phosphate
Protonated Schiff base Enamine
Glyceraldehyde-3-phosphate SCHEME 12
1286
F. Jordan
As is evident, the reaction proceeds with very high stereoselectivity, since the enzyme can perform stereospecific P-protonation (protonation from only one side) of the enamine leading to dihydroxyacetone phosphate. The imine mechanism for both acetoacetate d e c a r b ~ x y l a s eand ' ~ ~ class I aldolasesl" is also supported by the finding that the substrates that have "0 in their keto groups that undergo the putative Schiff base reaction lose this oxygen to solvent and introduce 1 6 0 from solvent water at the corresponding positions in the products. 6. Pyridoxal-dependent Enzymes
Pyridoxal-5-phosphate (PLP) is perhaps one of nature's most versatile coenzymes, capable of modifying a-amino acids by decarboxylation, racemization, transamination (conversion of the a-amino group to an a-keto group) as well as elimination or substitution of a leaving group at the or even elimination at the y carbon of the a-amino a ~ i d ' ~ ~ - ' ~ ~ . The first step in each of these reactions is formation of a p-imino group or a P-iminium ion between the aldehyde of the coenzyme and the amino group of the a-amino acid substrates, thereby providing the b-electron sink required for decarboxylation or ionization of the a-CH. In the 'resting state' of the enzyme the pyridoxal is covalently (ENHJ and the amino acid substrate sequestered to a lysine &-amino presumably gives initial transimination, prior to decarboxylation. After decarboxylation, there is yet a second transimination, that enables release of the decarboxylated product and regeneration of the pyridoxal for the next turnover. According to O'Leary the ki2/k13 KIE (for loss of CO,) varies between 1.01 and 1.03 for a variety of pyridoxal phosphate-dependent decarbo~ylases'~~. Assuming (based on models) that the intrinsic KIE is ca 1.05 for the decarboxylation step k,, these numbers suggest that decarboxylation is not totally rate-determining, rather Schiff-base interchange (transimination) and C-C scission are both participating in rate-limitation (k, 2 k,); see Scheme 13. Also of general importance is a hypothesis by Dunathan concerning the steric requirements for decarboxylation at the Ca142.143.According to this hypothesis, that sp3 hybrid at the Ca which is part of the scissile bond is aligned perpendicular to the plane of the quinonoidal iminium, so that the incipient 2p-orbital at Ca can maximally overlap with the K system of the pyridoxal imine. This conformation requirement is outlined in 21 for the decarboxylation of arginine. The presence of enamine intermediates is especially prominent in some of the elimination reactions catalyzed by the coenzyme, as exemplified by the reaction of serine dehydratase, an enzyme that performs a P-elimination process (Scheme 14). A variation on this theme is seen in P-substitution reactions catalyzed by PLP in which, instead of the hydrolysis step, a nucleophile different from water is added to the P-carbon, followed by reprotonation at the or-position (equation 13). A further PLP reaction involving enamine chemistry has to do with &elimination reactions, that probably commences analogously to the well-characterized transamination reaction. Instead of hydrolysis of the SchiR base, these reactions result in proton abstraction, this time at the p rather than the or carbon of the amino acid. The intermediate iminium ion is the electron sink that helps to acidify the P proton (equation 14). Finally, the decarboxylation of amino acids catalyzed by several pyridoxal phosphatedependent enzymes has been shown to proceed by a retention of configuration at the Ca atom1,,. The stereochemical course of the decarboxylation of 5-hydroxytryptophan to 5-hydroxytryptamine (serotonin) catalyzed by the pyridoxal phosphate-dependent aromatic L-amino acid decarboxylase (equation 15) exemplifies such studies'45.
21. Biochemistry of enamines
1287
"03POCH2 MICHAELIS + * COMPLEX
k3
k4
I
H
203POCH2
I
SCHEME 13
F. Jordan
H
O
W COO-
Enzyme-bound PLP
+
1. Cp-protonation
CH3C0C02H -2. hydrolysis of the enamine
(Pyruvic acid)
Hydrolysis of
+NH~
Product-precursor enamine
pyridoxalsubstrate complex
I H
Enzyme-bound enamine
SCHEME 14
C. Pyruvyl-dependent Decarboxylatlons
It was found by Snell and associates that a histidine decarboxylase isolated from Lactobacillus contained a covalently bound pyruvyl moiety attached as a pyruvamide to an amino group of the enzyme146. The mechanism of decarboxylation presumably proceeds according to the pathway indicated in equation 16. COO
a
NH+ 1. addition of n w k q h i l e Nu at p-
2. I. elimination ionization atatC! p
I
H
LG = Leaving group
2. Protonation at a
I H
a
(13)
I
H
21. Biochemistry of enamines
1289
transimination 2, elimination at y
I
I H
I H
H
protonation at y lransimination
LG = Leaving group
"KcoO0
hydrolysis
I
a-keto acid
H
There have been klZ/kl3KIEs measured on CO, release (1.033) by this enzyme which indicate that the ratio k4/k, is not very different from unity, i.e. that transimination and decarboxylation are both partially rate-limiting14'. Based on a comparison of a variety of KIEs, as well as steady-state kinetic parameters V,,, and V,, J K , for the pyruvyldependent and pyridoxal-dependent decarboxylases, no obvious reasons could be found why nature would preferentially select one pathway over the other. Models were also reported for the pyruvyl-dependent a-amino acid decarbo~ylases'~~. Using a variety of amino acids along with pyruvate or pyruvamide or ethyl pyruvate in DMF leads to decarboxylation via the irnine. The putative azomethine ylide
decarboxylation
w
F. Jordan
MICHAELIS COMPLEX
I
k3
k4
* EJ!/
CH3 0
intermediate can be trapped stereospecifically in a cycloaddition reaction with Nmethylmaleimide in yields ranging from 50-90%, depending on amino acid (equation 17). The reaction of pyruvic or benzoylformic acids with primary or secondary amines will generate imino acids that can be decarboxylated in benzene at 80 OC, or in CH,CI, to the corresponding imines via a 1,2-ylide that can be trapped by a tenfold excess of elementary sulfur, providing thioamides in good yields109.The mechanism of trapping suggests that the sulfur serves the role of electrophile Et (equation 18).
21. Biochemistry of enamines
IV. ENAMINES IN OXIDATION-REDUCTION COFACTORS A. Flavin Cofactors
Flavin adenine dinucleotide (FAD) and its reduced form dihydroflavin (FADH,) participate in a large number of oxidation/reduction reactions in m e t a b o l i ~ r n ' ~The ~. structure of the reduced form has a distinct enamine feature that has been hypothesized to participate in covalent bonds with a number of substrates. Of considerable recent interest is the glutathione reductase reactionl5' (glutathione, GSH, is a highly abundant tripeptide cofactor y-L-glutamyl-L-cysteinylglycine, that is involved in a number of coenzymatic reactions as well as in amino acid transport in the y-L-glutamyl cycle), a reaction responsible for the reduction of glutathione disulfide GSSG to two glutathiones:
GSSG
+ FADH2 + NADPH
-
2 GSH
+ FAD + NADP'
(19)
The isoalloxazine ring system in its various oxidation states and the reaction of FADH, with GSSG are shown in equation 20 (the semiquinone structure of flavins is
FADH
1292
F. Jordan
only shown to illustrate that such an intermediate oxidation state does exist for FAD reduction, not to imply its presence on the particular pathway illustrated). The 4a position of the reduced isoalloxazine is the C-terminus of the enamine that reacts with the GSSG, in a reaction that is formally analogous to the reaction of the thiamin-bound enamine with lipoic acid and other disulfides (Scheme 9). While there were proposals in the literature claiming that FAD-requiring oxidations which are believed to take place via carbanion intermediates also proceed by covalent adducts with FAD, a careful examination of the evidence led Bruice to conclude that this need not be the case15'. On the other hand, the covalent interaction with mercaptans is generally accepted. B. Nicotinamlde Cofactors
The nicotinamide ring of nicotinamide adenine dinucleotide can exist in both oxidized ( N A D f ) and reduced (NADH) forms, where the reduced form can be viewed as a double vinylogous amine, i.e. a double enamine. The hydrogen transfer from the C4 atom is widely believed to proceed by a hydride transfer mechanism, reminiscent of the mechanism of carbonyl reduction by metal hydrides. Equation 21 depicts the reaction of the simplest NADt/NADH-dependent enzyme, alcohol dehydr~genase"~.This enzyme performs the last reaction in ethanol fermentation. Indicated in the equation is the fundamental finding on such reactions first reported by Westheimer, Vennesland and c o w o r k e r ~ l ~ " .~Th ~ ' e hydrogen transfer is not only direct in both directions (as opposed to solvcnt-mediated), but is totally stereospecific in both directions for both the coenzyme and the substrate. The pro-R hydrogen is transferred from both the coenzyme and the substrate ethanol. This was an observation of enormous implications for NAD+-dependent reactions, in particular, and enzyme catalyzed reactions, in general, that has been borne out by literally hundreds of examples.
alcohol dehydrogenase
N
+ I
Y = Adenine dinucleotide
NAD+
NADH
The pattern of electron pair shifts drawn in this system is remarkably analogous to the redox chemistry of enamines previously described in this review; see, for example, the halide elimination reactions from the thiamin diphosphate-bound enamines (equation 9 for fluoropyruvate, and Scheme 7 for a system in which halide elimination is from a longer conjugated enamine). In the case of NADH, the rearomatization resulting from oxidation of the cofactor provides a strong driving force for the reaction, as indeed it may also be the driving force for elimination from the thiamin-bound enamines. The formally analogous nature of these two 'elimination' reactions merits illustration as shown below, since it may have applications in inhibitor design.
21. Biochemistry of enamines
C. Blopterin Cofactors
A number of very important aromatic hydroxylases are monooxygenases that use dioxygen to convert, for example, L-phenylalanine to L-tyrosine, L-tryptophan to Lhydroxylryptophan (on its way to being converted to serotonin) and L-tyrosine to 3,4-dihydroxy-L-phenylalanine(L-DOPA, on its way to being converted to dopamine, to norepinephrine, to epinephrine)15". Only half of the oxidizing equivalents provided by dioxygen are utilized, the other half being converted to water by the 5,6,7,8tetrahydrobiopterin/7,8-dihydrobiopterinredox system, the latter being reduced back to the former by NADH. The hydroxylation of phenylalanine to tyrosine by phenylalanine hydroxylase is shown schematically in equation 22.
H I
+ O2 + L-Phe CH(OH)CH(OH)CH3
I
NAD;
5,6,7,8-Tetrahydrobiopterin (22) NADH
H
I
xpIl
HN
CH(OH)CH(OH)CH3
7
+ H20 +
L-Tyr
0
V. ENAMINES IN TRYPTOPHAN METABOLISM
In the catabolic pathway of tryptophan there are a number of reactions, starting with the oxidation product of 3-hydroxyanthranilate, that involve conjugated enamines, the
1294
F. Jordan
Aminocarboxymuconate semialdehyde decarboxylase
1
Hydrogenase
NADH
NADH
Hydralase
-0Oc
Aminornuconate semialdehyde dehydrogenase
q l , -0oC
NH2
SCHEME 15
~ n u c o n a t e s ' ~The ~ . enamine is finally hydrated to the carbinolamine by a hydratase, saturating the last C=C bond, that loses ammonia giving a-ketoadipate (Scheme 15).
VI. RECENT APPLICATIONS OF BIOCHEMICAL ENAMINES
There are two exciting newer developments of biologically relevant enamines that may also exemplify some of the future directions in which the field is moving. Only a few of the many published examples will serve to illustrate the potential of these powerful concepts.
21. Biochemistry of enamines
1295
A. Enamines as Mechanism-based Enzyme inhibitors
The pyridoxal phosphate-dependent ornithine decarboxylase converts S-ornithine to 1,4-diaminobutane (equation 23). It was reported that (R)-hex-5-yne-1,4-diamineis an irreversible inhibitor of the enzyme and evidence was presented in favor of the proposition that the enzyme performs stereoselective proton abstraction of the pro (R)
7 NH~+
H2N COO-
Decarboxylation
"JN ' H~+ H2N
(23) HR
proton (invoking microscopic reversibility, since in the forward direction the decarboxylation is known to take place with retention of configuration) from the pyridoxal-bound inhibitor. This could lead to one of the two pathways for nucleophilic addition by an enzymic nucleophile E-Nu (equation 24), either to the central or to the terminal carbon of the alkynyl a-carbanion160. Silverman and associates explored a variety of potential inactivators for GABA [y-aminobutyric acid, H,~~(cH,),cooH] transaminase, another pyridoxal-dependent enzyme. In the reaction of the enzyme with 4-amino-5-fluoropentanoic acid, Silverman and lnvergo wrote the mechanism in equation 25 for the covalent interaction of the enzyme with the ina~tivator'~'.The mechanism, dubbed the 'enamine' mechanism, was earlier suggested by Metzler's group16', who had also proposed, as a test, alkaline treatment of the inactivated enzyme that would result in the release of the coenzymebound modified inactivator. It was shown thereafter by Silverman and George that such an 'enamine' mechanism is not universal, since 4-amino-2-fluorobut-2-enoic acid inactivated the same enzyme by a Michael-type reaction between an enzymic nucleophile and the bound isomerized ina~tivator'~~. In a very different enzyme system, Auchus and Covry used 13C NMR to demonstrate that the NADf-dependent estradiol dehydrogenase from human placenta was inactivated by acetylenic steroids via Michael addition of an enzymic LysNH, to the acetylenic ketosteroid generated during the reaction'64 and thereby forming an enaminone (equation 26).
B. Chirai Synthesis with Enzymes that Utilize Enamine intermediates
In a very imaginative piece of research Frost and coworkers have developed a 'plasmid-based' method for synthesizing aromatic amino acids, by incorporating the genes that code for the enzymes that perform the series of conversions from D-fructose6-phosphate to D-erythrose-4-phosphate to 3-deoxy-D-arabinoheptulosonic acid-7-phosphate (DAHP) near each other on a plasmid that can be transformed in E. coli. The enzymes are the thiamin diphosphate-dependent enzyme transketolase in the nonoxidative pentose shunt and DAHP synthase. The DAHP is then converted to the cyclic dehydroquinate, a precursor to all aromatic amino acids L-Tyr, L-Phe and ~ - T r p ' ~ ' . ' ~ ~ (equation 27). The Schiff base class of aldolases has also found a wide variety of applications. Whitesides and coworkers16' showed that the reaction shown in Scheme 12 for D-fructose-1,6-bis-phosphatealdolase can be used very effectively in the synthetic
F. Jordan
Enzyme, pyridoxal
H2N
-
'
b
N
H
3
+
HR
Covalently modified enzyme direction. The enzyme could utilize 50 different aldehydes in addition to glyceraldehyde3-phosphate, the natural substrate. There was much less flexibility in variations of the second substrate dihydroxyacetone phosphate. A variety of complex sugars were synthesized with excellent diastereoselectivity using the enzyme. Wong and coworkers have published a series of papers on the enzymatic synthesis of complex sugars, often using aldolases. In a very important study the key component of
21. Biochemistry of enamines
+H3N~ Y C
O
O
I
H PYr
4-Amino-5-fluoropentanoic acid
-:),-
E-Base
f'rf"cOOH
isY
COOH
0
Pyr
I
alkaline release of cofactorlinactivamr
Pyr
NH2+ (or keto)
Covalent enzyme/coenzyme/inactivator ternary complex
Pyr = pyridoxal5-phosphate
Estradiol
'Enamine'
-
1298
2-03P-0
OH
0
CVCVH OH
F. Jordan
2-03P -0 Transketolase
OH
H* OH
0
DAHP
Sialic acid aldolase,
pyruvate
H
OH
2-Deoxy-D-glucose
-
*
HOOC OH
'1
28)
2-Desacetylaminosialic acid glycoproteins, sialic acid and its derivatives, were synthesized using the enzyme sialic acid synthetase performing the following r e a ~ t i o n ' ~as ' exemplified by the reaction on 2-deoxy-D-glucose (the natural substrate has a 2-N-acetylamino group); see equation 28. The authors point out that the result indicates high stereoselectivity, in that the enamine formed between the lysine amino group and the keto group of pyruvate is added to the si face of the aldehyde acceptor. In a different study, 2-D-deoxyribose-5-phosphate aldolase (DRA) was used in the synthetic direction to synthesize with high stereospecificity a wide range of aldol products169according to equation 29 for a variety of X and Y substituents. The method proved to be an efficient one for the synthesis of some aza-sugars.
21. Biochemistry of enamines
VII. ACKNOWLEDGMENTS The author thanks his senior collaborators a n d the many doctoral a n d postdoctoral students listed a s coauthors in his publications for making the research enterprise continuously enjoyable, a n d the NIH, NSF, P R F a n d the Rutgers University Busch Biomedical F u n d for financial support of some of the work performed in his laboratory. Finally, the author is especially grateful to Gabriel Barletta for his assistance with many aspects of this review. VIII. REFERENCES 1. G. Stork, A. Brizzolara, H. Landesman, J. Szmuszkovicz and R. Terrell, J. Am. Chem. Soc., 85, 207 (1963). 2. R. Breslow, J. Am. Chem. Sac., SO, 3719 (1958). 3. Thiamin, Twenty Years of Progress (Eds. H . Z. Sable and C. J. Gubler), Ann. N. Y. Acad. Sci., 378, 1 4 7 0 (1982). 4. R. Kluger, Chem. Reu., 87, 863 (1987). 5. A. Schellenberger and R. L. Schowen (Eds.), Thiamine Pyrophosphafe Biochemistry, Vol. 1, CRC Press, Boca Raton, 1988, pp. 1-161. 6. H. Bisswanger and J. Ullrich (Eds.), Biochemistry and Physiology of Thiamin Diphosphate Enzymes, VCH Publishers, Weinheim, 1991, pp. 1453. 7. M. W. Washabaugh and W. P. Jencks, Biochemistry, 27, 5044 (1988). 8. H. W. Wanzlick, Angew. Chem., Int. Ed. Engl., 1, 75 (1962). 9. J. Metzger, H. Larive, R. Dennilaurer, R. Baralle and C. Gaurat, Bull. Chem. Soc. Fr., 2857 (1964). 10. M. B. Doughty, G. E. Risinger and S. J. Jungk, Bioorg. Chem., 15, 15 (1987). 11. Y.-T. Chen and F. Jordan, J. Org. Chem., 56, 5029 (1991). 12. A. Schellenberger, Angew. Chem., Int. Ed. EngL, 6, 1024 (1967). 13. L. J. Reed, Ace. Chem. Res., 7 , 40 (1974). 14. L. P. Hager, J. Biol. Chem., 226, 251 (1957). 15. R. Docampo, S. J. Moreno and R. P. Mason, J. Biol. Chem., 262, 12417 (1987). 16. C. J. Gubler, in Rcfcrence 6, pp. 311-321. 17. R. Kluger, J. Chin and T. Smyth, J. Am. Chem. Sac., 103, 884 (1981). 18. R. Kluger, in Reference 3 pp. 63-77. 19. H. Inui, K. Ono, K. Miyatake, Y. Nakano and S. Kitaoka, J. Biol Chem., 262, 9130 (1987). 20. W. H. Rastetter, J. W. Adams, L. J. Nummey, J. E. Frommer and K. B. Roberts, J Am. Chem. Soc., 101, 2752 (1979). 21. F. Jordan. Z. H. Kudzin and C. B. Rios. J. Am. Chem. Sac.., 109.4415 (1987). , 22. J. R. owe", Tetrahedron Lett., 2709 (1969). 23. F. G. Bordwell, A. V. Satish, C. B. Rios, A. C. Chung and F. Jordan, J. Am. Chem. Soc., 112, 792 (1990). 24. J. J. Mieyal, R. G. Votaw, L. 0. Krampitz and H. Z. Sable, Biochim. Biophys. Acta, 141, 205 (1967). 25. A. A. Gallo and H. Z. Sable, J. Biol. Chem., 251, 2564 (1976). 26. J. A. Zoltewicz and J. K. O'Halloran, J. Org. Chem., 43, 1713 (1978). 27. J. A. Zoltewicz and L. S. Helmick, J. Org. Chem., 43, 1718 (1978). \
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28. J. T. Stivers and M. W. Washabaugh, Bioorg. Chem., 19, 369 (1991). 29. J. T. Stivers and M. W. Washabaugh, Bioorg. Chem., 20, 155 (1992). 30. G. Barletta, W. P. Huskey and F. Jordan, J. Am. Chem. Sac., 114, 7607 (1992). 31. G. Barletta, W. P. Huskey and F. Jordan, submitted for publication. 32. C. F. Bernasconi, Acc. Chem. Res., 20, 301 (1987). 33. G. L. Barletta, Ph.D. Dissertation, Rutgers University Graduate Faculty, Newark, NJ, 1993. 34. S. Shinkai, T. Yamashita, Y. Kusano and 0. Manabe, J. Org. Chem., 45, 4947 (1980). 35. S. Shinkai, T. Yamashita, Y. Kusano and 0. Manabe, Tetrahedron Lett., 21, 2543 (1980). 36. LS. Shinkai, T. Yamashita and 0. Manabe, Chem. Left., 961 (1981). 37. D. Hilvert and R. Breslow, Bioorg. Chem., 12, 206 (1984). 38. Y. Yano, M. Kimura,K. ShimaokaandH. Iwasaki,' Chem. Sac., Chem. Commun., 160(1986). 39. T . Nabeshima, K. Moriyama and Y. Yano, J. Chem. Sac., Chem. Commun., 373 (1991). 40. Y. Lindquist, G. Schneider, U. Ermler and M. Sundstrom,, EMBO J.,11, 2372 (1992). 41. F. Dyda, Ph.D. Dissertation, Dept. of Crystallography, University of Pittsburgh, 1992. 42. F. Dyda, W. Furey, M. Sax, B. Farrenkopf and F. Jordan, Biochemistry, 32, in press (1993). 43. J. B. A. Green, FEES Lett., 246, 1 (1989). 44. C. F. Hawkins, A. Borges and R. N. Perham, FEES Lett., 255, 77 (1989). 45. A. Y. Tsou, C. Ransom, J. A. Gerlt, D. D. Buechter, P. Babbitt and G. L. Kenyon, Biochemistry, 29, 9856 (1990). 46. N. Bergmann and F. P. Schmidtchen, Tetrahedron Lett., 29, 6235 (1988). 47. S. Tam, L. Jimenez and F. Diederich, J. Am. Chem. Sac., 114, 1503 (1992). 48. G. Barletta, A. C. Chung, C. B. Rios, F. Jordan and J. M. Schlegel, J. Am. Chem. Sac., 112, 8144 (1990). 49. S. Mizuhara and P. Handler, J Am. Chem. Sac., 76, 571'(1954). 50. E. Yatco-Manzo, F. Roddy, R. G. Yount and D. E. Metzler, J. Biol. Chem., 234, 733 (1959). 51. C. S. Miller, J. M. Sprague and L. 0. Krampitz, Ann. N. Y. Acad. Sci., 98, 401 (1962). 52. J. P. Knebrich, R. L. Schowen, M. Wangand M. E. Lupes, J. Am. Chem. Soc.,93,1214(1971). 53. R. Breslow and E. McNelis, J. Am. Chem. Sac., 81, 3080 (1959). 54. For examples see: L. 0. Krampitz, Thiamin Diphosphate and its Catalytic Functions, Marcel Dekker, New York, 1970. 55. Y-T. Chen, Ph.D. Dissertation, Rutgers University Graduate Faculty, Newark, NJ, 1991. 56. J. Castells, F. Lopez-Calahorra and L. Domingo, J Org. Chem., 53, 4433 (1988). 57. Y-T. Chen, G. L. Barletta and F. Jordan, submitted for publication. 58. H. Stetter, W. Basse and J. Nienhaus, Chem. Ber., 113, 690 (1980). 59. D. H. G. Crout, E. R. Lee and D. P. I. Pearson, J. Chem. Sac., Chem. Commun.,331 (1990). 60. D. J. Kuo and F. Jordan, Biochemistry, 22, 3735 (1983). 61. D. J. Kuo and F. Jordan, J. Biol. Chem., 258, 13415 (1983). 62. F. Jordan, J. Adams, B. Farzami and Z. H. Kudzin, J. Enzym. Inhib., 1, 139 (1986). 63. F. Jordan, 0.Akinoyosoye, G. Dikdan, Z. H.'Kudzin and D. J. Kuo, in Thiamine Pyrophosphate Biochemistry, Vol. 1 (Eds. A. Schellenberger . and R. L. Schowen), CRC Press, Boca Raton, 1988, pp. 79-92. 64. X. Zeng, A. Chung, M. Haran, and F. Jordan, J. Am. Chem. Sac., 113, 5842 (1991). 65. F. Jordan. X. Zene. S. Menon-Rudoloh.. N. Annan. G. Barletta. A. C. Chune and C. B. Rios. in ~eference6, p L 3 4 5 0 . 66. X. Zeng, Ph.D. Dissertation, Rutgers University Graduate Faculty, Newark, NJ, 1992. 67. See entire volume of Ann. N. Y. Acad. Sci., 573 (1989) devoted to a-keto acid dehydrogenase multienzyme complexes and dedicated to L. J. Reed. 68. P. A. Frey, Ann. N Y Acad. Sci., in Reference 3, pp. 25&264. 69. P. A. Frey, D. S. Flournoy, K. Gruys and Y-S. Yang, Ann. N.Y. Acad. Sci., 573,21 (1989). 70. R. N. Perham, A. Borges, F. Dardel, L. D. Graham, C. F. Hawkins, E. D. Laue and L. C. Packman, in Reference 6, pp. 17&175. 71. M. L. Das, M. Koike and L. J. Reed, Proc. Natl. Acad. Sci. (I.S.A.,47, 753 (1961). 72. K. Daigo and L. J. Reed, J. Am. Chem. Sac., 84, 659 (1962). 73. F. G. White and L. L. Ingraham, J. Am. Chem. Sac., 84, 3109 (1962). 74. G. E. Lienhard, J. Am. Chem. Sac., 88, 5642 (1966). 75. L. S. Khailova, L. G. Korochkina and S. E. Severin, in Reference 6, pp. 251-265. 76. A. J. McNally, Ph.D. Dissertation, Rutgers University Graduate Faculty, Newark, NJ, 1992.
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127. S. A. Benner and T. H. Morton, J. Am. Chem. Sac., 103,991 (1981). 128. S. A. Benner, J. D. Rozell, Jr. and T. H. Morton, J. Am. Chem. Sac., 103, 993 (1981). 129. B. L. Horecker, S. Pontremoli, C. Ricci and T. Cheng, Proc. Natl. Acad. Sci. U.S.A.,47, 1649 (1961). 130. E. Grazi, T. Cheng and B. L. Horecker, Biochem. Biophys. Res. Commun., 7, 250 (1962). 131. B. L. Horecker, T. Orestes and C. Y. Lai, in The Enzvmes, 7, third edition, Academic Press, New York, 1973. 132. G. A. Hamilton and F. H. Westheimer, J. Am. Chem. Sac., 81,6332 (1959). 133. A. E. Braunstein and M. M. Shemyakin, Biokhimiya, 18, 393 (1953). 134. A. E. Braunstein, in The Enzymes, 2, second edition, Academic Press, New York, 1960, p. 113. 135. D. E. Metzler and E. E. Snell, J. Am. Chem. Sac., 74, 979 (1952). 136. D. E. Metzler and E. E. Snell, J. Bioi. Chem., 198, 353 (1952). 137. D. E. Metzler, J. B. Longenecker and E. E. Snell, J. Am. Chem. Sac., 76, 639 (1954). 138. D. E. Metzler, M. lkawa and E. E. Snell, J Am. Chem. Sac., 76, 648 (1954). 139. E. E. Snell and S. Di Mari, in The Enzymes, 7, third edition, Academic Press, New York, 1973. 140. W. T. Jenkins and I. W. Sizer, J. Am. Chem. Soc., 79, 2655 (1957). 141. M. H. O'Leary, Aec. Chem. Res., 21,450 (1988). 142. H. C. Dnnathan, Proc. Natl. Acad. Sci. U.S.A.,55, 712 (1966). 143. H. C. Dunathan and J. G. Voet, Proc. Natl. Acad. Sci. U.S.A., 71, 3888 (1974). 144. H. G. Floss and J. Vederas, in Stereochemistry C. Tamm), Elsevier, New York, 1982, . (Ed. . p. 161. 145. A. R. Battersby, A. Scott and J. Staunton, Tetrahedron, 46,4685 (1990). 146. P. Recsei and E. E. Snell, Annu. Rev. Biochem., 53, 357 (1984). 147. L. M. Abell and M. H. O'Leary, Biochemistry, 27, 5927, 5933 (1988). 148. R. Grigg, D. Henderson and A. J. Hudson, Tefrahedron Lett., 30, 2841 (1989). 149. M. F. Aly and R. Grigg, Tetrahedron,44, 7271 (1988). 150. C. Walsh, EnzymaticReaction Mechanisms, W. H. Freeman, San Francisco, 1979, pp. 358405. 151. G. E. Schulz and E. F. Pai, J. Biol. Chem., 258, 1752 (1983). 152. T. C. Bruice, Acc. Chem. Res., 13, 256 (1980). 153. H. Eklund and C.4. Branden, in Active Site of Enzymes (Eds. Fa. Jurnak and A. McPherson), Biological Macromolecules and Assemblies, 3, Wiley-Interscience, New York, 1987, p. 73. 154. F. H. Westheimer, H. F. Fisher, E. E. Conn and B. Vennesland, J. Am. Chem. Sac., 73, 2403 (1951). 155. H. F. Fisher, E. E. Conn, F. H. Westheimer and B. Vennesland, J. Biol. Chem.,202,687 (1953). 156. F. A. Loewus, F. H. Westheimer and B. Vennesland, J. Am. Chem. Sac., 75, 5018 (1953). 157. F. A. Loewus, P. Offner, H. F. Fisher, F. H. Westheimer and B. Vennesland, J. Bioi. Chem., 202, 699 (1953). 158. R. H. Abeles, P. A. Frey and W. P. Jencks, Biochemistry, Jones and Bartlett, Boston, 1992, p. 662. 159. D. Voet and J. G. Voet, Biochemistry, Wiley, New York, 1990, p. 695. 160. P. Casara, C. Danzin, B. W. Metcalf and M. J. Jung, J. Chem. Sac., Chem. Commun., 1190 119x7) ,A,--r
161. 162. 163. 164. 165. 166.
R. B. Silverman and B. J. Invergo, Biochemistry, 25, 6817 (1986). J. J. Likos, H. Ueno, R. W. Feldhaus and D. E. Metzler, Biochemistry, 21, 4377 (1982). R. B. Silverman and C. George, Biochemistry, 27, 3285 (1988). R. J. Auchus and D. F. Covey, J. Am. Chem. Sac., 109, 280 (1987). K. M. Draths and J. W. Frost, J. Am. Chem. Sac., 112, 1657 (1990). K. M. Draths, D. L. Pompliano, D. L. Conley, J. W. Frost, A. Berry. G. L. Dishrow, R. J. Staversky and J. C. Livense, J. Am. Chem. Sac., 114, 3956 (1992). 167. M. D. Bednarski, E. S. Simon, N. Bischofberger, W-D. Fessner, M J . Kim, W. Lees, T. Saito, H. Waldmann and G. M. Whitesides, J. Am. Chem. Sac., 111, 627 (1989). 168. C-H. Lin, T. Sugai, R. L. Halcomb, Y. lchikawa and C-H. Wong, J. Am. Chem. Sac., 114, 10138 (1992). 169. L. Chen, D. P. Dumas and C-H. Wong, J. Am. Chem. Sac., 114, 741 (1992).
CHAPTER
22
ZHI-TANG HUANG and MEI-XIANG WANG Institute of Chernistw. Academia Sinica. Beijing 100080. People's Republic of China
I . INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1304 I1. STRUCTURE AND PHYSICAL PROPERTIES . . . . . . . . . . . . . . . 1305 A. Structure and Reactivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1305 B. Spectroscopic Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1310 111. PREPARATION O F 1,1-ENEDIAMINES . . . . . . . . . . . . . . . . . . . 1311 A. Reaction of Amines with Ketene Dithioacetals . . . . . . . . . . . . . . . 1311 B. Reaction of Amines with Ketene Acetals and gem-Dihaloethylenes . . . 1314 C. Reaction of Amines with Ketene N,S-, orN,O-Acetals and a-Haloenamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1315 D. Reaction of Aliphatic Amides with Tetrakis(dimethylamino)titanium . . 1318 E. Reaction of Active Methyl and Methylene Compounds with Urea Acetals S-Alkylated Thioureas and Carbodiimides . . . . . . . . . . . . . . . . . . 1319 F. Acylation of 1-Alkyl-2-methylamidineDerivatives . . . . . . . . . . . . . 1322 G. Miscellaneous Preparative Methods . . . . . . . . . . . . . . . . . . . . . 1325 IV. 1,1-ENEDIAMINES AS NUCLEOPHILES IN SUBSTITUTION AND ADDITION REACTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1326 1326 A. Protonation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Alkylation and Arylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1327 1. With alkyl halides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1327 2. With acetylenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1329 3. With electrophilic olefins . . . . . . . . . . . . . . . . . . . . . . . . . . 1331 4. Arylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1335 5. With aldehydes and ketones . . . . . . . . . . . . . . . . . . . . . . . . 1337 C. Acylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1338 1. With carboxylic acid halides and ketenes . . . . . . . . . . . . . . . . 1339 2. With isocyanates and isothiocyanates . . . . . . . . . . . . . . . . . . . 1340 D . Reaction with Other Electrophiles . . . . . . . . . . . . . . . . . . . . . . 1344 1. With azodicarboxylate esters . . . . . . . . . . . . . . . . . . . . . . . . 1344 2. Halogenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1346 3. Miscellaneous reactions . . . . . . . . . . . . . . . . . . . . . . . . . . : 1346 V . CYCLOADDITION REACTIONS O F 1,1-ENEDIAMINES . . . . . . . . 1348 A. 1, 2-Cycloaddition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1348 B. 1,4-Cycloaddition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1349 C. 1,3.Dipolar Cycloaddition . . . . . . . . . . . . . . . . . . . . . . . . . . . 1352
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Tlze Chemistn of Enamines. Edited by Zvi Rappoport Copyright O 1994 Joh~iWilzy & Sons. Ltd . ISBN: 0-471-93339-2
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VI. MISCELLANEOUS REACTIONS . . . . . . . . . . . . . . . . . . . . . . . 1357 VII. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1359
I. INTRODUCTION
1,l-Enediamines, also known as ketene N,N-acetals or ketene aminals, are members of the enamine family. They can be divided into simple 1,l-enediamine~',~ and conjugated 1,l-enediamines, which are described in structures 1 and 2, respectively. Due to the stabilization effect of the conjugation with electron-withdrawing groups (EWG), both primary and secondary 1,l-enediamines 2 (bearing at least one proton on the nitrogen atom) are stable, while only tertiary 1,l-enediamines 1 are known. 1,l-Enediamines derived from diamines are called cyclic 1,l-enediamines or heterocyclic ketene aminals.
R1,R2= H, alkyl
= COR, COAr, C02R, NO2, CN etc EWG~,EWG~
(1)
(2)
In contrast to enamine~'.~, the chemistry of 1,l-enediamines have been only briefly studied although the earliest report^^,^ of such compounds may date back to the 1940s. This has been partly due to the relative difficulty of the synthesis of simple 1,lenediamines 1 in earlier years. A convenient method for the preparation of conjugated 1,l-enediamines 2 was reported by Gompper and coworkers in 1962' and later in 19676. However, these compounds had not attracted the curiosity of chemists, nor had they been considered as building blocks for further synthetic manipulations until the 1980s. Much attention has been given to them only in the last decade. With two amino groups attached to one carbon atom of the double bond, 1,lenediamines 1, and especially 2, display some intriguing physical and chemical properties. One marked feature of these species is the enhanced enaminic reactivity. The nucleophilicity of the P-carbon atom is higher than that of the nitrogen atoms of primary and secondary amino moieties. In addition, the double bond of 1,l-enediamines is highly polarized. X-ray diffraction of some compounds 2 have shown that the length of the double bond is 1.38-1.47 A, i.e. it is longer than that of normal olefins. The double-bond character of these compounds is alleviated with a concomiiant reduction of reactivity toward reduction and cycloaddition reactions. Furthermore, the amino substituents can also participate in the reactions of the system by acting as either the nucleophilic site or as a leaving group. Therefore, 1,l-enediamines have been used as di-nucleophiles or dipolar reagents in reactions with electron-deficient reagents, and a wide variety of interesting products, particularly heterocyclic compounds which are difficult to synthesize by other methods, have been obtained through a sequence of nucleophilic addition or substitution and cyclocondensation reaction of these species (Scheme 1). Finally, it may be noted that several cyclic 1,l-enediamines and their derivatives possess certain biological acti~ities'~-" and this feature stimulates chemists' interest in the study of the synthesis and derivatization of 1.1-enediamines.
E,E' = Electrophile; Nu = Nucleophile SCHEME 1
In this chapter we will survey the chemistry of 1,l-enediamines. Their structural and physical properties will be first reviewed in Section 11. We will see that their reactivity is critically dependent on their structures. Simple and conjugated or acyclic and cyclic 1,l-enediamines may lead to substantially different results and the correlation between structure and reactivity will be discussed. Spectroscopic characteristics will also be displayed in this section. Preparative methods of 1,l-enediamines will be summarized in Section 111, which is arranged in order of importance of the methods and their scope of applicability. The reactions of 1,l-enediamines are presented in Sections IV-VI. Emphasis will be placed on the synthetic applications of these versatile synthons in the construction of heterocyclic compounds. The literature coverage of the chapter is up to early 1992.
II. STRUCTURE AND PHYSICAL PROPERTIES A. Structure and Reactivity
The electronic structure of simple 1,l-enediamines can be simply described by the contributing resonance forms ( A X ) . Several physical properties as well as the chemical reactivities, e.g. the strong nucleophilicity of the p-carbon atom of 1,l-enediamines, indicate the important contribution of the mesomeric forms B and C, which indicate the presence of an appreciable negative charge on the p-carbon atom.
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In analogy to the parent enamine~'.~,the chemical properties of 1,l-enediamines reflect the extent of conjugation between the two lone-pair electrons on the two nitrogen atoms and the double bond. The increased orbital interaction would result in the delocalization of the electrons on the nitrogen atoms into the n-system of the carbon-carbon double bond, and thus in increase of electron density on the P-carbon atom. Consequently, the reactivity of an enediamine depends on the nature of the substituents both on the nitrogens and on the P-carbon atom as well as on the degree of substitution. 1,3-Dimethyl-2-methyleneimidazolidine(3)is one of the most reactive 1,l-enediamines". This is attributed to the maximal overlap of the parallel p orbitals and the lone-pair electrons on the nitrogens since 3 is a planar molecule. Steric and electronic effects of 8-substituents may decrease the reactivity of the P-carbon atom18. The reactivity of acyclic 1,l-enediamines appears lower than that of their cyclic 1,l-enediamine counterparts. This is ascribed to a stcric repulsion between the two amino groups in the former. For instance, in the energetically favorable conformation for 4, one of the dimethylamino substituents is out of, or perpendicular to, the plane of the rest of the mole~ule'~. Comparison of the spectroscopic data (videinfra) of 3 and 4 indicates a lower conjugation in 4 than in 3.
A similar influence of the amino groups on the reactivity can be expected for conjugated 1,l-enediamines. The reactivity of several nitro-substituted 1,l-enediamines was examined in their reaction with isothiocyanates2". The tertiary enediamine 5 was found to be more reactive than 6 due to the hyperconjugative and inductive effects of the methyl groups. It was also reported that the cyclic enediamine 7 showed lower reactivity than the acyclic counterpart 6, since no reaction was observed between 7 and alkyl and aryl isothiocyanates. This is doubtful since a planar conformation due to the constraints of the ring in 7 would give rise to increased conjugation with the substituted P-carbon atom and hence to increased charge on Cp.,In fact, a very recent investigation2' has demonstrated that nitro-substituted cyclic enedlamines are reactive toward isothiocyanates and they can readily add to phenyl isothiocyanate.
With an electron-withdrawing group at the P-carbon atom, the nucleophilic reactivity of the 1,l-enediamine is decreased. A systematic study on the influence of different
electron-withdrawing substituents on the reactivity is not available. However, a literature survey on the reaction of conjugated enediamines reveals the following reactivity order: C0,R > COR > NO, for P-substituents, which is in agreement with the prediction based on the 'H-NMR spectrum (vide infra). In the case of aroyl-substituted cyclic enediamines 8, electron-donating substituents X on the phenyl ring increase the reactivity of the P-carbon atom and six-membered compounds (n = 3) are more reactive than five-membered analogues (n = 2) when they react with alkyl halidesz2 and oc,p-unsaturated compoundsz3. H
n
The conjugation effect in the primary and secondary 1,l-enediamines is so large that the nucleophilicity of the 8-carbon atom exceeds that of the nitrogen atoms. When the enamines are treated with electron-deficient reagents, it is always the 8-carbon atom that attacks the electronpositive site of the reagent. Only when a strong base is used do enediamines give initially N-substituted products24. The higher nucleophilic reactivity of the p-carbon atom is consistent with theoretical consideration. CND0/2 calculations performed on 2-(benzoylmethylene)imidazolidine (8, n = 2, X = H) and 2-(benzoylmethy1ene)tetrahydropyrimidine (8,n = 3, X = H) indicate a larger negative charge on the p-carbon atom than on the nitrogen atoms25. An interesting structural characteristic of 1,l-enediamines is the polarization of the carbon-carbon double bond. Due to the strong electron-donating effect of the nitrogen atoms and the electron-withdrawing effect of the substituents at the P-carbon atom in 2, the conjugated carbon-carbon double bond is highly polarized. The barrier to rotation around this bond in tertiary enediamines has been measured by Sandstrom and coworker^^^-^^ using variable-temperature NMR technique, and has been found to be very low. At -63 "C, only one N-Me signal and one CH, signal are observed in the 'H-NMR spectrum of 1,3-dimethyl-2-(nitromethylene)imidazolidine(9)". With two P-electron-withdrawing substituents, the rotation barriers around the carbon-carbon double bond are even l o ~ e r ~ ' For , ~ ~example, . compound 10 shows only one AB multiplet of the benzylic protons down to - 140 OC, i.e. the barrier to rotation around the C=C bond is too low to be measuredz8. At ambient temperature secondary moiety corresponding enediamines 8 and 11give one singlet signal for the -CHzCHzto the imidazolidine ring, irrespective of the nature of the P - s u b s t i t ~ e n t s ~ ~ ~ ~ ~ . R
(9) R=Me, X = H , Y = N 0 2 (10) R = PhCH2, X = COPh, Y = COMe (11) R = H, X,Y = COR', C02R1,CN
1308
Z.-T. Huang and M.-X. Wang
Evidence of high polarization of the double bond in enediamines has been provided directly by the X-ray diffraction data7-14. As mentioned above, the C=C bond length of 1.38-1.47A in 1,l-enediamines is longer than that of normal olefins. Single-crystal structure analyses also demonstrate that the two nitrogen atoms, the double bond and the carbonyl group are almost coplanar in 88.9and in 1-benzyl-2-(acy1methylene)imidazolidinelO,which allows a maximum orbital overlap in these systems. In addition, there is an intramolecular hydrogen bond between the secondary amino and the carbonyl groupss-lo. X-ray crystallography of 1,l-enediamines having two electron-withdrawing P-substituents shows twisted double bonds, some possessing a twist angle greater than 85", i.e. the plane of electron-withdrawing substituents and the p-carbon atom [EWG1-C(P)-EWG2] is almost perpendicular to the plane formed by the cc-carbon atom and the two nitrogen atoms [N-C(G()-N]'~. The twist angle increases when two bulky substituents rather than hydrogcns substitute the nitrogen atoms12313.Thc polarization reduces the double-bond character in the conjugated 1,l-enediamines and is responsible for their special chemical properties. Tautomerism is another interesting featute of 1,l-enediamines. Secondary and primary 1,l-enediamines derived from primary amines and ammonia are capable of tautomerizing to the amidine isomers. However, several studies have pointed out that the enediamine structure is generally favored. This is due to the large conjugated system involving the amino groups, the double bond and the electron-withdrawing substituents which results in a significant amount of stabilization energy of the 1.1-enediamine tautomer. In addition, hydrogen bond formation in the latter further increases the stability. Although the enediamine form is predominant, the amidine tautomers exist in some the imidazole and benzimidazole forms in the crystals, whereas in solution, tautomeric equilibrium between 13 and 13' has been observed33 (equation 1). The equilibrium is affected by the substituent X, and electron-withdrawing chlorine of 13 favors the 1,l-enediamine form. The equilibrium lies well to the enediamine side in polar solvents such as DMSO-d,. Tautomeric equilibrium has also been reported in compounds 1434 and 1535(equations 2 and 3).
(a) X = C1 (b) X = H (c) X = Me (d) X = OMe
(13')
Except for 12 and 1 3 ' M , the isolation of the amidine tautomer has been reported only recently. Spectral data show that alkylated 1,l-enediamines such as 16 tautomerize predominantly to 4,s-dihydroimidazole derivatives (equation 4). More interestingly, the adducts of enediamines and dicthyl diazenedicarboxylate exist exclusively as the enediamine tautomer when RZ = H (17) and as the amidine tautomer when RZ = Et (equation 5). Since 17 and 17' differ only in a n ethyl group, it appears that the steric effect plays an important role in determining the tautomeric equilibrium.
H (16)
(16')
X = n-Pr, COR, CN, SOPh, S02Ph, PPh3
The E- or 2-configuration about the carbon-carbon double bond in asymmetric 1,l-enediamines is determined according to the ability to form an intramolecular hydrogen bond. Thus, 1,lunediamines 18 are present in the E-form due to such hydrogen bonding.
2.-T. Huang and M.-X. Wang
(18) EWG = COR', COAr, C02R', NO2 6 . Spectroscopic Data
No detailed investigation of the spectral properties of 1,l-enediamines has appeared in the literature. Simple 1,l-enediamines absorb strongly in the infrared spectrum at 162&1665 ~ m - ' , 'and ~ isomers with a more substituted double bond absorb at higher wave numbers. With a P-electron-withdrawing group, this absorption is significantly shifted to lower wave numbers. For instance, 1,3-dimethyl-2-(benzoylmethy1ene)imidazolidine3' shows a strong absorption at 1561 c m l , 74 c m l lower than 1,3-dimethyl-2methyleneimidazolidine 3(1635 c m l ) " . Besides, a large bathochromic shift of the group at Cpin conjugatcd 1,l-cnediamincs has been observed as a general phenomenon. The carbonyl absorption of benzoyl-substituted 1,l-enediamines 8 appears at 1600 cm-' or lesszy and the ester analogues give ester carbonyl absorption at 1640cm-I Considerable bathochromic shift of the nitro and c y a m absorptions has also been ituted respectively. recorded in the nitro" and c y a n ~ " ~ ~ ~ ~ ~ ~ - s u b s t1,l-enediamines, These bathochromic shifts of the absorption of the functional groups can serve as a diagnostic tool in deciding whether the 1,l-enediamine or the amidine tautomer is formed. It is also very useful in the study of reactions of enamines, since on electrophilic addition t o the P-carbon by a n electrophile the conjugation is lost and therefore the absorption of the b-functional groups would appear at their normal regionsz9. In the ultraviolet spectrum simple 1,l-enediamine 3 absorbs at 227 nm18 while the conjugated enediamine 8 shows two absorption bands at longer wavelengths of 240 and 320 nmz9. The mass spectra of 1,l-enediamines display M and M-1 ions and the molecular ion is usually the most abundant peak in the spectra of conjugated enediamines18~2y. The olefinic ' H chemical shift (6) of a number of acyclic and cyclic, simple and conjugated 1,l-enediamines are listed in Tables 1 and 218,29,38-44.These values reflect Me
I
RZ--N TABLE I . 'H- and I3C-NMR data of tertiary 1,l-enediamines
R2-N
\a B I C=C /
I
R'
\
in CDCI,
H
Me
R 2 = Me
R'
H
CH3
Ph"
COCH,
6,
3.15 69.2 163.0 2.98"
3.65
4.48
4.45
-
-
-
-
-
-
-
-
3.46" 68.1' 155.8'
4.63" 76.3" 157.1"
6~~ 6
R 2 R z = -(CHZ),-
SH 6~~ *cq
" In CCI,. In C,D,.
51.8" 159.3'
-
-
COPh 4.98 4.96 73.4 166.5
NO, 6.30 100.9 162.0 6.38 -
H
I
N
TABLE 2. 'H- and "C-NMR data of secondary 1,l-enediamines
[Nyzy
EWG in CDCI,
H
\
R
R
= H"
EWG
CO,EI
6,
-
k
6, 6~~ dcX
COPh
4.5 1
5.20 73.0 165.1 5.26 71.2 164.2
-
-
3.99 60.2 164.1
4.59 74.9 163.4
6cg
R = Me
COMe
NO2 6.40 -
-
6.50 95.9 159.1
" I n DMSO-d,.
the extent of charge delocalization and conjugation since the olefinic protons are shielded by increasing electron density on the /?-carbon atom. A correlation between the enamine reactivity and the chemical shift can therefore be expected (see below). An inspection of the vinyl proton shifts reveals that the delocalization effect in cyclic enediamines is larger than that in acyclic analogues, since the 6 value of the former appears at a higher field. The inductive effect of the methyl groups on the nitrogens increases the electron density on P-carbon atom. Substituting an electron-withdrawing group at the P-carbon atom shifts the vinyl proton signal downfield, and the b values differ greatly for different electron-withdrawing groups. The reactivity of 1,l-enediamine in chemical reactions generally parallels the 6 value of the vinyl proton. It should be noted, however, that only when the steric effects are identical o r similar, and the direct spatial shielding effects are negligible or identical, a correlation of reactivity and chemical shift is expected and is indeed observed. The 13C-NMR spectra of several 1,l-enediamines have been recorded and the 6 values of the olefinic carbons are given in Tables 1 and 218.29.38.39.43.44. The cc-carbon displays a signal in the range of 156-165 ppm whereas the signal corresponding t o the P-carbon covers a wider range (from 28 to 100 ppm) depending on the nature of substituents. In the 1,l-enediamines with none or with only one P-electron-accepting group, the P-carbon signal is at 5&80ppmls, with the exception of nitro-substituted l,l-enediamines. Extraordinary upfield signals are observed for cyano-substituted 1,l - e n e d i a m i n e ~ " . ~ ~ , ~ ~ , with the extreme case of 2-(dicyanomethylene)imidazolidine for which 6,, = 28 ppm30. Ill. PREPARATION OF 1,I-ENEDIAMINES A. Reaction of Amines with Ketene Dithioacetals
In 1962 Gompper and TopeI5 reported that ketene dithioacetals reacted with amines t o give 1,l-enediamines. When ethylenediamine reacted with ketene dithioacetals 19-21, derived from malononitrile, methyl cyanoacetate and dimethyl malonate, respectively, the cyclic 1,l-enediamines 22-24 were obtained in good yields. Similarly, o-phenylenediamine reacted with 19 and 20 t o afford benzimidazoline derivatives 25 and 26 (equation 6). The preparation of nitro-substituted acyclic and cyclic 1,l-enediamines by using the same method was later described by Gompper and Schaefer6 in 1967. 1,2-Ethylenediamine and morpholine reacted with ketene dithioacetal to give the enediamines 7 and 28 in excellent yields (equation 7). In this reaction, two methylthio groups are displaced
2.-T. Huang and M.-X. Wang H
\
X
SMe
\
Y'
X
- Y' \
c=c\1
+ H2NCH2CH2NH2
SMe
C=C'N]\ IN
(19) X = Y = C N (20) X = CN, Y = C02Me (21) X = Y = C02Me
+
19or20
a-
(22) X = Y = C N (23) X = CN, Y = C02Me (24) X = Y = C02Me
(6)
H
NH2
X
NH2
Y
\
\ /
\
N I H (5&94%) (25) X = Y = CN (26) X = CN, Y = C02Me H
OzN\
/
H'
\
C=C
SMe
(27)
\
SMe 89%
H
N
I
H (7)
n
by the two amino groups. The monoamino-substituted products, i.e., the ketene N,S-acetals, can be obtained when only one equivalent of amine is used5. This preparative method provides several advantages. First, the precursors ketene dithioacetals are easily accessible. Active methyl and methylene compounds react with carbon disulfide in the presence of an appropriate base to give the salts of ketene dithiols, which give the ketene dithioacetals by reaction with alkylation reagents. The overall reaction can be carried out in a one-pot procedure. Thus, on successive treatment with a base, carbon disulfide and methyl iodide, active methyl and methylene compounds are converted to ketene dithioacetals in moderate to excellent yields (equation 8)45-50. Second, ketene dithioacetals react readily with both aliphatic and aromatic amines to afford 1,l-enediamines with a variety of amino moieties. In addition, the preparative reaction can be conveniently controlled by monitoring the bubbling of the product methanethiol (equation 8). Furthermore, the yield of the reaction is generally good. A large number of 1,l-enediamines has been synthesized by this procedure from active
X
X
1.brse
2. cs2
Y
SMe
\
/
Y'
\
-Y' X
C=C
-MeSH
SMe
N R ~ R ~
\
HNR'R~
(8)
\
NR'R~
methyl and methylene substrates such as n i t r ~ m e t h a n e ~ . " ~ ~ ~ . ~ ~acetophe.~'.~~~~~, none^^^.^^, acetone55, cyclic ketone^^^-^^, 1 , 3 - d i k e t o n e ~ ~ malonic ~-~~, e s t e r ~ ~ . ~ l - ~ ~ , b-ketoacetic ester^^'.^^, ~ - c ~ a n o k e t o n e s ~cyanoacetic ~-~~, ester^^.^'.^', aryl acetonit r i l e ~ " , ~ ~m. a~l~~,n o n i t r i l eand ~ ~other ~ ~ precursors67-69.
Although this methodology is widely applicable for the preparation of many 1,lenediamines, 2-(aroy1methylene)benzimidazolines (29) cannot be obtained from the reaction of benzoyl-substituted ketene dithioacetals 30 and o-phenylenediamine. Instead of 29, 3H-1,s-benzodiazepines 31 are isolated from the reaction64. Similar results have been reported for the reaction of 30 and other primary aromatic diamine~'~.'~. A recent has revealed that an enamine-imine tautomeric equilibrium is involved in the reaction process (Scheme 2). This equilibrium between 33A and 33B is affected by the '4-CO
1
,c=c\ R1
I
n
SMe
\
+ NH2
NHR2
SMe
R2
'4-CO
I
N NH2 \C=C'w
-
-
.4-CO
R2=H
\
1
R1
SMe
L
R1
diamine = O-C&(NH~)~
(33A)
SMe (33B)
H
I
Ar-CO
c 2 )
\ /
\
R'
N
I
R2
Ar
(13,13',32)
SMe (31)
SCHEME 2
1314
Z.-T. Huang and M.-X. Wang
substituent R' and the diamines employed. In the case of aliphatic diamines, the enamine form can be stabilized by either one or two electron-withdrawing groups (R1 = H or EWG) and therefore cyclic 1,l-enediamines are obtained. When o-phenylenediamine is used, the enamine intermediate is stable only when two electron-withdrawing groups are presented (R1 = EWG). When only one aroyl substituent is present (R1 = H), the enamine form tautomerizes to the imine due to conjugation with the aromatic ring, and seven-membered heterocyclic products are finally obtained. Interestingly, when Nmethyl-o-phenylenediamine is used, the first substitution occurs via the methylamino group, and the enamine intermediate thus formed cannot tautomerize to the imine form. Consequently, cyclic 1,l-enediamines 13 and 13' are formed. In general, the reaction of ketene dithioacetals and amines serves well to prepare the conjugated 1,l-enediamines. B. Reaction of Amines with Ketene Acetals and gemDihaloethylenes
The reaction of amines and ketene acetals was used as a main synthetic approach to 1,l-enediamines in earlier years7'. Both simple and conjugated 1,l-enediamines can be obtained by this route. Displacement reaction of ketene acetal 34 with two equivalents of piperidine furnishes 1,l-dipiperidinoethene (35) in 62% yield (equation 9)73.Primary atnines and ammonia react with 34 to give amidine derivatives. Cyano-'" and trifluoroacetyl-substituted enediaminesT5have been synthesized from the corresponding ketene acetals in good to excellent yields (e.g. equation 10).
0 F3C-C
0
II
OEt
\
1
/c=C \ H o ~ t (36)
F3C-C excess HNR'R2
II
I
/
\
C=C
C
7&93%
NR'RZ
\
H
(10)
NR~RZ
(37)
HNR'R2 = NH3, NHzMe, H2NCH2CH,NH2 R' = H, RZ= H, Me; R1R2= -(CH 2)2-. Cyclic ketene acetals can also react with amines to give 1,l-enediamines with elimination of ethylene glyc01'~. Treatment of 2-[(methoxycarbonyl)cyanomethylene]1,3-dioxolane (38) with 1,3-diaminopropane o r with 4,5-dimethyl-l,2-phenylenediamine gives the hexahydropyrimidine and the benzimidazoline derivatives 39 and 40, respectively (equation 11). Similarly to the reaction of ketene dithioacetals with amines, the reaction between ketene acetals and amines proceeds via monoamino-substituted intermediates and ketene N,O-acetals can be isolated when one molar amine is used7'. The reaction of gem-dihaloethylenes with amines provides another preparative route to l,l-enediamines14~7'~'8. The halogens in activated gem-dihaloethylenes, like the
methylthio and alkoxy groups in ketene dithioacetals and acetals, act as leaving groups in their substitution by amines. 2-(Benzoylmethylene)benzimidazoline (29) has been synthesized by the reaction of 1,l-dichloro-2-benzoylethyleneand o-phen~lenediamine~~. 1,l-Diiodo-2,2-dinitroethylene(41), derived from the nitration of tetraiodoethylene, reacts with a number of amines to afford 1,l-enediamines 42 in yields of 61-91% (equation 12). A spiro product 43 has also been obtained from 41 and tetrakis(amin0methy1)methane in excellent yield14(equation 13).
C. Reaction of Amines with Ketene N,S or N,O-Acetals and a-Haloenamines
As we have mentioned above, ketene N,S- and N,O-acetals are the intermediates in the preparation of 1,l-enediamines from ketene dithioacetals and ketene acetals, respectively, and they can be isolated from the r e a c t i ~ n s ~ Further ~ ~ ~ ~substitution ~ ~ ~ ' ~ . of the methylthio or the alkoxy groups by amines yields 1,l-enediamines. A few asymmetric 1,l-enediamines, i.e. with different a-amino substituents, have been prepared from ketene N,S-acetals and amines5,51,52,79.80 . F or example, the primary 1,l-enediamines 45 are obtained by treating ketene N,S-acetals 44 with ammonia
1316
Z.-T. Huang and M.-X. Wang
(equation 14)79.Ketene dithioacetal 46 is transformed into asymmetric enediamine 48 bv two consecutive substitutions via 47 as illustrated in equation Except for the Geparation from ketene dithioacetals, ketene N,S-acetals can be also obtained directly from active methyl and methylene compounds by reacting with isothiocyanates, followed by S-alkylationS3.A convenient approach to ketene N,S-acetals makes this preparation attractive.
-
NHR OZN\ / C=C \ SMe
NH3/H20
MeSH
H'
F3CC0
\
C=C
H
SMe
-
F3CC0 \
R~R~NH
\
SMe
55-100%
-
NRLRZ
c=c
H
,
NHR OzN\ C=C / \ H NH2
\
SMe
F3CC0
NR1R2
R3R4NH
\
I
93-1008
/
\
C=C
H
(15)
NR3R4
Ketene N,O-acetals are converted to 1,l-enediamines when reacted with amines. For example, compound 45 has been fiepared by substitution of the methoxy with amine (equation 16)79.Symmetric 1,l-enediamines are obtained when both the alkoxy and the amino substituents are displaced by the amine employedR'. In this way, the reaction between ketene N,O-acetals 50 and piperidine leads to I,I-dipipetidinoethylene (35)' (equation 17)". Alternatively, 35 can be prepared from the reaction of piperidine with triethyl o r t h o a ~ e t a t e or ~ ~with , ~ ~ethoxyacetyleneR4,reactions which probably proceed via a ketene N,O-acetal intermediate. NH2 / OzN\ /c=C \ H OMe
RNH2
-MeOH
OzN\
NHR
/
,c=c\
H
NH2
The reaction of 2-amino-4,s-dihydro-3-furancarboxylic esters (51) with amines appears interestings5. In contrast to the structure assigned earlierR6-", the reaction products have been later identified as 1,l-enediamines attached to a lactone moietys5. Thus, substrate 51 reacts with methylamine to give acyclic 1,l-enediamines 52 with an approximate E/Z ratio of 40:60. The reaction involves 4,s-dihydrofuran ring-opening and lactone-formation steps (Scheme 3). In the case of ethylenediamine and 1,3diaminopropane, the reaction of 51 leads to the formation of cyclic l,l-enediamine
NH2 I
NHMe I
2-(52)
E-(52)
SCHEME 3
products 53. Apparently, ammonia is eliminated with the formation of the heterocycles in this reaction (equation 18).
Imino esters derived from benzoyl, nitro and ester-substituted acetonitriles behave as ketene N,O-aetals in yielding 1,l-enediamines when reacted with amines29,89,90 . For example, cyclic 1,l-enediamines 8 have been prepared by the reaction of imidates 54 and diamines (equation 19)'". X
\
,C-C
NH.HC1 //
excess H2N(CHdnNH2
X
32-70%
\OE~
H
Z.-T. Huang and M.-X. Wang
1318
a-Haloenamines 55'' can be converted to 1,l-enediamines 56 when reacted with amines o r their lithium salts (equation 20). Here, halide anion serves as a good leaving group. Relevant work conducted by a Russian groupy2is the reaction between enamine 57 and amines. Like the halogen in a-halogen enamines, the CCI, group is displaced by amines and the reaction proceeds to 58 in moderate to good yields (equation 21).
(57)
X,Y = electron-withdrawing groups
(58)
D. Reaction of Aliphatic Amides with Tetrakis(dimethylamino)titanium
In 1966, Weingarten and White9%eported a simple route to simple 1,l-enediamines. Under mild conditions, aliphatic amides underwent reaction with tetrakis(dimethy1amino)titanium (60) to afford 1,l-enediamines 61. The reaction could be carried out with most of the common acid derivatives such as free acid, ester and anhydride via the amide (equation 22). A probable mechanism involving intramolecular dehydration has been proposed in Scheme 442.
RCH=C'
\
+
HNMe2
NMez
SCHEME 4
+ titanium polymers
R 1= R2 = H (78%); R1 = Me, R2 = H (73%); RI = R2= Me (70%); R1 = Ph, R2 = H (88%); R1= RZ= C1(68%)
E. Reaction of Active Methyl and Methylene Compounds with Urea Acetals, SAlkylated Thioureas and Carbodiimides
It has been reported that urea acetals react with active methyl and methylene compounds to give 1,l-enediamines with loss of alcohol. Cyclic 1,l-enediamines 63 have been obtained by the condensation of the cyclic urea acetals 62 and nitromethane, acetophenone and cyanoacetic esters (equation 23)94.
~ - \ h1OEt C
R-N
1 \
I
OEt
X
\
+
CH2
/
Y
Me
-
R-N
-EtOH
I
/
\
C=C
R-N
I
X
\
Y
Me
Similarly, urea N,O-acetal 64 undergoes condensation reaction with weak carbon acids to afford acyclic (,I-enediamines with the elimination of alcohol and A number of active methyl compounds such as an aliphatic ketone, acetophenone, imino ester and thioacetoamide has been successfully converted to 1,l-enediamines. Lactones. lactams and thiolactams condense with 64 to give enediamines 65 in moderate yields (equation 24). Very weakly activated methyl groups are also reactive towards urea N,O-acetal 64, and 1,l-enediamines 6 6 7 1 are prepared from the corresponding rea c t a n t ~ ~5 .~ , '
(64 X,Y = 0; X = NMe, Y = 0, S
1320
Z.-T. Huang and M.-X. Wang
MezN
N-N
Me2N
NMe2 NMe2
(71) Condensation reaction between active methyl and methylene compounds and Salkylated thioureas provides another useful synthetic pathway to the 1,l-enediamines. Rajappa and coworkers20 reported that nitromethane condensed with S-methylated thioureas 72, prepared from the reaction of amines and methyl isothiocyanate followed by S-methylation, to form asymmetric nitro 1,l-enediamines 73 (Scheme 5). The method has been extended to the synthesis of cyclic 1,l-enediamines with nitro and other electron-withdrawing substituents on the P-carbon atom39396.For example, 1-methyl-2-methylthio-4,5-dihydroimidazoine (74) reacts with nitromethane, and diethy1 malonate, malononitrile and alkyl cyanoacetates at 100 "C to yield products 75 in 56-78% yield (equation 25)3y. Reaction between 74 and alkyl P-ketoacetates or acetylacetone under the same conditions, however, furnishes cyclic 1,l-enediamines 77 with loss of one acetyl group3'. The evidence available indicates the involvement of a consecutive reaction between the initially formed 1,l-enediamines 75 and the methanethiol released at the condensation stepy7.The methanethiol attacks the more reactive carbonyl group of the enediamine 75 to form the intermediate 76, which undergoes elimination to give the deacetylation products 77 and methyl thioacetate (78) (Scheme 6). 75 can survive in this reaction
MeNH NO2 \ / /C=C \ R~R~N H
MeN02
M~N=C-NR'R~
I
SMe
, NMePh
N R ~ R ~ -NJ =
SCHEME 5 I
ROC
\
CH2
-
Y
I
,C=C
Y
/
\
(77)
Y = COMe, C02R' SCHEME 6
provided that methanethiol is removed from the reaction mixture as soon as it is formed3'. 2-(Methylthio)imidazolidine, the analogue of 74, can undergo the same reaction, but more active methylene substrates are required39. Carbodiimides serve well in the 1,l-enediamine synthesis due to the 1,3-diazo arrangement in its structure. An earlier report on the preparation of 1,l-enediamines from carbodiimides appeared in 1965 by Gompper and Kunz9'. In the presence of base, carbon acids add to carbodiirnides 79 to give enediarnines 80 in moderate to excellent yields (equation 26)98.99.Due to the structural feature of carbodiimides, only acyclic 1,l-enediamines can be expected. However, cyclic structures at the b-carbon atom (80a) were also obtained.
Z.-T. Huang and M.-X. Wang
-
X
\
+
RN=C=NR
X RNH \ / /C=C
base
CH,
/
(79)
\
RNH
Y
Y
(80) R = c-C&l~, i-Pr, Ar X = Y = C N ; X=CN,Y=C02R; X=Y=C02R; X = Y = COPh; X = COMe, Y = COPh; X = COPh, Y = C02R
II C-W
RNH
\
/
1
\
C=C
RNH
C-W II
Z
Xz
Recently, a Russian g r o ~ p ' ~ ~ha-s ' developed ~~ a synthesis of primary 1,l-enediamines 82 from the addition of active methylene compounds to cyanamides 81 (equation 27). X R-NHCN (81)
+
\
CH2
/
N~(OAC)~
Y
X
\
C=C
/
Y
NHz \
NHR
(82) X = NOz, Y = COPh; X = NOz, Y = C02Et; X = Y = N 0 2 ; X=Y=COR; X=COR,Y=C02R
F. Acylation of 1-Alkyl-2-methylamidine Derivatives
2-Methylimidazole derivatives are unique starting materials for the synthesis of cyclic 1,l-enediamines. Activated by the heterocycle, the 2-methyl substituent of l-alkyl-2methylimidazoles is weakly acidic and can easily be functionalized.' Acylation of 1,2-dimethylimidazole (83) and 1-ethyl-2-methylbenzimidazole(85) with benzoyl chloride takes place readily in the presence of a base (usually tertiary amine). Hydrolysis of the en01 benzoate products 84 and 86 leads to 1,l-enediamine (e.g. 87)3',32 or to amidine tautomers (e.g. 12)32 (equations 28 and 29). (See also Section I1.A for tauiomerism between an 1,l-enediamine and an amidine.)
excess
R
N
PhCOCL R;N
x
R
\
Me
N
OCOPh /
\~c=c
N\ Me
N \
Et3N
A
-
xyFCH2COPh N R \ Me
'Ph
-
(28)
OCOPh
/
fJ&CH=C
\
N
Ph
H
,
COPh H
Preparation of 1,l-enediamines having a benzimidazoline ring has been reported recently by the acylation of 1,2-dimethylbenzirnidazole(88) with ethyl benzoates in the presence of excess sodium hydride. Both enediamine 13 and amidine 13' isomers were obtained (equation 30)33.
I
excess NaH
1324
Z.-T. Huang and M.-X. Wang
In contrast to 83 and 85, 1,2-dimethyl-4,5-dihydroimidazole(89, n = 2) and 1,2dimethyl-1,4,5,6-tetrahydropyrimidine(89, n = 3) underwent direct acylation with two equivalents of aroyl chloride to give diacylenediamines 90 rather than en01 benzoates. Their acid hydrolysis with sulfuric acid at water bath temperatures results in cleavage of one of the aroyl groups and benzoyl-substituted 1,l-enediamines 91 are formed in moderate yields (equation 31)ln3.
Only monoacylated products 93 are isolated when 1-benzyl- and 1-phenyl-2-methylimidazolines (92) are reacted with carboxylate esters under the reaction conditions illustrated in equation 3210.104.
(92) R1= PhCH2, Ph; R2 = alkyl, aryl
(93)
It appears that the acylation products depend upon the structure of the starting material, the acylation reagents and the reaction conditions (see Section 1V.C). It is relevant to the acylation that the 2-methyl group in 89 and 92 has also been thioacylated and esterified, respectively, but the reaction yields are I O W ' ~ ~ ' ~ ~ .
G. Miscellaneous Preparative Methods
The addition of secondary amines 95 to ynamines 941n6 leads to 1,le n e d i a m i n e ~ ~ ~ while ' - ~ ~ ~primary , amines give the amidine t a u t o m e r ~ Substituted ~~~. N-allylenediamines 96 have been synthesized from the corresponding allylic amines by this method (equation 33)lU9,a- and a-amino esters also react with ynamines, but in
(96)
R
= Ph, Et
most cases intramolecular cyclization of the initially formed adducts 97-97' occurs spontaneously to form the heterocyclic component 98 in good yields (Scheme 7)"'.
(98) R 1= H,Me, Ph; RZ= Me, Et; R3= Me, Ph; R4 = H, Me, i-Pr, i-Bu, PhCHz SCHEME 7
Deprotonation of amidinium salts gives 1,l-enediamines"' and the method is well suited for the preparation of simple cyclic l,l-enediamine~'~.~'. 4,5-Dihydroirnidazolium salts 99, prepared easily by alkylation of imidazolines or cyclization of ethylenediamine with orthoesters, reacl with sodium hydride lo afford 2-alkylideneimidazolidines 100 in good to excellent yields (equation 34)18.
Wang Z.-T. Huang and M.-X.
1326
Nair and Desai113 described another synthetic route to conjugated cyclic 1,lenediamines such as 8. Condensation of cyclic thiourea component 101 with arylacyl bromide furnishes arylacylmethylisothioureas 102, which are converted t o products 8 when treated with triphenylphosphine in the presence of base (equation 35). 1,lEnediamines having other diamine moieties are obtained similarly. Although this
triphenylphosphine-induced sulfur extrusion reaction takes place smoothly with moderate to excellent yields, no reaction occurs in the case of benzimidazole and diazepine derivatives and the yield for the reaction of N-methylthioureas appears low113.
IV. 1,l-ENEDIAMINES AS NUCLEOPHILES IN SUBSTITUTION AND ADDITION REACTIONS
As mentioned in Section I, one of the remarkable features of 1,l-enediamines is the enhanced enaminic reactivity of the P-carbon atom. 1,l-Enediamines can serve as nucleophiles in substitution of and addition reactions to a wide variety of electrondeficient reagents. In this section we discuss mainly the alkylation, arylation and acylation reactions of 1,l-enediamines, emphasizing their synthetic utilities, especially those of secondary enediamines. A. Protonation
Results obtained so far have shown that protonation occurs, without exception, on the 0-carbon atom of l , l - e n e d i a m i n e ~ ' ~This . ~ ~ .agrees well with the structural characteristics of 1,l-enediamines, i.e. with the increased electron density on the P-carbon atom due to the delocalization effect. 1,l-Enediamines 35,103 and 104, derived from piperidine, react readily with acids to form the amidinium salts 105107. The perchlorate salts are particularly easy to prepare since they crystallize in analytically pure form on titration of the parent compound with 0.1 N perchloric acid in acetic acid (equation 36)!j4. Secondary 1,l-enediamines 8 and 53 give amidinium salts almost quantitatively on treatment with hydrochloric acid in m e t h a n 0 1 ' ~ ~The ~ ~ .evidence for formation of amidinium salts has been provided by the
(35) RI=RZ=H (105) (103) R1 = H, RZ= CONHR or CSNHR (106) R1 = R2 = CONHEt (107) (104)
spectral data. The reaction product from 8 and hydrochloric acid, for example, shows a carbonyl stretching at 1675-1690 c m in the infrared spectrum, i.e. 75-90 c m higher than the parent enediamines 8. In 'H NMR spectra, the vinyl proton of 8 is replaced by a higher-field two-proton signalz9. The stability of 1,l-enediamines and their amidinium saltss4 merits comment. Secondary and tertiary 1,l-enediamines substituted by two fi-electron-withdrawing substituents such as 104 are quite stable, being unaffected by refluxing with aqueous sodium hydroxide. Treatment of their salts with base regenerates the parent enediamines. O n the other hand, 103 o r its salt 106, undergoes hydrolysis to give N-pentamethylene-Nphenylmalonamide. Simple 1,l-enediamines or their salts are very sensitive to hydrolysis, leading to a m i d e ~ " ~ , ~ ~ ~ .
'
'
B. Alkylation and Arylation 1. With alkyl halides
Simple 1,l-enediamines undergo ready alkylation with alkyl halides to give amidinium
salt^"^.^^^. C-Alkylation dominates due to the formation of the charge-stabilized amidinium cation. Hydrolysis of amidinium salts under basic conditions affords substituted amides. Thus, alkylation of 1,l-enediamines 61 provides a route to a-substituted carboxylic acid amides 109 (equation 37)l14. Different products have been reported with dihaloalkanes'17. A linear product, the glutaramidinium salt (110), is formed in the reaction of 4 with methylene iodide, and similar behavior was observed for 1,3-dimethyl2-(methylene)imidazoline (3) with methyl ~ h l o r i d e ' ~When . 1,2-dibromoethane, 1,4diiodobutane and 1,5-diiodopentane are employed in the reaction, cycloalkylamidinium salts 111 are formed as the major products. Hydrolysis of 111 results in cycloalkanecarboxamides 112 (Scheme 8). Surprisingly, 4 reacts with 1,3-diiodopropane to yield the tetrahydropyridinium salt 113 rather than a cyclobutane derivative (equation 38).
(61) R = H or Me, R'
(108) = Me, PhCH2, CH2=CHCH2, n-CqHg
(109)
Z.-T. Huang and M.-X. Wang
SCHEME 8
This has been attributed to the participation of the nitrogen atom in the reaction owing to more favorable energetics of formation of a six-membered rather than a fourmembered ring'". Hydrolysis of 113 gives 114.
Conjugated 1,l-enediamines undergo alkylation with alkyl halides at a slower rate than nonconjugated ones, and heat is usually required. Unlike the case of simple i,l-enediamines, treatment of the amidium salts with base furnishes alkylated 1,lenediamines. In addition, enediamines bearing two electron-withdrawing groups fail to react with alkyl halide^^^,^^,"^. The reaction between secondary cyclic 1,l-enediamines 8 and ethyl bromoacetate proceeds smoothly in refluxing acetonitrile or dioxane to afford the y-lactam-fused diazaheterocycles 116 in moderate yields22. In the reaction sequence, C-alkylation takes place initially with the formation of intermediates 115 which have been isolated in some cases, and cyclocondensation of 115 leads then to products 116 (equation 39). This demonstrates that secondary 1,l-enamines such as 8 act as dinucleophiles, and construction of fused heterocyclic compounds can take advantage of the nucleophilicity of enamines. Although secondary 1,l-enediamines always undergo C-alkylation under neutral conditions, N-alkylation is effected with the aid of a strong basez4. The nitro-substituted 1,l-enediamines 7 react with propargyl bromide in the presence of sodium hydride to give exclusively N-alkylated products 117 (equation 40)24n.
2. With acetylenes Different modes of reaction are known for the reaction of 1,l-enediamines with electrophilic acetylenes. Simple 1,l-enediamines undergo cycloaddition reaction which will be discussed in Section V.A119, whereas conjugated 1,l-enediamines act as nucleophiles towards activated acetylenes. The reaction between secondary enediamines and propiolic acid esters has been studied in detailz3. In aprotic solvents such as benzene and dioxane, 8 adds to methyl propiolate at ambient temperature t o give almost quantitatively product 118 with a trans-configuration of the new double bond, as indicated by a 3J,, coupling constant of around 16 Hz in the 'H NMR spectrum. It appears that the reaction proceeds via an ene-addition mechanismz3. In refluxing ethanol, the C-adducts 118 are converted to the heterocyclic compounds 119. The direct transformation of 8 to 119 is easily achieved in alcoholic solvents. 1,l-Enediamines with b-nitro, ester and acetyl substituents undergo analogous addition and cyclocondensation reactions to give heterocyclic compounds 11939.1Z0. N-Ethynylcarbonyl imidazole behaves similarly to propiolic acid esterslzO (equation 41). An analogous addition reaction has been observed between 1,l-enediamines 53 and methyl propiolate. In alcoholic solvents, the reaction leads via 120 or directly to compounds 121 formed by cleavage of a lactone ring (equation 42)lz1. In an attempted synthesis of the spiro compounds 123 from the cyclic 1,l-enediamines 122 derived from cyclic ketones, in contrast to the expectation, the cyclic ketone ring is cleaved under mild reaction conditions and fused heterocyclic compounds 124 are obtained in good yields from 122 and ethyl propiolate (equation 43)58.'z2.
1330
Z.-T. Huang and M.-X. Wang
:r:
H R1
R1
rA\ H
(CH2), C=C
L.'I
r\
H-CX-COzR2
I
( C H Z ) ~,C=C
dioxane, r t
\
EWG
LN I
H
C02RZ
H EWG
\
H
\
(118) R' = H, RZ= Me, EWG = COAr
H - c q - c o - ~ e ~
L=l
(41)
R' = H, EWG = COAr; R1 = Me, EWG = NOz, COMe, C02Me; R1 = PhCH2, EWG = C02Et
(42)
N
I
HOC-CH
I
I
C02R4
RL R3 (121)
H-C=C-C02Et ROH. 40-60T
Similar reaction occurs between secondary 1,l-enediamines and dimethyl acetylenedicarboxylate, leading to fused heterocycles 125 with an alkoxycarbonyl substituent on the pyridinone ring (equation 44)23.39,123.
R'NH
\
EWG
,C=C \ R'R~N H
+
Me02CC=C02Me
RL-N +-I. I
R2 R'R1 = -CH2CH2-, R2 = Me, EWG = NOz, COMe R1 = Ar or R'R1 = -(CH2)2-3-. EWG = COAr RIR1=
@.R2
C02Me (44) EWG (125)
= H, Me, EWG = CN. C02R
Interestingly, the lactone moiety of enediamines survives when lactones 53 react with dimethyl acetylenedicarboxylate. The spiro compounds 126 are obtained at &10 "C in benzene solution (equation 45)lZ4. 3. With electrophilic olefins
C-Alkylation of 1,l-enediamines takes place readily when they are treated with electrophilic olefins including a$-unsaturated aldehydes, ketones and carboxylic acid derivatives. Primary and secondary 1,l-enediamines usually lead to fused heterocyclic products due to the simultaneous intramolecular cyclocondensation between the amino and the carbonyl groups of the initially formed adducts. 6-Lactam-fused compounds 127 are obtained by the reaction of secondary 1,lenediamines with a$-unsaturated carboxylic acid derivatives such as methyl acrylate,
R3&7 Z.-T. Huang and M.-X. Wang
N
R2
H
R1
+ Me02CC3X02Me
1
benzene C-10T, 69-878
(53
(45)
R3
(126) R' = R3 = Me, RZ= H, n = 2 . 3 R L = R 2 = M e ,R3=H, n = 3 propenoyl chloride (when pyridine serves as acid acceptor) and a$-unsaturated carbonyl i m i d a z ~ l e ~ ~ (equation , ~ ~ . ' ~ " 46). 1,l-enediamines 53 react with methyl acrylate to yield the spiro compounds 128lZ4.
H
r 4
EWG , (CH& C=C + R~CH=CHCOX LN' 'H I R1
- LN I
R1
(127) R1 = H, Me, PhCH2; R2 = H, Me, Ph; EWG = NO2, COAr, C02Et
(46) EWG
A similar result has been reported for the reaction of primary 1.1-enediamine 129 with arylmethylene malonates 130 which gave the 2-pyridone derivatives 131 (equation 47)lZ5.
Cyclic 1,l-enediamines 8 (n = 2) react with maleic anhydride to give products to which y-lactam fused heterocyclic structure 132 had been assigned (equation 48)lZ6.
An investigation of alkylation of 1,l-enediamines with m,P-unsaturated aldehydes and ketones has been recently conducted by Jones and H i r ~ t ~ The ~ . reaction of 1,lenediamine 93 and a$-enals affords the fused 1,4-dihydropyridines 133, via a nucleophilic addition and intramolecular dehydration sequence (equation 49). 93 reacts with propenal, however, to give the cyclohexene carboxaldehyde 134 in almost quantitative yield (equation 50). The formation of 134 is most probably due to addition of 93 to two PhCH2
RZ
\
/
H
RI /
c=c \
I
/
[:c=c ' \
H
\
H
C02Et
cHO*
PhCH2 /
[@
C02Et
-
(93) (133)) R1 R' = H, R2 = Me (62%); R' = R2 = Me (32%); R1 = Me, R2 = H (32%); R1 = H, R2 = Ph (27%)
R2
(49)
Z.-T. Huang and M.-X. Wang
1334
propenal molecules, followed by intramolecular aldol condensation. It appears that these reactions are faster than the formation of the 1,4-dihydropyridine ring in the case of other a$-enals (equation 49). 1,l-Enediamine 93 undergoes an easy C-alkylation with a,B-unsaturated ketones under comparable conditions and no cyclocondensation products are observed36. Similar C-alkylations with other electrophilic olefins such as unsaturated lactones, propenonitrile, vinyl sulfoxide, sulfone and phenylphosphonium bromide have been achieved36. All the adducts 135 exist predominantly as the imine form (see Section 1I.A). Treatment with organometallic reagents transforms the C-alkylated products into 1,l-enediamines 136'" (equation 51). I
N [N+<
\
H
H
R2
+ C02Et
c=c
\/
H
I
R'
'COR~
MeCNreflux or dioxane
*
C>tc"el R2
c0R3
In contrast to these results, intramolecular cyclocondensation of the amino group with the carbonyl carbon takes place following the addition step in the reaction between 1,l-enediamine 137 and alkylidene or arylideneacetoacetic esters 138. Meyer and coworker^'^'^^^^ have shown that 137 reacts with 138 to produce 1,4-dihydropyridines 139 (equation 52). Acyclic 1,l-enediamines lead t o a n analogous result. It is worth noting
that the amino group condenses selectively in this reaction with the ketonic rather than the ester carbonyl group. When 137 is reacted with 1,3-cyclohexanedione and aromatic aldehydes, tricyclic compounds 140 are obtained. The reaction probably proceeds via addition and cyclization between 137 and 2-arylidene-1,3-cyclohexanedioneswhich are formed in situ from 1,3-cyclohexanedione and the aldehydes (equation 53).
Apart from the addition reaction to electrophilic olefins, the P-carbon atom of 1,l-enediamines can also substitute a$-unsaturated compounds carrying a leaving group. Schafer and G e ~ a l d ' ' have ~ shown that 141 and 142 react with 143 to give product 144 in moderate to good yields (equation 54). Ketene dithioacetals derived from an alkyl cyanoacetate and malononitrile behave similarly to 143130. When imine 145 is employed, the reaction results in the formation of 146 (equation 55)lZ9. Apparently displacement of ethoxy group and cyclocondensation by attack on the nitrile moiety are the key steps in the reaction. R-N RNH
\
C=c\
/
RNH
CN
NO2 /
H
+
EtOCH=C\
/
X
32-94%
R-N,
yNo2 (54)
>=(
(141) R = Et, Ar
No arylation was observed when 1,l-enediamines 8 reacted with 2,4-dinitrohalobenzenes 147 under neutral conditions. However, the cc-anion of 8, prepared with sodium hydride in DMF, can displace a halide ion from 147 to alTord C-arylated products 148. Excellent yield was obtained with 2,4-dinitrofluorobenzene (equation 56)13'. It has been demonstrated that the reaction proceeds via the radical nucleophilic substitution (S,,l) mechanism. The reaction of 1,l-enediamines with 19-benzoquinone takes a different course132. Acyclic 1,l-enediamines 149 react with 19-benzoquinone in refluxing acetic acid to give after workup two products 150 and 151, resulting from dehydration and deamination, respectively (equation 57). Only benzofurans 152 (21-27%) are isolated in the case of enediamines 8 derived from 4-bromoacetophenone. Cyclic 1,l-enediamine 8 (n = 2, R = H) examined in the reaction leads exclusively to a low yield (9%) of the tricyclic indole 153.
1336
Z.-T. Huang and M.-X. Wang
RNH
\
,c =C\ RNH
/
" H
+
O
n0
(14% R = Ph, Et EWG = NO2, COPh
1
AcOH A. 0.5 h
+ I
NHR
HO @ ' JEwG
NHR
5. With aldehydes and ketones
A detailed investigation of the reaction of simple 1,l-enediamine with aromatic aldehydes has been reported by Barton and coworker^"^. 1,l-Dimorpholinoethylene (154) reacts with aldehydes in refluxing benzene to give trans-cinnamoyl morpholides 156 in fair yields, along with aminals 157 and N-acetylmorpholine 158. The condensation proceeds by an initial attack by the P-carbon atom of the 1,l-enediamine on the aldehyde. Hydrolysis of the amidinium intermediate 155 by the water liberated in the initial condensation results in product 156 and morpholine. Thus, the liberating morpholine condenses with the aldehyde to yield the aminal 157 and water, which in turn hydrolyze the unreacted 154 to N-acetylmorpholine 158 (Scheme 9). In the case of salicylaldehyde,
SCHEME 9
Z.-T. Huang and M.-X. Wang
1338
the o-hydroxy group competes with the external water in the reaction with the amidinium moiety, and coumarin 159 is the reaction product (equation 58).
R
n
aOHmo CHO
P ++:no u -
R
(58)
(159)
(154) = H (57%), R = O H (34%) R Meyer and coworkers'25 have reported the condensation reaction between conjugated 1.1-enediamines and aldehydes. Acyclic 1,l-enediamines 160 react with aldehydes in a 2.1 ratio to give 2,6-diami~o-4,5-dihydropyridine-3,5-dicarboxylates (161) with elimination of water and amine (equation 59).
Unlike 160, cyclic 1,l-enediamines 137 react with aldehydes to yield lactam derivatives 162 with loss of water and ethanol (equation 60). The intermolecular reaction between 1,l-enediamines and simple ketones is not known. Nevertheless, acetylacetone has been reported to react with enediamine 142 to afford the condensation product 163 (equation 61)'33. have reported an intramolecular reaction of tertiary eneGompper and diamines bearing a keto group. Treatment of amidinium salt 164a with ethyldiisopropylamine in acetone results in the formation of the pyrrolopiperidine derivative 166 in 79% yield. Interestingly, reaction of 164b with sodium hydride in tetrahydrofuran very rapidly forms the pyrrolidinimine 167 in 91% yield (equation 62) (see Chapter 16). C. Acylation
1. With carboxylic acid halides and ketenes
Few examples have been known for the acylation of 1,l-enediamines with carboxylic acid d e r i ~ a t i v e s " ' ~ ' ~and ~ - ~k e t e n e ~ ' ~ ~ .
H Ar
HN NHHN (CH2),
Me
I
Et
Me
I
I
NH
(CH3,
Et
I
0 R
R
(164)
(165)
(a) R = Ph (b) R = OEt
R = OEt
Me
Et
I
I
Me
I
C02Et HO (166)
Ph
(167)
1340
Z.-T. Huang and M.-X. Wang
In a patent13' a nitro-substituted cyclic enediamine was acylated by l-methyl-3(phenoxycarbonyl)imidazolium chloride, prepared from the reaction of phenoxycarbonyl chloride and imidazole, to give product 168. Hydrolysis of 168 leads to the P-carbon atom acylated product 169. Unlike the alkylation which occurs only at the P-carbon atom, acylation takes place both at the P-carbon and at the secondary nitrogen atom giving 168 (equation 63).
As we have illustrated in Section IKF, acylation of active methyl substrates gives different products depending on the reactants, the acylation reagents and the reaction conditions. The formation of diacy1103or enol ester product^"^^^, presumably formed via further acylation of the initially formed 1,l-enediamines, indicates that the acylation of acyl-substituted 1,l-enediamines also depends on the nature of amino groups, the acylation reagents and the reaction conditions. It appears that the three sites in these molecules, i.e. the P-carbon atom, the secondary amino group and the oxygen of the carbonyl moiety, can react with the carboxylic acid chloride. Secondary 1,l-enediamines 170 undergo N-acylation to 171 when treated with oxalyl chloride. The reaction between 170 and phosgene or thiophosgene takes a different course and affords heterocyclic compounds 172 (equation 64)13'". Surprisingly, acylation of primary 1,l-enediamines with benzoyl chloride has been reported to give unsaturated P-lactamsgz. Simple 1,l-enediamines have been shown to undergo a vigorous acylation with ketenes with the formation of acyl-substituted 1,l-enediamines (equation 65)'".
2. With isocyanates and isothiocyanates
Simple 1,l-enediamines react with isocyanates and isothiocyanates to afford Cacylated and C-thioacylated products, respectively. Mono- (103) and diadducts (104) can be-formed when the rkactani ratios are 1-:1 and 1:2, respectively (equation 66)84. In contrast to the acylation with carboxylic acid chlorides, secondary 1,l-enediamines react with isocyanates and isothiocyanates to give cleanly the P-carbon acylated products. Carbamoyl-substituted enediamines (175) have been obtained from 174 and arylsulfonyl isocyanates (equation 67)140.'41.
I
X = 0, S; R = alkyl. my1
R'NH NO2 \ I F=C\ H R2R3N
+ ArS02NC0
-
(174) Rl,R2,R3= alkyl, or R1R2= -(CH2),-.
R~NH NO2 \ I /C=C \ R2R3N CNHSOzAr II 0 R3 = alkyl (175)
(67)
1342
Z.-T. Huang and M.-X. Wang
Rajappa and coworkers20 used isothiocyanates as a probe to examine the enaminic reactivity of nitro-substituted enamines and enediamines. The results were usually consistent with predictions based on the chemical shift of the vinyl proton and on extended Hiickel calculations. However, cyclic enediamine 7 was found to be unreactive toward aryl and alkyl isothiocyanates (see Section 1I.A). Very recently, the same reaction has been re-examinedz1 and it has been found that cyclic enediamine 7 indeed reacts easily with aryl isothiocyanate to give the addition products 176 in 54-65% yield (equation 68).
R ' = R2 = Me, R3 = Ph, Me, CH2CHCH2; R' = H, R2 = Me, R3 = Ph, CH2Ph; R' = H, R ~ =R-(CH2)2-3-, ~ R3 = Ph
(176)
The reaction of benzoyl-substituted 1,l-enediamines 8 with aryl isothiocyanates gives excellent yields of P-carbon adducts 177 (equation 69).
The thioacylated products are frequently useful intermediates and they have been transformed into sulfur-containing heterocyclic compounds. Reflux of acyclic 1,lenediamines 176 with phenacyl bromide or chloroacetone in ethanol gives the tetrasubstituted thiophenes 178142.The reaction includes S-alkylation and cyclization steps (equation 70). O n the other hand, oxidation of secondary 1,l-enediamines 176 with bromine results in the formation of isothioazole derivatives 179. The yields of the oxidation-cyclization reaction depend strongly on the substituent R2 (equation 71)21,143.It is noteworthy that oxidation of 177 under the same conditions does not furnish isothioazoles but, instead, benzothiazoles 180 are formed (equation 72)21.A similar product, 180, has been obtained in the case of the nitro-substituted enediamines of p y r r ~ l i d i n e ' ~The ~ . different outcomes of these reactions reveal that the reactivity of the secondary amino group of 1,l-
r:\ ,
NO2
(CH2)n /C=C\
LN I
I
- rN\ (CH2), C=C
LN' s> N R ~
(176) n = 2 , 3 , R' =Me, R2 = COPh (87-88%) n = 2,3, R1 = Me, R2 = C02Et (39-50%) n = 2 , 3 , RL= H, R2 = Ph (7-15%)
COAr
(179)
- LN Br2
(CH2h /C=C\
LN C-NHPh H II S
(71)
'
C-NHR~ II S
R1
/NO2
Brz
H
(72) \
1344
2.-T. Huang and M.-X. Wang
enediamines is greatly affected by the nature of the B-electron-withdrawing substituents. Therefore, investigation of the reaction at the nitrogen site would provide very useful information for better understanding of the structural characteristics of 1,lenediamines. Further transformation of the isothiazoles had been made. On treatment of 179 (R2 = COPh) with sodium methoxide in methanol, a fragmentation reaction takes place with the formation of 3,3-diamino-2-nitroacrylonitriles (181) in good yields (equation 73)'44. 181 can also be obtained in one step by reacting 176 with aqueous alkaline hydrogen peroxide. The preparation of cyano-substituted enediamines from 5-7, i.e. the introduction of a nitrile group in place of P-hydrogen, can be viewed as cyanolation. However, cyanolation of benzoyl substituted 1,l-enediamines either by using direct oxidation or through a fragmentation reaction is unsuccessful. This result supports the assumntion that the amidinium-nitronate structure 179 is responsible for the ease of fragmentation of the isothiazoles 179145.
R-N
+&oR-N -
-0Me
NO?
~
\
MeONa MeOH
,C=C
R-N
/
-
\
CN
D. Reaction with Other Electrophiles 1. With azodicarboxylate esters
Simple 1,l-enediamines react with diethyl azodicarboylate (182, R = Et) to give mainly, after hydrolysis, N,Y-dicarbocthoxyhydrazinylamidcs (183) in low to modcrate yields (equation 74). A small amount (6%) of [2 + 41 cycloaddition product was also isolated in the case of 1,l-dipiperidinylethylene 35 (X = CH,)146. Secondary cyclic 1,l-enediamines 8, 75a and 77 react with diethyl azodicarboxylate smoothly at room temperature to afford excellent yield of C-adducts 18429.39.1,l-Enediamines 185 also led to adduct 17 or 17' when refluxed with 182 in methylene chloride (Scheme 10)37,147(see Section 1I.A for tautomerization between 17, and 17'). An ene-addition
ri
(CH2), C=C
LN/I
I%. OEt I
,EWG \
NNHC02Et I
1346
Z.-T. Huang and M.-X. Wang
mechanism was suggested by the authors. Oxidation of 17 and 17' with bromine and diisopropylethylamine depends on the substrate. In cold methylene chloride, 17 was oxidized to the tricyclic compound 186 in moderate yield, whereas only a tiny amount of 187 was formed under various oxidizing conditions (Scheme 10). The mechanism of the oxidation was discussed14'. 2. Halogenation
Conjugated 1,l-enediamines react with halogens smoothly to afford P-carbon halogenated amidinium saltsa5. Elimination of hydrogen halide then converts the amidinium salts to b-halogenated 1,l-enediamines 188 (equation 75)148,'4y.
3. Miscellaneous reactions
Except for the electrophilic reagents discussed above, the reaction of other electro deficient reagents has been tried with 1,l-enediamines. Nitro-substituted 1,l-enediamines ediamines 174 easily undergo reactions with phenylsulfenyl chloride and with the aryldiazo cation to yield products 189'4y,150and 190n7, respectively (equations 76 and 77).
RNH
\
NO2 1
,C=C \ RNH H
RNH
+ ArN2+CI-
\
+
NO2
I
,C=C \ RNH N=NAr
A Mannich reaction of conjugated 1,l-enediamines has been reported 151-153. Cyclic 1,l-enediamines react readily with formaldehyde and primary amines to give the fused heterocycles 191 (equation 78)152,153 . Th e reaction proceeds through the Mannich reaction, which is then followed by condensation between the amino groups and formaldehyde.
EWG = NOa C02Et; n =2-4 Recently, Baum and coworkers'54 reported the nitration of 1,l-diamino-2,2-dinitroethylene. On treatment with nitric acid and trifluoroacetic anhydride in methylene chloride at 0 "C, 1,l-enediamines 42 are converted to 3-nitro-2-(trinitromethy1)-1,3diazacyclic compounds 192 in good yields (equation 79). Compounds 192 have also been prepared from the nitration of 7, although the yields are lower (1622%). Denitration of 192 to 193 includes a reductive denitration of 192 with potassium iodide and acidification of initially formed salts of 193. Nitration of 193 regenerates 192 (equation 79).
(CF3COhO P CH,CI (CHI),,
1 . KI 2. HCI
~ c ( N o ~ )H N,O ~ (CF3COh0
H NO2
CH~CI~
(CH2).
$=$
LN I
N02
NO2
Diphenylcyclopropenone (194) reacts with nitro-substituted 1,l-enediamines 7 in the presence of K,CO, to give a fused heterocyclic compound 195155(equation 80).
Z.-T. Huang and M.-X. Wang
1348
Surprisingly, acyclic 1,l-enediamine analogues react with 194 to give products 1% with elimination of HNO,. Oxidation of 196 leads to 2,3-diphenylmaleimides (197) (equation 81). The products were identified on the basis of spectral data and by comparison with authentic samples. The mechanism proposed starts with attack of the enamine nitrogen on the carbonyl moiety of 194.
ArNH
,c=c \ ArNH
H
+
'
2&56%
Ph
Ph
Ph
MCPBA
NHAr
1
1U1%
0
V. CYCLOADDITION REACTIONS OF 1.1-ENEDIAMINES
In this section, we will discuss the few, but interesting, cycloaddition reaction^"^ of 1,l-enediamines. These cycloadditions provide a useful synthetic approach to a variety of complex compounds, and reflect the differences between 1,l-enediamines and enarnines on the one hand, and between simple and conjugated 1,l-enediamines on the other.
Few examples of [2 + 21 cycloaddition reactions of 1,1-enediamines have appeared in the literature. As presented above, conjugated 1,l-enediamines always react with acetylenic esters to give the addition products. In contrast, simple 1,l-enediamine 35 undergoes a cycloaddition with dimethyl acetylenedicarboxylate to give a good yield of dimethyl 2-(dipiperidinornethy1ene)-3-methylenesuccinate(198), presumably arising from the rearrangement of the initially formed cyclobutene adduct (equation 82)"'. A [2 + 21 cycloaddition reaction between simple 1,l-enediamine and a sulfonyl chloride was also ~ b s e r v e d ' ~ ' - ' ~ In ~ . the presence of a base, 1,l-dimorpholinoethylene (154) reacted with methanesulfonyl chloride (199) in ether or in tetrahydrofuran to give 3-morpholinothietane 1,l-dioxide (200) in good yield (equation 83). However, the reaction takes a different course in chloroform, leading to the conjugated 1,lenediamine 201. Other reactants than 154 and 199 did not form cycloaddition products under the same condition^'^^.
Simple 1,l-enediamines act as electron-rich olefins in undergoing inverse electron demand Diels-Alder reactions with dienes. Efforts have been focused on their cycloaddition reactions with heterocyclic a ~ a d i e n e s ' ~ ' . ' For ~ ~ . example, 1,l-enediamines 35 and 154 react easily with 5-nitropyrimidine to give the pyridine derivatives 203 via the 1,4-addition intermediates 202 (equation 84)163. Investigation of the reaction of 1,l-bis(dimethylarnino)ethylene 4, ketene N,S- o r N,O-acetals, with 1,2,4-triazines and 1,2,4,5-tetrazines has been conducted by Miiller and S a ~ e r ' ~Unlike ~. ketene, N,S- or N,O-acetals, 1,l-enediamine 4 leads to both
Z.-T. Huang and M.-X. Wang
1350
ortho- (204 and 205) and meta- (204' and 205') isomers and their distribution is strongly affcctcd by the solvcnts used (equations 85 and 86). It has bcen found that 1,l-enediamine 4 is less reactive than ketene N,S- or N,O-acetals in these inverse electron demand Diels-Alder reactions, in contrast to anticipations based on the H O M O energies of these dienophiles.
N4N Ph
C02Me
Ak +
2. 1. -N2 addition
3. -HNMe2
-
b
m
e
2
(85)
+
me2
H2c==(NMe2 NMe2
30°C
(4)
MeOH
100
THF DMF
92 37
(4)
COzMe
Ph (204)
(204')
EtOH
99
1
THF MeCN
12 6
88 94
Recently, Gruseck and Heu~chrnann'~have ascribed the lower reactivity of 4 to the steric effect. Only when the steric effect for a series of compounds is identical, or at least similar, can correlation between reactivity and H O M O energies be expected.
Due to the interaction between the two amino groups, 1,l-enediamine 4 would adopt a perpendicular conformation which impairs attack on the n-system from both sides of 4. If 1,l-enediamine 4 would have a planar configuration, it would show greater reactivity than ketene N,S- or N,O-acetals. This has been convincingly demonstrated by comparing the reactivity of 1,3-dimethyl-2-(methylene)imidazoline(3) with 4, and with ketene N,S- or N,O-acetals. When the steric effect is removed, 3 indeed shows higher reactivity than its acyclic analogue 4 or ketene N,S- or N,O-acetals. In fact, 3 reacts vigorously at 0 "C with 1,2,4-triazine 206 to give 207, and nitrogen evolution is complete within a few seconds (equation 87). The reaction even occurs at - 20 "C, whereas all other substrates react
with 206 at 40 "C. The higher reactivity of 3 has been further demonstrated by cycloaddition to pyridazine. 3 reacts with 2OSa and 210 to give high yields of products 209 and 211 (equation 88). A mixture of regioisomers (209b, c) is obtained when 3-methylpyridazine (208b) is used.
(208) (a) R = H (b) R = Me
(20%
(a) R 1 = R~ = H (b) R1 = H, R2 = Me (c) R L= Me, R2 = H
The only 1,l-enediamines known to react with acyclic dienes in an all-carbon [2 41-cycloaddition are the alkylideneimidazolidines, as has been reported by Heuschmann and G r u s e ~ k ' ~ in ~ . recent ' ~ ~ years. Thus, cycloaddition products are formed at or below room temperature when 3 is treated with 2,4-dienoates. Hydrolysis of cycloadducts 212 by dilute acid leads to 2-cyclohexenone derivatives 215 or their enol tautomers 216 via 213 and 214 (Scheme 11). The reaction has been extended to
+
1352
2.-T. Huang and M.-X. Wang
chiral 2-(methylene)imidazolidines and optically active cyclohexenones and enols are obtained with ee of 346%16'. The evidence available indicates that the reaction proceeds by the multistep route of the cycloaddition m e c h a n i ~ m ' ~ ~ . ' ~ ~ .
C. 1,3-Dipolar Cycloaddition
Simple 1,l-enediamines undergo 1,3-dipolar cycloaddition readily with 1,3-dipolar reagents. The 1,3-cycloadducts, which are stable and have been isolated in some cases, undergo further deamination by heating or in the presence of acid to give heteroaromatic products. This behavior resembles that of the parent enamines'.'. Thus, 1,l-enediamines react with a ~ i d e s ' ~ ' . 'and ~ ~ nitrile i r n i n e ~ ' ' ~smoothly to give high yields of the cycloaddition products 217 and 219, and triazoles 218 and pyrazoles 220 after deamination (equations 89 and 90). 1,l-Enediamines react vigorously with nitrile oxides to give isoxazoles 221 in good yields (equation 91)171.
\
COR
R = Me, OMe, OEt
n
NR2 = N
X , X = CH2, 0 , NMe
u
In contrast to the cycloaddition of simple 1,l-enediamines, the reaction between conjugated 1,l-enediamines and nitrile oxides proceeds at a slower rate and the yields of products 222 are low (equation 92)'72.173.
The reaction of cyclic 1,l-enediamines 7 and 8 with azides appears interesting. Nitro-substituted 1,l-enediamines 7 reacted with benzenesulfonyl azide to give triazoles 225 in moderate yields. Other secondary 1,l-enediamines analogues gave similar products in comparable yields. The reaction has been postulated to proceed by a sequence of 1,3-cycloaddition to 223, a Dimroth rearrangement to 224 and deamination to 225 (Scheme 12)"". Junjappa and coworker^"^ have reported that 1,l-enediamines
1354
2.-T. Huang and M.-X. Wang
(a) R1 = H, R2R3= -(CH2)3-
(35%); (b) R1 = H, R2R3= -(CH2)2- (65%);
(e) NR1R2= NMePh, R3 = Me (15%); (d) NR1R2=
R3 = Me (12%);
(e) =
SCHEME 12
8 (n = 2) react with tosyl a i d e in the same way to afford compounds 226 in 6&73% yield (equation 93).
In contrast to benzenesulfonyl azide, the reaction between 8 and aryl azides gives only a small amount of 226. Instead, highly substituted triazoles 228 are formed as the major p r o d ~ ~ t s 1 7 6 , 1 When 7 7 . 4-nitrophenyl azide is used, the reaction furnishes 228 exclusively. It has been believed that the reaction involves two competitive pathways and benzoyl-substituted 1,l-enediamines 8 act mainly as nucleophiles rather than as 1,3-dipolarophiles toward aryl azides. Consequently, they add to the azide group and, following intramolecular cyclocondensation, give products 228. Only in the case of unfavorable electronic factors does 1,3-cycloaddition reaction to give 226 take place (Scheme 13)'77. Nitrile oxides have also been examined as reagents towards benzoyl-substituted 1,l-enediamines 8'78,179. Due to the rapid dimerization of the nitrile oxide, no reaction between 8 and 4-nitrobenzonitrile oxide took place. However, 8 reacts smoothly with
(228)
X = MeO, Me, H, CI; Y = NO2, C1, H, M e 0 SCHEME 13
4-nitrobenzhydroximic acid chloride, the precursor of the nitrile oxide, to give isoxazoles 229 (equation 94)17'. When 2,4,6-trimethylbenzonitrile oxide, which hardly dimerizes because of the steric effect, is used, it adds to enediamines 8 at ambient temperature to give isoxazoles 230 in moderate to good yields (equation 95)179. In these cases, benzoyl-substituted 1,l-enediamines 8 act only as nucleophiles rather than 1,3-dipolarophiles. The reactions between 1,l-enediamines and 1,3-dipoles displayed above show that conjugated 1,l-enediamines differ greatly from simple 1,l-enediamines. Normally, conjugated 1,l-enediamines are strong nucleophiles. The reason for conjugated 1,l-enediamines not behaving like 1,3-dipolarophiles can be rationalized as a leveling effectlS0 arising from the mutual presence of the amino and electron-withdrawing groups in the molecule. Based on Fukui's frontier electron theory, MO perturbation treatment of the reaction between phenyl azide and olefins shows that attaching either an electronreleasing o r an electron-withdrawing group to an olefin accelerates 1,3-dipolar addition, but decreases the reactivity when both kinds of substituents are incorporated in one molecule. Consequently, the influence of the amino groups of 1,l-enediamines may be
1356
2.-T. Huang and M.-X. Wang
at least partially cancelled by that of the electron-withdrawing group. In addition, the conjugation reduces the double-bond character in the conjugated 1,l-enediamines (see Section 1I.A).
X = MeO, Me, H, CI
VI. MISCELLANEOUS REACTIONS
A few examples of oxidation reactions of 1,l-enediamines are . An oxidative coupling reaction of simple 1,l-enediamines with silver ion1'' or carbon tetrabr~mide"~has been reported. Oxidation of dienetetramines 231 leads to the dication-substituted carbocyclic products 232 (equation 96). The most plausible mechanism involves dimerization of two radical cations181.
Benzoyl-substituted anilino 1,l-enediamines 233 underwent oxidative cyclization with lead tetraacetate (LTA) to give iminoisoxazolines 235 in moderate yields183. In some cases. substituted indoles 236 were also formed. The formation of 235 and 236 has been assumed to arise through the initially formed N-plumbylated adducts 234 (Scheme 14).
Ar
Ar
I
PhNH CO.4r2 \ 1 LTA/CH2C12 ,C=C \ PhNH H
H
I (233)
~h
1 3 P~(OAC), I
OAc
SCHEME 14
1358
Z:T. Huang and M.-X. Wang
Catalytic reduction of nitro-substituted 1,l-enediamines 174 gives the aminomethyl amidines 238 in good yields. Apparently, reduction of the nitro group gives the triamine intermediates 237 which undergo a rapid prototropic shift to afford 238 (equation 97)Is4. Attempts to reduce the benzoyl-substituted 1,l-enediamines 8 were unsuccessful185. These results are not unexpected, since the double-bond character in 8 is reduced due to the strong conjugation effect.
The reactions of the a-carbon atom of 1,l-enediamines have been little exploited104.139,186.Acyl-substituted 1,l-enediamines 173 react with hydrazine to give pyrazoles 239 (equation 98)139.The reaction occurs at the a-carbon and the carbonyl sites. Treatment of 3,3-di(benzy1amino)-2-nitroacrylonitrile(181) with hydrazine leads to a similar result (equation 99). It is strange that the five-membered cyclic enediamine 181a (n = 2) undergoes ring opening during the reaction with hydrazine to afford pyrazole 241 in 83% yield, while its six-membered analogue 181a (n = 3) does not give any characterizable product (equation 100)186.
1
H&OH CIHEtOWH201AcOH AcONa, pH = 4, A, 15 h
Ar = 4-XC6H4, X = H, C1, MeO, HO, NC, OzN, H2N, t-Bu, 3-CICsH4, 2-ClC6H4, 3-pyridinyl SCHEME 15 Ring transformation from benzoyl-substituted 1,l-enediamines 93 t o isoxazoles 244 has been achieved recently184. In acidic media, 93 reacts with hydroxylarnine t o give a moderate yield of substituted 5-(2-arninoethylarnino)isoxazoles 244, A reasonable mechanism which involves protonation, oximation, cyclization and deamination steps has been proposed (Scheme 15).
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1362 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130.
