General and Synthetic Methods Volume 10
A Specialist Periodical Report
General and Synthetic Methods Volume I 0
A Review of t h e Literature Published in 1985 Senior Reporter G. Pattenden, Department of Chemistry, University of Nottingham Reporters K. Carr, University of Nottingham K. Cooper, Pfizer Central Research, Sandwich, Kent D. J. Coveney, University of Nottingham S. G. Davies, University of Oxford T. Gallagher, University of Bath L. M. Harwood, University of Oxford D. W. Knight, University of Nottingham T. V. Lee, University of Bristol S. G. Lister, Wellcome Research Laboratories, Beckenham, Kent K. E. B. Parkes, Roche Products Limited, Welwyn Garden City, Herts. N. Simpkins, Queen Mary College, University of London P. J. Whittle, Pfizer Central Research, Sandwich, Kent
..*
-,
SOCIETY OF EMI STRY
"-a.
s"-
ISBN 0-85 186-9 14-9 ISSN 0141-2140 Copyright 0 1988 The Royal Society of Chemistry All Rights Reserved No part of this book may be reproduced or transmitted in any form or by any means-graphic, electronic, including photocopying, recording, taping or information storage and retrieval systems-without written permission from the Royal Sociery of Chemistry Published by The Royal Society of Chemistry, Burlington House, London, W 1V OBN Printed in England by Staples Printers Rochester Limited, Love Lane, Rochester, Kent.
Introduction This tenth Report on General and Synthetic Methods, and the second volume to be produced from camera-ready copy of manuscripts, covers the literature from January to December, 1985. The general aim of the Reports remains as set out in earlier volumes. Whilst our contributors strive to provide a critical and comprehensive summary and assessment of reactions and methods in synthetic organic chemistry which appear to be useful to the practitioner, this task has become increasingly onerous with time, as a consequence of the explosive and rapid development in the subject over the past decade or so. Nevertheless, these features, together with the theme of 'selectivity' i.e. chemo-, regio-, diastereo- and enantio-selectivity, in organic synthesis remain as our prime focus. We welcome any comments and suggestions for improving the coverage and presentation of future Reports in this series. G.
V
Pattenden
Contents
Chapter 1 Saturated and Unsaturated Hydrocarbons
1
B y N . Simpkins
1 1 11 13 17 21 24 26
1 Saturated Hydrocarbons 2 Olefins 3 Conjugated 1,3-Dienes 4 Non-conjugated Dienes 5 Allenes 6 Alkynes 7 Enynes and Diynes 8 Polyenes
32
Chapter 2 Aldehydes and Ketones By K . E . B .
Parkes
1 Synthesis of Aldehydes and Ketones Oxidative Methods Reductive Methods Methods Involving Umpolung Other Methods Cyclic Ketones 2 Synthesis of Functionalized Aldehydes and Ketones Unsaturated Aldehydes and Ketones a-Substituted Aldehydes and Ketones Dicarbonyl Compounds 3 Protection and Deprotection of Aldehydes and Ketones 4 Reactions of Aldehydes and Ketones Reactions of Enolates Aldol Reactions Conjugate Addition Reactions Chapter 3 Carboxylic Acids and Derivatives By D . W .
32 32 35 36 38 43 47 47 49 55 57 59 59 64 66 75
Knight
1 Carboxylic Acids General Synthesis Diacids Hydroxy-acids Keto-acids Unsaturated Acids Anhydrides Carboxylic Acid Protection Decarboxylation 2 Carboxylic Acid Esters Ester ification General Synthesis
vii
75 75 77 78 83 83 86 86 87 88 88 90
Contents
viii Diesters Hydroxy-esters Keto-esters Unsaturated Esters Aromatic Esters Acetylenic Esters Allenic Esters and Dienoates Thioesters 3 Lactones 0-Lactones Butyrolactones a-Methylenebutyrolactones Butenolides Tetronic Acids Phthalides Valerol actones Macrolides 4 Carboxylic Acid Amides General Synthesis Hydroxy-amides Keto-amides Unsaturated Amides Thio- and Seleno-amides 5 Amino-acids a-Amino-acids B-Amino-acids y -Amino-acids Unsaturated a-Amino-acids Carboxylic Acid Protection Amino Group Protection Thiol Group Protection Chapter 4 Alcohols, Halogeno-compounds, and Ethers By L . M .
93 96 101 109 117 120 120 122 124 124 124 135 136 140 142 142 146 150 150 151 153 153 156 156 156 165 167 167 169 169 172 187
Ha r w o o d
1 Alcohols Preparation by Addition to Alkenes Preparation by Reduction of Carbonyl Compounds Chemoselective Carbonyl Reductions Stereoselective Carbonyl Reductions Asymmetric Carbonyl Reductions Enzymic Asymmetric Carbonyl Reductions Preparation by Nucleophilic Addition General Methods of Preparation Protection and Deprotection Reactions of Alcohols Oxi da t ion Hydrogenation and Deoxygenation Miscellaneous Reactions 2 Halogeno-compounds Preparation from Alcohols Interhalide Conversions Miscellaneous Preparations React ions Dehalogenation Acylation and Coupling Reactions Miscellaneous Reactions 3 Ethers Preparation Reactions 4 Thiols and Thioethers
187 187 187 188 188 190 192 192 203 205 207 207 208 2 08 212 212 214 214 216 216 216 218 218 218 220 222
ix
Contents
Chapter 5 Amines, Nitriles, and Other Nitrogencontaining Functional Groups
230
B y S.G. L i s t e r 1 Amines Primary Amines Secondary Amines Tertiary Amines D iamines 2 Enamines 3 Allylamines, Homoallylamines, and Alkynylamines 4 Amino-alcohols and Related Compounds 5 Amino-carbonyl Compounds 6 Amino-esters 7 Amides, Thioamides, and Selenocarboxamides 8 Nitriles and Isocyanides 9 Nitro- and Nitroso-compounds 10 Hydrazines and Hydrazones 11 Hydroxylamines and Hydroxamic Acids 1 2 Imines, Iminium Salts, and Related Compounds 1 3 Oximes 1 4 Carbodi-imides 1 5 Azides and Diazo-compounds 1 6 Azo- and Azoxy-compounds 1 7 Isocyanates, Thiocyanates, Isothiocyanates, Selenocyanates, and Isoselenocyanates 1 8 Nitrones 1 9 Nitrates and Nitrites
Chapter 6 Organometallics in Synthesis B y S.G.
PART
230 230 235 240 241 242 245 249 2 64 264 265 275 284 294 294 295 300 301 301 304 304 307 307 320
Davies and T. Gallagher
I: The Transition Elements
320
B y S.G. Davies
1 Introduction 2 Reduction 3 Oxidation 4 Rearrangements and Isomerizations 5 Carbon-Carbon Bond Formation via Organometallic Electrophiles via Organometallic Nucleophiles via Coupling Reactions via Carbonylation Reactions 6 Miscellaneous Reactions PART 11: Main Group Elements
320 320 322 322 325 325 325 333 343 347 354
B y T . Gallagher 1 Group I Selective Lithiations Dianions and Alkenyl and Alkynyl Anions Sulphur-stabilized Anions 2 Group I1 Magnesium Zinc and Mercury
354 354 362 367 369 369 373
Contents
X
375 375 379 381 381 381 386 388 395 395 401 401 401 406
3 Group I 1 1
Boron Aluminium and Thallium 4 Group IV Si 1icon Allyl- and Vinyl-silanes Other Silicon-containing Reagents Tin and Lead 5 Group U Phosphorus Arsenic, Antimony, and Bismuth 6 Group V I Sulphur Selenium and Tellurium
416
Chapter 7 Saturated Carbocyclic Ring Synthesis By T . V . L e e
1 Three-membered Rings 2 Four-membered Rings 3 Five-membered Rings General Methods Fused Five-membered Rings Naturally Occurring Fused Cyclopentanoids 4 Six-membered Rings Diels-Alder Reactions Other Syntheses of Six-membered Rings Polyene Cyclizations 5 Seven-membered, Medium, and Large Rings 6 Ring Expansion Methods 7 Spiro-ring Compounds
416 4 18 418 4 18 424 434 437 437 440 443 446 446 450 457
Chapter 8 Saturated Heterocyclic Ring Synthesis By K . C o o p e r a n d P . J .
Whittle
1 Oxygen-containing Heterocycles Three- and Four-membered Rings Five-membered Rings Tetrahydrofurans Dihydrofurans Six-membered Rings Tetrahydropyrans Dihydropyrans [5.n]Spiroacetals Six-membered Rings with More than One Oxygen Seven- and Eight-membered Rings 2 Sulphur-containing Heterocycles 3 Heterocycles Containing More than One Heteroatom Nitrogen- and Oxygen-containing Rings Five-membered Rings Six- and Seven-membered Rings Nitrogen- and Sulphur-containing Rings Oxygen- and Sulphur-, and Nitrogen-, Oxygen-, and Sulphur-containing Rings 4 Nitrogen-containing Heterocycles
’
457 4 57 460 460 4 69 472 472 472 477 477 479 479 486 486 486 488 491 494 494
xi
Contents
Three- and Four-membered Rings Five-membered Rings Six-membered Rings Six-membered Rings Containing Two Nitrogens 5 8-Lactams, Penicillins, Cephalosporins, and Related Compounds Chapter 9 Highlights in Total Synthesis of Natural Products By K.E.B.
494 494 515 527 531 550
P a r k e s and G . P a t t e n d e n
1 Terpenes 2 Steroids 3 Anthracyclinones and Naphthaquinones 4 Alkaloids 5 Prostaglandins and Thromboxanes 6 Spiroacetals 7 Sugars 8 Macrolides and Ionophores 9 Other Natural Products Reviews on General and Synthetic Methods Compiled by K . Carr, D . J .
596
C o v e n e y , and G . P a t t e n d e n
1 Olefins 2 Aldehydes and Ketones 3 Esters and Lactones 4 Fluoroorganic Compounds 5 Organometallics General Transition Elements Main Group Elements 6 Carbocyclic Ring Synthesis 7 Heterocycles 8 Natural Products 9 Enzymic Reactions and Asymmetric Synthesis 10 Oxidation 11 Reduction 12 Protective Groups 13 Radical Chemistry 14 General 15 Miscellaneous Author Index
550 557 557 564 574 578 581 583 585
596 59 6 59 6 596 597 597 59 7 598 599 599 600 600 601 601 602
602 602 603 604
1 Saturated and Unsaturated Hydrocarbons BY N. SlMPKlNS
A c a t a l y s t c o m p r i s i n g f u s e d i r o n p r o m o t e d b y V205 i s e x t r e m e l y
e f f i c i e n t i n t h e gas-phase hydrodeoxygenation o f ketones and a l c o h o l s a t r e l a t i v e l y low p r e s s u r e s .
'
Reductive decyanation o f a
v a r i e t y o f n i t r i l e s can be accomplished very cleanly using potassium metal i n c o m b i n a t i o n w i t h a crown e t h e r . 2
The u s e o f u l t r a -
s o u n d a l l o w s f o r s h o r t r e a c t i o n t i m e s i n t h e r e a c t i o n o f gemd i h a l o g e n o p r o p a n e s w i t h v a r i o u s metals t o form t h e u s u a l c a r b e n o i d derived products.'
The r e d u c t i o n o f C-C
m u l t i p l e bonds h a s been
found t o t a k e p l a c e i n t h e presence o f p l a t i n i z e d Ti02 under i l l u minated
condition^.^
A variety of unsaturated substrates react,
a l t h o u g h t h e r e a c t i o n times a r e q u i t e l o n g method f o r c o n j u g a t e r e d u c t i o n o f
(c. 26
a,B-unsaturated
h).
A useful
ketones and alde-
h y d e s i n v o l v e s r e a c t i o n w i t h d i p h e n y l s i l a n e c a t a l y s e d by Pdo i n c o m b i n a t i o n w i t h ZnC12.
E x c e l l e n t y i e l d s o f r e d u c e d compounds
were o b t a i n e d u s i n g t h i s m e t h o d , w h i c h d o e s n o t a f f e c t
a,B-
u n s a t u r a t e d n i t r i l e s o r esters (Scheme 1 ) . T h e u s e o f a trialkylaluminium-alkylidene i o d i d e m i x t u r e t o e f f e c t c y c l o p r o p a n a t i o n has been re-examined.
f o u n d t o w o r k w e l l when c o n d u c t e d i n C H 2 C 1 2 ,
T h e r e a c t i o n was and shows c o n t r a s t i n g
r e g i o s e l e c t i v i t y t o t h e Simmons-Smith r e a g e n t i n r e a c t i o n w i t h g e r a n i o l ( S c h e m e 2 1. A new m e t h o d w h i c h a l l o w s e n a n t i o s e l e c t i v e c y c l o p r o p a n a t i o n o f
u,b-unsaturated
esters.
aldehydes employs acetals d e r i v e d from t a r t r a t e
The method a p p e a r s o p e r a t i o n a l l y s t r a i g h t f o r w a r d a n d
g i v e s good y i e l d s and enantiomeric e x c e s s e s ( e . e . )
(Scheme 3 ) .
2 Olefins S o d i u m b o r o h y d r i d e c a n now b e u s e d f o r t h e r e d u c t i o n o f acetylenes, system.
b y e m p l o y i n g a NaBH4-PdCl2-po1yethylene
glycol-CH2C12
A v a r i e t y o f r e d u c e d p r o d u c t s were o b t a i n e d i n c l u d i n g
cis-
For References see p - 29
1
General and Synthetic Methods
2
Scheme 1
Bd3Al, CH,I,
76
1
EtzZn, C H , I ,
2
74
+
4 3
Scheme 2
k 88 Scheme 3
- 94%
e.e.
3
I : Saturated and Unsaturated Hydrocarbons o l e f i n s and f u l l y reduced materials. The u s e o f t r a n s i t i o n m e t a l c a t a l y s t s f o r d e h y d r o g e n a t i o n o f a l k a n e s h a s r e c e i v e d more a t t e n t i o n . [(Pri3P)21rH
5
The i r i d i u m complex
] exhibits unusual selectivity f o r t h i s type of
reaction i n t h a t methyl groups a r e attacked preferentially. S i m i l a r l y , a p h o t o l y t i c d e h y d r o g e n a t i o n r e a c t i o n was o b s e r v e d u s i n g
[IrH ( C F C O ) ( P R ) 1 , e v e n i n t h e a b s e n c e o f t h e u s u a l h y d r o g e n 2 3 2 3 2 acceptor t-butylethylene. The r e d u c t i v e r e m o v a l o f a l l y l i c o x y g e n a t e d f u n c t i o n s c a n b e carried out effectively using nickel boride.
Allylic alcohols
a n d t h e i r s i l y l e t h e r s r e a c t , a l t h o u g h t h e y r e q u i r e much l o n g e r r e a c t i o n times t h a n t h e c o r r e s p o n d i n g a c e t a t e s (Scheme
4).
Another
new d e o x y g e n a t i o n p r o c e d u r e c o n s t i t u t e s t h e l a t e s t c o n v e r s i o n o f epoxides i n t o t h e corresponding o l e f i n s , and u t i l i z e s a r y l s e l e n o carboxamides. l 2
The method i s s t e r e o s p e c i f i c ( r e t e n t i o n ) a l t h o u g h
i t r e q u i r e s t h e p r e s e n c e o f a s t r o n g a c i d ( C F C O H) a n d d o e s n o t
3
2
c o n v e r t more s t e r i c a l l y h i n d e r e d e p o x i d e s s u c h a s n o r b o r n e n e o x i d e . Luche h a s r e p o r t e d t h e r e a c t i o n o f c a r b o n y l compounds w i t h a l l y l i c h a l i d e s i n aqueous media.
The r e a c t i o n c a n b e p e r f o r m e d
u s i n g e i t h e r z i n c or t i n , a n d d i s p l a y s g o o d c h e m o s e l e c t i v i t y b e t ween a l d e h y d e s a n d k e t o n e s (Scheme 5 ) . Asymmetric c o u p l i n g o f a r y l G r i g n a r d s w i t h a l l y l i c p i v a l a t e s i s p o s s i b l e i n good e.e.
by u s e o f N i C l 2 [ ( S , S ) - c h i r a p h o s I
c a t a l y t i c ( 1 mol % ) a m o u n t s . l 4
i n only
Another a l l y l i c coupling r e a c t i o n
u s e s palladium t o mediate displacement o f a n acetoxy-group a l l y l i c g e m i n a l d i a c e t a t e by a s t a b i l i z e d n u c l e o p h i l e ,
frbm a n
x.
Scheme 6 .
Depending upon t h e s u b s t i t u e n t s p r e s e n t on t h e r e a c t i n g
partners,
t h e r e g i o s e l e c t i v i t y alters and a v a r i e t y of products can
be prepared.
A number o f a l l y l a t e d a n d r e l a t e d p r o d u c t s h a v i n g q u a t e r n a r y c a r b o n a t o m s may b e p r e p a r e d b y r a d i c a l c h e m i s t r y s t a r t i n g f r o m 16 t e r t i a r y alcohols. A l l y l s t a n n a n e s h a v e b e e n p r e p a r e d i n a r e g i o s e l e c t i v e f a s h i o n by
a selenoxide elimination r o u t e , l7 of hydrocarbons.”
and a l s o v i a d i r e c t m e t a l l a t i o n
T h e l a t t e r p r o c e d u r e when c o m b i n e d w i t h a
protodestannylation s t e p enables isomerization of various terpenes,
e.g. S c h e m e 7.
A number o f r e p o r t s h a v e f o c u s e d i n t e r e s t o n t h e s y n t h e s i s o f v a r i o u s a l l y l i c s u l p h u r compounds. A one-pot procedure f o r t h e p r e p a r a t i o n o f a l l y l i c s u l p h i d e s from t h e c o r r e s p o n d i n g a l c o h o l s i n v o l v e s i n i t i a l r e a r r a n g e m e n t of t h e x a n t h a t e f o l l o w e d by
General and Synthetic Methods
4
7sH17
7aH17
Nickel boride, diglyrne, R T
*& R = COMe, 98% after 10 min R = SiMe3, 80% after 6 h Scheme 4
OH
92 -98"Io (one diastereomer 1
Scheme 5 C02Me
I Ph
C 0 2 Me
C02Me
10% P d k
T
O
OAC A '
R
'4
-CO,Me
BSA
C02Me
OAc
C0,Me C 0 2 Me
BSA = 0 , N - bis(trimethyl sily1)acetamide
MeOzC
Scheme 6
dSnMe3 _____) I1
_____) I
5 9 '1. Reagents
I,
Bu"LI
- TMEOA,
Me3SnCL,
C02Me
11,
HCI in MeOH -4.1.
Scheme 7
8 5 O/o H20
5
I : Saturated and Unsaturated Hydrocarbons
e x t r u s i o n o f COS ( S c h e m e 8 ) . 2 0 A l l y l i c s u l p h i d e s a n d s u l p h o n e s a r e a v a i l a b l e from t h e corresponding nitro-compounds. Thus ( 1 ) on t r e a t m e n t w i t h NaSPh i n HMPA g a v e t h e s u l p h i d e ( 2 1 , w h e r e a s t h e s u l p h o n e ( 3 ) was p r o d u c e d b y r e a c t i o n o f ( 1 ) w i t h PhS02Na i n DMF i n t h e presence o f [Pd(PPh3)4]
(Scheme 9 ) .
Although t h e c o n t r a s t i n g
r e g i o s e l e c t i v i t y of t h e reactions is i n t e r e s t i n g , the products are p e r h a p s m o r e r e a d i l y a v a i l a b l e b y o t h e r m e t h o d s [e.g.i n t h e c a s e of ( 3 ) by a l k y l a t i o n o f t h e a l l y l i c s u l p h o n e a n i o n ] . Another r e s e a r c h group h a s published similar chemistry s t a r t i n g from v i n y l n i t r o - c o m p o u n d s .22
Warren e t a l . h a v e p u b l i s h e d more c h e m i s t r y
l e a d i n g t o a l l y l i c ( a n d a l s o v i n y l i c ) s u l p h i d e s , u t i l i z i n g b o t h Bh y d r o x y - ~ u l p h i d e s a~n~d a l l y l i c p h o s p h i n e o x i d e s .24
Other appli-
c a t i o n s of t h e phosphine oxide chemistry t o t h e preparation o f a l l y l i c p r o d u c t s h a v e a l s o a p p e a r e d .25 V i n y l s u l p h i d e s h a v e a l s o been p r e p a r e d by benzyne-induced
fragmentation o f 1,3-
o x a t h i o l a n e s 2 6 and v i a h y d r o b o r a t i o n of 1-iodoalkynes
(Scheme
1 0 ~ ~ 7 V i n y l a l k y l s e l e n i d e s c a n b e p r e p a r e d from t h e more r e a d i l y o b t a i n a b l e v i n y l m e t h y l s e l e n i d e s b y a demethylation/alkylation sequence which r e t a i n s t h e s t e r e o c h e m i s t r y o f t h e s t a r t i n g
m a t e r i a l . 28
The c h e m i s t r y o f v i n y l i c compounds c o n t a i n i n g s i l i c o n
groups have received considerable a t t e n t i o n .
Acetylenes can be
d i s i l y l a t e d u s i n g a r e a g e n t d e r i v e d f r o m Me S i L i , MeMgI, a n d
3
MnC12.29
Distannylation can a l s o be achieved.
Addition of ( t r i -
r n e t h y l s i l y 1 ) t r i m e t h y l s t a n n a n e a c r o s s t h e t r i p l e bond o f a l k - l - y n e s gives products of type
(4) i n r e g i o - a n d s t e r e o - s p e c i f i c f a s h i o n . 3 0
V i n y l n i t r i l e s c o n t a i n i n g s i l i c o n g r o u p s h a v e b e e n o b t a i n e d by palladium-catalysed
a d d i t i o n o f TMSCN t o a c e t y l e n e s , 31 a n d b y t h e
a d d i t i o n o f H C N t o s i l y l a t e d a c e t y l e n e s m e d i a t e d by regioselectivity o f t h e copper-catalysed
The
silylzincation of terminal
a c e t y l e n e s d e s c r i b e d b y O ~ h i m ac a~n ~b e v e r y e f f e c t i v e l y c o n t r o l l e d by t h e c o r r e c t c h o i c e o f r e a g e n t ( S c h e m e 1 1 ) . C o r e y h a s now p u b l i s h e d a d d i t i o n a l d e t a i l s c o n c e r n i n g t h e c h e m i s t r y of t h e r e a g e n t d e r i v e d by t r e a t m e n t o f m e t h y l e n e t r i p h e n y l phosphorane w i t h a n a d d i t i o n a l e q u i v a l e n t o f alkyl-lithium.
"
The
reagent formulated as ( 7 ) methylenates even very s t e r i c a l l y h i n d e r e d k e t o n e s , a n d also o p e n s e p o x i d e s ( S c h e m e 1 2 ) .
In contrast
t o t h i s r e p o r t , S c h l o ~ s e rh ~a s~ p r o v i d e d g o o d e v i d e n c e f o r f o r m a t i o n o f ( 7 ) o n l y by halogen-metal
exchange o f (81, whereas base
t r e a t m e n t o f methylenetriphenylphosphorane r e s u l t s i n o r t h o l i t h i a t e d s p e c i e s ( 9 ) (Scheme 1 3 ) .
This d i s p a r i t y is probably due
6
General and Synthetic Methods
- /q Ill
‘R3ep
Me
OH
Me
Yo
Me
SMe
sKSMe 0
SMe
Reagents
I,
NaH, CSz, DMSO. MeI.
11,
Distil at reduced pressure,
III>
Pyrolysis
Scheme 8
>CHCH2SPh
“”13
/
Me
PhSNa. HMPA
‘GHl3
‘
Ch eC i=CH,
( 2 ) 77”/0, E / Z mixture
0,” (1)
C6H13\
CMeCH=CH2
Ph0,S’
( 3 ) 96’10 Scheme 9
- R22Bg R3sxH R 3S
i
IC-CR’
I
Reagents
1,
RZZBH,THF,
11,
LL
R’
R3SMg6r, -5O’C
to RT,
R*, B
111,
R’
Bu”L1, 6 M NaOH(aq 1
Scheme 10
n
7
1 : Saturated and Unsaturated Hydrocarbons
RXH
[ Pd(PPh3)41 1 m o l '1.
R-C
m
EC-H
48 h, 60 - 7 0 'C
+
Me3Sn
SiMe,
Me3Si -SnMe, (neat)
I,
RC=CH
Reagent, CuCN
+
ii, H,O+
H
SiMe,Ph
RXH PhMe2Si
(5)
R = THPOCH,CH,
H
(6)
Reagent =(PhMe2Si)3ZnMgMe
100
:0
97 % yield
1
: 99
87V0 yield
Reagent = PhMe2SiZnButzLi
Scheme 11
i
-eC 111
QoH ' 6 P h
Ph3pY (7) H
Li
Reagents: i, ButLi, - 7 8 *C, then at 2 3 'C for 2.5 h; ii; Cyclopentene oxide (17 h, 23.C); PhCHO(6 h, 2 3
*C); iii, Fenchone, HMPA; ButOH Scheme 12
General and Synthetic Methods
8
H Ph 3P =CH,
Ph3P=C/
‘Br
1
B ? L ~( 2 . 0 equiv.)
+ -
Ph,P-CH,
bLi
(7)
(9) Scheme 13
&OR
EtPPh3Br, K H M p
&OR
+
6
1
? T O R R =Ac R =CH,Ph
36 Scheme 14
Reagents
1,
BUnL1, Me3SnCH21,
11,
Bu4NF
Scheme 15
0
I : Saturated and Unsaturated Hydrocarbons
9
t o d i f f e r e n c e s e v i d e n t i n t h e r e a c t i o n c o n d i t i o n s u s e d by e a c h group and p a r t i c u l a r l y t h e temperatures used f o r t h e second metal-
l a tion. A v e r y d i r e c t e l e c t r o c h e m i c a l method f o r t h e p r e p a r a t i o n o f 1-
cycloalkenyltriphenylphosphonium s a l t s h a s b e e n r e p o r t e d , w h i c h uses simple c y c l i c alkenes and triphenylphosphine as s t a r t i n g
m a t e r i a l s . 36
Although y i e l d s a r e o n l y moderate, t h i s r o u t e should
p r o v e t h e method o f c h o i c e f o r p r e p a r a t i o n o f t h e s e v a l u a b l e i n t e r mediates.
S a l t - f r e e W i t t i g r e a c t i o n o f 2-oxygenated
e x h i b i t s good t o e x c e l l e n t Z - s e l e c t i v i t y nature of the 2-substituent
(Scheme
cyclohexanones
depending on t h e e x a c t '
14). 37
Amongst t h e a l t e r n a t i v e s t o p h o s p h o r u s - b a s e d dures, t h e use o f sulphones remains popular.
o l e f i n a t i o n proce-
Thus, f l u o r o m e t h y l
p h e n y l s u l p h o n e h a s b e e n u s e d t o p r e p a r e v i n y l f l u o r i d e s v i a afluoro- a,B-unsaturated
s u l p h o n e s , 38 a n d a n i m p r o v e m e n t o n a n
earlier methylenation procedure involves a l k y l a t i o n of sulphone a n i o n s w i t h R SnCH21 ( S c h e m e 1 5 1 . ~ '
Use o f R SnCH21 r a t h e r t h a n
3
3
its s i l i c o n analogue r e s u l t s i n a dramatic i n c r e a s e i n t h e rate of both t h e a l k y l a t i o n and fragmentation s t e p s .
T h e m e t h o d was a l s o
e x t e n d e d t o m e t h y l e n a t i o n o f n i t r i l e s a l t h o u g h somewhat h a r s h e r c o n d i t i o n s ( M e L i , -20
OC)
were r e q u i r e d f o r t h e s e c o n d f r a g m e n t a -
t i o n s t e p a s Bu4NF was f o u n d t o b e i n e f f e ~ t u a l . ~ ' S u l p h o n e s a r e a l s o u s e d i n a new m e t h o d f o r t h e s t e r e o s e l e c t i v e p r e p a r a t i o n o f a, 8 - u n s a t u r a t e d
amides. 41
T h e d i a n i o n o f t h e s u l p h o n e ( 10 1 was
s e q u e n t i a l l y a l k y l a t e d , a n d t h e n r e a c t e d w i t h NaBH4 t o f u r n i s h t h e d e s i r e d a m i d e s (Scheme 1 6 ) .
R e a c t i o n o f ( 1 0 ) w i t h e p o x i d e s was
a l s o p o s s i b l e , g i v i n g a d d u c t s w h i c h c o u l d b e c y c l i z e d u s i n g KOBut leading t o s u b s t i t u t e d dihydropyrans. U n s a t u r a t e d a m i d e s a n d e s t e r s a r e a l s o a v a i l a b l e by a n o v e l p a l l a d i u m - c a t a l y s e d c a r b o n y l a t i o n o f e n o l t r i f l a t e s . 42
T h i s method
g a v e u n i f o r m l y h i g h y i e l d s o n a number o f s t e r o i d a l s u b s t r a t e s ,
e.g. -
Scheme 17.
Wittig and P e t e r s o n methodologies have been used f o r t h e preparation of
a,8-unsaturated
t h i 0 e ~ t e r - sa~n d~ a - s i l y l - a, B-
u n s a t u r a t e d esters r e s p e c t i v e l y . 'lr
Selenoxide elimination i s well
e s t a b l i s h e d as a m i l d method f o r o l e f i n a t i o n , s e l e n i u m u s u a l l y being introduced i n t o t h e s u b s t r a t e molecule i n its divalent state. T h e u s e o f p h e n y l s e l e n i u m t r i c h l o r i d e now a l l o w s d i r e c t i n t r o d u c t i o n of t e r v a l e n t selenium and enables subsequent conversion i n t o t h e selenoxide and elimination without t h e use o f a n oxidant ( S c h e m e I 8 1. 4 5
Reduction o f t h e i n t e r m e d i a t e d i c h l o r o s e l e n i d e s t o
10
General and Synthetic Methods
CONHPh
___) I
PhSO
R F C . O N H P h
___) 'I
R d C O N H P h
PhSO, (10)
Reagents
I,
BULI ( 2 equiv 1, THF, HMPA; R X ;
11,
NaBHL
Scheme 16
NEt, Scheme 17 CI
0 PhSeCL3
N a H CO 3(aq.1
Scheme 18
Reagents
1,
CH2Br2, NaHMDS,
11,
BJLi, MgBr2, PhSCH21, c a t a l y t i c L I ~ C U C ~oxidant-oxone, ~,
MCPBA, o r MoO5*HMPT*H2O,
111,
BuLi, THF, HMPT
Scheme 19
0
d
f3r-
LDA,
f i h h 3 ( 2 equiv 1, KOH
gF
8 u'o
Bu'O
Scheme 2 0
11
1 : Saturated and Unsaturated Hydrocarbons t h e c o r r e s p o n d i n g s e l e n i d e s was a l s o a c h i e v e d b y r e a c t i o n w i t h thiourea.
A n u m b e r o f p a p e r s h a v e a p p e a r e d d e t a i l i n g new d e v e l o p m e n t s o f
e x i s t i n g a n n u l a t i o n methods which y i e l d c y c l i c o l e f i n s . D a n h e i ~ e rh ~a s~ m o d i f i e d h i s s t e r e o c o n t r o l l e d [ 4 + 1 ] a n n u l a t i o n approach t o cyclopentene derivatives, t h a n o x y g e n s u b s t i t u t i o n a t C-3
t o accommodate c a r b o n r a t h e r
(Scheme 1 9 ) .
sequence is t h e carbanion-accelerated
The k e y s t e p i n t h e
vinylcyclopropane-
cyclopentene rearrangement which a p p e a r s q u i t e e f f i c i e n t . Unfortunately t h e r a t h e r poor y i e l d s i n t h e i n i t i a l s t e p s o f t h e sequence and t h e lengthy n a t u r e o f t h e o v e r a l l procedure d e t r a c t somewhat from i t s a p p e a l . p o t , three-component
P o s n e r h a s developed a c o n v e n i e n t one-
c o n s t r u c t i o n o f cyclohexenes which i n v o l v e s
two c o n s e c u t i v e M i c h a e l a d d i t i o n s f o l l o w e d by a r i n g c l o s u r e reaction,47
e.g. S c h e m e 2 0 .
Fragmentation reactions o f c y c l i c s u b s t r a t e s containing s i l i c o n
or t i n p r o v i d e a u s e f u l r o u t e i n t o f u n c t i o n a l i z e d a c y c l i c o l e f i n s . Wilson h a s developed t h e CeIV-mediated o x i d a t i v e fragmentation o f 7-hydroxy-silanes
which a f f o r d s f a i r y i e l d s o f
a l d e h y d e s or k e t o n e s . 48
Cyclic B-stannyl-oximes
when t r e a t e d w i t h l e a d t e t r a - a c e t a t e , ring-contracted study5'
p r o d u c t s (Scheme 21 )
6,~-unsaturated fragment s i m i l a r l y
leading to either acyclic or
."
Both t h i s and a n o t h e r
indicate t h a t such fragmentations occur with e f f i c i e n t
t r a n s l a t i o n o f stereochemistry i n t o t h e o l e f i n i c products.
A
cyclopropane-opening c a r b o n y l a t i o n r e a c t i o n g i v e s good y i e l d s o f Y,6-unsaturated
carboxylic acid derivatives
(Scheme 2 2 ) . 51
The
r e a c t i o n o f f e r s a method of r e g i o s e l e c t i v e c a r b o x y l a t i o n o f a n a l l y l i c a l c o h o l or h a l i d e [ t h e p r e c u r s o r s t o c y c l o p r o p a n e s ( I I ) ] , b u t h a s t h e d i s a d v a n t a g e o f u s i n g 3-6 e q u i v a l e n t s o f [ N i ( C O ) , l .
3 Conjugated 1,3-dienes Taylor has n i c e l y c o n t r o l l e d t h e double carbocupration r e a c t i o n o f organocuprates with acetylenes t o provide a general entry t o dienes,52
e.g. S c h e m e 2 3 .
w i t h a c e t y l e n e ( i n i t i a l l y a t -50
OC
a n d t h e n a t 0 OC) t h e r e a c t i o n
can b e quenched w i t h a v a r i e t y o f e l e c t r o p h i l e s
etc.)
t o g i v e t h e Z-,Z-products
Terminal conjugated
(E)
z,z-
After t r e a t m e n t o f t h e d i a l k y l c u p r a t e
(RX,
enones, C02,
stereospecifically.
d i e n e s a n d t r i e n e s a r e a v a i l a b l e by
SnC12-mediated r e a c t i o n o f a n a l d e h y d e w i t h l-bromo-3-iodop r o p a n e , 5 3 e.g. S c h e m e 2 4 . The p r o c e d u r e i s o p e r a t i o n a l l y s i m p l e ,
General and Synthetic Methods
12
Ac +/
Pb (OA c l4 CH2CL2, -SO’C*
0-
6 Scheme 2 1
xb<” Br
[Ni(C0141 DMF, RQH
*
(11) X = C l or OMS
NaHC03 (aq.)
\
-
COQR
Q
=o, NH,
or NR’
Scheme 2 2
i, HC=CH
*d
( 2 portions)
Bu2CuLi
6u
Scheme 2 3
BrCH=CH-CHZI,
ZSnCLZ
PhCHO
Ph Scheme 2 1
*
I : Saturated and Unsaturated Hydrocarbons
13
and is chemoselective in that ketones are unreactive. Corey has used the amino-ylide (12) to convert the hindered aldehyde (13) into the 2-homoallylic amine ( 14). 54
Subsequent Cope elimination
then furnished the g,E diene (Scheme 25). Cyclic dienes are available by tellurolate l14-elimination of 1,4-dibromo-2-enes,55 and also by a new annulation sequence involving intramolecular Pd-catalysed reaction of an enol triflate with a vinylstannane appendage (Scheme 26). 56
A variety of polysubstituted dienes have been synthesized using a very high yielding sequence starting from a,al-diketo-sulphides (Scheme 2 7 1 . ~Even ~ very heavily substituted dienes can be made in this way, the products being formed stereoselectively in certain cases. Trost has described a new palladium(2+)-catalysed ene-type cyclization which furnishes either 1 ,3- or 1 4-dienes. 58 This method utilizes enynes such as ( 1 5 ) as starting materials, which themselves are readily available by previous Pd technology (Scheme 28). The method tolerates a variety of other functionality in the molecule, and both the enyne synthesis and subsequent cyclization can be combined in a one-pot procedure if desired. Cyclization of aromatic enynes such as (16) to give vinylphenanthrenes occurs on exposure to metal carbenes, e.g.
R 1 R2=W(CO)5 (Scheme 29
The intermediate metallocenes of type
(17) are proposed to undergo highly selective ring opening to give the products of cis stereochemistry. A number of papers report developments in the palladium- or ruthenium-catalysed coupling of various vinylic substrates with a variety of partners to give dienyl products; some examples are outlined in Scheme 30.60-63 A one-pot synthesis of l,l-bis(methylthio)alka-l,3-dienes has appeared, "and Wallace has outlined some useful stereoselective routes to various functionalized hexa-2,4-dienals starting from a readily available cyclobutene. 65 Phenylsulphonylmercuration of 1,3-dienes, followed by base-promoted d e m e r c u r a t i o n , c o n s t i t u t e s a regioselective route to dienyl-sulphones (Scheme 31). 66
4 Non-conjugated Dienes Allylic sulphones feature in the oxidative dimerization described by Buchi whereby lithio anions derived from allylic sulphones were treated with either iodine or FeC13-DMF complex, to provide 1,5dienyl bis-sulphones, e.g. Scheme 32.67 As can be seen, com-
General and Synthetic Methods
14
& T I I
\
(1 3 )
(14)
R = H or Me Scheme 25
Scheme 2 6
Reagents
1,
Zn,
11,
MCPBA.
III,
FVP, 500'c, 0.1
Scheme 27
mmHg
I : Saturated and Unsaturated Hydrocarbons
15
(p- :e E
I
E = C0,Me E
Reagents
i,
-
~r
=, [(Ph3P)4Pdl, NaH, THF, A ,
li,
€3
5 mol"lo [(Ph3P)2Pd(OAc)Zl or Pd(OAc)2,
THF
Scheme 28
Ph
'c=w(co
MeO'
(mainly c i s )
Via
Scheme 2 9
General and Synthetic Methods
16
(Ref. 6 0 )
C0,Me
b
OTf
b
t C o z M e , DMF Et3N, 2 mol ' l o [Pd(PPh3l21
5 " l o Pd(OAc),,
(Ref. 61)
PPh3
(Ref. 62)
so, C I A
r
w 150 'C, bz ( s e a l e d tube)
-
(Ref. 63)
Scheme 30
I
.
0
Reagents
1,
NaSO,Ph, HgCL,,
Y
H
I
I
C
SOZPh H,O.
11,
NaOH, N a 2 C 0 3
Scheme 31
I
-
SO, Ph
I: Saturated and Unsaturated Hydrocarbons
17
p l e m e n t a r y i s o m e r d i s t r i b u t i o n s were o b s e r v e d f o r e a c h o x i d a n t . 1,5-Disubstituted Z,Z-penta-l,q-dienes ( 2 1 ) were p r e p a r e d by t h e s e q u e n c e shown i n Scheme 3 3 . 6 a
The m e t h o d i s c o n c e p t u a l l y s i m i l a r
Z ,Z-l,3-dienes, t o t h e s e q u e n c e d e s c r i b e d a b o v e ( S c h e m e 2 3 ) for a l t h o u g h t h e y i e l d s a n d s t e r e o s e l e c t i v i e s a r e somewhat more modest. Hexa-1,5-dien-3-ols
are obtained ( a l b e i t with moderate regio-
s e l e c t i v i t y ) from t h e r e a c t i o n between a l l y l i c epoxides and tria l k y l a l k y n y l b o r a t e s ( S c h e m e 3 4 ) . 69
This s e l e c t i v i t y complements
t h e b e h a v i o u r o f v a r i o u s o t h e r o r g a n o m e t a l l i c s (M = L i , M g B r , Z n ,
e t c . ) which g i v e predominantly products o f t y p e ( 2 3 ) .
The u s e o f
allyloxybenzothiazoles as electrophiles i n organometallic coupling r e a c t i o n s h a s r e c e n t l y been extended t o r e a c t i o n s involving a l l y l i c G r i g n a r d s a s r e a c t i o n p a r t n e r s . 70
T h e s e r e a c t i o n s show h i g h r e g i o -
s e l e c t i v i t y , which c a n be c o n t r o l l e d t o g i v e 1 , 5 - d i e n e s o f t y p e
( 2 4 ) or ( 2 5 ) b y a p p r o p r i a t e c h o i c e o f r e a c t i o n c o n d i t i o n s ( S c h e m e 35). F i n a l l y , a c o n t r i b u t i o n from t h e T r o s t group d e s c r i b e s t h e intramolecular coupling of a n a l l y l i c acetate
with an i n s i t u
g e n e r a t e d a l l y l s t a n n a n e , i n e v i t a b l y c a t a l y s e d by p a l l a d i u m (Scheme 36)."
5 Allenes A s e r i e s o f s i m p l e a l l e n e s h a s b e e n p r e p a r e d by a v e r y s t r a i g h t -
forward m u l t i s t e p procedure,
37).72
s t a r t i n g from c r o t o n a l d e h y d e (Scheme
A n o t h e r r o u t e t o s u c h compounds u t i l i z e s t h e r e a c t i o n
b e t w e e n Bu S n L i a n d e t h e r s d e r i v e d f r o m B - p h e n y l s u l p h i n y l - B , y 3 u n s a t u r a t e d a l c o h o l s (Scheme 3 8 ) . 73 A l l e n i c k e t o n e s a r e a v a i l a b l e by a s i m p l e a n d h i g h - y i e l d i n g sequence s t a r t i n g from t h e acetal-aldehyde
(261, i t s e l f readily a v a i l a b l e f r o m e t h y l p y r u v a t e ( S c h e m e 3 9 ) . 74 I n a continuation o f earlier s t u d i e s on a l l y l i c d e r i v a t i v e s W e n k e r t h a s now d e v e l o p e d t h e n i c k e l - c a t a l y s e d silylpropargyl alcohols.75 above
r e a c t i o n of c e r t a i n
The m e t h o d i s v e r y s i m i l a r t o t h a t
(Scheme 3 9 ) , e x c e p t t h a t n o d e r i v a t i z a t i o n o f t h e s t a r t i n g
a l c o h o l s is needed.
S e v e r a l s t u d i e s have examined t h e s t e r e o -
chemical outcome i n t h e r e a c t i o n of o p t i c a l l y a c t i v e a l l e n i c h a l i d e s w i t h v a r i o u s o r g a n o m e t a l l i c r e a g e n t s . 76 and n i c k e l - c a t a l y s e d
I n t h e palladium-
r e a c t i o n s examined t h e s t a r t i n g bromoallenes
underwent s u b s t i t u t i o n p r e d o m i n a n t l y w i t h i n v e r s i o n (Scheme 4 0 ) . I n t h e Pd-mediated r e a c t i o n c h l o r o a l l e n e s a l s o g a v e i n v e r s i o n ,
General and Synthetic Methods
18
Scheme 32
(20)
Br-+
BuzCuLi
HC=CH
-
/
fi
nnL
/rr'2p,,
dPph3
Bu L
(211
R
Z:E
yield of (21)
phenyl
30%
87
:13
pentyl
50%
9
:1
Scheme 33 1
( 2 2 ) major
( 2 3 ) minor
Scheme 34
(2 4)
OBtz
then -MgBr
(25) Scheme 35
19
I : Saturated and Unsaturated Hydrocarbons
Reagent: i, Me3SnSnMe3, P ~ ( O A C ) ~ ( ~PPh3 " ~ ~(25'1.1, ) ,
hex-I-ene (excess), THF
Scheme 36
I,
MeCH =CH-CHO Reagents
I,
CL2, NaOH,
Cl OH
I t
ii
11,
RMgX,
MeCH=C -CHR III.
iii
MeCH=C=CHR
BULI, M e I , LI
Scheme 37
SOPh i, MeI, NaH
B u 3SnLi
HO
R3
ii. MCPBA
R2
_____)
_____)
Me0
R3
Scheme 38
d
gc
20
General and Synthetic Methods
gcqr
Me
Me BU'~AL
H
H
\
-
Ni catalyst 1- 3 mol "10
/
Et
Et
Br
H
H
R
Hkc=( R
Ph
Scheme 40
Et20
H
/
HO
R t
R = Me, Bun, B u , or Ph d.e. = 56'10, 70°/:, 100'10, 46%
Scheme 41
+ H20
1 +
Reagents: i, EtOH, H20, Pd catalyst, HCL04,
i02 ii,
Dioxane, H20, Pd catalyst, HCIO4
Scheme 4 2
1 : Saturated and Unsaturated Hydrocarbons
21
whereas iodoallenes gave retention. Alexakis and Normant have investigated the diastereoselection possible in the reaction of organometallics with chiral acetylenic acetals (Scheme 41 ) .77 The use of ether solvent, catalytic CuBr, and a five-membered ring chiral acetal was found to be important in this reaction for optimal diastereoisomeric excess (d.e.1 in the chiral alkoxyallene products.
6 Alkynes A new catalyst system which uses palladium acetate on an insoluble support allows efficient conversion of alkenes into either alkynes or ketones, depending on the solvent system employed (Scheme 4 2 ) . 7 8 Efficient one-step dehydrosilylation is now possible for the first time.79 Thus reaction of vinyl silanes with a mixture of iodosylbenzene and BF3.0Et2 resulted in smooth formation of the desired alkyne (Scheme 43). Another report from the same research group describes the reaction of alkenyltrimethylsilanes with the iodosylbenzene-BF3.0Et2 system to give alkynyliodonium salts (Scheme 44 1. 8o Acetylenic tosylates have now been prepared for the first time, and again hypervalent organoiodine compounds are important intermediates (Scheme 45). 81 These unusual products were fully characterized on the basis of both their spectral data and reactions, %. methanolysis and hydrogenation. The intermediate iodonium tosylates (27) could also be converted into alkynyl iodides by thermolytic or photolytic means. A very attractive extension of cobalt complexed acetylene chemistry provides a high-yielding route into functionalized acetylenes, starting with (28) (Scheme 4 6 ) . 8 2 The sequence works equally well if tertiary carbonium ions are used as the electrophiles in the first step, and allylsilanes can be used as nucleophiles in the second step. Phenyl(arylsulphony1)acetylenes react thermally o r photochemically with alkenes to give adducts such as (29) and (30), in fair yields (Scheme 47).83 The reaction appears limited to aryl(arylsulphony1)acetylenes; unsubstituted t o l y l s u l p h o n y l a c e t y l e n e , or I-tolylsulphonylpropyne did not react in the same fashion. Propargylic alcohols are available by methods which avoid the use of relatively basic acetylide anions. Brown has used B-1alkynyl-9-BBN compounds as acetylide equivalents and found that
22
General and Synthetic Methods
I R
Ph
( PhIO),
+RCECH
m uSiMe3 BF3.OEt2, C H Z C I Z , R T
Scheme 43
-+ (PhIO),, Et30BFq-, CHZClZ
R -C
=C -Si Me3
m
+ R- C E C -1
B F4-
-Ph
Scheme 44
OH
OTs
I
Ph -I -OS02 To1
m
RCECH
1
C u O T f (0.1 equiv.)
Ph-I-CSCR ( 2 7 ) 20
- 60%
Scheme 45
i,
BF3
,;, , J y 3
c o Z(C0) 6 iii, CAN
Scheme 46
R-CCC-OTS
I : Saturated and Unsaturated Hydrocarbons
23
Ph
/
\\\ \
Ph (291 Reagent:
I,
PhCEC-SOZTol,
A
-
Scheme 47
"#"
O-\OTMS
F3CC=C-CH
I
TBAF, THF
F
P(OEt),
OH
II 0
R SllYL e n d ether (2.5 equiv.)
R,CECH
5"10 HCL
TBAF. MeCN
H R, = perfluoroalkyl Scheme 48
OH
OHC
-
CN
Buc=c-I
D THF, CrCLZ
OH Scheme 49
0
II
R,CH,-C-CHR
OH
I
General and Synthetic Methods
24
they react smoothly and with exceptional chemoselectivity with a l d e h y d e s or k e t o n e s . 8 4 F l u o r o a l k y l p r o p a r g y l a l c o h o l s a r e a l s o a v a i l a b l e by t e t r a b u t y l a m m o n i u m f l u o r i d e m e d i a t e d r e a c t i o n o f l-alkenephosphonates,
e.g. ( 3 1 1 ,
f r o m a l d e h y d e s , 8 5 3 .S c h e m e 48.
i s conducted i n MeCN u s i n g 2.5
I!-E-
with s i l y l enol ethers derived I n t e r e s t i n g l y , when t h e r e a c t i o n
equivalents of s i l y l enol ether,
1,3-dioxolane d e r i v a t i v e s a r e o b t a i n e d , which can t h e n be hydrol y s e d t o a-hydroxy-ketones. Alkynyl i o d i d e s react s e l e c t i v e l y w i t h a l d e h y d e s r a t h e r t h a n k e t o n e s or n i t r i l e s , w h e n t r e a t e d w i t h C r C 1 2 i n DMF ( S c h e m e 4 9 ) . I n t h e absence o f a n aldehyde t h e l-halogeno-l-alkynes reductively dimerized t o produce Glazer-type good y i e l d .
86
could be
coupling products i n
S t e r e o c o n t r o l i n t h e r e d u c t i o n o f a-benzyloxy
acetylenic ketones is possible t o g i v e e t h e r threo-
or erthro-
acetylenic vicinal d i 0 1 . s . ~ ~ A l l e n e on t r e a t m e n t w i t h n - b u t y l - l i t h i u m
is converted i n t o a
d i a n i o n which acts as a n e f f e c t i v e p r o p a r g y l i c a n i o n e q u i v a l e n t i n a l k y l a t i o n r e a c t i o n s ( S c h e m e 5 0 ) .88
Success i n i s o l a t i n g the
d e s i r e d a c e t y l e n i c r a t h e r t h a n a l l e n i c p r o d u c t s (or m i x t u r e s o f t h e two) i s dependent on t h e s o l v e n t s y s t e m employed i n t h e r e a c t i o n . S i m p l e d i a l k y l and t e r m i n a l a c e t y l e n e s a r e formed by f l a s h v a c u u m p y r o l y s i s o f s t a b i l i z e d p h o s p h o r a n e s ( S c h e m e 51 ) . 8 9
The
m e t h o d h a s some a p p e a l d u e t o t h e r e a d y a v a i l a b i l i t y o f t h e fami-
l i a r phosphorane s t a r t i n g materials, and t h e fact t h a t t h e products are obtained pure d i r e c t from t h e p y r o l y s i s . 7 Enynes and Diynes
A f u l l report o f t h e ruthenium-catalysed acetylenes with 1,3-dienes has appeared. variable,
codimerization of terminal Y i e l d s a r e somewhat
b u t t h e method o f f e r s a n a t t r a c t i v e and d i r e c t r o u t e t o a
v a r i e t y of e n y n e s (Scheme 52).” C o n j u g a t e d e n y n e s were t h e m a j o r p r o d u c t s o b t a i n e d f r o m palladium-catalysed r e a c t i o n o f v i n y l bromides such as ( 3 2 ) w i t h a c e t y l e n e s ( S c h e m e 531.’’
A g a i n t h e y i e l d s o f s i m p l e e n y n e acet a t e s are v a r i a b l e , w i t h s t a r t i n g material and o t h e r p r o d u c t s such
as d i e n y n e s b e i n g i s o l a t e d .
The r e a c t i o n d e m o n s t r a t e s t h a t when a
s u b s t r a t e h a s a c h o i c e o f u n d e r g o i n g e i t h e r v i n y l i c c o u p l i n g or s u b s t i t u t i o n ( v i a a n-ally1 complex) t h e former process appears t o be favoured. Stereoselective formation of e i t h e r
E-
o r Z-enynes by dehydra-
I : Saturated and Unsaturated Hydrocarbons
25
/
PhCHZCI
=C=
BuLi 7 ether, hexane
C,H2Li2 i , PhCHZCl CH20
i i , para
-
-OH ph/\/6
Scheme 5 0
m -
Ph3P$ R2
750
‘c,
lo-’ mmHg
R’C-CR’ (-
Ph3PO)
Scheme 51
CO,Me
+
1‘
Scheme 52
Scheme 53
General and Synthetic Methods
26
t i o n o f propargylic a l c o h o l s h a s been demonstrated i n t h e s y n t h e s i s o f l e u k o t r i e n e a n a l o g ~ e s . ’ ~ A number o f p a p e r s h a v e d e s c r i b e d c h e m i s t r y a s s o c i a t e d w i t h e n y n y l a n d d i e n y n y l t r i f l a t e s . 93 r e p o r t s t h a t r e a c t i o n o f enyne t r i f l a t e s o f t y p e
Stang
(33) w i t h n u c l e o -
p h i l e s r e s u l t s i n enynes o r e n e d i y n e s depending on t h e n u c l e o p h i l e employed (Scheme 5 4 ) . 9 3 5 an
SN2’p r o c e s s :
The r e a c t i o n s a r e s u g g e s t e d t o p r o c e e d by
unfortunately the intermediate butatrienes
although observable could n o t be i s o l a t e d . The c y c l i c d i e n y n y l t r i f l a t e ( 3 4 ) was p r e p a r e d f r o m t h e p a r e n t k e t o n e ( 3 5 ) b y u s e o f a b a s e f o l l o w e d b y t h e McMurry r e a g e n t PhNTf2 ( S c h e m e 55).932
Subsequent s o l v o l y s i s o f ( 3 4 ) under a v a r i e t y o f
c o n d i t i o n s o c c u r r e d c l e a n l y t o g i v e m a i n l y t h e a r o m a t i c compound (36).
H y d r o s i l y l a t i o n o f 1,4-bis(trimethylsilyl)buta-l,3-diyne c a n
b e c o n t r o l l e d t o g i v e i n i t i a l l y t h e e n y n e r e s u l t i n g f r o m l,2-*a d d i t i ~ n . ’ ~Further reaction can then occur i n 1 ,h-fashion t o give an a l l e n i c product.
8 Polyenes A number o f n a t u r a l l y o c c u r r i n g p o l y e n e s y s t e m s . c o n t i n u e t o f o c u s
s y n t h e t i c a c t i v i t y i n t h i s area.
The h e p t a e n e p o r t i o n o f
a m p h o t e r o c i n B h a s b e e n t a c k l e d by b o t h Masamuneg5 a n d M c G a r ~ e y , ’ ~ u s i n g Horner-Emmons respectively.
phosphonate and l i t h i o - v i n y l e t h e r approaches
The same l i t h i a t e d v i n y l e t h e r ( 3 7 ) f e a t u r e s i n a
t o t a l s y n t h e s i s o f c i t r e o m o n t a n i n b y P a t t e n d e n ( S c h e m e 5 6 ) . 97
The
s y n t h e s i s was c o m p l e t e d u s i n g a W i t t i g c o u p l i n g a s t h e f i n a l s t e p , t h e product being one o f a family of n a t u r a l l y o c c u r r i n g polyene p y r o n e s w h i c h h a v e a t t r a c t e d a t t e n t i o n . 98 Wender h a s a p p l i e d h i s ‘ m a c r o e x p a n s i o n m e t h o d o l o g y ’ t o t h e s y n t h e s i s o f cembrene A i n o p t i c a l l y a c t i v e form, s t a r t i n g w i t h (+)c a r v o n e (Scheme
571.”
A s t u d y of t h i s c h e m i s t r y of a c y c l i c sub-
s t r a t e s was c o n s i s t e n t w i t h a r e a c t i o n i n w h i c h b o t h [ 5 , 5 1 a n d consecutive
C3,31 s i g m a t r o p i c r e a r r a n g e m e n t s a r e o p e r a t i v e . l o o
Leukotrienes and t h e i r p o t e n t i a l l y u s e f u l analogues c o n t i n u e t o attract synthetic interest.
Taylor has used t h e addition reaction
of organolithiums with pyrylium perchlorate t o provide an e n t r y t o a r a n g e o f d i e n e s a n d t r i e n e s (Scheme 5 8 ) .
Yields for the f i n a l
d o u b l e a d d i t i o n p r o d u c t s w e r e i n t h e r a n g e 32-60%.
The method
a p p e a r s t o o f f e r a v e r y e x p e d i e n t r o u t e t o LTB4 a n d r e l a t e d s u b stances.
1: Saturated and Unsaturated Hydrocarbons
27
OCH,CF,
I
0 OTf (35)
(34)
(36)
Scheme 55
OMe
0o $
c
CBr,
11.
NaBH,
IV,
PPh3, CHZCL2
111,
PPh,
H
rl OMe
Ci treomontanin
Scheme 56
28
General and Synthetic Methods
(+)
- Carvone
Cembrene A
Scheme 57
1
OH
OH
OH
CO, H R’
Scheme 58
I : Saturated and Unsaturated Hydrocarbons
29
References 1
2 3 4 5 6
7 8 9 10 11
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-
fi,
-
~
12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42
-
30 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69
70
71 72 73 74 75 76
77 78
79 80
81 82 83
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26,
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26,
k,
97 1 -
N.Kamigata, J.Ozaki, and M. Kobayashi, Chem. Lett., 1985, 705. Y.-A.Heus-Kloos, R.L.P.de Jong, H.D.Verkruijsse, L-Brandsma, and S.Julia, Synthesis, 1985, 958. S.Ingham, R.W.Turner, and T.W.Wallace, J. Chem. Soc., Chem. Commun. , 1985, 1664. O.S.Andel1 and J.E.Backval1, Tetrahedron Lett., 1985, 26, 4555. G.Buchi and R. M. Freidinger , Tetrahedron Lett., 1985, 26, 5923. G. Just and B. 0‘Connor, Tetrahedron Lett., 1985, 26, 1799. J.M.Mas, M.blacria, and J.Gore, J. Chem. SOC., Chem. Commun., 1985, 1161. V.Calo, L.Lopez, and G.Pesce, J. Chem. SOC., Chem. Commun., 1985, 1357. B. M.Trost and K. M.Pietrusiewicz, Tetrahedron Lett - , 1985, 26, 4039. J.Barluenga, J.R.Fernandez, and M.Yus, J. Chem. S O C . , Chem. Commun., 1985, 26, 203. T. Takeda, K.Suzuki, H. Ohshima, and T. Fu jiwara, Chem. Lett., 1985, 1249. D.Bernard and A-Doutheau, Tetrahedron Lett., 1985, 26, 4923. E.Wenkert, M.H.Leftin, and E.L.Michelotti, J. Org. Chem.., 1985, 50, 1122. C.J.Elsevier, P.Vermeer, A.Gedanken, and W.Runge, J. Org. Chem., 1985, 50, 364 ; A. M. Caporusso, F. Da Settimo, and L.Lardicci, Tetrahedron Lett. , 1985, 26, 5101; C.J.Elsevier and P. Vermeer, J. Org. Chem., 1985, 50, 3042. A.Alexakis, P.Mangeney, and J.F.Normant, Tetrahedron Lett., 1985, 26, 4197. G.Cum, R.Gallo, S.Ipsale, and A.Spadaro, J. Chem. SOC., Chem. Commun., 1985, 157 1. M.Ochiai, K.Sumi, Y.Nagao, E-Fujita, M.Arimoto, and H.Yamaguchi, J. Chem. Soc., Chem. Commun., 1985, 697. M. Ochiai , M. Kunishima, K. Sumi, Y. Nagao, E. Fu jita, M. Arimoto, and H. Yamaguchi , Tetrahedron Lett., 1985, 26, 4501. P.J.Stang and B.W.Surber, J. Am. Chem. Soc., 1985, 107, 1452. G.S.Mikaelian, A.S.Gybin, W.A.Smit, and R.Caple, Tetrahedron Lett., 1985, 26, 1269. 0.De Lucchi, G.Licini, L.Pasquato, and M.Senta, J. Chem. SOC., Chem. Commun. , 1985, 1599.
1 : Saturated and Unsaturated Hydrocarbons 84 85 86
H.C.Brown,
91 92 93
90
95 96 97 98 99 100 10 1
S.M.Singh,
and U.S.Racherla,
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87 88 89 90
G.A.blander,
31
I
26, 26,
6,
6,
6,
26,
~
w.,
107,
26,
26,
2 Aldehydes and Ketones BY K.
1
E. B. PARKES
Synthesis of Aldehydes and Ketones
Oxidative Methods. - Corey et a1.l have reported on the use of the cyclic chromate ester ( 1 ) as a catalyst for the peracetic acid oxidation of secondary alcohols. The reagent oxidises primary alcohols very slowly, and is compatible with tetrahydropyranyl protection of alcohols; furthermore, it has the great advantage of avoiding the toxicological and disposal problems associated with stoichiometric chromium reagents. The selective oxidation of benzylic alcohols in the presence of allylic alcohol functionality can be achieved in good yields by the use of Fremy's salt under phase-transfer conditions2. The oxaminium salt (2) efficiently oxidises a wide variety of allylic, benzylic, primary or secondary alcohols to the corresponding carbonyl compounds; benzoins however are oxidised 3 only very slowly by this reagent Several new chromium-based oxidants have been reported, including nicotinium dichromate ( 3 ) 4, isonicotinium dichromate (4) and a trimethylsilyl chloride - chromium trioxide reagent The which has been assigned the tentative structure (515.
.
advantage of these reagents over better established chromie species is unclear. In the presence of potassium fluoride, Jones' reagent will both deprotect and oxidise trimethylsilyland t-butyldimethylsilyl ethers, and in significantly higher yields than are obtained in a conventional two-pot deprotection, oxidation sequence6; t-butyldiphenylsilyl ethers are unaffected by the reagent, allowing selective oxidations to be performed [equation (1) I . Pyridinium chlorochromate (PCC), widely used as a mild oxidising agent, surprisingly cleaves double bonds bearing aryl substituents in good yields, although under significantly more vigorous conditions than would normally 7 be used .
32
For References see p . 70
2: Aldehydes and Ketones
33
An alternative protocol for the ruthenium tetroxide oxidation of alcohols uses sodium perbromate to generate the reagent situ from ruthenium trichloride in a chloroform - phosphate buffer phase transfer system'. Two slightly different methodologies have been reported for the use of catalytic palladium acetate in the oxidation of alcohols, which interestingly give quite different selectivities. Thus, when iodobenzene is used as re-oxidant in a buffered phase transfer system modest to quantitative gas chromatographic yields of aldehydes or ketones are obtained from a variety of primary or secondary alcohols9. In contrast, a system using carbon tetrachloride or bromotrichloromethane as re-oxidant, while giving comparable yields in the oxidation of secondary alcohols, gave principally esters from primary This system also gave anomalous products in the alcohols''. oxidation of allylic alcohols [equation (2)] and of 8-bromoalcohols [equation (3) 1 . Another transition metal catalyst, tetrakis-(tripheny1phosphine)rhodium hydride, in conjunction with an enone as hydrogen acceptor,allows the oxidation of B-silyl alcohols to a-silyl ketones". Another variation on the Swern-Moffat oxidation, using the isolable, and characterised, complex between antimony 12 pentachloride and DMSO, has been reported . Ireland et al. have published details of the preparation of several highly unstable aldehydes and ketones by Swern oxidation and their further reaction with Grignard or Wittig reagents at low temperatures. Perhaps the most impressive application of the technique is the preparation and use of formylsilane (6), a compound which polymerises on warming to 0 ° C but which may nevertheless be reacted with Wittig reagents to give vinyl 13 silanes [equation ( 4 1 1 . Oxidation of activated methylene groups can provide convenient access to carbonyl compounds which are otherwise difficult to prepare. Thus, t-butyl hydroperoxide and catalytic chromium hexacarbonyl may be used for the oxidation of both benzylic14 and allylic15 methylene groups, a process which is of note both for the wide range of functionality tolerated and for the fact that high oxidation state chromium species are apparently not involved. Studies of the use of Jones' reagent for benzylic oxidation16 and pyridinium dichromate for the preparation of enediones from y,&-unsaturated alcohols have
General and Synthetic Methods
34
0 CI
II
-Cr -mi Me3 II 0
OH
0
Br
MgSi-OH
Reagents: i,
SIlm -70 'Cc
&r2i, TWi
ti, C@(OMc+
iii. sodium salt of mcpba
scheme 1
2: Aldehydes and Ketones
35
also appeared17. A less common methylene oxidation is that of alkylcyclopropanes to cyclopropyl ketones, a transformation which can be achieved in very respectable yields with ruthenium tetraoxide generated in a catalytic ruthenium trichloride/sodium periodate system18. Methods for the oxidative replacement of hetero substituents considerably enhance the value of these groups in synthesis. Thus reports on the preparation of aldehydes from primary phenyl sulphones by a boration - oxidation sequence (Scharae 1)” and alternative procedures for the Nef reaction 2o together with the preparation of ketones from nitro-alkenes2lhave been published. Perhaps the most intriguing oxidative approach to ketones reported this year is the reaction of organovanadium dichlorides with aldehydes22. These reagents, which are prepared from vanadium trichloride and the corresponding organolithium or Grignard reagent, react chemoselectively with aldehydes to give ketones in one pot, without a separate oxidation step, and frequently in good yield. The reagents also add in a 1,2 sense to enals to give more modest yields of the a@-unsaturated ketones. Another unusual reaction is the pinacol type rearrangement of the iodo-ether (7) with hypervalent iodine as a leaving group to give a benzylic ketone [equation (511 23 .
-
Reductive Methods. Conjugate reductions of a8-unsaturated ketones to the corresponding saturated carbonyl wnpounds m y be achieved with sodium dithionite under phase-transfer conditions24 or with diphenylsilane catalysed by Pd(0) in the presence of zinc chloride25. The latter reagent may also be used for deuteration and introduces the label cleanly from the less hindered face of the molecule [equation ( 6 ) l . Tributyl- and triphenyl-antimony in acetonitrile are efficient reagents for the reduction of phenacyl bromides to acylophenones26. The reaction of organometallic reagents with carboxylic acid derivatives is a conceptually attractive approach to ketone synthesis, but one that is not always easy to realise in practice. Reports have appeared of the palladium(0) catalysed reaction of acid chlorides with organoaluminium reagents27, and the reactions of acid chlorides with alkyl manganese iodides28, The manganese reagents are and with organonickel reagents2’. generated from either organolithum or Grignard reagents and
36
General and Synthetic Methods
manganese (11) iodide, and the organo-nickel reagents from 'active' metallic nickel similarly to a Grignard preparation. Both reagents are compatible with a wide range of functionality including ketones, esters and carboxylic acids. The reaction of organozinc reagents and acid chlorides with palladium ( 0 ) catalysis, although well documented, has been relatively little exploited in synthesis due to the difficulty of preparing the reagents. However Yoshida et al.30 have now published details of an improved experimental protocol which allows good yields to be obtained from a wide variety of halides, including w-iodcesters.31 Larson et a1.32 have published full details of their studies of the reactions of a-silylesters with Grignard reagents which due to the bulky a-substituent only react once to give, after desilyation, good yields of the required ketones [equation ( 7 ) J . With care, and suitable modification of the workup to avoid protodesilylation, a-silyketones could also be prepared. The opening of lactones with the anion from diethyl methylphosphonate to give w-hydroxy-8-ketophosphonates has also been reported33. The acylation of a variety of malonate and acetoacetate derivatives with acid chlorides and triethylamine in the presence of magnesium chloride has been reported34'35. The same magnesium halide/triethylamine reagent has also been used for the direct carboxylation of ketones with carbon dioxide36. The reaction of acid chlorides with ketene silyl acetals to give 8-keto-esters has been found to be applicable to unsaturated acid chlorides provided they are BIB-disubstituted [equation (8)I 3 7 . Methods Involving Umpolung. - Seyferth et al.38 have published several papers on the preparation and use of acyl anion-species whose presumed unavailability has led to the idea of umpolung and the wealth of synthons now available! The acyl lithium reagents were prepared by adding an alkyllithium to a tetrahydrofuran-ether-pentane solvent mixture saturated with carbon monoxide at -110°C and containing the dialkyl carbodiimide trapping reagent. Despite their instability the acylamidates were isolated in 66 to 8 3 % yield. A very similar methodology allows the preparation of acyl cuprates, from dialkyl cyano cuprates, which were found to add with high specificity 1,4- to both cyclic and acyclic enones and to enals
2: Aldehydes and Ketones
Ph&'
37
mcpba
c
Me
P h q M e
0
(7)
sr4'r
0
C,H,,CH C0,Et
I
S iMe2Ph
phvwt + II \
OSiMe,
C02Et
,
,SMe
[ Co (NO)( CO) ( PPh3) I H2C
'S0,To
1
(9)
0: CN (10)
Reagents: i , NaHS03, PhNH2, KCN; ii, 2 LDA, ZMel; iii, Cu2+, EtOH, H20i
Scheme 2
IV,
HCI,THF, Hf3
(5)
38
General and Synthetic Methods
again in surprisingly high yields (52 - 8 9 % )3 9 . Acyl transition metal species such as Collman's reagent and the Corey-Hegedus nickel carbonyl system, although also formally acyl anions, have not found wide use in synthesis, possibly because of the problems of air stability and toxicity associated with the reagents. Hegedus et a1.40 have now reported on the use of the readily prepared, air-stable complex ( 8 ) as a precursor of acyl cobalt species. These were found to add 1,4 to enones and could be alkylated with allyl chloride, but were generally less reactive and therefore possibly less useful than the earlier systems. The formyl anion equivalent ( 9 ) , which may be alkylated by either phase transfer or conventional methodologies, is interesting in that the unmasking may be achieved by photolysis, although in rather variable yields (20 - 72%)"'. An extension of the use of a-cyanoaminesas acyl anion equivalents uses the Strecker product (10) to form either 1,5-diketones or cyclohexenones (Scheme 2 ) 42. Meyers et al. have now reported the full details of their use of the formyl dianion equivalent (11) for carbonyl homologation (Scheme 3) 43. Synthons of more specialised applicability reported this year include the ene-tetrol derivative (12) whose acylation renders it an equivalent of the glyoxylate anion (13)44, and the allyl sulphide (14) equivalent of the silyl homoenolate dianion (15)45. Giese et al. have reported interesting work using radical. methodology to give umpolung reactivity to the position B to an aldehyde or ketone46. Thus acetoxy mercuration of a
trimethylsilyloxycyclopropane gives an organomercury, which on treatment with sodium borohydride forms a free radical which can be trapped with a wide variety of Michael acceptors to give, after deprotection, a functionalised aldehyde or ketone in yields which, although variable, could be as high as 7 0 % from the cyclopropane (Scheme 4). Other Methods. - One of the most important and flexible approaches to ketone synthesis involves the manipulation of B-keto-esters. Tsuji et al. have reported that the use of allyl keto-esters, which are prepared from ketones and diallyl carbonate or allyl chloroformate, offer advantages over more common esters in that the ester hydrolysis/decarboxylation step
2: Aldehydes and Ketones
39
1 2 Reagents: i , BuSLi,R R CO; ii,ButLi;iii, RHaIiiv,N2H4,HOAc
Scheme 3
40
General and Synthetic Methods
may be achieved in one pot and in high (77
-
92%) yield with
palladium(11) catalysis47. B-Aldehydo-esters, and in particular, a,@-disubstituted 8-aldehydo esters, can be prepared by formylation of an ester derived silyl ketene acetal with cyanide4 8 . The isomerisation of a variety of primary allylic alcohols by treatment with N-lithio-ethylenediamine or N-lithioaminopropylamine in the amine as solvent have been reported. The reaction is somewhat capricious but in favourable cases very good yields of the expected aldehyde are obtained [equation (9)I 4 9 . The acid-catalysed isomerisation of some y-hydroxyenones to Y-diones has also been reported [equation (10) ] 50 .
-N-t-butylformimidoyl
Some unusual reagents for the acylation of Grignard or other organometallic reagents have been reported. One of these uses the reaction of the heterocumulene reagent (16) with a Grignard reagent to form phosphorane (17) which, on reaction with an aldehyde, gives an enone in moderate yield ( 3 6 - 5 4 % ) [equation (11)] 3 1 . An alternative organometallic acylation procedure also uses heterocumulenes, this time ketene imines which are prepared in situ either by deprotonation/elimination of an gphenylthioimidate or by conjugate addition /elimination as 52 illustrated (Scheme 5) A convenient and high yielding carbonyl homologation involves the reaction of excess sodium phenylselenide with a phenylsulphinyl epoxideS3. The required epoxides are most easily prepared by the reaction of the anion of an a-chloro-sulphoxide with a ketone and ring closure of the resulting chlorohydrin with potassium hydroxide (equation 1 2 ) . Reports on the insertion of acyl carbenes into benzene for the preparation of benzyl ketones54, and the use of B-chloroacrylic acid derivatives for the preparation of substrates for Claisen rearrangement by a route which avoids the 55 use of mercury catalysis in preparing the ally1 vinyl ether , have appeared. Interest in thiocarbonyl compounds continues to grow with a useful review of thionation with Lawesson's reagent56, and the publication of an apparently general route to t h i ~ a l d e h y d e s ~and ~ , thioket~nes~', by base-catalysed
.
decomposition of sulphonium salts [equation (13)I. Thioketones may be hydrolysed to the corresponding ketone with claysupported ferric nitrate in dichloromethane, the best yields
41
2: Aldehydes and Ketones
= C=O
Ph,P=C
P h 3 P d (17)
(1 6 )
+
___c
R'M~X
+
- LPo
R*CHO
RZ
d
J M
I
iii
-gents:
i , R'W,-7doC,MF;ii,R2M,-76.to 2OoC;iii, aq.AcOH
(11)
General and Synthetic Methods
42
TBDMSO
TBDMSO,
2FSiMe3 -
*'co'81
[CO 110 O C
SiMc,
&o
(15)
ti SiMe,
0
II
2: Aldehydes and Ketones
43
being obtained from t h i o b e n ~ o p h e n o n e s. ~ ~ Cyclic Ketones. - Unquestionably the most important preparative method for cyclobutanones is the [2+21 cycloaddition of ketenes to alkenes, and reports of the promotion of the dichloroketene-olefin cycloaddition by ultrasound6' and the reaction of bromomethyl ketene with allenes to form =-me thy1enecyc 1obutanones have been pub 1ished . Ma j or studies of the intramolecular variant of the reaction have been reported by the groups of Snider62 and G h o s e ~ ~Both ~ . research groups found that the reaction is highly variable in yield and that the more reactive ketene iminium group can sometimes advantageously replace the ketene function. The regiochemistry appears to be more strongly affected by the electronics of the double bond than by the connectivity pattern between ketene and olefin, and the products were always found to be cis-fused. Snider's group has also applied the reaction to the synthesis of a number of terpenoid natural products64. An alternative approach to cyclobutanones involves the acidcatalysed ring expansion of B-cyclopropyl enone derivatives [equation (14116 5 . The Pauson-Khand reaction, involving the formation of cyclopentenones by the reaction of an alkene and an alkyne with cobalt carbonyl, has been reviewed in a recent Tetrahedron Symposium in print66. The same issue alsb contains a paper describing the work of the Magnus group using an intramolecular variant of the reaction as a key step in the synthesis of the triquinanes (+I -coriolin [equation (15)1 and (5)-hirsutic acid67 [equation (16)] and a paper on the preparation of angularly 68 fused triquinanes by an intermolecular Pauson-Khand reaction . The iron carbonyl mediated reactions of a,a'-dibromoketones have been reviewed with particular emphasis on their use in natural product synthesis. A wide range of cyclic ketonic products is available from these reactions including cyclopentanone, cyclopentenone, 3-furanone and bicyclo[3,2,1169 octane derivatives . Sulphur chemistry has been exploited in two interesting approaches to cyclopentenones. In one approach treatment of a ketosulphoxide with toluenesulphonic acid leads, via a Pummer reaction intermediate, to a fused a-methylthiocyclopentenone [equation (17)3 70. In the second strategy a Ramberg-Backlund
44
General and Synthetic Methods
reaction is used to ring contract a cyclic sulphone, prepared in several steps from the disulphone (18), to the required cyclopentenone by treating with potassium carbonate in refluxing 71 tetrahydrofuran [equation (18)] . a-Hydroxyalkyl-substituted cyclopentenones may be prepared by the oxidation of triene alcohols with t-butyl hydroperoxide and vanadyl acetoacetonate catalysis [equation (19)] 72. The synthesis of a-methoxycyclopentenones from the readily available furfurols by acid-catalysed hydrolysis to a keto-aldehyde and aldol cyclisation has been reported73. The versatility of the carbene insertion reaction for the preparation of cyclopentanones has been exemplified f o r a sterically constrained example in a key step in a recent synthesis of (+)-pentalenolactone E methyl ester [equation ( 2 0 ) I 74. The Robinson annellation, although a very valuable reaction, suffers from a number of drawbacks, and problems in preparing the 1,5-diketone required for cyclisation are particularly common. It is now found that this Michael step can be achieved more satisfactorily by using the titanium(1V)75 or boron t r i f l ~ o r i d ecatalysed ~~ reaction of a silyl enol either with a vinyl ketone. The diphosphonium salt (19) has been reported as a reagent for the 'transposed Robinson' annellation of activated ketones (Scheme 6 ) 77, as has methodology for six-membered ring annellation to the positions a and 13 to a ketone, a sequence originally developed for the synthesis of ferruginol, but now found to be general providing that the substrate is blocked to aromatisation in the DDQ step (Scheme 7 ) 7 8 . An alternative approach to cyclohexanone annellation uses a crotonic or tiglic 79
acid dianion to introduce the extra carbon atoms (Scheme 8) . 4-Phenylthiocyclohexanones have been prepared by rearrangement of the potassium salts of l-vinyl-2-phenylthiocyclobutanols, yields were highest when the 2 position of the cyclobutanol did not bear any additional substitution [equation (21)l . Interestingly 2-alkylthiocyclohexanones may be obtained by 80
treating vinylcyclobutanones with trimethylsilyl cyanide and zinc iodide (Scheme 9) 81. An improved procedure for the conversion of enol lactones to cyc1i.c enones by treatment with excess lithium dimethyl methylphosphonate rather than the single equivalent normally used has been published [equation ( 2 2 ) 182, as has an adaption of the
45
2: Aldehydes and Ketones
Hoe
R h(OAc)
OMe
0
0
-
+
C02Mc
I
-
QWh
/
ii,iii
RcageMa: i, KZC03, DMF; ii, Tic$., AcOH, CH2C12, H20; iii, DBU
Scheme 6
(20)
C02Me
General and Synthetic Methods
46
J
iii
IV
laoH Reagents
I,
HC02Et, NaH , 1 1 , DDQ , I I I , ButO2CCH2C0CH2CHMe2,NaH, IV ,TsOH, HOAc
Scheme 7
+
R = H or Me
Reagents
I,
H2, Pd,
11,
PAA
Scheme 8
I , I1
0 Reagents
I,
LiXOMe,
11,
HBF,
THF,
III,
TMSCN, Z n s ,
Scheme 9
A . 1v,Bu4NF
2: Aldehydes and Ketones
47
reaction to the conversion of saturated lactones to enonesg3. Cyclohexanones and, although generally in lower yields, cyclopentanones can be prepared by the manganese(II1) acetate promoted oxidative cyclisations of unsaturated keto-esters [equation (23)1 84; the reaction shows considerable synthetic promise because the cyclised carbo-cation intermediate, rather than losing a proton to form a double bond may be intercepted by a nucleophile such as an aromatic ring as in a synthesis of the known ( 5 )-podocarpic acid precursor [equation (24)3 84. Detailed studies of the preparation of cycloctanones by an intramolecular Mukaiyama reaction,85 and of cyclononanones by Wharton fragmentation of the monosulphonates of hexahydroindanediols86 have appeared. Spirocyclic hexan-lI3-diones and octan-1,3-dionesI but not heptan-1,3-dionesI may be prepared by a boron trifluoride mediated epoxide rearrangement which was found to proceed specifically with migration of the acyl group with no observable competition from the alkyl group [equation (25)I 87. Generally the regioslectivity of the lithium halide mediated rearrangement of epoxides such as ( 2 0 ) is determined by electronic factors making (22) the preferred product. However when R is an oxygen functionality a chelation-controlled transition state leads to the formation of (21) as the sole product in high yields [equation (261188 . Wender et al. have applied their double oxy-Cope ring expansion to the preparation of ( - 1 - ( 3 3-cembrene A’’, and Paquette et al. have reported extensive studies on the use of the Claisen rearrangement €or the preparation of cyclo-octanones, and their use of this reaction as a key step in the synthesis of 90 (+)-precapnelladiene . 2
Synthesis of Functionalised Aldehydes and Ketones
Unsaturated Aldehydes and Ketones. - A five-step procedure f o r the synthesis of cyclic 3-nitroalkenones from the corresponding cyclic ketones has been described and provides a convenient route to these useful dienophilesgl. An arsonium salt (231, has been used in a reaction closely analogous to the Wittig reaction for the preparation of enals from aldehydes in high (81-98%) _yieldsg2. A one carbon homologation of enones to aa-unsaturated aldehydes has been
General and Synthetic Methods
48
&- & 0
\
0
(22)
0
0
g:-”
OMe
0
COzMc
C0,Me
a. Po H
H
(26)
HMPA LiBr
R
Me
R
+ Br-
P%AsCH,CHO
(23) OTMS
Reagents
I , Mc2CuLi, 1 1 , TMSCl vii, NaH,viii. HF, McCN
I
III,
0
m q h , i v , Et3NH5v,TBMSCI, imtdazolc, vi,Phf(O)CHLIOMc.
Scheme 10
2: Aldehydes and Ketones
49
disclosed which despite its multi-step nature gives fairly good overall yields (Scheme 10)93. Similar enal products can be obtained from a Friedel-Crafts based homologative 1,3-carbonyl transposition, the best yields being obtained from aryl ketone substrates (Scheme 11)9 4 . The palladium catalysed carbonylative cyclisation of w-iodoalkenes normally gives E - m e t h y l e n e products; however in a methanol-containing reaction mixture the initially formed alkyl palladium species will add a second equivalent of carbon
.
monoxide to give keto-ester products [equation (27)]95 Palladium catalysis is also crucial to the success of enone preparation by the reaction of aromatic acid chlorides with ketenes [equation (28)1 9 6 , and by the reaction of aryl or vinyl halides with allenyl methanols [equation (29)I 97. Tetrakis-(tripheny1phosphine)rhodium hydride has been found to
be an alternative catalyst to acid for the isomerisation of vinyl epoxides to enonesg8. A simple and mild approach to chalcone systems using an aldol approach in a solvent-free system with basic alumina as catalyst has been reported to give high yields and tolerate a wide range of other functionalityg9. a-Diethoxymethylenones have been prepared in generally fairly good yields by acylation of the vinyl-lithium (24) with dimethylamides, although the reaction fails with formamides and acetamides1 0 0 . A study of the conversion of amino acids to chiral a-amino a,B-ynones (25) has been published and the reaction of N-alkylcarbamate-protected amino-acid isoxazolidides with An alkynyl-lithiums proved to be the method of choice"'. alternative, boron-based, method for the preparation of ynones is summarised in Scheme 12. Although the yields were somewhat variable 9-BBN, in a THF-HMPA solvent mixture, seemed to be the hydroborating reagent of choice for this processlo2.
-
a-Substituted Aldehydes and Ketones. The oxidation of silyl enol ethers to a-hydroxyketones with i o d o s ~ b e n z e n e ' ~and ~ of trimethylsilyl dienol ethers with triphenyl phosphite ozonide, followed by reduction with triphenylphosphine has been reportedlo4. Triphenyl phosphite ozonide provides a source of singlet oxygen and the intermediacy of a peroxide such as ( 2 6 ) . . could explain the stereosectivity observed (Scheme 13). The reaction was used as key step in a synthesis of
General and Synthetic Methods
50
Scheme 1 1 t
n- Hex
ri' u +
- n-Hex'4-o (27)
LCOzMe
ArCOC I
R
OH
+
ArI
E'oY7Li ( 2 4)
1-
-R
1
I
/ 2 3 Reagents: i , R BH; i i , R 2
R3 - L i ; i i i , H 0 ,OH2 2
Scheme 12
2: Aldehydes and Ketones
51
( 5 )-oxylubiminlo5. a-Oxidation may also be achieved by the treatment of silyl enol ethers with arylsulphonyl peroxides, particularly 2-nitrophenylsulphonyl peroxide to give the corresponding a-arylsulphonoxy-ketone106 . The a,a'-dihydroxyketone functionality, which occurs in a number of molecules of biological interest, can be prepared by oxidative hydration of propargylic alcohol precursors with iodobenzene di-trifluoroacetate in an aqueous chloroformacetonitrile solvent mixture [equation (30)] lo7. Japanese workers have found that in the presence of small amounts of triethylamine in warm ethanol the thiazolium salt (27) efficien2:ly catalyses the cross benzoin reaction of aliphatic as well as aromatic aldehydes with formaldehyde to give solely the a-hydroxymethyl ketone productlo8. The reaction is not catalysed under similar conditions by cyanide or imidazolium salts. The acylation of a-alkoxylithium reagents, prepared by the transmetallation of the corresponding stannanes,with a tertiary amide, provides an interesting and flexible approach to acyloin products. Intramolecular condensations are also possible allowing the preparation of small and normal ring ketones [equation (31)I 109 . Fetizon and his group have examined the use of 1,4-dioxen-2-yllithium (28) for the preparation of a-hydroxy110 and a,a'-dihydroxyketones'''. The reagent, which is readily generated by the treatment of lf4-dioxene with t-butyllithium at -3OoC, adds to ketones in moderate to good yields. The intermediate hydroxyalkyl dioxenes can then be worked up either reductively to give a-hydroxyketones or oxidatively to give a,a'-dihydroxyketones (Scheme 14) . The reductive addition of alcohols and thiols to nitroalkenes leading to a-alkoxy- and a-alkylthioketones after oxime hydrolysis has been reported (Scheme 15)'12. Chlorination of ketones, along with a number of other functional groups, may be achieved with trichloroisocyanuric acid113 and per-a-chlorinated ketones may be prepared by reaction of manganese(II1) acetate with ketones in the presence of lithium chloride114. a-Bromomethyl ketones have been prepared from a-unsubstituted esters and l i t h i o d i b r ~ m o m e t h a n e ~ ~ ~The . reagent is prepared from dibromomethane and LDA in THF at -90°C, and reacts with
52
General and Synthetic Methods
I
ci
Me
HO O
he
n I
I
Me (26 1
(8 : 1 trans : c i s ) Reagents
I,
(ph0$P=O3; i i , Ph3P
Scheme 13 0
ii
(28)
-IV,V
0 Reagents: i, Bu'Li, -3O.C; v i i , NaBH4
Ho-,+--; 0-
0
1
ivii, iii
0
ii,R1COR2,TkF,-30*C; iii,widic s i l i c a g d ; i v . L i A l ~ ~ v , ~ + :mcpba,MeOH; vi,
Scheme 14
2: Aldehydes and Ketones
53
Reagents: i, %C$, M d m ; ii, lcwlinic a i d
S c h e m e 15
Reagents: i, LiCHBr2; ii, BunLi ;iii,
50’;iv. k , O Scheme 16
Rcagents i, BBr3;ii, pH5 Buffer1 i i i . m c ; iv, H202
Scheme 17
(33) n = O,l,or 2
x
I
CI, &,OAC, w X N
Reagents: i , PhSeX; ii, HZOr pvidim; iii, McOH,NaHCOj; i v , LiCOj. O W
Scheme 1(1
General and Synthetic Methods
54
esters at -9OOC; the dibromo intermediate (29) is then transmetallated with n-butyllithium to give an a-bromoketone enolate which can be worked up with acid to give the a-bromo ketone or with acetic anhydride to an enol acetate (Scheme 16). Haloboration of terminal acetylenes provides an alternative route to a-bromo-aldehydes which is compatible with halide, ester and alkene functionality (Scheme 17) The preparation of a number of a,a-difluorocarbonyl compounds by Claisen rearrangement of fluorinated ally1 vinyl ethers has been described117. The presence of fluorine appears to accelerate the rearrangement which was found to occur readily in refluxing carbon tetrachloride. The reaction of a-diazoketones with selenium reagents has been shown to be a general and high yielding route to a wide variety of a-hetero substituted a , @-unsaturated ketones118. The initial reaction products with benzeneselenyl chloride, bromide, acetate or thiocyanate are the a,a-adducts (30), which on oxidation and selenoxide elimination give the corresponding enones (31). Alternatively if X in (30) is halogen, treatment with methanolic bicarbonate and selenoxide fragmentation gives an a-methoxy enone (32) and with lithium carbonate in DMF gives an a-selenyl enone (33) (Scheme 18).
A recent Tetrahedron Symposium in print
on organo-selenium chemistry includes a useful paper on the preparation and synthetic applications of a-phenylselenyl enones from Liotta's group1", and a second paper on the copper(1) catalysed insertion of diazomethane into acyl selenides to give The introduction of selenomethyl ketones [equation (32)] 120. selenium a to a ketone is also achieved with phenylselenium trichloride in ether at room temperature. The resulting phenyldichloro selenyl derivatives may be reduced to the a-phenylselenylketone with thiourea, or, by hydrolysis to the 121 selenoxide with sodium bicarbonate, converted to the enone . Despite the ease of protodesilation of a-silylaldehydes these compounds may be prepared by epoxide rearrangement with silica gel in ref luxing toluene [equation (33)] 122. Although possibly
of somewhat restricted generality, a-silyl ketones can be prepared by treating the silylenol ethers of a-bromoketones with n-butyllithium [equation (34)1 123 . a-Alkylthio- and arylthio-aldehydes and -ketones may be prepared by treating phenylsulphinyl epoxides with excess sodium t h i ~ l a t e l ~The ~ . reaction allows the completely regiospecific
2: Aldehydes and Ketones
55
preparation of sulphinylated ketones in high yields [equation (35) and ( 3 6 ) ] , and by substituting a secondary amine for the thiolate, a-amino-ketones may be prepared125 [equation ( 3 7 ) I . The preparation of chiral 8-ketosulphoxides by acylation of
S-chiral
aryl alkyl sulphoxides with ester has been described126
Dicarbonyl Compounds. - In the presence of diazobicycloundecene (DBU) or triethylamine, triphenylantimony dibromide oxidises a-hydroxyketones to a-diketones in moderate to almost quantitative yields. The reagent may also be used catalytically provided a bromine donor, such as ethyl 1 ,2-dibromo-2-phenylpropanoate, is also present12'. Arylglyoxals may be obtained directly from acetophenones by treatment with dimethylsulphoxide and aqueous hydrogen bromide in yields ( > 70%) which are comparable with those obtained by selenium dioxide oxidation, but avoiding the problems of toxicity and product purification so frequently encountered with selenium dioxide128 . A series of cyclic lI2-diketones have been prepared via the a-methylthioketones prepared by sulphenylation of the ketone enolate with dimethyl disulphide, by treatment with a mixture of copper(I1) chloride and copper(I1) oxide in aqueous acetone [equation (3811. Both copper salts need to be present in at least stoichiometric quantities for the reaction to occur129 . Wasserman e't al.130 have published details of their studies on the synthesis of a-keto-derivatives of ketones, lactones, esters, lactams and amides, by an approach which involves the cleavage of enamino carbonyl systems by reaction with singlet oxygen [equation (39)l. Several methods for the preparation of the enamino compounds are described with different reagents being preferred for different substrates. Thus, with ketones Bredereck's reagent [BuCOCH(NMe2)2 l was used, but esters and L
lactones required the more reactive (Me2N)3CH, and amides, lactones and the more hindered, less reactive esters required enolate formation and treatment with dimethylformamidedimethyl sulphate. Complementary approaches to mono protected lI3-dicarbonyl systems in which either the starting or the introduced carbonyl is protected, have been reported. Thus ketone formylation with Vilsmeyer's reagent followed by treatment with ethylene glycol and base (Scheme 19) gave materia1.w.ith the starting carbonyl protected131, and thio or seleno acetal protected formyl may be
General and Synthetic Methods
56
-
SiEt,
R
(34)
+
PhSNa
(35)
SPh
Ph SNa
(36)
___Ic
SPh
Ph
,P\I R
- .+ 1 O2
x+w; R
R
Rmgmts: i , p 0 C l 3 , DMF; ii , NaOC%Ct$OH
Scheme 19
(39)
2: Aldehydes and Ketones
57
introduced by the Lewis acid catalysed reaction of a silyl enol ether with a thio or seleno orthoester in a variant of the Mukaiyama reaction [equation (40)I 132 . Japanese workers 133 have reported that dichloro-bis (trifluromethanesulphonato)titanium(IV) efficiently catalyses the acylative hydration of terminal acetylenes [equation (41)]. The conditions are compatible with a variety of other functionality including nitrile and ester, and both aliphatic and aromatic acid anhydrides may be used as the acylating reagent. An approach to 1,4-ketoaldehydes by three-carbon homologation of aliphatic acid chlorides has been reported (Scheme 20) 134. Unsaturated 1,4-diketones can be prepared by treatment of furans with bromine in aqueous acetone135. The reaction gives cis-products which isomerise to trans after longer reaction times, and the procedure has the advantage over alternative methods of being a single step and of working equally well with a-alkoxyalkyl-substituted furans [equation (42)1. Lastly a peroxide fragmentation has been used to prepare the bis-seco-steroid (34) [equation (43)I 136 . 3
Protection and Deprotection of Aldehydes and Ketones
The selective mono-acetalisation of a dicarbonyl compound is frequently a far from trivial synthetic operation, with the simplest and most useful examples often providing the greatest problems. A review of the synthesis (and uses) of the mono-acetals of malonaldehyde, succinaldehyde and gl~taraldehyde'~~ is thus particularly welcome. T.L.C. grade alumina in carbon tetrachloride or toluene has been reported to selectively catalyse the acetalisation of aldehydes with either ethane or propane diols in high yield138. Ketones react only to the extent of a few percent under these conditions. The reaction of aldehydes or ketones with 1,2-bis(trimethylsilyoxy)ethane catalysed by trimethylsilyl triflate is a useful mild method for the preparation of acetals with the advantage of avoiding proton acidic conditions. It has now been reported that these reagents in CH2C12 at -78°C allow the highly selective protection of the less hindered carbonyl of a difunctional molecule, and even allows the protection of an. aB-unsaturated ketone in the presence of a more sterically
58
RCOCl
*agents.
General and Synthetic Methods
I
i, + $ C = C T C L ,
AKC13; t i , NEt 3 in, MO)(,H+;iv,
Scheme 2 0
AcO
‘0
MI*/. NaOY,E$O;v,H30t
2: Aldehydes and Ketones hindered saturated ketone [equation (44)l.
59
It is also
noteworthy that no double bond shift occurs in this reaction13'. The complex PdC12(MeCN)2 catalyses the acetal exchange of dioxolanes with acetone providing a mild deprotection, compatible with other acid-labile protecting groups such as MEM, THP and t-butyldiphenylsilyl. Unfortunately, t-butyldimethylsilyl ethers are cleaved and the reaction fai?s in the presence of unprotected amine fun~tionalityl~~.The possibility of photolytic deprotection of acetals under mild neutral conditions has led to a study of the preparation of ortho-nitrobenzyl acetals which were found to be accesible either from the alcohol and ketone using 2,2-dimethoxypropane as a dehydrating agent or by treating the ketone with 2-nitrobenzyl trimethylsilyl ether with trimethylsilyl triflate catalysis. Deprotection was achieved by photolysis in benzene in 85-95% yield'll. Japanese workers have reported an interesting kinetic resolution of chiral ketones via their (-)(21114g)pentane-2,4-diol acetals, by selective ring-opening of one diastereomer on treatment with tri-iso-butylaluminium, followed by chromatographic separation and mild acid treatment of the products (Scheme 21)142. Lastly in this section dimethylboron bromide has been reported as a useful catalyst of thiol-alcohol exchange for the preparation of aldehyde 2,S-acetals from acetals and also of aldehyde mixed dithioacetals from 0,s- a~etals'~~. 4
Reactions of Aldehydes and Ketones
Reactions of Enolates. - The reaction of ketenes with organolithium reagents provides a convenient route to directed enolates (Scheme 22) '14. With unsymmetrical ketenes the nucleophile was found to approach selectively from the less hindered face of the ketone allowing preparation of silyl enol ethers of defined geometry as well as regiochemistry (Scheme 23)145. Similar results have been reported using the phenolic esters ( 3 5 ) with an extra equivalent of organolithium to generate the required ketene in situ116. In this case the enolates were used in aldol reactions which occurred to give products with high diastereoselectivity. The preparation of linear conjugated dienolates from enones, as opposed to the
General and Synthetic Methods
60
a .5 *Ir
77 *I*
+a n
0
(44)
2.9 *I*
0-OH
bS/*
+
8
20 *I*
Iiii
liii
6 Reagents: i, (2R,4R)-pentawdiol, pyridinium torylate,PhH, (kan-Stark;ii,AI(Bu' 111, 0.1N -HCI, CrCetOnC
Scheme 2 1
Ij
2: Aldehydes and Ketones
Reagents: i,
Z n ; ii, M c L i ; i i i ,
61
TMSCl
Scheme 2 2 Ph
Ph
i , ii /
Et )=c=o Reagents: i, Bu"Li
;
OTMS
Et /7sun
76%
ii, TMSCl
Scheme
23
But'
(35)
87 Reagents: i , KHMDS
;
ii, MeOCOCl
Scheme 2 4
- trans
+glR4
s
R2
0
s -cis Scheme 2 5
13
0
62
General and Synthetic Methods
normally favoured cross-conjugated isomers, can be achieved very cleanly by use of potassium hexamethyldisilazide in a 2:l dirnethylformamide-tetrahydrofuran solvent mixture. The reagent also favours exo over endo enolate formation (Scheme 24)147. The conjugate reduction of enones is a well known route to enolates and the conformational preferences of acyclic enones are now found to determine the geometry of the enolate produced (Scheme 25)148. Since the effects of the substituents R l , R 2 , R 3 and R4 on the s-cis to s-trans ratio are well known, this provides a potentially useful route to enolates of defined geometry. Molecular mechanics studies aimed at predicting the cis-trans enolate ratio which would be expected by kinetic deprotonation of simple ketones14' and on the conformation of enol borates of specified geometry150 have appeared. Both enol silanes151 and tin(I1) e n ~ l a t e s ' ~have ~ been found to react in a Michael sense with nitro-alkenes with high antistereoselectivity, in marked contrast to enamines which gave the syn product15 3 . Glyoxal-derived acyl imines react with enamines to give 6-aminoketones with anti stereoselectivity, and when either or both reactants were chiral high levels of asymmetric induction could be obtained154. The a-selenoalkylation of enol silanes has also been reported 155 . Houk's rule, an electrophilic analogue of Cram's rule which predicts the transition state depicted as(36) to be favoured, has been tested quite extensively by Fleming and co-workers for the methylation and protonation of enolates. Although the diastereoselectivity was frequently rather modest the rule was found to hold in the vast majority of cases156. The use of chiral ketone derivatives €or the enantioselective alkylation of ketones is well established, although new methods Thus both the organotin enamine (37)15' are always welcome. and the secondary enamine ( 3 8 ) 1 5 8 were found to react with a variety of Michael acceptors to give, after hydrolysis, ketones of good optical purity (generally > 9 0 % e.e.). a-Aryl ketones can be prepared by the reaction of arene diazonium salts with silyl enol ethers [equation (45)3 15', or alternatively per-phenylation of a ketone may be achieved by reaction of its enolate with triphenylbismuth carbonate [equation (46)] I6O. An equally suprising enolate reaction is
2: Aldehydes and Ketones
63
Reagents: i, Li, NH3 THF, -78OC; i i , BujSnCl; iii, R X , HMPA, - 5 O O C I
Scheme 26
Y = H,D, MtCO, M t o c O , ~8r , , Reagents: i , HgC$ ; ii , Y +
Schem 27
General and Synthetic Methods
64
that between 1-bromoadamantane and the cobalt(I1) or zinc(I1) salts of 8-diketones to give a-adamantyl-B-diketones161 ; unfortunately the reaction appears to be of limited generality. Tsuji et al. have reported on the palladium catalysed allylation of keto-esters with allylic carbonates162. The alkylation of 8-keto sulphones can prove troublesome due to the high stability, and consequent low reactivity, of the anion and the steric demand of the sulphone group. In view of the fact that it is the desulphonated product that is generally required a one-pot desulphonation alkylation procedure should prove useful, and gives nearly double the yields obtained by a conventional two-pot procedure (Scheme 2 6 ) Although dienolates generally react with electrophiles at the a-position, good y-selectivity may be obtained by the use of tin(11) dienolates, which will also add specifically 1,4 to enones allowing the preparation of 1,7-diketones in high yield [equation ( 4 7 ) I 164. Conia et al. have reported an alternative to their thermal enol ene reaction of acetylenic ketones, which not only has the advantage of milder conditions but also allows additional functionality to be introduced (Scheme 27) Aldol Reactions. - Reports have appeared on the use of dimethylaluminium chloride166, and of a variety of trityl salts167, to catalyse the aldol reaction of silyl enol ethers with aldehydes, moderate to fair diastereoselectivities were observed. Probably the most widely used catalyst for this process is titanium tetrachloride and optimised conditions for the reaction, in particular the use of aqueous stannous chloride in the work-up, have been reported to lead to a dramatic increase in yields168. Lewis acids, such as boron trif luoride, are reported to catalyse the reaction of morpholine enamines with aldehydes to give aldol products with moderate threo ~electivity'~'. erythro-Aldols of high purity were obtained in good (50-87%) yield by the chromium(I1) chloride mediated reaction of an a-bromoketone with an aldehyde. Interestingly the authors suggest that chromium endlates are not involved in the reaction [equation (4811 170
.
Tin(I1) aza enolates have been used to prepare anti-aldol products with high e.e. The aza-enolates, which are prepared by the lithiation and transmetallation of the (-)-norephedrine-
65
2: Aldehydes and Ketones
(39)
Me
)Iyle
Me major
minor
Scheme 2 8
EtCHO 0
(49)
____c
0
OH B
9
ScPh
66
General and Synthetic Methods
derived oxazoline (39), were found to react rapidly with aldehydes at room temperature to give, after hydrolytic work-up, the aldols in >92% e.e. and >86% d.e. (Scheme 28)171. Studies on the use of chiral a-sulphinyl hydrazones €or stereoselective aldol type condensations have been reported; in general the enantioselectivity found was poor, although in one example an e.e. of 88% was observed172.
The aldol type condensation of aldehydes with the a-position of enones can be achieved directly using tetrakis-triphenylphosphine rhodium hydride in the presence of some iso-propanol but no solvent. Yields of 18-79% were obtained [equation (49)] 173. The same transformation can be achieved less directly, but in better yield via a 6-seleno boron enolate although the reaction fails with 6,B-disubstituted enones (Scheme 29)174. The very mild conditions and high diastereoselectivity of the tin mediated crossed aldol reaction, which allow the formation of even a-bromoketone enolates, have been exploited in a convenient synthesis of = - a , O-epoxyaldehydes (Scheme 30) 175. Conjugate Addition Reactions.
-
A review of the very important
organocopper conjugate addition enolate trapping reactions has appeared176. One common enolate trapping reagent in these processes is trimethylsilyl chloride which is now not only found to be compatible with organo-cuprates below - 5 O O C but also to improve and accelerate their 1,4 addition reactions to give better yields of products containing a lower proportion of lf2-addition by-product than are obtained when the chlorosilane is not present in the reaction
With nickel
acetoacetonate catalysis organozinc reagents, which are readily prepared in toluene-THF by sonication of the appropriate organic halide with lithium and a zinc halide, add in a conjugate fashion to enones. The zinc reagents appear to have some advantages over their better known organocopper alternatives, in that they are stable at room temperature, will add well to BBdisubstituted enones, and are relatively inert to saturated ketones as well as much other common f~nctionality'~~. Several publications have appeared describing conjugate addition elimination processes of alkoxy-substituted enones179r180 ( i d Scheme 3 1 ) , and an extensive study of the reactions of organocuprates with a-oxoketene dithioacetals has
67
2: Aldehydes and Ketones TMsg T w & R O
-
H+Y
iii , iv
0
Reagents:
1,
Sn(OTf+, E t N s
O
I
RCHO; ii, Na2C03, MeOH;iil,NaBHq,
Scheme
30
1 Reagents: i , MeZCuLi; ii, R LI
Scheme
31
Reagents: i, PrMgBr; i i , NH4CI; iii, E#j*EtF, MeOH
Scheme
32
IV,
kI04
H
General and Synthetic Methods
68
shown that careful choice of reagent and conditions allows quite high stereoselectivity to be achieved [equation ( 5 0 ) gproducts are normally favoured. The same Michael reaction, this time with alkyl magnesium bromides (but not iodides) provides the first step in a 1,3-carbonyl transposition (Scheme 32)182. The 1,4-addition of e n e t h i ~ l a t e s ' ~to ~ enones has been studied and found to give S-alkylated products with thioketone derived enethiolates, C-alkylated products with thioester derived enethiolates, but interestingly 1,2-addition with thioamide anions. The conjugate addition of nitroalkane anions184 and the phase-transfer catalysed addition of substituted acetonitriles to enones has also been described18'. Heathcock and his group have reported a series of studies on the stereoselectivities of the Michael additions of and ester187 enolates and of enol silanes188 to enones. The product ratios of the enolate additions were rationalised using an open transition state non-chelate) model, and may be summarised as follows: (i) 1,2/1,4 ratios depend on steric demand at the B position. (ii) ester enolates show a greater intrinsic propensity for 1,4 addition than do amide enolates, (iii) 5enolates show a greater preference for 1,2 addition than do
(u.
z-
enolates, (iv) 1,2 additions are more freely reversible with ester than with amide enolates, (v) amide enolates and Z-ester enolates showed anti-selectivity and El-ester enolates synselectivity . In the stannic chloride catalysed reactions of enol silanes with enones a preference for anti-addition is observed which is higher in the case of 2-enol silanes188. Similar results have been reported for the reaction with trityl perchlorate catalysis189. The goal of introducing a nucleophile to an enone 1,4 enantioselectively has been reported by the use of both chiral enones and chiral nucleophiles. The former strategy is exemplified by a synthesis of natural (-)-methyl jasmonate by the addition of an acetate enolate equivalent to a chiral sulphoxide [equation (5111 which gave material of >98% purity"'. Sulphoxide chirality in the nucleophile also allows the achievement of high e.e. (96%), as is shown by the addition of an allylic sulphoxide anion to cyclopentenone in a recent 191 synthesis of ( + ) -hirsutene [equation ( 5 2 ) 1 Halovinyl boranes, which are readily prepared by haloboration
.
2: Aldehydes and Ketones
69
0
Scheme
R=Hor
33
Me 0 -80°C
Mt
0
70
General and Synthetic Methods
of terminal acetylenes, add readily in a conjugate fashion to enones to give 6-halo-yI6-unsaturated ketones in a convenient one pot procedure (Scheme 33) .Ig2 The 2-alkenyl substituted methyl-2-siloxycyclopropanecarboxylates (40) have been used as in situ precursors of the enones (41) which were trapped by a variety of acidic methylene compound in the presence of acid or fluoride. l g 3 Lastly, the subject of conjugate addition reactions cannot be left without mentioning a remarkable sequential triple Michael addition reaction which provides the key step in a recent, and very elegant, formal total synthesis of (5)-seychellene [equation (53)I .Ig4 References 1.
2. 3. 4.
E.J.Corey, E.P.Barrette, and P.A.Magriotis, Tetrahedron Lett., 1985, 26, 5855. J.Morey, A.Dzielenziak, and J.M.Saa, Chem. Lett., 1985, 263. J. Org. Chem., 1985, T.Miyazawa, T.Endo, S. Shiihashi, and M.Okawara, ______ 50, 1332. C.L6pz, A.Gonzslez, F.P.Cossio, and C.Palamo, Synth. Ccarp~lun.,1985, Is, 1197.
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11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.
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2: Aldehydes and Ketones 31.
Y.Tamaru, H.Ochiai, T-Nakamura,K.Tsubaki, and Z-Yoshida,Tetrahedron Lett., 1985, 26, 5559. G.L.Larson, D.Hemandez, I.M.de Lopez-Cepero, and L.E.Torres, J. Org. Chem., 1985, 50, 5260. K.Ditrich and R.W.Hoffmann, Tetrahedron Lett., 1985, 26, 6325. M.W.Rathke and M.A.Nwak, Synth. Comrmn., 1985, 15, 1039. M.W.Rathke and P.J.Cwan, J. Org. Chem., 1985, 50, 2622. R.E.Tirpak, R.S.Olsen, and M.W.Rathke, J. Org. Chem., 1985, 50, 4877. G.Rousseau and L.Blanco, Tetrahedron Lett., 1985, 26, 4195. D.Seyferth and R.C.Hui, J. Org. Chem., 1985, 50, 1985. D.Seyferth and R.C.Hui, J. Amer. Chem. SOC., 1985, 107,4551. L.S.Hegedus and R.J.Perry, J. O r g . Chem., 1985, 50, 4955. K.Ogura, K.Ohtsuki, M.Nakmra, N.Yahata, K.Takahashi, and H.Iida, Tetrahedron Lett., 1985, 26, 2455. K.Takahashi, T.Mikajiri, H.Kurita, K.Ogura, and H.Iida, J. Org. Chem., 1985, 50, 4372. A.I.Meyers, P.D.Edwards, T.R.Bailey, and G.E.Jagdmann, J. Org. Chem., 1985, 50, 1019. M.T.Reetz and S-H.Kyung, Tetrahedron Lett., 1985, 26, 6333. T.Mandai, H.Arase, J.Otera, and M.Kawada, Tetrahedron Lett., 1985, 26, 2677. B.Giese and H.Horler, Tetrahedron, 1985, 41, 4025. J.Tsuji, M.Nisar, and I.Shimizu, J. Org. Chem., 1985, 50, 3416. K.Okano, T.Morimoto, and M.Sekiya, J. Chem. SOC., Chem. Cmun., 1985, 119. H.M.R.Hoffmann, A.Kijver, and D.Pauluth, J. Chem. SOC., Chem. C m . , 1985, 812. J.B.P.A.Wijnberg, G.Jongedijk, and A.de Grmt, J. Org. Chem., 1985, 2, 2650. H. J.Bes&, M.Schn-tidt, and R.Schobert, Angew.Chem., Int. Ed. Engl. , 1985, 24, 405. M.E.Jazouli, S.Masson, and A.Thuillier, J.Chem.Soc. ,
[email protected]., 1985, 1598. T.Satoh, Y.Kaneko, T.Izawa, K.Sakata, and K.Yamakawa, Bull. Chem. S c c . Jpn., 1985, 58, 1983. =.McKervey, D.N.Russel1, and M.F.Twohig, J. Chem. SOC., Chem. Cmun., 1985, 491. G.Buchi and D.E.Voge1, J. Org. Chem., 1985, 50, 4664. M.P.Cava and M.I.Levinson, Tetrahedron, 1985, 41,5061. E.Schaurf~ann and G.R&ter, Tetrahedron Lett., 1985, 26, 5265. E.Schaumann and S.Scheiblich, Tetrahedron Lett., 1985, 26, 5269. S-Chalais,A.Cornelis, P.Laszlo and A.~&hy, Tetrahedron Lett., 1985, 26, 2327. G.Mehta and H.S.P.Rao, Synth. C m . , 1985, 15, 991. M.Bertrand, G.Gi1, A.Junino, and R.Maurin, Tetrahedron, 1985, 41, 2759. B.B.Snider, R.A.H.F.Hui, and Y.S.Kulkami, J. Amer. Chem. Soc., 1985, 107, 2194 and B.B.Snider and R.A.H.F.Hui, J. Org. Chem., 1985, 50, 5167. I.Marko, B.Ronsmans, A-M.Hesbain-Frisque, S.Dumas, and L.Ghosez, J. Amer. Chem. S o c . , 1985, 107, 2192. Y.S.Kulkami and B.B.Snider, J. Org. Chem., 1985, 2, 2809. J.H.Byers and T.A.Spencer, Tetrahedron Lett., 1985, 26, 717. P.L.Pauson, Tetrahedron, 1985, 5, 5855. P.Magnus, C.Exon and P.Albaugh-Robertson, Tetrahedron, 1985, 41, 5861. A.-M.Montai?ia, A.Moyano, M.A.Pericas, and F.Serratosa, Tetrahedron, 1985, 41, 5995. R.Noyori and Y-Hayakawa,Tetrahedron, 1985,g, 5879. H.Ishibashi, M.Okada, H.Kmtsu, and M.Ikeda, Synthesis, 1985, 643. ~
32. 33. 34. 35 36. 37. 38. 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. 65. 66. 67. 68
-
69. 70.
71
General and Synthetic Methods
72
71. 72. 73 * 74. 75. 76. 77.
78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88.
,
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168. 169. 170. 171. 172. 173. 174. 175. 176. 177. 178. 179. 180. 181. 182. 183. 184. 185. 186. 187. 188. 189. 190. 191. 192. 193. 194.
so,
3 Carboxylic Acids and Derivatives BY D. W. KNIGHT 1
Carboxvlic Acids
General Synthesis.- The principle of steric shielding has been applied by a number of research groups'
to the elaboration of
3-substituted carboxylic acids, with enantiomeric enrichments of 94-98%: one of the variants of these asymmetric Michael additions is outlined in Scheme 1. Overall yields are generally excellent, the chiral auxiliary can easily be recovered, and the sense of the chirality in the final product can in principle be varied simply by changing the order of introduction of the two substituents, given that both organo-copper species are available. An entirely different approach to chiral carboxylic acids is based on asymmetric hydroboration using monoisocamphenylborane ( I ~ C B H ~ )For . ~ example, reaction between IpcBH2 and 1-methylcyclopentene (1) (Scheme 2) gives borane (2) which is converted into the dioxaborinate (3) in three steps. Alkylation at boron using LiCH(0Me)SPh and Hg(I1)-induced alkyl migration then leads to the one-carbon homologue (4) which is finally converted into the acid (5) by a two-step oxidation sequence ( H 2 0 2 , aldehyde.
pH 8, then chromic acid)
2 the
corresponding
The length and complexity of this sequence are
somewhat ameliorated by high chemical yields and the excellent optical purity ( > 9 9 % ) of the final product. The radical chain decarboxylation method (see below) has been adapted to a one-carbon homologation procedure for carboxylic acids by trapping the intermediate carbon radicals with electron-deficient olefins, specifically nitro-olefins or vinyl
'.
sulphones (Scheme 3) This 'one down-two up' procedure is efficient enough for it to be considered as an alternative to the Arndt-Eistert method, especially in large-scale operations with acids which do not contain functionalities which are incompatible with a free-radical intermediate. A wide variety of organic halides can be carboxylated electrochemically using a magnesium anode and an atmospheric pressure of C 0 2 : the process overall has a mechanism reminiscent of the carboxylation bf 75
For References see p. 173
General and Synthetic Methods
76
i,
R ~ C U . B F ~B
P~P D
i i , NaOH-H20
HO,C
Scheme 1
(3)
I
Li
Scheme 2
X = NO, or S0,Ph Scheme 3
CI
R,C-X
c?= H2S04
~
R,CC H,CO,H
R
A
-
RC02H
77
3: Carboxylic Acids and Derivatives
4 Grignard reagents, and appears both practical and efficient. Full details have been given for the conversion of organomercurals (RHgX) into acids (RC02H) by palladium-catalysed ~arbonylation.~ The method appears to be quite flexible and is entirely regiospecific, carbonylation only occurring at the site of the C-Hg bond. Highly hindered acids (7) can be obtained readily from 1,l-dichloroethene, a carbonium ion precursor (6; X=Off,Cl) and concentrated sulphuric acid;6 the presence of a Lewis acid such as BF3 is not necessary as previously suggested. By quenching the reaction mixture with an alcohol rather than water, the
corresponding esters can be obtained. Sodium bromite (NaBr02) is a good reagent, in conjuction with sodium bromide and aqueous sodium hydroxide, for effecting haloform degradations I (8)+(9) I of methyl ketones: yields of carboxylic acids are generally equivalent to those obtained using conventional procedures. A full report has been given on the use of the cis-[Ru(bipy)2C12]-Na104 system as an alternative to Ru02-NaI04 for the degradation of aromatic rings to carboxylic acids. Yields are uniformly high within the obvious constraints associated with this method. Zinc iodide catalyses the addition of the tellurium reagent, PhTeSiMe3, to lactones (10) leading to w-telluro-acids (11) 9 after an aqueous work-up: yields are between 79 and 98%. Substantial improvements" have been made to,the tungstate-catalysed epoxidation of a,B-unsaturated acids which should make a wide range of epoxy-acids ( 1 2 ) more readily available.
.
Diacids.- Succinic acids have been obtained from olefins by a procedure amounting to vicinal dicarboxylation (Scheme 4 ) . 11 Thus, conversion of the olefin to the corresponding dichlorocyclobutanone using the well established method of dichloroketene cycloaddition is followed by conversion into the mono-chloro enol acetate (BU"Li-Ac20) and finally cleavage using Ru02-NaI04. Yields of the diacids are good ( 5 2 - 8 3 % overall); as expected the sequence is stereospecific and by using Me CuLi 2 in the enolization step, electrophilic groups such as C02Me can be accommodated without masking.
General and Synthetic Methods
78 Hydroxy-acids.-
Almost optically pure
( 5 )-mandelic
acid (15) has
been obtained by hydroxylation of the dilithio species (13) using Remarkably, the the oxaziridine (14), a useful source of +OH.12 corresponding disodio derivative gives
(R) - (15)
.
(93% e-e.)
An
alternative and at present much more general approach to a-hydroxy-acids involves alkylations of the benzyloxyacetyl-pyrrolidine (16); again the amide is hydrolysed under acidic conditions to give almost optically pure These research workers also mention benzyloxy-acids ( 1 7 ) .l 3 that the corresponding hydroxyacetyl derivative can be used in this type of asymmetric synthesis. By using THF containing a trace of methanol or ethanol rather than pure alcohol as solvent, sodium borohydride reduction of the ketoamides ( 1 8 ) gives, after acid hydrolysis, the a-hydroxy-acids (19) in 55-69% enantiomeric The a-isobutyl-carboxylic acid (20) has been excesses. l4 obtained with 85% optical purity by treatment of methyl phenylglyoxalate with a complex formed from Bu13A1 and the lithium alcoholate of (+)-Darvon alcohol. l 5
The best optical
yields are obtained at high dilution; hopefully more examples of this type will be forthcoming. Racemic 1,2-diols (21) are oxidized exclusively to L-a-hydroxy-acids (22) at 40% conversion upon treatment with a mixed enzyme system consisting of horse liver alcohol dehydrogenase and aldehyde dehydrogenase coimmobilized on polyacrylamide gels. Yields in the range 30-35% of these useful synthetic intermediates have been obtained on a Reaction conditions have been found for an 12-14 mmole scale.16 electrochemical synthesis of benzilic acids ( 2 3 ) by carboxylation of benzophenones; yields are usually good except when nitro, hydroxy, or bromo substituents are present.
17
Both a- and (3-hydroxy-acids can be obtained from 2,3-epoxy-acids (glycidic acids) l o by reactions with lithium organocuprates, the regioselectivity of attack being largely Thus the dependent upon the epoxide stereochemistry.l8
~
trans-epoxides (24) undergo attack predominantly at C-2, as do the corresponding qlycidic esters, whereas surprisingly the cis-epoxides (25) are cleaved largely by attack at C-3 (Scheme 5).
These useful findings will be greatly enhanced if the
glycidic acids can be obtained optically pure.
79
3: Carboxylic Acids and Derivatives
n
PhTeSi Mej _____)
0
ZnIq
0
R3
CO,H
PhTe
( 1 1)
( 10)
- xoAc ( 1 2)
3-
CI
CI Scheme 4
OLi
( 1 3)
OMOM
i , Bu"Li
Ry,;2H
ii, R X
0
iii, H C I - H 2 0
OMOM
Ph
Ph
(16)
R1+p
( 1 7)
i, NoBH4
C0,R2
R'v7H
HO
y.;:H
Ph
HO
R1 = Ph (151, Me, or Bu' (18)
-
( 1 9)
Enzymes
R \ C O H
OH
,R Q$ f
HO-
R = CH,OH, CH2Br, CH,NH,, (21)
(20)
R
CH=CH2,'etc. (22)
(23)
General and Synthetic Methods
80
Full details have been given for the complementary aldol condensations between aliphatic aldehydes and a-silyloxy-ketone enolatesl' or aryl propanoate enolates2' which lead to the erythro-8-hydroxy-acids (26) or the corresponding threo-isomers after appropriate degradations. The idea of steric shielding' has also been applied to the synthesis of chiral B-hydroxy-acids. For example, a Mukaiyama condensation between an 0-silyl enolate [ ( 2 7 ) ;R=H)] and an aldehyde leads almost exclusively to the B-hydroxy-acids (28).21 B y using the =-isomer of this enolate, the enantiomers of acids (28) can be obtained, and by extending the reactions to propanoate enolates (27; R=Me) condensations with aldehydes occur with equally impressive enantioselectivities to give acids (29), which have the reverse sense of chirality at the 8-carbon, relative to the products (28). Complementary to these observations is the finding that the zirconium enolate of the N-propionylpyrrolidine (30) reacts with aldehydes to give entirely the erythro [25,3SI-isomers (31)2 2 after hydrolysis. Racemates of both 8-hydroxy-acids (29) and (31) can be obtained starting from the iron complex [ (v5-C5H5) Fe (CO)(PPh3)COEtl.23 The threo-isomers [+- (29)I are derived from aldehydes and the aluminium enolate of the complex with excellent selectivities, especially in cases involving bulky substituents, whereas the corresponding copper enolate leads to the erythro-isomers [+- (31)= (26)1 . The copper enolate also reacts with symmetrical ketones to give C-3 disubstituted homologues of these hydroxy-acids.24 Dianions (32) derived from cyclohexane-1,2 diones also undergo stereoselective aldol condensations with aldehydes to give mainly the threo-isomers (33), useful as precursors to B-hydroxy-acids (34) following The method has been oxidative ring cleavage and reduction.25 used to prepare ( 5 )-Corynomycolic acid (34; R1=n-C1 lH23
'
R2=n-C lsH31) An approach to saturated 8-hydroxy-acids consists of a 26 three-carbon homologation sequence involving boron chemistry. Thus, sequential hydroboration and Grignard reaction using vinylmagnesium chloride is used to convert a terminal olefin (35) into borate (36). Reaction with C02 results in the migration of one alkyl substituent; final treatment with H202/-OH provides the hydroxy-acids (37) in
z. 80%
yields.
3: Carboxylic Acids and Derivatives
81
OH
R2
R',R2 = a l k y l R e a g e n t s : i, RZZCuLi or RZ2CuCNLiZ
Scheme 5
'2
OH
General and Synthetic Methods
82
OH
+MgCI
(35)
(37)
(36)
Zn Br
+
R' R'CO
Scheme 6
I
LiNEt2, R1R2C0, - 7 8
+ +20
Scheme 7
'C
t
3: Carboxylic Acids and Derivatives
83
A much more useful and general sequence would employ a dialkylborane containing groups of poor migratory aptitude and avoid the wastage of two of the initial olefin units. Keto-acids.-Up to 80% yields of B-keto-acids (39) can be obtained by acylation of the bis-silyl malonate (38) with acyl chlorides in the presence of triethylamine and magnesium chloride or lithium bromide, followed by mild h y d r ~ l y s i s . ~ ~ The method looks easy although all the reactants must be scrupulously dried. MgC12 and Et3N also feature in an alternative B-keto-acid synthesis which Optimization of this involves carboxylation of ketones (40).28 known method has led to a much improved procedure. Unsaturated Acids.- Reformatsky reactions between 4-bromocrotonic acid and aldehydes or ketones give mixtures of the a- and Yproducts (Scheme 6) ,29 in which the kinetic a-products (41) predominate (E. 80% of mixture) when brief reaction periods are used. However, when the reactions are left at reflux for E. l00h in THF, equilibration occurs and only the thermodynamically more stable v-products ( 4 2 ) are isolated, in generally good yields. This method is sufficiently simple and brief that it appears to represent a viable route to both types of acid [(41) and (42)l. The same pattern of reactivity is observed in reactions of the dianion of sorbic acid. At low temperatures (-78 "C), the a-products (43) are obtained in condensations with ketones whereas when the reactions are left at ambient temperature for 24 h, only the w-products (44) are i~olated.~' Yields are variable, mainly due to product instability (Scheme 7 ) . Conditions :or the mono-a-methylation of p,y-unsaturated 31 acids have also been established during a detailed sZitdy. While the selectivity of mono- versus di-methylafion ;-s generally good, it is often higher if the corresponding esters are used. Chiral 3-substituted pentenoic acids (45) can be obtained in good optical yields by enantioselective aza-Claisen rearrangements of 2-allyloxazolinium salts derived from (L)-valinol. The method has previously been used to obtain the corresponding 2-substituted isomers of acids (45) and should prove to be of Enolate Claisen rearrangements of ally1 considerable value. 3 2 fluoroacetates are also diastereoselective, although high stereochemical purities in the final products (46) are usually associated with lower chemical yields. 33 Similar rearrangements
General and Synthetic Methods
84
of propargylic esters (47), crucially using LiN(TMS)2 as base, give virtually pure allenic acids (48) in good yields. 34 A first preparation of cumulene (buta-2,3,4-triene)-carboxylic acids (50) features condensations between the anion (49) and ketones or a-keto-esters, the latter electrophiles leading to cumulene diacids (Scheme 8 ) . 35 Thermolysis of these acids can be used to prepare [4]radialenes. unsaturated acylsilanes have been found to be powerful electrophiles in conjugate allylations with allylsilanes; subsequent oxidation leads to carboxylic acids in good yields (Scheme 9 ) .36 The method is remarkably tolerant of steric constraints, in contrast to related anionic Michael additions to enone systems, and should be widely applicable. A detailed study of conditions €or effecting Ramberg-Bzcklund rearrangements of a-halogenosulphonecarboxylic acids has revealed that when KOBut in DMSO is used as base, essentially pure ( E )-unsaturated acids (51) are produced in excellent yields.37 A lengthier Wittig-Horner sequence can also be used to obtain both ( E ) - and (g)-isomers of acids (51) after chromatographic separation of the intermediate diastereoisomeric 6-hydroxyphosphine oxides (as the corresponding lactones).38 Organocuprates, R2CuLi, add regioselectively to the readily available benzyne (52): subsequent trapping by an electrophile, such as ally1 bromide or an acid chloride, and hydrolysis of the oxazoline function leads to benzoic acids ( 5 3 ) in good yields.39 Such additions are in complete contrast to the behaviour of alkyl-lithium reagents which react with benzyne (52) in the reverse sense, adding an alkyl group exclusively to the ortho-position. One limitation of these methods is the rather brutal conditions (4.5M HC1, 100 "C, 16 h) required to
z.
hydrolyse the oxazoline group. The anti-inflammatory activities of 2-arylpropanoic acids (54) continue to stimulate new methods for their preparation. Hydrocyanation of styrenes and other vinylarenes can be catalysed by nickel species to provide an effective route to the nitriles corresponding to acids (54).40 Enantiomers of acids (54) have been obtained by Friedel-Crafts alkylations of arenes using lactic acid derivatives (e.g . methyl (S) -2-mesyloxypropanoate) as electrophiles.41 Unusually, very little racemization occurs but a drawback is the lack of regioselectivity of alkylation when mono-alkylbenzenes are used as substrates. 2-Aryl derivatives of
3: Carboxylic Acids and Derivatives
85
R’
H i, R ~ R ~ C O
phYc
ii, TsCL - Et3N
>
CAR2
phYc4
iii, KOH - 18-C- 6
Me0,C
HO,C
R ’ = P h or
(49)
B u t ; R 2 = P h or CO,H (50)
Scheme 8
Scheme 9
* ( 5 11
R2
02H
R’
Et0,C-C02B~‘
(52)
(53)
-
,*:*R 2
----)
R’
Et 02CAC0,H
(54)
R*
R’
General and Synthetic Methods
86
acids (54), as well as diarylacetic acids, can be obtained by carbonylation of the corresponding alcohols under modified Koch-Haaf conditions using 97% H2S04 supersaturated with carbon monoxide, generated by the addition of formic acid.42 Anhydrides.
-
Symmetrical acyclic anhydrides can be easily
obtained from the corresponding carboxylic acids in 59-80% yields by treatment with tetracyanoethylene (TCNE) and a base such as pyridine in benzene.43 2-Methylbenzoic acids [e.g. (55)] are regioselectively nitrated by fuming nitric acid in acetic anhydride; subsequent Nef reaction and hydrolysis of the intermediate arylnitromethanes (56; R',
2 R =Me, C1, or H) leads
to phthalic anhydrides (57) and so provides one solution to the
problem of regioselective oxidation of methyl groups in The 3-nitro-group in polymethylbenzoic acids.44 3,5-dinitrophthalic anhydrides and phthalimides can be regioselectively displaced by a variety of soft nucleophiles leading to a wide range of 3-substituted-5-nitrophthalic anhydrides.45 Carboxylic Acid Protection. - Carboxylic acids have been converted into their trimethylsilyl esters by heating with trimethylsilyl trichloroacetate, C13CC02SiMe3, in the presence of A s the other reaction ca. 2 mol % of K2C03 and 18-crown-6. 4 6 products are chloroform and carbon dioxide, this 'salt-free' method could be extremely useful in some circumstances. Rather more stable t-butyldimethylsilyl esters can be prepared simply by treating a carboxylic acid with t-butyldimethylsilyl chloride in dichloromethane or benzene and using DBU as base.
47
Catechol boron halides have been found to be useful for the cleavage of a variety of alcohol, acid, and amino protecting Thus, groups such as OMEM, t-butyl and 3-benzyloxycarbonyl. 48
€or example, the malonate diester (58) can be converted into the half-ester (59) in quantitative yield. Of further interest is the observation that these boron reagents do not readily attack O-t-butyldimethylsilyl
functions used to protect alcohols.
Upon treatment with potassium carbonate in DMF, the 2-chloroethyl ester of acetoacetic acid is smoothly converted This unusual transformation can into the ketene acetal (60).49 also be applied to the corresponding malonate esters and could provide a basis for the protection of ester groups in
87
3: Carboxylic Acids and Derivatives 8-keto-esters and malonates.
Ketene acetals (61) undergo
cyclopropanation reactions with ethyl diazoacetate to provide the rather sensitive cyclopropanes (62) which on heating with methanol afford the differentially protected succinic acid derivatives (63), 5 0 which could find a number of synthetic applications. The p-methoxyphenyl group has recently been found suitable for alcohol protection, as the resulting ethers are stable both to acidic and basic conditions and can be cleaved by brief treatment with ceric ammonium nitrate.
The same principle can be applied
to carboxylic acid protection.51
Thus, the rather stable benzyl
(64) and phenyl (65) esters can be cleaved as indicated by oxidatioii with DDQ or cerium(1V)(;it pH 3) respectively.
A
recent total synthesis of (+)-Antimycin-A3 features the use of a 4,5-diphenyloxazole substituent as a masked carboxylic acid group 52 which is released by dye-sensitized photo-oxidation. Further carboxylic acid protection methodology is included in the later section on a-amino-acid protection. Decarboxylation.
-
Barton's group has further extended their
studies of radical-based decarboxylations in a number of ways (Scheme 1 0 ) .
One-carbon degradations of acids, RC02H, to
alkanes, RH, can be simply achieved by conversion into the thiohydroxamic esters derived from N-hydroxypyridine-2-thione followed by heating in benzene or toluene in the presence of t-butyl t h i 0 1 . ~ ~ This avoids the use of more expensive tin hydrides which produce organostannane by-products which can be difficult to remove.
By changing the traps available to the
intermediate alkyl radicals, R* , the final products can also be 2-substituted thiopyridines,53 alkyl halides,53r54 hydroperoxides,53 or alcohols.5 5 These methods, together with others which are doubtless being developed, will certainly find considerable utility in a wide area of synthesis especially now that many of the experimental details have been simplified and applied to a good range of substrates. Good yields of long-chain alkanes, alkenes, alkynes, ketones, alkyl bromides, and carboxylic acids can be obtained by another radical-based process, that of photolysis of unsymmetrical diacyl peroxides at
-78 " C .
This method is complementary to mixed Kolbe
electrolysis, especially as it can often be successful when the latter method fails or gives low yields.56
.
- t
88
General and Synthetic Methods
Unhindered aliphatic carboxylic acids such as those found in steroidal side-chains can be degraded by three carbons by a four-step procedure (Scheme ll), via dihydro-oxazole formation, dehydrogenation, and ozonolysis ,' w h i c h should be applicable to a good range of (saturated) substrates. a-Keto-acids (66) can be decarboxylated to give the imines (67) simply by heating (up to 80 " C ) with a primary amine, in a process which is reminiscent of enzymatic degradations of these acids. 58 Potentially as useful is the direct conversion of a-keto-acids to thioamides (68) again with the loss of one carbon, which occurs when the reactions are carried out in the presence of sulphur. An alternative method for the direct decarboxylation of malonic acid esters or 8-keto-esters consists of thermolysis (170-200 " C ) with stearic acid ( 1 equivalent) containing E. 3 mol% of tetra-n-butylphosphonium bromide. 5 9 Certainly the work-ups of these reactions should be much easier than is the case with the existing methods employing DMSO, D M F , or HMPA as solvents. Ally1 8-keto-esters can be readily decarboxylated at room temperature by treatment with palladium acetate (2.5 mol%) and Ph3 P (5 mol%) in THF containing an ammonium formate.60 The mildness of this procedure (even THP ethers are unaffected) suggest that in some cases, it would be worth starting a sequence with ally1 acetoacetate and thus avoid wet basic conditions or high temperatures usually needed in a final decarboxylation step. A similar reaction with a-disubstituted-8-keto-esters in the presence of Bu3SnH leads to the tin carboxylates ( 6 9 ) which on thermolysis (100-130 "C) decarboxylate to give tin enolates.61 Overall, this represents a useful regiospecific route to such enolates. 2
Carboxylic Acid Esters
Esterification. - A full account has been given of the preparation of esters from acids by formation of mixed anhydrides 10 mol% of DMAP using a chloroformate in the presence of which catalyses the degradation of the anhydrides to the esters Although ineffective with sterically and carbon dioxide.6 2
z.
hindered acids, the method does have the distinct advantages of directness and of not requiring a separate coupling reagent such as DCC. When the method is applied to half-esters of malonic acid, the intermediate anhydrides decarboxylate spontaneously
89
3: Carboxylic Acids and Derivatives
MeojN2CHC02Et,
MeOH
“ . O d R Me0
A
C0,Et
OMe
Rxe C0,Et
Me0
0 Me
R
OMe
(64) R-H
- RCO,H
(65) R-OH
Scheme 10
I
I,
PhSe02H, py
ii, CI3CCOCL
-
-
03 m
Scheme 11
90
General and Synthetic Methods
resulting in an extremely rapid, simple, and high-yielding ( > 9 5 % ) route to mixed esters of malonic acid.63 Full details have been given for the now well established DCC-DMAP method for the direct esterification of acids which can be applied successfully to hindered substrates.64
A polymer-bound 4-aminopyridine has been found to give slightly lower yields in such reactions but does
offer the advantages of ease of removal and recovery.65 Alcohols can be esterified by potassium carboxylates by heating them together with a mixture of triphenylphosphine and carbon tetrachloride, a reagent mixture more noted for its ability to convert alcohols into alkyl chlorides, which apparently are not intermediates in this reaction.6 6 Potassium carboxylates of aromtic acids are alkylated very efficiently under simple solid-liquid phase-transfer conditions by a variety This appears to be the method of choice for
of alkyl halides.67
this particular transformation.
Ammonium carboxylates have also
been alkylated but under electrochemical conditions using a much improved procedure which features the in situ generation of the carboxylate salts.6 8
Caesium carboxylates of !-protected
a-amino acids couple smoothly with (L)-a-halogeno-acids [derived from (L)-a-amino-acids by diazotization and trapping by HX] to give depsipeptides (70) containing a (D)-a-hydroxy-acid residue y the expected Walden in~ersion.~’ which arises & A variety of diacids are converted into their monomethyl esters in essentially quantitative yields using diazomethane if 70 they are first adsorbed onto alumina. A seemingly general route to enol esters (73) of unsaturated acids (71) is by ruthenium(I1)-catalysed additions of the latter to terminal acetylenes (72).71 Yields are usually excellent.
-
A general method for the direct homologation The of esters by one carbon is outlined in Scheme 11. 72 procedure is very rapid and efficient (53-75% yields) and can be General Synthesis.
applied to a wide variety of esters including conjugated alkenoates and alkynoates both of which are converted into the corresponding B , Y -unsaturated esters in 50-60% yields. Asymmetric centres a- to the starting ester group are not scrambled: one drawback, however, is the amount of BunLi required ( 7 mmol per mmol of ester), which will probably preclude applications to large-scale work.
3: Carboxylic Acids and Derivatives
91
A conformational model with predictive value has been proposed to explain the considerable preference for formation of the anti-products (74) in alkylations of the corresponding lithium enolates derived from Y -oxa-esters with methyl iodide. 73 A series of relatively simple aldehydes have been oxidized directly to esters by electrolysis in the presence of an alcohol and KBr or KI.74
Alternatively dimethyl acetals, RCH(0Me)
can
be oxidized to esters, RC02Me, by acetal exchange with t-butyl trimethylsilyl peroxide, ButOOSiMej, catalysed by trityl perchlorate followed by decomposition of the resulting peroxides in hot methanol containing piperidine. 7 5 This efficient method should be more widely applicable than related procedures which employ reagents such as peracetic acid or ozone. The selective reduction of a,@-unsaturated esters to saturated esters [ ( 7 5 ) + (7611 in the presence of isolated olefins using Et3 SiH and Wilkinson’s catalyst requires significantly less harsh 76 conditions (20 “C; C6H6) than have previously been reported. The reagent mixture can also reduce conjugated dienoates to 8 , v unsaturated esters. Nitro groups can assist in the introduction of alkyl groups into esters in two ways, either by conjugate addition of a nitro-alkane to an acrylate [ (77) ir (78)] or by the addition of methyl nitroacetate to an enone system [(79) i, (80)l.
In both
examples, 77 the nitro-groups are replaced by hydrogen in the final step by treatment with tri-n-butyltin hydride. Radicals generated by the denitration of tertiary nitro-compounds using this reagent add to acrylates to give highly substituted esters
[cf. (78)] containing yields. 78
a quaternary carbon, directly in 36-62%
A feature of this latter method is that various
functional groups such as ester, nitrile, ketone, and acetate can be included in the starting nitro-compound.
8-Carbonyl radicals
generated from solvomercuration of suitable cyclopropanes also add to acrylates to provide yet another entry into this type of Anion-mediated Michael additions of dithioacetals ester. 7 9 derived from benzaldehyde to alkenoates, in the presence of chiral complexing agents, afford esters (81) in up to 67% enantiomeric excess. 8o
General and Synthetic Methods
92
0Li RCO,Et
L iCHBr2 -go+ 0 "C
R%Li
_d
------j
n
R-=- -
Br
OLi
EtOH HC I
R-COzEt
Li
Scheme 11
'. O
{
L C0,Et
R
'
CO E t W
-
CO E t
'
?I-
I
Me
(77)
(76 1
(75)
(74)
(78)
R (81)
(80)
( 79)
(82)
h
t
R
CozE'
(83)
3: Carboxylic Acids and Derivatives
93
a-Substituted acetoacetates (82) can be deacetylated to give esters (83) in 60-79% yield simply by heating with 1 ,2-diaminobenzene (1,2-phenylenediamine) .81 A range of mixed diesters of diacids are thus available simply by incorporation of a further ester group into the ‘ R ’ group. Diesters. - Further developments in the area of enantioselective ester hydrolysis using enzymes as catalysts have been reported in A simple method for the immobilization of the past year. porcine liver esterase (PLE) has been described.82 Remarkably, 60 mg of the immobilized enzyme is capable of hydrolysing 0.5 mol (92 g ) of cis-1,4-diacetoxycyclopent-2-ene in 14 h to give a 59% isolated yield (42 g ) of optically pure cyclopentenyl acetate (84). (The 60 mg of enzyme can be recovered and re-used!) . This work will undoubtedly herald the advent of the routine use of such enzymes as ‘off the shelf‘ reagents for the preparation of large quantities of chiral starting materials. Further applications of soluble PLE are in the enantioselective preparations of half-esters (85; X=CH2, 0, or S)83 and (86)84 from the corresponding diesters. In both cases, a remarkable reversal of enantioselectivity is observed: when X = CH2 in (85), the product is as shown, but when X = 0 or S, the enantiomer of (85) is obtained (e.e.s 34-46%) , while (5)-(86) (shown) is only produced when n=2, 3, or 4. Longer chain lengths result in hydrolysis of the other prochiral ester group to give ( R ) - (86)(e.e.s 55-90%) . Relative rates of PLE-catalysed hydrolyses of mixtures of two esters have been measured to provide some useful data for planning extensions of this work. 85 PLE is also capable of catalysing the selective hydrolysis of the
l-ester group in dimethyl malate to give the half-ester (87).86 The hydrolysis is, however, not enantioselective. An alternative strategy for the preparation of chiral half-esters [e.g. (8911 is by the addition of methanol, catalysed by a cinchona a l k a l ~ i d . ~ ’ Optical yields can be as high as 82%. The carbonyl groups in 3-methylglutaric acid can also be distinguished by treatment with (~)-4-methoxycarbonyl-ll3-thiazolidine-2-thione, derived from (&I -cysteine.88 Diethyl dialkylmalonates can be easily obtained by PTC alkylations of diethyl malonate but only with reactive electrophiles such as allylic, propargylic, or benzylic halides. 89 By using chiral phosphine-pal ladium ( 0 ) complexes ,
General and Synthetic Methods
94
(85)
M e0,C
/YCoZH H02C
OH
C02Me
0
C02Me C '.O2Mes
Pd(0)
C02Me
R +, RZ
%R
~
y
C02Me
C
0
C02Me
C02 Me
NC
(93)
(94)
2
(95)
M
e
3: Carboxylic Acids and Derivatives
95
optical yields of up to 8 6 % can be achieved in allylations of dimethyl sodiomalonate by substituted allylic acetates.
These
detailed studies could well lead to more developments along these lines. Displacement of one acetoxy function from geminal diacetates ( 9 0 ) can also be achieved using this type of chemistry. The initial products ( 9 1 ) readily eliminate the Geminal elements of acetic acid to give dienes ( 9 2 ) when R 2 = H . dinitroalkanes ( 9 3 ) undergo a similar type of displacement reaction when treated with potassiomalonate or related soft nucleophiles derived from 8-keto-esters or a-diketones.9 2 rather crowded products ( 9 4 )
The
( 5 8 - 9 0 % yields) probably arise
an electron-transfer chain mechanism and can also be obtained, but usually in lower yields, by oxidative coupling of the salts of mono-nitroparaffins with the same type of enolate. Two new catalyst systems, KOBut adsorbed on xonotlite and KF on alumina, can be used to trigger Michael reactions between 8-dicarbonyls such as diethyl malonate and the reactive enones acrolein and methyl vinyl ketonemg3 Reaction times can be lengthy but yields are good ( 6 2 - 1 0 0 % ) under the mild conditions used (THF; 0-20°C). Phase-transfer catalysis has been used to effect a one-pot Michael addition-alkylation sequence leading to malonates ( 9 5 ; R=alkyl) in which the initial step is conjugate addition of cyanide to benzylidenemalonate.94 A survey of conjugate additions of various allylic nucleophiles ( 9 7 ) to ethylidenemalonate ( 9 6 ) has revealed that the highest selectivity, in favour of the threo-adduct ( 9 8 ) ( 9 : l ) , is obtained using either an organoborane (M = 9-BBN) or a titanium species [M=Ti(OPri)3]. 9 5 Claisen rearrangements of the adducts of allylic alcohols and 3,3-diethoxyacrylate An advantage of this method over lead to the malonates ( 9 9 ) . 9 6 others based on nucleophilic attack of malonates onto allylic systems (uncatalysed or Pd(0)-catalysed
e.) is the
unambiguous
regioselectivity, although the conditions required ( 1 5 0 - 1 8 0 "C, 1 6 h, ArC02H catalyst) will preclude the use of some substrates. A simple procedure for the C-acylation of malonates by acid chlorides has been developed which relies upon the ability of magnesium chloride to enhance the acidity of the diester.9 7 Yields of the products ( 1 0 0 ) are > 8 5 % . A detailed account has been given of the preparation of the chiral succinate ( 1 0 1 ) by enolization and alkylation of
( 2 )-diethy1 malate. 9 8
Various optically active 3,3-dialkyl
96
General and Synthetic Methods
homologues can be obtained by repetition of the sequence.
A
report of brief enantioselective syntheses of both isomers of acetoxycitramalate (102) using a chiral 1,3-oxathiane derived from pulegone suggests that this method could be widely 99 applicable to this structural type. Monosubstituted succinates can be prepared by the addition of radicals to diethyl fumarate; some generalizations on the stereoselectivities of such processes have been described.l o o When thiophenol is added to di-isopropyl maleate in the presence of a trace of the alkaloid cinchonine, the useful (1031, with up to 81% e.e., can be obtained.'" (S)-thiosuccinate
In general, alkylidenesuccinates (104) cannot be obtained satisfactorily using the Stobbe condensation because of the ease with which the desired product isomerizes under the reaction conditions. An alternative route to these succinates (104) also begins with an aliphatic aldehyde and involves base-catalysed condensation with methyl acrylate, carbonate formation, and Yields are good in the few Pd-catalysed carbonylation.lo2 examples quoted. Substituted glutarates (106; R3=H or Me) are available from condensations beween ketene acetals (105) and acryloyl chloride in 56-76% yields;
methacryloyl and crotonyl chlorides react
similarly to give the 4- and 3-methyl homologues of diesters (106) respectively. The principle of steric shielding" 99 has been used in enantioselective Michael reactions which proceed in the reverse sense to those described above (Scheme 1). Thus, the enolate (107) derived from (+)-pulegone condenses with (E)-methyl crotonate to give, very largely, the (2Rr3S)-isorner (108) . A useful rationalization of this observation is given which will assist in the development of this idea. Hydroxy-esters. - Once again, most contributions to this area involve the synthesis of chiral hydroxy-esters. Almost complete enantioselectivity is achieved in the reduction of a-keto-esters to a-hydroxy-esters using Alpine-Borane (13-(3-pinanyl)-g-BBN) derived from either ( + ) - or (-)-a-pinene when the reactions are carried out at relatively high concentrations (>2M). Many other types of prochiral ketones are also reduced with excellent asymmetric inductions although 6-keto-esters may not be particularly suitable substrates as ethyl acetoacetate is reduced to ethyl 3-hydroxybutanoate with an enantiomeric excess of only
3: Carboxylic Acids and Derivatives
COzEt
R C0,Et
(103)
OTMS
97
98
General and Synthetic Methods
55%.
a-Keto-esters can also be reduced asymmetrically using
di-isobutylaluminium hydride modified by the addition of SnC12 and a chiral pyrrolidine, although in these examples, optical yields are variable.
Asymmetric induction has also been
achieved in reactions between achiral reagents and a-keto-esters derived from a chiral alcohol.
For example, some simple
a-keto-esters obtained from chromium complexes of chiral secondary benzyl alcohols can be reduced with up to 90% e.e., lo7 whereas tetra-alkylaluminates (LiAlR ) transfer an alkyl group to 4 (-)-menthy1 phenylglyoxylate to give the tertiary alcohols (109) in ca. 70% e.e. A combination of (-)-menthy1 pyruvate and a Lewis acid (RA1C12 or TiC14) modified by the addition of (-)-menthol reacts with various phenols to give hydroxy-esters (110), in some cases with remarkably high stereoselectivities (up to 96%). log Extremely high selectivities have also been obtained in oxidations of sterically shielded enolates [cf.structure (107) and Scheme 11 by MoOPH
110
or Pb(OAc)4111 (of the derived 0-silyl-enolates), leading to a-hydroxy- and a-acetoxy-esters respectively. Both methods should be widely applicable. A generally efficient route to the a,B-dialkoxy-esters (111)
-
is by condensations between carbonyls
(R1R2co)and of methyl a-alkoxyacetates, catalysed by zinc Unfortunately little or no stereoselectivity is
0-silyl-enolates
chloride.
observed (see also ref.115) . Condensations of the dithiolane or dithiane enolates (112) with a-methyl-aldehydes lead to a-hydroxy-esters ( 1 1 3 ) (major isomer) with good to excellent stereoselectivities. These initial, rather sensitive adducts can be smoothly desulphurized using NiC12-NaBH4-H2 to give esters (114) in high yields. Heathcock's group has amply demonstrated the potential of the stereoselective aldol-type condensations which they have developed in syntheses of the C-1 to C-7 synthon (115) of Erythronolide and of the branched sugar Cladinose (116) T h e latter work features a highly stereoselective route to
trihydroxy-ester derivatives (117) by condensations between 0-si1yl -en01ates of a-methoxypropanoatesl
-
( 5 )-2-benzyloxypropanol
and
.
A detailed recipe has been given for the reduction'of ethyl acetoacetate to ethyl-(S)-3-hydroxybutanoate (118) by Baker's yeast. Various forms of immobilized Baker's yeast can also be used,ll7 resulting in improved optical yields in some cases.
3: Carboxylic Acids and Derivatives
n
99
n CO,E t
C0,Et OH
-
Rj r C 0 , E t OH
Bz? OMe d
AoAOH
C
0
,
R
OH (117)
OH
“FO2
H&;2Et
N3
0
(1 2 0 )
(119)
RH$C ,O
Me
TBDMSO+
-.H
OH
C02Me
100
General and Synthetic Methods
Dense polyurethane matrices are particularly useful in this respect and furthermore often give rise to the opposite enantiomer to that obtained using untreated yeast. Normal Baker's yeast can also be used to prepare cyclic B-hydroxy-esters [e.g. (119)1 and the 4-azido-esters (120) in high optical yields from the corresponding B-keto-esters; the latter examples are in direct contrast to the corresponding 4-halogeno-derivatives which are reduced largely to the opposite enantiomers. Purely chemical routes to a variety of chiral B-hydroxy-esters include reductions of 8-keto-esters by LiBH 4 modified by the addition of a cysteine derivative'120 and kinetic resolutions of a-(hydroxyalky1)acrylates by asymmetric hydrogenation using biphosphine-rhodium catalysts.12' Similar products (121) to those obtained in this latter approach can also be prepared by Mukaiyama-type aldol condensations using an ephedrine derivative to supply the asymmetry.1 2 2 A similar condensation of 2-O-benzyl-3-0-(t-butyldimethylsilyl)-glyceraldehyde derived from mannitol and the 2-silyl-enolate of methyl acetate leads almost exclusively to trihydroxy-ester (122)123 whereas B , y dihydroxy-esters, also largely or exclusively as the syn-isomers, result from condensations of sulphur-substituted silyl-enolates and a-alkoxy-aldehydes.124 An alternative but related route to the (achiral) anti-isomers (121) involves condensations of aldehydes and ketones, activated by a Lewis acid, with 'enolates' of transition metal-carbene complexes.1 2 5 It may be that the initial products [e.g. (123)l will be particularly useful in some circumstances as the ester function is present in a 'protected' form. The diazo-esters (124), prepared by condensations between aldehydes or ketones and ethyl (lithio)diazoacetate, can be converted into B-hydroxy-esters (125) by hydrogenation using 5% This simple homologation method is thus Pd/C in methanol.126 clearly limited to substrates which do not contain exposed olefinic bonds or sulphur functions. Similar homologations can also be carried out using anionic chain reactions induced by electroreduction of an a-halogeno-ester in the presence of an aldehyde.12' Two new methods €or the conversion of a,$-unsaturated esters into a-substituted-B-hydroxy-esters have been developed, both of
which can be used to prepare both possible diastereoisomers.
3: Carboxylic Acids and Derivatives
101
One method is based on conjugate additions of PhMe2Si groups to enoates (126; R2+H) leading largely to the e - a d d u c t s (127) which can be converted (HBF4 then MCPBA) into the corresponding 8-hydroxy-esters (128; R3=H) with the retention of stereochemistry.128 Alternatively, additions of the same nucleophile to simpler enoates (126; R2#H) followed by alkylation (by R2X) of the resulting enolates gives almost entirely anti-isomers of esters (127), precursors of the The second approach involves anti-hydroxy-esters (130; R3=H) . oxymercuration of esters (126) to give methoxy-esters (128a) which undergo demercuration by propane-1,3-dithiol with retention, or by NaBHq with inversion, to give mainly esters 3 129 ( 1 2 8 ; R =Me) or (128b; R3=Me) respectively. Dianionic Claisen rearrangements of 8-hydroxy-esters (129) give largely the substituted esters ( 1 3 0 1 , although only in moderate yields (z.4 0 % ) . Despite this, the method is brief and should find many applications, as such highly functionalized esters can be used as precursors to a wide variety of compounds. The homoenolate of methyl propanoate can be obtained by treatment of the readily available tin derivative ( 1 3 1 ) with TiC14; subsequent condensations with aldehydes or ketones lead to y-hydroxy-esters (132) (isolated as the derived butyrolactones The corresponding zinc homoenolate has also when Rl, R2#Ar) .I3' been generated, but in a rather different way, ring opening of a mixed acetal of cyclopropanone using a zinc halide catalyst.1 3 2 High yields of r-hydroxy-esters (132) are produced following 'homo-Reformatsky' condensations of this species with aldehydes or ketones (see also Ref. 1 5 7 ) . High levels of [1,3]-stereocontrol have been observed in hydrogenations of homoallylic alcohols [e.g. ( 1 3 3 ) -s (134)l using various rhodium and iridium catalysts.13rJudging from the examples quoted, this method will be applicable to a wide range of important structural types. Keto-esters. - Wasserman and have given full details of their method for the conversion of esters into a-keto-esters ( 1 3 6 ) by dye-sensitized photo-oxygenation of enamino-esters (135) which can be easily obtained from the parent esters using a variety of methods. Overall yields are excellent in this relatively mild procedure which can also be used to obtain a-keto derivatives of lactones, lactams, ketones, and amides. The
General and Synthetic Methods
102
C02E1
-
R'
C0,Et
-
SiMe2Ph
dTco2Me
C02Me R2
N2
J (1280)
( 1 28b)
R
Uo
(128)
OH L
C
d (129)
(130)
(131)
(132)
O Me
3: Carboxylic Acids and Derivatives
103
unsaturated keto-esters (137) are reduced regioselectivity to This observation has esters or other 1,4-dihydropyridines.135 preparative significance as other more conventional reductants show entirely different selectivities.
A general route to a,@-diketo-esters (141) consists of condensations between acyl chlorides and the oxalic acid derivative (139).136 The intermediate, partly protected adducts (140) can be isolated if required: the bis-acetal (139) is thus another equivalent of the unknown acyl anion (142). A practical electrochemical procedure for the preparation of the acetal (143), a masked form of unstable methyl formylacetate, 137 from methyl acrylate has been reported. Various homologues having a substituent at C-2 can also be obtained in this way. Disubstituted homologues of formylacetate itself can be prepared in moderate yields
by condensations of ketene silyl acetals
(144) with g-t-butylformimidoyl cyanide (ButN=CHCN).13* Acetals (144) can also be used as precursors to B-keto-esters in general by alkylations with dithiane-derived salts (145).
Yields of
the protected 8-keto-esters (146) are in the range 22-94%. A classical method for the elaboration of acetoacetates is by the addition of alcohols to diketene.
This unpleasant reagent can
be avoided by using the inexpensive dioxinone (147) (diketene-acetone adduct) which on heating above E. 120 "C decomposes to acetone and acetylketene (148); in situ trapping by an alcohol affords acetoacetates (149) in excellent yields.
140
6-Keto-thioesters and amides can also be obtained using this method.
An alternative route to acetoacetates (149) involves
transesterification of methyl acetoacetates with primary or secondary alcohols using 4-dimethylaminopyridine as catalyst.
141
This method can also be applied to methyl esters of homologous 6-keto-esters, but fails if the latter are disubstituted at C-2. The excellent procedure for preparing B-keto-esters by acylations of Meldrum's acid with acid chlorides has been described in detail. 142 The same type of approach to 6-keto-esters (152) can be carried out in one step by condensation of methyl or ethyl esters (150) with t-butyl lithio-acetate ( 1 5 1 ) . High yields of keto-esters are obtained only in the presence of an additional equivalent of a base such as LiOBut, which ensures that the product is fully enolized as it is formed, and thus protected 143 from further attack by the enolate (151).
