The Chemistry of Haloketones, Haloaldehydes and Haloimines (Chemistry of Functional Groups)

The chemistry of

a-haloketones, a-haloaldehydes and a-haloimines

THE CHEMISTRY OF FUNCTIONAL GROUPS

A series of advanced treatises under the general editorship of Professor Saul Patai 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 parts) The chemistry of the quinonoid compounds (2 volumes in 4 parts) The chemistry of the thiol group (2 parts) The chemistry of the hydrazo. azo and azoxy groups (2 parts) The chemistry of amidines and imidates 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 parts) Supplement B: The chemistry of acid derivatives (2 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 parts) Supplement F: The chemistry of amino, nitroso and nitro compounds and their derivatives (2 parts) The chemistry of the metal-carbon bond (4 volumes) The chemistry of peroxides The chemistry of organic selenium and tellurium compounds (2 volumes) The chemistry of the cyclopropyl group (2 parts) The chemistry of suiphones and sulphoxides

X

I -c-c I

X

X

4 0 H‘

-C-

I

I

4 0 c-h7

I

//NR

I

R‘

-c-c

The chemistry of

a- ha Io ketones,

a- ha Ioa Idehydes a nd a- ha Io imines BY N O R B E RDE T K I M P Eand R O L A N D V E R H E The State University of Gent Edited by

S A U LP A T A I and Z V I RAPPOPORT The Hebrew University of Jerusalem

Updates from the Chemistry of Functional Groups

1988

JOHN WILEY & SONS CHICHESTER

*

NEW YORK

*

BRISBANE

*

TORONTO

An Interscience@ Publication

*

SINGAPORE

Copyright

0 1988 by John Wiley & Sons Ltd.

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 Library of Congress Cataloging-in-Publication Data: De Kimpe, Norbert The chemistry of [alpha]-haloketones, [alpha]-haloaldehydes, and [alpha]-haloimines. (The Chemistry of functional groups) “Updates from the Chemistry of the functional groups.” 1. Ketones. 2. Imines. 3. Organohalogen compounds. I. Verhe, Roland. 11. Patai, Saul. 111. Rappoport, Zvi. IV. Title. V. Series. QD305.K2K55 1988 547.036 87-25448 ISBN 0-471-91708-7 British Library Cataloguing in Publication Data: De Kimpe, Norbert The chemistry of a-haloketones, a-haloaldehydes and a-ha1oimines.-(Updates from the chemistry of the functional groups). 1. Organohalogen compounds I. Title 11. Verhe, Roland 111. Patai, Saul IV. Rappoport, Zvi V. Series 547.02 QD305.Hl5 ISBN 0 471 91708 7 Typeset by Thomson Press (India) Limited and Printed in Great Britain by Bath Press

Contents 1. Synthesis and reactivity of a-halogenated ketones

1

Appendix to Chapter 1: Synthesis and reactivity of a-halogenated ketones

121

2. a-Halogenated imines

225

Appendix to Chapter 2: a-Halogenated imines

3. Synthesis and reactivity of

c1-

halogenated aldehydes

279 369

Author index

451

Subject index

489

Foreword ‘Updatesfrom the Chemistry of the Functional Groups’ is a new venture which is actually an offshoot of the main trunk, ‘The Chemistry of Functional Groups’. The aim of the Editors and the Publishers is to present selected chapters on a single topic or on closely related topics from the main series,thus making them available for individual chemists in the form of more modestly sized and priced volumes. However, we believed that the presentation of such chapters should be accompanied by appendices updating the material of the original chapters and in some cases even by the addition of new subjects if these dovetail naturally with the older material. This was the case in the present volume, which contains two original chapters from Supplement D of the main series (published in 1983), each updated by an extensive appendix by the same two authors and also a completely new chapter on a-halogenated aldehydes, which fits naturally in with the other two chapters. Thus a complete picture of the a-halogenated derivatives of the three most important carbon heteroatom doubly bonded functional groups (ketones, aldehydes and imines) is given, covering the preparation, properties, reactivity and synthetic applications of the title compounds. Other volumes in the ‘Updates’ series are already in active preparation and are due to appear shortly. These are a volume on ‘Nitrones, nitronates and nitroxides’; a volume on ‘Crownethers’; and one on ‘Cyclopropyl radicals, cations, anions, cation and anion radicals’. Other volumes, planned for a slightly later publication date, will be on ‘Halogenations’, on ‘Synthesis of lactams and lactones’, and on ‘Synthetic applications of quinones’. We will be very grateful to readers who would call our attention to omissions or mistakes in this and other volumes of the series.

JERUSALEM June 1988

SAUL PATAI ZVT RAPPOPORT

vii

Preface a-Halocarbonyl derivatives are an important class of organic compounds, the chemistry of which occupies a key position in modern organic chemistry. The field dates back to more than 150 years ago, when the chlorination of acetone was described and the first characterized a-haloketone was 1, 1-dichloroacetone, described by Fittig in 1859, while bromoacetone was presumably the first characterized a-bromoketone. Since these early results, many and ramified publications have appeared on the chemistry of a-halocarbonyl compounds and many hundreds of papers are added each year. Especially during the last three decades these compounds have received intensive attention, resulting in new and improved synthetic strategies. The high chemical reactivity of a-haloketones and ahaloaldehydes enables them to undergo a wide variety of reactions, and the literature indeed proves the wide synthetic potential of this class of compounds. The chemistry of a-haloimines, i.e. the nitrogen analogues of a-halocarbonyl compounds, started to be studied in depth only in the 1970s. r-Haloimines are now increasingly important, especially in view of their ability to act as masked a-halocarbonyl compounds and their wide synthetic potential. The attempt to publish in one book the most pertinent information on a-haloketones, ahaloaldehydes and a-haloimines is the result of a desire by both authors to present an upto-date treatise on these heteroallylic halides, to review the most significant advances in this area and to convey knowledge about the availability of the title compounds, their chemical properties and their role in modern organic synthesis. The chapters deal separately with the chemistry of a-haloketones, a-haloaldehydes and a-haloimines, and their reactivity towards selected carbon, nitrogen, oxygen and sulphur nucleophiles. The literature is reviewed up to the first half of 1986. The monograph is designed for the use of students, researchers and professional workers in industry and at academic institutions where organic synthesis and mechanistic organic chemistry are actively practised. The structure of the book needs some comment. The publishers and the Editors of the ‘Functional Groups’ series of books decided to produce some sections of the series as smaller, more accessible monograph volumes. As the first of these selections, the two chapters on a-haloketones and a-haloimines, which appeared in ‘Supplement D: The Chemistry of Halides, Pseudohalides and Azides, pp. 549-601 and 813-931, respectively (1983), have been brought together using the original text published in 1983 and, in addition, extensive up-to-date Appendices to both parts have been added. In order to complete the picture, an entirely new chapter on a-haloaldehydes has been included. Finally, both authors express their gratitude to Professor Niceas Schamp, Director of the Laboratory of Organic Chemistry, Faculty of Agricultural Sciences, State University of Gent, for his support of our research programme during the last two decades. The ix

X

Preface

Belgian Nationaal Fonds voor Wetenschapplijk Onderzoek (National Fund for Scientific Research) is thanked for generous support over the same period of time. Gent, Summer 1987

Norbert DE KIMPE,* Roland VERHE Laboratory of Organic Chemistry, Faculty of Agricultural Sciences, State University of Gent, Coupure Links 653, B-9000 GENT, BELGIUM

*‘Onderzoeksleider’ of the ‘Belgian National Fonds voor Wetenschappelijk Onderzoek’ (National Fund for Scientific Research).

The chemistry of a -haloketones, or-haloaldehydes and a-haloimines Edited by Saul Patai & Zvi Rappoport Copyright 0 1988 by John Wiley & Sons Ltd

CHAPTER

1

Synthesis and reactivity of a=halogenatedketones

I. INTRODUCHON . 11. SYNTHESIS OF a-HALOGENATED KETONES . A. Synthesis of a-Fluoroketones . 1. a-Fluoroketones from ketones and their derivatives . 2. a-Fluoroketones from a-haloketones by halogen exchange . 3. a-Fluoroketones from a-dimketones . 4. a-Fluoroketones from carboxylic acid derivatives . 5 . a-Fluoroketones from a-functionalized epoxides . 6. a-Polytluoroketones by condensation reactions . B. Synthesis of a-Chloroketones . . 1. Synthesisof a-chloroketones from ketones and their derivatives a. Chlorination with chlorine . b. Chlorination with sulphuryl chloride and selenium oxychloride . c. Chlorination with hypochlorites . d. Chlorination with N-chlorosuccinimide . e. Chlorination with cupric and femc chlorides . f. Miscellaneous chlorination agents . . 2. Synthesis of a-chloroketones from alcohols and phenols 3. Synthesis of a-chloroketones from a-diazoketones . . 4. Synthesisof a-chloroketones from alkenes and alkynes 5 . Synthesis of a-chloroketones from epoxides . 6. Synthesis of a-chloroketones from carboxylic acids and their derivatives 7. Synthesis of a-chloroketones from aromatic amines . C. Synthesisof a-Bromoketones . . 1. Synthesisof a-bromoketones from ketones and their derivatives a. Bromination with bromine b. Bromination with N-bromo compounds . c. Miscellaneous brominating agents . . 2. Synthesis of a-bromoketones from a-diazoketones . 3. Synthesis of a-bromoketones from epoxides . .

1

2

3 3 3 5 6 7 8 8 8 8 8

.

11 12 13 14 15 17 19 19 21 24 24

25 25 25

30

31 34

34

2

Norbert De Kimpe and Roland Verhe

4. Synthesis of a-bromoketones from miscellaneous substrates D. Synthesis of a-Iodoketones . E. Mechanisms of a-Halogenation of Ketones 111. REACTIVITY OF a-HALOGENATED KETONES

.

A. Reactivitv of a-Haloketones towards Nucleophilic Agents - and Bases . 1 . Introduction . 2. The effect of the carbonyl function on the relative reactivity of a-halocarbony1 compounds with respect to alkyl halides . 3. Reaction of a-haloketones with oxygen nucleophiles and bases a. Reaction with inorganic oxygen nucleophiles . b. Reaction with organic oxygen nucleophiles and bases . . 4. Reaction of a-haloketones with nitrogen nucleophiles and bases a. Reaction of a-haloketones with amines . b. Reaction of a-haloketones with enamines . c. Reaction of a-haloketones with amides, thioamides and derivatives . d. Reaction of a-haloketones with carbonyl reagents . e. Reaction of a-haloketones with sodium azide . 5. Reaction of a-haloketones with sulphur nucleophiles . a. Reaction of a-haloketones with inorganic sulphur compounds . b. Reaction of a-haloketones with organic sulphur nucleophiles . . 6. Reaction of a-haloketones with carbon nucleophiles . a. Reaction of a-haloketones with cyanides . b. Reaction of a-haloketones with carbanions, ylides and enolates . . . 7. Reaction of a-haloketones with organometallic reagents a. Reaction of a-haloketones with Grignard reagents b. Reaction of a-haloketones with organolithium compounds c. Reaction of a-haloketones with organoboron compounds d. Reaction of a-haloketones in the presence of metal complexes . . 8. Reaction of a-haloketones with complex metal hydrides . 9. Reaction of a-haloketones with phosphorus compounds B. Miscellaneous Reactions of a-Haloketones . . 1 . Electrophilic reactions of a-haloketones and their derivatives 2. Reaction of a-haloketones with alkali fluorides . 3. Acid-catalysed rearrangement of a-haloketones . 4. Formation of a-acylcarbenium ions from a-haloketones . 5. Photochemistry of a-haloketones . 6. Electrochemistry of a-haloketones . 7. Dehalogenation of a-haloketones .

IV. REFERENCES

35 36 37 38 39 39 41 44 44 49 66 66 72 72 75 76 78 78 80 82 82 83 86 86

90 92 93 96 96 100 100 102 102 103 105 106 107 107

1. INTRODUCTION Although much information on the synthesis and the chemistry of a-halogenated carbonyl compounds is scattered throughout the literature, there appear t o be few comprehensive sources of information in this important area, with the exception of a short chapter dealing with the preparation of halogenated ketones in Houben-Weyl's Methoden der organischen Chernie'.*. In addition, the Favorskii rearrangement of a-haloketones has been reviewed by several a ~ t h o r s ~ while - ~ , the reactivity of a-haloketones towards nucleophiles was described by Tchoubar in 195S9. The past two decades has seen a considerable expansion in synthetic procedures and mechanistic studies on the reactivity of a-halogenated ketones. It is our hope that putting together a survey of the widely scattered information on the synthesis and reactivity of a-haloketones will focus new attention on the broad potential of these compounds in synthetic and mechanistic organic chemistry.

1. Synthesis and reactivity of a-halogenated ketones

3

The presentation of this chapter is divided into two major sections. The first part deals with the synthetic methods for the preparation of a-haloketones. In the second section the reactivity will be considered, with emphasis on preparative applications, although some mechanistic interpretations of the results will be treated in some important cases. The section on reactivity has been subdivided according to the nature of the nucleophile, e.g. oxygen, nitrogen or carbon nucleophiles, and not on the basis of the reaction type, e.g. substitution, elimination. This chapter has been restricted to halogenated ketones which carry one or more halogen atoms at the a-carbon atom to a carbonyl function, excluding compounds derived from diketones, 8-keto esters and quinones. Other a-halogenated carbonyl compounds such as aldehydes, esters and acids will not be treated in this chapter. 11. SYNTHESIS OF a-HALOGENATED KETONES

While a number of reviews have been published during the last decade on the preparation of a - f l u o r o k e t ~ n e s ~ ~practically -~~, no general review deals with new syntheses of a-chloro-, a-bromo- and a-iod~ketones'~. The syntheses of a-fluoro-, a-chloro-, a-bromo- and a-iodoketones are treated separately and the procedures are classified according to the starting substrates. Some procedures, using the same class of reagents, are described separately for each class of haloketones.

A Synthesis of a-Fluomketones 1. a-fluoroketones from ketones and their derivatives Conventional methods for the synthesis of a-fluoroketones by direct fluorination of ketones often give rise to side reactions and are therefore of limited use (equation 1). R1CHzCOCHzR2

'F '

R'CHCOCHfi'

I

F

+

polyfluorinated and degradation products (1)

For example, treatment of acetone with fluorine yields a complex mixture of fluoroacetone, hexafluoroacetone and degradation products such as trifluoroacetyl chloride, tetrafluoromethane and carbonyl diflu~ride'~. The direct action of perchloryl fluoride on ketones has also met with little success because of degradation reactions. The reactions of a variety of fluorinating agents on derivatives of ketones appear to be more advantageous. Potential synthetic interest may be found in the reaction of perchloryl fluoride with enol ethers16, enol esters17, enamines18 and lithium (1) gives 2-fluorocyclohexanone (3) via e n ~ l a t e s * ~ 1~-Ethoxycyclohexene . l-ethoxy-l,2-difluorocyclohexane(2) on treatment with perchloryl fluoride in pyridine at 0°C (equation 2)16. The enamines of 3-OX0 steroids are transformed into 2a-fluoro-3-0x0 steroids on treatment with perchloryl fluoride followed by hydrolysis of the intermediate fluoroenamines.

4

Norbert De Kimpe and Roland Verht

2a-Fluorocholestan-3-one (5) is formed on treatment of 3-(N-pyrrolidinyl)Zsholestene (4) with this reagent in benzene in 72% yield (equation 3)19.

(5)

(4)

When fluorinated steroidal enamines (6) are treated with perchloryl fluoride, 2,2-difluoro compounds (7) and 2,2,4-trifluoro compounds (9) become accessible (equation 4)20,21.A related process for the synthesis of a-fluoroketones employs lithium enolates of ketones and perchloryl fluoride in tetrahydrofuran. In this manner o-fluoroacetophenone is obtained in 44% yield2*.

(OFcl03

.

(2) Hydrolyaia

(6)

:a} 0 A N

0

(9)

(8)

Fluorination of ketones with perchloryl fluoride is also performed via intermediate methoxalyl ketonesz3 (i.e. - COCOOMe) and hydroxymethylene ketonesz4. 2a-Fluorohydrocortisone is synthesized from the sodium salt of 20-ethylenedioxy2-methoxalyl-A4-pregnentriol-(118, 17a, 21)-3,20-di0ne~~ and 2a-fluorotestosterone from the sodium salt of 2-hydroxymethylenete~tosterone~~. Recently, a new and powerful method for the a-fluorination of carbonyl compounds was developed which utilizes trifluoromethyl hypofluorite with silyl enol ethers, as exemplified by the preparation of 2-fluorocyclohexanone (3) in 70% yield (equation 5)25. A similar method with enol acetates is used by Rozen, by passing fluorine

6 6 &. OSiMeg

LlNlVR)z

CFIo~

- 70%

kC,ICI

(5)

(3) into a suspension of sodium trifluoroacetate in Freon at -75°C. A considerable portion of the oxidizing ability of this solution is due to the presence of pentduoroethy1 hypofluorite (CF3CF20F) and other oxidizing compounds of the (10)

(11)

5

1. Synthesis and reactivity of a-halogenated ketones

perfluoroxyfluoride type. 2-Fluoro-1-tetralone (13) can be obtained by this procedure in 85% yield by starting from the enol acetate of 1-tetralone (12) (equation 6)26. 0

(13)

(12)

In attempts to react enol acetates with molecular fluorine, no a-fluoroketones could be isolated from the complicated reaction mixtures. Geminal a,a-difluoroketones are formed by decomposition of geminal difluorocyclopropanes (18, prepared by difluorocarbene addition to enol acetates. Reaction of these cyclopropanes with sodium hydroxide in methanol provides a,a-difluoroketones (15) in addition to other products (equation 7)27.28.The corresponding dichloro- and dibromocyclopropanes exhibit completely different pathways, resulting in the formation of halogenated enones. F

(12)

(16)

(15)

(14)

Finally, the action of a Lewis acid on a-fluorinated amines (17), easily obtained by addition of secondary amines to fluorinated alkenes, produces fluorinated immonium salts (U), which on arylation with electron-rich aromatic compounds and subsequent hydrolysis furnish a-halo-a-fluoroacetophenones(20) (equation 8)29. F

XCHF-CF2-NNR2

I

+

+ XCHF-CCNR,

F-

BF3

II

I

+

XCHF-C=NR,

'NR, BF4Ar-C-CHFX

F

w*

ArH

ArCOCHXF

2. a-Fluomketones from a-heloketones by halogen exchange The exchange of a chlorine atom in a-chlorinated ketones by fluorine on treatment with hydrogen fluoride only takes place when there is no possibility of hydrogen

6

Norbert De Kimpe and Roland Verht

chloride elimination, such as in perchloroketones and chloroacetone. Better results are obtained with potassium f l ~ o r i d e ~and ~ J potassium ~~ hydrogen fluoride ( K H F Z ) ~ ~ (equation 9). Excellent results of bromine-fluorine exchange are obtained by the use

0

0 R2’

I

F

X

of mercuric f l ~ o r i d e ~If~ .a~chlorine ~. atom is also present in the molecule, it is retained. l-Aryl-2,2-difluoro- and 1-aryl-2-chloro-2-fluoro-l-alkanones are prepared by this procedure in moderate yields. Another method involves the use of silver tetrafluoroborate in ether. However, this method is not applicable to primary bromoketones or to chloroketones (equation 10). The method does not seem to have a broad scope since several side products, mainly a,fi-unsaturated ketones, are formed,

making isolation on a preparative scale rather laborious. When the reaction is carried out in nucleophilic solvents (methanol, acetic acid), a-methoxy- and a-acetoxyketones are isolated as side products. Other procedures of bromine-fluorine exchange utilize potassium fluoride in dimethylformamide, glycerine and diethylene g l y c 0 1 ~ ~ - ~ silver ~, fluoride in a~etonitrile-water~~, thallium fluoride3’ and pyridinium poly(hydrogen fluoride) used in conjunction with mercuric oxide3*.

3. a-Fluoroketones from a-diazoketones Fluoromethyl ketones are easily formed when diazomethyl ketones, prepared by condensation of acid chlorides with diazomethane, are treated with hydrogen or pyridinium poly(hydrogen fluoride)38 (equation 11). a,a-DifluoroR-COCl R-COCHN,

+ CHZNZ +

HF

-

__.c

RCOCHN,

+

RCOCHzF

+ Nz

HCI (11)

ketones (e.g. 22) are obtained by fluorination of diazoketones such as diazocamphor (21) with trifluoromethyl hypofluorite; additionally, minor amounts of a-fluoro-a-trifluoromethoxyketones (e.g. 23) were isolated41. In the case of 21 a rearrangement also occurs, leading to the formation of a fluorotricyclanone (24) as another side product (equation 12).

1. Synthesis and reactivity of a-halogenated ketones 4. a- Fluoroketones from carboxylic acid derivatives

7

Reaction of fluorinated carboxylic acids and derivatives with organometallic reagents usually gives rise to a-fluoroketones. Treatment of trifluoroacetic acid with while the phenyllithium in ether at - 65°C affords w,w,o-trifluoroa~etophenone~~, reaction of lithium trifluoroacetate with butyllithium yields 1,l ,I-trifluoro2-he~anone~~. The condensation of organomagnesium compounds with a-fluorinated esters gives satisfactory yields of a-fluoroketones (equation 13)44,45. Condensation of R1CHCOOR2 + R3MgX

I

F

-

R'CHCOR3

I

(13)

F

a-fluoronitriles (25) with Grignard reagents affords a-fluoroketones in high yields (equation 14)46,47. o-Fluoroacetophenone is produced in good yield by the Friedel-Crafts method, provided that the reaction with fluoroacetyl chloride is carried out rapidly48.

An a-fluoroketone (29) is formed during the hydroxide-catalysed hydrolysis of an a-fluoro-/I-keto ester (27),while under the same circumstances the difluoro-8-keto ester (31) is transformed into the 1,Idifluoroketone (32)(equation 15)49.

I-

Norbert De Kimpe and Roland VerhB

8

5. a-Fluoroketones from a-functionalized epoxides A general synthesis of a-fluorocarbonyl compounds is developed from fluorocyanohydrins (M), obtained by the simultaneous action of hydrogen fluoride and boron trifluoride on epoxynitriles (33). Decomposition (34)with silver nitrate in the presence of an equimolecular amount of ammonia gives rise to the formation of a-fluoroketones in moderate yields (equation 16)50.Thermal isomerization of

R~-'c-c--

CN

Y

(33) (34) a-fluoroepoxides(X), prepared by epoxidation of fluorinated olefins (39, gives rise to the formation of a-fluoroketones by migration of the fluorine atom (equation 17)s'.

6. a-Polyfluoroketones by condensation reactions a-Polyfluoroketones are produced by several condensation reactions, e.g. Friedel-Crafts, Hoesch, Claisen, Knoevenagel and aldol condensations. These types of reaction are undoubtedly the most suitable for perfluoroketone synthesis. Much of the literature concerning the various aspects of this topic has been covered elsewhere2and will not be repeated here.

B. S y n t h l r of a-Chloroketomb 1. Synthesis of a-chloroketones from

ketones and their derivatives

The preparation of a-chloroketones starting from ketones and their derivatives can be achieved by various procedures. The choice of method is dependent upon the nature of the ketone and the degree of chlorination wanted. Therefore no general procedure seems to be available for the synthesis of a given chlorinated ketone. The substitution pattern in the starting ketone determines the method to be employed, as will be demonstrated below. u. Chlorination with chlorine. In general, reaction of aliphatic ketones with chlorine most commonly affords higher chlorinated products (equation 18). R1CH2COCH,R2

a R1CHCOCH2R2

+

CI I

R'CHCOCHR2

I

CI

I

CI

+

R'CH2COCHR2

R'CCOCH2R2

/ \

CI

CI I

+ R'CH2COCR2 + CI/

'Cl

+ Polychlorinated ketones

(18)

CI

During the monochlorination of acetone, minor amounts of dichloroacetone are always isolated. However, good results for the monochlorination of acetone and 3-pentanone are possible when the chlorination is carried out in aqueous solutions of

1. Synthesis and reactivity of a-halogenated ketones

9

calcium carbonate and calcium chloride; using this procedure 2-butanone furnishes a mixture of 75% 3-chloro-2-butanone and 25% 1-chloro-2-butanones2. Further chlorination of monochloroacetone at 100- 140°C in the presence of iodine, antimony pentachloride and ferric trichloride gives a mixture of 1,1,1,3-tetrachloroacetone and 1,1,3,3-tetrachloroacetone in a 1:4 ratio53. Chlorination of acetone in carbon tetrachloride at 50-70°C gives pentachloroacetone, which is transformed into hexachloroacetone by further chlorination in the presence of antimony trisulphide and iodines4. Hexachloroacetone is also formed during chlorination in an acetic acid-sodium acetate mediums5. In general, a-perchloroketones are produced in very good yields in the presence of light without catalysiss6. Photochlorination in the gas phase only affords a-substituted ketoness7. The degree of chlorination in alicyclic ketones is strongly dependent upon the reaction medium. Cycloalkanones are monochlorinated in the a-position in acetic acid5*, ~ a t e r ~methano161, ~ . ~ , or dichloromethane6*, while a,a'-dichloro compounds are produced upon further treatment with chlorine, except for a-tetralone, of course, where 2,2-dichloro-a-tetralone is obtained6* (equation 19). Tetrachloro- and hexachlorocyclohexanone are formed when the chlorination is carried out in the presence of rhodium(II1) chloride and iridium(1V) chloride63, respectively.

0

0

0

Chlorine in dimethylformamide seems to be a powerful reagent for the substitution of a-protons in aldehydes and ketone^^,^^. Usually all the a-protons are rapidly replaced at 5O-9O0C, except in aliphatic ketones, where the last a-proton is substituted only at 120"C, because of the sterically hindered enolization%. A clean conversion of cyclopentanone (37) into 2,2,5,5-tetrachlorocyclopentanone(38) is obtained using this procedure at 2O-3O0C, when a continuous excess of chlorine is maintained during the course of the reaction. Several intermediate a-chlorinated cyclopentanones are dehydrochlorinated in dimethylformamide (DMF), yielding chlorinated 2-cyclopentenones which are further chlorinated to afford penta- (39) and hexachlorocyclopentanone (40).Chlorination of cyclopentanone (37) in DMF at 120°C gives a mixture of the isomeric perchlorocyclopentenones (41) and (42) (equation 20)67. Chlorination of cyclopentanone with chlorine in dichloromethane and carbon tetrachloride is not a synthetically useful method as rather complex mixtures of mono-, di- and trichloro derivatives are formed67. However, 2,2,3-trichlorocyclopentanone can be prepared via chlorination of 2-chloro-2-cyclopentenone; the latter compound is produced upon treatment of 2-cyclopentenone with chlorine in carbon tetrachloridea. Direct chlorination of 2-methylcyclohexanone with chlorine yields 2-chloro2-methylcyclohexanone as the major product, besides cis- and trans-6-chloro2-methylcyclohexanone and substantial amounts of the 2,6-dichloro compound69. Treatment of cyclohexanones with chlorine in dimethylformamide results in substitution of all the a-hydrogens (equation 21)66. Aryl alkyl ketones are mostly monochlorinated in the aliphatic chain using solutions of chlorine in acetic acid, methanol or carbon tetrachloride at low temperat~res'~. At 60°C o,o-dichloroacetophenoneis produced7', which in turn is converted into w,o,o-trichloroacetophenone in the presence of sodium acetate on further treatment

10

Norbert De Kimpe and Roland Verhe

with chlorine72.Surprisingly, the higher homologues, 2,2-dichloro- 1-aryl-1-alkanones, could only be prepared by chlorination in dimethylformamide at 100”C73,with the exception of 2,2-dichloropropiophenone,which is also formed during the chlorination of propiophenone in a solution of sodium acetate in acetic acid74(equation 22). ArCOCHfi

ArCOCHR

I

Chlorination of enamines has been used for the preparation of a-chloroketones. A procedure for the regiospecific synthesis of chloromethyl ketones (43) via immonium salts is described by C a r l ~ o nBy ~ ~regioselective . deprotonation of these salts, mixtures of tautomeric enamines, derived from methyl ketones, are transformed into the less sterically hindered enamines, which upon reaction with chlorine and subsequent hydrolysis yield chloromethyl ketones (43) (equation 23). Enamines react with chlorine in ether at - 78°C under exclusion of oxygen and moisture to give the isolable a-chloroimmonium halides (44),after which acid hydrolysis leads to a-chloroketones (equation 24)76.

1. Synthesis and reactivity of a-halogenated ketones

1- isomer

11

2- isomer

b. Chlorination with sulphuryl chloride and selenium oxychloride. As in the case of the chlorination with chlorine, secondary hydrogens are more easily substituted than primary hydrogens and tertiary hydrogens more easily than secondary hydrogens on treatment with sulphuryl chloride. Hydrogens in the a-position next to a carbonyl function react with sulphuryl chloride at room temperature without m y catal y s t ~ ~Chloroacetone78, ~. 3-chlor0-3-methyl-2-butanone~~, 2-chloro-2-methylqclohexanonem, 2-chloropr0piophenone~~and l-benzoyl-l-chlorocyclohexaneslare prepared in high yields by treatment of the corresponding ketones with sulphuryl chloride (equation 25).

-

R'CH~COR~

%CIZ

R'CHCOR~

I

(25)

CI

Reaction of ketones with two moles of sulphuryl chloride generally leads to mixtures of products. For example, from acetone at 30°C a mixture of 72% 1,l-dichloro-, 6% 1,3-dichloro- and 20% 1,1,3-trichloroacetone is produced, while from 2-butanone a mixture of 42% 3,3-dichloro-, 7% 1,l-dichloro- and 46% 1,3-dichloro-2-butanone is obtained77. Chlorination of cyclopentanone with an excess of sulphuryl chloride affords a mixture of 2,2-dichloro- and 2,5-dichlorocyclopentanone,while in the case of cyclohexanone only 2,2dichlorocyclohexanone (45) is isolated when the reaction is carried out in dichloromethane or in acetic acid at 20°C82. Heating of a,a-dichlorocycloalkanonesin acetic acid-hydrogen chloride results in rearrangement of a chlorine atom with formation of a,a'-dichloro compounds but this rearrangement is not applicable to the acyclic series (equation 26).

12

Norbert De Kimpe and Roland Verht

0

0

0

(4) (W Chlorinated cyclohexanones are formed during the chlorination of cyclohexenones. Treatment of 2-cyclohexenone (47) with sulphuryl chloride affords a mixture of 2-chloro-2-cyclohexenone (a), 2,2,3-trichloro- (49) and 2,3,6-trichlorocyclohexanone while chlorination of flavone (51) gives rise to 2,3,3-trichloroflavone (S2)85 (equation 27). Thionyl chloride reacts with 6-methyl- and 7-methoxyflavone to yield 3-chloro derivatives in both case@.

6 (y & qm3QQ 0

0

SO2CIzr

+

+

.I&'

CI

(47)

(48) 110%)

CI

(50)(55%)

(49)t35%)

0

0

(51)

(52)

(27)

During the chlorination of methyl ketones with selenium oxychloride, the intermediate dichloroselenium compounds (53) are decomposed thermally to furnish a-chloroketones (equation 28)86. RCOCH,

S.OcI*

(RCOCH2)2SeC12

RCOCHpCl

(28)

(53)

c. Chlorination with hypochlorites. Methyl ketones react with sodium hypochlorite in aqueous alkaline solution to give intermediate trichloromethyl ketones which are further transformed into chloroform and carboxylic acids (i.e. the so-called haloform reaction) (equation 29). Trichloromethyl ketones are isolated when acetophenones are used as substrates8'. RCOCH,

moci

RCOCCIJ

nplcm-

CHCl3

+ RCmH

(29)

Alkyl hypochlorites react easily with ketones; chloroacetone and cu-chloroacetophenone are prepared in good yields using ethyl hypochlorite88. r-Butyl hypochlorite seems to be an excellent reagent for the chlorination of steroidal ketone^^^.^. By the latter method, 2-chloro-3-cholestanone (55) is prepared from 3-cholestanone (a), while in pregnantrione derivatives (56) chlorination takes place at the 4-position (equation 30).

1. Synthesis and reactivity of a-halogenated ketones

13

-

CI

d. Chlorination with Nchlorosuccinimide. Direct chlorination of ketones with N-chlorosuccinimide (NCS) is not a potential method for the synthesis of a-chloroketones because the reaction rate is often too slow and in most cases mixtures of reaction products are formed. Treatment of 2-heptanone with NCS in the presence of benzoyl peroxide gives a mixture of several mono-, di- and trichloro derivatives which are difficult to separate9]. However, NCS is an excellent chlorinating agent of the corresponding N-analogues of ketones and enol ethers, i.e. ketimines and enamines, yielding a-chlorinated ketimines and 8-chlorinated enamines. This subject has been reviewed elsewhereg2. The last-mentioned compounds are potential sources for a-haloketones by a simple hydrolysis procedure. 1,l-Dichloromethyl ketones (60) are prepared by chlorination of N-cyclohexyl methyl ketimines (58) with two equivalents of NCS in carbon tetrachloride at O'C, followed by hydrolysis in acidic m e d i ~ r n (equation ~ ~ - ~ ~ 31). By

0

N

14

Norbert De Kimpe and Roland VerhC ArCOCCIZR

(611

the same procedure l-Aryl-2,2-dichloro- 1-alkanones (61) have been successfully ~ y n t h e s i z e d ~A ~ . similar method has been developed in which steroidal N-(8-hydroxyethy1)methylketimines (62) are treated with NCS in ether at 25°C followed by mild acidic hydrolysis leading to the corresponding a-chloromethyl ketones (63) (equation 32). However, application of this halogenation method to 2-pentanone yields a mixture 1-chloro-, 3-chloro-, 1,l-dichloro- and l,l,l-trichIoro2-pentanone9'.

(62)

(a)

Chlorination of the pyrrolidine enamines derived from 2-methylcyclohexanone (64) (which exists as a 9:l mixture of two isomers) with NCS and subsequent hydrolysis gives 2-chloro-2-methylcyclohexanone(65), while the isomeric 6-chloro isomer (66) is not formed (equation 33)98.

(eel e. Chlorination with cupric and ferric chlorides. Cupric chloride is known as a chlorination catalyst but it has also been used for the preparation of chloroacetone from acetoneW,'O".Cyclohexanone and its methyl derivatives react with a large excess of cupric chloride in 50% aqueous acetic acid or 50% aqueous dioxan to give dichloro and trichloro derivatives of 1,2-~yclohexanediones(67, 68)'01 (equation 34). A convenient synthetic method consists of the reaction of silyl enol ethers (69)with cupric or ferric chlorides (equation 35)lo2.The mechanism involves a vinyloxy radical, generated from the collapse of the copper(I1) or iron(II1) enolate which is formed initially. The selection of specific solvents is important; for cupric chloride dimethylformamide must be used, while acetonitrile is the solvent of choice for ferric

1. Synthesis and reactivity of a-halogenated ketones

0

0

0

15

CI

chloride. This method possesses the interesting feature that a-chlorination of unsymmetrical ketones can be performed regiospecifically and that extra double bonds are left intact. (Note that this does not occur when ferric chloride is used, but only with cupric chloride.) f: Mbcellaneous chlorination agents. Several other reagents or procedures of minor importance have been used for a-chlorination of ketones and their applications are strongly dependent upon the substrate. Treatment of acetophenones and aryl benzyl ketones with phenylchloroiodonium chloride gives rise to a-monochlorination, but reaction of 2-butanone with this reagent affords a mixture of 3-chloro- and 3,3-dichlor0-2-butanone~~~. Pyridine hydrochloride perchlorideE9 and phosphorus pentachloride'" have also been used for a-chlorination of ketones. Ketones possessing a-hydrogens are easily chlorinated with a system consisting of carbon tetrachloride, powdered potassium hydroxide and t- butanol, but subsequent rapid reactions generally lead to the formation of a variety of products such as Favorskii rearrangement products, a-hydroxy ketones and cleavage product^^^)^*^^. Ketones with only one a-hydrogen, no a'-hydrogens and a sterically blocked carbonyl function such as 70 are especially suitable substrates and are easily converted into a-chloroketones (e.g. 71), which are resistant to further reaction (equation 36). The

(70)

cn)

a-chlorination of ketones with this reagent involves the reaction of enolate anions with carbon tetrachloride in a discrete electron transfer/chlorine atom transfer step proceeding through a radical anion-radical pair (RARP) mechanism. As shown in equation (37), the formation of C13C:- in the chlorination step leads to the generation of :CCI2 as well as of CC13. Hexachloroacetone acts as a source of positive chlorine in its reaction with enamines giving a-chloroketones after acid hydrolysis (equation 38)'O'. This reaction results in regioselective a-chlorination because of the availability of either a- or a'-enamines, thus making routes to 6-chloro-2-alkyl- or 6-chloro-3-alkylcyclohexanonesquite feasible. For example, 6-methyl-1-pyrrolidinocyclohexeneis transformed into a mixture of cis-6-chloro-2-methyI-, trum-6-chloro-2-methyl- and 2-chloro-2-methylcyclohexanone in a 93:6: 1 ratio. The pyrrolidine enamines of 2-methylcyclohexanone

16

Norbert De Kimpe and Roland VerhC

0

It

-c-c-

CI

I I

:cc12

+ c1,c:(37)

+ CI-

2C13C'

+ CI-

react with sulphuryl chloride or NCS to give primarily the 2-chloro-2-methyl isomer. Reaction of enamines with dimethyl(succinimido)sulphonium chloride (72) yields 2-amino- 1-cycloalkenylsulphoniumchlorides (73), which decompose into chlorinated enamines (74) under expulsion of dimethyl sulphide. Hydrolysis of these chlorinated enamines gives rise to a-chlorocycloalkanones (equation 39)lo8.

(74) A highly convenient electrolysis procedure for the preparation of a-halogenated ketones from enol acetates, enol ethers and silyl enol ethers has been developed (equation 40)Ioy. The method consists of an electrolysis with halide salts in an undivided cell. Reaction of dichlorocarbene with dioxolane derivatives (75) gives rise to dichloromethyl-l,3-dioxolanes(76) under phase transfer catalysis. These acetals are

1. Synthesis and reactivity of a-halogenated ketones

II

17

I

0 CI excellent starting materials for syntheses of a,a-dichloromethyl ketones (equation 41)"O. OR

CH2-0\

I CH2-0'

c

/R

\H

-

H

:cc12

I

CH2-0\ CH2-0'

/R

C

n o*

3 RCOCHCI,

(41)

'CHCI:,

(75)

A generally applicable synthesis of unsymmetrical a-chloroketones involves the chlorination of 8-oxoalkylidenephosphorane (77) with iodobenzene dichloride followed by alkaline hydrolysis of the intermediate triphenylphosphonium chlorides (78) (equation 42)"'.

R'CHCOR2

I

+ Ph3PO

(42)

CI 2. Synthesis of a-chloroketones from alcohols and phenols

It is obvious that chlorination agents, which are capable of oxidizing alcohols to ketones, will give rise to chlorinated ketones using secondary alcohols as starting materials. The chlorination of isopropanol and 2-octanol, respectively, with chlorine gives 1,1,1,3-tetrachloroacetone and 1,1,1,3,3-pentachloro-2-octanone112, while 2-chloro- and 2,2,6,6-tetrachlorocyclohexanonecould be obtained from cyclohexanol in high yield113J14. Sterols are simultaneously oxidized and chlorinated upon treatment with hypochloritesl 15. Other reagents substitute hydroxy functions for chlorine atoms. 2-Hydroxytropolone (79) is transformed into 2-chlorotropolone (80) upon treatment with thionyl chloride in benzene1I6 and 3-chloro-3-phenyl-tram-2-decalone (82) is formed from the 3-hydroxy derivative (81) by reaction with thionyl chloride in carbon tetrachloride1I7 (equation 43). Hydroxyl functions in the side chain of steroids are easily substituted for chlorine by the action of arylsulphonyl chlorides118. The chlorination of phenols and halophenols with chlorine gives rise to polychlorinated cyclohexanones and cyclohexenones11Y-122. For example 2,4,4,6tetrachloro-2,5-cyclohexadienone (84) and 2,2,4,5,6,6-hexachloro-3-cyclohexenone (85) are formed on chlorination of 2,4,6-trichlorophenoI (83) (equation 44)lZ3. 1-Aryl-1-chloro-2-propanones(87) are formed from l-aryl-2,2-dichloro1-propanols (86) in generally good yields (69-90%) by an acid-catalysed rearrangement involving a 1,2-chlorine shift (equation 45)124-126. Studies on the acid-catalysed tri5uoroacetolysis of l-(o-chlorophenyl)-2,2-dichloro1-propyl tri5uoroacetate (88) indicate that the rearrangement takes place through the intermediacy of a halonium ion (equation 46).

Norbert De Kimpe and Roland VerhC

18

o

w

(79)

(W

Ph

CI

I I

Ar- CH - C-CH3

I

CI

OCOCFs

TfA n,so, Ar-

CH

I

CI

-CII

CH3

(46)

0

Another procedure for the synthesis of chloromethyl ketones involves the reaction of trichlorosilyl ethers with butyllithium, generating dichlorolithium compounds (W), which upon heating furnish chlorinated silyl enol ethers (91). Hydrolysis yields a-chloroketones (equation 47)lZ7. It is evident that a-chloroketones are easily formed by oxidation of the corresponding @-chloroalcohols. However, @-chlorinatedalcohols are not accessible in a general way and are mostly prepared by reduction of a-chloroketones (vide infra).

1 Synthesis and reactivity of a-halogenated ketones

n-EuLi

-7O.C

R’ \ CHCHCCl2Li R20 I

..

-

19

A

OSiMe3

H30+

R’ \ R2’

CHCOCH2CI

(911

The oxidation is exemplified by the conversion of 3,3-dichlorobicyclo[2.2.2]octan-2-o1 (92) into the corresponding ketone (93) on treatment with chromic acid (equation 48)Iz8.

3. Synthesis of a-chloroketones from a-diazoketones

A general procedure for the preparation of a-chloroketones consists of decomposition of diazoketones in the presence of hydrogen chloride or chlorine yielding c h l ~ r o m e t h y land ~ ~ ~dichloromethyl respectively (equation 49). Excellent results are obtained for c h l ~ r o a c e t o n e l,1,1,3-tetrachloroacetone133 ~~~,

and chloromethyl benzyl ketone134on treatment of diazoketones, derived respectively from acetyl chloride, trichloroacetyl chloride and phenylacetyl chloride, with hydrogen chloride. 3,3-Dibromo-l,1-dichloro-2-butanone is synthesized by the reaction of chlorine in ether with the diazoketone derived from 2,2-dibromopropionyl brornidel3l. 4. Synthesis of a-chloroketones from alkenes and alkynes

Addition of nitrosyl chloride to alkynes affords chlorinated nitroso compounds which upon acid hydrolysis yield monochlorinated ketones in excellent yields (equation 50)13’.

20 \

Norbert De Kimpe and Roland VerhC

c=c\

NOCl

\

__.c

H0

I1 I

0

No CI

CI (50)

Oxidation of di- or trisubstituted olefins with chromyl chloride in acetone provides an efficient preparation of a-chloroketones (equation 51). For example, 2-chlorocyclododecanone is prepared by this method from trans-cyclododecene in 90% yield'36. R k H = CR2R3

CrOzCl2

R'COCR2R3

I

CI

Several mono- and dichlorocyclobutanones have been synthesized by cycloadditions of chloro- or dichloroketenes to olefins. The dehydrohalogenation of 2-haloalkanoyl chlorides with triethylamine generates the chloroketene in situ, which in turn adds rapidly to dienes. 7-Chlorobicyclo[3.2.O]hept-2-en-6-ones (94) have been prepared in such a way by addition of chloroketenes to cyclopentadiene (equation 52)13'. R

0

exo-alkyl

(94)

endo-alkyl

Chloro(2,2,2-trichloroethyl)ketene gives higher yields of [2 + 21 cycloadducts and a large variety of monochlorocyclobutanones (95) can readily be prepared (equation 53) 38.

'

CCI3CH2CHCICOCI

c=c=o

KH.J,2c=cH2

*

(95)

The cycloaddition of dichloroketene, generated in situ from trichloroacetyl chloride with triethylamine or with activated zinc in the presence of phosphorus oxychloride, constitutes a useful method for the synthesis of 2,2-dichlorocyclobutanone derivative^'^^. Styrene is converted into 2,2-dichloro-3-phenylcyclobutanone(W)in 87% yield (equation 54)140. Also silyl enol ethers seem to be suitable substrates for the ~ , the adducts of indene and preparation of functionalized c y c l o b ~ t a n o n e s ' ~while cyclopentadienes are valuable precursors in the synthesis of t r o p o l o n e ~ ' ~ ~ . 2,2-Dichlorocyclobutanones easily undergo regioselective one-carbon ring expansion by reaction with diazomethane, yielding 2,2-dichlorocyclopentanones(e .g. 97). The presence of a-chloro substituents accelerates this reaction. Epoxide formation is not significant, probably because of the strained nature of the four-membered ring'43.

1. Synthesis and reactivity of a-halogenated ketones

21

n

(54) Terminal alkynes can be converted into dichloromethyl ketones by treatment with hypochlorous acid (equation 55)14c146. 1,l-Dichloroacetone, l,l-dichloro-3,3-

dimethyl-2-butanone and o,o-dichloroacetophenone are obtained from propyne, 3,3-dimethyl-1-butyne and phenylacetylene, respectively. Treatment of phenylacetylene with chlorine in methanol gives 1-phenyl-1,l-dimethoxy-2,2-dichloroethane’47. a,a-Dichloroketones are also prepared by reaction of acetylenes with N-chlorosuccinimide in methanol, followed by hydrolysis of the resulting dichlorodimethyl acetals (equation 56)148. R‘C-CR~

NCS CH3W

R’C

/ \

Me0

OMe

CR2

c;’

‘Cl

HJO*

R’COCC12R2

(56)

5. Synthesis of a-chloroketones from epoxides

Ring opening of a-chloroepoxides, prepared by treatment of gem-dichloroalcohols with bases, gives rise to several halogenated ketones under various conditions (equation 57)149J50.

CI

Neat thermal rearrangement of chlorinated epoxides normally gives rise to the formation of a-chloroketones, while on treatment with boron trifluoride a rearrangement takes place with formation of the isomeric chloroketone. Bifunctional

22

Norbert De Kimpe and Roland VerhC

epoxides also afford a-chloroketones on thermal or acid-catalysed isomerization (equation 58)33J51-209.

-

ct

R-CCH,

It

0

Y = o M e , OAC

/ y

(58)

CI

A stereospecific chlorine migration occurs when a cb-truns mixture of l-chloroCmethylcyclohexene oxides (98) gives exclusively fruns-2-chloro-4-methylcyclohexanone (99) on heating, while a zinc chloride-catalysed rearrangement gives rise to a mixture of the cb and the mum isomers (equation 59)"*. If a hydride shift occurred, the other isomer (100) would be produced.

CH3 (100)

However, thermal rearrangement of 2-chlorobicyclo(2.2.l]hept-2-ene exo-oxide

(101) gives rise to two major products, exo-3-chlorobicyclo[2.2.l]heptan-2-one(102,

38%) and exo-2-chlorobicyclo[2.2.l]heptan-7-one(103,35%), while 2-chlorobicyclo[2.2.2Joct-2-ene oxide (104) produces 89% 3-chlorobicyclo(2.2.2]octan-2-one (105) (equation 60)153,154.

&: (101)

&: ACl H

(102)

H

+

(1m)

1. Synthesis and reactivity of a-halogenated ketones

23

It has been proved in the case of a-chlorostyrene oxides that such thermal rearrangements occur by disrotatory C, - 0 bond heterolysis to yield an a-acylcarbenium chloride ion pair (equation 61)155. Upon heating 2,3-dichloro-

0

R1R2C+-CC// ‘R3

CI-

-

CI R‘R2t!COR3

epoxides rearrange into a,a-dichloroketones, but the reaction course is strongly dependent upon the substitution pattern of the epoxide ring (equation 62)ls6.

R’CC12COR2

R’COCC12R2

R’R~CCOCI

I

Ring opening of glycidonitriles (formed by condensation of a ketone with an a-halonitrile) with anhydrous hydrogen chloride leads to chlorinated cyanohydrins, which in turn upon treatment with sodium hydroxide expel hydrogen cyanide, yielding a-chloroketones (equation 63)lS7. R1COR2

+ NCCHCHR3R4 I

-

CI

0

R’*CH\R4

HCI

CN

R2

OH

R’, I C-C-CH’ R2’1 I

P3

R3

‘R4

NIOH

16331 / R3 R1\ CCOCH R2’ I ‘R4

Another excellent conversion of epoxides into a-chloroketones involves the reaction of chlorodimethylsulphonium chloride (generated in situ by reacting molecular chlorine with dimethyl sulphide at -20°C) with epoxides in the presence of a tertiary amine (equation 64). For example, 2-chlorocyclohexanone is formed from cyclohexene oxide in 83% yieldIs8.

24

Norbert De Kimpe and Roland VerhC

6. Synthesis of a-chloroketones from carboxylic acids and their derivatives

Chlorination of diketene gives rise to the unstable y-chloroacetoacetic acid chloride which decomposes in aqueous medium to yield monochl~roacetone'~~. Dichloromethylketones have been synthesised by hydrolysis of lactone derivatives160, by treatment of a,a-dichloroesters with Grignard reagents149,and by the action of dichloromethyllithium on esters16*(equation 65).

R'CCOOEt / \ CI

+ A2MgCI

CI

RC
-

LiCHCI2

CI

R'-C-C-R2 I I

OL i

I

R-C-CHCl2

I

OMgCl

OEt

HIO'

I I CI OEt

H30+

ftl)C
(65)

CI

RCOCHC12

Acylation of alkynes with a,p-unsaturated acid chlorides provides S-chloro2-cyclopentenones (106) (equation 66)163.

7. Synthesis of a-chloroketones from aromatic amines Aromatic amines are converted into polychlorinated cyclohexanone compounds upon treatment with chlorine in acetic acid. For example, p-toluidine (107) gives 2,2,3,4,5,6,6-heptachloro-4-methylcyclohexanone (108) (equation 67)l6*-I6'

1. Synthesis and reactivity of a-halogenated ketones

25

C. Synthesls of a-BromOkaOnes The synthesis of a-bromoketones can be achieved by methods similar to those mentioned for the preparation of a-chloroketones, in addition to typical procedures and reagents for the introduction of bromine atoms in ketones. 1. Synthesis of a-bromoketones from ketones and their derivatives u. Brominution with bromine. Treatment of ketones with bromine gives rise to substitution of at least one a-hydrogen. However, some side reactions take place during the bromination of ketones which are not encountered during the chlorination166169. The bromination of ketones with bromine is a reversible process and the debrominated ketones are regenerated by reaction of the bromoketones with the liberated hydrogen bromide (equation 67a). In order to shift the equilibrium to the right,

RCOCH3 + B q

===

RCOCH2&

+ H&

(67a)

precautions have to be taken to evaporate the hydrogen bromide or to take it up by an acceptor. In principle all brominated ketones are reducible by hydrogen bromide, but with varying ease depending on their structure. More ‘positive’ bromine atoms are reduced more rapidly. The tendency to debromination is directly related to the difficulty of introducing more than one bromine atom on a carbon atom in the presence of hydrogen bromide; trapping of the liberated hydrogen bromide is necessary. Besides reduction, disproportionation reactions also take place, with the consequence that during the reaction of a ketone with an equimolecular amount of bromine some dibromoketone is always produced (equation 68). The monobromo:dibromo PRCOCY&

= RCOCH, + RCOCHBr2

(68)

compound ratio is dependent upon the solvent and reaction time. o,o,wTribromoacetophenone, with highly ‘positive’ bromine atoms, is able to brominate acetophenone, yielding phenacyl bromide (equation 69)‘. PhCOC&,

+ PhCOCH3

-

PhCOCH2&

(69)

Another side reaction occurring during the synthesis of bromoketones consists of a rearrangement of a bromine atom under the influence of hydrogen bromide. a,aDibromoketones rearrange to 1,3-dibromo compounds, but geminal dibromoketones are formed when the bromination is carried out in the presence of potassium acetateI7O.Bromomethyl cyclohexyl ketone (107a) is transformed to l-acetyl-l-bromocyclohexane ( l a )(equation 7O)l7l. In the case of 1-bromo-3-phenyl-Zpropanone RCH2COCH2&

RCH2COCH&2

5 RCHCOCH2& I Br

(109) an equilibrium is established between both isomers (109 and l l O ) I 7 l . In addition,

the solvent seems to have a great influence on the position of substitution, as exemplified by the bromination of l,l-diphenyl-2-propanone(111) (equation 71)Ia.

26

Norbert De Kimpe and Roland Verhe PhCH2COCH2Br

PhCHBrCOCH3

(109)

(110)

&2

Br

f

Ph, CHCOCH2Br Ph'

(113)

Various procedures have been employed for the bromination of aliphatic ketones with bromine. Direct treatment gives very impure products since the liberated hydrogen bromide tends to promote the formation of condensation products and resinous materials next to by-products which are formed during side reactions. These difficulties are minimized by bromination in an inert atmosphere, by the use of acetic acid as solvent or in the presence of calcium carbonate, potassium acetate and potassium chlorate. Bromination of acetone in a mixture of acetic acid and water provides bromoacetone in a 44% yield together with 1,l-dibromo- and 1,3-dibromoa~etone'~~. Better results are obtained when the bromination is carried out in an aqueous solution in the presence of potassium ~ h l o r a t e ' Further ~~. bromination of bromoacetone gives 1,1,3-tribromo- and 1,1,3,3-tetrabromoacetone, while reaction of acetone with an excess of bromine yields pentabrom~acetone'~~. Bromination of alkyl methyl ketones always leads to the formation of isomeric compounds. Normally bromo-substitution of methylene groups is faster than of methyl groups, but the rate is nearly identical for methylene and methine moieties (equation 72). For example, acid-catalysed bromination in the presence of potassium chlorate CH3COCH2R

CH3COCHR'R2

-%.

A

CH3COCHBrR + BrCH2COCH2R (72) CH3COCR1R2 + BrCH2COCHR1R2

I

Br

affords mixtures of 73% 3-bromo- and 27% 1-bromo-2-butanone from 2-butanone and 63% 3-bromo- and 37% I-bromo-2-pentanone from 2-pentanone while 3-methyl2-butanone ives rise to 76% 3-bromo-3-methyl- and 24% 1-bromo-3-methyl2 - b ~ t a n o n e ' ~ $ - -Pinacolone '~~. can be converted into the mono- and the dibromo compounds when the bromination is carried out in ether178,while tribromopinacolone is obtained in a refluxing carbon tetrachloride-water mixture in the presence of mercuric ~hloride''~. Monobromination of unsymmetrical aliphatic ketones is rarely a regiospecific reaction and seems to be strongly dependent upon the solvent used. While in carbon tetrachloride, ether and acetic acid the substitution mostly occurs at the most substituted a-carbon atom, yielding mixtures of reaction productslsO, bromination in

1. Synthesis and reactivity of a-halogenated ketones

27

methanol preferentially takes place at the less substituted carbon atom, as illustrated by the bromination of 3-methyl-2-butanone (114) (equation 73). The latter procedure constitutes an excellent method for the preparation of bromomethyl ketones, not readily accessible previously by direct brominationIs1. CH,

\

CH3/

C-

I

CO-CH,

A (116)

Bromination of ketones with bromine in carbon tetrachloride during irradiation with a 100 W tungsten lamp in the presence of 1,2-epoxycyclohexane gives monobromoketones in which bromine has entered exclusively the more highly substituted a-position or the benzylic position (equation 74). The extent of substitution a to the R’COCHR2R3

+ Er2 +

R’ = Me, Et R 2 = alkyl, phenyl R3 = H, alkyl

0 -i$-

R’COCR2R3

I

+

Bf

carbonyl group plays a decisive role in the reaction. Ketones with a secondary or a benzylic a-carbon atom are brominated at this position exclusively. With less substituted ketones (2-butanone, acetone) the reaction takes a different course, providing a mixture of 2-bromocyclohexane, 2-bromocyclohexanol and the starting ketone1**. Under the same reaction conditions a regiospecific introduction of bromine occurred at the C , , of Sa- and S/l-pregnane-3,20-dione (117). The selectivity of these reactions is due to the epoxide which, by scavenging the hydrogen bromide produced during the reaction, inhibits any ionic acid-catalysed bromination of the ketones.

Treatment of aliphatic ketones with two equivalents of bromine in acetic acid or ether results in the formation of stereoisomeric a,a’-dibromoketones and no geminal dibromo compounds are formed (equation 7S)183J84.

28

Norbert De Kimpe and Roland Verh6 R1CH2COCH2R2

R~CHCOCHR~

I

I

&

(75)

&

Monobromocycloalkanones, prepared from cycloalkanones with bromine in an acetic acid-water mixture at 50-70"C. are very air-sensitive and difficult to p ~ r i f y ~ * ~ - ~ ~ . Bromination of 2-chloro-, 2-cyano- or 2-fluorocyclohexanone (118) in carbon tetrachloride in the presence of calcium carbonate takes place mainly at the 6-position (equation 76)Ia7. Stereoisomeric a,a'-dibromocycloalkanones are formed by bromi-

(118)

(119)

X = CI, CN, F

nation with two equivalents of bromine in acetic acid or anhydrous etherIs3. Reaction of cyclohexanol with bromine in acetic acid containing 15% hydrogen bromide yields 20% crystalline ci.s-2,6-dibromocyclohexanoneand 80%of the truns compound, which decomposes upon distillation188. Dibromination of 4,4-dimethylcyclohexanone (120) in carbon tetrachloride gives cis-2,6-dibromo-4,4-dimethylcyclohexanone (121) in 66% yield (equation 77). Upon standing in ether, partial cis-truns isomerisation is

0

om

0

(la)

observed189.The cis isomers have higher melting points and higher infrared carbonyl stretching frequencies and are more polar as well as less soluble than the tram analogues, which are considered to be conformationally more mobile. Neat bromination of cyclohexanone affords tetrabromocyclohexanone'w, while bromination of cyclohexadecanone with 3.5 mole equivalents of bromine in dichloromethane at 25-30°C gives 2,2,16-tribromocyclohexadecanone in 92% yield'". Bromination of aryl alkyl ketones can be carried out selectively and o-bromo, owdibromo- and o,w,o-tribromoacetophenone are synthesised in high yields from a c e t o p h e n ~ n e ' ~ ~ -Monobromo'~~. and dibromopropiophenone are obtained from propiophenone, although for the disubstituted compound to be obtained the bromination must be performed in carbon tetrachloride at reflux temperature under irradiation and in the presence of benzoyl peroxide33J95.The bromination of indanone can be carried out selectively. Reaction in ether with one molar equivalent of bromine yields the 2-bromo compound while 2,2-dibromoindanone is obtained upon treatment with two molar equivalents of bromine in chloroform'%. In general, a,a-dibrominated alkyl aryl ketones are not easily accessible due to exchange processes in the presence of hydrogen b r o ~ n i d e ~ ~ ' . ~ ~ ~ .

1. Synthesis and reactivity of a-halogenated ketones

29

During the addition of bromine to a,/?-unsaturated ketones which yields a,/?dibromoketones, precautions have to be taken in order to avoid decomposition. The reaction has to be carried out very slowly and at low temperature (0°C) as exemplified by the preparation of 3,4-dibromo-3-methyl-2-butanone1~ and 3,4-dibromo-4phenyl-2-bu tanonezw. Alkoxybromination occurs when a,/?-unsaturated ketones are treated with bromine in an alcohol, giving rise to a-bromo-p-alkoxy ketones' (equation 78)201. R~CH=CHCOA~

RICH-CHCOR~

I

OR^

I

(78)

h 2-Bromo-2-cyclohexenone (123) is prepared by treatment of 2-cyclohexenone (122) with bromine in collidine, the initial adduct being dehydrobrominated (equation 79)202.

Q-iy (122)

(79)

(123)

Treatment of isophorone (124) with an excess of bromine in carbon tetrachloride gives 2,4,6-tribromo-3-bromomethyl-(125) and 2,6,6-tribromo-3-dibromomethyl5,5-dimethyl-2-cyclohexenone(126), respectively at 0 and 25°C. Further treatment of 125 affords the pentabmmocyclohexenone (127) (equation 80)202.

(126)

Just as in the preparation of a-chloroketones, various ketone derivatives serve as substrates for the synthesis of bromoketones. The bromination of trimethylsilyl enol ethers with bromine in carbon tetrachloride at -20°C represents an excellent method for the regiospecific introduction of a bromine atom into aliphatic and cyclic ketones (equation 81)203. Treatment of enol acetates with bromine gives rise to a-bromoketones: 2-bromo1-phenyl-1-propanone and 2-bromo~cloalkanonesare prepared according to this procedure (equation 82)20*.

30 R'

-

Norbert De Kimpe and Roland Verhe

\

R2/

CHCOR3

CWCH~I~

R'

NEtjlDMF

R2'

\

c=c

/

OSi(CH&

\R3

k2

R'CH=C-CH3

I

OAc

-

R'-CH-

I

Br

I

C-CH,

I

OAc

R~OH

R2/VCOR3 Br (811

II

I

Br

\

0

OSi(CH313

*Z

R'

R'CHCOCH,

I

Br

+

CH,COOR2 (82)

Bromination of enamines constitutes a suitable method for the preparation of bromoketones and the procedures mentioned for the synthesis of a-chloroketones are also applicable here75-76. b. Bromination with N-bromo compounds. The use of N-bromo compounds in the preparation of a-bromocarbonyl compounds, first reported by Schmid and KarrerZo5 using N-bromosuccinimide (NBS), shows the advantage that neither hydrogen bromide nor free bromine are present during the reaction, with the consequence that side reactions are largely eliminated. Monobromination occurs smoothly and geminal dibromination rarely takes place, so that brominated ketones which are not available by the bromine method can be synthesized. However, the reaction rate is much slower with N-bromo compounds and in some cases no bromination occurs at allzo6. Numerous examples of monobromination of aliphatic and acyclic ketones with N-bromosuccinimide are known, mostly in the presence of initiators (benzoyl peroxide (BPO), azo-isobutyronitrile) and/or illumination207-20s.Geminal dihaloketones (133, 135) are formed when a-chloroketones, such as a-chlorocyclohexanone and a-fluoropropiophenone, are treated with NBS (equation 83)33J87.209. Introduction of a bromine atom in a$-unsaturated ketones takes place at the allylic position and not at the carbon atom next to the carbonyl function210.Bromination of isophorone (124) with NBS gives rise to 4-bromoisophorone (136) (equation 84)202. Other N-bromo compounds, e.g. N-bromophthalimide, N-bromoacetamide, N-bromotolylsulphonylamide, 3-bromo- and 1,3-dibromo-5,5-dimethylhydantoin have been used less frequently as brominating agents2". Besides bromination of ketones with these reagents, derivatives such as enol acetates, enol ethers and enamines have also been treated and excellent yields of bromoketones are obtained, as in the case of the corresponding chloro derivative^^^.^^^. However, the bromination of ketimines and subsequent hydrolysis turns out not to be a useful method for the preparation of dibromoketones. Reaction of methylketimines with NBS in CC14 gives rise to a,a-dibromoketimines, but hydrolysis of the latter compounds provides a mixture of a,a-dibromo and a,a'-dibrom~ketones~'~. On the other hand, hydrolysis of N- 1-(2,2-dibromo-l-phenylalkylidene)cyclohexylamines affords a mixture of mainly l-aryl-2,2-dibromo-l-alkanonesand 1-aryl-12alkanedi~nes~~.

1. Synthesis and reactivity of a-halogenated ketones

-

(118)

NBWCCI,

PhCOCHCH,

I

h

F

(13 4

R'CH2CH=CHCOCH2R2

NBS

32

(133) PhCOC-CH3

/\

F

Br

(135)

RICHCH= CHCOCH2R2

I

Br

fi*oX.

0

(138)

(124)

c . Miscellaneous brominating agents. Copper(I1) bromide is an excellent reagent for the preparation of a-monobromoketones when the reaction is carried out in refluxing chloroform-ethyl a ~ e t a t e ~(equation l ~ . ~ ~ 85) ~ (RI,R2 = alkyl, phenyl, -(CH&-).

R~COCH,R~

cuerz

R ~ C O C H R+~ CUB^

I

+ HE,

(85)

Br Selective bromination of C-H a to a carbonyl function can also be achieved by pyridinium hydrobromide perbromide216, tetrazolium p e r b r ~ m i d e ~ ' ~ phenyl, trimethylammonium perbromide218, 2,4-diamino-l,3-thiazoleh y d r o p e r b r ~ m i d e ~ ~ ~ and 2-carboxyethyltriphenylphosphoniumperbromide (137)220. The last-mentioned compound, which is conveniently prepared by heating triphenylphosphine and acrylic acid in 49% hydrobromic acid followed by treatment with bromine in acetic acid, selectively gives monobromination at the a-position of a keto function even in the presence of double bonds. In the case of unsymmetrically substituted ketones, a-bromination occurs predominantly at the most substituted carbon atom due to the preferred enolization in that direction (equation 86). (C~H~)~;CH~CH~COOH

(137)

32

-

Norbert De Kimpe and Roland VerhC ArCH= CHCOCH3 ArCH2CH2COCH3

137

137 7

ArCH=CHCOCH,& ArCH2CHCOCH3

I

Br

R

R

Recently, an insoluble regenerable brominating polymer has been developed. This polymer is easily and safely prepared from the macroreticular anion exchange resin Amberlyst-A26 C1- (Rohm and Haas Co.) (equation 87).

(138)

Amberlyst-A26 bromide form is converted into the perbromide form (138) by treating with a carbon tetrachloride solution of bromine. Unsymmetrical ketones are selectively brominated at the more highly substituted position, in the presence of a free radical initiator and methyloxirane as scavenger of the hydrobromic acid. a,/?-Unsaturated ketones are completely converted into the corresponding dibromo saturated adducts. In the reaction of steroidal ketones, bromination occurs mainly from the less hindered side of the molecule (equation 88). The advantage of this reagent consists of the ease of operation, the work-up conditions and the capability for regeneration221-222.

33

1. Synthesis and reactivity of a-halogenated ketones

Brominated active methylene functions are also able to act as bromonium ion sources. Monobromo- and dibromomalononitrile are suitable reagents for the bromination of active methylene functions, but they are not active enough to introduce a bromine atom at the a-carbon of monocarbonyl f u n ~ t i o n s ~ * ~ - ~ ~ ~ . An excellent reagent, however, seems to be 5,5-dibromc-2,2-dimethyl-4,6-dioxo1.3-dioxan ( l a ) ,which is able to monobrorninate saturated aldehydes and ketones and the a'-carbon atom of aJ-unsaturated ketones with high selectivity (equation 89)2z5.

0.

In addition, 2-bromo-2-cyano-N,N-dimethylacetamide is also effective for the synthesis of a-monobromoketones223,while selective monobromination of a,fi-unsaturated ketones has been performed by the action of 2,4,4,6-tetrabromocyclohexa-2,5-dienone without affecting the double bond or any allylic position (equation 90)226.

R-ccH~-ccH=cH-CO-CCH~

+ OH

0

II

R- CH2- CH= CH - C- CH2Br

+

Dioxan dibromide has been used for bromination in the side chain of electron-rich hydroxy- and methoxy-substituted acetophenones, which often suffer nuclear bromination with other brominating agents227. Another procedure involves the attack of bromodimethylsulphonium bromide (138b) on enamines followed by hydrolysis of the intermediate brorninated immonium salt (equation 91)158.Sodium hypobromite is not a suitable reagent for the preparation of bromoketones. Methyl ketones give the haloform reaction; e.g. propiophenone has been oxidized to benzoic and acetic acidzz8.

34

Norbert De Kimpe and Roland VerhC

0

2. Synthesis of a-bromoketones from a-diazoketones Monobromo- and dibromoketones are produced by decomposition of diazoketones with hydrogen bromide and bromine, respectively (equation 92)130.229. Sometimes minor amounts of the corresponding chloroketones are produced when starting from acid chlorides (X = Cl). Therefore acid bromides are preferentially used for the preparation of the d i a z o k e t o n e ~ ~ ~ ' .

3. Synthesis of a-bromoketones from epoxides Most of the procedures mentioned in the section dealing with the synthesis of a-chlorinated ketones using epoxides as substrates are also applicable for the preparation of a-bromoketones. Nevertheless, some specific methods using epoxides are available for the synthesis of the corresponding bromoketones. Photocatalytic bromination of epoxides in carbon tetrachloride yields ketones directly, exclusively monobrominated at the less substituted a-carbon atom (equation 93)232.

R = alkyl, phenyl The majority of epoxides tested react with a stoichiometric amount of bromine to produce only the bromoketones and no bromohydrins, the latter arising from ring cleavage of the epoxide by the generated hydrogen bromide. However, cyclohexene

1. Synthesis and reactivity of a-halogenated ketones

35

oxide and styrene oxide give, besides the monobromo-, also the dibromoketones and the bromohydrins. The photocatalysis is indispensable and the choice of the solvent is critical. In ether only the two bromohydrins are formed. The mechanism must involve a free radical hydrogen abstraction process followed by a fast rearrangement to an a-oxoalkyl radical (equation 94).

R-CO-kH,

&Z

R-COCH2Br

Reaction of epoxysulphonyl compounds, now conveniently available from a-chlorosulphones and aldehydes under phase transfer conditions, with magnesium dibromide in ether at room temperature, affords a-bromo carbonyl compounds (equation 95)233.

-

0- R 2

I

I

I

I

PhS02-C-C-Br

0 PhSO2-

+

R3-C-C-Br

R3 R’ R’,

R2

I1 I I

(95)

R’ R 2 = H, alkyl, phenyl

The epoxysulphone route is more general than the a-chloroepoxide route’4yand can be carried out easily. For example, 1-bromo-1-phenyl-2-propanone can be obtained in a yield greater than 95%. Ring cleavage of nitroepoxides with hydrogen bromide also gives rise to the formation of a-bromoketones (equation 96)234.

4. Synthesis of a-bromoketones from miscellaneous substrates

Some of the procedures already mentioned in the section concerning the synthesis of a-chloroketones can be utilized for the preparation of bromoketones. Dibromomethyl ketones are formed by the action of dibromomethyllithium on esters162. Jones oxidation and oxidation with pyridinium chlorochromate of brominated cycloalkanols also give excellent results, as in the synthesis of

cis- 2,8-dibromocyclooctanone235.

Another method uses vinyl esters which are transformed into dibromoesters upon addition of bromine. These esters spontaneously decompose into acyl bromides and

Norbert De Kimpe and Roland VerhC

36

Br2

R1CO-0C=CH2

I

-

Br

I I

R'CO-OC-CH2Br

R2

R'COBr

+ R2COCH2Br (97)

R2

a-bromoketones (equation 97)236. 1-Bromo-2-heptanone is obtained from 2-acetoxy-1-heptene in 75% yield. Pyrolytic elimination of a-bromo-j-hydroxysulphoxides, obtained by reaction of aldehydes with lithiobromomethyl phenyl sulphoxide, produces a-bromomethyl ketones in excellent yields (equation 98)237.

0

R-CHO

II + PhS-CHBr

I

THF'-78*C

+

Li

R-CH-CH-SOPh

I

OH

Diglymo

I

RCOCH2Br

Br (98)

D. Syntheak of a-lodoketones a-Iodoketones are usually prepared by treatment of ketones with iodine in the presence of a strong base238,by exchange reaction of chloro- or bromoketones with inorganic iodides2'2.239,240, by treatment of ketones and their enol acetates with N-iodos~ccinimide~~~, by action of iodine(1) chloride on enol acetates212 and by decomposition of diazoketones in the presence of iodine242. Several of these procedures suffer from disadvantages such as condensation and decomposition reactions and the availability and stability of substrates and reagents. During the last few years successful methods have been developed for the synthesis of a-iodoketones. The reaction of enol acetates with thallium(1) a c e t a t e - i o d i r ~ eand ~~~ the oxidation of alkenes with silver chromate-iodine2" gives a-iodoketones in moderate yields. However, thallium(1) acetate is highly toxic, and, using the latter method, only 1-iodo-2-alkanones can be prepared from terminal alkenes. Cyclic a-iodoketones are obtained directly by oxidation of olefin-iodine complexes with pyridinium dichromate (PDC), but the reaction failed with linear olefins (equation 99)245.

Terminal alkynes react with iodine in methanol in the presence of silver nitrate to give mainly a,a-diiodoketones together with diiodoalkenes and iodoalkynes (equation i00)246.

RCECH

12, AgNO3

CHjOH

RCOCH12

+ RC(I)=CHI +

RCIC-I

(100)

At present the most general method consists of the sequential treatment of enol silyl ethers with silver acetate-iodine followed by triethylammonium fluoride. High yields of a-iodo carbonyl compounds are reported (equation 101)247.The mechanism can be envisioned as occurring with initial formation of an iodonium ion followed by acetate at tack.

37

1. Synthesis and reactivity of a-halogenated ketones OSiMe3 AgOAc

-0Ac

'2

H

H

Iodoketones are relatively unstable and are not widely used in synthesis. Therefore the reactivity of a-iodoketones will not be discussed in the following sections because of their limited applicability.

E. W h a n h s of a-Hakgenatkn of Ketones As already pointed out during the discussion of the various procedures for the preparation of a-halogenated ketones, the halogenation occurs according to three different types of mechanism^^^^.^^^. (1) In the presence of acids an electrophilic attack of the halogen on the enol takes place and subsequent loss of a proton from the intermediate oxonium ion leads to the a-haloketone (equation 102). For sufficiently high halogen concentrations, the rate-limiting step is the enolization while the rate of halogenation seems to be independent of the nature and concentration of the halogen.

I

R2

I

R2

In the halogenation of unsymmetrical ketones, the substitution position is determined by the relative ease of formation of the isomeric enols. Consequently, the predominant isomer produced on halogenation of a ketone is that in which the halogen enters the more highly substituted a-position, because enol formation is enhanced by the presence of a-alkyl substituents and by other substituents which stabilize the enol. However, the presence of an a-halo atom results in a decrease of the rate of enol formation and the substitution of each successive halogen atom becomes more difficult. (2) In base-catalysed halogenations the halogen reacts with the enolate anion rather than with the enol. The rate of enolate formation is retarded by alkyl substituents and enhanced by a-halogen substituents. Therefore, base-catalysed halogenation is not suitable for the preparation of a-monohaloketones (equation 103). (3) The halogenation can be carried out via halogen radicals, but further introduction of halogens proceeds via an ionic mechanism under the influence of the generated hydrogen halide.

38

Norbert De Kimpe and Roland VerhC

n-

X

In the traditional mechanism for halogenation of ketones, which involves halogenation of a reactive enol or enolate, the observed rate of halogenation is independent of the halogen concentration and the nature of the halogen, when the halogen concentration is sufficiently high. Under these conditions the rate of deuteration should also be equal to the rate of halogenation. At sufficiently low halogen concentrations, the reaction between the enol or enolate and the halogen becomes rate determining and the observed rates become dependent on both the nature and the concentration of the halogen species. At very low halogen concentration and high acidity, Bell demonstrated that the rate of the addition of the halogen to the enol form becomes slower in comparison with the e n o l i z a t i ~ n Nearly ~ ~ ~ . the same observations were made when the kinetics of the iodination, bromination and chlorination of acetone, diethyl ketone and diisopropyl ketone were studied at [Xz]= 10-7-10-5 M (equation 104)251.The apparent rate

k,,=

-1

k2 = KEk2

constants kll for iodination, bromination and chlorination are approximately equal and k2 is rate controlling only at very low concentrations of halogen (diffusion-controlled kinetics). The order of magnitude of such limiting rate constants of lo9 M-' s-l leads to new values for KE in solution, much smaller than those reported earlier252. After many years of unchallenged acceptance, the enolization mechanism for halogenation of carbonyl compounds was questioned by two groups. Rappe has postulated no less than five different mechanisms of halogenation for 2-butanone and other related ketones. Of these five reactions two are acid catalysed, two base catalysed and one is a free radical m e c h a n i ~ m ~ Rappe ~ ~ - ~has ~ ~claimed, . for example, that base-catalysed bromination of 2-butanone can result in a ratio of monohalides (3-Br/l-Br = 7-7.5) quite different from that predicted on the basis of relative exchange rates (CH2/CH3 = 0.6-0.7). In addition there is an apparent 20-30-fold (at pH 5.5-7) and a fivefold difference (at pH 12) in the reaction rates for bromine and iodine. In view of these results a mechanism is postulated which involves a reaction of unenolized ketone with hypohalite anions. Sytilin also claimed that the initial rate of bromination of acetone is dependent upon the concentration of brominez56. However, a few years later several groups proved independently that there is no reliable evidence to suggest that the base-catalysed halogenation of unsymmetrical ketones proceeds by alternative non-enolic halogenation routes other than by a traditional enolization m e c h a n i ~ m * ~ ~ - ~ ~ . 111. REACTIVITY OF a-HALOGENATED KETONES The interest in the reactivity of halogenated carbonyl compounds has grown since the discovery in 1895 of the Favorskii rearrangement, and numerous reports have dealt

1. Synthesis and reactivity of a-halogenated ketones

39

with theoretical studies and synthetic applications of a-haloketones. Therefore it is extremely difficult to review all the reactions in which a-haloketones are important intermediates. The main focus will be upon the reactivity with nucleophiles and bases, although other important reactions and transformations will be treated selectively.

A. ReactMty of a-Haloketones towards Nuckophllk Agents and Bases 1. Introduction

On treatment of an a-haloketone with various nucleophiles and/or bases, the attack can take place at six possible electrophilic sites: (6)

(5)

H

H

(4)

O

H

The nucleophile is able to attack the carbon of the carbonyl function (position I ) , the carbon atom carrying the halogen atom (position 2) and the halogen atom (position 3). In addition, due to the presence of two polar electron-withdrawing groups, namely the carbonyl function and the halogen atom, the hydrogen atoms in the a-, a’- and B-positions also become susceptible to attack by nucleophiles or bases (positions 4,5,6).

Theoretically, the following types of reaction can be envisioned during the reaction of an a-haloketone with a nucleophilic reagent. Besides nucleophilic substitution (a), elimination (b) and reduction (c), a nucleophilic addition to the carbonyl (d) can take place, followed by a nucleophilic intramolecular substitution (e) with formation of an epoxide which is able to give further reactions. In addition a Favorskii rearrangement, via an intermediate cyclopropanone, with formation of carboxylic acid derivatives is an alternative route ( f ) (equation 105). In most cases it is very difficult to predict which reaction type will occur on treatment of an a-haloketone with a nucleophile. This complexity is mainly due to the following factors: (1) Several reaction pathways are often occurring simultaneously, resulting in mixtures of reaction products. (2) The same reagent gives rise to different reaction products with different ketones. (3) The same ketone may show completely different reaction pathways with very similar nucleophilic reagents. (4) The reaction is strongly dependent upon the reaction conditions (solvent, temperature, etc.). (5) Structurally similar ketones which are substituted with different halogens give different reaction products with the same reagents. (6) The reaction products can undergo further transformations during the reaction, such as rearrangement, oxidation and dimerization, while the starting a-haloketones can also be transformed into different ketones which then react further, giving rise to unexpected compounds.

40

Norbert De Kimpe and Roland Verht

H H O R 3

I

I I I I

I

I

R~-C-C-C-C-H

H H O R 3

I I I I I

R~-C-C-C-C-H

I

I

I

R 2 Nu

R4

R2 H

I

0

H

I

R3

I1

I

R~-C=C-C-C-H

I

I

R4

R4

R2

t H H O R 3

I I I I I

R~-C-C-C-C-H

I

I

R2 X

H

I

~1-C-

H H O R 3

H P R 3

I

I

I

C- C-C-H

I I I I

R2CX

7

Nu R4

I

~ 1 -C-

1

I I I I I

C -C-

I

C- C-

I

I

R2 X

R4

I I

I

Nu R4

R2

1

R’-

R3

Lo,

R~-C-C-C-C-H

H

I

R4

H

Nu R3

C-

c -c1 1

1

1

1

1

R 2 OH Nu R 4

H H

I

H

I I

40

R’-C-C-C,

I

Nu

R 2 CH

/\

R3 R4 and/or

H

1

H

1

R’-C-C-C-C,

I

l

R2 H

R3

1

l

R4

// 0

Nu

1. Synthesis and reactivity of a-halogenated ketones

41

2. The effect of the carbonyl function on the relative reactivity of a-halocarbonyl compounds with respect to alkyl halides

The enhanced reactivity of a-halogenated ketones relative to the correswnding alkyl halides in bimolecular nucleophilic substitution is well known26*-265and is illustrated in Table 1.

TABLE 1. Relative reactivities? of a-halo carbonyl compounds, alkyl halides and benzyl halides in nucleophilic substitution ~~