2.-T. Huang and M.-X. Wang
G. Dannhardt and S. Laufer, Synthesis, 12 (1989). S. Rajappa, M. D. Nair, S. Sreenivasan and B. G. Advani, Tetrahedron, 38, 1673 (1982). J. Ficini, Tetrahedron, 32, 1449 (1976). Y. Sato, M. Kato, T. Aoyama, M. Sugiura and H. Shirai, J. Org. Chem., 43, 2466 (1978). V. Wolf and F. Kowitz, Justus Liebigs Ann. Chem., 638, 33 (1960). J. Ficini and C. Barbara, Tetrahedron Lett., 6425 (1966). G. Viehe, R. Fuks, and M. Reinstein, Angew. Chem., Int. Ed. Engl., 3, 581 (1964). R. Fuks and H. G. Viehe, Tetrahedron, 25, 5721 (1969). C. Jutz and H. Amschler, Chem. Ber., 96, 2100 (1963). M. D. Nair and J. A. Desai, Indian J. Chem., 218, 4 (1928). C. H. Hobbs and H. Weingarten, J. Org. Chem., 33,2385 (1968). D. H. R. Barton, G . Hewitt and P. G. Sammes, J Chem. Sac. ( C ) , 16 (1969). A. Etienne, G. Lonchambon and P. Giraudeau, C. R. Acad. Sci Paris, 285C, 321 (1977). C. F. Hobbs and H. Weingarten, J. Org. Chem., 39,918 (1974). R. C. F. Jones and S. C. Hirst, Tetrahedron Lett., 30, 5365 (1989). K. C. Brannock, B. D. Burpitt and J. G. Thweatt, J. Or#. Chem., 28, 1697 (1963). R. C. F. Jones and M. J. Smallridge, Tetrahedron Lett., 29, 5005 (1988). Z.-T. Huang and H. Wamho& Chem. Ber., 117, 1856 (1984). Z.-T. Huang and X.-J.Wang, Tetrahedron Lett., 28, 1527 (1987). V. Aggarwal, H. Ila and H. Junjappa, Synthesis, 147 (1983). Z.-T. Huang and H. Wamhoff, Chem. Ber., 117, 1926 (1984). H. Meyer, F. Bossert and H. Harstmann, Justus Liebigs Ann. Chem., 1476 (1978). A. K. Gupta, H. Ila and H. Junjappa, Synthesis, 285 (1988). H. Meyer, F. Bossert and H. Horstmann, Jlrstrrs Liebigs Ann. Chem., 1888 (1977). H. Meyer, F. Bossert and H. Hontmann, Jnstur Liebigs Ann. Chem., 1895 (1977). H. Schafer and K. Gewald, Z. Chem., 18, 335 (1978). K. Kurata, H. Awaya, Y. Tominaga, Y. Matsuda and G. Kobayashi, Bunseki Kiki, 15,413 (1977); Chem. Abstr., 88, 121047~(1978). 131. W.-Y. Zhao and Z.-T. Huang, J. Chem. Sac., Perkin Trans. 2, 1967 (1991). 132. V. Agganval, A. Kumar, H. Ila and H. Junjappa, Synthesis, 157 (1981). 133. H. Schafer and K. Gewald, Z. Chem., 16, 272 (1976). 134. R. Gompper and B. Kohl, Angew. Chem., Int. Ed. Engl., 21, 272 (1982). 135. S. Rajappa and R. Sreenivasan, Indian J. Chem., 248, 795 (1985). 136. H. Schafer, K. Gewald and M. Seifert, J. Prakt. Chem., 318, 39 (1976). 137. (a) H. Schafer and K. Gewald, J. Prakt. Chem., 322, 87 (1980). (b) M.-D. Ruan, W.-Q. Fan, Y:Z. Gu, H:J. Jiang and Y.-F. Bu, Synth. Commun., 21, 1307 (1991). 138. (a) W. D. Kollmeyer, US. Pat. 4,053,622 (1977); Chem. Abstr., 88, 37797h (1978). (b) P. E. Porter and W. D. Kollmeyer, US. Pat. 4,053,623 (1977); Chem. Abstr., 88, 37796g (1978). (c) C. H. Tieman and W. D. Kollmeyer, US. Pat. 3,948,934 (1976); Chem. Abstr., 85, 46680e (1976). 139. (a) R. H. Hasek, P. G. Gott and J. C. Martin, J. Org. Chem., 29, 2513 (1964). (b) J. C. Martin, US. Pat. 3,227,714 (1966); Chem. Abstr., 64, 8201e (1966). 140. N. Viswanathan, K. R. Ravindranath and P. K. Talwalkar, Indian J. Chem., 17B, 478 (1979). 141. W. D. Kollmeyer, S. A. Roman and S. B. Soloway, U.S. Pat. 4,029,791 (1977); Chem. Abstr., 87, 117871~(1977). 142. S. Rajappa and R. Sreenivasan, Indian .I. Chem., 158, 301 (1977). 143. S. Rajappa, B. G . Advani and R. Sreenivasan, Indian J Chem., 15B, 886 (1977). 144. S. Rajappa, B. G. Advani and R. Sreenivasan, Tetrahedron, 33, 1057 (1977). 145. S. Rajappa, M. D. Nair, B. G. Advani and R. Sreenivasan, J. Chem. Sac., Perkin Trans. I , 3161 (1981). 146. J. H. Hall and M. Wojciechowska, J. Org. Chem., 43, 3348 (1978). 147. N. Finch and C. W. Gemenden, J. Org. Chem., 35, 3114 (1970). 148. C. H. Tieman, W. D. Kollmeyer and S. A. Roman, U.S. Pat. 3,969,354 (1976); Chem. Abstr., 85, 192727s (1976). 149. C. H. Tieman, W. D. Kollmeyer and S. A. Roman, US. Pat. 3,971,774 (1976); Chem. Abstr., 86, 5460k (1977).
150. W. D. Kollmeyer, U S . Pat. 3,996,372 (1976); Chem. Abstr., 86, 121332~(1977). 151. M. Sone. Y. Tominana, Y. Matsuda and G. Kobavashi, Yakuyaku Zasshi, 97, 262 (1977); Chem. ~ b s t r .87, , 53195~(1977). 152. W. Hilmar, B. Benedikt. H. Bernhard and S. Wilhelm, EP 247477 (1987); Chem. Abstr., 108, 94588w (1988). 153. M. Augustin and E. Giinther, Z. Chem., 28,436 (1988). 154. K. Baum, N. V. Nguyen, R. Gilardi, J. L. Flippen-Andenon and C. George, J. Org. Chem., 57, 3026 (1992). 155. M. Takahashi, C. Nozaki and Y. Shibazaki, Chem. Lett., 1229 (1987). 156. R. Huisgen, Angew. Chem., Int. Ed. Engl., 7, 321 (1968). 157. R. H. Hasek, P. G. Gott, R. H. Meen and J. C. Martin, J. Org. Chem., 28, 2496 (1963). 158. G. Optiz and H. Schempp, Z. Naturforsch, 19b, 78 (1964). 159. G. Optiz and H. Schempp, Justus Liebigs Ann. Chem., 684, 103 (1965). 160. W. E. Trucc and P. N. Son, J. Org. Chem., 30, 71 (1965). 161. D. L. Boger, Chem. Rev., 86, 781 (1986). 162. D. L. Boger, Tetrahedron, 39, 2869 (1983). 163. V. N. Charushin and H. C. van der Plas, Tetrahedron Lett., 23, 3965 (198'). 164. K. Miiller and J. Sauer, Tetrahedron Lett., 25, 2541 (1984). 165. U. Gruseck and M. Heuschmann, Chem. Ber., 120, 2065 (1987). 166. M. Heuschmann, Chem. Ber., 121, 39 (1988). 167. U. Gruseck and M. Heuschmann, Tetrahedron Lett., 28, 2681 (1987). 168. G. Bolis, D. Pocar, R. Stradi and P. Trimarco, J. Chem. Soc., Perkin Trans. 1, 2365 (1977). 169. S. Fioravanti, M. A. Loreto, L. Pellacani and P. A. Tardella, Heterocycles, 25, 433 (1987). 170. D. Pocar, L. M. Ross, and R. Stradi, Synthesis, 684 (1976). 171. P. Rajagopalan and C. N. Talaty, Tetrahedron Lett., 4537 (1966). 172. S. Rajappa, B. G. Advani and R. Sreenivasan, Synthesis, 656 (1974). 173. T. Sasaki and A. Kojima, J. Chem. Soc. ( C ) , 476 (1970). 174. N. I. Viswanalhan and V. Balakrishnan, J. Chem. Suc., Perkin Truns. 1, 2361 (1979). 175. (a) R. T. Chakrasali, H. Ila and H. Junjappa, Synthesis, 851 (1988). (b) see Reference 49. p. 5498. 176. Z.-T. Huang and M.-X. Wang, Chinese Chem. Lett., 1, 5 (1990). 177. Z.-T. Huang and M.-X. Wang, J. Org. Chem., 57, 184 (1992). 178. Z. T. Huang and M.-X. Wang, Synth. Commun., 21, 1167 (1991). 179. Z.-T. Huang and M.-X. Wang, Synth. Commun., 21, 1909 (1991). 180. R. Sustmann, Pure Appl. Chem., 40, 569 (1974) and references cited therein. 181. H. Weingarten and J. S. Wager, J. Org. Chem., 35, 1750 (1970). 182. F. Effenberger and 0. Gerlach, Tetrahedron Lett., 1669 (1970). 183. A. Thomas, J. N. Vishwakarma, S. Apparao, H. Ila and H. Junjappa,, Tetrahedron, 44, 1667 (1988). 184. S. Rajappa and R. Sreenivasan, Indian J. Chem., 17B, 339 (1979). 185. Z.-T. Huang and M.-X. Wang, unpublished results. 186. S. Rajappa and B. G. Advani, Indian J. Chem., 15B, 890 (1977).
Heterocyclic synthesis from enamines GERHARD V . BOYD Department of Organic Chemistry. The Hebrew University of Jerusalem. Jerusalem. Israel
I . INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1366 I1. FORMATION O F FOUR-MEMBERED RINGS . . . . . . . . . . . . . . . 1366 A. Thietanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1366 B. Azetidines and Other Four-membered Nitrogen Rings . . . . . . . . . . . 1368 I11. FORMATION O F FIVE-MEMBERED RINGS . . . . . . . . . . . . . . . . 1372 A. Systems with One Heteroatom . . . . . . . . . . . . . . . . . . . . . . . . . 1372 1. Furans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1372 2. Thiophenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1374 3. Pyrroles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1376 4. A phosphole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1389 B. Systems . . with Two Heteroatoms . . . . . . . . . . . . . . . . . . . . . . . . 1389 1. D~th~oles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1389 2. Pyrazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1391 3. Imidazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1392 4 . Isoxazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1393 5. Oxazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1394 6. Isothiazoles and thiazoles . . . . . . . . . . . . . . . . . . . . . . . . . . 1394 C . Systems with Three Heteroatoms . . . . . . . . . . . . . . . . . . . . . . . 1396 1. Triazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1396 2. Dithiazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1398 IV. FORMATION O F SIX-MEMBERED RINGS . . . . . . . . . . . . . . . . . 1398 A. Systems with One Heteroatom . . . . . . . . . . . . . . . . . . . . . . . . . 1398 1. Pyrans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1398 2. Thiapyrans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1404 3. Pyridines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1406 B. Systems with Two or Three Heteroatoms . . . . . . . . . . . . . . . . . . 1420 1. 1,4-Dioxanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1420 2. Dithiins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1421 3. Pyridazines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1421 4. Pyrimidines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1423
Tlze Cheinistv of Enamines. Edited by Zvi Rappopon Copyright 0 1994 John Wilcy & Sons. Ltd . ISBN: 0-471-93339-2
1365
1366
Gerhard V. Boyd
5. Oxazines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1428 6. Oxadiazines and thiadiazines . . . . . . . . . . . . . . . . . . . . . . . . 1430 7. Azaphosphinines and diazaphosphinines . . . . . . . . . . . . . . . . . 1432 V. FORMATION O F SEVEN-MEMBERED AND LARGER RINGS . . . . 1433 VI. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1435
I. INTRODUCTION
In this chapter a selective account of reactions of enamines leading to heterocycles is presented. The ring systems are arranged according to ring size; in each section rings with one heteroatom precede those with two or more such atoms and each section is in the order of increasing unsaturation, so that the fully unsaturated 'aromatic' compounds are mentioned last. The material is organized according to the nature of the ring being produced rather than the structure of the product; thus, for example, both pyridopyrazines and tetrahydro-P-carbolines will be found in the section on pyridines because in each case it is the pyridine ring that is formed. Many reactions of enamines lead to mixtures of dimerent types of compound, e.g. pyrazoles and pyridines; in such cases the reaction will be found in the section dealing with the smaller heterocycle. Inevitably there is some overlap between the present chapter and that on 'Cycloaddilion reactions or enamines' because many such reactions result in the formation of heterocycles. The criterion for inclusion in this chapter is isolation of, or evidence for, discrete acyclic intermediates. Often the mechanism of the reaction is not known; the mere suspicion that the cycloaddition proceeds in a stepwise manner was thought sufficient justification for mentioning it here. In addition to several general reviews1 on enamine chemistry, all of which include heterocyclic syntheses, there is an extensive survey by Hickmott2 which is entirely concerned with the formation of heterocycles. More specialized reviews deal with heterocyclic enamines3, enaminones4, the photochemistry of enamides5, heterocyclic p-enamino esters6.', enamino thiones8, the synthesis of indole alkaloids via enamines9, formation of pyrimidines, pyridopyrimidines, pyridines and pyrrolizines from enamineslO, synthesis of lactams", formation of heterocycles from cyclic enamino ketones and 2-acetylcyclohexen-l-ones1z, the synthesis of 3-cyano-2(1H)-pyrimidinethiones and -selenones from p-enamino ketones13 and the chemistry of cyclic en-
am in on it rile^'^. II. FORMATION OF FOUR-MEMBERED RINGS A. Thietanes
Enamines reaction with methanesulphonyl chloride and its homologues in the presence of triethylamine to yield thietane 1,l-dioxides. Thus I-morpholinocyclohexene gives a bicyclic thietane dioxide15 and 2-methyl-1-pyrrolidinopropene and other enamines derived from aliphatic aldehydes react a n a l o g o u ~ l y '(equation ~ 1). It is thought that the reactions proceed by way of the unisolable sulphene 1, which adds to the enamine double bond in a stepwise o r concerted manner. This question has been much debated (for a critical discussion, see Reference 2, p. 3386) and will not be pursued here. It has been found that there is a lack of stereoselectivity in the addition of sulphene to the conformationally rigid enamines derived from 4-t-b~t~lcyclohexanone~~. The thietane dioxides can be converted into thietes by successive reduction, methylation and Hofrnann elimination of the resulting thietane derivatives (equation 2)".
23. Heterocyclic synthesis from enamines
1367
aSo2 - as-DS NR2
H
&R~M~
NR2
@s
()M (ii) OHe
H
heat
(2)
H OH-
Vinylsulphene (Z), generated from propene-3-sulphonyl chloride, reacts with enamines to give mixtures of vinylthietane dioxides and dihydrothiopyran 1.1-dioxides 3; the latter arise from the open-chain intermediate shown in Scheme 1 1 9 .
SCHEME 1
1368
Gerhard V. Boyd
Tosyl isothiocyanate adds to the dimethylamine or piperidine enamines of isobutyraldehyde to form isolable betaines 4, which in non-polar solvents are in equilibrium with (tosy1imino)thietanes 520(equation 3).
+
lNR2 TosNCS
Me
(3)
Me
Me
Me
NTos
6. Azetidines and Other Four-membered Nitrogen Rings
The high-pressure (12 kbar) reaction of isobutyraldehyde pyrrolidine enamine with benzylideneaniline or benzylidenemethylamine in I-butyl methyl ether gives azetidines (equation 4)21. r-7 r-7
Under different conditions other types of product are obtained from enamines and imines; thus treatment of 1-morpholinocyclohexene with benzylidene aniline in methanol gives the adduct 6 (equation 5)22.
The enamine N-vinylpyrrolidinone reacts with the complex imine 7, obtained from tetracyanoethylene and trifluoromethanesulphenyl chloride, CF,SCI, to yield, after hydrolysis, the azetidine 8 (equation 6)*j.
23. Heterocyclic synthesis from enamines
1369
Enamines possessing P-hydrogen atoms add hexafluoroacetone azine to form transient dipolar azomethine imines 9, as evidenced by low-temperalure 19F NMR spectroscopy, which rearrange to hydrazones. If there is no hydrogen atom in the P-position the betaines cyclize to unstable derivatives 10 of azetidine (equation 7)24.
Phenyl isocyanate adds to enamines derived from isobutyraldehyde to yield azetidinones (equation 8)25.26.
Mixtures of azetidinones 11 and dihydrooxazinones 12 are produced from ketone enamine and trichloroacetyl o r benzoyl isocyanate via a common zwitterionic intermediate (equation 9)".
Gerhard V. Boyd
N-Tosylazelines are formed from N-tosylbenzaldehyde imine and ketene aminals, e.g. 13, in hot benzene; the azosulphone PhN=NTos reacts analogously, giving 42diazetines 14 (equation 10)Z8.
a-Chloroenamines react with imines to yield azetinium salts 15 (equation 1 1)29.30;a related reaction is that of N,N-dimethylphenylacetamide with Schiffs bases in the presence of phosphorus oxychloride, which affords solely trans-substituted azetinium salts, isolated as the perchlorates 16 (equation 12)31.
23. Heterocyclic synthesis from enamines
%
MezN
xR
-
11 Me
R
Ph
Me
(11) Me
Me Ph CI-
Me
Me
CI-
Ph CI-
(15)
R = Me, r-Bu or Ph
J'
-
R
(i) POCI? (ii) HC1O4
Ph
'Ar
1,2-Diazetidin-3-ones 18 (R1,R2 = H or Me) can be prepared starting with pnitrophenyl a-chlorocarboxylates R'R2CCIC0,C,H,N0,-p. These esters are condensed with methylhydrazine in acetic acid; the resultmg hydrazides 17 react with dimedone to yield enehydrazine compounds, which cyclize to the products in the presence of sodium hydride (equation 13)32.
M:qO
Me
H2N\\
- -~
K 0
CI
", \ (17)
NaH
HN
*
Rl+(NMe R2
oql :
A
\
NMe
/
-HCI
R
-
'
~
7 .
~ ; N-Me
0 0
Treatment of ethyl sulphamoyl chloride with triethylamine generates a nitrogen analogue 19 of sulphene, which has been trapped by 2-methyl-I-pyrrolidinopropeneas the 1,2-thiazetidine 1,Zdioxide 20 (equation 14)33.
Gerhard V. Boyd Ill. FORMATION OF FIVE-MEMBERED RINGS A. Systems with One Heteroatom
I . Furans The a-cyanoenamine 21, which exists as a mixture of E- and Z-isomers, is deprotonated by lithium diisopropylamide to give the stabilized N,N-(dimethylamino)allylanion 22. This reacts with aldehydes RCHO (R = Ph, Ar or cyclohexyl) to afford products which are readily transformed into y-lactones by the action of dilute hydrochloric acid (equation 15)34.
Cycloalkanone enamines react with ethyl P-nitroacrylate to form adducts which yield y-lactones on treatment with sodium borohydride. Base-induced elimination of the elements of nitrous acid gives cc-methylenebutyrolactones 23 (equation 16)35.
1373
23. Heterocyclic synthesis from enamines
3-(Trimethylsi1yl)-1-morpholinopropene(24) and p-benzoquinone form the dihydrobenzofuran 26 by way of the zwitterionic adduct 25 (equation 17)36.
An analogous reaction of 2-acetoxy-1,4-naphthoquinone with 1-morpholinopropene gives the dihydronaphthofuran 27 (equation 18)37;similarly, enamines add to styrene oxide and 2-chlorotropone to yield the hydrogenated furans 2838 and 2939, respectively (equation 19).
Me
Me' AcO
AcO
OH
1374
Gerhard V. Boyd
Alkylation of cyclohexanone enamines with methyl chloro(methoxy)acetate, followed by alkaline hydrolysis, affords the y-keto acid 30, which readily cyclizes to the unsaturated lactone 31 on treatment with hydrogen chloride in acetic acid (equation 20)40.
2. Thiophenes
The adduct 32 of diphenylcyclopropenethione to the morpholine enamine of acetophenone reacts with dimethyl acetylenedicarboxylate to yield a mixture of 1,2-diphenyl cyclopropene and dimethyl 4-morpholino-3-phenylthiophene-1,2-dicarboxyat (equation 21)41.
Vinylogous thioamides 33 (NR, = dimethylamino o r morpholino) react with benzyl chloride to give thiophenes41, while thienyl ketones are produced from cc-bromo ketones43 (equation 22).
23. Heterocyclic synthesis from enamines
The action of 1,3-dithiole-2-thiones 34 (R = H or Ph) on pyrrolidinylcyclohexene leads to thiophenes by elimination of carbon disulphide from the initial dipolar adducts, followcd by loss of pyrrolidine (equation 23)44. (For the contrasting reaction of the dithiolethiones with pyrrolidinocyclopentene, see equation 168).
1376
Gerhard V. Boyd
The reactions of diphenylthiirene 1,l-dioxide (35) with enamines afford a variety of products which appear to arise from initial cycloadducts that react further. Thus I-pyrrolidinoindene yields the indenothiophene 1,l-dioxide 36 (equation 24)45.
3. Pyrroles Irradiation of the y-oxoenamines 37 (R = Me, Ph or CH2=CHCH2) induces a [2n + 2n] cycloaddition of the olefinic double bonds to yield derivatives of azabicylo[2.l.l]hexane (equation 25)46.
Quaternary hexahydroindolium salts 39 are produced from cyclohexanone enamines and cc-bromoacrylonitrile. In some cases bicyclic cyclobutane adducts 38 have been isolated, which rearrange thermally to the salts (equation 26)47.
23. Heterocyclic synthesis from enamines
Monochlorination of the morpholine enamine of N-methylpiperidin-4-one with Nchlorosuccinimide, followed by treatment with sodium cyanide, yields the exo-cyanoaza[3.1.O]bicyclohexane 40; in contrast, the dichlorinated enamine affords the endo-cyano compound 41 in this reaction (equation 27)48.
MeNa (40)
NR2 = morpholino
3 MeN
The action of cyanide ion on the enamine 42 results in the tricyclic compound 43 (equation 28)48; however, the tosylcarbamoylenamines 44 (n = 3, 4 or 9) are converted into bicyclic derivatives 45 of pyrrolidinone in this reaction (equation 29)49.
MeN
CONHPh 0
(42)
NR? = morpholino
(43)
Gerhard V. Boyd CI
H
CONHTos NR2 = morpholino
('14)
(45)
The course of the reductive photocyclization of enamines by irradiation in the presence of sodium borohydride depends on the nature of substituents. Thus the N-methyl-Sphenyl compound 46 yields a mixture of the pyrrolidinone 47, the piperidinone 48 and the tricyclic compound 49, whereas the dimethyl analogue 50 gives the piperidinone 51 as a mixture of Z- and E-isomers. The cyclopentene derivative 52 affords the spiropyrrolidinone 53, together with the cyclopentapiperidinone 54, the naphthylthio group being eliminated (Scheme 2)50. Me
0
SPh
Me,
0
SMe
A
0
N
SCHEME 2
SMe
0
N
'SMe
1379
23. Heterocyclic synthesis from enamines
Fischer's base (55) reacts with tetracyanoethylene to yield a mixture of spiro and fused pyrrolines, which are believed to arise from an initial zwitterionic adduct, as shown in Scheme 351. Me Me
N Me
-0 heat
NH Me
N
N
CN
Me H
CN
CN
SCHEME 3
Irradiation of the secondary enamine 56 results in a mixture of five- and sevenmembered heterocycles (equation 30)".
The course of the reaction of pyrrolidinostilbene with dimethyl acetylenedicarboxylate is solvent-dependent: in apolar solvents, such as ether or toluene, the dienamine 57 is formed by ring-opening of an intermediate cyclobutene, whereas in methanol the pyrrolizine 59 is the main product. The pyrrolizine is thought to arise from an initial betaine which rearranges to the ylide 58 by a proton shift. Cyclization then gives the pyrrolizine (equation 31)53.
Gerhard V. Boyd
Application of the dimethyl acetylenedicarboxylate reaction to enamines of cyclic ketones gave similar results: the pyrrolidine enamines of cyclopentanone and &-tetralone gave the ring-expanded products (60 and 62, respectively) in toluene, and pyrrolizidines (61 and 63, respectively) in methanol (equation 32)53.
23. Heterocyclic synthesis from enamines
1381
The adduct 65 of aziridine to the acetylenic phosphonium salt 64 readily rearranges to the enamine 66, which in refluxing acetonitrile is converted into the pyrroline derivative 68 by opening of the aziridine ring and recyclization of the resulting zwitterion 67 (equation 33)54.
The combined action of carbon tetrachloride, trioctylphosphine and N,N-dimethylaniline on N-(hydroxymethyl)pyrrole in ether gives the salt 70 via unstable I-(chloromethy1)pyrrole (69). Addition of the morpholine enamines of cyclic ketones of ring size six, seven or eight to the salt affords mixtures of tricyclic derivatives 72 and 73 of pyrrole, which are thought to be formed via 5-azoniafulvene chloride 71 (equation 34)55.
Photocyclization of variously substituted N-arylenamines yields 2,3-dihydroindoles (equation 35)56.
Gerhard V. Boyd
p-Nitrophenyl azide reacts with the morpholine enamine 74 in boiling benzene to afford a mixture of geometrically isomeric dihydroindoles 80, together with the amidine 77. It is proposed that the triazoline 75 is formed initially and that it extrudes nitrogen to yield the betaine 76, from which the amidine is produced by a hydrogen shift. Cyclization of the betaine to the azirine 78, followed by ring-opening in an alternative manner, gives the isomeric betaine 79, which yields the dihydroindoles (Scheme 4)".
SCHEME 4
Treatment of the silylated enamine 24 with phenacyl bromide affords the salt 81, which is hydrolysed by water to the keto aldehyde 82. Condensation with aniline then yields 3-(trimethylsilylmethyl)-1,5-diphenylpyroe83 (equation 36)36.
23. Heterocyclic synthesis from enamines
The secondary enamine 84 reacts with 1-bromo-3,3,3-trifluoro-2-propanone in refluxing toluene in the presence of acetic acid to give the pyrrole 85 (equation 37)58.
Pyrrolizine derivatives 86 or polyhydropyrrolo[1,2-alindoles, e.g. 87, are produced from L-ethyl proline and various ketones via intermediate enamines (equation 38)59.
N,N'-Dimethylhydrazine and ketones afford pyrroles in a reaction akin to the Fischer indole synthesis; intermediate bis-enehydrazines 88 have been isolated in some cases (equation 39)60.
1384
Gerhard V. Boyd
"-1 iR2 -.,h R2
MeNHNHM;
(3.)
R'
N-N
I
I
Me Me (88)
R1
N Me
R1
The action of methyl propiolate on the ene hydrazine 89 (from acetylacetone and N,N-dimethylhydrazine) results in a complex mixture containing the pyrrole 90, the pyridines 91 and 92, the dihydropyridines 93 and 94, the pyridones 95 and 96, and derivatives of isophthalic acid, such as 97 (equation 40)61.
23. Heterocyclic synthesis from enamines
1385
Treatment of a mixture of acetophenone phenylhydrazone and dimethyl acetylenedicarboxylate with aluminium chloride gives the ene hydrazone 98, which undergoes a spontaneous Fischer 'indole' reaction to yield the pyrrole 99 with elimination of aniline (equation 41)62.
The ene hydrazine 100, prepared from dimedone and methylhydrazine, forms the Michael adduct 101 with dimethyl acetylenedicarboxylate.The adduct is converted into a mixture of pyrrole and pyridone derivatives, 103 and 104, in boiling tetralin. These products arise by a [3.3]sigmatropic shift in the adduct with cleavage of the nitrogen-nitrogen bond to give 102, followed by cyclization and elimination of ammonia and methanol, respectively (equation 42)63.
1386
Gerhard V. Boyd
An analogous reaction of the enehydrazine 105 yields a mixture of derivatives of pyrrolo[2,3-dJpyridazine and pyrido[2,3-dpyridazine (equation 43)64.
0
I N\
E
-
+
P& r
N'
NEt
I \
\
N Me
Me (105)
E
E = C02Me
phy* N\
N
Me
0
1,5-Diaza-1,4-dienes 106 (or the tautomeric enamine form 107) are obtained by the addition of imines to nilriles in the presence of aluminium chloride (equation 44)65.
These dienes are transformed into pyrrole esters on treatment with ethyl glycine hydrochloride in hot pyridine, e.g. equation 4566.
Pyrroles are obtained from the reactions of primary P-carbonylenamines 108 (R = Me or OEt) with diazodeoxybenzoin (equation 46)67.
4
Me
NH2
ROC,
2
Ph
Ph H
(108)
23. Heterocyclic synthesis from enamines
1387
Treatment of the secondary enamines 109 (R1 = Bu, r-Bu or Ph)with nitroolefins 110 (R2, R3 = H, Me or Ph) leads to 7-0x0-4,5,6,7-tetrahydroindoles(equation 47)".
Reductive cyclization of P-(nitropheny1)enarnines 111, which are prepared by condensing o-nitrotoluenes with dimethylformamide dimethyl acetal, results in indoles (equation 48)69.
&+
MeO, ,NMe2 M ~ O ' C 'H
-
-
NO2
(48) N -.
(111) R = CN, C02Et or CH2C02H
H
The secondary enamine 112 is converted into the P-carboline derivative 113 on heating with copper(1) iodide in hexamethylphosphoric triamide (equation 49)".
Tetrahydrocarbazoles are produced from 1-(dimethylamino)cyclohexeneand perfluorinated aromatic compounds, e.g. hexafluorobenzene (equation 50)".
1388
Gerhard V. Boyd
The [3 + 21 cycloaddition of the azoalkene 114 to enamines results in transient azomethine imines 115, which are transformed into tricyclic N-tosyl 1-aminopyrroles 116 on heating (equation 51)".
II N,
Tos
The furazano[3,4-dlpyrimidine 117 adds morpholinocyclohexene reversibly; the product 118 eliminates acetamide on treatment with sodium methoxide to give 119, which undergoes a reductive cyclization to the pyrrolo[3,2-apyrimidine 120 (equation 52)13.
Heating pyrrole with pyrrolidinocyclohexene gives the 2-substituted pyrrole 121, which forms the azafulvene 122 by elimination of pyrrolidine. Addition of a second molecule of the enamine leads to the spiro compound 123 (equation 53)74.
1389
23. Heterocyclic synthesis from enamines
0 +rn-flVw NR2
NR2
N
H
(121)
(122)
NR2 = pyrrolidino
4. A phosphole
The adduct 126 of dimethyl acetylenedicarboxylate to the N-phenyl-P-enamino-L5phosphazene 124 (Ar = p-MeC,H,) is converted into the ,I5-phosphole derivative 127 by the action of butyllithium. The process involves the formation and ring-opening of the transient phosphazetine 125 (equation 54)75.
E = C02Me
1
BuLi
(54)
6. Systems with Two Heteroatoms
1. Dithioles
The combined action of sulphur and carbon disulphide on enamines results in the formation of 1,2-dithiole-3-thiones (equation 55)76.
Gerhard V. Boyd
In the case of enamines 128 derived from valerophenone, 1,3-dithiole-2-thiones are the main products and only minor amounts of the isomeric 1,2-dithiole-3-thiones are isolated (equation 56)76.
3-Anilinoinden-1-one (129) reacts with carbon disulphide in the presence of sodium hydroxide to yield, after acidification, the condensed 1,2-dithiole-3-thione 131. A suggested mechanism is shown in equation 57; the key step in the process is the formation and opening of the spiro intermediate 13017.
QJpqOTo (57)
SH
S
1
-2LH1
S-S
S
S~ fs
HO-
NHPh
1391
23. Heterocyclic synthesis from enamines 2. Pyrazoles
The enamines 132, formed from N-(cyanomethyl)-N-methylanilineand ethyl esters of aliphatic or aromatic carboxylic acids in the presence of sodium hydride, react with hydrazine to yield the pyrazoles 133 (equation 58)78.
The adduct 134 of methylhydrazine to dimethyl acetylene dicarboxylate readily cyclizes to a mixture of hydroxypyrazole carboxylic esters, 135 and 137. The reaction giving 137 is thought to proceed by way of the bis-adduct 136 (equation 59)79.
Eh
NH-NHMe
E
NMe -NH2
-MeNH-NH,
N-NHMe
N'
Annelated anilinopyrazoles 139 (n = 1 or 2) are produced from the complex cyclic enamines 138 and hydrazine (equation 60)''.
1392
Gerhard V. Boyd
N-Aryl-Ni-chloroamidines react with enamines, e.g. 140, by nucleophilic attack of the amidine anion on the initially formed chloroiminum cation. The resulting intermediate 141 cyclizes to the imidazoline 142. A second product, the amidine 145, is thought to originate from the nitrene 143, which adds to the enamine to yield the aziridine 144; ring-opening with concomitant migration of the morpholino group gives the amidine (Scheme 5)".
NR2 = morpholino SCHEME 5
The analogous reaction of 1-morpholino-2-phenylpropene with N-chloro-N'-tosylbenzamidine gives the imidazoline shown in equation 61g2.
+ 'Ph Tos The adducts 147 of diethyl azodicarboxylate to secondary enamino ketones 146 (R = Bu, t-Bu or Ph) are converted into 4-hydroxybenzimidazol-2-ones by the action of toluene-p-sulphonic acid (equation 62)g3.
23. Heterocyclic synthesis from enamines
o-Phenylene diisothiocyanate adds pyrrolidinocyclohexene to give the benzimidothiazine derivative 148 (equation 63)84.
+ NCS
4. lsoxazoles
The reaction of the azadienes 107 with hydroxylamine hydrochloride in hot pyridine affords isoxazoles 149 via isolable oximes (equation 64)". RZ R'
R3
- 'F0 RZ
R3
(64
NH
NOH
R
N
Enaminones 150 (R = Me or Pr) are converted into isoxazoles by the action of hydroxylamine (equation 65)86.
1394
Gerhard V. Boyd
Acetophenone and ring-substituted acetophenones condense with dimethylformamide diethvl acetal to ~ i v the e enaminones 151. which vield 5-arvlisoxazoles (152) by reaction ' with b y d r o x y ~ a ~ 0-sulphonic ne acid (equation b 6 ) ~ ~ .
5. Oxazoles
The p-acetoxy-N,N-bis(trimethylsilyl)enamine 153 cyclizes on heating to 2,4,5-trimethyloxazole (equation 67)".
Benzoyl peroxide converts the primary enaminone 154 into the benzoyloxy derivative 155, which is transformed into 5-acetyl-4-methyl-2-phenyloxazole (156) in boiling acetic acid (equation 68)89.
6. lsothiazoles and thiazoles
Sequential treatment of the enaminones 151 with phosphorus oxychloride and sodium sulphide yields the sulphur analogues 157, which yield isothiazoles by the action of hydroxylamine 0-sulphonic acid (equation 69)87.
The reaction of ethyl p-aminocrotonate (158) with isothiocyanates RNCS (R =p0,NC6H4, p-0,NC6H,C0, EtOCO or Et02CCH,) yields the thiocarbamates 159, which cyclize to isothlazoles on treatment with bromine (equation 70)90.
23. Heterocyclic synthesis from enamines Me
xMe -
H
RNCS
Et02C
RHN
(ii) H20
NH2
RHN
Thiazolidin-2-ones are produced by the joint action of sulphur and isocyanates on enamines, e.g. equation 719'.
CI.
MeNCO S
MeM 'e
2-Amino-5-nitrothiazoles 160 or 2-imino-5-nitrothiazolines 161 are obtained by the reaction of di(thiocyanogen) with p-nitroenamines, followed by a trace of acetic acid (equation 72)92.
The combined action of sulphur and cyanamide on ketone enamines in ethanol or DMF at room temperature leads to 2-aminothiazoles via reversible formation of the thiols 162 (equation 73)93.
1396
Gerhard V. Boyd
C. Systems with Three Heteroatoms
The azo compound PhN=NCONH, reacts with morpholinocyclohexene to yield the spiro-triazolinone 163, whereas with pyrrolidinocyclohexene the bicyclic 1,2,4-triazinone 164 is formed (equation 74)94.
0
0'""' \
+
271 H
/ '
R2N = morpholino
(163)
N=N
ph
\CONH2
Ph
XNND
0
The 1,2,3-triazole 168 is the product of the slow reaction (70°C, 7 days) of phenyl azide with the primary enamine ethyl 5-amino-2,3-dihydrofuran-4-carboxylate (165).The authors propose that the initial cycloadduct 166 is transformed into the betaine 167, which cyclizes lo the tria~oleas shown in equation 7595.
23. Heterocyclic synthesis from enamines
H+- fN~E 1397
The action of the C-azidohydrazone 169 on the morpholine enamine of isobutyraldehyde leads to a mixture of two 1,2,4-triazoles, 172 and 174, and the tetrahydro-1,2,4triazine 177. A plausible mechanism of the reaction is shown in Scheme 6. The process is initiated by the formation of an unstable cycloadduct, the 1,2,3-triazoline 170, which fragments to 2-diazopropane and the hydrazone 171, Cyclization and elimination of morpholine yields the triazole 172. A different mode of fragmentation of the triazoline 170 is formation of the betaine 173 by loss of nitrogen. A hydrogen shift, followed by ring-closure and loss of morpholine, results in the second triazole, 174, Finally, cyclization of the betaine 173 to the aziridine 175 and ring-opening in an alternative manner gives the isomeric betaine 176, from which the triazine 177 is produced96.
Me
(177)
(176)
R2N = morpholino; E = C02Me SCHEME 6
N-N
1398
Gerhard V. Boyd
2. Dithiazoles
Primary enaminones 178 (R1 = Me or PhCH,; RZ = Me, Ph or MeO) are converted into stabilized 1,2,3-dithiazolyl radicals 179 by the joint action of chlorine and sulphur (equation 76)".
IV. FORMATION OF SIX-MEMBERED RINGS A. Systems with One Heteroatom 1. Pyrans
The addition of 3-methyl-1-piperidinobutene (180) to the enone 181 yields the dihydropyran 182 with endoltruns stereoselectivity (equation 77)98; an analogous product, the pyranochromene 184, is formed from the benzylidenechromanone 183(equation 78)99.
The dihydropyran 186 is produced from 1-dimethylamino-2-methylpropene and methyl vinyl ketone by way of the iminium enolate zwitterion 185; the dihydropyran is in equilibrium with the cyclobutyl ketone 187 (equation 79)"'.
23. Heterocyclic synthesis from enamines
Other unsaturated ketones also react with enamines to yield dihydropyrans; e.g. enamines derived from cyclopentanone add 2-benzylidenecyclohexanone to give 188 For a critical discussion of these reactions, see Reference 2, p. 3401. (equation
Treatment of enamines with a,gunsaturated esters yields Michael adducts 189, which undergo reductive cyclization with lithium aluminium hydride to tetrahydropyrans 190. Elimination of the secondary amine moiety then affords dihydropyrans 191 (equation
1400
Gerhard V. Boyd
The dihydropyran 192 is formed from 2-acetylcyclohcx-2-enone and l-piperidinopropene (equation 82)'03.
ortho-Quinone methides 194 are generated by heating ortho-phenolic Mannich bases 193; in the presence of enamines dihydrobenzopyrans (chromans) 195 are formed. The products may be hydrolysed to hydr&ychromans 196, which in turn may be dehydrated to chromenes 197 (equation 83)lo4.
z a a,,""" CH2
[I
NR2
The synthesis has been applied to a great variety of Mannich bases derived from aromatic compounds and from heterocycles, such as indole, pyridine, quinoline, coumarin, etc.Io4 Compound 198, for instance, yields the pyranopyridine shown in equation 84'04.
Oxidative fission of the pyran ring in 199 (n = 4, 5, 6 or 10) with m-chloroperbenzoic acid has been used to obtain medium and macrocyclic ketolactones 200 (equation 85)lo5.
23. Heterocyclic synthesis from enamines
1401
Salicylaldehyde adds to various enamines to give hydroxychromans, e.g. 201 with morpholinocyclohexene106;on the other hand, only chromenes 202 and 203 were isolated from the reactions of salicylaldehyde with the morpholine enamine of phenylacetaldehydel"' and pyrrolidinocyclohexene'08, respectively (equation 86).
o-Hydroxyacetophenone and pyrrolidinocyclohexene yield the spiro-chromanone 204. The same compound is obtained when a mixture of o-hydroxyacetophenone and cyclohexanone is heated with pyrr~lidine'"~.
"it:, The reaction of benzaldehyde with the stabilized ally1 anion 205 (cf. equation 15) affords the hydroxy ester 206, which cyclizes to the dihydro-a-pyrone 207 on distillation (equation 87)34.
1402
Gerhard V. Boyd
3-Morpholino-1H-2-benzopyran-1-one (208) adds aromatic aldehydes in hot acetic acid or acetonitrile to form dihydro-4-morpholinocarbonyl-1H-2-benzopyran-l-ones 209 as mixtures of cis- and trans-isomers. The process is formally an ene reaction in which an acyl group is transferred (equation 88). Analogous reactions with imines, phenyl isocyanate, nitrosobenzene, arenediazonium salts and carbon disulphide lead to a variety of heterocycles (Scheme 7)"'.
Enolate anions 210 of methylene ketones (cyclopentanone, cyclohexanone, acetophenone, etc.) react with the enamine 211 to give adducts which are readily transformed into a-pyrones 212 (equation 89)"'.
23. Heterocyclic synthesis from enamines
R2N = morpholino SCHEME 7
1404
Gerhard V. Boyd
Treatment of enamines with the mixed anhydride 213 obtained from acetylsalicylic acid and ethyl chloroformate yields chromones 214 (equation 90); thiochromones are similarly produced from S-acetylthiosalicylic acid"'.
Ano dic oxidation of the enaminone 215, prepared from o-hydroxyacetophenone and dimethylformarnide dimethyl acetal, results in the bichromone 216 (equation 91)l13.
2. Thiapyrans Treatment of the enaminothione 217 (Ar =p-NO,C,H,; NR, = pyrrolidino) with a-chl~roacr~lonitrile gives the dihydrothiapyran 218; w ~ t hethyl propiolate the thiapyran 219 is produced, which rearranges on standing to compound 220 by a C1.31 shift of the pyrrolidinyl group (equation 92)",.
23. Heterocyclic synthesis from enamines
The enamino thione 221 adds electrophilic olefins 222 (R = C N or C0,Me) to yield dihydrothiapyrans 223, which eliminate the amine moiety on heating to form 2Hthiapyrans 224 (equation 93)'l5.
The thiones 225 (X = S) and their selenium analogues 225 (X = Se) react with 8-chloro-u,B-unsaturatedaldehydes in the presence of sodium hydroxide to give 2formylmethylene-211-thiapyrans or -selenapyrans 226 (equation 94)"'.
Ar 4
M CHO e
Gerhard V. Boyd
1406
The action of ketene on the enaminothiones 217 leads to adducts which afford thiapyran-2-ones 227 by elimination of a secondary amine (equation 95)'17.
Treatment of 3-methylthio-4-phenyl-1,2-dithiolium iodide with morpholine yields the enaminothione 228, which is converted into 6-methylthio-5-phenylthiapyran-2-one by the action of ketene (equation 96)"'.
. MeS
I-
MeS
MeS
(96)
0
Thiapyran-2-thiones are readily obtained from dienamines and carbon disulphide (e.g. equation 97)76.
3. Pyridines
A derivative 229 of decahydroacridine is obtained when morpholinocyclohexene is treated with benzylideneaniline in acetic acid. The authors propose that the reaction proceeds via the formation and cleavage of a series of fused azetidines (Scheme 8)'19.
23. Heterocyclic synthesis from enamines
I
-HNR2
R2N = morpholino
SCHEME 8
1408
Gerhard V. Boyd
Methyl acrylate reacts with the enediamine 230 to yield the spiro-tetrahydroimidazopyridone 232 via the transient intermediate 231 l Z 0 .The reaction with methyl propiolate gives an analogous intermediate 233, which, however, is stable. It is transformed into the bicyclic dihydropyridone 234 by the action of methanol12' (equation 98).
The dihydropyridine derivative 236, a cyclic enamine, is formed from crotonaldehyde and the phosphonium salt 235 by a Wittig reaction, followed by electrocyclization of the resulting 1,3,5-triene. The dihydropyridine readily rearranges to the tetrahydropyridine 237 by a [IS] hydrogen shift (equation 99)"'.
23. Heterocyclic synthesis from enamines
1409
Enamines derived from aldehydes react with Schifs bases in methanol in the presence of toluene-p-sulphonic acid to yield tetrahydroquinolines; thus 1-morpholino-2-methylpropene and benzylideneaniline afford 3,3-dimethyl-4-morpholino-2-phenyl-1,2,3,4-tetrahydroquinoline 238 (equation 100)123.
/O\
The enaminone 239, prepared from dimedone and ammonia, is converted into the spiro compound 240 by the action of formaldehyde in dilute hydrochloric acid, but under neutral conditions the di(enaminone) 241 is formed. The latter cyclizes under the influence of hydrochloric acid to a derivative 242 of decahydroacridine dione (equation 101)~~~.
1410
Gerhard V. Boyd
The 1,2,3,4-tetrahydro-P-carboline244 is obtained from the secondary enamine 243 by the action of trifluoroacetic acid (equation 102)'25.
The dihydropyridine 246 is produced by irradiating a mixture of the secondary enamine 245 and acrylonitrile. It undergoes a second cyclization under the influence of trifluoroacetic acid to yield the reduced quinolizine 247, accompanied by only minor amounts of the cis-isomer (equation 103)126.
Photocyclization of the thioenamide 248 in methanol affords the tetrahydroisoquinoline-2-thione 249, whereas in benzene solution the dehydrogenated product 250 is formed (equation 104)127. Me
I
23. Heterocyclic synthesis from enamines
1411
The photochemistry of enamides leading to dihydropyridones has been reviewed5. These reactions are based on Cleveland and Chapman's observation that the anilide of tiglic acid cyclizes to a mixture of cis- and trans-dihydroquinolones. It was proposed that the process involves a diradical or zwitterion, which undergoes a [1.3] shift of hydrogen (equation 105)lZR.
An analogous reaction of the pyridine derivative 251 results in compound 252, one of numerous examples of the formation of bi- and tricyclic heterocycles reported by Ogata and Matsumoto (equation 106)'29.
Similarly, the enamide 253, formed when N-cyclohexylidenebenzylamine is treated with acryloyl chloride in the presence of triethylamine, cyclizes to the hexahydroquinolone 254 on irradiation. The enamides derived from ar- and p-tetralone behave analogously (equation 107)'".
1412
Gerhard V. Boyd
The trans-fused hexahydrophenanthridinone 256 is produced by photocyclization of the N-benzoylenamide 255 (equation 108)13'.
The reaction has been applied to the enamides 257 and 258 (R = H, Me or PhCH,) derived from a- and B-tetralone (equation 109)'32,'33.
l-Benzylidene-2-ethoxycarbonyl-1,2,3,4-tetrahydroisoquinoline (259) is converted into the tetracyclic compound 260 on irradiation; the cyclization is preceded by a cis 4 trans isomerization (equation 1
23. Heterocyclic synthesis from enamines
1413
Reductive photocyclization of the enamide 261 by irradiating a methanolic solution containing sodium borohydride results in a mixture of four products: the hexahydrophenanthridone 262, two geometrically isomeric octahydrophenanthridones, 263 and 264, and the structurally isomeric octahydrophenanthridone 265 (equation 11
The outcome of the photocyclization of the enamide 266 (Ar = p-MeOC,H,) depends on conditions: irradiation under argon in methanolic sodium meihoxide gives the dihydroisoquinolone 267; if air is present the isoquinolone 268 is formed. Under reducing conditions,i.e. in the presence of sodium borohydride, the tetrahydroisoquinolone 266 is obtained136.
The 1,4-dihydropyridine 271 is produced from the primary enamine ethyl p-aminocrotonate and the perchlorate 270 (equation 1 12)13'.
Gerhard V. Boyd
The joint action of pyridine and thionyl chloride on aliphatic or aromatic aldehydes RCHO results in 1-chloromethylpyridinium chlorides 272, which react with ethyl p-aminocrotonate to give 19-dihydropyridines 273 (equation 113). The reaction constitutes a modified Hantzsch synthesis; it has the advantage over the latter that it proceeds under milder conditions and gives better yields138. The dihydropyridine 273 (R = H) is also readily obtained from ethyl p-aminocrotonate and formaldehyde in the presence of catalytic amounts of 4-(dimethylamino)pyridine'39. R
' N
I
RCHCI
+
2MN e'H2
C02Et
-
Et02cfi COzEt
(113)
Me
H
(273) (272) Lithium aluminium hydride reduces tosylacetonitrile to the primary enamine P-(ptoluenesulphony1)vinylamine 274. Treatment of the latter with sodium hydride in T H F at - 60°C furnishes the stabilized ti-azaallyl anion 275, which is converted into the dihydropyridine 276 by reaction with benzylideneacetophenone (equation 114)14'. Ph I
23. Heterocyclic synthesis from enamines
1415
Acetylenic ethers 277 (R = Me, Ph, PhCH, or allyl) add N-methylaniline under the influence of mercury(l1) chloride to yield the enamines 278, which form derivatives 279 of 1,Cdihydroquinoline under acid catalysis by the mechanism outlined in equation 115141.
6-Alkyl-3-cyano-a-pyridones 280(R = alkyl) are produced by the condensation of enamino ketones with cyanoacetamide (equation 116)86.
The pyridone 282 is obtained from methyl propiolate and 3-aminocyclohex-2-en-1-one via the Michael adduct 281 (equation 117)'42.
1416
Gerhard V. Boyd
cr-Pyridones are readily formed by heating the enamides prepared from enamines and cc$-unsaturated isocyanates. Cyclohexenyl isocyanate, for instance, adds pyrrolidinocyclohexene to form the eneamide 283, which is converted into compound 284 in high yield (equation 118)143.However, cyclization of enamides obtained from enamines and vinyl isocyanate itself does not occur144.
A variety of bicyclic heterocycles has been obtained from the cyclic enediamine 285. Ethyl phenylacetate and methyl propiolate give derivatives, 286 and 287, respectively, of 1,8-naphthyridine, while hydrogenated quinolizidinones, 288 and 289, are formed from diethyl malonate and ethyl acetoacetate (Scheme 9)'e5. The 1,6-naphthyridin-5(6H)-one 291 is produced by thermolysis of the carbamate 290 (equation 119)146.
Compounds possessing reactive methylene groups condense with dirnethylformamide diethyl acetal to give enamines, which may serve as precursors for heterocycles (cf. equations 48 and 66). Thus diethyl 2,6-dimethylpyridine-3,5-dicarboxylate(292) yields the enainine 293, which is converted into isolable secondary (Z)-enamines 294 by the action of primary aromatic amines. Thermal or base-catalysed cyclization then affords the naphthyridones 295 (equation 120)14'.
23. Heterocyclic synthesis from enamines
This type of reaction has been applied to the synthesis of a derivative 296 of the rare pyrido[4,3-clpyridazine system (equation 121)14' and of 1-arylpyrido[3,4-dlpyridazines 297 (equation 122)14'. Cyclization of the enehydrazine 298 gives the 4-quinolone 299 (equation 123)lS0.
Gerhard V. Boyd
The pyridine 2-thione 302 is readily produced by the reaction of the enaminoketone 300 (from acetylacetone and morpholine) with the thioamide 301 (Ar = p-FC,H,) in ethanol at room temperature (equation 124)15'.
3-Aminocyclohex-2-en-1-one reacts with propiolaldehyde to yield 5-0x0-5,6,7,8-tetrahydroquinoline (303) (equation 125)15'.
23. Heterocyclic synthesis from enamines
1419
SCHEME 10
A general synthesis of 3,5-disubstituted pyridines is based on the uncatalysed thermal reaction of imines with enamines which yields I-aza-1,3-dienes. The dienes afford the pyridines by a further reaction with the same or a different enamine. For example, methylene N-t-butylimine (304)and I-piperidinobutene give the diene 307, accompanied by 3,s-diethylpyridine (309; R 2 = Et). Heating the diene with I-piperidinopropene gives 3-ethyl-5-methylpyridine (309; R 2 = Me). It is proposed that the process is initiated by a cycloaddition reaction which yields azetidines 305 and thence azetines 306 by elimination of piperidine. The azetines undergo ring-opening t o the azadienes 307, which form tetrahydropyridines by cycloaddition to enamines. Elimination of piperidine then gives unisolable dihydropyridines 308, which yield the products 309 (Scheme Derivatives of dimethyl pyridine-2,3-dicarboxylate result from the action of dimethyl acetylenedicarboxylate on the dienamines 107 (equation 126)154.
The pyridopyrimidines 311 are obtained from enaminones and Caminouracil 310 (equation 127)155.
Gerhard V. Boyd
A tricyclic heterocycle incorporating the pyridine oxide structure, compound 314, is produced from 3,s-dimethyl-4-nitroisoxazole(312) and 1-morpholinocyclopentene via the intermediate 313 (equation 128)lS6.
B. Systems with Two or Three Heteroatoms
Enamines derived from isobutyraldehyde react with dimethyldioxirane (315) by oxygen transfer to yield unstable oxiranes which are isolated as the dimers 316 (equation
23. Heterocyclic synthesis from enamines
1421
2. Dithiins
Sulphene or phenylsulphene adds to the enaminothiones 217 in a two-step reaction to yield 1,2-dithiin dioxides 317 (equation 130)1'8,'58.
3. Pyridazines
A mixture of stereoisomeric tetrahydropyridazines 31S320 is obtained from methylhydrazine and two equivalents of dimethyl acetylenedicarb~xylate~~~.
Gerhard V. Boyd
1422
The Michael adduct of dimethyl acetylenedicarboxylate to the enehydrazine 321 cyclized to a mixture of the dihydropyridazinone 322 and the diazepinone 323 (equation 131)160.
E I
NHMe Me
+
C
111 C
I
E
cc-Bromoacetophenone semicarbazone (324) reacts with morpholine enamines to yield tetrahydropyridazines 32516' or l,4-dihydropyridazines 32616', depending on the structure of the enamine (equation 132).
23. Heterocyclic synthesis from enamines
1423
Treatment of the hydrazines 327 (R = H, Me or Ph) with dimethyl acetylenedicarboxylate in hot acetic acid gives intermediate enehydrazines 328, which undergo successive cyclization and dehydrogenation to afford the bicyclic heterocycles 329 (equation 133)64.
4. Pyrimidines
The reaction of tosyl isocyanate with 2-methyl-1-dimethylaminopropene yields the betaine 330. In contrast, the betaine formed from the less basic enamine 331, derived from N-methylaniline, adds a further molecule of the isocyanate to afford the hexahydropyrimidinedione 332 (equation 134)163.
xNMe2
~
~
e
2
+ TosNCO
Me
Me
Me&T Me 0
(330) Tos PhNMe N
N(Me)Ph
+ TosNCO e' MeM
+
Me 0
(331)
0
0
(332) The reaction of the dimethylamine enamine of isobutyraldehyde with aryl isothiocyanates at or below 50°C leads to the iminotetrahydrothiazine-thiones 333; these compounds rearrange on heating to hexahydropyrimidine-2,6-dithiones334 (equation 135)164.
Gerhard V. Boyd
1424
The combined action of formaldehyde and primary aliphatic arnines RZNH, on secondary p-nitroenamines 335 results in the 1,2,3,4-tetrahydropyrimidines336 (equation 136)165.
The dihydropyrimidinone 338 is produced from 1-pyrrolidinobutene and the silylated diazadiene 337 (equation 137)166.
The base-catalysed reaction of phenyl isocyanate with the morpholino enamines 339 (R1, R 2 = H or Ph) gives uracils 340 (equation 138)16'. Dithiouracils 341 (n = 1 or 2) are similarly produced from morpholinocyclopentene or -cyclohexene and aroyl isothiocyanates16'. Treatment of the dihydrofurans 342 with aryl isocyanates yields derivatives 343 of furo[2,3-apyrimidine by way of transient ureas (equation 139)169.
+ 2 PhNCO
-
+
"fxo R2 Ph
(339)
(.I N H
(138)
23. Heterocyclic synthesis from enamines
The urea, formed in the reaction of the enamine 344 with chlorosulphonyl isocyanate followed by water, cyclizes to the uracil 345, which lacks substituents on the nitrogen atoms (equation 140)'70. 0
COZEt
CL S (344)
m2
C02Et
(i) CISOzNCO (ii) NaOH/H,O
-d S
-
NHCoNH2 H
(345) The tetrahydropyridopyrimidinone 348 is produced from the enediamine 346 and ethyl benzimidate (347) in the presence of catalytic amounts of polyphosphoric acid (equation 141)17'. 0
The dienamines 107 are converted into 1,2-dihydropyrimidines 349 by the action of imines in the presence of aluminium chloride"'; aldehydes react analogously (equation 142)'73. R3
R3
1426
Gerhard V. Boyd
S,S-Dimethyl-N-(N-arylbenzimidoyl)sulphirnides 350 (R1 = Me o r MeO) react with morpholinoenamines 351 (R2 = Ph, R3 = H; R2 = Et, R3 = Me) to give 4,4-disubstituted 2-phenyl-3,4-dihydroquinazolines352174;heating a mixture of 350 and 1morpholinopropene in boiling tetralin results in the quinazolines 353 (equation 143)175.
The action of phenyl isocyanate on the dienes 107 gives the ureas 354, which cyclize to a mixture of the pyrimidin-2-ones 355 and 356 (equation 144)176.
R2
/ -RWH2
+ phNco f N H R 4
R2&4
R'
2 y
(107) (354)
NHPh
"' (355)
(144)
23. Heterocyclic synthesis from enamines
1427
Pyrimidones 357 or the corresponding pyrimidinethiones 358 are obtained from the dienes 107 and ethyl chloroformate or carbon disulphide, respectively (equation 145)'77.
Formamide converts the primary enamine 359 into 4-0x0-4,5,6,7-tetrahydro-3Hthiopyrano[2,3-dpyrimidine 360 (equation 146)17'.
Treatment of the p-nitroenamines 361 (R = Me or Ph) with benzoyl isothiocyanate gives ~-(benzoylthiocarbamoyl)-P-nitroenamines362, which are transformed into pyrimidine-4-thiones 363 on heating with ammonium acetate (equation 147)179.
Gerhard V. Boyd
1428
A general synthesis of pyrimidines 364 is the aluminium chloride-catalysed reaction of the azadienes 107 with aliphatic or aromatic cyanides (equation 148)la0.
The enamines 138 (n = 1 or 2) condense with amidines to yield the pyrimidines 365 (equation 149)80. NHPh
NHPh I
(yp+ N Me
SMe
HN
(149)
R
N
R
.Me
A variety of pyrimidines 366 (n = 3,4,6 or 10) has been obtained from trifluoroacetonitrile and various morpholine enamines (equation 150)181.
5. Oxazines The dihydro-1,2-oxazine 369 is produced from pyrrolidinocyclohexene and the bromooxime 367 by base-catalysed cyclization of the intermediate iminium salt 368 (equation 151)182. Ph
1429
23. Heterocyclic synthesis from enamines
Unstable dihydro-1,3-oxazines 372 result from the reaction of enamines with acylimines 371, which are generated by dehydrochlorination of the N-chloroalkylamides 370 (equation 152)lS3.
(370)
(371)
(372)
Acetaldehyde reacts with the enamino ketone 239 to yield the bicyclic dihydro-1,3oxazine 373 (equation 153)lZ4.
Dihydro-1,3-oxazin-4-ones 375 are obtained from various enamines 374 and benzoyl isocyanate; in contrast, trichloroacetyl isocyanate is reported to give only the azetidinone 376 (equation 154)". 0
Benzoylation of the enamino ester 359 gives the N-benzoyl derivative 377, which is converted into the thiopyranooxazinone 379 by the combined action of triphenylphosphine and hexachloroethane. The reaction proceeds via the intermediate acyl chloride 378 (equation 155)lS4.
Gerhard V. Boyd
1430
-
rxC02Et
s
NH2
(359)
s
NCOP~
H
aCo;
s
' A N
~h
H
(377)
The addition of enamines to 1-nitroso-Znaphthol results in N-hydroxy-1,4-oxazines 380 (equation 156) but the reaction could not be extended to o - n i t r o s ~ ~ h e n o l s ' ~ ~ .
6. Oxadiazines and thiadiazines Treatment of morpholinocyclopentene with N-aroyl-N'-aryldiazenes 381 leads to derivatives 382 of 1,3,4-oxadiazine (equation 157)186. Ar'
The dienamines 107 condense with sulphur dichloride or thionyl chloride in pyridine at room temperature to give the 1,2,6-thiadiazines 383 or their S-oxides 384, respectively.
23. Heterocyclic synthesis from enamines
1431
When heated in toluene, both types of compound form pyrazoles by extrusion of sulphur or sulphur monoxide (equation 158)18'.
The mesoionic dehydrodithizone (385) functions as the valence tautomer 386 in its reactions with enamines. Thus the 2-phenylazo-5,6-dihydro-1,3,4-thiadiazine 387 is formed from the morpholine enamine of N-methylpiperidin-4-one (equation 159)la8.
1432
Gerhard V. Boyd
7. Azaphosphinines and diazaphosphinines
The primary enamine 126 (Ar = p-MeC,H,) (see equation 54) cyclizes thermally t o the 4-aza-A5-phosphinine 388, while potassium hydride converts it into the azaphosphininone 389 (equation 160)15.
"IN% H
/
P
Ph2
E
NPh
1,2-Dihydro-1,3,2A-diazaphosphinines 390 are obtained from the azadienes 107 and phosphorus oxychloride; phenylphosphoryl chloride and phenylthiophosphoryl chloride react similarly, giving the analogues 391 and 392, r e s p e ~ t i v e l y ' ~The ~ . reaction of the dienamines with phosphorus trichloride or phenylphosphorus dichloride under argon 393 (R5 = C1 or Ph)190 (equation results in the 1,2-dihydro-1,3,2L3-diazaphosphorines 161).
23. Heterocyclic synthesis from enamines
1433
Treatment of the primary enamine 394 (Ar = p-MeC,H4) with ethyl azidoformate results in the evolution of nitrogen and the formation of compound 395; the latter is 396 on heating at 150°C (equation converted into the 2-0x0-1,3,4L5-diazaphosphinine 162)19'. u
V. FORMATION OF SEVEN-MEMBERED AND LARGER RINGS
Enamines of cyclic ketones yield [2 + 21 cycloadducts with dimethyl acetylenedicarboxylate, which on heating undergo ring-expansion by two carbon atoms (equation 163).
Application of this reaction to cyclic ketones containing heteroatoms has produced many seven- and eight-membered heterocycles, such as 39719' and 398'93. The azepinone 400 is obtained similarly from the pyrrolidinopyrrolin-2-one 399 (equation 164)'94.
Q
r3 H
N 0
~
(399)
N
E-CS-E
E = C02Me
:H N $0 (400)
1434
Gerhard V. Boyd
The enehydrazine 101 is converted into the diazepinone 401 in boiling toluene in the presence of polyphosphoric acid (equation 165)63.
The primary enamine 359 reacts with triphenylphosphorus dichloride to yield compound 402, which is converted into the eight-membered sulphur heterocycle 403 by the action of methyl propiolate (equation 166)lg5.
The enaminone 404, prepared from o-phenylenediamine and dimedone, affords 13-diazepines 405 on treatment with aldehydes (equation 167)'96.
+ RCHO
In contrast to the reaction of 1,3-dithiole-2-thiones 406 (R = H or Ph) with pyrrolidinocyclohexene, which leads to thiophenes (see equation 23), the analogous reaction with the more reactive pyrrolidinocyclopentene results in 1,3-dithionin-2-thiones 409. It is thought that the initial betaine 407 adds a second molecule of the enamine to give 408. Cyclization, followed by elimination of pyrrolidine, yields the product (equation 168)44.
23. Heterocyclic synthesis fromenamines
Vl. REFERENCES 1. (a) A. G. Cook, Enamines, Synthesis, Structure and Reactions, 2nd ed., Marcel Dekker, New York, 1988. (b) M. E. Kuehne, Synthesis, 510 (1970). (c) S. Hiinig and H. Hoch, Fortschr. Chem. Forsch., 14, 235 (1970). (d) S. F. Dyke, Chemistry of Enamines, Cambridge University Press, London and New York, 1973. (e) G. Pitacco and E. Valentin, in The Chemistry ofAmino, Nitroso and Nitro Compounds and Their Derivatives (Ed. S. Patai), Wiley, Chichester, 1982, pp. 623. 2. P. W. Hickmott, Tetrahedron, 38, 3363 (1982). 3. K. Blaha and 0 . Cervinka, Adv. Org. Chem., 4, 1 (1963). 4. J. V. Greenhill, Chem. Soc. Rev., 6, 277 (1977). 5. G. R. Lenz, Synthesis, 489 (1978). 6. H. Wamhoff, Lect. Heterocycl. Chem., 5, 61 (1980). 7. H. Wamhoff, Adu. Heterocycl Chem., 38, 299 (1985). 8. M. Pulst, D. Greif and E. Kleinpeter, Z. Chem., 28, 345 (1988). 9. C. Szantay, L. Szabo, G. Kalaus, P. Kolonits, E. Mamanyos, F. Soti, Z. Kardos-Balogh, M. Incze and I. Moldvai, Org. Synth.: Mod. Trends, Proc. IUPAC Symp., 6th (Ed. 0 . S. Chizhov), Blackwell, Oxford, 1986, p. 107. 10. V. G. Granik, Enaminy Org. Sint., 3 (1990); Chem. Abstr., 114, 1 6 4 0 4 9 ~(1991). 11. S. G. Agbalyan, K. K. Lulukyan and G. V. Grigoryan, Enaminy Org. Sint., 60 (1990); Chem. Abstr., 114, 1638812 (1991).
1436
G e r h a r d V. Boyd
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23. Heterocyclic synthesis from enamines
1437
(b) K. Hirai, K. Achiwa and S. Yamada, Chem. Pharm. Bull., 20, 246 (1972). (c) P. W. Hickmott and K. N. Woodward, J. Chem. Soc., Perkin Trans. 1, 904 (1976). 60. W. Sucrow and G. Chondromatidis, Chem. Ber., 103, 1759 (1970). 61. W. Sucrow, W. Turnschek, U. Wolf, H. d'Amour and C. Kriiger, Chem. Ber., 117,1620 (1984). 62. J. Barluenga, F. Palacios and V. Gotor, Synthesis, 642 (1975). 63. T. Yamasaki, H. Nakamura, Y. Okamoto, T. Okawara and M. Furukawa, J. Chem. Soc., Perkin Trans. 1, 1287 (1992). 64. T. Yamasaki, E. Kawaminami, T. Yamada, T. Okawara and M. Furukawa, J. Chem. Soc., Perkin Trans. 1, 991 (1991). 65. H. Hoberg and J. Barluenga, Synthesi.~,142 (1970). 66. J. Barluenga, V. Rubio and V. Gotor, J. Org. Chem., 47, 1696 (1982). 67. M. N. Eberlin and C. Kascheres, J. Org. Chem., 53, 2084 (1988). 68. F. Bcncdetti, F. Bcrti, P. Nitti, G. Pitacco and E. Valentin, Gazz. Chim. Ital., 120, 25 (1990). 69. G. S. Ponticello and J. J. Baldwin, J. Org. Chern., 44, 4003 (1979). 70. S. C. Yang, H. M. Wang, C. S. Kuo and L. C. Chen, Heterocycles, 32, 2399 (1991). 71. J.-C. Blazejewski and C. Wakselman, J. Chem. Soc., Perkin Trans. 1, 2485 (1980). 72. (a) S. Sommer, Angew. Chem., Int. Ed Engl., 9, 695 (1979). (b) S. Sommer, Chem. Lett., 583 (1977). 73. L. E. Crane, G. P. Beardsley and Y. Maki, J. Org. Chem., 45, 3827 (1980). 74. M. Tashiro, Y. Kiryo and 0 . Tsuge, Bull. Chem. Soc. Jpn., 48, 616 (1975). 75. J. Barluenga, F. Lopez and F. Palacios, J. Chem. Soc., Perkin Trans. 1,2273 (1989). 76. R. Mayer and K. Gewald, Angew. Chem., Int. Ed. Engl., 6, 294 (1967). 77. Y. Tominaga, H. Norisue, C. Kamio, T. Masunari, Y. Miyashiro and A. Hosomi, Hererocycles, 31, 1 (1990). 78. K. Takahashi, K. Shibasaki, K. Ogura and H. Iida, Synthesis, 794 (1985). 79. W. Sucrow, F. Liibbe and A. Fehlauer, Chem. Ber., 112, 1712 (1979). 80. H. Takahata, T. Nakajima and T. Yamasaki, Synthesis, 226 (1983). 81. (a) D. Pocar and R. Stradi, Tetrahedron Lett., 1839 (1976). (b) L. Citerio, D. Pocar, R. Stradi and B. Gioia, J. Chem. Soc., Perkin Trans. 1, 309 (1978). (c) L. Citerio, D. Pocar, M. L. Saccarello and R. Stradi, Tetrahedron, 35, 2375 (1979). 82. E. Rossi, R. Stradi and A. Benedus, Tetrahedron, 43, 4785 (1987). 83. F. Benedetti, S. Bozzini, S. Fatutta, M. Forchiassin, P. Nitti, G. Pitacco and C. Russo, Gazz. Chim. Ital., 121, 401 (1991). 84. A. W. Faull, D. Griffiths, R. Hull and T. P. Seden, J. Chem. Snc., Perkin Tram. I , 2587 (1980). 85. J. Barluenga, J. Jardon, V. Rubio and V. Gotor, J. Org. Chem., 48, 1379 (1983). 86. N. K. Kochetkov, Izv. Akad. Nauk SSSR, Otdcl. Khim. Nuuk, 47 (1954) Engl. Transl.: Bull. Acad. Sci. USSR, Div. Chem. Sci., 37 (1954). 87. Y. Lin and S. A. Lang, Jr., J. Org. Chem., 45, 4857 (1980). 88. R. F. Cunico and C. P. Kuan, J. Org. Chem., 57, 3331 (1992). 89. H. J. Jakobsen, E. H. Larsen, P. Madsen and S O . Lawesson, Arkiv. Kemi, 24, 519 (1965). 90. J. Goerdeler and H. Horn, Chem. Ber., 96,1551 (1963). 91. K. Ley and R. Nast, Angew. Chem., Int. Ed. EngL, 4, 519 (1965). 92. 1. Tokumutzu and T. Hayashi, J. Org. Chem., 50, 1547 (1985). 93. K. Gewald, H. Spies and R. Mayer, J. prakt. Chem., 312, 776 (1970). 94. M. Forchiassin and C. Russo, Gazz. Chim. Ital., 114, 243 (1984). 95. H. Wamhoff and P. Sohar, Chem. Ber., 104, 3510 (1971). 96. L. Bruche, L. Garanti and G. Zecchi, J. Chem. Soc., Perkin Trans. 1, 1427 (1984). 97. R. Mayer, G. Domschke, S. Bleisch and A. Bartl, Z. Chem., 21, 324 (1981). 98. F. Eiden and A. Eckle, Arch. Pharm. (Weinheim, Ger.), 322, 617 (1989). 99. F. Eiden and G. Felbermeir, Arch. Pharm. (Weinheim, Ger.), 317, 861 (1984). 100. 1. Fleming and M. H. Karger, J. Chem. Soc. ( C ) , 226 (1967). 101. G. Oszbach, D. Szabo and M. E. Vitai, Acta Chim. Acad. Sci. Hung., 101, 119 (1979). 102. S. Carlsson and S:O. Lawesson, Tetrahedron, 36, 3585 (1980). 103. B. B. Snider, Tetrahedron Lett., 21, 1133 (1980). 104. M. Von Strandtmann, M. P. Cohen and J. Shavel, J. Heterocycl. Chem., 7, 1311 (1970). 105. (a) J. R. Mahajan and H. C. Araujo, Synthesis, 111 (1976). (b) J. R. Mahajan and M. B. Monteiro, Bull. Chem. Soc. Jpn., 51, 1207 (1978).
23. Heterocyclic synthesis from enamines
1439
157. W. Adam, E. M. Peters, K. Peters, H. G. von Schnering and V. Voerckel, Chem. Ber., 125, 1263 (1992). 158. M. Bard, J. C. M e s h and H. Quiniou, J. Chem. Soc., Chem. Commun., 672 (1973). 159. W. Sucrow, K. H. Ellermann, U. Florke and H. J. Haupt, Chem. Ber., 121, 2007 (1988). 160. U. Wolf, W. Sucrow and H. J. Vetter, Chem. Ber., 112, 3237 (1979). 161. M. T. Cocco, C. Congiu, A. Maccioni and A. Plumitallo, Gazz. Chim. Ital., 113, 187 (1988). 162. (a) V. Sprio and S. Plescia, Ann. di Chim., 61, 391 (1971). (b) V. Sprio and S. Plescia, Ann. di Chim., 62, 345 (1972). 163. E. Schaumann, A. Sieveking and W. Walter, Tetrahedron Lett., 209 (1974). 164. E. Schaumann, H. G. Baeuch, S. Sieveking and G. Adiwidjaja, Chem. Ber., 116, 55 (1983). 165. N. A. Sokolov, I. G. Tishchenko, T. P. Raichonok and L. T. Buglakova, Vestsi Akad. Nauuk BSSR, Ser. Khim. Navuk, 70 (1985); Chem. Abstr., 103, 123430t (1985). 166. J. Barluenga, M. Tomas, A. Bnllesteros and L. A. Lopez, Tetrahedron Lett., 30, 4573 (1989). 167. L. Capuano, M. Kussler and H. R. Kirn, Ann. Uniu. Saran, Math.-Naturwiss. Fak., 16, 7 (1981); Chrm. Abstr., 96,85503w (1982). 168. M. Uher, J. Foltin and L. Floch, Collect. Czech. Chem. Commun., 46, 2696 (1981). 169. E. Campaigne, R. L. Ellis, M. Bradford and J. Ho, J. Med. Chem., 12, 339 (1969). 170. H. Wamhoff and M. Ertas, Synthesis, 190 (1985). 171. H. Wamhoff and L. Lichtenthaler, Chem. Ber., 111,2297 (1978). 172. V. G. Aranda, J. Barluenga, V. Gotor and S. Fustero, Synthesis, 720 (1974). 173. J. Barluenga, M. Tomas, S. Fustero and V. Gotor, Synthesis, 346 (1979). 174. E. Rossi, R. Stradi and P. Visentin, Tetrahedron, 46, 3581 (1990). 175. E. Rossi and R. Stradi, Synthesi,~,214 (1989). 176. J. Barluenga, V. Rubio and V. Gotor, J. Org. Chem., 45, 2592 (1980). 177. J. Barluenga, M. Tomas, V. Rnbio and V. Gotor, J. Chem. Soc., Chem. Commun., 675 (1979). 178. K. Gewald, Chem. Ber., 99, 1002 (1966). 179. T. Tokumitsu, Bull. Chem. Sac. Jpn., 59, 3871 (1986). 180. H. Hoberg and J. Barluenga, Synthesis, 363 (1970). 181. K. Burger, F. Hein, U. Wassmuth and H. Krist, Synthesis, 904 (1981). 182. (a) A. Maccioni, E. Marongiu and G. Bianchetti, Gazz. Chim. Ital., 100, 288 (1970). (b) P. Bravo, G. Gaudiano, P. P. Ponti and A. Umani-Ronchi, Tetrahedron, 26, 1315 (1970). 183. H. E. Zaugg, Synthesis, 49 (1970). 184. D. Achakzi, M. Ertas, R. Appel and H. Wamhoff, Chem. Ber., 114, 3188 (1981). 185. J. W. Lewis. P. L. Mvers and J. A. Ormerod. J. Chem. Soc.. Perkin Trans. 1. 1129 (1973) 186. F. ~enedetti,M. orc chi ass in, C. Russo and A. Risaliti, GUT;. Chim. Ital, 115, 663 (i985): 187. J. Barluenga, J. F. Lopez-Otiz, M. Tomas and V. Gotor, J. Chem. Sac., Perkin Trans. 1, 1891 (1981). 188. G . V. Boyd, T. Norris and P. F. Lindley, J. Chern. Soc., Perkirz Trans. 1, 1673 (1976). 189. J. Barluenga, J. Jardon, F. Palacios and V. Gotor, Synthesis, 370 (1983). 190. J. Barluenga, J. Jardon, F. Palacios and V. Gotor, Synthesis, 309 (1985). 191. J. Barluenga, F. Lopez and F. Palacios, Tetrahedron Lett., 28, 2875 (1987). 192. D. N. Reinhoudt and C. G. Kouwenboven, Tetrahedron Lett., 3751 (1973). 193. K. C. Brannock, R. D. Burpitt, V. W. Goodlett and J. G. Thweatt, J. Org. Chem., 28, 1464 (1963). 194. G. W. Heinicke, A. M. Morella, J. Orban, R. H. Prager and A. W. Ward. Aust. J. Chem., 38, 1847 (1985). 195. H. Wamhoff, G . Haffmanns and H. Schmidt, Chem. Rer., 116, I691 (1983). 196. S. Miyano and N. Abe, Chem. Pharm. Bull., 20, 1588 (1972).
Synthesis of N-acylenamines from carbonyl compounds and nitriles SERGE M . LUKYANOV Institute of Physical and Organic Chemistry, Rostov University, 34471 1 Rostovon Don, Russia
I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. REACTION O F ALDEHYDES WITH NITRILES . . . . . . . . . A. Formation of bis-Amides and Amidoalkylation Reagents . . . . . B. Syntheses of Heterocyclic Compounds . . . . . . . . . . . . . . . . 111. REACTION O F KETONES WITH NITRILES . . . . . . . . . . . A. Intramolecular Reactions of Ketonitriles, Cyanoamides and Cyanoesters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Intcrmolccular Reactions of Kctones with Nitrilcs . . . . . . . . . 1. Protic acid-catalyzed reactions of ketones with nitriles . . . . 2. A~roticacid-catalvzed reactions of ketones with nitriles . . . . 3. Electrophilic catalysis by acyl cations in reactions of ketones with nitriles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. REACTIONS O F NITRILES WITH CARBONYL COMPOUND DERIVATIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. TWO PATHS FOR THE REACTION O F CARBONYL COMPOUNDS WITH NITRILES . . . . . . . . . . . . . . . . . . . A. Reactions of Ketones with Nitrilium Salts. . . . . . . . . . . . . . B. Theoretical Calculations . . . . . . . . . . . . . . . . . . . . . . . . C. Rearrangements during Formation of N-Acylenamines . . . . . . VI. POLYFUNCTIONALIZED ENAMINES . . . . . . . . . . . . . . . VII. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . -
~~~~
p
p
~
-
~
. . . . 1441 . . . . 1444 . . . . 1444 . . . . 1446
. . . . 1451
. . . . 1451 . . . . 1457
. . . . 1457 . . . . 1463 . . . . 1467
. . . . 1473 .... .... .... .... .... ....
-~-- -
1481 1481 1485 1494 1498 1502
--
I. INTRODUCTION
The N-acylenamines 1 (enamides, n-vinylamides) are usually regarded as deactivated enaminesl,'. However the influence of acyl group attached to the nitrogen atom increases both the reactivity of enamides in their excited state and of the products of interaction of enamides with cationoid electrophiles, i.e. the N-acyliminium ions 2. The Cltemisrr?;of Enamines. Edited by Zvi Rappopon Copyright O 1994 John Wiley & Son&,Ltd. ISBN: 0-471-93339-2
S. M. Lukyanov
This reactivity of N-acylenamines 1 has opened up new possibilities for the use of enamides-in photochemical rearrangementsZ as well as in acid-catalyzed c y c l i z a t i ~ n s ~ , ~ , which lead to a variety of complex nitrogen-containing heterocycles from readily available simple precursors. These reactions have also been used to form a wide variety of natural products and polyfunctional compounds. Enamides can be also used as electrophilic reagents for a m i d ~ a l k y l a t i o n ~which , ~ , can occur under certain conditions as a [4 + 23 cycloaddition to form 1,3-oxazinium heterocycles7. The synthetic application of N-acylated enamines stimulated the search for efficient methods for the preparation of enamides. A larger number of such methods has been developed during the last three decades but reviews summarizing them were so far inadequate. The functionalized enamines were mentioned in a few review^'^^^^^^, and Reference 2 was until recently the most complete among them. A monograph by Ukrainian scientists has been recently published which contains a detailed description of the preparation approaches and applications of enamides9. The variety of synthetic methods for the synthesis of N-acylenamines can be subdivided into three types. The simplest and most general method is the direct acylation of an enamine 3 followed by tautomerism to the imines (equation 2)2.8,10." . H owever, since enamines 3 are ambident nucleophiles, the acylation can occur both at the nitrogen atom and at the P-carbon atom. A modification of this approach is the use of the N-organomagnesium derivatives of i m i n e ~ ' ~ as . ' ~well as of o x i m e ~ ' ~ . The second method is the vinylation of amides 4 at the nitrogen atom by their reaction with acetylcncs 515(equation 3), oxiranesL6and somc other compounds having the same oxidation level (of two1?)and containing good nucleofugic groups'8 such as 6 (equation 4). These reactions occur under base-catalysis conditions and presuppose a conversion of amides into anionoid nucleophiles, followed by reaction with covalent (i.e. uncharged) electrophiles. The third approach to enamides is based on the interaction of aldehydes and ketones 7 with amides 4. This general method can be also considered as a peculiar vinylation at the nitrogen atom of the amide because the carbonyl compounds 7 are the products of hydration of the acetylenes 5 and have the same oxidation level of two'? (equation 5). However, these reactions proceed under acid catalysis and assume an initial conversion of the carbonyl compound into cationoid electrophile which then reacts with a covalent nucleophile. The interaction of the carbonyl compounds with amides leads only seldom to the enamides9. Usually the a-hydroxyalkyl amides 8 or the bis-amides (amidals) 9 can be isolated under these The N-acylenamines can be then obtained by removal of water from 8, or by elimination of amide molecule from 919,20 (equation 5).
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
~ 1 ~ x +1 R2CONHR3 3
(6)
RI
+
base
(3)
R'CH=CHNR"OR'
(4)
(5)
EtOCH=C(COOEt)2
-
1443
R1NHCONHR2 (4)
EtONa 120PC
-
R2
1
RLNHCONHCH=C(COOEt)2
1
EtONa
= Et, i-Pr, Bu, i-Bu, n-C6H13, n-C7HI5,n-C8H17,HOCH2CH2,CH2=CHCH2, PhCH', Ar;
R2 = H, Me, Et
In a variant of this method the acetals were used instead of aldehyde^^'-^^. The modifications of this approach involve elimination reactions from other N-(1-Xalky1)amides where the leaving group X is an halogen atomZ4, alkoxyZS o r cyano groupZ6. Many of these reactions occur with formation of N-acyliminium inns 2 as intermediates (equation l), which give the enamides after elimination of the electrofuge E + from j-carbon atom, o r the N-acylimines by removal of R4 group from nitrogen atom. In that way, the N-acyliminium ions 2 appear not only as the intermediates in acid-catalyzed conversions of enamides3 but also as direct precursors of the latter. In other words, the chemistry of enamides and their N-acylimine tautomers is closely connected with N-acyliminium chemistry, a topic which has been reviewed comprehensively3,5-7.27-31 As can be seen from equations 2-5, the formation of N-acylenamines proceeds from derivatives of carboxylic acids (having an oxidation level equal to threei7), namely anhydrides o r acid halides RCOX o r amides RCONH,, on the one hand, and from carbonyl compounds or their derivatives (oxidation level equal to two"), namely enamines 3, acetylenes 5, or vinyl ethers 6, on the other. Indeed, the acetylenes 5, being the dehydration products of enols, may be regarded as having a 'masked carbonyl function'32, while the enamines 3 rank with vinyl ethers, vinyl esters and enols, as the heteroanalogs of these carbonyl derivatives (see Section IV). From such a viewpoint, further possibilities for the preparation of enamides seem obvious. Among them the most interesting is the application of acid derivatives such as
1444
S. M. Lukyanov
nitriles. The reactions of the nitriles with carbonyl compounds and their derivatives are attractive because the nitriles, being the dehydration products of amides, are more active than the latter under acid-catalyzed conditions due to the formation of nitrilium salts, and are able to give the enamides directly without forming intermediate gem-bifunctional compounds similar to 8 or 9. It should be noted that nitriles are used as precursors in the above-mentioned synthesis of enamides from N-organomagnesium derivatives of imineslz which are obtained by treatment of nitriles with Grignard reagents o r from cyanohydrinsz6. The synthesis of N-vinylperfluorobutyramide is based on the reaction of perfluoroalkyl nitriles with 2-chloroethanol in the presence of excess trimethylamine3? However, the acid-catalyzed reactions of nitriles with carbonyl compounds are more interesting since they involve the intermediacy of highly active cationoid intermediates such as carboxonium, iminium or nitrilium ions and enable one to obtain various heterocyclic and polyfunctional compounds by starting from available precursors in a one-pot synthesis. A number of papers on such reactions were published in recent years but the topic of chemistry dealing with reactions of nitriles with carbonyl compounds forming enamides has not yet been reviewed. II. REACTION OF ALDEHYDES WITH NITRILES
A. Formation of bis-Amides and Amidoalkylation Reagents
The reaction of aliphatic, aromatic and arylaliphatic nitriles and dinitriles with formaldehyde, aliphatic and aromatic aldehydes in the presence of acids leads to the N,N'-alkylidene- and N,K-arylalkylidene-his-amides 9a and has been known since 187634.
As mentioned above, the bis-amides 9a are used as precursors in the synthesis of N-acylenamines. The conditions used for this reaction depend on the purpose of the synthesis and are described in numerous works, and reviewed in a series of article^^^-^'. The acid catalyst is usually concentrated sulfuric acid, but a successful application of 85% phosphoric, chlorosulfonic, methanesulfonic and formic acids was reported, and reactions were also conducted in the presence of anhydrous hydrogen chloride3*. The solvents used are usually glacial acetic acid and chlorinated hydrocarbons. It is believed that the water necessary for the formation of the his-amides under anhydrous conditions is obtained from conversion of the carboxylic acid to the anhydride, or even the sulfuric acid35. The N-acylenamines and their precursors his-amides 9 are used as amidoalkylation reagents5s6. The main purpose of the latter is to produce the N-acyliminium ions 2 which act as highly reactive electrophilic reagents3. Consequently, the application of Nacyliminium ions 2 considerably extends the preparative possibilities for functionalization of aromatic, heterocyclic and unsaturated compounds. It is now believed that the acid-catalyzed reaction of the aldehydes with nitriles leads first to N-acyliminium ions 2 which can undergo both addition to the nucleophilic
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
1445
substrate and deprotonation to give enamides. The in situ formation of N-acyliminium ions 2 from aldehydes and nitriles is widely used for the amidoalkylation of various compounds. Thus, m-xylene 10 can be bis-amidomethylated to 11 by treatmerrt with formaldehyde and acetonitrile in the presence of a 1 + 12 mixture (v/v) of sulfuric acid and acetic a ~ i d ~ (equation ' . ~ ~ 7).
hMe
+ 2H2C0 + 2MeCN
(10)
?.:- Me
qNH (;)
NHCOMe
Compounds having active methylene groups, such as anhydrides, undergo the amidoalkylation reaction equally well by reacting either with bis-amides 12 or with the aromatic aldehyde-nitrile mixtures". A similar reaction can be also carried out by starting from the corresponding carboxylic acids. The intermediates formed are the 6-oxo-5,6-dihydro-4H-1,3-oxazines 15. G i ~ r d a n osuggested ~~ that in the course of the
CUUH
1446
S. M. Lukyanov
process the N-acyliminium ions 13 are initially formed and then they react with the enol form of anhydride 14 (equation 8). The acid catalysts used were sulfuric, p-toluenesulfonic, methanesulfonic and phosphoric acids or gaseous hydrogen chloride. In almost any case of in situ production of N-acyliminium ions from an aldehyde and a nitrile, a mixture of mineral acid with glacial acetic acid serves as the acid catalyst5-'. Probably the acetic acid is the source of the acylium ions which are necessary for the activation of carbonyl component (see Section III.B.3). 8. Syntheses of Heterocyclic Compounds
During the amidoalkylation of olefins 16 by their addition to the N-acyliminium ions 17, the products can undergo cyclization by a polar 1,4-~ycloaddition~~'~~~.
The 5,6-dihydro-4H-1,3-oxaziniumcations 18 formed can be isolated as salts of stable non-nucleophilic anions (e.g. SbCI;). Usually, the reaction mixtures are treated with water or with alkali solutions, and 5,6-dihydro-4H-1,3-oxazines19 are obtained by deprotonation (equation 9, R' = H). This reaction can be carried out as a two-
wR6 -
R4 20
+
R'CHO
+
I . H+ 2. OH-
R3
R5
2 R ~ * R6
RL =Me, Ph; R2 = Me, Ph, p-XC6H4, (X= N02, Br, Me) ~ 3~4, = H, Me; R5, R6 = H, Me, Et, Ph, COOMe, CH2=C(Me)
RI
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
1447
component4' or a three-component synthesis. The latter includes the intermediate formation in situ of N-acyliminium ions 17 from either the aldehyde and amide42s43or from an aromatic aldehyde and itri rile^^.^^. The intermediacy of bis-amides 20 was assumed43 due to the presence of acetic acid in the reaction mixture. The reaction of nitriles with aromatic aldehydes is carried out at heating the reactants t o 5&70°C with a 1 + 10 (v/v) mixture of concentrated sulfuric acid and glacial acetic acid43. The cycloaddition reaction is regiospecific. The oxazines 21 (equation 10) are formed as diastereoisomeric pairs which are free from their regioisomeric products in the limit of the NMR analysis. Precursors used were benzonitrile and acetonitrile as well as acetaldehyde, benzaldehyde and its substituted derivatives, and a number of the olefins having various structures. Until now, the reaction of aldehydes with nitriles was interpreted as an extension of the Ritter reaction36.The initial 0-protonation of aldehyde 22 is postulated to form in the presence of acid the hydroxycarbenium ion 23 which then reacts as a cationoid electrophile with the nitrile (equation 11) giving the nitrilium ion 24.
However, a considerable difference should be noted between a-hydroxyalkyl nitrilium ions 24 which contain an intramolecular nucleophilic center (OH group), and Nalkylnitrilium ions 26 which are the intermediates of a Ritter reaction45. The transformation of ions 24 into the N-acyliminium ions 25 (equation 11) is evidently an intramolecular rearrangement (see Sections V.B and V.C), while the nitrilium salts 26 can be converted into ions 25 only by an oxidative dehydrogenation of amides 273 (equation 12).
- .
O n the other hand. our own erouo and Jochims and coworkers in Germanv found rec;ntly and indepcndcnt~yanother pathway for formation of the N-acylimini;m ions from aldehydes and nitriles in which the order of activation of the reagents differs from that in the kitter reaction. The method involves an initial electrophilic activation of the
1448
S. M. Lukyanov
nitrile Cnd conversion of the latter into nitrilium salt 28, which then reacts as an electrophile with the a l d e h ~ d e ~ In ~ - this ~ ~ .pathway Jochims and coworkers48 have obtained the stable and isolable N-acyliminium hexachloroantimonates 29 (equation 13). Lukyanov and colleagues46 have found that the N-phenylbenzonitrilium salt 31 reacts with aromatic aldehydes 30 to form SchilT bases 34. The authors believe that N-phenyl-N-acyliminium ions 32 formed as intermediates undergo an easy and irreversible fragmentation to the stable benzaldehyde-antimony pentachloride complexes 33 (equation 14).
R' = XC6H4(X = 2-OMe, 4-OMe, 4-Me, 4-CI), 2,5-(Me0)2C6H3,2,4,6-Me3C6H2; R2 = Me, i-Pr,Ph
PhCHO
+
RCHO
+ P ~ C = N PS~~ C I G
(30)
(31)
+
+ PhC=NEt
SbC16
,
-
(CH2C1)2,ODC h, 65%
H Ph 1 ?. 1 RC=NCOP~ sbck(32)
I
1449
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
The assumption that the azomethine 34 is formed by an intermolecular hydride transfer from aldehyde 30 to the nitrilium salt 31 is not confirmed because the different Schiff bases 34 obtained carry the group R which are originated from the aldehyde 30. In this wav. , the Drocess described in eauation 14 can be reversed and applied as an cnamide synthesis by acylation of iminesi,! llowever, the N-rthylbcnronit;iiium slilt 35 reacts with henraldehyde to give the more stahle N-benzoyl-N-elhyliminium ions 3647.49 which add to trimethylethylene to form 5,6-dihydro-4~-1,3-oxazinium salt 37. On the other hand, the reaction of ions 36 with phenylacetylene leads to another type of 1,3-oxazinium heterocycle, namely to 4H-1.3-oxazinium hexachloroantimonate 38 (equation 15). It is known that nitrilium salts can be prepared by alkylation of nitriles5', via the reaction of imidoyl chlorides with Lewis acids5' as well as by Beckmann rearrangement of oximesS2.The application of nitrilium salts in organic synthesis is summarized in a number of r e v i e ~ s ~ ~In- ~this ~ . connection it is appropriate to mention another three-component one-pot synthesis of 5,6-dihydro-4H-1,3-oxazines 40 based on the reaction of aldehydes with N-tert-butylnitrilium salt 41 which, however, proceeds without the participation of N-acyliminium ions46. The reaction is carried out by mixing the aliphatic or aromatic aldehyde, tert-butyl chloride and Lewis acid (SbCI,,SnCI,) in benzonitrile solution (equations 16 and 17).
x
Me Me RCHO
+
Me
+ PhCN
C1
R = Me, i-Pr, 2,4--CI2C6H3
-I5
-
R2x Me Me
H
0
Ph
H
Me
Me
(16)
0
Ph
S. M. Lukyanov
FIGURE 1. Two distinct isomers of the 1,3-oxazininm cycle formed from three compounds: (a) by participation of N-acyliminium ions47,49(structure 45) and (b) by using N-lerl-butylnitrilium salt46 (structure 46). The ring fragments introduced by the three components are: (C,+aldehyde, (C+olefin and (NC,)-nitrile
the N-tert-butylnitrilium salt 41 easily dissociates in the As shown in the solution t o give benzonitrile a n d tert-butyl cation 42, rather than N-ethyl- a n d Nphenylnitrilium salts. The tert-hutyl cation 42 interacts with the aldehyde to form the alkene 43 a n d the hydroxycarbenium ion 23. A following nucleophile-electrophile Prins
I
COR'
COR'
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
1451
reaction of 43 and 23 leads to the tertiary carbocation 44 which then reacts with the nitrile in a Ritter reaction. In this way, the process (equation 17) is a combination of the Prins and the Ritter reactions. It should be emphasized that this method of synthesis of 5,6-dihydro-4H-l,3-oxazines 40 gives heterocycles which are isomeric to that obtained by participation of Nacyliminium ions, i.e. the products 40 have inverted location of the heteroatoms relative to the three-carbon fragment of the cycle. Indeed, if the N-acyliminium ions participate in the formation of the heterocycle, the carbon atom (C,) of starting aldehyde occupies position 4 of the heterocycle 45 (Figure 1) while N-tert-butylnitrilium salt 41 gives the heterocycles 46 with 'aldehyde' fragment C, at position 6, i.e. near the oxygen atom. The heterocyclic systems of 1,3-oxazinium ions are widely used in the organic s y n t h e ~ i s ~ ~Thus, , ~ ' . 5,6-dihydro-4H-1,3-oxazines40, being a cyclic derivative of 42aminoalcohols, can serve as C,-synthones for the preparation of aldehydes, ketones and carboxylic a ~ i d s ~ 'The , ~ ~4H-1,3-oxazines . 47 can undergo oxidative dehydrogenation by treatment with the trityl salt^'^^'^ or b e n z ~ q u i n o n eto~form ~ the 3-azapyrylium salts 48, which then give various N-acylenamine derivatives 49-52 by reaction with water or with active methylene compounds (equation 18)57,'8. Ill. REACTION OF KETONES WITH NITRILES
A. Intramolecular Reactions of Ketonitriles, Cyanoamides and Cyanoesters
The nitrile function reacts relatively easily with a carbonyl group if both are present in the same molecule and the reaction leads to the formation of stable cyclic derivatives3'. The cyclic N-acylenamines 54 are obtained by treatment of the 5-oxonitriles 53 with acids such as concentrated sulfuric acid or anhydrous hydrogen chlorides9 (equation 19).
R = Me, Pr,i-Pr, Bu
The ethyl (2-cyanoethyl)acetoacetate 55 cyclizes rapidly in the presence of the cold concentrated hydrochloric acid to give ethyl 1,4,5,6-tetrahydro-2-methyl-6-oxonicotinate 5@' (equation 20). The y-benzoyl-y-phenylbutyronitrile57 obtained by condensation of deoxybenzoin and P-chloropropionitrile in the presence of sodium ethoxide can undergo the cyclization when exposed overnight to 9&92% sulfuric acid to yield 5,6-diphenyl-l,2,3,4-tetrahydropyridine-2-one 5g6'. It is remarkable that the ketonitriles 59 having shorter or longer chain lengths are hydrolyzed under same conditions to the amides 60 without ~ ~ c l i z a t i o(equation n~~ 21).
S. M. Lukyanov
1452 COOEt
I
H-C-CH2CH2CN I
COMe
(55)
Ha
a;""
0
(20)
I
H (56)
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
1453
By refluxing the ketonitriles 61 with 95% ethanolic sulfuric acid, the corresponding 3-substituted isocarbostyrils 62 are isolated with excellent yields62(equation 22). On heating /3-ketonitriles 63 with ketones (acetone, phenylacetone, cyclohexanone)64 in the presence of polyphosphoric acid (PPA) they condense to give 2-hydroxypyridines 6563(equation 23).
H
+
kR3
PPA 130-14O0C. 5 9 4 3 %
-
HO R1)&R3
+
o%ph
Me
140-15O0C.55% PPA
(23) R4
R~
phtr
N
-
'.hph
Me
OH
(24)
However, the condensation of phenylacetone with acetophenone gives the corresponding 2-hydroxypyridine 65 (R' = R3 = H, R2 = R4 = Ph) with only 5% yield. In the article63 it is shown that the /3-ketonitriles are capable of self-condensation to 66 when heated alone with polyphosphoric acid at 14lL150 "C (equation 24). Meyers and Garcia-mu no^^^ assume that the cyclization of the 6-ketonitriles 67 by the action of concentrated sulfuric acid may be regarded as a still further extension of the Ritter reaction to the reactions of carbonyl compounds in the synthesis of nitrogencontaining heterocycles (equation 25). In this case the cyano-group reacts as a nucleophile with the positively charged center of the carboxonium intermediate BS However, Vill and coworkers65 have proposed a different scheme according to which an initial hydration of the cyano group of 69 to the amido group is followed by cyclization of 6-ketoamide 70 formed to 71 (equation 26). The same opinion is held by Hauser and coworkers for the condensation of the ketoaminonitriles 72 with acetophenone in the presence of the polyphosphoric acid66. They assume an initial conversion of precursors 72 into ketoaminoamides 73, which are then condensed with the ketone to give substituted 3-amino-2-pyridones 74 (equation 27). Cyclic enamides 79 are formed by treatment of the 2-arylaminonicotinonitriles 75 with either anhvdrous hvdroeen chloride in benzene. ethanol or dioxane.. or oerchloric . acid in glacial acetic acid, followed by the acylation of heterocycles 76 by acetic, succinic, trifluoroacetic anhydrides as well as benzoyl chloride6' (equation 28). The mechanism of this reaction apparently involves the intermediate amide since nitrile 77 transforms under the conditions described6' into the corresponding amide 80 (equation 29). Cyclic derivatives having the N-acylenamines or N-acylimines structure can be prepared starting from the cyano esters as well as from the enol forms of /3-ketonitriles.
- -
1454
S. M. Lukyanov
RI,RZ
(72) Y = H, OMe, C1
= H, Me; n = 3-5
H
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
Ac20
1455
- "'ICY R
N
NCOMe I
I
HC104 AcOH
(78) (79) R = R2 = H, Me; R1 = H, COOEt; R3 = H, 2-XC6H4 (X = MeO, Me, CI, Br), 2,4-(Me)2ChH3; R4 = Ph, CF3, Me, HOOCCH2CH2 CONH2 HCI
Me
R' CN
Y
R2 OCOR
-HClo4
75-98%
R2+-0
I
Et3N
0-+-NH YC, R,-
(81)
NCOCH2Ph
R2+f0
(30)
"YN R
(83) (82) = Me, Et, Pr, Ph; R' = H, Me; R2 = Me; R3R4 = -(CH2)5R
S. M. Lukyanov
1456
Thus, the 0-acylated cyanohydrins 81 are cyclized in the presence of perchloric acid to 2-oxazolin-4-onium salts 82, which are then deprotonated to the corresponding 2oxazolin-Cones 8368.69(equation 30). By acylation of the en01 form 85 of P-ketonitriles 84, 4-0~0-1,3-0~azini~m perchlorates 86 are obtained. Opening the cycle by hydrolysis to give 87 occurs under mild conditions70 (equation 31).
..
(85) (84) R' =Me, Ar; R2 = H, Et, Ph; R3 = alkyl
~10~-
(86) I
The benzo-derivatives of the salts 86, i.e. benzo-1,3-oxazin-4-oniumsalts 89, are formed under the same conditions by acylation of salicylonitrile 88, which is a structural analog of the enol form 85 of the P-ket~nitrile'~ (equation 32).
(90) 2 R = Alk, Ar; X = C104,0.5 SnCl6-
x(89)
Salts 91 having alkyl substituents in position 2 react easily with triethyl orthoformate to give the P-ethoxyvinyl derivatives 92. C deprotonation of 92 by reaction with amines leads to curious cyclic N-acylenamines 9S9572(equation 33).
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
R2 I Clod-
ClOi
(91) R1= H, Me, Ph; R2 = H, Me
1457
1 OEt
B. intermolecular Reactions of Ketones with Nitriles 1. Protic acid-catalyzed reactions of ketones with nitriles
In attempts to carry out the condensation of ketones with nitriles under Ritter reaction conditions, a-acylaminoketones 9698 were obtained73. Ketones such as acetone, cyclohexanone, mesityl oxide, diacetone alcohol and acetophenone and its substituted derivatives were applied in this reaction (equation 34). However, it has been found that many ketones such as cyclopentanone, 2-tetralone, 1-indanone, camphor, 4-heptanone and pinacolone did not react with nitriles under the conditions described. Neither substituted acetophenone nor propiophenone react with benzonitrile.
S. M. Lukyanov Me Me2C0
Me
PhCN
H2SO4
Me
e
H2so4
R I + & H I C O a R l NHCOR2
R' = H, Me, OMe; R2 = Me, PhCH2, CH2=CH
(98)
It is known also that the reaction of acrylonitrile with acetone leads to N-(1,ldimethyl-3-oxobutyl)acrylamide 9914 (equation 35). Me 2Me2C0
+
H2C=CHCN
-
Me
CH=CH2
(35)
Me
It was suggested7"hat the most probable mechanism of this reaction is an initial aldol condensation of the starting ketone leading to the a,/?-unsaturated ketone 100 or to the /?-hydroxyketone 101 which serve as precursors to the tertiary carbenium ions 102, which reacts in turn with nitriles by an acid-catalyzed Ritter reaction to give 103 (equation 36). This suggestion is confirmed by the results of a 'cross-reaction' experiment of benzaldehyde and diethyl malonate with acetonitrile to give 14 (equation 37). It was concluded from these results that ketones are incapable of intermolecular reactions with nitriles. Starting from a general concept on the stability and reactivity of carbenium ion^'^.'^ it can be explained that the carbenium ion intermediates 105 formed from ketones under acid catalysis are more stable than those (106)formed from aldehydes and, therefore, the former are less reactive in the reactions with the weak nucleophilic nitriles.
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
PhCHO
+ H2C(COOEt)2
MeCN
1459
PhCHCH(COOEt)2
I
NHCOMe (104)
Nevertheless, reactions are known for a long time in which an intermolecular binding of a carbonyl carbon atom with the nitrogen atom of a cyano group takes place. Thus, the a-ketoacids 107 are capable of undergoing condensation with some nitriles in the presence of either anhydrous hydrogen chloride or sulfuric to give enamides 108 or bisamides 109 (equation 38). However, only recently the acid-catalyzed reaction of the keto and cyano functional groups have been reported. In these articles the unreactivity of ketones in the Ritter reaction was noted and the search for conditions t o overcome this lack of reactivity was described. The reactions of camphor 110a8', isocamphanone 110b8' and their structural analogs isofenchone llOc and 5-exo-ethyl norcamphor 110d83 with acetonitrile in the
S. M.Lukyanov
Me2CHCH2COCOOH
CICH2CN
Me \
COOH
/
FHCH=C NHCOCH2CI \
Me
(107)
1
CICHKN, HzS04 conc.
Me
COOH CHCH2C-NHCOCH2CI / \ Me NHCOCH2CI \
/
(1lOa-d)
(llla-d)
(112a-d)
NHCOMe Rn
NHCOMe
1.MeCN
R,
ANHC .----
presence of concentrated sulfuric acid give the corresponding bis-amides 114a-d (equation 39) whose structures were assigned by IR,NMR and mass spectrometry. Kozlov and coworker^^'-^^ suggested that the formation of N,N'-diacetamides 114a-d is promoted by the 'nonclassical' stabilization of the cationoid intermediates 111 and 113. At the time that their work was published the reports on the participation of other ketones in the Ritter reaction had appeared. Vartanyan and coworkers have described the synthesis of bis-amides 116 from cycloalkanones 11584(equation 40). Lukyanov and colleagues85 used successfully trifluoromethanesulfonic (TfOH) acid as a catalyst for the reaction of pinacolone 117 with benzonitrile. When the mixture of these compounds is kept for five days at room temperature, the salt 119 is precipitated.
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
1461
Treatment of the latter by dilute potassium hydroxide solution gives the 26diphenyl-
4-methyl-4-tert-buty1-4H-l,3,5-oxadiazine 120 in 71% yield. The formation of 120 is ascribed to a polar [4 + 21 c y c l ~ a d d i t i o n 'of ~ ~benzonitrile ~ and the N-acyliminium intermediate 118. However, after heating the reaction mixture of the three components mentioned above at 100°C for 10 min or a solution of the salt 119 in benzonitrile under the same conditions, the same product 121 is precipitated. Its deprotonation leads to 2-phenyl-4,433-tetramethyl-2-oxazoline 12285(equation 41). f-Bu Me
X
Ph
'"'k"' N
KOH
Ph
Ph
Ph
KOH
Me
NH
Me
OY"
The analogous 1,3,5-oxadiazine 124 was obtained from 2,4-dichlorobenzaldehyde 123 (equation 42). However, neither the pivalophenone 125 nor the isobutyrophenone 129 react with benzonitrile in the presence of trifluoromethanesulfonic acid at room tempera-
S. M. Lukyanov
-Me
Me
0
TfOH IIOT
Me
NHCOPh
(125)
(126)
Me+Me O y N \ H
TfO-
Ph
I
I
Ph
Me Me
0
TfOH IIOT
Ph TfO
1:~; 1 Me
TfO-
MeHph LO%
NHCOPh
Me
NHCOPh
ture. Only by heating t o 110°C the 2-oxazoline 128 is obtained from pivalophenone 125 and the N-benzoylenamine 131 is obtained from isobutyrophenone 12986(equations 43 and 44). In these reactions attention should be paid to the 118 -t 121 as well as the 126 -t 127 rearrangements, which were unknown until recently for N-acyliminium ions. It is possible, however, that in this situation an alternative mechanism involving an isomerizathe stage of the 0-protonated intermediate, i.e. a 1,Zshift in the hydroxycarbenium ion 13386formed from 132 (equation 45), may take place. Me
+ TfOH
=
Me
Me
-Me
Me
Me Me
Me
Me Ph TfO-
CPh
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
1463
However, this suggestion was excludeda6 in view of the fact that the 1,3,5-oxadiazine 120 formed contains a tert-butyl group. Moreover, according to equation 45 the 2-oxazolines 134 must be obtained, whereas the isomeric 128 was actually isolated as
expected from equation 43. When R is a phenyl group the asymmetrical center is placed either near the nitrogen atom in structure 128 or near the oxygen atom in structure 134. It was established by mass spectrometry of 128 that the fragmentation of molecular ion (m/z 265 [Mf]) takes place with the loss of fragments [MeCOMe] (m/z 207) and [MeCNPh]' (m/z 147), which are typical for cleavage of 2-0xazolines~~. It should be noted that the 2-oxazolines are connected directly with enamides, being their products of cyclization on the one handa7, as well as being the heterocyclic precursors of N-acylenamines on the However, it is n o less important that the 2-oxazolines are cyclic derivatives (and precursors also)a9 of the 1,2-aminoalcohols. In essence, the reactions 117 + 122 (equation 41) and 125 + 128 (equation 43) are the transformations of ketones to 1,2-aminoalcohols, i.e. they are the reversal of one of the pinacol rearrangement variants, i.e. the Tiffeneau and MacKenzie reaction^^^,^'. These transformations which proceed via the N-acyliminium intermediates 118, 126 are examples of a real retropinacol rearrangement according t o structural, functional and redox feature^^^-^^ (see Section III.B.3). The reaction of benzil 135 with benzonitrile in the presence of the trifluoromethanesulfonic acid leads t o the bis-N-benzoylimine 136. Under the same conditions benzoylacetone 137 reacts to give the bis-N-benzoylimine 13ga6 (equation 46). NCOPh
(135)
7 days
NCOPh
HNCOPh
NCOPh
+
(136)
NCOPh Ph TfO-
J
NCOPh
Attempts to use other strong acids, such as perchloric or sulfuric acid, instead of TfOH in these reactions (equations 4 1 4 4 and 46) have failed. The ketones mentioned above did not react with nitriles, while under more drastic conditions a tar was formeda6. 2. Aprotic acid-catalyzed reactions of ketones with nitriles
The reaction of benzyl ketones with nitriles in the presence of the phosphorus oxides is considered by Z i e l i n ~ k i and ~ ~ by . ~ Garcia ~ and coworkers97 as a variant of the Ritter reaction. This reaction leads to isoquinoline and pyrimidine derivatives. Zielinskig5 supposes that phosphorus oxychloride (as well as anhydrous p-toluenesulfonic acid) activates the carbonyl group of benzyl ketone 139 for attack by the nitrile nitrogen atom (equation 47). The N-acetyl-1-methyl-2-arylvinylamine143 (when RZ = Me) produced in this reaction via the cationoid iminium intermediates 140, 141 and the phosphorus
1464
S. M. Lukyanov
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
1465
derivative 142 can undergo a fragmentation to arylallene 144 and to a nitrile as well as a cyclization to the isoquinoline derivatives 145. The addition of another nitrile molecule t o the intermediate 146 leads to pyrimidines 14795(equation 48). Referring to the initial formation of imidoyl compounds in the course of the acid-catalyzed ketone-nitrile r e a c t i ~ n ~ ~G. a~rcla ~. . ~and ' coworkers9' described a new one-pot synthesis of 1-substituted 3-arylisoquinolines 149 from deoxybenzoins 148 and nitriles (equation 49). The authors used two procedures applying either phosphorus oxychloride at reflux or phosphorus pentoxide at room temperature.
' #R
POCI,RICN or P205
R
00
(49)
I
(148)
R'
R = H, OMe; R1 = Me, Et, PhCH2, Ph, CH=CH2
(149)
The iminium ions created by reaction of ketones and nitriles can add not only to nitriles (equations 41,42 and 48) but also to ketones. After long reflux of aliphatic methyl ketones 150 with nitriles and phosphorus oxychloride (molar ratio 1 :3 :3, respectively) the pyridine derivatives 151 are obtained96 (equation 50). Me RCH2COMe
+
RICN
POCI, -HCI. I0 h
R1
I
RCH=C -N=COPOCI2
(151)
R = H, Me; R1 = Me, Ph, p-An, PhCH2 The yields of the pyrimidines 147 and the pyridines 151 are not high and vary greatly, depending on the structure of the starting materials. The latter can also determine the nature of the product. Thus, a mixture of 2,4-dimethyl-6-phenylpyrimidine, 2,4-dimethyl4,6-diphenyl-4H-1,3-oxazineand 1-chloro-1-phenylethene was obtained by refluxing a 1 : 3 : 3 ratio of the acetophenone-benzonitrile-phosphorus oxychloride mixture, followed by treatment of the crude product with sodium carbonate s ~ l u t i o n ~ ~has . I tbeen shown9' that addition of an additional ketone molecule t o the iminium intermediate is an alternative to the formation of the N-acylenamines and this route is catalyzed by aluminum chloride. Auricchio and coworkers believe also9' that the reaction of ketones with nitriles catalyzed with both protic and Lewis acids must be considered as a Ritter reaction (see, however, Section V.C). The cationic intermediate 152 thus formed can undergo either a proton shift giving enamide 153 or addition of another ketone molecule
1466
S. M. Lukyanov
-
R2
path o
oAIc~~
R'
1
path b R'COMe. R2 = H
R2 = Me, Et, n-Pr; R3 = Me, Et, n-F'r, Ph
yielding first the carboxonium ion 154, followed by cyclization to the 1,3-oxazine derivatives 155 (equation 51). The addition of the second ketone molecule (path b) is promoted by the fact that the formation of a double bond from intermediate 152 is unfavored when R2 = H9'. Consequently, the acid-catalyzed reaction between ketones and nitriles via intermediate formation of N-acyliminium ions and enamides provides various modes to connect the reactants as well as different ways of 'assembling' end products, depending on the conditions and the structure of the substrate. The reaction is therefore very promising as a synthetic tool for making polyfunctional and heterocyclic compounds. The scope of conditions of the ketone-nitrile reaction is very broad. For instance, the polyfluorinated ketones 156 and 158 react with nitriles in the presence of concentrated sulfuric acid99 and with cyanoamides 159 by reaction mixtures at room temperature in the absence of acid ~ a t a l y s t ' ~ (equations ~~'~' 52 and 53). In the latter reaction (equation 53) an initial [2 + 21 cycloaddition to form 1,3heterodiene 161 via 160 is assumed. It is then followed by a [4 + 21 cycloaddition to another nitrile molecule, giving 162"'.