General and Synthetic Methods
104
Eto$OEt
-
0
OTMS
zncl-,' RCOCl RIIXtOiEt EtO
OTMS
C0,Et
-If
0
OTMS
0
5
OMe &C02Me
I
3 X sB F i
I
R R'HoTMs
R~
Me0
OMe
(145)
(143)
OLi
0
+
-
0
LlOBUt
AOBU'
R
Co2Et
CO, But
CO, Me
3: Carboxylic Acids and Derivatives
105
The arylation of B-keto-esters to give, for example, the cyclopentanone derivative (153) using aryl-lead triacetates has been shown to be compatible with a range of aryl substituents (e.g. F, OMe, NO2). 144 The lead species are best generated in situ from diarylmercuries and P ~ ( O A C ) ~ . Enolates of 0-keto-esters can be similarly phenylated by various bismuth(V) compounds to give the same type of product.145 8-Keto-esters can also be efficiently allylated without the addition of a base by treatment with an allylic carbonate and a Pd(0) ~ a t a 1 y s t . l ~ ~ For example, ester (154) can be obtained in 98% yield from methyl 2-methyl-3-oxopentanoate using diallyl carbonate in THF at 30 "C, in only 10 min. Some cyclic O-keto-esters have been alkylated enantioselectively by optically active sulphonium salts; however, as yet yields, both chemical and optical, are poor.147 Further studies148 have revealed that enamines derived from cyclic B-keto-esters, especially six-membered examples, undergo regioselective alkylations at the y-position to give the derivatives (155) in good to excellent yields, with the usual restriction that only reactive electrophiles (allylic, benzylic halides, acrolein, MVK) couple efficiently with enamines. The strongly basic conditions required in the dianionic or Dieckmann routes to esters (155) are thus avoided, which allows the alkylations to be carried out in the presence of various base-sensitive ring substituents (e.g. OAc). Enolates of a-phenylthiocrotonates undergo regioselective C-acylation when treated with an acid chloride or anhydride to give B-keto-esters (156) in which a [1,3]-SPh shift to give esters (157) can be induced by heating with AIBN-PhSH.149 These latter products can be desulphurized, resulting in a reasonably efficient route to a-alkylidene-0-keto-esters. A sulphur extrusion reaction is the basis of yet another approach to 8-keto-esters.150 Thus, tretment of 0-acylthio-esters (157a) with LiNR2 at -78°C followed by warming to room temperature leads directly to 8-keto-esters (157b) in 54-93% yield. The'oxygen analogue of this rearrangement (i.e. starting with ester (157a) with 0 in place of S ) is already established as a route to a-hydroxy-0-keto-esters. The latter derivatives can also be obtained from the silyl enol ethers of 0-keto-esters by oxidation with 2-chloroperbenzoic acid. lS1 Conjugate additions of thioacetals (159) to a,B-unsaturated esters (158) followed by alkylation using iodomethane leads
106
General and Synthetic Methods
exclusively tothe syn-isomers (1601, useful as precursors to ~
keto-esters. 152
y-
In direct parallel to Fleming's
observations, 128 similar additions to the a-methyl hom'ologues of esters (158) followed by quenching with acetic acid give only the corresponding g i - i s o m e r s (161).
Acyl radicals generated from
aldehydes show a distinct preference for additions to electron-deficient olefins. This fact has been employed in the development of a novel cyclization procedure leading to the Y keto-ester derivatives (162) (Scheme 12)152 The highest yield obtained during this trial study of a potentially very useful reaction type was 57%. Following on from previous work, R e i s ~ i ghas ~ ~discovered ~ that cyclopropane carboxylates (163) smoothly rearrange to silyl enol ethers (164) when treated with small amounts of iodotrimethylsilane.
The initial products can be further
homologated to B,B-disubstituted-Y-keto-esters by condensations with electrophiles. A full account has been given of related work in which vinyl cyclopropanecarboxylates (163; R'=vinyl) undergo nucleophilic additions to give heterosubstituted y -
A completely different approach toy-keto-esters proceeds y & Michael additions of carboxylic acid dianions to an a-anilino-acrylonitrile followed by alkylation of the resulting anion and finally acidic hydrolysis (Scheme 13) .156
Overall
yields are in the range 47-79%; the method is also useful in the synthesis of y-keto-amides. An alternative anion-based route to keto-esters utilizes the homoenolate (166) as the intermediate which undergoes smooth acylation by a wide variety of acid chlorides. 157
The h ~ m o e n o l a t e l ~is ~ 'obtained ~~~ from the
corresponding iodoester using Zn-Cu couple, and it seems likely that the method can be used to prepare more highly substituted keto-esters although such reactions have not yet been reported. In the same way, the bis-homoenolate (167) can also be generated and used to make 6-keto-esters (168). Overall yields are excellent. Michael additions of ketene silyl acetals (169) to enones using Mukaiyama-type conditions result in the almost exclusive The stereochemical formation of the syn-isomers (170).lS8 outcome of these condensations is not dependent on the ketene geometry, whereas in related reactions of the lithium enolates of
y-
3: Carboxylic Acids and Derivatives
(1531
0
107
(154)
(155)
-
RZ
L I NR2
R'
( 1 56)
C0,Et
CO, Me
R2
( 1 57a)
(157b)
-
(157)
SMe
MeS
i, R Z x L i
R1/+C02Me
ii, Me1 ( 1 59)
R2&C02Me MeS MeS
(1 5 8 )
C0,Me MeS MeS
(1611
(1 6 0 )
- &(
COzMe
&OzMe
?If
0
0 (162) Scheme 12
I
General and Synthetic Methods
108
-
Scheme 13
IZn
C02Et
,R
OBu' (1 69)
4
(170)
&--A c 0,M e
3: Carboxylic Acids and Derivatives
109
t-butyl propanoate with enones, this is the key factor, as the (Z)-enolate gives the anti-adducts whereas the (El-enolate leads to only the =-isomers.l5' The chiral enamine (171) participates in a Michael reaction with methyl acrylate to give the 6-keto-ester (172) with >95% enantiomeric enrichrnent.l6' This isolated example which echoes the hydrazone work of Enders ('SAMP' and 'RAMP') no doubt illustrates a more widely applicable principle. Closely related organotin enamines afford the same product (172) with acrylates but usually in poorer chemical and A first example of an asymmetric additive optical yields. 16' Pummerer rearrangement, (173) (174), an uncommon reaction in its racemic form, is featured in a new route to the 6-keto-esterI (-)-methyl jasmonate (175), having 20% enantiomeric purity
-
s.
(Scheme 13) Organomanganese reagents are relatively unreactive species and so are useful for the synthesis of many types of keto-esters via couplings with acid chlorides derived from diacid monoesters 1i.e. ClCO(CH ) C02Etl.163 2 r !
Unsaturated Esters. - Following on from a recent report that the ionization of triethyl phosphonoacetate can be promoted by lithium chloride to such an extent that only DBU or Hunig's base is required, Rathke and N ~ w a k lhave ~ ~ discovered that even triethylamine is sufficiently basic when either lithium or The resulting enolate magnesium bromide is present. 164 condenses rapidly with a variety of aldehydes and cyclohexanone (but not methyl ketones) at ambient temperature to provide generally excellent yields of a,B-unsaturated esters. An alternative way in which the use of strong bases can be avoided in such reactions is to employ various phase-transfer conditions; examples reported this year include barium hydroxide, 165 potassium carbonate, 166' 167 and potassium fluoride on alumina. 16* A notable feature associated with some of these methods is that high yields of a,B-unsaturated esters are obtained even with rather sensitive aldehydes substituted by unprotected hydroxy-, nitro-, or keto-groups. Exceptionally sensitive aldehydes which may even defy isolation can be generated and trapped in situ by carrying out a Swern oxidation of the corresponding alcohol at -78 "C and then adding a stabilized phosphorane [e.g. (17611 (Scheme 1 5 ) Remarkably high yields can be obtained; in the example shown, the extremely reactive a-keto-aldehyde is trapped
110
General and Synthetic Methods c
Scheme 15
+
+
Ph3P=C=C=0
R~OH
Scheme 16
~
o
" "B""
R
c'
R
-4co, d
____jt
Et
OSiMe3
"ZEt
~
''+ / OEt R2
d C 0 , E t
:C ,cI
3R'
R3
OSi Me3
CI
R,+oEt
A R2
Scheme 17
~
'+
R3 /
R2
C02Me
"
3: Carboxylic Acids and Derivatives
111
to give the keto-crotonate (177) in 90% isolated yield (E:Z =85:5). A 'three component' synthesis of a,@-unsaturated esters is outlined in Scheme 16. 170 This unusual method is simple to perform (equimolar amounts of each component are heated together in toluene), affords generally high yields (81-94%) and presumably proceeds & y the phosphorane (176, Me=R 2 1 . Examples of the synthesis of macrolides (179) from a-hydroxy-aldehydes (178; "=8 or 10) (60-65% yields) and of the Diels-Alder adduct (180) by a four-component reaction, in which the additional reactant is 2,3-dimethylbutadieneI suggest that the method could be of considerable utility. Although Wittig reagents [e.g. (176)l condense efficiently with acrolein, the corresponding, cheaper, phosphonates give low yields of penta-2,4-dienoates (182). This difficulty can be circumvented by substituting 3-chloropropanal for acrolein; the initial adducts (181) undergo smooth and rapid elimination of the elements of HC1 when treated
s.
80% ~ i e 1 d s . l ~ ~ with DBN to give esters (182) in Ruthenium-catalysed co-dimerization of a terminal acetylene (183) with hexadienoate (184) gives, regioselectively, the formal Michael adduct (185) in 86% yield. 172 Unfortunately, similar reactions with pentadienoates lead to mixtures of 2-en- and 4-en-6-ynoates but presumably the method could be extended to higher homologues. A one-carbon homologation method (Scheme 17) for the conversion of esters into a,@-unsaturated esters has as the key step the addition of chloro-carbenes to silyl ketene acetals.173 Yields overall are generally excellent and largely ( E ) - or (Z)-isomers can be obtained with R 3 =H by controlling the stereochemistry of the ketene acetal. However, the remainder of the substrate must be inert to attack by chloro-carbenes which will clearly limit the utility of this method. Reformatsky reactions of oxoketene acetals (187) derived from aryl ketones (186) followed by dehydration and hydrolysis or just dehydration (I2) afford propene-lI3-dicarboxylates (188) or their partly 174 protected derivatives (189) respectively. A useful and efficient one-carbon homologation method for the conversion of ketones (190) into a,$-unsaturated esters (191) involves Pd(0)-catalysed carbonylation of enol triflates derived from ketones (190).175 The regioselective generation of these intermediates seems to be the only potential problem associated with this method.
(&)-Vinylsilanes
(192) can also be
converted into esters (1911, via the derived vinyliodonium
112
General and Synthetic Methods
SMe
Ar
Et0,C W
S
M
e
OH
\
€to$
+YSMe Ar
SMe
(189)
R’-X (193)
+
rf /
C02Me
R
(194)
4
R’rco (195)
113
3: Carboxylic Acids and Derivatives 176 salts. A useful polystyrene-bound palladium catalyst has been
developed for use in Heck-type coupling reactions [(193)-+ (195); R 1=Aryll The same overall transformation can be carried out by the addition of alkylradicals, generated from alkyl bromides (193; X=Br) , to B-stannyl acrylates (194; R2=Bu!$n) followed by elimination of the stannyl group.178 Respectable yields (43-79%) have been obtained with a variety of useful substrates suggesting that this experimentally simple method could find wide application. Peterson olefination reactions between lactones (196) and a-silylacetates have been used to obtain isomeric mixtures of the ylidene acetates (197). Yields are variable and best for six-membered lactones. The nitrogen analogues of heterocycles (197) can be prepared by the direct coupling of -N-alkyl-lactams with lithium t-butyl acetate,180 and a specific route to tetrahydro-2-furylidene acetates involves BF -catalysed reactions between epoxides and acetoacetate dianions.381 Baldwin et a1.182 have provided some useful information about the relationships between reaction conditions and substrate structure in conjugative isomerizations of $,v-unsaturated esters to the corresponding a,B-unsaturated isomers. A new asymmetric synthesis of cyclohexylidene esters (198) relies on the presence of a chiral sulphoxide function which allows the diastereoisomeric a-sulphinylester precursors to be separated and the facile introduction of the double bond by thermolytic 183 elimination of the sulphinyl group. Routes to useful functionalized a,8-unsaturated esters reported this year include a Peterson-type approach to the a-trimethylsilyl esters (199)184 and Lewis acid-catalysed condensations between acetylene (200) and aldehydes (or ketones) which efficiently produce the allylsilanes (201)185 (see also ref. 188). a-Thioesters (203) can be obtained by 'elminiative deoxygenation', using TMS triflate and a weak base, from the The Peterson reaction readily available sulphoxides (202) 18'
.
has been used in the same sense as in the preparation of a-silyl esters (199) to obtain a-stannyl esters ( 2 0 4 ) from aldehydes One value of (RCHO) and a-stannyl-a-trimethylsilylacetate. 187 the esters (204) is as precursors to the useful vinyl anions ( 2 0 5 ) into which they are converted following tin-lithium exchange using n-butyl-lithium.
A summary of the various
General and Synthetic Methods
114
Y
Si Mej
+CO,,d
R
MegSi
-*
,OE
t
R (199)
(198)
(200)
T I CI4
R
n = 0 , l or2
*
CO,R
(204)
(205)
(206)
Hoe< AC02Me
R A c o p e
(209)
(208)
(207)
3: Carboxylic Acids and Derivatives
115
equivalents of acrylate anions (205) has been given in a full paper by Hoffmann and Rabe in which is described the preparation of hydroxy-acrylates (206) by DABCO-catalysed condensations of aldehydes with methyl acrylate. 188 On treatment with N-halogenosuccinimides and Me2S, esters (206) are converted into allylic halides (207) stereoselectively, while reduction (LiBEt H) of the derived acetates leads to 3 (E)-a-methyl-a,B-unsaturated esters (208) via SN2' addition of hydride. An alternative phosphonate-based approach to silyl esters (201) is also described in this paper. Ene-type reactions between substituted a,@-unsaturated esters and singlet oxygen proceed with good to excellent regioselectivity of attack at the allylic position geminal to the ester group, leading largely to hydroperoxides 1e.g. ( 2 0 9 ) I .18' The g-silyl-enolate of methyl a-thiopropionate condenses with a-benzyloxy-aldehydes to give very largely the --isomers (210) after oxidation and elimination of the thio function. Weedon et al. have given a full account of their work on the photo-deconjugation of a,6- to a, y-unsaturated esters. 19' The more conventional method for effecting this transformation enolization and protonation has been used to obtain the useful
(z)-vinyl-stannanes
(211) from the corresponding
Likewise (2)-isomers of the latter can be converted exclusively into the (El-isomers of stannanes (211). Treatment of (cyclic) y -acetoxy-
( E )-a, a-unsaturated isomers.
a,B-unsaturated esters (212) with Bu 2CuLi generates copper enolate species which undergo smooth alkylations by primary halides to give esters (213), thus providing a useful Phenyl method for combined deconjugation and homologation.lg3 vinyl sulphoxide has been used as a vinyl cation equivalent in the conversion of enolates [e.g. (21411 into ethenyl homologues (215); yields for the two steps are in the order of 50% when this somewhat limited method is successful.lg4 Cyclopropane derivatives (216) can be converted into v , b unsaturated esters (217) by reaction with nickel carbonyl and an alcohol (R20H);lg5 yields of the esters are in the range 20-80%. The method can also be used to form amides by using an amine rather than an alcohol, but the returns are generally inferior. A common method €or the preparation of v , d unsaturated esters is to use one of the modifications of the Claisen rearrangement. One limitation of the Ireland version,
General and Synthetic Methods
116
BtO RA
C0,Et
A! O
2
M
(V
e
OAc
OH
IRX
BuzCuLi,
a
Cope
Ph
(214)
--A
C02Me
Ph
(213)
(215 )
CI E t OA
o
h
O
M
e
3: Carboxylic Acids and Derivatives
117
in which g-silyl-enolates are used, is the problem associated with competing elimination at the enolization step when the allylic ester contains a a-leaving group such as an alkoxide. This can be overcome by premixing the base (often LDA) and the silylating agent (TMSCl or TBDMSC1) before addition of the When a Claisen intermediate contains two allylic ester. lg6 alcohol residues, the less substituted component participates in the rearrangement; thus acetal (218) affords very largely the dienoate (219).lg7 Conjugate additions of vinylalanes, in the presence of a palladium catalyst, to orthoester (220) is an alternative route to yI6-unsaturated esters (221).lg8 Palladium is also used as a catalyst in the coupling of ketone enolate (222) with the allylic nitro-compound (223); the product (224) is obtained in 60% yield largely as the (E)-isomer.lg9 It seems likely that this type of reaction will be applicable to many other substrates. Rather unexpectedly, lead tetra-acetate has been found to effect a highly stereoselective %-bond cleavage of cyclopropanes (225) to give w-unsaturated esters (226) in good yie Ids.2oo In examples where the methyl and silyloxy groups are anti, the sole products are the (;)-isomers of esters (226). Full details have been given of a useful two-carbon degradation procedure for the conversion of unsaturated esters (e.g. methylundec-10-enoate) into w-unsaturated esters (e.g. methylnon-8-enoate), by treatment of alkoxy hydroperoxides produced by ozonolysis of the starting olefin with iron(I1) and copper ( 11 salts . O
-
Aromatic Esters. A relatively simple route to 4-hydroxybenzoates (228) has been developed during work directed towards Avermectin syntheses and consists of sequential addition-elimination of 1,3-diketone dianions (227) to (;)-3-bromopropenoate followed by mild base treatment; overall yields vary between 23 and 34% but are probably in excess of those of alternative routes to such compounds.202 In another approach to aromatic esters from aliphatic precursors Kang and Chan203 have discovered that the silyl crotonate (229) unexpectedly reacts with carbonyl electrophiles at the y-position leading to 9-hydroxybenzoates [e.g. (23011. Yields are around 60%. Related chemistry has been used to prepare the acetoacetate derivative (231)-204
Benzylic ethers (232) can be
118
General and Synthetic Methods
OSi Me3 I
OH
(227)
(228) R' = H, n-alkyl, Ph, or a l k e n y l
R2 = H or M e
3: Carbonylic Acids and Derivatives
119
converted into the corresponding esters (233), sometimes in excellent yields, by photo-oxygenation in the presence of titanium dioxide.205 The analgesic properties of various phenylacetic acids continue to stimultae the development of new routes to compounds of this type. Aryl bromides can be converted directly into phenylacetates by palladium-catalysed coupling with ethyl 206 a-(tri-n-butylstanny1)acetate in the presence of zinc bromide. Aryl iodides can also be directly coupled to the potassium enolate of a-cyanoacetate using a palladium catalyst to give In a rather different a-cyano-phenylacetates in fair yields.207 approach, nitroarenes (234) have been found to undergo fluoride-induced couplings with ketene silyl acetals leading to phenylacetates (235) after oxidation of the intermediate dihydroarene.208 An alternative strategy €or the preparation of phenylacetates is by carbonylation of benzylic halides. The dimer of chloro(hexa-1,5-diene)rhodium is an especially useful catalyst for such processes while the source of the alkoxide residue can be a titanium or zirconium a l k ~ x i d e , ~ ”a dialkyl ether,210 or a borate ester.211 The presence of iodide as a promoter is essential in the latter two recipes which afford generally excellent yields of a-aryl-alkanoates. Benzyl mercaptans can also be converted into a-arylacetates by carbonylation using [Co2( C O ) 8] as catalyst2I2 but high temperatures and pressures are necessary, in contrast to the foregoing methods using benzylic halides. Nevertheless, reasonable yields (25-83%) can be obtained. Various substituted phenylacetates can be prepared by phase-transfer catalysed Michael additions of t-butyl 213 phenylacetate to acceptors such as cinnamates or chalcone. The rearrangement of a-bromoacetophenones, or acetals thereof, by a [1,2laryl shift to a-arylacetates is somewhat limited because of the requirement of toxic and expensive thallium or silver salts asreagents. This limitation can be overcome by using zinc bromide2I4 (except when no other a-substituents are present in the acetophenone, when simple replacement of Br by OMe occurs), or simply by heating the substrates as their acetals in ethylene glycol containing sodium acetate or a similar weak base at 125 OC for 8-32 h.215 As isolated yields are >80%, this
z.
would appear to be the method of choice for effecting this transformation.
General and Synthetic Methods
120 Acetylenic Esters.
-
When the allene (236) is metallated using
BunLiin a 1:l mixture of ether and hexane, the intermediate dilithio species can .be sequenially alkylated by primary, benzylic, or allylic halides and ethyl chloroformate to give acetylenic esters (237) in high yield uncontaminated by the corresponding allenic isomers.216 5-Aminoisoxazoles (238) containing an electron-withdrawing substituent at the 4-position undergo ring cleavage upon diazotization using NaN02 in aqueous Yields of products such as the acetylenic ester acetic acid. 217 (239) are variable but there could be some potential in using this type of isoxazole as a masked acetylene in complex syntheses. Efficient syntheses of the hex- and hept-2-yn-dioates (240) have been described in which the acetylene function is generated by pyrolysis of the corresponding a-keto-phosphoranes derived from Wittig reactions between succinic or glutaric anhydrides and Ph3PCHC02Et.218 When the copper acetylide derived from ethyl propynoate is coupled with propargylic bromides, an unusual rearrangement takes place to give excellent yields of 3,5-diynoates (241).219 By contrast, similar couplings with primary allylic bromides lead to 5-en-2-ynoates (242) accompanied by small amounts of the SN2' products. Allenic Esters and Dienoates. - The Wittig approach to allenes from phosphoranes and ketenes or equivalents thereof has been extended to include both 2,4,5-trienoates (243) and the as yet Although yields are unreported 2,3,5-isomers (244).220 sometimes rather low, even in such cases this method probably is and will be the most expedient route to these classes of compounds. a-Allenic esters [cf. (244)l can also be obtained directly from carboxylic acids and phosphoranes by activating the former-with 2-chloro-1-methylpyridinium iodide; [ 3 ] - CUmUlene carboxylates can also be obtained using this method. 221 A range of (Z,Z)-dienes _ including dienoic acids (245) are readily obtainably by an extension of the Normant reaction in which lithium dialkylcuprates undergo double incorporation of acetylene to give a dienylcuprate which can be trapped by a variety of reactive electrophiles including C 0 2 [+(245)1, enones, allylic halides, or methyl propynoate, the latter leading to trienoates (246).222 Stereochemical mixtures of 2,4-dienoates can be efficiently obtained by Pd(OAc)2-catalysed
3: Carboxylic Acids and Derivatives
R'
121
R2
(240)n = 0 or 1, R ' - 4 = H, Me, Ph
(241 1
(242)
C0,Et
0
tu
CO, Et
Ho&
(248)
(2491
122
General and Synthetic Methods
coupling of vinyl iodides with methyl acrylate, under phase-transfer conditions.223
Much the same couplings can also
be carried out using vinyl triflates.224 2,4-Dienoates can prepared in high yields by Wiftig-typereactions between aldehydes 225 or ketones and arsonium ylides. 7-Aryl-hepta-2,4,6-trienoates (247) have been formed from cinnamaldehydes by coupling with acetylketene dithioacetals followed by NaBH4 reduction and hydrolysis using BF3 in methanol; Vinylogous Reformatsky reagents overall yields are 50-60%.226 derived from u-bromocrotonates undergo highly selective and condition-dependent reactions with enones. For example, cyclohexenone is converted to the '2-a' adduct (248) using 'polar' conditions (Zn/Cu, HOAc in ether) whereas with zinc in THF only the '4-Y' isomer (249) is formed.227 Thioesters.- A useful review of thionation reactions in general using Lawesson's reagent has been published;228 2,4-dialkyl analogues of the reagent can be used to convert carboxylic acids directly into s t h i ~ e s t e r s . ~ ~ ' It has been claimed that the best way to make thioacids is by treatment of an acid chloride with hydrogen sulphide in dichloromethane containing Disulphides have been found to dimethylthioformamide.230 undergo cobalt-catalysed carbonylations to give thioesters; however, at present, the method is only really useful for the preparation of symmetrical aromatic thioesters (ArCOSAr)231 (cf. ref. 212). High diastereofacial selection has been found in condensations between a-methyl-aldehydes (250) and the dithioacetate enolate (251); the =-isomers (252) predominate in these and homologous condensations using the lithium enolate of ethyl dithiopropionate, which give largely diastereoisomers (253).2 3 2 2,3-syn-3,4-anti- or 2,3-anti-3,4-syn-isomers of 6-hydroxy'thioesters related to adducts (253) can be obtained by various Lewis acid catalysed condensations of thioester silyl The thio analogue ketene acetals with a-methyl-aldehydes. 233 (254) of the well known phosphorane from bromoacetate can be prepared in much the same manner as the latter and reacts smoothly with aldehydes to give the unsaturated thioesters (255). The proportion of trans-isomer formed is usually greater than is the case with the oxygen analogue and furthermore (Z)+(E) isomerization of such unsaturated thioesters can be effected by
123
3: Carboxylic Acids and Derivatives
CS,Et
OH
CS2Me
R4 R3
0
Ph P
3
RKS-SeAr
R'
0 RKSeAr
(2631
(264) R1-5
= Hor a l k y l
(2651
124
General and Synthetic Methods
treatment with a catalytic amount of 4- (dimethylamino)pyridine. 2 3 4 Related phosphonates have also been synthesized and these will prove useful in the preparation Lithium of a,@-unsaturated thiono- and dithio-esters.235 enolates of both thiono- and dithio-esters are soft nucleophiles judging by their propensity to give very largely the 1,4(Michael) adducts with enones. 236 Lithium enolates of dithioesters can be converted into unsaturated esters (256) by coupling with activated derivatives of allylic alcohols; the sequence most likely involves 2-alkenylation followed by a thio-Claisen rearrangement237 (see also Beslin and Vallee in ref. 232). Se-Aryl-selenoesters (258) are available by desulphurization of the sulphenoselenoates ( 2 5 7 ) , obtained from RCO.SBr and a diary1 diselenide or a thiocarboxylate salt and ArSeBr. 238 Methyl selenoesters can be simply obtained by treating alkyl esters with the aluminium-based reagent Me2AlSeMe at 0-20 " C , 239 and a rather neat method has been developed for obtaining phenyl selenoesters from (hindered) carboxylic acids.240 3
Lactones
8-Lactones. - In model studies directed towards a synthesis of the naturally occurring B-lactone Anisatin, it has been found that oxetanes [e.g. (259)l can be oxidized to the corresponding @-lactones (260) ( a s a 1:l mixture of diastereomers) using ruthenium tetroxide, albeit in low yield (25-30%),241 Butyrolactones. - Butane-1,4-diol can be oxidized to butyrolactone itself using a 1-oxopiperidinium salt. 242
One further example suggests that the reagent reacts preferentially with primary alcohols and thus could be useful for the synthesis of a variety of higher homologues of butyrolactone. I n an ~ ~ ~found exploitation of earlier work, G r i m and R e i ~ s i ghave that the readily available silyloxycyclopropanecarboxylates (261) can be converted into butyrolactones (262) in excellent yields by treatment with potassium borohydride in methanol. 4-Methoxycarbonyl derivatives (264) can be obtained by ti related, fluoride-induced cleavage of cyclopropanes (263) followed by oxidation of the resulting lactol. 244 2,2,-Dichlorocyclopropane-l-propanoic
acids undergo direct
3: Carboxylic Acids and Derivatives
125
conversion into the vinylbutyrolactones (265) on treatment with hot 1% aqueous sulphuric acid: yields are variable (8-90%).245 Further examples of an alternative approach to butyrolactones (262) using carbamate-derived homoenolates have been reported in The allylsulphoxide carbanion (266) adds in a detail.246 Michael fashion to but-2-en-4-olide to give largely one diastereoisomer (267) accompanied only by the C - 1 ' ( * ) epimer.247 Presumably, therefore, optically active @-substituted butyrolactones could be obtained by starting with a chiral sulphoxide. Related conjugate additions to a-ethylidenebutyrolactones followed by trapping of the resulting enolate using ally1 bromide are also highly diastereoselective 248 leading to, for example, butyrolactones (268). a-Methylene-6-hydroxybutyrolactones such as compound (269) can be obtained by stereoselective condensations of 6-amino-acid esters with aldehydes followed by elimination. These useful products undergo highly selective reductions or bis-hydroxylation [to give (270) for example], although conjugate additions to the exposed enone system are not particularly attractive in terms of either stereoselection or yield; such reactions are probably best performed on the acyclic precursors to these lactones.249 5-Alkenylbutenolides (271) can be readily obtained from the corresponding but-2-en-4-olides by kinetic enolization and protonation at low temperature and serve as dienes in Diels-Alder Most of the reactions reactions leading to adducts (272).250 are carried out in water at ambient temperature and under these conditions the method seems limited largely to geminally activated dienophiles such as the example shown. Intramolecular Diels-Alder approaches to 3,4-annulated butyrolactones [(273) and Highly substituted [(274)] have also been reported.251 butyrolactones [e.g. (27711 can be prepared from pyrone esters (275) by a sequential intra- and inter-molecular Diels-Alder sequence.252 The isolable intermediates (276) may well be useful in a number of other reactions. Systematic studies253 have shown that intramolecular [2+21 cycloadditions of unsaturated ketenes or ketiminium salts (278) constitute a simple and reasonably general approach to cyclobutanones (279), which are useful as precursors to butyrolactones following Baeyer-Villiger oxidation. The potential of this method is clearly shown by the efficient formation of the bicyclo[5.2.0]nonane
(280) and of the
126
General and Synthetic Methods
HO
OTry
OTry
(271)
(270)
(269)
*YCozEt H20, 20°C
P
Et
h
S
O
A
___)
- co2
(275)
RJ &o
(276)
(277)
b0
127
3: Carboxylic Acids and Derivatives
w a
L y\=c=x
H
H
(279)
(278)
Y = CH, or 0
eaun F3c0
0
0
(282)
(283)
02 c.
H o 2 c q o (284)
(285)
(286)
128
General and Synthetic Methods
aflatoxin-type system (281), obtained after oxidation of the initial cyclobutanone. Further developments of a route to chiral butyrolactones based on Claisen rearrangements have resulted in highly selective syntheses of lactones (282) and the less stable (3S)-epimer, derived in five steps from compound (282). 2 5 4 Chiral butyrolactones Ie.g. (283)] can be obtained by Kolbe homologation of the corresponding optically active B-hydroxy-acid using monomethyl malonate followed by enolization 255 and trapping. Complete details have been given for the conversion of (L)-glutamic acid into the useful (5)-butyrolactone acid (284). 2 5 6 Remarkably, protonation of disodium 4-hydroxypimelate by (2)-camphorsulphonic acid (in EtOH at -78 "C) followed by lactonization gives a quantitative yield of the homologous The (R)-enantiomer can butyrolactone acid (285) in 9 4 % e.e. 257 be obtained by reduction (LiA1H4), lactonization, and Jones oxidation with slight loss of optical activity. By contrast, a standard resolution procedure using brucine has been employed to obtain the (5)-azidobutyrolactone (286), a useful precursor to 258 (L)-homoserine analogues. In work directed towards the elaboration of sesquiterpene lactones from sugars, Fraser-Reid's group has succeeded in preparing lactone (287) from glucose.259 The butyrolactone residue is subsequently homologated to a cyclohexanone function. The useful chiral starting material (288), a precursor of Lauraceae lactones, can be obtained from (D)-glucal triacetate.260 (D)-1soascorbic acid (erythorbic acid) can be easily converted into yet another useful, chiral butyrolactone 2 Racemic epoxylactones (290; R1 or R =HI can derivative (289).261 be obtained from the corresponding a-methylene derivatives by direct epoxidation using MCPBA at 80 "C in the presence of a radical inhibitor (nucleophilic methods failed), and disubstituted examples [ e. g. (290; R1=Me, R2=Ph) I can be obtained 262
from B-bromobutyrolactone by a Darzens condensation. Hydrolysis of the meso-diacetates (291; n=1-4) using porcine pancreatic lipase followed by oxidation uniformly gives the lactones (292) with very high optical purities. Yields vary between 56 and 82% overall on scales of up to 2 g of Similarly, rigid meso-dimethyl esters undergo substrate.263 highly selective hydrolyses of only one ester group by PLE leading to tricyclic butyrolactones [e.g. (293)I after
3: Carboxylic Acids and Derivatives reduction.264
129
An alternative approach to chiral bicyclic
butyrolactones (e.g. (292; 2 = 4 ) ] is by the oxidation Of meso-diols using horse liver alcohol dehydrogenase; full details of a suitable procedure have been given although an alternative 265 A set of conditions has also been published recently. variety of enzyme preparations as well as whole-cell systems have been found which can reduce bicyclo[3.2.0lhept-2-en-6-ones to the corresponding alcohols in high optical yields: among other cases, the products can be employed as butyro- and valero-lactone precursors.2 6 6 A further application of Baker's yeast reductions is in the conversion of a-ketothioacetals into optically pure a-hydroxy-derivatives (294; R=alkyl); the utility of these intermediates is shown by a conversion of dithian 267 [ (294); R=(CH2)30H] into the natural butyrolactones (295) (see also ref. 272). Optically pure (+)-eldanolide (296) has been obtained from (Sl-ethyl lactate by a route which features a novel pinacol rearrangement268 and the racemic compound has been prepared using some novel ketenethioacetal chemistry in which a synthetic equivalent of 8-lithioacrylate (297) is generated.269 Racemic pyrocin (298) can be prepared from monomethyl maleate in a 'one-pot' procedure which involves the sequential addition of MeMgI followed by a copper-catalysed Michael addition of 2-methylprop-1-enylmagnesium bromide to the resulting ethylenic Syntheses of the Paniculide B and C precursor carboxylate.270 (299)271 and of all four of the L-factors (295)267 rely on the attack of dilithioacetate on an epoxide to establish the lactone ring, a reaction more notable for its excellent regio- and stereo-selective properties than ,or its efficiency. Full details have been given for the preparation of
stereo isomer^^^^
-
(D) (-1 -pantoy1 lactone (300) by asymmetric hydrogenation of the corresponding keto-lactone; the initial e.e. of 78-84% is improved to 98.5% by two crystallizations.273
(+I-Blastmycinone (301) has been prepared in three different ways; two related methods involve high [1,2]-asymmetric induction in condensations using chiral a-substituted aldehydes as electrophiles which lead initially to the 6-hydroxy-ester 1302) 274 or vinylsilane (303).275 An alternative approach proceeds via an asymmetric [2,31 Wittig rearrangement which initially provides acetylene (3041,276 while ( - 1 -blastmycinone has been obtained from the chiral butenolide (305) by selective
130
General and Synthetic Methods
(291)
(292)
(294)
(293)
(296)
(295)
yr., SiMej
Bun
(3041
( 305)
3: Carboxylic Acids and Derivatives
131
trans epoxidation, conversion into the corresponding (3-hydroxybutyrolactone, and finally a-alkylation.277
The
synthetic methodology illustrated by these diverse approaches seems likely to find other applications in this and related areas. The useful prostaglandin precursor (308) has been prepared by de Mayo-type photo-addition of diol (306) to the dioxinone (307) followed by heating in water; the simplicity and brevity of this 278 procedure easily compensate for the moderate 30% yield. Closely related prostaglandin precursors have also been prepared from iridoids,2 7 9 norbornadiene,280 and via an iodolactonization procedure which features a pH-dependent O+O
acyl transfer.281
Butyrolactones [e.g. (309)l obtained from but-2-en-4-olide by an established conjugate addition-trapping sequence can be This cyclized to give useful lignan precursors [e.g. (310)I .282 approach has resulted in a synthesis of desoxyisopodophyllotoxin [(310); H in place of PhSl whereas desoxypodophyllotoxin has been obtained by trapping an 2-quinodimethane, generated from an O-silylmethylbenzyl
alcohol, with maleic anhydride followed by some relatively straightforward manipulations. 283 A full account has been given of a radical-based route to
butyrolactones (312) involving the addition of radicals derived from a-iodo-stannyl esters (311) to 0 1 e f i n s . ~ ~ ~ Some intramolecular versions of the reaction are also described in this paper which in addition contains a useful summary of recent radical chemistry aimed at lactone synthesis. A novel intramolecular radical cyclization onto a tetronic acid [(313)+ (314)l is a key feature in the first total synthesis of
alliacolide [B-epoxy-(314)1 . 285
5-Substituted butyrolactones
(315) can be prepared by heating simple methyl esters with t-bu tyl perpent-4-enoate286 and 5-hydroxymethy1 derivatives of butyrolactones can be similarly obtained from ally1 t-butyl peroxide. 287
This recent upsurge of interest in radical chemistry
is perhaps responsible for the resurrection of a method for the elaboration of butyrolactones (318) from olefins (316) and carboxylic acids (317) using manganese(II1) acetate. Rates are enhanced if the acid substituent 'XI is electron withdrawing, X=So2Ph, NO2, P(0) (OEt)21 although some such functionalities [x. lead to gross mixtures of products. However, when X=C1, CN, CH2C1, or C02Me, butyrolactones (318) are produced (yields are ofken between 50 and 6 0 % ) which can be further manipulated to
General and Synthetic Methods
132
OH
(307)
(306)
PhS
(308)
PhS
-
5
'I
T FA
0
Me0 \ OMe OMe
OMe
(310)
(309)
R1
nBu3
I -CO,S
-
R2
AIBN,
R2tko (312)
(311)
0
R'
0-
3: Carboxylic Acids and Derivatives
133
(321) X = Br, I or SePh
(328)
(329)
(330)
(331)
134
General and Synthetic Methods
give a-methylene- or a , 8-unsaturated lactones. 288
The method can
also be extended to intramolecular examples and to the elaboration
of bis-spiro-lactones. Major drawbacks with thisapproach can be a lack of regio- and stereo-selectivity and sometimes poor yields coupled with the requirement for substrate stability to hot acetic acid. A simple route to spiro-lactones (320) is by oxidation of the readily available precursors (319) using Cr03 in HOAc-Ac20.289 This one-carbon degradation probably proceeds via the chromate monoester and can also be used to prepare spiro-valerolactones; yields for the simple examples quoted are 42-80%.
Halogenolactones [e.g. (321)l have been found to
undergo smooth coupling with allylic sulphide (322) to give only 'SH2' products (323) by photolysis in the presence of Perhaps surprisingly, yields are quite respectable (Bu3Sn)2. 2 9 0 (33-74%; non-stereoselective) in view of the potential for side reactions; furthermore this method complements the related allylstannane chemistry which cannot be used to introduce a prenyl group. Simple allylstannanes as well as acetonyltributyltin can also be coupled efficiently with a-halogenobutyrolactones in the presence of a palladium(I1) catalyst to provide a useful homologation procedure which is unfortunately limited at present to these two types of 291 organotin. Further work by Alper's group has revealed that hydrocarboxylation of unsaturated alcohols [e.g. (324)I or allylic alcohols using an established set of conditions [PdC12, CuC12, HC1, CO, O2 (1 atm each), 20 " C I leads directly to butyrolactones [e.g. (325)l under sufficiently mild conditions that the method should be applicable to more complex substrates.292 Under different conditions (HOAc, NaOAc, CO, CuC12] palladium chloride catalyses a double cyclization of 3-hydroxypent-4-enoic acids (326) to give, stereoselectively, the his-lactones (327).293 The first step of this reasonably efficient procedure (39-84%) resembles a halogenolactonization. Similarly, pent-4-ene-1,3-diols can be converted into tetrahydrofurans (328);294 alternatively, treatment of 3-hydroxpent-4-enamide derivatives with MCPBA leads to good yields of hydroxybutyrolactones but with variable Dimethyl (methylthio)sulphonium stereoselectivities.2 9 5 fluoroborate (DMTSF) has been found to be an effective reagent for sulphenyl-lactonization, giving comparable yields of
135
3: Carboxylic Acids and Derivatives
5-methylsulphenylmethylbutyrolactones from y,b-unsaturated acids
relative to the coresponding halogeno- or seleno-lactonization unsaturated esters (330) are obtainable in high processes.296 yield by ene-type reactions btween thioacetate(329) and mono-olefins; subsequent saponification and selenolactonization provides the butyrolactones (331), useful as precursors to butenolides G . following sequential oxidative elimination of Selenolactonization of 4-ynoic the seleno- and thio-groups.2 9 7 acids to give v-phenylselenomethylidene-butyrolactones proceeds 298 smoothly using N-.phenylselenophthalimide (N-PSP). Simple 8-acyl-butyrolactones (333; R=Ph or Me) are formed in good yields by TiC14-induced condensations of enol ethers (332) with aldehydes or ketones. This non-stereoselective method can be extended to the elaboration of spiro-butyrolactones (from cyclic ketones) and to v-acylated valerolactones by using The excellent one-carbon homologues of enol ethers (332).299 control of both regio- and stereo-chemistry in reactions between nucleophiles and cyclohexadiene-molybdenum complexes is further exemplified by brief syntheses of various fused butyrolactones [e-g. (334)1 . 300 Further work on condensations of lithium enolates of acyliron complexes, in this case with but-2-ene epoxides,has revealed various stereochemical preferences which may well be of value in designing stereoselective syntheses of 2,3,4-trisubstituted butyrolactones.301
-
a-Methylenebutyrolactones. A useful systematic review of An a-methylenebutyrolactone synthesis has been published.302 improved preparation of the allyl-silane (335), useful as a precursor to a-methylenebutyrolactones by Lewis acid catalysed condensations with ketones or acetals, has been developed.303
A
closely related route to these lactones is by Reformatsky reactions between ethyl a-bromomethylacrylate [i.e. (335) but Br in place of SiMe3] and aldehydes or ketones; these are best carried out in a solution of THF and saturated aqueous ammonium chloride.304 Chiral lactones (336) have been prepared in high optical yields using bromomethylacrylate as the electrophile in condensations with chiral sulphoxides;305 similar optical yields of lactones (336) can also be obtained from condensations between aldehydes and chiral 2-(stannylmethy1)propenamides [cf. (335): Deconjugative alkylation of Bu3Sn in place of Me3Si; amidel. 306 cyclohexylidene acetate (337) by PhSeCH2Br followed by
136
General and Synthetic Methods
lactonization and elimination provides a new route to lactone 307 (338) which could well find use in much more complex systems. A novel synthesis of (5)-avenaciolide (341) centres on the stereospecific elaboration of the anti-ester (339) by an enolate Claisen rearrangement of the corresponding (g)-allylic glycolate and a highly stereoselective selenolactonization of the derived lactone (340).308 The synthesis of higher homologues, the a-alkylidene-butyrolactones (344), continues to attract interest. A new route proceeds by hydrocyanation of B-hydroxyalkyne derivatives (342) using HCN or acetone cyanohydrin and a The addition is highly regioselective nickel (0) catalyst.309 only when R1 is large (or HI, but in such cases acid hydrolysis of the predominant cyano-alkene (343) gives only the (E)-ylidene-lactones (344). a-Alkylidene substituents can be introduced directly into butyrolactones by a Peterson-type olefination following C-silylation of the unsubstituted lactone (LDA, MePh2SiC1), re-enolization, and condensation with an aldehyde or ketone.310 Often, only the (E) -isomers are obtained from aldehydes: the method appears quite general and can also be applied to a-silylvalerolactones. Essentially the same transformation can be effected by TiC14-catalysed condensations between 2-silyl-enolates of a-trimethylsilylbutyrolactones and aldehydes; in appropriate examples, high Cram diastereo311 selectivities are observed. A deconjugative alkylation procedure has been used to contruct B-methylenebutyrolactones and employed in a total synthesis of 312 the natural product bakkenolide A.
-
Butenolides. An expedient large-scale procedure for the preparation of the parent member of this group, but-a-en-4-olide, by Baeyer-Villiger-type oxidation of furfural using H202-HC02H, has been reported. 313 Hydroxybutenolides (346) are available by regiospecific singlet oxygenation of 2-silylfurans (345).3 1 4 The presence of the readily incorporated silicon function is beneficial to each stage of the reaction sequence. Alternatively, 5-substituted silylfurans (347)I readily obtainable using new carbanion methodology, can be easily oxidized to butenolides (348) using peracetic acid and then The isomerized to the conjugated isomers if desired.315 related but-3-en-4-olides (349) can be prepared in two steps from
3: Carboxylic Acids and Derivatives
137
4
ii, p - T S A
0
(332)
(333)
S i Me3
9 CO, E t
0
RHQ
COzH
(33 5 )
(342)
(336)
(337)
(343)
-----’ H Q ? 0 (338)
(340
General and Synthetic Methods
138
a 6-keto-ester by sequential alkylation with an a-bromo-acid and careful intramolecular dehydration; coupling of the intermediate keto-esters with simple allylzinc reagents provides the butyrolactones (350), formally Michael adducts of the butenolides (349).316 The easily prepared sulphinyl carbonates (351) undergo smooth intramolecular cyclization upon treatment with LDA; subsequent pyrolytic elimination provides the butenolides (352) in generally This method should find many applications excellent yields.317 and can also be used to prepare the corresponding valerolactone derivatives as well as the saturated analogues by desulphurization using A1-Hg.
4-Amino-butenolides (354) have
been obtained by a related cyclization from the cyanohydrin derivatives (3531, or by an acid-catalysed closure of 318 3-amino-alk-2-enoates derived from protected cyanohydrins. Direct lithiation of a-methoxyacrylic acid (or derived secondary amides) using ButLi produces the vinyl-lithium species (355) which condenses with aliphatic aldehydes to give methoxy-butenolides (356); the rapidity and simplicity of the method compensates for the rather low yields.319 The related mono-anion (357) can be generated from 3-bromoacrolein diethyl acetal by hydrogen-lithium exchange (BunLi, THF, -78 "C) and condenses with ketones to give bromobutenolides (358; X=Br) following mild acid treatment and oxidation of the intermediate Overall yields are high and the initial lactol using Mn02. 320 lactones can be further elaborated to give the corresponding debromo-derivatives (358; X=H) by reduction with Bu3SnH. An alternative method for constructing butenolide substituents of cardenolides features palladium-catalysed couplings of enol triflates derived from steroidal 17-ones and protected 4-hydroxybutenoatesI 321 and a synthesis of digitoxigenin also relies on the use of palladium catalysis, in this case to effect an allylic epoxide rearrangement and concomitant cyclization 322 [ (359)--3(360) 1 . A double carbonylation of styrene oxide using [ C O ~ ( C O ) ~ ] , NaOH, and a phase-transfer catalyst affords a 65% yield of the butenolide (361); further work is needed to define fully the Allenic acids or potential of this simple and mild method.323 esters can be cyclized in variable yields to butenolides ( 3 5 8 ; X=Br, I, H, HgOAc, SPh, or SePh) by a mechanism similar to halogeno- or seleno-lactonization. 324 Ring-fused butenolides.
3: Carboxylic Acids and Derivatives
139
*
CO, Et
CO,Et
R2
PhS=O
(351 1
(3521
L i y o M e
RCHO,
RQOMe
C0,L i
0
Br
X
R’
Li%*Et OEt (357)
-
R
2
(358)
q
140
General and Synthetic Methods
have been obtained from phenyl esters of allenic acids by intramolecular Diels-Alder reactions in which, unusually, the 325 aryl ring acts as the diene component. Rhodium(1) hydride complexes are known to be capable of effecting a variety of olefin isomerizations; a further example of this phenomenon is the facile and efficient conversion of a-alkylidene-butyrolactones into butenolides.326 Notable natural product syntheses in this area include an improved route to the seed germination stimulant strigol, in which the butenolide unit is introduced by 9-alkylation using 4-bromo-2-methylbutenolide [ (362)+ (363)I , 327 and a synthesis of 8,9-deoxyalliacol B (3651, in which lactonization was effected by acid treatment of the allylic alcohol (364).328 Finally, some methods €or preparing various 2,3-dideoxy-ascorbic acid derivatives, which could be useful synthetic intermediates, have been described in detail. 329 Tetronic Acids. - An attractive new route to tetronic acids (368) consists simply of a Blaise reaction between protected cyanohydrins (366) and Reformatsky reagents derived from bromo-esters (367).330 Yields are generally good (40-72%), although they are much lower when cyanohydrins derived from ketones are used. Rather unexpectedly, deprotonation of 4-ethylidenetetronic acid 2-methyl ether using LDA at -78 "C in THF leads directly to the vinyl anion (369) and thence to 2-substituted homologues.331 Extension of the 2'-position can be achieved by Wittig reactions of the phosphonium salt (370) derived from the parent ethylidenetetronic acid by NBS bromination and quaternization with PPh3. The former metallation method has been applied to the elaboration of structures [e.g. (371)1 proposed for the aspertetronin group of microbial metabolites; however, the non-identity of the natural and synthetic compounds led to the deduction that the natural 332 compounds are actually the 5-methoxyfuran-3(2g)-one isomers. The novel phosphonium salt (372) has been used in a non-stereoselective synthesis of members of the pulvinone group (373). This brief and useful method, which produces (E)-pulvinones for the first time, is complemented by an alternative approach to these compounds using a Dieckmann-type condensation of diester (374) to establish the tetronic acid ring, and which produces only the (Z)-isomers of acids (373).333
3: Carboxylic Acids and Derivatives
141
PhJo
d rl,
2
(359)
(360)
Go-
Ph
&OH
0 0
OMe
+rLi 0
(369)
OMe
1
General and Synthetic Methods
142
Phthalides. - In chemistry related to the foregoing work the phthalide phosphonates (375) have been shown to be useful precursors to ylidene-pthalides (376).334
The initial isomeric
mixture can be converted into solely the (Z)-isomer by base hydrolysis (KOH-H20, 100 "C) followed by re-closure (Et3N, C1C02Me). The phosphonates are derived from the corresponding phthalaldehydic acids and hence no regioselectivity problems arise. Decarboxylation of phthalide-3-carboxylic acid salts by thermolysis at 145 "C in the presence of aromatic aldehydes gives variable yields of the ylidene-phthalide precursors (377);335 the the phthalide anion, which can reaction probably proceeds JJ& also be generated from phthalide itself using a strong base. A variety of routes to substituted hydroxy-phthalides (378) have been developed which mostly rely on diverse types of metallations of benzene derivatives although a Diels-Alder approach from cyclohexadienes (379) and acetylene (380) The products (378) are useful represents a good alternative.3 3 6 as precursors of the corresponding 3-cyanophthalides. Under appropriate conditions 3-methoxy- and 3-nitro-phthalic anhydrides undergo almost regiospecific attack at the 'metal carbonyl by aryl Grignard reagents, thus providing a route to 337 3-aryl-3-hydroxyphthalides. Valerolactones. - Enantioselective reduction using Baker's yeast, a method most often associated with chiral 8-hydroxy-ester has also been applied to generation of the preparation, 116-119 useful diol (381) from the corresponding propanone (90% yield, 78% e.e.); the potential utility of the diol is demonstrated by its conversion into both enantiomers of the hornet pheromone 5-hexadecanolide (382), following conversion into the Alternative thio-epoxide and subsequent cuprate additions. 338 approaches to chiral 5-hexadecanolide (382) also include methodology which could be applicable to other asymmetric syntheses. Thus, Mori and Otsuka have prepared both enantiomers by resolution of 2-chloroacetylaminotridecanoic acid using Aspergillus amino acylase which hydrolyses only the (S)-acetyl enantiomer, 339 and other Japanese workers340 have developed a procedure for chelation-controlled reduction of chiral 8-keto-sulphoxides by Dibal-H and applied the method to the elaboration of both butyrolactones and valerolactones, such as the pheromone (382).
A synthesis of the acetoxy-valerolactone
143
3: Carboxylic Acids and Derivatives
(371) 0-
OH
(372)
(373)
(374)
R'C H O
R'R+@
____)
*
0
0
Ar
(375)
(376)
(377)
(378)
1
C0,Me
COzMe
General and Synthetic Methods
144
(383) in racemic form relies upon a stereoselective iodine(II1)-induced fragmentation of a 3-stannylycyclohexanol (384)+ (385)1 .341 isomer to generate an (E) - -en-5-enal precursor New routes to the related lactone Malyngolide (386) have also been reported; the (-)-enantiomer has been obtained from D-mannose,342a the ( + ) -enantiomer using an asymmetric Sharpless epoxidation,34223 and simple hydrogenation of the corresponding 2,3-dehydro-derivative obtained 2 a crossed-aldol condensation delivers (2) - (386) with high s t e r e o ~ e l e c t i v i t y . ~The ~~~ carpenter bee pheromone (389) has been prepared by Pd-catalysed 1,4-acetoxychlorination of (g,Z)-hexa-2,4-diene; the single diastereoisomer (387) of the acetoxychloride thus produced is then homologated to the sulphone (388) by Pd-catalysed attack of the corresponding lithiated sulphone, with retention of stereochemistry.343 By starting with (g,g)-hexa-2,4-dieneI the same sequence leads to trans-(389). That ever-popular traget, the Prelog-Djerassi lactone (390), has once again provided the motivation to develop new and useful methodology. Various allyl-stannanes condense with meso- or (5)-dimethylglutaric hemialdehyde with high anti-Cram and Cram selectivities respectively to provide a rapid route to the lactone (390) and
potentially many related structures.344 An alternative approach is based on allyl-silane chemistry and features some fascinating and potentially valuable methods for stereocontrol in acyclic Routes to optically pure material include examples systems .3 4 5 based on enantioselective aldol-type condensations346 and [2,31 sigmatropic (Wittig) rearrangements347 (see also ref. 353) . An essentially enantiospecific route to another popular valerolactone target, the terpene precursor mevalonolactone (392), has been developed based on Eliel's chiral benzoxathiane chemistry; the key intermediate is the (Rl-nitrile (391) which is - (392).348 The subsequently converted into both ( 5 ) and (2)
-
ability of the natural products c ~ m p a c t i nand ~ ~ mevinolin ~
to
suppress terpenoid biosynthesis by mimicking mevalonolactone (392) has continued to stimulate research into new routes to the key structural feature, the valerolactones (393). A general route to optically active lactones (393) begins with isoascorbic acid,350 whereas an alternative proceeds y & nucleophilic attack onto a (3R, 6~)-5,6-epoxy-3-alkoxyhexanoates derived ultimately Compactin analogues (393) have also from ( 5 )-malic acid. 351 been obtained from (D)-glucose in a brief sequence which relies
3: Carboxylic Acids and Derivatives
145
zoAc (387)
(388)
(389)
146
General and Synthetic Methods
heavily on Wittig olefinations.352 The synthetic potential of Lewis acid catalysed cycloadditions of aldehydes [e.g. (39411 and 'activated' dienes [e.g. (395)l has been amply demonstrated by Danishefsky's group353 in, for example, a further preparation of the Prelog-Djerassi lactone (390) via pyran (396). This methodology has also been elegantly applied to the synthesis of various sugars and amino-carbohydrates: the mechanism is either Diels-Alder or aldol-like depending upon the Lewis acid used. An alternative Diels-Alder approach to valerolactones consists of cycloadditions between dienes and ketomalonates (mesoxalates) followed by degradation of the geminal diester function; the method is thus the equivalent of using carbon dioxide as the dienophile and has been illustrated this year in a synthesis of (2)-Ambreinolide (397).354 The rather congested nature of the diene required the use of high pressure ( 2 0 kbar; 55 "C) to force the cycloaddition to proceed. Yet another Diels-Alder route to pyrans and hence valerolactones is to employ a,D-unsaturated carbonyls as the diene components. A good illustration of this method is a highly enantioselective synthesis of tricyclic lactones (398)
using a benzylidene-oxazepanedione easily derived from ( + ) - or (-)-ephedrine as the diene component.3 5 5 One example, [(399)-+ (400) + (401)], indicates that palladium-catalysed cyclizations
of 2-silyl-enolates (399) of butenyl esters could be developed into a viable route to many more highly substituted v a l e r o l a ~ t o n e s . ~An ~ ~alternative way to form the C-3 to C-4 bond in valerolactones by an intramolecular Claisen condensation has been illustrated.357 Given the choice, as in 4-alkenoic acids, iodolactonization will generally afford five- rather than six-membered lactones. However, bromolactonization of these systems tends to favour valerolactone formation, especially when the 3-position is s~bstituted.~~' Macrolides. - The Steglich esterification procedure (DCC-DMAP) can be applied to the macrolactonization of w-hydroxy-acids if, in addition, an excess of the hydrochloride salt of DMAP is present, presumably to assist in the proton-transfer steps and However, slow thus prevent the formation of N-acylureas. 359 addition and relatively dilute conditions
(z.35 ml
of solvent
per m o l ) are still required and yields tail off distinctly when medium-sized rings are formed: 16- and 17-rnembered, 9 5 % yield,
3: Carboxylic Acids and Derivatives
147
OMe
Ph
OSiMe3
Ph
(397)
(399)
(3981
General and Synthetic Methods
148
l3-memberedI 32% yield. Full details have been given for the Gerlach macrolactonization method which uses silver-ion promoted cyclization of w-hydroxy-pyridylthioesters.360 However, the main emphasis in this area recently with respect to the development of new methodology has been on macrolide formation by C-C rather than C-0 coupling. Intramolecular displacement of a methylthio-group by an allyl-stannane function, initiated by dimethyl(methy1thio)sulphonium fluoroborate (DMTSF), under high dilution conditions (0.01M) has been used to prepare 14- and 15-membered examples [e.g. (402)-(403) ] in 46-48% yields.361 An added bonus inherent in this procedure is that the thioacetal function is also a key element in the elaboration of the precursor (402).
Thiol groups are also crucial in a
related method consisting of EtAlCl 2-promoted condensations of a-chlorosulphides with an allyl-silane function [e.g. (404)(405)l. Significantly this method affords medium-sized lactones (8-11 membered), which are the most difficult to prepare, in
relatively good yields (34-55%) without recourse to high-dilution 362 conditions. A neat fragmentation approach to 14-membered lactones consists of ozonolysis of decalins [e.g. (406)] containing an hydroxypropyl substituent which traps the intermediate carbonyl oxide to give the isolable hydroperoxide (407), which is subsequently cleaved using Cu(OAcI2-Fe SO4 to give the macrolide Oxygenation as in [e.g. (408)1, in good overall yield. 36' substrate (406) may well be a minimum requirement for the success of this methodology. In a somewhat related route, phoracantholide I (decan-9-olide) has been prepared by 364 alkoxy-radical mediated ring cleavage of a bicyclic lactol. The rather unusual natural macrolide pyrenolide B (411) has been prepared by a route which features an oxidative cleavage [(409)-+ (410)l at the key lactonization stage as well as protection of the reactive enedione function as a Diels-Alder adduct. 365 Attempts to form medium-sized macrolides from w hydroxy-f3-keto-thioesters using a Masamune-type procedure results instead in the formation of bis-macrolides (diolides) in reasonable yields.366 This observation is a timely one as there has been considerable interest in the synthesis of natural diolides.
Both pyrenophorin (412) and the structurally similar
colletallol have been prepared by formation of the corresponding saturated diolides, using diethyl phosphorochloridate as coupling
3: Carboxylic Acids and Derivatives
(402)
149
(403)
SiMc,
PhS
H
General and Synthetic Methods
150
agent, followed by introduction of the two olefinic bonds (PhSeBr-LDA, oxidative elimination) thus avoiding any problems of Michael addition to the enoate functions.367
The latter steps are unfortunately not particularly efficient (<SO% yields). An alternative approach to nor-pyrenophorin and related macrolides
containing u-hydroxy- or v-keto-enoate functions consists of a combination of Bestman's macrolactonization procedure170 using
W-
hydroxy-aldehydes and ketenylidenetriphenylphosphorane and selenium dioxide oxidations either in dry dioxan, which leads to the v-keto-derivatives, or in dioxan-3% water which affords the Optically active corresponding Y-hydroxy-compounds.368 (-)-grahamimycin A1 ( 4 1 3 ) has been prepared by a relatively brief sequence in which the potentially awkward vicinal dione function is masked until the last stage as an acetylene group: sadly this final oxidation step was very inefficient.369 Another success has been a synthesis of (+)-l1,ll'-di-2-methylelaiophylidene, a diolide which, although possessing a C2 symmetry axis, is still a relatively fearsome target.370 Various simpler analogues of the dilactonic necine alkaloids have been obtained using the Corey-Nicolaou (pyridine-thiol ester) method to form the final lactonic bond,371 and some progress has been made towards the synthesis of pyridomycin, an unusual diolide lactam. 372
Finally,
a useful review of the total synthesis of macrolide antibiotics has been published.373 The macrolactonization of w-hydroxy-acids can sometimes be significantly assisted by restricting the mobility of the connecting chain. An extreme example of this is the efficient (74% yield) lactonization of (~)-ll-hydroxyundec-6-en-4,8-diynoic acid to give the macrolide (414) simply by treatment with p-TSA
in hot benzene; perhydrogenation then gave 11-undecanolide (85%) .374 Finally, Hesse has reported a further ring expansion method for converting cycloalkanones into macrolides by the overall 'insertion' of (CH2)2CH(Me)0.375 4
Carboxylic Acid Amides
General Synthesis. - Unsaturated secondary amides [ ( 4 1 5 ) and ( 4 1 6 ) l have been found to undergo largely anti-Michael additions The when treated with an excess of an alkyl-lithium.3 7 6
initially formed CON(Li)Me function is probably the key factor in triggering these very unusual reactions.
The N-tosyl-amides
3: Carboxylic Acids and Derivatives
151
(417) are particularly suitable €or the preparation of substituted amides 2 a conventional Michael reaction with alkyl-lithium or -magnesium species in the presence of copper salts.377 As such conjugate additions can be achieved in other ways, probably the main interest of this method is the possibilities offered by the N-tosyl-amide group €or facile transformations into other functionalities. TWO new methodsfor the conversion of carboxylic acids into primary amides may be of use in some circumstances. Acyl azides are reduced to the corresponding amides by potassium tetracarbonylhydridoferrate [KHFe(C0)41 in ethanol at -40 "C under an atmosphere of carbon monoxide378 and acid chlorides are directly converted into primary amides (50-92% yields) upon treatment with 2-3 equivalents of hexamethyldisilazane in This latter method methylene chloride at room temperature.379 could be particularly useful with sensitive substrates. The overall conversion of alkyl halides (418) into N-substituted acetamides (420) can be achieved by sequential N-alkylation of 2-methyl-2-oxazoline, ring cleavage of the resulting salt using NaSePh and oxidative elimination to give the N-vinyl derivative (419) and finally de-vinylation by oxymercuration-demercuration.380 The method is only practical for reactive halides (allylic or benylic). Primary amides can be specifically N-alkylated by primary alkyl halides using a mixture of potassium hydroxide and alumina as p r ~ m o t e r ~ ~ l a n d N-allylated under neutral conditions by treatment with 2-allylisourea (derived from DCC and an allylic alcohol) and a A new route to enamides (423) and palladium (0)complex.382 dienamides proceeds & y initial formation of sulphones (422) from a secondary amide (421) using formaldehyde and PhS02H followed by deprotonation (LDA), alkylation and base-induced elimination.383 Of course, the substituent 'R1' cannot contain a proton a- to the amide carbonyl; in the examples quoted, R1=Ph or OEt. Hydroxy-amides. - Wittig rearrangement of acetamide (424) [LDA, - 8 5 " C ] provides almost exclusively the erythro-a-hydroxy-amide (425). The likely transition-state geometry suggests that the presence of vinylic substituents larger than methyl should at least maintain this level of selectivity during rearrangement. Unfortunately similar reactions of chiral amides derived from prolinol result in only moderate asymmetric induction.3 8 4
152
General and Synthetic Methods
(417) R3MgX, Cul
R = P h o r MejSi
(418)
0
,IKI,, (4211
R’ !
R’
R2 = Ph or M e 3 S i
3: Carboxylic Acids and Derivatives
153
a-Hydroxy-amides can also be obtained from ring opening of a-hydroxy-acid acetonides by direct nucleophilic atack by amines; a study of the scope and limitations of this moderately useful method has been reported.385 O-Keto-amides (426) are available by asymmetric acylations of the corresponding amide enolate and on reduction with zinc borohydride provide
syn-2-alkyl-3-hydroxy-amides; however, the corresponding anti-isomers (427) which are the less common products in this type of chemistry, are obtained upon reduction of keto-amides Reductions of (426) using potassium triethylborohydride.386 B-keto-amides and esters in general by this reagent are anti-selective to a greater or lesser degree. Either 2-or anti-selectivity is observed in reductions of a-alkyl-0-keto-amides [cf. (42611 by PhMe2SiH depending upon the additive (either F- or )'H present. 387 This latter method looks especially useful as it is not particularly dependent on the nature of the amide substituents, and is generally extremely stereoselective. Keto-amides. - A detailed mechanistic study has been carried out on the useful palladium-catalysed double carbonylation of aryl halides leading to a-keto-amides which further establishes optimum conditions for the reaction.388 Another detailed study, this time of kinetic Michael additions of amide enolates to enones has resulted in the determination of various conditions for effecting such reactions with high diastereoselectivities, thus providing a useful route to substituted 6-keto-amides.389 Unsaturated Amides.
-
In further examples of conjugate additions
to unsaturated amides, various stannyl copper species have been found to add to acetylenic amides (428) to give either (El- (429) or (Z)-@-stannyl amides, depending on the reaction conditions. The intermediate enolates can be trapped by reactive Another group of electrophiles to provide higher homologues.390 useful synthetic intermediates are the a-chloroacrylamides (430) which can be obtained from simple saturated amides by chlorination of the derived a-chloro-enamines followed by A1C13-induced dehydrochlorination.391 The method is also applicable to the preparation of the corresponding thioamides and amidines. A full account has been given of B ' - l i t h i a t i o n ~of ~~~ unsaturated amides (431); yields of the trapped products (432)
154
General and Synthetic Methods 0
OwNMe2
NMe2
&NMe2
R'
R1+c, R
M e3Sn
(428)
( 4 3 01
(429)
CONE1,
CONE12
Li
(434)
R
E'2NK0 0
(437)
( 4 3 6 ) R = H or CI
(435)
I I -
(438)
(439)
(440)
0
II
d-
CO, R h ( l ) , HNR2R3
0 (441)
( 4 4 21
155
3: Carboxylic Acids and Derivatives are moderate to excellent.392
Over the past few years a number of research groups, especially that lead by Snieckus, have demonstrated that a wide range of substituted aromatics can be obtained by lithiations of aromatic amides. The novel dianionic species (433)-(435) can be obtained by metal-halogen exchange or direct metal-hydrogen exchange in the latter case. Reasonable yields of the expected disubstituted homologues are obtained on trapping with simple electrophiles.393 Upon warming, the dianion (435) undergoes a bis-anionic Fries rearrangement to give 2,5-dihydroxyterephthalamide; a combination of this rearrangement and the foregoing chemistry, but using stepwise metallations, has been used to prepare the isocoumarins 394 (436), precursors of the natural toxins ochratoxin A and B. Similarly, heterocyclic amides can be bis-metallated;395 the dianion (437) can be coupled with different electrophiles, the first attacking the more reactive 3-positionf although perhaps predictably yields of 2,3,5-unsymmetrically substitutedthiophenes are only moderate. The ability of amide groups in general to direct metallation to the usually less reactive 3-position in 396 these types of heterocycles has been summarized. The sulphone-stabilized dianion (438) undergoes efficient condensations with aldehydes to provide diols (439) after overall replacement of PhS02 by OH using selenium chemistry; the dianion can therefore be regarded as the equivalent of anion (440).397 Allylic phosphates (441) can be smoothly carbonylated using a rhodium carbonyl catalyst under strictly defined conditions; when a primary or secondary amine is present, B,v-unsaturated amides This could certainly (442) are obtained in good yields.398 prove to be a method of choice for at least small-scale homologations to such unsaturated amides.
A standard route to
y,b-unsaturated amides is the amide acetal version of the Claisen rearrangement, for which new and potentially useful conditions More have been described in a preliminary report. 399 conventional amide acetal rearrangements of chiral allenic alcohols can result in high asymmetric inductions to give Diethoxyallenes dienamides [e.g. (443)] in good yields.400 (444) can be derived from malonic acid diamides, and react with malonyl dichloride to give allenic dicarboxamides (445) in 401 variable yields.
General and Synthetic Methods
156
-
Thio- and Seleno-amides. Thioamides can be obtained in good yields by reactions between tj-methyl-nitrones derived from aldehydes and 1 I 1 '-thiocarbonyldiimidazole or related species. 402 This method could therefore also be valuable as an overall oxidation procedure although the conditions (80 "C, 8 h) probably preclude the possibility of having olefinic bonds in the An substrate due to competing [ 1 , 3 1 dipolar cycloadditions. alternative oxidative method for thioamide preparation is based on a very mild version of the Willgerodt-Kindler reaction in which primary alkyl chlorides (446) or a corresponding tertiary amine carrying an additional electron-withdrawing function (IRI) react with morpholine and elemental sulphur at room temperature in DMF to give amides (447) in generally respectable yields, exemplifying the special reactivities associated with 'captodative' compounds such as halides (446). 4 0 3 A further application of chiral sulphoxides is in an asymmetric synthesis of C-hydroxy-thioamides (448) with 40-90% e.e. from aldol condensations using optically pure p- to 1y 1su 1 phiny 1 -rJ ,g-dime thy 1 thioacetamide . [The absolute configuration of the products (448) varies with the nature of substituent 'R'.] Achiral 8-amino-thioamides (449) are available by condensations of 5-silyl-enolates of thioamides with aldimines in the presence of a Lewis acid.405 A seemingly straightforward method to prepare aromatic selenoamides (451) is to react the corresponding nitrile (450) with elemental selenium in aqueous THF containing Et3N under 5 Presumably the key reagent is atm of carbon monoxide.406 hydrogen selenide formed in a water-gas shift reaction: the method is unfortunately much less efficient when applied to aliphatic nitriles. Thioamides can be very efficiently desulphurized to afford the corresponding amides by treatment with 2-nitrobenzenesulphonyl chloride and potassium superoxide at -30 " C in acetonitrile.407 5
Amino-acids
a-Amino-acids. - Further examples of Sch6llkopf's bis-lactim ether approach to a-amino-acids serve to emphasize the value of the methodology. Condensation of the key intermediate (452; R'=H or Me) with epoxides in the presence of BF3.0Et2 provides the protected homoserines (453) after appropriate manipulations
157
3: Carboxylic Acids and Derivatives
(4451
(444)
R
( 4 4 6 ) R = NC or Ac
NHR~ s
R
1
(447)
NMe,
(448)
Se
vN Me2
(449)
General and Synthetic Methods
158
of the initial products.
Chiral inductions are usually very
high, as are kinetic resolutions when the anion (452; R'=Me) is 408 treated with two equivalents of a racemic epoxide. Hydrolysis of amino-esters (453) leads to
a-amino-butyrolactones (454).
Intermediate (452) has also been used to prepare chiral tryptophan and its a-methyl homologue409 as well as the chiral between (452; derivative (455) of a - m e t h ~ l a l a n i n e . ~Reactions ~~ R'=H) and a-chloroketones lead to the novel epoxy-a-amino-acids (456; R=Ph or Me); only the (3R)-enantiomer is obtained although 411 little stereoselection occurs at the epoxide carbon. Nucleophilic attack of azide provides the potentially useful azide derivative (457). High asymmetric inductions occur in condensations of the lithium carbanion (452; I ? ' = H ) or the corresponding titanium derivative with glyceraldehydes or (z)-lactaldehyde to give optically pure hydroxy amino-acids [e.g. Use of the titanium species also improves the
(458)3 .412
diastereofacial selectivity in condensations of bis-lactim ethers with simple aldehydes as exemplified in a synthesis of (D)- (2g,32)- t h r e ~ n i n e . ~ lA~ useful variant of this method is to homologate the chloro-derivative (459), obtained from (452; R1=H) and hexachloroethane, surprisingly as the &-isomer, addition of soft nucleophiles.
by the
For example, reaction with
sodio-malonates followed by degradation leads to the A powerful 8-carboxyaspartic acid (Asa) derivative (460).414 alternative to the foregoing Schb'llkopf method for asymmetric syntheses of a-alkylated homologues of a-amino-acids is the Seebach approach in which an a-amino-acid is converted into an oxazolidinone (461) or imidazolidinone by condensation with pivalaldehyde and cyclization; subsequent enolization and electrophilic attack anti to the bulky t-butyl group provides, after hydrolysis, essentially optically pure homologues (462). Whereas the oxazolidinones are formed as largely the &-isomers (461),415 the corresponding irnidaz~lidinones~'~ are produced mainly as trans-isomers, hence allowing the preparation of either enantiomer of the desired homologue. In contrast, alkylations of a nickel complex derived from the Schiff's base of (L)-alanine and (~)-2-~-(~-benzylprolyl)aminobenzaldehyde proceed with poor diastereoselectivities; however, separation of the two products is claimed to be straightforward and hence both enantiomers
of
the a-methyl-a-amino-acids (462; R=Me) can be obtained from one reaction417 (see also ref. 439).
A potentially general route to
3: Carboxylic Acids and Derivatives
159
RZ \
MEMO R2
R’
Me0
(453 1
(4521
(454)
H7Hco2H
R
O
N-3 (456)
(457)
0,Me N
-----’ RO,C
H%NX:Ye
Me0
CO, R
H
(459)
(460)
R\/\/C 0,
H
(4611
(462)
t
‘
OH
hH2
(663)
160
General and Synthetic Methods
(racemic) dihydroxyamino-acids (463), aldol condensations between aldehydes and the tin(I1) enediolate derived from furylglyoxal, has been exemplified by a synthesis of methyl (D)-glucosaminate (463; R=2,2-dimethyl-1,3-dioxolan-4-yl). 418 A new route to racemic a-amino-acids in general consists of an overall a-amination of simple carboxylic acid esters in a relative of the Japp-Klingermann reaction, a method which is usually only successful with active methylene compounds such.as malonates. Thus, 2-silyl-enolates of esters (464) condense with benzenediazonium tetrafluoroborate to give, after isomerization, the hydrazono-derivatives (465), precursors of the a-amino-esters (466), following hydrogenolysis. Perhaps surprisingly,
one
treatment of methyl hippurate (467) with equivalent of LDA followed by alkylation gives the C-alkylated products (468) in No 2-alkylated products were observed. 52-61% yields.420 Presumably dipole stabilization by the adjacent amido carbonyl group is the key to this reaction, which is certainly more economical than related methods in which the dianion of the ester (467) or even the trianion of hippuric acid itself have been used to effect the same overall homologation. N-Alkylation of a-amino-acids without racemization can often be difficult, so a new procedure for the 2-ethylation of N-Boc-a-amino-acids by dianion formation followed by addition of Et30BF4 will be of interest.421 The N-ethyl derivatives (469) are isolated in 70% yields with no racemization. Most of the general methods for preparing a-amino-acids are based around the intermediacy of a C-nucleophilic amino-acid equivalent. A departure from this pattern is the observation that the acetoxy function of the readily available glycine derivative (470) can be displaced by a range of nucleophiles including neutral alcohols and thiophenols but not amines or phenols. 4 2 2 More exciting is the finding that the acetate (470) undergoes similar reactions with organocopper species423 and o r g a n o b ~ r a n e sto ~ ~ provide ~ a whole range of a-amino-acids (after facile imine hydrolysis) with substituents such as aromatic,
z.
heteroaromatic [e.g. (472)I , 427 secondary and tertiary groups [e.g. (473)], which are difficult or impossible to incorporate by the more conventional anion chemistry. The future utility of this glycine cation (471) equivalent thus seems considerable. Nucleophiles potentially can attack a-imino-esters at three sites: the ester group, the imine carbon, or the imine nitrogen.
3: Carboxylic Acids and Derivatives
161
Allyl-BBN derivatives have been found specifically to attack the imine carbon in ester (474)to provide some examples of u , b unsaturated a-amino-acids; thus a-imino-esters (474) can also act as synthetic equivalents of the cation (471).425 When the imine is derived from optically pure 1-cyclohexylethylamine, very high asymmetric induction is observed. Similarly, enamines [e.g. (47511 attack the imine carbon in the related ester (475) 426 to give a-amino-esters [e.g. (47711 after acidic hydrolysis. When the ester group is (+)-menthyl, chiral induction is complete. The principle of asymmetric steric shielding has been used to control hydrocyanation of Schiff's bases formed between thienylcarboxaldehydes and a chiral dioxan; hydrolysis of the resulting amino-nitriles leads to optically active The highly activated imine (478), and thienylglycines (472).427 the related compound derived from chloral, behave as powerful enophiles in reactions with simple alkenes at ambient temperature with no additional catalyst leading to ally1 glycine derivatives (479) in 49-90% yields.428 A 8-cyclodextrin derivative has been used to effect reductive amination of some a-keto-esters to give 429 almost pure enantiomers of the expected a-amino-acids. Although this B6 enzyme mimic is as yet inefficient and small-scale, further developments will surely follow in this exciting area. A full account has been given430 of the rather unexpectedly efficient couplings of tosyl or halogeno derivatives (480) of serine and homoserine with organocuprates which can be used to prepare a wide range of optically pure a-amino-acids. As these reactions are free of racemization, an elimination-addition mechanism is ruled out; however, organocuprates [RMgX + CuIl do add efficiently to the serine elimination product, methyl 2-amidoacrylate, to give reasonable yields o f racemic Trapping the intermediate enolates with D + or a-amino-acids.431 Me1 provides further homologues. A rather unusual approach to chiral a-amino-acids begins with the chiral and very sensitive seleno-aldehyde (481), derived from ethyl (2)-lactate, which is homologated to the olefins (482) using a (Z)-selective Wittig reaction; these are subjected to an established [2,31 sigmatropic rearrangement to give allylamines (483) which are finally degraded to amino-acids (484) using ozonolysis and Jones Of particular note is that this method leads to oxidation.432 (D)-enantiomers (78-84% e.e.) but begins with the much cheaper
162
General and Synthetic Methods NH I,
LDA,TMSCI
H2 Pd IC
R-CO~M~
(465)
(464)
Ph
~
(4661
Ph
-
AN”
L0 DA RX
L 0 2 M e
Ph NAP,
(470)
(474)
R AC02Me
NH2
t‘C02H
(471)
(475)
d
;
O
2
(472)
(476)
H
JC02H
(473)
3: Carboxylic Acids and Derivatives
163
(S)-enantiomer of ethyl lactate and should therefore find some applications, within the obvious constraints of the methodology (see also ref. 458). The continuing interest in the role of aminocyclopropanecarboxylic acids in ethylene biosynthesis has resulted in the development of large scale routes to deuterium-labelled coronamic acid analogues [e.g. (485) and (48611 and methods for the optical resolution of such compounds433 (see also ref. 435) . Two natural cyclopropanes [(487) and (488)l have been successfully synthesized starting from allylic acetate ( 4 8 9 ) which undergoes smooth Pd-catalysed [3,3] sigmatropic rearrangement to give the isomeric acetate (490); cyclopropanation [CH2N2-Pd (cat.)1 then leads to the amido-ester (4911, the final precursor of both compounds.434 Four-, five-, and six-membered alicyclic amino-acids (493) can be obtained in ca. 50% overall yields by alkylations of the isocyanoacetate (492) with 1,~-dibromidesfollowed by mild hydrolysis; the effects of substituents have not been examined. 435 A wide range of.optically pure 6-substituted-a-amino-acids (495) have been obtained from 2 - 2 or 5-Boc-serine by formation of the corresponding @-lactone (494) using Mitsunobu conditions followed by nucleophilic attack by arange of soft heteroatomic Two useful starting materials, the reagents.436 B-hydroxy-amino-acid derivatives (496) and (4971, have been derived from tartaric acid by epoxide formation, azide ring opening, and reduction; as both L- and D-tartaric acid are freely available so are both enantiomers of these useful materials. 437 A reasonably general though rather poor-yielding route to 6-hydroxy-a-amino-acids is by aldol condensations between aldehydes and 2-silyl-enolates of N,N-dibenzylglycinates; the major isomer is usually t h r e ~ . However, ~ ~ ~ chiral, threo-B-hydroxy-a-amino-acids can be obtained in high yields by similar aldol condensations but with the nucleophilic component being a nickel complex of a chiral Schiff ' s base4I7 of g~ycine.~~'
A potentially widely applicable route to chiral 8-aminoalanines has been exemplified in a neat synthesis of ( L ) -quisqualic acid (498) from ( L ) -serine. 440 Eantiomerically pure a,y-diamino-acids have been obtained by Michael reactions between nitro-olefins and a 1,3-oxazoline-4-carboxylate derived from ( S ) - t h r e ~ n i n e . ~ This ~ ~ work could form the basis of a
General and Synthetic Methods
164
NHZ C0,H ( 4 8 2)
(481)
Me & H 3
H+LOi
H
D (485)
H
(486)
YHBoc
N H Boc
NHBoc
H
I I
I
H
OAc (489)
(490)
(491)
qHR
0
(493)
(492)
(494)X =O,NorS
(495)
+
CO, Et
(/7r-*"'"
E 1 o 2 C y NHBoc
0
NHBoc
H
COT
o*NH 0
(496)
(49 7 )
(498)
3: Carboxylic Acids and Derivatives
165
rather more general approach to these derivatives. Two complementary methods have been developed for replacing the t-butyl group in (5-t-buty1)-homocysteines by another alkyl group, either via thermaldecomposition of t-butylsulphonium salts 442 or by thiolactone formation followed by ring opening ( R X , N H 3 ) . New methods for the formation of 5-aryl-(L)-cysteines have also been described.443 Further syntheses of ( 5 )- [2-2H] glycine have been reported starting from either (D)-ribose or glutamic acid,444 and (L)-a-methyl DOPA and related phenylalanines (501) can be obtained with good to excellent optical purities from meso-esters (499) by selective hydrolysis using pig liver esterase82-86 or a-chymotrypsin, to give half-esters (500), followed by Curtius degradation.445 6-Amino-acids. - Whereas secondary amines attack qlycidic acids (502) only slowly and mainly at C-2, the addition of a stoicheiometric quantity of titanium isopropoxide results in a much increased rate of reaction and attack largely or exclusively at C-3; thus providing a useful route to 3-amino-2-hydroxy-acids 446 (503) from the readily available cis- or trans-acids (502). Tin enolates of the 6-alanine derivatives (504), generated using stannous triflate and 2-ethylpiperidine, condense with aldehydes to give high yields of virtually pure syn-aldol adducts, convertible into the corresponding N-protected hydroxy-acids (505) by base hydrolysis.4 4 7 A variety of routes to racemic isoserine (503; R=H) and related a-hydroxy-6-amino-acids have been developed such as nitro-aldol reactions with glyoxylic acid A simple or azide addition to glycidic esters [cf. (446)I .448 alternative to aldol condensations in B-amino-acid synthesis features TMS triflate-catalysed Schiff's base (507) formation from a bis-silyl-amine (506) and a carbonyl compound, followed by in situ condensation with an ester 2-silyl-enolate, also The simplicity of the method suggests catalysed by TMSOTF.449 that many B-amino-esters (508) could be prepared in this way. Intramolecular Michael reactions of carbarnates (509) triggered by potassium t-butoxide give almost exclusively the trans-oxazolidinones ( 5 1 0 ) , useful as precursors to anti- Y hydroxy- 6 -amino-acids . o Similar 1y, homo-a1 1yl ic carbamates lead to the corresponding six-membered adducts (511) again with excellent selectivities.
Sodium cyanoborohydride modified by
General and Synthetic Methods
166
A,.
%
OzMe
-
PLE
C0,Me
+
CO-R
aNws
I ‘
I,
BnN
R’ CHO
B n N CO,R
_____3
11,Base h y d r o 1 y 51s
(504)
(505)
( 506)
O I
?f-
’
C0,Me
R‘
i
’4”:
T2 R’*co*Me
C02Me
O Y N H
0 (509)
167
3: Carboxylic Acids and Derivatives the addition of zinc chloride is a useful reducing agent, for example in reductive aminations where P-keto-esters can be 451 converted into PJIN-dialkyl-8-amino-esters. v-Amino-acids. - A total synthesis of the amino-acid (514), a
component of the anti-tumour antibiotic carzinophilin, features a one-pot Payne rearrangement-azide opening of the chiral epoxide (512) in which the use of phase-transfer conditions is crucial to force the equilibrium over to the primary azideadduct (513).452 A simpler member of this series, v-amino-a-hydroxybutyric acid, a GABA series neuromodulator, has been prepared in either 453 enantiomeric form from ( g ) - or (Sl-malic acid. Unsaturated a-Amino-acids. - Oxazolinones (515), readily derived from N-benzoylglycine and ethyl chloroformate, condense smoothly with aromatic aldehydes, N-phenylaldimines, or cyclohexanone to provide unsaturated amino-amides (517) after aminolysis of the These modified recipes ylidene derivatives (516) by aniline.454 seem to be an improvement on previous work. A total synthesis of the petide alkaloid hexa-acetylcelenamide A features the use of Wadsworth-Emmons condensations at two stages where dehydroamino-acid residues are required.455
One example involves
reaction between the indole aldehyde (518) and the phosphonate (519): the product (520) is subsequently asymmetrically hydrogenated to provide the corresponding substituted tryptophan. It is also noteworthy that the chloromethyl group survives both the olefination and hydrogenation steps. a-Azidocinnamic acid esters can be reduced electrolytically to the rather sensitive 456 N,N-diacetyl derivatives (521), usually in good yields. Condensations between ethyl isocyanoacetate and unsaturated aldehyde (or ketones) in the presence of ZnC12 or CuC1-Et3N lead to oxazolines (522) in variable yields (29-95%).457 Subsequent treatment with 2.5 mol% of palladium acetate and PPh3 (THF, 20 "C) gives excellent yields of the formamido-dienoates (523). The mechanism probably involves initial oxidative addition of the palladium to the allylic C-0 bond of the oxazoline. Oxidative rearrangements
of the readi1y avai1ab 1e
selenoesters (524), induced by NCS-Hunig's base in the presence of an alkyl carbamate, give good yields (58-80%) of the B,uThe utility of the unsaturated amino-acid derivatives (525).458
route has been demonstrated by a synthesis of (+)-vinylglycine;
168
General and Synthetic Methods
( 5 1 2)
(514)
(513)
Ph
Ph
A or ArCHNR
Ar4CONHPh
0 (51 6 )
( 5 15 )
0
(517)
C02But
CHO
1
C02But
C\
-
P hSe
NH CO,R
NCS, P r I 2 N E t
R'
R20CONH2
(524)
R'
C 0 2M e
(5251
3: Carboxylic Acids and Derivatives
169
one limitation is the poor yields obtained with rearrangemets of disubstituted selenides [cf. (52411. Ene reactions between allylic a-amino-acid derivatives and ethyl glyoxaia.te have also been used to obtain various $,u-unsaturated amino-acids [e.g. (526)l but unfortunately mixtures of products are often Two routes to ( L ) - ~ i n y l g l y c i n ehave ~ ~ ~ been produced. 459 described in detail, both of which exploit aspects of the novel radical-mediated decarboxylation procedures recently developed by Barton and co-workers.4 6 0 Carboxylic Acid Protection. - Diphenylmethyl (Dpm) esters of N-protected
a-amino-acids can be prepared by treatment of the latter with benzophenone hydrazone, Ph2CNNH2, but using iodobenzene diacetate, PhI(OAc)2, as oxidant rather than peracetic acid.461 Many !-protecting groups survive and no racemization appears to occur and thus this modification could lead to more use being made of Dpm esters as viable alternatives to t-butyl esters. Full details have been given of the scope and limitations of carboxamidomethyl (CAM) esters (527) in peptide synthesis.462 CAM esters survive the removal of N - B w ,
N-FMoc,
and N-Z groups and are rapidily hydrolysed by 0.5M NaOH
or Na2C03. However, they are not always suitable for protecting one of the two acid groups in aspartic acids. Amino Group Protection. - Amino protecting groups such as benzyloxycarbonyl ( Z ) or 2,2,2-trichloroethoxycarbonyl (Tcc) can be introduced directly into amino-acids by treatment with the appropriate chloroformate in an inert solvent, usually ethyl acetate o r THF, without any added base. 4 6 3 Yields are moderate to good; the method is especially appropriate for lipophilic amino-acids and is superior to conventional Schotten-Baumann procedures in these cases. Alternatively, carbamates can be formed rapidily and efficiently from amines by reaction with bis (trimethylsilyl)acetamide followed by a chloroformate.4 6 4 Full details have been given for the preparation of N-Boc derivatives using two of the most popular reagents, di-t-butyl dicarbonate [ (Boc anhydride) or (Boc),Ol 465 and 2-(t-butyloxycarbonyloxyimino)-2-phenylacetonitrile [Boc-ON].4 6 6 The cheapness of the former would appear to be a distinct advantage. Yet another reagent for inkroducing N-Boc groups is 1,2,2,2-tetrachloroethyl t-butyl carbonate (528) [Boc-OTCEI.467
General and Synthetic Methods
170
The reagent is reasonably stable and crystalline, yields good to excellent returns of N-Boc-amino-acids (60-go%), and should be relatively cheap to produce. t-Butyl 2-pyridylcarbonate (529) is also very efficient in the synthesis of a range of ( 85- 90% ) .468 The corresponding benzyl analogue can also be used to obtain 3-Z-a-amino-acids. Should
N- Boc-amino-ac ids
-
these reagents become cheaply available they could well become popular. Rather stable amino protecting groups such as N-formyl, -acetyl, and -benzoyl (530) can be exchanged for !-Boc groups by first effecting N-acylation using (Boc) O-DMAP465 and 2 then treating the resulting bis-acylated amine (531) with a nucleophile such as hydrazine or 2-diethylaminoethylamine .469 The resulting N-Boc derivatives (532) are formed essentially quantitatively. The method has yet to be tried on a-amino-acid derivatives; attack at an ester group and racemization could present problems in these cases.
5-Boc groups themselves can be
transformed [(533)-+ (535)l into a variety of other N-alkoxycarbonyl functions by sequential treatment with TBDMS triflate (TBDMSOTF) and an alkyl halide in the presence of TBAF. 470
This efficient method could well add a new dimension to
synthetic planning in this area, as for instance, N-Boc functions can be readily transformed into N-Z groups.
__ N-Formyl derivatives (537) of primary and secondary amines can be prepared in excellent yield using the thiadiazoline (536) in a neutral solvent such as acetone; no additional base is required.471 The reagent (536) will also formylate alcohols but only in the presence of a weak base such as potassium carbonate. N-Allyloxycarbonyl functions can be efficiently removed by
-
treatment with a palladium ( 0 ) catalyst [Pd2(dba) .CHC13I and The method formic acid (3-4 equivalents) at 30 " C in THF.472 appears to be compatible with a wide range of other protecting '
groups.
A new !-protecting
group is the cinnamyloxycarbonyl
(Coc) function (538).473 The especially attractive feature of this group is that it can also be removed using a catalytic amount of a Pd(0) complex, in this case [Pd(PPh3)4], together with formic acid, pyridine,and N-hydroxysuccinimide scavenge the cinnamyl cations produced.
(HONSu) to
Notably, N-Z and 2-Boc
groups survive these conditions. The 2-nitrobenzenesulphenyl (Nps) group can be introduced into amino-acids using Nps-saccharin (539).474 stable to storage than Nps-C1
The reagent is more
(the usual reagent used to prepare
3: Carboxylic Acids and Derivatives
171
x0T0fc'3
XOTOD BOC
HN R ~
N R ~
AR,
R1 x H, M e o r Ph
0
OAR1
-
B ~ ~ N R Z H
(532)
(531)
(530)
0
0 NHBoc
TBDMSOTf
I?'-
X
____)
F-
RAC02Me
L
R
A
(535)
(534)
(533)
C02Me
0 N-N
/cHo
RNH2
ASAS
RNHCHO
I coc R+
0 (537)
(536 1
0
(538)
02N.
(539)
ry
(5411
(540)
172
General and Synthetic Methods
g-Nps derivatives) and provides comparable yields and purities of
-N-Nps-amino-acids. Sodium hypophosphite, NaH2P02, has been known to be an effective transfer hydrogenation reagent for some time and thus not surprisingly it has been found to be applicable to the 475 hydrogenolysis of benzyloxycarbonyl (PJ-Z) groups. Detailed kinetic studies have indicated that the diphenylphosphinoyl group, Ph2P(0), is the most suitable of this class of phosphinic acid-derived amino protecting groups for general peptide synthesis.476
Another useful phosphorus-based
roup is 2-(triphenylphosphonio)isopropyloxycarbonyl 277 Whereas the foregoing phosphinic acid derivatives (Ppoc) (540). are exceptionally acid labile, Ppoc groups and related phosphonium
N-protecting
species ( e d . Peoc groups) are very base labile and can even be An advantage of the Ppoc group is removed using NaHC03 (pH 8). that the propenyl phosphonium salt produced during deprotection does not undergo addition of the released amino-group; such additions can be serious side reactions with the Peoc function when vinylphosphonium salts are the initial products. Thiol Group Protection.
-
The
g - F l u , o r e n y l m e t h o x y c a r b o n y l group
(Fmoc) has been shown to be compatible with a range of thiol protecting groups such as g-acetamidomethyl, SBut and S-SBut during a solid state peptide synthesis of an oxytocin The idea of 2-deprotection being triggered by nonapeptide. 478 release of an amino-group in a substituent attached to the sulphur atom was first reported in 1973 but only this year have full experimental details been published concerning this ueful The S-acyl protecting groups (541) are derived from notion. 479 4-aminobutyric acids where the N-protecting group can potentially be any of the well established types.
(This current work uses
N-Boc and 1-Bpoc[(biphenylyl)isopropyloxycarbonyl] groups.) On deprotection at nitrogen, the intermediate amines (542) immediately collapse with the expulsion of the thiol group (543) and the formation of g-methylpyrrolidone (544). An alternative way to protect thiol groups is by formation of Michael adducts with aryl vinyl sulphones;4 8 0 the resulting 2-alkyl derivatives are easily unmasked by treatment with base in a manner 477 reminiscent of B-Ppoc groups. Clearly any amine functions must be protected before formation of these sulphur derivatives.
3: Carboxylic Acids and Derivatives
173
The usefulness of 1-adamantyl (Ad) groups in blocking thiol functions in cysteine has been demonstrated in a synthesis of a peptide (hCGRP).4 8 1 The S-Ad group is cleaved under acidic conditions using either CF3S03H-PhSMe or thallium trifluoroacetate in trifluroroacetate acid. References 1.
2.
W.Oppolzer, P-Dudfield,T.Stevenson, and T.Godel, Helv. Chim. Acta, 1985, 68, 121; W.Opplzer and P.Dudfield, Tetrahedron Lett., 1985, 26, 5037; F-Effenberger,T-Beisswenger,and H.Isak, g., p. 4335; G.Helmchen and G.Wegner, E., pp. 6047, 6051. See also K.Soni, H.Machida, and A-Ookawa,J. Chem. S o c . , Chem. Cmun., 1985, 469; P.Somfai, D.Tanner, and T.Olsson, Tetrahedron, 1985, 41, 5973. H.C.Brawn, T.Amai, M.C.Desai, and B-Singaram,J. Am. Chem SOC., 1985, 107 4980.
3. 4. 5.
D.H.R.Barton, H.Togo, and S.Z.Zard, Tetrahedron, 1985, 41, 5507; Tetrahedron Lett., 1985, 26, 6349. O.Sock, M.Troupel,and J. Perichon, Tetrahedron Lett., 1985, 2, 1509. W.C.Baird, Jr., R.L.Hartgerink, and J.H.Surridge, J. Org. Chem., 1985,
50,
4601. 6.
S.Randriamahefa, P.Deschamps, R.Gallo, and H-Grangette,Synthesis, 1985,
7.
S-Kajigaeshi,T.Nakagawa, N.Nagasaki, and S.Fujisaki, Synthesis, 1985,
8.
A.K.Chakraborti and U.R.Ghatak, J. Chem. S o c . , Perkin Trans. 1, 1985,
493. 674. 2605.
K.Sasaki, Y.Aso, T.Otsubo, and F.Ogura, Tetrahedron Lett., 1985, 26, 453. K.S.Kirshenbam and K.B.Sharpless, J. Org. Chem., 1985, 50, 1979; for an aldol route to cis-(12), see T.Mukaiyama, T-Yura,and N-Iwasawa,Chem. Lett., 1985, 8 0 r 11. J.-P.Depres, F.Coelho, and A.E.Greene, J. Org. Chem., 1985, 50, 1972. For a general discussion of the RuO4 cleavage step, see S.Torii, T-Inokuchi,and K.Kondo, E., p. 4980. 12. F.A.Davis and L.C.Vishwakarama, Tetrahedron Lett., 1985, 26, 3539; D.A.Evans, M.M.Morrissey, and R.L.Dorow, J. Am. Chem. SOC., 1985, 107, 9. 10.
4346. 13. 14. 15. 16. 17. 18. 19. 20. 21.
M.Enmto, Y.Ito, T.Katsuki, and M. Yamaguchi, Tetrahedron Lett., 1985, 26, 1343. -
K.Soai and H-Hasegawa,J. Chem. S o c . , Perkin Trans. 1, 1985, 769. D.Abenhaim, G.Boireau, and A.Deberly, J. Org. Chem., 1985, 4045. C.-H.Wong and J.R.Matos, J. Org. Chem., 1985, 50, 1992. Y.Ikeda and E.Manda, Bull. Chem. Soc. Jpn., 1985, 58, 1723. J.M.Chong and K.B.Sharpless, Tetrahedron Lett., 1985, 26, 4683. B.Ba1, C.T.Buse, K.Smith, and C.H.Heathcock, Org. Synth., 1985, 63, 89. S.H.Montgcanery, M.C.Pirrung, and C.H.Heathcock, Org. Synth., 1985, 63, 99. G-Helmchen,U.Leikauf, and 1.Taufer-Knopfel, Angew. Chem., 1nt.Ed. Engl.,
so,
1985,
22. 23.
24, 874.
T.Katsuki and M.Yamaguchi, Tetrahedron Lett., 1985, 26, 5807. S.G.Davies, 1.M.Dordor-Hedgecock, and P.Warner, Tetrahedron Lett., 1985, 26, 2125. -
26.
P.W.Ambler and S.G.Davies, Tetrahedron Lett., 1985, 3, 2129. M.Utaka, M.Hojo, and A.Takeda, Chem. Lett., 1985, 1471. For a synthesis of (+)-Corynqcolicacid, see Y.Kitano, Y.Kobayashi and F.Sato, J. Chem. Soc., Chem. C m . , 1985, 498. KZ.Deng, D.-A. Lu, and W.-H.Xu, J. Chem. Soc., Chem. C a ., 1985,
27.
M.W.Rathke and M.A.Nowak, Synth. C m . , 1985,
24. 25.
1478.
15, 1039.
General and Synthetic Methods
174
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General and Synthetic Methods
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378. S.C.Shim and K.M.Choi, Tetrahedron Lett., 1985, 26, 3277. 379. R-Pellegata,A.Italia, M.Villa, G.Palmisano, and G.Lesma, Synthesis, 1985, 517. 380. M.Inaba, T.Moriwake, and S.Saito, Tetrahedron Lett., 1985, 26, 3235. See also S.Brune1, B.Fixari, P.Le Perchec, and B.Sillion, p. 1013. 381. K.Sukata, Bull. Chem. SOC. Jpn., 1985, 58, 838. 382. Y.Inoue, M.Taguchi, and H.Hashimoto, Bull. Chem. SOC. Jpn., 1985, 58, 2721. 383. L.Berthon and D.Uguen, Tetrahedron Lett., 1985, 26, 3975. 384. K.Mikami, O.Takahashi, T-Kasuga,and T.Nakai, Chem. Lett., 1985, 1729. 385. A.Khalaj and E.Nahid, Synthesis, 1985, 1153. 386. Y.Ito, T.Katsuki, and M.Yamaguchi, Tetrahedron Lett., 1985, 26, 4643. See also M.G.Bock, R.M.DiPardo, B.E.Evans, K.E.Rittle, J.S.Boger, R.M.Freidlinger, and D.F.Veber, J. Chem. SOC., Chem. C m . , 1985, 109. 387. M.Fujita and T.Hiyama, J. Am. Chem. SOC., 1985, 107, 8294. 388. F.Ozawa, H.Soyama, H.Yanagihara, I.Aoyama, H.Takino, K.Izawa, T.Yamamoto, and A.Yamamoto, J. Am. Chem. SOC., 1985, 307, 3235; A.Yamamoto, T.Yatmmto, and F.Ozawa, pure Appl. Chem., 1985, 57, 1799. 389. C.H.Heathcock, M.A.Henderson, D.A.Oare, and M.A.Sanner, J. Org. Chem., 1985, 3, 3019. 390. E.Piers, J.M.Chong, and B.A.Keay, Tetrahedron Lett., 1985, 26, 6265. 391. C.Lambert, B.Caillaux, and H.G.Viehe, Tetrahedron, 1985, 2,3331. 392. P.Beak, D.J.Kempf, and K.D.Wilson, J. Am. Chem. S o c . , 1985, 107,4745. 393. R.J.Mills, R.F.Horvath, M.P.Sibi, and V.Snieckus, Tetrahedron Lett., 1985, 26, 1145. 394. M.P.Sibi, S.Chattopadhyay, J.W.Dankwardt, and V.Snieckus, J. Am. Chem. __ S o c . , 1985, 107, 6312. 395 * E.G.Doadt and V.Snieckus, Tetrahedron Lett., 1985, 26, 1149. 396. A.J.Carpenter and D.J.Chadwick, J. Org. Chem., 1985, 50, 4362. 397. K.Tanaka, H.Yoda, and A.Kaji, Tetrahedron Lett., 1985, 26, 4751. 398. S.-1.Murahashi and Y.Imada, Chem. Lett., 1985, 1477. 399. J.T.Welch and S.Eswarakrishnan, J. Org. Chem., 1985, 50, 5910. See also T.G.Schenck and B.Bosnich, J. Am. Chem. SOC., 1985, 107, 2058. 400. D.Hoppe, C.Gonschorrek, E.Egert, and D.ScWdt, Angew. Chem. , Int. Ed. Engl., 1985, 24, 700. 401. R.W.Saalfrank, F.Schutz, and U.Moenius, Synthesis, 1985, 1062. 402. D.N.Harpp, J.G.MacDonald, and C-Larsen,Can. J. Chem.,1985, 63, 951. 403, F.Dutron-Woitrin, R-Merenyi,and H.G.Viehe, Synthesis, 1985, 77 and 79. 404. M.Cinquini, A.Manfredi, H.Molinari, and A.Restelli, Tetrahedron, 1985, 41, 4929. 405. C.Goasdoue and M-Gaudemar,Tetrahedron Lett., 1985, 26, 1015. 406. A.Ogawa, J.-I.Miyake, Y.Karasaki, S.Murai, and N.Sonoada, J. Org. Chem., 1985, 50, 384; A.Ogawa, J.-I.Miyake, N.Kambe, S.Murai, and N.Son&, Bull. Chem. SOC. Jpn., 1985, 58, 1448. 407. Y.H.Kim, B.C.Chung, and H.S.Chang, Tetrahedron Lett., 1985, 26, 1079. 408. R.Gull and U.Schollkopf, _____ Synthesis, 1985, 1052. 409. U.Schollkopf, R.Lonsky, and P.Lehr, __________ Liebigs Ann. Chem., 1985, 413. 410. T.Weihrauch and D.Leifritz, Liebigs Ann. Chem., 1985, 1917. 411. H.-J.Neubauer, J.Baeza, J.Freer, and U.Schollkopf, Liebigs Ann. Chem. , 1985, 1508. 412. M.Grauert and U.Schollkopf, _______ Liebigs Ann. Chem., 1985, 1817. 413. U.Schollkopf , J-Nozulak,and M.Grauert, Synthesis, 1985, 55. 414. U.Schollkopf, H.-J.Neubauer, and M.Hauptreif, Angew. Chem., Int. Ed. Engl., 1985, 24, 1066. 415. D.Seebach and A.Fade1, Helv. Chim. Ace, 1985, 68, 1243; D.Seebach, p. 144; T.Weber and D.Seebach, J.D.Aebi, R.Naef, and T.W&r, ibid., p. 155. -
e.,
~
u.,
185
3: Carboxylic Acids and Derivatives
416. J.D.Aebi and D.Seebach, Helv. Chim. Acta, 1985, 68, 1507; D-Seebach, D.D.Miller, S.Muller, and T.Weber, g., p. 949. 417. Y.N.Belokon, N.I.Chemcglazova, C.A.Kochetkov, N.S.Garbalnskaya, and V.M.Belikov, J. Chem. SOC., Chm. C m u . , 1985, 171. 418. T.Mukaiyama, R-Tsuzuji,and J.-I.Kato, Chem. Lett., 1985, 837. 419. T.Sakakura and M.Tanaka, J. Chem. SOC., Chem. Cornnun., 1985, 1309. For a closely related method using nitrosobenzene as the nitrogen source, see T-Sasaki,K.Mori, and M.Ohno, Synthesis, 1985, 280. 420. T.R.Hoye, S.R.Duff, and R.S.King, Tetrahedron Lett. , 1985, 26, 3433. 421. D.W.Hansen, Jr., and D.Pilipauskas, J. Org. Chem., 1985, 50, 945. 422. M.J.O'Donnel1, W.D.Bennett, and R.L.Polt, Tetrahedron Lett., 1985, 26, 695. 423. M.J.O'Donnel1, and J.-B.Falmaqne, Tetrahedron Lett., 1985, 26, 699. 424. M.J.O'Donnel1, and J.-B.Falmaqne, J. Chem. Soc., Chem. Camun., 1985, 1168. 425. Y.Yamamoto, W.Ito, and K.Maruyama, J. Chem. Soc., Chem. Camnun., 1985, 1131.
426. R.Kober, K.Papadopulos, W .Miltz, D.Enders, W .Steglich, H .Reuter, and H.Fuff, Tetrahedron, 1985, 41, 1693. 427. K.Weinges, H.Brachmann, P.Stahnecker, H.Rodewald, M.Nixdorf, and H.Imgartinger, Liebigs Ann. Chem., 1985, 566. 428. H.Braxmeier and G.Kresze, Synthesis, 1985, 683. 429. I.Tabushi, Y-Kuroda,M.Yamada, H.Higashimra, and R.Breslow, J. Am. Chem. SOC., 1985, 107,5545. 430. J.A.Bajgrowicz, A.E1 Hallaoui, R.Jacquier, Ch.Pigiere, and Ph-Viallefont, Tetrahedron, 1985, 41, 1833. 431. C.Cardelliccio, V.Fiandanese, G-Marchese,F.Naso, and L-Ronzini, Tetrahedron Lett., 1985, 26, 4387. 432. J.N.Fitzner, R.G.Shea, J.E.Fankhauser, and P.B.Hopkins, J. Org. Chem., 1985, 50, 417. 433. J.E.Baldwin, R.M.Adlington, and B.J.Rawlings, Tetrahedron Lett., 1985, 26, 481; J.E.Baldwin, R.M.Adlington, B.J.Rawlings and R.H.Jones, ibid., p. 485. See also M.L.Izquierdo, I.Arena1, M.Bernabe, and E.F.Alverez, Tetrahedron, 1985, 41, 215; M.Pirrung and G.M.McGeehan, Angew. Chem., Int.Ed. Engl., 1985, 24, 1044; I.Arena1, M.Bernabe, E.F.Alrarez, and S.Penades, Synthesis, 1985, 773; C.Cativiela, M.d.Diazde Villegas, J.A.Mayora1, and E-Menendez, J. Org. Chem., 1985, 50, 3167. 434. K.Kurokawa and Y-Ohfune,Tetrahedron Lett., 1985, 26, 83. 435* D.Kalvin, K.Ramalingam, and R-woodard,Synth. Con'rnun., 1985, 15,267. 436. L.D.Amold, T.H.Kalantar, and J.C.Vederas, J. Am. Chem. S c c . , 1985, 107, 7105. 437. S.Saito, N.Bunya, M.Inaba, T-Moriwake,and S.Torii, Tetrahedron Lett., 1985, 26, 5309. See also K.J.Shaw, J.R.Luly, and H.Rapoport, J. Org. Chem., 1985, 50, 4515. 438. G.Guanti, L.Banfi, E.Narisano, and C.Scolastico, Tetrahedron Lett., 1985, 26, 3517; T.Oesterle and G.Simchen, Synthesis, 1985, 403. 439. Y.N.Belokon, A.G.Bulychev, S.V.Vitt, Y.T.Struchkow, A.S.Batsanov, T.V.Timofeeva, V .A.Tsyryapkin, M .G .Ryzhov, L .A.Lysava, v .I.Bakhumutov, andV.M.Belikov, J. Am. Chem. Soc., 1985, 107, 4252. 440. J.E.Baldwin, R.M.Adlington, and D.J.Birch, J. Chem. SOC., Chm. Ccmnun., 1985, 256; see also Tetrahedron Lett. , 1985, 26, 5931. 441. G.Calderari and D.Seebach, Helv. Chim. Acta, 1985, 68, 1592. 442. G.Chassaing, S.Lavielle, S.Julien, and A.Marquet, Tetrahedron Lett., 1985, 26, 623. 443. R.J.S.Hickman, B.J.Christie, R.W.Guy, and T.J.White, Aust. J. Chem. 1985, 38, 899. 444. H.Ohrui, T.Misawa, and H.Meguro, J. Org. Chem., 1985, 3, 3007; E.Santaniell0, R.Casati, and A.Manzocchi, J. Chem. Soc., Perkin Trans. 1, 1985, 2389. ~
General and Synthetic Methods
186
445. F.Bjorkling, J.Boutelje, S.Gatenbeck, K.Hult, and T.Norin, Tetrahedron Lett., 1985, 2389. 446. J.M.Chong and K.B.Sharpless, J. Org. Chem., 1985, 50, 1560. 447. N.Iwasawa, H.Huang, and T.Mukaiyama, Chem. Lett., 1985, 1045. 448. T.M.Williams, R.Cnnnbie, and H.S.Mosher, J. Org. Chem., 1985, 50, 91. 449. T.MorWto and M.Sekiya, Chem. Lett., 1985, 1371. 450. M.Hirama, T.Shigmto, Y.Yamazaki, and S.Ito, J. Am. Chem. Soc., 1985, 107, 1797; Tetrahedron Lett., 1985, 26, 4133. 451. S.Kim, C.H.Oh, J.S.Ko, K.H.Ahn, and Y.J.Kim, J. Org. Chem., 1985, 50, 1927. 452. P.Garner, J.M.Park, and V.Rotello, Tetrahedron Lett., 1985, 26, 3299. 453. B.Rajashekhar and E.T.Kaiser, J. Org. Chem., 1985, 50, 5480. 454. P.K.Tripathy and A.K.Mukerjee, Synthesis, 1985, 2857 455. U.Schmidt and J.Wild, Liebigs Ann. Chem., 1985, 1882. See also U.Schmidt, A.Lieberknecht, H.Griesser, and H.Bokens, , p. 785. 456. D.Knitte1, Monatsh. Chem., 1985, 116, 1133. 457. Y.Ito, T.Matsuura, and T.Saegusa, Tetrahedron Lett., 1985, 26, 5781. 458. J.N.Fitzner, D.V.Pratt, and P.B.Hopkins, Tetrahedron Lett., 1985, 26, 1959. 459. K.Agouridas, J.M.Girodean, and R.Pineau, Tetrahedron Lett., 1985, 26, 3115. 460. D.H.R.Barton, D.Crich, Y.Herve, P.Potier, and J.Thierry, Tetrahedron, 1985, 41, 4347. 461. L-Lapatsanis,G.Millias, and S.Paraskewas, Synthesis, 1985, 513. 462. J.Martinez, J.Laur, and B.Castro, Tetrahedron, 1985, 41, 739. 463. C.H.Kruse and K.G.Holden, J. Org. Chem., 1985, 50, 2792. 464. S.Raucher and D.S.Jones, Synth. C(xm-un., 1985, 15, 1025. 465. O.Kelle, W.E.Keller, G.van Look, and G.Wersin, Org. Synth., 1985, 63, 160. See also F.Houlihan, F.Bouchard, J.M.J.Frechet, and C.G.Wilson, Can. J.Chem., 1985, 63, 153. For exhaustive It-Ebcation' using (B~c)~C-CMAP, see L.Grehn and U.Ragnarsson, Angew. Chem., Int. Ed. Engl., 1985, 2, 510. 466. -PaleVeda, F.W.Holly, and D.F.Veber, Org. Synth., 1985, 63, 171. 467. G.Barcelo, J.-P-Senet,and G.Sennyey, J. Org. Chem., 1985, 50, 3951. 468. S.Kh, J.I.Lee, and K.Y.Yi, Bull. Chem. Soc. Jpn., 1985, 58, 3570. 469. L-Grehn,K.Gunnarsson, . And - U SOC., Chem. Cmun., 1985, 1317. 470. M.Sakaitani and Y.Ohfune, Tetrahedron Lett., 1985, 26, 5543. 471. H.Yazawa and S.GOt0, Tetrahedron Lett., 1985, 26, 3703. 472. I.Minami, Y.Ohashi, 1-Shimizu,and J.Tsuji, Tetrahedron Lett., 1985, 26, 2449. 473. H.Kinoshita, K-Inoanata,T.Kameda, and H.Kotake, Chem. Lett., 1985, 515. 474. S.Racanani, G.Bovermann, L.Moroder, and E.Wunsch, Synthesis, 1985, 512. 475. S.K.Boyer, J.Bach, J.McKenna, and E.Jagdmann, Jr., J. Org. Chem., 1985, 50, 3408; For a review of transfer hydrcgenation, see R.A.W.Johnstone, A.H.Wilby, and I.D.Entwistle, Chem. Rev., 1985, 85, 129. See also M.Makowski, B.Rzeszotarska, L.Smelka, and Z.Kibica, Liebigs Ann. Chem., 1985, 1457. 476. R.Rarmge, B.Atrash, D.Hopton, and M.J.Parmtt, J. Chem. Soc., Perkin Trans. 1, 1985, 1217. 477. H.Kunz and G.Schamloffe1, ________ Liebigs Ann. Chem., 1985, 1784. 478. E.Atherton, M.Pinori, and R.C.Sheppard, J. Chem. Soc., Perkin Trans. 1, 1985, 2057; E.Atherton, R.C.Sheppard, and P.Ward, p.2064. 479. N.G.Galakatos and D.S.Kemp, J. Org. Chem., 1985, 50, 1302. 480. L.Horner and H.Linde1, Liebigs Ann. Chem., 1985, 22, 34. 481. N.Fujii, H.Yajima, A.Otaka, S.Funakoski, M.Ndzu, K.Akaji, IsY-tO, K-Torizuka,K.Kitagawa, T.Akita, K.Ando, T.Kawamoto, Y.Skirranishi, and T.Taka0.J. Chem. Soc.. Chem. Ccrrrrom., 1985, 602. ~
s.
s.,
Alcohols, Halogeno-compounds, and Ethers BY L. M. HARWOOD
The p a t t e r n o f t h i s R e p o r t f o l l o w s t h a t u s e d p r e v i o u s l y .
Reactions
a r e c l a s s i f i e d a c c o r d i n g t o t h e t y p e o f compound p r e p a r e d w h e r e v e r possible.
E x c e p t i o n s are t h o s e r e a c t i o n s which a r e c o n s i d e r e d t o
be a l c o h o l p r o t e c t i o n o r d e p r o t e c t i o n procedures.
Miscellaneous
r e a c t i o n s o f a p a r t i c u l a r c l a s s o f compound a r e l i s t e d a t t h e e n d
Cross r e f e r e n c i n g i s g i v e n t o p r e v i o u s r e p o r t s u p
of each section. t o Volume 8 . 1 Alcohols
P r e p a r a t i o n by A d d i t i o n t o A 1 k e n e s . -
Low-activity
boranes i n the
p r e s e n c e o f r h o d i u m c o m p l e x e s (3. catecholborane-Wilkinson's c a t a l y s t ) a r e r e p o r t e d t o add p r e f e r e n t i a l l y t o a l k e n e s i n t h e p r e s e n c e of c a r b o n y l groups
'
(cf. V o l . 1 ,
p.158;
Vo1.2, p . 1 1 4 ) .
w i t h di-isopinocamphenylborane
Reaction of cyclohexa-l,3-diene
y i e l d s a l l y l i c b o r a n e i n t e r m e d i a t e s which a r e c o n f i g u r a t i o n a l l y s t a b l e a t -25
OC
and r e a c t w i t h a l d e h y d e s t o f u r n i s h o p t i c a l l y
a c t i v e l-(cyclohex-2-enyl)-l-alkanols
( 1 ) i n good d i a s t e r e o m e r i c
a n d e n a n t i o m e r i c e x c e s s .2 S o d i u m a c e t o x y b o r o h y d r i d e , g e n e r a t e d by t h e a c t i o n o f m e r c u r y ( I 1 ) a c e t a t e o n s o d i u m b o r o h y d r i d e i n THF, p r o v i d e s a u s e f u l means o f h y d r o b o r a t i n g o l e f i n s s e l e c t i v e l y i n t h e p r e s e n c e o f carboxylic acids.'
H y d r o b o r a t i o n s and r e d u c t i o n s u s i n g t h i s
r e a g e n t have been reviewed.ll
Amino-acids
have been used as c h i r a l
n u c l e o p h i l e s t o c o n v e r t o l e f i n s i n t o c h i r a l a l c o h o l s by a n a c y l o x y m e r c u r a t i o n p r o c e d u r e b u t t h e o p t i c a l y i e l d s were d i s a p p o i n t i n g (Scheme 1 ) . 5 P r e p a r a t i o n by R e d u c t i o n o f C a r b o n y l C o m p o u n d s . -
R e d u c t i o n s of
c a r b o n y l compounds h a v e b e e n r e p o r t e d u s i n g d i p h e n y l s t i b i n e , a n i o n i c Group 6 t r a n s i t i o n - m e t a l
6
c a r b o n y l h y d r i d e s (chromium and
tungsten),
and sodium h y p o p h o s p h i t e i n t h e p r e s e n c e of p a l l a d i u m -
charcoal.8
However,
t h e latter system only gave useful y i e l d s of
187
For References see p. 224
188
General and Synthetic Methods
a l c o h o l s w i t h b e n z y l i c c a r b o n y l compounds. Meerwein-Pondorf-Verley t y p e reductions have been described u s i n g zirconium oxide' and activated nickel s o u r c e (Vo1.2,
i n con j u n c t i o n w i t h propan-2-01
p.114;
Vo1.5,
p.152).
as t h e h y d r i d e
Both methods g i v e g e n e r a l l y
e x c e l l e n t y i e l d s w h i c h , i n t h e f o r m e r case, is a t l e a s t p a r t l y d u e t o t h e s i m p l i f i e d work-up
procedure,
f i l t r a t i o n and e v a p o r a t i o n .
t h e p r o d u c t b e i n g o b t a i n e d by
Amylose h a s b e e n shown t o i m p r o v e
s e l e c t i v i t y i n t h e 1,2-reduction of cyclohex-2-enones
w i t h sodium
borohydride,
t o t a l l y i n h i b i t i n g t h e f o r m a t i o n of o v e r - r e d u c e d
material.
Similarly
,
phase-transfer
c a t a l y s t s and crown e t h e r s
have been used t o s o l u b i l i z e l i t h i u m aluminium hydride f o r carbonyl group reduction i n non-polar
solvents. l2
Chemoselective Carbonyl Reductions.
Selective reducing agents f o r
aldehydes over ketones which have been r e p o r t e d t h i s y e a r i n c l u d e a f o r m i c acid-trialkylamine-ruthenium(I1) s y s t e m 1 3 ( V 0 1 . 2 ,
p. 1 1 5 ) ,
t e t r a e t h y l a m m o n i u m dimolybdenum(decacarbony1) h y d r i d e , l 4 a n d s o d i u m s u l p h i d e on a l u m i n a . l5
are u n a f f e c t e d .
With t h e l a t t e r s y s t e m a r o m a t i c n i t r o - g r o u p s
Aminoalcohol-borane
complexes s e l e c t i v e l y reduce
a r y l k e t o n e s , w h i l s t v a r i a n t s i n w h i c h t h e a m i n o a l c o h o l i s immobil i z e d on a p o l y m e r i c s u p p o r t show e n h a n c e d r e d u c t i o n r a t e s o f 16
aldehydes over ketones.
Sodium c y a n o b o r o h y d r i d e m o d i f i e d w i t h z i n c c h l o r i d e w i l l r e d u c e a l d e h y d e s , k e t o n e s , and a c i d c h l o r i d e s t o a l c o h o l s , b u t n o t a c i d s , a n h y d r i d e s , o r e s t e r s , l 7 and sodium b o r o h y d r i d e s e l e c t i v e l y r e d u c e s e n o n e s t o a l l y l i c a l c o h o l s when t h e r e a c t i o n i s c a r r i e d o u t i n methanol-THF a t 0
OC.
S t e r e o s e l e c t i v e Carbonyl Reductions. acyl-y-lactones
L-selectride
r e d u c t i o n of
4-
h a s b e e n shown t o f u r n i s h t h e s y n - r e d u c t i o n
p r o d u c t s i n g o o d y i e l d a n d h i g h d i a s t e r e o s e l e c t i o n w h i c h may b e hydrolysed t o threo-diols.
The s t e r e o c h e m i s t r y a p p e a r s t o b e
l a r g e l y i n d e p e n d e n t of t h e s i z e o f t h e a c y l g r o u p and i s i n a c c o r d w i t h r e d u c t i o n f o l l o w i n g t h e Felkin-Ahn
t r a n s i t i o n - s t a t e model
(Scheme 2 ) . A l t e r n a t i v e d i a s t e r e o s e l e c t i o n m o d e s i n t h e r e d u c t i o n o f aa l k o x y a c e t y l e n i c k e t o n e s h a v e b e e n a c h i e v e d by u s i n g z i n c b o r o h y d r i d e i n e t h e r a t -30
(cf. V o l . 8 ,
p.206)
erythro-isomers
,
OC,
t o f u r n i s h mainly t h e threo-product
and by K - s e l e c t r i d e
predominate. 2o
i n THF a t -95
OC
when t h e
Lithium aluminium hydride h a s been
shown t o r e d u c e a c y c l i c d i k e t o n e s w i t h a d i a s t e r e o s e l e c t i v i t y t h a t
4: Alcohols, Halogeno-compounds, and Ethers
0 R
e
i,
R b H g x H
189
-
OH
ii, iii
R
Reagents : i , N - protected amino-acid ( 2 equiv.), Hg(N0 1 ( 1 equiv.) , CH C I 22 2 2; ii , a q . NaOH iii , NaBH4
Scheme 1
&CH2-hOH
H
( a ) R = H or ~ r '
(b)
R
unti: Minor
r
dpo H
R L
Reagent z i , L
- select r ide , THF, r . t . Scheme 2
+yo
HO
syn: Major
190
General and Synthetic Methods
is dependent upon the relationship between the two carbonyl groups. 21 Thus , 1 , 2- and 1,4-diketones yield largely the mesodiols whereas 1,3- and Il5-diketones yield the d,l-isomers, possibly diastereoface differentiating reduction of the initial However, this effect can be reversed in intermediates (Figure 1). the case of 1,3-diketones by complexation with titanium(1V) chloride when the meso-diol is obtained .22 The authors rationalize this by invoking attack at the si face of the titanium complex in the preferred conformation shown in Figure 2. Asymmetric Carbonyl Reductions. Examples of hydride reagents modified with a chiral auxiliary published during the past year include lithium aluminium hydride partially decomposed with
(-)-E-
m e t h y l e p h e d r i n e - 2 - a l k y l a r n i n o p y r i d i n e ~ ~or ~ various 2 , 2 ' -diamino-
1 , 1 I-binaphthyls (3) , " diisobutylaluminium hydride complexed with tin(l1) chloride, and (S)-N-methyl-2-(piperidinomethyl)pyrrolidine - (derived from (?)-proline) , 25 sodium b o r o h y d r i d e - 8 - c y c l o d e x t r i n complexes,26 and lithium borohydride-N-benzoylcysteine. 27 In only
a few instances, however, do the reported enantiomeric excesses approach 90%. Boranes complexed with quinine and quinidine have been used in conjunction with boron trifluoride to produce selectively either enantiomeric benzyl alcohols in the reduction of aryl methyl ketones, with enantiomeric excesses of the products falling in the range 45-55%.28 Optical yields up to 90% have been obtained using chiral u-amino-alcohols (4) as the auxiliaries29 (v01.8, p.207), and the same research group has reported further studies in which similar enantiomeric excesses were obtained by binding these auxiliaries to a polymeric support (5). '3 Diisopinocampheylchloroborane has been demonstrated to reduce aromatic prochiral ketones, even those which prove to be less reactive towards Midland's reagent (Vo1.2, p.l15),in enantiomeric excesses approaching loo%, particularly if the reductions are 9carried out under high (several kbar) pressure. 31 Tris ( myrtany1)gallium (6) has also been developed as a chiral reducing agent for ketones with the optical purity of the product alcohols ranging from 21 to 75% when the reduction is carried out in the absence of solvent at 50 0 C . 3 2 Further details have been published on the use of g-(3-pinanyl)9-borabicyclononane in the reduction of prochiral ketones33 (Vol.2, p.115; Vo1.5, p.156). Raney nickel modified with (R),(E)-tartaric
4: Alcohols, Halogeno-compounds, and Ethers
191
H-(si 1
0 3 y H'
meso-dioIs
H
H-
H- ( r e )
I
d,/-diols Figure
1
H
+
H'(re)
meso- diol
d,l - d i o l
Figure
1-
2
(re)
192
General and Synthetic Methods
acid has been found to exhibit enantioface differentiation in the hydrogenation of alkyl methyl ketones, furnishing the (S)-alcohols in excesses of 63-80%.~' Enzymic Asymmetric Carbonyl Reductions. Microbial reduction of ketones continues to result in the highest optical yields of chiral alcohols. Baker's yeast has been the most frequently used system with a wide range of substrates such as B-keto-esters, 35 6-ketoacids , 36 a-keto-dithianes ,37 a-phenylthioketones, 38 and acetophenone derivatives. 39 In all instances optical yields close to quantitative are recorded, with variable but often excellent chemical yields. 37939 Preparation by Nucleophilic Addition.- The monoanion of 1,4-dioxene has been developed as a two-carbon homologating agent for converting carbonyl compounds into B-keto-alcohols &y an additionhydrolysis-reduction sequence (Scheme 3 ) . 40 Monocyclopentadienylalkyltitanium reagents (u. CpTiMeC12) prove to be stable and convenient reagents f o r alkylating ketones.4' Conversion of Grignard or lithium reagents into their titanium analogues with ClTi(0Pr' ) 3 converts them into chemoselective nucleophiles for aldehydes and ketones in the presence of halides, esters, amides, or cyano- or nitro-groups.42 In a related example of chemoselectivity, methyltris(isopropoxy)titanium has been found to methylate a- and B-hydroxycarbonyl compounds preferentially over the deoxy-analogues (Scheme 4) . 4 3 These reagents also react with aldehydes and ketones possessing an asymmetric a-carbon to yield mainly (195%) Cram addition products when the reaction is performed at low temperature (~01.8,p.213) .44 A procedure f o r selective a- or 7-thioallylation of carbonyl compounds with allylthiol and thioethers has been reported. y-Attack occurs with the complex prepared when allylthiol is converted into its bisanion and then reacted with t r i s ( i s o p r o p o x y ) t i t a n i u r n chloride (Scheme 5 , path a). However, the equivalent complexes derived from the monoanions of allyl thioethers add selectively at the a-position (Scheme 5, path b).45 Enantioselective alkylation of aromatic aldehydes has been achieved with 517-987~ enantiomeric excesses using the chiral titanium binaphthol derivatives ( 7 ) . 46 Cerium(II1) chloride has been reported to promote nucleophilic addition of Grignard reagents to ketones, generating tertiary
193
4: Alcohols, Halogeno-compounds,and Ethers
~
c
H
2
0
~
p
NH, OH
$hq C H , &
3
(6)
(5)
Reagents:
[
i . B u t L i , THF, - 3 0 ' C ,
ii. R'R'CO,
Scheme
THF, - 3 O ' C ; iii, L i A I H 4
3
42 "lo
1'lo
Reagents: i, ( P r ' 0 I 3 T i M e , THF, - 6 0 'C
Scheme
R e a g e n t s : i, BunLi , E t 2 0 / T M E D A , O ' C
iii , R' R*CO,
- 80 *c
;
Scheme
4
ii, Ti(OPr')gCI, -70-
5
-30.C;
Ga
194
General and Synthetic Methods
alcohols, even when the substrates are susceptible to side reactions (enolization, reduction) with Grignards alone.47 A procedure has been reported in which aldehydes may be allylated efficiently in an aqueous solvent system using aluminium metal and catalytic tin(I1) chloride.48 In the reaction cycle (Scheme 6), Sn(O), which is generated in situ, forms diallyltin dichloride; this then reacts with the aldehyde, generating the alcohol and a Sn(1V) species which is reduced back to Sn(0) by the aluminium. Metallic zinc has also been used to allylate carbonyl compounds in aqueous medium (sat. NH4C1-THF, 5: 1 ) .49 This reagent system is highly chemoselective for aldehydes but substitution of tin for zinc and use of ultrasound renders the process even more efficient (Scheme 7 ) . In a inore conventional use of alkyl tin reagents, allyltriphenylstannane has been found to add in a highly diastereoselective manner to a-methylthioaldehydes forming largely the anti-adducts (>94%) (Scheme 8 ) . 50 The presence or absence of HMPA in the reaction medium has been found to affect the stereochemical course of addition of diethylzinc to 2,3-dihydropyran-2-carboxaldehyde .51 In the absence of HMPA the chelation propensity of zinc results in selective formation of the threo-product whereas the erythro-Cram product is obtained when chelation is disrupted with HMPA and ethyl-lithium is the nucleophile (Scheme 9). Nickel, produced in situ by reduction of nickel(I1) iodide with lithium-naphthalene (Vo1.8, p.233), can be used to carry out Reformatski-type addition of bromoacetonitrile to aldehydes,5 2 a n d bismuth in DMF has been found to promote the addition of ally1 halides to aldehydes, leading to homoallylic alcohols .53 BAlkynyl-9-BBN reagents have been developed to convert carbonyl compounds into propargylic alcohols. " The reagents are very sensitive to steric factors such as a-substitution in aldehydes or Pfitzer strain in cyclic ketones. An effective means of benzylating carbonyl compounds has been reported using benzyltrimethylsilane in the presence of fluoride when the corresponding benzyl alcohols are obtained in good to excellent yields. 55 a-Halogenoketones react with aldehydes in the presence of chromium(I1) chloride to give the aldol products .56 Morpholine enamines have been shown to undergo efficient cross-aldol condensation with aldehydes under Lewis acid catalysis whereas the pyrrolidine and piperidine analogues gave low yields or no adducts at all.57
4: Alcohols, Halogeno-compounds, and Ethers
195
OH
Reagent : i , S n C t 2 ( 0 . 1 e q u i v . ) , A l ( 1 equiv.), MeOCH2CH20H/H20/AcOH,50*C, 6h
Scheme
6 Yield (%)
OH
0
Reagents: i ,
Zn, s a t . a q . NHbCI-THF ( 5 : 1 ) , r . t . s t i r r i n g
ii, Sn, H20-THF ( 5 : 1 ) , r . t . , u l t r a s o u n d .
Scheme
7
i
ii
196
General and Synthetic Methods
OH
Reagent :
OH
- 25.C
i , CH2= CHCH2SnPh3 , SnCL4( 2 e q u i v . ) , C H 2 C 1 2 , -70-
Scheme
8
- QJ.'
I
4
//
. .
\
/ \
Et
\
I
/
%;
1
Et-
J
L
Reagents:
i , E t 2 Z n , E t 2 0 . 0-
20'C, 5 h
Scheme
/ \ \/
ii
OH three
\
;
9
/ I
,/
\ \\ \
\
4
H crythro
ii, E t L i , Et20-HMPA
4: Alcohols, Halogeno-compounds, and Ethers
197
D i a s t e r e o s e l e c t i v e a l d o l c o n d e n s a t i o n s c o n t i n u e t o a t t r a c t much attention. y - A l k o x y b o r o n a t e s a d d t o a l d e h y d e s a t room t e m p e r a t u r e i n t h e a b s e n c e of s o l v e n t t o y i e l d a d d u c t s w i t h a b o u t 90% d i a s t e r e o s e l e c t i o n , d e p e n d e n t upon t h e i n i t i a l s t e r e o c h e m i s t r y o f t h e b o r o n a t e (Scheme 10;
cf.
Vo1.8, p . 2 1 7 ) .
Although r e l a t i v e l y s l u g -
g i s h a t a t m o s p h e r i c p r e s s u r e t h e r e a c t i o n s a r e a c c e l e r a t e d by t h e a p p l i c a t i o n of high (10 kbar) pressure.58 The same r e s e a r c h g r o u p h a s shown t h a t t h i s d i a s t e r e o s e l e c t i v i t y a l s o a p p l i e s t o t h e addition of crotyl boronates t o a-chiral
a l d e h y d e s , and t h e f a c t o r s
a f f e c t i n g t h e outcome o f t h e s e c o n d e n s a t i o n s have been c o n s i d e r e d 5 9
( ~ 0 1 . 6 , p.169).
O t h e r s have demonstrated t h a t a d d i t i o n s of t h e
simple a l l y 1 boronate system t o a - c h i r a l erythro-adducts
aldehydes favour the
( S c h e m e 1 1 ) . 60
A f u l l paper has appeared describing addition of the anion d e r i v e d f r o m t - b u t y l 2-(N,N-dimethylamino)propanoate t o c h i r a l a-
a l k o x y - a l d e h y d e s w h i c h , a f t e r quaternization-elimination, f u r n i s h anti-a-methylene-8-alkoxy-esters. 6 1 The same g r o u p h a s now p r e s e n t e d d e t a i l s of a c o m p l e m e n t a r y p r o c e s s l e a d i n g t o t h e products
via
chelation-oontrolled
a-thiosilylketene
syn-
L e w i s a c i d promoted a d d i t i o n of
a c e t a l s t o a-alkoxy-aldehydes
marked c o n t r a s t t o t h i s , t h e t - b u t y l
( S c h e m e 1 2 ) -6,2
In
t h i o e s t e r s i l y l ketene acetal
( 8 ) a d d s t o t h e s e a l d e h y d e s u b s t r a t e s w i t h good s e l e c t i v i t y f o r t h e anti-Cram a d d u c t s , r e g a r d l e s s of t h e s t e r e o c h e m i s t r y of t h e e n o l a t e , under L e w i s a c i d c a t a l y s e d c h e l a t i o n c o n t r o l c o n d i t i o n s . 63 Work h a s a p p e a r e d d e s c r i b i n g t h e a d d i t i o n o f a l l y l t r i m e t h y l silane t o the protected glyceraldehyde (9).
T h i s can be c a r r i e d o r non-chelation-controlled c o n d i t i o n s , d e p e n d i n g upon t h e c h o i c e o f L e w i s a c i d , l e a d i n g t o t h r e e cont i g u o u s o x y g e n a t e d c e n t r e s , two o f w h i c h h a v e d e f i n e d s t e r e o o u t under c h e l a t i o n -
c h e m i s t r y ( S c h e m e 1 3 ) .64 S i m i l a r c h e l a t i o n c o n t r o l h a s b e e n u s e d i n t h e TiC14 a d d i t i o n o f a l l y l t r i m e t h y l s i l a n e t o 3 - a l k o x y a c y l cyanides t o prepare 3-alkoxycyanohydrins
with high (99%) d i a s t e r e o meric p u r i t y , 65 a n d N-methylephedrine-derived s i l y l k e t e n e a c e t a l s have been u t i l i z e d w i t h T i C 1 4 i n t h e p r e p a r a t i o n o f a-methyl-@h y d r o x y - e s t e r s w i t h h i g h e n a n t i o m e r i c e x c e s s e s .66 Chelationc o n t r o l l e d a d d i t i o n o f Grignard r e a g e n t s t o a-benzyloxyaldehydes m e d i a t e d by z i n c b r o m i d e h a s b e e n r e p o r t e d t o f o r m t h e m o n o p r o t e c t e d t h r e o - d i o l s i n g o o d s e l e c t i v i t y a n d y i e l d . 67 T h e s e a l d e h y d e s w i l l u n d e r g o c h e l a t i o n o r d i p o l a r d i r e c t i o n o f a t t a c k by u s i n g t h e a n i o n d e r i v e d from t h e a - k e t o t h i o a c e t a l ( 1 0 ) o r L e w i s acid catalysed addition of the s i l y l enol ether (11) respectively
198
General and Synthetic Methods
erythn,
R3 k2
Reagent:
i , R 3 C H 0 , n e a t , r . t . , 6- 2 0 d a y s or
?-+-
+
.”+
I
I
OH
HO
erythro (major 1
Scheme
thrco
11
BzO
OSiMe3
\-/
10 kbar , several hours
Go
yo
MeS
R2 ‘OH
10
Scheme
OHC
v
threo
i , ii
OH
*
BzO
i)H
+ 1
Bz?
C02Me 18 : 1
SYn
C0,Mc
iii, i v
OH
unti
p z Reagents: i ,
j\CHO, MgBr2, CH2C12, - 78.C;
aq. McOH, i v , H e a t , dioxane
Scheme 12
ii, aq.‘AcOH
iii, N a I 0 4 ,
199
4: Alcohols, Halogeno-compounds, and Ethers
OSiMe,
Reagents: i , TiCI4,
%S,Meg
;
ii, BF3.EtZ0,
Scheme
mSiMe3
13
OTMS
AI
SMe
SMe
Yield
(11 1
(10)
(*I*)
i
ii
13
70
SMe OBz
0
ii
*
OH
’kv
SMe 002
R e a g e n t s : i , (10) , L O A , T H F
;
i i , ( 1 1 1 , M g B r 2 , CH2CI2, 0.C
Scheme 14
General and Synthetic Methods
200 (Scheme 14).68 Raney nickel.
The products can be readily desulphurized with
Dianions of cyclohexane-1,2-diones have been shown to undergo aldol condensation at the sterically more accessible position to yield mainly the threo-adducts (Scheme 15) .69 The chiral azaenolate (12) has been utilized in the enantioselective synthesis of anti-threo-aldols ,70 and the organometallic complexes (13) have been used in the stereoselective synthesis of a-methyl-B-hydroxy-acids. 7 1 ( a - L i t h i o a l k y 1 ) d i r n e s i t y l b o r o n reagents have been used in a boron-Wittig variant to convert aldehydes stereoselectively into erythro-1,2-diols after oxidative removal of the boron from the initial adduct .72 The epoxide moiety in glycidic acids has been shown to be opened with organocuprates in good yield with a regioselectivity which is dependent upon the stereochemistry of the epoxide; trans-epoxides favour B-hydroxy-acid formation and cis-epoxides the a-hydroxyacids. 7 3 The metal-halogen exchange induced cyclization of terminal iodoepoxides has been demonstrated to be dependent not only upon chain length and substitution pattern of the substrates but also on the presence of certain Lewis acids and metal halides.
For example, substrate ( 1 4 ) gave mainly cyclobutane-
methanol in the absence of additives and solely cyclopentanol when copper(1) bromide-dimethyl sulphide complex was present (Scheme 16). Epoxides may be converted into B-amino-alcohols by treatment with halogenomagnesium alkylamides, prepared in situ from the requisite amine and a Grignard reagent .75 Sodium hydrogen telluride has proven useful in the reductive SN 2 cleavage of epoxides,76 and the zinc tartrate catalysed opening of cyclohexene epoxide with thiols has been used to prepare optically active cyclohex-2-en-l01, after oxidation and elimination of the adduct initially formed, with enantiomeric excesses of up to 85% (Scheme 17).77 Cleavages of epoxides to 1,2-diol derivatives have been carried out using organotin phosphate catalysts,7 8 and palladium-catalysed conversion into cyclic carbonates (Scheme 1 8 ) , hydrolysis of which results in a two-step cis-dihydroxylation process f o r alkenes.” Lithiomethyl- and a-lithioethyl-dimesitylboron (15a,b) have been used as hydroxymethylene anion equivalents in the conversion of epoxides into 1,3-di0ls.~’ Alkyl hydroperoxides on alumina have been shown to convert epoxides into 2-peroxy-alcohols and (in lower yield) oxetanes into
20 1
4: Alcohols, Halogeno-compounds, and Ethers
&o-
w
R
R%o"
R
R
e ry t hro
thrco ( m a j o r )
Scheme
R
15
Et (13)
(12)
R = H , X = AIEt2 R = M e , X = Li
ol
OH
OH
(14)
Yield (%)
Reagents: i , ButLi ( 2 . 2 equiv.), - 78.C ii, ButLi ( 2 . 2 equiv.),
- 78 *C ,
72
10
-
30
CuBrMepS ( 0 . 5 equiv.)
Scheme 16
General and Synthetic Methods
202
oo-
ii, iii
Reagents: i , R S H , zinc t a r t r a t e (0.1 e q u t v . ) , CH2CIZi ii,
MCPBA
;
iii, CaC03, 1 5 O o C
Scheme
I
R
17
-
0 R3
Reagent:
i , Pd c a t a l y s t , C 0 2 , 40 p s i
Scheme
18
(15) a; R = H
b; R = Me
Reagents: i , TiCI4 ( 1 e q u i v . )
, CH2Ct2, -1OO*C Scheme
19
ii, aq: O . 1 M - K O H
4: Alcohols, Halogeno-compounds,and Ethers
203
3-peroxy-alcohols, which can be converted into the corresponding diols . 8 1 Oxetane has been opened by titanium(1V) chloride promoted attack of allylic trimethylsilanes (Scheme 1 9 ) , 8 2 and a combination of trimethylsilyl cyanide-zinc iodide has been used to convert oxetanes regioselectively into y-amino-alcohols via the intermediacy of the isocyanide silyl ethers (Scheme 20).83 General Methods of Preparation . 8 4 - A review has been published covering the use of titanium(II1) chloride to catalyse the pinacol condensation .85 A mild method for hydrolysing primary alkyl halides, of particular use if base-labile groups are present, has been described which uses sodium formate in HMPA followed by chromatography on neutral alumina . 8 6 A high-yielding conversion of carboxylic acids into the lower alcohol homologue has been developed which proceeds via decomposition of the mixed anhydride with thiohydroxamic acid with tris(pheny1thio)antimony in the presence of Boronic esters have been shown to react with oxygen and water.87 dic hloromethyl-li thium88 or ( phenyl thio)me thoxymethyl-li thium8’ to furnish products which can be converted into homologated alcohols (Scheme 21). The procedure has also been used to prepare chiral alcohols of high optical purity by initial asymmetric hydroboration followed by removal of the chiral auxiliary on conversion into the boronic ester. Regioselective a‘-hydroxylation of a,B-unsaturated ketones has been achieved in moderate yields by oxidation of the kinetically obtained silyl enol ethers with triphenyl phosphite ozonide Similarly, the silyl enol ethers of 8-keto-esters may be oxidized with m-chloroperbenzoic acid, resulting in a-hydroxylat ion. An efficient photoreductive cyclization of d , ~ - u n s a t u r a t e dketones in HMPA-triethylamine to cyclopentanols has been described . 9 2 Opening
of dihydropyrans with a base comprising LDA and potassium t-butoxide provides a means of regio- and stereo-controlled access to 2,4-dienols in moderate yields.93 A full paper has been published detailing work on the vanadium-molybdenum complex-catalysed isomerization of allylic alcohols with bis(trimethylsily1) peroxide, which produces the alcohol possessing the highest degree of a-substitution .94 The palladium-catalysed addition of aryl iodides to propargyl alcohols provides a route for the preparation of y , y diarylallylic alcohols (Scheme 2 2 ) , the best yields being obtained when the aromatic iodides are further substituted with electrondonating groups. 95
General and Synthetic Methods
204
-
R'
i i , iii
CNPosi Me R' R2 R' R2 Reagents: i , Me3SiCI, Z n 1 2 , CH2C12, reflux
Scheme
;
ii, HCI , MeOH
;
iii, aq. NaOH
20
iv( X
Reagents:
ii, P h S ( M e 0 ) C H L i ; iii, HgCI2; i v ; KB(OPr'I3H
i , LiCHC12, -1OO.C;
v , H 2 0 2 , aq. NaOH
;
v i , H 2 0 2 , pH 8
Scheme
R'
= CI)
;
vii, BH3Me2S
21
OH
x
R2
I
RH '
o
I R e a g e n t : i , [ Pd(OAc)2( PPh3)2] , pipcridinc
Scheme
- DMF-
22
HCOZH
dX
;
205
4: Alcohols, Halogeno-compounds, and Ethers
The p r e p a r a t i o n o f a n o r g a n o a l u m i n i u m r e a g e n t w h i c h , a l t h o u g h o f
is considered t o possess a tin-aluminium
undetermined composition,
bond, and i t s u s e i n c o n v e r t i n g a l l y l i c phosphonates
i n t o homo-
a l l y l i c a l c o h o l s i n t h e p r e s e n c e of a palladium c a t a l y s t have been described
(Scheme 2 3 )
.96
l 1 3 - D i o l s may b e p r e p a r e d by a p r o c e d u r e u s i n g a t a n d e m a l d o l addition-metal
a l l y 1 a d d i t i o n p r o c e d u r e w i t h e n o l b o r a t e s (Scheme
.
2 4 ) 97 P r o t e c t i o n and Deprotection.-
A review of t h e use of o r g a n o s i l i c o n
r e a g e n t s f o r t h e p r o t e c t i o n o f a l c o h o l s and o f
1 , 2 - and I l 3 - d i o l s
An i m p r o v e d p r o c e d u r e f o r
has appeared during t h e past year.98
p r e p a r i n g c h l o r o m e t h y l m e t h y l e t h e r f r o m m e t h o x y a c e t i c a c i d i n two s t e p s h a s been p u b l i s h e d g 9
(cf.Vol.4,
p. 153) and p r o c e d u r e s f o r
t h e i n s i t u preparation of t-butyldimethylsilyl described. loo
t r i f l a t e have been
The p r e p a r a t i o n and u s e o f t h e x y l d i m e t h y l s i l y l This
c h l o r i d e f o r t h e p r o t e c t i o n of a l c o h o l s h a s been r e p o r t e d . ” ’
g r o u p i s r e p o r t e d t o be c l e a v e d a r o u n d 2-3 t i m e s more s l o w l y t h a n t h e TBDMS p r o t e c t i n g g r o u p .
as a n a c i d - l a b i l e ,
The p r e p a r a t i o n a n d u s e o f I l 4 - d i o x e n e
a l t e r n a t i v e protecting group f o r alcohols t o
dihydropyran have been r e p o r t e d . I o 2
The r e a g e n t i s s t a b l e f o r
s e v e r a l months i f s t o r e d i n t h e c o l d and, w h i l s t similar i n r e a c t i v i t y t o dihydropyran, has t h e advantage t h a t t h e high-field of n.m.r.
s p e c t r a o f d e r i v a t i v e s is n o t masked.
region
Anisyl e t h e r s have
b e e n d e s c r i b e d a s a v e r s a t i l e means o f p r o t e c t i n g a l c o h o l s which c a n b e r e m o v e d by m i l d o x i d a t i o n w i t h c e r i c ammonium s u l p h a t e w i t h o u t a f f e c t i n g THP e t h e r s . I o 3
1,8-diazabicyclo[5.4.O]undec-7-ene
Two r e s e a r c h g r o u p s h a v e r e p o r t e d (DBU) t o b e a m i l d e r a n d m o r e
g e n e r a l b a s e f o r TBDMS e t h e r f o r m a t i o n t h a n t h e i m i d a z o l e - D M F system, t h e o r d e r of p r e f e r e n c e being primary > secondary > t e r t i a r y a l c o h o l s . lo‘
E l e c t r o g e n e r a t e d a c i d h a s been found t o be
a n e f f i c i e n t c a t a l y s t f o r THP e t h e r f o r m a t i o n o r c l e a v a g e . I o 5 Boron t r i f l u o r i d e e t h e r a t e - s o d i u m
(or p o t a s s i u m ) i o d i d e i s a
s e l e c t i v e r e a g e n t s y s t e m f o r c l e a v i n g c y c l i c e t h e r s J o 6 and benzyl ethers,lo7 and a s o l u t i o n o f ozone i n d i c h l o r o m e t h a n e a t 0
OC
has
proven u s e f u l f o r d e b e n z y l a t i n g c a r b o h y d r a t e d e r i v a t i v e s i n which a c e t a l s a r e present. Io8
S e l e c t i v e d e p r o t e c t i o n o f a l c o h o l i c and
p h e n o l i c s i l y l e t h e r s (TBDMS o r TBDPS) h a s b e e n c a r r i e d o u t u s i n g aqueous h y d r o f l u o r i c a c i d i n a c e t o n i t r i l e , t o r e g e n e r a t e t h e a l c o h o l s , a n d t e t r a b u t y l a m m o n i u m f l u o r i d e i n THF t o l i b e r a t e p h e n o l s (Scheme 2 5 ) . I 0 9
206
General and Synthetic Methods
0
It
i, ii
Rh+
RITop(ophi * R2
OH
R2
R1
R3
H
H
H
H
Me
Me
Me
H
Me
Reagents: i , Bun3SnLi ( 2 equiv.), Et2AICI ( 2 equiv.), [ Pd ( PPh3)&] ( 0 . 1 equiv.),
THF, 0.C;
i i , R4CH0
Scheme
R Reagents : i , RICHO
, THF,
- 78.C
;
R
;
R
i i , CH2= CHCH2MgBri i i i , H30i
Scheme
R e a g e n t s : i , aq. H F , MeCN
23
ii, BunhNiF-,
Scheme
24
THF
25
R
207
4: Alcohols, Halogeno-compounds, and Ethers
Q u a t e r n a r y ammonium i o d i d e s h a v e b e e n f o u n d t o i m p r o v e t h e y i e l d o f aluminium i o d i d e promoted a r o m a t i c e t h e r c l e a v a g e s t o phenols.
Simultaneous publications
lo
by t w o g r o u p s r e p o r t t h e u s e
of catecholboron halides (16) f o r s e l e c t i v e deprotections
(for
e x a m p l e , MEM e t h e r s i n t h e p r e s e n c e o f e s t e r s ) . H y d r o q u i n o n e d i m e t h y l e t h e r s h a v e b e e n shown t o b e o x i d a t i v e l y d e m e t h y l a t e d i n good y i e l d u s i n g manganese d i o x i d e i m p r e g n a t e d w i t h nitric acid.ll2
F u r t h e r work h a s b e e n p u b l i s h e d on t h e i n t e r -
c o n v e r s i o n o f p r o t e c t i n g g r o u p s u s i n g d i m e t h y l b o r o n bromide which h a s been used t o p r e p a r e m e t h y l t h i o m e t h y l e t h e r s and cyanomethyl e t h e r s from methoxyethoxymethyl e t h e r s . R e a c t i o n s of A l c o h o l s . -
Oxidation.
'
The u s e o f c l a y - s u p p o r t e d
c o p p e r ( I 1 ) and i r o n ( I I 1 ) n i t r a t e s a s o x i d i z i n g a g e n t s h a s been t h e s u b j e c t of a review."'
It h a s been demonstrated t h a t o x i d a t i o n s
w i t h P D C c a n b e e n h a n c e d by u s i n g a m o d i f i e d p r o c e d u r e i n w h i c h a
small q u a n t i t y o f a n h y d r o u s a c e t i c a c i d and f r e s h l y a c t i v a t e d molecular s i e v e s is added t o t h e system.
115
Amongst t h e new d e a c t i v a t e d c h r o m i u m ( V 1 ) r e a g e n t s w h i c h h a v e b e e n d e s c r i b e d a r e 3- a n d 4 - c a r b o x y p y r i d i n i u m
dichromate, derived
from n i c o t i n i c and i s o n i c o t i n i c a c i d r e s p e c t i v e l y , which o x i d i z e b e n z y l i c and a l l y l i c a l c o h o l s , l 6 and a p y r i d i n i u m c h l o r o c h r o m a t e b e n z o t r i a z o l e combination which o x i d i z e s a l l y l i c a l c o h o l s s e l e c t ively
. ''
Chromium t r i o x i d e - c h l o r o s i l a n e c o m b i n a t i o n s h a v e b e e n
shown t o b e e f f i c i e n t o x i d i z i n g a g e n t s 1 I 8 ( ~ 0 1 . 8 , p . 2 2 7 ) ,
and t h e
chromate e s t e r ( 1 7 ) a c t s as a c a t a l y s t i n t h e o x i d a t i o n o f secondary alcohols with peracid.
l9
In the l a t t e r case, product
i s o l a t i o n i s s i m p l i f i e d by t h e s m a l l a m o u n t o f c h r o m i u m s p e c i e s present. Primary and secondary a l c o h o l s are e f f i c i e n t l y o x i d i z e d t o a l d e h y d e s or k e t o n e s u n d e r s o l i d - l i q u i d
phase-transfer
conditions using
tetrabutylammonium s a l t s with palladium c a t a l y s i s i n t h e presence of iodobenzene
,I2O
and a similar method d e s c r i b e s t h e p a l l a d i u m -
mediated oxidation of secondary alcohols i n carbon t e t r a c h l o r i d e . 12'
Other r e a g e n t s which o x i d i z e secondary a l c o h o l s t h a t
have been r e p o r t e d i n c l u d e b u f f e r e d sodium bromate under ruthenium c a t a l y s i s 22 and t h e p i p e r i d i n y l o x y c h l o r i d e ( 1 8 ) . 123 Fremy's s a l t w i l l o x i d i z e b e n z y l i c and f u r y 1 a l c o h o l s under phase-transfer
c o n d i t i o n s b u t n o t a l l y l i c a l c o h o l s . 124 B e n z y l -
a l c o h o l s h a v e a l s o b e e n o x i d i z e d t o a l d e h y d e s w i t h ammonium m o l y b d a t e i n m o d e r a t e t o good y i e l d s . 125
208
General and Synthetic Methods
Hydrogenation and Deoxygenation. Nickel boride, produced in situ by the action of sodium borohydride on nickel(I1) chloride, has been used to carry out a two-step hydrogenolysis of allylic alcohols reductive cleavage of the trimethylsilyl ethers. 126 Tertiary alcohols may be deoxygenated in reasonable yields by means of radical decomposition of mixed oxalate esters with IJ-hydroxypyridinethione. Carrying out the reaction in the presence of electron-deficient olefins leads to alkylated products (Scheme 26). Miscellaneous Reactions. The adduct ( 1 9 ) from dimethylformamide and benzoyl chloride converts alcohols into formate esters in generally good yields. 128 1,2-Diols may be esterified regioselectively at the more substituted hydroxyl by means of a cyclic stannyl ether (Scheme 27).12’ The field of regioselective hydroxyl reactions via organotin derivatives has been reviewed during the past year. I3O Complexes of 3-acetyl-2-oxazolone ( 2 0 ) and organozirconium compounds have been found to acylate polyols with excellent selectivity for primary hydroxy-groups (Scheme 28). 13’ A series of diphenylmethanols has been converted into the corresponding diphenylacetic acids by carboxylation with carbon monoxide in a strong acid medium of formic and concentrated sulphuric acids. 32 Under milder conditions, palladium-catalysed carbonylation of allylic alcohols results in the formation of b u t y r o l a ~ t o n e s ’and ~ ~ similar treatment of allylic 1,3-diols permits the synthesis of 3-hydroxytetrahydrofuran-2-acetic acid lactones in generally good yield (Scheme 29). 13‘ Treatment of alcohols with chlorine and sulphur in the presence of pyridine and the requisite nucleophile provides a novel means for preparing triflates , tosylates, and perchlorates. 135 Inversion of configuration of alcohols has been achieved by the use of nucleophilic displacement of tosylates or mesylates with nitrate ion, either on Amberlyst resin or as tetrabutylammonium nitrate. 36 The low basicity of the system means that competing elimination is much reduced, even in substrates such as ( 2 1 ) (Scheme 30). Toluenesulphonic acid adsorbed on silica gel is an efficient reagent for dehydrating a variety of alcohols.137 In an extension
of w o r k reported previously (Vo1.8, p.229) allylic alcohols may be coupled regioselectively with dithioester enolates after first coupling with the pyrrolidine-a-chloroenamine (22) (Scheme 31 ) . 138 The end result of attack by the thioenolate at the more hindered
4: Alcohols, Halogeno-compounds, and Ethers
209
(16) X = Br or C I
OMc
$&
0, 00 ,Cr,
0’
II
‘0
0 (18 1
(17)
Reagent:
i , <2Et
SBU ,
0
P h C l , rcflux
5,
I ONa
Scheme
Ph
26
ci
210
General and Synthetic Methods
major i, 6 u 2 S n 0 , P h M e ; ii, PhCOCl ( 1 equiv.), C H C I 3 ;
Reagents:
iii, M e 2 P h S i C I ( 1 e q u i v . ) ; i v , aq. HCI
Scheme
27
1
RCH(CH,),CH20H
I
OH
RCH(CH2),CH20Ac
I
OH
R e a g e n t : ( 2 0 ) ( 1 . 5 e q u i v . ) , [ Z n ( a ~ a c )( ~0 l. 2 e q u i v . ) , M e C N , r . t .