Reaction

~~~

~

~~~

~~~~

n-C3H7X PhCH2X XCH2COOEt CH3COCH2X PhCOCHzX Ref,

R-CI + KI/acetone 1 R-CI + S203-/waterl R-CI + -OAc/ methanol I R-Br + pyridine/ methanol 1 R-Br + thiourea/ methanol 1 R-CI + -N3/ methanol 1 R-CI + -OCN/ methanol 1 R-CI + -SCN/ methanol 1

197 -

1720 220

35 700 1400

105 000

1600

261 263

-

28

198

228

263

286

56

208

406

261

300

640

-

10 700

262

-

33

210

276

263

75

156

176

263

-

83

40 1

770

263

'Relative reactivity to C3H7.

Ester, cyano and related groups also show this powerful activating effect, but surprisingly the sulphonyl group is deactivating, although the carbonyl and the sulphonyl groups exert the same inductive and resonance effects as expressed by their a-constants2-. It is also noteworthy that the activating effect of the carbonyl function is still operative when the group is situated at the 8- or y-carbon atom; PhCOCH2CH2CI and PhCOCH2CH2CH2CI are respectively 80 and 230 times as reactive as n-butyl chloridez6*.Various mechanisms have been postulated to explain the enhancement of reactivity due to the presence of the carbonyl function. Hughes2& ascribes the reactivity to the inductive effect of the carbonyl group which enhances the polarity of the carbon-halogen bond by increasing the electron deficiency at the a-carbon atom. The more polar the C-X bond, the faster is the reaction of nucleophiles in bimolecular substitution. Baker267has proposed a mechanism in which the first and ratedetermining step is the addition of the basic reagent to the carbonyl function, followed by a rapid intramolecular displacement (equation 106). The isolation of stable epoxides in the reaction of an a-haloketone with sodium methoxide and the evidence that these epoxides are reactive intermediates leading to other products268 gives rise to another explanation by Pearson and coworkers262 (equation 107). If any of the steps of the first reaction is slow, then this mechanism is in agreement with the second-order kinetics. A key point is that the reagent B' is not necessarily the same as B. The interaction between the carbonyl group and the nucleophile is mainly

42

Norbert De Kimpe and Roland VerhC

lo\ R-C-CH, I B+

0

+ B'

II

R-CCH2B'

+B

electrostatic and the high SN2reactivity is due to polarization interaction caused by the smaller steric requirement of RCO as compared to RCH2. Another interpretation by D e ~ a and r ~Winstein ~ ~ and coworkers270is based upon neighbouring group orbital overlap with the adjacent electron-deficient carbon atom. The transition state for the substitution of a-haloketones is envisaged as including partial bonding of the reagent with the p-orbital of the carbonyl carbon. An alternative explanation is that substitution products are formed via an enolization-solvolysis mechanism as expressed in equation (1 08)27i. OH

I

OH

I

RCH-$-CH, X-

RCH2COCH2B

+ RCHCOCH3 I

(roe)

B

Many cases have been reported in which this mechanism is operative. An example is the reaction of l-chloro-3-phenylmercapto-2-propanone (139) with acetic acid in the presence of potassium acetate, which yields 1-acetoxy-1-phenylmercapto-2-propanone (140) and the thiol ester (141) (equation 109)272. Another example involving solvolysis of an enol allylic chloride is responsible for the formation of the a-alkoxyketone (143) and the a-hydroxyketone (144) from the chloroketone (142) (equation 109)273. A fast rate of substitution could result from fast enolization-solvolysis and comparison with the rates of the corresponding alkyl halides is worthless. Several of

1. Synthesis and reactivity of a-halogenated ketones

OMe

I

43

OH

I

PhCH2COCHCH3 + PhCH2COCHCH3 (143) (76%)

(144) (24%)

the proposed rationales are in contradiction to experimental data, for example with the substitution of a-haloketones by weakly basic nucleophiles. The explanation of Hughes266 fails in these cases where electron-withdrawing a-substituents other than carbonyl should show the same rate enhancement. However, a-halogen, a-alkoxy and a-sulphonyl substituents cause a substantial decrease in the rate of nucleophilic substitution of alkyl halides; a-halosulphones and a-halonitro compounds are quite unreactive. Baker’s mechanismz67does not fit the observation that the rate of substitution of a-haloketones is dependent upon the nature of the halogen. Bromoketones react faster than the corresponding chloro compounds, phenacyl bromide being 120 times as fast as phenacyl chloride with thiourea in methanol. Although a number of epoxides have been isolated or are shown to be important intermediates in reactions of a-haloketones (especially a-halobenzyl ketones react with alkoxides to yield a-hydroxyacetals), cleavage of epoxide intermediates leading to substitution products is dependent on the system and the experimental conditions. Arguments against an epoxide intermediate are presented in the reaction of haloketones with weakly basic nucleophilic rea ents and against a rate-determining addition of the reagent to the carbonyl groupz6 . Lutz showed that optically active desyl chloride undergoes exchange and racemization at the same rate with radioactive C1-, while for an epoxide mechanism an exchange without racemization is predictedz74.However, Turro and coworkers proved that a-methoxy ketones are formed from a-bromoketones via an epoxide mechanism27s. Thorpe and Warkentin interpret the bimolecular substitution of a-haloketones with acetate and azide ion, which are remarkably insensitive to steric hindrance, in terms of a normal SN2transition state, not involving either special alignment of entering and leaving groups with the n-orbital of the carbonyl function (conjugation) or covalent interaction between nucleophile and carbonyl carbon (bridging) for reaction of conformationally mobile systems. Conformationally fixed systems, on the other hand, is 61 times may be affected by such factors. trans-4-tert-Butyl-2-chlorocyclohexanone more reactive than the cis-isomer in reaction with acetate ion. Activation parameters support the statement that only those a-haloketones which are set up for conjugation and bridging show substitution according to a different pathway from that operating in the corresponding reactions of alkyl halides276.

f

44

Norbert De Kimpe and Roland Verht

TABLE 2. Relative reactivity of phenacyl bromide and methyl iodide in nucleophilic substitution kz(PhCOCH2Br)

Nucleophile

c1-

(NH212CS

NCSNCSe-

Pyridine Ph3P Me2S

Ph3As Me2NPh

Et3N

k2(MeI) 110

63 30.5 26.6 7.07

4.44

3.22 2.15 0.37 0.14

A recent report of Halvorsen and Songstad concerning comparison of second-order rate constants for reactions of phenacyl bromide and methyl iodide with various nucleophiles in acetonitrile reveals that the rate enhancement due to the carbonyl group is not a general effect but is dependent upon the nucleophile (Table 2). Apparently, reactions with ionic nucleophiles tend to involve a ‘tight’ transition state (containing a mainly sp2 hybridized central carbon atom). On the other hand, reactions with uncharged nucleophiles (amines) react via an ‘early’ transition state (an sp3 hybridized central carbon atom) where no conjugation with the a-carbonyl group is possible. In the first case, the a-carbonyl function does exert a significant influence upon reaction rates due to its + E effect, while in the latter case a decrease of the reaction rate of phenacyl bromide is observed in comparison with methyl iodide277. Considering all these results it is reasonable to postulate that any favourable effect exerted by a carbonyl function on the nucleophilic reactivity stems in part from the absence of rate-retarding steric effects (the enhancement is much lower for propionyl or butyryl functions in comparison with an acetyl function33), coupled with a mildly rate-enhancing inductive effect. 3. Reaction of a-halokefones with oxygen nucleophiles and bases

a. Reaction with inorganic oxygen nucleophiles. The products of the reaction of a-halogenated ketones with oxygen nucleophiles and bases are strongly dependent upon the substrate, the nature of the nucleophile and the reaction conditions. Besides substitution reactions, eliminations and rearrangements are also occurring, with the result that in many cases the outcome of the reaction cannot be predicted and that several reaction pathways take place simultaneously, resulting in a mixture of products. Several examples are known in which hydrolysis of a-haloketones with hydroxide and carbonate solutions in various solvents (water, alcohols, ether, dioxan, etc.) gives rise to a - h y d r o ~ y k e t o n e s ~ ~ ”For ~ ~ .example, a-hydroxycyclohexanone is formed in 76% yield from 2-chlorocyclohexanone with an aqueous solution of potassium carbonate283,while w-hydroxyacetophenone is obtained by boiling o-chloroacetophenone in water2”. However, during the hydrolysis of a-haloketones, side reactions, and especially Favorskii rearrangements and elimination reactions, are able to occur.

1. Synthesis and reactivity of a-halogenated ketones

45

While treatment of 2-bromocyclododecanone (145) with aqueous potassium hydroxide gives 78% 2-hydroxycyclododecanone (la) the , reaction in isopropanol results in the formation of the Favorskii rearrangement product, i.e. cycloundecanecarboxylic acid (147)285. The same phenomenon is observed during the reaction of halogenated aryl cyclohexyl ketones (148) with potassium hydroxide (equation 110)2a.287.The nature of the halogen also plays an important role in the

+

G C O A r (1 10)

(150)

(140)

reaction course. Reaction of a-chlorinated dicyclohexyl ketone (151) with potassium hydroxide in dioxan gives mainly a carboxylic acid (152), while the corresponding bromo compound shows a completely different reaction resulting in a debromination (equation 111)288. The initially formed a-hydroxyketones sometimes undergo further

reactions under the basic reaction conditions, such as i s o m e r i z a t i ~ n ~oxidation ~~, with formation of diketones2w, benzylic rearrangement with formation of a-hydroxycarboxylic acids291and d i m e r i z a t i ~ n ~ ~ ~ . Numerous examples are known of Favorskii rearrangements of a-halogenated ketones with metal hydroxide~2~3, carbonates294,bicarbonates295and silver nitrate296 in water, as depicted below (equation 112). In some cases, such as polyhalogenated cycloalkanones, even treatment with water gives rise to Favorskii products293.

46

Norbert De Kimpe and Roland Verhe

Next to the Favorskii rearrangement, the Grob fragmentation is frequently encountered in reactions of halogenated cycloalkanones such as polychlorocyclopentanones with base162(equation 113)64.

& ~ l-+ -lc CI

AcetoneHHC03water

.

0

A similar fragmentation reaction leading to dichlorinated acids takes place during the synthesis of geminal dichloroketones with the system carbon tetrachloride-potassium hydroxide-t-butyl alcohol106.Also, in the reaction of cawone tribromide (165) with sodium hydroxide in water or ether, little or no Favorskii rearrangement occurs; instead the carbonyl group is attacked, leading to compounds

1. Synthesis and reactivity of a-halogenated ketones

47

166, 167 and 168 by a Grob fragmentation and to an epoxide (169). However, in the reaction of the trans isomer (171) with sodium hydroxide, the Favorskii rearrangement prevails with formation of unsaturated esters (after treatment with diazomethane) and a lactone (equation 114)297.

(174)

(175)

a-Hydroxycycloalkenones (177, 179) are prepared from a-brominated cycloalkanones (176,178) by hydrolysis with aqueous sodium hydroxide (equation 115)2y8,2y9. The reaction of 2,2-dihalo-l-arylalkanones(180) with hydroxide ion takes a completely different course, yielding a-hydroxycarboxylic acids (182) via a benzilic rearrangement of intermediate a-diketones (181) (equation 116)300. Although a number of dehydrohalogenation reactions by the action of carbonates on a-haloketones have been reported, this reaction has little synthetic value due to rearrangements and aldol condensations already mentioned. In most cases lithium carbonate in dimethylformamide or dimethyl sulphoxide has been used in the elimination reactions. Cyclohexenones are formed from a-halocyclohexanones. For example, 5-t-butyl-2-cyclohexenone (184) is produced from the chloro compound (183) using

Norbert De Kimpe and Roland Verht

48

0

OH-

ArCO-C-R

/I

x x

0

0-

I Arc-COR I

ArCOCOH

OH

(1w

-

(181)

OH

I I

Arc-R

(116)

COOH

(182)

lithium carbonate in dimethylformamide (DMF), while treatment of (183) with lithium chloride results in formation of a mixture of the isomeric cyclohexenones (184, 185) in a ratio 3.5:l (equation 117)301. Similar results are obtained during dehydrochlorination of 9-chloro-1-decalone with lithium chloride302.

bcJ t-Bub LI*CO$

r-&I

( I LlCl

DMF

(183)

' t-BU

(117)

+

(184)

(185)

Dehydrohalogenation readily occurs using alkali carbonates in DMF or dimethyl sulphoxide (DMSO) in reactions with y,bunsaturated a-haloketones, producing dienones (equation 118)303. A', R2'

C =CH

-CH2-

CHCOR3

I

CI

%CO3

A', R2'

C=CH-CH=CHCOR3

(118)

Dehydrobromination of a,a'-dibromocycloalkanones occurs easily and 4 4 tetramethyl-2,5-cyclohexadienone (187) and 2,4,6-~ycloheptatrienones(189) are formed from 2,6-dibromo-4,4-dimethylcyclohexanone(186) and 2,2,7-tribromo-

1. Synthesis and reactivity of a-halogenated ketones 0

49

0

cycloheptanone (la), respectively (equation 119)1899305.However, the reaction of ad-dibromocyclopentanone (190) with two equivalents of sodium hydrogen carbonate in DMF affords 2-bromocyclopent-2-enone in high yield (equation 120)306. 0

0

(190)

Hydroxide-catalysed cyclization takes place when a-bromo4-acyloxyaryl alkyl ketones (192) and a-bromo-8-methoxydihydrochalcones(194) are treated with aqueous sodium hydroxide, yielding respectively 3-substituted chromone epoxides (193)307and aurones (195)308.The bromohydrins (1%) are cyclized to chalcone epoxides (lW)309 by reaction with potassium carbonate in aqueous t-butanol (equation 121). Finally, treatment of bromoketones with sodium hydroxide or potassium carbonate in the presence of peroxides provides olefins as major products via intermediate cyclopropanones (equation 122)310. b. Reaction with organic oxygen nucleophiles and bases. There is no doubt that the reaction of a-haloketones with alkoxides is the most profoundly investigated in the field of the reactivity of a-halogenated carbonyl compounds. Nevertheless, prediction of the reaction products of a-haloketones with oxygen nucleophiles turns out to be very puzzling. Nearly all the reaction pathways proposed in the introduction to this section can take place, and the reaction outcome is dependent upon the nature of substrate and reaction conditions. A typical example of the complexity of this type of reaction was given by Turro during study of the isomeric pair of a-bromo-Zbutanone and a-bromo-fmethyl2-butanone with sodium methoxide. The reaction products consist of mixtures of Favorskii esters, a-hydroxy- and a-methoxyketones (198,199,199a) (equation 123)275. The ester formation is favoured in ether, while methoxy ketones are the dominant products in methanol. Turro proved that the Favorskii esters are formed via a cyclopropanone intermediate and the hydroxy- and methoxyketones are generated through epoxy ethers, which subsequently decompose directly or upon work-up.

Norbert De Kimpe and Roland VerhC

R’, R2’

0 II C-C-CH’

I

&

R3

‘R‘

&u

’ -

R’, C

/R3

‘R‘

Increasing the degree of substitution at the carbon atom to which the halogen is attached usually favours the Favorskii rearrangement by lowering the rate of side reactions, whereas substitution on the a‘-atom hinders rearrangement310. Replacement of chlorine by bromine favours Favorskii rearrangement most of allzz9. The competition between substitution, epoxide formation and Favorskii rearrangement is illustrated by the following examples, which emphasize the important influence of the structure of the substrate. Treatment of 3-bromo-3-methyl-2-butanone (200) with sodium methoxide gives the ester (201)312.313, while in compounds without a‘-hydrogen atoms such as brominated alkyl aryl ketones (202), epoxide formation (203)predominates (equation 12 4 p 4 .

1. Synthesis and reactivity of a-halogenated ketones

R

O

0

II

CH3-CH-C

-CH2Br

I

R

R CH3-C

I

I

O

II

-C -CH3

Br

51

> -0Me

-OM.

-0 OMe \ /

CH3-CH-C-CH2Br

I

-

R

RO- OMe I \ / CH3-C-C-CH3

I

Br

-

CH3\ ,CH-C R

R

0

\ / \ /

0 / \ I

-CH2

OMe

OMe

CH3/'-'\ CH3 (123)

R

O

I II CH3-CH-C-CH3 I OR'

R' = H, Me

(1993

Nucleophilic addition at the carbonyl function followed by intramolecular nucleophilic substitution yielding methoxy epoxides seems to be the most favourable pathway in the reaction of ketones without a'-hydrogen atoms such as in halogenated aryl benzyl ketones (203a)315-316, tetralones (206)317and steroidal a-bromoketones

Norbert De Kimpe and Roland VerhC

52

0

(203)

(202)

(209)318.A number of the epoxides (204, 207) are isolated, although they are readily converted into a-hydroxyacetals (205, 208, 210) on further treatment with alcohols (equation 125). However, tertiary a-haloketones, e.g. 2-bromo-2-benzyl-1-tetralones Ar-CO-CH-Ar

I

X

-*

(2033

Ar,

Meo/

0

I \ /H

c-c,

Ar

Wlon

I

Ar-C-CH-Ar

I

Me0

I

OH

(205)

(204)

(209)

Me0

(210 )

(211), are readily dehydrobrominated with alcoholic sodium methoxide to give excellent yields of a$-unsaturated ketones (212) (equation 126)319,320.

(2111

(219)

In the field of a-halocycloalkanones the reaction products with alkoxides are also

strongly dependent upon the substrate. While 2-chlorocyclohexanone gives rise to the

1. Synthesis and reactivity of a-halogenated ketones

53

Favorskii ester (213)321,treatment of 6-phenyl-2-chlorocyclohexanoneproduces the substitution product (214) in different solvents322(equation 127). On the other hand,

(214)

2-chloro-2,6,6-trimethylcyclohexanone (215) gives a stable epoxy ether (216)323,while 9-chloro- I-decalone (217) produces the rearranged substitution product (218)324 (equation 128).

(217 )

(218 )

Treatment of 1O-chloro-10-methylbicyclo[7.2.0lundec-1-en- 11-one (219) with sodium methoxide in methanol also results in allylic substitution rather than ring contraction to produce the methoxy ketone (220). The substitution apparently occurs through the enol of 219. Conversely, treatment of 2-chloro-4-isopropylidene-2,3,3-trimethylcyclobutanone (221) under identical conditions results in the unrearranged product. It seems unlikely that this substitution product (222) is the result of a direct displacement at the tertiary centre. The product probably results from an elimination proceeding through a bicyclobutanone intermediate which adds methoxide to produce 222 (equation 129)325. Not only does the nature of the substrate play an important role in the reaction pathway. The halogen atom also influences the reaction, as illustrated in the case of the triaryl ketone (223) where the chloro compound gives a methoxy epoxide (224) and the bromo compound a methoxyketone (225) (equation 130)316. Other important factors controlling the reaction course are the reaction conditions and especially the nature of the solvent and the concentration of the nucleophile. In the reaction of a-chlorocyclohexanone or 2-bromo-5-methyl-5-phenylcyclohexanone with sodium methoxide in methanol, the yield of the Favorskii esters has been found to increase markedly at the expense of the a-methoxyepoxide and the a-methoxyketone on increasing the methoxide concentration. The increased yield can be attributed

54

Norbert De Kimpe and Roland VerhC

A?\ ,C-CO-Ar Ar I X

mow -

OMe

(225)

partly to a positive salt effect favouring ionization of halide ion from the enolate ion. 2-Chloro- and 2-bromo-4-methyl-4-phenylcyclohexanoneare much less subject to this concentration effect due to steric factors: 40% yield of the Favorskii ester is obtained even at low methoxide concentration^^^^. Substituted a-chlorobenzyl methyl ketones (226) also give mixtures of Favorskii esters (227) and a-hydroxyacetals (228) (equation 131)327.The yield of the Favorskii ester increases from 9% at 0°C with 0.05 M sodium methoxide to 61% with 2 M sodium methoxide at 63°C. This is believed to be a consequence of a 2-3 kcal mol-'

1. Synthesis and reactivity of a-halogenated ketones

55

higher activation energy for the Favorskii reaction. The yield of the ester is increased to 68% for Ar =p-MeOC6H4 and is decreased to 0% for Ar =p-N02C6H4. Similar effects are observed in the reactions of 3-chloro-1-phenyl-Zbutanone(2%) and 1-chloro-1-phenyl-Zbutanone(231) with variable concentrations of methoxide ion yielding mixtures of ester (229) and a-methoxyketone (230)(equation 132)328*32y.

0

II

PhCH2CCHCH3

I

kz

-

0

II

PhCH2CHCOOCH3 + PhCH2CCHCH3

I

I

CI

OCH3

CH3

(2283

(229)

(230)

[-0Me],~

229, %

0.05 (inverse addition) 0.02 2

50 100

0

I1

PhCHCCH2CHS

I

mow

0

100 50

0

I1

PhCH2CHCOOCH3 + PhCH2CCHCH3

I

I

OCH3

CH3

(230)

(229) [-OMel, 0.05

M

(132)

0

CI

(2311

230, %

229, %

230, %

70

30

1-Halo-1,l-diphenyl-2-propanones (232) react with 0.05 M sodium methoxide to give essentially quantitative yields of Favorskii ester (233), while under inverse addition (addition of the nucleophile to the substrate) and low concentration of methoxide ion a mixture of 233, 234, and 235 is formed. Reaction of 3-chloro-l,l-diphenyl-2-propanone under the same conditions gives the same product distribution, while a-bromo-l,1,3-triphenyl-2-propanones (u6, 237) yield 1,3-diphenyI-2-indanone (238) (equation 133)330. The mechanisms leading to the various reaction products have been elucidated by Bordwe11273~322~325-330. The Favorskii rearrangement of a-chloroarylpropanones and a-chloroarylbutanones falls into two classes. The series ArCHCICOCH3 and ArCH2COCH2CI react with methoxide by way of reversible carbanion (enolate ion) formation followed by rate-limiting halide release, while for systems like ArCH2COCHXCH3,PhCHXCOCH2CH3and PhCH2COCHXPh, halide ion release is greatly accelerated and proton removal becomes rate limiting. The alkoxy ketones are formed through solvolysis of intermediate enol allylic chlorides. The various pathways are depicted in equation (134). The same mechanism is observed during the methanolysis of 3-chloro-1,3-dipheny1-2-propanonewith lutidine or lutidine-lutidine .H+buffer, yielding exclusively the a-methoxyketone3**.No reaction is observed when chloroacetone is treated under similar circumstance^^^^. The distribution of the products obtained by reaction of dichlorinated methyl ketones (239,240) with sodium methoxide in methanol is strongly dependent upon the

56

Norbert De Kimpe and Roland VerhC

0

II

PhzCCCH,

I

moM.

Ph2CHCH2COOCH3

+

Ph2CCOCH3

I OM8

x

+ N

O

P h CH2COOCH3

(232)

0

II

Ph2CCCH2Ph I

B

(133)

Ph2CHCCHPh

I

Br

(237)

structure of the ketone. Primary dichloromethyl ketones (R2 = H) give the normal cis acrylic esters (241), together with chloromethyl esters (242) whose amount increases with the increase in the bulk of the R' group, while the secondary dichloromethyl ketones (240) afford small amounts of methyl esters (242) but variable amounts of methoxyketones (243). The stereospecificity is complete for primary ketones and in the secondary derivatives the ratio between the cis and trans acrylic esters depends on the difference between both alkyl substituents (bulkiness) and on the chlorine substitution ( 1 , l - and 1,3-dichloroketones) (equation 135)95.The reaction takes a completely different course when a,a-dihaloalkyl aryl ketones (244) react with sodium alkoxides to produce a mixture of isomeric a,a-dialkoxy ketones (245,246) in variable In the cases where R' = H and R1= t-Bu small amounts of alkyl benzoates (247) are detected (equation 136). 2-Chloro-2-fluoro and 2-bromo-2-fluoro compounds give rearrangement to 246 exclusively while a,a-difluoroketones show exclusive reduction of the carbonyl function. It is reasonable that the dichloroketones react by an initial nucleophilic addition and subsequent intramolecular nucleophilic attack with halide displacement, furnishing a-halo-a'-alkoxyepoxide intermediates. The latter compounds rapidly rearrange spontaneously to a-halo-a-alkoxy ketones which further give rise to a,a-dialkoxy ketones by a direct route or via the hemiacetal. Alternatively, the latter product can be deprotonated by the alkoxide, after which intramolecular nucleophilic substitution yields the a,a'-dialkoxyepoxides. The diactivated epoxides are then opened at both sides to produce the final isomeric apdialkoxy ketones 245 and 246 (equation 137). The reaction mechanism was supported by the synthesis of reaction intermediate^^^.^^. The intermediacy of a-chloro-a'-methoxyoxiranes seems to be reasonable as compounds of this type have been observed during the reaction of tetrachlorocyclopentanone (38) which gives 248 and 249 (equation 1 3 8 ) v In addition, stable a-chloro-a'-methoxy oxiranes (251) have been isolated during the reaction of tetrachlorocyclohexanones (250) with sodium methoxide in methanol (equation 139)332.

57

1. Synthesis and reactivity of a-halogenated ketones PhCH2CHCOOCH3

I

CH3

OH

I /c\ PhCH 'CHCH3 I

-

CI

OH

OH

C phCH<'i'> CHCH,

C

I

I

====

PhCHb

'CHCI3

CI -

I

CI

0

II

PhCH2CCHCH3

I

OCH3

(230)

R' R2CHCOCHC12

(239) R' R2CCOCH2CI

I

CI

(240)

*

R' R ~ C = C H C O O M ~ Clt

(2411

R'R2CCOOMe

I

CH2CI

(242)

0

( 135)

It + R'R2CCCH2CI I (Me

(243)

a,a'-Dibromocycloalkanonesreact with sodium methoxide via the intermediacy of epoxides to yield a-hydroxy acetals (2S3)=, although earlier investigations claimed the formation of a Favorskii rearrangement product333.The acetals are formed by addition of methanol to the carbonyl group and substitution of one bromine with

58

Norbert De Kimpe and Roland Verhe ArCOCR’

/ \

x

-m2

ArCOC(OR212R’

+ ArC(OR2)2COR’ + ArCOOR2

(136)

v

(244)

(246)

(245)

(247)

X, Y = CI, Br, F A’ = H, dkyl A2

R20

z

X

\ /

Arc-COR’ RzO-

R20

I

i-Pr

-

ArC(OR2)2COR’

X

(-0 / \OR2

(137)

(246)

RzOH

\ /’

Ar-C-CR’

Me, Et,

-

R20, Ar

0

/ \ ,OR2

/c-c

ArC(OR2)2COR‘

(246)

‘R’

+ ArCOC(OR2),R’ (245)

methoxide, followed by elimination of hydrogen bromide to produce an epoxide which in turn is cleaved by reaction with methanol. The acetals are transformed into 254 at room temperature (equation 140). Another pathway observed during the reactions of polyhalogenated cycloalkanones with methoxide ions involves a Grob fragmentation, as illustrated by the reaction of a pentachlorocyclopentanone (39) yielding the esters 255, 256, or 257 (equation 141)64 (see also conversion 162 + 164). Monofluoroketones show a completely different route in the reaction with sodium alkoxides in ether at -60°C. The exclusive reaction product constitutes of a ketol (259) produced by aldol condensation (equation 142)334. Finally, reaction of a-bromoketones (260, 263) with methanol in the presence of silver hexafluoroantimonate affords substitution products (262) via an a-ketocarbenium ion (261) and Favorskii ester (265) via an intermediate hemiacetal (264) (equation 143)335. Reaction of the chlorinated bicyclic ketones (266, 267) with potassium t-butoxide (strong base, poor nucleophile) in t-butanol shows a regioselective elimination-rearrangement via a zwitterionic intermediate leading to a bicyclic enone (268) system (equation 144)336. Cyclopropanone derivatives are produced when specific a-bromoketones are

1. Synthesis and reactivity of a-halogenated ketones

59

/ Me0

0=QCI OMe

-

OMe (249)

(W)

yy (CH2In

(252)

~

(2511

~

MeoOMe

,-NM.oH

(253)

(140)

Meo OMe

(2s)

treated with potassium t-butoxide in THF. An example is the formation of 2,3-di-t-butylcyclopropanone(271) from a-bromodineopentyl ketone (270). When the reaction is carried out in t-butanol, not the t-butyl ester, but the corresponding acid (272) is formed, presumably from the action of adventitious hydroxide in the In addition, reaction of a,a'-dibromodineopentyl t-butoxide (equation 145)337-338. ketone (273) with potassium t-butoxide in THF provides di-t-butylcyclopropene (274) in 80% yield (equation 146)339.340. Addition of a solution of tris(chloroacetony1)methane (275) in THF to a solution of potassium t-butoxide in t-butanol affords a direct entry to the triasterane structure

60

Norbert De Kimpe and Roland VerhC

CH3OOC-C

I

=CH-

CH =C

CI

RCOCH2F

, ' Y

-

m m

n w

CHSOOC-C=CH-CH,-C(OCH,),

I

CI

OH

I

R-C-CH(F)COR

I

R = cycbhexyl, benzyl

&

OM9

(276) via a series of intramolecular transformations, as outlined in the following

scheme (equation 147)341. Just as in the case of the reaction of a-haioketones with alkoxides, attack of phenoxide anions gives rise to a variety of products, depending not only on the substrate and the reaction conditions but also on the nature of the phenoxide. While the reaction of 2-chlorocyclohexanone with sodium phenoxide affords the a-phenoxy ketone (277), treatment of the same ketone with sodium (2-isopropyl-5-methy1)phenoxide provides a mixture of the substitution product (277a) and the Favorskii ester (278) (equation 148)u2-3". Hypothetically, the formation of 2-phenoxycyclohexanone may occur by, first, a SN2 attack at the a-carbon (path l), second, a S N ~attack ' at C(*)in the enol (path 2), third, an attack at either the a- or a'-carbon of a symmetrical cyclopropanone intermediate (path 3). A decision between the various possibilities is offered by the use of [ 1,2-14CJ-2-chlorocyclohexanone and it is proved that only path 3 is consistent with the results (equation 149)345.

1. Synthesis and reactivity of a-halogenated ketones

>...-?-&O- K *

61

[ g-0

CN

(144)

(287)

Br

I

t-BuCH, t-&rCH

I

c=o

'

Br

I-&01(

MI-7O.C

*

Bu-t

1-Bu

(146)

(274)

(273)

The reaction of I-chlorocyclohexyl methyl ketone (279) with sodium phenoxide in phenol gives a mixture of the substitution and elimination products (280 and 281) together with the Favorskii ester (282) (equation 150)u6. On the other hand, a,a'-dibromocycloalkanones (252) provide a single reaction product, 2-phenoxy 2-cycloalkenones (283) with sodium phenoxide in methanol or DMF (equation 151)3M. The reaction of chloroacetone with activated phenols in the presence of potassium carbonate and potassium iodide in DMF gives substitution products347,but 1,3-dichloroacetone reacts with phenols under similar conditions to give mixtures

62

Norbert De Kimpe and Roland VerhC

110 I?

CH2-CI

HC(CH2COCH2C1)3

(275)

( 2 n a1

-

CIH&

Ck-CH -CI

O

U

O

-

(270)

where 1,l-bis(ary1oxy)acetone is the major product, while the more acidic p-nitrophenol (which is ionized under the reaction conditions) provides the expected 1,3-disubstituted compound348.Reaction of the dibromoketones (284) with catechol gives rise to the formation of 1 ,Cbenzodioxan derivatives (285) (equation 152)349.

1. Synthesis and reactivity of a-halogenated ketones

-

@-Om

Path 1

boPh

0

R-CH-CH-COCH3

I

&

I

&

0

+ OH

63

Norbert De Kimpe and Roland Verhe

64

a-Haloketones readily react with salts of carboxylic acids, especially sodium and potassium formate and acetate, to give substitution products. Hydrolysis of these esters affords a-hydroxyketones. Therefore, this particular reaction sequence constitutes the method of choice for the preparation of a-hydroxyketones because no major side reactions are taking place as in the case of the direct hydrolysis of a-haloketones (equation 153)350-352.Another interesting application involves the

R’COCHR~

R3C00- M’*

R’COCHR~

Hydrolysis

* R’COCHR~

I

I

i

OH

OCOR~

Bf

(153)

synthesis of 2,3-dihydro-6H-1,4-oxazin-2-ones (286) from a-halomethyl aryl ketones and protected amino acids (equation 154)353.

I

CbZ

I

CbZ

A number of isomerizations are observed during the reaction of a-haloketones with carboxylate anions. Treatment of 2-bromo-1-phenyl-1-propanone (287)with acetate (288) while with ion followed by hydrolysis provides 1-hydroxy-1-phenyl-2-propanone formate ion the normal product (289) is formed (equation 155)352.

Acetolysis of l-chloro-3,3-diphenyl-2-propanonein the presence of potassium acetate gives l-acetoxy-3,3-diphenyl-Zpropanone(291), 1-acetoxy-1,l-diphenyl2-propanone (293) and 1-phenyl-Zindanone (292), while 1-chloro-1,l-diphenyl-

1. Synthesis and reactivity of a-halogenated ketones

65

2-propanone (290) produces 293 exclusively. The reaction mechanism suggests the intervention of an allylic carbonium ion capable of capturing nucleophilic species at both C(,)and C(3)(equation 156)354. Ph2CCOCH3

I

(290) CI Ph2CHCOCH2CI

:I]

Ph2C=CCH&I

I

CI-

= P~~CQ+.,CH~ C

I

OH

I

\ /

Ph26CO CH3

fi2C-CC=CH2 CI I OH I

OH

(292)

Other examples of cine substitution are illustrated below (equation 157)'55,356. Rearrangement also occurs when 2,6-dibromo-4,4-dimethylcyclohexanone(186) PhS-CH-COCH2CI

I

CH(CH3)2

NIOAc 7 PhS-C-COCH3 II

(294)

Q}-

0

C(CH312

Ac;a} (2%)

(157)

reacts with sodium acetate in acetic acid yielding 298. The mechanism involves bromine substitution followed by a 1,3-hydrogen bromide elimination together with an acyl migrationIE9. Similar results are obtained in the cases of a,a'-dibromocycloalkanones (252) and tribromotetrahydro-4H-pyran-4-ones(300) with acetate anions357(equation 158). Bromoketones react with bromoacetic acid in the presence of triethylamine to give the substitution products, which, via intermediate phosphonium salts, can be cyclized to a$-unsaturated lactones (303)(equation 159)358.

0

ArCOCHR

I

ik

OH

BrCH2COOH E13N

-

ArCOCHR

OAc

(158)

PR3 ___)

I

OCO CH Br ArCOCHR

I

OCOCH2P+Ph3. &-

Et N

R

0

(159)

(=I The hexafluoroacetone-potassium fluoride complex behaves like a weak oxygen nucleophile and a strong base during its condensation with a-haloketones. Nucleophilic substitution produces a-perfluoroalkoxy ketones (303a). Abstraction of a proton leads to the formation of diones (304) and cyctic ethers (305 and 306) (equation 160y9. 4. Reaction of a-haloketones with nitrogen nucleophiles and bases

a. Reaction of a-haloketones with amines. Amines have been widely used to substitute a-haloketones. Numerous examples are known in which ammonia, primary and secondary amines produce a-aminoketones, while treatment with tertiary amines Geminal diaminoketones are formed gives rise to ammonium salts (equation 161)360. when a,a-dichloroketones react with an excess of a m i n e ~ ~ ~ l . Aminoketones are rather unstable compounds, and it is therefore advisable to isolate them as salts of strong acids.

67

1. Synthesis and reactivity of a-halogenated ketones A

+ (CF,),CO/KF

PhCOCH2&

PhCOCH,OCF(CF, J2 (ma)

-[ - %-

H

I

PhCOC-C(CF3),

\o/

]

PhCOCOCH(CF,),

(304)

0

0

Br

/

4 CFQJ2CO

Primary aminoketones are also synthesized by introduction of a protected amino function using the u r o t r ~ p i n eand ~ ~ the ~ phthalimide method363or by hydrolysis of N-ben~ylaminoketones~~. Substitution reactions of a-haloketones with heterocyclic amines often give rise to cyclized products; e.g. reaction of bromoketones with Caminopyrimidines (306a) and 3-amino-l,2,4triazines (308) affords

68

-

Norbert De Kimpe and Roland Verht R1COCHR2 + R3R4NH

I

R1COCHR2

I

X

NR3R4

-

R ~ C O C H R+~ N R ~

I

R~COCHR~

I

YRS X-

X

imidazo[ 1,2-c]pyrimidines (307)365 and imidazolotriazines (309)366, respectively (equation 162). R3

R3

R2

R2

The reaction between a-haloketones and amines is not always a simple substitution reaction. While the reaction of 2-bromo-2-methyl-1-aryl-1-propanones (160) with morpholine gives rise to the substitution product (310), reaction with the stronger base pipendine affords the elimination-addition product (311)367. From aniline and 1-bromo-1-phenyl-Zpropanone(312) and 2-bromo-1-phenyl-1-propanone(313) a mixture of the a-aminoketones (314,315) was obtained (equation 163)368. In general, a-halogenated ketones of the primary and secondary type (primary, CICH2CO; secondary, RCHCICO; tertiary, R1R2CClCO) are expected to give substitution, but tertiary ketones are able to give elimination products. High yields of a,b-unsaturated ketones are reported when a-haloketones are treated with pyridine, quinoline, collidine and N,N-dimethylaniline, especially with cyclic a-haloketones (equation 164)369-371, a,a'-Dibromoketones provide cyclopropenones (316) by double 1,3-dehydrobromination on treatment with tertiary amines (equation 165)372. The ordinary course of the reaction of a-haloketones with pyridines, resulting in dehydrohalogenation and displacement, is often apparently accompanied by varying amounts of reduction and double bond rearrangement products as illustrated for 2~-bromocholestan-3-one(317) (equation 166)373*374. Favorskii rearrangement amides are frequent1 encountered when a-haloketones are treated with ammonia375,primary secondary a m i r ~ e (equation s~~~ 167). The reaction course is dependent on the kind of base and solvent used. Ch-carvone tribromide (165) undergoes a Favorskii rearrangement to afford an iminolactone (320) when treated with primary amines in methanol but suffers

1. Synthesis and reactivity of a-halogenated ketones MPrpholina

Ar COC (CH,

I

H3C CH \/ ArCOC-N

30n

(310 )

l2

d

Br (160)

Piparidina

ArCOCH -CH2-N

I

CH3

I

Br

(312) PhCOCHCH3 PhCHC0CH3 I Br

(313)

I-

R-CH-CO-CH-R

I

Br

I

69

3

(311) (163)

PhCOCHCH3

I

NHPh

+ PhCHCOCH, I

NHPh

(315)

(314)

7

R

Br

Dl

+0

70

-

Norbert De Kimpe and Roland VerhC CH3OCH2-CH-COCH2R

I

w3

CH3OCH,-CH2-CH-CONH,

I

R

6r

(318)

(319) NR

Br

0

(=a dehydrobromination when the reaction is conducted in ether377.The configuration also plays an important role, as the trans isomer yields the lactone 320 in both solvents. Similar solvent effects are reported during the action of amines on a,a'-dibromocycloalkanones,e.g. 252 and 300a306,307(equation 168). In both cases the enamino ketones are the predominant products in polar aprotic solvents such as HMPA, whereas the Favorskii rearrangement products predominate in ether. Another type of frequently occurring reaction consists of an addition of the amine to the carbonyl function (e.g. of 202) followed by an intramolecular substitution yielding an aminooxirane (329) which can rearrange into an a-hydroxyketimine (330) (equation 169)378. Formation of k e t i m i n e ~ ~ ~normally ~ b ~ " does not take place when a-haloketones are treated with primary amines except for a-fluorinated ketones, and especially high yields of trifluoroketimines (331)are easily obtained (equation 170)379*380. However, we recently developed a general method for the preparation of a-halogenated ketimines (332) by condensing a-haloketones with primary amines in ether using titanium tetrachloride as condensing agent (equation 171)381.This method is also applicable to dihalo- and t r i h a l o k e t o n e ~ ~ ~ ~ . The formation of compounds containing C=N bonds will be discussed in the section dealing with reactions of carbonyl reagents. In general586, the condensation of a-halogenated ketones with secondary amines does not afford /&halogenated enamines

71

1. Synthesis and reactivity of a-halogenated ketones

0

0

(325)

+

(326)

(328)

R2NH = morpholine, piperidine, pyrrolidine

,CH3 ArCOC, I CH3

R%

Br

0

CH,

/ \ / Ar-C-C / \ RNH CH3

RCOCF3 + ArNH2

-

Bbnzeno

N

X

II

RC-

h

R', R 2 = H, alkyl, aryl

OH Ar-C-C,

CF,

I1 NR

I 0CH3

(169)

CH3

( 170)

(331)

X 3

(332)

R3 = alkyl. aryl

(333) except when the reaction is carried out in the presence of metal chlorides such as AsCI3, SbC13, FeCI3 and TiC14382-383, or by the use of tris(N,N-dialkyiamino)arsines3" (equation 172). In addition, reaction of 2-chlorocyclohexanone with pyrrolidine at - 100°C in the presence of magnesium sulphate produces an enamine (334) with the chlorine atom in allylic position and minor amounts of a bicyclic compound (335) (equation 173)385.

Norbert De Kimpe and Roland Verht

72

(334)

(335)

Chloromethyl ketones also react with lithium or sodium amide in liquid ammonia to produce oxazolines (336)386,while stable epoxyamines (337) are formed when brominated alkyl aryl ketones are treated with the lithium salt of e t h ~ l e n e i r n i n e ~ ~ ~ , ~ ~ ~ (equation 174). R

ArCOC,R2 A'

I

+ LiN3

-

Br

0 N

L l (337)

6. Reaction of a-haloketones with enamines. a-Bromoketones react with enamines of methyl ketones to provide immonium salts which upon hydrolysis afford 1,Cdicarbonyl compounds (338) (equation 175)389. R'COCHSBr

+ H&=C-R2 I

N / \

At tar

hvdrolyrir-

R'COCH2CH2COR2 (338)

(175)

Cycloaddition of /?-amino-a,/?-unsaturatedcarboxylic acids and derivatives with a-haloketones gives rise to pyrrole compounds (339) (Hantzsch ~ynthesis)'~,while reaction with B-aminovinyl thioketones (340) give 2-acylthiophenes (341)391 (equation 176). c. Reaction of a-haloketones with amides, thwamides and derivatives. Various heterocyclic compounds have been synthesized by the reaction of a-haloketones with amides, thioamides, urea, thiourea, amidines, guanidines and sulphonylamides. Reaction of a-bromoketones with amides produces oxazoles (342)392-393,while reaction with alkynyl thioamides (343)gives 1,3-oxathiazoles (344)394(equation 177). A cyclodehydrohalogenation leading to 2-azetidinones (346) is observed when

1. Synthesis and reactivity of a-halogenated ketones R’COCHR2

Br I

+ R3C=CHCOY NH2 I

Y = H, OR NHR

73

- R2ac I

R’

R3

anilides of a-bromoketones (345) are subjected to the action of various bases (equation 178)395. Ar-

NHCOCH2CHCOPh

I

Br

(345)

Base

Ar-

doPh N

0

(178)

(348)

Reaction of a-bromoketones with amidines or formimidates constitutes an excellent method for the synthesis of imidazole derivatives (347) (equation 1 79)3%v375. However, a pyrimidine ring (350) is formed during the reaction of

74

Norbert De Kimpe and Roland VerhC

a-bromochromanone (347a) with bemamidine (348) probably via an intermediate chromone (349)(equation 180)397. Another synthesis of imidazole compounds (351) involves the condensation of phenacyl bromides with guanidine using bromine in methanol as the condensing agent (equation 181)398..On the other hand, reaction of an a-haloacetone with

isothiosemicarbazones (352) gives rise to a competitive formation of imidazoles (353) and triazole compounds (354). The ratio is dependent upon the nature of the halogen and the reaction temperature (equation 182)399. CH3COCH2X + RICH=N-

N=C\

/NH2 SR2

-

(354) The Hantzsch reaction of a-haloketones with thioamides, thiourea and dithiocarbamates affords thiazolium derivatives (357). By isolation of intermediate thiazolines it is proved that the first step in this reaction is a direct substitution of the halogen atom and not an addition of the nitrogen atom at the carbonyl function (equation 183)400-402.

1. Synthesis and reactivity of a-halogenated ketones

75

x

(357)

Substitution of a-bromoketones with N-phenyltrifluoromethanesulphonamides (358) under mild conditions gives rise to the formation of a-iminoketones (359) which in turn can further be converted into pyrazines (360)(equation 184)403-404. R'COCHR2 + PhNHS02CF3 I

-CF3SOZH

kc03 7 R'COCHR2 I

NH / \ Ph SO2CF3

(184)

d. Reaction of a-haloketones with carbonyl reagents. The reactivity of a-halocarbonyl compounds towards the usual carbonyl identification reagents has been reviewed by De Kimpe and coworkers in reports dealing with the synthesis and reactivity of a-halogenated imino compounds4054~.Therefore, only the most typical reactions will be covered in this section. Except for 2,4-dinitrophenylhydrazonesof a-haloketones, which are easily formed when prepared in aqueous methanol in the presence of sulphuric acid407,a-haloimino compounds are not generally available by the condensation of a-haloketones with carbonyl reagents, due to the reactivity of the imino compounds which lead to further reactions under the normal reaction conditions. Consequently, only a limited number of a-halohydrazonesW8, s e m i c a r b a z o n e ~and ~ ~ o x i m e s 4 ' ~ ' *have been obtained by the direct condensation route (equation 185).

R'COCHR2

I

X

+ H2N-R3

-

A3

N

II

R'C-CHR2

I

X

R3 = OH, NH2, NHR, NHCOR, NHCSR, NHAr, NHTos

w

(1

76

Norbert De Kimpe and Roland Verh6

The most frequently encountered side reactions are the formation of azoalkenes

(361) by 1,4-dehydrohal0genation~'~*~'~, nitrosoolefins (362)410and the formation of

diimino corn pound^^'^, as illustrated in the following examples (equation 186). In

7

Pyridin.

(=1) R', X'

0

II

CH-CR2

-OH

-HX

, N=O

R'-cH=C

'R2

(-1

N=NPh CH3-C-

11 N I

H'

0

CH2NHNHPh

-

CH3- C-CH=NNHPh

It

NNHPh

N

'Ph NNHCOAr

(364)

addition, the initially formed a-haloimino compounds are able to undergo ring closure reactions to yield a variety of heterocyclic products. Reaction of phenacyl bromides with N,N-dimethylhydrazine and phenylhydrazine gives rise to the formation of pyrazoles (365)416 and tetrahydropyridazines (366)417, respectively. The reaction of dibromoketones with hydroxylamine and hydrazine furnishes isoxazoles (367)418and pyrazolidinones (31%)~'~(equation 187). 1,2,CTriazines (369)4209421, 1,3,4-thiadiazines (370)422and thiazolines (371)423are formed when a-haloketones are treated respectively with acylhydrazines, thioacylhydrazines and thiosemicarbazide (equation 188). e. Reaction of a-haloketones with sodium azide. Reaction of a-haloketones with sodium azide produces a-azidoketones, which on pyrolysis afford a-iminoketones via nitrene intermediates (equation 189)304-424.425. Action of sodium azide on chalcone dibromides furnishes a-azidochalcones (372) and isoxazoles (equation 189a)418.

-

-

1. Synthesis and reactivity of a-halogenated ketones ArCOCH2Br

+ H2NN(CH312

+ NH20H

ArCOCH-CHPh

I

Br

I

Br

[ArCOCH=NH]

-

77

Ar

0 3 ' ' /

Ar

R'COC, /

I

X

R2

R

N-

/

3 R1CO-C,R3

I

N3

R2

A

R'COC=NR3

I

R2

(189)

78

Norbert De Kimpe and Roland VerhC ArCOCHCH

I I

- Ph

N3-

ArCO

-C=

CH

I

-Ph

Br

Br Br

Ar CO-CH -CH

I

ArCO- CH-

I

N3

ArCO-

I

- Ph

CH -Ph

(189a)

ArCO-CH=C-Ph

I

I

N3

C= CH-

I

N3

Ph

0- N Ar U

N3

P

h

5. Reaction of a-haloketones with sulphur nucleophiles a. Reaction of a-haloketones with inorganic sulphur compounds. Reaction of a-haloketones with sodium hydrogen sulphide gives rise to a-mercaptoketones (374) in 50430% yield. However, when the reaction temperature is higher than O'C, sulphides (375) can be generated (equation 190)426,427. up'-Dimercaptoketones (376) (isolated

R'COC,

I

X

/R2

R

+ NaSH

-

R'COC,

HR2

I

SH

R

A

R2

I

R2

R~COC- S-

I

R3

(374)

I

CCOR' (190)

I

R3

(375)

as the cyclic dimers (377)) are also produced on treatment of a,a'-dihaloketones with sodium hydrogen sulphide (equation 191)428. CICH2COCH2CI

N8SH

HO

HSCH2COCH2SH

(3m)

H S C H 2 ~ ~ ~ O H CH2SH

(3m

(191)

3-Thietanones (378) have been synthesized by reaction of up'-dibromoketones and sodium hydrogen sulphide, together with minor amounts of dithiols (379), 1,2-dithiolan-4-ones (380) and polycondensates (381) (equation 192)429. Mercaptomethyl aryl ketones are also formed when aryl a-halomethyl ketones are treated with hydrogen sulphide in ~ y r i d i n e ~ ~ ~ .

1. Synthesis and reactivity of a-halogenated ketones

79

R’ &R,3 R2

s-s

R4

(380)

Reaction of a-haloketones with sodium sulphide affords sulphides (375)431. However, 2-chlorocyclohexanone produces a tricyclic compound (382) via aldol-type condensation of the intermediate sulphide in an inert atmosphere, while in the presence of oxygen a disulphide (383) is formed43z(equation 193). R2

R2

80

Norbert De Kimpe and Roland Verht

Finally, p-ketothiocyanates (384) are formed by the reaction of a-haloketones with potassium thiocyanate (equation 194)433. RCOCH2Br

KSCN

RCOCH2SCN

(194)

b. Reaction of a-haloketones with organic sulphur nucleophiles. Treatment of a-haloketones with mercaptans in the presence of bases mainly gives a-substitution to afford a-alkylthio and a-arylthio ketones (385) (equation 195)434-436.

R'COC, / R 2

I

X

R

+ R4SH

Bare

P2

7

R'CO-C-R3

(195)

I

Other reactions involve d e h a l ~ g e n a t i o nand ~ ~ transformation ~ of the initially formed (386)are prepared by mercaptans into the corresponding d i s ~ l p h i d e s1~,CDithienes ~~. cyclocondensation of a-haloketones with 1,2-ethanedithiol in the presence of acids (equation 196)439,"".

The reaction of chloroacetone with mercaptoacetamide proceeds smoothly to give 3-hydroxy-5-methyl-1 ,Cthiazine (387) (equation 197), while with phenacyl bromide the substitution product is formedM1.

- yly H

CH3COCH2CI

+ HSCH2CONH2

H3C

OH

(197)

(387)

Thioacids and their derivatives react readily with a-haloketones. Treatment with thioacids in the presence of ammonium acetate in refluxing acetic acid gives 1,3-thiazoles (388)(equation 198)M2.Reaction of thioacid salts normally gives rise to R'COCHR2

I

Br

R'

+ HSCOR3 7 NH,QAc

(198)

R2

(388)

substitution products (389)443.A useful synthetic application of this reaction is the formation of selenocarboxylates (389) on treatment with selenoacids. Selenium elimination from 389 with strong bases yields 1,3-diketones (390) (equation 199)M4. S-potassium hydrazino monothio- and dithioformate (391) react with a-haloketones to

-

1. Synthesis and reactivity of a-halogenated ketones R1COCH2Br + R2COYK

Y=S0

R1COCH2YCOR2

81

R'COCH2COR2

Y = S, Se

form acylmethyl (hydrazino)thioformates (392) which can be cyclked to 1.3-thiazolin-2-ones (393) or 1,3,4-thiadiazin-2-ones (394) dependent upon the substitution pattern of the ketone (equation 200)445.Dilithium salts of thioacids (395) also

R'CHCOR2

I

+ KS-C-NHNHR3

1

/'='

I

I1

X

HNNHR3

R 2 \ 40 C R'

Y

CH-S

3-zyNHR3 I

HO R2 R'

R' Y=O,S

(394)

react with a-chloroketones to yield 8-hydroxy thioacids (3%) which are cyclized to thiolactones (397) upon action with triethylamine, while unsaturated thiolactones (398) are formed with sodium hydride in DMF (equation 201)446.

R'COCHR2

I

CI

+ R3CH=C/

OLi 'SLi

(395)

THF

OH R ~ O

I I

R'C-

I I1

CHCSH

R~CHCI

(=I

Norbert De Kimpe and Roland VerhC

82

6. Reaction of a-haloketones with carbon nucleophiles

a. Reaction of a-haloketones with cyanides. a-Haloketones have been shown to give a variety of reactions when treated with sodium or potassium cyanide447. Earlier ~~; it is proved later reports claimed the formation of a - c y a n ~ k e t o n e s ~however, that in most cases the reaction products are a-cyanoepoxides (400) formed via an addition-substitution mechanism311*449,450(equation 202).

R'COCHR~

I

-

X

-CN

I

R'-C-CHR~

I

R' 0 H \ / \ /

c-c

7 I

CN

R'COCHR~

-

OH

I

NC'

x

'R2

(400)

CN

The a-cyanoketones could either be formed via direct substitution or via thermal rearrangement of the cyanoepoxides. Only when R1 is a t-butyl or an aryl substituent are a-cyanoketones p r o d ~ c e d ~ ~On ' - ~the~ ~ other . hand, a-fluoroketones undergo cyanation at the carbonyl function with formation of cyanohydrins (399) without substitution of the halogen453.Cyanohydrins (399) are also produced by condensation with hydrocyanic acid at 0°C in the presence of potassium cyanide as condensing agent454. Reaction of a-haloketones with tetraethylammonium cyanide in dichloromethane also gives rise to cyanoepoxides (400)which upon heating at 80-135°C in the presence of ammonium cyanide rearrange into a - c y a n o k e t o n e ~ ~ ~ ~ . Reinvestigation of the reaction of chloroacetone with alkali cyanides in aqueous solution at room temperature shows another route leading to an enaminoketone (401)456 and not to the tetrahydrofuran (402) as proposed earlier457(equation 203). CH3COCHOCl

- CN

CH3COCHCH2COCH3

I

CN

-

cn3cocH2ci

CH3COCHCN

-CN

CN

I I

CH3COCHCH2CCH3

I

c-4 1 1 1 3 N

CH3co

(401)

(203)

Another reaction involves the formation of a cyclopropane (a), induced by a Favorskii-type rearrangement on treatment of l-chloro-3-phenyl-2-propanone(403) with alkali cyanides in the cold (equation 204)458.

1. Synthesis and reactivity of a-halogenated ketones

’

PhCH2COCH2CI

(403)

0

II

PhCHCCH2CI

+

-

Ph

-0 CN

Ph

83

-

PhB

(204) PhA:OCH2CH2Ph

(404)

b. Reaction of a-hafoketones with carbanions, yIides and enofates. The reaction of a-haloketones with diethyl sodium malonate and ethyl sodium acetoacetate produces exclusively substitution products via an SN2r e a c t i ~ n ~ ~ ~ - ~ ~ l . The reaction course, however, is influenced strongly by the temperature. While diethyl (2-oxocyclohexyl)malonate (405) is formed during the reaction of 2-chlorocyclohexanone with diethyl sodium malonate in refluxing benzene460,6-[bis (ethoxycarbonyl) methyl]bicyclo[ 3.l.Olhexan-6-ol (406)is isolated at 0-25°C via a malonate anion-induced Favorskii-type rearrangement462(equation 205).

0

A

I

-CH(COOE1)2

Ht5H(c0 (408)

Condensation of a-chloroketones with P-keto esters in pyridine affords furans (407)463 while reaction of a-bromoacetone with dimedone anion furnishes 2-acetonyldimedone (408)464(equation 206). Alkylation of ethyl sodium acetoacetate with bromoacetylmethylene triphenylphosphorane (409) leads to an intermediate which undergoes an intramolecular Wittig reaction to give the cyclopentenone (410) (equation 207)465.

Norbert De Kimpe and Roland Verh6

84

- R2)i-J COOR~

R’COCHR2

I

Pyridino

+ R3COCH2COOR4

R3

R’

CI

(107)

0

II

&CH2CCH=PPh3

+ CH3COCHCOOEt

(409) It

0 II HC CH3

I

0

EtoM

-4 A

CH

H3C

I

COOEt

a,)-Unsaturated esters and cyanides (412) are formed in high yields by the Emmons-Wadsworth reaction of a-haloketones with the corresponding phosphoranes-., Knoevenagel condensation of a-haloketones with active methylene functions gives electrophilic allylic halides (413) by the action of titanium tetrachloride-pyridineu767.*68 (equation 208). R‘COC, I X

, R2

Nan

THF

R

I

X

+

C

I

X’

z = COOR~,

’R 2 R’COC,

R’\,C=C

R2,

,coot34

CH2,Z

R

Z = COCH,, COOR4, CN

TiCi, Pvridino

dH

%Z

R3

R’, R
x’l

COOR~ %Z

R3

(413)

1. Synthesis and reactivity of a-halogenated ketones

85

Another reaction type, namely aldol condensation yielding a,fl-enones (e.g. 414, 415), is reported when a-chloroketones are treated with pyridine in the presence of titanium tetrachloride (equation 209)469.

Reaction of a-haloketones with dimethylsulphoxonium methylide (416) results in cyclopropanation. First, the halogen is displaced by the methylide to give the intermediate salt. According to path a the salt can be converted to an olefin which reacts successively with the methylide (416) to give the cyclopropane (417). An alternative

R’-

C - C= CH2

I1

0

I

R’COCHR~

R2

b

0

R’CO

x

R2

(417 )

Norbert De Kimpe and Roland Verhe

86

route (path b) involves a nucleophilic displacement of the salt to afford an homologous salt which in turn affords a cyclopropane (417) by an intramolecular displacement (equation 210)470*471 Intramolecular cyclopropanation takes place when a-haloketones, carrying electron-withdrawing groups in the y-position, are treated with strong bases, providing, for example, nitrocyclopropanes (419)472. 1-Halocyclopropyl methyl ketones (421) may be obtained by simply heating the appropriate 3,5-dihalo-2-pentanones (equation 21 1). (420) with potassium fluoride as base in diethylene O2N-

CH-CH2-

CH2--OR2

R’

Br

I

I

(4.18) X’

-CH2-

CH2- CH

I

-COCH,

Base

R’

02N

COR2

(419)

(211)

I(F k C OX2 C H 3

X2

(120)

(4211

X’, X 2 = halogen

Lithium enolates (422) react smoothly with certain a-halocarbonyl derivatives, e.g. brdmoacetylmethylene triphenylphosphorane (409), which constitutes a useful annelIation reagent, to give cyclopentenones (423) (equation 2i2)465

&CH,COCH=

PPh,

(a)

+

ql;i

THF

R’

po (212)

R’

(423)

7. Reaction of a-haloketones with organometdlic reagents a. Reaction of a-haloketones with Grignard reagents. a-Haloketones react readily with Grignard reagents to afford mainly magnesium salts of halohydrins (which can be hydrolysed to the parent halohydrins) and rearranged ketones in variable proportions (equation 21 3)474-478. The majority of the rearrangements of halomagnesium derivatives of halohydrins can be accounted for by considering them to be pinacol-like rearrangements induced by an electrophilic attack of the MgX group on the neighbouring halogen atom (route A). A second way consists of an internal nucleophilic substitution (route B) (equation 214). Whether mechanism A or B is followed will be determined by structural factors. Route A should be favoured when the halogen atom is secondary or tertiary, when the migrating group R can participate in the process and contribute to the resonance stabilization of the transition state and when the -X and -0MgX moieties are in a cis relationship to one another. When the halogen atom is secondary or tertiary, route A seems always to be followed, but when it is primary the nature of the R3 and R4 roups directs the course of the rearrangement, as illustrated below (equation 215) 8 5 .

1. Synthesis and reactivity of a-halogenated ketones R’, R2

0 ,C-CR3

II

I

+ R4MgX

-

/

X

/

0

R’ \ 11 R2/C-C-R4 R3

+

I

H~O+

C-C-R4

R2/1

I

X

OMgX

R’, R2’1

R3

I

C- C- R 4 X

I

OH

0

R’ \ 11 R27C-C-R3 R4

, . i R‘ migration

R4

-

R3

R’,

87

0

R’ \ 11 R2~C-C-R3 R4

Route A

Mg

R3 migration

I

0

R’ \ 11 R2--,C-C-R4 R3

X

p

-Mgx2

X

CH3COCH2CI + RMgBr

-

-

R

I

CH3-C-CH2CI

I

R

OMgBr R

I CH3-C-CHO I

R4Mg%

R

I

CH3- CH-

H

CH - OH

I

(215)

R4 R4 = alkyl, benzyl

Ar CH3COCH2CI + ArMgBr

I I

CH,C-CH,CI OMgBr

CH3COCH2Ar

Norbert De Kimpe and Roland Verhe

88

The influence of stereochemical factors is illustrated by the rearrangement, via the halomagnesium derivative, of cb-l-methyl-2-chlorocyclohexanol,yielding mostly 2-methylcyclohexanone and a small amount of acetylcyclopentane, while the tram isomer exclusively affords a c e t y l ~ y c l o p e n t a n e ~ ~ ~ . Reaction of cyclic a-chloroketones with arylmagnesium bromide gives rise to a-arylketones (424)479,while with vinylmagnesium chloride 1,2-divinylcycloalkanols (425) are formed, except for a-chlorocyclobutanone which furnishes 1-cyclopropyl-4-penten-1-one(426) (equation 2 16)480.

0

0

CH?=CHMgCI

[ qoMgc' -p

COCH =CH,

CH=CH2

L

'CI CI

J

(126) A 'one flask' synthesis of olefins has been described by the reaction of a-chloroketones with Grignard reagents and further treatment with lithium metal at -60°C (equation 21 7)481. R'COCHR2

I

CI

+ R3Mg&

OW& R', R 3 , ~I - C H R ~

I

CI

-

Ll

6o'C

89

1. Synthesis and reactivity of a-halogenated ketones

1-Arylcyclopropanols (427) are produced when 1,3-dichlor0-2-propanonefirst reacts with arylmagnesium halides and the product is subsequently treated with ethylmagnesium bromide in the presence of ferric chloride (equation 21 8)482*483.

CICH2COCH2CI

ArMgBr

Ar OH

Ar

I I

CICH2C-CH2CI

EtMgEr F.CIJ

(218)

(427)

OMgBr

Reaction of phenacyl halides with Grignard reagents gives dibenzyl ketones or deoxybenzoins depending upon the aromatic substitution pattern and the reaction conditions which determine the relative migratory aptitudes of the aryl and phenyl

l-Aryl-2,2-dichloro-l-alkanones rearrange with methylmagnesium iodide to highly sterically hindered alcohols (428). The mechanism involves two pseudo-pinacol-type rearrangements of the carbonyl adducts (equation 21 9)485,486.

,

<-0 ArCOCC12R

~ 3 M g l

I

-

CI C i R CI

v-

Ar-C

R

I I

CH3COC-Ar

CH~MDI

CI

CH3

k Finally, non-addition reactions of a-haloketones and Grignard reagents (R'MgX) also occur which result in the formation of halomagnesium enolates with elimination of R'H or R'X487,488. Reaction of a,a,a-trichloroketones with isopropylmagnesium chloride gives, after hydrolysis, a mixture of alcohols and a,a-dichloroketones, the latter compounds resulting from intermediate magnesium enolates (equation 220)488. Magnesium

RCOCCI3

1-

- c,n,

OMgCl

I

RCHCC13

i-PrMgCl

&

H30*

OH

I

RCHCC13

H3O'

R-C=CC12

I

OMgCl

RCOCHC12

enolates are stable compounds possessing high nucleophilic reactivity. They can be prepared by reaction of a-haloketones with magnesium (equation 220a)487. R'COCHR~t

I

X

-

R~C=CHR~

I

OMgX

(220a)

90

Norbert De Kimpe and Roland VerhC

b. Reaction of a-haloketones with organolithium compounds. Reaction of a-haloketones with alkyllithium derivatives normally gives rise to halohydrins, which can be converted into epoxides by the action of bases (equation 221)477.

A very useful synthetic procedure for alkylation of a-chloroketones utilizes halohydrin formation by the action of alkyllithium compounds, followed by addition of Grignard reagents and thermal decomposition of the resulting magnesium salts into the a-alkylated ketones as illustrated below (equation 222)489.However, application of the same sequence to 2-chlorocyclohexanone gives rise to a mixture of 32% 2-methylcyclohexanone and 22% 2-acetylcy~lopentane~~~.

The reaction of a-chlorocycloalkanones with aryllithium reagents also proceeds to the formation of a-arylketones in high yields490.The alkylation of a-bromoketones with alkyllithium cuprates allows the regiospecific introduction of a primary, secondary or tertiary alkyl group on the ketone at the site initially brominated. Two concomitant mechanisms, halogen-metal exchange and nucleophilic substitution occur. While these two mechanisms co-exist in substitution by primary and secondary alkyl groups, only nucleophilic substitution seems possible in the case of tertiary alkyl groups (equation 223)491.492. R1\ C-C-R3 R2’l 11 & O

+

R;CuLi

-

\

R’\ C -.C R2’ -:I

/;;;;

R1\ R2-C - C -R3 R4’ 11

0

cut

-R3

0

91

1. Synthesis and reactivity of a-halogenated ketones

Complications arise during the action of di-r-butyllithium cuprate on a-bromoketones possessing hydrogen atoms at the j-position: products from the halogen-metal exchange are obtained together with alkylation not at the a-position but at the 8-position. The latter reaction is explained by a dehydrobromination yielding an a,j-unsaturated ketone, followed by a 1,4-addition (equation 224)493.494.

t-Bu*cuLI

I-”.,

R’COCHCHR3R4

I

R2

0R3

1

R’C-C-C,

I/0

I

H

cut

R2

R R’COC-

/ \

CHR3R4

R2 Rs

% R’COCHC,R y

R3

/..4

I

a2

&I-t

(224)

a,a’-Dibromoketones also react with dialkyllithium cuprates leading initially to enolates in which internal displacement of bromide produces cyclopropanones as in the Favorskii rearrangement. Further reaction with the organocoppex reagent affords a new enolate and exposure of the latter to various electrophiles yields a-substituted ketones (equation 225)495.

E = H, D, Me

Enolate formation is reported when a,a-dichloro- or a,a,a-trichloroketones are treated with isopropyllithium. These enolates are stable at - 75°C and are hydrolysed to a-chloroketones. Reaction with aldehydes provides C-alkylation, while en01 acetates are obtained with acetic anhydride (equation 226)496.

Norbert De Kimpe and Roland VerhC

92

R' = dkyl, phenyl R2 = alkyi, phenyl, CI (226) c. Reaction of a-hatoketones with organoboron compounds. a-Bromoketones are alkylated by 9-alkyl-9-borabicyclo[ 3.3.llnonanes via their enolates but this reaction is more sensitive to steric hindrance than the analogous reaction using cuprates (equation 22 7)497*498.

R'COCHR2

I

b

rduW

-[ RjB

R'C.-cR2

1:-

I

O b K+

R3,

R20c=CR1

I

OBRq

9' ] -

R3-BLC-CR'

K*

R3 Br 0

t-l*lon

II

R2

+ f-BuOBRq

(227)

Reaction of a-bromoketones with alkynyltrialkylborates (431) gives intermediate vinylboranes (432) which upon hydrolysis or oxidation afford olefins (433) and 1,Cdiketones (434), respectively (equation 228)499.

R' COCH2CHCOR2

I

R3

(494)

93

1. Synthesis and reactivity of a-halogenated ketones

d. Reaction of a-haloketones in the presence of metal complexes. Oxyallyl cations

(435) are generated when a,a’-dibromoketones are treated with sodium iodide in

acet~nitrile~ mercur&m, ~, zinc-copper c o ~ p l e ~iron ~ ~ carbonyl ~ ~ ~ ’ ,compounds502, zinc and triethylborate and copper powder with sodium iodide504.The formation of these cations, for example with diiron nonacarbonyl, can be envisioned by initial reduction of the dibromide producing an iron enolate (L = Br-, CO, solvent, etc), which eliminates a bromide ion to form the oxyallyl cations (equation 229)50s.

Fe(l I)L,

(229)

Oxyallyl species serve as highly versatile synthons for the construction of carbocyclic ~~~ frameworks by cycloaddition with alkenes50s, dienesso5, fur an^^^^^^^', p y r r o l ~and enaminesSo9(equation 230). Attempted formation of substituted cyclopentanones from oxyallyl species and 2n-systems failed; however, allenic compounds (443) and tetrahydrofurans (445) are isolated from the reactions of a,a’-dibromoketones with acetylenes (442) and respectively (equation 231)510. 1,l-dimethoxyethylene (a), 2-(N-Alkylimino)cyclobutanones (446) are produced on reaction of a,a’-dibromoketones with a copper/isonitrile complex (equation 232)511. One of the observed side reactions during the formation of oxyallyl cations is the formation of reduction products. Debromination of a,a’-dibromoketones with a zinc-copper couple in methanol yields the parent ketone and an a-methoxy ketone. The latter is suggested to arise from a selective 2-oxyallyl cation which is produced in an SN1 reactions1*. Debromination in DMF gives rise to 447 and reductive coupling products (448)(equation 233)513.Similar debromination and coupling reactions are obtained with dicobalt octacarbonyl under phase transfer conditions514. a-Monohaloketones also give a variety of reactions with various organometallic compounds. Iron pentacarbonyl reacts with a-haloketones in refluxing 1,2-dimethoxyethane, followed by treatment with water, to give 1,4-diketones (449), reduced monoketones (450) and P-epoxy ketones (451) (equation 234)515a-Bromoketones react with zinc in ether to provide organozinc compounds which on further reaction with alkyl chloroformates and aldehydes afford respectively /I-keto esters (452) and 8-hydroxy ketones (453) (equation 235)516,517. An efficient and regiospecific aldol condensation is reported which consists of a coupled attack on the a-haloketone by dialkylaluminium chloride and zinc generating an aluminium enolate regiospecifically. The enolate is sufficiently reactive to cause a facile addition to carbonyl compounds to give P-hydroxy ketones (453) (equation 236)518. During the debromination of a,a-dibromocamphor (454) with diethyl zinc in refluxing benzene, an a-elimination occurs to produce an a-keto carbene (455) which leads to the formation of (456) (equation 237)519.

Norbert De Kimpe and Roland Verhk

94

R’\ R2’

0

II

, R’ R2

c-c-c\

I

Br

Br

I

+

I

R2 = H

19. Synthesis and reactivity of a-halogenated ketones RCHCOCHR t HCECCH20H

I

&

I

R-CCOCH2R

I1

C

&

II

(442)

R’COC, I

/

-

R2

R

HCCH2OH

Emr

t Zn

R2

R’CO(!COOR4

I

R3

(152)

/R2 R’COC, I &

R 2 OH

I I

I

R’COC -CHR5 R3

(453)

95

Norbert De Kirnpe and Roland Verh6

96

$

‘II

&+o

I I R’-C-C-CH-R4 I 11

-

R3

R 2 OH

1 I

1

R1COC-CCHR4

(236)

R3

(453) V

V

V

8. Reaction of a-haloketones with complex metal hydfldes

Reaction of a-haloketones with sodium borohydride results in reduction of the carbonyl function with formation of halohydrins (equation 238)52”-5z2.Reduction with

lithium aluminium hydride provides the same h a l o h y d r i n ~ ~while ~ ~ -the ~ ~reduction ~, of phenacyl halides gives mixtures of l-aryl-l-ethanols and l-aryl-2-halo-l-ethan0ls~~~. However, if the aromatic ring is strongly electron-releasing, e.g. compound 4sI, the and not secondary alcohols aromatic ring migrates to give primary alcohols (458)526.527 (459) as proposed previously528(equation 239).

9. Reaction of a-haloketones with phosphorus compounds The reactions between a-haloketones and trivalent phosphorous compounds are of rather a complex naturesz9. Dialkyl phosphites normally react at the carbonyl group to give a-hydroxy and/or epoxy phosphonate esters (460,461) (equation 240)530. Trialkyl phosphites react with a-haloketones yielding enol phosphates (462) (Perkow reaction) and/or j-ketophosphonates (463)(Arbusov r e a c t i ~ n ) ~ In ~~-~~~. general the attack of phosphites can take place at four positions (equation 241): (1) attack on the carbon atom carrying the halogen, which gives rise either to an enol phosphate (462) or to a /3-ketophosphonate (463);(2) attack on the carbonyl oxygen; (3) attack on the carbonyl carbon, furnishing an epoxy phosphonate (461e) or a vinyl

1. Synthesis and reactivity of a-halogenated ketones

97

Bf

0

II

, R2

OH

I

(R40)2P-C-C,R3

I

I

phosphate (462); (4) attack on the halogen, leading to the enol phosphate (462) via an halophosphonium enolate. No general agreement has been reached concerning the mechanisms of the Perkow and the Arbusov reactions, and further work is still in progress to substantiate the nature of the i n t e n n e d i a t e ~ ~The ~ ~ratio . ~ ~ between ~. the Perkow and Arbusov reaction products is dependent upon the nature of the substrate and the phosphite and the reaction conditions employed. Substitution at the a-carbon atom e.g. by alkyl groups and by strongly electron-withdrawing groups, promotes the Perkow reaction, while a

98

R'COCHR~ X-

I

Pt(0R3)3

change in the halogen from chlorine to iodine decreases the yield of enol phosphates. An increase in the temperature favours the Arbusov reaction531~532~536. The reaction with phosphites in the presence of acids gives exclusively the Arbusov productss3'. In contrast to the results mentioned above, reaction of tris(trimethylsily1)phosphite with a-haloketones does not give the expected Perkow or Arbusov reaction but produces halogenated phosphonates (464)(equation 242)*38.

-0 O-SiMe3

0 R' \CR2' I X

II CR3

P(oSiM~sj3

e

R1

\

R2'1

C-CX

I

I

R3

I

Pt(OSiMe3)2

-

99

1. Synthesis and reactivity of a-halogenated ketones

Treatment of chlorinated acetophenones with monoalkyl phosphinites under the standard Perkow reaction conditions gives enol phosphonates (465) (equation

ArCOCC12

I

x

+

-

,

y P-OR2 R’ /

0

R’

,p-o-c=c,

OR^,

I

CI

(243)

AI

(465)

X = H, CI Y

/x

Y\II

NR:,

S R ~

243)53y*540. On the other hand, reaction of dialkyl phosphinites produces the Perkow (466)and/or the Arbusov (467) reaction product. With alkyl di-r-butylphosphinites only the Arbusov reaction takes place (equation 244)541*542.

0

XCH2COR’

+ R:POR3

i

I + X = Br

0

466

I1

R$PCH2COR’ (461)

a-Chloroketones react with tertiary phosphines to give phosphonium salts (a), while enol phosphonium salts (469) are generated in the case of a-bromoketones (equation 245)543. x r

= CI -

c

R$-CH2COR’

Br-

Phosphorous acid vinyl esters (470, 471) are produced on treatment of a-chloroketones with phosphorous o ~ y t r i c h l o r i d eand ~ ~alkyl ~ dichloroph~sphinites~~’, respectively, in the presence of triethylamine (equation 246). Epoxy phosphonates (473) have been prepared by the action of sodium alkoxide on a dialkyl phosphonate and an a-haloketone. When the reaction is performed in the

100

-r

Norbert De Kimpe and Roland VerhC POClJ

R~COCHCI

I

R2

0

I1

Ci2P- 0 -C=CR2

I

R’

(470)

R~O,

CI’II

(RJO)PC12

P -0

0

-C= I

C R 2CI

R’ (47l)

presence of triethylamine, the intermediate halohydrins (472) could be isolated (equation 247)546.547.

0

+

R‘COCHR~

I

II

( ~ 1 3 0 ) ~ ~ ~

X

OH X

I

I

R’ -C- C H R ~

I

o=P(oR~)~ (472)

0’ (473)

Monofluorophosphoranes (474), especially methyltri(n-butyl)fluorophosphorane, are used in exchange reactions to prepare a-fluoroketones. In addition, cyclopropanes (475) are produced, due to the high basicity of the reagent which causes the formation of an a-keto carbene by dehydrohalogenation (equation 248)54u. COR

B. Miscellaneous Reactions of a-Haloketones 1. Nectrophilic reactions of a-haloketones and their derivatives

Friedel-Crafts reactions of certain aryl activated a-chloroketones with aromatics in the presence of aluminium chloride gives rise to a-aryl k e t o n e ~Another ~ ~ ~ ~method ~ ~ ~ . for the synthesis of a-aryl ketones consists of an insertion reaction of an a-ketocarbenoid generated from up-dibromoketones in the presence of zincss’ (equation 249).

1. Synthesis and reactivity of a-halogenated ketones

Ar

X

ArCOCR

/\

101

(249)

Zn 7 ArCOCX-Ar

I

Br Br

R

Brominated phenylhydrazones (476) are obtained by treatment of a-bromoketones with diazonium salts (equation 250)s52. (BrCH2),C0

+ Ar-N;

-

ArNHN=CCOCH,Br

I

(250)

Br (476)

Finally, a-chloroketones have been converted to the corresponding enol acetates

(477) by acylation of the intermediate chbroenolates, generated by reaction with a suspension of sodium methoxide in ether at - 50°C. This procedure takes advantage of

the fact that in unsymmetrical ketones the C-H bond adjacent to both the carbonyl group and the chlorine atom is significantly more acidic (by 2 pK, units) than the C-H bond adjacent only to a carbonyl groups53.Certain a-haloketones also undergo rapid reaction with lithium diisopropyl amide (LDA) to produce enol acetates (478) in the presence of acetic anhydride in competition with reduction products (479) via hydride transfer554. Enolate formation also takes place when a-chloroketones are treated with trimethylchlorosilane in the presence of tertiary amines to yield trimethylsilyl enol ethers (480)55s(equation 250a).

Norbert De Kimpe and Roland VerhC

102

2. Reaction of a-haloketones with alkali fluorides The halogen-fluorine exchange on treatment of a-haloketones with fluoride anion to give a-fluoroketones has already been mentioned (vide supra). Another synthetic application involves a desilylbromination and specifically places a double bond between the carbon attached to the carbonyl group and the /?-atom to which the silicon atom has originally been bound. Synthetically important a-methylene ketones and lactones have been prepared by using this procedure in which the base- and acid-stable silyl function masks the a,/?-unsaturation of enones (equation 25 1 p 6 . Br

I

R'COC-

I

R2

F-

R'COCR~

II

CH2- SiMe3

CH2

3. Acid-catalysed rearrangement of a-haloketones

Numerous examples of a-haloketone rearrangements into the a'-isomers in the presence of acids are known. They occur via two mechanisms: (a) a cationic halogen path and (b) an anionic halogen path (equation 252)557. OH

I

0

X2

I1

OH

X2

X2

I

0

0

II

It

C

-C OH

I / \c/ I I\

OH

Equilibration of trans-carvone tribromide (171) with hydrogen bromide in acetic acid at 0°C gives a mixture of 45% rruns- and 55% cis-carvone tribromide; this isomerization involves the exclusive exchange of a halo substituent /? to the carbonyl The reaction of 2-bromocyclohexanone in concentrated sulphuric acid also provides rearranged enols of bromo-1 ,Zcyclohexanediones (481, 482) (equation 253)559.

pr.-&; WF

(4811

Br

+

(482)

(253)

1. Synthesis and reactivity of a-halogenated ketones

103

4. formation of a-acylcarbenium ions from a-haloketones

Silver salts of superacids are able to ionize a-halocarbonyl compounds to a-acylcarbenium ions, and silver hexafluoroantimonate in dichloromethane strikingly promotes this i o n i z a t i ~ n ~(for ~ *a~recent ~' review dealing with a-acylcarbenium ions, see Ref. 562). In a few cases the reaction leads to the formation of oxonium salts (equation 254).

Products Acylcarbenium ions are very reactive species which are able to undergo the following reactions: (a) nucleophilic substitution (equation 255)335,563 ( 1 ) AgSbF6

PhCHCoPh I

12) MoOH

Eir

(260) R = H

Br

(b) hydride shift (equation 256)561

Br

(260) R = H

* PhCHCOPh I OMe (262)R=H

(255)

Norbert De Kimpe and Roland Verht5

104

(c) Wagner-Meenvein-type rearrangement (equation 257)s61. H

H x C o c & H

AOSbFa

-

HIIIIIII

CaDa

CH3

:0

(486)

(257)

(d) El-type elimination (equation 258)561 Ph

I CH CH C-COPh *I

AOSbFO

7

CH3, H

,c=c\

/ COPh

Ph

+

CH3,

P ,h

H’ ‘=‘\COPh

When the structure of the precursor permits, a-acylcarbenium ions are transformed into oxonium salts via hydride shifts. These ambident salts enable further functionalization as illustrated for a-bromocyclohexyl ketones (equation 259)562.

1. Synthesis and reactivity of a-halogenated ketones

105

5. Photochemistry of a-haloketones

There are a few reports on the study of the photochemistry of a-haloketones involving different types of photoprocesses. a-Halocyclohexanones on irradiation in cyclohexane have been found to give competing radical and ionic photo-behaviour. The principal photoprocess is homolytic /?-cleavage of the carbon-halogen bond to afford radical products (496, 497), accompanied by ionic products such as cyclohexenones (49%) but in much lower proportions (equation 260)564.

R = H, Me

(497)

(4%)

(-1

Favorskii-type ring contraction takes place on irradiation of bicyclic a-chloroketones in methanol. A mechanism involving photoionization of chloride, followed by ring contraction to acylium ions which are trapped by solvent, is suggested (equation 26 1)5659566.

?+W

MeOOC CH3

@cot"'" CH3

H3C COOMe

106

Norbert De Kimpe and Roland Verh6

Irradiation of 2,5-dimethyl-a-chloroacetophenone (502) in benzene yields 6-methylindan-1-one (503) while in methanol the photosolvolysis product (504) is obtained. These transformations arise from photoenol intermediates (505, 506) (equation 262)567. The behaviour of a-chloro aryl ketones without ortho methyl groups is quite different, involving reduction and rearrangement568. Irradiation of a,a,cr-trichloroacetophenone in methanol affords the alcoholysis products methyl benzoate and methyl benzoylformate along with a,a-dichloroacetophenone. Formation of the benzoate is greatly favoured in the presence of oxygen whereas that of the benzoyl formate is favoured by sensitization (equation 263)569. ArCOCCI3

ArCOOCH3

+

+ ArCOCHCI2

ArCOCOOCH3

(263)

6. Electrochemistry of a-haloketones Electrochemical reduction of &,a’-dibromoketonesin acetic acid affords a mixture of the parent ketones and a-acetoxy ketones via an enol allylic bromide intermediate. The same results are obtained when the reduction is carried out by ultrasonically dispersed mercury (equation 264)s70*571. R’, R2’

0

J I c-c-c,

1

Br

, R3 I

R

Br

- *’, zs-

R2’

0-

I c=c-c,

/ R3

I

Br

R

M’

OM

R’,

R2,c=c

I

-c’

R3

1 \R4

A Br

OH I

R’,

R2’

R3

c .$.> + c’ Br-

\R4

R’\ R2’

M

= H, Hg, Br

II

c-c-c, 1

H

’R3 I R Br

Electroreduction of a,a‘-dihaloketones to cyclopropanones (507) (isolated as the hemiacetals or hemiacylals (508)) is accomplished with highly alkylated ketones (equation 265)572.

1. Synthesis and reactivity of a-halogenated ketones

107

7. Dehalogenation of a-hatoketones

Various reagents are able to effect dehalogenation of a-haloketones such as zinc in acetic acid573, metal carbonyls M o ( C O ) ~ ~Fe(CO)5575 ~~, and HFe(C0)j 576, transition metals in low valency states77,triphenylpho~phine~~~, pyridine followed by sodium d i t h i ~ n i t e tri-n-butyltin ~~~, h ~ d r i d e ~lithium ~, iodide-boron t r i f l u ~ r i d e ~ ~ l , sodium iodide-amine-sulphur dioxides8*, cerium t r i ~ d i d e ~sodium ~~, iodide~hlorotrimethylsilane~~~ and sodium iodide in aqueous acid-THF5@ (equation 266).

IV. REFERENCES 1. W. Hahn, in Merhoden der Organischen Chemie, Vol. 5/3 (Ed. Houben-Weyl), Georg Thieme Verlag, Stuttgart (1962), p. 1018. 2. 0. Bayer, in Merhoden der Organischen Chemie, Vol. 7/2c (Ed. Houben-Weyl), Georg Thieme Verlag, Stuttgart (1977), p. 2147. 3. R. Jacquier, Bull. Soc. Chim. France, 17, D35 (1950). 4. A. S. Kende, Org. Reactions, 11, 261 (1960). 5. A. A. Akhrem, T. K. Ustynyuk and Y. A. Titov, Russ. Chem. Rev., 39,732 (1970). 6. C. Rappe, in The Chemistry ofrhe Carbon-Halogen Bond (Ed. S . Patai), Wiley, Chichester (1973), p. 1071. 7. K. Sato and M. Oohashi, Yuki Gosei Kagaku Kyokai Shi, 32, 435 (1974). 8. P.J. Chenier, J . Chem. Educ., 55, 286 (1978). 9. B. Tchoubar, Bull. Soc. Chim. France, 1363 (1955). 10. N. P. Gambaryan, E. M. Rokhlin, Y. V. Zeifman, C. Ching-Yun and I. L. Knunyants, Angew. Chem., 78, 1008 (1966). 11. Y. A. Cheburkov and I. L. Knunyants, in Fluorine Chemistry Reviews, Vol. 1 (Ed P. Tarrant), Edward Arnold, London and Marcel Dekker, New York (1961), p. 107. 12. R. D. Chambers, Ruorine in Organic Chemistry, Wiley, New York (1973). 13. M. Hudlicky, Chemistry oforganic Fluorine Compounds,Ellis Horwood, Chichester (1 976). 14. RO&S Chemkrry ofCar6on Compounds, 1 C/D Suppl., Elsevier, Amsterdam (1973). 15. N. Fukuhara and L. A. Bigelow, J . Amer. Chem. Soc., 63, 788 (1941). 16. S. Nakanishi, K. Morita and E. V. Jensen, J. Amer. Chem. Soc., 81, 5259 (1959). 17. B. M. Bloom, V. V. Bogert and R. Pinson, Chem. Ind., 1317 (1959). 18. R. Joly and J. Warnant, Bull. Soc. Chim. France, 569 (1961). 19. R. B. Gabbard and E. V. Jensen,J. Org. Chem., 23, 1406 (1958). 20. S . Nakanishi,J. Med. Chem., 7, 108 (1964). 21. S. Nakanishi and E. V. Jensen, Chem. Pharm. Bull. (Tokyo), 25, 3395 (1977).

Norbert De Kimpe and Roland VerhC

108

M. Schlosser and G. Heinz, Chem. Ber., 102, 1944 (1969). H. M. Kissman, A. M. Small and M. J. Weis, J. Amer. Chem. Soc., 81, 1262 (1959). J. Edwards and H. J. Ringold, J. Amer. Chem. Soc., El, 5262 (1959). W. J. Middleton and E. M. Bingham, J . Amer. Chem. Soc., 102,4846 (1980). S. Rozen and Y. Menahem, Tetruhedron Lett., 725 (1979). P. Crabbk, A. Cervantes, A. CNZ, E. Galazzi, J. Iriarte and E. Velarde, J. Amer. Chem. Soc., 95, 6655 (1973). 28. P. Crabbk, J.-L. Luche, J. C. Damiano, M.-J. Luche and A. CN Z,J. Org. Chem., 44,2929

22. 23. 24. 25. 26. 27.

(1979).

29. 30. 31. 32. 33. 34. 35. 36. 37. 38.

C. Wakselman and M. Tordeux, JCS Chem. Commun., 956 (1975). E. D. Bergman, J. Chem. Soc., 3457 (1961). E. Cherbuliez, A. de Picciotto and J. Rabinowitz, Helv. Chim. Acta, 43, 1144 (1960). B. Modarai and E. Khoshde1,J. Org. Chem., 42,3527 (1977). N. De Kimpe, R. Verht, L. De Buyck and N. Schamp, J . Org. Chem., 45, 2803 (1980). A. J. Fry and Y. Migron, Tetrahedron Letr., 3357 (1979). T. E. Gough, W. S. Lin and R. E. Woolford, Canad. 1. Chem., 45, 2529 (1967). R. A. Shepard and A. A. Loiselle, J . Org. Chem., 23, 2012 (1958). P. C. Ray, A. C. Goswami and A. C. Ray, J . Indian Chem. Soc., 12, 93 (1935). G. A. Olah, J. T. Welch, Y. D. Vankar, M. Nojima, I. Kerekes and J. A. Olah, J. Org.

39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64.

R. R. Fraser, J. E. Millington and F. L. M. Pattison,J. Amer. Chem. Soc., 79,1959 (1957). E. D. Bergman and R. Ikan, Chem. Znd., 394 (1957). J. Leroy and C. Wakselman, JCS Perkin I , 1224 (1978). T. F. McGrath and R. Levine,J. Amer. Chem. Soc., 77, 3656 (1955). A. F. Blum, H. V. Donnand and H. D. Zook, 1. Amer. Chem. Soc., 77,4406 (1955). E. Elkik and H. Assadi-Far, Bull. Soc. Chim. France, 991 (1970). E. Elkik, R. Dahan and A. Parlier, Compr. Rend. Acad. Sci. Paris C , 286, 353 (1978). E. T. McBee, 0. R. Pierce and D. D. Meyer,J. Amer. Chem. Soc., 77, 917 (1955). E. D. Bergmann, S. Cohen, E. H o h a n n and J. Randmeier,J. Chem. Soc., 3452 (1961). F. Bergmann and A. Kalmus, J . Amer. Chem. Soc., 76,4137 (1954). H.Machleidt, Liebigs Ann. Chem., 667, 24 (1963). J. Cantacudne and D. Ricard, Bull. Soc. Cliim. France, 1587 (1967). E. Elkik and M. Le Blanc, Bull. Soc. Chim. France, 870 (1971). R. Justoni, Chimica e Znd., 24, 93 (1942). Z. Bankowska, Rocz. Chem., 32, 739 (1958). Fr. Pat., 837,741 (1938); Chem. Abstr. 33, 58655 (1939). E. G. Edwards, D. P. Evans and H. B. Watson, 1. Chem. Soc., 1944 (1937). M. Geiger, E. Usteri and C. Granacher, Helv. Chim. Acta, 34, 1340 (1951). A. Bruylants and J. Houssiau, Bull. Soc. Chim. Belg., 61, 492 (1952). P. D. Bartlett and R. H. Rosenwald,J. Amer. Chem. Soc., 56, 1992 (1934). H. W. Wanzlick, G. Gollmer and H. Milz, Chem. Ber., 88, 72 (1955). M. S. Newman, M. D. Farbman and H. Hipsher, Org. Synrh., Coll. Vol. 111, 188 (1955). G. Hesse and F. Urbanek, Liebigs Ann. Chem., 604, 54 (1957). C. L. Stevens, J. J. Beereboom and K. G. Rutherford,]. Amer. Chem. Soc., 77,4590 (1955). H. Brintzinger and H. Orth, Monarsh. Chem., 85, 1015 (1954). L. De Buyck, R. Verh6, N. De Kimpe and N. Schamp, Bull. Soc. Chim. Belg., 89, 307

Chem., 44, 3872 (1979).

(1980). 65. L. De Buyck, R. VerhC, N. De Kimpe, D. Courtheyn and N. Schamp, Bull. Soc. Chim. Belg., 89, 441 (1980). 66. L. De Buyck, R. Verhe, N. De Kmpe, D. Courtheyn and N. Schamp, Bull. Soc. Chim. Belg., 90, 837 (1981). 67. L. De Buyck, N. De Kimpe, R. Verhb, D. Courtheyn and N. Schamp, Bull. Soc. Chim. Belg., 89, 1043 (1980). 68. M. F. Guimon, G. Pfister-Guillouro, F. Metras and J. Petrissans, J . Mol. Struct., 53, 239 (1976). 69. P. A. Peters, R. Ottinger, J. Reisse and G . Chiurdoglu, Bull. Soc. Chim. Belg., 77,407 (1968). 70. H. Korten and R. Scholl, Chem. Ber., 34, 1902 (1901).

1. Synthesis and reactivity of a-halogenated ketones

109

71. J. G. Aston, J. D. Newkirk, D. M. Jenkins and J. Dorsky, Org. Synrh., Coll. Vol. 111, 538 (1955). 72. J. G. Aston, J. D. Newkirk, J. Dorsky and D. M. Jenkins, J . Amer. Chem. Soc., 64, 1415 (1942). 73. N. De Kimpe, L. De Buyck, R. Verhk, F. Wychuyse and N. Scharnp, Synthetic Comm.. 9, 575 (1979). 74. M. Ballester and J. Riera, Andes Real Soc. Espun. Fis. Quim. (Madrid), 56, 897 (1960). 75. R. Carlson. Acru Chem. Scund., 832, 646 (1978). 76. W. Seufert and F. Effenberger, Chem. Ber., 112, 1670 (1979). 77. D. P. Wyman and P. R. Kaufman,J. Org. Chem., 29, 1956 (1964). 78. E. R. Buchrnan and H. Sargent, J . Amer. Chem. Soc., 67,401 (1945). 79. P. Delbaere, Bull. Soc. Chim. Befg., 51, 1 (1942). 80. E. W. Warnhoff, D. G. Martin and W. S. Johnson, Org. Synrh., 37, 8 (1957). 81. C. L. Stevens and E. Farkas,J. Amer. Chem. Soc., 74, 619 (1952). 82. Dang Quoc Quan, Compt. Rend. Acud. Sci. Puris C, 264, 320 (1967). 83. F. Caujolle and Dang Quoc Quan, Compr. Rend. Acad. Sci. Park C, 265,269 (1967). 84. M. F. Grenier-Loustalot, P. Iratcabal and F. Mttras, Synthesis, 33 (1976). 85. J. R. Merchant and D. V. Rege, Terruhedron, 27, 4837 (1971). 86. J. P. Schaefer and F. Sonnenberg. 1. Org. Chem., 28, 1128 (1963). 87. G. C. Finger, F. H. Reed, E. W. Maynert and A. M. Weiner,J. Amer. Chem. Soc., 73,151 (1951). 88. S. Goldsmidt, R. Enders and R. Dirsch, Chem. Ber., 58, 572 (1925). 89. J. J. Beereboom, C. D. Djerassi, D. Ginsburg and L. F. Fieser, J. Amer. Chem. Sor., 75, 3503 (1953). 90. U.S. Pat. 2,714,601 (1952); Chem. Absrr. 50, 8753 (1956). 91. N. P.Buu-Hoi and P.Demerseman, J. Org. Chem., 18,649 (1953). 92. N. De Kirnpe and N. Schamp, Org. Prep. Proced. lnr., 11, 115 (1979). 93. W. Coppens and N. Schamp, Bull. SOC. Chim. Befg., 81,643 (1972). 94. N. De Kirnpe, N. Schamp and W. Coppens, Bull. Soc. Chim. Befg., 84,227 (1975). 95. N. Schamp, N. De Kimpe and W. Coppens, Terruhedron,31, 2081 (1975). 96. N. De Kimpe, R. Verht, L. De Buyck and N. Schamp, Synthelic Commun., 8,75 (1978). 97. J. F. W. Keana and R. R. Schumaker, Tetrahedron, 26, 5191 (1970). 98. I. J. Borowitz, E. W. Casper, R.K. Crouch and K. Y. Yee,J. Org. Chem., 37,3873 (1972). 99. J. K. Kochi, J . Amer. Chem. Soc., 77, 5274 (1955). 100. E. M. Kosower, W. J. Cole, G. S. Wu, D. E. Cardy and E. Meisten,/. Org. Chern., 28,630 (1963). 101. J. T. Satoh and K. Nishizawa, JCS Chem. Commun., 83 (1973). 102. Y. Ito, M. Nakatsuka and T. Saegusa, J . Org. Chem., 45, 2022 (1980). 103. A. S. Dneprovskii, I. V. Krainyuchenko and T. I. Temnikova, Zh. Org. Khim.,14, 1514 (1978); Chem. Absrr. 88, 146557 (1978). 104. A. Favorskii, Russ. Phys-Chem. Ges., 44, 1339 (1912). 105. C. Y. Meyers, A. M. Make and W. S. Matthews,J. Amer. Chem. Soc., 91, 7512 (1969). 106. C. Y.Meyers and V. M. Kolb, J . Org. Chem., 43, 1985 (1978). 107. F. M. Laskovics and E. M. Schulman, J . Amer. Chem. Soc., 99, 6672 (1977). 108. E. Vilsmaier, W. Troger, W. Spfigel and K. Gagel, Chem. Ber., 112, 2997 (1979). 109. S. Torrii, T. Inokuchi, S. Misima and T. Kobayashi, 1. Org. Chem., 45, 2731 (1980). 110. K. Steinbeck, Tetrahedron Lea., 1103 (1978). 111. E. Zbiral and M. Rasberger, Terruhedron, 25, 1871 (1969). 112. A. Brochet,Ann. Chim., 10, 135 (1897). 113. R. E. Meyer, Hefv. Chim. Acra, 16, 1291 (1933). 114. R. Riemschneider, Z.Nuturf., 8b, 161 (1953). 115. R. H. Levin, 1. Amer. Chem. Soc., 75, 502 (1953). 116. W. E. Doering and L. H. Knose, J . Amer. Chem. Soc., 74,5683 (1952). 117. S. Vickers and E. E. Srnissrnan, 1. Org. Chem., 40, 749 (1975). 118. US. Pat. 2,684,968 (1953); Chem. Absrr. 49, 11031k (1955). 119. C. H. R. Elston, J . Chem. Soc.. 367 (1948). 120. L. Denivelle and R. Fort, Bull. Soc. Chim. Frunce, 1837 (1956). 121. K. Fries and K. Schirnrnelschrnidt, Liebigs Ann. Chem., 484,297 (1930).

110

Norbert De Kimpe and Roland Verhe

122. L. E. Forman and W. C. Sears, J. Amer. Chem. Soc., 76, 4977 (1954). 123. P. Svec, A. M. Sorensen and M. Zbirovsky, Org. Prep. Proced. Int., 5, 209 (1973). 124. B. L. Jensen, S. E. Burke, S. E. Thomas and W. H. Klausmeier, Tetrahedron Lett., 2639 (1977). 125. B. L. Jensen and P. E. Peterson, J. Org. Chem., 42, 4052 (1977). 126. B. L. Jensen, S. E. Burke and S. E. Thomas, Tetrahedron, 34, 1627 (1978). 127. J. Villieras, C. Bacquet and J. F. Normant, J. Organometal. Chem., 97, 355 (1975). 128. R. M. McDonald and R. N. Steppel. J. Org. Chem., 35, 1250 (1970). 129. W. E. Bachman and W. S. Struve, Org. Reactions, 11, 48 (1948). 130. A. Roedig and R. Maier, Chem. Ber., 86, 1467 (1953). 131. C. Rappe and B. Albrecht,Acra Chem. Scand., 20, 253 (1966). 132. R. E. van Atta, H. D. Look and P. J. Elving, J. Amer. Chem. Soc., 76, 1185 (1954). 133. C. Granarher, E. Usteri and M. Geiger, Helv. Chem. A m , 32, 713 (1949). 134. W. D. McPhee and E. Klingsberg, Org. Synth., Coll. Vol. 111, 119 (1955). 135. B. W. Ponder and D. R. Walker, J. Org. Chem., 32,4136 (1967). 136. K. B. Sharpless and A. Y.Teranishi, J. Org. Chem., 38, 185 (1973). 137. W. T. Brady and R. Roe, J. Amer. Chem. Soc., 92,4618 (1970). 138. P. Martin, H. Greuter and D. Bellus, J. Amer. Chem. Soc., 101, 5853 (1979). 139. D. A. Bak and W. T. Brady, J. Org. Chem., 44,107 (1979). 140. L. R. Krepski and A. Hassner, J. Org. Chem., 43, 2879 (1978). 141. L. R. Krepski and A. Hassner,J. Org. Chem., 43, 3173 (1978). 142. B. M. Trost, Acc. Chem. Res., 7, 85 (1974). 143. A. E. Greene and J.-P. DeprCs, J. Amer. Chem. Soc., 101,4003 (1979). 144. N. Wittorf, J. Rms. Phys.-Chem. Ges., 32, 88 (1900). 145. A. Favorskii, J. Prakt. Chem., 51, 533 (1895). 146. F. Strauss, Chem. Ber., 63, 1868 (1930). 147. E. L. Jackson, J. Amer. Chem. Soc., 56, 977 (1934). 148. S. F. Reed, J. Org. Chem., 30,2195 (1965). 149. A. Kirrmann and R. Nouri-Bimorghi, Bull. Soc. Chim. France, 3213 (1968). 150. A. Kirrmann, P. Duhamel and R. Nouri-Bimorghi, Liebigs Ann. Chem., 691, 33 (1966). 151. J. J. Riehl, P. Casara and A. Fougerousse, Compt. Rend. Acad. Sci. Paris C , 279, 113 (1974). 152. R. N. McDonald and T. E. Tabor, J. Amer. Chem. Soc., 89, 6573 (1967). 153. R. N. McDonald and T. E. Tabor, J. Org. Chem., 33, 2934 (1968). 154. R. N. McDonald and R. N. Steppel, J. Org. Chem., 35, 1250 (1970). 155. R. N. McDonald and R. C. Cousins, J. Org. Chem., 45, 2976 (1980). 156. K. Griesbaum, R. Kibar and P. Pfeffer,Ann. Chem., 214 (1975). 157. G. Stork, W. S. Worrall and J. J. Pappas, J. Amer. Chem. Soc., 82, 4315 (1960). 158. G. A. Olah, Y.D. Vankar and M. Arvanaghi, Tefrahedron Lett., 3653 (1979). 159. A. B. Boese, Ind. Eng. Chem., 32, 20 (1940). 160. E. E. Blake, Bull. Soc. Chim. France, 728 (1915). 161. J. Leroy, J. Org. Chem., 46, 206 (1981). 162. C. Bacquet, J. Villieras and J. F. Normant, Compt. Rend. Acad. Sci. Paris C , 278, 929 (1974). 163. C. Rabiller and G. J. Martin, Tetrahedron, 34, 3281 (1978). 164. T. Zincke, W. Schneider and W. Emmerich, Liebigs Ann. Chem., 328, 286 (1903). 165. T. Zincke and 0. Preiss, Liebigs Ann. Chem., 417, 203 (1918). 166. F. Krohnke and F. Timmler, Chem. Ber., 69, 615 (1936). 167. F. Krohnke, Chem. Ber., 69, 921 (1936). 168. C. L. Stevens and C. T. Lenk, J . Org. Chem., 19, 538 (1954). 169. M. S. Newman,J. Amer. Chem. Soc., 73,4993 (1951). 170. F. Krohnke and 0. Luderitz, Chem. Ber., 83, 60 (1950). 171. M. Gaudry and A. Marquet, Bull. Soc. Chim. France, 4173 (1969). 172. P. A. Levene, Org. Synth., Coll. Vol. 11, 88 (1943). 173. J. F. Norris, lnd. Eng. Chem., 11, 828 (1919). 174. F. Weygand and U. Schmied-Kowarzik, Chem. Ber., 82, 335 (1949). 272 (1948). 175. J. R. Catch, D. F. Elliott, D. H. Hey and E. R. H. Jones, J. Chem. SOC., 176. H. M. E. Cardwell and A. E. H. Kilner, J. Chem. Soc., 2430 (1951).

1. Synthesis and reactivity of a-halogenated ketones

111

A. A. Sacks and J. G. Aston, J. Amer. Chem. SOC.,73, 3902 (1951). J. H. Boyer and D. Straw, J . Amer. Chem. SOC.,74, 4506 (1952). G. H. Hill and E. L. Kropa, J. Amer. Chem. SOC., 55, 251 1 (1933). Y. Yasor, M. Gaudry and A. Marquet, Bull. SOC. Chim.France, 2735 (1973). M. Gaudry and A. Marquet, Tetrahedron, 26, 5611 and 5617 (1970). V. Calo, L. Lopez and G. Ptsce,JCS Perkin I, 501 (1977). H. M. R. Hoffman and J. G. Vinter, J. Org. Chem., 39, 3921 (1974). B. Fohlisch and W. Gottstein Liebigs Ann Chem., 1768 (1979). R. M. Acheson, J. Chem. SOC., 4236 (1956). R. Belcher, W. Hoyle and T. S. West, J. Chem. Soc., 2744 (1958). D. Ricard and J. Cantacuztne, Bull. SOC.Chim.France, 628 (1969). E. J. Corey, J . Amer. Chem. SOC.,75, 3297 (1953). F. G. Bordwell and K. M. Wellman, J. Urg. Chem., 28, 2544 (1963). 0. Wallach, Liebigs Ann. Chem., 343,41 (1905). T. Kato, H. Kondo and H. Miyake, Bull. Chem. SOC.Japan, 53, 823 (1980). R.M. Cowper and L. H. Davidson, Org. Synrh., Coll. Vol. 11, 480 (1943). F. Krohnke, Chem. Ber., 83, 56 (1950). S. Winstein, T. L. Jacobs, G. B. Linden, D. Seymour, E. F. Levy, B. F. Day, J. H. Robson, R. B. Henderson and W. H.Florsheim, J . Amer. Chem. SOC., 68, 1831 (1946). 195. S. Wolfe, W. R. Pilgrim, T. F. Garrard and P. Chamberlain, Canud. J. Chem., 49. 1099 (1971). 196. H. 0. House and W. C. McDanie1.J. Org. Chem., 42, 2155 (1977). 197. K. S. Warren, 0. K. Neville and E. C. Hendley,J. Org. Chem., 28, 2152 (1963). 198. A. Iovchev and S. Spasov, Monatsh. Chem., 98, 2326 (1967). 199. R. B. Wagner,/. Amer. Chem. Soc., 71, 3216 (1949). 200. N. H. Cromwell and R. Benson, Org. Synth., Coll. Vol. 111, 105 (1955). 201. R. E. Buckles, R. Filler and L. Hiltinan, J . Org. Chem., 17, 233 (1952). 202. R. VerhC, N. Schamp, L. De Buyck and R. Van Loocke, Bull. SOC. Chim. Belg., 84, 371 (1975). 203. L. Blanco, P. Arnice and J. M. Conia, Synthesis, 194 (1976). 204. P. Z . Bedoukian, J. Amer. Chem. SOC.,67, 1430 (1945). 205. H. Schmid and P. Karrer, Helv. Chim. Acra, 29, 573 (1946). 206. J. D. Billimoria and N. F. Maclagan, J. Chem. SOC., 3067 (1951). 207. E. J. Corey, J. Amer. Chem. SOC.,75, 2303 (1953). 208. L. A. Paquette and R. F. Doehner Jr, J . Org. Chem., 45, 5105 (1980). 209. N. De Kimpe, R. Verhk, L. De Buyck and N. Schamp, Tetrahedron Lett., 2257 (1980). 210. C. Djerassi, Chem. Rev., 43,271 (1948). 211. 0. 0. Orazi and J. Meseri, Ann. SOC.Quim. Arg., 37, 192 (1949). 212. C. Djerassi and C. T. Lenk,J. Amer. Chem. SOC.,75, 3494 (1953). 213. N. De Kimpe, unpublished results. 214. L. C. King and G. K. Ostrum, J . Org. Chem., 29, 3459 (1964). 215. D. P. Bauer and R. S . Macomber,J. Org. Chem., 40, 1990 (1975). 216. C. Djerassi and C. R. Scholz, 1. Amer. Chem. Soc., 70,417 (1948). 217. D. Jerchel and H. Fischer, Liebigs Ann. Chem., 590, 224 (1954). 218. W. S. Johnson, J. D. Bass and K. L. Williamson, Tetrahedron, 19,861 (1963). 219. L. Forlani, Synthesis, 487 (1980). 220. V. W. Armstrong, N. H. Chishti and R. Ramage, Tetrahedron Lerr., 373 (1975). 221. S. Cacchi and L. Caglioti, Synthesis, 64 (1979). 222. A. Bongini, G. Cainelli, M. Contento and F. Manescalchi, Synthesis, 143 (1980). 223. T. Hata, Bull. Chem. SOC.Japan, 37, 547 (1964). 224. M. Sekiya, K. Ito and K. Suzuki, Tetrahedron, 31, 231 (1975). 225. R. Bloch, Synthesis, 140 (1978). 226. V. Calo, L. Lopez, G. Ptsce and P. E. Todesco, Tetruhedron, 29, 1625 (1973). 227. S. J. Pasaribu and L. R. Williams, A m . J . Chem., 26, 1327 (1973). 228. R. Levine and J. R. Stephens, J. Amer. Chem. Soc., 72, 1642 (1950). 229. R. B. Loftfield and L. Schaad, 1.Amer. Chem. SOC.,76, 36 (1954). 230. M. Schlosser and G. Heinz, Chem. Ber., 102, 1944 (1969). 231. J. R. Catch, D. H. Hey, E. R. H. Jones and W. Wilson, J. Chem. SOC., 278 (1948) 177. 178. 179. 180. 181. 182. 183. 184. 185. 186. 187. 188. 189. 190. 191. 192. 193. 194.

112

Norbert De Kimpe and Roland Verhe

232. V. Calo, L. Lopez and D. S . Valentino, Synthesis, 139 (1978). 233. F. de Reinach-Hirtzbach and T. Durst, Tetrahedron Lett., 3677 (1976). 234. N. A. Sokolov, I. G. Tishchenko and N. V. Kovganko, Zh. Org. Khim., 16, 281 (1980); Chem. Abstr. 93, 25853 (1980). 235. J. Wolinsky, J. Thorstenson and T. A. Killinger, J. Org. Chem., 43,875 (1978). 236. S. J. Slanina, G. F. Hennion and I. A. Nieuwland, J . Amer. Chem. Soc., 58, 891 (1936). 237. V. Reutrakul, A. Tiensripojamarn, K. Kusamran and S . Nimgirawath, Chem. Lett., 209 (1979). 238. H. J. Ringold and G. Stork, J . Amer. Chem. SOC.,80, 250 (1958). 239. P. L. Julian and W. J. Karpel, J. Amer. Chem. Soc., 72, 362 (1950). 240. P. D. Gardner and W. J. Horton, J. Org. Chem., 19, 213 (1954). 241. C. Djerassi, J. Grossman and G. H. Thomas, 1.Amer. Chem. Soc., 77, 3826 (1955). 242. L. Wolff, Liebigs Ann. Chem., 394,40 (1912). 243. R. C. Cambie, R. C. Hayward, J. L. Jurlina, P. S. Rutledge and P. D. Woodgate,J. Chem. Soc., 126 (1978). 244. G. Cardillo and M. Shimizu, J. Org. Chem., 42, 4268 (1977). 245. R. D’Axoli, M. D’Auria, L. Nucciarelli, G. Piancatelli and A. Scettri, Tetrahedron Lett., 4521 (1980). 246. V. L. Heasby, D. F. Shellhamer, L. E. Heasley, D. B. Yaeger and G. E. Heasley, J. Org. Chem., 45,4649 (1980). 247. G. M. Rubottom and R. C. Mott,J. Org. Chem., 44, 1731 (1979). 248. E. S. Gould, Mechanism and Structure in Organic Chemistry, Holt, Rinehart and Winston, New York (1959), p. 372. 249. H. 0. House, Modem Synthetic Reactions, W. A. Benjamin, Menlo Park, Calif. (1972), p. 459. 250. R. P. Bell and G. G. Davis, J. Chem. Soc., 902 (1964). 251. J. Toullec and J. E. Dubois, Tetrahedron, 29, 2851, 2859 (1973). 252. G. Schwarzenbach and C. Wittwer, Helv. Chim. Acta, 30,669 (1947). 253. C. Rappe and W. H. Sachs,J. Org. Chem., 32, 4127 (1967). 254. C. Rappe,Acta Chem. Scand., 22, 219 (1968). 255. C. Rappe, Acta Chem. Scand., 23,2305 (1969). 256. M. S. Sytilin, Zh. Fiz. Khim., 41, 1200 (1967); Chem. Abstr. 69, 464292 (1968). 257. C. G. Swain and R. P. Dunlap,J. Amer. Chem. Soc., 94, 7204 (1972). 258. J. W. Thorpe and J. Warkentin, Canad. J. Chem., 50, 3229 (1972). 259. R. A. Cox and J. Warkentin, Canad. J. Chem., 50, 3233 (1972). 260. A. C. Knipe and B. G. Cox, J. Chem. Soc., 1391 (1973). 261. J. B. Conant, W. R. Kirner and R. E. Hussey, J. Amer. Chem. Soc., 47,488 (1925). 262. R. G. Pearson, S. H. Langer, F. V. Williams and W. J. McGuue, J. Amer. Chem. Soc., 74, 5130 (1952). 263. A. J. Sisti and S. Lowell, Canad. J. Chem., 42, 1897 (1964). 264. F. G. Bordwell and W. T. Brannen, J. Amer. Chem. Soc., 86,4645 (1964). 265. A. Streitwieser Jr, Solvolytic Displacement Reactions, McGraw-Hill, New York (1 962). p. 28. 266. E. D. Hughes, Quart. Rev. (London), 5 , 245 (1951). 267. J. W. Baker, J. Chem. Soc., 848 (1938). 268. C. L. Stevens, W. Malik and R. Pratt, J . Amer. Chem. Soc., 72, 4758 (1950). 269. M. J. S. Dewar, The Electronic Theory of Organic Chemistry, Clarendon Press, Oxford (1949), p. 73. 270. S. Winstein, E. Grunwald and H. W. Jones, J. Amer. Chem. Soc., 73, 2700 (1951). 271. G. Richard, Bull. Soc. Chim. France, 5 , 286 (1938). 272. V. Rosnati, F. Sannicolo and G. Zecchi, Tetrahedron Lett., 599 (1970). 273. F. G. Bordwell and M. W. Carlson, J . Amer. Chem. Soc., 91, 3951 (1969). 274. R.P. Lutz, J. Amer. Chem. Soc., 90, 3788 (1968). 275. N. J. Turro, R. B. Gagosian, C. Rappe and L. Knutsson, Chem. Commun., 270 (1969). 276. J. W. Thorpe and J. Warkentin, Canad. J. Chem., 51, 927 (1973). 277. A. Halvorsen and J. Songstad,JCS Chem. Commun., 327 (1978). 278. S . H. McAllister, W. A. Bailey and C. M. Bouton, J. Amer. Chem. Soc., 62, 3210 (1940). 279. J. Cologne and J. C. Dubin, Bull. Soc. Chim. France, 1180 (1960).

1. Synthesis and reactivity of a-halogenated ketones 280. 281. 282. 283. 284. 285. 286. 287. 288. 289. 290. 291. 292. 293. 294. 295. 296. 297. 298. 299. 300. 301. 302. 303. 304. 305. 306. 307. 308. 309. 310. 311. 312. 313. 314. 315. 316. 317. 318. 319. 320. 321. 322. 323. 324. 325. 326. 327. 328. 329. 330. 331. 332. 333. 334.

113

C. L. Stevens and E. Farkas, J. Amer. Chem. SOC.,74, 5352 (1952). R. N. McDonald and P. A. Schwab, J. Amer. Chem. SOC.,85,4004 (1963). C. A. Buehler, H. A. Smith, K. V. Nayak and T. A. Magee,J. Org. Chem.,26,1573 (1 961). P. D. Bartlett and G. F. Woods, J . Amer. Chem. SOC.,62, 2933 (1940). R. Weidenhagen and R. Herrmann, Chem. Ber., 68, 1955 (1935). W. Ziegenbein, Chem. Ber., W,2989 (1961). B. Tchoubar, Compr. Rend. Acud. Sci. Paris, 234,2544 (1952). E. E. Smissman and J. L. Diebold, J. Org. Chem., 30,4005 (1965). M. Kopp and B. Tchoubar, Bull. SOC. Chim. France, 84 (1952). I. Elphimoff-Felkin and B. Tchoubar, Compt. Rend. Acud. Sci. Paris, 238, 1425 (1954). G. Richard, Bull. SOC. Chim. Frunce, 286 (1938). R. B. Loftfield and L. Schaad, J . Amer. Chem. SOC., 76, 35 (1954). R. Jacquier, Bull. SOC. Chim. France, 83, (1950). G. Hesse and F. Urbanek, Chem. Ber., 91, 2733 (1958). J. M. Conk and J. R. Salaun, Acc. Chem. Res., 5 3 3 (1972). C. Rappe and L. Knutsson, Acra Chem. Scand., 73,4702 (1964). A. C. Cope and E. S. Graham, J . Amer. Chem. SOC.,73,4702 (1964). J. Wolinsky and R. 0. Hutchins, J . Org. Chem., 37, 3294 (1972). C. Rappe, Acta Chem. Scand., 19, 270 (1965). M. Utaka, S. Matsushita and A. Takeda, Chem. Len., 779 (1980). K. S. Warren, 0. K. Neville and E. C. Hendley, J . Org. Chem., 28, 2152 (1963). P. Moreau and E. Casadevall, Compt. Rend. Acud. Sci. Paris C , 272, 801 (1971). M. Hanack, C. E. Harding and J.-L. Deroque, Chem. Ber., 105,428 (1972). Ger. Pat. 1,262,955 (1966); Chem. Absfr. 69, 577108 (1968). Ger. Pat. 2,819,264 (1978); Chem. Abstr. 90, 103450 (1979). G. Jones, J. Chem. SOC. C , 1230 (1970). K. Sato, S. Inoue, S.-I. Kuranami and M. Ohashi, JCS Perkin I, 1666 (1977). J. A. Donnelly and D. E. Maloney, Tetruhedron, 2875 (1979). J. A. Donnelly, M. J. Fox and T. C. Sharma, Tetrahedron, 35, 875 (1979). J. A. Donnelly, M. F. Cox and T. C. Sharma, Tetrahedron, 35, 1987 (1979). A. A. Sachs and J. G. Aston, J . Amer. Chem. SOC.,73, 3902 (1951). 0. E. Edwards and C. Grieco, Canud. J . Chem., 52, 3561 (1974). J. A. Aston, J. T. Clarke, K. A. Burgess and R. B. Greenburg,J. Amer. Chem. SOC.,64,300 (1942). T. Oda, Chem. Lett., 957 (1977). C. L. Stevens and J. Tazuma,J. Amer. Chem. SOC.,76, 215 (1954). C. L. Stevens, M. L. Weiner and R. C. Freeman,/. Amer. Chem. Soc., 75,3977 (1953). C. L. Stevens and J. J. De Young,J. Amer. Chem. SOC.,76,718 (1954). C. L. Stevens, J. J. Beereboom and K. G. Rutherford, J. Amer. Chem. SOC., 77, 4590 (1955). A. Hassner and P. Catsoulacos,J. Org. Chem., 31, 3149 (1966). A. Hassner and N. H.Cromwell,I. Amer. Chem. Soc., 110,901 (1958). N. H. Cromwell and R. P. Ayer, 1. Amer. Chem. SOC.,81, 133 (1959). R. B. Loftfield, J . Amer. Chem. SOC.,73,4707 (1951). F. G. Bordwell and J. Almy,J. Org. Chem., 38,571 (1973). B. Goyau and F. Rouessoc, Bull. SOC.Chim. France, 590 (1978). S. Vichers and E. E. Smissman, J. Org. Chem., 40, 749 (1975). W. T. Brady and A. D. Patel, J. Org. Chem., 39, 1949 (1974). F. G. Bordwell and J. G. Strong, J . Org. Chem., 38, 579 (1973). F. G. Bordwell and R. G. Scamehorn,J. Amer. Chem. SOC.,90, 6751 (1968). F. G. Bordwell and M. W. Car1son.J. Amer. Chem. SOC.,92, 3370 (1970). F. G. Bordwell and M. W. Carlson, J. Amer. Chem. SOC.,92,3377 (1970). F. G. Bordwell and R. G. Scamehorn,J. Amer. Chem. SOC., 93, 3410 (1971). A. W.Fort, 1. Amer. Chem. SOC.,84, 2620,4979 (1962). L. De Buyck, unpublished results. M. Mousseron, R. Jaquier and A. Fontaine, Compt. Rend. Acud. Sci. Paris, 232, 1562 (1951). E. Elkik and H. Assadifar, Buff. Soc. Chim. France 11, 129 (1978).

114

Norbert De Kirnpe and Roland Verhe

335. D. Baud7 and M. Charpentier-Morize, Tetrahedron Lett., 3013 (1973). 336. H. E. Zimmerman and R. J. Pasteris, J. Org. Chem., 45, 484, 4876 (1980). 337. J. F. Pazos, J. G. Pacifici, G. 0. Pierson, D. B. Slove and F. D. Greene, J. Org. Chem., 39, 1990 (1974). 338. P. S. Wharton and A. R. Fritzberg, J. Org. Chem., 37, 1899 (1972). 339. J. Ciabattoni, E. C. Nathan, A. E. Feiring and P. J. Kocienski, Org. Synth., 54, 97 (1974). 340. R. Breslow, T. Eicher, A. Krebs, R. A. Peterson and J. Posner,J. Amer. Chem. SOC.,87, 1320 (1965). 341. E. Herranz and F. Serratosa. Tetrahedron Lett.. 3335 (1975). 342. M. Mousseron and R. Jacquier, Compt. Rend. Acad. Sci. Pahs, 229, 374 (1949). 343. M. Kopp, Bull. SOC. Chim. France, 628 (1954). 344. M. Mousseron and R. Jacquier, Bull. SOC. Chim.France, 689 (1949). 345. W. B. Smith and C. Gonzalez, Tetrahedron Lett., 5751 (1966). 346. M. Charpentier-Morize, M. Mayer and B. Tchoubar, Bull. SOC.Chim. France, 529 (1965). 347. F. Bohlmann and G. Fritz, Tetrahedron Lett., 95 (1981). 348. J. Hill, J. Chem. SOC. C , 462 (1970). 349. V. Rosnati and A. Salimbeni, Gazz. Chim. Itaf., 107, 271 (1977). 350. P. A. Levine and A. Walti, Org. Synth., Coll. Vol. 11, 5 (1943). 351. E. B. Reid, R. B. Fortenbauch and H. R. Patterson,J. Org. Chem., 15, 579 (1950). 352. K. V. Auwers, H. Ludewig and A. Muller, Liebigs Ann. Chem., 526, 143, 158 (1936). 1355 (1978). 353. V. Caplar, A. Lisini, F. Kajfez, D. Kolbah and V. Sunjic, J. Org. Chem., 4, 354. P. Beltrame, V. Rosnati and F. Sannicolo, Tetrahedron Lett., 4219 (1970). 355. S. Gladiali, M. P. Porcu, V. Rosnati, A. Saba, F. Soccolini and A. Selva, Gau. Chim.Ital., 107, 293 (1977). 356. R. B. Wameboldt and L. Weiler, Tetrahedron Lett., 3413 (1971). 357. K. Sato, M. Ohashi, E. Aoki and Y. Murai,J. Org. Chem., 42, 3713 (1977). 358. S.F. Krauser and A. C. Watterson, J . Org. Chem., 43, 3400 (1978). 359. C. Wakselman and J. Leroy, J. Fluorine C h m . , 12, 101 (1978). 360. D. Mayer, in Methoden der Organischen Chemie, Vol. 7/2C (Ed. Houben-Weyl), Georg Thieme Verlag, Stuttgart (1977), p. 2253. 361. M. Kerfanto, A. Brault, F. Venien, J.-M. Morvan and A. Le Rouzic, Bull. SOC. Chim. France, 196 (1975). 362. D. G. Holland and E. D. Amstutz, Recl. Trav. Chim. Pays-Bas, 83, 1047 (1964). 363. L. P. Ellinger and A. A. Goldberg, J . Chem. SOC., 266 (1949). 364. Belgian Pat. 621,456 (1962); Chem. Abstr. 59, 9835d (1963). 365. G. K. Rogulchenko, I. A. Mazur and P. M. Kochergin, Farm. Zh. (Kiev), 4, 29 (1976); Chem. Absrr. 85, 192657 (1976). 366. M. V.Povstyanoi, V.P. Kruglenko and P. M. Kochergin, Ukr. Khim. Zh., 42,1166 (1976); Chem. Absrr. 86, 89770 (1977). 367. N. H. Cromwell and P. H. Hess, J. Amer. Chem. SOC.,83, 1237 (1961). 368. P. L. Julian, E. W. Meyer, A. Magnani and W. Cole,J. Amer. Chem. SOC.,67,1203 (1945). 369. E. W. Wamhoff and W. S. Johnson, J. Amer. Chem. SOC.,75, 494 (1953). 370. Ger. Pat. 1,262,995 (1966); Chem. Abstr. 69, 57710p (1968). 371. 0. I. Sorokin, Izv. Akad. SSSR, 460 (1961); Chem. Abstr. 55, 22310c (1961). 372. K. T. Potts and I. S. Baum, Chem. Rev., 74, 189 (1974). 373. E. W. Warnhoff,J. Org. Chem., 27,4587 (1962). 374. E. W. Wamhoff and D. R. Marshall, 32, 2000 (1967). 375. H. J. Sattler, H. G. Lennartz and W. Schunack, Arch. Pharm. (Weinheim), 312, 107 (1979). 376. J. Wolinsky, R. 0. Hutchins and T. W. Gibson, J. Org. Chem., 33, 407 (1968). 377. J. Wolinsky, J. J. Hamsher and R. 0. Hutchins, J. Org. Chem., 35, 207 (1970). 378. C. L. Stevens, P. Blumbergs and M. Munk, J. Org. Chem., 28, 331 (1963). 379. Y. Zeifman, N. Gambaryan and I. Knunyants, Izv. Akud. Nauk SSSR, Ser. Khim., 450 (1965); Chem. Absrr. 64, 6554f (1965). 380. W. Pirkle and J. Hauske, J. Org. Chem., 42, 2436 (1977). 381. N. De Kimpe, R. Verhk, L. De Buych, L. M&ns and N. Schamp, Synthesir, 43 (1982). 382. L. Duhamel, P. Duhamel and J.-M. Poirier, Tetrahedron Lett., 4237 (1973).

1. Synthesis and reactivity of a-halogenated ketones 383. 384. 385. 386. 387. 388. 389. 390. 391. 392. 393. 394. 395. 396. 397. 398. 399. 400. 401. 402. 403. 404. 405. 406. 407. 408. 409. 410. 411. 412. 413. 414. 415. 416. 417. 41 8. 419. 420. 421. 422. 423. 424. 425. 426. 427. 428. 429. 430. 431.

115