(156)
(157) (a) R = R1 = CF3; (b) R = R L= CF2CI; (c) R = CF3, R1 = CF2N02
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
1467
(162) R = CF,, CF2C1; R1 = H, Me, Et
3. Electrophilic catalysis by acyl cations in reactions of ketones with nitriles
Recently, a new effective method for electrophilic activation of carbonyl compounds was proposed in order to enable the latter to react with weak nucleophiles such as nitrileslo2. This method involves the conversion of aldehydes and ketones into highly active acyloxycarbenium ions 163. This new type of carboxonium ions is related to the hydroxycarbenium and alkoxycarbenium ions 105, whose high stability is well known76.
0
(105) R3 = H, Alk
(163) R3 = Alk, Ar
(164)
On the one hand, the acyloxycarbocations 163 differ from carboxonium ions 105 by the presence of a carbonyl group which considerably increases the electron deficiency on the carbenium center of 163 due to electron withdrawal. On the other hand, ions 163 are the heteroanalogs of N-acyliminium ions 164 and, as will be shown below, they possess many similarities to the latter. Acyloxycarbocations 163 can be generated in the following ways (equation 54): (a) by direct acid-catalyzed 0-acylation of both aldehydes and ketones93.94.103-'05. , (b) by ionization of cc-chloroalkyl acylates 16592;(c) by addition of cationoid electrophiles (e.g. E = R1) to the vinyl esters 1661°6;(d) by ionization of acylals 167"'; and (e) by oxidative dehydrogenation of esters 168108,109. The best illustration of the high reactivity of the acyloxycarbenium ions 163 is a reaction which is not quite typical for other carboxonium ions. This is the retropinacol rearrangement of a-branched aldehydes and ketones 169 to the 1.2-dioles 173 which involves the unusual 1,Zshift of the migrating group R3 to the carbon atom attached to the oxygen atom of the acyloxycarbocation 17092-94(equation 55).
S. M. Lukyanov
The isomerization of acyloxycarbocations 170 into tertiary carbenium ions 171 is due to the almost equal energies of both intermediatesl'O. Therefore, in comparison with the related hydroxy- and alkoxycarbocations 105, the acyloxycarbenium ions 163 have far lower stability and can be regarded as 'destabilized' carbo~ations"~. In the course of acyloxycarbocation investigations"' it has been noted that the reactions of both aldehydes and ketones follow an unusual course or are strongly accelerated if either acylium ions RCO' are present in the reaction mixtures or conditions to generate them in siru arise. These observations are explained by a transformation of carbonyl compounds into the highly reactive acyloxycarbocations 163 which easily react with weak nucleophiles such as vinyl ethers, vinyl esters, etc. Hence the electrophilic catalysis by acyl cations in carbonyl reactions takes place regardless of the origin of the latter. This catalysis was used in the reaction of ketones with nitriles. It has been shownlo2 that the reaction of both pinacolone 117 and pivalophenone 125 with benzonitrile can be catalyzed successfully by a mixture of 70% perchloric acid with acetic anhydride, although the reaction did not occur without the latter; see Section
1469
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
+
t Me Me+(
Me M e
Me
OCOMe clo4(174)
N-CP~ H+ H R -Me# -Ac+
/ / Me
-Me, 100°C
OCOMe
Me
R
Me
NHCOPh
I
C10~ NaOH ,
mN,l -ficN, 176)
m=c
R = Me. 20°C
t-Bu
Me
(56)
IILB.1. The products formed via cations 174177. 179 and 180 are the same derivatives of 1,3,5-oxadiazine(i.e. 120) as well as 2-oxazoline (122 and 128) obtained earlier, except that the reactions are considerably faster (equation 56). Likewise, mixtures of diisopropyl ketone 181, benzonitrile, perchloric acid and acetic anhydride give at room temperature the N-benzoylenamine 183'02 (equation 57). Moreover, it has been shownlo2 that under conditions of electrophilic catalysis by acetyl cations the addition of ketones to nitriles proceeds more rapidly than the self-condensation of ketones shown in equations 34-36. Thus, cyclohexanone reacts with both benzonitrile and acetonitrile in the presence of perchloric acidlacetic anhydride mixture to form N-acyliminium salts 186 which are then converted to the N-acylimines 187. The P-acylaminoketones 9713 did not form the salts 186 in a control experiment
S. M. Lukyanov
MezCHCOCHMez
~PhCN ~104AC2O
(181)
NHCOR
1
R = Me, Ph
Me2C0
+ MeCN
NaOH 85-90%
HC104, Ac20, 2092 51%
Me
Me
I
at the same conditions, i.e. the reaction proceeds by pathway a via the well-known dimerization of N-acyliminium ions3 (equation 58). This conclusion is also supported by the behavior of both acetone and its aldol condensation product, diacetone alcohol 189, whose reaction with acetonitrile leads to different products isolated as the crystalline perchlorates 188 and 190 (equations 59 and 60).
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
1471
Alkyl aryl ketones 191 react with benzonitrile in the presence of a perchloric acidlacetic anhydride mixture to yield the 3-azapyrylium salts 194'13. The structure of 194 indicates the intermediate formation of N-acylenamines 192 which are acylated at the carbon to 193, the precursor to 194 (equation 61).
r AczO
OCOMe
+
Ar
'OCOMe Clod-
Ar
N=CP~ ClO4-
(191) -AC+
(61)
Ar
NHCOPh
AC20,"+ -AcOH
Me
Ar
NHCOPh
R = H, Me; Ar = Ph, 4-To1 It should be noted that the alkyl aryl ketones 191 react with the mixture of perchloric acid and acetic anhydride under the same conditions (room temperature, 10-20 h) to give the unsymmetrical pyrylium salts 197114,115.AS shown in Reference 112 this reaction is also an example of electrophilic catalysis by acylium ions, proceeding via the cationic intermediates 195 and 196 (equation 62).
S. M. Lukyanov
1472
This reaction is completely depressed in the presence of the nitrile. The same authors116 showed that 1,3-diketones 198 react easily with benzonitrile in the presence of a HCIO,Ac,O mixture to form 3-azapyrylium perchlorates 199 (equation 63). This reaction did not occur without acetic anhydride, which is a catalyst since the acylium ions are not included in the end products. The application of the C-acylated ketones 198 leads to 3-azapyrylium salts 199 which are isomeric to those mentioned above (194), i.e. products 199 have an inverted orientation of heteroatoms comparatively to the three-carbon fragment of the The azapyrylium salts 199 can be hydrolyzed to the enamides 200. Me
OAc
+ R
Me NHCOPh R
OAc
H,O
HC104 70-77%
R
0
Ph
40-468
The 3-azapyrylium hexachloroantimonates 204 are also obtained by the reaction of alkyl ketones 201 with benzonitrile in the presence of acylium salts 202 prepared beforehand1l 7 (equation 64).
+ 202
R2fT
R3
f--
0 0
Ph
15-36% R' = Me, t-Bu, Ph; R2 = H, Me, Et; R3 = Me, Et; RLR2=
R21 RI
-(CH2)4-
NHCOPh
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
1473
Without deviating from the theme of this review, the 3-azapyrylium (1,3-oxazinylium"', 1,3-oxazin-1-ium119) salts formed by the reactions described above deserve particular attention. Their conversions to both b-N-acylaminovinyl ketones 49 and 200 and to polyunsaturated N-acylimines S 5 2 have been shown above (equations 18 and 63). Their properties and methods of their synthesis were investigated in detail by Schmidt and coworkerss7~s8~'20~122 and summarized in a number of resalts are easily converted in reactions with amino V i e W s 4 ~ . ~ ~ 8 ..~~h ~ 9e .3-azapyrylium ~z3 compounds into pyrimidine, 1,4-benzodiazepine, 4-hydroxyquinazoline, benzothiazole and 2-pyrazoline derivatives and to 1,2,4-triazolium salts"'. With sulfides they form the 3-azathiapyrylium salt^"^^'^' which are very useful ~ y n t h o n e s ' ~In~ .the course of many reactions the 3-azapyrylium salts behave as masked 1 , 3 - d i k e t o n e ~ activated '~~ by the presence of a positive charge. Moreover, very surprisingly, 3-azapyrylium salts can undergo attack by cationoid electrophilic reagents (see Section VI). Therefore, the reaction of ketones with nitriles with electrophilic catalysis by acyl cations may be considered as a new method of transforming simple available precursors into various heterocyclic and polyfunctional derivatives through 3-azapyrylium salts. Recently, another approach to P-acylaminovinyl ketones 207 through 3-azapyrylium salts 206, based on the acylamidation of acetylenes, was de~cribed'~'.The intermediacy of N-acylnitrilium complexes 205 in the reaction was suggested (equation 65).
,
,
R 1= C5HllrPh; R2 = H, Ph; R3 = Me, CH2CI
L
BF4-
1
(206)
This reaction resembles the reaction of ketones with nitriles in the presence of acyl cations (equation 64) since acetylenes are the dehydration products of the enols of carbonyl compounds32 (Sections I and IV).
IV. REACTIONS OF NITRILES WITH CARBONYL COMPOUND DERIVATIVES
The term 'carbonyl derivatives' covers here several types of organic compounds which, first, can be obtained by simple derivatization of carbonyl compounds 208 under conditions of isohypsic reactionslz6 and, second, possess an oxidation level of 2, equal to that for carbonyl compound^'^. The sense of this generalization is the intention t o
1474
S. M. Lukyanov
obtain various heterocarbenium ions suitable, as far as possible, for the purpose of synthesis, from carbonyl compounds through these derivatives. This series includes the geminal bifunctional derivatives of carbonyl compounds, such as acetals 209, acylals 210, a-haloethers 211, a-haloacylates (i.e., a-haloesters) 212, gem-dihalides 213, aminals 214, amidals 215 and N-(a-haloalky1)amides 216, as well as unsaturated compounds having the heterofunction at the double bond such as enols 217, vinyl ethers 218, enol acylates (i.e. vinyl esters) 219, vinyl halides 220, enamines 221 and acetylenes 222. By means of either addition of cationoid electrophiles or elimination of anionoid nucleofuges from carbonyl compounds and their derivatives, the various hydroxycarbenium 223, alkoxycarbenium 224, acyloxycarbenium 225 and halocarbenium ions 226lZ7,iminium ions 227 and 228 and vinyl cations 229lZ8can be generated. The same cations may be obtained from derivatives of carbonyl compounds (see, for example, equation 54). In addition, different ions can be generated from the same derivatives (e.g. reactions 212 + 225 and 212 + 226). It is obvious that this series can be considerably extended to include compounds substituted by other heteroatoms (S, P, Se, Te).
The reactions of nitriles with carbonyl compound derivatives have not been sufficiently investigated so far. Some papers, for example, describe the cyclizations of N-acylenamines 230 and 232 to pyrimidines 231"' and quinazoline derivatives 233I3O (equation 66; see also Reference 67 and equation 28).
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
aCN
1475
2E:oH-
NCOMe I
NHCOPh
/
H2C, CI
-J;,.(,, PhCN SnCI,
Ph
N
I
X NH 0.5 SnC16'Ph
Hz0
Me
H2C(NHCOPh)2
(67)
(236)
Starting with the knowledge of carbenium ion stability and the understanding that it is necessary to decrease this stability enabling the reaction of these ions with nitrileslo2 (Section III.B.l), it should be assumed that acetals 209, a-haloethers 211, enols 217 and vinyl ethers 218 are ineffective precursors since they are the sources of the highly stable hydroxy- (223) and alkoxycarbenium ions 224. In contrast, the carbonyl compound derivatives, which can produce 'destabilized' ions (in comparison to ions 223 and 224) are the most interesting for reactions with nitriles. This includes acyloxycarbocations 225 (see Section III.B.3), balocarbocations 226, N-acyliminium ions 228 and vinyl cations -mn
LLY.
It is known that N-chloromethyl benzamide 234 (i.e. derivative 216 of formaldehyde) reacts with benzonitrile in the presence of tin tetrachloride to yield 4H-1,3,5oxadiazinium salt 235, the hydrolysis of which gives bis-amide 236"' (equation 67). The condensation of P-chlorovinyl ketones 237 with nitriles promoted by Lewis acids is known as a synthetic method of 3-azapyrylium salts 23858,131(equation 68).
S. M. Lukyanov
1476
Recently, the reactions of both gem-dichloroalkanes (213, Hlg-CI) and vinyl chlorides (220, Hlg-CI) with nitriles were reported. These reactions proceed via the highly active chlorocarbenium intermediates 226. The a-chlorocarbenium ions 241a-c were generated by treatment of geminal dichloroalkanes 240a-c (obtained from isobutyraldehyde 239, pinacolone 117 and pivalophenone 125) with antimony pentachl~ride"~.The reaction involves the rearrangement of the intermediate chlorocarbenium ions 241a-c to tertiary carbocations 242, which then add acetonitrile according to the Ritter reaction mechanism. The hydrolysis of the reaction mixtures leads to the vicinal 1,2-chloroamides 243a-c. It is interesting that in the case of gem-dichloride 240c derived from pivalophenone 125, the reaction can be carried out following the migration of the chlorine because the cation 244 is more stable than ion 242c. For this purpose the ionization step of gem-dichloride 240c with antimony pentachloride was separated from the following step of acetonitrile addition (-8O0C, 5 minutes between the steps). The 1,2-chloroamide 245 obtained after addition of water is the positional isomer of product 243c formed by carrying out the ionization in acetonitrile solvent. The 1,2-chloroamides 243 and 245 can be easily converted into the corresponding 1,2-aminoalcohols ( e g 246) as well as the 2-oxazoliness9. Consequently, the reaction described (equation 69) is another variant of the above-mentioned retropinacol rea~-rangement~'-~~ (see Sections III.B.l and III.B.3). R1
R2
3
MeMe'
\\
0
R' Me-&(& Me'
R2
R1 MeCONI&R2 Me'
\
C1
-
Me
Meh+R2sbc16Me Cl
-
-R'
Me
MeCN
\
C1
R' MechNMft-R:
Me
C1
(239,240a-243a) R1 = R2 = H (117,240b-243b) R' = R2 = Me HO NHCOMe (125,240~-243c) R1 = Ph, R2 = M e (246) If the rearrangement of the chlorocarbenium intermediate is impossible, then the latter (e.g. 249) adds in consecutive order two nitrile molecules to form the pyrimidine 25386 (equation 70). 245
HzO. MeOH
M r g M e
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
1477
1
PhCN
It is assumeds6 that this reaction proceeds via the cationoid intermediates 251 and 252 which are analogous to those described by Z i e l i n ~ k i(equations ~ ~ . ~ ~ 48 and 50). The same type of nitrilium intermediates 258 and 259 are assumed to be formed by protonation of vinyl chlorides 255 by trifluoromethanesulfonic acid in the nitrile as a solvent (equation 71)86,133. The highly reactive vinyl cations 262 and 263 are generated from the vinyl triflates 261, obtained from corresponding ketone^"^. These cations react
S. M. Lukyanov
1478
"1OTf
R1
I
t TfOH
RICSR~ -
1-
R3
I . RICN 2. NaOH
R3
(264) R1 = I-Bu, Ph; R2 = H; R3 = Me, Et, Ph (54-71%) (264 + 265) R1 = i-Bu; R2 = i - h ;
)
R3 = Me, Et (yield 70% of a 56% 264 and 44% 265 mixture) with nitriles to yield the pyrimidines 264 and 265 (equation 72). The pyrimidine derivatives 267 and 269 are obtained by p r ~ t o n a t i o n 'and ~ ~ a c y l a t i ~ n ' ~of ' mixtures included alkyne 266, o r 268 and the nitrile. Highly reactive vinyl cations also take part in these reactions (equation 73). Although N-acyl enamines and their cationoid derivatives are not the intermediates in all the above-mentioned syntheses of pyrimidines, these reactions are listed here for demonstration of the synthetic applicability of the reaction between nitriles and carbonyl compounds and their derivatives. During the course of investigation of these processes interesting theoretical results were obtained which allow one to evaluate from a new viewpoint some concepts regarding this field.
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
~
2
$
~
-HCl ~
~
Ph
R
'
(278) ~1 = R2 = Me; R'R2 = -(CH2)3-; R3 = Me, Ph
R1
SbC16(277) [NH?
R3 I
~
~
1479
~
1480
S. M. Lukyanov
In this respect the acylation of vinyl chlorides 270 in benzonitrile medium turned out to be a very interesting process1". The action of acylium salts 271 on the vinyl chlorides is related to three problems, namely (a) the formation of the reactive chlorocarbenium ions 272, (b) the lengthening of the carbon chain as the first step of the future heterocycle construction and (c) the introduction of another functional group which shall have to subsequently ensure the cyclization. The chlorocarbenium ions 272 cannot rearrange, and therefore it is expected that the nitrile will add t o ion 272 to form 3-azapyrylium salts of structure 273 (equation 74). However, it has been found unexpectedly117 that the 3-azapyrylium salts 277 obtained under these conditions have the inverted orientation of the heteroatoms in cycle, i.e. they are the structural isomers of the salts expected. The constitution of products 277 was confirmed by comparison with 3-azapyrylium hexachloroantimonates obtained by other methods. Moreover, they were characterized by IR and NMR spectroscopy as well as by mass-spectral study of p-acylaminovinyl ketones 278, i.e. the products of opening of 3-azapyrylium cycles. It was observed136 that the P-oxochlorocarbenium ions 272 formed by acylation of vinyl chlorides 270 can undergo an intramolecular deprotonation to give the more stable hydroxycarbenium ions 274. In this case the carbonyl oxygen performs the function of an 'internal' base (equation 75). The formation of 3-azapyrylium hexachloroantimonates 277 can be then explained by reaction of nitriles not with the more reactive chlorocarbenium ions 272, but with the more stable and less reactive hydroxycarbocations 274 (equation 75, path b). However, this conclusion contradicts what has been said previously (see Section III.B.3). Indeed, the assumption of the advantage in using the less stable cations in reactions with nitriles over the more stable ones has been confirmed experimentally. Nevertheless, the lack of addition of nitriles to the chlorocarbenium ions 272 does not mean the absence of the reaction between these components. Therefore, the initial acid-base interaction of the nitrile with either the chlorocarbenium (272) o r the hydroxycarbenium ions 274 was assumed, leading to p,yunsaturated p-chloroketones 280'36 and the nitrilium salt 281. As mentioned in Section ILA, nitrilium salts are sufficiently reactive even for dehydratio? of acids. The nitrilium salts R ' C & N R ~ are the heteroanalogs of acylium ions RC=O, which were shown
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
1481
above to add easily to the carbonyl oxygen atom of both aldehydes and ketones to give the acyloxycarbenium cations (Section III.B.3)93,94.'04.'05.Consequently, it is highly likely that the acid-base interaction 272 + 280 + 281 is followed by a nucleophile-electrophile interaction of ketones 280 with nitrilium ions 281 to form a new carboxonium ion 282, which then rearranges to the N-acyliminium ions 275 which eventually cyclize to 277 (equation 76). V. TWO PATHS FOR THE REACTION OF CARBONYL COMPOUNDS WITH NITRILES
A. Reactions of Ketones with Nitrilium Salts
Carbonyl compounds can react with nitriles by two alternative paths: (a) by an initial electrophilic activation of the carbonyl component 283 followed by reaction of the formed carboxonium ion electrophile 284 with nitrile 286 as a covalent nucleophile, and (b) by an initial electrophilic activation of the nitrile component 286 to give the cationoid electrophile 287, which then attacks the carbonyl group of 28349 forming 288 in a reaction which resembles the 0-acylation by acylium ions (equation 77). +E+
R~R~CO
+
R~C=OE
"" Y + R2
(284)
(283)
N ~ C R ~
R1
E
(285)
,-Y
R~CN
+E+
+
RI
R'R~CO
R~CPNE
(286) (287) E+ = Electrophile
R2
NE
A
O ~
0
(28%
R3
(288)
It is assumed13' that the reaction proceeds by path a so long as the carboxonium ions 284 are sufficiently reactive for reaction with weak nucleophilic nitriles (e.g. as is the case when the ions 284 are acyloxycarbocations 225, E = acyl). Otherwise (284, E = H, Alk), path b is followed because in this case the highly reactive nitrilium ions 287 can be generated from weak nucleophilic nitriles. Both paths lead to the same N-acyliminium intermediate 28949 (equation 77). This assumption was confirmed by the reactions of nitrilium salts prepared beforehand50.52."2 with both aldehydes4649 (see Section 1I.B) and ketones. According to Jochims and coworkers'38, N-isopropylnitrilium hexachloroantimonates 290 react with chalcone 291 to yield 3-N-isopropyl-4H-1,3-oxadnium salts 293 (equation 78). 1,3Oxazinium salts having another structure 297 are obtained by the reaction of both crotonaldehyde 294a and (E)-2-methyl-2-butenal294bwith nitrilium salts 290 (equation 79). Besides, the reactions of cinnamaldehyde 298 with nitrilium salts 290 lead under the same conditions to the N-acyliminium salts 300 having a n open-chain structure (equation 80). The authors138 suggest that an initial stepwise (via intermediate 292) or concerted [2 + 2lcycloaddition of the nitrilium ion to the carbonyl group takes place forming intermediates 292 o r 295 and 299, respectively. Ring-opening of the oxazetium cycle forms either 292 o r 2% (as well as 300). The open-chain N-acyliminium salts 300 are
1482
S. M. Lukyanov
+
RC=NPr-i SbC16
+
PhCOCH=CHPh
CH2C12,5 h
-780C, then 230C 52-74%
(290) (291) R = Me, i-Pr, 4-Tol, MeCONCMe2
290 + ?IM. e H
(294) (a) R1 = H (b) RL= M e
1
CH2C12.3.5h
- 7 8 T to - 5 T 88-94%
i-Pr
0
Me (295)
i-Pr
R'
H SbC16
Me
0
R'
H
SbC16 (296)
R = Me, Ph
H I
1
Me
I
(1%
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
R = Me, Ph
1483
SbC16
stable enough to be isolated from the reaction mixtures. The possibility of rearrangement of the 6H-1,3-oxazinium salts 297 into 4H-1,3-oxazinium isomers 293 due to the high acidity of the hydrogen atom at position 6 of 297 was not excluded138.
S. M. Lukyanov
1484
+
RIC-NR2 X
+ R3CONR4R5
CH2CI2,23OC 2d h, 52-95a
(304) (305) R1 = Ph, AcN-Pr-i; R2 = i-PT, R3 = H, Ph, CECPh; R4 = Me, Ph; R5 = Me; R3R4= Ph2C=; R2R3= -(CH2)3-,
-
R I ~ i / R 2
X-
R3
1 R2 I
R4 I
Simultaneously and independently, similar results were obtained by the author's g r o ~ p ~ ' It . ~was ~ . observed that a short reflux (1-2 min) of an equimolecular mixture of chalcone 291 and N-ethylbenzonitrilium salt 35 in 1,2-dichloroethane furnishes the 2,4,6-triphenyl-3-ethyl-4H-1,3-oxazinium salt 38 (equation 81) obtained also by reaction of benzaldehyde with 35 and phenylacetylene (equation 15). If the salt 35 reacts with benzoylacetone 137 under the same conditions, 4-methylene-4H-1,3-oxazinium hexachloroantimonate 301 is formed4' (equation 82). When the N-ethylnitrilium salt 35 reacts with pinacolone 117, it gives the Nacyliminium intermediate 302 (equation 83)which can undergo a retropinacol rearrangement to yield the 2-oxazolinium salt 30386. It should be noted that Jochims and coworkers first carried out the reaction starting from c a r b o ~ a m i d e s ' ~Until ~ ~ ' ~recently ~. almost no acylated persubstituted amidinium salts 306 were obtained by reaction of nitrilium salts with tertiary carboxamides 305 (equation 84). Starting from secondary carboxamides 307, mixtures of N1-acylated N1,N3-disubstituted amidinium salts 308 and 309 are isolated (equation 85). Primary carboxamides 310 undergo dehydration by the nitrilium hexachloroantimonates 290 to
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
+ RLC=NPr-i SbCI6
+ R2CONHR3
CH2Cl2.l-2 h -3,,C to 230C-
(290) (307) R1 = Me, Ph, AcN-Pr-i; R2R3= -(CH2)3-,
i-Pr
R3
I
I
1485
R I ~ N ~ , N :
H SbC160
-(CH)4-
R2 (308)
290
+ R~CONH*
CH2CI2,3-17 h 23T
+ R~CEN
*
(310) RL= i-Pr, Ph; R2 = Me, Ph
OH SbCI6
(312)
(311) Pr-i
(290)
+
PhCOCH=CHNMe2 (313)
CH2C12. 2 h -300C,65-915b-
I
+
RICON-C=CHCH=NMe2
I
Ph
R1 = Ph, Me
(87)
SbCI6-
(314)
furnish the corresponding nitr~les312 (equation 86). If vinylogous tertiary carboxamide 313 is used as a carbonyl substrate, then the salts 314 are afforded by reactions of the former with nitrilium salts 290 (equation 87)139. In that way, two independent paths for the reaction of carhonyl compounds with nitriles under alternative electrophilic activation of either components have been found experimentally. Both are catalyzed by protic and Lewis acids. In this connection, the problem arises which of the two reaction mechanisms takes place. In order to solve this problem theoretical calculations on the reaction pathways have been performed. B. Theoretical Calculations
The AM 1 method143 was applied to the calculations of the two paths a and b of the reaction between the carbonyl and nitrile components according t o equation 77. Semiempirical quantum chemical calculations were also carried out for the syst$ms [HCHO HCN H f I L 4 ' and [H,&-0-CHO HCN and H2C = O HCNCHO]'42 which simulate the proton and foqmyl catalysis, respectively. As shown by the calculation^'^^ the first step of path a (E' = H R1 = R2 = R3 = H) for the system [HCHO + HCN + H'] leads to a stable tetrahedral adduct 317 from 315. This is then rearranged to the 1-hydroxy-2-azaallenium cationoid structure 320 (equation 88). There are two possible concerted mechanisms for such a rearrangement, namely a 1,3-sigmatropic shift of the hydroxy group (317 -t 318 + 320) and a 1,3-sigmatropic shift of one of hydrogen atoms (317 -t 319 -t 320). According to the calculation^'^^, the former route via 318 is energetically more favored. This conclusion is in agreement with the experimental results. Thus, the reaction of pinacolone 117 with benzonitrile gives
+
+
+
+
'.
1486
S. M. Lukyanov
Reaction coordinate FIGURE 2. Energy profile for the reaction between protonated formaldehyde and hydrocyanic acid (path a)14'. Energies are in kJ mol-I
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
1487
1.3.5-oxadiazine 120 (equations 41 and 56) bearing the methyl and the tert-butyl groups on the tetrahedral carbon atom in position 4 of c y ~ l e ~ ~i.e. . ~ the " ~ ,ketone-nitrile reactions occur with conservation of structure of the alkyl group introduced by the carbonyl compound molecule. In other words, no 1.3-alkyl shift takes place. The enthalpy of activation of the 317 + 320 step is very high (227.4 kJ mol-l, see Figure 2) and is partially due to both rehybridization of the nitrogen atom and the strain formed in the four-membered transition state. The next step of path n is the 1,3-sigmatropic
FIGURE 3. Geometries and energies of structures 316318 and 32C322 (see equation 88)I4l, calculated by the AM 1 method. The AH, values are in kJ m o l l , bond lengths in A and angles in deg
S. M. Lukyanov
-800 -H&O+ HCNH+
-
0
E
x -3
-
5700
600-
(323) Reaction coordinate
FIGURE 4. Energy pr~fiiefor the reaction between formaldehyde and protonated hydrocyanic acid (path b)14'. Energies are in kJ m o l
FIGURE 5. Geometries and energies of: (a) adduct H,CO-.HC~H (structure 323), (b) transition state for the rearrangement 323 + 324, (c) carboxonium ion 324 and (d) transition state for the rearrangement 324 + 322 calculated by the AM1 method. The AH, values are in kJ mol-I, bond lengths in A and angles in deg
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
1489
shift of hydrogen from the oxygen to the nitrogen in the I-hydroxy-2-azaallenium cation 320. It has been found that the 1,3-shift of hydrogen atom in this case occurs concertly with a high energy barrier (Figure 2). The geometries and energies of the structures 316318 and 32C322 are shown in Figures 2 and 3. The results obtained14' are in good agree-ment with ab initio calculations for N-formyliminium and 1-hydroxy-2-azaallenium cation^'^^.'^^. On the other hand, the conversion of the system [HCHO + HCN + H + ] by pathway b starts by attack of the protonated HCN molecule on the oxygen atom of the carbonyl group. The kinetically stable ion-molecule adduct 323 has an energy 56.5 kJ mol-I lower than the separated reagents and is formed already at a distance of 3.0A cation and the carbonyl oxygen atom (Figure 4). between the carbon atom the H ~ N H The carboxonium cation 324 rearranges by a 1,3-sigmatropic shift of the methylene group (324 + 322). As shown by the calculations141,the migrating group almost retains in the transition state (Figure 5, structure d) its tetrahedral configuration at the central atom, and the concerted 1,3-sigmatropic shift occurs with a quite low activation barrier (Figure 4). Consequently, the results obtained permit one to conclude that with proton catalysis the interaction of the carbonyl compounds with nitriles proceeds preferably by path b, i.e. starting by an initial electrophilic activation of the nitrile component by protons. Two reaction paths between carbonyl compounds and nitriles catalyzed by acylium ions were calculated by the AM 1 method for two model systems according to equation 77 (E+ = HCO', R' = R2 = R3 = H): (a) H2C*-0-CHO + HCN and (b) H 2 C = 0 + H C E N + C H 0 ' 4 2 . The formylated formaldehyde molecule (i.e. cation ,COCHO+) reacts with the hydrocyanic acid molecule in path a to give cation 325, which is more
S. M. Lukyanov
1490
stable by 126.9 kJ mol-' than the system of separated reagents. Among the following three variants of the rearrangement, namely 1,3-hydride shift 325 + 326 + 329, 1,3sigmatropic shift of the formyl group 325 + 327 + 329 and a 3,3-sigmatropic shift resembling the Cope rearrangement 325 + 328 + 329, the latter is calculated to be the most probable (equation 89). The next step of the reaction proceeds via the transition state (or intermediate) having the approximately tetrahedral configuration of the bonds around the central carbon atom of the migrating group (equation 90). CHO
/
H-C=O
-CHO
H
H
"yJNy "K" I
H
0
H
H
OYO "
H
(W
H
This rearrangement takes place via a four-membered transition state (Figure 6) and is the limiting stage of path a (energy barrier 142.8 kJ mol-I). The geometries and energies of the above-mentioned structures are given in Figures 6 and 7. According to the calculation^'^^, in the course of the reaction by path 6 (i.e. between formaldehyde molecule and the charged N-formylated hydrocyanic acid) the thermodynamically stable cation 334 (Figure 8) is formed. The isomerization of 334 leads Lo N,N-diformyliminium ion 332 resulting from a 1,3-sigmatropic O + N shift of the methylene group (Figures 8 and 9). However, according to the calculations, the ionic state [H,C+O-CHO + HCN] is energetically more favored than the combination [H,CO + HCN -CHO] in the three-component system of the reagents [H,CO + HCN HC'O]. Hence, it appears that under conditions of electrophilic catalysis by
+
+
I
Reaction coordinate
FIGURE 6. Energy profile for the reaction between the charged fomylated fomaldehyde and hydrocyanic acid (path Energies are in kJ mol-I
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
1491
FIGURE 7. Geometries and energies of structures 325, 32-30 and 332-333 (see equations 89 and 90 and Figure 6) calculated by the A M 1 method. The AH, values are in kJ mol-', bond lengths in A and angles in deg
S. M. Lukyanov
"[
800 H&O
+ + HCNCOH
I
Reaction coordinate FIGURE 8. Energy profile for the reaction of formaldehyde with forniylated hydrocyanic acid (path b)14'. Energies are in kJ mol-'
acyl cations the carbonyl component undergoes the initial activation, i.e. the reaction follows path a14'. The structures of the 2-oxazolinium, 1,3,5-oxadiazinium and 3-azapyrylium salts obtained by means of electrophilic catalysis by acylium ion^"'^,^'^ point to the fact that their formation proceeds not via N,N-bis-acyliminium ions 332 and 333, but via the N-acyliminium ions 322 (i.e. those protonated at the nitrogen atom). In our opinion142,the acetoxy azaallenium ions 335 can be transformed to the N-acyliminium cations 337 by a deacylation t o the N-acylimines 336, followed by protonation of the latter (equation 91). Such a process is quite possible under the conditions used for
FIGURE 9. Geometries and energies of: (a) carboxonium cation 334 and (b) the transition state for the rearrangement 334 -332, calculated by the AM 1 method'42. The AH, values are in kJ m o l l , bond lengths in A and angles in deg
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles R1
OAc
bk=( R2
R3 (335)
0
R'
RI
& ~ q )+'
R2
R3
H (91)
\
R2
(336)
1493
COR3
(337)
generating the acyl cations (perchloric acid-acetic anhydride mixture). It is known that N-acylimines can be protonated at the nitrogen a t ~ m ~ . ' ~ ~ . ' ~ ' . However, if no protons are present in the reaction mixture, then a thermodynamically favored intramolecular transfer of the allylic hydrogen in 338 to the nitrogen atom to form the 2-azabutadienium ions 339 is possible (equation 92)148.
The formation of N-acylenamine 131 by the reaction of N-acetylbenzonitrilium hexachloroantimonate 340 with isobutyrophenone 129 is explained by a similar hydrogen transfer'42 (equation 93). The catalytic effect of acylium ions in this reaction is seen by comparison with the same reaction in the presence of trifluoromethanesulfonic acid (see equation 44).
Ph SKI6e OCOMe
M
(341) PhCN
1
2 0 T . 30 min
Ph Ph 1 + 1 Me2CHC=N=COCOMe
~ e '
NHCOPh
SbC16-
(93)
1494
S. M. Lukyanov
C. Rearrangements during Formation of NAcylenamlnes
As indicated by the experimental and theoretical results described above, both pathways a and b of reaction of carbonyl compounds with nitriles (equation 77) include two variants of the rearrangement of nitrilium salts having an oxygen function at u-position (285) and a-iminoalkyloxycarbenium ions 288. Both rearrangements lead to N-acyliminium cations 289; see equation 94.
Jochims and coworker^^^.'^^.'^^ (cf equations 79, 80 and 84) as well as Lukyanov and colleague^"^ (cf equation 15) suggested that oxazetium salts like 344 and 346 are intermediates (or transition states) in these rearrangements. However, at the same time the opinion was advanced13' that the conversions of both nitrilium ions 285 and carboxonium ones 288 into N-acyliminium cations 289 are a second type of acidcatalyzed rearrangement of carbonyl compounds. Thefirst type of such rearrangements includes migration to an atom having a sextet of electrons in which the migrating group plays the role of an internal nucleophile attacking the carbenium center in ions 118, 126, 170, 176, 348, 351 and 354. This type of isomerization includes the retropinacol rearrangement via acyloxycarbenium and
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
1495
N-acyliminium ions (equations 41,43, 55 and 56); Danilov rearrangement of aldehydes 347 into ketones 349149(equation 95), the acyloin rearrangement 350 + 35290(equation 96) and dienone-phenol rearrangement 35>355IS0 (equation 97). The rearrangements of the second type also proceed with the participation of the internal nucleophile but the latter was formerly the electrophilic moiety 356 which was added to carbonyl oxygen atom to form the carbenium center on the carbonyl carbon atom"'. 356 contains the heteroatom having the n-electrons, and the intramolecular nucleophilic attack of the carbenium center proceeds according to the general scheme shown in equation 98. A number of reactions, namely the conversion of ketones into chlorocarbenium ions 357'" (equation 99) as well as reaction of carbonyl compounds with 1-oxa-2-azaallenium ions 358 behaving like acyl cations giving 359 (equation 100)148can be classified under this second type.
A simple approach to the 2-azaallenium ions 361, based on the reaction of carbonyl compounds with chlorocarbonyl isocyanates 360, was des~ribed"~.No mechanism for this reaction was suggested, but the scheme displayed in equation 101 can apply based on the considerations stated aboves6. The quite general character of this classification may be illustrated by another reaction, the formation of the heteroanalogs of N-acyliminium ions 362lS3(equation 102). The third type of acid-catalyzed rearrangement of carbonyl compounds, being a part of the classification proposed"', should he mentioned in order to complete the picture.
1496
S. M. Lukyanov
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
1497
In this case the carboxonium ion captures an external nucleophile which gains electrophilic properties due to this addition. The reaction of carbonyl compounds with nitriles stimulating by acylium ions14' (equation 103) as well as the known synthesis of chalcones 363 from aldehydes and acetylenes154(equation 104) belong to this type of rearrangement.
RLR2C0+ R3CO+
-
Based on these results it was c o n c l ~ d e d ~that ~,'~ the ~ acid-catalyzed reaction of carbonyl compounds with nitriles cannot be considered, in general, to be a variant of the Ritter reaction, in contrast to earlier proposals. In order to confirm this conclusion the following arguments were presented: The reaction differs from the Ritter reaction by the two types of electrophilic activation of the reagents and by the two types of rearrangement of nitrilium 285 and carboxonium ions 288 (equation 94). Besides, this interaction proceeds at an oxidation level of two, while the Ritter reaction occurs at an oxidation level of one". While it may be shown that N-acyliminium ions 365 can be obtained from a carbonyl compound and a nitrile via the Ritter reaction, then it is only the second step (b)in a three-step process where the first step (a) is the reduction of carbonyl compound 364 to alcohol 366 and the third step (c) is an oxidative dehydrogenation of amide 369 obtained3 (equation 105). The Ritter reaction proper is represented here by the conversion 366 + 367 + 368 + 369. In this scheme two changes between the oxidation levels 2 and level 1 (364 + 366 and 369 + 365) are obvious. The figures 1 and 2 on the carbons of ketone 364 and alcohol 366 correspond to the oxidation levels of these carbon atoms".
S. M. Lukyanov
VI. POLYFUNCTIONALIZED ENAMINES
Besides N-acylated enamines, enamides containing a functional group in the carbon skeleton are obtained in the acid-catalyzed reactions of carbonyl compounds with nitriles. Some of them were shown in equations 18, 28, 31, 33, 38, 58, 59, 63, 65, 75 and 87 and they are mainly the polyacylated enamines (e.g. P-acylaminovinyl ketones 79,87, 93, 200, 207 and 278). Most of them are intermediates in the synthesis of oxygen and nitrogen containing heterocycles or products of further conversions of the latter. In this connection the heterocyclic 3-azapyrylium system formed by acylation of both ketones and vinyl chlorides in nitrile solutions is most interesting (see Sections III.B.3 and IV). As shown above, the hydrolysis of 3-azapyrylium salts is accompanied by ring-opening to afford the double-acylated enamines, P-acylaminovinyl ketones (200,
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
1499
equation 63; 207, equation 6 5 ; 278, equation 75)58,116.125. The azomethine derivatives 371 of P-acylaminovinyl ketone, which is converted into pyrimidinium perchlorates 372, were obtained by treatment of 2,4,6-triphenyl-3-azapyryliumperchlorate 370 with primary amines118 (equation 106). The corresponding 1-acylaminovinyl ketones are intermediates in the transformation of the 3-azapyrylium salts into 3-azathiapyrylium (1,3-thiazin-1-ium119) ions121. Polyunsaturated enamides are isolable in reactions of salts 48 with active methylene compounds5' (equation 18). The action of bases on 4-alkyl-substituted 3-azapyrylium salts 373 leads to 4-alkylidene-1,3-oxazines374'". These anhydro bases can be regarded as cyclic enamides. It has been shownlzz that the treatment of 4-alkylidene-benzo-l,3oxazines 375 with acids results in protonation of the nitrogen to give 376 rather than at the alkylidene group (equation 107).
As shown recently155,refluxing 6-methyl-substituted 3-azapyrylium perchlorates 377 in DMF/AczO mixture gives the pyrido[1,2-c]pyrimidinium salts 379, while when carrying out this reaction at 20°C it gives the ,!I-acylaminovinyl pyridines 380. The authors assume that formation of anhydro base 378 takes place initially, and then 378 reacts with another molecule of 377155.The same products 379 and 380 were isolated from the condensation of 6-methylene-1,3-oxadnes 378 with 3-azapyrylium salts 377 prepared beforehandlS5 (equation 108). The structure of 379 (R = Et) was established by X-ray crystallography. 5,6-Dimethyl-2,4-diphenyl-3-azapyryliumperchlorate 381 is converted under the Vilsmeier-Haack reaction conditions into the N,N-dimethylaminovinyl derivative 382. By refluxing 382 in acetic acid mixed with either ammonium acetate or p-toluidine, compound 383 was obtained by an unusual recyclization via elimination of the N,N-dimethylaminovinyl group (equation 109).
S. M. Lukyanov
1500
R
Ph
NHCOPh
Ph
Ph CIO4-
24. Synthesis of N-acylenamines from carbonyl compounds and nitriles
1501
R =Me, t-Bu, Ph; R' = H, Me; R2 = Me, Ph
Recently, the surprising ability of 4-alkyl-substituted 3-azapyrylium salts to undergo acylation at the 4-alkyl group by acylium cations was dis~overed'~'.This reaction gives 4-acylmethyl-3-azapyrylium salts 385 (equation 110). By comparing the spectral characteristics of 385 with those of model compounds 388 and 391 (equation 111) it was shown15' that salts 385 exist preferably in the enol form 386. This conclusion is confirmed also by AM 1 quantum-chemical calculations. The authors believe15' that the electrophilic attack at the 4-methyl group of 3azapyrylium cation 384 becomes possible due to the intramolecular transfer of hydrogen
1502
S. M. Lukyanov
(395)
C 1 0 ~
(393)
1
(394)
HC104 -H20
R' = H, Me; R2 = Me, Ph; R3 = Me, Et
(1 13)
NHCOR~
I
NHCOPh
(397) R = Me, Ph; R1 = Me, t-Bu atom from the 4-methyl group to the nitrogen atom (cf equation 107 and Reference 122), leading to the charged anhydro base 392 (equation 112). This assumption is in agreement with the stability of the analogous N-ethyl-4-methylene-4H-1,3-oxazinium salt 301 which was isolated (equation 82). In that way, functionalization of the end-alkyl group of 1,3-diketones to form the 1,3,5-triketone derivatives 389 is possible via 3-azapyrylium salts which are, in essence, the masked forms of 1,3-diketones. Such enamines 395 which are tri-acylated derivatives are intermediates in the new recyclization of compounds 394 and 386 to 4-acylaminopyrylium salts 396 and 397' 5 7 (equations 113 and 114). The pyrylium salts can be easily ring-opened by hydrolysis to yield 1,s-pentened i o n e ~ " ~Consequently, . 4-acylaminopyrylium salts 396 and 397 can he precursors to enamides 395. It should be expected that P-acylaminovinyl ketones (e.g. 207 and 278) obtained by other methods ( e g by N-acylation of en am in one^'^^,'^^) can be converted into 3-azapyrylium salts1l6 and, by the reaction described above, they can undergo the functionalization together with lengthening of the linear carbon chain.
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90. C. K. Ingold, Srrucrure and Mechanism in Organic Chemistry, Cornell University Press, Ithaca, London, 1969. Izdatelstvo Nauka, Moscow, 1965; 91. A. P. Orechov, Vnutrimolekuiarnvie .. Peregruppirovki, - .. Chem. Abstr., 64, 15682~(1966). 92. S. M. Lukyanov, S. V. Borodaev and S. V. Borodaeva, Zh. Org. Khim., 19, 2154 (1983); J. Org. Chem. USSR (Engl. TransL), 19, 1872 (1983). 93. S. V. Borodaev. S. M. Lukvanov and Yu. A. Zhdanov. Dokl. Akad. Nauk SSSR. 287. 862 (1986); Chem. kbstr., 106, fi6217x (1987). 94. Yu. A. Zhdanov, S. M. Lukyanov, S. V. Borodaev and S. V. Borodaeva, Zh. Org. Khim., 22, 1173 (1986); J. Org. Chem. USSR (Engl. Transl.), 22, 1055 (1986). 95. W. Ziclinski, Pol. J. Chem., 56, 93 (1982). 96. W. Zielinski, Heterocycles, 23, 1639 (1985). 97. A. Garcia, E. Lete, M. J. Villa, E. Dominguez and M. D. Badia, Tetrahedron,44,6681 (1988). 98. S. Auricchio, 0 . Vaina De Pava and E. Vera, Synthesis, 116 (1979). 99. N. V. Sotnikov, V. 1. Gorban, G. A. Sokolskii and 1. L. Knunyanz, Izv. Akad. Nauk SSSR, Ser. Khim., 1671 (1980); Chem. Abslr., 94, 15690q (1981). 100. K. Burger and R. Simmerl, Justus Liebigs Ann. Chem., 982 (1984). 101. K. Burger and R. Simmerl, Synthesis, 237 (1983). 102. S. V. Borodaev, N. V. Shibaeva, 0. V. Zubkova, A. P. Knyazev, S. M. Lukyanov and A. I. Pyshchev, Zh. Org. Khim., 25, 2416 (1989); Chem. Abstr., 113, 227081 (1990). 103. S. V. Borodaev, Candidate Thesis, Rostov State University, Rostov-on-Don, Russia, 1985. 104. Yu. A. Zhdanov, S. M. Lukyanov, S. V. Borodaev and S. V. Borodaeva, Zh. Org. Khim., 22, 2376 (1986); J. Org. Chem. USSR (Engl. Transl.) 22, 2135 (1986). 105. S. M. Lukyanov and S. V. Borodaev, Zh. Org. Khim., 19, 458 (1983); J. Org. Chem. USSR (Engl. ~ruhsl.),19, 400 (1983). 106. Yu. A. Zhdanov, S. M. Lukyanov, S. V. Borodaev, Zh. Org. Khim., 21, 2067 (1985); J. Org. Chem. USSR ,(Enai. " Trans/.). 21. 1892 (1985). 107. G. N. Dorofeenko, S. M. ~ " k ~ a n oand v T. 1: Davidenko, Zh. Org. Khim., 11, 163 (1975); J. Org. Chem. USSR (Engl. Trans/.), 11, 159 (1975). 108. S. M. Lukyanov, L. N. Etmetchenko, A. V. Koblik, 0. A. Rakina and G. N. Dorofeenko, Zh. Org. Khim., 13, 287 (1977); J. Org. Chem. USSR (Engl. TransL) 13, 258 (1977). 109. T:L. Ho and G. A. Olah, Synthesis, 418 (1977). 110. M. E. Kletskii, S. M. Lukyanov, S. V. Borodaev, R. M. Minyaev and V. I. Minkin, Zh. Org. Khim., 25, 1345 (1989); Chem. Abstr., 112, 118037h (1990). 111. T. T. Tidwell, Angew. Chem., 96,16 (1984). 112. S. M. Lukyanov, S. V. Borodaev, S. B. Polovinko, A. G. Starikov and 0. V. Zubkova, Zh. Org. Khim., 27, 1588 (1991); Chern. Ahlr., 116, 128578a (1992). 113. N. V. Shibaeva, S. V. Borodaev, A. I. Pyshchev and S. M. Lukyanov, Zh. Org. Khim., 24, 2232 (1988); Chem. Abslr., 110, 212727g (1989). 114. G. N. Dorofeenko, E. I. Demidenko and S. V. Krivun, Izv. Vyssh. Ucheb. Zaved. Khim. Khim. Tekhnol., 10, 304 (1967); Chem. Abstr., 68, 29529u (1968). 115. A. T. Balaban, W. Schroth and G. Fischer, Adv. Heterocycl. Chem., 10, 307 (1969). 116. N. V. Shibaeva, S. V. Borodaev, A. 1. Pyshchev and S. M. Lukyanov, Zh. Org. Khim., 24, 1561 (1988); Chem. Absrr., 110, 2127191 (1989). 117. S. V. Borodaev, 0. V. Zubkova, N. V. Shibaeva, A. P. Knyazev, A. I. Pyshchev and S. M. Lukyanov, Zh. Org. Khim., 27, 1986 (1991); Chem. Ahstr., 117, 111546m (1992). 118. I. Shibuya, Bull. Chem. Soc. Jpn., 54, 2387 (1981). 119. I. Shibuya, Technocrat, 16, 27 (1983). 120. R. R. Schmidt, Tetrahedron Lett., 4357 (1965). 121. R. R. Schmidt and D. Schwille, Chem. Ber., 102, 269 (1969). 122. R. R. Schmidt, D. Schwille and H. Wolf, Chem. Ber., 103, 2760 (1970). 123. M. Sainsbury, in Comprehensive Heterocyclic Chemistry, Vol. 3 (Eds. A. R. Katritzky and C. W. Rees), Pergamon Press, New York, 1984, pp. 995-1038. 124. I. Shibuya, Bull. Chem. Soc. Jpn., 52, 3767 (1979). 125. 1. D. Gridnev and E. S. Balenkova,Zh. Org. Khim., 24,1605 (1988); Chem. Abstr., 110,192384n (1989). 126. J. ~ a t h i e u R. , Panico and J. Weill-Raynal, L 'Amenagement Fonctionnel en Synthese Organique, Hermann, Paris.
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,
Lithium enamides-lithium salts of azomethine derivatives SHIMON SHATZMILLER and RAM1 LIDOR The Beverly and Raymond Sackler Faculty of Exact Sciences. School of Chemistrv. Tel-Aviv University. Ramat-Aviv. Tel-Aviv 69978. Israel
I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1507 11. SALTS O F IMINES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1508 111. REGIOSELECTIVITY IN ELECTROPHILIC REACTIONS AT THE a-CARBON O F IMINES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1511 IV. STEREOSELECTIVITY IN ELECTROPHILIC REACTIONS AT THE a-CARBON O F IMINES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1512 v. AMIDES, ELECTROPHILIC REGIO AND STEREOSELECTIVE REACTIONS AT THE &-CARBON. . . . . . . . . . . . . . . . . . . . . . . . . 1514 VI. AMIDOESTERS. STEREOSELECTIVE, REGIOSELECTIVE AND ELECTROPHILIC REACTIONS AT THE a-CARBON . . . . . . . . . . 1516 VII. HYDRAZONES. ELECTROPHILIC-REACTIONS AT THE aCARBON O F HYDRAZONES . . . . . . . . . . . . . . . . . . . . . . . . . 1519 VIII. ELECTROPHILIC REACTIONS ON 1,CDIMETALLO-NPHENYLHYDRAZONES . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1520 IX. STEREOSELECTIVITY IN ELECTROPHILIC REACTIONS AT THE a-CARBON O F HYDRAZONES . . . . . . . . . . . . . . . . . . . . . . . . 1522 X. OXIMES. REGIOSELECTIVE AND STEREOSELECTIVE REACTIONS AT THE a-CARBON . . . . . . . . . . . . . . . . . . . . . . 1524 XI. OPEN-CHAIN OXIME ETHERS. ELECTROPHILIC REGIOAND STEREOSPECIFIC REACTIONS AT THE a-CARBON . . . . . . 1526 XII. CYCLIC OXIME ETHERS AS HETEROCYCLIC SYSTEMS WITH LATERAL FUNCTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1529 XIII. MISCELLANEOUS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1529 XIV. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1531 -
~
-
I. INTRODUCTION
The alkaline metal salts 2 of the carbonyl system 1 are characterized by the problem of enolate ion am bid en tit^"^ (equation 1). The lithium enolate hybrid 3 is one extreme The Clzemisty of Enamines. Edited by Zvi Rappoport Copyright O I994 John Wilcy & Sons, I.td. ERN: 0-471-93339-2
1507
S. Shatzmiller and R. Lidor
reprcscntative of the lithium salt 2 - 3 derived from the carbonyl compound. Formation of dilithium salts derived from a-halo carbonyl compounds is also possible (equation 2). Enolate anions exist in solution as tetrameric aggregates. The regioselectivity in reaction of 3 with e l e ~ t r o p h i l e s ~is~only - ~ ~partially solved. However, many procedures exist in the literature for carbon-carbon bond-forming reactions. For stereoselective carbon-carbon bond formation using 3, a general way does not exist. These disadvantages brought synthetic chemists to search for other solutions of the problem. One ~ o l u t i o n is ~ ~to- form ~ ~ ketone analogs by derivatizing the ketone with an appropriate amine such as primary amine, hydrazine and hydroxylamine derivatives to form azomethine derivatives 6 (equation 3). The derived anion 8 is the nitrogen analog of the lithium enolate 3. As in enolates, the lithio enamine 8 represents an extreme structure of the lithium salt of the carbon acid 6, to which 8 is the main hybrid contributor. The synthetic uses of 7 ++ 8 will be reviewed. Since azomethine derivatives 6 are the nitrogen analogs of carbonyl derivatives, related species such as the anions derived from imines, hydrazones, oximes, oxime ethers and amides will be also discussed.
II. SALTS OF MINES
Replacing the 0 atom of the aldehyde 9 by an N-R affords the simplest nitrogen carbonyl analog-the aldimine 10. In trying to overcome a few of the problems in alkylation reactions at the u-carbons of aldehydes and ketones (for example 9 + 13; equation 4) Stork and coworkers studied imines derived from enolizable aldehydes (evolved in the reaction with primary aliphatic amines)"". Stork found that, in contrast to C = O compounds, the reaction with ethylmagnesium bromide in T H F with 10 results in anionization forming 11. The magnesium salt 11, in reaction with primary and secondary alkyl halides, tends to form the alkylated enamine 12 which, after acid hydrolysis, gives monosubstituted carbonyl compounds (13) in high yield (equation 4). The advantage of this reaction is in obtaining only monoalkylation products. When the question of regioselective alkylation in asymmetrical ketones of imines emerged, it was found that under these conditions the products of alkylation at the less substituted carbon are preferred (70-85%).
25. Lithium enamides-lithium
salts of azomethine derivatives
X = Br, Cl
Similarly, the enamine salt 15 is obtained by lithiation of 14 (equation 5). In both cases the lower steric hindrance leads to higher stability of the enaminic system33 where the double bond is formed on the less substituted carbon. The N-metalated enamines 11 and 15 arc cnolatc analogs and thcir contribution to thc rcspcctive tautomer mixture of the lithium salts of azomethine derivatives will be discussed below. Normant and coworkers34 also reported complete regioselectivity in alkylations of ketimines that are derived from methyl ketones. The base for this lithiation is an active dialkylamide -the product of reaction of metallic lithium with dialkylamine in benzene/HMPA. Under these conditions ('hyperbasic media'), the iminc compound of mcthyl ketones 14 loses a proton from the methyl group and the lithium salt 15 reacts with various electrophiles or is oxidized with iodine to yield, after hydrolysis, 16 and 17, respectively (equation 5). Another use of imines is in a directed aldol condensation reaction, directing the condensation in a way that the aldehyde, after reacting with the base, will react with the other carbonyl compound, with no self-condensation. Imines, in contrast to their precursors, aldehydes, are too weak electrophiles to undergo self-condensation. However, after lithiation with LDA, the lithium salts 19 are sufficiently good nucleophiles to react
1510
S. Shatzmiller and R. Lidor
CH3-CH=N-R (18)
-
CH2=CH-NLi-R (1%
R'COR"
R'
I I
R2-C-CH2-CH=NR
(6)
OLi (20)
with inert carbonyl compounds like ketones to give 20. Wittig and Reiff35 used these facts in order to get directed aldol condensations (equation 6). The ability of the aldimine system to lose an a proton to a base becomes weaker as the u-carbon becomes more substituted; e.g. in the diethylacetaldimine case, there is no reaction. A studyj5<j6concerning the ambidentity of the lithium salts of imines resulted in the discovery that the lithium is bonded to the nitrogen, e.g. compare 8 (equation 3). However, the evolution of the products on the carbon or nitrogen is influenced by the nature of the electrophile: reactants like methyl iodide that ionize with difficulty will form a six-centered transition state 21 where the C-alkylation product will be evolved after elimination of lithium iodide. In the same way, the intermediate in aldol condensation is 22.
O n the other hand, for more easily ionizable electrophiles, like ethyl chloroformate or benzoyl chloride, the first reaction stage is ionization with formation of lithium chloride and a carbocation. The latter then reacts with the atom of highest electron density in the ambident anion, namely, with the nitrogen atom. A similar use of aldimines for the synthesis of a$-unsaturated aldehydes was reported by Corey and coworkers37 and by Nagata and coworkers38. All the investigations that have been performed so far suffer from the fact that the deprotonation of the imines by strong bascs gives metalation-aftcr which an clcctrophilic reaction takes place on the less substituted a-carbon. Lithiation that does not depend on the degree of substitution on the a-carbon was developed by Wender and coworker^^^^^^ using u,B- unsaturated ketones 23 via 24, 25 and the lithium salt 26 (equation 7) or primary ally1 imines via 29, 30 and the lithium salt 31 (equation 8). The products 27 and 32 are obtained after alkylation and hydrolysis.
25. Lithium enamides-lithium
salts of azomethine derivatives
1511
The success of the imines of ketones and aldehydes to prevent dialkylation of the carbon brought Stork and Benaim to investigate this method also in a$-unsaturated ketones. It was found that those ketimines that undergo lithiation with LDA give the monoalkylation product on reacting with mcthyl iodide4' (equation 9).
Ill. REGlOSELECTlVlTY IN ELECTROPHILIC REACTIONS AT THE a-CARBON OF IMINES
In the synthesis with imines, the configuration of the imine group can also be of importance. Fraser and coworkers checked the rate of H-D exchange of acetone-Nbenzyl ketimine in the presence of t-BuOK, and found that the a-syn isomer exchanged 50-fold faster than the a-unti isomer at 20 "C. In cyclohexanone imine, it was found that the lithiation and alkylation processes are stereoselective, so that the alkyl group attacks at the syn position, axial in the ketimine ring4'. This fact fits the findings of Spencer ~ ~ . findings, and coworkers about the preference for the a-axial proton a b ~ t r a c t i o nThese as well as the stability of the syn lithium aldimine that was measured by Fraser and B a n ~ i l l e point ~ ~ , to the presence of stabilizing effects of the syn lithium imine. As will be shown for other analogous carbonyl derivatives (like the hydrazones and oximes)
1512
S. Shatzmiller and R. Lidor
that underwent methylation, there indeed exists a syn stabilization that is explained in two ways: (a) the symmetry of the orbitals and (b) a chelation effect. (a) The electron configuration of the anion 33 (and therefore also of the transition state for its formation) include six n-electrons (see below), in a configuration that allows long-range nonbonded attractive interactions between the ar-carbon and heteroatom Z45. The symmetry of the fragment orbitals of the terminal groups ( C and Z ) allows a \ 1 more favorable interaction with the n and n* orbitals of the X=Y fragment in the syn than in the anti structure. X
Y
Z
References
OR S NR2
46 41% 47 48 49 50 51 52, 37 51c. 53
NTs
OR 0NR2 0
(b) In a chelate, polar groups are bonded to the ar-carbon and the heteroatom Z (e.g. nitrogen) by the metal as in A be lo^^^-^^. A nonchelated arrangement is shown in B. These two effects seem to be only vaguely capable of explaining the stereoselectivity in alkylation of the imine system (conjugation across the ends of 33 is possible only if the symmetry of the orbitals is proper and chelation is not possible in the system. However, the bonding of four nuclei by six electrons seem to be a stabilizing factor.
IV. STEREOSELECTIVITY IN ELECTROPHILIC REACTIONS AT THE u-CARBON OF IMINES
In view of the selectivity of lithiation of the imine system, to get u-syn deprotonation and subsequently substitution, Fraser investigated the scope of asymmetric induction of a chiral imine, i.e. cyclohexenone imine, that derives from N-u-phenethylamine 34. O n alkylation by McI or EtI, he obtained u-substituted cyclohexanones in ee of 50%66. Ma-Jacheet and Horeau6' and Yamada and c o ~ o r k e r s who ~ ~ , used this technique, obtained 2 5 4 5 % ee. Free rotation around the C-N bond, as well as the lack of control of the configuration of the alkylation product, were the reasons ascribed for the low amount of asymmetric induction. A better enantioselectivity was achieved when the imine had an inner ligand (OMe), that makes the lithioenamine 35 more rigid by intramolecular chelation. The spatial structure of this compound affects the direction of the electrophilic attack. Meyers and coworkers, who used this amine, obtained a substituted cyclohexanone in enantiomeric purity of 87-100%69. These results were obtained in rigid metaloenaminic
25. Lithium enamides-lithium
salts of azomethine derivatives
1513
systems of cyclohexanone. Several chiral amines with oxygen containing ligands such as those shown below can serve for the formation of chiral azomethine derivatives.
I
OBu
I
NH2 OMe
R = t-Bu, i-PI
In another work, Meyers and coworkers found that in asymmetric synthesis of macrocyclic ketones and cc-alkyl ketones by using chiral imines, two intermediate lithioenamines were obtained73. One of them was formed in the reaction with LDA at - 30 "C and is the kinetically controlled E-isomer 36. The second product formed on reflux with LDA is the Z-isomer 37, which is the thermodynamically more stable isomer. Both formed anion 38 on heating (equation 10).
Newcomb studied the transition from type 36 to 37 by temperature-dependent NMR of the aldimines, and found that for t-butyl acetaldimine there is a free rotation around the C=C bond on the N M R scale at - 77 "C74(equation 11). Methylation of 36 and 37 should have given a different enantiomer in each case. However, while one enantiomer was formed (after hydrolysis) in high optical yield (95%
1514
S. Shatzmiller and R. Lidor
ee) from 37, 36 gave the same enantiomer with low optical purity of 30% ee. Spatial interaction between the vinylic part and the aminic moieties in lithioenamine 36 causes its opening to the lithium azaallyl cation 38 that loses its rigidity and hence also its stereoselective properties. In contrast, 37 resembles the intermediate formed in the case of lithiocyclohexanone imine.
V. AMIDES. ELECTROPHILIC REGIO- AND STEREOSELECTIVE REACTIONS AT THE a-CARBON
In 1964, Hauser and coworkers used aryl amides for electrophilic reactions on the aromatic ring75. N-Methylbenzamide underwent dilithiation to give, after reacting with electrophiles, the orthu alkylamide compound 39. In those conditions, N-methyl ortho toluimide reacts with electrophiles on the urtho methyl group via the dililhium derivative 40 to give product 41 (equation 12).
Deactivation of the amide carbonyl by N-lithiation directs the second lithiation to the ortho position to the amide group. The dilithio compound is stabilized by intramolecular chelation. Larcheveque and coworkers used a chiral amide that was obtained from the reaction between an optically active epihydrin and an anhydride for the asymmetric synthesis of ketones or of substituted acids76 (equation 13). The epihydrin has a n hydroxyl group that allows intramolecular chelation of the anion, thus enabling one to bring a chiral nucleophile, that is responsible for the enantioselective synthesis, to the reaction center. The increase in the size of the cation from LiC to M g + + raises the optical purity of the product, whereas the decomposition to ketone causes some racemization. Enantioselective alkylation of chiral amide enolates was investigated by Evans and Takacs7' and by Sonnet and Heath7', who used amide 42, formed by condensation of an optically active methylol with a substituted acetyl chloride (equation 14).
25. Lithium enamides-lithium
\.-\
H 0
II
salts of azomethine derivatives
Ph
H
Ph
( R ~ C H ~ C+~ OH O
MeHN Me
K 0
2. Mel
I
MeMe
OMe
1515
1516
S. Shatzmiller and R. Lidor
This asymmetric synthesis in a reaction with electrophiles is due to the chirality of the amide enolate created by the generation of intramolecular chelate of the enolate and the oxygen atom. An interesting fact is the effect of the group that participates in the chelation on the induced asymmetric centers. Hydroxyl and methoxyl induce formation of opposing asymmetric centers. Neither this fact nor the mechanism of the reaction and the intermediates involved has been discussed and explained.
VI. AMIDOESTERS. STEREOSELECTIVE, REGIOSELECTIVE AND ELECTROPHILIC
REACTIONS AT THE a-CARBON Stork overcame the dialkylation problem at the a-carbons in aldehydes by using imines. The obvious disadvantages of this method are the unstable starting materials (Schiff bases). Meyers and coworkers found that the stable commercial starting material 2,4,4,6-tetramethyl-5,6-dihydro-1,3-4H-oxazine 43 can be used as a precursor for formation of various aldehydes7'. After lithiation of the methyl group in the 2 position it acts as an excellent nucleophile in reaction with various electrophiles E, and after reducing the double bond and hydrolysis the aldehyde group is formed (equation 15).
Beside the advantage of using commercial starting materials, this method has two other advantages: First, the use of t-BuLi, which is a commercial base that does not need an initial preparation; second, the ability to deuterate or tritiate the aldehyde. Except for the a-alkyl or cy,oc-dialkyl acetaldehyde that emerges in the reaction of the lithium compound 43 with alkyl halides, the reaction with dihaloalkanes can give acyclic aldehydes (by consecutive alkylationssO).The reaction with epoxides gives y-hydroxyaldehydic productss1, and aldol condensations take place in reaction with ketones and aldehydessz. There also are advantages when compared with Wittig's method for oriented aldol condensations, again by the use of commercially available starting precursor and base, by the convenient way of hydrolysis and by the ability of labelling. Other advantages of the oxazine system are the masked carboxyl group, and lack of reactivity with Grignard reagents, enabling synthesis of different carboxyl groups by using Grignard reagentss3 (equation 16). Similar amidoester groups offered Meyers and coworkers new abilities, especially in asymmetric synthesis. The systems discussed here are 1,3-oxazolinic systems that are
25. Lithium enamides-lithium
salts of azomethine derivatives
1517
generated from carboxylic acids and their derivatives when 2-alkyl-4,4-dimethyl-2oxazoline 44 undergoes lithiation with t-BuLi and electrophilic reactions similar to those of the oxazine system. On acid hydrolysis the masked carboxylic group can be revealedE4 (equation 17).
When R f E a chiral acid is created. Meyers and coworkers studied thoroughly synthetic asymmetric processes by heterocyclic systems of type 4485.In the first stage a proper oxazoline 45, which is chiral, cheap and easy to obtain and that after hydrolysis the chiral moiety can be recycled, was chosena6 (equation 18).
After lithiation (LDA), reaction with alkyl halide and hydrolysis, derivatives of a-alkyl acetic acid are obtained with high yield and optical purity of 7CL85%a6,87.In a mechanistic investigation that involved 13C-NMR studies of lithium derivatives of 45,
S. Shatzmiller and R. Lidor
and optical purity measurements of the acid formed as a function of the aminoalcoholic structuregg,the mechanism of equation 19 was established. The lithium salt 46 is present in 95% of the Z configuration and the electrophilic reagent is placed 'under' the surface of the ring, because of steric hindrance of the phenyl group. There is also a possibility of controlling both the configuration of the acid obtained and the optical purity by changing the bulk of R. According to this synthesis, the oxazoline acts as a chiral nucleophile, by rearranging to vinyl oxazoline which then reacts with an alkyl lithiumg9 (equation 20).
1
I . MeOH 2. H30t
The /?$-dialkylacetic acid derivatives were obtained in a very high optical purity (92-99%) for two reasons: (a) Only the E-isomer of the vinyl oxazoline derivative is formed. (b) Attack of the RLi from the 'downward' position. In contrast to the previous case, the presence of the hydrogen instead of the phenyl above the plane of the ring does not change the optical purityg0, but the replacement of the methoxy by hydroxyl reduces remarkably the optical purityy0. These facts point towards an initial bonding of the alkyl lithium to the nitrogen and oxygen, which places the nucleophile below the ring plane. The chiral oxazoline was used by Meyers and Nihelich also in asymmetric synthesis of 2-alkylbutyrolactoney' and by Meyers and Whitten in the synthesis of 3-alkyl v a l e r o l a ~ t o n e ~ ~ .
25. Lithium enamides-lithium
salts of azomethine derivatives
VII. HYDRAZONES. ELECTROPHILIC REACTIONS AT THE &ARBON HYDRAZONES
1519 OF
Until about 30 years ago, hydrazones derived from carbonyl compounds were not used in organic synthesis. They were used only for analytical purposes93, and as protecting groups of aldehydes and ketones94. Corey investigated dimethylhydrazones of ketones and aldehydes with a-hydrogens, and found that they undergo deprotonation with LDA or BuLi in THF at the a-carbons to the hydrazonic moiety in 9G100% yield. The formed lithium compounds, used as enolate anion equivalents, create new carbon-carbon bonds in their reaction with different electrophiles such as alkyl halides or oxiranes, ketones and aldehydess2 (equation 21).
B L H - 7 8 W 2 0 min
/Im
1. CH3CH=CHCH0
n-Pr
2. hvdrolvsis
n-Pr
There are several advantages to the lithium dimethylhydrazone derivatives over the use of enolate anions: (a) They are obtained in high yield. (b) They d o not undergo self-condensation, in contrast to aldol condensation. (c) They are stable at 25 "C in the absence of oxygen and water. (d) They have a higher affinity to electrophiles. (e) Only the products of mono substitution are obtained. These compounds are even better than amines regarding stability, reactivity, chemical yield and stereospecificity. Corey found that the lithiation reaction is very selective, and occurs only on the less substituted carbon, and that in the cyclohexanone there is high preference for axial m e t h y l a t i ~ n(equations ~~ 22 and 23). Besides being an enolate anion equivalent, the lithium dimethylhydrazone can also serve as an acyl carbocation e q ~ i v a l e n t ~(equation '.~~ 24). In this way, the a-substituted
S. Shatzmiller and R. Lidor
1
CuCl2/H20 THF
RLi
(24)
(47) R = Me 90°h COMe 97%
ketones 47, 48 and 49, which are not obtainable directly from the appropriate lithium compounds, can be obtained. Normant and coworkers96 uses the 'activated amide base', also for dimethyl hydrazone derivatives of aldehydes. In the case that these are a straight carbon chain, the a-carbon undergoes lithiation and afterwards alkylation, but when the chain is branched, a nitrile group at the a-carbon is obtained (equation 25). Formation of the nitrile is a result ofthe use of such a strong base that vinylic hydrogen abstraction is possible. When a weaker amide base like LDA is used, the reactants are recovered unchanged. When there is only one a-hydrogen, it can undergo deprotonation after formation of the nitrile (by the amide base that evolves during the reaction), and the anion formed reacts with electrophiles to obtain nitriles substituted at the aposition9' (equation 26). VIII. ELECTROPHILIC REACTIONS ON 1,4-DIMETALLO-N-PHENYLHYDRAZONES
Hauser and coworkers investigated phenylhydrazone derivatives and found that in the reaction with two equivalents of base (BuLi or KNH,), they undergo double metallation
25. Lithium enamides-lithium
salts of azomethine derivatives
1
R1,R2 H; R3 = H, Alkyl
R Z T c E N R3 71-96%
R1 \ CH-CEN R2
+ LiN\
-
1521
E ---N ----
Rz +
-N/
\
Li+C CEN
R3
OH
R4 83-90%
at thc carbon oc to thc hydrazonic group, and on the saturated nitrogen9'. In the same way as found for the 1,3-dianionic (e.g. 1,3-dipotassium acetylacetone) system, the second carbon that undergoes deprotonation is the more nucleophilic, and is the first to react with e l e c t r ~ p h i l i c s This ~ ~ . is exemplified by the double salt of the phenylhydrazone: alkylation at the nitrogen is obtained in reaction of an alkyl halide with the potassium salt of phenylhydrazone, whereas alkylation at thc a-carbon is obtained in the reaction of one equivalent of alkyl halide with the double potassium salt". Naturally, there is a possibility for successive alkylation by different alkyl halides on the nitrogen and afterwards on the carbon in the same reaction, or simultaneous alkylation on two of the nucleophilic atoms98 (equation 27). NNKPh
NNHPh
I . BzCl ( 1 eqj
KNH2 (2 eq)
PhKCH,
ph
2. N H d 3
1
BzCl(2 eqj
* Ph
S. Shatzmiller and R. Lidor NNKPh
NNHPh
NNHPh
It is possible to couple two phenylhydrazones by reacting the double salt with a d i h a l ~ a l k a n e(equation ~~ 28). Another electrophilic reaction of the double salt is with carbonyl compounds: on addition to benzophenone, the appropriate hydroxyphenylhydrazone 50 is obtainedloO. When the electrophile is an aroyl chloride, Cacetylpyrazole 51 is obtainedlo1 whereas reaction with an csterlo2 or with an aromatic nitrilelo3 gives pyrazole derivatives by addition, followed by an intramolecular cyclization (equation 29). NLi
(29) Ar
OH
Ar
H+
Ar
NNHAr'
Ar
I Ar'
I Af (51)
(50)
IX. STEREOSELECTIVITY IN ELECTROPHILIC REACTIONS AT THE a-CARBON OF HYDRAZONES
Similarly to the asymmetric synthesis by imines and oxazoline, there is also a chiral hydrazone, (S)-1-amino-2-(methoxymethyl)pyrrolidine 51a, which gives chiral hydrazones on reaction with aldehydes and ketoneslo4, and is able to form an intermolecular chelate with the methoxy group. Enders and coworkers used this system for enantioselective aldol reactionlo5, and for synthesis of chiral ketonelo4 and aldehydelo6 (equation 30). In a comprehensive study, using 'H-NMR measurements and trapping product analysis, that was designed for understanding the stcrcoselectivity in electrophilic substitutions of hydrazones that underwent lithiation, it was found that lithium dimcthylhydrazonc salts of aldehydes are obtained as a mixture of two stereoisomers 52 and 53lo7,lo8 (equation 31). When R = Ph, Me& 52 is the main product obtained by deprotonation by conditions (a) or (b). When R = Me, 52 is obtained in 95% yield by deprotonation conditions (a), and 53 is obtained under deprotonation conditions (b). When propionaldehyde is bound to a chiral analog of 52, the stereoselectivity is especially high: under conditions (a), the structure equivalent to 52 is obtained in a yield higher than 98% with E stereochemistry between carbons C, and C, and Z stereochemistry at the Cl-N bond, whereas under conditions (b) >95% of the structure equivalent to 53 ( Z at the Cl-C, bond and E at the C,-N bond) is obtained. The high selectivity is ascribed to the
25. Lithium enamides-lithium
RCH2CH0
salts of azomethine derivatives
1523
*
RR'CHCHO MeU3N HCUn-Pentane or 03/CH2C12/-78T
difference between the two transition states of the deprotonation process in the different solvent systems. In the absence of HMPA in the solution, a 'closed' transition state 54 is obtained for spatial reasons. When HMPA is added to the LDA solution in T H F bcforc thc deprotonation process, thcrc is solvation of the lithium ion, and a n open transition state 55 is obtained. In 54 there is a preference for eclipsed conformation, as R.
H
~ n ~ - ~ Me
Me
I
'Me
1524
S. Shatzmiller and R. Lidor
R is a large known from data on solutions of substituted carbonyl c o r n p ~ u n d s ~ ~When '. group (like phenyl or trimethylsilyl) there is a steric interaction between R and the hydrazonic nitrogen, and this fact explains that under these two sets of conditions structure 52 is mainly obtained. The possibility that HMPA causes a change in the stereochemistry after the deprotonation stage, leading to the thermodynamic equilibrium in both systems of solvents that were checkedllO, was excluded since it was found that no equilibrium is attained, and the products that evolve are formed under kinetic control. As a result of obtaining only one stereoisomer in the deprotonation stage of the two solvent systems, the aldehydes obtained after alkylation and hydrolysis are of opposite chirality. Consequently, it is possible to obtain an inversion of product chirality by a change in the reaction conditions, using the same chiral hydrazonic system. Nevertheless, the electrophilic substitution products are not obtained in equivalent enantiomeric excess, in spite of the high stereoselectivity in the deprotonation process, since the substitution process is so much less selective, i.e. the preference for electrophilic attack from one side of the lithium compound is not ~ o m p l e t e ' ~ ' . X. OXIMES. REGIOSELECTIVE AND STEREOSELECTIVE REACTIONS AT THE a-CARBON
Continuing their work on 1,4-dianions of phenylhydrazone, Hauser and coworkers inspected similar reactions with the 1,4-oxime dianionsg8. Acetophenone oxime gave the dilithium salt in reaction with t-BuLi and underwent C-alkylation with benzyl chloride and dialkylation with 14-dibromohutane (equation 32). Similarly to derivatives phenylhydrazone, 14-dilithio oximes also react with an achiral ester to give a heterocyclic isoxazole ringi0' (equation 33). When two of the a-carbons on an oxime of a ketone are able to undergo deprotonation, the question of the deprotonation site arises. It was found that the regioselectivity in the electrophilic reaction of 1,Cdilithioketoxime salts is especially high and the electrophile reacts with the carbon syn to the oximic oxygen. Kofron and Yeh proved that this is the case by
r-BuLi (2 eq)rCHF
NOH
NOH
NOLi I . Br(CH2J4Br
Ph L ( C H * , A P h 66%
-2.
H+
1;
PhKCH2Li i 4)
4 OH
Ph
Bz 68%
25. Lithium enamides-lithium
salts of azomethine derivatives
1525
consecutive reactions of a dilithium ketoxime with two different alkyl halides. The same ketone was obtained after hydrolysis from another sequence of alkylations5'" (equation 34). Also, when a symmetric oxime underwent alkylation through the 1,Cdilithio derivative, only the thermodynamically less stable oxime, i.e. the one in which the alkyl group is syn to the oxime hydroxyl, was obtained. The regioselectivity was ascribed to chelation that is directing the methylation reagent to the a-carbon syn to the oxime hydroxylS1".
Jung and coworkers51breported an exclusive regioselectivity in alkylation reactions of the dianionic oxime ketone. They showed that a primary o r secondary oxime undergoes lithiation when reacting with two equivalents of t-BuLi for 15 min at 0 "C only when it has a syn geometry. Oxime dianion with an anti configuration is formed after a long time, and in a very low yield (equation 35). The difference in the deprotonation rate of anti and syn oximes, the much higher kinetic acidity of the primary or secondary syn hydrogens than the primary anti hydrogens, and the fact that the anti dianion, in spite of the favorable deprotonation
1526
S. Shatzmiller and R. Lidor
conditions, is obtained only in low yield, hint at a large difference in the thermodynamic acidity of the a-syn hydrogens as compared with the anti hydrogens. The reason for these differences is the formation of a chelate between two negative charges and the metal atom, as well as the electronic stability that evolves from the six-rr-electron ~ y s t e m ~When ~ . ~ the ~ . alkylation products of cyclohexanone oxime were investigated, it was found that the electrophilic reaction of dilithium salts was both regioselective and stereospecific. The electrophile attacks the a-syn-axial position5''. In reduction of oximes by lithium aluminum hydride (LAH), a syn stereospecificity was also observed5' (equation 36).
Tanida and coworkers"' and Landor and c ~ w o r k e r s " ~explain the stereospecificity by a mechanism that initiates in nucleophilic attack of the LAH on the hydroxy group, forming hydrogen and an aluminum-oxime complex (equation 37).
XI. OPEN-CHAIN OXlME ETHERS. ELECTROPHILIC REGIO- AND STEREOSPECIFIC REACTIONS AT THE &-CARBON
After finding that 56 dehydrates faster to 57 than 58 (equation 38), and assuming that in the slow stage of the process an a- hydrogen to the oxime ether group is abstracted, Spencer and Leong investigated the regioselectivity of abstraction of the a-hydrogen from the methyl oxime ether of dibenzyl ketone5'" (equation 39). From 'H-NMR investigation it was stated that the deuterium atom incorporated in the product by deuteration of the anion 59 is bonded to the a-carbon syn to the methoxy
25. Lithium enamides-lithium
salts of azomethine derivatives
1527
1 M NaOH/70"U24 h
1:l H201EtOH
N
I
OMe
OH (56)
I
OMe (57)
N
OMe
group113, and it was suggested that anion 59 is a kinetic deprotonation product. This regiospecificity is due to the electronic structure of 59 in which six n-electrons on four atoms exist in a syn configuration which is assumed to be thermodynamically fa~ o r e d ~Fraser ~ . ~and ~ . haw an^'^ checked the stereochemistry in methylation of several derivatives of cyclohexanone methyl oxime ether 60 and found that only one product, derived from the attack on cc-carbon syn to the oxygen atom, is obtained (equation 40).
Since the methylation of 60 under the same conditions but in the presence of 5-15% crown ether gave the a-syn disubstituted product only in axial position (83% yield), the reason for the stereoselectivity probably lies in the electronic structure of the evolved anion, and not in the formation of a chelate. The stereoselectivity arises from the regioselectivity for the following reasons: (a) The equatorial substituent on a carbon syn to the methoxy group has a large steric interaction with the latter.
S. Shatzmiller and R. Lidor
1528
(b) For stereoelectronic reasons: the system is part of a six-membered ring that enables approach of the electrophile to the a carbon from a perpendicular direction to the six rc-electron system. However, stereoelectronically, the "axial' approach is preferred. Because previous investigations showed that there is no syn-anti isomerization in oxime diani~ns''~,in contrast to dimethylhydrazone anion where a syn-anti mixture gives after lithiation only one (syn)m ~ n o a n i o n ' ~Ensley , and Lohr6' checked the ability of the oxime ether to undergo isomerization of this type. An E and Z mixture of the 2-heptanone tetrahydropyranyl oxime gave, after lithiation and reaction with acetone, a substitution product only on the methyl group (equation 41).
fl
0
?
n
0
0
1 . LDA (1.1 eq)/THF/-50DC/3 h
0
-d0'Me2
2. MeCOMe
When studying the lithiation reactions it was found that from an E and Z mixture of oxime ether 61, syn and anti anions are obtained, but an equilibrium process enriches the Z lithium compound. In the reaction of the lithium salt of 62 with acetone after a short lithiation time of 30min, a 10% or 25% E : Z mixture of 63 was obtained together with the addition product 64 in 65% yield (equation 42)'j5. The formation of only one addition product, and the quick disappearance of the E-isomer, are due to a fast deprotonation process the E-isomer compared with the Z-isomer, and the high rate of equilibration between the lithium compounds that greatly favors the syn anion, which reacts with acetone to give 64. These results point out that the formation of the syn lithium compounds is favored in oxime ethers for kinetic as well as for thermodynamic reasons. The kinetic preference, according to Ensley and Lohr6', is due to coordination between the lithium amide and the oxime oxygen.
0
3
Ph
m
ii (62) E:Z (68:32)
rn
0
0
a
5
1. LDA(1.L eqYTHF 2. MeOH
0
Ph
95% (63) E:Z (955)
A: B: A: B:
E:Z(8020) E > 95% -7S0Cll h -50°C/3 h
(42)
25. Lithium enamides-lithium
salts of azomethine derivatives
1529
XII. CYCLIC OXlME ETHERS AS HETEROCYCLIC SYSTEMS WITH LATERAL FUNCTIONS
Different heterocyclic systems can undergo cleavage reaction that leads to a linear carbon skeleton with functional groups. The easier to get those systems, to modify them and to break them in several ways, the more their diversity. Two systems of cyclic oxime ethers that were studied in this connection are 2-isoxazoline and 1,2-oxazine. The former, which was obtained by 1,3-dipolar cycloaddition of a nitrile oxide, and a substituted double bond1I4,can be cleaved in several ways, in which the latent functions are revealed. One example in which cc$-enoximes and enones114are formed is shown in equation 43.
The generation of the anion on carbon 4 as the initial step for the cleavage to oxime has been proved by deuteration of the isoxazoline where Ph = R' = R 2 and H = R 3 = R4. The process is acylation of the double bond in which no intermediate carbocations are involved. The acylation controlling factor is mainly the steric hindrance which is reflected in the cycloaddition processes of nitrile oxide^"^."^. XIII. MISCELLANEOUS
Lee and coworkers1" used lithium enamines as synthetic intermediates in oxidation reactions with perbenzoic acid for the synthesis of 65 as a main intermediate in the synthesis of tansindiol 66 (equation 44).
S. Shatzmiller and R. Lidor
Hassner and Belinka118generated primary enamines in situ by reaction of vinyl azides 67 with alkyl lithium derivatives and converted them to ketones (equation 45). Duhamel and Poirier119 prepared P-lithioenamines from P-chloroenamines and applied them for a synthesis of hindered ketones (equation 46). Stork and coworkersiz0 studied the X-ray structure of 68 and found it to be dimeric. Knorr and coworker^'^', who examined the X-ray structure of the lithium N-phenylazaallyl derivative 69, concluded that it indicates a contribution of the phenyl ring to the through-space stabilization of the lithium atom.
25. Lithium enamides-lithium
salts of azomethine derivatives
1531
XIV. REFERENCES 1. A. Hassner, J. Org. Chem., 33, 2684 (1968). 2. (a) R. Gompper, Angew. Chem., Int. Ed. Engl., 3, 560 (1964). (b) N. Kornblum, R. H. Smily, R. K. Blackwood and D. C. Iffland, J. Am. Chem. Sac., 77,6269 (1955). 3. E. L. Eliel, Stereochemistry of Carbon Compounds, McGraw-Hill, New York, 1962. 4. L. M. Jackman and B. Lange, Tetrahedron, 33, 2737 (1977). 5. (a) L. M. Jackman and N. M. Szeverenyi, J. Am. Chem. Soc., 99, 4954 (1977). (b) L. M. Jackman and B. C. Lange, J. Am. Chem. Soc., 103,4494 (1981). 6. R. Amstutz, W. B. Schweizer, D. Seebach and J. D. Dunitz, Helv. Chim. Acta, 64,2617 (1981). 7. H. D. Zook, T. J. Russo, E. F. Ferand and D. S. Stotz, J. Org. Chem., 33, 2222 (1968). 8. D. G. Hill, I. Burkus, S. M. Luck and C. R . Hauser, J. Am. Chem. Soc., 81, 2787 (1959). 9. R. M. Fuoss and C. H. Kraus, J. Am. Chem. Soc., 55, 2387 (1933). 10. (a) H. E. Zaugg, B. W. Horrom and S. Borgwardt, J. Am. Chem. Soc., 82,2895 (1960). (b) G. H. Barlow and H. E. Zaugg J. Org. Chem.. 37. 2246 (1972). 11. H. 0 . House, R. A. Auerbach, M. Gall and N. P. Peet, J. Org. Chem., 38, 514 (1973). 12. (a) L. M. Jackman and R. C. Haddon, J. Am. Chem. Soc., 95, 3687 (1973). (b) H. 0. House and B. M. Trost, J. Org. Chem., 30,2502 (1965). 13. H. 0 . House, A. V. Prabhu and W. V. Phillips, J. Org. Chem., 41, 1209 (1976). 14. (a) H. D. Zook and W. L. Gumby, J. Am. Chem. Soc., 82, 1386 (1960). (b) H. D. Zook and T. J. Russo, J. Am. Chem. Sor., 82, 1258 (1960). 15. P. Fellmann and 1.-E. Dubois, Tetrahedron Left., 247 (1977). 16. (a) A. L. Kurts, S. M. Sakembaeva, I. P. Beletskaya and 0. A. Reutov, J. Org. Chem. USSR (Engl. Transl), 9, 1579 (1973). (b) H. D. Zook and J. A. Miller, J. Org. Chem., 36, 1112 (1971). 17. A. L. Kurts, A. Masias, I. P. Beletskaya and 0. A. Ruetov, Tetrahedron, 27,4759 (1971). 18. (a) F. Guib, P. Sarthou and G. Bram, Tetrahedron, 30, 3139 (1974). (b) A. L. Kurts, S. M. Sakembaeva, I. P. Beletskaya and 0. A. Reutov, J. Org. Chem. USSR (Engl. T~ansl.),10, 1588 (1974). 19. H. 0 . House, Rec. Chem. Prog., 28, 99 (1967). 20. (a) F. Chastrette, M. Chastrette and G. Santana-Tavares, Bull. Soc. Chim. Fr., 368 (1973). (b) C. Cambillau, P. Sarthov and G. Bram, Tetrahedron Lett., 281 (1976). 21. M. Yanagita, M. Hirakura and F. Seki, J. Org. Chem., 23, 841 (1958). 22. R. B. Woodward, F. Sondheimer, D. Taub, K. Heusler and W. M. McLamore, J. Am. Chem. Sac., 74, 4223 (1952). 23. W. S. Johnson, J. Am. Chem. Soc., 65, 1317 (1943); 66,215 (1944). 24. la) H. 0. House and B. M. Trost. J. Ora. Chem.. 30. 1341. 2502 11965) id) H. 0.House, L. J. Czuba, gall and H. M. ~ l m s t e h org. ~ ~ .dhem., 34, 2324 (1969). 25. R. E. Schaub, W. Fulmor and M. I. Weiss, Tetrahedron, 20, 373 (1964). 26. T. A. Spencer, R. W. Britton and D. S. Watt, J. Am. Chem. Soc., 89, 373 (1967). 27. C. J. R. Adderley, G. V. Baddeley and F. R. Hewgill, Tetrahedron, 23,4143 (1967). 28. H. M. Smith, B. I. L. Huff, W. I. Powers and D. Laine, J. Org. Chem., 32, 2851 (1967). 29. H. 0. House, M. Gall and H. D. Olmstead, J. Org. Chem., 36, 2361 (1971). 30. I. M. Conia and P. Brict, Bull. Soc. Chim. Fr., 3881, 3888 (1966). 31. (a) H. 0. House, B. A. Tefertiller and H. D. Olmstead, J. Org. Chem., 33,935 (1968). (b) H. 0. House and M. J. Umen, J. Org. Chem., 38, 1000 (1973). 32. (a) S. Dayagi and Y. Degani, in The Chemistry of the Carbon-Nitrogen Double Bond (Ed. S. Patai), Wiley, Chichester, 1970, pp. 6683. (b) R. W. Layer, Chem. Rev., 63, 489 (1963). 33. (a) G. Stork and R. Dowd, J. Am. Chem. Soc., 85,2178 (1963). (b) G. Stork, A. Brizzolarra, H. Landesman, J. Szmuszkovicz and R. Terrele, J. Am. Chem. Soc., 85, 207 (1963). 34. (a) T. Cuvigny, M. Larcheveque and H. Normant, Tetrahedron Lett., 1237 (1974). (b) T. Cuvigny and H. Normant, Synthesis, 198 (1977). (c) M. Larcheveque, G. Valette, T. Cuvigny and H. Normant, Synthesis, 256 (1975). 35. G. Wittig and H. ReiR, Angew. Chem., Int. Ed. Engl., 7, 7 (1968). 36. A. Brandstrom, Ark. Kemi., 6, 155 (1954).
25. Lithium enamides-lithium 76. 77. 78. 79. 80.
salts of azomethine derivatives
1533
M. Larcheveque, E. Ignatora and T. Cuvigny, Tetrahedron Lett., 3961 (1978). D. A. Evans and J. M. Takacs, Tetrahedron Lett., 21, 4233 (1980). P. H. Sonnet and R. R. Heath, J. Org. Chem., 45, 3137 (1980). A. I. Meyers, A. Nabeya, H. W. Adickes and I. R. Polizer, J. Am. Chem. Soc., 91,763 (1969). A. I. Meyers, H. W. Adickes, I. R. Polizer and W. N. Beuerung, J. Am. Chem. Soc., 91, 765 (1969). 81. H. W. Adickes, I. R. Polizer and A. I. Meyers, J. Am. Chem. Soc., 91,2155 (1969). 82. A. I. Meyers, A. Nabeya, I. R. Polizer, H. W. Adickes, J. M. Fitzpatrick and G. R. Malone, J. Am. Chem. Soc., 91, 764 (1969). 83. A. 1. Meyers, I. R. Polizer, B. K. Baudlish and G. R. Malone, J. Am. Chem. Soc., 91,5886(1969). 84. (a) A. 1. Meyers and D. L. Temple, Jr., J. Am. Chem. Soc., 92, 6644 (1979). (b) A. I. Meyers, D. L. Temple, R. L. Nolen and E. D. Mihelick, J. Org. Chem., 39,2778 (1974). 85. A. I. Meyers, Acc. Chem. Res., 11, 375 (1978). 86. A. 1. Meyers, G. Kraus, M. Ford and K. Kamata, J. Am. Chem. Soc., 98, 567 (1976). 87. (a) A. I. Meyers, E. S. Synder and J. J. Ackerman, J. Am. Chem. Soc., 100, 8186 (1978). (b) M. A. Hoobler, D. E. Bergbreiter and M. Newcomb, J Am. Chem. Soc., 100,8182(1978). 88. A. I. Meyers, A. Mazzu and C. E. Whitten, Heterocycles, 6, 971 (1977). 89. A. I. Meyers and C. E. Whitten, J. Am. Chem. Soc., 97, 6266 (1975). 90. A. I. Meyers and C. E. Whitten, Heterocycles, 4, 1687 (1976). 91. A. I. Meyers and E. D. Nihelich, J. Org. Chem., 40, 1186 (1975). 92. A. I. Meyers and C. E. WhitLen, Tetrahedron Lett., 1947 (1976). 93. G. R. Newkome and D. L. Fishel, J. Org. Chem., 31, 677 (1966). 94. A. Avano, J. Levisalles and H. Rudler, Chem. Commun., 445 (1969). 95. E. J. Corey and S. Knapp, Tetrahedron Lett., 3667 (1976). 96. T. Cuivigny, J. F. Le Borgne, M. Larcheveque and H. Normant, Synthesis, 237 (1976). 97. J. F. Le Borgne, T. Cuivigny, M. Larcheveque and H. Normant, Synthesis, 238 (1976). 98. F. E. Henoch, K. G. Hampton and C. R. Hauser, J. Am. Chem. Soc., 91, 676 (1969). 99. C. R. Hauser and T. M. Harris, J. Am. Chem. Soc., 80, 6360 (1958). 100. F. E. Henoch, K. G. Hampton and C. R. Hauser, J. Am. Chem. Soc., 89,463 (1967). 101. C. F. Beam, D. C. Reames, C. E. Harris, L. W. Dasher, W. M. Hollinger, N. L. Shealy, R. M. Sandifer, M. Perkins and C. R. Hauser, J. Org. Chem., 40, 514 (1975). 102. R. S. Foote, C. F. Beam and C. R. Hauser, J. Heterocycl. Chem., 7 , 589 (1970). 103. C. F. Beam, R. C. Foote and C. R. Hauser, J. Heterocycl. Chem., 9, 183 (1972). 104. D. Enders and H. Eichenauer, Angew. Chem., Int. Ed. Engl., 15, 549 (1976). 105. H. Eichenauer, E. Friedrich, W. Lutz and D. Enders, Angew. Chem., Int. Ed. Engl., 17, 206 (1978). 106. D. Enders and H. Eichenauer, Tetrahedron Lett., 191 (1977). 107. K. G. Davenport, H. Eichenauer, D. Enders, M. Newcomb, D. E. Bergbreiter, J..Am. Chem. SOC.,101, 5654 (1979). 108. M. Newcomb and D. E. Bergbreiter, J. Chem. S o c , Chem. Commun., 486 (1977). 109. G. J. Karabatsos and D. J. Fenoglio, Top. Stereochem., 5, 167 (1970). 110. K. G. Devenport, M. Newcomb and D. E. Bergbreiter, J. Org. Chem., 46 3143 (1981). 111. H. Tanida, T. Okada and K. Kotera, Bull. Chem. Soc. Jpn., 46, 934 (1973). 112. S. Landor, 0. 0 . Sonola and A. R. Tatchcll, J. Chem. Soc., Perkin Trans. 1, 1294 (1974). 113. G. J. Karabatsos and H. Hsi, Tetrahedron, 23, 1079 (1967). 114. V. Jaeger and H. Grund, Angew. Chem., Int. Ed. Engl., 15,50 (1976). 115. (a) V. Jaeger, V. Buss and W. Schwab, Tetrahedron Lerr., 3133 (1978). (b) V. Jaeger, W. Schwab and V. Buss, Angew. Chem., Int. Ed. Engl., 20,601 (1981). (c) W. Schwab and V. Jaeger, Angew. Chem., Znt. Ed. Engl., 20, 603 (1981). 116. V. Jaeger, H. Grund and W. Schwab, Angew. Chem., Int. Ed. Engl., 18, 78 (1979). 117. J. Lee, S. Oya and I. K. Snyder, Tetrahedron Lerr., 32, 5899 (1991). 118. A. Hassner and B. A. Belinka, J. Am. Chem. Soc., 102, 6185 (1980). 119. L. Duhamel and J.-M. Poirier, J. Org. Chem., 44, 3585 (1979). 120. R. L. Polt, G. Stork, G. B. Carpenter and P. G. Willard, J. Am. Chem. Soc., 108,4276(1986). 121. H. Dietrich, W. Mahdi and R. Knorr, J. Am. Chem. Soc., 108, 2462 (1986).
Reactions of dienamines P. W. H I C K M O n University of Natal, Durban. South Africa
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PROTONATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ALKYLATION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACYLATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OXIDATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REDUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CARBOCYCLIC SYNTHESIS . . . . . . . . . . . . . . . . . . . . . . . . . A. Three-membered Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Four-membered Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Six-membered Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Seven-membered and Larger Rings . . . . . . . . . . . . . . . . . . . . . VIII. HETEROCYCLIC SYNTHESIS . . . . . . . . . . . . . . . . . . . . . . . . A. Four-membered Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Five-membered Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Six-membered Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IX. MISCELLANEOUS REACTIONS . . . . . . . . . . . . . . . . . . . . . . . X.REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I. 11. 111. IV. V. VI. VII.
1535 1536 1537 1541 1541 1542 1545 1545 1546 1546 1558 1560 1560 1561 1561 1562 1563
I. INTRODUCTION
Dienamines differ from simple enamines in that (i) there is an additional nucleophilic site at the &position and (ii) an equilibrium mixture of three isomeric dienamines is frequently formed, consisting of the linear s-trans isomer 1, the linear s-cis isomer 2 and the cross-conjugated isomer 3' (Scheme 1). A variety of factors influence the outcome of electrophilic attack on such an equilibrium system. Hiickel molecular orbital calculations indicate a significantly higher electron density at the P-positions compared to the &positions of the dienatnine systemZ (Figure 1). It is therefore not surprising that, although N-alkylation, acylation, protonation etc. undoubtedly occurs, the reactions of the majority of electrophilic reagents result in substitution at the P-position. The higher electron density favours initial reaction at this position under conditions of kinetic control. However, where initial reaction at the nitrogen und the P-carbon is reversible, or when the transition state is product-like in character, the operation of thermodynamic control may result in preferential or even The Chemistn of Enamines. Edited by Zvi Rappopon Copyright O 1994 John Wiley & Sons, Ltd. ISBN: 0-471-93339-2
1535
1536
P.W.Hickmott
SCHEME 1
(3)
complete reaction at the &position. A further complication is that the mechanism of a reaction may change, from one of charge control in a protic solvent of high dielectric constant to one of orbital control in an aprotic solvent of low dielectric constant. Quite often the regioselectivity of reaction is therefore solvent-dependent, the same reagent giving entirely different products under different conditions. It is therefore difficult to predict the outcome of a given reaction and complex reaction mixtures are frequently formed. For example, although the cross-conjugated isomer 3 is frequently the minor component of a dienamine mixture, in some 'cases the major product is that derived from reaction of the cross-conjugated dienamine. The interplay of these various factors will be evident in the discussion which follows. II. PROTONATION
The conjugated eniminium salt (4) formed by &protonation of a linear dienamine, or ,!?'-prolonation of a cross-conjugated dienamine, is the favoured product under condi-
FIGURE 1. Calculated charge densities in linear and cross-conjugated dienamines.
26. Reactions of dienamines
(4) SCHEME 2
tions of thermodynamic control3 (Scheme 2). For example, although hydrocyanation of the pyrrolidine dienamine of cholestenone with potassium cyanide and acetic acid gives a mixture of the 3-cyano-3-pyrrolidinyl-A4 and A5-alkenes3",the corresponding reaction of the pyrrolidine dienamine of 19-nortestosterone and hydrogen cyanide and trialkylaluminium or diethylaluminium cyanide gives only the 5-cyano-3-ketone by conjugate addition to the bprotonated or 6-metallated eniminium salt3b(Scheme 3). However, reaction of acyclic dienamines with hydrazoic acid gives a mixture of products derived by 1,2-, 1,4- and 3,4 + 1,Zaddition of HN, to the diene system. In this case C-protonation is followed immediately by addition of the strongly nucleophilic azide anion, so that equilibrium of the C-protonated enamines cannot occur3'. Treatment of the morpholine dienamine of isophorone with trichloroacetic acid in boiling benzene resulted in decarboxylation and the 1,Caddition of a proton and the trichloromethyl anion. Basic hydrolysis of the adduct gave dienoic acid 54 (Scheme 4). which exists primarily The morpholine dienamine of 3,5,5-trimethylcyclopent-2-enone as the linear s-trans dienamine (9&96%) underwent deuteriation at C-2 and C-4, as expected, but the majority of the deuterium was incorporated at C-6 via the small amount of cross-conjugated dienamine in equilibrium with the linear isomer2b. This greater reactivity of the cross-conjugated dienamine presumably reflects the higher electron density at C-8' compared to that at C-P of the linear dienamine (see Figure 1). In the case of acyclic dienamines it is possible that the conjugated eniminium salt is derived directly from the N-protonated dienamine by a [l,S]sigmatropic suprafacial hydrogen transfer, rather than by direct C-6 protonation". Although hydrolysis of dienamines is usually accomplished by means of aqueous sodium acetate-acetic acid buffer1.=,hydrolysis under milder conditions results in a mixture of conjugated and deconjugated unsaturated ketones, the latter presumably being derived from the Pprotonated non-conjugated eniminium salP6. A biogenetic-type cyclization of citral to cc-cyclocitral involves 6-protonation of the derived pyrrolidine trienamine and cyclization of the resulting eniminium salt. Use of optically active trienamines gave optically active S( + )-cc-cy~locitral'.~(Scheme 5). Ill. ALKYLATION
Juliaga, Storkgband Velluz9' and coworkers were the first to show independently that C-p alkylation of dienamines occurred with alkylating agents such as ethyl cc-bromoace-
P. W. Hickmott
Reagents: (i) KCN, HOAc; R = Me, R' = C8HI7; (ii) HCN, AIEt3 or EtzAICN; R = H, R' = OH, L = H or Et2AI SCHEME 3
tate, methyl iodide and 1,3-dichlorobut-2-ene, respectively. This was in contrast to an earlier report by Johnson and coworkers" who found that N-alkylation of A4-3ketosteroid dienamines occurred with methyl iodide. Stork attributed the preference for 8- over 6-alkylation of the dienamine to the lowering of the transition state energy by release of the halide counter anion in close proximity to the positively charged iminium
Reagents: (i) C13CC02H. C6H, 70 "C; (ii) aq. NaOH, A SCHEME 4
26. Reactions of dienamines
Reagents: (i) Conc. HzS04-HzO (10:1), 0 "C, 3 h; (ii) aq. NaOH to pH 3 4 , A SCHEME 5
iongb. Later Pandit and coworkers showed that N-alkylation is favoured by low temperatures but, depending on the nucleophilicity of the counter anion, the N-alkylated product could revert to starting materials at elevated temperatures (160 "C) and thus lead to direct C-alkylationl'. Intramolecular N + C alkyl transfer was specifically excluded (Scheme 6).
I@
\i I
/
R
o@]
H
X-
R
Reagents: (i) RX, 0 "C; (ii) 160 "C; (iii) RX,160 "C; (iv) H 2 0 SCHEME 6
P. W. Hickmott
1540
8-Alkylation also occurs with acetals or trialkyl orthoformates in the presence of Lewis acids, to give the corresponding P,y-unsaturated a-(a-alkoxyalkyl) or a-dialkoxymethyl carbonyl compound, respectively, on hydrolysis". In the corresponding reaction with allylic halides, P-alkylated products were formed by direct C-alkylation as well as by N-alkylation followed by N + C [3,3]sigmatropic
mM; (y"; N
,
N+
:Hz=cHz-
.
z
lii
z
(6)
Reagents: (i) MeOH, A; (ii) CH2=CHZ, C6H6, A; (iii) NaOAc-HOAc-H20, A SCHEME 7
26. Reactions of dienamines
1541
rearrangement, depending on thk amine moiety1'. As stated previou~ly'~, the use of pyrrolidine dienamines favours C-alkylation, whereas morpholine and piperidine dienamines favour the N-alkylation followed by the [3,3]sigmatropic rearrangement pathway. 6-Alkylated products were assumed to arise via a further CP + C6[3,3]sigmatropic rearrangement1'. Methylation and benzylation of the pyrrolidine dienamine of 3-methyl-A1~8"-2-octalone gives a mixture of N- and P-alkylated products in protic and aprotic solvents. However, the position of attack by acrylonitrile and methyl acrylate is solventdependent14. In protic solvents the 0-alkylated octalone is obtained on hydrolysis, whereas in aprotic solvents the 6'-alkylated product is produced (Scheme 7). This change in the regioselectivity arises from the C-3 methyl group being forced into a quasi-axial orientation because of allylic strain in the equatorial orientation. As a consequence the carbanionic centre in the initially formed zwitterion 6 cannot be neutralized by an internal proton transfer of an axial proton at C-3. In protic solvents intermolecular protonation renders the reaction irreversible, but in aprotic solvent reversion to starting material occurs. This allows 6- or 6'-alkylation to occur and this is rendered irreversible by internal proton transfer from the 6'- or 6-position, respectively, to the carbanionic centre in the resulting zwitterion (Scheme 7). The fact that &-attack is preferred over 6-attack is interesting, since this is the only example of 6'-attack of an octalone dienamine that we are aware of. A possible explanation is that 7 arises from [4 + 21 cycloaddition across the a,6'-positions of the linear s-cis dienamine, followed by ring opening (Scheme 8).
SCHEME 8
A similar [4 + 21 cycloaddition across the a,#-positions has been observed in the reaction of isophorone dienamines with electrophilic alkenes (vide infra), and a similar ring opening has been postulated in the reaction of methyl vinyl ketone with dienamines in aprotic media (Section V1I.C). Confirmatory evidence for the role of the C-3 methyl group in the above reaction was obtained from reaction of 8-methyl-A1~sa-2-octalone dienamine with methyl acrylate; only the P-alkylated product was obtained in protic and aprotic solvents14. The reaction of dienamines with electrophilic alkenes is discussed further in the section on carbocyclic synthesis (Section V1I.C). IV. ACYLATION
Surprisingly little work appears to have been published on the acylation of dienamines. Annulations which may be effected with a,/hnsaturated acid chlorides and diketene are discussed in Sections V1I.C and VIILC, respectively. V. OXIDATION
a$-Unsaturated ketones are converted into their y-keto-derivatives in high yield by oxygenation of their derived dienamines under mild conditions in the presence of cuprous, cupric or ferric salts15"(Scheme 9). y-Substituted a$-unsaturated ketones give
P. W. Hickmott
-', i, iii
PI~"NH 0 Reagents: (i) 02,Fe3+or Cuzt; (ii) 0 2 , CuC1; (iii) H30t SCHEME 9
the corresponding y-hydroxy derivative. lmines react similarly via the secondary dienamine tautomer. The preference for attack at the terminal 6-position of the dienamine is presumably due to the intermediacy of radical cation 8. Since evidence exists for the reversibility of the coupling of molecular oxygen with dienylic radicalsL5bthen &attack will be favoured by the thermodynamic stability of the resulting peroxy radical. However, it is not clear whether the product 10 is formed by direct &attack or by initial P-attack followed by rearrangement of the peroxy radical 9 (Scheme 10). Photosensitized oxygenation of dienamines results in cleavage of the Ca-CP bond as in the case of simple enamines, presumably by 1,2-addition of singlet oxygen16. VI. REDUCTION
Sodium borohydride reduction of dienamines in the presence of a weak acid (acetic acid or methanol) results in kinetically favoured C-P protonation followed by rapid hydride addition at C-aL7.The method therefore provides a convenient method for converting an a$-unsaturated ketone into a y,6-unsaturated amine as in the synthesis of connessine17" (Scheme 11). Treatment of dienamines with hot formic acid results in protonation at C-P and C-6 followed by hydride transfer to C-a with elimination of carbon dioxide to give 1,2- and 14-dihydro derivatives1' (Scheme 12).
26. Reactions of dienamines
Reagents: (i) dienamine; (ii) hydrolysis SCHEME 10
SCHEME 11
1543
(10)
1544
P. W. Hickmott
Reagents: (i) HC02H, A (-C02) SCHEME 12
Catalytic hydrogenation gives a mixture of partially reduced products (enamine and allylamine) and/or saturated amine depending on the conditions used19. Partial reduction also occurs on treatment with lithium in ammonia2? Dienamines are resistant to reduction by lithium aluminium hydride2' which therefore provides a means for selective reduction of a less reactive carbonyl group in polyfunctional moleculesz2 (Scheme 13).
1
iii, iv
Reagents: (i) pyrrolidine (one equiv.); (ii) pyrrolidine (excess); (iii) LiAIH4; (iv) hydrolysis SCHEME 13
26. Reactions of dienamines
1545
Biomimetic-type reduction of preformed eniminium salts with the Hantzsch ester or
I-benzyl-1,4-dihydronicotinamideresults in stereospecific formation of cis ring fused ketonesz3 (Scheme 14).
Reagents: (i) pyrrolidine; (ii) 70% HC104-HOAc; (iii) Hantzsch ester or I-benzyl-l,4-dihydronicotinamide, A, 20 h in MeCN: (iv) hydrolysis SCHEME 14
VII. CARBOCYCLIC SYNTHESIS A. Three-membered Rings The reaction of carbenes with dienamines is complex and results in cycloaddition to either or both double bonds (Scheme 15) and ring expansion (see Section V1I.D). Ethoxycarbonylcarbene gives only the b- and 6-ethoxycarbonylmethyl derivatives, presumably by ring opening of the corresponding cycloadductsz4. OAc
t
F
OAc
OAc
F
F
Reagents: (i) CHC12F, BuLi, -15 "C; (ii) H30+ overnight SCHEME 15
F
B. Four-membered Rings
Dimethyl acetylenedicarboxylate reacts with s-cis dienamines to give the cyclobutene adduct or the cyclo-octatriene ring expansion product depending on the nature of the substituent at C-4 of the d i e n a m i n e ~(Scheme ~~ 16).
Reagents: (i) Me02CC32C02Me, 110 "C, 12 h (R = Me); (ii) H30+; (iii) M e 0 2 C C 3 3 3 2 M e , 20 OC, 30 min (R = OMe); (iv) 150 OC; (v) 20 OC SCHEME 16
C. Six-membered Rings
Acyclic dienamines undergo the Diels-Alder reaction with electrophilic alkenes to give the corresponding a m i n o c y c l ~ h e x e n e s ~ ~ -These ~ ~ " . cycloadducts eliminate the amine moiety under acid conditions30 or high temperatures to give the dihydrobenzene derivative or, in the case of cc-chloroacrylonitrile, elimination of hydrogen cyanide and hydrogen chloride gives the aromatic amine3' (Scheme 17). Interestingly, the role of methyl trans-2,4-pentadienoate changes from that of a diene, in its reaction with enamine~,'~to a y,b-dienophile in its reaction with dienamines3' (Scheme 18). Cyclic dienamines having an homoannular (s-cis) diene system also undergo the Diels-Alder reaction with electrophilic alkenes, but the regioselectivity is dependent on the experimental conditions and the nature of the electron-withdrawing group (EWG), and the amine moiety (R2N). Thus, the morpholine dienamine of isophorone on heating with acrylonitrile in dioxane gave the aJ-cycloadduct 11 (EWG = CN), whereas the piperidine dienamine gave 11, 12, and 1333.Methyl acrylate under the same conditions gave the K,y-cycloadduct 13, (EWG = C0,Me) after hydrolysis of the enamine function,
26. Reactions of dienamines
Reagents: (i) (iv) (v) (vi)
CH2=C(Cl)CN; (ii) 2-cyclohexenone; (iii) CH2=CHZ; CH2=C(Ph)Z (Z = CHO, COMe, C02R, CN); p-benzoquinone; CH2=CHC02Me; (vii) SO2, 80 "C30 SCHEME 17
SCHEME 18
1548
P. W. Hickmott
with both dienamines". Methyl vinyl ketone in boiling dioxane gave 14 (minor) and (13) (major) with the morpholine and piperidine d i e n a m i n e ~ ~but ~ , in toluene (13) (EWG = COMe) and 15 were isolated, and in methanol the P- and 6-alkylation products 14 and 16 (EWG = COMe) were formed34. Under high pressure at room temperature only a,&-cycloadducts 11 (EWG = CN, C0,Me) were isolatedz9" (Scheme 19).