Scheme
28
R
H
I
f
HO
Reagent:
OH
1,
Rfl H
PdC12 (0.1 e q u i v . ) , C u C 1 2 ( 3 e q u i v . ) , NaOAc ( 3 e q u i v . ) , C O ( 1 a t m ) ,
AcOH
Scheme
29
21 1
4: Alcohols, Halogeno-compounds, and Ethers
-
?Ts
/\/C02Et
I
ON02
&
C02Et
94% yield
(21) Reagents:
i , A m b e r l y s t A - 26 NO3- form
Scheme
or
B " " ~ N + NO;,
II
R'
S
R e a g e n t s : i , ( 2 2 ) , T H F , CH2Cl2,
O'C
;
~
H
~
30
___)
CI
C
lR1
R3
ii, R 4 C H = C ( S M e ) S L i , -30.12
Scheme
31
-
WR2 R'i-R2 I OH
O Y C O 2 E t
i , t r i m e t h y l b e n r o i c a c i d ( c a t .), 0
Scheme
___)
J
OE t Reagents:
I
32
- dichlorobcnzene, llO'C
General and Synthetic Methods
212
s i t e may b e a c o n s e q u e n c e o f t h e a m b i d e n t n a t u r e o f t h e n u c l e o phile. rearrangement of a l l y l i c alcohols after
The [ 3 , 3 ] - s i g r n a t r o p i c
condensation with e t h y l 3,3-diethoxyacrylate
leads t o regiospecific
s y n t h e s e s of s u b s t i t u t e d a l l y 1 m a l o n a t e s i n g o o d y i e l d s ( S c h e m e
3 2 ) . 139 T e r t i a r y c y c l o a l k a n o l s h a v e been shown t o u n d e r g o r i n g e x p a n s i o n i n d u c e d by i r o n ( I I 1 ) c h l o r i d e on s i l i c a i n a p r o c e s s w h i c h h a s u t i l i t y f o r preparing spiro-systems catalysed rearrangement of cyclopent-2-enones
(Scheme 3 3 a ) .
I-vinylcyclobutanols
(Scheme 33b)
Palladium-
y i e l d s 2-methyl-
and t r e a t m e n t o f 2-phenylthio-I-
v i n y l c y c l o b u t a n o l s p r o v i d e s a v e r s a t i l e s y n t h e s i s of c y c l o h e x a n o n e s (Scheme 3 3 c ) .
Solvolytic hydroperoxide rearrangement of spiro-
=
c y c l o p r o p y l c a r b i n o l s f u r n i s h e s o x a b i c y c l i c hemiacetal hydrop e r o x i d e s i n good y i e l d hydroperoxides
solvolytically generated cyclobutyl
(Scheme 3 3 d ) . 43
S e v e r a l a l l y l i c a l c o h o l s have been isomerized t o t h e c o r r e s ponding aldehydes i n moderate y i e l d s u s i n g N-lithioethylenediamine
at elevated temperatures.
144
2 H a l o g e n o Compounds P r e p a r a t i o n from Alcohols.-
I n a modification o f t h e Mitsonobu
p r o c e d u r e , a l c o h o l s are e f f i c i e n t l y c o n v e r t e d i n t o h a l i d e s o r c y a n i d e s by a d d i n g t h e r e q u i s i t e l i t h i u m s a l t a n d t h e n t h e a l c o h o l t o a preformed complex of d i e t h y l a z a d i c a r b o x y l a t e and t r i p h e n y l p h o s p h i n e i n THF a t 0 0 C . 1 4 5
The o r d e r o f a d d i t i o n is c r u c i a l f o r
good y i e l d s ; e x c e s s r e a g e n t s are r e q u i r e d f o r s e c o n d a r y a l c o h o l s and t h e r e a c t i o n s p r o c e e d c l e a n l y by a n S 2 p r o c e s s .
-N
Akyl i o d i d e s
may b e o b t a i n e d b y t r e a t i n g a l c o h o l s w i t h a - c h l o r o e t h y l c h l o r o formate-sodium
i o d i d e f o l l o w e d by t h e r m a l d e c o m p o s i t i o n o f t h e
intermediate iodoester. u s e of sodium iodide-boron
Two r e s e a r c h g r o u p s h a v e p u b l i s h e d t h e trifluoride etherate in acetonitrile t o
c o n v e r t a l l y l i c , b e n z y l i c , and t e r t i a r y a l c o h o l s i n t o t h e c o r r e s ponding i o d i d e s (Scheme 3 4 ) . 147 Q u a t e r n a r y ammonium f l u o r i d e s
(cf. Vol.4,
p.157) and toluene-p-
s u l p h o n y l f l u o r i d e i n t h e p r e s e n c e of m o l e c u l a r s i e v e s c o n s t i t u t e 148 systems f o r t h e chemoselective f l u o r i n a t i o n o f primary alcohols. C o n c e n t r a t e d h y d r o b r o m i c a c i d , u n d e r c o n d i t i o n s of Dean a n d S t a r k r e m o v a l o f w a t e r , h a s p r o v e d t o b e a g e n e r a l r e a g e n t for c o n v e r t i n g a,w-diols
e f f i c i e n t l y i n t o t h e corresponding w-bromo-alcohols
with
4: Alcohols, Halogeno-compounds, and Ethers
Reagent:
213
i, FcC13- S i 0 2 , n e a t , r.t
i . )
R e a g e n t s : i, benzoquinone ( 2 equiv.), [ PdC12(PhCN)21 ( c a t . ) , T H F , reflux
OH i, ii
6
*
SPh
SPh
Reagents : i , K H
Reagent:
, THF ,
HMPA, -11
-c
25'C
;
ii, AcOH
i , 9 0 % H202, T s O H , T H F
Scheme
33
I ______)
I
OH
Reagents : i, N a I ( 2 equiv.),BFj.Et20
( 2 equiv.), MeCN, r . t .
Scheme
34
214
General and Synthetic Methods
chain lengths of 2 to 12 carbon atoms.149 Interhalide Conversions.- Almost quantitative halogen exchange fluorination of cyclic and tertiary halides (secondary halides eliminate) has been carried out with copper(1) oxide-hydrofluoric acid in THF in which the solvent is acting as a base.15’ Aromatic iodides may be converted into bromides using a combination of potassium and copper(1) iodides in HMPA at elevated temperatures. 1 5 ’ Miscellaneous Preparations.- A combination of mercury(I1) salts and bromine or iodine constitutes a system for stereoselective transaddition of halogen and the anion of the mercury salt to alkenes. 152 Treatment of E-vinylboronic acids (obtained by standard procedures from acetylenes) with chlorine followed by heating furnishes the corresponding L-vinyl chlorides specifically, 1 5 3 whereas, in a modified iodination process, treatment with mercury(I1) acetate followed by sequential treatment with sodium iodide, 251-sodium iodide-chloramine T produces154 the 251-Evinyl iodides (Scheme 35) (Vol.6, p.182). In a similar procedure, treatment of the products obtained from syn-addition of boron tribromide to acetylenes with sodium halide-chloramine T yields l-halogeno-2-bromoalkenes (~01.8, p.231 ) . 155 This system has also been used to para-iodinate phenols in DMF.156 Vinyl halides may also be prepared from vinyl silanes by initial conversion into vinyl iodonium salts (23) with iodosobenzene-triethyloxonium fluoroborate followed by treatment with copper (I) halide. 157 Aldehydes may be converted into 1,l-di-iodoalkenes by a Wittigtype process with excess carbon tetraiodide-triphenylphosphine in the presence of zinc which may be beneficial by reacting with any triphenylphosphine di-iodide formed. 158 Procedures have been described for the selective conversion of 2-methylcyclohexanone into the two regioisomeric vinyl chlorides depending upon the phosphorus chloride used (Scheme 36). 15’ Both epoxides and aromatic ketones have been shown to be iodinated reductively with tetramethyldisiloxane-iodine to the corresponding benzyl iodides in good yields. I6O Allylic acetals
z-
will undergo reaction with trimethylsilyl chloride-sodium halide to produce B-iodoacetals on work-up in a sequence equivalent to overall conjugate addition of hydrogen iodide.
161
215
4: Alcohols, Halogeno-compounds, and Ethers
H
R
R e a g e n t s : i , CL2, CH2C12, 0.C THF; v , N a l
;
i i , aq. N a 2 S 0 3 ; iii, h e a t
;
iv, Hg(OAcI2,
v i , Na1251, chloramine T , MeOH
;
Scheme
35
VPh R2
R3
CI
CI
Cond tions A
89
11
49 %
Cond t i o n s 8
92
8
52 *I*
0
b b
0i , ii
Reagents:
Conditions A . i i , KOH
BFt
McOH
I,
Catechylphosphorus t r i c h l o r i d c , CH2C12, - 7 8 % ;
rcflux
;
C o n d i t i o n s B . i , PC15, h c x a n c , r e f l u x ;
ii, 4 0 V . aq. NaOH
Schema 36
216
General and Synthetic Methods
Reactions.- Dehalogenation. R e d u c t i v e d e h a l o g e n a t i o n o f 1,2dibromoalkanes has been r e p o r t e d u s i n g sodium t e l l u r i d e ( p r e p a r e d i n s i t u f r o m m e t a l l i c t e l l u r i u m a n d s o d i u m formaldehydesulphoxylate d i h y d r a t e 1 , 162 d i a r y l t e l l u r i u m compounds u n d e r p h a s e - t r a n s f e r d i t i o n s , 163 and n i c k e l b o r i d e . 164
con-
T h i s l a t t e r r e a g e n t , which is
p r e p a r e d i n s i t u from n i c k e l ( I 1 ) c h l o r i d e and sodium b o r o h y d r i d e , a l s o r e d u c t i v e l y debrominates a-bromoketones.
Bis(thieny1) tellu-
r i d e i n conjunction with sodium borohydride h a s been used i n t h e 1,4-elirnination o f Il4-dibromo-2-alkenes t o 1,3-dienes. 165 The b u l k y r e d u c i n g a g e n t l i t h i u m t r i ( s - b u t y 1 ) h y d r o b o r a t e h a s been found t o reduce primary h a l i d e s r a p i d l y i n e x c e l l e n t y i e l d , whereas s e c o n d a r y b r o m i d e s a r e o n l y s l o w l y r e d u c e d a n d t e r t i a r y a n d a r y l h a l i d e s are i n e r t . 166
Aryl h a l i d e s have been dehalogenated
r e d u c t i v e l y w i t h c o m b i n a t i o n s of z i n c - n i c k e l ( I 1 ) c h l o r i d e - w a t e r on u l t r a s o u n d t r e a t m e n t 67 a n d l i t h i u m a l u m i n i u m h y d r i d e - c e r i u m ( I11 ) 168 chloride. Acylation and Coupling Reactions.
Reagents used f o r t h e preparation
o f u n s y m m e t r i c a l k e t o n e s by c o u p l i n g a l k y l h a l i d e s w i t h a c i d
c h l o r i d e s i n c l u d e a c t i v a t e d n i c k e l , p r e p a r e d by t h e a c t i o n o f l i t h i u m a n d n a p h t h a l e n e o n n i c k e l ( I 1 ) c h l o r i d e i n g l y m e (Vo1.8, p.233)I6’ and zinc-copper c o u p l e w i t h a c a t a l y t i c q u a n t i t y o f tetrakis(tripheny1phosphine)palladium. I 7 O S o n i c a l l y p r e p a r e d a r y l z i n c b r o m i d e s h a v e b e e n f o u n d t o u n d e r g o c o n j u g a t e a d d i t i o n t o a ,B u n s a t u r a t e d a l d e h y d e s i n t h e p r e s e n c e o f n i c k e l ( a c a c ) 2 i n THF. l 7 B-Substitution of a,B-unsaturated ketones with vinyl iodides under palladium-catalysed
solid-liquid phase-transfer conditions provides a m i l d means o f g e n e r a t i n g d i e n o n e s (Scheme 3 7 ) . 1 7 2 The c o b a l t c o m p l e x ( 2 4 1 , o n t r e a t m e n t w i t h a l k y l - l i t h i u m reag e n t s , forms a n a c y l complex which w i l l react w i t h a l l y l i c h a l i d e s t o f u r n i s h B , y - u n s a t u r a t e d k e t o n e s . 173 B e n z y l i c h a l i d e s may b e c a r b o n y l a t e d t o t h e c o r r e s p o n d i n g e s t e r s by b u b b l i n g c a r b o n m o n o x i d e t h r o u g h a s o l u t i o n o f t h e h a l i d e i n t h e r e q u i s i t e e t h e r i n t h e presence of a c a t a l y t i c a l quantity of (hexaI l 5 - d i e n e ) r h o d i u m ( I ) c h l o r i d e d i ~ n e r ’o ~r ~w i t h t h e same c a t a l y s t i n h e x a n e c o n t a i n i n g t i t a n i u m o r z i r c o n i u m a l k o x i d e s . 175 A r y l h a l i d e s may b e c a r b o n y l a t e d t w i c e i n g e n e r a l l y g o o d y i e l d u n d e r 70 atm of c a r b o n monoxide i n a l c o h o l s o l v e n t s w i t h p a l l a d i u m c a t a l y s i s t o g i v e a - k e t o - e s t e r s (Scheme 38). An e l e c t r o s y n t h e t i c p r o c e d u r e h a s b e e n d e s c r i b e d f o r c o n v e r t i n g a l k y l h a l i d e s i n t o t h e homologous c a r b o x y l i c a c i d s . Carbon d i o x i d e
4: Alcohols, Halogeno-compounds, and Ethers
Bun
m
217
-
l I
0
Scheme
37
-
C O ( CO)2( N O ) ( PPh,)
Bun
RCOCO(CO)(NO)(PPhB)
(24)
1
ArI
*
A r COC02R
R e a g e n t : i , C PdC12{P(cyclohexyl)3)2], CO ( 7 0 a t m ) , ROH, 70 - l o O ° C
Scheme
Reagent :
i
,
R2X
, Et3N
or
38
N - m e t h y l p y r r o l i d i n e , Pd ( O A c I 2 ( c a t . I , PX3, DMSO
Scheme 39
218
General and Synthetic Methods
is bubbled through any of a series of aprotic solvents containing the halide and a quaternary ammonium salt as the supporting electrolyte. The cell contains a magnesium anode encircled by the cathode and electrolysis is carried out at 5 Reductive coupling of benzyl halides has been carried out with a nickel(0) complex generated in situ in the presence of tetraethylammonium iodide.178 The coupling of aryl halides to form biphenyls has been carried out with electrogenerated palladium(0) , 17’ and vinyl halides have been coupled intra- and inter-molecularly to form 1,3dienes with palladium(0) regenerated by triphenylphosphinepotassium carbonate. I8O A similar procedure has been used for the cross-coupling of aryl halides with aryl boronic acids. I8l Both zero-valent palladium and nickel have been used to catalyse the coupling of Grignard reagents with trichloroethylene to yield 1 , l dichloroalkenes,182 and the coupling of l-allenyl alcohols with aryl or vinyl halides is reported to yield a,B-unsaturated carbonyl compounds when mediated by palladium(0) (Scheme 3 9 ) . 183 Encouraging yields have been obtained in the tributylgermanium hydride mediated reductive addition of alkyl halides to activated olefins. 184 The dilithiated species derived from allene has been shown to react with halides to give the products of propargylic addition (Scheme 40). 185 Miscellaneous Reactions. A one-pot transforma-tion of alkyl bromides into primary amines via the Staudinger reaction has been reported (Scheme 41). 186 The overall yields are good and the procedure is compatible with the presence of esters, alkenes, and alkynes. In an improved version of the Sommelet-Hauser rearrangement benzyl halides have been reacted with (N,N-dimethy1amino)methyltrimethylsilane in acetone followed by caesium fluoride in H M P A to furnish the ortho-rearranged material as the major product (Scheme 42). 187
3 Ethers188 Preparation.- Symmetrical ethers have been prepared
2 trityl
perchlorate promoted reduction of carbonyl compounds with triethylsilane, and unsymmetrical ethers are obtained in the presence of alkoxytrimethylsilanes. 18’ The same research group has reported the trityl perchlorate or diphenylboryl triflate promoted reaction
4: Alcohols, Halogeno-compounds,and Ethers
Reagents : i , ...
111,
BunLi ( 2 e q u i v . 1 , Et20, - 7 8 ' C ;
ii
I
R- N,
.I__)
R e a g e n t s : i , N a N 3 , Bun4N+Br-, iii.
i i , RX,-15'C--
r.t.;
H30+
Scheme
RBr
219
40
R- N = P( OE t l3
C6H6, r e f l u x
iii
R
LHB~ I-
ii, P(OEtI3, r . t . ;
HCI , C 6 H 6 , r . t . Scheme
41
CH2SiMe,
I ,R& __L
R+x
R2 R2
XReagents
i , Me2NCH2SiMe3, acetone
Scheme
;
i i , CsF 1 H M P A , r.t
42
CH2NMe2
220
General and Synthetic Methods
of allylsilanes with acetals to form homoallyl ethers (Scheme 43)I9O (cf. Vol.1, p.179; Vol.4, p.164; Vo1.5, p.177; Vo1.6, p.186). Samarium trichloride catalyses the condensation of allylic alcohols to form symmetrical ethers in dichloroethane and unsymmetrical ethers in excess of a second alcohol.19’ Further work has been published on the synthetic utility of diethoxyphenylphosphorane as a cyclodehydrating agent for Q ,w-diols19* A polymeric variant has ~ HMPA at also been described for 1 1 2 - , 1,4-, and 1 , 5 - d i 0 l s , ’ ~and elevated temperatures has been reported to cyclodehydrate simple 1,4- and 1,5-diols efficiently. 194 Iodoetherification of pent-4en-1,3-diols has been shown to lead stereoselectively to cis-2iodomethyl-3-hydroxytetrahydrofurans in good yield using etheriodine-sodium bicarbonate or !-iodosuccinimide. 9 5 The procedure for stereocontrolled synthesis of 2,5-trans-disubstituted tetrahydrofurans % titanium(II1)-induced cyclization of pent-4-en-1-01 derivatives has been modified into a one-step process.196 3Methylenetetrahydrofurans have been prepared starting from the allylstannane (25) via Lewis acid catalysed addition to ketones followed by reductive cyclization with palladium(0). 197 Ally1 silanes (26) have also been converted into 3-methylenetetrahydrofurans with iodosobenzene-boron trif luoride etherate. 98 Homologues of (26) have been converted similarly into tetrahydropyrans. Certain acetals of five- and six-membered ring ketones lacking a-substituents have been shown to undergo double Baeyer-Villiger oxidation to form cyclic ethers. The preparation of 3homoallyl-substituted tetrahydrofurans successive inter- and intra-molecular radical reactions (Scheme 44 1 has been described. 2 o o
’
Reactions.
-
Tetrahydrofurfuryl alcohol has been cleaved regio-
selectively with trimethylsilyl chloride-sodium iodide (Vol.4, p.164; Vo1.6, p.186) in acetonitrile to yield (unstable) 5iodopentane-Il2-diol or the corresponding acetonide when the s o l vent is acetone.202 Cyclic ethers have also been shown to undergo nucleophilic cleavage with phenyltellurotrimethylsilane to trimethylsilyl ethers possessing a terminal phenyltelluryl substituent .203 Work has been published on the use of trimethylsilyl cyanide to cleave oxetanes to 3-isocyanopropyl trimethylsilyl ethers under zinc iodide catalysis. 204 Trifluoroperacetic acid has been shown to epoxidize allylic ethers stereoselectively syn to the oxygen, as opposed to MCPBA when anti-products predominate. 2 0 5
22 1
4: Alcohols, Halogeno-compounds,and Ethers
R’XoMe OMe
OMe
R2
Me,Si
R e a g e n t : i , TrC104, C H 2 C l 2 ,
- 23°C
or
Scheme
R e a g e n t s : i, N B S , cyclohexene A I B N ( c a t . 1 , C6H6
;
P h Z B T f , CHZCIz,
- 7 8 ‘C
43
ii, CH2= C H C H 2 S n B u n 3 ( 3 e q u i v . l .
, 80°C Scheme 44
Ph
ROCH(SMe)Li
(271 R = THP or T H F
CH2SH
Ph
hs (28)
222
General and Synthetic Methods
4 Thiols and Thioethers 2-Tetrahydrofuranyl- and 2-tetrahydropyranylthiomethyl-lithium (27) have been used as methanethiol carbanion equivalents. ‘06 Alkyl halides may be converted in a mild, one-pot procedure to thiols by reacting with the pyridine-2-thione (28) in benzene at room temperature ( ~ 0 1 .,2 p. I 34 1. 207 Aromatic iodides may be converted into thiophenols by nickel(0)catalysed reductive coupling with thiourea followed by alkaline treatment of the intermediate salt and liberation o f the desired product on acidification .208 Reaction o f organocuprates with dithioesters has been developed as a synthetic route to tertiary thiols .‘09 A polystyrene-bound diarylselenoxide has been used to oxidize thiols to disulphides,210 and aromatic thiols have been conveniently oxidized with stoicheiometric quantities of DMSO, removal of the dimethyl sulphide furnishing crystalline product .” Benzyl and aryl thiols may be carbonylated and desulphurized with carbon monoxide under pressure in the presence of hexacarbonyldicobalt in alcohol solvents to furnish esters, although the reaction fails with aliphatic thiols .212 Unsymmetrical thioesters have been obtained in good yields by sequential treatment of alkyl halides with tetramethylthiourea followed by sodium a l k o ~ i d e s . ’ ~ An ~ improved means of cyclizing u,w-dihalides to four-, five-, and six-membered-ring thiacycloalkanes utilizes sodium sulphide nonahydrate in DMSO at 150 OCa2I4 Thioacetals have been converted into B-keto-sulphides by reaction with TMS enol ethers, mediated by trityl perchlorate.215 A stereoselective synthesis of allylic sulphides has been described which utilizes the [3,3]-rearrangement of ally1 xanthates with concomitant loss of carbon oxysulphide (e.g.Scheme 45). 216 Allylic sulphides have also been prepared by reaction of thiolates with allylic nitro-compounds, nucleophilic attack occurring at the least substituted centre.217 Vinyl sulphides may be obtained from aldehydes by sequentially converting them into the corresponding trimethylsilyl hemithioacetal, deprotonating, alkylating, and eliminating the siloxy-substituent (Scheme 46). 218 In a stereospecific synthesis of E-vinyl sulphides, l-iodoalkenylboranes (prepared by hydroborating l-iodoacetylenes) are reacted with alkylthiomagnesium bromides, after which the boron substituent is removed reductively by treatment with n-butyllithium followed by aqueous base. 219 Unsymmetrical diary1 thio-
223
4: Alcohols, Halogeno-compounds,and Ethers i ,ii D
OH
SMe
I -f v
SMe
o=c=s
R e a g e n t s : i , N a H , C S 2 , DMSO pressure
;
;
ii, Me1
... Ill
Vo SMe
;
iii, d i s t i l l a t i o n a t r e d u c e d
i v , d i s t i l l a t i o n at a t m o s p h e r i c p r e s s u r e
S c h e m e 45
-
R e a g e n t s : i , H2S, M e 3 S i C I , p y r i d i n e
0°C
;
i i , NaH, DMF , 0°C
;
iii, R 3 X ,
r.t.
Scheme
16
0
B F4-
(29)
(30)
General and Synthetic Methods
224
ethers have been obtained in good yields by thermolytic extrusion of nitrogen from arenediazonium fluoroborates, themselves derived from the reaction of thiolates with arenediazonium salts . 2 2 0 Reagents for deoxygenating sulphoxides reported this year include thexyl chloroborane , 221 polystyryldiphenylphosphine, 2 2 2 and sodium iodide-boron trifluoride etherate. 148 The first reagent does not affect amides, esters, or epoxides and the second requires carbon tetrachloride as solvent for good conversions. Dimethyl(methy1thio)sulphonium fluoroborate has been described for the sulphenyletherification and sulphenyl-lactonization of alcohols and acids possessing 4-unsaturation. 223 Two thioether protecting groups have been reported. 4-Phthalimidobutylsulphonium salts (29), obtained from the thioether and 4-phthalimidobutyl bromide with silver fluoroborate, are decomposed with aqueous dimethylamine, whereas pmethoxybenzylsulphonium salts ( 3 0 1 , obtained similarly, are cleaved on warming in water. 224 The oxidation of sulphides to sulphoxides using polystyrene bound selenoxides has been reported,' l o and asymmetric oxidations have been achieved with varying success using sodium periodatebovine serum albumin,225 although incubation with the microorganisms Corynebacterium equi226 and Mortierella isabellina gave enantiomeric excesses up to 90%.227 Thioethers have been oxidized selectively to sulphones using a combination o f sodium periodatepotassium permanganate-magnesium sulphate in refluxing aqueous acetone. 228 The preparation o f cyclopentenyl phenyl thioether by Pummerer rearrangement of the sulphoxide has been found most efficient in the presence of triethylamine as well as trifluoroacetic acid to eliminate trifluoroacetoxysulphide formation .229 References 1
2 3 4 5 6 7
8 9 10
11
12 13
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4: Alcohols, Halogeno-compounds,and Ethers 14 15
16
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4: Alcohols, Halogeno-compounds, and Ethers 105 106 107 108 109 110 111 112 113 114 115 116
117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134
135 136 137 138 139 140 141 142 143 144 145 146 147 'I 48
149 150
58,
S . T o r i i , T . I n o k u c h i , K.Kondo, and H . I t o , B u l l . Chem. SOC. J p n . , 1985, 1347. A . K . Mandal , N . R . S o n i , and K . R . Ratnam, S y n t h e s i s , 1985, 274. Y.D.Vankar and C.T.Rao, J . Chem. Res. (S), 1985, 232. P Angi beaud , J Def a y e , A . Gad e l l e , and J - P U t i 1l e , Syn t h e s is , 198 5 , 1123. 2 6 , 681. E.W.Collington, H.Finch, and I . J - S m i t h , T e t r a h e d r o n L e t t . , 1985, S . A n d e r s s o n , S y n t h e s i s , 1985, 437. 141 1 ; P F King R.K.Boekmann and J . C . P o t e n z a , T e t r a h e d r o n L e t t . , 1985, and S.G.Stroud, p.1415. B . E r r a z u r i z , R.Tapia, and J . A . V a l d e r r a m a , T e t r a h e d r o n L e t t . , 198 5 , 819. H.E.Morton and Y.Guindon, J . Org. Chem., 1985, 5 0 , 5379. A . C o r n e l i s and P . L a z l o , S y n t h e s i s , 1 9 8 5 , 909. S . C z e r n i c k i , C . G e o r g o u l i s , C . L . S t e v e n s , and K .. V i j a y a k u m a r a n , T e t r a h e d r o n L e t t . , 1985, 1699. C.Lopez, A.Gonzalez, F . P . C o s s i o , and C.Palomo, Svn t h Commun , 1985, 1197. E . J . P a r i s h and S . C h i t r a k o r n , S y n t h . Commun., 1985, 393. 2903. J.M.Aizpura, M . J u a r i s t i , B.Lecea, and C.Palomo, T e t r a h e d r o n , 1985, E. J . Corey , E.-P . B a r r e t t e , and P. A.Magriot i s , T e t r a h e d r o n L e t t . , 1985, 5855. B.M.Choudary, N.P. Reddy, M.L.Kantam, and Z . J a m i l , T e t r a h e d r o n L e t t . , 1985, 2 6 , 6257. H-Nagashima, K.Sato, and J . T s u j i , T e t r a h e d r o n , 1985, K , 5645. Y.Yamamoto, H.Suzuki, and Y.Moro-oka, T e t r a h e d r o n L e t t . , 1985, 2107. T.Miyazawa, T.Endo, S . S h i i h a s h i , and M.Okawara, J . Org. Chem., 1985, 50, 1333. J.Morey, A . D z i c l e n z i a k , and J.M.Saa, Chem. L e t t . , 1985, 263. B.Sur, M.M.Adak, T . P a t h a k , B.Hazra, and A . B a n e r j e e , S y n t h e s i s , 1985, 652. 371. D.N.Sarma and R.P.Sharma, T e t r a h e d r o n L e t t . , 1985, 757. D.H.R.Barton and D.Crich, T e t r a h e d r o n L e t t . , 1985, J . B a r l u e n g a , P.J.Campos, E.Gonzalez-Nufiez, and (2-Asensio, S y n t h e s i s , 1985, 426. A.Ricci, S . R o e l e n s , and A.Vannucchi, J . Chem. S O C . , Chem. Commun., 1985, 1457. S.David and S . H a n e s s i a n , T e t r a h e d r o n , 1985, 643. T.Kunieda, T.Mori, T . H i g u c h i , and M-Hirobe, T e t r a h e d r o n L e t t . , 1985, 1977. Y.Takahashi, N.Yoneda, and H.Nagai, Chem. L e t t . , 1985, 1733. 5639. H.Alper and D.Leonard, T e t r a h e d r o n L e t t . , 1985, Y . Tarnaru, T.Kobayashi , S.Kawamura, H . O c h i a i , M.Hojo, and Z . Yoshida, T e t r a h e d r o n L e t t . , 1985, 3207. N . S . Z e f i r o v , V.V . Z h d a n k i n , V . D . S o r o k i n , and A.S.Koz 'min, T e t r a h e d r o n L e t t . , 6243. 1985, G - C a i n Z l i , F . M a n e s c a l c h i , G . M a r t e l l i , M.Panunzio, and L . P l e s s i , T e t r a h e d r o n L e t t . , 1985, 3369. F.D.Onofrio and A . S c e t t r i , S y n t h e s i s , 1985, 1159. T . F u j i s a w a , K.Umezu, and T . S a t o , Chem. L e t t . , 1985, 1453. 626 1 . S . R a u c h e r , K.-W.Chi, and D . S . J o n e s , T e t r a h e d r o n L e t t . , 1985, 1267. A.Fade1 and J . S a l a u n , T e t r a h e d r o n , 1985, 2503. G.R.Clark and S . T h i e n s a t h i t , T e t r a h e d r o n L e t t . , 1985, T.Cohen, L.-C.Yu, and W.M.Daniewski, J . Org. Chem., 1985, 4596. T . S . L i l l i e and R.C.Ronald, J . Org. Chem., 1985, 50, 5084. H.M. R Hof fmann, A . K'dver , and D. P a u l u t h , J . Chem SOC , Chem Commun , 1985, 812. S.Manna, J . R . F a l c k , and C.Mioskowski, S y n t h . Commun., 1985, 1 5 , 663. J . J . B r u n e t , H.Laurent, and P . C a u b e r e , T e t r a h e d r o n L e t t . , 1 9 8 5 , 5445. 2 7 1 7 ; A.K.Manda1 and Y.D.Vankar and C.T.Rao, T e t r a h e d r o n L e t t . , 1985, S.W.Mahajan, i b i d . , p.3863. 4207. M.Shimizu, Y . N a k h a r a , and H.Yoshioka, T e t r a h e d r o n L e t t . , 1985, S.-K.Kang, W.-S.Kim, and B.-H.Moon, S y n t h e s i s , 1985, 1161. N.Yoneda, T.Fukuhasa, S . N a g a t a , and A.Suzuki, Chem. L e t t . , 1985, 1693.
.
. .
.
. .
3,
w.,
26,
26,
. 15,
15,
5,
26,
26,
26, 26,
5,
26,
26,
26,
26,
26,
26,
5,
.
26,
.
.
26,
2, .
.
26,
26,
228 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 1-78 179 180
181 1 a2
General and Synthetic Methods H.Suzuki, A.Kondo, and T.Ogawa, Chem. Lett., 1985, 411. J.Barluenga, J.M.Martinez-Gallo, C.NAjera, and M. Yus, J. Chem. SOC., Chem. Commun., 1985, 1422. S.A.Kunda, T.L.Smith, M.D.Hylarides, and G.W.Kabalka, Tetrahedron Lett., 1985, 26, 279. P.C.Srivastava, F.F.Knapp, G.W.Kabalka, and S.A.Kunda, Synth. Commun., 1985, 355. S.Hara, T.Kato, H.Shimizu, and A.Suzuki, Tetrahedron Lett., 1985, 5, 1065. T.Kometani, D.S.Watt, and T.Ji, Tetrahedron Lett., 1985, 26, 2043. M.Ochiai, K.Sumi, Y.Nagao, and E-Fujita, Tetrahedron Lett., 1985, 26, 2351. F.Gavifia, S.V. Luis, P.Ferret-, A.M. Costero, and J. A-Marco, J. Chem. SOC., Chern. Cornrnun., 1985, 296. P.F.Hurdlick and A.K.Kulkarni, Tetrahedron, 1985, 1179. B. Lecea, J.M.Aizpura, and C.Palomo, Tetrahedron, 1985, 111, 4657. B.L.Feringa, Synth. Comrnun., 1985, 15,87. H.Suzuki and V m . Lett., 1985, 225. H.Suzuki, A.Kondo, and A.Osuka, Bull. Chem. SOC. Jpn., 1985, 58, 1335. J.C.Sarrna, M.Borbaruah, and R.P.Sharma, Tetrahedron Lett., 1985, 26, 4657. L.Engman and S.E.BystrBm, J. Org. Chem., 1985, 2, 3170. S.Kim and K.Y.Yi, Bull. Chem. SOC. Jpn., 1985, 58, 789. J.Yamashita, Y.Inoue, T.Kondo, and H.Hashimoto, Bull. Chem. SOC. Jpn., 1985, 58, 2709. T.Imamoto, T.Takeyama, and T.Kusurnoto, Chem. Lett., 1985, 1491. S.Inaba and R.D.Rieke, J. Org. Chem., 1985, 1373. Y.Tamaru, H.Ochiai , F.Sanda, and Z.Yoshida, Tetrahedron Lett., 26, 1985, 5529 J.C.deSouza Barboza, C.Pktrier, and J.-L.Luche, Tetrahedron Lett., 1985, 26, 8-29. ron Lett., 1985, 26, 2667. .Perry, J. Org. Chem., 1985, 50, 4955.
2,
-
so,
J.B.Woel1, S.B.Fergusson, and H.Alper, J. Org. Chem., 1985, 50, 2134. F.Ozawa, N-Kawasaki, T.Yamamoto, and A.Yamamoto, Chem. Lett., 1985, 567. O.Sock, M.Troupe1, and J.Perichon, Tetrahedron Lett., 1985, 26, 1509. M.Iyoda, M.Sakaitani, H.Otsuka, and M.Oda, Chem. Lett., 1985,127. S.Torii, H-Tanaka, and K.Moisaki, Tetrahedron Lett., 1985, 26, 1655. R.Grigg, P.Stevenson, and T.Worakun, J. Chem. SOC., Chem. Commun., 1985, 971. M.J.Sharp and V.Snieckus, Tetrahedron Lett., 1985, 26, 5997. V.Ratovelomanana, G.Linstrumelle, and J.-F.Normant, Tetrahedron Lett., 1985, 26., 2575. ~- I.Shimizu, T.Sugiura, and J.Tsuji, J. Org. Chern., 1985, 50, 537. P.Pike, S.Hershberger, and J.Hershberger, Tetrahedron Lett., 1985, 26, 6289. J.Hooz’, J.G.Calzada, and D.McMaster, Tetrahedron Lett., 1985, 271. A.Koziara, K.Osowska-Pacewicka, S.Zawadzki , and A-Zwierzak, Synthesis, 1985, 202. M.Nakano and Y.Sato, J. Chem. S O C . , Chem. Commun., 1985, 1684. See also Alcohols - Protection. J.Kato, N.Iwasawa, and T.Mukaiyama, Chem. Lett., 1985, 743. T.Mukaiyama, H.Nagaoka, M.Murakami, and M. Oshima, Chem. Lett., 1985, 977. M-Ouertani, J.Collin, and H.B.Kagan, Tetrahedron, 1985, 3689. P.L.Robinson, C.N.Barry, J.W.Kelly, and S.A.Evans, J. Am. Chem. SOC., 1985, 107, 5210. J.W.Kelly, P.L.Robinson, and S.A.Evans, J. Org. Chem., 1985, 50, 5007. J.Diab, M.Abou-Assalt, C.Gervais, and D.Anker, Tetrahedron Lett ., 1985, 26, 1501. Y.Tamaru, S.Kawamura, and Z.Yoshida, Tetrahedron Lett., 1985, 26, 2885. J.P.Michae1, P.C.Ting, and P.A.Bartlett, J. Org. Chem., 1985, 50, 2416. B.M.Trost and P.J.Bonk, J. Am. Chem. SOC., 1985, 107, 1778.
c,
5,
193 194 195
196 197
229
4: Alcohols, Halogeno-compounds, and Ethers 198
M.Ochiai, E.Fujita, M. Arimoto, and H.Yamaguchi, Chem. Pharm. Bull., 1985, 13. -
- _ ,
989. ~
~
20 1 20 2 20 3 20 4 205 206 207
W.F.Bailey and J.J.Bischoff, J. Org. Chem., 1985, 2, 3009. O.Moriya, M.Kakihana, Y. Urata, T.Sugizaki, T.Kageyama, Y .Ueno, and T.Endo, J. Chem. SOC., Chem. Commun., 1985, 1401. See also Alcohols - Deprotection. M.Jatczak, R.Amoroux, and M.Chastrette, Tetrahedron Lett., 1985, 26, 2315. K.Sasaki, Y.Aso, T.Otsubo, and F.Ogura, Tetrahedron Lett., 1985, 26, 453. S.A.Carr and W.P.Weber, Synth. Comrnun., 1985, 15,775. B.A.McKittrick and B.Ganem, Tetrahedron Lett ., 1985, 26, 4895. E.Block and M.Aslam, J. Am. Chem. SOC., 1985, 107,6729. P.Molina, M.Alajarin, M.J.Vilaplana, and A.R.Katritzky, Tetrahedron Lett .,
208 209 210 21 1 212 21 3
K-Takagi, Chem. Lett., 1985, 1307. S.H.Bertz, G-Dabbagh, and L.M.Williams, J. Org. Chem., 1985, 50, 4414. N.X.Hu, Y.Aso, T.Otsubo, and F.Ogura, Chem. Lett., 1985, 603. W.E.Fristad and J.R.Peterson, Synth. Commun., 1985, 5, 1 . S.C.Shim, S.Antebi, and H.Alper, J. Org. Chem., 1985, 50, 147. S.Fujisaki, 1-Fujiwara, Y.Norisue, and S.Kajigaeshi, Bull. Chem. SOC. Jpn.,
214 21 5 21 6 21 7
K.Nagasawa and A.Yoneta, Chem. Pharm. Bull., 1985, 2, 5049. M-Oshima, M.Murakami, and T.Mukaiyama, Chem. Lett., 1985, 1871. K.Harano, N.Ohizumi, and T-Hisano, Tetrahedron Lett ., 1985, 4203. N.Ono, I.Hamamoto, T.Yanai, and A.Kaji, J. Chem. S O C . , Chem. Comrnun., 1985,
218 21 9 220
D.N.Harpp, T.Aida, and T.H.Chan, Tetrahedron Lett., 1985, 26, 1795. M.Hoshi, Y.Masuda, and A.Arase, J. Chem. SOC., Chem. Commun., 1985, 1068. G-Petrillo, M.Novi, G.Garbarino, and C.Dell'Erba, Tetrahedron Lett., 1985,
199 20 0
1985,
1985,
26,
58,
469.
2429.
c,
523.
~
22 1 222 223 224 225
2 6 , 6365. -
J.S.Cha, J.E.Kim, and J.D.Kim, Tetrahedron Lett., 1985, 26, 6453. R.A.Amos, J. Org. Chem., 1985, 50, 1311. G.J.O'Malley and M.P.Cava, Tetrahedron Lett., 1985, 26, 6159. J.T.Doi and G.W.Luehr, Tetrahedron Lett., 1985, 26, 6143. S.Colonna, S.Banfi, F.Fontana, and M.Sammaruga, J. Org. Chem., 769.
1985,
2,
2,
226 227
H.Ohta, Y.Okamoto, and G.Tsuchihashi, Agric. Biol. Chem., 1985, 671. H.L.Holland, H.Popper1, R.W.Ninniss, and P.C.Chenchaiah, Can. J. Chem.,
228 229
S.T.Purrington and A.G.Glenn, Org. Prep. Proced. Int., 1985, P.Bakuzis and M.L.F.Bakuzis, J. Org. Chem., 1985, 2, 2569.
1985,
9, 1118.
17,227.
5 Amines, Nitr iles, and Other Nitrogen-
1 Amines
Primary Amines.- It is feasible to prepare amines by effecting reductions of other nitrogen-containing functional groups.
Indeed,
such methods constitute a highly significant proportion of amine syntheses.
Nickel-aluminium alloy, used under alkaline conditions,
has been presented as a versatile reagent system capable of cleaving various N-N and N-0 bonds leading to the synthesis of primary (plus also secondary and tertiary) amines (Scheme 1 ) . The application of both ultrasonification'
and phase-transfer
catalysis to the lithium aluminium hydride reductions of amides and nitriles to amines has been documented. Such nitrile reductions are well known and general, but a novel cobalt carbonyl catalysed hydrosilylation of aryl nitriles leading to N,N-disilylarnines4 also appears to have much promise. Hydrolyses of isocyanides have also been exemplified , and appear compatible with both hydroxy15 and ester6 functionality The versatility of nitro-compounds in terms of their synthesis and reactivity has ensured they remain as popular amine precursors. In particular, the action of various reducing agents upon nitroalkenes has been studied(videinfra)with reduction to primary amines achieved using both b o r a n e - t e t r a h y d r o f ~ r a nand ~ lithium aluminium hydride .8 Reductions of nitro-compounds with aluminium amalgam, tetracarbonyldichlorodirhodium/carbon monoxide/ sodium hydroxide , l o lithium aluminium hydride, 10% Pd-C in methanolic HC1 , sodium telluride (from tellurium powder and excess rongalite in 1M NaOH) , l 3 NaBH4/NiC12 (nickel boride) , " hydrazine hydratelgraphite,l 5 Pd-black/formic acid/sodium formate , l 6 plus Raney Nickel with 2-propanol , l 7 methanol, '18 and methanol containing dibenzyl ether"
are all illustrative of methods that now find use
in the preparation of primary amines. Treatment of a variety of nitroarenes with ethyl cyanoacetate and potassium hydroxide, followed by hydrolysis, has been shown to
230
For References see p . 308
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
23 1
lead to the corresponding amino-derivatives into which an 2-cyano substituent had been incorporated (Scheme In a similar vein reaction of l-nitronaphthalenes with dimethyl phosphite and base afforded g-aminonaphthylphosphonates .21 An improvement to the synthesis of aminobiphenyls by reductive phenylation of nitroarenes with trifluoromethanesulphonic acid plus iron pentacarbonyl as a reducing agent has been noted,22 along with a second aminobiphenyl preparation utilising the action of trifluoromethanesulphonic acid on aryl hydrazines in the presence of arenes.23 A hydroxylamine-to-amine reduction employing ammonium iron(I1) sulphatell-cystine has found an application in the synthesis of amino-acids , 24 whilst reduction of oximes by diborane was used in the carbohydrate area .25 Hydrogenolysis of oximes with palladium26 on-carbon allowed synthesis of some 2-arylethylamine derivatives. In an attempt to prepare bornylamines by rhodium-catalysed hydrosilylation of camphor oxime, a 2-[1(2,2,3-trimethylcyclopentyl)1ethylamine was isolated as the major product in an unprecedented C-C fragmentation reaction .27 The transformation of an azide into a primary amine is a well established one, and has been accomplished using P I11,2awhich also effected low-yield reductions of azo-, azoxy- and hydrazo-benzene to aniline, sodium borohydride,29 potassium tetracarbonylhydridoferrate/C0,30 Pd-C/K2C0 /sodium hypophosphite , 31 (conditions under
3
which aryl nitriles seem to be inert), and by Staudinger-type reactions using triphenylphosphine in aqueous tetrahydrofuran,32 or triethyl phosphite followed by gaseous HCl. 33 Azide hydrogenations have also appeared in the literature - 10% Pd-C,34 Pd/CaC03/ Pb2+/dioxane/ t-BuOH (in carbapenem synthesis), 35 and Pd-black (in iminosugar syntheses)36-38 have been used for this reaction. Reduction of an azo-compound with Na2S204 has been exemplified by a preparation of 2-chloro-4-trif luoromethylaniline. 39 Aminations of aromatic nuclei are of obvious synthetic importance and a photoreductive amination of arenes utilizing m-cyanobenzene have been described,40 with use of ammonia or primary amines leading to the synthesis of primary and secondary arylamines respectively. The amination o f oxo-arenes, too, has been the subject of much investigation highlighted by preparations of 5amino-8-hydroxy-l,4-naphthoquinones from 1,5-dinitronaphthalenes, 4 1 and of 9-amino-l-oxophenalenes by direct amination of the 9-hydroxy
'*
analogue. 2-Alkylamino- 1 -0xophena1enes were also prepared in-the latter study. Ammonolysis of quinizarins was shown to produce the
232
General and Synthetic Methods
H
qR’ NH,L L
R’-N=O
i
0R’-NNN
I-
R~\N//N R’-N
H -N
R ~
\ R2
H2
R~-NH-NH-R~
l
R ~ N H ~
R~-N H-NZN-R~ Reagent: i. N i - A l
alloy, KOH,H20, (MeOH).
Scheme 1
CN
WNH I
i,ii
A e a g e n t r : i , Et02CCH2CN, KOH, DMF; ii, 20%
H C I (aq.1, o r 5.1.
NaOH (aq.1
Ar1 CN
NC
NH2
Reagents: i , p i p e r i d i n e , ClCH2CH2Cl ; ii, NaOH, EtOH, 2 2 0 *C
Scheme 3
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
233
9-imino-derivatives; however, these tautomerised prior to trapping as Diels-Alder adducts .43 Intramolecular nucleophilic attack onto the carbon centres of nitriles constitutes a common strategy employed in the synthesis of heterocyclic amines. However, a recent preparation of 5'-amino-mterphenyls from arylidene and 1 - a r y l e t h y l i d e n e - m a l ~ n o n i t r i l e shas ~~ demonstrated that such reactions can be applied to the synthesis of carbocyclic amines (Scheme 3). In the heterocyclic field synthesis of 4-amino-2(5K)-furanones from a-hydroxynitriles (Scheme 4) ,45 2-amino-5,6-dihydro-4E-3,1 ,6benzothiadiazocines ,46 4-amino-2( 1 H ) -pyrimidinones,47 and 4-acyl-5a m i n o p y r a z ~ l e sall ~ ~ typify the more familiar application of such reactivity. Intermolecular variants involving addition-cyclisations have featured in syntheses of 2-amino-4(1H)-pyridones (Scheme 5 1 , 49 4,5( 3)-diaminopyrazoles, 50 2-amino-3-aminomethylquinolines, 5 1 and 2-amino-3-cyano-4,5-dihydrofurans. 52 The last synthesis involved reactions of 1,2-chlorohydrins with malononitrile which reacted similarly with epoxides, episulphides, and N-tosylaziridines leading to the synthesis of 2-amino-3-cyano-4,5-dihydro-furan, -thiophene, and -pyrrole derivatives respectively. 53 Treatment of 4-oxo-tetrahydro-B-carboline with hydrazine gave rise to 4-amino-p-carboline,54 with similar reactions in the tetrahydroisoquinoline series affording analogous aminoisoquinolines. A novel rearrangement of an azide intermediate to a tricyclic tetrazine was proposed in order to explain the formation of 9-amino-6,7dihydro- from 9-bromo-6,7,8,9-tetrahydro-4~-pyrido[l,2-~~pyrimidin4-ones. 55 Reactions in liquid ammonia have also served in the synthesis of amines. Birch reduction-alkylation of the chiral heterocycle ( l ) , formed from isatoic anhydride and L-proline, led to the preparation of enantiomerically pure cyclohexane derivatives. 56 Liquid ammonia was also used in the study of halogenonitropyridine amination,57 and in conjunction with potassium permanganate for effecting Chichibabin amination of t r i a ~ i n e s . ~5-Amino~ acridine derivatives were synthesized from the corresponding chloro-compounds by azide ion displacement followed by reduction. 29 Traditionally, nucleophilic ring opening of aziridines, in a way similar to that of an epoxide, has been regarded as a difficult reaction to achieve. However boron trifluoride diethyl etherate h a s been shown to promote addition of dialkyl cuprates to suitably
General and Synthetic Methods
234
0 . ..
I
'CN
R2 R e a g e n t s : i, T M S C N , Z n 1 2 ; ii, ( R 3 C H 2 C 0 ) 2 0 , F e C I 3 ; iii, ( R 3 C H 2 C 0 ) 2 0 o r R3CH2COCI.
py o r E t 3 N ; i v , L i N ( T M S ) 2 , T H F , - 7 8 0 C ;
v , N a H , T H F , reflux
Scheme 4
L D A ,T H F, -10
oc
[m"] H t O H , r.t.
qo Scheme 5
R,Cu L i
-
NHR* I
BF3 0 E t 2
R Scheme 6
R=C6H40Me-p
i"'
i
5: Amines, Nitriies, and Other Nitrogen-containing Functional Groups
235
functionalised aziridines to yield either primary or secondary amines (Scheme 6) . 5 9 ct ,a-Dimethylarylalkylamines were obtained by the action of aryl Grignard reagents on l-diphenylphosphinyl-2,2dimethylaziridine. 6o The reactions were carried out in diglyme since refluxing THF gave poor yields, and thermal rearrangement to N-( 2-methylally1 )diphenylphosphinamide occurred above 1 3OoC. A ’ Azirines were found to react with 1,2-dithiols to give aziridines which rearranged to yield 2-a-primary amino-l13-dithiolanes (protected aminoketones) .61 The amination of olefins can be achieved by mercuration in the presence of a nitrile. Thus, mercury(I1) nitrate and acetonitrile were used to prepare 10-amino- via 10-acetamido-undecanoic acid. 6 2 Synthesis of (R)- and (S)-2-aminobutanes from the corresponding (S)- and (R)-2-aminobutanols was reported. 6 3 Secondary Amines.- Selective monoalkylation of primary arnines is a goal still actively pursued. Modified borohydride reagents applied in reductive alkylations have been particularly successful in achieving this aim. Sodium cyanoborohydride was used in an efficient synthesis of alkylated a m i n o - ~ u g a r sand ~ ~ also in the synthesis of the imino-carbohydrates I-deoxynojirimycin and 1 deoxymannojirimycin, in which the reductive alkylation occurred in the same reaction mixture as a zinc-mediated reductive fragmentation of a 6-deoxy-6-bromopyranoside. 65 A zinc-modified cyanoborohydride reagent (NaCNBH /ZnC12 2:l) effected high-yield reductive 3 aminations of carbonyl compounds and reductive methylations of amines (tertiary amines were also prepared). 66 Providing reactions can be worked-up with the exclusion of oxygen, good yields of 2-sec- and 2-tert-alkylaminobenzenethiols can be obtained from 2,3-dihydro-ll3-benzothiazoles by reduction with excess sodium borohydride in methanol (Scheme 7).67 Since the heterocycles are conveniently prepared from 2-aminobenzenethiol and carbonyl compounds, the method provides a useful alternative to the previously described alkylation of 2,3-dihydro-l,3-benzothiazol-2ones with alkyl halides. Lithium aluminium hydride h a s been used in the reductive cleavage of axially disymmetric (based on the 1,11-binaphthyl system) tertiary amines to secondary amines, and quaternary ammonium salts. 68 Diacetoxytriphenylbismuth was found t o be capable of arylating primary amines in good yield, particularly when the reactions were
236
General and Synthetic Methods
carried out in the presence of copper(I1) salts, optimally cupric acetate. 69’70 Dialkylamines could also be arylated under these conditions 70 but diarylamines were found to be inert. Zinc sulphide catalysed photochemical conversions of primary to secondary amines7’ plus the role of phase-transfer catalysis in accelerating N-alkylation of arylamines (weak N-H acids) with inorganic bases72 have also been studied. Dealkylation methods constitute a complementary approach to that described above. A method involving catalytic use of iron(I1) chloride to prepare secondary amines from tertiary amine oxides appears to have much promise and also potential for extension to aldehyde synthesis .73 Oxidative N-dealkylations of !,!-dimethylbenzenes by both iodosylbenzene and t-butyl hydroperoxide catalysed by tetraphenylporphyrinato-iron(II1) or -manganese(III) chloride were also studied.74 As with primary amines, reductive methods are readily applied to the synthesis of secondary amines,-. the Ni-A1 alloy induced cleavage of N-N and N-0 bonds‘ mentioned previously led to the preparation of secondary amines from a variety of precursors (Scheme 8). N,N-Disubstituted hydroxylamines when treated with titanium trichloride in aqueous methanol gave rise to secondary arninesr15 in a procedure that can be regarded as a multistep a functionalisation of secondary amine precursors (Scheme 9 ) . N-Aryl- and N-alkyl-ketimines were reduced by isopropyl alcohol and aluminium isopropoxide in the presence of Raney which was required to suppress formation of N-isopropylamines observed in the absence of the metal catalyst. The Hantzsch ester [3,5-bis(ethoxycarbonyl)-2,6-dimethyl-l?4-dihydropyridine] has also been employed in imine reductions.77 The method can also be applied to the preparation of diamines from N,N-bisarylidene-ethylene diamines. Sodium hydrogen telluride has proved to be a versatile reductant since its selectivity can be modified according to the pH at which reductions are carried out. At pH6 reductions of both i r n i n e ~and ~ ~ nitrones” to secondary amines are possible. Imidoyl chlorides can be reduced to secondary amines using P d - B a S O q / NEt3/C6H6 at 1 2OoC. 8o Addition of an organometallic nucleophile to an imine is a well established procedure for the preparation of secondary amines. Such reactions have been exemplified although the nature o f the products arising from the types of nucleophile used,viz. crotyl allylmetals 82 allylstannanes,83 p l u s proparorganometallics
237
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
N H
R2
H R e a g e n t s : i , R ' R 2 C O ; i i , N a B H 4 , M e O H ; iii, A i r
Scheme 7
Reagent : i, N i - A 1 a l l o y , KOH
, H20
(MeOH)
Scheme 8 H *2O2 cat.
0-
I
R' -N
R2
/+\
OH
I
H ' ' y N \ R 2
~
i
Nu
R'
yN\ R2
Nu
Reagent : i , T i C I 3 , H 2 0 -MeOH
Scheme 9
General and Synthetic Methods
238
g y l i c a n d a l l e n i c o r g a n ~ b o r a n e sw~a ~ r r a n t s t h e i r d i s c u s s i o n i n more d e t a i l below. A p r e v i o u s l y d e s c r i b e d m e t h o d f o r t h e s y n t h e s i s of a - b r a n c h e d
s e c o n d a r y a m i r i e s by B e c k m a n n r e a r r a n g e m e n t o f o x i m e s u l p h o n a t e s , e f f e c t e d by o r g a n o a l u m i n i u m r e a g e n t s , h a s b e e n i n c l u d e d i n a r e v i e w . 85 Addition of a l k y l l i t h i u m s t o imines has f a c i l i t a t e d s y n t h e s i s of hindered s-alkyl-t-alkylarnines
i n moderate t o good y i e l d
(Scheme
1 0 ) . 86 An e x t e n s i o n o f a m e t h o d d e v e l o p e d f o r t h e p r e p a r a t i o n o f b u t y l r a d i c a l s from t-butylhydrazine s y n t h e s i s of hindered c h i r a l amines
t-
and l e a d d i o x i d e , a l l o w e d
via
generation of secondary
r a d i c a l s from bornylhydrazine and menthylhydrazine. were t r a p p e d w i t h n i t r o s o - t e r t - o c t a n e
The r a d i c a l s
and t h e r e s u l t a n t hydroxyl-
a m i n e m i x t u r e s r e d u c e d t o g i v e r e a d i l y s e p a r a b l e m i x t u r e s of bornyl-tert-octyl
a m i n e s (2),(3) a n d menthyl-tert-octylamines (4),(5) r e s p e c t i v e l y i n 1 : l a n d 20:l r a t i o s ( S c h e m e The
h y d r a z i n e d e r i v a t i v e s were i n i t i a l l y p r e p a r e d b y c o n d e n s a t i o n s b e t w e e n e t h y l c a r b a z a t e a n d e i t h e r ( + ) - c a m p h o r or ( - ) - m e n t h o n e , h y d r o g e n a t i o n and h y d r o l y s i s . F u r t h e r work on t h e s y n t h e s i s o f c h i r a l a - s u b s t i t u t e d ethylamines v i a Grignard additions t o 1,3-oxazolidines reported.
phen-
was
88 -
Two r e p o r t s c o n c e r n i n g p r e p a r a t i o n s o f d i a r y l a m i n e s a r e a l s o o f note.
A m o d e r a t e t o good y i e l d c o u l d be o b t a i n e d i n d i s p l a c e m e n t s
of a c t i v a t e d nitro-arenes
with a n i l i n e s with enhanced N-acidity
for
w h i c h u s e o f p o t a s s i u m (or c a e s i u m ) c a r b o n a t e i n d i p o l a r a p r o t i c s o l v e n t s was r e q u i r e d , 89 w h i l s t r a t h e r b e t t e r y i e l d s were o b t a i n e d i n r e a c t i o n s of some s u b s t i t u t e d m e t h y l a n t h r a n i l a t e s a n d d i p h e n y l i o d o n i u m c a r b o x y l a t e s m e d i a t e d by c u p r i c a c e t a t e , a g a i n i n a d i p o l a r a p r o t i c s o l v e n t ( S c h e m e 1 2 ) .”
The 2-(2-methoxycarbonyl-
p h e n y 1 a m i n o ) b e n z o i c a c i d s s o f o r m e d were u t i l i s e d f u r t h e r i n p r e p a r a t i o n s of 9-substituted
oxoacridan-4-carboxylic
acids.
T h e p o t e n t i a l u t i l i t y o f o r g a n o c u p r a t e a d d i t i o n s t o a z i r i d i n e s 59 f o r t h e p r e p a r a t i o n of s e c o n d a r y a m i n e s h a s a l r e a d y b e e n n o t e d
a b o v e ( S c h e m e 61, a s was t h e g e n e r a l a p p l i c a b i l i t y o f a m i n o m e r c u r a tion reactions.
Borohydride-mediated
r e d u c t i v e a l k y l a t i o n s of B -
a n i l i n o m e r c u r i a l s have been used t o o b t a i n I l 5 - f u n c t i o n a l i s e d systems, notably 5-aminonitriles,
I l 5 - d i a m i n e s a n d 5-amino-
alcohols.91
Direct p h o t o c h e m i c a l a m i n a t i o n s o f arenes4’
and p r e p a r a t i o n s of
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
*
&NN\R1
239
qL,$R2
R2
R' = But, 1 - a d o m a n t y l , or t-CSH,l R2 = Ph , B u n , Bus, B u t , M e , or 2 Reagents: i. R2Li, PhFle,O*C; ii, H 2 0 ; i i i , B u " L i . P h M e , 0
- picolyl
oc
S c h e m e 10
( 2 ) X = NHR, Y = H ( 3 ) Y = H, X = NHR
.I , I I a .
X
(2):(3) = 1 : l
'NH2
& &
&M Me
Y R
x
A i ii
H
Y = NHR
H
Me Reagents : i, P b O Z , M e 3 C C H 2 C M c 2 N 0
(4) X = NHR, Y = H ( 5 ) X = H,
N/NH2
H
= CMe2CH2CMe3
Me
;
i i , Na,NH3, THF
S c h e m e 11
( 4 ) : ( 5 )= 2 O : l
240
General and Synthetic Methods
9-alkylamino- 1 -oxophenalenes4* were also alluded to above. Tertiary Amines.- Many of the alkylative methods discussed in the previous section are also applicable to tertiary amine synthesis. Indeed it is often difficult to control reactivity well enough to prepare secondary amines selectively. As an alternative method for N -m
et h y 1at i o n of second a r y am ine s reductive carbo xy 1at ion appears attractive,with high yields of products obtained from carbamate esters which derive from direct carboxylation of lithium- o r trimethylsilyl-dialkylamides. Tertiary amines were also made by phenylation of dialkylamines with the aforementioned diacetoxytriphenylbismuth/cupric acetate system , 7 0 by lithium aluminium hydride mediated cleavage of axially disymmetric quaternary ammonium salts,68 and also in good yield by photo-Ernde degradation of 1 , 2,3,4-tetrahydroisoquinolinium salts.93 Sodium hydrogen telluride has proven to be a versatile reductant and may be used to prepare tertiary amines in high yield from quaternary ammonium salts ," immonium salts , 7 8 and tertiary amine oxides7' which were also found to be reduced by Ni-A1 alloy7 and acetic-formic anhydride.95 However, the last of these reactions could not be applied to reduce heteroaromatic N-oxides and sulphoxides. Formic acid reduction of enamines has been developed a s a generally useful tertiary amine synthesis . 9 6 The method usually affords high yields of the desired products, and was utilised in the formation of bornylamines.97 The synthesis of amines by lithium aluminium hydride reduction of amides is a long established procedure in which some evidence was presented for the beneficial effect of adding phase-transfer catalysts to reaction mixtures. A newer variation has been reported whereby cx-branched tertiary amines were synthesized in moderate to high yields by sequential treatment with alkyllithiums and a reducing agent . 9 8
o-Methylbenzylamines have been prepared fluoride ion induced desilylation-Sommelet-Hauser rearrangements of benzyldimethyl(trimethylsilylmethyl)ammonium halides bearing c h l o r o - , c y a n o - and acetoxy-substituents .99 2-(!-Methylanilino )hexa-2,4-dienenitriles proved useful in the synthesis of methyl-diarylamines after undergoing cycloaddition-aromatisation reactions with dienophiles typified by maleic anhydride, N-phenylmaleimide, benzoquinone and DMAD. l o o 6 a l k y l , N6- a r y l - S H - p u r i n - 6 - a r n i n e s N6 ,N6-Dialkyl- and N were '
prepared from 5-acetamido-6-arnino-2-methylpyrimidin-4~3~~-one1
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
24 1
p h o s p h o r u s p e n t o x i d e a n d s e c o n d a r y a m i n e s or t h e i r h y d r o c h l o r i d e salts.'" S e c o n d a r y a m i n e s were s h o w n t o s u b s t i t u t e h a l i d e i n 5halogenouracils using potassium fluoride. Io2 Diamines.-
T h e p r e p a r a t i o n o f v i c i n a l d i a m i n e s by f u n c t i o n a l i s a t i o n
o f o l e f i n s r e m a i n s a n area o f a c t i v e r e s e a r c h i n t e r e s t .
Full
d e t a i l s c o n c e r n i n g a p r e v i o u s l y r e p o r t e d s y n t h e s i s of +-primary d i a m i n e s v i a N-bromosuccinimide-mediated
a d d i t i o n of cyanamide t o
u n a c t i v a t e d d o u b l e b o n d s f o l l o w e d by f o r m a t i o n a n d s u b s e q u e n t hydrolysis of a 2-ethoxyimidazoline
have been published.
O3
Diamines have a l s o r e s u l t e d from r e d u c t i o n s of v i c i n a l d i a z i d e s w h i c h were o b t a i n e d from o l e f i n s by r e a c t i o n w i t h m a n g a n e s e ( I I 1 )
acetate and e x c e s s sodium a z i d e .
Diazide reductions proved
s o m e w h a t p r o b l e m a t i c a l , b e i n g a c h i e v e d most s a t i s f a c t o r i l y w i t h I n a more s p e c i a l i s e d e x a m p l e r i n g f r a g m e n t a -
Lindlar's catalyst.
t i o n of N - t o s y l h i s t a m i n e
w i t h di-tert-butylpyrocarbonate l e d u l t i -
m a t e l y , a f t e r two f u r t h e r s t e p s , t o 1,2-diamino-4-N-tosylaminobutane. Io5
I n a n o t h e r s t u d y N-phthalimido-aziridines ( p r e p a r e d
from o l e f i n s a n d p h t h a l i m i d o n i t r e n e ) r e a c t e d w i t h a n i l i n e , u n d e r
t h e influence of perchloric acid, to yield t h e corresponding phthalimidoamines.
E-
T r e a t m e n t w i t h Raney n i c k e l / h y d r a z i n e a l l o w e d
i s o l a t i o n of t h e B -functionalised
amines. Io6
A s mentioned above,
v i c i n a l secondary diamines r e s u l t e d from r e d u c t i o n s of
N,N-
bisarylidene-ethylenediamines w i t h H a n t z s c h e s t e r .77 1 , 5 - D i a m i n e s w i t h a t e r m i n a l p r i m a r y a m i n o - g r o u p were o b t a i n e d after aminomercuration of o l e f i n s with a n i l i n e , demercuration with NaBH4 i n t h e p r e s e n c e of a c r y l o n i t r i l e , a n d s u b s e q u e n t r e d u c t i o n o f
the resultant aminonitrile
N,"-dimethyl-1,w-alkane
P r e p a r a t i o n s of N , N ' - d i - n - a l k y l -
d i a m i n e s by s t a n d a r d r e d u c t i v e a m i n a t i o n s ,
two-step amidation-LiA1H4 r e d u c t i o n s and Menschutkin c o n d e n s a t i o n s were a l s o r e p o r t e d . 1 0 7
(+I-Camphor-IO-sulphonic a c i d was f o u n d t o e f f e c t r e a r r a n g e m e n t t o 2,2'-diamino-l,l'-binaphthyl w i t h a l o w , t e m p e r a t u r e - a n d s o l v e n t - d e p e n d e n t e n a n t i o s e l e c t i v i t y . '08 T h e
of 2 , 2 ' - h y d r a z o n a p h t h a l e n e
a p p l i c a t i o n of D i b a l t o t h e p r e p a r a t i o n of d i a m i n e s f r o m a m i n a l s , f o r m e d p a r t of a l a r g e r r e v i e w o n s e l e c t i v e r e a c t i o n s o f o r g a n o a l u m i n i u m r e a g e n t s . 85
242
General and Synthetic Methods 2 Enamines
T h e u t i l i t y o f s i m p l e e n a m i n e s i n C-C
bond-forming
reactions has
prompted c o n t i n u i n g e f f o r t s d i r e c t e d t o w a r d s improved m e t h o d s of s y n t h e s i s f o r more h i g h l y f u n c t i o n a l i s e d d e r i v a t i v e s . reagent
The Tebbe
(6) h a s f o u n d u s e i n t h e o l e f i n a t i o n o f e s t e r s a n d r e c e n t l y
( 6 ) h a s b e e n u s e d t o p r e p a r e e n a m i n e s by m e t h y l e n e a t i o n o f a m i d e s i n a n a t t r a c t i v e a l t e r n a t i v e t o more c l a s s i c a l p r o c e d u r e s . l o g
The
m e t h o d looks p a r t i c u l a r l y p r o m i s i n g f o r t h e p r e p a r a t i o n o f e n a m i n e s of m e t h y l k e t o n e s a n d a l k y l a t i o n s o f e n a m i n e s s o p r o d u c e d a r e formally equivalent t o a l k y l i d e n e a t i o n r e a c t i o n s performed w i t h homologues of reactions of
(6), w h i c h s o f a r h a v e y e t t o b e p r e p a r e d .
Similar
( 6 ) w i t h i m i d e s l e a d i n g t o mono- a n d / o r d i - m e t h y l lo
e n e a t e d p r o d u c t s were r e p o r t e d i n d e p e n d e n t l y .
A s t e r e o s p e c i f i c s y n t h e s i s o f e n a m i n e s f r o m a , $ - e p o x y s i l a n e s was
repor>ted.’”
(7) ( o f a c i s - t r a n s
Ring o p e n i n g of t h e c i s - e p o x i d e
m i x t u r e ) t o p r o v i d e a-amino-B-hydroxysilanes c o u l d b e a c h i e v e d i n reasonable yields.
Potassium hydride-induced syn-$-eliminations
could be c o n t r o l l e d t o provide trans-enamines glassware had been p r e - t r e a t e d
( l o ) , unless
w i t h b a s e w a s h i n g , i n which case
c i s - e n a m i n e s ( 9 ) were o b t a i n e d ( S c h e m e 1 3 ) . -
I n t h e examples s t u d i e d
a c i d - c a t a l y s e d c i s - t r a n s i s o m e r i s a t i o n of t h e e n a m i n e s was f o u n d t o be e x t r e m e l y f a c i l e , o c c u r r i n g r a p i d l y even i n c h l o r o f o r m . A n o t h e r a p p a r e n t l y g e n e r a l m e t h o d of e n a m i n e s y n t h e s i s u t i l i s e d Ross-Eberson-Nyberg of !-protected
amines. ’ I 2
electro-oxidative
a-methoxylation
The e l i m i n a t i o n s g i v i n g r i s e t o
t h e enamines could be c a r r i e d o u t u s i n g e i t h e r p-toluenesulphonic-
or e l e c t r o - g e n e r a t e d a c i d .
Y i e l d s f o r t h e o v e r a l l p r o c e s s (Scheme
1 4 ) were g e n e r a l l y h i g h . I n t h e l i g h t o f h i g h l y s u c c e s s f u l r e s u l t s w i t h t h e a l k y l a t i o n of h y d r a z o n e s , a t t e n t i o n h a s been f o c u s s e d upon t h e p o t e n t i a l of c h i r a l enamines.
Excellent y i e l d s of c h i r a l !-[2-(trimethylsilyl-
o x y ) a l k y l ] e n a m i n e s were o b t a i n e d o n t r e a t m e n t o f 2 - a l k y l o x a z o l i d i n e s w i t h c h l o r o t r i m e t h y l s i l a n e and N-isopropylamine. M a g n e s i u m c h l o r i d e p r o m o t e d M i c h a e l a d d i t i o n s of t h e s e c o m p o u n d s t o u n s a t u r a t e d c a r b o n y l c o m p o u n d s were a c h i e v e d w i t h m o d e r a t e t o g o o d asymmetric induction.
C h i r a l o r g a n o t i n e n a m i n e s were p r e p a r e d from
c y c l i c ketones, amino-acid-derived
aminolai-n-butylstannane. ’ I 4
amino-alcohols and bis(dimethy1-
Additions o f t h e enamines so formed
t o electron-deficient alkenes occurred readily to yield products i n variable
(10-98%) e n a n t i o m e r i c excess.
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
p<" Hex (7) X
Y
Si Me3
HO
243
- /=(" KH
H-7-c-H
Hex
(9)
R2
= H , Y = SiMe3
NR2
I
(8) X =SiHe,,Y = H
Hex
H (10)
S c h e m e 13
. ..
,
~ 1 7 iii ~
R ~ N
- "'Yx iv
R*N
Ac
-
R'XX Ac
OMe
R ~ N AC
R e a g e n t s : i , R2NH2, ii, A c 2 0 , i i i , - 2 e , M e O H , E t 4 N + C 1 0 4 - - ( C ) ;
- R17c Scheme 14
R 1 v = C H O
iv, p -TSA
R2 / N \ R 3
I
R'
YR4 R2/
Hq R4
I
R 4 y ' "
iii
/
\ R3
R2 / N \ R 3
R e a g e n + s : i , R2R3NHaHCI,KCN , H 2 0 ; i i , R & M g B r , T H F ; iii,
S c h e m e 15
THF
*
General and Synthetic Methods
244
The isomerisation of allylamines to enamines represents another potentially useful transformation, and bis[(R)-(+)-binaplrhodium(1) perchlorate has been identified as an efficient catalyst for performing this transformation with excellent asymmetric induction ( > 9 5 % e.e.1. 115 2-Morpholino-1,3-dienes can be obtained by selective aminomercuration of the alkynyl bond of alk-3-en-l-ynes. Catalytic amounts of Hg(OAc)2 in dry tetrahydrofuran appear to be the optimum conditions for this reaction to occur rather than l-aza-l,3-diene formation, which occurs with HgC12 and potassium carbonate in aqueous tetrahydrofuran. 4-Amino- 1 , 1 -dicyanobuta- 1 ,3-dienes were prepared by acid-catalysed iminoformylation of crotononitriles. Preparation of conjugated trienediamines from 1 , 9 diaminonona-2,7-diynes was also described. '18 It was shown (by subsequent hydrolyses to 1,3-diketones) that alkylation of 4-aminol-aza-butadienes occurred exclusively at the 2-position thus offering a potentially useful synthetic transformation, whilst B-amino-B-arythio-u,B-ethylene-imines were obtained from ynamines and thioiminoesters. 2o B-Amino-a,B-ethylene ketones were obtained transaminations Synthesis of similar of 1-nitroenamines with secondary amines. 12' compounds the reaction of oxime sulphonates and silyl enol ethers in the presence of Lewis-acidic organoaluminium reagents were reported as part of a review .85 B-Amino-8-azo-a, B-ethylene carboxylates resulted from base-induced fragmentations of a2pyrazoline-4-spiro-2 '-0xiran-5-ones~ "and 8-amino-a, fi-ethylene-adicarboxylic acid esters were isolated after tin-promoted additions of malonates to nitriles. 123 Simple 6-amino-a,B-ethylene-thioaldehydes have been made in moderate yield by treating enamines with DMF/POC13 followed by solvolysis with sodium hydrogen sulphide. 124 A treatise on the reactions of Lawesson's reagent summarised studies on the preparation of enamine-thiones important intermediates in thiopyran and thiophene synthesis - by thionations of the corresponding enaminones with this reagent. 125 In general nitrogen-, phosphorus- and sulphur-containing enamines are much sought after, since they are important intermediates in heterocyclic synthesis. Preparation of B-substituted nitroenamines has been reported, 126 along with that of B-aminO-
-
styryldiphenylphosphine N-oxides from which the corresponding phosphine oxides and phosphine sulphides were obtained by reaction with
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
245
c a r b o n d i o x i d e and c a r b o n d i s u l p h i d e r e s p e c t i v e l y l i s e d B-phosphonic
B-functiona-
e n a m i n e s were a l s o s y n t h e s i s e d b y c o n d e n s a t i o n
of functionalised phosphonates with dimethylformamide dimethyl
a c e t a l . 1 2 8 y-Amino-B , y - e t h y l e n e p h o s p h i n e o x i d e s were o b t a i n e d a f t e r a d d i t i o n s o f p h o s p h i n e o x i d e s t o a , B - e t h y l e n e a z o m e t h i n e s . 129 I t was d e m o n s t r a t e d t h a t e n a m i n e s u l p h o n e s c o u l d b e p r e p a r e d
y from alkynes &
s e l e n o s u l p h o n a t i o n f o l l o w e d by o x i d a t i o n t o t h e
s e l e n o x i d e a n d t h e n r e a c t i o n w i t h a m i n e s . I3O
T h i s s e q u e n c e when
applied t o terminal alkynes afforded selenenylated analogues.
B-
Arylsulphonylvinylamines were o b t a i n e d a f t e r l i t h i u m a l u m i n i u m hydride reduction of arylsulphonylmethyl cyanides being used t o prepare dihydropyridines.
its 2-trimethylsilyl
’”
the products
Anions of 1,3-dithiane or
d e r i v a t i v e were f o u n d t o r e a c t w i t h n i t r i l e s
t o provide primary aminoketene t h i o a c e t a l s .
32
Primary enamines
were a l s o o b t a i n e d u p o n h y d r o g e n a t i o n o f c y a n o m e t h y l e n e d e r i v a t i v e s o v e r 5% Pd-C
a t medium p r e s s u r e s . ’ 3 3
T h i s r e a c t i o n proved u s e f u l
i n t h e s y n t h e s i s o f a-(aminomethylene)purine-6-acetic
acid deriva-
tives. I n a few s p e c i a l i s e d e x a m p l e s 1 , 3 - d i e n - 2 - a m i n e s
were f o u n d t o
u n d e r g o a [4+21 c y c l o a d d i t i o n w i t h n i t r o o l e f i n s t o form t r i c y c l i c d e r i v a t i v e s o f 4-nitrocyclohexenylamine. 34 T h e c y c l o p r o p y l - i m i n i u m i o n r e a r r a n g e m e n t was i n v e s t i g a t e d a s a p o t e n t i a l r o u t e t o masked e n a m i n e s and dienamines.135
I t was s h o w n
t h a t enammonium s a l t s c o u l d b e u s e d a s p r o t e c t e d e n a m i n e s w h i c h c o u l d be l i b e r a t e d on removal o f a s u i t a b l y c h o s e n p r o t e c t i n g group.
3 Allylamines, Homoallylamines, and Alkynylamines A l l y l a m i n e s h a v e r e c e i v e d much a t t e n t i o n i n t h e r e c e n t l i t e r a t u r e , a t r e n d which a p p e a r s t o be c o n t i n u i n g .
a-see-Allylamines
have
been r a r e l y r e p o r t e d b u t a r e c e n t d i s c l o s u r e d e s c r i b e s t h e i r synthesis
via
application of the Bruylants reaction.136
The method i s
v e r s a t i l e i n t h a t e i t h e r e n a l s c a n b e c o n v e r t e d t o v i n y l aminon i t r i l e s p r i o r t o reaction with a Grignard reagent, or vinyl Grignard r e a g e n t s c a n be r e a c t e d w i t h a - a m i n o n i t r i l e s
(Scheme 1 5 ) .
Y i e l d s o f t h e p r o d u c t s were m o d e r a t e t o g o o d . E-Allylamine -
d e r i v a t i v e s have been found t o r e s u l t from t r a n s -
r e d u c t i o n o f 2 - a l k y n y l a m i n e s w i t h D i b a l i n t o l u e n e a t 4OoC. 137 This contrasted sharply with the e-stereochemistry
encountered i n
r e l a t e d hydroaluminations of disubstituted alkynes.
The r o l e o f
General and Synthetic Methods
246
palladium c a t a l y s i s i n t h e s y n t h e s i s of a l l y l a m i n e s h a s been f u r t h e r developed. P d - c a t a l y s e d r e a c t i o n of a l l y l i c s u b s t r a t e s with sodium p-toluenesulphonamide gave rise t o s u b s t i t u t i o n prod u c t s with r e t e n t i o n of configuration.i38 Pd-catalysed
1,4-acetoxychlorination
s e l e c t i v i t y and s t e r e o s p e c i f i c i t y . reacted regioselectively.
of
A more d e t a i l e d s t u d y o f
1,3-dienes revealed high
The c h l o r o a c e t a t e p r o d u c t s a l s o
D i s p l a c e m e n t of c h l o r i d e w i t h c l e a n
r e t e n t i o n or i n v e r s i o n s c o u l d b e r e a l i s e d w i t h a m i n e s i n t h e p r e s e n c c or a b s e n c e o f a p a l l a d i u m c a t a l y s t r e s p e c t i v e l y ( S c h e m e 16) Recently organoselenium chemistry has seen increasing use i n t h e
I t h a s now b e e n demon-
preparation of allylamine derivatives.
s t r a t e d t h a t o p t i c a l l y a c t i v e a l l y l a m i n e s c a n b e p r e p a r e d by o x i d a t i v e [ 2 , 3 1 r e a r r a n g e m e n t of c h i r a l a l l y l i c s e l e n i d e s (Scheme 17).
P r o d u c t s s y n t h e s i z e d i n t h i s way c o u l d b e e l a b o r a t e d i n t o
a m i n o - a c i d d e r i v a t i v e s by o x i d a t i v e c l e a v a g e o f t h e d o u b l e b o n d . R e l a t e d r e a r r a n g e m e n t s o f y-phenylseleno-a,B-unsaturated e s t e r s l e d d i r e c t l y t o protected B ,y-unsaturated
a-amino-acids.
T h e s y n t h e s i s of a l l y l a m i n e s a n d c o r r e s p o n d i n g a - a m i n o - a c i d s
as
i n h i b i t o r s of c l i n i c a l l y r e l e v a n t e n z y m e s h a s b e e n r e p o r t e d . Seventeen 2-aryl-3-haloallylamine
d e r i v a t i v e s were p r e p a r e d a n d
e v a l u a t e d a s p o t e n t i a l monoamine o x i d a s e i n h i b i t o r s , a n d found t o be enzyrne-activated
i r r e v e r s i b l e i n h i b i t o r s whose s e l e c t i v i t y f o r
t h e A o r B f o r m o f t h e enzyme c o u l d b e m a n i p u l a t e d by a s i m p l e change i n t h e a r y l s u b s t i t u t i o n .
A f u r t h e r study allowed syn-
t h e s i s of d e r i v a t i v e s incorporating a B-substituted (Scheme 1 8 ) .
The d i a m i n e ( 1 1 ) and t h e a m i n o - a c i d
t o be time-dependent
heteroatom ( 1 2 ) were f o u n d
i n h i b i t o r s of d i a m i n e o x i d a s e a n d y-amino-
butyric acid transaminase respectively. An e l e v e n - s t e p
s y n t h e s i s of
(El-B-fluoromethyleneglutamic a c i d
(from e t h y l 3 , 3 - d i m e t h y l a c r y l a t e ) as a p o t e n t i a l d u a l enzyme-activ a t e d i n h i b i t o r o f t h e GABA-t e n z y m e was a l s o r e p o r t e d . 1 4 4
Intra-
m o l e c u l a r e n e - r e a c t i o n s between e t h y l g l y o x y l a t e and a l l y l i c aminoacid derivatives yielded functionalised unsaturated pimelic acids.
45
Oxidation o f 2 , 2 , 2 - t r i c h l o r o e t h y l N-hydroxycarbamate
afforded
t r i c h l o r o e t h y l n i t r o s o f o r m a t e which u n d e r w e n t i n s i t u [4+21 a d d i t i o n with thebaine (13).
T r e a t m e n t of t h e c y c l o a d d u c t w i t h H C 1 i n
e t h y l e n e g l y c o l f o l l o w e d by r e d u c t i o n w i t h z i n c a n d d e p r o t e c t i o n allowed generation of t h e allylamine moiety of (14) i n n e a r l y 70% y i e l d . 1 4 6
14B-aminocodeinone
247
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
I
I
H
I
I
CI
NEt2
I
I
R e a g e n t s : i , L i C l , LiOAc , c a t . P d ( O A c ) 2 , p - b e n z o q u i n o n e , HOAc
, 25 OC ; ii,HN€tz,
Pd(0) , T H F ; iii, H N E t 2 , M e C N , A
S c h e m e 16
& Me
Me
NHCBr
I
iii -v
HO,C
R c a g e n t s : i , RCH2CH=PPh3
( 3 equiv.), P h M e , - 78 OC
;
NHCBr
i i , PhCH20CONH2(3 equiv.).
NEt3 ( 6 c q u i v . ) , N C S ( 3 e q u i v . ) , M e O H , 0 OC; i i i . 0 3 , C H 2 C I 3 - MeOH 5:1, -78OC -25
OC;
iV.
Me2S,-76-25
OC;V, CrOj, H2S04, H 2 0 , M t 2 C 0
Sc.hama 17
248
C02But
I
MeCHC02Et
-
General and Synthetic Methods
Me
NPhth
Br
NPhth X= H,Y=
F
X = F,Y = H
1
ii X = F , Y = H
RX
RX (11) X R = NH2
R e a g e n t s : i, NBS,CC14, 6M-HCI (aq)
A ; ii,
RXH ( N u ) , N a H ,
,It.
. (12) XR = C02H(fromCN) D M F , D M S O ; i i i , NZH4; a q . H C I Or
S c h e m e 18
wM 0 R'
OR'" Chelat ion products
R'O
S c h e m e 19
-
Non chclat ion prod u c t s
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
249
T h e r e h a v e b e e n many r e p o r t s c o n c e r n i n g r e a c t i o n s o f a l l y l i c organometallic reagents with imines. Diastereofacial selectivity o f s u c h r e a c t i o n s h a s been s t u d i e d .81
With c r o t y l - m e t a l
reagents
e r y t h r o s e l e c t i v i t y is o b s e r v e d r e g a r d l e s s o f t h e t y p e o f metal r e a g e n t u n l e s s R i s b u l k y a n d l o r R1is a r y l i n ( 1 5 ) i n w h i c h c a s e s threo-selective
a d d i t i o n s w o u l d be o b s e r v e d .
Reactions of allyl-metals
w i t h a- a n d 8 - a l k o x y i m i n e s
e n a n t i o d i v e r g e n t 1,2- and Il3-asymrnetric
allowed
induction respectively due
t o a c o m b i n a t i o n o f metal t u n i n g a n d s t e r e o d i f f e r e n t i a t i o n . " C h e l a t i o n " p r o d u c t s were o b t a i n e d f o r r e a c t i o n s w i t h a l l y l - M g C 1 , - A 1 E t 3 figC1, a n d -ZnBr
reagents, with "non-chelation"
obtained with ailyl-Ti(OPri)3,
products
-B(OMe)2 a n d -9BBN r e a g e n t s , t h e
l a t t e r o f which g a v e t h e b e s t s e l e c t i v i t y (Scheme 1 9 ) . 8 2
The
s t e r e o c h e m i s t r y o f a d d i t i o n o f c r o t y l s t a n n a n e s t o i m i n e s was f o u n d t o b e t e m p e r a t u r e - s e n s i t i v e , i n t h a t t h e b r i e f warming o f imine-
L e w i s a c i d m i x t u r e s , r e q u i r e d i n o r d e r t o a c c e l e r a t e i n i t i a l comp l e x a t i o n , a c t u a l l y d e c r e a s e d e r y t h r o : t h r e o s e l e c t i v i t y . 83 Homoallylamines a l s o r e s u l t e d from a d d i t i o n s o f C2-acetoxymethyl )-3-ally1] tri-n-butylstannane
t o imines.
47
o f t h e p r o d u c t s a f f o r d e d 4-methylenepyrrolidines.
Base treatment Hydrogenative
cleavage of trirnethylsilylmethylisoxazolidines ( r e s u l t i n g from a d d i t i o n s of a l l y l s i l a n e s t o n i t r o n e s ) f o l l o w e d by o l e f i n a t i o n l e d 148 t o f u r t h e r homoallylamines. The r e a c t i v i t y o f s t a n n y l a t e d ynarnines14'
and y n a n i l i n e s 1 5 '
has
been s t u d i e d f u r t h e r and t h e s y n t h e s i s o f 3-aminopropiolthioamides reported. l5
The p r e p a r a t i o n o f r i n g - a l k y n y l a t e d
anilines
treat-
w i t h t r i a l k y n y l a l a n e s was
m e n t of l-alkyl-!-arylhydroxylamines h i g h l i g h t e d i n a r e v i e w a r t i c l e .85
Stereospecific synthesis of
(2Rl5E)-hept-6-yne-2,5-diamine a s a p o t e n t a n d s e l e c t i v e i r r e v e r s i b l e i n h i b i t o r o f o r n i t h i n e d e c a r b o x y l a s e was r e p o r t e d . 1 5 2 Both 8 - a c e t y l e n i c and a - a l l e n i c
amines could be prepared from
i m i n e s by a d d i t i o n o f p r o p a r g y l i c a n d a l l e n i c o r g a n o b o r a n e s r e s p e c t i v e l y .84
Tertiary a-allenic
a m i n e s were a l s o o b t a i n e d a f t e r
t r e a t m e n t o f 4-dialkylamino-I-methoxy-2-butynes w i t h l i t h i u m a l u m i n i u m h y d r i d e - a l u m i n i u m c h l o r i d e i n d i e t h y l e t h e r . 153
4 A m i n o - a l c o h o l s a n d R e l a t e d Compounds With a p l e t h o r a o f n a t u r a l p r o d u c t s i n c l u d i n g amino- and iminosugars p l u s hydroxylated amino-acids
.
i n t h e l i t e r a t u r e it is h a r d l y
s u r p r i s i n g t h a t much r e s e a r c h e f f o r t h a s b e e n d e v o t e d t o t h e s y n -
250
General and Synthetic Methods
t h e s i s of amino-alcohol
derivatives.
The S h a r p l e s s a s y m m e t r i c
e p o x i d a t i o n m e t h o d i s now f i r m l y e s t a b l i s h e d a s t h e m e t h o d o f c h o i c e f o r preparing e n a n t i o m e r i c a l l y pure a c y c l i c 2,3-epoxy hols.
Despite t h e demonstration - a lengthy synthesis of
alco-
(-)-
s w a i n s o n i n e f r o m trans-174-dichloro-2-butene a n d N - b e n z y l - pt o l u e n e s u l p h o n a m i1 d e5 4- t h a t t h e m e t h o d o l o g y may b e a p p l i e d t o nitrogen-functionalised
s u b s t r a t e s , s t u d i e s on t h e i n t r o d u c t i o n o f
nitrogen nucleophiles i n t o 2,3-epoxy-alcohols
h a v e been made.
Indeed, r e l i a b l e methods f o r s e l e c t i v e E-nucleophilic C2-,156
and C
a t t a c k a t C1-
o f e p o x y - a l c o h o l s p l u s C3- o f e p o x y -
: ? c i d s a n d a r r ~ i d e s lh ~a v~e 'been d o c u m e n t e d . ion a t C1 of a 2,3-epoxy-alcohol
derivative
r e d u c t i o n of t h e a z i d e ) t o t h e s y n t h e s i s of
Introduction of azide led ultimately (after (22,35)-4-amino-2,3-
dihydroxy-3-methylbutyric a c i d ( 1 6 ) . 159 E l s e w h e r e , two m e t h o d s for t h e p r e p a r a t i o n o f 2 - ( N - a l k y l a m i n o ) 1,3-diols
from 2,3-epoxy-alcohols
w e r e d e s c r i b e d . I6O-
The f i r s t
involved s e q u e n t i a l transformation of t h e epoxy-alcohol i n t o an e p o x y - u r e t h a n e and t h e n c e t o a 2 - o x a z o l i d i n o n e ,
t h e second con-
s i s t i n g of t r e a t i n g t h e epoxide d e r i v a t i v e d i r e c t l y with benzyl i s o c y a n a t e a n d s o d i u m h y d r i d e i n THF ( S c h e m e 2 0 ) .
was u t i l i s e d i n t h e s y n t h e s i s o f
This methodology
(+I-erythro-dihydrosphingosine
from p a l m i t i c aldehyde. T h e r e a g e n t s u s e d i n t h e S h a r p l e s s e p o x i d a t i o n were a l s o e m p l o y e d i n t h e r e s o l u t i o n o f racemic B - h y d r o x y a m i n e s f a c i l i t a t e d 161 by e n a n t i o s e l e c t i v e N-oxide f o r m a t i o n . A s an a l t e r n a t i v e t o t h e above a p p r o a c h , i n t r a m o l e c u l a r Michael
a d d i t i o n s of 2-carbamates occupying a l l y l i c and homoallylic posit i o n s r e l a t i v e t o a,B-unsaturated
e s t e r s a s a means of d i a s t e r e o -
s e l e c t i v e a m i n a t i o n o f a c y c l i c s y s t e m s a p p e a r s t o h a v e much p o t e n t i a l . 162 l 1 2 - s y n - C y c l i s a t i o n s o f b o t h e r y t h r o - a n d t h r e o - y carbamoyloxy-u,B-unsaturated e s t e r d e r i v a t i v e s a f f o r d e d t r a n s i s o x a z o l i d i n e s which could be transformed i n t o N-acetyl-D,L-acosamine163 and ~ - b e n z o y l - C , 1 - 3 - e p i - d a u n o ~ a m i n e ~ r e~s~p e c t i v e l y . H o w e v e r , a l t h o u g h t h e e x p e c t e d 1,3-*
c y c l i s a t i o n was o b s e r v e d f o r
t h e erythro-6-~-carbamoyloxy-a,B-esterl t h i s l e a d i n g t o t h e s y n t h e s i s o f N-benzoyl-D,L-ristosamine, 1 6 3 t h e c o r r e s p o n d i n g t h r e o isomers underwent c y c l i s a t i o n with 1,3-anti d i a s t e r e o s e l e c t i v i t y due t o t h e antiperiplanar-like p o s i t i o n . 16'
e f f e c t o f t h e s u b s t i t u e n t a t t h e 4-
The l a t t e r c y c l i s a t i o n t h u s f a c i l i t a t e d p r e p a r a t i o n
of N-benzoyl-D,L-daunosamine ( S c h e m e 2 1 ) . ( * ) - D a u n o s a m i n e was also p r e p a r e d i n a n o t h e r r e p o r t , t h i s t i m e
25 1
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
0
\
l i ii
R e a g e n t s : i , P h C H 2 N C 0 , p y or N E t 3
;
i i , P h C H 2 N C 0 , N a H , T H F ; i i i . NaH,THF
Scheme 20
252
General and Synthetic Methods OCONH,
Me
? I
C02Et OCONH~
I Et
erythro
H NA
\
multistep
OH
N - A c e t y \ O,L-acosamine
OCONH,
O q o
H Me
/
C0,Et A M e f i HI
H
rn
OR threo
CO,Et
R = CONH2 or SiMezBut
OH N - Benzoy I - 0 , L- 3 e p i -daunosamine ?H
'ypH ?R
Me
H
CoPh
c 0 2 EtA
H
mu It istep
Me
OH
NH
OCONH,
0 R = SiEt, o r SiMe2But
ery t h r o
N - B e n z o y l - D ,L ristosamine
-
OH
I
,,,
C02Et I is p,
C02Et OCONH2
':,*, OP
OH
0 threo
-
R = S i E t j or SiMeiBu'
N - B e n z o y l - 0 ,L
daunosami ne
R e a g e n t : i , KOBut (1.1 e q u i v ) . T H F
S c h e m a 21
-
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
253
by f u n c t i o n a l i s a t i o n o f a c y c l i c a l l y l i c a l c o h o l d e r i v a t i v e ( 1 8 ) (Scheme 2 2 ) . 165 The method i n v o l v e d p e r f o r m i n g a Mitsunobu react i o n i n t h e p r e s e n c e of d i b e n z o y l i m i d e w h i c h a l l o w e d ( 1 8 1 , t h e m a j o r p r o d u c t o b t a i n e d on r e d u c t i o n o f ( I ” ) , t o b e u s e d i n t h e s y n t h e s i s w i t h o u t t h e n e e d of a n o x i d a t i o n - h y d r i d e r e d u c t i o n sequence t o achieve the desired epimerisation.
(+)-2-Amino-2-deoxytetritol d e r i v a t i v e s were a l s o s y n t h e s i s e d via f o r m a t i o n o f t h e t r i c h l o r o a c e t a m i d a t e (20). I o d o c y c l i s a t i o n of ( 2 0 ) t o ( 2 1 ) l e d u l t i m a t e l y t o t h e ( 4 ) e r y t h r o compound ( 2 2 ) w h i l s t t h e r m a l [ 3 , 3 ] - s i g m a t r o p i c r e a r r a n g e ment of ( 2 0 ) t o t h e a l l y l i c t r i c h l o r o a c e t a m i d e ( 2 3 ) p r i o r t o c y c l i s a t i o n t o ( 2 4 ) p l u s i t s *-isomer (cis: t r a n s = 1:4) f a c i l i t a t e d from a l l y l i c a l c o h o l s
multistep conversion t o (+I-erythro ( 2 6 ) was a l s o o b t a i n e d f r o m ( 2 4 ) .
( 2 5 ) (Scheme 2 3 ) . 166
(+I-Threo
T h e a l l y l i c a m i n e d e r i v a t i v e ( 2 7 ) was u s e d t o p r e p a r e t h r e e o f t h e f o u r d i a s t e r e o m e r s of 3 - a m i n o c y c l o p e n t a n e - l , 2 - d i o l ,
with t h e
r e m a i n i n g o n e b e i n g made f r o m t h e r e a d i l y a v a i l a b l e e p o x i d e ( 2 8 ) . 1 6 7 T h e f o u r d i a s t e r e o m e r s o f 2-amino-5-phenoxycyclopentanol were a l s o s y n t h e s i s e d s t e r e o s p e c i f i c a l l y . 1 6 8 I n a s o m e w h a t d i f f e r e n t m a n n e r a s e c o n d a r y a l l y l i c a m i n e may b e converted i n t o a 1,3-amino-alcohol phoromonoamidate d e r i v a t i v e .
via
p r o t e c t i o n as a N - a l l y l p h o s -
H y d r o b o r a t i o n o f t h i s compound t h e n
a l l o w s r e g i o s p e c i f i c i n t r o d u c t i o n o f t h e oxygen f u n c t i o n a l i t y w i t h t h e a m i n o - a l c o h o l l i b e r a t e d by s i m p l e d e p r o t e c t i o n . 1 6 9 Most of t h e a b o v e e x a m p l e s d e m o n s t r a t e t h a t t h e amino-alcohol moiety can be synthesised with a high degree of s t e r e o c o n t r o l . Furthermore, t h e formation of heterocyclic intermediates, i n p a r t i c u l a r o x a z o l i d i n o n e s and o x a z o l i n e s a b o v e , i s o f t e n a c r u c i a l factor in exercising this control. N,g-heterocycles,
Hence, r i n g fragmentations of
p r o d u c e d by m e t h o d s o t h e r t h a n a l l y l i c f u n c t i o n a -
l i s a t i o n , p e r s i s t a s an i m p o r t a n t area w i t h i n amino-alcohol synthesis. C l e a v a g e o f s u l p h u r - c o n t a i n i n g i s o x a z o l i n e s h a s b e e n a c h i e v e d by u s i n g both l i t h i u m aluminium hydride i n ether’” and z i n c boroI n t h e former report t h e hydride/NiC12.6H20 i n m e t h a n o l . 17’ h e t e r o c y c l e s were p r e p a r e d b y a d d i t i o n s of n i t r i l e o x i d e s t o 1 phenylthioprop-2-ene,
s e l e c t i v e N-benzoylation
of t h e c r u d e
cleavage products allowing o x i d a t i o n of t h e free hydroxy group t o a ketone.
I n t h e latter report E - m e t a l l a t i o n
o f racemic 3 - m e t h y l -
4 , 5 - d i h y d r o i s o x a z o l e s f o l l o w e d by r e a c t i o n w i t h ( - ) - ( z ) - m e n t h y l toluene-p-sulphinate
afforded diastereomeric 3-sulphinylmethyl-
General and Synthetic Methods
254
OMe
OMe
OMe
H
H
Me
+
HO
0-
HO
H
(19) m i n o r
(18) m a j o r
(17)
-
OMe H
I
...
Br
M e $ T H
A H
0
YNYPh Ph
L
N-COPh Of-Ph
EtO
0
iv
OH
-
H
OMe
v-v ii
I
HO F H 2 HC I
(*I
PhCOO
- Daunosamine
R e a g e n t s : i , N a B H 4 , ( 1 8 ) : ( 1 9 ) = 9 : l ; ii. D E A D , P h 3 P , ( P h C O ) Z N H ; i i i , N B S , C H C I 3 ; i v , i n s i t u a c i d h y d r o l y s i s ; V , Bun3SnH; v i , b a s e - c a t a l y s e d hydrolysis;
vii, acid hydrolysis
S c h e m e 22
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
(20)
/
255
\i
J
B
n
O
w
HNK 0
cc'3
(23)
1
(21 1
!
ii ,iii
no
I
:$
OH
CCI, (24)
NHAc
3 4O "
YN
I
ii,vii
OBn
(26)
Bnoq+o
CCI,
N y O iv , v l
NHAc
?Ac
J.
I cc13
Y !
NHAc
OAC
(25)
(22) Reagents : i , N I S , C H C 1 3 ; i i , MeOH-H20
6M-HCI, MeOH ; v , A c Z O , p y A26
iii, Amberiyst A 2 6 (CO:-), vi,
A
;
MeOH i v , v i i , MeQNa , C H Z C l Z i v i i i , Ambcrlyst
( O A c - ) , MeOH
S c h e m e 23
256
General and Synthetic Methods
isoxazolines.
Reduction afforded mixtures of
a l c o h o l s (Scheme 2 4 ) .
Work-up
syn-
and anti-amino-
of t h e reduction r e a c t i o n i n t h e
a b s e n c e of a q u e o u s NH40H d e c r e a s e d c h e m i c a l y i e l d s b u t improved t h e
-s y n : a n t i product r a t i o from %.2:1 A number o f D,L-aminodeoxysugars
of 2-isoxazolines.
to 9:l.
were s y n t h e s i s e d b y r e d u c t i o n
The o v e r a l l p r o c e s s r e q u i r e d t h r e e s t e p s
i n v o l v i n g a d d i t i o n of hydroxamic a c i d c h l o r i d e s ( g e n e r a t e d from a l d o x i m e s , NCS a n d t r i e t h y l a m i n e u s i n g b a s i c a l u m i n a or f l o r i s i l a s
a solid-phase
b a s e ) t o d i e n e s , f o l l o w e d by s t e r e o s p e c i f i c h y d r o x y -
l a t i o n a n d r e d u c t i o n o f t h e 5 - v i n y l i s o x a z o l i n e s s o o b t a i n e d . 172 A m i n o d e o x y - D , L - x y l o - or - a r a b i n o - p e n t o s e s h a v e b e e n i s o l a t e d 1 7 3 f o l l o w i n g o z o n o l y s e s o f f u r o i s o x a z o l i n e s . 17‘
Lithium aluminium
h y d r i d e r e d u c t i o n o f t h e p r o t e c t e d +-4-oxygenated
isoxazolines
r e s u l t i n g f r o m o z o n o l y s i s a l l o w e d p r e p a r a t i o n of t h e a r a b i n o - c o m p o u n d s w h i l s t t h e same c o n d i t i o n s a p p l i e d t o t h e 4 - h y d r o x y i s o x a z o l i n e s r e s u l t e d i n i s o l a t i o n of t h e x y l o - i s o m e r s . Several cleavages of isoxazolidines leading t o t h e preparation o f a m i n o - a l c o h o l s h a v e b e e n r e p o r t e d , for e x a m p l e t h o s e o c c u r r i n g w i t h dihydrolipoamide/ferrous ammonium ~ u l p h a t e ’a n~d ~ l i t h i u m a l u m i n i u m h y d r i d e / n i c k e l c h l o r i d e . 176 allylamines
*
Peterson-type
The p r e p a r a t i o n o f homo-
e l i m i n a t i o n of s i l y l a t e d amino-
a l c o h o l s d e r i v e d from 5-a-silyl-h2-isoxazolines was r e f e r r e d t o a b o v e . 148 R e d u c t i v e a l k y l a t i o n of B - a l k a n o l a m i n e s
was a c h i e v e d
via
f o r m a t i o n o f o x a z o l i d i n e s w i t h c a r b o n y l c o m p o u n d s , f o l l o w e d by t r e a t m e n t w i t h s o d i u m b o r o h y d r i d e . 17’ v i r t u a l s u p p r e s s i o n of o v e r - a l k y l a t i o n .
The p r o c e s s o c c u r r e d w i t h 2-Alkylamino-alcohols
c o u l d a l s o b e p r e p a r e d by r e d u c t i o n o f 3 - n i t r o s o o x a z o l i d i n e s e f f e c t e d by n i c k e l - a l u m i n i u m a l d e h y d e . 178
a l l o y , potassium hydroxide and a n
T h e s y n t h e s i s o f 2,2-disubstituted-~-nitroso-oxazoli-
d i n e s was a l s o r e p o r t e d . [4+2]-Cycloadditions
have a l s o been employed i n t h e p r e p a r a t i o n
o f h e t e r o c y c l i c systems from which amino-alcohols can be d e r i v e d . One s u c h s t r a t e g y i n v o l v e d i n t r a m o l e c u l a r h e t e r o - D i e l s - A l d e r r e a c t i o n of a N - s u l p h i n y l c a r b a m a t e t o g e n e r a t e t h e r e l a t i v e stereoc h e m i s t r y o f t h e t h r e e c h i r a l c e n t r e s i n a s y n t h e s i s o f racemic methyl-3-deoxy-3-methylaminoarabinopyranoside ( S c h e m e 2 5 ) . 1 8 0 Nitroso-Diels-Alder
c y c l i s a t i o n s have also proved t o be u s e f u l
i n t h i s area and i n t h e s y n t h e s i s o f n o n - c a r b o h y d r a t e n a t u r a l products,e.g.
tabtoxin (29).
Tabtoxinine 6-lactam
( 3 0 ) h a s also
been p r e p a r e d u s i n g t h i s methodology w i t h c y c l i s a t i o n of (31) a n d
257
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
(28)
(27)
0
J iii
H2N H
?" +
Me
RZ
R' anti
SYn Reagents : i , L D A ; i i , menthyl t o l u e n e - p - s u l p h i n a t e ;
MeOH
Scheme 24
iii, Z n ( B H L I 2 , N i C I 2 . 6 H 2 0
258
General and Synthetic Methods
Sn Bun,
-*,
AOE
.1 - 1 1..1 .
Me/
EEO
EE = ethoxyethyl Bn = PhCH2 Me
vii ,viii
BnO'
/ L O
ix,x
-
OH
xi-xiii
Me
Me0 Reagents: i , 6u"Li
;
i i , s o r b i c aldehyde
i v , AcOH, H20
; v.
;
H ; H NHMe
iii, KH ,18-crown-6
PhCHZBr,
Noli
NaOCN, T F A , PhH; v i , SOCLz , py , PhMe;
v i i . PhMgBr,THF; v i i i . piperidine, ib ,EtOH
THF,'xi, p -TSA; x i i , 0 3 , S i O z ; x i i i , M e z S t
;i
x , LAH ,THF;b; x , NalNHI,
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
(30) X = H
259
0 (311
(32)
p:"Ho H
0
Bu
(33)
(34)
Me H%
Me
(35)
(36)
(37 1
260
General and Synthetic Methods
benzyl nitrosoformate t o g i v e t h e heterocycle (32) being one of t h e 181
key s t e p s .
I n d e p e n d e n t l y , a n o t h e r g r o u p h a v e made d e t a i l e d s t u d i e s o f t h i s t y p e o f r e a c t i o n , and h a v e shown t h a t , i n a d d i t i o n t o t h e n o r m a l oxidation of N-hydroxycarbamate esters with p e r i o d a t e r e a g e n t s ,
e.g, a s u s e d a b o v e , n i t r o s o c a r b o n y l b e n z e n e a n d n i t r o s o c a r b o n y l methane c a n be g e n e r a t e d from t h e c o r r e s p o n d i n g hydroxamic acids,
and t h a t t h e C - n i t r o s o c a r b o n y l
c o m p o u n d s c a n be r e g e n e -
r a t e d from adducts w i t h cyclopentadiene182 (or 9,lOd i m e t h y l a n t h r a c e n e ) 8 3 by m i l d t h e r m a l d i s s o c i a t i o n . i t was s h o w n t h a t C - n i t r o s o c a r b o n y l
Furthermore,
d e r i v a t i v e s could be generated
by s i m i l a r t r e a t m e n t o f N - h y d r o x y u r e a s . 1 8 4
In addition t o their
s y n t h e t i c a l l y u s e f u l r e a c t i v i t y as d i e n o p h i l e s ( y i e l d i n g N-alkoxy-
carbonyl-3,6-dihydro-2g-l,2-oxazines) synthesis of
esters
-
-
t h i s being u t i l i s e d i n a
’
148 - a m i n o c o d e i n o n e f r o m t h e b a i n e , 4 6 2 - n i t r o s o f o r m a t e
generated from N-hydroxycarbamates
i n t u r n prepared from
h o m o a l l y l i c a n d a l l y l i c a l c o h o l s by t r e a t m e n t w i t h p h o s g e n e a n d h y d r o x y l a m i n e - were s h o w n t o u n d e r g o i n t r a m o l e c u l a r e n e r e a c t i o n s . 185
An i n t r a m o l e c u l a r v a r i a n t o f t h e D i e l s - A l d e r
r e a c t i o n was a c c o m p l i s h e d e l s e w h e r e .
T h u s , t h e h e t e r c y c l e ( 3 3 ) was
obtained as t h e s o l e product after o x i d a t i o n of t h e hydroxamic a c i d (34).
C l e a v a g e o f t h e N-0 b o n d w i t h z i n c i n a c e t i c a c i d t h e n
f a c i l i t a t e d further conversion of (33) resulting i n a stereos p e c i f i c t o t a l s y n t h e s i s of
(+I-gephyrotoxin
( 3 5 ) . 186
r e g i o s e l e c t i v i t y of intermolecular Diels-Alder
A study of
cyclisation of
m e t h y l n i t r o s o f o r m a t e a n d (nitrosocarbony1)benzene w i t h b o t h e l e c t r o n - r i c h and e l e c t r o n - d e f i c i e n t 2 - s u b s t i t u t e d d i e n e s was p r e s e n t e d . 1 8 7
1,3-cyclohexa-
1 , 2 - 0 x a z i n e d e r i v a t i v e s were a l s o f o r m e d i n c y c l o a d d i t i o n s o f nitrosobenzene with 1,2-dihydropyridines.
cis-Hydroxylation
f o l l o w e d by c l e a v a g e o f t h e N-0 b o n d w i t h H 1 1 0 % Pd-C a l l o w e d synthesis of amino-substituted iminosugars.
?88
A d i f f e r e n t conceptual approach t o amino-alcohol
involved use of c h i r a l N,O-heterocycles
preparation
as templates f o r
e n a n t i o s p e c i f i c s y n t h e s e s o f t h e s e compounds.
Alkylations of t h e
c a r b a n i o n d e r i v e d f r o m 2-cyano-6-oxazolopiperidine
( 3 6 ) had been
s u c c e s s f u l l y a p p l i e d t o t h e s y n t h e s i s o f a n u m b e r of a l k a l o i d s . The a n i o n c o u l d b e s i m i l a r l y quenched w i t h a n a l d e h y d e , and t h i s f o l l o w e d by s t e r e o s p e c i f i c d e c y a n a t i o n a n d h y d r o g e n a t i o n a l l o w e d i s o l a t i o n of (+)-B-conhydrine.189 from (-)-(R)-phenylglycinol
The p o t e n t i a l o f ( 3 7 ) d e r i v e d
a s a n e d u c t f o r t h e s y n t h e s i s of 8 -
26 1
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups a m i n o - a l c o h o l s was a l s o e x a m i n e d . l g o A m i n o - a l c o h o l s y n t h e s i s may a l s o b e a c h i e v e d b y t h e s i m p l e ,
classical a d d i t i o n of amines t o o x i r a n e s .
However, even t o d a y such
p r o c e d u r e s a r e o f t e n l i m i t e d by p o o r l y n u c l e o p h i l i c a m i n e s , i n c o m p a t i b i l i t y o f some e p o x i d e s w i t h r e a c t i o n c o n d i t i o n s a n d p o o r
I t h a s b e e n shown t h a t c o m p a r e d t o
regioselectivity of addition. t h e u s e of Si02 or A l p 3 ;
t h e Na-exchanged
Y-type
zeolite resin
ZCP-50 m e d i a t e s s u c h a d d i t i o n s w i t h c o n s i s t e n t l y i m p r o v e d r e g i o s e l e c t i v i t y . 19'
H a l o m a g n e s i u m a l k y l a m i d e s were a l s o d e m o n s t r a t e d
t o be v i a b l e a l t e r n a t i v e s t o dialkylaluminium amides i n highy i e l d i n g aminations of epoxides.
These r e a g e n t s had t h e
a d v a n t a g e o f greater ease o f m a n i p u l a t i o n i n large-scale procedures. Dimethylaluminium amides of
(R)-a-methylamine
f a c i l i t a t e d prepa-
r a t i o n o f trans-2-amino-cyclohexanol a n d - c y c l o p e n t a n o l .
After
r e a c t i o n with t h e appropriate cycloalkene oxide, separation of t h e r e s u l t a n t d i a s t e r e o m e r s a l l o w e d e l a b o r a t i o n of t h e a m i n o - a l c o h o l s i n e n a n t i o m e r i c a l l y pure form. '93 R e g i o s p e c i f i c n u c l e o p h i l i c r i n g o p e n i n g of oxetaries t o 3 - s i l y l oxyisocyanides with t r i m e t h y l s i l y l cyanide/Zn12 i n dichloromethane h a s been r e p o r t e d , and t h i s h a s l e d t o t h e s y n t h e s i s o f aminoa l c o h o l s by h y d r o l y s i s o f t h e i s o c y a n i d e g r o u p . R e d u c t i o n o f a m i n o - c a r b o n y l compounds i s a n o t h e r l o n g e s t a b l i s h e d m e t h o d for p r e p a r a t i o n o f a m i n o - a l c o h o l s , s t e r e o s e l e c t i v e s y n t h e s i s of y - a m i n o - a l c o h o l s c e n t r e s f r o m b o t h B-amino-
and B-acylamino-ketones
r e d u c t i o n h a s been r e p o r t e d . Ig4
and d i a -
with three chiral
after LiA1H4-
Lithium aluminium hydride h a s a l s o
b e e n f o u n d t o b e a n e f f e c t i v e r e a g e n t f o r t h e r e d u c t i o n o f aoximino-ketones
and - a l c o h o l s
t o erythro-2-amino-l-arylalkan-l-
01s. 195 A d d i t i o n s o f a-amino c a r b a n i o n s t o c a r b o n y l compounds s e r v e as a n o t h e r u s e f u l p r e p a r a t i v e method f o r a m i n o - a l c o h o l s . a t i o n s of a-phthalimido-,
a-morpholino-,
Desilyl-
a-acetamidobenzyl-,
and
phthalimidomethyl-silanes h a v e f u r n i s h e d s u c h s p e c i e s a n d t h e i r a d d i t i o n s t o a l d e h y d e s s t u d i e d . 9 6 B - A m i n o - a l c o h o l s were o b t a i n e d i n m o d e r a t e t o good y i e l d s . A d d i t i o n s o f c a r b o n n u c l e o p h i l e s t o c a r b o n y l compounds c o n s t i t u t e a complementary s t r a t e g y t o t h e preceding one. organometallic r e a g e n t s w i t h amino-acid
A c y l a t i o n s of
d e r i v a t i v e s had p r e v i o u s l y
been r e p o r t e d as a method o f amino-ketone
synthesis.
H o w e v e r , it
was f o u n d t h a t t h e s t e r e o c h e m i s t r y of t e r t i a r y c a r b i n o l c e n t r e s
262
General and Synthetic Methods
f o r m e d by s e q u e n t i a l a d d i t i o n o f t w o G r i g n a r d r e a g e n t s t o t h e l i t h i u m s a l t o f 1-(phenylsulphony1)-L-allothreonine, c o u l d b e c o n t r o l l e d according to t h e o r d e r of a d d i t i o n . l g 7 methyl
T h u s by u s e o f
and v i n y l G r i g n a r d s , m e t h y l - L - s i b i r o s a m i n i d e
pared along with its C -epimer.
could be pre-
a,a-Diphenyl-B-amino-alcohols
3
were
i s o l a t e d a f t e r a d d i t i - o n s of G r i g n a r d r e a g e n t s w i t h aminoesters.
'''' '''
T h e s e c o m p o u n d s were p r e p a r e d a s c h i r a l l i g a n d s f o r
use i n t h e preparation of c h i r a l l y modified borohydride reagents. V a r i o u s o t h e r r e d u c t i v e methods have been a p p l i e d t o aminoalcohol synthesis. L-glutamic
(?)-(-)-3-Piperidinol
a c i d a n d ( S ) - m a l i c a c i d .200
was s y n t h e s i s e d f r o m b o t h The r o u t e s i n v o l v e d c y c l i -
s a t i o n s o f a m i n o - a l c o h o l s i n w h i c h t h e a m i n o m o i e t y was e s t a b l i s h e d by a z i d e a n d n i t r i l e r e d u c t i o n s w i t h H2/Pd-C pectively,
a n d L i A 1 H 4 res-
A c y l c y a n i d e s were r e d u c e d t o o p t i c a l l y a c t i v e a m i n o -
a l c o h o l s by a l p i n e - b o r a n e
[B-(?-pinanyl)-9-BBNI
followed with
NaRH4/cobaltous chloride.207 Amino-alcohol m o i e t i e s w i t h i n imino-sugars have been e s t a b l i s h e d by a v a r i e t y o f r e d u c t i v e m e t h o d s i n c l u d i n g r e d u c t i v e a m i n a t i o n , o x i m e r e d u c t i o n ,202 a n d a z i d e r e d u c t i o n s . 36-38 1203 nitro-groups
65
Reduction of
h a s played a s i g n i f i c a n t p a r t i n t h e f i e l d o f amino-
sugar synthesis.12718719 Much r e c e n t a t t e n t i o n h a s b e e n g i v e n t o t h e s y n t h e s i s of h y d r o xylated amino-acids.
S t a t i n e ( 4 2 ) h a s been p r e p a r e d e n a n t i o -
s p e c i f i c a l l y u t i l i s i n g Evans
a l d o l methodology.204
Enantio-
s e l e c t i v e , e r y t h r o - s e l e c t i v e c o n d e n s a t i o n between N-Boc-L-leucinal
(39) a n d t h e d i - n - b u t y l b o r o n
e n o l a t e of (?)-4-(I-methylethyl)-3-
[(methylthio)acetyl]-2-oxazolidinone ( 3 8 ) r e s u l t e d i n (40) which was t h e n e l a b o r a t e d t o t h e p r o t e c t e d s t a t i n e d e r i v a t i v e ( 4 1 ) (Scheme 2 6 ) . A l d o l c o n d e n s a t i o n s b e t w e e n a-dibenzylaminotrimethylsilylketene a c e t a l s a n d a l d e h y d e s p r o m o t e d by L e w i s a c i d s a f f o r d e d a - a m i n o - B h y d r o x y - a c i d s w i t h C2 C 3 - t h r e o
c o n f i g u r a t i ~ n ; ~t h' ~r e o l e r y t h r o
p r o d u c t r a t i o s v a r i e d between 44:56 and 91:9. circumstances,
I n somewhat similar
r e a c t i o n o f g-trifluoroacetylglycine m e t h y l e s t e r
w i t h t r i m e t h y l s i l y l trifluoromethanesulphonate a n d c o n d e n s a t i o n o f t h e r e s u l t a n t s i l y l k e t e n e acetals w i t h c a r b o n y l compounds a f f o r d e d s i l y l a t e d 2-amino-3-hydroxy-acids
with erythro-selectivity
( e r y t h r o : t h r e o b e t w e e n 5 0 : 5 0 a n d 1OO:O).
206
y-Amino-8-hydroxybutyric a c i d h a s b e e n s y n t h e s i s e d from
(2)-
m a l i c a c i d 1 2 0 7 w h i l s t a n o v e l c l a s s of c o m p o u n d s were p r e p a r e d b y allowing protected amino-acids
t o react w i t h p a r t i a l l y p r o t e c t e d
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
1
263
MeS
J
(38)
I
ii iii
Me
(41)
H R2NH R’
R2
OEt
OCOBu’
(42) H
H
R e a g e n t s : i . Bunz B O S 0 2 C F 3 , E t N P r i 2 ; i i , R a n e y n i c k d ; i i i . N a O E t , E t O H
Scheme 2 6
General and Synthetic Methods
264
sugar triflates.208 Good yields of a-aminothioethers were obtained on electroreduction of N,N-disubstituted thioamides in acetonitrile containing tetrapropylammonium perchlorate and an alkylating agent 2-Aminothioethers and 2-aminoethers were obtained from N-phthalimidoaziridines by reaction with thiols and alcohols respectively, followed by reduction of the resultant B-hydrazino-thioethers and -ethers. 106
.''
5 Amino-carbonyl Compounds Amino-ketones may be easily prepared by oxidation of suitably protected amino-alcohols as described above. I 7 O Their preparation by additior, of organometallic nucleophiles to amino-acids was also alluded to in the previous section, and a subsequent report documented synthesis of a'-amino-a,B-ynones by reaction of alkynylorganometallic reagents with N-protected a-amino-acid isoxazolidides.210 The preparations of a-amino-ketones via addition of amines to and of N-protected a-aminoketones by hydroa , 8-epoxysulphoxides2 lysis of presumed aziridine intermediates resulting from addition of ethoxycarbonylnitrene to enamines were also reported. 2 1 2 It has also been shown that chiral N-trifluoroacetyl-a-amino-acid chlorides undergo Friedel-Crafts acylation reactions with > 9 9 % preservation of configurational identity,*13 and that in situ generation of boron trichloride from boron trifluoride diethyl etherate and silicon tetrachloride facilitates 0-acylation of alkylanilines with both alkyl and acyl cyanides. 2' 4- Optically active amino-ketones may also be derived from 2-serine formation of oxazoline-protected esters, addition of organometallic reagents and subsequent deprotection. 215
6
Amino-esters
Diastereocontrolled conjugate additions of amines to a , B unsaturated iron acyls where the q5-CpFe(CO) (PPh 1 moiety directed 3 the addition have been achieved. Addition of the amine occurred away from the bulky phosphine ligand. Oxidative cleavage of the iron moiety allowed preparation of the corresponding esters ( a n d also B -1actams ) .2 1 6 Synthesis of diastereomerically and enantiomerically pure a-
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
265
amino-y-oxo-acid esters was also reported, this being accomplished by additions of enamines derived from six-membered ketones to various acyliminoacetates. 217 A novel a-amino-ester synthesis consisted of the reduction of a hydrazono- (&-azo-) esters, resulting from additions o f benzenediazonium tetrafluoroborate to silylketene acetals, by hydrogenation. 218
7 Amides. Thioamides and Selenocarboxamides Recent interest in the synthesis of oligopeptides has led to the development of many methods of amide preparation. The search f o r new coupling reagents and effective activation processes remains a major area of interest, and away from the peptide area syntheses of unsaturated and oxygenated amides are actively pursued. Benzotriazol-l-yl diethyl phosphate (BPP) (43) , 2 1 9 1,2-benzisoxazol-3-yl diphenyl phosphate (44) ,220 diethyl 2-(3-0~0-2,3-dihydro-l,2benzisosulphonazolyl )phosphonate (DEBP) (451,221 3,3 - (phenylphosphinylidene)bis[2(3H)-benzoxazolone] (46) and the corresponding benzothiazolone (47 )222-p1us bis( 2-oxo-3-oxazolidinyl )phosphinic chloride (48)223 have all been cited as coupling reagents for amide synthesis. Preparation of aziridine-2-carboxamides via aminolyses of mixed anhydrides formed from potassium salts of the corresponding acids and trimethylacetyl chloride exemplified one of the longer established activation procedures. 224 2 , 2 -Dithiobis (4,6-dimethylpyridine)-3,3’-dicarbonitrile and triphenylphosphine were used to activate N,g-dimethylamino-acids for coupling as their 2-(3-cyano4,6-dimethylpyridine) thiolates. 2 2 5 The reagent was specifically designed to achieve racemisation-free couplings in what is normally considered a difficult reaction. An improvement of the classical formation of an amide from an acyl halide has been reported dicyclohexylammonium salts of acids being activated with thionylchloride-pyridine in less than one minute. 226 A synthesis of amides formation of syn-phenylpyridyl g-acyloximes (from either acids or acyl halides) has been described. 2 2 7 Yields reflected both the electronic and steric character of the amine. Addition of certain metal cations to the reaction mixture prior to the amine allowed isolation of amides even from sterically hindered reactants (Scheme 27). Amides have also been made by addition of tertiary phosphines to
General and Synthetic Methods
266
0;.
N>TJ j - - f
N-P
\
‘
N
\0 P(0)(0E t l2
(0E t l2
0
(45)
(431
QqlQ / \
/ \
(46) X = 0
ol-fN-ii-NYo 0
(47)
x
=
s CI
0
X
(48)
R’C02H
.
..
I * I 1 #
or iii
R’Yo
.
iv
0, P
N
h
k
Ph
R’
M = C u2+, Fe3+
A ; i i , PPKO, E t 3 N ; (PPKO = s y n - p h e n y l p y r i d i n y l ketoxime); P P K O , DCC, D M A P ; i v , MXn ; v , R2NHR3
Reagents: i, SOC12, iii,
S c h e m e 27
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
267
228 an azide followed by warming with carboxylic acids. Silylamines appear well suited to use in the preparation of Eunsubstituted amides from acyl chlorides by low-temperature addition followed by acid-mediated desilylation. 229 a-Chloro substituents were inert to the reaction conditions and additions of the silylamines to double bonds were not observed. Benzoyl cyanide was shown to be a particularly effective reagent for the selective N-benzoylation of amino-alcohols. 230 An unusually facile B-ketoester amination was shown not to proceed via direct attack on the carboxyl group. 23 Aminocarbonylations have also been applied to amide syntheses. Silylamines were employed in nickel tetracarbonyl-induced carbonylations of gem-dibromocyclopropanes (Scheme 28). 232 Nickelcarbenoid and -enolate complexes were proposed as key intermediates. Modification of reaction mixtures to include aldehydes allowed condensations of the metallo-enolates to afford hydroxyalkylated derivatives. The presence of a vicinal chlorornethyl or mesyloxymethyl group allowed carbonylation-fragmentation reactions to occur in the presence of amines, this leading to isolation of ,y-Unsaturated amides were y ,6-unsaturated amides (Scheme 28) .233 obtained by azacarbonylation of allylic phosphates with amines employing Rh6(CO)16 as a catalyst with tetrabutylammonium chloride as a co-catalyst under a CO atmosphere at 5OoC and high pressure. 234 Pd ( 0 1-catalysed carbonylations allowed preparation of a,B-unsaturated amides from mixtures of enol triflates, palladium acetate, triphenylphosphine and an amine in dimethylformamide. 235 In the preparation of various unsaturated amides, the dianion of
(49) proved to be a versatile synthon. Borohydride reduction of alkylation products of the dianion occurred in high yield to afford moderate overall yields of a ,B-unsaturated amides.236 The dianion of the corres-
N-phenyl-2-(phenylsulphonylmethyl)propenamide
ponding phenyl sulphide alkylated poorly giving small amounts of 0th a - and y-alkylation products, whereas the sulphone-ester corresponding to (49) was found to be labile under the deprotonation conditions. Compound (49) was also employed in the development of a general strategy f o r the synthesis of 3,4-epoxy-2methylene-alkanoic acid amides (Scheme 29 ) .237 a-Carbamido-sulphones could also be deprotonated and alkylated successfully, with a synthesis of enamides being completed by based-induced elimination of the sulphonyl moiety. 238 Four routks leading to the synthesis of (50) which was used in the preparation
General and Synthetic Methods
268
R'Jy(Br . ..
I , I I ,
Br
c H ( O H m6 C 0 N R 4 R5
'
II
0
R3 R e a g e n t s : i,Ni(C014 ,Me3SiNR4R5, D M F ; ii, H20 R'CHO
;
iii; N i ( C 0 I 4 , Me3SiNR4R5,
, D M F ; i v , N i ( C 0 1 4 , R4R5NH , D M F Scheme 2 8 TMSO
CONHPh
i- iii
R 3 V C O N H P h
_____)
PhSO,
PhSOz
~
~
A
~
S CONHPh
(49)
+
TMSO
OMS
H
+
viii
vi
H Ph
R3+C0N OH
H
OMS
R e a g e n t s : i, 6 u n 1 i , HMPA , THF
;
ii. R3CHO; iii. M c 3 S i C I ; i v . PhSe-Na',
v. m-CPBA,CH2CI2; v i , MsCI, v i i . KF,DMSO
Scheme 2 9
EtOH;
e
P
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
269
of n a t u r a l l y occurring i n s e c t i c i d a l l i p i d isobutylamides
-
-
by
h a v e b e e n d e s c r i b e d .239 T h e s t e r e o c h e m i s t r y o f t h e s u b s e q u e n t o l e f i n a t i o n s was a l s o s t u d i e d . 2 4 0
Wittig-type reactions
N i c k e l ( 0 ) c o m p l e x e s were shown t o c a t a l y s e f o r m a t i o n o f a c r y l amides from i s o c y a n a t e s and o l e f i n s i n t h e p r e s e n c e o f t r i p h e n y l A s o r b a n i l i d e d e r i v a t i v e was s i m i l a r l y s y n t h e s i s e d
phosphine.
from phenyl i s o c y a n a t e and 1 , 3 - ~ e n t a d i e n e . ~ ~ ~ B-Metallations
o f a-methoxyacrylamides
and t h e subsequent
r e a c t i o n s of t h e a n i o n s w i t h e l e c t r o p h i l e s were d e s c r i b e d 2 4 3 a l o n g w i t h @ ' - l i t h i a t i o n s of a , @ - u n s a t u r a t e d a m i d e s . 244 The p o t e n t i a l s y n t h e t i c u t i l i t y o f t h e 2-carboxamido-allyl-lithium r e a g e n t s o b t a i n e d i n t h e l a t t e r r e a c t i o n s was a s s e s s e d . Michael a d d i t i o n s of amide-derived
e n o l a t e s t o 2-(g-methyl-
a n i 1 i n o ) a c r y l o n i t r i l e a f f o r d e d 7-keto-carboxamides
after reaction
w i t h a n a l k y l a t i n g a g e n t (e.g.i o d o m e t h a n e ) a n d h y d r o l y t i c w o r k - u p i n t e r m e d i a t e . 245 S-Silyl ketenew e r e shown t o b e c a p a b l e o f a d d i t i o n t o i m i n e s i n t h e
of the resultant amino-nitrile
S,IJ-acetals
.
p r e s e n c e o f L e w i s a c i d s , t h i s a f f o r d i n g B-aminothioamides 246 An a c c e l e r a t e d d i a s t e r e o s e l e c t i v e v a r i a n t o f t h e a m i d e a c e t a l C l a i s e n r e a r r a n g e m e n t was u s e d t o p r e p a r e 7 , g - u n s a t u r a t e d a m i d e s from N,g-ketene
a c e t a l ~ . T~h e~s e~ i n t u r n were d e r i v e d by a d d i -
t i o n s o f t h e l i t h i u m a l k o x i d e s o f e i t h e r (E)- o r ( L ) - 2 - b u t e n - l - o l t o s a l t s p r e p a r e d by a l k y l a t i o n s o f e i t h e r p r o p i o n a m i d e s o r fluoroacetamides with methyl t r i f l a t e a n d / o r dimethyl s u l p h a t e .
In
r e a r r a n g e m e n t s of p r o p i o n a m i d e - b a s e d s u b s t r a t e s d i a s t e r e o s e l e c t i v i t y R e a r r a n g e m e n t s of a l w a y s e x c e e d e d 8 : l u p t o a maximum of 1 7 : l . fluorine-containing
substrates occurred with significantly poorer
d i a s t e r e o s e l e c t i v i t y (Scheme 3 0 ) . U n s a t u r a t e d a m i d e s a r e s u i t a b l e s u b s t r a t e s f o r e l a b o r a t i o n by a d d i t i o n of c a r b o n n u c l e o p h i l e s .
IJ-tosylated
a,@-unsaturated
amides react r e a d i l y w i t h b o t h d i a l k y l c u p r a t e r e a g e n t s and Grignard r e a g e n t s i n t h e p r e s e n c e o f c a t a l y t i c a m o u n t s o f c u p r o u s i o d i d e . 248 I t was d e m o n s t r a t e d t h a t a l k y l - l i t h i u m
a d d i t i o n s t o s i l i c o n - and
p h e n y l - s u b s t i t u t e d a , B - u n s a t u r a t e d amides - b o t h e t h y l e n i c and a c e t y l e n i c - occur i n an anti-Michael sense.249 Elsewhere, a study of the addition of trimethylstannyl-copper
r e a g e n t s t o a,B-
a l k y n y l a m i d e s c o n c l u d e d t h a t c o n t r o l of c o n d i t i o n s a l l o w e d p r e p a r a t i o n of e i t h e r
(El- o r (Z)-3-trimethylstannyl-2-alkenamides a n d
t h a t f u r t h e r r e a c t i o n s w i t h e f e c t r o p h i l e s o t h e r t h a n p r o t o n were p o s s i b l e .250 The p r e p a r a t i o n of a , B - e t h y l e n i c f r o m a ,Ba c e t y l e n i c a m i d e s was a c h i e v e d b y a s o d i u m b o r o h y d r i d e r e d u c t i o n
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
27 1
performed in the presence of catalytic amounts of lipoamide and FeC12. 25 Acetamidomercuration of olefins has been mentioned above in relation to aminat ion following a radical demercuration step. 62 Bis(pyridine)iodine(I) tetrafluoroborate was found to effect 1 , 2 iodofunctionalisation of olefins with a variety of nitrogen nucleophiles. Use of acetonitrile in the reaction afforded iodoacetamides . 2 5 2 Acetamidosulphenylation of olefins was achieved electrochemically via anodic oxidation of disulphides in the presence of acetonitrile. 253 Similar products were obtained by Ritter reaction of acetonitriles with trifluoroacetoxy sulphides obtained by reactions of disulphides and olefins mediated by lead(1V) salts in trifluoroacetic acid-dichloromethane. 254 Compounds with carbon-nitrogen multiple bonds can also serve as precursors of amides. 2-CPBA oxidation of imines afforded oxaziridines which rearranged to amides on contact with silica EAlkyliminochlorides afforded N-nitrosoamides upon treatment with silver nitrite in acetonitrile, whilst similar treatment of Naryliminochlorides gave amides with aromatic mononitration. 256 N(a-Methoxyalky1)amides were obtained by either addition of achloroethers to imidate-triethylamine mixtures followed by treatment of the adducts with pyridinium hydrochloride in anhydrous dimethylsulphoxide or alternatively by acylation of imidates with acyl halides and subsequent borohydride reduction. 257 Pummerer intermediates obtained from sulphoxides on treatment with trifluroacetic anhydrideltrifluoroacetic acid were trapped by nitriles to afford amides in a fashion analogous to that of the Ritter reaction (Scheme 31 ) . 2 5 8 Arylcarboxylic acid N-arylthioamides were obtained through Beckmann rearrangements of diary1 ketoximes initiated by 2,4-bis(pmethoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulphide. 259 Some of the reductive methods used in amine synthesis have been applied to the preparation of amides. Excellent yields of amides were obtained from acyl azides by tetracarbonylhydridoferrate(0) reduction,30 whilst reductions employing diphosphorus tetraiodide In addition, in refluxing benzene gave less satisfactory yields.28 a-acylamino-a,B-unsaturated ketones were prepared in good yield from a-azidoketones on treatment with trifluoromethanesulphonic acid plus catalytic amounts of sodium perrhenate. 260 Highly stereoselective reductions of a-substituted 8-ketoamides with phenyldimethylsilane were reported. In combination with tris-
272
General and Synthetic Methods
(diethy1amino)sulphonium difluoromethylsilicate (TASF) and 1 9 3 dimethyl-3,4,5,6-tetrahydro-2(lfi)-pyrimidone high-yielding reductions exhibiting threo-selectivity were achieved with this silane. Alternatively hydrosilylations performed in trifluoroacetic acid yielded erythro-aldol products .26 Considerable interest has been shown in the development of synthetically useful amide manipulations. Direct allylation of amides was accomplished using palladium(0) complexes of dibenzylideneacetone or 1,2-bis(diphenylphosphino )ethane. 262 Selective 1monoalkylation of amides with alkyl halides was observed in reactions employing alumina and potassium hydroxide .263 Mixtures of alumina and powdered potassium hydroxide were found to be superior to alumina impregnated with the base. N-Alkylations of some secondary styryl enamides were also reported. 264 A novel class of N-acyl-N-glycosides has been prepared by reaction of sugar peracetates with mixtures of 0- and N-trimethylsilylated(acyl)(aryl)amines under trimethylsilyl trifluoromethanesulphonate catalysis. 265 Treatment of trichloroacetamides with diethyl phosphite and triethylamine in benzene afforded the corresponding dichloro-
266
acetamides. Fragmentations of heterocycles have played an important role in the preparation of amide derivatives. Moderate to good yields of a-hydroxy-amides were obtained on reaction of a-hydroxy-acid acetonides with primary amines. 267 N-Alkyl-2-methyl-2-oxazolinium salts (obtained by mixing alkyl halides and 2-methyl-2-oxazoline in dichloromethane) were found to react with sodium benzeneselenolate to yield ~-(2-phenylselenoethyl)-~-alkylacetamides9which after oxidation to !-vinyl analogues with sodium metaperiodate in methanol, gave secondary amides on sequential treatment with mercuric acetate in aqueous tetrahydrofuran and sodium borohydridef3M aqueous sodium hydroxide. 268 A report concerning synthesis of alkylamides by treating cyclic 1,3-oxoimminium salts with dialkyl cuprate reagents also appeared . 2 6 9 Other notable reports on such fragmentation reactions included synthesis of a-acylaminoesters from A2-5-oxazolones ,270 formation of unsymmetrical phthalimides from isophthalirnides,27 preparation of ~-substituted-2-acylamino-2-alkenamidesvia formation of 4alkylidene-5-0~0-4,5-dihydro- 1 ,3-oxazoles 272use of 2-amino-A
-
azirines and carboxylic acids to form a-acylaminocarboxylic acid amides, and in particular those based on malonic acid,273 plus the
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
R e a g e n t s : i, ( C F 3 C O ) z 0
, CF3C02H
;
273
ii, R3C=N
S c h e m e 31
ArCHO
+
M
M e \s//NH Me
'
+NH Scheme 32
2 ArCN
274
General and Synthetic Methods
f o r m a t i o n o f a - o x i m i n o c a r b ~ x a m i d e sa~n~d~ B - h y d r a z o n o c a r b ~ x a m i d e sf r~o m ~ ~4 - a l k o x y - 4 - a - b r o m o - 2 3-isothiazolones
,5 - o x a z o l i d i n e d i o n e s
and
respectively.
The i n t r o d u c t i o n o f a m i d e f u n c t i o n a l i t y i n t o h e t e r o c y c l i c n u c l e i
is another s u b j e c t of c u r r e n t i n t e r e s t .
T h e p r e p a r a t i o n .of 3-
acylaminobenzofurans from a-acylamino-a-aryloxyketones
illustrates
w h e r e t h i s aim c a n b e a c h i e v e d c o n c u r r e n t l y w i t h h e t e r o 1 ,2 - d i h y d r o p y r i d i n e - 2 - a c e t i c
Amides o f
cyclisation.276
b e e n f o r m e d by t h e a d d i t i o n o f acetamides t o pyridines.
277
2,N
a-N-Amidoalkylations
t u t e d - p y r i d i n e s and -quinolines
acid have
d i a n i o n s of ! - s u b s t i t u t e d of both substi-
using N-acylaminoethanol
deriva-
t i v e s i n a q u e o u s ammonium p e r o x y d i s u l p h a t e c o n t a i n i n g s u l p h u r i c a c i d ( t o p r o t o n a t e t h e b a s e ) a n d a small amount o f s i l v e r n i t r a t e have been a c h i e v e d i n low y i e l d , t h i s r e f l e c t i n g a poor c o n v e r s i o n
o f s t a r t i n g m a t e r i a l - 278
P r e p a r a t i o n o f 2 - a c y l a m i n o t h i o p h e n e s by
B e c k m a n n r e a r r a n g e m e n t o f o x i m e - s u l p h o n a t e s was r e p o r t e d 1 2 7 9 a s were s o m e n o v e l thiocoumarin-3-carboxamides. 280
T h e a d d i t i o n of
isothiocyanates to 4-substituted
o x a z o l - 2 - a m i n e s was f o u n d t o g i v e rise t o p r o d u c t s w i t h a t h i o a m i d e m o i e t y a t C 281
5'
Amides a l s o r e s u l t e d f r o m c a t h o d i c r e a c t i o n s o f d i - a n i l s i n t h e p r e s e n c e of o x y g e n .
282
A p a r t from t h i o a m i d e p r e p a r a t i o n s a l r e a d y a l l u d e d t o , c o n d i t i o n s f o r t h e s y n t h e s i s of a l i p h a t i c thioamides, monothiooxamides, d i t h i o a m i d e s , and a - k e t o c a r b o x y l i c
a c i d t h i o a m i d e s were
d e s c r i b e d , 2 8 3 a l o n g w i t h t h o s e for t h e a m i n o s u l p h u r a t i o n o f c a p t o d a t i v e m e t h y l e n e compounds t o form t h i o a m i d e s w i t h a - c a p t o r stituents.
*"
sub-
T h e p r e p a r a t i o n of t h i o a m i d e s from y n a m i n e s 1 5 '
by a p p l i c a t i o n s o f f a c i l e a - k e t o a c i d
and
i m i n e d e ~ a r b o x y l a t i o n swere ~ ~ ~
reported. T r a n s f o r m a t i o n s of t h i o a m i d e s t o a m i d e s h a v e b e e n a c h i e v e d i n e x c e l l e n t y i e l d u s i n g p o t a s s i u m s u p e r o x i d e i n c o m b i n a t i o n w i t h 2n i t r o b e n z e n e s u l p h o n y l c h l o r i d e . 28 6 The d i s c o v e r y t h a t e l e m e n t a l s e l e n i u m c o u l d e a s i l y be r e d u c e d t o h y d r o g e n s e l e n i d e w i t h c a r b o n m o n o x i d e i n t h e p r e s e n c e o f water a n d t r i e t h y l a m i n e l e d t o t h e p r e p a r a t i o n o f s e l e n o c a r b o x a m i d e s .287
The
in s i t u g e n e r a t i o n o f h y d r o g e n s e l e n i d e was f u r t h e r e m p l o y e d u n d e r s l i g h t l y modified c o n d i t i o n s t o g i v e PI-substituted
and
!,N-
d i s u b s t i t u t e d s e l e n o c a r b o x a m i d e s by r e a c t i o n o f t h e i n i t i a l l y formed u n s u b s t i t u t e d a d d u c t s w i t h p r i m a r y and s e c o n d a r y a m i n e s respectively.
288
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
275
8 Nitriles and Isocyanides Classically, nitriles have been prepared in SN2-displacements of either active halides or sulphonate esters by cyanide anion. Sodium cyanide substitutions of benzylic halides in the presence of benzyltriethylammonium chloride thus serves as a typical More recently use has been made of supported cyanide example.289 reagents, but attempts to do so have often been problematical. This has been exemplified by the use of potassium cyanide impregnated on amberlite XAD-2 resin. Both benzyl and n-alkyl halides were successfully substituted, but yields were variable - from 26% (for octyl bromide) to 79% (for benzyl bromide) .290 Elsewhere more reliable reagents were found following infra-red spectroscopic and x-ray diffraction studies aimed at optimising the loading of the cyanide source on the solid (silica gel or alumina) support. 29 1 Cyanotrimethylsilane and Lewis acids have been shown to be effective in the cyanation of alkyl halides. Use of this silane and tin tetrachloride in refluxing dichloromethane allowed synthesis of bridge-head adamantoid nitriles from the chlorides and/or bromides .292 Direct cyanation of alcohols occurs with use of lithium cyanide under the Mitsunobu conditions, 1 2 . with a preformed triphenylphosphine-diethyl azodicarboxylate complex .293 Moderate yields of alkylnitriles were formed in this way, although the number of examples cited was limited. Carbonyl and carboxyl compounds have traditionally been regarded as viable sources of nitriles. Aryl aldehydes have been converted into nitriles in a novel reaction with 2,S-dimethylsulphur diimide (dimethylsulphone diimine) in refluxing acetonitrile (Scheme 3 2 ) .294 The analogous conversion of aliphatic aldehydes, however, could not be achieved. Nitriles were also obtained in high yield by refluxing aldehydes with a mixture of nitroethane, glacial acetic acid and sodium acetate, these conditions, atypically, not giving rise to nitroolefins .295 Aldoximes have been converted to nitriles through the agency of 1 , l - 0 x a l y 1 d i i m i d a z o l e ~ and ~ ~ 2 , 4-dichloro-5-nitropyrimidine ,297 the latter reagent also effecting dehydrosulphuration of thioamides to nitriles, a transformation that was also achieved with diphosphorus tetraiodide and triethylamine in benzene298 and, in addition , by reaction of thioamides with benzyl chloride under phase-transfer conditions. 299
276
General and Synthetic Methods
Amides c o u l d b e d e h y d r a t e d t o n i t r i l e s by b o t h t r i c h l o r o a c e t y l c h l ~ r i d e / t r i e t h y l a m i n e a~n~d~ e l e c t r o c h e m i c a l l y g e n e r a t e d t r i p h e n y l p h o s p h i n e r a d i c a l c a t i o n . 30
A report detailing preparation
o f n i t r i l e s d i r e c t l y from c a r b o x y l i c a c i d s by a t r a n s n i t r i l a t i o n of C o n v e r s i o n of a r y l - a n d h e t e r o a r y l -
a c e t o n i t r i l e a l s o a p p e a r e d . 302
c a r b o x a l d e h y d e p h e n y l h y d r a z o n e s t o n i t r i l e s was a c h i e v e d t h r o u g h t r e a t m e n t w i t h N,N-dimethyldichloromethaniminium c h l o r i d e i n 1 , 2 d i c h l o r o e t h a n e . 303 The u s e of p h o s p h o r u s - b a s e d
cyanation reagents has featured
prominently i n t h e recent l i t e r a t u r e .
I n p a r t i c u l a r d i e t h y l phos-
phorocyanidate has found varied a p p l i c a t i o n s .
When u s e d i n c o n -
j u n c t i o n w i t h t r i e t h y l a m i n e c o n v e r s i o n o f two i m i d a z o l e - 4 c a r b o x y l i c a c i d d e r i v a t i v e s t o t h e c o r r e s p o n d i n g a c y l n i t r i l e s was a c h i e v e d , ’04 a l t h o u g h t h e l a t t e r c l a s s o f c o m p o u n d s were p r e p a r e d i n a m o r e g e n e r a l f a s h i o n by o x i d a t i o n of c y a n o - h y d r i n s w i t h b i s (dipheny1phosphine)dichlororuthenium and t e r t - b u t y l hydroperoxide
i n b e n z e n e . 305
I n c o m b i n a t i o n w i t h l i t h i u m c y a n i d e p r e p a r a t i o n s of
2-cyano-3-indole-2-alkylnitriles a c c o m p l i s h e d . 306 of
from 3-acylindoles
could be
This reagent system a l s o f a c i l i t a t e d preparation
a-diethylphosphono-oxy
unsaturated ketones.
n i t r i l e s by a d d i t i o n s t o v a r i o u s
Boron t r i f l u o r i d e - d i e t h y l e t h e r a t e promoted
a l l y l i c r e a r r a n g e m e n t s were d e s c r i b e d , t h e s e l e a d i n g t o l - c y a n o - 3 diethylphosphono-oxy
d e r i v a t i v e s of both cyclic307 and acyclic308
systems, the latter affording 4-arylangelonitriles. sequence applied t o p-benzoquinones
T h e same
p r o v i d e d access t o cyano-
s u b s t i t u t e d b i a r y l s when t h e r e a r r a n g e m e n t s t e p was p e r f o r m e d i n t h e presence of an arene.309 A n i o n s o f dialkylcyanomethanephosphonates were f o u n d t o u n d e r g o arylation with iodoarenes i n t h e presence of cuprous iodide t o give
a-alkylarylacetonitriles f o l l o w i n g m i g r a t i o n o f t h e a l k y l g r o u p T h e r e a c t i o n was s u b j e c t t o
from o x y g e n t o t h e b e n z y l i c c a r b o n . 3 1 0 steric e f f e c t s since ortho-substituted
aryl iodides afforded aryl-
a c e t o n i t r i l e s u n d e r t h e same c o n d i t i o n s .
Such effects had n o t
p r e v i o u s l y b e e n e n c o u n t e r e d i n a r y l a t i o n s of e t h y l c y a n o a c e t a t e anions. butoxide,
T h e s e , g e n e r a t e d by d e p r o t o n a t i o n w i t h p o t a s s i u m t e r t could be a r y l a t e d w i t h iodoarenes i n t h e presence o f
bis(dipheny1phosphine)dichloropalladium as a c a t a l y s t . 31
This
c a t a l y s t was a l s o u s e d t o a c h i e v e s i m i l a r c o u p l i n g s t o d i i o d o arenes3’
a n d a l s o i n t h e p r e p a r a t i o n o f phenylenedimalononitriles
by c o u p l i n g o f m a l o n o n i t r i l e a n i o n s ( g e n e r a t e d by s o d i u m h y d r i d e deprotonation) with diiodoarenes.312 In contrast, a route t o the
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
277
s t e r i c a l l y c r o w d e d 2,3,5,6-tetramethyl-7,7,8,8-tetracyano-paraq u i n o d i m e t h a n e , w h i c h was s h o w n t o e x i s t i n a b o a t c o n f o r m a t i o n b y x-ray
crystallography, u t i l i s e d deprotonation of malononitrile with
sodium methoxide, cuprous i o d i d e mediated coupling w i t h 1,4-diiodo-
2,3,5,6-tetramethylbenzene a n d o x i d a t i o n . 3 1 3 The v a r i e d u s e s o f h i g h l y d i p o l a r c y a n o - s u b s t i t u t e d q u i n o d i m e t h a n e s h a s s t i m u l a t e d much s y n t h e t i c i n t e r e s t a s s h o w n a b o v e , e s p e c i a l l y i n t h e p r e p a r a t i o n of a r y l - s u b s t i t u t e d m a l o n o n i t r i l e s a s potential precursors.
A three-step
s y n t h e s i s o f t h e s e compounds
h a s b e e n d e v e l o p e d w i t h o u t u s e of a r y l a t i o n m e t h o d o l o g y above).
(cf.
A r o y l h a l i d e s were t r e a t e d s e q u e n t i a l l y w i t h c y a n o t r i -
-
m e t h y l s i l a n e and P0Cl3
both i n t h e presence of pyridine
-
to
y i e l d chlorodicyanomethylbenzenes w h i c h were t h e n r e d u c e d t o t h e d i c y a n o m e t h y l e n e c o m p o u n d s w i t h z i n c i n a c e t i c a c i d .31
The f i r s t t w o s t e p s o f t h i s s e q u e n c e were a p p l i e d t o t e r e p h t h a l o y l c h l o r i d e s
t o a f f o r d m i x t u r e s o f tetracyanoquinodi-methanes and t h e i r dichloro-analogues
w h i c h were c o n v e r t e d t o t h e f o r m e r b y b o r o -
h y d r i d e r e d u c t i o n . 315 a-Thio-substituted
a r y l a c e t o n i t r i l e s were i s o l a t e d a f t e r c y a n o -
s u b s t i t u t e d s u l p h o x i d e s had been t r e a t e d w i t h t r i f l u o r o a c e t i c a n h y d r i d e i n t h e p r e s e n c e of a n a r e n e a n d t i t a n i u m t e t r a chloride.316
A t O°C
t h e r e a c t i o n was f o u n d t o b e s e n s i t i v e t o t h e
r a t e of a d d i t i o n of t h e L e w i s a c i d . H i g h l y a c t i v a t e d n i t r o - a r o m a t i c s h a v e b e e n s u b s t i t u t e d , i n a few e x a m p l e s , w i t h K C N , as t h e c y a n i d e a n i o n s o u r c e , i n t h e p r e s e n c e o f a phase-transfer catalyst.317 Cyanation of toluene through t h e agency o f t h e cyanodiazonium i o n d e r i v e d from cyanamide h a s been examined.
0- a n d p - S u b s t i t u t e d
d i c y a n o b e n z e n e s were f o u n d t o u n d e r g o
photolytic mono-allylation when c o m b i n e d w i t h a l l y l i c
and mono-benzylation
in acetonitrile
and b e n z y l i c s i l a n e s r e s p e c t i v e l y . 319
Cyanation o f carbon-carbon m u l t i p l e bonds can be regarded as an a r e a of i n c r e a s i n g i m p o r t a n c e a n d o n e i n w h i c h m e t a l - c a t a l y s e d
methods predominate.
T h e w e l l known Nagata c o n d i t i o n s f o r o l e f i n
h y d r o c y a n a t i o n were e m p l o y e d i n t h e c o n v e r s i o n o f ( 5 4 ) t o (55) d u r i n g t h e e a r l y s t a g e s of a ( f ) - c y c l o e u d e s m o l
(56) synthesis.320
Nickel(0) c a t a l y s t s have f e a t u r e d prominently i n t h i s f i e l d with tetrakis(tri-p-tolyl
p h o s p h i t e ) n i c k e l ( O ) a l l o w i n g regio-
s e l e c t i v e M a r k o v n i k o v a d d i t i o n of h y d r o g e n c y a n i d e t o o l e f i n s a t t e m p e r a t u r e s above 5OoC. I n t e r e s t i n g l y , a d d i t i o n o f Lewis a c i d h y d r o c y a n a t i o n p r o m o t e r s r e d u c e d t h e s e l e c t i v i t y of t h e r e a c t i o n ,
278
General and Synthetic Methods
giving increased proportions of the anti-Markovnikov addition product. 321 Tetrakis( triphenyl phosphite)nickel(O) has been used to mediate addition of hydrogen cyanide to silyl acetylenes. Regiochemistry of addition was partially controlled by manipulation of the silicon ligands. X-Ray studies confirmed (E)-stereochemistry of the products, thus establishing a simple synthesis of (E)-2-alkyl-3-trialkylsilyl-2-enenitriles. 322 Another report documented palladium-catalysed addition of cyanotrimethylsilane to aryl acetylenes to afford ( z - 8 -cyan043 -arylalkenylsilanes. 323 The synthesis of unsaturated nitriles is an important task in which variants of old-established methods complement newer strategies. Xonotlite,alone or in combination with potassium tertbutoxide,catalysed Knoevenagel condensations between arylaldehydes and either malononitrile or alkylcyanoacetates which afforded (E)styrene derivatives. 324 A chromatographic procedure involving elution of reactants through a column of potassium fluoridealumina, however? produced (Z-)-styrene counterparts exclusively. 325 Of the more recently reported methods alkylation of 4-cyano-3oxotetrahydrothiophene followed by base-induced extrusion of the a-substituted acrylonitrile from the resultant intermediate appears to be the most versatile (Scheme 3 3 ) . 3 2 6 Vinyl iodonium salts, prepared by reaction of vinylsilanes with iodosylbenzene and triethyloxonium tetrafluoroborate, have been found to be excellent educts for nucleophilic substitution by a variety of nucleophiles. Reaction with KCu(CN)* in DMF was thus possible and acrylonitrile derivatives prepared accordingly. 327 y-Oxygenated acrylonitriles resulted from treatment of acylated cyanohydrins derived from a,B-unsaturated carbonyl compounds with trialkyltin alkoxides and tetrakis(tripheny1phosphine)palladium(0).328 A study aimed at the synthesis of various u-(oligosilanoxany1)acrylonitriles investigated Il4-eliminations of C,N-bis(trimethylsilyl)-~-trimethylsilyloxymethylketeniminesand retro Diels-Alder reactions of 2-oligosilanoxanyl-5-norbornene-2-carbonitriles as potential routes to these compounds. For the latter reaction the 2-trimethylsilyl derivative (57) afforded 2-trimethylsilylacrylonitrile, and three other oligosilanoxanyl derivatives by variation of the 2-silyl substituent . 3 2 9 Use of acidic alumina at 250°C promoted a novel decarbalkoxylation of f 3 - a m i n o - a l B - e t h y l e n e c a r b o x y l a t e s to yield the a , B unsaturated nitrile analogues. 330 a-Cyanosulphoxides have been used to provide a-arylthioacrylo-
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
Reagents: i . R X , K2C03, M e 2 C 0 ,
V
279
i i , 5"10 a q . NaOH
Scheme 33
4
SiMe,
CN
CN
R'
R2
H R e a g e n t s : i , H2C=C(SePh)CN,
T H F ; i i , PhC=C-Li+,
S c h e m e 34
R'
R2
(58)
H
Bun
Me
(59)
Pr"
H
Prn
R3
THF; i i i , PhgSn , AIBN, C6H6
General and Synthetic Methods
280
n i t r i l e s t h r o u g h t r e a t m e n t o f t h e f o r m e r compounds w i t h t r i m e t h y l s i l y l trifluoromethanesulphonate a n d h e x a m e t h y l d i s i l a z a n e i n d i e t h y l e t h e r . 331 radical traps
,
Similar compounds have been u s e d as c a p t o - d a t i v e
a n d r a d i c a l d i m e r i s a t i o n p r o d u c t s s o i s o l a t e d . 332
From t h e s e l a t t e r c o m p o u n d s e n e - 1 , 2 - d i n i t r i l e s
may b e o b t a i n e d by
t r e a t m e n t w i t h c h l o r i n e . 333 Allylic,
propargylic,
and b e n z y l i c i o d i d e s a l l a f f o r d e d
n i t r i l e s u p o n a l k y l a t i o n w i t h (bromozinco)acetonitrile. 334 Ring f r a g m e n t a t i o n r e a c t i o n s have a l s o e n a b l e d u n s a t u r a t e d n i t r i l e s t o be o b t a i n e d .
Cyclic a-(ary1thio)ketoximes underwent e t h e r s . 335 O x i d a oximes with lead
Beckmann r e a r r a n g e m e n t t o a f f o r d c y a n o - t h i o e n o l t i v e cleavage of c y c l i c (E)-B-tributylstannyl
tetraacetate l e d t o p r e p a r a t i o n of unsaturated n i t r i l e o x i d e s which r e a c t e d f u r t h e r t o b i c y c l i c A 2 - i s o x a z o l i n e s .336
a-Ketocyanoketenemercaptals were o b t a i n e d f r o m t h e c o r r e s p o n d i n g b r o m o k e t e n e m e r c a p t a l s on a d d i t i o n o f p o t a s s i u m c y a n i d e i n p y r i d i n e .337 Michael a d d i t i o n s o f c y a n i d e a n i o n s h a v e been s y n t h e t i c a l l y u s e f u l i n t h e p a s t , and such r e a c t i v i t y h a s been u t i l i s e d i n t h e
d e v e l o p m e n t o f a p h a s e - t r a n s f e r c a t a l y s e d t a n d e m Michael a d d i t i o n e l e c t r o p h i l i c a l k y l a t i o n p r o c e d u r e u s i n g b e n z y l i d e n e m a l o n a t e and e t h y l ( l - m e t h y l p r o p y l i d e n e ) c y a n o a c e t a t e . 338
Anions derived from
c y a n o - b e a r i n g a c t i v e m e t h y l e n e compounds are a l s o e x c e l l e n t n u c l e o Again p h a s e - t r a n s f e r p h i l e s a n d may b e u s e d i n M i c h a e l a d d i t i o n s .