L. Duhamel, P. Duhamel and J.-M. Poirier, Bull. SOC. Chim. France, 221 (1972). L. Duhamel and J.-M. Poirier, J. Org. Chem., 44, 3585 (1979). D. Cantacuztne and M. Tordeux, Tetrahedron Lett., 4807 (1971). C. Combet-Farnoux, J. F. Girardeau and H. Galens, Compt. Rend. Acud. Sci. Paris. 282, 469 (1976). C. L. Stevens and P. M. Pillai, 1. Org. Chem., 37, 173 (1972). C. L.Stevens, J. M. Cahoon, T. R. Potts and P.M. pillai, J. Org. Chem.,37,3130 (1972). L. Nilsson and C. Rappe, Acra Chem. Scand., B30, 1000 (1976). T. Kato, T. Chiba, M. Noda and M. Sasaki, Heterocycles, 10, 261 (1978). J. C. M e s h . Y. T. N’Guessan. H. Quiniore and F. Tonnard, Tetrahedron, 31,2679 (1975). H. Bredereck and R. Gompper, Chem. Ber., 87, 700 (1954). P. B. Terentiev, A. N. Kost, N. P. Lomakina and V. G. Kartev, Org. Prep. Proced. l n t . , 6, 145 (1974). W. Ried and L. Kaiser, Liebigs Ann. Chem., 958 (1975). R. F. Abdulla and J. C. Williams, Tetrahedron Lett., 997 (1980). G . Kempter, J. Spindler, H. Fiebig and G. Sarodnick, J. Prakt. Chem., 313, 977 (1971). M.-C. Dubroeucq, F. Rocquet and F. Weiss, Tetrahedron Len., 4401 (1977). J. P. Nath and G. N. Mahapatra, Indiun J. Chem. B , 19, 526 (1980). C. Yamazaki, Tetrahedron Lett., 1295 (1978). A. N. Mirskova, G. G . Levkovskaya, I. D. Kalikhman and M. G. Voronkov, Zh Org. Khim.,15, 2301 (1979); Chem. Abstr. 92, 128792 (1980). A. Babadjamian, J. Metzger and M. Chanon,J. Heterocycl. Chem., 12, 643 (1975) A. Babadjamian, R. Gallo, J. Metzger and M. Chanon, J. Heterocycl. Chem., 13, 1205 (1976). R. J. Bergeron and P. G. Hoffman, J. Org. Chem., 44, 1835 (1979). R. J. Bergeron and P. G. Hoffman, J. Org. Chem., 45, 161 (1980). N. De Kimpe, R. VerhC, L. De Buyck and N. Schamp, Org. Prep. Proced. lnt., 12, 49 (1980). N. De Kimpe and N. Schamp, Org. Prep. Proced. Int., 11, 115 (1979). F. Ramirez and A. F. Kirby, J. Arner. Chem. Soc., 75, 6026 (1953). A. G . Schultz and W. K. Hagman, J. Org. Chem., 43, 3391 (1978). H. Beyer and G. Bodicke, Chem. Ber., 93, 826 (1960). E. J. Corey, M. Petrzilka and Y. Ueda, Tetrahedron Lett., 4343 (1975). W. Oppolzer, M. Petrzilka and K. Batti ,Helv. Chim. Acta, 60,2964 (1977). A. Hassner and V. Alexanian, J. Org. them., 44, 3861 (1979). S. Bozzini, B. Cova, S. Gratton, A. Lisini and A. Risaliti, JCS Perkin I, 240 (1980). J. Schantl, Monatsh. Chem., 108, 325 (1977). N. I. Korotkikh, A. Y. Chervinskii, S. N. Baranov, L. M. Kapkan and 0. P. Shvaika, Zh. Org. Khim.,15, 962 (1979); Chem. Abstr. 91, 74124 (1979). M. Koga and J.-P. Anselme, Chem. Commun., 53 (1973). D. Y. Curtin and E. W. Tristam, J. Amer. Chem. SOC.,72, 5238 (1950). T. Patonay, M. Rakosi, G . Litkei, T. Mester and R. Bognar, in Proceedings ofthe 5th Hungarian Biojavonoid Symposium, Matrafured, Hungary, 227 (1977). R. J. Crawford and H. Tokunaga, Canad. J. Chem., 52, 4033 (1974). T. V. Saraswath and V. R. Srinivasan, Tetrahedron, 33, 1043 (1977). W. R. Mallory and R. W. Morrison, J. Org. Chem., 45, 3919 (1980). E. Bulka and W. D. Pfeiffer, J . Prakt. Chem., 318, 971 (1976). H. Beyer and G. Wolter, Chem. Ber., 89, 1652 (1956). J. H. Boyer and D. Straw, J . Amer. Chem. SOC.,75, 1642 (1953). G. Pasquet, D. Boucherot, W. R. Pilgrim and B. Wright, Tefrahedron Len., 931 (1980). F. Asinger, W. Schafer, M. Baumann and H. Romgens, Liebigs Ann. Chem., 672, 103 (1964). G. Geiseler and F. Stache, Chem. Ber., 94, 337 (1961). L. Schotte, Ark. Kemi, 5, 533 (1953). B. Fohlisch and W. Gottstein, Liebigs Ann. Chem., 1768 (1979). K. Nagata, Chem. Pharm. Bull. (Tokyo), 17, 661 (1969). J. Gierer and B. Alfredson, Chem. Ber., 90, 1240 (1957).

116

Norbert De Kimpe and Roland Verhe

432. D. Martinez and A. Hiller, Zeit. Chem., 16, 320 (1976). 433. Z. M. Ivanova, T. V. Kim, I. E. Boldeskul and Y. G. Gololobov, Zh. Obshch. Khim., 49, 1464 (1979); Chem. Abstr. 91, 157197 (1979). 434. H. Horstmann, in Merhoden der Organbchen Chemie, Vol. 7/2c (Ed. Houben-Weyl), Georg Thieme Verlag, Stuttgart (1977), p. 2352. 435. B. M. Trost, W. C. Vladuchick and A. J. Bridges,J. Amer. Chem. Soc., 102,3548 (1980). 436. Y. Nagao, M. Ochiai, K. Kaneko, A. Maeda, K. Watanabe and E. Fujita, Tetrahedron, 1345 (1977). 437. G.Buchmann and R. Schmuck, J. Prukt. Chem., 28, 141 (1965). 438. M. Oki, W. Fanakoshi and A. Nakamura, Bull. Chem. Soc. Japan, 44,828 (1971). 439. I. G. Mursakulov, F. F. Kerimov, N. K. Kasumov, E. A. Ramazanov and N. S. Zefuov, Azerb. Khim. Zh., 93 (1979); Chem. Abstr. 91, 56925b (1979). 440. G.Giusti and G. Schembri, Compt. Rend. Acad. Sci. Paris C , 287, 213 (1978). 441. H. Sokol and J. J. Ritter, J. Amer. Chem. Soc., 70, 3517 (1948). 442. P. Dubs and R. Stuessi, Synrhesb, 696 (1976). 443. T. Terasawa and T. Okada, J . Org. Chem., 42, 1163 (1977). 444. H. Ishihara and Y. Hirabayashi, Chem. Lett., 1007 (1978). 445. G. Ege, P. Arnold and R. Noronha, Liebigs Ann. Chem., 656 (1979). 446. A. M. Sarpeshkar, G. J. Gossick and J. Wemple, Tetrahedron Leu., 703 (1979). 447. D. T. Mowry, Chem. Rev., 42, 189,204 (1948). 448. A. E. Matthews and W. R. Hodginson, Chem. Ber., 15, 2679 (1882). 449. E. P. Kohler and F. W. Brown, J. Amer. Chem. Soc., 55, 4299 (1933). 450. R. Justoni, Gazz. Chim.ltal., 69, 378 (1939). 451. H. Behringer, M. Ruff and R. Wiedenmann, Chem. Ber., 97,1737 (1964). 452. 0. Widman and E. Wahlberg, Chem. Ber., 44,2067 (1911). 453. A. Y. Yakubovich, N. A. Bogolovskii, E. P. Pravova and S. M. Rozenshtein, Zh. Obshch. Khim.,28, 2288 (1958); Chem. Abstr. 55, 1330231 (1961). 454. C. D. Hurd and C. H. Rector, J. Org. Chem., 10, 441 (1945). 455. H. Kobler, K.-H. Schuster and G.Simchen, Justus Liebigs Ann. Chem., 1946 (1978). 456. H. Galons, C. Combet-Farnoux, J.-F. Girardeau and M. Miocque, Compt. Rend. Acud. Sci. Paris C , 286, 663 (1978). 457. R. Justoni and M. Terruzzi, Gazz. Chim.Itul., 78, 155, 166 (1948). 458. H. Galons, J. F. Girardeau and C. Combet-Farnoux, Bull. Soc. Chim.Frunce, 936 (1977). 459. M. M. Schemiakan, M. V. Kolozov, Y. A. Arbusov, V. V. Onoprienco and Y.-Y. Hsieh, Zh. Obshch. Khim., 30,545 (1960); Chem. Abstr. 54, 24576b (1960). 460. F. Ebel, F. Huber and A. Brunner, Helv. Chim. Acta, 12, 16 (1929). 461. R. T. Lalonde, N. Muhammad, C. F. Wong and E. R . Sturiale, J. Org. Chem., 45, 3664 (1980). 462. T. Sakai, E. Amano, A. Kawabata and A. Takeda, J. Org. Chem., 45,43 (1980). 463. 0. Campos and J. M. Cook, J. Heterocycl. Chem., 14, 71 1 (1977). 464. S. R. Ramadas and S. Padmanabhan, Curr. Sci., 48, 52 (1979). 465. H.-J. Altenbach, Angew. Chem., 91, 1005 (1979). 466. R. Verht and R. Thierie, unpublished results. 467. R.VerhC, D. Courtheyn, N. De Kimpe, L. De Buyck, R. Thierie, L.Van Caenegem and N. Schamp, Org. Prep. Proced. lnt., 13, 13 (1981). 468. W. Lehnert, Tefrahedron, 29, 635 (1973). 469. R. Verht, N. De Kimpe, L. De Buyck, R. Thierie and N. Schamp, B U N . Soc. Chim.Belg., 89, 563 (1980). 470. P. Bravo, G. Gaudiano, C. Ticozzi and A. Umani-Ronchi, TetrahedronLett., 4481 (1968). 471. J. A. Donnelly, M. J. Fox and J. G.Hoey,JCS Perkin I, 2629 (1979). 472. A. S. Sopova, N. W. Perekalin, 0. I. Jurczenko and G. M. Arnautova, Zh. Org. Khim., 5, 858 (1969); Chem. Abstr. 71, 38394k (1969). 473. L. Fitjer, Synthesb, 189 (1977). 474. M. Tiffeneau, Bull. Soc. Chim.France, 612 (1945) and references cited therein. 475. T. A. Geissman and R. Akawie,J. Amer. C k m . SOC.,73, 1993 (1951). 476. J. J. Riehl, A. Smolikiewicz and L. Thil, Tetrahedron Lett., 1451 (1974). 477. J. W. Cornforth, R. H. Cornforth and K. K. Mathew, J. Chem. Soc., 112 (1959). 478. E. Elkik, M. Le Blanc and A. Vailatti, Compr. Rend. Acad. Sci. Paris C, 270, 246 (1970).

1. Synthesis and reactivity of a-halogenated ketones

117

479. A. S. Hussey and R. R. Herr, J . Org. Chem., 2.4, 843 (1959). 480. T. Kato, H. Kondo, M. Nishino, M. Tanaka G. Hata and A. Miyake, Bull. Chem. Soc. Japan, 53, 2958 (1980). 481. J. Barbuenga, M. Yus and P. Bernad, Chem. Commun., 847 (1978). 482. C. H. De Puy, G. M. Dappen, K. L. Eilers and R. A. Klein, J. Org. Chem., 29,2813 (1964). 483. H. C. Brown and C. G. Rao, J . Org. Chem., 43, 3602 (1978). 484. R. L. Huang, J . Chem. Soc., 4089 (1957). 485. N. De Kimpe. R. Verhe, L. De Buyck and N. Schamp, Tetrahedron Left.,955 (1978). 486. N. De Kimpe, R. Verhe, L. De Buyck and N. Schamp, Bull. Soc. Chim. Belg., 88. 719 ( 1979). 487. J. Cologne and J. Grenet, Bull. Soc. Chim.France, 1304 (1954). 488. J. Villieras and B. Castro, Bull. Soc. Chim.France, 1189 (1970). 489. A. J. Sisti and A. C. Vitale, J . Org. Chem., 37, 4090 (1972). 490. H. H. Ong, V. B. Anderson, J. C. Wilker, T. C. Spaulding and L. R. Meyerson. J . Med. Chem., 23, 726 (1980). 491. J.-E. Dubois, C. Lion and C. Moulineau, Tetrahedron Lett., 177 (1971). 492. J.-E. Dubois and C. Lion, Tetrahedron, 31, 1227 (1975). 493. J.-E. Dubois, P. Fournier and C. Lion, Tetrahedron Lett., 4263 (1975). 494. J.-E. Dubois, P. Fournier and C. Lion, Bull. Soc. Chim.France, 1871 (1976). 495. G. H. Posner and J. J. Sterling, J . Amer. Chem. Soc., 95, 3076 (1973). 496. R. Noun-Bimorghi, Bull. Soc. Chim.France, 1876 (1975). 497. H. C. Brown, M. M. Rogic, M. W. Rathke and G. W. Kabalka, J . Amer. Chem. Soc.. 91, 2150 (1969). 498. J.-J. Katz, J.-E. Dubois and C. Lion, Bull. Soc. Chim.France, 683 (1977). 499. A. Pelter, K. J. Could and C. R. Harrison, JCS Perkin I, 2428 (1976). 500. R. C. Cookson, M. J. Nye and G. Subrahmanyam, J . Chem. Soc. C, 473 (1967). 501. H. M. R. Hoffmann, D. R. Joy and A. K. Suter, J . Chem. Soc. B , 57 (1968). 502. R. Noyori, S. Makino and H. Takaya, J . Amer. Chem. Soc., 93, 1272 (1971). 503. H. M. R. Hoffmann and M. N. Iqbal, Tetrahedron Len., 4487 (1975). 504. H. M. R. Hoffmann, R. Chidgey and G. Fierz, Angew. Chem., 13,444 (1974). 505. R. Noyori, Y. Hayakawa, M. Funakura, H. Takaya, S. Murai, R. Kobayashi and S. Tsutsumi, J. Amer. Chem. Soc., 94, 7202 (1972). 506. R. Noyori, Y. Baba, S. Makino and H. Takaya, Tetrahedron Len., 1741 (1973). 507. D. I. Rawson, B. K. Carpenter and H. M. R. Hoffman, J. Amer. Chem. Soc., 101, 1786 (1 979). 508. A. P. Cowling and J. Mann, JCS Perkin I, 1564 (1978). 509. Y. Hayakawa, K. Yokoyama and R. Noyori, J . Amer. Chem. Soc., 100, 1799 (1978). 510. A. P. Cowling and J. Mann, Chem. Commun., 1006 (1978). 511. Y. Ito, M. Asada, K. Yonezawa and T. Saegusa, Synrh. Commun., 4, 87 (1974). 512. H. M. R. Hoffmann, T. A. Nour and R. H. Smithers, Chem. Commun., 963 (1972). 513. H. M. R. Hoffmann, K. E. Clemens, E. A. Schmidt and R. H. Smithers,I. Amer. Chem. SOC., 94, 3201 (1972). 514. H. Alper, K. D. Logbo and H. des Abbayes, Tetrahedron Len., 2861 (1977). 515. H. Alper and E. C. H. Keung, J . Org. Chem., 37, 2566 (1972). 5 16. F. G. Saitkulova, T. P. Kadyrmatova, G. G. Abashev and I. I. Lapkin, Izv. Vyssh. Uchebn. Zaved., Khim. Khim. Teckhnol., 20, 1078 (1977); Chem. Abstr. 87, 201013 (1977). 517. I. 1. Lapkin, F. G. Saitkulova, G. G. Abashev, V. V. Fotin, Izv. Vyssh. Uchebn. Zaved., Khim. Khim. Tekhnol., 23, 793 (1980; Chem. Abstr., 94, 15339g (1981). 518. K. Maruoka, S. Hashimoto, Y. Kitagawa, H. Yamamoto and H. Nozaki, J . Amer. Chem. Soc., 99, 7705 (1977). 519. L. T. Scott and W. D. Cotton, J . Amer. Chem. Soc., 95, 2708 (1973). 520. J. Wolinsky, J. H. Thorstenson and T. A. Killinger, J . Org. Chem., 43,875 (1978). 521. H. Sugihara, K. Ukawa, A. Miyake, K. Itoh and Y. Sanno, Chem. Pharm. Bull., 394 (1978). 522. W. Sucrow, A. Fehlauer and U. Sandmann, Z . Nafurforsch., 32b, 1072 (1977). 523. H. Bodot, J.-A. Braun and J. Fedikre, Bull. Soc. Chim.France, 3253 (1968). 524. J. Sauleau, Bull. Soc. Chim.France, 474 (1978). 525. L. W. Trevoy and W. G. Brown, J . Amer. Chem. Soc., 71, 1675 (1949).

118

Norbert De Kimpe and Roland Verhe

526. L. H. Schwartz and R. V. Flor, J. Org. Chem., 34, 1499 (1969). 527. J. Bergman and J. E. Backvall, Tetrahedron, 31, 2063 (1975). Div. Chem. 528. A. A. Volod‘kin, N. V. Portnykh and V. V. Ershov, Bull. Acad. Sci. U.S.S.R., Sci., 1352 (1962). 529. A. J. Kirbv and S. G. Warren, The Ornanic Chemistry ofPhosphorw, Elsevier, Amsterdam (1967). p.’117. 530. K. V. Nikonorov, I. D. Neklesova, E. A. Gurylev, M. A. Kudrina, V. A. Nikonenko, I. S. Iraidova and N. N. Anisimova, Zh. Obshch. Khim., 46,560 (1976); Chem. Absfr. 85,5795 (1976). 531. P. A. Chopard, V. M. Clark, R. F. Hudson and A. J. Kirby, Tetrahedron, 21,1961 (1965). 532. L. Toke, I. Petnehazy and G. Szakal, J. Chem. Res. (M),1975 (1978). 533. E. M. Gaydou, G. Buono and R. Frirze, Bull. Soc. Chim. France, 2284 (1973). 534. I. J. Borowitz, S. Firstenberg, E. W. R. Casper and R. K. Crouch, J. Org. Chem., 36,3282 (1971). 535. E. M. Gaydou and J. B. Bianchini, Canad. J . Chem., 54, 3626 (1976). 536. F. Kienzle and P. Rosen, Helv. Chim. Acta, 62, 442 (1979). 537. T. K. Gazizov, Y. I. Sudarev and A. N. Pudovik, Zh. Obshch. Khim., 46, 2383 (1976); Chem. Abstr. 85, 4817 (1976). 538. M. Sekine, K. Okimoto and T. Hata, J. Amer. Chem. Soc., 100, 1001 (1978). 539. R. Malinowski and M. Mikolajczyk, Pi. IPO, 6, 95 (1974). 540. R. Malinowski and J. Legocki, Polish J. Chem., 53, 2149 (1979). 541. 0. Dahl and F. K.Jensen, Acra Chem. Scand. B , 30,863 (1975). 542. 0. Dahl, JCS Perkin I, 947 (1978). 543. I. J. Borowitz and R. Virkhaus, J. Amer. Chem. SOC., 85, 2183 (1963). 544. T. V. Kim, Z. M. Ivanova and Y. G. Gololobov, Zh. Obshch. Khim., 48, 1967 (1978); Chem. Absfr. 88, 190990 (1978). 545. Y. G. Gololobov, L. F. Kasukhin, G. V. Pesotskaya, V. S. Petrenko, T. V. Kim and Z. M. Ivanova, Zh. Obshch. Khim., 48, 1974 (1978); Chem. Abstr. 90, 18194 (1979). 546. B. Springs and P. Haake, J. Org. Chem., 41, 1165 (1976). 547. B. Springs and P. Haake, J. Org. Chem., 42, 472 (1977). 548. J. Leroy,J. Bensoam, M. Humiliere, C. Wakselman and F. Mathey, Tetrahedron, 36, 1931 (1980). 549. G. Richard, Bull. Soc. Chim. France, 286 (1938). 550. E. M. Schultz and S. Mickey, Org. Synth., Coll. Vol. 111, 343 (1960). 551. L. T. Scott and W. D. Cott0n.J. Amer. Chem. Soc., 95, 5416 (1973). 552. S. N. Kukota, V. P. Borisenko, V. N. Bodnar, N. I. Zhuravskaya, M. 0. Lozinskii, Fiziol. Akr. Veskchesfva, 10, 32 (1978); Chem. Abstr., 90, 6212a (1979). 553. D. J. Cooper and L. N. Owen, J. Chem. Soc. C, 533 (1966). 554. C. Kowalski, X.Creary, A. J. Rollin and M. C. Burke, J. Org. Chem., 43, 2601 (1978). 555. H. 0. House, W. F. Fischer, M. Gall, T. E. McLaughlin and N. P. Peet,J. Org. Chem., 36, 3429 (1971). 556. I. Fleming and J. Goldhill, JCS Perkin I, 1493 (1980). 557. E. Warnhoff, M. Rampersad, P. Sundara Raman and F. W. Yerhoff, Tetrahedron Lett., 1659 (1978). 558. J. Wolinsky, J. J. Hamsher and R. 0. Hutchins, J. Org. Chem., 35, 207 (1970). 559. I. V. Zavarzin, T. A. Klimova, M. M. Krayushkin, V. V. Sevost’yanova and S. S. Novikov, lzv. Akud. Nauk SSSR, Ser Khim., 868 (1978); Chem. Absrr. 89,42537 (1978). 560. J. P. B6gu6, D. Bonnet, M. Charpentier-Morize and C. Pardo, T e t r h d r o n , 31, 2505 (1975). 561. D. Baudry and M. Charpentier-Morize, Nouv. J . Chim., 2, 255 (1978). 562. J. P. BtguC and M. Charpentier-Morize, Acc. Chem. Res., 13, 207 (1980). 563. J. P. EguC and M. Malissard, Tetrahedron, 34, 2094 (1978). 564. P. C. Purohit and H. R. Sonawane, Tetrahedron, 37, 873 (1981). 565. G. Jones I1 and L. P. McDonnell, J. Amer. Chem. Soc., 98, 6203 (1976). 566. B. E. Kaplan and A. L. Hartwig, Tetrahedron Lett., 4855 (1970). 567. W. R. Bergmark, Chem. Commun., 61 (1978). 568. J. C. Anderson and C. B. Reese, Tetrahedron Lefr., 1 (1961).

-

~~

1. Synthesis and reactivity of a-halogenated ketones

119

569. Y. Izaua, H. Tomioka, M . Natsume, S. Beppu and H. Tsujii, J. Org. Chem., 45, 4835 (1980). 570. A. J. Fry and A. T. Lefor, J. Org. Chem., 44,1270 (1979). 571. A. J. Fry and G. S. Ginsburg, J. Amer. Chem. Soc., 101, 3928 (1979). 572. W. J. M . van Tilborg, R. Plomp, R. de Ruiter and C. J. Smit, Red. Trav. Chim. Puy5-Bus, 99, 206 (1980). 573. H. E. Zimmerman and A. Mais, J. Amer. Chem. Soc., 81, 3644 (1959). 574. H. Alper and L. Patter, J. Org. Chem., 44,2568 (1979). 575. T. H. Luh, C. H. Lai, K. L. Lei and S. W. Tam, J. Org. Chem., 44, 641 (1979). 576. H. Alper, Tetrahedron Lerr., 2257 (1975). 577. J. E. McMurry,Acc. Chem. Res., 7 , 281 (1974). 578. I. J. Borowitz and L. I. Grossman, Terrahedron Lerr., 471 (1962). 579. Tse-Lok Ho and C. M. Wong, J. Org. Chem., 39,562 (1974). 580. D. A. Bock and W. T. Brady, J. Org. Chem., 44, 101 (1979). 581. J. M . Townsend and T. A. Spencer, Tetrahedron Lett., 137 (1971). 582. G. A. Olah, G. D. Vankar and A. P. Fung, Synthesis, 59 (1979). 583. Tse-Lok Ho, Synrh. Commun., 9, 241 (1979). 584. G. A. Olah, M . Arvanaghi and Y.D. Vankar, J. Org. Chem., 45, 3531 (1980). 585. A. L. Gemal and J. L. Luche, Tetrahedron Len., 3195 (1980). 586. N. De Kimpe and N. Schamp, Org. Prep. Proced. Int., 13, 241 (1981).

The chemistry of a -haloketones, or-haloaldehydes and a-haloimines Edited by Saul Patai & Zvi Rappoport Copyright 0 1988 by John Wiley & Sons Ltd

APPENDIX TO CHAPTER 1

Synthesis and reactivity of ahalogenated ketones I . INTRODUCTION . . . . . . . . . . . . . . . . . . . . I1 . SYNTHESIS OF a-HALOGENATED KETONES . . . . . . . . . A . Synthesis of a-Fluoroketones . . . . . . . . . . . . . . . . B. Synthesis of a-Chloroketones . . . . . . . . . . . . . . . . C. Synthesis of a-Bromoketones . . . . . . . . . . . . . . . . D. Synthesis of a-Iodoketones . . . . . . . . . . . . . . . . E. Optically Active a-Haloketones . . . . . . . . . . . . . . . 111. REACTIVITY OF a-HALOGENATED KETONES . . . . . . . . A. Introduction . . . . . . . . . . . . . . . . . . . . . B. Reaction of a-Haloketones with Oxygen Nucleophiles and Bases . . . 1. Reaction with inorganic oxygen nucleophiles . . . . . . . . . 2. Reaction of a-haloketones with organic oxygen nucleophiles and bases C. Reaction of a-Haloketones with Nitrogen Nucleophiles and Bases . . . 1. Reaction of a-haloketones with amines . . . . . . . . . . . 2. Reaction of a-haloketones with imino compounds and enamines . . 3. Reaction of a-haloketones with amides, thioamides and derivatives . 4. Reaction of a-haloketones with carbonyl reagents . . . . . . . 5. Reaction of a-haloketones with sodium azide . . . . . . . . . D . Reaction of a-Haloketones with Sulphur and Selenium Nucleophiles . . 1. Reaction of a-haloketones with inorganic selenium nucleophiles . . 2. Reaction of a-haloketones with organic sulphur and selenium nucleophiles. . . . . . . . . . . . . . . . . . . . . E. Reaction of a-Haloketones with Carbon Nucleophiles . . . . . . . 1. Reaction of a-haloketones with cyanide . . . . . . . . . . . 2. Reaction of a-haloketones with carbanions, ylides and enolates . . . F. Reaction of a-Haloketones with Organometallic Reagents. . . . . . 1. Reaction of a-haloketones with Grignard reagents . . . . . . . . 2. Reaction of a-haloketones with organolithium compounds . . . . 3. Reaction of a-haloketones with organoboron compounds . . . . . 4. Reaction of a-haloketones with metal complexes . . . . . . . . G . Reaction of a-Haloketones with Phosphorus Compounds . . . . . . H . Miscellaneous Reactions of a-Haloketones . . . . . . . . . . . 1. Electrophilic reactions of a-haloketones and their derivatives . . . 2. Reaction of a-haloketones with alkali metal fluorides . . . . . . 3. Acid-catalysed rearrangement of a-haloketones . . . . . . . . 4. Formation of a-acylcarbenium ions from a-haloketones . . . . . 121

122 122 122 126 141 147 148 148 148 150 150 154 164 164 174 175 178 179 180 180 180 183 183 183 189 189 192 194 195 201 204 204 209 209 211

122

Norbert De Kimpe and Roland Verhe

5. Photochemistry of a-haloketones . . . . 6. Electrochemistry of a-haloketones . . . . 7. Dehalogenation of a-haloketones . . . . 8. Enzymatic transformations of a-haloketones IV. REFERENCES. . . . . . . . . . . . . .

. . . .

. . . .

. . . . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . . .

. . . .

212 214 214 214 215

1. INTRODUCTION

This Appendix on the synthesis and reactivity of a-halogenated ketones covers the literature from early 1980 until the first half of 1986. Whereas in the original chapter the general procedures for the synthesis of a-haloketones and the various reaction pathways were described, the Appendix emphasizes the regioselective introduction of halogens by a variety of methods and the selective transformation of a-haloketones with various reagents. Identical procedures and transformations which were described during the last 6 years and already treated earlier will not be mentioned unless a major breakthrough or application has been observed. The presentation of this Appendix is identical with that in the original chapter and the reader will find valuable information by referring to each subdivision in the original chapter and Appendix successively. Structures, equations and references are numbered in continuation of those in the original chapter. II. SYNTHESIS OF a-HALOGENATED KETONES

During the last 5 years, major progress has been achieved in the preparation of ahalogenated ketones. In this section the introduction of halogen atoms in a regiospecific manner with respect to the carbonyl functionality will be emphasized. A. Synthesis of a-Fluoroketones

An excellent review by Rozen and Filler587describes the synthesis of a-fluorocarbonyl compounds, but most of the references concern procedures published before 1980. We shall mention only references dealing with new methods. Up to several years ago it was commonly stated that fluorination by fluorine is not a useful procedure for the synthesis of a-fluorocarbonyl compounds588,but it has now been shown that direct fluorination can lead to a-fluoroketones. Addition of elemental fluorine to an enone system in a steroidal ring (509) furnished an a, p-difluoroketone (510) (equation 267)589.

(509)

(510)

a-Monofluorination of ketones or enol acetates was carried out by treatment with N fluoro-N-alkylsulphonamides in the presence of strong bases (equation 268)590.Geminal difluoroketones (514 and 516) were formed during the reaction of diazoketones (513 and 515) with fluorine, better than with CF,OF (equation 269)591.

App. 1. Synthesis and reactivity of a-halogenated ketones

123

(511)

'.&f'h

0

P F

p

h 0q

P

h

High yields of a-fluoroketones were obtained when silyl enol ethers reacted with dilute F, (5%) in N, at - 78 "C in Freon 11. This direct fluorination avoids the use of toxic reagents and by-products (equation 270)592. OSiMe3

I

R~C=CHR~

F2

CFCIa

-78OC

R + ll( R2

F

60-70

Me3SiF

(270)

O/o

Enol acetates are transformed into a-fluoroketones by the action of xenon difluorideSu3or caesium fluoroxysulphate (equation 271)594.595.

(271) In the anodic oxidation of enol acetates, Et3N.3HF served as both the fluorinating agent and the supporting electrolyte (equation 272)596.Depending on the structure of the enol acetate, a-acetoxyketones were formed as side products. Halogen exchange reactions of ahaloketones is feasible using potassium fluoride in the presence of a crown ether and tetraalkylammonium f l ~ o r i d e s ~ or ~ ~tertiary . ~ ~ ' amine tris(hydrofl~orides)~~~. Silver tetrafluoroborate can also be utilized as a fluorinating agent in ring-opening reactions of achlorooxiraness99~600 and a-fluorooxiranes (e.g. 517) (equations 273 and 274)601.

Norbert De Kimpe and Roland Verhe

124

R1MR3

+ FOAc

E t,N. 3HF

OAc

OAc

R2 F

>r 0

R R '2

R3

F

40-60 '/o

R1+R2

(273)

1

0

+

F

0

R1+R2

minor

major

*--

(517) Y=CI,Br,I

\

90%

(518)

CI

4-5%

j OA:lg)

B F4

I%

(520)

(274)

-/" F

Ring opening of azirines (521) with Olah's reagent (HF-pyridine) resulted in the formation of a-fluoroketones (522) in THF, whereas in benzene 1,fi-difluoroamines (523) were produced (equation 275)602.603. The reaction involved the formation of aimidoylcarbenium ions (524) followed by reaction with fluoride and hydrolysis (equation 276).

App. 1. Synthesis and reactivity of a-halogenated ketones

125

F

90% (522)

HF. PY

Ph

(521)

F F &NH? Ph

COHO

67O/o

(523)

H

N+ Ph

Ph

1276)

I'

2.HzO

t

(522)

(524)

Fluoromethyl ketones are formed by the condensation of aldehydes with lithiofluoromethyl phenyl sulphoxide (525) followed by pyrolysis of the generated b-hydroxya-fluoroalkyl phenyl sulphoxides (526) (equation 277)604. 0 RCHO

+

II

Ph-S-CHLI

(525)

THF

I

F

P -h ;HO (--)'

If

0 (526)

IYF

(277)

180°C

0

a, a-Difluoroketones were synthesized via Claisen rearrangement of substrates (527) containing fluorine atoms605and by fluorination of activated aromatic systems (529)with caesium fluoroxysulphate (equation 278)973.

Norbert De Kimpe and Roland Verhe

126

0 R

R

(527)

(528)

F F I0 - 24 Vo

(529) ( a ) R=NHAc

(530)

( b ) R=OH

B. Synthesis of a-Chloroketones

New developments are worth mentioning, especially in the field of the regiospecific chlorination. Chlorination of ketones by means of polymer-supported chlorine has become a routine procedure. The macroreticular anion-exchange resin Amberlyst A-26 (531) in the iodide form reacts with chlorine giving 532, probably carrying ICI, counter ions. This proved to be efficient in the chlorination of carbonyl compounds (equation 279)606. ~

CI

45-6 5 O/o

A crosslinked polymer (533) of styrene and 4-vinylpyridine was reacted with hydrogen iodide to give a polymer containing pyridinium iodide residues, which on reaction with chlorine gave a polymer containing pyridinium tetrachloroiodate residues (534). In a

App. 1. Synthesis and reactivity of &-halogenated ketones

127

similar manner using methyl iodide, polymers containing N-methylpyridinium tetrachloroiodide residues (535) were formed. Both reagents reacted with acetophenone, thus forming 2-chloro- (536) and 2-iodo- 1-phenylethanone (537) in ratios depending on the reagent used and the reaction time (equation 280)607. ICI4

(534)

)N-R

(538)

Iclq.Cl2

(535) PhCOCH2CI

(536)

+

PhCOCHZI

PhCOCH.

(337)

Regiospecific chlorination of aliphatic ketones in methanol has been examined in detail. The product distributions in methanol differ substantially from those obtained in CCI, (equation 281)608.In methanol addition ofchlorine to the least substituted carbon a to the carbonyl group is favoured. The effect is especially pronounced in an a-carbon bearing two substituents as illustrated in Table 1. 0

I

R2

h2 major

Chlorination of acetone was also investigated in detail (equation 282). Addition of slightly more than one equivalent of chlorine in methanol gave chloroacetone dimethylacetal (538) as the major product. Under anhydrous conditions, acetone chlorination in methanol yielded a 60:40 mixture of 1,3- (540) and 1, I-dichloroacetone dimethyl acetals (541) together with small amounts of dichloroketones. In acetic acid or carbon tetrachloride a 67:33 mixture of dichloroacetones together with minor amounts of other products was obtained. In ethanol similar results were obtained but chlorination in 2-propanol resulted in oxidation of the solvent. In ethylene glycol the cyclic acetal of chloroacetone was obtained. In water-methanol as solvent 1,l-dichloroacetone was the major product and in 1: 1 methanol-DMF a mixture of 1,l-dichloroacetone (So/,), 1.1,1trichloroacetone (5%) and 1 , l - (18%) and 1,3-dichloroacetone dimethyl acetal(22yJ was

Norbert De Kimpe and Roland Verhe

128

Me0 OMe

0

4

CI

Me0 OMe MeOH

( 539)

K

Me0 OMe

Me0 OMe

CI

CI

(540)

CI

(538)

+

'to CI

(541)

Table 1. Distribution (%) of the position of chlorine substitution on chlorination of ketones with chlorine ~

CCI, solvent

~

MeOH solvent

33,4,67 CI

Cl

.\AJ b

Cl

CI

~~

129

App. 1. Synthesis and reactivity of a-halogenated ketones

formed. The change in the regiospecificity was a result of a change in the species undergoing chlorination (equation 283). The distribution of products in an apolar solvent depends on the formation ofenols (539aand 539b).In methanol the isomer distribution is a function of the amount of enol ethers (53thand 538b)formed. The amount of each enol ether formed will reflect the relative stabilities of the various substrates. It might be expected that the more substituted enol ether would be more stable so that chlorination would proceed on the more substituted carbon, but, this is not the case, and the less substituted a-carbon is favoured in methanol. Stability of the enol ethers appears to be dependent on steric effects. The most stable configuration of enol ethers is assumed to be syn (544) in which the alkoxy group is coplanar to and eclipsed with the double bond. It is favoured over the anti configuration (545). The syn relationship between the alkyl group on oxygen and the double bond in 544 increases the strain as substitution on the a-carbon increases. During chlorinations in methanol the formation of tetrasubstituted enol ethers is avoided and addition at a carbon having two substituents is not favoured. Me0 OMe

Y

CI

(538)

(539)

A

OMe

3 CI

I I ii

CI

(5390)

+c

CI

CI

CI

(542)

(543)

'0

R

(538b)

K

Me0 OMe CI

CI

(540)

Me0 OMe

)t"' CI

(541)

A

R

In all chlorinations a small but significant amount of chlorinated products corresponding to the formation of the more sterically hindered enol ethers is also present. Hence, steric considerations are of importance but may not be the only factors determining product distribution. Although chlorination of the enol is a minor competing pathway, it can always take place if the formation of an enol ether is too difficult. A recent kinetic study of the hydrogen chloride-catalysed chlorination of cyclopen-

Norbert De Kimpe and Roland Verhe

130

tanone and cyclohexanone turned out to be more complicated than expected. This is mainly due to the fact that the substrate and product themselves also act as basic catalysts and to the self-association of the ketones in carbon t e t r a c h l ~ r i d e ~ ' ~ * ~ ~ ~ . Selective a-chlorination of alkyl aryl ketones can be performed using hexachlorocyclohexa-2,4-dienone(546), while the use of sulphuryl chloride often resulted in chlorination of activated aromatic rings (equation 284)609.The selectivity of this reagent is based on donor-acceptor and hydrogen-bonding interactions between the reagent and substrate. The enolic form of the alkyl aryl ketones is capable of a donoracceptor interaction with this reagent. The trimethylchlorosilane-dimethyl sulphoxide system is an efficient reagent for smooth chlorination of aliphatic ketones on the more substituted a-carbon atom. Phenyl alkyl ketones are poorly reactive (equation 284)98

'.

v

EtOH

'

OH

Arq

R

+

CI

CI

CI CI

CI ( 546 1

n* +

Me2S=0

MeJSi-CI

+

Me2SOSiMe3

+

MeZSCI

+

+ -0SiMe3

U

0

0

It

R'-C-CH2R2

DMSO/Me,SiCI

-Me,S

~

c

+

CI-SMe2

U

w

II

R'-C-CHR~

I

I

CI

57-8 9 010

Polvchlorocvcloalkanones can be conveniently synthesized bv chlorination with chlorihe in DMF. Similarly, cycloalkenones and cyclohexanediols can be chlorinated by this method (equation 285)610-615. a-Hydroxyketones were chlorinated preferentially at the hydroxy position by application of (PhO),PC1,616. Inorganic chlorides, e.g. KCI, NaCI, NH,CI, AICI,, CaCI, and LEI, were employed as sources of CI- ions in the a-chlorination of aryl ketones in the presence of manganese(II1) acetate6' *. By this procedure 2-arylchroman-4-ones, 1-phenylpropan-1-one, 1,2diarylethanones and a-tetralone yielded a, a-dichloro derivatives in good yields. 2,2,2Trichloroacetophenones were obtained from 2,2-dichloroacetophenones,but in the absence of LiCI, 2,2-dichloroacetophenones gave 1,4-diaryl-2,2,3,3-tetrachlorobutane1,Cdiones (549). The formation of the dimeric products (549,550) suggests a radical nature of the oxidation of aryl ketones with Mn(OAc),/LiCI (equation 286). 's6'

App. 1. Synthesis and reactivity of a-halogenated ketones

3 8%

b0

R e f 610

DMF 'Iz

CI CI

86 "10

80-90%

Refs 613,615

CI CI

CI CI

95%

Ref. 614

131

Norbert De Kimpe and Roland Verhe

132

0

0

(547)

(548)

(180) R=aIkyl,aryl,CI

0

7

ArCOCHCl2

CI

CI

II I I A r c -C-C-CAr

0

I1

I 1CI

CI

\

ArCOCCI,

(549)

ii

TI Arc-C-0-C

i C l 2

I

\

hr

CI

( 5 5 01

(286)

A variety of a-chloromethyl, a, a-dichloromethyl and a, a, a-trichloromethyl ketones were synthesized starting from aldehydes, utilizing cathodic reduction as the key reaction. The intermediates were trichloromethylcarbinols (equation 287)619. 1 OH-

RCHCHC12

I

2.H+

OMe

RCHO

+e

CCIo CHCII ~

DMF

RCHCCI,

I

6H

Nan

Me1

RCHCCI,

I

QMe

1

f-BuOK

2 H30+

.

RCCHzCI

II

0

RCCHCI,

I1 ij

RCCCI,

I1

0

(287) a-Functionalized ketones such as a-hydroxyketones620and a-diazoketones621.622 were easily converted into a-monochloroketones using thionyl chloride and benzeneselenyl chloride, respectively (equation 288).

App. 1. Synthesis and reactivity of a-halogenated ketones

R2

133

- ”91.. pyridina

CI

OH

Rl-”\E-

R2

.

LiZcoI

1 R

l

W

R

2

CI

(288) This method represents an easy route to a-chloro-a, B-unsaturated ketones on further treatment with lithium carbonate. A highly efficient regiospecific synthesis of achloroketones consisted in the chlorination of B-keto esters with sulphuryl chloride followed by decarboxylation with 50% sulphuric This is a very useful method for the synthesis of a-chloromethyl ketones, which are otherwise difficult to obtain in large quantities6”. 3-Chloroalkan-Zones can also be synthesized in this way but not dichloromethyl ketones (equation 289). A similar preparation of 1-chloroalkan-2-ones is based on the chlorination of 2-acyl derivatives of Meldrum’s acid (551) followed by acid hydrolysis (equation 289)624.

(551)

Synthesis of a-chloroketones from enol ethers is an established strategy, and especially the conversion of silyl enol ethers using sulphuryl chloride or sulphuryl chloride fluoride

134

Norbert De Kimpe and Roland Verhe

has attracted much attention625.Reaction of silyl enol ethers with N-chlorosuccinimide gave disappointing results, however, in contrast with previously reported results (equation 290)626. OSiMe3

I

x

S0,CI CH,CI,

*

X=CI,F

72%

(118)

(11)

OSiMe3 I

50%

6'10

(553)

(118)

A more recent regiospecific synthesis of a-haloketones is the halogenation of enol ethers or enol esters using a lead(1V) acetate-metal halide reagent. These reagents supplement the use of reagents such as bromine, N-halosuccinimides, silver acetate-iodine and thallium(1) acetate-iodine for the conversion of enol ethers to a-haloketones (equation 291)627.

60-95°/o

R 3 = Me,Et,Ar,Me3Si M = Na,K,Ca,Zn X =CI,Br,

I

The silyl enol ether 555 is very reactive in ketene cycloadditions and with dichloroketene afforded an a, a-dichlorocyclobutanone (556) as the major product (equation 292)628.

82 010

(555)

(556)

Haloenol silyl esters (559) were converted into a-chloroketone derivatives by a

App. 1. Synthesis and reactivity of a-halogenated ketones

135

Mukaiyama-type aldol condensation, via condensation of enol ethers in the presence of boron trifluoride etherate (equation 293)629*630.

(558)

(559)

a-Chloro-S, y-unsaturated ketones have been prepared from a, p-unsaturated ketones such as mesityl oxide, phorone and pulegone by the action of hypochlorous acidh31. 4Phenylpent-3-en-2-one (561) yielded a 1 :1 mixture of the allylic chloride and the vinyl chloride. The reaction of conjugated ketones, wherein an addition-elimination process can lead to two different allylic chlorides, yielded mixtures of products with varying composition depending on the ring size and ring substituents (equation 294).

HOCl

71- 7 6 %

-

phyy 0

HOCl

phAo

(562)

(561)

1

(564)

+

0

ph%

563) 1

(565)

(566)

1

1

(294) O n the other hand, the reaction of methyl vinyl ketones (567) with methyl hypochlorite and boron trifluoride provided a mixture of 4-fluoro- (568) and 4-methoxy-3chloro-2-butanones (569) (equation 295)632.

136

Norbert De Kimpe and Roland Verhe

Hydrolysis of chlorinated enol thioethers, prepared by addition of sulphenyl chlorides to alkynes, gave rise to a-chloroketones. The addition can occur in an anti-Markownikov (AM) or a Markownikov (M) fashion according to the reaction conditions. The hydrolysis of the AM products afforded a-chloroketones whereas the M products were converted into a-chloroaldehydes (equation 296)633*634.

A specific synthesis of an a, a-dichlorocyclobutanone (573) has been performed by hydrolysis of a ketimine (572), which was prepared via dimerization of perchlorobutenyne (570) to 571 and reaction with tert-butylamine (equation 297)635.

App. 1. Synthesis and reactivity of a-halogenated ketones

137

A variety of methods have been developed for the synthesis of chloroketones from olefins. Photooxidation in pyridine in the presence of iron(II1) chloride converted monoand disubstituted olefins into a-chloroketones, while tri- and tetrasubstituted olefins gave dichloroketones with C-C bond cleavage (equation 298)636.637.

0

(298)

Cl

30 '10

(575)

The mechanism involved the formation of a chlorine atom by the photolysis of FeCI,, its addition to the less substituted carbon atom of the double bond, combination of the radical thus formed with molecular oxygen and hydrogen abstraction from the solvent to produce the /3-chlorohydroperoxide. The secondary hydroperoxides from mono- or disubstituted olefins gave a-chloroketones by dehydration (type A), while the tertiary hydroperoxides from tri- and tetrasubstituted olefins gave C-C bond cleavage as the main pathway (type B) (equation 299). Another procedure for converting chlorinated olefins consisted in chlorination with chlorine or calcium hypochlorite in the presence of sodium hydrogen arbo on ate^^'.^^^ or chlorination in DMF followed by hydrolysis (equation 300)640. [2 + 23 Cycloaddition of monohalo- and dihaloketenes with alkenes and dienes yielding mono- and dichloro functionalized cyclobutanones (582, 583) with high regioselectivity has been widely used, as illustrated by the equation 301628,641645. The olefin-dichloroketene [2 + 21 cycloaddition can be accelerated by ultrasonic irradiation. Short reaction times (20-60 min), high yields (70-90%) and the use of ordinary zinc instead of activated zinc (Zn-Cu couple) are significant advantages646. The ring opening or isomerization of 2-chlorooxiranes is an excellent pathway for the regiospecific synthesis of a-chloroketones. Rearrangement of the dichlorooxiranes (584) gave the isomeric a, a'-dichloroketones (equation 302)600. Ring opening of dichlorooxiranes with AgBF, can give the a-chloroketones via intermediate a-ketocarbenium ions, but the reaction products are strongly dependent on the substitution pattern of the oxirane (equation 303)599*600*647.

-

Norbert De Kimpe and Roland Verhe

138

hv

FeCI,

+

CI'

FeCI2

H abstraction

A

OOH CI

I

HOO

,--. '

CI

0

CI

xR2 .

. . *--.

R'

- H r

F O L R 2

R'

OOH CI

CI CI

20-40%

(576)

(577)

(578)

App. 1. Synthesis and reactivity of a-halogenated ketones

k -.

Me3Si0

139

Me3Si0

L

CI,CHCOCI

(581)

EtIN

CI

Ref 626

7 I ‘/o

(582)

CI

c12c=c

CI

c’)qo

/cI

CI

‘CHCOCI

I

CI

CI

585

CI

36- 46%

I-.+

CI

CI

(301)

Norbert De Kimpe and Roland Verhe

140

(584)

(586)

'-""A CI

(587)

Cl

7 8'10

(see)

CI

22010 (589)

(303)

Regiospecific synthesis of a-haloketones has been performed by the condensation of ahaloalkyllithium reagents with esters followed by hydrolysis of the lithium salts of the halohydrins (equation 304)648-65'. X

I R1-CH-Br

X

RLI -115 W T H F

I R1-CHLi

X

OLi

x

o

R*COOMO

X=CI,Br

I II R~-CH-C-R~ 50-00%

(304) Acylation of organomanganese(I1)chlorides with chloro- or dichloroacetyl chloride gave rise to chloromethyl and dichloromethyl ketones, respectively (equation 305)652.

App. 1. Synthesis and reactivity of a-halogenated ketones R'Li

or

R'MgCI

+ +

MnC12 MnCI2

141

or

+

R'MnCI

2LiCI

ClCHrCOCl

CI~CHCOCI

0

(305)

0

I1 R' CCH2CI

R'CCHC12

50-90%

50-90~/0

II

A facile synthesis of dichloromethyl ketones (60)is the reaction of dichloroacetyl chloride (590) with Grignard reagents (equation 306). With allyl- and methallylmagnesium chlorides the tertiary alcohols 591 and the dichloroacetyl derivatives 592 were obtained654. CI2CHCOCI

(690)

-

+

R'CHMgX

I

R2

c-

-78.C THF

CI2CHCOCH

/R1 R '2

(60)

' CTI -

1 7 O/o

The electroreduction with a magnesium anode of benzyl chlorides in the presence of anhydrides afforded a-chloroketones (equation 306)974. Dichloro- and trichloromethyl ketones (593)have been prepared by the ene reaction of trisubstituted alkenes with electron-deficient nitriles in the presence of boron trichloride (equation 307)6s3. A general route to y, &unsaturated a, a-dichloroketones (597) from allyl 2,2,2trichloroethyl ethers (595) via the [3,3]sigmatropic rearrangement of intermediate 2,2dichlorovinyl ethers (5%) has been developed. The products can serve as effective synthons possessing three functional groups (equation 307)6ss*656. C. Synthesis of a-Bromoketones

The synthesis of a-bromoketones has been focused on the use of mild brominating agents in order to avoid the disadvantages of bromine and the many side-reactions due to its use. A novel reagent for a-monobromination of 3-keto steroids is benzeneselenenyl bromide. Whereas 3-keto Sa-steroids always gave the 2a-bromo compound, 3-keto-SBsteroids lead to the kinetically controlled 4B-bromo steroid, which isomerized to the thermodynamically stable 2B-bromo-3-keto steroid (equation 308)97s.

142

Norbert De Kimpe and Roland Verhe

70-90%

R 4 = CHClZ

, CCI,

ROH

R

(594)

CI

CI

a]Og]‘:a

0

H

(308)

PhSaBr_

Br

H

H

The use of polymer-supported bromine, such as poly-(4-vinylpyridine~tyrene)bromine~~’, and of bromine in the presence of crown ethers has been developed658

App. 1. Synthesis and reactivity of a-halogenated ketones

143

and the use of brominated complexes was stimulated owing to the mild reaction conditions, high yields and easy recovery of the brominating agent. 3-Bromoimidazo[1,2-b]pyridazine bromine and 3-bromo-6-chloroimidazo[l,2blpyridazine bromine (598,X = CI) gave monobromoketones when used in equimolecular amounts (equation 309)659.

X=CI,H

Br

0

?Lo

Br0

(309)

H

(600)

Also 4-(dimethy1amino)pyridiniumbromide perbromide (599)(equation 309) gave nearly quantitative yields in the a-bromination of aromatic ketones660, and 5 , 5 dibromobarbituric acid (600)was used in neutral medium to monobrominate saturated and unsaturated ketones661. tert-Butyl bromide-dimethyl sulphoxide has been used in the preparation of 2-bromo1-phenylpropanone (287) and 2-bromo-1-phenyl-2-methylpropanone (160). With acetophenone. however, phenacyldimethylsulphonium bromide (601) was obtained directly (equation 310)662*663.

\!R

/

t - BuBr -DMSO

Ri=R2=H

(160) R1= R2 = Me

,

(2 87) R’ = H R2 = Me

&gM-:

(601)

A similar reagent, trimethylbromosilane-dimethyl sulphoxide, introduced a bromine atom at the more substituted a-position of ketones9*’. Regiospecific monobromination was also observed on treatment of ketones with hexabromocyclopentadiene. For example, butan-2-one was converted into 3-

Norbert De Kimpe and Roland Verhe

144

bromobutan-2-one in 82% yield664. One-pot a-bromoacetalization of carbonyl compounds has been realized by reaction of ketones with 1-2 equivalents of phenyltrimethylammonium tribromide in THF-ethylene glycol (1:1) (equation 31 l)665. The a-bromoacetals are useful precursors to a, fl-unsaturated ketones, particularly in cyclic systems where the dehydrobromination is complicated by side-reactions. 0 Rl-C-

n 9

+

II

R~-C-CH-R~ 0 ,

PhNMe, Br-

(31 1)

I

Br 70-90%

Tetrabutylammonium tribromide has been very useful for the selective a-substitution of acetals666and in a convenient one-pot synthesis of l-bromo-4,4-diphenylbut-3-en-2-one (603)from l,l-diphenyl-3-(ethylenedioxy)butan1-01 (602) (equation 312)667.

93 % (60s)

(602)

N-Bromosaccharin (NBSac) has been used in benzylic and a-carboxylic bromination668. This reagent is sometimes superior to NBS, e.g. in the preparation of aphenylphenacyl bromide (91% versus 71% yield). However, bromination of several methyl vinyl and methyl aryl ketones gave lower yields than with NBS. The reaction requires visible or ultraviolet irradiation or the presence of a free radical initiator. However, a longer photostimulation could lead to dehydrobromination. The addition of halogens to a, fl-unsaturated ketones has been extensively studied. Bromination in methanol of (E)- and (Z)-2-chloro-l, 3-diphenylpropenone (604) led exclusively to the solvent-incorporated adduct 2-bromo-2-chloro-3-methoxy-1,3diphenylpropan-1-one (605). Chlorination of the 2-bromo analogue yielded a mixture of the 2-bromo-2,3-dichloro compound 606 and 605 (equation 313)669. 0

0

II

I

OMe

(605)

+

145

App. 1. Synthesis and reactivity of a-halogenated ketones

The acid-catalysed reaction of NBS in methanol with a, p-unsaturated ketones gave /Imethoxy-a-bromoketones670whereas the reaction with BrCl furnished /I-chloro-abromoketones (608) (equation 3 14y7'.

R* R1*4 OMe 0

ao- toovo

4

CI

Ph

br

( 607 1

100%

(606)

As the addition occurred regiospecifically, the mechanism cannot involve electrophilic attack of halogen on the C=C bond, and may involve either an initial attack on the oxygen or an initial addition of a trace of HCI to give a highly reactive enol (equation 3 15).

) + CI

OH

BrCl

CI

OH

CI

(315)

8-Fluoro-a-bromoketones (610) were formed when a, /I-unsaturated ketones (609)were treated with BrF. However, an easy H F elimination can take place, eventually producing a-bromoenones (611) (equation 316)672.

Norbert De Kimpe and Roland Verhe

146

90O/o

(610)

(609)

(611)

Other elegant procedures for the production of bromomethyl ketones have been established. The reaction of terminal olefins with NBS in aqueous acetone gave 1bromoalkan-2-ols, which were subsequently oxidized (equation 3 17)673.

R

A

-

RNBS

-

aq.mepCO

CrO,

R

Heso4

(3 17) B-Lithioenamines (613), prepared by the action of alkyllithium reagents on Bhaloenamines (612) through deprotonation, were transformed into bromoketones (160) via alkylation, bromination and subsequent acidic hydrolysis (equation 3 18)674.

-

R'

R' Li

(612) X = halogen

1%

(614)

(611)

R'

.

R'

+

"30

ph+Br

NMe,

Bromomethyl ketone enolate anions, generated by the reaction o esters with (dibromomethy1)lithium followed by n-butyllithium, could be quenched with acid to afford bromomethyl ketones or with acetic anhydride to afford bromoenol acetates or treated with tert-butyllithium to produce a-keto dianions (equation 3 19)651. An excellent synthesis of chiral bromoketones has been developed via enantioselective deprotonation of symmetrically substituted ketones under kinetically controlled conditions using a strong hindered chiral base (equation 320)976.

App. 1. Synthesis and reactivity of a-halogenated ketones

147

OLi

I

RC-CHBr2 I bEt

I

n-BuLi

?Li

RCOCH2Br

H+

70- 0 5 %

?Ac

I RC=CHBr

I

Ac20

+

I

RC=CHBr

(319)

t-BuLi

OLi

I

RC=CHLi

OSiMe3 Ms,SiCI

b

1

RC=CHSiMe3

ii D. Synthesis of a-lodoketones

A recent direct regiospecific synthesis of a-iodoketones involves a direct iodination of carbonyl compounds with mercury(I1) chloride and iodine (equation 321)675.

The reaction takes place under acidic conditions owing to the formation of hydrogen chloride. The iodination agent seems to be first (HgIClJI' and in a second step (HgI,CI)-I+ because the reaction is carried out using a 1 :2 mercury(I1)chloride to iodine molar ratio, the I + being the electrophilic agent. Unsymmetrical ketones give only the internal a-iodo derivatives, whereas cyclic ketones give the corresponding achloroketones in 100%yield. The synthesis of cyclic a-iodoacetals was described for the first time in 1984676. a-Iodoketones were recently synthesized by treatment of a-chloro- or a-bromo-ketones with sodium iodide in acetonitrile (equation 322)677.

148

Norbert De Kimpe and Roland Verhe

No1 or KI MeCN

Rl+Rz

Cl

.

0

I

E. Optlcally Active a-Haloketones So far little information is available concerning the preparations and reactivity of optically active a-haloketones. Owing to the increasing interest in the asymmetric synthesis of natural products and pharmaceuticals, it can be expected that chiral ahaloketones will be valuable bifunctional intermediates in the synthesis of enantiomerically pure compounds. Optical resolution of racemic a-haloketones is difficult because of their reactivity and the lack of resolving agents for carbonyl compounds. The synthesis of optically active ahaloketones has been carried out by halogenation of optically active ketones obtained by resolution of racemic compounds or from natural sources989.Direct asymmetric synthesis of 2-bromocycloalkanones involved bromination of cycloalkanone enamines of L-proline esters followed by hydrolysis (e.e. 15-31%)990 and bromination of chiral enolates (equation 320). Optically active aryl 1-chloroethyl ketones have been prepared from optically pure (R)- and (S)-2-~hloropropionylchloride by Friedel-Crafts reaction or by Grignard reaction with the corresponding aromatic derivatives. A slight and variable loss of enantiomeric purity (< 15%) related to the starting acids has been ~ b s e r v e d ~ ~ l . ’ ~ ~ . Chiral aryl a-bromoalkyl ketones were prepared via bromination with bromine of enantiomerically pure acetals derived from alkyl aryl ketones and the dimethyl esters of (2R, 3R)- and (2S, 3s)-tartaric acid followed by hydrolysis, without racemization, by treatment with methanesulphonic acid in methanol993.These a-haloketones were easily transformed into optically active 2-arylalkanoic acids, which are highly efficient antiinflammatory d r u g ~ ~One ~ ~enantiomer , ~ ~ ~ (. S ) showed higher biological and pharmaceutical activity than the other. 111. REACTIVITY OF a-HALOGENATED KETONES

A. Introduction

Further insight into the mechanisms of nucleophilic substitutions of a-haloketones has been gained in the acetolyses of a-phenoxy and a-thiophenoxy-a-chloro ketones6” and 1chloro-3-phenoxy-l-phenylthiopropan-2-ones679. The acetolysis of a’-arylthio- and a’aryloxy-a-chloroketones (616) has been shown to proceed through the enolizationsolvolysis mechanism, and the products arise from a normal substitution (619), cine substitution (617) and an elimination (618) (equation 323). The ratio of the solvolysis products 617 and 619 to 618 is largely dependent on the absence or presence of acetate ion. The easier solvolysis of the thioethers can be ascribed to the more efficient participation by sulphur in the ionization of the enol allylic chlorides and the accompanying delocalization of the charge in the cationic species involved in the solvolysis. The role played by the neighbouring heteroatom was further investigated with the achloroketones 620 and 624 (equations 324 and 325).

App. I. Synthesis and reactivity of a-halogenated ketones 0

II

HOAc KOAc

PhZ-CH-C-CH2CI

I

149

OAc 0

I

*

PhZ-C-C-CH3

0

II

+

I

PhZ-C-CCH3

I1

R

R

(617)

(616) Z=O,S

R

R =H,Me,i-Pr,Ph

(618)R'=H,Me

0

+

II

P hZ -CH

I

-CII -CH20Ac

R'

(619)

0

I

OH

OH

I1

slow

PhZ-CH-C-CH2CI

I

P h.q Z - C - A-CH2OI

I

R

R

PhZ\

U

I

(323)

0

II

I

R

4c+

Ce + .CH2 R

(616)

PhO-CH-C-CH-SPh

CI-

HOAc

I

0

OAc 0

II

PhO-CH-C-CH-SPh+

I

CI

R

I

I

R

OAc

(6211

(620)

II

I

PhO-C-CCH2SPh

(622)

0

+

II

RC-C=CH-SPh

I

OAc

(623)

(324)

0

0

II PhO-CH-C-CH-SPh

I Me

I

CI

(624)

HOAc KOAc*

Me-CH=C-CSPh

I

OAc

(625)

II

+

PhO-C-CH2SPh

II

CH2

(626)

(325) Different mechanisms are clearly operative in the acetolyses. The a-acetoxyketone (e.g. 621) is formed by solvolysis via the intimate ion pair (627), whereas, preliminary enolization of the substrate to the enol allylic chloride (628) is required for the formation of the isomeric a'-acetoxyketone (e.g. 622) which may originate via an ion pair (629, 630) (equation 326).

150

Norbert De Kimpe and Roland Verhe OH

0

I

I1 t C-CH-SPh

PhO-CH-

I

PhO-C=C-CH-SPh

I

CI-

R

-

(627) OH

P hO -C =C

I

I

+

-C H -SP h CI-

R

R

(628)

I

CI

OH

I

c

P hO -C d G - 3 CH -S P h

I

CI-

R

(629)

(326)

(630)

The formation of the unsaturated compounds 623 and 625 can be ascribed to intramolecular trans-acylation, ultimately leading to fragmentation of the acetoxyketones (equation 327). R

OAc 0

I PhO-C-C I

II

-CH2-

SPh

R

-PhO-

R -C-

II

0

C =CH

-SPh

I

OAc

(623)

(327)

0

I1 P hO -C H -C -C H -S Ph I I Me

OAc

(6311

Me Me-CH=C-C-SPh

0

I1

I

OAc

(625)

B. Reaction of a-Haloketones with Oxygen Nucieophiles and Bases

Several reagents that serve as nucleophilic sources of oxygen which replace the halogen have been developed. 1 , Reaction with inorganic oxygen nucleophiles

Attempts have been focused on procedures and reagents to provide the desired reaction

App. 1. Synthesis and reactivity of a-halogenated ketones

151

pathways exclusively and selectively. During the synthesis of daunomycinone derivatives a clean conversion of the bromoketone 632 to the corresponding hydroxyketone 633 was performed with cold dilute sodium hydroxide, presumably via a carbonyl-participating hydrolysis mechanism (equation 328)680,681.

0

0 0

(632)

NaOH

.0

0

T HF/ H ~ O

0

oc

0

0 5 '/o

(633)

1328) High yields of a-hydroxyketones were obtained using a combination of water and the polar aprotic solvent N-methyl-2-pyrrolidone in the presence of sodium hydrogen carbonate6*'. Base-catalysed oxygenation of a-bromo-a-methylcyclohexanones with sodium hydroxide (MeOH-H,O) and oxygen furnished the tetrahydropyrancarbolactone 634. The oxygenation proceeds via the hydroxy derivative and the oxy radical 636, generated from the corresponding oxyanions, is possibly involved in the carboncarbon bond cleavage. Similar treatment of 635 gave the keto acid 637 (equation 32Y)683.

64' A

(634) O*~"O"

6

B

HO

r

0

Norbert De Kimpe and Roland Verhe

152

Polychlorocyclopentenones (638) were smoothly hydrolysed to the enol of cyclopentane-l,2,4-triones (639)by sodium hydroxide in aqueous methanol (equation 330)612.

(6 38)

-90%

(639)

Synthesis of a, /?-unsaturated ketones from a-haloketones by the action of an alkali can be a very efficient procedure. The trichloroketone 640 gave with sodium carbonate the chlorinated unsaturated ketone 641, which can be transformed to the imidazoles 642 by condensation with acetamidine (equation 33 l)684.

75 %

(640)

(642)

The cyclopentane-dione 644 and -trione 647 can be prepared from the cyclopentanone 643 and cyclopentenone 646,respectively, by reaction with aqueous sodium hydroxide (equation 332)610.

(643)

(645)

(332)

(646)

6-Chloro-2-hydroxyisophorone(648) can be dehydrochlorinated with NaOH to yield a 2,5-cyclohexadienone (649), useful as a flavoring additive (equation 333)61I . An excellent synthesis of the flavones 651 involves cyclocondensation and elimination of chalcone dibromides (650) under the influence of potassium hydroxide (equation 334)685 . 6 8 6 .

153

App. 1. Synthesis and reactivity of r-halogenated ketones

(650)

(651)

A stereoselective and versatile synthesis of 3-substituted-2,2-dimethylcyclopropanecarboxylic acids (653 and 654) can be performed via a Favorskii rearrangement (equation 335). The 2,4-cis-isomer of 2-halo-3,3-dimethyl-4-(2.2,2trihaloethy1)cyclobutane (652) can be transformed predominantly to ciscyclopropanecarboxylic acid (653) (cis:rransratio = 10: 1). Further treatment results in cis3-(2,2-dihalovinyl)-2,2-dimethylcyclopropanecarboxylicacids (654). Esters of these acids are some of the most potent pyrethroids, known for their excellent insecticidal activity. The base-induced ring contraction of 2-halocyclobutanones proceeds via a semibenzilic acidtype mechanism (equation 335), differing from that in 2-halocyclohexanone, which proceeds via an unstable cyclopropanone intermediate644*66'.

-x^y X

NoOH

b x 3 c ~ c 0 0 HNoOH

HZO RT

&%

Me

0

Me

HZO 100 o c

Me

Me

OoH

0H

(335) The cis:trans ratio in the cyclopropanecarboxylic acids depends on the nature of the solvent and the temperature. Higher temperatures gave higher amounts of the transisomer (cis:trans ratio = 83: 17 at - 8 "C and 59:41 at 33 "C).Addition of ethanol and dioxane decreased the cis:trans ratio (dioxane, 75:25; ethanol, 68:32; toluene, 89: 11 )645. Treatment of the monochiorocyclobutanone 95 with an aqueous solution of sodium carbonate afforded the cine-substitution products 655 and 656 in a 2 : l ratio (equation 336)688.

Norbert De Kimpe and Roland Verhe

154

(655)

( 9 5 ) R=CH*CCIs

(656)

Deprotonation and intramolecular nucleophilic substitution leading to a dibrominated dicyclopropyl ketone was observed when an a, a', y, y'-tetrabromoketone (657) was treated with sodium hydroxide in diethylene glycol. The ketone 658 could not be obtained by direct bromination of the dicyclopropyl ketone (equation 337)689.

-dia NaOH

rB +rB Br

Br

(337)

Br Br

(657)

2 4 o/'

(658)

2 Reaction of a-haloketones with organic oxygen nucleophiles and bases

The reaction of a-halogenated ketones with alcohols in the presence of a base can give rise to a variety of products, as exemplified by the reaction of a-chlorocyclohexanone (1 18). O n treatment with sodium methoxide in methanol it afforded a mixture of amethoxycyclohexanone (659),methyl cyclopentanecarboxylate (213) and 1 -methoxy-7oxabicyclo[4.1 .O]heptane (660) (Equation 338)6'". &Cl

NaOMe

&OMe

+

MsOH

0+ COOMe

(659)

O

4 0'/o

28%

(213)

(660)

3% (118)

O

M

e

(338)

Other examples involve the reaction of 2,2-dihalo- 1,3-diphenylpropan- 1-ones (661,664 and 666)with isopropoxide and methoxide ions691,the iodine oxidation of arylacetones (669,672 and 674) in alkaline methanol692and the reaction of dichloroketones (677) with methoxide ion (equations 339-341)693.

(339) Br Br

(664)

Br

(665)

phg

155

App. 1 . Synthesis and reactivity of a-halogenated ketones Ph

CI

p

ji-PrONa -pro~

h

T

CI

c

'

CI

(666)

(6671

ph-lT-ph

(668)

COOMe

'2

NQOM0

0

Ph

(672 )

(673)

bl

52 %

A

-50

OC

1 3 *A

(680)

Meo+ Me0

+

1 6 *lo

(681)

+ &OM.

COOMe

+

-COOMe

(679)

0

(678)

OMe

+

(677)

13 %

(676)

(675)

(674)

+cl

+ PhCOOPr-i

0

& +& OH

Me0 OMe 1%

Me0

(682)

+ &ClMe0

OMe 1%

(683)

OMe

i%

3%

(684)

(685)

(341)

Changes in the conditions and in the nature of the ketone can influence to an appreciable extent the Favorskii rearrangements of a-halogenated acetylcycloalkanes,

156

Norbert De Kimpe and Roland Verhe

especially the stereochemistry and the competing formation of a - h y d r o x y k e t o n e ~ ~ ~ ~ . ~ ~ ~ . The complex stereochemical results of Favorskii rearrangements of ahaloacetylcycloalkanes, in particular of a-halo-20-keto steroids, in which cyclopropanones are considered to be intermediates, can be explained by the assumption that two mechanistic pathways may be operative, in some cases simultaneously. In one (route a), corresponding to a 'Loftfield-type' mechanism, the initially formed enolate is converted directly, concertedly and stereospecifically into a cyclopropanone, which is then opened to give rearrangement products with a unique stereochemistry at the originally halogenated carbon atom. In the other (route b), which corresponds to a 'Dewar-type' mechanism, the enolate is first transformed into a dipolar intermediate which may lead to two epimeric cyclopropanones, which are opened to give epimeric rearrangement products. A polar and protic medium would favour the formation of a dipolar intermediate whereas a non-protic and mildly polar medium would give a 'concerted ring closure' (equation 342).

(342) Engel and C O W O ~ have ~ established ~ ~ S ~that~ the~ formation ~ ~ ~of a~ dipolar intermediate prior to the formation of cyclopropanones can be ruled out. Indeed, an identical dipolar intermediate would have to be formed from both 21 -bromopregnenolone (686) and 17-bromopregnenolone (687), giving rise to the same mixture of rearrangement products.

AcO

AcO

(686)

(687)

This is true when the reaction is carried out in highly protic and polar medium (hydrogen carbonate-water-methanol), which should favour a dipolar intermediate, but

157

App. 1. Synthesis and reactivity of a-halogenated ketones

diametrically opposed stereochemical results were obtained in an aprotic medium (sodium methoxide-dimethoxyethane). The conclusion can be drawn that in an aprotic and mildly polar medium the reaction is concerted, that in a protic and polar medium a delocalized intermediate is involved and that in media of intermediate protonicity and polarity a concerted and non-concerted pathway may be operative simultaneously. The stereoselectivity, however, is strongly influenced by the presence of the 18-methyl function and its absence results in a significant diminution of the stereoselectivity.Also, the substitution was strongly influenced by the reaction medium and steric factors (methyl group in the 18position). A high proportion of substitution products was observed in dimethoxyethane, whereas in methanol virtually none were formed with 686.The epoxy ether formation is favoured in aprotic medium (equation 343).

xxo

I

'.._.

I

I

I

/

Favorrkii

xoR I

'.

.-A

I

,

(343)

In the case of the 17-bromo compound the complete absence of substitution products in all media is ascribed to the steric hindrance exerted by the angular methyl group, as proved by the high proportion of substitution product generated from the 18-nor compound in all media. The occurrence of competing reaction pathways constitutes a serious limitation in the useful conversion of a-haloketones into oxygenated carbonyl compounds and efforts have been exerted to obtain the desired compounds without contamination by side-products. When 2-chloro- and 2-bromopentan-3-one were allowed to react in methanol, ethanol and propan-2-01 and the corresponding sodium alkoxides were added, the hemiacetals of cis-2,3-dimethylcyclopropane(689) could be formed in a highly stereoselective manner, when the alkoxides were slowly added to the a-haloketone and an excess of base was

158

Norbert De Kimpe and Roland Verhe

avoided. When the a-haloketone was added to the methoxide solution, the a-methoxyketone 690 and the Favorskii ester 691 were formed. Reaction with methanol in the presence of triethylamine gave the methoxyketone 690 (equation 344)696.

A

X

I

30

I

NaOR

ROH

RT

Me

Me

2 7 - 70

(344)

(689)

690 50%

0

t

COOMe

609 41 '/a

9v e (691f

100%

(6901

The formation of the product is explained by the formation of a cyclopropanone (692) which is in equilibrium with an oxyallyl species (693) with a W-configuration, as illustrated in equation 345.

4- 0

bass -HX

MeOH

The formation of 8-oxabicyclo[3.2.I]oct-6-en-3-ones (694) in the reaction of a-haloketones with furans in the presence of methanol and triethylamine is explained by a stereoselective [4 + 3]cycloaddition with the respective oxyallyl species (equation 346)696-698.

X

(694 1

The oxabicyclic compounds were also formed using lithium perchlorateor sodium 2,2,2triethylamine699*700, trifluoroethanol-triethylamine

App. 1. Synthesis and reactivity of a-halogenated ketones

159

t r i f l u o r o e t h ~ x i d e ~and ~ ’ silver t e t r a f l u o r o b ~ r a t e ~2-(Trimethylsiloxy)allyl ~~. cations generated from various 2-(trimethylsiloxy)allyl chlorides with silver perchlorate showed iden tical reactivity 3. Other regiospecific reactions include the synthesis of the glyoxal derivatives 6%-698 by treatment of the a-chloro-a-(aryl- or alky1thio)ketones 695 with methanol or with sodium methoxide in methano1704 and the formation of the a-hydroxyacetal 699 from ubromopropiophenone (287), which served as an excellent precursor for a-arylalkanoic The Favorskii rearrangeesters (700)(potent anti-inflammatory and analgesic a~tivities)”~. ment of the y, &unsaturated a, a-dichloroketones 701 afforded the unsaturated esters 702, which could be converted into the unsaturated y-lactones 703 (equation 347)655*656.

4’

(696)

MeOH, 15

(695)

I

J

R~=MO

phYsMe

NaOMe,2 equiv. OC

OMe (697) OMe

MeOH

15 OC

R’\ri\...

0

OH

(700)

( 699)

(701)

(702)

(703)

The substitution pattern can also have an important influence on the nature of the products. Whereas o-nitrophenacyl bromide (704) gave a mixture of the keto epoxide 705 and the bis-epoxy compound 706 on treatment with sodium methoxide, the para isomer afforded only 706 (equation 348)706. Tertiary a-bromoalkyl aryl ketones were converted exclusively into 1-alkoxy- 1aryloxiranes by reaction with excess potassium carbonate in the corresponding dry alcohol. Secondary a-bromoketones afforded a-hydroxyacetals resulting from ring opening. Reaction with silver carbonate in dry methanol yielded competitively 2alkoxyoxiranes and a semi-benzilic rearrangement product. With silver hexafluoroantimonate in methanol the r-bromoketone afforded the latter product exclusively (equation 349)707.

Norbert De Kimpe and Roland Verhe

160

0

NaOMe

(705)

Br

The Favorskii rearrangement took place via a mechanism by which the methanol adduct undergoes a silver-assistedionization of the carbon-halogen bond with migration of the phenyl group. Whether or not a-acylcarbenium ions are involved is still a point of discussion. The hemiacetal could also be deprotonated to afford oxiranes. It seems that a less basic silver reagent would give a Favorskii-type rearrangement exclusively whereas a basic non-silver reagent eliminates the rearrangement. Silver or zinc bromide induced methanolysis of a-bromoalkyl aryl ketones, providing a-arylalkanoic esters in moderate to good yields together with a-methoxyketones (equation 350)708-710.

Arb:: Br

R' R 2 ZnBr, /MeOH or Ag2C0,/BF,-MeOH*

Ar

5 0 - 0 5%

(350)

161

App. 1. Synthesis and reactivity of a-halogenated ketones

An iron(II1) chloride-catalysed oxygenation of a-halocyclohexanones in methanol yielded adipic acid dimethyl esters (708). Without oxygen the reaction afforded the dehydrohalogenation product. A plausible mechanism involves dehydrochlorination of the pseudo-acid intermediate yielding an enolate intermediate, which is successively attacked nucleophilically by methanol (equation 351)71'. 0

(351)

The reaction of a-haloketones with phenols gave a variety of U-heterocyclic compounds. 1,4-Benzodioxane derivatives (709) have been formed with catechol and pyrocatechol under basic conditions712 * 713, and benzofuran compounds (710 and 711) were produced via cyclocondensation with hydroxy-substituted aromatic carbonyl compounds (equation 352)714-718.

ePh

R e f . 712

(709)

OH

0

I1

ph/c\/e'

+

0

K2C03,

W

P

h

Ph

(710)

R e f . 714

- Q T p 0

90%

R e f . 716

(7111

(352)

162

Norbert De Kimpe and Roland Verhk

Similar cyclocondensations with 2-aminophenols and 3-hydroxypyridine-2-thioneprovided 1,4-benzoxazines(712)"' and I , 4-pyridothioxines (713)"', respectively (equation 353).

34 - 5 6 % (712)

(353)

(713)

Reaction of phenacyl chlorides and a-haloisobutyrophenones with nitronate anions afforded C-alkylation products by a radical chain mechanism (SRNl)721*722. While the phenacyl chlorides gave the elimination products (714), the free-radical substitution of the isobutyrophenones is photostimulated and occurred in competition with ionic reactions, leading to oxiranes (716) and hydroxyketones (717) (equation 354). ArCOCH2CI

+

25 'C

Me2C =NO:

( ArCOCH2CMe2N02)

1

DMSO

ArCOCH=CMe2

(714)

SR,l mechanism: RCOCH,X RCOCH2X-' RCOCH,' + N U RCOCH,Nu-' RCOCH,X

+

RCOCH,X

+ Nu-

-

eRCOCH,X-' RCOCH,'

+X-

RCOCH,Nu-' RCOCH,Nu + RCOCH,X-'

-

RCOCH,Nu

+X-

(354)

163

App. 1. Synthesis and reactivity of a-halogenated ketones

However, reaction of a-haloketones with sulphinate anions mainly gave sulphone substitution products (718) (equation 355)722-723.

R+ lR2

R3

+

+/O-

R4-S

.-.

R'%R2

(355)

R3

h t 0 '

CI

o+R4

0

(718)

New syntheses of furan and isoxazole derivatives were found by using alkylation with ahaloketones on oxygen atoms. Reaction of 2-bromocyclohexanone (719) with (aformylethylidene) triphenylphosphorane (720) gave the oxophosphorane 721, which could be converted to isomenthofuran (722)724.Furylium cations (725) were prepared via the condensation of the sodium enolate of 3,4-dimethoxyacetophenone (724) with an tlbromoisobutyrophenone (723)'2', while the sodium salts of a-oximinonitriles (727) were converted into isoxazoles (729) via alkylation with phenacyl halides and subsequent ring closure (equation 356)726.

+

PPh3

Br

+

Ph3PC(Me)CH0

-d

(720) (719)

-Q^" + Br

Me0 OMe

(723)

qA

Me0

2 , mHCI ,x

.

B r

'

* I I

(720

1 . Bus2.HgS.0,

M eO OMe

(724)

OMe

OMe

(725)

OMe

164

Norbert De Kimpe and Roland Verhe (72 6) LIAIH,

1

1

OMe

OMe

55v e (726)

75 %

R =electron- withdrawing

I

(728)

group

qP LiOH

R

0

40- 60% (729)

(356) C. Reaction of a-Haloketones with Nitrogen Nucleophiles and Bases 1. Reaction of a-haloketones with amines

In this section, reactions of a-haloketones with amines which d o not give rise to ahaloimines and j-haloenamines will be described. The former are treated in another chapter and the latter are not discussed (see leading references 983 and 984). Reactions of ahaloketones with ammonia may give rise to heterocyclic compounds. Reaction of achlorocyclohexanone (118) afforded octahydrophenazine (730)727,while trans-aziridines (732) were formed from a,p-dibromoketones (731) (equation 357)728.Attempted dehydrohalogenation of a-bromo-a'-methylaminoketones using sodium amide in liquid ammonia produced p-lactams (733), probably via a quasi-Favorskii pathway. The suggested mechanism is depicted in equation 358730.Primary a-aminoketones are obtained by the treatment of a-haloketones with hexamethylenetetramine (equation 359)729.

a>n

a;l

App. 1. Synthesis and reactivity of a-halogenated ketones

:No:3

(118)

165

45-97%

(731)

(732) Me

R

NH

Me

1

B~

Ar

1 . (CH2),N, 2.HCI/EtOH

NH2.HCI

Ar

(359)

a-Haloketones and primary aromatic amines often yield imines or substitution prod u c t ~ ’ ~A ’ . special case is the synthesis of a-iminoketones (735)from a-chloro-a-alkoxy ketones (734) with aliphatic amines (equation 360)732. .R

R’O

2

CI R ~ N H ~

Ph%

R ~ CI2 CH2 N H ~

0

P

h

4

0

(360)

166

Norbert De Kimpe and Roland Verhe

a, a'-Dibromoketones (736) react with primary amines to provide a-iminoketones (737)

and a-diimines (738)(equation 361)733in variable ratios. Isopropylamine afforded 737 as the major product but less sterically hindered primary amines produced increasing amounts of 738, while sterically hindered ketones gave Favorskii rearrangement products733.The formation of 737 and 738 results from a more favourable nucleophilic action of the primary amine compared with the more basic and less nucleophilic secondary amines, which give Favorskii rearrangement. Aminolysis of a-bromoketones (736) via delocalized carbenium ions yields intermediates (739) which are converted to 737. Excess of amine causes the transformation of 737 to 738 (equation 362). /

n

n

Br

Br

N

R3

N R '3

(736)

(737)

(738)

9Br

Br

Br

Br

(736) OH

(737)

YH

(738)

(362)

The reaction of primary aromatic amines with a-haloketones is an attractive route to and carbazole derivatives (741) (equation 363)735-737. indoles (740)734*735 Cyclocondensation of a-haloketones with primary heterocyclic amines afforded condensed imidazole systems (742) with a common nitrogen atom (equation 364)738-744. The mechanism of the formation of imidazo[ 1,2-a]pyridines (746) from a-haloketones and a-aminopyridine has been studied in detail and two relatively long-lived intermediates (743 and 744), which are in equilibrium with each other, have been detected (equation 365)739.

App. 1. Synthesis and reactivity of a-halogenated ketones

(740) R e f . 735

& Ref. 736

+

(743)

A

&NH2

I

(744)

H

(741) R e f . 7 3 7

167

168

Norbert De Kimpe and Roland Verhe

Path (b) seems to be favoured over (a) as the transition state for the displacement of halogen, activated by an adjacent carbonyl group, is of lower energy than that for the addition followed by intramolecular displacement. Also, the reaction of 2-aminopyridine1-oxide and phenacyl bromides afforded 2-heteroary1imidazoC1,2-a]pyridin-3-ols (747) (equation 366)745.

OH

(747)

Several b e n ~ o x a z i n e s ~pyridooxazines ~~, and pyrid~thiazines'~~ (748) were obtained when 2-aminophenols and 2-aminothiophenols were treated with a-haloketones. A similar cyclocondensation took place with 1-amino-2-pyridones and 1-amino-2triazolethiones, yielding p y r i d o o x a d i a z i n e ~and ~ ~ ~triazolothiazines (749) respectively (equation 367)749.

I

NH2

R1

Y = 0,s

(749)

Stereoisomeric thiazanes (750) were prepared by cyclocondensation of aminothiols with a-halomethyl ketones (equation 368)750.

R' L

X

.

ROOC

XSH-/Q NH2

R'

H

(368)

COOR

(750)

Dehydrobromination of a-bromocycloalkanones with aniline yielded cyclic a, 8c y c l ~ a l k e n o n e*. s ~a-Haloketones ~ with a-aminoketones (751) could also give rise to substitution products (752), as exemplified by the synthesis of 3-ketopiperideines (753) (equation 369)752. Other reaction pathways included the formation of a ~ i r i d i n e s ~ and ' ~ of chlorinated amides (equation 370)753.

App. 1. Synthesis and reactivity of a-halogenated ketones

R‘

ACCI3

R’=CHCI2,CCl3,

+

R*NH2

MeCC12

R‘

NH/R2

169

(370)

83-1 00%

In general, the reactions of a-haloketones with secondary amines afford a-substitution p r o d u ~ t s ’ ~ ~ -Diethanolamine ~~’. reacted with 2-bromo-1-arylethanones with the formation of 2-hydroxymorpholines (754)758,while aminosulphuration with the formation of thioamides (755) was observed when chloroketones reacted with morpholine in the presence of sulphur (equation 371)759. 0

5

HO

7 3%

(755)

Reactions of a, j-dibromoketones with imidazole give both substitution and dehydro1-imidazo1yl)enones(756) (equation 372)760. bromination, yielding j-(

170

Norbert De Kimpe and Roland Verhe

Br

(756)

aNHR ay

Formation of indoles (757) took place when 2-N-alkylaminobenzoic acids were treated with chloroacetone (equation 373)761.

+

COOH L

OH

(373)

(757)

A highly unusual condensation occurred when 3-chloro-3-methylbutan-2-one (758) reacted with lithium diisopropylamide in THF. The product 2,2-dimethyl-5-(Nisopropylamino)-6-(2,2-dimethyll-hydroxycyclopropyl)hex-4-en-3-one (759)apparently resulted from the addition of two molecules of Favorskii-derived cyclopropanone with N(2-propylidene)isopropylamine, i.e. the Meerwein-Ponndorf-Verley oxidation product of LDA (equation 374)762.

’

LOB

T HF

0 OC/1 h

47% (759)

\

/

Y

-vN

App. 1. Synthesis and reactivity of a-halogenated ketones

171

Aliphatic tertiary amines are often used in dehydrohalogenations, giving rise to a, Bunsaturated ketones763. Similarly, a, B-dibromoketones could be converted into acetylenic ketones (760) with triethylamine (equation 375)764.

(760)

On the other hand, treatment of a-halocyclobutanones with tertiary amines or quaternary ammonium salts gave a stereoselectivecine-rearrangement to a’-halocyclobutanones (761) (equation 376)688.The 2,4-cis-disubstituted cyclobutanones 761 are valuable intermediates in a new synthesis of pyrethroids.

Proposed reaction pathways are shown in equations 377a and b. a. Via enol

dR X-

G

O

(377a)

H R

xgoH R

b. Via enolatelbicyclobutanones See equation 377b at the top of the next page.

However, triethylamine is capable of giving substitution products with formation of condensed compounds (762) (equation 378)688. The reaction of a-haloketones with N-heterocyclic compounds is completely different and leads to quaternization in most cases660*76s. This reaction has been used in the Chichibabin quaternization-cyclization for indolizine derivatives (763) starting from pyridazines and pyrimidines765, i s o q ~ i n o l i n e s ~ and ~ ~ pyridines (equation 379)767. However, 2-hydroxychalcone dibromide (764) gave 8-bromoflavone (765) on treatment with pyridine. It is assumed that the first stage involved both debromination and dehydrobromination, followed by bromination, ring closure and dehydrobromination (equation 380)768.

I72

Norbert De Kimpe and Roland Verhe

go-+ x-

I

xWo

-

CI-

I

R

(377b)

*W0

CI-

Pyridinium chloride is also able to cause dehydrohalogenation, e.g. 3-aryl-2,2dichlorocyclobutanones (766) yield 3-aryl-2-chlorocyclobutenones(767). When the same substrates were heated in a sealed tube the products were but-2-en-4-olides (768) (equation 381)769.

App. 1 . Synthesis and reactivity of a-halogenated ketones

173

25-65%

(763)Ref. 765

PY

0

0 (764)

11

0

0

&J;; -0

0

W A r Py.Brz

0

0

0 (765)

(380)

-Arwc'

Norbert De Kimpe and Roland Verhe

174

MeCN

-0

-

"'*I

(766)

2. Reaction of a-haloketones with imino compounds and enamines

Few reports have dealt with the reactivity of a-haloketones with imines. A novel synthesis of 4-azahomoadamantano[4,5]pyrroles (770) was attained via substitution and enamine cyclization by reaction of the imines 769 with phenacyl bromides (equation 382)770.

--HX

I

Et3N

16- 67 '/e

(770)

Imidates are much less basic than the corresponding primary amines from which they are derived but their nucleophilicity is still appreciable and N-alkylation occurs relatively readily. Diverse a-bromoketones yielded with excess methyl N-methylformimidate the expected N-methylformamides (771)771.On the other hand, substituted isohistamine derivatives (772) were formed from imidates with a-chloroketones in liquid ammonia (equation 383)772.a-Chloroketones reacted with a lithiated bislactim ether ofcyclo (L-ValGly) (773)in an extremely high diastereofacial way to give virtually only the (3R)-addition products (774)(equation 384)773.

App. 1. Synthesis and reactivity of a-halogenated ketones

175

I (383) Me/N\

CHO

36 -91 '/e (771)

I

CI

(772)

An excellent synthesis of a-alkylated cyclopentanones (776) involves reaction between abromoketones and cyclopentanone enamines (775)774.The Hantzsch pyrrole synthesis using the enamine 777 derived from dimethyl acetonedicarboxylate and ethanolamine was used similarly for the preparation of the pyrrole diesters 778775.The latter were converted into the bicyclic compounds 779 (equation 385). 3. Reaction of a-haloketones with arnides. thioarnides a n d derivatives

Whereas a-haloketones generally give with amides and urea derivatives oxazole derivatives, a-bromoketones with urea yield mainly imidazoles (780) and minor amounts of oxazoles (781) (equation 386)776.High yields of 2-aminooxazoles could be obtained by reaction of a-hydroxy- or a-bromoketones with cyanamide777. ~ . ~ ~ ~deriva, Cyclocondensation of a-haloketones with t h i o a m i d e ~ ~ ~thiourea tives7sn-7~5, thi~acylamidines~~~-'~~, isothiosemicarbazones79n and pyrimidine-2t h i ~ n e s gave ~ ~ ' a wide variety of thiazole derivatives (782-786) (equation 387).

Norbert De Kimpe and Roland Verhe

176

Ler

R'

COOMe

HO-~~*

-

(385)

COOMe

'

P

C

O

O

M

e

COOMe

(777)

J '

K

C

O

O

M

HO

(778)

e

R'

(782)

40-05%

(783)

Ref. 7 7 0

R e f , 700

177

App. 1. Synthesis and reactivity of a-halogenated ketones

J(/x

R'

-ATRl

+..AN
R2

NMe2

(784)

R3NH

R3HN

0

Ref. 786

R2

25-70%

Ref. 784

(785)

I

70-90%

R

Ref. 791

(387) In a few cases, reaction of phenacyl bromides with substituted thioureas gave minor amounts of 2-imino- 1,3-0xathioles together with the expected t h i a ~ o l i n e s ~Also ~ ' . the reaction of a-bromoacetophenone and thiobenzamides did not give the expected thiazoles but instead thiiranes (787)were formed via a 4a-electrocyclization (equation 388)792. (786)

0

k S . y A r Ph Ph

(787)

i

(388)

+' NR2

A similar procedure has been used for the preparation of simple pyrrolidine alkaloids (788) (equation 389)793.

178

Norbert De Kimpe and Roland Verhe

N-Acyl-l,3-oxathiol-2-imines (789) are formed from 0-alkyl acylcarbamothioates and a-chloroketones in the presence of methanolic sodium methoxide (equation 390)790.

(789)

(390)

Efficient syntheses of 1,3-thiazines (790)794,1,4-thiazines (791)795and 1,3,4-thiadiazines (792)796*797 are achieved via cyclocondensation of a-haloketones with N-substituted thioacyl derivatives (equation 391).

COOR (790)

(791)

R

Ph N"2

R

-

75 95% (792)

(391)

4. Reaction of a-haloketones with carbonyl reagents

N-Heterocyclic compounds such as pyrazines (793)798, imidazoles (794)799 and pyrazolines (795)"' are prepared from a-haloketones and the appropriate N-nucleophiles via cyclocondensation (equation 392).

App. 1. Synthesis and reactivity of a-halogenated ketones

Br

R

+

H2NNHCOOEt

-

179

45- 5 7 %

(793) NH

'YH

(392)

Ph

47-60%

(794) Ph

I

A

r

V

A

r

'

+

PhNHNH2

Bl Bl

A A rr /

0

A different reaction yielded 3,3-dimethylbutyne from l-bromo-3,3-dimethylbutan-2-one and arylsulphonylhydrazines (equation 392). The reaction is acid catalysed and mesitylsulphonylhydrazine was the most efficient reagent. The reaction does not proceed via an a-bromomesitylsulphonylhydrazone'o '. An excellent review on the synthesis of azoalkenes from a-haloketones with hydrazine derivatives appeared recentlyso2. 5. Reaction of a-haloketones with sodium azide

a-Azidoketones, formed via substitution of a-chloroketones with sodium azide, have been used in the total synthesis of peptides. They were hydrogenated and the resulting aaminoketones could be acylated with N-protected amino acid derivativesso3. In some cases a variety of reaction products were obtained, e.g., when the chalcone dibromides 764 reacted with the azide anion (equation 393)'04.

180

Norbert De Kimpe and Roland Verhe

/ OH

Ar

+

OH N3

0

-4OH

a-Bromomethyl ketones reacted more cleanly with sodium azide in DMSO to yield aazidomethyl ketones, which were converted into a-aminomethyl ketones by catalytic hydrogenation (equation 394)977.

R

)(,.

NaNI.

DMSO

L

R

N

3

NH2. HCI

H,/Pd-C HCI

w R

D. Reaction of a-Haloketones with Sulphur and Selenium Nucleophiles 7 . Reaction of a-haloketones with inorganic selenium nucleophiles

Whereas the reaction of I-chloroketones with sodium hydrogen sulphide gave amercaptoketones in excellent yields, treatment of a-haloketones with sodium hydrogen selenide or sodium or magnesium diselenide afforded only the dehalogenated ketones and selenium instead of the a-hydroselenoketones. This is due to the strong reducing power of hydrogen selenideEo5. 2. Reaction of a-haloketones with organic sulphur and selenium nucleophiles

The reaction of thiolate anions with a-haloketones in the presence of a base is a simple and efficient method for preparing a-alkyl- and a-arylthioketones8"0"-ROS. Th'IS method has been improved using phase-transfer catalysis under neutral conditions and a nonaqueous workupso'. Thallous phenyl selenide has been used for the preparation of aphenylselenoketones810.O n the other hand, substitution and elimination took place when 2-chlorocycloalkanones were treated with thiols yielding 1,2-bis(alkylthio)cycloalk-lenessl Both SN2and Favorskii rearrangements were observed when dichlorocyclobutenones and dichlorocyclobutanones reacted with sulphur nucleophiles. Cyclobutenones (798)"' and cyclopropanes (7W)81were the products when a, a-dichlorocyclobutenone (796)and

App. 1. Synthesis and reactivity of a-halogenated ketones

181

a,a’-dichlorocyclobutanone(797)were treated with thiophenoxide ion or with thiophcnol and potassium carbonate, respectively (equation 395).

1 . PhSH/KZCOa, 2 . adioxane q . NaOH

A

COOH

(800)

Base-catalysed condensation of 2-mercapto-3-methoxybenzaldehyde with chloroacetone furnished 2-acetyl-7-methoxybenzothiophene(800)814.A ring expansion method for the preparation of 2,3-dihydro-l,4-benzothiazines (803) from 2-aryl-2,3dihydrobenzothiazoles (801) was developed, involving ring opening to give 802, substitution with an cr-haloketone and ring closure (equation 396)’l 5 . Ar

(396)

182

Norbert De Kimpe and Roland Verhe

Reaction of a-haloketones with salts of thiocarbamatesE16, d i t h i o c a r b a r n a t e ~ ~ ~ ~ , dithiocarbonatesE18, thiocarbonyl cyanamidesM"~82",dithiolate dianionsE21.822or tetraethylammonium thiosulphate620 furnished substitution products. The latter products have been used as intermediates in the synthesis of thiazoles (804)818-820, tetrathiafulvalenes (805)817,1.3-dithiolanes (806)82' and a-thioxoketones (807) (equation 397)620.

90- 100*lo (804)

Lr +M"Nxs-""")+;y R

S-

2LI+

R

(397)

App. 1. Synthesis and reactivity of a-halogenated ketones

183

Similar Se-substitution products were obtained when a-haloketones reacted with Senucleophiles such as piperidinium s e l e n o ~ a r b o x y l a t e and s ~ ~diseleno~arbamates~~~.~~~. ~ Whereas a-haloketones gave with dialkyl or diary1 sulphides and selenides the corresponding salts826,an intramolecular rearrangement involving replacement of chlorine by a thiomethyl function was observed in 808, which was transformed into a pyrimidine derivative (809)(equation 398)684.

(398)

Treatment ofa-haloketones with the cyclic sulphoxide 810 in the presence of LDA resulted in alkylation with ring opening to 811 (equation 399)827.

II

0

(810)

31-76

*/e

(811)

E. Reaction of a-Haloketones with Carbon Nucleophiies 1. Reaction of a-haloketones with cyanide

a-Haloketones may undergo two competitive reactions with sodium or potassium cyanide. Nucleophilic addition and intramolecular substitution lead to 2-cyano~ x i r a n e s ~ ' ~ whereas - ~ ~ ' Favorskii rearrangement and nucleophilic addition generate The reaction is solvent dependent, with cyanocyclopropanes (818a) (equation 400)830. base-induced reactions in methanol or acetone and nucleophilic attack in a c e t o n i t r i l ~ ~ ~ ' . With conditions A and B the cyanide anion is acting predominantly as a base, giving rise to Darzens-type reaction products, whereas with condition C cyanide is a nucleophile attacking the carbonyl function and the halogen atom. 2. Reaction of a-haloketones with carbanions, ylides and enolates

The substitution or Favorskii rearrangement products formed from a-haloketones with

Norbert De Kimpe and Roland Verhe

184

0

x@ &

Condition KCN N A,BorC

1. c

& @

&/

+

1% 0 A. Methanol-H,O B. Acetone-H,O C. Acetonitrile-H,O

813

814

76

15

94

Yield

(x)

815

816

817

35

5

so (400)

X=CI,Br

(818 0 )

(818 b)

active methylene functions constituted excellent intermediates for the synthesis of acyl cyclopentanes (821)*3.3,furan (823) and indole (824) cyclopentenones (819)R-32, derivatives834 (equation 401).

45%

(819)

185

App. I . Synthesis and reactivity of a-halogenated ketones

5 3%

(821)

Ar

66-90

80-100%

e / '

(823) (824) (401) O n the other hand, reaction of a-haloketones with isocyanoacetates gave rise to 2oxazoline derivatives (825)835,which were easily transformed into b, y-unsaturated aaminocarboxylic acids (826) (equation 402). R2 R+

R3 CI

+

CNCH2COOEt

- $( cuzo

R'

J R2

COOH

(826)

COOEt

R2

(825) ( 402)

Norbert De Kimpe and Roland Verhe

186

Treatment of phenacyl chlorides with trichloromethyl carbanion afforded the stable oxiranes 827 via an addition-intramolecular substitution sequence (equation 403)836.

+

Ar%R

CI

CC13COONa phase I r a n s f e r

ca?alysir

- + rA

I

CI

R

C13C

(827)

Crown ether

Br

NaH/THF

(403)

R2wR'

~~4~+ (828)

Emmons-Horner condensations of a-haloketones with phosphonate anions constituted key steps in the synthesis of chlorinated furanones (828)837.8338 (equation 403) and retinal derivatives839. a-Haloketones have been alkylated by a-hydroxybenzyltriphenylphosphonium salts (829) in the presence of a base, giving 3-chromenes (830) (equation 404)840.

33- 57%

App. 1. Synthesis and reactivity of @-halogenatedketones

187

Carbanions substituted with electron-withdrawing groups act as homologating reagents, forming unsaturated alcohols and ketones. Lithium nitrile or ester carbanionsE4', [(phenylsulphonyl)methylene]dilithium (831)842and the isonitrile 832843 have been used in this procedure (equation 405). Reaction of (diethy1phosphinyl)difluoromethyllithium (833) with a-chloroketones took a different route, leading to difluorinated epoxides (834) (equation 405)844.

I

03

cSOZPh

A

NC

l

+

or phaae transfer

Norbert De Kimpe and Roland Verhe

188

The lithium salt of the N-benzylidene glycinate (835) gave rise to products 836, which can be transformed into a-amino acid derivative^'^', while the 1,4-dianion of acetophenone N-ethoxycarbonylhydrazone (837) provided pyrazoline derivatives (838) (equation 406)846.

R'

L

$-

1. n-BuLi

2.Girard T

(835)

X = C I ,Br

.'+"'

-Hok,.

PhCH=NCH2COOR

+

EtOOC -N

Ph

CI

reagent

R'

31 -90%

y2L i,

(836)

EtOOC-N

/L'

LI

+

Ph

(837)

(838)

(406)

An efficient regioselective synthesis of 2,4-diarylfurans (840) has been developed from metalated ketimines (derived from 839) and phenacyl bromides and successive treatment with methanolic hydrogen chloride (equation 407)847.

ho

Ph

Ph

Ar

+

n-BuLi

Ph

I

Ar'

(839)

Ph

ho + A &

I

(840)

Arl

App. 1. Synthesis and reactivity of a-halogenated ketones

189

The reaction of the lithium enolate of ethyl acetate (841)with a-chloroketones followed by reduction and lithiation led to homoallylic alcohols (842) in a regioselective manner (equation 408)848.

R1+R2

+

CI


R~ OLi

-70 TnFOC.~+COOE)

(841)

CI 1. LiAIH,

diethyi ether/-60

2.Li/-60-20

'c

C'

I

(408)

F. Reaction of a-Haloketones with Organometallic Reagents 1. Reaction of a-haloketones with Grignard reagents

While in most cases treatment of a-haloketones with aliphatic849, a l l y l i ~and ~~~ ~~ acetylenica51 * 8 3 2 Grignard reagents gave halohydrins, v i n y l i ~or~ thienylmagnesium halides854 provided 'substitution products' (843) (equation 409).

(843)

The Grignard reaction with a-chloroketones has been especially fruitful in the preparation of olefins (844)855-857 and conjugated enynes (845)858when the originally formed magnesium salts of halohydrins were allowed to react with lithium metal and lithium naphthalenide, respectively (equation 410). 1,3-Dichloroacetone gave the corresponding 1-substituted cyclopropanols (846) (equation 41 l)859. A vinyl oxirane (848) was formed when the r-bromoketone 847 was treated with vinylmagnesium bromide (equation 4 I I a)*'".

190

Norbert De Kimpe and Roland Verhe OMgBr R1COCR2R3

I

+

I

R4MgBr

R'R4CCR2R3

I

I

CI

CI

-78OC

LI

OMgBr R'R4C=CR2R3

20 oc

I

R1R4CCR2R3

I

21 -99%

Li

(844)

1 . A3C=CMgBr

II CI

R'CH =C -C I I

CR

R2

50- 65% (845)

.

1 R M g Br/MpBr2

3 HCI/H20

0

R

OLi

"X

40 - 6 7 Q/o (846) Br

(847)

(848)

The various reaction patterns with Grignard reagents are illustrated by using 4substituted-a-haloacetophenones861. The initial reaction of 849 with an excess of MeMgBr is attack at the carbonyl to form a halohydrin salt (850). The various reactions which then follow are substituent-dependent. In the 4-hydroxy case the only product is 1aryl-2-methylpropan-2-01 (852), arising from a [1,2]-aryl shift with simultaneous elimination of magnesium dihalide. When the substituent is 4-methoxy (853), epoxide formation and a subsequent [l, 21-hydride migration to the benzylic position become important or attack of the Grignard reagent at the benzylic carbon of the epoxide giving 854,855 and 856. With the 4-bromo compound 857, the reaction proceeds exclusively via the epoxide 859 and, following a [1,2]-hydride shift, leads to the isomeric butanols 861 and 862 (equation 412).

fiBr

App. 1. Synthesis and reactivity of a-halogenated ketones

&Br

.

6equ;:MgBr

191

OMgBr

BrMgO

HO

(849)

HO

moH BrMgO

100%

(852)

Me0

(851)

Me0

Me0

+ Me0

(857)

(858)

72V o

26%

(862)

(861)

(859)

192

Norbert De Kimpe and Roland VerhC

The formation of the reaction products is generalized in equation 413.

I

I"

I

I

MIMQX

OMgX

OH

OH

2. Reaction of a-haloketones with organolithium compounds

Whereas alkynyl chlorohydrins constitute the expected reaction products from treatment of a-haloketones with alkynyl lithiumss5'~"b2,reaction of a-chloroketones with n-butyllithium and lithium naphthalenide afforded oletins (863) (equation 414)863.

is-'

1. n - ~ u ~ i / - 7 8 ' C

~.L~+c,&'/-Ioo~c 47%

(863) 1. n-BuLi

coon 52 -03V e

App. 1. Synthesis and reactivity of a-halogenated ketones

193

Treatment of a-chloroketones with trimethylstannylmethyllithium gave rise to allylic alcohols via hydroxyalkyl~tannanes~~~. Dichlorocyclobutanones (864) can be converted into succinic acid derivatives (865) using n-butyllithium, acetic anhydride and sodium metaperiodate-ruthenium dioxideE6’. The reaction proceeds via oxidation of the corresponding /&chloroenolate (equation 414). Organodilithium reagents (866) with a-chlorocyclohexanone (1 18) yield indole derivatives (867-869) (equation 415)866. The regiochemistry is determined by the relative nucleophilicities and electrophilicities of the reactants and the regioselectivity realized in their formation. With a-haloketones as bis-electrophiles, the annelation process proceeds with complete regiochemical control in that the carbanioniccentre of the dilithium reagent reacts at the carbonyl carbon of the haloketone reactant. Overall regioselectivity is determined, therefore, by the regioselectivity achieved in reactant preparation, which can usually be accomplished by using heteroatom-directed deprotonation or site-specific halogen-lithium exchange.

(118)

0A

R

(866)

OJO I

0A

(868)

R

H

(869)

1415)

Lithium dimethylcuprate as a nucleophilic reagent for a-haloketones is less selective for alkylation than methyl cyanocuprate, especially in diethyl ether-dimethylformamide. The

194

Norbert De Kimpe and Roland Verhe

inverse addition and addition of ligands, such as dimethyl maleate, also improves the selectivity867.Whereas the reaction of acyclic aliphatic ketones with diphenylcopperlithium gave the normal alkylation products, cyclic a-haloketones afforded the rearranged alkylation product 870 nearly exclusively (equation 41 6)868.

This alkylation procedure has been applied in the synthesis of a-cuparenone (873) using a dichlorocyclopentane derivative (872) with dimethylcopperlithium and iodomethane (equation 417)869.

Me2CuLi

___*

(417)

Me1

52

(872)

(873)

Similarly, a, a’-dibromocycloalkanones can be converted into a, a’diphenylcycloalkanones (874) via the a, a’-dibromo-a-phenylcycloalkanones870. The reaction can also be stopped at the a-phenylcycloalkanone stage (equation 418).

3. Reaction of a-haloketones with organoboron compounds

B-3-Pinanyl-9-borabicyclo[3.3.l]nonane(Midland’s reagent) (875) has recently emerged as an exceptionally valuable reagent for the asymmetric reduction of ahaloketones. Thus a-bromoacetophenone, using 100%excess of reagent (derived from 92% e.e. (+)-a-pinene)produced the bromohydrin 876 in 95% yield and 86% e.e. However, the results proved less satisfactory in other cases (equation 419)871,872.

195

App. 1. Synthesis and reactivity of a-halogenated ketones

neat

Ph

25

OC/4

days

(875)

(419)

Ph

[(f?)-876](86%e.e.1

The bromohydrins may conveniently yield the corresponding chiral epoxides or can be dehalogenated to the parent alcohol with retention of optical activity. Reduction of afluoroketones to the corresponding fluorohydrins can be performed using lithium triethylborohydride' 7 3 . A 6-azabicyclo[3.l.l]heptane ring system (878,879) was formed during the sodium borohydride reduction of 2-bromo-6-(o-chlorophenyl)-6-(methylamino)cyclohexanone (877) via an intramolecular S,2 reaction (equation 420)874. Me\

R = o -chlorophenyl

7" N

T'

qRYR Me\

(877)

NH

NH

0-

OH

4. Reaction of a-baloketones with metal complexes

The generation of oxyallyl cations via reaction of a,a'-dihaloketones with a variety of metal complexes, especially Fe,(CO),, and subsequent ring closure leading to various ~ . principal widely used carbocycles, has been the subject of excellent r e v i e ~ s ' ' ~ . ~ 'The reactions are summarized in equation 421877. Reaction of a-haloketones with organometallic reagents takes place by a variety of pathways. Whereas the palladium-catalysed reaction of trimethylsilyltributyltin or of hexabutylditin gave rise to enol silyl ethers (880)878.879, oxiranes (881) were prepared with acetonyl- and allyl-tin reagents in a palladium-catalysed reaction (equation 422)880.I f the catalyst does not contain phosphane ligands a 1,Cdiketone (882) is formed, apparently through an initial oxidative addition at the a-halo position (equation 422)"l. However, the reaction of tributyltin enolates with a-haloketones afforded substituted furans (883), which were not derived from the normal cross-coupling products, i.e. 1,4-diketones. but through addition of the tin enolate (equation 422)882*883.

196

'AR .

Norbert De Kimpe and Roland Verhe OFeLn

e g . Fe2(COIe

x

x

R

A

+

R

Ln=Br-, C0,solvent OSiMeS BuaSnSiMoa

I

R-C=CH2 50-80°/o

App. 1. Synthesis and reactivity of a-halogenated ketones Br

n-Bu3Sn

+

J ,Pd

.

cat

197

%;;-nl3

R R’

I

R

+

Br

L

n-Bu3SnCH2COMe

Pd cat

(eel)

% . Me

-[ I /qf - [&$ Br

+

n-Bu3SnCH2COPh

P

h

R=CSH13 OSn(Bu-n)3

k

B

4

0

A

r

32 010 1883)

Ar

x

NlBr,P(Ph,), Zn/Ec,NI

A

r

b

r

--n-Bu,SnBr

Ph

Ph

0

66V o (882)

0

3

Norbert De Kimpe and Roland Verhe

198

1,4-Diketones (884,885) were also formed by coupling reactions of a-bromoketones in the presence of iron penta~arbonyl"~and an active Zn complex (equation 422)885. Reaction of x-allyldicyclopentadienyltitanium(I1I)complexes (886)with a-chloroketones gave homoallyl alcohols (887) after hydrolysis (equation 423)886.

95%

(886)

(887)

The first example of an intramolecular Simmons-Smith reaction was reported when the mixed x , a-dihaloketone 888 was decomposed in the presence of n-Bu,Sn', leading to the formation of the cyclopropane 889 (equation 424)'". Br AIBN/n-BunSnH

1

0

(424)

4 5%

(889)

Regiospecific aldol condensations have been demonstrated by the simultaneous addition of a-haloketones and aldehydes or ketones to a mixture of diethylaluminium chloride and zinc"'. Also, treatment of a-bromoketones with a reagent prepared from nBu,SnLi and Et,AICI or from SnCI, and Et,AIC1889 or by means of Bu,SnAIEt, or B U , P ~ A I E ~ afforded , ' ~ ~ aluminium enolates which reacted with ketones or aldehydes to give 8-hydroxycarbonyl compounds (890) (equation 425). Et,

R'CHO

A3

R5

App. 1. Synthesis and reactivity of a-halogenated ketones

199

Other cross-aldol condensations of a-haloketones with ketones or aldehydes involved divalent tin enolates formed in situ with Sn(OTf),89' - 8 9 3 by the oxidative addition of metallic tin894 or (equation 426). Cerium gave similar results.

EI t

(891) 4

61'10

Sn(0Tf )2 = tin trifluoromethanesulphonate

(892) 1

(426)

High diastereoselectivity was achieved in the directed aldol reaction of lithium enolates of ~-fluoro-3,3-dimethylbutan-2-one with aldehydes, whereas an apparent reversal of diastereoselection was found in Lewis acid-mediated reactions of the corresponding enol silyl ethersE9'. The cross-aldolization of a-bromoketones with aldehydes in the presence of chromium(I1) chloride is also an excellent stereospecific reaction899 but zinc900*90'and zinc-titanium(1V) chloride902 react less stereoselectively. The bromomagnesium enolate of tert-butyl ethyl ketone (893)crystallized as a dimeric, ether-solvated aggregate in the solid state with Z geometry (894) (equation 427)903.Since the stereochemistry of the aldols can be either thermodynamically or kinetically controlled, it is important to understand the aggregation state of the reactants and the steric requirements of the chelating ligands in order to predict and/or control aldol reaction stereochemistry. Magnesium enolates exist as dimeric aggregates in solution and the magnesium aldol reaction proceeds through dimeric intermediates.

JJy- A/ OMgBr

Mg

t-Bu

dirthyl ether

Br

(893)

The following reactions cannot be classified as reactions of metal complexes, but they are described here by analogy with the above reactions involving enolates. a-Keto dianions (895)can be trapped by ketones leading to aldol condensation products (896), but when the reaction was carried out in T H F rather than in diethyl ether a spiro b-lactone (897) could be obtained via an alkynolate anion (equation 42X)904. This reaction represents the carbon analogue of the Hofmann reaction involving deprotonation of an a-bromoketone enolate, followed by rearrangement with loss of bromide to afford a ketene anion (equation 428). Quenching of the chloroenolate anion of phenacyl chloride with methanol afforded methyl phenylacetate (898),whereas the use of benzaldehyde produced a-phenylcinnamic acid (899) (equation 429)'04.

Norbert De Kimpe and Roland Verhe

200

f'i

THF

i

6 -r t-BuLi

Ph -CHBr

PhC-CHLi

Et p 0

Ph

(895)

I-BuLi

OH

00%

ri

(806)

PhC-CBrLi

12 */a

(697)

l -

R-C-CHBr

0

e-

A

II

R-C-CBr

0-

I _

R-C-CHBr

r

PhC-CHCI

-

R-C-CBr

-6;

-

O===C=dR

-Or-

- p'i / I-BuLi

PhC-CHLI

-0 - C E C R PhCHZCOOMI

57% (898)

App. 1. Synthesis and reactivity of a-halogenated ketones

-

20 1

This procedure has been used in ester homologations via the a-bromo-a-keto dianions (equation 430)905.

I

RCOOEt

ROH

a

RCHzCOOEt

50-75

H+

RCGCOLi

LiCHBr,

riF

R -CHBrz

-l

0

Ve

Li

-d

bEt

-

TLi

n-BuLi

R-k-CBrX

(430)

R-C-CLiBr

X=H, B r

The Darzens condensation of phenacyl halides with aldehydes has been used in the preparation of oxiranes (9OO)(equation 43 1)9063907.

25-60°/o

(900)

(431) Tandem Michael ring closures have been developed recently for the efficient formation of cyclopropanes (902), via treatment of the ketone enolate with a vinylphosphonium salt (901) (equation 432)908. A similar Michael addition of a-chloroketones across methyl vinyl ketone gave the cyclopropane derivative 903 (equation 432)90'. G. Reactlon of a-Haloketones with Phosphorus Compounds

Further evidence for a common phosphonium salt intermediate (904)in the reaction of trialkyl phosphites with phenacyl chlorides and bromides leading to enol phosphates and phosphonates has been elaborated (equation 434)9' ". If both bromoacetophenone and chloroacetophenone are present, halogen exchange occurs between the phosphonium salt and the haloacetophenone. A new preparation of p-ketophosphonates by reaction of dialkyl chlorophosphate electrophiles with the dilithiated derivative of an a-bromoketone has been described985. This umpolung approach is complementary to the classical Arbuzov synthesis, allowing the use of secondary a-haloketones or a-bromoketones where the Arbuzov reaction often fails. It also extends the variety of phosphonates available by allowing, for example, the direct preparation of bis(trifluoroethy1) phosphonates, which are not readily available via the Arbuzov reaction (equation 433).

+

(Me0)3PCHzC0 e

R

1

X-

202

Norbert De Kimpe and Roland Verhe

Whereas the reaction of u-chloroketones with dialkyl phosphites gave rise to hydroxyalkylphosphonates without organic solvents, addition of solvent and potassium or caesium fluoride resulted in the formation of epoxides and vinyl phosphates (equation 434)’’ ‘-’14.

..p-..

X

R’

+

PhSP

/ MI&ULI

1

XX$R2 R’

70%

(903)

I

Br

R’C=C

II..O,. !CI k R 2 0

(433)

App. 1. Synthesis and reactivity of a-halogenated ketones

203

R2

I

CI

Using diphenyl phosphites and chlorodifluoromethyl ketones in the presence of triethylamine, 2,2-difluoro en01 diphenyl phosphates were synthesized. On treatment with '. Diethyltrimethylsilyl phosphite dibutylcopperlithium, they gave gem-difluor~olefins~~ afforded the diethyl enol phosphate and not the 1 :1 carbonyl adduct using trimethylsilyl phosphitegL6.Vinyl esters of phosphorus acids have been prepared by treatment of achloroketones with dialkylchloro- and monoalkyldichlorophosphonites9'7*9 *. Phosphonium salts and the derived phosphoranes, obtained by reaction of ahaioketones with tertiary phosphines, have been widely used in the Wittig olefination919-922 . On the other hand, reaction of a-bromoketones with tertbutyldialkynylphosphanes (905) gave rise to 1,4-oxaphosphorine salts (906) (equation 435)923*924. Phosphomanganous cycloalkanes (907) could also be prepared by reaction of 113-dichloroacetonewith manganophosphorus compounds (equation 43S)925.

60-90°/0 (906)

R2'

Norbert De Kimpe and Roland Verhe

204 R

/

\P/Mn(c0)4 \E-

4

+

-

Cl^rfCl

0

R\

/R

K

(C0I4MnNp\E

0

E=O,S

41-43%

R = Me, Ph

(907)

(435) Phenacyl bromides are able to alkylate phosphine boranes affording tertiary phosphine borane derivatives (908) (equation 436)926.

-60% (908)

H. Miscellaneous Reactions of @-Haloketones 1. flectrophilic reactions of a-haloketones and their derivatives

Novel preparative methods for the synthesis of arylacetone derivatives involving Friedel-Crafts reactions of aromatic compounds with a-chloro-a-(methy1thio)acetone in the presence of Lewis acids and successive desulphurization with Zn have been reported’”. The Meisenheimer adduct (909) of the 1-chloropropanoyl anion and 1,3,5trinitrobenzene has been isolated by reaction of chloroacetone with triethylamine in DMSO containing trinitroben~ene’~~. This reaction is also applicable for phenacyl chloride. 0

02Nr3--No2 ---.

‘

+

HNEt3

NO2

R = Me, Ph

(909)

Reaction of silyl enol ethers with a-chloro-a-(a1kylthio)ketones in the presence of titanium(1V) chloridegz9afforded furans (910) whereas in the presence of zinc bromideg3’ the regioselectivity is reversed and y-diketones (911) were generated. However, allylsilanes (912) gave exclusively substitution of the chlorine atom with formation of the corresponding a-ally1 sulphides (913) (equation 437)931.

App. 1. Synthesis and reactivity of a-halogenated ketones TiCI,

+

R

'

7

"

-78°C

*

205

R3f2-R2

R'

OSiMe3

OTiCI3

5 4- 88%

(910)

-

(437) R'

ZnBrt

R' CI

10 oc

SR2

(CHz),,

60-00% (011)

&JIR

R3

20--90% (913)

Trialkylsilyl enol ethers of a-haloketones have been prepared by treatment of the latter with trialkylsilyl triflates in the presence of triethylamine at room temperature932. The reaction of trimethylsilyl iodide in the presence of triethylamine in acetonitrile with achloroketones can give rise to the isomer 915 of chlorotrimethylsilyl enol ethers (914) (equation 438)9339934.

(914)

(916)

(438)

Norbert De Kimpe and Roland Verhe

206

a-Silyl ketones (916,917) serve as excellent transfer agents of a-ketocarbanions to an electrophilic centre935.Two general methods starting from a-haloketones involve either silylation of a-keto dianionsgJ6 or 1,3-0- to C-silyl migration in bromotrimethylsilyl enol ethers (equations 439 and 440)937. t-BuLi

LDA d

RCOCH2Br

____c

PLi

I

RC-CHLL M0,SiCI

OSiMe3 RCOCH2SiMe3

H+

1

RC=CHSiMe3

70-95%

(439)

(916)

-

R'COCHR~

I

LiN(SiM*&

OSiMe3

1

R'C- - 1 ~ r

A

R'COCHR'

I

R2

Br

SiMe3

50-80%

(917)

-P SiMe3

1. LiN(SiMo&

I

~1c-1~2

2. CISiMO,

n-BuLi

OSiMeS

1

R'C-CR'

Br

Br

I

Li

n

OLi aq.NH,CI

I

I

e--- R'C=CSiMe3

I

51-83%

A similar synthesis involved the formation of a vinyllithium species, silyl migration and quenching with aqueous ammonium chloride to give a-trialkylsilyl ketonesg3*.Homolog-

207

App. 1. Synthesis and reactivity of a-halogenated ketones

ation of a-haloketones has found application in the conversion of a-chlorocyclobutanones into cyclopentanones (918) and cyclopentenones (919)939using diazoalkanes and the transformation 920 + 921 using diazoacetates (equation 441)940.

0

1.

P

h

v

C

I

NoCHCOOEt BF,,E t,O

0

2 . Z n / HOAc

(920)

Ph

69'10 (921)

The reaction of halogenated a-diazoketones with benzene in the presence of rhodium(ll1) trifluoroacetatc provided benzyl ketones (923) via cycloheptatrienyl intermediates (922) (equation 442)941.

Cot.

R\

(,

I 8 0 v.

(923)

(442) Iodomethylation of a-haloketones utilizing diiodomethane and samarium yielded c y c l ~ p r o p a n o l s ~and ~ ~ , Ullmann coupling in the presence of Cu or Ag afforded unsaturated 1,4-diketones (equation 443)'43. The Passerini reaction of isocyanides with achloroketones in the presence of acids, followed by ring closure, afforded azetidinones (equation 444)944.

Norbert De Kimpe and Roland Verhe

208

7 CHp12/ S m

R1+'.

' ' HO

X

A

R

2

67-08 '10

Ph

CI

CI

xylrne

(924)

(443)

-

Ph PA

Ph

'Ph 28 010

(925)

JrR2 = R~COOH

CI

78- 97010 (927)

(444)

Acetoacetamides (929) were formed when chloroacetone reacted with fluorosulphonyl isocyanate (928). The products give oxathiazinones (930) on treatment with base (equation 445)945.

(928)

0ANS02F H

I-.

67 *lo

(929)

H

23 '10

(930)

(445)

App. 1. Synthesis and reactivity of a-halogenated ketones

209

New C-N bonds were formed on treating a-haloketones with alkyl thionitrites (931), resulting in the formation of a-oximino-a-haloketones (932) (equation 446)946.

+

R’

H+

R~S-N=O

(931)

-R%H

N-0

1 20-95

(446)

Vo

(932)

2. Reaction of a-haloketones with alkali metal fluorides

Treatment of 3,5-dibromopentan-2-one (933) with potassium fluoride resulted in ring closure to 1-acetyl-1-bromocyclopropane(934) (equation 447)689.

(447)

6 2 ‘10 (934)

3. Acid-catalysed rearrangement of a-haloketones

For the first time a reaction suitable for studying electronic effects on C-C1 bonds in an equilibrium was found (equatior! 448)947.

(935)

(936)

1448)

There is a considerable polar effect on the relative stability of the two chloroketones 935 and 936 which is largest for the Y = Me, Z = p-NO, pair. Since the only differencebetween the two isomers is the reversed location of a C-CI and a C-H bond, the substituent

Norbert De Kimpe and Roland Verhe

210

TABLE 2. Equilibrium constants for the process 935e936 when Y = Me (room temperature) K,, (936/935)

Z H

1.1 1.9

p-CI

m-CF, P-NO,

2.4 4.9

effect must be transmitted (mostly through space) to these two bonds. The Keq,values are given in Table 2947. In the course of studying the a,a’-rearrangement a new furan-forming reaction was encountered. a-Haloketones reacted with a-naphthol in the presence of strong acids to give naphtho[2,l-b]furans (937,938)via hydroxyallyl cation intermediates9,*. The reaction is not regiospecific in that more than one furan can result, but the predominant compound was 938.The same two furans were formed from all four a-chloro and a-bromo isomers whether the acid was HCI, HBr or HC10, (equation 449).

(937)

+

/ P

h0

b

(938)

(449)

0

An efficient synthesis of 2-arylpropanoic esters (939)from a-halopropiophenones involving a thallium(II1) nitrate-assisted 1,2-migration of the aryl group was found when orthoformates were used as the solvent and as the source of an alkoxy group (equation 450)949.

App. 1. Synthesis and reactivity of r-halogenated ketones

21 1

The acid hydrolysis of the 3,5-dibromopiperidine-4-one 940 did not give the previously reported piperidine-3,Sdione 942 but instead the reaction product was identified as the pyrroline 941 (equation 451)950.

Br&-r-*Br&r+oQo

H

H

(941)

Attempts to remove the p-tolylsulphonyl group from the azepin-8-one 943 with polyphosphoric acid (PPA)gave a novel heterocyclic system, viz. 6,7-dihydroazirino[ I , 2a]thieno[2,3-JJpyridine-8-one (944) (equation 452)95'. TOS

(943)

(944)