EWG
0
EWG
SCHEME 19
Similarly, Birch reduction products 17 and 18 react with acrylonitrile to give a,#-cycloadduct 19 derived from the linear dienamine, but with methyl acrylate to give P,y-cycloadduct 20 and p-alkylation product 21 (after hydrolysis) derived from the cross-conjugated dienamine3' (Scheme 20). Similar P,y-cycloadducts (23 and 24) are formed from methyl vinyl ketone (MVK) and A'~s"-2-octalone dienamines (22) in toluene, together with the a$-annulation product 25 (Scheme 21). However, in methanol as solvent the regioselectivity of the reaction changes dramatically and mainly products of y&annulation (27) and a$annulation (28) were isolated36. The explanation offered for this solvent-dependent regioselectivity is that, in methanol, products 27 and 28 are produced from zwitterionic intermediates formed from 26, which is stereoelectronically incapable of concerted cycloaddition. However, in aprotic solvents of low dielectric constant, charge separation in the ground state and transition state is less favoured and the reaction becomes orbital-controlled. In other words the activation enerev ' , , for a 14 + 21 cvcloaddition must be less than that for formation of zwitterionic intermediates in an aprotic solvent, and the equilibrium 2 6 s 22 is displaced as isomer 22 undergoes cycloaddition. Ring opening of the Diels-Alder adduct (23), initiated by the push of the N lone pair and the pull i f the acetyl group, could subsequently lead to a zwitterionic intermediate after the dienamine equilibrium 2 6 s 2 2 has been displaced, and hence to the linear annulation >
,
26. Reactions of dienamines
SCHEME 20
R
13
0 COMe R
R
Reagents: (i) MVK, C6HsMe, A, 43 h; (ii) NaOAc-HOAc-H20, (iii) MVK, MeOH, A, 4 h; R = H, Me SCHEME 21
A, 4 h;
1550
P. W. Hickmott
product 2536. The corresponding reaction of the A'.8'-2-octalone dienamine mixture 29, 30, and 31 with phenyl vinyl ketone (PVK) appears to be orbital-controlled in methanol and toluene since only the Diels-Alder adducts 32 and 33 were isolated from both solvents (Scheme 22). In this case initial attack at the P- or y-positions of the linear dienamine 29 cannot now be rendered irreversible by a,P- or y,b-annulation to give products like 27 and 28 as with MVK. Assuming that such attack occurred from an axial direction on the p-face of the dienamine, reversion to dienamine 29 would be stereoelectronically favoured and thus allow reaction with the minor cross-conjugated dienamine isomer 30 to become the dominant process even in methanol37. Interestingly, there was no evidence for cycloaddition to the major s-cis linear dienamine 31, so presumably 6'-alkylation or a,&-annulation is also reversible. Neither was there any evidence for p,h-annulation as observed with MVK and certain dienamines (vide infra).
Reagents: (i) PVK, MeOH, A, 4 h; (ii) PVK, C6H5Me, A, 43 h; (iii) hydrolysis SCHEME 22
The reaction of PVK with the dienamine (34) of 4a-methyl-A'.8a-2-octalone differed from that of the other dienamines in that the only product which could be isolated was 40, formed in low yield by reaction with two equivalents of PVK37. The explanation offered for this change in the course of the reaction is as follows. Axial attack at the b-position from the p-face of the dienamine (34 + 36) is now impeded by the angular &-methyl group. This therefore encourages less favourable 'equatorial' attack from the a-face (34 + 35). The new carbon-carbon bond is consequently orthogonal to the n-orbital of the 1,8a-double bond in intermediate zwitterion 35 and reversion to starting material is stereoeleclronically less favourable. The longer lifetime zwitterion 35 thus allows Michael addition of a second equivalent of PVK (35 + 37). This process can be rendered irreversible by intermolecular protonation by the solvent or by intramolecular transfer of the axial &proton via a cyclic six-membered transition state. Cyclization of the regenerated dienamine system onto the benzoyl group with loss of water (38 + 39) / then leads to 4037 (Scheme 23). A change in the course of the reaction of methyl vinyl ketone with A'~8'-2-octalones was o b ~ e r v e d ~ ~when . ~ ' a carbonyl group was introduced at C-5. In this case no y,&annulation occurred but, in addition to [4 + 21 cycloaddition to the cross-conjugated
26. Reactions of dienamines
Reagents: (i) PVK, MeOH. A, 4 h; (ii) hydrolysis SCHEME 23
dienamine to give 43, P,6-annulation of the linear dienamine occurred followed by loss of water and aromatization to give 41 and the disproportionation by-product 4234 (Scheme 24). A satisfactory explanation for the change in the course of the reaction, from one of y,S-annulation to P,b-annulation, has not been given. However, the presence of the C-5 carbonyl group is not an essential prerequisite for P,b-annulation since the same process
P. W. Hickmoll
tkA0o o0 + t b COMe
Me
H (42)
(43)
(41) Reagents: (i) MVK, toluene, A, 43 h; (ii) hydrolysis SCHEME 24
was observed in the reaction of hexahydroindenone dienamine 44 which gave the aromatized P,b-annulation product 45 in methanol as solvent34 (Scheme 25). An amazing example of the complexity of the formation and subsequent reaction of enamines experiencing steric effects is provided by the reaction of MVK with the dienamine of (+)-piperitone (46)40.Seven different annulation products were produced, and the expected product (47) was not formed (Scheme 26)!
1
iii,ii
COMe (45) Reagents: (i) MVK, MeOH, A, 4 h; (ii) hydrolysis; (iii) MVK, C6H5Me, A, 4 h SCHEME 25
Reagents: (i) pyrrolidine, 20 "C, 45 days; (ii) pyrrolidine, p-TosOH, benzene, A, 80 h; (iii) MVK, 20 "C, 96 h; (iv) N~OAPHOAC, C6H6. A, 30 min; (v) 20% KOH-MeOH, A, 6 h; (vi) 10% Na2C03, 20 OC, 4 h; (vii) p-TosOH, C6H6, A, 5 h
SCHEME 26
1554
P. W. Hickmott
Although dihydropyrans (48) are formed from MVK and enamines at low temperatures"', in refluxing benzene the pyrrolidine enamine of isobutyraldehyde gives tricyclic ketone 51 (R = Me) via the intermediacy of the cross-conjugated dienamine 4942a and of 50 (Scheme 27). A similar product to 50 but without the geminal methyl groups was obtained by self-condensation of cyclohex-2-enone in the presence of pyrrolidinium perchl~rate~~~.
Reagents: (i) MVK, C6H6, 20 "C; (ii) A, 15 h; (iii) HOAc, A, 4 h SCHEME 27
An analogous process, involving the interaction of a cross-conjugated dienamine with a linear dienamine, has been suggested in the self-condensation of acetone in the presence of pyrrolidine and hydroiodic acid, via the intermediacy of the dienamines of isophorone and mesityl oxide, to give a spiro-diket~ne"~ (Scheme 28).
26. Reactions of dienamines
SCHEME 28 However, reaction of MVK with linear dienamine 5244 and with the cross-conjugated dienamine 5445 gave only the corresponding a,B-annulation products 53 and 55, respectively (Scheme 29).
SCHEME 29 Aromatization processes have also been observed in the reaction of dienamines with acetylene carboxylic esters46, k e t e ~ ~ (Scheme e ~ ~ " 30) and arynes4'. Another general method for forming six-membered rings involves the reaction of enamines with a$-unsaturated acid chlorides48. Application of this reaction to diena-
P. W. Hickmott
-
QoH-
a
OAc
Reagents: (i) Y-CX-Z, & (i i) CH,=C=O; Y,Z = C02Me, C02Et, CN SCHEME 30
mines gave mainly the bridged bicyclic ketone 56 on hydrolysis, formed by P,/Yannulation. Small amounts of 8,s- and S,G'-annulation products (57 and 58, respectively) were also isolated49 (Scheme 31). Acyclic linear 59 and cross-conjugated 61 dienamines similarly underwent p,/Y-annulation to give cyclohexenones 60 and 62" (Scheme 32). Biphenyls (64) and dihydro-y-pyrones (63) are formed by the reaction of aromatic acid chlorides with cross-conjugated d i e n a m i n e ~ ~(Scheme ' . ~ ~ 33).
Reagents: (i) CH2=CHCOC1, C6H6,& (ii) H20; R = H, Me SCHEME 3 1
26. Reactions of dienamines
(62) Reagents: (i) CH2=CHCOCI, C6H6. A SCHEME 32
Reagents: (i) PhCOC1,20 "C, 24 h or Et3N, benzene, A, 20 h; (ii) PhCOCI*, benzene, A, 20 h; (iii) NaOAc-HOAc-H20, * added under reflux SCHEME 33
20 "C, 24 h;
1558
P. W. Hickmott
An approach to the synthesis of B-norsteroids involves b-alkylation of dienamine 65 with m-methoxybenzyl bromide and ring closure with H , P 0 4 and P,0553; (Scheme 34). The use of 2-(m-methoxyphenyl)allylbromide gave access to 6-methyl-19-nor~teroids~~. 13-Propyl-norestradiol has been prepared by a process involving b-alkylation of a dienamine with 1,3-dichlorobut-2-ene followed by hydrolysis to the methyl ketone and base-catalysed c y ~ l i z a t i o n ~ ~ . OAc
OAc
OMe
OAc
Reagents: (i) m-MeOCgH4CH2Br; (ii) H3PO4or P205, A SCHEME 34
D. Seven-membered and Larger Rings
In agreement with predictions based on frontier orbital argument^^^, dienamines undergo 16 41 cycloaddition to alkyl or aryl fulvenes to give dihydroazulenes 66 and hence azulenes 67 and 68 in moderate ~ i e l d ~(Scheme ' . ~ ~ 35). Ring expansion of dichlorocarbene cycloadducts may be followed by further carbene cycloaddition to give 70 and 71 (R,N = morphqino) (Scheme 36). In the case of the pyrrolidine enamine, the reaction stops at the eniminium salt stage (69) to give structures such as 72 and 73 on h y d r o l y s i ~ ~ ~ . ~ ~ . Cycloaddition of electrophilic acetylenes to dienamines is referred to in Section VILB (Scheme 16) and VI1.C (Scheme 30).
+
26. Reactions of dienamines
Reagents: (i) CH2=CHCH=CHNEt2, CC14 (or C6H6 or CHCI,), 25 "C, 7 h-1 day; X = Ph, OAC,OTOS,p-O2CC6H4No2 (ii) MeI, Si02; (iii) chloranil, C6H5Me,A, 15 min (X = Ph); (iv) -HOAc (or -HOTos or -p-H02CC6H4N02) SCHEME 35
(70)
Reagents: (i) CC12 SCHEME 36
P. W. Hickmott
VIII. HETEROCYCLIC SYNTHESIS A. Four-membered Rings
Sulphenes have been shown to undergo both [2 + 21 and [4 + 21 cycloaddition to d i e n a m i n e ~ ~ l Other - ~ ~ . methods of forming four-membered heterocyclic rings, such as 1,2-cycloaddition of i ~ o c y a n a t e sand ~ ~ N-s~lphonylimines~~, d o not seem to have been applied to dienamines.
qx 1
X
ii, iii
0
Reagents: (i) XC6H4N2BF4,DMF, 4 5 "C; (ii) POC13, 20 "C, 64 h; (iii) H 2 0 SCHEME 37
26. Reactions of dienamines
1561
6. Fke-membered Rings
Indolo-steroids have been obtained by &coupling of steroid dienamines with diazonium salts in dimethylformamide followed by Fischer-indole cyclization of the resulting h y d r a ~ o n e '(Scheme ~ 37). In methylene chloride the P-coupled product 75 was obtained, cyclization of which gave indazoles 74 and 76'". The oxidative role of dimethyl sulphoxide in the formation of 76 was attributed to nucleophilic attack by the solvent on 75 leading to intermediates 77 and 78, with elimination of dimethyl sulphide (Scheme 38). Furano-steroids 80 and 3-oxa-A-norsteroids 79 have been prepared by reaction of a-bromoketones with steroid d i e n a m i n e ~(Scheme ~ ~ . ~ ~ 39). C. Six-membered Rings
Although coupling of aryl diazonium salts at the a-position of dienamines yields indazoles on acid-catalysed cyclization, the presence of an electron-donor substituent may render the aromatic ring sufficiently nucleophilic to cyclize onto the iminium group to give cinnolines or 6,7-dia~asteroids~,~' (Scheme 40). Benzofurazan-1-oxide adds across the y,d-position of acyclic dienamines to give quinoxaline N,N'-dioxide~~~, whereas nitroso compounds undergo 19-cycloaddition to
(75)
(76)
tv
1
iii
0
OLSMe2 + N , ~ ~ ~ h
L~& N, N H O P~
Reagents: (i) CH3COC02H,a q HOAc, A, 0.5 h; (ii) DMSO, polyphosphoric acid, 20 "C, 18 h; (iii) DMSO; (iv) -Me2$ SCHEME 38
(v) -H20
P. W. Hickmott
OR'
OR'
SCHEME 39
give dihydro-1,2-oxazinesh"; cycloaddition of carbon disulphide Lo linear and crossconjugated dienamines gives thiopyran-2-thiones70 and 5,6-dihydrothiopyran-2thiones7', respectively. 4-Methyl-1-dimethylaminocyclohexa-1,3-diene gives 7,8-dihydro-2,6-dimethylchromone with diketene7'. IX. MISCELLANEOUS REACTIONS
Cyanogen chloride apparently reacts preferentially at the &position of dienamines, to give the 6-cyano d e r i ~ a t i v e ~ Linear ~ . and cross-conjugated dienamine tricarbonyliron complexes have been made and separated c h r ~ m a t o g r a p h i c a l l y Cross-conjugated ~~. dienamines are reported to react normally with phenylisocyanate and diethyl azodicarboxylate to give the corresponding /l'-substitution products75.Unlike non-conjugated enamines, little work has been carried out on the halogenation of dienamines. Pyrrolidine
26. Reactions of dienarnines
&
i, ii
*
@ a] pL COMe
1
Me0
&-w Me0
H YJ
Reagents: (i) m-MeOC6H4NZt BF4-, CH2CI2, -70 "C; (ii) A, 4 h; X = 0, P-OAc SCHEME 40 dienarnines of 3-0x0-A4-steroids react with perchloryl fluoride (FCIO,) a n d Ruoroxytrifluorornethane (CF,OF) t o give mixtures of 4-fluoro-3-0x0-A4 -steroids and 4,4-
difluoro-3-0xo-A~-steroids'~. X. REFERENCES 1. P. W. Hickmott. Tetrahedron., 411. 2989 11984). - ,. 2. (a) M. J. M. ~ d ~ ~ m a H. n nR. , Reus, U. K. Pandit and H. 0. Huisman, Reel. Trav. Chim. Pays-Bas, 89, 929 (1970). ( b ) ~ Mazarguil . and A. Lattes, Bull. Soc. Chim. France, 1880 (1972). 3. (a) J. L. Johnson, M. E. Hcrr, J. C. Babcock, A. E. Fonkcn, J. E. Stafford and F. W. Hcyl, J. Am. Chem Soc., 78,430 (1956). (b) W. Nagata, M. Yoshioka and M. Murakami, J. Am. Chem. Soc., 94,4654 (1972). (c) G . Opitz and W. Merz, Ann. Chem., 652, 158 (1962). (d) G. Opitz and W. Merz, Ann. Chem., 652, 139 (1962). 4. Ci. H. All and A. J. Speziale, J. Org. Chem., 31, 2073 (1966). 5. Ci. Stork, A. Brizzolara, H. Landesman, J. Szmuszkovicz and R. Terrell, J. Am. Chem Soc., 85, 207 (1963). 6. R. Bucourt and J. D u b 4 Bull. Soc. Chim. France, 479 (1974). 7. S. Yamada, M. Shibasaki and S. Terashima, Tetrahedron Lett., 377 (1973). 8. S. Yamada, M. Shibasaki and S. Terashima, Tetrahedron Lett., 381 (1973). 9. (a) M. Julia, S. Julia and C. Jeanmart, C. R. Acad. Sci. Paris, 251, 249 (1960). (b) G. Stork and G. Birnbaum, Tetrahedron Lett., 313 (1961). (c)L. Velluz, G. Nomine, R. Bucourt, A. Pierdet and P. Dufay, Tetrahedron Lett., 127 (1961). ~
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1564
10. U. K . Pandit, W. A. Z. Voorspuij and P. Houdewind, Tetrahedron Lett., 1997 (1972). 1 1 . 0 . Takazawa and T. Mukaiyama, Chem. Lett., 1307 (1982); 0. Takazawa, K. Kogami and K. Hayashi, Bull. Chem. Soc. Jpn., 57, 1876 (1984). 12. P. Houdewind and U. K. Pandit, Tetrahedron Lett., 2359 (1974). 13. P. W. Hickmott, Tetrahedron, 38, 1975 (1982). 14. P. W. Hickmott, A. Papaphilippou, D. H. Pienaar, R. D. Soelistyowati and C. T. Yoxall, S. Afr. J. Chem., 41, 75 (1988). 15. (a) S. K. Malhotra. J. J. Hostvneck and A. F. Lundin. J. Am. Chem. Soc.., 90., 6565 (1968): ~,~ ,, V. van Rheenen, Chem. ~ o m m u i .314 , (1969). (b) P. J. Barker, A. L. J. Beckwith and Y. Fung, Tetrahedron Lett., 24, 97 (1983) and references cited therein. 16. A. Murai, C. Sato, H. Sasamori and T. Masamune, Bull. Chem. Soc. Jpn., 49, 499 (1976). 17. (a) W. S. Johnson. V. J. Bauer and R. W. Franck, Tetrahedron Lett., 72 (1961). (b) J. A. Marshall and W. S. Johnson, J. Org. Chem., 28,421 (1963); A. J. Birch, J Chem. Soc., 1551 (1950). 18. G. Opitz and W. Merz, Ann. Chem., 652, 163 (1962). 19. H. Mazarguil and A. Lattes, Bull. Soc. Chim. France, 112 (1971). 20. A. J. Birch, E. G. Hutchinson and G. Subba Rao, J. Chem. Soc. ( C ) , 2409 (1971). 21. G. B. Spero, J. L. Thompson, B. J. Magerlein, A. R. Hanze, H. C. Murray, 0. K. Sebek and J. A. Hogg, J. Am. Chem. Soc., 78, 6213 (1956). 22. M. E. Herr and F. W. Heyl, J. Am. Chem. Soc., 75,5927 (1953); R. Bucourt and J. Dube, Bull. Soc. Chim. France, 11-33 (1978). 23. U. K. Pandit. F. R. Mas Cabrb R. A. Case and M. J. de Nie-Sarink. J. Chem. Soc.. Chem. Commun., 627 (1974). 24. S. A. G. De Graaf and U. K. Pandit, Tetrahedron, 29, 4263 (1973). 25. A. J. Birch and E. G. Hutchinson, .I. Chem. Soc. ( C ) , 3671 (1971). 26. For a review of dienamines as Diels-Alder dienes, see: M. Petrzilka and J. I. Grayson, Synthesis, 753 (1981). 27. S. Hunig and H. Kahanek, Chem. Ber., 90, 238 (1957) and referenced cited therein; W. Langenbeck, 0 . Godde, L. Weschky and R. Schaller, Ber. Dtsch. Chem. Ges., 75, 232 (1942). 28. G. Satzinger, Ann. Chem., 728, 64 (1969). 29. (a) W. G. Dauben and A. P. Kozikowsky, J. Am. Chem. Soc., 96,3664 (1974). (b) S. Danishefsky and R. Cunningham, J. Org. Chem., 30, 3676 (1965). 30. R. L. Snowden and M. Wuest, Tetrahedron Lett.., 27, 699 (1986). 31. J. 0 . Madsen and S. 0 . Lawesson, Tetrahedron, 24, 3369 (1968). 32. G. A. Berchtold, J. Ciabattoni and A. A. Turvick, J. Org. Chem., 30, 3679 (1965). 33. H. Nozaki, T. Yamaguti, S. Veda and K. Kondo, Tetrahedron, 24, 1445 (1968). 34. P. W. Hickmott and R. Simpson, J. Chem. Res. (S), 302 (1992);J. Chem. Res. ( M ) , 2447 (1992). 35. A. I. Birch and E. G. Hutchinson, J. Chem. Sor., Perkin Trans. 1, 1757 (1973). 36. P. W. Hickmott and R. Simpson, J. Chem. Sor., Perkin Trans. 1, 357 (1992). 37. P. W. Hickmott and R. Simpson, J. Chem. Res. ( S ) , 304(1992);J. Chem. Res. ( M ) , 2476 (1992). 38. P. Houdewind, J. C. Lapierre Armande and U. K. Pandit, Tetrahedron Lett., 591 (1974). 39. M. S. Manhas, I. W. Brown, U. K. Pandit and P. Houdewind, Tetrahedron, 31, 1325 (1975); M. S. Manhas, J. W. Brown and U. K. Pandit, Heterocycles, 3, 117 (1975). 40. Y. Bessiere and F. Derguini-Boumechal, J. Chem. Res ( S ) , 204 (1977). 41. I. Fleming and M. H. Karger, J. Chem. Soc. ( C ) , 226 (1967). 42. (a) J. W. Lewis and P. L. Myers, J Chem. Soc. ( C ) , 753 (1971); (b) N. J. Leonard and W. J. Musliner, J. Org. Chem., 31, 639 (1966). 43. M. Miocque, M. Duchon d'Engenieres and 0. Lafont, Tetrahedron Lett., 2133 (1976). 44. A. I. Birch, E. G. Hutchinson and G. Subba Rao, Chem. Commun., 657 (1970). 45. F. Weisbuch and G. Dana, Tetrahedron, 30, 2873 (1974). 46. (a) S. Tanimoto, Y. Matsumura, T. Sugimoto and M. Okano, Tetrahedron Lett., 2899 (1977). (b) R. L. Snowden and M. Wust, Tetrahedron Lett., 27, 703 (1986). 47. S. Tanimoto, Tetrahedron Lett., 2903 (1977); S. Tanimoto, R. Schafer, J. lppen and E. Vogel, Angew. Chem., 88,643 (1976). 48. P. W. Hickmott, Proc. Chem. Soc., 287 (1964); P. W. Hickmott and J. R. Hargreaves, Tetrahedron, 23, 3151 (1967); P. W. Hickmott, G. J. Miles, G. Sheppard, R. Urbani and C. T. Yoxall, J. Chem. Soc., Perkin Trans. 1, 1514 (1973). ~
26. Reactions of dienamines 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76.
N. F. Firrell and P. W. Hickmott, J. Chcm. Sor. ( C ) , 2320 (1968). N. F. Firrell, P. W. Hickmott and B. J. Hopkins, J. Chem. Soc. ( C ) , 1477 (1970). P. W. Hickmott, B. J. Hopkins and C. T. Yoxall, Tetrahedron Lett., 2519 (1970). P. W. Hickmott and C. T. Yoxall, J. Chem. Soc. ( C ) , 1829 (1971). U. K. Pandit, K. de Jonge, K. Erhart and H. 0 . Huisman, Tetrahedron Lett., 1207 (1969). H. Bieraugel and U. K. Pandit, Recl. Trau. Chim. Pays-Bas, 98,496 (1979). L. Velluz, G. Nomine, R. Bucourt, A. Pierdet and P. Dufoy, Tetrahedron Lell., 127 (1961). K. N. Houk, J. K. George and R. E. Duke, Tetrahedron, 30, 523 (1974). L. C. Dunn, Y.-M. Chang and K. N. Houk, J. Am. Chem. Soc., 98, 7095 (1976); L. C. Dunn and K. N. Houk, Tetrahedron I.ett., 341 I (1978). Y. N. Gupta, S. R. Marie and K. N. Houk, Tetrahedron Lett., 23, 495 (1982). S. A. G. De Graaf and U. K. Pandit, Tetrahedron, 29, 4263 (1973). S. A. G. De Graaf and U. K. Pandit, Tetrahedron, 30, 1115 (1974). G. Opitz and F. Schweinsberg, Angew. Chern., In!. Ed. Engl., 4, 786 (1965); H. Mazarguil and A. Lattes, Bull. Soc. Chim. France, 500 (1974) arid references cited therein. F. Benedetti, G . Pitacco and E. Valentin, Tetrahedron, 35, 2293 (1979). L. A. Paquette and R. W. Begland, J. Org. Chem., 34, 2896 (1969). M. Perelman and S. A. Mizsak, J. Am. Chem. Sor., 84, 4988 (1962); G. Opitz and J. Koch, Angew. Chem., Int. Ed. Engl., 2, 152 (1963); A. K. Bose and G. Mina, J. Org. Chem., 30, 812 (1965). F. Etlenberger and R. Maier, Angew. Chem., Int. Ed. Engl., 5, 416 (1966). U. K. Pandit, H. R. Reus and K. De Jonge, Recl. Trau. Chim. Pays-Bas, 89, 956 (1970). IJ. K. Pandit, M. J. M. Pollman and H. 0.Huisman, Chem. Commun., 527 (1969); M. J. M. Pollmann, U. K. Pandit and H. 0 . Huisman, Recl Trau. Chim. Paju-Bas, 89, 941 (1970). P. Devi, J. S. Sandhu and G. Thyagarajan, Chem. Commun., 710 (1979). G. Kresze and J. Firl, Tetrahedron Lett., 1163 (1965). R. Mayer and K. Gewald, Angew. Chern., Int. Ed. Engl., 6,294 (1967); R. Mayer, G. Laban and M. Wirth, Ann. Chem., 703, 140 (1967). J-P. Sauve and N. Lozac'h, Bull. Soc. Chim. France, 2016 (1970). B. B. Millward, J. Chem. Soc., 26 (1960). M. E. Kuehne and J. A. Nelson, J. Org. Chem., 35, 161 (1970). M. G. Ahmed, P. W. Hickmott and M. Cais, J. Chem. Soc., Dalton Trans., 1557 (1977). R. A. Ferri, G. Pitacco and E. Valentin, Tetrahedron, 34, 2537 (1978). S. Nakanishi, R. L. Morgan and E. V. Jensen, Chem. Ind., 1136 (1960); R. Joly and I. Warnant, Bull. Soc. Chim. France, 569 (1961); D. H. R. Barton, L. S. Godinho, R. H. Hesse and M. M. Pechet, Chem. Commun., 804 (1968).
The Chernistrj of Enamines. Edited by Zvi Rappopon Copyright O 1994 John Wiley & Sons, Ltd. ISBN: 0-471-93339-2
Author index This author index is designed to enable the reader to locate an author's name and work with the aid of the reference numbers appearing in the text. The page numben are printed in normal type in ascending numerical order. followed bv the reference numbers in parentheses. The numbers in italics refer to the pages on whichthe referenies are actually listed.
Abadie, P. 1200,1201(259), 1248 Abarca, B. 192(198), 215 Abbe, J.C. 685(16,17), 686(17), 693 Abbod. F.S. 1156(129). 1245 ~ b b o t t P.J. ; 182(1'25),213 Abboud, J.L.M. 697(8), 707(27h), 723, 724, 1097(116b), 1108 Abdel-Ghany, H. 1030(194), I046 Abdel-Rahman, M. 1030(194), I046 Abdulla, R.E 594(254,25Sa), 634, 731, 778(25), 862 Abe, 1. 544(75), 546(80), 630 Abe, N. 534(37), 572(183, 184), 629, 632, 1434(196), 1439 Abe, S. 1232(344), 1251 Abe, T. 190(185), 214 Abeles, R.H. 1293(158), I302 Abell, L.M. 1278(95), 1289(147), 1301, 1302 Aben, R.W.M. 1017(116), 1045, 1368(21), 1436 Abert, I.D.L. 406(4), 434 Abgaryan, E.A. 471(144), 510, 982(207), 991 Abis, L. 1447(43), 1503 Abraham, G.J. 1089(96), 1107 Abraham, S . 1192(238), 1248 Abramova, E.I. 1120(16), 1242 Abu-El-Halawa, R. 1481, 1483(138), 1484(140), 1493(146), 1494(138), 1506 Acerete, C. 722(80), 726 Achakzi, D. 1429(184), 1439 Acheson, R.M. 182(125), 213 Achiwa, K. 249(189), 254, 536(46), 630, 773(170, 171), 774(171), 865, 1383(59b), 1617
A
Acholonu, K.U. 470(94), 509, 740(75), 863
Ackerman, 1.1. 1517(87a), 1533 Acquaah, S.O. 495(521), 518 Adachi, 1. 670(55), 678 Adachi, K. 722(85b), 726 Adam, R. 709(33a), 724,964(124), 989, 994(17, 19, 20), 1043, 1377(49), 1436 Adam, W. 940(57,58), 988, 1420(157), . . 1439 Adams, D. 538(54), 630 Adams, G.E. 1128(4143), 1150(101), 1243, 1244 Adams, J. 1269(62), 1300 Adams, J.W. 1255, 1272(20), 1299 Adams, R. 52(273), 83, 489(399,400), 515, 516, 1055, 1065(21a), 1105 Adamson, R.H. 1156(123b), 1245 Addadin, M.J. 1022(138), I045 Adderley, C.I.R. 1508(27), 1531 Adelson, B.H. 606(293), 635 Adelstein, S.1. 1236(347-349), 1237(348, 350), I251 Adhikesavalu, D. 14(155, 158, 169), 18(155, 158), 21(169), 80, 166(20), 210, 1304, 1308(12), 1359 Adhikesvalu, D. 419(69,70), 421, 422(69), 435 Adickes, H.W. 1516(79-82), 1533 Adiwidijaja, G. 1017(115), 1045 Adiwidjaia, G. 170(48), . . 211, 1034(211), 1047, 1423(i64), 1439 Adler, M. 578(199), 633, 939(50,54), 988 Adoloh. H. 779(182). 784(200.205). 866. 1d14107), 1045,'1366(16),'1438 Advani, B.G. 1306, 1313, 1320(20), 1324(105), 1342(20,143), 1344(144,145), 1353(172), 1358(186), 1360,1362, 1363
1567
Author index
1568
Akah, El.-S. 538(55), 630 Afsah, E.M. 532(31, 32, 36), 629 Afsah, E.S. 572(182), 632 Agami, C. 48(248), 82 Agarwal, D.P. 1163(148), 1245 Agarwal, R.P. 1156(122a),1245 Agawa, T. 1027(167), 1046,1419(153), 1438 Agbalyan, S.G. 468(13), . . 502(632), . . 508, 520, -1366(11), 1435 Agganval, V. 1331(123), 1335(132),1362 Aeosta. W.C. 653(34). 678 ~ g u e r iA. , 479(2?6):513 Aguiar, A.M. 9(115), 79 Ahier, R.G. 1217(313), 1250 Ahlberg, P. 794(246), 867 Ahlbrecht, H. 5(52), 7(65),X(81)), O(Y4, 102), 77-79, 245(148), 254,282(5), 3@3(37, 38), 301, 310(5), 399, 400,486(350,351),
,.
~ h m e dG. , 8(i4), ?8 Ahmed, 1. 1128(4143), 1243 Ahmed, M.D. 472(146), 510 Ahmed, M.G. 282-284,286,287(7), 291(7, 25. 26). 292(7). 399. 446(18). 458. 821(3ik),8&:'1005'(63-65): I 044; 1562(74), 1565 Ahmed, S.A. 8(84), 78, 291(25), 399, 823(315-317), 869, 1005(60,62-65), I044 Ahn, K.H. 962(119), 989 Ahond, A. 476(203), 511 Ahouande, ES. 470472(56), 508 Aisaka, K. 550(92), 631 Aizikovich, A.Ya. 499(570), 500(592), 519, 520 -~ Aizpurea, J.M. 492(482), 517 Ajami, A.M. 1120(19), 1242 Akasaka, Y. 1136(64), 1243 Akhrem, A.A. 48(244), 82, 532(30), 629, 930(28), 984(218,219), 987, 991 Akbtor, P. 532(26), 629 Akhvlediani, R.N. 571(1 76), 632 Akinaga, S. 1163(150), 1245 Akinoyosoye, 0. 1269, 1275(63), 1281(109), 1300,1301 Akiyama, F. 1512(66), 1532 Akiyama, Y. 173(68), 211, 544(75), 546(80), 630 Akutagawa, S. 56(300), 84, 481(274,277), 482(279), 513 Alais, L. 53(268), 83 Alais, M.L. 711(41), 724 Alam, M. 740(78), 863 Alarez, J.M. 477(226), 512 Alhers-Schonberg, G. 167(27), 210 ~
Albert, A. 506(652), 521 Albert, K. 761(133), 864 Alberti, G. 1142(83),1244 Alhertson, N.E 1451(60), 1504 Albinati, A. 14, 16(148), 80 Albisetti, C.J. 606(293), 635 Albrecht, B. 699(15), 723, 843(384), 870 Albrecht, H. 309; 319(60, 61a-i), 4i10, 793(238), 867, 1512(48a), 1532 Albright, J.D. 1308, 1322, 1340, 1357(31), 1360 Alcalde, E. 1149(1W), 1244 Alcaraz, C. 450, 455(28), 458 Alcock, N. 167(24),210 Aldave. M.T. 240(113. 1181. ,, 253 ~ldrich,P. 490(442), 516 Aleksandrov, B.B. 5(43), 77, 475(186), 511, 973(163), 990 Alekseeva, L.M. 5W(590), 519, 535(42), 536(45), 559(130), 581(203), 629431,633 Aleshin, M.A. 688(26), 694 Alexander, AS. 1091-1093,1095(105), 1108 Alexander, I. 1155(12le), 1245 Alexandrovich, O.V. 1278(96), 1301 Alfassi, Z.B. 685(18), 693 A-Lim, D.S.T. 479(248), 512 Alison, R.A. 501(602), 520 Alivisatos, S.G.A. 1089(96), 1107 Alkalay, D. 475(187), 489(411), 511, 516, 845(388),871, 1127(36), 1243 Allade, 1. 719(69), 725 Allan, M. 699(15), 723,843(384), 870 Allan, R.D. 816(303), 868 Allen, G.R. 558(124,126), 631 Allinper, N.L. 24(176), 80, 746(85), 809(292), 863, 868 Allmann, R. 1489(145), 1493(147), 1506 Alloum, A.B. 1312(50),1360 Allred, J.E 1224, 1225(325), 1250 Allwood, B.L. 182(126), 213 Almirante, N. 1025(145,146), 1045 Alnajjar, MS. 875(17), 887 Alpegiani, M. 1188(222,223), 1247 Alt, G.H. 844(385fl, 871,1064(60), . . 1106, is37(4), 1563 Al-Talib, M. 1493(148), 1495(148,151), 1506 Altman, L.J. 1169(170), 1246 Altmann. J.A. 1087(93c). 1107 Alunni, S. 1085(92a), 1107 Alvarez, F.J. 1279(103-105), 1281(105), 1301 Alvarez. J.M. 90.5194). 921 Alvarez: M. 1143:1i44(84), 1244 Alvarez, R.M. 1477(134), 1506 Aly, M.E. 1290(149), 1302 Amann, A. 9(ll I), 79
Author index Amarego, W.L.E 70(358), 85 Amat-Guerri, F. 704(19d), 723 Amato, J.S. 1176(190), 1246 Amelichev, V.A. 721(76), 726 h e r , F.A. 538(55), 572(182), 630, 632 Amin, S.G. 567(164), 632 Amitai, G. 1192(238), 1248 Ammon, H.L. 1027(168), 1046 Amour, H.d' 1384(61), 1437 Amschler, H. 1325(112), 1362 Amstutz, R. 1507(6), 1531 Anand, N. 501(610), 502(614), 520, 574(187), 575(188), 594(187), 633 Andemichael, Y.W. 1015(99), 1045 Anders, E. 1414(138), 1438 Andersen, L. 175(76), 183(133), 211, 213 Anderson, A.G. 1089(94), 1107 Anderson, D.J. 901(73), 921 Anderson, J.E. 32(214, 215), 81, 224(29), 236(90), 251, 252, 287(13), 289(17), 290(20), 399,408(19), 434, 731(32), 862, 1056(24b), 1105 Anderson, M.W. 1304, 1308, 1310, 1324(10), 1359 Anderson, P.J. 1128(45), 1243 Anderson, P.S. 4(26), 77, 499(565), 519, 962(117, 118), 989, 1063(55), 1106, 1119(6, 8, 9), 1242 Andersson, R. 1005(64,65), 1044 Andler, S. 940(58), 988 Ando, K. 502(618), 520 Ando, M. 661(47), 678 Ando, T. 787(228), 867 Ando, W. 782(196), 866, 924,925(10), 987 Andreani, A. 187(167), 214 Andreetti, G.D. 14, 21(163), 80, 167(21, 23), 176(81), 181(122), 183, 18Y(137), 210, 212, 213 Andreev, V.A. 58(325), 84 Andreichikov, YuS. 394(211), 404 Andrews, D.W. 56(299), 84, 225(35), 251, 261, 269(29), 273, 290(22), 399 Andrews, G.C. 1512, 1526,1527(46a), 1532 Andreyeva, L.I. 686(22,23), 694 Andrianov, V.G. 386(203), 404,433(124), 436 Andrieux, C.P. 953(95), 989 Angelo, J.d' 474(170), 511, 731(22), 768(153), 846(394). 848(394. 39.5). 8.52. 857(395. 861(395), 86",n65,871: 401j, 1041(249,251,253), 1048 Angenot, L. 166(17), 210 Angermund, K. 1026(151), 1046 Angiuli, P. 1228(336), 1250 Angoh, A.G. 760(123, 124), 802(275), 864, 868 Anh, N.T. 875(14), 887 Anisimova, O.S. 552(107, 108), 631
~YY,
Anjaneyulu, B. 1184(214), 1247 Annan, N. 1269(65), 1276(65,88), 1278(93), 1300,1301 Annunziata, R. 268(66), 276 Ansell, M.E 470(59), 509 Antel, 1. 188(177), 214 Anthony, C. 1143(85), 1244 Antoni, G. 1206(275b), 1207(281), 1249 Anvia, E 704(19d), 707(27a), 713(50), 723-725,1097(116b), 1108 Anzeveno, P.B. 1003(56), 1044 Aoki, K. 180(1IS), 212 Aoki, T. 462(8), 465 Aoyagi, S. 501(606), 520, 583(214), 633 Aovama. , . H. 319. 345f71). 401 Aoyama, T. 9(87), 78: l324(107), 1362 Apparao, S. 1357(183), 1363 Appel, R. 1429(184), 1439 Appleton, R.A. 816(303), 868 k a i , S. 688(27-29), 690(28), 691(29), 694 Arai, Y. 470(73), 509 Arauda, V.G. 1425(172), 1439 Aranjo, H.C. 485(330), 514 Araujo, H.C. 1033(202), 1047 Araujo, H.G. Y34(40), 9x8 Arbuzov, B.A. 1369, 1429(27), 1436 Arcamone, E 1188(222), 1247 Archibald, TG. 390, 392, 393(205), 404, 424(84), 435 Archibold, T.G. 1304, 1308, 1314, 1315(14), 1359 k e n s , J.F. 1497(154), 1506 Aretakis, A.J. 874(8), 887 Argay, G. 751(98), 864, 1030(193), 1046 Arimoto, K. 470(73), 509 Arison, B.H. 167(27), 210 Armand, J. 169(39), 211 Armarego, W.L. 302, 307(44), 400 Armitage, M.A. 1229(340), 1250 Armstrong, F.M. 1177(193), 1246 Armstrong, M.D. 1170(176), 1246 Amdt, C. 484(301,304), 514 Amett, E.M. 48(254), 53(284), 82, 83, 697, 712(6), 723, 1065(63a), 1098(125), 1106, I109 Arnold, A. 1197(244), 1248 Arnold, J.R.P. 1147(95), 1244 Arnold, W.1011(80), 1044 Arnold, Z. 362(152), 402, 489(405), 516, 613(314), 6.75,735,737(52), 769(161), 862, 86 7 ...
Arnould, J.C. 624(332, 334), 636 Aroujo, H.C. 1400(105a), 1437 Arrian, J. 705, 710(21), 724 Arriau, J. 25(197, i98j, 81, 225(36,37), 251, 710(40d), 724 Arriortua, M.I. 14, 18(152), 80
1570
Author index
Arsenault, G.J. 486(336), 514 htico, M. 608(296), 612(312), 635 h a n a g h i , M. 794(247), 867 h y a , F. 611(307), 635 Asada, T. 495(525), 518 Asai, K. 644(13), 677 Ashcroft, W.R. 55(298), 83, 256(4b), 271 Ashizawa, M. 999(42), 1043 Asokan, C.V. 1312(49), 1353(175b), 1360, 1363 Asplund, M. 183(133), 213 Assadi-Far, H. 471(114), 510 Assaro, F. 1037(235), 1047 Atanassova, M. 1275(80,81), 1301 Atavin, AS. 688(26), 694 Atkin, , G.M. 1371(33), 1436 Auchus, R.J. 1295(164), 1302 Audia, I.E. 471(136), 510 Audier, H.E. 451(32), 458 Aue, D.H. 52, 53(270), 83, 699(14), 7W, 701(11), 723, 1065(63b), 1106 Auer, E. 964(127), 989 Auerbach, R.A. 1507(1I), 1531 August, E.M. 1225(326), 1250 Augustin, M. 1313(53,56, 59, 60, 65-69), 1316(53), 1321(99), 1346(153), 1360, 1361, 1363 Augustine, R.L. 749(95), 805(288), 864, 868, 939(51), 988 Aurell, C.-I. 175(76), 211, 1040(246), 1048 Auricchio, S. 543(66), 582(211a), 630, 633, 1465, 1466(98), 1505 Auriola, S. 1127(37), 1243 Ausloos, P. 52(279), 83 Auterhoff, G. 478(238b), 512 Autrey, R.L. 816(305), 868 Avano, A. 1519(94), 1533 Awaya, H. 1335(130), 1362 Ayer, W.A. 499(555), 519 Ayers, 0. 489(422), 516 Aziz-Elyusufi, A. 9(92), 79 Aznar, F. 9(98), 79, 188(175), 214, 295, 322, 323(2Sh), .?99,477(223-227), 512, 905(92-94). 921,1029(185), 1046, 1415(141), 1438 Azran, I. 1167(157), 1245 Azuma, S. 929(26), 987 Azzaro, M. 42(231), 55(290), 82, 83, 298(36), 343,345,394(128), 400, 402 Baasner, B. 1307, 1313, 1328(24b), 1360 Baassou, S. 171(50), 211 Baba, N. 489(382), 515 Baba, S. 442(i3),458 Babadjamian, A. 470(56,87), 471, 472(56), 508, 509,711(42b), 724, 732(33), 862 Babayan, A.T. 471(108), 480(267), 510, 513
Babbitt, P. 1261(45), 1300 Babcock, J.C. 470,496(60), . . 509, 1537, 1538(3a), 1563 Babcock, J.E. 1062(52), 1106 Babiano. R. 944162). 988 ~abievski,K.K. 41$49), 432(114), 435, 436 Babievskii, K.K. 244(131), 245(137), 253, 385(197), 387(200, 20l), 388(203), 403, 404; 719(67c), 725 Babievskv. K.K. 4331124). 436 Babu, M.K.M. 952(91), 989 Babudri, F. 492(495), 517 Bacchichetti, F. 601(277), 634 Bacchichetti, T. 601, 611(278), 634 Bach, N.J. 1228(337), 1250 Bach, R.D. 969(141), 990 Bach, S.R. 469(40), 508 Bachelor, F.W. 982(203), 991 Bachi, M.D. 168(35), 210 Rachman, G.L. 979(193), 991 Bachmann, M. 343, 354(125), 402, 1199(254), 1248 Back, T.G. 936(46), 988 Backvall, J.E. 1010(74,76, 77), 1037-1039(239), 1044, 1047 Badalyan, K.S. 481(271), 513 Baddeley, G.V. 1508(27), 1531 Bader, RE. 490(443), 516 Badger, E.W. 530(24), 629 Badia, M.D. 1463, 1465(97), I505 Badon, R. 1171(177), 1246 Baehler, B. 469(26), 508 Baer, L.H. 489(425), 516 Baench, H.G. 1423(164), 1439 Baganz, H. 9(88), 78, 1316(82), 1361 Bagdasaryan, H.B. 481(271), 513 Baggaley, K.H. 816(303), 868 Bagli, J. 1186(218), 1247 Bagli, J.F. 935(42), 988 Bagno, A. 1098,1103(118), 1108 Bahl, 1.J. 1139(72), 1243 Baier, H. 829(331; 333), 869, 1040(248), 1048 Bailey, AS. 178(96),212 Bailev. G.S. 11571132.133l ,, 11581133l1245 ,, ~ a i l e ; :P.D. 911(<07),'921 Baiocchi, L. 1374(40), 1436 Baird, M.S. 470(83), 509, 797(251), 867 Baker, A.P. 58,59(317), 84 Baker, D.C. 1155(119), 1244 Baker, J. 24(185), 81 Baker, R.H. 606(293), 635, 971(151), 990 Bakhmutov, V.I. 244(130, 131), 245(136, 137), 253,385(196,197), 387(200,201), 403, 415(49-51), 416(51), 432(114), 435, 436, 719(67c), 725, 891(35), 920 Bakhmutov, Y.I. 891(32), 920 Bakhumov, V.I. 719(68a), 725 \
Author index Bakker, B.H. 479(248), 512 Balaban, A.T. 1456(69), 1471(115), 1502(158). 1504-1506 Balakrishnan, V. 1353(174),1363 Balasubrarnanian, N. 1028(174, 175), 1046, 1416(143), 1438 Baldwin, J.C. 1310(40), 1360 Baldwin, J.E. 993, 1041(1), 104.3 Baldwin, J.J. 550, 599(95), 631, 1021(128), 1045, 1387(69), 1437 Baldwin, R.M. 1226(329), 1250 Baldwin, S. 506(677), 521 Baldwin, S.W. 1154(115), 1244 Balenkova, E.S. 617(321), 635, 1473(125), 1478(135), 1499(125), 1505, 1506 Baljon, Ya.G. 1443(25), 1503 Ball, R.G. 186(152), 213 Ballabio, M. 1025(146), 1045 Ballanato, 1. 243(128), 253, 344, 345(126), 354(134), 372-377,380(175), 381, 383-385,387,388(134), 394, 395(134, 175), 397(134), 402, 403 Ballesteros, A. 182(127), 213, 1027(169), 1036(224), 1046, 1047, 1424(166), 1439 Ballesteros, R. 192(198), 215 Ballotta, R. 1152(109), 1244 Balogh, M. 1416(147), 1438 Baker, J. 1180(200), 1247 Ban, Y. 965(132), 990 Bandlow, M. 409(27), 434 Banfi, D. 1144(88), 1180, 1181(202), 1244, 7 747 --.,
Bangerl, 1. 1226(328), 1250 Banks, W.R. 12(30(257),1248 Banville, J. 246(152, 153), 254, 1511(44), 1512(66), 1532 Baraldi, P.G. 500(591), 519, 765(152), 865 Baralle, R. 1255, 1264, 1266(9), 1299 Barbara, C. 904,905(85), 921, 1324(109), 1362 Barbarella, G. 620(326), 6.35, 1037, 1038(233), 1047 Barbry, D. 495(528), 518 Barbry, 0. 495(527), 518 Barbuch, R.J. 1003(56), 1044 Bdrcclos, F. 470(58), 509 Barcina, J.O. 1477(134), 1506 Barco, A. 765(152), 865 Birczai-Beke, M. 964(126), 989 Bard, M. 1421(158), 1439 Bargagna, A . 600(271), 634 Barhanin, J. 1192(237), 1248 Barieux, I.-J. 834(349), 870, 974(167, 168, 170), 990 Barker, P.J. 1542(15b), 1564 Barletta, G. 955(99), 989, 1258(30), 1259(30,
31), 1300' Barletta, G.L. 1259(33), 1266(57), 1300 Barlow, G.H. 1507(10b), 1531 Barluenga, 1. 9(98), 79, 182(127), 188(171, 175). 213. 214.295.322. 323(28b). 399. 477i223-227),512,626(34&343): 636, 905(92-94), 921, 1027(169), 1029(185), 1036(224), 1046, 1047, 1385(62), 1386(65, 66), 1389(75), 1393(85), 1408(122), 1415(141), 1419(154), 1424(166), 1425(172, 173), 1426(176), 1427(177), 142X(lXO), 1431(187), 1432(75,189, 1901, 1433(191), 1437-1 439 Barnard, M. 570(173), 632 Barnert, R. 9(111), 79 Barnes, K.K. 884(36), 887 Barney, C.L. 1003(56), 1044 Baron, J. 1200(258), 1226(327), 1248, 1250 Baron, J.C. 1200, 1201(259), 1248 Barrc, L. 1200, 1201(259), 1248 Barrilier, D. 284, 286, 288, 289, 291-293,316, 318, 319, 339(11a), 399 Barry, J.E. 476(213), 512 Barta, M. 489(403), 516 Barta, N.S. 737, 844(61), 863, 911(109), 921 Bartell, L.S. 17(149), 80 Barth, E 997(29), 1043 Barth, S. 994(24), 1043 Barthelerny, M. 710(40e), 724 Bartho, B. 1313, 1315(52), 1360 Bartl, A. 1398(97), 1437 Bartlett, F.A. 905(91), 921 Bartmess, J.E. 262(35), 273, 697, 699,701, 707(7b), 723, 1097(1IS), 1108 Barton, D.H.R. 502(621,622), 520, 794(243), 867, 1327, 1337(115), 1362,1442(14), 1503, 1512(53c), 1532, 1563(76), 1565 Barton, J.M. 1165(154), 1167(155), 1245 Barton, K.R. 599(268), 634, 97O(l49), 990 Barton, R.J. 170(45), 211 Bartulin, J. 221(13), 232(64), 237(105), 241(13), 251-253,414(45), 434 Basato, M. 14, 18(161), 80 Basmadjian, G.P. 1233, 1235(345), 1251 Bass, J.D. 650(27), 678 Basse, W. 1266(58), 1300 Bassindale, A.R. 307(56), 400 Bastide, J. 1171(177), 1246 Batcho, A.D. 769(158), 865 Bates, G. 890(20), 920 Bates, P.A. 186(157), 213 Batiz-Hernandez, H. 394(206), 404 Batra, M.S. 368(162), 403 Battersby, A.R. 1286(145), 1302 Battistini, C. 1188(222), 1247 Baty, J.D. 740(78), 86.3
1572
Author index
Bauch, H.-G. 1017(115), 1045 Baud'huin, M. 191(192, 193), 192(193, 194), 714
Baudlish, B.K. 1516(83), 1533 Baudoux, D. 769(164), 865 Bauer, G. 1226(328), I250 Bauer, H. 578(198), 633 Bauer, V.J. 961(113), 989, 1542(17a), 1564 Bauer, W 426(91), 435 Baueh. L.E. 572(181). 632 1284(l%), 1301 ~ a u g h nR.L. , Bauld, N.L. 1512(59), 1532 Baum, G. 181(118), 212 Baum, K. 390, 392, 393(205), 404, 424(84), 435. 1304.1308.1314.1315(14~. ,. 1347(154j, 1.~59: I.M' Baumann, T.W. 1182(203,206), 1247 Baumgarten, H.E. 735, 737(51a), 862 Baurle, P. 1091, 1093, 1094, 1100(102d), 1108 Bauville, J. 1511(42), 1532 Baxendale, J.H. 682(8), 693 Baxter, 1. 502(633), 520 Baydar, A.E. 179(104), 212 Bayer, E. 587(231), 589(238,239), 633, 634 Bayer, E 506(671), 521 Bayer, R. 657, 667(40), 678 Bayha, C.E. 764(139), 800(269), 865, 868 Bayod, M. 477(226), 512, 905(52-94), 921 ~ e a kP., 714(53c), 725 Beam, C.E 1522(101-103), 1524(102), 1533 Beaman, A.G. 1131(52), 1150(103), 1243, 1244 Reardsley, G.P. 1154(114, 116), 1244. 1388(73), 1437 ' Beaton, J.M. 471(109), 510 Beauchamp, J.L. 704(16a), 723, 1065(63a), 1106 Beck, A.K. 222(21), 251, 472, 480(145), 499(577), 510, 519, 760(118c), 864 Beck, H.P. 1495(152), 1506 Becker, G. 178(97), 212 Becker, P. 475(181), 511 Becker, R.S. 672(58), 679 Becker, W. 178(97), 212 Beckwith, A.L. 874(12), 887 Reckwith, A.L.J. 1542(15h), 1564 Beddoes, R.L. 183(135), 185(146), 213 Bedeschi, A. 1188(222), 1247 Bcdford, C.D. 390, 392(204), 404 Bedford, G.R. 343, 344(127), 402 Bednareck, E. 890(17), 920 Bednarek, E. 190(188), 214, 718, 719(63a), 725 Bednarski, M.D. 1295(167), 1302 Beeken, P. 11,55, 71(139), 79, 290(21), 399, 483(284), 513 Begland, R.W. 1560(63), 1565 \
Begley, M.J. 187(165), 214, 1304, 1308, 1310, 1324(10), 1359 Begue, J.P. 479(254), 513 Behrens, U. 185(149), 213 Bekkum, H.van 469(51), 508,823(319), 869 Beldie, C. 261(28), 272 Beletskaya, I.P. 1507(16a, 17, 18b), 1531 Belikov, V.M. 245(137), 253, 415(49), 4.35 Belinka, B.A. 493(505), 518, 1530(118), 1533 Bell, A. 471(105), 510, 799(263), 867, 997(25), 1043 Bell, A.J. 1316, 1326-1328,1340(84), 1361 Bell, E.A. 885(38), 887, 951(85), 989 Bell, R.P. 697, 707(4b), 723 Bellamy, L.J. 69(355), 85 Bellanato, 1. 14(160), 73(363), 75(363, 365, 366),80, 85, 226(51), 240(109, 119), 241(51,109), 242(123), 243(127), 244(133, 135), 252, 253, 35&358(139), 359(144), 360, 361(146, 149), 362(146), 363(146, 149), 364(146), 369,371(164), 381, 385-388,391, 394(193), 402, 403,411(30), 412(40), 415, 416(30,52), 431(40), 433(52), 434, 435 Bellanoba, J. 719(68e, 68h), 725 Bellasoued-Fargeau, M.C. 596(260), 599(266), 634 Bellec, C. 890(18), 920 Belleman, P. 1206(275a), I249 Belley, M. 1176(187), 1246 Bellinghoff, R. 409(27), 434 Relluci, E 89, 92, 153, 154, 156(4), 210 Belsky, 1. 432(112), 436,489(435), 516 Beltrame, P.L. 947(73), 988 Belyaev, E.Yu. 829(336), 869 Delyaeva, O.Y. 552(107), 631 Betiaitn, J. 245(146), 254, 1511(41), 1532 Benary, E. 728(1), 861 Benckova, M. 454(513), 496(531), 518 Bende, Z. 720(72), 726 Bendel, P. 191(192), 214 Bender, A. 785(211), 866 Bender, P.E. 1186(215,216), 1247 Benders, P.H. 178(98), 182(130), 185(148), 212, 213, 998(37,3R), 1015(37), 1043 Benedek, E. 1180(201), 1247 Benedetti, E. 323(78), 401,549(85), 615(324), 617(322), 618(324), 630, 635, 751(105, 115), 752(105), 837(355), 864, 870, 997(28), 998(30), 1016(111), 1040(244, 245), 1043, 1045,1047, 1387(68), 1392(83), 1430(186), 1437, 1439,1560(62), 1565 Benedikt, B. 1346(152), 1.363 Benedus, A. 1392(82), 1437 Benedusi, A. 1022(139), 1045 Benetollo, F. 185(147), 213
Author index Benetti, S. 765(152), 865 Benicewicz, B.C. 722(85c, 86, 87), 726 Ben-Ishai, D. 504(642), 521, 1442(19), 1503 Benner, S A . 1284(127,128), 1302 Bennett, A.J. 1072(75), 1107 Bennett, G.B. 904(87), 921 Bennett, M.H. 1128(45), 1243 Benneville, P.L.de 469,471(27), 508, 981(201), 991 Benoit, R. 986(222), 991 Ben-Shoshan, M. 168(33), 210 Bensoam, 1. 794(244), 867 Benson, S.W. 259, 264(9a, 9b), 271 Bent, H.A. 225(48), 252 Benzel, M.A. 42(227), 82 Benzing, E. 469(39,49), 471(49, 102), 501(39), 508, 509, 778(179), 781(186, 189), 785, 786(214), 865, 866 Berchold, G.A. 308(57), 400,779(182), 866 Berchtold, G.A. 4(15), 76, 760(127), 785, 786(212), 801(270), 826(328), 864, 866, 868, 869, 1010(73), 1044, 1546(32), 1564 Bercz, J.P. 478(236), 512 Berde, H. 595(255b), 634 Berg, C. 890(19), 920 Berg, ti. 502(620), 520, 1443(21),1503 Berg, U. 184(141), 213, 423,424(79), 432, 433(121), 435, 436,561(145), 632 Bergbreiter, D. 246(156), 254 Bergbreiter, D.E. 1513(74), 1517(87b), 1522(107, 108), 1524(107, 110), 1532, 1533 Berge, J.M. 800(268), 868,998(40), 1043 Berger, G. 1199(250,251), 1248 Berger, L. 489(404), 516 Bergmann, A. 610(305), 635 Bergmann, E.D. 814(296), 843(372), 868, 870 Bergmann, N. 1261(46),1300 Bergmann, S.R. 1222(321), 1250 Berg-Nielsen, K. 556(1 It?), 6.31 Bergson, G. 471(142), 510, 1207(281), 1249 Berkelhammer, G. 1089(94), 1107 Berkowitz, W.F. 802(276), 868 Berlin, A. 979(191), 991 Berlin, K.D. 471(121), 510 Berlioz, C. 1119(13), 1242 Bernard, H.O. 501(604), 520 Bernardi, R. 543(66), 582(211a), 630, 633 Bernasconi, C.F. 1079(83as), 1107,1259, 1281(32), 1300 Bernauer, K. 924,928(1 I), 987 Bernhard, H. 1346(152), 1363 Bernhard, H.O. 936(45), 988 Bernheim, R.A. 394(206), 404 Bernstein, J. 177(95), 178(101), 179(95), 212 Bernstein, M.D. 960(108), 989, 1199(249), 1248 Bernstein, R.B. 48(261,262), 83
Berrada, M. 1016(112),1045 Berry, A. 1295(166), 1302 Bertagnolli, B.L. 1276(90), 1301 Bertele, E. 669(53), 678, 901(74), 921 Bertelli, D. 416(56), 4.35 Berthaud, J. 1182(205),1247 Berthelot, M. 1097(116b), 1108 Berti, E 998(30), 104.3, 1387(68), 1437 Berti, G. 615, 618(324), 635 Bertini 1. 1142(83), 1244 Berlino, J.R. 1144(89), 1244 Bertolasi, V. 89, 92, 153, 154, 156(4), 210, 398(222-224), 404 Bertulucci, F, 398(222), 404 Besendorf, H. 505(648), 521 Besseliivre, C. 484(297), 514 Bessiere, Y. 497(537), 518, 710(40e), 724, 1552(40), 1564 Bethell, D. 1458(75), 1504 Betz, 1. 426(91), 435 Beuerung, W.N. 1516(80), 1533 Bcugclmans, R. 484(297), 514 Beveridge, D.L. 54(289), 83 Bevins, C.L. 1063(58), 1106 Bewton, T.A. 674(59a, 59b), 675, 676(59b), 679 Beyerlin, H.P. 1316(81), 1361 Beyler, A.L. 1197(244), 1248 Beynon, J.H. 438(7), 457 Bhala, A.R. 176(82),212 Bhalerao, U.T. 967(133), 990 Bharathi, S.N. 962(121), 963(122), 989 Bhaskar, K.R. 1276(89), 1301 Bhat, V.V. 476(210), 512 Bhupathy, M. 1176(190), 1246 Bianchetti, G. 220(2), 221(3), 223(33), 251, 468(20), 469(34), 470(66,69), 494(509-511), 497(542,543), 508, 509, 518,785, 786(213), 843(373,377), 866, 870, 892(39-41), 920, 943(60), 988, 1025(146), 1045,1428(182a), 1439 Biba, V.1. 1459, 1460(82), 1504 Bielka, S. 1313(60), 1.361 Biemann, K. 473(160), 511 Bier, D.M. 1120(20), 1242 Bieraugcl, H. 1558(54), 1565 Bierbaum, V.M. 48(258), 83 Biere, H. 536(50), 630 Bieri, J.H. 172(62), 211 Bigelow, S.S. 390, 392, 393(205), 404, 424(84), 435, 1304, 1308, 1314, 1315(14), 1359 Biggs, A.I. 1055(19), 1105 Bigley, D.B. 262, 268(31), 273 Bignardi, G. 600(271), 601(272,275, 276), 634 Bignebat, J. 409(23), 434
Author index Bigot, B. 676(62), 679 ~ i g o n o A. , 837(355), 870 Bilger, P. 347-349,352(133), 402 Bilinski, V. 8021278, 280). 868 Binev, 1.G. 506(678), 521 Bineham. R.C. 241173). 80. 1512.1526. ~ i n k l e ~ , ~ ~ . ~ : ' 2 4 (25(190, 1 8 5 ) , 193), 81 Birch, A.J. 488(366), 498(552, 553), 515, 519, 1542(17b), 1544(20), 1546(25), 1548(35), 1555(44), 1564 Birkhofer, L. 475(175), 511 Birkofer, L. 57(306,307), 84,764(146), 865, 919(126, 127), 922, 1016,1018(110), . . 1045, 1373, 1382(%), 1436 Birladeanu, L. 56(299), 84, 261, 269(29), 273, 290122). 399 ~irlade'na;; L. 225(35), 251 Birnbaum, G. 1537,1539(9b), 1563 Birney, D. 1000(47), 1043 Bischofberger, N. 1295(167), 1302 Bisenieks, E.A. 168(31), 210 Bishop, D.1. 185(146), 213 Bisswanger, H. 1255(6), 1299 Bitter, 1. 169(38), 210, 720(72), 721(75), 726 B j o e ~ p P,. 984(217), 991 Bjork, EA. 1178(198), 1247 Bjorkquist, D. 1512, 1526, 1527(45b), 1532 Bjorkuist, L. 1512, 1526, 1527(45b), 1532 Bjorup, P. 740(74a), 863, 880, 882(33), 887 Blackburn, D.W. 1186(217), I247 Blackwood, R.K. 1507(2b), 1531 Blade-Font, A. 178(103), 212 Blaha, K. 4(27), 77, 468(3), 507, 696, 709(3a), 723, 730(7), 861, 969(143), 990, 1050(6b), 1104, 1366(3), 1435 Blair, P.A. 226(49), 252, 1512, 1525, 1528151b). 1532 Blake, A.J. 426,427(95), 436 Blakemore, R.C. 1229(339), 1250 Blanchard, E.P.Jr. 471(119), 510 Blanchard, 1. 237, 238(102), 253 Blanchard, M.L. 426(93), 435 Blanchard-Desce, M. 406(2), 434 Bland, R. 101, 106, 109(10),210 Blanton, C.D.Jr. 1190(232), 1191(233), 1247 Blanton, C.WJr. 552(106), 631 Blarer, S.J. 499(575), 519, 760, 776(118a, 118b), 864 Blarer, St.1. 474(163, 164), 511 Blaser, S.J. 248(180, 181), 254, 499(576), 519 Blau, K. 931(33), 987 Blazejewski, 1.-C. 761(135), 764(137,144), 864, 865, 1387(71), 14.37
Blazejewski, J.C. 764(144), 865 Blecher, 1. 7(65), 78, 309, 319(60,61c, 61g), 400, 897(56, 57, 60), 898(57, 60), 920 Blechert, S. 499(560), 519 Bleehen, N.M. 1128(44), 124.3 Bleidelis, Ya.Ya. 168(31), 210 Bleisch, S. 1398(97), 1437 Blenderman, W.G. 186(153), 213 Blicke, F.E 1189(225), 1247 Blomberg, R.N. 843(368), 870 Blomquist, A.T. 471(139), 510, 712, 713(46a). 724 Bloom, A. 647(16b, 17), 677, 1022(131), 1045,1381(56a), 1436 Bloomer, W.D. 1236(347,348), 1237(348, 350), 1251 Blount, J.F. 188(170), 214, 769(158), 865 Blumental, H. 2(1), 76 Blumenthal, H. 1050(1), 1104 Boamah, P.Y. 1417(149), 1438 Boar, R.B. 502(621,622), 520, 1442(14), 1503 Bobitt, J.M. 534(40), 629 Bobowski, G. 573(185), 633 Bocelli, G. 14, 21(163), 80, 167(21,23), 183, 189(137), 210, 213 Bochkareva, M.N. 1322(100), 1361 Bochow, H. 470(86), 509 Bock, C.W. 262(33b), 265(55), 268(33b), 273, 275 Bock, H. 69, 74(357), 85 Bock, H. 14, 21(171), 58(320), 80, 84, 428(98), 436 Bock, M.G. 1510,1512(37), 1532 Bocz, A.K. 491(452), 517 Bodendorf, K. 816(305), 868 Boder, G.H. 1133(56), 1243 Bodganowicz-Szwed, K. 1033(201), 1047
Bodnarchuk, N.D. 506(672), 521, 1318, 1340192). 1361 Bodor, N. 46(237), 82 Boekelheide, V 735, 737(50), 862 Boelens, H. 236(88), 252, 806(291), 868, 1003(50), 1030(191), 1044, 1046 Boer, T.J.de 470(72, 80, 85), 509 Boeshagen, H. 1206(273), 1249 Bogachev, Yu.S. 394(211), 404 Bogdanov, V.S. 1322(10&102), 1361 Bogdanova, G.A. 500(590), 519 Bogdanowicz-Szwed, K. 1028(178), 1046, (368, 369), 1251 Bogdanski, D.F. 1214(301), 1249 Boger, D.L. 1021(130), 1026(155-158), 1034(214-216,218,219), 1039(241), 1045-1047,1349(161, 162), 1363 Bogri, T. 1186(218), 1247
Author index Bohlmann, F. 484(299-304,306), 485(318, 320), 488(359), 489(379), 514, 515, 555(111), 631 Bohm, S. 802(279), 868, 1374(41), 1436 Bohme, E.H.W. 650(29), 678 Bohme, H. 307(54), 400, 468(15), 478(238b), 502(620), 508, 512, 520, 538(56), 582(21 Ib), 6.30, 6-33, 889(6), 914(115), 919, 921, 1314(73), 1361,1443(21), 1503 Bohme, H. 696(3d), 723, 731(15), 769(157), 862, 865 Bohme, R. 182(124), 213 Bohmer, K.H. 1405(116), 1438 Bohr, K. 1226(328). 1250 Bohrer, H. 1313(68), 1361 Bois, C. 169(39); 211 Boivin, T.L.B. 760(124), 802(275), 864, 868 Boksa. J. 23711061.253. 410128). .. ,. 434 ~ o l a n dW. , 9$0(147), 990 Bolis, G. 1352(168), 1363 Bolotova, G.T. 174(75), 211 Bombieri, G. 185(147), 213 Bon, M. 7(64), 78, 896, 898(52), 920 Bonanomi, M. 1374(40), 1436 Bondavalli, F. 494(515), 518, 834(348), 870, 975(172), 978(181), 990, 991 Bonenfant, A. 469(26), 506: Bonet, G. 802(277), 868, 1376(45), 1436 Bonet, J.-J. 187(164), 214 Bonitz, G.H. 476(194), 511 Bonner, T.G. 570(173), 632 Bonnet-Delpon, D. 479(254), 513 Bonnot, S. 1201(262), 1209(287), 1248, 1249 Bono, ET. 498(550), 519 Boob, H. 669(53), 678,901(74), 921 Booth, B.L. 1449(55), 1504 Boquant, J. 611(307), 635 Borch, R.E 960(108), 989, 1199(249), 1248 Bordin, E 601(277,278), 611(278), 634 Bordwell, F.G. 875(17), 887, 1257(23), 1299 Bores, G.M. 538(52), 630 Borges, A. 1261(44), 1273(713), 1300 Borgwardt, S. 1507(10a), 1531 Borisov, E.V. 48(244), 82, 967(135), 990 Borisov, Y.A. 244(131), 253 Borisov, Yu.A. 432(114), 436,719(67c), 725 Bork, J.F. 1458(74), 1504 Borman, J. 1206(274), 1249 Bormann, H. 544(74), 630 Born, T. 802(282), 868 Bornmann, W.G. 57(310), 84, 188(170), 214, 470(55), 508, 905(95, 96), 907(95), 921 Bornowski, B. 327, 347, 348, 353(92), 401 Borodaev, S.V. 1448-1450(46,47, 49), 1460, 1461(85), 1463(92-94), 1467(92-94, 102-106), 1468(102,110,112), 1469(102),
1575
1471(112,113), 1472(116, 117), 1475(102), 1476(92-94,132), 1477,1478(133), 1480(117,136), 1481(46,47,49, 93,94, 104, 105, 112), 1484(47,49), 1485(141, 142), 1486(141), 1487(85, 102, 141), 1488(141), 1489(141,142), 1490(142), 1492(102,113, 142). 1493(142), 1494(49), 1497(49,141, 142), 1499(116, 155, 156), 1501(157), 1502(116), 1503-1506 Borodaeva, S.V. 1463(92,94), 1467(92,94, 104), 1476(92,94), 1481(94, 104), 1505 Borondy, P.E. 1156(126), 1245 Boroschewski, G. 484(302), 514 Borowitz, 1.J. 695(1c), 723, 784(200,202), 789(234), 832(345), 866, 867, 869, 975(171), 990, 1016(106), 1045, 1366(15), I436 Borrachero, P. 75(365), 85, 226(51), 236(94), 241(51, 120), 252, 25.3, 36&364(146), 369, 371(164), 402, 403,719(68e), 725 Borrmann, D. 1314,1315(72), 1361 Borrmann, H. 14, 21(171), 80 Borsotti, G. 1447(44), 1503 Burlhakur, N. 448(26), 458 Bomm, O.N. 1191(234), 1247 Borvomvinyanant, U. 930(30), 987 Boryski, J. 1199(255), 1246: Bos, H.J.T. 1497(154), 1506 Bose, A.K. 567(164), 632, 736(56), 786(218), 863,866,1560(64), 1565 Bosnjak, J. 802(274), 868, 919(125), 922, 947(72), 988 Bossert, E 530(19), 629, 1333(125), 1334(127, 128), 1338(125), 1362 Bota, A. 1456(69), 1504 Bothner-By, A.A. 312, 314(64), 401 Botsch, H. 596(258), 634 Bottini, A.T. 473(157), 511 Bottod E.M. 551(99), 631 Boucher, R.J. 1008(69), 1044 Bouchon, G. 6(58), 78, 589(237), 634 Bouchoux, G. 437(1), 443(15), 449(1), 450(28), 455(28, 42), 456(43), 457, 458 Bouillon, G. 610(302), 635 Boukobbal, B. 443(15), 458 Bounds, P.L. 1063(58), 1106 Bourgeois, J. 368, 370, 371(161), 403 Buurgery, G. 504(643), 521 Bourgois, J. 75(364), 85 Bourguignon, J. 984(22 I), 986(222), 991 Bourn, A.J.R. 299(39), 400 Boutagy, J. 478(239), 512 Bouvier, P. 1232(342,343), 1250 Bovio, B. 176(84), 212 Bovy, P.R. 1226(330), 1250 Bowen, R.D.438(4), 442(12), 451(35), 457, 458, 532(29), 629
1576
Author index
Bowers, M.T. 52, 53(270), 83, 699(14), 700, 701(11), 723, 1065(63b), 1106 Boyce, W.T. 1453(62), 1504 Boyd, G.V. 179(104), 212, 1370(31), l4O2(l lo), l4O4(ll2), 1431(188), 1436, 1438,1439 Bovlev, A S . 1064(62). 1106 ~ozzini,S. 549(85'), f30, 1392(83), 1437 Brabek, L. 1062(50b), 1106 Bracho. R.D. 1512153~).1532 Bradamante, P. 75i, 7$(116), 786(220), 864 866, 1016(109), 1037(231), 1045, 1047, 1366(17), 1367(19), 1436 Bradamante, S. 979(191), 991 Bradford, M. 1424(169), 1439 Bradley, W. 488(373), 515 Braibante, H.T.S. 470(62), 509 Braibante, M.E.E 470(62), 509 Bram, G. 1507(18a, 20b), 1531 Brambilla, E. 1228(334,336), 1250 Bramhilla, R.J. 736(56), 86.7 Branceni, D. 1232(342), 1250 Branchaud, B. 470(58), 509 Brandangc, S. 491(456), 517 Branden, C.-I. 1292(153), 1302 Brandsma, L. 500(578), 519 Brandstrom, A. 1510(36), 1531 Brannan, M.J. 816(306), 869 Brannock, K.C. 4(14), 57,58(313), 76, 84, 471(104, 105), 509, 510,736, 738(54a), 746(88b), 760(126, 128, 130), 764(140), 799(263,264), 801(270), 863-865,867, 868, 908,912(103), 921,997(25), 1043, 1050, 1051(7b), 1105, 1329,1348(119), 1.762, 1433(193), 1439 Brannon, M.J. 1006(67), 1044 Branzoli, U. 1160(141), 1245 Braun, H. 9(111), 79 Braun, S. 334,338,342(108), 343(108, 125), 354(125), 401, 402,425(89), 435 Braunell, E. 1214(299), 1249 Braunstein, A.E. 1286(133, 134), 1302 Bravaya, N.M. 686(21), 694 Bravo, A.A. 963(122,123), 989 Bravo, P. 1037(225), 1047, 1428(182b),1439 Brazier, J.L. 1119(12, 13), 1242 Breccia, A. 1150(101), 1244 Brcckwoldt, J. 247(163), 254 Bredereck, H. 596(258,259), 598(264), 634, 1316(81), 1361 Breederveld, H. 502(624), 520, 844(385a), 871 -
Breitmaier, E. 6(58), 78, 292(2), 333(104a, 104b, 105), 334(104b, 105), 399, 401, 526(5), 539(58), 587(231), 589(237239), 590(240), 591(243, 244), 594(250), 629, 630, 633, 634, 761(133), 864
Bremer, J. 1 138(69), 1243 Bremser, W. 270(72), 277 Bren', V.A. 411(31), 434 Bren', Zb.V. 411(31), 434 Brenninger, W. 469(36), 508, 782(192b), 866 Breslow, R. 181(119), 212, 1255(2), 1259(37), 1264(53), 1299,1300 Bressler, R. 1139(72), 1243 Bretschneider, H. 491(454), 517 Brianso, J.L. 187(164), 214 Briatico, G. 3228(334), 1250 Brich, Z. 715(58~),725 Briehl, H. 1097, 1098(121), (122), 1108 Briet. P. 1508(30\. 1531 rillo on, D. SO?(&), 521 Bringhen, A.O. 1021(124), 1045, 1381(55), 1436 Brinker, B. 1413(137), 1438 Brinkmeyer, R.S. 731,778(25), 862 Brisse, E 183(134), 21.7 Britten, A.Z. 3(11), 76 Britton, R.W. 1507, 1508(26), 1531 Brizzolara, A. 3, 4, 8, 10, 13, 58(8), 76, 469, 472(35), 508, 695(1e), 723, 728(3), 735(3, 46), 736(3), 737(46), 741(3), 746(3,46), 778, 782, 787, 804, 806(3), 861, 862, 1001(49), 1044, 1050, 1052(5b), 1104, 1254(1), 1299, 1537(5), 1563 Brizzolarra, A. 1508, 1509(33b), 1531 Broaddus, C.D. 476(215), 512 Brocas, J.-M. 7(67), 78, 492(492), 517 Brockmann, M. 492(484), 517 Brodie, R. 1214(301), 1249 Broeker, J.L. 1061(47d), 1106 Broekhof, N.L. 478(244), 512 Broekhof, N.L.J.M. 479(246,247,249), 512 Brook, A.G. 8(78), 78,307(56), 400 Brookes, K.B. 852(398), 871 Brossi, A. 502(626, 630), 505(648), 520, 72 . -1.
Brovaretz, V.S. 1442(9), 1503 Brown, C.D. 705,710,711(23), 724 Brown, H.C. 56(303), 84, 832(341,342), 834(346), 869, 1058(26), 1105, 1134(59), 1243, 1444(33), 150.7 Brown, J.L. 715(58b), 725 Brown, J.M. 980(196), 991 Brown, J.W. 1550, 1561(39), 1564 Brown, K.L. 13, 14, 16(144), 80, 88, 89(1), 210, 225, 226, 228(46), 251, 290(19), 399, 407(14), 434 Brown, L.D. 25, 28, 54(201), 81,225(38), 251, 290(18), 399, 408(15), 434 Brown, N.M.D. 337,340-342(115), 402 Brown, P.B. 650(28), 678 Brown, R.D. 32(218,219), 82
Author index Brown, R.S. 58, 59(321), 84, 696(29c), 704(19a, 19b), 708(29c), 723, 724, 1072(75), 1107 Brown, T.J. 1229(339), 1250 Browne, E. 1210, 1241(289), 1249 Browne, L.M. 499(555), 519 Brownlee, R.T.C. 369(169), 403 Bruce, W.F. 843(368), 870 Bruche, L. 1397(96), 1437 Bmckner, S. 620(326), 635, 799(265), 868, 1037, 1038(233), 1047 Briiggemann, K. 610(305,306), 635, 659(43), 678 Bmgger, M. 722(79), 726 Bruice, P.Y 470(77, 78), 509 Bruice, T.C. 1053,1055, 1065, 1066, 1076, 1078, 1081, 1084, 1090(20), 1105, 1292(152), 1302 Bmmfield. M.A. 581(207). 633 Bmndish,'~.~ 1167('159);,1246 . Bmndle, C.R. 58, 59(317), 84 Brunerie, P. 552(105), 631 Brunet, 1.1. 478(231), 512 Bmnner, H. 547(83), 598(265), 630,634 Bruno, D. 490(439), 516 Brysen, T.A. 564(155), 632 Bryson, T.A. 476(194), 511, 712(46e), 724 Bu, Y.-F. 1338, 1346(137b), 1362 Buback, M. 610(303), 635, 1029(183), 1033(200), 1046,1047 Buchborn, H. 594,598(252), 634 Biichel, K.H. 491(449451), 51 7 Biichi, G. 372(172), 403, 473(160), 511, 661(47), 678, 902(77), 921 Buchman, 0.1167(157, 166), 1245, 1246 Buchschacher, P. 1003(54), 1044 Buchwald, L.S. 494(512), 518 Buchwald, S.L. 498(546), 519 Buck, L.de 506(656), 521 Buckley, D. 486(345-347), 514 Buckwalter, B. 1512, 1526, 1527(46a), 7577
Bucourt, R. 1537(6,9c), 1544(22), 1558(55), 1563-1565 Budesinsky, M. 362(152), 402 Budzelaar, P.H.M. 1495(152), 1506 Budzikiewicz, H. 451(29, 39), 458 Buechter, D.D. 1261(45), 1300 Buerger, W. 478(238a), 512 Buglakova, L.T. 1424(165), 1439 Buiter, F.A. 471(120), 510 Bujadiew, M. 711(44), 724 Bujtas, G. 448(21), 458 Bulbrook, H. 489(420,421), 516 Bull, J.R. 930(29), 987 Bullock, E. 507(680), 521
1577
Bundel, Y.G.225(43), 251, 284, 287(12), 292, 293(27), 294, 296, 320(12), 399 Bundel, Yu.G. 46(240), 48(241,242a), 82, 587(232), 633 Bundule, M.F. 168(31), 210 Bunnett, J.F. 1071(73), 1107 Bunton, C.A. 1079, 1089, 1091(80), 1107 Burch, J.M. 489(423), 516 Burford, A. 924(7), 987 Burgada, R. 492(485487), 517 Burgemeisler, T. 551(101), 565(158), 568(165), 631,632 Burger, A. 491(466), 517, 983(21I), 991 Bureer. K. 176(85b 212. 773(169bl. 865.
.
.
101),'1s'05 Burger, U. 1021(124), 1045,1381(55), 1436 Burgess, E.M. 1371(33), 1436 Biirei. D. 525. 592(2). 629 Burke, A. 475,498(180b), 511 Burke, J.A. 471(97), 509 Burke. T.R.Jr. 1153(113~.1244 ~ u r k e h U. , 24(176): 80" Burkhart, C.A. 1159(139), 1245 Burkus, J. 1507(8), 1531 Burmistrov, V.A. 245(136, 137), 253,415(49, 50), 435, 891(32), 920 Burnell-Curty, C. 491(477), 517 Bumham, B.S. 1178(196), 1246 Burnier, J.S. 1008(72), 1044 Burpit, R.D. 4(14), 76 Burpitt, B.D. 1329, 1348(119), 1362 Burpitt, R.D. 57, 58(313), 84,471(104, 105), 509, 510, 736, 738(54a), 746(88b), 760(126, 128, 130), 764(140), 799(263, 264), 801(270), 8634765,867, 868,908, 912(103), 921,997(25), 1043, 1050, 1051(7b), 1105, 1433(193), 1439 Burridge, P.W. 1156(123a), 1245 Burrows, C.J. 907(99), 921 Burstein, N.A. 1236, 1237(348), 1251 Burton, R. 1156(129), 1245 Burzlaff, H. 182(124), 213 Busch, D.H. 167(24), 210 Buschck, J.M. 704(19h), 723 Busetta, B. 178(103), 212 Busi, F. 682(8), 693 Buss, V. 1529(115a, 115b), 1533 Buswell, R.L 1512(49), 1532 Busygin, I.G. 6(61), 62(330), 78, 84 Butler, A.R. 1091-1093,1095(105), 1108 Butler, R.N. 4(13), 76, 184(144), 185(145), 277 ..
Buttero, P.del 167(21), 210 Butz, V. 994(23), 1043 Buxton, V. 682(9), 693
1578
Author index
Buysch, H.-J. 779(184), 781(187,190), 866 Buzas, A. 490(445), 51 7 Bycroft, B.W. 187(165), 214 Bylsma, F. 952(88), 989 Cabal, M.-P. 188(175), 214, 295, 322, 323(28b), 399,477(225), 512, 1029(185), I046 Caballero, EJ. 359(144), 402 Caira, M.R. 722(82b), 726 Cais, M. 446(18), 458, 1562(74), 1565 Calas, R. 9(92), 79, 492(480), 517 Calcagno, M.A. 473(151), 510, 1381(54),
.--
7dZh
A
Caldeira, P.P. 905(90), 921 Calderari, G . 826(323), 869, 1003, 1005(57, 58), 1044 Callaert, M. 1192(239), 1248 Calligaris, M. 13(145), 80, 225, 226, 228(45), 251, 751(97,102, 112), 752(102), 759(112), 864 Cambillau, C. 1507(20b), 1531 Cambridge, D. 1190(226), 1247 Cameron, A.F. 184(139), 213 Cammelli, L. 1228(335), 1250 Campaigne, E. 1424(169), 1439 Campbell, A.C. 1008(69), 1044 Campbell, J.A. 944(63), 988 Campbell, M.M. 1008(69), 1044 Camps, P. 826(325a, 325b), 829(335), 869 Camsonne, R. 1209(284), 1249 Canadell, E. 874(13), 887 Candy, C.F. 417(57), 435 Cano, F.H. 188(171,175), 214 Cantacuzene, D. 740(67-69), 863,875, 876(22-24). 887 ~antreil,T. 651(30), 678 Capon, B. 302, 305, 306,312(47), 313(65), 314(47). 315(65). 316-320(47). 400. 401. 8951898(49), 920,' 1065, 1066, 1080-1082, 1084, 1099(69), 1107 Capon, G.L. 1101(132b), 1109 Capponi, M. l094,1095(109a), 1108 Caprioli, R.M. 438(7), 457 Capuano, L. 1424(167), 1439 Capuano, L.A. 1512(49), 1532 Carboni, R.A. 506(676), 521 Cardellini, M. 962(116), 989, 1119(10), 1242 Carelli, V. 962(116), 989, lll9(10), 1242 Cariou, M. 461(4), 464, 958(104), 989 Carlassare, E 601(277,278), 611(278), 634 Carlier, R. 461(4), 464, 958(104), 989 Carlsen, S. 1127(36), 1243 Carlson, R. 9(105), 53(269), 79, 83, 221(10), 251, 470(56, 74, 75, 87), 471(56, 101), 472(56), 508, 509, 71 1(42a<), 724,
car~soh,R.G. 811(293), 868 Carlsson, S . 787(225), 867, 971(158-160), 973(164), 990, 1376(47b), 1399(102), 1436, 1437 Cannack, M. 484(315), 514 Caron, N. 1155(121a), 1244 Carpenter, B.K. 907(99), 921 Carpenter, G.B. 14, 21(167), 80, 712, 714(48b), 725, 1530(120), 1533 Carr, C.S. 785(210), 866, 940(55, 56), 988 Carr, R.M. 944(69, 70), 988 Carrell, H.L. 171(56), 211 Carroll, PJ. 186(153), 213 Carrupt, P. 880, 882(33), 887 699(15), 723, 740(74a), C a r ~ p tP.A. , 843(384), 863, 870, 984(217), 991 Carruthers, J.R. 182(125), 213 Carruthers, R.A. 886(39), 887 Carsky, P. 24(179), 80 Carson, J.R. 1156(127, 130), 1245 Carter, B.G. 852(399), 871 Carter, M.L.C. 189(179), 214 Casara, P. 1295(160), 1302 Casarini, D. 236(Y0), 252, 28Y(17), 2Y0(2U), 399,408(19), 434, 731(32), 862, 1056(24b), 1105 Case, W.G. 1121(21), 1242 Caserini, D. 32(215), 81 Caserio, M.C. 473(155), 511 Casey, A.C. 572(177), 632 Cashyap, M.M. 1229(340), 1250 Casolari, A. 577(195), 633, 968(137), 990 Casper, E.W.R. 789(234), 867 Cass, C.E. 1155(121b), 1244 Cassady, R.E. 652, 668(32), 678 Cassal, J:M. 1003(54), 1044 Cassio, C. 222, 223(25), 251, 307, 308, 320(55), 400 Cassis, R. 1018(117), 1045 Castells, J. 1265, 1266(56), 1300 Catalan, J. 48(243), 82, 697(8), 704(16d-f, 19c, 19d), 705(20), 707(27b, 27d, 28), 713(50), 722(80), 723-726 Caton, M.P.L. 470(59), 509 Catt, J.D. 496(532), 518 Caubere, P. 478(231), 512 Caubre, P. 1512(63), 1532 Cauliez, P. 957(103), 989 Cava, M.P. 978(185, 186), 991 Cavalleri, B. 1150(101), 1244 Cavanough, R. 749(91), 863 Cave, A. 476(201-203), 511 Cekovic, Z. 802(274), 868, 919(125), 922, 947(72), 988
Author index Celerier, J.P. 552(105), 564(151), 631, 632, 719(66), 721(77, 78), 725, 726, 890(21), 920. 975(178). 991 cellai,'~.1i52(h0), 1244 Cerda, E. 470(82), 509, 797(251), 867 Cernf, M. 489(416,417), 516 Cemtti, E. 1016(112), 1022(135), 1045 Cewinka, 0. 4(27), 77, 468(3), 489(389, 412), 490(436,437), 496(533), 507, 515, 516, 518, 696, 709(3a), 723, 730(7), 861, 907(101), 921, 969(143), 990, 1050(6b), 1104,1366(3), 1435 Cesario, M. 165(15), 210 Chaaban, I. 975(177), YYU Chaaban, 1. 532(26), 546(79), 629, 630 Chafetz, H. 475(177), 511 Chakrasali, R.T. 1353(175a),1363 Chakravarti, K.K. 944(65), 988 Chalabi, P.M. 1158(137), 1159(139), 1245 Champagne, 1. 236(83), 252 Champion, E. 1176(187), 1246 Chan, D. 795(248), 867,875(20), 887 Chan, T.H. 183(134),213, 829(337), 869, 1013(95), 1044 Chan, Y. 469(47), 508 Chang, D.W.L. 9(107), 79 Chang, M. 735, 737(50), 862 Chang, P.L.F. 301(40), 400, 1366(18), 1436 Chang, T. 1156(126), 1245 Chang, Y.C. 924(7), 987 Chang, Y-H. 979(189), 991 Chang, Y.-M. 1558(57), 1565 Chao, H.M. 484(307,308), 514 Chao, L.-Y. 1195(241), 1248 Chao, S. 916(116b), 921 Chapman, J.D. 1222(319), 1250 Chapman, O.L. 647(16a, 17), 677, 1022(131), 1045, 1381(56a), 1411(128), 1436, 1438 Chapman, R.W. 1175(185),1246 Chardon, C. 836(350b), 870 Charette, L. 1176(187), 1246 Charles, M. 236(75, 81), 252 Charrier, A. 1182(205), 1247 Charton, M. 369(170), 403 Chartrousse, A.P. 1091-1093, 1095(104), 110s Chamshin, V.N. 1026(149), 1046, 1349(163), 1363 Chassin, M.M. 1156(123b), 1245 Chastrete, M. 343, 345, 394(128), 402 Chastrette, E 1507(20a), 1531 Chastrette, M. 1507(20a), 1531 Chatani, N. 841(367), 870 Chatelain, P. 1192(239), 1248 Chattha, M.S. 9(115), 79 Chau, D.D. 1136(63), 1243
Chaudhuri, N.K. 1127(35),1242 Chauvet, A. 170(43), 211 Chauvin, J. 9(99), 79 Chavoix, C. 1200(258), . . 1226(327), 1248, 1250 Chawla, H.P.S. 951(86), 989 Chaykin, S. 1089(97), 1107 Chekrovn. I. 478(245). 512 Chen, B.C. 14, 21(164), 80,380(190), 403 Chen, B.Ch. 221(17), 251 Chen, B.-M. 1304, 1308(7), 1359 Chen, G. 1277, 1280(91), 1301 Chen, H.J. 1052, 1055, 1057, 1084, 1090(14), 1095(108), 1101(132b), 1105,1108, 1109 Chen, H.L. 1101(128), 1109 Chen, L. 1298(169), 1302 Chen, L.C. 534(39), 567(161), 568(168), 629, 632. 1387170). 1437 Chen, T.-Y. i0, ?0(125), 79, 470(91), 509 Chen, Y 916(116b), 921 Chen, Y.-T. 1255(11), 1264, 1265(55), 1266(55,57), 1299,1300 Chenard, B.L. 1026(148), 1046 Chenery, R.J. 1229(339), 1250 Cheng, C.-W. 9(117), 79,712,714(48a), 725 Cheng, T. 1285(129, 130), 1302 Cheng, Y . 4 . 1027(168),1046 Cherif, S.E. 501(599), 520 Chernov, G.S. 625(339), 636 Cheunn, H.T.A. 1136(63), 1243 ~hevaliier,A. 426(93), 435 Chevelot, L. 479, 482(265), 513 Chevolot. L. 476. 479. 4821204). ~ ,. 512 Chi, D.Y: 1216(310), 1250 Chiacchio, U. 506(679), 521 Chiang, Y. 709(35), 724, 1052(14), 1053(18), 1055(14, 18), 1057(14), 1058(32,33), 1060(34,35a, 35b, 36, 3% 39-41), 1062(41,49), 1063, 1064(32,33), 1065(18), 1074(78), 1077(36), 1083(87), 1084, 1090(14), 1093, 1095(33), 1097(121, 123), 1098(34,35a, 35b, 38a. 87, 88, 117, 121, 123), 1099(36), 1101(36, 3% 129), 1103(34,35a, 35b, 36, 3% 39-41), 1105-1109 Chiara, A. ll60(141), 1245 Chiara, J.L. 48(245, 251), 73, 75(363, 366), 76(367), 82, 85, 242(123), 243(127, 128), 244(129, 132, 133, 135), 253, 354(134), 372(175), 373(175,185), 374377,380(175), 381(134, 185, 193, 194),
1580
Author index
Chiara, J.L. (cont.) 416(30,52, 53), 431(40), 433(52,123), 434-436,719(67a, 68h), 725, 890(23), 891(25-27), 920 Chiavan, G. 1124(30),'1242 Chiba, T. 460(3), 464, 953,958(93), 989 Chickos. J.S. 258(14. 151. 259(21a<. 22). chidesk, C.G: 470(82): 509, 797(251), 867 Chigira, Y. 1459(80), 1504 Chigr, M. 1011(82), 1044 Childs, R.F. 247(167, 172), 254 Chin, D.H. 1150(106), 1244 Chin, 1. 1255(17),1299 Chinchilla, R. 1037-1039(239), 1047 Chiong, K.N. 534(40), 629 Chirakal, R. 1216(307), 1250 Chirigos, M.A. 1156(123b),I245 Chiu, E.T. 564(156), 581(206), 632, 633 Chiu, I.C. 648(21), 677 Chiu, Y.-Y. 269(70b), 277 Chizhov. O.S. 1457. 1458. 1469(73). , . 1504 Cho, H.550(92), 631 Cho, Y.R. 494(514), 518 Choi, Y.M. 1196(243), 1248 Choodromatidis, G. 1383(60), 1437 Chou, SSP. 470(76), 509 Chou, T.S. 478, 479(242), 512 Choubar, B.T. 71 1(41), 724 Choudry, D. 484(290), 513 Chow, Y.L. 9(107), 79 Chowdhury, B.K.R. 1315(80), 1361 Christen. P. 1274(78. 79). 1278(78). 1301 christensen, ~ . ~ . ' 1 & ( 2 7210 ), ' '' Christie, B.D. 486(354), 515 Christie, J.E. 1117(4), 1242 Chu, C.C.C. 468(24), 508, 737(63), 863 Chu, C.W. 470(76), 509 Chuaqui-Offernianns, N. 246(154), 254 ~hubl;,EL. 491(467), 517 Chubb, S. 1155(121e),1245 Chuche. 1. 611(3071. 635.9751178). 991 Chun, K.S. 186(159), 213 Chunfanr, H. 1154(117),1244 1269,1276(64), 1300 Chung, Chung, A.C. 955(99), 989,1257(23), 1262(48), 1269.1276(651.1299.1300 Chung, M . w . 186(156), ~ 213 Chupp, 1.C. 502(627), 520 Chupp, 1.P. 843(370), 844(385b, 3850, 845(38Sb),870,871,1188(220), 1247 Chumsova, S.G. 187(161),214 Chwang, W.K. 1077(81), 1099, 1100(126b), 1101(129), 1107, I109 Ciabattoni, J. 826(328), 869, 1010(73), 1044,
A:
Ciapetta, F.G. 1099,1100(127a),1109 Cistone, F. 960(109), 989
Citerio, L. 1382(57), 1392(81b,81c), 1436, 1437 Citroreksoko, P.S. 1182(203),1247 Citterio, A. 874(7), 887 Claramunt, R.M. 722(80), 726 Clardy, J. 646(15b), 647(16b, 17), 677, 1022(131),1045, 1381(56a), 1436 Claremon, D.A. 550(94, 95), 599(95), 631 Clark, F.O. 5, 12, 25, 29(56), 78, 408, 431(17), 434, 843(383), 870 Clark, J.C. 1214(302), 1249 Clark, R.A. 308,309, 319(58), 400, 843(374), 870, 896, 898(54), 920 Clark, S. 978(183), 991 Clarke, R.L. 471(115), 510 Clausen, M. 1026(151),1046 Clemens, D.H. 1316, 132&1328,1340(84), 1361 Clement, B.A. 816,818(304), 868, 1005(66), 1044 Clerc, T. 63(340), 84 Clerici, F. 1025(147), 1046 Clesse, E 237, 238(i02), 253,409(23), 434 Cleveland, P.G. 1411(128), 1438 Clinton, R.O. 471(115), 510, 1197(244), 1248 Clive, D.L.J. 760(123,124), 802(275), 864, 868 Clizbe, L.A. 505(649), 521, 1188(221),1247 Cloke, J.B. 489(422,424-426), 491(460), 516, 517 Coates, G. 1199(252), 1248 Coates. R.M. 56(301). 84. 479, 482(262). 513. 544(71), 563(150), 630, 6.32 Cocco, M.T. 1036(222,223), 1047, 1422(161), 1439 Cochran, D. 180(116),212 Cochran, D.W. 551(100), 631 Coenen, M. 761(134), 864 Coffman, D.D. 506(676), 521 Cogoli-Greuter, M. 1274(79), 1301 Cohen, D.M. 1178(198), 1247 Cohen, M.P. 1400(104), 1437 Cohen, R.M. 1216(309),1250 Cohen, S.G. 484(307.308). 514 Cohn, J.J. 506(673), 521 Colapret, J.A. 5, 8, 9(51), 77 Coleman, C.N. 1131(51), 1243 Coleman, L.E. 1458(74), 1504 Colcman, R.S. 1021(130),1045 Colens, A. 22, 23, 39(172), 80, 177(90), 189, 205(178), 212,214,225(47), 252 Collie, J.N. 3, 6(4), 76, 728(1), 861 Collins, C.J. 1495(150), 1506 Colonna, EP. 53, 58, 59(287), 83, 235(73), 236(78-SO), 252,346(131), 402,422(74), 435, 499(572,573), 519, 696, 708(29a), 724, 734(40), 749(96), 751(96, 108, 108,
Author index
1581
110, 111),758(108,108, 110, 111),862, 864, 1030(189),1046 Colonna, M. 167(23), 183, 189(137),210, 213, 486(348), 514, 836(352), 870 Colosimo, M. 1152(1lo), 1244 Colthup, N.B. 69(356), 8 5 Colvin, E.W. 312, 314(62), 400,494(507), 518 Colwell, W.T. 1147(95), 1244 Comar, D. 1199(250,251), 1200(260),1248 Combret, J.C. 500(580), 519 Combrisson, S. 221(8), 222,224(24), 251, 304, 308, 309(50), 400 Combs, C.M. 1121(22), 1242 Comer, W. 1135(60), 1243 Comet, E 1119(12), 1242 Comi, R. 491(474), 517 Comoy, P. 978(182), 991 Compagnon, P.-L. 1416(146), 1438 Cone. E.J. 10, 73(131). 79, 316, 317, 329, 342, 344(66), 401 Congiu, C. 1036(223),1047, 1422(161), 1439 Conia, J.M. 1508(30), 1531 Conlev. D.L. 1295(166). 1302 ~ o n n , ' ~ 1292(154, .~. i55), 1302 Conrow, K. 485(328), 514 Conrow, R. 927(23), 987 Conti. P.S. 1199(256). 1248 ~ontriras,R. lG(ld5), 215 Cook, A.G. 4, 5(41), ll(136, 141, 143). 13(41), 52(275), 53, 54(41), 56(304),
1080(84), 1081(74b, 86), 1097(121), 1098(86,121), 1107, 1108 Cordiner, B.G. 816(303), 868 Cordonnier, G. 1034(208), 1047 Corelli, E 608(296), 612(312), 635 Corey, E.J. 503(635), 520, 650(27), 678, 1510(37), 1512(37,52a, 52b, 57), 1519(52a, 52b, 57,95), 1528(52a, 52b), 1532, 1533 Corey, R.A. 1304(15,17), 1360 Cornea, E 408(24), 434 Cornfeldt, M.L. 538(52), 630 Cornforth, J.W. 1463(89), 1504 Cornu, P.-J. 978(182), 991 Corriu, R.J. 481(272), 513 Corriu, R.J.P. 8(82), 78, 236(76), 252, 303, 304, 306, 311(49), 400, 841(363), 870 Corsaro, A. 506(679), 521 Cortez, H.V. 749(95), 805(288), 864, 868 Corti, M. 1026(164a),1046 Cosentino, U. 14, 18(156), 80, 1304, 1308(13), 1359 Cossy, J. 624(332-334,337), 636 Costa, G. 177(94), 212 Costin, R.C. 904(88), 921 Costisella, B. 9(95), 79, 506(658), 521, 1372, 1401(34), 1436 Cota, D.J. 1447(45), 1503 Cotelle, P. 495(528), 518 Cotter, R.J. 473(159), 511 Couchouron, B. 365(157), 402, 638(1), 677, 718(62), 725 Cooldwell, C. 178(96), 212 Coulter. J.M. 969. 970(144). 990
873(4), 886, 889(2), 919, 983(209,210), 991, 994(6), 1043, 1050(6c), 1104, 1304, 1306, 1352(1), 1359, 1366(1a), 1435, 1441, 1442(1), 1502 Cook, A.H. 530(21), 629 Cook, C.E. 1164(151), 1245 Cook, G.R. 737,844(61), 863, 911(108, 109), 921 Cook, N.C. 488(360), 515 Cook, P.M. 652(32), 653(35), 657(39), 668(32), 678 Cooks, R.G. 438(7), 451(30), 457, 458 Cooper, C.S. 332-334(101), 401 Cooper, M.M. 621(327), 635 Cope, A.C. 473(159), 511, 816(302), 868 Copeland, R.F. 247(171), 254, 1061(48), 1106 Corain, B. 14, 18(161),80 Corbani, F. 944(67), 988 Corbier, 1. 736, 740(54e), 863, 904, 905(84),
Courts, A. 549(88), 630 Coussemant, F. 1092, 1101(106d), 1108 Couture, A. 643(11), 677, 1410(127), 1413(136), 1429(127), 1438 Couturier, D. 495(527,528), 518, 957(103), 989 Covey, D.E 1295(164), 1302 Covington, R.R. 1121(22), 1135(62), 1242, 1243 Coward, J.K. 1053, 1055, 1065, 1066, 1076, 1078, 1081,1084, 1090(20), 1105 Cowling, S.A. 231(59), 252 Cox, J.D. 262, 263(34b), 273 Cox, P.J. 746(86), 820(311), 863, 869 Cox, R.A. 1098(120), 1101(132a),1108, 1109 Cozzi, P. 1160(141, 142), 1245 Crahh, T.A. 471(137, 138), 510 Crabtree, 1.H. 416(56), 435 Craig, C.M. 500(581), 519 Craig, J.C. 481(273), 513 Craig, L.C. 489(395,398,420), 515, 516 Craig, N.C. 42(227), 82
O? I
,-A
Cordes, E.H. 1072(74a, 74b), 1075(74b),
1582
Author index
Creger, P.L. 735, 73?(51a), 862 Crellin, R.A. 885(38), 886(39), 887, 951(85), 989 Cremer, J.E. 1217(313),1250 Crenshaw, M.D. 478(243d), 512 Cresson, P. 736, 740(54e), 863, 904, 905(84), 921 Croce, P.D. 494(511), 497(542,543), 518 Croce, P.D.la 470(66), 509 Crocker, L.S. 1058(29), 1105 Cronauer, R. 994(17, 19), 1043 Crosby, J. 1281(113, 114), 1301 Cross, A.D. 1154(116), 1244 Cross, H. 506(658), 521 Crossie, D.A. 722(82a), 726 Crossley, N. 489(384), 515 Crossley, N.S. 489(386), 515 Crouch, R.K. 789(234), 867 Crout, D.H.G. 1266(59), 1300 Crouzcl, C. 1198(248), 1201(262), 1209(284, 287), 1248,1249 ~ruickshank,ER. 259, 264(9a), 271 Csanalosi, I. 1121(21), 1242 Csizmadia. I.G. 24(178). 27(209). 80. 81 ~sizmadia;V.M. 1057,'i09i, lo&, i096, 1099, 1101,1103(103), 1108 Cuivigny, T. 1520(96, 97), 1533 Cunico, R.E 492(483), 51 7,1022(140), 1045, 1394(88), 14-77 Cunningham, D. 184(144), 185(145), 213 Cunningham, R. 826(327), 869, 1014(96), 1045, 1546(29b), 1564 Cupper, R.E. 499(567), 519 Cure, J. 62(332), 84 Curphey, T.J. 468(24), 508, 737(63), 738(64), 86.7 Curran, A.C.W. 588, 590(235), 634 Curtiss, L.A. 256, 265(6), 271 Cuvigny, T. 1509(34a-c), 1514(76), 1531, 1533 Cvekovic, M. 919(125), 922 CvetkoviE, M. 802(274), 868, 947(72), 988 Czenuinska, E. 237(106), 253, 410(28), 434, 584(220), 590(241), 633, 634 Czuba, L.J. 1507(24b), 1531 Czugler, M. 169(38), 210
124), 344(11 I), 401, 402,408(20, 21), 409(20, 21, 26), 411(32), 434, 891(31), 920 Dahl, L.E 175(78), 212, 1155(118a),1244 Dahlberg, D.B. 1074(78), 1107 Dahlquist, K.I. 719(68j), 725 Dahlqvist, K.4. 413, 414(42), 427(96), 434, 436 Dahne, S. 258(13), 271, 327(83, 86, 87, 89, 91, 92, 9 9 , 328(86, 87, 91). 347, 348, 353(92), 401 Dai, S. 683(11), 693 Daigo, K. 1274(72), 1300 Dale, J. 428,429(99), 430(103), 436 Dall'acqua, E 185(147), 213 Dalla Croce, P. 843(373, 377), 870, 8Y2(3941), 920 Dalley, N.K. 172(63), 211 Dalling, D.K. 290(23), 399 ~altonyD.R. 544(73); 630 Dalton, L. 183(135),213 Dalv. C.J. 119012281.1247 J.W. 973(i62);>90 Daly, L.H. 69(356), 85 Daly, W.H. lO(120, 123), 79, 318(70), 401, 470, 472(70), 509 Damico, R. 476(215), 512 Damm, L. 13, 14, 16(144), 80, 88, 89(1), 210. 225. 226. 228(46), , ,. 251,. 290(19). . , 399, 407(14), 434 Damrauer, R. 493(504), 518 Dana, G. 324(81), 401, 497(539,540), 518, 1555(45), 1564 Dancso, A. 797(260), 867 Dane, E. 567(162, 163), 632 Danen, W.C. 879(28), 887 Daneo, S. 1037(232), 1047 Dang, Q. 1034(216), 1047 Dang, T.-P. 979(192), 991 D'Angeli, E 14, 18(161), 80 D'Angelo, J. 478(232), 512 Daniel, H. 492(502), 518 Danilov, S.N. 1'495(149), 1506 Danishefsky, S. 749(91,92), 826(327), 863, 869. 1014(96). 1045. 1546(29b). 1564 ~anishevsk~,\~.'221(16),251 Dannals, F.R. 1204(269), 1248 Dannals, R.E 1199(256j, 1202(266), . . 1203(267),1248' Dannhardt, G. 14, 18(154),80, 477(220), 512.551(1011.564(152). 565(157.1581.