’”
c a t a l y s i s b e n e f i t t e d t h e s y n t h e s i s of a - c y a n o k e t o n e s enones.
from
K e t o n i t r i l e s were a l s o o b t a i n e d by a d d i t i o n o f o r g a n o m a n g a n e s e i o d i d e r e a g e n t s t o c y a n o - c o n t a i n i n g a c y l h a l i d e s . 340 b C y a n o k e t o n e s were p r e p a r e d f o l l o w i n g M i c h a e l a d d i t i o n s o f a l k y l n i t r i l e a n i o n s t o 2-(IJ-methylanilino)acrylonitrile, a l k y l a t i o n o f t h e a n i o n i c a d d u c t and h y d r o l y s i s o f t h e r e s u l t i n g a l k y l a t e d aminonitrile inter~nediate.~~’ The u s e o f u n s a t u r a t e d n i t r i l e s a s Michael a c c e p t o r s r e p r e s e n t s a facet o f t h e s y n t h e t i c u t i l i t y o f cyano-compounds t h a t n i c e l y c o m p l e m e n t s t h e r e a c t i v i t y d i s c u s s e d a b o v e . M i c h a e l a d d i t i o n o f 2lithio-Il3-dithianes t o a,b-unsaturated n i t r i l e derivatives appears t o be of u s e i n t h e p r e p a r a t i o n of p r o t e c t e d c y a n o k e t o n e s , a l t h o u g h t h e m e t h o d may b e l i m i t e d by t h e f a c t t h a t r e a c t i o n s of s u b s t r a t e s u n a b l e t o s t a b i l i s e t h e n e g a t i v e c h a r g e o f t h e a d d u c t b e f o r e worku p were d i f f i c u l t t o a c h i e v e s a t i ~ f a c t o r i l y . ~ ~ ~ Tri-n-butylgermanium h y d r i d e i n c o m b i n a t i o n w i t h AIBN i n r e f l u x i n g b e n z e n e h a v e t o g e t h e r f a c i l i t a t e d r e d u c t i v e a l k y l a t i o n of
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
28 1
a c r y l o n i t r i l e s w i t h a l k y l i o d i d e s w i t h minimal amounts of dehydrohalogenated products (from e l i m i n a t i o n w i t h i n t h e a l k y l i o d i d e ) b e i n g f o r m e d . 343 R a d i c a l a d d i t i o n s have been p a r t i c u l a r l y s u c c e s s f u l h e r e a n d , f o r example, c y a n o a l k y l g l y c o s i d e s have been p r e p a r e d from n i t r o s u g a r s and a c r y l o n i t r i l e s i n t h e p r e s e n c e of tri-;-butyltin h y d r i d e . 344
Radical e q u i v a l e n t s of homo-enolate a d d i t i o n s have been accomplished w i t h t h e " n u c l e o p h i l i c " p a r t n e r d e r i v e d from
fragmentations of silyloxycyclopropane derivatives i n t h e presence o f m e r c u r i c acetate and a n a c r y l o n i t r i l e . 6-Cyano-aldehydes and
- e s t e r s h a v e t h u s b e e n o b t a i n e d . 345 Michael a d d i t i o n s of a c t i v e esters t o c i n n a m o n i t r i l e under p h a s e - t r a n s f e r c o n d i t i o n s h a v e a l s o been d o c u m e n t a t e d . 346 A d d i t i o n s of e n a m i n e s t o 2-(phenylseleno)prop-2-enenitrile has f a c i l i t a t e d annulation of cyano-containing cyclopentanoid r i n g s , following a l k y n y l a t i o n of t h e ketones r e s u l t i n g from t h i s a d d i t i o n a n d s u b s e q u e n t r a d i c a l c y c l i s a t i o n ( S c h e m e 3 4 ) .347 O t h e r n o t a b l e r e p o r t s o f a n n u l a t i o n s i n v o l v i n g n i t r i l e s were concerned w i t h t h e p r e p a r a t i o n of 7 - l a c t o n e s p r e p a r e d from cyanoa c e t i c a c i d d e r i v a t i v e s and o l e f i n s i n t h e p r e s e n c e of m a n g a n e s e (111) a c e t a t e . 348 , 349 T h e " c a r b o n - z i p " r i n g e x p a n s i o n o f 2-oxocycloalkane-I - c a r b o n i t r i l e s h a s been i n v e s t i g a t e d 3 5 0 and a s y n t h e s i s o f 12-cyano-15-hexadecanolide, u t i l i s i n g t h i s m e t h o d , r e p o r t e d . 351 A l k y l a t i o n s of n i t r i l e s r a n k h i g h l y amongst i m p o r t a n t s y n t h e t i c transformations. Phase-transfer c a t a l y s i s employing copolyestera m i d e s a l l o w e d s e l e c t i v e m o n o a l k y l a t i o n o f a r y l a c e t o n i t r i l e s , 352 a l t h o u g h t h e s e l e c t i v i t y d i d n o t e x t e n d t o a t t e m p t e d monobenzylations. A n o t h e r i n t e r e s t i n g r e p o r t d e t a i l e d m o n o a l l y l a t i o n o f ab r o m o n i t r i l e s w i t h a l l y l c o b a l o x i m e s . 353 T h e i m p o r t a n c e of a m i n o - n i t r i l e s i s r e f l e c t e d i n t h e n u m b e r o f r e p o r t s i n which t h e y have a p p e a r e d . P r e v i o u s r e p o r t s o f a-aminon i t r i l e s y n t h e s i s from a - s i l y l o x y n i t r i l e s and amines have been s u p p l e m e n t e d by a r e p o r t e d i n s i t u p r e p a r a t i o n o f t h e s e i n t e r m e d i a t e s by t r e a t m e n t o f a l d e h y d e s a n d k e t o n e s w i t h c y a n o t r i m e t h y l s i l a n e , t h i s f u r n i s h i n g a simple one-pot p r e p a r a t i o n of t h e d e s i r e d c o m p o u n d s . 354 ' 355 A c o m p l e m e n t a r y s y n t h e s i s was f a c i l i t a t e d b y t h e p r e p a r a t i o n o f a - s i l y l o x y a m i n e s f r o m t e r t i a r y !-oxides following s e q u e n t i a l t r e a t m e n t w i t h t r i m e t h y l s i l y l trifluoromethanesulphonate a n d m e t h y l - l i t h i ~ r n . ~T r~e~a t m e n t o f t h e a - s i l y l o x y a m i n e s w i t h TiC14/Me S i C N a f f o r d e d a - a m i n o n i t r i l e s i n r e a s o n a b l e o v e r a l l
3
282
General and Synthetic Methods
yields. Palladous a c e t a t e h a s been found t o c a t a l y s e a d d i t i o n of cyanotrimethylsilane t o l-aza-Il3-dienes
i n dichloromethane, t h i s The u s e o f
opening up a f u r t h e r r o u t e t o a-aminonitriles.357 Pd(I1)Cl
2
ar?d t r i r n e t h y l s i l y l trifluoromethanesulphonate a s a l t e r -
n a t i v e c a t a l y s t s p l u s 1 , q - a d d i t i o n s t o t h e a z a - d i e n e s were a l s o described.
Furthermore,
i t h a s b e e n shown t h a t d e h y d r o g e n a t i o n o f
s e c o n d a r y a r n i n e s w i t h p h e n y l s e l e n i n i c a n h y d r i d e (or t h e a c i d ) c a n be u t i l i s e d i n t h e s y n t h e s i s of a - a m i n o n i t r i l e s ,
by r e a c t i n g t h e
r e s u l t i n g i m i n e w i t h a s o u r c e of c y a n i d e a n i o n . 3 5 8 The s y n t h e s i s a n d a l k y l a t i o n s o f
(37) have been r e p o r t e d , w i t h
g o o d y i e l d s o f mono- a n d d i - s u b s t i t u t e d d e r i v a t i v e s o b t a i n e d i n r e a c t i o n s t h a t a f f o r d e d m o d e r a t e d i a s t e r e o m e r i c e x c e s s e s . 359
The
r e l a t e d s y n t h o n ( 3 6 ) was e m p l o y e d i n t h e s y n t h e s e s o f ( - 1 m o n o m o r i n e I (58)360 a n d ( - ) - g e p h y r o t o x i n - 2 2 3 A B (59).3 6 1 Cyanohydrins a r e an e x t e n s i v e l y s t u d i e d g r o u p o f compounds.
In
t h e p r e s e n c e of t i t a n i u m t e t r a c h l o r i d e v i n y l s i l a n e s a n d s i l y l enol-ethers
both added t o alkoxy-substituted
a c y l cyanides.362
Near t o t a l 1 , 2 - a n d 1 , 3 - a s y m m e t r i c i n d u c t i o n was o b s e r v e d i n r e a c t i o n s o f a- and $ - a l k o x y a c y l
cyanides respectively, with t h e
t e r t i a r y cyanohydrins t o obtained being configurationally s t a b l e . S e c o n d a r y c y a n o h y d r i n s were o b t a i n e d a f t e r a d d i t i o n o f c y a n o s i l a n e s t o t h e acyl cyanides under similar conditions but with only p a r t i a l asymmetric induction.
The p o t e n t i a l a p p l i c a t i o n o f t h e s e m e t h o d s
t o t h e s y n t h e s i s o f c a r b o h y d r a t e s was n o t e d .
(S)-l-Acetoxy-2-aryloxypropionitriles were o b t a i n e d b y e n z y m i c h y d r o l y s e s of t h e r a c e m a t e s i n t h e p r e s e n c e of l i p a s e p r o d u c e d by
P s e u d o m o n a s s p p - , t h i s l e a d i n g t o a s y n t h e s i s of
(2)-
propranolol .363
Use o f s i l y l c y a n o h y d r i n s a s a c y l a n i o n e q u i v a l e n t s i s now a firmly established procedure.
A r e c e n t r e p o r t documented prepara-
t i o n o f t e r t - b u t y l d i m e t h y l s i l y l c y a n o h y d r i n s t h r o u g h a d d i t i o n of t h e s i l y l c h l o r i d e t o a l d e h y d e s i n t h e p r e s e n c e of p o t a s s i u m c y a n i d e a n d z i n c i o d i d e , r a t h e r t h a n by u s e o f c y a n o d i m e t h y l - t e r t - b u t y l si1ane.3~' The r e a c t i o n s o f c y a n o t r i m e t h y l s i l a n e w i t h e n o l i s e d B - d i c a r b o n y l systems365 p l u s sugar-ketones, -epoxides,
and -benzylidene
a ~ e t a l s ~ ~ ~
were s t u d i e d i n s o m e d e t a i l . M e t a l l i c n i c k e l was f o u n d t o r e a c t w i t h h a l o - a c e t o n i t r i l e s
to
form c y a n o m e t h y l n i c k e l h a l i d e s , w h i c h u n d e r w e n t R e f o r m a t s k y - t y p e a d d i t i o n s t o a l d e h y d e s w h i c h a f f o r d e d $ - h y d r o x y n i t r i l e s . 367
283
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups C o n v e r s i o n of MEM-protected
a l c o h o l s t o r e l a t e d cyanomethyl
e t h e r s by u s e o f d i m e t h y l b o r o n b r o m i d e i n d i c h l o r o m e t h a n e a t low t e m p e r a t u r e , f o l l o w e d by a d d i t i o n o f c y a n i d e , h a s a l s o b e e n r e p o r t e d . 368
Reissert compounds are r e a d i l y a v a i l a b l e from b o t h q u i n o l i n e s and i s o q u i n o l i n e s upon t r e a t m e n t w i t h a n a c y l h a l i d e and a c y a n i d e s o u r c e s u c h a s A l C l /TMSCN369 or t r i - n - b u t y l t i n
3
Pyridine-based
cyanide.
370
a n a l o g u e s o f R e i s s e r t c o m p o u n d s h a v e p r o v e d much
more e l u s i v e , a l t h o u g h t h e u s e o f e t h y l c h l o r o f o r m a t e w i t h e i t h e r p o t a s s i u m c y a n i d e 3 7 1 or a l u m i n i u m c h l ~ r i d e / c y a n o t r i m e t h y l s i l a n e ~ ~ ~ w o u l d seem t o h a v e o v e r c o m e t h i s p r o b l e m . O t h e r e f f o r t s t o a c h i e v e c y a n a t i o n of q u i n o l i n e s have been documented.
T h e p r e p a r a t i o n o f 3-amino-4-cyanoquinolines f r o m 3-
n i t r o q u i n o l i n e s h a s been r e f e r r e d t o a b o v e , 2 0 a n d , i n a d d i t i o n , d i i s o p r o p y l c y a n a m i d e was f o u n d t o b e a n e f f i c i e n t r e a g e n t f o r c y a n a t i o n o f 8-lithio-5,6,7,8-tetrahydro-quinolines.373 P r e p a r a t i o n of c y a n o i m i d a z o l e s seems t o b e a t t r a c t i n g c u r r e n t i n t e r e s t with s y n t h e s i s of
l-cyanoimidazoles from 4-azidopyrimi-
dines374 and p r e p a r a t i o n of 2-cyanoimidazoles from imidazoles, c y a n o g e n c h l o r i d e a n d t r i e t h ~ l a m i n er e~p~o r~t e d a l o n g w i t h c o n v e r s i o n s of both 4-nitro-5-methyl-
a n d 5-nitro-4-methyl-imidazoles t o t h e c o r r e s p o n d i n g n i t r o c y a n o i m i d a z o l e s . 376 S y n t h e s e s o f 1 cyano-2-substituted
i s ~ i n d o l e sa n~d ~ 3 ~- c y a n o i n d o L e ~h~a v~ e~ b e e n
reported. Various o t h e r p u b l i c a t i o n s have documented t h e s y n t h e s i s o f
3-
c y a n o - I ( 3 ~ ) - i s o b e n z o f u r a n o n e sf r o m h y d r o x y p h t h a l i d e s , 379 p r e p a r a t i o n o f 3-cyano-iminothiocoumarin-4-carboxylic thiophen-2,3-diones
a c i d s from b e n z o -
a n d m a l o n o n i t r i l e , 380 c o n v e r s i o n o f 2 - a z i d o -
thianaphthenes t o 4-cyanothiochromans,
38
c o n d e n s a t i o n s of B -
d i k e t o n e s and cyanoselenoacetamides t o form 3-cyanopyridine-
2 ( I g ) s e l e n o n e s , 382 a n d 1 - c y a n o m e t h y l a t i o n o f 2 , 2 , 6 , 6 - t e t r a m e t h y l p i p e r i d i n e s by a n o d i c o x i d a t i o n c a r r i e d o u t i n a c e t o n i t r i l e . A s mentioned above,
383
3 - s i l y l o x y i s o c y a n i d e s h a v e b e e n o b t a i n e d by
treatment of oxetanes with cyanotrimethylsilane i n t h e presence of zinc iodide.384
I s o c y a n i d e s h a v e a l s o b e e n made by t r e a t m e n t o f
f o r m a m i d e s w i t h p h o s p h o r y l c h l o r i d e a n d d i i s o p r o p y l a m i n e . 385 U n s a t u r a t e d i s o c y a n i d e s , t o o , h a v e b e e n t h e f o c u s of c o n s i d e r able attention. Cu20-catalysed
V i n y l i s o c y a n i d e s h a v e b e e n p r e p a r e d e i t h e r by i s o m e r i s a t i o n of a l l y l i c a n a l o g u e s or by t h e
S c h o l l k o p f m e t h o d of r e a c t i n g a l d e h y d e s w i t h i n s i t u m e t a l l a t e d m e t h y l i s o c y a n i d e f o l l o w e d b y d e h y d r a t i o n o f t h e a d d ~ c t s . T~h e~ ~
General and Synthetic Methods
284
s y n t h e s i s o f l-(ary1thio)alkenylisocyanides h a s b e e n r e p o r t e d . m e t h o d s i n v o l v e d were P e t e r s o n o l e f i n a t i o n b e t w e e n s i l y l a t e d
The
(ary1thio)methylisocyanides a n d c a r b o n y l c o m p o u n d s p l u s a W i t t i g Horner approach employing t h e previously unreported r e a g e n t s
diethyl[isocyano(arylthio)methyl]phosphonates. 387 T h e f i r s t p r e p a r a t i o n o f isocyanomethylene-triphenylphosphorane was a l s o d e s c r i b e d . 3a8 S u b s t i t u t i o n r e a c t i o n s of both sodium and s i l v e r cyanides with e r y t h r o - a n d threo-2-methylthio-3-halobutanes were r e c o r d e d . The sodium s a l t a f f o r d e d n i t r i l e s , w i t h i s o n i t r i l e s b e i n g o b t a i n e d upon u s e o f t h e s i l v e r s a l t . The r e a c t i o n s p r o c e e d e d w i t h c o m p l e t e r e t e n t i o n of configuration P r e p a r a t i o n of phenyl s i l a i s o c y a n i d e h a s been r e p o r t e d f o l l o w i n g p y r o l y t i c e l i m i n a t i o n o f n i t r o g e n f r o m t r i a z i d o p h e n y l s i l a n e . 390 This represented t h e first synthesis of an organosilicon d e r i v a t i v e w i t h a f o r m a l s i l i c o n - n i t r o g e n t r i p l e bond. 9 Nitro-
and Nitroso-compounds
The e x t e n s i v e u s e o f n i t r o - c o m p o u n d s
i n s y n t h e s i s stems n o t o n l y
from t h e i r a b i l i t y t o s t a b i l i s e simple a-carbanions but a l s o i n t h e i r a b i l i t y t o a c t i v a t e both aromatic and o l e f i n i c systems towards nucleophilic attack.
The a d d i t i o n a l r e a c t i v i t y o f n i t r o -
o l e f i n s as d i e n o p h i l e s i n Diels-Alder”
” a n d o t h e r C4+21 c y c l o -
a d d i t i o n s p l u s t h e number o f r e a g e n t s e f f e c t i n g n i t r o - t o - a m i n e r e d u c t i o n s s e r v e t o make t h e n i t r o - g r o u p a n e x t r e m e l y v e r s a t i l e functional group. Anions derived from nitro-compounds
a r e known t o r e a c t w e l l w i t h
M i c h a e l a c c e p t o r s , w i t h t h i s r e a c t i v i t y i l l u s t r a t e d by t h e a d d i t i o n of a n i o n s d e r i v e d f r o m 1 - d e o x y - l - n i t r o s u g a r s
p h o n a t e s . 391
t o v i n y l i c phos-
I n g e n e r a l , a l l y l i c nitro-compounds
undergo Pd(0)-
c a t a l y s e d a l l y l i c a l k y l a t i o n by s t a b i l i s e d a n i o n s a n d a r e c e n t example o f t h i s methodology l e d t o the s y n t h e s i s o f t e r p e n o i d compounds.392
Thus, a d d i t i o n of an anion of an a l l y l i c n i t r o a l k a n e
t o M i c h a e l a c c e p t o r s i n t h e p r e s e n c e of t e t r a k i s ( t r i p h e n y 1 ph0sphine)palladium resulted i n an alkylidene-transfer
reaction
which proved u s e f u l i n t h e s y n t h e s i s o f cyclopropane d e r i v a t i v e ~ . I t~ was ~ ~a l s o s h o w n t h a t t h i s t r a n s f e r r e a c t i o n c o u l d b e accomplished even i n t h e absence of t h e c a t a l y s t . I t h a s a l s o been shown t h a t l i t h i u m a - l i t h i o n i t r o n a t e s o b t a i n e d f r o m d o u b l e d e p r o t o n a t i o n s o f tetrahydropyran-protected v i c i n a l
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
285
n i t r o a l c o h o l s are s t a b l e t o w a r d s B-elimination and as s u c h are useful f o r t h e preparation of higher nitroalcohols, hydroxynitrok e t o n e s and n i t r o d i o l s . 394
R e a c t i o n s performed a t low t e m p e r a t u r e
i n tetrahydrofuran with e i t h e r hexamethylphosphoric a c i d triamide
o r dimethylpropyleneurea r e s u l t e d i n p r e f e r e n t i a l formation of one o f t h e two p o s s i b l e d i a s t e r e o m e r s (75-95% d s ) f u r t h e r e n r i c h m e n t o f Chemical and s p e c t r a l w h i c h was o f t e n p o s s i b l e by c r y s t a l l i s a t i o n . c o r r e l a t i o n s of products derived from a d d i t i o n s t o both a r y l
and
a l k y l a l d e h y d e s l e d t o a s s i g n m e n t o f t h e L - c o n f i g ~ r a t i o n ~t 'o~ t h e products. This presumably r e s u l t e d from diastereomeric protonation of t h e primary adducts ( n i t r o n a t e s or the corresponding n i t r o n i c a c i d s ) w i t h l f u l l ' r e l a t i v e t ~ p i c i t y ~( S' c~h e m e 3 5 1 . A more t r a d i t i o n a l r e a c t i o n is t h e c o n d e n s a t i o n o f n i t r o a l k a n e s
w i t h c a r b o n y l compounds (Henry r e a c t i o n ) .
Nitroaldol products can
b e i s o l a t e d b u t a r e m o r e commonly o x i d i s e d o r d e h y d r a t e d .
The
n i t r o a l d o l p r o d u c t s formed from m e t h y l - 8 - n i t r o o c t a n o a t e and a l d e h y d e s , i n t h e p r e s e n c e o f A m b e r l y s t A21 r e s i n , were o x i d i s e d w i t h pyridinium chlorochromate i n dichloromethane t o afford nitroketones w h i c h c o u l d b e f u r t h e r d e n i t r a t e d .396
The o v e r a l l s e q u e n c e t h u s
employed t h e n i t r o e s t e r as a s y n t h o n f o r t h e a n i o n o f 7-methoxycarbonylheptyl anion.
Nitroalkene formation has been achieved i n
t h e presence of alumina.
were
1-(2-Furyl)-2-nitro-alk-l-enes
p r e p a r e d from s u b s t i t u t e d f u r f u r a l d e h y d e s i n g o o d t o e x c e l l e n t y i e l d i n t h e a b s e n c e o f s o l v e n t , 397 w h i l s t D i e c k m a n n c y c l i s a t i o n s o f a c y l o x i m e s o f t y p e ( 6 0 ) t o 4 - n i t r o i s o x a z o l e s were also e f f e c t e d e f f i c i e n t l y i n dichloromethane solution.398
Use o f n - b u t y l a m i n e i n c o n j u n c t i o n w i t h n i t r o m e t h a n e was f o u n d t o b e m o r e e f f e c t i v e t h a n ammonium a c e t a t e / a c e t i c a c i d i n t h e p r e p a r a t i o n of 5-(2-nitroethenyl)salicylic c y l i c acid.399
a c i d from 5-formyl
sali-
T h e f o r m e r compound s e r v e d a s a p r e c u r s o r o f m o l -
l u s c i c i d a l a n d m i c r o b i c i d a l (nitroetheny1)salicylamides. S i m i l a r Henry-type
c o n d e n s a t i o n s were u t i l i s e d i n s y n t h e s e s o f
h e t e r o c y c l i c d e r i v a t i v e s from 2-hydroxy-benzaldehydes.
Condensa-
t i o n s with bromonitromethane afforded 2-nitrobenzoCblfurans
after
dehydration of i n t e r m e d i a t e n i t r o a l d o l s i n r e f l u x i n g acetic anhydride,
'''
w h i l s t Michael a d d i t i o n s t o n i t r o a l k e n e s p r i o r t o
i n t r a m o l e c u l a r condensation allowed p r e p a r a t i o n o f 3-nitro-3f l a v e n e s by u l t r a s o n i c a t i o n i n t h e p r e s e n c e o f a l u m i n a .
40 1
A d d i t i o n of n i t r i c a c i d t o m i x t u r e s o f 2 - h y d r o x y p h e n y l k e t o n e s a n d g l a c i a l a c e t i c a c i d a f f o r d e d 3 , 8 - d i n i t r o c o u m a r i n s by c y c l o - . 402 condensation of n i t r a t e d benzenoid intermediates.
2 86
General and Synthetic Methods
,*NTH
THPO
THPO.
../
-
0
~k
ul-protonation product
0
THPO
..
i/
- protonation product
R e a g e n t s : i , 6u”Li ( 2 e q u i v . ) , T H F , HMPT or D M P U ; i i , RCHO, i i i , A c O H
Scheme 35
and R 2 = M e 4 r a n i t i d i n e Reagents: i , M e w 2 ,NaH,DMF,
A S c h e m e 36
-
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
287
N i t r o n a t e s a l t s h a v e b e e n shown t o b e o x i d i z e d t o gee-dinitroc o m p o u n d s by n i t r i t e i o n a n d p e r s u l p h a t e i n t h e p r e s e n c e o f c a t a l y -
t i c a m o u n t s o f f e r r i c y a n i d e .‘03 gem-Cyanonitro- and a - n i t r o s u l p h o n e s were s i m i l a r l y o b t a i n e d from r e a c t i o n s i n v o l v i n g u s e of c y a n i d e and s u l p h i n a t e s a l t s r e s p e c t i v e l y . A I74-dinitro-compound was f o r m e d u p o n i r r a d i a t i o n o f t h e 2 - n i t r o p r o p a n o l l i t h i u m s a l t
404
w i t h (2-methyl-2-nitrocyclopropy1)methylketone. A ’RN’ m e c h a n i s m was p r o p o s e d i n e x p l a n a t i o n o f t h i s t r a n s f o r m a t i o n . A d d i t i o n s o f n i t r o n a t e a n i o n s t o v a r i o u s o t h e r s p e c i e s have been reported.
Notably, a d d i t i o n of t h e nitromethane carbanion t o
c a r b o d i i m i d e s l e d t o r e a s o n a b l e y i e l d s of l - n i t r o - 2 , 2 - b i s [ a l k y l a r y l a m i n o l e t h y l e n e s . ‘05
or
The m e t h o d was u s e d t o f a c i l i t a t e s y n t h e -
s i s of r a n i t i d i n e (Scheme 3 6 ) .
u-Nitrofurans with a’-acyl products of c i n e - s u b s t i t u t i o n
or - a l k o x y c a r b o n y l g r o u p s g a v e of t h e n i t r o - g r o u p
normal s u b s t i t u t i o n obtained with
E-, 0-,S- a n d
(rather than the 2-nucleophiles)
when t r e a t e d w i t h a n i o n s g e n e r a t e d f r o m s e c o n d a r y n i t r o a l k a n e s . 4 0 6 N i t r o a r e n e s c a n be n i t r o m e t h y l a t e d t h r o u g h r e a c t i o n w i t h t h e n i t r o m e t h a n e a n i o n f o l l o w e d by o x i d a t i o n o f t h e i n i t i a l p r o d u c t w i t h bromine.
The n i t r o m e t h y l g r o u p c a n b e c o n v e r t e d f u r t h e r
g i v i n g rise t o nitroaromatic aldehydes. “ 7
Similarly nitroarenes
undergo s u b s t i t u t i o n w i t h b o t h s i l y l e n o l e t h e r s and s i l y l k e t e n e This reactivity a c e t a l s i n t h e p r e s e n c e of a f l u o r i d e i o n donor. is i n sharp contrast with the behaviour of a l k a l i metal enolates. A g a i n o x i d a t i o n o f t h e i n t e r m e d i a t e d i h y d r o a r e n e n i t r o n a t e s was r e q u i r e d , t h i s b e i n g m e d i a t e d by e i t h e r D D Q or b r o m i n e . 4 0 8 By u s i n g e i t h e r a s t e r i c a l l y d e m a n d i n g or u n d e m a n d i n g s i l y l c o m p o n e n t i n t h e r e a c t i o n s u b s t i t u t i o n c o u l d be d i r e c t e d t o g i v e predomin a n t l y t h e para-
or o r t h o - s u b s t i t u t e d p r o d u c t . Obviously e x c l u s i v e c o u l d be a c h i e v e d w i t h p a r a - s u b s t i t u t e d n i t r o a r e n e s as s u b s t r a t e s . A d d i t i o n s o f G r i g n a r d r e a g e n t s t o n i t r o a r e n e s had p r e v i o u s l y b e e n d e m o n s t r a t e d t o be a method o f c o n s i d e r a b l e s y n t h e t i c potential. A f u r t h e r s t u d y h a s shown t h a t t h e o n l y r e a c t i o n t h a t is competitive i n terms of r a t e is a d d i t i o n of t h e Grignard t o an a l d e h y d e . ‘09 N i t r o o l e f i n s h a v e p r o v e n t o be e x c e l l e n t s u b s t r a t e s i n M i c h a e l reactions. T i n ( I 1 ) e n o l a t e s o f c y c l i c k e t o n e s were f o u n d t o r e a c t with B-nitrostyrene t o a f f o r d 4-nitroketones with an unprecedented ortho-substitution
a n t i - s e l e c t i v i t y o f u p t o 94% d s . (Metal e n o l a t e s and enamines normally g i v e --selectivity.) The r e a c t i o n c o u l d a l s o b e p e r -
General and Synthetic Methods
288
formed - albeit with reduced d i a s t e r e o s e l e c t i v i t y - w i t h a c y c l i c t i n e n o l a t e s . 410 H e t e r o c y c l i c l i t h i u m e n o l a t e s d e r i v e d f r o m b o t h hydroxy-
and amino-acids underwent a d d i t i o n s t o n i t r o o l e f i n s g i v i n g
only one of f o u r p o s s i b l e d i a s t e r e o m e r s ( g e n e r a l l y with b e t t e r than 90% d s ) . 4 1 1 '71k,ul-1,3tt.
T h e s t e r i c c o u r s e of t h e r e a c t i o n was s p e c i f i e d a s The s t e r i c c o u r s e o f M i c h a e l r e a c t i o n s between
a c y c l i c e n a m i n e s and n i t r o a l k e n e s h a s a l s o been s t u d i e d 4 I 2 and f o u n d t o b e p r e d i c t a b l e by a p p l i c a t i o n o f a t o p o l o g i c a l r u l e . 3 9 5 P r o d u c t s were f o r m e d by ( 1 k ) - c o m b i n a t i o n of t h e r e a c t a n t s ' t r i g o n a l centres. The r e l a t i v e t o p i c i t y o f t h e a d d i t i o n c o u l d n o t b e manip u l a t e d by u s e of a l t e r n a t i v e e n a m i n e g e o i s o m e r s s i n c e t h e p r i m a r y reaction step is reversible.
However, i n t h e p r e s e n c e o f e x c e s s
dichlorobis(isopropoxy)titanium, l-(trimethylsily1oxy)cyclohexene was f o u n d t o a d d t o p a r a - s u b s t i t u t e d 8 - n i t r o s t y r e n e s w i t h t h e r e v e r s e (cf. a b o v e ) ( u 1 ) - r e l a t i v e t o p i c i t y , t o g i v e p r o d u c t s of t h e L - d i a s t e r e o m e r i c c o n f i g u r a t i o n .4 I n i t i a l l y formed b i c y c l i c n i t r o n a t e s , w h i c h c a n be s e p a r a t e d p r i o r t o h y d r o l y s i s , were a b l e t o undergo f u r t h e r reactions,-. n i t r o a l d o l a d d i t i o n s and [3+2]d i p o l a r c y c l o a d d i t i o n s (Scheme 37). C o n j u g a t e r e d u c t i o n s o f n i t r o o l e f i n s have a l s o been w i d e l y s t u d i e d a n d a w i d e r a n g e of r e a g e n t s a r e a v a i l a b l e f o r t h e p r e p a r a t i o n of n i t r o a l k a n e s a n d v a r i o u s o t h e r c o m p o u n d s ( v i d e i n f r a ) f r o m these d e r i v a t i v e s .
R e d u c t i o n s t o n i t r o a l k a n e s were a c h i e v e d w i t h
sodium b o r o h y d r i d e u s e d i n e i t h e r methano1414 or d i o x a n / e t h a n o l ,415
2,6-dimethyl-3,5-dicarbethoxy-l,4-dihydropyridinelsilica g e l i n a n d by r e a c t i o n w i t h i n s i t u g e n e r a t e d 2 - p h e n y l b e n z i m i benzene4' dazolone. A l t e r n a t i v e r e a g e n t s such as borane-tetrahydrofuran c a n l e a d t o a l k y l a m i n e ~ ~o r' ~ e v e n k e t o n e s w h i c h a r e o b t a i n e d i n and l i t h i u m t r i - s e c - b u t y l r e d u c t i o n s w i t h c h r o m i u m ( 11) c h l o r i d e 4 ' b o r o h y d r i d e . 420 The p i v a l o a t e e s t e r of 2-nitro-2-propen-1-01
had p r e v i o u s l y been
d e m o n s t r a t e d t o b e a v e r s a t i l e m u l t i p l e c o u p l i n g r e a g e n t (VOlUme9, Ref.407, p.364). Analogues of 2'-nitroprop-2'-enIt-yl-2,2-dimethylpropanoate s u b s t i t u t e d a t t h e 1 ' - a n d 3 ' p o s i t i o n s c o u l d o n l y be prepared p r o v i d i n g these s u b s t i t u e n t s o r i g i n a t e d from a symmetrical system. A f o u r - s t e p s e q u e n c e was devised i n order t o synthesise t h e problematical unsymmetrically substituted analogues. This process involved trifluoroacetoxy42 p h e n y l s e l e n a t i o n o f n i t r o a l k e n e s (Scheme 38). 1 Chapter 5,
N i t r a t i o n o f a r e n e s s t i l l a t t r a c t s much a t t e n t i o n , a n d o f p a r t i c u l a r i n t e r e s t are s e l e c t i v e n i t r a t i o n s of p o l y c y c l i c aromatic
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
289
woTMs rN +
qgoOTMS
X
OTMS
OTMS
+
X
i{
(61)
x
x
iil
i i
(61)
(62)
X
X
(62)
(61 1 X = H ,Me,MeO, or C N
Reagents: i , T i ( O P r i I 4 ( 3 c q u i v . ) , T i C I 4 ( 3 cquiv.), CHzC12; ii, KF, MeOH
Scheme 37
General and Synthetic Methods
290
SePh
ii
R’
R2
1
ii i
iv
Reagents : i, PhSeCl , C F 3 C 0 2 A g , C H 2 C I Z ; ii, M e O H (aq. NaHC03) iv, (BU~CO)~O BF3 , -0Et2
i
iii H 2 0 2 , T H F ; I
Scheme 36
N O 2 - N 2 0 , ( g ) or N0,’6F;
C02N02
I
I
12 “25
12 H 2 5
S c h e m e 39
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
29 1
hydrocarbons. It was demonstrated that 4-nitrocyclopenta[fi]pyrene could be prepared by treatment of the parent hydrocarbon with silver nitrate, sodium nitrite and iodine in acetonitrile. 422 The synthetic and mechanistic aspects of nitrating polycyclic aromatics with dinitrogen tetroxide have been discussed423 and a study of the reactions of perylene radical cation with nitrogen dioxide and nitrite ion has also been presented. 424 Nitrations of bis(amid0)naphthalenes were also described,425 and the effects of crown ethers on the selectivity of electrophilic aromatic nitration studied. 426 Nitrations of phenolic systems remain a more specialised interest. It has been shown that activated nitro-derivatives of pyridinium salts give selective 2-nitration of phenol itself (Scheme 39). The reactive species was an acyl nitrate produced by addition of nitronium tetrafluoroborate to 1-dodecylpyridinium carboxylate in acetonitrile. The discovery that addition of NO2N 204 gas to the pyridinium salt also gave the reactive intermediate meant that the process can be economical since the expensive f luoroborate is not necessary. 427 Silica-gel-supported cerium(1V) ammonium nitrate has been proposed as a useful system for selective oxidative nitration of both phenols and polycyclic arenes , 428 whilst a description of regioselective phenol nitration by the more widely established clay-supported Cu(I1)- and Fe(II1)-nitrates was included in a review of the chemistry of these systems.429 Treatment of some bromophenol derivatives with fuming nitric acid resulted in formation of nitrodebrominated products . 4 3 0 Nitroarene coupling reactions have been described. Moderate to good yields of symmetrical o,o'-dinitrodiaryls resulted from treatment of 2-bromo- and ?-iodonitrobenzenes with stable enolate anions and cuprous iodide in hot DMF.431 Bis-
(acetonitrile)dichloropalladium(II) was found to be an efficient catalyst for coupling iodoarenes and organoalanes under a carbon monoxide atmosphere. 432 Under such conditions 4-iodonitrobenzene and triphenylaluminium afforded p-nitrobenzophenone and p-nitrodiphenyl in roughly equal amounts, whereas with phenyldi(isobuty1)aluminium
the benzophenone derivative was obtained
exclusively. The problem of a-C-allylation of nitro-compounds has been addressed. One report stated that a-nitroalkyl radicals, generated from a-nitrohalides in the presence of AIBN, were sufficiently
292
General and Synthetic Methods
r e a c t i v e t o undergo carbon-carbon coupling r e a c t i o n s with a l l y l t r i b u t y l s t a n n a n e , these c o u p l i n g s a f f o r d i n g r e a s o n a b l e y i e l d s o f m o n o a l l y l a t e d p r o d u c t s . 433
Cyclic a-nitroketones
were a l l y l a t e d
w i t h a l l y l i c c a r b o n a t e s u n d e r c a t a l y s i s by t e t r a k i s ( t r i p h e n y 1 p h o s p h i n e ) p a l l a d i u m ( O ) i n t e t r a h y d r o f u r a n (Scheme 40).
Carbonates
b e a r i n g c y a n o - , a l k o x y c a r b o n y l - a n d n i t r o - s u b s t i t u e n t s were a l s o found t o react s a t i s f a c t o r i l y as d i d t h e v i n y l epoxide (63).434 P r o d u c t s f r o m t h e a b o v e r e a c t i o n s resemble s u b s t r a t e s u s e d i n " c a r b o n - z i p " r i n g e x p a n s i o n s , a v a r i a n t o f w h i c h was e m p l o y e d i n t h e p r e p a r a t i o n o f n i t r o - s u b s t i t u t e d m a c r o c y c l i c lactams. 4 3 s N i t r y l i o d i d e h a s been shown t o a d d t o s u b s t i t u t e d s t y r e n e s , a n o b s e r v a t i o n which h a s t h u s f a c i l i t a t e d s y n t h e s i s o f s u b s t i t u t e d Bn i t r o s t y r e n e s by e l i m i n a t i o n o f h y d r o g e n i o d i d e f r o m t h e a d d u c t s w i t h t r i e t h y l a m i n e .436 Addition of aluminium c h l o r i d e t o B-ethylthio resulted i n formation of thienium cations,e.g.
nitroalkenes ( 6 4 ) which underwent Cleavage of t h e
[ 4 + 2 ] - t y p e c y c l o a d d i t i o n s t o 1 , 3 - d i e n e s . 437 c y c l o a d d u c t s y i e l d e d 1 , 4 - . s u b s t i t u t e d o l e f i n s (Scheme 4 1 ) . Radicals generated from thiohydroxamic a c i d esters gave a-nitros u l p h i d e s i n g o o d y i e l d s when a d d e d t o n i t r o a l k e n e s .438 D e p e n d i n g on t h e i r s t r u c t u r e , t h e s e a d d u c t s c o u l d b e c o n v e r t e d e i t h e r t o c a r b o x y l i c a c i d s (H202/K2C03) or c a r b o n y l c o m p o u n d s ( T i c 1 ) . 3 Fluoride ion-catalysed condensation of nitromethane with paraformaldehyde gave 2-&-nitropropane-l,3-diol m o l e c u l a r l y s t a b i l i s e d n i t r o n i c a c i d . 439
(651, a novel i n t r a -
I n t h e h e t e r o c y c l i c area p r e p a r a t i o n o f 1- and 3 - n i t r o c a r b a z o l e by f o r m a t i o n a n d s u b s e q u e n t r e a r r a n g e m e n t o f 9 ( N ) - n i t r o c a r b a z o l e h a s been d i s c u s s e d .
440
Acylaminomethyl-, a-acylaminobenzyl-, and
alkoxycarbonylaminomethyl-, a-alkoxycarbonylaminobenzyl-alkylnitramines h a v e b e e n
o b t a i n e d upon N - s u b s t i t u t i o n
of a l k y l n i t r a r n i n e s w i t h N - t o s y l r n e t h y l -
a l k y l E-tosylmethyl44 1 c a r b a m a t e s , a n d a l k y l N-(a-tosylbenzy1)carbamates r e s p e c t i v e l y . N i t r a m i n e s h a v e a l s o b e e n p r e p a r e d by o x i d a t i o n o f N - n i t r o s a m i n e s
c a r b o x a m i d e s , N-(a-tosylbenzyl)carboxamides,
w i t h hydrogen p e r o x i d e i n g l a c i a l a c e t i c a c i d . 4 4 2 The n i t r o s a m i n e s , i n t h i s i n s t a n c e , were p r e p a r e d by t h e a c t i o n of a c e t y l T e r t i a r y amines a l s o n i t r a t e (HNO /Ac20) on t e r t i a r y a m i n e s .
3
yielded 2-nitrosamines
when t r e a t e d w i t h d i n i t r o g e n t e t r a o x i d e . 4 4 3
A s an a l t e r n a t i v e N-nitrosamines
can be prepared, i n aqueous sodium
c a r b o n a t e s o l u t i o n , f r o m s e c o n d a r y a m i n e s by o x i d a t i o n w i t h F r e m y ' s s a l t and hydroxylamine, t h e a d d i t i o n o f which g r e a t l y improves t h e
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
X H CN Mc02C
CH2N02
293
Y H H H
n = l o r 7
Me
Reagent : i , ( P h 3 P I 4 P d ( 0 . 2 5 m o l
(63) %I, THF Scheme 10
I
ClJIO
*:: Reagent: i , A I C l j , C H Z C l 2
Scheme b l
\c/o-
R'
1
General and Synthetic Methods
294
yield of the reaction. 444 Alkynyl N-nitrosoalkanolamines have been synthesised by nitrosative eliminations performed on terpenyl alkanolamines 1445 and the synthesis of dibenzhydrylnitrosamine has been reported. 446
A review covering S-nitrosation and the reactions o f 2-nitrosocompounds has been published , 447 and the preparation of the thiol sulphonate derivatives of L-cysteine and glutathione via S-nitroso 448 precursors reported. 10
Hydrazines and Hydrazones
5-Hydrazino-A2-isoxazolines
have been prepared either from the
N,N-dialkylor acylcorresponding 5-hydroxy-compounds and either hydrazines upon refluxing in benzene with a cation exchange resin. Irii9 Hydrazones have also been obtained by the action of N-(alky1ideneamino)phthalimides in warm ethanol. 450 hydrazines on These phthalimides also reacted with sodium methoxide to afford Jalkylidenephthalic acid monohydrazides. Treatment of N-(trimethylsily1)-N-6-arylvinylhydrazines with bromines afforded enediazenium salts which reacted with nucleophiles (amines, alcohols, thiols, methyl-lithium and indole) to give a-substituted hydrazones. 45 Reaction of 1,3,4-oxadiazoles with concentrated hydrochloric acid in tetrahydrofuran followed by condensation with aldehydes afforded acylhydrazones .452 Silver tetrafluoroborate in tetrahydrofuran has been found to mediate cyclisations of chloroalkyl carboxylic acid hydrazides to hydrazono-esters. 45 3
1 1 Hydroxylamines and Hydroxamic Acids
Hydroxylamines have been obtained from reductions of nitroalkenes with borane-tetrahydrofuran, and it has also been shown that catalytic quantities of sodium borohydride greatly accelerate the rates of these reductions.454 This observation led to the development of a cheaper procedure with requires in situ generation of diborane f r o m boron trifluoride diethyl etherate and an excess of borohydride. 455 N,N-Dialkylhydroxylamines were obtained following hydrolyses of N,&-dialkyl-2-diphenylphosphinyl hydroxylamines which were in turn prepared by addition of secondary amines to bis[diphenylphosphinyl] peroxide at -4OOC in alcohol-free chloroform (Scheme 4 2 1 . ' ~ ~ The latter reagent was prepared by reaction of chloro-
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
295
diphenylphosphine oxide and sodium peroxide. Cyanotrimethylsilane was found to add in a 1,3-sense to nitrones, this addition giving rise to cyano-substituted c-trimethylsilylated hydroxylamines. 148 N-Glycosylhydroxylamine derivatives have been the subject of several reports. a-N-Glycosylhydroxylaminophosphonates resulted f r o m additions of dialkyl phosphite salts to !-glycosylnitrones .4577458 The stereochemistry of the reaction, which occurred with high asymmetric induction, was discussed. Synthesis of glycosides of N-hydroxy-1-arylamine derivatives has also been reported. 459 l 460 Hydroxamic acids resulted from additions of !-substituted hydroxylamines to carboxylic acids brought about by N,N-dimethylc h 1orome t han im in ium ch 1or id e and !-met hy lmo r p ho 1in e .667 The reagent was formed in situ from oxalyl chloride and dimethyl f ormamide . Dihydroxamic acids were synthesised from dicarboxylic acids 5 formation of the corresponding di-imidazolides on reaction with carbonyl diimidazole, followed by subsequent treatment with hydroxylamine in methanol. 462 12 Imines, Iminium Salts,and Related Compounds Classically, imines have been obtained derivatisation of carbonyl compounds although problems exist in the use of unreactive carbonyl compounds andlor volatile imines. This transformation has nevertheless been achieved in excellent yields in the absence of solvent merely by treating carbonyl compounds dispersed on alumina with amines that have been similarly dispersed on alumina.463 Trimethylsilyl trifluoromethanesulphonate has been found to catalyse formation of imines from carbonyl Compounds and N,N-bis(trimethysilyl)amines, these reactions also proceeding in excellent yield. 464 The same research group also discovered that sulphenimines could be isolated from reactions between N,N-bis(trimethylsily1)sulphenamides and carbonyl compounds in the presence of tetra-n-butylammonium fluoride as catalyst. 465 Sulphenimines also resulted from treatment of imines with silver nitrate, triethylamine and diphenyl disulphide in methanol. 466 The method was found to be well suited to imines derived from diar,yl ketones. The imines were prepared by the action of titanium tetrachloride and gaseous ammonia in toluene.
296
General and Synthetic Methods H+
J
ii,iii
Reagents: i , [ P h 2 P ( 0 ) 0 I 2 ( 0 . 5 e q u i v . ) , C H C l 3
;
ii, 1N.H2SO4(aq). MeOH; iii, NaOH
-
S c h e m e 42 TsN3
R2Te=NTS
+
R’CHO
~
R2%Ts 0--
R2Tc
c H R’
R’CH=NTS
+
R 2Te= 0
S c h e m e 43 PdC12( PPh3I2 H2/NEtj
y NEt3*HCI
P d ( PP h3I2
R’--ij-C{
R!-iH
R2R’-C-PdH(PPh3)2 2
R -N
11
NEt3’ H C I
N
C -P d C I ( P Ph l2 II
R-’ -R’
N
NEtjl H2
Scheme 4 4
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
297
N-Tosylimines have been synthesised in variable yields by a diisobutyl telluridelcopper Fowder induced reaction of aldehydes with tosylazide ,467 which does not normally react even under forcing conditions. An organotellurilimine was proposed as an intermediate (Scheme 4 3 ) . Imines may be obtained directly from amines when the latter are treated with tert-butyl hydroperoxide, catalytic amounts of dichlorotris (triphenylphosphine )ruthenium and 4 8 molecular sieves in benzene. 468 The method was applied to the synthesis of dihydrofrom tetrahydro-quinolines, this contrasting with the preparation of the corresponding nitrone derivatives with the previously reported Na 2WO 4-H 202 system. Di-tert-butyliminoxyl in pentane das likewise found to convert secondary, and also primary, amines to the corresponding imines. 469 Palladium(0)-catalysts, in particular, tetrakis(tripheny1ph0sphine)palladium have been found to catalyze 3-aza-Cope rearrangement of l-allylenamines to b,~-unsaturated imines when used in combination with trifluroracetic acid as co-catalyst .470 The same research group also found that imines may be prepared from N,g-disubstituted hydroxylamines upon treatment with titanium trichloride in anhydrous tetrahydrofuran at low temperature . 7 5 Imines were also formed during cationic carbon-to-nitrogen rearrangements of N-alkyl-2-(arylsulphony1)hydroxylamines which occurred in the absence of base. 47 N-H Aldimines may be produced by spontaneous or base-catalyzed decomposition of oxaziridines which are commonly prepared by oxidation of g-substituted imines with E - C P B A . ~ ~However, ~ such a preparation may be limited synthetically since the aldimines formed tend to react further under the reaction conditions. Dichlorobis( t r i p h e n y 1 p h o s p h i n e ) p a l l a d i u m and triethylamine proved useful for the dechlorination of iminochlorides by molecular hydrogen i n benzene at 12OoC (Scheme 44) .80 a,a-Dichloro-8-iminocarbonyl compounds afforded a,a-dichloroketimines on treatment with various reagents ( e a . NaOMe, KOBut, KCN, K CO ) in ether.473 These compounds have thus been identi2 3 fied as useful precursors of both 1,l-dichloro- and 1,l-dialkoxy-2alkanones. Regiospecific alkylations and dialkylations of a-haloketimines have also been demonstrated. 474 Nitrones have also served as a source of imines. Their reduction by sodium hydrogen telluride at pH10-1I7’ has been reported, and use of cyanotrimethylsilane in conjunction with triethylamine
298
General and Synthetic Methods
h a s l e d t o t h e i s o l a t i o n o f a - i m i n ~ n i t r i l e s (cf. ~ ~ ~ ref. P r e p a r a t i o n o f 2-[N-cyanoimino]piperidine -
148).
d e r i v a t i v e s h a s been
r e p o r t e d , t h e s e compounds r e s u l t i n g from a d d i t i o n o f c y a n o g e n a z i d e t o I l 2 - d i h y d r o p y r i d i n e s f o l l o w e d by t r e a t m e n t o f t h e r e s u l t a n t a d d u c t s w i t h e i t h e r a l u m i n a or h y d r o g e n a t i o n ( H 2 - P d / C ) . 47 6 The i n c r e a s i n g u s e of a z a b u t a d i e n e s y s t e m s i n s y n t h e s i s h a s l e d t o renewed e f f o r t s d i r e c t e d t o w a r d s t h e i r s y n t h e s i s .
a,B-Ethyl-
eneimines(l-aza-1,3-dienes) were p r e p a r e d by s i m p l e a d d i t i o n s o f a m i n e s t o 1 , 3 - e n y n e s m e d i a t e d by m e r c u r y ( I 1 ) c h l o r i d e a n d p o t a s s i u m 0 4: 1 ) . l 6 Elsewhere 2 e f f o r t s t o s y n t h e s i s e a l k y l t h i o - and a r y l t h i o - s u b s t i t u t e d e l e c t r o n -
c a r b o n a t e i n wet t e t r a h y d r o f u r a n (THF-H r i c h N--sulphonyl-I-azabutadienes
of t y p e ( 6 6 ) h a v e b e e n d e s -
c r i b e d , 477 a n d p r e p a r a t i o n of n o v e l B-hydroxy-y-imino-esters o f w h i c h may b e u s e d a s a z a d i e n e p r e c u r s o r s , I n t e r e s t i n 2-aza-l,?-dienes
, some h a v e been r e p o r t e d . 478
with respect t o t h e i r Diels-Alder
r e a c t i v i t y is c o n s i d e r a b l e , and t h u s t h e s e compounds h a v e been widely studied.
N o t a b l e r e s e a r c h h a s i n c l u d e d t h e i r s y n t h e s e s by
caesium fluoride-induced
protiodesilylation of N-(I-trimethyl-
s i l y l a l l y l I i m i n e s , 4 7 9 a n d by a n i m i n e d i m e r i s a t i o n r e a c t i o n In the
effected with t r i f l u o r o a c e t i c acid i n tetrahydrofuran.480
l a t t e r r e p o r t r e a c t i o n s of t h e azadienes with aldehydes t o g i v e
5,6-dihydro-2H-1,3-oxazines by C4+21 c y c l o a d d i t i o n s were d e s c r i b e d . I l l - A m i n o a z i n e s h a v e b e e n p r e p a r e d by a d d i t i o n o f s e c o n d a r y a m i n e s 48 1
t o 1,2,4,5-tetrazines.
I n t h e heterocyclic area 2-imidoylation
of p y r r o l e s a n d i n d o l e s 482
with methyl a l k y l n i t r i l i u m f l u o r o b o r a t e s h a s been d e s c r i b e d ,
a l t h o u g h n o a t t e m p t s were m a d e t o o p t i m i s e t h e y i e l d s o f i m i n e s o b t a i n e d f r o m i n t e r m e d i a t e imminium f l u o r o b o r a t e s a l t s .
1,3-Di-
i m i n o i s o i n d o l i n e s c a n b e p r e p a r e d f r o m 2 - c y a n o b e n z a l d e h y d e v i a N-
(2-cyanobenzy1idene)anilines b y r e a c t i o n o f t h e l a t t e r w i t h a r n i n e s and elemental sulphur i n l i q u i d S y n t h e s e s of h i g h l y f u n c t i o n a l i s e d i m i n e s c o n t i n u e t o b e reported.
N-Acylation
a l k y l N-acylimidates N-Acylimines
of a l k y l i m i d a t e h y d r o c h l o r i d e s t o a f f o r d 484
h a s been accomplished w i t h triethylarnine.
h a v e b e e n p r e p a r e d f r o m m e t h y l t r i c h l o r o p y r u v a t e , by
r e a c t i o n w i t h a m i d e s , c h l o r i n a t i o n a n d t r e a t m e n t of t h e r e s u l t i n g a - c h l o r o a c y l a m i n e w i t h t r i e t h y l a m i n e . 485
of m e t h y l p h e n y l g l y o x y l a t e were a c h i e v e d
Syntheses of g-acylamines
via
treatment of phenyl-
g l y c i n e m e t h y l e s t e r w i t h t e r t - b u t y l h y p o c h l o r i t e or b y d i r e c t e s t e r s w i t h N B S . 486 T r e a t dehydrogenation of !-acylphenylglycine ment o f t h i o c a r b a m y l p h o s p h i n e s w i t h n - b u t y l - l i t h i u m
f o l l o w e d by
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
299
0
L
R-
S R
O f M S -Je
N‘+
But N Me2 (67)
(66)
R = X = Y =
(68)
P h , 4 - M e C 6 H 4 , 4-CIC6H4Me, E t 2 N , or Me2N S M e , S E t , S 8 u t , or SPh NMe20r OEt
CI
1
CI
HO N ‘
I
\
iiil
C(
I
HO ‘N-Pd-
R
I
PY
M
;
HO N‘
R’
R3
Reagents : i, Na2PdClq. NaOAc,EtOH
- Po“’ vii,viii
ii, P P h 3 ; iii. p y i v , A c 2 0 , p y
R3
;
v.Pb(OAc)&;
vi, NaBH&; v i i , P b ( O A c ) & , ACOH : v i i i , NaBHL, 1N-NaOH; i x , C12. CC14;
x , NaCNBH3
;
x i , NaCNBDj , M t O H - T H F
S c h e m e 45
300
General and Synthetic Methods /
a d d i t i o n of a n a l k y l h a l i d e g a v e some p h o s p h i n o t h i o i m i n o e s t e r s . 487 M i c h a e l - t y p e a l k y l a t i o n s of c h i r a l i m i n e s h a v e f a c i l i t a t e d e n a n t i o s e l e c t i v e s y n t h e s i s of m o l e c u l e s c o n t a i n i n g q u a t e r n a r y c a r b o n c e n t r e s . 488
r e a g e n t ( 6 7 ) was u s e d f o r t h e
The a - s i l y l i m i n e
v i n y l o g a t i o n of a l d e h y d e s , 4 8 9 a n d ( 6 8 ) was r e p o r t e d a s t h e f i r s t s t a b l e s i l a k e t i m i n e t o be i s o l a t e d .490
13 O x i m e s Reductions of n i t r o o l e f i n s have served as a most u s e f u l s o u r c e of oximes.
R e d u c t i o n w i t h s o d i u m s t a n n i t e ( f r o m a q u e o u s SnC12 a n d
a q u e o u s NaOH) ,"I
a n d c h r o m i u m ( 11) c h l o r i d e 4 9 2 g a v e g o o d y i e l d s o f
o x i m e s w h i l s t u s e of SnC12 i n t h e p r e s e n c e o f a n a l c o h o l o r t h i o l g a v e h i g h y i e l d s of t h e c o r r e s p o n d i n g a - a l k o x y o x i m e s r e s p e c t i v e l y . 493
and a-alkylthio-
The l a t t e r compounds c o u l d a l s o b e
p r e p a r e d by m e t a l l a t i o n of s a t u r a t e d o x i m e s w i t h l i t h i u m d i i s o p r o p y l a m i d e , f o l l o w e d by r e a c t i o n of t h e r e s u l t a n t 2 , C - d i a n i o n d i p h e n y l d i s u l p h i d e .335 s i l y l a t e d ketooximes
S i l y l a t i o n of a - k e t o o x i m e s
(u. no s i l y l a t i o n
t o yield
with
0-
of t h e k e t o n e f u n c t i o n )
h a s b e e n a c h i e v e d u s i n g m i x t u r e s of z i n c c h l o r i d e and t r i e t h y l s i l a n e i n dioxane a t I O O ~ C . ~ ~ ~ a-Methyl groups of oximes could be f u n c t i o n a l i s e d through cyclop a l l a d a t i o n r e a c t i o n s i n v o l v i n g s o d i u m t e t r a c h l o r o p a l l a d a t e . 4 9 5 '496 T h u s a v a r i e t y of B - f u n c t i o n a l i s e d
p r o d u c t s c o u l d be i s o l a t e d i n
p r e p a r a t i v e l y u s e f u l amounts (Scheme 4 5 ) .
O-Aryloximes c a n b e p r e p a r e d
f o r m a t i o n of a r e n e t r i c a r b o n y l
c h r o m i u m ( 0 ) c o m p l e x e s f o l l o w e d by r e a c t i o n u n d e r p h a s e - t r a n s f e r c o n d i t i o n s (KOH,
tetra-octylammonium
bromide) w i t h oximes and sub-
s e q u e n t d e c o m p l e x a t i o n w i t h i o d i n e . 497 A d d i t i o n s of o x i m e s t o b u t y l v i n y l e t h e r l e d t o c - ( l - b u t o x y e t h y l ) o x i m e s . 498 Q u i n o n e m o n o o x i m e s r e s u l t e d f r o m p h o t o l y s e s of e q u i m o l a r a m o u n t s i n d i o x a n e . 499
of p h e n o l s a n d 2 - n i t r o s o d i m e t h y l a m i n e
S y n t h e s i s of a l d o n o h y d r o x i m i n o l a c t o n e s
via
oxidations of sugar
o x i m e s h a s b e e n r e p ~ r t e d . ~ " T h e o x i d a t i o n s were e f f e c t e d by manganese d i o x i d e , m e r c u r y ( I 1 ) acetate and oxygen i n t h e p r e s e n c e of c u p r o u s c h l o r i d e - p y r i d i n e .
Determination of t h e configuration
o f t h e o x i d a t i o n p r o d u c t s was a l s o d e s c r i b e d .
2,3-Dioximinopiperazines were f o r m e d i n a d d i t i o n s of 1,2d i a m i n e s t o d i c h l o r o g l y o x i m e i n m e t h a n o l . 50
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
301
14 Carbodi-imides Carbodi-imides have been obtained from thioureas upon treatment with both di-2-pyridylthionocarbonate and 4-dimethylamino~ acetonitrile. pyridine502 and 2 , 4 - d i c h l o r 0 - 5 - n i t r o p y r i m i d i n e ~ ~in Carbodi-imides also resulted from photolyses of hJ4-substituted phenyl t et razole th ione s 5 0
.
15 Azides and Diazo-compounds
As discussed above reductions of azides can provide access to both amines and amino-alcohols. The latter is particularly important in the carbohydrate area where classical methods of azide formation by displacements of halides and ~ u l p h o n a t e s ~plus ~ - ~ additions ~ to epoxides can all be readily achieved. It has been shown that allylic, benzylic, and tertiary alkyl halides may be substituted in good yields by using sodium azide and zinc chloride in benzene-pyridine solutions,504 and also that allenic azides can be prepared f r o m the corresponding halides and t r i b u t y l h e x a d e c y l p h o s p h o n i u m azide. 505 Displacement of a primary bromide, derived from acidic cleavage of an oxetane, by azide anion featured in a report concerning the synthesis of azido-derivatives of pentaerythritol .506 Epoxide openings performed with azidotrimethylsilane and diethylaluminium fluoride in dichloromethane afforded 3-azido-1,2diols with good stereo- and regio-selectivities (C3-N3:C2-N3 83:17 to 98:2), the latter improving both with increasing substrate:azide ratio and with increasing azide:Lewis acid ratio up to 1:2.507 Thus optimum conditions were substrate:azide:Lewis acid = 1:2:4. In combination with methanol, azidotrimethylsilane was used to generate hydrazoic acid in situ, and this in turn was responsible for ring opening of chiral epoxides derived from the tartaric acids.34 The addition of azide ion to benzene oxide was also reinvestigated . 5 0 8 Displacements of carbohydrate secondary tosylates have been employed in the synthesis of 3,4-diazido-3,4-dideoxy-L-arabinose from D-arabinose, 509 whilst azide ion displacement of a vinyl tosylate allowed synthesis of 2-azidocarbapenems. 35 A new method for introduction of the azido group into sugars has been developed. It involves displacement of cyclic sulphites by N3- in dipolar aprotic solvents, with the sulphites derived from
302
General and Synthetic Methods
s u g a r - d i o l s on r e a c t i o n w i t h t h i o n y l c h l o r i d e a n d p y r i d i n e . 51 G l y c o s y l a z i d e s w e r e o b t a i n e d o n t r e a t m e n t of s u g a r p e r a c e t a t e s w i t h a z i d o t r i r n e t h y l s i l a n e and t i n t e t r a c h l o r i d e i n d i c h l o r o m e t h a n e .51 Baker‘s y e a s t r e d u c t i o n of e t h y l 4-azido-3-oxobutyrate
gave t h e
corresponding hydroxyester with high o p t i c a l purity.512 I n t h e h e t e r o c y c l i c area t h e p r e p a r a t i o n o f g-azidoamino-acridine
from t h e 9 - c h l o r o - d e r i v a t i v e
,2 9
a n d t h e n 9-
a n d t h e s y n t h e s i s of
6 - a z i d o p u r i n e s from N-(6-purinyl ) p y r i d i n i u m s a l t s ? ’
were
r e p r e s e n t a t i v e of p r o c e d u r e s employed f o r t h e i n t r o d u c t i o n o f t h e azido group.
E l s e w h e r e t r e a t m e n t o f cyanimidothiocarboxylates w i t h
5-aminotetrazole
l e d t o t r i a z i n o t e t r a z o l e s which r e a r r a n g e d t o
afford a ~ i d o - s - t r i a z i n e s . ~ ’ ~ v i c - D i a z i d e s were o b t a i n e d a f t e r t r e a t m e n t of o l e f i n s w i t h -e x c e s s sodium a z i d e and m a n g a n e s e ( I I 1 ) a c e t a t e i n g l a c i a l a c e t i c a c i d [Mn O ( O A c ) 7 ( H O A c ) . 5 H 2 0 1 ( S c h e m e 4 6 ) . I o 4
Y i e l d s o b t a i n e d by
3
t h i s p r o c e d u r e w e r e f o u n d t o be h i g h l y d e p e n d e n t on t h e c o n c e n t r a t i o n s of t h e r e a c t a n t s . P r e p a r a t i o n of a-azidocinnamates h y d e s and a z i d o - a c e t a t e s
by c o n d e n s a t i o n o f b e n z a l d e -
under t h e i n f l u e n c e of a l k o x i d e i o n s h a s
been r e p o r t e d . The c l a s s i c a l B a m f o r d - S t e v e n s
preparation of a,B-unsaturated
diazo-compounds h a s been extended t o i n c l u d e t h e s y n t h e s i s o f adiazophosphonates bearing a 1,3-diene
u n i t .516
h a l i d e s w e r e c o n v e r t e d , by M i c h a e l i s - A r b u s o v methyl phosphite,
t o a-oxophosphonates
Dienoic a c i d
reactions with tri-
from w h i c h t h e c o r r e s p o n d i n g
t o s y l h y d r a z o n e s w e r e d e r i v e d ; b a s e t r e a t m e n t of t h e t o s y l h y d r a z o n e s t h e n g a v e t h e d e s i r e d compounds (Scheme 4 7 ) .
The D i e l s - A l d e r
r e a c t i v i t y o f t h e s e compounds was a l s o i n v e s t i g a t e d .
4-Phenyl-3;-
ll2,4-triazole-3,5(4K)-dione e n t e r e d i n t o a [ 4 + 2 1 c y c l o a d d i t i o n w i t h t h e d i e n e m o i e t y t o y i e l d tetrahydrotriazolopyridazines, w h i l e dimethyl acetylenedicarboxylate reacted exclusively with the diazo dipole. E l e c t r o p h i l i c d i a z o a l k a n e s u b s t i t u t i o n h a s b e e n r e v i e w e d ,5 1 7 a n d s e v e r a l examples of t h e r e a c t i o n have appeared i n t h e l i t e r a t u r e . T h e s e i n c l u d e s y n t h e s i s o f 7-diazomethylcycloheptatrienes
from
s i l v e r ( d i a z o m e t h y l ) p h o s p h o r y l compounds , 5 1 8 p r e p a r a t i o n o f
(tri-
methylsilyl)[bis(diisopropylamino)phosphinyl]diazomethane from t h e l i t h i u m s a l t o f trimethylsilyldiazomethane a n d c h l o r o b i s ( d i i s o propy1amino)phosphine
,519 C 1 - d i a m i n o m e t h y l a t i o n w i t h o r t h o -
f o r m a m i d e s , 520 c o n v e r s i o n of e t h y l d i a z o i c e t a t e t o e t h y l t r i e t h y l silyldiazoacetate using i n s i t u generated t r i e t h y l s i l y l perchlorate
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
RCH=CH
303
2
+
Mn(I1)
+
RCH-CHZN3
N3-
I N3
S c h e m e 46
0
R-+lfc'
II
I c
0
0
p%!2
0
It R--lfp=oMe N2
OMe
...
*
Ill
Reagents : i, P ( O M e I 3 , P h H ; i i , H 2 N N H T s . H C I . M e O H ; i i i , N a 2 C 0 3 (aq.)
S c h e m e 47
General and Synthetic Methods
304
(trityl perchlorate/triethylsilane) ,521 and preparation o f silylated derivatives of l-aryl ( o r heteraryl-)-2-diazo-l-ethanones by reaction with trialkylsilyl trifluoromethanesulphonates in diethyl ether .522 The silylated a-diazo-compounds formed in the last reaction rearranged at o r above room temperature to afford 1 aryl-2-silyloxyalkynes. Reactions of alkene diazonium salts with primary amines led to the isolation of diazoimines .523 Oxidation of 3-aryl-l-( tetrazol5'-yl)-triazines with lead tetraacetate resulted in a fragmentation producing aryl diazocyanides .524 Trifluoromethanesulphonic anhydride effected transformation of o- and p-quinonoid diazoketones to trifluoromethanesulphonyloxyarene diazonium salts in dichloromethane solution .525 Similar heteroarene derivatives could also be obtained by this method although in lower yields. The products were found to be rapidly hydrolysed, and thus azo-coupling reactions required use of nonaqueous solvent systems.
16 Azo- and Azoxy-compounds Treatment of aromatic amines with sodium nitrite and hydrochloric acid followed by addition of an amino-alcohol plus formaldehyde resulted in formation of 2-azo-I ,3-oxazines and -0xazo1idines .526 Base-induced fragmentations of 3-amino-l-ary1-3~,3'-dimethylpyrazolin-4-spiro-2'-oxiran-5-ones afforded methyl 3-amino-3arylazopropenoates. 527 The reaction of nitrosobenzene with alkylamines has been examined as a potential source of (phenylazolalkanes, with moderate yields of the desired products having been obtained in some cases. '28 Studies concerning the activating effect of arylazo groups on olefins have been recorded and these have afforded a convenient synthesis of 2,2-diamino- from 2,2-dichloro-enazo compounds and arnines. 529 Addition and cyclisation reactions of 8 -chloro-azo olef ins were also investigated. 530
17 Isocyanates, Thiocyanates, Isothiocyanates, Selenocyanates, and Isoselenocyanates Isocyanates have been obtained by treatment of nitrile oxides with trifluoroacetic acid531 and also, in high yield, by reactions of
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
305
amines with carbon disulphide and benzyl chloroformate in the presence of sodium hydroxide (Scheme 48) .532 An attempt to synthesise 2,2,2-trinitroethyl isocyanate was successfully completed, and the methodology thus established was developed into a general isocyanate preparation (Scheme 49) .533 Aromatic acyl isocyanates have been isolated from thermolyses of 1 , 1 -diacyl-3,3-dialkylureas. 534 Trichloroacetylisocyanate underwent dipolar cycloadditions with nitrile oxides to form 2-isocyanato-2-trichloromethyl-I , 3 , 4-dioxazoles .535 Acetylative cleavages of (arylsulphony1)ureas afforded isocyanates in addition to N-acetylarenesulphonamides. 5 3 6 Methylthiomethyl-, phenylthiomethyl- and bis(pheny1thio)methylisocyanates were prepared from the corresponding thioacetic acid derivatives through chlorination followed by acyl azide formation and thermal rearrangement .537 The same starting materials afforded methylthioacetyl- and phenylthioacetyl-isothiocyanates by reaction of their acyl halide derivatives with lead thiocyanate in refluxing benzene. Isothiocyanates have been obtained directly from primary amines by reaction with a single equivalent of di-2-pyridylthionoformation of dithiocarbamates and their subcarbonate ,502 and sequent reaction with 2,4-dichloro-5-nitropyrimidine in acetonitrile .297 Mercury(I1) thiocyanate has been found to catalyze addition of thiocyanic acid to alkynes, the structure of which apparently determines the nature of the products. Vinyl isothiocyanates were obtained from symmetrically disubstituted alkynes whereas vinyl thiocyanates resulted specifically from additions to terminal acetylenes. 5 38 The synthesis o f (E)-and (Z)-l-thiocyanatobuta-ll3-dienes has been reported along with a description of their Diels-Alder reactions .539 In the latter 3-isothiocyanatocyclohexenes were obtained after [3,31 sigmatropic rearrangement of the initial thiocyanate adducts .539 Glycosyl isoselenocyanates - a novel class of sugar derivatives were prepared, in reasonable yields, by treatment of the corresponding glycosyl isocyanides with elemental selenium in the presence of triethylamine .540
-
General and Synthetic Methods
306
RNH2
+
R -NH
A
c-u,+
I
L
cs2
-
RN=C=O
Ph
R e a g e n t s : i , NaOH
, H20
;
ii, PhCH20COCI
S c h e m e 48
R e a g e n t s : i. R N H 2
;
i i , P h S C l ; iii,
A or b a s e
Scheme 4 9
+ CS, +
PhCH20H
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
307
18 Nitrones Recently, increasing synthetic use of nitrones has been made. Such topics have been the subject of a review.541 Of particular importance are the cycloaddition reactions of nitrones. The regioand stereo-chemistry of intramolecular l-alkenylnitrone additions have been studied,542 as has the regiochemistry of intramolecular cycloadditions of 5- and 6-alkenylnitrones . 5 4 3 Nitrones have been obtained by alkylation of c-trimethylsilyloximes with either trialkyloxonium tetrafluoroborates or alkyl triflates in dichloromethane solution .544 The same research group also prepared medium-ring cyclic nitrones by heterolytic fragmentation reactions of bicyclic y-l-hydroxylaminosulphonates. This enabled conversions of decahydroquinolines to perhydroazulenes to be performed. 5 4 5 N-Methylnitrones have been generated in excellent yield by reacting carbonyl compounds with l-methyl-N,g-bis(trimethylsilyl )hydroxylamine . 5 4 6 u-Aroyl-l-phenylnitrones have been obtained upon silver oxide oxidation of adducts derived from silyl enol ethers and nitrosobenzene .547 Addition of 2-methyl-2-nitropropane and activated zinc dust to a cold ethanolic solution of a p-substituted benzaldehyde afforded derivatives of phenyl-tertbutylnitrone in high yields . 5 4 a Oxidations of hydroxylamines with Pb02 in methylene dichloride afforded 1,4-dinitrones-dehydrodimers of vinylaminyl oxides. 549 The latter species presumably resulted from isomerisation of initially formed mono-nitrones to vinyl-substituted hydroxylamines followed by abstraction of a hydrogen radical. 1 9 Nitrates and Nitrites
Nitrates have been formed by reaction of tetra-n-butylammonium nitrate550’ 5 5 1 or the nitrate form of Amberlyst A-26 resin550 with various sulphonate esters. The former report550 also documented hydrolyses of the nitrates thus effecting a three-step inversion procedure for alcohols, whilst the second report55 consisted of a more general treatment of preparation of sugar nitrates by displacements of trifluoromethanesulphonates. Addition of mercury(I1) nitrate to olefins in the presence of halogens afforded a-halonitrate derivatives. 552 It has been suggested that the active species in the ceric
308
General and Synthetic Methods
ammonium n i t r a t e - i n d u c e d p h o t o l y t i c n i t r o o x y l a t i o n of a l k y l b e n z e n e s is n i t r a t e r a d i c a l and f u r t h e r t h a t t h i s s p e c i e s a c t s most probably as a o n e - e l e c t r o n
o x i d a n t .553
T h e n i t r o s a t i o n o f o r g a n i c h y d r o p e r o x i d e s by n i t r o g e n d i o x i d e and d i n i t r o g e n t e t r a o x i d e has been s t u d i e d . 5 5 4
Cumyl
and tert-
b u t y l h y d r o p e r o x i d e s reacted r e a d i l y i n o r g a n i c s o l v e n t s g i v i n g n i t r a t e s a s t h e major p r o d u c t s a l o n g w i t h s m a l l e r a m o u n t s of t h e corresponding n i t r i t e s p l u s v a r i o u s o t h e r minor products. References 1
2 3 4 5 6 7 8 9
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599. 18 19 20 21 22 23 24 25 26 27 28 29 30 31
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32 33
N.Knouzi, M.Vaultier, and R.Carrik, Bull. SOC. Chim. Fr., 1985, 815. A.Koziara, K.Osowska-Pacewicka, S.Zawadzki, and A.Zwierzak, Synthesis, 1985,
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S.Saito, N.Bunya, M.Inaba, T.Moriwake, and S.Torii, Tetrahedron Lett., 1985, 26, 5309. -
J.C.Chabala, B.G.Christensen, R.W.Ratcliffe, and M.F.Woods, Tetrahedron
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5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups 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 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81
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26,
c,
26,
2,
26,
-
118,
26,
26,
26,
26,
.
26,
26,
-
26,
-
26, 26,
General and Synthetic Methods
3 10 82 83 84 85 86 87 88
Y.Yamamoto, T-Komatsu, and K-Maruyana, J. Chem. SOC., Chem. Commun., 1985, 814. G.E.Keck and E.J.Enholm, J. Org. Chem., 1985, 50, 146. S.S.Nikam and K.K.Wang, J. Org. Chem., 1985, 50, 2193. 668. K.Maruoka and H.Yamamoto, Angew. Chem., Int. Ed. Engl., 1985, I.A.Cliffe, R.Crossley, and R.G.Shepherd, Synthesis, 1985, 1138. E.J.Corey and A.W.Gross, J. Org. Chem., 1985, 50, 5391. H.Takahashi, Y.Chida, K.Higashiyama, and H.Onishi, Chem. Pharm. Bull., 1985, 33. 4662. J.H.Gorvin, J. Chem. S O C . , Chem. Commun., 1985, 238. G.W.Rewcastle acd W.A.Denny, Synthesis, 1985, 220. J.Barluenga, P. J.Campos, J.Lbpez-Prado, and G.Asensio, Synthesis, 1985, 1125. S.Ram and R.E.Ehrenkaufer, Tetrahedron Lett., 1985, 26, 5367. V.Partali, S.Jolidon, and H.-J.Hansen, Helv. Chim. Acta, 1985, 68, 1952. 6197. D.H. R.Barton, A.Fekih, and X. Lusinchi, Tetrahedron Lett., 1985, N.Tokitoh and R.Okazaki, Chem. Lett., 1985, 1517. 187. A.Nilsson and R-Carlson, Acta Chem. Scand., Ser. B, 1985, 2, 181. R.Carlson and A.Nilsson, Acta Chem. Scand., Ser. B, 1985, 3, Y.C.Hwang, K.Chu, and F.W.Fowler, J. Org. Chem., 1985, 50, 3885. M.Nakano and Y.Sato, J. Chem. SOC., Chem. Commun., 1985, 1684. J.-M.Fang and C.-C.Yang, J. Chem. S O C . , Chem. Commun., 1985, 1356. K.A.M. El-Bayouki, F.E.Nielsen, and E.B. Pedersen, Liebigs Ann. Chem., 1985, 1223. J.Hung and L.M.Werbe1, Synthesis, 1985, 80. S.-H.Jung and H.Kohn, J. Org. Chem., 1985, 50, 2931. W.E.Fristad, T.A.Brandvold, J. R.Peterson, and S.R.Thompson, J. Org. Chem., 1985, 50, 3647. J.Altman, N.Shoef, M.Wilchek, and A.Warshawsky, J. Chem. SOC., Chem. Cornnun., 1985, 1133. M.Egli, L.Hoesch, and A.S.Dreiding, Helv. Chim. Acta, 1985, 68, 220. E.G.Knapick, P.Ander, and J. A.Hirsch, Synthesis, 1985, 58. F.Sannicol6, Tetrahedron Lett ., 1985, 6 , 119. S.H.Pine, R.J.Pettit, G.D.Geib, S.G.Cruz, C.H.Gallego, T.Tijerina, and R.D.Pine, J. Org. Chem., 1985, 50, 1212. L.F.Cannizzo and R.H.Grubbs, J. Org. Chem., 1985, 50, 2316. P.F.Hudrlik, A.M.Hudrlik, and A.K.Kulkarni, Tetrahedron Lett., 1985, 26, 139. S.Torii, T.Inokuchi, and M.Kubota, J. Org. Chem., 1985, 50, 4157. Y.Ito, N.Sawamura, K.Kominami, and T.Saegusa, Tetrahedron Lett., 1985, 5303. 3863. C.Stetin, B.De Jasa, and J.-C.Pommier, J. Org. Chem., 1985, K.Tani , T.Yamagata, Y .Tatsunof Y .Yamagata, K.-i .Tomitat S.A.Kutagawa, 217. H.Kumobayashi, and S.Otsuka, Angew. Chem., Int. Ed. Engl., 1985, J.Barluenga, F.Aznar, R.Liz, and M.-P.Caba1, J. Chem. SOC., Chem. Commun., 1985, 1375. P.K&hritz, R-Sattler, and J-Liebscher, J. Prakt. Chem., 1985, 327, 567. 5347. R.Epsztein and N.Le Goff, Tetrahedron, 1985, J.Barluenga, J . Jard&, .-dna Org. Chem., 1985, 802. R.A.Abramovitch, B.Mavunke1, J.R.Stowers, M.Wegrzyn, and C.Riche, J. Chem. Soc., Chem. Commun., 1985, 845. L.I.Vereshchagin, L.P.Kirillova, G.M.Luzgina, and G.A.Gareev, Zhur. Org. Khim., 1985, fi, 886. m r s c h k e , A.PIhller, and E.Schmitz, J. Prakt. Chem., 1985, 327, 893. F.Scavo and P.Helquist, Tetrahedron Lett., 1985, 2603. M.Maruoka and T-Yamamoto, J. Chem. S O C . , Chem. Commun., 1985, 1299. 5061. M.P.Cava and M.I.Levinson, Tetrahedron, 1985, T-Tokomitsu and T.Hayashi, J. Org. Chem., 1985, 50, 1547. J.Barluenga, F-Lopez, and F.Palacios, J. Chem. Res. ( S f ,1985, 211. E.E.Aboujaoude, N.Collignon, and P.Savignac, Tetrahedron, 1985, 427. A.A.Sobanov, I.V.Bakhtiyarova, M.G.Zimin, and A.N.Pudovik, Zh. Obshch. Khim., 1985, 55, 1187.
e,
~~
89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106
107 108 109 110 111
112 113 114 115 116 117 118
119 120 121 122 123 124 125 126 127 128 129
26,
26,
so,
2,
5,
~
so,
26,
5,
5,
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups 130 131 132
133 134 135 136 137 138 139 140
141 142 143 144 145 146
147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174
311
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313
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223 224 225 226
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General and Synthetic Methods
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5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
315
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I
-
~
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~
General and Synthetic Methods
316 369 370 37 1 372 373 374 375 376 377 378 37 9 380 38 1 38 2 38 3 384 38 5 386 38 7 38 8 389 390 39 1 392 39 3 39 4 39 5 39 6 39 7 398 39 9 40 0 40 1 402 403 404 405 40 6 40 7 408 409 410 41 1 412 413 414 41 5 416
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41,
3,
c,
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417 41 8 419 420 42 1 42 2
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General and Synthetic Methods
318 467 468
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26,
473 474 475 476 477 478 479 480
1181 482 483 484 485 486 487 488 489 490 49 1 492 493 494 495 496 497 498 499 500 50 1 502 503 504 505 506 507 508 509 510 51 1 512
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211,
5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups
319
51 3 R.W.Adamiak, E-Biala, and B.Skalski, Angew. Chem., Int. Ed. Engl., 1985, 211, 1054. 51 4 W.Ried, G.Beller, B.KUmbe1, and D.Kuhnt, Synthesis, 1985, 31 1. 51 5 D.Knitte1, Synthesis, 1985, 186. 516 W.Theis and M.Regitz, Tetrahedron, 1985, 41, 2625. 9 8 5 , :965 51 7 J.Fink and M.Regitz, S 51 8 W.Bethauser, B.Weber, H.Heydt, and M.Regitz, Chem. Ber., 1985, 118,1315. 51 9 A.Baceiredo, G.Bertrand, and G.Sicard, J. Am. Chem. S O C . , 1985, 107,4781 520 M.Regitz and W.Schoder, Synthesis, 1985, 178. 521 C.S.Wilcox and R.E.Babston, Synthesis, 1985, 941. 522 G.Maas and R.BrUckmann, J. Org. Chem., 1985, 50, 2802. 523 R.W.Saalfrank and B.Weiss, Chem. Ber., 1985, 118,2626. 524 R.N.Butler and D.P.Shelly, Tetrahedron Lett., 1985, 26, 3401. 525 G.Maas and A-Tretter, Liebigs Ann. Chem., 1985, 1866, 526 R.J.LaFrance, H.W.Manning, and K.Vaughan, J. Org. Chem., 1985, 50, 2229. 527 K.Kirschke, A.MOller and E.Schmitz, J. Prakt. Chem., 1985, 327, 893. 528 Y.M.Wu, L.Y.Ho, and C.H.Cheng, J. Org. Chem., 1985, 50, 392529 T.L.Gilchrist , J. A. Stevens, and B. Parton, J. Chem. Soc., Perkin Trans. 1 , 1985, 1737. 530 T.L.Gilchrist , J. A.Stevens, and B. Parton, J. Chem. S O C . , Perkin Trans. 1 , 1985, 1741. 53 1 G.A.Taylor, J. Chem. S O C . , Perkin Trans. 1 , 1985, 1181. 532 A.Danopoulos, M.Avouri, and S.Paraskewas, Synthesis, 1985, 682. 5879. 533 M.E.Sitzmann and W.H.Gilligan, J. Org. Chem., 1985, 534 W.Schroth, R.Krieg, H.Kluge, and M.Gubler, Z. Chem., 1985, 25, 398. 535 A.V.Prosyanik, P.N.Belov, N.Yu Kol ‘tsov, and V. I.Markov, Zhur . Org. Khim., 1985, 911. 536 H.T.Nagasawa, W.E.Smith, C.-H.Kwon, and D.J.W.Goon, J. Org. Chem., 1985, 50, 4993. 537 Y.Ohshiro, N.Ando, M.Komatsu, and T.Ogawa, Synthesis, 1985, 276. 801. 538 M.Giffard, J.Cousseau, L.Gouin, and M.-R.Crahe, Tetrahedron, 1985, 5, 539 S.Huber, P.Stamouli, and R-Neier, J. Chem. S O C . , Chem. Commun., 1985, 533. 4781. 540 Z.J.Witczak, Tetrahedron, 1985, 5, 541 N.Balasubramanian, Org. Prep. Proced. Int., 1985, 17,23. 542 W.Oppolzer, S.Siles, R.L.Snowden, B.H.Bakker, and M.Petrzilka, Tetrahedron, 1985, 41, 3497. 543 S.W.Baldwin, J.D.Wilson, and J.Aubi?, J. Org. Chem., 1985, 50, 4432. N.A.LeBe1 and N.Balasubramanian, Tetrahedron Lett., 1985, 26, 4331. 544 545 N.A.LeBe1 and B.W.Caprathe, J. Org. Chem., 1985, 50, 3938. 5913. 546 J.A.Robl and J.R.Hwu, J. Org. Chem., 1985, 547 T.Sasaki, K.Mori, and M.Ohno, Synthesis, 1985, 279. 54a R.Huie and W.R.Cherry, J. Org. Chem., 1985, 50, 1531. 1105. 549 H.G.Aurich, M.Schmidt, and T-Schwerzel, Chem. Ber., 1985, 9, 550 G.Cainelli, F.Manescalchi, G.Martelli, M.Panunzio, and L.Plessi, Tetrahedron Lett., 1985, 26, 3369. 551 N.Afza, A.Malik, F.Latif, and W-Voelter, Liebigs Ann. Chem., 1985, 1929. J.Barluenga, J.M.Marthez-Gallo, C.Nhjera, and M.Yus, J. Chem. S o c . , Chem. 552 Commun., 1985, 1422. 553 E.Baciocchi, T.Del Giacco, C.Rol, and G.V.Sebastiani, Tetrahedron Lett., 1985. 26, 541. 554 W.A.PrGr, L.Castle, and D.F.Church, J. Am. Chem. S O C . , 1985, 107,211. ~
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Organometallics in Synthesis BY S. G. DAVIES AND T. GALLAGHER Part I:
The Transition Elements
BY S. G. DAVIES 1 Introduction The format o f this Report is similar to previous years. Several books on general organotransition metal chemistry have appeared. '2' Particularly noteworthy is the excellent and comprehensive review of palladium reagents in organic synthesis, containing many detailed experimental procedures, by Heck.4 Topics reviewed this year include various applications of cyclopalladated compounds to organic synthesis, n-allylnickel halides as selective reagents in organic synthesis ,€I reactions of some transition-metal diene complexes , the cocyclization of alkynes and organonitriles using organocobalt complexes to achieve the synthesis o f pyridines, the use of various transition-metal complexes to promote dcuble asymmetric synthesis, the Pauson-Khand reaction for the synthesis of cyclopentenones, l o and metal-promoted syntheses of a-methylene-y-butyrolactones. 1 1 2 Reduction The hydrogenatiorl of a-(hydroxyalky1)acrylate esters in the presence of cationic biphosphine rhodium catalysts occurs with high anti selectivity (Scheme 1 ) . l 2 Asymmetric catalysts derived from the chiral biphosphines dipamp and chiraphos give up to 7 : l discrimination between the enantiomers of a-(hydroxyalky1)acrylate esters, allowing their kinetic resolution to be achieved with >90% e.e. at 70% conversion. Aromatic nitriles are reduced to N,N-di(trimethylsily1)benzylamines by trimethylsilane in the presence of [Co,(CO) 8 3 as catalyst (Scheme 2),l 3 and the reduction of imidoyl chlorides by hydrogen is catalysed by [(PPh3I2PdCl2] in the presence of triethylamine (Scheme 3 ) . Alkylazides are reduced at 20 O C to the corresponding amines in good yields by KHFe(C0)4 under an atmosphere of carbon monoxide
320
For References see p. 352
322
General and Synthetic Methods
(Scheme
4). l 5
U n d e r t h e same c o n d i t i o n s b u t a t - 4 0
OC
acyl azides
are reduced t o amides. Reduction of t h e alcohol function of a c e t y l e n i c a l c o h o l s without a f f e c t i n g t h e t r i p l e b o n d may b e a c h i e v e d b y t r e a t i n g t h e i r [CO,(CO)~]
complexes w i t h t r i f l u o r o a c e t i c a c i d and sodium boroThis
hydride and subsequently decomplexing w i t h f e r r i c n i t r a t e . l 6
method p r o v i d e s a u s e f u l s y n t h e s i s o f s e c o n d a r y a l k y l a c e t y l e n e s ( S c h e m e 5).
F o r e x a m p l e b o t h 1 7 ~ -a n d 1 7 ~ - m e s t r a n o l g i v e 1 7 8 -
d i o x y m e s t r a n o l b y t h i s m e t h o d , c o n s i s t e n t w i t h a common m e t a l s t a b i l i z e d carbonium ion intermediate.
3 Oxidation Cyanohydrins are e f f i c i e n t l y oxidized t o t h e corresponding a c y l c y a n i d e s by BuLOOH i n t h e p r e s e n c e o f c a t a l y t i c a m o u n t s o f [ ( P P h 3 ) 3RuC121 ( S c h e m e 6 1. l 7
B e n z o y l c y a n i d e g e n e r a t e d i n t h i s way
smoothly benzoylates amines i n t h e presence o f a l c o h o l s (91-99%). Secondary amines are oxidized t o imines under similar mild conditions.
18
Cycloalkenes are converted i n t o ~ , B - u n s a t u r a t e dketones using B ~ ~ O O i Hn t h e p r e s e n c e o f c a t a l y t i c a m o u n t s o f [ c r ( c o ) 6 ] . ’ 9
Some
s e c o n d a r y a l c o h o l s h a v e been shown t o be i n e r t t o t h e s e o x i d i z i n g c o n d i t i o n s (Scheme 7 ) . C y c l o p a l l a d a t e d o x i m e s a r e o x i d i z e d by P b ( O A c ) 4 t o g i v e a f t e r NaBH4 r e d u c t i o n t h e c o r r e s p o n d i n g a c e t a t e s i n n e a r q u a n t i t a t i v e
y i e l d (Scheme 8 ) . 2 0
T h u s s e l e c t i v e o x i d a t i o n of t h e u n a c t i v a t e d a-
m e t h y l g r o u p o f l i p a n o n e o x i m e may b e a c h i e v e d
cyclopalladation
and s u b s e q u e n t o x i d a t i o n t o g i v e t h e 2 3 - a c e t o x y - d e r i v a t i v e yield.
i n 90%
21
4 Rearrangements and Isomerizations A l l y l a m i n e s a r e i s o m e r i z e d by c a t i o n i c r h o d i u m c o m p l e x e s t o t h e c o r r e s p o n d i n g E - e n a m i n e s . 22
U s i n g t h e c a t a l y s t [ R h ( R - b i n a p ) (COD) I +
containing t h e o p t i c a l l y pure biphosphine ligand 5-binap,
high
a s y m m e t r i c i n d u c t i o n i n t h i s i s o m e r i z a t i o n c a n b e a c h i e v e d (Scheme
9). 1,3-Diene
monoepoxides are rearranged t o a,B-unsaturated
i n t h e p r e s e n c e o f c a t a l y t i c a m o u n t s of [ ( P P h and t h e 3-aza-Cope
) RhH]
ketones
(Scheme l o ) , 23
3 4 r e a r r a n g e m e n t of N - a l l y l e n a m i n e s t o y , 6 -
u n s a t u r a t e d i m i n e s i s c a t a l y s e d by [ ( P h P ) P d ] i n t h e p r e s e n c e o f 3 4
323
6: Organometallics in Synthesis
OH
OH
I
I
-
OH
1
I
RZC-Z-CRZ
-
OH
-
R,C-=-CR,
I
ii,iii
I
RZCH-E-CHR2
46-85'10
CO,(CO)~
> 90 " l o R e a g e n t s : i;[Coif(CO)8
3 ; ii, CF3C02H, N a B H 4 ; iii, F e ( N O 3 I 3 . 9 H 2 0
Scheme
5
I
6 5 - 99"Io
R = a r y i or vinyl OH H
i, ii
Ph' N 2 O H
PhXCN
a
H
A
R e a g e n t s : i , B u t O O H , [ ( P h 3 P I 3 R u C L 2 ] ; ii,
Scheme
65 "lo
H N 2 o H
6
[CI-(CO)61
B ~ ~ O ~ H
HO
HO Scheme
9 9 "I0
7
324
General and Synthetic Methods
I , V , 11-IV
HO
Ac 0
69"lo OAc Reagents:
I,
Na2PdC14 ,NaOAc
i i , p y r ; iii, P b ( O A c I 4
Scheme
iv, NaBH4
;
L
N
E
v, Ac20
8
[ R h ( R- bina p ) (C 0 D) 3
&NEtz
;
-
'
____t
t
t
5 -99 "lo e.e. Scheme
9
Scheme
10
6: Organometallics in Synthesis
325
the co-catalyst trifluoroacetic acid (Scheme 1 1 ) ;24 whereas the corresponding thermal reactions require 170-250 OC , the catalysed isomerizations occur at 50-100 OC. I-Vinylcyclobutanols undergo ring expansion to 2-methylcyclopent-2-enones in the presence of catalytic amounts of [ ( PhCN l2PdCl2I and an excess of benzoquinone (Scheme 12). 25
Allylic acetates couple with dimethyl propargylmalonate anion in the presence of [(Ph P) Pdl to give Il6-enynes. In the presence of 3 4 [(g-toly13)P12Pd(OAc)2 these 1,6-enynes isomerize to Il4-dienes unless the l14-diene product would contain a trisubstituted olefin in which case Il3-dienes are obtained (Scheme 13) .26 1 ,3-Dienes are also obtained when the enyne contains an allylic oxygen substituent .27
5 Carbon-Carbon Bond Formation via Organometallic Electrophi1es.- 4,6-Isopropylidene-3-(trifluoroacety1)-D-glucal reacts with stabilized carbanions in the presence of catalytic amounts of bis(dibenzy1ideneacetone)Pd [(dba) Pdl and bis(dipheny1phosphino)ethane (dppe) to give the 2 corresponding B -C-glycosides (Scheme 14 1. 28 Aryl ketones may be converted into the corresponding benzylic compounds arenetricarbonylchromium chemistry
gem-dimethyl
(Scheme 15 1 . 29 Controlled polyfunctionalization of cycloheptene can be achieved via nucleophilic addition and subsequent decomplexation of cycloheptadiene molybdenum cationic complexes (Scheme 16). 30 via Organometallic Nucleophi1e.s.- Simple 2,3-dialkylated thian-4ones have been prepared using tandem organocopper conjugate addition-enolate alkylation reactions of 3-methoxycarbonyl-5,6dihydrothiin-4-one (Scheme 17). 3 1 This methodology has been applied to the synthesis of thiathromboxane analogues. 3-Substituted lithium cyclopentenolates, which are readily available via a conjugate addition of organocopper reagents to cyclopentenone, react with Z-allylic acetates in the presence of an excess of BEt3 and catalytic amounts of [(Ph P) Pd] to give trans2,3-disubstituted cyclopentanones (Scheme 18).33 Stereoselective Michael additions of organocopper reagents to the trans-crotonyl ester of the chiral auxiliary 10-sulphonamidoisonorborneol generates, after hydrolysis, B-substituted carboxylic
326
General and Synthetic Methods
a 2 elo
90 "lo
Reagent:
i , [ (PPh314Pd
I , c F 3 C 0 2 ~( c a t . ) Scheme
11
6 7 "lo
58 ' 1 0
Reagent
1,
[ ( P h C N ) 2 P d C 1 2 1( c a t 1, p - b e n z o q u i n o n e
Scheme
R
q
12
Meo2ccA -
i
OAc
Me0,C
-
R R+ OAc
OSi M e But
R
MeO,C Meozc=R
50 - 80 "lo
M eO,C
R
-q
91"lo
\os Reagents:
I,
[(Ph3PI1,Pd1, (Me02C12C(Na)CH2C = C H
Scheme
13
;
ii,
6: Organometallics in Synthesis
327
I , II
6 3 "lo Reagents
I,[
56 "lo
OCOCF, P d ( d b a I 2 J ,d p p e ,
11.
KCH (C02Me)2,
Scheme
111,
K+-
14
Cr (CO) 3
Cr KO), R e a g e n t s : i , [ C r (CO) 1; i i , M e L i ; iii, Me3AI , T i c [ & 6
Scheme
;
iv,
O2
15
c-V--
( J 4 c H ~ z p h
76 " l o
CH2C0, H Mo(C0) ,Cp R e a g e n t s : i , [ M o ( C 0 ) 6 ] , MeCN ; ii, LiC5H5 v, Na2HP04 ; v i , K O H ; vii, I 2
;
Scheme
/
C02Me
Mo(CO),Cp
iii, P h 3 C + B F i ; i v , NaCH (SO2Ph)CO2Me,
16
328
General and Synthetic Methods
0
bco2Me i - iii
I
4 9 "lo
iv
0
0
- GM v,vi,iii,vii
6 S i Me 2 B d
OH
88 "lo Reagents:
i , B u C u S M e 2 ; ii, CH2=CHCH2Br; iii, L i I , DMF, H 2 0 ; iv. Me2SCuCH=CHCH (OSiMe2But)C5HIli vi, Z-BrCH2CH=CH(CH2)3C02Me
Scheme 0
v, N a H
;
vii, a q . HF
;
17
OLi
0
88 OIo
90"10
R e a g e n t s : i , Li2Cu(CH= CH2I2CN; ii, Me3SiCl; iii, B u L i ; i v , 2 B E t 3 ; V,
Z-ACOCH2CH=CHEt
, [ ( Ph3P),+Pd
Scheme
R e a g e n t s : i, R C u ( R
= Pr, B u , v i n y l
3
18
or 2 - p r o p e n y l 1 ; ii, NaOH
Scheme
19
6: Organometallics in Synthesis
329 ^ ^
acids with high optical purity (Scheme 1 9 ) . ” 3-Alkyl-2,3-epoxy-acids undergo epoxide ring opening with lithium organocuprates (Scheme 20). 34 The regioselectivity is dependent on the epoxide geometry; cis-epoxides open at C-3 preferentially whereas trans-epoxides open at C-2. Organocuprates convert 4-acetoxy-2-azetidinone into 4-substituted-2-azetidinone (Scheme 21 ) .35 Stereoselective reactions of acyl ligands attached to the iron chiral auxiliary [(C H )Fe(CO)(PPh )] have been reported. Thus, 5 5 3 the aluminium enolate derived from the iron acetyl complex [(C H )Fe(CO)(PPh )COMe] functions a s a chiral acetate enolate 5 5 3 equivalent. Decomplexation of the resultant 0-hydroxyacyl complexes yields B-hydroxy-acids o r -esters (Scheme 22) . 3 6 The aluminium and copper enolates derived from [(C5H5)Fe(CO)(PPh )COEtl are 3 chiral propionate enolate equivalents which on reaction with aldehydes provide stereoselective syntheses of threo- and erythro-amethyl-0-hydroxy-acids respectively (Scheme 23). 37 The chiral copper propionate enolate complex also undergoes stereoselective addi.tions to symmetrical ketones. 3a a,B-Unsaturated acyl complexes of [(C H )Fe(CO),l undergo 5 5 Michael addition reactions with amines to give B-amino-acyl complexes which on oxidative decomplexation yield 0-lactams (Scheme 2 4 1 . ~ ~ The cis-crotonyl complex of [ ( C H )Fe(CO)(PPh ) ] undergoes 5 5 3 exclusive deprotonation with BuLi to form a dienolate which undergoes stereoselective a-methylation. 40 In contrast the transcrotonyl complex undergoes stereoselective tandem Michael additions and subsequent alkylation reactions where both the nucleophile and electrophile add to the same face of the trans-crotonyl ligand the case where the nucleophile is lithium (Scheme ~ 5 ) ~ In ~ ’ benzylamide decomplexation of the methylated products gives the cis-3,4-dimethyl-B-lactam. 41 In the presence of Et2A1C1 the lithium enolate derived from the iron acetyl complex [(C H )Fe(CO)(PPh 5 5 3 )COMe] discriminates between
the enantiomers of monosubstituted epoxides, e.g. propylene oxide, to provide essenti.ally only one product (Scheme Z6).42 The resultant y-hydroxy-acyl complex may be decomplexed to y-lactones. Tricarbonyl-N-methyltetrahydroisoquinolinechromium undergoes stereo- and regio-selective 4-exo-deprotonation and subsequent electrophilic additions to generate the corresponding 4-exo-derivatives which after decomplexation yield 4-alkyl-, 4-phenyl-, and 4-
330
General and Synthetic Methods
OH
Eu2CuLi n-C7H15
0
O -H
+
Bu
OH 12
OH
:
1
0
Bu
0
Bu2CuL i 88
"lo
OH
OH
BU
0
: 11
1 Scheme
20
GOA C fiR R~CULI
0'
0
R = a l k y l , v i n y l , a r y l , etc.
Scheme
0
-
21
0
i - iv
H
>loo Reagents : i , BuLi
;
ii, E t 2 A l C I
;
iii, R C H O
Scheme
: 1 ;
i v , B r 2 , MeOH
22
80 - 98%
6: Organometallics in Synthesis
33 1
0
0
0
C
-
C
i,iv, iii
GFe* 0
R
OH
0
OH
lv
lv
Me I
HO,Ci/"
OH
OH
R e a g e n t s : i , BuLi
;
ii, E t 2 A I C I ; i i i , R C H O ;
Scheme
0
Reagents: i , NaFp
iv, C u C N ; v ,
23
0
0
;
ii, P h C H 2 N H 2 ; iii, B r 2 , E t 3 N
Scheme
24
Br2, H20
332
General and Synthetic Methods
.
..
I , II
0
C
I, II
ii, iii
0 C
""
iv ____)
78 "I,
Reagents:
i, B u L i
;
ii, M e 1
;
iii, L i N H C H 2 P h
Scheme
0 C
Reagents:
pbPh
0
;
iv,
Br2, CS2
25
0 C
i, B u L i
;
ii. p r o p y l e n e o x i d e , E t 2 A I C I
Scheme
26
;
iii, B r 2
6: Organometallics in Synthesis
333
hyd r ox y-N-me t hy 1tetrahyd roi soquinol i nes ( Scheme 27 ) . The pro-! hydrogen of tricarbonyl-(+)-N,N-dimethylamphetaminechromium can be stereospecifically substituted, 2 sequential treatment with BuLi and an electrophile, with retention of configuration to give, for example, N-methylpseudoephedrine after 44 complexation (Scheme 2 8 ) . via Coupling Reactions.- The organocopper derivative generated by lithiation of tricarbonylfluorobenzenechromium and transmetallation with the cuprous bromide-dimethyl sulphide complex couples with the vinyl bromide 2-bromo-l-trimethylsiloxyprop-2-ene. Subsequent desilylation of the product results in spontaneous cyclization, promoted by the tricarbonylchromium moiety, to tricarbonyl-3methylene-2,3-dihydrobenzofuranchromium (Scheme 29). 45 Decomplexation yields 3-methylbenzofuran. The regio- and stereo-specific synthesis o f conjugated dienes can be achieved 2 the palladium-catalysed coupling of alkenylboranes and vinyl bromides (Scheme 30). 46 The stereochemistry of the intermediate alkenyl boranes and of the vinyl bromides is maintained. The nickel-catalysed substitution of aryl methylthiol groups for alkyl groups has been extended to aromatic heterocycles. Treatment of 4-methylthiopyridines with Grignard reagents in the presence of bisphosphinenickel dichloride catalyst generates the corresponding 4-alkylpyridines (Scheme 31 1 .47 6-(Methylthio)purines are converted into the corresponding 6-alkyl- and 6-aryl-purines by nickel-catalysed coupling with Grignard reagents (Scheme 32). 48 The reaction is also applicable to purine nucleosides. The coupling of trimethylaluminium and terminal acetylenes promoted by [(C H ) ZrC12] has been successfully employed in a carbo5 5 2 hydrate-based synthesis of the goldinonolactone intermediate in the total synthesis of the antibiotics aurodox and efrotomycin (Scheme 3 3 ) *49 Conjugated 5,Z-dienes may be prepared readily by carbocupration of acetylenes (Scheme 34) .50 This methodology has been employed in the synthesis of a novel orange-worm pheromone.50 Vinyl triflates couple with Michael acceptors in the presence of triethylamine and palladium catalysts (Scheme 3 5 ) .51 The reaction conditions are mild enough so that even acrolein gives good yields without significant polymerization. The intra- and inter-molecular reductive self-coupling of vinyl bromides may be achieved using a catalytic amount of palladium
3 34
General and Synthetic Methods
I
1
ii, iii
KO),
E = Reagents
Me, E t , PhCH,, I ,
Ph or OH
[ C r (C0l6 1, ii, B U L I
IV.
,
- 65'10
15
iii, E+[ Me1 , E t I ,PhCH2Br,(PhF)Cr(CO)3,0r MoOPHl,
0 2 , hW
Scheme
m''
27
m''
1
/'
/
/'
Cr
(+>
KO13
I
.. ...
11, I l l
E I
-
E I
iv
Cr E = D , M e or OH
Y - met hyl pse u doe phedr i ne),
R e a g e n t s : i , [ C r ( C 0 I 6 3 ; ii, B u L i ; iii, E + ( C D 3 0 D , Me1 or M o O P H ) ; i v , 0,. hv
Scheme
28
6: Organometallics in Synthesis
335
a-a CuSMe2
I. ll
/
'.!-'
Cr (CO13
'd-)
F
/
F
Cr
;
7 5 OO I
Cr (CO),
90 "lo R e a g e n t s : i , B u L i ; ii, C u B r . S M e 2
Cr
(COl3
(CO),
iii, CH2=C(Br)CH20SIMe3;
Scheme
IV,
B u 4 N F ; v, 0
29
42 - 0 9 "lo
R'
R , R 1 = alkyl or Ph Scheme
8 9 "10
30
49
- 93'10
2
General and Synthetic Methods
336
SMe
Ph
b
+
R
I
RMgX
Ph
86 - 89"Io Ph&Ph
R = Me, P h , B u n , or C,H, Reagent :
i , c a t . [ ( P h 3 P I 2 N i C l 2 J or [ { P h 2 P ( C H 2 ) 3 P P h 2 ] N i C 1 2 ]
Scheme
Reagent: RMgX
,
31
cat. [ { P h 2 P ( C H 2 ) 3 P P h d N i C l , 1
Scheme
32
I ____)
Reagent :
i
,
A1 Me3, [ ( C 5 H 5 I 2 Z r C12 1
Scheme
- m2CuLi
4HC=CH
Bu2CuLi
33
Bu
Scheme
Me
Me1
34
Bu
71 "lo
6: Organometallics in Synthesis
D
O
T
f
+
337
- rZ
tZ
Z = C02Me (91 'lo), COMe ( 8 9 O l 0 ) CN (99Ol0) or CHO (86'10)
C0,Me +
/;COzMe
b +I;,,,,. OTf
92 '10
~
.
~
&COzMe a4 'lo
R e a g e n t : E t 3 N , c a t . [ ( P h 3 P ) 2 P d C 1 2 1 , 75OC, D M F
Scheme
35
9 5 "lo Et02C
Reagent :
C0,Et
i , c a t . Pd ( O A c I Z
Et0,C
,
PPh3, KZCO3
Scheme
36
C0,Et
General and Synthetic Methods
338
acetate in the presence of stoicheiometric amounts of triarylphosphines (Scheme 36) .52 Double bond isomerization is not observed under these conditions. Terminal acetylenes are oxidatively coupled to diynes by chloroacetone in the presence of catalytic amounts of [(Ph P ) Pd] 3 4 and CuI (Scheme 37).53 Heck arylation of 1,5-dienes leads to cyclized products (Scheme
38) .54 Similar cyclizations are observed for. 1 ,5-enynes. 1,6- and 1,7-Enynes react with ‘Cp2Zr‘ to give zirconabicyclic intermediates which yield bicyclic pentenones with carbon monoxide, di-iodides with iodine, and vinyl derivatives with protons (Scheme 39) .55 The palladium-catalysed [3+2] ring annulation reaction has been directed towards a synthesis of a loganin aglucon fragment.56
Thus
palladium-catalysed cycloaddition of a substituted 2-[(trimethylsilyl)methyl]allyl carboxylate with cyclopentenone generates the required substitution pattern for loganin (Scheme 40). The palladium catalysed [3+2] cycloaddition reaction has been extended to aldehydes and imines. One method employs the Lewis acid-catalysed to the addition of 2-[(acetoxymethyl)-3-allyl]tributylstannane aldehyde o r imine fol-lowed by palladium-catalysed cyclization (Scheme 41) .57 Under the appropriate conditions the whole process can be catalysed by palladium (Scheme 42).58 Of note in this latter reaction is the lack of cycloaddition to the double bond of a,B-unsaturated aldehydes. The complex pentacarbonyl-(2-furylmethoxycarbene)chromium couples with alkoxyacetylenes to generate benzofurans (Scheme 43).59 met hod
The total synthesis of Khellin has been achieved by this
.
In the *presence of the [(Ph P) Pd] catalyst organoaluminiurn 3 4 60 reagents convert acyl chlorides into ketones (Scheme 44). Grignard reagents in the presence of nickel catalysts couple with S-phenyl
carbanochloridothioate to give the corresponding 2-phenyl carbanothioates. These in turn couple with Grignard reagents in
the presence of iron catalysts to give symmetrical or unsymmetrical ketones (Scheme 45). 61 Unsymmetrical a-diketones are readily accessible by the [(Ph P) PdC12]-catalysed cross coupling of acyltributyltin reagents 3 2 62 with acyl chlorides (Scheme 46). The rhodium-catalysed C-H bond insertion reaction of a-diazo-Bketo-esters has been shown t o proceed with retention of configura-
6: Organometallics in Synthesis
339
i
2 RCECH
R C r C - C G CR
___1_1)
50- 94"/0
R = a r y l or a l k y l Reagent :
i , [ ( Ph3PIL Pd 1, C u I , CICH, COMe , E t 3 N
37
Scheme
phsozc
5 0%
P h S O Z d
I
PhSO,
PhSO;!
CI PhSO, PhSO, Reagent : i,
PhSO, P h H g C l , CuC12, c a t . P d C I Z
Scheme
38
&:
55-65"/0
(
-
Si Me3
Si Me3
r=siMe3 I
CH,),
Ill
61 - 70'10
\=
6 3 "lo
Reagents'
I .
Cp,ZrCI,,
Mg,
HgCIZ,
Scheme
li, CO;
39
III,
I,
; IV,
H+
General and Synthetic Methods
340
111
I Pd:
' L Reagents:
1 iii,
i , P d ( O A c ) p , P P h 3 ; it, B u " L i ;
@.
40
Scheme
Ph'
PhNH
N/ph
+
r " " c L p h J & A c
Ph SnBu,
81 "10 R e a g e n t s : i , BF O E t 2 ; ii, P d ( O A c I 2 , P P h 3 / B u L i , DBU 3'
Scheme
41
0
AH
Ph
I
+
P
A
C
100"10
____)
Ph
SnBu3
8 0"In
Reagent : i, Pd(OAc)2, PPh3
Scheme
42
6: Organometallics in Synthesis
34 1
OAC OSiMe2Bu'
I
OMe
OEt
OMe
4 3 OIO Reagent :
i , Ac20, NEt3
, THF, 6 5 O C ,
1Oh
Scheme
-k
)$Cl
43
-
Et3AI
( P h 3P
Pd ]
Ph
J$Et
'
68%
Ph Scheme
0
0 I
CI
44
___)
R'
A
SPh
85 - 9 6 'lo
0
-
R'
AR2
58
- 99 'lo
0 86'10 overall yield
General and Synthetic Methods
342
41
- 65
'/e
R 1 , R 2 = a l k y l or a r y l Scheme
46
(+)
Scheme
47
-OSiMe2Bu'
Reagents :
i , [ C O ~ ( C O ) ~ Ii ;i , C O , 1 6 O o C , 3 d
Scheme
- a-cuparenone
48
H
6: Organometallics in Synthesis
343
tion. This reaction has been employed in an enantiospecific synthesis of (+)-a-cuparenone which involves the enantiospecific generation of a quaternary carbon centre (Scheme 4 7 ) . 6 3 via Carbonylation Reactions.- The Pauson-Khand reaction has been used to effect the synthesis of the perhydrotriquinacene skeleton by a bis-annulation process (Scheme 48).64 In certain cases the Pauson-Khand reaction to prepare bicyclo[3.3.0]octenones proceeds stereoselectively (Scheme 49) .65 Carbonylation of allylic and hornoallylic alcohols catalysed by PdCl gives y-butyrolactones in moderate yield .66 Unfortunately 2 little stereoselectivity is observed (Scheme 50) .67 3-Hydroxyalkenes possessing a nucleophilic group on C-5 cyclize, via palladium-catalysed addition of the nucleophile to the alkene and subsequent carbonylative lactonization to the 3-hydroxy-group, to give bicyclic c3.3.01 systems. This general process has been used to prepare bicyclic bis-lactones ,68 &-3-hydroxypyrrolidine2 ac e t ic ac id 1ac tone , and cis-3-h yd r ox y te tr a h yd r ofu r an -2- ac e t ic acid lactones (Scheme 51 ) .70 Enol triflates are carbonylated to the corresponding a , B unsaturated esters and amides under the influence of palladium
-
-
catalysis (Scheme 52) .71 2-Bromoallylamines are similarly converted into a-methylene-6-lactams (Scheme 53) .72 This latter 8 lactam synthesis has been applied to the ( f ) - 3 - a r n i n o n o c a r d i c i n i c acid .73 l-Iodo-1,4- and -1,5-dienes undergo two successive carbonylation reactions to generate substituted cyclopentenones and cyclohexenones respectively (Scheme 54) .74 Protected glucosyl bromides react with NaMn(C0) via an SN2 5process with inversion of configuration to give the corresponding glycosyl pentacarbonylmanganese complexes. These undergo a variety of carbonylative coupling reactions to give C-glycosides (Scheme 5 5 ) .75 Allylic and homoallylic alcohols undergo amidocarbonylation in the presence of two catalysts: [HRh(PPh3)3(CO)] to isomerize to the corresponding aldehydes and [CO~(CO)~] to achieve the amidocarbonylation of the aldehydes (Scheme 5 6 ) .76 Epoxides undergo a similar reaction in the presence of C C O ~ ( C O ) ~ ]and a Lewis acid such as Ti(OPr1I4, the latter presumably causing rearrangement of the e oxide to the aldehyde required for amidocarbonylation (Scheme 5 7 ) -7 %
General and Synthetic Methods
344
SiMe3
)FSiMe3 I
I
7 8 'lo
,
iH
OMOM
Reagent :
i
I
OMOM
, [ C O ~ ( C O 1) ,~ CO , 115 OC ,
36 h
Scheme
49
>- a-
HO
0-
1
2'
R e a g e n t : i , C O , C u C 1 2 , 0 2 , H C I , c a t . PdCI2
Scheme
50 Pr"
H
I ______)
88 Ole
0,-0
ti
dH
brn
H I
Z
90OIO
I ______)
Ph
Reagent :
i,
c a t . PdC12, CuC12
, NdOAc , CO Scheme
51
80 'lo
345
6: Organometallics in Synthesis
0
i _____i.)
X=OorNH
-
75 '10
Tf 0 Reagents :
I ,
CO , R X H , c a t . Pd (OAc12, PPh3 ; ii, CO , MeOH , c a t . Pd (OAc12, PPh 3
Scheme
52
wo
Br I _____)
NH Ph Reagent
1
6 7O l e
LN-Ph
i , C O , 6un3N, c a t . P d ( O A c I 2 , PPh3
Scheme
/J
53
I
C6H13
8*' 73 OIO
'6*
Reagent : i , CO, MeOH
, c a t . [ ( P h 3 P I 2 PdCI2 1
Scheme
ILL
13
346
General and Synthetic Methods
M e 0 7
M
e
0
9 C02Me
Me0
Me0 OMe
Br
63 "lo
Mn (CO),
Me0
-
Me0
C0,Me
OMe
OMe
\
47
"10
M e 0 4 Me0 OMe
69 ' 1 0 Reagents :
I ,
N a M n (CO),
;
ii , CO, M e O H ; iii, CHZ= C H C 0 2 M e , 6 kbar
%OH
OH
+A
i v , hV,MeCN
;
Scheme
55
+
o
c
i
63 "lo
NH2
0
+
A,,, +
R e a g e n t : i , [ H R h ( PPh313CO
co
'
NHCOMe
5 5 OIO
AC02H
I , Co2(C0)8lI H2 Scheme
0
/Ao+ A
Ph
;
H30+
v, HCECCO2Me, 6 kbar, vi,
+
co
"2
R e a g e n t : i , [ C O ~ ( C O I) ,~ [ T i ( O P r ' I 4
56
-
I , H2
Scheme
57
NHCOMe Ph
92 OIO
6: Organometallics in Synthesis
347
6 Miscellaneous Reactions Ethylene glycol derived acetals are hydrolysed under mild conditions in the presence of [(MeCN)2PdC121 (Scheme 58) ;77 this deprotection can be performed in the presence of various alcohol protecting groups. Allyl esters are stable to acids and bases and can be cleaved under very mild conditions using [(PPh RhCl] or 3 3 This acid protection methodo[(Ph P ) Pd] catalysts (Scheme 59).78 3 4 logy has been used in the synthesis of a g l y ~ o p e n t a p e p t i d e . ~ ~ Owing to its ready removal under mild conditions by brief treatment with [(Ph P) Pdl in the presence of amines the allyl group provides 3 4 a useful protecting group for an internucleotide bond (Scheme 60).79 The phospho(II1)triesters are prepared from (allyl)OP(NMe2)2. The allyl group is quite stable under conditions needed to deprotect other oxygen substituents such as ButMe2Si, and p-MeOC6H4Ph2C. Amides can be N-allylated with a 2-allylisourea in the presence of [Pd(dbaI21 as catalyst (Scheme 61).80 Allyl acetates and chlorides undergo substitution with retention of configuration with sodium toluene-p-sulphonamide in the presence of catalytic amounts of [ (Ph3P)4Pd] (Scheme 62) .81 In combination with known methods for the cleavage of the toluene-p-sulphonyl group this represents a good method for generating primary allylamines. Oximes may be O-arylated using halogenoarene tricarbonylchromium complexes (Scheme 63). 82 Aromatic amines are converted into carbamate esters on treatment with an alcohol and CO ( 1 atm) in the presence of 02, CuC12, and catalytic amounts of PdC12 (Scheme 64).83 Vinyl epoxides react with C 0 2 in the presence of a palladium(0) catalyst, generated in situ from Pd(OH2)2, P(OPr1)3, and BuLi, to give the corresponding vinyl carbamates (Scheme 65) .84 The epoxide stereochemistry is retained and this methodology corresponds overall to a cis-dihydroxylation process. Selective methylation of an aldehyde in the presence of a ketone occurs with CH212-Zn-Ti(OPr1)4. The reverse selectivity is observed if the keto-aldehyde is pretreated with Ti(NEt,)4 prior to CH212-Zn-TiC14 (Scheme 66). 85
348
General and Synthetic Methods
n
i
L
0
&OR
OR
R = H , M E M , SiPh,Bu'
or THP
R e a g e n t : i , MeZCO , 2 0 OC , c a t . [ ( MeCN 1, PdCI, 1
Scheme
58
NHBoc
NHBoc
i A c o @ H d C 002 H
AcO v H + c o * w
AcO
AcO NHAc
NHAc
R e a g e n t : i , E t O H , H 2 0 , 7OoC, c a t . [ ( P h 3 P I 3 R h C r ] or [ ( P P h 3 ) 4 P d J
Scheme
59
1
PhzCO
Q
i
0
4
_.__)
OMe Th = t h y m i d i n e
Ph$O
Q OMe
B = thymidine or a d e n o s i n e
Scheme
1
0-P-0
OSiBu'Me,
60
'J-,si~u~,e~
I
OH >95
'10
6: Organometallics in Synthesis
349
+'<
0
+ I
0
NCY
2
R 1 ' N W
45-87'/0
1
N HCy
R*
R2
86 'lo
Reagent : i , c a t . [ P d ( d b a $
I,
dppe
Scheme
61
+
NHTos
CI I
8 0'10
OAc
OAc
N H Tos
CI
!
I
v
I
81 '10 OAc
OAc
0
77 O/O NHTos
Reagent : i , N a NHS02C6H4Me, cat'. [ ( P h 3 P I 4 P d
Scheme 62
J
350
General and Synthetic Methods
I
R = H , M e or O M e
Cr (CO),
X = F or CI R e a g e n t s . i , K O H , B u 4 N B r ; ii , I 2
Scheme
ArylNH,
+
CO
+
-
ROH
yN:
CO -f- MeOH
63
ArNHC0,R
-
NHC0,Me
99"lo
'0 Reagent :
i ,
HCI , CuC12 , 0 2 , c a t . P d C I 2
Scheme
64
0
Reagent.
I ,
Pdo
( c a t . ) [ Pd(OAc),,
P(OPri),
S c h e m e 65
,BuLi
16-99%
I
6: Organometallics in Synthesis
3
351
_I
I
rc---------
CHO
83 'lo
R e a g e n t s : i , C H Z I Z , Zn
, Ti(OPr'I4
;
ii, T i ( N E t 2 I 4
Scheme 66
CHO 76 '10
iii, CHZIZ , Z n , T i C 1 4
General and Synthetic Methods
352 References 1.
2. 3. 4.
5. 6. 7. 8. 9. 10. 11.
12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45 *
A.J.Pearson, 'Metallo-organic Chemistry', J. Wiley, New York, 1985. C.M.Lukehart, 'Fundamental Transition Metal Organometallic Chemistry I , BrooksfCole, Monterey, 1985. J. D.Atwood, 'Inorganic and Organometallic Reaction Mechanisms', Brooks/Cole, Monterey, 1985. R.F.Heck, 'Palladium Reagents in Organic Syntheses', Academic Press, London, 1985. A.D.Ryabov, Synthesis, 1985, 233. D.C.Billington, Chem. SOC. Rev., 1985, 93. H.Yasuda. K.Tatsumi. and A.Nakamura. Acc. Chem. Res.. 1985. 18. 120. H.Bonnemann, Angew. Chem., Int. Ed. Engl., 19 S.Masamune, W.Choy, J.S.Petersen, and L.R.Sita, Azew. Chem., Int. Ed. Engl., 1985, 24, 1 . P.L.Pauson, Tetrahedron, 1985, 5855. H.M.R.Hoffmann and J.Rabe, Angew. Chem., Int. Ed. Engl., 1985, 94. J.M.Brown and I.Cutting, J. Chem. SOC., Chem. Commun., 1985, 578. T.Murai, T.Sakane, and S.Kato, Tetrahedron Lett., 1985, 26, 5145. M.Tanaka and T.Kobayaski, Synthesis, 1985, 967. S.C.Shim and K.N.Choi, Tetrahedron Lett., 1985, 26, 3277. K.M.Nicholas and J.Siege1, J. Am. Chem. SOC., 1985, 2,4999. S.-I.Murahashi, T.Naota, and N.Nakajima, Tetrahedron Lett., 1985, 26, 925. S.-I.Murahashi, T.Naota, and H.Taki, J. Chem. SOC.. Chem. Commun.. 1985 , 613. A. J. Pearson, Y. -S.Chen, G. R. Han , S.-Y.Hsu, and T.Ray, J. Chem. SOC., Perkin Trans. 1 , 1985, 267. J. E.Baldwin, R.J. Jones, C. Najera , and M.Yus, Tetrahedron, 1985, 699. J.E.Baldwin, C.Najera, and M.Yus , J. Chem. SOC., Chem. Commun., 1985, 126. K.Tani, J. Yamagata, Y. Tatsuno, Y .Yamagata, T.Tomita, S.Akutagawa, H.Kumobayashi, and S.Otsuka, z g e w . Chem., Int. Ed. Engl., 1985, 2, 217. S.Sato, I.Matsuda, and Y.Izumi, Tetrahedron Lett., 1985, 26, 1527. S.-1.Murahashi and Y.Makabe, Tetrahedron Lett., 1985, 26, 5563. C.R.Clark and S.Thiensathit, Tetrahedron Lett., 1985, 26, 2503. B.M.Trost and M.Lautens, J. Am. Chem. SOC., 1985, 107, 1781. B.M.Trost and J.Y.L.Chung, J. Am. Chem. SOC., 1985, 107,4586. T.V.RayanBabu, J. Org. Chem., 1985, 50, 3642. M.Uemura, K.Isobe, and Y.Hayashi, Chem. Lett., 1985, 9 1 ; Tetrahedron Lett., 1985. 26, 767. A.J.PeKson and M.N.I.Khan, J. Org. Chem., 1985, 50, 5276. S.Lane, S.J.Quick, and R.J.K.Taylor, J. Chem. SOC., Perkin Trans. 1 , 1985, 893. F.T.LuQ and E.Negishi, Tetrahedron Lett., 1985, 26, 2177. W.Oppolzer, P.Dudfield, T.Stevenson, and T.Gode1, Helv. Chim. Acta, 1985, 68, 212. ; W.Oppolzer and P.Dudfield, p.216. J.M.Chong and K.B.Sharpless, Tetrahedron Lett., 1985, 26, 4683. D.H.Hua and A.Verma, Tetrahedron Lett., 1985, 547. S.G.Davies, 1.M.Dordor-Hedgecock, P.Warner, R.H.Jones, and K.Prout, J. Organometal. Chem., 1985, 285, 213. S.G.Davies, 1.M.Dordor-Hedgecock, and P.Warner, Tetrahedron Lett., 1985, 26, 61. P.W.Ambler and S.G.Davies, Tetrahedron Lett., 1985, 26, 2129. I.Ojima and H.B.Kwon, Chem. Lett., 1985, 1327. S.G.Davies and J.C.Walker, J. Chem. SOC., Chem. Commun., 1985, 209. L.S.Liebeskind and M.E.Welker, Tetrahedron Lett., 1985, 26, 3079. S.L.Brown, S.G.Davies, P.Warner, R.H.Jones, and K.Prout, J. Chem. SOC- 9 Chem Commun., 1985, 1446; S.G.Davies and P.Warner, Tetrahedron Lett., 1985, 26, 4815. J.Blagg, S.G.Davies, and B.E.Mobbs, J. Chem. SOC., Chem. Commun., 1985, 619. J.Blagg and S.G.Davies, J. Chem. SOC., Chem. Commun., 1985, 653. P.J.Beswick and D.A.Widdowson, Synthesis, 1985, 492.
14,
2,
5,
5,
x., g,
353
6: Organometallics in Synthesis 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70.
N.Miyaura, K.Yamada, H.Suginome, and A.Suzuki, J. Am. Chem. SOC., 1985, 107, 972. E.Wenkert, J.M.Hanna, M.H.Leftin, E.L.Michelotti, K.T.Potts, and D.Usifer, J. Org. Chem., 1985, 50, 1125. H.Sugimura and H.Takei, Bull. Chem. SOC. Jpn., 1985, 58, 664. R.E.Dolle and K.C.Nicolaou, J. Chem. SOC., Chem. Commun., 1985, 1016. M.Furber, R.J.K.Taylor, and S.C.Burford, Tetrahedron Lett., 1985, 26, 3285. W.J.Scott, M.R.Rena, K.Sward, S.J.Stoesse1, and J.K.Stille, J. Org. Chem., 1985, 50, 2302. R.Grigg, P.Stevenson, and T.Worakun, J. Chem. SOC., Chem. Commun., 1985, 971. R.Rossi, A-Carpita and C.Bigelli, Tetrahedron Lett., 1985, 523. B.M.Trost and K.Burgess, J. Chem. SOC., Chem. Commun., 1985, 1084. E.Negishi, S.J.Holmes, J.M.Tour, and J.A.Miller, J. Am. Chem. SOC., 1985, 107, 2568. B.M.Trost and T.N.Nanninga, J. Am. Chem. SOC., 1985, 3, 1293. B.M.Trost and P.J.Bonk, J. Am. Chem. SOC., 1985, 107, 1778. B.M.Trost and P.J.Bonk, J. Am. Chem. SOC., 1985, 107, 8277. A.Yamashita, J. Am. Chem. SOC., 1985, 3, 5823. K.Wakamatsu, Y.Okuda, K.Oshima, and H.Nozaki, Bull. Chem. SOC. Jpn., 1985, 58, 2425. C.Cardellicchio, V.Fiandanese, G.Marchese and L.Ronzini, Tetrahedron Lett. , 1985, 26, 3595. J.-B.Verlhac, E.Clanson, B.Jousseaume and J.-P-Quintard, Tetrahedron Lett., 1985, 6075. D.F.Taber, E.H.Petty, and K.Raman, J. Am. Chem. SOC., 1985, 107,196. E.Carceller, V.Centellas, A.Moyano, M.A.Pericas and F.Serratosa, Tetrahedron Lett., 1985, 26, 2475. P.Magnus and L.M.Principe, Tetrahedron Lett., 1985, 26, 4851. H.Alper and D.Leonard, Tetrahedron Lett., 1985, 26, 5639. H.Alper and D.Leonard, 2 . Chem. SOC., Chem. Commun., 1985, 511. Y.Tamuru, H.Higashimura, K.Naka, M.Hojo, and Z.Yoshida, Angew. Chem., Int. Ed. Engl., 1985, 24, 1045. Y.Tamura, T.Kobayashi, S.Kawamura, H.Ochiai, and Z.Yoshida, Tetrahedron Lett., 1985, 26, 4479. Y.Tamuru, T.Kobayashi, S.Kawamura, H.Ochiai, M.Hojo, and Z.Yoshida, Tetrahedron Lett.. 1986. 26. 1207. .S.Cacchi, E.Morera, and G.Ortar, Tetrahedron Lett., 1985, 26, 1109. M.Mori, K.Chiba, M.Okita, I.Kayo, and Y.Ban, Tetrahedron Lett., 1985, “1, 375. K.Chida, M.Mori, and Y.Ban, Tetrahedron, 1985, 387. J.A.Tour and E.Negishi, J. Am. Chem. SOC., 1985, 107,8289. P.Deshong, G.A.Slough, and V.Elango, J. Am. Chem. SOC., 1985, 107,7788. I.Ojima, H.Hirai, M.Fuchikami, and T.Fujita, J. Organomet. Chem., 1985, 279, 203. B. H. Lipshultz, D.Pollart , J. Ponforte, and H.Kotsuki , Tetrahedron Lett., 1985, 26, 705. H.Kunz and H-Waldmann, &lv. Chim. Acta, 1985, 68, 618. Y.Hayakawa, M.Uchiyama, H.Kato, and R.Noyori, Tetrahedron Lett., 1985, 26, 6505. Y.Inoue, M.Toguchi, and H.Hashimoto, Bull. Chem. SOC. Jpn., 1985, 58, 2721. S.E.Bystrom, R-Aslanian, and J.E.Backval1, Tetrahedron Lett., 1985, 26, 1749. A-Alemagna, C.Baldoli, P.D.Buttez-o, E.Licandt-o, and S.Maiorana, J. Chem. SOC., Chem. Commun., 1985, 417. H-Alper and F.W.Hartstock, J. Chem. SOC., Chem. Commun., 1985, 1141. B.M.Trost and S.R.Angle, J. Am. Chem. SOC., 1985, 107,6123. T.Okazoe, J.Hibino, K.Takai, H.Nozaki, Tetrahedron Lett., 1985, 26, 5581.
g,
c,
-
r
71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85.
-
I
_ I
+-
fi,
General and Synthetic Methods
354
Part 11:
Main Group Elements
BY T. GALLAGHER
1
Selective
Group I Lithiations.- The 1-(alkoxycyclopropy1)lithium
reagents
( 1 ) are useful f o r the synthesis of cyclobutanones and cyclopent-
anones, but access to these reagents can be limited. For largescale work I-bromo-I-ethoxycyclopropane (2) appears to be a viable precursor, and undergoes smookh halogen-lithium exchange (ButLiTransmetallation of the Et20, -78 OC) to generate ( 1 ; R = Et). stannane (3) has also been accomplished but this route is compromised by the relative inaccessibility of ( 3 ) . Direct deprotonation of (4) is also feasible, but the resulting anion has, because o f steric hindrance, limited reactivity. The (alkoxymethy1)lithium reagents ( 5 1 , prepared by tin-lithium exchange, react with aldehydes and ketones to give monoethers o f 1,2-diols. Benzyl selenides undergo a facile alkyl-lithiuminduced cleavage to give the corresponding benzyl-lithiums in good yield (Scheme This mild cleavage reaction tolerates a number of substituents on the aryl ring. The intramolecular reactions of alkyl-lithiums, generated in situ, have continued to attract attention. In the case of w lithioepoxides (6), generated by iodine-lithium exchange, cyclization by both and endo-modes is ~ b s e r v e d . ~The ratio of products obtained i s , however, dependent on both the structure of the substrate and the presence of Lewis acids o r metal salts. The alkylation of secondary amides, on carbon, usually requires either N-protection or the generation of a polyanionic species. Benzamidoacetone undergoes deprotonation to give a monoanion that undergoes 2-alkylation (Scheme 2 ) . 5 Protection o f N-H is avoided, and it is presumed that a kinetic deprotonation to give ( 7 ) is
x-
followed by isomerization to give a thermodynamically more stable species, represented as (8) or (9). Further studies on the site of kinetic deprotonation of u , 8 unsaturated acids and esters have been reported.6 As a rule For References see p. 410
355
6: Organometallics in Synthesis
HoEt
MoR
Br
Li
(21
(11
LXSnBu3 OEt ( 3 1
R
R
R ' , R2= a l k y l or H R = 0 - C I ,p-CI , p - F , o r p - M e 0
Scheme 1
OH
Reagents
: i , L D A , -78
"C,
ii,
RX
Scheme 2
356
General and Synthetic Methods
kinetic deprotonation takes place syn- to the carboxy function to give (10). Deuteration studies have shown that a kinetic deprotonation anti- to the carboxy-group may be observed in the presence of hexamethylphosphoramide to give (11). Alkenyl N,N-dialkylcarbamates are deprotonated at low temperature to provide ( 1 2 1 , a homoenolate equivalent .7 The carbamate function is not cleaved at -70 O C , but this group may be readily deblocked after reaction of (12) with various electrophiles, e.g. aldehydes, to give tetrahydrofurans (Scheme 3). Allylic anions are important synthetic building blocks, and they may be obtained by direct deprotonation of simple alkenes and dienes. Propene and 2-methylpropene are readily deprotonated to give (13; R H ) and (13; R = Me) respectively (Scheme 4), but under these conditions isoprene undergoes oligomerization. However, on using a hindered amide base, rather than an alkyllithium, metallation of isoprene is facile, leading to (14).8 The anions (13) and (14) are efficiently trapped by electrophiles, and provide a convenient source of nucleophilic alkene and diene units. Pentadienyl-lithium has been shown to react with several electrophiles to provide a range of new organometallic substituted ( 3 . AsPh2, SiMe3, GeMe3, SnMe ) penta-2,4-dienes. 9 3 The reaction of alkyl-lithium reagents with symmetrically substituted ketenes provides a valuable route to directed enolates (15) (Scheme 5 ) .lo This ketene-based methodology often gives isomeric enolates to those obtained from ketones under !standard' conditions. This chemistry has been used to prepare, for the first time, the highly substituted enolate ( 15; R = R1 = But). An independent study has provided an alternative regioselective synthesis of ketone enolates by reaction of enolates derived from 2,6-di(tbuty1)-4-methylphenol esters with organolithiums (Scheme 5 ) . The intermediate ester enolates (16) undergo fragmentation at temperatures above -20 O C to generate a ketene which is trapped by the organolithium component. Directed lithiations of aromatic and heteroaromatic systems, as well as those involving non-aromatic heterocycles, are processes that have continued to evolve this year. Various 3,5-dialkoxy-4substituted phenols (18) have been prepared by a selective lithiation reaction. The use of a bulky silyl substituent inhibits metallation of (17) at C-2, and the application of this chemistry to a concise synthesis of sophoraflavanone A has been presented 2-Oxazolinylthiophenes ( 1 9 ) may be metallated at (Scheme 6 1.
357
6: Organometallics in Synthesis
OR
Me Li
(101
(111
R = L i or a l k y l OH
(121 E - A C " O Reagents : i I Bun L i
TMEDA -70 "C ; i i , R'CHO ; i i i M e O H , H+, H g ( 0 A c l 2 ~
Scheme 3 R
R
. ..
I, II
+ (131
L
. ..
I II
___)
(111 L i B r ; iii, K B u t O ,
Reagents: i, E u n L i , KBut0,THF,-90"C;ii,
l i t h i u m tetramethylpiperidide,
THF
Scheme L
R
R' L i +
+c=o
R
R
(
.'
R'
A
R
But
Reagents: i, B u " L i i ii, R'Li, > - 2 O o C
RXoLi R
OAr
Scheme 5
RxoL R
R'
General and Synthetic Methods
358
Me0
Me 0
OMe
OMe
E (181
( 1 7) Reagents:
I,
OMe
Me0
Li
ButLi , t o l u e n e , - 7 8 t o 25
O C ; 11,
electrophile
(E'), F -
(17) \I
\
OH 0 S o p ha r a f I a v o n e A
f 0 s i Me2But
OMe Reagents
I , ButLl , t o l u e n e , -78
t o 25
O C ,
g e r a n y i bromtde. 3
"/o
C u B r . Me+
Scheme 6
&y E
.E Ill
0
0R e a g e n t s : i , Bu'Li
, E t 2 0 , -78
t o 0 "C,
MeOCH CH OMe , - 7 8 2 2
OC
E';
;I, L i t h i u m d i - i s o p r o p y l a m i d e I L D A 1 ,
, E +; I I I ,
NaOCI, e t h y l a c e t a t e
Scheme 7
, H 2 0 , ButLNSOL ,OH-
6: Organometallics in Synthesis
359
either C-3 or C - 5 by careful control of conditions (Scheme 7).13 The resulting anions are trapped by a broad spectrum of electrophiles (alkyl halides, C02, enones, halogens) and the oxazolinyl moiety may then be cleaved under Weinreb's conditions to liberate the corresponding carboxylic acid. Direct deprotonation of l-methyl-4-pyridone with BunLi gives the 2-lithio-derivative (20) which may then be trapped to provide 2substituted-4-pyridones. An attempt to extend this methodology to the corresponding 2-pyridone (21) failed, deprotonation of the N-methyl group predominating. Full details of a comprehensive study of the lithiation of oxygen-containing heterocycles (flavone, chromones? coumarins , and benzofurans ) have appeared ! and a 16 simple synthesis of 3-lithiofuran (22) has also been described. Meyers has continued to develop the chemistry of a-aminocarbanions in impressive style (Scheme 8). Metallation of the = 1 , 2 , or 3 ) followed by selenation and eliminaamidines (23; tion leads to enamidines (24). These intermediates undergo stepwise metallation and alkylation, giving the disubstituted derivatives (25), and a successful synthesis of solenopsin A aptly illustrates the overall potential of the method. l 7 The asymmetric alkylation of 6-carbolines (261, incorporating a chiral formamidine unit, has also been described by Meyer's research group.18 The alkylated products (27) are obtained in high optical purity after cleavage of the directing and protecting groups, and the mechanistic aspects of this deprotonation-alkylation sequence have also been discussed. Lithiation of the tricarbonylchromium complex of tetrahydroisoH) with BunLi takes place in a highly specific quinoline (28; R fashion to give the 4-%-derivative (28; R = Li).I9 This species reacts with a wide range of electrophiles to provide, after oxidative removal of chromium, 4-substituted tetrahydroisoquinolines. Progress in the enantioselective synthesis of amino acids has been made, most notably this year by Seebach's research group. Simple amino acids, such as (S)-alanine, are converted into cis(29) and trans-(29) imidazolidinones. These heterocycles undergo deprotonation to afford chiral enolates, alkylation of which takes place on the opposite face of the heterocycle to the bulky But group (Scheme 9). 2 0 Hydrolysis of the alkylated imidazolidinones, such as ( 3 0 ) and ( 3 1 1 , under acidic conditions, liberates the a,adisubstituted amino acids. Both (El- and ( 2 ) - a-methyldopa have been prepared in this way from (S)-alanine. Other amino acids,
360
General and Synthetic Methods
pjLi (lLi 0
Me
0 Me
(201
0
(21 1
(22)
d,, (23I
Me'*
H
11 2 3
Solenoprin A
4
V,VI
R'
t
i-N+
R1= n=C 2 llH23
Reagents:
I
~
ButLl
TMEDA
, THF, t h e n
b,+
(25)
R = Me Ph2Se2
j
ii , H C O C ; iii BunLi ,THF,then RX;Iv,ButLi
then R'Br ; v , N 2 H L J MeC02H ;
V I , LiAIHL
Scheme 8
,
6: Organometallics in Synthesis
361
130) ( S1 - alanine
I
Me
Me
+-{yo1 cis Reagents : i , LDA
, THF,
Me
.Me
I
PhAo
Ph
- (29)
t h e n R X ; ii
(311
, 8N-HCI , A Scheme 9
% COPh ( S )- 0
- benzylserine
f
+-?yo
Me
N
COPh
Reagents
...
H OzC
I
COPh
: i, H 2 / P d , e t h y l a c e t a t e j ii, R u C 1 3 , N a I O L , CCLL, H 2 0 , MeCN; iii , LDA , T H F , t h e n RX
,
t h e n B N - HCL , A
Scheme 10
General and Synthetic Methods
362 s u c h as g l u t a m i c and a s p a r t i c a c i d s ,
t o g e t h e r w i t h 4-hydroxy-
p r o l i n e , 22 a l s o u n d e r g o e n a n t i o s e l e c t i v e a l k y l a t i o n u s i n g t h i s a n d c l o s e l y r e l a t e d methodology.
O b v i o u s l y t h e c h e m i s t r y shown i n
Scheme 9 c o u l d n o t b e d i r e c t l y a p p l i e d t o t h e e n a n t i o s e l e c t i v e alkylation of glycine.
Seebach's research group has developed a
s o l u t i o n t o t h i s i m p o r t a n t p r o b l e m b a s e d o n t h e u s e o f a n a-
(S)-O-
s u b s t i t u t e d amino a c i d bearing a degradable ~ i d e - c h a i n . ~ ~ Benzylserine f u l f i l s t h i s r u l e admirably, and once again t h e a v a i l a b i l i t y of both imidazolidinone isomers,
(32) a n d ( 3 3 ) ,
provides access t o e i t h e r enantiomer of t h e a-monosubstituted glyc i n e d e r i v a t i v e ( S c h e m e 10). Metallation
( L D A , ButOK) o f c y c l i c ( a n d a c y c l i c ) h o m o a l l y l i c
e t h e r s ( 3 4 ) r e s u l t s i n a smooth r i n g opening r e a c t i o n , l e a d i n g t o 24 penta-2,Q-dienols ( 3 5 ) i n a s t e r e o c o n t r o l l e d manner. The u s e o f
' n u c l e o p h i l i c c a r b o h y d r a t e s ' f o r t h e s y n t h e s i s of
pyranosides h a s been extended t o i n c l u d e g l y c o s y l - l i t h i u m
C-
(36; M =
L i ) which i s g e n e r a t e d under s t a n d a r d c o n d i t i o n s from t h e c o r r e s -
p o n d i n g s t a n n a n e ( 3 6 ; M = SnBu"
25
3).
The B-anomer
of ( 3 7 ; M =
SnBun3) i s a l s o a v a i l a b l e and b o t h l i t h i a t e d d e r i v a t i v e s h a v e been shown t o b e c o n f i g u r a t i o n a l l y s t a b l e . The i s o m e r i z a t i o n o f a l k y n e s u s i n g l i t h i u m a m i n o p r o p y l a m i d e (LAPA) h a s s e e n a n u m b e r o f s y n t h e t i c a p p l i c a t i o n s , b u t o n e o f t h e m o s t i m p r e s s i v e e x a m p l e s i n v o l v e s t h e p e r d e u t e r a t i o n of c y c l i c a l k y n e s (Scheme
Y i e l d s o f t h e p e r d e u t e r a t e d p r o d u c t s a r e of
t h e o r d e r o f 60%. Dianions and Alkenyl and Alkynyl Anions.-
Although t h e d i l i t h i a t i o n
o f p h e n o l was o r i g i n a l l y r e p o r t e d by G i l m a n some f o r t y y e a r s a g o , t h e p r o c e s s was t o t a l l y i m p r a c t i c a l , a n d a m u c h m o r e e f f i c i e n t Deprotonation (ButLi s y n t h e s i . ~o f ( 3 8 ) h a s now b e e n r e p o r t e d . 2 7 THF) o f p h e n o l f i r s t l e a d s t o t h e i n s o l u b l e p h e n o x i d e i o n w h i c h
,
t h e n u n d e r g o e s a slow s e c o n d m e t a l l a t i o n t o g i v e t h e s o l u b l e i o n
(38).
This species can be trapped t o g i v e d i r e c t l y 2-substituted
phenols.
D i a n i o n s d e r i v e d from more h i g h l y s u b s t i t u t e d p h e n o l s
have a l s o a t t r a c t e d i n t e r e s t .
Thus, t h e dianion (39) is prepared
from t h e p a r e n t a r y l w i t h BunLi ( 2 e q u i v a l e n t s ) ; t h e need f o r a c o r r e c t l y p o s i t i o n e d m e t h o x y s u b s t i t u e n t was d e m o n s t r a t e d b y t h e f a i l u r e of
(40) and (41) t o undergo d i l i t h i a t i o n .
Dianions (42)
a n d ( 4 3 ) c a n b e p r e p a r e d by b r o m i n e - l i t h i u m e x c h a n g e .
28
M e t a l l a t e d t e r t i a r y b e n z a m i d e s a r e u s e f u l p r e c u r s o r s of p o l y substituted benzoic acids.
Benzamide
(44; X = B r ) r e a c t s w i t h a n
363
6: Organometallics in Synthesis
R
R
& (351
%WM OR
RO
( 3 7 ) R ' CHzPh
( 3 6 )R=CH,Ph
S c h e m e 11
Li "
Me0
W
N
M
e
2
L
Me0
i
m
N
M
e
2
Li0&NMe2
Me0
364
'
General and Synthetic Methods
e x c e s s of B u t L i t o g i v e t h e d i l i t h i a t e d s p e c i e s ( 4 4 ; X = Li:]; a d o u b l e d e p r o t o n a t i o n o f ( 4 4 ; X = H ) 'was u n s u c c e s s f u l . Dian'ion ( 4 5 ; X = L i ) was a l s o p r e p a r e d f r o m t h e c o r r e s p o n d i n g d i b r o m i d e ' : ( 4 5 ; X =
Br).
Interestingly,
t r e a t m e n t o f e i t h e r ( 4 4 ; X = H) o r (45; X = H)
( 2 e q u i v a l e n t s ) i n t h e ' p r e s e n c e of Me S i c 1 g a v e , ' t h e
w i t h BuSLi
3
d i s i l y l a t e d a d d u c t s ( 4 4 ; X = TMS) a n d ( 4 5 ; X = TMS).
Bearing i n
m i n d t h a t Me S i c 1 r e a c t s w i t h . . a l k y l - l i t h i u m s o n l y s l o w l y a.t - 7 8
3
OC
i t i s a s s u m e d t h a t a s t e p w i s e lithiation/silylation-lithiationl s i l y l a t i o n s e q u e n c e t a k e s p l a c e . 29 The s u c c e s s f u l u s e o f t h e f u r a n d i a n i o n ( 4 6 ) f o r t h e . s y n t h e s i s of 2,5-disubstituted metallation.
f u r a r p d e p e n d s o n t h e p r e s e n c e of.TMEDA d u r i n g
I n t h e a b s e n c e of TMEDA, n u c l e o p h i l i c a t t a c k a t t h e
o x i m e may b e o b s e r ~ e d . ~ ' T h e c o u r s e o f t h e l i t h i a t i o n o f f u r a n and t h i o p h e n e - 2 - c a r b o x y l i c
a c i d s is c r i t i c a l l y d e p e n d e n t on t h e
i d e n t i t y of t h e lithium base 2,5-
u s e d , a n d c a n be c o n t r o l l e d t o g i v e
a n d 2 , 3 - d i s u b s t i t u t e d h e t e r o c y c l e s . 31
Trisubstituted furans
a n d t h i o p h e n e s h a v e * a l s o b e e n o b t a i n e d by d i l i t h i a t i o n of t h e a m i d e ( 4 7 ) 3 2 a n d t h e o x a i k l i n e ( 4 8 ) ( S c h e m e 12).33 I t i s c l a i m e d t h a t t h e o x a z o l i n e moie-ty i s more r e a d i l y c l e a v e d t h a n t h e d i e t h y l carboxamide.
A new a p p r o a c h t o s u b s t i t u t e d i n d o l e s ( 5 0 ) i n v o l v e s
t h e r e a c t i o n o f t h e d i a n i o n ( 4 9 ) w i t h esters (RC02Et).34 I n comparisun with t h e isomerization of alkynes, t h e basec a t a l y s e d r*ear,rangements o f a l k e n e s a r e l e s s well known. r e a c t i o n s d e s e r v e f u r t h e r a t t e n t i o n , however
,
Such
a s r e c e n t w o r k demon-
strates. A l l y l i c a l c o h o l s , f o r example, rearrange t o g i v e a l d e h y d e s ( 2 5 - 7 4 % y i e l d ) ( S c h e m e 1 3 ) .35 O f p a r t i c u l a r i n t e r e s t i s t h e c o n v e r s i o n o f undec-10-en-1-01 t o undecanal, a l b e i t i n low yield (3%).
The i n t e r m e d i a c y o f a s t a b i l i z e d d i a n i o n ( 5 1 ) i s
plausible
w h i c h i s s u p p o r t e d by t h e o b s e r v a t i o n s t h a t ,
hexen-3-01
f a i l e d t o rearrange.
e.g. c y c l o -
F u n c t i o n a l i z e d c y c l o p r o p e n e s h a v e b e e n p r e p a r e d by a c y c l i z a t i o n Hydro- and ( 5 2 ) (Scheme 14).36
reaction of an alkenyl-lithium carbo-metallation
r e a c t i o n s o f t h e trimethylsilylcyclopropenes ( 5 3 )
have a l s o been d e s c r i b e d . S e v e r a l r e p o r t s h a v e a p p e a r e d d e s c r i b i n g new a p p l i c a t i o n s o f previously developed organolithium reagents. ( 5 4 1 , d e r i v e d from 2 , 3 - d i m e t h y l b u t a d i e n e ,
Thus, t h e dianion
is a u s e f u l synthon o f
s u b s t i t u t e d b u t a d i e n e s a n d d i o l s , 37 w h e r e a s t h e B - l i t h i o t r i m e t h y l s i l y l e n o l e t h e r ( 5 5 ) r e a c t s w i t h a l d e h y d e s a n d k e t o n e s t o g i v e , on h y d r o l y s i s , 0 - s u b s t i t u t e d e n o l s i n good y i e l d s . 3 8 T h e h o m o l o g a t i o n o f e s t e r s via t h e r e a r r a n g e m e n t o f a-bromo-u-
6: Organometallics in Synthesis
365
CONEt,
CONEt,
( 4 5I
(441
OL i
( 4 6I ,Li
CONEt,
Li
CONEt,
CONEt,
Li
El
Li
*,!-LiA%f,yLE2A%f 0
0
0
(481 X = S or 0 Reagents: i , Bu'Li,TMEDA,THF,
- 20
THF,
F1 (
-78 oC;ii,E'+followed
by E 2 + ; i i i , B u S L i ( 2 e q u r v . ) ,
"C[X=S), 78°C(X=0)
Scheme 12
R'
NLi i
y
H
TMS
( 4 91
( 501
CHO
63
$H
O *H
-%
n L i--
-0
74
"10
3"/0
- OLi
. (51) Reagents : i , L i N P N H 2 , H2N/vNH2,120-130 "C; i i , K N H w N H 2 , N H 2 - N H 2 ,
Scheme 13
12OoC
General and Synthetic Methods
366
BunLi
-78 "c
'
Li
Scheme 1 1
Me0
C02Me
Oudemansin P -h
Reagents : i '
, LiCHBr?, - 9 0 "C,
0
t h e n BunLl >-9O t o 0 "C,
CO, M e
II
, MeOH, HCI ; III , LiCHBr2
f o l i o w e d by B I J ~ L I
Scheme 15
LI
Reagents : i , RMgX
, THF
then
Li, - 15 "C ; ii, E ', t h e n H t
S c h e m e 16
then
& Organometallics in Synthesis
367
k e t o d i a n i o n s i s a r e a c t i o n o f some g e n e r a l i t y . V a r i o u s s t e r e o chemical and m e c h a n i s t i c a s p e c t s o f t h e p r o c e s s have been i n v e s t i g a t e d , and t h i s m i l d p r o c e d u r e has been used a s a key s t e p i n t h e s y n t h e s i s o f t h e a n t i f u n g a l a n t i b i o t i c o u d e m a n s i n (Scheme 1 5 ) . O f p a r t i c u l a r i n t e r e s t is t h e h o m o l o g a t i o n of (563 and ( 5 7 ) w i t h complete r e t e n t i o n o f a l k e n e geometry.39 2-Chloropropenal has been c o n v e r t e d i n t o t h e d i a n i o n ( 5 8 ) and used t o s y n t h e s i z e v a r i o u s l y s u b s t i t u t e d a l l y l i c a l c o h o l s (Scheme 1 6 ) . 4 0 ' T h e s e i n t e r m e d i a t e d i a n i o n s ( 5 8 ) show n o t e n d e n c y t o u n d e r go B - e l i m i n a t i o n t o a l l e n e s , a l t h o u g h u n d e r a p p r o p r i a t e c o n d i t i o n s 41 t h i s r e a c t i o n may b e o b s e r v e d . The d i r e c t C - l i t h i a t i o n o f 2 - m e t h o x y p r o p e n o i c a c i d ( 5 9 ; X = O H ) w i t h ButLi a t -100 O C r e s u l t s i n t h e f o r m a t i o n o f t h e d i a n i o n ( 6 0 ; X = O L i 1, a n d t h e c o r r e s p o n d i n g m o n o a l k y l a m i n e s ( 5 9 ; X = N H P r ') u n d e r g o a s i m i l a r t r a n s f o r m a t i o n . 42 The c h e m i s t r y o f l i t h i a t e d c y c l i c e n o l e t h e r s c o n t i n u e s t o be a pr-oductive f i e l d . M e t a l l a t i o n o f l , 4 - d i o x e n e leads t o t h e therma l l y s t a b l e 2 - l i t h i o - d e r i v a t i v e ( 6 1 ) . T h i s s p e c i e s h a s been used t o e f f e c t a two-carbon homologation of a l d e h y d e s and k e t o n e s t o g i v e a-hydroxy- a n d Q , U ' - d i h y d r o x y - k e t o n e s (Scheme 1 7 ) .43 A v e r y c o n v e n i e n t p r e p a r a t i o n of 2 - l i t h i o b u t a - 1 , 3 - d i e n e has been A l l e n e i s well d e s c r i b e d , s t a r t i n g from 2-chlorobuta-I ,3-diene.44 known t o u n d e r g o m o n o l i t h i a t i o n b u t t r e a t m e n t w i t h a n e x c e s s o f BunLi g e n e r a t e s a s p e c i e s ( C H L i ) t h a t i s a h i g h l y e f f e c t i v e 3 2 2 The p r e c i s e s t r u c operational equivalent of a propargyl dianion. t u r e o f t h i s s p e c i e s , i s n o t known b u t i t r e a c t s w i t h a l k y l h a l i d e s t o g i v e a l k y n e s i n good y i e l d (Scheme 1 8 ) a n d n o n e o f t h e i s o m e r i c a l l e n e a d d u c t s have been o b s e r v e d .45 S u l p h u r - s t a b i l i z e d A n i o n s . - As i n p r e v i o u s y e a r s a number o f carba n i o n r e a c t i o n s h a v e r e l i e d on t h e s t a b i l i z i n g e f f e c t o f a s u l p h u r s u b s t i t u e n t a- t o t h e a n i o n c e n t r e . 1 - A l k y l c a r b a z o l e s ( 6 2 ; X = a l k y l ) , f o r e x a m p l e , a r e known t o u n d e r g o C - I l i t h i a t i o n , b u t i n c o n t r a s t t h e FJ-(phenylthio)methyl d e r i v a t i v e (62; X = SPh) c l e a n l y metallates a d j a c e n t t o s u l p h u r and t h i s f e a t u r e h a s been used t o p r e p a r e a v a r i e t y o f % - s u b s t i t u t e d c a r b a ~ o l e s . ~S u~ l p h u r - d i r e c t e d m e t a l l a t i o n of t h e s i l y l a t e d f u r a n s ( 6 3 ) a n d ( 6 4 ) i s a f a c i l e p r o c e s s , a n d t h e r e s u l t i n g a n i o n s may be r e g a r d e d a s s y n t h e t i c a l l y e q u i v a l e n t t o t h e b u t e n o l i d e n u c l e o p h i l e ( 6 5 1. 4 7 Sulphones are e s p e c i a l l y powerful a n i o n s t a b i l i z i n g subs t i t u e n t s . B o t h a- a n d B - 5 - p y r a n o s i d e s h a v e b e e n o b t a i n e d f r o m 2-
General and Synthetic Methods
368
Meo+x
Meo<x (591
Reagents
I,
B I J ~ L I,THF, - 3 0 "C;
11,
(60)
RCOR';
111,
; ' H
IV,
L i A I H l ; v , rn-chloroperoxybenzoic
a c i d f o l l o w e d by NaBHlc
Scheme 17
CH2,jC=CH,
*
[C3H2Li2]
II
R
n . R e a g e n t s : i, Bu L i ( 3 . 5 e q u i v . l ; i i , R X ( R = a l k y l or a l l y [ )
S c h e m e 18
q
a-
TMSO+SPh
0
T MSO
SPh
(63)
SPh ( 641
(65)
6: Organometallics in Synthesis deoxy-D-glycopyranosyl
369 p h e n y l s u l p h o n e ( 6 6 ) ‘(Scheme 1 9 ) .