4. Formation of a-acylcarbenium ions from r-haloketones

The first isolable a-acylcarbenium ion (946) was obtained by treatment of 1,2,24ri(4methoxyphenyl)-2-chloroethan-l-one (945) with AgSbF, (equation 453)952.953.Intra-

molecular cyclization gave 948, and capture by methanol gave 947. In an intramolecular reaction, action of AgSbF, on the linear terminally unsaturated abromoketone 949 led, via the oxonium salt 950, to the regio- and stereospecifically substituted cyclohexanol 951 (equation 454)454.

212

Norbert De Kimpe and Roland Verhe

1. AgSbFe/CH2CI2

Ar

Ar

2.pentone

Ar

CI

8 7 e/'

(946) m.p. 5 7 'C, stable at - 2 0 'C

/

decomposes a t R T 50

1453)

oc cI-c' Ar

9 4%

(947)

(948)

'I I

(949)

(454)

Ph

&Ph

HO

NoHCO,

33%

(95t1

(9601

5. Photochemistry of a-haloketones

The photoenolization mechanism of phenacyl chlorides in methanol has been elucidated as illustrated by the photolysis of 2,5-dimethyl-a-chloropropiophenone(952) (equation 455)955. Photoinduced alcoholysis of tribromoacetophenone derivatives gave benzoyl formates (7545%) together with minor amounts of benzoates and debromination Synthetically useful photochemical transformations of a-haloketones involve the ring cleavage of dichlorocyclobutanones (956) with the formation of dichloromethyl ketones (958)957and the formation of cyclopentane-l,3-diones (961) from brominated diones (959) (equation 456)958.

App. 1. Synthesis and reactivity of a-halogenated ketones

0

CI

0

(CHp )4COOMe

CI OSiMe3

h” :lxOSiMe3

213

“$(CH CI

2 ),+COOMe

214

Norbert De Kimpe and Roland Verhe

6. Electrochemistry of a-haloketones Electrochemical reduction of phenacyl bromide mainly gave rise to 2,4-diphenylfuran (%2) togehter with minor amounts of 3,j-diphenyl-Z(3H)-furanone (963) (equation 4S7)959*960.

7. Dehalogenation of a-haloketones

Conversion of a-haloketones into the parent ketones is sometimes used in syntheses and several new reagents have been introduced. Nickel b ~ r i d e ~ lithium ~’, and sodium 2-thiophenetell~rolates~~~~~~~, zinc and ammonium acetate in THF964, sodium PZ14967, sodium 0,Od i t h i ~ n i t e ~ ~ ’ samarium , d i i ~ d i d e ~ ~PI, ~ , or diethylphosph~rotelluroate~~~, LDA969,970,iod~trimethylsilane~~’, sodium iodide, metal chloride^^'^, organotin hydridesgs6 and 1, 3-dimethyl-2-phenylbenzimida~oline~~’ have been shown to reductively dehalogenate a-haloketones. Reductive dechlorination of the bicyclic diketone 964 with an active Ni complex afforded, however, the unsaturated diketone 965 (equation 458)960.

n

0

43-60%

( 0 64)

(965)

8. Enzymatic transformations of a-haloketones The use of fermenting baker’s yeast has been shown to provide a versatile means of chiral reduction in organic synthesis. The asymmetric reduction of (2)-3-chloroalk-3-en-2ones (966)produces initially optically active a-chloroketones (967),which are then reduced Interestingly, the reduction of the C=C bond is to optically pure chlorohydrins (968,969). relatively fast and seems to be independent of the length of the carbon chain, whereas that of the C=O bond is slow and is retarded as the carbon chain length becomes longer (equation 459)’”.

(966)

44-04% [(S)-967]

e.e.

(459)

App. 1. Synthesis and reactivity of a-halogenated ketones

215

[(S)9671

I

(968)(syn)

(969)(anti)

syn ( 2 5 , 3 5 ): anti (2S,3R) = 2.6-18.3

>98% e.e.

Optically active 2-halo-1-phenylethanols have been prepared by microbial reduction of 2-haloacetophenones with Candida, Rhodotorula and Hansenula with high optical purity (ca. Io00/,)9aa. IV. REFERENCES 587. 588. 589. 590. 591. 592. 593. 594. 595. 596. 597. 598. 599. 600. 601. 602. 603.

604.

605. 606.

607. 608.

609.

610.

611. 612. 613. 614. 615. 616.

S. Rozen and R. Filler, Tetrahedron, 41, 1111 (1985). C. Gal, G. Ben-Shushan and S. Rozen, Tetrahedron Lett., 21, 5067 (1980). D. H. R.Barton, J. L. James, R. H. Hesse, M. M. Pechet and S. Rozen, J . Chem. Soc., 1105 (1982). W. E. Barnette, J. Am. Chem. SOC., 106, 452 (1984). T. B. Patrick, J. J. Scheibel and G. L. Cantrell, J. Org. Chem., 46, 3917 (1981). S. T. Purrington, N. V. Lazaridis and C. L. Bumgardner, Tetrahedron Lett., 27, 2715 (1986).

B. Zajc and M. Zupan, J. Org. Chem., 47, 573 (1982). S. Stavber and M. Zupan, J . Chem. Soc., Chem. Commun., 148 (1981). S. Stavber and M. Zupan, J. Fluorine Chem., 17, 597 (1981). N. Ishikawa, T. Kitazume, T. Yamazaki, Y. Mochida and T. Tatsumo, Chem. Lett., 761 (1981). I. Kuwajima, E. Nakamura and M. Shimizu, J. Am. Chem. Soc., 104, 1025 (1982). R. Franz, J . Fluorine Chem., 15, 423 (1980). K. Griesbaum, H. Keul, R. Kibar, B. Pfeffer and M. Spraul, Chem. Ber., 114, 1858 (1981). K. Griesbaum, G. 0. Lie and E. Raupp, Chem. Ber., 114, 3273 (1981). M. Spraul and K. Griesbaum, Chem. Ber., 116, 2641 (1983). G. Alvernhe, S. Lacombe and A. Laurent, Tetrahedron Lett., 21, 1437 (1980). R. Flammang, S. Lacombe, A. Laurent, A. Maquestiau, B. Marquet and S. Novkova, Tetrahedron, 42, 315 (1986). V. Reutrakul and V. Rukachaisirikul, Tetrahedron Lett., 24, 725 (1983). B. W. Metcalf, E. T. Jarvi and J. P. Burkhart, Tetrahedron Lett., 26, 2861 (1985). A. Bongini, G. Cainelli, M. Contento and F. Manescalchi, J. Chem. Soc., Chem. Commun., 1278 (1980). B. Sket and M. Zupan, Tetrahedron, 40,2865 (1984). R. R. Gallucci and R. Going, J. Org. Chem., 46, 2532 (1981). A. Guy, M. Lemaire and J.-P. Guette, Synthesis, 1018 (1982). L. De Buyck, R.Verh6, N. De Kimpe, D. Courtheyn and N. Schamp, Bull. Soc. Chim. Belq., 90, 837 (1981). L. De Buyck, Y.Zi-Peng, R.Verhk, N. De Kimpe and N. Schamp, Bull. Soc. Chim. Belg., 94,75 (1985). L. De Buyck, H. De Pooter, R. VerhC, N. De Kimpe and N. Schamp, Bull. Soc. Chim. Bely., 90, 825 (1981). L. De Buyck, R. Verhe, N. De Kimpe and N. Schamp, Bull. Soc. Chim. Belg., 91, 797 (1982). L. De Buyck, J. Vanslembrouck, N. De Kimpe, R. Verhe and N. Schamp, Bull. SOC.Chim. Belg., 93, 913 (1984). L. De Buyck, N. De Kimpe, R. Verhe and N. Schamp, Bull. Soc. Chim. Belg., 92, 241 (1983). L. D. Hatfield, W. H. Lunn, G. G. Jackson, L. R. Peters, L. C. Blaszczak, J. W. Fisher. J. P. Gardner and J. M. Dunigan, Spec. Publ. R. Soc. Chem., 38, 109 (1981).

216

Norbert De Kimpe and Roland Verhe

617. K. Kurosawa and K. Yamaguchi, Bull. Chem. Soc. Jpn., 54,1757 (1981). 618.T. Tsuruta, T. Harada, H. Nlshino and K . Kurosawa, Bull. Chem. Soc. Jpn., 58, 142 (IYX5). 619. T. Shono, N.Kise, A. Yamazaki and H. Ohmizu, Tetrahedron Lett., 23,1609 (1982). 620. B. Hahn, B. Kopke and J. Voss, Justus Liebigs Ann. Chem., 10 (1981). 621. D. J. Buckley and M. A. McKervey, J . Chem. SOC., Perkin Trans. 1, 2193 (1983). 622. M. A. McKervey and P. Ratananuhul, Tetrahedron Lett., 24,117 (1983). 623.N. De Kimpe, W. De Cock and N. Schamp, Synthesis, 188 (1987). 624. S . I. Zav’yalov, G. I. Ezhova, T. K. Budkova, Izu. Akad. Nauk SSSR, Ser. Khim.,2165 (1981); Chem. Abstr., 96,34486 (1981). 625. G. A. Olah, L. Ohannesian, M. Arvanaghi and G. K. Surya Prakash, J . Org. Chem., 49,2032 (1984). 626. G. F. Hambly and T. H. Chan, Tetrahedron Lett., 27,2563 (1986). 627. S . Motohashi and M. Satomi, Synthesis, 1071 (1982). 628. W. T. Brady and R. M. Lloyd, J . Org. Chem., 46, 1322 (1981). 629. M. C. Pirrung and J. R. Hwu, Tetrahedron Lett., 24,565 (1983). 630.J.-M. Poirier, L. Hennequin and M. Fomani, Bull. SOC. Chim. Fr., 436 (1986). 631. S . G. Hegde and J. Wolinsky, Tetrahedron Lett., 22,5019 (1981). 632. V. L. Heasley, R. K. Gipe, J. L. Martin, H. C. Wiese, M. L. Oakes, D. F. Shellhamer, G. E. Heasley and B. L. Robinson, J . Org. Chem., 48,3195 (1983). 633.G. Capozzi, C. Caristi, V. Lucchini and G. Modena, J . Chem. SOC.,Perkin Trans. I , 2197(1982). 634.G. Capozzi, G. Romeo, V. Lucchini and G . Modena, J . Chem. Soc., Perkin Trans. 1,831(1983). 635.A. Roedig and E. M. Ganns, Justus Liebigs. Ann. Chem., 406 (1982). 636.A. Kohda, K. Ueda and T. Sato, J . Org. Chem., 46, 509 (1981). 637.A. Khoda and T. Sato, J . Chem. Soc., Chem. Cornmun., 951 (1981). 638. E. E. Kaplanyan, G. G. Mkryan and G. M. Mkryan, Arm. Khim. Zh., 33,594 (1980);Chem. Abstr., 94,30133 (1981). 639.G. G. Mkryan, E. E. Kaplanyan and G. M. Mkryan, Zh. Org. Khim.,17,2054 (1981);Chem. Abstr., 96,68250 (1982). 640. G. G. Mkryan, S . K. Akopyan and G. T. Martirosyan, Arm. Khim. Zh., 35,241 (1982);Chem. Abstr., 97, 91666 (1982). 641.W. T. Brady, Tetrahedron, 37,2949 (1981). 642. P. Martin, H. Greuter and D. Bellus, Helv. Chim. Acta, 64, 64 (1981). 643. P. Martin, E.Steiner and D. Bellus, Helu. Chim. Acta, 63,1947 (1980). 644. H. Greuter, J. Dingwall, P. Martin and D. Bellus, Helu. Chim.Acta, 64, 2812 (1981). 645. P. Martin, Helu. Chim. Acta, 66, 1189 (1983). 646.G. Mehta and H. S . Prakash Rao, Synth. Commun., 15,991 (1985). 647. H. Keul, 9. PfeNer and K. Griesbaum, Chem. Ber., 117,2193 (1984). 648.J. Villieras, M. Rambaud, R. Tarhouni and B. Kirschleger, Synthesis, 68 (1981). 649. R. Tarhouni, B. Kirschleger, M. Rambaud and J. Villieras, Tetrahedron Lett., 25, 835 (1984). 650.J. Villieras, B. Kirschleger, R. Tarhouni and M. Rambaud, Bull. Soc. Chim. Fr., 470 (1986). 651.C. J. Kowalski and M. Hague, J . Org. Chem., 50, 5140 (1985). 652.G. Friour, G. Cahiez and J. F. Normant, Synthesis, 37 (1984). 653. H. Hamana and T. Sugasawa, Chem. Lett., 575 (1985). 654. 9. Fohlisch and R. Flogaus, Synthesis, 734 (1984). 655.T. Morimoto and M. Sekiya, Synthesis, 308 (1981). 656.T. Morimoto and M. Sekiya, Chem. Pharm. Bull., 30, 3513 (1982). 657.Y.Johar, M. Zupan and B. Sket, J . Chem. Soc., Perkin Trans. I , 2059 (1982). 658. K. H. Pannel, A. J. Mayr, J . Chem. SOC.,Perkin Trans. 1, 2153 (1982). 659. B. Stanovnik, M. Tisler and I. Drnovsek, Synthesis, 987 (1981). 660.A. Arrieta, I. Ganboa and C. Palomo, Synth. Commun., 14,939 (1984). 661. G. Grundke, W. Keese and M. Rimpler, Chem. Ber., 118,4288(1985). 662. A. Dossena, R. Marchelli, E. Armani, G. G. Fava and M. F. Belicchi, J . Chem. Soc., Chem. Commun., 1196 (1983). 663. E. Armani, A. Dossena, R. Marchelli and G. Casnati, Tetrahedron, 40,2035(1984). 664. S . Magen, J. Oren and B. Fuchs, Tetrahedron Lett., 25,3369 (1984). 665. S . Visweswariah, G. Prakash, V. Bhushan and S . Chandrasekaran, Synthesis, 309 (1982). 666. M. Fournier, F. Fournier and J. Berthelot, Bull. Soc. Chim. Belg., 93,157 (1984). 667.J. Berthelot, F. Fournier and M. Fournier, Synth. Commun., 15,213 (1985).

App. 1. Synthesis and reactivity of a-halogenated ketones

217

668. E. I. Sdnchez and M. J. Fumarola, J. Ory. Chem., 47, 1588 (1982). 669. M. C. Cabaleiro, N. N. Giagante and R. 0. Garay, J . Chem. Res. ( S ) , 240 (1983). 670. V. L. Heasley, K. E. Wade, T. G. Aucoin, D. E. Gipe, D. F. Shellhamer and G. E. Heasley, J. Org. Chem., 48, 1377 (1983). 671. V. L. Heasley, D. F. Shellhamer, T. L. Carter, D. E. Gipe, R. K. Gipe, R. C. Green, J. Nordeen, T. D. Rempel, D. W. Spaite and G. E. Heasley, Tetrahedron Lett., 22, 2467 (1981). 672. S. Rozen and M. Brand, J. Org. Chem., 50, 3342 (1985). 673. S. 1. Zavyalov, I. V. Sitkareva, Izu. Akad. Nauk SSSR, Ser. Khim.,2408 (1985); Chem. Abstr .105, 23926 (1986). 674. L. Duhamel and J.-M. Poirier, Bull. Soc. Chim. Fr., (II), 297 (1982). 675. J. Barluenga, J. M. Martinez-Gallo, C. Najera and M. Yus, Synthesis, 678 (1986). 676. C . Daubie, C. Bacquet-Einhorn and D. Lelandais, Can. J. Chem., 62, 1548 (1984). 677. J.-M. Poirier, Org. Prep. Proced. Int., 18, 79 (1985). 678. A. Pusino, V. Rosnati and A. Saba, Tetrahedron, 40,1893 (1984). 679. A. Pusino, A. Saba and V. Rosnati, Tetrahedron, 40, 3709 (1984). 680. M. V. Lakshmikantham, K. Ravichandran, D. Gosciniak and M. P. Cava, Tetrahedron Lett., 26, 4703 (1985). 681. K. Ravichandran, F. A. J. Kerdesky and M. P. Cava, J. Org. Chem., 51, 2044 (1986). 682. R. 0. Hutchins and I. M. Taffer, J. Org. Chem., 48, 1360 (1983). 683. M. Utaka, H. Makino, Y. Oota, S. Tsuboi and A. Takeda, Tetrahedron Lett., 24, 2567 (1983). 684. L. A. Reiter, J. Org. Chem., 49, 3494 (1984). 685. H. Matsumura, T. Tsuchiya, T. Takeda and K. Imafuku, Bull. Chem. Soc. Jpn., 56, 2037 (1983). 686. H. Matsumura, T. Tsuchiya and K. Imafuku, Bull. Chem. Soc. Jpn., 56, 3519 (1983). 687. P. Martin, H. Greuter and D. Bellus, Pestic. Sci., 11, 141 (1986). 688. P. Martin, H. Greuter, G. Rihs, T. Winkler and D. Bellus, Helu. Chim. Acta, 64, 2571 (1981). 689. L. Fitjer, Chem. Ber., 115, 1035 (1982). 690. J. Gasteiger and C. Herzig, Angew. Chem., 93, 933 (1981). 691. M. C. Cabaleiro and R. 0. Garay, J. Chem. Res. ( S ) , 154 (1983). 692. Y. Ogata and K. Nagura, J . Chem. Soc., Perkin Trans. 2, 628 (1976). 693. K. Griesbaum, G. 0. Lie and H. Keul, J. Org. Chem., 49, 679 (1984). 694. C. R. Engel, P. Lachance, J. Capitaine, J. Zee, D. Mukherjee and Y. Merand, J. Org. Chem., 48, 1954 (1983). 695. C. R. Engel, Y. Merand and J. Cbte, J. Org. Chem., 47, 4485 (1982). 696. B. Fohlisch, E. Gehrlach, J. J. Stezowski, P. Kollat. E. Martin and W. Gottstein, Chem. Ber., 119, 1661 (1986). 697. B. Fohlisch, W. Gottstein, R. Kaiser and 1. Wanner, Tetrahedron Lett., 21, 3005 (1980). 698. B. Fohlisch, W. Gottstein, R. Herter and I. Wanner, J . Chem. Res. (S), 246 (1981). 699. R. Herter and B. Fohlisch, Synthesis, 976 (1982). 700. B. Fohlisch, R. Flogaus, J. Oexle and A. Schadel, Tetrahedron Lett., 25, 1773 (1984). 701. B. Fohlisch, E. Gehrlach and R. Herter, Angew. Chem., 94, 144 (1982). 702. J. Mann and A. A. Usmani, J . Chem. Soc.. Chem. Commun., I 1 19 (1980). 703. N. Shimizie, M. Tanaka and Y. Tsuno, J . Am. Chem. SOC.,104, 1330 (1982). 704. L. Duhamel and J. Chauvin, Tetrahedron Lett., 23, 1665 (1982). 705. G.4. Tsuchihashi, K. Kitajima and S. Mitamura, Tetrdudron Lett., 22, 4305 (1981). 706. J. H. Scott, T. A. Smith and J. H. Hutchinson, J. Heterocycl. Chem., 21, 903 (1984). 707. N. De Kimpe, L. De Buyck, R. VerhC and N. Schamp, Chem. Ber., 116, 3631 (1983). 708. C. Giordano, G. Castaldi, F. Casagrande and L. Abis, Tetrahedron Lett., 23, 1385 (1982). 709. C. Giordano, G. Castaldi and F. Uggeri, Angew. Chem.. Int. Ed. Engl., 23,413 (1984). 710. C. Giordano, G. Castaldi, F. Uggeri and F. Gurzoni, Synthesis, 436 (1985). 711. S. Ito, K. Aihara and M. Matsumoto, Tetrahedron Lett., 25, 3801 (1984). 712. W. Adam, E.-M. Peters, K. Peters, H. Platsch, E. Schmidt, H. G. Von Schnering and K. Takayama, J. Org. Chem., 49, 3920 (1984). 713. A. S. Avakyan, S. 0. Vartanyan and E. A. Markaryan, Arm. Khim.Zh., 37, 265 (1984); ('hem. Abstr., 101, 72679 (1984). 714. V. K. Mahesh and R. Sharma, Indian J. Chem.. Sect. B, 17, 382 (1979). 715. J. Einhorn, P. Demerseman, R. Royer, R. Cavier and P. Gayral, Eur. J. Med. Chem. Chim. '/'her., 19, 405 (1984); Chem. Abstr., 102, 131847 (1985).

218

Norbert De Kimpe and Roland Verhe

716. G. L. Papayan and S. M. Davtyan, Khim. Geterotsikl. Soedin., 57(1979);Chem. Ahstr., 84,15464 (1981). 717. J. Novik and C. A. Salemik, J. Chem. Bull. Prrkin Truns. I . 72Y (1984). 718. Y. Geetanjali, B. Rajitha and M. K. Rao, Bull. Chrm. Soc. Jpn., 59. l2YY (1986). 719. D. R. Shridhar, C. V. Sastry, B. 0. P. Reddy and P. P. Rao, Synthesis. 912 (1981). 720. A. R. Katritzky and N. E. Grzeskowiak, J. Chem. Res. (S), 208 (1981). 721. G . A. Russell and F. Ros, J . Am. Chem. SOC., 104,7349 (1982). 722. G. A. Russell and F. Ros, J. Am. Chem. SOC., 107,2506 (1985). 723. G. D. S. Ananda and R. J. Stoodley, Tetrahedron Lett., 26,497 (1985). 724. M. E. Garst and T.A. Spencer, J . Org. Chem., 48,2442 (1983). 725. T. Biftu, J. Heterocycl. Chem., 21,881 (1984). 726. K. Gewald, P.Bellmann and H.-J. Jansch, Justus Liebigs Ann. Chem., 1623 (1980). 727. F. Benayache, Y. Gounelle and J. Jullien, J. Chem. Res. (S), 158 (1981). 728. V. D. Orlov, F. G. Yaremenko and V. F. Lavrushin, Khim. Geterotsikl. Soedin., 1489 (1980); Chem. Abstr., 95, 6925 (1981). 729. H.S. Bevinakatti and V. V. Badiger, J. Heterocycl. Chem., 19,69 (1982). 730. R. F. Parcell and J. P. Sanchez, J. Org. Chem., 46,5055 (1981). 731. B. Miller and E. R. Matjeka, J . Am. Chem. Soc., 102,4772 (1980). 732. N.De Kimpe, R. Verhe, L. De Buyck and N. Schamp, Bull. Soc. Chim. Belg., 91,99 (1982). 733. N.De Kimpe, L. Moens, R. Verhe, L. De Buyck and N. Schamp, Tetrahedron Lett., 23,789 (1982). 734. F. Sanchez-Yiesca and M. R. Gomez, Reu. Latinoam. Quim., 14,106 (1984);Chem. Ahstr., 101. 38297 (1984). 735. S. F. Vice, R. W. Frisen and G. I. Dmitrienko, Tetrahedron Lert., 26,165 (1985). 736. P.A. Wender and A. W. White, Tetrahedron, 39,3767 (1983). 737. M. Kuroki and Y. Tsunashima, J . Heterocycl. Chem., 18, 709 (1981). 738. A. J. Elliott, H. Guzik and J. R. Soler, J. Heterocycl. Chem., 19,1437 (1982). 739. E. S. Hand and W. W. Paudler, Tetrahedron, 38,49 (1982). 740. C. Sablayrolles, G. H. Cros, J. C. Milhavet, E. Recheng, J.-P. Chapat, M. Boucard, J. J. Serrano and J. H. McNeill, J. Med. Chem., 27,206 (1984). 741. T.Itaya, T.Watanabe and H. Matsumoto, J. Chem. Soc.. Chem. Commun., 1158 (1980). 742. M. V. Povstyanoi, V. P. Kruglenko, A. A. Timoshin, N. A. Klyuev, 1. 1. Grandberg and Y. Y. Stoilov, Izu. Timiryuzerk. S-kh. Akud., 155 (1984);Chrm. Ahsfr., 102,45885 (1985). 743. V. A. Chuieuk and A. G. Maidannik, Khim. Geterotsikl. Soedin., 1695 (1980);Chem. Ahstr., 94, 175032(1981). 744. V. A. Chuiguk and E. L. Komar, Khim. Geterotsikl. Soedin., I134 (1983);Chem. Abstr., 99, 221491 (1983). 745. L. W. Deady and M. S. Stanborough, Aust. J . Chem., 34, 1295 (1981). 746. E. Surender, R. B. Reddy. P. B. Reddy, G. V. P. Chandramouli and Y. D. Reddy, J. Indian Chem. Soc., 61,534 (1984). 747. C. Temple, G. P. Wheeler, R. N. Comber, R. D. Elliott and J. A. Montgomery, J. Med. Chem., 26, 1614 (1983). 748. P. Molina, A. Ferao, P. M. Fresneda, A. Lorenzo and A. Tarraga, J. Hererocycl. Chem., 20,381 (1983). 749. M. A. El-Daway, A. M. M. E. Omar, A. M. Ismail and A. A. B. Hazzaa, J. Pharm. Sci., 72,45 ( 1 983). 750. K. Sakai and N. Yoneda, Chem. Pharm. Bull., 29,1554 (1981). 751. S. B. Sahni and S. M. Gupta, J . Inst. Chem. (India), 56, 81 (1984);Chem. Abstr., 101, 170750 ( 1984). 752. H. T.Katvalyan, A. S. Shashkov and E. A. Mistryukov, J. Heterocycl. Chem., 22,53 (1985). 753. I. V. Migaichuk and 1. G. Khaskin, Zh. Prikl. Khim. (Leningrad), 55, 2066 (1982);Chem. Abstr., 97,215503 (1984). 754. C. Montignoul, M.-J. Richard, C. Vigne and L. Giral, J. Heterocycl. Chem., 21,1509 (1984). 755. E.Puech-Costes and A. Lattes, Bull. Soc. Chim. Fr., (II), 96 (1982). 756. J. Rouchaud and J. Meyer, J . Labelled Compd. Radiopharm., 14,11 1 (198I). 757. H. Ehrhardt and R. Handte, Justus Liebigs Ann. Chem., 1088 (1985). 758. D. R. Meyer and P. M. Weintraub, J . Heterocycl. Chem., 18, 451 (1981). 759. F.Dutron-Woitrin, R. Merknyi and H. G. Viehe, Synthesis, 79 (1985).

App. 1. Synthesis and reactivity of a-halogenated ketones 760. 761. 762. 763. 764. 765. 766. 767. 768. 769. 770. 771. 772. 773. 774. 775.

776. 777. 778. 779. 780. 781. 782. 783. 784. 785. 786. 787. 788. 789. 790. 791. 792. 793. 794. 795. 796. 797. 798. 799. 800. 801. 802. 803. 804.

219

I. Saji, K. Tarnoto, H. Yamazaki and H. Agui, Heterocycles, 15, 943 (1981). K. Goerlitzer and E. Engler, Arch. Pharm. (Weinheim), 313, 405 (1980). N. De Kimpe, M. Palamareva and N. Schamp, J. Org. Chem., 50,2993 (1985). E. M. Gordon, J. PluScec, N. G. Delaney, S. Natarajan and J. Sundeen, Tetrahedron Letr., 25, 3277 (1984). A. M. Zvonok, N. M. Kuz’menok, I. G. Tishchenko and L. S. Stanishevskii, Vestsi Akad. Nauuk BSSR, Ser. Khim. Naouk, 80 (1984); Chem. Abstr., 102, 149000 (1985). R. Buchan, M. Frases and P. V. S. Kong Tho0 Lin, J . Org. Chem., 50, 1324 (1985). M. D. Nair and J. A. Desai, Indian J. Chem.. Sect. B, 19, 65 (1980). H. Goto, K. Kurata, H. Awaya, Y. Torninaga, Y. Matsuda and G. Kobayashi, Heterocycles, 325 (1982). N. J. Reddy, M. Bokadia, T. Sharma and J. A. Donnelly, J . Org. Chem., 46,638 (1981). P. Buttinelli, M. A. Loreto, L. Pellacani and P. A. Tardella, J. Chem. Res. (S), 158 (1985). S. Eguchi, Y. Wakata and T. Sasaki, J. Chem. Res. (S), 146 (1985). A. Guzman, J. M. Muchowski and J. T. Naal, J. Org. Chem., 46, 1224 (1981). A. Buschauer, K. Wegner and W. Schunack, Arch. Pharm. (Weinheim), 317, 9 (1984). H. J. Neubauer, J. Baeza, J. Freer and U. Schollkopf, Justus Liebigs Ann. Chem., 1508 (1985). R. A. Roberts and L. A. Paquette, unpublished results, cited in L. A. Paquette, Topics Curr. Chem., 119, 129 (1984). H. Carpio, E. Galeazzi, R. Greenhouse, A. Guman, E. Velarde, Y. Antonio, F. Franco. A. Leon, V. Perez, R. Salas, D. Valdts, J. Ackrell, D. Cho, P. Gallegra, 0. Halpern, R. Koehler, M.L. Maddox, J. M. Muchowski, A. Prince, D. Tegg, T. C. Thurber, A. R. van Horn and D. Wren, Can. J. Chem., 60,2296 (1982). G. Crank and H. R. Khan, Aust. J. Chem., 38,447 (1985). Y. A. Sharanin, Zh. Org. Khim.. 16, 2185 (1980); Chem. Ahstr.. 94, 192195 (1981). R. H. Bradburry and K. A. M. Walker, Tetrahedron LPtt., 23, 1335 (1982). P. Krey and H. Dehne, Pharmazie, 37, 145 (1982). M. J. Korohada and A. B. Bojarska, Pol. J. Chem., 58,447 (1984). T. L. Hough and G. P. Jones, J. Heterocycl. Chem., 21, 1377 (1984). E. Mitzner and J. Liebscher, 2. Chem., 23, 19 (1983). L. Somsak, I. Romhanyi and K. Peseke, Wiss.2.Wilhelm Pieck Uniu. Rostock, Naturwiss. Reihe, 31, 23 (1982); Chem. Abstr., 99, 194863 (1983). F. Arndt, W. Franke, W. Klose, J. Lorenz and K. Schwarz, Justus Liebigs Ann. Chem., 1302 (1984). T. Hara, Y. Kayarna and H. Fukushima, J. Heterocycl. Chem., 18, 1089 (1981). S. Rajappa, V. Sudarsanam, B. Advani and A. V. Rane, Indian Acad. Sci.. [Ser.]: Chem. Sci., 91, 445 (1982); Chem. Abstr., 98, 143314 (1983). F. Sharrard, J.-C. Meslin, A. Reliquet and F. Reliquet, Sulfur Lett., 2,5 1 (1984);Chem. Abstr.. 101, 90383 (1984). A. Corsaro, A. Compagnini, G. Perrini and G. Purrello, J . Chem. Soc., Perkin Trans. I . 897 (1984). M. A. Riahi and J.-P. Pradtre, C.R. Acad. Sci., Ser. 11, 293, 671 (1981). M. Kulka, Can. J . Chem., 59, 1557 (1981) H. Singh, P. Singh and K. Deep, Tetrahedron, 39, 1665 (1983). A. Corsaro, M. Tarantello and G. Purrello, Tetrahedron Lett., 22, 3305 (1981). R. Ghirlando, A. S. Howard, R. B. Katz and J. P. Michael, Tetrahedron, 40, 2879 (1984). X. Wang, Z. Wang and R. Lian, Huaxue Xuebao, 40,459 (1982);Chem. Ahstr., 97. 127334 ( 1 982). H. Fenner, H. J. Meier and R. Anschuetz, Arch. Pharm. (Weinheim),314, 729 (1981). P. Molina, A. Arques and A. Ferao, Synthesis, 645 (1982). P. Molina, A. Tarraga and M. L. Pena, Synthesis, 697 (1984). P. A. Reddy and V. R. Srinivasan, Indian J. Chem., Sect. B, 18,482 (1979). A. V. Ivashchenko, V. T. Lazareva, E. K. Prudnikova, S. P. Ivashchenko and V. G. Rumyantsev, Khim. Geterotsikl. Soedin., 236 (1982); Chem. Abstr., %, 181202 (1982). M. G. Joshi and K. N. Wadodkar, Indian J. Chem., Sect. B, 20, 1090 (1981). M. W. Bryant, R. A. J. Smith and L. Wong, Aust. J. Chem., 35, 2529 (1982). 0.A. Attanasi and I. L. Caglioti, Org. Prep. Proced. Int., 18, 299 (1986). U. Schmidt, A. Lieberknecht, H. Griesser and H.Bokens, Justus Liebigs Ann. Chem., 785 (1985). T. Patonay, R. Bognar and G. Litkei, Tetrahedron, 40, 2555 (1984).

Norbert De Kimpe and Roland Verhe

220 805. 806. 807. 808.

809. 810. 811. 812. 813. 814. 815. 816. 817.

818. 819. 820. 821. 822. 823. 824. 825. 826. 827. 828. 829. 830. 831. 832. 833. 834. 835. 836. 837. 838. 839. 840. 841. 842. 843. 844. 845. 846. 847. 848. 849. 850. 851. 852. 853.

F. Asinger and M. K. Schmitz, Monatsh. Chem., 113, 1191 (1982). N. J. Curtis and R. S. Brown, Can. J. Chem., 59, 65 (1981). R. Seshadri, W. J. Pegg and M. Israel, J. Org. Chem., 46, 2596 (1981). F. Leyendecker and M.-T. Compte, Tetrahedron Lett., 23, 5031 (1982). M. Lissel, J. Chem. Res. ( S ) , 286 (1982). M. R. Detty and G. P. Wood, J . Org. Chern., 45, 80 (1980). E. A. Ramazanov, F. F. Kerimov, I. G. Mursakulov and A. M. Moiseenkov, Izu. Akad. Nauk SSSR, Ser. Khim., 1161 (1984); Chem. Abstr., 101, 170748 (1984). L. S. Liebeskind and S. L. Baysdon, Tetrahedron Lett., 25, 1747 (1984). H. Greuter, P. Bissig, P. Martin, V. Flueck and L. Gsell, Pestic. Sci., 11,148 (1980); Chem. Abstr., 94, 102874 (1981).

L. K. A. Rahman and R. M. Scrowston, J. Chem. Soc., Perkin Trans. I , 2973 (1983). S. H. Mashraqui and R. M. Kellogg, Tetrahedron Lett., 26, 1457 (1985). W. Chin-Hsien, Synthesis, 622 (1981). C. Polycarpe, E. Torreilles, L. Giral, A. Babeau, N.-H. Tinh and H. Gasparouse, J. Heterocycl. Chem., 21, 1741 (1984). M. D. Brown, D. W. Gillon, G. D. Meakins and G. A. Whitham, J. Chem. SOC..Chem. Commun., 444 (1982). T. Fuchigami, M.-Y. Yeh, T. Nonaka and H.-J. Tien, Bull. Chem. Soc. Jpn., 56, 3851 (1983). T. Fuchigami and T. Nonaka, J. Org. Chem., 48, 3340 (1983). T. Tanaka, T. Hashimoto, K. Iino, Y.Sugimura and T. Miyadera, Tetrahedron Lett., 23, 1075 (1982). L. A. Suba, P. G. Ruminski and J. J. DAmico, Phosphorus Su!fur, 20, 251 (1984). H. Ishihara, S. Muto and S. Kato, Synthesis, 128 (1986). F. Wudl and D. Nalewjek, J. Chem. SOC.,Chem. Commun., 866 (1980). A. Moradpour, V. Peyrussan, I. Johansen and K. Bechgaard, J. Org. Chem., 48, 388 (1983). A. S. Prochukhan, E. M. Baranovskaya and A. S. Lukmanova, Org. Soedin. Sery, 2,204 (1980), Chem. Abstr., 96, 103566 (1982). R. L. Crumbie and D. D. Ridley, Aust. J. Chem., 34, 1017 (1981). M. Numazawa, M. Satoh, S. Satoh, M. Nagaoka and Y. Osawa, J. Org. Chem., 51,1360 (1986). K. Takahashi, T. Nighizuka and H. Iida, Synth. Commun., 11, 757 (1981). A. Abad, C. Agull6, M. Am6 and F. Seoane, Tetrahedron, 42, 2429 (1986). H. Galons, H. H. Ibrahim, C. Combet Farnouse and M. Miocque, C.R. Acad. Sci., Ser. 11,292, 1517 (1981). G. Pattenden and D. Whybrav, J. Chem. SOC., Perkin Trans. I , 1046 (1981). T. Sakai, H. Tabata and A. Takeda, J. Org. Chem., 48,4618 (1983). C. Dagher, R. Hanna, P. B. Terentiev, Y. G. Boundel, A. N. Kost and B. I. Maksimov, J . Heterocycl. Chem., 19, 645 (1982). F. Heinzer and D. Bellus, Helu. Chim. Acta, 64, 2279 (1981). M. Makosza, A. Kwast, E. Kwast and A. Jonczyk, J. Org. Chem., SO, 3722 (1985). G. Falsone and H. P. Wingen, Arch. Pharm. (Weinheim), 317, 802 (1984). A. A. Padmapriya, G. Just and N. G. Lewis, Can. J. Chem., 63,828 (1985). H. H. Kaegi, J. E. Bupp and J. I. DeGraw, J . Labelled Compd. Radiopharm, 19, 745 (19E2). B. Begasse and M. Le Corre, Tetrahedron, 36, 3409 (1980). M. Larcheveque, P. Perriot and Y. Petit, Synthesis, 297 (1983). J. J. Eisch, S. K. Dua and M. Behrooz, J. Org. Chem., 50, 3674 (1985). M. Jawdosiuk and M. Uminski, J . Chem. SOC.,Chem. Commun., 979 (1982). M. Obayashi, E. Ito, K. Matsui and K. Kondo, Tetrahedron Lett., 23, 2323 (1982). T. Hashimoto, T. Watanabe, Y. Kawano, T. Tanaka and T. Miyadera, Chem. Pharm. Bull., 28, 2980 (1980). N. Matsumura, A. Kunugihara and S. Yoneda, Tetrahedron Lett., 25, 4529 (1984). P. Molina, A. Lorenzo and P. M. Fresneda, Synthesis, 49 (1983). J. Barluenga, F. Alvarez, J. M. Concellon and M. Yus, Synthesis, 654 (1986). R. Menicagli, S. Vecchiani, C. Malanga and L. Lardici, J . Org. Chem., 49, 313 (1984). J. Barluenga, J. R. Fernande: and M. Yus, Synthesis, 277 (1985). P. A. Wender, D. A. Holt and S. M. Sieburth, J. Am. Chem. SOC., 105, 3348 (1983). P. Ribereau and G. Queguiner, Can. J. Chem., 61, 334 (1983). D. A. Holt, Tetrahedron Lett., 22, 2243 (1981).

App. 1. Synthesis and reactivity of a-halogenated ketones 854. 855. 856. 857. 858. 859. 860. 861. 862. 863. 864. 865. 866. 867. 868. 869. 870. 871. 872. 873. 874. 875. 876. 877. 878. 879. 880. 881. 882. 883. 884. 885. 886. 887. 888.

22 1

P. Stanetty, J. Chem. Res. ( S ) , 100 (1981). J. Barluenga, M. Yus, J. M. Concellon and P. Bernad, J . Chem. Res. (S), 41 (1980). J. Barluenga, M. Yus, J. M. Concellon and P. Bernad, J. Chem. Res. (S), 324 (1980). J. Barluenga, M. Yus, J. M. Concellon and P. Bernad, J. Org. Chem., 46, 2721 (1981). J. Barluenga, M. Yus, J. M. Concellon, P. Bernad and F. Alvarez, J. Chem. Res. (S), 128 (1985). J. Barluenga, J. Florez and M. Yus, Synthesis, 647 (1983). S. Sato, I. Matsuda and Y. Izumi, Tetrahedron Lett., 26, 1527 (1985). L. Crombie, R. Hardy and D. W. Knight, J. Chem. Soc., Perkin Trans. I, 1373 (1985). A. G. Angoh and D. L. J. Clive, J. Chem. Soc.. Chem. Commun., 980 (1985). J. Barluenga, J. Florez and M. Yus, J. Chem. Soc.. Perkin Trans. I, 3019 (1983). E. Murayama, T. Kikuchi, K. Sasaki, N. Sootome and T. Sato, Chem. Lett., 1897 (1984). J.-P. Depres, F. Coelho and A. E.Greene, J . Org. Chem., 50, 1972 (1985). P. A. Wender and A. W. White, Tetrahedron, 39, 3767 (1983). L. Hamon and J. Levisalles, J. Organomet. Ctiem., 253, 259 (1983). P. A. Wender, J. M. Erhardt and L. J. Letendre, J . Am. Chem. SOC., 103, 21 14 (1981). A. F. Greene, J.-P. Lansard, J.-L. Luche and C. Petrier, J . Org. Chem., 48, 4763 (1983). X. Lei, C. Doubleday and N. J. Turro, Tetrahedron Lett., 27, 4671 (1986). H. C. Brown and G. G. Pai, J. Org. Chem., 48, 1784 (1983). H. C. Brown and G. G. Pai, J. Org. Chem., 50, 1384 (1985). S. Brandange, 0. Dahlman and J. Olund, Acta Chem. Scand., Ser. B, 37, 141 (1983). R. F. Parcell and J. P. Sanchez, J. Org. Chem., 46, 5228 (1981). R. Noyori and Y. Hayakawa, Org. React., 29, 163 (1983). J. Mann, Tetrahedron, 42, 4611 (1986). R. Noyori and Y. Hayakawa, Tetrahedron, 41, 5879 (1985). M. Kosugi, T. Ohya and T. Migita, Bull. Chem. SOC.Jpn., 56, 3539 (1983). M. Kosugi, M. Koshiba, H. Sano and T. Migita, Bull. Chem. SOC.Jpn., 58, 1075 (1985). I. Pri-Bar, P. S. Pearlman and J. K. Stille, J. Org. Chem., 48, 4626 (1983). M. Kosugi, I. Takano, M. Sakurai, H. Sano and T. Migita, Chem. Lett., 1221 (1984). S. T. Vijayaraghavan and T. R. Balasubramanian, J. Organomet. Chem., 282, 17 (1985). M. Kosugi, I. Takamo, I. Hoshino and T. Migita, J. Chem. SOC..Chem. Commun.,1031 (1983). G. Maier, C. Roth and R. K. Schmitt, Chem. Ber., 118, 704 (1985). M. Iyoda, M. Sakaitani, A. Kojima and M. Oda, Terrahedron Lett., 26, 3719 (1985). F. Sato, S. Iijima and M. Sato, Tetrahedron Lett., 22, 243 (1981). T. Hudlicky, B. C. Ranu, S. M. Naqvi and A. Srnak, J . Org. Chem., 50, 123 (1985). K. Maruoka, S. Hashimoto, Y. Kitagawa, H. Yamamoto and H. Nozaki, Bull. Chem. SOC.Jpn., 53, 3301 (1980). 889. S. Matsubara, N. Tsuboniwa, Y. Morizawa, K. Oshima and H. Nozaki, Bull. Chem. Soc. Jpn.. 57, 3245 (1984). 890. N. Tsuboniwa, S. Matsubara, Y. Morizawa, K. Oshima and H. Nozaki, Tetrahedron Lett.. 25, 2569 (1984). 891. R. W. Stevens, N. Iwasawa and T. Mukaiyama, Chem. Lett., 1459 (1982). 892. T. Mukaiyama, T. Haga and N. Iwasawa, Chem. Lett., 1601 (1982). 893. T. Mukaiyama, N. Iwasawa, R. W. Stevens and T. Haga, Tetrahedron, 40, 1381 (1984). 894. T. Harada and T. Mukaiyama, Chem. Lett., 467 (1982). 895. S. Shoda and T. Mukaiyama, Chem. Lett., 723 (1981). 896. T. Imamoto, T. Kusumoto and M. Yokoyama, Tetrahedron Lett., 24, 5233 (1983). 897. S.-i. Fukuzawa, T. Fujinami and S. Sakai. J . Chem. Soc.. Chem. Commun., 777 (1985). 898. J. T. Welch and K. W. Seper, Tetrahedron Lett., 25, 5247 (1984). 899. J.-E. Dubois, G. Axiotis and E. Bertounesque, Tetrahedron Lett., 26,4371 (1985). 900. F. G. Saitkulova, G. G. Abashev, I. A. Kyuntsel, G. B. Soifer and I. I. Lapkin, Khim. Elementoorg. Soedin., 66 (1981); Chem. Abstr., 27, 215676 (1982). 901. F. G. Saitkulova, I. I. Lapkin, T. S. Prokhorova, G. G. Abashev, V. A. Demakov, N. V. Golyasnaya and G. V. Batueva, K h i m - f a r m . Zh.,19,51 (1985);C h e w Ahstr.. 103.53766(1985). 902. T. Ishira, T. Yamanaka and T. Ando, Chem. Lett., 1165 (1984). 903. P. G. Williard and J. M. Salvino, J. Chem. SOC..Chem. Commun., 153 (1986). 904. C. J. Kowalski and K. W. Fields, J . Am. Chem. SOC., 104, 321 (1982). 905. C. J. Kowalski, M. S. Hague and K. W. Fields, 1.Am. Chem. Soc., 107, 1429 (1985). 906. R. K. Bansal and K. Sethi, Bull. Chem. Soc. Jpn., 53, 1147 (1980).

222 907. 908. 909. 910. 911. 912. 913. 914. 915. 916. 917. 918. 919. 920. 921. 922. 923. 924. 925. 926. 927. 928. 929. 930. 931. 932. 933. 934. 935. 936. 937. 938. 939. 940. 941. 942. 943. 944. 945. 946. 947. 948. 949. 950. 951. 952. 953. 954. 955.

Norbert De Kimpe and Roland Verhe K. Tomisawa, K. Kameo, M. Goi and K. Sota, Chem. Pharm. Bull., 32,3066 (1984). G. H. Posner, J. P. Mallamo and A. Y. Black, Tetrahedron, 37, 3921 (1981). R. Jullien. H. Stahl-Lariviere, D. Zann and L. Nadjo, Tetrahedron, 37, 3159 (1981). L. Toke, 1. Petnehazy and G. Szakal, Acta Chim. Acad. Sci. Hung., 106,179 (1981); Chem. Abstr., 95, 114431 (1981). F. Texier-Boullet, Bull. SOC.Sci. Bretagne, 56, 57 (1984); Chem. Abstr., 102, 113620 (1985). F. Texier-Boullet and A. Foucaud, Tetrahedron Lett., 21, 2161 (1980). F. Texier-Boullet and A. Foucaud, Synthesis, 165 (1982). F. Texier-Boullet and A. Foucaud, Synthesis, 916 (1982). T. Ishihava, M. Yamana and T. Ando, Tetrahedron Lett., 24, 5657 (1983). M. Sekine, M. Nakajima and T. Hata, J. Org. Chem., 46, 4030 (1981). T. V. Kolodka and Y. G. Gololobov, Zh. Obshch. Khim.,53,1013 (1983);Chem. Abstr.,99,88278 (1983). T. V. Kim, E. I. Kiseleva, Y.T. Struchkov, M. Y.Antipin, A. N. Chernegaand Y. G. Gololobov, Zh. Obshch. Khim., 54, 2486 (1984). K. S. Kim and W. A. Szarek, Can. J. Chem., 59, 878 (1981). J. Skolimowski and R. Skowronski, Phosphorus Sulfur, 19, 159 (1984). 0. M. Buckachuk and M. I. Shevchuk, Zh. Obshch. Khim., 55, 752 (1985); Chem. Abstr., 103, 196156 (1985). N. Hanold, H. Kalbitz, M. Pieper, 0. Zimmer and H. Meier, Justus Liebigs Ann. Chem., 1344 (1986). G. Markl., K. Hock and D. Matthes, Chem. Ber., 116, 445 (1983). G. Markl and K. Hock, Chem. Ber., 116, 1756 (1983). E. Lindler, K. A. Starz, N. Pads and W. Winter, Chem. Ber., 116, 1070 (1983). T. Imanoto, T. Kusumoto, N. Suzuki and K. Sato, J . Am. Chem. Soc., 107, 5301 (1985). Y. Tamura, H. D. Choi, M. Mizutani, Y. Ueda and H.Ishibashi, Chem. Pharm. Bull., 30,3574 (1982). V. Gold and W. N. Wassef, J . Chem. Res. (S), 24 (1986). R. Tanikaga, K. Miyashita, H. Sugihara and A. Kaji, J. Chem. Soc., Chem. Commun., 1 106 (1981). L. Duhamel, J. Chauvin and C. Goument, Tetrahedron Lett., 24, 2095 (1983). M. Wada, T. Shigehisa and K.-i. Akiba, Tetrahedron Left., 24, 171 1 (1983). H. Emde, A. Gotz, K. Hofmann and G. Simchen, Justus Liebigs Ann. Chem., 1643 (1981). R. D. Miller and D. R. McKean, Synth. Commun., 12, 319 (1982). J. M. Poirier and L. Hennequin, Synth. Commun., 15, 217 (1985). M. Fiorenza, A. Mordini, S. Papaleo, S. Pastorelli and A. Ricci, Tetrahedron Lett.,26,787 (1985). C. J. Kowalski, M. L. ODowd, M. C. Burke and K. W. Fields, J. Am. Chem. Soc., 102, 5411 (1980). P. Sampson and D. F. Wiemer, J . Chem. SOC.,Chem. Commun., 1746 (1985). I. Fleming and B. W. Au-Yeung, Tetrahedron, 37, 13 (1981). A. E. Greene and F. Charbonnier, Tetrahedron Lett., 26, 5525 (1985). V. Dave and E. W. Warnhoff, J. Org. Chem., 48, 2590 (1983). M. A. McKervey, D. N. Russell and M. F. Twohig, J. Chem. Soc., Chem. Commun., 491 (1985). T. Imamoto, T. Takeyama and H. Koto, Tetrahedron Lett., 27, 3243 (1986). C. Mijares, B. Ortiz and F. Walls, Reo. SOC.Quim. Mex., 24, 164 (1980); Chem. Abstr., 95,42570 (1981). S. Sebti and A. Foucaud, Synthesis, 546 (1983). K. Clauss, Justus Liebigs Ann. Chem., 494 (1986). Y. H. Kim and S. H. Jung, Tetrahedron Lett., 22, 2371 (1981). E. W. Warnhoff and A. Nakamura, Tetrahedron Lett., 25, 503 (1984). E. W. Warnhoff and F. W. Verhoff, Heterocycles, 15, 777 (1981). K. Fujii, K. Nakao and T. Yamauchi, Synthesis, 444 (1983). P. Hofmann, A. Sieber, E. Beck and V. Schubert, Z. Naturforsch., Teil. B, 38, 1192 (1983). K. Satake, K. Itoh, M. Kimura and S. Morosawa, J. Chem. Soc., Perkin Trans. I , 729 (1986). K. Okamoto, K. Takeuchi and T. Kitagawa, Bull. Soc. Chim. Belg., 91,410 (1982). K. Takeuchi, T. Kitagawa and K. Okamoto, J. Chem. Soc., Chem. Commun., 7 (1983). C. Cambillau and M. Charpentier-Morize, J. Chem. Soc., Chem. Commun., 211 (1982). W. R. Bergmark, C. Barnes, J. Clark, S. Paparian and S. Marynowski, J . Org. Chem., 50, 5612 (1 985).

App. 1. Synthesis and reactivity of a-halogenated ketones

223

956. Y. Izawa, K. Ishiguro and H.Tomioka, Bull. Chem. SOC.Jpn., 56, 1490 (1983). 957. E. Lee-Ruff, A. C. Hopkinson and H. Kazarians-Moghaddam, Tetrahedron Lett., 24, 2067 (1983). 958. N. K. Hamer, Tetrahedron Lett., 27, 2167 (1986). 959. F. Barba, M. D. Velasco and A. Guirado, Synthesis, 625 (1981). 960. F. Barba, M. D. Velasco and A. Guirado, J . Heterocycl. Chem., 19, 669 (1982). 961. J. C. Sarma, M. Borbaruah and R. P. Sharma, Tetrahedron Lett., 26,4657 (1985). 962. L. Engman and M. P. Cava, J. Org. Chem., 47, 3946 (1982). 963. N. Petragnani and J. V. Comasseto, Synthesis, 1 (1986). 964. R.G. Micetich, S. N. Maiti, M. Tanaka, T. Yamazaki and K. Ogawa, J . Org. Chem., 51. 853 ( 1986). 965. S. K. Chung and Q. Y. Hu, Synth. Commun., 12,261 (1982). 966. G . A. Molander and G. Hahn, J. Ory. Chum.. 51. 1135 (1986). 967. J. N. Denis and A. Krief, Tetrahedron Lett., 22, 1431 (1981). 968. D. L. J. Clive and P. L. Beaulieu, J . Orq. Chem.. 47. 1124 (1982). 969. J.-E. Dubois, C. Lion and J. -Y. Dugast, Tetrahedron Lett., 24, 4207 (1983). 970. C. Lion, J.-E. Dubois, K. Lebbar, Bull. SOC.Chim. Belg., 95, 119 (1986). 971. T.-L. Ho, Synth. Commun., 11, 101 (1981). 972. A. Ono, E. Fujimoto and M. Ueno, Synthesis, 570 (1986). 973. T. B. Patrick and D. L. Darling, J. Org. Chem., 51, 3242 (1986). 974. E. d'Incan, S. Sibille and J. Perichon, Tetrahedron Lett., 27, 4175 (1986). 975. Y. J. Abul-Haj, J. Org. Chem., 51, 3380 (1986). 976. N. S. Simpkins, J. Chem. SOC..Chem. Commun., 88 (1986). 977. J. Ackrell and J. Muchowski, J. Org. Chem., 51, 3374 (1986). 978. M. Utaka, S. Konishi and A. Takeda, Tetrahedron Lm., 27, 4737 (1986). 979. E. J. Stamhuis, H. Maatman, H. StinissenandG. E. H. Joosten, Can. J. Chern.,64,1681 (lY86). 980. E. J. Stamhuis, H. Maatman and G. E. H. Joosten, Can. J. Chem., 64, 1690 (1986). 981. F. Bellesia, F. Ghelli, R. Grandi and U.M. Pagnoni, J. Chem. Res. (S), 426 (1986). 982. F. Bellesia, F. Ghelli, R. Grandi and U. M. Pagnoni, J. Chem. Rex (S), 428 (1986). 983. N. De Kimpe and N. Schamp, Org. Prep. Proced. fnt., 13, 241 (1981). 984. N. De Kimpe and N. Schamp, Org. Prep. Proced. fnt., 15, 71 (1983). 985. P. Sampson, G. B. Hammond and D. F. Wiemer, J. Org. Chem., 51, 4342 (1986). 986. D. D. Tanner and H. K. Singh, J. Org. Chem., 51, 5182 (1986). 987. H. Chikashita, H. Ide and K. Itoh, J. Org. Chem., 51, 5400 (1986). 988. Eur. Pat., E.P. 198440 (1986); Chem. Abstr., 106,48667 (1987). 989. D. Seebach, R.Imwinkelried and T. Weber, Modern Synthetic Methods, Vol. 4, Springer Verlag, Berlin, 1986, p. 128. 990. K. Hiroi and S. Yamada, Chem. Pharm. Bull., 21, 54 (1973). 991. Eur. Pat., E.P. 81993 (1983); Chem. Abstr., 99, 175386 (1983). 992. 0. Piccolo, F. Spreafico, G. Visentin and E. Valoti, J. Org. Chem., 52, 10 (1987). 993. G. Castaldi, S. Cavicchioli, C. Giordano and F. Uggeri, Angew. Chem., f n t . Ed. Engl., 25. 259 ( 1986). 994. Eur. Pat., E.P. 158913 (1985); Chem. Abstr., 104, 148566 (1986).

The chemistry of a -haloketones, or-haloaldehydes and a-haloimines Edited by Saul Patai & Zvi Rappoport Copyright 0 1988 by John Wiley & Sons Ltd

CHAPTER 2

&Halogenated imines

I. INTRODUCTION

225

.

11. SYNTHESIS OF a-HALOGENATED IMINES . A. Condensation of a-Halogenated Carbonyl Compounds with Primary Amines . B. Halogenation of Imino Compounds . C . Synthesis of a-Halogenated Imino Compounds by Halogenation of Enamines . D. Miscellaneous Methods . 111. REACTIVITY OF a-HALOGENATED IMINES . A. Nucleophilic Substitutions B. Carbon-Carbon Bond Formation . 1. Reactions of a-halogenated imino compounds with carbanions 2. Reactions of a-halogenated imino compounds with cyanide ion . 3. Reaction of a-halogenated imino compounds with organometallicreagents . C. Elimination Reactions of a-Halo Imino Compounds . D. Nucleophilic Additions to N-Activated a-Halogenated Imino Compounds . E. Rearrangement of a-Halogenated Imino Compounds . 1. The Favorskii-type rearrangement . 2. Rearrangement of a-halo imines via activated aziridine intermediates 3. Rearrangement of chloroindolenine derivatives . 4. Beckmann rearrangement of a-bromo oximes . F. Cycloadditions G. Miscellaneous Reactions of a-Halogenated Imino Compounds . IV. PROPERTIES AND APPLICATIONS OF a-HALOGENATED IMINO COMPOUNDS

226 227 230 235 236 241 242 252 253 254 255 256 257 259 259

260 261 262 263 264 265 267

V. REFERENCES

I. INTRODUCTION a-Halogenated imino compounds (1) are the nitrogen homologues of a-halogenated ketones (2). While the latter class of compounds has been studied extensively in the literature, a-halo imines have only recently come t o be used regularly in organic synthesis despite the fact that they were proven earlier t o be valuable synthetic reagents.

225

226

N. De Kimpe and R. VerhC NdR

X = halogen

0

X = halogen

Information regarding the use of a-halogenated imino compounds (1) in organic synthesis remained scattered until very recently when this matter was compiled in a review covering the synthesis’ and reactivityZ of these compounds. It is to focus attention on the versatility and potential of these reagents that this information has been brought together. The literature has been reviewed up to early 1980. Only a-halogenated imino compounds having a structural similarity with a-halogenated carbonyl compounds will be treated in this review. However, when necessary, some leading references to the chemistry of a-halo imidates, a-halo amidines and a-halo imidoyl cyanides will be provided. In general, a-halogenated imino compounds (l), having at least one a-hydrogen, do not tautomerize into the corresponding enamines, except when conjugation in the molecule with such substituents as CN, C O O R , NO2, etc. is possible. Such B-halo enamines are not subject to discussion here. Some novel aspects of the chemistry of a-halo ketones will be discussed in another chapter in this monograph. Throughout the text some comparisons will b e made between the reactivities of a-halo carbonyl compounds and a-halo imines.

II. SYNTHESIS OF a-HALOGENATED MINES Comprehensive studies in the area of the synthesis of a-halo imines are of rather recent origin. The growing success of the use of these reagents in synthetic organic chemistry is predominantly due to the development of readily available syntheses of the title compounds. Indeed, early investigations in the field of a-halo imines met with difficulties, since no suitable conditions could be found for halogenation of imino compounds. Additionally, several a-halo imines were found to be unstable, especially towards hydrolytic and thermal reaction conditions. Two main strategies for the synthesis of a-halo imines (1) may be considered. The first one is the condensation of an a-halogenated carbonyl compound (2) with a primary amine under suitable reaction conditions, similar to the usual synthesis of imines starting from carbonyl compounds and primary a m i n e ~ ~The . ~ .second approach involves the halogenation of imines (4). In both cases, carbonyl compounds (3) are the starting materials for such syntheses. The first method gives rise to the desired a-halo imines (1) only in special cases. Most often, a variety of side reactions is encountered, among others nucleophilic a - s u b s t i t u t i ~ nelimination ~~~, of hydrogen halide’, haloform-type reaction^^.^^, Favorskii rearrangement%” and rearrangement via intermediate e p o ~ i d e s l ) - ~ ~In~ *many ~~. cases, intermediately formed a-halo imino compounds were further transformed under the given reaction conditions to various final product^^^-^^. The second approach to a-halo imines via halogenation of imines also met with major difficulties, especially in the older literature, because unstable immonium-type compounds resulted from this reaction. The latter were usually transformed into

2. a-Halogenated imines

227

R' $R3

/

"&R3

x

HalogenationR 2

(2)

\

R'$i3 R2

R2

(3)

/

X (1)

Halogenation

R 31 J ;

R2

(4)

a-halo carbonyl compounds by aqueous work-up. The medium in which the imine is halogenated plays a predominant role, as will be demonstrated in the following sections. Attention will be given now to the two aforementioned synthetic methods leading to a-halo imines, while the halogenation of enamines giving rise to the title compounds will also be discussed. Additionally, some miscellaneous methods for the synthesis of a-halogenated imines will be treated.

A. Condensatlonof a-Halogenated Carbonyl CompoundswAh Primary Amlner The reaction of a-fluoro carbonyl compounds with primary amines usually gives no difficulties in synthesizing the a-fluoro imines. l,l,l-Trifluoroacetone (7) reacted with aniline in benzene for 2 days to give N-(l,l ,l-trifluor0-2-propylidene)aniline (9) in 25% yield3', while 2,2-difluorononanal (5) condensed smoothly with t-butylamine at room temperature to give the a,a-difluoro aldimine ( 6 ) ' 0 5 . In similar way, aromatic

- --A 4" t-BuNMp

F F

(5)

(6)

k

F F

N. De Kimpe and R. Verhe

228

a-fluorinated ketones such as 2,2,2-trifluoroacetophenone(8) condensed with a-methylbenzylamine to afford a,a,a-trifluoroketimine ( Iminophosphoranes can also be used in such iminations of a-fluorinated ketonesIo5, as exemplified by the synthesis of 9 from 7 by using lI3'. When N-trialkylstannyltriphenylphosphonimines (13) were used as reagents, hexafluoroacetone (12)was converted into the N-trialkylstannyl-substitutedperfluoro ketimine ( 14)3y. When applied to trimethylsilyltriphenylphosphonimine, the

17) R (12) R

~

-

Me

C F ~

t

(C&),P=NSnRj

-

N/ SnR3

F3c

K

CF3

(13) (14) corresponding N-trimethylsilylimine could only be isolated in 1%yield39. Oximation of u - f l u o r ~ k e t o n e s ~ with ~ ~ hydroxylamine in ethanol in the presence of sodium acetate gives no side reactions, as exemplified by the synthesis of 5a-fluoro-6-oximinocholestane-3~-ol acetate ( 16)428. The same is true for the synthesis of a-fluoro h y d r a ~ o n e s ~ ' ~ . CBHl7

AcO

0

"FKNOH

(15 ) (16) Less reactive amino compounds, e.g. thiobenzamide derivatives (17), can also be used for direct condensation with hexafluoroacetone (12). Initially, however, 2.2,6.6-tetrakis(trifluoromethyl)-6H-1,3,5-oxathiazines(18) were formed, which could be pyrolysed into 2H- 1,3-thiazetes (19), existing in thermal equilibrium with N-( perfluoroisopropy1idene)thiocarboxamides (20)4M2. It will be demonstrated (vide infra) that the activated perfluoroketimines (20)show a fascinating reactive behaviour toward a variety of reagents with which they can undergo cycloadditions. Besides the direct imination of a-fluorinated carbonyl compounds, the direct condensation of @-halogenated ketones with aliphatic o r aromatic primary amines to give u-halogenated ketimines has never been described*. Only less sterically hindered carbonyl compounds such as a-chloro- and a-bromoaldehydes (21 and 22) react in a straightforward manner with aliphatic primary amines in ethereal medium at -30°C in the presence of molecular sieves to afford a-chloro- and a-bromoaldimines (23,24)in Compounds 23 and 24 are rather unstable and sensitive to moisture, 27-73% the N-t-butyl derivatives being the most stable ones. In the presence of excess primary amine. cr-halo imines 23 and 24 are slowly converted into a-alkylamino aldimines (25). The latter compounds (25) are also obtained in a more rapid reaction from u-halo

*See novel developments in the Appendix.

229

2. a-Halogenated irnines Ar

aldehydes and primary amines, indicating that the a-halo aldimines 23 and 24 are not intermediates in these reactions4'. In more drastic conditions, chloral condensed with primary amines under catalytic influence of zinc chloride and under azeotropic water removal to give trichl~roethylideneamines~~~-'~~. The usual carbonyl identification reagents such as 2,4-dinitrophenylhydrazine, hydroxylamine, semicarbazide, etc., also react with a-halo carbonyl compounds to afford the corresponding a-halo imino derivatives. Care should be taken, however, as regards the reaction conditions employed, since side reactions such as elimination, nitrosoolefin formation, etc., may take place.

X

~.~-ONPNHNH~

rg m.on.n2so, RT = 5-10min

(26) x = CI, b

(27) X = CI,Br

The Brady reagent4', i.e. an aqueous methanolic solution of 2.4-dinitrophenylhydrazine sulphate containing excess sulphuric could be successfully applied for the synthesis of a-halocyclohexanone 2,bdinitrophenylhydrazones (27). The reaction of a-bromocycloalkanones (28; n = 3,5,9) with tosylh drazine in ether produced crystalline a-bromo tosylhydrazones (29; n = 3,5,9)4Y*48*50, In a similar way, a-halogenated aldehydes gave the corresponding a-halogenated dinitrophenylhydraz~nes~~'~~~.This method was also applied for the synthesis of aliphatic a-bromo t o s y l h y d r a z ~ n e s ~The ~ ~ conversion ~ ~ ~ ~ ~ ~ . into a-bromo

230

N. De Kimpe and R. VerhC

(28;n = 3. 5.9)

( 2 9 ; n = 3'5.9)

tosylhydrazones seems to be a general reaction, occurring also with complex molecules like 14-bromodaunomycine (30)".

(30)

(31)

In a similar way again, a-halo semicarbazones and related compounds were isolated under appropriate reaction condition^^^-^^^'^^ but these compounds were subject to further transformations'1° into heterocyclic compounds'. Oximation of a-halo carbonyl compounds (32) requires controlled reaction conditions because of the possibility of side reactions of the initially formed a-halo oxime. Base-induced 1,4-elimination of hydrogen halide from a-halo oximes (33) yields nitrosoolefins (34)which are apt to undergo a variety of transformations6w2.

(35)

The intermediacy of these nitrosoolefins (34)was demonstrated by their isolation under In order to appropriate reaction conditions (see for example compound 3563-659218). avoid nitrosoolefin formation, it is recommended that oximations be performed in a slightly acid medium, such as in an aqueous calcium chloride s o l ~ t i o nor ~ ~with ,~~ ~ . ~ ~ . of a-halo equimolecular amounts of sodium acetate in acetic a ~ i d ~Oximations ketones can also be performed under milder conditions (such as NHzOH/methanol/THF/room temperature, 18 h)'56~'57~206~220~26. B. Halogenation of lmlno Compounds Several halogenating agents have been found to convert imino compounds (4) into a-halo imines (1). However, most of them were not proven to be of general synthetic

231

2. a-Halogenated imines NdR

NdR

(4)

(1)

interest and in many cases the a-halo imine formed could not be isolated, making hydrolysis to the more stable a-halo carbonyl compounds necessary. For example, halogenation with chlorine or bromine met with major difficulties by virtue of the instability of transient a-halogenated immonium halides7G72. Brominated acetophenone azines (37; X = Br) and (38; X = H) could be synthesized from the parent azine (36) with bromine in di~hloromethane’~or

(37;x = Br) (38;X = H ) methanol (0-5°C)74, respectively. 2-Alkyloxazolines were halogenated with chlorine or b r ~ m i n e ’ ~ ,while 2-pyrazolin-5-ones and 2-isoxazolin-5-ones (and related compounds) were also reported to be chlorinated at the active methylene function at the 4-position76.77.208.2a6, Probably due to their unstable nature, a-iodo ketimines have not been isolated hitherto. Recently, it was reported that a transient a-iodo ketimine (40)was used to transform methylketimines (39) into symmetric 1,4-diones (41) via lithiation (using lithium diisopropylamide = LDA), iodination, coupling of a-iodo ketimine (40) with the lithiated ketimine (anion of 39) and acidic hydrolysis of the 1,4-diimine thus formed7E.

R

0 A (39)

( 1 ) LDA

( 2 ) I,/lHf

* R

x> Ll (40)

(1 I Coupling

rraction

(21 HJO*

-

R

k (411

R

0

Among the halogenating agents of imines, N-halosuccinimide has been found to be the superior reagent for the synthesis of aliphatic and aromatic a-halogenated imino compounds. Ketimines are chlorinated at the less substituted a-position with N-chlorosuccinimide (NCS). The reaction is more regiospecific in carbon than in etherE4. The steroidal N-(2-hydroxyethyl)ketimines (42) were conveniently monochlorinated in ether, the resulting chloromethylketimine bein hydrolysed in acidic medium to the corresponding a-chloroketone (43) . N-Cyclohexyl and N-aryl methylketimines (44 and 45) were regiospecifically dichlorinated at the methyl function to produce dichloromethylketimines (46 and

!J

N. De Kimpe and R. VerhC

232

2 NCS

CCI,IO *C

R (44) R’ = cyclohexyl (45) R’= aryl

CI

R’ = cyclohexyl (47) R’= aryl

(&)

47)’-? together with negligible amounts of 1,3-dichloromethylketirninesand 1,l,l-trichloromethylketimines.The mechanism proceeds via chlorination of the less substituted enamine (48) in a non-radical manner. Steric interactions play an MR’

+NH#

R

‘I

(U)K=cyckhexyl (45) #=awl

Rq.‘ CI

(46) K= cvddrexvl (47)w = aryl

-H‘

+ ww R)ycl

NCS

M R

&I

CI

(52)

(511

important role in these halogenations and determine the regiospecific dichlorination of methylketimines. Even when the R-group in 44 or 45 is tertiary (R = 1-Bu), the reaction proceeds to dihalogenation, but N-alkyl imines of diisopropyl ketone (53) did not suffer chlorination with N-chlorosuccinimide in carbon tetrachloride. a,&.&Trichlorination of acetophenone imines (45; R = Ar) proceeds rapidly and quantitatively at reflux with NCS in carbon tetrachloride ( 5 min), while imines derived from dichloropinacolone (46,47; R = r-Bu) could not be further chlorinated under drastic conditions9’.

233

2. a-Halogenated imines

The reaction of imines with N-halosuccinimide requires an initiation period, after which the reaction proceeds smoothly to completion. As expected, and concordant with the proposed reaction mechanism, secondary enamines, i.e. enamines in which stabilizing groups such as a nitrile moiety force tautomerizable substrates to occur exclusively as enamines, react instantaneously with N-halosuccinimide (vide i n f " ) l ' s , ' ' h .Imines having no a'-hydrogen atoms, such as 54, 55 and 58, are easily chlorinated with NCS in CC1,8s-yo.Substitution of all available a-hydrogen atoms by chlorine atoms is accomplished without problems. However, methylketimines (44 and 45) o r imines having an a-CH2 function, e.g. 54 and 55, cannot be converted by this method into a-monochloro imines, because the rate of introduction of the first and the second halogen are of the same magnitude. This seems to be a general observation and points to the major limitation of the chlorination procedure of imines with N-chlorosuccinimide.

(54; R' = H ) (55; R' = Ar)

(58; R ' = H) (57; R' = Ar)

(59)

(58)

The same comments as given for the a-chlorination of imines using NCS are applicable for N-bromosuccinimide (NBS). Bromination of imines 44,M and 55 with NBS in CCI4 yielded a-bromo imines 609',619*and 628s in good yield. In many cases

(W

(61)

(62)

the use of NBS required the aid of benzoyl peroxide, irradiation or acid catalysisy3,or the combined action of these influences. A variety of classes of imino compounds have been a-brominated with N-bromosuccinimide, including oximine benzoates (a)'*, nitrones (65)ys-y7,2-methoxycarbonyl-1 - p y r r o I i n e ~ ~cyclic ~ , imino ethers (imidates) (67)yy.'"",hydrazone-type compounds (69)101-'"3, amidinesIo4 and l - p y r r o l i n e ~ ~ ~ ~ . Other sources of positive chlorine, which have been used for a-chlorination of imines, are sodium hypochloritelM,lmand t-butyl hypochlorite107~108. These reagents converted steroidal methylketimines (71) into mixtures of a-halogenated imines, while

234

N. D e Kimpe and R. VerhC

0

0

II

.,/OCPh

II

NBS/CCI,

BPO

Ok$'R

-a

R

P

r

NBS A

RO

RO

(67; R = Me,Etl

\Q

B

or "OC' r-EuOCI

*

Br

(a)

\ -

only the a,a,a-trichloromethyl derivative (72) was obtainable in a synthetically useful manner'"'. Monobromination of ketimines can be performed with 2,4,4,6-tetrabromocyclohexadienone,as exemplified for the N-t- butyl imine of 3,3,5,5-tetramethylcyclohexanone, but the monobromo compound existed in equilibrium with its enamino form93. A superior reagent for the a-bromination of hydrazones (73) seemed to be phenyltrimethylammonium perbromide (PTAB) in With two equivalents of the brominating reagent a,a'-dibromination occurredl1l.ll2.

2. a-Halogenated imines

235

C. Synthedr of a-Halogenated Imlno Compounds by Halogenation of

Enamlnes

Only those cases in which secondary enamines (76), i.e. enamines having one hydrogen bonded to nitrogen, are converted into a-halo imines will be discussed in this section. Halogenation of other enamines to produce p-halogenated enamines is discussed elsewhere' 1 3 .

(76)

(1)

Halogenation of enamines with chlorine or bromine to give a-haloimines has not 19, while the halogenation with N-halosuccinimide has been amply been mainly applied to enamines carrying electron-withdrawing a-Cyanoenamines (77) were halogenated to produce a-halo imidoyl cyanides (78; X = CI, Br)II5.lL6,while indoles were converted into 3-bromoindolenines by reaction

I

R2

(m

I'

x

(78) X = CI. Br

with NBS in carbon tetrachloride1z0J21. Similarly, the conversion of a-cyanoenamines (77) into 78 (X = Cl) was accomplished with aqueous sodium hypochloritells. On the other hand, indoles (79) were transformed into 3-chloroindolenines (81) with sodium h y p ~ c h l o r i t e ' ~but ~ - ~it~was ~ , shown that the reaction proceeded via intermediately formed N-chloroindoles (8O)lz4.

&R-(Q+j-QygR H

rn)

CI

(a)

(811

t-Butyl hypochlorite has been proven to be a very efficient reagent for the conversion of indoles into c h l o r o i n d ~ l e n i n e s ~and ~ ~ ~this ~ ~ ~ method ~ ~ ~ , found widespread application in the alkaloid field. In the latter field, various indole-type alkaloids have been chlorinated to chloroindolenines such as y ~ h i m b i n e ' ~ ~ * ' ~ ? ~, 135, ibogaine'34, cleavamine (82)135, 14,15-dehydro ~ e b r a c h a m i n e ' ~voaphylline ~ a c u b i n e ' ~tetraphyllir~e'~~, ~, hirsutine N-oxide pseudoyohimbine N - ~ x i d e ' ~ ~ , ~ a t h a r a n t h i n e and ~ ~ ~ several other examples13B~139~153~215~270~271~373~4174z6. It was recently shown that the chloroindolenines derived from cleavamine, 14,15-dehydroquebrachamine, voaphylline and some related derivatives have their chloro substituent ((2-7 position) in a b-orientation, a conclusion which was drawn from detailed investigation of their "C-NMR spectra135. Another source of positive chlorine which was found to be efficient for the

',

236

qJ+2-m N. De Kimpe and R. VerhC

H

(W

(83)

Cleavamine

conversion of indole alkaloids into chloroindolenines was N-chlorobenzotriazole'2s.i40, as reported for deserpine, yohimbine, catharanthine and (5)-dihydrocorynanthealI4O.

D. Miscellaneous Methods a-Halo imines carrying electron-withdrawing groups, e.g. alkoxycarbonyl, sulphonyl, acyl, aroyl, etc., at the nitrogen atom have a very electrophilic imino carbon, suitable for various reactions, including cycloadditions. So-called 'anhydrochloralurethanes' (86) were synthesized from carbamate adducts of chloral (84) via conversion into the chlorides (85) and subsequent dehydromethodology was applied to the synthesis of other related ~ h l o r i n a t i o n ' ~A~similar .

1 ,COOR

,COOR

OH

(84)

I EtjN

SOCI,

C13C

,COOR

c13c

CI

c13c A

(85)

H

(W

classes ofN-activated a-halogenated aldimines like a,a,/?-trichloroimines (87 and N-acetyl-a,a,a-trichloroacetaldimines a,a-dichloroaldimines (89)143, and N-sulphonyl-a,a,a-trihaloacetaldimines (91, 92 and 93)lUJ45.

8,.

.GH x x

(87) R = CH2CI; X = CI, R ' = Me, Et, n-Pr. Ph = CH2CI; X = CI; R ' = OEt (89) R = alkyl; R'=Me, Ph; X = C I (90) R = X = CI; R ' = Me

(88) R

.&YR' X X

(91) X = CI; R' = P-MeC& (92) X = F; R' = P-MeC6H4 (93) X =CI; R'=NMe2

Several other papers have reported the synthesis of N-activated a,a,a-trihaloacetaldimines, some of which are shown above147-152-155. The reaction of 1,2,2,2-tetrachIoroethylisocyanate (94) with alkyl orthoformates, N-silylamines or sulphur trioxide led to compounds 86, 96 and 97, r e s p e ~ t i v e l y ' ~ ~ - ' ~ ~ . In many instances, these N-activated a-halogenated aldimines were postulated as sulphinate elimination from 98 under the influence i n t e r r n e d i a t e ~ ' ~ "For ~ ~ ~instance, .

2. a-Halogenated imines

237

of vinylmagnesium bromide produced the intermediate imine, to which the Grignard reagent added to give adduct

(mi

(W

(100)

a-Halogenated oximes are available by the direct oximation of a-halo carbonyl compounds (vide supra), but can be obtained by two other general routes, namely the addition of nitrosyl halides to alkenes and the reduction of nitroalkenes. The Markovnikov addition of nitrosyl chloride to olefins (101) yields /3-chloronitroso compounds (102) which isomerize into a-chloro oximes (provided that at least one olefinic hydrogen is present in the starting alkene)'5a162.Dimerization of the intermediate /3-chloronitroso compound (102) is frequently observed, but thermal dissociation or acid-catalysed conversion of the dimer (104) into the monomer can generate a-chloro oximes (103)163-'64*435. The addition of nitrosyl chloride to olefins is acid catalysed or can be ph~to-induced'~~. Simple alkenes'66,167~2'6~2'7.449, endocyclic'65*168~170~429~435 and exocyclic alkenesIM or functionalized alkenes (e.g.

N. D e Kimpe and R. VerhC

238

a c r y l ~ n i t r i l e ) react ' ~ ~ ~with ~ ~ ~nitrosyl chloride in a general mode to produce a-halo oximes. Nitrosyl chloride adds preferentially to the more substituted olefin as illustrated by the reaction of NOCI with a 4: 1 mixture of 2-butene (105)and 1-butene (106)in decalin in the presence of dry hydrogen chloride, to afford the hydrochloride of the oxime of 3-chloro-2-butanone (107)16'. 1-Butene (106) remained unaffected under these conditions. Nitrosyl sulphate, in the presence of hydrogen chloride, also converts alkenes into a-chloro ~ x i m e s l ~ ~ .

/=/

-+

NOH. HCI

NOCI. Decahn. HCIlgW

+

(105) 4 : l

(106)

0-5'CtlO

min

CI

+ -

w

(1

(107)

Nitrosyl fluoride has been reported to add to alkenes to give unstable a - f l u o r o ~ x i r n e s ~while ~ ~ , steroidal olefins (steroid 5-enes) are known to react with excess N O F at 0°C in dichloromethane or carbon tetrachloride to furnish 5a-fluoro-6-nitrimines (i.e. N-nitro-a-fluoro i m i n e ~ ) ~ " .Another valuable route to a-halo oximes, mainly a-chloro derivatives, entails the reduction of nitroalkenes with Sterically stannous chloride in ether in the presence of hydrogen hindered a-chloro oximes are accessible by this m e t h ~ d ~ . ~ but ' , a recent report R1-C=C-R3

I

1

R 2 NO;! (108)

NOH

Snl II )CI, /ether dry

HCI. -10-0 OC

*

"+R3 R2

CI (109)

claimed an unexpected reduction of nitroolefin (110) with stannous chloride in tetrahydrofuran, containing hydrogen chloride, to give the non-halogenated oxime (1 11) I 74.

An important route to N-unsubstituted a-halo imino compounds, e.g. imidoyl cyanides (116). amidines (113) and imidates (123), involves the addition of nucleophilic reagents (amines, cyanide, methoxide) to a-halogenated nitriles. Even sulphur nucleophiles added to the carbon-nitrogen triple bond, as exemplified by the reaction of phosphorus dithioacids with a-chlorinated ace ton it rile^^^^. All kinds of amines (ammonia, primary and secondary amines) have been shown to add to a-halo nitriIes'7s~'81~'90~'91~2~3~204~40~. An equilibrium between isomeric amidines can exist when tautomerism is possible'82. Alkylations of amidines (113)with methyl fluorosulphonate or trime thyloxonium tetrafluoroborate are easily accomplished. Other approaches to a-haloamidines involved the reaction of /3-halogenated or /?-halogenated a-cyanoenarnines (119)i45J77 with a-chloroenamines (118)iy3.'y4 primary amines.

239

2 a-Halogenated imines ,R

R'RzY R* = n

TI

NH

'$CN

x x

(118) z = CI (119) Z = CN

The base-catalysed addition of hydrogen cyanide to a-halo nitriles provides a-halo which tautomerize to the more stable a-cyanoenamine imidoyl cyanides (116)'83.184, (117) when an hydrogen atom a to the imino function is and Similarly, base-induced addition of alcohol^'^^^'^^^^^^, including propargylic a l ~ o h o ltosa-halo ~ ~ nitriles ~ ~ ~(mainly ~ ~ ~ trichloroacetonitrile) ~ ~ ~ to produce a-halogenated imidates (123) is a well known reaction. A cyclic functionalized imidate (122) was obtained from the reaction of sulphur trioxide with trichlor~acetonitrile~~~. The condensation of a-bromo imidoyl chlorides (125), prepared from a-bromo carboxylic amides (124), with Grignard reagents in ether at low temperature yielded a-bromo ketimines (126) in 50-9096 yield1y5-'yx, Some sophisticated a-halo imines in the small ring series have been synthesized by elegant strategies. Dichlorocarbene addition to azidoalkenes (127) gave l-azido-2,2-dichlorocyclopropanes (129), which rearranged thermally under nitrogen ~ ~ . azidocyclopropanes (129) were expulsion to give 3,3-dichloro- 1-azetines ( 1 3 0 ) ~ The also synthesized from aminocyclopropanes (128) via magnesium salt formation and treatment with tosyl azide (Anselme reaction210)21', and their pyrolysis furnished the four-membered heterocycles 13OZ1 l. 3-Chloroazirines (133 and 134) are available from photolysis of /3-chlorovinyl azides (132), the latter being obtained by iodine azide addition to vinyl chlorides (131) and

240

N. De Kimpe and R. Verht

\/

-N2 A

R3

dR2 CI CI

(128)

subsequent base treatment213-214. Compound 132 (R = Ph) is photolysed to a 5: 1 ratio of 133and 134, respectively, in carbon tetrachloride while a 3.3: 1 ratio was observed in a ~ e t o n i t r i l e ~However, ~~. low temperature (-40°C) photolysis of 132 (R = Ph)

(131)

(132)

(1

(134)

produced 3-chloro-3-methyl-2-phenylaziririne (133, R = Ph) exclusively. The equilibrium mixture of 133 and 134 can be explained by interconversion via the azacyclopropenyl cation (135), but it was reasoned that an alternative mechanism involving a polar bridged transition state (136) cannot be excluded. Many other reports dealing with the synthesis of less general types of a-halogenated imino compounds exist in the literature, some of which are reported in a recent review I.

2. a-Halogenated imines

241

111. REACTIVITY OF a-HALOGENATED MINES

As discussed in the foregoing sections, a great variety of synthetic methods for the

synthesis of a-halo imines have become available, especially as a result of efforts in the last decade. Because of these efforts, many useful transformations of a-halo imines have been performed and it will be demonstrated here that their reactivity constitutes, among other things, a broadening of the possibilities for the widely used chemistry of a-halo carbonyl compounds. Indeed, a-halo imines can be regarded as masked a-halo carbonyl compounds and hence very specific transformations of a-halo imines, which cannot be executed with a-halo carbonyl derivatives, may be carried out. Simple hydrolysis of the resulting imines provides the carbonyl compounds. This strategy is outlined in the following scheme by means of an example. Dehydrohalogenation of a-halo aldehydes (137) to form a$-unsaturated aldehydes (138) is not applicable in a synthetically useful manner454,but this transformation is easily accomplished via the corresponding a-bromo N,N-dimethylhydrazone 139, which is subsequently dehydrohalogenated in the same reaction; finally, acidic hydrolysis affords the desired Many other applications will follow in the forthcoming unsaturated aldehydes (1313)~’~. text.

(139)

(140)

a-Halogenated imino compounds and a-halogenated carbonyl compounds are related substances in which the heteroatom determines the difference in reactivity. Also allylic halides can be compared in this context, in that the heteroatom is replaced by carbon. The difference in reactivity between compounds 141,142 and 143 is mainly based on the difference in electronegativity between oxygen, nitrogen and carbon.

242

N. De Kimpe and R. VerhC

>f"X

(141) Z = O (142) Z = NR (143) z = C R ' R ~

X = halogen

Nitrogen holds an intermediate position in this series and it is therefore expected that reactivity of (142) will be situated between the reactivity of a-halo carbonyl compounds and allylic halides. Many reactions will demonstrate the intermediate character of a-halo imines (vide infra) . The reactivity of a-halo carbonyl compounds has already received considerable attention in the literature and, in an accompanying chapter in this book, some general trends and novel developments in this field will be discussed. Allylic halides (143; 2 = CRiR2)can be considered as the carbon analogues of a-halo imines and a-halo carbonyl derivatives and their chemistry is well known, mainly because of its various nucleophilic substitutions, e.g. sN1, SN2,&2', e t ~ . ~ ~ ~ , ~ ~ ~ . When combining an imino function and a halide into an a-halo imino system, one can expect a reactivity which depends on one or other of these functional groups or one can expect a greater versatility of the system by the combined interaction of the halide and the imine. In several aspects, the reactivity of a-halo imines parallels the reactivity of a-halo carbonyl compounds. Reactions such as rearrangements via three-membered heterocycles, elimination, nucleophilic substitution, addition to the carbon-heteroatom bond, Favorskii-type rearrangements, elimination-addition, etc., are frequently encountered. These possibilities have recently been treated in detail2. The decreased electronegativity of nitrogen as compared to oxygen lowers the electrophilic character of the imino carbon atom and reduces the acidity of the a-protons. These two fundamental characteristics account for a substantial decrease in reactivity of a-halo imines with respect to a-halo carbonyl compounds. The drop in reactivity permits other reactions to become more important. As already discussed above, the infrequently encountered elimination reaction of a-halo carbonyl derivatives will be shown to be an important characteristic of a-halogenated imines. In the a-halo carbonyl series, this reaction can usually not compete with other reactions such as a-deprotonations and following reactions, substitutions, rearrangements via epoxides, etc. The discussion of the reactivity of a-halo imines will be divided into several sections, each one dealing with different pertinent reaction types.

A. Nucleophiik Substitutions Many nucleophilic substitutions of a-halo carbonyl compounds have been reported in the literature, but this reaction cannot be regarded as a general feature of these substrates as the substitution pattern in the starting material is determinative in these cases. For example, the well known nucleophilic substitutions of phenacyl halides224.225by a variety of nucleophilic rea ents, including nitrogen226, l , is not applicable that much o ~ y g e n ~ ~s ' ~ . ~ l~ p~ ,h ~and r ~carbon ~ ~ nucleophiles2 . ~ ~ ~ to a-substituted and a,a-dis~bstituted~~~-~~* phenacyl halides (secondary and tertiary derivatives) as only good nucleophiles (e.g. azide) were found to substitute the latter tertiary a-halo ketones. Other nucleophiles, such as methoxide in methanol, were reported to react with aromatic secondary and tertiary a-halogenated ketones, such as I-aryl-2-halo-l-alkanone~~~~~~~' and I-aryl-2,2-di~hloro-l-alkanones~~~, via an epoxide rearrangement. Several mechanistic propositions concerning the pronounced

B

2. a-Halogenated imines

243

SN2reactivity of phenacyl halides have been formulated in the literature

228.234-237.

Introduction of one or two a-alkyl substituents in phenacyl halides drastically reduced the SN2reactivity238.It seemed that steric factors determine this behaviour, although it was reported that nucleophilic substitutions of a-halo carbonyl compounds are almost unaffected for steric reasons239. All these arguments can be considered when overlooking the chemical behaviour of a-halo imines towards nucleophilic substitution. The reduced electronegativity of nitrogen as compared to oxygen is responsible for a less positively induced imino carbon, thus resulting in a decreased repulsive effect of the latter with the adjacent positively induced halocarbon atom. Due to the latter feature, a-halo imines show a reasonable tendency to give a-substitution, despite its decreased general reactivity. Since no mechanistic details for substitutions of a-halo imines are available, distinction between a classical SN2-type displacement243,or cases in which considerable positive charge develops in the transition state247. o r displacement on an ion pair intermediate, is, at present, Strong nucleophiles, e.g. thiolates, gave a-substitution of a-halogenated imines ( 144) to afford 14587.116.246.247, but with other nucleophiles competition with other reactions frequently occurred.

(144) X = CI.Br

(145) R' = H , CN

R"= alkyl, Ph

R ' = H , CN

Alkoxides in the corresponding alcohol often yield a-alkoxy imines. N-Cyclohexyl a,a-dichloromethylketimines (46) gave a,a-dimethoxymethylketimines (146) exclusively when refluxed with concentrated methanolic scdium methoxide solution for a prolonged period80. Similarly,N-aryl a,a-dimethoxyketimines (147) were obtained but a Favorskii-type rearrangement to a$-unsaturated imidates was a competing reaction (vide in~?u)~~.248. & R'

+I

R CI

(46)R'

= C6Hll (47) R' = aryl

7z? A , NeOMe

.ji & R'

OMe OMe (146) R'=C6H,1 (147) R' = aryl

5R%w

(148)

Haloindolenines (149) are readily converted into a-alkoxyindolenines (150) by treatment with alkoxides, because of the stabilizing effect of the aryl substituent on the halogenated carbon atom; the aryl group participates in the resonance stabilization of

N. De Kimpe and R. VerhC

244

the developing carbonium ions during nucleophilic substitution. When treated with while at elevated cold base, the products are alkoxyindolenines (150)"v~'2z~'zs temperature'21~'22~'25~'3z~133~.13R or with mild acid~2Y~24y~2s') the product is a rearranged spiro compound (see Section 1II.E). Alcoholysis of the bromo- or chloroindolenines derived from tetrahydrocarbazole or 2,3-dimethylindole produced the alkoxyindolenine 150"y.2s1,but the fact that a-bromoindolenines did not react with methanol in the presence of triethylamine strongly suggested that the methanolysis of the haloindolenines is an acid-catalysed process and thus probably proceeded via a transient N-protonated bromoindolenine (151)' I y .

R

OR'

&

R"R*s

R,,*R, H

OR'

-

R R,,f)$" \

'N+ H

OR'

(150)

(154) (153) SN2 displacement of halide ion from the cx-bromo immonium derivative (151) is unlikely for steric reasons. Additionally, the immonium moiety in the molecule would strongly disfavour development of additional positive charge, as would be required in a transition state for nucleophilic displacement (either SN1or sN2). The enhanced electrophilic character of the imino function after protonation will favour nucleophilic addition to give 152 and subsequent loss of the halide anion affords the resonance-stabilized compound 153. The latter will be substituted by the alcohol and expelling of the elements of the alcohol from the adduct would generate the alkoxyindolenine (150). Support for this mechanism was found in the isolation of dimethoxyindoline 156 from the bromination-methanolysis of 2,3-cyclopentanoindole ( 155) I Iy.

H

(1%)

(158)

Silver trifluoroacetate in methanol gave an instantaneous reaction with

3-chlor0-2,3-dimethylindolel~~, but it was recently shown that the reaction also proceeded without the aid of silver salts119. When an a'-hydrogen is present in a-halo imino systems, tautomerism to allylic halides (158) is possible and these substances produce a delocalized carbonium ion (159), which is trapped by the solvent. Depending on the stabilizing effect of the substituents in 159, the solvolysis leads to one or other (or both) of the two a-methoxy

ketimines. Many papers about topic ‘22.1 25.1 28.130.’ 32.24*252373. The

chloroindolenines have dealt with this conversion of secondary N-phc n yl1,l-dichloromethylketimines (162) with sodium methoxide in methanol under reflux into N-phenyl-l,3-dimethoxymethylketimines (164) was explained by a solvolysis mechanism (additionally, nucleophilic substitution and Favorskii-type rearrangement occurred) via an enamine allylic halide248. The intermediacy of a-chloro-a‘-methoxyketimine (163)was substantiated by spectral evidence248.

Similarly to the solvolyses in the chloroindolenine series (vide supra), the prescnce of an a-phenyl substituent in a-chloro aldimines (165) is of major importancc in determining the course of the reaction. With methoxide in methanol, a-chloro aldimines (165) afforded a-methoxy aldimines (166) exclusively, while a-methoxyacetals (167) were produced in methanol, indicating methanolysis via a-methoxy aldimines (166)87. Silver ion-assisted alcoholysis of the a-bromo tosylhydrazone of 14-bromodaunomycine (31) proceeded smoothly at room temperature, giving rise to a-alkoxy t o s y l h y d r a ~ o n e s(168; ~ ~ R = Me, Et, i-Pr). Of course, questions arise here concerning the structure and the stability of a carbonium ion at the a-carbon of imines. N o mechanistic studies have been directed hitherto towards the identity of a-imidoyl carbonium ions. The terminology ‘a-imino carbonium ion’ is incorrect as positional labelling in carbonium ions assigns a to the charge-centre carbon atom. Analogously, in the oxygen series, the well-known species As a-keto carbonium ions are better referred to a a-acyl carbonium

246

N. De Kimpe and R. VerhC

d

'Cl

(166) R = CH3, Ph

OMe (166) 0

OH

NNHTos

(168) R = Me, Et. i-Pr

discussed above, electronic effects reduce markedly the stability of a-imidoyl carbonium ions, but, similar to the case of a-acyl carbonium ions427,the electronic configuration of an imino group is capable of stabilizing the positive charge on the adjacent carbon by overlapping of the vacant orbital of the carbonium ion with either the occupied lone pair orbital of nitrogen or the n-orbital of the imino function. Accordingly, the intermediacy of an azirinium species, formed by intramolecular nucleophilic halide displacement, seems to be attractive and warrants serious consideration in mechanistic explanations. Quantitative data of a-acyl carbonium ions only very recently became a ~ a i l a b l e ~ ~but ~ .the ~ * corresponding ~, nitrogen analogues have only been postulated as intermediates (vide supra). Other examples of nucleo hilic substitutions using oxygen nucleophiles entailed sodium acetate in acetic acid2R,intramolecular substitution of a,a-dichloroimidates by a r y I o ~ i d e s ~ ~a-substitutions ~~*~~, with silver itra rate^^-^^."^, sodium nitrite96J16, hydroxideY8, bicarbonateY6 or phenoxide9*. The bromination in acetic acid and

''

NR

R 2 $CN

-. A

(78) X = CI, Br

NR orN.NO2 AQNO?

fDMSO or MeCN)

"$CN R2 ..

2

(169) 2 = O W , ON02

subsequent hydrolysis of tetrahydrocarbazole also provided an example of a-hydroxylati~n~~~.

2. a-Halogenated imines

247

a-Substitutions with amino compounds are n o t frequently reported. Ordinary aliphatic a-halo imines show a complete lack of reactivity towards amines. Halomethyl irnino compounds seem to be the substrates of choice for a-aminations, a-chloro as demonstrated by reactions of a-brominated diazines (170)74.258, a m i d i n e ~ ~and ~ ’ a-bromo hydra zone^^^^^^^^ A

r

p

N

r

- Af3At F%-NH*

El”/&

Ar L

B

r

Ll

(1711

(170)

The introduction of an amino substituent a to an oxime can be accomplished by substituting an a-bromo oxime (172) with potassium phthalimide in acetonitrile in the presence of crown-18 ether, after which the a-phthalimido oxime (173) is subjected to hydrazinolysis in ethanol, the resulting a-amino oxime (174) being used as a key intermediate for the construction of 11-oxahomofolic acid, a potential antiturnour agent156. 0

Azide ion, usually in acetone, acetonitrile or acetic acid, converts a-halogenated imino derivatives into unstable a-azido imines87.253*261. Phosphorus-containing nucleophiles like trialkyl phosphites do not react with a-chloro aldimines (59), but are known to substitute trichloroacetimidates and trichloroacetamidines at the a-positionLb2(or at the imino-nitrogen atomJh’ in analogy to the Arbuzov or Perkow reaction of a-halo carbonyl compoundsza). Triphenylphosphine easily substituted the protected a-bromo oximes (175). the a-substituted derivatives (176) subsequently yielding oximes (177)157.The latter

248

N. De Kimpe and R. Verhe

underwent ring closure under basic conditions to give five-membered heterocycles (178) which were converted into azirines (179) by thermolysis'". When the group replacing the halogen is sensitive to nucleophilic reagents, intramolecular nucleophilic

..

(178) attack by the oxime oxygen can take place to afford 0 . N - heterocyclic compounds. According to this principle, a-chloromethylketoximes (180) reacted with phosphines or dirnethylsulphoxoniurn rnethylide to give a-substituted oxirnes 181 or 183 and further heterocycles 182 or 184, respectively26s268. It has not been stated whether these reactions involved direct nucleophilic displacement or elimination of hydrogen chloride and subsequent addition of the nucleophile to the nitrosoolefin thus formed (vide infra). (179)

FhM - HCI

- DMSO

Finally, some displacements by direct attack of the nucleophile (iodide, thiophenolate, triphenylphosphine) at the halogen in chloroindolenines were reported to yield the parent in dole^^^^. Nucleophilic substitutions involving carbon nucleophiles are included in the next section. As pointed out above, a-halogenated oximes (187) are known to react with nucleophiles to yield the corresponding a-substituted oximes (19Q but the reaction involves elimination to a nitrosoolefin (189) and Michael-type addition of the nucleophile to the latter intermediate (189). A similar type of elimination-addition is known for a-halogenated hydrazones (188), which are transformed by nucleophiles

2. a-Halogenated imines

249

(187)

Z=0

(188) 2 = NR”

R’

R &,

Nu (193)

lel

4 R+R ’Y

NuH (d)

Nu (191) (192)

z= 0

Z = NR“

:JR

z=

(189) 0 (190) Z = NR”

into a-substituted hydrazones (192) via the intermediacy of azoalkenes (190). As outlined in the accompanying scheme, carbonyl compounds (185) are transformed into a-substituted derivatives (193) by a sequence involving (a) halogenation, (b) oximation o r hydrazone formation, (c) elimination of hydrogen halide to form a nitrosoolefin (189) o r an azoalkene (190), (d) addition of the nucleophile and (e) hydrolysis. Steps (c) and (d) are usually performed in one treatment when the nucleophile displays basic properties. Secondary amines have been widely used to substitute cr-halo 0xjmesY4.165.168~172.287-289~40Y but also primary amines2872W449 and ammonia287 gave a-amino oximes. a-Alkoxylations, usually a-methoxylations, proceed smoothly for

(W

(187)

(1W)

certain substrates with alcohols172~291~40y, but are facilitated when bases, e.g. t ~ i e t h y l a r n i n eo~r ~alkoxides166,16E~2y1, ~ are used. Other nucleophilic reagents such as sulphur nucleo hiles’65*447,cyanide ionzY3, sodium borohydrideZy7,sodium nitrite2E7,sodium nitrateyE7 and sodium azideZE7also provided elimination-addition reactions of a-halo oximes to generate a-substituted oximes (191). Carbon-carbon bond formation447was accomplished usin carbanions derived from ethyl a c e t o a ~ e t a t e ~ ~3-phenyl-2-isoxazolin-5-onefys, ~, diethyl malonatezE7and 2,4-pentanedioneZE7,while Grignard reagents gave the a-alkylated oximes2E7~2ys. The generality of such reactions was shown by the reaction of a-bromo oxime (1%) with the lithium enolate 197, upon which cyclization resulted6Y,and by the substitution of an a-bromo cyclohexanone oxime derivative with 1-lithio-1-butyne, which furnished the a-( l-butynyl)oxime6E. In similar fashion, a-bromo oximes were

250

N. D e Kimpe and R. VerhC

alkylated by e n a m i n e ~ *a-Halo ~~. oximes (187) are in fact useful synthons for the base-induced generation of nitrosoolefins (189). which are apt to undergo a variety of cycloadditions. Either the carbon-carbon double bond o r the nitroso function can participate as a dienophile in cycloaddition, but examples are also known in which the nitrosoolefin acts as a heterodiene. OH

+

N

R

Applications of cycloadditions in which transient nitrosoolefins operate as dienophiles are the reaction of a-chloro oximes (180) with cyclopentadiene in the presence of sodium carbonate, the initial adducts (202) being transformed spontaneously into cis-fused oxazine derivatives (203)292.

(1W

(202)

The nitroso function of nitrosoolefin (205), generated from chloral oxime (204) and sodium bicarbonate, underwent cycloaddition with cyclopentadiene to give oxazine derivative 206, which rearranged to the tricyclic compound 207292,297. An example in which the intermediate nitrosoalkene acts as a heterodiene in cycloadditions was found recently with a-chloro oximes (208). carrying an electron-withdrawing

2. a-Halogenated imines

251

(210) R = Me, H

~ u b s t i t u e n t ~ ~Related ~ ~ ~ ~ ~ .reactions are the cyclocondensations of a - c h l o r o n i t r o n e ~ ~ ~e.g. ' ~ ~ 211, ~ , with cycloalkenes (212)and alkenes4" to give bicyclic adducts (213).This reaction was recently shown to be applicable also with ketones and a-chloro nitrones to generate 4H- 1,5,2-dioxazinium salts456.

0

:zoc - (p .+ a:: -0.k CI

/o (2111

cicn.pc,ci.

+

62

(212)

R

H

(213)

BF4-

According to the general principle of base-promoted elimination-addition of a-halo hydrazones (la)a,wide variety of a-substituted hydrazones (192) are obtainable. and Azoalkenes (190)have been isolated in many casesa10~47~48~111~306~307-309~317-31y~334 their stereochemistry was investigated to some extent308,3L71434. However, the in situ preparation of azoalkenes is most often applied18*23*46*310. Addition of nucleophiles, e.g. acetatez3.&,amines23~46*307, organocopper reagent^^^^'^*^^, Grignard reagent^^^'-^^^ or carbanions112to azoalkenes (isolated or prepared in situ) provided a-substituted hydrazones (192)but also cycloaddition products, in which azoalkenes act as diene or dienophile, have been reported (see, for instance, 218)308.311*312. a-Halogenated hydrazone-type compounds (219), contained in a ring system, have been used for the a$-unsaturated carboxylic a ~ i d s ~ 5-316 ~.~' synthesis of a-vinylcarboxylic acids (22O)lo1,

N. De Kimpe and R. Verht

252

COOMe

NNHCOOMe

I

NanC03/H~O

N4N

Elher

%COO.

L C O O R

A r W

R = El

CI

cow I

NONH

+COOEt NHAr

(215)

(214)

(216)

COOMe (218 )

and 1,5-diazabicyclo[3.3.0loctadienediones (221 and 222)76.286.Additionally, tosylazoalkenes derived from aldehydes have been used to generate alkylidene ~arbenes~’~.

CI

+

CI

.CI

8. Carbon-Carbon Bond Formation Because of the importance of carbon-carbon bond formation in synthetic organic chemistry, emphasis to this topic is given in a separate section covering reactions of a-halogenated imino compounds with carbanions, cyanide ion and organometallic reagents.

2. a-Halogenated imines

253

1 . Reactions of a-halogenated imino compounds with carbanions

Few reports have been published on the reaction of a-halo imines with carbanions. Tertiary a-chloro aldimines (59) are completely resistent to reaction with carbanions derived from active methylene functions87,but a-halomethyl imino derivatives proved to be more successful in nucleophilic substitutions. Chloroacetone semicarbazone pave a-substitution with the active methylene compound 224 and the resulting product was subjected to ring closure with hydrogen chloride in alcoholic medium to afford functionalized pyrroles (226) I(''.

OYCOOR'

VR

NaOR

0

(225)

1

ROH HCI

Y R

COOR'

0

(226)

In a similar way, a-bromoacetophenone azine (170) gave two fold nucleophilic substitution with diethyl malonate (227), to provide 5,5-bis(ethoxycarbonyl)-5,6-dihydro-3,7-diaryl-4H-1,2-diazepines(228)26y. The thallium salt

5°C Br

Ar

s. A

+

r

CCOOEt OOEt

Br

(170)

r N-N y A

COOEt COOEt

(227)

(228)

of diethyl malonate in benzene reacted with the chloroindolenine derived from tetrahydrocarbazole (229) to produce the nucleophilic addition product (DO), which rearranged into compound BlZ7'. Such a rearrangement was applied to a

Q& 254

TI' -CH<

N. De Kimpe and R. VerhC COOEt COOEt

COOEt (230)

(229)

The aforementioned synthesis leading to the alkaloid vincadifformir~e~~~.~~~. was similarly base-induced coupling reaction of a-iodomethylketimines derivatives430. observed with 2-bromomethyl-l,3-oxazine

2. Reactions of a-halogenated imino compounds with cyanide ion Although nucleophilic displacement of a-halogens by cyanide ion are known272,the preferred reaction of cyanide is addition to the imino f u n c t i ~ n ~ ~and ~ ~ eventually ~", ~ ~ ~ ~ aldimines ~ ~ ~ . (59), further reaction of intermediately formed a d d ~ c t s a-Chloro a,a-dichloro aldimines (232) and a,a,a-trichloro aldimines (233)react with potassium cyanide in methanol to give a-cyanoenamines 235,236 and 237, r e s p e c t i ~ e l y ~ ~The "~~~. last-mentioned compound (237), however, is accompanied by several by-products,

(58) R'. R2 = alkyl

(232)R 2 = CI (233) R ~ = R ~ = c I ; R = ~ - &

(235)R1 = R 2

(234)

= alkyl

(236) R 2 = CI

(237)R'

=

R2 = CI; R = t - h

originating from further reaction of this reactive a-cyanoenamine with methanol278. The reaction involves addition of cyanide to the imino function and subsequent dehydrochlorination of the transient adduct (234). a-Cyanoenamines (235) were found to be valuable synthons as they can be transformed into t r i a l k y l k e t e n i m i n e ~and ~~~ carboxylic amidesZ80.457. The preferred addition of cyanide to an imine was demonstrated by incorporation of I4C-labelled cyanide into a-chloro imidoyl cyanide (78; X = Cl) on reflux with KI4CN in methanolli6. With potassium cyanide in dimethyl sulphoxide, a,a-dichloro aldimines (238)gave 2-amino-5-cyanopyrroles (241) by a sequence involving elimination of hydrogen NNR

CN

R' GH

[RJ+L)

-

CN

NHR

R A JN )[

CI CI

CI

(=I

(239)

-

(240)

R I

H2N*cN

255

2. a-Halogenated imines

chloride, Michael addition, a-cyanoenamine formation and ring closurez8". When non-displaceable halogens were incorporated in the starting a-halo imine, e.g. N-activated trifluoroacetaldimines (242), the adduct 243 was easily isolated and could be hydrolysed into trifluoroalanine (244)285.

0

0

The behaviour of cyanide ion towards a-halo imines parallels the reactivity of this nucleophile towards a-halo carbonyl compounds as the latter are also known to give nucleophilic addition to the carbonyl function, but the adduct is dehydrohalogenated in a different way, namely by intramolecular nucleophilic substitution to produce a-cyano e p o ~ i d e s ~ ~All ~ -the ~ ~above-mentioned ~ - ~ ~ ~ . examples in the imine series belong to the class of a-halo aldimines and give rise to 1,2-dehydrohalogenation,but aliphatic a-halo ketimines behave like a-halo ketones in that they undergo 1,3-dehydrohaIogenation,generating a-cyano aziridinesgl.

3. Reaction of &-halogenated imino compounds with organometallic reagents Grignard reagents usually add to the carbon-nitrogen double bond of N-activated a-halogenated imines (245 and 246)146,154,320. Aliphatic a-bromo aldimines (247) with

R'b

R1R'J

x '' 7

I

R

(250)

R'

R1 R2

gR H

x

R2

(248) R1 = R 2 = X = CI; R = COOEt (249) R' = R 2 = X = CI or F; R = C6H5CO

isopropylmagnesium chloride produced 1,2,4-trisubstituted pyrroles (250), while 1,3,4-trisubstituted pyrroles (251) were obtained with lithium in ether32'*323. On the other hand, coupling reactions to produce 1,4-diimines (252) were observed when secondary and tertiary a-haloimines reacted with sodium in liquid ammonia or with

256

N. De Kimpe and R. VerhC

methylmagnesium i ~ d i d e ~ ~ - ~Metallation *'. of a,a-dibromoaldimines (253) with butyllithium in tetrahydrofuran produced lithiated a-bromo aldimines (254), which underwent protolysis with methanol at low temperature to give the first non-conjugated secondary p-halo enamines (255), while a-alkylation of anions (254) was accomplished with ally1 bromide324.

x

I(

RGH j ! ~ i +

&Li

T H F . -7O'C

Br Br

(253,

R

H

Br

(254)

R = H, Me, Et. n-Pe

As mentioned above organometallic reagents, e.g. organoco e r comp o u n d ~ ~ ~ , ~alkyllithium ".~"~, compounds6y and Grignard reagentsL02J03.E'*295-325-327, substitute halogens a with respect to an oxime o r an hydrazone moiety, but the reaction proceeds through intermediacy of nitrosoolefins or azoalkenes.

C. Elimination Reactions of a-Halo Imino Compounds The elimination of hydrogen halide from simple a-halogenated imines is one of their basic reactions, as recently demonstrated. a-Chloro aldimines (258) were converted into a,p-unsaturated aldimines (259) by reaction with sodium methoxide in methanol, but a competitive rearrangement via an a-methoxyaziridine was noticed for isobutyraldimines (258; R' = H; R2= Me) by which a-aminoacetals (260) resultedB7.

Several simple a-halogenated imines were reported to react with alkoxides in the corresponding alcohol to give initial elimination of hydrogen halide86.90. a-Bromo compounds (261) suffered elimination of hydrogen hydrazone-t pe bromidez'b23146~32a33n when heated in acetic acid, and this method was proposed to introduce a double bond at C4-C5 in 3 - k e t o ~ t e r o i d s ~ O - ~ ~ . Finally, 3-bromo-2-cyano-1-pyrroline 1-oxides (65; R = CN)Y5-y7 and a-halogenated imidoyl cyanides (78)II6 readily underwent base-induced elimination reactions to afford the corresponding a,$unsaturated imino compounds.

257

2. a-Halogenated imines

br

(2611

Z = Ar, CONH2

D. Nucleophiilc Additions to N-Activated a-Halogenated lmino Compounds Imino compounds (263), especially aldimines, having an electron-withdrawing N-substituent and a-perhalogenation, add nucleophiles at the imino function under very mild conditions141,143,145.154.335.336,410. The high electrophilic character of the imino

(265)

(283) X = halogen R = halogen or alkyl R ’ = usually H Z = COOR“. COR“. S02R”

Nu = OR’, OAr, NR’R2, NHR’. SR SAr, OH, OOCR’ , NHCOR~. NHNHR’

’,

carbon originates from the inductive effect of the a-halogens and the mesomeric effect of the N-activating group. The extreme form of the polarization in, for example, N-acyl a-halo imines (266) can be expressed as dipolar structure (267), clearly indicating the tendency to give Michael-type additions to such heteroenones. Various

-0 R&

0 -A

R”

xx

(268) kinds of nucleophiles have been reported to give stable adducts (265; R’ = H), among (266)

(267)

thiols143.335.336, hydrogen others a~coho~s141.143,154,337 amines141.143.145.335.336 carboxylic acids143.33S*336, amides143.335.336 and ~ u l p h i d e water335, ~~~, h y d r a ~ i n e s ‘ ~This ~ . ~ tendency ~~. for nucleophilic addition to the imino function IS at maximum for a-halogenated aldimines (266; R‘ = H) and originated from the decreased steric hindrance as compared to the ketimine case (266; R’ f H). An analogous aptitude for nucleophilic addition is well known for a-halogenated aldehydes, which practically always react by such an initial addition reactionw3 w4. Similarly, several examples with a-halo ketimines37~117.118.247~33~341 or imidate derivatives452have been found. However, the nucleophilic addition can be followed by an expelling of a leaving roup (R’) an elimination of hydrogen halide (270)278-3331343, connected to the imino carbon (269)34 or a haloform-type reaction (271)3 3. Of major importance is the reaction of a-halogenated imino compounds with mixed metal hydrides (usually lithium aluminium hydride), which add to the imino function

8

258

N. De Kimpe and R. Verhe

R "$

Nu

~

R$'/

0.0.N uR ' = CN

x x

R'

xx

(-1

Nu R' = H. -HX

X (270)

(283) X = halogen -RCX2-

I

Nu-

N

(2711 in a very general way. When the halogen is displaceable (X = CI, Br), the reaction proceeds further by intramolecular nucleophilic attack giving aziridines85,143-321*344*345,347. If the reaction is performed with a,a-dihalogenated imines (272; R2 = X = C1)853143.345f46, the intermediate a-haloaziridine (274; R2 = Cl) is transformed into the final aziridines (276) by expelling of a halide anion to generate an azirinium halide (275), which is stereospecifically attacked from the less hindered side (most remote from substituent R3) to give c i s - a ~ i r i d i n e sRing ~ ~ ~ .openin however, of transient a-haloaziridines by hydrides has also been e n ~ o u n t e r e d l ~ * ~ ~ ~ ~ ' ~ . These results are in sharp contrast to the reactivity of a-halo carbonyl compounds towards mixed hydrides, from which only P-halohydrins and/or alcohols result.

R I

x-

(275)

(278)

When a-fluorinated imino compounds (277) react with mixed metal hydrides, the exclusive addition reaction leads to B-fluorinated amino compounds (278)37.38.349-351 , a

Flip

R2

F

R1J2

F

(278)

2. a-Halogenated imines

259

reaction which was also observed with some a-chloro- or a-bromo imino compounds2\ 1.278.351,352,

E. Reanangemsnt of a-Halogenated lmlno Compounds Three types of more or less frequently encountered rearrangements of a-halo imines will be discussed here, namely, the Favorskii-type rearrangement, the rearrangement via activated aziridines and the Wagner-Meerwein-type rearrangement of chloroindolenines. Finally, a single case of the Beckmann rearrangement of an a-bromo oxime will be discussed. 1. The Favorskii-type rearrangement

The base-induced skeletal rearrangement of a-halo ketones to afford carboxylic acid derivatives, known as the Favorskii r e a ~ ~ a n g e m e n t ~has ’ ~ -also ~ ~ ,been encountered with a-halo imines. Quast and coworkers performed the first transformation of an a-halo ketimine (279) into a carboxylic amide (281) via a two-step sequence, which could be accounted for in terms of the Favorskii rearrangement 1y5.361. 1.3-Dehydrobromination of a-bromo ketimine (279) was obtained with potassium r-butoxide to generate cyclopropylidene amines (SO), which underwent hydroxide-induced opening to give amide (281). The opening of the nitrogen analogues of cyclopropanones (280)is directed by the stability of the intermediate anion. Accordingly, 280 is opened via path a , giving rise to the more branched carboxylic amide (281). No trace of the alternative route 6 was observed. Another

qR AR KOBu THF -I

a q . KOH dioxane

Br

\ (285)

(284)

R I

(282)

\ (263)

Favorskii-type rearrangement was observed by reaction of N-aryl a,a-dichloromethylketimines (286) with sodium methoxide in methanol, affording ‘The a$-unsaturated imidates (289) via transient cyclopropylideneamines (287)82.248. reaction of primary derivatives (2%; R 2 = H) was shown to be stereospecific and gave rise to a regiospecific opening of the chlorocyclopropylidenzamine (287)u224M. Secondary derivatives (2%; RZ# H) also afforded a regiospecific opening of the transient cyclopropylideneamine (287) because of the directive aid of the chloride anion expulsion. The latter reaction was not stereospecific in that a mixture of E- and

N. De Kimpe and R.Verhe

260

Z-imidates (289) was produced248.Side reactions, e.g. nucleophilic substitution and solvolysis of 286 with sodium methoxide in methanol could be avoided by working in ethereal medium248.

2. Rearrangement of a-halo imines via activated aziridine intermediates As exemplified for mixed metal hydrides (vide supra), the addition of nucleophiles to the imino function of a-halo imines can be followed by intramolecular attack with halide expulsion, by which aziridines result. In the case of nucleophiles other than hydride, but most often with alkoxides (or alcohol), the aziridine thus formed is a very reactive species and undergoes alcoholysis when the reaction is carried out in an when treated with sodium methoxide in alcohol. a-Chloro isobutyraldimines (DO), methanol, are converted into a-alkylaminoacetals (292) and a$-unsaturated a l d i m i n e ~ The ~ ~ . latter competitive elimination reaction was removed by working in methanol only. The intermediacy of a-methoxyaziridines (291) was established by trapping these transient species (see dipolarophilic form 293) with the ambident thiocyanate or cyanate anions362.363,resulting in 2-imidazolidinethiones (294) and 2-imidazolidinones (295). Nucleophilic additions of alkoxides across the imino function

z

(294) = s (295) z = o and subsequent intramolecular nucleophilic attack of the nitrogen atom were observed with a,a-dichloroaldimines (56)%, a-monochloroaldimines87 and a-halo immonium halide^^'^,^^. These transpositions are completely comparable to the alkoxideinduced rearrangements of a-halo carbonyl compounds (186) to a-hydroxyacetals (297) via intermediate alkoxyepoxides (2%)41e424.

(293)

R

+

0

R

*

s~\rR. R"0 OR"

-OR' ~

OR"

X (1

(296)

OH (297)

2. a-Halogenated imines

261

3. Rearrangement of chloroindolenine derivatives Chloroindolenines, obtained by reaction of indoles with r-butyl hypochlorite, yield rearranged iminoethers, e.g. 299 (and/or oxindoles), upon treatment with base (methoxide, hydroxide) at elevated temperature, while a-substitutions were noticed when treated with cold base. This general rearrangement was applied to simple

Me006 (298)

(299)

indolenine derivatives, like the chloroindolenine derived from tetrahydrocarbazole, From the and more complex indole-type alkaloids125-128~132.'33~138~249~250~z70~271.37(1. mechanistic point of view, the rearrangement of chloroindolenines (300) was explained by initial nucleophilic addition of methoxide at the C = N double bond, followed by Wagner-Meerwein-type rearrangement to give 302. This transformation requires cis disposition of the chlorine atom and the methoxy group in adduct 301.

(300)

(302)

(3011

Not only under basic conditions but also under neutral conditions were rearrangements of chloroindolenine and related alkaloids observedz5". 2-Functionalized 3-chloroindolenines (303) rearranged in protic solvents into

I d

R"

H

o

R,,&R,

N'

CI

262

N. De Kimpe and R. Verhk

oxindoles with migration of the functional group from the 2-position to the 3-positionlZY.In this case a carbonium ion (309,mesomeric with chloronium ion 304, is involved and migration of the carbonyl group furnishes imidoyl chloride (a), which leads to 307 upon hydrolysis. Many other migrations of substituents from the 2-position to the 3-position, starting from 3-chloroindolenines by treatment in acidic medium, are knowna8~121~2s3~371~372;

CI

Ph

(-1

(W)

one example is given here, namely the spontaneous rearrangement of chloroindolenine (308)in acetic acid solution into oxindole (309). 4. Beckmann rearrangement of a-bromo oximes

The reaction of para-substituted phenacyl bromide oximes (310) with triphenylphosphine in acetonitrile at room temperature produced imidoyl bromides (31 1) and triphenylphosphine oxide226.The rearrangement is explained by addition of the phosphine to the imino function after which debrominated oxime derivative (314) is formed via a series of tranformations, visualized by the arrows in the accompanying scheme. Compound 314 is then susceptible to the well known Beckmann

Br-

b

rearrangement to give 311. It is important to notice that in the presence of slight amounts of base (e.g. a few drops of an aqueous potassium cyanide solution), the course of the reaction is changed in favour of oximino phosphonium salt (315)266, indicating the importance of the nitrosoolefin route (vide supra).

2. a-Halogenated imines

263

NOH

F. Cycloclddttlonr Numerous cycloadditions have been reported with a-halo imines, practically all of them a-perhalogenated and having an activating N-substituent, e.g. alkoxycarbonyl, tosyl, benzoyl, etc. a-Halo imines having a carbonyl substituent directly bonded to nitrogen can act as dienophile or as heterodiene in Diels-Alder reactions. N-Alkoxycarbonyl and N-tosyl chloralimines (86 and 91) gave cycloadducts with dienes, e.g. acyclic and cyclic 1,3-dienes, functionalized 1,3-dienes, e t ~ . ~ ~ ~ v ~ ~ ~ - ~ ~ 9 . 4 3 The N-acetyl analogue 316 reacted with 2,3-dimethylbutadiene as dienophile to give adduct 319, but adduct 320 was also isolated, indicating that 316 acted as a h e t e r ~ d i e n e ~On ~ ~the . other hand, N-alkoxycarbonyl chloralimines (86) behaved exclusively as heterodienes towards electron-rich alkenes, e.g. ketene acetals, resulting in an oxazine derivative (321), which was hydrolysed to carbamate derivative 322400. a-Perfluorinated ketimines such as hexafluoroacetone imines especially have been found to give a variety of cycloadditions, but these reactions are not dealt with here in detail because of lack of space.

(318) R = CH3CO

R'O

(319)

(320)

Only some examples of the various possible types of cycloadditions of a-perfluorinated imines are reported in the following scheme, together with some leading references in this area2,41,42.154~37639s~401~4s*. Among the reagents found to give cycloadditions to a-perfluorinated imines are included nitriles, nitrones, enol ethers, carbenes, ketenes, alkenes, ketones, ynamines and isonitriles.

264

N. De Kimpe and R. Verht R P h A " 78%. R = Ph Ref. 395

(323)

T

:cncooEt I d . 379

G. M l s c e l l ~ u s Reactions of a-HalogcMaed lmlno Compounds A large number of a-halogenated imino compounds have been used for the synthesis of various heterocyclic compounds. A detailed description has been given in a recent reviewz. This survey will be limited to mentioning some particular examples. a-Halogenated thiosemicarbazones, e.g. 331 and 332, and related compounds are known to give intramolecular syclizations to p y r a ~ o l e s ~2-iminothiazolines52~s3~ss ~~~*,

S

x

(331) X = CI; R =Me (332)X = Br; R = H

and thiadiazines (333)52-55+403, while a-halo oximes produced thiazoles (335) and thiadiazines on reaction with thiourea and dithiocarbazic acid, r e s p e c t i ~ e l y ~ ~ ~ . ~ ~ ~ . As pointed out already in the section describing cycloadditions. perfluoroacetone imines (336,323,326)are versatile substrates for syntheses of nitrogen heterocycles as they are known to give rise to imidazoles (337)4M,oxazoles (338)4M,thiazoles (339)*, dithiazolines, thiaselenazolines and d i s e l e n a z ~ l i n e s ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ . This section will be closed by discussing briefly the acidic hydrolysis of a-halo imines as a path in the specific a-halogenation of certain ketones. The acid-catalysed

265

2. a-Halogenated imines

(336)Z = NR' (323)2 = 0 (326)2 = s

(337) Z = NR'

(338)2=0

(339)2=S

hydrolysis of a-halo imines affords a-halo carbonyl compounds. Direct halogenation of carbonyl compounds can be problematic from the viewpoint of regioselectivity, but in some cases the halogenation of carbonyl compounds via imination, subsequent halogenation and hydrolysis offers a complementary method. Via this three-step sequence, the regiospecific mono- and dihalogenation of methyl ketones (340) has been a c c ~ m p l i s h e dbut ~ ~ in ~ ~cases ~ , where no competitive a'-halogenation can take place,

R

1

121 ( 1 I 2NCS/CC14. R " H Z / CsHg /H' O°C

RhC'

*

CI

(31 HCI-MeOH-H20

(340)

(3411

this method has been developed as the synthesis of choice for a,a-dichloroaldehydes (344)y2, a,a-dibromoaldehydes (345)92 and a,a-dichloroalkyl aryl ketones (346)*'. However, the direct chlorination of aldehydes (342) or alkyl aryl ketones (343) with

0

(342)R (343)R

0

( 3 ) H30'

=H = Ar

x x

(344)R = H ; X = C I (345)R = H ; X = B r (346)R = Ar; X = CI

chlorine in dimethylformamide has been shown very recently to be an improved synthetic method for the preparation of a,n-dichlorocarbonyl derivatives 344 and 346445*446.

IV. PROPERTIES AND APPLICATIONS OF a-HALOGENATED IMlNO COMPOUNDS Several a-halo imino compounds have been found to have pharmaceutical and phytopharmaceutical properties, while they have also been used for the synthesis of

266

N. De Kimpe and R. Verht

products. a-Halo oxime derivatives e.g. 17fl-acetoxy2a-chloro-3-(p-nitrophenoxy)imino-5a-androstane (347)220*431and 1,fdichloroacetone oxime acetate (348)414, displayed postimplantive antifertility activity and slimicide activity, respectively. The contact acaricide Tranid (350) belongs to the important class of oxime carbamates, which were recently successfully applied in various pest ~ o n t r o l s ~The ~ ~fungicidal . ~ ~ ~ . activity of the 2,4-dinitrophenylhydrazone of chloroacetaldehyde (351) is well known, the compound being referred to as ‘Fungicide 1763’ in pesticide scienceM2.Very recently, a great variety ofa-halogenated hydrazones (352) have been found to display fungicidal activity460.

medical

0

Cl,C A 4

(W)R = alkvl (204) R = O H 0

(362) R

x x

= H. F, CI. &. CH,, CHCICH3 X=C1, &

2. a-Halogenated imines

267

The insecticidal activity of a large number of trifluoroacetophenone oxime carbamates (353) and trifluoroacetophenone oxime thiophosphates (354) was recently evaluated"'. Some of these compounds were good aphicides and some were strong cholinesterase inhibitors"'. Trichloroacetamidines (113; X = Y = Cl) showed enzyme inhibitory activity besides bacterial mutagenic and inotropic activity'80.203.a-Bromoacetimidate acted as cross-linking agent for proteins415,while choral imines (349) were found to be useful as compounding agents for rubber332.Imino derivatives of chloral, e.g. 349, and oxime (204), have been proposed as insecticide^^^'.^'^. Besides these industrial uses, a-halo imines have been used for the synthesis of medicinal products, among others a n t i ~ p a s m o d i c s ~ ~vasodilators246, ~, convulsantsIZ6, glycine antagonists'26, radioprotective agents204and products having gastric antisecretory activityI8'. An area of major importance is the transformation of various indole-type alkaloids via their chloroindolenines'32-139Js3~2~s~27~272~4~7, but also their application as intermediates in the total synthesis of steroids69 and antitumour agents, e.g. 11-oxahomofolic acid'56 and anthracyclines", deserves attention.