Dabrowski, J. 6, 7(62), 42(228), 65(347), 68(347, 348), 75(348), 78, 82, 85, 237(96-101), 238(96, 97), 252, 253, 327(93, 94), 329(96), 334(94,96), 335(109), 337(111), 338(94, 96, 110, I l l ) , 342(93,
1358(104),1362 Danusso, F. 468(18), 508 Danzin. C. 1295(160). 1302 ~apporio,P. 1420(1;6), 1438 Daran, J.C. 193(201), 215
Cram, D.J. 715(55b), 725 Crane. L.E. 1388(731. 1437
D~G;
\
,
Author index Dardel, F. 1273(70), 1300 Dardis, R.E. 476(194), 511 Dargelos, A. 225(36,37), 251, 705(21), 710(21, 40d), 724 Dargent, F. 1199(254), 1248 Darlegos, A. 25(197, 198), 81 Das, M.L. 1274(71), I300 Das, P.K. 406(4), 434 Dasher, L.W. 1522(101), 1533 Dashwood, R.H. 1157, 1158(133), 1245 Date, T. 173(68), 192(199), 211, 215, 965(132), 990 Daub, 1. 426(91), 435 Dauben, W.G. 826,829(329),869, 1546, 1548(29a), 1564 Daum, G. 57(306,307), 84, 475(175), 511, 919(126,127), 922 D'Auria. M. 944(66). 988 ~ausmann,D. 7<7(i57), 867 Dauth, W. 994(24), 1043 Dauzonne, D. 797(261), 867 Dave, K.G. 488(364), 515 Davenport, K.G. 1522, 1524(107), 1533 Davidcnko, T.I. 1467(107), 1505 Davidsen. H. 3,. 715). , ,. 76,. 468114). 508, l050(2), 1104 Davies, D.W. 532(29), 629 Davies, J.M. 816(303), 868 Davis. C.S. 983(211). 991 ~ a v i sD.A. ; 1167(162), 1246 Davis, D.W. 54(288), 83, 704(18), 723 Davis, F.A. 947(78), 988, 1366(18), 1436 Davis, H.E. 764(140), 865 Davis, K.L. 538(52), 630 Davis, R.E. 979(194), 991 Davison, G.J. 846(392), 871 Dawson, D.J. 1442(20), 1503 Dayagi, S. 502(625), 520, 1508(32a), 1531 Dean, C.S. 816(303), 868 Dean, D.C. 190(186), 214, 1176(189), 1246 Dean, EM. 1401(107), 1438 Dean, R.T. 476(197), 488(370), 511, 515 Dehacker, M. 957(103), 989 Debaerdemaeker, T. 14, 18(154), 80, 188(173), 214 Deblaton, M. 1192(239), 1248 Debleds, EL. 1091-1093,1095(104), 1108 Debmyene, D. 1200,1201(259), 1248 De Buyck, L. 9(90), 78 Decker, H. 475(181), 511 Decker, O.H.W. 917(120-122), 918(122), 921, 922 Deckers, F.H.M. 919(124), 922 Declercq, J.P. 22, 23, 39(172), 80, 166(16), 167(25), 175(77), 177(89, 90), 189(178, 182, 183), 193(124), 205(178), 210,212, 214, 215
De Clerq, E. 1199(255), 1248 Declerq, 1.P. 225(47), 252 De Corte, B. 736, 845(60), 863, 913(113), 921 Didek, V. 11(135), 79, 489(402,403), 516 Dedina, J. 366, 367, 371(159), 402 Defrees, D.J. 24(185), 81 Degani, Y. 502(625), 520, 1508(32a), 1531 De Graaf. S.A.G. 1545(24). ~ ,. 1558159.60). ~ . ,, 1564,1565 De Gmff,S.A.G. 288,289,291,316, 317,319, 344,345(15), 399 DeGraw, 1.1. 1147(95), 1244 DeHaven. R.N. 1176f187). 1246 Dehnel, A. 47~(250):512 Deitchman, D. 1135(60, 61), 1243 De Jeso, B. 474(171), 511, 843, 856, 858(380), - ,
78
Dejonghe, J:P. 9(8$), Dejroongraung, K. 261(26), 272 Dekarch, G.I. 506(672), 521 Dekerk, 1.-P. 1020(123), 1045 De Kimkpe, N. 913(113), 921 De Kimpc, N. 9(90), 78, 731(10), 736, 845(60), 861, 863 Dekker, T.G. 761(133), 864 Dekker, Th.G. 289, 291, 318, 344(16),399 Dekkers, A.W.J.D. 1003(55), 1044 De La Cmz, C. 721(75), 726 Delaney, R.D. 715(57a), 725 Delarbi, D. 368,370, 371(161), 403 Delbecq, E 875(14), 887 Del Bene, J. 46(238), 82 Delhalle, J. 1097(114), 1108 Della Bmna, C. 1188(222), 1190(230), 1247 Della Croce, P. 223(33), 251, 1030(195), 1046 Deloisy, E. 721(78), 726 Delpech, B. 479(253), 513 Demerseman, P. 797(261), 867, 1183(209), 1184(210), 1247 Demerson, C.A. 1172(178), 1246 Demidenko, E.T. 1471(114), 1505 Deming, S.N. 99(9), 210 Demir. AS. 1851151). 213. 1402(111b , ,. 1438 ~ c m o t t cR. , 11&(2$), 12'48 Dem'yanets, Z.K. 1322(100), 1361 Dence, C.S. 1217,1218(315), 1222(321), 1250 Denhez, J.P. 451(32), 458 De Niro, M.J. 1279(102), 1301 Denise, B. 193(201), 215 Denissen, J.F. 1241(358), 1251 Denmark, S.E. 372(i74j, 403 Dennilaurer, R. 1255, 1264, 1266(9), 1299 Dennis. R. 1135(60). 1243 Deno, N.C. 1092, lh1(106c), 1108 De Paulis, T. 1167(162), 1246
1584
Author index
De Porteere, M. 1370(29), 1436 DePuy, C.H. 48(258), 83 Dereppe, J.M. 189(183), 214 Derguini-Boumechal, E 497(537), 518, 1552(40), 1564 Derrick, P.J. 451(31), 458 Desaee. M. 1119(13b 1242 Desai, M.C. 951(86), 989 Descotes, G. 236(75,81), 252 Deshayes, C. 603(282), 635 Desilvestro, H. 10(124), 58, 59(323), 79, 84, 225(41), 251, 283, 290, 303, 304, 307, 311, 312, 314(10), 399, 408(16), 434, 696, 708(29e), 724, 1058(30b), 1105 Desimoni, G. 600(269), 634, 751(99), 864, 994, 1011(2), 1043 Desmaele, D. 731(22), 848, 852, 857, 859, 861(395), 862, 871, 1041(249), 1048 deSolms, S.J. 653(33,36), 678 Destro, R. 14, 18(156), 80, 1304, 1308(13), 1359
Deswarte, S. 890(18), 920 DeTar, M.B. 647(18b), 677 DeTitta, G.T. 1280(107), 1301 Dev, S. 951(86), 989 Devasagayaraj, A. 968(140), 990 Devenport, K.G. 1524(110), 1533 Devi, P. 1561(68), 1565 De Voe, R.J. 997(27), 1043 devries, L. 676(61), 679 De Wall, H.L. 491(447), 517 Dewar, M.J.S. 24(173-175), 39, 45(174), 48(174, 175), 80, 907(100), 921, 924(14), 987, 1485(143), 1506 Dezhu, W. 1154(117), 1244 Dhawan, K. 246(152), 254 Dhawan, K.L. 1511(42), 1512, 1527(50b), 1532
Dhimane, H. 975(178), 991 Dhout, J. 491(469), 51 7 Dhumrongvaraporn, S. 1015(99), 1045 DiAnez, M.J. 240(110), 253,360(147), 402
Diassi, P.A. 484(309, 311), 514 Dibo, A. 179(109), 212 Dickmann, S. 1138(67), 1243 Dideberg, 0. 166(17), 210 Dieck, H. 492(484), 517 Diederich, E. 1261(47), 1300 Dieter, R.K. 1312(45), 1360 Dietrich, H. 1530(121), 1533 Dietz, F. 432(116), 436 Digenis, G.A. 1138(66), 1200(257), 1243, 1248
Dijkink, J. 1003(55), 1044
Dikdan, G. 1269,1275(63), 1300 Diksic, M. 1205(270), 1248 Dillen, J.L.M. 180, 181(117), 212 Dillmenn, R. 484(296), 513 Di Mari, S. 1286(139), 1302 DiMartino, M. 1186(215), 1247 DiMartino, M.J. 1186(216), 1247 Dinculescu, A. 1502(158), 1506 Dinkel, R. 488(374), 515 Dinur, U. 247(168), 254 Dion, H.W. 1155(118a, 118b), 1244 Dipple, A. 171(56), 211 Di Salle, E. 1228(334), 1250 Disbrow, G.L.1295(166), 1302 Dische, S. 1128(45), 1243 Dischino, D.D. 1121(22), 1222(320), 1242, 1250
Disselknotter, H. 1443, 1444(26), 1503 Disselnkotter, H. 503(641), 521 Distefano, G. 53, 58, 59(287), 83, 422(74), 435, 696, 708(29a), 724 Ditchfield, R. 25(191, 192), 81 Dittmer, D.C. 301(40), 400, 1366(18), 14.76 Dittus, G. 1304(3), 1359 Dixon, C.S. 816(303), 868 Dixon, D.A. 25(206), 33(220), 48(263), 49(264), 52, 53(263), 81-83, 256, 258,262, 263(5a<), 271, 698(9, lo), 699(10), 700(9, lo), 701(10), 705(24), 723, 724, 1062(50e), 1097(50e, 113), 1106,1108 Dixon, K. 500(585, 587), 519, 1078, 1079, 1086,1089(79), 1107 Djarrah, H. 180(112), 212 Djerassi, C. 10(122), 79, 441(11), 451(29, 39), 456(44), 458, 470(53), 489(384,386), 503(637), 508,515,520 Doh& J. 489(408), 516 Doble, A. 1217(312), 1250 Dobrovolny, M. 264(52a), 275 Docampo, R. 1255, 1263(15), 1299 Docherty, V.J. 406(3), 434 Dockner, T. 567(162,163), 632 Dodiuk, H. 432(112), 436 Dodson, R.M. 606(293), 635 Doering, E.E.von 225(35), 251 Doering, W.V.E. 261, 269(29), 27.7 Doering, W.von 290(22), 399 Doering, W.von E. 56(299), 84 Doetz, K.H. 797(252), 867 Doi, M. 641(6d), 677 Dolak, T.M. 1135(62), 1243 Dolan, L.A. 502(626), 520 Dolfini, J.E. 695(1g), 723 Dolling, W. 1313(67-69), 1361 Dolmazon, R. 816(308), 869 Domalski, E.S. 259(19), 264(48), 267(19), 271, 274
Author index Domaschke, L. 9(88), 78, 1316(82), 1361 Domeier, L.A. 490(438), 516 Domelsmith, L.M. 225(40), 251 Domelsmith, L.N. 58, 59(322), 84, 696, 708(29d), 724 Domiano, P. 165(14), 210 Domingo, L. 1265, 1266(56), 1300
Domscike, G . 558(12ij, 560(140), 561(143, 144), 631, 632, 764(143a, 143b), 865, 1021(129), 1045,1398(97), 1437 Donaghue, E. 760(129), 864 Donchi, K.E 451(31), 458 Dondoni, A. 176(81), 181(122), 212, 213 Donia, R.A. 944(63, 64), 988 Donner, D.B. 506(666), 521 Donoghue, E. 580(202), 633 Donskikh, V.I. 492(497), 518 Dooyewaard, G. 470(85), 509 D'Orazio, P. 1414(138), 1438 Dorfman, L. 240(116), 253, 580(202), 633 Dorfmann, L. 760(129), 864 Dorie, 1. 294, 296(32), 298(34), 328, 329(97), 348(32, 97), 400, 401, 709(30a), 724 Dorie, J:P. 321, 325(75), 401 Dorman, L.C. 70, 71(360),85, 221, 235, 236(15), 251, 732(34), 862 Dorme, R. 740(67, 68), 863,875, 876(22,23), 887 Domei, G. 964(126), 989 Domhoffer, MS. 1175(184), 1246 Dornow, A. 544(74), 630 Dorofeenko, G.N. 1456(68-72), 1467(107, 108), 1471(114), 1502(158), 1504-1506 Dorokhov, V.A. 1322(100-102), 1361 Dorr, E 428(100), 436 Dorrenbacher. R. 994(21). 1043 Doshi, H.544(73), 630 Datz, K.H.994(14), 1043 Doughty, M.B. 1255,1264,1266(10), 1299 Douelas. A.W. 224(30). 251.287(13). . ,. 399 ~ouglas;B. 484(3i5),'514 Douglas, J.E. 230(55), 252, 407,414(7), 434 Douglass, C.H. 231(57), 252 Douglass, C.H.Jr. 25(206), 81, 256, 258, 262, 263(5b), 271, 705(24), 724, 1062, 1097(50e), 1106 Dowd, R. 1508, 1509(33a), 1531 Dowd, S.R. 7, 8(68), 78, 245(139), 253, 695(1f), 723 Downing, A.P. 236(92), 252, 416, 417(55), 435 Dovle. G. 1123(27). 1242 ~ r a c h B.S. ; 1442(9), 1443(24), 1503 Draganic, I.D. 682(10), 693 Draganic, X.D. 682(10), 693 \
Dralle, H. 530(20), 629 Draper, H.H.330(106), 401 Draths, K.M. 1295(165, 166), 1302 Dreiding, A.S. 168, 169(34), 210, 473(154), 475(154, 179, 180a), 498(180a), 511, 800(268), 802(278,280), 868, 998(40), 1043 Dreier, C. 414(43), 434 Dreme, M. 173(64),211 Dressler, V. 816(305), 868 Drexler, A.J. 1120(20), 1242 Drodack, J.W. 1216(310), 1250 Drouet, J.P. 834(349), 870, 974(167), . . 990 Drucy, J. 473(156), 511 Dmelinger, M. 245(142), 253, 843(369), 870, 1512(55).1532 Druet, ~.~:1098(120),1108 Dmey, I. 488(361), 515 Dmlinger, M. 1512(69), 1532 Drummond, G.S. 1241(359,361), 1251 Dub&,1. 1537(6), 1544(22), 1563, 1564 Diiber, E:O. 8(80), 78 Dubiez, R. 1410, 1429(127), 1438 Dubini, A. 1228(335), 1250 Dubois, J. 59(326), 84 Dubois, J.-E. 1507(15), 1531 Dubois, P. 719(69), 725 Dubonosov, A.D. 1501(157), 1506 Dubur, G.Y. 550(97), 631 Dubur, G.Ya. 168(31), 210 Duburs, G. 530(17), 629 Duchamp, D.J. 470(82), 509, 797(251), 867 Duchon d'Engenieres, M. 1554(43), 1564 Duc Van Pham, I. 1125(34), 1242 Dudek, B.Y. 342, 349(121, 123), 351, 352(121), 402 Dudek, G.O. 6, 7(60), 78, 240(112), 253, 337(114). 340(114, 116). 342(114, 116, 920 Dudek, V 489(407), 516 Dueber, E.O. 491(478,479), 517, 845(390), R77 ",=
Duelfer, T. 1175(186), 1246 Dufay, P. 1537(9c), 1563 Duff. S.R. 10261158L 1046 Duffaut, N. 9(92j, 79; 492(480), 517 Duffield, A.M. 441(1 I), 458 Duflos, I. 986(222), 991 Dufoy, P. 1558(55), 1565 Dugas, H. 501(602), 520 Duhamel, L. 9(96, 97, 99, 100, 103, 104, 116), 79, 221(8, 9), 222(1&20,24), 224(24), 251, 304,308,309(50), 400,468(17,22), 471(99), 472(22), 494(516), 508, 509, 518,
1586
Author index
Duhamel, L. (cont.) 735(43), 790(236), 862, 867, 952(90), 989, 1530(119), 1533 Duhamel, P. 9(96, 97,99, 103, 104), 79, 221(8, 9), 222(20), 251, 304,308, 309(50), 400, 468(22), 471(99), 472(22), 508, 509, 592(245), 634 Duhamel, P.D. 222, 224(24), 251 Duke, R.E. 1558(56), 1565 Dulou, R. 64, 70(352), 85, 469,472(29), 508, 1084(89), 1107 Dumas, D.P. 1298(169), 1302 Dumas, F. 731(22), 848, 852, 857, 859, 861(395), 862, 871, 1041(249), I048 Dumas, S. 476(207), 512 Dunathan, H.C. 1286(142,143), 1302 Dunaway-Mariano, D. 916(116a), 921 Duncan, D.R. 1197(245), I248 Dunham, D.J. 823(320), 869 Dunitz, J.D. 13, 14, 16(144), 80, 88(1, 3), 89(1), 93, 146(3), 210, 225, 226, 22X(46), 251, 290(19), 399, 407(14), 434, 669(53), 678, 901(74), 921, 1507(6), 1531 Dunn, L.C. 1016(100), 1045, 1558(57), 1565 Dunoguks, J. 9(92), 79, 492(480), 517 Dunstan, S. 486(344-346), 514 Dupas, G. 984(221), 986(222), 991 Duplatre, G . 685(16, 17), 686(17), 693 Dupon-Durat, H. 1199(249), 1248 Dupont, L. 166(17), 210 Du Pree, L.E.Jr. 475(190), 511 Dupuis, P. 64(351), 85 Dupuy, J.M. 1184(210), 1247 Duquette, L.G. 70, 71(360), 85, 221, 235, 236(15), 251, 732(34), 862 Durin, C. 944(62), 988 Durand, H. 237(103), 253 Durant, G.J. 1229(339), 1250 Durbeck, H.W. 358(143a, 143b), 359(143b), 402 Durham, L.J. 1155(1Ma), 1244 Durst, H.D. 960(108), 989 Duschinsky, R. 1131(52), 1150(103), 1243, 1244 Dutta, C.P. 534(40), 629 Duttka, L.L. 358, 359(143b), 402 Dutton, RE. 796(250), 867, 994(13), 1043 Dutuit, 0. 450, 455(28), 458 Duvoisin, R.C. 1235(346), 1251 Dvortsak, P. 597(262), 634, 720(72), 726 Dvoryantseva, G.G. 171(51), 211 Dwuletzki, H. 491(465), 517 Dvachkovskii, F.S. 686(19, 21), 693, 694 ~ i d aF., 1261(41,42), 1266, 1278(41), 1281(41,42), 1283(41), 1300 Dyke, S.E 4(33), 5(33, 50), 53(33), 77, 468(7, 8), 508, 873(5), 887, 1366(1d), 1435
Dykes, S.F. 280(la), 399 Dykstra, C.E. 24(182), 42(227), 81, 82 Dyomina, L.M. 1453(67), 1504 Dyong, I. 837(358), 870 Dyusenova, Z.M. 844(385e), 871 Dzakpasu, A.A. 924(18), 987 Dzurion, P. 1227(331), 1250 Eades, R.A. 25(206), 33(220), 49(264), 8 1 4 3 , 231(57), 252, 256, 258, 262, 263(5a, 5b), 271, 698, 700(9), 705(24), 723, 724, 1062, 1097(50e), 1106 Eastham, J.F. 1495(150), 1506 Eberle, M. 826(323), 869, 1003, 1005(58), 1044 Eberlein, M.N. 530(15), 629 Eberlin, M.N. 48(246), 82, 719(65), 725, 890(22), 920, 1386(67), 1437 Eberz, W.F. 1098(124), 1109 Ehner, C.R. 500(597), ,520,971(1 54), 990 Eby, C.J. 1453(63), 1504 Eckardt, W. 781, 782(191), 866 Eckelman, W.C. 1216(309), 1250 Eckle, A. 1398(98), 1437 Edelson, E.H. 672, 676(57), 679 Edlund, U. 471(142, 143), 510 Edoho, B.J. 167(26), 210 Edwards, O.E. 936(46), 988 Edwards, R.M. 1190(227),1247 Effenber~er,E 598(264), 634, 789(233),
.
,.
Egan, c.-81'6(303), 868 Egan, R.W. 1175(185), 1246 Egberink, R.J.M. 182(130), 185(148),213, 998(37,38), 1015(37), 1043 Ege, S.N. 189(179),214 Egert, E. 173(69), 180(112),211, 212 Eguchi, S. 644(13), 677 Ehler, D.S. 1139(73), 1243 Ehrenkaufer, R.L. 1217(311), 1250 Ehrenson, S. 369(169), 403, 684(14), 693 Eian, G.L. 647(16a, 17), 677, 1022(131), 1045, 1381(56a), 1436 Eibler, E. 551(101), . .~564(152), . .~576(191), . , 631633 Eichenauer, H. 1522(104-107), 1524(107), (71), 1532, 1533 Eicher, T. 189(180), 214, 802(279,282), 868, 1374(41), 1436 Eicken, K.R. 901(71), 921 Eickhoff, K. 1163(148), 1245 Eiden, F. 10(134), 73(362), 79, 85, 471(124), 498(548), 510, 519, 594, 598(252), 605(286), 634, 635, 1398(98, 99), 1437
Author index Eiglsperger, A. 423,424(79), 435 Eilenberg, W . 462(6), 465, 569(171, 172), 632, 954(97), 989 Eisenbraun, E.J. 10(122), 79 Eisner, U. 182(125), 213, 483(285), 499(559), 513, 519, 530(18), 629 Eissenstat, M.A. 1510(39), 1532 Eklund, H. 1292(153),1302 Ekwuribe, N.N. 481(273), 513 El-Barbary, A. 971(159), 990 El-Barbary, A.A. 171(54), 211, 973(164), 990 Elburg, P.van 479(249), 512 Elder, R.C. 478(243d), 512 Eldin, S. 1060, 1062(43a, 43b), 1106 Elekes, 1. 1367(158), 1245 Elfert, K. 826(324), 869 Elguero, J. 25(197, 198), 53(267), 81, 83, 178(103), 187(166), 212, 214, 225(36, 371,251, 697(8), 704(16e, 16f), 705(21), 707(27b), 709(38), 710(21,38, 40d), 713(50), 722(80), 723-726, 1051, 1053, 1065(12), 1105, 1123(26,28), 1124(26), 1149(97, loo), 1242,1244 Eliel, E.L. 746, 809(87), 863, 1058(30a), 1105, 1507(3), 1531 Elitsov, A.V. 721(76), 726 Elkik, E. 57, 58(312a, 312b), 64, 70(352), 84, 85, 469(29), 471(114), 472(29), 508, 510, 735(53), 863, 875(21), 887, 1050, 1051(7a, 7c), 1084(89), 1105, 1107 Ellenberg, H. 468(15), 508 Ellenberger, M.R. 25(206), 33(220), 48(263), 49(264), 52, 53(263), 8143,231(57), 252, 256, 258, 262,263(5a-c), 271, 698(9, lo), 699(10), 700(9, lo), 701(10), 705(24), 723, 724, 1062(50e), 1097(50e, 113), 1106, 1108 Ellermann, K.H. 1421(159), 1439 Elliot, J.E. 182(126),213 Ellis, M.C. 489(427,431), 516 Ellis, R.L. 1424(169), 1439 Ellsworth, R.L. 1176(189), 1182(207), 1192(236), 1246-1248 Elmaleh, D.R. 1204(268), 1206(272), 1223(324). 1248-1250 ~lmasmbdi,A. 495(527), 518 Elsinger, E 669(53), 678, 901(74), 921 El'tsov, A.V. 829(336), 869 Elvidge, J.A. 1 lh9(l68), 1246 Elyusufi, A. 492(482), 517 Elyusufi, A.A. 492(480), 51 7 El-Zimaity, M.T. 538(55), 572(182), 630, 632 Emmick, I.L. 594(254), 634 Emmons, W.D. 369, 373(167), 403,478(235), 512 Emrani, J. 907(98), 921
Emsley, 1. 14, 17(151), 80, 433(125), 436 Enders, D. 185(151),213,248(186), 254,295, 322, 323(29), 399, 474(167), 511, 775(174), 865, 1039(240),1047,1510(37), 1512(37, 52a, 52b), 1519(52a, 52b), 1522(104-107), 1524(107), 1528(52a, 52b), (71), 1532, 1533 Enders, D.E. 1512(53a), 1532 Eneback, C. 568(166), 632 Engelhardt, G. 327,328(87), 401 Engelhardt, V.A. 506(675), 521, 1314(74), 1361 Ongelhart, D.A. 952(91), 989 Engels, H.D. 764(146), 865 Ensley, H.E. 1512,1528(65), 1532 Ent, H. 1442(4), 1502 Epiotis, N.D. 1512, 1526, 1527(45b), 1532 Epstein, S. 1279(102), 1301 Epstein, W.W. 469(47), 508 Erhart, K. 1558(53), 1565 Erian, A.W. 506(654), 521 Erickson, G.W. 1512(69), 1513(73), 1532 Erickson, K.L. 471(98), 509 Ericsson, E. 431(108), 436 Eriksen, 0.1. 430(103), 436 Ermer, J. 1279,1281(105), 1301 Ermler, U. 1261, 1266, 1283(40), 1300 Ermoli, A. 1228(336), 1250 Erpelding, A.M. 963(122), 989 Ershov, A.Yu. 367(160), 403 Ertas, M. l414(139), 1425(170), 1429(184), 1438,1439 Erzhanov, K.B. 14, 21(168), 80, 507(684), 521, 844(385e), 871 Eschmmoser, A. 13, 14, 16(144),80, 88, 89(1), 210, 290(19), 399, 407(14), 434, 669(53), 678, 901(74), 904(82, 83), 921 Eschenmoser, A.A. 225, 226, 228(46), 251 Espenbetov, A.A. 14, 21(168), 80 Esser, A. 769(159), 865, 1028(170), 1046 Estape, J. 187(164), 214 Esteban-Calderon, C. 184(143), 213 Etienne, A. 1327(116), 1362 Etmetchenko, L.N. 1467(108), 1505 Eto, M. 469(41), 508 Ettel, S . 4(21), 77 Ettlinger, H.G. 473(158), 511 Evans, D.A. 55(297), 83, 245(147), 254, 475(189), 490(189,438), 511, 516, 1512(46a), 1514(77), 1526, 1527(46a), 1532,1533 Evans, D.B. 1178(198), 1247 Evans, E.A. 1169(168), 1246 Evans, G.G. 475(182), 511 Evleth, E.M. 46, 69(236), 82 Exner, 0. 411(33), 418(63), 419(33), 434, 435 Eynde, J.J.vanden 578(197), 633
Author index Fillion, H. 1011(82), 1044 Finch, N. 1309(37), 1344(37, 147), 1346(147). 1360, 1362 Finck, E. 571(174), 572(179), 632 Fine, 1. 431,432(105), 436 Finet, J.P. 479(250), 512 Finkelstein, M. 476(213), 512 Finley, K.T. 558(125), 631 Finn, R.D. 1214(303), 1216(309), 1249,1250 Finncgan, R.A. 715(55a), 725 Fioravanti, S. 840(362a, 362b), 870, 1016(103-105), 1026(105), 1045, 1352(169), 1363 Firestone, R.B. 1210, 1241(28Y), 1249 Firl, 1. 9(11 I), 79, 837(356a, 356b), 870, 1562(69),is65 Firnau, G. 1199(252), 1216(307), 1248, 1250 Firrell, N.E 65,68, 71, 74(345), 84, 321(74), 324(79), 325(74,79), 401, 497(538), 518, 746, 747(83), 748(89), 806(290), 863, 868, 1556(49,50), 1565 Fischer, E.H. 1283(119), 1301 Fischer, G. 1471(115), 1505 Fischer, G.W. 1502(158), 1506 Fischer, H. 874(12), 887, 1448, 1481, 1494(48), 1504 Fischer, M. 456(44), 458 Fischer, R.H. 932(35), 988 Fischer, S. 7(65), 78, 309,319(61b, 61d, 61f), 400, 897,898(59), 920 Fischer, T.E. 479(255), 513 Fishel, D.L. 1519(93), 1533 Fisher. G.B. 832(3421869 ish her; H.F. 1292(154; 155, 157), 1302 Fishman, M. 650(29), 678 Fishwick, C.W.G. 532(29), 629 Fitzpatrick, J.M. 1516(82), 1533 Fitzpatrick, M. 501(601), 520 Fixari, B. 478(231), 512 Flammang, R. 1097, 1098(121), (122), 1108 Flattum, R.F. 1304(16), 1360 Flegal, C.A. 816(303), 868 Fleischhacker, W 500(598), 520 Fleming, 1. 648(23), 678, 746(88a), 749, 8 l6(94c), 863, 864, 1030(188), 1046, 1398(100), 1437, 1554(41), 1564 Fletcher, H.G. 1463(88), 1504 Fletcher, H.G.Jr. 504(646), 521 Fletcher, S.R. 1154(114), 1244 Fleury, J.-P. 427, 428(97), 436,498(549), 519, 802(271), 868, 1379(51), 1436 Flippen-Anderson, J.L. 424(84), 435, 1304, 1308, 1314, 1315(14), 1347(154), 1359, 1363 Flitsch, W. 489(418), 516, 979(188), 991 Floch, L. 1424(168), 14.39
Flood, L. 181(123), 213 Florencio, E 14(160), 80 Florian, W. 1319(94), 1361 Florke, U. 1421(159), 1439 Floshach, C. 1029(179), 1046 Floss, H.G. 1286(144), 1302 Flournoy, D.S. 1272, 1273(69), 1300 Flowers, W.T. 477(230), 512 Fluornoy, D.S. 1275(84), 1301 my"", G.A. 740(77), 863 Foces-Foces, M.de la C. 188(171, 175), 214 Foeaenolo. M. 176(81). 212 Foley, L.' 752,757(1i7), 864 Foltin, J. 1424(168), 1439 Fong, A.T. 1157,1158(133), 1245 Fonken, A. 1062(52), 1106 Fonken, A.E. 470,496(60), 509,1537, 1538(3a), 1563 Fontana, E. 1160(142), 1188(223), 1190(231), 1228(336), 1245,1247, 1250 Foote, C.S. 924(4,5, IS), 987 Foote, R.S. 1522(102, 103), 1524(102), 1533 Forbes, C.P. 475(192), 511 Forchiassin, M. 13(145), 80, 225, 226, 228(45), 235(73), 236(85,87), 251, 252, 549(85. 86). 583(215). 617(322.323). 630.
Ford, M. 1517(86), 1533 Ford-Hutchinson, A.W. 1176(187), 1246 Foresman, J.B. 24(185), 81 Forsin, S. 427(96), 436 Forshult, S. 682(6), 693 Forst, W. 438(2), 457 Forsyth, D.A. 394(208), 404 Fossheim, R. 187(162), 214 Foucaud. A. 179(106). 212. 1022(132). 1045 ourt ti no", M. ~($9).?8, 931(31),'98;' Fowler, F.W. 11, 55, 71(139), 79, 290(21),399: 479(264), 483(284), 499(564), 513, 519 Fowler, J.S. 1213(297), 1214(303), 1249 Fox, D.J. 24(185), 81 Fraenkel, G. 715(58e), 725,975(175), 990 Fraile, A.G. 1477(134), 1506 Frampton, R.D. 1101(130), 1109 Francesch, C. 57, 58(312b), 84 Franceschi, G. 1188(222), 1247 Francese, C. 740(71), 863, 876(26), 887 Franck, R.W. 491(474), 517,536(47), 630, 81 1(293), 868, 1542(17a), 1564
1590
Author index
Franck-Neumann, M. 997(29), 998(32-34), 1043 Francque, M. 444,445(16), 458 Frank, J. 184(140), 213 Frank, R. 845(387b), 871 Frank, R.W. 961(113), 989,1383(59a), 1436 Franke. W. 504(645). 521. 1442(16). ,. 1503 ~ranke",S . 18$151'j, 213 Franklin, J.L. 48(257), 83 Fraser, R. 246(152-154), 254 Frascr, R.R. 1511(42,44), 1512(50b, 53b, 66), 1527(50b), 1532 Fravolini, A. 606(287), 635 Fray, A.H. 607(294), 635 Frazier, H.W. 735, 737(49), 862 Freeman., F. 506(66R. 6701.521 ~, Freeman, J.P. 369, 373(167), 403, 1022(138), 1045 Freeman, N.J. 14, 17(151), 80, 433(125), 436 Freeman, R.C. 492,493(499), 518 Freeman, W.J. 165(13), 210 Freemann, R.C. 493(503), 518 Freer, A.A. 184(139), 213 Freisinger, A. 710(40c), 724 French, J.C. 506(674), 521 Frenette, R. 1176(187), 1246 Freund, R. 641(6c), 677 Frey, A.J. 490(443), 516 ~ r e y G. , 343,354(i25), 402 Frey, P.A. 1272(68,69), 1273(69), 1275(83, 84), 1276(83), 1293(158), 1300-1.302 Friarv. R.J. 536(47). 630. 1383(59a). 1436 ~ribu'sh,H.M. G l i , 1526(51c): 1532 Friedman, H.Z. 189(179), 214 Friedrich, E. 1522(105), 1533 Friedrichhen, W. 188(173), 214 Friesea, V. 485(320), 514 Frigola, J. 187(l h9), 214 Frisch, M.J. 24(185), 25, 27, 32, 38, 39, 49, 55(195), 81,432(118), 436 Frish, M.J. 373(189), 403 Fristad. W.E. 715(55c1. ~ . , , 725 Fritsch: J.M. 884(35), 887, 953(94), 989 Fritsch, W. 489(385), 502(628,629), 504(385), 515, 520,935(44), 988 Fritz, H. 171(54), 211, 802(271), 868, 1379(51), 1436 Fritz, I.B. 1138(71), 1243 Frolow, F. 168(35), 210 Frommeld, H.D. 245(140), 253 Frommelt, H.D. 8(77), 78 Frommer, J.E. 1255, 1272(20), 1299 Frost, J.J. 1203(267), 1204(269),1248 Frost, J.R. 178(102), 212 Frost, J.W. 1295(165, 166), 1302 Frostl, W. 505(647), 521 \
~
~
~\
Fruchicr, A. 1149(97, loo), 1244 Fmhauf, H:W. 191(191), 214 Frump, J.A. 1463(87), 1504 Fu, C.-J. 1189(225), 1247 Fu, S.-C.J. 1459(78), 1504 Fu, W.Y. 647(18a), 677 Fuchs. B. 172(58). 211 Fuchs, R. 829(33'2), 869 Fueno, T 924(13,15), 987, 1063(57), 1106 Fuentes, J. 944(62), 988 Fuentes-Rodriguez. F. 186(157),213 Fuhr, K.H. 59i(255a), 634 ' Fuji, K. 378,379(184), . . 380(192), . . 403, 499(571), 519 Fujii, H. 885(38), 887, 951(85), 989 Fuiii. S. 9791187). 991 ~ujimori,K. '981(198), 991 Fuiimoto, H. 924(17), 987 ~u$mura,Y. 1019(118), 1045 Fujinami, T. 802(273), 868, 1000(44), 1043 Fuiio, M. 1097(116b),1108 ~u)siwn, T. 616(320), 635 Fujita, M. 534(39), 629, 962, 974(120), 989 Fujitani, Y. 179(1lo), 212 Fujito, H. 1313(71), 1361 Fukatsu, S. 543(67), 630 Fuks, R. 9(91), 78, 769(164), 865, 1324(110), 1325, 1338(111), 1362 Fukuda, M. 9(93),'79 Fukui, K. 924(17), 987 Fukumori, S. 668(52), 670(55), 678 Fukumoto. K. 488(369). 515.567(1601. 632. Fukunaga, T. 42(22'7), 82 Fukushima, M. 802(273), 868, 1000(44), 1043 Fukutome, H. 924(13), 987 Fukuzawa, S . 802(273), 868, 1000(44), 1043 Fulea, C. 408(24), 434 Fulmer, R.W. 484(288), 485(317), 513,514, 709(33b), 724, 1055, 1065(21b), 1105 Fulmor, W. 1507(25), 15-71 Fung, Y. 1542(15b), 1564 Funk, W. 7(65), 78,309, 319(61e, 61h), 400, 889(6), 897, 898(58), 920 Funke, C.W. 1169(171), 1246 Fuoss, R.M. 1507(9), 1531 Furey, W. 1261, 1281(42), 1300 Furst, A. 1003(54), I044 Fumkawa, H. 179(110), 212 Fumkawa, M. 785(209), 866,978(184), 991, 1385(63), 1386, 1423(64), 1434(63), 1437 Furumi, N. 173(68), 211 Fumta, T. 1120(14), 1242
1592
Author index
Gcorgcs, D. 11 19(12), 1242 Geribaldi, G. 343, 345, 394(128), 402 Geribaldi, S. 42(231), 55(290), 82, 83 Gerlach, 0. ~50(82);988, 1357(182), 1363 Gerlt, J.A. 1261(45), 1300 Germain. G. 22. 23. ~ 39(172). . , ~,80. ~ , lhh(l6). ,~-,--,, 167(25), 175(77), 177(89, YO), 187(164), 189(178, 182. 183). 205(178), 210. 212. 214,' 225(47), 252 Gerribaldi, S. 298(36), 400 Geske, D.H. 953(92), 989 Getoff,N. 684(15), 693 Gevorkyan, A.Zh. 471(108), 510 Gewald, K. 538(53), 607(295), 630, 635, 731(21), 862, 1191(235), 1248, 1313, 1315(52), 1335(129), 1338(133, 136, 137a), 1340, 1346(137a), 1360, 1362, 1389, 1390(76), 1395(93), 1406(76), 1427(178), 1437, 1439, 1562(70), 1565 Gey, E. 327(89), 401 Geyer, Y. 565(157), 575(190), 627(157), 632, 633 Ghattas, A.B.A.G. 971(161), 990 Gholami, A. 947(77), 988 Ghosez, L. 5(53), Y(53, 89), 77, 78, 167(25), 210, 476(205-207), 512,731(9), 861, 1318(91a, 91b), 1361, 1370(29,30), 1436 Giacobbe, T.J. 3(12), 76, 236(86), 252, 790(235), 832(343), 867, 869,947(75), 988 Gianchetti, G. 470(84), 509 Giandinoto, S. 1011(81), 1044 Giannangeli, M. 1374(40), 1436 Giarda, S. 1190(231), 1247 Gibbons, C.S. 183(136), 213 Gibs, G.J. 558(126), 631 Gibson, R. 1143, 1144(84), 1244 Gieren, A. 176(85), 212 Giese, B. 873(3), 874(6,9, lo), 875(19), 886,
.
887 --.
Giessner-Prettre, C. 25(205), 81 Gigee, R. 504(642), 521 Giger, R. 1442(19), 1503 Gil, G. 506(659), 521 Gilardi, R. 424(84), 435, 1304, 1308, 1314, 1315(14), 1347(154), 1359, 1363 Gilbert, J.C. 479(251,252), 513, 736(59), 863, 912(112). 921 1037(22&228), 1047 ~ i l c h r k t T.L. , Gill, S. 986(223), 991 Gillan, A.M. 184(144), 185(145), 213 Gillard, M. 1318(91b), I361 Gilles, A. 507(683), 521 Gillet, A. 1119(12), 1242 Gilli, G. 89, 92, 153, 154, 156(4), 210, 398(222-224), 404
Gilli, E! 398(224), 404 Gilligan, J.M. 1383(59a), 1436 Gilligen, J.M. 536(47), 630 Gillin, J.C. 1117(3), 1209(285), 1242, 1249 Gilman, H. 712(47a), 725 Gilman, N.W. 736(58a), 863, 908, 909, 9 ll(lO4), 921 Gingrich, H.L. 1012(93), 1044 Gioia, B. 57(305), 84, 786(219), 866, 1392(81b), 1437 Giomi, D. 1026(164a, 164b), 1046, 1420(156), 1438 Giordano, C. 1445(39), 1447(43,44), 1503 Giraudeau, P. 1327(116), 1362 Gish, G. 1276(86), 1280(107), 1281(110), 1301 Giumanini, A.G. 1124(30,31), 1242 Givens, R.S. 447(20), 458,492(494), 517 Glasbey, T.O. 532(29), 629 Glaser, R. 245(149, 150), 254 Glass, R.D. 489(381), 515 Glazer, R.1. 1155(121c, 121d), 1245 Glazko, A.J. 1156(126), 1245 Gleichcr, G.J. 874(8), 887 Glen, A.I.M. 1117(4), 1242 Glennon, R.A. 1159(138), 1245 Gless, R.D. 1442(20), 1503 Glidewell, C. 45(231), 82, 225(42), 251 Glocker, M.O. 1448(48), 1481(48, 138), 1483(138), 1484, 1485(139), 1494(48, 138, 139), 1504,1506 Gloriozov, LP. 46(240), 48(241, 242a), 82, 225(43), 251, 284, 287(12), 292, 293(27), 294, 296,320(12), 399 Glott, P.G. 599(268), 634 Glukhikh, N.G. 492(497), 518 Glushkov, R.G. 552(107; 108), 631, 986(228, 229), 992 Glusker. J.P. 171(56). 211 ~luziriski,P. 14,21(163), 80 Go, K. 175(79). 212 Gober, B. 5?7(i96), 633 Godde, 0. 496(535), 518, 1546(27), 1564 Godefroi. E.F. 1308. 1322. 1340132). ,,1360 Godfrey, J.J. 1453((5), 15b4 Godfrey, P.D. 32(218, 219), 82 Godinho, L.S. 794(243), 867, 1563(76), 1565 Goedde, H.W. 1163(148), 1245 Goerdeler, 1. 475(183), 511, 1394(90), 14.Z7 Goff, S.D. 473(150, 152), 510 Goglio, M. 1188(222), 1247 Gogte, V.W. 595(255b), 634 Golankiewicz, B. 1199(255), 1248 Golberg, S.I. 964(125), 989 Gold, V. 1099, 1100(12Tb), 1109, 1458(75), 1504 \
Author index Goldberg, I. 168(33), 169(40), 177(95), 178(101), 179(95), 191(192, 193), 192(193, m j , 21'0-212; 2i4 Goldberg, I.H. 1150(105,106), 1244 Golden, D.M. 259, 264(9a), 271 Goldstein. E. 177. 179i95). 212 g old stein; J.H. 3i5(82j, 401,431, 432(105), 436 Colic, L. 184(142), 185(150), 213 Golino, C. 8(78), 78 Golinski, 1. 222(21), 251, 472, 480(145), 499(574,577), 510,519 Golinsky, 1. 760(118c, 119), 864 Goljer, I. 363, 368, 370(155), 402,550(96), 631 ~~Golovin, A.V. 1451(59), 1504 Golubev, V.B. 686(23), 694 G6mez-Guillh, M. 342(117b), 402 Gbmez-Sanchez, A. 48(245, 251), 73(363), 75(363, 365,366), 76(367), 82, 85, 226(51, 52), 236(94), 240(109, 111, 113, 115, 118, 119), 241(51, 109, 120), 242(123), 243(127, 128), 244(129,132, 133, 135), 252, 253, 330(99, 102), 331, 332(99), 333(102), 334(99, 102, 103), 342(117b), 344,345(126), 353(138), 354(134), 355(137, 138), 356, 357(137, 139))358(139), 359(144), 360, 361(146, 149), 362(146), 363(146, 149), 364(146), 369, 371(164), 372(175), 373(175,185), 374-377,380(175), 381(134, 185, 193), 383, 384(134), 385(134, 193), 386(193), 387(134,185, 193, 195),388(134,185, 193). 391(193), 394(134, 175,193), 395(134, 175), 397(134), 401-403,411(30), 412(40), 415, 416(30,52), 431(40), 433(52, 123), 434-436,719(67a, 68e, 68h), 725, 890(23), 891(25-27), 920 Gompper, R. 478(238c), 512, 712(46f), 724, 9 l8(123), 922, 1064(61a,61b), 1106, 1304, 1311(5, 6), 1312(5), 1313(5, 6), 1315(5), 1321(98), 1338(134), 1359, 1361, 1362, 1507(2a), 1531 Gompper, R.Z. 231,237(58), 252 Gonesnard, J.P. 709(30a), 724 Gonzalez, C. 24(185), 81, 875(18), 887 Goodlett, V.W. 4(14), 76, 746(88b), 760(126, 128, 130), 799(264), 801(270), 863, 864, 868, 1433(193),1439 Gopinathan, M.B. 1175(183),1246 Goralski, C.T. 832(341,342), 834(346), 869 Gorban, V.I. 1466(99), 1505 Gordeev, M.E. 1322(100-102), 1361 Gordon, M.E. 493(504), 518 Gore, J. 832(344), 834(349), 843(375), 869, 870, 892(38), 920, 947(76), 974(167-170), 988, 990
Gorocholinskij, 1. 489(415), 516 Gorokhova, M.A. 617(321), 635 Gose, Y. 499(571), 519 Goswami, M. 448(26), 458 Goto, K. 471(106, 107), 510 Goto, N. 712, 714(46h), 725 Gotor, V. 182(127), 213,626(340-343), 636, 1027(169),1046,1385(62), 1386(66), 1393(85), 1419(154), 1425(172, 173), 1426(176), 1427(177), 1431(187), 1432(189, 190), 1437-1439 Gott, P.G.4(16), 76, 779(182), 866, 970(149), 990, 1338, 1340(139a), 1348(157), . . 1358(139a),1362,1363 Gotthardt, H. 171(55), 211, 491(472), 517, 10291179). 1046 Gotz, H: 470(79), 509 Gouesnard, I.-P. 32(213), 81, 294(31f), 298(34), 328, 329(97), 347(31f),348(97), 400, 401,408(18), 434 Gouesnard, J.P. 222(28), 251 Gould, R.G. 606(290), 635 Goulding, R.W. 1214(302), 1249 Govindachari, T.R. 490(441), 516 Goya, P. 187(166),214 Graaf, B.van der 823(319), 869 Graaf, S.A.G.de 222(26), 251, 796(249), 867, 994(9-12), 1043 Grabowski, E.J.J. 1176(190), 1246 Graden, D.W. 247(169); 254 Graffe, B. 596(260), 599(266), 634 Graham. L.D. 1273170). 1300 ~raharn;S.H. 816(i03j; 868 Gramain, J.C. 581(208,209), 633,641(7, 8), 648(22a-d), 677, 678 Grandberg, 1.1. 587(230), 633 Grandclaudon, P. 643(11), 677, 1413(136), 1438 Grandolini, G. 606(287), 635 Granik, V.G. 4(40), 77, 500(590), 519, 535(42), 536(45), 552(107, log), 559(130), 581(203), 593(247), 625(339), 629631, 633, 634, 636,986(228-230), 987(231), 992, 1366(10). 1435 Grant, AS. lb83(87), 1097(121), 1098(87, 88, 117, 121), 1107,1108 Grant, D.M. 290(23), 399, 1138(67), 1243 Grassivaro. N. 1025i144). 1045 ~rbsman",W. 782(192;; 192b), 866 Gratz, J.G.von 582(21 Ib), 633 Graubaum, H. 722(81), 726 Gravel, D. 359(145), 402, 1003(59), 1044 Gray, A.P. 70(359), 85 Gray, R.W. 168, 169(34), 210 Grayson, J.I. 488(374), 515, 1011(78), 1044, i546(26), 1564 Grazi, E. 1285(130), 1302
1594
Author index
Greaves, P.M. 477(222), 512 Greci, L. 167(23), 183(137), 187(167), 189(137), 210, 213, 214 Green, J.B.A. 1261,1277(43), 1300 Green, J.P. 1146(92), 1244 Green, J.R. 495(521), 518 Green, M.A. 1237(351,352), 1251 Greenawav, A. 236(77). 252 ~reenawa;, A.R. 236(84), 252
1502(159), 1506 Greenhill, V.I. 532(26), 629 Greenlee, R.B. 322, 325(77), 401, 498(547), 519
Greenstein, J.P. 1459(77-79), 1504 Gregory, B. 507(680), 521 Greif, D. 4, 5(45), 77, 731(26), 862, 890, 891(12), 919, 1366(8), 1405(115), 14.35, 1438
Greig, N.H. 1118(5), 1242 Grellman, K.H. 647(20), 677 Grcllmann, K.H. 1134(362), 1251 Grenetz, S.C. 802(276), 868 Gribi, H. 901(74), 921 Gribi, H.P. 669(53), 678 Gridnev, I.D. 1473, 1499(125), 1505 Grieb, R. 168, 169(34), 210 Griego, J. 1143, 1144(84), 1244 Griesinger, A. 10(126), 79, 1051-1053(10), 1105
Griffin, G.W. 764(139), 800(269), 865,868 Griffiths, D. 1393(84), 1437 Grigg, R. 1289(148), 1291)(149), 1.702 Grigor'ev, A.B. 552(108), 631, 986(228-230), 987(231), 992 Grigoryan, D.V. 471(108), 494(520), 510, 518 Grigoryan, E.A. 480(267), 513 Grigoryan, G.V. 468(13), 508, 1366(11), 1435 Griller, D. 876(25'), 887 Grindel, J.M. 1156(128), 1245 Grindev. G.B. 1133661.1243 ~rintsevich,P.P. 58(325), 84 Griss, G. 786(223), 867 Griswold, D.D. 1186(215), 1247 Griswold, D.E. 1186(216), 1247 Grob, C.A. 11(140), 52(265,278), 68(265),
79, 83, 246(160), 254, 709(36), 724, 1052, 1055(16), 1056(25), 1065(16), 1105 Grobe, A. 575(189), 627(345), 633, 636 Grohe, K. 1417(150), 1438 Gronchi, P. 418,433(61), 435 Grosjean, D. 59(326), 84 Gross, A. 168(35), 210 Gross, H. 9(95), 79, 478(237,238), 512, 1372, 1401(34), 1436 Gross, S. 429, 430(102), 436, 1216(308), 1250 Grosse. D. 232(66). 252 ~ r o s s m a n n0. , b89(392), 515 Grossnickle, T.T. 735, 737(50), 862 Groth, Ch. 1313(56,59), 1360 Groth, P. 430(103), 436 Grotyohann, L.W. 1139(74), 1243 Gmen, L.C. 1095(110b), 1108 Gmnberg, E. 1150(104), 1244 Gmnd, H. 1529(114,116), 1533 Gmndemann, E. 722(81), 726 Gmnze, M. 1214(299), 1249
Gmseck, U. 1306(18, 19), 1310, 1311, 1325, 1327(18), 1350(19), 1351(165), 1352(165, 167), 1360, 1363 Gruys, K. 1272,1273(69), 1300 Gschwend, H. 669(53), 678 Gschwend, H.W. 712(47b), 725 Gsohwend, H. 901(74), 921 Gu, J.-M. 916(116b), 921 Gu, Y.-Z. 1338, 1346(137b), 1362 Guan, J.H. 1206(271,272), 1248, 1249 Gubin, J. 1192(239), 1248 Gubler, C.J. 1255(3, 16), 1299 Gudmundson, A.G. 1170(176), 1246 Guenther, D. 785(21 I), 866 Guerry, P. 657(41), 678 GuibC, E 1507(18a), 1531 Guilhem, J. 174(72), 211 Guillen, M.G. 535(43), 629 Guilloteau, M. 836(350b), 870 Guingant, A. 474(170), 511, 731(22), 768(153), 846(394), 848(394,395), 852, 857(395,401), 859, 861(395), 862, 86.5, 871, 1041(249,250), 1048 Guise, L.E. 592(246), 634 Gullberg, P. 1206(276), 1249 Gulyakevich, O.V. 930(28), 987 Gulyas, S. 1128(46, 47), 1243 Gumby, W.L. 1507(14a), 1531 Gunatilaka, A.A.L. 1512(53c), 1532 Gund, P. 39(222), 82 Gunda, T.E. 568(166), 632 Giinther, E. 1321(99), 1346(153), 1361, 1363 Giinzler, H. 69, 74(357), 85 Guo, E. 1304, 1308(8,9), 1359 Guo, Q.X. 683(1 I), 693 Gupta, A.K. 1333(126), 1362
Author index Gupta, S.K. 764(148), 865 Gupta, Y.N. 1016(101), 1045, 1558(58), 1565 Gurka, D. 387(202), 403 Gurowitz, W.D. 234(70), 235(71, 72), 252, 317, 318, 320(68), 401, 440(10), 458 Gumdata, J.B. 320(73), 401 Gussmann, St. 575(189), 633 Gut, I. 1094, 1095(109a), 1108 Guthrie, J.P. 259(10), 271, 1062(50c), 1065, 1066(68a), 1068(70), 1078,1080,1085, 1089(68a), 1106, 1107, 1283(121-124), 1301 Gutowski, J.A. 1280(108), 1301 Haag, ti. 797(257), 867, YY4(16), 1043 Haake, M. 478(238b), 512 Haarstad, V.B. 494(519), 518 Hadag, Ch.M. 245(150), 254 Haddad, M. 975(178), 991 Haddad, N. 663(49), 678 Haddon, R.C. 1507(12a), 1531 Hadley, M. 330(106), 401 Haede, W. 489(385), 502(628,629), 504(385), 515, 520, 935(44), 988 Haeager, W. 594(251), 634 Hafelinger, G. 24-26(184), 27(184, 196), 28(196), 29(184,211), 33(184), 38(221), 39(184), 40(196), 41(226), 42(221), 46(226), 49(184), 81, 82, 88, 94(2), , . 210, 246(15$, 2 3 Haffmanns, G. 333, 334(105), 401, 591(244), 634, 1434(195), 1439 Hafner. K. 425(88.89). 435 Hagan, W.J.Jr. 672, 6?6(57), 679 Hagen, R. 270(72), 277 Hager, L.P. 1255(14), 1276(90), 1299, 1301 Haggerty, J.C.111 1281(111), 1301 Haglid, F. 488(364), 515 Hahne, W.F. YW(Yl), 921 Haider, N. 1012(92), 1044, 1417(149), 1438 Hakka, L.E. 1095(108), 1108 Halamandaris, A. 971(155), 990 Halcomb, R.L. 1298(168), 1302 Halczenko, W. 182(129), 21.3 Haleen, S.J. 530(24), 629 Halgren, T.A. 25(202), 81 Hall, H.K. 797(262), 867, 997(26), 1043 Hall, H.K.Jr. 1052, 1055(15), 1105 Hall, I.H. 1177(195), 1178(196), 1246 Hall, J.H. 1344(146), 1362 Halldin, C. 1206(273), 1207(281), 1249 Halleux, A. 787(226), 867 Hallot, A. 978(182), 991 Halsey, J. 1l3l(5l), 1243 Ham, A.L. 471(140), 510 Hamada, Y. 32, 53(217), 81, 187(160), 214, 802(285), 868
1595
Hamaguchi, E 552(104), 556(117), 631 Hamaguchi, H. 459(2), 464,957(102), 989 Hamama, W.S. 532(31, 32, 36), 629 Hamana, M. 1019(118), 1045, 1119(7), 1242 Hamberger, H. 1308(35), 1360 Hamed, A. 1495(151), 1506 Hamill, O.P. 1206(274), 1249 Hamill, W D J r 1138(67), 1243 Hamilton, G.A. 1286(132), 1302 Hamkens, W. 1197(246), 1248 Hammami, H. 1041(250), 1048 Hammer, C.F. 1228(338), 1250 Hammer, J. 1143, 1144(84), 1244 Hammerum, S. 438(6), 451(31), 457, 458 Hammett, L.P. 707(26), 724 Hammond, W.B. 470(81), 509 Hammons, G. 1284(126), 1301 Hammouda, M. 532(31, 32, 36), 629 Hampton, K.G. 1521(98). . , 1522(98. 100). 1524(98), 15.33 Han, Y.K. 715(55c), 725 Hanaee. J. 502615). 520. 526C3.629 Hanck, E P J ~ .i055:'106~(21cj, iios Hancock, S. 1131(51), 1243 Handler, P. 1263(49), 1300 Hangeland, J.J. 1186(219), 1247 Hanin, 1. 102Y(182), 1046 Hanisch, H. 7(65), 78, 793(238), 867, 897, 898(58,60), 920 Hanish, H. 309, 319(61e, 61g), 400 Hanke, H.G. 484(300), 514 Hanke, R. 539(58), 630 Hanners, J. 1143, 1144(84), 1244 Hansen, H.-J. 482(282), 513, 736(55), 863 Hansen, J.F. 1022(138), 1045 Hansen, P.E. 394(207, 212, 215-219), 395(215), 398(221), 404,720(70a, 70c, 70d, 71), 726, 1116(1), 1117(2), 1242 Hanson, A.W. 176(80), 212 Hanson, J. 52(272), 83 Hanson, R.N. 1236(348,349), 1237(348), 1251 Hansson, C. 490(440), 516 Hantawong, K. 930(30), 987 Hantraye, P. 1200(260), 1209(284), 1248, 1249 Hantschmann, A. 1405(116), 1438 Hantzsch, A. 6(59), 78, 1162, 1197(145), 1245 Hanus, 1. 1208(283), 1249 Hanus, V. 447(19), 458 Hanze, A.R. 971(156), 990, 1544(21), 1564 Haran, M. 1269, 1276(64), 1300 Haran, T.E. 168(28), 172(61), 210, 211 Harano, K. 173(66), 211 Harding, K.E. 816, 818(304), 868, 1005(66), 1044 Harding, T.T. 501(609), 520
Author index Hayes, A.J.Jr. 486(341), 514 Hayes, A.W. 10, 73(131), 79 Hayman, S. 1177(192), 1246 Haynes, A.W. 316, 317,329, 342, 344(66), 401 Haynes, L.W. 1050(4), 1104 ~ a i sS.J. , 1178(199), 1247 Hazell. A. 14. 21(165). 80. 411135). ,,434 ~ a z e l l :R.G. i80(ii3j2'21i He, J. 874(9), 875(19), 887 Head-Gordon, M. 24(185), 32, 38, 53(216), 81 Headley, A.D. 707(27c), 724, 1097(116b), 1108 Healy, E.F. 24,48(175), 80, 907(100), 921, 1485(143), I506 Healy, M.J. 1274, 1278(78), 1301 Hearing, E.D. 264(48), 274 Heath, R.R. 1514(78), 1533 Heathcock, C. 731(27), 862 Heathwck, C.H. 4(42), 77, 249(193), 254, 775(175), 865, 1032(197), 1047 Heatley, F. 185(146), 213 Hebd, C.R. 952(90), 989 Heber, D. 1413(137), 1438 Hecht, T.A. 11(143), 80,471(129), 510 Hedgecock, H.C. 834(347), 869 Hegarty, A.F. 1449(54), I504 Hegde, V. 1028(172), 1046 Hegedus, L.S. 495(526), 518 Hehl, S. 1449, 1481(52), 1504 Hehre, W.J. 24(181, 189), 25(190-192), 81 Heibel, G.E. 650(28), 678 Heijdenrijk, D. 191(191),214 Hcikkila, R.E. 1235(346), 1251 Heil, M. 940(58), 988 Heilbron, I.M. 530(21), 629 Heilbronn, E. 1201(261), 1248 Heilbronner, E. 270(72); 277,428(98), 436 Heimgartner, H. 172(62), 211, 736(55), 863 Hein, F. 773(169b), 865, 1369(24), 1428(181), 1436. 1439 ~ e i n d l , ' ~1180(2OO), . 1247 Heineman, S.D. 489(404), 516 Heinicke, G.W. 1433(194), 1439 Heinisch, G. 1417(149), 1438 Heinrich, B. 42(230), 82 Heinrichs, P.M. 429, 430(102), 436 Heinstein, P. 965(131), 990 Heinzer, J. 715(57c), 725 Heiszwolt. G.J. 475(188). 511 ~eitmeier,'D.E. 70(%9):k5 Heitzer, H. 1401(108), 1417(150), 1438 Hellberg, L.H. 471(133), 510, 814(297), 868 Heller, G. 1021(129), 1045 Hellin, M. 1092, 1101(106d), 1108 Hellman, H. 1051(9), 1105 Hellman, S. 1236(348,349), 1237(348), 1251 \
1597
Hellmann, H. 64(343,350), 67(343), 70(350), 74(343), 84, 85,469(28), 508,736, 740(54c), 863 Helmers, R. 782(194), 866 Helmick, L.S. 1258(27), 1299 Helus, F. 1214(299); 1249 Henaff, P.L. 469(25), 508 Henbest, H.B. 486(343-347), 514,764(142), 865 Henderson, D. 1289(148), 1302 Henderson, J.F. 1156(123a), 1245 Henderson, W.G. 1065(63a), 1097(116b), 1106,1108 Hendricks, J.D. 1157(132,133), 1158(133), 1245 Hendrikx, G. 1414(139), 1438 Hengartner, U. 769(158), 865 Henke, H. 184(140), 213 Henning, H:G. 409(27), 434 Henning, R. 1037(229), 1047 Hcnnion, G.F. 736. 740(54d), 863 Henoch, F.E. 1521(98), '1522(98, loo), 1524(98), 1533 Henrichs, M. 715(58e), 725 Henriksen. L. 414(43). 434 Henry, A.C. 1304('15,'17), 1360 Henschmann, M. 425(87), 435 Hensens, O.D. 167(27), 210 Hepp, E. 1444(34), 1503 Herbert, G. 488(363), 515 Herbig, K. 237(107), 253,354, 357(135), 402, 411, 433(29), 434, 719(68c), 725 Herbke, J. 532(34), 629 Herbort, H.P. 485(322), 514 Herboth, O.E. 468(15), 508 Herbst, R.M. 1142(82), 1244 Herman, R.J. 1125(34), 1242 Hermecz, I. 169(38), 210, 597(262), 634, 720(72, 73), 721(75), 726, 1416(147), 1438 Hermecz, J. 606(292), 635 Hermolin, J. 191(192), 214 Hermosin, I. 330, 333(102), 334(102, 103), 401 Hernandez, J.M. 192(195), 215 Hernecz, I. 360(151), 402 Herr, M.E. 7(70), 78, 469(30-33), 470(60), 496(32, 60), 508, 509, 934(39), 971(157), 988, 990, 1050(3), 1062(52), 1104, 1106, 1537, 1538(3a), 1544(22), 1563, 1564 Herrendorf, W. 184(140), 213 Herrmann, C. 1091-1094,1100(102b), 1108 Herrmann, J.L. 740(79), 863 Herscher, S.B. 471(97), 475, 498(180b), 509, 577 - - -
Hershbach, D.R. 48(260), 83 Hershberger, P.M. 657(42), 678 Hertel, L.W. 1133(55, 56), 1243
1598
Author index
Herten, B.W. 949(79), 988 Herz, A. 1153(112), 1202(265), 1244, 1248 Herzberger, S. 1449, 1481(52), 1504 Hesbain-Frisque, A.M. 476(207), 512 Hesse, D.G. 258(14), 259(21b, 21c, 22), 271, 2 72 Hesse, R.H. 794(243), 867, 1563(76), 1565 Heublein, A. 845(387b), 871, 898(63), 920 Heuschmann, M. 1306(18, 19), 1310, 1311, 1325,1327(18), 1350(19), 1351(165,166), 1352(165-167), 1360, 1363 Heusler, K. 1507(22), 1531 Hevesi, L. 1097(114),1108 Hewgill, F.R. 1508(27), 1531 Hewitt, G. 1327, 1337(115), 1362 Hewitt, M. 715(58e), 725 Hewson, A.T. 178(100), 212 Hewson, D. 1404(112), 1438 Heyl, F.W. 7(70), 78,469(3&33), 470(60), 49h(32, hO), 508, 509,934(39), 971(157), 988, 990, 1050(3), 1062(52), 1104, 1106, 1537, 1538(3a), 1544(22), 1563, 1564 Heymes, A. 478(245), 512 Heys, J.R. 1164(152), . . 1186(217), . . 1190(229), . . i245,1247 Hichmott, P.W. 321, 322(76), 401 Hickmott, P.W. 4(32, 34, 37, 39), 5(37), 8(37. 84). 9(39). 65(345). 68(39. 345). 71.
8611863, 865-871,'889b-5),'890(3), 919, 923(1), 987,994(4, S), 998(41), 1005(41, 60, 62, 63), 1011(86), 1021(126), 10431045, 1050(6f), 1056, 1058(24a), 1083(87), 1084(6f), 1098(87, 117), 1/05, 1/07, 1108, 1304, 1306, 1352(2), 1359, 1366(2), 1383(59c), 1435, 1437, 1442(10, 11), 1503, 1535, 1537(1), 1541(13, 14), 1548(34,36), 1550(36,37), 1551, 1552(34), 1555(48), 1556(49-52), 1562(74), 1563-1565 Hicks, D.R. 1172,1173, 1175(181), 1186(219), 1246, 1247 Hicks, J.L. 1142(79), 1144(90), 1244
Hidalgo, El. 75(366), 85, 243(127), 244(132), 253,354,381,383-385,387,388,394, 395; 397(134), 402,411,415, 416(30), 434, 891(25), 920 Hiemstra, H. 247(173), 254, 1442-1444, 1447, 1470.1493. 1497(3). 1502 ~ i ~ a s hEi ;72'2(85bi 526 Higashino, T. 1012(90,91), 1026(163), 1044, 1046 Higashiyama, K. 964(128), 989 Highcock, R.M. 852(399), 871 Higo, A. 653(34), 678 Higuchi, S. 760(121), 844(385d), 864, 871, 1029(181), 1046, 1411(130), 1438 Hilbig, K. 188(174), 214 Hilgenberg, W. 1230(341), 1250 Hilgeroth, A. 549(91), 631 Hill, D.G. 1507(8), 1531 Hill, D.T. 1186(2i5), 1247 Hill, R.K. 57(311), 84, 736(58a, 58b), 863, 908(104), 909(104-106), 911(104), 921 Hill. R.P. 1128(46). 1243 ~ilmar,W. 1346(152), 1363 Hiltanen, J. 1167, 1168(165), 1246 Hiltunen, L. 167(22), 210 Hilvert, D. 1259(37), 1300 Hine, J. 56(302), 84, 1061, 1062(46a, 46h), 1087(72,93d), 1101(46a), 1106, 1107 Hinman, R.L. 53(285), 83, 711(43), 724, 1055(22), 1058(22,31, 32), 1060(22), 1063, 1064(32), 1098(31), 1/05 Hirai, K. 1383(59b), 1437 Hirai, M. 654, 668(37), 678, 1376(46), 1436 Hirakura, M. 1507(21), 1531 Hirano, H. 174(70), 211 Hirayama, H. 1120(17), 1242 Hirayama, N. 192(196), 215 Hiroaka, T. 564(154), 632 Hirobe, M. 1211(291,292), 1212(293,294), 1213(295),1249 Hiroi, & 248(183), 249(189), 254,474(162), 511,536(46), 630,773(170, 171), 774(171), 775(173). 776(177). 865. 1512(68). 1532 Hirota, T. 712(46b),'724 Hirsch, J.A. 471(122), 510, 809(292), 868 Hinchfield, J. 550(94), 631 Hirshfield, J. 167(27), 180(116), 182(129), 210, 212, 213 Hirst, S.C. 1309(36), 1328(118), 1333(36), 1334(36,118), 1360, 1362 Hirst, V.K. 1131(51), I243 Hishimura, H. 661(47), 678 Hitchcock, P.B. 14, 21(170), 80, 176(83), 183(131), 212, 213 Hiusman, H.O. 1415(142), 1438
Author index Ho, E. 1027(168), 1046 Ho, J. 1424(169), 1439 Ho, T. 997(27), I043 Ho, T.-L. 740(66), 863, 1467(109),1505 Hobbs, C.H. 1327(114),1362 Hoberg, H. 1386(65), 1428(180), 1437,1439 Hobeood. R.T. 325(82). 401 R. 13, 14, 16(144), 80, 88,89(1), 210, 225, 226, 228(46), 251, 290(19), 399, 407(14), 434 Hobson, R.E 413(41), 434 Hoch, H. 4(30), 77,468(5), 507,731,778(25), 779(183, 184), 862, 866, 1050(6e), 1105, 1366(1c), 1435 Hoch, J. 470,494(95), 509 Hochrainer, A. 4(25), 77, 731(17), 862 Hochstetler, D.C. 1147(96), 1244 Hochstrasser, R. 1097, 1098(123), 1108 Hochu, M. 1512(63),I532 Hoerr, D.C. 1156(130), 1245 Hofelich, T.C. 1098(125), 1109 Hoff, D.I. 479(249),512 Hoffman,R.V. 785(210), 866, 940(55, 56), 988 Hoffman,R.W. 729,731,843(5), 861 Hoffmann, E. 489(396), 515 Hoffmann, R. 53,57, 58(282),83, 1306, 1313, 1320,1342(20), 1360, 1512,1526, 1527(45c), 1532 Hoffmann,R.W. 901(71), 921, 1061(47c,47d), 1106 Hofmann, D. 530(23), 629 Hofmann, F. 1230(341), 1250 Hofmann, H.J. 48(250), 82 Hofnlann, J. 1448, 1481, 1494(48), 1504 Hofmann, I.M. 551(100), 631 Hoft, E. 478(237), 512 Hoge, R. 172(60), 211 Hogg, H.J. 1072(75), 1107 Hoee. J.A. 971(156). 990. 1544(21). 1564
obi
Hohn, 1. 947(77), 988' Hojatti, M. 1060, 1098, 1103(34), 1105 Hojo, M. 1314,1316(75), 1361 Hoke, D.I. 1458(74), 1504 Holden, M S . 495(526), 518 Hallenberg, J.L. 42(227), 82 Hollinger, W.M. 1522(101), 1533 Holloway, M.P. 1281(111), 1301 Hollowell, C.D. 17(14Y), 80 Holm, R.H. 6, 7(60), 78, 340(116), 342(116, 118), 402, 891(34), 920 Holmes, J.L. 256(6), 262(33c, 35), 265(6), 268(33c), 271, 273,697, 699,701, 707(7b), 723, 1097(115), 1108 Holoubek, J. 487(356), 515 Holroyd, R.A. 684(14), 693
1599
Holschbach, M. 1197(246), 1248 Holtmann, H. 749, 816(94a), 864 Holtz, D. 1065(63a), 1106 Holysz, R.P. 944(63, 64), 988 Honda, T. 638(5), 677, 964(128), 989 Hondo, Y. 917(119), 921 Hang, J.H. 672(58), 679 Honig, B. 247(168), 254 Honig, L.M. 816(303), 868 Honigbcrg, I.L. 1190(232), 1247 Honikel, K.O. 1152(107), 1244 Hoobler, M.A. 1517(87b), 1533 Hoogsteen, K 167(27), 210 Hooijer, S.0. 643(11), 677, 1413(136),I438 Hoops, P. 1275(82), 1301 Hoowen-Claassen, A.A.M. 495(524), 518 Hope, H. 14, 18(159), 80, 917(120), 921 Hopff, H. 8(72), 78 Hopkins, B.J. 65,68, 71, 74(345), 84, 321(74, 76), 322(76), 325(74), 401,470(71), 497(71,538), 509, 518, 779(181), 816(307), 817(309), 818(310), 829(334), 865, 869, 1442(11), 1503, 1556(50, 51), 1565 Hopkins, H.F!lr. 264(50), 275 Hoppe, D. 173(69), 211 Hordvik, A. 179(10Y),212 Horeau, A . 245(i44); 253, 503(638,639), 521, 1442, 1444(12), 1503, 1512(67), 1532 Horecker, B.L. 1285(129-131), 1286(131), 1302 Horenstein, B.A. 638(2), 677 Horler, H. 874(10), 887 Horn, H. 1394(90), 1437 Hornc, C.A. 1304(15, 17), I360 Horowitz, H. 14, 17, 18(153),80 Horrom, B.W. 1507(10a), 1531 Horstmann, C. 485(324), 514 Horstmann, H. 1334(127,128), 1362 Hortenstine, l.T.11. 70(359), 85 Horton, W.J. 1138(67), 1243 Howath, A. 720(73), 726 Howell, D.C. 502(621), . . 520, 978(180), . . 991, 1442(14), 150.7 Howitz, H. 360(150), 402,407(8), 434 Hosain-Nia. A. 357(142). 402 Hosmane, R.S. 500(58l j; 519 Hosomi, A . 1390(77), 1437 Hosoya, H. 1091,1093(101), 1108 Hospital, M. 178(103),212 Hostyneck, J.J. 1541(15a), 1564 Hostynek, J.J. 885(37), 887, 933(37), 988 Houdewind, P. 57(308), 84, 735(53), 736(56), 863, 912(111), 921, 1539(10), 1541(12), 1550(38,39), 1561(39), 1564 Houk, K.N. 48(249), 58, 59(322), 82, 84, 225(40), 246(154), 251, 254, 696,708(29d), 714, 715(54), 724, 725, 875(18, 19),
1600
Author index
Houk, K.N. (cont.)887, 1000(47), 1008(71), 1016(100-102), 1024(143), 1043-1045, 1061(47d), 1106, 1558(56-58). 1565 Houriet,'~.52,59(266), 83, 704(19d), 723, 1097(112, 114), 1108 Houriet, R.M. 699-701,708(12), 723 House. H.O. 733. 734i38). 746182). 811(293). 13, 19, 24a, 24b), i508(29, 31a, 31h); 1531 Houwen-Claassen, A.A.M. 9(113), 79 Howard, E.Q. 506(676), 521 Howc, I. 438(4), 457 Howery, D.G. 343(129), 402 Howes, B.R. 312, 314(63), 400 Hsi, H. 1527(113), 1533 Hsi, R.S.P. 469(44), 508 Hsiao, Y. 980(195), 991 Hsu, E.T. 959(105), 989 Hu, S. 170(45),211 Hua, D.H. 962(121), 963(122,123), 989 Hua, M. 1175(182), 7246 Huang, C.C. 1142(79), 1144(90), 1244 Huang, G.T. 1161(144), 1245 Huang, S.J. 9(101), 79, 443(14), 458, 722(85c, 86, 87), 726, 793(238), 867, 959(105), 989 Huang, Y. 826(326), 869, 1008(68), 1044 Huang, Y.Z. 495(522,523), 518 Huang, Z. 1408(120,121), 1438 Huana, Z.-T. 424(83), 435,899(64-67). 920,
34,54, ss, sx, 8244), ixi;(8s), i3ii(29), 1320(39,97), 1321(39), 1323(33), 1326(29, 85), 1327(29), 1328(22), 1329(23a, 23b, 39, 58, 121, 122), 1331, 1332(23a, 23b, 39, 124), 1335(131), 1342(21), 1344(29,39), 1354(17&179), 1355(178,179), 1358(185), 1359-1363 Hub, L. 489(412), 516 Huber, H. 62(329), 84, 237(107), 253, 354, 357(135), 402, 411,433(29), 434, 719(68c), 725 Huber, J.E. 924, 927(9), 987 Huber, K. 968(136), 990 Huber, M.K. 473(154), 475(154,179), 511 Hubert, A.J. 55(295), 83,479,481(259), 513 Hiibner, G. 1275(80), 1276(85), 1279(98, 105), 1281(105), 1301 Hubner, K. 785(214), 786i214,224), 866, 2 /37 --,
Hubner, T. 176(85),212 Hubsch, T. 1033(200,201), 1047 Hubschwerlen. C. 498(549). ,. 519.802(271). 868, 1379(51), 1436 Huche, M. 552(105), 631 Hudgins, W.R. 171(56), 211
Hudrlik, A.M. 473(149), 510 Hudrlik, P.E. 473(149), 510 Hudson, A.J. 1289(148),1302 Huebner, C.F. 580(202), 633, 760(129), 864 Huegi, B.S. 712, 713(46d), 724 Huesmann, P.L. 916(116a), 921 Huet, 1. 1017(114), 1045 Huff, B.J.L. 1508(28), 1531 Huffman, J.W. 621(327), 635, 746, 806, 807(84), 863, 1003(51), 1030(192),1044, 1046 Huger, EP. 538(52), 630 Hughes, P. 646(15b), 677 Hiihnermann, W. 559(134), 632 Huisgen, R. 62(329), 84, 237(107), 253, 354, 357(135), 402,411,433(29), 434, 491(472). 517,719(68c), 725, 1348(156),1363 Huisman, A.D. 555(116), 631 Huisman, H.O. 471(135), 510, 539(59), 630, 748(90), 863,919(124), 922, 1003(55), l044,1535(2a), 1558(53), 1561(2a, 67), 1563,1565 Hulett, J.R. 431(106), 436 Hull, R. 1393(84), 1437 Hiiller, G. 1206(277), 1249 Humber, L.G. 1172(178), 1246 Hume, S.P. 1217(313),1250 Huml, K. 184(138),213 Hummel, G.J.van 13(146), 80, 168(30), 170(49), 171(52, 53), 175(53), 178(98), 182(130), 185(148),210-213,998, 1015(37), 1043 Hummet, G.J.van 998, 1015(36), 1043 Hundeshagen, H. 1206(278,279), 1249 Hung, J.C. 468(24), 508, 737(63), 738(64), 86 7 . . . Hung, M.-H. 963(122), 989 Hung, T.S. 264(50), 275 Hiinig, S. 4(30), 77, 468(5), 469(36), 496, 497(536), 507, 508, 518, 731(25), 778(25, 179), 779(183,184), 781(185-187, 188a, 188b, 189-191), 782(191, 192a, 192b, 195), 785(214), 786(214,221, 224), 862, 865-867,950(84), 988, 1050(6e), 1105, 1366(1c), 1435, 1546(27), 7564 Hiinig, S.E. 469,501(39), 508 Hunter, D.H. 715(55b), 725 Hunter, J.E. 714(53c), 725 Hurd, C.D. 494(508), 518 Hursthouse, M.B. 186(157), 213 Huskey, W.P. 1258(30), 1259, 1281(30,31), 1300 Huss, O.M. 171(55), 211 Husson, A. 479, 482(265), 513 Husson, H.-P. 177(94), 212, 964, 979(129), 986(226), 989, 992
Author index Husson, H.P. 476(203, 204). 479, 482(204, 633, 648(22a-c), 678 Hutchins, R.O.960(109), 989 Hutchinson. E.G. 49N552.553). 519. 1544(20), 1546(2sj, 1548(3ij, 1555(44), 1564 Huttner, G. 1481, 1483(138),1493(146), 1494(138), 1506 Huybrechls, L. 166(16), 210 Huynh, V. 8(82), 78, 303, 304, 306, 311(49), 400, 481(272), 513 Huynk, V. 236(76), 252 Hwang, D.-R. 1217, 1218(315), 1222(321), 1250 Ichikawa, Y. 1298(168), 1302 Ida, Y. 173(66),211 Ide, Y. 187(160),214 Ideda, S. 59(328), 84 Idell-Wenger, J.A. 1139(74), 1243 Ido, T. 1209(286), 1215(305), . . 1222(322), 1249,1250 Iffland, D.C. 1507(2h),1531 Ieartua. A. 14. 181152). 80 lglesias, L.P. 147?(13ij, 1506 Ignatora, E. 1514(76), 1533 Ihara, M. 567(160), 632 Ihikawa, N. 248(182), 254,474(173), 511 Iida, H. 535(41), 556(119-121), 557(119, 120), 568(167), 581(204, 2051%582(213), 583(214), 629, 631633,1391(78), 1437 Iida, K. 1140, 1142(75), 1243 lido, H. 501(60&608), 520 Iino, Y. 1026, 1027(165),I046 Ikawa, M. 1286(138),I302 Ikeda, M. 624(335,336), 636, 654(37), 656(38), 668(37,51), 678, 1376(46), 1436 Ikeda, S. 696, 708(29h), 724, 841(367), 870 Ikewawa, N. 475(185), 511, 845(389), 871 Ila, H. 1312(49), 1315(80), 1331(123), 1333(126), 1335(132), 1353(175a, 175b), 1357(183), 1360-1363 Ilavsky, D. 363,368,370(155), 402,875(14), 887 Illi, V.O. 1180(200), 1247 Imai, Y. 722(85a), 726 Imamoto, T. 1312(46), 1360 Imamura, M. 688(27-29,31), 690(28), 691(29), 693(31), 694 Imanishi. T. 957(102). 989 lmmend&er, E. >01(613), 520 Immer, H. 935(42), 988 Imuta, M. 926(19), 987 Imwinkelried, R. 248, 249(179), 254, 474(161), 511
Inaha, A. 526(6, 7), 528(11, 12), 629 Inagaki, M. 1017(113), 1045 Inagaki, S. 712, 714(46h), 725,924(17), 987 Inaeaki. T. 448(22-24). 458.981(197), 991
.
,.
1436 Incze, M. 1366(9), 1435 Indzhikyan, H.G. 481(271), 513 Indzhikyan, M.G. 480(267), 513 Ingemann, S. 256, 265(6), 271 Ingold, C.K. 1463, 1495(90), 1505 Ingraham, L.L. 1274(73), 1300 Inokuchi, T. 544(76), 630, 951(87), 939 Inomata, K. 495(525), 518 Inooye, Y. 489(382), 515 Inoue, H. 552(104), 556(117), 631 Inoue, J. 749(93), 772(168), 863, 865, 998(31), 1 M." 7 -"
Inoue, K. 769(157), 865, 959(107), 989, 1029, 1030(187), 1046 Inoue, M. 174(70), 179(110), 211, 212, 641(6d), 677 Inoue, 0. 1211(290-292), 1212(293,294), 1213(295,296), 1249' Inoue, S. 482(280), 513, 612(309,311), 635 Inoue. Y. 190(185). 214 lnouye, Y. 1&5(6?), 1044 Inui, H. 1255(19), 1299 Inukai, T. 779(180), 865 Invergo, B.J. 1295(161), 1302 Ippen, 1. 1555(47), 1564 Iranzo, G.Y.1123(28), 1242 Ireland, R.E. 916, 917(117), . .. 921 Irie, H: 616(319); 635 Irie, T. 1211(290), 1212(294), 1213(295, 296), I249 Iriondo, C. 14, 18(152), 80 Isaksson, G. 418(66), 435, 1307, 1313(27), 1360 Isaksson, R. 175(76), 211,423,424(79, SO), 435 Ise, 1. 501(605), 520 Ishehenko, LK. 718(60), 725 Ishihashi, H. 624(335, 336), 636, 654(37), 656(38), 668(37, 51), 678, 1376(46), 1436 Ishida, H. 1026(163), 1046 Ishida, N. 564(154), 632,712(46h), 724 Ishida, T. 174(70),211 Ishidaa, T. 641(6c), 677 Ishiguro, M. 191(189), 214 Ishihara, S. 740(70), 863 Ishihara, T. 550(92), 631, 787(228), 867 Ishii, E 1034(212,213), 1047,1375,1434(44), 1436 Ishii, K. 173(68),211 Ishikura, M. 192(199), 215, 896(53), 920
Author index Ishiwata, K. 1209(286), 1215(305), 1222(322), 1249, 1250 Isomura, Y 528(13), 629, 1026(166), 1046 Ito, S. 916(118). 917(118, 119). 921 Ito, Y. 248(18i), 254,. 474(166), 511, 776(176), 86 --"F
Itoh, M. 1215(305), 1249 Itoh, T. 59(328), 84, 696, 708(29b), 724, 933(38). 988 hersen', <E. 981(202), 991 Ives, J.L. 927(20-22), 987 Ivsl~in,V.P. 8(75), 78 Iwakura, K. 880(31), 887 Iwamoto, K. 1012(91), I044 Iwanami, M. 1366(18), 1436 Iwanami, Y. 448(22-25), 458 Iwasaki, H. 1260(38), I300 Iwase, K. 712,714(46h), 725 Iwata, N. 495(525), 518 Iwata, R. 1209(286), 1215(305), 1222(322), 1249, 1250 Izhboldina, L.P. 492(497), 518 Izumi, T. 1021(127), 1045 Izo, P.T. 901(72), 921 Jabes, D. 1190(230), 1247 Jack, J . 735, 737(50), 862 Jackman, L.M. 407(10), 434, 1507(4,5a, 5b, 12a), I531 Jackson, R.I. 606(293), 635 Jackson, R.W. 794(242), 867 Jackson, W. 264(50), 275 Jacob, J.N. 1511(43), 1532 Jacob, L. 426(91), 435 Jacobs, W.A. 606(290), 635 Jacobsen, H.J. 236(82), 252, 439, 440,444, 445,447,449(8), 458 Jacobson, A.E. 1153(113), 1244 Jacquet, J.P. 490(445), 517 Jacquier, R. 53(267), 83,470(67), 471(117), 509, 510, 709,710(38), 724, 782(194), 866,1051,1053, 1065(12), 1105,1123, 1124(26), 1242 Jaeger, V 1529(114, 115a-c, 116), 1533 Jaenicke, L. 970(147), 990 Jaffk, H.H. 46(238), 63, 67(333), 82, 84, 1053, 1077(23), 1105 ldgun, K.H. 1091, 1093, 1094,1100(102d), 1108 Jahng, Y. 1028(171, 172), 1046 Jahreis, G. 1313(65), 1361 Jaime, C. 826(325a, 325b), 829(335), 869 Jain, P.C. 501(610), 502(614), 520, 574(187), 57S(l88), 594(187), 633 Jain, R.S. 10(130), 79 Jakas, D. 1164(152),1245 Jakoben, P. 890(19), 920
Jakobsen, H.J. 579(200), . , 633, 939(52), . . 988, 1394(89), 1437 Jakobsen, P. 1020(119), 1045, 1373(38), 1436 James. D.R. 840f360). 870 ~ameson,C.J. 394(209,210), 404 Jameson, D.L. 592(246),634 JaneEkovi, E. 488(365), 515 Jankowski, B. 785(210), 866 Jankowski, B.C. 940(55,56), 988 Jano, J. 710(39), 724 Janousek, Z. 193(200), 215,525(3), 629, 769(163), 665 Janssen, M.J. 1051, 1053, 1056, 1057, 1065-1067,1069, 1070, 1072, 1073, 1081, 1090,' 1092(1Id), 1105 Janzen, E.G. 682(5), 693 Jarczewski, A. 1134(363-367), 1251 Jardon, J. 626(341), 636, 1393(85), 1432(189, 190), 1437, 1439 Jeanmart, C. 1537(9a), 1563 Jeannin, S . 166(19),210 Jecny, J. 184(138), 213 Jedrych, Y 409(27), 434 Jefford, C.W. 924, 926(6), 987 Jeffrey,S. 488(373), 515 Jelenc, P. 904, 905(84), 921 Jemison, R.W. 481(270b), 513 Jencks, D.A. 1079(82a), 1107 Jencks, W.P. 1072(74a, 74b), 1075(74b), 1079(82a, 82b), 1080(84), 1081(74b, 86), 1085(92a, 92b), 1098(85,86), 1107, 1255(7), 1293(158), 1299, 1302 Jenkins, T.C. 1128(42), 1243 Jcnkins, W.T. 1286(140), 1302 Jennings, K.E. 471(115), 510 Jenny, E.E 473(156), 511 Jensen, A.O. 944(64), 988 Jensen, E.M. 528(10), 629 Jensen, E.V. 794(242), 867, 1563(76), I565 Jensen, J.L. 262(32), 273, 1091, 1093(99), 1108 -Jensen, W.B. 697, 707(4c), 723 Jephcote, V.J. 182(126), 213 Jepson, J.B. 1170(172), 1246 Jerabeck, P.A. 1222(320), 1250 J ~ N s s R.A. ~ , 471(118), 486(338), 510, 514, 931(32), 987 Jeso, B.de 7(66, 67), 8(79), 78,305, 306(52), 400, 843(371), 870, 893(46,47, 50), 894(46,47), 920 Jewett, D.M. 1223(323),1250 Jiang, H.-J. 1338, 1346(137b),1362 Jibodn, K.O. 1449(55),1504 Jibril, I. 1493(146),1506 Jimenez, L. 1261(47), 1300 Jindra, V. 1021(124),1045, 1381(55), 1436 Jinguji, M. 999(42), 1043 ~
Author index Jirkovsky, I. 650(29), 678 Jitsukawa, K. 933(38), 988 Jkaczorowski, G. 550,599(95), 631 Jochims, J.C. 1448(48), 1449(52), 1481(48, 52, 138), 1483(138), 1484(139, 140), 1485(139), 1493(146, 148), 1494(48, 138, 139), 1495(148,151), 1504,1506 Joel, P. 507(683), 521 Joergensen, K.A. 971(161), 990 John, D.I. 182(126), 213 John, E. 1237(352),1251 Johns, D.G. 1156(123b),1245 Johnson, A. 494(517), 518 Johnson, B.A. Y44(63,64), 988 Johnson, E.F. 56(301), 84, 266(59), 275, 479, Johnson, F. 70, 71(360), 85, 221(15), 234(69), 235115). 236(15.89). 251. 252. 729. 1449(53); 1504 Johnson, H.G. 1191(233), 1247 Johnson, J.L. 269(70b), 277, 470, 496(60), 509, 944(64), 988, 1062(52), 1106, 1537, 1538(3a), 1563 Johnson, K.E. 170(45), 211 Johnson, P.C. 1135(62), 1243 Johnson, R. 98(7), 210 Johnson, R.A. 58(316), 84 Johnson, S.L. 1089(98), 1107 Johnson, W.S. 961(113,114), 989, 1063(53), 1106, 1507(23), 1531, 1542(17a, 17b), 1564 Johnston, C.G. 1089(95), 1107 Johnston, D. 1197(245), 1248 Johnstone, R.A.W. 231(59), 252 Jolly, D. 1205(270), 1248 Joly, R. 1563(76), 1565 Jonczyk, A. 506(657), 521 Jones, C.D. 471(136), 510, 1133(55,57), 1243 Jones, E.R.H. 500(594), 520 Jones, F.M.111 1065(63a),1106 Jones, G. 192(198),215,740(78), 863 Jones, J.R. 1165(154), 1169(168),1245,1246 Jones, M.J. 1304, 1308, 1310, 1324(10), 1359 Jones, M.Jr. 471(100), 509 Jones, N.D. 176(82),212 Jones, P.F. 307(~6),400 Jones, R.A. 186(157),213, 417(57), 435 Jones. R.C.F. 1309(36). 1328f118). 1329. Jones, R.G. 551(99), 631 Jones, T.R. 1176(187), 1246 Jones, W.A. 794(245), 867 Jones, W.A.Jr. 1283(116), 1301 Jonge, K.de 471(135), 510, 1558(53), 1565 Jongejan, E. 470(72), 509
1603
Jonkers, EL. 479(246, 247), 512 Jordan, F. 25(203), 81, 705(22), 724, 955(99), 989, 1065, 1066(68a, 68b), 1068(70), 1078(68a), 1080, 1085,1089(68a, 68b), 1107, 1255(11,21), 1257(21,23), 1258(30), 1259(30,31), 1261(42), 1262(48), 1266(57), 1268(60,61), 1269(6245), 1274(77), 1275(63, 77, 82), 1276(64,65,88), 1277(YI), 1278(77,93, 94), 1279(97,99, loo), 1280(91), 1281(30,31, 42), 1283(123, 124), 1299-1301 Jorgensen, FS. 704(19b), 723 Joreensen. W.L. 1008(72). ,, 1044 JO& L. 387(202), 403 Josef, J. 907(101), 921 Joseph, M.A. 234(70), 235(71,72), 252,317, 318, 320(68), 401, 440(10), 458 Joseph-Nathan, P. 192(195),215 Joshi, B.C. 471(141), 510 ~oshi;P.C. 672,'676(57), 679 Josien, H. 797(261),867 Joule, J.A. 55(298), 83, 183(135), 185(146), 213.256(4a. 4b). 271. 480.4831266X ~ ,. 513 ~oullie;M.M.k ( i 5 3 ) , 213 Jozwiak, A. 10(128), 79 Jugelt, W. 986(227), 992 Ju-Ichi, M. 179(110),212 Julia, M. 1512(48b),1532, 1537(9a), I563 Julia, S. 504(643), 521, 1537(9a), 1563 Jumax, A. 491(470), 517 Jun, Y.M. 714(53~),725 Junek, H. 42(229), 82, 542(63), 552(102), 593(248. 249). 597(261). 608(297). 634,.635, 89 1(29),'920, i 4 1 9 j m j , 1438 Jung, M.E. 226(49), 252, 1512, 1525, f528(51b), 1 ~ 3 2 Jung, M.J. 1295(160), 1302 Junek. S.J. 1255. 1264. 1266(101. 1299 1357(183j, 13602363 Junod, A.F. 1199(253,254), 1248 Juntunen. S.K. 1010(74). 1044 Juri, P.N.' 979(194), 99i' Jutle, K.K. 790, 793(237), 848,850(397), 852(400), 867, 871 Jutz, C. 232(66), 252,489(434), 516, 968(138, 139). 990. 1325(112h 1362 Jutz, ~:'544(68),630 Jutz, J.C. 544(70), 630 Kaars, P. 173(69), 211 Kabalka, G.W. 834(347), 869 Kabanov, V.A. 686(22,23), 694 Kabbe, H.J. 1401(108, 109), 1438 Kaczka, E.A. 167(27), 210
1604
Author index
Kaczmar, B.U. 1195(240), 1248 Kadokura, M. 981(199), 991 Kaeppeler, W. 785(215), 866 Kaertner, A. 483(286), 513 Kagabu, S. 1307,1313,1328(24b), 1360 Kagaku Kenkyusho 506(660), 521 Kagan, F. 794(242), 867 Kagan, H.B. 503(638-640), 521,979(192), 991, 1442(12,13), 1444(12),1503 Kagan, H.R. 481(276), 513 Kahan, EM. 167(27), 210 Kahan, J.S. 167(27), 210 Kahanek, H. 496,497(536), 518, 1546(27), 1564 Kahn, L.D. 469(44), 508 Kahn, L.R. 24(185), 81 Kaim, W. 180(114), 212 Kaiser, A. 11(140), 52, 68(265), 79, 83, 709(36), 724, ios2, 1oss(i6), 1os6(25), 1065(16),1105 Kaiser. C. 9831211). 991 Kiitar, M. 964126), 989 Kaitner, B. 169(41), 211 Kajigaeshi, S. 528(13), 629, 1026(166), 1046 Kajikawa, Y. 841(367), 870 Kajiwara, M. 1136(64), 1140(75), 1142(75, 76). 1243 ~ajtar-peredy,M. 797(260), 867 Kakisawa, H. 1005(61), 1044, 1373(37), 1436 Kalabin, G.A. 283(9), 287(9, 14), 288(14), 289, 294, 298(9), 317(14), 339,354(9), 399 Kalas, R.-D. 7(65), 78, 309, 319(61e, 61i), 400, 843, 848(376a), 870, 897,898(58,62), 920 .-. Kalaus, G. 187(168), 214, 797(260), 867, 1366(9). 1435 Kalbron; j: 1156(128), 1245 Kalesse, M. 548(84), 630 Kalikhman, I.D. 500(579), 519, 1314, 1315(77). 1361 Kalino~skl','~.-0. 407,427(9), 432(111), 434, 436 Kblman, A. 187(168),214,751(98), 864, 1O3O(l'W), 1046 Kalsi, P.S. 944(65), 988 Kamata, K. 1517(86),1533 Kamath. N. 14.21(164). ~ ,. 80.. 221(17). ~ ,. 251.. 380(190), 403 Kamath, N.U. 174(74), . . 211,418(60), 419, 421, 422(69), 435 Kamatsuzaki, S. 471(106), 510 Kambe. N. 9811197). 991 ~ a m e i , ' 380(i91i'403 ~. Kameswaran, V. 1383(58), 1436 Kametani, T. 488(369), 515, 567(160), 632, 638(5), 677, 964(128), 989
Kamieiiska-Trela, K. 46(239), 65(239,347), 68(239,347-349), 72(349), 75(348,349), 82, 85, 327(93), 190(188), 214, 237(99), 253,329,334(96), 337(113), 338(96, 113), 339(113), 342(93, 124), 34%350,352, 3 5 4 356, 358, 362, 365(132), 388(113), 401, 402,409(26), 434,709(30c), 724,891(30, 31), 920 Kamio, C. 1390(77), 1437 Kamiya, K. 174(71), 211 Kan, K. 9(93), 79 Kanabus-Kaminska,J.M. 876(25), 887 Kanagapuahpam, D. 186(154, 155), 213 Kanazawa, T. 462(8), 463(10), 465 Kanda, Y. 1163(150), 1245 Kane, V.V. 816(298), 868 Kaneda, K. 59(328), 84,696, 708(29b), 724, 933(38), 988 Kaneko, C. 1026(162), 1046 Kaneko, H. 943(61), 988 Kanemasa, S. 485(331), 514 Kanematsu, K. 760(125), 864 Kan-Fan, C. 476(201,203), 479,482(265), 511, 513, 964, 979(129), 986(226), 989, 992 Kang, G.J. 829(337), 869, 1013(95), 1044 Kang, J. 494(514), 518 Kang, S. 1216(308), 1250 Kania, L. 46, 65(239), 68(239,348, 349), 72(349), 75(348, 349), 82, 85, 190(188), 214,337-339(113), 348-350,352,354356, 358, 362, 365(132), 388(113), 401, 402, 709(30c), 724, 891(30), 920 Kanishcheva, A.S. 174(75), 211 Kanke, R. 590(240), 634 Kantlehner, W. 1310, 1318(42), 1319(42,95), 1326(95), 1360, 1361 Kao, , B.C. 544(73), 630 Kaplan, A.M. 686(23), 694 Kaplan, E. 1138(71), 1243 Kaplan, H.R. 1142(77), 1178(198), 1243, 1247 Kaplan, J. 1209(285), 1249 Kapon, M. 1005(63), 1044 Kappas, A. 1241(359-361) 1251 Kappe, T. 536(44), 630 Kappen, L.S. 1150(106), 1244 Kapples, J.F. 538(52), 630 Kapst, U. 931(33), 987 Karabatsos, G.J. 1524(109), 1527(113), 1533 Karafiloglou, P. 431(107, 110), 432(110), 436 Karapetyan, H.A. 171(51),211 Kardos-Balogh, Z. 1366(9), 1435 Karelson, M. 261(30), 273 Karger, M.H. 749, 816(94c), 864, 1030(188), 1046, 1398(100), 1437, 1554(41), 1564 Karimian, K. 1280(107), 1301 KarliEkova, L. 489(410), 516 Karlsson, S. 414(43), 434
1605
Author index Karpenko, V.D. 1456(6&70), 1504 Karrer, P. 488(362, 367,368), 515 Kartha, G. 175(79), 212 Kasahara, A. 1021(127), 1045 Kasai, M. 192(196), 215, 1163(150), 1245 Kascheres, C. 48(246), 82, 530(15), 629, 719(65), 725,890(22), 920, 1386(67), 1437 Kashima, C. 319, 345(71), 401,576(192), 577(194), 599(267), 633, 634,1040(242), I047 Kashimura, S. 769(157), 865, 1029, 1030(187), 1046 Kaska, W.C. 1310(40), 1360 Kaspersen, EM. 1169(171),1246 Kasum, B. 612(313), 635 Kasuya, Y. 1120(14, 17), 1242 Katagiri, N. 1026(162),1046 Katayama, S. 1034(207),1047 1032(197),1b47 ~ a t h J.C. ; Kato, H. 10, 70(125), 79, 470(91), 509 Kato. M. 9(87). 78. 1324(107). ~ ,. 1362 ~ a t oS. ; 1026(163), 1046 Kato, T. 169(36),210 Kalo-Amma, M. 1239(354),1251 Katritzky, A.R. 10(128), 25(198), 79, 81, 225(37), 251, 261(30), 273, 1020(122), 1045,1063(54), 1098(119a, 119b), 1106, 1108 Katsumi, K. 638(4a), 677 Katzenellenbogen, J.A. 1216(310),1250 Kau, D.L.K. 1228(337),1250 Kaufman, L. 99(9), 210 Kaufmann, G. 1281(110), 1301 Kausen, H. 428(100), 436 Kawai, N. 470(57), 509 Kawajiri, Y. 1136(64), 1243 Kawaminami, E. 1386,1423(64), 1437 Kawano, K. 583(214), 633 Kawasaki, T. 544(75), 546(80), 547(81), 630, 11 1917). -1242 -- Kawashima, K. 1209(286), 1215(305), 1249 Kawecki. R. 9(112). 14. 21(163). 79. 80. 394. 395(215), 404, ?i8,719(63aj;720(71), 725, 726, 890(17), 920, 1116(1), 1242 Kayukova, L.A. 14,21(168), 80, 507(684), 521, 844(385e), 871 Keeffe, J.R. 1060(34,37,38b, 42, 44), 1061(37,44), 1062(42,44, 50d), 1075, 1076, 1083,1084(44), 1085(92b), 1092(106a, 106b), 1098(34,38h), 1101(106a, 106b), 1103(34,37,38b, 42), 1105-1108 Keely, S.L.Jr. 489(429,430), 516 Keiko, N.A. 500(579), 519 Keitel, I. 9(95), 79 Kelling, H. 387(198), 403 \
,.
Kellogg, R.M.489(383), 515 Kelly, C.A. 471(105), 510,799(263), 867, 997(25), 1043 Kelly, P. 414(47), 435 Kelusky, E.C. 1316(83), 1361 Kemme, A.A. 168(31), 210 Kempf, H. 998(32,33), 1043 Kende, A S . 901(72), 921 Kenna, M.J. 484, 485(291), 513 Kennedy, F. 473(158), 511 Kent, A.B. 1283(119),1301 Kcnyun, G.L. 1261(45), 1276(87), 1300, 1301 Kepler, J.A. 1156(124), 1175(183), 1245, 1246 Kerbal, A. 1022(135), 1045 Kerber, R.C. 879(28), 887 Kercher, K.A. 496(532), 518 Kereszturi, G. 360(151), 402, 606(292), 635 Kern, J.-M. 998(34), 1043 Kerr, J.M. 1226(329), 1250 Kessick, M.A. 1099, 1100(127b), 1109 Kessler, H. 246(1.61, 162), 247(162), 254, 407(9), 418(62), 427(9), 432(11 I), 434-436 Kester, D.E. 715(57a, 57b), 725 Kesztler, E 491(455), 517 Kettelhack, D. 484(314), 514 Keune, H. 1143(86), 1244 Keyton, D.J. 764(139), 800(269), 865, 868 Kizdy, EG. (91), 1107 Khachidze, M.M. 571(176), 632 Khailova, L.S. 1274(75), {278(96), 1300, 1301 Khalaf, M.M. 182(126),213 Khan, A.Z.-Q.422(77), 423,424(77, 80, 82), 435 Khan, M.Y. 471(125), 510 Khandelwal, J.K. 1146(92), 1244 Khandelwal, P.K. 471(141), 510 manna, R.K. 740(72), 863, 879(29), 887 Kharasch, M S . 264(51), 275 Kharchenko, V.1. 58(325), 84 Khatipov, S.A. 394(211), 404 Khatri, H.N. 57(311), 84, 736(58h), 863, 909(106), 921 Khetan. S.K. 944(68). -,, .988 .Khmelevskii, V.I. 1120(16), 1242 Khorlin, A.Ya. 1457, 1458,1469(73), 1504 Khoudary, K. 1313(69), 1361 Khripach, N.V. 967(135), 990 Khripach, V.A. 930(28), 967(135), 987, 990 Kibavashi, C. 501(606408), 520.535(41). \ -
Kida, N. 641(6b), 677 Kido, M. 624(335,336), 636 Kieczykowski, G.R. 740(79), 863 ~ielckwski,M.A. 451(39),458, 489(384, 386), 515
1606
Author index
Kielty, J.K. 1155(120),1244 Kienzle, F. 1011(80), 1044 Kierstead, R.W. 490(443), 516 Kiesewetter, D.O. 1216(309), 1250 Kiffer, D. 1183(208),1247 Kiguchi, I. 642(9a, 9b), 677 Kiguchi, T. 638(3b), 641(6a), 677, 1378(50), 1412(131). 1436. 1438 Kihlman, B.A.1182(204), 1247 Kii, N. 933(38), 988 Kijima, A. 883(34), 887 Kikelj, D. 1314(76), 1361 Kikkawa, I. 169(37),210 Kikta, E.J.Jr. 1156(125), 1245 Kikuchi, T. 1021(127),1045 Kikugawa, K. 330(107), 401 Kilbourn, M.R. 1216(310), 1217(314), 1222(320), 1223(323), 1250 Killean, R.D.G. 168(32), 210 Kilpatrick, M. 1099, 1100(127a),1109 Kiltz, H.H. 476(216), 512 Kim, C.S.Y. 1089(97), 1107 Kim, D. 638(2), 677 Kim, K. 471(98), 509 Kim, M.-J. 1295(167), 1302 Kim, S. 962(119), 989 Kim, S.M. 764(146), 865 Kim, Y.C. 177(92), 212 Kim, Y.J. 962(119), 989 Kim, Y.K. 4(20), 8(85), 76, 78, 220(12), 221(6, 7), 222(22), 251, 309(59), 400, 470(65), 487(357), 509, 515 Kimamoto, M. 248(183), 254 Kimball, A.P. 1155(121a),1244 Kimny, T. 1416(146), 1438 Kimpe, N.de 256(1c), 270, 506(656), 521 Kimura, M. 1029(186),1046, 1260(38), 1300, 1409(123), 1438 Kinell, H. 1170(174), 1246 Kin-Fai Cheng 189(184), 191(190),214 King, J.C. 994(7), 1043 King, S.W. 180(116),212 Kino3hita, H. 489(380), 495(525), 515, 518 Kinoshita, J.H. 1177(192), 1246 Kinoshita, N. 1119(7), 1242 Kipnis, D.M. 1120(20), 1242 Kipphardt, H. 248(186), 254, 474(167), 511 Kira, A . 688(27,31), 693(31), 694 Kirby, S.P. 256,258, 259(2), 264(45), 270, 274, 1058(28), 1105 Kirfel, A. 170(42), 211 Kirillova, M.A. 555(109), 631 Kirin, V.N. 266(59), 275 Kirkpatrick, A. 1410(125),1438 ~ i r n H.R. ; 1424(167), 14'39 Kirollos, K.S. 571(175), 632 Kirrmann, A . 9(97), 79, 779(183), 866
Kirschner, A.F. 968(138), 990 Kirvo. Y. 1388(74). 1437 Kiriu; Y. 1021:125), 1045 Kisch, H. 179(105), 212 Kish, EA. 1092, 1101(106c),1108 Kislyi, V.P. 1322(102), 1361 Kistenmacher, T.J. 189(181),214 Kita, Y 534(39), 547(81), 629, 630, 654(37), 668(37,52), 670(55), 678, 1376(46), 1436 Kitada, A. 1063(57), 1106 Kitagawa, T. 612(311), 616(319), 635 Kitahara, Y. 473(155), 511,802(284), 868, 1020(120), 1045, 1373(39), 1436 Kitamoto, M. 474(162), 511, 1512(68), 1532 Kitamura, M. 980(195), 991 Kitane, S. 1016(112), 1022(134),1045 Kitaoka, S. 1255(19), 1299 Kitazume, T. 474(173), 511 Kittler, L. 582(212), 633 Klages, F. 1449(51), 1504 Klausner, A.E. 1098(120), 1108 Klee, W.A. 1153(113), 1244 Kleemann, M. 4(17), 76, 779(182), 800(266), 866,868 Kleibomer, B. 32(218,219), 82 Klein, C.M. 9(109), 79, 797(256, 257), 867 Klein, 1. 39(223), 82 Klein, J.-L. 9(96), 79, 500(580), 519 Kleine, K.M. 484(302), 514 Kleinman, E.E. 607(294), 635 Kleinpeter, E. 4, 5(45), 42(230), 77, 82, 433(122), 436, 1366(8), 1435 Kleipctcr, E. 890, 891(12), 919 Klemmensen, P. 770(165), 865 Klessinger, M. 327(85), 401 Kletskii, M.E. 1448-1450(49), 1468(110), 1481,1484(49), 1485(141,142), 14861488(141), 1489(141, 142), 1490, 1492, 1493(142), 1494(49), 1497(49, 141, 142), 1504-1506 Klicnar, J. 890(16), 920 Kloetzel, M.C. 491(467), 517 Kloosterziel, H. 475(188), 511 Klop, W. 500(578), 519 Kloster, G. 1208(283), 1249 Klotzer, B. 192(197),215 Kloubek, 1. 4(22), 77, 500(583), 519 Klug, J.T. 476(214), 512 Kluger, R. 1255(4, 17, IS), 1276(86), 1280(107), 1281(1lo), 1284(126), 1299, I301 Klusener, P.A.A. 500(578), 519 Klysa, T. 1142(81), 1244 Knabe, J. 484(298), 485(321-3233,514 Knann. S. 1512157). 1519(57.95). 1532. I533
. index Knebrich, J.P. 1263(52), I300 Kneen, G.468(11), 508 Kniezo, L. 181(122),213 Knippel, E. 387(198), 403 Knippel, M. 387(198), 403 Kniss, E. 498(544), 519 Knobler, C. 193(201), 215 Knoche, W. 1091(102a-c), 1092(102b), 1093, 1094(102a-c), 1095(102c), 1100(102a-c), 1108 Knoll, E. 1316(87), 1361 Knorr, K. 843(381), 870 Knorr, P. 245(151), 254 Knon; R. 7, 8(69), 40(224), 78, 82, 301-305, 307, 308,310,311,319(42), 400,476(217), 493(506), 500(588), 512, 518, 519, 715(56), 718(63c), 725, 890(15), 893(48), 920, 1530(121), 1533 Knowles, W.S. 979(193), 991 Knunyanz, I.L. 1443(22), 1466(99), 1503, 1505 Knusel, E 1152(107),1244 Knyazev, A.P.1448-1450(46), 1467-1469(102), 1472(117), 1475(102), 1480(117), 1481(46), 1487, 1492(102), 1501(157), 1503,1505, I506 KO,J.S. 962(119), 989 Kobayashi, G. 170(47), 211, 1313(51,70, 71), 1315(51), 1335(130), 1346(151), 1360-1363 Kobayashi, K. 937(48), 988 Kobayashi, M. 169(36), 210 Kobayashi, S. 1232(344), 1251 Kobayashi, T. 178(99), 212, 495(525), 518 Kobayashi, T.J. 1147(96), 1244 Kobelt, M. 1058(27), 1105 Kober, R. 775(174), 865, 1039(240),I047 Koblik, A.V.1467(108), 1502(158), 1505, 1506 Koch, D. 461(5), 464, 954(96), 989 Koch, 1. 4(19), 76, 786(217), 866, 1369(26), 1436, 1560(64), 1565 Koch, T.H. 675(60), 679 Kochctkov, K.A. 387(201), 403 Kochctkov, N.K. 597(263), 634,971(152), 990, 1393,1415(86), 1437,1457,1458, 1469(73), 1504 Kochi, J.K. 873(1), 886 Kodama, Y 178(99), 212 Koe, B.K 115Y(139), 1245 Koehn, W. 11(143), 80 Koehn, W.A.471(129), 510 Koelle, U. 411(34), 414, 415(46), 416(34), 434 Koenig, J.L. 1167(156), I245 Kofod, H. 534(40), 629 Kofron, W.G.226(50), 246(155), 252, 254, 1512,1525(51a), 1532
1607
Koga, K. 245(145), 253, 1512(56), (70a, 70b), 1532 Kogami, K. 765(151), 772(167), 865, 1540(11), 1564 Kogan, G.A.471(116), 510 Kohl, B. 918(123), 922, 1338(134), 1362 Kohler, H. 1091, 1093(100), 1108 Kohli, D.K. 587(233), 634 Kohno, M. 192(196),215 Kohra, S. 528(14), 629 Koike, M. 1274(71), 1300 Koike, T.406(1), 434 Koikov, L.N. 46(240), 48(241, 242a), 82, 225(43), 251,284,287(12), 292, 293(27), 294, 296, 320(12), 399 Kojic-Prodic, B. 170(46), 177(87), 211, 212 Kojima, A. 1353(173), 1363 Kojima, M. 1218(316), 1250 Kojima, N. 641(6d), 677 Kojima, T. 1005(61), 1044 Kolb, B. 220, 234(68), 252, 414, 415(46), 417(58), 434, 435 Kolb, M. 1312(48), 1360 Kolle, U. 220(68), 233(67), 234(68), 252 Kolle, U.U. 232(63), 252 Kollenz, G. 186(158), 213 Koller, H. 423(78), 435 Koller, W. 491(471), 517 Kollman, V.H. 1138(68), 1243 Kollmeyer, W.D. 1304(15,17), 1307, 1313(24a), 1320(96), 1328(24a), 1338(138a-c), 1340(138a-c, 141), 1346(148-150), 1360-1363 Kulunicny, A. 394(216), 404 Kolonits, P. 187(168),214, 1366(9), 1435 Kolonka, K.J. 1512(49), 1532 Kolozyan, K.R. 1460(84), 1504 Koltai, E. 1180, 1181(202), 1247 Komatsu, M. 1027(167), 1046, 1419(153), 1438 Komeshima, N. (70b), 1532 Kominami, K. 474(166), 511, 776(176), 865 Komkov, A.V. 1322(101), 1361 Komobayshi, H. 481(274), 513 Komori, T. 173(66), 211 Komorowski, K. 471(11 I), 510, 823(322), 869 Konakahara, T. 492(481), 517 Kondo, K. 951(87), 989,1546, 1548(33), 1564 Kondo, M. 356(141), 402 Kondo, Y. 569(169), 632 Koning, H.de 1442(4), 1502 Konshin, M.E. 1453(67), 1504 Konst, W.B.M. 236(88), 252 Konst, W.M.B. 806(291), 868, 1003(50), 1030(191\. , ,. 1044. 1046 Konstantinuvska-Djokic,D. 1238(353), 1251 Koop, G. 170(42),211
1608
Author index
Koopmans, T. 58, 59(319), 84 Koppel, I. 704(16b, 16c), 723,1097(116b), 1108 Koppel, LA. 707(27a), 724 Koian, '1. 489(407), 516 Kornblum, N. 879(28), 887, 1507(2b), 1531 Kornfeld. E.C. 551i99). 631 ~orochkha,L.G. 1274(75), 1300 Korshuk, E.F. 1459, 1460(82), 1504 Korte, E 63, 65(339), 84, 491(449453), 517, 722(79). 726 ~oshmina,N.V. 367(160), 403 Koshy, K.M. 1057, 1091,1093, 1096(103), 1099i103. 126~).1100(126c~.1101. 1103j103), IIOS,IIO~' Kosley, R.W. 498(545,546), 519 Kosley, R.W.Jr. 57(309), 84,494(512), 518, 905(97), 921 Kosman, W.M. 11(143), 80,471(129), 475(176),510, 511 Kosower, E. 530(23), 629 Kosower, E.M. 52(277), 83, 168(33), 178(101), 191(192, 193), 192(193, 194), 210, 212, 214 Kossakowski, 1. 560(141), 632 Kotara, M. 592(245), 634 Kotera, K. 1526(111), 1533 Kothari, M. 555(113), 631 Kotschy, J. 428(100), 436 Kouba, J.E. 1095(108),1108 Kouwenhoven, C.G. 1433(192),1439 Kovit, J. 494(513), 496(530,531), 518 Kovaleva, V.N. 612(310), 635 Kovalskaja, S.S. 1459, 1460(83), 1504 Kovai, J. 488(375), 515 Kovar, K.-A. 289, 291, 318, 344(16),399, 711(44), 724, 761(132, 133), 864 Koves, E M . 1125(33),1242 Koves, G.J. 1125(32), 1242 Kowalski, P. 492(482), 517 Kowitz, F. 1324(108),1362 Koyama, H. 172(57), 177(91), 211, 212 Koyama, J. 1026(152-154), 1046 Koyama, S. 1026, 1027(165), 1046 Kozarich, J.W. 1276(87), 1301 Kozell, L. 1162(147), 1245 Kozerski. L. 9(106. 112). 14. 21(163). 79. SO.
.
.
1116(1), 1242 Kozerski. L.J. 42(228). 82. 237/96-98., 100., 101), 238(96,97), 552,253 ' Kozicka, M. (368), 1251 Kozikowski, A.P. 168(29), 210,826, 829(329), 869, 1029(182), 1041(254), 1046, 1048 Kozikowsky, A.P. 1546, 1548(29a), 1564 Kozina, M.P. 266(59), 275 Kozlov, N.G. 1459, 1460(81-83), 1504 Kozlov, N.S. 612(310), 635 Kozlov, V.A. 187(161),214 Kraatz, A. 968(139), 990 Kradepohl, A. 552(103), 631 Krajewski, J.W. 14, 21(163), 80 Kramer, H.E. 231, 237(58), 252 Kramer, H.E.A. 327, 353(84), 401, 1064(61a<), 1106 Kramer, W. 1314(76),1361 Krampitz, LO. 1257, 1258(24), 1263(51), 1264(54), 1299,1300 Kraska, A. 627(346), 636 Krasnansky, R. 875(16), 887 Krasnaya, Z.A. 426-428(94), 435 Krasnaya, Zh.A. 363(154), 402 Kratky, C. 13, 14, 16(144),80, 88, 89(1), 210, 225,226, 228(46), 251, 290(19), 399, 407(14), 434 Krauch, H. 3(9), 76 Kraus, C.H. 1507(9), 1531 Kraus, G. 1517(86), 1533 Kraus, J. 547(83), 630 Kraus, W. 657, 667(40), 678 Krause, D. 189(180), 214 Kray, L.R. 247(165), 254,484(293-295), 513 Krebs, A. 247(163,177), 254 Krebs, E.G. 1283(119), 1301 Kreienbuhl, P. 247(166), 254 Kreighhaum, W.E. 1135(62), 1243 Kreindel, M.Ya. 686(23), 694 Kresge, A.J. 709(35), 724, 1052(14), 1053(18), 1055(14, 18). 1057(14), 1060(34,35a, 35b, 36, 37, 38a, 38b, 39-42, 44), 1061(37, 44), 1062(41,42, 44,49, 50d), 1065(18), 1074(76,78), 1075, 1076(44), 1077(36), 1083(44,87), 1084(14,44), 1090(14), 1094(107a, 107b), 1095(107a, 108),
.
.
.
.
38b, &ij, 110;-1109 Kress, J. 479(256), 513 KfestZnovi, V. 54-56(291), 83, 259(16), 271, 479(261), 513
.