Reductive
c l e a v a g e of t h e s u l p h o n e g e n e r a t e s a n u c l e o p h i l e t h a t r e a c t s w i t h e l e c t r o p h i l e s t o g i v e t h e a-C-pyranoside alkylation of t h e sulphone-stabilized c l e a v a g e l e a d s t o t h e 8-5-pyranoside
(67).
Alternatively,
anion before reductive ( 6 8 ) . 48
S p i r o a c e t a l s have
b e e n o b t a i n e d f r o m ( 6 9 ) by a l k y l a t i o n w i t h o - a l k o x y a l k y l h a l i d e s f o l i o w e d by a m i l d a c i d ~ o r k - u p , ~ ’a n d t h e u s e o f c y c l i c s u l p h o n e s ( 7 0 ) a s s y n t h e t i c e q u i v a l e n t s of t h e c o r r e s p o n d i n g b u t a d i e n y l a n i o n s ( 7 1 ) h a s been e x p l o i t e d i n t h e s y n t h e s i s of p o l y c y c l i c c a r b o c y c l e s . 50
2-Lithio-2-phenylsulphonylpropane
(72) acts as an alkylidene
t r a n s f e r a g e n t t o w a r d s e l e c t r o p h i l i c a l k e n e s (Scheme 2 0 ) .51
A new h o m o e n o l a t e e q u i v a l e n t h a s b e e n d e v e l o p e d b a s e d on t h e s u l p h o n e -
s t a b i l i z e d a l k o x y c y c l o p r o p y l a n i o n ( 7 3 ) .52 D i a n i o n s b a s e d on s u l p h o n e s a r e a l s o u s e f u l s y n t h e t i c t o o l s . T h u s , t h e [(phenylsulphonyl)methylene]dilithium s p e c i e s (74) undergoes a series of u s e f u l t r a n s f o r m a t i o n s w i t h b i f u n c t i o n a l subs t r a t e s ( S c h e m e 21 and t h e d i a n i o n ( 7 5 ) , d e r i v e d from a - t r i f y l s u l p h o n e s , h a s b e e n u t i l i z e d i n a g e n e r a l s y n t h e s i s of 2 , 3 - d i s u b s t i t u t e d c y c l o p e n t e n o n e s by e x p l o i t i n g t h e d i f f e r e n t i a l r e a c t i v i t y o f t h e two a n i o n i c s i t e s i n ( 7 5 ) . 5 4 The s u b s t i t u t e d k e t e n e S , S - d i t h i o a c e t a l ( 7 6 ) h a s been d e v e l o p e d as a 6 - l i t h i o a c r y l a t e e q u i v a l e n t (Scheme 2 2 ) . D e p r o t o n a t i o n of (76) l e a d s t o an a l l y l i c a n i o n ( 7 7 ) t h a t reacts w i t h a wide range of e l e c t o p h i l e s t o g i v e t h e ? ‘ - s u b s t i t u t e d a d d u c t ( 7 8 ) , a s t h e o n l y observed product. Hydrolysis of t h e ketene t h i o a c e t a l then r e l e a s e s t h e c a r b o x y l r e s i d u e , and t h i s a c t i v a t e s t h e system towards e l i m i n a t i o n of t h i o p h e n o l , t h e r e b y unmasking t h e a c r y l a t e unit.55 D i a n i o n ( 7 9 ) may a l s o b e r e g a r d e d a s a m o d i f i e d B - l i t h i o b u t t h e c h e m i s t r y of t h i s s p e c i e s i s d i v e r s e . Not o n l y h a v e 8 - s u b s t i t u t e d a , 8 - u n s a t u r a t e d a m i d e s b e e n s y n t h e s i z e d , b u t t h e same r e a g e n t r e a c t s , f o r e x a m p l e , w i t h e p o x i d e s t o g i v e u l t i m a t e l y dihydropyrans; t h e s p e c i e s (79) is t h e r e f o r e perh a p s more a c c u r a t e l y r e p r e s e n t e d a s e q u i v a l e n t t o t h e d i p o l a r s p e c i e s ( 8 0 ) .56 acrylate equivalent,
Magnesium.-
An e f f i c i e n t o n e - p o t
synthesis of 2-terphenyls
h a s been
reported t h a t involves t h e reaction of an a r y l Grignard reagent ~ l a t t e r component is (ArMgBr w i t h a t e t r a h a l ~ g e n o a r e n e . ~The
370
General and Synthetic Methods
RO‘
Y I
OR (67)
RO‘
OR ( 6 6 ) R = Si Me2But
Y” RO’ OR (681 Reagents : 1 , L i t h i u m n a p h t h a l i d e , - 7 8 ‘C;
I ~ , E + ( R c H o R, X ,
D~o),
LDA
S c h e m e 19
R1
R
(69)
MeY
71)
Rk52M
OL i 2
Me
X Reagents:
I,
C02Me
( X = H or C02Me
1, THF ;
11
, MeOH , ref l u x
Scheme 20
Me
37 1
6: Organometallics in Synthesis
SO, P h
(73) P h S 0 2 u
b
Li
Li
(743
Y -%
S02Ph
HoV
ti
Ph S OzMe n . R e a g e n t s : i , B u L I ( 2 e q u i v . ) ii, C I / V c '
; ii i,
0
&"
0
h~~ ; iv
S c h e m e 21
CFISOzy i L , , , OS
Li (75)
I PhS
PhS
SPh
Li+ (771
(761 (771
=
--cop ..
.
4-
PhSYYSPh E
Reagents : i , L D A , T H F ;
11,
E +;
iii,
SPh
(78) DBU
R'OH, HgC12 or CF3COZH; i v ,
Scheme 2 2
General and Synthetic Methods
372
I SO, Ph
SO, Ph
Li
1791
R CONHPhRdCONHPh
(801 Reagents : i , Bu"L1
,
H M P A , T H F ; i i , R X , t h e n N a B H L , iii, R / B ,
t h e n KOBut
Scheme 2 3 Mg Br /
-*
-
-
Ph@--Ph
p h - - @ - - - P h
I Mg Br
Br
Z
= H 54 "/o I ( Z = I J 50"/aI
( 82 I ( Z
(811
I
Me
, Ill
Me
Br
60 " / a Reagents :
I ,
PhMgBr
( Lequlv.),
THF;
11,
H 3 0 f or I 2 ;
Scheme 2L
III,
H30+
6: Organometallics in Synthesis
373
e q u i v a l e n t t o a d i - a r y n e , and b o t h s y m m e t r i c a l and unsymmetrical p o l y a r y l s h a v e b e e n p r e p a r e d (Scheme 2 4 ) . The i n i t i a l p r o d u c t , t h e bis-organomagnesium
( 8 1 1 , c a n be s i m p l y p r o t o n a t e d on work-up t o
g i v e ( 8 2 ; Z = HI, o r q u e n c h e d w i t h a n o t h e r e l e c t r o p h i l e , iodine, t o give (82; Z = I).
x.
Obviously o t h e r e l e c t r o p h i l e s could
be u s e d a n d t h i s m e t h o d o f f e r s c o n s i d e r a b l e p o t e n t i a l .
The
r e a c t i o n o f n i t r o a r e n e s w i t h G r i g n a r d r e a g e n t s t o g i v e o r t h o - and para-substituted
n i t r o a r e n e s h a s a l s o b e e n s t u d i e d a n d t h e s c o p e of
t h i s s u b s t i t u t i o n r e a c t i o n , i n terms o f t h e r a n g e o f f u n c t i o n a l g r o u p s t h a t may b e t o l e r a t e d , h a s b e e n d e t e r m i n e d . 58 A l l y l i c a c e t a t e s undergo an asymmetric coupling w i t h ArMgX,
in
t h e presence of a c h i r a l n i c k e l ( I 1 ) c a t a l y s t , t o g i v e (83) i n up t o 89% e n a n t i o m e r i c e x c e s s ( S c h e m e 2 5 ) .59
Bromomagnesium a l k y l a m i d e s
( 8 4 ) , p r e p a r e d from a d i a l k y l a m i n e a n d EtMgBr, r e a c t w i t h e p o x i d e s 60 u n d e r m i l d c o n d i t i o n s t o g i v e 6 - a m i n o a l c o h o l s ( 8 5 ) i n good y i e l d . P r e s u m a b l y c h e l a t i o n of m a g n e s i u m t o t h e e p o x i d e p l a y s a n i m p o r t a n t part in t h i s reaction. Although sulphones have developed a c e n t r a l r o l e i n s y n t h e t i c c h e m i s t r y , t h e removal of t h i s r e s i d u e , a f t e r , f o r example, an a l k y l a t i o n s t e p , can be problematic. Sodium amalgam i s f r e q u e n t l y used, but t h e t o x i c i t y of t h i s r e a g e n t can be a l i m i t i n g f a c t o r . I t h a s now b e e n r e p o r t e d t h a t m a g n e s i u m i n m e t h a n o l i s a n e f f e c t i v e a l t e r n a t i v e r e a g e n t f o r r e d u c t i v e d e s u l p h o n y l a t i o n . 61 Zinc and Mercury.-
There h a s n o t been a great d e a l of a c t i v i t y i n R e f o r m a t s k y r e a g e n t s r e a c t w i t h 0-
t h e organozinc area t h i s y e a r .
s i l y l a t e d c y a n o h y d r i n s t o p r o v i d e t e t r o n i c a c i d s i n good y i e l d s (Scheme 2 6 ) . 6 2 U l t r a s o n i c t e c h n i q u e s h a v e p r o v e d u s e f u l i n t h e p r e p a r a t i o n o f d i o r g a n o - z i n c s (R2Zn) ( f r o m t h e c o r r e s p o n d i n g h a l i d e and Z n ) , a n d t h e p o i n t i s made t h a t R2Zn, w h i c h c l e a n l y u n d e r g o c o n j u g a t e a d d i t i o n t o enones, are well worth c o n s i d e r i n g as an a l t e r n a t i v e t o c u p r a t e - b a s e d methodology .63 U l t r a s o u n d a l s o p r o m o t e s t h e r e a c t i o n o f R2R3C=CHCH2ZnBr t o g i v e homoallylic a l c o h o l s . 64
w i t h aldehydes and k e t o n e s
A new r e d u c i n g a g e n t , made u p o f a m i x t u r e o f N a B H 4 a n d ZnC12 i n a r a t i o of 2 : 1 , h a s b e e n r e p o r t e d t o r e d u c e a v a r i e t y o f c a r b o n y l -
c o n t a i n i n g compounds.65
However, a n h y d r i d e s , a c i d s , e s t e r s , a n d
amides a r e i n e r t , a l t h o u g h a l d e h y d e s and k e t o n e s c a n be deoxyg e n a t e d by r e a c t i o n b e t w e e n t h e r e d u c i n g s y s t e m a n d t h e c o r r e s ponding t o s y l hydrazones. S t e r e o c h e m i c a l c o n t r o l h a s d e v e l o p e d a s a major theme i n s o l v o -
3 74
General and Synthetic Methods
R’-fR’ O
Ar L
I
R
2
Y Me 0
(83) Reagents :
I,
A r M g B r , N1C1~L(S’S)-ChiraphosJ
Scheme 2 5
&Rl
R,NMgBr
(84)
OH ( 85)
HO
--+ Rkosi
R2
Reagent:
I,
CN M e 3
Z n / C u , B r C H CO E t , t h e n H 3 0 t 2 2
Scheme 2 6
&
Me
R
R
l
R
OR’
bR’
0
Me &M
R1
Me
( 9 2 1 R: R ’ = a l k y l , H , o r
R aryl
(931
6: Organometallics in Synthesis
375
m e r c u r a t i o n r e a c t i o n s t h i s y e a r , and t h e i m p o r t a n c e of a neighbouring group i n t h e alkoxymercuration of a c y c l i c a l l y l i c a l c o h o l s has been e s t a b l i s h e d . 6 6
Reaction of t h e f r e e hydroxyl (86; X = H )
leads, after demercuration, t o t h e erythro-adduct
( 8 7 ) , b u t u s e of
( 8 6 ; X = O C O M e o r OCOPh) r e s u l t s i n a p r e d o m i n a n c e o f t h e t h r e o adduct (88; X
O C O M e o r OCOPh).
D e m e r c u r a t i o n of a - m e r c u r o c a r b o x y l a t e s
( 8 9 ) can be c a r r i e d o u t
s e l e c t i v e l y t o g i v e e i t h e r of t h e d i a s t e r e o m e r i c B-hydroxy-esters ( 9 0 ) or ( g l ) , d e p e n d i n g on t h e c o n d i t i o n s u s e d . 6 7 of
NaBH4 r e d u c t i o n
(89) r e s u l t s i n n e t i n v e r s i o n l e a d i n g t o ( g o ) , but propane-1,3-
d i t h i o l removes mercury w i t h r e t e n t i o n of c o n f i g u r a t i o n t o g i v e (91 ). A l l e n i c ketones ( 9 2 ) undergo a c l e a n c y c l i z a t i o n i n t h e presence of Hg(OCOMeI2 i n a c e t i c a c i d t o g i v e 3 ( 2 H ) - f u r a n o n e s 68 in excellent yield.
(93) directly
F u n c t i o n a l i z e d c a r b o c y c l e s may b e s y n t h e s i z e d by t h e c y c l i z a t i o n of t h e s i l y l e n o l e t h e r of a n a c e t y l e n i c k e t o n e (Scheme 2 7 ) . 69 F u r t h e r m o r e t h e p r o d u c t of c y c l i z a t i o n , a Z--vinylmercurial
(95),
undergoes e l e c t r o p h i l i c s u b s t i t u t i o n w i t h r e t e n t i o n of a l k e n e geometry.
C y c l i z a t i o n of
( 9 4 ) t h r o u g h c a r b o n r a t h e r t h a n oxygen i s an
i m p o r t a n t f e a t u r e of t h i s r e a c t i o n , a s a r e t h e m i l d c o n d i t i o n s used.
Enol e t h e r s (96;
fl. = 3 or 4) c y c l i z e t o g i v e ( 9 7 ; ; 3 or
4) i n g o o d y i e l d . P h o t o l y s i s o f RHgC1, i n c l u d i n g t h o s e d e r i v e d by a l k o x y m e r c u r a t o n of
l-alkenes,
i n t h e presence of p y r i d i n e l e a d s t o t h e c o r r e s -
p o n d i n g 2- a n d 4 - a l k y l - p y r i d i n e s
by a f r e e - r a d i c a l
process.”
B e a r i n g i n mind t h e v a l u e of H g ( I 1 ) i n t h e e l e c t r o p h i l i c c h e m i s t r y of a l k e n e s , a l k y n e s t i o n s o f t h e C-Hg
e. (see
b e l o w ) , a n y new m a n i p u l a -
bond a t t r a c t i n t e r e s t .
A l t h o u g h a number o f
t r a n s f o r m a t i o n s of t h i s b o n d a r e a v a i l a b l e t h e d i r e c t c o n v e r s i o n of RCH2-CH2HgX
i n t o RCH=CH2 i s a t p r e s e n t a l o w - y i e l d i n g
process.
A
s o l u t i o n t o t h i s p r o b l e m h a s b e e n p r o p o s e d and r e l i e s on t h e e f f i c i e n t c o n v e r s i o n of C-HgC1
i n t o C-SePh
(Scheme 2 8 ) .7
3 G r o u p I11 Boron.-
The c h e m i s t r y o f o r g a n o b o r a n e s h a s s e e n s i g n i f i c a n t
developments a c r o s s a r a n g e of d i f f e r e n t f r o n t s .
A s with zinc,
u l t r a s o u n d h a s had a n i m p a c t i n t h e b o r o n a r e a .
Alkyl and a r y l
h a l i d e s r e a c t w i t h BF3.Et20 g i v e organoboranes.72
a n d Mg u n d e r u l t r a s o n i c c o n d i t i o n s t o
The r e a c t i o n s a r e r a p i d a n d a l l o w access t o
General and Synthetic Methods
376
Reagents :
5""1
HgCL2 CH2C12 ; 1 1 ) N - b r o m o s u c c i n i m i d e ;
i J
+
*
III
I
MeCOCL; i v , CO, MeOH
S c h e m e 27
Reagents :
I
I
Ph2Se2, PhH , hV ;
11
,
NaI04
S c h e m e 28
J+ OR (99)
*
.+*.
R1
L
0 I
OR2
OR2
( 1 00)
( 1 011
"
6: Organometallics in Synthesis
377
p r o d u c t s s u c h a s t r i a r y l b o r a n e s , t h a t a r e n o t a v a i l a b l e by d i r e c t hydroboration. Ultrasound can a l s o d r a m a t i c a l l y enhance t h e rate A s e r i e s o f commonly u s e d h y d r o -
o f h y d r o b o r a t i o n of a l k e n e s . 7 3
b o r a t i n g a g e n t s h a s been examined i n t h i s c o n t e x t . new s y n t h e s i s of g-alkyl-9-BBN
An e f f i c i e n t
d e r i v a t i v e s ( 9 8 ) h a s been p u b l i s h e d ,
a n d i n v o l v e s r e a c t i o n o f 9-BBN w i t h a homo- o r h e t e r o - c u p r a t e . 7 4 A t t e n t i o n h a s a l s o been paid t h i s y e a r t o t h e h y d r o b o r a t i o n of heteroatom-substituted
alkenes.
hydroboraion-oxidation
of s u b s t i t u t e d e n o l e t h e r s ( 9 9 ) h a s b e e n
studied.
The d i a s t e r e o s e l e c t i v i t y o f t h e
syn ( 1 0 0 ) r a t h e r t h a n a n t i ( 1 0 1 ) p r o d u c t s a r e o b t a i n e d ,
but t h e underlying s t r u c t u r a l f e a t u r e s c o n t r o l l i n g t h e s t e r e o c h e m i c a l o u t c o m e of t h e a d d i t i o n a r e n o t y e t f u l l y u n d e r ~ t o o d . ~A ~ c o m p r e h e n s i v e s t u d y o f t h e h y d r o b o r a t i o n of t h e h e t e r o c y c l i c a l k e n e s ( 1 0 2 ; X = 0 , S , o r N R ; p. = 1 , 2 , o r 3 ) h a s b e e n p u b l i s h e d , and t h e s e r e a c t i o n s show g o o d s y n t h e t i c p r ~ m i s e . ’ ~ P r o b a b l y t h e most i m p o r t a n t a s p e c t of b o r o n c h e m i s t r y t h i s y e a r concerns i t s use i n t h e c o n t r o l of a b s o l u t e stereochemistry. Masamune h a s d e s c r i b e d t h e s y n t h e s i s o f t h e ( R , R ) - b o r o l a n e
well as t h e
a l k e n e s , r e a c t w i t h ( 1 0 3 ) t o g i v e a d d u c t s of h i g h
1,l-disubstituted optical purity.
T h i s r e a g e n t i s c l a i m e d t o be s u p e r i o r t o t h e more
t r a d i t i o n a l terpene-derived (Q)-(103)
(103) as
A wide range of a l k e n e s , a l t h o u g h n o t
o r g a n o b o r a n e s and t h e a v a i l a b i l i t y o f
is a l s o s i g n i f i c a n t .
Once a v a i l a b l e , o p t i c a l l y p u r e
o r g a n o b o r a n e s c a n b e m a n i p u l a t e d i n v a r i o u s w a y s a n d nebi m e t h o d o logy h a s appeared.
Boronic esters ( 1 0 4 ) undergo homologation t o
t h e a-methoxyalkyl
d e r i v a t i v e (105) which is t h e n o x i d i z e d t o g i v e
t h e a l d e h y d e ( 1 0 6 ) .78
Successvie homologations,
( 1 0 8 1 , may b e a c h i e v e d u s i n g t h e o n e - c a r b o n
( 104) t o
u n i t LiCHC12,
by r e d u c t i o n w i t h p o t a s s i u m t r i - i s o p r o p o x y b o r o h y d r i d e (Scheme 2 9 ) . 7 9
or
( 107 )
followed
(KIPBH)
B o t h p r o c e d u r e s a r e a p p l i c a b l e t o a n u m b e r of
boronic esters r e l a t e d t o (104). A l l y l i c boranes g e n e r a l l y undergo r a p i d a l l y l i c rearrangement, but hydroboration of cyclohexa-1,3-diene pinocamphenylborane
with
( + I - or (-)-a-iso-
(Ipc2BH) g i v e s t h e f i r s t example of an o p t i -
c a l l y a c t i v e a l l y l i c b o r a n e ( 1 0 9 ) t h a t is s t a b l e t o w a r d s r e a r r a n g e ment a n d t h e r e f o r e r a c e m i z a t i o n . 8 0
A l l y 1 b o r a n e s are good n u c l e o p h i l e s towards a l d e h y d e s , and t h e s t e r e o c h e m i c a l a s p e c t s of t h i s
r e a c t i o n have f e a t u r e d prominently t h i s year. and L - c r o t y l b o r o n a t e s , dialkoxy-aldehydes,
E-(110)
and L - ( l l O ) ,
The r e a c t i v i t y o f
E-
t o w a r d s c h i r a l a,B-
e.g. ( 1 1 1 ; R = H o r Me) h a s b e e n s t u d i e d .
With
b o t h a l d e h y d e s 2-(110) reacts i n a h i g h l y s t e r e o s e l e c t i v e f a s h i o n ,
General and Synthetic Methods
378
"ec'
CHO
299
>,99O/. Reagents :
I)
LI<"~
,
HgCL2 ;
iil
"j0
e.e
2 9 9 "j0 e.e.
e.e.
H202, NaOH ;
111,
L i C H C L 2 , t h e n KIPBH
OMe
Scheme
(1091
29
(1101 R = H or Me
(111)R = H or Me
379
6: Organometallics in Synthesis whereas a d d i t i o n of a d d i t i o n of t h e
E-
E-( 1 1 0 )
is e s s e n t i a l l y non-selective.81
and 2 - a l k o x y - s u b s t i t u t e d
a l l y l boronate
a l d e h y d e s h a s been e x p l o i t e d i n a s y n t h e s i s of E-brevicomin, a n d t h e r e a c t i o n of t h e t a r t r a t e - b a s e d
The (112) t o a2
boronates (113; R = E t , Pri
or a d a m a n t y l ) w i t h a l d e h y d e s s h o w s h i g h d i a s t e r e o - a n d e n a n t i o s e l e c t i v i t y . 83 Good l e v e l s o f a s y m m e t r i c i n d u c t i o n h a v e a l s o b e e n o b s e r v e d i n t h e s y n t h e s i s o f a m i n o a c i d s by t h e a d d i t i o n o f a l l y l b o r a n e s t o a 84 i m i n o e s t e r s (Scheme 3 0 ) . The a s y m m e t r i c r e d u c t i o n o f c a r b o n y l c o m p o u n d s u s i n g b o r a n e s h a s been f u r t h e r developed,
p r i n c i p a l l y by B r o w n ' s r e s e a r c h g r o u p .
g-
(3-Pinanyl)-9-borabicyclo~3.3.l~nonane, ' A l p i n e b o r a n e ' , r e d u c e s prochiral ketones with high enantioselectivity i f t h e reagent is u s e d e i t h e r i n n e a t or h i g h l y c o n c e n t r a t e d (12M) f o r m . 8 5 If used i n d i l u t e s o l u t i o n t h e r e a g e n t t e n d s t o d i s s o c i a t e t o 9-BBN a n d ap i n e n e and l i t t l e asymmetric r e d u c t i o n i s o b s e r v e d .
Midland had
p r e v i o u s l y s o l v e d t h i s p r o b l e m by p e r f o r m i n g t h e r e d u c t i o n a t h i g h (>5000 a t m ) b u t B r o w n ' s p r o c e d u r e i s m o r e c o n v e n i e n t t o Di-isopinacamphenylchloroborane ( 1 1 4 ) h a s b e e n p r e p a r e d a n d 86 r e d u c e s a r o m a t i c p r o c h i r a l k e t o n e s (298% e.e.1. R e a c t i o n of K H w i t h B-alkoxy-9BBN g e n e r a t e s a new g r o u p o f borohydrides (115; R = a l k y l ) t h a t reduce c y c l i c ketones with a
pressure use.
s e l e c t i v i t y t h a t i s d e p e n d e n t on t h e s t e r i c r e q u i r e m e n t s o f t h e alkoxy residue,
2. the
n a t u r e of R-87
Chiral boronates
( R * B ( O E t ) 2 ) , w h i c h a r e a v a i l a b l e by a s y m m e t r i c h y d r o b o r a t i o n , a r e r e d u c e d w i t h LiAlH,,
t o g i v e t h e monoalkylborohydride
(R*BH3Li).
D i a l k y l b o r o h y d r i d e s ( R * 2 B H 2 L i ) may b e p r e p a r e d i n a s i m i l a r m a n n e r , and a l t h o u g h t h e i r r e a c t i v i t y h a s n o t been e x p l o r e d t h e s e would be 88 e x p e c t e d t o be u s e f u l r e d u c i n g a g e n t s . F i n a l l y t h e s y n t h e s i s of
1,8-naphthalenediylbis(dimethylA l t h o u g h l i t t l e i s known o f t h e
b o r a n e ) ( 1 1 6 ) h a s been r e p o r t e d . c h e m i s t r y of
( 1 1 6 ) , r e a c t i o n w i t h KH t o f o r m a b o r o h y d r i d e d o e s
o c c u r , and ( 1 1 6 ) h a s been a p t l y
named
'hydride
Aluminium a n d T h a l l i u m . -
Two new r e a g e n t s , m e t h y l a l u m i n i u m b i s ( 2 , 6 -
di-t-butyl-4-phenoxide)
(MAD) ( 1 1 7 ) , a n d m e t h y l a l u m i n i u m
bis(2,4,6-tri-t-butyl-4-phenoxide)
(MAT) ( 1 1 8 1 , h a v e b e e n p r e p a r e d
and t h e s e b u l k y Lewis a c i d s h a v e b e e n u s e d t o c o n t r o l t h e s t e r e o s e l e c t i v i t y of n u c l e o p h i l i c a t t a c k t o c y c l i c ketones."
Reaction
of s u b s t i t u t e d c y c l o h e x a n o n e s w i t h a l k y l - l i t h i u m s or G r i g n a r d r e a g e n t s , i n t h e p r e s e n c e o f MAD o r MAT, r e s u l t s i n a x i a l a t t a c k t o
3 80
General and Synthetic Methods
Me
L
( 1121
(113)
7
phyN I
YcozB P h y N H
Me
I
Me Scheme 30
R 0-At-0 (117) M A D , R = H
(118) M A T , R = B U *
S c h e m e 31
6: Organometallics in Synthesis
38 1
give the equatorial t e r t i a r y alcohol. I n a d d i t i o n M A D a n d MAT promote a h i g h l e v e l of anti-Cram s e l e c t i v i t y i n a d d i t i o n s t o acyclic aldehydes.
C o n t r o l experiments have demonstrated t h a t an
aluminium 'ate'-complex
i s n o t l i k e l y t o be i n v o l v e d ; r a t h e r MAD
a n d MAT c o - o r d i n a t e o x y g e n and t h i s b u l k y c o m p l e x r r e f e r s a n equatorial orientation.
MAC h a s a l s o b e e n u s e d t o c o n t r o l t h e
o u t c o m e of t h e r e d u c t i o n o f c y c l o h e x a n o n e s . The n u c l e o p h i l i c p r o p e r t i e s o f a l a n e s h a v e been e x p l o i t e d i n some u s e f u l w a y s .
Furanosyl and pyranosyl f l u o r i d e s r e a c t w i t h a
wide r a n g e of o r g a n o a l a n e s t o g i v e C - g l y c o s i d e s U n s a t u r a t e d a c e t a l s and o r t h o e s t e r s
( S c h e m e 31 ) . 9 2
undergo a palladium-catalysed
a d d i t i o n o f o r g a n o a l a n e s (Scheme 32 .93
An S N 2 ' - t y p e d i s p l a c e m e n t
i s o b s e r v e d a n d i n t h e c a s e of o r t h o e s t e r s t h e r e a c t i o n p r o c e e d s t o g i v e an e s t e r ; k e t e n e a c e t a l s are n o t o b s e r v e d . A s y n t h e s i s of t r a n s - 2 , 5 - d i s u b s t i t u t e d
tetrahydrofurans
(120)
h a s b e e n d e v e l o p e d t h a t i s b a s e d on t h e c y c l i z a t i o n o f 4 - a l k e n o l s ( 1 1 9 ) i n t h e p r e s e n c e of T l ( I I I ) . 9 4
Although an o r g a n o t h a l l i u m i s
presumably involved t h i s i n t e r m e d i a t e is n o t i s o l a b l e , but underg o e s d e t h a l l a t i o n with concomitant
1,2-oxygen m i g r a t i o n t o g i v e
(120). 2 - P h e n y l i n d o l e s may b e c o n v e n i e n t l y s y n t h e s i z e d by r e a c t i o n o f a 2-thallated
a n i l i d e w i t h a C u ( 1 ) - a c e t y l i d e f o l l o w e d by c y c l i z a t i o n
o f t h e i n t e r m e d i a t e a l k y n e w i t h P d ( I 1 ) (Scheme 3 3 ) . 9 5
4 GrouD I V S i l i c on . - A11y1-
and V i n y l - s i l a n e s .
S e v e r a l new m e t h o d s h a v e b e e n
developed for t h e p r e p a r a t i o n of a l l y l s i l a n e s .
Fleming h a s a l r e a d y
shown t h a t t e r t i a r y a l l y l i c a c e t a t e s r e a c t w i t h t h e s i l y l c u p r a t e This chemistry has r e a g e n t (PhSiMe ) CuLi t o g i v e a l l y l s i l a n e s . 2 2 now b e e n e x t e n d e d t o s e c o n d a r y a l l y l i c a c e t a t e s a n d u r e t h a n e s t o
.
g i v e a l l y l s i l a n e s w i t h r e a s o n a b l e l e v e l s o f s t e r e o s e l e c t i v i t y 96 r e l a t e d r e a g e n t , Me SiCH2Cu, w h i c h i s p r e p a r e d f r o m L i C u B r 2 a n d
3
Me SiCH2MgC1, h a s b e e n u s e d t o p r e p a r e a r a n g e of f u n c t i o n a l l y 3 s u b s t i t u t e d a l l y l s i l a n e s (Scheme 3 4 ) .97 T h e s e l e c t i v i t y s h o w n by a l l y l s i l a n e s t o w a r d s e l e c t r o p h i l e s makes asymmetric s y n t h e s i s v i a c h i r a l s i l a n e s an a t t r a c t i v e p r o s pect.
A s e r i e s of o p t i c a l l y a c t i v e a l l y l s i l a n e s h a s b e e n p r e p a r e d
by c a t a l y t i c a s y m m e t r i c h y d r o s i l y l a t i o n o f l - a r y b u t a d i e n e s 35).98
(Scheme
Good s e l e c t i v i t y i s o b s e r v e d f o r t h e f o r m a t i o n o f t h e
z-
isomer ( 1 2 1 ) a n d e n a n t i o m e r i c e x c e s s e s a r e i n t h e r a n g e 2 9 - 6 4 % .
A
General and Synthetic Methods
382
R
w OMe
OMe
RVKoEt 0
Reagent :
I ,
R 3 A l , [Pd(PPh3)J
Scheme 32
9
H
R
(119 I
(120)
‘NCOM~
R
R
Reagents :
I ,
Cu-CEC-Ph,
MeCN
,A
., i i , P d C L 2 , MeCN Scheme 33
H
f o l l o w e d by KOH
6: Organometallics in Synthesis
383
R C02Me
R-
- C02Me
i
- S02Ph
R-
S02Ph Scheme 3d Ar
V
A
r
mSi(0E
I
Me
H
(121 1 Reagents :
I,
H S I C I ~ ,PdCL2
R ) - PPFA], t h e n
EtOH
, NEt3
Scheme 3 5 Me3Si
'1 HC02H
Et O Ph
Ph
b Ac
Ac
Me,S i H C02H
Ph Ac Scheme 36
General and Synthetic Methods
3 84
T h i s m e t h o d d o e s c o m p l e m e n t a s y m m e t r i c c o v F l i n g r e a c t i o n s b a s e d on Grignard r e a g e n t s which t e n d t o g i v e a predominance of t h e
E-
allylsilane. The i n t r a m o l e c u l a r r e a c t i o n o f a l l y l - a n d p r o p a r g y l - s i l a n e s c y c l i c 1-acyliminium
.”
with
ions has led t o several applications for
Acyclic 1-acyliminium i o n s , generated & s i t u , are a l s o r e a d i l y trapped, i n an intramolecular fashion, with
alkaloid synthesis
a l l y l - and p r o p a r g y l - s i l a n e s allenyl-substituted
(Scheme 3 6 ) t o g i v e a l k e n y l - and
heterocycles respectively. loo
T h i s mode o f r e a c t i v i t y is a l s o l i k e l y t o find synthetic application. T r a p p i n g o f a s u l p h o n i u m i o n by a n a l l y l s i l a n e h a s b e e n u s e d t o generate large-ring (Scheme 3 7 ) .
l a c t o n e s , e x e m p l i f i e d by p h o r a c a n t h o l i d e ( 1 2 2 )
The s u l p h o n i u m i o n i s g e n e r a t e d f r o m a n a - c h l o r o -
s u l p h i d e u s i n g a Lewis a c i d and t h i s p a r t i c u l a r c y c l i z a t i o n r e a c t i o n d o e s n o t r e q u i r e t h e u s e of h i g h d i l u t i o n c o n d i t i o n s . 101 S u b s t i t u t e d h y d r i n d a n o n e s h a v e b e e n p r e p a r e d by a n i n t r a m o l e c u l a r Sakurai reaction but t h e stereochemistry of t h e products obtained d e p e n d s g r e a t l y on t h e c a t a l y s t , f l u o r i d e or L e w i s a c i d , u s e d (Scheme 3 8 ) . I o 2
The g e o m e t r i c a l l i m i t a t i o n s o f t h e i n t r a m o l e c u l a r
a d d i t i o n o f a n a l l y l s i l a n e t o a n e n o n e , a s i n Scheme 3 8 , h a v e a l s o been d e f i n e d . l o 3
The s a m e r e s e a r c h g r o u p h a s a l s o s t u d i e d t h e
r e g i o s e l e c t i v i t y of a d d i t i o n t o d i e n o n e s s u c h a s ( 1 2 3 ) .
Allyl-
s i l a n e s u s u a l l y undergo an i n t e r m o l e c u l a r 1 , 4 - a d d i t i o n
t o dienones
a n d t h i s s e l e c t i v i t y , t o g e t h e r w i t h some 1 , 2 - a d d i t i o n ,
is observed
with (125).
However, a Lewis a c i d - p r o m o t e d
e x c l u s i v e l y t o t h e 1,6-adduct
(124).
cyclization leads
Regioselectivity
is a l s o a
f u n c t i o n of s t r u c t u r e , a n d a p p a r e n t l y s u b t l e c h a n g e s can h a v e dramatic consequences.
The d i e n o n e ( 1 2 5 1 , f o r e x a m p l e , u n d e r g o e s
o n l y 1 ,6 - a d d i t i o n u s i n g b o t h s e t s o f r e a c t i o n c o n d i t i o n s . S u b t l e Lewis a c i d e f f e c t s have a l s o been observed i n t h e a d d i t i o n
of a l l y l s i l a n e (CH2=CH-CH2SiMe t o carbohydrate-derived alde3 hydes. Io5 A l l y l s i l a n e s undergo an i n t e r e s t i n g p h o t o s u b s t i t u t i o n r e a c t i o n with p-dicyanobenzene t o g i v e monoallylated products (126; R
various alkyl).
2-Dicyanobenzene
a l s o undergoes photo-
s u b s t i t u t i o n a n d b e n z y l s i l a n e s may b e u s e d i n p l a c e o f a l l y l s i l a n e s . 106 Although s i l y l g r o u p s are v e r y u s e f u l , f o r example i n d i r e c t i n g m e t a l l a t i o n i n r e a c t i o n s , m a n i p u l a t i o n of t h e C-Si problematic.
bond c a n b e
A l l y l s i l a n e s c a n , however, be d i r e c t l y c o n v e r t e d i n t o
e n o n e s by a P d ( I 1 ) - c a t a l y s e d p h o t o - o x i d a t i o n ( S c h e m e 3 9 ) . l o 7 T h e r e a c t i o n i s t h o u g h t t o i n v o l v e e l e c t r o p h i l i c s u b s t i t u t i o n by P d ( I 1 )
385
6: Organometallics in Synthesis
Me3Si
PAo
EtA'C'2,
CI
SPh
Go -+
~
(122)
SPh
Scheme 37
Scheme 3 8
(124)
(1231
I1251
R (126)
I
0
SiMe3 Scheme 3 9
0
General and Synthetic Methods
3 86
t o g i v e a n i n t e r m e d i a t e r ~ ~ - p a l l a d i u mc o m p l e x , w h i c h i s known t o undergo photo-oxidation. The c h e m i s t r y o f v i n y l s i l a n e s h a s a l s o s e e n some i n t e r e s t i n g developments.
A high l e v e l of regio-
observed i n t h e Pd(I1)-catalysed a r y l a c e t y l e n e s (ArC-CH)
is
and s t e r e o - s e l e c t i v i t y
a d d i t i o n o f Me S i C N t o t e r m i n a l
3
t o give 2-(127)
i n good y i e l d .
O8
Similarly
v i n y l s i l a n e s ( 1 2 8 ) a n d ( 1 2 9 ) h a v e b e e n o b t a i n e d by a N i ( 0 ) catalysed hydrocyanation
(Scheme 4 0 ) ; t h e r e g i o c h e m i s t r y o f
a d d i t i o n o f H C N i s c o n t r o l l e d by t h e b u l k o f t h e s i l y l r e s i d u e . l o 9 E l e c t r o c h e m i c a l methods have a l s o been used t o p r e p a r e a r a n g e o f and e f f i c i e n t r o u t e s t o a series 111
s i l i c o n - c o n t a i n i n g compounds, l o
of s i l y l a t e d d i e n e s ( 1 3 0 ) - ( 1 3 3 ) have a l s o been r e p o r t e d . Nucleophilic silanes,
e.g. B u t 2 ( P h S i M e 2 ) Z n L i
c a t i o n i n t h e s y n t h e s i s of v i n y l s i l a n e s
have found a p p l i -
(Scheme 41 )
.
l2
The r e g i o -
c h e m i s t r y o b s e r v e d i s a f u n c t i o n of a l k y n e s t r u c t u r e and t h e catal y s t [ C u ( I ) or P d ( O ) l u s e d ; t h e i n t e r m e d i a t e a l k e n y l z i n c ( 1 3 4 ) c a n be t r a p p e d w i t h v a r i o u s e l e c t r o p h i l e s ,
thereby increasing t h e scope
of t h e process. Although v i n y l s i l a n e s have o f t e n been p r e p a r e d from a l k y n e s , t h e r e v e r s e r e a c t i o n was u n t i l t h i s y e a r u n k n o w n .
Dehydrosilylation
c a n , h o w e v e r , be e f f e c t e d u s i n g PhIO a n d a s u i t a b l e L e w i s a c i d . ’ 1 3 Other Silicon-containing Reagents.
A s a group, a c y l s i l a n e s have
been u n d e r v a l u e d as f a r as t h e s y n t h e t i c c h e m i s t i s c o n c e r n e d .
A
mild and f l e x i b l e s y n t h e s i s of a c y l s i l a n e s h a s been r e p o r t e d t h a t
i s b a s e d o n t h e a l k y l a t i o n o f methoxy(pheny1thio)trimethylsilylmethane ( 1 3 5 ) (Scheme 42 )
.
T h e h i t h e r t o unknown p a r e n t a c y l -
s i l a n e , Me SiCHO, h a s a l s o b e e n p r e p a r e d a n d u s e d a s a s u b s t r a t e i n 3 W i t t i g r e a c t i o n s . 115 a,B-Unsaturated allyl-
a c y l s i l a n e s undergo conjugate addition with
and a l l e n y l - s i l a n e s .
The l a t t e r r e a g e n t s have been u s e d
i n c a r b o c y c l i c s y n t h e s i s (Scheme 4 3 ) .
The f i r s t example o f a
c y c l o p r o p y l a c y l s i l a n e ( 1 3 7 ) h a s a l s o been d e s c r i b e d . expansion of
l6
Ring
( 1 3 7 ) w i t h TiC14 o c c u r s a t low t e m p e r a t u r e and w i t h a
much g r e a t e r f a c i l i t y t h a n t h e a n a l o g o u s r e a r r a n g e m e n t o f c y c l o propyl ketones t o give a-silylated
cyclobutanone (138).
c i e n t s y n t h e s i s of a , B - u n s a t u r a t e d
a c y l s i l a n e s based on a c l e v e r
a p p l i c a t i o n of t h e s i l y l Wittig-Brook
An e f f i -
r e a r r a n g e m e n t h a s been
d e v e l o p e d by t h e same r e s e a r c h g r o u p .
New a p p l i c a t i o n s of t h e Peterson r e a c t i o n have appeared.
Thus,
t h e benzylsilane (139) undergoes l,4-fragmentation1 t h e benzyl
387
6: Organometallics in Synthesis Ar
NC
h
S i Me3
( 1271
NilO),HCN
ph3s+R NC (1281
*
Me,Si
Ni(O), HCN
R,Si-=-R’
_____)
R = Ph
R=Me
CN (129 1 S c h e m e LO OMe
Me3Si
1
M e 3 S i d
(1301
OMe
M e 3 S i d
(1311
(1321
Me,Si
fi
pR’ (1331
R
P h M e2S i
R-E-R’
RxR’
R)qR’
R2X
ZGBu;
PhMe,Si
Lit (1341
__J
PhMe2Si
R~
*HO
R Ph M e2Si
Reagent: i , E 4 ( P h M e 2 S i ) Z n L I
a n d either
C u C N or [PdIF‘Ph,)J
S c h e m e dl
R Si Me,
S i Me3
S i Me,
(1351 Reagents : i , B u n L i , HMPA t h e n ‘ R X ; i i , N a I O L
S c h e m e 42
388
General and Synthetic Methods
equivalent of a Peterson reaction, to give an 2-quinodiaethane, 118 and enolates derived from a-silyl-lactones (140) react with aldehydes and ketones to give (El-a-alkylidene-lactones in good The stereospecific fragmentation of a 8-hydroxysilane yield. has been exploited in the synthesis of isomerically pure enamines. 120 r-Hydroxysilanes (141) undergo oxidative fragmentation to give keto-olefins of predictable structure (Scheme 44). This process has been shown to be quite general. 121 Two new organosilyl protecting groups (142) and (1431, bound to a styrene-divinylbenzene copolymer, have been prepared, and their use for hydroxyl protection has been demonstrated. 122 Finally the chiral acid (1441, obtained in optically pure form by resolution, has been used to assess the optical purity of alcohols, amines, by 'H n.m.r.123 The advantage of (144) is that the signal observed for Si-Me is always sharp, and appears in an uncluttered part of the spectrum.
'"
a.,
Tin and Lead.- The synthetic scope, in terms of bcth the preparation and available transformations, of organoztannanes has seen further developments this year. Two research groups have reported on the reactivity of (trialkylsily1)trialkylstannanes towards a range of n-systems (Scheme 45); the silylstannane (145) undergoes a regio- and stereo-specific Pd(0)-catalysed addition to terminal alkynes to give (146), and the regioselectivity of the addition of (145) to Ill-dimethylallene depends on the amount of palladium catalyst used. 124 Larger quantitites of catalyst favour addition to the less hindered n-bond to give (147). Similar reactions have been observed between al.l.ynes and ButMe2SiSnMe 125 The research 3' group at Dupont has also carried out the addition of Me SiSnBu" 3 3 (148) to cyclohexenone. The initial addition is catalysed by KCN, but not fluoride, and the intermediate enol ether is converted into the 8-stannyl-ketone ( 149) in 75% overall yield. 125 Ketones related to (149) prcvide ready access to y-stannyl tertiary alcohols (150), which Ere known to undergo oxidative fragmentation in the presence of Pb(OAc)4 or an acid-catalysed cyclization to give cyclopropanes (Scheme 46). 126 A variety of mixed-metal trialkylstannanes (151)-(153) react with terminal alkynes ( R C X H ) to give mainly vinylstannanes (154) in the presence of a transition metal catalyst. 127 Under similar conditions vinyl iodides (155; X = I) react with (153) to give the
3 89
6: Organometallics in Synthesis
SI Me3
Reagents:
I ,
T I C I ~ , -78OC; ii,(136),TiCI4,-5O0C; 111,warm t o -5OOc;1v,
=C< (136) Me
H 2 0 2 , NaOH
Scheme 43 SiMe3
LA
Me S i PhMe,
ToSiph~.,
&OH
Me ( 1371
R&siphMe2 R ( 1 391
(1381
(1401
Scheme bd
R Polymer-Si
Ph
I
I
-Cl
Me-
I
R
Six/\
Ph
( 1 4 2 )R = Me
(1441
(1431 R = P h Me3Si Sn Me, ( 1 L5)
CO, H
390
General and Synthetic Methods
Me
(145)
Me >C=
[Pd( PPh3kl
*
Me
M bSi Me3 SnMe3
>--c
Me
SiMe3Me3
(1L7)
( 1 491 Reagents:
I ,
Me3SiSn B u n 3 ( 1 4 8 1 , c a t a l y t i c K C N , 1 8 - c r o w n - 6 ;
Scheme L5
R’
(150)
R’
S c h e m e 46
I I
;F-
391
6: Organornetallics in Synthesis
-
Bun3Sn A l E t2
(151)
R
( 6un3Sn1,Zn
Bun3SnMgMe
(1521
(153)
SnBun3
x
f15L1
(1551
Me3Sn(SPh1CuL i
Me3SnCu. Me, S
(157)
( 156)
RYcoNMe R-
= - -c
If \
\ NMe,
Me3Sn E - ( I 58)
)-7CONMe2
Me3Sn
Z- (158)
e2
RHcoNM
M e3S n
"
Cu "
392
General and Synthetic Methods
isomeric stannane (155; X SnBun3). Enol triflates (155; X = OSO CF 1 are also precursors of vinyl stannanes (155; X = SnBu" 2 3 3)' The nucleophilic addition of the (trimethylstanny1)cuprates (156) and ( 1 5 7 ) to propiolamides can be controlled to give E-(158) or 2-(158) selectively (Scheme 47). Tetrasubstituted vinylstannanes may be obtained by alkylation of the initial product of addition, a vinylcopper species (159). 128 An efficient synthesis of 2-(tri-n-butylstannyl)buta-l,3-diene (1601, an established precursor of 2-lithiobuta-l,3-diene, has been developed. 129 The Diels-Alder reactions of (160) also offer considerable potential since the cycloadduct retains a vinyltin moiety. a-Substituted allylstannanes (161) have been obtained from 8 stannyl esters using a selenoxide elimination as the key step (Scheme 48). 3 0 In the case of secondary selenides such as ( 1621, the orientation of elimination is dependent on the nature of R 3 , but homoallylic stannanes (163) tend to predominate. Allylstannanes (161) were also shown to be stable towards allylic rearrangement. One of the most interesting chemical transformations described this year involves the stereospecific oxidative fragmentation of the B-stannyl oximes (164) and (165).131 The products of the cleavages are nitrones which can be trapped in an intramolecular fashion to give AL-isoxazolines. Bifunctional stannanes (166) and (167) have played a central role in a number of recent annulation sequences (Scheme 50). Lee et al. have used (166) in a one-pot annulation of cyclic ketones, 32 and bicyclic 1 ,3-dienes ( 168) have been prepared by Piers using, as a key step, the Pd(0)-catalysed coupling of an en01 triflate and a vinylstannane. 33 Another bifunctional stannane (169) has been developed by Trost for use in a two-step [ 3 + 2 1 addition of C = X (X = 0 or N R ) (Scheme 51). Imines derived from ketones do not apparently undergo this C3+21 addition, but aldehydes, ketones, and aldimines may all be used successfully. 34 Allylstannane (770) reacts with aldimines, in the presence of TiC14 or B F 3 , to give homoallylic amines. 135 In the case of the butenyl derivative (171) the stereoselectivity of the addition is very sensitive to the reaction conditions used. The allylstannane (170) also reacts with N - - ( a l k o x y c a r b o n y l ) p y r i d i n i u m salts to give the 2-allylated adducts with a much higher regioselectivity than that observed with the corresponding Grignard reagents
6: Organometallics in Synthesis
393
(161) R ' , R 2 = Me, Ph, or H
R3nMe SnR3 S e A r
SnR3
(162) Reagents: i , L i A I H L ;
11,
(163)
2-N02C6HLSeCI, Bun3P,
ill,
MCPBA
Scheme 4 8
Ho,
hMe N
f ,
+ ,
G
0-
M
e
N-0
+ I,
&Me
SnBu"3 ( 1 64)
6 +/
Ho,
&Me
i,
0-
1 1 )
Sn~u"3 (1651 Reagents
:
Pb(OAc14
I
- 60 C'
; 1 1 , NaHC03, 20aC
Scheme L9 OH
Me0 Me0
k
SnMe3
[ 166)
0 Me
(1 67)
(1681
Scheme 50
General and Synthetic Methods
394
A
c
O
A Sn6un3
( 1 69)
\ R Reagents:
I,
RRICO, BF3. E t 2 0 , t h e n P d ( O A d 2 , Ph3P; ii, RCI-i=NR2, BF3. Et20,then Pd[OAc)*,
Ph3P
Scheme 51
R
wS n B u n 3 (170) R = H (171 1 R =
(1721
Me
R1
R'
R
>S02Ph
-&
> R
R1 4
4
R
>CN
Reagents: i , BunL! , ( 1 7 2 1 , t h e n 6 u n L N F ; 1 1 , L D A , ( 1 7 2 ) , t h e nM e L i . L i B r
I
R' B u 3 S n /+ A -K 0
R e a g e n t : i , [Pd(Ph3P),C12]
Scheme 5 3 Sn CI 2
I
RCHO
Scheme 5 4
6: Organometallics in Synthesis ( CH2=CHCH2MgBr).
395
36
(1odomethyl)tri-n-butylstannane (172) is a useful reagent for the methylenation of moderately hindered sulphones and nitriles (Scheme 52). 137 This reagent is considerably more reactive than the corresponding silane. Palladium(I1)-catalysed cross-coupling reactions involving stannanes have continued to be developed. a-Halogeno-esters and -1actones couple with allylstannanes and a-stannyl-ketones in good yield (Scheme 53 1 . 138 Symmetrical and unsymmetrical a-diketones are available from coupling of acyl halides and acylstannanes. 39 These types of coupling procedures, though useful, may be limited by the availability of the requisite stannane. A promising solution to this problem involves reaction of readily available allylic acetates with aryl halides in the presence of hexa-n-butyldistannane (Bun3SnSnBun3).140 This avoids the need to prepare the previously used substrate, the arylstannane, and it will be interesting to see whether this technique becomes applicable to processes such as those shown in Scheme 53. Stannous chloride, in conjunction with l-bromo-3-iodopropene1 has been used to convert aldehydes directly into conjugated dienes, in fair to good yield (Scheme 54). a,B-Unsaturated aldehydes have also been used to obtain trienes. 141 Two new organolead reagents (173) and (174) have been described. Both anions are good nucleophiles, reacting with a wide range of electrophiles to give adducts incorporating one or two Ph Pb 3 residues respectively. 142 5 Group V Phosphorus.- As in previous years the chemistry of the Wittig reaction and related processes has been the subject of a large proportion of the publications in this area. Various stereochemical aspects of the Wittig reaction have been described. a Oxygenated cyclohexanones and 2,3-epoxycyclohexane react with Ph P-CHMe to give the L-ethylidene derivatives in a highly stereo3 selective fashion (Scheme 55) under both Li-base and Li-free con-
'
ditions. 43 The presence of anionic nucleophilic groups in the side-chain of triphenylphosphonium ylides (175; X OH, C02H, or is known to influence dramatically the stereochemistry of a l k e n e s formed by the Wittig reaction. This phenomenon has been NH2)
the subject of a detailed study, and although the effect is most
396
General and Synthetic Methods
Ph, P b C H2Li
(
(173)
Ph,Pbl,CHLi (17-L)
Ph P=CHMe
&OR
" ? T O R
R = a l k y l or SIR'
3
Ph3P=CH Me
"b0
Scheme 5 5
I
HO
Reagents
qCHO' II
: i , (EtO)2POCH2C02Et,K 2 C 0 3 , H20; i i , KOH
Scheme 56
Ph,P+ OH
BF
6: Organometallics in Synthesis
397
p r o n o u n c e d w i t h a r y l a l d e h y d e s , i t i s a l s o h i g h l y d e p e n d e n t on t h e d e g r e e o f s e p a r a t i o n of t h e y l i d e and t h e n u c l e o p h i l i c r e s i d u e 144 X. Generally t h e c o n d i t i o n s r e q u i r e d t o c a r r y o u t t h e Horner-Wittig r e a c t i o n are n o t compatible with s e n s i t i v e f u n c t i o n a l groups such
as hydroxy-, n i t r o - , mally be p r o t e c t e d .
and keto-aldehydes; t h e s e r e s i d u e s must norHowever, t h e u s e o f a h e t e r o g e n e o u s b a s e s u c h
as K 2 C 0 3 i n e i t h e r a q u e o u s o r o r g a n i c m e d i a a l l o w s t h e c o n d e n s a t i o n of t h e s e s e n s i t i v e s u b s t r a t e s w i t h a c t i v a t e d phosphorates t o t a k e place directly. The s y n t h e s i s o f ' R o y a l J e l l y ' a c i d f r o m 8 h y d r o x y o c t a n a l a p t l y i l l u s t r a t e s t h e method (Scheme 5 6 ) . 145 S c h l o s s e r h a s d e s c r i b e d v a r i o u s a p p l i c a t i o n s of h i s ' i n s t a n t y l i d e ' m e t h o d o l o g y . 1 4 6 T h i s r e l i e s on t h e c o n v e n i e n t u s e o f a p r e m i x e d b a s e (NaNH2) a n d p h o s p h o n i u m s a l t t h a t a r e s t a b l e i n t h e absence of a solvent. A number o f s u c h c o m b i n a t i o n s a r e c o m m e r c i a l l y a v a i l a b l e and y l i d e f o r m a t i o n t a k e s p l a c e ' i n s t a n t l y '
on
dissolution. P r o b l e m s h a v e , h o w e v e r , b e e n e n c o u n t e r e d when u s i n g phosphonium s a l t s s u c h a s ( 1 7 6 ) t h a t c o n t a i n ' k i n e t i c a l l y a c i d i c ' protons. The ' i n s t a n t y l i d e ' m i x t u r e s w e r e f o u n d t o b e u n s t a b l e b u t t h i s was r e s o l v e d by p r e - c o a t i n g t h e p a r t i c l e s o f N a N H 2 w i t h p a r a f f i n ; t h e s e new m i x t u r e s a r e now s t a b l e u n t i l a s o l v e n t i s a d d e d , a n d t h e b a s e becomes a v a i l a b l e . The s y n t h e s i s a n d r e a c t i v i t y o f t h e a - l i t h i o - y l i d e g e n e r a t e d some c o n t r o v e r s y t h i s y e a r ( S c h e m e 5 7 ) .
(178) has
This reagent,
f i r s t d e s c r i b e d by C o r e y , was g e n e r a t e d by d e p r o t o n a t i o n o f t h e y l i d e ( 1 7 7 ) w i t h BuSLi o r B u t L i . I n r e s p o n s e t o a p u b l i c a t i o n from S c h l o s s e r , 47 t h e H a r v a r d g r o u p h a s now p u b l i s h e d f u l l e x p e r i m e n t a l d e t a i l s t o support t h e i r earlier report. Almost s i m u l t a n e o u s l y t h e L a u s a n n e g r o u p h a s r e F , c r t e d o n t h e i r own work i n t h e a r e a . 1 4 9 They claim t h a t r e a c t i o n o f ( 1 7 7 ) w i t h BuSLi o r B u t L i d o e s n o t g i v e (178) but instead t h e ortho-lithiated s u p p o r t e d by 'H n . m . r .
species (179).
T h i s was
s t u d i e s , a n d a d d i t i o n o f Me1 t o ( 1 7 9 ) g a v e
(180). On w a r m i n g , ( 1 7 9 ) d e c o m p o s e d t o g i v e a d i b e n z o p h o s p h a t e a n d b e n z e n e ; t h i s e x p e r i m e n t e l i m i n a t e d t h e p o s s i b i l i t y of a t h e r m a l c o n v e r s i o n o f ( 1 7 9 ) t o ( 1 7 8 ) t h a t h a d b e e n s u g g e s t e d by C o r e y . The a - l i t h i o - y l i d e ( 1 7 8 ) was p r e p a r e d b y t h e L a u s a n n e g r o u p by b r o m i n e l i t h i u m exchange i n v o l v i n g (181).
Clearly t h i s situation has not
been f u l l y r e s o l v e d .
New m e t h o d s f o r t h e s y n t h e s i s o f p h o s p h o r u s - c o n t a i n i n g compounds T h e P-Ph bond i n PhPR2 may b e have also been developed. r e d u c t i v e l y c l e a v e d ( L i , THF, u l t r a s o u n d ) t o p r o v i d e t h e d i s u b s t i -
General and Synthetic Methods
398
Ph,P=CH2
BU’L~ or ButLi 7 ( r e f . 1L8)
*-~ButLi
Ph3P-\
Ph 3 ,P
7 Br
Li
(1771
I1781
(181 1
( 1 801
( 1 791 Scheme 57
R
1831
(
(1821 0
0
0
Li ( 1841
0
0
II
(1851
4
0
0
II
+
Ph-P-CH-C-0 2
n
PhcP4CH2C02H
t
t
(1861
( 1 881
(1871 Scheme 5 8 yo2
(1891
+
0
CIO, R e a g e n t s : i P h 3 P J 2 .6
- lutidinium
(1901
perchlorate ; ii NaOH , E t O H , H20
Scheme 5 9
II
PhtPaMe
(1911
6: Organometallics in Synthesis
399
t u t e d phosphide anion (R2PLi), which i s u s e f u l f o r t h e s y n t h e s i s of t e r t i a r y p h o s p h i n e s . 50 A r y l p h o s p h o n a t e s (182) a r e p r e p a r e d i n g o o d y i e l d from a n a r e n e and e i t h e r a t r i - o r d i - a l k y l
cal oxidant respectively.
p h o s p h i t e , u s i n g a n i o n i c or a c h e m i -
The s c o p e of t h i s p r o c e s s h a s been
e x t e n d e d a n d v a r i o u s c h e m i c a l o x i d a n t s h a v e b e e n e v a l u a t e d . 15’ A s i m p l e s y n t h e s i s o f dialkylalkoxycarbomethanephosphonates ( 1 8 3 )
h a s been a c h i e v e d u s i n g p h a s e - t r a n s f e r
c a t a l y s i s ,152 and v i n y l -
p h o s p h o n a t e s ( 1 8 5 ) h a v e b e e n p r e p a r e d by r e a c t i o n o f a n a l k y l i d e n e d i p h o s p h o n a t e a n i o n ( 1 8 4 ) w i t h a n a l d e h y d e or k e t o n e . 1 5 3
Access t o o p t i c a l l y p u r e p h o s p h i n e o x i d e s i s i m p o r t a n t f o r t h e preparation of c h i r a l bidentate l i g a n d s t h a t have found a p p l i c a t i o n i n asymmetric hydrogenation.
T e r t i a r y phosphine oxides are avail-
a b l e i n high enantiomeric excess using menthyl 2-phosphinylacetate ( 1 86) ( S c h e m e 5 8 1. 154
The two d i a s t e r e o i s o m e r s c o r r e s p o n d i n g t o
( 1 8 6 ) a r e s e p a r a t e d by f r a c t i o n a l c r y s t a l l i z a t i o n ( o n e i s o m e r i s shown).
Hydrolysis t o (187) and decarboxylation g i v e s (188) which
c a n t h e n be used a s a b a s i c b u i l d i n g b l o c k f o r t h e s y n t h e s i s of more complex d e r i v a t i v e s .
(~)-(-)-~-(3,5-Dinitrobenzoyl)-a-
p h e n y l e t h y l a m i n e (189) h a s b e e n d e v e l o p e d f o r u s e a s a c h i r a l s h i f t r e a g e n t for t h e a n a l y s i s o f c h i r a l p h o s p h i n e o x i d e s . 155
This
reagent h a s previously been used t o analyse c h i r a l sulphoxides. Alkenylphosphonium s a l t s and a l k e n y l p h o s p h i n e o x i d e s are b o t h o f u s e i n t h e s y n t h e s i s of c a r b o c y c l i c a n d h e t e r o c y c l i c s y s t e m s , a n d new r o u t e s t o t h e s e d e r i v a t i v e s a r e o f v a l u e .
Cycloalkenes react
with triphenylphosphine using constant current electrolysis t o give
l-cycloalkenylphosphonium s a l t s (190) ( S c h e m e 59). 156 T h e p r o c e d u r e i s s i m p l e a n d t h e c o r r e s p o n d i n g p h o s p h i n e o x i d e s (191) a r e a v a i l a b l e by h y d r o l y s i s .
Vinyltriphenylphosphonium b r o m i d e (VTB) (192) h a s b e e n u s e d b y Posner i n an e f f i c i e n t one-pot,
three-component
[2+2+2] a n n u l a t i o n
p r o c e s s , coined t h e M I M I R C (Michael-Michael Ring C l o s u r e ) r e a c t i o n (Scheme 6
0
~ G’e n e~r a l~l y b o r o n or l i t h i u m e n o l a t e s a r e u s e d , a n d
t h e r e a c t i o n , i n terms o f t h e c a r b o n y l c o m p o n e n t , i s q u i t e g e n e r a l , though aldehyde e n o l a t e s tend t o g i v e lower y i e l d s . products,
e.g. (193) a n d
The a n n u l a t e d
( 1 9 4 ) , were c o n v e r t e d i n t o t h e c o r r e s -
ponding phosphine o x i d e s f o r easier handling. F u l l d e t a i l s o f t h e s t e r e o s p e c i f i c s y n t h e s i s of y , 6 - u n s a t u r a t e d a c e t a l s h a v e b e e n p u b 1 i ~ h e d . l ~T~h e s u c c e s s o f t h i s m e t h o d l i e s i n t h e e f f i c i e n t s y n t h e s i s o f e i t h e r t h e t h r e o - or e r y t h r o - B - h y d r o x y phosphine o x i d e s (195) and (1961, t h e fragmentation of which g i v e s
General and Synthetic Methods
400
A PPh,Br(192)
0
II If (y-JPPh3 ,
+
.I .. ll
m
P
P
h
(193)
\iL (-=+
Ill,($
PPh,
PPh,
II
0
(19Ll R e a g e n t s : i, LIBU~,BH t h e n (192)
2 equiv ;
II
L I NPr12 , t h e n (1921, Zequiv., iii ,KOH
Scheme 6 0
0
P-l
0
OH
II
0
I 1
, ? & - y ! 2P h
A'
Me
R'
(200)
( 201)
R'
2
401
6: Organometallics in Synthesis
E-
the corresponding and L-alkenes r e s p e c t i v e l y . The e p o x i d a t i o n o f a l l y l i c p h o s p h i n e o x i d e s ( 1 9 7 ) w i t h p e r a c i d h a s b e e n shown t o be h i g h l y s t e r e o s e l e c t i v e t o g i v e ( 1 9 8 1 , w h i c h u n d e r g o e s n u c l e o p h i l i c r i n g o p e n i n g , l e a d i n g t o s y n t h e t i c a l l y u s e f u l B-hydroxyphosphine oxides. I n t h e case o f ( 1 9 9 ) and (2001, t h e e p o x i d a t i o n s a r e c o n t r o l l e d by t h e a l l y l i c h y d r o x y l f u n c t i o n t o g i v e ( 2 0 1 ) a n d (202).
159
Polymer-bound
r e a g e n t s h a v e become p o p u l a r l a t e l y , a n d d i e t h o x y diphenylpolystyrylphosphorane h a s b e e n u s e d f o r t h e c y c l i c d e h y d r a t i o n o f d i o l s . I 6 O An u n b o u n d v e r s i o n o f t h i s r e a g e n t i s a l s o . available. A r s e n i c , Antimony, and Bismuth.-
(Dipheny1arsino)methyl-lithium or tin-lithium exchange from (204) o r (205) r e s p e c t i v e l y . 16' Interestingly the r e a c t i v i t y o f ( 2 0 3 ) d e p e n d s on t h e method o f p r e p a r a t i o n u s e d , a l t h o u g h t h e r e a s o n s f o r t h i s a r e n o t known. A stereoselective s y n t h e s i s o f & - a , B - u n s a t u r a t e d a l d e h y d e s h a s b e e n a c h i e v e d by r e a c t i n g a l d e h y d e s w i t h t h e a r s o n i u m s a l t (206) i n t h e p r e s e n c e o f a weak b a s e . 1 6 2 T h e y l i d e d e r i v e d f r o m (206) s h o w s a r e a s o n a b l e d e g r e e of c h e m o s e l e c t i v i t y , r e a c t i n g w i t h a l d e h y d e s i n t h e p r e s e n c e A combination of aluminium c h l o r i d e and d i p h e n y l of ketones. s t i b i n e (Ph2SbH) r e d u c e s a l d e h y d e s a n d k e t o n e s t o g i v e a l c o h o l s . Enones undergo con j u g a t e r e d u c t i o n u n d e r t h e s e c o n d i t i o n s . " The c o n v e r s i o n of c a r b o x y l i c a c i d s , v i a t h e c o r r e s p o n d i n g t h i o hydroxamic e s t e r (2071, i n t o n o r - a l c o h o l s ( R O H ) has been a c h i e v e d 164 i n h i g h y i e l d u s i n g ( P h S ) S b i n t h e p r e s e n c e of O2 a n d H20; ( 2 0 3 ) h a s b e e n p r e p a r e d by e i t h e r h a l o g e n - l i t h i u m
3
(PhS) Sb p r o v i d e s a s o u r c e of p h e n y l t h i y l r a d i c a l s ( P h S ' ) , t h e
3
r a d i c a l chain carrier. A l l y l i c h a l i d e s r e a c t w i t h a l d e h y d e s and metallic bismuth t o g i v e good y i e l d s o f h o m o a l l y l i c a l c o h o l s (Scheme 6 1 ) . 165
6 Group V I Sulphur.-
A s i n p r e v i o u s y e a r s a l a r g e component o f t h e s u l p h u r
chemistry reported has involved t h e reactions of sulphur-stabilized c a r b a n i o n s , a n area t h a t h a s been c o v e r e d i n S e c t i o n 1 .
There h a s ,
h o w e v e r , b e e n a g o o d d e a l of a c t i v i t y i n t h e s y n t h e s i s a n d r e a c t i o n s o f o r g a n o s u l p h u r compounds.
Two i n t e r e s t i n g f r a g m e n t a t i o n s o f a - t r i m e t h y l s i l y l s u l p h i d e s h a v e b e e n u s e d t o g e n e r a t e t h i o c a r b o n y l y l i d e ( 2 0 8 ) 166 a n d t h i o a l d e h y d e s
General and Synthetic Methods
402
+
Ph, A s C H, X
Ph3AsCH2CH0 Br-
(2031X = L i
( 206)
(2041X = I (205) X = SnBun3
Me
O II RCH,’
h
‘0’NyS S
(2071 OH
R = a \ k y l or a r y l
S c h e m e 61
Br
J
( 208)
(209)
Scheme 6 3
6: Organometailics in Synthesis (209)
403
both u s e f u l i n t h e synthesis of sulphur heterocycles
(Scheme 6 2 ) . A g e n e r a l method f o r t h e a c e t a m i d o s u l p h e n y l a t i o n o f a l k e n e s i s
b a s e d on t h e a n o d i c , o r m e t a l - i o n p h i d e s (Scheme 6 3 ) . 168
promoted, o x i d a t i o n of d i s u l -
Both B-aminosulphides
s u l p h i d e s a r e a v a i l a b l e by t h i s m e t h o d .
and B-acetamido-
High d i a s t e r e o s e l e c t i v i t y
( u p t o 97%) h a s been observed i n t h e low-temperature
a d d i t i o n of
b e n z e n e s u l p h o n y l c h l o r i d e t o t h e b o r n y l a c r y l a t e s ( 2 1 0 ) and ( 2 1 1 ) . The a b s o l u t e c o n f i g u r a t i o n s o f t h e a d d u c t s ( 2 1 2 ) h a v e been established.
Dimethyl(methythi0 )sulphonium t e t r a f l u o r o b o r a t e
,
a
c o n v e n i e n t s o u r c e o f MeS+, h a s f o u n d a p p l i c a t i o n i n t h e s y n t h e s i s of l a c t o n e s and c y c l i c ethers'"
a n d h a s been u s e d t o e f f e c t macro-
c y c l i c r i n g c l o s u r e s . '7' A number o f r e a r r a n g e m e n t s i n v o l v i n g s u l p h u r h a v e b e e n r e p o r t e d . A novel a n n u l a t i o n of a-alkylthiomethylene ketones t o cyclohexenones
(Scheme 6 4 ) i n v o l v e s a s u l p h u r - a s s i s t e d
r i n g o p e n i n g and s u b s e q u e n t
r e c l o s u r e o f a c y c l o b u t a n o n e 2-trimethylsilylcyanohydrin. 7 2 R e a r r a n g e m e n t o f 2,2-bis(phenylthio)ethanols
( 2 1 3 ) c a n be con-
t r o l l e d i n a number o f s y n t h e t i c a l l y u s e f u l w a y s , f u l l d e t a i l s o f w h i c h a r e now a v a i l a b l e . 1 7 3 A r a n g e o f f u n c t i o n a l i z e d c y c l o p e n t e n e s a r e a v a i l a b l e by m a n i -
p u l a t i o n of b i c y c l i c s u l t e n e s ( 2 1 5 ) (Scheme 6 5 ) .
These r e l a t i v e l y
r a r e h e t e r o c y c l e s a r e o b t a i n e d by s t e r e o s p e c i f i c r e a r r a n g e m e n t o f t h e c y c l o a d d u c t s ( o n e isomer i s shown) o b t a i n e d from a l k a n e t h i a l o x i d e s ( 2 1 4 ) and c y c l o p e n t a d i e n e . 174
2-
Asymmetric s y n t h e s i s b a s e d on c h i r a l s u l p h o x i d e s i s a r a p i d l y developing f i e l d .
Two s y n t h e s e s o f
(-)-methyl
jasmonate have been
accomplished s t a r t i n g from t h e c h i r a l a l k e n y l s u l p h o x i d e ( 2 1 6 ; A r 4-MeC6H4).
The k e y i n t e r m e d i a t e ( 2 1 7 ) i s a r r i v e d a t by e i t h e r a
c o n j u g a t e a d d i t i o n o f a n a - l i t h i ~ a c e t a t e ' t~o~ ( 2 1 6 ) or by a p p l i c a t i o n of t h e
' a d d i t i v e Pummerer'
rearrangement.
I n v i e w o f t h e i r i m p o r t a n c e i n a s y m m e t r i c s y n t h e s i s new r o u t e s have been developed t o c h i r a l s u l p h o x i d e s and r e l a t e d s p e c i e s . S u l p h i n a t e s , u s e f u l as p r e c u r s o r s of c h i r a l s u l p h o x i d e s , have been p r e p a r e d i n 40-70% e n a n t i o m e r i c e x c e s s a n d t h e s y n t h e s i s a n d d i e n o p h i l i c p r o p e r t i e s of t h e i s o m e r i c s u l p h i n y l a c r y l a t e s ( 2 1 8 ) a n d ( 2 1 9 ) ( A r = 4-MeC6H4) h a v e b e e n d e s c r i b e d .
(E)-Vinyl s u l -
phoxides have been prepared i n h i g h o p t i c a l p u r i t y v i a l-alkynyl s u l p h o x i d e s (Scheme 6 6 ) . 1 7 '
The f i n a l s t e r , o f t h i s s e q u e n c e i s
i n t e r e s t i n g , an unusual trans-hydroalumination observed.
of the alkyne being
General and Synthetic Methods
404
0 Reagents:
I ,
1- L r t h i o - 1 -
m e t h o x y c y c l o p r o p a n e , t h e n HBFL ; i i I M e g S i C N , Z n I , t h e n F -
Scheme 6 4
HO (2131
\sR, -
0-
q R
f H
Scheme 65
7
6: Organometallics in Synthesis
405
..
(2171
R-=-
-
0-
0-
MgCl
-*
( 218)
0-
R
-*
R - = - S - -+ -:/
-
(2191
A+/'S.
\
**:
Ar Ar
R e a g e n t s : i, (S)-(-)-menthyi - p - t o l u e n e s u l p h i n a t e ;
it,
.& '
Scheme 6 6
H& ;
s3
B u ~ A L H t, h e n H 2 0
4
502ph
PhOzS (221 1
X i 220)
R
( 2 2 2 R : a l k y l or a r y l )
PhSO2
Gck (2231
Reagents : i
, ButOCl
(2241
( 22 51
; i i , P(NMeZl3 t h e n NHLPF6 ; ii , n u c l e o p h i l e f N u - )
Scheme 67
General and Synthetic Methods
406
norbornadienes relies
An a s y m m e t r i c s y n t h e s i s o f 2 - s u b s t i t u t e d
on t h e d i a s t e r e o s e l e c t i v e c y c l o a d d i t i o n o f c y c l o p e n t a d i e n e t o t h e These activated alkenyl sulphoxides (220; X CO Me or S 0 2 P h ) . I8O 2 d i e n o p h i l e s w e r e o b t a i n e d by a s e l f - i n d u c e d c h i r a l o x i d a t i o n o f t h e corresponding sulphide. Although a l k e n y l s u l p h o x i d e s are w e l l e s t a b l i s h e d as Diels-Alder dienophiles,
t h i s year h a s s e e n t h e f i r s t e f f e c t i v e u s e o f a s u l 4-MeC H ) a s a c h i r a l e n o p h i l e i n a n 6 4 181
phinyl diene (221; A r
i n v e r s e e l e c t r o n demand c y c l o a d d i t i o n r e a c t i o n .
The r e a c t i v i t y o f a n u m b e r o f o t h e r d i e n e s a n d d i e n o p h i l e s carrying sulphur s u b s t i t u e n t s i n a range of oxidation l e v e l s has a l s o been examined.
E x a m p l e s i n c l u d e ( 2 2 2 ) , 1 8 2 ( 2 2 3 1 , 1 8 3 ( 2 2 4 ) , 18‘
and s u l p h o n a t e ( 2 2 5 ) 1 8 5 h a s b e e n shown t o b e c o n s i d e r a b l y more r e a c t i v e than phenyl v i n y l sulphone towards f u r a n . Two r e s e a r c h g r o u p s h a v e r e p o r t e d o n t h e e f f i c i e n t 1 , 3 asymmetric r e d u c t i o n of c h i r a l B-keto-sulphoxides
w i t h Bui2A1H.
C o m p l e m e n t a r y s t e r e o s e l e c t i v i t y may b e o b t a i n e d i f r e d u c t i o n i s 186 c a r r i e d o u t under c o n d i t i o n s of c h e l a t i o n c o n t r o l . The f i r s t e x a m p l e o f d i r e c t n u c l e o p h i l i c s u b s t i t u t i o n o f a t h i o l from a n a s y m m e t r i c c a r b o n c e n t r e , w i t h i n v e r s i o n of c o n f i g u r a t i o n , h a s b e e n c l a i m e d ( S c h e m e 6 7 ) . 187
A c t i v a t i o n of t h e t h i o l i s
r e a d i l y a c h i e v e d , and a range of heteroatom and carbon n u c l e o p h i l e s h a s been u t i l i z e d .
3-Bromo-2-(t-butylsulphonyl)prop-l-ene
(226) is an extremely
f l e x i b l e r e a g e n t t h a t s h o w s a b r o a d s p e c t r u m o f r e a c t i v i t y . 188
Two
p r i n c i p a l p a t h w a y s ( a ) and ( b ) , (Scheme 6 8 ) h a v e b e e n e s t a b l i s h e d a n d t h e r e a c t i v i t y o f ( 2 2 6 ) may b e r e p r e s e n t e d a s t h e d i p o l a r e q u i v a l e n t s ( 2 2 7 ) and (228) c o r r e s p o n d i n g t o pathways ( a ) and ( b ) respectively
.
Cyclic sulphones (229) undergo a r e g i o s e l e c t i v e cleavage with u l t r a s o n i c a l l y d i s p e r s e d potassium t o g i v e , after a l k y l a t i n g t h e r e s u l t i n g s u l p h i n a t e with an a l k y l h a l i d e ( R ’ X ) , phone ( 2 3 0 ) . 189
the acyclic sul-
The p o t e n t i a l o f s u l p h o n e s , o f t h e t y p e d e s c r i b e d a b o v e , h a s b e e n e x t e n d e d w i t h new m e t h o d s b e i n g d e v e l o p e d f o r t h e c o n v e r s i o n
of s u l p h o n e s i n t o k e t o n e s . ” ’
Finally,
s e v e r a l new m e t h o d s f o r t h e
r e d u c t i o n of s u l p h o x i d e s have been r e p o r t e d . Selenium and Tellurium.-
T h i s a r e a h a s s e e n c o n t i n u e d p r o g r e s s this
y e a r a n d , i n a d d i t i o n t o new d e v e l o p m e n t s i n s e l e n i u m c h e m i s t r y , t h e s y n t h e t i c u t i l i t y o f t e l l u r i u m i s now b e g i n n i n g t o e s t a b l i s h
407
6: Organometallics in Synthesis
Nu’
Nu2=RS-,
(228)
Do-.
R 2 C u L i ; E ’ = R C H O , R,CO,
Reagents: i , Nu’ then N u * ;
ill
RCN
E’,Zn,then Nu1
S c h e m e 68
i SO, R1
QR (2291
R
(230) P h S 0 e - N m
Me2A l SeMe
6’
( 2 3 11
(2321
R
R (2331
R
(234)
Reagents : i , PhSeH , H’ ; i i , B u ’ ~ A I H t h e n PhSeH , BF3.Et20
Scheme 6 9 Ph Se SeR’
R
R
iUR’ SCPh
II
( 2 3 5 ) R1= a l k y \ or aryl (236)
0
General and Synthetic Methods
408
itself. One o f t h e m o s t s i g n i f i c a n t c o n t r i b u t i o n s h a s b e e n t h e p u b l i c a t i o n of a Tetrahedron ’Symposia i n P r i n t ‘ l a r g e l y devoted t o selenium chemistry.
T h i s volume c o v e r s a wide r a n g e o f t o p i c s , b u t
only t h o s e w i t h a s y n t h e t i c b i a s can be d i s c u s s e d here. chemistry of t h e v e r s a t i l e selenenylating agents methaneselenolate (231
The
dimethylaluminium
9 2 a n d N-phenylselenophthalimide ( 2 3 2 ) 1 9 3
h a s been covered and u s e f u l overviews o f t h e s y n t h e s i s and reactiv i t y o f ~ e l e n o a c e t a l s ~a’n~d 2-phenylselenenylenones’ 95 h a v e a l s o been i n c l u d e d . cx-Selenyl e t h e r s ( 2 3 4 ) a r e c o n v e n i e n t l y p r e p a r e d f r o m e i t h e r a l a c t o l ( 2 3 3 ) o r a l a c t o n e l g 6 (Scheme 6 9 ) a n d u n d e r g o , n o t s u r prisingly, a facile oxidative elimination t o give enol ethers. Diazomethane undergoes a c o p p e r - c a t a l y s e d i n s e r t i o n i n t o t h e a c y l S e bond o f s e l e n o e s t e r s t o g i v e c x - ( a l k y l (235). of
or aryl-se1eno)ketones
A l t h o u g h m e t h y l k e t o n e s h a v e b e e n o b t a i n e d by r e d u c t i o n
(2351, t h e c h e m i s t r y o f t h e s e systems h a s y e t t o be f u l l y
exploited. D i r e c t s e l e n a t i o n o f C-C n-bonds i s a n i m p o r t a n t s y n t h e t i c A l k e n e s r e a c t w i t h 2-benzoylphenylselenosulphide
process.
(PhCOSSePh), i n t h e p r e s e n c e o f A I B N , t o g i v e t h e a d d u c t s ( 2 3 6 ) . 199 Allenes a l s o undergo f r e e - r a d i c a l
s e l e n o s u l p h o n a t i o n w i t h PhSeS02Ph
t o g i v e t h e a l l y l i c s e l e n i d e s ( 2 3 7 ) (Scheme 7 0 ) . 2 0 0
These adducts
h a v e f o u n d a p p l i c a t i o n i n t h e s y n t h e s i s o f a u s e f u l c l a s s of a l l y l i c a l c o h o l s [see a l s o ( 2 2 6 1 , Scheme 6 8 1 . The r e g i o s e l e c t i v e s y n t h e s i s o f t h e r e l a t e d n i t r o a l l y l i c a l c o h o l s ( 2 3 8 ) ,201 a n o t h e r g r o u p o f u s e f u l m u l t i p l e c o u p l i n g r e a g e n t s , i s a l s o shown, and involves t h e addition of a selenyl residue t o a nitroalkene. A tandem a l d o l c o n d e n s a t i o n - r a d i c a l
c y c l i z a t i o n a p p r o a c h (Scheme
7 1 ) t o c a r b o c y c l i c s y n t h e s i s r e l i e s on a n i n i t i a l c o n j u g a t e a d d i t i o n of a n a r y l s e l e n i d e t o an enone.202
T h i s can be achieved
u s i n g e i t h e r PhSeA1Me2 o r [ P h S e T i ( O P r i I 4 ] L i a n d t h e r e s u l t i n g e n o -
late then undergoes a l d o l condensation.
Use o f a n a p p r o p r i a t e
c a r b o n y l c o m p o n e n t c o m b i n e d w i t h h o m o l y t i c c l e a v a g e of t h e C-Se bond p r o v i d e s a p a t h w a y t o a s e r i e s o f b i c y c l i c c a r b o c y c l e s . The c h e m i s t r y o f s e l e n o x i d e s h a s a l s o s e e n some a d v a n c e s t h i s year.
The f i r s t c a s e o f a n a s y m m e t r i c o x i d a t i o n o f a n a c h i r a l
s e l e n i d e , u s i n g a c h i r a l 2 - s u l p h o n y l o x a z i r i d i n e 7 h a s been reported.203
T h i s r e a c t i o n i s n o t as e f f i c i e n t a s t h e c o r r e s -
ponding s u l p h i d e t o s u l p h o x i d e c o n v e r s i o n , and e n a n t i o m e r i c e x c e s s e s o f l e s s t h a n 10% h a v e b e e n o b t a i n e d .
Peracid oxidation
o f a l k y l p h e n y l s e l e n i d e s ( R S e P h ) i n t h e p r e s e n c e of a l c o h o l s
6: Organometallics in Synthesis
409
OH
SePh
(2371 F
R
1
CF3CO0Ph f i NSe o2
MeOH
CF3 C02 A g
I
RG R'
H202
R
R
R'
NO2
(2381 S c h e m e 70 OH
Me
b
1 [ O
f i R
Me
Mk
Me Me
R R e a g e n t s : i , PhSeALMeZ or [phSeTi(OPri)l]Li
, t h e n RCH=CH-CH2CHO;
ii, Bun3SnH, A
S c h e m e 71 R A N / R ' H
t
-
R3N-O R3N
kTeH ),
I
OH
NaTeH Rdo*
NIB
~
R
Scheme 7 2
Ar2Te C I,
P h T e S i Me3
(2391
(
240) Ar = Ph or L- MeOC,H,
Me
General and Synthetic Methods
410
(R 'OH) g i v e s g o o d y i e l d s o f d i a l k y l e t h e r s , R O R
'.
B-Elimination
c a n be s u p p r e s s e d and a l k y l phenyl t e l l u r i d e s undergo a similar 204 transformation. Phenylselenenic anhydride, (PhSe0)20, and phenylselenenic a c i d , PhSe02H, a r e b o t h shown t o e f f e c t t h e m i l d o x i d a t i o n o f i n d o l i n e s t o i n d o l e s . 205 T h e c h e m i s t r y o f t e l l u r i u m h a s b e e n r e v i e w e d 2 0 6 a n d new u s e s o f NaTeH h a v e b e e n d e m o n s t r a t e d ( S c h e m e 7 2 ) . opening t o give B-telluroalcohols,
Epoxides undergo r i n g
w h i c h may b e f u r t h e r r e d u c e d .
Q u a t e r n a r y ammonium s a l t s a r e a l s o c l e a v e d b y t h i s r e a g e n t . 207 NaTeH a l s o r e d u c e s i m i n i u m a n d p y r i d i n i u m s a l t s 1 2 0 8 a s w e l l a s n i t r o n e s and amine
oxide^.^"
Disodium t e l l u r i d e , Na2Te, r e d u c t i v e l y d e h a l o g e n a t e s 1 , 2 dibromoalkanes t o g i v e a l k e n e s i n e x c e l l e n t y i e l d .210
An
a t t r a c t i v e f e a t u r e of t h i s method i s t h a t o n l y a c a t a l y t i c q u a n t i t y of t e l l u r i u m is required.
Phenyltellurotrimethylsilane ( 2 3 9 ) i s a r e a d i l y a c c e s s i b l e r e a g e n t , a n d i n terms of i t s r e a c t i v i t y t o w a r d s e s t e r s , l a c t o n e s , 21 1 e p o x i d e s , a n d e t h e r s , i s e q u i v a l e n t t o NaTePh. The o x i d a t i o n o f a l k y l p h e n y l t e l l u r i d e s w i t h p e r a c i d i n t h e p r e s e n c e of a l c o h o l s , t o g i v e d i a l k y l e t h e r s , h a s been mentioned. Oxidative elimination of these substrates t o give alkenes can a l s o I n some c a s e s s t a b l e T e ( 1 V ) i n t e r m e d i a t e s c a n be
be o b s e r v e d . 212
i s o l a t e d , b u t t h e s e u s u a l l y undergo e l i m i n a t i o n a t h i g h (200-250 OC)
temperatures. The 2 , 3 - s i g m a t r o p i c
rearrangement chemistry of sulphoxides and
s e l e n o x i d e s i s w e l l known, and a l t h o u g h r e a r r a n g e m e n t s i n v o l v i n g t e l l u r o x i d e s have o n l y r e c e n t l y been examined2
their reactivity
p a r a l l e l s t h a t o f t h e b e t t e r known G r o u p V I e l e m e n t s .
Finally,
v i n y l and a r y l t e l l u r i d e s undergo a n i n t e r e s t i n g P d ( I 1 ) - c a t a l y s e d c a r b o n y l a t i o n t o g i v e a c r y l i c and benzoic a c i d d e r i v a t i v e s
.
r e s p e c t i v e l y *I4 b i a r y l s . 21 4
U n d e r t h e same c o n d i t i o n s , ( 2 4 0 ) r e a c t s t o g i v e
References 1
R.C.Gadwood
,
M.R.Rubino, S. C.Nagarajan, and S.T.Miche1, J. Org. Chem., 1985,
5 0 , 3255. 2
3 4
2
A.Duchene, D.Monko-Mpegna, and J.-P-Quintard, Bull. SOC. Chim. France, 1985, 787. 1093. M. C 2 6 , 364 3 . M. P 1 9 8 5 , 6, 3433. T.R 1985, 1 1 2 4 ; F.L 1939. F.L
6: Organometallics in Synthesis 7 8 9 10 11 12
13
14 15
411
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211 212
213 214
S O C . , Chem. Commun., 1985, 1670. Y.Arai, S.Kuwayama, Y.Takeuchi and T-Kuizumi, Tetrahedron Lett., 1985, 6205. H.Kosugi, M-Kitaoka, K.Tagami, and H.Uda, Chem. Lett., 1985, 805. O.DeLucchi, C-Marchioro, G.Valle, and G.Modena, J. Chern. SOC., Chern. Commun., 1985, 878. ( 2 ) G.H.Posner and W.Harrison, J. Chem. S O C . , Chem. Commun., 1985, 1786 C27. G.H.Posner and W.Harrison, J. Organomet. Chem., 1985, Y.Masuyama, H.Sato, and Y.Kurusu, Tetrahedron Lett., 1985, 67. K.Hayakawa, H.Nishiyama, and K.Kanematsu, J. Org. Chem., 1985, 2, 512. P.D.Croce, C.LaRosa, and G.Zecchi, J. Chem. S O C . , Perkin Trans. 1 , 1985 2621. 1915. L.L.Klein and T.M.Deeb. Tetrahedron Lett.., 1985. 26., _ , .__ -~ ( a ) H.Kosugi, H.Konta, and H.Uda, J. Chem. SOC., Chem. Commun., 1985, 211; (Ip.1 G.Solladie, G.Demailly, and G.Greck, Tetrahedron Lett., 1985, 435. 4867. G.A.Krafft and T.L.Siddal1, Tetrahedron Lett. , 1985, ( g ) P.Knoche1 and J.F.Normant, Tetrahedron Lett., 1985, 425; ( 5 ) P.Auvray, P.Knoche1, and J.F.Normant, p.2329. 4495. T.Chou and M.Li You, Tetrahedron Lett., 1985, (a) J.B.Baldwin, M.Julia, and C.Rolando, Tetrahedron Lett., 1985, 2333; (b) K-Ogura, K.Ohtsuki , M.Nakamura, N. Yahata, K-Takahashi, and H. Ida, p.2455. (a) R.A.Amos, J. Org. Chem., 1985, 50, 1311 ; ( b ) Y.D.Vankar and C.T.Rao, J.D.Kim, ibid., p.6453. ibid., p.2717; (2)J.S.Cha, J.E.Kim,and 4821. A.P.Kozikowski and A.Ames, Tetrahedron, 1985, K.C.Nicolaou, N.A.Petasis, and D.A.Claremon, Tetrahedron, 1985, 4835. A.Krief , J.Lucchetti, and D.Van Ende, Tetrahedron, 1985, 4793. D.Liotta, M.Saindane, C.Barnum, and G.Zima, Tetrahedron, 1985, 4881. D.J.Goldsmith, D.Liotta, M.Volmer, W.Hoekstra, and L.Waykole, Tetrahedron, 1985, 3, 4873. 4759. T.G.Back and R.G.Kerr, Tetrahedron, 1985, 4765. S.V.Ley, P. J.Murray , and P. D.Palmer , Tetrahedron, 1985, 3263. T.Toru, T-Sako, and E.Maekawa, Tetrahedron Lett., 1985, 4739. J.L.Kice and Y.H.Kang, Tetrahedron, 1985, D.Seebach, G-Carlderari, and P.Knoche1, Tetrahedron, 1985, 4861. 6431. W.R.Leonard and T-Livinghouse, Tetrahedron Lett., 1985, F.A.Davis, O.D.Stringer, and J.P.McCauley,Jr., Tetrahedron, 1985, 4747. S.Uemura, and S-Fukuzawa, J. Chem. SOC., Perkin Trans. 1 , 1985, 471. (5) D.H.R.Barton, X-Lusinchi, and P.Milliet, Tetrahedron, 1985, 4727; ( b ) I.Ninomija, T.Kiguchi, C.Hashimoto, D.H.R.Barton, X.Lusinchi, and 4183, 4187. P.Milliet, Tetrahedron Lett., 1985, L.Engman, Acc. Chem. Res., 1985, 274. D.H.R.Barton, A.Fekih, and Z.Lusinchi, Tetrahedron Lett., 1985, 6197. D.H.R.Barton, A.Fekih, and X.Lusinchi, Tetrahedron Lett., 1985, 26, 3693. D.H.R.Barton, A.Fekih, and X.Lusinchi, Tetrahedron Lett., 1985, 2, 4603. H.Suzuki and M.Inouye, Chem. Lett., 1985, 225. K.Sasaki, Y.Aso, T-Otsubo, F.Ogura, Tetrahedron Lett., 1985, 453. S.Uemura, K-Ohe, and S.Fukuzawa, Tetrahedron Lett., 1985, 26, 8951. S.Uemura, S.Fukuzawa, and K.Ohe, Tetrahedron Lett., 1985, 921. S.Uemura, K.Ohe, J.R.Kim, K.Kudo, and N.Sugita, J. Chem. SOC., Chem. Commun.. 1985. 271.
26,
285, 3,
x., 26, 5,
2,
5,
26,
26, 26,
26,
m.,
2, 5, 2,
5, 26, 5, 26,
5,
5,
26, 18,
26,
26, 26,
7 Saturated Carbocyclic Ring Synthesis BY T. V. LEE
1 Three-membered Rings
The appearance of a 'Symposium-in-Print' on aspects of carbene chemistry is obviously relevant to those interested in cyclopropane chemistry . Sonication reactions are becoming increasingly popular and now permit the use of dibromomethane and a zinc-copper couple for cyclopropanation .2 By using a trialkylaluminium compound and methylene iodide in dichloromethane a new cyclopropanation of alkenes has been achieved in a reaction thought to go via the species ( 1 1 . Two research groups have independently reported studies on the l,4-addition of dihalogenocarbenes to 1,3-dienes in which cyclopropanes are major It has been shown that metal-halogen exchange of the vinyl iodide (2) results in rapid formation of cyclopropene derivatives . 6 1- (Pheny1thio)cyclopropylsilanes are highly useful synthetic reagents and can now be prepared by the addition of a sulphur-stabilized anion to the vinylsilane (3) .7 An intramolecular cyclopropanation an iron carbene intermediate has been described which gives access to fused three-membered rings. 8 The previously developed coupling of the dianions of diesters with 1,w-dihalides has now been made into an efficient asymmetric process by the use of menthyl esters (Scheme I ) . ' Interestingly the use of a homochiral acetal such as (4) allows a diastereoselective cyclopropane-forming reaction to be performed in a reaction which could be widely applicable in natural product synthesis. l o 2-Lithio-2-phenylsulphonylpropane ( 5 ) acts as an alkylidene transfer reagent in reactions with a,B-unsaturated esters to allow the facile preparation of gem-dimethylcyelopropanecarboxylic acids. Furthermore, 1 -aminocyclopropanecarboxylates can be obtained by the addition of diazomethane to the oxazolone ( 6 ) . 12 The addition of 2-nitropropane tp a-cyanoacrylates, under the influence of base, proceeds to give the acid component of the
416
For References see p. 453
7: Saturated Carbocyclic Ring Synthesis
IC H,-A
417
I\/ R
ph
-78 BU'Li *C
R
I
CH,CI
-
bSPh
1
+
ii
SPh
Si Me3
(3)
SiMe3
h
S
P
h
CO, R R02Cw
C0,R R = I - menthyl
Scheme 1
mfH2
H
C V ,
___)
'CH,OCH,Ph H2Ph
(4)
Zn-Cu
'CH ZOCH ,P h OL -cyctopropyl :
p - cyclopropyl
9:l
General and Synthetic Methods
418
pyrethroids. l 3 synthesized
Additionally (+)-cis-chrysanthemic acid has been a well planned use of the alicyclic Claisen
rearrangement as shown by the conversion of (7) into (8), in a route developed independently by two groups. ' 2 Four-membered Rings
This area is dominated by [2+2] cycloadditions in their various guises. Thus a new, and useful route to cyclobutane-l,3-dione involves the dimerization of t-butoxyethyne (9), which is thought to go formation of ketene from (9) followed by a [2+2] cycloaddition to the adduct (lo), which can then be hydrolysed.i6 Contrary to previous reports, the cyclobutane derivative ( 1 1 ) is the major product of the high-pressure reaction of a ketene acetal and acrolein.17 A range of chiral auxiliaries used in Diels-Alder reactions have been used in efforts to achieve induction in the ketene cycloaddition of the enol ether (12), with the sultam (13) giving the best degree of induction of 90% diastereoisomeric excess.18 Similar studies on esters such as (14)19 and enols such as (15)20 have also been reported, although in these cases the degree of induction is only modest. [2+21 Cycloadditions are the latest reactions to be extensively studied in an intramolecular manner, although this variant has been known for many years. The reactions are very facile, giving access to a range of bicyclic frameworks possessing a cyclobutane. 21-24 Interestingly the reaction has also been shown for the intramolecular reaction of allenes and c y c l o h e x e n o n e ~ ,26 ~~ (')-Lineatin has been synthesized by using the [2+2] cycloaddition of dichloroketene to a cyclic ally1 ether,27 and finally some interesting mechanistic studies have shown that the reaction
of t-butylcyanoketene and silyl enol ethers is a non-concerted process. 28
3 Five-membered Rings General Methods.- The current high level of activity in using radical ring closure reactions to form cyclopentanes will engender great interest in a set of force-field calculations which correlate the rate and stereochemical outcome of such cyclizations with the transition-state strain energies.29 A good example of the use of the reaction is in a new route to hydroxylated cyclopentanes from
7: Saturated Carbocyclic Ring Synthesis
419
Me
SOzPh )(Li
Ph (5)
-
(6)
-
C F, C 0, H
Sealed tube
B~O-CGC-H
30 'C, 86 h
BU'O
H,
/OMe +
Me
A C H O
12lkbar
420
General and Synthetic Methods
c‘Kc‘
.,.B
+
C
II0
/
\
R*6
(12)
P
‘Me
R*o)Q
R*O, C
0
( 1 4)
(1 5)
C0,Et
,Bun3SnH -* AIBN
HO
52
HO
..
I
.
11, I
___.)
q
=
-0
‘CHo
Scheme 2
O
H
7: Saturated Carbocyclic Ring Synthesis
42 1
t h e c a r b o h y d r a t e - d e r i v e d b r o m i d e ( 1 6 ) .30 A s s h o w n i n Scheme 2 t h e known p h o t o c h e m i c a l s y n t h e s i s o f t h e i r i d o i d s k e l e t o n h a s b e e n resulting in a
applied t o t h e preparation of (2)-speciorin, r e v i s i o n of i t s s t r u c t u r e . ” The vinylcyclopropane-cyclopentene
r e a r r a n g e m e n t h a s b e e n popu-
l a r f o r c y c l o p e n t e n e f o r m a t i o n o v e r a number o f y e a r s , a n d h a s now been modified t o permit a c a r b a n i o n - a c c e l e r a t e d v e r s i o n t o be d e v e l o p e d w h i c h o f f e r s p r o m i s e i n i t s f u t u r e u s e (Scheme 3 ) . 3 2 A new c y c l o p e n t e n o n e s y n t h e s i s h a s b e e n d e s c r i b e d w h i c h u s e s t h e Ramberg-Backlund r e a c t i o n o f t h e s u l p h o n e ( 1 8 1 , which i s d e r i v e d
from t h e a-trif lyl-sulphone
( 17 )
.
( S c h e m e 4 ) 33
A p r e v i o u s l y known
r o u t e t o cyclopentenones is % t h e conversion o f 2-hydroxyalkylf u r a n s , w h i c h h a s now b e e n e x t e n d e d t o t h e s y n t h e s i s o f a c y c l o p e n t e n o n e b e a r i n g a p h o s p h o n a t e g r o u p . 34 It h a s been demonstrated t h a t f o r less e l e c t r o p h i l i c c a r b o n y l d e r i v a t i v e s t h e metal-halogen exchange of i o d i d e s such as ( 1 9 ) can r e s u l t i n good y i e l d s o f c y c l i z a t i o n p r o d u c t s . 3 5 Better results a r e o b t a i n e d h o w e v e r by u s i n g t h e G r i g n a r d r e a g e n t d e r i v e d from t h e
bromide ( 2 0 ) , which undergoes s t e r e o s p e c i f i c i n t r a m o l e c u l a r a d d i t i o n t o t h e a l k e n y l s i l a n e t o a f f o r d t h e c y c l o p e n t a n e ( 2 1 ) .36 I n c o n t r a s t , some r e g i o c h e m i c a l s t u d i e s o f w - l i t h i o - e p o x i d e s s u c h a s ( 2 2 ) show t h a t c y c l i z a t i o n t o a f i v e - o r s i x - m e m b e r e d r i n g depends upon t h e a d d i t i v e s used d u r i n g g e n e r a t i o n o f t h e l i t h i u m species. A d d i t i o n o f a c o p p e r ( 1 ) s a l t f a v o u r s six-membered r i n g f o r m a t i o n , p r e s u m a b l y via a n o r g a n o c o p p e r i n t e r m e d i a t e , whereas a d d i t i o n of a L e w i s a c i d a c t i v a t e s t h e o x i r a n e t o o p e n i n g a t t h e s e c o n d a r y p o s i t i o n s o g i v i n g a f i v e - m e m b e r e d r i n g . 37 An e a r l i e r r e p o r t on t h e s t e r e o c h e m i c a l c o n s e q u e n c e s o f a r h o d i u m - c a t a l y s e d i n t r a m o l e c u l a r C-H i n s e r t i o n o f t h e B - k e t o - e s t e r (23),
l e a d i n g t o an e n a n t i o s e l e c t i v e s y n t h e s i s o f a-cuparenone,
has
now b e e n d e s c r i b e d i n f u l l . 3 8
F u r t h e r m o r e , owing t o t h e r e q u i r e -
ment t h a t t h i s r e a c t i o n o c c u r s
% a chair-like transition state,
t h e r e a c t i o n o f ( 2 4 ) p r o c e e d s d i a s t e r e o s e l e c t i v e l y t o form a 2,4d i s u b s t i t u t e d c y c l o p e n t a n e d e r i v a t i v e . 39 [3+21 A n n u l a t i o n s a r e c u r r e n t l y r e c e i v i n g much a t t e n t i o n , w i t h many g r o u p s r e s o r t i n g t o allyl-palladium
complexes t o a c h i e v e t h i s .
For e x a m p l e t h e
z w i t t e r i o n i c n - a l l y l p a l l a d i u m complex ( 2 6 ) can be g e n e r a t e d from t h e v i n y l c y c l o p r o p a n e ( 2 5 ) and t h e n r e a c t e d w i t h a Michael adduct t o f o r m a c y c l o p e n t a n e , a s o n e w o u l d e x p e c t by a n a l o g y w i t h previous studies.40 By a v a r i a t i o n i n t h e s u b s t r a t e i n t h e i n t e r n a l t r a p p i n g o f a n-ally1 complex, t h e c y c l i z a t i o n of t h e a l l e n i c
422
General and Synthetic Methods
I
&CHz
SO2 Ph
____)
9 7% Reagents.
I>
Bu"LI,
THF-HMPA,
- 7 8 t o -30 ' C
Scheme 3
I, II
C F , S O , v S02Me Me
( 1 7)
(18) Reagents
i , BuLi(3 equiv.), i i , M e 1 (excess); iii, BuLi (2 equiv.) i v , A C H O ; v, Mn02; v i , K2C O3
Scheme 4
( 2 2)
7: Saturated Carbocyclic Ring Synthesis
423
I
Ph
Ph
(24)
(23) Reagents. i, MeS0,N3, Et,N; ii, [Rh,(OAc),]
Me0,C
pdO
Me02C
MeOzC
T+Az MeOzC
>a/=, - M e 0 2 C
MeOzC
Pd
CO, M e PhI
+ Me
+
=C
-
Ph
Pdo
&C02Me C0,Me
I
+
=,=(
CO, M e
0 Si Me, But
Me3si*
S i Me,
&
Me
SiMe,
Scheme 5
424
General and Synthetic Methods
e s t e r (27) w i t h a n a r y l p a l l a d i u m c o m p l e x c a n b e p e r f o r m e d t o g i v e t h e c y c l o p e n t e n e ( 2 8 ) . 41 a,B-Unsaturated a c y l s i l a n e s react w i t h a l l e n y l s i l a n e s i n a r e a c t i o n which c a n be d i r e c t e d t o form e i t h e r f i v e - o r six-membered r i n g s a s s h o w n i n S c h e m e 5.'*
I n t r a m o l e c u l a r c y c l i z a t i o n of v i n y l -
g e r m a n e s ( 2 9 ) h a s l e d t o a new c y c l o p e n t a n e s y n t h e s i s a s p a r t o f a s t u d y o f t h e c o m p a r i s o n of t h e r e a c t i v i t y of v i n y l g e r m a n e s w i t h vinylsilanes. ' 3 A new s y n t h e s i s o f c h i r a l c y c l o p e n t a n o i d i n t e r m e d i a t e s i n v o l v e s
the stereospecific reaction of t h e carbanion (30) with t h e tartaric a c i d d e r i v e d e p o x i d e ( 3 1 ) .44 alkylation,
An i n t r a m o l e c u l a r e n o l a t e a n i o n
i n d u c e d by a M i c h a e l r e a c t i o n , h a s b e e n u t i l i z e d i n t h e
p r e p a r a t i o n o f c y c l o p e n t a n e s ( S c h e m e 6).
Additionally, variation
i n t h e solvent i n t h e s e r e a c t i o n s allows c o n t r o l of an exocyclic centre.45
U n s a t u r a t e d s u l p h o n e s s u c h as ( 3 2 ) h a v e b e e n shown t o
undergo 5-endo-trigonal
r i n g c l o s u r e s , so overcoming t h e s t e r e o -
e l e c t r o n i c r e s t r a i n t s upon s u c h a c y c l i z a t i o n .
46
T h e r e a c t i o n o f t h e w-(phenylthiol-w-chloro-alkyl a c e t a t e ( 3 3 ) with methyl-lithium
results in cyclization,
t h i o c a r b e n e i n s e r t i o n i n t o t h e a-C-H from ( 3 3 ) . 4 7
presumably
via
phenyl-
bond o f t h e a l k o x i d e d e r i v e d
A f u r t h e r c y c l i z a t i o n t o be d e s c r i b e d i n v o l v e s
t h e r m o l y s i s o f t h e d i a l k a l i metal s a l t s o f t h e w - h y d r o x y a l k y l ketone t o s y l hydrazone (34).
48
An i n s p i r e d v a r i a n t i n t h e p r e p a r a t i o n o f d i v i n y l k e t o n e s , w h i c h then undergo Nazarov-type i n Scheme 7 .
c y c l i z a t i o n s t o c y c l o p e n t e n o n e s , i s shown
The r e a c t i o n i n v o l v e s t h e t r e a t m e n t of a t e t r a h y d r o -
o x a p y r a n w i t h i o d o t r i m e t h y l s i l a n e a t 120 i n t e r m e d i a t e d i v i n y l k e t o n e ."
OC,
so g e n e r a t i n g t h e
Although t h e u s e o f c a t i o n i c c y c l i -
z a t i o n t o f o r m c y c l o p e n t a n e s i s n o t new a n i n t e r e s t i n g v a r i a t i o n i s t o i n i t i a t e the process
via
t h e Pummerer r e a c t i o n i n t e r m e d i a t e
o b t a i n e d f r o m t h e k e t o n e ( 3 5 ) .50
An u n e x p e c t e d t r a n s f o r m a t i o n of
camphor oxime ( 3 6 ) i s worthy o f n o t e i n v o l v i n g h y d r o s i l y l a t i o n t o g i v e a c h i r a l c y c l o p e n t a n e a s t h e major p r o d u c t .51 Fused Five-membered
Rings.-
Radical cyclizations continue t o give
ready access t o f u s e d c y c l o p e n t a n o i d s .
For example t h e s t e r e o -
controlled formation of (37) allows a radical-induced r i n g closure t o t h e c y c l o p e n t a n o l (38) i n a p r o c e s s which h a s been d e s c r i b e d as
a tandem a l d o l c o n d e n s a t i o n - r a d i c a l c y c l i z a t i o n sequence. 52
A
l e n g t h y b u t f a c i l e r a d i c a l a n n u l a t i o n i n v o l v e s t h e r e a c t i o n of t h e selenonitrile (39) with a t i n h ~ d r i d e . T ~ h~e same a u t h o r s h a v e
7: Saturated Carbocyclic Ring Synthesis
425
phcH~oYCH
PhS-CH-CN
I
zBr
4
Na
0
(30)
(31)
CO, Et
&
CO, Et
qoLi 0 Bu'
COz Et
Scheme 6
KH
&C02Et Et0,C
COZEt C0,Et
Et 0, C
C0,Et
COZEt C0,Et
(32)
svoco - phs9 3 x MeLi
Ph
Me
-80
.c
HO
CI
(33)
i, KH
phY-oH NNHTs
426
General and Synthetic Methods
0
II
qo SMe
P - TsOH
(35)
SMe
I
Me
427
7: Saturated Carbocyclic Ring Synthesis
also reported the sequence shown in Scheme 7 , whereby conjugate addition of a radical and subsequent 5 - z - d i g o n a l ring closure combine to form a fused five-membered ring. 54 The previously described tandem radical cyclization strategy has now been applied to the synthesis of ( ?)-A9 12-capnellane55 and (+)-hirsutene.56 757 An interesting reaction involves the photoreduction of a G,~-unsaturated ketone such as (40) which proceeds in excellent yield in the presence of hexamethylphosphoramide. 58 An electroreductive cyclization of the unsaturated ester (41) gave the cyclopentanol (42) with good s t e r e o ~ e l e c t i v i t y . ~Addition~ ally, full details of the radical-mediated intramolecular cyclization of terminal allenic ketones have been described.60 Also this year the intramolecular 1,3-diyl trapping reaction has been used to synthesize ( + )-coriolin. 61 The Pauson-Khand reaction is currently undergoing a renaissance after lying dormant for many and has now been applied to the synthesis of polyquinones. Thus, the alkynyl cobalt complex (43) cyclizes, with insertion of carbon monoxide, to the tricyclic enone (44) .64 A 'working mechanistic hypothesis' for the reaction has been proposed which should enhance its use further,65 and an overview of his reaction, by Pauson, is also worthy of note. 66 Besides being used in a synthesis of f u r a n o ~ e s q u i t e r p e n e sthis ~~ upsurge in interest has spawned a zirconium equivalent of the reaction as shown in Scheme 8 by the conversion of (45) into
(46).68 One way of achieving the synthesis of annulated cyclopentanes is
via the intramolecular cyclization of a variety of silicon and tin derivatives. F o r instance the enol ether (47) has been shown to undergo a mercury(I1)-induced
cyclization to form a vinylcyclo-
pentane .69 The diastereoselectivity of the intramolecular additions of the allylsilane (48) has been shown to be catalyst dependent, thus enhancing the synthetic utility of the process. It is suggested that the observed selectivity arises from the orientation (49) being favoured over (50) in the transition state for the Lewis acid reactions with the reverse being true for fluorideinduced reactions .70 An identical preparation of the hydrindane system has been developed independently .7 A new process leading to some potentially useful dienes involves treatment of the enol triflate ( 5 1 ) with a Pd(0) catalyst.72 Additionally, the new type of bifunctional annulating reagent (52), in which the two centres are sequentially activated by one set of
General and Synthetic Methods
428
BujSnH AIBN
(37)
- R: Ph,SnH A IBN
OH
(39)
. ..
I, II
'Ph Reagents:
1,
Ph3SnH, A I B N ; ii,
e C N
Scheme 7
hv HMPA
e.
&OzMe (41)
H
8 1'10
(40) 0
& &" COzMe
(42) 76'10
429
7: Saturated Carbocyclic Ring Synthesis
co
50,
+
(44)
- mo SiMe3
,SiMe,
/
. ..
I, II
(45)
(46)
Reagents: i, [ C I Z Z r C p Z l , Mg, HgCIZ; i i ,
CO
Scheme 8
cat.:
FEtAlCIz
4:l 1 :5
General and Synthetic Methods
430
Me3Si
(49)
(50)
A
(52 )
Me3$?'% I
(53)
'\
OMe
43 1
7: Saturated Carbocyclic Ring Synthesis c o n d i t i o n s (Lewis a c i d s ) offers p o t e n t i a l f o r t h e r a p i d cons t r u c t i o n of p o l y c y c l i c five-membered
r i n g s .73
Of related interest
i s a s t u d y w h i c h h a s s h o w n t h a t c y c l i z a t i o n o f t h e a l d e h y d e (531, by n u c l e o p h i l i c a t t a c k o f t h e c a r b o n - t i n
bond, proceeds w i t h
r e t e n t i o n of c o n f i g u r a t i o n a t t h e t i n - b e a r i n g c a r b o n .
This is i n
c o n t r a s t t o t h e alcohol (54) which c y c l i z e s with i n v e r s i o n a t t h a t carbon.74 F u r t h e r e x c e l l e n t s t u d i e s on t h e p a l l a d i u m complex of t r i m e t h y l e n e m e t h a n e h a v e f o c u s e d upon t h e r e g i o c h e m i c a l outcome of t h e r e a c t i o n of u n s y m m e t r i c a l c o m p l e x e s s u c h a s ( 5 5 ) w h i c h d i s p l a y t o t a l r e g i o c o n t r o l , as i n d i c a t e d . methylenemethane complexes, v i t y problems. observed.75
Additionally substituted tri-
e.g. ( 5 6 ) ,
pose p o t e n t i a l chernoselecti-
However, t o t a l s e l e c t i v i t y t o g i v e ( 5 7 ) i s
F u r t h e r m o r e i t h a s now b e e n s h o w n t h a t i n t h e s e
r e a c t i o n s t h e a c c e p t o r group approaches t h e complex on t h e o p p o s i t e s i d e t o t h e p a l l a d i u m ( d i s t a l a t t a c k ) , s o s h o w i n g t h a t p r i o r coo r d i n a t i o n of t h e a c c e p t o r t o t h e m e t a l ( i n v o l v i n g proximal a t t a c k ) does not occur.76
F i n a l l y , t h i s complex h a s been used i n a syn-
t h e s i s o f l o g a n i n .77 I n o r d e r t o enhance stereochemical c o n t r o l i n annulation reactions the 'Claisen rearrangement-nitrile been developed.
oxide' annulation has
The o v e r a l l s t r a t e g y o f t h i s l e n g t h y s e q u e n c e
r e s u l t s i n t h e i n t r o d u c t i o n of a r i n g o n t o a c y c l i c a l l y l i c a l c o h o l
c i s t o t h e hydroxy-group, w i t h t h e hydroxy-group e v e n t u a l l y being retained with its original stereochemistry. A s s e e n i n Scheme 9 t h e a l l y l i c ester (58) undergoes a c o n v e n t i o n a l C l a i s e n rearrangem e n t , t h e p r o d u c t of w h i c h c a n b e c o n v e r t e d i n t o t h e n i t r o - a l k e n e (59).
N i t r i l e o x i d e a d d i t i o n and r e d u c t i o n t h e n g i v e s t h e k e t o n e
(60).78
[3+21 A n n u l a t i o n r e a c t i o n s a r e b e c o m i n g i m p o r t a n t f o r t h e
s y n t h e s i s o f c y c l o p e n t a n e s a n d i t h a s now b e e n d e m o n s t r a t e d t h a t n i c k e l ( 0 ) c o m p l e x e s c a n c a t a l y s e t h e [3+2] c y c l o a d d i t i o n o f m e t h y l e n e c y c l o p r o p a n e s t o e l e c t r o n - d e f i c i e n t a l k e n e s . 79
A neat
[3+2] a d d i t i o n s t r a t e g y i s s h o w n i n S c h e m e 1 0 , w h e r e b y t h e c y c l o p r o p y l d e r i v a t i v e ( 6 1 ) i s o p e n e d by f l u o r i d e a n i o n , a n d t h e r e s u l t i n g ester e n o l a t e t h e n reacts 2 a Michael a d d i t i o n t o a phosphonium s a l t .
The p r o d u c t of t h i s l a s t r e a c t i o n t h e n u n d e r g o e s
a n i n t r a m o l e c u l a r Wittig r e a c t i o n w i t h h y d r o l y s i s a f f o r d i n g t h e o c t a n o n e (62).80
A c o m p r e h e n s i v e a c c o u n t of t h e u s e o f p h o s p h o n i u m 81
s a l t s s u c h as ( 6 3 ) i n c y c l o p e n t a n o i d s y n t h e s i s is t i m e l y .
I n a n i m p o r t a n t e x t e n s i o n o f t h e vinylcyclobutanol-cyclop e n t e n o n e r e a r r a n g e m e n t , a p a l l a d i u m ( 0 ) complex h a s been shown t o
432
General and Synthetic Methods
L
0
N-?
?H tvii -
f-iv
~""0
Reagents: i, L D A , Me2SiButCI; i i , 6 0 'C; iii, KF, M e l , KzC03; i v - , D I B A I - H ; v, MeNOZ, KF, A c Z O , NaBH4; vi, PhNCO, EtJN; vii, Ra-Ni,
Scheme 9
Hz
7: Saturated Carbocyclic Ring Synthesis
-ah
433
OSiE t
cop
+ I
H C0,Et (61)
SMe
.cli
II
C0,Et
CO, Et (62) Reagents: i , P h 3 P + y S M e BF4- (63); i i , CF3COLH
Scheme 10
Pd
0
Me
Me 0
(64)
(65)
General and Synthetic Methods
434
c a t a l y s e t h e r e a c t i o n a s e x e m p l i f i e d by t h e c o n v e r s i o n o f ( 6 4 ) i n t o (65), i n t h e p r e s e n c e o f b e n z o q u i n o n e . 8 2 A l s o of i n t e r e s t a r e f u r t h e r s t u d i e s upon t h e u s e of e l e c t r o n - d o n a t i n g
g r o u p s on t h e
v i n y l m o i e t y i n t h e vinylcyclopropane-cyclopentene r e a r r a n g e m e n t . 8 3 T h e u s e f u l o c t a n o n e ( 6 6 ) i s now a v a i l a b l e b y p h o t o l y s i s o f a bicyclo[2.2.2]ketone
,84 a n d t h e b i c y c l o [ 3 . 2 . 2 ] k e t o n e
( 6 7 ) reacts
w i t h l i g h t t o a f f o r d t h e hydrindane system i n a r e a c t i o n which h a s been a p p l i e d t o t h e s y n t h e s i s o f
(')-pinguisone
.85 H e x a h y d r i n d a n e s
a r e a l s o known t o b e t h e p r o d u c t s o f t h e a c i d - c a t a l y s e d m e n t of some b i c y c l o [ 3 . 3 . 1 ] n o n a n e
o f t h i s p r o c e s s have been d e s c r i b e d . The d i e n e
rearrange-
d e r i v a t i v e s and f u r t h e r d e t a i l s
86
(68) r e a c t s u n d e r p h a s e - t r a n s f e r c a t a l y s i s c o n d i t i o n s
with benzyl cyanide t o g i v e a c c e s s t o five-membered r i n g s which undergo f a c i l e Diels-Alder
r e a c t i o n t o form a fused system.87
N a t u r a l l y O c c u r r i n g Fused Cyc1opentanoids.-
An e x c e p t i o n a l r e v i e w o n
polycyclic sesquiterpene synthesis justifies the detailed attention o f a l l modern s y n t h e t i c c h e m i s t s . 8 8
A s part of a study involving
t h e use of c h i r a l s u l p h i n y l a l l y l anions i n s y n t h e s i s ,
(')-hirsutene
h a s been p r e p a r e d u s i n g , as t h e key s t e p , t h e c y c l i z a t i o n o f t o (70).89
(69)
A f u l l a c c o u n t o f t h e s y n t h e s i s o f t h e same n a t u r a l
product using an organoselenium-mediated c y c l i z a t i o n is of value. (')-Pentalenolactone
E m e t h y l e s t e r h a s b e e n p r e p a r e d a s p a r t of
a demonstration of t h e s y n t h e t i c u t i l i t y of a rhodium-mediated i n s e r t i o n r e a c t i o n as i l l u s t r a t e d by t h e c o n v e r s i o n o f
(71) i n t o
(72) T h e a r e n e - o l e f i n c y c l o a d d i t i o n r e a c t i o n h a s now b e e n a p p l i e d t o t h e s y n t h e s i s of
( + ) - s i l p h i n e n e , 9 2 and l i n e a r t r i q u i n a n e s have been
f o r m e d by a s e r i e s o f t h r e e r a d i c a l r i n g c l o s u r e s .
However, t h e
low y i e l d s and t h e complex m i x t u r e s o b t a i n e d from t h i s p r o c e s s s u g g e s t t h a t f u r t h e r work i s n e e d e d b e f o r e t h e method i s s y n t h e t i c a l l y useful -93 The r e g i o s p e c i f i c a l k y l a t i o n o f t r o p y l i u m i r o n t r i c a r b o n y l s a l t s s u c h a s ( 7 3 ) h a s now b e e n e x t e n d e d t o t h e c a t i o n ( 7 4 ) g i v i n g a c c e s s t o t h e skeleton o f t h e pseudoguaianolides
.94 An i n t e r e s t i n g b i o m i -
m e t i c t r a n s f o r m a t i o n o f d e h y d r o c u r d i o n e ( 7 5 ) i n t o c u r c u m e n o l (76) h a s been d e s c r i b e d , whereby b a s e t r e a t m e n t c a u s e s c y c l i z a t i o n t o p r o c e e d , p r e s u m a b l y a s i n d i c a t e d , i n 80% y i e l d . 9 5 The p l o y o f r i n g e x p a n d i n g a s t e r e o s p e c i f i c a l l y f o r m e d c y c l o b u t a n e t o a c y c l o p e n t a n o n e h a s been p u t t o good u s e i n a p r e p a r a t i o n o f (5 ) - b a k k e n o l i d e - A ,96 i n a n e n a n t i o c o n v e r g e n t s y n t h e s i s o f
435
7: Saturated Carbocyclic Ring Synthesis
hu
OMe
PhCH, NEt3CI+
+
PhCH,CN
NaOH
OCOMe
ATiCL,,
AcOH
Tol S
4 .i
*
”&
To1S
I
H (70)
(69)
R h( O A c l4
COzMe
0
COLMe
General and Synthetic Methods
436
OSiMe,
I
L
(75)
(
POMe NS0,Ph
+
QJ$O f Me
d
NSOzPh
CH,OCOMe
MeOCO
0-r
0
(80)
YHSO, Ph
(79)
NHSO, Ph
7: Saturated Carbocyclic Ring Synthesis
437
h i r s u t i c a c i d , d e s c r i b e d i n f u l l l g 7 and i n t h e t o t a l s y n t h e s i s of (')-b~onein.'~ 4 Six-membered R i n g s Diels-Alder
Reactions.-
A r e g i o s e l e c t i v e Diels-Alder
reaction bet-
ween t h e d i e n e (77) a n d t h e q u i n o n e ( 7 8 ) g i v e s a n a d d u c t w h i c h i s a k e y i n t e r m e d i a t e i n a s y n t h e s i s of t h e l e f t - h a n d p o r t i o n o f t h e a n t i b i o t i c CC-1065
."
Although attempts at using chiral precursors
t o a-quinodimethanes, s u c h as ( 7 9 ) , t o i n d u c e asymmetry i n t o t h e i r D i e l s - A l d e r p r o d u c t s were n o t t o o s u c c e s s f u l , t h e s t u d i e s o n s u c h s p e c i e s are o f m e c h a n i s t i c i n t e r e s t . " ' stannylbuta-l13-dienes
A s i m p l e r o u t e t o 2-
is worthy o f n o t e s i n c e it should g i v e
e a s i e r a c c e s s t o 2 - s u b s t i t u t e d d i e n e s . 'I High-pressure cycloa d d i t i o n r e a c t i o n s c o n t i n u e t o b e p o p u l a r a n d c r o t o n a t e s h a v e now been s t u d i e d w i t h r e s p e c t t o b o t h t h e i r i n t r a - and i n t e r - m o l e c u l a r Diels-Alder reactions.lo2 D e t a i l s o f t h e u s e o f t h e d i e n a m i n e (80) have a l s o appeared. Io3 T h e i n t e n s e a c t i v i t y o f t h e p a s t few y e a r s i n t h e s y n t h e t i c a p p l i c a t i o n s of t h e D i e l s - A l d e r r e a c t i o n a p p e a r s t o h a v e a b a t e d . However, f u r t h e r u s e s of t h e i n t r a m o l e c u l a r v a r i a n t have been r e p o r t e d , c o n f i r m i n g t h i s p o w e r f u l s t r a t e g y a s a now s t a n d a r d p i e c e of s y n t h e t i c methodology. Amongst t h e s e are a s e r i e s o f p a p e r s c o n c e r n i n g t h e s t e r e o s e l e c t i v i t y of t h e r e a c t i o n of v a r i o u s l y s u b s t i t u t e d n o n a t r i e n e s a n d d e c a t r i e n e s , lo' o f u n d e c a t r i e n o a t e s , l o 5 and of dienamines w i t h a c r y l a t e s . Io6 An i n t r i g u i n g s t u d y o f t h e b i s - d i e n e ( 8 1 ) i n w h i c h i n t e r n a l c o m p e t i t i o n is p o s s i b l e i s w o r t h a c l o s e s c r u t i n y , w i t h t h e react i o n s s h o w i n g a m a r k e d d e p e n d e n c e u p o n t h e n a t u r e o f R.Io7 D e t a i l e d s t u d i e s o f t r i e n e s s u c h a s ( 8 2 ) may a l s o b e of v a l u e . l o 8 The r e a d i l y a v a i l a b l e a l l - t r a n s - t r i e n e h a l f - e s t e r ( 8 3 ) u n d e r g o e s a f a c i l e i n t r a m o l e c u l a r c y c l o a d d i t i o n , i n t h e now e x p e c t e d s t e r e o chemical manner, t o form a h i g h l y u s e f u l s u b s t i t u t e d cycloh e x e n e . 109 F u r a n o i d c h e m i s t r y h a s been u t i l i z e d t o p r e p a r e t r i e n e p r e c u r s o r s f o r t h e i n t r a m o l e c u l a r D i e l s - A l d e r r e a c t i o n a s s h o w n by t h e c h e r n o s e l e c t i v e o x i d a t i o n o f t h e f u r a n i n Scheme 1 1 . ' l o Arguably t h e most i m p o r t a n t a d v a n c e i n t h i s area i n v o l v e s t h e u s e o f t h e s u l t a m (84) t o p r o v i d e a n a s y m m e t r i c v e r s i o n o f t h e i n t r a m o l e c u l a r D i e l s - A l d e r r e a c t i o n of p o t e n t i a l l y wide a p p l i c a b i l i t y , g i v i n g t h e a l c o h o l (85) a s a n e n a n t i o m e r i c a l l y p u r e
438
General and Synthetic Methods Me
RO, C
Me (81)
R = Et, H,
or
Na
i
PhCO,
Reagents: i, MCPBA, ii, E t 3 N
Scheme 11
439
7: Saturated Carbocyclic Ring Synthesis
-b HO
EtAlCI, -20
*c
A
(84)
(05)
HO
I
Br
(86)
;
OCH, Ph
(87)
M
COPh
(881
General and Synthetic Methods
440
product. A t h i r d r e s e a r c h g r o u p h a s r e p o r t e d s t u d i e s aimed a t u s i n g t h i s s t r a t e g y a s t h e key s t e p i n a s y n t h e s i s o f f o r s k o l i n , l l 2 and a well planned e n a n t i o s p e c i f i c approach t o t h e octahydronaphthalene p o r t i o n o f d i h y d r o m e v i n o l i n u t i l i z e s t h e p r o t o c o l t o good e f f e c t and is o f i n t e r e s t . l l 3
A c h i r a l synthesis of androsterone u t i l i z e s
t h e t r i e n e (86) i n its i n t r a m o l e c u l a r c y c l o a d d i t i o n t o form t h e w h i l s t t h e t e t r a e n e ( 8 7 ) , o b t a i n a b l e f r o m D-
s t e r o i d AB r i n g s , ’ ”
glyceraldehyde, is t h e precursor f o r t h e f i r s t enantioselective s y n t h e s i s of t h e bottom h a l f of c h l o r o t h r i c o l i d e .
l5
Finally the
t r i e n e (88) h a s been u s e d i n a n a p p r o a c h t o t h e s y n t h e s i s o f 116,117 cytochalasins. O t h e r S y n t h e s e s o f Six-membered Rings.the proline-assisted
Comprehensive details of
a s y m m e t r i c a l d o l c y c l i z a t i o n s o f (89) l 8 a n d
( 9 0 ) ” ~ w i l l be of immense v a l u e .
The problem o f u t i l i z i n g r e g i o -
s e l e c t i v e l y generated e n o l a t e a n i o n s i n t h e Robinson a n n u l a t i o n can b e s o l v e d by t h e u s e o f 2 - s i l y l a t e d
enolates.lZ0
A d d i t i o n a l l y some
new i n s i g h t s i n t o t h e a l d o l s t e p o f t h i s a n n u l a t i o n a r e w o r t h s t u d y i n g . 12’ Scheme 12 shows a n e x a m p l e o f a f u l l y d e t a i l e d a n n u l a t i o n r e a c t i o n which i n v o l v e s a Michael a d d i t i o n - c y c l i z a t i o n sequence f o r a-formyl-enones.
22
A previously described intramolecular double
Michael r e a c t i o n h a s been used i n t h e t o t a l s y n t h e s i s o f a t i s i r a n 15-one. 123 M u l t i p l e c a r b o n - c a r b o n bond f o r m i n g r e a c t i o n s a r e o f c o u r s e i n v a l u a b l e a n d now a M i c h a e l - M i c h a e l - r i n g
c l o s u r e (MIMIRC) p r o c e s s
h a s been d e v e l o p e d t o p r o v i d e a [2+2+2] s y n t h e s i s o f c y c l o h e x a n e s a s shown i n Scheme 1 3 . 1 2 4
An a l t e r n a t i v e a n d p r e v i o u s l y d e s c r i b e d
[2+2+2] a n n u l a t i o n r o u t e t o p o l y c y c l i c s y s t e m s h a s r e c e n t l y been a p p l i e d t o t h e s y n t h e s i s of 3 - d e s m e t h y l - a f l a v i n i n e . 1 2 5 B-Keto-esters
containing an alkene w i l l undergo a manganese(II1)
o x i d a t i o n r e a c t i o n r e s u l t i n g i n r i n g c l o s u r e as shown i n t h e reaction of (91). only.
However o t h e r e x a m p l e s p r o c e e d i n p o o r y i e l d
a,w-Bis-allylic
acetates such as ( 9 2 ) undergo a p a l l a -
dium(0)-induced r e d u c t i v e c y c l i z a t i o n i n t h e p r e s e n c e of hexam e t h y l d i t i n i n a v e r y m i l d p r o c e s s which g i v e s d i r e c t access t o dihydronaphthalenes.
27
I n a f u r t h e r e l e g a n t example of t h e u t i l i t y o f i n t r a m o l e c u l a r r a d i c a l c y c l i z a t i o n s i n r i n g formation, ( k ) - a l l i a c o l i d e h a s been s y n t h e s i z e d u s i n g t h e c y c l i z a t i o n of ( 9 3 ) . 1 2 8 I n a well conceived
7: Saturated Carbocyclic Ring Synthesis
441
(89) n = 1 (90) n = 2
Reagents: i ,
DDQ; i i , NaH, B u ~ C O C H ~ C O ~ Bi iUi , ~ p; - T s O H , AcOH Scheme 12
'PPh,
Br'
Bt'
+
f'Ph3
\
PPh, Br'
Reagents: i , LiBuS3BH; ii, KOH
Scheme 13
General and Synthetic Methods
442
P
I
Bu3SnH AIBN
0
443
7: Saturated Carbocyclic Ring Synthesis
s t u d y , r a d i c a l c y c l i z a t i o n h a s been used t o c o n t r o l r i n g f u n c t i o n stereochemistry. Thus, t h e r e a c t i o n of (94) w i t h a t i n hydride f o r m s a %-fused
five-membered
r i n g which d i c t a t e s , f o r conforma-
t i o n a l r e a s o n s , t h a t d e l i v e r y of a hydrogen atom o c c u r s from t h e 'convex'
s i d e of t h e r a d i c a l (95) t o form t h e trans-fused
s y s t e m . 29 I n t r a m o l e c u l a r a l l y l s i l a n e a d d i t i o n t o an enone, which h a s p r e v i o u s l y been d e s c r i b e d i n a r e a c t i o n t o form h y d r i n d a n e s , c a n a l s o g i v e t h e d e c a l o n e s y s t e m ( 9 6 P 3 O or t h e f u s e d e n o n e ( 9 7 ) . 1 3 ' The g e o m e t r i c c o n s t r a i n t s o f t h e s e c y c l i z a t i o n s have been c a r e f u l l y s t u d i e d 1 3 2 and t h e y are o b v i o u s l y o f u s e i n n a t u r a l p r o d u c t s y n t h e -
s i s a s w i t n e s s e d by a s y n t h e s i s o f ( ' ) - n o o t k a t o n e A new f o u r - c a r b o n
( 9 8 ) . 33
a n n u l a t i o n p r o c e d u r e i s shown i n Scheme 1 4 ,
whereby t h e d i e n o l a t e a n i o n o f a n u n s a t u r a t e d c a r b o x y l i c a c i d ( 9 9 )
i s added t o a k e t o n e t o g i v e a n a c i d which upon r e a r r a n g e m e n t a t higher temperature forms t h e y-substituted
acid ( 1 0 0 ) .
t i o n and c y c l i z a t i o n t h e n form t h e a n n u l a t e d p r o d u c t
HydrogenaAnother
novel cyclohexene-forming process i n v o l v e s t h e a d d i t i o n o f 1-
lithio-l-methoxycyclopropane t o a n a - m e t h y l t h i o k e t o n e
such as
( I O I ) , f o l l o w e d by t r e a t m e n t w i t h a c i d t o f o r m a c y c l o b u t a n o n e (Scheme 1 5 ) .
Formation of t h e s i l y l a t e d cyanohydrin, thermolysis,
a n d d e s i l y l a t i o n a f f o r d t h e f u s e d e n o n e (102) Polvene Cvc1izations.-
Of relevance t o a l l those interested i n
t h e s e r e a c t i o n s are some o b s e r v a t i o n s w h i c h i n d i c a t e t h a t b i o m i m e t i c o l e f i n c y c l i z a t i o n i s a s t e p w i s e p r o c e s s , a s s h o w n by t h e t r a p p i n g o f s o m e c a t i o n i c i n t e r m e d i a t e s . 36
N i t r i l e s have been
shown t o be e x c e l l e n t t e r m i n a t o r s o f c a r b o c a t i o n i c o l e f i n c y c l i z a t i o n s u s e d i n a n a p p r o a c h t o a m p h i l e c t a n e d i t e r p e n e s . 137 More u s e s o f 2,4,4,6-tetrabromocyclohexadienone ( 1 0 3 ) i n p o l y e n e c y c l i z a t i o n s have been r e p o r t e d , w i t h t h e c o n v e r s i o n o f (104) i n t o (105) being t h e key s t e p i n a biogenetic-type
c o n c i n n d i o l and ( 5 ) - a p l y s i n 20.138
synthesis of (*)-
The g r e a t v a l u e o f u s i n g a
s i l y l g r o u p t o c o n t r o l t h e r e g i o c h e m i c a l outcome of a p o l y e n e c y c l i z a t i o n is e l e g a n t l y demonstrated i n an approach t o t h e synthe-
sis o f d i h y d r o c o m p a c t i n
(Scheme 16).
39
90% O p t i c a l l y p u r e a l c o h o l ( 1 0 7 ) h a s b e e n p r o d u c e d by t h e cyclization of an aldehyde with t h e c h i r a l zinc reagent (106).
140
General and Synthetic Methods
444
wsiMe EtAICI;
0
OH
OH
(99)
(1 0 0 )
0 Reagents: i, L i N E t 2 , - 7 0 'C; i i ,
0';
iii, 6 5 'C;
Scheme 1 4
i v , H,,Pd/C;
V,
PPA
out
Gutiii & -
7: Saturated Carbocyclic Ring Synthesis
' -
SBu . . .
445
iv,"
I, I I
__j
Me,SiO
0
(101)
(102)
CN
Li
Reagents: i .
KOMe ;
ii, HBF4; iii, Me3SiCN, Z n 1 2 ; i v , heat; v, B U 4 N f F -
Scheme 15
v
SbCL, .___)
/
-78
'c
S
O
H
Si Ph Me2 Me Scheme 16
M
e
General and Synthetic Methods
446
5 Seven-membered, Medium, and Large R i n g s An i n t e r e s t i n g r o u t e t o t h e g u i a n o l i . d e s y s t e m h a s b e e n d e s c r i b e d i n v o l v i n g L e w i s a c i d c y c l i z a t i o n of t h e h e m i a c e t a l ( 1 0 8 ) . 1 4 '
Also
r e c e n t l y d e s c r i b e d i s t h e s y n t h e s i s o f t h e h o m o l o g u e of t h e
via
Wieland-Mischler ketone 142 trione (109).
an enamine-induced
cyclization of t h e
F u l l d e t a i l s of t h e u s e of a n a l i p h a t i c C l a i s e n r e a r r a n g e m e n t t o
as w i l l d e t a i l s
prepare annulated cyclo-octenones w i l l be
o f t h e i n t r a m o l e c u l a r c y c l i z a t i o n of c - s i l y l a t e d
t a l s t o a c h i e v e t h e same eight-membered
e n o l a t e s a n d ace-
An a l t e r n a t i v e s y n t h e s i s o f
r i n g s involves t r e a t i n g t h e acetal (110) with acid
t o e s t a b l i s h an equilibrium i n which t h e ketone (111) is t h e major 146 product . Titanium(0)-induced
c y c l i z a t i o n of t h e a l d e h y d e ( 1 1 2 ) r e s u l t s i n
t h e f o r m a t i o n of b i c y c l o g e r m a c r e n e and l e p i d o z e n e p l u s t h e i r i s o analogues.
V e r t i c e l l e n e (113) is reputed t o be t h e biogenetic
p r e c u r s o r o f ' t h e t a x e n e a l k a l o i d s a n d i t h a s now b e e n s y n t h e s i z e d , t h e t i t a n i u m ( 0 ) coupling of t h e bisaldehyde (114) being t h e key
After s u c h a n i m p r e s s i v e s y n t h e t i c
step in the synthesis.
a c h i e v e m e n t i t m u s t h a v e b e e n d i s a p p o i n t i n g t o b e u n a b l e t o demon-
s t r a t e t h e chemical c y c l i z a t i o n of t h e v e r t i c e l l a n e s k e l e t o n t o t h e t a x a n e r i n g s y s t e m . "9 F u r t h e r work on t h e ' z i p '
r e a c t i o n h a s f o c u s e d u p o n t h e u s e of
t h e cyano-group as an a n i o n i c c h a r g e s t a b i l i z e r .
Thus c y c l i z a t i o n
of t h e k e t o n e ( 1 1 5 ) w i t h b a s e r e s u l t s i n c y c l i z a t i o n and 'unzipping'
t o g i v e an eleven-membered
r i n g . I5O
6 Ring Expansion Methods Two m o r e p a p e r s o n t h e s y n t h e s i s o f c y c l i c a l l e n e s h a v e a p p e a r e d which u t i l i z e t h e alkyl-lithium-induced
opening of a fused dihalo-
g e n o c y c l o p r o p a n e s u c h as ( 1 1 6 ) . 151'152
Access t o t h e o p h i o b o l i n
r i n g s y s t e m h a s b e e n a c h i e v e d by r i n g e x p a n s i o n of t h e k e t o - a c i d ( 1 1 7 1 , a l b e i t a s a m i x t u r e of i s o m e r s . 1 5 3 p r e p a r i n g eight-membered
s y n t h e s i s o f a m o d e l for t h e A , by t h e c o n v e r s i o n o f
T h e d e Mayo s e q u e n c e f o r
r i n g s h a s been used i n a n a p p r o a c h t o t h e B , C r i n g s of t h e t a x a n e s a s shown
( 1 18) i n t o ( 1 19)
I n t e r e s t i n g l y , thermoly-
sis of t h e s t e r o i d a l p e r o x i d e ( 1 2 0 ) r e s u l t s i n r i n g o p e n i n g t o t h e m a c r o c y c l e ( 1 2 1 ) , b u t o n l y i n low y i e l d . 1 5 5 The s e l e n o n e ( 1 2 2 ) r e a c t s w i t h e n o l a t e a n i o n s t o form e i t h e r t h e
447
7: Saturated Carbocyclic Ring Synthesis
SnC I,
OH
Q
CL
Eto2c 0
q:
0’
U (110)
(111)
General and Synthetic Methods
448
(113)
(114)
COzMe
I
[acoz CN
(115)
J
Br
L i , NH, ____)
H-
H
449
7: Saturated Carbocyclic Ring Synthesis
0 (119)
(118)
OCOMe
OCOMe
MeOCO
0 (121)
(120)
5
0
co, Et
II
+
wMe & (122)
IF-
(1221
z - (122)
+
cop 5 7% 0 *I.
OH
SPh Reagents: i, KH; ii, A c O H
Scheme 17 0
Reagents.i;McSOjH, P20s (10: 1,O.l equiv. 1 ; ii, 17cquiv. MeS03H ,P2Os
Scheme 18
dcop
2 5% 6 0 *lo
General and Synthetic Methods
450 cyclopropanated ring-expanded
ketone or t h e v i n y l a t e d ring-expanded
p r o d u c t d e p e n d i n g u p o n t h e s t e r e o c h e m i s t r y of
( 1 2 2 ) . 156
A further
i n t e r e s t i n g r i n g e x p a n s i o n r e a c t i o n i s t h e f o r m a t i o n of 4-phenylt h i o c y c l o h e x a n o n e s by a s u l p h u r atom a s s i s t e d e x p a n s i o n o f a v i n y l c y c l o b u t a n o l as shown i n Scheme 17.157
T h e same t y p e ' o f r e a r r a n g e -
ment is i n v o l v e d i n t h e r e a c t i o n f o l l o w i n g t h e a c i d t r e a t m e n t of The f i r s t formed p r o d u c t i s a
the cyclopropanol derivative (123).
c y c l o b u t a n o n e (Scheme 1 8 ) w h i c h upon s t r o n g e r a c i d t r e a t m e n t f o r m s
a c y c l o p e n t e n o n e . 158
Anhydrous f e r r i c c h l o r i d e on s i l i c a g e l h a s
been shown t o be a n e x c e l l e n t r e a g e n t f o r t h e r i n g e x p a n s i o n o f t e r t i a r y c y c l o b u t a n o l s , 15' and i s o l a u r o l e n e . 160
having been used t o p r e p a r e (k)-cuparene
7 S w i r o - r i n g ComDounds The a n t i t u m o u r p r o p e r t i e s of f r e d e r i c a m y c i n A h a v e l e d t o a good d e a l of i n t e r e s t i n t h e s y n t h e s i s of spirohydrindanones.
One
a p p r o a c h t o its s p i r o c y c l i c c e n t r e ( 1 2 5 ) i n v o l v e s a phenoxy r a d i c a l c o u p l i n g o f t h e p h e n o l ( 1 2 4 ) i n 6 7 % y i e l d w i t h o n l y 8% o f t h e ortho-product
b e i n g formed. 16'
two a l t e r n a t i v e methods.
Another r e s e a r c h group has reported
The f i r s t i n v o l v e s a F r i e d e l - C r a f t s
r e a c t i o n o f t h e d i a c i d ( 1 2 6 ) w h i c h o n l y p r o c e e d s i n 10% y i e l d .
162
S l i g h t l y b e t t e r was t h e r e a c t i o n o f i n d e n e w i t h t h e d i h a l i d e ( 1 2 7 ) using phase-transfer
conditions. 163
A new d e s c r i p t i o n o f t h e g e n e r a t i o n o f
l-alkoxycyclopropyl-
l i t h i u m r e a g e n t s w i l l g i v e i n c r e a s e d access t o s p i r o c y c l o b u t a n o n e s
a s s h o w n i n t h e p r e p a r a t i o n o f ( i 2 8 ) , 16'
a n d a s t u d y of t h e a c i d -
catalysed rearrangement of a-vinylcyclobutanones is a l s o o f i n t e r e s t . 165
t o spiro-compounds
By v a r i a t i o n o n a r a d i c a l c y c l i z a t i o n t o g i v e f u s e d r i n g s , a procedure f o r t h e preparation of spiro-systems which u s e s t h e s e l e n i d e (129). 166 reaction of
h a s been r e p o r t e d
The i n t r a m o l e c u l a r D i e l s - A l d e r
( 1 3 0 ) i n S c h e m e 1 9 h a s b e e n u s e d a s a b a s i s f o r a new
s y n t h e s i s of t h e s p i r o C 4 . 5 l d e c a n e s y s t e m , 167 a n d t h e a c o r o n e i n t e r mediate (131) h a s been prepared using an a-alkynone c y c l i z a t i o n 168 process. The D i e l s - A l d e r
r e a c t i o n is undoubtedly a very u s e f u l r o u t e t o
s p i r o c y c l i c c o m p o u n d s , a n d h a s now b e e n e x t e n d e d t o a l l e n i c k e t o n e s ,
s o g i v i n g r e a d y access t o p o l y f u n c t i o n a l s p i r o - s y s t e m s a s shown i n t h e p r e p a r a t i o n of ( 1 3 2 ) . 16'
Furan-terminated
cationic cycliza-
t i o n s h a v e b e e n a p p l i e d t o t h e s y n t h e s i s o f s p i r o - c o m p o u n d s s u c h as
7: Saturated Carbocyclic Ring Synthesis
45 1
HO K3Fe(CNI6
0 (125)
(124)
C02H
&co2H
+
*&
Meoa 0Me
MeS03H
5'2'
OMe (126)
\
OMe NaOH
Ph3SnH
@ph
AIBN
OH (129)
OH
452
General and Synthetic Methods CHO
(130) Reagents: 1 .
Bun3N, 190 * C i
11,
H2, 5'1.
Pd/C/BaS04,
iii, 03; iv, Me2S
Scheme 19
&-'
H+
(133) 0
(134)
7: Saturated Carbocyclic Ring Synthesis
453
( 1 3 3 ) , 1 7 0 a s t r a t e g y which h a s been a p p l i e d t o t h e s y n t h e s i s of (+I-aphidicolin. 17' Two L e w i s a c i d c a t a l y s e d r e a r r a n g e m e n t s o f e p o x i d e s h a v e b e e n d e s c r i b e d w h i c h r e s u l t i n t h e f o r m a t i o n of s p i r o - r i n g The f i r s t i n v o l v e s t h e r e a c t i o n o f t h e e p o x y - k e t o n e
compounds.
(134) t o give a
s p i r o 1 , 3 - d i k e t o n e , 172 w h e r e a s t h e s e c o n d i n v o l v e s a n e x a m p l e of t h e e p o x i d e ( 1 3 5 ) r e a r r a n g i n g t o a k e t o n e . 173
References 1 2 3 4
5
6
7 8 9 10
11 12
13 14 15
16
17 18 19 20
21
22 23 24 25 26 27
28 29 30 31 32 33 34
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General and Synthetic Methods
454 37 38 39 40 41 42 43 44
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51 52 53 54 55 56
57 58 59 60 61 62 63 64
65 66 67 68 69 70
71 72 73 74 75 76
77 78 79
80 81 82
83 84 85
86
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26, 26, 26, 26,
26,
26,
26,
24,
26,
2,
11,
5,
26,
26,
26,
26,
26,
26,
24,
.
5,
7: Saturated Carbocyclic Ring Synthesis 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106
107 108 109 110 111
112
455
26,
A.Commercon and G.Fonsinet, Tetrahedron Lett., 1985, 4093. 1767. M.Vandewalle and P.De Clerq , Tetrahedron, 1985, D.H.Hua, G .Sinai-Zingde, and S.Venkataraman, J. Am. Chem. S O C . 1985 , 107, 4088. 4765. S.V.Ley, P.J.Murray, and B.D.Palmer, Tetrahedron, 1985, D.F.Taber and J.L.Schuchardt, J. Am. Chem. S O C . , 1985, 107,5289. 2625. P.A.Wender and R.J.Ternansky, Tetrahedron Lett., 1985, A.L.J.Beckwith, D.H.Roberts, C.H.Schiesser, and A-Wallner, Tetrahedron Lett., 1985, 26, 3349. 3531. J.C.Watkins and M.Rosenblum, Tetrahedron Lett., 1985, Y.Shiobara, T.Iwata, M.Kodama, Y.Asakawa, T.Takemoto, and Y.Fukazawa, 913. Tetrahedron Lett., 1985, A.E.Greene, J.-P.Depr&s, F.Coelho, and T.J.Brocksom, J. Org. Chem., 1985, 50, 3943. A.E.Greene, M.-J.Luche, and A.A.Serra, J. Org. Chem., 1985, 50, 3957. T.V.Lee, J.Toczek, and S.M.Roberts, J. Chem. S O C . , Chem. Commun., 1985, 371. G.A.Kraus, S.Yue, and Y.Sy, J. Org. Chem., 1985, 50, 283. 3413. J.L.Charlton, Tetrahedron Lett., 1985, 1.Fleming and M.Taddei, Synthesis, 1985, 899. C.Ferroud, G.Revia1, and J-d’Angelo,Tetrahedron Lett., 1985, 26, 3981. A.Mezzetti, P.Nitti, G.Pitacco, and E.Valentin, Tetrahedron, 1985, 1415. 2269. Y.-T.Lin and K,N.Houk, Tetrahedron Lett., 1985, 2517. Y.-T.Lin and K.N.Houk, Tetrahedron Lett., 1985, 3, 2293. T.-C.Wu and K.N.Houk, Tetrahedron Lett., 1985, 1391. D.R.Williams, R.D.Gaston, and I.B.Horton, Tetrahedron Lett., 1985, A.Guy, M.Lemaire, M.Negre, and J.P.Guette, Tetrahedron Lett., 1985, 6 , 3575. A.Ingendoh, J.Becher, H.Clausen, and H.C.Nielsen, Tetrahedron Lett., 1985, 26, 1249. 1367. F.D.Williams and E.LeGoff, Tetrahedron Lett., 1985, 5437. W.Oppolzer and D.Dupuis, Tetrahedron Lett., 1985, F.E.Ziegler, B.H.Jaynes, and M.T.Saindane, Tetrahedron Lett., 1985, 6 ,
fi,
5, 26,
26,
26,
2,
fi,
26, 26,
26,
26, 26,
3307. 113 A.M.Davidon, C.D.Floyd, A.J.Jones, and P.L.Meyers, J. Chem. SOC., Chem. Commun., 1985, 1662.
114 M.Ihara, I.Sudow, K.Fukumoto, and T.Kametani, J. Org. Chem., 1985, 50, 144. 115
116 117 118 119 120
121 122
123 124 125
26,
W.R.Roush and M.Kageyama, Tetrahedron Lett., 1985, 4327. D.J.Tapolczay, E.J.Thomas, and J.W.F.Whitehead, J. Chem. S O C . , Chem. Commuri . , 1985, 143. A.Craven, D.J.Tapolczay, E.J.Thomas, and J.W.F.Whitehead, J. Chem. S O C . , Chem. Commun., 1985, 145. 26. Z.G.Hajos and D.R.Parrish, Org. Synth., 1985, 37. P.Buchschacher and A.Furst, Org. Synth., 1985, J.W.Huffman, S.M.Fotris, and A.V.Satish, J. Org. Chem., 1985, 50, 4266. J.W.Muskopf and R.M.Coates, J. Org. Chem., 1985, 50, 69. W.L.Meyer, M.J.Brannon, C.da G. Burgos, T.E.Goodwin, and R.W.Howard, J. Org. Chem., 1985, 50, 438. M.Ihara, M.Toyota, K.Fukumoto, and T.Karnetani, Tetrahedron Lett., 1985, 1537. G.M.Posner and S.-B.Lu, J. Am. Chem. SOC., 1985, 107, 1424. S.Danishefsky, S.Chackalamanni1, P-Harrison, M.Silvestri, and P.Cole, J. . Am. SOC.. 1985. 107. 2474. .... Chern. .... , _ -’ B.B.Snider, R.Mohan, and S.A.Kates, J . Org. Chem., 1985, 50, 3659. B.M.Trost and K.M.Pietrusiewicz, Tetrahedron Lett., 1985, 26, 40139. M.Ladlow and G.Pattenden, Tetrahedron Lett., 1985, 26, 4413. G.Stork and M.Khan, J. Am. Chem. SOC., 1985, 107,500. 2751. G.Majetich, K.Hul1, and R.Desmond, Tetrahedron Lett., 1985, G.Majetich, K.Hul1, J.Defauw, and R.Desmond, Tetrahedron Lett., 1985, 2747. G.Majetich, K.Hul1, J.Defauw, and T.Shawe, Tetrahedron Lett., 1985, 2755. G.Majetich, M.Behnke, and K.Hul1, J. Org. Chem., 1985, 50, 3615.
63, 63,
I
126 127 128 129
130 131 132
133
26,
7
26,
26, 26,
General and Synthetic Methods
456 134 135 136
137 138 139 140
141 142 143 144
145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170
171 172
173
P-Ballester, A.Garcia, and R.Mestres, Synthesis, 1985, 802. J.H.Byers and T.A.Spencer, Tetrahedron Lett., 1985, 713. M.Nishizawa, H.Takenaka, and Y.Hayashi, J. Am. Chem. SOC., 1985, 107,522. R.V.Stevens and K.F.Allizati, J. Org. Chem., 1985, 50, 632. Y.Yamaguchi, T.Uyehara, and T.Kato, Tetrahedron Lett., 1985, 26, 343. S.D.Burke, J.O.Saunders, J.A.Oplinger, and C.W.Murtiashaw, Tetrahedron 1131. Lett., 1985, K k a n e , K.Maruoka, and H.Yamamoto, Tetrahedron Lett., 1986, 25, 5535. T.Hudlicky, S.V.Crovindon, and J.O.Frazier, J. Org. Chem., 1985, 50, 4166. V.T.Ravikumar, K.Thangaraj, S-Swaminathan, and K.Rajagopalan, Synthesis, 1985, 985. W.A.Kinney, M.J.Coghlan, and L.A.Paquette, J. Am. Chem. S O C . , 1985, 107, 7352. G.S.Cockeril1, P-Kocienski, and R.Treadgold, J. Chem. SOC., Perkin Trans. 1 , 1985, 2093. G.S.Cockeril1, P.Kocienski, and R.Treadgold, J. Chem. S O C . , Perkin Trans. 1 , 1985, 2101. M.Botta, S.Catelli, and A-Gambacorta, Tetrahedron, 1985, 2913. 2167. J.E.McMurry and G.K.Bosch, Tetrahedron Lett., 1985, C.B.Jackson and G.Pattenden, Tetrahedron Lett., 1985, 26, 3393. M. J .Begley, C.B. Jackson, and G.Pattenden, Tetrahedron Lett., 1985, 3397. M.Susse, J.Hajicek, and M.Hesse, Helv. Chim. Acta, 1985, 68, 1986. G.H.Perez and P-Weyerstahl, Synthesis, 1985, 174. H.Traver and H.Haufe, Synthesis, 1985, 343. R.H.Coates, J.W.Muskopf, and P.A.Senter, J. Org. Chem., 1985, 50, 3541. W.F.Berkowitz, J.Perumatton, and A-Amarasekara, Tetrahedron Lett., 1985, 26, 3665. Lj.Lorenc, L.Bondarenko, and M.Lj.Mihailovic, Tetrahedron Lett., 1985, 26, 389. 5571. T.Sugawara and I.Kuwajima, Tetrahedron Lett., 1985, T.Cohen, L.-C.Yu, and W.M.Daniewski, J. Org. Chem., 1985, 50, 4596. J.-P.Barrier, B.Karkour, and J.Salaun, J. Chem. S O C . , Chem. Commun., 1985, 1270. 413. A.Fade1 and J.Salaun, Tetrahedron, 1985, 1267. A.Fade1 and J.Salaun, Tetrahedron, 1985, A.S.Kende, F.H.Ebetino, and T.Ohta, Tetrahedron Lett., 1985, 26, 3063. G.Eck, M.Julia, B.Pfeiffer, and C.Rolando, Tetrahedron Lett., 1985, 4723. G.Eck, M.Julia, B.Pfeiffer, and C.Rolando, Tetrahedron Lett., 1985, 26, 4725. R.C.Gadwood, M.R.Rubino, S.C.Nagarajan, and S.T.Miche1, J. Org. Chem., 1985, 50, 3255. D.A.Jackson, M.Rey, and A.S.Dreiding, Helv. Chim. Acta, 1985, 68, 439. L.Set, D.R.Cheshire, and D.L.J.Clive, J. Chem. S O C . , Chem. Commun., 1985, 1205. J. E.Nystrom, T.D.McCanna, P. Helquist, and R.S.Iyer, Tetrahedron Lett., 198'59 26, 5393. J.Ackroyd, M.Karpf, and A.S.Dreiding, Helv. Chim. Acta, 1985, 68, 338. J.-L.Gras and A.Guerin, Tetrahedron Lett., 1985, 26, 1781. S.P.Tanis, P.M.Herrinton, and L.A.Dixon, Tetrahedron Lett., 1985, 26, 5347 S.P.Tanis, Y.-H.Chuang, and D.B.Head, Tetrahedron Lett., 1985, 26, 6147. R.~.Bach and R.C.Klix, J. Org. Chem., 1985, 50, 5438. N.Takaishi, H.Takahashi, and Y.Inamoto, Tetrahedron Lett., 1985, 26, 2361.
26,
26,
c,fi,
26,
26,
fi, 41,
c,
Saturated Heterocyclic Ring Synthesis BY K. COOPER AND P. J. WHITTLE
1 Oxygen-containing Heterocycles
T h r e e - a n d Four-membered
Rings.-
The i n c r e a s i n g i m p o r t a n c e o f
p r o d u c i n g o p t i c a l l y p u r e compounds i n o r g a n i c s y n t h e s i s h a s l e d t o an explosion of asymmetric methodology and nowhere is t h i s b e t t e r i l l u s t r a t e d t h a n i n t h e f i e l d of e p o x i d e c h e m i s t r y .