V. REFERENCES 1. N. De Kimpe and N. Schamp, Org. Prep. Proced. Int., 11, 115 (1979). 2. N. De Kimpe, R. Verhk, L. De Buyck and N. Schamp, Org. Prep. Proced. Int., 12, 49 (1980). 3. R. W. Layer, Chem. Rev., 63, 489 (1963). 4. The Chemistry of the Carbon-Nitrogen Double Bond (Ed. S . Patai), Interscience, London (1970). 5 . E. F. Janetzky and P. E. Verkade, Rec. Trav. Chim.Pays-Bar, 65,691 (1946). 6. Y. A. Shaikh, Org. Prep. Proced. Int., 8, 293 (1976). 7. J. Wolinsky, R. 0. Hutchins and T. W. Gibson, J. Org. Chem., 33, 407 (1968). 8. I. Migaichuk and I. Khaskin, Zh. Prikl. Khim. (Leningrad), 52,946 (1976); Chem. Absrr., 91, 39092 (1979). 9. H. Pauly and I. Rossback, Ber., 32, 2000 (1899). 10. H. Pauly and C. Boehm, Ber., 33, 919 (1900). 11. J. G. Aston and R. B. Greenburg, 1,Amer. Chem. SOC.,62, 2590 (1940). 12. J. Wolinsky, J. J. Hamsher and R. 0.Hutchins, J. Org. Chem., 35, 207 (1970). 13. C. L. Stevens, P. Blumbergs and M. Munk,1. Org. Chem., 28, 331 (1963). 14. M.Miocque, C. Combet-Farnoux, J.-F. Givardeau and H.Galons, Compr. Rmd. C. 282, 469 (1976). 15. P. Catsoulacos and A. Hassner, J. Org. Chem., 32, 3723 (1967). 16. P. Catsoulacos, Bull. SOC. Chim. Fr., 642 (1976). 17. J. Van Alphen, Rec. Trav. Chim. Pays-Bas, 64, 109 (1945). 18. B. T. Gillis an J. D. Hagerty, J. Amer. Chem. Soc., 87,4576 (1965). 19. L. Caglioti, G. Rossini and F. Rossi, 1. Amer. Chem. SOC.,88, 3865 (1966). 20. V. R. Mattox and E. C. Kendall, 1. Amer. Chem. Soc., 70,882 (1948). 21. C. Djerassi, J . Amer. Chem. Soc., 71, 1003 (1949). 22. V. R. Mattox and E. C. Kendall, J. Amer. Chem. Soc., 72, 2290 (1950). 23. F. Ramirez and A. F. Kirby, J. Amer. Chem. SOC.,74,4331 (1952). 24. 0. Hess, Ann., 232, 234 (1886). 2 5 . J. Culman, Ann., 258, 235 (1890). 26. S . Bodforss, Ber., 52, 1762 (1919). 27. S . Bodforss, Ber., 72, 468 (1939). 28. D. Y. Curtin and E. W. Tristam, 1. Amer. Chem. SOC.,72, 5238 (1950). 29. K. H. Ongania and J. Schantl, Monars. Chem., 107,481 (1976). 30. J. Schantl, Monats. Chem., 108, 599 (1977). 31. J. Schantl, Monats. Chem., 108, 325 (1977). 32. P. A. Reddy, S. Singh and V. R. Srinivasan, Indian J. Chem.. B , 14, 793 (1976). 33. L. Duhamel and J. Y. Valnot, Compr. Rend. C. 286,47 (1978).

268

N. De Kimpe and R. VerhC

34. T. Kametani and 0. Umezawa, Chem. Pharm. Bull. (Tokyo), 14, 369 (1966). 35. T. Kametani and 0. Umezawa, Yakugaku Zasshi, 85, 514,518 (1965); Chem. Abstr., 63, 68514, 6959h (1965). 36. A. Roedig, F. Hagedorn and G. Markl, Chem. Ber., 97, 3322 (1964). 37. Y. Zeifman, N. Gambaryan and I. Knunyants, Izv. Akad. Nauk SSSR, Ser. Khim., 450 (1 965). 38. W. Pirkle and J. Hanske, J. Org. Chem., 42, 2436 (1977). 39. E. W. Abel and C. A. Burton, J. Fluorine Chem., 14, 105 (1979). 40. K. Burger, J. Albanbauer and M. Eggersdorfer,Angew. Chem., 87, 816 (1975). 41. K. Burger, J. Albanbauer and W. Foag, Angew. Chem., 87, 816 (1975). 42. K. Burger, R. Ottlinger and J. Albanbauer, Chem. Ber., 110.21 14 (1977). 43. L. Duhamel, P. Duhamel and J. Y . Valnot, Compr. Rend. C. 271, 1471 (1970). 44. L. Duhamel and J.-C. Plaquevent, Tetrahedron Lett., 2285 (1977). 45. 0. L. Brady, J. Chem. Soc., 757 (1931). 46. F. Ramirez and A. F. Kirby, J. Amer. Chem. Soc., 75, 6026 (1953). 47. A. Dondoni. G. Rossini, G. Mossa and L. Caglioti, J . Chem. SOC. B , 1404 (1968). 48. L. Caglioti, P. Grasselli, F. Morlacchi and G. Rossini, Chem. Ind., 25 (1968). 49. C. A. Bunnell and P. L. Fuchs, J. Org. Chem., 42, 2614 (1977). 50. W. E. Fristad, Y.-K. Han and L. A. Paquette, J. Organomeral. Chem., 174, 27 (1979). 51. P. Masi, A. Suarato, P. Giardino, L. Bernardi and F. Arcamone, I1 Farmuco, Ed. Sci., 34, 907 (1 979). 52. H. Beyer, W. Gssig and E. Bulka, Chem. Ber., 87, 1385 (1954). 53. H. Beyer, W. Essig, E. Bulka and D. Behrens, Chem. Ber., 87, 1392 (1954). 54. H. Beyer, W. LBssig and U. Schultz, Chem. Ber., 87, 1401 (1954). 55. H. Beyer and G. Wolter, Chem. Ber., 89, 1652 (1956). 56. H. Beyer and T. PyI, Chem. Ber., 89, 2556 (1956). 57. H. Beyer and G. Badicke, Chem. Ber., 93, 826 (1960). 58. S. C. De, 1. Indian Chem. SOC.,3, 30 (1926). 59. S. C. De and P. C. Rakshit, 1. Indian Chem. SOC.,13, 509 (1936). 60. A. Hantzsch and W. Wild, Ann., 289, 285 (1896). 61. R. Scholl and G. Matthaiopoulos, Ber., 29, 1550 (1896). 62. N. Tokuro and R. Oda, Buff. Inr. Phys. Chem. Res. (Tokyo), 22, 844 (1943). 63. P. Ciattoni and L. Rivolta, Chim. h d . (Rome), 49, 1186 (1967). 64. K. Wieser and A. Berndt, Angew. Chem., 87, 73 (1976). 65. W. Ahrens, K. Wieser and A. Berndt, Tetrahedron, 31, 2829 (1975). 66. D. Bertin, J. Peronnet and J. Caumartin, French Patent 2,029,890, Appl. 30 Jan 1969; Chem. Abstr., 75, 35134 (1971). 67. H. Brintzinger and R.Titzmann, Chem. Ber., 85, 344 (1952). 68. E. J. Corey, M. Petrzilka and Y. Ueda, Tetrahedron Lett., 4343 (1975). 69. W. Oppolzer, M. Petrzilka and K. Battig, Helv. Chim.Acra, 60,2964 (1977). 70. J. Turcan, Bull. SOC. Chim. Fr., 486 (1932). 71. M. A. Berg, Bull. SOC.Chim. Fr., 637 (1925). 72. J . Turcan, Bull. SOC. Chim. Fr., 283 (1936). 73. D. S. Malament and N. Levi, J . Org. Chem., 40,3285 (1975). 74. 0.Tsuge, M. Tashiro, K. Kamata and K. Hokama, Org. Prep. Proced. Inr.. 3, 289 (1971). 75. E. Aufderhaar and W. Seelinger, Jusrus Liebigs Ann. Chem., 701, 166 (1967). 76. E. M. Kosower, B. Pazhenchevsky and E. Hershkowitz, J. Amer. Chem. Soc., 100, 6516 (1978). 77. A. Silveira, Jr, Y.R. Mehra and M. A. Atwell, J. Org. Chem., 42, 3892 (1977). 78. M.Larchevique, G. Valette, T. Cuvigny and H. Normant, Synfhesis, 256 (1975). 79. W. Coppens and N. Schamp, Bull. Soc. Chim. Belg., 81, 643 (1972). 80. N. De Kimpe and N. Schamp, Bull. SOC.Chim. Belg., 83, 507 (1974). 81. N. De Kimpe, N. Schamp and W. Coppens. Bull. SOC. Chim. Belg., 84, 227 (1974). 82. N. De Kimpe and N. Schamp, Tetrahedron Lert., 3779 (1974). 83. N. De Kimpe and N. Schamp, Bull. Soc. Chim. Belg., 84, 235 (1 975). 84. J. F. W . Keana and R. R. Schumaker. Tetrahedron, 26, 5191 (1970). 85. N. De Kimpe, R.VerhC, L. De Buyck and N. Schamp, Synthetic Commun., 5,269 (1975). 86. N. De Kimpe, R. Verhe, L. De Buyck and N. Schamp, Bull. Soc. Chim. Belg., 84, 417 (1 975).

2. a-Halogenated imines

269

87. N. De Kimpe, R. Verht, L. De Buyck, H. Hasma and N. Scharnp, Tetruhedron, 32, 2457 (1976). 88. N. De Kimpe, R. Verht, L. De Buyck and N. Schamp, Synthetic Commun., 8.75 (1978). 89. N. De Kimpe, R. VerhC, L. De Buyck and N. Schamp, J. Org. Chem., 43,2933 (1978). 90. N. De Kimpe, R. Verht, L. De Buyck, Sunari Tukiman and N. Schamp, Tetrahedron, 35. 789 (1979). 91. N. De Kimpe, Unpublished results. 92. R. Verht, N. De Kimpe, L. De Buyck and N. Schamp, Synthesis, 455 ( 1 975). 93. H. Quast and A. Heublein, Terrahedron Leu., 3317 (1975). 94. H. P. Fischer and C. A. Grob, Helv. Chim. Ada, 45, 2528 (1962). 95. D. S. C. Black, N. A. BIackman and R. F. Brown, Tetrahedron Len., 3423 (1975). 96. D. S. C. Black, N. A. Blackman and R. F. Brown, Ausf. J . Chem., 32, 1785 (1979). 97. D. S. C. Black and N. A. Blackman, Aust. J. Chem., 32, 1795 (1979). 98. J. Hausler and U.Schmidt, Jusrus Liebigs Ann. Chem., 1881 (1979). 99. T. Yamazaki, K. Matoba, S. Imoto and M. Terashima, Chem. Pharm. Bull. (Tokyo), 24, 3011 (1976). 100. Y. Yamada, T. Emori, S. Kinoshita and H. Okada, Agr. Biol. Chem., 37, 649 (1977). 101. L. A. Carpino and G. S. Rundberg, Jr,J. Org. Chem., 34, 1717 (1969). 102. M. Flammang, Compt. Rend. C. 283, 593 (1976). 103. M. Flamrnang, Compt. Rend. C. 286, 671 (1978). 104. M. Z. Kirmani and S. R. Ahmed, Indiun 1. Chem. B , 15, 892 (1977). 105. B. Erni and H. G. Khorana, 1. Amer. Chem. Soc., 102, 3888 (1980). 106. A. Picot and X . Lusinchi, Tetrahedron Lett., 679 (1974). 107. A. Picot, M. Dendane and X.Lusinchi, Tetrahedron, 32, 2899 (1976). 108. M. Poutsma and P. Ibarbia, J. Org. Chem., 34, 2849 (1969). 109. 0. Migliara, S. Petruso and V. Spiro, 1. Heterocycfic Chem., 16, 833 (1979). 110. N. I. Korotkikh, A. Y.Chervinskii, S. N. Baranov, L. M. Kapkan and 0. P. Shvaika. Zh. Org. Khim., 15, 962 (1979); Chem. Abstr., 91, 74124 (1979). 111. G. Rosini and G. Baccolino, J . Org. Chem., 39, 826 (1974). 112. S. Cacchi, D. Misiti and M. Felici, Synthesis, 147 (1980). 113. N. De Kimpe and N. Schamp, Org. Prep. Proced. lnf., 13 241 (1981). 114. A. I. Fetell and H. Feuer, J . Org. Chem., 43, 1238 (1978). 115. N. De Kimpe, R. VerhC, L. De Buyck, J. Chys and N. Schamp, Synthelic Commun., 9,901 (1979). 116. N. De Kimpe, R. VerhC, L. De Buyck, J. Chys and N. Schamp, Bull. SOC. Chim. Belg ,88, 695 (1979). 117. C. Shin, Y. Sato and J. Yoshimura, Bull. Chem. Soc. Japan, 49, 1909 (1976). 118. C. Shin, Y. Sato, H. Sugiyama, K. Nanjo and J. Yashimura, Bull. Chem. SOC.Japan, 50, 1788 (1977). 119. G. I. Dmithenko, E. A. Gross and S. F. Vice, Canad. J. Chem., 58, 808 (1980). 120. H. Tohru, E. Mamoru, T. Masakatsu and N. Masako, Heterccycles, 2, 565 (1974). 121. T. Hino, M. Endo, M. Tonozuka, Y. Hashimoto and M. Nakagawa, Chem. Phamt. Bull. (Tokyo), 25, 2350 (1977). 122. P. G. Gassman, G. A. Campbell and G. Metha, Tetrahedron, 28, 2749 (1972). 123. M. De Roza, Chem. Commun., 482 (1975). 124. M. De Roza and J. L. T Alonso, J . Org. Chem., 43, 2639 (1978) and references cited therein. 125. R. J. Owellen, J. Org. Chem., 39, 69 ( 1 974). 126. F. M. Hershenson, K.A. Rodan, R.L. Kochman, J. L. Bloss and C. R. Mackerer,J. Med. Chem.. 20, 1448 (1977). 127. F. M. Hershenson, L. Swenton and K. A. Prodan, Tetrahedron Len., 2617 (1980). 128. R. J. Owellen and C. A. Hartke,J. Org. Chem., 41, 102 (1976). 129. A. Walser. J.-F. Blount and R. I. Fryer, J. Org. Chem.., 38,3077 (1973). 130. S. Sakai. E. Yamanaka and L. Do1by.J. Phurm. SOC.Japan, 97, 309 (1977). 131. J. Y. b r o n z e , J. b r o n z e , D. Royer, J. E v y and J. Le Men, Bull. SOC. Chim. Fr., 1215 (1977). 132. N. Finch and W. Taylor, J . Amer. Chem. SOC.,84, 1319 (1962). 133. N. Finch and W.Taylor, 1. Amer. Chem. SOC.,84, 3871 (1962). 134. G. Buchi and R. E. Manning, J. Amer. Chem. SOC.,88, 2532 (1966). ~~

270

N. De Kimpe and R. Verhe

135. E. Wenkert, E. W. Hagaman, N. Wang and N. Kunesch, Heterocycles, 12, 1439 (1979). 136. F. Titeux, L. Le Men-Olivier and J. Le Men, Bull. SOC. Chim. Fr., 1473 (1976). 137. N. Aimi, E. Yamanaka, M. Ogawa, T. Kohmoto, K. Mogi and S. Sakai, Heterocycles, 10,73 ( 1 978). 138. E. Wenkert, J. S. Bindra, C.-J. Chang, D. W. Cochram and D. E. Rearick,J. Org. Chem., 39, 1662 ( 1 974). 139. D. Herlem and F. Khuong-Huu, Tetrahedron, 35, 633 (1979). 140. K. V. Lichman,J. Chem. SOC. C, 2539 (1971). 141. H. Ulrich, B. Tucker and A. A. R. Sayigh, J. Org. Chem., 33, 2887 (1968). 142. H. Zinner, W. Siems, D. Kuhlrnan and G. Erfurt, 1. Prakr. Chem., 316, 54 (1974). 143. N. De Kimpe, R. Verht, L. De Buyck, W. Dejonghe and N. Schamp, Bull. SOC.Chim. Belg., 85, 763 (1976). 144. G. Kresze and R. Albrecht, Chem. Ber., 97, 490 (1964). 145. B. Drach, A. Martynyuk, G. Miskevich and 0.Lobanov,Zh. Org. Khim., 13,1404 (1977). 146. H. E. Zaugg, Synthesis, 49 (1970). 147. F. Weygand, W. Steglich and F. Fraunberger, Angew. Chem., 79, 822 (1967). 148. A. D. Sinitsa, N. A. Parkhomenko and E. A. Stukalo,Zh. Obshch. Khim., 47,2077 (1977). 149. A. D. Sinitsa, S. V. Bonadyk and L. N. Markovskii, Zh. Org. Khim., 15, 2003 (1979). 150. A. D. Sinitsa, N. A. Parkhomenko and S. V. Bonadyk, Zh. Org. Khim., 12, 974 (1976). 151. A. D. Sinitsa, S. V. Bonadyk and L. N. Markovskii, Zh. Org. Khim., 13, 721 (1977). 152. F. Weygand, W. Steglich, I. Lengyel, F. Fraunberger, A. Maierhofer and W. Oettmeier, Chem. Ber., 99, 1944 (1966). 153. M. E. Kuehne, US Patent 4,154,943 (Cl. 546-51; C07D487/16), 15 May 1979, Appl. 865,657, 29 Dec. 1977; Chem. Abstr., 91, 91816 (1979). 154. F. Weygand and W. Steglich, Chem. Eer., 98,487 (1 965). 155. E. Schmidt and K. Kuehlein, Ger. Offen., 2,645,280 (Cl. C07C145/00) 13 Apr. 1978, Appl. 7 Oct 1976; Chem. Absrr., 89, 5908 (1978). 156. M. G. Nair, C. Saunders, S.-Y. Chen, R. L.Kisliuk and Y. Gaumont, 1. Med. Chem., 23,59 (1980). 157. A. Hassner and V. Alexanian, J . Org. Chem., 44, 3861 (1979). 158. Houben-Weyl's Methoden der Organischen Chemie, Vol. X/4, p. 92, G. Thieme, Stuttgart (1968). 159. 0. V. Schickh and H. Metzger, Ger. Offen. 1,082,253, 25 May, 1960 (C1.120); Chem.. Absrr., 55, 17547~(1961). 160. J. Schmidt, Ber., 35, 3729 (1902). 161. N. Thorne,J. Chem. SOC., 2587 (1956). 162. N. Thome, J. Chem. SOC.,4271 (1956). 163. M. Ohno, M. Okamoto and K. Nukada, Tetrahedron Lett., 4047 (1965). 164. S. N. Danilov and K. A. Ogloblin, J . Gen. Chem. USSR, 22, 2167 (1952). 165. M. Ohno, N. Naruse, S. Torimitsu and I. Terasawa,J. Amer. Chem. Soc., 88,3168 (1966). 166. 0. Wallach,Ann.,306,278 (1899);332,305 (1904);360,26(1908); 374, 198 (1910); 389, 185 (1912); 414, 257 (1918). 167. M. Nishi, T. Komukai and K. Oikawa, Japan Kokai Tokyo Koho, 79, 24,809 (CI.C07C131/00), 24 Feb. 1979, Appl. 77/89,789, 28 Jul. 1977; Chem. Absrr., 91,38928 (1979). 168. M. Ohno, N. Naruse, S. Torimitsu and M. Okamoto, Bull. Chem. Soc. Japan, 39, 1119 (1966). 169. K. A. Ogloblin and V. P. Semenov,Zh. Org. Khim., 1, 1361 (1965); Chem. Abstr.,64,588a ( 1966). 170. P. Ciattoni, L. Rivolta and C. Divo, Chim. Ind. (Rome), 46,875 (1964). 171. A. Nenz, Belg. Patent. 627932 (1962); Chem. Abstr., 60, 14406c (1964). 172. A. Dornow, H. D. Jorden and A. Miiller, Chem. Eer., 94, 67 (1961). 173. A. Dornow and A. Miiller, Chem. Ber., 93, 41 (1960). 174. M. J. Haire,J. Org. Chem., 45, 1310 (1980). 175. R. L. Shriner and F. W. Neumann, Chem. Rev., 35, 351 (1944). 176. Houben-Weyl's Merhoden der Organkchen Chemie, 4th edn, Vol. XI(2). p. 39, G. Thieme, Stuttgart (1958). 177. B. S. Drach and G. N. Miskevich, Zh. Org. Khim., 13, 1398 (1977).

2. a-Halogenated imines

271

178. I. C. Grivas and A. Taurius, Canad. J. Chem., 36,771 (1958). 179. W. Kantlehner, U. Dinkeldein and H. Bredereck,Justus Liebigs Ann. Chem., 1354 ( I 979). 180. W. S. Saari, M. B. Freedman, J. R. Huff, S. W. King, A. W. Raab, S. J. Bergstrand. E. L. Engelhardt, A. Scriabine, G. Morgan, A. Morris, J. M. Stavorski, R. M. Noll and D. E . Duggan, 1. Med. Chem., 21, 1283 (1978). 181. W. A. Bolhofer, C. N. Habecker, A. M. Pietruszkiewicz, M. L. Torchiana, H. I. Jacohy and C. A. Stone, 1. Med. Chem., 22, 295 (1979). 182. A. G . Moritz, Specrrochim. A m , 20, 1555 (1964). 183. K. Matsumura, T. Saraie and N. Hashimoto, Chem. Pharm. E d . (Tokyo), 24,912 (1976). 184. K. Matsumura, T. Saraie and N. Hashimoto, Chem. Commun., 705 (1972). 185. F. Cramer, K. Pawelzik and H. J. Baldauf, Chem. Eer., 91, 1049 (1958). 186. F. Cramer and H. J. Baldauf, Chem. Eer., 92, 370 (1959). 187. L. E. Overman, 1. Amer. Chem. SOC..96.597 (1974). 188. L. E. Overman, J. Amer. Chem. SOC.,98, 2901 (1976). 189. L. E. Overman and L. A. Clizbe, 1. Amer. Chem. Soc., 98, 2352 (1976). 190. W. Steinkopf and L. Bohrmann, Ber., 40, 1635 (1907). 191. V. Shevchenko, V. Kalchenko and A. Sinitsa, Zh. Obshch. Khim., 47, 2 157 (1977). 192. A. A. Michurin, E. A. Lyandaev and I. V. Bodrikov, Zh. Org. Khim., 13, 222 (1977). 193. A. J. Speziale and R. C. Freeman, J. Amer. Chem. SOC.,82, 909 (1 960). 194. C. TKint and L. Ghosez, Unpublished results, mentioned as Ref. 99 by L. Ghosez and J. Marchand-Brynaert in Advan. Org. Chem., 9, 421 (1976). 195. H. Quast, E. Schmitt and R. Frank,Angew. Chem., 83, 728 (1971). 196. H. Quast, R. Frank and E. Schmitt, Angew. Chem., 84, 316 (1972). 197. H. Quast, R. Frank, B. Freundenzeich, P. Schafer and E. Schmitt, Jusbus Liebigs Ann. Chem., 74 (1979). 198. H. Quast, R.Frank, A. Heublein and E. Schmitt, Justus Liebigs Ann. Chem., 83 (1979). 199. A. Ross and R. N. Ring,J. Org. Chem., 26,579 (1961). 200. B. Yamada, R. W. Campbell and 0. Vogl, 1. Polym. Sci., 15, 1123 (1977). 201. D. W. Lipp and 0. Vog1,J. Pofym. Sci., 16, 1311 (1978). 202. R. W. Campbell and 0. Vogl, Monars. Chem., 110,453 (1979). 203. R. M. Noll and D. E. Duggan, J. Med. Chem., 21, 1283 (1978). 204. B. A. Titov, P. G. Zherebchenko, E. A. Krasheninnikova, V. Y. Kovtun and A. V. Terekhov, Khim.-Farm. Zh., 13, 26 (1979). 205. L. A. Overman, C. K. Marlowe and L. A. Clizbe, Tetrahedron Lett., 599 (1979). 206. J. Wrobel, V.Nelson, J. Sumiejski and P. Kovacic, 1. Org. Chem., 44, 2345 (1979). 207. M. Numazawa and Y. Osawa, Steroids, 32, 519 (1978). 208. A. Silveira, Jr and S. K. Satra, 1. Org. Chem., 44, 873 (1979). 209. A. B. Levy and A. Hassner, J. Amer. Chem. SOC.,93, 2051 (1971). 210. W. Fischer and J.-P. Anselme, J. Amer. Chem. Soc., 89, 5284 (1967). 21 1. J. Harnisch and G. Szeimies, Chem. Eer., 112, 3914 (1979). 212. K. Bott, Chem. Eer., lOS, 402 (1975). 213. J. Ciabattoni and M Cabell, Jr,J. Amer. Chem. SOC., 93, 1482 (1971). 214. A. Padwa, T. J. Blacklock, P. H. J. Carlsen and M. PulwerJ. Org. Chem.. 44,3281 (1979). 215. F. Sigaut-Titeux, L. Lemen-Olivier, J. Uvy and J. Le Men, Heterocycles, 6, 1129 (1977). 216. J. Beger and P. D. Thong, East Ger. Patent 127,811 (CI.C07D285/16), 12 Oct. 1977, Appl. 194,777, 14 Sep. 1976; Chem. Absrr., 88, 121250 (1978). 217. J. Beger and P. D. Thong, East Ger. Patent 127, 813 (Cl.C07D277/38), 12 Oct. 1977, Appl. 194, 779, 14 Sep. 1976; Chem. Abstr., 88, 121164 (1978). 218. N. Barbulescu, S. Moga-Gheorghe, E. Andrei and A. Sintamarian, Rev. Chim. (Bucharest), 30, 598 (1979); Chem. Abstr., 91, 1 5 7 2 0 6 ~(1979). 219. L. Duhamel and J. Y. Valnot, Compt. Rend. C 286, 47 (1978). 220. L.S. Abrams, H. S. Weintraub, J. E. Patrick and J. L. McGuire, J. Pharm. Sci., 67. 1287 (1978). 221. Y.Komeichi, S. Tomioka, T. Iwasaki and K. Watanabe, Tetrahedron Lett., 4677 (1 970). 222. A. Streitwieser, Solvolyric Displacement Reactions, McGraw-Hill, New York (1962). 223. R. M. Magid, Tetrahedron, 36, 1901 (1980). 224. J. B. Conant, W. R. Kirner and R. E. Hussey,J. Amer. Chem. Soc., 47,488 (1925). 225. A. Streitwieser, Chem. Rev., 56, 600 (1956).

212

N. De Kimpe and R. Verhe

226. J. Sadet, J. Lipszyc, E. Chenu, C. Gansser, G. Deyson, M. Hayat and C. Viel, Eur. J . Med. Chem.-Chim. Therap., 13, 277 (1978). 227. L. E. S. Barata, P. M. Baker, 0. R. Gottlieb and E. A. Ruveda, Phytochemisrry, 17, 783 (1978). 228. M. J. Hunter, A. B. Cramer and H. Hibbert, J. Amer. Chern. Soc., 61, 516 (1939). 229. Y. Nagao, K. Kaneko and E. Fujita, Tetrahedron Lerr., 41 15 (1978). 230. Y. Nagao, M. Ochiai, K. Kaneko, A. Maeda, K. Watanabe and E. Fujita, Tetrahedron Lett., 1345 0977). 231. H. Kobler, K.-H. Schuster and G. Simchen, Justus Liebigs Ann. Chem., 1946 (1978). 232. J. H. Boyer and D. Straw, J. Amer. Chem. Soc., 75, 1642 (1953). 233. N. De Kimpe, R. Verhe, L. De Buyck and N. Schamp, J. Org. Chem.. 45, 2803 (1980). 234. M. J. S. Dewar, The Electronic Theory of Organic Chemistry, Clarendon Press, Oxford (1948), p. 73. 235. R. G. Pearson, S. H . Langer, F. V. Williams and W. J. McGuire, J . Amer. Chem. Soc., 74, 5130 (1952). 236. P. D. Bartlett and E. N. Trachtenberg, J. Amer. Chem. Soc., 80. 5808 (1958). 237. A. Halvorsen and J. Songstad,JCS Chem. Commun.,327 (1978). 238. W. Reeve, E. L. Caffary and T. E. Keiser, J. Amer. Chem. Soc., 76,2280 (1954). 239. J. W. Thorpe and J. Warkentin, Canad. J. Chem., 51, 927 (1973). 240. T. I. Temnikova and E. N. Kropacheva, Zh. Obshch. Khim., 19. 1917 (1949); Chem. Absrr., 44, 1919 (1950). 241. C. L. Stevens, W. Malik and R. Pratt. J . Amer. Chem. Soc., 72, 4758 (1950). 242. 0. E. Edwards and C. Grieco, Canad. J . Chem., 52, 3561 (1974). 243. U. Miotti and A. Fava, 1. Amer. Chem. Soc., 88,4274 (1966). 244. C. A. Grob, K. Seckinger, S. W. Tam and R. Traber, Terrahedron Left., 3051 (1973). 245. F. G. Bordwell and T. G. Mecca 1. Amer. Chem. Soc., 94, 2119 (1972). 246. T. Kishimoto, H. Kochi and Y. Yaneda, Japan Kokai, 76 32, 569 (CI.C07D401/12), 19 Mar. 1976, Appl. 74/104,520 10 !kp. 1974; Chem. Absrr., 85, 177266 (1976). 247. B. S. Drach, G. N. Miskevich and A. P. Martynyuk, Zh. Org. Khim.,14, 508 (1978). 248. N. De Kimpe and N. Schamp, J . Org. Chem., 40,3749 (1975). 249. J. Shavel Jr. and H. Zinnes, J . Amer. Chem. Soc., 84, 1320 (1 962). 250. H. Zinnes and J. Shavel, Jr., J. Org. Chem., 31, 1765 (1966). 251. G. I. Dmitrienko, Heterocycles, 12, 1141 (1979). 252. S. Sakai and N. Shinma, J. Pharm. SOC.Japan, 97, 309 (1977). 253. Y. Tamura, M. W. Chun, H. Nishida and M. Ikeda, Heterocycles, 8, 313 (1977). 254. W. Gauss and H. Heitzer, Justus Liebigs Ann. Chem., 733, 59 (1970). 255. K. Dickore, K. Sasse and K. Bode, Justus Liebigs Ann. Chem., 733. 70 (1970). 256. S. G. P.Plant and M. L. Tomlinsan,/. Chem. Soc., 298 (1933). 257. P.Stoss. Arch. Pharm., 310, 509 (1977). 258. D. A. Trujillo, K. Nishiyama and J.-P. Anselme, Chem. Commun.,13 (1977). 259. M. V. Povstyanoi, E. V. Logachev and P. M.Kochergin, Khim. Gererotsikf. Soedin., (S), 715 (1976); Chem. Absrr., 85, 94322 (1976). 260. T. Sarawatki and V. Srinivasan, Tetrahedron, 33, 1043 (1977). 261. M. Ikeda, F. Tabusa and Y. Nishimura, Tetrahedron Lett. 2347 (1976). 262. V. P. Kukhar and E. 1. Sagina, Zh. Obshch. Khim., 49, 1025 (1979). 263. V. Shevchenko, V. Kalchenko and A. Sinitsa, Zh. Obshch. Khim.,47, 2157 (1977). 264. (a) F. W. Lichtenthaler, Chem. Rev., 61, 607 (1961); (b) A. J. Kirby and S. G. Warren, The Organic Chemistry of Phosphorus, Elsevier, Amsterdam (1 967). 265. G. Gaudiano, R. Modelli, P. P. Ponti, C. Ticozzi and A. Umani-Ronchi,J. Org. Chem., 33, 4431 (1968). 266. M. Masaki, K. Fukui and M.Ohta, J. Org. Chern., 32, 3564 (1 967). 267. P. Bravo, G . Gaudiano, C. Ticozzi and A. Umani-Ronchi, C k m . Commun.,131 1 (1968). 268. P. Bravo, G. Gaudiano and A. Umani-Ronchi, Gazz. Chim. ltal., 97. 1664 (1967). 269. 0. Tsuge, K. Kamara and S. Yogi, Bull. Chem. Soc. Japan, 50. 2153 (1977). 270. M. E. Kuehne and R. Hafter. J. Org. Chem., 43, 3702 (1978). 271. M. E. Kuehne, D. M. Roland and R. Hafter, J . Org. Chem.. 43, 3705 (1978). 272. R. Child and F. L. Pyman, J. Chem. Soc.. 36 (1971). 273. W. J. Middleton and C. G. Krespan, 1. Org. Chern., 30. 1398 (1 965).

2. a-Halogenated imines

273

274. W. J. Middleton and C. G. Krespan, J. Org. Chem.. 35, 1480 (1970). 275. W. J. Middleton and D. Metzger. J. Org. Chem., 35, 3985 (1 970). 276. N. De Kimpe, R. VerhC, L. De Buyck, H. Hasma and N. Schamp, Tetrahedron, 32, 3063 (1976). 277. R. VerhC, N. De Kimpe, L. De Buyck, M. Tilley and N. Schamp, Tetrahedron, 36. 131 ( 1 980). 278. R. Verhe, N. De Kimpe, L. De Buyck, M. Tilley and N. Schamp, Bull. Soc. Chim. BelX., 86, 879 (1977). 279. N. De Kimpe, R. Verhe, L. De Buyck, J. Chys and N. Schamp, J . Org. Chem., 43, 2670 (1978). 280. N. De Kimpe, R. VerhC, L. De Buyck, J. Chys and N. Schamp, Org. Prep. Proced. In(., 10, 149 (1978). 281. For some leading references in the field of tertiary a-cyanoenamines, see Refs 282 and 283. 282. H. Ahlbrecht and D. Liesching, Synthesis, 495 (1977). 283. N. De Kimpe, R. Verhk, L. De Buyck and N. Schamp, Synthesis 741 (1979). 284. G. Costa, C. Riche and H. P. Husson, Tetrahedron, 33, 315 (1977). 285. F. Weygand, W. Steglich and F. Fraunberger, Angew. Chem., 79, 822 (1967). 286. E. M. Kosower and B. Pazhenchevsky, J. Amer. Chem. Soc., 102,4983 (1980). 287. M. Ohno, S. Torimitsu, N. Naruse, M. Okamoto and I. Sakai, Bull. Chem. Soc. Japan. 39, 1129 (1966). 288. J. H. Smith, J. H. Heidema, E. T. Kaiser, J. B. Wetherington and J. W. Moncrief, 1.Amer. Chem. Soc., 94, 9274 (1972). 289. J. H. Smith, J. H. Heidema and E. T. Kaiser, J . Amer. Chem. Soc.. 94, 9276 (1972). 290. W. Hobold, U. Prietz and W. Pritzkow, J . Prakt. Chem., 311, 260 (1969). 291. C. L. Stevens and P. M. Pillai, J . Amer. Chem. Soc., 89, 3084 (1967). 292. (a) E. Francotte, Ph.D. thesis, University of Louvain-La-Neuve, Belgium (1978); (h) E. Francotte, Personal Communication. 293. M. Ohno and N. Naruse, Bull. Chem. Soc. Japan, 39, 1125 (1966). 294. J. H. Smith and E. T. Kaiser, J. Org. Chem., 39, 728 (1974). 295. A. Dornow and H. D. Jorden, Chem. Ber., 94, 76 (1961). 296. P. Bravo, G. Gaudiano, P. P. Ponti and A. Umani-Ronchi, Tetrahedron, 26, 1315 (1970). 297. H. G. Viehe, R. Merenyi, E. Francotte, M. Van Meerssche, G. Gemain, J. P. Declercq and M. Bodart-Gilmont, J . Amer. Chem. SOC.,99, 2940 (1977). 298. T. L. Gilchrist and T. G. Roberts, Chem. Commun., 847 (1978). 299. U. M. Kempe, T. K. Das Gupta, K. Blatt, P. Gygax, D. Felix and A. Eschenmoser, Helv. Chim. Acra, 55, 2187 (1972). 300. T.K. Das Gupta, D. Felix, U. M. Kempe and A. Eschenmoser, Helv. Chim. Acra, 55,2198 (1972). 301. M. Petrzilka. D. Felix and A. Eschenmoser, Helv. Chim. Acta, 56. 2950 (1973). 302. P. Gygax, T. K. Das Gupta and A. Eschenmoser, Helv. Chim. Acra, 55, 2205 (1972). 303. S. Shatzmiller and A. Eschenmoser, Helv. Chim. Acta, 56, 2975 (1973). 304. A. Ruttimann and D. Ginsburg, Helv. Chim.Acta, 58, 2237 (1975). 305. S. Shatzmiller, P. Gygax, D. Hall and A. Eschenmoser, Helv. Chim. Acta, 56, 2961 (1973). 306. F. D. Chattaway and T. E. W. Browne, J. Chem. SOC., 1088 (1931). 307. A. G. Schultz and W. K. Hagmann, J. Org. Chem., 43, 3391 ( 1 978). 308. S. Sommer, Tetrahedron Lett., 1 17 (1 977). 309. C. A. Sacks and P. L. Fuchs, J . Amer. Chem. SOC., 97, 7372 (1975). 310. S. R. Sandler and W. Karo, Organic Functional Group Preparations, Vol. 11, Academic Press, New York (1971). p. 307. 31 1. J. Schantl, Monars. Chem., 105, 322 (1974). 312. V. Sprio and S. Plescia,Ann. Chim. (Roma), 62, 345 (1972). 313. L. A. Carpin0.J. Amer. Chem. SOC.,80, 601 (1958). 314. L. A. Carpino, P. H. Terry and S. D. Thatte,J. Org. Chem., 31, 2867 (1966). 315. A. Silveira, Jr, T. J. Weslowski, T. A. Weil, V. Kumar and J. P. Gillespie, 1. Amer. Oil Chem. Soc., 48, 661 (1971). 316. P. J. Kocienski, J. M. Ansell and R. W. Ostrow, J . Org. Chem., 41,3625 (1976). 317. J. Schantl, Monars. Chem., 103, 1705 (1972). 318. J. Schantl, Monats. Chem., 103, 1718 (1972).

214

N. De Kimpe and R. Verhe

J. Schantl and P. Karpellus. Monats. Chem., 109. 1081 (1978). C. Kashima, Y. Aoko and Y. Omote, JCS Perkin I, 2511 (1975). L. Duhamel and J.-Y. Valnot, Tetrahedron Lett., 3167 (1974). P. Duhamel, L. Duhamel and J.-Y. Valnot, Tetrahedron Lett., 1339 (1973). L. Duhamel, P. Duhamel and J.-Y. Valnot, Compt. Rend. C. 278, 141 (1974). L. Duhamel and J.-Y. Valnot, Terrahedron Lett., 3319 (1979). S. Bouini, S. Gratton, A. Risaliti, A. Stener, rn. Calligaris and G. Nardin, JCS Perkin 1. 1377 (1977). 325. S. Bouini, S. Gratton, A. Risaliti, A. Stener, M. Calligaris and G. Nardin, JCS Perkin I, 327. S. Bozzini, B. Cova, S. Gratton, A. Lisini and A. Risaliti. JCS Perkin I, 240 (1980). 328. F. J. McEvoy and G. R. Allen, 1. Med. Chem., 17. 281 (1974). 329. W. V. Curran and A. Ross, J . Med. Chem., 17. 273 (1974). 330. J. D. Albright, F. J. McEvoy and D. B. Moran, J.Heterocyclic Chem.. 15, 881 (1978). 331. S. C. Dorman, US Patent 2,468,592, Apr. 26, 1949; Chem. Abstr., 43, 5153f (1949). 332. S. C. Dorman, US Patent 2,468,593, Apr. 26, 1949; Chem. Absrr., 43, 7499 (1949). 333. D. Borrmann and R. Wegler, Chem. Ber.., 100, 1814 (1967). 334. S. Brodka and H. Simon. Chem. Ber., 102, 3647 (1969). 335. H. Zinner, W. Siems and G. Erfurt, J . Prakt. Chem., 316, 443 (1974). 336. H. Zinner, W. Siems and G. Erfurt. J . Prakr. Chem., 316, 491 (1974). 337. E. Schmidt and K. Kuehlein, Ger. Offen. 2,645,280 (Cl. C07C145/00), 13 Apr. 1978, Appl. 7 Oct. 1976; Chem. Abstr., 89, 5908 (1978). 338. R. E. Banks, M. G. Barlow and M. Nickkhoamiry, J . Fluorine Chem., 14,383 (1979). 339. R. K. Olsen and A. J. Kolar, Tetrahedron Lett., 3579 (1975). 340. Y. G. BaIon and V. A. Srnirnov, Zh. Org. Khim. 14, 668 (1978). 341. K. Burger, G . George and J. Fehn, Justus Liebigs Ann. Chem., 757, 1 ( 1 972). 342. B. S. Drach and G. N. Miskevich, Zh. Org. Khim., 14, 501 (1978). 343. T. Hino, H. Miura, T. Nakamura, R. Murata and M. Nakagawa, Heterocycles, 3, 805 (1975). 344. N. De Kimpe, R. Verhe, L. De Buyck and N. Schamp, Rec. Trav. Chim. Pays-Bas, 96,242 ( 1977). 345. N. De Kimpe, N. Schamp and R. Verhe, Synthetic Cornmun., 5,403 (1975). 346. N. De Kimpe, R. Verhe, L. De Buyck and N. Schamp, J. Org. Chem., 45, 5319 (1980). 347. A. Hassner and A. B. Levy, J . Amer. Chem. SOC.,93, 5469 (1971). 348. N. De Kimpe, R. Verhe and N. Schamp, Bull. SOC. Chim. Belg., 84, 701 (1975). 349. K. Burger, J. Albanbauer and F. Manz, Chem. Ber., 107, 1823 (1974). 350. G. A. Boswell, Jr, J . Org. Chem., 33, 3699 (1968). 351. M. J. Haire, J . Org. Chem., 42. 3446 (1977). 352. M. Takeda, M. Inoue, M. Konda, S. Saito and H. Kugito, J. Org. Chem., 37,2677 (1972). 353. R. Jacquier, Bull. Soc. Chim. Fr.. [5] 17, D35 (1950). 354. A. S. Kende, Org. Reacrions, 11, 261 (1960). 355. A. A. Akhrem, T. K. Ustynyuk and Y. A. Titov, Russian Chem. Rev., 39,732 (1970). 356. C. Rappe in The Chemistry ofthe Carbon-Halogen Bond (Ed. S . Patai), Wiley, Chichester (1973). p. 1071. 357. K. Sat0 and M. Oohashi, Yuki Gosei Kagaku Kyokai Shi, 32, 435 (1974). 358. J. March in Advanced Organic Chemistry: Reactions Mechanisms and Structure, McGraw-Hill, New York (1968), p. 804. 359. W. J. le Noble in Highlights ofOrganic Chemisrry, Marcel Dekker, New York (1974). p. 864. 360. P. J . Chenier, J . Chem. Educ., 55, 286 (1978). 361. R. Frank, Ph.D. thesis, University of Wiirzburg (1971). 362. N. De Kimpe, R. Verhe, L. De Buyck, N. Schamp, J. P. Declercq, G. Germain and M. Van Meerssche, 1. Org. Chem., 42, 3704 (1977). 363. N. De Kimpe, R. Verhk, L. De Buyck and N. Schamp, Bull. SOC. Chim. Belg., 86, 663 ( 1 977). 364. P. Duhamel, L. Duhamel, C. Collet and A. Hai'der, Compr. Rend. C 273. 1461 (1971). 365. L. Duhamel, P. Duhamel, C. Collet, A. Harder and J-M. Pokier, Terrahedron Lett.. 4743 ( 1 972). 366. L. Duhamel and J.-M. Pokier, Bulf. Soc. Chim. Fr., 329 (1975). 367. A. Buzas, C. Retourne, J. P. Jacquet and G. Lavielle, Heterocycles, 6, 1307 (1977).

319. 320. 321. 322. 323. 324. 325.

2. a-Halogenated imines 368. 369. 370. 371. 372. 373. 374. 375. 376. 377. 378. 379. 380. 381. 382. 383. 384. 385. 386. 387. 388. 389. 390. 391. 392. 393. 394. 395. 396. 397. 398. 399. 400. 401. 402. 403. 404. 405. 406. 407. 408. 409. 410. 41 1. 412. 413. 414. 415.

275

A. Picot and X . Lusinchi, Tetrahedron, 34, 2747 (1978). G . Costa, C. Riche and H. P. Husson, Tetrahedron, 33, 315 (1977). J.-Y. b r o n z e , J. Laronze-Fontaine, J. Uvy and J. Le Men, Tetrahedron Lett., 491 (1974). T. Hino, H. Yamaguchi, M. Endo and M. Nakagawa, JCS Perkin I, 745 (1976). T. Hino and M. Nakagawa, Heterocycles, 6, 1680 (1977). J. P. Kutney, J. Beck, F. Bylsma, J. Cook, W. J. Cretney, K. Fuji, R. Imhof and A . M. Treasurywala, Helv. Chim. Acta, 58, 1690 (1975). K. Burger and R. Ottlinger, J . Fluorine Chem., 11, 29 (1978). K. Burger, W.-D. Roth, K. Einhellig and L. Hatzelmann, Chem. Ber., 108, 2737 (1975). K. Burger, H. Schikaneder and A. Meffert, Z. Naturforsch., B, 30, 622 (1975). K. Burger and S. Penninger, Synthesis, 524 (1978). R. W. Hoffmann, K. Steinbach and W. Lilienblum, Chem. Ber., 109, 1759 (1976). K. Burger and R. Ottlinger, Chem. Zeit., 101, 402 (1977). R. W.Hoffmann, K. Steinbach and B. Dittrich, Chem. Ber., 106, 2174 (1973). K. Burger, W. Thenn and H. Schickaneder, J . Fluorine Chem., 6, 59 (1975). K. Burger, J. Fehn and A. Gieren, Justus Liebigs Ann. Chern., 757, 9 (1 972). K. Burger, S. Tremmel and H. Schickaneder, J . Fluorine Chem.,. 6 , 471 (1975). K. Burger, W. Thenn and A. Gieren, Angew. Chem., 86, 481 (1974). K. Burger, W. Thenn, R. Rauk and H. Schickaneder, Chem. Ber., 108, 1460 (1975) K. Burger and F. Hein, Justus Liebigs Ann. Chem., 133 (1979). N. P. Gambaryan, I. L. Knunyants et al., Dokl. Akad Nauk SSSR, 166, 864 (1966). F. Weygand, W. Steglich, W. Oettmeier, A. Maierhofer and R. S. b y , Angew. Chem., 78, 640 (1966). Y.V. Zeifman, N. P. Gambaryan, L. A. Simonyan, R. B. Minasyan and I. L. Knunyants, Zh. Obshch. Khim., 37, 2476 (1967); J . Gen. Chem. USSR, 37, 2355 (1967). Y. V. ikifman and I. L. Knunyants, Dokl. Akad. Nauk. SSSR, 173, 354 (1967). I. L. Knunyants, Y. V. Zeifman and N. D. Gambaryan, Izv. Akad. Nauk. SSSR, Ser. Khim., 1108 (1966). I. L. Knunyants, N. P. Gambaryan and R. B. Minasyan, Izv. Akad. Nauk. SSSR, Ser. Khim., I910 (1965). F. Hein, K. Burger and J. Firl, JCS Chem. Commun., 792 (1979). L. Kryukov, L. Y. Kryukova, M. A. Kurykin, R. N. Sterlin and I. L. Knunyants, Zh. Vses. Khim. 0 - v a , 24, 393 (1979); Chem. Abstr., 91, 193269 (1979). D. P. Del’tsova, Z. V. Safronova, N. P. Gambaryan, M. Y. Antipin and Y. T. Struchkov, Izv. Akad. Nauk. SSSR, Ser. Khim., (8). 1881 (1978); Chem. Abstr., 89, 215280 (1978). R. Albrecht and G. Kresze, Chem. Ber., 98, 1431 (1965). G. R. Krow, C. Pyun, R. Rodebaugh and J. Marakowski, Tetrahedron, 30, 2977 (1974). T. Imagawa, K. Sisido and M. Kawanisi, Bull. Chem. SOC.Japan, 46, 2922 (1973). Y. A. Arbuzov, E. 1. Klimova, N. D. Autonova and Y. T. Tomilov, Zh. Org. Khim , 10, 1164 (1974). T. Akiyama, N. Urasato, T. Imagawa and M. Kawanisi, Bull. Chem. Soc. Japan, 49, I105 (1976). K. Burger and S. Penninger, Synthesis, 526 (1978). H. Beyer, G. Wolter and J. Lemke, Chem. Ber., 89, 2550 (1956). H.Beyer, W.Lissig and G. Ruhlig, Chem. Ber., 86, 764 (1953). R. Ottlinger, K. Burger, H. Goth and J. Firl, Tetrahedron Lett., 5003 (1978). K. Burger, J. Albanbauer and W. Strych, Synthesis, 57 (1975). K. Burger and R. Ottlinger, Synthesis, 44 (1978). K. Burger and R. Ottlinger, Tetahedron Lett., 973 (1978). D. Maytum, Chem. Brit., 14, 382 (1978). K. Isogai, T. Sasaki, C. Sato, J . Syn. Org. Chem. Japan, 36, 1104 (1978). B. S. Drach, T. P. Popovich, A. A. Kisilenko and 0. M. Polumbrik, Zh. Org. Khim., 15. 31 (1979). V. J. Lee and R. B. Woodward, J . Org. Chem., 44,2487 (1979). E. Elkik and H. Assadifar, Bull. SOC. Chim. Fr., 129 (1978). J. Patrick, H. Weintraub and J. McGuire, Steroids, 32, 147 (1978). P. Swered and M. A. Girard, Canadian Patent 1,035,698 (CI,AOlN9/20), 01 Aug. 1978, US Appl. 545,678, 30 Jan. 1975; Chem. Abstr., 90, 98550 (1979). J. Diopoh and M. Olomucki, Hoppe-Seyler’s Z . Physwl. Chem., 360, 1257 (1979).

276

N. De Kimpe and R. VerhC

416. Shell Intern. Res. Maatsch. N.V., British Patent 963.055, U S Appl. 13 May, 1962; Chem. Abstr., 61, 11252b (1964). 41 7. N. Langlois, F. Gueritte, Y. Langlois and P. Potier. J . Amer. Chem. SOC.,98, 7017 (1976). 418. G. A. Boswell, Jr J . Org. Chem., 33. 3699 (1968). 419. T. I. Temnikova and E. N. Kropacheva, Zh. Obshch. Khim., 19, 1917 (1949); Chem. Abstr., 44, 1919 (1950). 420. C. L. Stevens, W. Malik and R. Pratt, J. Amer. Chem. SOC.,72. 4758 (1950). 421. C. L. Stevens, M. L. Weiner and R. C. Freeman, J . Amer. Chem. SOC..75, 3977 (1953). 422. C. L. Stevens and J. J. DeYoung, J . Amer. Chem. SOC., 76, 718 (1954). 423. T. I. Temnikova and E. N. Kropacheva, Zh. Obshch. Khim., 22, 1150 (1952); Chem. Absrr.. 47, 6901 (1953). 424. N. De Kimpe, R. Verhi. L. De Buyck and N. Schamp. J . Org. Chem., 45,2803 (1980) and references cited therein. 425. L. E. Overman, Acc. Chem. Res., 13. 218 (1980). 426. N. Kunesch, P.-L. Vaucamps, A. Cave. J. Poisson and E. Wenkert, Tetrahedron Lett., 5073 ( 1979). 427. J.-P. Begue and M. Charpentier-Morize. Acc. Chem. Res., 13, 207 (1980). 428. X.Creary, 1. Org. Chem., 44, 3938 (1979). 429. Y. L. Chow, K. S. Pillay and H. Richard, Canad. J. Chem., 57, 2923 (1979). 430. A. 1. Meyers, H. W. Adickes, I. R. Politzer and W. N. Beverung, 1. Amer. Chem. SOC.,91, 765 (1969). 431. A. F. Hirsch, G. 0. Allen, B. Wong, S. Reynolds, C. Exarhos, W. Brown and D. W. Hahn, J . Med. Chem., 20, 1546 (1977). 432. R. Wegler in Chemie der Pjlanzenschutz- und Schadlingsbekampfungsmittel, Springer-Verlag, Berlin, Heidelberg and New York (1 970). 433. B. Unterhalt, Pharm. Zeit. 125, 361 (1980). 434. J. Schantl. Org. Magn. Resonance, 12, 652 (1979). 435. E. W. Della, M. P. Reimerink and B. G . Wright, Aurt. J . Chem., 32, 2235 (1979). 436. M. G. Zimin, N. G. Zabirov, V. N. Smirnov, R. A. Cherkasov, and A. N. Pudovik, Zh. Obshch. Khim., 50, 24 (1980). 437. T. N. Maksimova, V. B. Mochalin and B. V. Unkovskii, Khim. Geterotsiklich. Soedin, 273 ( 1980) 438. J . Cantacuzene and D. Ricard, Bull. SOC. Chim. Fr. 1587 (1967). 439. J. Cantacuzene, M. Atlanti and J. Anibie, Tetrahedron Lett. 2335 (1968). 440. D. Ricard and J. Cantacuzene, Bull. SOC. Chim. Fr., 628 (1969). 441. D. D. Rosenfeld and J. R. Kilsheier, J. Agr. Food Chem.. 22, 926 (1974). 442. K. Packer, Nanogen Index - A Dictionary of Pesticides and Chemical Pollutants (Ed. K. Packer), Nanogens Int., Freedom, USA (1975). 443. A. Kirrmann, Bull. SOC. Chim. Fr., 657 (1961). 444. F. 1. Luknitskii, Chem. Rev., 75, 259 (1975). 445. L. De Buyck, R. Verht, N. De Kimpe, D. Courtheyn and N. Schamp, Bull. SOC. Chim. Belg., 89, 441 (1980). 446. N. De Kimpe, L. De Buyck, R. VerhC, F. Wychuyse and N. Schamp, Synthetic Commun., 9, 575 (1979). 447. T. L. Gilchrist, D. A. Lingham and T. G. Roberts, JCS Chem. Commun., 1089 (1979). 448. K. H. F'foertner and J. Foricher, Helv. Chim. Acta. 63, 658 (1980). 449. C. J. Barnett, U.S. 4,199,525 (C1.260-453RW; C07C119/00), 22 Apr 1980, Appl. 27,627, 6 Apr. 1979; Chem. Abstr., 93, 94970 (1980). 450. K. A. Ogloblin and A. A. Potekhin, J . Org. Chem. U.S.S.R., 1, 1370 (1965). 451. T. L. Gilchrist and T. G. Roberts, JCS Chem. Commun., 1090 (1979). 452. A. Roedig, W. Ritschel and M. Foure. Chem. Ber., 113, 811 (1980). 453. P. J. Stang and D. P. Fox, J . Org. Chem., 42, 1667 (1977). 454. D. R. Williams and K. Nishitani, Tetruhedron Lett., 4417 (1980). 455. R. Z. Andriamialisoa. N. Langlois. Y. Langlois and P. Potier, Tetrahedron, 36, 3053 (1980). 456. R. Neidlein, S. Shatzmiller and E. Walter, Justus Liebigs Ann. Chem., 686 (1980). 457. N. De Kimpe, R. Verhe, L. De Buyck and N. Schamp, Bull. SOC.Chim. Belg., 88,59(1979). 458. K. Burger and H. Goth, Angew. Chem., 92, 836 (1980).

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459. K. Burger, R. Ottlinger, H. Goth and J. Firl, Chem. Eer., 113, 2699 (1980). 460. K . Aoki, T. Shida, S. Kamawawa, M. Ohtsuru and S. Yamazaki. UK Patent Appl.. 2.019.402 (CI.C07C109/10), 31 Oct. 1979; Japan Patent Appl., 78/4&493,24 Apr. 1Y78; Chem. Absrr.. 93, 204296 (1980). 461. N. De Kimpe, R. Verht, L. De Buyck, L. Moens and N. Schamp, Synthesis, 43, (1982). *Note added in proof A very recent paper described a straightfonuard general synthesis of a-haloketimincs by condensation of a-halocarbonyl compounds with primary amines in the presence of titanium(1V) chloride 4 6 1

The chemistry of a -haloketones, or-haloaldehydes and a-haloimines Edited by Saul Patai & Zvi Rappoport Copyright 0 1988 by John Wiley & Sons Ltd

APPENDIX TO CHAPTER

2

a-Halogenated imines I . INTRODUCTION . . . . . . . . . . . . . . . . . . . . I1. SYNTHESIS O F a-HALOGENATED IMINES . . . . . . . . . . A . Condensation of a-Halogenated Carbonyl Compounds with Primary Amines . . . . . . . . . . . . . . . . . . . . . . . B. Halogenation of Imino Compounds . . . . . . . . . . . . . C. Synthesis of a-Halogenated Imino Compounds by Halogenation of Enamines . . . . . . . . . . . . . . . . . . . . . . D . Miscellaneous Methods . . . . . . . . . . . . . . . . . . 111. REACTIVITY OF a-HALOGENATED IMINES . . . . . . . . . A . Nucleophilic Substitutions . . . . . . . . . . . . . . . . . B. Carbon-Carbon Bond Formation . . . . . . . . . . . . . 1 . Reactions of a-halogenated imino compounds with carbanions . . . 2. Reactions of a-halogenated imino compounds with cyanide ion . . 3. Reactions of a-halogenated imino compounds with organometallic reagents . . . . . . . . . . . . . . . . . . . . . . C. Elimination Reactions of a-Halogenated Imino Compounds . . . . . D . Nucleophilic Additions to a-Halogenated Imino Compounds . . . . E. Rearrangements of a-Halogenated Imino Compounds . . . . . . . 1 . The Favorskii-type rearrangement . . . . . . . . . . . . . 2. Rearrangement of a-halogenated imines via activated aziridine intermediates . . . . . . . . . . . . . . . . . . . . 3. Rearrangement of chloroindolenine derivatives . . . . . . . . 4. Beckman rearrangements of a-halogenated oximes . . . . . . . 5. Other rearrangements of a-halogenated imines . . . . . . . . F. Cycloadditions . . . . . . . . . . . . . . . . . . . . . G. Generation of a-Imidoylcarbenium Ions from a-Halogenated Imines . . IV . PROPERTIES AND APPLICATIONS OF a-HALOGENATED IMINO COMPOUNDS . . . . . . . . . . . . . . . . . . . . . V. REFERENCES . . . . . . . . . . . . . . . . . . . . . .

.

279 280 282 287 290 292 296 296 309 309 3 14 317 323 329 332 332 339 341 345 345 347 350 357 359

.

1 INTRODUCTION

This Appendix covers the literature on a-haloimines published from early 1980 up to the first half of 1986. Occasionally. some references earlier than 1980 and not mentioned in the original chapter are given. Nearly the same subdivisions as in the original review have been used. but a section on the generation of a-imidoylcarbenium ions from a-haloimines was added . Only those a-halogenated imino compounds having a structural similarity 219

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Norbert De Kimpe and Roland Verhe

with a-halogenated ketones and a-halogenated aldehydes are covered in this supplementary review. However, some valuable and very often some leading references to ahaloimidates, a-haloamidines and a-haloimidoyl cyanides will also be given. a-Haloimines (1) can tautomerize to the corresponding 8-haloenamines (355) if at least one a-hydrogen with respect to the imino functionality (i.e. R2)is present. The chemistry of 8-haloenamines parallels to some extent the chemistry of a-haloimines because the latter can react by intermediacy of the former (cf. the relationship between ketones and enols). /IHaloenamines having a tautomerizable structure, i.e. a hydrogen substituent on the nitrogen, are not stable entities and usually rearrange to their stable a-haloimino isomers. If the tautomerization of /I-haloenamines is structurally blocked by an additional N substituent different from hydrogen, i.e. if enamines (356)(R # H) derived from secondary amines and a-halocarbonyl compounds are involved, then their chemistry is well defined and distinguished from a-haloimine chemistry. The chemistry of /I-haloenamines will not be covered here, but their synthesis' l 3 and reactivity462have been reviewed.

NR

N

(1) X=halogan

RNH

(355) X=halogen

R\N/R

(356)X=halogen

II. SYNTHESIS OF a-HALOGENATED MINES

Two main strategies for the synthesis of a-halogenated imines (1) have been applied extensively in the last few years. The first involves the condensation of an a-halocarbonyl compound (2) with a primary amine and the second entails the halogenation of imines (4) or their corresponding tautomerizable enamines. Historically, the first method met with major difficulties and the a-haloimines (1) were only obtained in limited cases. Exceptions are the reactions of a-halocarbonyl compounds with the usual carbonyi identification reagents which provided a-halooximes, a-halohydrazones, a-halosemicarbazones, etc., with reasonable success. However, in other cases the never ending list of side-reactions during the condensation of a-halocarbonyl compounds with primary amines continues to build up. Indeed, the latter condensation in general does not lead to the a-haloimines as could be expected when the reactivity of the heteroallylic halogen is neglected. This reactive halogen, at either the carbonyl or the imine stage, is readily displaced and leads to a great variety of side-reactions, including nucleophilic s u b s t i t ~ t i o n ~, ~Favorskii ~-~~' rearrangement^^^^-^^^, a-iminoketone f ~ r m a t i o n ~haloform-type ~ ~ . ~ ~ ~ , reactions477and d e h y d r o h a l ~ g e n a t i o nSome ~ ~ ~ . representative recent examples of these side-reactions are now discussed. The most common of these is nucleophilic substitution, especially with less sterically hindered substrates. Examples are the transformation of functionalized phenacyl chloride (357) and a-chloropropiophenones (358) with primary amines to a-(Nalky1)aminoketones (359),which display antidepressant and central nervous system (CNS) stimulant a ~ t i v i t y ~In~contrast, ~ , ~ ~ the ~ . reaction of 2-carbamoyl-6-bromocyclohexanone (360) with ammonia, primary aliphatic amines or 4-chloroaniline yielded the ringcontracted cyclopentane-I, 2-dicarboxamides 361 via a Favorskii rearrangement472. Aliphatic a, a'-dibromoketones (362) reacted with primary amines to afford aiminoketones (363) and/or a-diimines (364),depending on the amount of amine presumably by aminolysis of an intermediate enolic allylic bromide. The a, a, a-

App. 2. a-Halogenated imines

28 1

trichloroketone 365 underwent a haloform-type reaction on treatment with aniline o r aaminocarboxylic acids in dimethyl sulphoxide to give 366477.An example of a dehydrohalogenation is the reaction of a-bromocycloalkanones (367)with aniline, a hich yielded enones (368)478. Frequently, the a-haloimine expected from the condensation of an a-halocarbonyl compound and a primary amine was formed, but it was further transformed into various products, including a - a l k o x y ~ x i m e s ~a,~j-unsaturated ~, ~ x i m e s ~ i' s~o, x a z ~ l e s indoles4*' ~~~, and a-chloro-a, b-unsaturated t o s y l h y d r a z o n e ~ ~ ~ ~ . However, many such condensations gave successfully a-halogenated imines, and these syntheses will be treated below.

(357)R'=H

(359) R'=H, Me

(358) R'=Me

(360)

23-100%

(361)

R1+R2

RNH.

R1*R2 Br

Br

+

dlethyl othor or

pontono

R1

N R'

(362)

(363)

F3CCCCIs

+

PhNH2

OMS0 25-35

OC

(364)

F3CCNHPh

282

Norbert De Kimpe and Roland Verhe 0

0

(368)

(367) n=l-4

R =Me, Et, Pr

A. Condensation of a-Halogenated Carbonyi Compounds with Primary Aminer

The most successful and general synthesis of a-halogenated imines (1) is the condensation of an a-halogenated ketone (2) or aldehyde (2R3 = H) with a primary amine in the ' , ~reaction ~ ~ . can usually be performed between presence of titanium(1V) ~ h l o r i d e ~ ~The 0 "Cand room temperature, but increasing steric hindrance in either reagent requires a higher temperature. The stoichiometry requires a 6 : l molar ratio of the amine to titanium(1V) chloride, but in practice some excess is used 4 6 1 . Titanium(1V) chloride has a dual role: as a Lewis acid activating the carbonyl function and by removing the water formed during the reaction by forming titanium(1V) oxide. The method was originally ' ~ e n a m i n e ~ ~ ~and ~ . ~a 'modification ~, developed for the synthesis of simple i m i n e ~ ~and ~ . variety of awas introduced for the synthesis of f l - h a l ~ e n a m i n e s ~ " ~A~ ~great halogenated imines ( I ) were synthesized by this method, and the formation of 369380 examplifies the scope of the method. Primary, secondary and tertiary a-haloimines and a-polyhalogenated imines are accessible.

b

TiCI,

X

31$.

R2

RNH,

R2 R 1 y L R 3

diathyl ather,

banzana or toluana

(2) X=CI,Br,F

X

(1)

CI

CI (369) Ref. 461

(370) Ref. 489

&,

(371) Ref. 490

i-Pr\N

CI

(372) Ref. 4 6 1

CI

CI

(373) Ref. 4 9 1

CI (374) Ref. 4 6 1

App. 2. a-Halogenated imines

(375)Ref. 461

(376)Ref. 492

283

(377)Ref. 490

i-pr\N

F

(378)Ref. 493

(379)Ref. 493

(380)Ref. 461

The method is also applicable to the synthesis of functionalized imines other than ahaloimines, e.g. a, a-di(ethy1thio)aldimine(381)497,a-(N-alky1)aminoaldimine(382)494and 8-chloroimines (383)495.

(381)

The method is very useful when side-reactions, other than imination, are plausible between the substrate and the primary amine (see above). However, when these are not expected, the usual condensation procedure for imine formation is applicable. Substrates which do not often give these side-reactions are a-halogenated aldehydes and afluorinated carbonyl compounds. a, a, 8-Trihaloaldehydes (384) reacted with 78aminocephalosporins (385) with azeotropic removal of water to provide the corresponding a, a, 8-trihaloaldimines (386)496,while excess of chloral (387) was condensed with 7aamino-3-methyl-1-oxacephem(388) to afford the chloral imine 389497, and with substituted o-aminophenols (390) to yield the chloral imines 391498.The chloral imines 394, useful in peptide synthesis, were prepared by a two-step procedure involving condensation of 387 with a-amino acid ester hydrochlorides in the presence of N methylmorpholine, after which the adduct formed (393) was dehydrated with thionyl chloride to 394499.This method was also applicable to the synthesis of N-tert-butyl- and N-benzyl-chloral i m i n e ~ The ~ ~ ~reaction . of the a, a, y-trichloroaldehyde 395 with ammonia in glyme probably proceeds via a sequence involving nucleophilic addition and ring closure to generate a 3,3-dichloro-l -pyrroline derivative (396)”’.

Norbert De Kimpe and Roland Verhe

284

(385)R2= I -Bu,

(384) R'= Me, Ph

Ph2CH

X , Y = halogen

Me

X

/

Y

-

COOCHPh2

A"

0

CI 3c

Co" 0

4 A rnol. sieves

COOCHPh2

(387)

CI3C

(388)

b 60 O C / l S min

OH

CI3C

(387)

(390)

c13c (391)

"Throughout, A represents boiling under reflux or heating at a given temperature.

App. 2. a-Halogenated imines

285 R

Mo-NnO

-+

Ct3CH'

MeOOC

(307)

NH2.HCI

w

diothyl ether RT

(392)

(393)

P (394)R=Me, i - B u , CHZPh

(396)

(395)

Owing to the strong carbon-fluorine bond, a-fluorinated carbonyl compounds usually give only imination with primary amines, although some exceptions (e.g. haloform-type reactions) are known, as discussed in a review on fluorine-containing a, a'-difluoroketimines (e.g. 398)505and i m i n e ~ ~a-Fluoroketimines ~'. (e.g. 397)502*503, perfluoroacetone imines (e.g. 399)504*505 were obtained by reaction of the appropriate a-fluorinated carbonyl compounds with primary amines.

i-

FCHZ CCHSHex-c

(397)

1-

FCH2CCH2 FHex-c

(398)

F3 CCCF3 rHeX--'

(399)

A doubtful result, in the opinion of the authors, is the reported conversion of the a, a', p, 8'-tetrabromoketone 400 with benzylamine or 4-methylaniline into the a, a'dibromoketimine (401)5"6.The precursor tetrabromide (400) would be expected to undergo a double dehydrobromination with loss of bromide from the a- and a'-positions rather than to give imination and concomitant bis-substitution. When repeating the

Norbert De Kimpe and Roland Verhe

286

experiment with the diphenyl ketone 400 (Ar=Ph) and benzylamine we could isolate neither the previously reported product (401) nor any other well defined product. NHR'

PhCHpNHp

N/

R'

NHR'

or 4--MeC,H,NHp

A

r

w

A

r

toluene b,8h

( 4 0 1 ) R'= PhCHZ, 4-MoC6H4

( 4 0 0 ) Ar=Ph, 4-ClC6H4

The usual carbonyl identification reagents such as hydroxylamine, 0-substituted hydroxylamines or hydrazines have been frequently condensed with a-halogenated carbonyl compounds because the resulting a-haloimino compounds are valuable synthons for various reactions, including cycloadditions (see below). aa-Halooximes have been synthesized from aliphatic a - h a l ~ k e t o n e s ~aliphatic ~~, bromomethyl ketonesso7, bromopyruvates508~509, cr-chlorocyclohexanones510~51 ', substituted phenacyl l 4 , a-chlorocyclobutanones5'', a, a-di- and a, a, a-trihalogenated ace top hen one^^'^.^^^ and 2,2-dichloro-l,3-diphenylpropane-l,3-dione(but *. a-Halogenated the oxime gave further ring closure to the corresponding 2-i~oxazoline)~' oxime ethers have been obtained from a-chlor~acetone~'~, a-iodoacetone519, substituted ' ~ *a~~~ phenacyl halides"3~520,a, a-di- and a, a, a-trichlorinated a ~ e t o p h e n o n e s ~and chlorocyclohexanones'l '. Representative products are the a-halo oxime derivatives 403, 406,407and 409.

-

KOAc

' /

HOAc

(402)

L

(403)

R d . SO?

x

PhCHpONHp MoOH-H,O

.

5 h,RT

( 4 0 4 ) X=CI

( 4 0 6 ) X=CI

R e f . 519

(407) X = I

(405) X=I

N/O-SiMepBu-t

,9

II

/CI

f

w \

R

(408)

0

4 A mol. iievea

R d . 511

'R (409)

App. 2. %-Halogenated imines

287

Reactions of a-halocarbonyl compounds with hydrazine-type reagents usually form ahalohydrazones, although exceptions are k n o ~ n ~Such ~ ~ reactions * ~ ~ ~have . been chforalSz6, b r ~ m a l ~a-halomethyl ~~, conducted with a,a-dichloroaldehydes524*szs, ketone^^*^-^^^, a-chlorocy~loalkanones~~~, a, a - d i c h l o r ~ k e t o n e s methyl ~ ~ ~ , bromopyruate^^ ', alkyl 2-chloro-3-oxobutyrates"32 and ~ , a , r - t r i f l u o r o a c e t o n eThe ~ ~ ~syntheses . of a-halohydrazone-type compounds (412, 415 and 416) are representative examples.

+

R /(x

R T , 4 5 min

(411)

(410) X=CI, Br

'>K

(412) X=CI, Br

Rmf. 5 2 9

0

O OR

N/N

H

+

NH2NHCOOR

CI

EtCOOH 7 h, 0 O C

H

c cl$I

Ref. 525

(413)

(414)

(415) R = M e 66% (416) R = t - B u 71%

a-Haloimino compounds have sometimes been prepared from a-haloketones using as exemplified for the synthesis of iminophosphoranes or lithio-N-trimethylsilylamides, the trifluoromethytketimine 418534.Other methods, which involve an isolable intermediate adduct, especially in the condensation of a-polyhalogenated ketones with primary amides, make use of dehydrating agents such as thionyl chloride53s or o l e ~ m ~ ~ ~ . (a) 4 -Me CsH 4N=PPha toluene,

A,?&

'*?

(b)

4 -Me CeH4 N ( L i 1Si Me, THF

RT, 2 0 h

(a)

13

25%

(b) 69%

(418)

B. Halogenation of lmino Compounds

N-Halosuccinimides are good halogenating agents for a great variety of imino compounds. The most recent examples focused on imino compounds with no a'-

288

Norbert De Kimpe and Roland Verhe

hydrogens, which could not give rise to regioisomers. Chlorination of N-aryl acetophenone imines (419)with N-chlorosuccinimide (NCS) in carbon tetrachloride occurred with quantitative yields537.The nitroxyl heterocycle 421 was also readily trichlorinated to 422,but dichlorination was more d i f l i c ~ l t ~ ~ ~ .

xAr ; 3NCS

Ph

Ph

Cl 4

100%

(420)

(419)

95%

(421)

(422)

1-Pyrrolines could be successfully monohalogenated with NCS and NBS in CCI, in the presence of catalytic amounts of trifluoroacetic acid539, but bicyclic 1-pyrrolines could only be brominated to mixtures of a-brominated derivative^^^'. Other brominations with NBS involved nitrones5,' and N-methoxy i m i d a t e ~ ' ~ ~ . The older literature did not report many successful halogenations using chlorine or bromine, but some more recent halogenations have led to useful a-halogenated imino compounds. In addition to the classical chlorinations (with CI,) and brominations (with Br,) of 2-pyrazolin-5-0nes~~~-~~~ to 4-halo- or 4,4-dihalo-2-pyrazolin-5-ones, the brominations of oxime ethers were executed with or without generation of the a-anion. The monobromination with bromine of 0-benzylacetophenone oximes proceeded in the dark546,but it is advantageous to monobrominate 0-methylacetone oxime (423) via the The (2)-425isomer was obtained exclusively but initial generation of the a-anion (424)547. could be isomerized with hydrogen bromide to the more stable (E)-425.A similar ,OM0

N

(423)

BuLi THF-

hrxonr

-65

OC, 5 min

-65

OC,

15 min [(

(424)

HBr CHCIs

z ) -42 51

App. 2. a-Halogenated imines

289

bromination of the r-anion of camphor nitrimine (427) led successfully to the 3-t’xobromonitrimine 428, which could be epimerized into the 3-endo-bromonitrimine 431 by Further bromination of the potassium salt of 428 furnished the morpholine in a, a-dibromoimino compound 429, while gaseous ammonia in ethanol converted both 428 and 431 into thc 3-endo-bromoimine 430s4*.

bNNo2 & EtOH/H,O KOH

(426)

-

(427) 1. KOHlEtOH-

Br2

6 N HCI

H,O

2. Brp

60

Br

dyNH ‘Br

(430)

(431)

a-Monobromination of the 2,4-dinitrophenylhydrazone of methyl pyruvate occurred of the smoothly with two equivalents of bromine in d i ~ h l o r o m e t h a n e ~but ~ ~iodination , bicyclic hydrazone 432 gave a complex mixture in which the vinyl iodide 433, the indane 434 and the azine 435 were identified549.

diathyl Bther

EtaN (excess)

7%

(432)

(433)

+

Norbert De Kimpe and Roland Verhe

290

Tosylhydrazones derived from heptanal and isobutyraldehyde were amonobrominated with phenyltrimethylammonium perbromide (PTAB)528.Monohalois difficult owing to dihalogenation, but genation of 4-unsubstituted-2-pyrazolin-5-ones 4,4-dichlorination or 4,4-dibromination using 1,3-dihalo-5,5-dimethylhydantoinin acetic acid followed by reduction with ascorbic acid-triethylamine offers a new method for the synthesis of 4-monohalo-2-pyrazolin-5-ones5so. tert-Butyl hypochlorite, a well known chlorinating agent in the indole field (see below), also converts 5,6-dihydr0-3,5,5-trimethyl-l,4-oxazin-2-one (436) into the unstable chloromethyl derivative (437)5s1. (dark)

t -BuOCI CHOCIZ

0 ‘C, 3 h

0

0

(436)

The a-chlorination of bicyclic amidines, e.g. 438, by carbon tetrachloride (and other tetrahalomethanes) is a very peculiar reaction and deserves to be m e n t i ~ n e d ~ ” -A~ ~ ~ . detailed mechanistic study suggested a redox process involving an initial single electron transferss4.

a>CJf, 14 d

H

H

100%

(438)

(439)

C. Synthesis of a-Halogenated lmino Compounds by Halogenatlon of Enamlnes

Enamines carrying 8-electron-withdrawing groups were easily halogenated with N halosuccinimidess55-557, tert-butyl h y p ~ c h l o r i t e ~sulphuryl ~~, chloridess6, N,Ndibromoben~enesulphonamide~~~, bromines6’ or sodium hypohalitess6’, as exemplified for the 1,3-diimines(occurring in the stable enaminimine forrn)44Os5’and 442556*557 and the enamino diester 444558. CI

4.4 equiv. NCS CHCI,

(440)

CI

b

42 ‘/o

(441)

29 1

App. 2. a-Halogenated imines

..-‘R -Jt.

toluene, N X S RT

R2J&:: CI

(442)

(443)

,SiMe3 EtOOC

PhSOaNBr,

EtOOC

(444)

EtOOC EtOOC

Br

(445)

A related bromination of 1,4-unsubstituted pyrazoles with bromine gives 4,4-dibromo1,3-diimino compounds559. Side-reactions occurred during the bromination with bromine or sodium hypobromite of certain enaminones (cleavage)560 and during photochemical brominations with NBS in acetic acid of a-alkoxycarbonylenamides (yhal~genation)’~~. As already pointed out in the original chapter, the halogenation of indoles received considerable attention owing to the potential of halogenated indoline derivatives as precursors in natural product syntheses. Classical reagents for the halogenation of indoles included tert-butyl h y p o ~ h l o r i t e ~ ~ NCS568-570, ’-~~~, NBS569*570*572, N-chlor~isatin~~~, - c~ h, l o r o b e n z ~ t r i a z o l e ~bromine571 ~ ~ ~ ~ ~ ~ ~and ~ ~ ~iodines76. , sodium h y p ~ c h l o r i t e ~N ~ Depending on the structure of the indole and the reaction conditions, halogenation takes place at the 3-position (most common), the 2-position (radical h a l ~ g e n a t i o n ) ~and ~~.~~” ~ ~ ’ halogenation . of N-unsubstituted the a-carbon of a side-chain at the 2 - p 0 s i t i o n ~ ~ ’ .The indoles is reviewed only because N-substituted derivative^^^^.^^' cannot lead to ahaloimino derivatives, i.e. 3-haloindolenines. An example of the formation of the latter is the conversion of the indole 446 with tert-butyl hypochlorite into 447563.Major applications in the alkaloid field include the halogenation of ethyl pseudovincamanate (448)564, i ~ o b o r r e n i n e3-oxotabersonine ~~~, (a pentacyclic 3-substituted indoline derivative with an exocyclic double bond on the indoline ring)566 and other indole alkaloids567.575. An interesting and unexpected result during the attempted Swern oxidation of is the introduction of chlorine by the hydroxymethyl group of the indole derivative 450574 oxalyl chloride followed by oxidation by the medium to give the formyl moiety. Under the same conditions the epimeric alcohol 452 yielded the unchlorinated aldehyde 453”‘.

H

(446)

(447)

292

Norbert De Kimpe and Roland Verhe CI

\

\-,

/

COOMe

COOMe

/

(449)

(448)

CI

7y QTGN, HO

(450)

H

(COCI), OMSO

cn,ci,

*

9 "'"0

D. Miscellaneous Methods

This section contains a wide variety of reactions leading to a-halogenated imino compounds. Owing to the variable nature of these reactions, only a selection of some promising or peculiar syntheses will be discussed in detail and references will be given to others. Straightforward routes to a, a-dichloroimines are the dehydrochlorination of N-alkylp, p, /3-trichloroamines (454)577,the nucleophile-induced fragmentation of p-imino-a, adichloro esters (456)578 and the reaction of dichlorinated iminium halides (458) with primary a m i n e ~ ~The ' ~ . latter is an example of a transimination reaction which has also been applied to the synthesis of N-phenyl-a-bromoketirnine~~~~ and a-chloro oxime ethers5". The perchloro bicyclic compound 460, obtained from the dimerization of perchlorobutenyne, reacted with tert-butylamine to provide the strained a, adichloroketimine q61581. t-BuOK

Ph

Ph

(454)

I

CI 6 2 - 7 2 '10

(455)

App. 2. a-Halogenated imines

61

293

C I Cl

CI

(4518)

(459) R ’ z E t, t - B u R =t-Bu, c-Hex

CI

CI

N-Bu-t

t-BuNH2

CHCI,

or THF

CclI*

CI

CI

Cl

(461)

(460)

Various halogenations of imino compounds or other nitrogen-containing compounds were reported to afford, often unexpectedly and albeit in low yields, a-halogenated imino compounds. Such substrates include p y r a z o l e ~ ~i ~ ~o x, a z o l e s ~5-phenacyl-3~~, phenylisoxazole (E)-oximeSa4, a,S-unsaturated o ~ i m e s ~ carboxylic ~ ~ ~ ~ ’ ~amidessS7, , carbodiimides (462)”’ and methyl N-trityl prolinate (466)589.Some reagents, such as acetyl chlorides90 and p-toluenesulphonyl chlorides91, have been found to transfer their halogen to compounds such as four-membered nitrones and 2-phenyl-I-pyrroline, respectively. i-Pr

t

N=C=N-Bu-t

Ph

(462) i-Pr

N=C=N-Bu-t Ph Br

(463)

Br

(464) -t-BuBrlNBS

294

Norbert De Kimpe and Roland Verhe CI

G C O O M e

I

t - BUOCI

CPh3

&iOOMe

(467)

(466)

The conversion of the 2-formyl-1-pyrroline 468 into the 2-bromomethyl- 1-pyrroline 469 was a part of the vitamin B , , synthesis by W ~ o d w a r dThis ~ ~ ~transformation, . which

proceeds by reduction of the formyl group to a hydroxymethyi moiety followed by 0mesylation and nucleophilic substitution of the mesylate by lithium bromide in dimethylformamide, may be a more general approach to the generation of halomethylketimines. /\COOMI /\COOMI 1 .NaBH./MeOH

2 . MsCl 3,LiBr/OMF

MeOOC

\

COOMe

(468)

MeOOC

/

(469)

Various a-halogenated oximes have been obtained by the classical method of addition of nitrosyl chloride to olefins593-596.The addition of nitrosyl chloride to the alkyne 470 in the presence of aluminium chloride gave, after hydrolysis, the a, a-dichlorooxime 471597. Other oxygen-functionalized a-halooximes were obtained from nitro ole fin^^^^ and bis(trifluoromethy1)aceticacid599, but the addition of nitrosyl fluoride to cycloalkenes furnished a-fluoronitrimines6". The functionalized a-chlorooximes 472 and 474 were obtained by reaction of the appropriate a, /?-unsaturated carbonyl compound (473) with nitrosyl chloride or with ethyl nitrite in the presence of gaseous hydrogen chloride, respectively509.

I-BuCECH

(470)

(472)

2. H20

0

NOH

II CICHZCCHO

1 , NOCl /AIC18

NOCl

I' CHzZCHCR (473) R=H,Me

NOH

II

t-BuCCl2CH

(471)

EtONO HCI/EtOH R-Me

NOH

II

CICH2CCOR

(474 1

295

App. 2. a-Halogenated imines

A fairly general synthesis of a, a, a-trihaloacetaldimines substituted with electronwithdrawing groups involves addition of alkyl N, N-dichlorourethanes (476)"', N , Ndichlorobenzenesulphonamide (478)602 or ethyl N , N-dibromourethane (q80)6'13to trichloroethene (475). /COOR

76 -92% (417 1 HS02Ph

+ CI

(475)

87 oc 12 h

PhSOzNC12

(478 1

I

CI3C A H

(479)

I

+

,coon

AH

EtOOCNBr2

(480)

CI2BrC

67 */e

(481)

The attempted synthesis of 3,3-dichloro-2-phenylazirine from 1,2-dichloro-lphenylethene and chlorine azide failed604,but 3,3-dichloroazirines (484)became accessible by boron trichloride-promoted addition of trichloroacetonitrile across monosubstituted ethenes (qS2)605.(Di- and tri-substituted ethenes afforded functionalized a, a, atrichloroketonesh"5~h06 ). CCI, (

CCI,CN/BCI,

(482)

R

A

*

N-6C13

(483)

)-

CI R

N

4 4 -92%

(484)

R =Bu ,t-Bu, Hex,PhCH2

The last paragraph of this section provides an encyclopaedic coverage of various reactions leading to compounds having an a-haloimino functionality. These reactions include the rearrangement of a 2,2,3-trichloroaziridine to a chloral hydrazone derivative (485)526, cycloaddition of a chlorinated azoalkene across indene affording an achlorohydrazone (486)607, cycloaddition of a trifluoromethylnitrilimine with styrene608, the reaction of a five-membered nitrone with a-chloroacrylonitrile affording 487609,the condensation of a fluorinated azoalkene with perfluoroisobutene" ", the reaction of perfluoropent-2-ene with amrnonia6l ', the cyclization of 8-arylhydroxylamines with trifluoroacetic anhydride6 the reaction of perfluorinated nitrosoalkanes with potassium hydrogen sulphite6' or diphenyldia~omethane~ 14, the radical reaction of 2,3dichloropropene with N,0d6' and the reaction of pentachloropentafluorocyclohexanone N-chloroimine with hydrogen chloride6I6. Other reactions are the fluoride-induced

'',

',

296

Norbert De Kimpe and Roland Verhi

ring opening of a perfluoroaziridinone affording an N-acylhexafluoroacetone imine (488)617,the NH insertion of bis(trifluoromethy1)diazomethane into hexafluoroacetone imine61s, the reaction of 0-nitrosohexafluoroacetoneoxime with ole fin^^'^, the fluorination of quinoline with a caesium tetrafluorocobaltate at high temperature to give a perfluoroimine (489)620,the condensation of chloral with N-sulphinylperfluorobutanesulphonamide yielding a chloral imine (490)621, the condensation of chlorinated carbodiimides with carboxylic acidP’, the reaction of the phenylhydrazone of trifluoroacetyl bromide with trieth~lamine~’~, the SCI,-mediated cyclocondensation of ethyl 3amin0-4,4,4-trichlorocrotonate~’~ and the reaction of hexafluoroacetone with sodium ’ ~ . a-haloimino intermediates626.627 are discusthiocyanate or potassium ~ y a n a t e ~ Many sed in the sections dealing with the reactivity of a-haloimines.

(485) Ref. 5 2 6

FmF

(487) R e f . 6 0 9

(486) Ref. 607

/s02c4F9

F

N

F

CI3C

(488) Ref. 617

F

F

A

(490) R i f . 621

(489) R e f . 6 2 0

111. REACTIVITY OF a-HALOGENATED IMINES

The discussion of the reactivity of a-haloimines will be divided into the same sections as those used in the original chapter. It is necessary to emphasize that the reactivity of ahaloimines can be treated to some extent as the reactivity of masked a-halocarbonyl compounds and the differences between the two classes are useful when the final products still contain the imino functionality. Hydrolysis of the latter into the corresponding carbonyl compounds often leads to functionalized products which are not accessible via reactions of a-halocarbonyl compounds. The fact that a-halocarbonyl compounds can be generally masked into a - h a l ~ i m i n e sbroadens ~~~ the a-halocarbonyl chemistry via ahaloimines and provides a vehicle for the development of the chemistry of a useful class of bifunctional heteroallyl halides, i.e. a-halogenated imino compounds. A. Nucleophllic Substitutions

Nucleophilic substitution of a-haloimines affords a-functionalized imines. Many of

297

App. 2. a-Halogenated imines

these reactions have been reported in recent years but mechanistic details have not yet been unravelled. Strongly nucleophilic thiolates easily displace the heteroallylic halide in r-chloroaldimines (59) t o afford a-sulphenylated aldimines (491) in good yields. With higher homologues (R’or R2 # Me) a small proportion ( < 10%)of competitive 1,2-dehydrochlorination was observed628.A similar a-sulphenylation was described for 2-substituted The most 3-hal0-l-pyrrolines~~’and for various N-alkyl a-hal~rnethylketimines~’~. useful application of the substitution with sulphur nucleophiles was found in the synthesis of p ~ r p h y r i n s ~ ~c’~, r r i n o i d s ~and ~ ’ vitamin B, 2 5 9 2 . Five-membered thioamide-type reagents served as good nucleophiles for the displacement of a halogen a to an imino function, even when the halogenated substrate occurred as its more stable fl-haloenamine tautomer. As an example, the enamino ester 492 was brominated with NBS to the labile pbromoenamino ester 493, which was immediately treated with a thioamide (495) in the presence of DBU to afford the substitution product 496629.The latter appears in the enamino form exclusively but its formation was explained by intermediacy of the tautomeric a-bromoimine 494. The product 496 was further used in the directed synthesis of chlorin systems ( p ~ r p h y r i n s ) ~ ~It’ .was found earlier630that in substrates without an alkoxycarbonyl group, e.g. 497, the formal substitution with the thioamides 499 proceeded much better with the iodo than the bromo analogues. The removal of the sulphur atom in 500 with triethyl phosphite provided ready access to the semicorrinoid system 501630.It was suggested that the tautomeric a-iodoimino derivative 498 served as the substrate for the nucleophilic substitution.

CI

(59)

(4921

(493 1

2h,RT

CN

(494 1 COOMe \

298

Norbert De Kimpe and Roland Verhe

0

(497)

I

(500)

(498)

P P(OEt+

n

(501 1

a-Alkoxylation of a-haloimines frequently occurs in alcoholic media. Treatment of ahalomethylketimines (502) with alkoxides in alcohols or dimethyl sulphoxide yielded aalkoxymethylketimines (503),which were readily hydrolysed into a-alkoxymethyl ketones (% which I) were , not accessible from reactions of a-halomethyl ketones with a l k o x i d e ~ ~ ~ ) . Double nucleophilic substitution takes place with a,a-dichloromethylketimines80*82-248*’78. Very often the a-alkoxylation products are side-products when a-haloimines are treated under Favorskii rearrangement conditions, e.g. alkoxides in ~ . ~ ~ ’ . a-alkoxyketimines (508) are accessible diethyl ether or t e t r a h y d r o f ~ r a n ~ ~Tertiary from ~ o l v o l y s i sor ~ ~via ~ metal ion-associated through the intermediacy of either a pseudo-a-imidoylcarbenium ion (507) or delocalized 24Na1kylamino)allylcarbenium ion (506). However, the compounds 508 are usually only minor side-products. For instance, the a-haloketimines 505 reacted with alcohols in the

( 5 0 2 )X = C I , B r

(503)

(504)

299

App. 2. a-Halogenated imines

presence of a nitrogen base such as triethylamine, DABCO, DBU or DBN to give mainly the geminally functionalized cyclopropane 509, presumably via 506632.In addition, some rearrangement via a-alkoxyaziridine intermediates to afford 8-(alkylamino)acetals (510) was observed (see Metal ion-assisted alcoholysis of tertiary a-haloketimines was found to be a side-reaction when good nucleophiles such as cyanide were present in the m e d i ~ m ~ but ~ ~without * ~ ~a competing ~ , ~ ~ nucleophile ~ , the reaction can be directed exclusively towards a-alkox ylation, as demonstrated by the silver-induced conversion of the a-bromoaldimine 511 into the a-isopropoxyaldimine 512494.

"YHR

OR^ '&OR3 R

NHR

(510)

Ap,CO,

P

or AgOAc

1-PrOH

OPr-1

7 2 - 86%

(512 1

a-Alkoxylations of 3-chloroindolenines to afford 3-alkoxyindolenines can be performed ~ ~ 3-methoxyindolenines .~~~. (514) have been under b a s i ~or~acidic ~ ~~ *a t ~a l ~y s~i s ~Such used as intermediates for the C(2)side-chain alkylation of 2-methyl-3-alkylindoles (513) to

516636.

R 1 , Brz/CHzCI,/Et,N

2 . p-TosOH/MeOH

l.LDA/THF

Z.R'I/THF

a-Aryloxylations of a-haloimino compounds are known for 3 - h a l o i n d o l e n i n e ~and ~~~ especially for 3-bromo-2-methoxycarbonyl-1-pyrroline (517)638-640 . The reactions are and have mostly conducted in DMF, e.g. for a-acetoxylation of a-chloromethylimine~~~~, been used as a key step in the synthesis of the peptide alkaloid zizyphine A638 and the cyclopeptide alkaloid dihydromauritine A639.

300

Norbert De Kimpe and Roland Verhe N\

I

0 NHBoc

oQ)HJ+ph

(519)

An intramolecular displacement of halogen a both to an imino function and to a carbonyl group by an aryloxy anion was postulated during the ring contraction of 520 into 521 by means of primary a m i n e ~ ~After ~ ' . Michael addition of the amine, the intermediate a-bromoaldimine (523) formed undergoes an intramolecular nucleophilic substitution.

I

H

(522)

(523)

(524)

Various nucleophilic displacements have been performed on the 3-chloroazirines 133 and 134, a peculiar class of a-haloimines. Ab initio calculations and experimental observations support the intermediacy of 'azirinyl cations (135)-chloride anion' ion pairs. Nucleophilic substitutions with potassium acetate, lithium thiomethylate, lithium azide (525)642.The sulphenylated and methanol were reported for 3-chloro-2,3-dimethylazirine derivative (526) (Nu = SMe) could be characterized but not isolated and the azido derivative (526) (Nu = N3) decomposed completely into acetonitrile (527)642.Chloroazirines (528) are reactive bifunctional electrophiles, and were used as precursors for the 5H-1,4-benzodiazepines 532 by reaction with diamines (529)643.Benzil also reacted with

App. 2. r-Halogenated imines

301

these diamines (529) to yield the rare benzodiazepine derivatives 532 (R = Ph), thus showing that 3-chloroazirines are equivalents of 1 , 2 - d i o n e ~ ~ ~ ~ .

jNvl (525)

MeCN

Nu=N,,

Nu-

CD&N

(526)Nu=OAc,SMe,

(527)

N3,OMe

R'

I

30- 5 0 %

(5311 (332) Nitrogen nucleophiles give nearly clean substitution only when the halide is primary, i.e. when a-halomethyl imines are involved. The a-chloromethylketimine 533 underwent substitution with 1,2,4-triazole to provide the ketimine 534, which showed useful agricultural fungicidal properties644.Intramolecular substitutions with nitrogen nucleophiles are exemplified by the decomposition of phenacyl bromide N, N-dimethylhydrazone (535) via a four-membered intermediate (536) into benzonitrile (537)645and the cyclization of N-(2-pyridyl)chloroacetimidate (541) [from 2-aminopyridine (539) and the chloroketene acetal5401 into 542646.Unexpected reactions were found during the condensation of a, a-dibromoamidines with arylhydrazines, affording the corresponding a-diimino derivatives by nucleophilic s ~ b s t i t u t i o n ~ ~and ' , in the &?"type substitution of the 3chloroindolenine 543 with dimethylamine562. CI

I

qj

A,2 h

H K,CO,/MIOH

e

302

Norbert De Kimpe and Roland Verhe Me

(540)

(541)

(545)

Substitutions with phosphorus nucleophiles are still rare and have concerned ahalogenated five-membered iminoxyl radicals and chloromethyl cyclic imidates, which gave Arbuzov-type p r o d ~ c t s ~ ~ ~ . ~ ~ ~ . As already discussed in the original chapter, nucleophilic substitution of a-halogenated oximes5" and a-halogenated hydrazones is well documented and involves a 1,4dehydrohalogenation followed by addition of the nucleophile across the intermediate nitro so ole fin^^^^ and azoalkenes. a-Halooxime ethers also give rise to nucleophilic substitution products, while 0-silylated a-halooximes (409) can even afford nitrosoolefins (546)by a fluoride ion-induced process5". Further examples of nucleophilic substitutions of a-halooximes and related structures such as 2-isoxazolines, nitrones and oxime ethers are reactions with a l k o x i d e ~ ~hydroxide65 ~ ~ . ~ ~ ~ , phenolate^^^^*^^^ (e.g. the synthesis of the herbicide 549652),a ~ e t a t e ~ s~ ~' .l ~p ~h ~ i d, e s ~~ ~a ~n .t ~h ~a ~t e, s ~ ~ ~ * ~ ~ ~ , secondary amines657*658, tertiary a m i n e ~ ~ ~ 'y, r i d i n eand ~ ~1~, 2 , 4 - t r i a ~ o l e ~(e.g. '~*~~~ the synthesis of the fungicide 5515'O).

',

PC1 -6 App. 2. a-Halogenated imines

/O-

303

SiMeZBu-t

~-Bu~N+F-

R

R

(546)

(409)

NaI

(5611

(550)

The a-amination of a-chlorocyclohexanone oxime with ammonia was reported to give a major by-product (552)287,but it was shown later6” that the actual structure was.14-oxa7,15,16-triazatetracyclo[1 1.2.1.01~6.08~’3]hexadecan-16-ol (555). Analogously, methylamine yielded the corresponding N-methylated tetracyclic compound as major sideproduct of the a-amination reaction6”. Other interesting results are 1,Cdehydrochlorination with sodium hydrogencarbonate of the a-chloromethyloximes 180 and the achloro-a, a-difluorooxime 560’’’. The resulting nitrosoolefins (556 and 561) underwent intramolecular cyclization into oxazetes (557 and 562) which decomposed to the corresponding nitriles (558and 537, respectively). A stable oxazete (565) was prepared from the bulky a-bromooxime 563 using DBN as dehydrobrominating agent659.

mNoH

uND HON

Norbert De Kimpe and Roland Verhe

304

(553)

H

H

(554)

(555)

t-BuhsMO -( PH

SMe

N40

"N:th

D

'-Bu

SMe

Br

(563)

S

M

t-Bu

(564)

e

SMo

21 01.

(565)

Related to the 1.4-elimination of a-halooximes is the preparation of aliphatic cyclic and acyclic nitroolefins (567) from sr-halooximes (187) by oxidation with trifluoroperacetic acid, disodium hydrogen phosphate and CF,CO,H

Na2HP0,

R'

(567 1

X

(187) X=CI,Br

(566)

a-Halohydrazone-type compounds underwent nucleophilic substitutions at the aposition by mer~aptides~'~, selenidessZ8,azide"', hydrazides660, phosphites5", phos-

App. 2. a-Halogenated imines

305

phinitesS3O, nitroso c o m p o u n d P ’ and h y d r a ~ i n e sand ~ ~ some ~ examples are given below. The Arbuzov reaction of 571 into 572 provides ready access to a-phosphorylated carbonyl compounds on hydrolysis of 572 and circumvents in this way the side-reactions, i.e. the Perkow reaction, with a-haloketones by protecting the ketone as a hydraLone moietysJ0 (few Perkow reactions with a-haloimines are known662).The reaction of the ahaloketones 573 with phenylhydrazine proceeded via the a-halohydrazone 574 and the corresponding azoalkene 575, but finally gave the substitution product 576, in which the more substituted nitrogen of the phenylhydrazine is linked to the a - ~ a r b o n ~ ~ ~ . N

,NHTos

dNHTo PhSH or PhSaH

EtBN / THF

-78’C

Br

Z Ph

(569) z = s 7 2 % ( 5 7 0 ) Z = 5 e 69%

Ref. 5 2 8

R3

CI

(571) R ’ = M e , A r R2= H , M e

toluma

NNHCOOMe

,A,3 h

R’

Ref. 5 3 0

7 (

hR2 80-I00% ( 5 7 2 ) R 3 = OMe,OEt, Ph

x

PhNHNH2

“*R2

0

NNHPh

(575)

(578)

In contrast, 2-bromo-2-phenylacetaldehyde and 2-chloro- 1,2-diphenyIethanone gave the a-hydrazinohydrazones with the terminal less substituted nitrogen atom linked to the a - ~ a r b o nThe ~ ~ ~reaction . of chloral tosylhydrazone (577) with sulphide ion gave, after benzylation, access to 1,2,3-thiadiazole (579) while the reaction with primary amines afforded 1,2,3-triazoles (580)482.These reactions proceeded via 1,4-dehydrochIorination and subsequent nucleophilic addition at the 4-position of the intermediate a ~ o a l k e n e ~ ~ ~ .

306

Norbert De Kimpe and Roland Verhe

(576)

a-Halooximes and a-halohydrazones have been successfully used in recent years for the synthesis of heterocyclic compounds via [4 + 2]cycloadditions of intermediately formed nitrosoolefins and azoalkenes. The pioneering research of Gilchrist and coworkers and the literature on nitrosoolefin cycloadditions have been reviewed650.Many useful cycloadditions of nitrosoolefins, generated from base-induced 1,4-dehydrohaIogenation of ahalooximes, with dienes or alkenes as a heterodiene, heterodienophile or d i e n ~ p h i l e ~ ~ ~ were executed. Substrates added include f ~ r a n s ~ ~indene663, ~ * ~ ~ cycloal~ . ~ ~ ~ , ~ ~ . ~ ~ a~l ,l y l s i l a n e ~ ~styrene^'^^*^ ~~, 14, enokadienes514*597*663*666,e n a m i n e ~ ~alkenes509, latesso7, enol ether^^'^.^^^, 3-methylindole (although indole itself gave nucleophilic substitution)509and l-alkoxycyclohexa-l,3-diene~~~~. Most oximes were a-halomethyl derivatives but higher homologues also reacted in c y c l o a d d i t i ~ n s ~as~ ~did * ~a,~a~, d i ~ h l o r o and - ~ ~u,~u,a - t r i c h l o r o ~ x i m e sPertinent ~~~. transformations are the conversion of functionalized a-chlorooximes (581) with enol ethers into 3-acyl-6-alkoxy-5,6-dihydro4H- 1,2-oxazines(582)664and the formation of the oxazine 584 together with some nitrone 585 from the (Z)-a-chlorooxime 583514. Higher yields of cycloadducts were obtained from (Z)-a-chloro~ximes~~~. Both 583 and the E-isomer gave with 2-methoxypropene in the presence of sodium carbonate the same ratio of 584 to 585, indicating that C=N bond rotation must have occurred before cycloadduct formation' 14. The intramolecular version of these cycloadditions overcomes problems such as the use of a large excess of olefins and in complete regioselectivity668.Fluoride-induced cleavage of the 0-silylated achlorooxime 586 to the corresponding a-chlorooxime and then to the nitrosoolefin yielded a suitable substrate in the first example of an intramolecular [4 + 2]cycloaddition, which gave the two epimers of the tricyclic compounds 587 in different ratios. The best results were obtained when the nitrosoolefin was slowly formed with caesium fluoride (20 h)668. The related a-chloronitrones behaved similarly towards styrenes in a silver-catalysed reaction to yield oxazine derivatives669,but an exception is the cycloaddition of the a, pdichloronitrone 588 with bicyclic olefin 589 in the presence of silver tetrafluoroborate, followed by reaction with cyanide, which formed the spiro compound 591 and not the expected oxazine 590670.One carbonyl of 589 apparently underwent cycloaddition yielding 591.

App. 2. a-Halogenated imines

301

../

PI

t -0u

I

Me-Si-Me

M+ F-

R

( 5 8 6 ) R =H,Me

(5R2 ~

R

( 5 8 7 ) R ' , R 2 = H,OMe

Heteroanalogous cycloadditions to nitrosoolefins are known for azoolefins, accessible from a-halohydrazone-type compounds. The latter reacted with bases, often sodium carbonate or triethylamine, in the presence of c y ~ l o a l k a d i e n e s(see ~ ~ ~the conversion of 592 into 593), enamineP7' and enol ethers672 to form 1,4,5,6-tetrahydropyridazines. Without a dienophile present, a-halohydrazones (592; 2 = 2,4-dinitrophenyl) were transformed into 594663. The a-halohydrazones 412, carrying remote unsaturation in the N-acyl moiety, on treatment with base provided the intermediate azoalkenes 595, which cycloadded in an intramolecular fashion to afford pyrrolo[ 1,2-b]pyridazine derivatives (5%)529. A number of a-halogenated hydrazones have been converted into various heterocycles by transformation via isolable azoalkenes. N-Alkoxycarbonyl and N-2,4-dinitrophenyl a, a-dichloroacetaldehyde hydrazones (597) were dehydrochlorinated to the chlorinated azoalkenes (598), which underwent cycloaddition with electron-rich dienophiles. e.g. indene, ethoxyethene and furan, each providing a novel cyclic a-chloroimino compound (e.g. 599)525.

308

Norbert De Kimpe and Roland Verhe

2

I

(593) NHZ

Lx /

Ph

Y

tosyl,

N , N ‘Z

(594)

309

App. 2. sr-Halogenated imines 0

rR

J ?

(412) X = C l , B r R =Me,Ph,COOEt

CI

(597) Z = COOMe, COOBu-t, 2,4- DNP

2 = 2,4 -DNP

8. Carbon-Carbon

-

Bond Formation

1. Reactions of a-halogenated imino compounds with carbanions

Carbon-carbon bond formation by reaction of a-haloimino compounds with carbanions or equivalent reagents, e.g. enamines or electron-rich aromatics, increased in importance compared with the period before 1980,when only a few reports appeared. The general trend that a-haloimino compounds which are not functionalized on the nitrogen d o not react with carbanions continues, but a-halooximes (600)673, a-halooxime ethers (407)5'9,a - h a l ~ n i t r o n e sand ~ ~ a-haloazines ~.~~~ (170)269give formal nucleophilic suhstitution with carbanions, derived from active methylene functions (such as malonates, cyanoacetates, p-ketoaldehydes, indene, phenylacetonitrile and benzoyldimethylsulphonium and ester a-anions. The diazepine derivative 228 (Ar = Ph) was brominated with bromine in methanol to give the bromo compound 607 as an intermediate, which underwent intramolecular dehydrobromination to afford 7,7bis(ethoxycarbonyl)-2,5-diphenyl-3,4-diazanorcaradiene (608)269.

clFH 310

Norbert De Kimpe and Roland Verhe piperidine acetate

+

COOMe

CI

(600)

.

MeOOC MeOOC

86%

(601)

Li

+

THF

PhA

N

(603)

(407)

(604)

0 t Li

(407)

(605)

N-N

4rrPh

EtOOC

(228)

N-N

Br COOEt

(607)

(608)

a-Halooximes give [4 + 2]cycloaddition of the intermediate nitrosoolefins with electron-rich alkenes, but cases have been reported in which e n a ~ n i n e s ' ~and ~.~~~ indolesS08.S09.676.677 afforded instead formal nucleophilic substitution and no cyclization (sometimes both reaction types were observed678 or an additional rearrangement of substituents occurredez6). The a-bromohydrazone 609 reacted with the enamine 610 to yield the immonium bromide 611, which was further converted in two steps into vincamine 61253'.

Pyrrole (614) and 1,3-dimethoxybenzene were alkylated by the a-bromooxime 613 with low regioselectivity but anisole gave no reactionso9.

Coupling with aromatic substrates at the a'-position was achieved with the 7chloroindolenine 617, which reacted with vindoline (618) in methanolic hydrogen chloride to afford 55% of the coupled product (619)and 11% of the deacetylated coupled compound (620)s75.This reaction is related to the boron trifluoride etherate-catalysed coupling of vindoline and a tautomer of a chloroindolenine structure used in the synthesis of new vinblastine derivative^^^'. O n the other hand, an acid-catalysed coupling of the 2-position of 3-bromoindoles with the 3-position of indoles was explained in terms of the intermediacy of a-bromoimmonium derivatives6".

31 1

App. 2. a-Halogenated imines

I

N'

B

r

NH

a

= J J (61

+

)

EtOAc / EfsN 16h

COOMe

(609) (611)

-aqueous

cleavage

Zn

PH8

HOAc

HO

(612)

\

NOH

A coupling reaction of aliphatic carbons is that of the a-lithiated oxime ether 424 with iodine giving the (Z, Z)-1,4-dioxime ether 621, which isomerized thermally or with acid catalysts into the E,E-isomer 622681.It is not clear whether the coupling proceeded via an a-iodoimine and subsequent nucleophilic substitution or via intermediate radicals (see Section III.B.3). This coupling reaction could be used for the construction of cyclic derivatives (623)673. Such carbon-carbon bond formation is also known for achloromethyl hydrazones682 and can be performed similarly in an electrochemical way683. An application of a-haloimines as modified a-haloketones opened new entries in the field of a-hetero-substituted carbanions. The latter reagents are rarely prepared from ahalocarbonyl compounds, with the exception of a-halo esters (cf. the Darzens reaction) and a-halocarboxylic acids. a-Haloketones are usually not used for the generation of stabilized a-anions because of their high reactivity. Some haloenolate anions (624) have been d e s ~ r i b e d ~ ~but ~ - most ~ " of them lack hydrogens at the a'-position. By masking a-

Norbert De Kimpe and Roland Verhe

312

(617)

n

‘i II

Me

(619)

R = AC

(620) R =H

-

COOMe

55% 11%

BuLi

THF/hexane

-65OC

(423)

(424)

MeO,

4

Me0/N

-

MeO’

I

N

[(z, Z)- 6211

1

2 BULi

2 12

MeO, N

n+h

N\OMe

72O/o [(z,z)-623]

haloketones as a-haloimines having a’-hydrogens it was possible to circumvent these limitations. a-Chloroketimines (626) were easily deprotonated with lithium diisopropylamide in THF at 0 ° C to give 3-chloro-1-azaallylic anions (627), which reacted with (functionalized) alkyl halides to afford C-alkylated products (628) exclusively689.

+

App. 2. a-Halogenated imines

____) bola

IA

R2

313

-R3 s X 't*

X

(32)X=CI,Br

(625)

(624)

T

i-PrNHe

TiCI.

2 M HCI

N

LDA TW,OOC R ' , Rz= Ma,Ph

PX'

*

x=cI

X

X

(CH2)fir,(CH2),CH=CH2

(627)

(626)

R3

X

(628)

When the phenyl-substituted azaallylic anion 629 was treated cautiously with water at 0 "C,protonation occurred exclusively, on nitrogen, to generate /I-chloroenamine 630, which slowly rearranged to the corresponding a-chloroketimine 628a689.

CI (630)

CI

CI

(628a)

(629)

The strategy outlined above allowed the a-alkylation of a-haloketones having a'hydrogens, since hydrolysis of the a-alkylated a-haloimines 628 provided the a-alkylated a-haloketones 625689.The related alkylation of anions derived from N-cyclohexvl-afluoroacetone imine (397)revealed a temperature-dependent regioselectivity, as shown by the 631:632 ratios690.The tendency of the metalated ketimine to alkylate on the carbon bearing fluorine at low temperature ( - 80 "C) may be rationalized by suggesting that the increased acidity of the protons near the fluorine acts in concert with steric effects of the (E)-C=N configuration of the a-fluoroketimine.

/o d (397)

2 h

L~N(SIMO,)~ THF HMPA

*-A RX H 0' 2h

$F R

Me1 / - 8 O " C

{

Me1 / - 3OoC

(631)

96

(632)

4

11

89

97

3 97

3

3 14

Norbert De Kimpe and Roland Verhk

It may be mentioned that a-haloimine a-anions have been implicated already in some reactions3 24,548.69 1-694 2. Reactions of a-halogenated imino compounds with cyanide ion

Only a few nucleophilic substitutions of halogens a to an imino function are known, Surlargely in a-halomethylimines such as 1-chloromethyl-3,4-dihydroisoquinolines695. prisingly, the tertiary a-chlorooxime 633 afforded the a-cyanooxime 634, but a 1,4dehydrochlorination-additionof cyanide must account for this Secondary ahalooximes, generated from nitrosyl chloride addition to alkenes, also reacted in this way, but the substitution products (636) ring-closed spontaneously to 5-aminoisoxazoles (638)696.

J:

NaCN

OMSO or MeCN

CI

CN

(633)

(636)

(634)

(636)

(637)

(638)

Cyanide has a marked propensity for nucleophilic additions across the imino bond. The adducts are usually not isolated owing to further reactions of the halogen. However, the adduct of cyanide (see 640) across the perfluoroimine 639 was isolated501. R

I

NNR H CN

(639)

(640)

Similarly to the conversion of a-chloroaldimines (59) into tautomerizable a-cyanoenamines (235)276,the addition of cyanide across a-hromoimmonium bromides (642) generated in situ from bromination of enamines (641), formed tertiary a-cyanoenamines (644)via dehydrobromination of isolable cyanide adducts (643)697.An alternative and better method for the synthesis of a-cyanoenamines is the addition of cyanogen bromide across enamines (641) and subsequent dehydrobromination of the adducts (643) with methanolic sodium m e t h o ~ i d e ~ ~ ~ . ~ ~ ~ . The most general reaction of cyanide with a-haloimines is the nucleophilic addition across the imino bond, which, when applied to a large number of aliphatic a-halogenated ketimines (645), led to an excellent synthesis of a-cyanoaziridines (646)6333*634*698. Secondary N-alkyl a-chloroketimines gave a mixture of cis- and trans-a-cyanoaziridines (646).The tertiary a-chloroketimines 647 reacted with potassium cyanide in methanol to

1'

App. 2. a-Halogenated imines

315

R

I

R' (641f

1I

-5O.C

Erp/pontanm

Br

(643)

(644)

Br

(642)

afford mainly the a-cyanoaziridines 648, together with the 1-(N-a1kylamino)cyclopropanecarbonitriles 649 and ring-opened products, i.e. the 2-alkoxy-3-(N-alkylamino)nitriles 650. The formation of the a-cyanoaziridines 646 and 648 was explained by nucleophilic addition of cyanide across the imino function of 651 to yield the adduct 652 (or its anion), which subsequently underwent intramolecular cyclization. The a-cyanoaziridines (653) with R = H could not be prepared in this way because the cyanide adduct of the a-chloroaldimines 652 (R'= H) furnished the a-cyanoenamines 235 by 1,2dehydrochlorination, initiated by deprotonation of the acidic hydrogen a to the nitrile moiety. The cyclopropane derivatives 649 originated from trapping by cyanide of the strained cyclopropylideneamines 656, formed by formal base-induced 1,3-dehydrochlorination of the a-chloroketimines 647. Therefore, this reaction can be classified as a variant of the Favorskii rearrangement (see below), which is initiated by a-deprotonation of 647 to generate the delocalized anion 654, which loses a chloride anion spontaneously. The resulting zwitterion 655 is in equilibrium with the cyclopropylideneamine 656 via a disrotatory ring closure according to the Woodward-Hoffmann r ~ l e s ~ ~ ~ * ~ ~ ~ * ~ R

Norbert De Kimpe and Roland Verhe

316

R$lR R2

R'

CI

(651)

KCN

CN

>( C' N R2

CI

(652)

R'XN CN

R2

(215)

(649)

(656)

The scope and limitations of the cyanation of a-haloketimines was studied in detail by investigating the nature of the halogen, the carbon skeleton, the nitrogen substituent, the solvent and the source of the ~ y a n i d e ~Increasing ~ ~ . ~ ~steric ~ . hindrance of the nitrogen substituent favoured slightly the formation of cyclopropane derivatives. Alcohols were the preferential solvents for the formation of the cyclopropanes 649 from 647. The secondary a-chloroketimines 645 were quantitatively converted into 646 with cyanide in acetonitrile, DMSO and DMF. Sodium, potassium and tetrabutylammonium cyanide gave similar results but zinc, copper(1) and silver cyanide in methanol gave complex reaction mixtures containing a-cyanoaziridines, a-methoxyketones, cyclopropanes and unidentified products. The latter metal cations induced a solvent-assisted ionization of the achloroketimine to an intermediate a-imidoylcarbenium ion (507), which reacted with the alcoholic medium. On changing the r-halogen from chlorine to bromine, 649 was no longer formed and a-cyanoaziridines were obtained in excellent yields (in addition to small amounts of 1,2-dehydrobromination products as exemplified by the transformation of 657 into 658 and 659. The r-bromo atom is apparently more readily displaced by intramolecular nucleophilic substitution than by a Favorskii-like process.

317

App. 2. a-Halogenated imines

R

K

(667)

(659) R = H 0%

( 6 5 8 ) R = H 100% R = Me 94%

R =Me 5%

Introduction of one or two methyl groups at the a’-position has a major influence on the cyanation reaction in methanol since a-cyanoaziridines (648) are formed exclusively. This observation supported the proposed mechanism for the Favorskii-type rearrangement of 647 to 649 since it is initiated by a’-deprotonation. Hence the factor influencing the production of the cyclopropanes 649 is the acidity of the a‘-hydrogens. The a-phenyl-achloroketimines 660 with cyanide also did not afford a cyclopropane but yielded the cis-acyanoaziridines 661 stereospecifically. The highest proportion of cyclopropane was achieved with cyclohexyl derivative 662, which with potassium cyanide in methanol afforded a 2 :3 mixture of the a-cyanoaziridine 663 and the cyclopropanecarbonitrile 664634.

R Ph$R

R’

K0 CN

CI

(660)

MeOH or MeCN

*

R

I

‘ NK

:

Ph

(661)

54 %

(662)

(664)

The importance of these reactions is that the a-cyanoaziridines 646 and 648 are precursors of azomethine ylides, which are valuable substrates for 1,3-dipolar cycloadditions, while the 1-(N-alkylamino)cyclopropanecarbonitriles 649 are precursors of homologues of 1-aminocyclopropanecarboxylic acid (ACC), the natural precursor for the generation of the phytohormone ethylene. 3. Reactions of a-halogenated imino compounds with organometallic reagents

Carbon-carbon bond formation from a-halogenated imines with organornetallic reagents has great synthetic potential, but is still an underdeveloped area. This reaction

318

Norbert De Kimpe and Roland Verhe

differs considerably from the reactions of a-halocarbonyl compounds with organometallics. The reaction of tertiary a-chloroaldimines (59), bearing at least one a-methyl substituent (Rz= Me), with methyllithium (2 molar equivalents) in diethyl ether gave a mixture of aziridines (665) and the homologated methylketimines (666)490.When no r-methyl group was present, e.g. when R' = R2 = Et, no aziridine was formed and the homologation was the sole reaction. A similar homologation with phenyllithium afforded phenylketimines (667),which were hydrolysed into aromatic ketones (668),giving a new acylation of arenes under non-Friedel-Crafts conditions. Since the acylating agents, i.e. a-chloroaldimines (59). originate in two steps from aldehydesE7,they are used as modified aldehydes, useful as acylating reagents, for a r e n e ~ ~ ~ ' .

MeLi/diethyl ether

25-50°/., (666) N

/R

(59) X = C I , B r

(668)

R, R1,R2=olkyl

H *%

MeLi or MeCu ot Me2CuLi/diethyl ether(X=Br) RT

or MeCu/diethyl ether( X =CI)/A R

/N

R'

R2

(252)

O n the other hand, tertiary a-chloroaldimines (59)were transformed into 1,4-diimines (252) on prolonged reflux with methylcopper in diethyl ether490.The same products were obtained under milder conditions (room temperature) with a-bromoaldimines ( 5 9 X = Br) and methyllithium, methylcopper or lithium dimethylcuprate in diethyl ether490. The reaction probably proceeds by dimerization of imidoyl-substituted radicals and not via metal-halogen exchange and subsequent nucleophilic substitution, because the former three organomethyl reagents converted the a-bromoaldimine 669 into the diimine 670in 90-100% yield. The high steric hindrance in 669 precludes nucleophilic substitution by a tertiary imine a-anion at the tertiary halide centre. A similar coupling of abromoimines (671)into 1,4-diimines (673)was achieved with lithium diisopropylamide (LDA) in T H F and was likewise ascribed to a single-electron transfer from the base to the substrate to generate an imidoyl-substituted Again the difference in reactivity between a-bromoimines and a-bromoketones is remarkable because totally different reaction products are obtained, namely 1,4-diimines (673)699and a-debrominated ketones (3)700370'.

319

App. 2. =-Halogenated imines t

MoLi or M O C U

H

or Mo,CuLi diothyl other

b u -t

-Bu@H

90-100

(670)

(669)

N/R

N Y R ~

R2

Ve

~

R ~1+R3

~

R

:

~

SR$ : :

THF

R3

R2

Br

R2 "R

40 -09 '/a (671) R 3 = H , P h , i - P r

(672)

(673)

(3)

(671) Z = N R (674) 2 = 0

a, a-Dichloroaldimines, e.g. 675,with methyllithium underwent mainly r-methylation to afford a-monochloroaldimines, e.g. 676490.

+

A

H -

CI

ci

(675)

A

MoLi diothyl oithor

0 oc

7+H CI

79 % (676)

a-Haloketimines were also subjected to coupling reactions with organometallic reagents. Both primary and tertiary a-haloketimines (677and 377)with methyllithtum,

320

Norbert De Kimpe and Roland Verhe

methylcopper or lithium dimethyicuprate could be converted cleanly into 1,4-diimines (678 and 679) in high yields (86-100%)490. With N-(3-chloro-3-methylbut-2y1idene)isopropylamine (680), the 1,4-diimine (682),formed by coupling with methylcopper, could not be isolated but underwent intramolecular condensation via 683 and 684 to generate the bismethylenepyrrolidine 681490.

MoLi or MrCu

X

dlothyl rthrr

(677) X=CI, Br

MrLi dirlhyl rthor

YN

A

(678)

CI

(377)

(679)

dirlhyl r t h r r

(682)

App. 2. ?-Halogenated imines

321

A related coupling reaction is the conversion of 3-chloroazirines (685) with lithium metal into a transient ‘1,4-diimine’, which rearranged further into a pyrazine (687) and a pyrimidine (688)”’. Ph

Li

CI

Ph RT, 3 0 m i n

(686)

Ph

Ph

(686)

(687) Ph

+ Ph

Ph

(688)

Secondary or primary a-haloimino compounds are usually deprotonated by alkyllith~ readily handled, in iums at the a-position to give azaallylic carbanions (689), which C P be contrast to the corresponding oxygen analogues (see above)689. Such anions are easily alkylated to 690, as discussed in Section III.B.1689,690.693. However, when tertbutyllithium was used to deprotonate the 1,3-oxazine derivative 691, followed by a reaction with methyl iodide, the desired a-chloro-a-methyl derivative (692) was obtained in 24-70‘;;, yield, together with products of a-tert-butylation (693) and couplingdehydrochlorination (694)693.The latter two processes were also obtained with substrate 691 and phenylmagnesium bromide693.a-tert-Butylation of the a d loroaldimines 59 to 695 occirred- witk tert-butyllithium, but it was -accompanied by a-hydroxylation to 696494.

Lithium metal converted the bicyclic a-bromoimine 697 within a few seconds at - 78 “C into the tricyclic compound 698, probably via halogen-metal exchange, after which the delocalized I-azaallylic carbanion displaced the bromide in the neighbouring ring540.As expected, the a-bromoimine 699 also afforded 698 on treatment with potassium tertbutoxide. The preponderant reactions of a, a-dichloroimmonium chlorides (701) are nucleophilic additions across the immonium moiety. Consequently, methyl- and ethylmagncsium halides afforded alkylation at the 1-position to 702 but hindered reagents such as isopropyl- and tert-butylmagnesium halides gave reduction of the immonium bond to 700579.

(645) X=halo

(689)

(690)

Norbert De Kimpe and Roland Verhe

322

(691)

20-38

3-24

'/o

(695)

'/o

(694)

1. t-BuLi/diothyl ooc othor

: / $R R2

2. HpO

CI

t -eu

OH

(59)

ph$$$--Ph 8r

(697)

Ph+Ph

N

(698)

App. 2. a-Halogenated imines

323

CI-

-

R R'MgX

R'=

R\N/R

"&R2

i-Pr, t-Bu

CI

CI

(7011

(700)

(702)

A large number of chloral imines (703) give with acetyl chloride in the presence of zinc the N-acetyl F, P-dichloroenamines 704703.Reductive fluoride elimination with tin(I1) chloride of the heterodienes 705 produced the delocalized anion 706, which was transformed into oxazoles (708 Z = 0),thiazoles (708; Z = S) or imidazoles (708 Z = NR)704. A

MoCOCI / Zn

CI3C

H

EtOAc -diothyl other

CI

-

(703) R=alkyl

44 7 9 % (704)

-fd

x

N/

Z

M

F3C

F

C. Elimination Reactions of &-Halogenated lmino Compounds

Base-promoted 1,2-dehydrohaIogenation of a-haloimines occurs frequently and affords 1-azabutadienes. Treatment of a-haloketimines with strong bases (alkoxides, hydroxides) either gave 1,3-dehydrohalogenation to a cyclopropylideneamine (711) if 2'-hydrogens are available or 1,2-dehydrohaIogenation to 710. Lower alkoxides such as methoxide or ethoxide often produced other reaction types, thereby affording rearranged aaminoacetals (see below) and nucleophilic substitution products. More hindered alkoxides

324

Norbert De Kimpe and Roland Verhe

such as sodium isopropoxide rather converted a-chloroketimines, e.g. 680, into 1azabutadienes (see 712) but use of the more powerful potassium tert-butoxide resulted predominantly in a Favorskii rearrangement4”. However, with a-bromoketimines 1,2dehydrobromination predominated over a Favorskii rearrangement with strong bases, as illustrated by the conversion of the a-bromoketimine 713 to the a, ,!3-unsaturated ketimine 712491.

....I strong

& , , l R

x

(709) X =CI, Br

R2

A

A

$.( % + . CI (680)

___, ...

(711) d NaOMo or t-BuOK/THF or Triton B / i - P r O H

80-82%

Br

(712)

(713)

Since the competition between all these reaction types is strongly dependent on the structure of the starting a-haloimine, the halide, the base and the base c o n ~ e n t r a t i o nit~ ~ ~ , is difficult to make generalizations. The dehydrohalogenation and formylation at nitrogen of the cyclic @,a-dichloroimine 396 using phosphorus oxychloride in D M F found application in the synthesis of the (715) were easily converted fungicidal pyrrole 714500.4-Bromo-5-phenyl-2-isoxazolines into isoxazoles (716), either spontaneously or under the influence of potassium hydroxide705 or silver salts706.

I

CH=O

(396)

(714)

325

App. 2. @-Halogenatedimines -HBr

KOH or Ag r a l t s

Br

R

(715)

(716)

Dehydrohalogenation of a, a-dihalo I-tetralone imines (717) with sodium methoxide in methanol proceeded without side-reactions and after aromatization gave 2-halo- 1naphthylamines (719)493.

78-92% (717) X=CI,

(718)

Br

(719)

Chloroindolenines such as 7205b5 and otherssb4 did not undergo 1,2dehydrohalogenation at the original a, P-positions to the imino function but produced unsaturation at the a', F-position (cf. 721) when treated with trifluoroacetic acid. This was ascribed to neighbouring group assistance of the nitrogen atom in the adjacent ring. CF3COO-

1. CF,COOH/25

\Me

(720)

'C/5

min

2 . -OH (workup)

(721)

T

C FgCOO-

H

(722)

(723)

In addition to 1,2- and 1,3-dehydrohalogenation,a-haloimines carrying hydrogen atoms at C-1 of the N-substituent are able to undergo 1,4-dehydrohalogenation.The

Norbert De Kimpe and Roland Verhe

326

fluorinated nitrone 724 was dehydrofluorinated with methanolic potassium hydroxide, and the intermediate fluorinated 2-azabutadiene was isomerized to the aromatic compound 7256”. 1,4-Dehydrohalogenation is not limited to endocyclic imino systems, but an activating N-substituent is apparently necessary to induce the reaction. The acidity ofthe hydrogens at C-1 position ofthe N-alkyl substituent play a dominant role in the 1,4dehydrohalogenation. Increasing their acidity by substitution of C(’)with a phenyl group or a carbonyl moiety results in a base-induced 1,4-dehydrohalogenation.Accordingly, the N-benzyl-a-chloroaldimines 726 were dehydrochlorinated with potassium tert-butoxide in tetrahydrofuran to the 2-azabutadienes 728 in good yields493.

Ph

CI

( 7 2 6 ) R’ ,R2=-alkyl

This process found an interesting application in the field of cephalosporins. Treatment of the a, a, j?-trichloroaldimine 386,derived from 7/l-aminocephalosporins, with lithium methoxide or borax in methanol produced the methoxylated 1-azabutadiene 730 via the intermediacy of the 2-azabutadiene 729496.Hydrolysis of 730 provided the 7/l-amino-7amethoxycephalosporin derivative 731, which was used as a key intermediate for the synthesis of cephamycin antibiotics496. Another application involved the conversion of 7a-amino-3-methyl- 1-0xacephem (388) into 7/l-amino-3-methyl-1-oxacephem (734)via the chloral imine 389497.1,4-Dehydrochlorination of 389 with ethyldiisopropylamine (Hiinig base) in dichloromethane at low temperature afforded the dichlorinated 2-azabutadiene 732,which was reduced from the a-face with high stereoselectivity into the labile /l, /I-dichloroenamine 733 (we suggest that this compound, which was not characterized, occurs as its more stable a, a-dichloroaldimine form). Hydrolysis of 733 gave 734 in excellent yield. The same conversion was applied to the synthesis of 7/l-aminodesacetoxycephalosporanic acid benzhydryl ester497. The importance of this four-step procedure for the epimerization of 7a-amino-loxacephems is that a useful biological activity of these species is exhibited only when cis stereochemistry is present at the 6- and 7-positions. A final example of 1,4-elimination concerns the a-chloroimine 737,obtained in situ by reaction of an a-azido acyI chIoride 735 with the ynamine 736, which afforded the azacyclopentadienone 738.The latter underwent cycloaddition with the ynamine 736 and was further decarbonylated into functionalized pyridines (740)707,708.

327

App. 2. a-Halogenated imines

qyo

LiOMe

or NaeB407. 10H20

R'

MoOH

X

Y

(386) X,Y=CI, R'=Me,

Br

(729)

Ph

Me\

1. Girard T / H *

Meob&onCOOR

P 2 . ag. NaHCO,

H2N

(731)

(730)

I-PreNEt CH2Clg

- 4 0 OC

COOCHPh2

0 COOCHPh2

91v o

(389)

(732)

328

I HY L:

Norbert De Kimpe and Roland Verhe

(732)

NaBH,

H2Ny& Y+ CI

I

2MaCN N HCI

0

0

COOCHPh 2

0 oc

(734)

COOCHPh2

(733)

3-20

a/a

(739)

(740)

The 1,4-dehydrohaIogenation of a-haloimines resembles the heteroanalogous 1,4dehydrohalogenation of a-halooximes into nitro so ole fin^^^^ and a-halohydrazones into azoolefins (see Section 1II.A). Salient features of azoalkenes, generated from a-haloimines, of tetrolic acid (742) from 4,4include the synthesis of bimanes (see 221 and 222)545,709, dibromo-3-methyl-2-pyrazolin-5-one (741)544 and of alkynes (748) from 4-halo-3,4disubstituted-2-pyrazolin-5-ones(743)''". H ..

0

1. -OH

MeC=CCOOH

Br

(741)

(742)

329

App. 2. a-Halogenated imines NH

(743) R' ,R2= Ph, alkyl

(744)

-N,

(748)

I

(745)

(747)

-H'

(746)

D. Nucleophilic Additions to a-Halogenated lmino Compounds

a-Haloimines carrying an electron-withdrawing substituent on the nitrogen have a pronounced electrophilic imino carbon atom and therefore readily form adducts with a great variety of nucleophiles. In addition to the adducts listed in the original chapter, many more examples have been reported recently. These include mainly reactions of aalcohols7'' - 7 1 6 perhalogenated imines with nucleophiles such as a r n i n e ~ ~ ~ ' . ~ amides7' ' ~ . ~ ' ~297 , ~ulphonamides~ ", phosphorus nucleophiles7 u.720: amidines7' 1 - 7 2 3 , hydride (generated unexpectedly from trieth~lamine)~'~, 1,3-dione~~~~, 8-keto esters72s,carboxylic acids6'*, thiols602,hydroxylarnine~~~', i n d ~ l e ~ ' ethyl ~.~~~, diazoacetate7" and alkenes (ene reaction)62'.729.Some representative reactions are discussed in more detail below. Phosphorus dithioacids (750) were added to the N-acetylchloral imine 316 and to the Nphenyl analogue (749) to afford stable adducts (751)719.

'',

+ CI3C

-SH

- 1 C13C

i,OR'

s-P

O ' R'

(749) R=Ph

The powerful electrophilic character of a-perhaloimines carrying electron-withdrawing nitrogen substituents was demonstrated by the spontaneous addition of indole across hexafluoroacetone imines (752)"'.

330

Norbert De Kimpe and Roland Verhe

CHCll

+ H

( 7 5 2 ) R=COCF3,

63-74

'/e

(7 53)

SOzPh

An intramolecular version of the nucleophilic addition across a-haloimines was found during the condensation of 1,1,1-trichloro-3,3,3-trifluoroacetone(754) with the hydrazine derivative 755. The resulting hydrazone (756) was not isolable but it underwent an intramolecular nucleophilic addition with expulsion of chloroform affording l-aryl-3trifluoromethyl-Smethylthio- 1,2,4-triazoles (757)723. Ar

I

(754)

(7 5 5 )

(756) Ar

A good example of nucleophilic addition is involved in the synthesis of 8-lactamase inhibitors and 8-lactam inhibitors. The reaction of (3S,4R)-3-chloro-4methylsulphinylazetidin-2-one (758) with alcohols produced the alkoxy derivative 760 via the intermediacy of the reactive four-membered a-haloimine 759716.The bulky chloro atom of 759 directed the addition of the alcohol to the less hindered a-side.

(758)

(759)

59-60 % (760) R=Et2CH, H C = C C M e 2

331

App. 2. a-Halogenated imines