Author index Kresze, G.1562(69), 1565 Kretchmer, R.A. 695(1h), 723 Kreutner, W. 1175(185), 1246 Kreutzmann, J. 362, 363, 367, 369(153), 371(165), 402, 403 Krieger, H. 830(339b), 869 Krieghbaum, W. 1135(60),1243 Krim, H. 843,848(376b), 870 Krimen, L.1. 1447(45), 1503 Krishnan, R. 25(193), 81 Krisl, H. 1428(181), 1439 Kristen, H. 370(163), 387(198), 403 Kristian, P. 181(122),213 Kritskaya, D.A. 686(19), 693 Krivdin, L.B. 283(9), 287(9, 14), 288(14), 289, 294. 298(9), 31704). 339, 354(9), 399 Krogh, E.T. 1062(49),.1106 Krohnke. F. 7(651. 78. 309. 319(60. 61~1.400. Krouwer, J.S. 8(83), 7 8 Kr6wczynski, A. 9(106), 79, 242, 244(125), 253, 373(177), 375, 377, 378(177, 178), 3801177). 394.395(215). 403. 404.412(38. 39),'43<'499(568),'51~'71~(68~); 720(71), 725, 726, 891(33), 920, 1116(1), 1242 Kmeger, C. 507(681), 521 Krueger, W.E. 1119(9), 1242 Kruger, C. 172(58), 179(105), 182(127), 211-213, 1026(151),1046, 1384(61),
-7 6.",7 7
Kruger, T.L. 451(30), 458 Krygowski, T.M. 27, 28(196), 38(221), 40(1961. 421221). 81. 82 ~ u a nc.P:'492(483j, ; 5i7, 1022(140),1045, 1394(88), 1437 Kubler, W. 1214(299), 1249 Kubota, M. 544(76), 630 Kubota, N. 1120(17), 1242 Kucharczyk, N. 1196(243),1248 Kucherov, V.F. 426-428(94), 435 Kuchitsu, K. 17(149),80 Kucklander, U. 167(26),210, 530(22), 532(28). 536(49), 549(91), 550(22), 558(129), 559(134-139), 560(142),561(14&148), 563(149), 569, 572(170), 584(218,221), 586(222-227,229), 587(227), 612(308), 613(315,316), 615(317), 621(328), 629--63i 635 Kuder, J.E. 507(682), 521, 672, 675, 676(56b), 6 78 Kudzin, Z.H. 1255, 1257(21), 1269(62,63), 1274(77), 1275(63, 77, 82), 1278(77), 1299-1301 Kuehne, M. 784,785(206), 790(235), 866, 867
1609
Kuehne, M.E. 3(12), 4(31), 10(121, 129), 76, 77, 79, 188(170),214, 236(86,91), 252, 256(1d), 270,468(6), 499(558), 508, 519, 731(23,24), 735(53), 752, 757(117), 761, 762(131), 764(131, 139), 787(227), 794(241), 800(269), 832(343), 862465, 867469,947(75), 988, 1050(6d, 7d), 1051(7d), l105,1366(1b), 1435, 1562(73), 1565 Kuehnle, W. 647(20), 677 Kuene, M.E. 994(7), 1043 Kuhar, M.J. 1203(267), 1248 Kuhne, M.E. 469,472(42), 508 Kukhar, U.U. 492(496), 518 Kulkami, C.L. 534(40), 629 Kulkami, S.V. 740(72), 863, 879(29), 887 Kullnig, R.K. 1022(137), 1045 Kulpe, S. 327(89, 95), 401 Kumagai, T. 190(185), 214 Kumar, A. 1335(132), 1362 Kumobayashi, H. 56(300), 84, 481(277), 17 -5 --
Kumohayshi, H. 482(279), 513 Kuna, K 536(49), 560(142), 561(147), 569, 572(170), 584(218), 586(223, 225, 226, 22Y), 613(316), 621(328), 630, 632, 633,
-"-
675
Kung, E-A. 916(116b), 921 Kunita, K. 737(62), 863, 903, 915(80), 921 Kuno. S. 9(1181. 79 ~ u n zH. ; 773(<69a), 865 Kunz, R. 1321(98), 1361 Kunz, W. 3(9),76' Kuu, C.S. 567(161), 632, 1387(70), 1437 Kuo. D.J. 1268160.61L 1269(63). 1274(77). Kuo, S.C. lO(120, 123), 79, 318(70), 401, 470, 472(70), 509 Kupfer, R. 1489(145), 1493(147), 1495(152), 1506 Kupper, R. 8(76), 78 Kuragi, K. 785(209), 866 ~urara,K. 1335(130),1362 Kurbako, V.Z. 930(28), 984(219), 987, 991 Kurechi. T. 330(1071. 401 ~urfiirstA. 49&ij, 519 Kurihara, T. 551(98), 631 Kuriyama, Y. 952(89), 989 Kuroda, R. 14, 17(151), 80, 433(125), 436 Kuroda, S. 1000(48), 1044 Kurodo, E. 642(10), 677 Kuroiwa, I. 1215(304), 1249 Kurosaki, Y. 492(481), 517 Kurosowa, H. 879(30), 887 Kurth, M.J. 917(120-122), 918(122), 921, 922 Kurts, A.L. 1507(16a, 17, 18b), 1531
1610
Author index
Kurtz, A.N. 322,325(77), 401,498(547), 519 Kurtz, P. 503(641), 521, 1443,1444(26), I503 Kummaya, K. 1136(64), 1142(76), 1243 Kumsu, Y. 829(330), 869, 1014(97,98a), 1045 Kusano, Y. 1259(34,35), 1300 Kuske,F.K.H. 24-27,29, 33(184), 38(221), 39(184), 42(221), 49(184), 81, 82 Kuske, K.H. 246(157), 254 Kussler, M. 14%(167), 1439 Kutani, J. 530(18), 629 Kuthan, J. 366, 367, 371(159), 402, 488(365), 499(559,561), 515, 519 Kutney, J.P. 952(88), 989 Kutschabsky, L. 184(138), 213 Kuwata, K. 953(Y2), YXY Kuzemko, M.A. 1074(78), 1107 Kvick, A. 180(111), 212 Kvita, V. 601(279), 635 Kvitko, LYa. 721(76), 726 Kyba, E.P. 492(498), 518, 979(194), 991 Laasch, P. 1449, 1481(50), 1504 Laban, G. 4, 8(29), 77, 468(16),508, 731(20), . . 862, 1562(70),'1565 L'abb&,G. 166(16), 210, 1020(123), I045 Labelle. M. 359(1451.402 ~abille,'M.-C.193(i00), 215 Lablanche-Combier, A. 1410, 1429(127), 1438 Lacey, E. 1136(63), 1243 Lacroix, E. 998(34), 1043 Ladd, C.B. 1186(215), 1247 Ladon, L.H. 259(21a), 268(66), 272, 276 Lafont, 0 . 1554(43),1564 Lagercrantz, C. 682(6), 693 Lai, C.Y. 1285, 1286(131), 1302 Lai, T.-F. 181(121), 186(156), 213, 1020(122), 1045 Laidler, K.J. 230(56), 252 Laikhter, A.L. 1322(102), 1361 Laine, D. 1508(28), 1531 Laing, M. 1011(86), 1044 Lakhvich, F.A. 48(244), 82, 984(218,219), 991 Lakhvich, O.F. 967(135), 990 LaLonde, R.T. 784(i07), 566,964(127), 989 Lam, Y.-T. 263(41), 273 La Mattina. J.L. 840(361). 870 ~amazouerk,A,-M. i313is7), 1360 Lambert, J.B. 299(39), 400 Lambrecht, R.M. 1201(264), 1214(303), 1248, 1249 Lam-Chi, Q. 837(358), 870 Lamm, B. 175(76),211, 1040(246), 1048, 1092, 1101(106a), 1108 Lammerink, B.H.M. 9(113), 79,495(524), 518
Landenbeck, W. 496(535), 518 Landesman, H. 469,472(35), 508, 695(1b, le), 723, 728(2, 3), 735, 736, 741, 746,778, 782, 787(3), 804(2,3), 806(3), 816(2), 861, 1001(49), 1044, 1050, 1052(5b), 1104, 1254(1), 1299, 1508, 1509(33b), 1531, 1537(5), 1563 Landesman, H.K. 3(7, 8), 4, 8, 10, 13, 58(8), 76,469(38), 508, 845(389), 871 Landor, S. 1526(112), 1533 Landor, S.R. 477(222), 512 Landvattcr, S.W. 1190(229), 1247 Lang, J. 1058, 1098(31), 1105 Lang, S.A.Jr. 1394(87), 1437 Lange, B. 1507(4, Sb), 1531 Lange,P.P.M.de 191(191),214 Lange, S.M. 1155(118a), 1244 Langenbeck, W. 1546(27), 1564 Langer, V. 1010(77), i04'4 Langheld, K. 491(446), 517 Lanelois. - . Y. 476. 479. 482(204). ~ ,. 512 Langs, D.A. 18i(noj, 212 Ungstrom, B. 1206(275b,276), 1207(280, 281), 1249 Lanleri, S. 834(348), 870, 975(172), 990 Lantos, I. 1186(215,216), 1247 Lapachev, V.V. 365(158), 402 Lapierre, J.M. 1003(59), 1044 Lapierre Armande, J.C. 1550(38), 1564 Lapinjoki, S.P. 1127(37), 1243 Lappert, M.F. 176(83),212 Lappin, G.R. 606(293), 635 Larcheveque, M. 1509(34a, 34c), 1514(76), 1520(96,97), 1531, 1533 Large, G.L. 816(299),868 Larice, J.L. 172(59),211 LarivC, H. 1255, 1264,1266(9), 1299 Lark. J.C. 816(303). 868 ~a Rosa, C. 11'13o(i$s), 1046 LaRossa, R.A. 1277(92), 1301 Larov, V.I. 688(26), 694 Larscheid, M.E. 769(158), 865 Larsen, E.H. 579(200), 633, 939(S2), 988, 1394f89).1437 Larson, S.M. 1216(309), 1250 Lascovics, EM. 793(240), 867 Laszlo, P. 422(73), 435 Latham, H.G. 475(184, 185), 511,845(389), 871 Lattes, A. 7(64), 10(127), 55(294), 70, 71(127), 78, 79, 83, 236(74), 252, 320, 324(80), 401, 470(88,89), 479(263), 481(263,268, 269), 509, 513, 732(35), 862, 896(51,52), 898(52), 920, 961(115), 989, 1535(2b), 1544(19), 1560(61), 1561(2b), 1563-1565 Lattes, E.307, 316-318(53), 400
Author index Lattke, E. 715(56), 725 Lau, K.C.M. 1057,1091, 1093,1096, 1099, 1101, 1103(103), 1108 Laube, T. 222(21), 251,472,480(145), 499(577), 510, 519, 760(118c), 864 Laude, B. 1022(134,135), 1045 Laue, E.D. 1273(70), 1300 Laufer, S. 565(158), , ,. 632,. 1324, 1358(104), 1362 Laugraud, S. 768(153), 865 Launay, J.C. 222(20), 251 Laurent, H.484(302), 514 Laus, G. 965(130), 989 Lautenschlager, H.J. 547(83), 630 Lautie, M.-F. 1134(58), 1243 Lavagnino, E.R. 484(312), 514 Lavanchy, P. 1186(215),1247 Lavaud, C. 174(72), 211 Lavielle, G. 321, 325(75), 401, 479(250), 490(445), 512, 517 Lavrenyuk, T.Ya. 1443(24), 1503 Law. K.W. 10201122).1045 ~awison,S.-0. i02@ l9), 1045 Lawesson, S.-0. 171(54),211, 236(82), 252, 439,440(8), 441(11), 444,445, 447, 449(8), 458, 470(68), 497(541), 509, 518, 579(200), 627(344), 633, 636,764(149), 770(165), 787(225), 799(263), 865, 867, 939(52), 971(158-161), 973(164), 988, 990, 1034(209,210), 1047, 1373(38), 1376(47a, 47b), 1394(89), 1399(102), 1404(114), 143&1438,1546(31), 1564 Lawhorn, D.E. 471(136), 510 Lawless, J.G. 672, 676(57), 679 Lawrence, J.L. 168(32),210 Lawson, H.E. 10(130), 79 Lawton, R.G. 823(318,320), 869 Layer, R.W. 7(63), 78, 843(373), 870, 892(36), 920, 1508(32b),1531 Lazdunski, M. 1192(237),1248 Leazer, J.L. 1176(190), 1246 Leban, I. 184(142), 185(150),213 Lebel, L.A. 1159(139), 1245 Le Blanc, M. 9(119), 79,440(9), 458, 477(228,229), 512 Le ~ o k n eJ.F. , 1520(96,97), 1533 Le Breton, C. 1209(287), 1249 L e b ~ n H. .
[email protected]. . . . 310(3), 399,843(382), 870 Lecte, E. 491(457), 517 Ledford, T.G. 486(352), 515 Lednicer, D. 845(388), 871 Ledoux, 1. 406(2), 434 Ledwith, A. 885(38), 886(39), 887, 951(85), 989 Lee, A.W.M. 469(46), 508 Lee, C. 488(377), 515
1611
Lee, E.R. 1266(59), 1300 Lee, J. 489(404), 516, 939(53), 988, 1529(117),1533 Lee, J.H. 494(514), 518 Lee, J.Y. 1513(74), 1532 Lee, L.E 1188(220), 1247 Lee, S.H. 1155(121a),1244 Lee, T.Y. 48(259), 83 Lee, Y.K. 489(380), 515 Lee, Y.Y. 476(198), 511 Leeming, P.R. 471(140), 510 Lees, W. 1295(167), 1302 Leete, S.A.S. 491(457), 517 Lefkvre, 0. 443(15), 451(38), 454(41), 458 Lefour, J.M. 875(14), 887 Leger, S. 1176(187), 1246 Lehman, P.G. 488(366), 515 Lehn, J.-M. 406(2), 434 Lehners, N. 468(15), 508 Lehr, F. 494(507), ~ 1 8 Leibfritz, D. 246(161, 162), 247(162), 254 Leibovitch. M. 1100(133). 1109 L e ~ a i i e u R. , 650(27), 678 Lemal, D.M. 5(54), 78 Le-Marechal. A.M. 1851150). ,, 213 Le Men, 1. 4'76(201), 5 i l Le Men-Olivier, L. 174(72), 211 Lendle, W. 779(184), 781(185), 782(195), ~. . . 866 Lenhard, J.R. 955(100), 989 Lenz, G.R. 5, 8(49), 77, 502(623), 520, 638(3e). 646(14). 669(3e. 54). 677. 678.
Leonard, N.J. ii(136, 138), 52(275), 63-65038). 71(136. 138. 361). 74f361). 79.
Leong, C.W. i512:1526(50a), 1532 Leoni, M. 751(99), 864 LePage, M.E. 648(22d), 678 LePage, T. 181(119),212 Le Perchec, P. 173(64), 211 ~ ~ ~ l a t t e n iF.A. e r , 609(301), 635 Leq muan, L.T. 502(634), 520 Lerbscher, J.A. 183(136),213 Lerch, U. 1037(229), 1047 Lerche, H. 740(81), 863 Lerouge, P. 841(366), 870 Leroy, C. 984(221), 991 Leroy, F. 178(103), 212
Author index Livense, J.C. 1295(166), 1302 Livni, E. 1204(268), 1206(272), 1248, 1249 Liz. R. 9198). 79. 4771224.225. 227). 512. Lobanova, G.M. '174(75), 211 Ldber, G. 582(212), 633 Ldbering, H;G. 544(68), 630, 968(139), 990 Lock. C.J.L. 247(172). 254 Locke, D. 249(194), 2 ~ 4 Locke, D.M. 6345(338), 84 Lockwood, A.H. 1214(300), 1249 Loew, P. 476(217), 512 Loewus, F.A. 1292(156,157), 1302 Ldfas, S. 794(246), 867 Liifstrom, C. 1010(77), 1044 Loghman-Khovzani, H. 721(74), 726 Lohr, R. 1512,1528(65), 1532 Lohrie, M. 1091,1093-1095,1100(102~), 1108 Loic, R. 501(599), 507(683), 520, 521 Loiseleur, H. 173(64), 211 Lonchambon, G. 1327(116), 1362 London, R.E. 1138(68), 1243 Long, F.A. 1095(110b, I l l ) , 1108 Long, 0.-H. 10(128), 79 Longenecker, J.B. 1286(137), 1302 Longevialle, P. 438(5), 443(15), 451(3&38, 40), 453(40), 454(41), 455(42), 457, 458 Longobardi, M. 600(271), 634 Longridge, J.L. 1095(111), 1108 Lonnberg, H. 247(170), 254 Loo, T.L. 1155(121e), 1245 Looker, J.J. 784(203), 866 Looney, FS. 230(55), 252, 407, 414(7), 434 Loosli, H.R. 715(58g), 725 Lopez, F. 1389,1432(75), 1433(191), 1437, 1439 Lhpez, L.A. 1036(224), 1047, 1424(166), 1439 Lopez-Calahorra, F. 1265, 1266(56), 1300 Upez Castro, A. 240(110), 253, 360(147),
1613
Louie, A.C. 1156(123b), 1245 Lovas, F.J. 5, 12, 25, 29(56), 78, 408, 431(17), 434,843(383), 870 Lovisolo, P.P. 1160(141), 1245 Liiw, P. 7, 8(69), 78,245(151), 254, 301-305, 307, 308,310, 311, 319(42), 400,493(506), 518, 718(63c), 725, 843(381), 870, 893(48), 920 Lowe, J.A. 226(49), 252, 1512,1525, 1528(51b), 1532 Lowe, W. 552(103), 631 Lown, J.W. 802(281), 868 Lozac'h, N. 179(109), 212,1034(213), 1047, 1562(71), 1565 Lu, X. 826(326), 869, 1008(68), 1044 Lubbe, F. 1391(79), 1437 Lucas, H.J. 1098(124), 1109 Lucas, J. 180(112), 212 Lucchini, V. 1098, 1103(118), 1108 Lucci, R.D. 489(380), 515 Luchinat, C. 1142(83), 1244 Liick, R. 327(89), 401 Luck, S.M. 1507(8), 1531 Lucke, E. 469,501(39), 508, 778(179), 781(186, 189, 190), 782(192a, 192b), 865, 866 Ludwig, P.K. 682(7), 693 Lue, P. 10(128), 79 Luecke, E. 469(36), 508 Lueoend, R. 372(174), 403 Luettke, W. 506(661), 521 Lui, T.M.H. 749,816(94b), 864 Luitjen, W.C.M.M. 1124(29), 1242 Luke, H.-W. 8, 45(81), 78, 282, 283, 301, 302, 310, 311(4), 399,491(475), 517 Luke:, R. 11(135), 79, 485(326), 488(375),
489(387-394,401,402,405410,413417), 490(437), 514-516 Lukyanov, S.M. 1448-1450(46,47,49), 1460, 1461(85), 1463(92-94), 1467(92-94,102, 104-108),
402 Lopez-Ortiz, J.F. 1431(187), 1439 Lorch, E. 6(58), 78 LorenEak, P. 1097, 1098(121), (122), 1108 Loreto, M.A. 840(362a, 362b), 870, 1016(103-105), 1026(105), 1045, 1352(169), 1363 Lorimer, J.P. 1209(288), 1249 Loschmann, I. 816(301), 868 Lossing, F.P. 256(6), 263(41), 265(6), 271, -27.3 . . Loth, P.de 481(269), 513 Lon, T.J. 1155(121~),1245 Lotz, W. 506(666), 521 Loub, W.D. 1157(131), 1245
94,104, ios, i i z , 137)~i4&(47, 49), 1485(141,142), 1486(141), 1487(85, 102, 141), 1488(141), 1489(141,142), 1490(142), 1492(102, 113, 142), 1493(142), 1494(49, 137), 1495(137), 1497(49, 141, 142), 1499(116,155, 156). 1501(157), 1502(116), 1503-1506 Luk'yanova, V.A. 266(59), 275 Lulukyan, K.K. 468(13), 508, 1366(11), 1435 Lum, T. 1156(123c), 1245 Lumbroso, H. 62(332), 84
1614
Author index
Lumm, M. 181(118),212 Lumma, P.K. 550(94, 95), 599(95), 631 Lunazzi, L. 32(215), 81, 236(90), 252, 289(17), 290(20), 399, 408(19), 434, 731(32), 862, 1056(24b), 1105 Lundin, A.F. 885(37), 887, 933(37), 988, 1541(15a), 1564 Lundquist, R. 1138(67), 1243 Luo, Y.-R. 262, 268(33c), 273 Lupes, M.E. 1263(52), I300 Lupon, P. 187(164), 214 Lusinchi, X. 935(43), 937(43,47), 988 Luskus, L.J. 1024(143), 1045 Luthra, S.K. 1217(313), 1250 Lutz, R.P. 890(8), 904(81), 908(8), 919, 921 Lutz, W. 1522(105), 1533 Lycka, A. 394(216), 404,1117(2), 1242 Lyle, G.G. 1512, 1526(51c), 1532 Lyle, R.E. 4(26), 77,499(565), 519, 962(117, 1242, 1512, 1526(51c), 1532 Lynch, P.P. 449(27), 458,969(144), 970(144, 146). 990 ~ ~ n c h , ' 1513(74), ~ . ~ . 1532 Lyons, J.E. 488(360), 515 Lysaght, E.A. 185(145), 213 Lyubchanskaya, V.M. 625(339), 636 Maas, G. 172(60), 211, 964(124), 989, 994(20, 23), 1043, 1377(49), 1436 Maas, W. 8(73), 52(274), 78, 83, 709(34), 710(40a, 40b), 724, 1051(11a-d), 1052(llc), 1053(11a4), 1054, 1055(11b, llc), 1056(11a-d), 1057(11d), 1061(11b, 1lc), 1065(1la-d), 1066, 1067(1Id), 1068(11b), 1069,1070, 1072,1073(11d), 1081,1090,1092(11a4), 1105 Mabiala, G. 581(210), 633 Mabon, F. 237, 238(104), 253, 408,409(22), 434 Mabry, T.E. 1133(57),1243 Mabry, T.J. 653(34), 678 MacAlpine, G.A. 936(46), 988 Macartney, J.H. 469,471(27), 508, 981(201), 991 Macartney, P.L. 469, 471(27), 508 ~accioni;A. 1036(222,223), 1047, 1422(161), 1428(182a), 1439 Maccoll. A. 263141). 273 ~acdonald.T.L. 1512146b., 62). ,, 1526. 1527(46b), 1532 Mach, R.H. 1217(311), 1250 Machacek, V. 890(16), 920 Mach-Bindl, M. 568(165), 632 Machida, K. 380(192), 403 Machida, S. 749(93), 772(168), 863, 865, 998(31), 1043 \
,.-
\
Machida, Y. 330(107), 401 Machleidt, H. 786(2%3),867 Macholin, L. 491(461-464), 517 Mack, H.-G. 88, 94(2), 210 Mack, S.W. 1138(66), 1243 Maclaren, J . A . 1410(125), 1438 MacManus, P.A. 563(150), 632 Macor, J.E. 1026(160), . . 1046, 1158(137), 1159(139),1245 Madbuike, U.P. 1213(298), 1249 Maddaluno. J. 48(248L 82 Maddock, A.G. 685(16), 693 Madelniont, J.C. 1183(209), 1184(210), 1247 Mader, H. 491(449), 517 Madhusudanan, K.P. 448(26), 458 Madronero, R. 1449(53),1504 Madsen, 1.0. 799(263), 867, 981(202), 991, 1376(47a), 1436, 1546(31), 1564 Madsen, P. 470(68), 497(541), 509, 518; 579(200), 63.7, 1394(89), 14.77 Maeda, K. 1150(102), 1244 Maeda, M. 1218(316), 1250 Macda, S. 1000(48), 1044 Maeno, H. 1215(304), 1249 Maetzke, T. 192(197), 215 Maffei, M. 1010(77), 1044 Magerlein, B.J. 794(242), 867, 971(156), 990, 1544(21), 1564 Maggi, N. 1152(109), 1244 Maggiulli, A.C. 500(593), 520 Magidson, 0.Yu. 1451(61), 1504 Magin, R.W. 811(293), 868 Magnestiau, A. 578(197), 633 Mahajan, J.R. 485(330), 514, 934(40), 988, 1033(202), 1047, 1400(105a, 105b), 1437 Mahan, J.E. 52(273), 83, 489(399), 515, 709(33a), 724, 1055, 1065(21a), 1105 Mahdi, W. 1530(121), 1533 Mahiou, B. 874(8), 887 Mahmoud, M.M. 1402(110), I438 Mahomed, H. 852(400), 871 Maier, R. 1370(28), 1436, 1560(65), 1565 Mailman, R.B. 1167(160), 1246 Maiorana, S. 167(21), 210 Maischein, J. 797(259), 867 Maitland, D.J. 721(74), 726 Maitte, P. 596(260), 599(266), 634, 721(78), 726, 890(18), 920 Majeda, E.A. 59(327), 84 Majeste, R. 1061(48), 1106 Mak, T.C.W. 181(121), 213, 1020(122), 1045 Makabe, 0 . 543(67), 630 Makabe, Y. 737(62), 863, 903,915(79, 80), 92 - -1 Maki, Y. 1388(73), 1437 Makino, S. 802(272), 868 Malarek, D.H. 1167(162), 1246 ~
1615
Author index Milek, J. 489(409), 516 Malhorta, N. 261(30), 273 Malhotra, S.K. 236(89), 252, 733(36), 735, 737(48), 862, 885(37), 887, 933(37), 988, 1061(47a), 1106, 1541(15a), 1564 Malinowski, E.R. 343(129), 402 Mall, G. 1214(299), 1249 Mallar, W.G. 697, 699, 701, 707(7b), 723 Mallard, W.G. 262(35), 273, 1097(115), 1108 Malmhorg, P. 1207(280,281), 1249 Malune, G.R. 1516(82,83), 1533 Maloney, T.W. 802(281), 868 Malthtte, J. 406(2), 434 Malusa, N. 751, 752(103), 864 Malysheva, S.F. 492(497), 518 Mamada, K. 1120(14), 1242 Mamaev, V.P. 365(158), 402 Manabe, 0. 1259(34-36), 1300 Mancera, M. 359(144), 402 Mancera, 0. 503(637), 520 Mancuso, A.J. 1122(25), 1242 Mandell, G.L. 1201(263), 1248 Manderlier, R. 578(197), 633 Manfredini, S. 500(591), . . 519, 577(195), . . 633, 968(137), 990 Mangili, R. 1228(335), 1250 Mangner, T.J. 1223(323), 1250 Manhas, M.S. 567(164), 632, 1550, 1561(39), 1564 Manjil, I. 1217(313), 1250 Mann, C.K. 476(209,210, 214), 512,884(36), 887 Mann, M.J. 551(99), 631 Mannich, C. 3, 7(5), 76, 468(14), 498(544), 508, 519, 1050(2), 1104 Mannschreck, A. 220(68), 232(63), 233(67), 234(68), 252,411(34), 414,415(46), 416(34), 417(58), 423(78,79), 424(79), 434, 435, 1279(106), 1301 Manske, R.H. 927(24), 987 Manson, A.J. 471(115), 510, 1197(244), 1248 Mantegani, S. 1228(334,336), 1250 Manzino, L. 1235(346), 1251 Mao, D.T. 1513(74), 1532 Maqucstiau, A. 1097, 1098(121), (122), 1108, 1414(138), 1438 Mara, A.M. 170(44), 211 Marahashi, S. 501(600), 520 Maraver, 1.1. 48(245), 82, 244(129), 253, 373, 381, 387,388(185), 403, 433(123), 436, 890(23), 920 Maraver, J.P. 719(67a), 725 Marazano, C. 451,453(40), 458 Marcelis, A.T.M. 1026(150), 1046 March, J. 3(9), 76 March, L.A. 178(100), 212
Marchand, E. 179(106), 212 Marchand-Bryanaert, J. 476(205, 206), 512 Marchand-Brynaert, J. 5, 9(53), 77, 731(9), 861, 1370(29,30), 1436 Marchenko, N.B. 593(247), 634 Marchesini, A. 943(60), 988 Marcnetti, L. 167(23), 183, 189(137), 210, 213,486(348, 349), 514, 836(352,353), 837(353,354), 870 Marchi, E. 1152(110), 1244 Marciano, D. 191(192, 193), 192(193, 194), 214 Marcos, E.S. 244(129, 133), 253, 890(23), 891(26,27), 920 Marcot, B. 488(371), 515 Marcus, E. 11(142), 80, 471(128), 510 Mareda, J. 1016(101), 1045 Marelli, P. 1025(145), 1045 Maretina, LA. 283, 287, 289, 294, 298, 339, 354(9), 399, 555(109, 110), 591(242), 631, 6 74 .. ~
Margaretha, P. 1011(83), 1044 Mariano, P.S. 501(609), 520,564(156), 581(206,207), 632, 633, 916(116a, 116b), 921, 1027(168), 1046, 1379(52), 1436 Marie, S.R. 1558(58), 1565 Marion, L. 484(313), 514 Markl, G. 829(331-333) 869, 1040(248), 1048 Marko, I. 476(207), 512 Markova, N.K. 591(242), 634 Markstein, J. 471(98), 509 Markus, B. 1127(35), 1242 Marnung, T. 431(108), 436 Marongiu, E. 1428(182a), 1439 Marques, R. 240(1 lo), 253 Mirquez, R. 360(147), 402 Marsh, , R.E. 189(181), 214 Marshall, A.G. 48(256), 8 2 Marshall, J.A. 740(77), 863, 961(114), 989, 1063(53), 1106, 1542(17b), 1564 Marshall, J.L. 1512, 1526(51c), 1532 Marshall, J.T.R. 236(82),252, 439, 440, 444, 445,447, 449(8), 458 Marston, C.R. 543(65), 630 Marta, M. 536(51), 630 Martani, A. 606(287), 635 Martel, R.R. 1172(178), 1246 Marti, E. 978(183), 991 Martin, D. 722(81), 726 Martin, de G.G. 75(365), 85 Martin, E.W. 484(315), 514 Martin, F. 582(211b), 633 Martin, G. 237, 238(102), 253 Martin, G.J. 32(213), 81, 222(28), 237(103, 104), 238(104), 251, 253, 294(31f, 32), 296(32), 298(34), 321, 325(75), 347(31f),
1616
Author index
Martin, G.J.(conr.) 348(32), 400, 401, 407(12), 408(18,22), 409(22,23), 426(93), 434,435 Martin, J.C. 4(16), 76, 236(75, 81), 252, 599(268), 634, 779(182), 866, 970(149), 990, 1338,1340(139a, 139b), 1348(157), 1358(139a, 139h), 1362,1363 Martin, M. 646(15b), 677 Martin, M.G.G. 236(94), 252 Martin, M.L. 294(31f), 298(34), 321, 325(75), 328, 329(97), 347(31f), 348(97), 400, 401, 407(12), 434,709(30a), 724 Martin, N. 14(160),80 Martin, N.H. 924, 926(6), 987 Martin, N.S.E 478(238c), 512 Martin, R. 473, 475(154), 511 Martin, R.B. 52(271), 83, 220(11), 223(31), 251, 709(31), 724, 1051-1054.1056, 1057, 1065, 1066(13), 1069(71), 1070, 1073,1076, 1081,'1090, 1092,1098, 1101, 1103(13), 1105,1107 Martin, R.L. 24(185), 8g, 704(17), 723 Martin, S.E 5, 8, 9(51), 77, 478(240, 242), 479(242). 512. 816(298), 868 arti in; ~.~:709(30a),'724'. Martin, W.B. 1443(28), 1503 Martin, W.R. 1153(111), 1244 Martinez, A. 713(50), 725 Martinez, A.G. 1477(134), 1506 Martinez, S.J. 55(298), 83, 256(4a, 4b), 271, 480, 483(266), 513 Martinez-Ripoll, M. 184(143), 187(166),213, 214 Martin-Zamora, E. 341(117a), 342(117a, 117b), 402 Martirosyan, G.T. 480(267), 513 Martirosyan, V.O. 1460(84), 1504 Mamyama, T. 330(107), 401 Ma~anyos,E. 1366(9), 1435 Marx, M. 978(183), 991 Marx, R. 177(93), 212 Maryanoff, B.E. 247(169), 254, 960(110, I l l ) , 989 Maryanoff, C.A. 247(169), 254 Marynick, D.S. 49(264), 83 Masahiro, T. 638(5), 677 Masaki, M. 5(57), 78, 1459(80), 1504 Masamune, T. 929(27), 937(48), 987, 988, 1542(16),1564 Masashi, Y. 48(253), 82 Mas Cabr.4, F.R. 986(224,225), 992, 1545(23), 1564 Maschewske, E. 1156(126), 1245 Masclet, P. 59(326), 84 Mashima, M. 1232(344),1251 Masias, A. 1507(17),1531 Mason, J.S. 470(59), 509
Mason, R.P. 1255, 1263(15), 1299 Massa, S. 608(296), 612(312), 635 Massa, W. 167(26), 181(118),210, 212 Massart, D.L. 99(9), 210 Massiot, G. 174(72), 211, 931(34), 988 Masson, P. 1176(187), 1246 Masson, T.J. 1209(288), 1249 Masterova, M.N. 686(22), 694 Masterovo, M.N. 686(23), 694 Masuda, R. 1314, 1316(75), 1361 Masui, M. 476(208, 211), 512, 955(101), 989 Masurnarra, G. 506(679), 521 Masunari, T. 1390(77), 1437 Masure, D. 25(205), 81 Masuyama, Y. 829(330), 869, 1014(97, 98a), 1045 Mateme, C. 1316(86-88), 1317(90), 1361 Mathey, F. 794(244), 867 Mathias, N.P. 1178(198),1247 Mathieu, A. 368, 370, 371(161), 403 Mathieu, D. 47&472(56), 508 Mathieu, J. 1442, 1443(17), 1445(38), 1473(17,126), 1497(17), 1503,1505 Matier, W. 1135(60), 1243 Matos, M.A.R. 268(67), 276 Matsubara, F. 169(37),210 Matsuda, Y. 170(47), 211, 1312(47), 1313(47,51, 70, 71), 1315(51), 1335(130), 1346(151), 1360-1363 Matsugo, S. 926(19), 987 Matsui, M. 174(70),211,550(93), 559(131, 132), 631 Matsumoto, H. 1411(129), 1438 Matsumoto, K. 661(47), 678 Matsunloto, T. 929(26), 987 Matsurnura, Y. 459(2), 462(8), 463(10), 464(11), 464, 465, 769(157), 865,957(102), 959(106, 107), 989, 1029, 1030(187), 1046, 1555(46a), 1564 Matsunaga, Y. 621(330), 636 Matsuno, C. 621(330), 636 Matsuo, K. 534(38), 629 Matsushita, H. 53(280, 281), 83, 248(187), 254,474(169), 511, 710(40f), 724, 735(42, 43), 862 Matsushita, T. 676(62), 679 Matsuura, T. 924(15), 926(19), 987 Matter, U.E. 369(166), 403 Mattern, E. 8(78), 78 Matthews, D.P. 1003(56), 1044 Matthews, D.W. 1120(20), 1242 Matthews, E.J. 746, 806, 807(84), 863, 1003(51), 1030(192),1044, 1046 Mattinen, J. 247(170), 254 Matusch, R. 582(211b), 633 Matveeva, E.D. 587(232), 633
Author index Matwiyoff, N.A. 1138(68), 1243 Matzke. K.H. 1199(252), 1248 Mauel, S. 641(8), 6 j 7 Maurey, G. 782(194), 866 Maurizis, J.C. 1183(209), 1184(210), 1247 Maurv. G. 471(1171.510 ~ a u r ; : G.de ij0(4ij, 211 May, G.L. 764(136), 864, 947(74), . . 988 ~ a ; ,R.W. 262; 268(31), 273 Maya, I. 330,333(102), 334(102,103), 401 Mavbere. H.S. 1203(2671. 1248 M & ~ ~ < E . A .476(233), 512 Mayence, A. 1414(138), I438 Mayer, B. 621(328), 635 Mayer, K.K. 575(190), 633 Mayer, P.M. 256,265(6), 271 Mayer, R. 4, 8(29), 77,468(16), 508, 731(20, 21), 862, 1389, 1390(76), 1395(93), 1398(97), 1406(76), 1437, 1562(70), 1565 Mayes, E.A. 1061(48), 1106 Mayo, P.de 649(24), 678 Mazarguil, H. 10, 70, 71(127), 79, 307, 31&318(53), 320,324(80), 400, 401, 470(88,89), 509, 732(35), 862,961(115), 989, 1535(2b), 1544(19), 1560(61), 1561(2b), 1563-1565 Mazarquil, H. 236(74), 252 Mazikre, M. 1199(250), 1200(258,260), 1209(284), 1226(327), 1248-1250 Mazume, H. 528(14), 629 Mazur, Y. 250(195), 254 Mazza, S.M. 1202(266), 1248 Mazzu, A. 1518(88), 1533 McAdoo, D.J. 451(34), 458 McAlees, A.J. 486(336), 514 McAndrew, B.A. 814(295), 868 McArdle, P. 184(144), 185(145), 213 McBride, B.J. 1226(329), 1250 McCapra, F. 924(7), 987 McClelland, R.A. 1057, 1091, 1093, 1096, 1099, 1101,1103(103), 1108 McClure, D.E. 550(94,95), 599(95), 631 McComsey, D.F. 247(169), 254 McComsey, D.J. 960(110, I l l ) , 989 McConnell, H.M. 346(130), 402 McCormick, M.R. 486(338), 514 McCoy, G.D. 952(91), 989 McCrindle, R. 486(336), 514 McCully, K.S. 14, 21(167), 80 McCurry, P.M.Jr. 912(110), 921 McDaniel, D.H. 56(303), 84 McDaniel, K.E. 1026(159), 1046 McDonald, G.J. 1134(59), 1243 McDonald, J.M. 1214(300), 1249 McElrain, S.M. 1304(4), 1359 McEuen, J.M. 823(318), 869
McFarland, J.W. 9(113), 79, 4Y5(524), 518 McFarlane, C.S. 1176(187), 1246 McGarrity, J.F. 715(58f, 58g), 725 McGhie, J.F. 502(621,622), 520, 1442(14), 1503 McGirr, L.G. 330(106), 401 McGrath, J.C. 1190(228), 1247 McGregor, R.R. 1213(297), 1249 Mclntosh, J.M. 495(521), 518 McKay, G. 1128(39), 1243 McKeever, L.D. 715(58c), 725 McKillop, A. 5(47), 77, 506(650), 521, 696(3b), 723, 731(11), 861, 890, 891(9), 919, 1366(14), 1436 McLafferty, E.W. 438(3). 457 Mclamore, W.M. 1507(22), 1531 McLaughlin, W.H. 1236, 1237(348), I251 McMillan, A. 1170(176), 1246 McMillan, R.M. 372(173), 403 McMullen, H. 477(221), 512 McMurray, J.E. 1372(35), 1436 McMurry, J.E. 760(122), 864 McMurry, T.B.H. 531(25), 629 McNab, H. 332(100), 364(156), 401, 402, 426, 427(95), 436. McNally, A.J. 1274(76), 1300 McNamara. J.M. 1176(190). 1246 ~ c ~ a u ~ h tD.o n32(219), , 82 McNeil, S.S. 1128(42), 1243 McNelis, E. 1264(53), 1300 McPhail, A.T. 179(110), 188(172), 212, 214, 1164(151), 1245 McQuillan, J. 1186(218), 1247 Mea-Jacheet, D. 245(144), 253, 1512(67), 1532 Mechin, 8. 294, 296, 348(32), 400 Medici, A. 176(81), 212 Medion-Simon, M. 1011(87), 1044 Meek, M.A. 14, 21(166),80, 243(126), 253, 373(176), 403, 412,433(37), 434, 719(67h), '
-7-c
ILJ
Meen, R.H. 599(268), 634, 970(149), 990, 1348(157), 1363 Meerssche, M.van 22, 23, 39(172), 80, 166(16), 167(25), 175(77), 177(89, 90), 189(178,182, 183), 205(178), 210, 212, 214 Meerssche, P.M.van 225(47), 252 Meerwein, H. 1319(94), 1361, 1449, 1481(50), 1504 Mehendale, S.D. 606(288), 635 Mehl, W. 874(9), 887 Mehlhorn, A. 432(116), 436 Mehra, R.K. 489(378), 515 Mehra, S.R. 901(75), 921 Mehri, H. 171(50), 211 Mehrsheikh, M.E. 1188(221), 1247
1618
Author index
Meier, M.M. 1026(156), 1046 Meier, W. 1003(54), 1044 Meille, S.V. 418, 433(61), 435 Meinardi, G. 165(14), 210 Meister, A. 1459(79), 1504 Melillo, D.G. 1176(189), 1246 Melius, C.F. 24(185), 81 Meller, M. 657, 667(40), 678 Meltzer, N.M. 1190(232), 1247 Meng-Yan, Y. 268(67), 276 Menon-Rudolph, S. 1269, 1276(65), 1279(97), 1300, 1301 Menozzi, G. 601(273,274,277,278), 602(280), 604(283,284), 611(278), 634, 6.35 .-.
Mentzafos, D. 190(187),214 Meotner, M. 712(45), 724 Meou, A. 506(659), 521 Merenyi, R. 193(200), 215, 525(3), 629 ~ e r ~ e i s b e I.r ~lb11(80), , 1044 Mergen, W.W. 1310, 1318(42), 1319(42,95), 1326(95). 1360.1361 ~ e r i n o , ' l .ih08(122), 1438 Merino, L. 187(164),214 Meriwether, H.T. 1192(236), 1248 Merritt, A. 816(306), 869, 1003, 1005(57), 1U06(67), 1044 Mersch, R. 1449, 1481(50), 1504 Mertel, H.E. 1192(236), 1248 Merten, R. 1443(27), 1503 Mellens, H. 596i256.257). 634, 1315, 1316(79), 1361 Mertz. T.E. 1142177. 78). 1243.1244 ~ e r t z k l E. , 1167<156),i245 Mcrz, W. 65, 68(346), 84, 1062(51), 1106, 1537(3c, 3d), 1542(18), 1563, 1564 Meslin, J.C. 1374(43a, 43b), 1406(117, 118), 1421(118, 158), 1436, 1438, 1439 Mesureur, D. 479(254), 513 Meszaros, Z. 169(38), 210, 448(21), 458, 597(262), 634, 720(72,73), 721(75), 726 Meszmilyi, A. 1180(201), 1247 Metcalf, B.W. 1295(160),1302 Meth-Cohn, 0. 179(108), 180, 181(117), 212 Metni, M.R. 192(198),215 Metwally, M.A. 538(55), 572(182), 630, 632 Metz, B. 998(34), 1043 Melzgcr, J. 470(56,87), 471,472(56), 508, 509, 711(42b), 724, 732(33), 862, 1255, 1264, 1266(9), 1299 Metzler, D.E. 1089(95), 1107, 1263(50), 1286(135-138), 1295(162), 1300, 1302 Meuer, V. 782(192a, 192b), 866 Meyer, E.F. 669(53), 678, 901(74), 921 Meyer, E.V. 506(662,663), 521 Meyer, G.J. 1199(252), 1206(278,279), 1248, 1249
Meyer, H. 486(332,333), 514,530(19), 547(82), 629, 630, 1197(247), 1248, 1333(125), 1334(127,128), 1338(125), 1362 Meyer, K.H. 8(72), 78 Meyer, 0. 295, 322, 323(29), 399 Mever, R. 25(199,200), 81, 225(39), . . 251, 468(23), 470(54), 508 Meyer, U. 563(149), 632 Mever. W.C. ll(141). ,. 79.. 471(127). ~ ,. 510. 683'(209), 991 Meyer, W.L. 816(306), 869, 1003, 1005(57), 1006(67), 1044 Meyers, A.I. 245(142), 253, 499(562), 501(601,603), 519,520,843(369), 870, 1162(146), 1245, 1453(64), 1504, 1512(55, 69), 1513(73), 1516(79-83), 1517(84a, 84b, 85,86, 87a), 1518(88-92), 1532, 1533 Meyers, E.A. 247(171), 254' Meyers, H.V. 1032(196,198), 1047 Mevniel. , , J.M. 1183(209). 1184(210). 1247 Mezheritskii, V.V. 1456(71, 72): 1502(158), 1504,1506 Miao, S.W. 963(123), 989 Micca, P.L. 1177(195), 1246 Michael, F. 489(418), 516 Michaelis, W. 1167(161), 1246 Michalik, M. 42(232), 82, 362, 363, 367, 369(153), 370(163), . . 371(165), 387(198), 402,' 403 Micheel, F. 530(20), 629 Micheida. C.J. 8(76\. 78 ~ i c h e i A.D. , ll6l(i43), 1245 Michel, R.E. 879(28), 887 Michelot, M.R. 711(41), 724 Michelot, R. 53(268), 83,476(202), 511 Michida, T. 955(101), 989 Michotte, Y. 99(9), 210 Middleton, S. 57Y(ZUl), 633 Middleton, W.J. 484(290), 506(675), 513, 521, 1314(74), 1361 Midha, K.K. 1128(39,40), 1243 Miesch, M. 997(29), 998(32-34), 1043 Mieval. J.J. 1257. 1258124). 1299 ~ i i h t , ~1222(318),\1250 . ~ . Migita, T. 924, 925(10), 987 Mihelick, E.D. 1517(84b), 1533 Mibina, J.S. 1142(82),1244 Mikerova, N.I. 559(130), 631 Mikhail, E.A. 1233, 1235(345), 1251 Mikhailov, Yu.N. 174(75),211 Mikhailovski, A.G. 475(186), 511 Mikheeva, S.V. 571(176), 632 Milata, V. 363, 368, 370(155), 402 Mildenberger, H. 736(54c, 57). 738(65), 740(54c), 830(339a), 863, 869, 914(114), 921
Author index Miles, G.J. 800, 804, 817(267), 868, 998, 1005(41), 1043, 1555(48), 1564 Milewich, L. 968(136), 990 Miller, C.P. 1041(254), 1048 Miller, C.S. 1263(51), I300 Miller, E.A. 1155(120), 1244 Miller, J.A. 1507(16h), I531 Miller, L.A. 485(319), 514 Miller, L.L. 59(327), 84 Miller, M. 696(3c),'723 Miller, M.A. 746(85), 809(292), 863, 868 Miller, S.L. 266(58), 275 Milliet. ~~,A. 451(32\. 458 Milliet, P. 93563):'937(43, 47), 988 Milligan, R.J. 471(133), 510 ~ i l l i n i R. , 179(105), 212 Mills, O.S. 183(135), 185(146),213 Mills. S.L. 1233. 1235(345). 1251 illw ward, B.B. k52(72), 1565 Millward, B.S. 498(554), 519 Miltz, W. 775(174), 865, 1039(240), 1047 Mina, G. 786(218), 866, 1560(64), 1565 Minard, P. 1183(208), 1247 Minchington, A. 1128(45), 1243 Minielli, J. 1135(60), 1243 Minisci, E 874(7), 887 Minkin, V.I. 411(31), 434, 1468(110), 1505 Minyaev, R.M. 1448-1450(49), 1468(110), 1481, 1484(49), 1485(141, 142), 148&1488(141), 1489(141,142), 1490, 1492, 1493(142), 1494(49), 1497(49, 141, 142), 1504-1506 Minyaeva, L.G. 1456(72), 1504 Miocque, M. 1554(43), 1564 Mirskova, A.N. 4, 7, 32(36), 77, 889(7), 919, 1314, 1315(77), 1361 Mishima, M. 1097(116h), 1108 Miskevich, G.N. 1443(24), 1503 Misshach, M. 826(323), 869, 1003, 1005(58), 1044 Mitch, C.H. 55(297), 83 Mitchell, M.J. 978(186), 991 Mitkidou, S. 190(187),214 Mitra, D.K. 969(141), 990 Mitra, R.B. 650(27), 678 Mitsudo, T. 984(220), 991 Mitsue, Y. 501(600), 520 Mitsuhashi, K. 621(330), 636 Miura, Y. 1019(118),1045 Mixon, R.M. 489(420,421,423), 516 Miyake, A. 892(37), 920 Miyano, K. 929(26), 987 Miyano, S. 534(37), 572(183, 184), 629, 632, 979(187), 991, 1434(196),I439 Miyano, T. 549(89), 631 Miyashiro, Y. 1390(77), 1437
1619
Miyashita, A. 481(274), 513, 1012(90,91), 1026(163),1044, I046 Miyata, 0. 638(3c), 641(6b4), 642(10), 677 Miyatake, K. 1255(19),1299 Miyoshi, N. 981(197), 991 Mizsak, S.A. 4(18), 76, 786(216), 866, 1369(25), 1436,1560(64), 1565 Mizuhara, S. 1263(49), 1300 Mizuno, A. 550(92), 631 Mizuno, S. 1152(108),1244 Mo, 0. 704(16d, 16f, 19c), 723 Mo, Y.K. 1474(127), 1506 Moakley, D.E. 236(89), 252 Modro, T.A. 1098(120), I108 Moehrle, H. 491(465),'517 Moeller, P.D.R. 188(172),214 Moerlein, S.M. 1217, 1218(315),1250 Mohamed. M.I. 546(77), 630 Mohlau, R. 240(114), 253 Mohrle, H. 532(33-35), 588(236), 629, 634 Moiorana. S. 1367(19). 1436 ~oiseeukov,A.M. 532(30), 629, 973(165), 990 Mojarrad, E 192(198), 215 Molas, J. 829(335), 869 Molder, V. 704(16h, 16c), 723 Moldvai, 1. 1366(9), 1435 Molhant, N. 177(89), 212 Molinari, H. 1030(195), 1046 Molines, H. 816(300), 868 Moller, C. 24(187), 81 Mollova, N. 451(37, 38), 455(42), 458 Molyneaux, J.M. 1188(220), 1247 Momot, V.V. 492(496), 518 Monahan, L. 364(156), 402 Monahan, L.C. 426,427(95), 436 Mondon, A. 469(43), 470(63), 508, 509 Monma, M. 1222(322), 1250 Monse, E.U. 1279(99, loo), 1301 Monson, R.S. 492(488), 517,942(59), 988 Monteil, R.L. 1402(110), 1438 Monteiro, M.B. 1400(105b), 1437 Montin, J. 830(339h), 869 Montury, M. 832(344), 843(375), 869, 870, 892(38), 920, 947(76), 974(169), 988, 990 Moore, C. 179(108),212, 740(78), 863 Moore, G.W. 506(667), 521 Moore, J.A. 165(13), 179(107), 210, 212 Moore, K.A. 486(341), 514 Moran, R.G. 1154(114,115), 1244 Morasso, S. 601(275), 634 Moreau, J.J.E. 8(82), 78, 236(76), 252, 303, 304, 306, 311(49), 400, 481(272), 513, 841(363), 870 Moreaux, C. 175(77), 212 Morel, D.R. 1199(254), 1248
1620
Author index
Morel, G. 179(106),212 Morella. A.M. 14331194). 1439 L. 816, 818(304), 868, 1005(66), 1044 Moreno, S.J. 1255,1263(15), 1299 More O'Ferrall, R.A. 1098, 1103(118), 1108 Morgan, K.M. 1058(29), 1105 Morgan, R.L. 1563(76), 1565 Morgan, T.M. 500(597), 520,971(154), 990 Mori, T. 760(121), 864, 900(70), 921, 1029(181), 1046, 1412(132,133), 1438 Mori, Y. 566(159), 632 Moriconi, E.J. 471(139), 510, 712, 713(46a), 724 Moriie, K. 1314(78), 1361 Morimoto, H. 1154(116), 1244 Morimoto, K. 1314, 1316(75), 1361 Morimoto, T. 782(198), 866 Morin, L. 281(11b), 284, 286, 288, 289, 291-293,316, 318, 319, 339(11a, llb), 399, 472(148), 510,935(41), 988 Morin, R.B. 167(27), 210 Morinaga, T. 470(73), 509 Morioka, T. 495(525), 518 Morishima, 1. 53,58, 59(286), 83 Morishita, T. 442(13), 458 Moritani, 1. 830(338a), 869 Moriya, K. 1307, 1313, 1328(24b), 1360 Moriyama, K. 1260(39), 1300 Morley, J.O. 406(3), 434 Moro, G. 14, 18(156), 80, 1304, 1308(13), 1359 Morris, G.F. 1453(66), 1504 Morrishow, A.M. 1146(92,93), 1244 Morrison, H. 650(26), 678, 1170(173), 1246 Morrow, C.J. 904(88), 921 Morrow, D.F. 484(305), 514 Murtikov, V.Yu. 1418(151), 1438 Morton, J.W.Jr. 712(47a), 725 Morton, T.E. 1217(311),'1250 Morton, T.H. 451(33), 458, 1284(127, 128), 1302 Morvillo, E. 1190(230), 1247 Moschel, R.C. 171(56),211 Moses, R.S. 648(23), 678 Mosettig, E. 475(184), 511, 845(389), 871 Moshuber, 1. 1417(149), 1438 Mosihuzzaman, M. 1005(64,65), 1044 Mosnaim, A.D. 1213(298), 1249 Musti, L. 185(147),213,601(273,274, 276-278), 602(280), 604(283, 284), 611(278), 634, 635 Moten, A. 546(78), 630 Moten, M.A. 539(58), 564(153), 590(240), 630, 632, 634 Mothenuell, S. 106(11), 210 Motto, M. 247(168), 254
oren no;
Moulin, M. 1200, 1201(259), 1248 Mourlevat, E 1232(343), 1250 Mouslouhouddine, M. 500(580), 519 Mouvier, G. 59(326), 84 Moxey, J.R. 1037(228), 1047 Mozumder, A. 681(4), 693 Mrotzek, H. 170(48), 211 Muchowski, J.M. 979(190), 991 Muck, D.L. 994(8), I043 Mueller, B. 773(169a), 865 Mueller, H.J. 489(379), 515 Mueller, R.H. 11(141), 79, 486(353), 515, 983(209), 991 Mukaiyama, T. 772(167), 865, 1540(11), 1564 Mukhejee, D. 1000(47), 1016(100), 1043, 1045 Mukhopadhyay, A. 14, 21(165), 80, 411(35), 434 Mukkavilli, L. 567(164), 632 Mulholland, G.K. 1223(323),1250 Muller. C.L. 659.661(45a. 45b). ,,663(45b).678 ,, ~iiller;E. 1495(151),i506 Muller, G. 1443(27), 1503 Miiller, K. 10(124), 25, 28(201), 46(234), 54(201), 58(234,323, 324), 59(323, 324). 79, 81, 82, 84, 225(38,41), 229(54), 251, 252, 283(10), 290(10, 18). 301(41), 303(10,41), 304(10), 306(41), 307(10), 310(41), 311, 312, 314(10, 41), 399, 400, 408(15, 16), 434, 705, 710, 711(23), 724, 1349(164), 1363 Muller, K. 470(93), 509, 696, 708(29e, 299, 724, 1034(217), 1047, 1058(30b). , , 1105 Muller, L. 99h(21), 1043 Miiller, M. 735, 737(50), 862, 1405(116), 1438 Miiller, R. 14, 21(164), SO, 221(17), 251, 294, 347(31d). 380(190). 400. 403 ~ u l l e r ;R. 471(127), ;lo ' Muller, W.M. 722(82a, 82b), 726 Mullican, M.D. 1034(214,215), 1047 Mundt, 0. 180(114), 212 Mundy, B.F! 57(310), 84, 470(55), 508, 905(95,96), 907(95), 921 \
~ u n kM.E. , 4(20), 8(85), 76, 78, 220(12), 221(6,7), 222(22), 223(32), 251, 309(59), 400. 470165). 4871357). 509. 515 ~ u n r o ;H.N. 1:20(lg), 1ibZ Munson, M.S.B. 53(283), 83 Murahashi, S:I. 737(62), 830(338a), 863, 869, 903,915(79, go), 921 Murai, A. 929(27), 937(48), 987, 988, 1542(16). 1564 Murai, S. 841(367), 870 Murai, Y. 543(67), 630 Murakami, M. 1537(3b), 1563 Muraoka, M. 769(162), 865
Author index Murata, I. 999(42), 1043 Murata, S. 178(99), 212 Murphee, S.S. 1010(75), 1044 Murray, H.C. 971(156), 990, 1544(21), 1564 Murray, J.V. 489(426), 516 Murray, W.P. 473(150), 510 Murray-Rust, P. 98(8), 101(10), 106(10, l l ) , 109(10), 210 Murrell, J.N. 63, 67(334), 84 Murrer, B.A. 980(196), 991 Murugova, E.Y. 535(42), 536(45), 581(203), 629, 630, 633 Mum, W.E. 498(550), 519 Mushegyan, A.V. 502(632), 520 Musiani, M. 1124(30), 1242 Musil, V. 651(31), 678 Musio, R. 492(495), 51 7 Musker, W.K. 485(327,329), 514 Musliner, W.J. 1554(42b), 1564 Musso, H. 184(140), 213 Muthukrishnau, R. 1512, 1526, 1527(46c), 1532 Myers, P.L. 764, 768(147), 865, 1430(185), 1439, 1554(42a), 1564 Myers, R. 1217(313), 1250 Mvlari. B.L. 1176(191\. 1246 ~;lonekis,S.G. 1094,'1095, 1102(107a), 1108 Naaranlahti, T.1127(37), 1243 Naar-Colin, C. 312,314(64), 401 Nabeshima, T. 1260(39), 1300 Nabeya, A. 1516(79,82), 1533 Nagai, H. 460(3), 464,953,958(93), 989 Nagai, T. 1017(113), 1045 Nagano, T. 569(169), 632 Nagao, M. 1184(211), 1247 Nagao, Y. 190(185), 214 Nagar, B.S. 498(548), 519 Nagarajan, K. 14, 21(164), 80, 221(17), 251, 316-319(67), 375,376(181), 380(190), 401, 403, 1074(77), 1107, 1310, 1311(44), 1360 Nagasaka, T. 552(104), 556(117), 631 Nagasawa, H. 378, 379(184), 380(192), 403 Nagase, S. 875(18), 887 Nagashima, K. l69(36), 210 Nagata, M. 896(53), 920 Nagata, W. 1510(38), 1532, 1537(3b), 1563 Nagel, M. 1489(145), 1493(147), 1506 Nigren, K. 1207(281), 1249 Nair, M.D. 901(75), 921, 1324(103, 105), l326(l l3), 1340(103), 1344(145), 1361, 1362 Nair, V. 332-334(101), 401 Naito, T. 538(57), 630, 638(3a, 4a, 4h), 641(6a-d), 642(3a, 9a, 9b, lo), 643(12), 677, 760(121), 844(385d), 864, 871, 900(70), 921, 1029(181), 1046, 1378(50),
1411(130), 1412(131-133), 1413(135), 1436,1438 Najarian, J.S. 1156(123c), 1245 Nakada, T. 247(176), 254 Nakagawa, S. 549(89), 631 Nakagura, S. 1091,1093(101), 1108 Nakai, H. 169(36, 37), 172(57), 177(91), 187(160), 210-212,214 Nakajima, T 1391, 1428(80), 1437 Nakamura, H. 1385, 1434(63), 1437 Nakanishi, K. 247(168), 254, 638(2), 677 Nakanishi, S. 1037(230), 1047, 1563(76), 1565 Nakano, Y. 1255(19), 1299 Nakaoka, K. 1284(126), 1301 Nakashita, Y.1034(207), 1047 Nakasuji, K. 181(11Y), 212 Nakazawa, T. 999(42), 1043 Nakazawa, Y. 470(73), 509 Namoto, K. 641(6b), 677 Naniwa, Y.378,379(184), 380(192), 403 Napier, J.J. 489(380), 575 Narang, R.S. 672(56d), 674(59a), 678, 679 Narasaka, K. 880(31), 887,998(35), 1043 Narayana, C. 968(140), 990 Nardin, G. 1037, 1038(236), 1047 Naringrehar, V.H. 500(589), 519 Namto, S. 943(61), 988 Naso, F. 4Y2(4Y5), 51 7 Nast, R. 764(141), 865, 1395(91), 1437 Natale, N.R. 14, 18(159), 80 Natsuki, R. 170(47), 211 Natzeck, U. 1021(129), 1045 Naumann, A. 927(25), 987 Nauyen, N.V. 1304, 1308, 1314, 1315(14), 1359 Naylor, R.D. 256, 258, 259(2), 264(45), 270, 274, 1058(28), 1105 Ncdly, D.L. 816(302), 868 Nechayuk, 1.1. 1499(155,156), 1506 Nee, G. 479(254), 513 Neelakantan, P. 967(133), 990 Neely, J.R. 1139(74), 1243 Neidlein, R. 1314(76), 1361 Neier, R. 657(41), 678 Nelson, D.A. 962(117), 989, 1119(6), 1242 Nelson, J.A. 1562(73), 1565 Nelson, J.D. 1133(55), 1243 Nclson, J.T. 549(87), 630 Nelson, N.A. 469(44), 508 Nrlson, P. 492(493), 517 Nelson, P.H. 979(190), 991 Nelson, R.P. 823(318), 869 Nemeroff, N.H. 186(153), 213 Nemoto, H. 247(176), 254 Nemtoi, G. 261(28), 272 Nene, D.M. 478(243c), 512 Nenitzescu, C.D. 558(127), 631
1622
Author index
Nersesyan, L.A. 502(632), 520 Nes, G.J.H.van 17(150),80 Nesi, R. 1026(164a, 164b), 1046, 1420(156), 1438 Nesterov, G.V. 1459, 1460(83), 1504 Neszmelyi, A. 751(98), 864, 1030(193), 1046 Neubeck, R. 572(177), 632 Neuenschwander, M. 525, 592(2), 629 Neuhaus, L. 699(15), 723,843(384), 870 Neumann, W.P. 177(93), 212 Neumeyer, J.L. 1206(271),1248 Neunhoeffer, H. 1012(88,89), 1026(151), 1044, 1046 Newberry, R.A. 1404(112), 1438 Newcomb, M. 246(156), 254, 1513(74), 1517(87b),1522(107,108), 1524(107,110), 1532,1533 Newcombe, R. 543(65), 630 Newkome, G.R. 909(105), 921, 1519(93), 1.533 Newman, H. 476(196), 511 Newmann, W.P. 488(372), 515 Newton, T.A. 672(56d), 678 Ng, L.K. 1512(53b), 1532 Nguyen, M.T. 437,449(1), 457 Neuven. N.V. 390.392.393(205~.404. ~ i b b e r h ; ~ . ~ .256, ~ . 265(6), 271 Nickel. P. 571(174), 572(179), 632 Nicolae, A. 261(28), 272 Nicolaou, G.A. 1370(31), 14.36 Nicolas, C. 1183(209), 1184(210), 1247 Niedrich, H. 542(61,62), 630 Nielsen, A.T. 390, 392(204), 404 Nielsen, S.F. 875(15), 887 Niemann, J. 459(1), 464 Nienhaus, J. 1266(58), 1300 Nie-Sarink, M.J.de 986(224,225), 992, 1545(23), 1564 Nietsch, K.H. 525, 530(16), 629 Nieves, R. 187(166),214 Nigam, M.B. 501(610), 520,574,594(187), 633 Nihelich, E.D. 1518(91), 1533 Niketic, S.R. 24(177), 80 Nikol'skii, A.L. 6(61), 62(330), 78, 84, 502(619), 520 Nikonovich, S.D. 718(59), 725 Nilson, A. 221(10), 251 Nilson, I. 561(145), 632 Nilsson, A. 470(74, 75),471(101), . . 509, 982(204,205), 991 Nilsson, L. 53(269), 83, 470(87), 509, 576(193), 633, 71 1(42a-c), 724, 732(33), 735, 737(51b), 740(76), 862, 863, 967(134), 990
Ninomiya, 1. 538(57), 630, 638(3a-d, 4a, 4b), 641(6a-d), 642(3a, 9a, 9b, lo), 643(12), 677,760(121), 844(385d), 864, 871, 900(70), 921, 1029(181), 1046, 1378(50), 1411(130), 1412(131-133), 1413(135), 1436,1438 Ninomiya, K. 802(285), 868, 1028(173), 1046 Nishiguchi, Y. 1413(135), 1438 Nishikawa, F. 999(42), 1043 Nishikawa, M. 174(71), 211 Nishikawa, S. 1279(97), 1301 Nishimoto, K. 676(62), 679 Nishimura, H. 943(61), 988 Nishio, M. 178(99), 212 Nishio, T. 319, 345(71), 401 Nisole. C. 1017(114). 1045 Nitta, K. 1152(108),'1244 Nitta, M. 1026, 1027(165),1046 Nitti, P. 549(85), 615(324), 617(322), 618(324), 619(325), 6.30, 6.35, 998(31)), 1000(45,46), 1037(234,23&238), 1038(234,236,238), 1040(245), 1041(252), 1043, 1047, 1048, 1387(68), 1392(83), 1437 Nixon, J.E. 1157(132), 1245 Niznik, H.B. 1206(271),1248 Node, M. 378, 379(184), 380(192), 403, 499(571), 519 Noe, E.A. 422(75, 76), 435 Noggle, J.H. 1169(169), 1246 Noguchi, M. 53(280,281), 83, 248(187), 254, 474(169), 485(331), 511, 514, 528(13), 629, 735(42,43), 862, 1026(166), 1046 Noguchi, T. 550(92), 631 Noguchi, Y. 785(209), 866, 978(184), 991 Noland, W.E. 1157(134),1245 Nolde, C. 764(149), 865 Nolen, R.L. 1517(84b), 1533 Nolte, K.-D. 327(95), 401 Nolte, K.-0. 327, 328(87), 401 Noltemeyer, M. 180(112), 212, 1410(126), 1438 Nomine, 6. 1537(9c), 1558(55), 1563, 1565 Nomura, Y.768(155), 841(365), 865, 870, 1029(186),1046, 1368(22), 1406(119), 1409(123),1436, 1438 Nondheimer, E 503(637), 520 Nonhebel, D.C. 337, 34@342(115), 402, 873(2), 886 Nonnenmacher, E. 3(9), 76 Nordhlom, G.D. 59(327), 84 Nordman, C.E. 189(179), 214 Norisue, H. 1390(77), 1437 Norisue, N. 1313(71), 1361 Norman, R.O.C. 944(70), 988 Normant, H. 492(486), 517, 1509(34a-c), 1520(96,97), 1531, 1533 Normant, J.F. 9(89), 78
Author index Norris, T. 1431(188), 1439 Nortey, S.O. 960(111), 989 Noshiro, 0 . 1215(304), 1249 Noth, H. 568(165), 632 Novak, H.J. 532(33), 629 Novak, R. 795(248), 867 Nave, J.J. 1236, 1237(348),1251 Novotnj:, L. 11(135), 79 Nowak, R.M. 688(25), 694 Nowell, I.W. 178(100),212 Nowlan, V.J. 1057, 1091, 1093, 1096(103), 1099(103,126a, 126b), 1100(126a, 126b), 1101, 1103(103), 1108, 1109 Nowland, V.J. 1077(81), 1107 Noyce, D.S. 982(203), 991, 1101(131), 1109 Novce. S.J. 532(29). 629 ~ o i o r iR. , 48(253):'82, 481(274), 482(280, 281), 513, 802(272), 868,980(195), 991, 1000(43), 1043 Nozaki, C. 1347(155), 1363 Nozaki, H. 1546,1548(33), 1564 Nsunda, K.M. 1097(114), 1108 Nudelman, A. 168(28), 172(61),210, 211 Nuesch, J. 1152(107), 1244 Nuguchi, M. 710(40f), 724 Nuikin, A.Ya. 174(75),211 Nummey, L.J. 1255, 1272(20), 1299 Nunes, B.J. 485(330), 514, 934(40), 988 Nurkeyava, Z.S. 688(24), 694 Nygaard, S.P. 441(11), 458 One, S. 981(198), 991 Oare, D.A. 4(42), 77, 249(193), 254, 731(27), 775(175), 862, 865 Obergrusberger, 1. 576(191), 633 Oberg~sberger,J. 564(152), 632 Obergrusberger, R. 477(220), 512, 565(157), 575(189,190), 627(157,345), 632, 633, 636 Oberhammer, H. 14, 21(171), 80 O'Brien, J.L. 1316,1326-1328, 1340(84), 1361 O'Brien, T.A. 1281(112), 1301 O'Callaghan, C.N. 531(25), 629 Ochoa. C. 187(166).214
Oddon, Y. 172(59), 211 Odermann, L. 1003,1005(57), 1044 O'Donnell, J.H. 681(1), 693 Oelhafen, P. 704(19d), 723 Oelman, H. 764(143b), 865 Oelmann, H. 561(143), 632 Oestercamp, D.L. 719(68d), 725 Offen, P.H. 1186(215), 1247 Offner, F! 1292(157), 1302
Ogaki, M. 463(10), 464(11), 465 Oganesyan, N.R. 494(520), 518 Ogasawara, K. 606(289), 635, 883(34), 887 Ogata, M. 1411(129),1438 Ogata, Y. 952(89), 989 Ogawa, A. 981(197), 991 Ogilvie, R.J. 663(49), 678 O&U, M. 1000(48), 1044 Ogle, C.A. 715(58f, 58g), 725 Oeura. K. 962.974(120). 989. 1391(78). 1437
allora or an, J.K. 1258(26), 1299 Ohashi, M. 451(39), 458,612(309), 635 Ohe, K. 841(367), 870 Ohfune, Y. 929(26), 987 Ohl, H. 1026(151), 1046 Ohmizu, H. 769(157), 865, 1029, 1030(187), 1046 Ohmori, H. 955(101), 989 Ohno, M. 795(248), 867 Ohno, T. 1120(17), 1242 Ohnuma, T. 661(47), 678, 965(132), 990 Obshima, T. 1017(113),1045 Ohsbiro, Y. 1027(167), 1046, 1419(153), 1438 Ohta, M. 5(57), 10, 70(125), 78, 79, 470(91), 509,534(38), 629,980(195), 991 Ohta, T. 980(195), 991 Oikawa, A. 1184(212), 1247 Oishi, E. 1012(90,91), I044 Okada, E. 1314, 1316(75), 1361 Okada, H. 879(30), 887 Okada, K. 1314,1316(75), 1361 Okada, N. 582(211c), 633 Okada, T. 1526(111), 1533 Okamoto, Y 9(93), 79, 1385, 1434(63), 1437 Okamura, K. 192(199),215 Okano. M. 1555146a). 1564 ~katani,T. 1026(153,' 154), 1046 Okauchi, T. 880(31), 887 Okawara, T. 978(184), 991, 1385(63), 1386, 1423(64), 1434(63), 1437 Okazaki, R. 1034(212), 1047, 1375, 1434(44), I436 Okazaki, T. 1136(64), 1142(76), 1243 Okecha, S.A. 506(655), 521 Okimoto, M. 460(3), 464, 953, 958(93), 989 Okuda, H. 528(14), 629 Oknyama, S. 670(55), 678 Oknyama, T. 1063(57), 1106 Olah, G.A. 247(166), 254, 486(339,340), 514, 794(247), 867, 1467(109), 1474(127),1505, 1506 Olano, B. 188(171),214 O'Leary, M.H. 1279(101), 1284(125), 1286(141), 1289(147), 1301, 1302 Olesen, S.O. 1376(47b), 1436 Olivera, E.S. 931(34), 988
1624
Author index
Ollinger, P. 42(229), 82 Ollis, W.D. 236(92), 252, 416,417(55), 435, 481(270b), 513 Olmstead, H.D. 733,734(38), 862, 1508(29, 31a), 1531 Olmstead. H.M. 1507(24b\. 1531 olofson, R.A. 1512, k26:1527(45c), 1532 Olsson, T. 425,432(86), 435 Omote, Y. 1040(242),1047 O'Neal, H.E. 259, 264(9a), 271 O'Neill, P. 1128(42), 1243 O'Neill, P.J. 1156(128), 1245 Onimura, K. 528(13), 629, 1026(166), 1046 Ono, K. 1255(19),I299 Onomura, 0. 463(10), 464(11), 465 Onoue, H. 830(338a), 869 Onu, A. 261(28), 272 Opie, L.H. 1138(70), 1243 Opitz, G. 4(17, 19), 10(126), 57,58(314), 64(343,350), 65(346), 67(343), 68(346), 70(350), 74(343), 76, 79, 84, 85, 469(28), 508, 600(270), 634, 710(40c), 724, 736(54b, 54c, 57), 738(54b, 65), 740(54c), 749(94a), 779(182), 784(200, 201, 205), 786(217), 800(266), 816(94a, 301), 830(339a), 863, 864,866, 868, 869, 908,912(102), 914(114), 921, 1016(107),1045, 1051(9, lo), 1052, 1053(10), 1062(51), 1105, 1106, 1366(16), 1369(26), 1436, 1537(3c, 3d), 1542(18), 1560(61, 64), 1563-1565 Oppenheimer, E. 814(296), 868 Oppolzer, W. 505(647), 521 Optiz, G. 1348(158, 159), 1363 Orban, J. 1122(24), 1242, 1433(194),1439 Orchin, M. 63, 67(333), 84 Orechov, A.P. 1463(91), 1505 Orestes, T. 1285, 1286(131), 1302 Orgel, L.E. 672(56a), 678 Orita, K. 1218(316), 1250 Orito, K. 927(24), 987 Ormerod, J.A. 1430(185), 1439 Om, J. 1156(129), 1245 Ortoleva, E. 14, 18(156), 80, 1304, 1308(13), 1359 Owis, R.L. 494(519), 518 Osamura, Y 676(62), 679 Osapay, K. 1097(114), 1108 Osato, T. 1150(102), 1244 Osawa, A. 471(106), 510 Osborn, J.A. 479(256), 513 Oshima, K. 688(27,28), 690(28), 694 Osiecki, J. 10(122), 79 Osman, R. 432(113), 436 Osmers, K. 769(157), 865 Ostercamp, D.L. 66(354), 85, 373, 375-377(179), 403, 411(36), 434, 891(24), 920, 1502(160),1506
Osterholz, A. 1199(252), 1206(279),1248, 1249 Ostlund, N.S. 24(180), 81 Ostroumov, I.G. 283, 287, 289, 294, 298, 339, 354(9), 399 Osuka, A. 566(159), 632 Oszbach, G. 751(98), 864, 1030(193), 1046, 1399(101),1437 Oszczapowiu, J. 41, 46(226), 82 Otaira, K. 722(85a), 726 Otaka, K. 776(178), 865, 998(35), 1043 Otani, G. 1003(52), 1044 Oth, J.E 715(57c), 725 Otha, M. 1459(80), 1504 Otika, S. 485(331), 514 Otomasu, H. Y64(128), 989 Otsuka, S. 56(300), 84, 481(274,275, 277, 278), 482(279,280), 513 Ott, A:C. 944(63,64), 988 Ott, E. 1304(3), 1359 Ott. W. 186(158\. 213 otto, A. io(i32j2'79 Otto, H.H. 604(285), 635 Overill, R.E. 14, 17(151), 80, 433(125), 436 Overman, L.E. 505(649), 521,904(81), 921, 939(49), 988 Ovsyannikov, I S . 502(619), 520 Owada, J. 1005(61), 1044 Owczarczyk, Z. 506(657), 521 Owen, C.R. 477(230), 512 Owen, J.R. 1257(22), 1299 Owen, W.S. 3(11), 76 Oya, S. 939(53), 988, 1529(117), 1533 Oyama, Y. 191(189), 214 Ozola, A.Y. 550(97), 631 Pachter, 1.J. 469(48), 508, 837(359), 870 Packman, L.C. 1273(70),I300 Paddon-Row, M.N. 875(18), 887 Padgett, H.C. 476(197, 198), 511 padLett, W.M. 1304(15, 17j, 1360 Padmanabhan, K. 186(155), 213 Padmanabhan, V.M. 221(17), 251,380(190), 40.3 Padmanhabhan, V.M. 14, 21(164), 80 Padwa, A. 182(128), 190(186),213, 214, 676(63), 679, 1010(75), 1014(98b), 1044, 1045 Paetkau, V. 1156(123a), 1245 Pagani, G. 1367(19), 1436 Pagani, G.A. 979(191), 991 Pagnotta, M. 56(299), 84, 261, 269(29), 273, 290(22), 399 Pahor, N.B. 13(145),80,225, 226, 228(45), 251, 751, 752(102), 864 Pai, E.E 1291(151), 1302 Pakkanen, Ta. 167(22),210
Author index Pakkanen, Tu. 167(22),210 Palacios, E. 1385(62), 1389(75), 1408(122), 1432(75,189, 190), 1433(191), 1437-1439 Palaghita, M. 558(128), 631 Palameta, B. 1186(218), 1247 PaleCek, M. 54-56(291), . . 83, 259(16), 271, 479(261), 513 Palecer, J. 366, 367, 371(159), 402 Palmer. A.J. 1214(302). 1249 palmer; K.H. 1164(15i), 1245 Palmisano, G. 490(439), 516 Panangadan, J.A.K. 963(122), 989 Pandit, U.K. 57(308), 64(353), 84, 85, 222(26), 251,288,289,291,316,317,319, 344, 345(15), 399,471(134, 135), 510, 539(59), 555(116), 630, 631, 735(53), 736(56), 748(90), 796(249), 863, 867, 912(111),
156311565 Panek, J.S. 1026(155-158), 1034(214), 1046, 1047 Panfilova, E.A. 721(76), 726 Pangborn, W.A. 1280(107), 1301 Panico, R. 1442, 1443(17), 1473(17, 126), 1497(17), 1503, 1505 Panisheva, E. 559(130), 631 Pankratz, M. 247(167), 254 Panouse, J.J. 978(182), 991 Panshin, S.Y. 258(14), 259(21b), 271, 272 Paoli, P. 1420(156), 1438 Pap, A.A. 48(244), 82 Papadopoulos, E.P. 528(10), 629 Papadopoulos, K. 775(174), 865, 1039(240), 1047 Papadopoulos, S. 190(187),214 Papaleo, S. 1026(164a, 164b), 1046, i420(156), 1438 Papaphilippou, A. 1541(14), 1564 Paoke. G . 7(65). 78.. 300137.38l ~ . ,309.,, >19(61g); 400 Papp, G. 1180(201),1247 Pappalardo, R.R. 40, 42(225), 48(252), 82, 373(186-188), 381,387, 388(186), 403, 416(54), 432(54, 117, 119, 120), 435, 436 Pappata, S. 1200(258), 1226(327),1248, 1250 Paquer, D. 281(11b), 284, 286, 288, 289, 291-293,316,318,319, 339(11a, llb), 399, 472(148), 510, 935(41), 988 Paquette, L. 715(55c), 725 Paquette, L.A. 471(126, 132), 510, 768(154), 784(201,204), 865, 866, 1016(108), 1033(204),1045,1047, 1401(106),1438, 1560(63),1565 Parcell, R.F. 471(130), 510 ~
1625
Paredes Ledn, R. 330-332,334(99), 401 Parfitt, R.T. 471(131), 510 Parikh, A . 1233, 1235(345), 1251 Parikh, V.D. 607(294), 635 Paris, R. 1276(88), 1301 parkanyi, L. 187(168),214 Parker, D.C. 308, 309, 319(58), 400, 843(374), 870.896.898(54).920 ~arker,'K.A: 57(i09j, 84,494(512), 498(545, 546), 518, 519,905(97), 921 Parker, R.J. 14, 17(151), 80,433(125), 436 Parkincn, A. 247(170), 254 Parlier, A. 193(201), 215 Parnes, H. 1161(144), 1245 Parnes, Z.N. 984(218), 991 Parr, R.G. 46, 69(235), 82 Parr, R.W. 559(133), 632 Parric, J.E 608(298), 635 Parsons, M.E. 1229(339), 1250 Parsons, W.H. 188(170),214 Parton, R.L. 955(100), 989 Partscht, H. 176(85), 212 Pascali, C. 1217(313),1250 Pascard, C. 174(72),211 Pascard-Billy, C. 165(15), 210 Pascual, C. 369(166), 403 Pashkevich, K.I. 6(61), . . 62(330), . . 78, 84, 500(592), 520 Pasqualucci, C.R. 1152(109),1244 Pasto. D.J. 875(16). 887 ~ataud-Sat,M. 8(82), 78, 236(76), 252, 303, 304, 306, 311(49), 400, 841(363), 870 Patel, B.P. 653(36), 678 Patel, H.V. 572(178), 632 Patel, M. 1034(214, 215), 1047 Patmore, E.L. 475(177), 511 Patrick, J.B. 558(122), 631 Patrick, T.B. 1222(320), 1250 Patterson, J.W. 549(87,90), 630, 631, 760(122), 864, 1372(35), 1436 Patud-Sat, M. 481(272), 513 Patzelt, G. 594, 598(252), 605(286), 634, 635 Paukstelis, J.V. 247(164), 254,476(195), 511, 731(16), 862, 1119(11), 1242 Pauling, L. 146, 148(12), 210 Paulini, H. 282, 284, 302, 310(6), 399 Paulini, K. 797(253), 867, 994(15), 1043 Paulmier, C. 841(366), 870 Paulus, B. 551(101), 631 Paulus, E.F. 173(65), 211 Paulvannan, K. 1042(255),I048 Paventi, M. 476(218), 512 Paveti, M. 477(219), 512 Pavlisko, J . k 722(85c, 86, 87), 726 Pawda, A. 1022,1024(133), 1045 Pawlowski, N.E. 1157(132), 1245 Payne, C.W. 478, 479(242), 512
1626
Author index
Paz, J.L.G. 704(16f, 19d), 707(27d, 28), 713(50), 723-725 Paz. J.L.G.de 48/243). 82 ~azhenchevsk~, B. 191(192), 214 Peale, A.L. 1155(121c, 121d), 1245 Pearce, A.A. 831(340), 869, 970(148), 974(166), 990 Pearlman, R. 46(237), 82 Pearson, D.P.J. 1266(59), 1300 Pearson, R.G. 697,707(4a), 723 Pech, H. 6(58), 78 Pechrr, J. 189(182), 214 Pechet, M.M. 794(243), 867, 1563(76), 1565 Pecka. K. 54-56(291). , , 83, 259(16), , . 271. 479(261), 513 Pedersen, K.J. 1283(115,117), 1301 Pedersen, R.L. 944(64), 988 Pederson. R.L. 944(63). 988 Pedlar, A.D. 840(360):870 Pedley, J.B. 256, 258, 259(2), 264(45), 270, 274, 1058(28), 1105 Pedrini, P. 176(81), 181(122), 212, 213 Peel, J.B. 683(12), 693 Peerhoom, R.A.L. 256, 265(6), 271 Peet, N. 572(181), 603(281), 632, 635 Peet, N.P. 1507(11), 1531 Pegg, J.A. 431(106), 436 Pehk, T. 327, 328(87), 401 Pelah, Z. 451(39), 458 Pelissier, M. 481(269), 513 Pellacani, L. 840(362a, 362b), 870, 1352(169), 1363 Pellaconi, L. 1016(103-105), 1026(105),1045 Pellegrin, V. 1123, 1124(26), 1149(97), 1242, 1244 Pellissier, H.506(659), 521 Pellmont, B. 505(648), 521 Pelter, A. 492(493), 517 Penaud-Bermyer, F. 456(43), 458 Peng, C.T. 1167(165-167), 1168(165),1246 Penn, G. 186(158), 213 Pensionerova, G.A. 492(497), 518 Pereira, C.B. 1157(132), 1245 Perelman, M. 4(18), 76, 786(216), 866, 1369(25), 1436, 1560(64), 1565 Perez, P. 704(16d, 16f, 19c), 723 Perez-Carreno, E. 192(198),215 Perhach, J.Jr. 1135(60,61), I243 Perham, R.N. 1261(44), 1273(70), 1300 Perianayagam, C. 1512(58), 1532 Periasamy, M. 968(140), 990 Perkampus, H.-H. 63(337), 84 Perkins, C.M. 1177(193), 1246 Perkins, M. 1522(101), 1533 Perlmutter, J.S. 1217(314), 1250 Peroutka, S.J. 1158(135, 136), 1208(282), 1245, 1249
Perrin, C.L. 246(158), 254 Perrin, D.D. 710(37), 724 Perrini, G. 506(679), 521 Perrone, E. 1188(222,223), 1247 Perst, H. 181(118),212, 1458, 1467(76), 1504 Pemzzo, G. 468(18), 508 Pesaro, M. 669(53), 678, 901(74), 921 Pete, B. 169(38), 210, 721(75), 726 Pete, J.P. 624(332-334, 337), 636 Peter-Katalinic, J. 816, 818(304), 868, 1005(66), 1044 Pelrrmann, J. 1182(203,206), 1247 Peters, E.-M. 186(158), 213, 940(57), 988, 1420(157), 1439 Peters, J.A. 823(319), 869 Peters, K. 186(158), 188(174), 213, 214, 940(57), 988, 1420(157), 1439 Petersen, H.1443(30), 1503 Peterson, H.J. 1092, 1101(106c), 1108 Peterson, M.R. 27(209), 81 Peterson, W.D. 1149(99), 1244 Pethon, P. 489(397), 515 Petit, P. 264(51), 275 Petrachenko, N.E. 58(325), 84 Petraitis, J.J. 494(512), 498(546), 518, 519 Petrenko, O.P. 365(158), 402 Petrov, A.A. 555(109, 110), 631 Petrow, V. 549(88), 630 Petms, E. 470(67), 509 Petms, R. 470(67), 509 Petrzilka, M. 1011(78), 1044, 1546(26), 1564 Petter, W. 192(197), 215 Pfau, M. 25(204,205), 81,474(170), 511, 843(378), 845(391), 846, 848(394), 857(402), 870, 871,892(4244), 893(4245), 920, 1041(251,253), 1048 Pfeifer, A. 1153(112), 1244 Pfeiffer, G. 578(198), 633 Pfeiffer, T. 188(177), 214 Pfoertner, K. 924, 928(1I), 987 Pham, C.C. 281,284, 286,288,289,291-293, 316,318, 319, 339(11b), 399 Phan-Tan-Luu, R. 470-472(56), 508 Philipp, A.H. 1172(178), 1246 Philips, J.C. 1512(58), 1532 Philipsborn, W.V.709(30b, 30c), 724 Philipshorn, W.von 14, 21(164), 32, 42(212), 80, 81,221(17), 231(62), 251, 252, 294(31d, 33), 295-299(33), 338, 339(112),
Phillips, B.T. 182(129),213, 551(100), 631 Phillips, G.W. 5, 8, 9(51), 77 Phillips, W.V. 1507(13), 1531
Author index Philoche-Levisalles, M. 169(39), 211 Piancatelli, G. 944(66), 988 Picard, J.-P. 9(92), 79 Picard, J.P. 492(480,482), 517 Piccinni-Leopardi, C. 408(24), 434 Picconi, G. 1374(40), 1436 Pichat, L. 1232(343), 1250 Pichon, R. 718(61), 725 Pickl, W. 426(91), 435 Pick-Schlicbs, H. 1011(83), 1044 Picot, A. 935(43), 937(43,47), 988 Piddacks, C. 558(126), 631 Piechuta, H. 1176(187), 1246 Pienaar, D.H. 790,793(237), 848,850(397), 867, 871, 1541(14), 1564 Pierdet, A. 1537(9c), 1558(55), 1563, 1565 Pierlot, A.P. 32(219), 82 Pierrat, F.A. 538(52), 630 Pierrot, M. 184(141),213 Pierson, W.G. 580(202), 633,760(129), 864 Pieter, K. 1512(64), 1532 Pieter, R. 1512(47), 1532 Piettre, S. 1032(197), 1047 Piettre, S.R. 188(172),214 Pianataro, S. 53, 58, 59(287), 83, 696, 708(29a), 724 Pihlaja, K. 247(170), 254 Pike. J.E. 794(242\. 867 ~, Pike, V.W. 12i7(3K), 1250 Piker, R. 704(16b, 16c), 723 Pilati, T. 14, 18(156), 80, 1304, 1308(13), 1359 Pilcher, G. 262, 263(34b), 268(67), 273, 276 Pillan, A. 1160(142), 1245 Pillon, L.Z. 494(518), 518 Pilon, L.Z. 495(521), 518 Pinchas, S. 843(372), 870 Pinckard, J.H. 428(101), 436 Pindur, U. 1011(87), 1044 Pinhey, J.T. 764(136), 864,947(74), 988 Piniella, J.E. 187(164),214 Pinkerton, F.H. 1142(80), 1244 Pinkus, J.L. 491(467), 517 Pinnick, H.W. 979(189), 991 Pipe, L.G. 42(227), 82 Piret-Meunier, 1. 193(200), 215 Pirmng, M.C. 646(15a), 677 Pispisa, G. 617(322), 635, 1040(245),1047 Pitacco, G. 10(133), 53, 58,59(287), 64-66, 72, 73(133), 79, 83, 235(73), 236(78-80), 252, 280, 294(1b), 302(46), 323(78), 346(131), 399402,471(123), 499(572,573), 510, 519,549(85,86), 583(215), 615(324), 617(322,323), 618(324), 619(325), 620(326), 630, 633, 635, 696(3e, 29a), 708(29a), 723, 724, 734(40), 751(97,108-116), 758(108-1 ll),
-
~
1627
759(112, 114, 116), 786(220), 799(265), 862, 864, 866, 868, 923(2), 987, 998(30), 1000(45,46), 1016(109, I l l ) , 1037(231-238), 1038(233,234, 236, 238), 1040(245), 1041(252),1043, 1045, 1047, 1048, 1050(6h), 1105, 1366(1e, 17), 1387(68), 1392(83), 1435-1437,1442(8), 1503, 1560(62), 1562(75), 1565 Pittacco, G. 836(350a), 870 Pittman, K.A. 1189(224), 1247 Pitzenberger, S.M. 182(129), 213 Pitzer, K.S. 42(227), 82 Pitzler, H. 586(227-229), 587(227, 228), 633 Placeway, C. 490(444), 517 Plancher, G. 11(137), 79 Plappert, P. 307(54); 400 Plaquevent, J.C. 222(18-20), 251, 735(43), 790(236). ,. 862.867 . Plas, H'.C.van der 1349(163), . . 1363 Plat, M. 171(50), 211 Plattner, D.A. 192(197),215 PI& G. 9/96). 79. 952f90). 989 ~ l e ~ e k 485(326), ,'~. 514 Plesset, M.S. 24(187), 81 Pletcher, J. 173(67), 211 Pliml, J. 482(283), 513 Pluchet, H. 978(182), 991 Plumet, J. 944(62), 988 Plumitallo, A. 1036(222,223), 1047, 1422(161),1439 Plunkett. W. 1155(121e). 1245 ~ocar,D. 57(305):84, 220(2), 221(3,4), 222(23,25), 223(23,25, 33), 238(23), 251, 302(45), 304(51), 305(45, 51), 307, 308(55), 313, 315(51), 320(55), 400, 468(20), 470(66, 69, 84), 473,475(153), 494(509-511), 497(542,543), 508, 509, 511, 518, 786(219), 843(373,377), 866, 870, 892(3941), 920, 943(60), 988, 1024(141), 1025(145-147), 1045, 1046, 1352(168,170), 1363, 1392(81a-c), 1437 Pochter, I.J. 714(52), 725 Podbienszinska, T. 584(220), 633 Podszun, W. 950(83), 988 Poetsch, E. 485(320), 514 Pognotta, M. 225(35), 251 Pohjala, E. 167(22),210 Poindexter, G.S. 496(532), 518 Poirier, J:M. 9(100, 103, 104, 116), 79, 494(516), 518,564(151), 632, 1530(119), 1533 Polak, L.S. 686(22), 694 Polak, S. 686(23), 694 Polanc, S. 193(200),215
1628
Author index
Polborn, K. 425(87), 435 Poletto, J.F. 558(126), 631 Polietkov, M.K. 986(228-230), 987(231), 992 Polievtkov, M.K. 552(108), 631 Polizer, I.R. 1516(79-83), 1533 Poll, W. 561(147, 148), 632 Pollack, R.M. 259, 268(8), 271, 1060, 1062(43a,43b), 1063(58), 1101(131),1106, 7 700
Pollman, M.J.M. 1561(67), 1565 Pollmann, M.J.M. 1535, 1561(2a), 1563 Polonovski, M. 476(199,200), 511 Polovinko, S.B. 1468, 1471, 1481(112), 7 $07
--*"
Polozov, G.I. 615,616(318), 621(329), 6251338). 635. 636 POI^, R.L. 9(117j, 48(249), 79,82, 712(48a, 48b), 714(48a, 48b, 54), 715(54), 725, 1530(120), 1533 Polyakova, 1.N. 187(161), 274 Pommelet, J.C. 975(178), 991 Pommier, J.-C. 7(66, 67), 8(79), 78, 305, 306(52), 400,474(171), 492(490492), 511, 517, 843(371,380), 856, 858(380), 870, 893(46,47,50), 894(46,47), 920, 931(31), 987 Pomogailo, A.D. 686(19,21), 693, 694 Pompliano, D.L. 1295(166), 1302 Pomponi, M. 536(51), 630 Pomytkin, LA. 1478(135), 1506 Poncipe, C. 1165(154),1245 Pong, S.S. 1176(187), 1246 Ponomarev. A.N. 686(19), 693 Ponti, P.P. 1037(225),'1047, 1310(40), 1360, 1428(182b), 1439 Ponticello, G.S. 1021(128), 1045, 1387(69), 1437 Ponliroli, A.E. 1228(335), 1250 Pontremoli, S. 1285(129), 1302 Poore, G.A. 1133(56), 1243 Pople, J.A. 24(181, 185, 189), 25(190-195), 27(195). 32. 381195. 216). 39. 49(195>. 53(216j; 54(2s9'), sj(i95'j; 81; 83: 25i: 265(6), 271 Popova, L.A. 1459,1460(82), 7504 Porta, 0. 874(7), 887 Porter, H.D. 1149(99), 1244 Portcr. P.E. 1338. 1340(138b).1362 portis; LC. 476(210,2i4), 5 i i Portnoy, R.C. 1147(96), 1244 Portoghese, P.S. 927(23), 987 Poss, A.J. 740(80), 863 Postigo, C. 474227), 512 Potier, P. 476(201,203, 204), 479, 482(204, 265), 511-513 Potkina, T.N. 1459, 1460(82), 1504 Potoczak, R.E. 1142(77), 1243
Potts, G.O. 1197(244),1248 Pouet, M:J. 169(39), 211 Poulter, C.D. 1144(87), 1244 Poulton, G.A. 949(79), 988 Powell, J.E. 1304(15, 17), 1360 Powell, M.F. 1074(78), 1101(132b), 1107, I109 Powers, W.J. 1508(28), 1531 Pownall, H.J. 672(58), 679 Prabhu, A.V. 1507(13), 1531 Pradere, J.P. 1406, 1421(118), 1438 Prager, R.H. 612(313), 635, 786(222), 867, 1028(177),1046, 1416(144), 1433(194), 1438,1439 Prahl, H. 55(293), 83, 224(34), 251,302, 303, 310,311(48), 400,479(258,260), 480(258), 513 Prell, G.D. 1146(92-94), 1244 Prelog, V. 489(413), 516, 1058(27), 1105
Preses, J.~.'684(14),693 Pretsch, E. 63(340), 84,369(166), 403 Preuss, H. 354, 357(136), 402 Preut, H. 177(93), 189(180), 212, 214 Previdoli, E 10(124), 58, 59(323,324), 79, 84, 225(41), 229(54), 251, 252, 283, 290(10), 301(41), 303(10, 41), 304(10), 306(41), 307(10), 310(41), 311, 312, 314(10,41), 399, 400,408(16), 434, 470(93), 509, 696, 708(29e, 290, 724 Previdoll, F. 1058(30b),1105 Prewo, R. 172(62),211 Price, C.C. 55(292), 83, 479,480(257), 513, 606(291), 635, 1512(60), 1532 Price, G.W. 1217(313),1250 Price, VE. 1459(77, 78), 1504 Prici, S. 997(28), 7043 Pridgen, H.S. 764(140), 865 Priest, D.N. 492(488), 517, 942(59), 988 Pring, A. 415(48), 435 Procbazka, M. 54-56(291), 83, 259(16), 271, 479(261). 513 ~roenca,M.F. 1449(55), 1504 Profft, E. 491(470), 517 Proidakov, A.G. 283, 287, 289, 294, 298, 339, ~rokof'ev,E.P. 363(154), 402,426428(94), 435 Proll, T. 1034(211), 1047 Prornonenkov, V.K. 1418(151), 1438 Pross, A. 369(166), 403 Prosser, T.J. 1512(61), 1532 Protiva, M. 487(356), 515 Protopopova, T.V. 1443(23), 1503 Protopova, G.V. 492(496), 518
Author index Prout, K. 178(96),212 Prouteau, M. 1232(342), 1250 Pmdhommeaux, E. 1232(342), 1250 Pmskil, 1. 797(252), 867,994(14), 1043 Pmsoff, W.F. 1225(326), 1250 Pmszynski, P. 1060(40), 1083(87), 1097(121), 1098(87,88, 117, 121), 1103(40), 1106-1108,1134(364), 1251 Pshenichnyi, V.N. 930(28), 967(135), 987, 990 Puckette, T.A. 5, 8, 9(51), 77 Puff, H. 185(151),213, 775(174), 865, 1039(240), 1047 Pugh, D. 406(3), 434 Pugsley, T. 1172(180), 1246 Pugsley, T.A. 530(24), 629, 1170, 1172(179), 1246 Puig, M. 187(164),214 Pulay, P. 24(183), 81 Pulcini, P. 840(362a), 870 Pulst, M. 4, 5(45), 42(230), 77, 82, 433(122), 436, 731(26), 862, 890,891(12), 919, 1366(8), 1405(115,116), 1435, 1438 Purdum, W.R. 1188(221),1247 Purrelo, G. 506(679), 521 Purrington, S.T. 794(245), 867 Pusztay, L. 1416(147),1438 Puterbaugh, W.H. 1514(75), 1532 Putt, S.R. 1155(119), 1156(124), 1244, 1245 Pye, P.L. 176(83), 212 Pyrko, A.N. 1366(12), 1436 Pyshchev, A.I. 1448-1450(47,49), 1467-1469(102), 1471(113), 1472(116, 117), 1475(102), 1480(117), 1481, 1484(47,49), 1485(141, 142), 1486(141), 1487(102,141), 1488(141), 1489(141,142), 1490(142), 1492(102, 113, 142), 1493(142), 1494(49), 1497(49, 141, 142), 1499(116, 155, 156), 1501(157), 1502(116), 1503-1506 Qahar, M. 1028(176), 1046 Qian, H.-Y. 1225(326),1250 Qian, J.H. 704(19d), 723, 1097(116b), 1108 Qin, X.Z.684(13), 693 Quast, H. 845(387b), 871,898(63), 920 Queguiuer, G. 984(221), 986(222), 991 Querou, Y. 236(75,81), 252 Quin, L.D. 10(130), 79, 984(212), 991 Quiniou, H. 1374(43a,43h), 1406(117, 118), 1421(118,158), 1436,1438, 1439 Quinn, EX. 736,740(54d), 863 Quirk, R.P. 715(57a, 57b), 725 Quiroga, E. 722(85c), 726 Quittmann, W. 1016, 1018(110), 1045, 1373, 1382(36), 1436
Raab, W. 282, 301,310(5), 399, 486(350, 351), 514, 515 Raabe, G. 295,322,323(29), 399 Rabalais, J.W. 54(288), ~ ,. 58(318), .. 83,. 84,. 704(18), 723 Raban, M. 422(75,76), 435 Rabiller, C. 298(34), 400 Rabinovitch, B.S. 230(55), 252 Rabinowitch, B.S. 407, 414(7), 434 Radeglia, R. 327(8&90,92), 328(8&88,90), 329(88), 347, 348,353(92), 401, 426(92), 435 Radernacher, D.R. 447(20), 458,492(494), 517 Radhe, R. 1063(56), 1106 Radom, L. 24(181), 25(207), 27(210), 28, 29(207), 81, 256(6), 262(38), 265(6), 267(38), 271, 273, 705, 712(25), 724 Rae, B. 822(314), 846(393), 848(396), 852(399,400), 861(403), 869, 871 Rae, D. 1008(69), 1044 Rae, I.D. 415(48), 435 Ragade, 1. 964(125), 989 Ragan, J.A. 1032(197), 1047 Raghavachari, K. 24(185), 81 Rahappa, S. 221(17), 251 Rahkit, S . 1186(218), 1247 Rahman, A.U. 471(125), 510 Rahtz, D. 484(301), 514, 555(111), 631 Raichle, M.E. 1217(314),1250 Raichonok, T.P. 1424(165), 1439 Raileanu, D. 558(127, 128), 631 Rajagopalan, P. 1352(171),1363 Rajapa, S. 499(566), 519 Rajappa, S. 5, 9(46), 14, 21(164), 77, 80, 242(122), 253,316-319(67), 369(168), 375, 376(181), 380(190), 401, 403, 731(13), 861, 890, 891(10), 919, 1306(20), 1310, 1311(43,44), 1313, 1320(20), 1324(103, 105), 1338(135), 1340(103), 1342(20,142, 143), 1344(144,145), 1353(172), 1358(184, 186), 1359(184), 1360-1363 Rakina, O.A. 1467(108), 1505 Rakshys, J.W. 387(202), 403 Ram, B. 567(164), 632 Raman, P. 1172, 1173, 1175(181), 1246 Ramanathan, R. 489(380), 515 Ramasesha, S . 406(4), 434 Ramaswamy, S. 890(20), 920 Rami, H.K. 608(298), 635 Ramli, M. 975(176, 177), 990 Rampal, J.B. 471(121), 510 Ramsch, K.-D. 826(324), 869 Randall, E.W. 299(39), 400 Randolph, A.E. 1178(198),1247 Rangaishenvi, M.V. 832(341,342), 869 Ranise, A. 494(515), 518, 834(348), 870, 975(172), 978(181), 990, 991 ~
Author index Reus, H.R. 1535(2a),1561(2a, 66), 1563,1565 Reusch, W. 544(72); 630 Reuter, H. 775(174), 865, 1039(240), 1047 Reutov. O.A. 1507116a. 17.. 18b). ,. 1531 ~evankar,G.R. 172(63j, 211 Revial, G. 166(19), 210,474(170), 511, 846, 848(394), 871, 1041(251,253), 1048 Rey, M. 475,498(180a), 511, 800(268), 868, 998(40), 1043 Reyes-Rivera, H. 544(73), 630 Reynolds, L.J. 1276(87), 1301 Reynolds, S. 572(177), 632 Rbeenen, V.van 1541(15a), 1564 Rheingold, A.L. 179(107), 212 Rhodes, R.E. 167(27), 210 Ribaldone, G. 1447(44), 1503 Ribeiro da Silva, M:A.L 268(67), 276 Ribek, H.J. 539,541(60), 630 Ribiere, C. 843(378), 870, 892, 893(42-44), 920 Ricca, A. 543(66), 582(211a), 630, 633 Riccabona, G. 1226(328), 1250 Ricci, C. 1285(129), 1302 Rice, F.O. 1087(93a), 1107 Rice, K.C. 1153(113), 1244 Richards, C.P. 890(14), 920 Richardson, S.K. 178(100), 212 Riche, C. 177(94), 212 Richey, EA.Jr. 902(78), 921 Richman, J.E. 503(635), 520 Richmond, J.P. 8(83), 78 Richter, R. 902(76), 921 Rickels, K. 112i(2i), 1242 Rico, 1. 740(69), 863,875,876(24), 887 Ried. W. 7851215). 866 ~iegkl,B. 606(293), 635 Riess, J.G. 9(119), 79,440(9), 458,477(228, 229), 512 Rigby, J.H. 1028(17&176), 1046, 1416(143), 1438 Righetti, P. 751(99), 864 Rigo, B. 957(103), 989 Rihs, G. 171(54), 211, 601(279), 635 Rimek, J. 555(112), 631, 1418(152),1438 Rimland, A. 1207(281), 1249 Rinaldi, D. 40,42(225), 82,373(187, 188), 403, 432(119, 120), 436 Rinaldi, V. 1037, 1038(234), 1047 Rindone, B. 944(67), 947(73), 988 Rink, M. 484(314), 514 Rinne, U.K. 1227(333), 1250 Rinus, 0. 167(26), 210 Rinzel, S.M. 1133(56), 1243 Rios, C.B. 955(99), 989, 1255(21), 1257(21, 23), 1262(48), 1269, 1276(65), 1299, 1300
Ripoll, J.L. 281-283,300-302, 304, 305, 310(3), 399, 843(382), 870 Risaliti, A. 13(145), 80, 225, 226, 228(45), 235173). 236178. 79. 85, 87). 251. 252.