Oppolzer and
h i s g r o u p h a v e now s h o w n t h a t t h e c h i r a l a u x i l i a r y w h i c h t h e y h a v e p u t t o good e f f e c t i n Diels-Alder
chemistry is a l s o a useful
auxiliary f o r t h e synthesis of c h i r a l epoxides.
Asymmetric h a l o -
g e n a t i o n o f t h e e n o l a t e o f ( 1 ) f o l l o w e d by c a r e f u l r e d u c t i o n l e a d s t o 8-halogeno-alcohols
which c y c l i z e t o e p o x i d e s ( 2 ) i n good y i e l d
(>54%) a n d w i t h h i g h e . e . s
(>96%).'
Both enantiomers of t h e
a u x i l i a r y are a v a i l a b l e , enabling both isomers t o be prepared. R e d u c t i o n of t h e c h i r a l B - k e t o - s u l p h o x i d e s
(3) can be adjusted t o
g i v e e i t h e r i s o m e r of t h e B - h y d r o x y - s u l p h o x i d e
which can then be
c y c l i z e d t o g i v e t h e r e q u i r e d e p o x i d e s (4) a n d ( 5 ) a s s h o w n i n Scheme
As w i t h O p p o l z e r ' s m e t h o d t h e y i e l d s a r e g o o d (>60%) e x c e l l e n t (>95%).
and t h e e.e.s
W i t h o u t d o u b t t h e most g e n e r a l method f o r t h e s y n t h e s i s o f c h i r a l e p o x i d e s t o d a t e i s t h a t of S h a r p l e s s a n d c o - w o r k e r s s u c h t h a t t h e s t e r e o c h e m i c a l o u t c o m e o f t h e e p o x i d a t i o n of t h e a l l y l i c a l c o h o l ( 6 ) h o l d s t r u e a l m o s t n o matter t h e n a t u r e o f R 1 t o R
4.
However, r e c e n t s t u d i e s h a v e shown t h a t i f t - b u t y l g r o u p s a r e incorporated a t e i t h e r t h e c a r b i n o l carbon or a t t h e B-Z-position t h e n t h e e . e . s o f t h e a - h y d r o x y - e p o x i d e s a r e much r e d ~ c e d . ~T h e s y n t h e s i s of a - k e t o - e p o x i d e s b y t h e D a r z e n s c o n d e n s a t i o n i s w e l l k n o w n , b u t t h i s y e a r h a s s e e n t h e f i r s t e x a m p l e of c h i r a l , a q u e o u s catalysed Darzens condensation t o g i v e t h e epoxy-ketones ( 7 ) a l b e i t i n o n l y m o d e r a t e o p t i c a l a n d c h e m i c a l y i e l d s ( 2 - 6 2 % a n d 5-43% r e s p e c t i v e l y 1.
4
S e v e r a l new o r m o d i f i e d g e n e r a l s y n t h e s e s of e p o x i d e s h a v e a l s o appeared t h i s year.
For e x a m p l e M o s s e t a n d Gree h a v e f o u n d t h a t
trimethylsulphonium methylsulphonate 457
(8) is a highly reactive For References see p. 544
458
General and Synthetic Methods
R X/O
7-J 0
i, L D A , T M S C l ii, N B S or NCS
/
2
O
d
X
Halogen
0
I
i , Ca ( BH4$
ii, NaOMe
R
\ti 0
0
I
0
Reagents : i , D I B A L ;
I
i i , D I B A L , Z n C l 2 ; i i i , L i A I H 4 ; i v , Me30+BF,-;
Scheme
1
v, NaOH
459
8: Saturated Heterocyclic Ring Synthesis
R’
R’
Ti(OR14,
R2
-
4
(+IDET,
R3
R3
TBHP
R4
X =
0 - , rn-,
or p-NO2 or 0 - C I
(7)
Y = Br or CL
+
Me+. CH3S04-
(8)
S’
Reagents:
i, L i C H 2 S M e
ii, Me1
;
iii, K + B u t O - , THF
Scheme
2
460
General and Synthetic Methods
ketone epoxidizing reagent undre biphasic reaction conditions and indeed needs no phase-transfer ~ a t a l y s t . ~Also, yields in the Corey procedure for epoxidation of cyclic a,B-unsaturated ketones are much improved by carrying out the procedure in three discrete steps with some modification to the conditions (see Scheme 2). 6 The conversion of a ketonic carbonyl into a functionalized epoxide presents much more of a synthetic challenge, and a useful method for doing just that has been published by Cookson and Crumbie. Thus, addition of ally1 Grignard reagents to the ketones (9) affords the homoallylic alcohols (lo), which are converted into the epoxides ( 1 1 ) by treatment with NBS followed by cyclization with NaH.7 Kirschenbaum and Sharpless have shown that by altering the conditions of the Payne method for tungstate-catalysed epoxidation of a,B-unsaturated acids the yields are greatly improved and the scope of the reaction is increased. It was also concluded from this study that a-alkyl and B-cis-alkyl substitution of the acid is rate enhancing.' F u l l details of the incorporation of vanadium(1) and molybdenum(I1) complexes onto polymer, and their subsequent use as epoxidation reagents, have appeared, and the development of polymer-supported dioxyphosphorane as a cyclodehydration reagent (giving epoxides from 1,2-diols) from the previously known diethoxytriphenylphosphorane has been published. Finally on epoxides, contrary to their original publication, Bloch et al. have found that potassium hydrogen sulphate alone is capable of epoxidizing alkenes, giving yields of 62-94%. 1 1 The system developed by Edwards and Curci to generate dimethyldioxirane in situ has been modified by Murray and Jeyaraman to allow the distillation of a number of dioxiranes ( 1 2 ) as solutions, thus allowing spectroscopic characterization and a study o f their chemical properties. 12 2-0xabicyclo[2.2.0]hexanes (14) are formed in high yield ( 8 0 -
90%) by the cycloaddition of aldehydes with the cyclobutadiene (13) at room temperature in pentane. ' 3 Five-membered Rings.- Tetrahydrofurans. The halogenoetherification procedure and related reactions have been extensively used for the formation of tetrahydrofurans and in recent years attention has turned to the stereochemical outcome o f the reaction and to the use of more complex starting materials. This year has been no exception. F o r example, the pentene-l,3-diols (15) cyclize under
8: Saturated Heterocyclic Ring Synthesis
46 1
R'
i, N B S
*
ii, 1 5 - c r o w n - 5 , NaH,THF
R2
R'&= R2
R3
0-0
CO28U'
EL
+
(13)
RCHO
-
C02Bu'
*R
(14)R = Me, Ph or CI,C
R
m-
OH
OH
-J
462
General and Synthetic Methods
carefully controlled iodoetherication conditions to give predominately the &-isomers (16) (usually better than 5:l) in excellent yield (73-99%),14 and Davies et al. have reported the bromineassisted epoxide ring expansion of epoxy-olefins (Scheme 3 ) . 15 The stereocontrol of the previously reported bromoetherification of 4-alkenols to give trans-tetrahydrofurans (17) can be improved
by using thallium salts as the electrophile,16 and the mixture of lead(1V) acetate and either NaI or ZnBr2 is a useful addition to the armoury of halogenoetherification reagents giving high yields ( > 75%)
. 17
The addition of phenylselenenyl chloride to the dienes (18) leads to the cyclic ethers ( 19) in variable yield, l 8 addition of dimethyl(thiomethy1)sulphonium alkenes also leads to ether formation.
and the
fluoroborate to hydroxy-
For example, the oxa-
bicyclo[3.3.0]octane (21) is formed on treatment of the hydroxyalkene (20), the reaction presumably proceeding through an episulphonium intermediate. The similar ring closure onto an epoxide has been further developed by Nicolaou's group into a potentially general 'zip'-type reaction to give a string of tetrahydrofurans such that treatment of the triepoxide (22) with a base gives the bis-tetrahydrofuran
(23) in >go% yield.20 Ring expansion of epoxides by the addition of the dianion of ethyl acetoacetate under Lewis acid conditions followed by cyclization generates a-methylenetetrahydrofurans (24) in generally good yield," whereas ring expansion of the cyclopropane esters (25) by addition of their corresponding enolates to ketones followed by fluoride treatment gives the lactols (26) which are readily converted into tetrahydrofurans. 22 The vinylsulphones (27) undergo an intramolecular Michael reaction in the presence of a catalytic amount of potassium hydride giving tetrahydrofurans in high yield (>81%),23 and the diols (28) can be cyclized to the corresponding tetrahydro-furans or -pyrans by simply heating at 220
OC
in the presence of 0.3 mole equivalents
of H M P A .24 Reactions which proceed through radical intermediates are gaining in popularity mainly because of the higher degree of con-
*
trol that can now be achieved, and several more examples of tetrahydrofuran synthesis
radicals have been published this year.
The radical produced on reductive removal of nitro-groups can be captured by a remote double or triple bond to give the tetrahydro-
8: Saturated Heterocyclic Ring Synthesis
463
+
Scheme
3
f l O H R
X = OAc, OH OMe, ONO, or NHAc R
M e C N / H,0
*
P h S e d L S e P h
0
General and Synthetic Methods
464
Pr',NE
t,
MeCN, DMTMF
(201
0
0
4
H
Meo2c& ,
'
,
O X 0
O X 0
(22)
(23)
O S i Me3
OSi Me, I,
LDA
R~
C0,Me
C0,Me
(26)
(25)
n R2 \
R' ) \ 7 \ 0 R4
,
o
R3 /
BF3.Et ,O, -78
4
O°C
-
465
8: Saturated Heterocyclic Ring Synthesis
KH
TH F
k2
Rl+---so2+
R2
HMPA v
2 2 0 OC
Bu3SnH
Scheme
4
General and Synthetic Methods
466
f u r a n s (29)7 2 5 a n d t h e r e a c t i o n c a n a l s o b e c a r r i e d o u t i n a n i n t r a m o l e c u l a r s e n s e a s o u t l i n e d i n S c h e m e 4.26 The t r e a t m e n t of a l k y l h a l i d e s w i t h a l l y l t r i a l k y l s t a n n a n e s t o g i v e a l l y l i c compounds h a s been combined w i t h a r a d i c a l c y c l i z a t i o n reaction so that treatment of the vinyl ethers (30) with a l l y l t r i n-butylstannane
gives t h e a l l y l a t e d tetrahydrofurans.27
Although
y i e l d s a r e o n l y m o d e r a t e (25-48%) t h e r e a c t i o n h a s t h e a d v a n t a g e o f being c a r r i e d out i n one pot. Many o f t h e r a d i c a l r e a c t i o n s u s e t r i - n - b u t y l t i n reagent of choice, but t h e tin-derived t o remove.
hydride as t h e
residues are o f t e n d i f f i c u l t
T o r i i e t a l . h a v e s h o w n t h a t c o b a l o x i m e I , g e n e r a t e d by
e l e c t r o c h e m i c a l means, can r e p l a c e t h e t i n h y d r i d e and c o n v e r t s t h e ethers (31) i n t o t h e corresponding tetrahydrofuran derivatives i n 28 without g i v i n g any p u r i f i c a t i o n problems.
g o o d y i e l d (35-877;)
The DDQ o x i d a t i o n o f t h e m e t h o x y s t y r e n e a l c o h o l s ( 3 2 ) g i v e s a mixture of tetrahydrofurans
,
(33) and (34) i n which (33) pre-
oxidation of acetals a t room t e m p e r a t u r e g i v e s o r t h o c a r b o n a t e s , when t h e same r e a c t i o n i s
d o m i n a t e s ,29 a n d
whereas Baeyer-Villager
c a r r i e d o u t a t r e f l u x t h e c y c l i c e t h e r s ( 3 5 ) are formed i n v a r i a b l e y i e l d (6-63%). 3 0 Two r e a c t i o n s f o r m e r l y u s e d w i d e l y i n t h e f o r m a t i o n o f c a r b o c y c l e s h a v e now b e e n s u c c e s s f u l l y e x t e n d e d t o t h e s y n t h e s i s o f heterocyclic systems.
Thus t h e i n t r a m o l e c u l a r c y c l o a d d i t i o n o f t h e
o l e f i n i c alkoxyketenes (36) leads t o cyclobutanone annulated h e t e r o c y c l e s ( 3 7 ) , w h e r e b e t t e r y i e l d s a r e o b t a i n e d by u s i n g t h e ketene g e n e r a t e d from t h e a c i d c h l o r i d e r a t h e r t h a n from t h e k e t e n i m i n i u m i n t e r ~ n e d i a t e . ~ ’A l s o , L i t t l e ’ s 1 , 3 - d i y l c y c l o a d d i t i o n r e a c t i o n h a s b e e n shown t o work w i t h h e t e r o a t o m - c o n t a i n i n g
x-
systems, such as carbonyl groups, t o afford mixtures of regioi s o m e r i c h e t e r o c y c l e s ( S c h e m e 5) . 3 2 T h e trichloromethyl-3-bromoalkanes ( 3 8 ) a l s o a d d t o c a r b o n y l groups i n a formal [3+2]-type
cycloaddition r e a c t i o n under electro-
l y t i c c o n d i t i o n s where t h e intermediate i s thought t o be t h e d i c h l o r o m e t h y l a n i o n ( 3 9 ) .33
Trost has extended t h e scope of h i s
[3+2] c y c l o a d d i t i o n r e a c t i o n t o i n c l u d e t h e s y n t h e s i s o f t e t r a hydrofurans.
He f o u n d t h a t t h e s t a n n y l a c e t a t e ( 4 0 ) r a t h e r t h a n
t h e corresponding s i l y l acetate g i v e s high y i e l d s of t h e t e t r a h y d r o f u r a n s ( 4 1 ) w i t h b o t h e x c e l l e n t d i a s t e r e o - a n d chemos e l e c t i v i t y u n d e r p a l l a d i u m c a t a l y s i s . 34
I n t r a m o l e c u l a r palladiurn-
c a t a l y s e d o x y c a r b o n y l a t i o n o f t h e p e n t e n e d i o l s ( 4 2 ) a t room t e m p e r a t u r e l e a d s t o t h e t e t r a h y d r o f u r a n a n n u l a t e d l a c t o n e s ( 4 3 ) , 35
8: Saturated Heterocyclic Ring Synthesis
467
B u 5n 3
-
L
A1 BN
(30)
Br Co( I )
R2 R3 R4 R5
R2 R3 R4
R5
R’ 0
(33)
(34)
General and Synthetic Methods
468
Scheme
+
5
3 moloI0 Pd(OAcI2
RCHO 15 moloI0 Ph3P
-J3 R
(411
(40) R 2 R3 R 4
R+’
OH
OH
R (43 1
0
0
469
8: Saturated Heterocyclic Ring Synthesis
where t h e carbonyl i n s e r t i o n proceeds w i t h high s t e r e o s e l e c t i v i t y and i n h i g h y i e l d . The i n t r a m o l e c u l a r i n s e r t i o n o f a c a r b e n e g e n e r a t e d from t h e diazo 8-keto-ester
( 4 4 ) g i v e s t h e p r e v i o u s l y unknown t e t r a h y d r o -
f u r a n ( 4 5 ) a l t h o u g h t h e r e a c t i o n h a s b e e n e x t e n s i v e l y u s e d f o r N-H
insertion^,^^
and t h e r i n g e x p a n s i o n o f o x e t a n e s by c a r b e n e i n s e r t i o n t o g i v e t e t r a h y d r o f u r a n s a s t h e main p r o d u c t has been r e p o r t e d by two g r o u p s o f w o r k e r s . 3 7
The g e n e r a t i o n o f o x a c a r b e n e s
b y u - c l e a v a g e of c y c l o b u t a n o n e s a n d s u b s e q u e n t c a p t u r e by a r e m o t e hydroxy-group had p r e v i o u s l y b e e n o n l y o f m e c h a n i s t i c i n t e r e s t , b u t t h e r e a c t i o n h a s now b e e n s h o w n t o h a v e s y n t h e t i c p o t e n t i a l , f u r n i s h i n g t h e b i c y c l i c a c e t a l s ( 4 6 ) i n m o d e r a t e y i e l d ( 4 5 - 7 0 % ) .38 F i n a l l y , when t h e a l l y 1 e n o l e t h e r s ( 4 7 ) a r e t r e a t e d w i t h Pd(OAcI2 i n a c e t o n i t r i l e t h e t e t r a h y d r o f u r a n s ( 4 8 ) a r e t h e exclusive products rather than the alternative Claisen products w h i c h a r e f o r m e d b y s i m p l y h e a t i n g t h e e n o l e t h e r s . 39 Dihydrofurans. T h e i n t r a m o l e c u l a r c y c l i z a t i o n of a p h e n y l s u l p h o n y l v i n y l a n i o n o n t o a n epoxide leads t o t h e d i h y d r o f u r a n s ( 4 9 ) i n average y i e l d (50-72%), where t h e v i n y l sulphone moiety is e a s i l y c o n v e r t e d i n t o o t h e r f u n c t i o n a l g r o u p s . 40 The i n t e r m o l e c u l a r a d d i t i o n o f m a l o n o n i t r i l e t o e p o x i d e s or c h l o r o - a l c o h o l s 41 p r e s e n c e of e t h o x i d e g i v e s t h e d i h y d r o f u r a n s ( 5 0 ) .
in the
H y d r o b o r a t i o n of t h e B - a c e t y l e n i c a l c o h o l s ( 5 1 ) f o l l o w e d b y basic peroxide oxidation leads t o t h e tetrahydrofuranols (52), which are r e a d i l y c o n v e r t e d i n t o t h e d i h y d r o f u r a n s ( 5 3 ) i n y i e l d s
of u p t o 9 5 % , 4 2 w h e r e a s m e r c u r i c a c e t a t e h y d r a t i o n o f t h e a l l e n i c k e t o n e s ( 5 4 ) a f f o r d s h i g h y i e l d s of t h e d i h y d r o f u r a n o n e s ( 5 5 ) p r o v i d i n g a n o t h e r s y n t h e s i s o f b u l l a t e n o n e .43 A l l e n y l - s i l a n e s a r e known t o r e a c t w i t h e l e c t r o n - d e f i c i e n t o l e f i n s t o g i v e c y c l o p e n t e n e s a n d t h i s r e a c t i o n h a s now b e e n e x t e n d e d t o t h e s y n t h e s i s o f t h e dihydrofurans (56) where t h e aldehyde c a r b o n y l i s a c t i n g a s a h e t e r ~ a l l e n o p h i l e . ~T~h e b u l k y s i l y l g r o u p
is e s s e n t i a l f o r t h e s u c c e s s of t h e r e a c t i o n . 1 , 3 - D i c a r b o n y l compounds h a v e f e a t u r e d i n s e v e r a l a p p r o a c h e s t o d i h y d r o f u r a n s u n d e r a v a r i e t y of r e a c t i o n c o n d i t i o n s . palladium-catalysed
The
reaction of propargyl carbonates with ethyl
a c e t o a c e t a t e g e n e r a t e s 4-methylene-4,5-dihydrofurans ( 5 7 ) i n h i g h y i e l d (79-94%) i n n e u t r a l media b u t t h e u s e o f B - d i k e t o n e s l e a d s t o f u r a n s . 45 E t h y l a c e t o a c e t a t e a d d s t o CL - c h l o r o v i n y l - s u l p h o n e s ( 5 8 under b a s i c c o n d i t i o n s to a f f o r d t h e dihydrofurans (59) and t h e
General and Synthetic Methods
470
hv
Me0,C *OH
Me02C
R’
R2 R’
SO2Ph
S0,Ph
(49)
OH
R3
R3
8: Saturated Heterocyclic Ring Synthesis
47 1
kcaR2 R’
(54)
R1
+
-
R3CH0
v
R’
R3
SiMeZBut R2
(56)
R2 OC02Me +
u
C0,Me
0
2
M
e
[Pd2(dba)33 CHC13
PhSO;!
Ar
0
&x
C02Et
PhSO,
(59)
(58)
0
AR2-
R3 *CH(COMeI2
R’
[ Mn ( a ~ a c ) ~ ]
(60)
R2 (61)
R2 BugSnH w
( 6 2 ) X = N o r COMe
General and Synthetic Methods
472 r e a c t i o n is thought t o proceed
i n i t i a l Michael addition
f o l l o w e d by i n t r a m o l e c u l a r 2 - a l k y l a t i o n . 4 6
The d i k e t o r a d i c a l ( 6 0 )
is claimed t o be t h e r e a c t i v e s p e c i e s i n t h e s y n t h e s i s o f t h e d i h y d r o f u r a n s ( 6 1 ) f r o m o l e f i n s by h e a t i n g w i t h t h e m a n g a n e s e complex of a c e t o a c e t o n e i n a c e t i c a c i d a t
re flu^.^^
L i t t l e a t t e n t i o n h a s b e e n p a i d t o t h e c a p t u r e of a r y l r a d i c a l s b u t an example o f d i h y d r o b e n z o f u r a n s y n t h e s i s p u b l i s h e d t h i s y e a r uses just this reaction.
Thus t h e a r y l h a l i d e s ( 6 2 ) c y c l i z e i n t h e
presence of t i n hydride t o g i v e dihydrobenzo- and dihydro-pyrido48 f u r a r i s i n good y i e l d s (52-88%). The i n t e r m o l e c u l a r c y c l o a d d i t i o n of o r t h o q u i n o n e d i a z i d e s t o vinyl e t h e r s t o give t h e dihydrobenzofurans (63) proceeds i n moderate y i e l d
(46-55%)
,"
whilst t h e dihydrobenzofurancyclo-
b u t a n o n e s a r e g e n e r a t e d i n h i g h y i e l d by t h e i n t r a m o l e c u l a r k e t e n e / o l e f i n [ 2 + 2 ] c y c l o a d d i t i o n o f t h e e t h e r s ( 6 4 ) .50 inverse electron-demanding
Diels-Alder
The
r e a c t i o n of t e t r a z i n e s h a s
a l s o been a p p l i e d i n an i n t r a m o l e c u l a r s e n s e t o g i v e t h e d i h y d r o p y r i d a z i n o f u r a n s (65) i n v a r i a b l e y i e l d . 5 1 Six-membered
Rings.-
t h e hydroxy-silanes
Tetrahydropyrans.
O x i d a t i v e c y c l i z a t i o n of
( 6 6 ) c a n b e a c c o m p l i s h e d by t r e a t m e n t w i t h
i o d o s y l b e n z e n e and a L e w i s a c i d a f f o r d i n g t h e t e t r a h y d r o p y r a n s
(67)
i n m o d e r a t e y i e l d ( 3 8 - 6 8 % ) . 52 The a c e t a l s ( 6 8 ) a r e r e a d i l y c o n v e r t e d i n t o t h e t e t r a h y d r o p y r a n s ( 6 9 ) on r e a c t i o n w i t h TiC14.53
T h e r e a c t i o n p r o c e e d s by l o s s o f
a l k o x i d e , g e n e r a t i n g a n oxonium s p e c i e s , which s u b s e q u e n t l y c y c l i z e s g i v i n g almost e x c l u s i v e l y e q u a t o r i a l s u b s t i t u t i o n where possible. The p o l y e t h e r n a t u r a l p r o d u c t s have p r o v i d e d a n e x c e l l e n t t e s t i n g g r o u n d for o x y g e n h e t e r o c y c l i c s y n t h e s i s , a n d h a v e a l s o i n s p i r e d many new m e t h o d s .
N i c o l a o u ' s g r o u p h a s shown t h a t i n
c o n t r a s t t o t h e u s u a l mode o f c y c l i z a t i o n o n t o a n e p o x i d e , t h e r e a c t i o n c a n b e made t o g o e n d o , g i v i n g t e t r a h y d r o p y r a n s Scheme 6 ) .54
(see
T h i s i s b r o u g h t a b o u t by s t a b i l i z i n g t h e d e v e l o p i n g
p o s i t i v e c h a r g e a t t h e d e s i r e d c e n t r e and h a s been a p p l i e d t o t h e s y n t h e s i s o f t h e ABC r i n g s y s t e m o f b r e v e t o x i n B .
Kozikowski and
Ghash h a v e d e v e l o p e d a s t e r e o s e l e c t i v e p y r a n o a n n u l a t i o n method s p e c i f i c a l l y designed f o r p o l y e t h e r s y n t h e s i s which is o u t l i n e d i n Scheme 7.55 Dihydropyrans.
The h y d r o x y a l k e n e s ( 7 1 ) f o r m e d by a d d i t i o n o f t h e
8: Saturated Heterocyclic Ring Synthesis
473
R’
d-”‘ oY
R~
(cocI)z ____)
Et3N
COzH
(64)
SMe
A
PhIO, _____t
B F3. E t *O ,
OH
dioxane
R
(66)
(67)
R
R
(68)
(69)
General and Synthetic Methods
474
R
Br
H
Br
Scheme
Me02C,
*m
HO'
H 0
6
n
(yJ*-
WSPh m"sp Scheme
7
JHF
475
8: Saturated Heterocyclic Ring Synthesis ( 7 0 ) t o e p o x i d e s c y c l i z e t o t h e d i h y d r o p y r a n s ( 7 2 ) on
anion of
treatment with potassium t-butoxide.
The r e a c t i o n p r o c e e d s by
i n i t i a l i n t r a m o l e c u l a r M i c h a e l a d d i t i o n f o l l o w e d bv e l i m i n a t i o n o f s u l p h i n i c a c i d a n d y i e l d s a r e g o o d ( 6 5 - 7 3 % ) . 56
Dihydropyranones
(7'1) a r e s y n t h e s i z e d by t h e r e a c t i o n o f t h e a n i o n of r e a c t i o n i s t h o u g h t t o go
via
1,3-dicarbonyl
( 7 3 1 , 57 a n d h e r e t h e
c o m p o u n d s w i t h t h e a ,CI - d i h a l o g e n o - k e t o n e s
nucleophilic addition of t h e diketo-
e n o l a t e t o t h e Favorski i n t e r m e d i a t e from
(73).
F u r t h e r s t u d i e s on t h e h e t e r o - D i e l s - A l d e r
r e a c t i o n by
D a n i s h e f s k y ' s g r o u p have f o c u s e d on t h e s t e r e o c h e m i s t r y o f t h e r e a c t i o n and t h e e x a c t mechanism i n v o l v e d .
Thus c y c l i z a t i o n o f
d i e n e s w i t h a l d e h y d e s i n t h e p r e s e n c e o f BF3.Et20 t e n d s t o g i v e cis-dihydropyranones
(76)
(75) i n toluene whereas trans-dihydropyranones
predominate i n CH2C12.18
However, t h e s e c o n d i t i o n s (BF3 i n
C H C1 ) p u s h t h e m e c h a n i s m t o w a r d a s t e p w i s e s i l o x o n i u m a l d o l - t y p e 2 2 cycladdition. T h e u s e o f ZnC12 i n THF, o n t h e o t h e r h a n d , i s
thought t o b i a s t h e hetero-Diels-Alder n a n t l y t r a n s - p r o d u c t s . 59
r e a c t i o n and g i v e s predomi-
a-Alkoxy-aldehydes
a l s o undergo t h e
r e a c t i o n , and are a l s o s u b j e c t t o c h a n g i n g mechanism u n d e r d i f ferent catalysis.
For e x a m p l e , t h e a d d i t i o n o f t h e d i e n e ( 7 7 ) t o
t h e aldehyde (78) goes
9c h e l a t i o n
c o n t r o l and hetero-Diels-Alder
( 7 9 ) u s i n g MgBr2 i n THF, w h e r e a s u s i n g
t o g i v e t h e &-product
BF3.Et20 a s c a t a l y s t d r i v e s t h e r e a c t i o n t o a Mukaiyama-type mechanism and m i x t u r e s o f i s o m e r s are o b t a i n e d . 6 0
The w e a l t h of
k n o w l e d g e t h a t D a n i s h e f s k y ' s team h a s b u i l t u p a r o u n d t h i s r e a c t i o n h a s l e d t o t h e s u c c e s s f u l u s e o f t h e methodology i n t h e s y n t h e s i s o f t h e s u b u n i t s of monensin and tirandamycin. The h e t e r o - D i e l s - A l d e r
reaction of
hydes normally requires high pressures
61
I-methoxybutadiene with alde-
(>I5 k b a r ) , a n d t h e u s e o f
L e w i s a c i d c a t a l y s t s s u c h as ZnC12 a n d B F 3 . E t t i o n of t h e d i e n e . [Eu(fod)
3
1
0 causes polymeriza2 However, by u s i n g t h e m i l d L e w i s a c i d s s u c h a s
p r e s s u r e s o f o n l y 10 k b a r a r e n e c e s s a r y .
A f u l l s t u d y on t h e hetero-Diels-Alder
62
reaction using
U , B -
u n s a t u r a t e d c a r b o n y l compounds as t h e d i e n e c o m p o n e n t h a s b e e n p u b l i s h e d , 6 3 a n d i n a n e x t e n s i o n t o t h e m e t h o d o l o g y t h e same a u t h o r s , S c h m i d t a n d Maier, h a v e shown t h a t a p h e n y l t h i o s u b s t i t u e n t is t o l e r a t e d on t h e d i e n e and t h a t i n c o r p o r a t i o n of a n a s y m m e t r i c a u x i l i a r y l e a d s t o d i a s t e r e o s e l e c t i v e r e a c t i o n s (Scheme 64
8).
Enamine-aldehydes
( 8 0 ) can a l s o s e r v e
i n t h e hetero-Diels-Alder
as t h e diene equivalent
r e a c t i o n w i t h v i n y l e t h e r s and y i e l d s o f
476
General and Synthetic Methods
(73)
(74)
(75)
koTMs + H Q 6 . Et H
TMSO
(77)
(78)
+ Et$
Et$
He' H OB u (79)
Scheme
8
(76)
H0**
H
OBu
477
8: Saturated Heterocyclic Ring Synthesis
t h e d i h y d r o p y r a n s (81) are u s u a l l y good .65 V i n y l e t h e r s w i l l a l s o a d d t o o r t h o q u i n o n e m e t h i d e s ( s e e S c h e m e 9) a n d t h i s r e a c t i o n h a s b e e n s y s t e m a t i c a l l y s t u d i e d by A r d u i n i e t a l . , p r o p o s e s e v e r a l g u i d e l i n e s .66
l e a d i n g them t o
Thus t h e c o n f o r m a t i o n a l e q u i l i b r i u m
i s d e t e r m i n e d by t h e p s e u d o e q u a t o r i a l p r e f e r e n c e o f t h e 4 - a l k y l E c o n f i g u r a t i o n , and
g r o u p , t h e orthoquinone methides react i n t h e
t h e r e a c t i o n is u s u a l l y endo w i t h r e s p e c t t o t h e ethoxy-group. [5.n]Spiroacetals.
The s u r g e o f i n t e r e s t i n t o t h e s y n t h e s i s of
s p i r o a c e t a l s a p p e a r s t o have no end b u t a l t h o u g h t h e r e have been many p u b l i c a t i o n s i n t h e a r e a t h e r e a r e v e r y f e w new a p p r o a c h e s t o t h e r i n g system.
For e x a m p l e B r i n k e r e t a l . h a v e shown t h a t t h e
c y c l o p r o p y l c a r b e n e g e n e r a t e d from MeLi t r e a t m e n t o f ( 8 2 ) a f f o r d s t h e s p i r o a c e t a l ( 8 3 ) w h o s e c y c l o p r o p a n e r i n g i s r e a d i l y c l e a v e d by h y d r o g e n o l y s i s , 67 a n d c h i r a l s y n t h e s i s o f t h e s p i r o a c e t a l s ( 8 5 ) a n d
( 8 6 ) c a n b e a c h i e v e d by i n t r a m o l e c u l a r M i c h a e l r e a c t i o n o f t h e c h i r a l s u l p h o x i d e (84) a n d e i t h e r r e d u c t i v e r e m o v a l o f t h e s u l p h o x i d e g r o u p o r e p i m e r i z a t i o n f o l l o w e d by r e d u c t i o n t o g i v e t h e o t h e r e n a n t i o m e r . 68 The b u l k o f t h e o t h e r p u b l i c a t i o n s a r e r e p o r t s o f t o t a l s y n t h e s e s , s u c h a s t h a t o f m i l b e m y c i n B 3 by K o c i e n s k i ' s g r o u p , 69 and t h e e r y t h r o n o l i d e A d e r i v a t i v e by Deslongchamps 170 o r p a r t i a l s y n t h e s e s s u c h as t h e s y n t h e s i s o f t h e n o r t h e r n h e m i s p h e r e o f t h e m i l b e m y c i n s by L e y ' s g r o u p .7 S i x - m e m b e r e d R i n g s w i t h More t h a n One O x y g e n .
Without doubt t h e
g r e a t e s t a c c o m p l i s h m e n t i n t h i s area h a s been t h e t o t a l s y n t h e s i s o f t h e l o n g s o u g h t a f t e r a n d e v a s i v e TXA2 by t h e r e s e a r c h g r o u p o f T h e m e t h o d e m p l o y e d was t o c o n s t r u c t t h e s e n s i t i v e o x e t a n e r i n g by a n i n t r a m o l e c u l a r M i t s u n o b u r e a c t i o n o n t h e i n t e r m e d i a t e (871, where t h e Br a c t s as a s t a b i l i z i n g g r o u p .
Reductive
r e m o v a l o f t h e B r g r o u p f o l l o w e d by l a c t o n e c l e a v a g e g a v e s y n t h e t i c m a t e r i a l w h i c h i s i n d i s t i n g u i s h a b l e f r o m n a t u r a l TXA2, b u t t h e a u t h o r s add t h a t t h i s is
not
c o n c l u s i v e proof t h a t S a m u e l s s o n ' s
s t r u c t u r e i s TXA2. The method u s e d s h o u l d p r o v e g e n e r a l as model s t u d i e s g a v e a TXA2 a n a l o g u e . 7 3 The s t e r e o c h e m i c a l outcome and s c o p e o f t h e s i n g l e t oxygen a d d i t i o n t o d i e n e s t o g i v e endoperoxides (88) h a s been s t u d i e d and t h e order of r e a c t i v i t y is t r i s u b s t i t u t e d > 2-substituted s t i t u t e d .74
> disub-
478
General and Synthetic Methods
qoH - qo +
\
R'
R
Scheme
MeLi
HZPd
(83)
NoH/THF ____)
9
R R3 *lJo
479
8: Saturated Heterocyclic Ring Synthesis
Seven- and Eight-membered Rings.- A new total synthesis of zoapatanol has been published which uses as the key step an acidcatalysed intramolecular epoxide opening reaction (see Scheme Model studies predicted that S n C l l l would give the best ratio of seven-membered to six-membered ring ether formation. The unusual [(20+2n)+2n]
cycloaddition reaction has been used to
prepare the oxabicyclo[3.2.l]octane (90) where homofuran (89) is acting as the ( 2 ~ + 2 n )component,76 and finally Mann’s group has reported a synthesis of the 2,6-dioxatricyclo[3.3.1 .03’7]nonanes ( 9 1 ) by a Combination of oxoallyl and iodoetherification chemistry. 77
2 Sulwhur-containing Heterocvcles
Sections on the synthesis of sulphur-containing heterocycles have appeared in three review articles published this year. The reviews are on organothiophosphorus compounds ,78 the thionation reactions of Lawesson‘s reagent,79 and the photochemistry of thiocarbonyl compounds. 80 The use of lasers in photochemistry is far from common, but Bertaina et al. have found that pulsing a mixture of s8 and cyclohexene with laser at 266 nm affords cyclohexane episulphide.
81
Whether this hails the start of a general method depends on whether the yield (E. 1%) can be improved and the scope extended; further studies are underway. In variant of the previously olefins to thioamides has amides (92) are converted yield. 8 2
a more familiar vein the intramolecular reported [2+21 photocycloaddition of been published where the alkenyl thiointo the tricycles (93) in 31-82%
Rao and Ramamurthy have studied the intermolecular [ 2+2]
cycloaddition of olefins to thienones (94).
The stereochemistry
and regiochemistry of the products have been determined and then rationalized on the basis of molecular orbital coefficients. 83 The thiol group has not seen regular use as a terminating group in polyene cyclization, but now Saito et a l , have shown that it behaves quite satisfactorily giving tetrahydrothiophene annulated polycycles (Scheme 1 1 ) in good yield and with a high degree of
84
stereocontrol. A new and potentially very useful method for the synthesis of substituted tetrahydrothiophenes by the addition of the thioThe ylide is carbonyl ylide (96) to olefins has been disclosed.85 generated by thermal extrusion of Me SiBr from the bromide ( 9 5 ) ,
3
General and Synthetic Methods
480
OH
TXA2
R5
H oB )ou
1
zoa p at ano I Scheme
x,. -
R’
+
(89)
R’
10
R2
R2
(90)
48 1
8: Saturated Heterocyclic Ring Synthesis
OH
(94)
R
/r'
X = C N or C02Me, R = Ph or Me
R
Scheme
11
General and Synthetic Methods
482
and t h e s u b s e q u e n t c y c l o a d d i t i o n s p r o c e e d i n h i g h y i e l d (>91”/0. T h e McMurray c o u p l i n g o f k e t o n e s h a s p r o v e d t o b e a v e r y u s e f u l m e t h o d o f c a r b o c y c l i c s y n t h e s i s a n d t h i s h a s now b e e n e x t e n d e d t o the synthesis of sulphur heterocycles.
Thus t r e a t m e n t o f t h e
( 9 7 ) w i t h l o w - v a l e n t T i ( f r o m T i C 1 4 a n d Z n ) a t low t e m p e r a t u r e g i v e s t h e 3,4-dihydroxytetrahydrothiophenes ( 9 8 ) i n
diketo-sulphides
good t o e x c e l l e n t y i e l d (50-93%).86
If t h e r e a c t i o n i s c a r r i e d o u t
a t r o o m t e m p e r a t u r e or a b o v e t h e n t h e d i h y d r o x y i n t e r m e d i a t e s cannot be i s o l a t e d and only t h e dihydrothiophenes are i s o l a t e d (Scheme 1 2 ) .87,88
A general synthesis of t h e thiophene-Z(3H)-thione
r i n g system
h a s b e e n d e s c r i b e d w h e r e t h e d i a n i o n s o f e i t h e r a l l e n e s or a l k y n e s
a r e t r e a t e d s u c c e s s i v e l y w i t h CS2, a n e l e c t r o p h i l e , a n d t h e n acid.89
The whole s e q u e n c e i s c a r r i e d o u t i n o n e p o t a n d t h e
y i e l d s of t h e r e q u i r e d p r o d u c t s
(99) a r e b e t w e e n 45 a n d 81%.
The i n t r a m o l e c u l a r a z a - D i e l s - A l d e r
reaction of 2-alkynyl-
t r i a z i n e s a f f o r d s dihydrobenzothiophenes ( 100)
and f u l l d e t a i l s
of t h e g e n e r a t i o n o f e t h y l a n d m e t h y l t h i o x o a c e t a t e s and t h e i r u s e i n t h e hetero-Diels-Alder
r e a c t i o n h a v e a l s o a p p e a r e d .”
Trimethyl-
s i l y l e n o l a t e s react w i t h t h i o n y l c h l o r i d e t o g i v e B-oxosulphinyl c h l o r i d e s ( 1 0 1 ) w h i c h r a p i d l y e l i m i n a t e HC1, g e n e r a t i n g aoxosulphines; these then p a r t i c i p a t e i n hetero-Diels-Alder r e a c t i o n s w i t h d i e n e s t o g i v e dihydrothiophene ?-oxides
(102) i n
v a r i a b l e y i e l d , 9 0 and t h e p a r e n t s u l p h i n e ( 1 0 4 ) c a n be g e n e r a t e d by fluoride treatment of
(103) a n d t h i s a l s o u n d e r g o e s C4+23 c y c l o -
addition reactions.93
S i m i l a r l y t h e sulphenes ( 105) a l s o g i v e
hetero-Diels-Alder
adducts.
The f l u o r i d e - i n d u c e d
B-elimination
of
t h e d i s u l p h i d e s ( 1 0 6 ) is a m i l d method f o r g e n e r a t i o n o f t h i o a l d e h y d e s w h i c h are s u b s e q u e n t l y c a p t u r e d by c y c l o p e n t a d i e n e t o g i v e predominantly endo-products
( 1 0 7 ) .94
The a - c h l o r o s u l p h i d e s
( 108),
when t r e a t e d w i t h S n C 1 4 g e n e r a t e p h e n y l t h i o n i u m c a t i o n s w h i c h u n d e r g o [4+21 c y c l o a d d i t i o n r e a c t i o n s w i t h s t y r e n e t o g i v e d i h y d r o b e n z o t h i o p y r a n s i n v a r i a b l e y i e l d s . 95 with trans-stilbene
The r e a c t i o n a l s o s u c c e e d s
a s t h e 2x c o m p o n e n t a n d h a s b e e n a p p l i e d i n t r a -
molecularly. If t h e n o r m a l c o n d i t i o n s f o r t h e W i t t i g r e a c t i o n a r e u s e d t o
p r e p a r e t h e d i h y d r o t h i o p y r a n s (110) from t h e phosphonium s a l t (109) and a-thioketones, of isomers.
then the reaction e i t h e r fails or gives mixtures
H o w e v e r , by p e r f o r m i n g t h e r e a c t i o n i n a s t e p w i s e
manner t h e r e q u i r e d d i h y d r o t h i o p y r a n s (110) are formed i n approxim a t e l y 50% y i e l d
.96 D e p r o t o n a t i o n o f t h e d i e n e s u l p h o x i d e s
( 11 1 )
8: Saturated Heterocyclic Ring Synthesis
Me 3Si,,
483
-
S iMe,
S Br
(96)
(95)
Ph . .. 0
X=Y=CO,Me,CN,
0
y/
0
X
0
o
r
~
N
~
o
u
y
SiMe3
TiCI4/ Zn _______)
T H F , O°C
(97)
(98)
Scheme
12
R’ R’
R’ R2+= Li
- Li
i, C S 2
T-Fiii, H ~ O +
R2-j-J S ’ S
E
General and Synthetic Methods
484
R?0siMe3
+
-
SOCI,
R2
F-
Me3SiCH2SOCI (103)
(Me3SiCHS02 I2O
I
CH,=S=O
(104)
Cs F
>-%
vR SCO),
RCH=S=O
R
(105)
Ph Ph A SnC14
-
oclx,
8: Saturated Heterocyclic Ring Synthesis
485
0
’ “3
OE t
--
4
+PPh3
I i, Bu”Li
ii, E+
A3
01j$ R’
(112)
(1111
RF2)n
R2
OH
(114)
(1131
$3 ‘2’5
OH
Scheme 13
Toduene
R2
486
General and Synthetic Methods
affords the dihydrothiopyrans (112) only when R is aryl or ally1.97 The yields are moderate (32-68%) and the reaction is thought to proceed
via
a concerted disrotatory electrocyclization.
In an attempt to dehydrate the B-hydroxy-dithianes (113) using P205 only the ring-expanded products (114) were isolated, and this has been developed into a general ring expansion method which also works for the a-hydroxy-dithiane (115) (Scheme 13) .98
3 Heterocycles Containing More than One Heteroatom Nitrogen- and Oxygen-containing Rings.- Five-membered Rings. Nitrone cycloaddition chemistry continues to dominate the literature on the synthesis of isoxazolidines.
More attention is now
being paid to the stereochemical outcome of the reaction o f both the intra- and inter-molecular varieties of the reaction.
For example
the preference for fused o r bridged products from the intramolecular reaction of nitrones (116) depends on the substitution pattern of the olefin moiety where bridged products are preferred, H , when the fused products predominate.99 1-Benzyl-Cunless R alkyl- and ~ - b & n z y l - C - - B - a l k o x y a l k y l - n i t r o n e s
add to methyl croto-
nate to give predominantly 3,5-trans-products ( 1 1 7 1 , whereas
E-
benzyl-C-a-alkoxyalkyl-nitrones add to give the 3,5-%-products ( 1 18) as the major isomer. l o o The use of nitrones in cycloaddition reactions has been reviewed,”’ and two new methods for the generation of nitrones have been developed by LeBel’s group. The first involves 1alkylation of c-trimethylsilyl-oximes,I o 2 and the second uses an interesting Grob-type fragmentation of the decahydroquinoline (119) (Scheme 14). I o 3 The commonly used reactive intermediates for isoxazoline synthesis are nitrile oxides, and two new ways of generating these have appeared this year. Thus alkyl carbonocyanidate N-oxides are generated by thermolysis of nitromalonates,Io4 and the furoxan (120) reversibly generates the nitrile oxide (121) at high temperature; the latter sequence allows stoicheiometric amounts of the olefin and nitrile oxide to be used in the reaction f o r the first time, giving high yields of the isoxazolines ( 122). O5 Most methods for the formation of oxazolines from b-hydroxyamines and -acids call for vigorous conditions often leading to polymeric side-products. However Roush and Pate1 have found that treatment of the easily obtained hydroxy-amides (123) with
8: Saturated Heterocyclic Ring Synthesis
P h O k f i R
I
0-
4-
*cO,Me
487
-
0-N U
-
+ *
I 1
I
C02Me
C0,Me (117)
Scheme
(120)
R
4" GR (11 8)
14
(122 1
General and Synthetic Methods
488
DEADIPh P a f f o r d s t h e o x a z o l i n e s u n d e r v e r y m i l d c o n d i t i o n s , ' I o 6 3 M e y e r s a n d H o y e r h a v e s h o w n t h a t t h e Ph P / C C 1 4 / E t N m e t h o d f o r
and
3
3
o x a z o l i n e s y n t h e s i s from a c i d s and a m i n o - a l c o h o l s p r o c e e d s w i t h i n v e r s i o n a t t h e c a r b i n o l c e n t r e , c o n t r a r y t o w h a t was p r e v i o u s l y thought.lo7
O x a z o l i n e s c a n a l s o b e s y n t h e s i z e d b y t h e ZnC12-
catalysed cycloaddition of a,B-unsaturated t o i s o c y a n i d e s (Scheme 1 5 ) . Io8
and aromatic a l d e h y d e s
Y i e l d s are g e n e r a l l y good and a
CuClIEt N c a t a l y s t c a n also be u s e d ; i n f a c t t h i s is t h e c a t a l y s t
3
o f c h o i c e for t h e c y c l o a d d i t i o n r e a c t i o n w i t h a l i p h a t i c a l d e h y d e s .
Dimethyl N--ethoxycarbonylmethyliminodithiocarbonate
adds t o benz-
a l d e h y d e s t o g i v e o x a z o l i n e s ( 1 2 4 ) i n 52-96% y i e l d i n t h e p r e s e n c e o f p o t a s s i u m t - b u t o x i d e , log and t h e a u t h o r s claim t h a t t h e r e a g e n t s h o u l d be o f g e n e r a l a p p l i c a b i l i t y f o r t h e a d d i t i o n o f a C-N=C
unit
t o unsaturated systems. The c y c l o a d d i t i o n r e a c t i o n between e p o x i d e s and i s o c y a n a t e s h a s b e e n c a r r i e d o u t u n d e r n u m e r o u s c o n d i t i o n s , most o f w h i c h r e q u i r e e i t h e r e l e v a t e d t e m p e r a t u r e s or p o l a r s o l v e n t s , b u t t h e u s e o f L e w i s b a s e c a t a l y s t m i x t u r e s , s u c h as Bu2Sn12/Ph P , a l l o w s t h e
3
r e a c t i o n t o be conducted under mild c o n d i t i o n s and even works w i t h carbodi-imides t o g i v e imino-oxazolidines
(Scheme 1 6 ) . ' l o
The
d i a n i o n ( 1 2 5 ) h a s been f o u n d t o be a u s e f u l i n t e r m e d i a t e f o r t h e f o r m a t i o n o f a r a n g e o f h e t e r o c y c l e s s u c h as o x a z o l i n e t h i o n e s , o x a z o l i n o n e s , o x a z o c i n e s , and o x a z o n i n e s ( s e e Scheme 1 7 ) . S i x - and Seven-membered R i n g s .
F u l l d e t a i l s of t h e r e g i o s e l e c t i -
v i t y of t h e intramolecular hetero-Diels-Alder
reaction of acyl
n i t r o s o compounds and n i t r o s o f o r m a t e s h a v e been p u b l i s h e d
,
and
n i t r o s o i n t e r m e d i a t e s a l s o f e a t u r e i n two p u b l i c a t i o n s f r o m K i r b y ' s g r o u p on [ 4 + 2 1 c y c l o a d d i t i o n r e a c t i o n s t o g i v e o x a z i n e d e r i v a t i v e s . T h u s o x i d a t i o n o f h y d r o x a m i c a c i d s i n t h e p r e s e n c e of d i e n e s g i v e s t h e oxazines (126),
and f u l l d e t a i l s of t h e o x i d a t i o n of
K-
h y d r o x y - u r e a s i n t h e p r e s e n c e of d i e n e s t o g i v e o x a z i n e s ( 1 2 7 ) h a v e T h e f i r s t e x a m p l e of a n a z a d i e n e [ 4 + 2 ] c y c l o a d d i t i o n r e a c t i o n t o a l d e h y d e s a s t h e 2 r c o m p o n e n t h a s b e e n r e p o r t e d . 115
appeared. 'I4
T h e p r o d u c t s a r e 5,6-dihydro-2~-1,3-oxazines( 1 2 8 ) from p r e d o m i n a n t l y endo r e a c t i o n and y i e l d s are h i g h (70-95%). The r e a c t i o n o f e p o x i d e s w i t h i s o c y a n a t e s is well known, b u t
l e s s w e l l known i s t h e r e a c t i o n o f o x e t a n e s w i t h i s o c y a n a t e s . H o w e v e r , t h e m o d i f i e d r e a c t i o n c o n d i t i o n s r e p o r t e d for e p o x i d e a d d i t i o n have been found t o promote t h e oxetane v a r i a n t t o a f f o r d t h e oxazin-2-ones (129) i n good y i e l d (58-87%). ' I 6 The s y n t h e s i s
8: Saturated Heterocyclic Ring Synthesis
-
0
Ph3P/ DEAD
R’+;KR2
“il
OH
O f N R2
(123)
Erk, C02Et
ZnCl2
+
RY-fco2E N ’0-
or CuCIIEt3N
RCHO
15
Scheme
H
--+
Et02C
EtozcVNKSMe S
v
/
i , K+
N q s M e
BU~O-
ii, ArCHO
COZEt (124)
R’
R’
R’
Lewis b a s e
Lewis base R ~= N c = NR*
0 0 Scheme
16
SMe
General and Synthetic Methods
490
-
Ph
R
NR
i, R N H 2
ii,NalEt20
cs2
Ph
Scheme
Ph
17
0 (126)
0
II
0 (127 1 R’
R2
+
- 3 0
R3CH0
R
v R~
1 R2
(128)
+
Bu25n12
R*--N=C=O
N\
Ph3P0
0 (129)
R2
8: Saturated Heterocyclic Ring Synthesis
49 1
of the previously unknown 2-amino-6K-I13-oxazin-6-one ring system has been reported by the base-mediated addition of 0-cyano-esters to N-cyano-imines and subsequent ring closure (see Scheme 1 8 ) , 47 and the 0-allenic oximes ( 1 3 0 ) cyclize to give 4,7-dihydro-1,2oxazepines
via
a silver-mediated process. 118
Nitrogen- and Sulphur-containing Rings.- In contrast to 8-lactams1 0-sultams have been little studied and most approaches have used
[2+21 cycloaddition as the obvious strategy. However, two research groups have independently developed similar approaches which get away from the cycloaddition methodology, and which involve intramolecular sulphonylation as the key ring-forming step. Champseix et al. have shown that both 0-amino-thiols and 0-aminosulphonic acids can be converted to the 0-ammoniumsulphonyl chlorides (131) which cyclize in the presence o f base to the 0 sultams (1321, and that amines add to vinyl sulphonyl fluoride also to give B-sultams.ll9
On the other hand Meyle et al. have found
that amines add to the vinylsulphonate (133), and the resultant product can be cyclized by conversion into the sulphonyl chloride and subsequent ring closure. Thiazolidine-2-thiones can be prepared with complete control over stereochemistry from the olefins (134).
Addition of iodoiso-
cyanate to the olefins in MeOH generates the known 8-iodocarbamates (135) which on treatment with potassium ethylxanthate followed by base give the thiazolidine (136).
The opposite stereoisomer (138)
is formed by addition of the xanthate to the aziridine (137) formed from base treatment of (135). ’I2’
A new method for the formation of the dihydro-l13-thiazines (140) from the thioureas (139) using BF3.Et20 in refluxing chloroform has been reported,122 and a new approach to the synthesis o f the dihydro-1,4-thiazines (143) has also been disclosed. This entails the reaction o f a - a l k y l t h i o - 0 - d i c a r b o n y l compounds (141) with 0-amino-halides as a one step procedure or the reaction of (141) with the more readily available 6-amino-alcohols (142) and subsequent ring closure by mesylation then displacement. 23 The fact that attempted 2-alkylation of dihydrobenzothiazoles (144) leads to the 2-alkylated amines has been used to advantage in the synthesis of dihydrobenzothiazines.
Thus alkylation of (144)
with an a-halogeno-ester, -ketone, or -nitrile affords the dihydrobenzothiazines (145) initial 2-alkylation followed by 124 cyclization onto the imine in generally g o o d yield (41-93%).
General and Synthetic Methods
492
,YNCN X
+
-
N ~ O R ~
(,OZR’ CN
R’OH
HCIIEt20 -R’CI
0
Scheme
18
R’ Ag’, CHC13
I,
RNH2
Ph ___)
RNh 0 , C l
RNN
8: Saturated Heterocyclic Ring Synthesis
493
n
0 R' R
R3
')=I(
Me
INCO ___)
MeOH
R4
1
(134)
"
EtO%'
(135)
S
R 2 R4
"G-R3
KS
OEt
sKNH S (138)
(136)
(137)
BF3.Et20
+ R'
N R'
R3
(140)
General and Synthetic Methods
494
The benzothiadiazine oxides (148) are formed by an unusual [4+21 cycloaddition reaction between the sulphinyl anilines (146) and the SchiPf bases (147) where the sulphinyl aniline is serving as the diene unit.125
The reaction fails for N-alkyl Schiff bases.
Oxygen- and Sulphur-, and Nitrogen-, Oxygen-, and Sulphurcontaining Rings. Chiral Il3-oxathianes have been shown to be 'usefiil reagents for the synthesis of optically pure hydroxyaldehydes, and DeLucchi et al. have developed a new approach to chiral oxathianes using a photochemically induced ring closure of 126 the vinyl sulphides (149) and (150) (Scheme 19). Cyclohexane monothioacetals rearrange in the presence of CuBr2 in diglyme to give the Zl3-dihydrobenzoxathiines (151) in moderate yield (35-68% 1 . No mechanistic rationale is offered. Nitrosoalkenes act as heterodienes in cycloaddition reactions with thiocarbonyl compounds to afford the first examples of the 4KI l ~ , 2 - o x a t h i a z i nring e system (152) in high yields (60-99%) and the low-temperature cycloaddition o f dioxadithiazine tetroxides to olefins gives mixtures of 8-sultams (153) and the 1,4,5-oxathiazin4,4-dioxides (154) depending on the substitution pattern. 129 4 Nitronen-containinn Heterocvcles Three- and Four-membered Rings.-
A convenient synthesis of sub-
stituted aziridines (157) has been described which utilizes a Darzens-type reaction between diarylimines (155) and isopropyl dichloroacetate (156). I3O The reaction is limited to aromatic imines ( R ' and ' R
= aryl) but is capable of easy scale-up and is
stereospecific, although the stereochemistry of the aziridines (157) has yet to be determined.
The first example of a spiroFormation of the
aziridine of type (160) has been reported.13'
iodoazide (159) from the alkene (1581, followed by immediate reduction,gave the spiro-aziridine (160) as an unstable oil which was characterized as the N-methoxycarbonyl derivative (161). 2-Cyano-3,3-dimethylazetidines (164) have been prepared by a novel procedure which involves nucleophilic addition of cyanide to B-chloroimines (162) followed by intramolecular alkylation of the anion (163) to give products in excellent yields. 132 Five-membered Rings.- The trend of previous years has continued in the 1985 literature with the synthesis of five-membered rings
8: Saturated Heterocyclic Ring Synthesis
X = Br or CI Y = C O P h , C0,Et
N=S=O
495
or CN
+
R3 k N R 5 R4 (147 1
(146)
L&o"
2 z
h'J.
SH
&
OH
3
S
(149)
(150)
X
X = PhSO,,
-
H
C I 0-S O 2 . or M e 0 2 C
S c h e m e 19
(X
General and Synthetic Methods
496
R'
"x;"'
CuBr2, D
R3 @ $R
d i g l y m e , llO°C
R3
R4
R4
(151)
x%
Br
-
NOH
(152)
R R'
R2
R3
R4
R~C= H NR'
-k
.
CHC12C02Pr'
' 0
Y
R
-
Ct R'-CH-C N
(156)
(155)
I
Pr'OK/Pr'OH
I
R2
(157)
& (158)
-
I C I , NaN3
LiAIH4
______)
MeCN,-40°C
\
(1 59)
& \
(160) R = H (161) R = C0,Me
8: Saturated Heterocyclic Ring Synthesis
497
containing one nitrogen now constituting by far the most popular area for study in nitrogen heterocyclic synthesis. Two reviews have appeared. Giese has included several examples of the formation of oxygen and nitrogen heterocycles in his review of synthetic applications of radical C-C bond formation via organotin and organomercury intermediates’” and Speckamp and Hiemstra have produced a comprehensive review of the synthesis of nitrogen heterocycles by intramolecular cyclization of 1-acyliminium intermediates. 34 The intense interest in the formation of five-membered nitrogen heterocycles by a 1 , 3-dipolar cycloaddition of ah azomethine ylide, or related species, and an alkene or alkyne has been maintained this year. The majority of synthetic effort continues to be
’
directed towards the mild generation of non-stabilized azomethine ylides, in particular by desilylation procedures. The groups of Vede js, 35 Achiwa, 36 Livinghouse , 37 and Padwa’ 38 have all published full accounts of their earlier work in this area and the latter group has also reported the first examples of diastereoselective azomethine ylide cycloadditions. 39 In this preliminary study the best diastereoselectivity obtained was in the cycloaddition between the azomethine ylides formed from precursor Ecyanomethyl-N-trimethylsilylmethylamines (165) and (1661, and the electron-deficient alkene (167). Pyrrolidines (168) and (169) are produced in good yields as a 4:l mixture of diastereomers and undoubtedly this ratio will be improved when a larger range of substituents and dipolarophiles is investigated.
x-
Two reports from Achiwa and co-workers illustrate well the ease with which non-stabilized azomethine ylides can now be generated and trapped to give pyrrolidines or 2,5-dihydropyrroles. 5-BenzylN-(methoxymethyl)trimethylsilylmethylamine (170) reacts in the presence of a catalytic amount of trifluoroacetic acid and the appropriate dipolarophile at room temperature to give generally excellent yields of products (172) or (173)140 and the 3- or 3 , 4 substituted 2-acylpyrrolidines (175) are produced, also in high yields, by the reaction sequence shown in Scheme 20. The advantages of this method are that the triazine (174) is stable to long storage and a range of acyl halides can be utilized in the reaction, although yields are best with acyl fluorides. This type o f cycloaddition methodology also lends itself very conveniently to the synthesis of 1 - and 2-pyrrolines simply by incorporation of a potential leaving group in the azomethine ylide precursor. Thus,
General and Synthetic Methods
498
(165) R = H
(167)
(166) R = OMe
(168) R = H, 30% (169) R = OMe,20%
X
-1 CF3C02H(cat.)
Me ,SiCH2N- CHzOMe
I
CH,Ph
CH2CI2, r .t
I CH2Ph
CC H ,;H 2i,Z
.,
(172)
XCH=CHY .____._)
C!.H,Ph]
or
xc=
CY
X
Y
3h
(170)
(171)
1 CH,Ph
X = COZMe (173) H,Ph or COZMe
Y =
I
COPh
SiMe3
(175) R1= C02Me or CN
(174)
R2- R4= H, C0,Me br Ph Scheme
20
8: Saturated Heterocyclic Ring Synthesis
499
pyrrolines (178) can be prepared conveniently and in good yields by the reaction of the thioimidate (176) with alkenes (177).142 Other 2-substituted pyrrolines are also potentially available this method starting from the appropriate substituted thioimidate. In an alternative procedure cycloaddition of the N-protonated azomethine ylide tautomer of benzylideneaminoacetonitrile (179) adds to substituted alkenes to give, after base- or thermally-induced 1 ,2-elimination , 1 - or 2-pyrrolines ; for example, ( 182) and (183) are produced in moderate yield from precursors (180) and
''
(181). Full details have appeared of the generation of the nonstabilized ylide (184) by treatment of trimethylamine N-oxide with L D A , and subsequent trapping with alkenes to give pyrrolidines (185).144 The great advantage of this ylide compared with those such as (171) that are generated by desilylation procedures is that (184) is sufficiently reactive to undergo cycloaddition with unactivated alkenes. Extension of this methodology to the cyclic N-oxides (186) and (187) provides a novel procedure for constructing the pyrrolizidine and indolizidine systems (188) and (189) in a stereospecific or highly stereoselective manner. 145,146 Thus (192) is formed stereospecifically and in high yield by reaction of (190) with cyclopentene (191). Product yields are lower for the pyrrolidine N-oxide (186) compared with the piperidine N-oxide (187) and in trapping reactions with monosubstituted alkenes regioselectivity is generally low but, nevertheless, this method of generating cyclic non-stabilized ylides does allow ready access to quite complex bi- and tri-cyclic nitrogen systems in synthetically useful yields. The related azabicyclic enaminones (195) have been prepared by electrocyclization of the conjugated azomethine ylide (194), formed by FVP of the Meldrum's acid derivatives (193).147 Grigg and co-workers have published full details of their studies on the synthesis of substituted pyrrolidines and dihydropyrroles by intramolecular cycloaddition of imines of amino-acid esters with alkenes or alkynes. 14' In a similar type of reaction, intermolecular trapping of ylides (197) with electron-deficient alkenes has been shown to provide a general route to pyrrolidines of type (198).149 The ylide (197) is generated in situ by reaction of benzaldehyde with the appropriate amino-acid ester (196). Cycloaddition generally occurs with only low stereoselectvity but this is compensated by the high yields obtainable in a one-pot procedure and the potential versatility of the reaction.
General and Synthetic Methods
SMe
+
H20, HMPA
XCH=CHY
( c i s or truns 1
(176)
Ph
H
H
n
PhCN=NCH,CN
(179)
X
(178) X = COMe or C02Me Y = H , M e or Ph
(1 77)
andlor
Me Me
Me
(180)
(181 1
$; 0’
I+ Me-N-
LDA
Me
I
‘0
Me
Me
(1 8 2 )
(183)
- [-;I.]
Me
7
0’
‘0
N,.
R
w
I
R
R
0-
(185) R = a l k y l
(184)
an
LDA
R
R
____)
T HF, O°C
Me’
‘0-
(186) n = 1 (187) n = 2
R = H or Ph or RR=(CH2), (188) n = 1 (109)n= 2
8: Saturated Heterocyclic Ring Synthesis
50 1
i, L D A
ii.
0 (191)
-1-
92"lo
L.j - %
n
Me
(192)
0
0
(194)
(195)
PhCHO
HN
I
- CHC0,R3 I
R'
R2
(196)
A
\CN 02Me
-+N/\COzMe
R*CH=CHR;
L
I
,
R' (199) R = a
O
M
e or PhCH,
vyo I
CH2Ph (202)
COZMe
k'
(200)
(201)
FVP
&o
I
H O CH,Ph
(203 1
502
General and Synthetic Methods
Aziridines containing two stabilizing substituents are known to undergo thermal ring opening and subsequent trapping with reactive dipolarophiles to give five-membered nitrogen heterocycles. De Shong and co-workers have now shown that this reaction is synthetically viable with only one stabilizing substituent. I5O Aziridines (199) undergo a thermally induced ring opening to azomethine ylides (200) which can be trapped intermolecularly by a range of alkenes to give pyrrolidines (201). Products are formed generally with high regio- and stereo-selectivity but, as expected, yields are
dependent upon the electronic character of the dipolarophile: alkenes substituted with electron-withdrawing or -donating groups react in good yields but unactivated aikenes do not form cycloadducts under intermolecular conditions.
In the intramolecular
version of the reaction, however, cycloadducts can be obtained under FVP conditions even with unactivated alkenes to form bicyclic systems in moderate to good yields. For example, the adduct (203) is formed in good yield, as a single stereoisomer, from the precursor aziridine (202). A similar study of the intramolecular trapping of azomeLhine ylides generated by thermal ring opening of This group has aziridines has been reported by Weckert et a1.I5' shown that the hydroindole system (205) can be generated efficiently in a thermally induced ring opening and cycloaddition process
from 2-aikenoylaziridines (204). The possibility that fused pyrrolines (207) may be generally available by a route involving intramolecular cycloaddition and subsequent ring expansion of dienic azides (206) has been explored by two groups, with essentially the same result (Scheme 21). 152,153
via radical or 'b' in the intermediate vinylaziridine (208) but yields are moderate at best and the major product is the monocyclic pyrroline (209), formed by a 1,5-homodienyl rearrangement. The route therefore could provide a useful access to the pyrrolizidine framework if conditions could be identified which would allow more controlled and efficient breakdown of (208). The synthesis of substitute pyrrolines by ring expansion of vinyl aziridine derivatives has also been accomplished in a palladium-catalysed reaction. N-Tosyl-2-vinyl five- and sixmembered nitrogen heterocycles (213) are obtained in generally high yields under mild conditions from precursor dienyl nitrogen heterocycles (212) in the presence of a catalytic amount of The complete diene unit is required for the [Pd(PPh3I4l. 15' Tetrahydropyrrolizines (210) and (211) can be formed scission of either bond
8: Saturated Heterocyclic Ring Synthesis
503
-
R2 3R+R
#’
N
Rm
Ph
H
I
Me
(205)
(204)
&-[&I-&
I H O Me
C02Et
C0,Et
C02Et
(209)
(208)
C02E t ( 211 1
(210) Scheme
21
R’
y-;N(Tos
d
R’
34_ [Pd(PPh 1 1 DMSO, 50y
N
- TOS
R2
(212) n = 0 or 1
(213)
504
General and Synthetic Methods
reaction t o proceed: vinyl-substituted heterocycles do not g i v e ring-expanded products. a-Methylene-pyrrolines (216) have been produced i n a d i f f e r e n t kind o f palladium-catalysed
r i n g expansion
p r o c e s s , by a [ 3 + 2 1 c y c l o a d d i t i o n of m e t h y l e n e c y c l c p r o p a n e s ( 2 1 4 ) w i t h k e t e n i m i n e (215).
Y i e l d s are e x c e l l e n t f o r t h e two
examples reported. Rapoport and co-workers
have reported a g e n e r a l s y n t h e s i s of
n i t r o g e n , o x y g e n , and s u l p h u r h e t e r o c y c l e s ( 2 1 8 ) by rhodiumc a t a l y s e d i n t r a m o l e c u l a r N-H, diazo-!3 - k e t o - e s t e r
0-H,
or S-H i n s e r t i o n r e a c t i o n s . o f a -
p r e c u r s o r s ( 2 1 7 ) .36
T h i s r e a c t i o n i s well
d o c u m e n t e d as a n e f f i c i e n t r o u t e t o B-lactams b u t t h i s g r o u p h a s now s h o w n t h a t t h e r e a c t i o n w o r k s w e l l f o r t h e s y n t h e s i s o f f i v e and six-membered
n i t r o g e n h e t e r o c y c l e s (Scheme 2 2 ) .
f a i l s f o r seven-membered n i t r o g e n h e t e r o c y c l e s :
The r e a c t i o n
i n t h i s c a s e C-H
i n s e r t i o n t o g i v e a c y c l o p e n t a n o n e i s t h e p r e f e r r e d r e a c t i o n mode. I n common w i t h t h e g e n e r a l i n c r e a s i n g i n t e r e s t i n s y n t h e t i c applications of free-radical
cyclizations, t h i s year has seen a
h i g h l e v e l o f i n t e r e s t i n t h e s y n t h e s i s o f n i t r o g e n h e t e r o c y c l e s by such processes.
Padwa e t a l . h a v e r e p o r t e d t h e s y n t h e s i s o f a
r a n g e o f N-benzenesulphonyl-pyrrolidines ( 2 2 0 ) a n d - p i p e r i d i n e s
(221) via a c a r b o n r a d i c a l c y c l i z a t i o n , s t a r t i n g f r o m b r o m o a l l y l o r d i a l l y l - s u b s t i t u t e d s u l p h o n a m i d e s ( 2 1 9 ) 1 5 6 1 5 7 For e x a m p l e s where R3=H,
1,5-cyclization occurs e x c l u s i v e l y and i n high y i e l d
(>85%) e v e n when t h e a l k e n e i s d i s u b s t i t u t e d , b u t i n t h e c a s e o f v i n y l r a d i c a l c y c l i z a t i o n s ( 2 2 0 ) or ( 2 2 1 ) may b e o b t a i n e d d e p e n d i n g upon t h e a l k e n e s u b s t i t u t i o n p a t t e r n .
Hart a n d c o - w o r k e r s h a v e
published f u l l d e t a i l s of t h e i r earlier s t u d i e s on t h e a d d i t i o n o f acylamino-radicals
t o alkynes t o g i v e p y r r o l i z i d i n o n e s and
i n d o l i z i d i n o n e s . 158
I n a similar type of c y c l i z a t i o n t h e a l l y l -
s t a n n a n e (223) h a s been used as a r a d i c a l t r a p t o g i v e t h e v i n y l pyrrolizidinone (2241, an intermediate i n t h e synthesis o f (?)i s o r e t r o n e c a n o l ( 2 2 5 ) i n m o d e r a t e (45"/0) y i e l d b u t w i t h h i g h stereoselectivity (11.3:l).
The p y r r o l i z i d i n o n e ( 2 2 4 ) c a n a l s o
b e o b t a i n e d more e f f i c i e n t l y a n d w i t h g r e a t e r s t e r e o s e l e c t i v i t y
( 7 4 : l ) d i r e c t l y from (222)
via
a 'two-electron'
cyclization.
The
key s t e p i n an a l t e r n a t i v e s y n t h e s i s o f i s o r e t r o n e c a n o l (225) i n v o l v e s a photoinduced r a d i c a l c y c l i z a t i o n of t h e a-keto-ester ( 2 2 6 ) t o g i v e t h e b i c y c l i c p r o d u c t ( 2 2 7 ) i n good y i e l d . I6O
The
e n o l form of (226) is n o t photoreducible. The s y n t h e s i s o f y - l a c t o n e s
by o x i d a t i v e a d d i t i o n o f a c e t i c a c i d
t o a l k e n e s i n t h e p r e s e n c e of Mn(OAcI3 h a s b e e n d o c u m e n t e d f o r some
8: Saturated Heterocyclic Ring Synthesis
505
(217)
(218)
I
I
Z
2 n
= 1-3
n = 1, n n
100'/0
= 2 , 100°/o = 3, 67'L \
Scheme
BugSnH
I
k1
jXshl
R3
AIBN
-
22
506
General and Synthetic Methods
0
OH
(222)
SPh
Q-
0
2
(224)
i, MsCl , NEt3
Reagents
(225)
SnBu3
;
ii, ( P h S I 2 , Bu"3P
iii, hv
--
Me hv ButOH
W
(225)
II
0
(227)
(226)
R'
M n ( OAc 1 _____)
R2
CON H
HN
CONH,
AcOH
0
507
8: Saturated Heterocyclic Ring SyMhesis
time b u t a n example o f a n a p p l i c a t i o n o f t h i s p r o c e s s t o t h e s y n t h e s i s o f y - l a c t a m s h a s now a p p e a r e d . 16' a ,r3 - U n s a t u r a t e d y -1actams ( 2 2 9 ) c a n b e p r e p a r e d by r e a c t i o n o f s u b s t i t u t e d a l k e n e s ( 2 2 8 ) w i t h malonamide,
probably
via
a c a r b o n r a d i c a l c y c l i z a t i o n mechanism.
Y i e l d s are v a r i a b l e , however, and t h e corresponding y - l a c t o n e s are u s u a l l y a l s o o b t a i n e d b u t t h e s e d i s a d v a n t a g e s may b e o f f s e t i n s o m e a p p l i c a t i o n s by t h e s i m p l i c i t y o f t h e e x p e r i m e n t a l p r o c e d u r e . Two r o u t e s t o t h e p y r r o l i d i n e s y s t e m i n v o l v i n g t h e g e n e r a t i o n o f nitrogen-centred
r a d i c a l s have appeared. N - M e t h y l - e - 2 , 5 -
d i s u b s t i t u t e d p y r r o l i d i n e s ( 2 3 2 ) may b e o b t a i n e d i n m o d e r a t e y i e l d s by c y c l i z a t i o n o f a m i n y l r a d i c a l s ( 2 3 l ) , g e n e r a t e d by a n o d i c o x i d a t i o n of l i t h i u m alkenylamides (230). 162 i s o m e r s were n o t d e t e c t e d . sulphonyl-pyrrolidines
The c o r r e s p o n d i n g t r a n s -
I n t h e s e c o n d s t u d y , N-methane-
( 2 3 4 ) h a v e b e e n p r e p a r e d s i m p l y b u t i n low
y i e l d s by o x i d a t i v e c y c l i z a t i o n o f N - m e t h a n e s u l p h o n a m i d e s (233)
16'
2-substituted
The N - s u b s t i t u e n t
c a n be e a s i l y removed t o p r o v i d e
pyrrolidines (235).
L i t t l e e t a l . have extended t h e scope of t h e i r intermolecular d i y l t r a p p i n g r e a c t i o n t o i n c l u d e a range o f d i y l o p h i l e s which i n c o r p o r a t e h e t e r o a t ~ m s . ~T h~ u s , t h e b i -
and t r i - c y c l i c
nitrogen
h e t e r o c y c l e s ( 2 3 8 ) a n d ( 2 3 9 ) are p r o d u c e d by t h e r m o l y s i s of t h e d i a z e n e ( 2 3 6 ) i n t h e p r e s e n c e of t h e i m i n e ( 2 3 7 ) . however,
Yields are low,
a n d s o f a r t h i s is t h e o n l y r e a c t i o n e x a m p l e b u t t h e
p r o d u c t s ( 2 3 8 ) and (239) are u n u s u a l s t r u c t u r e s and t h e method c o u l d h a v e some s p e c i a l i z e d u t i l i t y . R e p o r t s on t h r e e u s e f u l t r a n s i t i o n metal c a t a l y s e d c y c l i z a t i o n r o u t e s t o nitrogen heterocycles have appeared t h i s year.
In an
e x t e n s i o n o f t h e i r e a r l i e r work on t h e s y n t h e s i s of t r i c h l o r i n a t e d y-butyrolactams
by c o p p e r - o r r u t h e n i u m - c a t a l y s e d
E-
cyclization of
a l l y l - t r i c h l o r o a c e t a m i d e s , I t o h a n d c o - w o r k e r s h a v e now s h o w n t h a t t h e method p r o v i d e s a n e f f i c i e n t r o u t e t o b i c y c l i c l a c t a m s . 165 Products (240) are g e n e r a l l y obtained i n e x c e l l e n t y i e l d s , and r e d u c t i v e d e c h l o r i n a t i o n t o g i v e (241) i s e a s i l y accomplished.
The
c y c l i z a t i o n i s h i g h l y s t e r e o s e l e c t i v e i n t h a t o n l y *-fused
Full d e t a i l s h a v e a l s o a p p e a r e d from M o r i p r o d u c t s are o b t a i n e d . e t a l . of t h e i r s y n t h e s i s o f f i v e - a n d s i x - m e m b e r e d n i t r o g e n h e t e r o c y c l e s by p a l l a d i u m - c a t a l y s e d a c e t a m i d e s . 166
c y c l i z a t i o n of N - a l l y l - i o d o -
The p y r r o l i d i n e l a c t o n e s ( 2 4 3 ) a r e formed i n good
y i e l d s by p a l l a d i u m - c a t a l y s e d
i n t r a m o l e c u l a r a m i n o c a r b o n y l a t i o n of
3-hydroxypent-4-enylamides ( 2 4 2 ) . 1 6 7 T h e r e a c t i o n i s h i g h l y s t e r e o s e l e c t i v e f o r f o r m a t i o n o f *-isomers a n d i n most c a s e s
General and Synthetic Methods
508
Me
R(CH2)4NHS02Me
Me
Me
(230)
(231 1
Na2S208, CuC12
dNS02Me
HBr P h O H
(233 1
THF,ref lux PhN=CHPh
(237)
Aph
+
@NPh
H
Ph
Ph
(236)
R2 C u C l , MeCN D
or t R U C L ~ ( P P ~ ~ ) ~ I
I
R’ n = 1 o r 2
R’
(240)X = C I
I
Bu
nH
(241) X = H
509
8: Saturated Heterocyclic Ring Synthesis
equivalent results are obtained for both nitrogen substituents. Two other useful procedures for the generation of nitrogen heterocycles attack of a nitrogen nucleophile on an alkene unit have appeared. An ‘iodolactamization’ procedure has been reported which allows efficient conversion of substituted pentenamides into iodolactams. The key step is conversion of the starting carboxamide into the corresponding N,O-bis(trimethylsilyl) derivative prior to treatment with iodine. Thus, iodolactam (245) can be prepared from the 4-pentamide (244) in good yield: direct iodocyclization of (244) gives only the iodolactone (2461, as does the N-monosilylated derivative of (244). A new synthesis of cyclic nitrones (248) and (249) has been reported based upon Ag(1)catalysed cyclization of allenic oximes (247) (249) is too unstable to isolate but both (248) and (249) can be trapped in fair yields with a range of alkenes to afford cycloadducts (250). Danishefsky and his group have described a route to the aziridino-mitosenes which involves as one of the key steps a stereospecific double cyclization of (251) to (252) using gphenylselenophthalimide . 7 0 The formation of nitrogen heterocycles by N-acyliminium ion cyclizations and related processes continues to be a subject of interest to many groups. Several interesting new developments have appeared this year, mainly from Speckamp and co-workers who remain major contributors in this area. In addition to a review of nitrogen heterocycle formation by cyclization of N-acyliminium interm e d i a t e ~ ’full ~ ~ details have appeared of the group‘s earlier work on silicon-directed N-acyliminium cyclizations to produce pyrrolizidine, indolizidine, or quinolizidine ring systems. l 7 This methodology has now been extended to the synthesis of monocyclic systems ( 2 5 4 ) from ethoxyamide precursors (253). 172’173 For cyclization of propargyl-silanes, products are formed generally in good yields as mixtures of amide rotamers. When formic acid is used as solvent cyclization yields can sometimes be low owing to competing hydrolysis but this side reaction can be completely suppressed by using Et2A1C1 as Lewis acid. Allylsilanes also cyclize efficiently, in this case to give products generally as mixtures of cisand trans-isomers, although the pyrrolidine (255) is formed stereo-
’
specifically in 8 1% yield. 1 7 3 Overman and co-workers continue to report new applications of their tandem cationic aza-Cope rearrangement-Mannich cyclization route to nitrogen heterocyclic systems. Perhaps the nicest illus-
General and Synthetic Methods
5 10
PdCI,. C u C l , CO, AcOH /AcONa ‘
I
R
X
(242)X = C 0 2 M e or S02ToI R = H,
Me
or
(243)
Ph
0
0
OSiMe, Me S i O T f
NH2
i ’ ‘2lTHF
3 E t 3N
~
i i , aq. Na2S03
I
(244)
(245)
0
I (246)
AgBF4,0 5- 1 equiv
OH
(247)n = 1 or 2
0(248)n = 1 (249)n = 2
(250)
8: Saturated Heterocyclic Ring Synthesis
NPSP
Me
NH2 \
r*T$1 51 1
-
OAc
OBn
SePh
Me
OMe
-- H
OMe Br
Br
(251)
J SePh
Me OMe
Me ,Si
\
----
-7 OEt
(CH2
HC02H or 1c
Et2AICI
O A R
(253) n = 1 o r 2 R = Me or OEt
(254)
General and Synthetic Methods
5 12
t r a t i o n o f t h e s y n t h e t i c u t i l i t y of s u c h p r o c e s s e s i s t h e s y n t h e s i s of t h e h e x a h y d r o - l ~ - p y r r o l e [ 2 ~ 3 - d ] c a r b a z o l e (257).
This complex
h e t e r o c y c l i c system is formed i n q u a n t i t a t i v e y i e l d from t h e p r e c u r s o r (256) under mild c o n d i t i o n s and w i t h complete s t e r e o c o n t r o l . 174
Two r o u t e s t o f i v e - m e m b e r e d
n i t r o g e n h e t e r o c y c l e s from imines
v i a a [ 3 + 2 ] c o n s t r u c t i o n mode h a v e b e e n r e p o r t e d . -
Trost et al.
have used t h e b i f u n c t i o n a l reagent (258) t o prepare 2 - s u b s t i t u t e d
4-methylene-pyrrolidines
i n a s t e r e o c o n t r o l l e d m a n n e r . 34
(261
the first s t e p t h e allylstannane u n i t of
In
(258) adds cleanly t o
imines (259) i n t h e presence of boron t r i f l u o r i d e t o g i v e t h e intermediate adducts (260).
Palladium-catalysed
cyclization of
(260) then a f f o r d s (261) i n e x c e l l e n t y i e l d s d e s p i t e t h e unfavourable nature of the 5-endo-trig
geometry f o r r i n g closure.
In the
second r e p o r t , t h e p y r r o l i d i n e ( 2 6 2 ) h a s been p r e p a r e d i n two steps, again
via
a 5-endo-trig
cyclization.23
Only one example o f
t h i s r e a c t i o n as a r o u t e t o s u b s t i t u t e d p y r r o l i d i n e s h a s so f a r been r e p o r t e d , however, and t h e r e f o r e i t s g e n e r a l i t y r e m a i n s uncertain. P y r r o l i d i n e s (263) have been prepared
2an
unusual cyclization
mode, i n what c o n s t i t u t e s t h e f i r s t e x a m p l e s o f a n a n t i - M i c h a e l a d d i t i o n o f a c a r b a n i o n t o an a c e t y l e n i c amide.lc15
Amide s t a b i l i -
z a t i o n o f t h e d e v e l o p i n g a n i o n would r e q u i r e t h e f o r m a t i o n o f a n a l l e n e u n i t i n t h e six-membered r i n g and t h e s t r a i n a s s o c i a t e d w i t h t h i s p r o c e s s t h e r e f o r e m a k e s a n i o n s t a b i l i z a t i o n by t h e p h e n y l g r o u p a more f a v o u r a b l e p r o p o s i t i o n . Meyers and co-workers
have continued t h e i r s t u d i e s t o e x p l o i t
t h e synthetic p o t e n t i a l of a-lithio-formamidines d e s c r i b e d a n e f f i c i e n t s y n t h e s i s of 2 - a r y l p y r r o l i d i n e s and - p i p e r i d i n e s
(266).
a n d h a v e now
or 2 - h e t e r o a r y l -
Alkylation of formamidines
(264) g i v e s i n t e r m e d i a t e s (265) which c y c l i z e i n s i t u after cleavage of t h e amidine u n i t .
The a z a - W i t t i g r e a c t i o n h a s been
u t i l i z e d i n a general synthesis of heterocyclic vinylogous uret h a n e s and a m i d e s ( 2 6 8 ) . 177
Staudinger reaction of azides (267)
with triphenylphosphine gives t h e corresponding phosphinimines which c y c l i z e i n h i g h y i e l d t o g i v e p r o d u c t s ( 2 6 8 ) .
Eight-membered
r i n g s c a n a l s o b e f o r m e d by t h i s p r o c e d u r e b u t i n t w o s t e p s : t h e a z i d e is f i r s t reduced t o t h e primary amine which c y c l i z e s o v e r f i v e d a y s a t room t e m p e r a t u r e t o g i v e ( 2 6 8 ; Hindered l-aryl-pyrrolidines p r e p a r e d by a g a s - p h a s e ,
n=4),i n
and - p i p e r i d i n e s
38% y i e l d .
(271) have been
alumina-mediated r e a c t i o n of primary aro-
8: Saturated Heterocyclic Ring Synthesis
513
'1 HC02H ______)
Ph
A O E t
O A O E t
/Ph
Ph
/OSiBu'Me2
<"r>l.1 0 ;
b
C S A (0.4equiv.)
Me
N a 2 S 0 4 ( 2 . 5 equiv.)
Me
(256)
(257)
R'
R' \
DBU
R2 (258)
(259)
( 2 6 0 ) 64-88'10
(2611
General and Synthetic Methods
5 14
Ph
I
111 0
ArAN’
I
R
R
R
Me
RLI
I,
l l > I q - p L
Ar
HOAcl EtOH
t
Ar
I
+ (265)
(264)
Me
(266)
Ph3P, _____)
ether
OH
0
(267) n = 1 - 3
or
benzene
(268)
515
8: Saturated Heterocyclic Ring Synthesis
matic amines (269) with cyclic ethers ( T ~ O ) . ’ ~ ~Yields are somewhat variable and halogen substituents are not compatible with the reaction conditions but the simplicity of the experimental procedure makes this a useful addition to available synthetic routes to such compounds. In the course of extending their studies of the generation of azomethine ylides from a-amino-acid esters Grigg et al. have discovered a simple one-step synthesis of g-substituted isoindolin-lTreatment of 2-phthaldialdehyde (272) with ones (Scheme 23). 17’ a-amino-acids, their methyl esters, or a range of aryl or heterocyclic amines leads to isoindolin-l-ones (273) in moderate to good yields, probably via the mechanism shown. The reaction also works with aliphatic amines although less efficiently (26-40%).
A full account of the synthesis of indolin-2-ones and 1 , 4 by photoinduced cyclization of gacyl-o-chloroanilines or N-acyl-o-chlorobenzylamines has also appeared. 180 dihydro-3(2H)-isoquinolinones
Six-membered Rings.- Two reviews in this area have appeared. report on selective reactions using organoaluminium reagents
A
includes a section on the synthesis of six- and seven-membered nitrogen heterocycles by organoaluminium-promoted Beckmann rearrangement of oxime sulphonates , 8 1 and Weinreb has reviewed approaches to alkaloid total synthesis utilizing intramolecular imino-Diels-Alder cycloadditions. 182 The major interest this year has undoubtedly been the use of the aza-Diels-Alder reaction in nitrogen heterocyclic synthesis. In terms of general synthetic methodology, the most significant report
’
in this area comes from Grieco and co-workers who have found that simple, unactivated iminium salts can be generated in situ and trapped with a range of dienes to give products in moderate to good yields (Scheme 24). 183 Reaction times and temperatures are dependent upon the reactivity of the diene and the high regio- and stereo-selectivity of the reaction is consistent with a true concerted cycloaddition mechanism, rather than a stepwise process. Acetaldehyde can also be used instead of formaldehyde but yields are lower and the reaction much slower. Preliminary studies on two further aspects of this reaction indicate ways in which this chemistry could be developed. Firstly, an asymmetric aza-DielsAlder reaction of (-)-a-methylbenzylamine hydrochloride (274) with cyclopentadiene gives a 4:l mixture of diastereomers (275) and
General and Synthetic Methods
516
-
+ 0n KH,),,
$NH2
A'203
W
R'
n
@-NGHzIn
275- 350 O C
R2
R2
(271 1
(270)n = 4 or 5
(269)
+ UCH0 HZNR
AcOH
reflux
-
o(;.R
CHO
0 (272)
(273)
H -H
H
&IR
+
'3
0-H
OH Scheme
25 - 55 O C , 3-96 h
23
ci
35 - 95 "1.
R' = H , M e , or PhCHZ
Scheme
24
8: Saturated Heterocyclic Ring Synthesis
(-1-
PhCH(Me)NH2.HCI
+
5 17
0
0 OC
+ Ph
(2741
(275)
HCHO, H20
I4 *. H C I
(277)
L
&NAi: (276)
4.1
e
N.HCI
(278)
General and Synthetic Methods
518
( 2 7 6 ) i n 86% y i e l d , and s e c o n d l y t h e f i r s t e x a m p l e s o f a n i n t r a m o l e c u l a r a z a - D i e l s - A l d e r r e a c t i o n i n v o l v i n g iminium i o n s h a v e been described.
'The b i c y c l i c a m i n e ( 2 7 8 ) , f o r e x a m p l e , i s f o r m e d s i m p l y
and i n e x c e l l e n t y i e l d from t h e p r e c u r s o r ( 2 7 7 ) . r o u t e t o t h e lactam ( 2 8 0 ) h a s been d e s -
A neat aza-Diels-Alder
c r i b e d where b o t h i m i n e and d i e n e u n i t s a r e g e n e r a t e d i n s i t u by t h e r m o l y s i s o f t h e s u l p h o l e n e ( 2 7 9 ) . 18' of
The r e m a r k a b l e h i g h y i e l d
( 2 8 0 ) , t o g e t h e r w i t h t h e r e a d y a v a i l a b i l i t y of s t a r t i n g
materials, makes t h i s one-pot
r o u t e t o b i c y c l i c lactams p o t e n t i a l l y
very a t t r a c t i v e . D a n i s h e f s k y r e p o r t e d some y e a r s a g o t h a t a c y c l i c , u n a c t i v a t e d imines undergo L e w i s a c i d catalysed cycloaddition with siloxydienes t o g i v e six-membered n i t r o g e n h e t e r o c y c l e s .
Two r e p o r t s h a v e now
extended t h e s e o b s e r v a t i o n s t o i n c l u d e t h e r e a c t i o n of c y c l i c imines with dienes.
Danishefsky's group has a l s o described t h e
cycloadaition of aihydro-6-carbolines
with three siloxydienes t o
g i v e yohimbine p r e c u r s o r s . 185
For e x a m p l e , t h e p e n t a c y c l i c l a c t a m (283) is formed s t e r e o s p e c i f i c a l l y from t h e r e a c t i o n o f 3,4-
dihydroindolopyridine (281) with the diene (282), interestingly without acid catalysis.
The same p r e c u r s o r
(281) has been used i n
a s y n t h e s i s o f t h e t e t r a c y c l i c s y s t e m ( 2 8 5 ) by r e a c t i o n w i t h t h e diene (284).186 Aza-Diels-Alder
r e a c t i o n s , where t h e n i t r o g e n i s p a r t o f t h e
d i e n e component, have a l s o f e a t u r e d prominently t h i s y e a r .
Fowler
and co-workers,
i n a c o n t i n u a t i o n of t h e i r s t u d i e s o f t h e f o r m a t i o n
a n d t r a p p i n g of
I-aza-dienes
g e n e r a t e d by t h e r m a l e l i m i n a t i o n of
a c e t i c a c i d f r o m h y d r o x a m i c a c i d d e r i v a t i v e s , h a v e now d e s c r i b e d a n a p p l i c a t i o n of t h e r e a c t i o n t o t h e t o t a l s y n t h e s i s of t h e quinol i z i d i n e alkaloid (-)-deoxynupharidine
( 2 8 8 ) ( S c h e m e 2 5 ) . 187
Reaction t o g i v e (286) and (287) probably proceeds v i a exo, c h a i r t r a n s i t i o n s t a t e s where t h e major product (286) is d e r i v e d from t h e t r a n s i t i o n s t a t e which h a s t h e methyl group on t h e connecting chain i n an e q u a t o r i a l p o s i t i o n .
Kametani and co-workers have r e p o r t e d a
u s e f u l e x t e n s i o n t o t h e i r e a r l i e r work on t h e i n t r a m o l e c u l a r a z a Diels-Alder
reaction.
C y c l o a d d i t i o n c a n now b e c a r r i e d o u t u n d e r
much m i l d e r c o n d i t i o n s t h a n t h o s e p r e v i o u s l y d e s c r i b e d by u s i n g a t r i a l k y l s i l y l trifluoromethanesulphonate a s c a t a l y s t .
BenzoCal-
q u i n o l i z i d i n e (29O), for e x a m p l e , i s o b t a i n e d i n e x c e l l e n t y i e l d 188 from t h e enamide (289). Mariano and co-workers
have c a r r i e d o u t a d e t a i l e d i n v e s t i g a t i o n
o f t h e s y n t h e t i c u t i l i t y a n d mechanism of L e w i s a c i d c a t a l y s e d
5 19
8: Saturated Heterocyclic Ring Synthesis
OMe
OMe (284)
(282)
OMe
( 283 1
(281 1
(284)
O 3 H
0
(285)
FVP
k 0& OAc M e
-
@
+
Me
Me
0 (2861
Scheme
3 : l
25
0 (287)
520
General and Synthetic Methods
cycloaddition of 2-aza-Il3-dienes (291) with electron-rich dienophiles, such as enol ethers and enamines (2921, to give substituted piperidines (293).189 The products are formed in only low yields owing to a competing cyclodimerization of the starting azadiene. In addition, reaction only occurs with 2-azadienes which can adopt low energy S-cis conformations and with electron-rich alkenes: substitution with simple alkyl or electron-withdrawing substituents does not lead to cyclized products. The reaction does proceed with high stereoselectivity, however, as would be expected from a concerted mechanism, and conditions are mild so the method may find useful application. In a similar type of reaction, N-vinyl-2-ethoxypyrrolidinium tetrafluoroborate (294) has been utilized as a novel enophile in a cycloaddition-reductive elimination route to the octahydroindolizines (295) and (2g6).Ig0 As with the previous report, no reaction is observed with electron-deficient alkenes. In view of the ready availability of the imidate (294), this novel way of constructing the indolizidine skeleton should find many applications despite the low yields obtained with the examples so far studied. The intramolecular ene reaction has been utilized by Overman et al. in a synthesis of 6-alkylidene-8-hydroxyindolizidines (298). Treatment of the ketone precursors (297) with AlCl
3
under the conditions shown gave the products (298) as an isomeric mixture about the double bond. Other Lewis acids were ineffective (3. BF .0Et2, Me2A1C1) or gave complex product mixtures (%. 3 EtA1C12). The reaction is highly diastereoselective at C ( 8 ) and selectivity for formation of (El-alkylidene products increases with the size of the R substituent as would be expected from a concerted mechanism involving an A1C13 complex of (297): H transfer occurs from a conformation in which the R substituent of (297) occupies
the least hindered position. Two useful additions to acyliminium ion cyclization methodology have appeared. Firstly, hydroxylactams (299) can be cyclized in excellent yields to the e x o methylene cyclic lactams (300) by using an allyl-silane as the iminimum ion trap , 92 and secondly ozonolysis of substituted alkenes ( 3 0 1 ) provides a new and useful alternative method for generating hydroxy-lactams (302) which can be cyclized in the normal way to give products (3O3).lg3 The synthesis of six-membered nitrogen hetrocycles by a photochemically induced cyclization of iminium salts has received attention in two reports. Mariano and co-workers, in a continu-
8: Saturated Heterocyclic Ring Synthesis
52 1
Me0
Me0 Me B ut SiOTf , .-__)
Me0
Me0
Et3N ,CH2CI2
Ph
Et0,C
! Ph
(291 1
(293
(294)
1
B F4-
522
General and Synthetic Methods
AICL3 ( 2 equiv.)
0
Me
(297)
(290)
WiMe (300)
(299) n = 1 or 2
-
Meo&N
03
M eO
CH,=CH
M Meeo& 0N
Fo
-X-Y
OHC-X-Y
(3011
1 R
- MeoyJ+N H+
Me0
Me0
x-Y
(303)
yo
H0'"C x-Y
(3021
8: Saturated Heterocyclic Ring Synthesis
523
ation of their studies on cyclizations of diradicals generated by an excited-state electron transfer-desilylation pathway, have now shown that the tetracyclic product berbine (305) can be formed in high yield by cyclization of the hydroisoquinolinium perchlorate (304). In the second report , 1 , l-diphenyl-3-arylisoquinolin-4ones (307) have been prepared, in moderate yields, by a novel photochemical cyclization of 2 - a ~ a b u t a - 2 ~ 3 - d i e n e s(306) which involves attack of an iminium carbon atom on the ortho position of an aromatic ring.Ig5 Shono et al. have described an efficient synthesis of substituted piperidines (310) which involves a novel [3+3]-type annulation between allyltrimethylsilane (309) and a , & ' dimethoxylated amides (308). Yields are generally excellent and the reaction works for a wide range of cyclic and acyclic substrates (308), thus allowing easy access to a variety of mono- and bi-cyclic nitrogen systems. The bicyclic amide (3121, for example, can be synthesized in two high-yielding steps from the a-methoxylactam (311). Two interesting extensions to methodology available for nitrogen heterocycle formation 2 cyclization of an electron-deficient carbon onto an aromatic ring have been reported. N-Hydroxytetrahydro-8-carbolines (314) can be prepared in good yields by cyclization of nitrones (313), 197 and l-acyl-3,4-dihydroisoquinolines (318) are produced by an exceptionally mild cyclization procedure from the isocyanides (315) and acyl halides (316), the imidoyl halides (317). Piperidines and related heterocycles (321 ) can be synthesized from amines (319) and 1,5-diols (320) by a ruthenium-catalysed cyclization procedure. The efficiency of the catalytic system depends markedly on the nature of the phosphine ligand but moderate to good yields are generally attainable. Meyers and his group have continued their studies on asymmetric alkylation of chiral formamidine derivatives and now report that 8 carbolines can be alkylated with high stereoselectivity to afford indole alkaloids and derivatives .2001201 Thus ( - )-indoloquinolizine (323) is produced in excellent yield and enantiomeric purity by stereoselective deprotonation and alkylation of (322), followed by amidine cleavage and subsequent cyclization. A new chiral synthesis of L-proline and L-pipecolic acid derivatives (325) and (326) has been reported based upon N-nitrososulphonamide-sulphonate rearrangement of (324). *02 Rearrangement occurs exclusively at the terminal N-nitrososulphonamide. The same group has also utilized this rearrangement in the synthesis of a
General and Synthetic Methods
524
4
ph p:h
T,T p h NH
PhCO,
MeCN
(____) A > hV 300 nm)
Ph
PhC02 Ar
+ NH
++
PhCO,
' NH Ar
Ar
/
hydrolysis
Ar
(307)
8: Saturated Heterocyclic Ring Synthesis
525
MeOH
R’ = H o r a l k y l , Y =OMe or
R’
+Y
y2<:ye ( R2
=
H or Me)
Na H
= -(CH2),-
z
OMe OMe
(308)
Y A O
(310) 2 = C I or OCHO
R’ A N
R*
Y A O R’, R 2 = a l k y l
Y = OMe
HZ,RaNi, ____t
KO H ‘OMe (312 1
(311)
(313)
(314)
General and Synthetic Methods
526
Me O
\
w
Me0
N
111
Me0
C
RNH,
+
HO-’AOH
t R u 1 PR13(cat.) 150
(322)
- 180 “C
*
/-7
RN
Y
U
8: Saturated Heterocyclic Ring Synthesis
527
An interesting range of macrocyclic polyamine derivatives.203 double cyclization route to the indolizidine system has been reported by Hashimoto and co-workers, as part of their synthesis of (+)-castanospermine (329) from D-mannose .204 Heating the amine (327) under reflux in methoxyethanol gave the indolizidinone (328) which was then carried through to the target compound (329). The same group has also reported a synthesis of the related alkaloid ( - ) -swainsonine by a similar route. 205 Two one-pot procedures for the preparation of 3,4-dihydro-2(1;)pyridones, based upon 1,q-addition of ketones to substituted acrylamides, have been reported (Scheme 26). Using methacrylamide as the Michael acceptor, 1,4-addition of ketones (330) catalysed by CsF/Si( OMe)4 gives generally good yields of products (33 1 1, 206 and 5-aryl-2(lE)-pyridones (334) are formed in fair yields by reaction of aryl ketones (332) with acrylamides (333) in the presence of potassium t-butoxide. 207 4-Hydroxy-di- and -tetra-hydropyridines (337), potentially useful heterocyclic intermediates, have been prepared by an acidcatalysed cyclization of unsaturated aldehydes (335).208 In the dihydro-series the chloride (336) is sufficiently stable to allow isolation but the tetrahydro-derivative undergoes hydrolysis on attempted chromatography to give (337). A novel route to 5,6-dihydro-4-pyridones (341) which utilizes the well known propensity of isoxazole derivatives to undergo thermal N-0 bond heterolysis has been reported. 209 Thermolysis of 4,5-dihydro-isoxazole-5-spirocyclopropanes (338) gives a mixture of enaminones (340) and dihydropyridones (341) in moderate yields, possibly via the diradical (339). Finally, a one-pot synthesis of 4-substituted glutarimides has been reported, based upon freeradical addition of iodoacetamide (343) to a ,B-unsaturated esters (342 .21 Intermediate amido-esters (344) are also obtained initially but further heating converts (344) into (345). Disadvantages of the procedure are that the tributylstannane needs to be added slowly, over 15 h , and that good yields are obtained only after recycling of unchanged starting materials, but the convenience of a one-pot addition-cyclization procedure may offset these drawbacks in some applications. Six-membered Rings Containing Two Nitrogens.-
5-Methyl-2,3-di-
hydropyrazines (348) can be prepared efficiently in a one-pot oxidative aminomercuration procedure, starting from propargylic
General and Synthetic Methods
528
L - L y s i n e or L - O r n i t h i n e i - iii
f'3i;. zMe TsN
TsN
I
I
No
i v ( n => l)
TsO
*H
*
JyCO,Mr? HN 'H Ts
DH C02Me
I Ts
NO Q
(324)
iv(n= 0 )
(325), 4 9 ° / 0 from (324; n = 0 ) (3261, 25°/0 from (324; n = 1 )
Reagents : i , H C I , MeOH
i v , 80
OC
;
ii, T s C l , p y r i d i n e
, benzene
;
;
iii, N a N 0 2 , A c 2 0 , A c O H
;
v , K 2 C 0 3 ,DMF
OTBDMS
OTBDMS
H &Ox
MeOCHZCHzOH, reflux
0
Bu'02C
0
H 0'
0
0 II
R'C CH R~
-k
CH2=C,
,CoNHz
CSF, Si(OMe)4
Me
* R'
(3301
RZ
(331)
0
I1
Me CCH, A r
R
t
CONHZ
(332)
B ~ ~ O K
H,C=CC
Me+R
Ar
(333)
(334)
Scheme
26
OH
529
8: Saturated Heterocyclic Ring Synthesis
1
E t 0 2 C C0,Et
r,,,,
HCI,
P
CI
1
HO
'0
Ac
OH
CI
AC
AC
(336)
(337)
1
2oooc
[Rm=] N*
0
General and Synthetic Methods
530
R w c o z M e
Bun3SnH, AIBN
+ ICH,CONH,
(342)
R_Cco2Me
80 - 9 0 "C , t u n g s t e n lamp
CON H,
(343)
I
+
I
-
'
R4 R 3 R l
+
0 R2
HZN, F R '
HN
( 3 4 51
(344)
OH R~-CH-C=CH
120°c
_____)
R4
Acetone
4Aslevess_
~
r t
R2
'fl R'
R'
OH
R2
H
R4
53 1
8: Saturated Heterocyclic Ring Synthesis
Dihydropyrimidines (352) a l c o h o l s ( 3 4 6 ) and 1 , 3 - d i a m i n e s ( 3 4 7 ) . 21 are r e a d i l y a v a i l a b l e 2 a two-step sequence involving i n i t i a l reaction of enones
(349) a n d a m i d i n e s ( 3 5 0 ) t o g i v e h y d r o x y t e t r a -
h y d r o p y r i m i d i n e s ( 3 5 1 ) , f o l l o w e d by d e h y d r a t i o n . 2 1 2
I s o l a t i o n of
intermediates p r i o r t o t h e dehydration s t e p allows easier optimiz a t i o n of r e a c t i o n c o n d i t i o n s , which l e a d s t o h i g h e r y i e l d s o f (352) i n comparison with previous one-step procedures. 1,2-Dihydropyrimidine (354) is formed, as a mixture of d i a s t e r e o m e r s , by h y d r o x i d e i o n - m e d i a t e d
r i n g e x p a n s i o n o f t h e 2-
The g e n e r a l i t y of t h i s r e a c t i o n h a s
v i n y l p y r a z o l i u m s a l t (353) .213
y e t t o b e e s t a b l i s h e d , b u t i t may h a v e s o m e s y n t h e t i c u t i l i t y . 5 8-Lactams,
P e n i c i l l i n s , Cephalosporins, and Related
Compounds A comprehensive review c o v e r i n g t h e s y n t h e s i s and b i o l o g i c a l a c t i -
v i t y of
$-lactam a n t i b i o t i c s h a s a p p e a r e d . 2 1 4
T h e s y n t h e s i s o f 8-
lactams by r o u t e s b a s e d u p o n t r a n s i t i o n metal c h e m i s t r y h a s b e e n a major t h e m e t h i s y e a r .
I n a c o n t i n u a t i o n of t h e i r e a r l i e r w o r k ,
(356) b y a h i g h l y
Liebeskind e t a l . have synthesized t h e 8-lactam
s t e r e o s e l e c t i v e conjugate addition of N-lithiobenzylamine a,B-unsaturated
I n a similar r e a c t i o n s e q u e n c e , a d d i t i o n o f benzylamine
zation,215
t o t h e a,B-enoyliron t h e 8-lactam b i l i t y of
t o the
i r o n a c y l ( 3 5 5 1 , f o l l o w e d by o x i d a t i v e c y c l i c o m p l e x ( 3 5 8 1 , f o l l o w e d by o x i d a t i o n , g i v e s
( 3 5 9 ) i n g o o d o v e r a l l y i e l d . 126
The r e a d y a v a i l a -
(358) from t h e a c i d c h l o r i d e (3571, t o g e t h e r with t h e
s i m p l i c i t y of t h e e x p e r i m e n t a l p r o c e d u r e , m a k e t h i s a p o t e n t i a l l y u s e f u l g e n e r a l method f o r 8 - l a c t a m s y n t h e s i s .
F u l l d e t a i l s have
a p p e a r e d from L e y a n d c o - w o r k e r s o f t h e i r s y n t h e s i s o f
(+I-
t h i e n a m y c i n by a r o u t e b a s e d upon o x i d a t i v e c y c l i z a t i o n o f a
IT-
a l l y l t r i c a r b o n y l i r o n lactam c o m p l e x t o f o r m t h e $-lactam s y s t e m . 2 1 7 Oxacepham d e r i v a t i v e s ( 3 6 2 ) - ( 3 6 4 ) c a n b e p r e p a r e d i n m o d e r a t e y i e l d s by p h o t o l y t i c a d d i t i o n o f t h e molybdenum c a r b e n e c o m p l e x (360) t o t h e oxazine (361).218
8-Lactam f o r m a t i o n i t s e l f is
s t e r e o s p e c i f i c a n d p r o d u c t m i x t u r e s a r i s e o n l y t h r o u g h t h e racemic n a t u r e of t h e s t a r t i n g o x a z i n e s .
Mori e t a l . have r e p o r t e d f u l l
d e t a i l s o f t h e f o r m a t i o n of a - m e t h y l e n e - B - l a c t a m s c a t a l y s e d r e a c t i o n o f CO w i t h 2 - b r o m o a l l y l a m i n e
by p a l l a d i u m derivatives2”
a p p l i c a t i o n of t h i s p r o c e d u r e t o t h e s y n t h e s i s of 220 nocardicinic acid. T h e f o r m a t i o n o f B-lactams
and
(-1-)-3-amino-
by r e a c t i o n o f e s t e r e n o l a t e s w i t h
General and Synthetic Methods
532
Me
Me
CHC0,Me
I
OH
I
i, PhCH2NHLI
OC-Fe
ph36
~
Q
Me
- B2r ' CS w
OC-Fe,
M
Me
o NCH, P h
ii, Me1
k$CH2Ph
"3'
H
F
Me
H
H
9 5 "lo
(355)
(356)
2 4 :1 d iast ereomer ratio
Me Me
Na[FeCp(C0)21Meq
Me?/"'
(FeCp (C0l2
ii, Br2 ,NEt3
-Me
0 (3571
i,PhCH2NH2
0 ( 358 1
(3591
8: Saturated Heterocyclic Ring Synthesis
533
M e 0, 5 T R
hv
(CO15Mo
=C / \Me
+ RJ?2 N
0
___f OC
OMe R3
2
0
R3
R3
~3
(360) ( 3 6 2 ) R1,R2,R3 = H
(361)
(363) R1 = E t , R2, R 3 = M e
( 3 6 4 ) R ' = PhCH2,R2,R3=Me
R2 \
-L D A or
CHC0,Et
R3 R,
R1 N H cH2c N
LHMDS
(366)
0
R3/
(365)
(367)
-
H
\Si/ LDA or [ S . ; ~ ~ ~ z ~ ~ z ~ t LHMDS
(368)
--
( > 95'1. e.e.1
/\
H
Z
0
N1
w
r
-
--
p
H
OCHzPh
(369)(3s : 3 R =10:1)
NccH2N OCH,Ph
(368)
General and Synthetic Methods
5 34
imines is a well documented procedure but interesting new developments continue to appear. Overman has described a very useful method for the synthesis of 4-unsubstituted B-lactams (367) which makes use of his recently disclosed method for generating unsubstiN-(cyanomethyl)-amines.221 tuted imines from Treatment of the lithium enolate of' substituted esters (365) with !-(cyanomethyl)amiries (366) gives, in one step, B-lactams (367). A wide range of substituted esters are amenable to this procedure, including Eprotected a-amino-esters, and if the starting cyanoamine (366) is non-racemic the method provides a concise route to enantiomerically pure 3-amino- and 3-acylarnino-B-lactams.
The monocyclic B-lactam
(3691, for example, is formed from the (S)-cyanoamine (368) in 65% yield and 1O:l diastereoselectivity. Reaction of the dianion of ethyl (S)-b-hydroxybutyrate (371) with a range of imines continues to be employed by several groups as a route to 3-('l-hydroxyethyl)-2-azetidinones.
In a continuation
of their preliminary studies published last year, Hart et al. have now reported that reaction of the dianion of (371) with the imine (370) affords' a mixture of 6-lactams (372) and (373) which serve as useful precursors to the carbapenem system.222 Thus , 4-acetoxy-3(1-hydroxyethy1)azetidinone
(374), an intermediate in the synthesis
of thienamycin (3751, is available in good yield from (372) and
(373) via a straightforward reaction sequence. Essentially the same procedures have been employed by Cainelli et al. in their (376), except synthesis of the 3-[(~)-l-hydroxyethyl1azetidinone that inversion of the side-chain hydroxy-group from S to R configuration is undertaken at an earlier stage.223 The generality of the ester-imine cyclization route to 3-(l-hydroxyethyl)-2-azetidinones has been investigated by Georg and co-workers who have studied the reaction of the dianion of racemic ethyl-3-hydroxybutyrate (378) with non-enolizable N-arylaldimines (377).224 The trans-3-[(S)-l-hydroxyethyl]azetidinones (379) are generally formed as major products, although product ratios are dependent both upon the nature of the N-substituent and the precise reaction conditions. The presence of HEPA and higher reaction temperatures leads to cis-trans isomerization of the B-lactams. As an alternative procedure to the reaction of N-trimethylsilylimines with ester enolates Colvin et al. have now reported that silyl ketene acetals can be employed in a one-pot synthesis of &unsubstituted B-lactams. 225 Reaction of the ketene acetal ( 3 8 0 ) with the imine (381) in the presence of Zn12, and t-butyl alcohol
8: Saturated Heterocyclic Ring Synthesis
535
w T I
OSi+
1
i,LDA,-7045'C
-
N Si Me3
(370)
zlyph
I '
OH
C0,Et
ii, ButMe2SiCi,
*
I
OSi+ : I H H
'sit
NEt 3
Si+
I
(371)
I
(372) 16%
(373) 27'10
,i
i ,03 ii,Jones o x i d a t i o n iii, P b ( O A c I 4
OSi
+
I
(375)
I (376 1
R
MeCH(OLi)CH=C(OEt)(OLi)
(378)
*
xR 9+%" QHti
+
H
OH
OH
THF or HMPA
Ar
(377)
0 50 -95
\
Ar
Ole
0
\
Ar
5-5Oo/o
O
\ Ar 15 - 8 0 %
536
General and Synthetic Methods
a s a weak p r o t o n s o u r c e , g i v e s B - a m i n o - e s t e r s cyclized i n s i t u t o N-unsubstituted
o f t h e r e a c t i o n m i x t u r e p r i o r t o work-up
w i t h MeMgBr.
t r a n s s e l e c t i v i t y is g e n e r a l l y observed. a d d i t i o n r o u t e t o t h e B-lactam
(382) which can be
a z e t i d i n o n e s ( 3 8 3 ) by t r e a t m e n t Moderate
The k e t e n e - i m i n e
cyclo-
system has been extensively s t u d i e d
o v e r r e c e n t y e a r s a n d s y n t h e t i c e f f o r t s a r e now m a i n l y d i r e c t e d towards t h e establishment of asymmetric r o u t e s t o s u b s t i t u t e d a z e t i d i n o n e s by t h i s p r o c e d u r e . chiral oxazolidinones B-lactarns
E v a n s e t al. h a v e s h o w n t h a t t h e
(384) react with N-benzylimines
(385) t o give
(386) i n g o o d y i e l d s a n d w i t h a h i g h d e g r e e o f s t e r e o -
c h e m i c a l c o n t r o l . 226
The c h i r a l o x a z o l i d i n o n e a u x i l i a r y c a n b e
e a s i l y r e m o v e d by a d i s s o l v i n g metal r e d u c t i o n t o f u r n i s h e n a n t i o merically pure azetidinones (387).
T h e same g r o u p h a s a p p l i e d t h i s
procedure t o t h e first enantioselective synthesis of t h e carbac e p h a l o s p o r i n n u c l e u s ( 3 8 9 ) from t h e c h i r a l o x a z o l i d i n o n e ( 3 8 8 ) by making u s e o f t h e a b i l i t y o f d i h y d r o a n i s o l e s t o act as B-keto-ester e q u i v a l e n t s ( S c h e m e 2 7 ) . 277
O p t i c a l l y a c t i v s cis-B-lactams
c a n b e p r e p a r e d i n m o d e r a t e y i e l d s from ' D a n e ' i m i n e ( 3 9 1 ) d e r i v e d from D - t h r e o n i n e . 228
(392)
salt (390) and t h e
The bulky t r i p h e n y l s i l y l
s u b s t i t u e n t is t h e b a s i s of t h e high d i a s t e r e o f a c i a l s e l e c t i v i t y of addition t o t h e imine (391).
A u s e f u l s y n t h e s i s o f 3-hydroxy-
a z e t i d i n o n e s h a s b e e n r e p o r t e d by P a l o m o a n d c o - w o r k e r s . 229 T r i m e t h y l s i l y l o x y a c e t i c a c i d s ( 3 9 3 ) h a v e been found t o react w i t h i m i n e s (394) i n t h e p r e s e n c e o f p h e n y l p h o s p h o r o d i c h l o r i d a t e a n d triethylamine t o give products (395) directly, thus obviating the n e e d for a n a d d i t i o n a l h y d r o x y - g r o u p sequence.
protection-deprotection
I n c a s e s w h e r e R=H i n ( 3 9 3 1 , m a j o r p r o d u c t s g e n e r a l l y
have cis-stereochemistry. F o u r i n t e r e s t i n g new p r o c e d u r e s f o r f o r m a t i o n o f m o n o c y c l i c B -
lactams
via N-C(4) or C(3)-C(4)
c l o s u r e have been r e p o r t e d .
Hanessian et a l . have demonstrated t h a t t h e imidazolylsulphonate g r o u p is a n e f f i c i e n t l e a v i n g g r o u p i n t h e r i n g c l o s u r e of s u b s t i t u t e d L-serine
d e r i v a t i v e s ( 3 9 6 ) t o g i v e B-lactams
x-
( 3 9 7 ) .230
C y c l i z a t i o n i n t h i s case p r o c e e d s w i t h o u t r a c e m i z a t i o n , e l i m i n a t i o n , or a z i r i d i n e f o r m a t i o n b u t f o r t h e c o r r e s p o n d i n g L t h r e o n i n e d e r i v a t i v e s a z i r i d i n e formation is t h e predominant pathway.
Miller a n d c o - w o r k e r s
observation t h a t B ,y-unsaturated
have a p p l i e d Ganem's earlier N-tosyl-amides
undergo bromine-
i n d u c e d o x i d a t i v e c y c l i z a t i o n t o t h e p r e p a r a t i o n of !-acyloxy-8-
l a c t a m s ( 3 9 9 1 from h y d r o x a m a t e s ( 3 9 8 ) . 2 3 1
The N-hydroxy-B-lactam
( 4 0 0 ) is a v a i l a b l e by t h i s p r o c e d u r e i n e x c e l l e n t o v e r a l l y i e l d .
8: Saturated Heterocyclic Ring Synthesis
HoMe +
R’ R2
R3CH=NSiMe3-
537
wH
R’ ZnIZ (1 equiv.)
R3
-----,
R* OSiMe3
MeOzC
R’
BJOHR
Z
u
R3 H
(1 equiv.)
Me02C
N-Znj
I
SiMe,
’
NH,
(382 1
J
MeMgEr
(
0 H % ( y 0-f N p R H
R
Ph
0
\ CH ,Ph
(384)
(385)
Ph
0 H
+
NCH,Ph
0
k0 9 N FH .
ph
H# R
NCH,Ph
0
( 3 8 6 ) 92-97
H
3 equiv.)
H
8-3
HZNwR (387)
General and Synthetic Methods
538
(388) H
H
mo
BocH N
BocHN
!
vii,viii
0
CO,CH,
so Ph F 2r 3 c
OCH,Ph
/
J J
J
PhO
Scheme
ECHZ
I
27
E t OCOC I
+
OSiPh,
COZCH, Ph
COZCH, Ph
(390)
(391)
(392) Me
CO, C H Ph
539
8: Saturated Heterocyclic Ring Synthesis
i, RZCH= NR3, (394) PhOP(0)C121NEt3 ii,
H,O
OS0,-
N GN
RHNYoH - RHNY IrnSOpIm,
NaH/DME
0
0
OMe
OMe
RHN
0 OMe
(398)
(399)
(4001
540
General and Synthetic Methods
A novel route to 3-acetylazetidinone-2,2-dicarboxylates (402) has been reported, based upon the reaction of aminomalonates (401) with diketene and subsequent cyclization using sodium ethoxide and iodine (Scheme 28).232 Protection of the acetyl group as the ethylene acetal, followed by partial decarboxylation and some straightforward synthetic manipulation provides access to the potentially useful intermediate (403). The phenyl thiolesters (406) are useful intermediates for carbapenem synthesis and are usually prepared from the corresponding 4-acetoxyazetidinones. Maruyama et al. have now reported an alternative synthesis of (406) which involves as the key step cyclization of the phenylthiopropargyl epoxide (404) to the 3,4-trans-azetidinone (405; R=H): no cisproduct is produced. 233 An interesting ring-contraction route to
N-substituted 8-lactams which may have relevance to penicillin biosynthesis has been reported by Procter and co-workers .234 Photolytic or thermolytic cleavage of the N-0 bond of tetrahydro1,2-oxazine-3,6-diones (4071, followed by decarboxylation, gives intermediate 1,4-diradicals (408) which close to form B-lactams (409), albeit in poor yields. Diradical intermediates analogous to (408) may be formed in the biosynthesis of isopenicillin N from tripeptide precursors. In a similar vein, Easton has published full details of the synthesis of 8-lactams by ring contraction o f isothiazolidinones, a reaction which may also be relevant to penicillin biosynthesis although via a mechanism involving ionic intermediates .235 Monocyclic 8-lactams (411), containing a sulphur substituent at C(4) can be formed in variable yields from thioimides (410) via a photochemical Norrish Type I1 mechanism involving y-hydrogen abstraction by the thiocarbonyl group.236 Ueda et al. have reported the first successful attempt to trap an unsaturated azetidinone (412) as a Diels-Alder adduct. 237 Reaction of 4-acetoxy-2-azetidinone (413) with siloxydienes (414), in the presence of zinc chloride, gives the displacement product (416) as the major component but low yields of cycloaddition products (415) are also obtained, making this a novel one-step synthesis of the carbacephalosporin framework from a monocyclic azetidinone precursor. Two other routes to the carbacepham system involving cyclization of monocyclic azetidinone intermediates have also appeared, Beckwith et al. have described a radical-induced ring closure of 4-phenylthioazetidinones (417) to afford cyclized products (418) and (419).238 No other cyclization products were
8: Saturated Heterocyclic Ring Synthesis
54 1
OH )(/COzEt
Scheme
&<=0
28
SPh
H SPh PMB
uo2
NoOEt
LH MDS
I,
O°C, 5 min
OR
H TFA
*
~
ii, CAN
‘PMB
0
(405)R = H
hV or ___)
190°c
~
[oq]
(406 1
R
‘
R
~
s
p
542
General and Synthetic Methods
[ R5*' 1 3] Rri*: -
R'
hv
PhCOCl
SCOPh
____)
NPh
R02 X : Ik R 3
0
Ph
(411)
(410)
(412 1
-
OSiMe3
reflux
0
R (413)
R
(414 )
ai'"
B un3sn H ,
(CHz),,CH
-
AIBN, benzene,
0
80°C
=CH2
(41 6 1
(415)
D: -
0
(CH21nCH=CHZ
0
1
(417)
Bun3Sn H
( 4 1 8 ) n = 2 Z6"lO
(419)n = 3 55% ( n
= 1, Oolo yield)
8: Saturated Heterocyclic Ring Synthesis
543
SPh
___)
___)
0
'Si Me2But
'Si Me, But COSPh
(420) n = 0 or 1
(421 1
( 4 2 2 ) n = 0, 83'10
('423)n = 1, 53'10
H
R e a g e n t s : i , PhSCH2NOZ, ButOK
;
i i , N E t 3 , M e S 0 2 C I ; iii, H F , p y r i d i n e
iv, B ~ ~ O B K ~,~ O H I T H F ; v,
o3
v i , B ~ ~ N TFH,F ;
;
o3
-78OC I
C0,PNB
(4261
CO, PNB
(427)
I
C02H
(428)
General and Synthetic Methods
544
detected, indicating that ring closure occurs exclusively i n the endo-mode.
R e a c t i o n of t h e c o r r e s p o n d i n g N - a l l y l a z e t i d i n o n e u n d e r
t h e same c o n d i t i o n s f a i l e d t o g i v e a n y c y c l i z e d p r o d u c t s .
Barrett
and co-workers
h a v e d e s c r i b e d t h e u s e o f (pheny1thio)nitromethane as a g e n e r a l r e a g e n t f o r t h e s y n t h e s i s o f b i c y c l i c B-lactams. 2 3 9 Thus, base-induced
c y c l i z a t i o n o f n i t r o a l k e n e s (4211, which a r e
r e a d i l y a v a i l a b l e from t h e corresponding aldehydes ( 4 2 0 ) , l e a d s t o formation of b i c y c l i c 6-lactams
( 4 2 2 ) a n d ( 4 2 3 ) as a m i x t u r e of
d i a s t e r e o m e r s i n moderate t o good y i e l d s .
The oxadethiapenam
i s a l s o a v a i l a b l e from m o n o c y c l i c a l d e h y d e
(424) i n good y i e l d
(425)
via
t h e same p r o c e d u r e . F i n a l l y , a n e f f i c i e n t s y n t h e s i s of t h e a z a p e n e m s y s t e m ( 4 2 8 ) features a high-yielding,
based-induced
cyclization of the isothio-
c y a n a t e d e r i v a t i v e ( 4 2 6 ) to g i v e t h e b i c y c l i c 8 - l a c t a m
( 4 2 7 ) . 240
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8 9 10 11 12
13 14 15
16 17
18 19 20 21 22 23
24 25 26 27 28 29 30 31
26,
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26,
26, 2,
118,
26,
26,
5,
26,
26,
5,
8: Saturated Heterocyclic Ring Synthesis 32 33 34 35 36 37 38 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 65 66 67 68
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m.,
-
69 70 71 72 73 74
545
I
,
5,
General and Synthetic Methods
546 75 76
77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 I01 102 103 104
105 106 107 108 109 110 111 112
113 114 115 116
117 118 119 120 121
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2,
26, 5,
5,
5,
26,
26,
26,
g, 26,
E,
26,
26, 26,
26,
26,
.
118,
I
I
v
547
8: Saturated Heterocyclic Ring Synthesis 122 123 124 125 126 127 128 129 130
131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166
167 168 169
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26,
26,
g,
5,
24, 5,
~
5,
2,
26,
5,
26,
26,
26,
26,
5,
2,
26,
5,
5,
General and Synthetic Methods
548 170 17 1 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 20 1 202 203 20 4 20 5 206 20 7 208 20 9 21 0 21 1
212 21 3 214 215 21 6 217 218 219
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26,
2,
18,
c,
26,
*t
26,
c,
5, 5,
549
8: Saturated Heterocyclic Ring Synthesis 220
K.Chiba, M.Mori, and Y.Ban, Tetrahedron, 1985, 41, 387. L.E.Overman and T.Osawa, J. Am. Chem. Soc., 1985, 107, 1698. 222 D.J.Hart and D.-C.Ha, Tetrahedron Lett., 1985, 26, 5493. 223 G.Gainelli, M.Contento, D.Giacomini, and M-Panunzio, Tetrahedron Lett., 1985, 26, 937. 224 G.I.Georg, H.S. Gill, and C.Cerhardt, Tetrahedron Lett., 1985, 26, 3903. 225 E.W.Colvin and D..McGarry, J. Chem. SOC., Chem. Commun., 1985, 539. 226 D.A.Evans and E.B.Sjogren, Tetrahedron Lett., 1985, 26, 3783. 227 D.A.Evans and E.B.Sjogren, Tetrahedron Lett., 1985, 26, 3787. 228 A.K.Bose, M.S.Manhas, J.M.van der Veen, S.S.Bari, D.R.Wagle, V.R.Hegde, and 33. L.Krishnan, Tetrahedron Lett., 1985, 3, F.P.Cossio and C.Palomo, Tetrahedron Lett., 1985, 26, 4239. S.Hanessian, C.Couture, and H.Wyss, Can. J. Chem., 1985, 3, 3613. G.Rajendra and M.J.Miller, Tetrahedron Lett., 1985, 26, 5385. G.Simig, G.Doleschal1, G.Hornyak, J.Fetter, K.Lempert, J.Nyitrai, P.Hus.zthy, T.Gizur, and M.Kajtar-Peredy, Tetrahedron, 1985, 5, 479. 233 H.Maruyama, M.Shiozaki, S.Oida, and T.Hiraoka, Tetrahedron Lett., 1985, 26, 4521. 234 J.Nally, N.H.R.Ordsmith, and G.Procter, Tetrahedron Lett., 1985, 26, 4107. 235 C.J.Easton, J . Chem. S O C . , Perkin Trans. 1 , 1985, 153. 236 M.Sakamoto, H.Aoyama, and Y.Omote, Tetrahedron Lett., 1985, 26, 4475. 237 Y.Ueda and S.C.Maynard, Tetrahedron Lett., 1985, 3, 6309. 238 A.L.J.Beckwith and D.R.Boate, Tetrahedron Lett., 1985, 26, 1761. 239 A.G.M.Barrett, G.G.Graboski, and M.A.Russel1, J. Org. Chem., 1985, 50, 2603. 240 T.Shibata, Y-Sugimura, S.Sato, and K.Kawazoe, Heterocycles, 1985, 3, 3069. 221
~
Highlights in Total Synthesis of Natural Products BY K. E. B. PARKES AND G. PATTENDEN
The arene-olefin meta-photocycloaddition approach to triquinane natural products is further illustrated this year with a three-step total synthesis of (2)-silphinene (5) starting from 2-bromotoluene (I).' Thus, irradiation of the arene-olefin ( 2 ) derived from ( 1 ) gave a 1:l mixture of the photoadducts (3) and (4) in 70% yield. Regioselective reductive cleavage of the cyclopropane bond in (31, using Li-MeNH2, then led to (+)-silphinene (5). In another approach to (2)-silphinene, Sternbach and co-workers* have highan intralighted the use of the tricyclic adduct ( 7 1 , derived molecular Diels-Alder reaction of the substituted cyclopentadiene (6), as a central intermediate. An interesting chelation-controlled regioselective ring enlargement, by means of an epoxide-carbonyl rearrangement, (8) (9), has been used as the basis for a new synthesis of the angular triquinane sesquiterpene isocomene ( 10 1 described by Tobe et al., and other workers have highlighted an unusual rhodium-mediated intramolecular C-H insertion step, (11) (121, in a synthesis of pentalenolactone E methyl ester (13) .4 The [3.3.31propellane carbon framework present in modhephene (16) has been elaborated in a number of ingenious ways, and this year Mehta and Subrahmanyam5 have illustrated the scope for the photochemical oxa-di-n-methane rearrangement, G. (14) (15), to access this unusual molecule. Photochemistry, in the shape of the de Mayo reaction, also features in a new synthesis of the linear fused triquinane hirsutene (20) .6 Thus, photocycloaddition between dimedone and Z-methylcyclopent-2-en01 was accompanied by spontaneous retro-aldolization of the intermediate adduct (171, leading to (18a). McMurry coupling of the dione (18b), derived from (18a), followed by manipulation of the functional groups in (19) then led to (+I-hirsutene
=
=. -
e.
-
-
(20). In an alternative synthesis of (+)-hirsutene, Hua et al." have been able to highlight the useful stereochemical aspects of
550
For References see p . 594
55 1
9: Highlights in Total Synthesis of Natural Products
t
111-
v
CHO
Reagents:
I ,
16OoC, b e n z e n e ; i i , 0 3
Cu(OAc12
0-
j VI
i, = c = , h ~ 11,
; III,KOH,M~OH; Iv,CrO3, Me2CO;vJPb(OAcIL,
J M e 2 C u L i ; v i i , N2HL,KOH
LiEt3BH
&OH
-iB mcpba
OH
(8)
OH
552
General and Synthetic Methods
9: Highlights in Total Synthesis of Natural Products
553
r e a c t i o n s between c h i r a l s u l p h i n y l - a l l y 1 a n i o n s and c y c l i c enones i n a s y m m e t r i c s y n t h e s i s , &. ( 2 1 ) (22), together with a f a c i l e
-
f i v e - r i n g c l o s u r e r e a c t i o n i n v o l v i n g e n o l a c e t a t e and e n o l t h i o e t h e r moieties i n t h e presence of Lewis a c i d s ,
G. (23)
-
(24).
The l a s t few y e a r s h a v e w i t n e s s e d a r e n a i s s a n c e o f i n t e r e s t i n t h e use of carbon r a d i c a l i n t e r m e d i a t e s i n t h e s y n t h e s i s o f a l l t y p e s of r i n g s y s t e m s . A s i g n i f i c a n t e x a m p l e o f t h e power o f t h i s s t r a t e g y i s shown by C u r r a n ' s n e a t s y n t h e s i s o f ( 5 ) - h i r s u t e n e which u s e s a 'tandem' C u r r a n a n d Chen'
(20)
r a d i c a l c y c l i z a t i o n s e q u e n c e f.rom ( 2 5 ) .
8
h a v e a l s o a p p l i e d t h e same s i n g l e - s t e p r a d i c a l
c y c l i z a t i o n sequence t o e l a b o r a t e t h e marine m e t a b o l i t e (?)-capnell e n e ( 2 7 ) s t a r t i n g from t h e iodoenyne ( 2 6 ) .
It is i n t e r e s t i n g t o
n o t e t h e s i m i l a r i t y i n d e s i g n between t h i s r a d i c a l approach t o c a p n e l l e n e a n d t h e s t r a t e g y u s e d by t h e a u t h o r a n d h i s c o - w o r k e r s 1 ° t o t h e c a p p e l l e n e d i o l ( 2 8 ) , which c o - o c c u r s w i t h ( 2 7 ) i n C a p n e l l a i m b r i c a t a (Scheme 1 ) . I n f u r t h e r i l l u s t r a t i o n s of t h e u s e o f f r e e - r a d i c a l c y c l i z a t i o n r e a c t i o n s i n t e r p e n e s y n t h e s i s S n i d e r e t a1.l' have d e s c r i b e d the 5-=-trig
c y c l i z a t i o n from t h e i m i d a z o l i d e ( 2 9 ) t o produce b o t h B-
copaene ( 3 0 a ) and B-ylangene
( 3 0 b ) , S t o r k and Baine12 have synthe-
s i z e d s e y c h e l l e n e ( 3 2 ) [ f r o m ( 3 1 ) I , and Ladlow a n d P a t t e n d e n 1 3 h a v e featured a novel, stereoselective intramolecular radical cyclizat i o n s t e p o n t o an e n o l i c double bond,
G. (33)
-
(34), in their
synthesis of (+)-alliacoli.de (35). The r e p o r t e d a n t i t u m o u r a l a c t i v i t y o f t h e f u n g a l m e t a b o l i t e
I
quadrone (401, t o g e t h e r with its unusual s t r u c t u r e , c o n t i n u e s t o a t t r a c t s y n t h e t i c c h e m i s t s , a n d t h i s y e a r Wender a n d W o l a n i n 1 4 h a v e d e s c r i b e d a n a p p r o a c h t o t h e m o l e c u l e which f e a t u r e s t h e Diels-
-
Alder c y c l o a d d i t i o n
-
( 3 9 ) as key s t e p s .
The i n t r a m o l e c u l a r c y c l o a d d i t i o n ( 4 1 )
r i n g expansion sequence (36)
whereby a seven-membered
(37)
-
-
(38)
-
(421,
r i n g is constructed using the synthetic
e q u i v a l e n c e of an i n t r a m o l e c u l a r D i e l s - A l d e r
r e a c t i o n between a
d i e n e a n d a c a r b e n e , h a s b e e n u s e d i n a n e l e g a n t m a n n e r by S c h u l t z
-et
a l . i n t h e i r t o t a l synthesis of (-1-longifolene
(43).15
S y n t h e t i c r o u t e s t o germacrenes are always of i n t e r e s t .
This
y e a r , McMurry h a s a p p l i e d h i s l o w - v a l e n t t i t a n i u m b a s e d m e t h o d t o b i c y c l o g e r m a c r e n e ( 4 5 ) , from ( 4 4 1, l 6 and S c h r e i b e r e t a l . l 7 h a v e summarized a s h o r t s y n t h e s i s o f germacrene D ( 4 8 ) which r e l i e s h e a v i l y on t h e s i t e - a n d s t e r e o - s e l e c t i v e
e n o l i z a t i o n of ( 4 6 ) t o ( 4 7 ) u s i n g t h e c o n f o r m a t i o n a l b i a s i n t h e ten-membered r i n g i n t e r 1 4 membered) mediate (46). I n a f i r s t e x a m p l e of t h e oxy-Cope ( 6
-
General and Synthetic Methods
554
Bu3SnH
* H
H
(26)
woAc TIC(&
H
Scheme 1
e Y h Bu3SnH
P 130 h M eOJC’
S
(29)
(
3 0 ) a ; cl - CHMe, b; - C H M e 2
555
9: Highlights in Total Synthesis of Natural Products
EtAlCL2
Me
PhMe, *5"?
C02Me /
C02Me
But02C
"'zc
0 CO,Me
Q (411
0
(43)
(42)
COzMe
General and Synthetic Methods
556
175’C
LHMDS T f 2 NPh
(?”
steps
A OMe
m-
(491 18 - cr o w n - 6 KH
i
steps
A OMe
(51)
(50)
I
557
9: Highlights in Total Synthesis of Natural Products
r i n g e x p a n s i o n m e t h o d o l o g y , W e n d e r a n d Holt18 h a v e d e s c r i b e d a n e a t s y n t h e s i s of (3Z-)-cembrene A ( 5 1 ) which u s e s t h e c e n t r a l s t e p (49) -.
(50). D e s c r i p t i o n s o f t h e t o t a l s y n t h e s e s o f t h e two demanding targets
r e t i g e r a n i c a c i d (551, found i n v a r i o u s l i c h e n s , and s t e r e p o l i d e ( 5 8 1 , a m e t a b o l i t e of t h e f u n g u s Stereum purpureum which is a c a u s e o f t h e s i l v e r l e a f d i s e a s e , make w o r t h w h i l e r e a d i n g .
Corey’s syn-
t h e s i s of r e t i g e r a n i c a c i d f e a t u r e s , amongst o t h e r t h i n g s , t h e
-
-
annulation reaction (52) ( 5 3 ) and t h e r i n g e x p a n s i o n ( 5 3 ) ( 5 4 ) , I’ a n d T r o s t ‘ s a p p r o a c h t o s t e r e p o l i d e i n e v i t a b l y h i g h l i g h t s some i n t e r e s t i n g p a l l a d i u m - m e d i a t e d (56)
-
c y c l i z a t i o n c h e m i s t r y , e.g.
(57).20 2 Steroids
The i n t r a m o l e c u l a r D i e l s - A l d e r
r e a c t i o n continues t o dominate the
developments i n s t e r o i d synthesis.
T h u s , De C l e r c q e t a 1 . ”
have
p u b l i s h e d f u l l d e t a i l s o f t h e i r e l e g a n t s y n t h e s i s of a d r e n o s t e r o n e (60) which f e a t u r e s t h e high-yielding s t e r e o s e l e c t i v e i n t r a molecular Diels-Alder OC,
r e a c t i o n o f t h e f u r a n d i e n e ( 5 9 ) i n water ( 2 5
0.5 h ) a s a k e y s t e p .
described a step-wise
I n a d d i t i o n Kametani e t al.2T-have
s y n t h e s i s of
A’-progesterone
(62) which u s e s
t h e i n t r a m o l e c u l a r c y c l o a d d i t i o n of a n 2 - q u i n o d i m e t h a n e g e n e r a t e d i n s i t u from t h e r m o l y s i s of t h e benzocyclobutene ( 6 1 ) . I n an e n a n t i o s p e c i f i c s y n t h e s i s of (-)-oestrone (65) from
(+I-
c a m p h o r H u t c h i n s o n a n d Moneyz3 h a v e u s e d t h e r i n g c l e a v a g e o f 9 , l O dibromocamphor ( 6 3 ) t o t h e hydroxy-acid
(64) a s a c e n t r a l s t e p .
3 A n t h r a c y c l i n o n e s and Naphthaquinones The e n o r m o u s power o f chromium c a r b e n e c h e m i s t r y f o r t h e cons t r u c t i o n o f h i g h l y s u b s t i t u t e d q u i n o n e s h a s b e e n r e c o g n i z e d by a number o f g r o u p s t h i s y e a r , a n d has l e d t o t h e p u b l i c a t i o n o f s e v e r a l e l e g a n t s y n t h e s e s of quinone and hydroquinone n a t u r a l products.
Thus, i n a s y n t h e s i s of k h e l l i n (701, f o r example, t h e
r e a c t i o n between t h e f u r a n chromium c a r b e n e ( 6 6 ) and t h e a c e t y l e n e ( 6 7 ) g a v e t h e p r o t e c t e d h y d r o q u i n o n e ( 6 8 ) i n 43% y i e l d a n d i n a t o t a l l y r e g i o s p e c i f i c menner ( p r o b a b l y due t o t h e s t e r i c b u l k o f t h e s i l y l p r o t e c t i n g g r o u p f a v o u r i n g a t t a c k by t h e c a r b e n e c a r b o n a t o m a t t h e e t h o x y e n d of t h e a c e t y l e n e ) . The s y n t h e s i s o f ( 7 0 ) f r o m ( 6 8 ) was t h e n c o m p l e t e d via ( 6 9 ) i n a f u r t h e r f i v e s t e p s . 2 4
General and Synthetic Methods
558
(COCL 12
+base
H ozc& -
Reagents :
I ,
(521
1531
(55)
(54)
C u ( 0 T f 12 ; 1 1 1 , NaIOL ; IV , ALHg ; v , H2,Pd/C ; v l , NaOMe; , C a t e c h o l B H 2 ; v i i ~ , O s O ~ , P b ( O A c )I X~ ,; aldolizatlon;x,NaOCl
L I CH2CH(SMeI2 ; 1 1
vil,TsNHNH*
(58)
R'= P M B ; R = Si M e p u t
559
9: Highlights in Total Synthesis of Natural Products
H2 P d I B a SOL
0 steps
H 0'
General and Synthetic Methods
560
I
OMe
OE t
(661
(67)
t
OEt
0 Me
OMe 0
0 Me
(68)
OMe
Me0
Me0
Cr(CO),
+ n OH
(711
(72)
J
-'wTy$ (731
Me0
\
0
0
C02Me
0
'1COzH
9: Highlights in Total Synthesis of Natural Products
561
An alternative method for overcoming the lack of regio-control often exhibited by the chromium carbene reaction is illustrated by a synthesis of deoxyfrenolicin (771, which uses an intramolecular version of it. This reaction relies on the anhydride-like reactivity of acetoxymethylidenechromium complexes, which allows the replacement of acetoxy in the 2-bromoanisole-derived carbene ( 7 1 ) with the glycol derivative ( 7 2 ) to give ( 7 3 ) which, after warming and oxidative decomplexation, leads to the quinone ( 7 4 ) . The second key step in the synthesis is another organometallic reaction, a palladium-promoted alkoxycarbonylation, which both closes the pyran ring and introduces the methoxycarbonyl group to give (76) from (75). The synthesis was then completed by deprotection of the ester and phenol f u n c t i o n a l i t i e ~ . ~ ~ Also of interest is an application of chromium carbene chemistry tc the preparation of an anthracyclinone BCD ring synthon (Scheme 26 2). A recent synthesis of (+)-averufin (86) and (+)-nidurufin (841, two Aspergillus metabolites and potential biosynthetic precursors of aflatoxin B.,, uses a double Diels-Alder reaction between the quinone (78) and the diene (79) to give the key precursor 1,3,6,8tetrahydroxyanthraquinone (80).27 Protection and elaboration of (80) by a Claisen rearrangement followed by a chloro-selenation oxidative elimination process then gave the allylic chloride (81). Condensation between ( 8 1 ) and t-butyl acetoacetate next led to (821, the key intermediate f o r both syntheses. Thus, (')-nidurufin (84) was prepared by epoxidation of (821, followed by treatment of the resulting epoxide ( 8 3 ) with aqueous acid to effect deprotection, de-butoxycarbonylation, and cyclization to the natural product. Related procedures gave the epimer (85) and (')-averufin (86), all from the one pivotal intermediate (82). A Japanese research group has published syntheses of the natural products nanaomycin D (93) and its enantiomer kalafungin (941, in an enantiodivergent approach from the common intermediate (90). 28 Thus, lithium t-butoxide mediated condensation between the sulphone ( 8 7 ) and the L-rhamnose derived enone (88) first gave the hydroquinone (89) in 80% yield. After conversion into (go), treatment with e t h o x y c a r b o n y l m e t h y l e n e t r i p h e n y l p h o s p h o r a n e then gave a mixt u r e of the lactone (91) and the epimeric ester (921, which served a s precursors for (-)-nanaomycin D (93) and (+)-kalafungin (94) respectively.
General and Synthetic Methods
562
OMe
OMe
OMe
.1 OMe
OH
Scheme
MOMO
0
OMe
2
OMOM (81)
MOMO
0
OMOM
(83)
(84)
OH
563
9: Highlights in Total Synthesis of Natural Products
Hog \
HO
I
0
0
6H
(85)
(861
N
WO OMe OH
+
QOMe-*
0 Ph
Me
0 OH
0
OMe
Me
OMe
OH
Me 0
Me0 '0
(93)
Me0
(91)
OH
w
Me0
t
\
Me0
/
Me0
0
Me
OH
'1
CO, Et
564
General and Synthetic Methods 4 Alkaloids
K i s h i a n d h i s g r o u p h a v e now a c h i e v e d t h e s y n t h e s i s o f t h e f r o g neurotoxin h i s t r i o n i c o t o x i n ( 9 6 ) , perhaps t h e most sought after a l k a l o i d o f r e c e n t years.*'
The s y n t h e s i s , which i s t h e c u l m i n a t i o n o f s e v e r a l y e a r s work o n t h i s class o f n a t u r a l p r o d u c t s , u s e s
(95), a compound p r e p a r e d o r i g i n a l l y f o r t h e s y n t h e s i s o f p e r h y d r o a n d octahydro-histrionicotoxin, a s t h e k e y p r e c u r s o r . A s mentioned i n an earlier s e c t i o n i n t h i s Report, free-radical
carbon-carbon bond-forming p r o c e s s e s are becoming i n c r e a s i n g l y important i n s y n t h e s i s , and t h i s y e a r t h e y have proved themselves particularly useful for the synthesis of pyrrolizidine alkaloids. T h u s , Hart a n d h i s g r o u p h a v e now a p p l i e d t h e i r i n t r a m o l e c u l a r t i n hydride generated u-acylamino r a d i c a l t o alkyne c y c l i z a t i o n
[G.
(97)
(991,
- (98)l
and t o t h e s y n t h e s i s o f (-)-dehydrohastanecine
( + I - h e l i o t r i d e n e (100)
,
and (+)-hastanecine
free r a d i c a l in'mechanism'is
( 1 0 1 .30
In addition,
t h e photochemical c y c l i z a t i o n of t h e
N-acylpyrrolidine (102) t o t h e p y r r o l i z i d e n e (1031, a key i n t e r mediate i n a s y n t h e s i s of ( 5 ) - i s o r e t r o n e c a n o l (104). A synthesis of
(5)-isofumigaclavine B (107) and ( * ) - l y s e r g i c
acid (108) a l s o u s e s a photochemical c y c l i z a t i o n t o a r r i v e a t a p i v o t a l i n t e r m e d i a t e . 32
T h u s , i r r a d i a t i o n of t h e e n a m i d e ( 105) i n
t h e p r e s e n c e of e x c e s s s o d i u m b o r o h y d r i d e w i t h a h i g h - p r e s s u r e m e r c u r y l a m p g a v e ( 1 0 6 ) a l o n g w i t h a t o t a l o f a b o u t 30% of t w o other diastereomers. The D i e l s - A l d e r
r e a c t i o n is unquestionably t h e pre-eminent peri-
c y c l i c r e a c t i o n i n o r g a n i c s y n t h e s i s , and t h i s y e a r h a s been applied t o t h e synthesis of i l l i c i o l i n H (114).33
Thus, t h e diene-
e n a l ( 1 1 0 1 , w h i c h was p r e p a r e d i n t w e l v e s t e p s f r o m c i t r o n e l l o l
a c e t a t e ( l o g ) , was c o n d e n s e d w i t h t h e a c y l p y r i d o n e ( I l l ) , a comp o u n d p r e v i o u s l y p r e p a r e d a s a n i n t e r m e d i a t e i n t h e s y n t h e s i s of t e n e l l i n , t o g i v e t h e polyene (112).
Refluxing (112) i n chloro-
b e n z e n e for 5 m i n u t e s e f f e c t e d t h e i n t r a m o l e c u l a r D i e l s - A l d e r r e a c t i o n t o g i v e ( 1 1 3 1 , a l o n g w i t h a b o u t 20% o f t h e k e t o n e c o n jugated t o o c t a l i n isomer, which only r e q u i r e d d e p r o t e c t i o n t o complete t h e synthesis. A hetero-Diels-Alder
r e a c t i o n between t h e imine (115) and t h e
cyclohexadiene (116) produces t h e aza-bicyclo-octane after Baeyer-Villiger
(1171, which
r i n g e x p a n s i o n f o l l o w e d by r e d u c t i o n , g a v e
t h e t r i o 1 ( 1 1 8 ) , an advanced i n t e r m e d i a t e w i t h a l l t h r e e c h i r a l c e n t r e s i n t h e i r c o r r e c t r e l a t i v e stereochemistry, for t h e synthe-
565
9: Highlights in Total Synthesis of Natural Products
Me-S i
"aHotEH
&OH
doH(25 HO
( 1041
(1031
CO,Me
566
General and Synthetic Methods
$ vNMe \
+
BzN (105)
Bz
'
/
(106)
Me
e :&
HN ( 1 07)
(109)
(110)
+
G I
I
I
OBn (112)
(111 1
(1131
(114)
O\
I
Ph
Bn 0
OBn
9: Highlights in Total Synthesis of Natural Products
&
OSiMe3
+
iHCOzMe
567
A-
TSHN
C02Me
OH OH
Ts Ts
(119)
(120)
- p ‘\I 0
(121)
(124)
C02Me
(123)
568
General and Synthetic Methods
sis o f ('1-isoprosopinine
B (119) and (2)-desoxoprosopinine
(1201 .34 A synthesis of t h e frog neurotoxin
t h e intramolecular Diels-Alder
(2)-gephyrotoxin
(124) uses
reaction of an a c y l nitroso-
c o m p o u n d , g e n e r a t e d by i n s i t u p e r i o d a t e o x i d a t i o n o f t h e h y d r o x a -
mic a c i d ( 1 2 1 ) , t o f o r m t h e p i p e r i d i n e p o r t i o r , ( 1 2 2 ) o f t h e m o l e cule.
After i n t r o d u c t i o n of t h e propyl r e s i d u e , reduction and
p r o t e c t i o n t o ( l 2 3 ) , t h e s y n t h e s i s was c o m p l e t e d b y h y d r o g e n a t i o n over palladium-charcoal
which removes t h e n i t r o g e n p r o t e c t i n g group
allowing t h e c y c l i z a t i o n t o t h e n a t u r a l product (124) t o occur.35 Except f o r t h e c o n s t r u c t i o n o f i s o p r e n y l aromatic n a t u r a l p r o d u c t s , t h e C l a i s e n rearrangement o f a l l y l phenyl e t h e r s h a s been r e l a t i v e l y l i t t l e exploited i n natural product synthesis.
The
p o t e n t i a l v a l u e o f t h e r e a c t i o n , h o w e v e r , h a s now b e e n d e m o n s t r a t e d i n a synthesis of
( & ) - l a t i f i n e ( 1 2 8 ) .36
e t h e r ( 1 2 5 ) was f o u n d t o r e - a r r a n g e
Thus, t h e a l l y l phenol
s m o o t h l y i n r e f l u x i n g N,N-
d i m e t h y l a n i l i n e t o g i v e ( 1 2 6 ) i n 7 5 % y i e l d , w h i c h was t h e n e l a b o rated t o the natural product
via
t h e amine (127) i n a f u r t h e r seven
steps. A key s t e p i n a s y n t h e s i s o f t h e c a r b a z o l e a l k a l o i d murraya-
quinone-B
(132) is t h e concomitant i n d o l e r i n g formation and regio-
s e l e c t i v e C l a i s e n r e a r r a n g e m e n t f'rom t h e a z i d e ( 1 2 9 ) , w h i c h o n t h e r m o l y s i s i n t o l u e n e g a v e t h e 6 - h y d r o x y i n d o l e ( 1 3 0 ) i n 53% y i e l d . 37
B e n z o a n u l a t i o n t o form t h e c a r b a z o l e ( 131
and photo-
chemical oxidation then completed t h e s y n t h e s i s . The i n t r a m o l e c u l a r 1 , 3 - d i p o l a r c y c l o a d d i t i o n o f a n i t r o n e h a s been used t o assemble t h e carbon s k e l e t o n o f t h e unusual g u a n i d i n e natural product (-)-ptilocaulin aldehyde (134), prepared
( 137).
38
Thus, treatment of t h e
(133) from 3-methylcyclohexanone,
with
b e n z y l h y d r o x y l a m i n e i n r e f l u x i n g benzene g a v e d i r e c t l y i n 80% y i e l d t h e isoxazolidine (135).
A f t e r a d j u s t m e n t of t h e f u n c t i o n a l i t y t o
( 1 3 6 1 , t h e s y n t h e s i s was t h e n c o m p l e t e d i n r e m a r k a b l y h i g h y i e l d by thermolysis of
( 1 3 6 ) w i t h t h e g u a n i d i n e d e r i v a t i v e (138) a t 150
t o give (-)-ptilocaulin
OC
i n i s o l a t e d y i e l d s of 58-65%.
T h e e n o r m o u s v a l u e of t h e i n t r a m o l e c u l a r n i t r i l e o x i d e c y c l o a d d i t i o n (INOC) r e a c t i o n h a s b e e n f u r t h e r d e m o n s t r a t e d by two s y n t h e s e s from Kozikowski and h i s g r o u p .
I n one s y n t h e s i s , t h a t of
( + ) - s i b i r i n e ( 1 4 1 ) (Scheme 3 ) , 3 9 t h e r e a c t i o n i s u s e d t o f o r m t h e s p i r o c y c l e ( 1 4 0 ) i n a m o d e s t 30% y i e l d , a y i e l d t h a t i s p e r h a p s t o b e r e g a r d e d a s r e m a r k a b l y h i g h when d u e a c c o u n t i s t a k e n o f t h e u n f a v o u r a b l e r e g i o - d i r e c t i n g c h a r a c t e r o f t h e double bond a n d t h e
569
9: Highlights in Total Synthesis of Natural Products
OBn
A
OH
OBn
C0,Me
-
HO P
(1291
O
M0
e
(130)
0 Me
Me
Me0
N
Me0
H
0
OMe
General and Synthetic Methods
570
( 133)
1
(135)
I NH
H (1381
( 1 37)
I 1 ,111
1
Cbz
(139)
l
y
Lbz
OH
(1401
I Me (1411 Reagents:
I,
NaOCl;
11,
H2
, Raney
N I ; I I I , H S ( C H ~ ) ~ S,8F3.Et,0; H
-
wi
v i
I
Reagents :
I
NaOCL,Et3N; ii, 9 s t e p s ;
I
0 J-0
CO, E t III
,NaOAc
--OH
0- ’ ; :1
11
C0,Et I,
Bu3SnH,AIBN
Scheme 3
OH
C0,Et
IV,
(142) AcOH;
Scheme 4
(143) IV,
NaOMe
57 1
9: Highlights in Total Synthesis of Natural Products
s e r i o u s non-bonded i n t e r a c t i o n s p r e s e n t i n t h e t r a n s i t i o n s t a t e . The s e c o n d e x a m p l e , a s y n t h e s i s o f ( + ) - s t r e p t a z o l i n ( 1 4 3 ) , ( S c h e m e 4 ) , 4 0 is l e s s remarkable f o r its use of the INOC reaction than i n t h e e l e g a n c e w i t h which t h e carbamate moiety of t h e n a t u r a l product
is c o n s t r u c t e d u s i n g r e a g e n t s which i n d i l u t e s o l u t i o n a l l o w chara c t e r i z a t i o n by p r o t o n n . m . r . o f a n o t h e r w i s e h i g h l y u n s t a b l e
molecule. Thus, t r e a t m e n t o f t h e e p o x i d e ( 1 4 2 ) w i t h sodium a c e t a t e i n a c e t i c a c i d g a v e a 71% y i e l d o f t h e c o r r e s p o n d i n g a l l y l i c acetate a l c o h o l which, a f t e r HPLC s e p a r a t i o n o f t h e r e q u i r e d
2-
i s o m e r , was t r e a t e d w i t h m e t h a n o l i c s o d i u m m e t h o x i d e t o e f f e c t b o t h a c e t a t e c l e a v a g e and carbamate r i n g c l o s u r e t o g i v e t h e n a t u r a l product (143). Meyers and h i s g r o u p have developed a s h o r t e n a n t i o s e l e c t i v e r o u t e t o ( f ) - m e t a z o c i n e ( 1 4 6 ) b a s e d on t h e a s y m m e t r i c a l k y l a t i o n o f T h u s , d e p r o t o n a t i o n o f ( 1 4 4 ) w i t h n-
t h e c h i r a l formamide (144) .41 butyl-lithium
a t - 7 8 OC a n d t r e a t m e n t w i t h a n e x c e s s o f p - m e t h o x y -
benzyl c h l o r i d e gave, a f t e r d e p r o t e c t i o n ,
t h e 2-benzyltetrahydt-o-
p y r i d i n e ( 1 4 5 ) o f g r e a t e r t h a n 98% e n a n t i o m e r i c p u r i t y a l o n g w i t h a b o u t 30% o f t h e 4 - b e n z y l i s o m e r . Reductive methylation of (145) f o l l o w e d by t r e a t m e n t w i t h h y d r o g e n b r o m i d e , t o e f f e c t b o t h c y c l i z a t i o n and phenol d e p r o t e c t i o n , completed t h e s y n t h e s i s . A r e c e n t s y n t h e s i s o f t h e sea s p o n g e m e t a b o l i t e a n d a - a d r e n o -
r e c e p t o r b l o c k e r a a p t a m i n e ( 1 4 8 ) i s s u m m a r i z e d i n Scheme 5.'*
-
The
f i n a l cyclization s t e p (147) (148) a l s o y i e l d s an approximately e q u a l q u a n t i t y of t h e a l t e r n a t i v e c y c l i z a t i o n product (149) showing how f i n e l y b a l a n c e d a r e t h e o p p o s i n g f a c t o r s o f t h e r e l a t i v e l y m o r e electron-rich
c a r b o c y c l i c r i n g ( f a v o u r i n g a a p t a m i n e ) and t h e e n t r o -
p i c f a c t o r s f a v o u r i n g f i v e - o v e r six-membered r i n g f o r m a t i o n [favouring (149)l. An u n u s u a l c y c l i z a t i o n o f a q u i n o n e i m i d e h a s p r o v i d e d t h e k e y s t e p i n a s y n t h e s i s o f n e c a t o r o n e ( 1 5 3 ) . ~ A~ e r i a l o x i d a t i o n o f t h e
p-hydroxyaniline d e r i v a t i v e ( 1 5 1 ) , prepared i n f o u r s t e p s from t h e a m i d e ( 1 5 0 ) , i n a l k a l i n e s o l u t i o n g a v e t h e n a t u r a l p r o d u c t via t h e p r e s u m e d i n t e r m e d i a t e ( 1 5 2 ) i n a y i e l d t h a t was s t r o n g l y d e p e n d e n t on s c a l e b u t c o u l d b e a s h i g h a s 67%. A rather different phenolic oxidation,
t h a t o f t h e oxime ( 1 5 4 )
with thallium(II1) trifluroacetate t o give the isoxazole (155), f o l l o w e d by z i n c b o r o h y d r i d e r e d u c t i o n , h a s b e e n u s e d t o g i v e ( 1 5 6 ) w h i c h i s a v e r s a t i l e i n t e r m e d i a t e f o r t h e s y n t h e s i s of t h e s p o n g e metabolites (+I-aerothionin 44 (+)-aerophobin-I (158).