The reaction of a-haloimines with nucleophilic hydrides predominantly afforded nucleophilic addition across the imino function. Sodium borohydride reduced only the ~ ~ ~ , a - h a l ~ i m i n e sand ~ ~ ~acarbon-nitrogen double bond of a - f l ~ o r o i m i n e s cyclic bromoimmonium bromides731,while only in a few cases was concomitant reduction of the . more powerful nucleophilic LiAIH, usually gives a fast halide ~ b s e r v e d ' ~ ' The nucleophilic addition across the imino bond but the addition is mostly followed by intramolecular nucleophilic substitution to generate aziridines which are isolable or rearrange The earlier synthesis of aziridines85.143*345.346 from a-haloimines and LiAIH, was extended to N-aryl a, a,a-trichloro ketimines (420), which were converted (762)537,which were previously usually prepared by into 2,2-dichloro-l,3-diarylaziridines dichlorocarbene addition to benzylidene anilines. When an excess of hydride was avoided and the reaction was run at lower temperature, the initial hydride adduct (protonated 761) could be isolated. However, if a large excess of LiAIH, was used, 762 rearranged further into the phenethylanilines 765537.It was not possible to extend the synthesis of 762 to the synthesis of N-alkyl-a, a-dichloroaziridines owing to various competitive products'37.

A -

-

A

LiAlHq

Ph

cc13

diothyl mthor

Ph

Ar

1

Ph

66-01

(420)

(761)

./a

('162)

1

LiAIH,

(765)

(764)

(763)

Aziridine formation is not restricted to simple model compounds, as demonstrated by the transformation of 16-chloro-1-dehydrovincadifformine (766) with sodium cyanoborohydride in acetic acid into the hexacyclic compound 767732.The same transformation applied to the chloroindolenine derived from A'*-tabersonine provided an analogous aziridine which was further converted into the tetrahydroquinolone alkaloids scandine and r n e l o ~ c i n e ~ ~ ~ . O n the other hand, a, a, a-trifluoromethyloximes were reduced with lithium aluminium hydride to the corresponding b, /3, b-trifluorinated primary a m i n e ~ ~ ~ ~ . The electrophilic reduction of a-haloimines using the borane-dimethyl sulphide complex in refluxing dichloromethane is an alternative approach to the synthesis of bhalogenated amines. a - H a l o a I d i m i n e ~and ~ ~ ~a - h a l ~ k e t i m i n e swere ~ ~ ~reduced . ~ ~ ~ with-

332

Norbert De Kimpe and Roland Verhe

NaBHICN

_____, HOAc 1 h, R T

70 Ole (766)

(767)

out interference from side-reactions. The reaction was applicable to a-chloro-, a, adichloro- and a, a, a-trichloroimines (e.g. 768,770 and 374), as exemplified by the synthesis of 8-chlorinated amines 769, 771 and 772.

>r. ,Bu-t

CI

A

Pu-

BH,--MI,S

+

CH2C12

Cl

80 % (769)

(768)

VN

"x

Ph

CI

CI

A

BH,--Ma,S

_____, CH2Clp

Ph

4C CI

CI

95 %

(770)

(771)

A

BHI--MS2S

C13 C

Ct3C

,Bu-t NH

89* l o (374)

(772)

E. Rearrangements of a-Halogenated lmino Compounds 1. The Favorskii-type rearrangement

In recent years, the Favorskii rearrangement of a-haloimines has been well documented and a clear view of the scope and limitations of this reaction has been ~ b t a i n e d ~ ~ 'a-. ' ~ ~ . Haloketimines are suitable substrates for a base-induced Favorskii rearrangement. They are less reactive than a-haloketones, owing to the lower electronegativity of nitrogen with

App. 2. a-Halogenated imines

333

respect to oxygen. This certainly influences both possible Favorskii mechanisms in that the cyclopropanone mechanism would be influenced by the reduced acidity of the ahydrogens while the weaker electrophilic character of the imino function would have an impact on the semibenzilic-type mechanism. Although N-alkyl-a, a-dichloromethylketimines (46) undergo substitution with alkoxides in the corresponding alcohols to a, a-dialkoxyketiminessO, the reaction of the aliphatic N-alkyl-a-monochloroketimines 773 (Rz= H) and 647 (Rz# H) with potassium tert-butoxide in T H F but not with other base-solvent systems (e.g. sodium methoxide in diethyl ether, diisopropyl ether, THF or DABCO in T H F or benzene) afforded the *~~'. branched carboxylic amides 774 and 775, r e ~ p e c t i v e l y ~ ~ ' N-Alkyl-a-chloro-aphenylketimines (776) reacted with a five-fold molar excess of sodium alkoxides in tetrahydrofuran to provide non-branched rearranged carboxylic imidates (777) in nearly In a more polar medium, N-(3-chlorobut-2quantitative y1idene)isopropylamine (778) gave with potassium tert-butoxide in tert-butanol a 1:3 mixture of the Favorskii amide 779 and 4-tert-butoxybutan-2-one (780), the latter resulting from an elimination-addition and subsequent hydrolysis. Tertiary achloroketimines often showed competitive 1,2-dehydrochlorinations,and this reaction type is the main route for a - b r o m ~ k e t i m i n e s ~except ~', for cyclic and sterically hindered substrates736. The cyclic a-bromoketimine 781 and the bulky a-bromoketimines 279 reacted with potassium tert-butoxide in T H F in a Favorskii manner, but the reaction could be intercepted at the stage of the 1,3-dehydrobromination product, i.e. the The dibromo compound 783, which did not cyclopropylideneamines 782 and occur as the imine, could be converted to the Favorskii amide 784 by treatment with 2,2,6,6-tetramethylpiperidine in acetonitrile or with silver oxide in d i ~ h l o r o r n e t h a n e ~ ~ ~ .

-

-

1. t-BuOK

f -BuOK

R2 R$R

2. Ha0

TH F

CI

(773) R ~ = H

CH3

(714) R'=H

(656)

(775) R*+H

(647) R 2 # H A

N H R

N H R

5 NaOR'

Ph

61 (776) R=i-PI,

c-Hex

1 . t-BuOK/t-BuOH/A,

2.H,O

CI

(778)

97-100 '10 (777)

2h

f-BuO

72 */.

(780)

334

Norbert De Kimpe and Roland Verhe

(781)

60 %

(782 1

,Bu-/

(783)

I

16

-2 5 %

(784)

The mechanism of the Favorskii rearrangement of a-haloimines with bases into amides or imidates is explained analogously to the so-called cyclopropanone mechanism for ah a l ~ k e t o n e s ~The ~ l . base abstracts an a'-proton from the a-chloroketimine to form a delocalized anion (654),which by loss of a chloride anion produces a zwitterion (655). This species might be viewed as being in equilibrium with the cyclopropylideneamine 656, which undergoes a rapid addition across the strained imino function. The resulting adduct anion (785)opens giving the most stable carbanion. This feature explains the formation of the branched amides 774 and 775 from aliphatic a-haloimines and of linear imidates (789 Nu = OMe) or amides (790)from a-chloro-a-phenylketimines. Evidence was presented for the exclusion of the alternative semibenzilic-type mechanism491.The reaction of the a-chloromethylketimine 791 with potassium tert-butoxide in T H F afforded, after aqueous workup, a mixture of a rearranged amide (792)and l-tertbutoxypentan-2-one (793).The semibenzilic rearrangement of 791 would involve addition of tert-butoxide across the imino function (giving 795), followed by regeneration of an imino moiety and concomitant migration of the propyl group with expulsion of the chloride anion. This process would provide the linear amide 797 (or the imidate 7%), which was not isolated. Instead, the isolation of the branched amide 792 was sufficient to establish the cyclopropylideneamine mechanism via 794 as the operating process. Further support for the proposed mechanism is the reaction of tertiary N-alkyl-achloroketimines (647)with potassium cyanide in methanol, which afforded 1-(alkylamino)cyclopropanecarbonitriles (649) together with the major product, a-cyanoThe formation of these geminally substituted cyclopropanes aziridines (648)633*634*698. (649)was discussed earlier. The acidity of the a'-hydrogens in the starting material is a major limiting factor in the Favorskii rearrangement. Lowering this acidity by alkyl substitution reduced the tendency for the rearrangement491.736. The Favorskii rearrangement is not limited to mono- and dichloroketimines. The tetrachloroketimine 373 reacted with excess sodium methoxide in T H F to afford the ortho ester 799 in 95% yield491.

335

App. 2. a-Halogenated imines /R

/R

-cr

boss

CI

-

/R

CI

(647H7731

(654)

(655)

R

(785)

Nu

Ph

(788)

I

Ph

(6561

Nu CHF

(786)

1

U’lU (789) /H*O

Nu CH3

(787)

NHR

(790)

CH3

( 774), ( 775)

An interesting side-reaction was observed during the reaction of the a-chloro-aphenylketimines 776 with potassium tert-butoxide in T H F or DMS04”. In addition to the expected Favorskii amide (800), N,N’-dialkyl-2,5-diphenyl-p-phenylenediamines (801) were also formed. Formation of these condensation products was ascribed to intermolecular nucleophilic substitution of the doubly activated chloride (776) by the a’anion (802), followed by an analogous ring closure which furnished the aromatic 801 after an additional air oxidation. An alternative mechanism for the generation of 801 via formation of the zwitterion 806 and subsequent cyclocondensation was also considered491.

336

Norbert De Kimpe and Roland Verhe

A OBu-l

(7911

I

21 %

71e/'

(792)

(795)

(793)

(796)

(373)

(797)

(798)

(799) NHR

(801)R=i-Pr, c- Hex

t

oxidation

NHR i.t-BuOK

Ph

CI

(802)

/

R

(803)

NR

(804)

Ph

NHR

(805)

337

App. 2. a-Halogenated imines 801

fR P

h

q

R Y

CI

P -N

(776)

h

R'

800

(808)

Other types of side-reactions were found when 776 were reacted with bases (sodium methoxide, triethylamine, potassium hydroxide) in alcohols491.The Favorskii amide 800 and the imidate 807 were the main products but were always accompanied by the substitution product 808 and the rearranged acetal 809. The extent of substitution increased on increasing the concentration of sodium methoxide in methanol, whereas the extent of Favorskii rearrangement was independent of the base concentration. Formation of 808 and 809 could be eliminated by using hindered alkoxides, such as sodium isopropoxide in isopropyl

I

1

OR'

NHR

(808)

(809)

ph4 AR

i-PrONa

A

I

CI

(776)

OPr-i

Ph

100%

(elO)R=i-Pr,

c-Hex

1,3-Dehydrochlorination of the a-chloroketimines 811 with lithium diisopropylamide in T H F led to non-isolable cyclopropylideneamines (813), which underwent selfcondensation to cyclic amidines (812)737.It was proposed that the dimerization of 813 passed via an abnormal opening of a functionalized cyclopropane (818). 1,3-Dehydrochlorination of chloroindolenines was also considered as a possible explanation for some rearrangements, but was finally rejected738.

338

Norbert De Kimpe and Roland Verhe

-t

(811) R = Me EtJi-Pr

(813)

812

9’R

-

/R

(819)

(818)

(817)

In view of the suggested mechanism of the Favorskii rearrangement, it is worth noting that 2-bromocyclobutanone (820)with o-phenylenediamine (821)gave the ring-contracted although it was previously reported that the reaction gave the tricyclic compound 824739, heterocycle 822740,741. The intermediate 823 rearranged in a semibenzilic-type manner to the cyclopropane derivative 824, and this is probably the first example of a Favorskii-type rearrangement of a transient a-haloimine. In this way, a-haloimino chemistry parallels ahaloketone chemistry because a-halocyclobutanones usually give Favorskii rearrangements via a semibenzilic-type m e c h a n i ~ m ~ ’ ~ .

(820)

I

(8211

oq.MeOH or CHCll

H

(822)

App. 2. a-Halogenated imines

339

2. Rearrangement of a-halogenated imines via activated aziridine intermediates

a-Halomethylketimines and alkoxides in alcoholic medium gave mainly nucleophilic substitution493, but the secondary a-haloketimines 645 readily rearranged into a(alky1amino)acetals (825) via the intermediacy of a-alkoxyaziridines (827)742.The acetals 825 are valuable synthons in heterocyclic chemistry and are viewed as protected aaminoketones. In contrast, the tertiary a-chloroketimines 505 give only low yields of a(alky1amino)acetals since the major reaction with nitrogen bases in alcohols is cyclopropanation and, to a minor extent, a l c o h ~ l y s i s Geminally ~~~. functionalized cyclopropanes (W),obtained in up to 80% yield, and a-alkoxyketimines (508) were formed via the intermediacy of 2-alkylaminoallylcarbenium ions (506),but possible interconnections with the formation of a-(alky1amino)acetals (510) via valence tautomerism of cycloptopylideneamines (656) were also considered632.When cyanide was present in the methanolic medium, the tertiary a-chloroketimines 647 mainly gave a-cyanoaziridines (648) and cyclopropanecarbonitriles (649) and minor amounts of P-alkylamino-amethoxynitriles (650)634.The latter rearranged compounds indicated that intermediate amethoxyaziridines (832) were more readily trapped by cyanide than by methano16j4.

x (645)X=CI,Br

~ H R

33- 0 5 % (825)

a-Halogenated immonium halides are reactive substrates and nucleophile-induced reactions most often proceed via initial nucleophilic addition across the iminium bond. Rearrangement of the a-bromoimmonium bromides 833 and 836, synthesized by bromination of the corresponding enamines, with aqueous triethylamine gave access to the ring-contracted pyrrolidines 835 or the ring-expanded heterocycles 838, respect i ~ e l y ~ ~The ~ . intermediacy ’~~. of a-hydroxyaziridines 834 and 837, which rearranged into 835 and 838, is a likely possibility. However, an alternative mechanism involving ring opening and subsequent intramolecular nucleophilic substitution was suggested for the conversion of 6,7-dihydrothieno[3, 2-~Jpyridinium derivative 839 into 6-(2chlorobenzyl)-5,6,7,8-tetrahydrothieno[2,3-6J-azepin-4-one (842)745. A peculiar rearrangement converts the heterocyclic compound 843 with cyanogen bromide in methanol-chloroform into 1-substituted-9,10-dimethoxy-3,4.6,7tetrahydro-lH-l,S-methano-2,5-benzoxazonines (844). Suggested intermediates are the a-bromoimmonium derivative 846 and the a-alkoxy-substituted aziridinium derivative 847, which was ring opened by cyanide or

340

Norbert De Kimpe and Roland Verhe

dAR

R

I

HN

N-bare

OR^

e, g. EtaN, DAECO, DBU,DEN

R2

+

R .J,(

R~OH

R2

(509)

;dR OR^

(508)

R' R2

(656) R

I

(830)

(8311

& -

34 1

App. 2. a-Halogenated imines

S

.CI

-oPoCl2

CI

(840)

(839)

Me0 BrCN MeOH-CHCI,

Me0

b

K2C03

M Me0 eo*!

Some rearrangements of a-chloroindolenines to compounds which underwent ring expansion of the indolenine five-membered ring into a 3-piperidone moiety (see 850) can also be explained via transient a-hydroxyaziridines (e.g. 849). These rearrangements have been effected on chloroindolenines derived from 3-oxotabersonine (848)566,tabersoand l - d e h y d r ~ t a b e r s o n i n e 'by ~ ~using silver salts, nine747,l-dehydrovin~adifformine~~~ dilute sulphuric acid, aqueous acetic acid or hydroxylic solvents, respectively. 3. Rearrangement of chloroindolenine derivatives

The classical rearrangements of chloroindolenines derived from alkaloids such as deserpine, reserpine and yohimbine with hydroxide or methoxide in methanol were reexamined in detail. It was shown that the rearrangements into spiroimino ethers occurred in a stereospecific manner, i.e. chloroindolenines with an a-chloro atom produced aspiroimidates whereas substrates with a @-chloroatom gave P - s p i r o i m i d a t e ~ ~ ~ ~ .

342

Norbert De Kimpe and Roland Verhe

z

@/ 0, CI

COOMe

(848)

0

I1

AQCIO.

aq. acetone

RT

* dOOMe

(849)

8 4% (850)

Neighbouring groups play an important role in the occurrence of rearrangements of chloroindolenines. The chloroindolenine 851, obtained by chlorination of the corresponding indole with tert-butyl hypochlorite in dichloromethane, underwent spontaneous rearrangement into the pyridinium salt 853562.

(851)

(852) COOMe

343

App. 2. a-Halogenated imines

In contrast to the rearrangement of 16-chloro-1-dihydrovincadifformine(766) in aqueous acetic acid at room temperature (see Section lII.E.2)748,the rearrangement in glacial acetic acid at 100°C produced 33% of rearranged compound 854 with a novel skeleton, in addition to 9% of the acetoxy substitution produ~t'~'.The rearrangement was initiated by dehydrochlorination of a ring-opened intermediate (855) to 856. This was followed by an amazing set of ring closures and openings of immonium species which furnished 854.

glacial HOAc

A , 1 h / 1 0 0 OC/N2

COOMe

33 % (854)

(766)

-HCI

Q @ ! !

CI COOMe

4COOMe

(861)

H

854

I COOMe

H

COOMe

Norbert De Kimpe and Roland Verhe

344

The r, r-dichloroimine 862 rearranged with methanolic hydrogen chloride to 19oxoeburnamonine (863)in 95% yield751.Again, the neighbouring amide nitrogen initiated the ring opening and afforded 863 after appropriate bond reorganization. 0

0

(862)

--

(863)

H

2

O

y

+ci

\

-

&

1 T

\

ci

Finally, the rearrangement with sodium methoxide of the chloroindolenine 864 to the spiroimidate 865 was accompanied by the rearranged aminal The chloroindolenines 864 and 447 rearranged spontaneously or after chromatography on silica gel into the aminals 867 and 868. from which 865 and 866 were d e r i ~ e d ' ~ ' . ~ ~ ' .

I

(864)R=Me (447) R = C H 2 P h R=Me,CH,Ph

I

spontaneous or on SI-gel

2 5 '10

(866)

1 I

R

(867) R = M e

Me

69%

(868)R = C H 2 P h 85%

345

App. 2. 2-Halogenated imines 4. Beckman rearrangements of a-halogenated oximes

Beckman rearrangements of a-halooximes remain rare. The attempted Beckman rearrangement of the a, a, a-trifluorooxime 869 in trifluoroacetic acid yielded instead the tetracyclic heterocycle 870752,but aromatic a-perfluoroketoximes, such as 871, and some aliphatic analogues rearranged into N-substituted a-perfluorocarboxamides (e.g. 872) by treatment with PCI, in chloroform753. Further examples were reported for the %,adichlorooxime derivatives 873754and 875755,which provided the corresponding %, adichlorocarboxamides 874 and 876, respectively.

(870)

(869)

(8711

(872)

Cl

(874)

(873)

(875)

/

H

6 8 '/e

(876)

5. Other rearrangements of a-halogenated imines

Although a-haloimidates are not treated in detail in this review, it is useful to mention that allylic trichloroacetimidates (877)and propargylic trichloroacetimidates are valuable synthons because of their potential to give allylic amides (878)and dienic amides via a 3,3sigmatropic rearrangement425.Various extension^^'^ have emerged since the publication

Norbert De Kimpe and Roland Verhe

346

of a review on this and trichloroacetimidates also proved especially useful in glycosyl transfers757,i o d o a m i n a t i ~ n s ~ ~ *and - ~ ~am ~ *in*at~ ion^^^', ~ in the phosphorylation of p ~ l y p r e n o l and s ~ ~as ~ benzylating reagents763.Further, the use of trichloroacetimidates has been fully exploited in the synthesis ofmethyl a-L-ristosaminide (881)76', O-aand O - / ? - g l y c ~ s y l i m i d a t e s ~a-aminocarboxylic ~~*~~~, ~ i n y l g l y c i n e ' ~ ~( *,) erythro-sphingosine t r i a ~ e t a t esphingamine ~~~, triacetatesZ5and amino s u g a r ~ ~ ~ ~ .

CI3C

JI~I

rearrangement 3,3-sigmatropic

C'3C

1877)

= y ' o M e 0

(878 )

*

CI,CCN

HOa

J-----?

THF Cat. NaH

0 "c

(879)

0

i ( Br)

95 - 100o/' MIOH

cl-

-

aq.HCI

HP Jv 4.

CI

4.

NH3 OMe

NHJ

A

HO

I

OMe

EuSnH

8 avo

-

COHO M.OH

HO

100Y o I(Br1

(881)

In addition to the rearrangements of trichloroacetimidates, some other reactions of ahaloimino compounds involving skeletal rearrangement and rearrangements of the halide can be mentioned. The reaction of 2-bromo- 1,3-diphenylpropane-l, 3-dione (882) with methylhydrazine in ethanol produced 1-methyl-3,4-diphenyl-2-pyrazoline-5-one (885) via the a-bromohydrazone 883, ring closure to 884 and subsequent halohydrin rearrangement769.Certain a-haloketones are known to rearrange to the isomeric a'-haloketones. The only example of an analogous reaction of a-haloketimines is the slow rearrangement of the a-bromomethylketimine 886 at room temperature to an equilibrium mixture with the isomeric 887736.Another type of halogen migration is the thermal rearrangement of the labile bromine atom in 3-bromoindolenine (888) into 6-bromoindole (889)635.

App. 2. a-Halogenated imines

341

Me

B ,uRT

(886)

F. Cycloaddltions

Many examples of cycioadditions of a-haloimino compounds in which they react as dienophile or heterodiene in Diels-Alder-type reactions ([4 + 2lcycloadditions) have been found in recent years. In addition, a rich heterocyclic chemistry has evolved from cycloadditions of a-haloimines in a [2 + 21, [4 + 13, [3 + 21 or [2 + 11 mode. Generally these reactions involve a-polyhaloimines (mainly a-perfluoro derivatives) having an electron-withdrawing activating substituent on the nitrogen atom, such as alkoxycarbonyl, acyl, thioacyl or imidoyl. The potential of Diels-Alder-type cycloadditions in which the imino bond of ahaloimines acts as a dienophile have been recognized for a long time in heterocyclic s y n t h e s i ~ ~ " ' *However, ~~~. most developments in [4 + 2lcycloadditions have been achieved with a-perfluoroimines having a heterodiene structure. Cycloadditions of these N-activated a-fluorinated imines included reactions with nit rile^^^'*^^^, aromatic aldeh y d e ',~t e~t r~a ~ y a n o e t h e n eN ~ ~- c~y, a n ~ a m i n e ssulphoxides ~~~, (e.g. the conversion of the N-acylimine 890 into the dioxathiazines 8917 7 5 ) and a l k y n e ~ " ~ .

348

Norbert De Kimpe and Roland Verhe

F3cx:“ _.

(090)

07- 96% (800

[2 + 21Cycloadditions remain rare, but this reaction occurred between the Narylhexafluoroacetone imine 892 and 4-(dimethylamino)benzaldehyde(893).The resulting 1,3-oxazetidine 894 decomposes into hexafluoroacetone and the aldimine 895’ I . However, the a, a’-difluoroketimine 398 could be photochemically dimerized into the diazetidine 8%504.

-

0

(893)

(892) A r = 4-N02C6H,

Ar

CF3

H

(895)

(894)

hu

acatonr

[3 + 2]Cycloadditions with 1,3-dipolar compounds, e.g. nitrile oxides, have only rarely been reported501, but the construction of five-mernbered heterocycles via cyclocondensation of N-activated imines (heterodiene structure) with c a r b e n e ~ ’ ~and ~ phosp h i t e ~ ’ ” *[e.g. ~ ~ the ~ synthesis of the new heterocycles 2,2-dihydro-l, 4,2-diazaphosphol4-enes (898) from 8971is an alternative route. Diazomethane has often been reacted with awhich perhaloimines to afford five-membered heterocycles, i.e.

App. 2. %-Halogenatedimines

349

is the synthesis of the triazoline 900 from were precursors of a z i r i d i n e ~ ~ ~An ~ . example ~”. the a-perfluorooxime ether 899 and photochemical expulsion of nitrogen to give the aziridine 901, which was separated into its two optically active antipodes780. The cycloaddition of N-tosyl chloral imine with 2,2,2-trifluoroethyldiazomethane also furnished the corresponding pyrazoline7” but the cycloadduct 902 of diazomethane and the chloroazirine 685 rearranged thermally into the 1,2,3-triazine 903,the azirine 904 and traces of acetophenone and b e n ~ a m i d e ~ ~ ’ .

I\,,, ANR - $ii Ph

P(OR’1,

< o’c

F3C

/..ow

F3c

CF3

CF3

(897)

ORoR’

(898)

(899)

88%

71‘/o

(900)

(901)

N Ph

Ph

toluene

ph

Ph

(903)

(902)

(685)

-

10 20010

Ph

(904)

Three-membered oxaziridines (905782and 906493)are accessible via epoxidation of a perfluoroketimine or a-halogenated aldimines with caesium carbonate-chlorine or mchloroperbenzoic acid, respectively. CF F+3CF3

R‘

I

R$/Ao CF3

(906)

R2

x

(906) R‘=alkyl; R2,R3=alkyl,CI,Br X=CI,Br

Diaziridine formation (cf. 908) could be accomplished by reaction of 0-tosyl oximes. e.g. 907, with functionalized primary a m i n e ~ ’ ~a ~ m, m ~ n i a ”and ~ a-amino acid esters7R3.

350

Norbert De Kimpe and Roland Verhe H liq. NHS dirthyl e t h r r

I

OR

1908)

(901)

Finally, special types of cyclocondensations involve the reaction of hexafluoroacetone imine (909)with guanidine (910), affording the heterocycle 9117n4,the reaction of the azetine 912 with diphenylketene (913) giving the 1:2 adduct 914785,and the reaction of perfluoroacetone azine (915) with norbornadiene (916) yielding adduct 917786. NH

(909)

Ph’

(913)

(912)

h-

F3CKCF3

KCF3 +

F3C

(916)

(915)

7 5 O/Q ( 917 )

G. Generation of a-lmldoylcarbenium Ions from a-Halogenated lmines

There has been increasing interest in the intermediacy of highly electron-deficient carbenium ions. As a result, it has been recognized that carbenium ions, substituted with electron-withdrawing groups, are not necessarily as unstable as previously thought. A review covers the chemistry of the long neglected a-acylcarbenium ions4”, while

35 1

App. 2. a-Halogenated imines

numerous studies have focused on carbenium ions substituted with cyano, alkoxycarbonyl, dialkoxyphosphoryl and other electron-withdrawing g r o ~ p s ~The ~ nitro~ * ~ ~ ~ . gen analogues of a-acylcarbenium ions, i.e. a-imidoylcarbenium ions (918),have not been treated extensively in the older literature, but in the 1980s the gap in this area has been filled. The resonance stabilization of the latter species should be considerable, but it is coupled with an important inductive destabilization. Therefore, it seems appropriate to consider the tautomeric vinylnitrenium ions 919and the bridged azirinium ions 920also in this context. Ab initio calculations revealed that the unsubstituted azirinium ion (C2H4N+)is more stable than the corresponding a-formimidoyl carbenium ion78u-79'. The conclusion is that a-imidoylcarbenium ions exist in a bridged structure, and that the energy difference between the planar and the bridged structures is much larger than that for the corresponding a-acylcarbenium ions79'. Compared with other a-electronwithdrawing groups, the a-imidoyl substituent does not destabilize the carbenium ion and, therefore, a-imidoylcarbenium ions have to be considered as potentially useful synthetic intermediates.

,d (918)

R

I+

N

(919)

(920)

Several reports, especially before the 1980s, have hesitatingly suggested a-imidoylcarbenium ions as reaction intermediates, but most of them concerned ring opening of a z i r i n e ~ ~.~An ~ other - ~ ~ 'source of a-imidoylcarbenium ions and the bridged azirinium ions are reactions of a-halogenated aziridines346*537-735~800, which spontaneously ionize and react further with the nucleophiles present in the medium. It was also proposed that aaryloxyoximes react with alcoholic hydrogen chloride to give a-alkoxy-a-aryloxyketones via the intermediacy of a-imidoylcarbenium ions"'. a-Haloimines have been shown to be good precursors of a-imidoylcarbenium ions or their isomeric o r tautomeric ionic structures. Simple ionization of the carbon-halogen bond assisted by reagents such as silver salts and aluminium(II1) chloride provides a route to these species. a-Chloroaldimines, which could create a more stable a-imidoylcarbenium ion, reacted under Friedel-Crafts conditions with aromatic compounds, e.g. benzene, toluene o r xylene, to give a-arylaldimines802. Aluminium(II1) chloride was used as a condensation agent but boron(II1) fluoride etherate gave similar r e s ~ l t s ~ N~ ~ * ~ ~ ~ . Isopropyl-a-chloro-a-phenylaldimine (921)reacted with aluminium trichloride in benzene or toluene at room temperature to yield a-arylaldimines (922)*02. Aliphatic a-chloroaldimines were less reactive and required higher temperatures to induce arylation, but owing to the side-reaction of 1,2-dehydrochlorination the a-arylation yields never exceeded The reaction of the a-chloroaldimine 923 with toluene led to 30% atolylaldimine, with a paralortho ratio (924:925)of 93: 7493.Only the a-phenylation of 923 showed a side-reaction from which 12% I-isopropyl-3,3-dimethylindoline (933)resultedEo2.The a-arylation, the formation of the 1-azadienes 928 and the side-product 933 were all explained by the intermediacy of a-imidoylcarbenium ions (927).Loss of a proton from 927provides 928,while trapping of927 with the aromatic nucleus (shown for benzene in the scheme) afforded 930,which lost a proton to give the a-arylaldimines 931.The acomplex 930 can also be trapped by the weakly nucleophilic imino nitrogen to form 929, which by a net shift of a double bond and deprotonation generates the indoline 933.The last step can be visualized as occurring via deprotonation to a n azomethine ylide (932)and a subsequent hydride shift493.

Norbert De Kimpe and Roland Verhe

352

ph$A H

-

A

N

ArH

AICI, RT,4-5 h

CI

Ar

80 -0 2 %

(921)

(922)

$ : CI

AlCl A,2h

3 toluene

(924) 93

A

N

AICIs

R'

R'

(925)

A H

(926)

(929)

Y-

(0110)

Y

7

-H

H

App. 2. a-Halogenated imines

353

The usefulness of aluminium(II1) chloride as an initiator for generating aimidoylcarbenium ions was demonstrated by the conversion of the a-bromoketimine 934 into 935 or 936, depending on the amount of Lewis catalyst usedEo3.It is reasonable to assume that an intermediate a-imidoylcarbenium ion (937) is trapped by the olefin in an intramolecular fashion to give 938, which loses a proton giving 935 or undergoes another electrophilic aromatic substitution giving 936.

*/. & A

CH2C12

...,..’

2O0C/3O 2.qulv. AICI, min

(934)

AICI,

(936)

(937)

I+

80% (935)

/

--H

(938)

An alternative route to a-imidoylcarbenium ions consists of a silver salt-assisted ionization of the carbon-halogen bond of a-haloimines. Such ions were postulated to explain the silver-induced conversion of the chloroazirine 685 into the oxazole 940, together with the dione 939 and b e n z ~ n i t r i l e ’ ~In ~ . this particular case the ion 941 is already a bridged entity. Such azirinyl cations were also considered in explaining nucleophilic substitutions of 3 - c h l o r o a ~ i r i n e s ~ ~ ~ . When silver salts were applied with simple a-haloimines in alcoholic solvents, the corresponding a-alkoxyimines were obtained, often accompanied by the 1,2-dehydroof carbonyl compounds via ahalogenation p r o d u ~ t ~ This ~ ~ .a-alkoxylation ~ ~ ~ . haloimines and acidic hydrolysis is a useful method starting with precursors such as the abromoaldimine 511 and the aliphatic or aromatic a-bromoketimines 713 or 946, but generalizations cannot be made as the structure of the starting a-haloimine determines the course of the reaction. For example, the a-bromoaldimine 669 was exclusively dehydrobrominated to the corresponding 1-azabutadiene when treated with silver carbonate in methanol493. These a-alkoxylations can be ascribed to alcoholysis of intermediate pseudo-a-imidoylcarbenium ions. This type of reaction was also observed during cyanation of a-haloimines in alcoholic medium in the presence of silver, copper or zinc ions633.634

354

Norbert De Kimpe and Roland Verhe Ph

fi

-

Ph

rn

(944)

Ph

>r"

& A

Br

OMe

100%

(945)

(946)

70-95% (947)

0-2 8 % (946)

When the tertiary a-chloroketimines 370 and 680 were treated with silver tetrafluoroborate or silver hexafluoroantimonate in dichloromethane in the presence of furan, they afforded bicyclic adducts (949)489.2-Aminoallylcarbenium ions (951) were postulated as intermediates, which were trapped by furan in a [4 + 21-type cycloaddition to yield 949. The cycloaddition could be either concerted (route a) or stepwise (route b), but route c via intermediacy of an a-imidoylcarbenium ion (918) should be considered as an alternative for the formation of 949489.

355

App. 2. a-Halogenated imines

CI

60-95% (949)

( 3 7 0 ) R = Me (6eO) R = i-Pr

I

Q

C

(951)

LNHR I

(952)

(951)

C3+41 a

. (949)

HN +/R

(954)

The a-bromooxime ether 425 was shown to be a source of an a-imidoylcarbenium ion. The reaction of 425 with silver tetrafluoroborate in 1,2-dichloroethane generated carbenium ion (955), which could be intercepted by electron-rich aromatic compounds547 or alkenesSo4to afford a-aryloxime ethers (956) or cyclic immonium compounds (957), the latter being isolated as their cyanide adducts (958). The reaction of 955 with alkenes was shown to be both stereoselective and regioselective and allowed the synthesis of the propellane 959804. Other reactions of a-imidoylcarbenium ions, generated from a-haloimino compounds, involve migrations of aromatic and alkyl groups from adjacent positions. The 4-bromo-2isoxazolines 960gave with silver nitrate in ethanol the isoxazoles 963. This was explained by an initial ionization of the carbon-halogen bond to form 961 and subsequent phenyl

356

Norbert De Kimpe and Roland Verhe

In migration (pinacol-type rearrangement) to 962 which lost a proton to give 963705.706. (W) the same way, the silver-induced rearrangement of 4-bromo-3-phenyl-2-isoxazoline into phenanthro[9,10-~-5-phenylisoxazole(%5) was achieved7".

OMe

I

(960) R1 = Me,Ph

(961)

R2= Me,Ph

(964)

(965)

351

App. 2. a-Halogenated imines

A Wagner-Meerwein type of rearrangement was observed during the reaction of the sterically hindered a-bromoketimine 966 with silver hexafluoroantimonate in dichloromethane. The products were the rearranged ketimine 967,the fragmented ketimine 968 and the debrominated ketimine %9493.While the unsaturated ketimine %7 can be formed via Wagner-Meerwein migration of a methyl group and loss of a proton, the fragmented ketimine 968might result from trapping of the carbenium ion 971 by traces of water to give 972 and a subsequent retro-aldol reaction to yield the ketimine 968 and acetone. Similar Wagner-Meerwein rearrangements have been observed for a-acylcarbenium ions427and also for a steroidal a-imidoylcarbenium ion, generated from an azirine

IV. PROPERTIES AND APPLICATIONS OF @-HALOGENATEDIMlNO COMPOUNDS

In addition to the properties and applications reported in the original chapter, there are new reports on several properties, mainly in the field of pesticide science. The chloral imine 973 and several other ring-substituted analogues, displayed plant growth-regulating The insecticidal /3, /3, /3-trichloroamines 974,structurally related to DDT but biodegradable, were shown to degrade and to metabolize via the a, a-dichloroketimines 975805.806. Mo st of the applications are for a-halooximes and a-halooxime ethers 1,3Dichloroacetone 0-acyl oximes (976)807-8' and 1,3-dichIoroacetone oxime carbamates (977)8 showed a variety of pesticidal activities, including slimicide, fungicide, bactericide and herbicide activity, but the parent oxime (978)is useful as an antidote against herbicidal use814.

,Ar'

c13c

H

(973)

Ar

(974)

Cl (975)

358

Norbert De Kimpe and Roland Verhe

(978)

(977)

(976)

Other a-halogenated oximeethers, such as97952',980815,98151',E16 and others81'-819, also display insecticidal and acaricidal properties. Of particular interest is the relationship between the activity and the stereochemistry of these oximes, which in general occur as isolable E- and Z-isomers. It was observed that the E-isomer of 979 is a more effective insecticide than 979 with the Z-configuration5' However, the Z-isomer of 01, adichlorooxime ethers with a m-phenoxybenzyl substituent on the oxygen showed the greatest activity" '. Further, the (E)-a, a-dichlorooxime ether 982 was 14 times more The potent than the standard permethrin by topical testing against BIatella gerrnanica816. usual synergists such as piperonyl butoxide and sesamex also activated these ahalogenated oxime ethers816.

(961) R ' = CHCI,, R

(982)

CC13, CFC12, CF3

= holo, EtO, MeO, Pro

n =1-5

The recently expanding area of herbicide antidotes was enriched by a-fluorinated oxime ethers, e.g. 983820,and the functionalized trichloroacetamidines 984 exhibited bactericidal, fungicidal and herbicidal activity"

x

0-CN

F3C

CF3

(983)

'.

A

CI3C

N H f CH

I R

COOR'

(984) R = H, Ph,CH2Ph, C1-4 alkyl n =1,2 R'= CI-4 olkyl

App. 2. a-Halogenated imines

359

In addition to these intrinsic properties, a-halogenated imino compounds have also been used as key intermediates in the synthesis of pharmaceutical^^^^, f ~ n g i c i d e s ~ ~ insecticides8”, ~ * ~ ~ ~ * ’ ~ acaricides8”, h e r b i ~ i d e s ~and ~ ~ .defoliants542. ~~’ I t should be emphasized that the developments in recent years in the chemistry of the bifunctional a-haloimines have established the potential of the a-haloimino functionality in synthetic organic chemistry. A wealth of transformations became available, many of which were not possible via the well developed chemistry of a-halocarbonyl compounds or by other synthetic approaches. Consequently, a-haloimines can be utilized as modified ahalocarbonyl compounds and both classes of heteroallylic halides often become complementary. An important feature of a-haloimines is the possibility of variation of the N-substituent, leading to (although not yet in a tailor-made manner) important changes in the reactivity. Finally, a-haloimines are very useful synthons for the construction of threemembered rings and, in this respect, their chemistry parallels to some extent that of ahalocarbonyl compounds.

’,

V. REFERENCES

462. N. De Kimpe and N. Schamp, Org. Prep. Proced. Int., 15, 71 (1983). 463. Tanabe Seiyaku Co., Jpn. Kokai Tokkyo Koho, J P 58 103344 (83,103344), (CI.C07C97/10),20 June 1983, Appl. 81/200536, 11 Dec. 1981; Chem. Abstr., 99, 104976 (1983). 464. L. Lafon, Eur. Pat. Appl., EP 138 715 (CI.C07C103/44),24 April 1985, Fr. Appl. 83/16405, 14 Oct. 1983; Chem. Abstr., 103, 37203 (1985). 465. L. Lafon, Eur. Pat. Appl., EP 138 714 (CI.C07C103/44),24 April 1985, Fr. Appl. 83/16408, 14 Oct. 1983; Chem. Abstr., 103, 37204 (1985). 466. L. Lafon, Eur. Pat. Appl., EP 143711 (CI.C0797/10),5 June 1985, Fr. Appl. 83/18 868,25 Nov. 1983; Chem. Abstr., 103, 123159 (1985). 467. G. T. Katvalyan, N. A. Semenova, A. S. Shashkov and E. A. Mistryukov, Izu. Akad. Nauk SSSR. Ser. Khim., 468 (1976). 468. V. N. Sozinov, L. M. Orlova, M. D. Mashkovsky and N. N. Suvorov, Khim.-Farm. Zh., 15,65 (1981). 469. J. G. Schantl, P. Karpellus and M. Prean, Tetrahedron, 38, 2643 (1982). 470. H. E. Ulmer and C.T. Mathew (Allied Chem. Co.), U S Pat., 4237069 (C1.564-258; C07C131/00), 2 Dec. 1980, Appl. 54205,2 July 1979; Chem. Absfr., 94, 120866 (1981). 471. F. Benayache, Y. Gounelle and J. Jullien, J. Chem. Res. (S), 158 (1981). 472. C. Bischoff and E. Schroder, J. Prakt. Chem., 323, 616 (1981). 473. Y. Yost, C. F. Polnaszek and J. L. Holtzman, J . Labelled Compd. Radiopharm., 20, 709 (1983); Chem. Abstr., 100, 22537 (1984). 474. N. De Kimpe, L. Moens, R. Verhe, L. De Buyck and N. Schamp, Tetrahedron Lett., 23, 789 (1 982). 475. K. Hideg, 0. Hankovszky, L. Frank, I. Body and J. Csak, East Ger. Par., DD 215538 (CI.C07/D207/16),14 Nov. 1984, Hung. Appl. 84/242, 20 Jan. 1984; Chem. Abstr., 103, 87768 (1985). 476. N. De Kimpe, R. Verhe, L. De Buyck and N. Schamp, Bull. Soc. Chim. Belg., 91, 99 (1982). 477. C. A. Panetta, Org. Synth., 56, 122 (1977). 478. S. B. Sahni and S. M. Gupta, J. Inst. Chem. (India),56, 81 (1984). 479. T. Sakakibara, Y. Ikeda and R. Sudoh, Bull. Chem. Soc. Jpn., 55, 635 (1982). 480. S. H. Mashraqui and P. M. Keehn, J. Org. Chem., 48, 1341 (1983). 481. Chisso Corp., Jpn. Kokai Tokkyo Koho, 80, 162770 (Cl.C07D209/08), I8 Dec. 1980, Appl. 79/69592,4 June 1979; Chem. Abstr., 95, 24811 (1981). 482. K. Sakai, N. Hida and K. Kondo, Bull. Chem. Soc. Jpn., 59, 179 (1986). 483. L. Fitjer, Chem. Ber., 115, 1035 (1982). 484. H. Weingarten, J. P. Chupp and W. A. White, J. Org. Chem., 32, 3246 (1967). 485. H. Weingarten and W. A. White, J . Org. Chem., 32, 213 (1967). 486. H. von Hirsch, Chem. Ber., 100, 1289 (1967). 487. L. Duhamel, P. Duhamel and J.-M. Poirier, Bull. Soc. Chim. Fr., 221 (1972). 488. L. Duhamel, P. Duhamel and J.-M. Poirier, Tetrahedron Lett., 4237 (1973).

360

Norbert De Kimpe and Roland Verhe

489. N. De Kimpe, M. Palamareva, R. Verhe, L. De Buyck and N. Schamp, J . Chem. Res. ( S ) , 190 (1986). 490. N. De Kimpe, B. De Corte, R. Verhe, L. De Buyck and N. Schamp, Tetrahedron Lett., 25, 1095 (1984). 491. N. De Kimpe, P. Sulmon, L. Moens, N. Schamp, J.-P. Declercq and M. Van Meerssche, J. Org. Chem., 51, 3839 (1986). 492. N. De Kimpe, R. Verhe, L. De Buyck and N. Schamp, Tetrahedron Lett., 26, 2709 (1985). 493. N. De Kimpe, unpublished results; see also N. De Kimpe, Habilitation Thesis, State University of Gent, 1985. 494. N. De Kimpe, R. Verhe, L. De Buyck and N. Schamp, Can. J. Chem., 62, 1812 (1984). 495. P. Sulmon, N. De Kimpe, R. Verhe, L. De Buyck and N. Schamp, Synthesis, 192 (1986). 496. K. Atsumi, K. Katano, K. Nishihata, F. Kai, E. Akita and T. Niida, Tetrahedron Lett., 23,2977 (1982). 497. T. Aoki, N. Haga, Y. Sendo, T. Konoike, M.Yoshioka and W. Nagata, Tetrahedron Lett., 26,339 (1985). 498. D. P. Clifford, R. V. Edwards and R. T. Hewson, J . Agric. Food Chem., 29, 640 (1981). 499. G. Giesemann and I. Ugi, Synthesis, 788 (1983). 500. A. Ueda, F. Nagasaki, Y. Takakura and S. Kojima (Nippon Soda Co.), PCT f n t . Appl., WO 8401 773 (CI.C07D207/22), 10 May 1984, Jpn. Appl. 82/188 191, 28 Oct. 1982; Chem. Abstr., 101, 171082 (1984). 501. A. V. Fokin, A. F. Kolornietsand N. V. Vasik'ev, Usp. Khim., 53,398 (1984);Russ. Chem. Rev., 53, 238 (1984). 502. J. T. Welch and K. W. Seper, J. Org. Chem., 51, 119 (1986). 503. M. C. Salon, S . Hamman and C. G. Beguin, Org. Magn. Reson., 21, 265 (1983). 504. P. Margaretha, Helv. Chim. Acta, 65, 290 (1982). 505. K. Burger, D. Huebl and P. Gertitschke, J. Fluorine Chem., 27, 327 (1985); Chem. Abstr., 102, 204255 (1985). 5 0 6 A. Essawy, M. M. Habashy and M. M. Hamad, Egypt. J. Chem., 23.49 (1980);Chem. Abstr.. %, 162292 (1982). 507. W. Oppolzer, K. Battig and T. Hudlicky, Tetrahedron, 37, 4359 (1981). 508. H. C. J. Ottenheijm, R. Plate, J. H. Noordik and J. D. M. Herscheid, J . Org. Chem., 47, 2147 (1982). 509 T. L. Gilchrist and T. G. Roberts, J. Chem. Soc., Perkin Trans. I, 1283 (1983). 510 H.Poslinska, J. Piechaczek and R. Palanowski, Pol. Pat., PL 116828 (CI.C07C131/04),30 June 1981, Appl. 203 501, 29 Dec. 1977; Chem. Abstr., 99, 57896 (1983). 51 I S. E. Denmark and M. S. Dappen, J . Org. Chem., 49, 798 (1984). 512 G. Mixich and K. Thiele. Arzneim.-Forsch.. 29, 1510 (1979); Chem. Abstr., 92, 94298 (19801. 513. W. Kraemer (Bayer AG), Ger. Offen., 2907972 (CI.C07C131/00),11 Sept. 1980, Appl. 1 Mar. 1979; Chem. Abstr., 94, 65325 (1981). 514. D. E. Davies, T. L. Gilchrist and T. G . Roberts, J . Chem. Soc., Perkin Trans. 1 , 1275 (1983). 515. L. Gsell and J. C. Gehret (Ciba-Geigy AG), Eur. Pat. Appl., EP 39 308 (CI.C07C131/02),4 Nov. 1981, Swiss Appl. 80/3170, 24 Apr. 1980; Chem. Abstr., %, 85116 (1982). 516. M. Nassal, Justus Liebigs Ann. Chem., 1510 (1983). 517. G. Holan, W. M. P. Johnson, K. Rihs and C. T. Virgona, Pestic. Sci., 15, 361 (1984); Chem. Abstr., 101, 210639 (1984). 518. S. D. Sokolov, V. Rudchenko, K. F. Turchin, A. P. Pleshkova, A. B. Zolotoi, 0. A. Dyachenko, L. 0. Atovmyan and R. G. Kostyanovskii, Dokl. Akad. Nauk S S S R , 258, 906 (1981); Chem. Abstr., 95, 187128 (1981). 519. T. Severin and H. Lerche, Synthesis, 305 (1982). 520. E. Buschmann, B. Zeeh, R. Becker and P. Schaefer, Ger. Ofen., 2924401 (CI.C07C131/00),I8 Dec. 1980, Appl. 16 June 1979; Chem. Abstr., 94, 191936 (1981). 521. Commonwealth Scientificand Industrial Research Organization, Jpn. Kokni Tokkyo Koho, JP 57 185255 [82, 1852551 (CI.C07C131/00), 15 Nov. 1982, Aust. Appl. 81/8653, 30 Apr. 1981; Chem. Abstr., 98, 143124 (1983). 522. I. L. Knunyants, M. D. Bargamova and S . 1. Pletnev, fz u. Akad. Nauk S S S R , Ser. Khim., 1861 (1980); Chem. Abstr., 94, 30631 (1981). 523. E. K. Dora, B. Dash and C. S. Panda, Indian J. Chem., Sect. B, 19, 68 (1981). 524. Takeda Chem. Industries, Jpn. Kokai Tokkyo Koho. JP 5939873 [84,39873]

App. 2. a-Halogenated imines

361

(CI.C07D231/18),5 Mar. 1984,Appl. 82/149631,27 Aug. 1982;Chem. Abstr., 101,151838(1984). 525. T. L.Gilchrist, J. A. Stevens and B. Parton, J . Chem. Soc., Perkin Trans. 1, 1741 (1985). 526. D. J. Anderson, T. L. Gilchrist, D. C. Horwell and C. W. Rees, J. Chem. Soc. C , 576 (1970). 527. Mitsubishi Chem. Industries Co., Jpn. Kokai Tokkyo Koho, J P 82,31649 (C1.C07C109/14), 20 Feb. 1982, Appl. 80/104729, 30 July 1980 Chem. Abstr., %, 199074 (1982). 528. C. B. Reese and H. P. Sanders, J . Chem. Soc., Perkin Trans. I , 2719 (1982). 529. T. L. Gilchrist and P. Richards, Synthesis, 153 (1983). 530. B. Cordel, L. Medinger, J. P. Haelters and G. Sturtc Synthesis, 1048 (1985). 531. G. Rossey, A. Wick and E. Wenkert, J. Org. Chem., 47, 4745 (1982). 532. 0. Attanasi, M. Grossi and F. Serra-Zanetti, Org. Prep. Proced. Int., 17, 385 (1985). 533. F. J. Weigert, J. Org. Chem., 37, 1314 (1972). 534. W. Verboom, M. R.J. Hamzink, D. N. Reinhoudt and R. Visser, Tetrahedron Lett., 25.4309 ( 1984). 535. D. Matthies and I. Malassa, Synthesis, 177 (1985). 536. V. L. Vershinin, N. V. Vasil'ev, A. F. Kolomiets and G. A. Sokol'skii, Zh. Org. Khim., 20. 1333 (1984); Chem. Abstr., 102, 78343 (1985). 537. N. De Kimpe, R. Verhe, L. De Buyck and N. Schamp, J. Org. Chem., 46, 2079 (1981). 538. V. A. Reznikov and L. B. Volodarskii, Izu. Akad. Nauk SSSR. Ser. Khim., 2565 (1984); Chem. Abstr., 102, 185008 (1985). 539. J. Hausler, Justus Liebigs Ann. Chem., 1073 (1981). 540. C. Schnieders, J.-J. Altenbach and K. Muller, Angew. Chem., Suppl., 1353 (1982). 541. V. A. Samsonov and L. B. Volodarskii, Khim. Geterotsikl. Soedin. 808 (1980). 542. H. Foerster, W. Fuehrer, J. Stetter, L. Eue, R. R. Schmidt and K. Luerssen (Bayer AG). Ger. Ofen., DE 3220526 (CI.C07C131/105), 1 Dec. 1983, Appl. 1 June 1982; Chem. Abstr. 100, 174421 ( 1 984). 543. G. Weber, G. Mann, H. Wilde and S. Hauptmann, Z. Chem., 20,437 (1980). 544. F. M. Simmross and P. Weyerstahl, Synthesis, 72 (1981). 545. E. M. Kosower, D. Faust, M. Ben-Shoshan and I. Goldberg, J. Org. Chem., 47, 214 (1982). 546. P. Schaefer and D. Mangold (BASF AG), Eur. Pat. Appl., E P 52 744 (C1.C07C131/00), 2 June 1982, Ger. Appl. 3044564, 26 Nov. 1980 Chem. Abstr., 97, 144577 (1982). 547. S. Shatzmiller, R. Lidor, E. Shalom and E. Bahar, J. Chem. Soc., Chem. Commun., 795 (1984). 548. A. Ranise, F. Bondavalli and P. Schenone, J. Chem. SOC., Perkin Trans. I , 1251 (1985). 549. M. E. Jung and G. L. Hatfield, Tetrahedron Lett., 23, 3991 (1982). 550. M. J. Spitulnik, Synthesis, 299 (1985). 551. R. J. Himmelsbach, A. D. Barone, D. L.Kleyer and T. H. Koch, J. Org. Chem., 48,2989 (1983). 552. S. Lofis and P. Ahlberg, J . Chem. Soc., Chem. Commun., 998 (1981). 553. S. Lofis and P. Ahlberg, J. Heterocycl. Chem., 21, 583 (1984). 554. S. Lofis and P. Ahlberg, J. Am. Chem. Soc., 107, 7534 (1985). 555. T. Tokumitsu and T. Hayashi, Bull. Chem. Soc. Jpn., 54, 2348 (1981). 556. J. Barluenga, M. Tomas, J. F. Lopez-Ortiz and V. Gotor, J . Chem. Soc., Perkin Trans. 1 . 2273 (1983). 557. J. Barluenga, M. Tomas, J. F. Lopez-Ortiz and V. Gotor, Synthesis, 935 (1984). 558. V. V. Momot and L. I. Samarai, Zh. Org. Khim., 17,439(1981);Chem. Abstr., 95,97882(1981). 559. R. Ketari and A. Foucaud, Synthesis, 844 (1982). 560. V. A. Reznikov, T. 1. Reznikova and L.B. Volodarskii, Izu. Sib. Old. Akad. Nauk SSSR. Ser. Khim. Nauk, 125 (1982); Chem. Abstr., 98, 215525 (1983). 561. 1. Miskolczi, F. Sztaricskai and R. Bognar, Org. Prep. Proced. Int., 13, 15 (1981). 562. R. M. Wilson, R. A. Farr and D. J. Burlett, J. Org. Chem., 46, 3292 (1981). 563. M. E. Kuehne, J. C. Bohnert, W. G. Bornmann, C. L. Kirkemo, S. E. Kuehne, P. J. Seaton and T. C. Zebovitz, J. Org. Chem., 50, 919 (1985). 564. G. Massiot, F. S. Oliveira and J. Levy, Bull. SOC. Chim. Fr., 185 (1982). 565. M. Doe de Maindreville, J. Levy, F. Tillequin and M. Koch, J. Nat. Prod., 46, 310 (1983). 566. N. Aimi, S. Tanabe, Y.Asada, Y.Watanabe, K. Yamaguchi and S. Sakai, Chem. Pharm. Bull. Jpn., 30,3427 (1982). 567. E. Yamanaka, E. Maruta, S. Kasamatsu, N. Aimi, S. Sakai, D. Ponglux, S. Wongseripipatana and T. Supavita, Tetrahedron Lett., 24, 3861 (1983). 568. C. Berti, L. Greci, R. Andruzzi and A. Trazza, J. Org. Chem., 47, 4895 (1982). 569. R. S. Phillips and L. A. Cohen, Tetrahedron Lett., 24, 5555 (1983).

362

Norbert De Kimpe and Roland Verhe

570. R. S. Phillips and L. A. Cohen, J. Am. Chem. Soc., 108, 2023 (1986). 571. K. Ishizumi, M. Muramatsu and J. Katsube, Jpn. Kokai, 78, 59663 (CI.C07D209/10) 29 May 1978, Appl. 76/135014, 9 Nov. 1976; Chem. Abstr., 89, 129397 (1978). 572. D. Nagarathnam and P. C. Srinivasan, Synthesis, 926 (1982). 573. M. De Rosa, L. Carbognani and A. Febres, J. Org. Chem., 46, 2054 (1981). 574. Y. Langlois, A. Pouilhk, D. Genin, R. Andriamialisoa and N. Langlois, Tetrahedron, 39,3755 (1983). 575. R. Andriamialisoa, N. Langlois and Y . Langlois, Heterocycles, 15, 245 (1981). 576. M. G. Beal, W. R. Ashcroft, M. M. Cooper and J. A. Joule, J. Chem. Soc.. Perkin Trans. I , 435 (1982). 577. M. Takamatsu and M. Sekiya, Chem. Pharm. Bull. Jpn., 28, 3098 (1980). 578. N. De Kimpe, R. Verht, L. De Buyck and N. Schamp, Tetrahedron Lett., 26,2709 (1985). 579. J.-M. Poirier, Bull. SOC. Chim. Fr., 17 (1982). 580. P. Schaefer and D. Mangold (BASF AG), Eur. Pat. Appl., EP 52 742 (Cl.C07C131/00), 2 June 1982, Ger. Appl. 3044517, 26 Nov. 1980; Chem. Abstr., 97, 144370 (1982). 581. A. Roedig and E. M. Ganns, Justus Liebigs Ann. Chem., 406 (1982). 582. V. P. Perevalov, M. A. Andreeva, M. I. Bolotov and B. I. Stepanov, Khim. Geterotsikl. Soedin., 993 (1983); Chem. Abstr., 99, 139840 (1983). 583. S. D. Sokolov, S. Vinogradova, V. S. Ignatov, V. V. Paramonova, I. S. Bogdanova and G. N. Pershin, Khim.-Farm. Zh., 15, 27 (1981); Chem. Abstr., 96,104125 (1982). 584. C. Caristi and M. Gattuso, J. Chem. Soc.. Perkin Trans. I , 679 (1974). 585. V. P. Tashchi, A. F. Rukasov. T. I. Orlova, Y. G. Putsykin and Y. A. Baskakov, Khim. Geterotsikl. Soedin., 6, 751 (1982). 586. V. P. Tashchi, A. P. Ivanov, A. F. Rukasov, Y. G. Putsykin, T. I. Orlova and Y. A. Baskakov, Zh. Org. Khim., 18, 2190 (1982); Chem. Abstr., 98, 53739 (1983). 587. K. Grohe, E. Degener, H. Holtschmidt and H. Heitzer, Justus Liebigs Ann. Chem., 730, 133 (1969). 588. J. C. Jochims and M. Abdur Rahman, Chem. Ber., 117,502 (1984). 589. A. V. Eremeev, F. D. Polyak and E. Liepins, Khim. Geterotsikl. Soedin., 707 (1984); Chem. Abstr., 101, 90709 (1984). 590. M. L. M. Pennings, D. N. Reinhoudt, S. Harkema and G. J. van Hummel, J. Org. Chem., 48,486 (1983). 591. G. Dannhardt and R. Obergrusberger, Arch. Pharm. (Weinheim),318,257 (1985). 592. R. B. Woodward, Pure Appl. Chem., 17, 519 (1968). 593. N. Barbulescu, S.Moga-Gheorghe, A. Sintamarian, E. Andrei and M. Marinescu (Combinatul Chimic, Rimnicu-Vilcea),Rom. Pat., RO 74 946 (C1.C07C131/00),30 Nov. 1980, Appl. 94 923,9 Aug. 1978; Chem. Abstr., 99. 121812 (1983). 594. E. J. Corey and J. E. Richman, J. Am. Chem. Soc., 92, 5276 (1970). 595. A. D. Treboganov, R. S. Astakhova, A. A. Kraevskii and N. A. Preobrazhemskii, Zh. Org. Khim., 2, 2178 (1966); Chem. Abstr., 66, 75730 (1967). 596. R. E. Banks, N. Dickinson, A. P. Morrissey and A. Richards, 1.Fluorine Chem., 26.87 (1984). 597. E. Francotte, R. Merenyi, B. Vandenbulcke-Coyette and H.-G. Viehe, Helu. Chim. Acta, 64,1208 (1981). 598. J. Guillaumel, P. Demerseman and R. Royer, Tetrahedron, 37,4215 (1981). 599. R. G. Kostyanovsky, G. V. Shustov and N. L. Zaichenko, Tetrahedron, 38,949 (1982). 600. W. S. Johnson, G. W. Daub, T. A. Lyle and M. Niwa, J. Am. Chem. Soc., 102,7800 (1980). 601. Y. G. Balon and V. E. Paranyuk, Zh. Org. Khim., 19,1346 (1983); Chem. Abstr., 99,87625 (1983). 602. A. N. Mirskova, T. I. Drozdova, G. G. Levkovskaya, 0. B. Bannikova, I. D. Kalikhman and M. G. Voronkov, Zh. Org. Khim., 18, 1407 (1982). 603. A. N. Mirskova, I. T. Gogoberidze, G. G. Levkovskaya and M. G. Voronkov, Zh. Org. Khim., 20, 2235 (1984); Chem. Abstr., 102, 148703 (1985). 604. R. D. Bowen, J. N. Crabb, C. W. G. Fishwick and R. C. Storr, J. Chem. Res. (S), 124 (1984). 605. H. Hamana and T. Sugasawa, Chem. Lett., 571 (1985). 606. H. Hamana and T. Sugasawa, Chem. Lett., 575 (1985). 607. T. L. Gilchrist, B. Parton and J. A. Stevens, Tetrahedron Lett., 22. 1059 (1981). 608. K. Tanaka, T. Igarashi and K. Mitsuhashi, Chem. Lett., 507 (1983). 609. H. Schneider, Helu. Chim. Acta, 65, 726 (1982). 610. S. I. Pletnev, M. D. Bergamova and I. L. Knunyants, Zh. Vses. Khim. Om., 27, 100 (1982).

App. 2. a-Halogenated imines

363

611. M. A. Kurykin, L. S. German and I. L. Knunyants, fzu. Akad. Nauk. S S S R , Ser. Khim.. 2827 (1980); Chem. Abstr., 95, 6431 (1981). 612. M. Kawase and Y. Kikugawa, Chem. Pharm. Bull., 29, 1615 (1981). 613. R. E. Banks and N. Dickinson, J. Fluorine Chem., 19,97 (1981);Chem. Abstr., 96,19698 (1982). 614. R. E. Banks and A. Richards, J . Chem. Soc., Chem. Commun., 205 (1985). 615. A. D. Nikolaeva and R. N. Ziyatdinov, Iru. Vyssh. Llchebn., Khim. Khim. Tekhnol., 24, 1342 (1981); Chem. Abstr., 96,68237 (1982). 616. Y. G. Shermolovich, V. Y. Abramov and V. I. Staninets, Zh. Obshch. Khim., 55, 1620 (1985); Chem. Abstr., 104, 186023 (1986). 617. D. P. Del'tsova, 2.V. Safronova, N. P. Gambaryan and I. L. Knunyants, Dokl. Akad. Nauk SSSR, 267, 856 (1982); Chem. Abstr., 98, 125778 (1983). 618. D. Sohn and W. Sundermeyer, Chem. Ber., 115,3334 (1982). 619. T. D. Truskanova, A. F. Kolomiets and G. A. Sokol'skii, Zh. Oru. Khim.. 18. 1165 (19821. ~, 620. R.G. Plevey, R. W. Rendell and J. C. Tatlow, J . Fluorine Chem.r21, 413 (1982). 621. H. Braxmeier and G. Kresze, Synthesis, 683 (1985). 622. V. N. Tetyukhin, M. V. Vork and L. I. Samarai, Zh. Org. Khim., 19,1232(1983);Chem. Absrr.,99, 175319 (1983). 623. K. Tanaka, S. Maeno and K. Mitsuhashi, Bull. Chem. Soc. Jpn., 58, 1841 (1985). 624. L. F. Lee, M. G. Dolson, R. K. Howe and B. R. Stults, J . Org. Chem., 50, 3216 (1985). 625. H. W. Roesky, J. Lucas, K. Keller, K. S. Dhathathreyan, M. Noltemeyer and G. M. Sheldrick, Chem. Ber., 118, 2659 (1985). 626. M. Julia, J. Bagot and 0. Siffert, Bull. SOC. Chim. Fr., 1424 (1973). 627. M. E. Mustafa, A. Takaoka and N. Ishikawa, Heterocycles, 24, 593 (1986). 628. N. De Kimpe, R. Verhe, L. De Buyck and N. Schamp, Synthesis, 632 (1983). 629. F.-P. Montforts and U. M. Schwartz, Justus Liebigs Ann. Chem., 1228 (1985). 630. E. Gotschi, W. Hunkeler, H.-J. Wild, P. Schneider, W. Fuhrer, J. Gleason and A. Eschenmoser, Angew. Chem., 85, 950 (1973). 631. N. De Kimpe, R. Verhe, L. De Buyck, L. Moens and N. Schamp, Tetrahedron Lett., 22, 1837 (1981). 632. N. De Kimpe, R. Verhe, L. De Buyck, P. Sulmon and N. Schamp, Tetrahedron Lett., 24,2885 (1983). 633. N. De Kimpe, P. Sulmon, R. Verhe, L. De Buyck and N. Schamp, J. Org. Chem., 48,4320 (1 983). 634. N. De Kimpe, P. Sulmon and N. Schamp, Bull. Soc. Chim. Belg., 95, 567 (1986). 635. M. W. Chun and M. H. Kim, YakhakHoe Chi, 25, 83 (1981); Chem. Abstr., 96, 142623 (1982). 636. S. F. Vice, E. A. Gross, R. W. Friesen and G. I. Dmitrienko, Tetrahedron Lett., 23, 829 (1982). 631. E. A. Gross, S. F. Vice and G. 1. Dmitrienko, Can. J . Chem., 59, 635 (1981). 638. U. Schmidt, H. Bokens, A. Lieberknecht and H. Griesser, Justus Liebigs Ann. Chem., 1459(1983). 639. U. Schmidt, A. Lieberknecht, H. Bokens and H. Griesser, J . Org. Chem., 48,2680 (1983). 640. R. F. Nutt, K.-M. Chen and M. M. Joullie, J. Org. Chem., 49, 1013 (1984). 641. R. B. Gammil, S. A. Nash and S. A. Mizsak, Tetrahedron Lett., 24, 3435 (1983). 642. K. Krogh-Jespersen, C. M. Young, R. A. Moss and M. Wlostowski, Tetrahedron Lett., 23,2339 ( 1982). 643. K. R. Randles and R. C. Storr, J . Chem. Soc., Chem. Commun., 1485 (1984). 644. Hokko Chem. Industry Co. Jpn. Kokai Tokkyo Kohu, JP 59 88 473 [84,88 4731 (Cl.C07D249/08), 22 May 1984, Appl. 82/198854, 15 Nov. 1982; Chem. Abstr., 101, 151861 (1984). 645. K. Kano and J.-P. Anselme, Bull. Chem. Soc. Jpn., 57, 905 (1984). 646. K. A. Cruickshank, K. Sumoto and N. J. Leonard, Tetrahedron Lett., 26, 2723 (1985). 647. J. Kokosi, I. Hermecz, B. Podanyi, G. Szasz, and Z. Meszaros, J . Heterocycl. Chem., 21, 1301 (1984). 648. V. V. Martin, L. B. Volodarskii, G. I. Shchukin, L. A. Vishnivetskaya and I. A. Grigor'ev. 120. Akad. Nauk SSSR. Ser. Khim., 161 (1985); Chem. Abstr., 102, 185009 (1985). 649. G. R. Malone and A. I. Meyers, J . Org. Chem., 39, 623 (1974). 650. T. L. Gilchrist, Chem. Soc. Rev., 12, 53 (1983). 651. E. M. Beccalli, A. Marchesini and F. Sannicolo, J . Org. Chem., 49, 2071 (1984). 652. H. Foerster, W. Fuehrer, J. Stetter, L. Eue, R. R. Schmidt and K. Luerssen (Bayer AG), Ger. Ofen, DE 3 220 524(CI.C07Cl31/00), 1 Dec. 1983,Appl. 1 June 1982;Chem. Abstr., 100,102965 ( 1984).

364 653. 654. 655. 656. 657. 658.

Norbert De Kimpe and Roland Verhe Y. M. Belousov, G. A. Gareev and L. I. Vereshchagin, Zh. Org. Khim., 17, 1112 (1981). D. H. R. Barton, D. Crich and P. Potier, Tetrahedron Lett., 26, 5943 (1985). H. Sato, S. Imamura, Y. Kitano, T. Kanda and T. Ashida, Bull. Chem. Soc. Jpn., 57,2162 (1984). Toray Industries Inc., US Par., 3839448 (1974). R. Lidor and S. Shatzmiller, Justus Liebigs Ann. Chem., 226 (1982). T. Kawakita, M. Setoguchi and T. Muro, PCT Int. Appl., WO 81 01 554 (CI.C07D413/06), I I

June 1981, Jpn. Appl. 79/154715, 28 Nov. 1979; Chem. Abstr., 96, 6712 (1982). 659. H. G. Corkins, L. Storace and E. R. Osgood, Tetrahedron Lett., 2025 (1980). 660. P. Anjireddy and K. R. Srinivasan, Indian J. Chem., Sect. B, 18,482 (1979). 661. G. Tacconi, P. P. Righetti and G. Desimoni, J . Prakt. Chem., 322, 679 (1980); Chem. Abstr., 94, 65541 (1981). 662. I. V. Konovalova, R. D. Gareev, E. G. Yarkova, L. A. Burnaeva, M. V. Cherkina, N. M. Aleksanina and A. N. Pudovik, Zh. Obshch. Khim., 52, 1491 (1982); Chem. Abstr., 97, 163117 (!982). 663. R. Faragher and T. L. Gilchrist, J. Chem. Soc.. Perkin Trans. 1, 249 (1979). 664. T. L. Gilchrist, G. M. Iskander and A. K. Yagoub, J. Chem. SOC..Perkin Trans. I , 2769 (1978). 665. T. L. Gilchrist, G. M. Iskander and A. K. Yagoub, J. Chem. Soc., Chem. Commun., 696 (1981). 666. G. M. Iskander and V. S. Gulta, J . Chem. Soc.. Perkin Trans. I , 1891 (1982). 667. S. Nakanishi, Y. Shirai, K. Takahashi and Y. Otsuji, Chem. Lett., 869 (1981). 668. S. E. Denmark, M. S. Dappen and J. A. Sternberg, J. Org. Chem., 49,4741 (1984). 669. D. Marciano and S. Shatzmiller, Justus Liebigs Ann. Chem., 1495 (1982). 670. L. R. Hepp, J. Bordner and T. A. Byson, Tetrahedron Lett., 26, 595 (1985). 671. M. T. Cocco, A. Maccioni and A. Plumitallo, Gazz. Chim. Ital., 114, 521 (1984); Chem. Abstr., 103, 6292 (1985). 672. S. J. Clarke and T. L. Gilchrist, J. Chem. Res. ( S ) , 310 (1985). 673. H. Lerche, J. Treiber and T. Severin, Chem. Ber., 113, 2796 (1980). 674. R. Neidlein, S. Shatzmiller and D. Sinnreich, Ann. Chem., 8 (1983). 675. P. Bravo, G. Gaudiano, P. P. Ponti and C. Ticozzi, Tetrahedron, 28, 3845 (1972). 676. L. Szabo, E. Marvanyos, G. Toth, C. Szantay, Jr., G. Kalaus and C. Szantay, Heterocycles, 24, 1517 (1986). 677. R. Plate, P. H. H. Hermkens, J. M. M. Smits and H. C. J. Ottenheijm, J. Org. Chem., 51, 309 (1986). 678. R. Plate and H. C. J. Ottenheijm, Tetrahedron Lett., 27, 3755 (1986). 679. G. Schill, C. U. Priester, U. F. Windhovel and H. Fritz, Helu. Chim. Acta, 69, 438 (1986). 680. V. Bocchi and G. Palla, Tetrahedron, 40,3251 (1984). 681. S. Shatzmiller and R. Lidor, Synthesis, 590 (1983). 682. N. Matsumura, A. Kunugihara and S. Yoneda, Tetrahedron Lstt., 25, 4529 (1984). 683. F. Barba, M. D. Velasco, A. Guirado and N. Moreno, Synth. Commun., 15, 939 (1985). 684. H. 0. House, W. F. Fischer, Jr., M. Gall, T. E. McLaughlin and N. P. Peet, J. Org. Chem., 37, 3429 (1972). 685. C. Kowalski, X.Creary, A. J. Rollin and M. C. Burke, J. Org. Chem., 43, 2601 (1978). 686. C. Kowalski, M. ODowd, M. Burke and K. W. Fields, J. Am. Chem. Soc., 102, 5411 (1980). 687. C. Kowalski and K. W. Fields, J. Am. Chem. Soc., 104, 321 (1982). 688. J. T. Welch and K. W. Seper, Tetrahedron Lett., 25, 5247 (1984). 689. N. De Kimpe, P. Sulmon and N. Schamp, Angew. Chem., 97, 878 (1985). 690. J. T. Welch and K. W. Seper, J. Org. Chem., 51, 119 (1986). 691. S. Shibata, H. Matsushita, H. Kaneko, M. Noguchi, M. Saburi and S. Yoshikawa, Bull. Chem. SOC.Jpn., 55, 3546 (1982). 692. S. Shibata, H. Matsushita, H. Kaneko, M. Noguchi, T. Sakurai, M. Saburi and S. Yoshikawa, Bulf. Chem. Soc. Jpn., 57, 3531 (1984). 693. G. R. Malone and A. I. Meyers, J. Org. Chem., 39, 618 (1974). 694. R. Liddell and C. Whiteley, J. Chem. Soc., Chem. Commun., 1535 (1983). 695. G. Zolyomi, E. Koltai, D. Banli and K. Harsanyi, J . Labelled Compd. Radiopharrn, 18, 813 (1981). 696. M. Dines and M. L. Scheinbaum, Tetrahedron Lett., 4817 (1969). 697. N. De Kimpe, R. Verhk, L. De Buyck and N. Schamp, Chem. Ber., 116, 3846 (1983). 698. N. De Kimpe, L. Moens, R. Verhe, L. De Buyck and N. Schamp, J. Chem. Soc.. Chem. Commun., 19 (1982).

App. 2. &-Halogenatedimines

365

699. N.De Kimpe, Z. Yao and N. Schamp, Tetrahedron Lett., 27, 1707 (1986). 700. J. E. Dubois, C. Lion and J.-Y. Dugast, Tetrahedron Lett., 23,4207 (1982). 701. C. Lion, J. E. Dubois and K. Lebbar, Bull. SOC. Chim. Belg., 95,119 (1986). 702. T. C. Gallagher and R. C. Storr, Tetrahedron Lett., 2905 (1981). 703. V. V. Shchepin, N. Y. Russkikh and I. I. Lapkin, Zh. Org. Khim., 18,538(1982);Chem. Absrr., 96, 217215 (1982). 704. K. Burger, R. Ottlinger, H. Goth and J. Firl, Chem. Ber., 115,2494 (1982). 705. J. F. Hansen and S. A. Strong, J. Heterocycl. Chem., 14,1289 (1977). 706. J. F.Hansen, Y. I. Kim, S. E. McCrotty, S. A. Strong and D. E. Zimmer, 1.Heterocycl. ('hem., 17,475 (1980). 707. G. L'abM, Bull. SOC. Chim. Belg., 93, 579 (1984). 708. G. L'abM, M. Mahy, M. Bollyn, G. Germain and G. Scheefer, Bull. SOC.Chim. Belg., 92,881 (1983). 709. T. Y. Chan and M. P. Sammes, J. Chem. Res. (S), 92 (1986). 710. P. J. Kocienski, J. M. Ansell and B. E. Norcross, J . Org. Chem., 41,3650 (1976). 711. H.W. Thompson and J. K. Wong, J. Org. Chern., 50,404(1985). 712. Y. V. Zeifman, N. P. Gambaryan and I. L. Knunyants, Izu. Akad. Nauk SSSR, Ser. Khim.. 2046 (1965);Chem. Abstr., 64,6554 (1966). 713. R. Royer, S. Risse and P. Demerseman, J. Heterocycl. Chem., 17, 1125 (1980). 714. C. Shin, Y. Sato, H. Ohmatsu and J. Yoshimura, Bull. Chem. SOC.fpn., 54, 1137 (1981). 715. Y.Sato, Y. Yonezawa and C. Shin. Heterocycles, 19, 1463 (1982). 716. M. D. Bachi and A. Gross, J . Chem. Soc., Chem. Commun., 959 (1981). 717. T.Nakagawa, S.Mochizuki, K. Ornori, S. Shimano and K. Koike (Nippon Kagaku Co.), Ger. Ofen., 3006 160 (CI.C07C103/82), 28 Aug. 1980,Jpn. Appl. 79/17248,19 Feb. 1979; ('hem. Abstr., 94,30389 (1981). Chem. Abstr.. 718. G. F. Il'in,A. F. Kolomietsand G .Sokol'skii. Zh. Vses. Khim.O-ua.,26,714(1981); 96, 103762 (1982). 719. M.G. Zimin, N. G. Zabirov, R. A. Cherkasov and A. N. Pudovik, Zh. Obshch. Khim., 50, 1458 ( 1980). 720. I. V. Konovalova, R. D. Gareev, L. A. Burnaeva, M. V. Cherkina, A. I. Khayarov and A. N. Pudovik, Zh. Obshch. Khim., 50, 1446 (1980). 721. T. K. Vinogradova, G. N. Miskevich and B. S. Drach, Zh. Org. Khim., 16,1869 (1980). 722. N.A. Kapran, Y. L. Yagupol'skii and V. M. Cherkasov, Zh. Org. Khirn., 19,1192(1983);('hem. Abstr., 99, 139910 (1983). 723. K. H. Pilgram and R. D. Skiles, J . Heterocycl. Chem., 20, 1533 (1983). 724. Z. V. Safronova, L. A. Simonyan and N. P. Gambaryan, Arm. Khim. Zh., 32,315(1979);Chern. Abstr., 92,6481 (1980). 725. G. F. Win, A. F. Kolomiets and G. Sokol'skii, Zh. Org. Khim., 16,1096 (1980). 726. A. V. Fokin, N. D. Chkanikov, V. L. Vershinin and A. F. Kolomiets, Izu. Akad. Nauk SSSR. Ser. Khim., 728 (1984);Chem. Abstr., 101,90715 (1984). 727. A. V. Fokin, N. D. Chkanikov, V. L. Vershinin, A. F. Kolomietsand M. V. Galakhov, Izu. Akad. Nauk SSSR,Ser. Khim., 1364 (1985);Chem. Abstr., 104, 19469 (1986). 728. M. Dun,PhD Thesis, Munich, 1971 [cited in J. Fink and M. Regitz, Synthesis, 569 (1985)l. 729. Y. Z. Zeifman, N. P. Gambaryan and I. L. Knunyants, Izu. Akad. Nauk SSSR, 1472 (1965). 730. T. Tsushima, J. Nishikawa, T. Sato, H. Tanida, K. Tori, T. Tsuji, S. Misaki and M.Suefuji, Tetrahedron Lett., 21,3593 (1980). 731. R. E. Brown, H. V. Hansen, D. M. Lustgarten, R. J. Stanaback and R. I. Meltzer, J. Org. Chem., 33,4180 (1968). 732. G. Hugel and J. Gvy, J. Org. Chem., 49,3275 (1984). 733. G. Hugel and J. Levy, J. Org. Chem., 51, 1594 (1986). 734. K. R. Gassen and W. Kirmse, Chem. Ber., 119,2233 (1986). 735. N. De Kimpe, R. Verhe, L. De Buyck and N. Schamp, Bull. SOC. Chim. Belg., 92,233 (1983). 736. H.Quast, R. Frank, A. Heublein and E. Schmitt, Justus Liebigs Ann. Chem., 1814 (1980). 737. N.De Kimpe, M.Palamareva, P. Sulmon, R. Verhe, L. De Buyck, N. Schamp, J.-P. Declercq, B. Tinant and M. Van Meerssche, Tetrahedron, 42,71 (1986). 738. D. V. C. Awang, A. Vincent and D. Kindack, Can. J . Chem., 62,2667 (1984). 739. R. C. De Selms, Tetrahedron Lett., 3001 (1970). 740. J. H. Markgraf, W. P. Homan, R. J. Katt and W. J. Scott, J . Heterocycl. Chem., 6, 35 (1969).

366

Norbert De Kimpe and Roland Verhe

741. C. W. Koch and J. H. Markgraf, J. Heterocycl. Chem., 7, 235 (1970). 742. N. De Kimpe, R. Verhe, L. De Buyck, L. Moens, P. Sulmon and N. Schamp, Synthesis, 765 (1982). 743. J.-M. Poirier, N. Tedga, G. Lhommet and J.-P. Celtrier, J. Chem. Res. (S), 66 (1984). 744. P. Duhamel and M. Kotera, J . Org. Chem., 47, 1688 (1982). 745. D. Frehel, A. Badorc, J.-M. Pereillo and J.-P. Maffrand, J. Heterocycl. Chem., 22, 101 I (1985). 746. J. B. Bremner and K. N. Winzenberg, Heterocycles, 14, 1085 (1980). 747. Omnium Chimique, Belg. Pat., 826066 (CI.C07D), 16 June 1975, Appl. 826066,27 Feb. 1975; Chem. Abstr., 84, 135917 (1976). 748. G. Hugel and J. Levy, Tetrahedron, 39, 1539 (1983). 749. Omnium Chimique, Belg. Pat., 826065 (CI.C07D), 16 June 1975, Appl. 826065,27 Feb. 1975; Chem. Abstr., 84, 135918 (1976). 750. G. Lewin, J. Poisson and J. Lamotte-Brasseur, Tetrahedron, 38, 3291 (1982). 751. P. Magnus, P. Pappalardo and I. Southwell, Tetrahedron, 42, 3215 (1986). 752. A. S. Baily, J. B. Haxby, A. N. Hilton, J. M. Peach and M. H. Vandrevala, J . Chem. Soc.. Perkin Trans. 1 , 382 (1981). 753. Y. Jia and J. Xu, Huaxue Xuebao, 39, 897 (1981); Chem. Abstr., 97, 144503 (1982). 754. S. D. Sokolov, V. Rudchenko, K. F. Turchin, A. P. Pleshkova, A. B. Zolotoi, 0. A. Dyachenko, L. 0. Atovmyan and R. G. Kostyanovskii, Dokl. Akad. Nauk SSSR, 258, 906 (1981); Chem. Abstr., 95, 187128 (1981). 755. T.-Y. Luh, H.-F. Chow, W. Y. Leung and S. W. Tam, Tetrahedron, 41, 519 (1985). 756. L. E. Overman, L. A. Clizbe, R. L. Freerks and C. K. Marlowe, J. Am. Chem. SOC.,103, 2807 (1981). 757. R. R. Schmidt and M. Hoffmann, Tetrahedron Lett., 23,409 (1982). 758. G. Cardillo, M. Orena, G. Porzi and S. Sandri, J. Chem. SOC., Chem. Commun., 1308 (1982). 759. G. Cardillo, M.Orena, G. Porzi and S. Sandri, J. Chem. Soc., Chem. Commun., 1309 (1982). 760. G. Cardillo, M. Orena, S. Sandri and C. Tomasini, Tetrahedron, 42, 917 (1986). 761. A. Bongini, G. Cardillo, M. Orena, S. Sandri and C. Tomasini, Tetrahedron, 39, 3801 (1983). 762. L. L. Danilov, V. N. Shibaev and N. K. Kochetkov, Synthesis, 404 (1984). 763. T. Iversen and D. R. Bundle, J. Chem. Soc., Chem. Commun., 1240 (1981). 764. K. Laesecke and R. R. Schmidt, Justus Liebigs Ann. Chem., 1910 (1983). 765. R. R. Schmidt, J. Michel and M. Roos, Justus Liebigs Ann. Chem., 1343 (1984). 766. S. Takano, M. Akiyama and K. Ogasawara, J. Chem. Soc.. Chem. Commun., 770 (1984). 767. D. M. Vyas, Y.Chiang and T. W. Doyle, J. Org. Chem., 49, 2037 (1984). 768. I. Dyong, J. Weigand and J. Thiem, Justus Liebigs Ann. Chem., 577 (1986). 769. M. J. Nye and W. P. Tang, Can. J . Chem., 51, 338 (1973). 770. S. M. Weinreb and R. N. Staib, Tetrahedron, 38, 3087 (1982). 771. Z. V. Safronova, L. A. Simonyan, Y. V.Zeifman and N. P. Gambaryan, lzu. Akad. Nauk SSSR, Ser. Khim., 1826 (1979); Chem. Abstr., 92, 41900 (1980). 772. K. Burger, S. Penninger, M. Greisel and E. Daltrozzo, J . Fluorine Chem., 15, 1 (1980). 773. K. Burger, H. Goth, W. Schontag and J. Firl, Tetrahedron, 38,287 (1982). 774. K. Burger and R. Simmerl, Justus Liebigs Ann. Chem., 982 (1984). 775. L. N. Kryukov, L. Y. Kryukova, A. F. Kolomiets and G. A. Sokol’skii, Zh. Org. Khim., 16,463 (1980); Chem. Abstr., 92, 198368 (1980). 776. K. Burger, E. Huber, W. Schontag and R. Ottlinger, J . Chem. Soc.. Chem. Commun., 945 (1983). 777. K. Burger, S. Penninger and S. Tremmel, Z. Naturforsch., Teil, B 35, 749 (1980). 778. K. Burger, H. Goth and E. Burgis, 2.Naturforsch., Teil B, 36, 353 (1981). 779. R. G. Kostyanovskii, G. K. Kadorkina, I. I. Chervin, S. S. Nasibov and S. V. Varlamov, Khim. Geterotsikl. Soedin., 1495 (1980). 780. R. G. Kostyanovskii, G. K. Kadorkina, G. V. Shutov, I. I. Chervin, S. H. Nasibov and S. V. Varlamov, lzu. Akad. Nauk SSR, Ser. Khim., 1, 145 (1982). 781. T. C. Gallagher and R. C. Storr, Tetrahedron Lett., 22, 2909 ( I 98 I ). 782. C. T. Ratcliffe (Allied Corp.), U S Pat., 4287 128 ((31.260-348.23; C07D301/03), 1 Sep. 1981, Appl. 50585, 21 June 1979; Chem. Abstr., %, 6550h (1982). 783. G. V. Shustov, A. B. Zolotoi, N. L. Zaichenko, 0.A. Dyachenko, L. 0. Atovmyan and R. G. Kostyanovsky, Tetrahedron, 40,2151 (1984). 784. A. V. Davydov, Zh. Obshch. Khim., 51, 915 (1981); Chem. Abstr., 95, 97743 (1981). 785. A. Hassner, M. J. Haddadin and A. B. Levy, Tetrahedron Lett., 1015 (1973).

App. 2. a-Halogenated imines

367

786. V. L. Vershinin, N. V. Vasil'ev, A. F. Kolomiets and G. A. Sokol'skii, Zh. Org. Khim., 20. 1806 (1984); Chem. Abstr., 102, 95211 (1985). 787. P. G. Gassman and T. T. Tidwell, Acc. Chem. Res., 16, 279 (1983). 788. T. Tidwell, Angew. Chem., %, 16 (1984). 789. E. U. Wurthwein, J. Org. Chem., 49, 2971 (1984). 790. M. T. Nguen and T. K. Ha, J. Chem. SOC.,Perkin Trans. 2, 1401 (1984). 791. D. Bonnet-Delpon, M. Charpentier-Morize and A. Loupy, Chem. Phys. Lett., 116,478 (1985). 792. N. J. Leonard and B. Zwanenburg, J. Am. Chem. SOC., 89,4456, (1967). 793. G. Alvernhe, S. Lacombe and A. Laurent, Tetrahedron Lett., 21, 1437 (1980). 794. D. Klamann, H. Wache, K. Ulm and F. Nerdel, Chem. Ber., 100, 1870 (1967). 795. J. A. Deyrup and W. A. Szabo, Tetrahedron Lett., 1413 (1976). 796. B. F. Bonini, G. Maccagnani, G. Mazzanti and B. Zwanenburg, J . Chem. SOC.,Chem. Commun., 237 (1985). 797. H. Bader and J.-J. Hansen, Helu. Chim. Acta, 61, 286 (1978). 798. M. Rens and L. Ghosez, Tetrahedron Lett., 3765 (1970). 799. R. Flammang, S. Lacombe, A. Laurent, A. Maquestiau, B. Marquet and S. Novkova, Tetrahedron, 42, 3 15 ( 1 986). and references cited therein. 800. J. M. Gaillot, Y. Gelas-Mialhe and R. Vessiere, Can. J. Chem., 57, 1958 (1979). 801. J. C. Hardy and M. Venet, Tetrahedron Lett., 23, 1255 (1982). 802. N. De Kimpe, R. Verht, L. De Buyck, N. Schamp and M. Charpentier-Morize, Tetrahedron Lett., 23, 2853 (1982). 803. J. P. Btgue, D. Bonnet-Delpon, M. Charpentier-Morize and A. Richard, Tetrahedron Lett., 26, 5681 (1985). 804. S. Shatzmiller, E. Shalom and E. Bahar, J. Chem. SOC.,Chem. Commun., 1522 (1984). 805. A. S. Hinve, R. L. Metcalf and I. P. Kapoor, J. Agric. Food Chem., 20, 818 (1972). 806. L. L. Miller, G. D. Nordblom and G. A. Yost, J . Agric. Food Chem., 22, 853 (1974). 807. P. Swered and D. B. Ellis (Betz Laboratories) US Pat. 3994772 (Cl.162-161; D21D3/00), 30 Nov. 1976, Appl. 625285, 23 Oct. 1975; Chem. Abstr., 86, 84741 (1977). 808. D. R. Baker (StaufferChem. Co.), US Pat., 4 018 894(Cl.424-301;A01N9/24), 19 Apr. 1977, Appl. 542 159, 20 Jan. 1975, Division of US Pat. 3988 357; Chem. Abstr., 87, 22409 (1977). 809. A. D. Gutman (Stauffer Chem. Co.), US Pat., 3 733 419 ((31.424-327; AOln), 15 May 1973, Appl. 649024, 26 June 1967; Chem. Abstr., 79, 101159 (1973). 810. A. D. Gutman and D. R. Baker (Stauffer Chem. Co.), US Pat., 3 771 995 (CL71/121; AOln), 13 Nov. 1973, Appl. 746309, 22 July 1968; Chem. Abstr., 80, 141816 (1974). 81 1. A. D. Gutman and D. R. Baker (StaufferChem. Co.), U S Pat., 3 732 306(C1.260-566AE;C O ~ C 8) , May 1973, Appl. 746309, 22 July 1968; Chem. Abstr., 79, 42185 (1973). 812. A. D. Gutman and D. R. Baker (Stauffer Chem. Co.), US Pat., 3 708 590 (Cl.424/327; AOIn), 2 Jan. 1973, Appl. 746309, 22 July 1968; Chem. Abstr., 79, 1363 (1973). 813. I. C. Guillot, G. Wetroff, J. C. Debourge and D. Horriere (Rhone-Progil), Ger. Oflen., 2434821 (CI.C07c, AOIN), 13 Feb. 1975, Fr. Appl. 73 27 308.20 July 1973; Chem. Abstr., 83,78927 (1 975). 814. D. R. Baker and A. D. Gutman (Stauffer Chem. Corn.), US Pat., 4441916 (C1.71-100, AOlN37/00), 10 Apr. 1984, Appl. 313057, 19 Oct. 1981; Chem. Abstr., 101, 50147 (1984). 815. A. C. Henry (Shell Oil Co.), US Pat., 4079 149 ((31.424-327;A61K31/15), 14 Mar. 1978, Appl. 811 645, 30 June 1977; Chem. Abstr., 89, 23972 (1978). 816. G. Holan, K. Rihs and W. Johnson, Wynona Marguerite Phillips (Commonwealth Scientific and Industrial Research Organization), PCTInt. Appl., WO 8600894(CI.C07C131/00).13 Feb. 1986, Aust. Apply. 84/6308. 31 July 1984; Chem. Abstr., 104, 202338 (1986). 817. Lmitomo Chem. Co., Jpn. Kokai Tokkyo Koho, J P 59 164702 (CI.A01N39/00), 17 Sep. 1984, Appl. 83/39 798, 9 Mar. 1983; Chem. Abstr., 102, 74221 (1985). 818. Sumitomo Chem. Co., Jpn. Kokai Tokkyo Koho, J P 59 163 302 (CI.A01N35/10), 14 Sep. 1984, Appl. 83/37 742, 7 Mar. 1983; Chem. Abstr., 102, 57842 (1985). 819. W. J. Middleton (E. I. du Pont de Nemours), US Pat., 4 323 578 (C1.424-298; A01N37/52), 6 Apr. 1982, Appl. 65485, 10 Aug. 1979; Chem. Abstr., 97, 127084 (1982). 820. H. Martin and U. Fricker (Ciba-Geigy AG), Eur. Pat. Appl., E P 94348 (CI.C07C131/00), 16 Nov. 1983, Swiss Appl. 82/2804,6 May 1982; Chem. Abstr., 100, 102946 (1984). 821. E. F. Rothgery (Olin Corp.), US Pat., 4282371 (C1.560-35; C07C101/24), 4 Aug. 1981, Appl. 144744, 28 Apr. 1980; Chem. Abstr., %, 69425 (1982).

368

Norbert De Kimpe and Roland Verhe

822. G. Staehler, W. Knauf, A. Walterdorfer and B. Sachse (Hoechst AG), Ger. Oflen, DE 3 208 187 (Cl.C07F9/05);6 Oct. 1983, Appl. 6 Mar. 1982; Chem. Abstr., 100, 68526 (1984). 823. D. H. R. Barton, D. Crich and G . Kretzschmar, J . Chem. Soc., Perkin Trans. I , 39 (1986). 824. S. Nakanishi, M. Higuchi and T. C. Flood, J . Chem. Soc., Chem. Commun., 30 (1986). 825. A. Bongini, G . Cardillo, M. Orena, S. Sandri and C. Tomasini, J . Chem. Soc.. Perkin Trans. I , 1345 (1986). 826. R. Plate. H. C. J. Ottenheijm and R. J. F. Nivard, J . Org. Chem., 49, 540 (1984).

The chemistry of a -haloketones, or-haloaldehydes and a-haloimines Edited by Saul Patai & Zvi Rappoport Copyright 0 1988 by John Wiley & Sons Ltd

CHAPTER

3

Synthesis and reactivity of mhalogenated aldehydes I . INTRODUCTION . . . . . . . . . . . . . . . . . . . . I1. SYNTHESIS OF 2-HALOGENATED ALDEHYDES . . . . . . . . A. Synthesis of a-Haloaldehydes from Aldehydes . . . . . . . . . . B. Synthesis of a-Haloaldehydes from Alcohols . . . . . . . . . . C . Synthesis of a-Haloaldehydes from Aldehyde Derivatives . . . . . . D . Synthesis of a-Haloaldehydes from Halogenated Oxiranes and Ozonides E. Synthesis of a-Haloaldehydes via Homologation of Carbonyl Compounds F. Synthesis of a-Haloaldehydes from Alkynes . . . . . . . . . . . G . Miscellaneous Syntheses of a-Haloaldehydes . . . . . . . . . . H . Oligomerization of a-Haloaldehydes . . . . . . . . . . . . . 111. REACTIVITY OFa-HALOGENATEDALDEHYDES . . . . . . . A. Reactivity of a-Haloaldehydes Towards 0-Nucleophiles . . . . . . B. Reactivity of a-Haloaldehydes Towards N-Nucleophiles . . . . . . 1 . Reaction of a-haloaldehydes with ammonia . . . . . . . . . 2. Reaction of a-haloaldehydes with primary amines . . . . . . . 3. Reaction of a-haloaldehydes with secondary amines. . . . . . . 4. Reaction of a-haloaldehydes with tertiary amines . . . . . . . 5 . Reaction of a-haloaldehydes with imidates, amidines and enamines . 6 . Reaction of a-haloaldehydes with amides, thioamides and isocyanates 7. Reaction of a-haloaldehydes with carbonyl reagents . . . . . . . C. Reactivity of a-Haloaldehydes Towards S-Nucleophiles . . . . . . D . Reactivity of a-Haloaldehydes Towards C-Nucleophiles . . . . . . 1. Reaction of a-haloaldehydes with cyanide . . . . . . . . . . 2. Reaction of a-haloaldehydes with carbanions, enolates and ylides . . 3. Reaction of a-haloaldehydes with Grignard reagents . . . . . . 4. Reaction of a-haloaldehydes with organocadmium compounds . . . 5 . Reaction of a-haloaldehydes with organolithium compounds . . . E. Reaction of a-Haloaldehydes with Phosphorus Compounds . . . . . F. Reaction of a-Haloaldehydes with Complex Metal Hydrides . . . . . G. Reaction of a-Haloaldehydes with Organometallic Complexes . . . . H . Electrophilic Reactions of a-Haloaldehydes . . . . . . . . . . . 1. Cycloaddition Reactions of a-Haloaldehydes . . . . . . . . . . IV. REFERENCES . . . . . . . . . . . . . . . . . . . . . .

369

370 370 370 377 379 384 389 391 391 393 394 394 401 401 403 405 407 410 41 1 411 413 413 413 418 428 43 1 43 1 432 435 435 438 439 443

370

Norbert De Kimpe and Roland Verhe 1. INTRODUCTION

Although a-halogenated ketones have been the subject of numerous investigations from the end of the nineteenth century, the study of the chemistry of a-halogenated aldehydes was started only in the mid-1950s when general methods for the preparation of amonohaloaldehydes became accessible. No comprehensive review of the synthesis and reactivity of a-monohalo- and a, a-dihaloaldehydes has been published, except for limited descriptions of nucleophilic substitution reactions of a-monohaloaldehydes by Muller in 1954' and Kirrmann in 19612. However, the chemistry of chloral3 and monochl~roacetaldehyde~ has been covered in reviews in 1975. In this chapter, a survey will be given of developments in the chemistry of ahaloaldehydes in synthetic procedures, in mechanistic pathways and in potential applications in organic synthesis. The review is limited to aldehydes which possess one or two halogen atoms in the a-position, thus excluding chloral and bromal. Also, the synthesis and reactivity of mono- and dichloroacetaldehyde will not be treated extensively owing to the exceptional reaction conditions used (often in aqueous solution), unless the reaction is generally applicable to other a-haloaldehydes. The chapter is divided into two parts. The first deals with synthetic procedures, and is subdivided according to the starting materials. The second part treats the reactivity, and is subdivided according to the nature of the reagents and not according to the observed reaction type. The review covers the literature up to the first half of 1986. II. SYNTHESIS OF a-HALOGENATED ALDEHYDES

Except for the limited information given in Houben- Weyl: Methoden der organischen C h e n ~ i e ' *on ~ *the ~ synthesis of a-haloaldehydes and their acetals, no comprehensive review has been published hitherto. Whereas in the chapter on a-haloketones the syntheses of chloro-, bromo-, fluoro- and iodoketones were treated separately, this section will describe the general procedures for the preparation of the various a-haloaldehydes according to the nature of the starting materials, because of the limited number of several of the compound types available. A. Synthesis of a-Haloaldehydes from Aldehydes

Owing to the higher reactivity of the carbonyl function in aldehydes compared with that in ketones, the direct treatment of aldehydes with chlorine or bromine often results in low yields of the corresponding a-haloaldehydes. In addition to the formation of monoand dihalo compounds, which are difficult to separate, chlorination or bromination gave rise to side-reactions such as the production of the corresponding acyl halides, and the occurrence of aldol condensations, oxidations in alkaline media and the formation of acetals when the reaction was carried out in alcohols2*s*6. Therefore, the first preparations of a-bromoaldehydes (3) were carried out via bromination of the corresponding paraldehydes (1) (i.e. the aldehyde trimers = 1,3, 5-trioxanes) followed by pyrolysis7 or alcoholysiss of the bromo derivative 2 (equation 1). Direct monobromination of aliphatic aldehydes (5) could be achieved by using bromine under carefully controlled conditions: low temperature (- 10 "C) and dilution with dry or chloroformlo. The presence of stoichiometric'1*12 or catalytic dichl~romethane~ a r n o ~ n t s of ' ~ dioxane, acetic acidI4 or calcium carbonate" increased the yields of the amonobromoaldehydes (3) (equation 2). It should be pointed out that under these conditions only minor amounts of a, a-dibromoaldehydes (6)were produced16. Nevertheless, 2-bromo-2-chlorobutanal was prepared by bromination of 2-chlorobutanal with bromineI7. 2,2-Dibromopropanal(8),however, could be prepared as the main product by

3. Synthesis and reactivity of a-halogenated aldehydes

371

bromination of propanal (7) in the presence of N-formylpyrrolidine hydrochloride (10) (equation 3)lS.

(2)

/.

YOH

Br

(3)

90 %

(8)

10 %

(9)

Other brominating agents which have been successfully used in the monobromination of aldehydes such as 11, 14 or 17 are the dioxane-bromine adduct 1219320,the ionexchange resin Amberlyst A-26 in the perbromide form ( 1q2’, polyvinylbenzyltri3-dioxane phen lphosphonium perbromide”, 5,5-dibromo-2,2-dimethy1-4,6-dioxo-l, (18)’ Y, 5,5-dibromobarbituric acid (20)24, tert-butyl bromide-DMSO (21)25 and trimethylbromosilane-DMSO (22)26(equation 4).

Norbert De Kirnpe and Roland Verhe

312

63 VO

(13) R e f . 20

(12)

(11)

I

Br

95 v* (14)

(16) R e f . 21

(16)

(4)

(20)

-

t-BuBr

/

Me2S0

(21) (14)

-

Me3SiBr

/

93%

.4 H

Me2S0

(22)

Reaction of 2-chlorobutanal (23) or a bulky a-chloroaldehyde (e.g. 25) with Nbrornosuccinirnide resulted in the formation of the corresponding acid bromide” or of a dihalide” (equation 5).

3. Synthesis and reactivity of a-halogenated aldehydes

I

CI (23)

373

CI

(24)

Procedures for the direct chlorination of aldehydes with chlorine to produce a-monoand a, a-dichloroaldehydes were not generally available until 1980. However, monochlorination and in a few cases dichlorination were successfully performed in aqueous acidic medium. Chlorination of lower aliphatic aldehydes (5) without side-reactions takes place in chlorine-water mixtures at low temperature and with high concentrations of hydrochloric and in 90% sulphuric acid30. Only 2-methylpropanal could be amonochlorinated using chlorine in water3 'v3', while the chlorination of propanal in dilute hydrochloric acid could be controlled in such a manner as to produce either 2chloropropanal or 2,2-dichloropropanal in yields exceeding 85% (equation 6)33.

40-90%

(5)

(27)

When a, a-dichloroaldehydes are the target molecules, the main disadvantage of the chlorination with acid catalysts is the relative slowness of the second enolization step, since the basicity of the carbonyl group is decreased considerably by an a-halogen substituent. This procedure therefore frequently yields products contaminated with substantial amounts of a-monochloroaldehydes, rendering the method useless owing to difficulties in the separation of a-mono- and a, r-dihaloaldehydes. A general synthesis of a, a-dichloroaldehydes (29) consisted in direct chlorination of aldehydes (28) with chlorine gas in N, N-dimethylformamide (DMF)solution at 40-90 "C (equation 7)34*35.The procedure is based on the special efficiency of DMF-HCI mixtures for catalysis of enolization. In addition to the usual acid catalysis, an efficient basecatalysed enolization of the a-chlorocarbonyl function is observed. Whereas the introduction of the first chlorine substituent into the aldehydes is clearly acid catalysed, the second chlorination is base catalysed or combined acid-base catalysed. The second chlorination step is so rapid that monochloroaldehydes were not detected in samples excess of chlorine must be which underwent incomplete ~ h l o r i n a t i o n ~A~continuous . maintained in order to minimize the acid-catalysed aldol condensation, as illustrated in equation 8.

314

Norbert De Kimpe and Roland Verhe

50-90 %

(7)

20%

A similar synthesis of a, a-dichloroaldehydes, involving the chlorination of aldehydes using 1,1,2,2-tetrachloroethaneor carbon tetrachloride as solvent in the presence of Nformylpyrrolidine hydrochloride as catalyst, was developed later (equation 9)’8.

(27,291 R2=CI

whrn R2=H

in 5

High yields of a-monochloroaldehydes were also obtained using sulphuryl &loidel 5.35.36.38-40 . On the other hand, addition of diphenyl sulfide resulted in the formation of a, a-dichloroaldehydes (equation

0

H CI

CI

65-71 ‘18

(28)

(29)

315

3. Synthesis and reactivity of a-halogenated aldehydes

Butanal and 2-methylpropanal undergo a-chlorination in almost quantitative yield on refluxing with copper(I1) chloride in aqueous isopropanol or acetone4', and 3(pheny1thio)butanalcould be chlorinated with NCS43.Chlorination by means of polymercan also give rise to high yields supported chlorine44and trimethyl~hlorosilane-DMS0~~ of a-monochloroaldehydes. a-Fluoroaldehydes cannot be obtained directly from aldehydes via fluorination. Tertiary a-fluoroaldehydes (30)were synthesized by reaction of a-bromoaldehydes (3)with silver tetrafluoroborate in diethyl ether (equation 11). When the reaction was carried out in nucleophilic solvents the corresponding substitution products by the solvent were isolated, suggesting that neighbouring group participation by the carbonyl oxygen may account for the products46. 0 H , $R2 1R

diethyl AgBF, ether

Br

.

H

R2 R1$ F

50-70 '10

(3)

(30)

a-Iodoaldehydes (31) have been synthesized by treatment of aldehydes with iodine i n the presence of mercury(I1) chloride4', direct iodination of aldehyde enolates4' and by reaction of a-chloro- or a-bromoaldehydes (32) with sodium iodide49 (equation 12).

57-

89 %

65-93

(51)

0

0 H

I

I

X

(32) X=CI,

H

MeCN

I Br

*A

376

Norbert De Kimpe and Roland Verhe

Although the transformation of a, @-unsaturatedaldehydes into a, fi-dihaloaldehydes two mechanisms were proposed to account for has been established for a long the evidence that a,&unsaturated aldehydes do not react with halogens by the expected attack on the C=C bond. The higher rates of the halogenation of acrolein compared with hept-1-ene and of crotonaldehyde compared with crotonic acid, together with the regiochemistry of the BrCl addition, excluded an electrophilic attack of halogen on the C=C bond. One mechanism (A) involves initial attack ofthe halogen on the oxygen atom and the other (B) involves initial addition of a trace of HX to give a highly reactive enol (equation 13)s3*54.

+f\

o\x

$5fH x

X

o

X

OH

X

(13)

OH

Other useful transformations of a,p-unsaturated aldehydes into a-haloaldehydes involve reactions with selenium tetrahalidesS5 or copper(I1) chlorides6 and the acidcatalysed reaction of N-bromosuccinimide in methanols7 (equation 14).

35

x

-100

- 4fH (34)

CUCI,

r-euon

t-BuO

0

78 %

(36) Br

*/a

3. Synthesis and reactivity of a-halogenated aldehydes

377

Polyhalogenated aldehydes (41, 42) have been prepared via halogenation of a, bunsaturated aldehydes (S),followed by halogenation in the presence of water or via a dehydrohalogenation-halogenation sequence (equation 15)37*57-62. The Chlorination of a, b-unsaturated aldehydes should be conducted in carbon tetrachloride, because otherwise chlorinated acid chlorides are formed as side-products.

I

XI

I

X e or Y e

or Y s

(42)

(41)

(15) B. Synthesis of @-Haloaldehyde8from Alcohols

The excellent chlorination procedure using CI,-DMF is also applicable in converting directly primary alcohols (43) into a, a-dichloroaldehydes (29), by combining chlorination and oxidation in a one-pot reaction (equation 16)34.This procedure involves a very rapid formation of the chlorinated hemiacetal44, which in turn is gradually converted into the 2.2-dichloroaldehyde 29 (equation 17). The yields obtained in the chlorination of aromatic substrates were only moderate, owing to competing ring chlorination. From pentane-l,Sdiol (46)the stable cyclic hemiacetal3,3-dichloro-2-hydroxytetrahydropyran (47) was obtained, and it was partly converted to the trichlorotetrahydropyran 48 (equation 18). However, the chlorination of hexane-l,6-diol produced 2,2,5,5-tetrachlorohexanedialin 63% yield34. Other procedures for converting alcohols into a-haloaldehydes involved hydrolysis (via rearrangement) of dichlorohydrins (50)63and oxidation of b-chloro-a-hydroxyketones (S2)64(equation 19).

47-78

(45)

(29)

Vm

Norbert De Kirnpe and Roland Verhe

378

C'Z DMF

CI

CI

(45)

(46)

R ~ H O

(47)

LiCHCI,

KOH

R1

CHClz

MOOH

H

CI

91 '1.

(52)

(53)

Acetals (55) of a-chlorinated aldehydes, which can be easily hydrolysed to the corresponding aldehydes, have been synthesized by chlorination of alcohols with chlorine65and by electrolysis of primary alcohols in the presence of anhydrous hydrogen chloride66 (equation 20).

3 79

3. Synthesis and reactivity of a-halogenated aldehydes 3R1R2CHCH20H

+

2 C I 2 -R'R2CCH(OCH2CHR'R2)2

+

HCI -R'R2CCH(OCH2CHR'R2)2

I

+

3HCI

+

H20

+

2H2

+

H20

(54)

3R1R2CHCH20H

elrctrolyeir

I

CI

(54)

C. synthesis of a-Haloaldehydes from Aldehyde Derlvatives

It is evident that halogenation of acetals should be a very attractive route for the preparation of a-haloaldehydes via acidic hydrolysis of the halogenated acetals. This indirect method gave high yields except for the lower (C,-C,) derivatives. The bromination of acetals (56) was performed using bromine67,phosphorus dibromide t r i c h l ~ r i d e ~or~ NBS7'. .~~ In order to capture the liberated hydrogen bromide, the reactions were carried out in the presence of a base, such as calcium sodium e t h ~ x i d or e ~~~y r i d i n eExcept ~ ~ . for the formation of 2,2-dibr~moheptanal~", this procedure gave a-monobromoaldehydes (58) after hydrolysis (equation 21). OR

Hydrolysis of fluorinated acetates (59)with sulphuric acid gave a, a-difluoroaldehydes (60)". The a-chloroethers 61 could be brominated to 62 and transformed into the corresponding brominated acetals 5776 (equation 22). Halogenation of enol derivatives of aldehydes has proved to be very successful in the synthesis of a-halogenated aldehydes. Enol acetates (66) can be transformed into amonobromoaldehydes (3) via the corresponding dibromides (67) and acetals (4)77*78, while enamines (63) on treatment with bromine afforded the intermediate a-bromoimmonium salts (a), which can be hydrolysed to the corresponding a-bromoaldehydes (3)79. In addition, silyl enol ethers (65) can be transformed directly into a-chloro- and abromoaldehydes on treatment with chlorine or bromine in CC1,80, and a-fluoroaldehydes were generated on fluorination with 5% F, in N, in Freon 11" (equation 23). Three general methods for the preparation of a, a-dibromo- and a, a-dichloroaldehydes via halogenation of either enamines or aldimines have been developed. Halogenation of enamines (68)followed by treatment with triethylamine afforded b-haloenamines (70).The latter can also be obtained via condensation of a-haloaldehydes (32) with secondary amines. Treatment of the /I-haloenamines 70 with bromine or chlorine gave the a, adihalogenated immonium salts 71, which were easily hydrolysed to the a, adihaloaldehydes 72 (equation 24)82*83.

Norbert De Kimpe and Roland Verhe

380

(61)

(62)

“H: . Mo,SiCI

R2

40-95%

EtlN

R2 “

e Br

(65)

“$ OAc

CCI,

R’OH

R2

Br

Br

o

(23)

3. Synthesis and reactivity of a-halogenated aldehydes

381

x (69)

X,Y

=CI, Br

MCl,=AsC13,

x-

H

SbC13, BiCI3,

Y-

R'

p G R 2

FoCI3, TiCI,, X

Y

25-88

X

Y

'10

(72)

(71)

The second method involved halogenation of aldimines (73) with two equivalents of Nchloro- or N-bromosuccinimide to give 74. Hydrolysis of 74 with dilute hydrochloric or hydrobromic acid gave u, a-dichloro- and a, a-dibromo-aldehydes (75), respectively. The advantage of this procedure is that there is no need to isolate the intermediate imines (73 and 74) (equation 25)84. In similar manner, 2,2-dichlorobutanal (81) was formed, together with minor amounts of a-chlorobutanal(23), via hydrolysis of the corresponding The latter were formed by halogenation during the autooxidation of aldimines (79,W). benzaldehyde in the presence of dibutylammonium chloride, which was successively transformed into N-chlorodibutylamine (77) and an aldimine (78) (equation 26)85.

I

(73)

(28)

CCI,

NXS

(X=Ci,Br)

x 57-88

(75)

x

%

(74)

382

Norbert De Kimpe and Roland Verhe

O'

PhCHO

+

Bu2NH.HCI

Bu2NH2CI-

(76)

PhCOOH

BuZNH

+

+

PhCOOH

CI-

CI'

d

+

CI'

+

-OH

Bu2NCI

1

-HCI

1

7%

40 V w

(23)

(81)

In the third method, aldehyde p-tosylhydrazones (82) having two a-hydrogen atoms are transformed into a, a-dichloroaldehydes (29). The mechanism suggested involves a sulphinate participated [2,3]-sigmatropic rearrangement (equation 27)86. An alternative route in converting N-derivatives of aldehydes into a-haloaldehydes consists in the halogenation of enamines (84) with N-halosuccinimide, which affords the adducts 85. The latter in turn can be hydrolysed into a-monohaloaldehydes (86) by treatment with silica gel (equation 28)".

383

3. Synthesis and reactivity of a-halogenated aldehydes

,NHS02Tol

0

SOpCI,

H

2

CI

& R H -1C I

R1+H CI

59-7 5 % (29)

(51) Tol= p - t o l y l

NXS

X=CI, Br, I

RlyJ

R2

R2 R 1 $ (

0 (84)

CI

H

x 50-90

Ve

Norbert De Kimpe and Roland Verhe

384

A very efficient method for the synthesis of dichloroacetaldehyde (89)from chloral (87) was elaborated via the hydrolysis of the enol phosphate 88, obtained by the Perkow reaction of chloral with trimethyl phosphite (equation 29)".

CISCCHO

P(OMd,

ii

CIZC=C-OP(OMO)~

I

HcSO4

H

(87)

Clp CHCHO

89 v.

(89)

(88)

(29)

The sterically hindered a,a-dichloroaldehyde 92 could also be obtained via hydrolysis of 1,2,2-trichloro-3,3-dimethylbutaniminotrichlorophosphorane(91), synthesized by reaction of the amine 90 with phosphorus pentachlorideE9. A particular case of transforming a protected aldehyde function into chlorinated aldehydes (51) consisted in alkylation of the 2-(chloromethyl)oxazine 93 followed by reduction with sodium borohydride and hydrolysis (equation 30)90.

-

1.

1. LiN(SiMaa)a

CI

(93)

en;

2. R'X

H

(94)

D. Synthesis of c+Haloaldehyder from Halogenated Oxlraner and Ozonldes

Thermal rearrangement of halogenated oxiranes (W), prepared via base-catalysed ring closure of B, B-dihaloalcohols(93,often resulted in the formation of a-haloaldehydes (32) (route a), although a-haloketones (97)are plausible reaction products via route b (equation 31)91-9'*235. The inductive effect of the halogen atom caused ring opening via path a (bond b is stronger than bond a) followed by a rearrangement of the halogen anion, while the mesomeric effect resulted in ring opening via b accompanied by a hydride shift. From kinetic studies it was concluded that the thermal rearrangements of halogenated oxiranes (98)occurred by disrotatory C,-0 bond heterolysis to yield the corresponding aketocarbonium-chloride ion pairs (99)(equation 32)95.

3. Synthesis and reactivity of a-halogenated aldehydes

385

1

X

I

(97)

X

R2

(100)

R3 cl-

The formation of halogenated aldehydes or ketones is strongly dependent on the reaction conditions. Whereas rearrangement of 2-chloro-2-phenyloxirane(102) at room temperature9* or at reflux in carbon tetrachloride resulted in the formation of phenacyl chloride (103), slow heating of the oxirane to 100 T9* afforded a mixture of the aldehyde 104 and ketone 103 (equation 33). On the other hand, heating of trans-8-chlorostyrene oxides (105) gave the a-haloaldehydes (106) exclusively (equation 33)95. Another entry to the synthesis of a-chloroaldehydes (27) via thermal rearrangement of intermediate chlorooxiranes (lots), which were not isolated, involved the action of dichloromethyllithium (107) (prepared in situ from dichloromethane and n-butyllithium) on ketones (equation 34)27*98*99. In addition to thermal rearrangements, catalytic ring opening of halooxiranes, e.g. 102, '~~, 109, 110 and 116, under the influence of acid^^'.^', magnesium b r ~ m i d e ~ ' *boron trifl~oride~', silver tetrafluor~borate'~'~*~~ and bases102.-" has been performed (equation 35).

386

Norbert De Kimpe and Roland Verhe PhCOCH2CI

(103) CI

100

(102)

oc

PhCOCH2CI

+

PhCHCHO

I

(103)

CI

(104)

(106)

R’

R2

+

.“qc1 I (106)

LiCHC12

-l0OOC*[

(107)

CI

-L1CI

Cl

(108)

5 2 - 80%

(27)

phfi HCI

CI

Ph

CI

(102 1

(33)

H 7 7%

R e f . 91

(34)

387

3. Synthesis and reactivity of a-halogenated aldehydes

(35)

R’CHCHO

R’CHCHO

I

(113)

I

F

CI

(112)

(61)

(114)

/

100%

(117)

(116)

a-Fluoroaldehydes (30)have been obtained in a similar way by the simultaneous action of H F and BF, on cyanooxiranes (118), which afforded fluorocyanohydrins (119).These, in turn, are treated with silver nitrate and ammonia (equation 36)’03.

(118)

F

(119)

;

10-60%

(30)

(36) A synthetically more useful procedure involved ring opening of epoxysulphones ( 122) under the influence of magnesium(I1) bromide, which led to a-bromoaldehydes (3).The required epoxysulphones (122) are accessible from a Darzens-type condensation of chloromethyl phenyl sulphone (121) and ketones (120) (equation 37). The epoxysulphone route has a number of advantages over the a-haloepoxide route. The condensation between a-chlorosulphones and aldehydes or ketones can be carried out conveniently

388

Norbert De Kimpe and Roland Verhe

under phase-transfer conditions, whereas the synthesis of a-haloepoxides requires the generation of dihalomethyllithium at very low temperatures. The epoxysulphones (122) are stable, whereas many a-chloroepoxides are not stable enough under the purification conditions (equation 37)'04-'06. A

R

2

+

PhS02CH2CI

KOH

R'

(120)

(121)

other

(37)

0

Br

a-Haloaldehydes were also generated when trans-2,3-dichlorooxirane(123) reacted with dimethyl sulphide, affording dimethyl(1-chloro-2-hydroxyethenyl)sulphonium chloride (124). On pyrolysis, 124 provided 2-chloro-2-(methylthio)acetaldehyde (125) and dichloroacetaldehyde (89) (equation 38)'".

(123)

IA

(124)

0

Nearly quantitative yields of a-monohaloaldehydes have been obtained via ring cleavage of epoxyacetates (126) with Grignard reagents followed by hydrolysis of 127 in acidic medium (equation 39)'08*'09. Reaction of epoxides with the thioanisole-chlorine complex produced a-chlorosulphoxonium intermediates, which on treatment with triethylamine afforded a-chloroaldehydes3". In a similar way, monoozonides (e.g. 128) are converted into a,bdibromoaldehydes (e.g. 130) via bromination and reduction of the stable dibromoozonides (129) with dimethyl sulphide (equation 40)"'. In this respect, a very efficient synthesis of bromoacetaldehyde (56%) has been developed by treatment of the ozonide of 1,4-dibromo-trans-but-2-ene with triphenylphosphine at 0 "C' ' I .

3. Synthesis and reactivity of a-halogenated aldehydes

389

. "u"\. A -R1xoAc n

RzMqBr

R'

HSO*

Br

OAc

OMgBr

Rr

E. Syntheslr of a-Haloaldehydes via Homologation ot Carbonyi Compounds

Carbonyl compounds have been converted into a-haloaldehydes via a variety of methods. A related transformation involving ring cleavage of oxiranes has been described in a previous section. Methyl formate gave rise to a-haloaldehydes (32) by reaction with 1haloalkyllithiums (131)'12- ' l 4 via intermediate hemiacetals. a, a-Dihaloaldehydes (75) have been prepared in similar way using 1,l-dihaloalkyllithium carbenoids (133)' 5. aMonohaloaldehydes (32) can also be formed in lower yields using N,Ndimethylformamide as the carbonyl substrate' l 6 (equation 41). R'CHLi

I i

+

HCOOMe

(lil) R'CHCHO

I

X

60--80%

(32)

R'CXZLi

+

HCOOMe

-1oooc

A

-

(133) R'CHLi

I

x (131)

OLi

I

(R'CHCHOMe)

I

X

I

H*O

OH

I

R'CHCHOMe

I

X

R'CX2CH0

50-8O0/e

(75)

+

HCONMe2

7

R'CH=CHR'

(1321

+

R'CHCHO

I

x

(32)

390

Norbert De Kimpe and Roland Verhe

a-Halo-a, /?-unsaturated aldehydes have been the subject of chain elongation with the formation of a-haloaldehydes via the reaction of 2-bromoacrolein (134) with organoboranes"' and via a 1,4-addition of lithium dimethylcuprate to a-chloro- and a-fluoro-a, /?unsaturated aldehydes (136, 138)(equation 42)' Acrolein (35)was also converted into 2chloro-3-phenylpropanal (143) via the simultaneous addition of phenylmercury(I1) chloride (142) and chlorination with copper(I1) chloride (equation 43)' 19.

''.

65-97 T o

(134)

(135)

CI

CI 1 Me,CuLi

2.nIo+

R2

0

* Me

R2

0

70--80°/o

(136)

(137)

Jt F

33--37O/o

(141)

(33)

(142)

63%

(143)

Reaction of hemiacetal vinylogues (145) with silyl enol ethers (144), derived from ahaloaldehydes in the presence of boron trifluoride etherate, yielded a-halo-dketoaldehydes (146)(equation 44)'".

39 1

3. Synthesis and reactivity of a-halogenated aldehydes 0

R3

0

F. Synthesis of a-Haloaldehydes from Alkynes

Terminal acetylenic compounds (e.g. 147), on treatment with an excess of sulphenyl chlorides, furnished the corresponding a-chloroaldehydes (e.g. 151) via hydrolysis of the mixtures of Markownikov and anti-Markownikov chlorinated enol thioethers (148-150) (equation 45)121v122.An excess of the sulphenyl chloride is essential because otherwise chloromethyl ketones are produced. t-Bu

CI

X

RS t-BuCGCH

+

RSCl

(1481

H

?-By

-

,

H

n

(147)

I

CI

75%

(1511

(45)

Haloboration of alkynes (152) followed by oxidation of the 2-haloalkenylboranes (153) formed served as an excellent procedure for the preparation of a-bromoaldehydes (58) (equation 46)Iz3. The sterically hindered a-fluoroaldehyde 158 could be synthesized from tertbutylacetylene (147) by addition of hypofluorous acid. They key intermediate in the reaction mechanism is probably a protonated oxirene (1!%), which reacts with the fluoride anion to generate the final product (equation 47)Iz4. 0. Mlscellaneous Syntheses of a-Haloaldehydes

In this section less synthetically suitable formations of a-haloaldehydes will be discussed, although some reactions may possess potential applications.

392

- BrXBBr2

Norbert De Kimpe and Roland Verhe

R'CECH

+

BBr,

(152)

R'

H

(153)

55--70%

(50)

t-BuCECH

+

HOF

(147)

-

(154) t

F-

t-Bu-C=CI.).I.OH

I

(155)

t-Bu.

(47)

H

60%

(158)

(157)

(156)

The interaction of vinyl azides (159) with bromine in methanol gave rise to abromoaldehydes (58). When the reaction was conducted in diethyl ether, a mixture of abromo-(58) and a, a-dibromoaldehydes (6) was formed, together with a-bromonitriles (161) (equation 48)lZ5.

I

(159)

-

3 2 5 3% (50)

(160)

B r a dirthyl ether

RlYCN

Br

0

+

0

+

R1+H

Br

R'*

H

Br Br

Although the hydride reduction of a, a-dichloroacid chlorides (162)can be regarded as a suitable procedure for the synthesis of halogenated aldehydes (29), the results are

3. Synthesis and reactivity of a-halogenated aldehydes

393

disappointing, mainly owing to the further reduction of the aldehyde function to 164 (equation 49)' 2 6 * 1 '.

(162 1

(29)

(164)

a, a-Difluoroaldehydes (167) were synthesized by reduction of a, a-difluorocarboxylate esters (165) using diisobutylaluminium hydride (DIBAL). The fluorinated aldehydes were isolated as their hydrates (166), which on azeotropic distillation with benzene afforded the free a, a-difluoroaldehydes (167) (equation 50)'28.Finally, Claisen rearrangement of the difluorovinyl ethers 169 provided the functionalized a, a-difluoroaldehyde 170 (equation 51)Iz9.

Ph 1. L DA, - 7 0 O C

F3C -0

cc14A

2 . ~ ~ 0

F

G

(51)

F

(1691

H

(170)

H. Ollgomerlzation of a-Haloaldehydes

During the preparation of a-monohaloaldehydes (86) it was generally observed that trimerization readily occurred with formation of the corresponding 1,3,5-trioxane derivatives (171). Traces of acid catalyse the trimerization (equation 52)36*37. The reaction is reversible and the a-haloaldehydes can be easily regenerated from the 1,3,5-trioxanes by heating the trimers at 100-150°C. tB

R R'$H2 X

(86) X = C l , Br

hr%~$:

yx

R'

RZ

(171)

(52)

394

Norbert De Kimpe and Roland Verhe 111. REACTIVITY OF a-HALOGENATED ALDEHYDES

In analogy with the section dealing with the reactivity of a-haloketones, the reactivity of ahaloaldehydes will be discussed according to the nature of the attacking reagent. While transformations of a-haloketones have been widely used in organic synthesis, applications using a-haloaldehydes have found only limited use in synthetic procedures, although the potential value of the a-haloaldehyde as a ‘synthon’ can be recognized. Therefore, in this section emphasis will be given to valuable preparative aspects hidden in the reactions of ahaloaldehydes with various reagents, without ignoring, however, the mechanistic aspects of the reactions, which can be completely different from those observed in similar reactions of a-haloketones. A. Reactlvlty of a-Haloaldehydes Towards ONucleophiles

Alkaline hydrolysis of a-monohaloaldehydes with sodium or potassium hydroxide in water or water-dioxane mixtures gave ‘substitution’ products, i.e. a-hydroxyaldehydes (In),in low to moderate yields ( < 4O%)l3O-132. Kinetic experiments have shown that the formation of 173 was not a result of a direct substitution reaction. Instead, the reaction pathway involved a ring cleavage of an intermediate oxirane (172),formed via carbonyl addition and intramolecular nucleophilic substitution (equation 53)’ 33. 0

I

(86)

(53)

(172 1

(173)

Using insoluble metal hydroxides such as lead hydroxide, the reaction afforded carboxylic acids (174)via an electrophilic attack of the metal atom on the halogen followed by a simultaneous migration of the aldehyde hydrogen and cleavage of the carbonhalogen bond (equation 54)132*134.On the other hand, treatment of a, adichloroaldehydes (29)with sodium hydrogen carbonate or sodium hydroxide in water gave a-ketoaldehydes, isolated as hydrates (175),and a-hydroxycarboxylic acids (176). respectively. The latter compounds arise from a benzylic acid rearrangement of the intermediate ketoaldehydes (equation 55)135.

/-I R’-$H-C=O

H

-

R’CH2COOH

(174)

+

XPbOH

(54)

3. Synthesis and reactivity of a-halogenated aldehydes

395

on

(29) RT

RYcooH OH

50

-

00'/a (118)

In analogy with chloral, a, a-dihaloaldehydes formed stable hydrates'30, whereas with a-monohaloaldehydes the hydrates cannot be isolated but can be d e t e ~ t e d ' ~ ~In. ' an ~~. analogous reaction, treatment of a-monohaloaldehydes with sodium alkoxides in the corresponding alcohols gave a-hydroxyacetals (178).The reaction involves a nucleophilic addition, followed by intramolecular nucleophilic substitution with formation of an intermediate a-alkoxyoxirane (177), which subsequently undergoes solvolytic ring The a-alkoxyoxiranes 177 could be isolated in opening (equation 56)36-37*138-144. moderate yields when the reaction was performed with sodium alkoxides in dry diethyl e~her14.15.36.138-140,14Z . However, performing the reaction in an inert solvent could yield rearranged esters (la),in addition to methoxyoxiranes (179)(equation 57)'45.

( 8 8 )X = C I , B r OR

ROH

R2, "$OR OH 40--90%

(118)

The epoxide formation is a stereospecific reaction which gives nearly exclusively the trans compound (181) (equation 57)'46. a-Methoxyaldehydes (182), which are not accessible via a direct substitution route, could be prepared via methoxylation of the anion of a-hydroxyacetals with dimethyl sulphate followed by hydrolysis (equation 58)' 'O. The nature of the metal counter ion of the alkoxide has a dramatic influence on the outcome of the reaction. This effect has been carefully investigated using 2-chloro-2methylpropanal (183)and 2-chlorobutanal (23)14'. Whereas potassium methoxide gave results identical with those obtained with sodium methoxide, although the yields were lower, a completely different route was observed using magnesium a l k o ~ i d e s ' ~ ~ . ' ~ ~ .

Norbert De Kimpe and Roland Verhe

396

Treatment of a-chloroaldehydes with the mixed magnesium alkoxides ROMgBr resulted in the formation of a-alkoxyketones (184). These were formed via ring opening of the nonisolable a-alkoxyoxiranes 177 with migration of a hydrogen or a methyl group under the influence of the magnesium bromide present in the reaction mixture (equation 59).

R’>K..e 0

0

+

Nooma diathyl ethrr

_____*

R2

75% (179)

0

n

(SO

OMI (182)

CI

(177)

2 5 - 7 0 */a (184)

Magnesium dialkoxides gave a Tishchenko dismutation with formation of a-chloro esters (185,187) together with minor amounts of alcohols (186,188) (equation 60). On the other hand, treatment of 183 with lithium methoxide gave the Favorskii esters 189 exclusively whereas 23 afforded a mixture of 187 (70%) and 190 (30%) (equation 61). Reaction of both aldehydes with thallium ethoxide gave the Tishchenko ethyl ester analogues of 185 and 18714’. The nature ofthe reaction products formed in the reaction of a, a-dihaloaldehydes with alkoxides in the corresponding alcohol is strongly dependent on the kind of substrate, alkoxide and reaction conditions as illustrated in Table 1. Treatment of the a,adichloroaldehydes 29 with 2.5 equivalents of sodium alkoxide at room temperature (197)and 2.2-dialkoxyproduced an unseparable mixture of l,l-dialkoxyalkan-2-ones aldehydes (198),except in the case of sodium isopropoxide, which led exclusively to 1,ldiisopropoxyalkan-2-ones(197;R2 = i-Pr), albeit in lower yields’ 50-1 5 2 .

3. Synthesis and reactivity of a-halogenated aldehydes

391

0 dlethyl Mg(oMe)z ether

2

+Ma

4-

r

o

M

CI

90%

(188)

-r

I.

g

(185)

T OH O

(lee)

21 ..Mg(OMe)2/diethyl 40 other b

+

+OM@

T

CI

CI

(23)

Me Me Me Me Et i-Pr Me Me Me Me Me

1,l-Dialkoxyalkan-2-ones

2.2-Dialkoxyalkanals

(197

(198)

28 74 65 76 58 100 65

72 26

50 50 44 33

(60)

(188)

75 %

~

Me Et n-Pr i-Pr i-Pr i-Pr C-BU n-pel4' n-He~'~' Ph PhI4'

H

CI

(187)

R2

T

O

TABLE I. Reaction of a,a-dihaioaldehydesR'CCI,CHO with sodium alkoxides R20Na in alcohols'51.152

R'

o

35

24 42 0 35 50 50 56 67

H

Norbert De Kimpe and Roland Verhe

398

A plausible mechanism consists in hemiacetal (191) formation followed by deprotonation. Indeed, the anion can be trapped with dimethyl sulphate giving 192.Intramolecular nucleophilic substitution affords a very reactive a-alkoxy-a'-chlorooxirane(193), which spontaneously rearranges into a 1-alkoxy-l-chloroalkan-2-one (194). The latter in turn reacts further via another oxirane intermediate (196) or via solvolytic ring opening as reported earlier with l-aryl-2,2-dichloroalkan-l-ones (equation 62)' 53.

R1$.

rc

OR2

R1$

CI

CI

CI

R'ONa

CI

CI

(29)

I R'ONo

-cI-

.RdpOOr

R1&. R%

R)(iOR2 R20

I\

CI

(192)

CI

R20

OMa

R1&,

Re=Me

&,R 1

&,R 1

OR2

0

OH

0

P

CI

OR2

OR2