190), 1037(231,2$), 1040(243,244), 1043, 1046, 1047, 1430(186), 1439 Kisaliti, ti. 617(323), 635 Risalti, A. 549(86), 630 Risch, N. 769(159), 865, 1028(170),1046 Rise, F. 1010(76), 1044 Risinger, G.E. 1255, 1264, 1266(10), 1299 Rivail, J.-L. 40, 42(225), 82, 373(187, 188), 403, 432(119, 120), 436 Rivera, F. 1079, 1089, 1091(80), 1107 RiviCre, M. 55(294), 83,479(263), 481(263, 268, 269). 513 Rizzo, C. 1175(185), 1246 Robb, M. 24(185), 81 Robbins, J.M. 489(425), 516 Robert, A. 185(150), 213 Roberts, B.W. 299(39), 400 Roberts, G.C.K. 1147(95), 1244 Roberts, J.D. 294, 295,297,298(30), 299(39), 347, 351(30), 399, 400, 473(155, 157), 511 Roberts, J.L. 1144(87), 1244 Roberts, J.T. 1128(44), 1243 Roberts, K.B. 1255, 1272(20), 1299 Roberts, R.D. 1511(43), 1532 Roberts, R.M. 606(291), 635 Roberts, T.G. 1037(227), 1047 Robertson, B.E. 170(45), 211 Robey, R.L. 55(297), 83 Robiller, C. 709(30a), 724 Robins, R.K. 172(63), 211 Robinson, C.H. 968(136), 990 Robinson, L.H. 1101(129),I109 Robinson, M. 502(621, 622), 520, 1442(14), 1503 Robinson, M.M. 580(202), 633,760(129), 864 Robinson, P.D. 962(121), 989 Robinson, R. 728(1), 861 Robinson, R.A. 1055(19), 1105 Rocheville-Divorne, C. 172(59),211 Rochlin, E.M. 1443(22), 1503 Roddy, F. 1263(50), 1300 Rodehurst, R.M. 675(60), 679 Rodellas, C. 187(166),214 Roden, W. 1197(246), I248 Rodes, R. 477(224), 512 Rodgers, A.S. 259, 264(9a), 271
1632
Author index
Rodier, N. 171(50), 211 Rodinovskaya, L.A. 1366(13), 1418(151), 1436, 1438 Rodrigo, R. 927(24), 987 Rodriguez, A. 1014(98b),1045 Rodriguez, H.R. 712(47b), 725 Rodriguez, J.G. 184(143), 213 Rodriguez, 0. 650(26), 678 Roduit, J.P. 499(563), 519 Roelofsen, D.P. 469(51), 508 Roeskv. H.W. 180(112). 212 ~ o ~ e rD.W. s ; 258(14),'261(26), 263(42), 271, 272, 274 Rogers, E.F. 489(400), 516 Roggero, J.P. 172(59), 211 Rokach, J. 1176(187), 1246 Roland, P. 1206(273), 1249 Roller, G.G. 473(159), 511 Rolli, E. 704(19d), 723, 1097(114),1108 Roloff, H. 4R5(321), 514 Romin, E. 944(62), 988 Roman, S.A. 1304(15, 17), 1340(141), 1346(148, 149), 1360, 1362 Romanet, R.F. 740(79), 863 Romanova, O.B. 535(42), 536(45), 581(203), 629, 630, 633 Romer. G. 491f449k 517 Romey, G. 1l<2(237), 1248 Romussi, G. 601, 611(278), 634 Ronau, R.T. 1026(148),1046 Rondan, N.G. 246(154), 254, 875(18), 887 Ronman, P.E. 1165(153), 1245 Ronsmans, B. 476(207), 512 Roothaan, C.C.J. 24(188), 81 Rooyen, P.H.van 179(108), 212 Roschester, J. 184(141),213 Rosen, M. 471(132), 510, 784(201,204), 866 Rosen, M.H. 802(277), 868, 1376(45), 1436 Rosenbaum, J.S. 1202(265), 1248 Rosenblatt, D.H. 486(341), 514 Rosenkranz, G. 503(637), 520 Rosenthal, S.A. 550, 599(95), 631 Rosenzweig, H.S. 975(175), 990 Roskamp, E. 491(477), 517 Rosner, A.L. 1236, 1237(348), 1251 Ross, A.M. 1060, 1062(43a), 1063(56),1106 Ross, L.M. 1352(170), 1363 Ross, S.D. 476(212,213), 512 Rossi, E. 1022(139), 1025(144), 1035(220, 221), 1045, 1047, 1392(82), 1426(174,175), 1437,1439 Rossi, G.V. 1167(164),1246 Rossi, P. 1124(30),1242 Rossi, S. 469(34), 508, 785, 786(213), 866 Rossini, ED. 263(40), 273
Rosso, V.L. 538(54), 630 Rostolan, J.de 476(203), 511 Roth. C. 797(259). 867 ~ o t hEA. , i?(i49), 80 Roth, H.J. 596(257), 634, 1315, 1316(79), 1361 Roth, R.W. 1158(137), 1159(139), 1245 Rotovskii, G.V. 492(497), 518 Rottendorf, H. 320(72), 401 Roubineau, A. 492(490,491), 517 Rougny, A. 1011(82), 1044 Roush, D.M. 1012(93), 1044 Ruussel, J. 492(487), 517 Roux, D. 676(62), 679 Rovnyak, G. 74$(91,92), 863 Rowe, C.D. 746, 806, 807(84), 863, 1003(51), 1030(192).1044. 1046 ~owlett,'R.s.' 1142(81), 1244 Roxell, J.D.Jr. 1284(128), 1302 Roy, D. 1099, 1100(126c),1109 Roychaudhuri, D.K. 484(310), 514 Royer, R. 375, 376(180), 403 Rozinov, V.G. 492(497), 518 Rozzi, A. 1025(147), 1046 Ruan, M:D. 1338, 1346(137b), 1362 Ruangsiyana, C. 539,541(60), 630 Ruangsiyanand, C. 1418(152), 1438 Rubio, V. 626(340,341), 636, 1386(66), 1393(85), 1426(176), 1427(177), 1437, I439 Ruchirawat, S. 930(30), 987 Rudaya, M.N. h(hl), 62(33(1), 78, 84 Rudler, H. 193(201), 215, 1519(94), 1533 Rudorf, W.-D. 1313(53,66), 1316(53), 1360, -1767 --Ruf, F. 500(588), 519, 890(15), 920 Ruggeri, R.B. 1032(197), 1047 Ruis, H. 1170(174), 1246 Ruiz-Upez, M E 40, 42(225), 82, 373(187, 188), 403, 432(119, 120), 436 Rukosueva, A.V. 718(59), 725 Rulev, A.Yu. 500(579), 519 Rumof, P. 488(371). 515 ~um&tsev, EA. 535(42), 536(45), 581(203), 629, 630, 633 Runge, E 491(470), 517 Ruotsalainen, H. 830(339b), 869 Ruooert. K. 14.21(171180 ~ u i i n ~ s i ~ a n a nC.i d555(112), , 631 Rusakov, V.I. 1448-1450, 1481(46), 1503 Riischig, H. 489,502(628,629), 504(385), 515,520,935(44), 988 Russegger, P. 713(49), 725 Russell, G.A. 740(72,73), 863,876, 878(27), 879(28, 29), 887 Russell, M.M. 1222(318), 1250 Russell, S.W. 814(295), 868 ~
~
Author index Russo, C. 10(133), 13(145), 6466,72, 73(133), 79, 80, 225, 226,228(45), 236(85, 87), 251, 252,549(85, 86), 583(215), 617(322,323), 630, 633, 635, 734(39), 749(96), 751(96,97, 102, 112). 752(102), 759(112), 786(220), 836(351), 837(355, 357), 862,864,866,870,1016(109), 1030(189), 1040(243-245), 1045-1047, 1366(17), 1392(83), 1396(94), 1430(186), 1436,1437,1439 Russo, T.J. 1507(7, 14b), 1531 Ruswinkle, L.J. 167(27), 210 Ruthenberg, M. 327(89), 401 Ruzic-Toros, Z. 170(46), 177(87), 211, 212 Ryabova, S.Y. 500(590), 519 Ryabukhin, Yu.1. 1456(68-72), 1504 Ryan, K. 1158(137), 1245 Ryan, K.J. 1147(95), 1244 Ryan, M.J. 1178(198), 1247 Rybalkin, V.P. 411(31), 434 Ryder, A. 1155(118b), 1244 Rynbrandt, R.H. 796(250), 867, 994(13), 1043 Kys, B. (36Y), 1251
Sainsbury, M. 1473(123), 1505 Saisu, K. 442(13), 458 Saito, I. 924(15), 926(19), 987 Saito, N. 776(178), 865, 998(35), 1043 Saito, T. 1295(167), 1302 Sajjad, M. 1201(264), 1248 Sakaguchi, S. 547(81), 630 Sakai, E 764(150), 865 ~akai;M. 917(11$, 921 Sakai, S. 802(273), 868, 1000(44), 1043 Sakamoto, M. 173(68),211, 544(75), 546(80), 630 Sakamoto, T. 569(169), 632 Sakata, H. 448(23). 458 Sakembaeva, S.M. 1507(16a, 18b), I531 Sakman, B. 1206(274), 1249 Sako, Y. 917(119), 921 Sakurai, H. 9(93), 79 Sakurai, T. 470(90), 509 Sakya, S.M. 1034(218), 1047 Salamon, G. 425(85), 435 Salathiel, R. 489(423), 516 Saliou, C. 975(178), 991 Salo, W.L. 504(646), 521, 1463(88),1504
Saad, D. 169(40), 211 Saalfrauk, R.W. 188(174), 214 Saari, W.S. 479(255), 513 Saavedra, J.E. 1512, 1526(51c), 1532 Sabacky, M.J. 979(193), 991 Sable, H.Z. 1255(3), 1257, 1258(24,25), l28l(ll I), 1299, 1301 Saburi, M. 53(281), 83, 735(42,43), 862 Saccarello, M.L. 1382(57), 1392(81c), 1436, 1437 Sachs, W. 1091-1094,1100(102b), 1108 Sacquet, M.C. 596(260), 599(266), 634 Sadan Dam, Y.S. 502(617), 520 Sadee, W. 1202(265), 1248 Sadeghi, M.M. 483(285), 513 Sadek, S.A. 1233,1235(345), 1251 Sadlej, J. 48(242b), 82 Saebo, S. 27(210), 81 Saegura, T. 474(166), 511 Saegusa, T. 776(176), 865 Sagaidak, S.U. 984(219), 991 Sagatys, D.S. 1101(128,129), 1109 Sagitullin, R.S. 587(232), 633 Sahm, H. 1143(86), 1244 Sahota, R.I.K. 986(223), 991 Sahr, H. 914(114),'921' Saigo, K. 749(93), 772(168), 863, 865, 998(31), 1043 Saiki. T. 924. 925(10). 987 ~aiki'yeva,s . L . 688(24), 694 Sain, B. 1013(94), 1044
~ammes,M. 1020(122), 1045 Sammes, M.P. 13, 14, 16(147),80, 186(156), 213,225(44), 228(53), 251, 252 Sammes, P.G. 1327,1337(115),1362 Sampo, K.K. 506(660), 521 Samson, Y. 1200(258), 1226(327), 1248, 1250 Samuel, S.D. 261(26), 272 Sanchez, A.G. 535(43), 629 Sanchez, E. 944(62), 988 Sanchez-Cabezudo, M. 707(27d), 722(80), 724, 726 Sanchez Marcos, E. 373(185-188), 381,387, 388(185, 186), 403, 415(52), 416(52,54), 431(107, 110). 432(54, 110, 117, 119, 120), 433(52, 123),'435, 436 Sbncbcz-Marcos, E. 40,42(225), 48(245,251, 252). 76(367), 82, 85, 243(128), 253,381, 385.386(193). 387(193.195). , . .. 388.391. 394(193); 403' Sanchez Marcos, F. 719(67a), 725 Sande, M.A. 1201(263),1248 Sander, H. 484(300), 514 Sandhu, J.S. 1013(94), 1044, 1561(68),1565 Sandifer, R.M. 1522(101), 1533 Sandmeier, R. 978(183), 991 Sandorfy, C. 63(335), 64(351), 84, 85 Sandstrom, J. 14, 18(157),80, 231(61), 236, 242(95), 252, 298(35), 400,407(5, 11, 13), 408(25), 414(43), 418(64-66), 419(68,71), 422(71,72,74,77), 423(68,71, 77,79-82),
1634
Author index
Sandstrom, J. (cont.) 424(77,79-82),425(86),
426(90), 431(104, 108,log), 432(86), 433(64), 434436,561(145),632,719(68i), 725,1307(2&28), 1313(27,61), 1360,1361 Sandstrom, J. 175(76), 184(141), 211,213 Sanfilippo, A. 1188(222), 1190(230), 1247 Sangster, D.F. 681(1), 693 Sanitanin, Z. 462(7), 465,955(98), 989, 1404(113), 1438 Sannicolb, F. 979(191), 991 Sansius, A. 530(17), 629 Sansoulet, J. 969(145), 990 Santaballa Lopez, J.A.1060,1077,1099, 1101,1103(36), 1105 Santana-Tavares, G. 1507(20a), 1531 Santini, G. 9(119), 79,440(9), 458,477(228, 229), 512 Sanz. J.E 431(107). 436 saqui-~annes,'G.d;'481(268), 513 Sardana, M.K. 1241(359), 1251 Sardana, V. 502(614), 520,575(188), 633 Sarkanen, S. 1512,l526,1527(45b),1532 Sarkisova, E.A.481(271), 513 Sarokhvostuva, V.E. 987(231), 992 Sanhou, P. 1507(18a), 1531 Sarthov, P. 1507(20b), 1531 Sasaki, 0. 916(118), 917(118, 119), 921 Sasaki, T. 644(13), 677,1353(173), 1363 Sasamori, H.929(27), 987,1542(16), 1564 Sasse, P.A. 496(532), 518 Sastre, J. 1198(248), 1199(250,25I), 1200(260), 1209(284), 1248,1249 Satchell, D.P.N. 1102(134), 1109 Satish, A.V. 1257(23), 1299 Sato, C.929(27), 987,1542(16), 1564 Sato, H.829(330), 869,1014(97), 1045 Sato, K.612(309,311), 635,1184(212), 1247 Sato, N. 32,~3(217),81 Sato, S. 170(47), 211,776(177), 865 Sato. T. 178199). 212.482(280). 513. Sato, . i9(8j,1i8),78,'79,475(184,
185), 511,845(389),871,1094,1095, 1102(107a), 1108,1324(107), 1362 Sattar, A.B.M.A. 649(24), 678 Sattler, K.538(53), 630 Sdyamurthy, N. 471(121), 510 Satyanarayana, N. 968(140), 990 Satzinger, G. 1546(28), 1564 Sauer, J. 55(293), 58(320), 83,84,224(34), 251,302,303,310,311(48), 400,479(258, 260), 480(258), 513,994(3), 1008(70), 1034(217), 1043,1044,1047,1349(164), I363 Sauers, R.R. 475(174), 485(328), 511,514, 981(200), 982(206), 991 Saugier, J.H. 1175(184), 1246
Sauleau, A. 896,897(55), 920,975(173, 174),
990 Saunders, D. 1229(340), 1250 Saunders, E.K. 558(122), 631 Saunders, J. 1304,1308,1310,1324(10), 1359 Saunders, M. 258(14), 271 Saunders, M.I. 1128(45), 1243 Saunders, P.P. 1195(241), 1248 Sauter, H. 601(279), 635 Sauve, G.507(685), 521 Sauvt, J:P. 1562(71), 1565 Savkant, J.M. 953(95), 989 Savignac, A.de 7(64), 78,896(51,52),
898(52), 920 Sawaki, Y. 952(89), 989 Sawamura, M. 474(166), 511,776(176), 865 Sax, M. 173(67), 211,1261,1281(42), 1300 Sayer, B.G. 1216(307), 1250 Sayo, H.476(208,211),512 Sayre, L.M. 952(91), 989 Sazonov, S.K. 571(176), 632 Scahus, J.M. 245(141), 253 Scanton, K.49(264), 83 Scardiglia, F. 473(155), 511 Scendes, I.G. 476(198), 511 Schaafsma, S.E. 470(80), 509 Schachschneider, G.1240(357), 1251 Schade, A. 1206(275a), 1249 Schaefer, EC.491(472), 517,1444,1445(37),
1503 Schaefer, H. 1304,1311,1313(6), 1359 Schaefer, J.P. 733(37), 816(3 . 03), . 862,868 Schaefer, T. 299(39),400 Schafer, H.538(53), 607(295), 630,635,
954(96.97). 989.1313.1315(52). ~ c h i f e r , ' ~4 .6~1(.5), 462(6), 464,465,
569(171,172),632 Schafer. R. 1555(47). 1564 ~challei,R. 49663ij,518,1546(27), 1564 Schamp, N. 9(90), 78,256(1c), 270,444,
445(16), 458,506(656), 521,731(10),861 Schank, K. 578(199), 610(302), 633,635,
939(50,54), 988 Scharer, D. 1021(124), 1045,1381(55), 1436 Scharf, A.T. 1156(130), 1245 Schaub, R.E. 1507(25), 1531 Schaumann, E. 170(48), 211,1017(115), 1045,
1368(20), 1423(163,164),1436,1439 Schaus, J.M. 1510(40), 1532 Schechter, H.486(342), 514 Scheck, T. 598(265), 634 Scheef, W. 1196(242), 1248 Scheeren, J.W. 1017(116), 1045,1368(21),
1436 Scheffel, U. 1204(269), 1248
Author index Scheffold, R. 669(53), 678, 901(74), 921 Scheibe, H. 1091,1093(100), 1108 Scheiber, L. 797(255), 867 Scheibye, S. 171(54),211 Scheidegger, U. 240(113,118), 253,353(138), 355(137, 138), 356,357(137), 402 Scheinbaum, M.L. 469(48), 508, 714(52), 725, 837(359), 870 Scheiner, P. 816(302), 868 Scheinmann, F. 572(180), 632 Schell, E.M. 652(32), 653(35), 657(39,40), 667(40), 668(32), 678 Schellenbaum, M . 746(82), 863 Schellenberger, A. 1255(5, 12), 1275(80), 1279(98, 105), 1281(105),1299, 1301 Schempp, H. 784(200), 866, 1348(158,159), 1363 Schenk, K. 740(74a), 863, 880, 882(33), 887, 984(217), 991 Schenker, K. 488(361), 515 Schenone, P. 185(147), 213,494(515), 518, 600(271), 601(272-278), 602(280), 604(283, 284), 611(278), 634, 635, 834(348), 870, 975(172), 978(181), 990, 991 Schepherd, R.C. 1308,1322, 1340, 1357(31), 1360 Schepp, N.P. 1060(34,35b, 37,40), 1061(37), 1083(87), 1097(121), 1098(34,35b, 87, 88, 117, 121), 1103(34,35b, 37,40), 1105-1108 Scherer, H.J. 994(20), 1043, 1377(49),1436 Scherer, J. 964(124), 989 Schick, H. 10(132), 79, 542(61, 62), 544(69), 630, 1372, 1401(34), 1436 Schied, D. 471(110), 510 Schielein, E 289, 291, 318, 344(16), 399, 761(133), 864 Schiemenz, G.P. 490(444), 517 Schierhorn, A. 1313, 1316(53), 1360 Schiewald, E. 722(81), 726 Schildberg, M . 188(173),214 Schinzer, D. 548(84), 630 Schioppacassi, G. 1190(230), 1247 Schlack, P. 491(471), 517 Schlag, W.-R.994(22), 1043, 1377(48), 1436 Schlecht, M.E. 1011(81), I044 Schlegel, H.B. 24(185), 81, 875(18), 887 Schlegel, J.M. 955(99), 989, 1262(48), 1300 Schlesinger, A.H. 971(151), 990 Schlessinger, R.H. 695(1h), 723, 740(79), 863 Schleyer, P.v.R. 24(181), 81,387(202), 403 Schloss, J.V. 1277(92), 1278(95), 1301 Schlosser, M . 714(53a, 53b), 725, 1512(46c, 54), 1526,1527(46~),1532 Schlueter, J.A. 62, 63(331), 84
Schmid, A. 1192(237),1248 Schmid, H. 488(368), 515,736(55), 863 Schmid, R. 482(282), 513 Schmidt, A.O.R. 593(249), 634 Schmidt, A.W. 1158(136),1245 Schmidt, D.E.Jr. 1283(120),1301 Schmidt, H. 1434(195), 1439 Schmidt, H.W. 552(102), 631 Schmidt, R.R. 713(49), 725, 1446(40), 1447(41,42), 1451(41,57, 58), 1461(40), 1473(41,57,58, 120-122), 1474(129), 1475(58, 131), 1499(57,58, 121, 122), 1502(122), 1503-1506 Schmidt, V. 939(54), 988 Schmidtchen, F.P. 1261(46), 1300 Schmidt-Dunker, M.S. 478(241), 512 Schmidt-Thomt, J. 489,502(628, 629), 504(385), 515,520, 935(44), 988 Schmiegel, K.K. 749(95), 805, 806(289), 864, 868 Schmitt, E. 845(387b), 871 Schmitt, J . 978(182), 991 Schneider, B. 612(308), 613(315,316), 615(317), 621(328), 635 Schneider, G. 1261, 1266, 1283(40), 1300 Schneider, 0 .502(630), 505(648), 520, 521 Schneider, R. 1495(153), 1506 Schneider, W. 470(79,86), 471(112,113), 484(296), 509,510,513 Schnering, H.G.von 186(158), 188(174),213, 214, 940(57), 988, 1420(157),1439 Schoeeller, W.W. 950(83), 988 Schoeller, W.W. 459(1), 464 Schoeni, J.P. 427, 428(97), 436 Schoknecht, A. 370(163), 403 Scholler, W.W. 1091, 1093, 1094, 1100(102a), 1108 Schollkopf, K. 1091,1093, l094,1100(102d), 1108 Scholz, D. 784(208), 866 Schomacker, R. 1091,1093, 1094, 1100(102a), 1108 Schon, N . 1319(94),1361 Schonwtilden, K.H. 1091,1093, 1094, 1100(102d), 1108 Schopf, C. 488(358,363), 491(447), 515, 517 Schouteelen, A. 1512(48b), 1532 Schowen, R.L. 1255(5), 1263(52), 1279(103-105), 1281(105), 1299-1301 Schraml, J. 366, 367, 371(159), 402 Schreibe, G. 232(66), 252 Schreiber, K. 485(324), 514 Schreiber, S.L. 1032(196, 198), 1047 Schrimer, R.E. 1169(169), 1246 Schroder, G. 488(363), 515 Schroeder, M . E . 1304(16), 1360
Author index Schroll, G. 236(82), 252, 439,440(8), 441(11), 444, 445, 447, 449(8), 458, 770(165), 865 Schroth, W. 1443(32), 1471(115), 1502(158), 1503,1505,1506 Schrotter, E. 542(61, 62), 544(69), 630 Schubert, H.W. 64(343, 350), 67(343), 70(350), 74(343), 84, 85, 469(28), 508, 1051(9), 1105 Schubert, S. 740(74a, 74b), 863, 874, 875(11), 880(ll, 32,33), 881(11,32), 882(33), 887, 984(215-217), 991 Schubert, W.M. 1091(99), 1092(106a, 106h), 1093(99), 1101(106a, 106b), 1108 Schubiger, P. 1226(328), 1250 Schuck, J.M. 469(44), 508 Schuda, P.F. 500(597), 520, 971(154), 990 Schueter, J.A. 372(171), 403 Schulemberg, J.W. 695(1d), 723 Schulman, E.M. 793(240), 867 Schulte, G.K. 1026(148), 1046 Schultz, A.G. 181(123), 213, 489(380), 515, 621(331), 636, 647(18a, 18b), 648(21), 677, 768(156), 865 Schultz, D. 475, 498(180b), 511 Schultz, D.J. 471(97), 509 Schulz, C.R. 475(178), 511,983(210), 991 Schulz, ti. 1308(35), 1360 Schulz, G.E. 1291(151), 1302 Schulz, H. 484(303), 514 Schulze, H.H. 491(449), 517 Schulze-Steinen, H.J. 491(453), 517 Schumacher, J. 1034(214), 1047 Schumann, D. 484(303,304), 485(320), 489(379), 514,515,927(25), 987 Schunack, W. 1227(331), 1250 Schuster, D.I. 650(28), 678 Schul, R.N. 749,816(94b), 864 Schutz, F. 188(174), 214 Schutz, J. 1495(153), 1506 Schuyl, P.J.W. 823(319), 869 Schwab, W. 1529(115a-c, 116), 1533 Schwalbe, C.H. 14, 21(166), 80, 243(126), 253, 373(176), 403,412, 433(37), 434, 719(67b), 725 Schwartz, W. 1180(200), 1247 Schwarzenbach, G. 488(362), 515 Schweinsberg, F. 1560(61), 1565 Schweitzer, E. 1184(213), 1247 Schweizer, E. 1121(21), 1242 Schweizer, E.E. 473(150-152), 510, 1381(54), 1436 Schweizer, W.B. 248(180), 254,474(163), 499(575), 511, 519, 760, 776(118a), 864, 1507(6), 15.31 Schwenner, E. 1206(273), 1249 Schwiecker, U. 761(132), 864 Schwille, D. 1451(58), 1473(58, 121, 122),
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~
,- -
--
Schworer, F. 684(15), 693 Schwotzer, W. 32,42(212), 81, 231(62), 252, 294-299,347,349-351,357,380(33), 400, 709(30b), 724 Sciavovelli, 0. 492(495), 517 Scilimati. A. 492(495). 517 ~cnhabel,R. 258(13):271 Scola, P.M. 1442, 1443, 1446, 1461(7), 1503 Scolastico, C. 944(67), 988 Scorrano, G. 1098, 1103(118), 1108 Scott, A. 1286(145), 1302 Scott, J.W. 249(192), 254, 769(158), 865 Scott, R.D. 659(45a), 661(45a, 46), 662(48), 6.. 78 . Scozzafava, A. 1142(83), 1244 Scripko, J.G. 1217(311), 1250 Sebek, O.K. 971(156), 990, 1544(21), 1564 Seden, T.P.1393(84), I437 SedlAkovP, D. 489(407), 516 Seebach, D. 58(320), 84, 192(197), 215, 222(21), 248(179-181), 249(179), 251, 254,472(145), 474(161, 163, 164, 172), 480(145), 494(507), 499(574577), 510,511,518,519,715(57~,58d),725, 760(118a-c, 119), 776(118a, 118b). 816(306), 826(323), 864, 869, 1003, 1005(57,58), 1006(67), 1044, 1507(6), 1512(47,53a, a ) , 1531, 1532 Seeger, R. 24(185), 25(193), 81 Seelen, W. 536(50), 630 Seeles, H. 489(419), 516 Seeman, P. 1206(271), 1248 Seemuth, P.D. 478(243b), 512 Segre, A. 468(21), 508 Sehring, S. 1175(185),1246 Seibl, J. 63(340), 84 Seido, N. 1136(64), 1243 Seifert, M. 1338(136), 1362 Seiffert, W. 232(66), 252 Seip, R. 418(59), 435 Seitov, A.Z. 688(24), 694 Seitz, D.E. 1236(348,349), 1237(348), 1251 Seki, F. 1507(21), 1531 Seki, T. 787(228), 867 Sekioka, M. 785(209), 866 Sekiya, M. 772(166), 782(198), 865, 866 Selin, T.C. 491(473), 517 Sell, R. 596(259), 598(264), 634 Selner, M. 1155(121b), 1244 Semenov, V.V. 1322(102), 1361 Semmelhack, M.F. 470(61), 509 Sempere, E. 240, 241(109), 253, 360, 361, 363(149), 402 Sen, N. 14, 18(157), 80, 177(86), 212, 419(67), 423, 424(81), 435
Author index Scnaratnc, K.P.A. 736(59), 863,912(112), 921 Senderoff, S.G. 1186(217),1247 Senning, A. 180(113), 212,414(47), 435 Sensi, P. 1152(109), 1244 Sensing, H. 1206(277), 1249 Sentenac-Roumanou, H. 1183(209), 1184(210), 1247 Seoane, C. 14(160),80 Sepulveda, L. 1079,1089,1091(80), 1107 Sepulveda-Arques, J. 186(157),213 Sergienko, L.M. 492(497), 518 Scrmck, V. 907(101), 921 Serrano, J.A. Y44(62), 988 Sesana, G. 874(7), 887 Seuhe, S. 1313(57), 1360 Scufert, W. 789(233), 867 ~eufert;W.G. 950(83), 988 Seuring, B. 1512(47,64), 1532 Severin. S.E. 1274(75). 1278196). ,,1300. 1301 severin; T. 740(81j, 863 Sevems, B. 1170(173),1246 Sevin, A. 25(204,205), 48(248), 81, 82, 857(402), 871 Sevrin, A. 1232(343), 1250 Seyferth, D. 493(504), 518 Sgarabotto, P. 167(21, 23), 183(137), 187(167), 189(137), 210, 213, 214 Sha, C;K. 621(331), 636 Shabana, R. 627(344), 636,1034(209,210), 1047, 1404(114), 1438 Shah, K.R. 552(106), 631 Shaik, S.S. 874(13), 887 Shaikhutdinov, Ye.M. 688(24), 694 Shainyan, B.A. 4, 7, 32(36), 77, 889(7), 919 Shakked, Z. 168(28), 172(61),210,211 Shalom, E. 169(40),211 Shamma, E.M. 490(442), 516 Shanan-Atidi, H. 14, 17, 18(153),80, 232(65), 241(121), 252, 253, 360(150), 402, 407(6, 8), 414(6,44), 434 Shane, H.P. 1222(318), 1250 Shani, A. 1412(134),1438 Shannon, P. 489(380), 515 Shapet'ko, N.N. 394(211), 404 Shapiro, R.H. 1512(49), 1532 Sharanin, Yu.A. 1366(13), 1418(151),1436, 1438 Sharma, A. 168(32), 210 Sharma, V.K. 986(223), 991 Shalzmillcr, S. 169(40),211 Shavel, J. 1400(104), 1437 Shavel, J.Jr. 573(185), 633 Shavitt, I. 24(186), 81 Shaw, B.R. 1178(197),1247 Shaw, D.R.D. 1176(188), 1246 Shaw, G. 1033(206), 1047 Shaw, G.S. 247(172), 254 \
Shaw, J.E. 544(71), 630 Shaw, K.N.E 1170(176), 1246 Shaw, P.E. 471(115), 510 Shaw, R. 259, 264(9a), 271 Shchclokov, R.N. 174(75), 211 Shcherbakov, V.V. 283, 287, 289, 294, 298, 339, 354(9), 399 Shealy, N.L. 1522(101),1533 Shealy, Y.E 944(64), 988 Shcinkcr, Y.N. 500(590), 519 Sheinker, Yu.N. 559(130), 631 Sheldon, P.W. 1128(41,43), 1243 Sheldrick, G.M.173(69), 180(112), 188(177), 189(180). 211.212.214.610(304). 635 sheltbn, M.E. 1222(Gl), 1250 Shemyakin, M.M. 1286(133),1302 Shen, J.T. 489(433), 516 Shepherd, D.A. 944(63), 988 Sheppard, A.C. 947(78), 988 Sheppard, G. 800, 804, 817(267), 843(379), 844, 845(385c), 868, 870, 871, 998, 1005(41), 1043,1555(48), 1564 Sheptun, I.N. 499(570), 519 Shering, A. 1117(4), 1242 Shenvood, J. 1175(185), 1246 Shenvood, L.T.Jr. 494(508), 518 Shcstopalov, A.M. 1366(13), 1418(151), 1436, 1438 Shetty, H.U. 1118(5), 1242 she&, M.M. 502('617), 520 Shi, Q.X. 1239(355),1251 Shi, X. 899(66), 920, 1313(63), 1361 Shihaeva, N.V. 1448-145lX47.49). 1467-.1469(102), 1471(113), 1472(116, 117), 1475(102), 1480(117), 1481, 1484(47,49), 1485(141, 142), 1486(141), 1487(102, 141), 1488(141), 1489(141, 142), 1490(142), 1492(102,113, 142), 1493(142), 1494(49), 1497(49, 141, 142), 1499(116, 155, 156), 1501(157), 1502(116), 1503-1506 Shibasaki, K. 1391(78), 1437 Shibasaki, M. 1537(7,8), 1563 Shibata, K. 550(93), 631 Shibazaki, Y. 1347(155),1363 Shibuya, I. 1473(118, 119, 124), 1499(118, 119), 1505 Shields, A.E 1162(147), 1245 Shih, C. 1154(115), 1244 Shih, Y.H. 530(24), 629 Shiiya, K. 965(132), 990 Shimaoka, K. 1260(38), 1300 Shimizu, E. 192(196),215 Shimizu, H. 190(185),214 Shimizu, N. 183(132), 213 Shimoni, M. 1167(157), 1245
1638
Author index
Shims, 1. 1024(143), 1045 Shin, C. 5(57), 78, 1459(80), 1504 Shin, W. 173(67), 177(92), 186(159), 188(176), 211-214 Shinada, T. 641(6c), 677 Shiner, C.S. 9(117), 79, 712, 714(48a), 725 Shinkagi, T. 1017(113), 1045 Shinkai, S. 1259(34-36), 1300 Shioiri, T.802(285), 868, 1028(173), I046 Shiokawa, K. l307,1313(24h), 1314(78), 1328(24h), 1360, 1361 Shirai, H. 9(87), 78, 1324(107), 1362 Shiraki, W.W. 1142(81), 1244 Shirley, D.A. 704(17), 723 Shirley, K.R. 979(194), 991 Shiro, M. 169(36,37), 187(160), 210, 214 Shiue, C.-Y. 1227(332), 1250 Shklyaev, V.S. 475(186), 511,973(163), 990 Shmueli, U. 14, 17, 18(153),80, 360(150), 402, 407(8), 434 Shofield, K. 471(137, 138), 510 Shoji, 1. 169(36), 210 Shold, D.M. 52(279), 83 Shono, T. 247(174), 254,459(2), 462(8), 463(9a, 9h, lo), 464(11), 464, 465, 769(157), 865, 957(102), 959(106, 107), 989, 1029,1030(187), 1046,1443(31), 1503 Shostakovskii, M.E 688(26), 694 Showalter, H.D.H. 1156(124), 1245 Shreve, D.S. 1281(111), 1301 Shu, A.Y.L. 1164(152),1245 Shukla, U.R. 485(321), 514 Shusherina, N.P. 1451(59), 1504 Shute, R.E. 187(165), 214 Shutske, G.M. 538(52), 630 Shvarts, G.Y. 535(42), 536(45), 581(203), 629, 630, 633 Shvo, Y. 14, 17, 18(153), 80, 221(13), 232(64, 65), 241(13, 121), 251-253,360(150), 402, 407(6, X), 414(6, 44, 45),432(112, 113), 434, 436, 1474(130), 1506 Sidani, A. 476(205), 512 Siddall, T.H. 246(159), 254 Siddhanta, A.K. 313,315(65), 401 Siegel, M.G. 664, 670(50), 678 Siegel, M.I. 1175(185),1246 Siegl, A. 354, 357(135), 402,719(68c), 725 Sielisch, T. 185(149), 213 Sieveking, H.U. 506(661), 521 Sieveking, S. 1017(115),1045, 1368(20), 1423(163,164), 1436,1439 Sigimura, T. 1184(211), 1247 Sigmund, G. 1308(35), 1360 Silberman, N. 1169(170), 1246 Silver, A.R.J. 1128(42,48), 1243 Silverman, R.B. 1295(161, 163), 1302 Silvestri, R. 608(296), 612(312), 635
Sim, G.A. 174(73),211, 746(86), 820(311), 863, 869, 1164(151), 1245 Simandoux, 1.-C. 1092,1101(106d),1108 Simchen, G. 971(153), 990 Simkins, N.S. 579(201), 633 Simmerl, R. 1466(100, 101), 1505 Simmons, J.W. 431,432(105), 436 Simmons, R.L. 1226(330), 1250 Simms, J.A. 67(344), 84 Simon, A. 14, 21(171), 80 Simon, E.S. 1295(167), 1302 Simon, H. 712(46g), 725 Simon, K. 169(38), 210, 1416(147), 1438 Simon, W. 63(340), 84,369(166), 403 Simonds, W.E. 1153(113), 1244 Simonet, 1. 461(4), 464, 958(104), 989 Simoni, D. 500(591), 519,577(195), 633, 765(152), 865, 968(137), 990 Simonnin, MP :. 169(39), 211 Simonsen, S.H. 13,1'4, 16(147),80, 225(44), 228(53), 251, 252 Simonvan. L.A. 1443(22h 1503 ~ i m ~ s o m ,1011(86), '~. 1044 Simpson, R. 814(294), 868, 1548(34,36), 1550(36,37), 1551,1552(34), 1564 Sims, M. 178(96), 212 Sindeli?, K. 487(356), 515 Sing, Y.L. 1188(220), 1247 Singaram, B. 832(341,342), 834(346), 869 Singer, G.M. 1512, 1526(51c), 1532 Singh, H. 368(162), 403, 1188(221),I247 Singh, 1. 502(614), 520, 575(188), 6-73 Singh, 0. 170(44), 211 Singh, P. 368(162), 403 Singh, R.K. 912(110), 921 Singh, S. 501(601), 520,986(223), 991 Singh, T.P. 166(18),210 Sinharay, A. 1317(89), 1361 Sinke, G.C. 262, 263(34a), 264(45), 267(34a), 273. 274 ~innh"her, R.O. 1157(132), 1245 Sion, R. 1l!X(239), 1248 Sircar, J.C. 501(60l, 603), 520 Siret, P. 221(8, 9), 222, 224(24), 251, 304, 308. 309(50). 400. 468(17. 22). 471(99). ~irokm'an;E 1167(158), 1245 Sirrenherg, W. 486(334,335), 514 Sitaram, N. 1117(3), 1242 Sitkina, L.M. 411(31), 434 Sivakumar, R. 960(109), 989 Sizer, LW. 1286(140), 1302 Sjoherg, S. 1207(281), 1249 Sjostrand, U. 419(68, 71), 422(71, 72, 74), 423(68,71, 79), 424(79), 432,433(121), 435, 436, 1307(28), 1360 Skattehol, L. 556(118), 631
Author index Skeean, R.W. 1144(90), 1244 Skoglund, M.J. 56(302), 84, 1061, 1062(46b), 1106 Skoldinov, A.P. 1443(23), 1503 Skorynin, I.Yu. 18(244), 82 Skotsch, C. 6(58), 78, 333,334(105), 401, 526(5), 591(243,244), 629, 634 Skurskq, L. 491(461,463), 517 Slade, P. 486(347), 514, 764(142), 865 Slaydcn, S.W. 259(10), 271 Slehocka-Tilk, H. 1072(75),1107 Sliwa, H. 1034(208), 1047 Sloan, B.J. 1155(120),1244 Slomp, G.Jr. Y44(63,64), 988 Slopianala, M. 905(90), 921 ~luiter,M.A.T. 539(59), 630, 1415(142), . . 1438 slyier, K.A. 555(116), 631 Smallridge, M.J. 1329, 1332(120), 1362 Smetitkovi. M. 489(391). 515 Smiekus, ~.'501(60d,60$, 520 Smily, R.H. 1507(2b), 1531 Smirnov, V.A. 1443(25), 1503 Smirnov, VE 8(75), 78 Smit, R. 1368(21), 1436 Smith, B.J. 25, 28, 29(207), 81, 256, 265(6), 271, 705,712(25), 724 Smith, B.L. 262,267(38), 273 Smith, D. 236(93), 237(108), 252, 253, 36M148). 402. 719(68fl. 725. 891(28). 920 smith, G.F. 709(32hj,' 724,1170(175), 1246 Smith, G.M. 550,599(95), 631 Smith, H.A. 1167(162), 1246 Smith, H.G. 1170(172), 1246 Smith, H.M. 1508(28), 1531 Smith, J. 246(156), 254 Smith, L.R. 492(500), 518 Smith, M.B. 456(45), 458 Smith, N.K. 264(52b), 275 Smith, P.J. 476(209), 512 Smith, R. 1017(116),1045 Smith, R.E. 1453(66), 1504 Smith, S.L. 1138(66),1243 Smith-Magowen, D. 266(58), 275 Smolanoff, J. 676(63), 679 Smolck, K. 489(406,414), 516 Smolij, O.B. 1442(9), 1503 Smolinski, B. 240(116), 253 Smolka, S.J. 478(243d), 512 Smrckova, S. 907(101), 921 Smuszkovics, J. 969(142), 990 Smyth, J.F. 1156(122b), 1245 smith, M.S. 740(80), 863 Smyth, T. 1255(17), 1276(86), 1299, 1301 Snatzke. G. 380(192). 403 Snell, E:E. 1286(13~:139), 1288(146), 1302 Snider, B.B. 1400(103), 1437
1639
Snieckus, V. 936(45), 988, 1040(247), 1048 Snowden, R.L. 1011(79,84,85), 1044,1546, 1547(30), 1555(46b),1564 Snyder, D.C. 841(364), 870,984(213,214), 00 ,,7-
Snyder, E.R. 1283(119),1301 Snyder, J.K. 939(53), 988, 1529(117), 1533 Snvder. , . R. 1135(61). 1243 Snyder, S.H. 1208(282), 1249 Snyder, W.H. 55(292), 83,479, 480(257), . . 513 SO; S. 816(299), 868' Sodd, A. 1177(195), 1178(197), 1246,1247 Soeda, H. 1026,1027(165), 1046 Soelistyowati, R.D. 291(26), 399, 1541(14), 1564 Sofia, R.D. 1196(243),1248 Sohir, P. 358(143a), 402,1396(95), 1437 Sokolov, N.A. 499(569), 519,1424(165), 1439 Sokolskii, G.A. 1466(99), 1505 Solans, X. 14, 18(152), 80 Soldan, E 1314(7'3), i361 Sollenherger, P.Y. 52(271), 83, 220(11), 223(31), 251,709(31), 724,1051-1054, 1056.1057. 1065. 1066(13). 1069(71). 1101, 1103(13), 1'105, 1107 Soloway, A.H. 1177(194), 1246 Soloway, S.B. 1304(15, 17), 1340(141), 1360, 1362 Somawardhana, C.W. 1201(264),1248 Sommer, S. 837(356a, 356b), 870, 1388(72a, 72h), 1437 Sommer, U. 1451, 1473, 1475, 1499(58), 1504 Sommerville, P. 1011(86), 1044 Son, P.N. 1348(160), 1363 Soncrant, T.T. 1118(5), 1242 Sondheimer, F. 1507(22), 1531 Sonc, M. 1313,1315(51), 1346(151),1360, 1363 Sone, T. 1003(53), 1044 Sonn, A. 491(468), 506(664), 517, 521 Sonnet, P.H. 1514(78),1533 Sonoda, N. 981(197), 991 Sonola, 0.0. 1526(112), 1533 Sonveaux, E. 1318(91b), 1361 Sood, A. 1178(196), 1246 Sorensen, K. 1170(172), 1246 Sorensen, T.S. 52(277), 83 Sorgi, K.L. 247(169), 254 Sorm, E 489(393,405), 515, 516 Sosa, C. 875(18), 887 Sosnovskikh, V.Y. 502(619), 520 Soti, E 1366(9), 1435 Sotiropoulos, J. 1313(57), 1360 Sotnikov, N.V. 1466(99), 1505 Soubeyrand, J. 1119(12), 1242
1640
Authc)r index
Sowinski, F. 1120(15),1242 Sozzi, G. 45 1(32), 458 Spangler, R.J. 978(186), 991 Spasskii, S.S. 686(20), 693 Spath, E. 491(454,455), 517 Speckamp, W.M. 539(59), 630 Speckamp, W.N. 247(173), 254, 555(116), 631, 919(124), 922, 1003(55), 1044, 1415(142), 1438,1442(3,4), 1443,1444,1447,1470, 1493,1497(3), 1502 Spellmeyer, D.C. 875(18), 887 Spencer, R.L. 189(179),214 Spcncer, T.A. 749(95), 805,806(289), 864, 868, 1507, 1508(26), 1511(43), 1512, 1526(50a), 1531,1532 Speranza, M. 704(19e), 723 Sperling, E.M.G. 1169(171), 1246 Sperna Weiland, J.H. 471(120), 510 Spero, G.B. 971(156), 990, 1544(21), 1564 Speziale, A.J. 492(499,500), 493(499,503), 518, 735,737(49), 862, 1064(60), 1106,' 1537(4), 1563 Spielvogel, B.F. 1177(195), 1178(196, 197), 1246. 1247 Spies, H. 1395(93), 1437 Spiess, G. 1444(34), 1503 Spille, J. 1449, 1481(50), 1504 Spinks, J.W.T. 681(2), 693 Spitzer, T.D. 188(170),214 Spitzer, W.A. 176(82), 212 Spohn, K.-H. 6(58), 78, 589(237), 634 Sprague, J.M. 1263(51),1300 Sprangler, R.J. 978(185), 991 Springer, J.P. 168(29), 180(116), 181(123), 182(129),210, 212, 213, 550(94), . ,. 631,. 653(33,36), 657(42), 678 Sprintschnik, H. 542(63), 593, 609(248), 630, 634 Sprio, V. 1422(162a, 162b), 1439 Spriigel, W. 9(110), 79, 793(239), 867 Spry, D.O. 176(82),212 Sreenivasan, R. 1306, 1313, 1320(20), 1338(135), 1342(20,142,143), 1344(144, 145). 1353(172), 1358,1359(184), 1360, 1362,1363 Sreenivasan, S. 1324(105),1362 Srivastava, P.C. 1224, 1225(325), 1250 Stadeli, W.347-349,352(133), 402 Stadlwieser, J. 1011(80), 1044 Stafford, J.E. 470,496(60), 509, 944(63), 988, 1062(52), 1106, 1537, 1538(3a), 1563 Staley, R.H. 704(16a), 723 Stam, C.H. 177(88), 191(191),212,214 Stamhuis, E.J. 8(73), 52(274), 78, 83, 709(34), 710(40a, 40b), 724, 1051(11a-d), 1052(llc), 1053(11a-d), 1054, 1055(11b,
llc), 1056(11a-d), 1057(11d), 1061(11h, llc), 1065(11a-d, 67), 1066(11d, 67), 1067(11d), 1068(11h), 1069, 1070, 1072, 1073(11d, 67), 1075, 1076(67), 1081, 1090(11a-d), 1092(11a-d, 67), 1105,1107 Stamm, T. 994(24), 1043 Stamos, LK. 1366(18), 1436 Stankevich, E.I. 550(97), 631 Starikov, A.G. 1468, 1471, 1481(112), 1505 Starikova, Z.A. 187(161), 214 Stark, E. 6(58), 78 Starr, D.E 489(421), 516 Starren, J.B. 1120(20), 1242 Staunton, J. 1286(145), 1302 Stavaux, M. 179(109),212, 1034(213), 1047 Staversky, R.J. 1295(166), 1302 Stavrovskaja, A.V. 1443(23), 1503 Steadman, T.R. 489(424), 516, 1453(65), 1504 Steel, P.J. 526(8), 629,722(83), 726 Steele, W.V. 264(52b), 275 Steen, K. 904(82,83), 921 Stefancic, G. 608(296), 635 Stefancich, G. 612(312), 635 Stefaniak, L. 294, 347(31a-c), 400 Stcffc, T.J. 1142(77, 78), 1243, 1244 Steffen, R.P. 530(24), 629 Steger, L. 530(21), 629 Steglich, W. 775(174), 865, 1039(240), 1047 Stehr, E. 489(424), 516 Steieel. A. 621(328). 635 Steiie, Th. 32?(89j; 401 Stein, M.L. 491(466), 517 Stein, N. 484(308), 514 Steinberg, H. 470(72,8(1, XS), 509 Steinfels, M.A. 802(278, 280), 868 Steinhardt. C.K. 488(377), 515 Stella, L. 525(3), 629 Stclla, V.J. 500(589), 519 Stclzcl. H.F! 536(44). 630 stenvail, K. 14, i8(i57), 80, 175(76), 211, 423,424(81), 435 Stephanidou-Stephanatou, J. 190(187),214 Stcphcn, J.E 11(142),80, 471(128), 510 Stephenson, D.K. 486(336), 514 Stephenson, E.F.M. 1149(98), 1244 Sterchi, A. 525,592(2), 629 Stercho, Y.P. 960(109), 989 Sternberg, J.A. 372(174), 403 Sternhell, S. 231(60), 252,320(72), 369(166), 401, 403 Stetin, C. 474(171), 511, 843(371), 870 Stette;, H. 471(llij, 510, 823(32i, 322), 826(324), 869, 1266(58), 1300 Steven. S.A. 1307. 1313. 1328124a). ,. 1360 stevens, C.L. 506(674), 521 Stevens, E.D. 19(162), 80 Stevens, G.de 240(116), 253,971(155), 990 \
Author index Stevens, M.F.G. 14,21(166),80, 243(126), 253, 373(176), 403,412, 433(37), . . 434, 719(67b), 725 Stevens, R.V. 475(190, 191), 489(191,378, 427.428.431433). , . ,,499(556.557). , ,, 511., 515, 516, 519 Stewart, J.A.G. 307(56), 400 Stewart, J.J.P. 24(175, 185), 48(175), 80, 81, 1485(143), 1506 Stewart, R. 697,707(4d), 723, 1074(77), 1107 Stcwart, R.E 24(189), 81 Stewart, T.D. 476(193), 511 Stewart, W.E. 246(159), 254 Stezowski, J.J. 1091, 1093, 1094, 1100(102d), 1108 Stick, R.V. 502(621), 520, 1442(14), 1503 Stierl, M. 327(89), 401 Stierli, F. 172(62), 211 Stikes, G.L. 1188(220),1247 Still, W.C. 830(338b), 869, 1512(46b, 62), 1526, 1527(46b), 1532 Stille, J.R. 737, 844(61), 863, 911(108, 109), 921, 1042(255),1048 Stillman, R. 1209(285), 1249 Stirling, C.J.M. 477(221), 512 Slivers, J.T. 1258, 1259(28,29), 1281(29), 1300 Stockigt, J. 986(226), 992 Stocklin, G. 1208(283), 1249 Stocks, R.C. 984(212), 991 Stocckigt, J. 965(131), 990 Stohmann, F. 259(17), 271 Stohrer, W.-D. 950(83), 988, 1091, 1093, 1094, 1100(102d),1108 Stoll, G. 184(140), 213 Stolz, G. 593(249), 634 Stone, R. 1281(113), 1301 Stone-Elander, S. 1206(273), 1249 Stonner, F.W. 471(115), 510, 1197(244), 1248 Stopp, G. 1319(94),1361 Stork, G. 3(&8), 4(6, 8), 7(68), 8(8,68), 9(117), 10, 13(8), 48(249), 58(8), 76, 78, 79, 82, 245(139,146), 253, 254,469(35, 37, 38), 472(35), 508,695(la-h), 712(48a, 48b), 714(48a, 48b, 54), 715(54), 723, 725, 728(2,3), 735, 736, 741, 746(3), 760(120), 778, 782(3), 784(200), 787(3), 804(2,3), 806(3), 816(2), 861, 864, 866, 88Y(1), YIY, 1001(49), 1016(106), 1029(180), 1044-1046, 1050(5a, Sb), 1051(5a), 1052(5a, 5b), 1104, 1254(1), 1299, 1366(15), 1436, 1508, 1509(33a, 33b). 1511(4ij, is30(120), 1531-1533,1~37(5, 9b), 1539(9b), 1563 Storr, R.C. 532(29), 629 \
Stothersand, J.B. 320(73), 401 Stotz, D.S. 1507(7), 1531 Slough, M.E 814(297), 868 Stout, D.M. 499(562), 519, 1162(146), 1245 Strachan, P. 580(202), 633, 760(129), 864 Stradi, R. 57(305), 84, 220(2), 221(3-5), 222(23,25, 27), 223(23, 25), 238(23), 251, 283-287(8), 302(45), 304(51), 305(45, Sl), 307, 308(55), 313,315(51), 320(55), 399, 400, 470(69,84), 472(147), 473, 475(153), 497(543), 509-511,518, 786(219), 866, 892(41), 920, 1022(139), 1025(144), 1035(220,221), 1045,1047,1352(168, 170), 1363, 1382(57), 1392(81a-c, 82), 1426(174,175), 1436,1437, 1439 Stratford, 1.1. 1128(4143,48), 1243 Stratford, M.J.W. 486(343), 514 Stratford, M.R.L. 1128(45), 1243 Streaty, R.A. 486(341), 514 Street, J.D. 183(135), 185(146), 213 Strehlke, P. 485(318), 514 Streitwiesser, A. 245(149, 150), 254 Slremok, I.P. 612(310), 635 Stribling, D. 1177(193), 1246 Stringer, O.D. 1186(215), 1247 Strobel, C . 1495(152), 1506 Strobel, M.P. 281(11b), 284, 286, 288, 289, 291-293,316,318, 319, 339(11a, lib), 399, 472(148), 510,935(41), 988 Stromqvist, M. 470(74), 509 Strozier, R.W. 246(154), 254 Stmchko, Yu.T. 719(67c), 725 Stmchkov, Y.T. 244(131), 253 Stmchkov, Yu.T. 14, 21(168), 80, 171(51), 211,388(203), 404,432(114), . . 433(124), . . 436, 1499(15'5), 1506 Stucki, H. 768(154), 865, 1401(106),1438 Studt. P. 484(302). 514 ~turlz,'G.321,325(75), 401 Su, B.M. 715(58e), 725 Su, W.Y. 960(109), 989 Subach, G.A. 829(336), 869 Subba Rao, G. 498(552,553), 519, 1544(20), 1555(44), 1564 Subbarao, H.N. 764(148), 865 Suchinek, P. 8(77), 78, 245(140), 253 Suchitzky, H. 1050, 1084(6f), 1105 Sucrow. W. YUS(89. 90). 921, 1383(60), -
~
,-
-
,
Suelter, C.H. 1089(95), 1107 Suemitsu, R. 981(199), 991 Suen, Y.H. 503(638-640), 521,1442(12,13). 1444(12), 15'03 Sugai, T. 1298(168), 1302
Author index
1642
Sugc, O.T. 485(331), 514 Sugihara, Y. 462(8), 465 Sugimoto, T. 1555(46a), 1564 SU&, T. 1026(152), 1'046 Sugiura, M. 9(87), 78, 174(70), 211, 1324(107). 1362 ~ugiyaAa,K: 168(29), 174(70), 210,211 Suhr, H. 736(54c, 57), 740(54c), 863 Sukari, M.A. 944(69,71), 988 Summewille, R.H. 1306,1313,1320, 1342(20), 1360 Sumoto, K. 572(183, 184), 632, 979(187), 991 Sun, T.-H. 1156(129),1245 Sun, X.Y.407(12), 434 Sundelin, K.G.R. 447(20), 458,492(494), 517 Sunder. S. 572(181). 632 ~ u n d s t k n~, . ' 1 2 6 i :1266, 1283(40), 1300 Sung, M.-S. 1127(35), 1242 Sunthankar, S.V. 606(288), 635 Suschitzky, H. 4(32), 77, 731(17), 820(312), 862, 869 Suschitzky, J.L. 572(180), 632 Suss, H. 484(315), 514 Sustmann, R. 994(3), 1008(70), 1024(142), 1043-1045,1355(180), 1363 Suter, P.M. 1199(254), 1248 Sutherland, D.E.R. 1156(123c),1245 Sutherland, 1.0.236(92), 252, 416,417(55), 435, 481(270b), 513, 1444, 1447, 1451(36), 1503 Sutton, B. 1186(215), 1247 Sutton, B.M. 1186(216), 1247 Sutton, L.E. 431(106), 436 Suvorov, N.N. 571(176), 632 Suya, K. 776(177), 865 Suzuki, H. 566(159), 632 Suzuki, K. 549(89), 631, 772(166), 865, 1211(29&292), 1212(293,294), 1213(295), 1249 Suzuki, M. 883(34), 887 Suzumura, H. 469(45), 508 Suzuta, Y. 1026(152,153), 1046 Svard. H. 1206(276). 12071281). 1249 svensson, C. 7i2(xij, 726 Svetlik, J. 495(529), 518, 550(96), 631 Swallow, A.J. 681(3), 693 Swan, G.A. 502(633), 520 Swartzendmber, J.K. 176(82), 212 Sweet, R.M. 175(78),212 Swern, D. 1122(25), 1242 Swigor, J.E. 1189(224), 1247 Swindell, C.S. 653(33,36), 678 Swistok, J. 8(74), 78, 318,319(69),401, 470, 473(92), 509 Sworin, M. 939(49), 988 Synder, E.S. 1517(87a), 1533 Synder, W.H. 1512(60), 1532 \
Syrota, A. 1198(248), 1199(250,251), 1248 Szabo, A. 24(180), 81 Szabb, D. 751(98), 864,1030(193), . . 1046, 1399(101), 1437 Szabo. L. 187(168). 214. 1366(9). 1435 szajekski, R.; 5G(47),'630, i383(59a), 1436 Szakacs, C.B.N. 1125(34), 1242 Szantay, C. 187(168), 214,797(260), 867, 964(126), 989, 1366(9), 1435 Szantay, C.Jr. 720(73), 726 Szekeres, L. 1180(201), 1247 Szeverenyi, N.M. 1507(5a), 1531 Szewczak, M.R. 538(52), 630 Szmuskovicz, J. 797(251), 867,1001(49), 1044 Szmuszkovicz, J. 3(6, 8), 4(6, 8, 23), 5(23), 8, 10, 13, 58(8), 76, 77,468(1), 469(35, 37), 470(82), 472(35), 507-509,695(1a, le), 723, 728(2,3), 731(17), 735,736, 741, 746, 778, 782, 787(3), 804(2, 3), 806(3), 816(2), 861, 862, 889(1), 919, 1050(5a, 5b, 6a), 1051(5a), 1052(5a, 5b), 1104, 1254(1), l299,1508,1509(33h), 1531, 1537(5), 1563 Szollosy, A. 720(73), 726 Taagepera, M. 1065(63a), 1097(116b), 1106, 1108 Tahacik, V. 1123, 1124(26), 1242 TabakoviC, 1. 462(7), 465,955(98), 989, 1404(113), 1438 Tahata, Y. 688(27-32), 690(28), 691 (29,30), 693(31.32). 694 Tabe, M. 965(132), 990 Tabor, H. 1146(91), 1244 Tacconi, G. 600(269), 634, 751(99), 864,994, 1011(2), 1043 Tada, M. 1184(212), 1247 Tada, Y. 638(4a, 4b), 677, 1413(135), 1438 Tadzer, I. 1238(353), 1251 Tafel, J. 483(28j), ~ 1 3 Taft, R.W. 48(255), 82, 369(169), 387(202), 403,697(5), 699, 701(13), 704(19d), 707(13.27a. 27b. 27di 708(13). 713(50). Taga, T.' 380(192), 403 Tagahara, K. 1026(152-154), 1046 Tagawd. S. 688(27-29.31. 32). 690128). ~ a ~ u c hK. i , 7, 70, i l ( j i ) , 78,469(50), 508 Taguchi, T. 173(66), 211, 469(41), 508 Tahk, EC. 816(305), 868 Tabk, EC.T. 489(429,430), 516 Tai, A. 722(85b), 726 Taido, N. 1012(91), 1026(163), 1044, 1046 Takacs, J.M. 1514(77), 1533
Author index Takics, K. 1180(201), 1247 Takagi, N.638(5), 677 Takahashi, H. 1120(17), 1242 Takahashi, K. 470(73), 509,567(160), 632, 892(37), 920, 1209(286), 1249, 1366(18), 1391(78), 1436, 1437 Takahashi, M. 1347(155), 1363 Takahashi, T. 612(309,311), 635, 1209(286), 1249 Takahashi, Y. 926(19), 987 Takahata, H. 896(53), 920, 1391, 1428(80), 1437 Takahata, Y. 48(246), 82, 719(65), 725, 890(22), 920 Takaku, S. 1019(118), 1045 Takamatsu, S. 1027(167), 1046, 1419(153), 1438 Takamoto, M. 174(71),211 Takano, S. 606(289), 635, 883(34), 887 Takano, T. 544(75), 546(80), 630 Takase, K. 802(283), 868 Takasugi, M. 937(48), 988 Takasuka, M. 187(160),214 Takdta, Y.953, 958(93), 989 Takaya, H. 481(274), 482(280), 513, 980(195), 00 7 , , A
Takayuki, T. 470(57), 509 Takazawa, 0. 765(151), 772(167), 865 Takeda. A. 7641150). 865 ~akeda;K. 572(183;'184), 632 Takeda, S. 616(319), 635 Takcgami, Y. 984(220), 991 Takemasa, Y. 502(618), 520 Takcmoto, D.J. 963(123), 989 Takcshima, T. 718(63h), 725 Takeshita, H. 649(24), 678 Taketon, T. 481(274), 513 Takeuchi, H. 644(13), 677 Takcuchi, K.J. 167(24), 210 Takeuchi, N.582(211c), 633 Takeuchi, Y. 768(155), 841(365), 865,870, 1029(186),1046, 1368(22), 1406(119), 141)9(123), 14.76, 1438 Takewaki, M. 760(125), 864 Takusagawa, E 963(122), 989 Takzawa, 0. 1540(11), 1564 Talamoni, 1. 685(16, 17), 686(17), 693 Talaly, C.N. 1352(171), I363 Talbiersky, 1. 713(49), 725 Talman, J.D. 320(73), 401 Talwalkar, P.K. 1340(140), 1362 Tam, S. 1261(47), 1300 Tamalen, E.E. 469(40), 508 Tamas, 1. 448(21), 458 Tamelen, E.E.van 840(360), 870 Tamura, C . 170(47),211 Tamura, Y. 534(39), 547(81), 624(335), 629,
1643
630, 636, 654(37), 656(38), 668(37,51, 52), 670(55), 678, 1376(46), 1436 Tan, T.H. 1155(121b), 1244 Tanahe, K. 55(296), 83, 481(270a), 513 Tanahc, M. 764(150), 865 Tanada, H. 1378(50),1436 Tanaka, H. 676(62), 679 Tanaka, K. 406(1), 434, 534(38), 629 Tanaka, M. 984(220), 991 Tanaka, R. 191(189), 214 Tang, D.Y. 901(73), 921 Tang, G.Z. 1167(167), 1246 Tang, 1. 1133(55), 1243 Tang, P.W. 500(593), 520 Tang, X.C.1029(182), 1046 Tang, Y.S. 1060, 1098, 1103(35a),1105 Tani, K. 481(274,275), 482(279,280,280), 513 --Tanida, H. 1526(11I), 1533 Tanimoto, S. 1555(46a, 47), 1564 Tanji, K. 1012(90), 1044 Tannock, J. 481(270b), 513 Tanycli, C . 1402(111), 1438 Tapia, R. 1018(117), 1045 Tappe, H. 425(88), 435 Tarakanova, A.V. 266(59), 275 Tarashima, S. 248(183), 254,474(162), 511 Tarasov, A.P. 686(20), 693 Tardella. P.A. 840(362a. 362h). 870. 1016(103-105); 1026(105),'1045: 1352(169),1363 Tarrago, G. 53(267), 83, 1051, 1053, 1065(12), 1105 Tarrago, J. 709, 710(38), 724 Tashiro, M. 1021(125), 1045, 1388(74), 1437 Tatchell, A.R. 1526(112), 1533 Tate, B.E. 1304(4), 1359 Tateishi, M. 1373(37), 1436 Taub, D. 1507(22),1531 Taurins, A. 506(673), 521 Tautz, W. 1131(52), 1150(103), 1243, 1244 Taylor, C.C. 237(105), 253 Tajlor, D.A. 169(41), 211 Taylor, E.C.5(47), 77,221(13), 232(64), 241(13). 251. 252. 414(45). 434. 506(650). 521: 696(3bj, 723; 73ijiij; 840(361)3861; 870, 890, 891(9), 929, 1026(159-161), 1046,1120(15), 1147(96), 1154(114, 115), 1242, 1244, 1366(14), 1371(32), 1436 Taylor, G. 1156(124), 1245 Taylor, H.M. 486(352), 515, 594(254, 255a), 634 Taylor, M.D. 530(24), 629 Taylor, P.J. 66(354), 85, 236(93), 237(108), 252. 253. 343. 344(127). 360(148). 373.
3r
Taylor, R.C. 1474(130), 1506 Taylor, W.I. 4, 5(28), 77, 468(2), 507, 1127(38). 1243 ~choubar,B. 53(268), 83 Tedder, J.M. 874(12), 887 Tedga, N. 9(100), 79, 564(151), 632 Tee, O.S. 1087(93b, 93c), 1107 Tefertiller, B.A. 733, 734(38), 862, 1508(31a), 1531 Teien, G. 428, 429(99), 436 Teitel, S. 502(626), 520 Teller, E. 1087(93a), 1107 Telschow, J.E. 544(72), 630 Tempel, E. 600(270), 634 Temperilli, A. 1228(334), I250 Temple, D.L. 1517(84b), 1533 Temple, D.L.Jr. 1517(84a), 1533 Temprano, F. 184(143), 213 Tena Aldave, M. 355-357(137), . . 402 Terai, M. 1215(304), 1249 Teranishi, S. 59(328), 84,696, 708(29b), 724, 933(38). 988 Tcrao, S . 924, 925(8), 987 Terashima, M. 192(199),215 Terashima, S. 1003(53), 1044, 1512(68), 1532, 1537(7,8), 1563 Terawaki, Y. 978(184), 991 Tercel, M. 648(23), 678 Terent'ev, P.B. 46(240), 48(241, 242a), 82, 225(43), 251,284,287(12), 292, 293(27), 294, 296,320(12), 399 Tcrol, A. 170(43),211 Terrel, R. 695(1a, le), 723 Terrele, R. 1508, 1509(33b), 1531 Terrell, R. 3, 4(6, 8), 8, 10, 13, 58(8), 76, 469(35,37), 472(35), 508,728(2, 3), 735(3, 47), 736(3), 737(47), 741(3), 746(3,47), 778, 782,787(3), 804(2, 3), 806(3), 816(2), 861, 862, 889(1), 919, 1001(49), 1044, 1050(5a, 5b), 1051(5a), 1052(5a, 5b), 1104, 1254(1), 1299, 1537(5), 1563 Terrett, N.K. 579(201), 633 Terrier, F.G. 1091-1093,1095(104), . ,. 1108 T e ~ iY. , 169(36), 210 Terzis, A. 190(187),214 Tesseyre, 1. 705(21), 710(21, 40d), 724 Tetzlaff, C. 994(19,22-24), 1043, 1377(48), 1436 Teuber, H.-J. 947(77), 988 Tewson, T.J. 1200(257), 1248 Texier, F. 75(364), 85, 368,370, 371(161), 403 Teysseyre, J. 25(197, 198), 81, 225(36,37), 251 Thal, C. 476,479, 482(204), 512 Tham, F.S. 1022(137), 1045 Thames, S.F. 1142(80), 1244 Thebtaranonth, Y 930(30), 987
index Thesing, J.486(332-335), 514 Thiagarajan, V. 56(302), 84 Thiel, W. 24, 39, 45, 48(174), 80, 924(14), 987 Thiessen, W.E. 652, 668(32), . . 678 Thijs, L. 9(113), 79 Thomas, A. 477(230), 512,1357(183), 1363 Thomas, B. 362,363,367, 369(153), 402 Thomas. E.J. 170(44). 211 Thomas; H.G. 823(321), 869 Thomas, P.D. 484(289,290), 485(319), 513, 514 Thomas, R. 478(239), 512 Thomas, R.C. 55(297), 83 Thompson, H.W. 8(74), 78, 318, 319(69),401, 470, 473(92), 509, 712, 713(46d), 724 Thompson, J.L. 971(156), 990, 1544(21), 1564 Thompson, M.E. 486(353), 515 Thomsen, M.W. 27(210),81, 256, 258, 262, 263(5a), 271,698, 7W(9), 723 Thon, D. 471(112, 113), 510 Thoraval, D. 183(134),213 Thorpe, J.E 506(667), 521 Thrcadgill, M.D. 14, 21(166), 80, 243(126), 253,373(176), 403, 719(67b), 725, 1130(49), 1131(53), 1243 Thuijl, J.van 1124(29), 1242 Thuiller, A. 843(382), 870 Thuillier, A. 281-283,30&302, 304, 305, 310(3), 399 Thullier, G. 488(371), 515 Thummel, R.P. 587(233,234), 634, 1028(171, 172), 1046 Thweatt, J.G. 4(14), 76, 746(88b), 760(126, 128,130), 764(140), 799(264), 801(270), 863365,868, 1329, 1348(119), 1362, 1433(193), 1439 Thyagarajan, G. 967(133), 990, 1561(68), 1565 Tidwell. T.T. 1057(103h 1077(81). 1091. 1093, 1096(103)', lk9(103'1Z6a-c), 1100(126a-c), llOl(103, 130), 1103(103), 1107-1109,1468(111), 1505 Tieman, C.H. 1304(15,17), 1307, 1313, 1328(24a), 1338, 1340(138c), 1346(148, 149), 1360,1362 Tiemann, E. 5, 12, 25,29(56), 78, 408, 431(17), 434 Ticmann, E.J. 843(383), 870 Tictze, L.E. 188(177), 214, 610(303-306), 635,659(43,44), 678, 1029(183, 184), 1033(199-201), 1046, 1047, 1410(126), 1438 Tilak, B.D. 595(255b), 634 Timarco, P. 283-287(8), 399, 472(147), 510 Timms, G.H. 503(636), 520,978(180), 991 Timofeeva, L.P. 266(59), 275 Tinant, B. 193(200),215
Author index Tinar-Harding, T. 1379(52), 1436 Ting-Fang Lai 189(184), 191(190),214 Tin-Tau Chan 189(184), 214 Tin-Yau Chan 191(190), 214 Tishchenko, G I . 621(329), 636 Tishchenko, I.G. 499(569), 519,615, 616(318), 625(338), 635, 636, 1424(165), 1439 Titsworth. E. 1150(104), 1244 Titus, D.D. 544(73), 6% T'Kint, C. 1318(91b), 1361 Toberich, H. 536(49), 584(221), 586(222-225), 630. 633 Tobias; P.S. (91), 1107 Tobias, R.S. 1123(27), 1242 Tobinga, S. 582(2ilc), 633 Tochtermann, W 487(355), 492(501), 515, 518 Todd. G.C. 1133(56\. 1243 ~odeschini,R. 4;2(i15), 436 Todorova, M.R. 506(678), 521 Tokmakov, G.P. 587(23(1), 63.7 Tokuhisa, S. 442(13), 458 Tokumitsu, T. 244(134), 253,998(39), 1043, 1427(179), 1439 Tokumutzu, 1. 1395(92), 1437 Toledano, E. 226(52), 252,344, 345(126), 402, 535(43), 629 Tollin, G. 486(337), 514 Toman, J. 890(16), 920 Tomas, M. 182(127), 213,626(342,343), 636, 1027(169), 1036(224),1046, 1047, 1424(166), 1425(173), 1427(177), 1431(187),1439 Tomassini, T. 975(176), 990 Tomimatsu, Y. 173(68), 211 Tominaga, T. 1211(290-292), 1212(293,294), Tominaga, Y. 170(47), 211, 1312(47), 1313(47,51, 70, 71), 1315(51), 1335(130), 1346(151). 1360-1363.1390(771.1437 ,, ~ominga,~.'528(14),629 Tomioka, K. 502(618), 520 Tomita, K.4. 174(70), 211 Tomkins, R.P.T. 264(52a), 275 Tomoda, S. 768(155), 841(365), 865, 870, 1029(186), 1046, 1368(22), 1406(119), 1409(123), 1436, 1438 Tomori, H. 962,974(120), 989 Tomotake, A. 1040(242), 1047 Tonnard, F. 1374(43b),1436 Tonneson, G.I. 1236(349),1251 Tonneson, G.L. 1236,1237(348),I251 Toorn, J.M.van der 823(319), 869 Topel, W. 1304,1311-1313,1315(5), 1359 Topiol, S. 24(185), 81 Toppet, S. 166(16), 210 Topsom, R.D. 699, 701(13), 707(13, 27a), 708(13), 723, 724, lO97(l l6a), 1108 \
Toraishi, N. 979(187), 991 Torajada, J. 857(402), 871 Torck, B. 1092,1101(106d),1108 Tordeux, M. 740(71), 863,876(26), 887 Torii, S. 544(76), 630, 951(87), 989 Torocheshnikov, V.N. 284, 287, 294, 296, 320(12), 399 Torochesnikov, V.N. 48(241), 82 Tortajada, J. 25(204), 81 Toshibe, S. 1314(78), 1361 Tosi, G. 187(167), 214 Toso, R. 836(350a), 870 Tost, W. 1029(183), 1033(200), 1046, 1047 Toth, G. 169(38), 210,597(262), 634, 720(72, 73), 721(75), 726, 1167(158), 1245 Tothill, M. 1128(45), 1243 Touillaux, R. 167(25), 210 Toullec, J. 1060, 1098, 1103(38b), 1104(135, 136). 1105, 1109 Toupet, L. 179(106),212,1017(114), 1045 Tourand, E. 527(9), 629 Tourw&,D. 222(26), 251, 288, 289, 291, 316, 317, 319,344,345(15), 399, 965(130), 989 Towart, R. 1206(275a),1249 Trachtman, M. 262(33b), . . 265(55), 268(33b), 273, 275 Tracv. M. 1147f95). 1244 ~rai&r,G.L. 7i6(jb), 863 Tranka, M. 538(56), 630 Trefonas, L.M. 247(171), 254, 1061(48), 1106 Treiber, J. 740(81), 863 Tremper, A. 676(63), 679 Treppendahl, S. 890(19), 920 Trevisan, M.L. 751(113),864 Triggle, D.J. 181(120), 212 Trimarco, P. 221(5), 222(27), 251, 302, 305(45), 400, 473,475(153), 511, 1024(141),1045, 1352(168), 1363 Trimmer, R.W. 672, 676(56c), 678 Trinkl, K.H. 544(68), 630 Triplett, J.W. 1138(66), 1243 Trivedi, G.K. 944(65), 988, 1033(205), 1047 Trizna, W.A. 1190(227), 1247 Trofimkin, Y.I. 500(590), 519 Trofimov, B.A. 688(26), 694 Troger, W. 9(110), 79, 793(239), 797(254,257, 258), 867, 994(16), 1043 Troin, Y. 581(208,209), 633, 641(7, 8), 648(22a4), 677, 678 Trojanek, J. 485(326), 514 Trompenaars, W.P. 13(146), 80, 168(30), 171, 175(53),210, 211,998, 1015(36),1043, 1379, 1380(53), 1436 Tronchet, J.M.J. 469(26), 508 Troschiitz, R. 525,530(16), 596(256,257), 629, 634,1315, 1316(79), 1361
1646
Author index
Trost, B.M. 811(293), 868, 1507(12b, 24a), 1531 Trost, W. 610(303), 635 Trotter, J. 183(136), 213 Truce, W.E. 67(344), 84, 1348(160), 1363 Trucks, G.W. 24(185), 81 Trumble. M.J. 550.599(95). 631 Tsai, A,[.-M. 784(207), 8 6 6 Tsapkin, V.V. 174(75), 211 Tsay, Y.-H. 182(127),213 Tse, A. 704(19a), 723 Tshiamala, K. 1022(134), 1045 Tsilku, A.E. 591(242), 634 Tsopelas, C. 612(313), 635 Tsou, A.Y. 1261(45), 1300 Tsubata, K. 462(8), 465 Tsuboi, M. 32,53(217), 81 Tsuboi, S. 764(150), 865, 1307, 1313, 1328(24b),1360 Tsucbiya, M. 471(107), 510 Tsuda, T. 442(13), 458 Tsuda, Y. 476(208), 512 Tsugc, 0.526(6, 7). 528(11,12), 629, 1021(125), 1045, 1388(74), 1437 Tsuji, N. 169(36),210 Tsujimoto, A. 962(121), 963(122), 989 Tsujino, Y. 53(280,281), 83, 248(187), 254, 474(169), 511, 710(40f), 724, 735(42, 43), 862 Tsukiyama, S. 1218(316),1250 Tsumaki, H. 782(196), 866 Tsumiama, T. 501(600), 520 Tsunoda, T. 916(118), 917(118, 119), 921 Tuazon, P.T. 1089(98), 1107 Tuckmantel, W. 1029(182), 1046 Tuinmdn, A. 930(29), 987 Tulley, A. 484,485(291), 513 Tungusova. E.D. 587(232), 633 Tunick, A.A. 826(328), 869, 1010(73), 1044 Turchi, S. 1026(164b), 1046,1420(156), 1438 TureEek, E 259(10), 271, 447(19), 458, 550(96), 631, 1062(50a, 50b), 1106 Turner, D.W. 58, 59(317), 84 Turnschek, W. 1384(61), 1437 Turro, N.J. 470(81), 509,650(25), 678 Tursch, B. 470(53), 508 Tuwick, A.A. 1546(32), 1564 Tyminski, I.J. 809(292), 868 Tzai, L.-H. 1310, 1311(39), 1320(39,97), 1321, 1329,1331,1332, 1344(39),1360, 1361 Tze-Tat Wong 191(190), 214 Uchic, J.T. 1175(184), 1246 Uchino, T. 624(335,336), 636 Ueda, C. 955(101), 989 Ueda, M. 550(92), 631, 722(85a), 726
Ucno, H. 1295(162), 1302 Uesaka, M. 1027(167), 1046, 1419(153), 1438 Uffer, P.M. 258(14), 271 Ughetto-Monfrin, J. 845(391), 871, 893(45), 920 Ugozzoli, E 181(122), 187(167), 213, 214 Uher, M. 1424(168), 1439 Uhl, G. 178(97), 212 Uhlig, G.F. 760(127), 801(270), 864, 868 Ujszaszy, K. 448(21), 458 Ulatowski, T.G. 186(153),213 Ulbricht, H. 582(211), 633 Uldrikis, Ya.R. 168(31),210 Ulin, J. 1207(280), 1249 Ullrey, J.C. 492(488), 517,942(59), 988 Ullrich. EW. 5941250). 634 ~llrich;J. 1255(6), 1279(106), 1299,1301 Ullrich, J.W. 564(156), 581(206), 632, 633 ulmer, P. 530(2zj, 53'2(28),'536(49), 550(22), 561 (146), 629, 630, 632 Umani-Roncbi, A. 1037(225), 1047, 1428(182bh 1439 ~marovs,Z.N: 14, 21(168), 80, 507(684), 521, 844(385e), 871 Umemoto, T. 740(70), 863 Umen, M.J. 1508(31b), 1531 Umezawa, H. 1150(102), 1152(108),1244 Underwood, J.G. 10(120), 79 Ungar, F. 1089(96), 1107 Ungheri, D. 1190(230), 1247 Ungrodt, K.E. 11(141), 79,471(127), 510, 983(209), 991 Unkefer, C.J. 1139(73), 1143, 1144(84), 1243, 1244 Uno, T. 183(132), 213,551(98), 631 Urano, K. 550(93), 631 Uraoka, J. 668(52), 678 Uray, G. 891(29), 920 Urbach, H. 1037(229), 1047 Urban, M. 24(179), 80 Urbariczyk-Lipowska, Z. 14, 21(163), . . 80, 584(219), 633 Urbani, R. 800, 804, 817(267), 820(312,313), 868.869.998. 1005(41L 1043.1555148). Uriac, I? 1017(114), 1045 Urlasun, R.C. 1131(51), 1243 Urtiaga, M.K. 14, 18(152), 80 Ushijimara, R. 549(89), 631 Ushirogochi, A. 1313(70, 71), 1361 Usuda, S. 1215(304), 1249 Usui, M. 959(107), 989 Utzinger, G.E. 488(362), 515 Uyetake, L. 1157,1158(133), 1245 Vaina De Pava, 0. 1465,1466(98), 1505 Vaissermann, J. 193(201), 215
Aurnor index Valdcrrama, J. 764(145), 865 Valderrama, J.A. 1018(117),1045 Valdks, C. 295, 322,323(28b), 399, 1029(185), 1046 ValdCs G6mez, A.C. 295, 322, 323(28a), 399 Valenta, Z. 501(602), 520, 650(29), 678 Valentin, E. 10(133), 53, 58, 59(287), 64-66, 72,73(133), 79, 83, 235(73), 236(78-SO), 252, 280, 294(1b), 302(46), 323(78), 346(131), 399402,471(123), 499(572,573), 510, 519,549(86), 583(215), 615(324), 617(322, 323), 618(324), 620(326), 630, 633, 635,696(3e, 29a), 708(2Ya), 723, 724,734(39,40), 751(10&111,113-116), 757(106,107), 75S(lOS-11 I), 759(114,116), 786(220), 799(265), 836(350a), 862, 864,866,868, 870, 923(2), 987, 998(30), lOOO(45, 46), 1016(109, I l l ) , 1030(190), 1037(231-238), 1038(233,234,236,238), 1040(245), 1041(252),1043, 1045-1048, 1050(6h), 1105, 1366(1c, 17), 1387(68), 1435-1437,1442(8), 1503, 1560(62), 1562(75), 1565 Valentin, G. 619(325), 635 Valentine, D.J. 249(192), 254 Valette, G. 1509(34c),1531 Valle, A.M. 240(111, 115), 253, 353, 355(138), 402 Valle, G. 14, 18(161),80 Valnot, J.-Y. 9(96), 79 Van Binst, G. 288,289, 291,316, 317,319, 344, 345(15), 399,965(130), 989 Vandcnbcrg, G.E. 794(242), 867 Van dcn Eyndc, J.-J. 1414(138),1438 Van der Gen, A. 478(244), 479(24&249), 512 Van der Plas, H.C. 1026(149,150), 1046 Van der Vlugt, F.A. 471(134), 510 Vandcwallc, M. 444,445(16), 458 Vandrevala, M. 178(96),212 Vandrevla, M.H. 1064(62), 1106 Vankar, Y.D. 794(247), 867 Van Rheencn, V. 933(36), 988 Van Saun, W.A. 1012(93), 1044 Van Stappen, P. 1020(123), 1045 Van Tamclcn, E. 490(442), 516 Van Tamelen, E.E. 490(444), 494(519), 517, 518 Van Tilborg, W.J.M. 470(80,85), 509 Varma, R.S. 1401(107), 1438 Vartanyan, R.S. 1460(84), 1504 Vartanyan, S.A. 471(144), 510,982(207),
1647
Vcalc, C.A. 179(107), 212 Vebrel, J. 1016(112), 1022(134, 135), 1045 VeSeia, M. 489(401), 516 Veda, S. 1546,1548(33), 1564 Vederas, J. 1286(144), 1302 Vega, J.C. 764(145), 865 Vegh, D. 494(513), 496(530,531), 518 Veillar, A. 1084(89), 1107 Veillard, A. 64, 70(352), 85, 469, 472(29), 508 Veji, S. 1097(116b), 1108 Velarde, K. 1143, 1144(84), 1244 Velluz, L. 1537(9c), 1558(55), 1563, 1565 Vendeginste, B.G.M. YY(Y), 210 Venimadhavan, S . 1074(77), 1107 Venkataraman, B. 952(91), 989 Venkatesan, K. 14(155, 157, 158, 164, 169), lS(1.55, 157, 158), 21(164,169), 80, 166(20), 174(74), 177(86), 186(154, I S ) , 210-213,221(17), 251, 380(190), 403, 418(60), 419(67,69,70), 421,422(69), 423, 424(81), 435, 1304, 1308(12), 1359 Venncsland, B. 1292(154-157), I302 Vcra, E. 1465, 1466(98),1505 Verardo, G. 1124(31),1242 Verbestel, W. 1172, 1173, 1175(181), 1246 Verboom, W. 13(146),80, 168(30), 170(49), 171(52,53), 175(53),210, 211, 782(199), 866, 998(36,38), 1015(36), 1043 Vercauteren, J. 174(72), 211 Verchere, J.R. 1091-1093,1095(104), 1108 Vcrhk, R. 9(90), 78,506(656), 521 Verhoeven, J.W. 64(353), 85,471(134), 510 Vermandcr, M. 193(200),215 Vernon, J.M. 944(69-71), 988 Vemy-Doussin, C. 1104(136), 1109 Veronese, A.C. 14, 18(161),80 Veselovskii, V.V. 532(30), 629 Vesclf, Z. 489(388,394), 515 Vessiere, R. 527(9), 581(210), 629, 633 Vetter, H.J. 1422(160), 1439 Veyre, A. 1183(209), 1184(210), 1247 Viberti, G.C. 1228(335), 1250 Vicario, G.P. 1160(142), 1188(223), 1190(231): 1228(336), 1245, 1247, 1250 Videau, B. 42(231), 55(290), 82, 83,298(36), 343, 345,394(128), 400, 402 Viehe, G. 1324(110), 1362 Viehe, H.G. 9(91), 78, 193(200), 215, 525(3), 629, 696(3d), 723, 731(15), 76Y(163), 787(226), 862, 865, 867,889(6), 914(115), 919, 921,1318(91a), 1325,1338(111),
OO 1 , , A
Vasvari-Debreczy, L. 360(151), 402, 597(262), 606(292), 634, 635 Vaudescal, P. 875(21), 887 Vaulx, R.L. 1514(75), 1532
--. ~
Vieth, B. 986(227), 992 Vietti, D.E. 332-334(101), 401
Author index Vigevani, A. 221(5), 222(27), 251,283-287(8), 399, 472(147), 510, 892(40), 920 Vigevani, E. 843(377), 870 Vijayan, M. 166(18), 210 Vilar, E.T. 1477(134), 1506 J.J. 1453(65), 1504 Villa, M.J. 1463, 1465(97), 1505 Villars, C.E. 735, 737(51a), 862 Villemin, D. 1312(50), 1360 Villieras, J. 9(89), '78' Vilsmaier, 0.Y(109, 110), 79, 793(239), 797f254-259). 867. 964f124). 989. 994<16-24), ioa, i377<48, 49), 1436, 1495(153), 1506 Vinayak, V.K. 471(100), 509 Vincc, R. 1175(182), 1246 Vincent, J.E. 567(164), 632 Vineyard, B.D. 979(193), 991 Vinogradova, L.P. 471(116), 510 Vioglio, S. 1190(231), I247 Virmini, V. 501(610), 520 Vmami, V 574, 594(187), 633 Visentin, P. 1035(221), 1047, 1426(174), 1439 Vishwakama, J.N. 1315(80), 1357(183), 1361, 1363 Visser, G.W. 13(146), 80, 168(30), 171(52, 53), 175(53), 210,211,998,1015(36), 1043 Viswanathan, N. 175(79), 212, 543(64), 630, 1340(140), 1362 Viswanathan, N.I. 1353(174), 1363 Vitai, M.E. 1399(101), 1437 Vitullo, V.P. 1094, 1095, 1102(107a), 1108 Viverios, D.M. 1121(23), 1242 Vlasova, T. 552(108), 631 Vlasova, T.F. 552(107), 631 Vlugt, F.A.van de; 64(353), 85 Vocelle, D. 64(351), 85, 236(83), 252 Voelter. W. 292f2). 333. 334f104b). 399. 401 voerckel, V. 93i($3), 940(5$, ~8;,'988; 1420(157), 1439 Voet, D. 1294(159), 1302 Voet, J.G. 1286(143), 1294(159), 1302 Vogel, E. 270(72), 277, 1555(47), 1564 Vogel, S. 1091, 1093, 1094, 1100(102a), 1108 Vogelbacher, V.J. 1097, 1098(121), (122), 1108 Voges, R. 1208(283), 1249 Vogiazoglou, D. 764(138), 865 Vogler, B. 657, 667(40), 678 Vogt, J. 52,59(266), 83,699-701,708(12), 723, 1097(112), 1108 Vogtle, F. 722(82a, 82b), 726 Volford, J. 1144(88), I244 Volk, J. 1127(36), 1243 Volodina, V.J. 686(20), 693 Volpe, T. 1041(251,253), 1048 Volpp, G.P. 240(112), 253,337,340(114), 342(114,120), 356(114), 401, 402
Volz, H. 476(216), 512 Vonderheid, C. 486(350), 514, 1512(48a), 1532 Von Hinch. H. 492f489). 517 Von ~trandtmann,hi. 1400(104), 1437 Voorspuij, W.A.Z. 1539(10), 1564 Voorspuiji, W.A.Z. 735(53), 863 Voronkov, M.G. 500(579), 519, 1314, 1315(77), 1361 Vors, J.-F! 1417(148), 1438 Vos, A. 17(150); 80' Vos, G.J.M. 178(98), 182(130), 185(148), 212, 213.998. 1015(37). 1043 Voss, E. 6l0(303)3 6% Voo, E. 1029(183), 1033(199-201), 1046, I047 Voss, S. 62(329), 8 4 Votaw, R.G. 1257, 1258(24), 1299 Votter, H.-D. 1026(151), 1046 Vovna, V.I. 58(325), 84 Vrieze, K. 191(191), 214 Vuitel, I. 609(301), 635 Vyas, K.A. 572(178), 632 Vyve, T.van 769(163), 865 Waack, R. 715(58c), 725 Wache, R. 506(665), 521 Wada, A. 670(55), 678 Wada, Y. 174(71), 211 Wadsworth, W.S.Jr. 478(235,243a), 512 Waffenschmidt, R. 647(19), 677, 1381(56b), 1436 Wagenaars, G.N. 1169(171), 1246 Wager, J.S. 949(80, 81), 988, 1357(181), 1363 Wagner, F. 1143(86), 1244 Wagner, G. 58(320), 84 Wagncr, H.N.Jr. 1199(256), 1202(266), ~ a ~ n e r , '7~1 2. (~4 .6 ~ 724 , Wagner, 0. 964(124), 989,994(20), 1043, 1377(49). 1436 ~ a g n e r , ' ~?69(157), . 865 Wagner, R. 431,432(105), 436 Wagner, R.-M. 968(138, 139), 990 Wahnert, M. 327,328(91), 401 Wai Tan, W.H.-L. 1022(132), I045 Wakselman, C. 740(68, 69,71), 761(135), 764(137, 144), 779(183), 816(300),
~ a l d m a n nH: , 12'%(167), 1302 Walker, B.H. 473(160), 511 Walker, C.N. 489(41 I), 516 Walker, G.N. 475(187), 511, 845(388), 871, 970(150), 990 Wall, M.E. 1164(151), 1165(153),1245 Wallace, D.J. 816(299), 868 Wallace, T.J. 784(201), 866
Author index Wallenfels, K. 530(23), 629 Walling, J.M. 1128(48), 1243 Walsh, C. 1291(150), 1302 Walsh, P.A. 709(35), 724, 1053, 1055(18), 1060(3941), 1062(41), 1065(18), 1103(3941),1105,1106 Walsh, R. 259, 264(9a), 271 Walter, A. 432(111), 436 Waller, K.B. 604(285), 635 Walter, M. 505(648), 521 Walter, W. 8, 45(81), 78, 282, 283, 301, 302, 310.311(4).399.491(475~.517. 1034(211h Walton, E. 167(27); 210 Walton, J.C. 873(2), 874(12), 886, 887 Walton. M.I. 1130(50). 1243 waltz, D.T. 1l86(il6j; 1247 Walz, D.T. 1186(215), 1247 Wamhoff, H. 5, 9(48), 77,358(143a), 402, 501(611), 506(651, 653), 520, 521,525(4), 629, 722(79), 726, 1316(85-88), 1317(90), 1326(85), 1329(121), 1331,1332(124), 1361,1362,1366(6,7), 1396(95), 1408(120, 121), 1414(139), 1416(145), 1425(170, 171), 1429(184), 1434(195), 1435, 1437-1439 Wan, P. 1098(120), 1108 Wananabe, I. 59(328), 84 Wang, A. 56(302), 8 4 Wang, H.M. 1387(70), 1437 Wang, H.-T. 1313(62), 1361 Wang, H.W. 567(161), 632 Wang, J.-C. 1307(25), 1360 Wang, J.T. 683(1 I), 693 Wang, K. 740(73), 863, 876, 878(27), 887 Wang, K.K. 1015(99), 1045 Wang, M. 1263(52), 1300 Wang, M:X. 899(67), 920, 1307(23b), 1308(33), 1310, 1311(38), 1313(64),
Wang, s.-L. 423,424(82), 435 Wang, X.-J. 424(83), 435, 1304(8,9, 11), 1307(30), 1308(8,9, l l ) , 1310, 1311(11, 30), 1313(11,30, 55,58, 62), 1329(58, 122), 1359-1362 Wang, X.L.471(122), 510 Wana, Y. 1000(47), 1043 w a n i M.C. 1164(i51), 1165(153),1245 Wanner, H. 1182(203,206), 1247 Wanner. K.T. lO(134). 73(362). 79. 85. 471(i24), 4s$288j, 51b, 5 i j Wanzlick, H.W. 1255,1264(8), 1299 Ward, A.W. 1433(194), 1439 Wamant, J. 1563(76), 1565
1649
Warner, J.C. 1026(159, 161), 1046 Warner, P.M. 269(69), 276 Warrell, D.C. 1169(168), 1246 Washabaugh, M.W. 1255(7), 1258,1259(28, 29), 1281(29), 1299, 1300 Washio. M. 688.693(31.32), 694 ~ a s s e i n a nH.H. , 797(251),867,924,925(8), 927(20-22), 987 Wasserman, T.H. 1131(51), 1243 Wassermann, H.H. 470(83), 509 Wassmuth, U. 176(85), 212, 1428(181), 1439 Wasylishen, R. 299(39), 400 Watanabe, H. 1026(162), 1046 Watanabe, I. 696, 708(29b), 724 Watanabe, K. 1020(121), 1045 Watanabe, T. 1034(207), 1047 Watanabe, W. 616(320), 635 Watanabe, Y. 624(336), 636, 984(220), 991, 1206(276), 1249 Watkin, D. 178(96), 212 Watkin, D.J. 182(125), 213 Watson, M.I. 1128(44), 1243 Watson, W.H. 722(82a, 82b), 726 Watt, C.1.E 183(135), 213 Watt, D.S. 1507, 1508(26), 1531 Wattenberg, L.W. 1157(131), 1245 Watts, C.R. 1024(143), 1045 Wayner, D.D.M. 876(25), 887 Weaner, L.E. 1156(128, 130), 1245 Weaver, A. 1233,1235(345), 1251 Webb, G.A. 294, 347(31a-c), 400, 890(14), 920 Webb, H.M. 52, 53(270), 83, 699(14), 723, 1065(63b), 1106 Webb, P. 1130(49), 1131(53), 1243 Weber, ti. 176(85), 212 Weber, J. 782(197), 866 Weher, J.D. 1228(338), 1250 Weher, K.-L. 180(112), 212 Weber, T. 248, 249(179), 254, 474(161), 511 Wedegaertner, D.K. 470(94), 509 Wedegaether, D.K. 740(75), 863 Weedon, B.C.L. 500(594), 520 Weerasooriya, U. 479(251,252), 513 Weerdt, A.J.A.van der 185(148), 213 Wehinger, E. 530(19), 629 ~ e h n e ,I. 582(21lb), 633 Weichselbaum. R.R. 1236. 1237(348>.1251 Weidhase. R. i279(98). 1301 ' Weidmann, H. 501(601'), 520 Weigold, J.A. 415(48), 435 Weil. D.A. 25(206).81. 23167). 252. 256. ,. . ,. . 109'7(50& 1106 Weill-Raynal, J. 1445(38), 1473(126), 1503, 1505 ~
Author index
1650
Weimaster, J.E 1063(56), 1106 Weinberg, D.S. 733(37), 862 Weiner, M.A. 715(58a), 725 Weiner, M.J. 1223(324), 1250 Wciner, P.H. 343(129), 402 Weingarten, H. 9(86), 78, 220(1), 251,301, 302(43), 400,468(19), 470, 474(64), 492(19), 508, 509, 843(370), 870, 884(35), 887, 949(80,81), 953(94), 988, 989, 1310(41), 1318(93), 1325(41), 1327(114, 117), 1328(117), 1357(181), 1360-1363 Wcingartncr, H. 1117(3), 1242 Weinkauff, D.J. 979(193), 991 Weinreb, S.M. 491(474), 517, 1442, 1443, 1446, 1461(7), 1503 Weisbuch, E 324(81), 401, 497(539,540), 516, 1555(45), 1564 Weise, W. 484(300,301), 514 Weisenberger, H. 1304(3), 1359 Weisenhorn, F.L. 484(309,311), 514 Weiser, R. 488(376), 515 Weishaar, R.E. 530(24), 629 Weismueller, J. 773(169a), 865 Weisner, K. 501(602), 520 Wciss, A. 7, 8(69), 78, 301-305,307, 308, 310, 311, 319(42), 400, 718(63c), 725, 843(381), 870, 893(48), 920 Wciss, E.R. 502(627), 520, 844, 845(385b), 871 Weiss, J.F. 486(337), 514 Weiss, M.J. 1223(324), 1250, 1507(25), 1531 Weiss. M.T. 558(126). 631 ~eissenfels,M. i40<(ll5, 1l6), 1438 Weitkamp, H. 63, 65(339), 84 Weitz, H.M. 932(35), 988 Welch, J. 486(339), 514 Wclch, J.T. 736,845(60), 863,913(113), 921 Welch. M.J. 1216(310). 1217(314.315). 1218(315), 12h(320,321); 1250 ' Welch, W.M. 1121(23), 1242 Welke, J.M. 500(595), 520 Weller, Th. 494(507), 518 Wells, R.J. 816(303), 868 Welvart, Z.969(145), 990 Wender, P.A. 245(141), 253,1510(39,40), 1532 Wcnkcrt, E. 188(172),214, 468(4), 484(292, 310), 488(364), 507,513-515 Wcnnerbeck, 1. 418(64,65), 419,423(68), 431(108), 433(64), 435, 436, 1307(27,28), 1313(27,61), 1360, 1361 Went, C.W. 3(11), 76 Wenteler, G.L: 475(192), 511 Wentland, M.P. 489(427,428,432), 516, 1022(136.137). 1045 Wentrup, C. 109;~' 1098(121), (122), 1108 Wenzel, M. 1240(356,357), 1251 \
,
Wcpplo, PJ. 740(79), 863 Wepster, B.M. 1053(17), 1105 Were, S.T. 1028(177), 1046, 1416(144), 1438 Were, S.Y. 786(222), 867 Wcrner, G. 1012(88,89), 1044 Werner, W. 240(117), 253,356(140), 402 Wernicke, R. 423(78), 435 Wernsmann, P. 979(188), 991 Weschky, L. 496(535), 518, 1546(27), 1564 Weselowsky, W.W. 973(165), 990 West, J.A. 4(24), 77 Wcst, R. 715(58a), 725 Westcott, L.C. 489(424), 516 Westerman, P.W. 294, 295, 297,298, 347, 351(30), 399 Wcsthcimcr, F.H. 7, 70, 71(71), 78, 469(50), 508, 1283(116, 118, 120), 1284(126), 1286(132), 1292(154-157), 1301, 1302 .westrum, E.F.Jr. 262, 263(34a), 264(45), 267(34a), 273, 274 Wetzel. C.R. 1444133). 1503 weyga"d, D. 492(30$, 518 Whalen, D.L. 1060, 1062(43a, 43b), 1063(56), 1106 Whaley, W.M. 490(441), 516 Whalley, W.B. 169(41),211, 236(77,84), 252 Wheeler, W.J. 1133(57), 1228(337), 1243, 1250 Wheller, V.L. 42(227), 82 Whipple, E.B. 1058, 1063, 1064(32,33), 1093, 1095(33), 1105 White, F.G. 1274(73), 1300 White, G.S. 495(521), 518 White, S. 1512(69), 1513(73), 1532 White, W. 470, 474(64), 509 White, W.A. 9(86), 78, 220(1),251, 301, 302(43), 400,843(370), 870, 1310(41), 1318(93), 1325(41), 1360, 1361 Whitehcad, A. 70, 71(360), 85, 221, 235, 236(15), 251,732(34), 862 Whitehead, C.W. 1442(18),1503 Whitesell, J.K. 4(38), 77, 245(138, 143), 248(178, 184, 188), 249(190, 191), 253, 254,25h(lb), 270, 468(10), 469(52), 474(52, 168), 508, 511, 774(172), 865, (72), ,c,-
lJJL
Whitesell, M.A. 4(38), 77, 245(138, 143), 248(188), 249(191), 253, 254, 256(1b), 270, 468(10), 492(498), 508, 518,. (72). , . 1532 W h i t e s ~ lJ.K.'105'0(6~); l~ 1105 Whitesells, M.A. 1050(6g), 1105 Whiteside, R.A. 24(185), 25, 27, 32,38, 39, 49,55(195), 81 Whitesides, G.M. 1295(167), 1302 Whiting, R.I. 1161(143),1245 Whitmore, G.F. 1128(46,47), 1243 Whitsell, J.K. 843(369), 870
Author index Wbitscll, M.A. 843(369), 870 Whitten, C.E. 1518(8&90,92), 1533 Whittle, R. 478(243d),512 Wiaux-Zamar, C. 9(89), 78 Wibaud, J.P. 491(455), 517 Wibaut, J.P. 491(469), 517 Wiberg, K.B. 245(150), 254,373(189), 403, 432(118), 436, 1032(196), 1047, 1058(29), I105 Wiberley, S.E. 69(356), 85 Wichmann, J. 1033(201), 1047 Wick, A.E. 178(102), 212, 904(82,83), 921 Wickberg, B. 484(292), 490(440), 513, 516 Widdowson, D.A. 1512(53c), 1532 Widen, L. 1206(273), 1249 Widler, L. 474(172), 511 Wiechers, A. 475(192), 511 Wiedenfeld, H. 170(42), 211 Wieland, A. 491(448), 517 Wiesner, K. 650(29), 651(31), 678 Wiesner, K.J. 651(31), 678 Wijnkoop, M.van 191(191), 214 Wilbur, E.D. 500(596), 520 Wilbur, J.M.Jr. 500(596), 520 Wildsmith, E. 503(636), 520 Wiley, R.A. 447(20), 458,492(494), 517 Wiley, R.H. 1191(234), 1247 Wilhelm, S. 1346(152), 1363 Wilke, R.N. 471(133), 510 Willard, A.K. 916, 917(117), 921 Willard, P.G. 1530(120), 1533 Willct, G.D. 683(12), 693 William, R.D. 1170(172), 1246 Williams, , D.H. 438(4), 457 Williams, C.A.J. 650(29), 678 Williams, D.H. 236(82), 252, 439,440, 444, 445, 447,449(8), 451(29), 458 Williams, D.J. 170(44), 182(126), 211, 213 Williams, D.R. 245(142), 253, 843(369), 870, 1512(55,69), 1513(73), 1532 Williams, E 683(11), 684(13), 693 Williams, G.J. 832(345), 869,975(171), 990 Williams, H. 1176(l R7), 1246 Williams, H.W.R. 1176(188), 1246 Williams, P.G. 1154(116), 1244 Williamson, W.R.N. 290(24), 399 Williard, P.G. 661(46), 678,712,714(48b), 725 Willms, L. 785(211), 866 Wilmshorst, J.R. 320(72), 401 Wilson, A.A. 1199(256), 1202(266), 1203(267), 1204(269), 1248 Wilson, E.R. 994(8), 1043 Wilson, G.E. 779(182), 866 Wilson, G.E.Jr. 4(15), 76, 308(57), 400 Wilson, J.D. 884(35), 887,953(94), 989 Wilson, J.M. 451(39), 458
Wilson, V.G. 1190(228), 1247 Winand, M. 1192(239), 1248 Windels, J.C. 1158(137), 1159(139), 1245 Wingard, R.E. 1442(20), 1503 Wingcn, R. 785(211), 866 Winkler, J.D. 657(42), 659(45a), 661(45a, 46), 663(49), 678 Winneker, R.C. 1222(318), 1250 Winquist, R.J. 550, 599(95), 631 Winter, H.-W. 1097, 1098(121), (122), 1108 Winterfeld, E. 484(300,302), 514 Winterfeld, K. 484(314), 489(396,397), 514, 5. 1. 5 .
Winterfeldt, E. 354, 357(136), 402, 500(595), 520. 641(6c). 677, 736155). 863 ~ i r t h , ' 1562(70),'1565' ~. ' Wirz, J. 1060(34,35a, 36, 38a), 1077(36), 1083(87), 1094, 1095(109a), 1097(121, 123), 1098(34,35a, 38a, 87, 88, 117, 121, 123), 1099(36), 1101(36,38a), 1103(34, 3 5 4 36,38a), 1105, 1107,1108 Witaanowski, M. 294,347(31a-c), 400 Witanowski, M. 46, 65(239), 68(239,349), 72, 75(349), 82, 85,891(30), 920 Witczak, Z. 1275(82), I301 Withemp, T.H. 1216(308), 1250 Witkop, B. 843(372), 870,89&892(13), 919, 973(162), 990 Wittel, K. 58(320), 84 Wittereen, J.G. 806(291), 868 Witteveen, J.G. 236(88), 252, 1003(50), 1030(191), 1044,1046 Wittig, G. 2(1), 8(77), 76, 78, 245(140), 253, 492(501), 518, 1050(1), 1104, 1510(35), 1531 Wittig, P. 468(23), 470(54), 508 Wohl, A. 491(458), 517 Wojciechowska, M. 1344(146), 1362 Wolf, A.P. 1213(297), 1214(303), 1227(332), 1249, I250 Wolf, H. 1473, 1499, 1502(122), 1505 Wolf, M.E. 1213(298), 1249 Wolf, U. 1384(61), 1422(160), 14.77, 1439 Wolf, V. 1324(108), 1362 Wolfbeis. 0. 542(63). 609(301). 630. 635 wolfbeis; O.S. 4i(2i4), si, 38'7(19$, 403, 502(616), 520, 593(248), 608(297), 609(248,299,300), 610(297), 634, 635, 891(29), 920 Wolfbeis, S. 719(68b), 725 Wolff, R. 327,347,348,353(92), 401 Wolff, S. 653(34), 678 Wolff, T. 647(19,20), 677, 1381(56b), 1436 Wolf-Gmber, D. 1196(242), 1248 Wolinsky, J. 795(248), 867,875(20), 887 Wollast, P. 189(182), 214 Wolmershauser, G. 994(18), 1043
Author index
1652
Wolny, H. 542(63), 593, 609(248), 630, 634 Wolowyk, M.W. 186(152), 213 Wong, C. 784(207), 866 Wong, C.F. 964(127), 989 Wong, C.-H. 1298(168,169), 1302 Wong, C.M. 501(602), 520, 740(66), 863 Wong, M.W. 373(189), 403,432(118), 436 Wong, S. 1156(127),1245 Woo, P.W.K. 1155(118a, 118b), 1244 Wood, G. 816(302), 868 Wood, R.J. 681(2), 693 Wood, S. 823(316,317), 869, 1005(60,63), 1044 Wood, S.G. 172(63),211 Woodard, S.S. 1188(220), 1247 Woodward, K.N. 536(48), 630,731, 733, 734(29), 820(313), 862, 869, 1021(126), 1045, 1383(59c), 1437 Woodward, R.B. 53, 57, 58(282), 63(341), 83, 84, 469(48), 490(443), 508, 516, 71 4(52), 725, 837(359), 870, 1507(22), 1531 Woolever, J.T. 964(127), 989 Workman, P. 1128(44), 1130(50), 1243 Worms, K.H. 478(241), 512 Wortel, Th.M. 823(319), 869 Wozniak, K. 27, 28, 40(196), 81 Wright, I.G. 490(444), 517 Wright, W.W. 1165(154), 1245 Wu, J.-L. 1226(329),1250 Wu, S.W. 479(254), 513 Wu, T.-C. 1016(101,102), 1045 Wu, T.4. 179(1lo), 212 Wu, WN. 1156(128), 1245 Wu, Z.M. 1239(355), 1251 Wu, Z:P. 302, 305, 306, 312,314, 3 l&32O(47), 400, 731, 732,843(30), 862, 893,895-898(49), 920,1065,1066, 1080-1082,1084, 1099(69), 1107 Wucnsch, J.R. 1410(126),1438 Wuest, H. 372(172), 403,902(77), 921 Wuest, M. 1546,1547(30), 1564 Wunsch, J.R. 659(44), 678, 1029(184), 1046 Wiirsch. J. 502(630), 520 ~iirthbein,E.-U. 1489(144,145), 1493(147), 1495(152), 1506 Wurlman, R.J. 1216(306), 1249 Wiist. M. 1011185L 1044. 1555(46b1. ,, 1564 wyat;, R.J. 1209(i85), 1249 Wyle, H.J. 499(564), 519 Wyler, H. 499(563), 519 Wyman, D.P. 1458(74), 1504 Wynberg, H. 52(274), 83,471(120), 510, 709(34), 724, 1051, 1053, 1056,1057, 1065-1067,1069,1070, 1072, 1073,1081, l090,1092(11d), 1105 Wynn, H. 186(152), 213 Wyrick, S.D. 1167(160), 1178(196), 1246 \
Xia, Y. 1029(182), 1046 Xiuzhen, Q. 1154(117), 1244 Yagi, M. 482(279), 513 Yagoub, A.K. 1037(228),1047 Yahagi, T. 1184(211), 1247 Yahng, Y. 587(234), 634 Yakirnovich, S.I. 367(160), 403,507(684), 521, 844(385c),871 Yakubov, R.D. 688(26), 694 Yamaata, T. 481(274), 513 Yamabc, S. 924(17), 987 Yamabe, Y. 406(1), 434 Yamada, A. 1012(90),1044 Yamada, H. 178(99), 212 Yamada, K. 319,345(71), 401 Yamada, S. 248(183), 249(189), 254, 474(162), 511, 536(46), 630,773(170, 171), 774(171), 775(173), 802(285), 865, 868, 1003(52,53), 1028(17'3), i044,1046,1383(59h), i437, 1512(68),(70b), 1532,1537(7,8), 1563 Yamada. T. 1386.1423(64h 1437 ~amada;Y. 559(131, 132),'631 Yamagami, C. 324(81), 401, 497(539,540), 518 ---
Yamagata, T. 482(279), 513 Yamaguchi, K. 48(247), 82, 924(12, 13, 15, 16). 987 ~amaiuchi,M. 248(185), 254, 474(165), 511 Yamaguti, T. 1546, 1548(33), 1564 Yamamoto, H. 1314,1316(75), 1361 Yamamoto, K. 984(220), 991, 1n26(l63), 1046 Yamamoto, 0.642(9b), 677 Yamamoto, S. 1027(167),1046, 1160(140), 1245,1419(153), 1438 Yamamoto, T. 769(162), 865 Yamamoto. Y. 24711761.254. 319.3451711. Yamanaka, H. 569(169), 632 Yamanaka, S. 406(1), 434 Yamane, S. 462(8), 465 Yamane, S.A. 959(107), 989 Yamano, M. 624(336), 636 Yamaoka, T. 1091,1093(101),1108 Yamasaki, T. 1211(291,292), 1212(293, 294), 1213(295,296), 1249, 1385(63), 1386(64), 1391(80), 1423(64), 1428(80), 1434(63), 1437 Yamashita, M. 174(70), 211,981(199), 991 Yarnashita, 0. 979(187), 991 Yamashita, T. 1259(34-36), 1300 Yamato, C. 1232(344), 1251 Yamatsu, I. 1232(344), 1251 Yamauchi, M. 1034(207), 1047 Yamazaki, H. 180(115),212, 1014(98a), 1045, 1152(108),1244 Yamazaki, T. 896(53), 920
Author index Yamochi, H. 999(42), 1043 Yanagita, M. 1507(21), 1531 Yanai, K. 1209(286), 1249 Yanaka, Y. 460(3), 464 Yancz, M. 704(16d, 16f, 19c, 19d), 705(20),
--
7 ,7 7
Yang, C:C. 1150(105), 1244 Yang, 1:K. 1306, 1342(21), 1360 Yang, N.C. 669(54), 678,900(69), 921, 1412(134), 1438 : . 802(283), 868 Yang, PW Yang, S.C. 567(161), 632, 1387(70), 1437 Yang, S.Y. 568(168), 632 Yang, Y.-S. 1272, 1273(69), 1300 Yang, Z.C. 1167,1168(165), 1246 Yano, Y. 1260(38,39), 1300 Yanuck, M.D. 917(120), 921 Yasuda, M. 173(66), 211, 1026(158), 1046 Yasukova, O.A. 8(75), 78 Yasunami, M. 802(283), 868 Yatco-Manzo, E. 1263(50), 1300 Yates, K. 1087(93c), 1098(120), 1101(132a), 1107-1109 Yates, R. l512,1526,1527(45b),1532 Yatsisin, A.A. 1318, 1340(92), 1361 Yavari, 1. 357(142), 402 Yee, K.C. 789(234), 867 Yce, Y.K. 768(156), 865 Yefsah, R. 193(201), 215 Yeh, M.K. 226(50), 246(155),252, 254, 1512, 1525(51a), 1532 Yen, B. 1125(33), 1242 Yerhoff, E.W. 170(45), 211 Ycskc, P.E. 1010(75), 1044 Yin, M. 544(73), 630 Yin, Y. 1060, 1062, 1103(41,42), 1106 Ykman, P. 797(262), 867, 997(26), 1043 Ymen, I. 722(84), 726 Yogcv, A. 250(195), 254 Yoke, J.T. 486(337), 514 Yokelson, H.B. 165(13), 210 Yokowo, Y. 470(90), 509,735(42), 862 Yokoyama, K. 802(272), 868, 1000(43), 1043 Yokoyama, M. 718(63b), 725,1312(46), 1360 Yom-Tov, B. 722(84), 726 Yoon, U.C. 581(207), 633 Yoshida, K. 957(102), 989 Yoshida, M. 534(38), 629 Yoshikava, S. 710(40f), 724 Yoshikawa, H. 442(13), 458 Yoshikawa, K. 53, 58, 59(286), 83 Yoshikawa, S. 53(280,281), 83,248(187), -,>
--
Yoshimoto, H. 981(198), 991 Yoshimoto, M. 564(154), 632, 712(46b), 724 Yoshimoto, T. 1160(140), 1245
Yoshioka, H. 653(34), 678 Yoshioka, M. 1537(3h), 1563 Yoshizawa, R. 779(180), 865 Young, C.I. 1101(129), 1109 Young, D.M. ll56(122b), 1245 Young, J.E.Jr. 17(149), 80 Young, R.C. 1156(122h), 1245 Young, R.N. 1176(187,188), 1246 Young, V.A. 1101(130), 1109 Young, V.R. 1120(18), 1242 ~ o u n i R.G. , 1263(50), 1300 Yoxall, C.T. 321, 322(76), 401, 445, 446(17), 458.470.497171). 509. 800.804. 817(267).
Yoyoda, T. 1014(98a), I045 Yu, K.T.N. 1138(71), I243 Yuan. S . 4 . 1120(19). 1242 ~ u a n f a n gWang i91?l91), 214 Yuasa, f 501(607,608),'520,535(41), 556(119-121), 557(119, 120), 568(167), 581(204.205). 582(213). 629. 6 3 1 4 3 3 , , Yudilcvich, I.A.'1501(157j,'l506 Yufit, D.S. 1499(155), 1506 Yukhnovski, 1. 506(678), 521 Yun-Cheung Kong 189(184), 214 Yuta, K. 606(289), 635 Zacharias, D.E. 171(56), 211 Zacharias, G. 552(102), 609(299), 631, 635 Zadorozhnyi, B.A. 718(60), 725 Zaichenko, YA. 555(109,110), 631 Zaichcnko, Yu. 591(242), 634 Zaima, T. 621(330), 636 Zamhoni, R. 1176(187,188), 1246 Zang, L.M. 1165(154), 1245 Zanirato, V. 577(195), 633, 968(137), 990 Zanotti, G. 14, 18(161), 80 Zarini, F. 1188(222), 1247 Zaugg, H.E. 247(175), 254, 1429(183), 1439, 1442(5,6), 1443(5,6, 28, 29), 1444, 1446(5,6), 1462(6), 1502,1503, 1507(10a, lob), 1531 Zavialov. S.I. 471f116). 510 Zhaida, D. 192(194), i i 4 Zbikowski, I. 236(83), 252 Zecchi, G. 1397(96), 1437 Zechmeister, L. 428(101), 436 Zeddler, A. 327(95), 401 Zehringer, R. 704(19d), 723 Zeifman, Yu.V. 1443(22), 1503 Zembrowski, W.J. 1176(191), 1246 Zemlicka, I. 735, 737(52), 862 Zeng, X. 1269(64,65), 1271(66), 1276(64-66), 1278(66,94), 1279(97), 1300, 1301 Zenk, M.H. 965(131), 986(226), 990, 992
Author index
1654
Zcrchcr, C. 875(16), 887 Zerta, G. 530(22), 532(28), 550(22), 561(146, 147), 629, 632 Zezza, C.A. 456(45), 458 Zhang, M. 1034(219), 1047 Zhang, P. 782(193), 866,975(179), 991 Zhang, P.-C. 899(65), 920 Zhang, X. 875(17), 887 hang, Y. 616(319), 635 Zhao, H.Y. 1239(355), 1251 Zhao. W.-Y. 1335(131). 1362 ~ h a o Y. ; 261(26),272" Zhaochang Fan 187(163),214 Zhdanov, Yu.A. 1463(93,94), 1467(93,94, 104, 106), 1476(93,94), 1481(93,94, 104), 1505 Zhidkova, A.M. 552(108), 631 Zhou, O.L. 495(522,523), 518 Zhou, Y.G. 1239(355), 1251 Zhu, N.-J. 1304, 1308(8, 9), 1359 Zhu., T- 1239(355). 1251 - - ~ Ziegenbein, W. 3(10), 76, 504(645), 521, 769(160). 865. 1442(16). 1503 ziegler; E. 536(44), 609(300), 630, 635 Ziegler, EE. 904(87), 921 Zielinski, M. 1132(54), 1243 Zielinski, T.J. 27(209), 81 Ziclinski, W. 1463, 1465, 1477(95,96), 1505 Ziereis, K. 551(101), 565(157, 158), 575(189), 627(157), 631433 Ziering, A. 489(404), 516 Zilberman, E.N. 1444, 1451(35), 150.7 Zimkin, E. 843(372), 870 Zimmer, Ii. 478(236,243b-d), 512 Zimmcrman, D. 408(24), 434 Zimmerman, F. 779(182), 866 \~
~
~
,.