(157a), (*)-homoaerothionin
( 1 5 7 b ) , and
General and Synthetic Methods
5 72
Q
MeN
Me Me
OMe
'
(1441
( 145)
M eO
NHZ
M eO OMe
OMe
I
3.
eh(0Me12
Ill
]
IV
Me0
I'
g@
Me0 OMe
OMe
Me0
H
Me0
OMe
OMe
(1481 Reagents : i,
BunLi
(149)
t h e n Me3SiCH2N3 ; ii, HC-CCO2Me,
v, CF3 S03H, S b F 5 , CF3C02H
Scheme 5
A;iii,POC13; ivJH2NCH2CH(OMd2;
9: Highlights in Total Synthesis of Natural Products
573
CO, Me
CO;,Me
I
N
'
Br
Br
Br
Br
OMe
OMe (
I
Me
d
-
0
OMe ( 1 56 1
(155)
15d) 0
OMe (1 58)
574
General and Synthetic Methods
The a n t i l e u k a e m i c a l k a l o i d ( f ) - s e s b a n i n e ( 1 6 2 ) c o n t i n u e s t o a t t r a c t s y n t h e t i c a t t e n t i o n , and t h i s y e a r h a s s e e n t h e p u b l i c a t i o n of a remarkably high-yielding
s y n t h e s i s (40% o v e r a l l ) .
In this
synthesis, introduction of the quaternary carbon substituent t o the 4-position
o f t h e p y r i d i n e was a c h i e v e d by c o n d e n s a t i o n o f t h e
ketene s i l y l a c e t a l (160) with t h e pyridinium salt (159) t o give t h e d i h y d r o p y r i d i n e ( 1 6 1 .45
Rearomatization w i t h DDQ, s t e r e o -
s p e c i f i c o x y m e r c u r a t i o n w i t h a b o r o h y d r i d e work-up,
and t r e a t m e n t
w i t h ammonia t o f o r m t h e i m i d e t h e n c o m p l e t e d t h e s y n t h e s i s . T h e r m o l y s i s of t h e o x a z o l i n o n e ( 1 6 4 1 , which i s p r e p a r e d i n s i x s t e p s from t h e i n d o l e ( 1 6 3 ) , i n chlorobenzene l e a d s t o decarboxyla t i o n and t h e a l l e n e ( 1 6 5 ) .
Tautomerization of
(165) t o (166)
f o l l o w e d by e l e c t r o c y c l i c r i n g c l o s u r e t h e n l e a d s t o t h e o r t h o q u i n o n e ( 1 6 7 ) which o n l y r e q u i r e s h y d r o l y s i s of t h e t h r e e e s t e r f u n c t i o n a l i t i e s t o complete a s y n t h e s i s of m e t h o x a t i n ( 1 6 8 ) ) a co46 f a c t o r f o r methanol dehydrogenase i n methylotrophic b a c t e r i a . Other a l k a l o i d syntheses of note include (& )-anatoxin (-)-paspaline
a ( I 6 9 ) ,4 7
( 1 7 0 ) , 4 8 a n d ( f ) - q u i n o c a r c i n o l m e t h y l e s t e r ( 1 7 1 ) . 49
5 P r o s t a g l a n d i n s and Thromboxanes N o y o r i a n d h i s c o - w ~ r k e r s h~a ~ v e now d e s c r i b e d t h e s h o r t e s t r o u t e yet to prostaglandins. neat
'one-pot'
T h e i r r o u t e i s based on t h e c o n c e p t u a l l y
conjugate addition of the 8-side-chain
oxygenated cyclopent-2-enone,
to a
4-
f o l l o w e d by t r a p p i n g o f t h e r e g i o -
chemically defined enolate with t h e a-side-chain.
This h a s been a
much s o u g h t a f t e r a p p r o a c h , a n d i t s s u c c e s s l i e s s i m p l y i n l i t h i u m
(or c o p p e r ) t o t i n t r a n s m e t a l l a t i o n a t t h e c r u c i a l e n o l a t e s t a g e . Thus, c o n j u g a t e a d d i t i o n o f t h e o r g a n o c u p r a t e r e a g e n t d e r i v e d from t h e v i n y l b r o m i d e ( 1 7 2 ) t o t h e c h i r a l e n o n e ( 1 7 3 1 , f o l l o w e d by treatment of t h e r e s u l t i n g enolate (174a) with t r i p h e r y l t i n chlor i d e [producing (174b)l and t h e a l l y l i c i o d i d e (175) a f f o r d s stereoselectively
t h e PGEl d e r i v a t i v e
( 1 7 6 ) i n 78% y i e l d .
T h e b i c y c l i c o x e t a n e s t r u c t u r e ( 1 8 2 ) p r o p o s e d for t h e u n s t a b l e s u b s t a n c e thromboxane A2
(TXA2) ( t g . 3 2
prostaglandin endoperoxide,
s a t 37
OC)
d e r i v e d from
and which is an important blood p l a t e -
l e t a g g r e g a t i o n f a c t o r , h a s now b e e n c o n f i r m e d b y ~ y n t h e s i s . ~ ' ( 1 7 7 ) was f i r s t c o n v e r t e d i n t o t h e 1 , 1 5 -
T h u s , t h r o m b c x a n e B2
m a c r o l i d e ( 1 7 8 ) w h i c h , a f t e r d e h y d r a t i o n t o ( 1 7 9 ) , was e l a b o r a t e d i n t o t h e bromohydrin ( 1 8 0 ) .
A modified Mitsunobu r e a c t i o n w i t h
( 1 8 0 ) n e x t p r o d u c e d t h e 1 0 - b r o m o t h r o m b o x a n e A2 d e r i v a t i v e ( 1 8 1 a )
575
9: Highlights in Total Synthesis of Natural Products
OMe Me0 (161 1
CO, E t
(1631
(165)
(1641
1 C02R'
-
I
CO, R 2 0 ( 1 6 7 ) R 1 =E t , R2=Me ( 168) R ' = R 2 = H
C 0 2 Et I
-i
HO (1661
General and Synthetic Methods
576
(170 1
(169)
02Me
OM
I
OR
I
OR (172)
OR
OR
(17L) a ; M = L i / Cu
(173)
b; M = SnPh,
0
CO, Me
-1
C0,Me I
OR
(1 75)
I
OR ( 1 7 6 ) R = SiMe2But
9: Highlights in Total Synthesis of Natural Products
577
?H
HO
HO
OH
53
(177)
(178)
eH
s7
OH I
0
(179)
I
OH 1181) a ; X = B r b;X=H
OH I
(182)
General and Synthetic Methods
578
w h i c h on r e d u c t i o n w i t h t r i b u t y l t i n h y d r i d e c l e a n l y p r o d u c e d t h e 1,15-anhydro-TXA2
(181b).
When ( 1 8 1 b ) i s d i s s o l v e d i n 1 : l M e O D - D 2 0
c o n t a i n i n g t e n e q u i v a l e n t s o f NaOD, it is s a p o n i f i e d t o y i e l d t h e s o d i u m s a l t o f TXA2 ( 1 8 2 ) . The l i p o x i n s are a s e r i e s o f newly d i s c o v e r e d , b i o l o g i c a l l y a c t i v e c o m p o u n d s f o r m e d from a r a c h i d o n i c a c i d i r human l e u k o c y t e s . Owing t o t h e i r b i o l o g i c a l i m p o r t a n c e a n d d o u b t s c o n c e r n i n g t h e i r s t e r e o c h e m i s t r i e s , t h e r e s e a r c h g r o u p s l e d by c 0 1 - e ~ a n~d ~b y N i c ~ l a o uh a~v~e now c a r r i e d o u t some i n t e r e s t i n g s y n t h e t i c w o r k which c o n f i r m s t h e s t e r e o s t r u c t u r e s shown i n f o r m u l a e ( 1 8 3 ) a n d ( 1 8 4 ) for l i p o x i n A a n d l i p o x i n B r e s p e c t i v e l y .
6 Spiroacetals A n u m b e r o f new a n d i n t e r e s t i n g a p p r o a c h e s t o t h e s p i r o a c e t a l
s e g m e n t of t h e a n t i p a r a s i t i c m a c r o c y c l i c m i l b e m y c i n s h a v e b e e n putlished during t h e period under review.
Thus, i n one approach,
K o c i e n s k i a n d h i s c o - ~ o r k e r sh~a v~e d e s c r i b e d t h e n o v e l i n t r a m o l e c u l a r Lewis a c i d c a t a l y s e d d i r e c t e d a l d o l r e a c t i o n o f t h e spiroc y c l i c o r t h o l a c t o n e ( 1 8 7 ) p r e p a r e d from t h e f r a g m e n t s ( 1 8 5 ) a n d (186), t o set up t h e spiro-acetal portion (188).
Milbemycin B
3
( 1 8 9 ) was t h e n s e c u r e d f r o m ( 1 8 8 ) b y s e q u e n t i a l s u l p h o n e - b a s e d ( J u l i a ) o l e f i n a t i o n r e a c t i o n s t o produce t h e double bonds a t CIOC11 a n d C l 4 - C I 5 .
I n a n a l t e r n a t i v e a p p r o a c h , b y t h e same r e s e a r c h
g r o u p 155 t h e c e n t r a l s p i r o - a c e t a l i n t e r m e d i a t e ( 1 9 3 ) was e l a b o r a t e d by m e t a l l a t i o n o f 3 , 4 - d i h y d r o - 2 H - p y r a n
( 1 9 0 ) , f o l l o w e d by a d d i t i o n
o f t h e o x i r a n e ( I g l ) , and c y c l i z a t i o n o f t h e r e s u l t i n g 1 , 3 - d i o l d e r i v a t i v e (192) i n t h e presence of camphorsulphonic acid. spiro-acetal
The
( 1 9 3 ) was t h e n c o n v e r t e d i n t o t h e a l d e h y d e ( 1 9 4 ) , a n
i n t e r m e d i a t e u s e d i n S m i t h ' s e a r l i e r d e s c r i b e d s y n t h e s i s of m i l b e mycin B
3'
I n a n a l t e r n a t i v e s y n t h e s i s of
(+)-milbemycin B3,
have applied t h e i r previously described s p i r o - a c e t a l
Baker e t al.56 intermediate
( 1 9 5 ) p r e p z r e d from l a e v o g l u c o s a n , i n c o m b i n a t i o n w i t h t h e u n i t s ( 1 9 6 ) a n d ( 1 9 8 ) , a n d made u s e o f v i n y l - l i t h i u m
t o aldehyde [ t o
( 1 9 7 ) l and s u l p h o n e - a l d e h y d e [ t o ( 1 9 9 ) l c o u p l i n g r e a c t i o n s t o p r o d u c e i m p o r t a n t C-C mycins,
e.( 2 0 3 ) ,
bonds.
T h e C 1 1 t o C25 f r a g m e n t o f t h e m i l b e -
which i n c o r p o r a t e s t h e important s p i r o - a c e t a l
u n i t , h a s a l s o b e e n s y n t h e s i z e d by L e y e t a 1 . , 5 7 who h a v e a p p l i e d t k e c y c l i c e t h e r phosphonium s a l t ( 2 0 2 ) , p r e p a r e d from ( 2 0 0 ) and (2011,
as a c e n t r a l precursor.
9: Highlights in Total Synthesis of Natural Products
/OH
I'c(185)
579
rw y 1.c-
5 80
OSi Ph2But
General and Synthetic Methods
\
SPh
SPh
O S i Ph,But
CO,Me
OMe
v:1
mlO S i Ph2But
Ph
OMe (199)
OCH2 Ph ( 2 0 11
(200)
'2 ,
PPh 6FL- AcO
0 SiPhZBut
OCH2 Ph
- # ,
0 Si Ph, But
OCH2Ph
581
9: Highlights in Total Synthesis of Natural Products
B o t h F r a ~ e r - R e i d a~n d~ K o ~ i k o w s k ih~a v~ e p u b l i s h e d d e t a i l s o f t h e i r i n d e p e n d e n t work u s i n g a n i n t r a m o l e c u l a r n i t r i l e o x i d e c y c l o a d d i t i o n a p p r o a c h t o t h e oxahydrindene component ( 2 0 4 ) o f t h e avermectins. The s y n t h e t i c a l l y d e m a n d i n g d i o x a b i c y c l o n o n a n e u n i t f o u n d i n t i r a n d a m y c i n A ( 2 0 5 ) h a s p r o v e d t o be a p o p u l a r t a r g e t , w i t h t h e p u b l i c a t i o n of t h r e e a p p r c a c h e s d u r i n g t h e p e r i o d o f t h e R e p o r t , a l l of w h i c h a r e w o r t h y o f c l o s e s t u d y . 6 0
7 Sugars The h e t e r o - D i e l s - A l d e r
r e a c t i o n c o n t i n u e s t o be t h e r e a c t i o n of
c h o i c e f o r t h e s y n t h e s i s of s u g a r s from non-carbohydrate
precursors. T h i s y e a r W e i n r e b a n d h i s g r o u p h a v e a p p l i e d t h e i r s u l p h i n y l d i e n o p h i l e a p p r o a c h t o t h e s y n t h e s i s o f 3-deoxy-3methylaminoarabinopyranoside ( 2 1 0 ) , a c o m p o n e n t o f b o t h t h e 5 c h e r i n g a m i n o g l y c o s i d e a n t i b i o t i c 66-40D a n d a l s o o f some g e n t a mycin a n t i b i o t i c s . 6 1 T h u s , t r e a t m e n t of t h e d i e n e ( 2 0 6 ) w i t h
c-
t h i o n y l c h l o r i d e i n p y r i d i n e gave an N-sulphinyl-carbamate underwent d i r e c t l y an i n t r a m o l e c u l a r Diels-Alder
reaction
which
via
the
favoured t r a n s i t i o n s t a t e (207) t o g i v e (208) as an i n s e p a r a b l e 1 5 : l m i x t u r e of s u l p h u r e p i m e r s , b u t w i t h c o m p l e t e c o n t r o l o f a l l other stereocentres.
C l e a v a g e o f t h e N-S bond w i t h p h e n y l m a g n e s i u m
b r o m i d e a n d [ 2 , 3 1 r e a r r a n g e m e n t of t h e r e s u l t i n g s u l p h o x i d e t h e n
I
gave t h e a l l y l i c a l c o h o l (2091, which o n l y r e q u i r e d carbamate r e d u c t i o n , d e b e n z y l a t i o n , a n d o z o n o l y s i s o f t h e d o u b l e bond t o complete t h e synthesis. Danishefsky et peracetyl-a-hikosaminide
have achieved a s y n t h e s i s of a methyl (216), an undecose degradation product of
t h e a n t h e l m i n t i c h i k i z i m y c i n , i n w h i c h u s e i s t w i c e made o f t h e siloxy-diene
aldehyde Diels-Alder
reaction.
Thus, t h e r e a c t i o n
between t h e d i e n e ( 2 1 1 ) and f u r f u r a l w i t h [Eu(fod) 1 c a t a l y s i s 3 l e a d s t o t h e pyrone (212) which, after e l a b o r a t i o n t o (2131, is a g a i n c o n d e n s e d w i t h ( 2 1 1 1 , b u t t h i s t i m e w i t h magnesium b r o m i d e c a t a l y s i s , which c a u s e s a d d i t i o n o f t h e remaining f o u r carbon atoms o f t h e undecose i n a c h e l a t i o n - c o n t r o l l e d exo reaction.
and, notably, a t o p i c a l l y
Elaboration of (215) t o t h e required protected
hikosamine ( 2 1 6 ) t h e n f o l l o w s i n a s t r a i g h t f o r w a r d manner. I n w h a t c a n o n l y be r e g a r d e d a s a m a r a t h o n o f o l i g o s a c c h a r i d e s y n t h e s i s , Nicolaou e t a l . 6 3 have a c h i e v e d a s y n t h e s i s of s i x r h y n c h o s p o r o s i d e s ( 2 1 7 1 , w h i c h a r e members o f a f a m i l y o f f u n g a l
582
General and Synthetic Methods
0 Ph
(206) ( 2 07)
I
\ HO
/
Me0
Ph
o+/
0
H
H
Ph
Me0
\
OTBDMS 0 Bz
(212)
'0
CH20Ac
H
Ac 0
H OAc OAc H
AcNH @OMe OAc
*
( 2 14 )
'0
'O-f-
9: Highlights in Total Synthesis of Natural Products
583
metabolites responsible for scald disease in barley and other grasses. The syntheses are an impressive demonstration of the power of the two-stage activation procedure in which a phenylthioglycoside building block is first converted into a glycosyl fluoride by treatment with NBS-DAST and then, with silver perchlorate mediation, coupled with an unprotected OH in a second phenylthioglycoside. The process is then repeated to build up the required oligomer, with control over the anomeric centre being exercised by appropriate choice of solvent and 0 - 2 protecting group. Interesting syntheses have been reported of Escherichia coli lipid A (218) ,64 of the pseudo-trisaccharide destomycin C (219),65 which as well as a cyclitol fragment contains an unusual spiroorthoester interglycosidic linkage, and of the anthracyclinone sugars daunosamine (220) and acosamine (221). 66
8 Macrolides and IonoDhores Nicolaou and his group have reported this year their syntheses of two members of the elfamycin group of ionophore antibiotics, aurodox (234) and efrotomycin ( 2 2 d 7 These are molecules of impressively high complexity; indeed efrotomycin has a total of 21 chiral centres and 7 geometrical stereosites, all of which are fully controlled in the synthesis. These syntheses, which must surely rank as some of the major synthetic achievements of 1985, are briefly summarized in Schemes 6 and 7. The disaccharide portion of efrotomycin (222) is synthesized by the coupling of the two sugar fragments (230) and (231) prepared from D-allose and L-rhamnose respectively using the two-stage activation method, which Nicolaou has pioneered and which is discussed more fully in the sugars and cyclitols section of this chapter. The other building blocks required in the synthesis are all constructed from achiral precursors. The pyran fragment (225) (goldinonolactone) was derived ultimately from (229) with the chirality being introduced by an asymmetric reduction with a Wilkinson-type catalyst, and by Sharpless epoxidation. The right-hand portion of the molecule was prepared by the coupling of the achiral pyridone Wittig reagent (228), derived from the known pyridone aldehyde (233), with the enal (2271, which was prepared in ten steps from the propargylic alcohol (232) using the Sharpless epoxidation to introduce the chirality. The aglycone aurodox (234), a l s o a natural product, was synthe-
General and Synthetic Methods
584
OH
HO f H&
OH+
HO
H
9
( 2 1 7 ) R’= H , R 2 = O H 1 2 R=OH, R = H n=2-L
0
II HO”’/‘ HO
HO OH
aoH HO
I
MeNH
NHMe
( 2 1 9)
OH
OH
9: Highlights in Total Synthesis of Natural Products
585
s i z e d by t h e d i r e c t c o u p l i n g o f g o l d i n o n o l a c t o n e ( 2 2 5 ) w i t h t h e a m i n e ( 2 2 4 ) . A s i f t h e i r a c h i e v e m e n t s i n t h e f i e l d of e l f a m y c i n a n t i b i o t i c s were n o t e n o u g h , N i c o l a o u a n d h i s g r o u p h a v e a l s o p u b l i s h e d a n a p p r o a c h t o t h e ABC r i n g s y s t e m o f b r e v o t o x i n ( 2 3 5 ) 6 8 and t h e i r f u l l p a p e r d e s c r i b i n g a s y n t h e s i s of t h e i o n o p h o r e a n t i b i o t i c X-14547A ( 2 3 6 ) . 6 9 A novel free-radical
f r a g m e n t a t i o n p r o v i d e s t h e key s t e p i n a
r e c e n t s y n t h e s i s o f b r e f e l d i n A.70
T h u s , t r e a t m e n t o f t h e y-
h y d r o x y s t a n n a n e ( 2 3 9 ) , w h i c h was p r e p a r e d 2 ( 2 3 8 ) f r o m ( 2 3 7 ) i n f i v e s t e p s , with l e a d tetra-acetate i n r e f l u x i n g benzene gave an
82% y i e l d o f t h e k e t o - o l e f i n ( 2 4 0 ) , a r e a c t i o n t h a t c a n b e r e g a r d e d a s t h e r a d i c a l a n a l o g u e of t h e Grob f r a g m e n t a t i o n . T e t r a h y d r o p y r a n h y d r o l y s i s , o x i d a t i o n , and e p i m e r i z a t i o n t h e n gave t h e p r o t e c t e d brefeldin A seco-acid
( 2 4 l ) , a known p r e c u r s o r o f t h e n a t u r a l
product. A Japanese group has published preliminary d e t a i l s of s t r u c t u r a l a n d s y n t h e t i c s t u d i e s on t h e p a t e l l a m i d e g r o u p o f c y c l i c pep-
t i d e s .71
A f t e r a n unambiguous s y n t h e s i s of t h e o r i g i n a l l y proposed
s t r u c t u r e of p a t e l l a m i d e A ( 2 4 2 ) had g i v e n m a t e r i a l n o t i d e n t i c a l w i t h t h e n a t u r a l p r o d u c t , t h e r e v i s e d s t r u c t u r e ( 2 4 3 ) was p r o p o s e d a n d p r o v e d by s y n t h e s i s .
A closely r e l a t e d procedure led t o similar r e v i s i o n of t h e s t r u c t u r e s of p a t e l l a m i d e s B and C . Also
of n o t e i n t h e a r e a of p e p t i d e a n t i b i o t i c s i s a s y n t h e s i s o f a l t h i o m y c i n ( 2 4 4 ) .72 9 Other Natural Products
C i t r e o v i r a l (247)
,
c i t r e o v i r i d i n (2481, and c i t r e o v i r i d i n o l (255)
a r e members o f a b i o g e n e t i c a l l y c o n n e c t e d g r o u p o f p o l y e n e - p y r o n e t e t r a h y d r o f u r a n s p r o d u c e d by P e n i c i l l i u m s p p . , w h o s e s y n t h e s e s h a v e a t t r a c t e d c o n s i d e r a b l e a t t e n t i o n d u r i n g t h e p e r i o d c o v e r e d by t h i s d o f Pattenden74 have T h u s , t h e g r o u p s o f Y a m a m ~ r aa~n ~ Report. d i s c l o s e d a c l o s e l y r e l a t e d r o u t e t o c i t r e o v i r a l (2471, which i s b a s e d on p r e p a r a t i o n o f t h e d i e n e - d i o l i n t e r m e d i a t e ( 2 4 5 1 , f o l l o w e d by e p o x i d a t i o n a n d c y c l i z a t i o n t o t h e s u b s t i t u t e d t e t r a h y d r o f u r a n ( 2 4 6 ) .75
I n two a l t e r n a t i v e a n d c o n c e p t u a l l y d i s t i n c t a p p r o a c h e s
to citreoviral reaction, c z .
,
Williams e t a l . 7 6 h a v e u s e d a n i o d o e t h e r i f i c a t i o n
(249)
-. ( 2 5 0 ) ,
t o elaborate the tetrahydrofuran
i n t e r m e d i a t e ( 2 5 0 ) , whereas S h i z u r i e t a l . 7 7 have used t h e DielsAlder adduct (251) from 2,4-dimethylfuran and a v i n y l c a r b o n a t e as a c e n t r a l p r e c u r s o r t o t h e d i h y d r o f u r a n i n t e r m e d i a t e ( 2 5 2 ) (Scheme
General and Synthetic Methods
586
I "
r O* 0
y;
m Q,
L
0
0
aJ
+
0
9: Highlights in Total Synthesis of Natural Products
587
11'
+ r"
I
I
d
X i
588
General and Synthetic Methods
m<
.CHO H '
/A
0
05
H
H'
011
7
H
H
H
H
Me
he (2351
MOMO--
H (237)
THP
OH
MOMO-H
9: Highlights in Total Synthesis of Natural Products
589
0
0
0
OH
+ - ..&A OH
HO.
C0,Me
H
OH
C0,Me
590
8).
General and Synthetic Methods C i t r e o v i r a l (247) h a s then been used as a b u i l d i n g block f o r
t h e s y n t h e s i s o f c i t r e o v i r i d i n ( 2 4 8 ) , by c o n d e n s a t i o n w i t h t h e p o l y e n e - p y r o n e W i t t i g r e a g e n t ( 2 5 3 1 , a n d a l s o for t h e s y n t h e s i s o f t h e 2,6-dioxabicyclo[3.2.1]octane
u n i t (255) of c i t r o v i r i d i n o l
( 2 5 6 ) , f o l l o w i n g c o n v e r s i o n i n t o t h e e p o x i d e ( 2 5 4 ) and c y c l i z a t i o n a c i d .78 1 7 9
i n t h e p r e s e n c e of t o l u e n e - p - s u l p h o n i c
I n w h a t a m o u n t s t o a b i o m i m e t i c s y n t h e s i s , B a l d w i n e t a1.80 h a v e s h o w n t h a t when e i t h e r t h e t h i o l ( 2 5 7 ) o r , b e t t e r , t h e d i s u l p h i d e ( 2 5 8 ) , i s t r e a t e d w i t h d i o x y g e n or h y d r o g e n p e r o x i d e c a t a l y s e d by i r o n ( I 1 ) i o n , a s c o r b i c a c i d , or ethylenediaminetetra-acetic a c i d , d i r e c t C-S
r i n g c l o s u r e o c c u r s , producing t h e p e n i c i l l i n (259) and
t h e cepham ( 2 6 0 ) . F u l l d e t a i l s o f t h e s y n t h e s i s o f t h e B-lactam a n t i b i o t i c (+Ithienamycin ( 2 6 5 ) , which u s e s t h e r e a c t i o n between t h e x - a l l y l t r i c a r b o n y l i r o n l a c t o n e complex ( 2 6 1 ) and benzylamine, l e a d i n g t o t h e 8-lactam
complex ( 2 6 2 )
,
as a key s t e p , have been d e s c r i b e d . 8 1
On
o x i d a t i o n w i t h Ce(IV), t h e complex (262) a f f o r d e d t h e azetidin-2o n e ( 2 6 3 ) , w h i c h was t h e n c h e m i c a l l y m o d i f i e d t o ( 2 6 4 ) , a k n o w n i n t e r m e d i a t e i n a n e a r l i e r s y n t h e s i s of t h i e n a m y c i n . h a v e now c o m p l e t e d a s y n t h e s i s o f ( + ) - b e n z o y l -
Nakata e t
selenopederic a c i d (266) which they have then used i n combination w i t h t h e p r e v i o u s l y s y n t h e s i z e d a m i d e ( 2 6 7 ) t o e l a b o r a t e (+Ipederin (269).
T h e c o u p l i n g b e t w e e n ( 2 6 6 ) a n d ( 2 6 7 ) was a c h i e v e d
by r e d u c t i o n o f t h e N - a c y l i m i d a t e c h l o r i d e of
(2681, produced from t h e a c i d
( 2 6 6 ) a n d t h e i m i d a t e of
( 2 6 7 ) , i n t h e p r e s e n c e of
sodium borohydride. A s y n t h e s i s of c o m p a c t i n ( 2 7 2 ) h a s been d e s c r i b e d , which u s e s
t h e Wadsworth-Emmonscondensation b e t w e e n ( 2 7 0 ) a n d ( 2 7 1 ) a s a k e y
s t a g e , 8 3 a n d Lee e t a l . 8 4 h a v e o u t l i n e d a n e a t s y n t h e s i s o f t h e unusual n a t u r a l acylcyclopentenedione lucidone (2751, which is based on t h e i n t e r e s t i n g r e a r r a n g e m e n t s (275).
(273)
-
(274) and (274)
+
59 1
9: Highlights in Total Synthesis of Natural Products
MEMO,. steps ----+
<
Ph (2L9)
Reagents :
i J
(250)
12, M e C N ;
VI,
II
NaOH,MeOH;
A C 0, C H N ; 2 5 5
VII
111,
NaIOL,
(247)
t
steps
~v,Na(CN)BH~;v,R~S~Cl,~m~dazole;
,OSOL
Scheme 8
OMe
1
General and Synthetic Methods
592
I
I
I
I
C02H
CO,H
A Ph OMe
O’M e
Me0
(261)
0 Me
(262)
Me0
OMe
v
4 q steps
Ph
(2651
(263)
9: Highlights in Total Synthesis of Natural Products
593
Tco2H bCOPh
1
SePh
0,
COPh (267)
(266) ?Me
0
OMe
p ) L ON C O P/h *
OMe I I
SePh
O'COPh (268) OMe I
Meowph NaOMe
Ac2 0
0
0
(273)
OMS0
Meo$o
Ph
(275)
General and Synthetic Methods
594 References 1. 2.
3. 4. 5. 6. 7. 8. 9. 10 11. 12. 13.
14. 15. 16.
17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.
33. 34. 35. 36.
37. 38.
39. 40.
41. 42. 43. 44. 45. 46. 47.
26,
P.Wender and R.J.Ternansky, Tetrahedron Lett., 1985, 2625. D.D.Sternbach, J.W.Hughes, D.F.Burdi, and B.A.Banks, J. Am. Chem. SOC., 1985, 107,2149. Y .Tobe, T.Yamashita, K.K.Kakiuchi , and Y. Odaira, J. Chem. S O C . , Chem. Commun., 1985, 898. D.F.Taber and J.L.Schuchardt, J. Am. Chem. SOC., 1985, 107,5289. G.Mehta and D-Subrahmanyam, J. Chem. S O C . , Chem. Commun., 1985, 768. B.W.Disanayaka and A.C.Weedon, J. Chem. S O C . , Chem. Commun., 1985, 1282. F.H.Hua, G.Sinai-Zingde, and S.Venkataraman, J. Am. Chem. SOC., 1985, 107, 4088. D.P.Curran and D.M.Rakiewicz, J. Am. Chem. S O C . , 1985, 107, 1448. D.P.Curran and M.-H.Chen, Tetrahedron Lett., 1985, 26, 4991. G.Pattenden and S.J.Teague, Tetrahedron Lett., 1982723, 5471 ; M. Ladlow, G.Pattenden, and S.J.Teague, 1986, 27, 3279. B.B.Snider and Y.S.Kulkarni, Tetrahedron Lett., 1985, 26, 5675. G.Stork and N.H.Baine, Tetrahedron Lett., 1985, 5927. M.Ladlow and G.Pattenden, Tetrahedron Lett., 1985, 4413. P.A.Wender and D.J.Wolanin, J. Org. Chem., 1985, 50, 4418. A.G.Schultz and S.Puig, J. Org. Chem., 1985, 50, 916. 2167. J.E.McMurry and G.K.Bosch, Tetrahedron Lett., 1985, S.L.Schreiber and R.C.Hawley, Tetrahedron Lett., 1985, 5971. P.A.Wender and D.A.Holt, J. Am. Chem. SOC., 1985, 107,7771. E.J.Corey, M.C.Desai, and T.A.Engler, J. Am. Chem. SOC., 1985, 2'7, 4337. B.M.Trost and J.Y.L.Chung, J. Am. Chem. SOC., 1985, 107,4586. 41, 4667. L.A.Van Royer, R.Mijngheer, and P.J.De Clercq, Tetrahedron, 1985, H.Nemoto, M.Negai, K.Fukumoto, and T.Kametani, Tetrahedron Lett., 1985, 6, 4613. J.H.Hutchinson and T.Money, Tetrahedron Lett., 1985, 1819. A.Yamashita, J. Am. Chem. SOC., 1985, 107,5823. M.F.Semmelhack, J.J.Bozel1, L.Keller, T.Sato, E.J.Spiess, W.Wulff, and 5803. A.Zask, Tetrahedron, 1985, 5797. K.H.D'irtz and M.Popal1, Tetrahedron, 1985, G.J.O'Malley, R.A.Murphy, and M.P.Cava, J. Org. Chem., 1985, 50, 5533. K.Tatsuta, K. Akimoto, M. Annaka, Y .Ohno, and M.Kinoshita, Bull. Chem. SOC. Jpn., 1985, 58, 1699. S.C.Carey, M.Aratani, and Y.Kishi, Tetrahedron Lett., 1985, 26, 5887. J.-K.Choi and D.J.Hart, Tetrahedron, 1985, 5, 3959. J.-C.Gramain, R.Remuson, and D.Vallee, J. Org. Chem., 1985, 50, 710. I.Ninomyia, C.Hashimoto, T.Kiguchi, and T.Naito, J. Chem. SOC., Perkin Trans. 1 , 1985, 941. D. R.Williams, M. L .Bremmer , D. L .Brown, and J. D. Antuono, J. Org. Chem., 1985, 50, 2809. A.B. Holmes , J. Thompson, A. J. G .Baxter , and J. Dixon, J. Chem. SOC , Chem. Commun., 1985, 37. H.Iida, Y.Watanabe, and C.Kibayashi, J. Am. Chem. S O C . , 1985, 107,5534. S.Takano, M-Akiyama, and K-Ogasawara, Chem. Lett., 1985, 505; J. Chem.j30c,lPerkin Trans. 1 , 1985, 2447. T.Martin and C.J. Moody, J. Chem S O C . , Chem. Commun., 1985, 1391. ' 1, 3463. A.E.Walts and W.R.Roush, Tetrahiedron, 1985, 1 A.P,Kozikowski and P.-W.Yuen, J. Chem. So(:., Chem. Commun., 1985, 847. A.P.Kozikowski and P.Park, J. Am. Chem. S(x.,1985, 107,1763A.I.Meyers, D.A.Dickman, and T.R.Bailey, J. Am. Chenn. SOC., 1985, 107, 7974. T.R.Kelly and M.P.Maguire, Tetrahedron, 1985, L 4 1 , 3033. C.S.Hilger, B.Fugmann, and W.Steglich, Tetrahedron Lett., 1985, 5975. S.Nishiyama and S.Yamamura, Bull. Chem. SOC. Jpn., 1985, 58, 3453. M.Wada, Y.Nishihara, and K.Akibe, Tetrahedron Lett., 1985, 26, 3267. G.Buchi, J.H.Botkin, G.C.M.Lee, and K.Yakushijin, J. Am. Chem. SOC., 1985, 107. 5555. R.L.Danheiser, J.M.Morin, and E.J.Salaski, J. Am. Chem. S O C . , 1985, 107, 8066.
m.,
26, 26,
26, 26,
~
~
26,
fi,
41,
.
.
9: Highlights in Total Synthesis of Natural Products 48. 49.
-
50 51. 52. 53.
54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73 * 74. 75. 76. 77. 78. 79. 80.
A.B.Smith and R.Mewshaw, J. Am. Chem. SOC., 1985, 107, 1769. S.J.Danishefsky, P.J.Harrison, R.R.Webb, and B.T.O'Neil1, J. Am. Chem. SOC 1985, 9, 1421. M.Suzuki, A.Yanagisawa, and R.Noyori, J. Am. Chem. SOC., 1985, 107,3348. S-Bhagwat, P.R.Hamann, and W.C.Stil1, J. Am. Chem. S O C . , 1985, 107,6372. E.J.Corey and W.-g.Su, Tetrahedron Lett., 1985, 26, 281. K.C.Nicolaou, C.A.Veale, S.E.Webber, and H.Katerinopoulas, J. Am. Chem. SOC., 1985, 107,7515; K.C.Nicolaou and S.E.Webber, J. Chem. SOC., Chem. Commun., 1985, 297. S.D.A.Street, C.Yeates, P.Kocienski, and S.F.Campbel1, J. Chem. SOC., Chem. Commun., 1985, 1386. S.D. A.Street , C.Yeates, P.Kocienski, and S.F. Campbell, J. Chem. Soc., Chem. Commun., 1985, 1388. R.Baker, M.J.O'Mahony, and C.J.Swain, J. Chem. S O C . , Chem. Commun., 1985, 1326. D.Culshaw, P.Grice, S.V.Ley , and G.A.Strange, Tetrahedron Lett., 1985, 26, 5837. M.Prashad and B-Fraser-Reid, J. Org. Chem., 1985, 50, 1566. A.P.Kozikowski and K.E.MaloneyHuss, Tetrahedron Lett., 1985, 26, 5759. R.H.Schlessinger, G.R.Bebernitz, P.Lin, and A.J.Poss, J. Am. Chem. S O C . , 1985, 107, 1777; P-DeShong, S.Ramesh, V.Elango, and J.J.Perez, p.52193.R.Kelly and N.S.Chandrakumar, Tetrahedron Lett., 1985, 26, 2173. S.W.Remiszewski, T.R.Stouch, and S.M.Weinreb, Tetrahedron, 1985, 5, 1173. S.Danishefsky and C.Maring, J. Am. Chem. SOC., 1985, 107,7762. K.C.Nicolaou, J.L.Randal1, and G.J.Furst, J. Am. Chem. S O C . , 1985, 107, 5556. M.Imoto, H.Yoshimura, N-Sakaguchi, S.Kusumoto, and T.Shiba, Tetrahedron Lett., 1985, 26, 1545. J. Yoshimura, S.Horito, J. Tamura, and H-Hashimato, Chem. Lett., 1985, 1335. P.M.Wovkulich and M.R.Uskokovic, Tetrahedron, 1985, 3455. R.E.Dolle and K.C.Nicolaou, J. Am. Chem. S O C . , 1985, 107, 1691, 1695. K.C.Nicolaou, M.E.Duggan, C.-K.Hwang, and P.K.Somers, J. Chem. S O C . , Chem. Commun., 1985, 1359. K.C.Nicolaou, D.P.Papahatjis, D.A.Claremon, R.L.Magolda, and R.E.Dolle, J. Org. Chem., 1985, 50, 1440. K.Nakatani and S.Isoe, Tetrahedron Lett., 1985, 26, 2209. Y.Hamada, M.Shibata, and T.Shioiri, Tetrahedron Lett., 1985, 26, 5155, 5159, 6501. K.Inami and T.Shiba, Bull. Chem. SOC. Jpn., 1985, 58, 352. S-Nishiyama, Y.Shizuri, and S.Yamamura, Tetrahedron Lett., 1985, 26, 231. M.C.Bowden, P.Pate1, and G.Pattenden, Tetrahedron Lett., 1985, 26, 4793. cf S.Hatakeyama, Y .Matsui, M.Suzuki, K.Sakurai , and S.Takano, Tetrahedron Lett., 1985, 26, 6485. D.R.Wil1iam.s and F.H.White, Tetrahedron Lett., 1985, 26, 2529. Y. Shizuri , S.Nishiyama , H. Shigemori , and S.Yamamura , J . Chem . SOC . , Chem . Commun., 1985, 292. S.Nishiyama, Y.Shizuri, D.Imai, S.Yamamura, Y.Terada, M.Niwa, K.Kawai, and H.Furukawa, Tetrahedron Lett., 1985, 26, 3243. M.C.Bowden and G.Pattenden, Tetrahedron Lett., 1985, 26, 4797. J.E.Baldwin, R.M.Adlington, and R.Bohlmann, J. Chem. SOC., Chem. Commun., 1985. 357. S.T.Hodgson, D.M.Hollinshead, and S.V.Ley, Tetrahedron, 1985, 5871. T.Nakata, S.Nagao, and T.Oishi, Tetrahedron Lett., 1985, 26, 6465. T.Rosen and C.H.Heathcock, J. Am. Chem. SOC., 1985, 107,3731. H.-H.Lee, Y.-T.Que, and S.Ng, J. Chem. SOC., Perkin Trans. 1 , 1985, 453. ~
~
u.,
~
fi,
.
,
81. 82. 83. 84.
595
-
fi,
Reviews on General and Synthetic Methods COMPILED BY K. CARR, D. J. COVENEY, AND G. PATTENDEN 1 Olefins
'Olefin Metathesis Cyclo-Olefins',
and
Ring-Opening
Polymerisation
of
V. Dragutan, A.T. Balaban and M. Dimonie, John Wiley, 1985. M.-C. Lasne [4n
+
2
TI
and
1
J.-L. Ripoll, 'New
Developments
of
the
Cycloreversion', Synthesis, 1985, 121.
2 Aldehydes and Ketones
I. Kuwajima and E. Nakamura, 'Reactive Enolates from Enol Silyl Ethers', Acc.Chem. Res., 1985, 2,181. S. Rozen and R. Filler, 'a-Fluorocarbonyl Compounds and Related Chemistry',Tetrahedron, 1985, 41, 1111.
Botteghi and F. Soccolini, 'Malonaldehyde, Succinaldehyde, and Glutaraldehyde Monoacetals: Syntheses and Applications', Synthesis,
C.
1985 , 592. G.A. Grevorqyan, A . G . Aqababyan and D.L. Mudzhoyan, 'Chemical Reactions of B-Aminoketones', Russ. Chem-Rev., 1985, 54, 495. M.B. Rubin, 'Recent Photochemistry of a-Diketones', Top. Curr. Chem., 1985, 129, 1. 3 Esters and Lactones
K.I. Pashkevich and V.I. Salontin, 'Fluorine Containing 8-Ketoesters', Russ.Chem. Rev., 1985, 54, 1185. H.M.R. Hoffmann and J. Rabe, 'Synthesis and Biological Activity of a-Methylene-Y-Butyrolactones', Angew. Chim. Int. Eng. Edn., 1985, 24,94. 4 Fluoroorganic Compounds I.L. Knunyants and G . G . Yokobsen, 'Synthesis of Fluoroorganic Compounds', Springer-Verlag, Berlin, Heidelberg, New York & Tokyo, 1985. 596
Reviews on General and Synthetic Methods
597
C.-L.J. Wang, 'Fluorination by Sulphur Tetrafluoride', Organic Reactions, Vol. 34, Ed. A.S.Kende, John Wiley and Sons: New York, 1985. 5 Organometallics Genera 1 R.H. Crabtree, 'The Organometallic Chemistry of Alkanes', Chem. Rev., 1985, 85, 245. 'Metallo-Organic Chemistry', A.J. Pearson, John Wiley and Sons, New York, 1985. 'The Chemistry
of the Metal-Carbon Bond: Vol. 3 , Carbon-Carbon
Bond Formation using Organometallic Compounds', eds. F.R. Hartley and S. Patai, John Wiley and Sons, New York, 1985. 'The Chemistry of the Metal-Carbon Bond: V o 1 . 2, The Nature and Cleavage of Carbon-Metal Bonds', eds. F.R. Hartley and S. Patai, John Wiley and Sons, New York, 1985. T.L. Ho, 'Chemoselectivity of Organometallic Reactions. A HSAB Appraisal', Tetrahedron, 1985, 41, 3. 'Application of Newer Organometallic Reagents to the Total Synthesis of Natural Products', ed. M. F. Semmelhack, Tetrahedron (Symposium in Print), 1985, 41, 5741. C . Narayana and M. Periasamy, 'Organic Synthesis Carbonylation of Organometallic Reagents with Carbon Monoxide', Synthesis, 1985, 253. J.R. Long, 'Lanthanides in Organic Synthesis,' Aldrichimica Acta, 1985, 18, 87. Transition Elements R.F. Heck, 'Best Synthetic Methods - Palladium Reagents in Organic Synthesis', Academic Press, London and Orlando FL, 1985. A.D. Ryabov, 'The Application of Cyclopalladated Compounds in Synthesis', Russ.Chem. Rev., 1985, 54, 153. A.D. Ryabov, 'Cyclopalladated Complexes in Organic Synthesis', Synthesis, 1985, 233. P.W. Jolly, 'n3-Allylpalladiurn Compounds' , Angew. Chim. Int. Eng. 24, 283.
Edn., 1985,
R.J.K. Taylor, 'Organocopper Conjugate Addition Reactions', Synthesis, 1985, 364.
-
Enolate Trapping
D.C. Billington, 'n-Allylnickel Halides as Selective Reagents in Organic Synthesis', Chem. SOC. Rev., 1985, 14, 93.
General and Synthetic Methods
598
E.-I. Negishi and T. Takahashi, 'Organozirconium Compounds as New 31. Reagents and Intermediates,' Aldrichimica Acta, 1985, 5, R.S. Dickson, 'Homogenous Catalysis with Compounds of Rhodium and Iridium', D. Reidel Publishing Company, Dordrecht, 1985. Main Group Elements R.C. Larock, 'Organomercury Compounds in Organic Synthesis', Springer-Verlag, Heidelberg and New York, 1985. K. Smith, 'Organometallic Compounds of Boron', Chapman and Hall
Ltd., London, 1985. A. Suzuki and R.S. Dhillon, 'Selective Hydroboration and Synthetic Utility of Organoboranes thus Obtained', Top. Curr.Chem., 1985, 130, 23. E.I. Negishi and M.J. Idacavage, 'Formation of Carbon-Carbon and Carbon-Heteroatom Bonds Organoboranes and Organoborates', Organic Reactions, Vol. 33, Ed. A.S. Kende, John Wiley and Sons, New York, 1985. K . Maruoka and H. Yamamoto, 'Selective Reactions using
Organoaluminium Reagents', Angew. Chim. Int. Eng. Edn., 1985,
24,
668. R. Anderson, 'Synthetic Applications of Chloromethyltrimethylsilane', Synthesis, 1985, 717. S. David and S. Hanessian, 'Regioselective Manipulation of Hydroxyl Groups via Organotin Derivatives', Tetrahedron, 1985, 41, 643. R.A. Cherkasov, G.A. Kutyrev and A.N. Pudovik, 'Organothiophosphorus 2567. Reagents in Organic Synthesis', Tetrahedron, 1985, 5, 'Organo-Sulphur Compounds', Parts 1 and 2 . Organic Chemistry. 4th Edition. Verlag: Stuttgart, 1985.
Houben-Weyl Methods in
Supplement Volume Ell: Ed. D.Klamma
C.R. Johnson, 'Applications of Sulfoximines in Synthesis' Aldrichimica Acta, M.P.
Cava
and
1985,
18, 3.
M.I. Levinson, 'Thionation Reactions of Lawessons
Reagents', Tetrahedron, 1985,
41,
5061.
V.I. Drovov and Y.E. Nikitin, 'Thioalkylation Reactions', Russ.Chem. Rev.,
1985,
54,
554.
'Recent Aspects of Organoselenium Chemistry', ed. D. Liotta, Tetrahedron
(Symposium in Print), 1985,
5,4727.
L. Engman, 'Synthetic Aspects of Organotellurium Chemistry', Acc. Chem. Res., 1985,
2,274.
Reviews on General and Synthetic Methods
599
6 Carbocyclic Ring Synthesis T. Hudlicky, T.M. Kutchan and S.M. Naqvi, 'The VinylcyclopropaneCyclopentene Rearrangement', Organic Reactions, Vol. 33. Ed. A.S. Kende, John Wiley and Sons, New York, 1985.
7 Heterocycles 'Heterocyclic Chemistry', T.L. Gilchrist, Pitman Publishing Inc., Marshfield MA, 1985. S. Mickel, '4-Acetoxy-2-Azetidinone: A Useful Heterocyclic
Synthon,' Aldrichimica Acta,
1985,
18, 95.
W.D. Ollis, S.P. Stanforth and C.A. Ramsden, 'Heterocyclic Mesomeric Betaines', Tetrahedron, 1985, 41, 4239.
H. Wamhoff, 'Heterocyclic $-Enamino Esters, Versatile Synthons in Heterocyclic Synthesis', Adv. Heterocycl. Chem., 1985, 38, 300. H. Bonnemann, 'Organocobalt Compounds in the Synthesis of Pyridines - An Example of Structure-Effectivity Relationships in Homogenous Catalysis', Angew. Chim. Int. Eng. Edn., 1985, 24, 248. N.R. El-Rayyes and N.A. Al-Awadi, 'Synthesis of 2-Pyrazolines and 3,5-Pyrazolidinediones', Synthesis, 1985, 1028. M.H. Elnagdi, G.E.H. Elgemeie and F.A.E. Abd-elaal, 'Recent Developments in the Synthesis of Pyrazole Derivatives', Heterocycles, 1985, 22, 3121. R.G. Melik-Ogandzhanyan, V.E. Khachatryan and A . S . Gapoyan, 'Furo-, Thieno- and Pyrrolo-I2,3-~lPyridines',Russ. Chem. Rev., 1985, 54, 262. F. Garcia and C. Galvez, 'The Synthesis of Thienopyrroles', Synthesis, 1985, 143. B.A.
Trofimov, A.I. Mikhaleva and L.V. Morozova, 'Polymerisation
of g-Vinyl Pyrroles', Russ. Chem. Rev., 1985,
2,609.
W. Sliwa, G. Matusiak and A. Postawka, 'The Chemistry of N-Substituted Pyridinium Salts', Heterocycles, 1985, 22, 1513.
I
R.M. Davidson, '1,4-Benzothiazinesl Dihydro-1,4-Benzothiazines and Related Compounds', Adv. Heterocycl. Chem., 1985,
38, 135.
K.C. Joshi, R. Jain and P. Chand, 'Indoles with C-3 as Spiro Atom,' Heterocycles, 1985, 22, 957. A.L. Weis, 'Recent Advances in the Chemistry of Dihydroazines', Adv. Heterocycl. Chem., 1985, 2, 3 .
General and Synthetic Methods
600
8 Natural Products 'The Chemistry of Natural Products', Ed. R.H. Thomson, Blackie and Son Ltd., Glasgow, 1985. M. Vandewalle and P. De Clercq, 'Total Synthesis of Polycyclic Sesquiterpenes. A Survey of Novel Methods and Reactions', Tetrahedron, 1985, 41, 1767. J . S . Roberts, 'Sesquiterpenoid Synthesis', Nat. Prod. Rep., 1985, 97. P.G. McDougal and N.R. Schmuff, 'Chemical Synthesis of the Trichothecanes', Prog. Chem. Org. Nat. Prod., 1985, 47, 153.
2, -
J. E l k s ,
'Steroids: Reactions and Partial Synthesis', Nat. Prod.
1985, 2 , 461. K. Wiesner, 'Some Highlights in the Structural and Synthetic Chemistry of the Aconite Alkaloids. A Personal Historical
Rep.,
Perspective', Tetrahedron, 1985, 9, 485. S.M. Weinreb, 'Alkaloid Total Synthesis by Intramolecular Imino Diels-Alder Cycloadditions', Acc. Chem. R e s . , 1985, 18, 16. J . E . Saxton, 'Recent Progress in the Chemistry of Indole Alkaloids and Mould Metabolites', Nat. Prod. Rep., 1985,
R.
2,
49.
Southgate and S. Elson, 'Naturally Occurring 6-Lactams',
Prog.Chem. Org.Nat.Prod., 1985, 5, 1. W. Durckheimer, J . Blummbach, R . Lattrell and K.H. Scheunemann, 'Recent Developments in the Field of B-Lactam Antibiotics', Angew. Chim. Int. Eng. Edn., 1985,
24, 180.
D.A. Whiting, 'Lignans and Neolignans', Nat. Prod. Rep., 1985, 2 , 191. J. Rokach and J. Adams, 'Synthesis of Leukotrienes and Lipoxygenase Products', Acc. Chem. Res., 1985, 2 , 87.
-
I . Paterson and M.M. Mansuri, 'Recent Developments in the Total Synthesis of Macrolide Antibiotics', Tetrahedron, 1985, 41, 3569.
9 Enzymic Reactions and Asymmetric Synthesis G.M. Whitesides and C.-H. Wong, 'The use of Esterases, Lipases and other Enzymes in Organic Synthesis', Angew. Chim. Int. Eng. __ Edn.,
1985,
24, 617.
J.M. Whitesell, 'New Perspectives in Asymmetric Induction', Acc. Chem. Res., 1985,
5,280.
'Asymmetric Synthesis: Chiral Catalysis', Volume 5. Morrison, Academic Press: Orlando, FL, 1985.
Ed. J . D .
60 1
Reviews on General and Synthetic Methods
T. Money, 'Camphor: A Chiral Starting Material in Natural Product Synthesis', Nat. Prod. Rep., 1985, 2, 253. B. Fraser-Reid, 'Some Progeny of 2,3-Unsaturated Sugars They Little Resemble Grandfather Glucose: Ten Years Later', Acc. Chem.Res., 1985, 2 , 347. S. Masamune, W. Choy, J . S . Petersen and L.R. Sita, 'Double Asymmetric Syntheis and a New Strategy for Stereochemical Control in Organic Synthesis', Angew. Chim. Int. Eng. Edn., 1985, 24, 1. H. Simon, J. Bader, H. Gunther, S. Neumann and J. Thanos, 'Chiral Compounds Synthesised by Biocatalytic Reductions', Angew. Chim. Int. Eng. Edn., 1985, 3,539. A.I. Meyers, 'Formamidines as Precursors to u-Amino Carbanions and Their Application to Asymmetric C - C Bond-Forming Reactions,' Aldrichimica Acta, 1985, 18, 59. 10 Oxidation
A.H. Haines, 'Best Synthetic Methods - Methods for the Oxidation of Organic Compounds: Alkanes, Alkenes, Alkynes and Arenes', Academic Press, London and Orlando FL, 1985. Enikolopyan, K.A. Bogdanova, L . V . Karmilova and K.A. Askarov, 'Catalysis by Metalloporphyrins of Reactions Involving Oxidation by Molecular Oxygen and Oxygen Containing Compounds', Russ. Chem. Rev., 1985, 54, 215.
N.S.
1 1 Reduction P.N. Rylander, 'Best Synthetic Methods
-
Hydrogenation Methods',
Academic Press, London and Orlando FL, 1985. R.A.W. Johnstone, A.H. Wilby and I.D. Entwistle, 'Heterogeneous Catalytic Transfer Hydrogenation and its Relation to Other Methods for Reduction of Organic Compounds', Chem. Rev., 1985, 85, 129. E.A. Karakhanov, A.G. Dedov and A.S. Loktev, 'Metal Complex Catalysts for the Hydrogenation of Aromatic and Heterocyclic Compounds', Russ. Chem. Rev., 1985,
54,
171.
J. Malek, 'Reductions by Metal Alkoxyaluminium Hydrides',
Organic Reactions, Vol. 34, Ed. A.S. Kende, New York, 1985.
John Wiley and Sons,
602
General and Synthetic Methods
12 Protective Groups
M. Lalonde and T.H. Chan, 'Use of Organosilicon Reagents as Protective Groups in Organic Synthesis', Synthesis, 1985, 817. 1 3 Radical Chemistry
'Selectivity and Synthetic Applications of Radical Reactions', ed. B. Giese, Tetrahedron (Symposium in Print), 1985, 41, 3887. B. Giese, 'Synthesis with Radicals - Carbon-Carbon Bond Formation via Organotin and Organomercury Compounds', Anqew. Chim. 1nt.Eng. Edn., 1985, 24, 5 5 3 . K. Dimroth, 'Arylated Phenols, Aroxyl Radicals and Aryloxenium Ions', Top. Curr. Chem., 1985, 129, 99. R.K. Freidlina, R.G. Gasanov, N.A. Kuz'mina and E.T. Chukovskaya, 'Transition Metal Carbonyls Combined with Hydrogen Donors as Initiators of the Radical Reduction of Trichloromethyl Compounds', Russ. Chem. Rev., 1985,
54,
662.
14 General
K. Matsumoto, A. Sera, and T. Uchida, 'Organic Synthesis Under High Pressure: 1', Synthesis, 1985, 1. K. Matsumoto and A. Sera, 'Organic Synthesis Under High Pressure; 11', Synthesis, 1985, 999. R.B. Merrifield, 'Solid Phase Synthesis', Angew. Chim. Int. Eng. ~
Edn., 1985,
24, 799.
A. Cornelis and P. Laszlo, 'Clay-Supported Copper (11) and Iron (111) Nitrates: Novel Multi-Purpose Reagents for Organic Synthesis', Synthesis, 1985, 909. V.G. Dryuk, 'Advances in the Development of Methods for the
Epoxidation of Olefins', Russ. Chem. Rev., 1985,
54,
986.
Reuman and A.I. Meyers, 'The Synthetic Utility of Oxazolines in Aromatic Substitution', Tetrahedron, 1985, 41, 837.
M.
K.L. Bhat, S . Y . Chen and M. Joullie, ID-Ribonolactone in Organic Synthesis-A Review,' Heterocycles, 1985, 22, 691.
603
Reviews on General and Synthetic Methods
15 Miscellaneous 'Synthetic Applications of Dipolar Cycloaddition Reactions', ed. W. Oppolzer, Tetrahedron (Symposium in Print), 1985, 41, 3447. W.N. Speckamp and H. Hiemstra, 'Intramolecular Reactions of
-N-Acyliminium
Intermediates', Tetrahedron, 1985,
41,
4367.
O.V. Drygina, A.D. Garnovskii and A.V. Kazantsev, 'The Interconversions of Pyrylium Salts, Pyrans, Pyrones and Their Open Chain Forms', Russ. Chem. Rev., 1985,
54,
D. Moderhack, 'Four-Membered Rings from Isocyanides
1167.
-
Recent Advances', Synthesis, 1985, 1083.
J.
Funk and M. Regitz, 'Electrophilic Diazoalkane Substitution',
Synthesis, 1985, 569. V.F. Zarytova, and D.G. Knorre, 'Intermediate Compounds and Intermediate Reactions in the Synthesis of Oligonucleotides', Russ. Chem. Rev., 1985, 54, 185. 'Recent Aspects of Carbene Chemistry', ed. M. Platz, 1423. Tetrahedron (Symposium in Print), 1985, 5, 'Recent Aspects of Singlet Oxygen Chemistry of Photooxidation', ed. I. Saito and T. Matsuma, Tetrahedron (Symposium in Print), 1985, 41, 2037. 'Stereochemistry of Heterogeneous Metal Catalysis', M. Bartok, J.Czombos, K. Felfoldi, L. Gera, Gy. Gondos, A. Molnar, F.Notheisz, I. Palinko, Gy. Wiltmann and A.G. Zsigmond, John Wiley and Sons: New York. 1985. H.C. van der Pas, 'Ring Degenerate Transformation of Azines', Tetrahedron, 1985,
41,
237.
P.L. Watson and G.W. Parshall, 'Organolanthanides in Catalysis', Acc. Chem. Res., 1985, 18, 51. T.P. Vishnyakova, I.A. Golubeva and E.V. Glebova, 'Substituted Ureas. Methods of Synthesis and Applications', Russ. Chem. Rev., 1985,
54,
249.
A. Yoshikoshi and M. Miyashita, 'Oxoalkylation of Carbonyl Compounds with Conjugated Nitro Olefins', Acc. Chem. Res., 1985, 18, 284. I
B.
Iddon, 'Metallation and Metal-halogen Exchange Reactions of
Imidazoles, Heterocycles, 1985,
22, 417.
F.D. Popp and B.C. Uff, 'Ring Annelations via Reissert Compounds', Heterocycles, 1985,
22,
731.
Author Index
I n t h i s i n d e x t h e number g i v e n i n p a r e n t h e s i s i s t h e C h a p t e r number of t h e c i t a t i o n a n d t h i s i s f o l l o w e d by t h e r e f e r e n c e number o r n u m b e r s of t h e r e l e v a n t c i t a t i o n s within t h a t Chapter
A b b a s , N . ( 8 ) 131 A b e c a s s i s , J. ( 8 ) 11 A b e l l , A.D. ( 3 ) 218 Aben, R . W . ( 7 ) 1 7 Abenhaim, D. (3) 1 5 , 1 0 8 A h i d i , S.L. (5) 445 Aboa-Assali, M. ( 4 ) 194; ( 8 ) 24 A b o u j a o u d e , E.E. ( 5 ) 1 2 8 ; ( 6 i i ) 153 Abramovitch, R . A . ( 5 ) 120 Abrams, S . ( 6 i i ) 26 A c h i , S.S. ( 5 ) 3 5 3 Achiwa, K . ( 5 ) 4 6 5 ; ( 8 ) 8 5 , 136, 1 4 0 , 141 Achuva, A . ( 6 i i ) 1 6 6 A c k r o y d , J. ( 7 ) 1 6 8 Acuna, C. ( 3 ) 187 Adak, M . M . ( 4 ) 1 2 5 Adam, M . A . ( 5 ) 160; ( 6 i i ) 81 Adarniak, R.W. ( 5 ) 5 1 3 Adams, C . E . ( 5 ) 1 5 4 A d e n i y i , A.E. ( 3 ) 67 A d l i n g t o n , R . M . (3) 4 3 3 , 4 4 0 ; ( 9 ) 80 A e b i , .J.D. ( 3 ) 9 8 , 4 1 5 , 4 1 6 ; ( 6 i i ) 2 0 , 21 A f z a , N . ( 5 ) 2 0 8 , 551 Agawa, T. ( 1 ) 5 1 ; ( 2 ) 2 2 ; ( 3 ) 195 A g e r , D.J. ( 6 i i ) 30 A g o s t a , W.C. ( 6 i i ) 68; (8) 43 Agouridas, K. ( 3 ) 459; ( 5 ) 145 A h l b r e c h t , H. ( 3 ) 156; ( 5 ) 1 3 6 , 245, 3 4 1 Ahmar, M. ( 7 ) 4 1 Ahn, K . H . ( 3 ) 4 5 1 ; ( 4 ) 17; (5) 66; (6ii) 65 A i d a , T. ( 4 ) 2 1 8
A i t k e n , R . A . ( 1 ) 89 Aizpurua, J . M . ( 2 ) 5 ; ( 3 ) 47; ( 4 ) 100, 104, 118, 160 A k a j i , K. ( 3 ) 481 A k e y o s h i , M. ( 3 ) 150 A k i b a , E. ( 7 ) 4 7 , 4 8 Akiba, K. ( 2 ) 26, 127; ( 3 ) 297, 362; ( 4 ) 5 3 ; ( 6 i i ) 1 0 1 , 165; ( 9 ) 4 5 Akirnoto, K . (1) 5 7 ; ( 9 ) 28 A k i t a , T. (3) 4 8 1 Akiyama, M . ( 9 ) 36 A k u t a g a w a , A . ( 6 i ) 22 A l a j a r i n , M . ( 4 ) 207 A l b a u g h - R o b e r t s o n , P. ( 2 ) 67; ( 7 ) 62 A l c a i d e , 8. ( 5 ) 478 A l c a l a , H. ( 5 ) 47 A l c o c k , S.G. ( 3 ) 1 8 2 Alemagna, A . ( 5 ) 4 9 7 ; ( 6 i ) 82 A l e s s a n d r i , P . ( 7 ) 86 A l e x a k i s , A. ( 1 ) 77 A l e x a n d r e , C. ( 3 ) 2 5 0 A l - H u s a i n i , A.H. ( 7 ) 2 8 A l i , S.F. ( 3 ) 1 6 2 ; ( 6 i i ) 176 A l l i z a t i , K.F. ( 7 ) 1 3 7 A l l m a n n , R . ( 5 ) 484 A l p e r , H. ( 3 ) 209-212, 231, 292, 323; ( 4 ) 1 3 3 , 1 7 4 , 1 7 5 , 212; ( 5 ) 10; ( 6 i ) 66, 67, 83 A l t e n b a c h , H . - J . ( 2 ) 83 A l t m a n , J . ( 5 ) 105 A l v a r e z , E.F. ( 3 ) 4 3 3 A l y , M.F. ( 3 ) 5 8 ; ( 5 ) 2 8 5 A m a i , T. ( 3 ) 2 A m a r a s e k a r a , A. ( 7 ) 1 5 4 A m b l e r , P.W. ( 4 ) 7 1 ; ( 6 i )
604
38 Arnedio, J . C . , j u n . ( 3 ) 141 Ames, A. ( 3 ) 2 3 9 ; ( 6 i i ) 192 Amrnon, H.L. ( 8 ) 189 Arnoroux, R . ( 4 ) 202 Amos, R . A . ( 4 ) 2 2 2 ; ( 6 i i ) 191 Ampleman, G. ( 4 ) 11 A n a n ' e v , N.P. ( 5 ) 3 0 2 Anda, M. ( 5 ) 3 2 0 A n d e l l , O.S. (1) 66 Ander, P. (5) 107 A n d e r s o n , R.C. ( 3 ) 308 A n d e r s o n , W . K . ( 5 ) 369 A n d e r s s o n , C. (3) 1 7 7 A n d e r s s o n , C.-M. ( 3 ) 177 A n d e r s s o n , S. ( 4 ) 110 Ando, K . ( 3 ) 4 8 1 Ando, N. ( 5 ) 5 3 7 Ando, T. ( 1 ) 8 5 ; ( 5 ) 3 5 7 A n d r i a m i a l i s o a , R.Z. ( 3 ) 1 5 1 ; ( 4 ) 91 A n d r i a n o m e , M. ( 1 ) 18, 1 9 A n g e l i , C. ( 5 ) 4 0 5 A n g i b e a u d , P. ( 4 ) 108 A n g l e , S.R. ( 4 ) 7 9 ; ( 6 i ) 8 4 ; (8) 174 Angoh, A.G. ( 5 ) 3 4 7 A n k e r , D. ( 4 ) 1 9 4 ; ( 8 ) 24 Annaka, M. ( 9 ) 2 8 Annunziata, R. (2) 172; ( 5 ) 1 7 1 ; (8) 4 Anowski, W.K. ( 3 ) 335 A n t e b i , S. ( 3 ) 2 1 2 , 231; ( 4 ) 212 A n t u o n o , J . D . ( 9 ) 33 A o a i , T. ( 8 ) 18 Aoyago, T. ( 3 ) 193 Aoyama, H. (8) 236 Aoyama, I. ( 3 ) 388
605
Author Index A p e l , M. ( 7 ) 83 Apparao, S. ( 3 ) 174 ApSimon, J . W . ( 5 ) 4 3 9 Ara, K . - I . ( 8 ) 165 Arai, H . (1) 4 9 ; ( 5 ) 3 3 6 ; ( 6 i i ) 131 Arai, T. ( 1 ) 7 Arai, Y. ( 6 i i ) 1 7 8 A r a k i , H . ( 5 ) 314 Arase, A. ( 1 ) 27; ( 2 ) 1 0 2 ; ( 4 ) 219 A r a s e , H. ( 2 ) 4 5 ; ( 6 i i ) 114 A r a t a n i , M. ( 9 ) 29 A r c a d i , A. ( 4 ) 9 5 A r c e l l i , A . ( 4 ) 13 A r d u i n i , A. (8) 6 6 A r e n a l , I. ( 3 ) 433; ( 5 ) 270; ( 7 ) 1 2 Arimoto, M. (1) 7 9 , 80; ( 4 ) 198; ( 6 i i ) 113; (8) 52 Armesto, D. (8) 1 9 5 Armstrong, P. (8) 148 A r n o l d , L.D. ( 3 ) 436 A r s i t o f f , P.A. ( 2 ) 8 2 Arzoumanian, H . ( 3 ) 322 Asakawa, Y. ( 7 ) 9 5 Asami, M. ( 4 ) 6 7 Asaoka, M. ( 3 ) 365 Asensio, G . (4) 128; ( 5 ) 9 1 , 252 A s i r v a t h a m , E. ( 2 ) 1 9 0 ; (3) 1 6 2 ; ( 6 i i ) 1 7 5 , 176 A s k i n , D. ( 3 ) 353; (8) 5 9 Aslam, M. ( 4 ) 206 A s l a n i a n , R. ( 5 ) 138; ( 6 i ) 81 Aso, Y. ( 3 ) 9; ( 4 ) 203, 210; ( 6 i i ) 211 Asokan, C.V. (3) 226 Assad, F.M. ( 5 ) 399 A t h e r t o n , E. ( 3 ) 478 A t h e r t o n , J.I. (1) 8 9 A t r a s h , B. (3) 476 A t t e p e t e r , B. ( 6 i i ) 161 Atwood, J . D . ( 6 i ) 3 Aub6, J. ( 5 ) 5 4 3 ; (8) 9 9 Auburn, P.R. (3) 9 0 Augb, J. (1) 5 3 ; ( 6 i i ) 141 Augelmann, G. (5) 188 A u r i c h , H.G. ( 5 ) 549 Auvray, P. ( 6 i i ) 1 8 8 ; ( 7 ) 46; ( 8 ) 23 A v o u r i , M. (5) 532 Awata, T. (3) 68 A x i o t i s , G. ( 2 ) 1 7 0 ; ( 4 ) 56 Ayaguchi, Y. (1) 8 Az, R . (5) 260
A z n a r , F. ( 5 ) 1 1 6 ; ( 8 ) 211 Baba, A. ( 8 ) 110, 116 B a b l e r , J . H . ( 7 ) 13 B a b s t o n , R.E. ( 5 ) 521 B a c e i r e d o , A. ( 5 ) 519 Bach, J . ( 3 ) 475; ( 4 ) 8; ( 5 ) 31 Bach, R.D. ( 2 ) 8 7 ; ( 7 ) 172 Bachand, C. ( 5 ) 7 3 B a c i o c c h i , E. ( 5 ) 5 5 3 Back, T.G. ( 2 ) 120; ( 5 ) 1 3 0 ; ( 6 i i ) 197 B a d e r , J. ( 3 ) 265 B a d e r t s c h e r , U. ( 3 ) 114 Backvall, J.E. ( 1 ) 66; ( 3 ) 3 4 3 ; ( 5 ) 1 3 8 , 139; ( 6 i ) 81 B a i g r i e , L.M. ( 2 ) 1 4 4 , 145; ( 6 i i ) 10 B a i l e y , T.R. ( 2 ) 43; ( 6 i i ) 17 B a i l e y , W.F. ( 4 ) 199; (8) 30 B a i n e , N.H. ( 9 ) 1 2 B a i r d , W.C., j u n . ( 3 ) 5 B a i z e r , M.M. ( 3 ) 6 8 ; ( 7 ) 59 B a j g r o w i c z , J.A. ( 3 ) 430 Bajwa, J.S. ( 6 i i ) 7 5 B a k e r , R . ( 3 ) 271; ( 9 ) 56 Bakhtiyarova, I . V . ( 5 ) 129 Bakhumutov, V.I. ( 3 ) 439 B a k k e r , B.H. ( 5 ) 542 B a k s h i , R . K . ( 6 i i ) 79 B a k u z i s , M.L.F. ( 4 ) 229 B a k u z i s , P. ( 4 ) 229 B a l , B. ( 3 ) 1 9 Balasubramanian, N . ( 5 ) 541, 544; ( 8 ) 1 0 1 , 102 B a l a v o i n e , G. ( 3 ) 6 1 B a l d o l i , C. ( 5 ) 497; ( 6 i ) 82 Baldwin, J . B . ( 6 i i ) 1 9 0 Baldwin, J . E . ( 3 ) 1 7 8 , 1 8 2 , 4 3 3 , 440; ( 5 ) 181, 4 4 6 , 4 9 5 , 496; ( 6 i ) 2 0 , 21; ( 9 ) 80 B a l d w i n , S.W. ( 5 ) 543; ( 8 ) 99 B a l l e s t e r , P. ( 2 ) 7 9 ; ( 3 ) 30; ( 7 ) 134 B a l l i n i , R . ( 5 ) 3 9 6 , 397 Ban, Y. ( 3 ) 367; ( 6 i ) 7 2 , 7 3 ; (8) 1 6 6 , 219, 220 B a n e r j e e , A. ( 4 ) 1 2 5 B a n e r t , K. (5) 5 0 5
B a n f i , L. ( 3 ) 438; ( 5 ) 205 B a n f i , S. ( 4 ) 225; ( 8 ) 4 Banks, B.A. ( 9 ) 2 B a n n e r , B.L. ( 3 ) 261 B a r a l d i , P.G. ( 5 ) 326 B a r b o t , F. ( 5 ) 1 5 3 B a r b o u r , R . H . ( 3 ) 371 Barbuch, R . ( 5 ) 168 B a r c e l o , G. ( 3 ) 467 B a r c o , A . (5) 326 B a r d i l i , B. ( 3 ) 295 B a r i , S.S. ( 8 ) 228 B a r l u e n g a , J. ( 1 ) 72; ( 4 ) 5 , 128, 152; ( 5 ) 91, 116, 119, 127, 194, 252, 4 8 0 , 5 5 2 ; ( 6 i i ) 4 0 , 4 1 ; ( 8 ) 115, 211 B a r n e s , B . J . ( 5 ) 406 Barnum, C. ( 2 ) 119; ( 6 i i ) 195 B a r r a t t , A.G.M. ( 8 ) 239 B a r r e a u , M . (8) 9 6 B a r r e t t e , E.-P. ( 2 ) 1; ( 4 ) 119 B a r r i e r , J.-P. ( 7 ) 158 B a r r i e r e , F. ( 7 ) 44 B a r r i e r e , J.-C. ( 7 ) 44 B a r r y , C.N. ( 4 ) 1 9 2 ; ( 6 i i ) 160 B a r r y , J. ( 3 ) 67 B a r t l e t t , P . A . ( 4 ) 196; ( 6 i i ) 94; ( 8 ) 16 Bartman, D. ( 6 i i ) 6 6 B a r t o l i , G. ( 5 ) 409; ( 6 i i ) 58 B a r t o n , D.H.R. (1) 1 6 ; ( 2 ) 160; ( 3 ) 3 , 53-55, 5 7 , 1 4 5 , 460; ( 4 ) 7 6 , 8 7 , 127; ( 5 ) 7 8 , 7 9 , 9 4 , 3 5 8 , 438; ( 6 i i ) 1 6 4 , 205, 207-209; ( 7 ) 44 B a r t s c h , B. ( 5 ) 276 B a r t s c h , R . ( 3 ) 183 B a r t z , W . J . ( 5 ) 257 B a r u a h , J.N. ( 5 ) 475 B a s c h a , F.Z. ( 5 ) 342 B a t c h e l o r , M.J. ( 3 ) 251 B a t s a n o v , A.S. ( 3 ) 439 B a u d i n , J . - B . ( 2 ) 19 B a u e r , T. ( 8 ) 6 2 Baum, K. ( 5 ) 4 0 3 Bawa, A. ( 2 ) 9 1 Baxter, A.J.G. (9) 34 Beak, P. ( 3 ) 392; ( 5 ) 244 Beau, J.-M. ( 6 i i ) 25, 48 B e b e r n i t z , G.R. ( 9 ) 6 0 Beccalli, E.M. ( 3 ) 217 B e c h e r , J. ( 3 ) 251; ( 7 ) 109
606
General and Synthetic Methods
Beck, A . K . ( 2 ) 153; ( 4 ) 4 6 ; ( 5 ) 412 B e c k e r , M. (7) 7 1 B e c k e r , R. ( 5 ) 2 7 ; ( 7 ) 51 Beckwith, A.L.J. ( 7 ) 29;
(7) 9 3 ; (8) 238 B e e d l e , E . C . ( 3 ) 200 B e e r , D . ( 5 ) 500 B e g l e y , M . J . ( 7 ) 149 Behrnann, G . ( 3 ) 81 B e h n i k e , M. ( 6 i i ) 104;
(7) 13’3 Behrens, C.H.
( 5 ) 155,
156 B e h r o o z , M. ( 6 i i ) 5 3 B e i s s w e n g e r , T. ( 3 ) 1 ; ( 5 ) 2 6 0 ; ( 6 i i ) 169 B e l e t s k a y a , I . P . ( 5 ) 432 B e l i c c h i , M.F. ( 3 ) 109 B e l i k o v , V . M . ( 3 ) 439 B e l l , X . R . ( 6 i i ) 28 B e l l a s s o u e d , M. ( 3 ) 29 B e l l e r , G. ( 5 ) 514 Relokon, Y.N. ( 3 ) 417, 439 B e l o t t i , D. ( 4 ) 9 2 ; ( 7 )
58 B e l o v , P.N. ( 5 ) 535 B e l s k i i , V.K. ( 8 ) 129 B e n a d j i l a - I g u e r t s i r a , L. ( 8 ) 144 B e n a r d , D. ( 5 ) 255 B e n a r d j , A. ( 3 ) 122 B e n e t t i , S . ( 5 ) 326 B e n e z r a , C . ( 3 ) 8 6 , 304 Benrnaarouf-Khalaayoun, 2 .
( 5 ) 169 B e n n e t a u , B. ( 4 ) 55 B e n n e t t , W.D. ( 3 ) 422 B e r c h t o l d , G . ( 5 ) 508 B e r e t t a , M.G. ( 3 ) 2 4 9 ;
( 4 ) 61 Bergrnan, R.G. ( 3 ) 115 B e r k o w i t z , W.F. ( 7 ) 154 Berrnan, E.M. ( 8 ) 170 B e r n a b 6 , M. ( 3 ) 4 3 3 ; ( 5 )
270; (7) 12 B e r n a r d , D. ( 1 ) 7 4 Bernardi, A. ( 3 ) 190,
233, 249; ( 4 ) 61-63, 66 B e r n e t , B. ( 5 ) 4 5 8 ; ( 8 ) 70 B e r n o t a s , R.C. ( 5 ) 6 5 B e r n s t e i n , M.A. ( 3 ) 351 B e r t a l n a , C . ( 8 ) 81 B e r t h a , F. ( 5 ) 46 B e r t h o n , L. ( 3 ) 3 8 3 ; ( 5 )
238 B e r t o u n e s q u e , E. ( 2 ) 1 7 0 ;
( 4 ) 56 B e r t r a n d , G . ( 5 ) 519
B e r t r a n d , M. ( 2 ) 6 1 B e r t z , S.H. ( 4 ) 209 B e r w i c k , A . ( 6 i i ) 168 B e s l i n , P. ( 3 ) 232 Bestrnann, H . J . ( 2 ) 5 1 ;
( 3 ) 1 7 0 , 368 B e s w i c k , P.J. (6i) 45 B e t a n c o u r t d e P e r e z , R.M. ( 3 ) 3 1 0 ; ( 6 i i ) 119 B e t h a u s e r , W. ( 5 ) 518 B e t z , R . ( 3 ) 319; ( 5 ) 243; ( 6 i i ) 42 B e u g e l m a n s , R. ( 8 ) 144 B e v i n a k a t t i , H.S. ( 3 ) 327 Bewick, A . ( 5 ) 2 5 3 , 254 B e y , P. ( 5 ) 142-144 B e z h a n , I.P. ( 5 ) 449 B h a g w a t , S.S. ( 8 ) 7 2 , 7 3 ;
( 9 ) 51 Bhan, A . ( 5 ) 376 B h a t , K.L. ( 5 ) 200 B h a t , K.S. ( 6 i i ) 8 0 B h a t t a c h a r j y a , A . ( 5 ) 415 B h u p a t h y , M. ( 4 ) 5 1 B i a l a , E. ( 5 ) 513 B i - c h i , W. ( 3 ) 341 B i c k e l h a u p t , F. ( 7 ) 5 B i e n z , S . ( 5 ) 435 B i g e l l i , C . ( 6 i ) 53 B i g i , F. ( 3 ) 109 B i l l i n g t o n , C.D. ( 6 i ) 6 B i l l i o n , A . ( 5 ) 358 B i n g e r , P . (7) 7 9 ; ( 8 )
155 B i n n s , M.R. ( 3 ) 247 B i r c h , D . J . ( 3 ) 440 B i s c h o f f , J.J. ( 4 ) 199; ( 8 ) 30 B i s h o p , P.M. ( 8 ) 7 0 B i t t e r , I . ( 5 ) 55 B j o r k l i n g , F. ( 3 ) 8 4 , 445 B l a d o n , C.M. ( 8 ) 9 1 B l a g g , J . (6i) 4 3 , 4 4 ; ( 6 i i ) 19 B l a n c o , L. ( 2 ) 3 7 ; ( 3 )
103 B l a r e r , S.J. ( 5 ) 215 B l a s e r , G . ( 6 i i ) 146 B l a t c h e r , P . ( 6 i i ) 173 B l a z e j e w s k i , J.-C. (2)
1 6 0 ; ( 3 ) 145 B l o c h , R. ( 3 ) 2 6 4 ; ( 8 ) 11 B l o c k , E. ( 4 ) 2 0 6 ; ( 6 i i ) 174; ( 8 ) 93 Blumbach, J . ( 8 ) 214 B l u m e n t h a l , M. ( 6 i i ) 37 B o a t e , D.R. ( 8 ) 238 B o a v e n t u r a , M.-A. ( 2 ) 1 6 5 ; ( 6 i i ) 69; ( 7 ) 6 9 B o a z , N.W. ( 2 ) 177 B o c k , H . ( 5 ) 390
Bock, M.G. ( 3 ) 386 B o d e , H. ( 8 ) 3 2 Boden, E.P. ( 1 ) 4 3 ; ( 3 )
2 3 4 , 359 Boeckrnan, R.K.,
jun.
(1)
4 4 ; ( 3 ) 4 8 , 184; ( 4 ) 1 1 1 ; ( 5 ) 135 Boerekamp, J . ( 3 ) 329 B o e s , M. ( 8 ) 201 B o g e r , D.L. ( 5 ) 1 8 7 ; ( 8 ) 112 B o g e r , J . S . ( 3 ) 386 Bohlrnann, R . ( 3 ) 1 8 2 ; ( 9 ) 80 B o i r e a u , G . ( 3 ) 1 5 , 108 B o i v i n , J . ( 5 ) 358 B o k e n s , H. ( 3 ) 455 B o l a n d , W. ( 3 ) 2 1 9 , 265 B o l d r i n i , G.P. ( 4 ) 10 Boltanski, A. ( 3 ) 63 B o n d a r e n k o , L. ( 2 ) 1 3 6 ; ( 7 ) 155 B o n g i n i , A. ( 5 ) 166 B o n i n i , B.F. ( 8 ) 128 B o n i n i , C. ( 3 ) 279 Bonk, P . J . ( 4 ) 1 9 7 ; ( 5 ) 147; ( 6 i ) 5 7 , 5 8 ; ( 6 i i ) 1 3 4 ; ( 8 ) 34 Bonnernann, H . ( 6 i ) 8 B o r b a r u a h , M. ( 4 ) 164 B o r d e a u , M. ( 4 ) 5 5 B o r o d i n s k y , L. ( 5 ) 386 Bosch, G.K. ( 7 ) 147; ( 9 ) 16 B o s c h e l l i , D. ( 1 ) 95 B o s c o , M. ( 5 ) 4 0 9 ; ( 6 i i ) 58 B o s e , A . K . (8) 228 B o s i , A . ( 8 ) 66 B o s n i c h , B. ( 3 ) 9 0 , 399 B o t k i n , J . H . ( 9 ) 46 B o t t a , M. ( 5 ) 7 6 ; ( 7 ) 146 B o t t e g h i , C . ( 2 ) 137 B o u c h a r d , F. ( 3 ) 465 B o u j l e l , K . ( 5 ) 282 B o u r g u i g n o n , J. ( 5 ) 11 B o u t e l j e , J . ( 3 ) 8 4 , 445 B o u t i n , R . H . ( 2 ) 101; ( 5 ) 210 Boverrnann, G . ( 3 ) 474 Bowden, M.C. ( 1 ) 9 8 ; ( 9 ) 7 4 , 79 B o w e r s , K.G. ( 8 ) 77 Boyd, D . R . ( 5 ) 4 7 2 B o y e r , J . H . ( 5 ) 4 4 2 , 443 B o y e r , S.K. ( 3 ) 4 7 5 ; ( 4 ) 8 ; ( 5 ) 31 B o y l e , J.M. ( 5 ) 277 B o z e l l , J . J . ( 9 ) 25 Brachmann, H. ( 3 ) 427 B r a d y , W.T. ( 3 ) 2 5 3 ; ( 7 )
Author Index 2 4 ; ( 8 ) 50 Bram, G . ( 3 ) 67 B r a n d , S . ( 3 ) 355 B r a n d a n g e , S. ( 3 ) 3 5 7 ; ( 5 ) 12 B r a n d i , A. ( 8 ) 209 Brandsma, L. ( 1 ) 6 4 ; (6ii) 8 B r a n d v o l d , T.A. ( 5 ) 104 B r a n n o n , M.J. ( 2 ) 7 8 ; ( 7 ) 122 B r a n z , S.E. ( 5 ) 446 B r a u e r - S c h e i b , S . ( 5 ) 453 B r a u n , M . ( 3 ) 337 B r a v o , P. ( 2 ) 1 2 6 ; ( 3 ) 305 B r a x m e i e r , H. ( 3 ) 428 Bremmer, M.L. ( 9 ) 3 3 B r e n n e r , D.G. ( 5 ) 466 B r e s l o w , R. ( 3 ) 429 B r e t t l e , R . ( 5 ) 264 B r i d o , D. ( 6 i i ) 164 B r i d o n , D. ( 3 ) 5 5 ; ( 4 ) 87 Brilkina, T.G. ( 5 ) 69, 70 B r i n k e r , U.H. ( 8 ) 67 B r o a d h u r s t , M.D. ( 3 ) 49 Brocksom, T . J . ( 3 ) 3 1 2 ; ( 7 ) 96 Bronneke, A. ( 3 ) 246; (6ii) 7 Bronson, J . J . ( 1 ) 46; ( 7 ) 32 Brook, M.A. ( 2 ) 1 5 1 ; ( 5 ) 413 B r o o k s , D.W. ( 3 ) 327 Brow, A.C. ( 6 i i ) 6 1 Brown, C.A. ( 6 i i ) 87 Brown, D.A. ( 5 ) 462 Brown, D.L. ( 9 ) 3 3 Brown, E. ( 3 ) 282 Brown, H.C. ( 1 ) 8 4 ; ( 3 ) 2 , 105; ( 4 ) 2 , 3 1 , 3 3 , 54, 88, 89; ( 6 i i ) 72, 7 3 , 7 6 , 7 8 - 8 0 , 85-88 Brown, J . M . ( 3 ) 1 2 1 ; ( 6 i ) 12 Brown, L. (1) 3 7 ; ( 6 i i ) 143 Brown, P.S. (1) 25 Brown, R.S. ( 5 ) 170 Brown, S.L. ( 6 i ) 4 1 Browne, T.E. ( 5 ) 425 Bruckmann, R . ( 5 ) 522 Bruckner, C. ( 3 ) 244; ( 8 ) 22 Brugman, A . ( 3 ) 3 7 6 ; ( 5 ) 249 B r u n e l , S . ( 3 ) 380; ( 5 ) 269 B r u n e t , E. ( 8 ) 121 B r u n e t , J . J . ( 4 ) 146
607 C a l d e r a r i , G. ( 3 ) 4 4 1 ; ( 5 ) 4 1 1 , 421 C a l l a n t , P. ( 7 ) 31 C a l o , V . (1) 7 0 Calvo-Mateo, A . ( 5 ) 366 Calzada, J . G . ( 1 ) 88; ( 3 ) 216; ( 4 ) 1 8 5 ; ( h i i ) 45 Cameron, A.G. ( 7 ) 14 C a m p b e l l , A.C. ( 3 ) 333 C a m p b e l l , M.L. ( 5 ) 450 C a m p b e l l , M.M. ( 8 ) 131 Campbell, S.F. ( 8 ) 6 9 ; ( 9 ) 5 4 , 55 Campos, P . J . ( 4 ) 128; ( 5 ) 9 1 , 252 C a n e l l a , K . A . ( 6 i i ) 27 C a n n i z z o , L . F . ( 5 ) 110 Capek, K . ( 3 ) 280 C a p l e , R . ( 1 ) 82 C a p o r u s s o , A.M. ( 1 ) 76 C a p r a t h e , B.W. (5) 5 4 5 ; ( 8 ) 103 C a r a n i , S. ( 4 ) 6 3 C a r c e l l a , E. ( 7 ) 6 4 C a r c e l l e r , E. ( 6 i ) 6 4 C a r d , P . J . ( 5 ) 203 C a r d a n i , S . ( 3 ) 190; ( 4 ) 62 C a r d e l l a c h , J . ( 3 ) 277 C a r d e l l i c c i o , C. ( 3 ) 431; ( 6 i ) 61 C a r d i l l o , G. ( 5 ) 166 C a r d i n a l e , G . ( 3 ) 201 C a r e y , S.C. ( 9 ) 29 C a r l d e r a r i , G. ( 6 i i ) 201 C a r l s o n , R . ( 5 ) 9 6 , 97 Carmeno, M . ( 3 ) 119; ( 4 ) 3 5 ; ( 5 ) 512 C a r o n , J.M. ( 5 ) 157 C a r o n , M. ( 8 ) 7 0 C a r o z z a , L. ( 3 ) 261 Carpenter, A . J . ( 3 ) 396; ( 6 i i ) 13, 3 1 , 33 C a r p i a , A. ( 6 i ) 53 C a r p i n o , L.A. ( 6 i i ) 6 1 C a r l , C.S. ( 2 ) 106 C a r r , S . A . ( 4 ) 8 2 , 204; C a b a l , M.-P. ( 5 ) 1 1 6 ; (8) ( 5 ) 384 211 C a r r e , M.C. ( 2 ) 1 2 9 ; ( 4 ) Cacchi, S . (1) 4 2 ; ( 3 ) 7 5 ; ( 5 ) 192; ( 6 i i ) 60 C a r r e i i o , M.C. ( 8 ) 121 175; ( 4 ) 9 5 ; ( 5 ) 235; ( 6 i ) 71 C a r r e t e r o , J . C . ( 5 ) 389 C a d i z , V . ( 3 ) 67 Carrig, R. ( 5 ) 32; ( 8 ) Cahiez, G. ( 2 ) 28; ( 3 ) 177 163; ( 5 ) 340 C a s a r a , P . ( 5 ) 152 Cahn, M . ( 5 ) 4 5 2 C a s a t i , P. ( 3 ) 1 1 9 ; ( 4 ) C a i l l a u x , B. ( 3 ) 391 3 5 ; ( 5 ) 512 C a i n e , D. ( 2 ) 86 C a s a t i , R. ( 3 ) 444; ( 5 ) C a i n e l l i , G . ( 4 ) 136; ( 5 ) 63 550 C a s c a v a l , A . ( 5 ) 402 C a l a n d r a , M. (5) 228 C a s i r a g h i , G . ( 3 ) 109
B r u n n , W . ( 5 ) 150 Brunner, H . ( 5 ) 27; ( 7 ) 51 B r u n s , A . ( 5 ) 487 Buchan, C. ( 3 ) 2 1 0 ; ( 4 ) 174 Buchowiecki, W. ( 5 ) 6 0 B u c h s c h a c h e r , P. ( 7 ) 119 B u c k l e y , D . J . ( 2 ) 118 Buchi, G. ( 1 ) 6 7 ; ( 2 ) 5 5 ; ( 9 ) 46 Bugden, G . ( 4 ) 8 0 Buk, J . ( 3 ) 331 B u l g a k o v a , V . N . ( 5 ) 279 B u l l , M.J. ( 4 ) 86 Bulman-Page, P.C. ( 5 ) 132 B u l y c h e v , A . G . ( 3 ) 439 Bumagin, N . A . ( 5 ) 432 B u n i n g , G.H.W. ( 3 ) 105 Bunya, N. ( 3 ) 4 3 7 ; ( 5 ) 34 B u r d i , D.F. ( 9 ) 2 B u r f o r d , S.C. ( 1 ) 5 2 ; ( 3 ) 2 2 2 ; ( 6 i ) 50 B u r g e s s , K . ( 6 i ) 54 B u r g o s , C.daG. ( 2 ) 7 8 ; ( 7 ) 122 B u r k , M . J . ( 1 ) 10 B u r k e , S.D. ( 7 ) 139 B u r k h a r t , J . P . ( 2 ) 117 B u r n s , H . D . ( 5 ) 452 B u r t o n , M. ( 3 ) 371 B u r t s c h e r , P . ( 3 ) 37 B u s e , C.T. ( 3 ) 19 B u s s , D. ( 4 ) 7 2 B u t l e r , R.N. ( 5 ) 524 B u t t , S . ( 3 ) 266 B u t t e r o , P.D. ( 6 i ) 8 2 B u z z i , A. ( 5 ) 398 By, A.W. ( 5 ) 436 Byers, J . H . ( 2 ) 65; ( 2 ) 8 1 ; ( 3 ) 290; ( 6 i i ) 172; ( 7 ) 135 Bystrom, S.E. (1) 5 5 ; ( 3 ) 343; ( 4 ) 165; ( 5 ) 138; ( 6 i ) 81
608 C a s n a t i , G . ( 3 ) 109 C a s t a g r i n o , E. ( 7 ) 34 C a s t e d o , L. ( 5 ) 444 C a s t l e , L. ( 5 ) 554 C a s t r o , B. ( 3 ) 462 C a t a l d i , G . ( 3 ) 214, 215 C a t a n i , V . ( 2 ) 155 C a t e a u - O l e s k a r , A. ( 7 ) 44 C a t e l l i , S . ( 7 ) 146 C a t i v i e l a , C. (3) 433 C a u b e r e , P. ( 2 ) 129; ( 4 ) 7 5 , 146; ( 5 ) 1 9 2 ; ( 6 i i ) 60 C a v a , M.P. ( 2 ) 5 6 ; ( 3 ) 228, 296; ( 4 ) 223; ( 5 ) 125, 364; ( 6 i i ) 170; ( 8 ) 1 9 , 7 9 , 197; ( 9 ) 27 C a z e s , B. ( 7 ) 4 1 C e c c h e t t i , S. ( 3 ) 126 C e n t e l l a s , V. ( 6 i ) 64; ( 7 ) 64 C e r e c e d a , J.A. ( 8 ) 109 C e r f o n t a i n , H. ( 3 ) 31, 194 C e r m e e r , P . ( 1 ) 76 Cha, J . S . ( 4 ) 221; ( 6 i i ) 87, 191 Chabala, J . C . ( 5 ) 35 C h a c k a l a m a n n i l , S. ( 7 ) 125 Chadwick, D . J . ( 3 ) 3 9 6 ; ( 6 i i ) 1 3 , 31, 33 C h a i , O.L. ( 3 ) 247 C h a k r a b o r t i , A.K. ( 3 ) 8 C h a k r a b o r t y , T.K. ( 3 ) 289 C h a l a i s , S. ( 2 ) 5 9 ; ( 3 ) 168; ( 5 ) 324 C h a m b e r l a i n , G . ( 7 ) 20 C h a m b e r l i n , A.R. ( 2 ) 1 4 8 Champseix, A. ( 8 ) 119 Charnson, E . ( 6 i i ) 139 Chan, T.H. ( 3 ) 4 6 , 203; ( 4 ) 9 8 , 218; ( 6 i i ) 122 Chandrakumar, N.S. ( 9 ) 6 0 C h a n d r a s e k a r a n , S. ( 2 ) 7 ; ( 3 ) 289 Chandrasekharan, J. ( 4 ) 31; ( 6 i i ) 86 C h a n e t , J . ( 8 ) 119 Chang, H.S. ( 3 ) 4 0 7 ; ( 5 ) 1 0 4 ; ( 5 ) 219, 286 Chang, L . J . ( 6 i i ) 50 Channe Gowda, D. ( 5 ) 16 ( 8 ) 58 Chao, K.-H. C h a r b o n n i e r , F. ( 7 ) 18 C h a r l t o n , ( 7 ) 100 C h a r p i o t , B. ( 2 ) 160; ( 3 ) 145 C h a s s a i n g , G . ( 3 ) 442 C h a s t a n e t , J . ( 8 ) 144-146 C h a s t r e t t e , M. ( 4 ) 202
General and Synthetic Methods C h a t a n i , N . ( 1 ) 31 ( 5 ) 3 2 3 ; ( 6 i i ) 108 C h a t t e r j e e , S . ( 3 ) 198; ( 6 i i ) 93 C h a t t o p a d h y a y , S . 3 ) 394 Chawla, H . M . ( 5 ) 428 Chen, C. ( 4 ) 6 ; ( 6 i i . ) 1 6 3 (7) 55; (9) 9 Chen, M.-H. Chen, S.-F. ( 5 ) 479 Chen, T.-S. ( 6 i i ) 150 Chen, Y.-S. ( 2 ) 1 5 ; ( 6 i ) 19 Chen, Y.-Y. ( 8 ) 138, 139 C h e n a r d , B.L. ( 6 i i ) 125 C h e n a u l t , J . ( 3 ) 166 C h e n c h a i a h , P.C. ( 4 ) 227 C h e n e v e r t , R. ( 4 ) 11 Cheng, C.H. ( 5 ) 528 Cheng, Y.4. ( 8 ) 189 C h e r k a s o v , R.A. ( 3 ) 228; ( 8 ) 78 Chernoglazova, N . I . ( 3 ) 417 C h e r r y , W.R. ( 5 ) 548 C h e s h i r e , D.R. ( 7 ) 166 Cheung, C.K. ( 5 ) 1 7 (3) 96; ( 4 ) C h i , K.-W. 139 C h i a c c h i o , U. ( 8 ) 1 3 9 C h i a n e l l i , D. ( 1 ) 28 Chiba, K . ( 6 i ) 72, 73; ( 8 ) 219, 220 C h i c h e s t e r , S.V. ( 5 ) 42 C h i d a , Y . ( 5 ) 88 Chiem, P.V. ( 8 ) 37 C h i h a r a , T. ( 3 ) 7 0 C h i k a s h i t a , H . ( 5 ) 417 Chirniak, A. ( 5 ) 461 C h i m i c h i , S . ( 5 ) 4 8 , 398 C h i n n , R.L. (1) 4 4 ; ( 3 ) 184 C h i t r a k o r n , S. ( 4 ) 117 Cho, S.Y. ( 5 ) 15 C h o i , J.-K. ( 8 ) 1 5 8 ; ( 9 ) 30 Choi, K.N. (3) 378; (5) 3 0 ; ( 6 i ) 15 C h o i l e a i n , N . N . ( 5 ) 462 Chong, J . M . ( 3 ) 1 8 ; ( 3 ) 390, 446; ( 4 ) 73; ( 5 ) 1 5 8 , 250; ( 6 i ) 3 4 ; ( 6 i i ) 128 C h o r b a d j i e v , S. ( 5 ) 51 Chou, T. ( 6 i i ) 5 0 , 189 Choudary, B.M. ( 2 ) 9 ; ( 4 ) 120 Chow, H.-F. ( 3 ) 3 4 5 , 370 Chow, Y.L. ( 5 ) 499 Choy, W. ( 6 i ) 9 C h r i s t e n s e n , B.G. ( 5 ) 3 5 C h r i s t i e , B . J . ( 3 ) 443
C h r i s t i e , C . C . ( 5 ) 184; ( 8 ) 114 C h r i s t i e , K.O. ( 5 ) 318 Chu, M. ( 5 ) 9 8 ( 7 ) 171 Chuang, Y.-H. Chuche, J . ( 8 ) 147 Chung, B.C. ( 3 ) 407; ( 5 ) 286 Chung, J.Y.L. ( 6 i ) 2 7 ; ( 9 ) 20 Church, D.F. ( 5 ) 554 Chuvashev, Yu.A. ( 5 ) 4 9 8 C i c i a n i , G. ( 5 ) 48 C i n q u i n i , M. ( 2 ) 172; ( 3 ) 404; ( 5 ) 1 7 1 C i r o d e a n , J . M . ( 3 ) 459 C i t t e r i o , A. ( 2 ) 2 3 C i u f o l i n i , M. (8) 170 C l a n s o n , E. ( 6 i ) 6 2 C l a r d y , J . C . ( 3 ) 300 Clarernbeau, M. ( 6 i i ) 3 Claremon, D.A. ( 6 i i ) 1 9 3 ; ( 9 ) 69 C l a r k , G.R. ( 4 ) 1 4 1 ; ( 6 i ) 25; ( 7 ) 8 2 C l a r k , J . H . ( 5 ) 291 C l a r k , M.T. ( 5 ) 26 C l a u s , H . ( 8 ) 33 C l a u s e n , H . ( 3 ) 251; ( 7 ) 109 Clemens, R.J. ( 3 ) 1 4 0 Clerno, N.G. ( 3 ) 331, 332 C l e o p h a x , J. ( 7 ) 4 4 C l e r i c i , A. ( 4 ) 8 5 C l i f f e , I.A. ( 5 ) 8 6 C l i v e , D.L.J. ( 5 ) 3 4 7 ; ( 7 ) 5 3 , 5 4 , 166 C o a t e s , R . H . ( 7 ) 1 2 1 , 153 C o c k e r i l l , G.S. ( 2 ) 8 5 ; ( 7 ) 1 4 4 , 145 Coe, D.E. ( 5 ) 253; ( 6 i i ) 168 C o e l h o , F. ( 3 ) 11, 3 1 2 ; ( 7 ) 96 Coghlan, M . J . ( 2 ) 9 0 ; ( 7 ) 143 Cohen, N . ( 3 ) 261 Cohen, T. ( 2 ) 8 0 ; ( 4 ) 51, 142; ( 7 ) 7 , 157 C o l e , P. ( 7 ) 1 2 5 C o l e , T.E. ( 6 i i ) 88 Collignon, N . ( 5 ) 128; ( 6 i i ) 153 C o l l i n , J. ( 4 ) 1 9 1 C o l l i n g t o n , E.W. ( 4 ) 1 0 9 C o l l i n s , S. ( 5 ) 130 Colombo, L. ( 2 ) 172; ( 3 ) 1 2 2 , 249; ( 4 ) 6 1 , 6 6 Colonna, S. ( 4 ) 225; (8) 4 C o l v i n , E.W. (8) 225
609
Author Index C o l w e l l , B.L. ( 3 ) 227 Cornasseto, J . V . ( 2 ) 155 Cornisso, G. ( 5 ) 405 Commerqon, A . ( 7 ) 8 7 ; ( 8 ) 89 Conia, J.-M. ( 2 ) 165; ( 6 i i ) 69; ( 7 ) 6 0 C o n t e n t o , M. ( 8 ) 223 Cook, J . M . ( 5 ) 54 Cooke, M.P., j u n . ( 6 i i ) 4 ; ( 4 ) 7 4 ; ( 7 ) 3 5 , 37 Cookson, R . C . ( 8 ) 7 , 7 5 Cooney, J.V. ( 5 ) 371 Corey, E . J . ( 1 ) 3 4 , 5 4 ; ( 2 ) 1 , 177; ( 3 ) 1 0 4 , 2 8 8 ; ( 4 ) 119; ( 5 ) 8 7 , 3 4 9 ; ( 6 i i ) 148; ( 9 ) 1 9 , 52 C o r l e y , E.G. ( 3 ) 350 Corrnons, A . ( 8 ) 118 C o r n e j o , J . J . ( 5 ) 469 C o r n e l i s , A. ( 2 ) 59; ( 4 ) 114; ( 5 ) 429 C o r n e l i s s e , J . ( 5 ) 422 C o r n i s h , C . A . ( 6 i i ) 158 C o r r i e , J.E.T. ( 5 ) 182 C o r r i u , R.J.P. ( 8 ) 206 C o r s a n o , S . ( 7 ) 34 C o s s e n t i n i , M. ( 2 ) 185; ( 5 ) 339 C o s s i o , F.P. ( 2 ) 4 ; ( 4 ) 1 1 6 ; ( 8 ) 229 Cossy, J. ( 4 ) 9 2 ; ( 6 i i ) 107; ( 7 ) 58 C o s t a , A . ( 3 ) 30 C o s t a , A.M.B.S.R.C.S. ( 6 i i ) 15 C o s t e r o , A.M. ( 4 ) 158 C o t t i n e a u , F. ( 5 ) 68 C o u l t e r , P.B. ( 5 ) 472 C o u s s e a u , J . ( 5 ) 538 C o u t r o t , P. ( 8 ) 130 C o u t u r e , C. ( 8 ) 230 C o u t u r i e r , D. ( 5 ) 330 Cowan, P.J. ( 2 ) 3 5 ; ( 3 ) 97 C o y l e , J . D . ( 8 ) 80 C o z z i , F. ( 2 ) 172; ( 5 ) 171 C r a b t r e e , R.H. (1) 10 C r a h e , M.-R. ( 5 ) 538 C r a n k , G . ( 5 ) 281 C r a v e n , A. ( 7 ) 117 C r i c h , D. (1) 16; ( 3 ) 5 3 , 460; ( 4 ) 127 C r o c e , P.D. ( 6 i i ) 184 Crornbie, L. ( 5 ) 2 3 9 , 240 C r o s s l e y , R . ( 5 ) 8 6 , 373 C r o v i n d o n , S.V. ( 7 ) 141 Crumbie, R . ( 3 ) 4 4 8 ; ( 8 ) 7
C r u z , S.G. ( 5 ) 109 C u f f i g n a l , R . ( 3 ) 316 Culshaw, D . ( 8 ) 7 1 ; ( 9 ) 57 Cum, G . (1) 7 8 Cun-heng, H . ( 3 ) 300 Cupps, T.L. ( 2 ) 101; ( 5 ) 210 C u r r a n , D.P. ( 7 ) 55-57, 7 8 ; ( 8 ) 105; ( 9 ) 8 , 9 C u t t i n g , I. ( 3 ) 1 2 1 ; ( 6 i ) 12 C z e r n i c k i , S . ( 4 ) 115 Dabbagh, G . ( 4 ) 209 Dai-Ho, G . ( 8 ) 194 Dal P i a z , V. ( 5 ) 48 Dalpozzo, R. ( 5 ) 409; ( 6 i i ) 58 Darnmel, R . ( 5 ) 390 Dana, G . ( 8 ) 42 d'Angelo, J. ( 2 ) 158; ( 5 ) 4 8 8 ; ( 7 ) 102 D a n h e i s e r , R.L. (1) 4 6 ; ( 3 ) 3 6 ; ( 6 i i ) 1 1 6 , 117; ( 7 ) 32, 42; ( 8 ) 44; ( 9 ) 47 D a n i e w s k i , W.M. ( 2 ) 8 0 ; ( 3 ) 3 5 4 ; ( 4 ) 142; ( 7 ) 157 D a n i k i e w i c z , W. ( 5 ) 2 1 , 407 Danishefsky, S.J. ( 3 ) 353; ( 6 i i ) 105; ( 7 ) 125; ( 8 ) 58-61, 1 7 0 , 185; ( 9 ) 4 9 , 6 2 Dankwardt, J . W . ( 3 ) 394 D a n n e c k e r , R . ( 8 ) 32 Danopoulos, A . ( 5 ) 532 D a n z i n , C. ( 5 ) 152 D a r e n s b u r g , M.Y. ( 4 ) 7 Da S e t t i r n o , F. ( 1 ) 76 D a s g u p t a , R . ( 2 ) 94 D a s z k i e w i c z , Z. ( 5 ) 340 D a t a , A . ( 3 ) 174 Dauben, W.G. ( 2 ) 1 4 9 ; ( 7 ) 2 5 , 26 Daugan, A. ( 3 ) 282 Dauphin, B. ( 5 ) 153 D ' A u r i a , M. ( 2 ) 1 7 D a v i d , S . ( 4 ) 130 D a v i d s o n , A.M. ( 7 ) 113 D a v i d s o n , F. ( 6 i i ) 125 D a v i e s , H.G. (3) 266, 269 D a v i e s , M. ( 3 ) 258 D a v i e s , S.G. ( 3 ) 2 3 , 2 4 , 301; ( 4 ) 7 1 ; ( 6 i ) 363 8 , 4 0 , 42-44; ( 6 i i ) 1 9 ; ( 8 ) 15 D a v i s , F.A. (3) 1 2 ; ( 6 i i )
203 Davy, H . ( 3 ) 229 Dawson, M . J . ( 3 ) 266 Dean, F.M. ( 6 i i ) 15 De A n g e l i s , F. ( 5 ) 76; ( 7 ) 86 D e b e r l y , A . ( 3 ) 1 5 , 108 D e B e r n a r d i s , J . F . ( 5 ) 342 d e B i e , D . A . ( 5 ) 57 De Buyck, L. ( 5 ) 473 De C a r v a l h o , E. ( 5 ) 256 D e c i c c o , C. ( 7 ) 20 D e c k e r , O.H.W. ( 3 ) 32 De C l e r c q , P . J . ( 7 ) 8 8 ; ( 9 ) 21 D e c o d t s , G . ( 3 ) 67 D e c o r t e , E. ( 5 ) 405 Dedolph, D.F. ( 5 ) 404 Deeb, T.M. ( 6 i i ) 189 Defauw, J. ( 6 i i ) 102-104; ( 7 ) 7 0 , 131, 132 D e f a y e , J . ( 4 ) 108 De F u s c o , A . A . ( 5 ) 425 d e G r o o t , A . ( 2 ) 50 D e g u c h i , R . ( 3 ) 102 Dehrnlow, E.V. ( 3 ) 5 9 , 9 4 ; ( 5 ) 7 2 , 338 De J e s o , B. ( 2 ) 1 5 7 ; ( 3 ) 8 5 , 161; ( 5 ) 114 d e J o n g , R.L.P. (1) 6 4 ; (6ii) 8 De Kimpe, N. ( 5 ) 4 7 3 , 4 7 4 ; ( 8 ) 132 de l a Hoz, A . ( 8 ) 213 DeLano, J. ( 8 ) 49 De l a s H e r a s , F.G. ( 5 ) 366 Del B u t t e r o , P. ( 5 ) 497 Del G i a c c o , T. ( 5 ) 553 D e l l a F o r t u n a , G. ( 5 ) 352 D e l l ' E r b a , C. ( 4 ) 220 Delmas, M. ( 3 ) 1 6 5 , 167 Delmond, B. (1) 1 8 , 19 de Lopez-Cepero, I . M . ( 2 ) 32 DeLucchi, 0 . (1) 8 3 ; ( 6 i i ) 1 8 0 ; ( 8 ) 126 D e m a i l l y , G. ( 6 i i ) 186; (8) 2 de Meijere, A. ( 7 ) 8 3 Demersman, P. ( 5 ) 400 De Mico, A. ( 2 ) 17 Demuth, M. ( 7 ) 84 Deng, M.-Z. ( 3 ) 26 DeNinno, M. ( 6 i i ) 105 Denmark, S.E. ( 2 ) 93 Denny, W.A. ( 5 ) 90 D e n t , W. (8) 1 3 8 , 139 Depezay, J.-C. ( 2 ) 100, 180 D e p r Q s , J.-P. ( 3 ) 11,
610 312; ( 7 ) 9 6 De R u i t e r , J . ( 5 ) 369 D e s a i , M.C. (I) 54; ( 3 ) 2 ; ( 4 ) 8 9 ; ( 6 i i ) 78; (9) I9 De S a r l o , F. ( 8 ) 209 Deschamps, P . ( 3 ) 6 Deshong, P . ( 6 i ) 7 5 ; ( 8 ) 150; ( 9 ) 6 0 Deslongcharnps, P. ( 3 ) 179; ( 8 ) 7 0 Desmond, R . ( b i i ) 1 0 4 ; ( 7 ) 1 3 0 , 131 de Souza B a r b o s a , J . C . ( 2 ) 178; ( 4 ) 171; ( b i i ) 63 DeVos, M.J. ( 6 i i ) 5 1 ; ( 7 ) 11 D e V r i e s , J.G. ( 3 ) 1 0 5 de W o l f f , W . H . ( 7 ) 5 Dhimane, H . ( 8 ) 147 D i a b , J . ( 2 ) 7 2 ; ( 4 ) 194; ( 8 ) 24 Diazde V i l l e g a s , M.D. ( 3 ) 433 D i b b e n s , J . A . ( 3 ) 335 Dicke, R . (1) 30; ( b i i ) 124 Dicknran, D . A . ( 9 ) 4 1 D i e t e r , K.K. ( 2 ) 181 D i e t r i c h , S. ( 8 ) 51 D i e t z , M. ( 3 ) 156; ( 5 ) 245 D i Fabio, R . ( 3 ) 279 DiPar-do, R.M. ( 3 ) 386 D i s a n a y a k a , B.W. ( 9 ) 6 D i t r i c h , K . ( 2 ) 3 3 , 150 D i x i t , V. (1) 93 Dixon, J. ( 9 ) 34 Dixon, L . A . ( 7 ) 170 D o a d t , E.G. ( 3 ) 395; ( 6 i i ) 32 D o b a s h i , S . ( 8 ) 74 Dodonov, V . A . ( 5 ) 6 9 , 7 0 D o e t z , K . H . ( 9 ) 26 D o i , J . T . ( 4 ) 224 D o l e s c h a l l , G . ( 8 ) 232 D o l l e , R.E. ( 6 i ) 4 9 ; ( 8 ) 20; ( 9 ) 6 7 , 6 9 D o l l i n g e r , H. ( 5 ) 136 Dombroski, M . A . ( 3 ) 113 Donek, J . M . ( 7 ) 2 Doney, J . J . ( 3 ) 115 D ' O n o f r i o , F. ( 2 ) 17 Dordor-Hedgecock, Z.M. ( 3 ) 23; ( 4 ) 71; ( 6 i ) 3 6 , 37 Dorokhov, V . I . ( 5 ) 266 Dorow, R . L . ( 3 ) 1 2 Doutheau, A . ( I ) 74; ( 2 ) 72
General and Synthetic Methods E g e r t , E. ( 3 ) 400 E g l i , M . ( 5 ) 106 E h r e n k a u f e r , R.E. ( 5 ) 9 2 E i c h b e r g e r , G . ( 4 ) 39 E i n h o r n , J. ( 1 ) 1 3 ; ( 4 ) 49; ( 6 i i ) 64 E i s , M.J. ( 5 ) 59 E i s c h , J.J. ( 6 i i ) 5 3 Eisenbraun, E.J. ( 2 ) 16 E l a n g o , V. ( 6 i ) 7 5 ; ( 9 ) 60 E l - B a r b a r y , A . A . ( 5 ) 259 El-Bayouki, K . A . M . ( 5 ) 101 E l G a d i , A . ( 8 ) 130 E l g u e r o , J . (8) 213 E l H a l l a o u i , A . ( 3 ) 430 E l i e l , E.L. (3) 9 9 , 348 E l ' k i n s o n , R.S. ( 5 ) 6 1 , 273 E l l i o t t , J. ( 6 i i ) 173 E l n a g d i , M . H . ( 5 ) 380 El-Omrani, Y.S. ( 4 ) 1 4 E l s e v i e r , C.J. ( 1 ) 76 E n d e r s , D. ( 2 ) 1 5 4 ; ( 3 ) 426; ( 5 ) 2 1 7 , 453 Endo, T. ( 2 ) 3 ; ( 3 ) 2 4 2 ; ( 4 ) 1 2 3 , 200; ( 5 ) 2 4 , 1 7 5 , 251; ( 8 ) 27 E n g l e r , T.A. ( 9 ) 19 Engrnan, L. ( 1 ) 4 5 , 5 5 ; ( 2 ) 1 2 1 ; ( 4 ) 165; ( 6 i i ) 206 Enholm, E.J. (3) 290; ( 5 ) 83; ( 6 i i ) 135; ( 8 ) 159 Enhsen, A . (3) 3 1 9 ; ( 6 i i ) 42 Enhsen, E. ( 5 ) 243 Enornoto, M . ( 3 ) 13 E n t w i s t l e , I . D . ( 3 ) 475 E p s z t e i n , R . ( 5 ) 118 Eremeev, A . V . ( 5 ) 2 , 6 1 , 273 E r i o n , M.D. ( 6 i i ) 7 1 E r n s t , A.B. ( 3 ) 288; ( 5 ) 348 E r n s t , B. ( 3 ) 253; ( 7 ) 21 E r r a z u r i z , B. ( 4 ) 112 E r s h o v , A.Yu. ( 5 ) 449 Erskine, G . J . ( 4 ) 41 E s w a r a k r i s h n a n , S. ( 3 ) 1 2 3 , 3 9 9 ; ( 5 ) 247 E t h e r e d g e , S . J . ( 8 ) 170 E a s t o n , C.J. ( 8 ) 235 G t i e n n e , A . ( 8 ) 119 E b e r s o n , L,. ( 5 ) 4 2 3 , 424 E v a n s , B.E. ( 3 ) 386 E b e t i n o , F.H. ( 7 ) 161 E v a n s , D.A. (3) 1 2 , 133; Eck, G. ( 7 ) 1 6 2 , 1 6 3 ( 8 ) 2 2 6 , 227 Edwards, P.D. ( 2 ) 43; E v a n s , L.T. ( 2 ) 99 ( 6 i i ) 17 E v a n s , S.A., j u n . ( 4 ) E f f e n b e r g e r , F. ( 3 ) 1; 192, 193; ( 6 i i ) 160; (5) 260; ( 6 i i ) 151, 169 (8) 10
Doutron-Woitrin, F. ( 3 ) 403; ( 5 ) 283, 284 DOW, R.L. ( 3 ) 1 3 3 Drabowicz, J . ( 6 i i ) 177 D r e i d i n g , A.S. ( 5 ) 1 0 6 ; ( 7 ) 1 6 5 , 168 D r e n e s , S.E. ( 3 ) 304 D r o u i l l a r d , S. ( 3 ) 8 5 Drouin, J. ( 2 ) 165; ( 6 i i ) 6 9 ; ( 7 ) 69 D r y a n s k a , V . ( 3 ) 213; ( 5 ) 346 Du, N.T. ( 2 ) 1 2 8 Dua, S.K. ( 6 i i ) 5 3 D u b o i s , J.-E. ( 2 ) 1 7 0 ; ( 4 ) 56 Duchene, A . ( 6 i i ) 2 D u d f i e l d , P. ( 3 ) 1 , 111; ( 6 i ) 33; ( 8 ) 1 Dudman, N.P.B. ( 3 ) 258 D u f f , S.R. ( 3 ) 420; ( 6 i i ) 5 Duggan, M.E. ( 8 ) 54; ( 9 ) 68 Duhaime, R.M. ( 3 ) 191 Duhamel, L. ( 6 i i ) 38 Duhamel, P . ( 2 ) 7 6 ; ( 5 ) 255 Duhl-Emswiler, B.A. ( 6 1 i ) 144 Duke, C . V . A . ( 5 ) 291 Dumas, S. ( 2 ) 6 3 ; ( 3 ) 253; ( 7 ) 21 Dunach, E. ( 6 i i ) 155 Duncan, M.P. ( 2 ) 103 Dunogues, J . ( 4 ) 55 Dupin, J . F . E . ( 3 ) 166 D u p u i s , D. ( 7 ) 111 D u p u i s , J . ( 5 ) 344 Dupuy, C. ( 2 ) 1 7 8 ; ( 6 i i ) 63 Durckheirner, W. ( 8 ) 214 Durrnan, J . ( 3 ) 1 4 9 ; ( 6 i i ) 173 D u t t a , D . K . ( 5 ) 475 D v i n s k i k h , V . V . ( 5 ) 494 D z i a d u l e w i c z , E. ( 3 ) 269; ( 6 i i ) 55 D z i e l e n z i a k , A. ( 2 ) 2; ( 4 ) 124 D z u r i l l a , M. ( 8 ) 122
61 1
Author Index E v a n s , S.V. ( 5 ) 3 6 , 38 Exon, C. ( 2 ) 6 7 ; ( 7 ) 6 2 E y e r , M. ( 5 ) 394 E y l e y , S.C. ( 5 ) 1 7 0 , 482 F a a s , M. ( 5 ) 509 F a b e r , K . ( 4 ) 39 F a b i o , P.F. ( 2 ) 128 F a b r i c h n y i , B.P. ( 5 ) 279 Fadel, A. ( 3 ) 415; ( 4 ) 140; ( 7 ) 1 5 9 , 160 F a k u d a , N . ( 5 ) 54 F a k u t a n i , Y. ( 1 ) 6 F a l c k , J . R . ( 4 ) 145; ( 5 ) 292 F a l l o n , G.D. ( 5 ) 3 2 2 ; ( 6 i i ) 109 Falmagne, J . - B . ( 3 ) 423, 24 F a l o r n i , M . ( 4 ) 32 F a n g , J.-M. ( 5 ) 100 Fankhauser, J.E. ( 3 ) 432; ( 5 ) 140 F a r i n a , F. ( 5 ) 4 1 , 43 F a r m a r , J . G . ( 3 ) 197 F a r n i a , M. ( 5 ) 318 F a r o o q , 0 . ( 5 ) 293 F a t o p e , M.O. ( 3 ) 67 F a v a , G . G . ( 3 ) 109 F e g u s o n , S.B. ( 4 ) 175 Fehlhammer, W.P. ( 5 ) 388 Fekih, A. ( 4 ) 7 6 ; ( 5 ) 7 8 , 7 9 , 9 4 ; ( 6 i i ) 207-209 F e l d h u e s , M. ( 3 ) 56 Feldman, P . L . ( 8 ) 36 F e l i x , A . S . ( 5 ) 366 F e l k i n , H. (1) 9 F e l l e r , A . ( 5 ) 46 F e l l o w s , L . E . ( 5 ) 3 6 , 38 F e l l o w s , R . ( 8 ) 81 Fenk, C.J. ( 8 ) 105 F e r g u s o n , I.E.G. ( 8 ) 91 F e r g u s s o n , S.B. ( 3 ) 2 0 9 ; ( 8 ) 151 F e r i n g a , B.L. ( 4 ) 161; ( 5 ) 131 F e r n a n d e z , J . R . (1) 7 2 ; ( 6 i i ) 4 0 , 41 F e r n h d e z - A l v a r e z , E. ( 5 ) 2 7 0 ; ( 7 ) 12 Fernandez de la P r a d i l l a , R. ( 3 ) 269 F e r n h d e z - R e s a , P. ( 5 ) 366 F e r r a z , H.M.C. ( 3 ) 307 F e r r e r , P. ( 4 ) 158 F e r r o u d , C . ( 7 ) 102 F e t i z o n , M . ( 2 ) 110, 111; ( 4 ) 4 0 , 1 0 2 ; ( 6 i i ) 43 F e t t e r , J. ( 8 ) 232
F e y , P. ( 5 ) 453 F i a n d a n e s e , V . ( 3 ) 431; ( 6 i ) 61 F i a s c h i , R . ( 3 ) 334 F i c k e s , G.N. ( 3 ) 299 F i e l d s , K.W. ( 3 ) 7 2 ; ( 6 i i ) 39 F i g a d e r e , B. ( 8 ) 42 Fillebeen-Khan, T . ( 1 ) 9 F i n c h , H . ( 4 ) 109 F i n e t , J.-P. ( 2 ) 1 6 0 ; ( 3 ) 145 F i n k , D.M. ( 3 ) 3 6 , 3 2 5 ; ( 7 ) 42 F i n k , J. ( 5 ) 5 1 7 ; ( 8 ) 13 F i n k l e r , S.H. ( 2 ) 8 3 F i o r a v a n t i , S . ( 5 ) 212 F i s c h e r , G. ( 5 ) 490 F i s c h e r , H . ( 5 ) 451 F i s c h e r , J . W . ( 5 ) 257 F i s c h e r , W. ( 3 ) 45 F i s h e r , D . ( 5 ) 2 3 9 , 240 F i s h p a u g h , J . R . ( 2 ) 181 F i t z m a u r i c e , N.J. ( 1 ) 3 2 ; ( 5 ) 3 2 2 ; ( 6 i 1 ) 109 F i t z n e r , J.N. ( 3 ) 4 3 2 , 4 5 8 ; ( 5 ) 1 4 0 , 141 F i x a r i , B. ( 3 ) 380; ( 5 ) 269 F l e e t , G . W . J . ( 5 ) 36-38 Fleming, I. ( 2 ) 156; ( 3 ) 128, 345; ( 6 i i ) 1 6 , 9 6 , 101, 126, 129; ( 7 ) 7 4 , 101 F l e m i n g , J . A . (1) 3 9 , 4 0 ; ( 6 i i ) 137 F l i p p i n , L . A . ( 3 ) 113 F l o y d , C . D . ( 7 ) 113 F l o y d , M.B. ( 2 ) 128 F o l e y , L . H . ( 5 ) 365 F o n t , J . ( 3 ) 277 F o n t a n a , F. ( 4 ) 225 F o o t e , C . S . ( 3 ) 189 F o r e s t i , E. ( 8 ) 128 F o r n a s i e r , R . ( 4 ) 26 F o r t g e n s , H . P . ( 6 i i ) 100; ( 8 ) 1 7 2 , 173 F o r t o u l , C . ( 3 ) 187 F o s s e y , .J. ( 3 ) 56 F o u c a r d , A . ( 3 ) 168 F o w l e r , F.W. ( 5 ) 9 8 ; ( 8 ) 187 F o x , C . M . J . (3) 366 Fox, D.P. ( 7 ) 59 Fox, M.A. ( 3 ) 205 F r a n k e l , M.B. ( 5 ) 506 F r a s e r - R e i d , B. ( 3 ) 2 5 0 , 2 5 9 , 3 0 8 ; ( 9 ) 58 F r a u e n r a t h , H. ( 3 ) 269 F r a y , M . J . ( 8 ) 100 F r a z i e r , J . O . ( 7 ) 141;
( 8 ) 152 F r e c h e t , J . M . J . ( 3 ) 465 F r e i d l i n g e r , R.M. ( 1 ) 6 7 ; ( 3 ) 386 F r e s k o s , J.N. ( 3 ) 336; ( 5 ) 379 F r e y , H. ( 3 ) 81 F r i e d r i c h , E.C. ( 7 ) 2 F r i e d r i c h , K. ( 8 ) 37 F r i e s e n , R.W. ( 1 ) 5 6 ; ( 6 i i ) 133; ( 7 ) 72 F r i n g u e l l i , R . ( 3 ) 126 F r i o u r , G . ( 2 ) 28; ( 3 ) 163; ( 5 ) 340 F r i s t a d , W.E. ( 3 ) 2 8 8 ; ( 4 ) 211; ( 5 ) 104, 348 F r i t z , H . ( 5 ) 188; ( 8 ) 117 F r o e c h , S. ( 2 ) 150; ( 4 ) 97 F r o s t , B.M. ( 4 ) 197 F r o s t i n - R i o , M. ( 5 ) 353 F r y e , S . V . ( 3 ) 348 F u c h i g a m i , T. ( 3 ) 68 F u c h i k a m i , M. ( 6 i ) 76 F u c h s , P.L. ( 2 ) 77 Fugami, K . ( 1 ) 2 9 ; ( 8 ) 154 F u g a n t i , C. ( 3 ) 119; ( 5 ) 512 Fugmann, B. ( 9 ) 43 F u j i , K. ( 3 ) 257; ( 5 ) 437 F u j i i , M . ( 5 ) 416 F u j i i , N . ( 3 ) 481 F u j i k u r a , S . ( 7 ) 36 F u j i m o t o , Y . ( 8 ) 17 Fu-jisaki, S . ( 3 ) 7 ; ( 4 ) 213 F u j i s a w a , T. ( 3 ) 3 4 , 237, 267, 3 3 8 ; ( 4 ) 3 7 , 3 8 , 138 F u j i t a , E. ( 1 ) 5 0 , 7 9 , 8 0 ; ( 3 ) 8 8 , 176, 3 4 1 , 3 4 6 ; ( 4 ) 157, 198; ( 5 ) 327; (6j.i) 1 1 3 ; ( 8 ) 52 F u j i t a , M. ( 3 ) 387; ( 5 ) 2 6 1 ; ( 8 ) 68 F u j i t a , S . ( 3 ) 298 F u j i t a , T. ( 3 ) 245; ( 6 i ) 76 Fujiwara, I . ( 4 ) 213; ( 6 i i ) 44 F u j i w a r a , M. ( 8 ) 116 F u j i w a r a , S. ( 3 ) 314 F u j i w a r a , T. ( 1 ) 7 3 Fukazawa, Y. ( 7 ) 95 F u k u h a s a , T. ( 4 ) 150 Fukumoto, K . ( 7 ) 1 1 4 , 123; ( 8 ) 1 8 8 ; ( 9 ) 22 Fukunaga, T. ( 3 ) 208; ( 5 ) 408
612 Fukutani, Y. ( 7 ) 3 Fukuyama, K . (8) 4 6 Fukuyama, T. ( 4 ) 103 Fukuzawa, S . ( 6 i i ) 204, 212, 213 F u n a k o s h i , S. ( 3 ) 481 F u n a k o s h i , Y. ( 5 ) 299 Funk, D.M. ( 6 i i ) 1 1 6 , 117 Funk, R.1,. ( 7 ) 1 5 F u n u h a s h i , H . ( 6 i i ) 110 Furber, M. (1) 52, 101; ( 3 ) 222; ( 6 1 ) 50 F u r s t , A . ( 7 ) 119 Furst, G.J. (9) 63 Furukawa, H . ( 9 ) 7 8 Furuta, K. (7) 9 F u r u t a , T. ( 7 ) 8 5 F u s t e r o , S. ( 5 ) 1 9 4 , 4 8 0 ; ( 8 ) 115 G a d e l l e , A . ( 4 ) 108 Gadwood, R.C. ( 6 i i ) 1 ; ( 7 ) 164 G a e o v i , E.G. (5) 302 Gaeton Angoh, A. ( 7 ) 5 3 , 54 G a g n i e u , C.H. ( 5 ) 5 1 0 G a i n e l l i , G . (8) 223 ( 6 i i ) 53 Gais, H.-J. G a l a k a t o s , N . G . ( 3 ) 479 G a l l a g h e r , T. ( 3 ) 2 6 9 ; ( 6 i i ) 55; (8) 1 6 9 Gallego, C.H. ( 5 ) 109 G a l l o , R . ( 1 ) 78; ( 3 ) 6 G a l l o n , G.D. ( 1 ) 32 Gambacorta, A. ( 5 ) 76; ( 7 ) 8 6 , 146 Garnbale, R.J. ( 3 ) 52 Gamboni, R . ( 3 ) 110 Gandolfi, M. ( 2 ) 23 Ganem, B. ( 4 ) 205; ( 5 ) 14, 59, 65 Ganguly, A.K. ( 8 ) 40 G a n g u l y , R. ( 8 ) 9 8 G a n i n , E.V. ( 5 ) 271 G a r b a l n s k a y a , N.S. ( 3 ) 417 G a r b a r i n o , G. ( 4 ) 220 G a r c i a , A . ( 7 ) 134 G a r c i a , J . ( 5 ) 378 Garcia-Raso, A. ( 2 ) 79; ( 3 ) 30 G a r c i a Ruano, J . L . (5) 389 G a r d r a t , C. ( 3 ) 286 Gareev, G.A. ( 5 ) 121 G a r n e r , P. ( 3 ) 4 5 2 ; ( 5 ) 159 G a r v e r , L.C. ( 5 ) 4 0 3 G a s e t , A . ( 3 ) 1 6 5 , 167
General and Synthetic Methods Gassman, P.G. ( 4 ) 8 3 ; ( 5 ) 5 Gastambide, B ( 3 ) 43 7 ) 107 G a s t o n , R.D. G a t e n b e c k , S. ( 3 ) 8 4 , 445 Gaudemar, M. 3 ) 2 9 , 405; ( 5 ) 246 Gaudemar-Bardone , F . ( 3 ) 316 Gaudemer, A. ( 5 ) 3 5 3 Gaus, P.L. ( 4 ) 7 G a v a i , A . V . (3) 192 G a v i n a , F. ( 4 ) 158 Gaydoul, K.R. ( 6 i i ) 9 Gedanken, A . (1) 7 6 G e i b , G.D. ( 5 ) 109 G e l b a r d , G . ( 2 ) 24 G e n n a r i , C. ( 2 ) 1 7 2 ; ( 3 ) 122; ( 3 ) 1 9 0 , 2 3 3 , 249; ( 4 ) 61-63, 6 6 Georg, G . I . ( 5 ) 294; (8) 224 G e o r g e s , M. ( 3 ) 259 G e o r g o u l i s , C. ( 4 ) 1 1 5 G e r a t y , R . A . ( 5 ) 462 G e r h a r d t , C . (8) 224 GGro, S.D. ( 7 ) 44 G e r t s y u k , M . N . ( 5 ) 266 G e r v a i s , C. ( 4 ) 194; ( 8 ) 24 G e u r t s e n , B. ( 5 ) 57 Gevorgyan, V . ( 4 ) 1 2 ; ( 5 ) 3 G h a t e k , U.R. ( 2 ) 9 4 ; ( 3 ) 8 G h o s e z , L. ( 2 ) 6 3 ; ( 3 ) 253; ( 7 ) 21 Ghosh, A . K . ( 8 ) 5 5 G i a c o m e l l i , G . ( 4 ) 32 G i a c o m i n i , D. ( 8 ) 223 Giammanco, L. ( 5 ) 374 G i a n g , Y.F. ( 3 ) 2 5 3 ; ( 7 ) 24; ( 8 ) 50 G i b s o n , C.L. ( 3 ) 271 G i b s o n , D.H. ( 4 ) 1 4 G i b s o n , R.S. ( 2 ) 179 Giese, B. ( 2 ) 4 6 ; (3) 7 9 , 100; ( 5 ) 3 4 4 , 3 4 5 ; ( 6 i i ) 6 6 ; ( 8 ) 133 G i f f a r d , M. ( 5 ) 538 G i l , G. ( 2 ) 61 G i l a r d i , A. (5) 171 G i l b e r t s o n , S.R. ( 3 ) 1 2 5 G i l c h r i s t , T.L. ( 5 ) 5 2 9 , 530 G i l e s , R.G. ( 5 ) 482 G i l l , G.B. ( 3 ) 324 G i l l , H.S. ( 8 ) 224 G i l l , S. ( 5 ) 77 G i l l i g a n , W.H. ( 5 ) 5 3 3 G i n g e r i c h , S.B. ( 3 ) 3 6 3
Giomi, D. ( 5 ) 3 9 8 G i o r d a n o , C. ( 3 ) 214, 215; ( 5 ) 278 G i o v a n n i n i , F. ( 3 ) 119 G i r a r d , C . ( 3 ) 264 G i r g i s , N.S. ( 5 ) 399 G i r o d e a u , J.M. ( 5 ) 145 G i u l i a n o , R . M . ( 3 ) 250 G i z u r , T. ( 8 ) 232 G l e b o v , L.S. ( 1 ) 1 G l e n n , A . G . ( 4 ) 228 G l e n n o n , J . D . ( 5 ) 462 G l u s h k o v a , E.N. ( 5 ) 494 Goasdoue, C. ( 3 ) 4 0 5 ; ( 5 ) 246 G o d e f r o i , E.F. ( 3 ) 329 G o d e l , T. ( 3 ) 1 ; ( 6 i ) 33 G o e h r i n g , R . R . ( 8 ) 180 Gorge, L. ( 8 ) 5 1 G o l ' d f a r b , Ya.L. ( 5 ) 279 G o l d s m i t h , D . J . ( 6 i i ) 196 Golebiowski, A. ( 8 ) 62 G o l f n s k i , J. ( 2 ) 153; ( 5 ) 412 Gomann, K . ( 8 ) 6 7 Gomez-Solivellas, A. ( 3 ) 30 G o n s c h o r r e k , C. ( 3 ) 400 G o n z a l e z , A. ( 2 ) 4 , 1 6 1 ; ( 4 ) 116 GonzAlez, J.M. ( 5 ) 252 Gonzalez-Mufiez, E. ( 4 ) 128 Goodwin, T.E. ( 2 ) 7 8 ; ( 7 ) 122 Goon, D.J.W. ( 5 ) 536 Gopalan, A.S. (3) 1 1 9 Gordon, B . , 111 ( 6 i i ) 3 7 G o r e , J. (1) 6 9 ; ( 2 ) 7 2 ; ( 7 ) 41 G o r i s c h , H . ( 3 ) 8 2 , 265 Gorvin, J.H. ( 5 ) 89 Goswami, R. ( 3 ) 1 3 1 G o t i , A. ( 8 ) 209 G o t o , S. ( 3 ) 471 G o t o , T. ( 5 ) 4 8 3 Gotor, V. (5) 119, 480; (8) 1 1 5 G o t t s c h a l k , P. (3) 153 G o u i n , L. ( 5 ) 538 G o u l a o u i c , P. ( 2 ) 111; ( 6 i i ) 43 G o u l d , T . J . ( 3 ) 308 G o u z o u l e s , F.H. (3) 1 2 9 ; ( 6 i i ) 67 G r a b o s k i , G.G. ( 8 ) 239 G r a f , M. ( 6 i i ) 1 4 5 G r a f f , M. ( 3 ) 1 6 7 G r a k a u s k a s , V. ( 5 ) 403 Gramain, J.-C. ( 8 ) 160, 1 9 2 ; ( 9 ) 31
Author Index
613
G r a n g e t t e , H. (3) 6 G r a n i t z e r , W. (5) 137 G r a n t , N . (5) 399 G r a s , J.-L. (7) 169 Grasselli, P. (3) 119;
(4) 35; (5) 512 G r a u e r t , M. (3) 412, 413 G r a v e l , D. (2) 141; (3)
148; (5) 231 G r a y , B.D. ( 3 ) 112 G r a z i a n o , M . L . (3) SO,
314 G r e c k , C. (8) 2 G r e c k , G . ( 6 i i ) 186 G r b e , R . (8) 5 G r e e n , M . J . (1) 92 G r e e n e , A.E. (3) 11, 312; (7) 18, 96, 97 G r e e n h o u s e , R . (5) 378 Greenspoon, N . (1) 5; (2)
25 Grehn, L. (3) 465, 469 G r e u t e r , H. (3) 253; (7)
21 G r i b b l e , G.W. (4) 4 G r i c e , P. (8) 71; (9) 57 G r i e c o , P.A. (8) 183 G r i e n g l , H. (4) 39 Griesser, H . (3) 455 G r i g g , R . (1) 62; (3) 58; (4) 180; (5) 285; ( 6 i )
52; (8) 148, 179 G r i m a l d i , J . (8) 118 Grim, E.L. (2) 193; (3)
155, 243 G r i n g o r e , O.H. (3) 256 Grosman-Zjawiona, Z. (5)