The reaction of a, a-dichloroaldehydes (29)with sodium alkoxides has been successfully applied in the synthesis of a-ketoacetals, which are important synthons in organic synthesis' 54. Selective hydrolysis of 2,2-dialkoxyalkanals (198) from the mixture of (197). Higher 197 and 198 with 10% phosphoric acid afforded l,l-dialkoxyalkan-2-ones yields of the latter compounds were obtained in a one-pot procedure involving treatment with thionyl chloride of the reaction mixture of the a, a-dichloroaldehydes with alkoxides. The resulting tetraalkoxy compounds (199) can be regioselectively hydrolysed. Acidic hydrolysis of the reaction mixture of 197 and 198 provided an elegant and fast method for the preparation of aliphatic a-ketoaldehydes (200) (equation 63)' 54. Whereas the reaction of a-monochloroaldehydes with sodium phenoxide in methanol afforded the mixed acetal201, treatment with sodium phenoxide in diethyl ether gave the substitution product 202, presumably via rearrangement of an intermediate a-

3. Synthesis and reactivity of a-halogenated aldehydes

399

phenoxy~xirane'~~. With a, a-dichloroaldehydes, mixed acetals (205) were also isolated together with reaction products (203,204) arising from attack of methoxide (equation 64)13'.

1291

1197)

(63)

OMe

0

OMe

Me0

(200)

(199)

1 .,$ OMe

0 H $2:.I

PhONo

diethyl

(27)

ether

H

R2

OPh

RIGH PhONa MaOH

CI

CI

(29)

(202)

R1& Me0

H OMe

(2031

+ &,R 1

OMe

0

( 2 0 41

+

& R,i

OPh

0 34-42 'A (205)

Treatment of a-haloaldehydes and especially a, a-dihaloaldehydes with alcohols gave the hemiacetals (191)' 5 0 . The hemiacetals derived from a, a-dichloroaldehydes can be converted into l-alkoxy-2,2-dihaloacetates(206) on treatment with acetic anhydride or acetyl chloride in the presence of pyridine, whereas addition of thionyl chloride furnished 1,2,2-trichloro-l-alkoxyalkanes (207) (equation 65)'35. On the other hand, treatment of

400

Norbert De Kimpe and Roland Verhe

a-haloaldehydes with alcohols in the presence of acids gave acetals (208)' 5 5 * 1 5 6 except when using gaseous hydrogen chloride, which caused substitution of an alkoxy by chlorine giving 209 (equation 65)'".

R%H

H

-

L

Ac,O

OR2

/

or AcCl

OAc "+OR2

CI

OR2 CI

CI

(206)

CI

(207)

OR^

(209)

a-Acyloxyaldehydes are an important class of starting materials for the synthesis of heterocycles such as furam'" and y-butyrolactones' '*. Tertiary a-monohaloaldehydes (86)were easily transformed into the corresponding a-acetoxyaldehydes (210) on reaction with sodium a ~ e t a t e ' ~ ~Secondary . ' ~ ~ . a-monohaloaldehydes, on the other hand, gave the isomeric a-acyloxyketones (211) if the reaction was performed with the sodium carboxylate in the corresponding acid anhydride'61*'62or the a-acyloxyaldehydes (212) if the ~ * ' ~ ~ 66). reaction was carried out in polar, aprotic s ~ l v e n t s ' ~(equation

3. Synthesis and reactivity of a-halogenated aldehydes 0

'IX

40 I

0

HOAs

OAc

55-85

Ve

(210)

(32)

O K 0 " 24-58

'10

(212)

The formation of the acyloxyketones 214 can be envisaged to arise from a rearrangement of an intermediate a-acetoxyoxirane (213) (equation 67)16'. a, fl-Unsaturated lactones (217) have been prepared via a similar substitution. On reaction with potassium phenylacetate (215) in the presence of 18-crown-6, a-bromoaldehydes (3)afforded the substitution product 216, which could be cyclized to a five-membered unsaturated lactone (217) on heating (equation 68)164. The action of acetate anion on a-haloaldehydes (218) can also result in elimination of hydrogen halide, giving the a, 84219) and 8, y-unsaturated aldehydes (220) (equation 69)"j5. B. Roactlvlty of a-Haloaldehydes Towards N-Nucleophiles 1 . Reaction of a-haloaldehydes with ammonia

Very few reports have dealt with the reaction of a-halogenated aldehydes with ammonia. On the other hand, the reaction of a-chlorinated aldehyde acetals with ammonia is well documented . Treatment of aryl-substituted butanals (221) with ammonia afforded pyrrole derivatives (222,223) (equation 70)'66.'67.

'

Norbert De Kirnpe and Roland Verhe

402

(213)

R'w3

R1$H AcO

0 .?.

0

Y

H

C-OAc

R1+tH RIXH R'yo -O o-("

0

0

H$ R2 "

+

Br

(3)

P

h

T

°

0 (215)

K 18-crown-6

*

R2 R$

H '

.I

T

P

0 (216)

20-90 V w (217)

h

403

3. Synthesis and reactivity of a-halogenated aldehydes

x (220)

(219)

(218)

Ar

CI

9 9 CI

(69)

CI

(222)

Ar

H

L=L

(221)

100 o c

Ar

(223)

Condensation of chloroacetaldehyde (224) with ammonia in the presence of sodium hydrogen sulphide and acetone gave rise to a thiazoline (225) which can be converted into racemic cysteine (226) by addition of hydrogen cyanide and hydrolysis (equation 71)16*.

H

NHI,

NaHS

0-10

oc

-

(224)

I

(225)

HSdCOOH

1. HCN

2 . HIO+

2. Reaction of a-haloaldehydes with primary amines

The course of the reaction of a-haloaldehydes with primary amines is strongly dependent on the reaction conditions. Condensation of a-monohaloaldehydes with primary amines in the presence of molecular sieves169or titanium tetrachloride' 70*17 ' or

404

Norbert De Kimpe and Roland Verhe

with azeotropic removal of water'" gave the corresponding a-haloaldimines (227).Using an excess of amine, the reaction products were a-aminoaldimines (228)'69, except in the case of 2-bromo-2-methylpropana1, which afforded a-aminoaldehydes (229)'73 (equation 72). NAR3 R3/$R!

H I diothyl othor/mol. R'NH, alovoa

R2

R$'H R2

-50 o c

NHR'

X

30-80

(227)

(228)

t

t

diothyl othor mol. siovoa

-50 OC

'1s

R2

" A (86)

diothyl othor/mol. r i r v o a / - b O

OC

other/ 0-20

OC

or TiCl,/diothyl

(229)

172)

8-Halogenated enamines (232) were the reaction products when, for instance, achloropropanal (230) was treated with guanine (231) (equation 73)' 74.

CI

(230)

(231)

(232)

3. Synthesis and reactivity of a-halogenated aldehydes

405

and - p y r a z i n e ~ ' ~79~ *(234) ' were synA series of imidazo[1,2-a]-pyridines1 thesized by condensation and ring closure of a-haloaldehydes with 2-aminopyridines and 2-aminopyrazines (233),respectively. The reaction can be viewed as an initial displacement of halide by the amino moiety, followed by cyclization and dehydration (equation 74).

+. x

(32)

(233) 0

Br 'R

ie % (235)

(236)R e f . 182

Similar cyclizations (e.g. to 236) have been observed on treatment of 3-methylwith a-monohaloaldehydes (equation 74). guanine'" and guanosine (235)'81*182 3. Reaction of a-haloaldehydes with secondary arnines

Reaction of secondary amines with a-haloaldehydes is strongly dependent on the substitution pattern of the aldehyde (secondary or tertiary aldehyde), the nature of the halogen atom and the reaction conditions. Reaction of secondary a-chloro- and a-bromoaldehydes with secondary amines at room temperature gave rise to a-aminoketones (237)via rearrangement of an intermediate a - a m i n ~ e p o x i d e ' ~ ~ -If' ~the ~ . same reaction was conducted under carefully controlled conditions using a-bromoaldehydes at - 10 "C in diethyl ether, a-aminoaldehydes (238) were isolated as reaction productsla6. In addition, tertiary a-haloaldehydes always showed the formation of substitution products (241)'87.Reaction of a-fluoroaldehydes with amines involved attack on the carbonyl function with formation of fluorinated enamines (240)via intermediate aminals (239)'88(equation 75). The formation of both the 1-aminoalkan-Zones (237)and a-aminoaldehydes (238)can be explained by rearrangement of an intermediate a-aminoepoxide (242).On migration of a hydride, 242 afforded ketones whereas migration of the amino function furnished aldehydes (equation 76). Reaction of secondary a-haloaldehydes with an excess of amines gave 1,1,2-triamines (243) which, on heating and hydrolysis, furnished enediamines (244) and aaminoaldehydes (238),respectively. The reaction should be conducted under carefully controlled conditions as a-aminoaldehydes easily isomerize to a-aminoketones (237) (equation 7 7 ) l 5 5 . 1 8 6 . 1 8 9 . 1 9 0

Norbert De Kimpe and Roland Verhe

406

R +H '

X

rI

-10

R' Y

N

R

:

0

(237)

*c

diethyl ethor

I

H

NR;

(238)

(239) X=F

(75)

(240) X=F

The action of 1,2-bis(alkylamino)ethanes(245) on a-haloaldehydes afforded exclusively the corresponding cyclic aminals (246). The latter can be converted into pyrazine derivatives (247) by treatment with potassium tert-butoxide in tert-butanol (equation 77)19'. On treatment ofa, B-dibromoaldehydes (248) with stoichiometric amounts ofsecondary amines, the corresponding disubstitution products, i.e. a, p-diaminoaldehydes (249), were formed after hydrolysis of the crude reaction mixture. At room temperature the latter are transformed into a-amino-a, /%unsaturated aldehydes (250) and/or 1,2bis(alky1amino)ethenes(251). Using an excess of the amine, B, y-diaminoenamines (252) could be obtained (equation 78)192. A plausible reaction mechanism involving iminium salts (253)is outlined in equation 79. A general synthesis of fl-haloenamines (240) involved either the reaction of aor their reaction with secondhaloaldehydes with tris(N, N-dialkylamino)arsines193-196 ary amines in the presence of metal chlorides (AsCI,, SbCl,, BiCI,, FeCI, and TiCI,) a-Haloaminals are available from a-haloaldehydes: one a(equation 80)82.194. fluoroaminal was obtained by direct amination"' and a-chloro and a-bromo compounds by the AsCI,-HNRZ m e t h ~ d ' ~ ~ . ' ~ ~ . ' ~ ' .

3. Synthesis and reactivity of a-halogenated aldehydes

/ii

407

(242)

Rz = H

(237)

(241)

a-Cyanoenamines (255) were formed when brominated aldehydes were allowed to react with secondary amines in the presence of sodium cyanide. The intermediate brominated uaminonitriles (254) afforded the enamines (255) on reaction with triethylamine (equation

gO)198.199.

4. Reaction of u-haloaldehydes with tertiary arnines

Dehydrohalogenation with tertiary amines such as triethylamine, pyridine or collidine of a-monohalo- and a, a-dihaloaldehydes could be an excellent procedure for the

Norbert De Kimpe and Roland Verhe

408

synthesis of a, P-unsaturated and a-halo-a, /%unsaturated aldehydes. Unfortunately, most attempts provided unsatisfactory results and only 1-bromocyclohexane carboxaldehyde (19)’0°, 2-chloro-3-(phenylthio)aldehydessuch as 25720l q 2 0 2and a, 8-dibromoaldehydes (248)’03 on treatment with diethylaniline and triethylamine, respectively, generated the corresponding a, 8-unsaturated aldehydes in acceptable yields (equation 81). In addition, 1,3-dimethyl-2-phenylbenzimidazoline has been found to be an efficient reagent for the mild reductive dehalogenation of a-halo aldehyde^^ ”.

20-60

Va

(244)

(238)

R’

0

R3

“3

R3

t -BuOl< -R3-N

N-R3

W

R3

(247)

(77)

409

3. Synthesis and reactivity of a-halogenated aldehydes

(240)

(249)

"'8 "xN 62-95

(262)

RigH 0

'/a

(261)

(260)

HNR:

-HI0

__.*

R ~ N

N R ~

R~N:

NR:

R:N

NR~,

(79)

Norbert De Kimpe and Roland Verhe

410

PhNEtl ____)

100

*c

75 *I*

(19)

(256)

I CI Rof.201

(257)

Br

er

5. Reaction of a-haloaldehydes with imidates, amidines and enamines

Imidazoles (261,263) have been prepared from a-haloaldehydes via cyclocondensation Pyrrole dicarboxylate esters (265) have been with imidates (260)204and amidines (262)205. obtained using the enamine (264) derived from dimethyl acetonedicarboxylate and ethan~larnine~~~~~~'.

41 1

3. Synthesis and reactivity of a-halogenated aldehydes NH.HCI

N-

40-50

(260)

-/a

(261)

6. Reaction of a-haloaldehydes with arnides. thioarnides and isocyanates

Cyclocondensation of a-haloaldehydes with amides and thioamides (266)provided a of oxazoles (267)and thiazoles (269)respectively general p r o c e d ~ r e ~for ~~ the* synthesis ’~~ (equation 83). In a similar way, a-haloaldehydes are easily converted into a-aminooxazoles and -thiazoles (271)via condensation with urea’ lo and thiourea derivatives (270)211-21’, respectively. On the other hand, reaction of chloroacetaldehyde (224)with the thioformamide 272 provided the thiazine 273 (equation 83)’ 14, while reaction of 32 with N-alkyldithiocarbamic acid salts (274)or methyl N-alkyldithiocarbamates gave thiazoline-2-thiones (275)(via intermediate hydroxythiazolidinethiones) or 2-methylthiothiazolium salts, respectively’ ’5 * 2 1 6 . Finally, cycloaddition of monoisocyanates of PI1’acids (276)afforded the P-containing heterocyclic compounds 277’l’ (equation 83).However, reaction of z, adichloroaldehydes with primary amides did not give ring closure but instead the addition products 278 were isolated. These can be dehydrated to the corresponding aldimines (279) (equation 84)218.219. 7. Reaction of a-haloaldehydes with carbonyl reagents

Reaction of 2, 4-dinitrophenyIhydra~ine”~*”~ or alkoxycarbonylhydrazines”’ with ahaloaldehydes gave only the corresponding hydrazones under carefully controlled conditions. Otherwise, depending on the temperature, solvent, acidity and

Norbert De Kimpe and Roland Verhe

412

V

R

y

L

+

H

X

(266)

(32)

(267) Y=O,S HO

0

H

(269) R e f . 209

(268)

(224)

V

+

R + .’ X

(270)

(32)

CI

H

H

(271) Y=O,S

-

(83) OH

EtOOC

COOEt

As-- kLs R’

1. E t O H

R3 NH

I

(224)

(476)

3. Synthesis and reactivity of a-halogenated aldehydes

41 3

aldehyde: reagent ratio the initially formed 2,4-dinitrophenylhydrazones (280) can undergo dehydrohalogenation to 281, substitution of the halogen by the anion derived from the solvent (alkoxide, acetate) to give 282 or osazone (284) formation (equation

85)3 7 . 2 2 3 , Z 2 4

R17& CI

1 . SOCI)

A

(29)

In an identical procedure, a-bromoaldehydes (286) have been converted into z,/Iunsaturated aldehydes (288) by the action of N, N-dimethylhydrazine (equation 861225. Other examples and leading references concerning the reactions of a-haloaldehydes with hydrazines, oximes and related reagents have been included in the chapters on ahaloimines. C. Reactivity of a-Haloaldehydes Towards S-Nucleophlles

a-Sulphenylated aldehydes (289) are the most commonly encountered reaction products when a-monohaloaldehydes are treated with metal thiolates, (R3S),M202*226-23'. Under appropriate conditions nearly quantitative yields can be obtained (equation 87)202,231.267. Secondary a-sulphenylated aldehydes are easily converted into the isomeric ketones (290) on standing or on treatment with traces of acidszz'. Performing the reaction in nucleophilic solvents (water, alcohols) can lead to the formation of products arising from attack on the solvent. Therefore, the use of dimethoxyethane or tetrahydrofuran is favourable for the formation of a-sulphenylated aldehydesz3'. Reactions of a, a-dihaloaldehydes with sodium thiolates have also been investigated under various conditions. Reaction in dimethoxyethane gave rise to mono-asulphenylated (291) and/or a, a-disulphenylated aldehydes (292). When an excess of thiolate was used, the amount of the monosulphenylated product increased significantly. a, a-Disulphenylated aldehydes were isolated as the sole products on performing the reaction in water. On the other hand, performing the reaction in methanol changed the nature of the products dramatically, producing significant amounts of the rearranged ketones 293 (equation 88)231. Cyclocondensation of chloroacetaldehyde with sodium hydrogen sulphide gave 2,sdihydroxy-l,4-dithiane (294) (equation 89)z32. D. Reactivity of a-Haloaldehydes Towards C-Nucleophller 7 . Reaction of a-haloaldehydes with cyanide

The reaction of cyanide ion with a-haloaldehydes occurs by a variety of reaction pathways, which are mainly influenced by the substitution pattern of the aldehyde. Two

Roland Verhe and Norbert De Kimpe

414

H-:B

+

R2 " > r XH

-

ArNHNH2

R+rr

R2 R$f-ArX

H

R

iH

-OR

NHAr

(285)

(281) /aH Ref. 2 2 4

Rk Ref.37

,NHAr

OR Ar /N\

NH2

(283)

I

(284)

(282)

415

3. Synthesis and reactivity of a-halogenated aldehydes

H R

3

Br

(286)

x (86)

MO~NNH~

9

,

H

R3

-

(290)

(289)

DME

R

H

R3

I

F

R3

H

+

&,1R

R3S

(87)

H SR3

(29)

(291)

competitive routes give cyanooxiranes (297) or esters (296). However, when the reaction medium is not basic enough, cyanohydrins (298) are isolated. With primary and tertiary aldehydes the sole reaction products were the esters 2% and the cyanooxiranes 297, respectively, whereas with secondary aldehydes a mixture of both reaction products was

Norbert De Kimpe and Roland Verhe

416

If the reaction was formed when the reaction was carried out in aqueous performed in methanol, methyl esters (180) were isolated (equation

NaSH

H

He0

HO 04 %

(224)

(294)

R'

CN CI

-

R'R1$H CI

(27)

CI

(295)

(297)

''$

R2

CI

(27)

"$- xlMa MoOH

H -

-CN MaOH

R'

CN

R'

(295)

R'

(180)

a, a-Dihaloaldehydes on treatment with cyanide ion react by an identical mechanism and, depending on the nature of the aldehyde and the solvent, a-chloroesters (307), achloroacyl cyanides (299) and a-chloro-a-cyanoketones (301, 304,306) are formed, the latter compounds being generated from intermediate cyanooxiranes (300)(equation 91)17.135.

[

3. Synthesis and reactivity of a-halogenated aldehydes

___, -CN

R$.

CI

R$

CN

H2O

CI

cI

Rof.135

cI

417

"+CN CI

(299)

(29) R'=Et, Pr

CN

4 R o f . 235

CI

CI

0C

Br troce

(302)

(303)

H

A -C H2O N R d . 235

H -

CI

CI

MoOH R o t . 135

(304)

ph+CN

0

CI

N

Norbert De Kimpe and Roland Verhe

418

On the other hand, 2-(trimethylsiloxy)-2-alkenenitriles(309) can be synthesized via reaction of a-haloaldehydes with trimethylsilyl cyanide and subsequent dehydrohalogenation of the cyanohydrins (308)(equation 92)236.

$ H " R2

Me,SICN

CI

OSiMa3

R1$cN

R2

-Rrxo base

-HCI

CN

CI

40-70

(308)

%

(309)

(92) 2. Reaction of a-haloaldehydes with carbanions, enolates and ylides

The base-catalysed condensation of a-monohaloaldehydes with active methylene compounds has been investigated in depth by Takeda and coworkers and is of particular interest in the synthesis of natural products. with a dialkyl malonate in the presence of Reaction of 2-chloro-2-methylpropanal(l83) potassium carbonate provided the substitution product 310 if one equivalent of malonate was used. The y-butyrolactone 311 was obtained by reaction of 310 with a base, whereas the y-butyrolactone 312 was obtained by using an excess of malonate (equation 93)237. In

$,

H

fOOR

K CO

L

+

44-60%

(510)

la..

$T:OOR

M e O O C q m e

COOR

1

(511) COOR

(93)

419

3. Synthesis and reactivity of a-halogenated aldehydes

an analogous manner, treatment of a-haloaldehydes with potassium ethyl malonate gave the butyrolactone 314, which was transformed into avenaciolide (316)238,while reaction with potassium 1-ethyl 2-tert-butyl ethane-1, 1,2-tricarboxylate afforded canadensolide (318) (equation 94)239in a similar way. COOEt $,R 1

+

H

X

(32)

1

-H*O

%

R1 ..

0

COOEt

(3131

(314)

I

R’

COOEt

R‘

= Ca H

I ~

oR *

(94) 0

0

(315)

R’

I

OH

69%

(317) R’= n-Bu

Norbert De Kimpe and Roland Verhe

420

The reaction of 2-chloro-2-methylpropanal(183) with malonic esters, conducted in aqueous potassium carbonate, proceeded in a different way, giving the lactone 320 via ring opening of an intermediate oxirane (319) (equation 95)237. IOR

KXO.

' I

CI

70-82%

(320)

COOR

(319)

The condensation of a-haloaldehydes with j-keto esters is strongly dependent on the reaction conditions. Using sodium ethoxide in ethanol or diethyl ether or using potassium carbonate in THF, a tautomeric mixture of the substitution product 321 and the dihydrofuran 322 were obtained. This mixture equilibrated to give a 322:321 ratio of 40: 1. In contrast to reactions under non-aqueous conditions, the enolate anion attacked the carbonyl group in aqueous medium to give the butyrolactone 324, which on distillation afforded the butenolide 323. It is reasonable to consider that 323 is produced first in the reaction and then undergoes Michael addition. In aqueous alkaline solution, a-halo-amethylpropanal promptly undergoes displacement of halogen to give the a-hydroxy compound. Therefore, it is possible that the hydroxyaldehyde is the substrate undergoing the reaction240. The latter reaction sequence has been successfully applied in the preparation of pyrocin (326) and related compounds (equation 96)241. The reaction of a, a-dichloroaldehydes (29) with methyl acetoacetate established a similar course and furan derivatives (329,330) were generated via ring closure of intermediate 1,4-diketones (328) (equation 97)242. However, under similar reaction conditions, reaction of a, a-dihaloaldehydes with malonate or with cyanoacetate anions only gave the addition products (331),which were transformed into the corresponding Knoevenagel compounds (333) via successive treatment with thionyl chloride and triethylamine (equation 98)' 35. Condensation of a-haloaldehydes with pentane-2,4-dione in the presence of sodium hydride in dimethoxyethane gave the corresponding dihydrofurans (334)exclusively.If the reaction was performed with potassium carbonate in dimethoxyethane, the main products consisted of 1,4-diones (335),whereas in water a, /%unsaturated ketones (336)were isolated (equation 99)' 35. On the other hand. condensation of chloroacetaldehvde with cvclohexane-l,3-diones (337) in aqueous base formed tetrahydrobenzofuran derivatives (338), which were successively transformed into tetrahydroindoles (339) with amines (equation 100)243*244. The reaction of a,a-dihaloaldehydes with 1,3-diketones (340) in the presence of potassium carbonate in THF took a completely different course and an excellent stereospecific synthesis of @)-a, P-unsaturated ketones (341 or 342) was devel-

3. Synthesis and reactivity of a-halogenated aldehydes

I

42 1

R = M e , Ph

X

c H EtO

EtO

R

0

0

(321)

d

160 OC

I

R

U

O

91% (324)R-Me

0

0

COOEt

E

t

422

Norbert De Kimpe and Roland Verhe

/

CI

(327)

(29)

-HCIl

COOMe

COOMe

distillation

0

5 4- 6 5 % (329)

44 - 51%

(328)

(330)

R'GH +

CI CI

('OR

bosr,

R 1 ~ c o o R

Y

(331)

(29)

1

SOCI,

CI

R1$, R2

H CI

+

I

3. Synthesis and reactivity of a-halogenated aldehydes

(224 1

423

(337 1

oped242,245-246. The reaction mechanism involved the addition of the enolate across the carbonyl function followed by an intramolecular nucleophilic addition, furnishing an oxetane derivative (343). Ring opening and expulsion of a carboxylate anion gave 341 or 342. It is worth pointing out that in cases of unsymmetrical diketones (R3 # R4) the less sterically hindered carboxylate is expelled. Thus 341 or 342, with the bulkiest R3 or R4 group, is produced. When there is no significant differencein the steric hindrance of R3 and R4, mixtures of the two possible a, /%unsaturated ketones were isolated246(equation 101). Similar condensations in water led to different compounds, namely a mixture of the furans 344 and 345 (equation 102)246.

and /or

I Ri*R4

I

I

i

I R4

CI

CI

(342)

Norbert De Kimpe and Roland Verhe

424

R3

R3 OH

I

--RSCOOH

rnR3

R3

OH

(102)

0-

The behaviour of dichloroacetaldehyde (89)towards 2-acetylcyclopentanone (346)was in a striking contrast to the previous results and 5-acetyl-7,7-dichlorohept-5-enoic acid (347) has been isolated via a mechanism which has not been clearly established (equation 103)24'.

425

3. Synthesis and reactivity of a-halogenated aldehydes

Darzens-type condensations of a-haloaldehydes with methyl chloroacetate and methyl dichloroacetate in the presence of sodium methoxide turned out to be an elegant entry to the synthesis of epoxyalkanoates. Whereas the reaction of a-chloroaldehydes with methyl (349),the corresdichloroacetate (348)usually gave 2,4-dichloro-2,3-epoxyalkanoates ponding a-bromoaldehydes afforded the isomeric dichloroepoxides (350)as a result of the better nucleofugality of the bromine atom attached to the y-carbon atom of the addition intermediatez4’. Similar oxiranes (352)have been isolated from a-chloro- and a-bromo-aldehydes using methyl chloroacetate (351)but, in addition, butenolides (354)were isolated as major reaction products starting from a-bromoaldehydes (equation 104)z49.

f2>Sc

CO 0 Me

CI CI

10-1 5 ‘10

(350)

0

d& X

CI OM’

3 0 - 5 5% (349)

( 104)

II

i4 %

( 3 5 4 )R’ =R2= Me

(353)

Darzens condensations of GI, a-dichloroaldehydes with mono- and dichloroacetates also resulted in a stereospecific formation of oxiranes (355 and 356). In all cases the activated chlorine atom in the attacking nucleophile was expelled from the intermediate addition product (equation 105)135.

Norbert De Kimpe and Roland Verht

426

& R ,i

H

C I CI

(29)

H

R1$

CI CI

(348)

(29)

A versatile synthetic pathway for the preparation of b, y-unsaturated a-amino acids (359) was developed making use of Cu'-catalysed addition of ethyl isocyanoacetate to achloroaldehydes, affording 2-oxazolines (357),which in turn are transformed into 359 (equation 106)250. " e H 4-

(""

R'

04N

COOEt

I

(27)

R1YYNH2 R2

COOH

2.

0

,MIOH

' R2

NHCHO COOEt

The classical procedures utilized for Knoevenagel condensations of aldehydes with active methylene functions failed to give the desired productsz5'. However, Knoevenagel condensation of a-halo- and a, a-dihaloaldehydes using titanium(1V) chloridepyridineZS2gave halogenated a, b-unsaturated esters (360,361). In all cases the reaction occurred stereospecifically with formation of the E-isomer, except when Y = Ac, when both stereoisomers were obtained (equation 107)246. a, a-Dibromopropanal(8)could be converted into 4,4-dibromopent-2-enoic acid (363) by a Knoevenagel-type condensation using pyridine and trifluoroacetic anhydride (equation 107)253. Only a few reactions of a-haloaldehydes with Wittig reagents have been reported. From a-chloroaldehydes a stereoisomeric mixture of (E) and (Z)-a,p-unsaturated esters

3. Synthesis and reactivity of a-halogenated aldehydes

427

(365,R

= OR”)2542255 and ketones (365)254 could be synthesized using the appropriate (364), whereas with c c - b r ~ m o - ~ ~and ~ a.atriphenylphosphoranes dibromoaldehydes253~257 the E-isomers (367)were exclusively obtained. The E : Z ratio is usually higher than 1, but can be decreased using protic solvents or via addition of lithiumzs4 (equation 108).

+ COOR

H

x

x Y =COOR

CN COMe

x x

( 3611

Y

1

(107)

rco P (CF,CO),O

100%

(363)

Norbert De Kimpe and Roland Verhe

428

The Emmons-Wadsworth-Horner condensation of phosphonates with ahaloaldehydes usually afforded the corresponding a, @-unsaturated esters246*258and ketonesz59~260 in the E-configuration, except for Y = CN, when a stereoisomeric mixture of unsaturated nitriles was formed (equation 109)246. n

x (3681

X = C l ,Br

RZ=alkyl,CI

70-95%

(369)

Y =COOR,COR',CN

In contrast to the previous results, reaction of fluorenylidene triphenylphosphorane

(370)with an a-bromoaldehyde (3)gave the phosphonium salt 371 instead of the Wittig product (equation 1

B r+

A

R

2

Br

(3)

(370)

Reaction of a-haloaldehydes with a variety of anions and dianions derived from ketones, esters and cyanides has been used in chain elongation reactions with formation of homoallylic alcohols (372),bromohydrins (374),oxiranes (375),@-hydroxybutyrolactones (377)and amino acid derivatives (378)(equation 11 1). 3. Reaction of a-haloaldehydes with Grignard reagents

Organomagnesium compounds readily reacted with a-monohaloaldehydes with formation of the normally expected halohydrins (380),together with ketones (381)and their The reaction occurred via addition reaction products with Grignard across the carbonyl resulting in the halohydrin magnesium bromide salt, which is transformed into the ketone 381 via a semi-pinacol type of rearrangement involving hydrogen migration. Further reaction of 381 can give a tertiary alcohol (382),which can be successivelytransformed into an alkene derivative (383).A similar reaction giving 384took place during the reaction of 2,2-dichloropentanal with an excess of methylmagnesium iodide (equation 112)269. At low temperature (- 70 "C), however, reaction of a, a-dichloroaldehydes with Grignard reagents resulted mainly in reduction with formation of a, a-dichloroalkanols (385)together with the expected chlorohydrins (386)(equation 113)13? Direct and regioselective transformations of a-chloroaldehydes to alkenes (389)have been performed via reaction with Grignard reagents followed by treatment with lithium metal (equation 114)270-272.

3. Synthesis and reactivity of &-halogenated aldehydes

"$ H

CI(51)

R'

-

OLi

OLi

A

+

/

R -R1+cooR

O

+; !1C

1.LiAIH4

2.L1

OH

43

-5 4 %

(372) OLi

B

r

T

+

H

OLi

'' uOEt

0

(376)

(51)

(3761

co O

CI

(3731

-Br/yK\ COOEt

Ref. (I!

0

85 %

"FH <' CI

R1+

OH

+

R

429

LDA REf.263

R=COOEt,CN

.A

(374)

Rt

55 - 6 7 %

(375)

61

- 99

Vo

(377)

Norbert De Kimpe and Roland Verhe

430

1

(112)

-Hfl

R3

-"T 5 equiv.

"*H

MeMgI

CI

diethyl ether

I

CI

(29)

"fiH ."r"fi 0

OH

R e =R2MgX n-Bu,i-Pr

CI

CI

-+

OH

CI

R'=Me

R2

CI CI

CI

0-24% (386)

7 6- 100'10 (386)

(29) 0

"fi OMgBr

R2 Ri+H

R3MgBr -6OOC

*

R2

R3

x

CI

I

(387)

(27)

Li - 6 O O C

OMgBr

R

1

F

R

R

3

*

2ooc

R "+R3 2

Li

(389)

(388)

(113)

43 1

3. Synthesis and reactivity of a-halogenated aldehydes 4. Reaction of a-haloaldehydes with organocadmium compounds

The reaction of organocadmium compounds, prepared via treatment of the corresponding alkylmagnesium halides with cadmium chloride, with a, a-dichloroaldehydes turned out to possess no preparative value, as a mixture of the halohydrins (386),a-chloroketones (390) and reduction products (385) was formed135.The ratio of the reaction products is dependent on the reaction time because the halohydrin is gradually transformed into the ketone, whereas the amount of the reduction product rapidly increased with the increase in the steric hindrance of the dialkylcadmium compounds (equation 115)' 35.

Ri$

diethyl R i C dether

CI

CI

20

oc

.

R

(29)

CI

1

h

CI

CI

R

3

+

R

I

F R3

CI

(390)

+

R' CI CI (3855)

CI

5. Reaction of a-haloaldehydes with organolithium compounds

The condensation of a-haloaldehydes with alkyllithium reagents provided an excellent procedure for the preparation of halohydrins (391), which in turn were converted into oxiranes under the influence of strong The stereochemistry of the addition of n-butyllithium to a-chlorobutanal (23) has been investigated and the observed stereoselectivity (cf. 393 and 395) could be explained by a preferential attack of the reagent at the less sterically hindered site of the aldehyde (equation 116)273.

(86)

n-BuLi

(23)

-I

(391)

(392)

(393)

(394)

(395)

432

Norbert De Kimpe and Roland Verhk

Whereas the reaction ofa, a-dichloroaldehydes with methyllithium exclusivelyafforded the corresponding /3, /3-dichloroalcohols (3%), reaction with higher homologues of alkyllithium compounds gave a mixture of the dichlorohydrin (386) and the dehydrochlorination product (398) (equation 117)'35. Rf+ CI

CI

"

MeLi

HZS0.l

CI

CI

CI C I

0

'

oc

CI

(396)

(29)

diethyl R'Liether.

'

4

3+

~

CI

( 398 1

Ph-1 H

HCI

CI

PhLi

~

1

CI

(29)

%

OLi ~

3

~

(a)

R' = C H ~ R

CI

CI

(117)

R1+ph

ltd

"$PhCI

CI

( 3971

R+R3

CI (386)

CI

(29)

R$

.

R1+

CrO,

diethyl ether 0 oc

c1 "$ph

(399)

1

CI (400)

In addition, using phenyllithium the corresponding dichlorohydrins (399) were accompanied by a-chloroketones (400), formed via dehydrochlorination under the influence of the phenyl anion. Using an excess of phenyllithium, the chloroketones 400 constituted the major reaction product (equation 117)'j5. A method based on the use of an organodilithium reagent (402) was described for the synthesis of indole (403) from, chloroacetaldehyde (224) acting as a biselectrophile (equation 118)274. E. Reactlon of &-Haloaldehydeswith Phosphorus Compounds

In contrast with the halogenated ketones, which on reaction with phosphites gave rise to

Arbuzov and/or Perkow reaction products, a-haloaldehydes only exhibited the Perkow reaction with formation of vinyl phosphates (404, 405) (equation 119)'35,275-283.

The mechanism involved in the Perkow reaction is similar to that proposed for a-haloketones as described in Chapter 1. The reactivity decreases as the number of halogen atoms on the a-carbon decreases and (Ekeno1 phosphates are formed predominantly. However, the E/Z ratio is dependent on the nature of the halogen and the phosphite whereas the influence of the solvent and the temperature is negligible135~281~282.

3. Synthesis and reactivity of a-halogenated aldehydes

433

Chlorinated vinyl phosphates have found many useful applications in the field of inse~ticides'~~. It is remarkable that the brominated acetal406 reacted with triethyl phosphite to give the phosphonate 407 via an Arbuzov reaction. The latter compounds can give rise to formylphosphonates (408) via acidic hydrolysis (equation 120)285.

cl'K" 0

+

(224)

aLi I ti

0 &F3 (402)

MeLi

t-%uLi

(401

x

Rd

H

R1$

x x

OEt ( 406 1

89

(407

&) H

60'ID (403

434

Norbert De Kimpe and Roland Verhe

In contrast with the trialkyl phosphites, silyl phosphites reacted with a-haloaldehydes to form phosphonates (409)286,287. Related phosphonates (410) have been prepared from a, a-dichloroaldehydes by treatment with dialkyl p h o s p h i t e ~ ' ~while ~ , reaction of monoand dichlorophosphinites with dichloroacetaldehyde afforded 2,2-dichlorovinyl phosphites (411, 412)288. Phosphorodichloridates (413) were prepared by reaction with phosphorus pentachloride and subsequent treatment with sulphur dioxideza9, while phosphorylation with phosphoroxy and phosphorthioxy trichloride afforded the dichlorovinyl phosphates (414) (equation 121)2a8.

.Riy(." I O--S

P(OSiMe,),

H

c;I

i Me

P (OSiMe3I2

R2

(27) OSiMe3 I

9 0 -95% (409)

. ''+ "fiH HOP(OR),

CI

CI

CI

RT

0

CI

75 - 9 5'/a (410)

(29)

0 C I PR'R R3=

'

R'=CI,OEt

or R'=OEt,

*

R'=Et,N

(89)

Rf+ CI

(29)

35 - 46% (411)

OPC14

H CI

R3R4P 0 C H =C

CI

CI

+

.

E t 0 P (OC H =C C 12)2 43 % (412 1

R ' y o [ \ c l

CI

0 (413)

2

31- 35-10 (414 )

435

3. Synthesis and reactivity of a-halogenated aldehydes

In analogy with a-haloketones, alkylation of o-hydroxybenzyl triphenylphosphonium salts (415) with a-chloroaldehydes, in the presence of base, gave 2H-benzo[b]pyrans (416) (equation 122)290. + PPh3

0

1

X-

F. Reactlon of a-Haloaldehydes with Complex Metal Hydrides

Whereas treatment of a-haloaldehydes with sodium borohydrideZg1and LiA1H4314 resulted in the formation of the corresponding /%haloalcohols(417), terminal olefins (418) have been synthesized via a selective reduction of the carbonyl group using LiAlH4/AlC13 followed by treatment with lithium powder (equation 123)272. 0

-

$ H "

l.LiAIH,/AICI,

R2 X

2. Li

52-61

%

0. Reaction of a-Haloaldehydes with Organometallic Complexes

In comparison with a-haloketones, little information concerning the reactivity of ahaloaldehydes in the presence of organometallic complexes is available. The palladium-

Norbert De Kimpe and Roland Verhe

436

catalysed reaction of a-bromoaldehydes with acetonyltin (419) and allyltin (420) reagents gave the corresponding oxiranes (421, 422). However, with cr-chloroaldehydes no cyclization occurred292(equation 124). Cross-aldol reaction via tin(I1)enolates gave 425 when a-bromoaldehydes were allowed to react with aliphatic and aromatic aldehydes in the presence of tin(I1) chloride and potassium293(equation 125), whereas the reaction with the manganese complex (426) afforded trimethylsilyl enol ethers (427)294.Other /l-trialkylsilyl-fi,y-unsaturatedaldehydes (429) were formed when cc-bromoaldehydes were allowed to react with silylated acetylenes (428) and Grignard reagents in the presence of dicyclopentadienyltitanium(II1) chloride295(equation 126).

I

80 %

Br

(421)

(419)

(58)

85 %

Br

(420)

(58)

Cl

(23)

RH $"2

Sr

+

RCHO

SnClz

"

K

R2

e

H

HO 64-74

(3)

(425)

'/a

(125)

3. Synthesis and reactivity of a-halogenated aldehydes

Br

56

(58)

(426)

H

+

Bu-E--SiMe3

Br

(9)

Va

(126)

(427) R1=PhCH2

Cp2TiCl

i-0uMgX

Me3Si

(428)

45 %

(429)

(184)

437

(430)

I

(431) N(CH2CH20H),

(432) e.e.70

O/O

(S)

0

438

Norbert De Kimpe and Roland Verhe

In addition, reaction of allylic boron esters (430) with a-chloroaldehydes constitutes an enantioselective synthesis of homoallyl alcohols (432) via treatment of the intermediate boron esters (431) with triethanolamineZg6(equation 127). H. Electrophilic Reactions of aHaloaldehydes

The FriedelLCrafts reaction of a,a-dichloroaldehydes with chlorinated aromatics led to compounds analogous to DDT. For example, l,l-dichloro-2,2-bis(pchloropheny1)ethane (433), obtained by condensation of chlorobenzene and dichloroacetaldehyde, is a powerful insecticide with a lower toxicity than DDTZs4.

CI

95 Va

(433)

6

OH

uH

40 %

(434) R=H

+

CI

I

CI

(435) Lewis

acid

1

CI

(434) R=Me

(436)

+

CI

(437)

The FriedelLCrafts reaction of 434 with c y c l o h e x e n e ~and ~ ~ ~methallyl chloride2'* furnished the carbonyl addition products (435-437) (equation 128). Reaction of a, a-dichloroaldehydes with acrylonitrile in the presence of a copper(1)

3. Synthesis and reactivity of a-halogenated aldehydes

439

chloride catalyst gave the chlorinated nitriles (438), which can be transformed to chlorinated pyridine derivatives (439) by heating (equation 129)299.300.

CuCl-PPh3

H +”

+

CI

A

C

N

200

catalyst

R’

oc

(29)

i

170 O C

(439)

Exposure of brominated phenylacetaldehydes to fluorosulphonic acid did not result in aldol condensation or cyclotrimerization, but gave instead a bimolecular reaction with formation of a bicyclic compound (441) together with a minor amount of 9-anthrylaldehyde (442)301.The mechanism of this particular reaction is outlined in equation 130. Treatment of a-bromocyclohexanecarboxaldehyde (19) with sulphur tetrafluoride in the presence of potassium fluoride afforded a mixture of the fluorinated cycloalkanes (443,444). Subsequent dehydrohalogenation of 443 with potassium hydroxide gave rise to the difluorocyclohexene (445) and difluoromethylidenecyclohexane (446) (equation 131)302. a, P-Unsaturated aldehydes were obtained in high yields when a-chloroaldehydes were treated with lithium perchlorate and calcium carbonate in hexamethylphosphoric triamide”. Enolate formation occurred when a-haloaldehydes were treated with triethylamine in the presence of trimethylchlorosilane to yield the corresponding trimethylsilyl enol ethers 44749*303*304 or with potassium hydride in the presence of I-acetyl-b(N, N dimethy1amino)pyridinium chloride to give the enol acetates (448) (equation 132)305. 1. Cycloaddition Reactions of a-Haloaldehydes

a-Haloaldehydes have been used in cycloaddition reactions with a variety of dienophiles. Addition of a, a-dibromo- or a-bromoacetaldehyde across 1,1,2-trichloro-4morpholinobut-1-en-3-yne (449) resulted in a stereospecific synthesis of (Z)-penta-l,3dienes (451)306,while Diels-Alder reaction of a-chlorobutanal with 2-azabuta-l,3-dienes such as 452 afforded 1,3-0xazines (453) (equation 133)307. Using a q ~ i n i d i n e - ~ ~ ~or* ~b’r’u c i n e - ~ a t a l y s e dcycloaddition ~~~ reaction of a, adichloroaldehydes with ketene, an excellent procedure has been developed for the preparation of chiral 4-substituted 2-oxetanones (454). The latter compounds served as excellent precursors for several optically pure (S)-methyl 3-hydroxyalkanoates (456)309 (equation 134).

phy!-(H ____, phqoy Norbert De Kimpe and Roland Verhe

440

FSO,H

Br

Br

P

h

d

Br

B

r

F ' h $ o v P h

0

Br

Br

C-alkylation

,VPh H*

+OH

.$'

Br6

Br

21 %

(441)

\

(440)

0 - H

CHO

5% (442)

CHO

Br

3. Synthesis and reactivity of a-halogenated aldehydes F

I

L

y

H

+ 2 0 o (c

y 14 % (443)

(19)

KOH

F

55 % (444)

I

HOCH2CH20H

30 V n

49 %

(4 4 5 )

(446)

x X=CI, B r ,

X=CI

I

50-70

'/*

(447)

1

KH

0

M e 2 N 9 - A c

CI-

R'\

I

CI

75 %

(448)

44 1

Norbert De Kimpe and Roland Verhe

442

CI

+

__

X

CI

X=H,

Br

(449)

28-40 (451)

Vo

* kh

R = C H 2 B r , CHBr2

^jl, + T N y BF,. E t 2 0

Ph

C6H6

CI

Ph

Ph

$

Me

CI

Rlg 78 010

!453)

(452)

(23)

+

$H '.

-

CH2=C=0

or qburi u n ci di ni nes

CI

CI

(133)

CI

67-96 % (454)

(29)

I

HCI MeOH

R

'

L

C

O

O

M

83-87 % (456) e . e . > 98%

e

K,CO, H 2 / P d /MEOH /C

Rl+coOM CI

CI 75--80

(455)

e

'10

(134)

3. Synthesis and reactivity of a-halogenated aldehydes

443

IV. REFERENCES

1. E. Miiller, in Houben- Weyl: Methoden der organischen Chemie, Band V I I j l .Sauerstoffverbindungen I I , Georg Thieme, Stuttgart, 1954, p. 362. 2. A. Kirrmann, Bull. SOC. Chim. Fr., 657 (1961). 3. F. I. Luknitskii, Chem. Rev., 75, 259 (1975). 4. R. Jira, E. Kopp and W. Moellering, in Ullmanns EncyklopGdie der Technischen Chemie. (Eds. E. Bartholome, E. Biekert and H. Hellmann), 4 Aufl., Band 9, Verlag Chemie, Weinheim, 1975, p. 373. 5. A. Roedig, in Houben- Weyl: Methoden der organischen Chemie, Band VJ4.Halogenverbindungen, Georg Thieme, Stuttgart, 1960, p. 164. 6. R.Stroh, in Houben- Weyl: Methoden der organischen Chemie, Band VJ3.Halogenverbindungen, Georg Thieme, Stuttgart, 1962, p. 611. 7. A. Stepanov, N. Preobrashinski and M. Shuchukina, Chem. Ber., 59, 2533 (1926). 8. R. Dworzak and E. Enenkel, Monatsh. Chem., 52, 141 (1929). 9. J.-J. Riehl, C.R. Acad. Sci., Ser. C, 245, 1321 (1957). 10. E. Erlenmeyer and J. P. Jung, Helu. Chim. Actn, 32, 37 (1949). 11. M. Poite and J. Metzger, Bull. SOC.Chim. Fr., 2084 (1962). 12. V. Kravets, G. Chervenyuk and G. Grinev, Zh. Org. Khim., 7, 1244 (1966). 13. P. Duhamel, L. Duhamel and J.-Y. Valnot, Bull. SOC.Chim. Fr., 1465 (1973). 14. A. Mori, M. Porzio and L. Schaleger, J . Am. Chem. SOC.,94, 5034 (1972). 15. C. Stevens and B. Gillis, J . Am. Chem. Soc., 79, 3448 (1957). 16. M. N. Shchukina, Zh. Obshch. Khim., 18, 1653 (1948); Chem. Abstr., 43, 2575b (1949). 17. D. Ricard and J. Cantacuzene, Bull. SOC. Chim. Fr., 628 (1969). 18. R. G. Pews and 2. Lysenko, Synth. Commun., 15, 977 (1985). 19. L. A. Yanovskaya and A. P. Terent’ev, Zh. Obshch. Khim., 22, 1598 (1952); Chem. Abstr., 47, 9258f (1953). 20. L. Birkofer and W. Quittmann, Chem. Ber., 118,2874 (1985). 21. A. Bongini, G. Cainelli, M. Contento and F. Manescalchi, Synthesis, 143 (1980). 22. A. Akelah, M. Hassanein and F. Abdel-Gabl, Eur. Polym. J., 20, 211 (1984). 23. R. Bloch, Synthesis, 140 (1978). 24. G. Grundke, W. Keese and M. Rimpler, Chem. Ber., 118,4288 (1985). 25. E. Armani, A. Dossena, R. Marchelli and G. Casnati, Tetrahedron, 40,2035 (1984). 26. F. Bellesia, F. Ghelfi, R. Grandi and U. M. Pagnoni, J . Chem. Res. (9,428 (1986). 27. P. Hofmann, L. A. Perez Moya and I. Kain, Synthesis, 43 (1986). 28. H. Guinot and J. Tabeteau, C.R. Acad. Sci., Ser. C , 231, 234 (1950). 29. A. Krattiger, Bull. SOC.Chim. Fr., 222 (1953). 30. K. Bott, Chem. Ber., 108, 402 (1962). 31. US Pat., 4096 187 (1978); Chem. Abstr., 89, 196960 (1978). 32. Rom. Pat., 78437 (1982); Chem. Abstr., 99, 139328 (1983). 33. C. R. Dick, J . Org. Chem., 27, 272 (1962). 34. L. De Buyck, R. VerhB, N. De Kimpe, D. Courtheyn and N. Schamp, Bull. SOC.Chim. Belg., 89, 441 (1980). 35. Jpn. Pat., 58 172337 (1982); Chem. Abstr., 100, 57841 (1984). 36. C. L. Stevens, E. Farkas and B. Gillis, J . Am. Chem. SOC.,76, 2695 (1954). 37. US Pat., 4489098 (1984); Chem. Abstr., 102, 108251 (1985). 38. H. Brown and A. Ash, J . Am. Chem. SOC.,77,4019 (1955). 39. C.-H. Wong, F. P. Mazenod and G. M. Whitesides, J . Org. Chem., 48, 3493 (1983). 40. U. Hertenstein, Angew. Chem., 94, 548 (1982). 41. US Pat., 3804645 (1974); Chem. Abstr., 80, 145416 (1974). 42. A. Lorenzini and C. Walling, J . Org. Chem., 32, 4008 (1967). 43. S. A. Godleski and E. B. Villhauer, J . Org. Chem., 49, 2246 (1984). 44. A. Bongini, G. CaineIIi, M. Contento and F. Manescalchi, J . Chem. SOC.,Chem. Commun., 1278 (1980). 45. F. Bellesia, F. Ghelfi, R. Grandi and U. M. Pagnoni, J . Chem. Res. (S), 426 (1986). 46. A. J. Fry and Y. Migron, Tetrahedron Lett., 3357 (1979). 47. J. Barluenga, J. M. Martinez-Gallo, C. Najera and M. Yus, Synthesis, 678 (1986). 48. P. Groenewegen, H. Kallenberg and A. van der Gen, Tetrahedron Lett., 2817 (1979). 49. J.-M. Poirier, Org. Prep. Proced. Int., 18, 79 (1985).

444

50. 51. 52. 53. 54.

Norbert De Kimpe and Roland Verhe

S. V. Anatakrishnan and C. K. Ingold, J . Chem. Soc., 1396 (1935). E. P. White and P. W. Robertson, J . Chem. SOC.,1509 (1939). Br. Pat., 576435 (1946); Chem. Abstr., 42, 2268b (1948). V. L. Heasley, D. Spaite, D. F. Shellhamer and G. E. Heasley, J . Org. Chem., 44,2608 (1979). V. L. Heasley, D. F. Shellhamer, T. L. Carter, D. E. Gipe, R. K. Gipe, R. C. Green, J. Nordeen, T. D. Rempel and D. W. Spaite, Tetrahedron Lett., 22, 2467 (1981). 55. Y. V. Migalina, S . V. Calla-Bobik, V. G. Lendel and V. I. Staninets, Zh. Obshch. Khim.,52,1563 (1982); Chem. Abstr., 97, 162474 (1982). 56. US Pat., 3 259641 (1966); Chem. Abstr., 65, 8763%(1966). 57. C. Moureu, M. Murat and L. Tampier, Bull. SOC.Chim. Fr., 31 (1921). 58. V. L. Heasley, K. E. Wade, T. G. Aucoin, D. E. Gipe, D. F. Shellhamer and G. E. Heasley, J . Org. Chem., 48, 1377 (1983). 59. F. Chattaway, H. Irving and G. Outhwaite, J . Chem. SOC.,993 (1933). 60. US Pat., 2 351 OOO (1944); Chem. Abstr., 38, 5226' (1944). 61. G. A. Ropp, W. E. Craig and V. Raaen, Org. Synth., Coll. Vol. IV, 130 (1963). 62. A. Roedig, F. Hagedorn and G. Markl, Chem. Ber., 97, 3322 (1964). 63. Y. G. Bal'on and M. D. Shul'man, Zh. Org. Khim., 12,1973(1976);Chem. Abstr., 86,55099(1977). 64. J. M. Domagala and R. D. Bach, J . Org. Chem., 44,3168 (1979). 65. P. J. De B i k e , G. P. Van der Kelen, G. Cornille and Z . Eeckhaut, Bull. SOC.Chim. Belg., 68,550 (1959). 66. D. A. White and J. P. Coleman, J . Electrochem. SOC., 125, 1401 (1978). 67. A. Pinner, Chem. Ber., 5, 147 (1872). 68. A. Kirrmann, Ann. Chim., 11, 323 (1929). 69. P. Chancel, Bull. SOC.Chim. Fr., 714 (1950). 70. E. Marvel1 and M. Joncich, J . Am. Chem. SOC., 73, 973 (1951). 71. J. Johnson, A. Larsen, A. Holley and K. Gerzon, J. Am. Chem. SOC.,69, 2364 (1947). 72. E. Alexander, J. Am. Chem. SOC.,70, 2592 (1948). 73. Ger. Pat., 639507 (1936); Chem. Abstr., 31, 3940 (1937). 74. S. McElvain and P. Waltero, J . Am. Chem. SOC.,64, 1963 (1942). 75. Czech. Pat., 217 162 (1985); Chem. Abstr., 103, 123708 (1985). 76. A. Madinaveita and J. Puyol, An. SOC.Esp. Fis. Quim.,16, 329 (1918). 77. E. Filachione, J. Am. Chem. SOC.,61, 1705 (1939). 78. P. Bedoukian, J. Am. Chem. SOC.,66, 1325 (1944). 79. R. Tiollais, H. Bouget, J. Huet and A. Le Pennec, Bull. SOC.Chim. Fr., 1205 (1964). 80. R. H. Reuss and A. Hassner, J . Org. Chem., 39, 1785 (1974). 81. S. T. Purrington, N. V. Lazaridis and C . L. Bumgardner, Tetrahedron Lett., 27, 2715 (1986). 82. L. Duhamel, P. Duhamel and J.-M. Poirier, Tetrahedron Lett., 4237 (1973). Poirier, Bull. SOC.Chim. Fr., 11, 18 (1982). 83. J.-M. 84. R. Verhk, N. De Kimpe, L. De Buyck and N. Schamp, Synthesis, 455 (1975). 85. H. Bredereck, K. Biihler, K. Posselt, T. Haug and H. Sonneborn, Chem. Ber., 102,2190(1969). 86. F. Bellesia, R. Grandi, U. Pagnoni and A. Pinetti, J . Chem. Res. (S),16 (1983). 87. J.-J. Riehl and F. Jung, C.R. Acad. Sci., Ser. C , 270, 2009 (1970). 88. J. Swietoslawski and A. Silowiecki, Rocz. Chem., 50,375 (1976);Chem. Abstr., 85,45914 (1976). 89. I. Zhmurova and B. Drach, Zh. Obshch. Khim., 34, 3055 (1964). 90. G. R. Malone and A. I. Meyers, J . Org. Chem., 39, 618 (1974). 91. A. Kirrmann, P. Duhamel and M. R. Nouri-Bimorghi, Justus Liebigs Ann. Chem., 691,33(1966). 92. A. Kirrmann, P. Duhamel and M. R. Nouri-Bimorghi, Bull. SOC.Chim. Fr., 3264 (1964). 93. P. Duhamel, L. Duhamel and J. Gralak, C.R. Acad. Sci., Ser. C , 269, 1658 (1969). 94. P. Duhamel, L. Duhamel and J. Gralak, Bull. SOC.Chim. Fr., 3641 (1970). 95. R. N. McDonald and R. C. Cousins, J . Org. Chem., 45, 2976 (1980). 96. J. Gralak and J.-Y. Valnot, Org. Prep. Proced. Int., 11, 107 (1979). 97. A. Kirrmann and M. R. Nouri-Bimorghi, Bull. SOC.Chim. Fr., 3213 (1968). 98. G. Kobrich and W. Werner, Tetrahedron Lett., 2181 (1969). 99. H. Taguchi, S. Tanaka, H. Yamamoto and H. Nozaki, Tetrahedron Lett., 2465 (1973). 100. R. Nouri-Bimorghi, Bull. SOC. Chim. Fr., 2812 (1969). 101. K. Griesbaum, H. Keul, R. Kibar, B. Pfeffer and M. Spraul, Chem. Ber., 114, 1858 (1961). 102. J. Villieras, C. Bacquet, D. Masure and J. F. Normant, J . Organomet. Chem., 50, 7 (1973). 103. J. Cantacuzene and D. Ricard, Bull. SOC.Chim. Fr., 1587 (1967).

3. Synthesis and reactivity of a-halogenated aldehydes

445

104. F. de Reinach-Hirtzbach and T. Durst, Tetrahedron Lett., 3677 (1976). 105. T. Durst, K.-C. Tin, F. de Reinach-Hirtzbach, J. M. Decesare and M. D. Ryan, Can. J . Chem., 57, 258 (1979). 106. J.-P. BCgue, D. Bonnet-Delpon, M. Charpentier-Morize and J. Sansoulet, Can. J . Chem., 60, 2087 (1982). 107. K. Griesbaum, P. M. Scaria and T. Dohling, J . Org. Chem., 51, 1302 (1986). 108. J.-J. Riehl, P. Casara and A. Fougerousse, C.R. Acad. Sci., Ser. C, 279, 79 (1974). 109. J.-J. Riehl, P. Casara and A. Fougerousse, C.R. Acad. Sci., Ser. C , 279, 113 (1974). 110. K. Griesbaum and G. Zwick, Chem. Ber., 118, 3041 (1985). 111. G. A. Kraus and P. Gottschalk, J . Org. Chem., 48, 21 11 ( 1 983). 112. J. Villieras and M. Rambaud, Synthesis, 644 (1980). 113. J. Villieras, M. Rambaud, B. Kirschleger and R. Tarhouni, Synthesis, 68 (1981). 114. J. Villieras, B. Kirschleger, R. Tarhouni and M. Rambaud, Bull. SOC.Chim. Fr., 470 (1986). 1 1 5 . J. Villieras, P. Perriot and J. F. Normant, Synthesis, 968 (1979). 116. J. Villieras, M. Rambaud, B. Kirschleger and R. Tarhouni, Bull. SOC.Chim. Fr., 837 (1985). 117. H. C. Brown, G. W. Kabalka, M. W. Tathke and M. M. RogiC, J . Am. Chem. SOC.,90, 5709 (1968). 118. C. Chuit, R. Sauvitre, D. Masure and J. F. Normant, Tetrahedron, 35, 2645 (1979). 119. R. F. Heck, J . Am. Chem. SOC.,90, 5538 (1968). 120. J.-M. Poirier, L. Hennequin and M. Fomani, Bull. SOC.Chim.Fr., 436 (1986). 121. G. Capozzi, C. Caristi, V. Lucchini and G. Modena, J . Chem. Soc., Perkin Trans. I , 2197 (1982). 122. G. Capozzi, G. Romeo, V. Lucchini and G. Modena, J . Chem. SOC.,Perkin Trans. I , 831 (1983). 123. Y. Satoh, T. Tayano, H. Koshino, S . Hara and A. Suzuki, Synthesis, 406 (1985). 124. K. G. Migliorese, E. H. Appelman and M. N. Tsangaris, J . Org. Chem., 44,1711 (1979). 125. A. Hassner and A. B. Levy, J . Am. Chem. SOC.,93, 5469 (1971). 126. R. E. White, M. B. Nazareno, M. R. Gleissner and P. Kovacic, J . Org. Chem., 38, 3902 (1973). 127. H. C. Brown and B. Subba Rao, J . Am. Chem. Soc., 80,5377 (1958). 128. B. Erni and H. G. Khorana, J . Am. Chem. SOC.,102, 3888 (1980). 129. B. W. Metcalf, E. T. Jarvi and J. P. Burkhart, Tetrahedron Lett., 26, 2861 (1985). 130. R. Dworzak and P. Pfifferling, Monatsh. Chem., 48, 251 (1927). 131. S. Danilow and E. Venus-Damilowa, J . Chem. Phys. (URSS), 18, 1816 (1948). 132. A. Kirrmann, P. Chancel, M. Vignalon and P. Federlin, Bull. SOC.Chim.Fr., 707 (1950). 133. A. Kirrmann, P.Federlin, A. Krattinger and T. Yvernault, Bull. SOC. Chim. Fr., 1288 (1954). 134. A. Kirrmann and A. Krattiger, Bull. SOC.Chim. Fr., 225 (1953). 135. R. Verhe, unpublished results. 136. P. Federlin, C.R. Acad. Sci., Ser. C , 235, 44 (1952). 137. A. Kirrmann and P. Federlin, Bull. SOC. Chim. Fr., 944 (1958). 138. A. Kirrmann and J.-J. Riehl, C.R. Acad. Sci., Ser. C , 243, 808 (1956). 139. A. Kirrmann, R. Muths and J.-J. Riehl, Bull. SOC.Chim. Fr., 1469 (1958). 140. C. Stevens, W. Malik and R. Pratt, J . Am. Chem. SOC.,72,4758 (1950). 141. H. Keul, B. Pfeffer and K. Griesbaum, Chem. Ber., 117, 2193 (1984). 142. A. L. Mori and L. L. Schaleger, J . Am. Chem. SOC.,94, 5039 (1972). 143. C.-H. Wong, F. P. Mazenod and G. Whitesides, J . Org. Chem., 48,3493 (1983). 144. K. Griesbaum, G. 0. Lie and H. Keul, J . Org. Chem., 49,679 (1984). 145. A. Kirrmann and H. I. Joschek, Bull. Soc. Chim. Fr., 2483 (1963). 146. J.-J. Riehl and L. Thil, Tetrahedron Lett., 1913 (1969). 147. A. Kirrmann and F. Druesne, Bull. SOC.Chim. Fr., 1098 (1964). 148. A. Kirrmann and R. Hamelin, C.R. Acad. Sci., Ser. C, 251, 2990 (1960). 149. R. Hamelin, Bull. SOC. Chim. Fr., 919 (1961). 150. A. Fougerousse and J.-J. Riehl, Tetrahedron Lett., 3593 (1973). 151. R. Verhe, N. De Kimpe, L. De Buyck, C. Swyngedouw,D. Courtheyn and N. Schamp, European Symposium on Organic Chemistry I, Koln, FRG, 1979, Abstracts, p. 406. 152. R. Verht, L. De Buyck, N. De Kimpe, D. Courtheyn and N. Schamp, 5th IUPAC Conference on Physical Organic Chemistry, Santa Cruz (USA), 1980, Abstracts, p. 147, No. P68. 153. N. De Kimpe, R. Verhe, L. De Buyck and N. Schamp, J . Org. Chem., 45, 2803 (1980). 154. R. Verhk, D. Courtheyn, N. De Kimpe, L. De Buyck and N. Schamp, Synthesis, 667 (1982). 155. L. Duhamel, P. Duhamel and R. Nouri-Bimorghi, Bull. SOC.Chim. Fr., 1186 (1967). 156. M. Okabe and M. Tada, J . Org. Chem., 47, 5382 (1982).

Norbert De Kimpe and Roland Verhe

446 157. 158. 159. 160. 161. 162. 163. 164. 165. 166. 167. 168. 169. 170. 171. 172.

H. Siege1 and W. Himmele, Angew. Chem.. Int. Ed. Engl., 19, 1780 (1980). J. P. Corbet and C. Benezra, Tetrahedron Lett., 4003 (1979). J.-J. Riehl, C.R. Acad. Sci., Ser. C , 255, 725 (1962). J.-J. Riehl, P. Casara and A. Fougerousse, C.R. Acad. Sci., Ser. C , 279, 113 (1974). J.-J. Riehl, J. M. Lehn and F. Hemmert, Bull. Soc. Chim. Fr., 224 (1963). T. Sakai, K. Seko, A. Tsuji, M. Utaka and A. Takeda, J . Org. Chem., 47, 1101 (1982). J.-J. Riehl and A. Fougerousse, Bull. SOC. Chim. Fr., 4083 (1968). A. Padua and D. Dehm, J . Org. Chem., 40, 3139 (1975). Br. Pat., 902790 (1962); Chem. Abstr., 58, 588 (1963). Eur. Pat., 92 890 (1983); Chem. Ahstr., 100. 103170 (1984). PCT Int. Appl., 84 01 773 (1984); Chem. Abstr., 101, 171082 (1984). V. J. Martens, H. Offermans and P. Scherberich, Angew. Chem., 93, 680 (1981). L. Duhamel, P. Duhamel and J.-Y. Valnot, C.R. Acad. Sci., Ser. C , 271, 1471 (1970). N. De Kimpe, R. Verhe, L. De Buyck, L. Moens and N. Schamp, Synthesis, 43 (1982). L. Fitjer, Chem. Ber., 115, 1035 (1982). K. Atsumi, K. Katano, K. Nishihata, F. Kai, E. Akita and T. Niida, Tetrahedron Lett., 23,2977

( 1982).

U S Pat., 2468493 (1949); Chem. Abstr., 43, 7499 (1949). B. M. Goldschmidt, B. L. Van Duuren and R. C. Goldstein, Tetrahedron Lett., 1177 (1979). H. L. Blewitt, Chem. Heterocycl. Compd., 30, 117 (1977). E. S. Hand and W. W. Paudler, J . Org. Chem., 45, 3738 (1980). R. Rydzkowski, D. Blondeau, and H. Sliwa, Tetrahedron Lett., 26, 2571 (1985). G. D. Hartman and R. D. Hartman, J . Heterocycl. Chem., 20, 1089 (1983). C. Sablayrolles, G. H. Cros, J. C. Milhavet, E. Recheng, J.-P. Chapat, M. Boucard, J. J. Serrano and J. H. McNeil, J . Med. Chem., 27, 206 (1984). 180. H. Kasai, M. Goto and K. Ikeda, Biochemistry, 15, 878 (1976). 181. P. D. Sattsangi, N. J. Leonard and C. R. Frihart, J . Org. Chem., 42, 3292 (1977). 182. V. Nair and G. A. Turner, Tetrahedron Lett., 25, 247 (1984). 183. P. Duhamel, C.R. Acad. Sci., Ser. C , 253, 483 (1961). 184. A. Kirrmann, P. Duhamel and L. Duhamel, Bull. Soc. Chim. Fr., 1732 (1966). 185. L. Duhamel and P. Duhamel, Bull. SOC.Chim. Fr., 1999 (1969). 186. A. Kirrmann, P. Duhamel and L. Duhamel, Bull. SOC.Chim. Fr., 1091 (1968). 187. A. Kirrmann, R. Muths and J.-J. Riehl, Bull. SOC. Chim. Fr., 1469 (1958). 188. E. Elkik and H. Assadi-Far, C . R . Acad. Set., Ser. C , 263, 945 (1966). 189. P. Duhamel, L. Duhamel, J.-L. Klein and A. Jarry, Bull. SOC.Chim. Fr., 3883 (1969). 190. P. Duhamel, L. Duhamel, C. Collet and A. Ha'ider, C . R . Acad. Sci., Ser. C , 273, 1461 (1971). 191. P. Duhamel, L. Duhamel and P. Siret, C.R. Acad. Sci., Ser. C , 276, 1319 (1973). 192. J.-L. Klein and J.-C. Combret, Bull. Soc. Chim. Fr., 11, 28 (1983). 193. P. Duhamel, L. Duhamel and J.-M. Poirier, C.R. Acad. Sci., Ser. C , 270, 957 (1970). 194. L. Duhamel, P. Duhamel and J. M. Poirier, Bull. SOC.Chim. Fr., 221 (1972). 195. L. Duhamel and J.-M. Poirier, J . Org. Chem., 44, 3585 (1979). 196. L. Duhamel and J.-M. Poirier, Bull. SOC. Chim. Fr., 11, 297 (1982). 197. L. Duhamel, in The Chemistry of Amino, Nitroso and Nitro Compounds and Their Derivatives (Ed. S. Patai), Wiley, Chichester, 1982, Ch. 20, p. 854. 198. H. Ahlbrecht and D. Liesching, Synthesis, 495 (1977). 199. J.-L. Boucher and L. Stella, Tetrahedron, 41, 875 (1985). 200. I. Heilbron, E. R. H. Jones, R. W. Richardson and F. Sondheimer, J . Chem. SOC.,737 (1949). 201. S. A. Godleski and E. B. Vilhauer, J . Org. Chem., 49, 2246 (1984). 202. L. Duhamel, J. Chauvin and A. Messier, Tetrahedron Lett., 21, 4171 (1980). 203. A. Marsura, C. Luu-Duc and G . Gellon, Synthesis, 537 (1985). 204. A. Buschauer, K. Wegner and W. Schunack, Arch. Pharm. (Weinheim), 317,9 (1984). 205. G. Kempter, J. Spindler, H. J. Fiebig and G. Sarodnick, J . Prakt. Chem., 313, 977 (1971). 206. H. Carpio, E. Galeazzi, R. Grrenhouse, A. Guzmln, E. Velarde, Y.Antonio, F. Franco, A. Leon, V. Perkz, R. Salas, D. Valdes, 5. Ackrell, D. Cho, P. Gallegra, 0. Halpern, R. Kochler, M. L. Maddox, J. M. Muchowski, A. Prince, D. Tegg, T. C. Thurber, A. R. Van Horn and D. Wun, Can. J . Chem., 60,2295 (1982). 207. U S Pat., 4410534 (1983); Chem. Abstr., 100, 85595 (1984). 208. C. T. Ho, Q. Z. Jin, K. N. Lee, J. T. CarIin and S. S. Chang. J . Food Sci., 48, 1570 (1983). 173. 174. 175. 176. 177. 178. 179.

3. Synthesis a n d reactivity of a-halogenated aldehydes

441

209. W. J. Krzyzosiak, J. Biernat, J. Ciesiolka, P. Gormicki and M. Wiewiorowski, Tetrahedron Lett., 2647 (1979). 210. G. Crank and H. R. Khan, Aust. J . Chem., 38,447 (1985). 211. Lin, C. M. Seifert, S. M. Kang, J. P. Dusza and S. A. Lang, J . HeterocycL Chem., 16, 1377 (1979). 212. F. Arndt, W. Franke, W. Klose, J. Lorenz and K. Schwartz, Justus Liebigs Ann. Chem., 1302 (1984). 213. D. W. Gillon, I. J. Forrest, G. D. Meakings, M. D. Tire1 and J. D. Wallis, J . Chem. Soc.. Perkin Trans. 1, 341 (1983). 214. T. Hashimoto and T. Miyadera, Heterocycles, 11, 203 (1978). 215. W. J. Humphlett and R. W. Lamon, J . Org. Chem., 29, 2146 (1964). 216. D. M. McKinnon, M. E. Hassan and M. S . Chaunan, Can. J . Chem., 57, 207 (1979). 217. R. I. Tarasova, T. A. Dvoinishnikova, N. I. Sinitsyna, T. V. Zykova and M. V. Alparova, Zh. Obshch. Khim., 53, 1254 (1983); Chem. Abstr., 99, 140054 (1983). 218. H. Zinner, W. Siems, D. Kuhlman and G. Erfurt, J . Prakt. Chem., 216, 54 (1974). 219. N. De Kimpe, R. Verhe, L. De Buyck, W. Dejonghe and N. Schamp, Bull. SOC.Chim. Belg., 85, 763 (1976). 220. A. Ross and R. N. Ring, J . Org. Chem., 26, 579 (1961). 221. R. W. Campbell and 0. Vogl, Monatsh. Chem., 110, 453 (1979). 222. T. L. Gilchrist, J. A. Stevens and B. Parton, J . Chem. SOC.,Perkin Trans. 1, 1741 (1985). 223. N. De Kimpe and N. Schamp, Org. Prep. Proced. Int., 11, 115 (1979). 224. J. G. Schantl, P. Karpellus and M. Prean, Tetrahedron, 38, 2643 (1982). 225. L. Duhamel and J.-Y. Valnot, C.R. Acad. Sci., Ser. C , 286, 47 (1978). 226. A. Kirrmann, L. Vio, J. Cantacuzene and M. Martin, C.R. Acad. Sci., Ser. C , 255. 728 (1962). 227. P. Duhamel, L. Duhamel and J. Chauvin, C.R. Acad. Sci.,Ser. C , 274, 1233 (1972). 228. U S Pat., 4096 187 (1977); Chem. Abstr., 89, 196960 (1978). 229. M. Brink and E. Schjanberg, J . Prakt. Chem., 318, 907 (1976). 230. A. Schutz and I. Ugi, J . Chem. Res. (S), 157 (1979). 231. R. Verhe, N. De Kimpe, L. De Buyck and N. Schamp, Synthesis, 46 (1984). 232. Ger. Offen., 3 149653 (1983); Chem. Abstr., 99, 105262 (1983). 233. R. M. Nowak, J . Org. Chem., 28, 1182 (1963). 234. J. Cantacuzene and D. Ricard, Tetrahedron Lett., 2237 (1966). 235. I. A. Voronima, A. I. Chernyarskii, I. V. Dobrov, V. A. Poluektov and N. V. Fomina, Zh. Org. Khim., 17, 918 (1981); Chem. Abstr., 95, 96656 (1981). 236. U. Hertenstein, S. Hunig, H. Reichelt and R. Schaller, Chem. Ber., 115, 261 (1982). 237. A. Takeda, S. Tsuboi and Y. Oota, J . Org. Chem., 38, 4148 (1973). 238. T. Sakai, H. Horikawa and A. Takeda, J . Org. Chem., 45, 2040 (1980). 239. T. Sakai, M. Yoshida, S. Kohmoto, M. Utaka and A. Takeda, Tetrahedron Lett., 23,5185 (1982). 240. A. Takeda, S. Tsuboi and T. Sakai, J . Org. Chem., 39,2601 (1974). 241. A. Takeda, T. Sakai, S. Shinohara and S . Tsuboi, Bull. Chem. SOC.Jpn., 50, 1133 (1977). 242. R. Verhe, N. De Kimpe, L. De Buyck, C. Swyngedouw and N. Schamp, Bull. SOC.Chim. Belg., 86, 893 (1977). 243. M. Matsumoto and N. Watanabe, Heterocycles, 22, 2313 (1984). 244. Eur. Pat., 101 003 (1984); Chem. Abstr., 101, 23319 (1984). 245. S. Tsuboi, T. Uno and A. Takeda, Chem. Lett., 1325 (1978). 246. D. Courtheyn, R. Verhe, N. De Kimpe, L. De Buyck and N. Schamp, J . Org. Chem., 46,3226 (1981). 247. A. Takeda, S. Tsuboi, F. Sakai and M. Tanabe, J . Org. Chem., 39, 3098 (1974). 248. A. Takeda, S. Tsuboi, S. Wada and H. Kato, Bull. Chem. SOC.Jpn., 45, 1217 (1972). 249. A. Takeda, S. Tsuboi and T. Hongo, Bull. Chem. Soc. Jpn., 46, 1844 (1973). 250. F. Heinzer and D. Bellus, Helo. Chim. Acta, 64, 2279 (1981). 251. A. Cope, C. Hofmans, G. Wychoff and E. Hardenbergh, J . Am. Chem. Soc., 63, 3452 (1941). 252. W. Lehnert, Tetrahedron, 29, 635 (1973). 253. S. Zahr and I. Ugi, Synthesis, 266 (1979). 254. H. 0. House, V. K. Jones and G. A. Frank, J . Org. Chem., 29, 3327 (1964). 255. P. L. Stotter and K. A. Hill, Tetrahedron Lett., 1679 (1975). 256. J. Font and P. DeMarch, Tetrahedron, 37, 2391 (1981). 257. S. Bakker, PhD Thesis, Katholieke Universiteit Nijmegen, The Netherlands (1977).

448

Norbert De Kimpe and Roland Verhe

258. 259. 260. 261. 262. 263. 264. 265.

M. F. Semmelhack, J. C. Tomesch, M. Czarny and S. Boettger, J . Org. Chem., 43, 1259 (1978). R. Paugam-Dreves, M. Baboulene and G. Sturtz, Eur. J . Med. Chem.,Chim. Ther., 12,333 (1977). M. P. Cooke and J. Y. Jaw, J . Org. Chem., 51, 758 (1986). M. I. Shevchuk, V. N. Kushnir and A. V. Dombrovskii, Zh. Obshch. Khim., 47,2513 (1977). J. Barluenga, F. Alvarez, J. M. Concellon and M. Yus, Synthesis, 654 (1986). M. Larchevique, P. Perriot and Y. Petit, Synthesis, 297 (1983). G. A. Kraus and P. Gottschalk, J . Org. Chem., 48, 5356 (1983). T. Hashimoto, T. Watanabe, Y. Kawano, T. Tanaka and T. Miyadera, Chem. Pharm. Bull., 28,

266. 267. 268. 269. 270. 271. 272. 273. 274. 275.

A. Kirrmann and P. Chancel, Bull. SOC.Chim. Fr., 227 (1951). USSR Pat., 1214661 (1986); Chem. Abstr., 105, 225779 (1986). J. Sauleau, Bull. SOC.Chim. Fr., 11, 274 (1978). N. De Kimpe, R. Verhe, L. De Buyck and N. Schamp, Bull. SOC.Chim. Belg., 88, 719 (1979). J. Barluenga, M. Yus, J. M. Concellon and P. Bernad, J . Chem. Res. (S), 41 (1980). J. Barluenga, M. Yus, J. M. Concellon and P. Bernad, J . Chem. Res. (S), 324 (1986). J. Barluenga, M. Yus, J. M. Concellon and P. Bernad, J . Org. Chem., 46, 2721 (1981). J. W. Cornforth, R. H. Cornforth and K. K. Mathew, J . Chem. SOC.,112 (1959). P. A. Wender and A. W. White, Tetrahedron, 39, 3767 (1983). W. Perkow, K. Ullerich and F. Meyer, Naturwissenschafen, 39, 353 (1952); Chem. Abstr., 47,

276. 277. 278. 279. 280. 281. 282. 283. 284. 285. 286. 287. 288. 289. 290. 291. 292. 293. 294.

2980 (1980).

8248 (1953).

W. Perkow, Chem. Ber., 87, 755 (1954). J. F. Allen and 0. H. Johnson, J . Am. Chem. Soc., 77, 2871 (1955). F. W. Lichtenthaler, Chem. Rev., 61, 607 (1961). A. K. Bhattacharya and G. Thyagarajan, Chem. Rev., 81,415 (1981). Y. G. Gololobov, T. V. Kim and E. I. Kiseleva, Dokl. Akad. Nauk SSSR, 272,1388 (1983); Chem. Abstr., 100, 103483 (1984). E. M. Gaydou, Tetrahedron Lett., 4473 (1972). E. M. Gaydou and J.-P. Bianchini, Can. J . Chem., 54, 3626 (1976). A. M. Kibardin, P. I. Gryaznov, T. K. Gazizov, I. S. Iraidova and A. N. Pudovik, Izv. Akad. Nauk SSSR, Ser. Khim., 700 (1982); Chem. Abstr., 97, 55902 (1982). G. T. Brooks, Chlorinated Insecticides: Technology and Application, CRC Press, Cleveland, OH

(1976).

J. M. Varlet, G. Fabre, F. Sauveur, N. Collignon and P. Savignac, Tetrahedron, 37,1377 (1981). M. Sekine, K. Okimoto and T. Hata, J . Am. Chem. SOC.,100, 1001 (1978). M. Sekine, K. Okimoto, K. Yamada and T. Hata, J . Org. Chem., 46, 2097 (1981). D. M. Malenko and Y. G. Gololobov, Zh. Obshch. Khim., 52, 2794 (1982); Chem. Abstr., 98, 107427 (1983).

G. Erfurt, M. Schnell and H. Zinner, J . Prakt. Chem., 319, 29 (1977). B. Begasse and M. Le Corre, Tetrahedron, 36, 3409 (1980). J. Barluenga, J. Florez and M. Yus, J . Chem. SOC.,Perkin Trans. f, 3019 (1983). I. Pri-Bar, P. S. Pearlman and J. K. Stille, J . Org. Chem., 48, 4629 (1983). J. Kato and T. Mukaiyama, Chem. Lett., 1727 (1983). M. Marsi, K. C. Brinkman, C. A. Lisensky, G. D. Vaughn and J. A. Gladysz, J . Org. Chem., 50,

3396 (1 985). 295. Jpn. Kokai Tokkyo Koho, 60 185 791 (85 185 791) (1985); Chem. Abstr., 104, 69006 (1986). 296. T. Herold and R. W. Hoffmann, Angew. Chem., 90,822 (1978). 297. M. A. Akhmedov, S. I. Sadykh-Zade, S. K. Kyazimov, R. I. Akhundova, R. A. Kurbanova, L. M. Babaeva and M. B. Shukyurova, Dokl. Akad. Nauk SSSR, 37,46 (1981); Chem. Abstr., 95, 132214 (1981). 298. S. I. Sadykh-Zade, M. A. Akhmedov, S. K. Kyazimov, Z. G. Mustafaeva and L. S. Guseinova, Azerb. Khim. Zh., 35 (1976); Chem. Abstr., 87, 52842 (1977). 299. US Pat., 4468354 (1983); Chem. Abstr., 101, 191173 (1984). 300. U S Pat., 4469896 (1984); Chem. Abstr., 101, 211002 (1984). 301. J. Kagan, D. A. Agdeppa, A. I. Chang, S.-A. Chen, M. A. Harmata, B. Melnick, G. Patel, C. Poorker, S. P. Singh, W. H. Watson, J. S. Chen and V. Zabel, J . Org. Chem., 46, 2916 (1981). 302. A. Haas, R. Plumer and A. Schiller, Chem. Ber., 118, 3004 (1985). 303. J.-M. Poirier and L. Hennequin, Synth. Commun., 15, 217 (1985). 304. L. Duhamel, F. Tombret and J.-M. Poirier, Org. Prep. Proced. lnt., 17, 99 (1985).

3. Synthesis and reactivity of a-halogenated aldehydes

449

305. D. Ladjama and J.-J. Riehl, Synthesis, 504 (1979). 306. A. Roedig, M. Foure and M. Forsch, Chem. Ber., 110, 322 (1977). 307. J. Barluenga, J. Joglar, S. Fustero, V. Gotor, C. Kriiger and M. J. Romlo, Chem. Ber., 118,3652 ( 1985). 308. H. Wynberg and E. G . J. Staring, J. Org. Chem., 50, 1977 (1985). 309. P. E. F. Ketelaar, E. G. J. Staring and H. Wynberg, Tetrahedron Lett., 26, 4665 (1985). 310. C. Lavallire, G. Lemay, A. Leborgne, N. Spassky and R. E. Prud’homme, Macromolecules, 17, 2457 (1984). 311. H. Nakai and M. Kurono, Chem. Lett., 995 (1977). 312. USSR Pat., 1214661 (1986); Chem. Abstr., 105, 225779 (1986). 313. P. Blumbergs, M. P. LaMontagne and J. I. Stevens, J. Org. Chem., 37, 1248 (1972). 314. E. J. Corey, E. J. Trybulski and J. W. Suggs, Tetrahedron Lett., 4577 (1976). 315. H. Chikashita, H. Ide and K. Itoh, J. Org. Chem., 51, 5400 (1986).

The chemistry of a -haloketones, or-haloaldehydes and a-haloimines Edited by Saul Patai & Zvi Rappoport Copyright 0 1988 by John Wiley & Sons Ltd

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 numbers are printed in normal type in ascending numberical order, followed by the reference numbers in parentheses. The numbers in italics refer to the pages on which the references are actually listed. Abad, A. 183 (830), 220 Abashev, G. G. 93 (516,517), 117,199 (900, 901), 221 Abbayes, H. des 93 (514), 117 Abdel-Gabl, F. 371 (22), 443 Abdulla, R. F. 73 (395), 115 Abdur Rahman, M. 293 (588), 362 Abel, E. W. 228 (39), 268 Abis, L. 160(708),217 Abramov, V. Y. 295 (616), 363 Abrams, L. S. 230,266 (220), 271 Abul-Hajj, Y. J. 141 (975),223 Acheson, R. M. 28 (185), 111 Ackrell, J. 175 (775), 180 (977), 219,223,410 (206), 446 Adam, W. 161 (712),2I7 Adickes, H. W. 254 (430), 276 Advani, B. 175,177 (786), 219 Agdeppa, D. A. 439 (301), 448 Agui, H. 169 (760). 219 Agullo, C . 183 (830), 220 Ahlberg, P. 290 (552-554), 299 (544), 361 Ahlbrecht, H. 314 (281,282),273,407 (198), 446 Ahrens, W. 230,238 (65), 268 Aihara, K. 161 (711),217 Aimi, N. 235,267, (137), 270,291 (566,567), 341 (566), 361 Akawie, R. 86 (475), 116 Akelah, A. 371 (22), 443 Akhmedov, M. A. 438 (297,298), 448 Akhrem, A. A. 2 (5). 107,259 (355), 274 Akhundova, R. I. 438 (297), 448 Akiba, K.-Y. 204 (931), 222 Akita, E. 283,326 (496), 360,404 (172), 446

Akiyama, M. 346 (766), 336 Akiyama, T. 263 (400), 275 Akopyan, S. K. 137 (640), 216 Albanbauer, J. 228 (40-42), 258 (349), 263 (41,42), 264 (405), 268,274,275 Albrecht, B. 19 (131), I10 Albrecht, R. 236 (144), 263 (144,396), 270, 2 75 Albright, J. D. 256 (330), 274 Aleksanina, N. M. 305 (662). 364 Alexander, E. 379 (72), 444 Alexanian, V. 75 (412), 115,230,247,248, (157),270 Alfredson, B. 79 (431), 115 Allen, G. 0 . 2 6 6 (431), 276 Allen, G. R. 256 (328), 274 Allen, J. F. 432 (277), 448 Almy, J. 53,55,68 (322), 113 Alonso, J. L. T. 235 (124), 269 Alparova, M. V. 411 (217), 447 Alper, H. 93 (514,515), 107 (574,576), 117, I19 Altenbach, H . - J . 83,86 (465), 116 Altenbach, J.-J. 228,321 (540), 361 Alvarez, F. 189 (848,858), 220,221,429 (262), 448 Alvernhe, G. 124 (602), 215,351,357 (793), 367 Amano, E. 83 (462), 116 Ananda, G. D. S. 163 (723). 218 Anatakrishnan, S. V. 376 (SO), 444 Anderson, D. J. 287,295,296 (526), 361 Anderson, J. C. 106 (568), 118 Anderson, V. B. 90 (490), 117 Ando, T. 199 (902), 203 (915), 221,222

45 1

452

Author Index

Andreeva, M. A. 293 (582), 362 Andrei, E . 230 (218), 271,294 (593), 362 Andriamialisoa, R. 291 (574,575), 310 (5759, 362 Andriamialisoa, R. Z. (455), 276 Andruzzi, R. 291 (568), 361 Angoh, A. G. 192 (862), 221 Anibie, J. 255 (439), 276 Anisimova, N. N. 96 (530), 118 Anjireddy, P. 304 (660), 364 Anschuetz, R. 178 (795), 219 Ansell, J . M. 251 (316), 273,328 (710), 365 Anselme, J.-P. 76 (416), 115,239 (210), 247 (258), 271,272,301 (643,363 Anstutz, E. D. 67 (362), 114 Antipin, M. Y. 203 (918), 222.263 (395), 275 Antonio, Y. 175 (775), 219,410 (206), 446 Aoki, E. 65 (357), 114 Aoki, K. 266,287 (460). 277 Aoki, T. 283,326 (497), 360 Aoko, Y. 255 (320), 274 Appelman, E. H. 391 (124), 445 Arbusov, Y. A. 83 (459), 116 Arbuzov, Y. A. 263 (399). 275 Arcamone, F. 230,245,267 (51), 268 Armani, E. 143 (662,663), 216,371 (25), 443 Armstrong, V. W. 31 (220), 111 Arnautova, G. M. 86 (472), 116 Arndt, F. 175,177 (784), 219,411 (212), 447 Arnice, P. 29 (203), 111 Arn6, M. 183 (830), 220 Arnold, P. 81 (445), 116 Arques, A. 178 (796). 219 Arrieta, A. 143, 171 (660), 216 Arvanaghi, M. 23 (158), 107 (584), 110,119, 134 (625), 216 Asada, M. 93 (511), 117 Asada, Y. 291,341 (566),361 Ash, A. 374 (38), 443 Ashcroft, W. R. 291 (576). 362 Ashida, T. 302,303 (655), 364 Asinger, F. 78 (426), 115,180 (805),220 Assadi-Far, H. 7 (44), 108,405 (188), 406 (190), 446 Assadifar, H. 58 (334), 113,228 (412), 275 Astakhova, R. S. 294 (595), 362 Aston, J . A. 50 (312), 113 Aston, J. G. 9 (71), 10 (72), 26 (177), 49,50 (310),109,111,113,226(11),267 Atlanti, M. 255 (439), 276 Atovmyan, L. 0 . 2 8 6 (518), 345 (754), 349 (783), 360,366 Atsumi, K. 283,326 (496), 360,404 (172). 446 Atta, R. E. van 19 (132), 110 Attanasi, 0 . 2 8 7 (532), 361 Attanasi, 0. A. 179 (802), 219 Atwell, M. A. 231,251 (77), 268 Aucoin, T. G. 145 (670). 217,377 (58), 444

Aufderhaar, E . 231 (75), 268 Autonova, N. D. 263 (399), 275 Auwers, K. V. 65 (352), 114 Au-Yeung, B. W. 206 (938), 222 Avakyan, A. S. 161 (713), 217 Awang, D. V. C. 337,341 (738), i Awaya, H. 171 (767), 219 Axiotis, G. 199 (899), 221 Ayer, R. P. 52 (320), 113 Baba, Y. 93 (506). I17 Babadjamian, A: 74 (401,402), 115 Babaeva, L. M. 438 (297), 448 Babeau, A. 182 (817), 220 Baboulene, M. 428 (259), 448 Baccolino, G. 234,251 (111),269 Bach, R. D. 377 (64), 444 Bachi, M. D. 329,330 (716). 365 Bachman, W. E. 19 (129), 110 Backvall, J. E. 96 (527), I18 Bacquet, C. 18 (127), 24,35,46 (162), 110,385 (102), 444 Bacquet-Einhorn, C. 147 (676), 217 Bader, H. 351 (797), 367 Badicke, G. 230,264 (57), 268 Badiger, V. V. 164 (729), 218 Badorc, A. 339 (745), 366 Baeza, J. 174 (773), 219 Bagot, J. 296 (626), 363 Bahar, E. 288,302 (547), 355 (547,804), 361, 367 Bailey, W. A. 44 (278), 112 Baily, A. S. 345 (752), 366 Bak, D. A. 20 (139), 110 Baker, D. R. 357 (808,810-812,814), 367 Baker, J. W. 41,43 (267), 112 Baker, P. M. 242 (227), 272 Bakker, S. 427 (257), 447 Balasubramanian, T. R. 195 (882), 221 Baldauf, H. J. (185,186), 271 Ballester, M. 10 (74), 109 Bal’on, Y. G. 337 (63), 444 Balon, Y. G. 257 (340), 274,295,329 (601), 362 Banfi, D. 314 (695), 364 Bankowska, Z. 9 (53), 108 Banks, R. E . 257 (338), 274,294 (596). 295 (613,614), 348 (614), 362,363 Bannikova, 0. B. 295,329 (602), 362 Bansal, R. K. 201 (906), 221 Baranov, S. N 76 (415), 115,230 (110), 269 Baranovskaya, E. M. 183 (826), 220 Barata, L. E . S . 242 (227), 272 Barba, F. 214 (959,960), 223,311 (683), 364 Barbuenga, J. 88 (481), I17 Barbulescu, N. 230 (218), 271,294 (593), 362 Bargamova, M. D. 287 (522), 360 Barlow, M. G. 257 (338), 274

Author Index Barluenga, J. 147 (675), 189 (848,850,855859), 192 (863), 217,220,221,290 (556, 557), 361,375 (47), 428 (270-272), 429 (262), 435 (272,291), 439 (307). 443,448, 449 Barnes, D. 212 (955), 222 Barnett, C. J. 237,249 (449), 276 Barnette, W. E. 122 (590), 215 Barone, A. D. 290 (551), 361 Bartlett, P. D. 9 (58), 44 (283), 108,113,243 (236), 272 Barton, D. H. R. 122 (589), 215,302 (654, 823), 364,368 Baskakov, Y. A. 293,302 (585,586), 362 Bass, J. D. 31 (218), 111 Battig, K. 75 (411), 115,230,249,256,267 (69), 268,286 (507), 360 Batueva, G. V. 199 (901), 221 Baudry, D. 58 (335), 103 (335,561), 104 (561), 114,118 Bauer, D. P. 31 (215), 111 Baum, I. S. 68 (372), 114 Baumann, M. 78 (426), 115 Bayer, 0.2 , 8 (2), 107 Baysdon, S. L. 180 (812), 220 Beal, M. G. 291 (576). 362 Beaulieu, P. L. 214 (968),223 Beccalli, E. M. 302 (651), 363 Bechgaard, K. 183 (825). 220 Beck, E. 211 (950), 222 Beck, J. 235,245 (373),275 Becker, R. 286,302 (520), 360 Bedoukian, P. 379 (78), 444 Bedoukian, P. 2 . 2 9 (204), 111 Beereboom, J. J. 9 (62), 12, 15 (89), 51 (317), 108,109,113 Begasse, B. 186 (840), 220,435 (290), 448 Beger, J. 237,264 (261,217),271 Btgut, J.-P. 245,246,350,357 (427), 276,388 (106), 445 Btgut, J. P. 103 (560,562,563), 104 (562). 118,353 (803). 367 Buguin, C. G. 285 (503), 360 Behrens, D. 230 264 (53), 268 Behringer, H. 82 (451), 116 Behrooz, M. 187 (842), 220 Belcher, R. 28 (186), 111 Belicchi, M. F. 143 (662), 216 Bell, R. P. 38 (250), 112 Bellesia, F. 130 (981), 143 (982), 223,371 (26), 375 (45), 382 (86), 443,444 Bellmann, P. 163 (726), 218 Bellus, B. 137 (642), 216 Bellus, D. 20 (138), 110,137 (643,644), 153 (644,687,688), 171 (688), 185 (835), 216, 217,220,426 (250), 447 Belousov, Y. M. 302 (653), 364 Beltrame, P. 65 (354), 114

453

Benayache, F. 164 (727), 218,280 (471), 359 Benezra, C. 400 (158), 446 Ben-Shoshan, M. 228,328 (545). 361 Ben-Shushan, G. 122 (588), 215 Bensoam, J . 100 (548), 118 Benson, R. 29 (200), 111 Beppu, S. 106 (569), 119 Berg, M. A. 231 (71), 268 Bergamova, M. D. 295 (610). 362 Bergeron, R. J. 75 (403,404), 115 Bergman, E. D. 6 (30,40), 108 Bergman, J. 96 (527), 118 Bergmann, E. D. 7 (47), 108 Bergmann, F. 7 (48), 108 Bergmark, W. R. 106 (567), 118,212 (955), 222 Bergstrand, S. J. 238,267 (180), 271 Bernad, P. 88 (481), 117,189 (855-858), 221, 428 (270-272), 435 (272), 448 Bernardi, L. 230,245 267 (51), 268 Berndt, A. 230,238 (64,65), 268 Berthelot, J. 144 (666,667), 216 Berti, C. 291 (568), 361 Bertin, D. 230 (66), 268 Bertounesque, E. 199 (899), 221 Beverung, W. N. 254 (430), 276 Bevinakatti, H. S. 164 (729), 218 Beyer, H. 75 (409), 76 (423), 115,230 (52-57), 264 (52-55,57,402,403), 268,275 Bhattacharya, A. K. 432 (279), 448 Bhushan, V. 144 (665), 216 Bianchini, J. B. 97 (535), 118 Bianchini, J. P. 432 (282), 448 Biernat, J. 411 (209), 447 Biftu, T. 163 (725), 218 Bigelow, L. A. 3 (15), 107 Billimoria, J. D. 30 (206), 111 Bindra, J. S. 235,244,261,267 (138), 270 Bingham, E. M. 4 (25), 108 Birkofer, L. 371,372 (20), 443 Bischoff, C. 280 (472), 359 Bissig, P. 180 (813), 220 Black, A. Y.201 (908), 222 Black, D. S. C. 233,246,256 (95-97), 269 Blacklock, T. J 240 (214). 271 Blackman, N. A. 233,246,256 (95-97), 269 Blake, E. E. 24 (160), I10 Blanco, L 29 (203), 111 Blaszczak, L. C. 130 (616), 215 Blatt, K, 251 (299), 273 Blewitt, H. L. 405 (175), 446 Bloch, R. 33 (225), 111,371 (23), 443 Blondeau, D. 405 (177), 446 Bloom, B. M. 3 (17). 107 Bloss, J. L. 235,261,267 (126), 269 Blount, J.-F. 235,244,262 (129), 269 Blum, A. F. 7 (43), 108

454

Author Index

Blumbergs, P. 70 (378), 114,226 (13), 267,385 (313), 449 Bocchi, V. 310 (680), 364 Bock, D. A. 107 (580), 119 Bode, K. 246 (255), 272 Bodforss, S. 226 (26,27), 267 Bodicke, G. 75 (409), 115 Bodnar, V. N. 101 (522), 118 Bodot, H. 96 (253), 117 Bodrikov. I. V. 239 (192), 271 Body, I. 280 (475), 359 Boehm, C. 226,251 (lo), 267 Boese, A. B. 24 (159), 110 Boettger, S. 428 (258), 448 Bogdanova, I. S. 293 (583), 362 Bogert, V. V. 3 (17). 107 Bognar, R. 179 (804), 219 Bognar, R. 76 (418), 115,291 (561), 361 Bogolovskii, N. A. 82 (453), 116 Bohlmann, F. 61 (347), 114 Bohnert, J. C. 291,344 (563), 361 Bohrmann, L. 238 (190), 271 Bojarska, A . B. 175,176 (780),219 Bokadia, M. 171 (768),219 Bokens, H. 179 (803), 219,299 (638,639). 363 Boldeskul, I. E. 80 (433), I16 Bolhofer, W. A. 238,267 (181), 271 Bollyn, M. 326 (708), 365 Bolotov, M. I. 293 (582), 362 Bonadyk, S . V. 236 (149-151),270 Bondavalli, F. 289,292,314 (548), 361 Bongini, A. 32 (222), 111,126 (606), 215,346 (761,825), 366,368,371,372 (21), 375 (44). 443 Bonini, B. F. 351 (796), 367 Bonnet, D. 103 (560), 118 Bonnet-Delpon. D. 351 (791), 353 (803). 367, 388 (106), 445 Borbaruah, M. 214 (961), 223 Bordner, J. 306 (670), 364 Bordwell, F. G. 28 (189), 41 (264), 42 (273), 49 (189), 53 (322), 54 (326,327), 55 (273, 322,326-330), 65 (189), 68 (322), 111113,243 (245), 272 Borisenko, V. P. 101 (522). 118 Bornmann, W. G. 291,344 (563). 361 Borowitz, 1. J. 14,30 (98), 96 (534), 99 (543), 107 (578), 109,118,119 Borrmann, D. 229,257 (333), 274 Boswell, G. A. Jr. 238 (418), 258 (350), 274, 2 76 Bott, K. 229 (212), 271,373 (30), 443 Boucard, M. 166 (740), 218,405 (179), 446 Boucher, J.-L. 407 (199), 446 Boucherot, D. 76 (425), 115 Bouget, H. 379 (79), 444 Boundel, Y. G. 184 (834), 220 Bouton, C. M. 44 (278), 112

Bowen, R. D. 295 (604),362 Bover, J . H. 26 (178), 76 (424), 111,115,242 (232), 272 Bozzini, S. 76 (413), 115,251,256 (325-327), 2 74 Bradburry, R. H. 175,176 (778), 219 Brady, 0. L. 229 (45), 268 Brady, W. T. 20 (137, 139), 53,55 (325), 107 (580), 110,113,119, 133, 134 (628), 137 (628,641), 216 Brand, M. 145 (672). 217 Brandange, S. 195 (873), 221 Brannen, W. T. 41 (264), 112 Brault, A . 66 (361), 114 Braun, J.-A. 96 (523), 117 Bravo, P. 86 (470), 116,248 (267,268), 250 (296), 272,273,309 (675), 364 Braxmeier, H. 296,329 (621), 363 Bredereck, H. 72 (392), 115,238 (179), 271, 381 (85), 444 Bremner, J. B. 339 (746), 366 Breslow, R. 59 (340), 114 Bridges, A . J . 80 (435), 116 Brink, M. 413 (229). 447 Brinkman, K . C. 436 (294), 448 Brintzinger, H. 9 (63), 108,230 (67), 268 Brochet, A . 17 (112), 109 Brodka, S . 251 (334), 274 Brooks, G . T. 433,438 (284), 448 Brown, F. W. 82 (449), 116 Brown, H. 374 (38), 443 Brown, H. C. 89 (483), 92 (497), 117,194 (871,872),221,390(117),393(127),445 Brown, M. D. 182 (818), 220 Brown, R. E. 331 (731), 365 Brown, R. F. 233,246,256 (95,96), 269 Brown, R. S. 180 (806), 220 Brown, W. 266 (431), 276 Brown, W. G. 96 (525), 117 Browne, T. E. W. 251 (306), 273 Brunner, A. 83 (460), 116 Bruylants, A . 9 (57), 108 Bryant, M. W. 179 (801), 219 Buchan, R. 171,173 (765),219 Buchi, G. 235,267 (134), 269 Buchman, E. R. 11 (78), 109 Buchmann, G . 80 (437), 116 Buckachuk, 0. M. 203 (921), 222 Buckles, R. E. 29 (201), 111 Buckley, D. J . 132 (621), 216 Budkova, T. K. 133 (624), 216 Buehler, C. A . 44 (282), 113 Buhler, K. 381 (85), 444 Bulka, E. 76 (422), 115,230,264 (52,53), 268 Bumgardner, C. L. 123 (592), 215,379 (81), 444 Bundle, D. R. 346 (763), 366 Bunnell, C. A. 229,251,256 (49), 268

Author Index Buono, G. 96 (533), I18 Bupp, J. E. 186 (839), 220 Burger, K. 228 (40-42), 257 (341), 258 (349). 263 (41,42,374-377,379,381-386,393, 401,458), 264 (404-407,459), 268,274277,285 (505), 323 (704), 347 (722-774, 776), 348 (777,778), 360,365,366 Burgess, K. A. 50 (312), 113 Burgis, E. 348 (778), 366 Burke, M. 311 (686), 364 Burke, M. C. 101 (554), 118.206 (936), 222, 311 (685),364 Burke, S. E. 17 (124,126), 110 Burkhart, J. P. 125 (605), 215,393 (129), 445 Burlett, D. J. 291,301,342 (562), 361 Burnaeva, L. A. 305 (662), 329 (720), 364,365 Burton, C. A. 228 (39), 268 Buschauer, A. 174 (772), 219,410 (204), 446 Buschmann, E. 286,302 (520), 360 Buttinelli, P. 172 (769). 219 Buu-Ho~,N. P. 13 (91), 109 Buzas, A . 260 (367), 274 Bylsma, F. 235,245 (373), 275 Byson, T. A. 306 (670), 364 Cabaleiro, M. C. 144 (669), 154 (691), 217 Cabell, M. Jr. 240 (213), 271 Cacchi, S. 32(221), 111,234,251 (112),269 Caffary, E. L. 243 (238), 272 Caglioti, I. L. 179 (802), 219 Caglioti, L. 32 (221), 111,226 (19), 229,251 (47,48), 267,268 Cahiez, G. 140 (652), 216 Cahoon, J. M. 72 (388), 115 Cainelli, G. 32 (222), 111,126 (606), 215,371, 372 (21), 375 (44), 433 Calligaris, M. 251,256 (325,326), 274 Calo, V. 27 (182), 33 (226), 34 (232), 111,112 Cambie, R. C. 36 (243), I12 Cambillau, C. 211 (954), 222 Campbell, G. A . 235,244,245 (122), 269 Campbell, R. W. 229 (200,202),271,411 (211), 447 Campos, 0 . 8 3 (463), I16 Cantacuzkne, D. 71 (385), 115 Cantacuztne, J. 8 (50), 28,30 (187), 108,111, 255 (438-440), 276,370,372 (17), 387 (103), 413 (226), 416 (17,234), 443,444, 447 Cantrell, G. L. 122 (591), 215 Capitaine, J. 156 (694), 217 Caplar, V. 64 (353), I14 Capozzi, G. 136 (633,634), 216,391 (121, 122), 445 Carbognani, L. 291,299 (573), 362 Cardillo, G. 36 (244), 112,346 (758-761,825), 366,368 Cardwell, H . M. E. 26 (176), 110

455

Cardy, D. E. 14 (loo), 109 Caristi, C. 136 (633), 216,293 (584), 362,391 (121,122), 445 Carlin, J. T. 411 (208), 446 Carlsen, P. H. J. 240 (214), 271 Carlson, M. W. 42 (273), 55 (273,328,329), 112,113 Carlson, R. 10,30 (75), 109 Carpenter, B. K. 93 (507), 117 Carpino, L. A. 233 (101), 251 (101,313,314). 269,273 Carpio, H. 175 (775), 219,410 (206), 446 Carter, T. L. 145 (671), 217,376 (54), 444 Casadevall, E. 48 (301), 113 Casagrande, F. 160 (708), 217 Casara, P. 22 (151), 110,388 (108,109), 400 (108,160), 445,446 Casnati, G. 143 (633), 216,371 (25), 433 Casper, E. W. 14,30 (98), I09 Casper, E. W. R. 96 (534), 118 Castaldi, G. 148 (993), 160 (708-710). 217, 223 Castro, B. 89 (488), 117 Catch, J. R. 26 (175), 34 (231), I l 0 , I I I Catsoulacos, P. 52 (318), 113,226 (15,16), 267 Caujolle, F. 11 (83). I09 Caumartin, J. 230 (66), 268 Cava, M. P. 151 (680,681), 214 (962), 217,223 Cavt, A. 235 (426), 276 Cavicchioli, S. 148 (993), 223 Cavier, R. 161 (715),217 Celerier, J.-P. 339 (743), 366 Cervantes, A . 5 (27), 108 Chamberlain, P. 28 (195), 111 Chambers, R. D. 3 (12), 107 Chan, T. H. 134,139 (626), 216 Chan, T. Y. 328 (709), 365 Chancel, P. 379 (69), 394 (132), 428 (266), 444,445,448 Chandramouli, G. V. P. 168 (746), 218 Chandrasekaran, S. 144 (655), 216 Chang, A. I. 439 (301), 448 Chang, C.-J. 235,244,261,267 (138), 270 Chang, S. S. 411 (208). 446 Chanon, M. 74 (401,402), 115 Chapat, J.-P. 166(740),218,405 (179),446 Charbonnier, F. 207 (939), 222 Charpentier-Morize, M. 58 (335), 61 (346), 103 (335,560-562), 104 (561,562), 114, 118,211 (954), 222,245,246,350,357 (427), 276,351 (791,802), 353 (803), 367, 388 (106), 445 Chattaway, F. 337 (59), 444 Chattaway, F. D. 251 (306), 273 Chaunan, M. S. 411 (216), 447 Chauvin, J. 159 (704), 204 (930), 217,222,408 (202), 413 (202,227), 446,447 Cheburkov, Y. A. 3 ( l l ) , 107

456

Author Index

Chen, J. S.439 (301), 448 Chen, K.-M. 299 (640), 363 Chen, S.-A. 439 (301), 448 Chen, S.-Y. 230,247,267 (156), 270 Chenier, P. J. 2 (8), 107,259 (360), 274 Chenu, E. 242,262 (226), 272 Cherbuliez, E. 6 (31), 108 Cherkasov, R. A. 238 (436), 276,329 (719), 365 Cherkasov, V. M. 329 (722), 365 Cherkina, M. V. 305 (662), 329 (720), 364,365 Chernega, A. N. 203 (918), 222 Chernyarskii, A. I. 384,417 (235), 447 Chervenyuk, G. 370 (12), 443 Chervin, I. I. 348,349 (799,780), 366 Chervinskii. A. Y. 76 (415), 115,230 (110), 269 Chiang, Y. 346 (767), 366 Chiba, T. 72 (390), 115 Chidgey, R. 93 (504), 117 Chikashita, H. 214 (987), 223,408 (315), 449 Child, R. 254,267 (272), 272 Ching-Yun, C. 3 (lo), 107 Chin-Hsien, W. 182 (816), 220 Chishti, N. H. 31 (220), 111 Chiurdoglu, G. 9 (69). 108 Chkanikov, N. D. 329 (726,727), 365 Cho, D. 175 (775), 219,410 (206), 446 Choi, H. D. 204 (927), 222 Chopard, P. A. 96,98 (531), 118 Chow, H.-F. 345 (759,366 Chow, Y. L. 237 (429), 276 Chuiguk, V. A. 166 (743,744), 218 Chuit, C. 390 (118), 445 Chun, M. W. 246-248,262 (253), 272,299, 346 (635), 363 Chung, S. K. 214 (965), 223 Chupp, J. P. 282 (484), 359 Chys, J. 233,235 (115,116), 243,246 (116), 254 (116,279,280), 255 (280), 256 (116), 269,273 Ciabattoni, J. 59 (339), 114,240 (213), 271 Ciattoni, P. 230 (63), 237 (170), 268,270 Ciesiolka, J. 411 (209), 447 Clark, J. 212 (955), 222 Clark, V. M. 96,98 (531), 118 Clarke, J. T. 50 (312), 113 Clarke, S. J. 307 (672), 364 Clams, K. 208 (945), 222 Clemens, K. E. 93 (513), 117 Clifford, D. P. 283,357 (498), 360 Clive, D. L. J. 192 (862), 214 (968), 221,223 Clizbe, L. A. 239 (189), (205), 271,345 (756), 366 Cocco, M. T. 307 (671), 364 Cochram, D. W. 235,244,261,267 (138), 270 Coelho, F. 193 (865), 221 Cohen, L. A. 291 (569,570), 361,362

Cohen, S. 7 (47), 108 Cole, W. 68 (368), 114 Cole, W. J. 14 (loo), 109 Coleman, J . P. 378 (66), 444 Collet, C. 260 (364,365), 274 Collignon, N. 433 (285), 448 Cologne, J. 44 (279), 89 (487). 112,117 Comasseto, J. V. 214 (963), 223 Comber, R. N . 168 (747), 218 Combet Farnouse, C. 183 (831), 220 Combet-Farnoux, C. 72 (386), 82 (456,458). 115,116,226(14),267 Combret, J.-C. 406 (192), 446 Compagnini, A. 175 (788), 219 Compte, M.-T. 180 (808), 220 Conant, J. B. 41 (261), 112,242 (224), 271 Concellh, J. M. 428 (270-272), 435 (272). 448 Concellon, J . M. 189 (848,855-858),220,221, 429 (262), 448 Conia, J . M. 29 (203), 45 (294), I l l , 113 Contento, M. 32 (222), 111,126 (606), 215, 371,372 (21), 375 (44), 443 Cook, J. 235,245 (373), 275 Cook, J. M. 83 (463), 116 Cooke, M. P. 427,428 (260). 448 Cookson, R. C. 93 (500),117 Cooper, D. J. 101 (533), 118 Cooper, M. M. 291 (576), 362 Cope, A. 426 (251), 447 Cope, A. C. 45 (296), 113 Coppens, W. 13 (93-95). 56 (95), 109,231, 232 (79,81), 265 (79), 268 Corbet, J. P. 400 (158). 446 Cordel, B. 287,304,305 (530). 361 Corey, E. J. 28 (188), 30 (207), 75 (410). 111, 115,230,249 (68). 268,294 (594), 362, 435 (314), 449 Corkins, H. G. 303 (659), 364 Cornforth, J. W. 86.90 (477), 116.431 (273). 448 Cornforth, R. H. 86,90 (477), 116,431 (273), 448 Cornille, G. 378 (65), 444 Corsaro, A. 175 (788), 177 (792), 219 Costa, G. 254 (284), 260 (369). 273,275 C6tC, J. 156 (695), 217 Cotton, W. D. 93 (519). 100 (551). 117,118 Courtheyn, D. 9 (65-67). 84 (467). 108.116. 130, 131, 152 (610), 215,265 (445). 276, 373.377 (34). 396,397 (151. 152), 398 (154), 423.426,428 (246). 443,445,447 Cousins, R. C. 23 (155), 110,384,385 (95), 444 Cova, B. 76 (413), 115,251,256 (327), 274 Cowling, A. P. 93 (508,510). 117 Cowper, R. M. 28 (192), 111 Cox, B. G. 38 (260), 112 Cox, M. F. 49 (309). 113

Author Index Cox, R. A. 38 (259). 112 Crabb, J. N. 295 (604), 362 Crabbt, P. 5 (27,28), 108 Craig, W. E. 377 (61), 444 Cramer, A. B. 242,243 (228), 272 Cramer, F. (185, 186), 271 Crank, G. 175 (776), 219,411 (210), 447 Crawford, R. J. 76 (419), I15 Creary, X . 101 (554), 118,245,246 (428). 276, 311 (685). 364 Cretney, W. J. 235,245 (373), 275 Crich, D. 302 (654,823), 364,368 Crombie, L. 190 (861), 221 Cromwell, N. H. 29 (200), 52 (319,320), 68 (367), III,113,114 Cros, G. H. 166 (740), 218,405 (179), 446 Crouch, R. K. 14,30 (98). 96 (534), 109,118 Cruickshank, K. A. 301 (646), 363 Crumbie, R. L. 183 (827), 220 Cruz, A. 5 (27,28), 108 Csak, J. 280 (475), 359 Culman, J. 226 (25), 267 Curran, W. V. 256 (329), 274 Curtin, D. Y. 76 (417), 115,226 (28), 267 Curtis, N. J. 180 (806),220 Cuvigny, T. 231 (78), 268 Czamy, M. 428 (258), 448 Dagher, C. 184 (834), 220 Dahan, R. 7 (45), 108 Dahl, 0 . 9 9 (541-542), 118 Dahlman, 0 . 1 9 5 (873), 221 Daltrozzo, E. 347 (772), 366 Damiano, J. D. 5 (28), 108 D’amico, J. J. 182 (822), 220 Dang Quoc Quan 11 (82,83), 109 Danilov, L. L. 346 (762), 366 Danilov, S. N. 237 (164), 270 Danilow, S. 394 (131), 445 Dannhardt, G. 293 (591), 362 Dappen, G. M. 89 (482), 117 Dappen, M. S. 286,302 (511), 306 (668), 360, 364 Darling, D. L. 125 (973), 223 D’Ascoli, R. 36 (245), I12 Das Gupta, T. K. 251 (299,300,302), 273 Dash, B. 287 (523), 360 Daub, G. W. 294 (600), 362 Daubit, C. 147 (676), 217 D’Auria, M. 36 (245), 112 Dave, V. 207 (940), 222 Davidson, L. H . 28 (192), 111 Davies, D. E. 286,306 (514), 360 Davis, G. G. 38 (250). 112 Davtyan, S. M. 161(716), 218 Davydov, A. V. 350 (784), 366 Day, B. F. 28 (194), 111 De, S. C. 230 (58,59), 268

457

Deady, L. W. 168 (745), 218 De Bievre, P. J. 378 (65), 444 Debourge, J. C. 357 (813), 367 De Buych, L. 70 (381), 114 De Buyck, L. 6 (33), 9 (64-67), 10 (73). 11 (33), 14 (96), 22 (33,209), 28 (33), 29 (202), 30 (33,96,202,209), 44 (33), 46 (64), 56 (33,64,209,332), 58 (64). 70.75 (405), 84 (467), 85 (469), 89 (485,486), 108,109,111,113,115-117,130(610615), 131 (610,613-615). 152 (610-612), 159 (707). 165 (732). 166 (733), 215,217, 218,226 (2), 233 (85-90,92,115,116),235 (115,116), 236 (143), 242 (233), 243 (87, 116), 245 (87), 246 (116), 247,253 (87), 254 (116,276-280,457), 255 (280), 256 (86,87,90,116), 257 (143,278), 258 (85, 143,344,346), 259 (278). 260 (86.87,362, 363,424). 262 (88),263,264 (2), 265 (88. 92,445,446), 277 (461), 282,283,296 (461), 314 (276), 318 (87), 331 (85,143, 346). 351 (346), (281,283). 267-270,272274,276,277,280 (474,476), 282 (489, 490), 283 (490,492,494,495), 288 (537), 292 (578), 297 (628), 298 (494,578,631633). 299 (494,632,633), 314 (633,697, 698), 315 (633,698). 316 (633), 318-320 (490), 321 (494), 331 (537,733,333 (631), 334 (633,698), 337 (737), 339 (632, 742). 351 (537,735,802). 353 (494,633). 354 (489), 359-367,373,377 (34). 381 (84), 396,397 (151, 152). 398 (153,154), 403 (170). 411 (219), 413 (231), 420 (242). 423 (242,246). 426 (246), 428 (246,269), 443-448 Decesare, J. M. 388 (105), 445 Declercq, J.-P. 282,298,324,332-335 (491), 337 (491,737). 360,365 Declercq, J.-P. 260 (362), 274 De Cock, W. 133 (623), 216 De Corte, B. 282,283,318-320 (490), 360 Deep, K. 175,177 (791). 219 Degener, E. 293 (587), 362 DeGraw, J . I. 186 (839). 220 Dehm, D. 401 (164), 446 Dehne, H. 175 (779). 219 Dejonghe, W. 236,257,258,331 (143), 270, 411 (219), 447 De Kimpe, N. 6 (33), 9 (64-67). 10 (73), 11 (33). 13 (92,94,95), 14 (96). 22 (33,209), 28 (33), 30 (33,96,209,213), 44 (33). 46 (64). 56 (33,64,95,209), 58 (64), 70 (381, 405,406,586). 75 (405,406). 84 (467). 85 (469). 89 (485,486), 108.109,111,114117,119,130 (610-615). 131 (610,613615), 133 (623). 152 (610-612), 159 (707), 165 (732). 166 (733). 170 (762). (983, 984). 215-219,223,226 (1,2), 231 (80-

458

Author Index

83). 232 (80-83,91), 233 (85-92, 115, 116), 235 (113, 115,116), 236 (143), 240 (I), 242 (233), 243 (80,82,87,116,248), 245 (87,248), 246 (116), 247,253 (87), 254 (116,276-280,457), 255 (91.280), 256 (86,87,90, 116), 257 (143,278). 258 (85,143,344-346.348). 259 (82,248, 278), 260 (86,87,248,362,363,424), 262 (88), 263,264 (2), 265 (88,92,445,446), 267 (248), 277 (461). 280 (113). 282,283. 296 (461), 298 (80,82,248), 314 (276). 318 (87), 331 (85,143,345,346), 333 (80), 351 (346), (281,283), 267-270,272-274, 276,277,280 (462,474,476), 282 (489491). 283 (490,492-495), 288 (537), 292 (578), 297 (628), 298 (491,493,494,578, 631-634). 299 (494,632-634). 312,313 (689), 314 (633,634,697.698), 315 (633, 634,698), 316 (633,634), 317 (634), 318 (490,699), 319,320 (490), 321 (494,689), 324 (491). 325,326 (493). 331 (493,537, 735), 332 (491), 333 (491,631), 334 (491, 633,634,698), 335 (491), 337 (491,737), 339 (493,632,634,742). 349 (493), 351 (493,537,735,802), 353.493,494,633. 634). 354 (489), 357 (493). 359-367,373. 377 (34), 381 (84), 396,397 (151,152), 398 (153,154). 403 (170), 411 (219), 413 (223,231), 420 (242), 423 (242,246), 426 (246). 428 (246.269), 443-448 Delandais, D. 147 (676), 217 Delaney, N . G. 171 (763). 219 Delbaere, P. 11 (79), 109 Della, E. W. 237 (435). 276 Del’tsova, D. P. 263 (395), 275,296 (617), 363 Demakov, V. A. 199 (YOl), 221 DeMarch, P. 427 (256), 447 Demerseman, P. 13 (91), 109, 161 (715). 217. 294 (598), 329 (713). 362,365 Dendane. M. 233,234 (107). 269 Denis, J. N . 214 (967), 223 Denivelle, L. 17 (120). 109 Denmark, S . E. 286,302 (511). 306 (668), 360, 364 De Pooter, H. 130, 152 (612). 215 Deprts. J.-P. 20 (143), 110. 193 (865), 221 De Puy, C. H. 89 (482). 117 Deroque, J.-L. 48 (302). 113 De Rosa, M. 291,299 (573), 362 De Roza. M. 235 (123,124). 269 Desai, J. A . 171 (766),219 De Selms, R. C. 388 (739), 365 Desimoni, G . 305 (661), 364 Detty, M. R. 180 (810). 220 Dewar, M. J. S. 42 (269), 112.243 (234). 272 De Young, J. J. 51,53 (316), 113 DeYoung. J . J. 260 (422), 276 Deyrup, J . A . 351 (795),367

Deyson, G. 242.262 (226), 272 Dhathathreyan. K. S. 296 (625), 363 Dick, C . R. 373 (33). 443 Dickinson, N. 294 (596), 295 (613). 362,363 Dickore, K. 246 (255), 272 Diebold, J. L. 45 (287). 113 Dines, M. 314 (696). 364 Dingwall, J. 137, 153 (644). 216 Dinkeldein, U. 238 (179), 271 Diopoh, J. 267 (415), 275 Dirsch. R. 12 (88). 109 Dittrich, B. 263 (380), 275 Divo, C. 237 (170). 270 Djerassi, C. 30 (210,212), 31 (216), 36 (212, 241). 111,112,226,256 (21), 267 Djerassi, C. D. 12,15 (89). 109 Dmitrienko, G. I. 166,167 (735), 218,235 (119),244(119,251),245(251),269.272, 299 (636,637), 363 Dneprovskii. A . S . 15 (103). 109 Dobrov, I. V . 384,417 (235), 447 Doe de Maindreville. M. 291.325 (565). 361 Doehner, R. F. Jr. 30 (208). 111 Doering, W. E. 17 (116), 109 Dohling, T. 388 (107), 445 Dolby, L. 235,245 (130), 269 Dolson, M. G. 296 (624). 363 Domagala. J . M. 377 (64). 444 Dombrovskii. A. V. 427,428 (261). 448 Dondoni, A . 229,251 (47), 268 Donnand, H. V. 7 (43). 108 Donnelly, J. A. 49 (307-309), 70 (307). 86 (471), 113,116,171(768), 219 Dora, E. K. 287 (523). 360 Dorman. S. C. 229,267 (331,332). 274 Dornow, A. 238 (172, 173), 249 (172,295). 256 (295), 270.273 Dorsky. J. 9 (71), 10 (72). I09 Dossena, A. 143 (662.663). 216,371 (25). 443 Doubleday, C. 194 (870). 221 Doyle, T. W. 346 (767), 366 Drach, B. 236,238,257 (145). 270,384 (89), 444 Drach, B. S. 238 (177). 243 (247). 257 (247, 342,410). 270,272,274,275,329 (721), 365 Drnovsek. I. 143 (659). 216 Drozdova. T. 1.295.329 (602), 362 Druesne, F. 395,396 (147), 445 Dua, S . K. 187 (842). 220 Dubin. J. C. 44 (279). 112 Dubois. J.-E. 90 (491,492). 91 (493.494). 92 (498). 117, 199 (899), 214 (969,970). 221. 223 Dubois. J. E. 38 (251). 112,318 (700.701). 365 Dubroeucq, M.-C. 74 (397), 115 Dubs, P. 80 (442). 116 Dugast. J.-Y. 214 (969), 223,318 (700). 365

Author Index Duggan. D. E. 238,267 (180.203), 271 Duhamel, L. 71 (382-384). 114.115. 146, (674). 159 (704). 204 (930), 217,222,226 (33). 228 (43.44). 229 (43), 241 (219). 255 (321,323). 256 (322,324). 258 (321). 260 (364-366), 314(324),267,268.271.274, 282 (487,488). 359.370 (13). 379 (82). 384 (93,94). 400 (155), 403,404 (169). 405(155, I84-186, 189),406(82. 191. 193-197), 408 (202). 413 (202,225.227). 439 (304), 443-448 Duhamel. P. 21 (150), 71 (382.383), 110.114. 115,228 229 (43). 255 (323). 256 (322). 260 (364,365). 268,274,282 (487,488), 339 (744). 359.366,370 (13). 379 (82). 384 (91-94), 385 (91.92). 400 (155). 403, 404 (169), 405 (155, 183-186. 189). 406 (82. 191. 193. 194), 413 (227). 443-447 Dunigan, J. M. 130 (616), 215 Dunlap, R. P. 38 (257), 112 Durr, M. 329; 349 (728), 365 Durst, T. 35 (233), 112,388 (104, 105), 445 Dusza, J. P. 411 (211), 447 Dutron-Woitrin, F. 169 (759), 218 Dvoinishnikova, T. A. 411 (217). 447 Dworzak, R. 370 (8), 394,395 (130). 443,445 D’yachenko. 0. A. 286 (518), 345 (754), 360, 366 Dyachenko, 0. A. 349 (783),366 Dyong, I. 346 (768), 366 Ebel, F. 83 (460), 116 Edwards. E. G. 9 (SS), 108 Edwards, J. 4 (24), 108 Edwards, 0. E. 82 (311). 113,242 (242),272 Edwards, R. V. 283,357 (498), 360 Eeckhaut, Z . 378 (65), 444 Effenberger, F. 10,30 (76), 109 Ege, G . 81 (445), 116 Eggersdorfer, M. 228 (40), 268 Eguchi, S. 174 (770), 219 Ehrhardt, H. 169 (757), 218 Eicher, T. 59 (340), 114 Eilers, K. L. 89 (482), 117 Einhellig, K. 263 (375), 275 Einhorn, J . 161 (715),217 Eisch. J. J. I87 (842), 220 El-Daway, M. A. 168 (749), 218 Elkik, E. 7 (44.45), 8 (51). 58 (334), 86 (478), 108,113,216,228 (412), 275,405 (188), 406 ( 190), 446 Ellinger, L. P. 67 (363), 114 Elliott, A. J. 166 (738), 218 Elliott, D. F. 26 (175), 110 Elliott, R. D. 168 (747), 218 Ellis, D. B. 357 (807),367 Elphimoff-Felkin, I. 45 (289), 113 Elston, C. H. R. 17 (119). 109

459

Elving, P. J . 19 (132), 110 Emde, H. 205 (932), 222 Emmerich, W. 24 (164), 110 Emori, T. 233 (loo), 269 Enders, R. 12 (88). 109 Endo, M. 235,244 (121), 262 (121,371),269, 2 75 Enenkel. E. 370 ( 8 ) , 443 Engel, C. R. 156 (694,695), 217 Engelhardt, E. L. 238,267 (180),271 Engler, E . 170 (761), 219 Engman, L. 214 (962), 223 Eremeev, A . V. 293 (589), 362 Erfurt, G. 236 (142), 257 (335,336), 270,274. 411 (218), 434 (289), 447,448 Erhardt, J. M. 194 (868). 221 Erlenmeyer, E . 370 (10),443 Erni, B. 227,228 (105),269,393 (128), 445 Ershov, V. V. 96 (528), 118 Eschenmoser, A. 251 (299-303,305), 273,297 (630), 363 Essawy, A. 285 (506),360 Eue, L. 288 (542), 302,359 (542,652). 361, 363 Evans, D. P. 9 (55). 108 Exarhos, C. 266 (431), 276 Ezhova, G . I. 133 (624), 216 Fabre, G. 433 (285), 448 Falsone, G. 186 (837), 220 Fanakoshi, W. 80 (438), 116 Faragher, R. 306,307 (663), 364 Farbman, M. D. 9 (60),108 Farkas, E. 11 (81), 44 (280), 109,113,374, 393,395 (36), 443 Farr, R. A. 291,301,342 (562), 361 Faust, D. 288,328 (545), 361 Fava, A . 243 (243). 272 Fava, G . G . 143 (662), 216 Favorskii, A. 15 (104), 21 (145), 109,110 Febres, A. 291,299 (573), 362 Federlin, P. 394 (132,133), 395 (136,137). 445 Feditre, J. 96 (523). I17 Fehlauer, A . 96 (522), 117 Fehn, J. 257 (341). 263 (382), 274,275 Feiring, A. E . 59 (339). 114 Felici, M. 234,251 (112). 269 Felix, D . 251 (299-301), 273 Fenner, H. 178 (795), 219 Ferao, A. 168 (748), 178 (796). 218,219 Fernandez, J. R. 189 ( S O ) , 220 Fetell, A. I. 23.5 (114),269 Feuer, H. 235 (114),269 Fiebig, H. 73 (396), 115 Fiebig, H. J . 410 (205), 446 Fields, K. W. 199 (904), 201 (905). 206 (936), 221,222,311 (686,687), 364 Fierz, G. 93 (504), 127

460

Author Index

Fieser, L. F. 12, 15 (89), 109 Filachione, E. 379 (77), 444 Filler, R. 29 (201), 111,122 (587), 215 Finch, N. 235,244 (132,133), 245 (132), 261, 267 (132,133), 269 Finger, G. C. 12 (87), 109 Fink, J. 329,349 (728), 365 Fiorenza, M. 206 (935), 222 Firl, J. 263 (393), 264 (404,459), 275,277,323 (704), 347 (773), 365,366 Firstenberg, S. 96 (534), 118 Fischer, H. 31 (217), 111 Fischer, H. P. 233,249 (94), 269 Fischer, W. 239 (210). 271 Fischer, W. F. 101 (555),118 Fischer, W. F. Jr. 311 (684), 364 Fisher, J. W. 130 (616), 215 Fishwick, C. W. G. 295 (604), 362 Fitjer, L. 86 (473), 116,154,209 (689), 217, 282 (483), 359,403 (171), 446 Flammang, M. 233,234,256 (102, 103),269 Flammang, R. 124 (603), 215,351,357 (799), 367 Fleming, I. 102 (556), 118,206 (938), 222 Flogaus, R. 141 (654), 158 (700), 216,217 Flood, T. C. 306 (824), 368 Flor, R. V. 96 (526), 118 Horez, J. 189 (859), 192 (863), 221,435 (291), 448 Florsheim, W. H. 28 (194), I11 Flueck, V. 180 (813), 220 Foag, W. 228,263 (41), 268 Foerster, H. 288 (542), 302,359 (542.652), 361.363 Fohlisch, B. 27 (184), 78 (429). 111.115,141 (654), 158 (696-700), 159 (701), 216,217 Fokin, A. V. 285,314 (501). 329 (726,727). 347,348 (501), 360,365 Fomani, M. 135 (630), 216,390,395 (120). 445 Fomina, N. V. 384,417 (235), 447 Font, J . 427 (256), 447 Fontaine, A. 57 (333). 113 Foricher, J. 233 (448), 276 Forlani, L. 31 (219), Ill Forman, L. E. 17 (122), 110 Forrest, I. J. 411 (213), 447 Forsch, M. 439 (306), 449 Fort, A. W. 55 (331), 113 Fort, R. 17 (120), 109 Fortenbauch, R. B. 64 (351), I14 Fotin, V. V. 93 (517), 117 Foucard, A. 199 (914), 202 (912-914), 207 (944), 222 Foucaud, A. 290,291 (559), 361 Fougerousse, A. 22 (151), 110,388 (108,109), 396,399 (150), 400 (108,160,163), 445, 446 FourC, M. 257 (452), 276,439 (306), 449

Fournier, F. 144 (666,667), 216 Fournier, M. 144 (666,667), 216 Fournier, P. 91 (493,494), 117 Fox, D. P. 234,252 (453), 276 Fox, M. J. 49 (308), 86 (471), 113,116 Franco, F. 175 (775), 219,410 (206), 446 Francotte, E. 249 (297). 250 (292a, 292b, 297), 273,294,302,303,306 (597). 362 Frank, G. A. 427 (254), 447 Frank, L. 280 (475), 359 Frank, R. 239 (195-198), 259 (195,361),271, 274,332-334,346 (736), 365 Franke, W. 175,177 (784), 219,411 (212), 447 Franz, R. 123 (598), 215 Fraser, R. R. 6 (39), 108 Frases, M. 171,173 (765),219 Fraunberger, F. 236 (147,152), 255 (285), 270, 2 73 Freedman, M. B. 238,267 (180), 271 Freeman, R. C. 51 (315), 113,238 (193), 260 (421), 271,276 Freer, J. 174 (773),229 Freerks, R. L. 345 (756), 366 FrChel, D. 339 (749,366 Fresneda, P. M. 168 (748), 188 (847), 218,220 Freundenzeich, B. 239 (197), 271 Frtze, R. 96 (533), 118 Fricker, U. 358 (820), 367 Fries, K. 17 (121), 109 Friesen, R. W. 299 (636), 363 Frihart, C. R. 405 (181), 446 Friour, G. 140 (652), 216 Frisen, R. W. 166,167 (735), 218 Fristad, W. E. 229,251,256 (SO), 268 Fritz, G. 61 (347), 114 Fritz, H. 310 (679), 364 Fritzberg, A. R. 59 (338), 114 Fry, A. J . 6 (34), 106 (570,571), 108,119,375 (46), 443 Fryer, R. I. 235,244,262 (129),269 Fuchigami, T. 182 (819,820), 220 Fuchs, B. 144 (664), 226 Fuchs, P. L. 229 (49), 251,256 (49,309), 268, 2 73 Fuehrer. W. 288 (5421,302,359 (542,652). . , 361,363 Fuhrer. W. 297 (630). 363 Fuji, K: 235,245 (373), 275 Fujii, K. 210 (949), 222 Fujimoto, E. 214 (972), 223 Fujinami, T. 199 (897), 221 Fujita, E. 80 (436), 116,242 (229,230), 272 Fukuhara, N. 3 (15). 107 Fukui, K. 230,248,262 (266), 272 Fukushima, H. 175 (785), 219 Fukuzawa, %-I. 199 (897), 221 Fumarola, M. J. 144 (668), 227 Funakura. M. 93 (505), 117

Author Index Fung. A. P. 107 (582). 119 Fustero, S. 439 (307), 449 Gabbard, R. B. 4 (19), 107 Gagel, K. 16 (108). 109 Gagosian, R. B. 43,49 (275), 112 Gaillot, J . M. 351 (800). 367 Gal, C. 122 (588), 215 Galakhov, M. V. 329 (727), 365 Galazzi, E. 5 (27). 108 Galeazzi, E. 175 (775), 219,410 (206), 446 Galens, H. 72 (386). 115 Gall, M. 101 (555), 118,311 (684), 364 Galla-Bobik, S. V. 376 (55), 444 Gallagher, T. C. 321 (702), 349 (781), 353 (702), 365,366 Gallegra. P. 175 (779,219,410 (206), 446 Gallo, R. 74 (402), 115 Gallucci, R. R. 127 (608), 215 Galons, H. 82 (456,458), 116,183 (831), 220, 226 ( 14), 267 Gambaryan, N. 70 (379). 114,227,228,257, 258 (37), 268 Gambaryan, N. D. 263 (391,392), 275 Gambaryan, N. P. 3 (lo), 107,263 (387,389, 395), 275,296 (617), 329 (712,724,729), 347,348 (771), 363,365,366 Gammil, R. B. 300 (641), 363 Ganboa, I. 143,171 (660), 216 Ganns, E. M. 136 (635), 216,292 (581), 362 Gansser, C. 242,262 (226), 272 Garay, R. 0. 144 (669), 154 (691), 217 Gardner, J. P. 130 (616). 215 Gardner, P. D. 36 (240), 112 Gareev, G. A. 302 (653), 364 Gareev, R. D. 305 (662), 329 (720), 364,365 Garrard, T. F. 28 (195), 111 Garst, M. E. 163 (724), 218 Gasparouse, H. 182 (817), 220 Gassen, K. R. 331 (734), 365 Gassman, P. G. 235,244,245 (122), 269,351 (787), 367 Gasteiger, J. 154 (690), 217 Gattuso, M. 293 (584), 362 Gaudiano, G. 86 (470), 116,248 (265,267, 268), 250 (296), 272,273,309 (675), 364 Gaudry, M. 25 (171), 26 (180), 27 (181), 110, 111

Gaumont, Y. 230,247,267 (156), 270 Gauss, W. 246 (254), 272 Gaydou, E. M. 96 (533), 97 (535), 118,432 (281,282), 448 Gayral, P. 161 (715), 217 Gazizov, T. K. 98 (537). 118,432 (283), 448 Geetanjali, Y. 161 (718), 218 Gehret, J. C. 286 (515), 360 Gehrlach, E. 158 (696). 159 (701), 217 Geiger, M. 9 (56), 19 (133), 108, I10

46 1

Geiseler, G. 78 (427), 115 Geissman, T. A. 86 (475), 116 Gelas-Mialhe, Y. 351 (800), 367 Gellon, G. 408 (203), 446 Gemal, A. L. 107 (585), 119 Gen, A. van der 375 (48), 443 Genin, D. 291 (574). 362 George, G. 257 (341). 274 Germain, G. 249,250 (297), 260 (362), 273, 274.326 (708), 365 German, L. S. 295 (611), 363 Gertitschke, P. 285 (505),360 Gerzon, K. 379 (71), 444 Gewald, K. 163 (726), 218 Ghelfi, F. 130 (981), 143 (982),223,371 (26), 375 (45), 443 Ghirlando, R. 177 (793), 219 Ghosez, L. 238 (194),271, 351 (798),367 Giagante, N. N. 144 (669), 217 Giardino, P. 230,245,267 (51), 268 Gibson, T. W. 68 (376). 114,226 (7), 267 Gieren, A. 263 (382,384), 275 Gierer, J. 79 (431), 115 Giesemann, G. 283 (499), 360 Gilchrist. T. L. 249 (447), 251 (298,451), 273. 276,286 (509,514), 287 (525,526,529). 294 (509), 295,296 (526,607), 302 (650). 306 (509,514,650,663-665), 307 (525, 529,663,672). 310 (509), 328 (650), 360364,411 (222), 447 Gillespie, J. P. 251 (315).273 Gillis, B. 370 (15). 374 (15,36), 393 (36). 395 (15,36), 443 Gillis, B. T. 226,251 (18).267 Gillon. D. W. 182 (818). 220,411 (213), 447 Ginsburg, D. 12,15 (89), 109,251 (304), 273 Ginsburg, G. S. 106 (571), 119 Giordano, C. 148 (993), 160 (708-710). 217, 223 Gipe, D. E. 145 (670,671), 217,376 (54), 377 (58), 444 Gipe, R. K. 135 (632), 145 (671),216,217,376 (54), 444 Giral, L. 169 (754), 182 (817), 218,220 Girard, M. A. 266 (414), 275 Girardeau, J.-F. 82 (456), 116 Girardeau, J. F. 72 (386), 82 (458), 115,116 Giusti, G. 80 (440), 116 Givardeau, J.-F. 226 (14),267 Gladiali, S.65 (355), 114 Gladysz, J. A. 436 (294), 448 Gleason, J. 297 (630), 363 Gleissner, M. R. 393 (126), 445 Godleski, S.A. 375 (43), 408 (201). 443,446 Goerlitzer, K. 170 (761), 219 Gogoberidze, I. T. 295,329 (603), 362 Goi, M. 201 (907),222 Going, R. 127 (608), 215

462

Author Index

Gold, V. 204 (928). 222 Goldberg, A. A. 67 (363), 114 Goldberg, I. 288,328 (545), 361 Goldhill, J. 102 (556), 118 Goldschmidt, B. M. 404 (174), 446 Goldsmidt, S. 12 (88),109 Goldstein, R. C. 404 (174), 446 Gollmer, G. 9 (59), 108 Gololobov, Y. G. 80 (433), 99 (544,545), 116, 118,203 (917,918), 222,432 (280), 434 (288), 448 Golyashnaya, N. V. 199 (901), 221 Gomez, M. R. 166 (734), 218 Gompper, R. 72 (392), 115 Gonzalez, C. 60 (345), 114 Gordon, E. M. 171 (763), 219 Gormicki, P. 411 (209), 447 Gosciniak, D. 151 (680), 217 Gossick, G. J. 81 (446), 116 Goswami, A. C. 6 (37), 108 Goth, H. 263 (458), 264 (404,459), 275-277, 323 (704), 347 (773). 348 (778), 365,366 Goto, H. 171 (767), 219 Goto, M. 405 (180), 446 Gotor, V. 290 (556,557), 361,439 (307), 449 Gotschi, E. 297 (630), 363 Gottlieb, 0. R. 242 (227), 272 Gottschalk, P. 388 ( l l l ) , 429 (111,264), 431 ( I l l ) , 445,448 Gottstein, W. 27 (184), 78 (429), I l l , 115,158 (696-698), 21 7 Gotz, A . 205 (932), 222 Gough, T. E. 6 (35), 108 Gould, E. S. 37 (248), 112 Gould, K. J. 92 (499), I17 Goument, C. 204 (930), 222 Gounelle, Y. 164 (727), 218,280 (471), 359 Goyau, B. 53 (323), I13 Graham, E. S. 45 (296), 113 Gralak, J. 384 (93,94,96), 444 Granacher, C. 9 (56), 19 (133), 108,110 Grandberg, I. I. 166 (742), 218 Grandi, R. 130 (981), 143 (982), 223,371 (26), 375 (49,382 (86), 443,444 Grasselli, P. 229,251 (48), 268 Gratton, S. 76 (413), 115,251,256 (325-327), 2 74 Greci, L. 291 (568), 361 Green, R. C. 145 (671), 217,376 (54), 444 Greenburg, R. B. 50 (312), 113,226 ( l l ) , 267 Greene, A. E. 20 (143), 110, 193 (865), 207 (939), 221,222 Greene, A. F. 194 (869), 221 Greene, F. D. 59 (337), 114 Greenhouse, R. 175 (775), 219,410 (206), 446 Greisel, M. 347 (772), 366 Grenet, J. 89 (487), I17 Grenier-Loustalot, M. F. 12 (84), 109

Greuter, H . 20 (138), 110,137 (642,644), 153 (644,687,688), 171 (688), 180 (813), 216, 217,220 Grieco, C. 82 (311), 113,242 (242), 272 Griesbaum, K. 23 (156), 110,123 (599-601), 137 (599,600,647), 154 (693), 215-217, 385(101,141),388(107,110),395(141, 144), 444,445 Griesser, H. 179 (803), 219,299 (638,639), 363 Grigor’ev, I. A . 302 (648), 363 Grinev, G. 370 (12), 443 Grivas, I. C. 238 (178), 271 Grob, C. A. 233,249 (94), (244), 269,272 Groenewegen, P. 375 (48), 443 Grohe, K. 293 (587). 362 Gross, A. 329,330 (716), 365 Gross, E. A. 235,244 (119), 269,299 (636, 637), 363 Grossi, M. 287 (532), 361 Grossman, J. 36 (241), 112 Grossman, L. I. 107 (578), 119 Grundke, G. 143 (661), 216,371 (24), 443 Grunwald, E. 42 (270), 112 Gryaznov, P. I. 432 (283), 448 Grzeskowiak, N. E. 162 (720),218 Gsell, L 180 (813),220286 (515),360 Gutritte, F. 235,267 (417), 276 Guette, J.-P. 130 (609), 215 Guillaumel, J. 294 (598), 362 Guillot, J. C. 357 (813), 367 Guimon, M. F. 9 (68), I08 Guinot, H. 373 (28), 443 Guirado, A. 214 (959,960), 223,311 (683), 364 Gulta, V. S. 306 (666), 364 Gupta, S. M. 168 (751), 218,281 (478), 359 Gurylev, E. A. 96 (530), 118 Gurzoni, F. 160 (710), 217 Guseinova, L. S. 438 (298), 448 Gutman, A. D. 357 (809-812,814), 367 Guy, A. 130 (609), 215 Guzik, H. 166 (738), 218 Guzman, A. 410 (206), 446 Guzman, A. 174 (771), 175 (775),219 Gygax, P. 251 (299,302,305),273 Ha, T. K. 351 (790), 367 Haake, P. 100 (546,547), 118 Haas, A. 439 (302), 448 Habashy, M. M. 285 (506), 360 Habecker, C. N. 238,267 (181), 271 Haddadin, M. J. 350 (785), 366 Haelters, J. P. 287,304,305 (530), 361 Hafter, R. 235 (270,271), 253,254 (271), 261, 267 (270,271), 272 Haga, N. 283,326 (497), 360 Haga, T. 199 (892,893), 221

Author Index Hagaman, E. W. 235,267 (135), 270 Hagedorn, F. 226 (36), 268,377 (62), 444 Hagerty, J. D. 226,251 (18), 267 Hagman, W. K. 75 (408), 115 Hagmann, W. K. 251 (307), 273 Hague, M. 140,146 (651), 216 Hague, M. S. 201 (905),221 Hahn, B. 132,182 (620), 216 Hahn, D. W. 266 (431), 276 Hahn, G. 214 (966), 223 Hahn, W. 2 (l), 107 Haider, A . 260 (364,365), 274 Haire, M. J. 238 (174), 258,259 (351), 270, 2 74 Hall, D. 251 (305), 273 Halpern, 0. 175 (775), 219,410 (206), 446 Halvorsen, A. 44 (277), 112,243 (237), 272 Hamad, M. M. 285 (506), 360 Hamana, H. 141 (653), 216,295 (605,606), 362 Hambly, G. F. 134,139 (626), 216 Hamelin, R. 395 (148,149), 445 Hamer, N. K. 212 (958), 223 Hamman, S. 285 (503), 360 Hammond, G. B. 201 (985), 223 Hamon, L. 194 (867), 221 Hamsher, J. J. 68,70 (377), 102 (558), 114, 118,226(12),267 Hamzink, M. R. J. 287 (534), 361 Han, Y.-K. 229,251,256 (50), 268 Hanack, M. 48 (302), 113 Hand, E. S. 166 (739), 218,405 (176), 446 Handte, R. 169 (757), 218 Hankovszky, 0 . 2 8 0 (475), 359 Hanna, R. 184 (834), 220 Hanold, N. 203 (922), 222 Hansen, H. V. 331 (731), 365 Hansen, J. F. 324,356 (705,706), 365 Hansen, J.-J. 351 (797), 367 Hanske, J. 228,258 (38), 268 Hantzsch, A . 230 (60), 268 Hara, S. 391 (123), 445 Hara, T. 175 (785), 219 Harada, T. 130 (618), 199 (894),216,221 Hardenbergh, E. 426 (251), 447 Harding, C. E. 48 (302), 113 Hardy, J. C. 351 (Sol), 367 Hardy, R. 190 (861), 221 Harkema, S. 293 (590). 362 Harmata. M. A . 439 (301), 448 Harnisch, J. 239,259 (211), 271 Harrison, C. R. 92 (499), 117 Harsanyi, K. 314 (695), 364 Hartke, C. A. 235,245,261 (128), 269 Hartman, G. D. 405 (178), 446 Hartman, R. D. 405 (178). 446 Hartwig, A . L. 105 (566), 118 Hashimoto, N. 239 (183,184), 271