Zimmermann, D.M. 55(297), 83 Zimmermann, F. 800(266), 868 Zimmermann, R.L. 489(378), 515 Zinger, B. 191, 192(193), 214 Zipse, H. 875(19), 887 Zirkle, C.L. 983(211), 991 Zirngibl, L. 983(211), 991 Ziv, J. 648(23), 678 Zmbova, B. 1238(353), 1251 Zobova, N.N. 1369, 1429(27), 1436 Zocchi, M. 14, 16(148), 80 Zocbisch, E.G. 24, 48(175), 80, 1485(143), 1506 Zoltewicz, J.A. 1258(26,27), 1299 Zdyomi, G. 1167(158), 1180,1181(202), 1245,1247 Zook, H.D. 1507(7,14a, 14b, 16b), 1531 Zoretic, P.A. 470(58), 509 Zsolnai, L. 1481, 1483, 1494(138), 1506 Zubieta, J. 188(170),214 Zubkova, O.V. 1448-1450(46,47), 1460, 1461(85), 1462, 1463(86), 1467(102), 1468(102,112), 1469(102), 1471(112), 1472(117), 1475(102), 1476(86, 132), 1477(86, 133), 1478(133), 1480(117, 136), 1481(46,47, 112), 1484(47,86), 1485(142), 1487(85, 102), 1489, 1490(142), 1492(102, 142), 1493(142), 1495(86), 1497(142), 1503-1506 Zubov, V.P. 686(22,23), 694 Zunger, A. 432(113), 436 Zwanenburg, B. 9(113), 79 Zymalkowski, F. 539,541(60), 555(112, 113), 630, 63l,l418(152), 1438 Zyss, J. 406(2), 434
Index compiled by K. Raven
The Chemisfty of Enamines. Edited by Zvi Rappopolt Copyright 0 1994 John Wiley & Sons, Ltd. ISBN: 0-471-93339-2
Subject index Ab initio calculations, for acceptor-substituted enamines 431 in structural determination 2-8 of molecular orbital energies 5 H 1 Acelaldehydc imine, EIZ iwmers of 32, 33 Acetaldehydcs, cnamincs of, oxidation of 951 electrochemical 957 photochemical 924 Acetals, as alkylating agents 772 reactions with a-ketocnamincs 612, 613 N,O-Acetals-see N-Allyl-N,O-acetals Acetoacetate decarboxylation 1283-1285 Acetones, enamines of, electrodimerization of 954 photooxidation of 925 Acetoxycycloalkenes, synthesis of 832, 833 2-Acetoxyketones, synthesis of 944, 945, 947 Acetylcyclohexenes, reactions with enamines 814 Acetylenecarboxylates, cycloaddition to cnamines 830 reactions with dienamines 1555, 1556 Acetylenedicarboxylates, as alkylating agents 760 reactions with dienamines 1546 [5-2~]-3'-0-~cetylthymidine, synthesis of 1122,1123 Acid catalysis, general 1056 Acidity 712-717 Acridinediones, synthesis of 539,543,590 Acridines-see also 9-Aminoacridines synthrs~sof 528,532, 595 Acridones, synthesis of 532, 541 Acroleins-see Aminoacroleins Acrylaldehydes, as alkylating agents 749, 750 Acrylamidcssee also @-Aminoacrylamides as alkylating agents 760 reactions with enamines 1029, 1031
A c r y l a t e s s e e also 3-Aminoacrylates, a Bromomethylacrylates, Methacrylates, Nitroacrylates, y-Oxoacrylates as alkylating agents 746746,773, 774, 776, 778,806,848-852,854,857,859,860 Acrylic acids-see also Indoleacrylic acid as alkylating agents 770 Acrylonitriles-see also Aminoacrylonitriles, Methacrylonitriles as alkylating agents 746746,773, 774, 806, 848-852,854,855 reactions with dienamines 1 5 4 6 1 5 4 8 Acryloyl halides, as acylating agents 81&824 Activation entropies 407 @-Acylaminovinylketones 1473, 1498, 1499, 1502 N-Acylalion, reversibilily of 778, 779 3-Acylbenzofurans, synthesis of 594 Acylcycloalkanones, synthesis of 779, 780, 782 N-Acylenamines-see also Enamides acyl migration in 669, 900-902 synthesis of, from carbonyls and nitriles 1441-1502 thermochemistry of 267 2-Acylenamines-see also 2.2-Diacylenamines, PKetoenamincs, 2-Nitro-2-acylcnamines electronic structure of 406 stereochemistry of 4 0 8 4 1 1 Acyl halidcs-see ulsu Diacyl halides, Enaminoacyl halides as acylating agents 779-783 reactions of, with dicnamincs 155-1557 with a-ketoenamines 613 a,@-unsaturated-see a,@-Unsaturated acyl halides w-unsaturated-see w-Unsaturatcd acyl halides a-Acylimines, synthesis of 782
Subject index N-Acyliminium ions 247, 1441-1445, 1448, 1475 Acyliminoacetates, as alkylating agents 775-777 4-Acylisoxazoles, synthesis of 604 Acylium ions 1446,1468,1497 19-Acyl migration, in N-acylenamines 646,669,900-902 in vinylogous imidcs 668 2-Acyl-2-nitroenamines, NMR spectra of 381-391 Acyloxycarhocations 1467, 1468, 1474, 1475, 1481,1494 a-Acyloxyeuamines 9 a-Acyloxymethyl-a-nitroalkenes, as annulating agents 826 3-Acylpyridines, synthesis of 591 3-Acylpyridinium ions, synthesis of 590 3-Acylpyrroles, synthesis of 581 Adamantanes, synthesis of 820, 822, 823, 825-827 Adams catalyst 965, 975, 978 Adcninc, synthesis of 672, 674 Adenosine, 13~-labelled,synthesis of 1211 Agroclavines, synthesis of 641 Ag(1) salts, as oxidizing agents 949 Ajmalicine, deuterium-labelled, synthesis of 1127 Aldehydes-see also Acrylaldehydes, Aminoaldehydes, Butyraldehydes, Enaminothioaldehydes, @-Ketoaldehydes, Propionaldehydes, Pyrimidine-4aldehydes C-alkylated, synthesis of 738 as alkylating agents 764-768 enamines of, allylic cleavage of 439, 440 homologous series of 840,841 a,@-unsaturated-see a,@-Unsaturated aldehydes y,6-unsaturated-see y,6-Unsaturated aldehydes Aldolases, Class 1 1285, 1286 Aldol condensation 1085 Aliphatic enamines, rearrangements in cleavage of 4 4 3 4 4 5 Alkencs-see also Cycloalkcncs, Dihaloalkenes, Nitroalkenes electron-deficient 995, 997 electrophilic, as alkylating agcnts 741-760,823-826, 836.848461.1331-1335 as annulating agents 823-830 as enamine precursors 477, 478 cycloaddition to enamines 797-799, 1546 hydration of 1077 nucleophilic, basicity of 1097-1104 synthesis of 832, 833
Alkcnoncs-see also Butcnoncs, Cycloalkenones synthesis of 576 Alkenylpiperidines-see also Cycloalkcnylpipcridincs thermochemistry of 54, 55 @-Alkoxycarbonyl compounds, synthesis of 772 2-Alkoxycarhonylcnamincs-see Enaminoesters Alkoxycarbonylnitrenes, reactions with enamincs 840 PAlkoxyenamines 9 0-Alkylaminoacrylamides,UV spectra of 68 Alkylation, C- versus N-, in dicnamincs 1538-1541 in enamines 735 Alkylcycloalkanones, synthesis of 735 Alkyl halides, as alkylating agents 735-741, 774 2-Alkylidcnc kctoncs, synthcsis of 764: 765 -. 1-Alkyl-2-mcthylimidazoles, acylation of 1322-1324 2-Alkylthiazolium ions, acidity at C2a 1257, 1258 deprotonation of 1258, 1259 0-(Alky1thio)enamines 9 Alkynes, electron-deficient 1040 electrophilic, as alkylating agcnts 760, 761, 1329-1331 as enamine precursors 477 cycloaddition to enamines 801 Allcncs, reactions with amincs 477 N-Allyl-N, 0-acetals, rearrangement of 916 Allylamines-see also Diallylamine, NDideuterioallylamine ESR spectra of 683 hydrogen migration in 55, 56 isomerization of 48, 4 7 9 4 8 3 PE spectra of 683 polymerization of 686-688 radiolysis of 683, 684 C-Nlylation 776, 778 N-Allylenamines, rearrangement of 908-919 N-Allylenammonium ions, formation of 915 rearrangement of 908,912, 916 Ally1 halidcs, as alkylating agcnts 735, 736, 738,774 Allylic alcohols, reactions of 904, 905 Allylic 1,l-dial diacetates, as annulating agents 826 Allylic strain 290, 731, 1061 N-Allylketene N,O-acetals, rearrangement of 917
Subject index 0-Allylketene N,O-acetals, rearrangement of 904.918 N-Allylketene aminals, rearrangement of 918 @Allyloxyenamines, synthesis of 905, 907 Alprazolam, "c-labelled, synthesis of 1200 AM1 calculations, for acceptor-substituted enamines 431 Amidals-see Bis-amides h i d e acetals, reactions of 904 A m i d e s s e e also Bis-amides, Enaminoamides, Ketoamides, a-Methoxyamides, Thioamides reactions of, electrophilic at a-carbon 1514-1516 with tetrakis(dimethylamino)titanium 1318, 1319 synthesis of 779,785-787,1327 y,bunsaturated-see y,6-Unsaturated amides vinylogous-see Vinylogous amides hidine-see nlso Formamidines as tautomers of 1,l-enediamines 1308, 1309 hydrogen bonding in 264 reactions with enaminones 595,597, 604, 6115 synthesis of 535, 1022 Amidinium ions-see also Formamidinium Ions reactions of 1325 synthesis of 1326, 1327 Amidoalkylation 1442, 1444 Amidoesters, electrophilic reactions at a carbon 1516-1518 Aminals, formation of 468-470 Amine moiety, nature of, effect on alkylation of enamines 736,737 Amine reduction 983, 984 A m i n e s s e e also Cycloalkylamines, 4Ketoamines, Phenylthiomethylamines aromatic-see Aromatic amines "N-labelled. evaluation as tracers 1213, 1214 synthesis of 1212 reactions of, with gem-dihaloethylenes 1314, 1315 with a-haloenamines 1315, 1318 with ketene acetals 1314-1317 with ketene dithioacetals 1311-1314 6,~-unsaturated-see 6,e-Unsaturated amines vinylogoussee Vinylogous amines Amino acids, synthesis of 781, 782, 978, 979 9-Aminoacridines, synthesis of 538 Aminoacroleins 6 s e e nlso N f l Dimethylaminoacroleins charge distributions for 326, 327 NMR spectra of 327-334 PPP-type calculations for 69
UV spectra of 68, 69 PAminoacrylamides-see also 0-a-Alkylaminoacrylamides IR spectra of 75 3-Aminoacrylates, configuration of 240, 241 Aminoacrylonitriles, charge distributions for 365 Aminoalcohols, synthesis of 577, 599, 832, 834,975 Aminoaldehydes, synthesis of 769, 770, 837, 840 Aminoarenes, hydrolysis of 1091-1056 Aminoazetidinones, synthesis of 567, 785, 786 Aminobenzocyclobutenes, formation of 800 2-Aminohenzofi~rans,synthesis of 584
4-Amino-l,2-benzoxathiin-2,2-dioxides, synthesis of 600, 601 Aminobutadienessee also Dimethylaminobutadienes PPP-type calculations for 69 Aminochloroangelicinic acids, synthesis of 601,602 Amino-Claisen rearrangement 556, 908 Aminocoumarins, synthesis of 561 Aminocrotonates-see also 4-Trimethylsilyl-3dialkylaminocrotonates configuration of 240 NMR spectra of 353,355-358 Aminocycloalkenones, NMR spectra of 342-345 rearrangement of 617 synthesis of 624, 816 Aminocyclobutanones, synthesis of 779 Aminocyclohexenes, formation of 829 NMR spectra of 290,291 tautomerism in 320 Aminocyclopropanes, synthesis of 794, 994
2-Amino-4,s-dihydro-3-furancarboxylates, reactions with amines 1316, 1317 2-Aminoethyl vinyl ether, polymerization of 688 I-Aminofmctoses, enaminones of 535 6-Aminufulvenes, stereochemistry of 416 Aminofurans, synthesis of 1020 2-Aminoglucoses, enaminones of 535 Amino group, conjugation of, in vinylamine
--
7X
3-Aminoharman, 14~-labelled,synthesis of 1184, 1185 Amino-2,4,6-heptatrienals,NMR spectra of 327-329 Aminohydrouracils, formation of 786 2-Amino-6-hydroxyacetophenones, synthesis of 611, 612 ~Aminoisohutyricacid, tritium-labelled, synthesis of 1162, 1163
1658
Subject index
Aminoketones, synthesis of 769, 770, 840, 931,940,944,945,947 2-Amino-ylactones, synthesis of 644 6-Aminoluvelinic acid, regioselectively I3clabelled, synthesis of 1136-1138 Aminomercuration 477 PAminomethacrylates, IR spectra of 75 /3Aminomethacrylonitriles, IR spectra of 75 3-Amino-2-nitroacrylates, configuration of 388 IR spectra of 75, 76 stereochemistry of 416 1-Amino-2-nitroalkenes, charge distributions for 372 NMR spectra of 369,372-381 4-Amino-3-nitro-3-buten-2-ones, configuration of 388 3-Amino-2-nitrocrotonates, configuration of 388 IR spectra of 75, 76 stereochemistry of 416 Aminoorganoboranes, synthesis of 831 a-Amino-yoxo acid esters, synthesis of 775 Amino-2,4-pentadienals-~eealso 5Dimethylamino-2.4-pentadienals NMR spectra of 327-329 o-Aminophenols, synthesis of 625 Aminoquinolines, synthesis of 535-537,606, 607 5-Amino-I-pd-ryhofuranoxylimidazole-4[N-@-iodophenyl)]carboxamide,1251labelled, synthesis of 1224. 1225 Aminosteroids--see 3-Dimethylaminosteroids, 1-Methylaminosteroids Aminostyrenes, hydrolysis of 1092, 1093 2-Amino-3,4,5-tricyanopyridines,synthesis of 552 Aminovinyl ketones-see also 0Acylaminovinyl ketones NMR spectra of 334,335 AM1 methods 24,48 Ammonia, loss of, from cycloalkylamines 455 '3~-labelled1213 Ammonium ions, synthesis of 3 Analytical gradient evaluation 24 Angular deformation parameters 88-92, 123, 129-I3l,l44, 165 correlations involving 149-158 frequency histograms for 132-137 Anhydrides, as acylating agents 782 Anilides-see Carboxanilides Anilines-see also Bromoanilines enthalpies of formation of 262 Anilinium ions, reactions with enamines 1021 Anilinostyrenes, NMR spectra of 298, 299
Annulation reactions 730, 804-829, 1003, 1005 Anodic oxidation 459-464 of enaminones 461,462 of enecarbamates 463, 464 Antidepressant drugs, tritium-labelled, synthesis of 1167 Antitumour agents, synthesis of 1022 Apomorphine, "c-labelled, synthesis of 1207 Arecoline, deuterium-labelled, synthesis of 1117-1119 Arenes-see Aminoarenes, Perfluoroarenes Aromatic amines, deuterium-labelled, synthesis of 1124, 1125 reactions with P,@-diketoenamines606-608 Aromatic enamines, cyclodimerization of 885, 886 Gmatization, in reactions of dienamines 1555 Aroyloxyation 939, 940 N-Arylenamines, hydrolysis of 1080-1084 photocyclization of 1022 synthesis of 895 0-Arylenamines, hydrolysis of 1084-1086 4-Arylpyridines, synthesis of 530 PArylselenoenamines, synthesis of 841 a-Arylselenoketones, synthesis of 841 Arynes, as arylating agents 764 cycloaddition to enamines 798, 800 reactions with dienamines 1555, 1556 Aspidosperma alkaloids, synthesis of 648, 649 Asymmetric induction 735, 773-778 in enamine cycloadditions 998, 1003 Asymmetric oxidation 939 Asymmetric reduction 978, 979 Asymmetric synthesis, of @amino acids 978 Atom deviations from planes 103, 114-116, 118, 123, 126, 127 Average values 98, 102, 103,116-118 7-Azabicyclo[2.2.l]heptanecarboxylates, synthesis of 621, 623 Azahutadienes-see also I-Dimethylamino3-azabutadienes, I-Morpholino3-azabutadienes, l-Piperidino-3azahutadienes synthesis of 841, 842 Aza-Claisen reaction, of vinylogous amides 667,668 3-Aza-Cope rearrangement, asymmetric 911 of N-allylenamines 908-919 Azadienes-see also Diazadienes reactions with enamines 1026, 1027
Subject index I-Aza-2-methoxy-I-cycloheptene, tritium-
labelled, synthesis of 1168 Azaphosphinines-see also Diazaphosphinines synthesis of 1432 Azapyrylium ions 1471-1473, 1475, 1480, 1498,1501,1502 Aza-Wittig reaction 1027, 1028 Azepines-see Benzazepines, Diazepines, Dihenzocyclopenlazepines, Hexahydroazepines, Thienoazepines Azepinones, synthesis of 1433 Azetidines, enamines of 473 synthesis of 1017, 1018, 1368,1369 Azetidinones-see also Aminoazetidinones, a-Ketoazetidinones synthesis of 1369 Azetines-see also a-Ketoazetines as intermediates 676 Azetinium ions, synthesis of 1370, 1371 Azidcs, reactions of 1024, 1353, 1354 Azidines, reactions of 1352 3'-Aridu-2', 3'-didcoxy-5-iodouridine,'=Ilabelled, synthesis of 1225, 1226 Aziridines-see also N-Viny laziridines as intermediates 840, 841 enamines of 472,473 Azirines, as intermediates 676 reactions with enamines 1020 Azocines, synthesis of 549 Azodicarboxylates, reactions of, with dienamines 1562 with enamines 8 3 6 8 3 7 with I ,1-enediamines 1344-1 346 Azomethine derivatives, lithium salts of 1507-1529 Barhituric acid, synthesis of 786 Basicity, carbon, of indoles 1058, 1059 carbon versus nitrogen 1052, 105&1056, 1069 condensed-phase 709-712 experimental determination of 50-52 gas-phase 697-709,1065 analysis of intrinsic effects on 707, 708 comparison of enamine with saturated amine 702,703 theoretical calculation of 705-707 nitrogen, of 0-cyanoenamines 1055 of enolates 1059, 1060 solvent effects on 5 3 structure effects on 53 substitution effects on 1062 Basis sets, in calculation of molecular geometry 24-48
1659
in calculation of protonation energies 49 Benzazepines, peroxidation of 938 photooxidation of 928 synthesis of 552, 557, 569, 577,581, 954 Benzimidazoles, synthesis of 583 Benzimidazolinones, synthesis of 617 N-(1H-Benzimidazol-2-yl)carbamates,multi13~-lahelled,synthesis of 1136 Benzocarbazoles, synthesis of 586 Benzocarhazolquinones, synthesis of 586 ~ e n z o c ~ c l o ~ e n i o x a z e ~synthesis in&, of 613 Benzodiazepines--see also Dihenzodiazepines, Iodobenzodiazepines "c-labelled 1209 synthesis of 568, 572, 1313 tritium-labelled 1167, 1168 Benzodioxepines, synthesis of 584 Benzodioxins, synthesis of 1040 Benzodipyrroles, synthesis of 979 Benzofuranoazocines, synthesis of 561 Benzofuranols, synthesis of 1018 Benzofurans-see also 3-Acylhenzofurans, 2-Aminobenzofurans, Dihenzofurans, Dihydrohenzofurans, 3-Nitrohenzofi~rans synthesis of 621 Benzoindolediones, synthesis of 559 Benzoindoles, synthesis of 559 Benzopyranones-see aLso Furobenzopyranones synthesis of 1402 Benzopyranopyrawles, synthesis of 599 Benzo[c]quinolizine derivatives, hydride reduction of 966 Benzoquinones, as arylating agents 764 reactions with enamines 1018 Benzothiazines, synthesis of 528 Benzothiazoles, synthesis of 1342, 1343 Benzoxazines, synthesis of 532 Benzoxazin-N-oxide, synthesis of 619 Benzoylmethylmercury chloride, photoreactions with enamines 879
3-Benzylamino-8,9-dimethoxy-5,6-dihydro[5,1a]isoquinoline hydrochloride, 14Clabelled, synthesis of 1180, 1181 N-Benzylenaminones, anodic oxidation of 462 Benzylic halides, as alkylating agents 735 2-Benzylidene ketones, synthesis of 764 Benzyne intermediates 556, 566 Bichromones, synthesis of 462,955 Bicyclic aminocyclopropanes, synthesis of 994 Bicyclic enamines 11, 12 Bicycloalkanes-see also Bicyclo[2.2.2]octanes synthesis of 619, 797, 799 Bicycloalkanones, synthesis of 548, 830, 852, 853
1660
Subject index
Bicycloalkenones, synthesis of 818 Bicyclo[3.3.l]nonanediones, synthesis of 816 Bicyclo[2.2.2]octanes, enamines of, borane reduction of 975 catalytic hydrogenation of 978 Biochemical oxidation 952, 953 Biopterin cofactors 1293 Bis-amides 1442,1444,1447,1460 6,6-Bis(dimethylamino)fulvene, stereochemistry of 425
10,lO-Bis(dimethylamino)methylenecyclononatetraene, stereochemistry of 425 Np-Bis(trimethylsilyl)enamines,reactions of 84G842 Bond angles 96,97,100-102,106,117,118 frequency histograms for 106-109,121-123 in acetaldehyde imine 32, 3 3 in enamines, N-cyclic tertiary 15, 17 a-substituted 23 /%substituted 15, 22 in 8-enaminones 15, 19, 20 in vinylamine 27-31 protonated 34 in vinylamines, substituted 39-41, 43, 46, 47 PCA for 141-143 Bond lengths 88-90,96, 97, 100-102,113, 116,118,123 correlations involving 146, 148-158 frequency histograms for 101, 104, 105, i i j , ii9,i20 in acetaldehyde imine 32, 3 3 in enamines, acceptor-substituted 430-433 crystalline 228 N-cyclic tertiary 13, 14, 17 a-substituted 22, 23 D-substituted 14, 20, 22 in penaminones 14, 17, 19, 20 in vinylamine 27-31 protonated 33,34 in vinylamines, substituted 3 9 4 5 4 6 , 47 PCA for 137-139 Boranc reduction 974, 975 Boranes-see Aminoorganoboranes (5'-10-Bromoacetamido~uethylcamptothecin, tritium-labelled, synthesis of 1164, 1165 Bromoanilines, reactions with enamines 1021 4-Bromoantypyrine, 62~r-labelled,synthesis of 1227 a-Bromocycloalkanones, synthesis of 794 Bromoenamines, synthesis of 788, 789 5-Bromo-6-(2-imidazolin-214 ylamino)quinoxaline, C-labelled, synthesis of 1190
a-Bromoiminium ions, synthesis of 788, 789 a-Bromoketones, reactions with dienamines 1561 synthesis of 788, 789 y-Bromomesaconates, as annulating agents 823,824 or-Bromomethylacrylates, as annulating agents 823,824 Brvlnsted correlations, in enamine hydrolysis 1074,1076, 1077,1079, 1085, 1094, 1100, 1102 Bucindolol hydrochloride, [ ~ ~ a n o - ' ~ ~ ] , synthesis of 1135 Buffer saturation curvature 1075, 1081, 1085 Buprenorphine, "C-labelled, synthesis of 1202, 1203 Butadienes--see Aminobutadienes, Azabutadienes, Diacylbutadienes Butenones-see 4-Amino-3-nitro-3-buten-2ones, Methoxybutenones p-Bulyl-IDA complex, 99m~c-labelled, synthesis of 1238 Butyraldehydes, enamines of, nitric oxide oxidation of 952 photooxidation of 925
Cabergoline, 3 ~and - '4~-labelled,synthesis of 1227 Cambridge Structural Database System (CSDS) 92.93 Camphor, enamines of, catalytic hydrogenation of 978 formic acid reduction of 982 Camptothecin, deuterium-labelled, synthesis of 1165 Cannabinols-see Diazacannabinols Caprolactam, tritium-labelled, synthesis of 1168 Carbacephames, synthesis of 568 Carbamatessee a,@-Diacetoxycarbamates, Enecarbamates, or-Methoxycarbamates C2a-Carbanions 1255 Carbapenames, synthesis of 568 Carbazoles-see also Benzocarbazoles, NVinylcarbazoles synthesis of 536, 566, 568,569,581,586 2-Carbazolones, phenylhydrazonesof 616, 617 synthesis of 624 Carbenes-see also Chlorocarbenes, Dihalocarbenes reactions with enamines 794-797,994, 1545 Carbenium ions--see Carbocations, Halocarbenium ions Carbinolamines, in enamine hydrolysis 1068, 1071, 1072,1076,1087,1089,1095
Subject index Carbocations-see also Acyloxycarhocations destabilized 1468, 1475 Carbocyclic synthesis 619, 794-831, 994-1016,1545-1560 of five-membered rings 801-804,999-1001 of four-membered rings 798-801,995-999, 1546 of seven-membered and larger rings 830, 83l,lOl5, 1016, 1558-1560 of six-membered rings 804-829,10011015, 15461558 of three-membered rings 794-798, 994-996, 1545 Carhodiimides, as 1,l-enediamine precursors 1321, 1322 BCarboethoxyenamines, hydrolysis of 1080, 1081 Carholines, synthesis of 534, 567, 573, 587 Carbon<arbon bonds, double, in 1,l-enediamines 1307, 1308 enantioselective creation of 861 Carbon-nitrogen bonds, double, stereochemistry of 246-248 single, rotation around 17 Carbovir, '4~-labelled,synthesis of 1174, 1175 Carboxamides-see Cycloalkanecarboxamides, N-Vinylcarboxamides Carboxanilides, synthesis of 786 a-Carboxyenamides, photocycloaddition with olefins 646 S-(2-Carboxyethy I)-N-(2-t-butyl-5methoxyhenzthiazol-6-yl)dithiocarbamate, 14c-labelled, synthesis of 1184, 1186 Carboxylic acids, chain elongation of 781 Carboxvlic esters.. svnthesis of 787 . I-Carnitine, 13c-labelled, synthesis of 1138-1140 Catalytic hydrogenation 975-981 Catharantbine, deuterium-labelled, synthesis of 1127, 1128 Cathenamine, hydride reduction of 965, 966 Cephalosporin, 14~-lahelled, synthesis of 1189, 1190 Cerium(1V) salts, as oxidizing agents 949 Charge control, in reactions of dienamines 1536 Charge distributions, in acceptor-substituted enamines 4 3 0 4 3 2 Chemical shifts,
"c.
for acyclic enamines 282-287 for aminobutadienes 294, 295 for cyclic enamines 288-291 for 2,2-diacylenamines 362-364 for enaminoesters 354-357 for enaminoketones 329, 331-334,336, 337, 340-346
for enaminonitriles 368, 370, 371 for nitroenamines 376379,382-387, 392.393 'N 31,231' for acyclic enamines 296 for cyclic enamines 297, 298 for 2,2-diacylenamines 362-364 for enaminoketones 348-351 for enaminonitriles 370, 371 for nitroenamines 374-379 proton, for acyclic enamines 299-309 for cyclic enamines 3 1 6 3 1 9 for 2,2-diacylenamines 362-364 for dienamines 320-325 for enaminoesters 354-357 for enaminoketones 329,331-333, 335-337,340,341, 344,345 for enaminonitriles 366, 368, 370, 371 for nitroenamines 374379,382-387, 392,393 Chiral cyclohexanones, synthesis of 774 Chiral enamines 248-251 alkylation of 773-778 cycloaddition of 1003, 1010. 1025, 1026 formation of 56, 474, 475 Chiral synthesis, using enzymes 1295-1299 Chloral, as alkylating agent 764, 765 Chloramine-T, reaction with enamines 837, 840 Chlorocarbenes, cycloaddition to enamines 830 Chlorodicarbethoxypyrimidines, as arylating agents 762 Chloroenamines-see also Dichloroenamines hydride reduction of 964 Chloroformates, as acylating agents 787 Chloroketones, synthesis of 793 Chloronitropyridines, as arylating agents 762 Chromanones-see also Tetrahydrochromanones reactions of 599 Chrouians, synthesis of 1400 Chromenes, synthesis of 574, 594, 1033, 1401 Chromones, synthesis of 594, 1404 CI-9261927, L4~-labelled, synthesis of 1178-1180 Cisltrans isomerism 88, 90-93, 144 Claisen rearrangement 902, 904-907,916, 918 Clebopride, "C-labelled, synthesis of 1206 Clomipramine, deuterium-labelled, synthesis of 1126. 1127 Clozapin, "c-labelled, synthesis of 1207 Clozepine, tritium-labelled, synthesis of 1168, 1169 CNDOiS methods 68 for acceptor-substituted enamines 431
Subject index CNDOIS methods (cont.) for 0-amino-a,@-substituted carbonyls 46 CNDOR methods 54 Combe synthesis 570-572 Configuration interaction methods 24 Conformational energies, calculation of 433 Conjugated species, thermochemistry of 260264 Conjugation, extent of 58 indicators of 708, 709 Conjugative effect, of double bond with nitrogen 63, 1116 Conrad-Limpach synthesis 572,606 Cope rearrangement 904, 907, 908 Comer(l1~ derivatives. ~,bis(thiosemicarbazone) , 6 2 ~and ~ -67~u-labelled,synthesis of 1237. 1238 Correlation coefficients 142 Correlation matrices 134, 137-142, 144, 145 Correlations between geometrical parameters 144, 146-158 Cotarnines, hydrogenation of 577 Coumarins-see Aminocoumarins, Tetrahydrocoumarins Coupling constants, for acyclic enamines 287, 299, 300, 310-315 for 2,2-diacylenamines 362-364 for dienamines 325 for enaminoesters 354-357 for enaminoketones 329,331-345,34&353 for enaminonitriles 366, 368, 370,371 for nitroenamines 373-379,382-386,392, 393 Crotonate-ee Aminocrotonates, Nitrocrotonates Crotonyl halides, as xylating agents 820-824 Cupric halides, as autoxidation catalysts 932, 933 Cuprous halides, as catalysts, for autoxidation 932 for photooxidation 930 3-Cyano-4,5-dimethyl-2-pyrrolyloxamic acid, 14C-labelled, synthesis of 1190, 1191, 1193 Cyanoenamines-see also Enaminonitriles formation of 787 a-Cyanoenamines 9 fiCyanoenamines 9 hydrolysis of 1076-1080 nitrogen basicity of 1055 stereochemistry of 411, 413 Cyanogen halides, as acylating agents 787, 788 2-Cyanoisonicotinic acid hydrazide, "clabelled, synthesis of 1201, 1202 a-Cyanoketones, formation of 787
..
3-Cyanopyridines-see also 2-Amino-3,4,5tricyanopyridines synthesis of 550 1,2-Cyanoselenylation 841 Cyclic enamines-see also Bicyclic enamines NMR spectra of 287-291,294,295,297, 315-319 radical reactions of 880, 881 reactions with nitrodienes 1037, 1039 Cyclic enaminones, IK spectra of 75 Cyclic p-ketoenamines 10 Cyclic ketones, enamines of, allylic cleavage of 440,441 Cyclic nitronic esters, formation of 759 Cyclic oxime ethers, as heterocyclic systems with lateral functions 1529 N-Cyclic tertiary enamines, experimental geometries of 13-17 Cycloaddition+cycloreversion456 Cycloaddition reactions 794-804, 829, 830, 993-1042-5ee ulso DielgAlder reaction asymmetric induction in 998, 1003 1,3-dipolar 4, 1352-1356 enamine-nal1030, 1033 mechanism for 993, 994 of dienamines 1011,1013 of 0,P-diketoenamines 610, 611 of enaminotbiones 1034 of 1,l-enediamines 1348-1356 of a-ketoenamines 617-621 of Pketoenamines 580,581,60CL602 palladium-catalysed 1008, 1021 [2+2] 4, 998,999, 1015,1017, 1040 [3+2] 619,621,999, 1000, 1024 [3+3] 1005 [4+2] 600,601,617-620,1010,1013, 1014, 1026, 1030, 1034,1036,1037, 1039 [6+4] 1016 Cycloalkabenzofuranones, synthesis of 613, 614 Cycloalka[c]isoquinolinium ions, synthesis of 621Cycloalkanecarboxamides, synthesis of 1327 Cycloalkanoncs--see also Acylcycloalkanones, Alkylcycloalkanones, Bicycloalkanones, a-Bromocycloalkanones, Cyclobutanones, Cyclohexanones, Cyclopentanones, Hydroxycycloalkanones, 2Methoxycycloalkanones, Methylenecycloalkanones enamines of, autoxidation of 931, 932 borane reduction of 974,975 catalytic hydrogenation of 976 dehydrogenation of 449 disproportionation of 942, 943 electrooxidation of 957, 958 formic acid reduction of 981 ~
Subject index Hantsch ester reduction of 986 hydride reduction of 960-962,969,970 lead tetraacetate oxidation of 945, 947 ozonization of 935 peroxidation uf 940, 941 phosphorous acid reduction of 983 photooxidation of 925 sulphonyloxaziridine oxidation of 948 trichlorosilane reduction of 984 Cycloalkanopyridines, synthesis of 587, 588 Cycloalkenes--see Acetoxycycloalkenes, Cyclobutenes, Cyclohexenes Cycloalkenones-see Aminocycloalkenones, Bicycloalkenones, Cyclohexenones, Cyclopentenones Cycloalkenopyridines, synthesis of 589 Cycloalkenopyridones, synthesis of 593 Cycloalkenylpiperidines, thermochemistry of 261,262 Cycloalkylamines, rearrangement of 450-456 Cyclobutane carboxaldehyde derivatives, enamines of, photooxidation of 929 Cyclobutanes-see also Dicarbazylcyclobutanes synthesis of 746, 798, 995-999 Cy clobutanonessee also Aminocyclobutanones. Vinylcyclobutanones synthesis of 800 Cyclobutenes-see also Aminobenzocyclobutenes cnamincs of, synthesis of 473,474 Cyclodimers 691, 692 Cycloheptindoles, synthesis of 586 Cyclohexadienes, formation of 829 Cyclohexadiones, synthesis of 816 Cyclohexane-1,3-dials, reactions with aminoacetaldehyde acetals 534 Cyclohexane-l,2-diones, synthesis of 837, 838 Cyclohexanes, enamines of, synthesis of 474 Cyclohexanones-see also Sulphenylcyclohexanones cnamincs of, alkylation of 746 borane reduction of 974 conformation of 234-236 disproportionation of 942 formic acid reduction of 981 hydride reduction of 960, 961 hydrolysis of 1081-1084 reactions with tetracyanoethylene 801 thallium triacetate oxidation of 947 Cyclohexene carboxaldehydes, synthesis of 1333 Cyclohexenes-see also Acetylcyclohexenes, Aminocyclohexenes
synthesis of 831 Cyclohexenones-see also Formylcyclohexenones synthesis of 814, 816 Cyclohexyl ketone, enamines of, peroxidation of 941 Cyclooctindoles, synthesis of 586 Cyclopentanones-see Nitrocyclopentanones Cyclopeota[c]pyrroles, synthesis of 964 Cyclopentenones, synthesis of 801, 802 Cyclopentindoles, synthesis of 615 Cyclopropanation 794-798 Cyclopropanes-see also Aminocyclopropanes, Mercaptocyclopropanes, Vinylcyclopropanes enamines of, synthesis of 473 reactions with enamines 802, 803 Cyclopropaniminium ions 797 Cyclopropene esters, reactions of 998 Cycloreversion 456 Cytostatic activity 586 Dane's salt 567, 568 3-Deazapteridines, synthesis of 596 Decarboxylation, acetoacetate 1283-1285 pymvyl-dependent 1288-1291 Decahydrobenw[c]quinolizine, hydride reduction of 966 De Mayo reaction 649, 654 Deoxyhenzoin, enamines of, oxidation of 945 electrochemical 959 2'-Dcoxycytidinc, 14~-labcllcd1178 2'-~eox~c~tidine-~~-c~anoborane, 14clabelled, synthesis of 1177, 1178 2'-Deoxy-2', 2'-difluorocytidine hydrochloride, isotopically labelled, synthesis of 1133, 1134 3'-Deoxythymidin-2'-ene, 14C-labelled, synthesis of 1225 Desogestrol, tritium-labelled, NMR spectra of 1169 Deutcrium isotopc cffects, and hydrogcn bonding 3 9 6 3 9 8 a,@-Diacetoxycarbamatea, synthesis of 463 Diacylbutadienes-see 1-Dimethylamino-4,4diacylbutadienes, I-N-Methylanilino-4,4diacylbutadienes Diacyl diimides, as alkylating agents 8 3 6 8 3 9 2,2-Diacylenamines-see also @,p Diketoenamines IR spectra of 75 NMR spectra of 360-365 Diacyl halides, as acylating agents 781 Nfl-Dialkylaminovinylindoles,hydride reduction of 973
Subject index
1664
.
of 4 1 9 4 2 4 1,l-Diamino-2,2-dinitroethenes, stereochemistry of 424 Diaminofumaronitrile 674, 675 Diaminomaleonitrile, photoreaction of 672, 674 Diaminopurine, synthesis of 672 1,l-Diamino-2,2-thioacylethenes, stereochemistry of 423 Diaryliodonium ions, as arylating agents 762 1,3-Diaxial versus allylic strain 820 1,s-Diazabicyclo-[5.4.0]undec-7-ene, tritiumlabelled, synthesis of 1168 Diazacannabinols, synthesis of 596, 597 Diazadienes, reactions with enamines 1036 synthesis of 1386 Diazaheptalenediones, synthesis of 558 Diazaheterocycles, y-lactam-fused, synthesis of 1328. 1329 Diazaphusphinines, synthesis of 1432, 1433 Diazepines-see also Benzodiazepines, Indenodiazepines synthesis of 1434 Diazepinones, synthesis of 1434 1,2-Diazetidines, formation of 837, 839 1,2-Diazetidin-3-ones, synthesis of 1371 Diazines, reactions with enamines 1026 Diazonium ions, reactions with dienamines 1561 Dibenzocyclopentazepines, synthesis of 615 Dibenzodiazepines, synthesis of 534 ~ibenzofuran;, synth&is of 584 Dibenzoylethene, as alkylating agent 749, 75 1 Dibromoketones, reactions with enamines 802,999, 1000 synthesis of 788, 789 Dicarbazylcyclobutanes, formation of 690 P-Dicarhonyl compounds, synthesis of 778 Dichloroenamines, synthesis of 793 1,3-Dichloropropanes, as annulaling- agents 826-828 5,lO-Dideaza-5,6,7,8tetrahydrofolic acid, tritium-labelled, synthesis of 1154 N-Dideuterioallvlamine. radiolvsis of 684 Dieckmann conhensatidn 578 ' Diels-Alder reaction 48, 581, 600402, 1546-see also Hetero-Diels-Alder reaction, Retro-Diels-Alder reaction catalytic 1026 inverse electron demand 1008, 1009, 1012, 1034,1349,1350 Dienamides, synthesis of 504,505 Dienamines 9 acylation of 1541
alkylation of 1537-1541 autoxidation of 933 cleavage of, rearrangements in 445,446 cycloaddition of 1011, 1013 deuteriation of 1537 Diels-Alder reaction of 1546 halogenation of 1562, 1563 IR spectra of 74 NMR spectra of 320-325 oxidation of 1541, 1542 photocyclization of 647-649 protonation of 1062, 1063, 1536, 1537, 1542 reactions of, with acetylenecarboxylates 1555, 1556 with acetylenedicarboxylates 1546 with acrylonitriles 1546-1548 with acyl halides 1555-1557 with arynes 1555, 1556 with azodicarboxylates 1562 with benzofurazan-l-oxide 1561 with a-bromoketones 1561 with carhenes 1545 with carbon disulphide 1562 with cyanogen chloride 1562 with diazonium ions 1561 with dihaloalkenes 1558 with dihalocarhenes 1558, 1559 with diketene 1562 with fulvenes 1558, 1559 with hydrazoic acid 1537 with isocyanates 1560, 1562 with ketene 1555, 1556 with methoxyaryl halides 1558 with methyl acrylate 1546, 1548 with methyl trans-2,4-pentadienoate 1546,1547 with MVK 1548-1555 with nitroso compounds 1561, 1562 with PVK 1550,1551 with sulphenes 1016, 1560 with N-sulphonylimines 1560 with trichloroacetic acid 1537 reduction of 970, 1542-1545 stereochemistry of 42&428 steroidal-see Steroidal dienamines synthesis of 4 9 6 4 9 9 UV spectra of 68 Dienediamines, oxidation of 949 Dienediones, synthesis of 576 Dienes-see also Azadienes, Butadienes, Hexadienes, Nitrodienes, Propadienes electron-deficient 1008, 1009, 1014 synthesis of 832, 833 Dienolate anions 1063 Diethyl acetal enaminones, reactions with amides 535
Subject index (Diethylphosphono)enamines 9 Difluorodihalomethanes, as alkylating agents 740 Dihaloalkenes, reactions with dienamines 1558 Dihalocarhenes, reactions with dienamines 1558,1559 1,3-Dihalo-1,3-dimethoxypropanes, as annulating agents 829 gem-Dihaloethylencs, reactions with amines 1314, 1315 Dihydrobenzofurans, synthesis of 1373 Dihydrofurans, formation of 641, 802 Dihydroindoles, synthesis of 6 4 7 4 4 9 , 1381, 1382 Dihydroindolones, synthesis of 612 Dihydroisoquinolines 5 oxidation of 943 synthesis of 566 Dihydronaphthofurans, synthesis of 1373 Dihydronaphthopyridines, synthesis of 589 l,4-Dihydronicotinic acids, synthesis of 610, 611 Dihydro-1,2-oxazine-N-oxides, synthesis of 1037 Dihydro-1,2-oxazines, synthesis of 1036, 1037 5,6-Dihydro-4H-1,3-oxazines 1446, 1449 Dihydropyrans, as intermediates 809 857, 861 synthesis of 746, 749-751, 815, 816, 1030, 1032,1033 Dihydropyridines, allylic cleavage of 441, 442 "c-labelled 1197, 1198 hydride reduction of 962 hydrolysis of 1089-1091 synthesis of 549,550, 555, 1333 thermochemistry of 266, 267 Dihydropyridones, synthesis of 603 1,4-Dihydroquinolines, synthesis of 535 Dihydroquinolinones, synthesis of 590 Dihydroquinolones, synthesis of 1411 Diimides, diacyl-see Diacyl diimides Diiminium ions, synthesis of 952 P,P-Diketoenamines-see also 2,2Diacylenamines aromatization of 61 1, 612 cycloaddition of 610, 611 pyrolysis of 611 reactions of, with CH-acidic compounds 609 with amidines 604, 605 with aqueous base 609 with aromatic amines 606-608 with electrophiles 610 with guanidine 604,605 with hydrazines 6 0 2 4 0 4 with hydroxylamine 604
with indoles 606-608 with pyridines 606-608 with radicals 610 Diketones-see a-Diketones, PDiketones, Enamino-diketones a-Diketones, synthesis of 925, 927, 959 PDiketones, enamines of, allylic cleavage of 440, 441 synthesis of 769, 771, 1087 Dimedone, enamines of, acyloxylation of 939 electrocyclization of 954 peroxidation of 942 reactions of, with carbonyls 532 with a-ketoacids 543 reductive cyclization of 975, 977
1,4-Dimetallo-N-phenylhydrazones, electrophilic reactions on 1520-1522 6,7-Dimethoxy-4(y-chlorobenzyl)isoquinoline, isotopically labelled, synthesis of 1232 Dimethoxyquinolines, synthesis of 570, 571 Nfl-Dimethylaminoacroleins,stereochemistry of 408,409 4-Dimethylaminoantypyrine, "c-labelled, synthesis of 1206
1-Dimethylamino-3-azabutadienes, stereochemistry of 428 6-Dimethylamino-1-azafulvenes, stereochemistry of 417 Dimethylaminobutadienes, NMR spectra of 292-294 stereochemistry of 427 1-Dimethylamino-4, 4-diacylbutadienes, stereochemistry of 426, 427 Nfl-Dimethylaminoethene, synthesis of 8 5-Dimethylamino-2, 4-pentadienals, barriers to C-N rotation in 426 3-Dimethylaminosteroids, rearrangement of 451,453 6,7-Dimethyllumazine, 13c-labelled, synthesis of 1138 3,3'-Dimethylthiacarb~c~anine, 'ZS~-lahelled, synthesis of 1223, 1224 1,3-Dimethyluric acid, deuterium-labelled, synthesis of 1120 Dimroth rearrangement 1353, 1354 2,2-Dinitroenamines, NMR spectra of 390, 392,393 2,2-Dinitropropane, photoreactions with enamines 879 1,3-Diones, alkaline cleavage of 779-781 1,4-Dioxanes, synthesis of 1420, 1421 Dioxepines-see Benzodioxepines Dioxetanes, as epoxidizing agents 940, 941 Dioxins-see Benzodioxins Dioxiranes, as epoxidizing agents 940, 941
Subject index Dipole moments, effect of conjugation on 62, 63 Disproportionation 942,943 Distances from planes 96, 97, 123, 128, 130 absolute values of 100, 101, 113 Distonic immonium radical cations (DIRC) 451,453,456 Dithianes, synthesis of 837, 840 Dithiazoles, synthesis of 1398 Dithiins, synthesis of 1421 Dithioles, synthesis of 1389, 1390 I,3-Dithiole-2-thiones, synthesis of 1390 1,2-Dithiole-3-thiones, synthesis of 1389, 1390 DNMR spectroscopy, of 1,l-diamino-2,2diacylethenes 422 Donetidine, '4~-labelled,synthesis of 1229, 1230 Donetidine trihydrochlodde, tritium-labelled, synthesis of 1229 synthesis of 1195 DTIC, '"-labelled, E-07 10, isotopically labelled, synthesis of 1232.1233 Electron diffraction studies 12 Electronic structures, in acceptor-substituted enamines 430-433 Electron spin resonance spectroscopy, of allylamine radicals 683 Electrooxidation 953-959 Electrophilic activation, of carbonyl compounds 1467,1481,1485 of nitriles -1481. 1485 - -~ -Electrophilic catalysis, by acyl cations 1469, 1471, 1492 ~ l e c t r o ~ h i lreagents, ic reactions with enamines, effect of experimental conditions on 729, 746 kinetic control in 759 regioselectivity in 728, 729 stereocontrol in 730, 741, 746, 751, 752, 758, 760, 774, 775 transition state effects in 729, 730, 732-734, 747.. 752. 774 Electroreduction 986, 987 Electrostat~cpotentials 710, 711 Enamides 5,8-see also N-Acylenamines, a Carboxyenamides, Dienamides catalytic hydrogenation of 979, 980 heterocyclic-see Heterocyclic enamides hydride reduction of 967, 973 hydrolysis of 1091-1096 NADH reduction of 984, 985 ozonization of 934 photocyclization of 638-646 reactions of, photochemical 1411-1413
with electrophiles 463 synthesis of 462,502-504,844, 845 Enamidofurans, photocyclization of 641 P-Enamidones-see also Vinylogous imides photoreactions of 6 4 9 4 5 4 , 6 6 8 Enamine-enal cycloaddition, intramolecular 1030,1033 Enamine-imine tautomerism 2, 5, 7, 32, 33, 447449,843-861,890-899, 1041, 1042, 1313 NMR studies of 319, 320 Enamines-see also N-Acylenamines, 2Acylenamines, a-Acyloxyenamines, 2-Alkoxycarhonylenamines, f l Alkoxyenamines, @-(Alkylthio)enamines, P-Allyloxyenamines, @ Carboethoxyenamines, Dienamines, (Diethylphosphono)enamines, Haloenamines, a-Ketoenamines, p Ketoenamines, Metalloenamines, Morpholinoenamines, Nitroenamines, N-Nitrosoenamines, P Nitrosoenamines, Oximinoenamines,
P-Perfluoroalkylenamines, N-Phenylenamines, @ (Phenylselenyl)enamines, Polyenamines, Selenoenamines, 0(Selenoketo)enamines, Silylenamines, NSilyloxyenamines, o-Sulphinylenamines, PSulphonylenamines, 0(Thioket0)enamines acceptor-substituted, stereochemistry of 405433 acylation of 778-788,816829 effect of experimental conditions on 778, 779.816 kinetic control in 817 reversible 817 stereocontrol in 818 with acyl halides 779-783 with isocyanates 785, 786 with isothiocyanates 785, 786 with ketenes 779 acyclic, general aspects of 8, 9 aliphatic-see Aliphatic enamines alkylation of 735-778 free radical mechanism for 740 kinetic control in 810 regioselectivity of 741, 751, 758 reversible 741, 746, 747, 749, 752, 806, 810 sterwcontrol in 810 stereoselectivity of 751 thermodynamic control in 810 transition state effects in 806, 807 with alkyl halides 735-741 with carbonyls 764-769
Subject index with electrophilic alkenes 741-760 with electrophilic alkynes 760, 761 with iminium ions 769-771 annulation of 8 0 6 8 2 9 anti-Bredt, thermochemistry of 269, 270 aqueous solutions of, radiolysis of 684-686 aromatic-see Aromatic enamines arylation of 761-764 autooxidation of 885 biochemical 1254-1294 applications of I 2 9 6 1 2 9 9 bromination of 788-794 reversible 788 stereoselectivity of 790-793 transition states in 790, 793 buried 259 thermochemistry of 262, 263 chiral-see Chiral enamines chlorination of 789, 790, 792, 793 condensation reactions at C2cu 1263-1267 conformation of 230-236 conjugation of amino group with C = C bond 3 cross-conjugated 1029 crystalline, X-ray studies of 225-230 cycloaddition of 79&804,993-1042 definition of 2 endocyclic 10, 11 enzyme-bound 1266, 1280,1281 generation of 1268-1271 kinetic competence of 1279 redox properties of 1272-1278 stereochemistry of 1279, 1280 trapping by flavins 1276-1278 visible spectra of 1271, 1272 exocyclic 11 EIZ isomers of 2211-224,237-245 fluorination of 794 geometrical parameters of 2 2 4 2 2 6 halogenation of 788-794 effect of experimental conditions on 788 thermodynamic control in 788, 793 heterocyclic-see Heterocyclic enamines hydrogenolysis of 831 in oxidation-reduction cofactors 1291-1293 in Schiff base enzymes 1283-1291 in tryptophan metabolism 1293, 1294 iodination of 789, 790 Plithiation of 48 molecular structure of, ab initio calculation of 24-48 experimental determination of 12-24 variations in 23, 24 nitrogen pyramidality of 225
nomenclature of 12 organometallic 8 9 3 4 9 5 oxidation of 802, 9 2 4 9 5 9 , 1278 photoreactions of 877-879 primary-see Primary enamines propenylation of 740 properties of 4 propynylation of 740 protonation of, regioselectivity of 731-733 stereoselectivity of 733, 734 push-pull-see Push-pull enamines radical cations of 876, 885, 886 radical reactions of 873-886 reactions of, with acrylamide 1029, 1031 with anilinium ions 1021 with azadienes 1026,1027 with azides 1024 with azirines 1020 with p-benzoquinones 1018 with bromoanilines 1021 with carbenes 7 9 6 7 9 7 , 9 9 4 with 1,3-diazadienes 1036 with diazines 1026 with dihromoketones 802, 999, 1000 with electron-deficient alkynes 1040 with electron-deficient dienes 1008, 1009, 1014 with electron-deficient olefins 995, 997 with electrophiles 3, 4 with heterocumulenes 1039 with imines 1017,1018, 1029 with immonium ions 1028, 1029 with isoxazoles 1026 with nitrones 1022 with nitroolefins 1037 with pyridazines 1012 with semicarhazones 1035, 1036 with sulphenes 1016 with sulphenyl derivatives 784, 785 with sulphonyl derivatives 784, 785 with sulphonylimides 1017 with tetrazines 1034, 1035 with triazines 1026, 1027, 1034, 1035 with vinyl isocyanates 1028. with vinyl ketones 816, 1001-1005 with vinylnitroso compounds 1037 redox chemistry of 1259-1263 reduction of 960-987 secondary-see Secondary enamines selenation of 841 separation of 732, 735, 790 sterically hindered-see Sterically hindered enamines steroidal-see Steroidal enamines
Subject index Enamines (conr.) synthesis of 4 by allylamine+namine rearrangement 479483 by condensation reactions 490,491 by elimination reactions 484-488 by Horner-Wittig reaction 478,479 by reduction methods 488, 489 by titanium tetrachloride method 220 from aldehydes and ketones 4 6 8 4 7 5 from alkenes 477, 478 from alkynes 477 from allenes 477 from imines 4 7 5 4 7 7 using organometallic reagents 489, 490 using phosphorus, arsenic, tin and boron compounds 492 using silicon compounds 491, 492 synthetic uses of 4 tertiary-see Tertiary enamines thermal equilibration of 221 transannular reactions of 5 8 UV absorption hands of 249,250 Enamine versus en01 pathways, in aminecatalysed reactions 1104 Enaminoacyl halides, formation of 787 Enaminoamides 6 hydride reduction of 971 polarographic reduction of 986 Enamino-diketones, conformation of 238 X-ray studies of 240 Enaminocstcrs 6 configuration and conformation of 237-241 electrodimerization of 954 NMR spectra of 353-360 oxidation of 943-945 electrochemical 957 reduction of 975,976,978 electrochemical 986 hydride 965,971-973 0-Enaminoesters, heterocyclicsee Heterocyclic @-enaminoesters Enaminoethers, electrooxidation of 958 Enaminoimines, reactions of 626, 627 Enaminoketones 5, 6 s e e also Enaminoncs configuratiou and conformation of 237-240 cycloaddition of 997, 998 electrodimerization of 954 hydrolysis of 1086-1089, 1096 NMR spectra of 325-353 oxidation of 940, 944, 949 photochemical 927 oxidative coupling of 955 protonation of 1064, 1080 reduction of 975-977,984 hydride 967,968, 970, 971,973
polarographic 987 synthesis of 769, 771 Enaminolactams, hydride reduction of 967 ozonization of 935 peroxidation of 937 Enaminone esters, hydride reduction of 968 Enaminone-ketoimine-iminoenol equilibrium 342 Enaminones-see also 2-Acylenamines, 2-Alkoxycarhonylenamines, NBenzylenaminones, Enaminoesters, Enaminoketones, a-Ketoenamines, pKetoenamines. Methvlenbisenaminones. PPhenethylenaminones anodic oxidation of 461, 462 cyclic-see Cyclic enaminones synthesis of 500-502, 900-902 tautomerism in 890, 899 UV spectra of 68, 69 @-Enaminones5, 9-see also Vinylogous amides experimental geometries of 17-20 IR spectra of 74, 75 photoreactions of 649, 6 5 6 6 6 8 push-pull conjugation in 6 Enaminonitriles-see also Cyanoenamines cyclocondensation of 530,531 electrooxidation of 958 NMR spectra of 365-369 photoreactions of 672, 674-676 polarographic reduction of 986 synthesis of 506, 507 tautomerism in 890 0-Enaminonitriles, cyclic 5 Enaminosulphonium ions 797 reactions with nucleophiles 994 Enaminosulphoxides 9 reduction of 962, 974 Enaminothioaldehydes, synthesis of 769 Enaminothioketones, tautomerism in 890 Enaminothiones, cycloaddition of 1034 reactions of 627, 628 synthesis of 627 Enammonium complexes 91 1 Enammonium ions 1050,1053,1056, 1061,1062,1080,1090--see also NAllylenammonium ions Enantioselective reactions 249, 774, 775 Enantioselective synthesis 861 of a-amino-yoxo acid esters 775 Ene-addition mechanism 894, 1329, 1344-1 346 Enecarhamates, anodic oxidation of 463, 464 oxidation potentials of 463
Subject index reactions with electrophiles 463 synthesis of 462 Enediamides, catalytic hydrogenation of
978 1,l-Enediamines 9-see also Ketene aminals acylation of 1338-1344 akylation of 1327-1335,1338 aroyl-substituted 1307 arylation of 1335-1337 carbamoyl-substituted 1340,1341 conjugated 1304 cycloaddition to 1348-1356 halogenation of 1346 IR spectra of 1310 Mannich reaction of 1346,1347 mass spectra of 1310 nitration of 1347 nitro-substituted 1306 NMR spectra of 1310,1311 oxidation of 950,1357 protonation of 1326,1327 reactions of, with aryldiazo cation 1346 with azodicarboxvlates 13461346 with diphenylcyclopropenone 1347,
1348 with sulphenyl halides 1346 reduction of 1358 structure and reactivity of 1305-1310 synthesis of, from 1-alkyl-2-methylimidazoles
132211324 from amides 1318,1319 from amidinium ions 1325 from amines 1311-1318 from carbodiimides 1321,1322 from thioureas 1319-1321 from urea acetals 1319,1320 from ynamines 1324,1325 tautomerism in 1308,1309 UV spectra of 1310 1,2-Enediamines 9 oxidation of 952 electrochemical 958 Ene-diones, thermochemistry of 268 Energy harriers 407 Energy surface 90,92 Eniminium ions 1062-1064 Enolates, basicity of 1059,1060,1097,1100,1102 protonation of 1084 stabilization of 1062,1087 Enol-keto tautomerism 2,48,1061 Enols, acidity of 1087 basicity of 1097,1102 ketonization of 1077,1083
protonation of 1084 Enones, synthesis of 577 Enthalpies of activation 407 of tertiary enamines 32 Enthalpies of deprotonation 263 Enthalpies of formation 256,258,259 of akenylpiperidines 54,55 of buried enamines 262,263 of dihydropyridines 267 of indigotin 268,269 of merocyanines 264 of simple enamines 260,261 of tropones 265,266 Enthalpies of hydrogenation 267 of akenylpiperidines 54,55 of cycloalkenylpiperidines 262 of ene-diones 268 of simple enamines 261 Enthalpies of sublimation, of indigotin 268 Enzyme inhibitors 1295 Equatorial attack, in reactions of dienamines
1550 Ergot alkaloids, synthesis of 641 Erythina alkaloids, synthesis of 616 Etanidazole, deuterium- and tritium-labelled, synthesis of 1131-1133
2-(4-Ethoxybenzy1)-l-diethylaminoethyl-5isothio~~anobenzimidazole-4,6-~~~, synthesis of 1153,1154 Ethylideneimine, as vinylamine isomer 449 Exciplexes 650 EIZ isomerism 220-224,237-245 in acetaldehyde imine 32,33 in 2-acylenamines 409411 in enamide synthesis 502 in enamine synthesis 472,480,481,487 in enaminonitrile synthesis 507 in 1,l-enediamines 1309 in Psubstituted vinylamines 39-43 FCE 22178,tritium-labelled, synthesis of 1160,
1161 Fischer base, oxidative dimerization of 947,
948,950 Fischer indole synthesis 616 Fisher cyclization 599 Fisher reaction 587 Flavin cofactors 1291,1292 Flowing afterglow technique, in calculation of proton affinities 48 Flumazenil, "C-labelled, synthesis of 1200,
1201 Flumtrazepam, "c-labelled, synthesis of 1209 Fluorinating agents 1214 4-Fluorobenzyl iodide, %abelled, synthesis of 1217
Subject index 5-Fluoro-2'-deoxyuridine, 'R~-labelled, synthesis of 1222, 1223 Fluoroethylspiperones, '8~-labelled,synthesis of 1216. ~,1217 -Fluoromelatonins, 'R~-labelled,synthesis of 1216
3-Fluoro-1-(2-nitro-1-imidazo1yl)-2-propanol, L8~-labelled, synthesis of 1222 p-Fluorophenylhydrazine,"F-labelled, synthesis of 1222 Flupitrine maleate, 14C-lahelled, synthesis of 1196 Force-field studies, empirical 433 Formamidines, hydride reduction of 968, 969 Formamidinium ions, hydride reduction of 968, 969 Formates-see Chloroformates Formic acid reduction 981, 982 Formylcyclohexenones, reactions with enamines 816 a-Formyl ketones, synthesis of 769 Free energies of activation 407 Frcqucncy histograms, for angular deformation parameters 132-137 for atom deviations from the plane 114, 115, 126, 127 for bond angles 106-109,121-123 for bond lengths 101, 104, 105, 113, 119, 120 for torsion angles 110, 111, 124, 125 Friedel-Crafts reaction 607, 608 Friedlinder cyclocondensation 587 Fmctoses-see 1-Aminofructoses FTCP, '%-labelled, synthesis of 1218, 1219, 1221 FTICR spectrometry 456 Fulvenes-see 6-Aminofulvenes, 6, 6Bis(diniethylamino)fulvene, 6Dimethylamino-1-azafulvenes reactions with dienamines 1558, 1559 Fumigaclavines, synthesis of 641 Furanoazocines-see Benzofuranoazocines Furanols-see Benzofuranols Furanones-see Cycloalkabenzofuranones Furans--see also Aminofurans, Benzofurans, Dihydrofurans, Enamidofurans, Naphthofurans synthesis of 1372-1374 Furobenzopyranones, formation of 601 GAUSSIAN 90 program 24 Gaussian-type basis functions 24, 25 Gelsemine, synthesis of 648 Gepirone, deuterium-labelled, synthesis of 1121,1122 Gibbs free energies 256
Glucoses-see Aminoglucoses Glycines, isotopically labelled, synthesis of 1144 Glyoxylic esters, as alkylating agents 765, 767 Grob fragmentalion 653 Guanidine, reactions with enaminones 596, 597, 604,605 Guanine, synthesis of 672 Halocarbenium ions 1474, 1475, 1480 a-Halocarhonyl compounds, as alkylating agents 735,740 Haloenamines 5, 9-see also Bromoenamines, Chloroenamines reactions of 904 with amines 1315, 1318 with nucleophiles 994 vinylic cleavage of 443 a-Haloethers, as alkylating agents 735 IIaloketones, synthesis of 787-790 a-Halonilriles, as alkylaling agents 735 Halo-a,@-unsaturatedacyl halides, as annulating agents 829 Hammett p values 1053, 1073, 1075, 1076, 1081 Hammett u values 56 Hantsch ester, as reducing agent 986 Hantzsch reaction 530, 532, 549,555, 583, 590 Hantzsch-type cyclocondensation 1197 Hartree-Fock SCF MO methods 24 Heptaldehyde citronellal, enamines of, electrooxidation of 959 Heptatrienals-see Amino-2,4,6-heptatrienals Herr-Heyl synthesis 469, 470 Heterocyclic enamides, ozonization of 935 Heterocyclic enamines 11 IR spectra of 74 oxidation of 932, 936-939, 949, 951 biochemical 953 photochemical 926, 928, 929, 931 rearrangement of 907, 908 reduction of 977-980 formic acid 981 hydride 962,963, 965-967,973 NADH 984,985 Heterocyclic @-enaminoesters5 Heterocyclic synthesis, of eight-membered rings 1040, 1041 of five-membered rings 1018-1026,1561 of four-membered rings 1016-1018,1560 of seven-membered rings 1040, 1041 of six-membered rings 10261041, 1561, 1562 of three-membered rings 1016 Hetero-Diels-Alder reaction 528, 549, 610, 611,621, 1032, 1033
Subject index Hexachloroacetone, as chlorinating agent 793 Hexadienes-see Cyclohexadienes Hexahydroazepines, tritium-labelled, synthesis of 1168, 1169 Hexahydroindoles, hydride reduction of 973 Hexahydroindolizines, hydride reduction of 963,966 Hexahydroisoquinolines, photooxidation of 926 Hexahydropyridines, peroxidation of 939 Hexahydroquinolinediones, synthesis of 609 Hexahydroquinolizines, catalytic hydrogenation of 977 formic acid reduction of 981 hydride reduction of 963,965 photooxidation of 928 HOMO-LUMO properties, of simple and conjugated enamines 46 of vinylamine 69 Homopiperaz~ne,tritium-labelled, synthesis of 1168 Horner-Wittig reaction 478, 479 (5-HTlB) receptors, tritium-labelled, synthesis of 1158-1160 Hiickel molecular orbital calculations, for dienamines 1535 Hydrazones, electrophilic reactions at a-carbon 1519, 1520,1522-1524 Hydride reduction 960-973 Hydroboration-oxidation 975 Hydroboration-protonolysis 831-834 Hydrogen atom affinities 699-702 Hydrogen bonding 717-722 and deuterium isotope effects 394-398 in amidines 264 in 1-amino-2-nitroalkenes 373 in enaminoesters 240, 241 in enaminoketones 237, 238, 328, 352 in indigotin 267, 268 in nitroenamines 243, 719, 720 in Psulphinylenamines 718, 719 in tropones 266 Hydroindoles--see also Dihydroindoles, Hexahydroindoles, Tetrahydroindoles synthesis of 1022 Hydrolysis, acid catalysis of, general 1068, 1073, 1074, 1076, 1080,1081,1083, 1085, 1087, 1090, 1092,1096 base catalysis of 1096 general 1069 electrostatic effects on 1074 mechanisms of 1065-1096 pH-rate profiles of 1066, 1067, 1071, 1073, 1076, 1077, 1081,1087,1089 rate laws in 1067, 1069, 1074, 1080, 1081 salt and micellar effects on 1091
1671
solvent kinetic isotope effects on 1068, 1080, 1081, 1083, 1085,1087, 1090, 1092, 1096 steric hindrance in 1083, 1084, 1096 Hydromorfon, "c-labelled, synthesis of 1207, 1208 Hydroxycycloalkanones, synthesis of 616 5-Hydroxyfluorotryptophans, '*F-labelled, synthesis of 1216 Hydroxyindoles, synthesis of 557-559,569 Hydroxyketones, synthesis of 935, 936, 940, 947,948,959,968 Hydroxymcthylenccyclohcxanoncs, synthesis of 782
2-Hydroxymell~yl-1-rnelhyl-4-nitro-5imidazolcarbonitrile, 14~-labelled, synthesis of 1192, 1194 4-Hydroxyphenylquinolines, synthesis of 572 3-Hydroxypyrroles, synthesis of 610 Hydroxyquinolines, synthesis of 563,572, 606 5-Hydroxytryptamine, "c-labelled, synthesis of 1199 Hypoxaothooe, synthesis of 672
Imidazoleacetic acid, iS~-labelled,synthesis of 1146, 1147 Imidazoles-see also l-Alkyl-2methylimidazoles, Benzimidazoles 1Z5~-labelled1226, 1227 synthesis of 672,674-676,1392,1393 tritium-labelled 1165-1167 Imidazolinessee also 2-Methyleneimidazolines, 2Methylthio-4,s-dihydroimidazolines, 2-(Methylthio)imidazolines synthesis of 1022 Imidazolinones-see Benzimidazolinones Imides-see Carbodiimides, Vinylogous imides Imine-enamine tautomerism-see Enamineimine tautomerism Imines-see ulro u-Acylimioes, Enaminoimines, Ketenimines, Nitroimines, Propenimines acylation of 844, 845 alkylation of 845, 846, 848-861 mechanism of 852 regioselectivity of 852, 858, 859, 861 solvent effects on 859 stereocontrol in 857, 858, 861 transition states in 848, 852, 857, 858 bromination of 845, 847 cyclization of, via enamine tautomers 1041, 1042 electrophilic reactions at a-carbon 1511-1514 nitrile-see Nitrile imines
Subject index Imines (conf.) pyrimidine-see Pyrimidine imines quinone-see Quinone imines reactions with enamines 1017, 1018, 1029 rearrangement of 5, 7, 456,457 salts of 1508-1511 silylation of 845, 848 y,h-unsaturated-see y,h-Unsaturated imines Iminium ions 1050, 1051, 1053, 1056, 1061, 1081, 1083-see also a-Bromoiminium ions, Cyclopropaniminium ions, Diiminium ions, Eniminium ions, Keteniminium ions as alkylating agents 769-771 deprotonation of 1070 hydride reduction of 968, 969 imine conjugate bases of 1081 nucleophilic hydration of 1069-1071, 1074-1076,1080, 1085,1095, 1096 stability of 1072, 1073 synthesis of 3, 476 Iminoesters, reactions with amines 1317 Iminoisoxazolines, synthesis of 1357 3-lminopropyl radical cation 683 Iminostilhene, tritium-labelled, synthesis of 1168 Iminotosylates, as acylating agents 781, 782 Immonium double bond, stereochemistry of 246-248 Immonium ions, reactions with enamines 1028, 1029 Indanedione enamines, reactions with carbonyls 532 Indanone enamines, reactions of 1022 Indazoles, LS~-labelled 1149, 1150 synthesis of 1022 Indazolones, synthesis of 603 Indenodiazepines, synthesis of 532, 534 Indigotin, thermochemistry of 258, 267-269 Indole-3-acctaldehydc, radioactively labcllcd, synthesis of 1230, 1231 Indole-3-acetaldoxime, radioactively labelled, synthesis of 1230, 1231 Indole-3-acetonitrile, radioactively labelled, synthesis of 1230, 1231 Indoleacrylic acid, I4c-labelled, synthesis of 1170, 1171 Indolealkylamines, "c-labelled, synthesis of 1209 Indole-3-carbinol, tritium-labelled, synthesis of 1157, 1158 Indolediones-see Benzoindolediones Indolenines-see Methyleneindolenines
lndoles-see also Benzoindoles, Cycloheptindoles, Cyclooctindoles, Cyclopentindoles, N f l Dialkylaminovinylindoles, Hydroindoles, Hydroxyindoles, Pyrano[3,4-blindoles, Pyrrolo[l, 2-alindoles photooxidation of 926, 929 protonation of 1058, 1059 reactions of, with P,/%diketoenamines 606-608 with Pketoenamines 57&574 structure of 94, 142, 156 synthesis of 461, 566, 581, 958, 1021, 1357, 1387 Indolines, synthesis of 557,581,583, 607, 621,623 Indolizidines, synthesis of 963 Indolizines-see also Hexahvdroindolizines. 5-Oxoindolizines synthesis of 556 Indolones-see also Dihydroindolones, Tetrahydroindolones synthesis of 530, 535, 556, 581, 586, 616, 618 Indometacin farnesil, isotopically labelled, synthesis of 1232. 1233 INDO methods 48 Indoxyl derivatives, synthesis of 536 Infrared spectroscopy 69-76 of penaminones 1 7 of 1,l-enediamines 1310 of pyramidal vinylamine 32 Inversion path 89 Iodine-125, cytotoxicity of 1236, 1237 4-lodoantypyrine, 'I I-labelled, synthesis of Iodobenzodiazepines, ''I- and '"I-labelled, synthesis of 1226 Ion cyclotron resonance, in calculation of proton affinities 48 Ionic hydrogenation 984 Ionization energies 704, 705 Ionization potentials, correlation with proton affinities 5 3 effect on positronium formation 686 experimental 58, 59 Ion-neutral complexes 451 Isobutyraldehyde, enamines of, catalytic hydrogenation of 975, 976 hydride reduction of 969 hydrolysis of 1066-1073,1081-1084 peroxidation of 941 photooxidation of 924, 925 Isocyanates, as acylating agents 785, 786 Isodesmic reactions 55 Isoguanine, synthesis of 672
Subject index Isomerism, around a double bond 230 cisitrans-see Cisitrans isomerism EiZ-see EIZ isomerism Isonitroso-pdicarbonyl compounds, condensation with enamines 829 Isoquinolines-see also Dihydroisoquinolines, Hexahydroisoquinolines, Tetrahydroisoquinolines synthesis of 542,569,954 Isoquinolinium ions-see Cycloalka[c]isoquinolinium ions .....
Isothiazoles, synthesis of 627, 628, 1342, 1343. 1394.1395 , Isothiocyanates, as acylating agents 785, 786 ~-{1-[2-(4-lsothiocyanatophen~l-3,5-~~~)ethyl]-4-piperidininyl}propanamides, synthesis of 1153, 1154 Isoxazoles-see also 4-Acylisoxazoles isomerization of 604 reactions with enamines 1026 synthesis of 57&576,597,626,1022,1352, 1353, 1355, 1359,1393,1394 Isoxazolidines, synthesis of 1022 Isoxazolincs--see Iminoisoxazolincs Isoxazolones, reactions of 578 Ketene acetals, reactions with amines 1314 Ketene N#-acetals-see 1,l-Enediamines Ketene N,O-acetals 9-see also N-Allylketene N, 0-acetals, 0-Allylketene N.0-acetals reactions of 904 with amines 1315-1317 with triazines and tetrazines 1349 Ketene NJ-acetals 9 reactions of, with amines 1315,1316 with triazines and tetrazines 1349 synthesis of 1312 Ketene aminal-see also N-Allylketene aminals, 1,l-Enediamines, Nitroketene aminals stereochemistry of 417, 418 tautomerism in 899 Ketene dithioacetals, reactions with amines 1311-1314 Ketenes, as acylating agents 779, 817 as cycloaddition intermediates 1005 cycloaddition to enamines 798, 800, 830 Ketenimines, as intermediates 676 Keteniminium ions 5 Ketoacids, synthesis of 779, 780 fiKetoaldehydes, synthesis of 779 Ketoamides, synthesis of 769-772,927 0-Ketoamines, synthesis of 937, 938,959
a-Ketoazetidinones, synthesis of 624 a-Ketoazetines, synthesis of 624 a-Ketoenamines, aromatization of 625 cycloaddition of 617-621 photochemistry of 621-625 reactions of, with acetals 612, 613 with CH-acidic compounds 615, 616 with acyl halides 613 with aqueous base 617 with hydrazines 616, 617 with nitroolefins 1000, 1001 with organometallics 616 with phenol ether 616 with quinones 613-615 steroidal-see Steroidal a-ketoenamines 0-Ketoenamines 6, 7-see also 2-Acylenamines, /3,/3-Diketoenamines alkylation/arylation/acylation of 5 6 6 5 6 8 anodic oxidation of 569, 570 aromatization of 582-584 cyclic-see Cyclic p-ketoenamines cycloaddition of 580, 581, 600-602 photochemistry of 581, 582 reactions of, with CH-acidic compounds 578, 592, 593 with activated aromatic compounds 594 with aliphatic amines 594, 595 with alkynesiarynes 555-557 with amidines 596, 597 with aromatic amines 570-574,594, 595 with bromine 564, 592 with carbonyls 530-534,587-589 with carboxylic acids 536-539 with 0-dicarbonyls 539-544, 589-591 with guanidine 596, 597 with heterocumulenes 526-530, 591 with hydrazine 574576,597-599 with hydridesihydrogen 576, 577, 599, 600 with hydroxylamine 576576,597-599 with indoles 570-574 with metal complexes 568 with nitroketene aminals 596 with nitronium ions 564 with phenols 570-574 with quinone imines 5 8 4 5 8 7 with quinones 557-564,584-587 with radicals 578, 579 with a,punsaturated carbonyls 544-555 a-Ketoesters, enamides of, photocyclization of 643-645 synthesis of 927 BKetoesters, synthesis of 787 BKeto-0'-hydroxyethers, synthesis of 940, 941 Ketomalonates, as alkylating agents 768, 769
1674
Subject index
Ketones-see also 2-Acetoxyketones, Aminoketones, Chloroketones, aCyanoketones, Dibromoketones, Enaminothiokelones, Ilydrox! ketones, ( I Nu>\lkcloneb. Pmtatluoro-I. 3-Jikcluncs. Selenoketones, a-Siloxyketones, Sulphonyloxyketones cyclic-see Cyclic ketones cnamincs of, allylic cleavage of 439, 440 &-unsaturated-see a,PUnsaturated ketones 0-Ketosulphonamides, synthesis of 785 0-Ketosulphones, synthesis of 784, 796 PKetosulphoxides, synthesis of 785 Kinetic control 759 in reactions of dienamines 1535 versus thermodynamic control 731, 810 Koopmans' theorem 58, 59 Kurtosis coefficient 98,101-103,116-118 synthesis of 1182, L-637, 510, 14~-labelled, 1183 Lactam-fused compounds, synthesis of 1328, 1329, 1331-1333 Laclams--see also Enaminolactams synthesis of 624, 625, 638, 640, 643 Lactones-see 2-Amino-~lactones,a Methylenebutyrolactones Lawesson's reagent 627 Lithium enamides 1507-1529 Lithium enamines 714 oxybenzoylation of 939 Lone-pair interaction, nitrogen 234 Lorazepam, deuterium-labelled, synthesis of 1125, 1126 of 1138 Lumichrome. 13c-labelled., svnthesis , Lycopodines, synthesis ot 651, 652 Lysergine, synthesis of 641 Lysergol analogues, radiolabelled, synthesis of 1233-1236 Macroincrementation reactions 259, 269 Madelungs method 1180 M a l o n a t e s s e e Ketomalonates Mannich base 782 Mannich-Davidsen synthesis 468, 469 Mannich reaction 532, 588, 659, 661, 1346, 1347 Manzamine A 665,666 Mapindolol, 14C-labelled, synthesis of 11XU Mass analysed ion kinetic energy (MIKE) spectrometry 438 Mass spectrometry, high-pressure 48 of 1,l-enediamines 1310 Mepivakain, "c-labelled, synthesis of 1207, 1208 Mercaptocyclopropanes, formation of 796
Mercaptopyrimidines, synthesis of 591 Merocyanines, thermochemist of 263, 264 Mesoporphyrin IX dichloride, %Im Sn-labelled, synthesis of 1241 Mesulergin, "c-labelled, synthesis of 1208 Metalloenamines 5, 9 in asymmetric synthesis 248 reactivity of 8 stereochemistry of 245, 246 Methacrylates--see PAminomethacrylates Methacrylonitrilessee 0Arninomethacrylonitriles Methanoprolines, synthesis of 646 Methotrexate, 15~-labelled,synthesis of 1147-1149 a-Methoxyamides, elimination reactions of 462 Methoxybutenones, reactions with enamines 814, 816 a-Methoxycarbamates, reactions of 462, 464 2-Methoxycycloalkanones, synthesis of 957 . . N-Methylacyclovir, "c-labelled, synthesis of 1199. 1200 1-~ethylaminosteroids,rearrangement of 454 9-Methylamino-1,2,3,4-tetrahydroacridine,"clabelled, synthesis of 1201 I -N-Methylanilino-4,4-diacylbutadienes,
stereochemistry of 426 N-Methyldexetimide, "c-labelled, synthesis of 1207, 1208 Methylenhisenaminones, synthesis of 532 a-Methylenebutyrolactones, synthesis of 1372
Methylenecycloalkanonessee Hydroxymethylenecycloalkanones 2-Methyleneimidazolines, reactivity of 1306, 1307 Methyleneindolenines, oxidative dimerization of 947 2-Methylenetetrahydropyrimidines, reactivity of 1307 Methyl group, conformation of, in vinylamine tautomers 3 3 (S)-N-[D3]Methylhistidine, synthesis of 1120, 1121 N-Methylketanserin, "c-labelled, synthesis of 1203,1204,1207,1208 synthesis N-Methylnomifensine, lL~-labelled, of 1206,1207 N-Methylparoxetine, "c-labelled, synthesis of 1204 Methylpyrazoles, deuterium-labelled, synthesis of 1123,1124 Methylpyridines, deuterium-labelled, synthesis of 1134,1135 2-Methylthio-4,5-dihydroimidazolines, as 1 , l enediamine precursors 1320
Subject index 2-(Methylthio)imidazolidines, as 1 , l enediamine precursors 1321 Methyl vinyl ketones, as alkylating agents 746, 749, 750, 776, 778,804,806-814 cycloaddition to dienamines 1548-1555 Michael addition 549, 551, 578, 599, 606, 615, 618,619,626 Michael multicoupling reagents 1003 Microscopic reversibility 1072 Microwave studies 12 MIND013 methods 24, 46 Misonidazole, '5~-labelled,synthesis of 1150-1152 Mitomycin C, tritium-labelled, synthesis of 116\4 MK-571, C-labelled, synthesis of 1176 MNDO methods 24,48 Modes 98, 102,103,11&118 Molecular beam experiments, in calculation of proton affinities 48 Molecular orbital diagrams 58-61 Molecular orbital energies, a b initio calculations of 59-61 Mailer-Plesset treatment 24 l-Morpholino-3-azabutadienes,stereochemistry of 428 1-(4-Morpholino)-l,2-diphenylethylene, EIZ isomerism of 220 Morpholinoenamines, NMR spectra of 282-286,288, 289, 292, 293 radical reactions of 879, 880 MP216 calculations 32 M m , l l ~ - l a b e l l e dsynthesis , of 1207 NADH model reduction 984, 985 NADPH reduction 986 Naphthofurans-see also Dihydronaphthofurans synthesis of 559, 560 Naphthopyridines-see Dihydronaphthopyridines 1,6-Naphthyridines, synthesis of 542 Naphthyridinones, synthesis of 1416 Naphthyridones, synthesis of 539 Naucleficine, synthesis of 642 Nenitzescu reaction 557-564,584, 613 analogues Neuroleptics, ['*~]fluoroalk~lated of, synthesis of 1215 Newmans projection 229 Nicardipine, tritium-labelled, synthesis of 1161, 1162 Nicotinamide, '3~-lahelled,synthesis of 121 1 Nicotinamide cofactors 1292, 1293 Nicotinic acids-see Dihydronicotinic acids Nicotoxins-see Perhydrohistrionicotoxins Nifedipine, "c-labelled, synthesis of 1197
1675
Nimodipine, "c-labelled, synthesis of 1206 Nisoldipine, "c-labelled, synthesis of 1197 Nitrendipine, "c-labelled, synthesis of 1197 Nitrile imines, reactions of 1352 Nitrile oxides, reactions of 1352-1355 Nitriles-see Enaminonitriles, a-Halonitriles, Phenylselenonitriles Nitrilimine-enamine cycloadducts 1022 Nitrilinm ions 1447-1451,1480, 1481, 1484, 1485, 1497 as iminoalkylating agents 769, 771 Nitroacrylates-see also 3-Amino-2nitroacrylates as alkylating agents 760 2-Nitro-2-acylenamines, stereochemistry of 415,416 Nitroalkenes-see also a-Acyloxymethyl-anitroalkenes, 1-Amino-2-nitroalkenes as alkylating agents 751-760,776, 777 reactions of, with enamines 1037 with enaminones 1000,1001 Nitroallylic esters, as annulating agents 826 3-Nitrobenzofurans, synthesis of 625 p-Nitrobenzyl chloride, as alkylating agent 740 photoreactions with enamines 876-879 Nitrochlorobenzenes, as arylating agents 761, 762 Nitrocrotonatessee 3-Amino-2nitrocrotonates Nitrocyclopentanones, synthesis of 619,620 Nitrodienes. reactions with cvclic enamines 1037,'1039 Nitroenaminessee also 2-Acyl-2nitroenamines, 2,2-Dinitroenamines configuration and conformation of 242-245 hydrogen bonding in 243,719,720 NMR spectra of 369,372-393 polarographic reduction of 986 synthesis of 499, 500 tautomerism in 890 N-Nitroenamines 8 thermolysis of 902 fl-Niitroenamines 5, 9 dipole moments for 63 electron dislributions in 431 electronic structure of 406 IR spectra of 75 reactions with quinones 625 stereochemistry of 4 1 1 4 1 3 UV spectra of 69 Nitroimines 902 Nitroketene aminals, reactions with P ketoenamines 596 Nitronic esters, cyclic-see Cyclic nitronic esters
Subject index Nitronium ions, reactions with pketoenamines 564 Nitropyridines--see also Chloronitropyridines synthesis of 551 N-Nitrosoenamines, reactivity of 8 0-Nitrosoenamines 9 NMR bandshape technique 407 Norbornanone, enamine of 983 Norcamphor, cnamine of 983 a-Nosylketones, synthesis of 940 Nuclear magnetic resonance spectroscopy, "C 281-294,327-334,336347,354-357, 361-364,368,376388,392,393 'H 299-325,327-347,353-364,366,368, 376388,392,393 3 ~ nuclear , Overhauser effects in 1169, 1170 1 5 294-299,347-357,361-364,370-380 ~ of enamine E/Z isomers 222-224 of enaminones 325-365 of enaminonitriles 365-369 of 1,l-enediamines 1310, 1311 of nitroenamines 369, 372-393 of simple enamines 281-325 Nuclear Overhauser effects 1169, 1170 Nuclear shielding, deuterium isotope effects on 1116, 1 1 1 1 Nucleophilic vinylic substitution 1085, 1096
Octahydroquinolines, oxidation of 951 Octalones, enamines of, hydride reduction of 970 formation of 804,806 Orbital bias 734, 735 Orbital control, in reactions of dienamines 1536,1548,1550 Orthoformates, as alkylating agents 772, 773 Overhauser effect 222, 223 Oxadiazines, synthesis of 837439, 1430, 1431 Oxadiazolones, synthesis of 617, 618 Oxazepines-see Benzocyclopentoxazepines 1,2-Oxazine-N-oxides 1000--see also Dihydro1,2-oxazine-N-oxides synthesis of 619, 1038 O x a z i n e s s e e also Benzoxazines, Dihydro1,2-oxazines, 5,6-Dihydro-4H-1,3oxazines synthesis of 1428-1430 Oxazinium ions 1449,1451,1456,1481,1484 Oxazoles, synthesis of 579, 1022, 1394 Oxazolidinylalkenoates, as alkylating agents 776 Oxetanes-see Dioxetanes
Oxidants, one-electron, reactions with enamines 884-886 Oxidation levels 1442, 1443, 1473, 1497 Oxidation-reduction cofactors 1291-1293 Oxime ethers, cyclic-see Cyclic oxime ethers electrophilic reactions at a-carbon 1526-1528 Oximcs, rcgio- and stcrco-sclcctivc reactions at a-carbon 1524-1526 Oximu~oenaniines,autoxidation of 932 Oxiranes-see Dioxiranes y-Oxoacrylates, synthesis of 577, 968 4-Oxo-p-carbolines, synthesis of 568 Oxogambirtanine, synthesis of 642 2-Oxoindolin-3-ylidene derivatives, as alkylating agents 751, 754 5-Oxoindolizines, synthesis of 552, 553 4-Oxo-2-quinolinecarboxylates, synthesis of 572 4-Oxotetrahydroindoles, synthesis of 534, 547 5-Oxotetrahydroquinolines, synthesis of 547 Oxybenzoylation 939 Ozonization 933-935
Pariser, Parr and Pople (PPP)-type r-electron calculations 46 Pauling rule 146, 165 PC variables 99, 100 Penem antibiotics, '4~-labelled,synthesis of 1188, 1189 Pentadienal-see Amino-2,4-pentadienals Pentafluoro-I ,3-diketones, synthesis of 787 Pcntalcnoncs, synthcsis of 619, 620 2J-Pentandione methylpymvate, enamines of, photooxidation of 927 3-Pentanones, enamines of, electrooxidation of 958 hydride reduction of 969 ozonization of 935 photooxidation of 925 Pentostatin, tritium-labelled, synthesis of 1155, 1156 0-Perfluoroalkylenamines9 Perfluoroalkyl iodides, as alkylating agents 740 a-Pertlnoroalkyl ketones, synthesis of 740 Pertluoroarenes, as arylating agents 764 u-Perfluoroaryl ketones, synthesis of 764 Pergolide analogues, radiolabelled, synthesis of 1233-1235 Perhydrohistrionicotoxins, synthesis of 657, 659 Perlinone, '4~-labelled,synthesis of 1186, 1187 Permanganate oxidation 943, 944 Peroxidation 935-942
Subject index Phenanthridines, synthesis of 528, 529, 541, 581,595 ~henanthkdiniumions, synthesis of 561 Phenanthridones, synthesis of 556, 606 P-Phenethylamine, 13~-labelled,synthesis of 1212 @-Phenethylenaminones,anodic oxidation of 462 Phenols-see also o-Aminophenols reactions with 0-ketoenamines 570-574 Phenones, enamines of, electrooxidation of 958 hydrolysis of 1073-1076 lead tetraacctate oxidation of 945 peroxidation of 941 photooxidation of 925 reductive alkylation of 984, 985 snlphonyloxaziridine oxidation of 948 Phenoxazinones, synthesis of 536,537 Phenylalanine, determination of, in blood 442 N-Phenylenamines, photocyclization of 647-649 o-Phenylendiamine enaminones, reactions of 532,534 ~hen~lselenonitriles, as alkylating agents 760 0-(PLe~~ylselenyl)e~~a~lines 9 Phenylthiomethylamines, as alkylating agents 772Phenyl vinyl ketone, as alkylating agent 751-753 reactions with dienamines 1550, 1551 Phosgene, as acylating agent 787 Phosphinines-see Azaphosphinines Phospholanone oxides, enamines of 984 0-Phospholene sulphide enamines 1 0 Phospholes, synthesis of 1389 Phosphoric acids, effect on polymerization 686 Photoelectron spectroscopy, and MO diagrams 58-61 of allylamine 683 Photo-Fries reaction, of vinylogous imides 668, 669 Photoisomerization, cisltrans 638, 662, 663 Photooxidation 924-931 Pimonidazole, deuterium- and tritium-labelled, synthesis of 1128, 1130, 1131 Pindolol, "c-labelled, synthesis of 1198, 1199 Piperidine-2-carboxaldehydes,synthesis of 592 Piperidine-3, 5-diones, enaminones of 534 Piperidines-see Alkenylpiperidines 1-Piperidino-3-azabutadienes,stereochemistry of 428 Piperidones, enamines of, formic acid reduction of 982 Pirmenol hydrochloride, 13c- and '4~-labelled, synthesis of 1142
1677
PK 14105, 'R~-labelled,radiosynthesis of 1217, 1220 pK, values 709-712,1051,1053,1065 Planarity, of enamine system 123, 156 distortion from 123, 128-137 synthesis of 1239 5-PMT, 99m~c-labelled, Polarographic reduction 986, 987 Polyenamines 9 stereochemistry of 4 2 6 4 2 8 Polymerization, by radiation 6 8 6 6 9 3 graft 686 Polymethine dyes, stereochemistry of 4 2 8 4 3 0 Positronium formation 685, 686 Post-Hartree-Fock calculations, of harriers of inversion 32 Prazosin, "c-labelled 1205 tritium-labelled 1154, 1155 PRDDO method 25, 26 Prebiotic synthesis 672 Primary enamines 5-7 hydrolysis of 1065,1076-1080 NMR spectra of 281-283,301,302,304, 305,310, 313,315 pK, values for 1053 synthesis of 493 Principal Component Analysis (PCA) 99, 100, 134, 137, 158 for bond angles 140-143 for bond lengths 137-139 for torsion angles 123, 142, 144-147, 156 Principle of least motion 1087 Prodolic acid, 14c-labelled, synthesis of 1173 Propadienessee Sulphonylpropadienes Propargylic halides, as alkylating agents 735, 736,738,740 Propen-2-enylamine radical cation 683 Propenimines, X-ray studies of 247 Propenyl ketones, reactions with enamines 814 P-Propiolactone, as alkylating agent 770, 772 Propiolates, as alkylating agents 760, 761 Propionaldehydes, enamines of, oxidation of 951 - Propionates, '3~-labelled,synthesis of 1140-1142 Proton affinities, correlation with first ionization constants 53, 54 gas-phase 48 Protonation 1051-1065 agents for 53 C- versus N- 731, 1092 intermolecular 807 intramolecular 747, 748, 752 of activated arenes 1094, 1095 ~
1678
Subject index
Protonation (conr.) rate-controlling 1067-1069, 1074, 1076-1079,1095 sites for 698, 699, 709-712,731, 732 steric effects on 1093 Protonation energies 48 basis set dependence of 49 of vinylamine and tautomers 33 Push-pull enamines 226, 227,230 configuration and conformation of 2 3 6 2 4 5 Push-pull ethylenes, potential energy curves for 420, 421 stereochemistry of 406, 407 Push-pull through-conjugation effect 6, 94, 118, 141,156, 158, 165 Pyramidality coefficients 123, 128-137, 155, 156 Pyramidalization 63 after rotation 30 energy of 3 9 , 4 5 in-plane 28 of nitrogen atom 89, 90, 106 percentage of 13 Pyrano[3,4-bjindoles-see also Thiopyrano[3,4-blindoles 14c-labelled, synthesis of 1172, 1173 Pyranones-see Benzopyranones, Tetrahydropyranones, Thiapyranones Pyranopyrazoles-see Benzopyranopyrazoles Pyranoquinolines, synthesis of 546 Pyrans-see also Dihydropyrans, Selenapyrans, Thiapyrans synthesis of 1398-1404 Pyrazoles-see also Methylpyrazoles, Pyranopyrazoles, 3-Vinylpyrazoles deuterium-labelled 1123, 1124 synthesis of 574,575, 598, 602, 603,605, 627,628, 1352, 1353, 1358, 1391 Pyrazolones, reactions of 578 Pyrazoloquinolones, synthesis of 536,537 Pyrazolylpyridines, synthesis of 598 Pyridazines-see also Pyridopyridazines reactions with enamines 1012 synthesis of 1034,1036,1421-1423 synthesis of Pyridinealdoxime-4, L4~-lahelled, 1183,1184 Pyridinecarboxylic acids, '4~-labelled1188 synthesis of 544 Pyridines-see also 3-Acylpyridines, 4Arylpyridines, 3-Cyanopyridines, Cycloalkanopyridines, Cycloalkenopyridines, Dihydropyridines, Hexahydropyridines, Methylpyridines, 3-Nitropyridines, Pyrazolylpyridines, Pyrrolo[3, 4-clpyridines, Tetrahydropyridines
reactions with fl,fl-diketoenamines 606-608 synthesis of 542-544,555,556,589, 597, 610,626, 1026-1028,1406-1420 Pyridinethiones, synthesis of 526, 1418 Pyridinium ions-see 3-Acy lpyridinium ions, Tetrahydropyridinium ions 2-Pyridinones, synthesis of 1028, 1029 Pyridones-.see also Cycloalkenopyridones, Dihy dropy ridones synthesis of 528, 536, 543,594, 608, 611, 626,944, 946, 1415, 1416 Pyridopyridazines, synthesis of 1417, 1418 Pyridopyrimidines, synthesis of 538, 597, 608, 1419, 1420 Pyridoxal-dependent enzymes 1286-1288 N-Pyridoxal-5-methyltryptophan, *TClabelled, synthesis of 1239 Pyrimidine-4-aldehydes, synthesis of 596 Pyrimidine imines, synthesis of 591 Pyrimidines-see also Chlorodicarbethoxypyrimidines, Mercaptopyrimidines, Pyridopyrimidines, Pyrimidopyrimidines, Tetrahydropyrimidines synthesis of 588, 593, 596, 598, 604, 605, 626-628,1034,1035,1423-1428 Pyrimidinethiones, synthesis of 1427 Pyrimidones, synthesis of 626, 1426 Pyrimidopyrimidines, synthesis of 597 Pyrimidoquinazolines, synthesis of 538 Pyrimidoxime, 14~-labelled, synthesis of 1183 Pyrimidylsulphometuron methyl, 14c-labelled, synthesis of 1171, 1172 a-Pyrones. cycloaddition to enamines 829 synthesis of 1402 Py rrole-see also 3-Acy lpy rroles, Benzodipyrroles, Cyclopenta[c]pyrroles, 3-Hydroxypyrroles hydrolysis of 1091-1095 protonation of 1058, 1063, 1064 synthesis of 461,528, 530, 536, 944, 946, 954, 1376-1389 Pyrrolidine-2-carboxaldehydes, synthesis of 592 Pyrrolidines, enamines of, reactions with perhaloalkanes 875, 876 Pyrrolinones, synthesis of 544,578 Pyrrolizidines, synthesis of 977, 1021, 1380 Pyrrolizines--see Tetrahydropyrrolizines Pyrrolo[l,2-alindoles, synthesis of 567 Pyrrolo[3,4-clpyridines, synthesis of 552, 554 Pyrroloquinolines, synthesis of 571 Pyruvate decarboxylase 1266 enamines bound to 1268-1271
Subject index Pyruvate dehydrogenase multienzyme complex
1266 Pymvyl-dependent decarboxylations
1288-1291 Pyrylium ions-see ulso Azapyrylium ions cycloaddition to enamines 829 Quantum-chemical variational principle 24 Quinazolinediones, synthesis of 604 Quinazolines-see ulso Pyrimidoquinazolines synthesis of 572,1035,. 1036,1426 Quinolinecarboxylates, synthesis of 606,607 Quinolinediones-see ulso Hexahydroquinolinediones synthesis of 555 Quinolines-.see also Aminoquinolines, 1,4Dihydroquinolines, Dimethoxyquinolines, 4-Hydroxyphenylquinolines, Hydroxyquinolines, Octahydroquinolines, Pyranoquinolines, Pyrroloquinolines, Tetrahydroquinolines synthesis of 538,544,552,555, 556 Quinolinones,see also Dihydroquinolinones synthesis of 539 Uuinolizidines, catalytic hydrogenation of 977 synthesis of 963,965,981 Quinolizinessee Decahydrobenzo[c]quinolizines, Hexahydroquinolizines Quinolones-.see also Dihydroquinolones, Pyrazoloquinolones synthesis of 536,537,546,572,581,608,
609 Quinone dihenzenesulphonimide, as arylating agent 764 Quinone imines, reactions with enaminones
584-587 o-Quinone methides, synthesis of 1400 Quinones--see also Benzocarbazolquinones, Benzoquinones reactions of, with enaminones 557-564,584-587,
613615 with 0-nitroenamines 625 Radiation, ionizing, chemical effects of 681 Radical addition, regiochemistry of 874,875 stereoselectivity of 88&883 to C = C bond of enamines 875-883 Radical cyclization, intramolecular 883 Radiopharmaceuticals, "c-labelled 1207,1208 %labelled 1214-1223 Reductive amination 960,962, 978 Regioisomerism 55-58
Regioselective oxidation 942 Regioselective reduction 961,962,971-973,
975 Regioselectivity, of dienamine reactions 1536,1548 of electrophilic reactions at a-carbon, of amides 1514-1516 of amidoesters 15161518 of imincs 1511,1512 Resonance energies 256 for anti-Bredt enamines 269,270 for tropones 265 Resonance stabilization, in cycloalkenylpiperidines 262 in dihydropyridines 266 in simple enamines 259-261 in tropone 264 Retroaldol cleavage 1087 Retro-Diels-Alder reaction 447,619 Retro-Mannich fragmentation 653,654,
656-659,661-663 Retropinacol rearrangement 1463,1467,1476,
1484,1494 Rifabutin, L4~-labelled, synthesis of 1190,
1192 Rifamycin L 105,tritium-labelled, synthesis of
1152,1153 Rimexolone, tritium-labelled, NMR spectra of
1169 Ring contraction 802 Ring expansion 760,800,801,830 Ring formation-see Carbocyclic synthesis, Hctcrocyclic synthcsis Ring opening, disrotatory 994 Ritter reaction 1447,1451,1453,1457-1460,
1476 Ko 15-1788, "c-labelled,
synthesis of 1200, 1201 Ro-03-8799, deuterium- and tritium-labelled, synthesis of 1128,1130,1131 Robinson annelation 544 Rotational harriers, around C-N bond 231-234,236 in p-enaminones 48 in vinylamincs 31,32,42 solvent effects on 432,433 RS 86,"C-labelled, synthesis of 1204 RSU-1069,deuterium- and tritium-labelled, synthesis of 1128,1130,1131 Ruhottom oxidation 653 Rule of five 653 Ruthenocene compounds, '"Ru-labelled, synthesis of 1240 Sample standard deviation 98 Sample variation, total 100 Scatter plots 100 of angular parameters 130,155
Subject index
1680
Scatter plots (cont.) of bond angles 144 of bond lengths 139,148-155 of pyramidality coefficients 128, 129 of torsion angles 147 principal-components 139, 144, 147 Sch 37224, 14c-labelled, synthesis of 1175 Schiff base enzymes 1283-1291 Schiff bases, iminium ions derived from 1075 Schotten-Baumann reaction 657 Secondary enamines 7 hydrolysis of 1065, 1076-1084 NMR spectra of 301-313,315 pK, values for 1053 reactions of 844-847 with electrophilic alkenes 730, 848-861 synthesis of 493, 494, 843, 893, 895 tautomerism in 843-861,890,891 Selenapyrans, synthesis of 1405 Selenoenamines-see PArylselenoenamines fl-(Selenoketo)enamines 9 Selenoketones-see a-Arylselenoketones Semicarbazones, reactions with enamines 1035, 1036 I-Serines, isotopically labelled, synthesis of 1143, 1144 Sigmatropic rearrangement 740 [1,3]Sigmatropic rearrangement 57, 728, 899-903 [1,5]Sigmatropic rearrangement 1015 [3,3]Sigmatropic rearrangement 57, 728, 908-9 19 in acylation ot enamines 817 in alkylation of dienamines 1540, 1541 in alkylation of enamines 736 in cycloadditions 1005 a-Siloxyketones, synthesis of 841,842 Silylenamines-.ee also NTrimethylsilylenamines synthesis of 8, 9 N-Silyloxyenamines, hydride reduction of 971 Skewness coefficients 98, 101-103,116-118 SK&F 86002, 14~-labelled,synthesis of 1186 Slater-type atomic functions 24 Solvated electrons 682 Solvent effects, on configuration of nitroenamines 244, 245 Sonification, use in methylation 1209, 1210 Spin trapping 682 Spiperone, %labelled, synthesis of 1217, 1218,1220 Spiroannulation 816 Spiro compounds, synthesis of 532,538,539, 561,563,573,574,579, 587, 621, 623425.802 Spirocyclization 575
.~~
Spiro-piperidylrifamycins, '4~-lahelled, synthesis of 1190, 1192 SR 2508, deuterium- and tritium-labelled, synthesis of 1131-1133 SR 33557, '4~-labelled,synthesis of 1192, 1195 Stabilization energies, for tropones 265 Standard error of the mean 98, 102, 103, 116-118 Stanozolol, 14~-labelled,synthesis of 1197 STATGRAPHICS PLUS program 96,100 Statistical analysis, descriptive 96-98, 101-134, 158 multivariate 99, 100 Stereodifferentiation, double 775 Stereoselective oxidation 947 Stereoselective reduction 9 6 S 9 6 5 , 975, 978, 979,981,982, 984 Stereoselectivity, in electrophilic reactions at a-carbon, of amides 1514-1516 of amidocsters 1516-1518 of imines 1512-1514 Sterically hindered enamines, acylation of 779 alkylation of 738 Steric effects, on tautomerism of 1,lenediamines 1309 Steric interactions 231, 234 Steroidal dienamines, Hantsch ester reduction of 986 hydride reduction of 961 Steroidal enamines, horane reduction of 974 chemical oxidation of 944 formic acid reduction of 982 Hantsch ester reduction of 986 hydride reduction of 971 oxidative cleavage of 951 ozonization of 934 peroxidation of 936, 937 photooxidation of 929, 930 Steroidal a-ketoenamines, hydride reduction of 968 STO-3G basis sct studics 48 Stork aza-annulation 1029 Stork reaction 3, 1001 Strain, A(', and A(', 3I 234, 236, 359 Structural correlation principle 88, 90, 165 S t ~ c t u r a data l retrieval 93-96 Styrenes-see Aminostyrenes, Anilinostyrenes Substituent effects 158-164 Substituents 96 specific 113-123 unrestricted 96, 98, 101-113, 131, 134 Sulphamoyl halides, reactions with enamines
,
,!2
Subject index Sulphenes, as intermediates 784, 1366, 1367 reactions with enamines 1016, 1560 Sulphenium enamines 9 Sulphenylcyclohexanones, synthesis of 785 Sulphenyl halides, reactions of, with enamines 785 with 1,l-enediamines 1346 Sulphir~icacids, reactions with enamines 784, 785 /%5ulphinylenamines, hydride reduction of 962, 963 hydrogen bonding in 718,719 Sulphonamides-see @Ketosulphonamides Sulphones-see ulso 0-Ketosulphones as reductive alkylating agents 740 synthesis of 784 Sulphonium ions-see Enaminosulphonium ions Sulphonyl compounds, reactions with enamines 784,785 &Sulphonylenamines 9 Sulphonylimides, reactions with enamines 1017 N-Sulphonylimines, reactions with dienamines 1560 S~~lphonyloxyketones, synthesis of 7x5 Sulphonyl peroxides, reactions with enamines 785 Sulphonylpropadienes, as alkylating agents 759. 760 ~ul~hoxides-see Enaminosulphoxides, /3 Ketosulphoxides Tabersonine, deuterium-labelled, synthesis of 1127, 1128 Tandamine hvdrochloride. 14~-labelled. " synthesis of 1175 Tautomerism, enamine-imine-see Enamine-imine tautomerism 1,l-encdiamine-amidine 1308, 1309 enol-ketesee Enol-keto tautomerism Taxancs, synthesis of 653 Terpyridine, synthesis of 592 Tertiary enamines 7, 8 N-cyclic-see N-Cyclic tertiary enamines hydrolysis of 1065-1076,1083, 1084 NMR spectra of 281-287,294-296, 301-314 N-oxides of 8 protonation of 1056, 1057 reactions with electrophiles 1050 thermochemistry of 3 2 Tetraaminoethylenes 5 Tetracyanoethylenes, reactions with enamines 801
Tetrahedral intermediates, in enamine hydrolysis 1072 Tetrahydrochromanones, synthesis of 816, 817 Tetrahydrocoumarins, synthesis of 601 Tetrahydroindoles-see ulso 4Oxotetrahydroindoles synthesis of 552 Tetrahydroindolones, synthesis of 618 Tetrahydroisoquinolines, catalytic hydrogenation of 978, 980 hydride reduction of 973 NADH reduction of 984,985 photooxidation of 931 Tetrahydrooxazinones, formation of 620 Tctrahydrophcnylcyclopcntatriazoloncs, synthesis of 621, 623 Tetrahydropyranones, enamines of, formic acid reduction of 982 Tetrahydropyridines, Ag(1) or Ce(1V) oxidation of 949 autoxidation of 932 biochemical oxidation of 953 peroxidation of 938 ruthenium tetroxide oxidation of 951 Tetrahydropyridinium ions, synthesis of 531, 1327, 1328 Tetrahydropyrimidinessee also 2-
Methylenetetrahydropyrimidines svnthesis of 532 Tetrahydropyrrolizines, catalytic hydrogenation of 977,979 Tetrahydroquinolines-see also 5Oxotetrahydroquinolines synthesis of 1029, 1030 Tctrakis(dimethylamino)titanium, reactions with amides 1318, 1319 2-Tetralones, enamines of, oxidation of 948 Tetramethyluric acids, '4~-labelled,synthesis of 1182 Tetrazines, reactions with enamines 1034, 1035 synthesis of 1142 Tetrazole, L3~-labelled, Theophylline, deuterium-labelled, synthesis of 1119 Thcrmodynamic control, in reactions of dienamines 1535, 1537 Thiadiazines, synthesis of 1430, 1431 Thiamin diphosphate 1254, 1255 Thiapyranones, synthesis of 1406 Thiapyrans, synthesis of 1404-1406 Thiapyran-2-thiones, synthesis of 1406 1,2-Thiazetidine-1,2-dioxide, synthesis of 1371 Thiazines-see Benzothiazines Thiazinethiones, synthesis of 627 Thiazoles-see also Benzothiazoles, Dithiazoles synthesis of 1394, 1395
1682
Subject index
Thiazolium ions--see ulso 2-Alkylthiazolium ions electrooxidation of 955 Thienoazepines, synthesis of 627, 628 Thietane-1,l-dioxides, synthesis of 784, 1016, 1017 Thietanes, synthesis of 1366-1368 Thioamides, synthesis of 786 Thiocyanates, "c-labelled, synthesis of 1206 0-(Thioket0)enamines 9 Thiones-.see Enaminothiones Thiophenes, synthesis of 1342, 1343,
.. synthLsis of'1172, 1173 Thioridazine, deuterium-labelled, synthesis of 1128, 1129 Thiosulphonates, reactions with enamines 784 Thioureas, as 1,l-enediamine precursors 1319-1321 synthesis of 845 Thorpe-Ziegler cyclization 506 Titanium tetrachloride method, for enamine synthesis 470-472 Torsional barriers, in 1,l-diamino-2,2diacylethenes 4 1 9 4 2 1 Torsional processes 230 Torsion angles 88, 89, 96, 97, 100, 101, 103, 106, 109,112,113, 117, 118 frequency histograms for 110, 111, 124, 125 of crystalline enamines 228 PCA for 123,142,144-147,156 Tosylate-see Iminotosylates Transition state energy, in alkylation of dienamines 1538 Transition state imbalance 1079 Transition states, product-like, in reactions of dienamines 1535 Transketolase 1281-1283 Triaminobenzenes, hydrolysis of 1091-1094 Triazines, reactions with enamincs 1026, 1027, 1034,1035 Triazinylmetsulphuron methyl, 14c-labelled, synthesis of 1171, 1172 synthesis of 1024~1026,1352,1354,1355, 1396,1397 Tricarbonyl(dienamine)iron complexes, fragmentation of 446 Trichlorosilane, as reducing agent 984 TriHuoromethyldihenzothiopheniumtriflate, as alkylating agent 740 TriHuoromethyl metal reagents, as alkylating agents 740
Trimethylene dithiotosylate, reactions with enamines 837, 840 Trimethyloxonium tetraHuorohorate, effect on alkylation of enamines 737 4-Trimethylsilyl-3-dialkylaminocrotonates, condensation with enamines 829 N-Trimethylsilylenamines-see also NflBis(trimethylsilyl)enamines acylation of 782 Trimetrexate, isotopically labelled, synthesis of 1144-1146 Triquinans, synthesis of 621 Tropones, thermochemistry of 264-266 Tryptophan metabolism 1293, 1294 Tunichromes, synthesis of 638 Twist angles 131, 134, 144, 156, 419
Ultraviolet spectroscopy 63-69 of Bamino-a,@-unsaturated carbonyls 46 of chiral enamines 249, 250 of dihydronicotinamides 46 of 1,l-enediamines 1310 cr,aUnsatnrated acyl halides, reactions with enamines 816 w-Unsaturated acyl halides, as acylating agents 782 a,SUnsaturated aldehydes, reactions with enamines 815,816 synthesis of 769, 770 y&Unsaturated aldehydes, synthesis of 903, 908, 909 y,6-Unsaturated amides 904 6,dJnsaturated amines, synthesis of 909 y,bUnsaturated imines, formation of 908-919 n,@-llnsaturated ketones, synthesis of 576, 577.782 Uracils--see also Aminohydrouracils "c-labelled 1138 synthesis of 528, 1424 Urea acetals, as 1,l-enediamine precursors 1319, 1320 Urea-see also Thioureas synthesis of 845 vinylogous--see Vinylogous ureas PUreidoisobutyric acid, tritium-labelled, synthesis of 1162, 1163 Urethanes, vinylogous-see Vinylogous urethanes Uric acid-see 1,3-Dimethyluric acid, Tetramethyluric acids
Variance 98, 102, 103,11&118 percentage of 134, 144, 145 Vilsmeier reaction 538, 594, 769 Vindorosinc, synthesis of 661, 663
Subject index Vinylamine, calculated molecular orbital energies for 59-61 charge distribution for 280 dipole moments for 6 2 enthalpy of formation of 258, 262 geometry of 5 ground state 25-29 IR spectrum of 3 2 isomerization of 449 MW studies of 1 2 NMR spectrum of 281, 300, 301,310 PPP-type calculations for 69 protonated, calculated geometry of 33, 34 N-IC-protonation in 33-39 tautomerism in 32, 3 3 torsion of the NH2 group in 29-32 Vinylamines, formulae for 34, 35 N-fluorinated, geometry of 46, 47 N-methylated, dipole moments for 62, 63 geometry of 4 3 4 6 molecular orbital energies for 61 a-substituted, cross-conjugated 3 9 dipole moments for 62 geometry of 39, 40 @-substituted, dipole moments for 63 EE isomerism in 3 9 4 3 synthesis of 492 total energies of 36-38, 45 N-Xnylaziridines, conformation of 229 N-Vinylcarbazoles, cyclodimerization of 885, 886 polymerization of 688-693 N-Vi~~ylcarboxamides, synthesis of 786 Vinylcyclobutanones, synthesis of 998 Vinylcyclopropanes, as alkylating agents 749 Vinyl ketone-see also Aminovinyl ketones as alkylating agents 852, 853 reactions with enamines 816, 1001-1005 Vinylugous amides 6, 406,408-see also P Enaminones aza-Claisen reaction of 667, 668 P-keto, photoreactions of 670-673 photocycloaddition of 649, 654-666 synthesis of 779 Vinylogous amines 2 Vinylogous hides--see also @-Enamidones 1,3-acyl migration in 668
photocycloaddition of 649-654 photo-Fries reaction of 668, 669 =nylogous ureas 6 =nylogous urethanes 6 3-Vinylpyrazoles, synthesis of 603 Vinyl sulphones, as alkylating agents 751, 755, 760,848,85&852 Weights of variables 100, 137-139, 141, 143, 146 Wilkinson complex, as isomerization catalyst 48 1 WIN 44577, %labelled, synthesis of 1222 Woodward-Fieser rules 63 Woodward-Hoffmann rules 638, 993 Xanthanes, synthesis of 1033, 1034 Xanthones, synthesis of 672 X-ray studies 12, 1 3 of crystalline enamines 225-230 of N-cyclic tertiary enamines 13-17 of enamino-diketones 240 of Penaminones 17-20 of propenimines 247 of a-substituted enamines 22, 23 of Bsuhstituted enamines 20-22 Xylopinine, synthesis of 638, 640 Ynamines 5 pK, values for 1097, 1098 reactions of, with allylic alcohols 904, 905 with amines 1324, 1325 Ynolates, basicity of 1097 Ynols, basicity of 1097 Yohimbine, deuterium-labelled, synthesis of 1127, 1128 Zimelidine, "c-labelled, synthesis of 1207, 1208 Zomepirac, tritium-labelled, synthesis of 1156, 1157 Zopolrestat, '4~-labelled,synthesis of 1176, 1177 Zwitterions, as intermediates 807-813, 861 in alkylation of enamines 741, 747, 749, 751-754 in cycloadditions 799, 993, 994, 997, 1003, 1016, 1020, 1022, 1030,1040 in hydrolysis of enamines 1071, 1072, 1076, 1087, 1095
Index compiled by fi Raven