463

Hashimoto, S. 93 (518), 117,198 (888),221 Hashimoto, T. 182 (821), 188 (845), 220,411 (214), 429 (265), 447,448 Hashimoto, Y. 235,244,262 (121), 269 Hasma, H. 233,243,245,247,253 (87), 254 (276), 256,260 (87), 314 (276), 318 (87), 269,273 Hassan, M. E. 411 (216), 447 Hassanein, M. 371 (22), 443 Hassner, A. 20 (140,141), 52 (318,319), 75 (412), 110,113,115,226 (15), 230 (157), 239 (209), 247,248 (157), 258 (347), 267, 270,271,274,350 (785), 366,379 (80), 392 (125), 444,445 Hata, G. 88 (480), 117 Hata, T. 33 (223), 98 (538), 111,118,203 (916), 222,434 (286,287), 448 Hatfield, G. L. 289 (549), 361 Hatfield, L. D. 130 (616), 215 Hatzelmann, L. 263 (375), 275 Haug, T. 381 (85), 444 Hauptmann, S. 288,304 (543), 361 Hasuke, J. 70 (380), 114 Hausler, J. 233,246 (98), 269,288,297,331 (539), 361 Haxby, J. B. 345 (752), 366 Hayakawa, Y. 93 (505,509), 117,195 (875, 877), 221 Hayashi, T. 290 (559,361 Hayat, M. 242,262 (226), 272 Hayward, R. C. 36 (243), 112 Hazzaa, A. A. B. 168 (749), 218 Heasby, V. L. 36 (246), 112 Heasley, G. E. 36 (246), 112,135 (632), 145 (670,671), 216,217,376 (53), 377 (58), 444

Heasley, L. E. 36 (246), 112 Heasley, V. L. 135 (632), 145 (670,671), 216, 217,376 (53,54), 377 (58), 444 Heck, R. F. 390 (119), 445 Hegde, S. G. 135 (631), 216 Heidema, J. H. 249 (288,289), 273 Heilbron, I. 408 (200), 446 Hein, F. 263 (386,393), 275 Heinz, G. 3(230), 4 (22), 108,111 Heinzer, F. 185 (835), 220,426 (250), 447 Heitzer, H. 246 (254), 272,293 (587), 362 Hemmert, F. 400,401 (161), 446 Henderson, R. B. 28 (194), 111 Hendley, E. C. 28 (197), 47 (300), 111,113 Hennequin, L. 135 (630), 205 (934), 216,222, 390,395 (120), 439 (303), 445,448 Hennion, G. F. 36 (236), I12 Henry, A. C. 358 (815), 367 Hepp, L. R. 306 (670), 364 Herlem, D. 235,267 (139), 270 Hermecz, I. 301 (647),363 Hermkens, P. H. H. 310 (677), 364

464

Author Index

Herold, T. 438 (296), 448 Herr, R. R. 88 (479). 117 Herranz. E. 60 (341); 114 Herrmann, R. 44 (284), 113 Herscheid, J. D. M. 286,310 (508), 360 Hershenson, F. M. 235,261 (126,127), 267 (126),344(127),269 Hershkowitz, E. 231,252 (76), 268 Hertenstein, U. 374 (40), 418 (236), 443,447 Herter, R. 158(698,699), 159 (701), 217 Herzig, C. 154 (690), 217 Hess, 0.226 (24), 267 Hess, P. H. 68 (367), 114 Hesse, G. 9 (61), 45 (293), 108,113 Hesse, R.H. 122 (589), 215 Heublein, A. 233,234 (93), 239 (198), 269, 271,332-334,346 (736), 365 Hewson, R. T. 283,357 (498), 360 Hey, D. H. 26 (175), 34 (231), 110,111 Hibbert, H. 242,243 (228), 272 Hida, N. 281,287,305 (482), 359 Hideg, K. 280 (479,359 Higuchi, M. 306 (824), 368 Hilfman, L. 29 (201), 111 Hill, G. H. 26 (179), 111 Hill, J. 62 (348), 114 Hill, K. A. 427 (255), 447 Hiller, A. 79 (432), 116 Hilton, A. N. 345 (752), 366 Himmele, W. 400 (157), 446 Himmelsbach, R. J. 290 (551), 361 Hino, T. 235,244 (121), 257 (343), 262 (121, 371,372), 269,274,275 Hipsher, H. 9 (60), 108 Hirabayashi, Y. 80 (444),116 Hiroi, K. 148 (990), 223 Hirsch, A. F. 266 (431), 276 Hirsch, H. von 282 (486), 359 Hinve, A. S. 357 (805), 367 Ho, C. T. 411 (208), 446 Ho, T.-L. 214 (971), 223 Hobold, W. 249 (290), 273 Hock, K. 203 (923,924), 222 Hodginson, W. R. 82 (448), 116 Hoey, J. G. 86 (471), 116 Hoffman, H. M. R. 27,28 (183), 111 Hoffman, P. G. 75 (403,404), 115 Hoffmann, E. 7 (47), 108 Hoffmann, H. M. R. 93 (501,503,504,507, 512,513), 117 Hoffmann, M. 346 (757), 366 Hoffmann, R. W. 263 (378,380), 275,438 (296), 448 Hofmann, K. 205 (932), 222 Hofmann, P. 211 (950), 222,372,385 (27), 443 Hofmans, C. 426 (251), 447 Hokama, K. 231,247 (74), 268 Holan, G. 286 (517), 358 (517,816), 360,367

Holland, D. G. 67 (362), 114 Holley, A. 379 (71), 444 Holt, D. A. 189 (851,853), 192 (851),220 Holtschmidt, H. 293 (587), 362 Holtzman, J. L. 280 (473), 359 Homan, W. P. 338 (740), 365 Hongo, T. 425 (249), 447 Hopkinson, A. C. 212 (957), 223 Horikawa, H. 419 (238), 447 Horn, A. R. van 175 (779,219 Horriere, D. 357 (813), 367 Horstmann, H. 80 (434), 116 Horton, W. J. 36 (240), 112 Honvell, D. C. 287,295,296 (526), 361 Hoshino, I. 195 (883), 221 Hough, T. L. 175 (781), 219 House, H. 0 . 2 8 (196), 37 (249), 101 (555), 111,112,118,311 (684), 364,427 (254), 447 Houssiau, J. 9 (57), I08 Howard, A. S. 177 (793),219 Howe, R. K. 296 (624), 363 Hoyle, W. 28 (186), 111 Hsieh, Y.-Y. 83 (459), 116 Hu, Q. Y. 214 (965), 223 Huang, R. L. 89 (484), I17 Huber, E. 347 (776), 366 Huber, F. 83 (460), 116 Hudlicky, M. 3 (13), 107 Hudlicky, T. 198 (887), 221,286 (507), 360 Hudson, R. F. 96,98 (531), 118 Huebl, D. 285 (505), 360 Huet, J. 379 (79), 444 Huff, J. R. 238,267(180),271 Hugel, G. 331 (732,733), 341,343 (748), 365, 366 Hughes, E. D. 41,43 (266), 112 Humiliere, M. 100 (548), 118 Hummel, G. J. van 293 (590), 362 Humphlett, W. J. 411 (215), 447 Hiinig, S. 418 (236), 447 Hunkeler, W. 297 (630), 363 Hunter, M. J. 242,243 (228), 272 Hurd, C. D. 82 (454), 116 Hussey, A. S. 88 (479), 117 Hussey, R. E. 41 (261), 112,242 (224),271 Husson, H. P. 254 (284), 260 (369), 273,275 Hutchins, R. 0 . 4 7 (297), 68 (376,377), 70 (377), 102 (mj,ii3,114,118,i
Author Index Iida, H. 183 (829), 220 Iijima, S. 198 (886), 221 Iino, K. 182 (821), 220 Ikan, R. 6 (40), 108 Ikeda, K. 405 (180), 446 Ikeda, M. 246 (253), 247 (253,261), 248,262 (253), 272

Ikeda, Y. 281,286,304 (479), 359 Win, G. F. 329 (718,725), 365 Imafuku, K. 152 (685,686), 21 7 Imagawa, T. 263 (3Y8,400), 275 Imamoto, T. 199 (896), 207 (942), 221,222 Imamura, S. 302,303 (655), 364 Imanoto, T. 204 (926), 222 Imhof, R. 235,245 (373), 275 Imoto, S. 233 (9Y), 269 Imwinkelried, R. 148 (989), 223 Incan, E.d’ (974), 223 Ingold, C. K. 376 (50), 444 Inokuchi, T. 16 (109), 109 Inoue, M. 259,260 (352), 274 Inoue, S. 49,57,61,70 (306), 113 Iovchev, A. 28 (198), 111 Iqbal, M. N. 93 (503), 117 Iraidova, I. S. 96 (530), 118,432 (283), 448 Iratcabal, P. 12 (84), 109 Iriarte, J. 5 (27), 108 Irving, H. 377 (59), 444 Ishibashi, H. 204 (927),222 Ishiguro, K. 212 (956), 223 Ishihara, H. 80 (444),116, 183 (823), 220 Ishihava, T. 203 (915), 222 Ishikawa, N. 123 (596), 215,296 (627), 363 Ishira, T. 199 (902), 221 Ishizumi, K. 291 (571), 362 Iskander, G. M. 306 (664-666), 364 Ismail, A. M. 168 (749), 218 Isogai, K. 249 (409), 275 Israel, M. 180 (807), 220 Itaya, T. 166 (741),218 Ito, E. 187 (844), 220 Ito, K. 33 (224), 111 Ito, S. 161 (711),217 Ito, Y. 14 (102), 93 (511), 109,117 Itoh, K. 96 (521), 117,211 (951), 214 (987),

222,223,408 (315), 449 Ivanov, A. P. 293,302 (586), 362 Ivanova, Z. M. 80 (433), 99 (544,545), 116, 118 Ivashchenko, A. V.178 (799), 219 Ivashchenko, S. P. 178 (799), 219 Iversen, T. 346 (763),366 Iwasaki, T. 238 (221), 271 Iwasawa, N. 199 (891-893), 221 Iyoda, M. 198 (885), 221 Izaua, Y. 106 (569), 119 Izawa, Y. 212 (956), 223 Izumi, Y. 189 (860), 221

465

Jackson, E. L. 21 (147), 110 Jackson, G. G. 130 (616), 215 Jacobs, T. L. 28 (194), 111 Jacoby, H. I. 238,267 (181), 271 Jacquet, J. P. 260 (367), 274 Jacquier, R. 2 (3), 45 (292), 60 (342,344), 107, 113,114,259 (353),274

James, J. L. 122 (589), 215 Janetzky, E. F. 226 (5), 267 Jansch, H.-J. 163 (726),218 Jaquier, R. 57 (333), 113 Jarry, A. 405 (189), 446 Jarvi, E. T. 125 (605), 215,393 (129), 445 Jaw, J. Y. 427,428 (260), 448 Jawdosiuk, M. 187 (843), 220 Jenkins, D M. 9 (71), 10 (72), 109 Jensen, B. L. 17 (124-126), 110 Jensen, E. V. 3 (16), 4 (19,21), 107 Jensen, F. K. 99 (541), 118 Jerchel, D. 31 (217), 111 Jia, Y. 345 (753), 366 Jin, Q. Z. 411 (208), 446 Jira, R. 370 (4), 443 Jochims, J. C. 293 (588), 362 Joglar, J. 439 (307), 449 Johansen, 1. 183 (825), 220 Johar, Y. 142 (657), 216 Johnson, J. 379 (71), 444 Johnson, 0.H. 432 (277), 448 Johnson, W. M. P. 286,358 (517). 360 Johnson, W. S. 11 (80). 31 (218), 68 (369), 109,111,114,294(600),362

Joly, R. 3 (18), 107 Joncich, M. 379 (70), 444 Jonczyk, A. 186 (836), 220 Jones, E. R. H. 26 (175), 34 (231), 110,111, 408 (200), 446

Jones, G. 49 (305), 113 Jones, G. I1 105 (565), 118 Jones, G. P. 175 (781), 219 Jones, H. W. 42 (270), 112 Jones, V. K. 427 (254), 447 Joosten, G. H. H. 130 (979,980), 223 Jorden, H. D. 238 (172), 249 (172,295), 256 (295), 270,273

Joschek, H. I. 395 (145), 445 Joshi, M. G. 178 (800), 219 Joule, J. A. 291 (576),362 JoulliB, M. M. 299 (640), 363 Joy, D. R. 93 (501), 117 Julia, M. 296 (626), 363 Julian, P. L. 36 (239), 68 (368), 112,114 Julien, R. 201 (909), 222 Jullien, J. 164 (727), 218,280 (471). 359 Jung, F. 382 (87), 444 Jung, J. P. 370 (lo), 443 Jung, M. E. 289 (549), 361 Jung, S. H. 209 (Y46),222

466

Author Index

Jurczenko, 0. I. 86 (472), 116 Jurlina, J. L. 36 (243), 112 Just, G. 186 (838), 220 Justoni, R. 9 (52), 82 (450,457), 108,116 Kabalka, G. W. 92 (497), 117,390 (117), 445 Kadorkina, G. K. 348,349 (779,780), 366 Kadyrmatova, T. P. 93 (516), 117 Kaegi, H. H. 186 (839), 220 Kagan, J. 439 (301), 448 Kai, F. 283,326 (496), 360,404 (172), 446 Kain, I. 372,385 (27), 443 Kaiser, E. T. 249 (288,289), (294), 273 Kaiser, L. 72 (394), 115 Kaiser, R. 158 (697), 217 Kajfez, F. 64 (353), 114 Kaji, A. 204 (929), 222 Kalaus, G. 310 (676), 364 Kalbitz, H. 203 (922), 222 Kalchenco, V. 247 (263), 272 Kalchenko, V. 238 (191), 271 Kalikhman, I. D. 74 (400), 115,295,329 (602), 362 Kallenberg, H. 375 (48), 443 Kalmus, A. 7 (48), 108 Kamara, K. 253,309 (269), 272 Kamata, K. 231,247 (74), 268 Kamawawa, S. 266,287 (460), 277 Kameo, K. 201 (907), 222 Kametani, T. 226 (34,35), 268 Kanda, T. 302,303 (655), 364 Kaneko, H. 314 (691,692), 364 Kaneko, K. 80 (436), 116,242 (229,230), 272 Kang, S. M. 411 (211), 447 Kano, K. 301 (649,363 Kantlehner, W. 238 (179), 271 Kapkan, L. M. 76 (415), 115,230 (110),269 Kaplan, B. E. 105 (566), 118 Kaplanyan, E. E. 137 (638,639), 216 Kapoor, I. P. 357 (805), 367 Kapran, N. A. 329 (722), 365 Karo, W. 251 (310), 273 Karpel, W. J. 36 (239), 112 Karpellus, P. 251 (319), 274,280,305 (469), 359,413,414 (224), 447 Karrer, P. 30 (205), 111 Kartev, V. G. 72 (393), 115 Kasai, H. 405 (180), 446 Kasamatsu, S. 291 (567), 361 Kashima, C. 255 (320), 274 Kasukhin, L. F. 99 (545), 118 Kasumov, N. K. 80 (439), 116 Katano, K. 283,326 (496), 360,404 (172), 446 Kato, H. 425 (248), 447 Kato, J. 436 (293), 448 Kato, S. 183 (823), 220 Kato, T. 28 (191), 72 (390), 88 (480), 111,115, 117

Katritzky, A. R. 162 (720), 218 Katsube, J. 291 (571), 362 Katt, R. J. 338 (740), 365 Katvalyan, G. T. 280 (467), 359 Katvalyan, H. T. 168 (752), 218 Katz, J.-J. 92 (498), I17 Katz, R. B. 177 (793), 219 Kaufman, P. R. 11(77), 109 Kawabata, A. 83 (462), 116 Kawakita, T. 302 (658), 364 Kawanisi, M. 263 (398,400), 275 Kawano, Y. 188 (845), 220,429 (265), 448 Kawase, M. 295,326 (612), 363 Kayama, Y. 175 (785),219 Kazarians-Moghaddam, H. 212 (957), 223 Keana, J. F. W. 14 (97), 109,231,265 (84), 268 Keehn, P. M. 281 (480), 359 Keese, W. 143 (661),216,371(24), 443 Keiser, T. E. 243 (238), 272 Keller, K. 296 (625), 363 Kellogg, R. M. 181 (815), 220 Kempe, U. M. 251 (299,300), 273 Kempter, G. 73 (396), 115,410 (205), 446 Kendall, E. C. 226,256 (20,22), 267 Kende, A. S. 2,25 (4), 107,259,338 (354), 274 Kerdesky, F. A. J. 151 (6811,217 Kerekes, I. 6 (38), 108 Kerfanto, M. 66 (361), 114 Kerimov, F. F. 80 (439), 116,180 (811), 220 Ketari, R. 290,291 (559), 361 Ketelaar, P. E. F. 439 (309), 449 Keul, H. 123,137 (599), 154 (693), 215,217, 385 (101,141), 395 (141,144), 444,445 Keul, K. 137 (6471,216 Keung, E. C. H. 93 (515), 117 Khan, H. R. 175 (776), 219,411 (210), 447 Khaskin, I. 226,251 (8), 267 Khaskin, E. G. 168 (753), 218 Khayarov, A. I. 329 (720), 365 Khoda, A. 137 (637), 216 Khorana, H. G. 227,228 (105), 269,393 (128), 445 Khoshdel, E. 6 (32), 108 Khuong-Huu, F. 235,267 (139), 270 Kibar, R. 23 (156), 110,123,137 (599),215, 385 (101), 444 Kibardin, A. M. 432 (283). 448 Kienzle, F. 98 (536), 118 Kikuchi, T. 193 (864). 221 Kikugawa, Y. 295,326 (612), 363 Killinger, T. A. 35 (235), 96 (520), 112,117 Kilner, A. E. H. 26 (176), 110 Kilsheier, J. R. 228,267 (441). 276 Kim, K. S. 203 (919), 222 Kim, M. H. 299,346 (635), 363 Kim, T. V. 80 (433). 99 (544,545). 116,118, 203 (918), 222,432 (280), 448

Author Index Kim, Y . H. 209 (946), 222 Km, Y. I. 324,356 (706). 365 Kimura, M. 211 (951), 222 Kindack, D. 337.341 (738), 365 King, L. C. 31 (214), 111 King, S . W. 238,267 (180),271 Kinoshita. S . 233 (loo), 269 Kirby, A. F. 229,251 (46). 268 Kirby, A . F. 75 (407), 115,226,229,251,256 (23). 267 Kirby, A. J. 96 (529,531), 98 (531), 118,247 (264b3.272 Kirkemo, C. L. 291,344 (563), 361 Kirmani, M. Z. 233 (104), 269 Kirmse, W. 331 (734), 365 Kirner, W. R. 41 (261), 112,242 (224), 271 Kirrmann, A. 21 (149,150), 24,35 (149), 110, 257 (443), 276,370 (2), 379 (68), 384 (91, 92,97), 385 (91,92), 394 (132-134), 395 (137-139,145,147,148), 396 (147), 405 (184,186,187), 413 (226), 428 (266), 443488 Kirschleger, B. 140 (648-650), 216,389 (113, 114,116), 445 Kise, N. 132 (619), 216 Kiseleva, E. I. 203 (918), 222,432 (280), 448 Kishimoto, T. 243,267 (246), 272 Kisilenko, A. A. 257 (410), 275 Kisliuk, R. L. 230,247,267 (156), 270 Kissman, H. M. 4 (23), 108 Kitagawa, T. 211 (952,953),222 Kitagawa, Y . 93 (SlS), 117,198 (888), 221 Kitajima, K. 159 (705), 217 Kitano, Y . 302,303 (655), 364 Kitazume, T. 123 (596), 215 Klamann, D. 351 (794), 367 Klausmeiet, W. H. 17 (124), 110 Klein, J.-L. 405 (189), 406 (192), 446 Klein, R. A. 89 (482), 117 Kleyer, D. L. 290 (551),361 Klimova, E. I. 263 (399), 275 Klimova, T. A. 102 (559), 118 Klingsberg, E. 19 (134), 110 Klose, W. 175,177 (784), 219,411 (212), 447 Klyuev, N. A. 166 (742), 218 Knauf, W. 359 (822), 368 Knight, D. W. 190 (861), 221 Knipe, A. C. 38 (260), 112 Knose, L. H. 17 (116), 109 Knunyants, I. 70 (379), 114,227,228,257,258 (37), 268 Knunyants, I. L. 3 (10, ll), 107,263 (387,389, 390,394), 275,287 (522), 295 (610,611), 296 (617), 329 (712,729). 360,362,363, 365 Knutsson, L. 43 (275), 45 (295), 49 (275), 112, 113 Kobayashi, G . 171 (767), 219

467

Kobayashi, R. 93 (505), I17 Kobayashi, T. 16 (109), 109 Kobler, H. 82 (459,116,242,255 (231), 272 Kobrich, G. 385 (98), 444 Koch, C. W. 338 (741), 366 Koch, M. 291,325 (565), 361 Koch, T. H. 290 (551), 361 Kochergin, P. M. 68 (365,366), 114,247 (259), 272 Kochetkov, N. K. 346 (762), 366 Kochi, H. 243,267 (246), 272 Kochi, J . K. 14 (99), 109 Kochler, R. 410 (206), 446 Kochman, R. L. 235,261,267 (126),269 Kocienski, P. J. 59 (339), 114,251 (316), 273, 328 (710), 365 Koehler, R. 175 (775), 219 Koga, M. 76 (416), 115 Kohda, A. 137 (636), 216 Kohler, E. P. 82 (449), 116 Kohmoto, S. 419 (239), 447 Kohmoto, T. 235,267 (137), 270 Koike, K. 329,359 (717), 365 Kojima, A. 198 (885), 221 Kojima, S . 283,324,359 (500),360 Kokosi, J. 301 (647). 363 Kolar, A. J. 257 (339), 274 Kolb, V. M. 15,46 (106), 109 Kolbah, D. 64 (353), I14 Kollat, P. 158 (696), 217 Kolodka, T. V. 203 (917), 222 Kolomiets, A. F. 285 (501),287 (536). 296 (619), 314 (501), 329 (718,725-727). 347 (501,773,348 (501),'350 (786), 360,361, 363,365-367 Kolozov, M. V. 83 (459), I16 Koltai, E. 314 (695), 364 Komar, E. L. 166 (744), 218 Komeichi, Y. 238 (221), 271 Komukai, T. 237,238 (167), 270 Konda, M. 259,260 (352), 274 Kondo, H. 28 (191), 88 (480), 111,117 Kondo, K. 187 (844), 220,281,287,305 (482), 359 Kong Tho0 Lin, P. V. S. 171,173 (765), 219 Konishi, S . 214 (978), 223 Konoike, T. 283,326 (497), 360 Konovalova, I. V. 305 (662), 329 (720), 364,365 Kopke, B . 132,182 (620), 216 Kopp, E. 370 (4), 443 Kopp,, M. 45 (288), 60 (343), 113,114 Korohada, M. J. 175,176 (780), 219 Korotkikh, N. I. 76 (415), 115,230 (110), 269 Korten, H. 9 (70), 108 Koshiba, M. 195 (879), 221 Koshino, H. 391 (123), 445 Kosower, E. M. 14 (loo), 109,231,252 (76, 286), 268,273,288,328 (545), 361

468

Author Index

Kost, A. N. 72 (393). 115,184 (834). 220 Kostyanovskii, R. G. 286 (518), 345 (754). 348,349 (779,780), 360,366 Kostyanovsky, R. G. 294 (599). 349 (599, 783). 362,366 Kosugi, M. 195 (878,879,881,883),221 Kotera, M. 339 (749,366 Koto, H. 207 (942), 222 Kovacic, P. 230 (206), 271,393 (126), 445 Kovganko, N. V. 35 (234), 112 Kovtun, V. Y.238,267 (204), 271 Kowalski, C. 101 (554), 118,311 (685-687), 364 Kowalski, C. J. 140,146 (651), 199 (904), 201 (905), 206 (936),216,221,222 Kraemer, W. 286,302 (513), 360 Kraevskii, A. A. 294 (595), 362 Krainyuchenko, I. V. 15 (103), 109 Krasheninnikova, E. A. 238,267 (204), 271 Krattiger, A. 373,428 (29), 443 Krattinger, A. 394 (133, 134), 445 Kraus, G. A. 388 ( l l l ) , 429 (111,264), 431 ( I l l ) , 445,448 Krauser, S. F. 65 (358), 114 Kravets, V. 370 (12), 443 Krayushkin, M. M. 102 (559), 118 Krebs, A. 59 (340), 114 Krepski, L. R. 20 (140,141), I10 Krespan, C. G. 254 (273,274), 272.273 Kresze, G. 236 (144), 263 (144,396), 270,275, 296,329 (621), 363 Kretzschmar, G. 302 (823), 368 Krey, P. 175 (779), 219 Krief, A. 214 (967), 223 Krogh-Jespersen, K. 300,353 (642), 363 Krohnke, F. 25 (166,167,170) 28 (193), 110, 111 Kropa, E. L. 26 (179), 111 Kropacheva, E. N. 242 (240), 260 (419,423). 272,276 Krow, G. R. 263 (397), 275 Kriiger, C. 439 (307), 449 Kruglenko, V. P. 68 (366), 114,166 (742), 218 Kryukov, L. 263 (394), 275 Kryukov, L. N. 347 (779,366 Kryukova, L. Y. 263 (394), 275,347 (775). 366 Krzyzosiak, W. J. 411 (209), 447 Kudrina, M. A. 96 (530), 218 Kuehlein, K. 236 (155), 257 (337), 270,274 Kuehne, M. E. 235 (153,270,271), 236 (153), 253 (271), 254 (153,271). 261 (270,271), 267 (153,270,271), 270,272,291,344 (563), 361 Kuehne, S. E. 291,344 (563), 361 Kugito, H. 259,260 (352). 274 Kuhlman, D. 236 (142), 270,411 (218). . , 447 Kukhar, V. P. 247(262), 272 Kukota, S. N. 101 (552), 118

Kulka, M. 175,178 (790), 219 Kumar, V. 251 (315),273 Kunesch, N. 235 (135,426), 267 (135),270, 2 76 Kunugihara, A. 188 (846), 220,311 (682), 364 Kuranami, S.-I. 49,57,61,70 (306), 213 Kurata, K. 171 (767),219 Kurbanova, R. A. 438 (297), 448 Kuroki, M. 166,167 (737), 218 Kurono, M. 388 (311), 449 Kurosawa, K. 130 (617,618), 131(617), 216 Kurykin, M. A. 263 (394). 275,295 (611),363 Kusamran, K. 36 (237), 112 Kushnir, V. N. 427,428 (261), 448 Kusumoto, T. 199 (896), 204 (926), 221,222 Kutney, J. P. 235,245 (373), 275 Kuwajima, I. 123 (597), 215 Kuz’menok, N. M. 171 (764), 219 Kwast, A. 186 (836), 220 Kwast, E. 186 (836), 220 Kyazimov, S. K. 438 (297,298), 448 Kyuntsel, I. A. 199 (900), 221 L’abbt, G. 326 (707,708), 365 Lachance, P. 156 (694), 217 Lacombe, S. 124 (602,603), 215,351,357 (793,799), 367 Ladjama, D. 439 (305), 449 Laesecke, K. 346 (764), 366 Lafon, L. 280 (464-466), 359 Lai, C. H. 107 (575), 119 Lakshmikantham, M. V. 151 (680), 217 Lalonde, R. T. 83 (461), 116 Lamon, R. W. 411 (215), 447 LaMontagne, M. P. 385 (313), 449 Lamotte-Brasseur, J. 343 (750), 366 Lang, S. A. 411 (211), 447 Langer, S. H. 41,43 (262), 112,243 (235),272 Langlois, N. 235,267 (417), (455), 276,291 (574,575), 310 (575). 362 Langlois, Y. 235,267 (417), (455). 276,291 (574,575), 310 (575). 362 Lansard, J.-P. 194 (869), 221 Lapkin, I. I. 93 (516,517), 117,199 (900,901), 221,323 (703), 365 Larchevtque, M. 231 (78),268,429 (263), 448

Larcheveque, M. 187 (841), 220 Lardici, L. 189 (849), 220 Laronze, J. 235 (131), 269 Laronze, J.-Y. 261 (370), 275 Laronze, J. Y. 235 (131), 269 Laronze-Fontaine, J. 261 (370), 275 Larsen, A. 379 (71), 444 Laskovics, F. M. 15 (107). 109 Lassig, W. 230 (52-54), 264 (52-54,403), 268, 275 Lattes, A. 169 (755), 218

Author Index Laurent, A. 124 (602,603), 215,351,357 (793, 799), 367 LaVallee, C. 439 (310), 449 Lavielle, G. 260 (367),274 Lavrushin, V. F. 164 (728), 218 Layer, R. W. 226 (3), 267 Lazareva, V. T. 178 (799), 219 Lazaridis, N. V. 123(592), 215,379 (81), 444 Lebbar, K. 214 (970),223,318 (701), 365 Le Blanc, M. 8 (51),86 (478), 108,116 Leborgne, A. 439 (310), 449 Le Corre, M. 186 (840), 220,435 (290), 448 Lee, K. N. 411 (208), 446 Lee, L. F. 296 (624), 363 Lee, V. J. 251 (411), 275 Lee-Ruff, E. 212 (957), 223 Lefor, A. T. 106 (570), 119 Legocki, J. 99 (540). 118 Lehn, J. M. 400,401 (161), 446 Lehnert, W. 84 (468), 116,426 (252), 447 Lei, K. L. 107 (579, I19 Lei, X. 194 (870), 221 Lemaire, M. 130 (609), 215 Lemay, G. 439 (310), 449 Le Men, J. 235 (131,136,215), 261 (370), 267 (136,215),269-271,275 Le Men-Olivier, L. 235,267 (136). 270 Lemen-Olivier, L. 235,267 (215), 271 Lemke, J. 264 (402), 275 Lendel, V. G. 376 (59,444 Lengyel, I. 236 (152),270 Lenk, C. T. 25 (168), 30,36 (212), 110,111 Lennartz, H. G. 68,73 (375),114 Leon, A. 175 (775), 219,410 (206), 446 Leonard, N. J. 301 (646), 351 (792), 363.367, 405 (181), 446 Le Pennec, A. 379 (79), 444 Lerche, H. 286 (519), 309 (519,673), 311 (673), 360,364 Le Rouzic, A. 66 (361), 114 Leroy, J. 6 (41), 66 (359), 100 (548), (161), 108,110,114,118 Letendre, L. J. 194 (8684,221 Leung, W. Y. 345 (755), 366 Levene, P. A. 26 (172), 110 Levi, N. 231 (73), 268 Levin, R. H. 17 (115), 109 Levine, P. A. 64 (350), 114 Levine, R. 7 (42), 33 (228), 108,111 Levisalles, J. 194 (867), 221 Levkovskaya, G. G. 74 (400), 115,295,329 (602), 362 Levy, A. B. 239 (209), 258 (347), 271,274,350 (785), 366,392 (125), 445 Levy, E. F. 28 (194), 111 Levy, J. 235 (131,215), 261 (370), 267 (215), 269,271,275,291,325 (564,565), 331 (732,733), 341,343 (748), 361,365,366

469

Lewin, G . 343 (750), 366 Lewis, N. G. 186 (838), 220 Leyendecker, F. 180 (808), 220 Lhommet, G. 339 (743), 366 Lian, R. 178 (794), 219 Lichman, K. V. 236 (140),270 Lichtenthaler, F. W. 247 (264a), 272,432 (278), 448 Liddell, R. 314 (694), 364 Lidor, R. 288 (547), 302 (547,657), 309 (657), 311 (681), 355 (547), 361,364 Lie, G. 0. 123,137 (W),154 (693),215,217, 395 (144), 445 Lieberknecht, A. 179 (803), 219,299 (638, 639), 363 Liebeskind, L. S. 180 (812), 220 Liebscher, J. 175 (782), 219 Liepins, E. 293 (589), 362 Liesching, D. 314 (282), (281), 273,407 (198), 446 Lilienblum, W. 263 (378), 275 Lin, W. S. 6 (39,108 Lin, Y. i. 411 (211), 447 Linden, G. B. 28 (194), 111 Lindler, E. 203 (925), 222 Lingham, D. A. 249 (447), 276 Lion, C. 90 (491,492), 91 (493,494), 92 (498), 117,214 (969,970),223,318 (700,701), 365 Lipp, D. W. 229 (201), 271 Lipszyc, J. 242,262 (226), 272 Lisensky, C. A. 436 (294), 448 Lisini, A. 64 (353), 76 (413), 114,115,251,256 (327), 274 Lissel, M. 180 (809), 220 Litkei, G. 76 (418), 115,179 (804),219 Lloyd, R. M. 133,134,137 (628), 216 Lobanov, 0.236,238,257 (145), 270 LOfAS, S . 290 (552-554), 299 (554), 361 Loftfield, R. B . 34 (229), 45 (291), 50 (229), 53 (321), 111,113 Logachev, E. V. 247 (259), 272 Logbo, K. D. 93 (514), 117 Loiselle, A. A. 6 (36), 108 Lomakina, N. P. 72 (393), 115 Look, H.D. 19(132), I10 Lopez, L. 27 (182), 33 (226), 34 (232), I l l , 112 Mpez-Ortk, J. F. 290 (556,557), 361 Lorenz, J. 175,177 (784), 219,411 (212), 447 Loremini, A. 375 (42), 443 Lorenzo, A. 168 (748), 188 (847), 218,220 Loreto, M. A. 172 (769),219 Loupy, A. 351 (791), 367 Lowell, S. 41 (263), 112 Loy, R. S. 263 (388), 275 Lozinskii, M. 0. 101 (552), 118 Lucas, J. 296 (625), 363

470

Author Index

Lucchini, V. 136 (633,634), 216,391 (121, 122), 445 Luche, J.-L. 5 (28), 108,194 (869), 221 Luche, J. L. 107 (585), 119 Luche, M.-J. 5 (28), 108 Liideritz, 0 . 2 5 (170), 110 Ludewig, H. 64 (352), I 1 4 Luerssen, K. 288 (542), 302,359 (542,652), 361,363 Luh, T. H. 107 (575), 119 Luh, T.-Y. 345 (759,366 Lukmanova, A. S. 183 (826), 220 Luknitskii, F. I. 257 (444), 276,370 (3), 443 Lunn, W. H. 130 (616), 215 Lusinchi, X. 233 (106,107), 234 (107), 258 (106), 260 (368), 269,275 Lustgarten, D. M. 331 (731), 365 Lutz, R. P. 43 (274), 112 C. 408 (203), 446 LUU-DUC, Lyandaev, E. A. 239 (192), 271 Lyle, T. A. 294 (600), 362 Lysenko, Z . 371,374 (18), 443 Maatman, H. 130 (979,980), 223 Maccagnani, G. 351 (796), 367 Maccioni, A. 307 (671), 364 Machleidt, H. 7 (49), 108 Mackerer, C. R. 235,261,267 (126), 269 Maclagan, N. F. 30 (206), 111 Macomber, R. S. 31 (215), Ill Maddox, M. L. 175 (775), 219,410 (206), 446 Madinaveita, A. 379 (76), 444 Maeda, A. 80 (436), 116,242 (230), 272 Maeno, S. 296 (623), 363 Maffrand, J.-P. 339 (745), 366 Magee, T. A. 44 (282), 113 Magen, S. 144 (644), 216 Magid, R. M. 242 (223), 271 Magnani, A. 68 (368), 114 Magnus, P. 344 (751), 366 Mahapatra, G . N. 74 (398), 115 Mahesh, V . K. 161,168 (714), 217 Mahy, M. 326 (708), 365 Maidannik, A. G. 166 (743), 218 Maier, G . 198 (884), 221 Maier, R. 19,34 (130), 110 Maierhofer, A. 236 (152), 263 (388), 270,275 Mais, A. 107 (573), 119 Maiti, S. N. 214 (964), 223 Makino, H. 151 (683), 217 Makino, S . 93 (502,506), 117 Makosza, M. 186 (836), 220 Maksimov, B. I . 184 (834). 220 Maksimova, T. N. 263 (437), 276 Malament, D. S. 231 (73), 268 Malanga, C. 189 (849), 220 Malassa, I. 287 (535), 361 Malenko, D. M. 434 (288), 448

Malik, W. 41 (268), 112,242 (241), 260 (420), 272,276,395 (140), 445 Malinowski, R. 99 (539,540), 118 Malissard, M. 103 (563), I18 Mallamo, J. P. 201 (908), 222 Mallory, W. R. 76 (421), 115 Malone, G. R. 302 (649), 314,321 (693), 363, 364,384 (90), 444 Maloney, D. E. 49,70 (307), 113 Malte, A. M. 15 (105), 109 Mamoru, E. 235 (120), 269 Manescalchi, F. 32 (222), 111,126 (606), 215, 371,372 (21), 375 (44), 443 Mangold, D. 288 (546), 292 (580), 359 (546), 361,362 Mann, G. 288,304 (543), 361 Mann, J. 93 (508,510), 117,159 (702), 195 (876), 21 7,221 Manning, R. E. 235,267 (134), 269 Manz, F. 258 (349), 274 Maquestiau, A. 124 (603),215,351,357 (799), 367 Marakowski, J. 263 (397), 275 March, J. 259 (358), 274 Marchand-Brynaert, J. 238 (194), 271 Marchelli, R. 143 (662,663), 216,371 (25), 443 Marchesini, A. 302 (651), 363 Marciano, D. 306 (669), 364 Margaretha, P. 285,348 (504), 360 Marinescu, M. 294 (593), 362 Markaryan, E. A. 161 (713), 217 Markgraf, J. H. 338 (740,741), 365,366 Markl, G. 203 (923,924), 222,226 (36), 268, 377 (62), 444 Markovskii, L. N. 236 (149,151), 270 Marlowe, C. K. (205), 271,345 (756), 366 Marquet, A. 25 (171), 26 (180), 27 (181), 110, 111 Marquet, B. 124 (603), 215,351,357 (799). 367 Marshall, D. R. 68 (374), I14 Marsi, M. 436 (294), 448 Marsura, A. 408 (203), 446 Martens, V. J. 403 (168), 446 Martin, D. G. 11 (80), I09 Martin, E. 158 (696), 217 Martin, G . J. 24 (163), 110 Martin, H. 358 (820), 367 Martin, J. L. 135 (632), 216 Martin, M. 413 (226), 447 Martin, P. 20 (138), 110,137 (642-645), 153 (644,645,687,688), 171 (688), 180 (813), 216.217.220 Martin, V. V: 302 (648), 363 Martinez, D. 79 (432), 116 Martinez-Gallo, J. M. 147 (675), 217,375 (47), 443

Author Index Martirosyan, G. T. 137 (640), 216 Martynyuk, A. 236,238,257 (145), 270 Martynyuk, A. P. 243,257 (247), 272 Maruoka, K. 93 (518), 117, 198 (888), 221 Maruta, E. 291 (567). 361 Marvanyos, E. 310 (676), 364 Marvell, E. 379 (70), 444 Marynowski, S. 212 (955), 222 Masakatsu, T. 235 (120), 269 Masaki, M. 230,248,262 (266), 272 Masako, N. 235 (120), 269 Mashkovsky, M. D. 280 (468), 359 Mashraqui, S. H. 181 (815), 220,281 (480), 359 Masi, P. 230,245,267 (Sl), 268 Massiot, G. 291,325 (564), 361 Masure, D. 385 (102), 390 (118), 444,445 Mathew, C. T. 280 (470), 359 Mathew, K. K. 86,90 (477), 116,431 (273), 448 Mathey, F. 100 (548), I18 Matjeka, E. R. 165 (731), 218 Matoba, K. 233 (99), 269 Matsubara, S. 198 (889,890), 221 Matsuda, I. 189 (860), 221 Matsuda, Y. 171 (767), 219 Matsui, K. 187 (844), 220 Matsumoto, H. 166 (741), 218 Matsumoto, M. 161 (711), 217,420 (243), 447 Matsumura, H. 152 (685,686), 217 Matsumura, K. 239 (183, 184), 271 Matsumura, N. 188 (846), 220,311 (682), 364 Matsushita, H. 314 (691,692), 364 Matsushita, S. 47 (299), 113 Matthaiopoulos, G. 230 (61), 268 Matthes, D. 203 (923), 222 Matthews, A. E. 82 (448), 116 Matthews, W. S. 15 (105), 109 Matthies, D. 287 (535), 361 Mattox, V. R. 226,256 (20,22), 267 Mayer, D. 66 (360), I f 4 Mayer, M. 61 (346), 114 Maynert, E. W. 12 (87), 109 Mayr, A. J. 142 (658),216 Maytum, D. 238 (408), 275 Mazenod, F. P. 374 (39). 395 (143), 443,445 Mazur, I. A. 68 (365), I14 Mazzanti, G. 351 (796), 367 McAllister, S. H. 44 (278), 112 McBee, E. T. 7 (461,108 McCrotty, S. E. 324,356 (706), 365 McDaniel, W. C. 28 (196), 111 McDonald, R. M. 19 (128), 110 McDonald, R. N. 22 (152-154), 23 (155), 44 (281), 110,113,384,385 (95), 444 McDonnell, L. P. 105 (565), 118 McElvoin, S. 379 (74). 444 McEvoy, F. J. 256 (328,330), 274

47 1

McGrath, T. F. 7 (42), 108 McGuire, J. (413). 275 McGuire, J. L. 230,266 (220), 271 McGuire, W. J. 41,43 (262), 112,243 (235), 2 72 McKean, D. R. 205 (933), 222 McKervey, M. A. 132 (621,622), 207 (941), 216,222 McKinnon, D. M. 411 (216). 447 McLaughlin, T. E. 101 (555). 118,311 (684), 364 McMurry, J. E. 107 (577), 119 McNeiI, J. H. 405 (179), 446 McNeill, J. H. 166 (740), 218 McPhee, W. D. 19 (134), 110 Meakings, G. D. 411 (213), 447 Meakins, G. D. 182 (818), 220 Mecca, T. G. 243 (245), 272 Medinger, L. 287,304,305 (530), 361 Meffert, A. 263 (376), 275 Mehra, Y. R. 231,251 (77),268 Mehta, G. 137 (646), 216 Meier, H. 203 (922), 222 Meier, H. J . 178 (795), 219 Meisters, E. 14 (loo), 109 Melnick, B. 439 (301), 448 Meltzer, R. I. 331 (731), 365 Menahem, Y. 5 (26), 108 Menicagli, R. 189 (849), 220 MCrand, Y. 156 (694,695), 217 Merchant, J. R. 12 (85), 109 Merenyi, R. 169 (759), 218,294,302,303,306 (597), 362 Merenyi, R. 249,250 (297), 273 Meseri, J. 30 (211), 111 M e s h , J.-C. 175 (787), 219 M e s h , J. C. 72 (391), 115 Messier, A. 408,413 (202), 446 Mester, T. 76 (418), 115 MCszaros, Z. 301 (647), 363 Metcalf, B. W. 125 (605), 215,393 (129), 445 Metcalf, R. L. 357 (805),367 Metha, G. 235,244,245 (122), 269 MCtras, F. 12 (84), 109 Metras, F. 9 (68), 108 Metzger, D. 254 (275), 273 Metzger, H. 237 (159), 270 Metzger, J. 74 (401,402), 115,370 ( l l ) , 443 Meyer, D. D. 7 (46), 108 Meyer, D. R. 169 (758),218 Meyer, E. W. 68 (368), 114 Meyer, F. 432 (275), 448 Meyer, J. 169 (756), 218 Meyer, R. E. 17 (113), 109 Meyers, A. I. 254 (430), 276,302 (649). 314, 321 (693), 363,364,384 (90), 444 Meyers, C. Y. 15 (105,106), 46 (106), 109 Meyerson, L. R. 90 (490), 117

472

Author Index

Micetich, R. G. 214 (964), 223 Michael, J. 346 (765), 366 Michael, J. P. 177 (793), 219 Michurin, A. A. 239 (192), 271 Mickey, S. 100 (550), I18 Middleton, W. J. 4 (25), 108,254 (273-275). 272,273,358 (819), 367 Migaichuk, I. 226,251 (8), 267 Migaichuk, I. V. 168 (753), 218 Migalina, Y. V. 376 (55), 444 Migita, T. 195 (878,879,881,883), 221 Migliara, 0,230,253 (109), 269 Migliorese, K. G. 391 (124), 445 Migron, Y. 6 (34), 108,375 (46), 443 Mijares, C . 207 (943), 222 Mikolajczyk, M. 99 (539), 118 Milhavet, J. C . 166 (740), 218,405 (179), 446 Miller, B. 165 (731), 218 Miller, L. L. 357 (806), 367 Miller, R. D. 205 (933), 222 Millington, J. E. 6 (39), 108 Milz, H. 9 (59), I08 Minasyan, R. B. 263 (389,392). 275 Miocque, M. 82 (4561,116,183 (831), 220,226 (14),267 Miotti, U. 243 (243), 272 Mirskova, A. N. 74 (400), 115,295,329 (602, 603), 362 Misaki, S. 331 (730), 365 Misima, S. 16 (109), 109 Misiti, D. 234,251 (112), 269 Miskevich, G. 236,238,257 (145), 270 Miskevich, G. N. 238 (177), 243 (247), 257 (247,342), 270,272,274,329 (721), 365 Miskolczi, I. 291 (561), 361 Mistryukov, E. A . 168 (752), 218,280 (467), 359 Mitamura, S. 159 (705),217 Mitsuhashi, K. 295 (608), 296 (623), 362,363 Mitzner, E. 175 (782), 219 Miura, H. 257 (343), 274 Mixich, G. 286 (512), 360 Miyadera, T. 182 (82l), 188 (8451,220,411 (214), 429 (265), 447,448 Miyake, A . 88 (480), 96 (521), 117 Miyake, H. 28 (191), 111 Miyashita, K. 204 (929), 222 Mizsak, S. A . 300 (641), 363 Mizutani, M. 204 (927). 222 Mkryan, G. G. 137 (638-640), 216 Mkryan, G. M. 137 (638,639), 216 Mochalin, V. B. 263 (437), 276 Mochida, Y . 123 (596), 215 Mochizuki, S. 329,359 (717), 365 Modarai, B. 6 (32), 108 Modelli, R. 248 (265), 272 Modena, G. 136 (633,634), 216,391 (121, 122), 445

Moellering, W. 370 (4), 443 Moens, L. 70 (381), 114,277,282,283,296 (461), 277,280 (474). 282 (491), 298 (491, 631), 314,315 (698), 324,332 (491), 333 (491,631), 334 (491,698), 335,337 (491), 339 (742), 359,360,363,364,366,403 (170), 446 Moens, L. 166 (733), 218 Moga-Gheorghe, S. 230 (218), 271,294 (593), 362 Mogi, K. 235,267 (137), 270 Moiseenkov, A . M. 180 (811), 220 Molander, G . A. 214 (966), 223 Molina, P. 168 (748), 178 (796,797). 188 (847), 218-220 Momot, V. V. 290 (558). 361 Moncrief, J. W. 249 (288), 273 Montforts, F.-P. 297 (629), 363 Montgomery, J. A. 168 (747). 218 Montignoul, C . 169 (754), 218 Moradpour, A. 183 (825). 220 Moran, D. B. 256 (330), 274 Mordini, A. 206 (935), 222 Moreau, P. 48 (301), 113 Moreno, N. 31 1 (683), 364 Morgan, G. 238,267 (180), 271 Mori, A. 370,395 (14), 443 Mori, A. L. 395 (142), 445 Morimoto, T. 141,159 (655,656),216 Morita, K. 3 (16), 107 Moritz, A. G. 238 (182), 271 Morizawa, Y. 198 (889,8901,221 Morlacchi, F. 229,251 (48), 268 Morosawa, S. 211 (951), 222 Morris, A. 238,267 (NO), 271 Morrison, R. W. 76 (421), I15 Morrissey, A. P. 294 (596), 362 Morvan, J.-M. 66 (361), 114 Moss, R. A. 300,353 (642), 363 Mossa, G . 229,251 (47), 268 Motohashi, S. 134 (627), 216 Mott, R. C . 36 (247), 112 Mouiineau, C . 90 (491), 117 Moureu, C . 376,377 (57), 444 Mousseron, M. 57 (333), 60 (342,344), 113, 114 Mowry, D. T. 82 (447), 116 Muchowski, J. 180 (977), 223 Muchowski, J. M. 174 (771), 175 (775), 219, 410 (206), 446 Muhammad, N. 83 (461). 116 Mukaiyama, T. 199 (891-895), 221,436 (293), 448 Mukherjee, D. 156 (694), 217 Miiller, A. 64 (352), 114,238 (172, 173), 249 (172),270 Miiller, E. 370,401 (l), 443 Miiller, K. 288,321 (540), 361

Author Index Munk, M. 70 (378), 114,226 (13), 267 Murai, S. 93 (505), 117 Murai, Y. 65 (357), 114 Muramatsu, M. 291 (571), 362 Murat, M. 376,377 (57), 444 Murata, R. 257 (343), 274 Murayama, E. 193 (864), 221 Muro, T. 302 (658), 364 Mursakulov, I. G. 80 (439), 116,180 (811), 220 Mustafa, M. E. 296 (627), 363 Mustafaeva, Z. G. 438 (298), 448 Muths, R. 395 (139), 405 (187), 445,446 Muto, S. 183 (823), 220 Naal, J. T. 174 (771), 219 Nadjo, L. 201 (909), 222 Nagao, Y. 80 (436), 116,242 (229,230), 272 Nagaoka, M. 183(828), 220 Nagarathnam, D. 291 (572), 362 Nagasaki,F. 283,324,359 (500),360 Nagata, K. 78 (430), 115 Nagata, W. 283,326 (497), 360 Nagura, K . 154 (692), 217 Nair, M. D. 171 (766), 219 Nair, M. G . 230,247,267 (156), 270 Nair, V. 405 (182), 446 Najera, C. 147 (675), 217,375 (47), 443 Nakagawa, M. 235,244 (121), 257 (343), 262 (121,371,372),269,274,275 Nakagawa, T. 329,359 (717), 365 Nakai, H. 388 (311), 449 Nakajima, M. 203 (916), 222 Nakamura, A. 80 (438), 116,210 (947), 222 Nakamura, E. 123 (597), 215 Nakamura, T. 257 (343). 274 Nakanishi, S. 3 (16), 4 (20,21), 107,306 (667, 824), 364,368 Nakao, K. 210 (949), 222 Nakatsuka, M. 14 (102), I09 Nalewjek, D. 183 (824), 220 Nanjo, K. 235,257 (118),269 Naqvi, S. M. 198 (887), 221 Nardin, G. 251,256 (325,326), 274 Naruse, N. 237 (165,168), 249 (165,168,287, 293), 256,303 (287), 270,273 Nash, S. A. 300 (641), 363 Nasibov, S. S. 348,349 (779,780), 366 Nassal, M. 286,349 (516), 360 Natarajan, S. 171 (763), 219 Nath, J. P. 74 (398), 115 Nathan, E. C. 59 (339), 114 Natsume, M. 106 (569). 119 Nayak, K. V. 44 (282), 113 Nazareno. M. B . 393 (126), 445 Neidlein, R. 251 (456), 276,309 (674), 364 Neklesova, I. D. 96 (530), 118 Nelson, V. 230 (206), 271

473

Nenz, A. 238(171),270 Nerdel, F. 351 (794), 367 Neubauer, H. J. 174 (773), 219 Neumann, F. W. 238 (175), 270 Neville, 0.K. 28 (197), 47 (300), 111,113 Newkirk, J. D. 9 (71), 10 (72), I09 Newman, M. S. 9 (60), 25 (169), 108, 110 Nguen, M. T. 351 (790), 367 "Guessan, Y. T. 72 (391), I15 Nickkhoamiry, M. 257 (338), 274 Nieuwland, I. A. 36 (236), I12 Nighizuka, T. 183 (829), 220 Niida, T. 283,326 (496), 360,404 (172), 446 Nikolaeva, A. D. 295 (615), 363 Nikonenko, V. A. 96 (530), 118 Nikonorov, K. V. 96 (530). I 1 8 Nilsson, L. 72 (389), 115 Nimgirawath, S. 36 (237), I12 Nishi, M. 237,238 (167), 270 Nishida, H. 246-248.262 (253), 272 Nishihata, K. 283,326 (496), 360,404 (172). 446 Nishikawa, J. 331 (730). 365 Nishimura, Y . 247 (261), 272 Nishino, M. 88 (480), 117 Nishio, H. 130 (618), 216 Nishitani, K. 241 (454), 276 Nishiyarna, K. 247 (258), 272 Nishizawa, K. 14 (101), I09 Nivard. R. J. F. 310 (826), 368 Niwa, M. 294 (600), 362 Noble, W. J. le 259 (359), 274 Noda, M. 72 (390), 115 Noguchi, M. 314 (691,692), 364 Nojima, M. 6 (38), I08 Noll, R. M. 238,267 (180,203), 271 Noltemeyer, M. 296 (625). 363 Nonaka, T. 182 (819,820), 220 Noordik, J. H. 286,310 (508), 360 Norcross, B. E. 328 (710), 365 Nordblorn, G. D. 357 (806), 367 Nordeen, J. 145 (671),217,376 (54), 444 Normant, H. 231 (78). 268 Normant, J. F. 18 (127). 24,35,46 (162), 110, 140 (652), 216,385 (102), 389 (115), 390 (118), 444,445 Noronha, R. 81 (445), 116 Norris, J. F. 26 (173), 110 Nour, T. A. 93 (512). 117 Nouri-Bimorghi, M. R. 384 (91,92,97), 385 (91,92), 444 Nouri-Bimorghi, R. 21 (149,150), 24,35 (149), 91 (496), 110,117,385 (loo), 400, 405 (155), 444,445 Novhk, J. 161 (717), 218 Novikov, S. S. 102 (559), I18 Novkova, S. 124 (603), 215,351,357 (799). 367

474

A u t h o r Index

Nowak, R. M. 416 (233),447 Noyori, R.93 (502,505,506,509), 117,195

(875,877),221

Nozaki, H.93 (518),117,198 (888-890),221,

385,439(99).444

Nucciarelli, L. 36 (245),112 Nukada, K. 237 (163),270 Numazawa, M. 183 (828),220,226(207),271 Nutt, R.F. 299 (640),363 Nye, M. J. 93 (500),117,346(769),366

Ong, H. H . 90(490),117 Ongania, K . H.226 (29),267 Ono, A. 214 (972),223 Onoprienco, V. V. 83 (459),I16 Oohashi, M. 2(7),107,259(357),274 Oota, Y. 151 (683),217,418,420 (237),447 Oppolzer, W. 75 (411),115,230,249,256,267

(69),268,286(507),360

Orazi, 0.0.30(211),111 Oren, J. 144(664),216 Orena, M. 346 (758-761,825),366,368 Orlov, V. D. 164 (728),218 Orlova, L. M. 280 (468),359 Orlova, T.I. 293,302(585,586),362 Orth, H. 9(63).108 Ortiz, B . 207 (943),222 Osawa, Y.183 (828),220,226(207),271 Osgood, E.R. 303 (6591,364 Oshima, K.198(889,890), 221 Ostrow, R.W. 251 (316),273 Ostrum, G. K. 31 (214),111 Otsuji, Y. 306 (667),364 Ottenheijm, H.C . J. 286 (508),310 (508,677,

Oakes, M. L. 135 (632),216 Obayashi, M. 187(844),220 Obergrusberger, R.293 (591),362 Ochiai, M.80 (436),116,242(230),272 Oda, M. 198 (885),221 Oda, R.230 (62),268 Oda, T.50 (313),113 O’Dowd, M. 311 (686),364 O’Dowd, M. L. 206 (936),222 Oettmeier, W. 236 (152),263 (388),270,275 Oexle, J. 158 (700),217 Offermans, H.403 (168),446 Ogasawara, K. 346 (766),366 678,826),360,364,368 Ogata, Y . 154(692),217 Ottinger, R. 9(69),I08 Ogawa, K. 214 (964),223 Ottlinger, R.228 (42),263 (42,374,379), 264 Ogawa, M. 235,267(137),270 (404,406,407,4591,268,275,277,323 Ogloblin, K. A. 237 (164),238 (169,450), 270, (704),347(776),365,366 276 Outhwaite, G. 377 (59),444 Ohannesian, L. 134 (625),216 Overman, L. A. (205),271 Ohashi, M. 49,57,61 (306),65 (357),70 (306), Overman, L. E.239 (187-189,425),345,346

113,114

(425).271,276,345(756),366

Ohmatsu, H. 329 (714),365 Ohmizu, H . 132(619),216 Ohno, M. 237 (163,165,168), 249 (165,168,

Owellen, R. J. 235 (125,128),236,244(125),

Ohta, M. 230,248,262 (266),272 Ohtsuru, M.266,287(460),277 Ohya, T.195 (878),221 Oikawa, K. 237,238(167),270 Okabe, M. 400(156),445 Okada, H.233 (loo), 269 Okada, T.80 (443),116 Okamoto, K.211 (952,953), 222 Okamoto, M. 237(163,168),249 (168,287),

Pacifici, J. G. 59 (337),114 Packer, K. 266 (442),276 Padmanabhan, S. 83 (464).116 Padmapriya, A . A . 186 (838),220 Padua, A. 401 (164),446 Padwa, A. 240 (214),271 Pagnoni, U.382(86),444 Pagnoni, U.M. 130(981),143 (982),223,371

287,2931,256,303 (287),270,273

256,303(287),270,273 Oki, M. 80 (438),116 Okimoto, K.98(538),118,434(286,287), 448 Olah, G. A. 6(38),23 (158),107 (582,584), 108,llO,II9,134 (625),216 Olah, J. A . 6(38),108 Oliveira, F. S. 291,325(564),361 Olomucki, M.267 (415),275 Olsen, R.K.257(339),274 Ulund, I.I95(873),22I Omar, A. M. M. E.168 (749),218 Omori, K. 329,359(717),365 Omote, Y.255 (320),274

245,261(125,128), 269

Owen, L. N. 101 (553), 118

(26), 375 (45), 443

Pai, G. G. 194(871,872), 221 Palamareva, M. 170(762),219,282(489),337

(737),354(489),360,365

Palanowski, R.286 (510),360 Palla, G. 310 (680),364 Palomo, C. 143,171(660),216 Panda, C. S. 287 (523),360 Panetta, C. A. 280,281(477),359 Pannel, K.H.142(658),216 Papaleo, S.2U6 (935),222 Paparian, S. 212 (955),222 Papayan, G. L. 161 (716),218 Pappalardo, P. 344 (751),366

Author Index Pappas, J. J. 23 (157), 110 Paquette, L. A. 30 (208), 111,175 (774),219, 229,251,256 (50),268 Paramonova, V. V. 293 (583), 362 Paranyuk, V. E. 295,329 (601), 362 Parcell, R. F. 164 (730), 195 (874), 218,221 Pardo, C. 103 (560), I18 Parkhomenko, N. A. 236 (148, 150), 270 Parlier, A. 7 (45), I08 Parton, B. 287 (525), 295.296 (607), 307 (525), 361,362,411 (222), 447 Pasaribu, S. J. 33 (227), 111 Pasquet, G. 76 (425), 115 Pasteris, R. J . 58 (336), 114 Pastorelli, S. 206 (935), 222 Patel, A. D. 53,55 (325), 113 Patel, G. 439 (301), 448 Patonay, T. 76 (418), 115,179 (804), 219 Patrick, J. (413), 275 Patrick, J. E. 230,266 (220), 271 Patrick, T. B. 122 (591), 125 (973), 215,223 Pattenden, G. 184 (832), 220 Patter, L. 107 (574), 119 Patterson, H. R. 64 (351), 114 Pattison, F. L. M. 6 (39), 108 Paudler, W. W. 166(739),218,405(176),446 Paugam-Dreves, R. 428 (259), 448 Pauls, N. 203 (925), 222 Pauly, H. 226,251 (9, lo), 267 Pawelzik, K. (185), 271 Pazhenchevsky, B. 231,252 (76,286), 268,273 Pazos, J. F. 59 (337), 114 Peach, J. M. 345 (752), 366 Pearlman, P. S. 195 (880), 221,436 (292), 448 Pearson, R. G. 41,43 (262), 112,243 (235), 2 72 Pechet, M. M. 122 (589), 215 Peet, N. P. 101 (555), 118,311 (684), 364 Pegg, W. J. 180 (807), 220 Pellacani, L. 172 (769), 219 Pelter, A. 92 (499), 117 Pena, M. L. 178 (797), 219 Penninger, S. 263 (377,401), 275,347 (772), 348 (777). 366 Pennings, M.’L. M. 293 (590),362 Pereillo, J.-M. 339 (745), 366 Perekalin, N. W. 86 (472), I16 Perevalov, V. P. 293 (582), 362 PCrez, V. 175 (775), 219,410 (206), 446 Perez Moya, L. A. 372,385 (27), 443 Perichon, J. (974), 223 Perkow, W. 432 (275,276), 448 Peronnet, J. 230 (66), 268 Perrini, G. 175 (788), 219 Perriot, P. 187 (841), 220,389 (115), 429 (263), 445,448 Pershin, G. N. 293 (583), 362 Ptsce, G. 27 (182), 33 (226), 111

475

Peseke, K. 175 (783), 219 Pesotskaya, G. V. 99 (545), 118 Peters, E.-M. 161 (712),217 Peters, K. 161 (712),217 Peters, L. R. 130 (616), 215 Peters, P. A. 9 (69), 108 Peterson, P. E. 17 (125). 110 Peterson, R. A. 59 (340), 114 Petit, Y . 187 (841), 220,429 (263), 448 Petnehazy, I. 96-98 (532), 118,201 (910), 222 Petragnani, N. 214 (963), 223 Petrenko, V. S. 99 (5459,118 Petrier, C. 194 (869), 221 Petrissans, J. 9 (68), 108 Petruso, S. 230,253 (109), 269 Petrzilka, M. 75 (410,411), 115,230 249 (68, 69), 251 (301), 256,267 (69), 268,273 Pews, R. G. 371,374 (18), 443 Peyrussan, V. 183 (825), 220 Pfeffer, B. 123 (599), 137 (599,647), 215,216, 385 (101,141), 395 (141), 444,445 Pfeffer, P. 23 (156), 110 Pfeiffer, W. D. 76 (422), 115 Pfifferling, P. 394,395 (130), 445 Pfister-Guillouro, G. 9 (68), 108 Pfoertner, K. H. 233 (448), 276 Phillips, R. S. 291 (569,570), 361,362 Piancatelli, G . 36 (245), 112 Picciotto, A. de 6 (31), 108 Piccolo, 0. 148 (992), 223 Picot, A. 233 (106,107), 234 (107), 258 (106), 260 (368), 269,275 Piechaczek, J . 286 (510), 360 Pieper, M. 203 (922), 222 Pierce, 0. R. 7 (46), 108 Pierson, G. 0 . 5 9 (337), I14 Pietruszkiewicz,A. M. 238,267 (181), 271 Pilgram, K. H. 329,330 (723), 365 Pilgrim, W. R. 28 (195), 76 (425), 111,115 Pillai, P. M. 72 (387,388), 115,249 (291),273 Pillay, K. S. 237 (429), 276 Pinetti, A. 382 (86), 444 Pinner, A. 379 (67), 444 Pinson, R. 3 (17), 107 Pirkle, W. 70 (380), 114,228,258 (38). 268 Pirrung, M. C. 135 (629),216 Plant, S. G. P. 246 (256), 272 Plaquevent, J.-C. 228 (44), 268 Plate, R. 286 (508), 310 (508,677,678,826), 360,364,368 Platsch, H. 161 (712), 217 Plescia, S. 251 (312), 273 Pleshkova, A. P. 286 (518), 345 (754), 360,366 Pletnev, S. I. 287 (522), 295 (610), 360,362 Plevey, R. G. 296 (620), 363 Plomp, R. 106 (572), 119 Pliimer, R. 439 (302), 448 Plumitallo, A. 307 (671), 364

476

Author Index

PluSCec, J. 171 (763),219 PodPnyi, B. 301 (647), 363 Poirier, H.-M. 205 (934). 222 Poirier, J.-M. 71 (382-384), 114,115,135 (630), 146 (674), 147 (677), 216,217,260 (365,366), 274,282 (487,488), 292,321 (579), 339 (743), 359,362,366,375 (49), 379 (82,83), 406 (82,193-196), 439 (49, 303,304). 443,444,446,448 Poirier, J. M. 390,395 (120), 445 Poisson, J. 235 (426), 276,343 (750), 366 Poite, M. 370 ( l l ) , 443 Politzer, I. R. 254 (430), 276 Polnaszek, C. F. 280 (473). 359 Poluektov, V . A . 384,417 (235), 447 Polumbrik, 0. M. 257 (410), 275 Polyak, F. D. 293 (589), 362 Polycarpe, C. 182 (817), 220 Ponder, B. W. 19 (135), 110 Ponglux, D. 291 (567), 361 Ponti, P. P. 248 (265), 250 (296), 272,273,309 (675), 364 Poorker, C. 439 (301), 448 Popovich, T. P. 257 (410), 275 Porcu, M. P. 65 (355), 114 Portnykh, N. V. 96 (528), I18 Porzi, G . 346 (758,759), 366 Porzio, M. 370,395 (14), 443 Poslinska, H. 286 (510), 360 Posner, G. H. 91 (495), 117,201 (908), 222 Posner, J. 59 (340). 114 Posselt, K. 381 (85), 444 Potekhin, A. A. 238 (450). 276 Potier, P. 235,267 (417), (455). 276,302 (654), 364 Potts, K. T. 68 (372), I14 Potts, T. R. 72 (388). I15 Pouilhts, A . 291 (574), 362 Poutsma, M. 233 (108), 269 Povstyanoi, M. V. 68 (366), 114, 166 (742), 218,247 (259), 272 Pradkre, J.-P. 175 (789), 219 Prakash, G . 144 (665), 216 Prakash Rao, H. S. 137 (646), 216 Pratt, R. 41 (268), 112,242 (241), 260 (420), 272,276,395 (140), 445 Pravova, E. P. 82 (453), 116 Prean, M. 280,305 (469), 359,413,414 (224), 447 Preiss, 0 . 2 4 (165), I10 Preobrashinski, N. 370 (7), 443 Preobrazhemskii, N. A. 294 (599,362 Pri-Bar, I. 195 (880), 221,436 (292), 448 Priester, C. U. 310 (679), 364 Prietz, U. 249 (290), 273 Prince, A. 175 (775), 219,410 (206), 446 Pritzkow, W. 249 (290), 273 Prochukhan, A. S. 183 (826), 220

Prodan, K. A. 235,261 (126,127), 267 (126), 344 (127), 269 Prokhorova, T. S. 199 (901), 221 Prud’homme, R. E. 439 (310), 449 Prudnikova, E. K. 178 (799), 219 Pudovik, A. N. 98 (537), 118,238 (436), 276, 305 (662), 329 (719,720). 364,365,432 (283), 448 Peuch-Costes, E. 169 (759,218 Pulwer, M. 240 (214), 271 Purohit, P. C. 105 (564), I18 Purrello, G. 175 (788), 177 (792), 219 Purrington, S. T. 123 (592), 215,379 @I), 444 Pusino, A. 148 (678,679), 217 Putsykin, Y . G . 293,302 (585,586), 362 Puyol,J .379 (76), 444 Pyl, T. 230 (56), 268 Pyman, F. L. 254,267 (272), 272 Pyun, C. 263 (397),275 Quast, H. 233,234 (93), 239 (195-198), 259 (195), 269,271,332-334,346 (736), 365 Queguiner, G. 189 (852), 220 Quiniore, H. 72 (391), 115 Quittmann, W. 371,372 (20), 443 Raab, A. W. 238,267 (180), 271 Raaen, V. 377 (61), 444 Rabiller, C. 24 (163), 110 Rabinowitz, J. 6 (31), 108 Rahman, L. K. A. 181 (814), 220 Rajappa, S. 175,177 (786),219 Rajitha, B. 161 (718), 218 Rakosi, M. 76 (418), 115 Rakshit, P. C. 230 (59), 268 Ramadas, S. R. 83 (464), 116 Ramage, R. 31 (220), 111 Ramazanov, E. A. 80 (439), 116,180 (811), 220 Rambaud, M. 140 (648-650), 216,389 (112114,116), 445 Ramirez, F. 75 (407), 115,226 (23), 229,251 (23,46), 256 (23), 267,268 Rampersad, M. 102 (557), I18 Randles, K. R. 300,301 (643), 363 Randmeier, J. 7 (47), I08 Rane, A . V. 175,177 (786), 219 Ranise, A . 289,292,314 (548), 361 Ranu, B. C. 198 (887), 221 Rao, C. G. 89 (483), 117 Rao, M. K. 161(718), 218 Rao, P. P. 162 (719), 218 Rappe, C. 2 (6), 19 (131), 38 (253-255), 43 (275), 45 (295), 47 (298), 49 (275), 72 (389), 107,110,112,113,115,259(356), 2 74 Rasberger, M. 17 ( l l l ) , 109 Ratananuhul, P. 132 (622), 216

Author Index Ratcliffe, C. T. 349 (782). 366 Rathke, M. W. 92 (497), 117 Rauk, R. 263 (385), 275 Raupp, E. 123,137 (600), 215 Ravichandran, K. 151 (680,681), 217 Rawson, D. I. 93 (507), 117 Ray, A. C. 6 (37), I08 Ray, P. C. 6 (37), 108 Rearick, D. E. 235,244,261,267 (138), 270 Recheng, E. 166 (740), 218,405 (179), 446 Rector, C. H. 82 (454). 116 Reddy, B. 0. P. 162 (719), 218 Reddy, N. J. 171 (768), 219 Reddy, P. A. 178 (798), 219,226 (32). 267 Reddy, P. B. 168 (746), 218 Reddy, R. B. 168 (746), 218 Reddy, Y. D. 168 (746), 218 Reed, F. H. 12 (87), 109 Reed, S. F. 21 (148), I10 Rees, C. W. 287,295,296 (526), 361 Reese, C. B. 106 (568), 118,287,290,304 (528), 361 Reeve, W. 243 (238), 272 Rege, D. V. 12 (85), 109 Regitz, M. 329,349 (728). 365 Reichelt, H. 418 (236). 447 Reid, E. B. 64 (351), 114 Reimerink, M. P. 237 (435), 276 Reinach-Hirtzbach, F. de 35 (233), 112,388 (104,105), 445 Reinhoudt, D. N. 287 (534), 293 (590), 361, 362 Reisse, J. 9 (69), 108 Reiter, L. A. 152,183 (684), 217 Reliquet, A. 175 (787), 219 Reliquet, F. 175 (787), 219 Rempel, T. D. 145 (671), 217,376 (54), 444 Rendell, R. W. 296 (620), 363 Rens, M. 351 (798), 367 RetournC, C. 260 (367), 274 Reuss, R. H. 379 (80). 444 Reutrakul, V. 36 (237), 112,125 (604),215 Reynolds, S. 266 (431), 276 Reznikov, V. A. 288 (538), 290,291 (560), 361 Reznikova, T. I. 290,291 (560), 361 Riahi, M. A. 175 (789), 219 Ribereau, P. 189 (852), 220 Ricard, D. 8 (50), 28,30 (187), 108,111,255 (438,440), 276,370,372 (17), 387 (103), 416 (17,234), 443,444,447 Ricci, A. 206 (939,222 Richard, A. 353 (803), 367 Richard, G. 42 (271), 45 (290). loo (549), 112, 113,118 Richard, H. 237 (429), 276 Richard, M.-J. 169 (754), 218 Richards, A. 294 (596), 295,348 (614), 362, 363

477

Richards, P. 287,307 (529), 361 Richardson, R. W. 408 (200), 446 Riche, C. 254 (284), 260 (369), 273,275 Richman, J. E. 294 (594), 362 Ridley, D. D. 183 (827), 220 Ried, W. 72 (394), 115 Riehl, J.-J. 370 (9), 382 (87), 388 (108, 109), 395 (138,139,146), 396,399 (150). 400 (108,159-161,163), 401 (161). 405 (187), 439 (305), 443-446, 449 Riehl, J. J. 22 (151), 86 (476), 110,116 Riemschneider, R. 17 (114), 109 Riera, J. 10 (74). 109 Righetti, P. P. 305 (661), 364 Rihs, G. 153,171 (688), 217 Rihs, K. 286 (517), 358 (517,816), 360,367 Rimpler, M. 143 (661), 216,371 (24), 443 Ring, R. N. 229 (199),271,411(220), 447 Ringold, H. J. 4 (24),36 (238), 108,112 Risaliti, A. 76 (413), 115,251,256 (325-327), 2 74 Risse, S. 329 (713), 365 Ritschel, W. 257 (452), 276 Ritter, J. J. 80 (441), 116 Rivolta, L. 230 (63), 237 (170), 268,270 Roberts, R. A. 175 (774), 219 Roberts, T. G. 249 (447), 251 (298,451), 273, 276,286 (509,514), 294 (509),306 (509, 514), 310 (509), 360 Robertson, P. W. 376 (51), 444 Robinson, B. L. 135 (632), 216 Robson, J. H. 28 (194), 111 Rocquet, F. 74 (397), 115 Rodebaugh, R. 263 (397), 275 Roe, R. 20 (137), I10 Roedig, A. 19,34 (130), 110,136 (635), 216. 226 (36), 257 (452), 268,276,292 (581), 362,370 ( 9 , 3 7 7 (62), 439 (306), 443,444, 449 Roesky, H. W. 296 (625), 363 RogiC, M. M. 390 (117), 445 Rogic, M. M. 92 (497), 117 Rogulchenko, G. K. 68 (365), 114 Rokhlin, E. M. 3 (lo), I07 Roland, D. M. 235,253,254,261,267 (271), 2 72 Rollin, A. J. 101 (554), 118,311 (685), 364 Romlo, M. J. 439 (307), 449 Romeo, G. 136 (634), 216 Romgens, H. 78 (426), I15 Romhanyi, I. 175 (783), 219 Roos, M. 346 (765), 366 Ropp, G. A. 377 (61), 444 Ros, F. 162 (721,722), 163 (722), 218 Rosen, P. 98 (536), 118 Rosenfeld, D. D. 228,267 (441), 276 Rosenwald, R. H. 9 (58), I08 Rosini, G. 234,251 ( l l l ) , 269

478

Author Index

Rosnati, V. 42 (272), 62 (349), 65 (354,355), 112,114,148(678,679),217 Ross, A. 229(199),256(329),271,274,411 (220). 447 Rossback, I. 226,251 (9), 267 Rossey, G. 287,289,310 (531), 361 Rossi, F. 226 (19), 267 Rossini, G. 226 (19), 229,251 (47,48), 267, 268 Roth, C. 198 (884), 221 Roth, W.-D. 263 (375). 275 Rothgery, E. F. 358 (821), 367 Rouchard, J. 169 (756), 218 Rouessoc, F. 53 (323), 113 Rover. D. 235 (131).269 Roier: R. 161 (715j,’217,294 (598), 329 (713), 362,365 Rozen, S. 5 (26), 108,122 (587-589), 145 (672). 215.217 Rozenshtein, S. M. 82 (453), 116 Rubottom, G. M. 36 (247), 112 Rudchenko, V. 286 (518), 345 (754), 360,366 Ruff, M. 82 (451), 116 Ruhlig, G. 264 (403), 275 Ruiter, R. de 106 (572), 119 Rukachaisirikul, V. 125 (604), 215 Rukasov, A. F. 293,302 (585,586), 362 Ruminski, P. G. 182 (822), 220 Rumyantsev, V. G. 178 (799), 219 Rundberg, G. S. Jr. 233,251 (101), 269 Russell, D. N. 207 (941),222 Russell, G. A. 162 (721,722), 163 (722), 218 Russkikh, N. Y. 323 (703), 365 Rutherford, K. G. 9 (62), 51 (317), 108,113 Rutledge, P. S. 36 (243), I12 Ruttimann, A. 251 (304), 273 Ruveda, E. A. 242 (227), 272 Ryan, M. D. 388 (105), 445 Rydzkowski, R. 405 (177), 446 Saari, W. S. 238,267 (NO), 271 Saba, A. 65 (355), 114,148 (678,679), 217 Sablayrolles, C. 166 (740), 218,405 (179), 446 Saburi, M. 314 (691,692), 364 Sachs, A. A. 49,50 (310), 113 Sachs, W. H. 38 (253), 112 Sachse, B. 359 (822), 368 Sacks, A . A. 26 (177), 111 Sacks, C. A. 251,256 (309), 273 Sadet, J. 242,262 (226),272 Sadykh-Zade, S. I. 438 (297,298), 448 Saegusa, T. 14 (102), 93 (511), 109,117 Safronova, Z. V . 263 (395), 275,296 (617), 329 (724), 347,348 (771), 363,365,366 Sagina, E. I. 247 (262), 272 Sahni, S. B. 168 (751), 218,281 (478), 359 Saitkulova, F. G. 93 (516,517), 117,199 (900, 901), 221

Saito, S. 259,260 (352), 274 Saji, I. 169 (760), 219 Sakai, F. 424 (247), 447 Sakai, I. 249,256,303 (287). 273 Sakai, K. 168 (750), 218,281,287,305 (482), 359 Sakai, S. 199 (897), 221,235 (130,137), 245 (130,252), 267 (137), 269,270,272,291 (566,567), 341 (566), 361 Sakai, T. 83 (462), 116,184 (833), 220,400 (162), 419 (238,239), 420 (240,241), 446, 447 Sakaitani, M. 198 (885), 221 Sakakibara, T. 281,286,304 (479), 359 Sakurai, M. 195 (881). 221 Sakurai, T. 314 (692), 364 Salas, R. 175 (775), 219,410 (206), 446 Salaun, J. R. 45 (294), 113 Salemik, C. A. 161 (717). 218 Salimbeni, A. 62 (349), 114 Salon, M. C. 285 (503). 360 Salvino, J. M. 199 (903), 221 Samarai, L. I. 290 (558), 296 (622), 361,363 Sammes, M. P. 328 (709), 365 Sampson, P. 201 (985), 206 (937), 222,223 Samsonov, V. A. 288,302 (541), 361 Sanchez, E. I. 144 (668), 217 Sanchez, J. P. 164 (730), 195 (874), 218,221 Sanchez-Yiesca, F. 166 (734), 218 Sanders, H. P. 287,290,304 (528), 361 Sandler, S. R, 251 (310),273 Sandmann, U. 96 (522). 117 Sandri, S. 346 (758-761,825), 366,368 Sannicolo, F. 42 (272), 65 (354), 112,114,302 (651), 363 Sanno, Y . 96 (521), 117 Sano, H. 195 (879,881), 221 Sansoulet, J. 388 (106), 445 Saraie, T. 239 (183,184), 271 Saraswath, T. V. 76 (420), 115 Sarawatki, T. 247 (260), 272 Sargent, H. 11 (78), 109 Sarma, J. C. 214 (961), 223 Sarodnick, G. 73 (396). 115,410 (205), 446 Sarpeshkar, A. M. 81 (446), 116 Sasaki, K. 193 (864), 221 Sasaki, M. 72 (390), I15 Sasaki, T. 174 (770), 219,249 (409), 275 Sasse, K. 246 (255), 272 Sastry, C. V. 162 (719), 218 Satake, K. 211 (951), 222 Sato, C. 249 (409), 275 Sato, F. 198 (886), 221 Sato, H. 302,303 (655), 364 Sato, K. 2 (7), 49,57,61(306), 65 (357), 70 (306), 107,113,114,204(926), 222,259 (357),274 Sato, M. 198 (886), 221

Author Index Sato, S. 189 (860), 221 Sato, T. 137 (636,637), 193 (864), 216,221, 331 (730), 365 Sato, Y. 235,257 (117,118), 269,329 (714, 715), 365 Satoh, J. T. 14 (101), 109 Satoh, M. 183 (828), 220 Satoh, S. 183 (828), 220 Satoh, Y. 391 (123), 445 Satomi, M. 134 (627), 216 Satra, S. K. 231 (208), 271 Sattler, H. J. 68,73 (379,114 Sattsangi, P. D. 405 (181), 446 Sauleau, J. 96 (524), 117,428 (268), 448 Saunders, C. 230,247,267 (156), 270 SauvCtre, R. 390 (118), 445 Sauveur, F. 433 (285), 448 Savignac, P. 433 (285), 448 Sayigh, A . A. R. 236,257 (141), 270 Scamehorn, R. G. 54 (327), 55 (327,3301, I13 Scaria, P. M. 388 (107), 445 Scettri, A. 36 (245), 112 Schaad, L. 34 (229), 45 (291), 50 (229), 111, 113 Schadel, A. 158 (700), 217 Schaefer, J. P. 12 (86), 109 Schaefer, P. 286 (520), 288 (546), 292 (580), 302 (520), 359 (546), 360-362 Schafer, P. 239 (197), 271 Schafer, W. 78 (426), 115 Schaleger, L. 370,395 (14), 443 Schaleger, L. L. 395 (142), 445 Schaller, R. 418 (236), 447 Schamp, N. 6 (33), 9 (64-67), 10 (73), 11 (33), 13 (92-95), 14 (96), 22 (33,209), 28 (33), 29 (202). 30 (33,96,202,209), 44 (33), 46 (64), 56 (33,64,95,209), 58 (64), 70 (381, 405,406,586), 75 (405,406), 84 (467), 85 (469), 89 (485,486), 108,109,111,114117,119,130 (610-615), 131 (610,613615), 133 (623), 152 (610-612), 159 (707), 165 (732), 166 (733), 170 (762), (983, 984),215-219,223,226 (1,2),231,232 (79-83), 233 (85-90,92,115,116), 235 (113,115,116), 236 (143), 240 (I), 242 (233), 243 (80,82,87,116,248), 245 (87, 248), 246 (116), 247,253 (87), 254 (116, 276-280,457), 255 (280), 256 (86,87,90, 116), 257 (143,278), 258 (85,143,344346,348), 259 (82,248,278), 260 (86,87, 248,362,363,424), 262 (88), 263,264 (2), 265 (79,88,92,445,446), 267 (248), 277 (461), 280 (113), 282,283,296 (461), 298 (80,82,248), 314 (276), 318 (87), 331 (85, 143,345,346), 333 (go), 351 (346), (281, 283), 267-270,272-274,276,277,280 (462,474,476), 282 (489-491), 283 (490, 492,494,495), 288 (537), 292 (578), 297

479

(628), 298 (491,494,578,631-634), 299 (494,632-634), 312,313 (689), 314 (633, 634,697,698), 315 (633,634,698). 316 (633,634), 317 (634), 318 (490,699), 319, 320 (490), 321 (494,689), 324 (491), 331 (537,735), 332 (491), 333 (491,631), 334 (491,633,634,698), 335 (491), 337 (491, 737), 339 (632,634,742), 351 (537,735, 802), 353 (494,633,634), 354 (489), 359367,373,377 (34), 381 (84). 396,397 (151,152), 398 (153,154), 403 (170), 411 (219), 413 (223,231), 420 (242). 423 (242, 246), 426 (246), 428 (246,269), 443-448 Schantl, J . 76 (414), 115,226 (29-31), 251 (311,317-319,434), 267,273,274,276 Schantl, J. G. 280,305 (469), 359,413,414 (224), 447 Scheefer, G. 326 (708), 365 Scheibel, J. J. 122 (591), 215 Scheinbaum, M. L. 314 (696), 364 Schembri, G. 80 (440), 116 Schemiakan, M. M. 83 (459), 116 Schenone, P. 289,292,314 (548), 361 Scherberich, P. 403 (168), 446 Schickaneder, H. 263 (381,383,385), 275 Schickh, 0. V. 237 (159), 270 Schikaneder, H. 263 (376), 275 Schill, G. 310 (679), 364 Schiller, A. 439 (302), 448 Schimmelschmidt, K. 17 (121), 109 Schjanberg, E. 413 (229), 447 Schlosser, M. 3 (230), 4 (22), 108,111 Schmid, H. 30 (205), 111 Schmidt, E. 161 (712), 217,236 ( I S ) , 257 (337), 270,274 Schmidt, E. A. 93 (513), 117 Schmidt, J. 237 (160), 270 Schmidt, R. R. 288 (542), 302 (542,652), 346 (757,764,765), 359 (542,652), 361,363, 366 Schmidt, U. 179 (803), 219,233,246 (98), 269, 299 (638,639), 363 Schmied-Kowarzik, U. 26 (174), 110 Schmitt, E. 239 (195-198), 259 (195),271, 332-334,346 (736), 365 Schrnitt. R. K. 198 (884),221 Schmitz, M. K. 180 (805), 220 Schmuck, R. 80 (437), 116 Schneider, H. 295,296 (609), 362 Schneider, P. 297 (630), 363 Schneider, W. 24 (164), 110 Schnell, M. 434 (289), 448 Schnieders, C. 288,321 (540), 361 Scholl, R. 9 (70), 108,230 (61), 268 Schollkopf, U. 174 (773), 219 Scholz, C. R. 31 (216), 111 Schontag, W. 347 (773,776), 366 Schotte, L. 78 (428), 115

480

Author Index

Schroder, E. 280 (472), 359 Schubert, V. 211 (950), 222 Schulman, E. M. 15 (107), 109 Schultz, A . G. 75 (408), 115,251 (307), 273 Schultz, E. M. 100 (550). 118 Schultz, U. 230,264 (54), 268 Schumaker, R. R. 14 (97), 109,231,265 (84), 268 Schunack, W. 68,73 (375), 114,174 (772), 219,410 (204), 446 Schuster, K.-H. 82 (455), 116,242,255 (231), 2 72 Schutz, A. 413 (230), 447 Schwab, P. A . 44 (281). 113 Schwartz, K. 411 (212), 447 Schwartz, L. H. 96 (526), 118 Schwartz, U. M. 297 (629), 363 Schwarz, K. 175,177 (784), 219 Schwarzenbach, G. 38 (252), I12 Scott, J. H. 159 (706),217 Scott, L. T. 93 (519), 100 (551), 117,118 Scott, W. J. 338 (740), 365 Scriabine, A. 238,267 (180), 271 Scrowston, R. M. 181 (814), 220 Sears, W. C. 17 (122), 110 Seaton, P. J. 291,344 (563), 361 Sebti, S. 207 (944),222 Seckinger, K. (244), 272 Seebach, D. 148 (989), 223 Seelinger, W. 231 (75), 268 Seifert, C. M. 411 (211), 447 Sekine, M. 98 (538), 118,203 (916), 222,434 (286,287), 448 Sekiya, M. 33 (224), 111,141,159 (655,656), 216,292 (577), 362 Seko, K. 400 (162), 446 Selva, A. 65 (355), I14 Semenov, V. P. 238 (169), 270 Semenova, N. A . 280 (467), 359 Semmelhack, M. F. 428 (258), 448 Sendo, Y. 283,326 (497), 360 Seoane, F. 183 (830), 220 Seper, K. W. 199 (898), 221,285 (502), 311 (688), 313,321 (690), 360,364 Serrano, J. J. 166 (740), 218,405 (179), 446 Serratosa, F. 60 (341), 114 Serra-Zanetti, F. 287 (532), 361 Seshadri, R. 180 (807), 220 Sethi, K. 201 (906), 221 Setoguchi, M. 302 (658), 364 Seufert, W. 10,30 (76), I09 Severin, T. 286 (519), 309 (519,673), 311 (673), 360,364 Sevost’yanova, V. V. 102 (599), 118 Seymour, D. 28 (194), I l l Shaikh, Y . A. 226 (6), 267 Shalom, E. 288,302 (547), 355 (547,804), 361, 367

Sharanin, Y. A. 175 (777). 219 Sharma, R. 161, 168 (714),217 Sharma, R. P. 214 (961), 223 Sharma, T. 171 (768), 219 Sharma, T. C . 49 (308,309), 113 Sharpless, K. B. 20 (136), 110 Sharrard, F. 175 (787), 219 Shashkov, A . S. 168 (752), 218,280 (467), 359 Shatzmiller, S. 251 (303,305,456), 273,276, 288 (547), 302 (547,657), 306 (669), 309 (657,674), 311 (681), 355 (547,804), 361, 364,367 Shavel, J. Jr. 244,245,261 (249,250), 272 Shchepin, V. V. 323 (703), 365 Shchukin, G. I. 302 (648), 363 Shchukina, M. N. 370 (16), 443 Sheldrick, G. M. 296 (625), 363 Shellhamer, D. F. 36 (246), 112,135 (632), 145 (670,671), 216,217,376 (53,54), 377 (58), 444 Shepard, R. A. 6 (36), 108 Shermolovich, Y. G. 295 (616), 363 Shevchenko, V. 238 (191), 247 (263), 271,272 Shevchuk, M. I. 203 (921), 222,427,428 (261), 448 Shibaev, V. N. 346 (762), 366 Shibata, S. 314 (691,692), 364 Shida, T. 266,287 (460), 277 Shigehisa, T. 204 (931), 222 Shimano, S. 329,359 (717), 365 Shimizie, N. 159 (703). 217 Shimizu, M. 36 (244), 112,123 (597), 215 Shin, C. 235,257 (117,118), 269,329 (714, 715), 365 Shinma, N. 245 (252), 272 Shinohara, S. 420 (241), 447 Shirai, Y. 306 (667), 364 Shoda, S. 199 (895), 221 Shono, T. 132 (619), 216 Shridhar, D. R. 162 (719), 218 Shriner, R. L. 238 (175), 270 Shuchukina, M. 370 (7), 443 Shukyurova, M. B. 438 (297), 448 Shul’man, M. D. 377 (63), 444 Shustov, G. V. 294 (599), 349 (599,783), 362, 366 Shutov, G. V. 348,349 (780), 366 Shvaika, 0. P. 76 (415), 115,230 (110), 269 Sibille, S. (974), 223 Sieber, A. 211 (950), 222 Sieburth, S. M. 189,192 (851), 220 Siegel, H. 400 (157), 446 Siems, W. 236 (142), 257 (335,336), 270,274, 411 (218), 447 Siffert, 0.296 (626), 363 Sigaut-Titeux, F. 235,267 (215), 271 Silowiecki, A. 384 (88), 444

Author Index Silveira, A. Jr. 231 (77,208),251 (77,315),

268,271,273 Simchen, G. 82(455),116,205(932),222,242, 255 (231),272 Simmerl, R.347(774). 366 Simmross, F. M. 288 (544),361 Simon, H.251 (334),274 Simonyan, L.A. 263 (389),275,329(724), 347,348(771),365,366 Simpkins, N.S. 146 (976),223 Singh, H. 175,177(791),219 Singh, H.K. 214 (986),223 Singh, P.175,177(791),219 Singh, S. 226 (32),267 Singh, S. P.439(301), 448 Sinitsa, A. 238 (191),247 (263),271,272 Sinitsa, A. D. 236 (148-151),270 Sinitsyna, N.I. 411 (217),447 Sinnreich, D. 309 (674),364 Sintamarian,A. 230 (218),271,294(593),362 Siret, P.406 (191),446 Sisido, K. 263 (398),275 Sisti, A. J. 41 (263),90(489),112,I17 Sitkareva, I. V. 146 (673),217 Sket, B. 127(607),142(657),215,216 Skiles, R.D.329,330(7231,365 Skolimowski, J. 203 (920),222 Skowronski, R.203 (920),222 Slanina, S. J. 36 (236),112 Sliwa, H.405 (177),446 Slove, D. B. 59 (337),114 Small, A. M. 4(23),I08 Smirnov, V. A. 257(340), 274 Smirnov, V. N.238 (436),276 Smissman, E.E.17(117),45 (287),53 (324), 109,113 Smit, C. J. 106(572), I19 Smith, H. A. 44(282),113 Smith, J. H. 249 (288,289),(294),273 Smith, R.A . J. 179 (801),219 Smith, T.A. 159 (706),217 Smith, W. B. 60(343,114 Smithers, R.H.93(512,513),117 Smits, J. M.M. 310 (677),364 Smolikiewicz, A. 86 (476),116 Soccolini, F. 65 (355), 114 Sohn, D.296 (618),363 Soifer, G. B. 199 (900),221 Sokol, H. 80 (441),I16 Sokolov, N.A. 35 (234),I12 Sokolov, S. D.286 (518), 293 (583),345 (754), 360,362,366 Sokol’skii, G. 329 (718,725), 365 Sokol’skii, G. A . 287 (536),296 (619),347 (779,350(786),361,363,366,367 Soler, J. R. 166 (738),218 Sommer, S. 251 (308),273 Somsak, L.175 (783),219

Sonawane, H. R.105 (564),I18 Sondheimer, F. 408 (200),446 Songstad, J. 44(277),112,243(237),272 Sonneborn, H. 381 (85),444 Sonnenberg, F. 12(86),109 Sootome, N.193(864),221 Sopova, A. S. 86 (472),116 Sorensen, A. M.17(123),110 Sorokin, 0. I. 68(371),114 Sota, K. 201 (907),222 Southwell, I. 344(751),366 Sozinov, V. N.280 (468),359 Spaite, D. 376 (53), 444 Spaite, D.W. 145 (671),217,376(54),444

481

Spasov,S.28(198),111 Spassky, N.439 (310),449 Spaulding, T.C. 90(490),117 Spencer, T.A. 107(581),119,163(724),218 Speziale, A . J. 238(193),271 Spindler, J. 73 (396),115,410(205),446 Spiro, V. 230,253(109),269 Spitulnik, M.J. 290 (550), 361 Spraul, M.123 (599,601),137(599),215,385 (101),444 Spreafico, F. 148(992),223 Springs, B. 100(546,547),118 Sprio, V. 251 (312),273 Sprugel, W. 16 (108),109 Srinivasan, K. R.304(660),364 Srinivasan, P.C. 291 (572),362 Srinivasan, V. 247 (260),272 Srinivasan, V. R.76 (420),115,178(798),219, 226(32), 267 Srnak, A. 198(887),221 Stache, F. 78 (427),115 Staehler, G. 359 (822),368 Stahl-Lariviere,H. 201 (909),222 Staib, R.N.347(770),336 Stamhuis, E.J. 130(979,980), 223 Stanaback, R.J. 331 (731),365 Stanborough, M.S. 168(749,218 Stanetty, P.189 (854),221 Stang, P.J. 234,252(453),276 Staninets, V. I. 295 (616), 363,376(55), 444 Stanishevskii, L. S. 171 (764),219 Stanovnik, B. 143 (659),216 Staring, E. G. J. 439 (308,309),449 Starz, K.A. 203 (925),222 Stavber, S. 123 (594,599,215 Stavorski, J . M.238,267(180),271 Steglich, W. 236 (147,152,154),237(154), 255 (154,285),257 (154),263 (154,388), 270,273,275 Steinbach, K. 263 (378,380), 275 Steinbeck, K.17(110), 109 Steiner, E.137(643),216 Steinkopf, W. 238 (190),271 Stella, L. 407(199),446

482

Author Index

Stener, A. 251,256 (325,326), 274 Stepanov, A. 370 (7), 443 Stepanov, B. I. 293 (582), 362 Stephens, J. R. 33 (228), 111 Steppel, R. N. 19 (128), 22 (154), 110 Sterlin, R. N. 263 (394). 275 Sterling, J. J. 91 (495), 117 Sternberg, J. A. 306 (668), 364 Stetter, J. 288 (542), 302,359 (542,652), 361, 363 Stevens, C. 370,374 (15), 395 (15,140), 443, 445 Stevens, C. L. 9 (62), 11 (81), 25 (168), 41 (268), 44 (280), 50 (314), 51 (315-317), 53 (316), 70 (378), 72 (387,388), 108-110, 112-115,226 (13), 242 (241), 249 (291), 260 (420-422), 267,272,273,276,374, 393,395 (36), 443 Stevens, J. A. 287 (525), 295,296 (607), 307 (525), 361,362,411 (222), 447 Stevens, J . I. 385 (313), 449 Stevens, R. W. 199 (891,893), 221 Stezowski, J. J. 158 (696), 217 Stille, J. K. 195 (880), 221,436 (292), 448 Stinissen, H. 130 (979), 223 Stoilov, Y. Y. 166 (742),218 Stone, C. A. 238,267 (181), 271 Stoodley, R. J. 163 (723), 218 Storace, L. 303 (659), 364 Stork, G. 23 (157), 36 (238), 110,112 Storr, R. C. 295 (604), 300,301 (643), 321 (702), 349 (781), 353 (702), 362,363,365, 366 Stoss, P. 247 (257), 272 Stotter, P. L. 427 (255), 447 Strauss, F. 21 (146), 110 Straw, D. 26 (178), 76 (424), 111,115,242 (232), 272 Streitwieser, A. 242 (222,225), 271 Streitwieser, A. Jr. 41 (265), 112 Stroh, R. 370 (6), 443 Strong, J. G. 54,55 (326), 113 Strong, S. A. 324,356 (705,706), 365 Struchkov, Y.T. 203 (918),222,263 (395), 275 Struve, W. S. 19 (129), 110 Strych, W. 264 (405),275 Stuessi, R. 80 (442), 116 Stukalo, E. A. 236 (148), 270 Stults, B. R. 296 (624), 363 Sturiale, E. R. 83 (461), 116 Sturtz, G. 287,304,305 (530), 361,428 (259), 448 Suarato, A. 230,245,267 (51), 268 Suba, L. A. 182 (822), 220 Subba Rao, B. 393 (127), 445 Subrahmanyam, G. 93 (500), 117 Sucrow, W. 96 (522), 117 Sudarev, Y. I. 98 (537), 118

Sudarsanam, V. 175,177 (786), 219 Sudoh, R. 281,286,304 (479), 359 Suefuji, M. 331 (730), 365 Sugasawa, T. 141 (653), 216,295 (605,606), 362 Suggs, J. W. 435 (314), 449 Sugihara, H. 96 (521), 117,204 (929). 222 Sugimura, Y.182 (821), 220 Sugiyama, H. 235,257 (118), 269 Sulmon, P. 282 (491), 283 (495), 298 (491, 632-634), 299 (632-634), 312,313 (689), 314-316 (633,634), 317 (634), 321 (689), 324,332,333 (491), 334 (491,633,634), 335 (491), 337 (491,737), 339 (632,634, 742), 353 (633,634), 360,363-366 Sumiejski, J. 230 (206), 271 Sumoto, K. 301 (646), 363 Sunari Tukiman. 233,256 (90), 269 Sundara Raman, P. 102 (557), 118 Sundeen, J. 171 (763), 219 Sundermeyer, W. 296 (618), 363 Sunjic, V. 64 (353), 114 Supavita, T. 291 (567), 361 Surender, E. 168 (746), 218 Surya Prakash, G. K. 134 (625), 216 Suter, A. K. 93 (501), 117 Suvorov, N. N. 280 (468), 359 Suzuki, A. 391 (123), 445 Suzuki, K. 33 (224), 111 Suzuki, N. 204 (926), 222 Svec, P. 17 (123), 110 Swain, C. G. 38 (257), 112 Swenton, L. 235,261,344 (127), 269 Swered, P. 266 (414), 275,357 (807), 367 Swietoslawski,J. 384 (88), 444 Swyngedouw,C. 396,397 (151), 420,423 (242), 445,447 Sytilin, M. S. 38 (256), 112 Szabo, L. 310 (676), 364 Szabo, W. A. 351 (795), 367 Szakal, G. 96-98 (532), 118,201 (910), 222 Szantay, C. 310 (676), 364 Szantay, C. Jr, 310 (676), 364 Szarek, W. A. 203 (919), 222 Szisz, G. 301 (647), 363 Szeimies, G. 239,259 (211), 271 Sztaricskai, F. 291 (561), 361 Tabata, H. 184 (833), 220 Tabeteau, J. 373 (28), 443 Tabor, T. E. 22 (152,153), 110 Tabusa, F. 247 (261), 272 Tacconi, G. 305 (661), 364 Tada, M. 400 (156), 445 Taffer, I. M. 151 (682), 217 Taguchi, H. 385,439 (99), 444 Takahashi, K. 183 (829), 220,306 (667), 364 Takakura, Y.283,324,359 (500), 360

Author Index Takamatsu, M. 292 (577), 362 Takamo, I. 195 (883), 221 Takano, I. 195 (881), 221 Takano, S. 346 (766), 366 Takaoka, A. 296 (627), 363 Takaya, H. 93 (502,506), 117 Takayama, K. 161 (712), 217 Takeda, A. 47 (299), 83 (462), 113,116,151 (683), 184 (833), 214 (978), 217,220,223, 400 (162), 418 (237), 419 (238,239), 420 (237,240,241), 424 (247), 425 (248,249), 446,447 Takeda, M. 259,260 (352), 274 Takeda, T. 152 (685), 217 Takedo, A. 423 (245), 447 Takeuchi, K. 211 (952,953), 222 Takeyama, T. 207 (942), 222 Tam, S. W. 107 (575), 119, (244), 272,345 (755), 366 Tamoto, K . 169 (760),219 Tampier, L. 276,377 (57), 444 Tamura, Y. 204 (927),222,246-248,262 (253), 272 Tanabe, M. 424 (247), 447 Tanabe, S. 291,341 (566), 361 Tanaka, K. 295 (608), 296 (623), 362,363 Tanaka, M. 88 (480), 117,159 (703), 214 (964), 217,223 Tanaka, S. 385,439 (99), 444 Tanaka, T. 182 (821), 188 (845), 220,429 (265), 448 Tang, W. P. 346 (769), 366 Tanida, H. 331 (730), 365 Tanikaga, R. 204 (929), 222 Tanner, D. D. 214 (986), 223 Tarantello, M. 177 (792), 219 Tarasova, R. I. 411 (217), 447 Tardella, P. A. 172 (769), 219 Tarhouni, R. 140 (648-650), 216,389 (113, 114,116), 445 Tarraga, A. 168 (748), 178 (797), 218,219 Tashchi, V. P. 293,302 (585,586), 362 Tashiro, M. 231,247 (74), 268 Tathke, M. W. 390 (117), 445 Tatlow, J. C. 296 (620), 363 Tatsumo, T. 123 (596), 215 Taurius, A. 238 (178), 271 Tayaka, H. 93 (505), 117 Tayano, T. 391 (123) 445 Taylor, W. 235,244 (132,133), 245 (132), 261, 267 (132,133), 269 Tazuma, J. 50 (3141,113 Tchoubar, B. 2 (9), 45 (286,288,289), 61 (346), 107,113,114 Tedga, N. 339 (743), 366 Tegg, D. 175 (775), 219,410 (206), 446 Temnikova, T. I. 15 (103), 109,242 (240), 260 (419,423), 272,276

483

Temple, C. 168 (747), 218 Teranishi, A. Y. 20 (136), I10 Terasawa, I. 237,249 (165), 270 Terasawa, T. 80 (433), 116 Terashima, M. 233 (99), 269 Terekhov, A. V. 238,267 (204), 271 Terent'ev, A. P. 371 (19), 443 Terentiev, P. B. 72 (393), 115,184 (834), 220 Terruzzi, M. 82 (457), 116 Terry, P. H. 251 (314), 273 Tetyukhin, V. N. 296 (622), 363 Texier-Boullet, F. 199 (914), 202 (911-914), 222 Thatte, S. D. 251 (314),273 Thenn, W. 263 (381,384,385), 275 Thiele, K. 286 (512), 360 Thiem, J. 346 (768), 366 Thieme, G. 237 (158), 238 (176), 270 Thierie, R. 84 (466,467), 85 (469), I16 Thil, L. 86 (476), 116,395 (146), 445 Thomas, G. H. 36 (241), 112 Thomas, S. E. 17 (124,126), 110 Thompson, H. W. 329 (711), 365 Thong, P. D. 237,264 (216,217), 271 Thorne, N. 237 (161,162), 270 Thorpe, J. W. 38 (258), 43 (276), 112,243 (239), 272 Thorstenson, J. 35 (235), I12 Thorstenson, J. H. 96 (520), 117 Thurber, T. C. 175 (775), 219,410 (206), 446 Thyagarajan, G. 432 (279), 448 Ticozzi, C. 86 (470), 116,248 (265,267), 272, 309 (675), 364 Tidwell, T. 351 (788), 367 Tidwell, T. T. 351 (787), 367 Tien, H.-J. 182 (819), 220 Tiensripojamarn, A. 36 (237), 112 Tiffeneau, M. 86,88 (474), 116 Tilborg, W. J. M. van 106 (572), 119 Tillequin, F. 291,325 (565),361 Tilley, M. 254 (277,278), 257,259 (278), 273 Timmler, F. 25 (166), 110 Timoshin, A. A. 166 (742), 218 Tin, K.-C. 388 (105), 445 Tinant, B. 337 (737), 365 Tinh, N.-H. 182 (817), 220 Tiollais, R. 379 (79), 444 Tirel, M. D. 411 (213), 447 Tischchenko. I. G. 35 (234), 112,171 (764), 219 Tisler, M. 143 (659), 216 Titeux, F. 235,267 (136), 270 Titov, B. A. 238,267 (204), 271 Titov, Y. A. 2 ( 5 ) , 107,259 (359,274 Titzmann, R. 230 (67), 268 T K i n t , C. 238 (194),271 Todesco, P. E. 33 (226), 111 Tohru, H. 235 (120), 269

484

Autholr Index

Toke, L. 96-98 (532), 118,201 (910), 222 Tokumitsu, T. 290 (555), 361 Tokunaga, H. 76 (419), 115 Tokuro, N. 230 (62), 268 TomBs, M. 290 (556,557), 361 Tomasini, C. 346 (760,761,825), 366,368 Tombret, F. 439, (304), 448 Tomesch, J. C. 428 (258), 448 Tomilov, Y. T. 263 (399), 275 Tominaga, Y. 171 (767),219 Tomioka, H. 106 (569), 119,212 (956), 223 Tomioka, S. 238 (221), 271 Tomisawa, K. 201 (907), 222 Tomlinson, M. L. 246 (256), 272 Tonnard, F. 72 (391), 115 Tonozuka, M. 235,244,262 (121), 269 Torchiana, M. L. 238,267 (181), 271 Tordeux, M. 5 (29), 71 (385), 108, I15 Tori, K. 331 (730), 365 Torimitsu, S. 237 (165,168), 249 (165,168, 287), 256,303 (287), 270,273 Torreilles, E. 182 (817), 220 Torrii, S. 16 (109), 109 Toth, G. 310 (676), 364 Toullec, J. 38 (251), 112 Townsend, J. M. 107 (581), 119 Traber, R. (244), 272 Trachtenberg, E. N. 243 (236), 272 Trazza, A. 291 (568), 361 Treasurywala, A. M. 235,245 (373), 275 Treboganov, A. D. 294 (595), 362 Treiber, J. 309,311 (673), 364 Tremmel, S. 263 (383), 275,348 (777), 366 Trevoy, L. W. 96 (525), 117 Tristam, E. W. 76 (417), 115,226 (28), 267 Troger, W. 16 (108), 109 Trost, B. M. 20 (142), 80 (435), 110,I16 Trujillo, D. A. 247 (258), 272 Truskanova, T. D. 296 (619), 363 Trybulski, E. J. 435 (314), 449 Tsangaris, M. N. 391 (124), 445 Tse-Lok Ho 107 (579,583), I19 Tsuboi, S. 151 (683), 217,418 (237), 420 (237, 240,241), 423 (245), 424 (247), 425 (248, 249), 447 Tsuboniwa, N. 198 (889,890),221 Tsuchihashi, G.-I. 159 (705), 217 Tsuchiya, T. 152 (685,686), 217 Tsuge, 0,231,247 (74), 253,309 (269), 268, 2 72 Tsuji, A. 400 (162), 446 Tsuji, T. 331 (730), 365 Tsujii, H. 106 (569), 119 Tsunashima, Y. 166,167 (737), 218 Tsuno, Y. 159(703),217 Tsuruta, T. 130 (618), 216 Tsushima, T. 331 (730), 365 Tsutsumi, S. 93 (505), 117

Tucker, B. 236,257 (141), 270 Turcan, J. 231 (70,72), 268 Turchin, K. F. 286 (518), 345 (754), 360,366 Turner, G. A. 405 (182), 446 Turro, N. J. 43,49 (275), 112,194 (870), 221 Twohig, M. F. 207 (941), 222 Ueda, A. 283,324,359 (500), 360 Ueda, K. 137 (636), 216 Ueda, Y. 75 (410), 115,204 (927), 222,230, 249 (68), 268 Ueno, M. 214 (972), 223 Uggeri, F. 148 (993), 160 (709,710), 217,223 Ugi, I. 283 (499), 360,413 (230), 426,427 (253), 447 Ukawa, K. 96 (521), 117 Ullerich, K. 432 (275), 448 Ulm, K. 351 (794), 367 Ulmer, H. E. 280 (470), 359 Ulrich, H. 236,257 (141), 270 Umani-Ronchi, A. 86 (470), 116,248 (265, 267,268), 250 (296), 272,273 Umezawa, 0 . 2 2 6 (34,35), 268 Uminski, M. 187 (843), 220 Unkovskii, B. V. 263 (437), 276 Uno, T. 432 (245), 447 Unterhalt, B. 266 (433), 276 Urasato, N. 263 (400), 275 Urbanek, F. 9 (61), 45 (293), 108,113 Usmani, A. A. 159 (702), 217 Usteri, E. 9 (56), 19 (133), 108,110 Ustynyuk, T. K. 2 (5), 107,259 (355), 274 Utaka, M. 47 (299), 113,151 (683), 214 (978), 217,223,400 (162), 419 (239), 446,447 Vailatti, A. 86 (478), 116 Valdes, D. 175 (775), 219,410 (206). 446 Valentino, D. S. 34 (232), 112 Valette, G. 231 (78), 268 255 (321,323), 256 (322,324), Valnot, J.-Y. 258 (321), 314 (324), 274,370 (13), 384 (96), 403,404 (169), 413 (225), 443,444, 446,447 Valnot, J. Y. 226 (33), 228,229 (43), 241 (219), 267,268,271 Valoti, E. 148 (992),223 Van Alphen, J. 226 (17), 267 Van Caenegem, L. 84 (467), I16 Vandenbulcke-Coyette, B. 294,302,303,306 (597), 362 Van der Kelen, G. P. 378 (65), 444 Vandrevala, M. H. 345 (752), 366 Van Duuren, B. L. 404 (174), 446 Van Horn, A. R. 410 (206), 446 Vankar, G. D. 107 (582), I19 Vankar, Y.D. 6 (38), 23 (158), 107 (584). 108, 110,119 Van Loocke, R. 29,30 (202), 111

Author Index Van Meerssche, M. 249,250 (297), 260 (362), 273,274,282,298,324,332-335 (491), 337 (491,737). 360,365 Vanslembrouck, J. 130,131 (614), 215 Varlamov, S. V. 348,349 (799,780). 366 Varlet, J. M. 433 (285), 448 Vartanyan, S. 0. 161 (713), 217 Vasil’ev, N. V. 285 (501), 287 (536), 314,347, 348 (501), 350 (786), 360,361,367 Vaucamps, P.-L. 235 (426), 276 Vaughn, G. D. 436 (294), 448 Vecchiani, S. 189 (849), 220 Velarde, E. 5 (27), 108, 175 (775), 219,410 (206), 446 Velasco, M. D. 214 (959,960), 223,311 (683), 364 Venet, M. 351 (801). 367 Venien, F. 66 (361), 114 Venus-Damilowa, E. 394 (131), 445 Verboom, W. 287 (534), 361 Vereshchagin, L. I. 302 (653), 364 VerhC, R. 6 (33), 9 (64-67). 10 (73), 11 (33), 14 (96), 22 (33,209), 28 (33), 29 (202), 30 (33,96,202,209), 44 (33), 46 (64), 56 (33, 64,209), 58 (64), 70 (381,405), 75 (405), 84 (466,467), 85 (469), 89 (485,486), 108, 109,111,114-117,130 (610-615). 131 (610,613-615), 152 (610-612), 159 (707), 165 (732). 166 (733). 215,217,218,226 (2), 233 (85-90,92,115,116), 235 (115, 116), 236 (143), 242 (233), 243 (87,116), 245 (87), 246 (116), 247,253 (87), 254 (116,276-280,4571,255 (ZSO), 256 (86, 87,90, 116), 257 (143,278), 258 (85, 143, 344-346,348), 259 (278), 260 (86,87,362, 363,424). 262 (88), 263,264 (2), 265 (88, 92,445,446), 277 (461), 282,283,296 (461), 314 (276), 318 (87), 331 (85,143, 345,346), 351 (346), (281,283), 267-270, 272-274,276,277,280 (474,476), 282 (489,490), 283 (490,492,494,499,288 (537), 292 (578), 297 (628), 298 (494,578, 631-633), 299 (494,632,633), 314 (633, 697,698), 315 (633,698), 316 (633), 318320 (490), 321 (494), 331 (537,735), 333 (631), 334 (633,698). 337 (737), 339 (632, 742), 351 (537,735,802) 353 (494,633), 354 (489), 359-367,373,377 (34), 381 (84), 394 (135), 396,397 (151,152), 398 (153,154),399,400(135),403 (170),411 (219), 413 (231), 416,417 (135), 420 (135, 242), 423 (242,246), 425 (135), 426 (246), 428(135,246,269),431,432(135),443448 Verkade, P. E. 226 (5), 267 Vershinin, V. L. 287 (536), 329 (726,727). 350 (786), 361,365,367 Vessiere, R. 351 (800),367

485

Vice, S. F. 166, 167 (735), 218,235,244 (119). 269,299 (636,637), 363 Vichers, S. 53 (324), 113 Vickers, S. 17 (117), 109 Viehe, H.-G. 294,302,303,306 (597), 362 Viehe, H. G. 169 (759), 218,249,250 (297), 273 Viel, C. 242,262 (226), 272 Vignalon, M. 394 (132), 445 Vigne, C. 169 (754), 218 Vijayaraghavan, S. T. 195 (882), 221 Vilhauer, E. B. 408 (201), 446 Villhauer, E. B. 375 (43), 443 Villieras, J . 18 (127), 24,35,46 (162), 89 (488), 110,117,140 (648-650), 216,385 (102), 389 (112-1 16), 444,445 Vilsmaier, E. 16 (log), 109 Vincent, A. 337,341 (738), 365 Vinogradova, S. 293 (583), 362 Vinogradova, T. K. 329 (721), 365 Vinter, J. G. 27,28 (183), 111 Vio, L. 413 (226), 447 Virgona, C. T. 286,358 (517), 360 Virkhaus, R. 99 (543), 118 Visentin, G. 148 (992), 223 Vishnivetskaya, L. A. 302 (648), 363 Visser, R. 287 (534), 361 Visweswariah, S. 144 (665), 216 Vitale, A. C. 90 (489), 117 Vladuchick, W. C. 80 (435), 116 Vogl, 0 . 2 2 9 (200-202), 271,411 (221), 447 Volodarskii, L. B. 288 (538,541), 290,291 (560), 302 (541,648). 361,363 Volod’kin, A. A. 96 (5281,118 Von Schnering, H. G. 161 (712), 217 Vork, M. V. 296 (622), 363 Voronima, I. A. 384,417 (235), 447 Voronkov, M. G. 74 (400), 115,295,329 (602, 603), 362 Voss, J. 132,182 (620), 216 Vyas, D. M. 346 (767), 366 Wache, H. 351 (794), 367 Wada, M. 204 (931), 222 Wada, S. 425 (248), 447 Wade, K. E. 145 (670), 217,337 (58), 444 Wadodkar, K. N. 178 (SOO), 219 Wagner, R. B. 29 (199). 111 Wahlberg, E. 82 (452), 116 Wakata, Y . 174 (770),219 Wakselman, C. 5 (29), 6 (41), 66 (359), 100 (548), 108,114, I18 Walker, D. R. 19 (135), 110 Walker, K. A. M. 175,176 (778), 219 Wallach, 0.28(190),111,237,249(166),270 Walling, C. 375 (42), 443 Wallis, J. D. 411 (213). 447 Walls, F. 207 (943), 222

486

Author Index

Walser, A. 235,244,262 (129), 269 Walter, E. 251 (456), 276 Walterdorfer, A. 359 (822), 368 Waltero, P. 379 (74), 444 Walti, A. 64 (350), 114 Wang, N. 235,267 (135), 270 Wang, X. 178 (794), 219 Wang, 2. 178 (794), 219 Wanner, I. 158 (697,698), 217 Wanzlick, H. W. 9 (59), 108 Warkentin, J. 38 (258,259), 43 (276), 112,243 (239), 272 Warnant, J. 3 (18), 107 Warneboldt, R. B. 65 (356), 114 Warnhoff, E. 102 (557), 118 Warnhoff, E. W. 11 (80), 68 (369,373,374), 109,114,207 (940), 210 (947,948). 222 Warren, K. S. 28 (197), 47 (300), I l l , I13 Warren, S. G. 96 (529), 118,247 (264b), 272 Wassef, W. N. 204 (928), 222 Watanabe, K. 80 (436), 116,238 (221), 242 (230), 271,272 Watanabe, N. 420 (243), 447 Watanabe, T. 166 (741). 188 (845), 218,220, 429 (265), 448 Watanabe, Y. 291,341 (566),361 Watson, H. B. 9 ( 5 5 ) ,108 Watson, W. H. 439 (301), 448 Watterson, A. C . 65 (358), 114 Weber, G. 288,304 (543), 361 Weber, T. 148 (989), 223 Wegler, R. 229,257 (333), 266 (432), 274,276 Wegner, K. 174 (772), 219,410 (204), 446 Weidenhagen, R. 44 (284), 113 Weigand, J. 346 (768), 366 Weigert, F. J. 287 (533), 361 Wed, T. A. 251 (315), 273 Weiler, L. 65 (356), 114 Weiner, A. M. 12 (87), 109 Weiner, M. L. 51 (315), 113,260 (421), 276 Weingarten, H. 282 (484,485), 359 Weinreb, S. M. 347 (770), 366 Weintraub, H. (413), 275 Weintraub, H. S. 230,266 (220), 271 Weintraub, P. M. 169 (758), 218 Weis, M. J. 4 (23), 108 Weiss, F. 74 (397), 115 Welch, J. T. 6 (38), 108,199 (898), 221,285 (502), 311 (688), 313,321 (690), 360,364 Wellman, K. M. 28,49, 65 (189), 111 Wemple, J. 81 (446), I16 Wender, P. A. 166,167 (736), 189,192 (851). 193 (866), 194 (868), 218,220,221,432 (274), 448 Wenkert, E. 235 (135,138,426), 244,261 (138), 267 (135,138), 270,276,287,289, 310 (531). 361 Werner, W. 385 (98), 444

Weslowski, T. J. 251 (315), 273 West, T. S. 28 (186), 111 Wetherington, J. B. 249 (288), 273 Wetroff, G. 357 (813), 367 Weyerstahl, P. 288 (544), 361 Weygand, F. 26 (174), 110,236 (147,152, 154), 237 (154), 255 (154,285), 257 (154), 263 (154,388), 270,273,275 Wharton, P. S. 59 (338), 114 Wheeler, G. P. 168 (747). 218 White, A. W. 166,167 (736). 193 (866), 218, 221,432 (274). 448 White, D. A. 378 (66), 444 White, E. P. 376 (51), 444 White, R. E. 393 (126), 445 White, W. A. 282 (484,485), 359 Whiteley, C . 314 (694), 364 Whitesides, G. 395 (143), 445 Whitesides, G. M. 374 (39), 443 Whitham, G. A. 182 (818), 220 Whybrav, D. 184 (832), 220 Wick, A. 287,289,310 (531), 361 Widman, 0.82 (452), I16 Wiedenmann, R. 82 (451), 116 Wiemer, D. F. 201 (985), 206 (937), 222,223 Wiese, H. C . 135 (632), 216 Wieser, K. 230,238 (64,65), 268 Wiewiorowski, M. 411 (209), 447 Wild, H.-J. 297 (630), 363 Wild, W. 230 (60), 268 Wilde, H. 288,304 (543), 361 Wilker, J. C. 90 (490), 117 Williams, D. R. 241 (454), 276 Williams, F. V. 41,43 (262), 112,243 (235), 272 Williams, J. C . 73 (395), 115 Williams, L. R. 33 (227), 111 Williamson, K. L. 31 (218). 111 Williard, P. G. 199 (903), 221 Wilson, R. M. 291,301,342 (562), 361 Wilson, W. 34 (231), I l l Windhovel, U. F. 310 (679), 364 Wingen, H. P. 186 (837), 220 Winkler, T. 153,171 (688), 217 Winstein, S. 28 (194). 42 (270), I l l , 112 Winter, W. 203 (925), 222 Winzenberg, K. N. 339 (746), 366 Wittorf, N. 21 (144), I10 Wittwer, C. 38 (252), 112 Wlostowski, M. 300,353 (642), 363 Wolfe, S. 28 (195), 111 Wolff, L. 36 (242), I12 Wolinsky, J. 35 (235), 47 (297), 68 (376,377). 70 (377), 96 (520), 102 (558),112-114, 117,118,135 (631), 216,226 (7, 12), 267 Wolter, G. 76 (423), 115,230 (55), 264 (55, 402), 268,275 Wong, B. 266 (431), 276

Author Index Wong, C. F. 83 (461). 116 Wong, C.-H. 374 (39), 395 (143), 443,445 Wong, C. M. 107 (579), 119 Wong, J. K. 329 (711), 365 Wong, L. 179 (801), 219 Wongseripipatana, S. 291 (567), 361 Wood, G. P. 180 (NO), 220 Woodgate, P. D. 36 (243), 112 Woods, G. F. 44 (283), I13 Woodward, R. B. 251 (411), 275,294,297 (592), 362 Woolford, R. E. 6 (35), 108 Worrall, W. S. 23 (157), I10 Wren, D. 175 (775), 219 Wright, B. 76 (425), 115 Wright, B. G. 237 (435),276 Wrobel, J. 230 (206), 271 Wu, G. S. 14 (IOO), I09 Wudl, F. 183 (824). 220 Wun, D. 410 (206), 446 Wiirthwein, E. U . 351 (789), 367 Wychoff, G. 426 (251), 447 Wychuyse, F. 10 (73), 109,265 (446),276 Wyman, D. P. 11 (77), 109 Wynberg, H. 439 (308,309), 449

Xu, J. 345 (753), 366 Yaeger, D. B. 36 (246), 112 Yagoub, A. K. 306 (664,665). 364 Yagupol’skii, Y. L. 329 (722), 365 Yakubovich, A . Y. 82 (453), I16 Yamada, B. 229 (200), 271 Yamada, K. 434 (287), 448 Yamada, S. 148 (990). 223 Yarnada, Y. 233 (100),269 Yamaguchi, H . 262 (371), 275 Yamaguchi, K. 130,131 (617). 216,291,341 (566), 361 Yamamoto, H. 93 (518), 117,198 (888), 221, 385,439 (99), 444 Yamana, M. 203 (915), 222 Yamanaka, E. 235 (130,137), 245 (130), 267 (137), 269,270,291 (567), 361 Yamanaka, T. 199 (902), 221 Yamauchi, T. 210 (949), 222 Yamazaki, A. 132 (619), 216 Yamazaki, C. 74 (399), I15 Yamazaki, H. 169 (760), 219 Yamazaki, S. 266,287 (460), 277 Yamazaki, T. 123 (596), 214 (964), 215,223, 233 (99), 269 Yaneda, Y. 243,267 (246), 272 Yanovskaya, L. A. 371 (19), 443 Yao, Z. 318 (699), 365 Yaremenko, F. G. 164 (728), 218 Yarkova, E. G. 30.5 (662), 364 Yastiimura, J. 235,257 (118), 269

487

Yasor, Y. 26(180), I11 Yee, K. Y. 14,30 (98), 109 Yeh, M.-Y. 182 (819), 220 Yerhoff, F. W. 102 (557), 118,210 (948), 222 Yogi, S. 253,309 (269), 272 Yokoyama, K. 93 (509), 117 Yokoyama, M. 199 (896), 221 Yoneda, N. 168 (750), 218 Yoneda, S. 188 (846), 220,311 (682), 364 Yonezawa, K. 93 (Sll), 117 Yonezawa, Y. 329 (715), 365 Yoshida, M. 419 (239), 447 Yoshikawa, S. 314 (691.692), 364 Yoshimura, J. 235,257 (117). 269,329 (714), 365 Yoshioka, M. 283,326 (497), 360 Yost, G. A. 357 (806), 367 Yost, Y. 280 (473),359 Young, C . M. 300,353 (642), 363 Yus, M. 88 (481), 117,147 (675), 189 (848, 850,855-859), 192 (863), 217,220,221, 375 (47), 428 (270-272). 429 (262), 435 (272,291), 443,448 Yvernault, T. 394 (133), 445 Zabel, V. 439 (301), 448 Zabirov, N. G. 238 (436), 276,329 (719), 365 Zahr, S. 426,427 (253), 447 Zaichenko, N. L. 294 (599). 349 (599,783), 362,366 Zajc, B. 123 (593), 215 Zann, D. 201 (909), 222 Zaugg, H. E. 236,255 (146), 270 Zavarzin, I, V. 102 (559), I18 Zav’yalov, S. I. 133 (624), 216 Zavyalov, S. I. 146 (673). 217 Zbiral, E. 17(111), 109 Zbirovsky, M. 17 (123), 110 Zebovitz, T. C. 291,344 (563), 361 Zecchi, G. 42 (272), 112 Zee, J. 156 (694),217 Zeeh, B. 286,302 (520), 360 Zefirov, N. S. 80 (439), 116 Zeifman, Y. 70 (379), 114,227,228,257,258 (37), 268 Zeifman, Y. V. 3 (lo), 107,263 (389-391), 275,329 (712), 347,348 (771), 365,366 Zeifman, Y. Z. 329 (729), 365 Zherebchenko, P. G. 238,267 (204), 271 Zhmurova, I. 384 (89), 444 Zhuravskaya, N. I. 101 (552), 118 Ziegenbein, W. 45 (285), I13 Zimin, M. G. 238 (436), 276,329 (719), 365 Zimmer, D. E. 324,356 (706). 36.5 Zimmer, 0 . 2 0 3 (922), 222 Zimmerman, H. E. 58 (336), 107 (573). 114, I19 Zincke, T. 24 (164,165), 110

488

Author Index

Zinner, H. 236 (142), 257 (335,336), 270,274, 411 (218), 434 (289), 447,448 Zinnes, H. 244,245,261 (249,250), 272 Zi-Peng, Y. 130,152 (611),215 Ziyatdinov, R. N. 295 (615), 363 Zolotoi, A. B. 286 (518), 345 (754), 349 (783), 360,366 Zdlyomi, G. 314 (695), 364

Zook, H. D. 7 (43), I08 Zupan, M. 123 (593499,127 (607), 142 (657), 215,216 Zvonok, A. M. 171 (764), 219 Zwanenburg, B. 351 (792,796), 367 Zwick, G. 388 (110), 445 Zykova, T. V. 411 (217), 447

The chemistry of a -haloketones, or-haloaldehydes and a-haloimines Edited by Saul Patai & Zvi Rappoport Copyright 0 1988 by John Wiley & Sons Ltd

Subject index

Acetals, bromination of 379 synthesis of 400 Acetophenone imines, halogenation of 232, 288 Acetophenones, chlorination of 15 a-Acetoxyaldehydes, synthesis of 400 a-Acylcarbenium ions 103,211,212 Acyloxathiolimines, synthesis of 178 a-Acyloxyaldehydes, synthesis of 400 a-Acyloxyketones, synthesis of 400 Alcohols, allylic -see Allylic alcohols chlorination of 17-19 reactions of 377-379 with a-haloaldehydes 399,400 with a-haloketones 154 Aldehydes, halogenation of 370-377 a-sulphenylated 413 a , /3-unsaturated -see a , /3-Unsaturated aldehydes Aldimines, halogenation of 379,381 a-sulphenylated 297 synthesis of 283 Aldol condensation 85,198, 199 Al kenes, halogenation of 20,36, 137, 146 reactions with nitrosyl halides 237,238,294 synthesis of 88,92,189,192,429,430 Alkoxides, reactions of, with a-haloaldehydes 395-398 with a-haloimines 243,298,299 with a-haloketones 49-60,155-158 a-Alkoxyaziridines, as intermediates 339 a-Alkoxyimines 353 synthesis of 243 a-Alkoxyindolenines, synthesis of 243,244, 299

a-Alkoxyketimines 298 synthesis of 339 a-Alkoxyketones, synthesis of 160,396 a-Alkoxyoxiranes, ring opening of 396 synthesis of 395 a-(Alkylamino)acetals, synthesis of 339 a-Alkylaminoaldimines, synthesis of 228 Alkyloxazolines, halogenation of 231 Alkynes, halogenation of 19,21,36,136,391 Allylic alcohols, reactions of 239 synthesis of 193 Allylic amides 345 Allylic halides, synthesis of 84 Allylic substitution 53 Amides, allylic -see Allylic amides dienic -see Dienic amides halogenation of 293 reactions of, with a-haloaldehydes 411 with a-haloketones 72,175, 176 synthesis of 259,334,337 Amidines, reactions of 290 with a-haloaldehydes 410 with a-haloketones 73 Aminals, synthesis of 406 a-Amination 303 Amines, aromatic -see Aromatic amines a-fluorinated 5 reactions of, with a-haloaldehydes 227-229,282-285, 403-4 10 with a-haloketones 66-72,164-175,227230,282,283,285-287 a-Aminoacetals, synthesis of 256 a-Amino acids, synthesis of 188 a-Aminoaldehydes, synthesis of 404,405

489

490

Subject Index

a-Aminoaldimines, synthesis of 404 Aminoalkanones. synthesis of 405 2-Aminoallylcarbenium ions, as intermediates 354 Aminocyanopyrroles, synthesis of 254 Aminoisoxazoles, synthesis of 314 a-Aminoketones, synthesis of 66.67, 164, 165, 405 a-Aminooximes, synthesis of 247,249 Ammonium salts, synthesis of 66 Arbuzov reaction 96-99,201,302,305 Aromatic amines, chlorination of 24 Arylbutanals. reactions of 401 Arylcycloalkanols, synthesis of 89 N-Aryl-a-haloketimines, synthesis of 292 Arylhydrazines, reactions of 301 a-Aryloxime ethers 355 a-Aryloxylation 299 Azabutadienes, synthesis of 323,324,326 Azacyclopentadienones 326 Azetidinones, synthesis of 207 Azides, reactions with a-haloketones 76,179, 180 Azidoalkenes, reactions of 239 a-Azidoimines 247 a-Azidoketones 76 synthesis of 179,180 Aziridines 318 as intermediates 260 synthesis of 164, 165, 168,258,331 Azirines, ring opening of 124, 125 synthesis of 248 Azirinium species, as intermediates 246 Azirinyl cations 353 Azoalkenes, reactions of 251,307 synthesis of 251,328 Beckmann rearrangement of a-halooximes 262,263,345 Benzeneselenenyl bromide, as brominating agent 141 Benzeneselenenyl chloride, as chlorinating agent 132 Benzothiazines, synthesis of 181 Benzothiophenes, synthesis of 181 1,2-Bis(alkylamino)ethanes,reactions of 406 Bromine, as brominating agent 25-30,34,235, 290,370,379,392 Bromoacetophenone azines, synthesis of 231 a-Bromoaldehydes, reactions of 405,425,436 synthesis of 370-372,379,387,391,392 a-Bromoaldimines, reactions of 353 a-Bromoimidoyl chlorides, reactions of 239 a-Bromoketimines, reactions of 324,353,357

synthesis of 239 a-Bromoketones, synthesis of, from a-diazoketones 34 from epoxides 34,35 from ketones and their derivatives 25-34, 141-145 from miscellaneous substrates 35,36 Bromomalononitriles, as brominating agents 33 a-Bromooximes, reactions of 247,262,263 N-Bromosuccinimide, as brominating agent 30,31,145,146,233-235,288,291,379, 381,383 Butenolides, synthesis of 172 y-Butyrolactones, synthesis of 400,418 Caesium fluoroxysulphate, as fluorinating agent 123,125 Carbanions. reactions of, with a-haloaldehydes 418-428 with a-haloimines 253,254,309-314 with a-haloketones 83-86, 183-189 Carbazoles, synthesis of 166,167 Carbodiimides, halogenation of 293 Carbon-carbon bond formation 252-256, 309-323 Carbonyl reagents, reactions with ahaloketones 75.76 Carboxylic acid derivatives, halogenated 7, 24 Carboxylic acids, synthesis of 394,395 a, P-unsaturated -see a , @-Unsaturated carboxylic acids Carboxylic acid salts, reactions with ahaloketones 64 Cephalosporins, synthesis of 326 Chloral imines, reactions of 323 Chlorides, as chlorinating agents 130 Chlorine, as chlorinating agent 8-11,19,21,

24,127-131,235,370,373,379

a-Chloroaldehyde acetals, reactions of 401 a-Chloroaldehydes, reactions of 425 with alkoxides 396 with carbanions 419,420 with cyanide ion 416 with phenoxides 398 with secondary amines 405 synthesis of 373-375,385,391 a-Chloroaldimines, reactions of 315 with alkoxides 245,256 with cyanide ion 254 with organometallics 318,321 with thiolates 297 Chlorocycloalkanones, reactions of 20 a-Chloroepoxides, reactions of 21-23 a-Chloro esters, synthesis of 396

Subject Index p-Chloroimines. synthesis of 283 Chloroindolenines, rearrangement of 261, 262,341-344 Chloroketenes, reactions of 20 a-Chloroketimines, as rearrangement products 313 reactions of 312,333,334. 337.354 a-Chloroketones, synthesis of, from alcohols and phenols 17-19 from alkenes and alkynes 19-21, 136,137 from aromatic amines 24 from carboxylic acids and their derivatives 24, 140. 141 from a-diazoketones 19, 132 from epoxides 21-23,137, 139 from ketones and their derivatives 8-17, 126-135 a-Chloronitrones, reactions of 251.306 a-Chlorooximes, synthesis of 237 Chlorooxiranes, ring opening of 137, 139 N-Chlorosuccinimide, as chlorinating agent 13, 14.21.231-233,288,290,291.381, 383 Chromenes. synthesis of 186 Cine rearrangement 171 Cine substitution 65,153 Claisen rearrangement 125,393 Cyanides, reactions of, with a-haloaldehydes 413-418 with a-haloimines 254,255,314-317 with a-haloketones 82,83, 183 a,/?-unsaturated -see a,/?-Unsaturated cyanides a-Cyanoaziridines 339 synthesis of 255,314,315,317 a-Cyanoenamines. halogenation of 235 synthesis of 254,314,407 a-Cyanoepoxides, synthesis of 82 Cyano esters, synthesis of 415,416 Cyanohydrins. synthesis of 415.416 a-Cyanoketones 82 a-Cyanooximes, synthesis of 314 Cyanooxiranes. as intermediates 416,417 reactions of 387 synthesis of 415,416 Cycloaddition reactions 20, 137.263.264.306, 439 Cycloalkanecarboxylic acids, synthesis of 45, 153 Cycloalkanes, synthesis of 180 Cycloalkanones, reactions of 9-11.28, 129,130, 152 synthesis of 82.91 Cycloalkenones, halogenation of 12.29

49 1

synthesis of 83,86,168,180,184 Cyclopentylanes, synthesis of 184 Cyclopropanation 85 Cyclopropanones, synthesis of 58 Dehalogenation 107,214 De hydrohalogenation. of N-alkyl-/?,/?.P-trichloroamines 292 of a-haloaldehydes 407,408 of a-haloimines 255.302,323-329 of a-haloketones 47,48,171. 172 Dialkoxyindolines, synthesis of 244 a,/?-Diaminoaldehydes406 Diazepines, reactions of 309 synthesis of 253 Diaziridines, synthesis of 349 a-Diazoketones. halogenation of 6.19.34.36. 122. 123,132 Diazonium salts, reactions of 101 a,a-Dibromoaldehydes. synthesis of 370,371, 379,381 a,/?-Dibromoaldehydes, reactions of 406 synthesis of 388 a.a-Dibromoaldimines, reactions of 256 a,a-Dibromoamidines, reactions of 301 Dibromoketones, rearrangement of 25 a,a-Dichloroaldehydes, reactions of 396.438 synthesis of 373,374,377,379,381,382,384 a,a-Dichloroaldimines, reactions of 319 a,a-Dichloroalkanols 428 /?,/3-Dichloroalkanols, synthesis of 432 a,a-Dichloroimmonium chlorides, reactions of 321 a,a-Dichloromethylketimines, reactions of 243 245 a,a-Dichlorooximes, synthesis of 294 Diels-Alder reaction 347,439 Dienic amides 345 a,a-Difluoroaldehydes, synthesis of 379.393 *.a-Dihaloaldehydes -see also a,aDibromoaldehydes, a,aDichloroaldehydes, a,aDifluoroaldehydes. reactions of 420.424. 425 cycloaddition 439 with alcohols 399 with alkoxides 395-398 with cyanide ion 416,417 a,/?-Dihaloaldehydes 376 Dihaloazetines. synthesis of 239 a,a-Dihalomines, rearrangement of 344 synthesis of 285,292,294 Dihaloiminium halides, reactions of 292 a,a-Dihaloketenimines, synthesis of 285

492

Subject Index

a,a-Dihalo-a-tetralone imines, reactions of 325 1,3-Diimines, halogenation of 290 1,4-Diimines, synthesis of 318,320 a-Diimines, synthesis of 166 Diketones, synthesis of 92,198 Dinitrophenylhydrazones, reactions of 289 Dioxazinium salts 251 Dioxolanes, chlorination of 16 Dithienes, synthesis of 80 Dithiocarbamates, reactions of 74 Dithiolanes, synthesis of 182 Emmons-Horner condensation 186 Emmons-Wadsworth reaction 84 Enamines, halogenation of 3.4, 10,13-16,235,236, 379,382,383 reactions of, with a-haloaldehydes 410 with a-haloketones 72,174, 175 Enamino diesters, halogenation of 290 Enamino esters, bromination of 297 Enaminoketones, synthesis of 82 Enediamines 405 Enol acetates, reactions of 379 Enolates, as reaction intermediates 89.91 fluorination of 3 , 4 reactions with a-haloketones 83-86,183189 Enol esters, halogenation of 3-5, 16,29,36, 122,123,134 Enol ethers, halogenation of 3.4, 14-16,29,36, 123, 133-136,379 reactions with a-chlorooximes 306 synthesis of 195 Enol phosphates, synthesis of 96,99 Enol thioethers 136 Enones, fluorination of 122 a$-Enones, synthesis of 85 Enynes, synthesis of 189 Epoxides, ring opening of 8,21-23,34,35, 123,124, 137,139,387,388,405,407 synthesis of 51,52,90,187,189,190,395, 396 Epoxyacetates, ring opening of 388 Epoxyalkanoates, synthesis of 425 Epoxynitriles, reactions of 8 Epoxyphosphonates, synthesis of 99 Epoxysulphones, ring opening of 387 Favorskii rearrangement, of a-haloimines 259,260,298,315,324, 332-338

of a-haloketones 38,44-47,49,50,53-55, 57,58,61,68,82,83,91, 153,155-160, 183 Flavones, synthesis of 152 Fluorides, as fluorinating agents 5.6 Fluorine, as fluorinating agent 3,5,122,123, 379 a-Fluoroaldehydes, reactions of 405 synthesis of 375,379,387,391 N-Fluoro-N-alkylsulphonamides,as fluorinating agents 122 Fluoroenamines, synthesis of 405 a-Fluoroepoxides, reactions of 8 a-Fluoroimines, N-activated, cycloaddition reactions of 347,348 a-Fuoroketimines, synthesis of 285 a-Fluoroketones, reactions of 227,288 synthesis of, from carboxylic acid derivatives 7 from a-diazoketones 6,122,123 from a-functionalized epoxides 8, 123, 124 from a-haloketones by halogen exchange 5,6,123 from ketones and their derivatives 3-5, 122,123 a-Fluorooximes, synthesis of 238 a-Fluorooxiranes, ring opening of 123,124 Forrnimidates, reactions of 73 Friedel-Crafts reaction 7, 100,351,438 Fungicides 266,301 Furanones, synthesis of 186 Furans, reactions of 158 synthesis of 83,163,184,195,204,210,400 Grignard reagents, reactions of, with acetyl chlorides 141 with a-bromoimidoyl chlorides 239 with epoxyacetates 388 with fluorinated carboxylic acid derivatives 7 with a-haloaldehydes 428,430,436 with a-haloimines 255,256,321,323 with a-haloketones 86-89,189-192 Grob fragmentation 46,47,58 a-Haloaldehydes -see also aBromoaldehydes, a-Chloroaldehydes, aFluoroaldehydes, a-Iodoaldehydes oligomerization of 393 reactions of, cycloaddition 439,442 electrophilic 438,439 with C-nucleophiles 413-432

Subject Index with N-nucleophiles 228,282-287,401413 with 0-nucleophiles 394-401 with S-nucleophiles 413 synthesis of, by homologation of carbonyl compounds 389-391 from alcohols 377-379 from aldehyde derivatives 379-384 from aldehydes 370-377 from alkynes 391 from halogenated oxiranes and ozonides 384-389 a-Haloaldimines, reactions of 257,326,331,351,353 with alkoxides 245,256 with cyanide ion 254 with organometallics 256,318,319,321 with thiolates 297 rearrangement of 260 synthesis of 227,228,236,404 a-Haloamidines, reactions of 247 synthesis of 238 a-Haloaminals, synthesis of 406 a-Haloarylalkanones, reactions of 55 Haloarylisoxazolines, reactions of 324 a-Haloazines, reactions of 309 Haloazirines, reactions of 300,321,353 synthesis of 239,295 a-Halocycloalkanone oximes, reactions of 303 a-Halocycloalkanones, reactions of 44-49,53, 57,60,161 a-Halodiazines, reactions of 247 B-Haloenamines, synthesis of 404,406 Halogen exchange reactions 5,6,36,123, 147 a-Halohydrazones, reactions of 247,248,251,302,304,306, 307,310 synthesis of 75,228-230,287 Halohydrins 431 synthesis of 86,90,189,428 a-Haloimidates, rearrangement of 345 synthesis of 238 a-Haloimidoyl cyanides, synthesis of 235,238, 239 a-Haloimines, applications of 265-267,357-359 biological properties of 265-267,357-359 generation of a-imidoylcarbenium ions from 350-357 reactions of 264,265 cycloaddition 263,264,347-350 elimination 256,257,323-329 nucleophilic addition 257-259,329-332

493

nucleophilic substitution 242-252,296309 with carbanions 253,254,309,314 with cyanide ion 254,255,314-317 with organometallics 255,256,317-323 reactivity of 241,242,296 rearrangement of 259-263,332-347 via activated aziridine intermediates 260, 339-341 synthesis of 226,280,281 by condensation of a-halocarbonyls with primary amines 227-230,282-287 by halogenation of enamines 235,236, 290-292 by halogenation of imines 230-234.287290 a-Haloimmonium halides, reactions of 339 Haloindolenines, reactions of 248,253,310,325,337 with alkoxides 243,244,299 rearrangement of 261,262,341-344,346 synthesis of 235 Haloindoles, reactions of 244,310 synthesis of 346 a-Haloisobutyrophenones, reactions of 162 Haloisoxazolines, reactions of 355 Haloketenes, reactions of 137 a-Haloketimines, reactions of 231,255,312,331,337,353, 354 cycloaddition 263 with alkoxides 299,323,324 with cyanide ion 314,316 with organometallics 319 rearrangement of 259,332,333,339,357 synthesis of 228,239,285 a-Halo-6-ketoaldehydes, synthesis of 390 a-Haloketones -see also a-Bromoketones, a-Chloroketones, a-Fluoroketones, aIodoketones electrochemistry of 106, 107,214 enzymatic transformations of 214 optically active 148 photochemistry of 105,106,212,213 reactions of 305 dehalogenation 107,214 electrophilic 100-102,204-209 with alkali metal fluorides 102,209 with amines 227,228,282-287 with carbon nucleophiles 82-86,183-189 with chalcogen nucleophiles 78-81,180183 with complex metal hydrides 96 with nitrogen nucleophiles and bases 6678,164-180 with organometallics 86-96.189-201

494

Subject Index

a-Haloketones (conf.1,reactions with oxygen nucleophiles and bases 4466,150-164 with phosphorus compounds 96-100, 201-204 reactivity of 39-44,148-150 rearrangement of 102,209-211 synthesis of 3-37.122-148,265 a-Halomethylketimines, reactions of 254,297,301 with alkoxides 298,334,339 rearrangement of 259,346 a-Halomethylketoximes, reactions of 248 Halomethylphenylazirines, synthesis of 240 Halonaphthylamines, synthesis of 325 a-Halonitriles, reactions of 238,239 a-Halonitrones, reactions of 309 a-Halooxime ethers, as pesticides 357,358 reactions of 302,309,355 synthesis of 286,292 a-Halooximes, as pesticides 357 reactions of 230,247-250,302,304 cyclization 264 cycloaddition 306 with carbanions 309,310 synthesis of 237,238,286,294 Halooxiranes, rearrangement of 384-386 a-Halo-a-phenylketimines, reactions of 335 Halopyrrolines, reactions of 297 a-Halosemicarbazones, synthesis of 230 a-Halothiosemicarbazones, cyclization of 264 /3-Halovinyl azides, photolysis of 239 Hantzsch reaction 74 Hemiacetals, synthesis of 399 Homoallylic alcohols, synthesis of 189, 198 Homologation, 206,207 Hydrazines. reactions with a-haloaldehydes 411,412 a-Hydrazinohydrazones, synthesis of 305 Hydrazones, reactions of 234,289,305,382 synthesis of 411,413 Hydrogen bromide, as brominating agent 34 Hydrogen chloride, as chlorinating agent 19 a-Hydroxyacetals, synthesis of 57,395 a-Hydroxyaldehydes, synthesis of 394,395 a-Hydroxyaziridines, as intermediates 339 a-Hydroxyketones, chlorination of 132 162 svnthesis of 151. .. ~.~ Hypochlorites, as chlorinating agents 12, 13, 233,235,290,291 Hypofluorites, as fluorinating agents 4.6

P-Lactam inhibitors 330 /3-Lactams, synthesis of 164, 165 /3-Lithioenamines, reactions of 146

Imidates, reactions with a-haloaldehydes 410

Magnesium enolates 89 a-Mercaptoketones, synthesis of 78

synthesis of 334.337 a,P-unsaturated -see a,@-Unsaturated imidates Imidazoles, synthesis of 74,166,167, 175,178, 323,410 Imidazolylenones, synthesis of 169 Imidazopyrazines, synthesis of 405 Imidazopyridines, synthesis of 166,167,405 a-Imidoylcarbenium ions 350-357 a-Imidoylcarbonium ions 245 Imines, halogenation of 230-234,287-290 reactions with a-haloketones 174 a$-unsaturated -see a,@-Unsaturated imines P-Imino-a,a-dichloro esters, reactions of 292 Imino ethers, synthesis of 261 a-Iminoketones, synthesis of 165,166 Iminothiazolines, synthesis of 264 Immonium compounds, cyclic 355 Indanones, bromination of 28 Indoles, halogenation of 235,291 synthesis of 166,167,170,184,193,248 Insecticides 267 Iodine, as iodinating agent 36,375 a-Iodoaldehydes, synthesis of 375 a-Iodoketimines, reactions of 231 a-Iodoketones, synthesis of 36,37,147,148 N-Iodosuccinimide, as iodinating agent 36 Isonitriles, reactions with a-haloketones 207 Isoxazoles, halogenation of 293 synthesis of 163.324.355 Isoxazolinones, halogenation of 231 Ketenimines, reactions of 136 Ketimines, halogenation of 13, 14,30,231-234 synthesis of 70,301,318 a-Ketoacetals, synthesis of 398 a-Ketoaldehydes 394 P-Keto esters, reactions of 83,133,420 Ketones, a-halogenation of 3-5,8-17,25-34,36-38 mechanism of 37,38 a,P-unsaturated -see a,P-Unsaturated ketones /3-Ketophosphonates, synthesis of 96 a-Ketothiocyanates, synthesis of 80 Knoevenagel condensation 84,426

Subject Index Metal bromides, as brominating agents 31 Metal chlorides, as chlorinating agents 14,15 Metal complexes, reactions with ahaloketones 195-201 Metal hydrides, reactions with ahaloaldehydes 435 Morpholines, synthesis of 169

495

with a-haloaldehydes 428,432-435 with a-haloketones 96-100,201-204 Polychlorocycloalkanones, synthesis of 130 a-Polyfluoroketones, synthesis of 8 Polyhaloaldehydes, synthesis of 377 Polymers, as brominating agents 32 as chlorinating agents 126,127 Nitrimines, bromination of 289 Propellanes, synthesis of 355 Nitrosoolefins 230 Pyrazines 321 cycloaddition reactions of 250,306,307,310 synthesis of 178 synthesis of 250,328 Pyrazoles, Nitrosyl chloride, as chlorinating agent 19 halogenation of 291,293 synthesis of 264 Organoboron compounds, reactions with aPyrazolines, synthesis of 178,188 haloketones 92,194,195 Pyrazolinones, halogenation of 231 Organocadmium compounds, reactions with Pyrethroids, synthesis of 171 a-haloaldehydes 431 Pyridines, Organolithium compounds, reactions of, reactions of 68 with a-haloaldehydes 431 synthesis of 326 with a-haloimines 256,318-322 Pyrimidines 321 with a-haloketones 90-92,192-194 Pyrrole dicarboxylate esters 410 Organometallic complexes, reactions with aPyrroles, synthesis of 253-255,401 haloaldehydes 435-438 Pyrrolidine alkaloids, synthesis of 177 Oxathiazinones, synthesis of 208 Pyrrolines, halogenation of 288,294 Oxazines, synthesis of 168 Oxaziridines, synthesis of 349 Selenium oxychloride, as chlorinating agent Oxazoles, synthesis of 175,323,353,411 11,12 Oxazolines 426 Semicarbazones, synthesis of 75 synthesis of 185 Silver tetrafluoroborate, as fluorinating agent Oxime ethers, reactions of 288,311 123 Oximes, synthesis of 75 Silyl enol ethers, Oxindoles, synthesis of 262 reactions of 14-16,29,36,123,133,134, Oxiranes 425 204,205,379,390 as intermediates 394,401,420 synthesis of 195 synthesis of 56,159,162,186,189, 190,195, Simmons-Smith reaction 198 201 Steroids, Oxyallyl cations 93,195 halogenation of 4,14,141 Ozonides, reactions of 388,389 rearrangement of 156,157 Succinic acid derivatives, synthesis of 193 Paraldehydes, bromination of 370 Sulphenyl chlorides, as chlorinating agents 136 Passerini reaction 207 Sulphides, synthesis of 79 Perbromides, as brominating agents 31 Sulphuryl chloride, as chlorinating agent 11, Perchloryl fluoride, as fluorinating agent 3,4 12,130,133,290,374 a-Perfluoroketimines, reactions of 349 a-Perfluoroketoximes, rearrangement of 345 2,4,4,6-Tetrabromocyclohexadienone, as a-Perhaloimines, reactions of 263,264,329, brominating agent 234 349 Tetrathiafulvalenes, synthesis of 182 Perkow reaction 96-99,305,384,432 Thiadiazines, synthesis of 178,264 Pesticides 357,358 Thiadiazinones, synthesis of 81 Phenols, reactions of 17,18,161 Thiadiazoles, synthesis of 305 Phenoxides, reactions of, Thiazanes, synthesis of 168 with a-haloaldehydes 398 Thiazines, synthesis of 80,168,178,411 with a-haloketones 60-63 Thiazoles, synthesis of 80,175,182,264,323, Phenyltrimethylammonium perbromide, as 411 brominating agent 234 Thiazolines, synthesis of 177,403 Phosphonium salts 99,435 Thiazolinones, synthesis of 81 Phosphorus compounds, reactions of, Thiazolium derivatives, synthesis of 74

496

Subject Index

Thietanones, synthesis of 78 Thiiranes, synthesis of 177 Thioamides, reactions of, with a-haloaldehydes 411 with a-haloketones 72,74,175-178 Thiocyanates, reactions with a-haloaldehydes 411 Thioketones, synthesis of 80,180 Thiolates, reactions of, with a-haloaldehydes 413 with a-haloimines 243,297 with a-haloketones 180 Thionyl chloride, as chlorinating agent 17,132 Thioureas, reactions with a-haloketones 74 Thioxoketones, synthesis of 182 Tosylhydrazones, reactions of 305,382 Transimination 292 Triazoles, reactions of 301 synthesis of 330 Triazolines, synthesis of 348,349 Trichloroacetamidates, rearrangement of 345, 346 a ,a,/3-Trichloroaldimines, reactions of 326 a,a,a-Trifluoroketirnines, synthesis of 228 a,a,a-Trihaloacetaldimines, synthesis of 295 Trimethylsiloxyalkenenitriles418 Ullmann coupling 207 a,B-Unsaturated aldehydes, reactions of 376,390 synthesis of 408,439

a,/34Jnsaturated carboxylic acids, synthesis of 25 1 a,p-Unsaturated cyanides, synthesis of 84 a$-Unsaturated esters, synthesis of 84,426428 a,P-Unsaturated imidates, synthesis of 259 a,P-Unsaturated imines, halogenation of 293 synthesis of 256,260,324 a@-Unsaturated ketones 423 as reaction intermediates 91 halogenation of 12,29,30,32,33. 135,144, 145 synthesis of 52,152,171 a,P-Unsaturated lactones, synthesis of 401 Vinyl azides, reactions of 392 Vinylboranes 92 a-Vinylcarboxylic acids, synthesis of 251 Vinyl esters, bromination of 35,36 Vinyl ketones, chlorination of 135 Vinyl phosphates, synthesis of 432 Wagner-Meenvein-type rearrangement 104, 261.262.357 Wittig reaction 83,426 Woodward-Hoffmann rules 315 Xenon difluoride, as fluorinating agent 123 Ylides, reactions of, with a-haloaldehydes 418-428 with a-haloketones 83-86,183-189