60 G r o s s , A.W.
(3) 288; ( 5 )
87, 349 G r u b b s , R.H. ( 5 ) 110 G r u b e r , L. (3) 281 G r u s e l l e , M. (3) 56 G u a n t i , G. (3) 438; (5)
205 Guarna, A . (8) 209 G u b l e r , M. (5) 534 Giiell, F. (2) 1 6 1 G u e r i n , A . (7) 169 G u e t t e , J . P . (7) 108 G u i b e , F. ( 3 ) 61 Guibe-Jampel, E. (3) 264 Guidon, Y. (3) 351 G u i g a n t , A. (2) 158 G u i l l e r , A . (5) 510 G u i l l e r m , D. (3) 374 Guindon, Y. (2) 143; (4)
113; (5) 368 G u i n g a n t , A. (5) 488 G u l a c s i , E. (3) 281 G u l b e n k i a n , A . R . (1) 92
G u l l , R . (3) 408 G u n a r a t n e , H . Q . N . (8) 179 G u n n a r s s o n , K . (3) 469 G u n t h e r , H . (3) 265 Guo, D . ( 6 i i ) 70 Guo-giang, L. (3) 341 Guong-zhong, G . (3) 341 G u r u s i d d a p p a , S. (5) 16 G u r z o n i , F. (3) 214 G u s h c h i n , A . V . (5) 69, 70 Gutman, A.L. (3) 63 Guy, A . (7) 108 Guy, R.W. (3) 443 GuzmAn, F. (5) 47 G y b i n , A.S. (1) 82 GyorgydeBk, Z. (5) 511
H a n a f u s a , T. (1) 4 , 31;
(5) 313, 315, 323; ( 6 i i ) 108 Hanakawa, M. ( 5 ) 306 H a n a z a k i , Y . (5) 467 H a n e s s i a n , S . (4) 130; (5) 19; (8) 230 Hanko, R . (3) 246; ( 6 i i ) 7 Hanna, I . (2) 110, 111; (4) 40, 102; ( 6 i i ) 43 Hanna, J.M. ( 6 i ) 47 Hannaby, M . (1) 23 Hansen, D.W., j u n . (3) 421 Hansen, H.-J. (3) 220, 221; (5) 93 Haque, M.S. (2) 115; (3) Ha, D.-C. (8) 222 72; ( 6 i i ) 39 H a r a , M. (2) 159 Haake, M. (5) 294 H a b b a c h i , F. (3) 29 H a r a , S . (2) 1 1 6 , 192; (4) 155 Haberman, L . M . (4) 83; H a r a d a , K . ( 6 i i ) 57 (5) 5 Haddad, M. (8) 147 Harada, T. (2) 1 1 4 ; (7) Haddon, R . C . (5) 42 47, 48 H a n e r , R . (2) 1 4 6 ; ( 6 i i ) Harano, K . (1) 20; (4) 11 216 H a s s i g , R . (3) 186; (5) Harms, K . (8) 6 5 331 H a r n i s c h , H . ( 3 ) 100, 321 Hagen, J . P . (3) 114 Harpp, D.N. (3) 402; (4) H a g h a n i , A. (8) 67 218 Hagiwara, H . (2) 194; (3) H a r r i s , D . J . ( 6 i i ) 81 342 H a r r i s , F.L. (3) 31, 193; Hagiwara, Y. (3) 346 (6ii) 6 H a i d e r , A. (3) 303 H a r r i s , M . (4) 86 H a i - J i a n , X. (3) 341 H a r r i s o n , P. (7) 125 H a i n e s , S.R. ( 6 i i ) 92 H a r r i s o n , P . J . (9) 49 HBjiCek, J. (5) 350; ( 7 ) H a r r i s o n , W. ( 6 i i ) 181 150 Hart, D . J . (8) 158, 222; H a j o s , Z.G. (7) 118 (9) 30 H a l l b e r g , A . (3) 177 H a r t , H . ( 6 i i ) 57 I l a l l e r , R. (4) 28 H a r t , T.W. (5) 448 Hamada, Y . (9) 71 H a r t g e r i n k , R.L. (3) 5 Hamamichi, N . (5) 133 H a r t k e , K . (3) 235 Hamamoto, I . (1) 21; (2) H a r t s h o r n , M.P. (5) 430 184; (3) 77, 199; (4) H a r t s t o c k , F.W. (6i) 83 217; (5) 392, 393; (8) H a r t u n g , J . (5) 344 26 Harusawa, S. (5) 306-309 Hamann, P.R. (8) 72, 73; H a r u t a , A . M . (8) 127 H a r u t a , J. (2) 107 ( 9 ) 51 Hamdan, A . (5) 8 Harvey, D.F. (3) 353; (8) H a m e l , N . (3) 210, 211; 60, 61 (4) 174 Harwood, L.M. (3) 182 Hamelin, J. ( 8 ) 149 Hasegawa, H. (3) 14 H a m i l t o n , R . (5) 472 Hasegawa, T. (2) 18 Han, B.H. (5) 15 Hashimoto, C. ( 6 i i ) 205; Han, G . R . (2) 14, 15; (9) 32 ( 6 i ) 19 Hashimoto, H . (3) 382; (4) 24, 167; ( 6 i ) 80; Han, I.-S. ( 2 ) 6 Han, S.-Y. (8) 197 ( 9 ) 65 Hashimoto, M. (5) 202; Hanack, M. (1) 93
614 ( 8 ) 204, 205 H a s s a n , D . ( 8 ) 11 Hatakeyama, S. ( 9 ) 7 5 I l a t a n a k a , M . ( 8 ) 123 Hathaway, J. ( 3 ) 327 l i a t t o r i , K . (8) 68 H a t t o r i , N . ( 5 ) 226 H a u f e , H . ( 7 ) 152 H a u p t r e i f , M. ( 3 ) 414 Hawley, R.C. ( 9 ) 17 Hay, J . N . ( 2 ) 1 5 3 ; ( 5 ) 412 Hayakawa, K . ( 6 i i ) 183 Hayakawa, S. ( 3 ) 143 Hayakawo, Y . ( 2 ) 69; ( 6 i ) 79 Hayashi, J . ( 3 ) 74 H a y a s h i , I(. ( 1 ) 2 2 ; ( 2 ) 1 6 9 ; ( 4 ) 57 H a y a s h i , T. ( 5 ) 126; ( 6 i i ) 98 H a y a s h i , Y . ( O i ) 29; ( 7 ) 1 3 6 ; ( 8 ) 104 Haynes, R . K . ( 3 ) 247 H a z e l l , A . C . ( 5 ) 172 H a z e l l , R . G . (5) 172 H a z l e t t , R . N . ( 5 ) 371 H a z r a , B. ( 4 ) 125 ? l e a d , D.B. ( 7 ) 171 Heaney, H . ( 5 ) 482 I I e a r n , M.J. ( 5 ) 450 H e a t h c o c k , C . H . ( 2 ) 1861 8 8 ; ( 3 ) 19, 2 0 , 1 1 4 , 115, 158, 159, 349, 389; ( 9 ) 8 3 Heck, R.F. ( O i ) 4 H e c k e r , S . J . ( 3 ) 349 l l e d g e , V.R. ( 8 ) 228 Ilegedus, L.S. ( 2 ) 4 0 ; ( 4 ) 1 7 3 ; ( 8 ) 218 H e i d e r , A . R . ( 5 ) 369 H e i g , U.W. ( 7 ) 4 Heilmann, S.M. ( 3 ) 330 H e i n d e l , N.D. ( 5 ) 452 H e i n i c k e , G.W. ( 3 ) 218 Hellman, S.M. ( 6 i i ) 62 Helmchen, G . ( 3 ) 1 , 21 H e l q u i s t , P. ( 5 ) 123; ( 7 ) 8 , 167 Henderson, M . A . ( 2 ) 1 8 6 ; ( 3 ) 389 Hendrickson, J . B . ( 2 ) 71; ( 6 i i ) 54; ( 7 ) 33 Hennequin, L . ( 2 ) 7 6 H e r g e s , R. ( 8 ) 76 Herman, L.W. ( 5 ) 439 Hermecz, I . ( 5 ) 5 5 H e r n a n d e z , D. ( 2 ) 32 Hernandez, E. ( 5 ) 242 H e r r i n g t o n , P.M. ( 7 ) 1 7 0 ; (8) 6
General and Synthetic Methods Herrmann, R . ( 5 ) 385 Hershberger, J. ( 4 ) 184; ( 5 ) 343 H e r s h b e r g e r , S . ( 3 ) 288; ( 4 ) 1 8 4 ; ( 5 ) 343 H e r v e , Y . ( 3 ) 460 H e r z i g , J. ( 5 ) 328 H e s b a i n - F r i s q u e , A.-M. ( 2 ) 6 3 ; ( 3 ) 2 5 3 ; ( 7 ) 21 H e s s e , M. ( 3 ) 3 7 5 ; ( 5 ) 3 5 0 , 3 5 1 , 4 3 4 , 435; ( 7 ) 150 Heus-Kloos, Y.-A. (1) 6 4 ; (6ii) 8 H e v e s i , L . ( 2 ) 132 Hewson, A.T. ( 7 ) 81 H e y d t , H . ( 5 ) 518 Hibino, J . (1) 29; ( 6 i ) 8 5 ; ( 6 i i ) 127 Hickman, R . J . S . ( 3 ) 443 H i e d a , T. ( 2 ) 147 H i e g e l , G . A . ( 2 ) 113 I l i e m s t r a , H . ( 6 i i ) 99, 1 0 0 ; ( 8 ) 1 3 4 , 171-173 H i g a k i , M. ( 3 ) 117 H i g a s h i m u r a , H. (3) 2 9 3 , 429; ( 6 i ) 68 H i g a s h i y a m a , K. ( 5 ) 88 I I i g u c h i , T. ( 4 ) 131 H i j f l e , L.V. ( 7 ) 6 1 Hikima, H . ( 3 ) 120; ( 4 ) 27 H i l g e r , C.S. ( 9 ) 4 3 Hill, J.H.M. ( 3 ) 128 H j l l e r , W. ( 5 ) 487 H i l l i s , L . R . (3) 369 H i m b e r t , G . ( 3 ) 325; (5) 149- 1 51 H i n k s , R.S. ( 3 ) 83 H i r a c , 1. ( 8 ) 21 H i r a i , H. ( 6 i ) 76 H i r a i , J.-I. ( 5 ) 309 Hirakawa, K . ( 4 ) 7 8 Hirama, M . ( 3 ) 4 5 0 ; ( 5 ) 162- 164 H i r a o , A. ( 4 ) 1 6 , 2 9 , 3 0 ; ( 5 ) 1 9 8 , 199 H i r a o , I . ( 3 ) 1 0 4 , 180, 1 8 1 , 225; ( 7 ) 45 H i r a o , T. ( 1 ) 5 1 ; ( 2 ) 2 2 ; ( 3 ) 1 9 5 ; ( 5 ) 232, 233 H i r a o k a , T. ( 8 ) 233 H i r a t a k e , J. ( 3 ) 87 H i r a t s u k a , I. ( 5 ) 222 H i r o b e , M. ( 4 ) 1 3 1 H i r o i , K . (5) 335 H i r o s e , M. ( 8 ) 127 H i r s c h , J.A. ( 5 ) 107 H i s a d a , H . ( 5 ) 329 H i s a n o , T. (1) 2 0 ; ( 4 ) 216
H i t o m i , T. ( 2 ) 147 I l i t z , W.D. (5) 203 H i y a m a , T. (1) 1 4 , 9 4 ; ( 3 ) 318, 3 8 7 ; ( 5 ) 4 5 , 261; ( 6 i i ) 5 9 H l a s t a , D . J . ( 6 i i ) 28 Ho, E. ( 8 ) 1 8 9 Ho, L.Y. ( 5 ) 528 Ho, P.-T. ( 3 ) 342 Hoberg, H. ( 5 ) 2 4 1 , 242 H o b e r t , K . ( 3 ) 147 Hodgson, S.T. ( 8 ) 217; ( 9 ) 81 H o e d e r a t h , W. ( 3 ) 235 H o e k s t r a , W. ( 6 i i ) 196 Hoesch, L. ( 5 ) 106 Hoffman, R . V . ( 2 ) 1 0 6 ; ( 5 ) 471 Hoffmann, H . M . R . ( 2 ) 4 9 ; ( 3 ) 188, 302; ( 4 ) 1 4 4 ; ( 6 i ) 11; ( 6 i i ) 35 Hoffmann, R . W . ( 2 ) 3 3 , 150; ( 4 ) 5 8 , 5 9 , 9 7 ; ( 6 i i ) 81, 82 Hofman, N . ( 5 ) 280 H o j o , M. ( 2 ) 1 3 8 ; ( 3 ) 2 5 , 293, 294; ( 4 ) 1 5 , 6 9 , 134; ( 6 i ) 68, 70; ( 8 ) 35 Holden, K . G . ( 3 ) 4 6 3 H o l l a n d , H.L. ( 4 ) 227 H o l l i n s h e a d , D.M. ( 8 ) 217; ( 9 ) 81 H o l l y , F.W. ( 3 ) 466 Holmes, A.B. ( 9 ) 3 4 Holrnes, S.J. ( 6 i ) 5 5 ; ( 7 ) 68 Holmes-Smith, R. (1) 9 I l o l t , D . A . (1) 99; ( 2 ) 8 9 ; ( 9 ) 18 H o l z a p f e l , W. ( 2 ) 83 Honer, H . ( 5 ) 345 Hoole, R.F.A. ( 3 ) 304 Hoong, L.K. ( 6 i i ) 83 Hooz, J . ( 1 ) 8 8 ; ( 3 ) 216; ( 4 ) 1 8 5 ; ( 6 i i ) 45 Hope, H . ( 3 ) 3 2 ; ( 7 ) 6 7 H o p k i n s , P.B. ( 3 ) 4 3 2 , 458; ( 5 ) 1 4 0 , 1 4 1 Hoppe, D . ( 3 ) 2 4 6 , 400; (6ii) 7 Hopton, D. ( 3 ) 476 H o r i , K . ( 3 ) 314 I f o r i , Y . (1) 90; ( 3 ) 7 1 , 172 H o r i t a , K . ( 8 ) 29 H o r i t o , S. ( 9 ) 6 5 H o r l e r , H. ( 2 ) 46; ( 3 ) 79 H o r n e r , L. (3) 480 HornyAk, G . (5) 4 6 ; ( 8 ) 232
615
Author Index H o r s p o o l , W.M. ( 8 ) 1 9 5 H o r t o n , I.B. ( 7 ) 107 H o r v a t h , R.F. ( 3 ) 393; ( 6 i i ) 29 H o s h i , M. ( 1 ) 2 7 ; ( 2 ) 1 0 2 ; ( 4 ) 219 H o s h i n o , M . ( 1 ) 26, 5 7 ; ( 8 ) 86-88 Hosmane, R.S. ( 5 ) 376 Hosomi, A . ( 5 ) 148; ( 6 i i ) 111 H o t c h k i s s , L.M. ( 4 ) 1 0 3 H o t t h a r d t , H. ( 5 ) 280 Houk, K . N . ( 7 ) 104-106 H o u l i h a n , F. ( 3 ) 465 Houmounou, J.P. ( 4 ) 7 5 ; ( 5 ) 192; ( 6 i i ) 6 0 Houpis, I . N . ( 4 ) 74; ( 6 i i ) 4 ; ( 7 ) 3 5 , 37 Howard, R.W. ( 2 ) 7 8 ; ( 7 ) 122 Hoye, T.R. ( 3 ) 420; ( 6 i i ) 5 Hoyer, D. ( 8 ) 107 Hsu, S.-Y. ( 2 ) 1 5 ; ( 6 i ) 19 Hu, N . X . ( 4 ) 210 Hua, D.H. ( 2 ) 1 0 1 ; ( 6 i ) 35; (7) 89 Hua, F.H. ( 9 ) 7 Huang, H . ( 3 ) 447 ( 6 i i ) 122 Huang, W.-Q. Huang, Y . ( 2 ) 9 2 ; ( 3 ) 225; ( 6 i i ) 162 Huang, Y.Z. ( 4 ) 6 ; ( 6 i i ) 163 Huber, R . ( 5 ) 457 Huber, S. ( 5 ) 539 Huber-Patz, U . ( 3 ) 35 H u b e r t - H a b a r t , M. ( 5 ) 303 H u d l i c k y , T. ( 3 ) 227; ( 7 ) 1 4 1 ; ( 8 ) 152 H u d r l i k , A.M. ( 5 ) 111; ( 6 i i ) 120 H u d r l i k , P.F. ( 4 ) 1 5 9 ; ( 5 ) 111; ( 6 i i ) 1 2 0 Hulsmeyer, K. ( 5 ) 209 H u e t , F. ( 2 ) 131 Huffman, J . C . ( 5 ) 1 6 8 Huffman, J . W . ( 2 ) 7 5 ; ( 7 ) 120 Hughes, J.W. ( 9 ) 2 Huh, K.-T. (8) 1 9 9 Hui, R . ( 7 ) 22, 23 H u i , R.A.H.F. ( 2 ) 6 2 ; ( 3 ) 253; ( 8 ) 31 Hui, R.C. ( 2 ) 38, 39 H u i e , R. ( 5 ) 548 H u l l , K. ( 6 i i ) 102-104; ( 7 ) 7 0 , 130-133 H u l t , K . ( 3 ) 8 4 , 445
H u l t i n , P.G. ( 3 ) 83, 263 Hung, J. ( 5 ) 102 H u n t e r , B.K. ( 4 ) 4 1 Husson, H.-P. ( 5 ) 1 8 9 , 1 9 0 , 359-361 H u s z t h y , P. ( 8 ) 232 Hutchinson, J.H. ( 9 ) 23 H u t t e r , P. ( 3 ) 1 4 3 ( 8 ) 54; (9) Hwang, C.-K. 68 ~Hwang, Y.C. ( 5 ) 9 8 ; ( 8 ) 187 Hwu, J . R . ( 2 ) 1 3 9 ; ( 5 ) 546 H y a t t , J . A . ( 3 ) 140 H y l a r i d e s , M.D. ( 4 ) 153 l a v a r o n e , C . ( 3 ) 279 T b a r r a , C . A . ( 8 ) 109 I b e , M. ( 5 ) 341 I b r a h e i m , M . A . ( 5 ) 380 I b u k a , T. ( 3 ) 1 9 3 I c h i h a r a , J. ( 1 ) 4 ( 3 ) 295 Ichikawa, Y.-I. I c h i n o s e , H. ( 4 ) 9 I d a , H. ( 6 i i ) 1 9 0 I d r i s , M.S.H. ( 3 ) 324 I e s c e , M.R. ( 3 ) 5 0 , 314 I h a r a , M. ( 7 ) 1 1 4 , 1 2 3 ; ( 8 ) 188 I i d a , H. ( 2 ) 41, 42; ( 5 ) 5 0 , 1 8 6 , 377; ( 9 ) 3 5 I k e d a , M. ( 2 ) 7 0 ; ( 5 ) 319; ( 6 i i ) 1 0 6 ; ( 7 ) 50; ( 8 ) 95 I k e d a , N . ( 2 ) 166 I k e d a , T. ( 3 ) 88 I k e d a , Y. ( 3 ) 17 I l a , H. ( 2 ) 182; ( 3 ) 1 7 4 , 226; ( 5 ) 337 I l e y , J. ( 5 ) 256 Imada, Y. ( 3 ) 3 9 8 ; ( 5 ) 234 I m a i , D. ( 9 ) 7 8 I m a i , N . ( 6 i i ) 166; ( 8 ) 85, 140 I m a i , T. ( 4 ) 88, 8 9 ; ( 6 i i ) 77-79 Imamoto, T. ( 4 ) 4 7 , 1 6 8 ; ( 6 i i ) 154 I m a n i s h i , T. ( 2 ) 1 0 4 , 1 0 5 ; ( 4 ) 90; ( 8 ) 6 8 I m i , K . ( 7 ) 36 Imoto, M. ( 9 ) 64 I n a b a , M. ( 3 ) 3 8 0 , 437; ( 5 ) 3 4 , 268 I n a b a , S. ( 2 ) 29; ( 4 ) 5 2 , 169 I n a b a , S.-I. ( 5 ) 367 I n a m i , K. ( 9 ) 7 2
Inamoto, Y . ( 7 ) 1 7 3 I n b a s e k a r a n , M. ( 1 ) 38 I n d e n d o h , A . ( 3 ) 251 l n d i v a t a , F.P. ( 5 ) 374 Lngendoh, A . ( 7 ) 109 Ingham, S. ( 1 ) 6 5 I n o k u c h i , T. ( 3 ) 11, 1 3 7 , 260; ( 4 ) 1 0 5 ; ( 5 ) 1 1 2 ; (8) 28 I n o m a t a , K . ( 3 ) 473 I n o u e , I . ( 3 ) 346 Inoue, K. ( 3 ) 74 I n o u e , S. ( 2 ) 108 I n o u e , T. ( 3 ) 8 8 I n o u e , Y. ( 3 ) 3 8 2 ; ( 4 ) 1 6 7 ; ( 5 ) 262; ( 6 i ) 8 0 I n o u y e , M. ( 4 ) 1 6 2 ; ( 5 ) 13; ( 6 i i ) 210 I p s a l e , S . ( 1 ) 78 I r e l a n d , R.E. ( 2 ) 13; ( 3 ) 1 6 9 , 1 9 6 , 240; ( 6 i i ) 115 I r n g a r t i n g e r , H. ( 3 ) 3 5 , 427 I s a k , H. ( 3 ) 1 ; ( 6 i i ) 169 I s h i b a s h i , H. ( 2 ) 70; ( 7 ) 50; (8) 95 I s h i d a , S. ( 5 ) 28 I s h i g e , M. (3) 327 I s h i g u r o , S. ( 4 ) 9 I s h i h a r a , H . ( 3 ) 238 I s h i h a r a , T. ( 1 ) 8 5 ; ( 5 ) 357 I s h i i , H . ( 3 ) 327 I s h i k a w a , M . ( 8 ) 57 I s h i k a w a , T. ( 3 ) 327 I s h i m a r u , T. ( 8 ) 1 2 3 Ishimaru, Y. ( 5 ) 71 (8) 95 Ishiyama, K.-I. I s o b e , K . ( 6 i ) 29 I s o b e , Y . ( 3 ) 306 I s o e , S. ( 3 ) 3 1 4 ; ( 6 i i ) 126; ( 9 ) 7 0 I t a b a s h i , K. ( 3 ) 230; (5) 299 I t a l i a , A . ( 3 ) 379; ( 5 ) 229 I t o , A. ( 5 ) 437 I t o , H. ( 4 ) 105 T t o , K . ( 4 ) 1 6 ; 2 9 , 30; ( 5 ) 1 9 8 , 199 I t 6 , S. ( 2 ) 12; ( 3 ) 450; ( 5 ) 162-164; ( 6 i i ) 140 I t o , W. ( 3 ) 425; ( 6 i i ) 84 I t o , Y. ( 3 ) 1 3 , 1 6 0 , 3 8 6 , 457; ( 5 ) 1 1 3 ; ( 8 ) 108 I t o h , F. (3) 1 2 3 I t o h , K . (1) 49; ( 3 ) 3 7 7 ; ( 5 ) 248, 3 3 6 , 4 1 7 ; ( 6 i i ) 1 3 1 ; ( 8 ) 165 I t o h , S. ( 5 ) 226
616
General and Synthetic Methods J a z o u l i , M.E. ( 2 ) 52 . J e f f r e y , T. ( 3 ) 2 2 3 ; ( 4 ) 172 J e n n e s k e n s , L.W. ( 7 ) 5 J e n n i n g s , P . W . ( 3 ) 363 J e n n y , T. ( 6 i i ) 147 J e p h c o t e , V.J. ( 1 ) 1 7 ; ( 6 i i ) 130 J e r i n a , D.M. ( 5 ) 508 J e y a r a r n a n , R . ( 8 ) 12 J i , T. ( 4 ) 156 J i a n g , J.B. ( 5 ) 49 J o g l a r , J. ( 5 ) 480; ( 8 ) 115 J o h n s o n , B. ( 5 ) 54 J o h n s o n , C . R . ( 6 i i ) 154 J o h n s t o n , B.D. ( 2 ) 1 2 8 ; ( 7 ) 27 J o h n s t o n , M.I. ( 3 ) 358 ,Johnstone, R.A.W. ( 3 ) 475 J o k a , T. ( 3 ) 44 J o l i d o n , S . ( 5 ) 93 J o n e s , A . J . ( 7 ) 113 J o n e s , D . S . ( 3 ) 96, 4 6 4 ; ( 4 ) 139 J o n e s , J.B. ( 3 ) 8 3 , 2 6 3 , 265 J o n e s , M.A. ( 6 i i ) 15 J o n e s , R.H. ( 3 ) 4 3 3 ; ( 5 ) 496; ( 6 i ) 3 6 , 42; ( 8 )
K a b a l k a , G.W. ( 2 ) 2 1 , 9 9 , 112; ( 4 ) 1 8 , 1 5 3 , 154; ( 5 ) 7 , 4 0 1 , 4 1 4 , 41890 4 2 0 , 4 5 4 , 4 5 5 , 491-493 I t o h , Y . ( 2 ) 147 Kabasawa, Y. ( 7 ) 85 Itsuno, S . ( 4 ) 16, 29, K a b a t , M.M. ( 3 ) 322 3 0 ; ( 5 ) 1 9 8 , 199 K a b e t a , K. ( 6 i i ) 9 8 I v a n o v , Ch. ( 5 ) 51 K a b u t o , H . ( 3 ) 238 I v e s , .J.L. ( 2 ) 130; ( 3 ) Kabuto, K . ( 4 ) 24 134 Kadokura, M. ( 2 ) 96 I w a k i r i , H . ( 2 ) 167 Kagan, H.B. ( 4 ) 191; Iwanaga, K . ( 7 ) 9 ( 6 i i ) 155 I w a s a k i , F. ( 3 ) 7 4 Kageyama, M. ( 7 ) 115 I w a s a v a , N. ( 2 ) 175; ( 3 ) Kageyama, T. ( 4 ) 200 1 0 , 7 5 , 4 4 7 ; ( 4 ) 189 Kageyama, Y . ( 8 ) 27 I w a t a , C. ( 2 ) 104, 105; K a i s e r , E.T. ( 3 ) 4 5 3 ; ( 5 ) ( 4 ) 90 207 I w a t a , M. ( 8 ) 2 0 2 , 203 K a j i , A. (1) 2 1 , 4 1 ; ( 2 ) I w a t a , T . ( 7 ) 95 184; ( 3 ) 7 7 , 7 8 , 1 9 9 , I y e r , R . S . ( 7 ) 8 , 167 306, 3 9 7 ; ( 4 ) 2 1 7 ; ( 5 ) I y o d a , M . ( 4 ) 178 236, 237, 3 9 2 , 3 9 3 , Tzawa, K . ( 3 ) 388 4 3 3 ; ( 6 i i ) 56; ( 8 ) 2 5 , I z a w a , T , ( 2 ) 53 26, 56 I z a w a , Y. ( 1 ) 8 K a j i , E . ( 5 ) 25 l z q u i e r d o , H . L . ( 3 ) 433 Kajigaeshi, S . ( 3 ) 7 , Izumi, A . ( 4 ) 9 2 5 2 ; ( 4 ) 213 I z u m i , Y . ( 2 ) 11, 9 8 , K a j t a r - P e r e d y , M. ( 8 ) 232 173; ( 3 ) 326; ( 5 ) 191; K a k i h a n a , M. ( 1 ) 2 2 ; ( 4 ) ( 6 i ) 23 200; ( 8 ) 27 Kakirnoto, S. ( 3 ) 252 100 J a b r e , S . ( 5 ) 330 Kakiuchi, K. ( 2 ) 8 8 ; ( 9 ) J o n e s , R . J . ( 6 i ) 20 3 J a c k s o n , C.B. ( 7 ) 148, K a l a n t a r , T.H. ( 3 ) 436 J o n e s , T.K. ( 2 ) 93 149 Kalikhman, I . D . ( 5 ) 498 J a c k s o n , D.A. ( 7 ) 165 J o n g e d i j k , G . ( 2 ) 50 K a l l m e r t e n , J . ( 3 ) 308 J a c k s o n , P . F . ( 5 ) 135 JOG, F. ( 5 ) 10 K a l v i n , D. ( 3 ) 4 3 5 ; ( 5 ) 6 J a c k s o n , R.F.W. ( 3 ) 370 J o r d a n , M.W. ( 8 ) 148 Kamaki, N . ( 4 ) 48 J a c k s o n , W.R. ( 1 ) 3 2 ; ( 3 ) J o u c l a , M. ( 8 ) 149 Kambe, N. ( 3 ) 4 0 6 ; ( 5 ) 3 0 9 ; ( 5 ) 3 2 2 ; ( 6 i i ) 109 J o u i n , P . ( 3 ) 105 288 J a c o b , L.A. ( 2 ) 128 J o u l e , J.A. ( 6 i i ) 14 J o u s s e a u m e , B. ( 6 i ) 6 2 ; Kamber, M. ( 3 ) 258 J a c o b s , P.B. ( 7 ) 7 8 Kameda, T. ( 3 ) 473 J a c q u i e r , R . ( 3 ) 430 ( 6 i i ) 139 Kamei, M. ( 6 i i ) 123 J a d h a v , P.K. ( 4 ) 2 ; ( 6 i i ) J u a r i s t i , M. ( 2 ) 5 ; ( 4 ) Kametani, T. ( 7 ) 1 1 4 , 80 118 J a g e r , V . ( 5 ) 173, 174 J u l i a , M. ( 2 ) 1 9 ; ( 6 i i ) 123; ( 8 ) 188; ( 9 ) 22 Kameyama, M. ( 3 ) 206 J a e n i c k e , L. ( 3 ) 265 190; ( 7 ) 162, 163 K a m i g a t a , N . ( 1 ) 63 J u l i a , S . (1) 6 4 ; ( 6 i i ) Jagdmann, E . , j u n . ( 3 ) Kamirnura, A. ( 2 ) 1 8 4 ; ( 3 ) 4 7 5 ; ’ ( 4 ) 8 ; ( 5 ) 31 8 ; ( 8 ) 97 7 7 ; ( 5 ) 3 9 3 ; ( 8 ) 26 J u l i e n , S . ( 3 ) 442 Jagdmann, G . E . ( 2 ) 4 3 ; K a r n i t o r i , Y. ( 2 ) 138; ( 4 ) ( 6 i i ) 17 J u l i n a , R . ( 5 ) 391 J a h n , R . ( 3 ) 35 J u n g , A. ( 5 ) 362 15 J a k o v a c , I . J . ( 3 ) 265 J u n g , K . 4 . ( 5 ) 509 Kanda, N. ( 4 ) 3 0 ; ( 5 ) J u n g , M . ( 3 ) 122; ( 5 ) J a l a s s , U. ( 4 ) 28 199; ( 8 ) 166 K a n e f u s a , T . ( 3 ) 238 J a m i l , Z . ( 2 ) 9 ; ( 4 ) 120 1 4 4 , 152 J a n k o w s k i , B.C. ( 2 ) 106 J u n g , S.-H. ( 5 ) 103 Kaneko, C. ( 3 ) 278 J a n o u s e k , Z. ( 5 ) 3 3 2 , 333 J u n i n o , A . ( 2 ) 61 Kaneko, H . ( 8 ) 84 J a n s e n , U. ( 8 ) 37 J u n j a p p a , H . ( 2 ) 182; ( 3 ) Kaneko, Y. (1) 8; ( 2 ) 53, 125; ( 5 ) 211 1 7 4 , 2 2 6 ; ( 5 ) 337 J a r d 6 n , J . ( 5 ) 119 J u r c z a k , J . ( 2 ) 135; ( 3 ) Kanernasa, S . ( 5 ) 1 9 6 ; J a r u p a n , P. ( 3 ) 317 J a r v i , E.T. ( 2 ) 117 ( 6 i i ) 4 4 ; ( 8 ) 1 4 2 , 143 354; ( 8 ) 6 2 J u s t , G . (1) 68; ( 3 ) 2 0 4 , Kanernatsu, K. ( 6 i i ) 183 J a t c z a k , M. ( 4 ) 202 J a y n e s , B.H. ( 7 ) 1 1 2 258; ( 8 ) 210 Kang, G . J . ( 3 ) 203
I t o h , T. ( 3 ) 7 4 , 2 6 7 , 338; ( 4 ) 37, 38; ( 6 i i )
Author Index Kang, J . (1) 34; ( 6 i i ) 148 Kang, S.-K. ( 4 ) 149 Kang, Y.H. ( 6 i i ) 200 Kano, S. ( 8 ) 193 Kanoka, H. ( 8 ) 82 Kant, J . ( 5 ) 370, 372 Kantam, M.L. ( 2 ) 9 ; ( 4 ) 120 Kao, S.C. ( 4 ) 7 K a r a b e l a s , K . ( 3 ) 177 Karakhanov, R.A. ( 5 ) 302 K a r a s a k i , Y . ( 3 ) 406; ( 5 ) 287 Karkour, B. ( 7 ) 158 Karmarkar, S.N. ( 5 ) 295 Karpf, M. ( 7 ) 168 K a s e l , W. ( 3 ) 263 K a s t n e r , M.E. ( 2 ) 181 Kasuga, T. ( 3 ) 384 K a t e r i n o p o u l a s , H. ( 9 ) 5 3 K a t e s , S.A. ( 2 ) 8 4 ; (7) 126 Kato, H. ( 6 i ) 79 Kato, J . ( 3 ) 75, 418; ( 4 ) 189 Kato, M. ( 3 ) 241; ( 6 i i ) 123 Kato, N . ( 3 ) 353; ( 8 ) 59 Kato, S. ( 3 ) 238; ( 5 ) 4 ; ( 6 i ) 13 Kato, T. ( 4 ) 155; ( 7 ) 8 5 , 138 K a t r i t z k y , A . R . ( 4 ) 207; ( 6 i i ) 46 K a t s i f i s , A . A . ( 3 ) 247 K a t s u k i , T. ( 3 ) 13, 22, 386 Katsumura, S. ( 3 ) 314 Katz, A.H. ( 6 i i ) 95 Katz, H.E. ( 6 i i ) 8 9 Katz, T . J . (1) 59 Kauffmann, T. ( 4 ) 43; ( 6 i i ) 9 , 142, 161 Kaupp, G. (3) 8 1 Kawabata, N. ( 6 i i ) 110 Kawabata, T. ( 5 ) 437 Kawada, M. ( 2 ) 45; ( 6 i i ) 114 Kawaguchi, A . ( 8 ) 123 Kawai, K. ( 9 ) 78 Kawai, M. ( 5 ) 191 Kawakaki, H. ( 3 ) 248 Kawakami, Y. ( 5 ) 329 Kawamata, T. ( 8 ) 70 Kawamoto, T. ( 3 ) 481 Kawamura, S. ( 4 ) 139, 195; ( 6 i ) 6 9 , 70; ( 8 ) 1 4 , 35 Kawamura, S.-I. ( 3 ) 294; ( 8 ) 167
617 Kawanabe, E. ( 3 ) 327 Kawanisi, M. ( 2 ) 147 Kawasaki, H . ( 3 ) 152 Kawasaki, M. ( 4 ) 23 Kawasaki, N. ( 4 ) 176 Kawazoe, K . (8) 240 Kawonisi, M . ( 6 i i ) 136 Kay, I . T . ( 3 ) 282 Kayo, I. ( 6 i ) 72; ( 8 ) 219 Ke, Y.Y. ( 3 ) 123 Keay, B.A. (1) 5 6 ; ( 3 ) 390; ( 5 ) 250; ( 6 i i ) 128, 133; ( 7 ) 72 Keck, G.E. ( 1 ) 43; ( 3 ) 234, 290, 359; ( 6 i i ) 135; ( 8 ) 159 Keiko, N . A . ( 5 ) 498 Keinan, E. (1) 5 ; ( 2 ) 25; ( 5 ) 328 K e l k a r , S.L. ( 5 ) 295 Kell, D.A. ( 8 ) 150 Kelle, 0. ( 3 ) 465 Keller, E. ( 8 ) 120 K e l l e r , L. ( 9 ) 25 K e l l e r , W.E. ( 3 ) 465 K e l l o g g , R . N . ( 3 ) 105; ( 8 ) 124 K e l l y , D.R. ( 3 ) 178 K e l l y , J.W. ( 4 ) 192, 193; ( 6 i i ) 160; ( 8 ) 10 K e l l y , T.R. ( 9 ) 4 2 , 60 K e l l y , W . J . ( 3 ) 92 Kemp, D . J . ( 5 ) 244 Kemp, D.S. ( 3 ) 479 Kemper, B. ( 4 ) 58; ( 6 i i ) 82 Kempf, D . J . ( 3 ) 392 Kenan, W.R., jun. ( 3 ) 99 Kende, A.S. ( 3 ) 356; ( 7 ) 161; ( 8 ) 39 Kennedy, E. ( 3 ) 327 K e r r , R . G . ( 2 ) 120; ( 6 i i ) 197 Kesseler, K . ( 3 ) 123; ( 5 ) 362 Kessler, K. ( 4 ) 6 4 , 65 K e s t n e r , M.M. ( 3 ) 92 Ketelaar, P.E.F. ( 3 ) 116 Keumi, T. ( 3 ) 44 Keyaniyan, S. ( 7 ) 83 Kezdi, M. ( 5 ) 29 Khai, B.T. ( 4 ) 13 K h a l a j , A . ( 3 ) 385; ( 5 ) 267 Khan, H.R. ( 5 ) 281 Khan, M. ( 7 ) 129 Khan, M . N . I . ( 3 ) 300; ( 6 i ) 30 Khanapure, S.P. ( 5 ) 437 Khanna, R.K. ( 6 i i ) 70 K h a r r a t , A . ( 3 ) 286
Khouz, B. ( 3 ) 185 K h r u s t a l e v , V . A . ( 5 ) 449 K i b a y a s h i , C. ( 5 ) 186; ( 9 ) 35 K i b i c a , Z. ( 3 ) 475 K i c e , J . L . ( 6 i i ) 200 Kiguchi, T. ( 6 i i ) 205; ( 9 ) 32 Kijima, M . ( 5 ) 175, 251 Kikuchi, M. (3) 342 K i k u c h i , T . ( 6 i i ) 126 K i l e n y i , S.N. ( 3 ) 202 K i l l i n g , H . (1) 30; ( 6 i i ) 124 K i m , B.M. ( 6 i i ) 77 K i m , C. ( 6 i i ) 121 Kim, C.U. ( 3 ) 51 K i m , C.-W. (1) 48; ( 3 ) 200 ( 3 ) 289 Kim, H . - J . Kim, J . D . ( 4 ) 221; ( 6 i i ) 191 K i m , J . E . ( 4 ) 221; ( 6 i i ) 191 Kim, J.R. (6ii) 214 Kim, S. ( 3 ) 62, 451, 468; ( 4 ) 1 7 , 104, 166; ( 5 ) 6 6 , 219, 502; ( 6 i i ) 6 5 K i m , W.-S. ( 4 ) 149 Kim, Y.C. ( 3 ) 62 Kim, Y.H. ( 3 ) 4 0 7 ; ( 5 ) 286 Kim, Y.J. ( 3 ) 451; ( 4 ) 17; ( 5 ) 66; ( 6 i i ) 65 Kimura, M. ( 2 ) 109; ( 3 ) 238 Kimura, R . ( 4 ) 67 Kimura, T. ( 8 ) 9 King, P.F. ( 3 ) 48; ( 4 ) 111 King, R.B. ( 5 ) 386 King, R.S. ( 3 ) 420; ( 6 i i ) 5 Kinney, W . A . ( 2 ) 90; ( 7 ) 143 K i n o s h i t a , H. ( 3 ) 473 K i n o s h i t a , M. ( 3 ) 372; ( 9 ) 28 K i r b y , G.W. ( 5 ) 146, 182185; ( 8 ) 9 1 , 113, 114 K i r i l l o v a , L.P. ( 5 ) 121 Kirisawa, M. ( 5 ) 221 K i r k , D.N. ( 3 ) 282 Kirmse, W. ( 8 ) 37 Kirschenbaum, K.S. ( 3 ) 10; ( 8 ) 8 K i r s c h k e , K. ( 5 ) 122, 527 K i s e , N . ( 3 ) 127 K i s h i , Y. ( 9 ) 29 K i s h i d a , T. ( 2 ) 88 Kita, Y. ( 2 ) 107; ( 3 ) 123
618 K i t a g a w a , I;. ( 3 ) 481 K i t a g a w a , T. ( 5 ) 296 K i t a h a r a , E. ( 3 ) 347 K i t a h a r a , H . ( 3 ) 241 K i t a h a r a , T. ( 3 ) 118; ( 4 ) 35 Kitajima, H. (3) 44 K i t a n o , Y. ( 3 ) 25 K i t a o k a , M. ( 6 i i ) 179 Kizumoto, H . ( 5 ) 71 Klas, N . ( h i i ) 161 K l e i j n , 1 1 . ( 6 i i ) 97 K l e i n , L . L . ( h i i ) 185 K l i g e r , G.A. ( 1 ) 1 K l i x , R.C. ( 2 ) 8 7 ; ( 7 ) 172 K l o s s , J . ( 5 ) 19 K l o t z , U.J. ( 5 ) 477 Kluge, H . ( 5 ) 534 Klumpp, G . W . ( 3 ) 3 7 6 ; ( 5 ) 249 Knapick, E.G. ( 5 ) 107 Knapp, F.F. ( 4 ) 154 Knapp, S. ( 8 ) 1 6 8 Knaus, E . E . ( 5 ) 476 K n e i s l e y , A. ( 3 ) 254 K n i e r z i n g e r , A. ( 5 ) 457 Knight, D.W. ( 7 ) 14 K n i t t e l , D. ( 3 ) 4 5 6 ; ( 5 ) 515 Knochel, P. ( 5 ) 421; ( 6 i i ) 188, 201; ( 7 ) 46; ( 8 ) 23 K n o u z i , N . ( 5 ) 32 Knudsen, C . G . ( 5 ) 197 Knudsen, M.J. ( 7 ) 67 K O , J . S . ( 3 ) 451; ( 4 ) 1 7 ; ( 5 ) 6 6 ; ( 6 i i ) 65 KO, Y . K . ( 5 ) 219 K o b a y a s h i , H . ( 8 ) 196 K o b a y a s h i , K . ( 2 ) 147 K o b a y a s h i , M. (1) 6 3 ; ( 3 ) 146 Kobayashi, S. ( 2 ) 167, 189 K o b a y a s h i , T. ( 1 ) 2 ; ( 3 ) 294; ( 4 ) 1 3 4 ; ( 6 i ) 1 4 , 6 9 , 7 0 ; (8) 3 5 , 167 K o b a y a s h i , T.-A. ( 5 ) 8 0 Kobayashi, Y. ( 3 ) 25, 230, 275 Kober, K . ( 2 ) 1 5 4 ; (3) 426; ( 5 ) 217 Kochet-kov, C.A. ( 3 ) 417 K o c i e n s k i , P. ( 2 ) 8 5 ; ( 7 ) 1 4 4 , 145; ( 8 ) 6 9 ; ( 9 ) 54, 55 Kodama, M . ( 7 ) 9 5 Kodera, Y . ( 5 ) 7 5 K o c h r i t z , P. ( 5 ) 117 Kohn, A. ( 5 ) 6 4
General and Synthetic Methods Koppen, J. ( 5 ) 486 Kover, A. ( 2 ) 4 9 ; ( 4 ) 144; ( 6 i i ) 35 Koga, K . ( 3 ) 8 0 , 1 5 2 , 248 Kogami, K . ( 2 ) 1 6 9 ; ( 4 ) 57 Kogure, T. ( 3 ) 273 Kohama, H. ( 3 ) 34 Kohima, E. ( 3 ) 267 K o h l e r , B.A.B. ( 2 ) 1 6 8 Kohl-Mines, E. ( 3 ) 220, 221 Kohn, H . ( 5 ) 1 0 3 Kojima, E. ( 4 ) 37 Kokel, B. ( 5 ) 303 K o l a s a , T. ( 5 ) 4 6 1 K o l ' t s o v , N . Y u . ( 5 ) 535 Komanura, C. ( 5 ) 297 Komatsu, H. ( 2 ) 7 0 ; ( 7 ) 50 Kornatsu, M. ( 5 ) 537 Komatsu, T. ( 5 ) 8 1 , 8 2 Kometani, T. ( 4 ) 156 Kominami, K . ( 3 ) 1 6 0 ; ( 5 ) 113 Kondo, A. ( 4 ) 151, 1 6 3 Kondo, K . ( 3 ) 1 1 ; ( 4 ) 1 0 5 ; ( 5 ) 297 Kondo, T. ( 4 ) 167 Konig, R. ( 6 i i . ) 142 Kono, K . ( 8 ) 7 4 Konta, H. ( 3 ) 340; ( 6 i i ) 186 Koo, S.Y. ( 5 ) 155 K o r e e d a , M. ( 1 ) 3 7 ; ( 6 i i ) 143 Korenova, A. ( 3 ) 108 Kornblum, N . ( 3 ) 9 2 K o r o s t o v a , S.E. ( 5 ) 498 K o s h i n o , H . ( 2 ) 116 Kosugi, H. (3) 340; ( 6 i i ) 1 7 9 , 186 K o s u g i , M. (3) 206 K o t a k e , H. ( 3 ) 4 7 3 K o t a k i , H. ( 8 ) 140 Kotsuki, H . ( 2 ) 140; ( 6 i ) 77 Kottrnann, H . ( 6 i i ) 1 5 1 K o w a l l i k , W. ( 5 ) 208 Kowalski, C.J. ( 2 ) 115; ( 3 ) 72; ( 6 i i ) 39 K o w a l s k i , M. (1) 9 3 K o z i a r a , A. ( 4 ) 186; (5) 33 K o z i k o w s k i , A.P. ( 3 ) 239, 3 5 2 ; ( 6 i i ) 1 9 2 ; ( 8 ) 55; ( 9 ) 39, 4 0 , 59 Kozima, S. ( 2 ) 1 4 7 Koz'min, A.S. ( 4 ) 1 3 5 Kozyrod, R.P. (3) 144 K r a f f t , G.A. ( 6 i i ) 1 6 7 ,
187; ( 8 ) 94 K r a u s , G.A. (3) 2 8 4 ; ( 7 ) 99; ( 8 ) 49 Krawczyk, E. ( 5 ) 458 K r e p s k i , L.R. (3) 330; ( 6 1 i ) 62 K r e s z e , G. (3) 4 2 8 R r e u t n e r , W . (1) 9 2 K r i e f , A . ( 6 i i ) 3, 51, 1 9 4 ; ( 7 ) 11 K r i e g , R. ( 5 ) 534 K r i e g e r , C. ( 5 ) 313 Kriegesmann, R . ( 6 i i ) 142, 161 K r i s h n a n , L. ( 8 ) 228 K r i s t i a n , P. ( 8 ) 122 K r i s t i n s s o n , H. ( 8 ) 117 K r o p f , H. ( 4 ) 81 K r u g e r , C. ( 5 ) 4 8 0 ; ( 8 ) 115 K r u s e , C.H. ( 3 ) 4 6 3 Kubak, E. ( 3 ) 354 Kubelka, V . ( 3 ) 280 K u b o t a , H. ( 2 ) 105 K u b o t a , M. ( 3 ) 1 3 7 ; ( 5 ) 112 Kudo, K . ( 6 i i ) 214 Kurnbel, B. ( 5 ) 514 Kuhnt, D. ( 5 ) 514 Kuizumi, T. ( 6 i i ) 1 7 8 K u l i n k o v i c h , O.G. ( 2 ) 134 K u l k a r n i , A.K. ( 4 ) 1 5 9 ; ( 5 ) 111; ( 6 i i ) 1 2 0 K u l k a r n i , Y.A. ( 9 ) 11 K u l k a r n i , Y.S. ( 2 ) 6 2 , 6 4 ; (3) 253 Kumagawa, T. ( 2 ) 1 2 4 , 1 2 5 Kurnar, A. ( 5 ) 289, 471 Kurnobayashi, H. ( 5 ) 115; ( 6 i ) 22 Kurnpf, R . J . ( 6 i i ) 3 7 Kunda, S.A. ( 4 ) 1 5 3 , 154 Kunesch, E. ( 3 ) 5 9 , 9 4 ; ( 5 ) 338 Kunieda, T. ( 4 ) 131 K u n i s c h , F. (3) 147 Kunishima, M. (1) 80 Kunz, H . ( 3 ) 6 9 , 4 7 7 ; ( 6 i ) 78 Kunze, 0. ( 3 ) 235 Kunze, U. ( 5 ) 487 Kuo, E. ( 5 ) 17 Kuo, G.H. ( 7 ) 8 K u p f e r , R . (5) 484 K u r i h a r a , T. ( 5 ) 306-309 K u r i t a , H . ( 2 ) 42 Kuroda, K. ( 8 ) 7 4 Kuroda, T. ( 1 ) 8 6 ; ( 2 ) 105 Kuroda, Y. (3) 429 Kurokawa, K . ( 3 ) 434
619
Author Index Kurosawa, K . ( 2 ) 114 K u r t h , M.J. ( 2 ) 163; ( 3 ) 3 2 , 130 Kurusu, Y . ( 6 i i ) 182 Kusumoto, S. ( 9 ) 6 4 Kusumoto, T. (1) 9 4 ; ( 4 ) 168 Kutagawa, S.A. ( 5 ) 115 K u t s c h y , P. ( 8 ) 122 K u t y r e v , G.A. ( 3 ) 228; ( 8 ) 78 Kuwajima, I . ( 3 ) 1 3 2 , 3 1 5 ; ( 6 i i ) 4 7 ; ( 7 ) 156 Kuwayama, S. ( 6 i i ) 1 7 8 K u z n e t s o v a , L . A . ( 5 ) 302 K u z u h a r a , H. ( 8 ) 202, 203 Kvita, V. (3) 45 Kwart, L . D . ( 3 ) 227; ( 8 ) 152 Kwasigroch, C.A. ( 8 ) 44 Kwon, C.-H. ( 5 ) 536 Kwon, H.B. ( 6 i ) 3 9 ; (8) 216 K y l e r , K . (1) 3 4 ; ( 6 i i ) 148 Kyung, S.-H. ( 2 ) 44; ( 3 ) 136 K y z i o l , J . B . ( 5 ) 440 L a a l i , K . ( 5 ) 318 L a a n , J . A . M . ( 3 ) 201 L a b b i e n t o , L. ( 5 ) 7 6 L a B e l l e , B.E. ( 7 ) 67 L a b e l l e , M . (3) 1 4 8 ; ( 5 ) 231 L a b o r d e , E. ( 7 ) 80 L a c h e r , B. ( 3 ) 54 L a c o s t e , J . M . ( 5 ) 142 Ladlow, M. (3) 285; ( 7 ) 1 2 8 ; ( 9 ) 10, 13 Ladouceur, G. (2) 141 L a f a r g e , C. (3) 8 5 L a F r a n c e , R . J . ( 5 ) 526 L a g a n i s , E.D. ( 6 i i ) 1 2 5 L a i r d , A.A. ( 4 ) 103 Lakshmikantham, M . V . ( 8 ) 197 L a l a n d e , J. ( 4 ) 1 9 L a l o n d e , M. ( 3 ) 4 6 ; ( 4 ) 98 Lamatsch, B. (3) 1 1 9 L a m b e r t , C. ( 3 ) 3 9 1 ; ( 5 ) 224 L a m b e r t , P.H. ( 8 ) 177 Lan, A . J . Y . ( 8 ) 194 L a n d g r e b e , K . ( 3 ) 284 Lane, S. ( 6 i ) 31 Lang, R.W. ( 3 ) 220 Langa, F. ( 8 ) 1 9 5 L a n g e , G.L. ( 7 ) 19, 20
L a n g e r , M.E. ( 8 ) 185 L a n g l o i s , N. ( 3 ) 151; ( 4 ) 91 L a n g l o i s , Y. ( 3 ) 151; ( 4 ) 91 L a p a t s a n i s , L. ( 3 ) 461 L a p k i n , 1.1. ( 5 ) 494 LarchevGque, M. ( 4 ) 1 9 L a r d i c c i , L. ( 1 ) 7 6 ; ( 4 ) 32 LaRosa, C. ( 6 i i ) 184 L a r s e n , C. ( 3 ) 402 L a r s e n , S. ( 8 ) 1 3 5 , 183 L a r s o n , E. ( 3 ) 353; ( 8 ) 59 L a r s o n , G.L. ( 2 ) 3 2 ; ( 3 ) 310; ( 6 i i ) 119 L a r s o n , K . D . ( 5 ) 469 L a s z l o , P. ( 2 ) 5 9 ; ( 3 ) 9 3 ; ( 5 ) 324, 429 L a t h b u r y , D. ( 8 ) 169 L a t i f , F. ( 5 ) 551 L a t i f , N . ( 5 ) 399 L a t r o f a , A . ( 5 ) 67 L a t t e s , A . ( 5 ) 169 L a t t r e l l , R. ( 8 ) 214 L a u b e , T. ( 2 ) 1 4 6 , 153; ( 5 ) 4 1 2 ; ( 6 i i ) 11 Laumen, K . ( 3 ) 8 2 , 263 L a u r , J. ( 3 ) 462 L a u r e n t , H. ( 4 ) 146 L a u r e n z a n o , A.J. ( 3 ) 261 L a u t e n s , M . (1) 5 8 ; ( 6 i ) 26 L a v i e l l e , S. ( 3 ) 442 ( 5 ) 130 Law, K.-W. Lawesson, S.-0. ( 5 ) 259 Lawrence, G.C. ( 3 ) 266 Lawson, A.M. ( 3 ) 282 Lawson, K. ( 3 ) 370 L a z a r e v a , M . I . ( 8 ) 163, 164 L a z l o , P. ( 3 ) 1 6 8 ; ( 4 ) 114 L e a v e r , J. ( 3 ) 266 LeBel, N.A. ( 5 ) 5 4 4 , 545; ( 8 ) 1 0 2 , 103 LeBerre, A. ( 8 ) 119 L e c e a , B. ( 2 ) 5; ( 4 ) 118, 160 Lechen, H.-G. ( 3 ) 69 L e e , G.C.M. ( 9 ) 4 6 (9) 84 Lee, H.-H. L e e , J.I. (3) 4 6 8 ; (3) 62 L e e , L.G. ( 3 ) 265 L e e , M. ( 7 ) 19 L e e , P.E. ( 5 ) 201 L e e , T.-J. ( 3 ) 352 L e e , T.V. ( 6 i i ) 1 3 2 ; ( 7 ) 73. 9 8 L e f o r t , D. ( 3 ) 5 6
L e f t i n , M . H . (1) 7 5 ; ( 6 i ) 47 L e g e d z , S . ( 6 i i ) 177 LeGoff, E. ( 7 ) 110 Le Goff, N . ( 5 ) 118 Lehmeier, T. ( 4 ) 5 8 ; ( 6 i i ) 82 L e i j o n m a r c k , H. ( 3 ) 357 L e i k a u f , U. ( 3 ) 21 L e i s u n g , M. ( 5 ) 344 L e m a i r e , F. ( 8 ) 81 L e m a i r e , M. ( 7 ) 108 Le Merrer, Y . ( 2 ) 100 Lempert, K . ( 5 ) 4 6 ; ( 8 ) 232 LeNard, G. ( 5 ) 11 Le N o b l e , W.J. ( 5 ) 17 L e n o i r , D. ( 2 ) 1 4 4 ; ( 6 i i ) 10
Lenz, B.G. ( 8 ) 92 Lenz, G.R. ( 3 ) 171 L e o n a r d , D. ( 3 ) 292; ( 4 ) 133; ( 6 i ) 6 6 , 67 L e o n a r d , W.R. ( 2 ) 1 7 4 ; ( 6 i i ) 202; ( 7 ) 52 Le P e r c h e c , P. ( 3 ) 380; ( 5 ) 269 L e r c h e , H. ( 5 ) 451 L e s i m p l e , P . ( 6 i i ) 25 Lesma, G. ( 3 ) 379; ( 5 ) 229 L e s u i s s e , D. ( 8 ) 1 9 1 LeTourneau, M.E. (1) 38 L e v i n , D. ( 3 ) 38 Levinson, M . I . ( 2 ) 56; ( 3 ) 228; ( 5 ) 1 2 5 ; ( 8 ) 79 L e v o r s e , A.T. (8) 1 6 8 L e w i s , J . J . ( 2 ) 156 Ley, S.V. ( 3 ) 366; ( 6 i i ) 4 9 , 198; ( 7 ) 90; (8) 7 1 , 217; ( 9 ) 5 7 , 81 Lhommet, G . ( 8 ) 147 L i , C.-S. (3) 352 L i a o , X . ( 6 i i ) 152 L i c a n d r o , E. ( 5 ) 4 9 7 ; ( 6 i ) 82 L i c h t e n b e r g , F. ( 3 ) 246; (6ii) 7 L i c h t e n t h a l e r , F . W. ( 5 ) 25 L i c i n i , G. ( 1 ) 83 L i e b e r k n e c h t , A . ( 3 ) 455 L i e b e s k i n d , L.S. ( 5 ) 216; ( 6 i ) 4 1 ; ( 8 ) 215 L i e b s c h e r , J. ( 5 ) 117 L i e p i n ' s h , E.E. ( 5 ) 61 L i e t j e , S. ( 6 i i ) 1 5 3 Liew, W.-F. ( 3 ) 3 6 3 L i l l i e , T.S. ( 4 ) 1 4 3 L i n , P. ( 5 ) 4 8 9 ; ( 9 ) 6 0
General and Synthetic Methods
620 L i n , Y.-T. ( 7 ) 1 0 4 , 105 L i n d e l , H . ( 3 ) 480 L i n d q u i s t , B. ( 5 ) 1 2 Linstrurnelle, G. ( 3 ) 374; ( 4 ) 182 L i o t t a , D. ( 2 ) 1 1 9 ; ( 6 i i ) 1 9 5 , 196 L i p s c h u t z , B.H. ( 2 ) 140; ( 6 i ) 77 L i s o , G. ( 5 ) 67 L i t t l e , R.D. ( 7 ) 5 9 , 6 1 ; ( 8 ) 32 L i t v i n o v , V.P. ( 5 ) 382 L i u , H.-J. ( 2 ) 6 ; ( 3 ) 76 L i u , T.M.H. ( 3 ) 350 L i v e r t o n , N.J. ( 8 ) 7 5 L i v i n g h o u s e , T. ( 2 ) 1 7 4 ; ( 6 i i ) 202; ( 7 ) 5 2 ; ( 8 ) 137, 198 L i You, M . ( 6 i i ) 1 8 9 L i z , R. ( 5 ) 1 1 6 ; ( 8 ) 211 Lock, G.A. ( 8 ) 5 3 Lockhead, A.W. ( 8 ) 9 1 Loewe, M.F. ( 6 i i ) 1 8 ; ( 8 ) 2 0 0 , 201 Lok, K.P. ( 3 ) 265 L o k e n s g a r d , J . P . ( 5 ) 257 L o k t e v , S.M. ( 1 ) 1 Lombardo, D.A. ( 3 ) 1 9 1 L b p e z , C. ( 2 ) 4 ; ( 4 ) 116 Lopez, F. (5) 127 L o p e z , L. (1) 7 0 L6pez-Prado, J. ( 5 ) 9 1 L o r e n c , L. ( 2 ) 1 3 6 ; ( 7 ) 155 L o r e t o , M . A . ( 5 ) 212 Louis-Andre, 0. ( 2 ) 24 Loupy, A . ( 3 ) 6 7 Lu, D.-A. ( 3 ) 26 Lu, D.L.-L. ( 5 ) 1 6 1 Lu, S.-B. ( 1 ) 4 7 ; ( 6 i i ) 1 5 7 ; ( 7 ) 124 L u a t a , C. ( 8 ) 6 8 L u c c h e t t i , J . ( 6 i i ) 194 L u c c h i n i , V. ( 8 ) 126 L u c h e , J.-L. (1) 13; (2) 178; ( 4 ) 4 9 , 1 7 1 ; ( 6 i i ) 63, 64 Luche, M.-J. ( 7 ) 97 L u e h r , G.W. ( 4 ) 224 L u g t e n b u r g , J. ( 5 ) 422 L u i s , S.V. ( 4 ) 1 5 8 L u k a s , K.L. ( 6 i i ) 53 L u k e h a r t , C.M. ( 6 i ) 2 L u k e v i c s , E. ( 4 ) 1 2 ; ( 5 ) 3 L u l y , J . R . (3) 437 L u n i n g , U . ( 3 ) 100 Lunn, G. ( 5 ) 1 Luo, F.T. ( 6 i ) 3 2 L u s i n c h i , X. ( 4 ) 76; ( 5 )
78, 79, 94; ( 6 i i ) 205, 207-209 L u z g i n a , G.M. (5) 1 2 1 Lygo, R . ( 6 i i ) 49 Lynch, L.E. ( 3 ) 3 3 0 ; ( 6 i i ) 62 Lysova, L.A. ( 3 ) 439
McMills, M.C. ( 8 ) 6 McMurry, J.E. ( 6 i i ) 7 1 ; (7) 147; ( 9 ) 1 6 McNamara, J . M . ( 3 ) 350 Macor, J.E. ( 8 ) 9 0 McPhail, A.T. ( 8 ) 1 5 1 MacPherson, D.T. ( 7 ) 81 Maddox, M.L. ( 2 ) 122 Maehata, E. ( 3 ) 34 Maekawa, E. ( 3 ) 2 3 8 , 298; Maas, G . ( 5 ) 5 2 2 , 525 ( 6 i i ) 199 Maat, L. ( 5 ) 9 Maekawa, T. ( 5 ) 357 Mabury, S.A. ( 1 ) 4 3 ; ( 3 ) Mannig, D. ( 4 ) 1 234 Magnus, P. ( 2 ) 67; ( 6 i ) Maccagnani, G. ( 8 ) 1 2 8 McCann, D.J. ( 3 ) 65 65; ( 7 ) 6 2 , 6 5 McCanna, T.D. ( 7 ) 167 Magolda, R.L. ( 9 ) 6 9 M a g r i o t i s , P.A. ( 2 ) 1 ; McCarthy, J . R . (1) 3 8 ; ( 5 ) 1 6 7 , 168, 375 ( 4 ) 119 M a g u i r e , M.P. ( 9 ) 42 McCauley, J.P., j u n . Mahajan, S.W. ( 4 ) 147 ( 6 i i ) 203 Mai, K . ( 5 ) 3 5 4 , 355 McClean, D. ( 8 ) 113 McCloskey, C.J. ( 2 ) 86 Maidment, M.S. ( 3 ) 333 McCloskey, P . J . ( 5 ) 5 6 M a i e r , G. ( 4 ) 21, 22 McCombie, S.W. ( 8 ) 4 0 M a i e r , M. ( 8 ) 6 3 , 64 M a i g r o t , N. ( 5 ) 68 McCowan, J . D . ( 4 ) 4 1 McCoy, R . K . ( 2 ) 1 7 9 M a i l l a r d , B. ( 3 ) 8 5 , 286, McDonald, I . A . ( 5 ) 142287 144 M a i o r a n a , S. ( 5 ) 497; ( 6 i ) 82 MacDonald, J.G. ( 3 ) 402 McDougall, D . C . ( 8 ) 9 1 M a j e t i c h , G . ( 6 i i ) 102McElroy, A . B . (1) 24, 25; 1 0 4 ; ( 7 ) 7 0 , 130-133 ( 6 i i ) 159, 173 Makabe, Y. ( 5 ) 4 7 0 ; ( 6 i ) McGarry, D. ( 8 ) 225 24 McGarvey, G . J . (1) 96; Makamura, M . ( 6 i i ) 1 9 0 ( 2 ) 109; ( 3 ) 73; ( 6 i i ) Makarov, V.F. ( 5 ) 271 75 Makosz, M. ( 5 ) 2 1 , 407 Makowski, M. ( 3 ) 475 McGeehan, G.M. ( 3 ) 4 3 3 McGrath, D . V . (1) 10 M a l a c r i a , M. ( 1 ) 69 McGuigan, H. ( 5 ) 183-85; M a l a s s a , I . (5) 4 8 5 (8) 1 1 3 , 114 M a l i k , A . ( 5 ) 208, 5 5 1 Machida, H. (1) 5 7 ; ( 3 ) 1 M a l l i a r , F. ( 5 ) 330 Machida, K. ( 3 ) 257 Malone, J . F . ( 8 ) 1 4 8 Machida, M. ( 8 ) 8 2 Maloney HUSS, K.E. ( 9 ) 5 9 Machioro, C. ( 8 ) 126 Manabe, H . ( 5 ) 13 Manda, E. ( 3 ) 17 McKenna, J. ( 3 ) 4 7 5 ; ( 4 ) Mandai, T. ( 2 ) 45; ( 6 i i ) 8 ; ( 5 ) 31 Mackenzie, P.B. ( 3 ) 9 0 114 McKervey, M.A. ( 2 ) 5 4 , Mandal, A . K . ( 4 ) 1 0 6 , 147 118 Mandel, G.S. ( 3 ) 240 McKillip, A. ( 6 i i ) 95 Mandel, N.S. ( 3 ) 240 McKinney, R . J . ( 3 ) 4 0 ; M a n e s c a l c h i , F. ( 4 ) 1 3 6 ; ( 5 ) 550 ( 5 ) 321 Mackinnon, J.W.M. ( 5 ) M a n f r e d i , A. ( 3 ) 217, 404 182-184; (8) 113, 114 M a n f r e d i , K. (3) 363 Mangeney, P. ( 1 ) 77 M c K i t t r i c k , B.A. ( 4 ) 205 McLaughlin, L.M. ( 3 ) 282 M a n g i a r a c i n a , P. (1) 9 2 McLean, D. ( 5 ) 146, 183, Manhas, M.S. (8) 228 Mann, J . (8) 77 185 McManus, M . J . (5) 508 Manna, S. ( 4 ) 1 4 5 ; ( 5 ) McMaster, D. ( 1 ) 88; ( 3 ) 292 216; ( 4 ) 185; ( 6 i i ) 4 5 Manning, H.W. (5) 5 2 6
Author Index Masuda, H. ( 4 ) 29; (5) 198 Masuda, K. (8) 110 Masuda, M. (3) 127, 207; (5) 311, 312 Masuda, R. (2) 138; (4) 15 Masuda, Y. (1) 27; (2) 102; (4) 219 Masui, M. (1) 36; (5) 301, 383; (6ii) 156 Masuyama, Y. (6ii) 182 Mathy, A . (2) 59; (3) 168; (5) 324 Matos, J . R . (3) 16 Matsubara, S. (1) 29; (4) 94, 96; (6ii) 127 Matsuda, F. (5) 226 Matsuda, H. (8) 110, 116 Matsuda, I . (2) 11, 98, 173; (3) 326; (6i) 23 Matsuda, K. (8) 142 Matsuda, T. (5) 52; (8) 41 Matsui, Y. (9) 75 Matsurnoto, M. (8) 74 Matsumoto, T. (2) 108; (5) 40, 226 Matsuo, N. (5) 364 Matsumura, Y. (3) 74; (8) 196 Matsushima, Y. (3) 327 Matsushita, H. (4) 9; (8) 84 Matsuura, T. (3) 457; (8) 108 Matsuyama, H. (3) 147 Matsuzaki, K. (8) 46 Mattes, H . (3) 304 Matthews, P.D. (5) 375 Matthies, D. (5) 276, 485, 486 Maurer, P . J . (5) 197 Maurin, R. ( 2 ) 61 Maus, S. (4) 42 84 Mavunkel, B. (5) 120 Maryanoff, B . E . (6ii) 144 Maynard, S.C. (8) 237 Mayo, S.L. (5) 42 Mas, J.M. (1) 69 Masamune, S. (1) 95; (6i) Mayoral, J . A . (3) 433 9 ; (6ii) 77 Mayr, H. (7) 4 Masatsugu, Y. (3) 260 Mazaleyrat, J.-P. (5) 68 Masci, B . (5) 426 Mazzanti, G. (8) 128 Meckler, H. (5) 176 Mash, E . A . (7) 10 Meguro, H. (3) 444 Mashida, H. (8) 86-88 Mashraqui, S.H. (8) 124 Mehrotra, K.N. (8) 111 Mason, C.M. (6ii) 46 Mehta, G. (2) 60 Masse, G . (5) 456 Meijer, L.H.P. (3) 135 Masson, J.C. (8) 119 Meinke, P.T. (6ii) 167; Masson, S. (2) 52 (8) 94 Massy-Westropp, R . A . (3) Meinwald, J. (5) 257 Melany, M.L. (8) 53 zia
Mansuri, M.M. (3) 373 Mantecon, A . (3) 67 Manzocchi, A . (3) 444 Marcelis, A.T.M. (5) 481 Marchese, G. (3) 431; (6i) 61 Marchesini, A . (3) 217 Marchioro, C. (6ii) 180 Marco, J . A . (4) 158 Marco, J.L. (5) 190, 359 Mardamingo, C.L. (5) 478 Margot, C. (4) 93; (6ii) 24, 146 Mariano, P.S. (5) 479; (8) 189, 194 Marinelli, F. (4) 95 Maring, C . J . (3) 353; (8) 61; (9) 62 Marino, J . P . (3) 269; (7) 80 Marko, I. (2) 63; (3) 253; (7) 21 Markov, V . I . (5) 535 Marquet, A . (3) 442 Marquet, J . (2) 161 Marra, J.M. (8) 176 Marshall-Weyerstahl, H. (3) 295 Marsili, A . (3) 334 Martelli, G. (4) 136; (5) 550 Martin, T. ( 9 ) 37 Martinez, J . (3) 462 Martinez, P . A . (3) 67 Martinez-Gallo, J . M . (4) 5, 153; (5) 552 Martinez-Utrilla, R. (5) 41 Maruoka, K. (1) 6; (5) 85, 507; (6ii) 90, 91; (7) 3, 140; (8) 181 Maruoka, M. (5) 124 Maruyama, H . (8) 233 Maruyama, K. (3) 95, 344, 425; (5) 81, 82; (6ii)
62 1 Mellor, J.M. (3) 251; (5) 253, 254; (6ii) 168 Mendelson, S.A. (7) 7 Mendenhall, G.D. (5) 469 Menendez, E. (3) 433 Menger, F.M. (3) 65 Meninchi, G. (5) 303 Mensler Cavolowsky, K. (5) 466 Mera, A . E . (6ii) 37 Merenyi, R. (3) 403; (5) 283, 284, 332, 333 Mertes, K. (3) 219 Mestres, R. (2) 79; (3) 30; (7) 134 MeszAros, Z. (5) 55 Metcalf, B. (2) 117; (5) 152 Metternich, R. (4) 58; (6ii) 82 Metzner, P. (2) 183; (3) 229, 236; ( 9 ) 48 Meyer, W.L. (2) 78; (7) 122 Meyers, A . I . (2) 43; (3) 39, 232, 320; (6ii) 17, 18; (8) 107, 176; 200, 201; (9) 41 Meyers, M. (7) 7 Meyers, P.L. (7) 113 Meyle, E. (8) 120 Mezzetti, A . (5) 134; (7) 103 Michael, J . P . (4) 196; (6ii) 94; (8) 16 Michel, S.T. (6ii) 1; (7) 164 Michelotti, E.L. (1) 75; (6i) 47 Midland, M.M. (3) 347; (5) 201 Mierop, A . J . C . (3) 376; (5) 249 Miginiac, L. (3) 185 Miginiac, P. (5) 153 Migita, T. (3) 206 Mignani, S. (5) 332, 333 Mihailovic, M.L. (2) 136; (7) 155 Mijngheer, R. (9) 21 Mikaelian, G.S. (1) 82 Mikajiri, T. (2) 42 Mikami, K. (3) 384 Mikhaleva, A . I . (5) 498 Miki, M. (5) 307-309 Mikolajczyk, M. (6ii) 177 Milani, F. (5) 63 Milchereit, A. ( 5 ) 241 Milenkov, B. (3) 375; (5) 351 Milewska, M. (5) 461
622 M i l l a r , P. ( 5 ) 44 M i l l e r , D . D . ( 3 ) 416; ( 5 ) 26 M i l l e r , D.M. ( 6 i i ) 23 M i l l e r , .J.A. ( 6 i ) 55; ( 7 ) 68 M i l l e r , M.J. ( 3 ) 122; ( 8 ) 231 M i l l e r , R.D. ( 3 ) 1 8 6 , 209; ( 5 ) 331 M i l l i a s , G. ( 3 ) 461 M i l l i e t , P. ( 6 i i ) 205 M i l l s , R.J. ( 3 ) 393; ( 6 i i ) 29 M i l n e r , D . J . ( 5 ) 317 M i l t z , W . ( 2 ) 154; ( 3 ) 426; ( 5 ) 217 Minami, I . ( 2 ) 162; ( 3 ) 146; ( 3 ) 472; ( 8 ) 45 Miriami, T. ( 3 ) 22.5 M i n i s c i , F. ( 5 ) 278 Mioskowski, C . ( 4 ) 145 Misawa, N. ( 1 ) 90; ( 3 ) 172 Misawa, T. ( 3 ) 444 Misayaka, T. ( 5 ) 227 Misco, P.F. ( 3 ) 5 1 M i s u , D. ( 2 ) 22 M i s u m i , A. ( 7 ) 9 M i t c h e l l , T.N. ( 1 ) 30; ( 6 i i ) 124 Mitsudo, T. ( 1 ) 90; ( 2 ) 96; ( 3 ) 71, 172 M i t t a l , R.S. ( 5 ) 428 Mitzui , T. ( 3 ) 44 Miwa, T. ( 2 ) 171; ( 3 ) 295; ( 4 ) 70 Miyaka, A . I . ( I ) 1 Miyake, H. ( 2 ) 184; ( 3 ) 77, 78; ( 8 ) 25, 26 Miyake, J. ( 1 ) 12 Miyake, J.-I. ( 3 ) 406; (5) 287, 288 Miyake, M . ( 5 ) 222 Miyake, S. ( 5 ) 22, 23 Miyano, S. ( 4 ) 24; ( 5 ) 161 Miyasaka, T. ( 5 ) 133 Miyata, K . ( 7 ) 49; ( 8 ) 57 Miyaura, N . ( 1 ) 6 0 ; ( 6 i ) 46 Miyazaki, K . ( 4 ) 29; ( 5 ) 198 Miyazawa, M . ( 1 ) 8 7 ; ( 4 ) 20 Miyazawa, T. ( 2 ) 3; ( 3 ) 242; ( 4 ) 123 Miyoshi, N . ( 3 ) 75 Mizuguchi, Y. ( 1 ) 2 Mizuki Y. ( 5 ) 301 Mizuno, K . ( 5 ) 319; ( 6 i i )
General and Synthetic Methods 106 Mizusaki, S. ( 4 ) 9 Mladenova, M . ( 3 ) 316 Mobbs, B . E . ( 6 i ) 43; ( 6 i i ) 19 Mochizuki, A . ( 5 ) 222 Modena, G. ( 6 i i ) 180; ( 8 ) 126 M o l l e r , A. ( 5 ) 1 2 2 , 527 Moenius, U, ( 3 ) 401 Mohan, R. ( 2 ) 8 4 , 126 Mohr, P. ( 3 ) 110; ( 5 ) 441 Moirnas, F. ( 5 ) 405 Moisaki, K . ( 4 ) 179 Moiseenkov, A.M. ( 6 i i ) 146 Moison, H . ( 3 ) 168 Molander, G.A. ( 1 ) 8 4 ; ( 4 ) 54 Molina, M.T. ( 5 ) 43 Molina, P. ( 4 ) 207 M o l i n a r i , H . (3) 404 Moll, G . ( 3 ) 337 M o l l e r , T. ( 4 ) 43 M o l l i e r , Y. ( 6 i i ) 38 Money, T. ( 9 ) 2 3 Monforte, J . ( 2 ) 140; ( 6 i ) 77 Monko-Mpegna, D. ( 6 i i ) 2 MonkoviE, I . ( 5 ) 7 3 Montaiia, A.-M. ( 2 ) 68; ( 7 ) 63 Montanari, F. ( 5 ) 352 Mohtanucci, M. ( 1 ) 28 Montaudon, E. ( 3 ) 286, 287 Montgomery, S.H. ( 3 ) 20, 115 Monyla, J. ( 5 ) 487 Moody, C . J . ( 9 ) 37 ( 4 ) 1149 Moon, B.-H. Moore, D.W. ( 5 ) 501 Moore, H.W. ( 7 ) 28 Moreland, D.W. ( 2 ) 149 Moreno-Manas, M. ( 2 ) 161 Morera, E. (1) 42; ( 3 ) 175, 321; ( 5 ) 235; ( 6 i ) 71 Morey, J . ( 2 ) 2; ( 4 ) 124 Mori, A. ( 1 ) 7 ; ( 2 ) 142 Mori, €1. ( 3 ) 119 Mori, K . ( 3 ) 118, 119, 272, 339, 343, 348, 419; ( 4 ) 35; ( 5 ) 547 Mori, M. ( 6 i ) 72, 73; ( 8 ) 166, 219, 220 Mori, T. ( 4 ) 131 Mori, Y. ( 3 ) 372 M o r i a r t y , R.M. ( 2 ) 103 Morimoto. T. ( 2 ) 48: ( 3 ) 138, 449; ( 5 ) . 4 6 4 , 465;
( 8 ) 141 Morin, J.M. ( 9 ) 47 M o r i t a , Y . ( 5 ) 417 Moriwake, T. ( 3 ) 380, 437; ( 5 ) 3 4 , 268 Moriya, A . ( 4 ) 48 Moriya, 0. ( 4 ) 200; ( 8 ) 27 Moriyasu, M . ( 6 i i ) 136 Morizawa, Y . ( 4 ) 96; ( 6 i i ) 127; ( 8 ) 154 Moroder, L. ( 3 ) 474 Moro-oka, Y. ( 2 ) 8; ( 4 ) 122 M o r r i s s e y , M.M. (3) 1 2 , 133 Morrow, G.W. ( 3 ) 336; ( 5 ) 379 M o r t i a , T. ( 3 ) 44 M o r t i e r , J . ( 8 ) 149 Mortikov, V.Yu. ( 5 ) 382 Mortirner, D.N. ( 5 ) 74 Morton, H.E. ( 2 ) 143; ( 3 ) 351; ( 4 ) 113; ( 5 ) 368 Moscova, B. ( 5 ) 5 1 Mosher, H.S. ( 3 ) 448; ( 5 ) 18 Moskal, J. ( 5 ) 387 Mosset, P. ( 8 ) 5 Mostecky, J . ( 3 ) 280 Motherwell, W.B. ( 2 ) 160; ( 3 ) 53, 57, 145 Motohashi, S. ( 8 ) 17 Mott, R . C . ( 3 ) 200 Mouloungui, Z. ( 3 ) 165, 167 Mourad, M.S. ( 5 ) 420, 454 Mousurnzada, E.M. ( 5 ) 302 Moyano, A. ( 2 ) 68; ( 6 i ) 64; ( 7 ) 6 3 , 64 Moyer, M.P. ( 8 ) 36 Muchowski, J . M . ( 2 ) 122; ( 5 ) 378 M d l l e r , I . ( 5 ) 173, 174 Mukaiyarna, T. ( 2 ) 133, 152, 164, 167, 175, 189; ( 3 ) 1 0 , 75, 101, 106, 418, 447; ( 4 ) 25, 77, 189, 190, 215; ( 5 ) 410 Mukerjee, A . K . ( 3 ) 454; ( 5 ) 272 Mukhopadhyay, R . ( 5 ) 415 M u l l e r , S. ( 3 ) 416; ( 6 i i ) 23 Munger, J . D . , j u n . ( 7 ) 15 Murahashi, S.-I. ( 3 ) 398; ( 5 ) 75, 230, 234, 305; 468, 470; (6i) 1 7 , 18, 24 Murai, S. ( 1 ) 12; ( 3 )
Author index 172 Nakahama, S. ( 4 ) 1 6 , 29, 30; ( 5 ) 1 9 8 , 199 N a k a h a r a , Y. ( 4 ) 1 4 8 N a k a i , E. ( 3 ) 347 N a k a i , E.-I. (3) 276 N a k a i , M . ( 3 ) 3 3 8 ; ( 4 ) 38 N a k a i , T. ( 3 ) 2 7 6 , 3 4 7 , 384 Nakajima, N . ( 5 ) 230, 305; ( 6 i ) 17 Nakamura, A . ( 2 ) 1 0 4 ; ( 4 ) 90; ( 6 i ) 7 Nakamura, E. ( 3 ) 132 Nakamura, K . ( 3 ) 1 1 7 ; ( 4 ) 4 7 ; ( 5 ) 416 Nakamura, M. ( 2 ) 4 1 Nakamura, T. ( 2 ) 3 1 ; (3) 157 Nakano, M. ( 4 ) 2 9 , 3 0 , 153 M u z a r t , J. ( 6 i i ) 107 1 8 7 ; ( 5 ) 9 9 , 1 9 8 , 199 N a k a t a , T. ( 9 ) 8 2 Nakatani, K. ( 6 i i ) 126; Nader, F.W. ( 3 ) 3 5 ( 9 ) 70 Nakatsukasa, S. (1) 29, N a e f , R . ( 2 ) 122; ( 3 ) 4 1 5 ; ( 6 i i ) 20 8 6 ; ( 3 ) 304 N a g a i , H . ( 3 ) 4 2 ; ( 4 ) 132 Nakayama, J. (1) 26, 5 7 ; N a g a i , N. ( 5 ) 301 ( 8 ) 86-88 Nakayama, M . ( 5 ) 483 Nagao, S. ( 9 ) 8 2 Nagao, Y. ( I ) 50; 7 9 , 8 0 ; Nakayama, Y. ( 6 i i ) 114 N a k o n i e c z n a , L. ( 5 ) 461 ( 3 ) 88, 341; ( 4 ) 1 5 7 ; ( 5 ) 327; ( 6 i i ) 113 N a l l y , J. ( 8 ) 234 Nagaoka, H. ( 4 ) 190 Nambu, Y. ( 5 ) 2 4 , 1 7 5 , 25 1 N a g a r a j a n , S.C. ( 6 i i ) 1; Nanninga, T.N. ( 6 i ) 5 6 ; ( 7 ) 164 N a g a s a k i , N. ( 3 ) 7 ( 7 ) 75-77 Nagasawa, H . ( 3 ) 257 N a o t a , T. ( 5 ) 230, 3 0 5 , 4 6 8 ; ( 6 i ) 1 7 , 18 Nagasawa, H.T. ( 5 ) 5 3 6 N a p i e r a l a , C. ( 8 ) 1 1 9 Nagasawa, K . ( 4 ) 214 Nagashima, H. ( 2 ) 10; ( 3 ) N a p o l i t a n o , E. ( 3 ) 334 N a r a s a k a , K . ( 2 ) 171; ( 3 ) 3 7 7 ; ( 4 ) 1 2 1 ; ( 5 ) 248; 295; ( 4 ) 70 ( 8 ) 165 Narasimhan, V . ( 2 ) 7 N a g a t a , S. (1) 5 1 ; ( 3 ) 195; ( 4 ) 150; ( 5 ) 232, Narayana, C. ( 3 ) 292; ( 4 ) 3 233 N a r i s a n o , E. ( 3 ) 4 3 8 ; ( 5 ) N a g e l , M. ( 5 ) 484 Nago, Y . ( 3 ) 346 205 N a r u s e , Y. ( 2 ) 166 Nagra, B.S. ( 5 ) 304 Nagy, J . O . (8) 49 Nash, R . J . ( 5 ) 36 Nasman, J . - A . H . ( 3 ) 313 Nahid, E. ( 3 ) 385; ( 5 ) 267 Naso, F. ( 3 ) 431 N a t a l i n i , B. (3) 126 Nahr, U. ( 5 ) 503 N a t c h u s , M.G. ( 3 ) 227 N a i k , R.G. ( 6 i i ) 79 N a z e r , B. ( 6 i i ) 8 7 N a i t o , S. (3) 365 N a i t o , T , ( 9 ) 32 Nebout, B. ( 3 ) 1 6 1 Neck, G.E. ( 5 ) 83 NQjera, C. ( 4 ) 5 , 1 5 2 ; ( 5 ) 4 9 5 , 4 9 6 , 552; ( 6 i ) N e c k e r s , D.C. (3) 1 5 3 20, 2 1 ( 3 ) 56 N e d e l e c , J.-Y. Naka, K. ( 3 ) 293; ( 6 i ) 6 8 N e g a i , M. ( 9 ) 22 N e g i s h i , E. ( 2 ) 9 5 ; ( 3 ) Nakagawa, T. (3) 7 198; ( 6 i ) 3 2 , 5 5 , 7 4 ; Nakagawa, Y . (1) 9 0 ; ( 3 )
406; ( 5 ) 2 8 7 , 288 M u r a i , T. ( 3 ) 238; ( 5 ) 4 ; ( 6 i ) 13 Murakami , M. ( 2 ) 1 6 7 , 189; ( 4 ) 1 9 0 , 215; ( 5 ) 297 Murakami, Y. ( 6 i i ) 140 M u r a k i , K . ( 6 i i ) 110 M u r a t a , M. ( 3 ) 257 Murayama, E. ( 6 i i ) 126 Murphy, R.A. ( 9 ) 27 Murray, A.W. ( 3 ) 262 Murray, P . J . ( 6 i i ) 1 9 8 ; (7) 90 Murray, R.W. ( 8 ) 1 2 Murray, S. ( 2 ) 1 4 1 M u r t i a s h a w , C.W. ( 7 ) 139 Mushrush, G.W. ( 5 ) 371 Muskopf, J.W. ( 7 ) 1 2 1 ,
623 ( 6 i i ) 36, 93; ( 7 ) 6 , 68 N e g i s h i , Y . ( 3 ) 206 N e g r e , M . ( 7 ) 108 Negron, G. ( 8 ) 144 Nehta, G. ( 9 ) 5 N e i d l e i n , R . ( 5 ) 477 N e i e r , R . ( 5 ) 539 Neises, B. ( 3 ) 64 Nelson, K . A . ( 7 ) 10 Nemoto, H. ( 9 ) 22 N e s i , R . ( 5 ) 398 Neubauer, €1.-J. ( 3 ) 414 Neumann, S . (3) 265 Newcombe, P . J . ( 5 ) 406 Nezu, Y. ( 5 ) 465; ( 8 ) 141 Ng, S. ( 9 ) 8 4 Ngao, Y . ( 3 ) 176 Nguyen-van-Duong, K . ( 5 ) 353 Nicholas, K.M. ( 6 i ) 16 N i c h o l a s , S.>J. ( 5 ) 3 6 Nickon, A. ( 8 ) 9 8 N i c o l a o u , K.C. ( 6 i ) 4 9 ; ( 6 i i ) 193; ( 8 ) 2 0 , 5 4 ; ( 9 ) 5 3 , 6 3 , 67-69 N i c o l e t t i , R . ( 5 ) 76 Nidhiyama, H . (1) 49 Niedermeyer, U . ( 3 ) 265 N i e l s e n , A.T. ( 5 ) 425 N i e l s e n , F.E. ( 5 ) 101 N i e l s e n , H.C. ( 3 ) 251; ( 7 ) 109 Nikam, S.S. ( 5 ) 8 4 Nikishin, G . I . (8) 163, 164 N i l s s o n , A. ( 5 ) 9 6 , 97 Nimmesgern, H . ( 8 ) 1 3 8 , 1 5 6 , 157 N i n n i s s , R.W. ( 4 ) 227 Ninomyia, I. ( 6 i i ) 205; ( 9 ) 32 Nisar, M. ( 2 ) 47; ( 3 ) 6 0 N i s h i g a k i , M. ( 3 ) 238 N i s h i h a r a , Y. ( 9 ) 4 5 N i s h i i , S. ( 3 ) 9 5 N i s h i n o , €1. ( 2 ) 114; ( 8 ) 4 7 , 161 N i s h i o , H. ( 6 i i ) 126 N i s h i t a n i , Y. (1) 9 5 Nishiyama, H. ( 5 ) 336; ( 6 i i ) 1 3 1 , 183 Nishiyama, S. ( 9 ) 4 4 , 7 3 , 7 7 , 78 N i s h i z a w a , M. ( 7 ) 1 3 6 ; (8) 9 N i t t a , H. ( 8 ) 1 2 3 N i t t i , P. ( 5 ) 1 3 4 ; ( 7 ) 103 N i w a , H . ( 2 ) 18 N i w a , M. ( 9 ) 78 N i x d o r f , M. ( 3 ) 427
624
General and Synthetic Methods
8 0 ; ( 3 ) 1 7 6 , 3 4 1 , 346; N j o r o g e , F.G. ( 5 ) 213 ( 4 ) 1 5 7 , 198; ( 5 ) 327; Nkwelo, M . M . ( 3 ) 270 ( 6 i i ) 113; ( 8 ) 52 Noda, Y . ( 3 ) 342 Node, M. ( 3 ) 257; ( 5 ) 437 O'Connor, B. (1) 68 Oda, D. ( 1 ) 22 Noth, H. ( 4 ) 1 Oda, H. ( 7 ) 4 3 Noguchi, M . ( 3 ) 252 Noguchi, S. ( 5 ) 227 Oda, I. ( 8 ) 166 Nohira, H . ( 6 i i ) 123 Oda, J . ( 3 ) 8 7 Nomizu, M. ( 3 ) 481 Oda, K. ( 8 ) 8 2 Nomoto, T. ( 1 ) 8 ; ( 8 ) 184 Oda, M. ( 4 ) 178 Odaira, Y. (2) 88; (9) 3 Nomura, Y . ( 3 ) 239 O ' D o n n e l l , M.J. ( 3 ) 422Nonaka, T. ( 3 ) 6 8 424 Norbeck, D.W. ( 2 ) 1 3 ; ( 3 ) O e h l s c h l a g e r , A.C. ( 7 ) 27 1 6 9 , 1 9 6 , 240; ( 6 i i ) Oertle, K. ( 3 ) 360; ( 4 ) 115 101 N o r b e r t o , F. ( 5 ) 256 O e s t e r l e , T. ( 3 ) 438; ( 5 ) N o r d b e r g , R.E. ( 5 ) 139 N o r d l a n d e r , J . E . ( 5 ) 213 206 Ogasawara, K . ( 3 ) 283; N o r i n , T. ( 3 ) 8 4 , 445 N o r i s u e , Y . ( 4 ) 213 ( 6 i i ) 118; ( 9 ) 36 Ogawa, A. (1) 1 2 ; ( 3 ) Norma, M . H . ( 2 ) 1 8 8 ; ( 3 ) 4 0 6 ; ( 5 ) 287, 288 158 Normant, J . F . ( 1 ) 7 7 ; ( 2 ) Ogawa, H. ( 3 ) 70 2 8 ; ( 3 ) 163; ( 4 ) 1 8 2 ; Ogawa, T. ( 4 ) 1 5 1 ; ( 5 ) 232, 233, 537 ( 5 ) 3 4 0 ; ( h i i ) 188; ( 7 ) Ognyanov, V . I . ( 5 ) 434 46; ( 8 ) 23 O g u r a , F. ( 3 ) 9 ; ( 4 ) 2 0 3 , N o r r i s , R . K . ( 5 ) 406 Novi, M. ( 4 ) 220 210; ( 6 i . i ) 211 O g u r a , K . ( 2 ) 4 1 , 4 2 ; (5) Nowak, M . A . ( 2 ) 3 4 ; ( 3 ) 5 0 , 3 7 7 ; ( 6 i i ) 190 2 7 , 164 Oh, C.H. ( 3 ) 4 5 1 ; ( 4 ) 1 7 ; Noyori, R. ( 2 ) 69; ( 6 i ) (5) 66; ( 6 i i ) 65 79; (9) 50 O h a s h i , Y. ( 2 ) 1 6 2 ; ( 3 ) N o z a k i , H. ( 1 ) 2 9 , 3 3 , 1 4 6 , 472; ( 7 ) 4 0 8 6 ; ( 2 ) 27; ( 3 ) 3 0 4 ; Ohe, K. ( 6 i i ) 212-214 ( 4 ) 94, 96; ( 6 i ) 60, O h f u n e , Y. ( 3 ) 4 3 4 , 470 85; ( 6 i i ) 112; (7) 36, O h i s h i , M. ( 2 ) 108 4 3 ; ( 8 ) 154 Ohizumi, N . (1) 2 0 ; ( 4 ) N o z a k i , N . ( 6 i i ) 127 216 N o z u l a k , J. ( 3 ) 413 O h k a t a , K . ( 2 ) 2 6 , 127 Nsunda, K . M . ( 2 ) 132 O h k i , T. ( 1 ) 49; ( 5 ) 336; Nudelman, A. ( 5 ) 3 2 8 ( 6 i i ) 131 N u g e n t , W.A. ( 3 ) 40; ( 5 ) 321 Ohkubu, K . ( 5 ) 20 N u r d i n o v , R. ( 5 ) 2 Ohkuma, T. ( 3 ) 268 N u t a i t i s , C.F. ( 4 ) 4 Ohmori, H . (1) 3 6 ; ( 5 ) 301, 383; ( 6 i i ) 156 Nwokogu, G.C. (1) 9 1 O h n a r i , H. ( 2 ) 2 6 , 1 2 7 N y i t r a i , J. ( 8 ) 232 Ohno, A. (3) 1 1 7 ; ( 5 ) 416 Nystrom, J . E . ( 3 ) 343; Ohno, M. ( 3 ) 4 1 9 ; ( 5 ) 547 ( 5 ) 1 3 9 ; ( 7 ) 167 Ohno, Y. ( 9 ) 2 8 O h r u i , H. ( 3 ) 444 Ohsawa, T . (1) 2 O a r e , D.A. ( 2 ) 186, 1 8 7 ; Ohshima, H. (1) 7 3 ( 3 ) 1 5 9 , 389 O h s h i r o , Y . (5) 537 O b r e c h t , J.-P. ( 5 ) 457 O h s u g i , Y. (8) 1 9 9 O b r e c h t , R. ( 5 ) 385 O'Brien, M.J. (2) 163 O h t a , H. ( 4 ) 226 O h t a , K . (8) 46 O c h i a i , H. ( 2 ) 30, 31; O h t a , S. ( 3 ) 1 4 3 ( 3 ) 1 5 7 , 294; ( 4 ) 1 3 4 , O h t a , T. (5) 22, 23; ( 7 ) 170; ( 6 i ) 6 9 , 70; (8) 161 3 5 , 167 O h t s u k i , K. ( 2 ) 4 1 ; ( 6 i i ) O c h i a i , M. (1) 5 0 ; 79,
190 O i d a , S. ( 8 ) 233 Oikawa, H. ( 5 ) 220, 222 Oikawa, Y. ( 3 ) 1 4 2 ; ( 8 ) 29 O i s h i , H. ( 3 ) 318; ( 5 ) 45 O i s h i , T. ( 1 ) 2 ; ( 4 ) 50; (9) 82 O j i m a , I. (3) 273; ( 6 i ) 3 9 , 76; ( 8 ) 216 Oka, S. ( 3 ) 1 1 7 ; ( 5 ) 416 Okada, K . ( 3 ) 348 Okada, M. ( 2 ) 7 0 ; ( 7 ) 5 0 ; ( 8 ) 95 Okamoto, M. ( 3 ) 1 4 3 Okamoto, Y. ( 4 ) 226 Okano, A. ( 2 ) 194 Okano, K. ( 2 ) 4 8 ; ( 3 ) 138; ( 6 i i ) 1 1 7 ; ( 7 ) 32 Okano, M . ( 8 ) 18 Okawara, M. ( 2 ) 3 ; ( 4 ) 123 O k a z a k i , R. ( 5 ) 9 5 , 356 Okazoe, T. ( 4 ) 9 4 ; ( 6 i ) 85 O k i t a , M. ( 6 i ) 72; (8) 219 Oku, A . ( 7 ) 4 7 , 4 8 Okuda, Y. (1) 33; ( 2 ) 27; ( 3 ) 304; ( 6 i ) 60; ( 6 i i ) 112 O l a h , G.A. ( 5 ) 293, 318 O l a n o , B. ( 5 ) 194 O l m s t e a d , M.M. ( 7 ) 67 O l s e n , R.K. ( 5 ) 200 O l s e n , R.S. ( 2 ) 3 6 ; ( 3 ) 28 O l s s o n , T. ( 3 ) 1 O'Mahony, M . J . ( 9 ) 5 6 O ' M a l l e y , G . J . ( 3 ) 296; ( 4 ) 223; ( 6 i i ) 1 7 0 ; (8) 1 9 ; ( 9 ) 27 Omote, Y. ( 8 ) 236 Omura, S. ( 3 ) 150 Onaka, M. (5) 1 9 1 Onan, K.D. (3) 113 Ondrus, T . A . ( 5 ) 476 O ' N e i l l , B.T. ( 9 ) 4 9 O n i s h i , H. ( 5 ) 88 Ono, N . (1) 21; ( 2 ) 1 8 4 ; ( 3 ) 77, 78, 199; ( 4 ) 217; ( 5 ) 296, 3 9 2 , 393, 4 3 3 ; (8) 25, 26 O n o f r i o , F.D. ( 4 ) 137 Ookawa, A. (3) 1 O p l i n g e r , J.A. ( 7 ) 139 O p p o l z e r , W. (3) 1, 1 1 1 ; (5) 5 4 2 ; ( 6 i ) 33; ( 7 ) 111; (8) 1 Oppong-Boachie, F.K. (5) 195
625
Author Index O r a n g e , C. ( 3 ) 6 7 O r d s m i t h , N . H . R . ( 8 ) 234 O r e n a , M. ( 5 ) 1 6 6 O r f a n o p o u l o s , M. ( 3 ) 1 8 9 O r i t z , P. (8) 109 Oriyama, T. ( 3 ) 1 0 6 ; ( 4 ) 25 Ornaf, R.M. ( 8 ) 168 O r s i n i , F. ( 5 ) 334 O r t a r , G. (1) 4 2 ; ( 3 ) 1 7 5 , 3 2 1 ; ( 5 ) 235; ( 6 i ) 71 O r t i z , M.J. (8) 195 O r t o n , W.M. ( 6 i i ) 1 6 8 O r t u n o , R.M. ( 3 ) 277 Osawa, T. ( 4 ) 3 4 ; ( 8 ) 221 Osby, J . O . ( 5 ) 1 4 Oshima, K . (1) 2 9 , 33, 8 6 ; ( 2 ) 27; ( 3 ) 3 0 4 ; ( 4 ) 94, 96; ( 6 i ) 60; ( 6 i i ) 112, 1 2 7 ; ( 7 ) 4 3 ; ( 8 ) 154 Oshima, M. ( 4 ) 215 O s h i n o , H. ( 3 ) 132 Osowska-Pacewicka, K . ( 4 ) 1 8 6 ; ( 5 ) 33 O s t a r e k , R. ( 4 ) 42 Osuka, A . ( 4 ) 1 6 3 O t a k a , A . ( 3 ) 481 O t a k i , S. (3) 283; ( 6 i i ) 118 O t e r a , J. ( 2 ) 4 5 ; ( 4 ) 7 8 ; ( 6 i i ) 114 O t s u b o , T. ( 3 ) 9 ; ( 4 ) 203, 2 1 0 ; ( 6 i i ) 211 O t s u j i , Y. ( 5 ) 3 1 9 ; ( 6 i i ) 106 O t s u k a , H. ( 4 ) 1 7 8 O t s u k a , M. ( 5 ) 1 8 1 , 335 O t s u k a , S. ( 5 ) 115; ( 6 i ) 22 O t s u k a , T. ( 3 ) 272, 339 ( 8 ) 120 O t t o , H.-H. O u e r t a n i , M. ( 4 ) 1 9 1 Overman, L.E. ( 5 ) 1 9 3 ; ( 8 ) 1 7 4 , 1 9 1 , 221 Owa, M. ( 4 ) 3 0 ; ( 5 ) 199 Owada, H. ( 8 ) 18 Owton, W.M. ( 5 ) 2 5 3 , 254 Oyamada, H. ( 3 ) 1 2 0 ; ( 4 ) 27 O z a k i , J. (1) 6 3 O z a k i , N . ( 3 ) 377; (5) 248 O z a k i , Y . ( 3 ) 367 Ozawa, F. (3) 388; ( 4 ) 176 P a c , C. ( 5 ) 4 0 , 7 1 P a c h e c o , H. (5) 510
Padwa, A . ( 8 ) 1 3 8 , 1 3 9 , 1 5 6 , 157 P a g n i , R.M. ( 2 ) 9 9 P a i , G.G. ( 3 ) 1 0 5 ; ( 4 ) 3 3 ; ( 6 i i ) 85 P a k r a s h i , S.C. ( 5 ) 415 P a l a c i o s , F. ( 5 ) 127 P a l e c e k , J. ( 3 ) 280 P a l e v e d a , W . J . (3) 466 P a l f r e y m a n , M.G. ( 5 ) 1 4 2 , 144 P a l k o w i t z , A . D . ( 5 ) 197 P a l m e r , B.D. ( 7 ) 90; ( 6 i i ) 198 P a l m i s a n o , G . (3) 379; ( 5 ) 229 Palomo, C. ( 2 ) 4 , 5 ; ( 3 ) 47; ( 4 ) 1 0 0 , 1 0 4 , 116, 118, 1 6 0 ; ( 8 ) 229 Palumbo, P.S. ( 2 ) 71; ( 6 i i ) 5 4 ; ( 7 ) 33 Pandey, B. ( 7 ) 8 4 P a n d i t , U.K. ( 3 ) 135 P a n s e g r a u , P.D. ( 3 ) 39 P a n u n z i o , M. ( 4 ) 1 3 6 ; ( 5 ) 5 5 0 ; ( 8 ) 223 Papadopoulos, K. ( 2 ) 154; ( 3 ) 4 2 6 ; (5) 217 P a p a h a t j i s , D.P. ( 9 ) 6 9 P a p o u l a , M.T.B. ( 2 ) 1 6 0 ; (3) 145 P a q u e t t e , L.A. ( 2 ) 9 0 ; (7) 143 P a r a d e s , M.C. ( 5 ) 4 1 , 4 3 P a r a s k e w a s , S. ( 3 ) 4 6 1 ; ( 5 ) 532 P a r d o , C. ( 8 ) 213 P a r i s h , E . J . ( 4 ) 117 P a r i z a , R . J . ( 2 ) 77 P a r k , J . M . ( 3 ) 452; ( 5 ) 159 P a r k , P. ( 9 ) 4 0 P a r k e r , D. ( 3 ) 1 2 8 P a r k e r , K.A. (3) 197 P a r r i s h , D . R . ( 7 ) 118 P a r r o t t , M.J. ( 3 ) 476 P a r s o n s , P . J . ( 5 ) 170 P a r t a l i , V. ( 5 ) 9 3 P a r t o n , B. ( 5 ) 5 2 9 , 5 3 0 P a s p a g e o r g i o u , C. ( 3 ) 8 6 P a s q u a t o , L. (1) 83 P a t e l , M. ( 5 ) 187 P a t e l , M.M. (8) 1 0 6 , 112 P a t e l , P. (1) 9 7 , 9 8 ; ( 5 ) 256; ( 6 i i ) 1 4 ; ( 9 ) 7 4 P a t e l , P.D. ( 1 ) 3 7 ; ( 6 i i ) 143 P a t e l , S.K. ( 3 ) 282 P a t e l , Y.K. (3) 1 4 1 P a t h a k , T. ( 4 ) 1 2 5 P a t i l , - G . ( 5 ) ' 3 5 4 , 355
P a t t e n d e n , G . (1) 9 7 , 9 8 ; ( 3 ) 285, 3 3 1 , 332; ( 7 ) 60, 128, 148, 149; ( 9 ) 10, 13, 7 4 , 79 P a u l u s , E.F. ( 5 ) 1 7 3 P a u l u t h , D. ( 2 ) 4 9 ; ( 4 ) 144; ( 6 i i ) 35 Pauson, P.L. ( 2 ) 6 6 ; ( 6 i ) 10; ( 7 ) 6 6 Payne, M.J. ( 5 ) 213 Payne, N.C. (3) 90 P e a r l m a n , B.A. ( 1 ) 3 9 , 4 0 ; ( 6 i i ) 137 P e a r s o n , A . J . ( 2 ) 1 4 , 15; (3) 300;. ( 6 i ) 1, 1 9 , 30 P e a r s o n , W.H. ( 3 ) 3 5 3 ; ( 8 ) 6 0 , 153 P e d e r s e n , E.B. ( 5 ) 101 P e d n e k a r , P.R. ( 5 ) 476 P e e t , N.P. (1) 38 P e i c h o n , J . ( 4 ) 177 P e l l a c a n i , L. ( 5 ) 212 P e l l e g a t a , R . ( 3 ) 379; ( 5 ) 229 P e l l i c c i a r i , R . ( 3 ) 126 P e l t e , A. ( 4 ) 72 P e l t e r , A . ( 3 ) 282; ( 4 ) 80 P e n a , M.R. ( 1 ) 6 1 ; ( 3 ) 224 Penades, S . ( 3 ) 433; ( 5 ) 270; ( 7 ) 1 2 P e n n e t r e a u , P. ( 3 ) 9 3 P e n s a r , K.G. ( 3 ) 313 P e n s o , M . ( 5 ) 352 P e r e z , G.H. ( 7 ) 1 5 1 P e r e z , J.J. ( 9 ) 60 P e r & z , M.A. ( 5 ) 47 Perez-Ossorio, R. ( 5 ) 478; ( 8 ) 195 P e r i a s a m y , M. ( 3 ) 292; (4) 3 P e r i c a s , M . A . ( 2 ) 68; ( 6 i ) 6 4 ; ( 7 ) 1 6 , 6 3 , 64 P e r i c h o n , J. (3) 4 P e r l m u t t e r , P. (1) 3 2 ; ( 3 ) 309; ( 5 ) 322; ( 6 i i ) 109 P e r r y , R.J. ( 2 ) 4 0 ; ( 4 ) 173 P e r t h u i s , J. ( 5 ) 6 2 P e r u m a l , P.T. ( 4 ) 8 8 ; ( 6 i i ) 79 P e r u r n a t t o n , J. ( 7 ) 154 P e r v e z , H . ( 5 ) 427 P e r z , R. (8) 206 P e s c e , G . (1) 7 0 P e t a s i s , N.A. ( 6 i i ) 193 P e t e , J.P. ( 4 ) 92; ( 6 i i ) 1 0 7 ; ( 7 ) 58 P e t e r , R . - ( 4 ) 4 2 , 44
626 P e t e r s , J.A. ( 5 ) 9 P e t e r s e n , J.S. ( 6 i ) 9 ; ( 6 i i ) 77 P e t e r s o n , I . ( 3 ) 373 P e t e r s o n , J.K. ( 3 ) 2 8 8 ; ( 4 ) 2 1 1 ; ( 5 ) 1 0 4 , 348 P e t e r s o n , R.T. ( 3 ) 104 P e t i t , A. ( 3 ) 67 P e t r a g n a n i , N . ( 3 ) 307 P k t r i e r , C . ( 1 ) 13; ( 2 ) 178; ( 4 ) 4 9 , 171; ( 6 i i ) 6 3 , 64 P e t r i g n a n i , J.-F. ( 3 ) 322 P e t r i l l o , G . ( 4 ) 220 P e t - r i n i , M. ( 5 ) 3 9 6 , 397 P e t r z i l k a , M. ( 5 ) 542 P e t t i t , R . J . ( 5 ) 109 P e t t y , E . H . (6i.) 6 3 ; ( 7 ) 38 P e y t o n , K.B. ( 2 ) 113 P f a u , M. ( 2 ) 158; ( 5 ) 488 P f e i f e r , S.A. ( 5 ) 294 P f e i f f e r , B. ( 7 ) 1 6 2 , 163 P f e i f f e r , T . ( 3 ) 355 P h i l l i p s , T. ( 3 ) 269 P i c c o l o , 0 . ( 3 ) 41 P i c k , J . H . ( 3 ) 333 P i e r s , E. ( 1 ) 56; ( 3 ) 1 9 2 , 3 9 0 ; (5) 2 5 0 ; ( 6 i i ) 1 2 8 , 133; ( 7 ) 7 2 P i e t r u s i e w i c z , K.M. ( 1 ) 7 1 ; ( 7 ) 127 P i g i e r e , Ch. ( 3 ) 430 P i k e , P. ( 4 ) 184; ( 5 ) 343 P i k u l , S . ( 2 ) 135 P i l i p a u s k a s , D. ( 3 ) 4 2 1 P i l l a i , T.P. ( 5 ) 4 4 2 , 443 P i l l i , R. ( 3 ) 114 P i n c o c k , A.L. ( 3 ) 205 P i n c o c k , J.A. ( 3 ) 205 P i n e , R.D. ( 5 ) 109 P i n e , S.H. ( 5 ) 109 P i n e a u , R. (3) 4 5 9 ; ( 5 ) 145 P i n k e y , J.T. ( 3 ) 144 P i n o r i , M . ( 3 ) 478 P i - r r u n g , M. ( 3 ) 2 0 , 4 3 3 ; ( 8 ) 38 P i s i p a t i , J . S . ( 8 ) 180 P i s k u n o v a , I . P . ( 5 ) 273 Pisutjarenpong, S . ( 6 i i ) 52 P i t a c c o , G. ( 5 ) 1 3 4 ; ( 7 ) 103 P i t c h f o r d , A. ( 4 ) 7 2 P j e c z k a , E. ( 5 ) 46 P l a q u e v e n t , J.-C. ( 5 ) 255 P l a t z , M. ( 7 ) 1 P l e s s i , L. ( 4 ) 1 3 6 ; ( 5 ) 550 P l u m e t , J . ( 5 ) 478
General and Synthetic Methods P o c h i n i , A. (8) 66 Pohmakotr, M. ( 3 ) 317; ( 6 i i ) 52 P o i r i e r , J.-M. ( 2 ) 76 P o i r i e r , N . ( 2 ) 76 P o i s s o n , P. ( 5 ) 62 P o l i , G . ( 2 ) 172; ( 3 ) 1 9 0 , 2 3 3 , 249; ( 4 ) 61-63 P o l l a r t , D. ( 2 ) 140; ( 6 i ) 77 P o l l i n i , G.P. ( 5 ) 326 Polywka, M.E.C. ( 8 ) 15 Pommelet, J . C . ( 8 ) 147 Pommier, J.4. ( 2 ) 157; ( 3 ) 161; ( 5 ) 114 Pong, R.Y. ( 7 ) 2 Ponomaryov, A.B. ( 5 ) 432 Ponsinet, G. ( 7 ) 87; ( 8 ) 8 9 , 96 P o p a l l , M. ( 9 ) 26 Popp, F . D . ( 5 ) 3 7 0 , 372 P o p p e r l , H . ( 4 ) 227 P o r n e t , J . ( 3 ) 185 P o r t a , 0 . ( 4 ) 85 P o r t e l l a , C. ( 4 ) 92; (7) 58 P o r t e r , B. ( 8 ) 151 P o s n e r , G.H. ( 1 ) 4 7 ; ( 2 ) 190; ( 3 ) 162; ( 6 i i ) 2 7 , 9 2 , 1 5 7 , 1 7 5 , 1 7 6 , 181; ( 7 ) 124 P o s s , A.J. ( 9 ) 60 P o s s , M . A . ( 5 ) 489 P o t e n z a , D. ( 3 ) 233 Potenza, J.C. ( 3 ) 48; ( 4 ) 111 P o t i e r , P . ( 3 ) 460 P o t r i s , S.M. ( 2 ) 7 5 ; ( 7 ) 120 P o t t s , K.T. (6i) 47 P o u p a r t , M.-A. ( 2 ) 20 P o v a r n i t s y n a , T.N. ( 5 ) 494 P r a h e r , R.M. ( 3 ) 335 P r a j a p a t i , D. ( 5 ) 475 P r a k a s h , 0. ( 2 ) 103 P r a s a d , J.V.N. ( 6 i i ) 76 P r a s h a d , M. ( 9 ) 58 P r a t t , D.V. ( 3 ) 458; ( 5 ) 141 P r a y e r , R . H . ( 3 ) 335 P r a z e r e s , M.A. ( 5 ) 9 P r e l o g , V. ( 5 ) 395 P r i n c i p e , L.M. ( 6 i ) 6 5 ; ( 7 ) 65 P r i t c h a r d , M.C. ( 3 ) 282 P r o c t e r , G . ( 8 ) 234 P r o s y a n i k , A.V. ( 5 ) 535 P r o u t , K. ( 6 i ) 3 6 , 42 P r y o r , W . A . ( 5 ) 554
P u d o v i k , A.N. ( 3 ) 2 2 8 ; ( 5 ) 129; ( 8 ) 78 P u f f , €I. ( 2 ) 154; ( 3 ) 4 2 6 ; ( 5 ) 217 P u i g , S . ( 9 ) 15 P u j o l , D. ( 5 ) 353 P u r k a y a s t h a , M.L. ( 2 ) 182 P u r r i n g t o n , S.T. ( 4 ) 228 P u s h p a n d a , K . ( 5 ) 176 P u t t , S.R. ( 1 ) 3 9 , 4 0 ; ( 6 i i ) 137 Pyun, C . ( 6 i i ) 7 9 Q u a l l i c h , G. ( 3 ) 353 Q u a s t , H . ( 5 ) 503 Que, Y.-T. ( 9 ) 84 Q u e g u i n e r , G . ( 5 ) 11 Q u i , Y. ( 5 ) 310 Q u i c k , S.J. ( 6 i ) 31 Q u i n t a r d , J.-P. ( 6 i ) 6 2 ; ( 6 i i ) 2 , 139 Q u i r o g a , M.L. ( 8 ) 109 Q v a r n s t r o m , A . ( 8 ) 151 Rabe, J. ( 3 ) 188; ( 3 ) 302; (6i) 11 R a c h e r l a , U.S. ( 1 ) 8 4 ; ( 6 i i ) 72, 73 R a d n e r , F. ( 5 ) 4 2 3 , 424 Ragnarsson, U. ( 3 ) 465, 469 R a j a g o p a l a n , K . ( 7 ) 142 RajanBabu, T.V. ( 3 ) 2 0 8 ; ( 5 ) 408; ( 6 i ) 28; ( 6 i i ) 125 R a j a s h e k h a r , B. ( 3 ) 4 5 3 ; ( 5 ) 207 R a j e n d r a , G . ( 8 ) 231 R a k i e w i c z , D.M. ( 7 ) 5 6 , 57; ( 9 ) 8 Rakotornanana, F. (3) 2 8 6 , 287 R a k o t o n i r i n a , R. ( 2 ) 183; ( 3 ) 236 Ram, S . ( 5 ) 92 Ramachandran, P.V. ( 4 ) 3 1 ; (6ii) 7 6 , 86 Ramage, R . ( 3 ) 476 Ramaiah, M. ( 3 ) 66 R a m a k r i s h n a n , V.T. ( 5 ) 442 Ramalingam, K . ( 3 ) 4 3 5 ; (5) 6 Rarnarnurthy, V . ( 8 ) 83 Raman, K. (6i) 6 3 Ramani, B. ( 3 ) 76 Rambaud, M. ( 3 ) 167; ( 6 i i ) 145 Ramesh, S. (9) 60
Author Index R a n d a l l , J . L . ( 9 ) 63 R a n d r i a m e h e f a , S. ( 3 ) 6 Rangarajan, R . ( 2 ) 16 Rao, C.T. ( 4 ) 1 0 7 , 1 4 7 ; ( 5 ) 258; ( 6 i i ) 1 9 1 Rao, H.S.P. ( 2 ) 6 0 Rao, J . A . ( 5 ) 364 Rao, V.P. ( 8 ) 83 Raomani, S. ( 3 ) 474 Raphael, R.A. ( 3 ) 328 R a p o p o r t , €I. ( 2 ) 1 0 1 ; ( 3 ) 437; ( 5 ) 197, 210; ( 8 ) 3 6 , 175 Rasmussen, J . K . ( 3 ) 330; ( 6 i i ) 62 R a t c l i f f e , R.W. ( 5 ) 35 R a t h k e , M.W. ( 2 ) 34-36; ( 3 ) 2 7 , 2 8 , 9 7 , 164 Rathore, R. (2) 7 Ratnam, ( 4 ) 106 Ratovelomanana, V . ( 4 ) 1 8 2 ; ( 5 ) 189 R a u c h e r , S. ( 3 ) 9 6 , 4 6 4 ; ( 4 ) 139 R a u s e r , M.E. ( 5 ) 376 Ravikumar, V . T . ( 7 ) 142 R a v i n d r a n a t h , B. ( 5 ) 504 R a w l i n g s , B.J. ( 3 ) 433 Ray, T. ( 2 ) 1 5 ; ( 3 ) 300; ( 6 i ) 19 Re, A . ( 5 ) 352 Reddy, G.S. ( 3 ) 208; ( 5 ) 408 Reddy, N.P. ( 2 ) 9 ; ( 4 ) 120 R e e s , L. ( 5 ) 427 R e e t z , M.T. ( 2 ) 4 4 ; ( 3 ) 123, 136; ( 4 ) 42, 44, 6 4 , 6 5 ; ( 5 ) 362 R e g e l i n g , H. ( 8 ) 9 2 R e g i t z , M. ( 5 ) 516-518, 5 2 0 ; ( 8 ) 13 R e g l i e r , M. ( 8 ) 9 7 Reho, A. ( 5 ) 6 7 R e i c h , S.H. ( 2 ) 1 4 8 R e i d , R.G. ( 3 ) 262 R e i m e r d e s , E.H. ( 3 ) 8 2 R e i s s i g , H.-U. ( 2 ) 1 9 3 ; ( 3 ) 1 5 4 , 1 5 5 , 243, 244; ( 8 ) 22 R e i t z , A.B. ( 6 i i ) 144 Rerniszewski, S.W. (5) 180; (9) 61 Remuson, R. (8) 1 6 0 , 192; ( 9 ) 31 Rena, M.R. ( 6 i ) 51 Renaud, P. ( 3 ) 255 Renga, J.M. ( 3 ) 46 R e n i e r o , F. ( 4 ) 26 R e n n e f e l d , H. ( 4 ) 4 3 Rens, J. ( 2 ) 110; ( 4 ) 4 0
627 R e s n a t i , G. ( 2 ) 126; ( 3 ) 305 Restelli, A. ( 3 ) 404; ( 5 ) 171 Reuman, M. ( 3 ) 39 R e u s , J. ( 6 i i ) 4 3 R e u s i n g , A . ( 6 i i ) 142 R e u t e r , H. ( 2 ) 1 5 4 ; (3) 4 2 6 ; ( 5 ) 217 R e v i a l , G. ( 2 ) 1 5 8 ; ( 5 ) 4 8 8 ; ( 7 ) 102 R e w c a s t l e , G.W. ( 5 ) 9 0 Rey, M. ( 7 ) 1 6 5 R i a h i , A. ( 6 i i ) 107 Ricard, M . ( 3 ) 168 Ricci, A. ( 4 ) 129 R i c h , D.H. ( 5 ) 223 Richardson, K.A. ( 6 i i ) 132; ( 7 ) 73 R i c h a r d s o n , S. ( 5 ) 489 R i c h a u d , M.G. ( 8 ) 147 R i c h e , C. ( 5 ) 120 Richmond, J . P . ( 7 ) 83 R i e d , W. ( 5 ) 5 1 4 R i e k e , R.D. ( 2 ) 2 9 ; ( 4 ) 5 2 , 1 6 9 ; ( 5 ) 367 R i e t h , R. ( 1 ) 9 3 R i g o , B. ( 5 ) 330 R i g u e r a , R . ( 5 ) 444 R i h s , G . ( 8 ) 117 R i t t l e , K.E. ( 3 ) 386 R o b e r t s , D.C. ( 5 ) 228 R o b e r t s , D.H. ( 7 ) 9 3 R o b e r t s , S.M. ( 3 ) 266, 269; ( 7 ) 98 R o b e r t s o n , G.M. ( 7 ) 6 0 R o b i n s , D.J. ( 3 ) 3 7 1 R o b i n s o n , D.H. ( 5 ) 304 R o b i n s o n , P.L. ( 4 ) 1 9 2 , 1 9 3 ; ( 6 i i ) 1 6 0 ; ( 8 ) 10 Robinson, W.T. ( 5 ) 430 Robl, J . A . ( 5 ) 546 Rodewald, H . (3) 35, 427 R o d r i g u e z , A . D . (8) 9 8 R o d r i q u e s , K.E. ( 8 ) 1 6 8 R o d u i t , J.-P. ( 8 ) 208 R o e l e n s , S. ( 4 ) 1 2 9 Roggo, S. ( 4 ) 46 R o l , C. ( 5 ) 553 Rolando, C. ( 2 ) 1 9 ; ( 6 i i ) 190; ( 7 ) 1 6 2 , 1 6 3 Romano, S. (8) 195 Romiio, M . J . ( 5 ) 4 8 0 ; ( 8 ) 115 Rona, P. ( 8 ) 1 2 5 R o n a l d , R.C. ( 3 ) 369; ( 4 ) 143 Ronsmans, B. ( 2 ) 6 3 ; ( 3 ) 253; ( 7 ) 21 R o n z i n i , L. (3) 4 3 1 ; ( 6 i ) 61
R o s a , E. ( 5 ) 256 Rosen, T. ( 3 ) 349; ( 9 ) 83 Rosenau, B. ( 5 ) 313 R o s e n b e r g , J. ( 5 ) 450 R o s e n b e r g , S.H. ( 8 ) 175 Rosenblum, M. ( 7 ) 9 4 R o s i n i , G . ( 5 ) 3 9 6 , 397 R o s s e r , R . ( 4 ) 80 R o s s i , R. ( 6 i ) 5 3 K o t e l l o , V. ( 3 ) 4 5 2 ; ( 5 ) 159 R o t h , C. ( 4 ) 21 R o t h , S . ( 5 ) 137 R o t h , 2. ( 5 ) 328 R o u e s s a c , F.P. ( 3 ) 256 Roush, D.M. ( 8 ) 106 Roush, W . R . ( 4 ) 6 0 ; ( 5 ) 1 6 0 ; ( 6 i i ) 81, 8 3 ; ( 7 ) 115; ( 9 ) 38 R o u s s e a u , G. ( 2 ) 3 7 ; ( 3 ) 103, 1 7 3 Roussex, F. ( 3 ) 250 R o u s s i , G . ( 8 ) 144-146 Rowley, M. ( 7 ) 74 Roy, B.L. ( 8 ) 7 0 Roy, J. ( 8 ) 111 Royer, J. (5) 189, 190, 359-36 1 R o y e r , R . ( 5 ) 400 Rozynov, B.V. ( 5 ) 271 Ruano, J . L . G . ( 8 ) 1 2 1 Rubino, M.R. ( 6 i i ) 1; ( 7 ) 164 Rubottom, G.M. ( 3 ) 200 R u c k l e , R . E . , j u n . ( 7 ) 39 R u e h t e r , G . ( 2 ) 57 R u e s t , 1,. ( 8 ) 7 0 R u i z , J . A . ( 5 ) 378 Runge, W . ( 1 ) 76 R u s s e l l , D.N. ( 2 ) 5 4 R u s s e l l , G.A. ( 5 ) 4 0 4 ; ( 6 i i ) 70 R u s s e l l , M . A . ( 8 ) 239 Ryabov, A.D. ( 6 i ) 5 Rykowski, A . ( 5 ) 5 8 Ryzhov, M.G. ( 3 ) 439 R z e s z o t a r s k a , B. ( 3 ) 475 S a a , J . M . ( 2 ) 2 ; ( 4 ) 124 S a a l f r a n k , R.W. ( 3 ) 401; (5) 523 S a a v e d r a , J . E . ( 5 ) 177179 S a b a t i n o , P. ( 8 ) 1 2 8 S a b a t u c c i , J . P . ( 5 ) 135 S a c h d e v a , Y.P. ( 8 ) 180 S a c r i p a n t e , G. ( 3 ) 204; ( 8 ) 210 S a c z e w s k i , F. ( 6 i i ) 46 S a d e k , K.U. ( 5 ) 380
General and Synthetic Methods
628 S a e d n y a , A. ( 5 ) 300 Saegusa, T. ( 3 ) 160, 457; ( 5 ) 113; ( 8 ) 108 S a h a i , M . ( 5 ) 328 S a h o t a , R.I.K. ( 5 ) 77 S a i m o t o , H. ( 3 ) 3 1 8 ; ( 5 ) 45 S a i n d a n e , M . ( 2 ) 119; ( 6 i i ) 1 9 5 ; ( 7 ) 112 S a i n s b u r y , M . ( 8 ) 131 S a i t i - F a n t o n i , P . ( 5 ) 398 S a i t o , A . ( 8 ) 84 S a i t o , M. ( 5 ) 483 S a i t o , R . (1) 5 7 ; ( 8 ) 8 6 S a i t o , S. ( 3 ) 3 8 0 , 4 3 7 ; ( 5 ) 3 4 , 268 S a i t o h , T. ( 1 ) 2 Sakaguchi, N . ( 9 ) 64 S a k a i , K . ( 5 ) 301 S a k a i , T. ( 7 ) 4 9 ; ( 8 ) 4 6 , 57 S a k a i t a n i , M. ( 3 ) 4 7 0 ; ( 4 ) 178 Sakakura, T. ( 2 ) 159; ( 3 ) 419; ( 5 ) 218 Sakamoto, M. ( 8 ) 236 S a k a n e , S. ( 7 ) 140 S a k a n e , T . ( 5 ) 4 ; ( 6 i ) 13 Sakata, K . ( 2 ) 125; ( 5 ) 21 1 S a k a t a , T. ( 2 ) 5 3 S a k a t a , Y . ( 6 i i ) 111 S a k o , T. ( 6 i i ) 199 S a k s e n a , A.K. ( 1 ) 9 2 S a k u r a i , H. ( 5 ) 7 1 , 1 4 8 ; ( 6 i i ) 111 Sakurai, K. ( 9 ) 75 Sakurai, M. ( 6 i i ) 91 S a l a s k i , E . J . ( 9 ) 47 S a l a u n , J. ( 4 ) 140; ( 7 ) 158-160 Saldana-Maldonado, M . ( 3 ) 323 Salgado-Zamora, H. ( 6 i i ) 95 S a l l a m , M . M . M . ( 5 ) 380 S a m a r a i , L . I . ( 5 ) 266 S a m a r t i n o , J . S . ( 3 ) 33 Sammaruga, M. ( 4 ) 225 Sammes, P.G. ( 5 ) 1 6 5 Sampson, P. ( 2 ) 1 2 3 S a n c h e z , M . M . ( 5 ) 478 S a n d a , F. ( 2 ) 3 0 ; ( 4 ) 1 7 0 Sandhu, J . S . ( 5 ) 475 S a n d r i , S. ( 5 ) 166 S a n d r i s , C. ( 5 ) 275 S a n i e r e , M. ( 2 ) 100, 180 S a n n e r , M.A. ( 2 ) 1 8 6 ; ( 3 ) 389 S a n n i c o l d t , F. ( 5 ) 108 Sano, H . ( 5 ) 507
S a n s o n e , E.B. ( 5 ) 1 S a n s o u l e t , J . ( 3 ) 67 S a n t a n i e l l o , E. ( 3 ) 4 4 4 ; ( 5 ) 63 Sarma, D.N. ( 1 ) 11 Sarma, J.C. ( 4 ) 164 S a r t o r i , G . ( 3 ) 109 S a s a k i , A . ( 5 ) 22 S a s a k i , H. ( 5 ) 296 S a s a k i , K. ( 3 ) 9 ; ( 4 ) 203; ( 6 i i ) 1 2 6 , 211 S a s a k i , T. ( 3 ) 4 1 9 ; ( 5 ) 547 S a s a k u r , K . ( 5 ) 214 Sasson, Y. ( 5 ) 72 S a t i s h , A.V. ( 2 ) 75; (7) 120 S a t o , F. ( 3 ) 2 5 , 275 S a t o , H . ( 6 i i ) 182 S a t o , K. ( 2 ) 1 0 ; ( 4 ) 1 2 1 ; ( 6 i i ) 154; ( 8 ) 9 5 S a t o , M . ( 3 ) 278 S a t o , R. ( 5 ) 483 S a t o , S. ( 2 ) 11, 9 8 , 1 7 3 ; ( 3 ) 326; ( 5 ) 335; ( 6 i ) 2 3 ; ( 8 ) 240 S a t o , T. ( 3 ) 3 4 , 237, 267, 338, 3 6 1 ; ( 4 ) 3 7 , 38, 1 3 8 ; ( 6 i i ) 77, 1 7 1 ; ( 9 ) 25 S a t o , Y. ( 4 ) 1 8 7 ; ( 5 ) 9 9 , 274 S a t o h , J.Y. ( 8 ) 127 S a t o h , T. ( 2 ) 5 3 , 1 2 4 ; ( 5 ) 211 S a t o h , Y . ( 2 ) 1 1 6 , 192 S a t o m i , M. ( 8 ) 17 S a t t l e r , K. ( 5 ) 117 S a u l n i e r , M.G. ( 6 i i ) 1 2 Saunders, J . O . ( 7 ) 139 S a u v e , G. ( 3 ) 1 7 9 S a v i g n a c , P. ( 5 ) 128; ( 6 i i ) 153 S a v o i a , D. ( 4 ) 10 Sawamura, M . ( 3 ) 1 6 0 ; ( 5 ) 113 Sayo, N. ( 3 ) 276, 347 S c a r p a t i , R . (3) 314 S c a v o , F. ( 5 ) 1 2 3 S c e t t r i , A . ( 2 ) 1 7 , 73; ( 4 ) 137 S c h a c k , C . J . ( 5 ) 318 S c h a f f e r , H.J. ( 8 ) 33 S c h a f f n e r , K. ( 7 ) 84 S c h a f t e r , H.J. ( 3 ) 5 6 S c h a k e l , M. ( 3 ) 3 7 6 ; ( 5 ) 249 Schamp, N . ( 5 ) 4 7 3 , 4 7 4 ; ( 8 ) 132 S c h a u b , B. (1) 3 5 ; ( 6 i i ) 146, 147, 149
Schaumann, E. ( 2 ) 5 7 , 5 8 S c h a u m l o f f e l , G. ( 3 ) 477 S c h e e r e n , H.W. ( 7 ) 17 S c h e f e n a c k e r , K . ( 5 ) 225 S c h e i b l i c h , S. ( 2 ) 58 S c h e n c k , T.G. ( 3 ) 399 Scheunemann, K . H . ( 8 ) 214 S c h i a v e l l i , M.D. ( 1 ) 9 3 S c h i e s s e r , C.H. ( 3 ) 3 3 5 ; ( 7 ) 29, 9 3 S c h i n z e r , D. ( 7 ) 7 1 S c h l e c h t , M.F. ( 3 ) 289 S c h l e s s i n g e r , R.H. ( 5 ) 489; ( 9 ) 60 S c h l o s s e r , M. ( I ) 3 5 ; ( 4 ) 93; ( 6 i i ) 24, 146, 147, 149 S c h m i d t , D. ( 3 ) 400 S c h m i d t , M. ( 2 ) 5 1 ; (5) 549 Schmidt, R.R. ( 3 ) 318; ( 5 ) 64, 243, 509; ( 6 i i ) 42; ( 8 ) 63, 64 S c h m i d t , U. ( 3 ) 4 5 5 ; ( 5 ) 225 S c h m i t t , R . K . ( 4 ) 2 1 , 22 S c h m i t z , E. ( 5 ) 1 2 2 , 527 S c h n e i d e r , M . ( 3 ) 8 2 , 263 S c h n e i d e r , R. ( 5 ) 452 S c h o b e r , P.A. ( 3 ) 247 S c h o b e r t , R. ( 2 ) 5 1 ; ( 3 ) 170, 368 S c h o d e r , W. ( 5 ) 5 2 0 Schollkopf, U. ( 3 ) 408, 4 0 9 , 411-414 S c h o l z , D. ( 3 ) 37 S c h o r e , N.E. ( 7 ) 6 7 S c h r e i b e r , S.L. ( 3 ) 3 4 4 , 3 6 3 ; ( 9 ) 17 S c h r o t h , W. ( 5 ) 5 3 4 S c h u c h a r d t , J.L. ( 2 ) 7 4 ; ( 7 ) 9 1 ; (9) 4 S c h u l t e , G. ( 8 ) 5 8 S c h u l t z , A.G. ( 5 ) 5 6 ; ( 9 )
15 S c h u l t z e , L.M. ( 8 ) 218 S c h u r z , K . ( 5 ) 490 S c h u s t e r , A . J . ( 5 ) 168 S c h u t z , F. ( 3 ) 401 Schweim, H. ( 5 ) 486 S c h w e i t e r , M . J . (8) 3 S c h w e r z e l , T. ( 5 ) 549 S c o l a s t i c o , C. ( 2 ) 1 7 2 ; ( 3 ) 1 2 2 , 190, 233, 249, 4 3 8 , ( 4 ) 61-63, 6 6 ; ( 5 ) 205 S c o t t , F. ( 3 ) 270 S c o t t , W.J. (1) 6 1 ; (3) 224; ( 6 i ) 5 1 S c r i m i n , P. ( 4 ) 26 S e a r l e s , S. j u n . ( 8 ) 178
629
Author Zndex S e b a s t i a n i , G.V. ( 5 ) 5 5 3 S e e b a c h , D. ( 2 ) 1 4 6 , 151, 153; ( 3 ) 98, 116, 119, 2 5 5 , 3 7 0 , 415, 4 1 6 , 441; ( 4 ) 45, 46; (5) 3 9 4 , 3 9 5 , 411-413, 421; ( 6 i i ) 11, 20-23, 201 Seeman, J.I. ( 3 ) 182 S e g m u l l e r , B.E. ( 8 ) 170 S e i k a l y , H.R. ( 2 ) 1 4 4 , 1 4 5 ; ( 6 i i ) 10 S e i p p , U. ( 4 ) 22 S e i t z , G. ( 8 ) 5 1 S e k i g u c h i , K. ( 3 ) 278 S e k i y a , M. ( 2 ) 4 8 ; ( 3 ) 138, 449; ( 5 ) 464, 465; ( 8 ) 136 S e k o , T. (3) 238 Semmelhack, M.F. ( 9 ) 25 S e n a r a t n e , A. ( 5 ) 176 S e n d a , S. ( 3 ) 3 4 3 S e n e t , J.-P. ( 3 ) 467 Sennyey, G. (3) 467 S e n t a , M. (1) 83 S e n t e r , P.A. ( 7 ) 153 S e p i o l , J. ( 5 ) 44 S e r i z a w a , H . ( 2 ) 192 S e r r a , A. ( 3 ) 6 7 ; ( 7 ) 97 S e r r a t o s a , F. ( 2 ) 6 8 ; ( 6 i ) 64; (7) 16, 63, 64 S e t , L. ( 7 ) 166 ( 3 ) 282 S e t c h e l l , K.D.R. S e t o , K . ( 3 ) 207; (5) 311, 312 S e t o , N . (1) 4 S e t o i , H. (5) 202; ( 8 ) 2 0 4 , 205 S e v e r i n , T. ( 5 ) 4 5 1 Seyden-Penne, J. ( 2 ) 1 8 5 ; ( 5 ) 339 S e y f e r t h , D. ( 2 ) 3 8 , 3 9 S e y m u l l e r , B.E. ( 3 ) 3 5 3 S h a b a n a , R . ( 5 ) 259 S h a h k a r a m i , N. (5) 353 S h a n k a r , B.B. (8) 4 0 Shankaran, K. ( 8 ) 48 S h a p i r o , G. ( 7 ) 25, 26 S h a r a n i n , Yu.A. ( 5 ) 382 Sharma, D.N. ( 4 ) 126 Sharma, N.D. (5) 472 Sharma, R.P. ( 1 ) 11; ( 4 ) 1 2 6 , 1 6 4 ; ( 5 ) 1 8 3 ; (8) 113 Sharma, V.K. (5) 77 S h a r p , M . J . ( 4 ) 181 S h a r p l e s s , K.B. ( 3 ) 10, 18, 4 4 6 ; ( 4 ) 7 3 ; ( 5 ) 154-158, 161; ( 6 i ) 3 4 ; (8) 3, 8 Shaw, A. (5) 38; ( 6 i i ) 26 Shaw, G. ( 5 ) 304
Shaw, K . J . ( 3 ) 437 Shawe, T. ( 6 i i ) 102, 103; Shawe, T. ( 7 ) 7 0 , 132 S h e a , R.G. ( 3 ) 4 3 2 ; ( 5 ) 140 S h e l d r i c k , G.M. ( 8 ) 6 5 S h e l l y , D.P. ( 5 ) 524 S h e n , Y. ( 3 ) 225; ( 4 ) 6 S h e n , Y.C. ( 6 i i ) 1 6 3 S h e p a r d , K.L. ( 5 ) 466 Shepherd, R.G. (5) 86, 373 S h e p p a r d , R.C. (3) 478 Sherbine, J.P. (7) 7 S h e s t o p a l o v , A.M. ( 5 ) 382 S h i , L. ( 2 ) 9 2 ; ( 6 i i ) 162 S h i b a , T. ( 9 ) 6 4 , 7 2 S h i b a s a k i , K. (5) 50 S h i h a t a , M. ( 9 ) 7 1 S h i b a t a , T. (8) 240 S h i b i h , S.M. ( 5 ) 264 S h i b i t a , I. ( 8 ) 110, 1 1 6 S h i h u y a , S. ( 8 ) 1 9 3 ( 3 ) 119 S h i e h , W.-R. S h i g e h i s a , T. ( 3 ) 362; ( 6 i i ) 101 S h i g e m o r i , H . ( 9 ) 77 S h i g e m o t o , T. ( 3 ) 4 5 0 ; ( 5 ) 162-164 S h i h , J. ( 5 ) 318 S h i i h a s h i , S. ( 2 ) 3; ( 4 ) 123 Shim, S.C. ( 3 ) 2 1 2 , 3 7 8 ; ( 4 ) 212; ( 5 ) 3 0 ; ( 6 i ) 15 Shima, K . ( 5 ) 4 0 S h i m a b a y a s h i , A. (3) 1 4 3 S h i m a g a k i , M. ( 4 ) 50 S h i m i z u , A . ( 2 ) 26 S h i m i z u , H. ( 4 ) 1 5 5 Shirnizu, I . ( 2 ) 4 7 , 9 7 , 162; ( 3 ) 6 0 , 1 4 6 , 472; ( 4 ) 183; ( 7 ) 4 0 ; (8) 4 5 S h i m i z u , M. ( 4 ) 1 4 8 S h i m i z u , T. ( 8 ) 1 0 4 S h i m o n i s h i , Y. ( 3 ) 481 ( 5 ) 274 S h i n , C.-G. S h i n , D.H. (5) 15 S h i n m i , Y. ( 3 ) 80 S h i o b a r a , Y. ( 7 ) 9 5 S h i o i r i , T. ( 9 ) 7 1 S h i o t s u k i , A. (1) 26 S h i o z a k i , M. ( 8 ) 233 S h i r a g a m i , H. ( 7 ) 36 S h i r h a t t i , V. (8) 98 S h i r o , M. ( 3 ) 88 S h i z u r i , Y. ( 9 ) 7 3 , 7 7 , 78 S h o e f , N . ( 5 ) 105 She-ji, H. ( 5 ) 1 4 8 Shono, T. (3) 7 4 , 127;
( 8 ) 196 S h r o f f , H . N . ( 8 ) 190 Shudo, K . ( 5 ) 2 2 , 2 3 S i b i , M.P. ( 3 ) 3 9 3 , 3 9 4 ; ( 6 i i ) 29 S i c a r d , G. ( 5 ) 519 S i d d a l l , T.L. ( 6 i i ) 187 S i d l e r , D . R . ( 8 ) 150 S i e b u r t h , S.M. ( 1 ) 100 S i e g e l , J. ( 6 i ) 1 6 S i h , C . J . ( 3 ) 119 S i l e s , S. ( 5 ) 542 S i l k s , L.A. ( 2 ) 181 S i l l i o n , B. ( 3 ) 380; ( 5 ) 269 S i l v e i r a , C.C. ( 2 ) 155 S i l v e s t r i , M . ( 7 ) 125 Simchen, G. (3) 438; (5) 206 S i m i g , G. (8) 232 Simon, H. ( 3 ) 265 Sirnonet, J. ( 5 ) 282 Sirnpson, J.H. ( 3 ) 291; ( 6 i i ) 138 S i n a i - Z i n g d e , G . ( 2 ) 191; (7) 89; (9) 7 S i n a y , P. ( 6 i i ) 25, 48 S i n g a r a m , B. ( 3 ) 2 ; ( 4 ) 88, 89; ( 6 i i ) 78, 79, 88 S i n g h , B. ( 8 ) 207 S i n g h , B.P. ( 5 ) 318 S i n g h , G. ( 2 ) 1 8 2 ; ( 5 ) 337 S i n g h , I . S . ( 8 ) 111 S i n g h , N.P. ( 5 ) 289 Singh, R.K. ( 3 ) 89 S i n g h , S. ( 5 ) 77 S i n g h , S.M. (1) 8 4 S i n i s t e r r a , J.V. ( 3 ) 165 S i t a , L.R. ( 6 i ) 9 S i t z m a n n , M.E. ( 5 ) 533 S i v a n a n d a i a h , K.M. ( 5 ) 16 S i v a v e c , T.M. ( 1 ) 5 9 S j o g r e n , E.B. ( 8 ) 226, 227 S k a l s k i , B. ( 5 ) 5 1 3 Skinner, I.A. ( 3 ) 191 S k j o l d , A.C. ( 5 ) 39 S l a w i n , A.M.Z. ( 3 ) 366 S l e e v i , M.C. ( 8 ) 180 S l e s s o r , K . N . ( 7 ) 27 S l e t z i n g e r , M. (3) 350 S l o a n , C.P. (8) 4 8 Slough, G.A. ( 6 i ) 75 S l o u g u i , N. ( 3 ) 1 7 3 S m a l l r i d g e , A.J. ( 3 ) 309 Smelka, L. (3) 475 S m e r a t , G . ( 2 ) 83 S m i t , W.A. ( 1 ) 8 2 S m i t h , A . B . , I11 (3) 202;
630 ( 6 i i ) 34; ( 9 ) 48 Smith, D.J.H. ( 3 ) 211 Smith, I.J. ( 4 ) 109 Smith, J.R.L. (5) 74 Smith, K. ( 3 ) 19 Smith, M.B. (8) 190 Smith, P.W. (5) 36, 37 Smith, R . ( 8 ) 137 Smith, T.L. ( 4 ) 153 Smith, W.E. ( 5 ) 536 Snatzke, G. ( 5 ) 265 S n i d e r , B.B. (2) 62, 64, 84; ( 3 ) 253, 358; ( 7 ) 22, 23, 126; ( 8 ) 31; ( 9 ) 11 Snidharan, V. ( 8 ) 179 Snieckus, V. ( 3 ) 393-395; ( 4 ) 181; ( 6 i i ) 29, 32; ( 8 ) 48 Sno, M.H.A.M. (8) 171 Snowden, R.L. ( 5 ) 542 S o a i , K. ( 3 ) 14, 120; ( 4 ) 27 Sobanov, A . A . ( 5 ) 129 S o c c o l i n i , F. ( 2 ) 137 Sock, 0 . ( 3 ) 4; ( 4 ) 177 S o l l a d i e , G. ( 3 ) 183; ( 6 i i ) 186; ( 8 ) 2 S o l l a d i e - C a v a l l o , A. ( 3 ) 107 Solyom, S. ( 7 ) 7 Somers, P.K. ( 8 ) 54; ( 9 ) 68 Somfai, P. ( 3 ) 1 Sonay, P. (8) 70 S o n c i n i , P. (3) 09 S o n i , K. ( 3 ) 1 S o n i , N.R. ( 4 ) 106 Sonoda, N. ( 1 ) 12; ( 3 ) 406; ( 5 ) 287, 288 Sorba, J. ( 3 ) 56 Sorokin, V.D. ( 4 ) 135 Sorokin, V.L. ( 2 ) 134 S o r r e n t i , P. ( 5 ) 397 S o t o , J.L. ( 5 ) 47 Soyama, H. ( 3 ) 388 Spadaro, A. ( 1 ) 78 Spagnolo, P. (5) 381 S p a n g l e r , C.W. ( 2 ) 179 Spanton, S. ( 5 ) 342 Speckamp, W'.N. ( 6 i i ) 99, 100; ( 8 ) 134, 171-173 Spencer, T.A. ( 2 ) 65, 81; ( 6 i i ) 172; ( 7 ) 135 S p i e s s , E.J. ( 9 ) 25 S p i n a , K.P. ( 7 ) 13 S p i n e l l i , G. (3) 334 Spohn, R.F. ( 3 ) 320 S p r e a f i c o , F. ( 3 ) 4 1 S p r i n g e r , J.P. ( 3 ) 353; ( 5 ) 56; (8) 60
General and Synthetic Methods S r i n i v a s , P. ( 5 ) 504 S r i v a s t a v a , P.C. ( 4 ) 154 S r i v a s t a v a , S. ( 5 ) 17 S t a a b , H.A. ( 5 ) 313 S t a d l w i e s e r , J. ( 4 ) 99 S t a h l , I. ( 3 ) 139 S t a h n e c k e r , P. (3) 427 Stamos, I . K . ( 5 ) 316 Stamouli, P. ( 5 ) 539 S t a n e k , J. ( 3 ) 280 S t a n f o r t h , S.P. ( 2 ) 160; ( 3 ) 145 Stang, P.J. (1) 81, 93 S t a r i n g , E.G.J. ( 3 ) 116 S t e f a n i , V. ( 5 ) 41 Stegenga, S. ( 6 i i ) 100; ( 8 ) 172 S t e g l i c h , W. ( 2 ) 154; ( 3 ) 64, 426; ( 5 ) 217; (9) 43 S t e i n b a c h , R. ( 4 ) 42, 44 S t e i n s e i f u r , F. ( 6 i i ) 142 S t e l i o u , K. ( 2 ) 20 S t e r n b a c h , D.D. ( 9 ) 2 S t e t i n , C. ( 2 ) 157; ( 3 ) 161; ( 5 ) 114 S t e v e n s , C.L. ( 4 ) 115 S t e v e n s , J.A. (5) 529, 530 S t e v e n s , R.V. ( 7 ) 137 S t e v e n s , R.W. ( 2 ) 152, 164; ( 5 ) 410 Stevenson, D.F.M. ( 3 ) 333 Stevenson, P. (1) 62; ( 4 ) 180; ( 6 i ) 52 Stevenson, T. ( 3 ) 1; ( 6 i ) 33 S t i b o r , I. ( 3 ) 280 S t i l l , W.C. (8) 72, 73; ( 9 ) 51 S t i l l e , J.K. ( 1 ) 61; ( 3 ) 224, 291; (€5)51; ( 6 i i ) 138 S t o e s s e l r S.J. (1) 61; (3) 224; ( 6 i ) 51 S t o l l , A.T. ( 6 i i ) 36; ( 7 ) 6 S t o n e , K . J . (8) 32 S t o r k , G. ( 7 ) 129; ( 9 ) 12 Stouch, T.R. (5) 180; ( 9 ) 61 S t o v e r , L.R. ( 5 ) 39 Stowers, J . R . (5) 120 S t r a n g e , G.A. ( 8 ) 71; ( 9 ) 57 S t r a p p a v e c c i a , G.P. ( 7 ) 34 S t r e e t , S.D.A. (8) 69; (9) 54, 55 S t r e i t h , J. ( 5 ) 186 S t r i n g e r , O.D. ( 6 i i ) 203
S t r i n g e t , R. (8) 81 S t r o u d , S.G. (3) 48; ( 4 ) 111 Struchkow, Y.T. ( 3 ) 439 Stubbs, M.E. ( 5 ) 472 S t u t z , A. (5) 137 S t u r t z , G. ( 5 ) 456 SU, W.-G. (9) 52 SuavB, G. ( 8 ) 70 Subrahmanyam, D. (9) 5 S u c k l i n g , C.J. ( 5 ) 427 Sudani, M. (3) 80 Sudow, I. ( 7 ) 114 Siirnmermann, K. ( 5 ) 241 Suenobu, K. (5) 377 Siisse, M. ( 3 ) 375; ( 5 ) 350, 351; ( 7 ) 150 S u f f e r t , J. ( 3 ) 107 Suga, K. ( 3 ) 245 Sugahara, K. ( 3 ) 245 Sugai, S. (5) 193 Sugano, K. (3) 142 Sugasawa, S. ( 5 ) 214 Sugawara, T. ( 7 ) 156 Sugimoto, K. ( 3 ) 245 Sugimura, H. ( 6 i ) 48 Sugimura, Y. ( 8 ) 240 Suginome, H. (1) 60; ( 3 ) 364; ( 6 i ) 46; (8) 162 S u g i u r a , N. ( 1 ) 26 Sugiura, T. ( 2 ) 97, 162; (3) 146; ( 4 ) 183 Sugiyama, K. ( 8 ) 136 S u g i z a k i , T. ( 4 ) 200; ( 8 ) 27 Sugugai, T. ( 3 ) 119 Sukata, K. ( 3 ) 381; ( 5 ) 263, 290 S u l k a r n i , Y.S. ( 7 ) 22 Sulmon, P. ( 5 ) 474; ( 8 ) 132 Sumi, K. (1) 79, 80; ( 3 ) 176; ( 4 ) 157; ( 5 ) 327; ( 6 i i ) 113 Sumino, M. (3) 143 Sun, K.-M. ( 3 ) 250 Sundararaman, P. ( 5 ) 56 S u n j i c , V. (5) 405 Suo, M.H.A.M. ( 6 i i ) 99 S u r , B. ( 4 ) 125 S u r b e r , B.W. ( 1 ) 81 S u r r i d g e , J . H . (3) 5 Surya Prakash, G.K. ( 5 ) 293 S u t t e r , M.A. ( 3 ) 116, 370 Suzuki, A. ( 1 ) 60; ( 2 ) .116, 192; ( 4 ) 150, 155; ( 6 i ) 46 Suzuki, H. ( 2 ) 8; ( 4 ) 122, 151, 162, 163; (5) 13, 28, 298, 310, 431,
63 1
Aurhor Index 467; (6ii) 210 Suzuki, K. (1) 73; (3) 268 Suzuki, M. (9) 50, 75 Suzuki, N . (1) 8 Suzuki, T.M. (8) 9 Suzuki, Y. (4) 23 Suzumoto, T. (3) 127 Swain, C . J . (3) 271; (9) 56 Swaminathan, S. (7) 142 Sward, K. (1) 61; (3) 224; (6i) 51 Swenton, J.S. (3) 336; (5) 379 Sy, W.-W. (5) 436 sy, Y. (7) 99 Szczepanski, S.W. (6ii) 117 Szilagyi, L. (5) 511 Szmulik, P. (3) 84 Szollclsy, A . (5) 55 Taber, D.F. (2) 74; (3) 141; (6i) 63; (7) 38, 39, 91; (9) 4 Tabti, B. (3) 250 Tabushi, I. (3) 429 Taddei, M. (6ii) 16, 111, 129; (7) 101 Tadj, F. (7) 44 Taga, T. ( 3 ) 257 Tagami, K. (6ii) 179 Tagliavini, E. ( 4 ) 10 Taguchi, M. (3) 382; (5) 262 Takagi, K. (4) 208 Takagi, T. (8) 162 Takahashi, H. (5) 88; (7) 173 Takahashi, K. (2) 41, 42, 162; (3) 146; (5) 50, 377; (6ii) 190 Takahashi, 0. (3) 384 Takahashi, S. (3) 207; (5) 311, 312 Takahashi, T. (1) 87; (4) 20 Takahashi, Y. (3) 42; (4) 132; (6ii) 140 Takai, K. (1) 86; ( 4 ) 94; (6i) 85 Takaishi, N. (7) 173 Takamani, T. (1) 36 Takamatsu, N. (5) 274 Takanami, T. (6ii) 156 Takano, S. (3) 283; (6ii) 118; (9) 36, 75 Takano, Y. (3) 315; (6ii) 47
Takao, T. (3) 481 Takase, K. (5) 320 Takasu, Y. (3) 297 Takayama, H. (8) 184 Takazawa, 0. (2) 169; (4) 57 Takeda, A. (3) 25; 338; (4) 36, 69; (7) 49: (8) 57 Takeda, S. (5) 467 Takeda, T. (1) 73 Takei, H. (3) 365; (6i) 48 Takemasa, T. (1) 95 Takemoto, T. (7) 95 Takemoto, Y. (2) 104, 105; (4) 90 Takenaka, H. (7) 136 Takeno, H. (5) 202; (8) 204, 205 Takeuchi, S. (5) 298 Takeuchi, Y. (3) 239: (6ii) 178 Takeyama, T. (4) 168 Taki, H. (5) 468; (6i) 18 Takido, T. (5) 299 Takino, H. (3) 388 Takiyama, N. (4) 47 Takubo, H. (4) 50 Takusagawa, F. (5) 187; (8) 112 Talma, A . G . ( 3 ) 105 Tam, T.-F. (3) 259 Tamaru, Y. (2) 30, 31; (3) 157, 293, 294; (4) 134, 170, 195; (8) 14, 35, 167 Tamm, C . (3) 110 Tamura, J. (9) 65 Tamura, 0. (3) 123 Tamura, R. (1) 22; (8) 26 Tamura, Y. (2) 107; (3) 123; (6i) 68-70; (7) 50; (8) 95 Tan, C. (8) 210 Tan, R.P.K. (2) 179 Tan, S.L. (7) 20 Tanabe, Y. (2) 133 Tanaka, H. (4) 179 Tanaka, J. (5) 196 Tanaka, K. (1) 41; (3) 281, 306, 397; (5) 236, 237; (6ii) 56; (8) 56 Tanaka, M. ( 2 ) 159; (3) 419; (5) 80, 218; (6i) 14; (6ii) 166; (8) 85 Tani, H. (5) 28, 298 Tani, K. (5) 115; (6i) 22 Taniguchi, K. ( 3 ) 344 Tanis, S.P. (7) 170, 171; (8) 6
Tanner, D. ( 3 ) 1 Tao, F. (1) 3 Tapia, R. (4) 112 Tapolczay, D . J . (3) 271; (7) 116, 117 Tardella, P.A. (5) 212 Tatsumi, K. (6i) 7 Tatsuno, T. (8) 17 Tatsuno, Y. (5) 115; (6i) 22 Tatsuta, K. (9) 28 Taufer-Knopfel, I. ( 3 ) 21 Taya, K. (3) 70 Tayano, T. (2) 116 Taylor, E.C. (6ii) 95; (8) 90 Taylor, G . A . (5) 531 Taylor, R . J . K . (1) 52, 101; (2) 176; (3) 222; (6i) 31, 50 Teague, S . J . (9) 10 Telfer, S.J. (3) 328 Terada, S. (3) 257 Terada, Y. (9) 78 Teramura, K. (8) 104 Terao, Y. (6ii) 166; (8) 85, 140 Terashima, S. (4) 23 Teratani, S. (1) 4 Ternansky, R.J. (1) 100; (7) 92; (9) 1 Terui, Y. (5) 214 Terunuma, D. (6ii) 123 Testaferri, L. (1) 28 Teulade, M.P. (6ii) 153 Texier-Boullet, F. (3) 168; (5) 463 Thaisrivongs, S. ( 3 ) 370 Thalmann, A . (3) 360 Thangaraj, K. (7) 142 Thanos, J. (3) 265 Theis, W. (5) 516 Thetford, D. (5) 165 Thiemig, H.-A. (5) 53 Thiensathit, S. (4) 141; (6i) 25; (7) 82 Thierry, J. (3) 460 Thieser, R. (5) 72 Thiruvikraman, S.V. (5) 431 Thomas, A.P. (6ii) 96 Thomas, E.J. (1) 17; (6ii) 130; (7) 116, 117; (8) 100 Thomas, S.E. (8) 15 Thomasco, L.M. (7) 30 Thompson, D.W. (8) 53 Thompson, J. (9) 34 Thompson, N.T. (5) 472 Thompson, S.R. (5) 104 Thuiller, A . (2) 52
632 T i d w e l l , T.T. ( 2 ) 1 4 4 , 1 4 5 ; ( 6 i i ) 10 T i e c c o , N. ( 1 ) 2 8 T i e t z e , L.-F. ( 3 ) 3 5 5 ; ( 8 ) 65 T i j e r i n a , T. ( 5 ) 1 0 9 T i m o f e e v a , T.V. ( 3 ) 4 3 9 T i n g , P.C. ( 4 ) 1 9 6 ; ( 6 i . i ) 94; ( 8 ) 16 T i n g o l i , M. ( 1 ) 28 T i r p a k , R.E. ( 2 ) 3 6 ; ( 3 ) 28 T i s c h e n k o , I . G . ( 2 ) 134 T o b e , Y. ( 2 ) 8 8 ; (9) 3 T o c z e k , J. ( 7 ) 9 8 ‘ r o d a , F. ( 3 ) 281 T o t h , C . ( 5 ) 4 6 , 55 Togo, fi. ( 3 ) 3 ; ( 5 ) 438 T o g u c h i , M . ( b i ) 80 ‘Tohojoh, T. ( 3 ) 327 T o k r t o h , N . ( 5 ) 9 5 , 356 T o k o m i t s u , T. ( 5 ) 1 2 6 Tokuda, M . ( 8 ) 162 Tokumasu, S. ( 3 ) 225 T o k u t a k e , N . ( 5 ) 221. T o m a s i n i , C. ( 5 ) 166 T o m b r e t , F. ( 6 i i ) 38 Tomimori, K . ( 3 ) 1 0 6 ; ( 4 ) 25 Tomioka, K . ( 3 ) 80, 1 5 2 , 248 ‘Tomioka, Y. ( 5 ) 2 0 , 5 2 ; (8) 41 T o m i t a , K.-T. (5) 115 T o m i t a , T. ( 6 i ) 22 Tomizawa, K . ( 3 ) 171 Tomo, Y . ( 3 ) 311 Tomoda, S. ( 3 ) 239 Tomoskozi, I. ( 3 ) 281 I’omozane, H . ( 3 ) 1 2 4 , 274; ( 4 ) 6 8 T o n e l l a t o , U. ( 4 ) 26 T o r i i , S. ( 3 ) 11, 1 3 7 , 2 6 0 , 4 3 7 ; ( 4 ) 4 8 , 105, 179; (5) 3 4 , 112; ( 8 ) 28 T o r i z u k a , K. ( 3 ) 481 T o r k l e r , A . ( 4 ) 81 T o r o , J . ( 8 ) 218 T o r r e s , L.E. ( 2 ) 32 T o r s s e l l , K.G.B. ( 5 ) 172 T o r t e l l i , V. ( 5 ) 278 T o r u , T. ( 3 ) 2 3 8 , 298; ( 6 i i ) 199 T o s h i m i t s u , A . ( 8 ) 18 T o u b o u l , E. ( 8 ) 4 2 T o u r , J.M. ( 2 ) 9 5 ; ( 6 i ) 55, 7 4 ; ( 7 ) 6 8 T o y o t a , M. ( 7 ) 1 2 3 T r a p a n i , G. ( 5 ) 67 T r a v e r , H. ( 7 ) 1 5 2
General und Synthetic Methods Treadgold, R. ( 2 ) 85; ( 7 ) 144, 145 T r e t t e r , A . ( 5 ) 525 Trimmer, R.W. ( 5 ) 3 9 T r i p a t h y , P.K. ( 3 ) 4 5 4 ; ( 5 ) 272 T r o f i m o v , B.A. ( 5 ) 4 9 8 Trogolo, C. ( 3 ) 279 T r o m b i n i , C. ( 4 ) 10 T r o m e l i n , A . ( 5 ) 400 T r o o s t w i j k , C.B. ( 3 ) 105 T r o s t , B.M. ( 1 ) 15, 58, 71; (3) 9 1 , 3 6 1 ; ( 4 ) 79; (5) 147; ( 6 i ) 26, 2 7 , 5 4 , 56-58, 8 4 ; ( 6 i i ) 13, 1 3 4 , 1 7 1 ; ( 7 ) 75-77, 1 2 7 ; ( 8 ) 3 4 ; ( 9 ) 20 T r o u p e l , M. (3) 4 ; ( 4 ) 177 T r o y a n s k y , E.I. ( 8 ) 1 6 3 , 164 T r u d e l l , M.L. ( 5 ) 54 T s a i , D.J.-S. ( 3 ) 3 4 7 T s a i , Y.-M. ( 6 i i ) 1 1 7 ; ( 8 ) 44 T s a o , C.-H. ( 6 i i ) 150 T s o , H.-H. ( 6 i i ) 50 T s o l o m i t i s , A . ( 5 ) 275 Tsubaki, K. (2) 31; ( 3 ) 157 T s u b o i , T. ( 2 ) 1 2 Tsuboniwa, N . ( 4 ) 9 6 T s u c h i h a s h i , G. ( 4 ) 226 T s u c h i h a s h i , G.-l. ( 3 ) 268 T s u g e , 0. ( 5 ) 1 9 6 ; ( 8 ) 142, 143 T s u j i , J. (1) 8 7 ; ( 2 ) 1 0 , 47, 97, 162; ( 3 ) 60, 102, 146, 472; ( 4 ) 20, 121, 183; ( 7 ) 40; ( 8 ) 45 T s u j i , M. (1) 22 T s u j i , Y. (8) 199 T s u j i m o t o , K. ( 7 ) 4 7 Tsukamoto, M. ( 3 ) 1 0 4 ; (7) 45 T s u k a n a k a , T. (1) 8 T s u k i h a r a , K. ( 2 ) 12 T s u n g e , 0. ( 6 i i ) 4 4 T s u r u t a , M. ( 8 ) 188 T s u r u t a , T. ( 2 ) 1 1 4 T s u z u j i , R. ( 3 ) 4 1 8 T s u z u k i , K . ( 3 ) 150 T s y r y a p k i n , V.A. ( 3 ) 439 T u c h m a n t e l , W. (1) 3 3 ; ( 6 i i ) 112 T u f a r i e l l o , J.J. ( 5 ) 176 Tung, R.D. ( 5 ) 2 2 3 T u r k , W . ( 5 ) 3333
T u r n e r , M . K . ( 3 ) 266 T u r n e r , R.W. (1) 6 5 Twohig, M.F. ( 2 ) 5 4 Uang, B . J . ( 3 ) 353 Uchida, H. ( 6 i i ) 123 Uchida, K. ( 8 ) 196 U c h i d a , S. (8) 6 8 Uchiyama, H . ( 3 ) 275 Uchiyama, M. ( 6 i ) 7 9 Uda, H . ( 2 ) 1 9 4 ; ( 3 ) 3 4 0 , 342; ( 6 i i ) 179, 186 Ueda, C. ( 5 ) 383 Ueda, M. ( 5 ) 220, 222 Ueda, W . ( 5 ) 311, 312 Ueda, Y. ( 8 ) 237 Uedo, W. ( 3 ) 207 U e h l i n g , D.E. ( 3 ) 158 U e h l i n g , D.W. ( 2 ) 188 Uematsu, M. ( 6 i i ) 1 2 6 Uematsu, T. ( 5 ) 4 5 9 , 460 Uemura, M. ( 6 i ) 29 Uemura, S. ( 6 i i ) 2 0 4 ; 212-214; (8) 18 U e n i s h i , J.-I. ( 3 ) 1 2 4 , 274; ( 4 ) 6 8 Ueno, K . ( 8 ) 1 4 3 Ueno, Y. ( 3 ) 3 4 7 ; ( 4 ) 200; ( 8 ) 27 U g g e r i , F. ( 3 ) 214, 2 1 5 U g i , I . ( 5 ) 385; ( 8 ) 7 6 Uguen, D. ( 3 ) 3 8 3 ; (5) 238 U k a i , J. ( 2 ) 1 6 6 U k i t a , T. (1) 50; ( 3 ) 3 4 1 Umani-Ronchi, A. ( 4 ) 10 Umezu, K . ( 3 ) 2 3 7 ; ( 4 ) 138 Unemura, K. ( 3 ) 1 4 7 Uneyama, K . ( 4 ) 4 8 Ungaro, R . ( 8 ) 6 6 Uno, M. ( 3 ) 207; ( 5 ) 311, 312 U n t e r h a l t , B. ( 5 ) 4 4 1 Urabe, H. ( 3 ) 315; ( 6 i i ) 47 Urata, Y. ( 4 ) 2 0 0 ; ( 8 ) 27 Urbanski, M . J . (5) 49 Urch, C . J . ( 6 i i ) 126 U s h i o , K . (3) 1 1 7 U s i f e r , D. ( 6 i ) 47 U s k o k o v i c , M.R. ( 9 ) 66 U t a k a , M. ( 3 ) 2 5 , 3 3 8 ; ( 4 ) 36, 69 U t i l l e , J.-P. ( 4 ) 108 U t i m o t o , K. ( 7 ) 3 6 U y e h a r a , T. ( 7 ) 85, 138 Vacca, J.P.
( 8 ) 186
Author index Valderrama, J . A . ( 4 ) 112 V a l e n t i n , E. ( 5 ) 134; ( 7 ) 1 6 , 103 Valle, G. ( 6 i i ) 180 Vallee, D. ( 8 ) 160; ( 9 ) 31 Vallee, Y. ( 3 ) 232 V a l o t i , E. ( 3 ) 41 van den Braken-van Leersum, A.M. ( 5 ) 422 Van d e r Eycken, E. ( 7 ) 31 van d e r P l a s , H.C. ( 5 ) 57, 5 8 , 481 van d e r Veen, J . M . ( 8 ) 228 van d e r Veen, R.H. ( 3 ) 31, 194 Van D e r v e e r , ( 2 ) 86 Vandewalle, M, ( 7 ) 31, 88 Van D o r t , M. ( 5 ) 452 Van Ende, D. ( 6 i i ) 194 van Hemert, A.W. ( 5 ) 387 van Hulsen, E. ( 3 ) 246; (6ii) 7 Vankar, Y.D. ( 2 ) 91; ( 4 ) 107, 147; ( 5 ) 258; ( 6 i i ) 191 van Leusen, A.M. ( 5 ) 387 van Look, G. ( 3 ) 465 van Niel, M.B. ( 5 ) 132 Vannucchi, A. ( 4 ) 129 Van Royer, L.A. ( 9 ) 21 van Rozendaal, H.L.M. ( 8 ) 92 Varma, M. ( 2 ) 21; ( 5 ) 419, 491, 492 Varma, R.S. ( 2 ) 21, 9 9 , 112; ( 4 ) 18; ( 5 ) 7 , 401, 414, 418-420, 454, 455, 491-493; ( 6 i i ) 15 V a s e l l a , A. ( 5 ) 391, 457, 458, 500 Vaughan, K. ( 5 ) 526 V a u l t i e r , M. ( 5 ) 32; ( 8 ) 177 Vazquez T a t o , M.P. ( 5 ) 444 Veale, C.A. ( 9 ) 53 Veber, D.F. ( 3 ) 386, 466 Vedejs, E. ( 8 ) 135 Vederas, J.C. ( 3 ) 436 V e e n s t r a , S . J . ( 6 i i ) 77 V e i t h , R . ( 3 ) 337 (3) Vekemans, J . A . J . M . 329 Venkataraman, S. ( 2 ) 191; (7) 89 V e r c a u t e r e n , J. ( 1 ) 15; ( 3 ) 91 Vereshchagin, L . I . ( 5 ) 121
633 Verhe, R . ( 5 ) 473 Verhoeven, T.R. ( 3 ) 350 V e r k r u i j s s e , H.D. ( 1 ) 6 4 ; (6ii) 8 V e r l h a c , J.-B. ( 6 i ) 62; ( 6 i i ) 139 Verma, A. ( 6 i ) 35 Vermeer, P. ( 6 i i ) 97 Vesely, I . ( 3 ) 280 V e s s i g r e , R . ( 8 ) 119 V i a l l e f o n t , Ph. ( 3 ) 430 V i a n i , F. ( 3 ) 305 V i c e n t e , A . ( 8 ) 109 Viehe, H.G. ( 3 ) 391, 403; ( 5 ) 224, 283, 284, 332, 333 Vijayakumaran, K. ( 4 ) 115 V i j n , R . J . ( 6 i i ) 99; ( 8 ) 171 V i l a p l a n a , M . J . ( 4 ) 207 Villa, C.A. ( 1 ) 48; ( 6 i i ) 121 V i l l a , M. ( 3 ) 379; ( 5 ) 229 Villernin, D. ( 3 ) 168, 232; ( 5 ) 325 V i l l i e r a s , J. ( 3 ) 167; ( 6 i i ) 145 Vinourov, V.A. ( 5 ) 302 V i r e l i n k , J.J. ( 3 ) 376 V i s e n t i n , G. ( 3 ) 41 Vishwakarama, L.C. ( 3 ) 12 Vismara, E. ( 5 ) 278 V i s n i c k , M . ( 6 i i ) 34 V i s s c h e r , J. ( 3 ) 105 V i t i , S.M. ( 5 ) 161 V i t t , S.V. ( 3 ) 439 Vlahov, J. ( 5 ) 265 Vlassa, M. ( 5 ) 29 V o e l t e r , W. ( 5 ) 208, 551 Vogel, C. ( 8 ) 185 Vogel, D.E. ( 2 ) 55 V o i s i n , D. ( 3 ) 4 3 V o l a n t e , R.P. ( 3 ) 350 V o l l h a r d t , J. ( 6 i i ) 53 Volmer, M. ( 6 i i ) 196 V o n w i l l e r , S.C. ( 3 ) 247 Voronkov, M.G. ( 5 ) 498 Voss, E. ( 8 ) 6 5 Voss, J. ( 5 ) 209 V r i e l i n k , J.J. ( 5 ) 249
Waespe-Sarcevic, N . ( 3 )
110
Wagle, D.R. ( 8 ) 228 Wakamatsu, H . ( 8 ) 165 Wakamatsu, K . (1) 33; ( 2 ) 27; ( 4 ) 96; ( 6 i ) 60; ( 6 i i ) 112 Wakamatsu, T. ( 3 ) 367 Wakasa, N . (1) 1 4 ; ( 6 i i ) 59 Wakasugi, T. ( 4 ) 16 Wakefield, B . J . ( 3 ) 266, . 269 Wakita, T. ( 5 ) 306, 308 Walborsky, H.M. ( 3 ) 183 Walker, F.J. ( 5 ) 154, 155 Walker, J . C . ( 6 i ) 40 Walkup, R.D. ( 3 ) 232 Walkup, R.E. ( 8 ) 178 Wall, A. ( 6 i i ) 174; ( 8 ) 93 Wall, W.F. ( 3 ) 266 Wallace, P.M. ( 5 ) 181 Wallace, T.W. ( 1 ) 65 Wallner, A. ( 7 ) 93 W a l l q u i s t , 0. ( 8 ) 32 Walmann, H . ( 6 i ) 78 W a l t s , A.E. ( 4 ) 6 0 ; ( 6 i i ) 83; ( 9 ) 38 Wamhoff, H. ( 5 ) 5 3 Wang, K.K. ( 5 ) 84 Wang, P.-C. ( 3 ) 46 Wang, Z. ( 3 ) 344 Waninge, J.K. ( 3 ) 105 Ward, J.P. ( 3 ) 201 Ward, P. ( 3 ) 478 Ward, R.S. ( 3 ) 282 Wardle, R.B. ( 5 ) 200 Warman, D. ( 5 ) 213 Warner, P. ( 3 ) 23, 301; ( 4 ) 71; ( 6 i ) 36, 37, 42 Warren, S. ( 1 ) 23-25; ( 3 ) 38, 149; ( 6 i i ) 158, 159, 173 Warshawsky, A. ( 5 ) 105 Washiyama, M. ( 3 ) 377; ( 5 ) 248 Wasley, J.W.F. ( 5 ) 8 Wasmuth, D. ( 3 ) 9 8 Wasserman, H.H. ( 2 ) 130; ( 3 ) 52, 134 Watabu, H. ( 3 ) 338; ( 4 ) 36 Watanabe, H. ( 1 ) 90; ( 3 ) ( 3 ) 35 Wacker, C.-D. Wada, E. ( 6 i i ) 44 172; ( 8 ) 45 Watanabe, K. (1) 90; ( 3 ) Wada, K. ( 5 ) 320 172; ( 5 ) 310 Wada, M. ( 3 ) 297, 362; ( 4 ) 5 3 ; ( 6 i i ) 101, 165; Watanabe, N . ( 3 ) 147 Watanabe, S. ( 3 ) 245 ( 9 ) 45 Watanabe, Y. (1) 90; ( 2 ) Wadia, M.S. ( 5 ) 295 W a l c h l i , R. (5) 435 96; ( 3 ) 71, 172; (5)
634 186; ( 8 ) 199; (9) 35 Wateson, D. ( 3 ) 128 Watkins, J.C. ( 7 ) 94 W a t t , D.S. (3) 1 7 1 ; ( 4 ) 156 W a t t s , A.E. ( 6 i i ) 81 Waykole, L. ( 6 i i ) 196 Webb, R . R . ( 9 ) 49 Webber, S.E. ( 9 ) 5 3 Weber, R. ( 5 ) 518 Weber, R . H . ( 3 ) 116 Weber, T. ( 3 ) 4 1 5 , 4 1 6 ; ( 4 ) 4 5 ; ( 6 i i ) 20, 2 2 , 23 Weber, W.P. ( 4 ) 8 2 , 204; ( 5 ) 384 Wedernan, P. ( 7 ) 7 9 Weedon, A.C. ( 3 ) 191; ( 9 ) 6 Wegner, G . ( 3 ) 1 Wegrzyn, M. ( 5 ) 120 Weidrnann, U . ( 4 ) 5 9 ; ( 6 i i ) 81 W e i l e r , L . ( 3 ) 31, 193; (6ii) 6 Weinges, K . ( 3 ) 427 Weinreb, S.M. ( 5 ) 180; ( 8 ) 182; ( 9 ) 61 Wej.ntz, H . - J . (8) 155 Weis, A.L. ( 8 ) 212 Wci-shan, Z. ( 3 ) 3 4 1 W e i s s , B. ( 5 ) 5 2 3 Welch, J . T . ( 3 ) 3 3 , 123, 3 9 9 ; ( 5 ) 247 Wel.ke, S. ( 4 ) 4 3 W e l k e r , M.E. ( 5 ) 216; ( 6 i ) 4 1 ; ( 8 ) 215 Wells, A . J . ( 3 ) 335 W e l z e l , P. ( 3 ) 147 Wender, P.A. (1) 99, 100; (2) 8 9 ; ( 7 ) 9 2 ; ( 9 ) 1, 1 4 , 18 Wenderoth, B. ( 4 ) 4 2 , 44 W e n k e r t , D. ( 8 ) 1 5 1 W e n k e r t , E. (1) 7 5 ; ( 6 i ) 47 Weprek, S. ( 5 ) 25 W e r b e l , L.M. ( 5 ) 102 W e r s i n , G. ( 3 ) 465 W e s t , F.G. ( 8 ) 135 Westerrnann, J . ( 4 ) 4 2 , 4 4 W e s t l i n g , M. ( 8 ) 198 W e t t e r , H. ( 4 ) 101 W e t z e l , J.M. ( 2 ) 1 3 9 W e y e r s t a h l , P. ( 3 ) 295; (7) 151 Whalon, M . R . ( 5 ) 1 6 7 W h e e l e r , K . J . ( 5 ) 264 Whelan, J . (3) 9 0 W h i t e , F.H. ( 9 ) 76 W h i t e , H.F. ( 3 ) 258
General and Synthetic Methods W h i t e , 5.13. ( 3 ) 112 White, T . J . ( 3 ) 443 W h i t e h e a d , J.W.F. ( 7 ) 1 1 6 , 117 W h i t e l y , C.G. ( 6 i i ) 7 4 W h i t e s i d e s , G.M. ( 3 ) 265 Whitney, R . A . ( 3 ) 1 2 9 ; ( 5 ) 277; ( 6 i i ) 67 W h i t t e n , J . P . (5) 1 6 7 , 1 6 8 , 375 Wiberg, N . ( 5 ) 490 Wicha, J. ( 3 ) 322 Wickenkarnp, R. ( 1 ) 3 0 ; ( 6 i i ) 124 Widdowson, D.A. ( 6 i ) 4 5 W i d l e r , L. ( 4 ) 4 5 Wiedman, P.E. ( 5 ) 1 6 8 Wiegand, G. ( 5 ) 209 Wiemer, D.F. ( 2 ) 1 2 3 W i e s c h o l l e k , K. ( 4 ) 4 3 W i e t f i e l d , B. ( 7 ) 8 4 W i j n b e r g , J.B.P.A. ( 2 ) 50 Wilby, A . H . ( 3 ) 475 Wilchek, M . ( 5 ) 105 W i l c o x , C.S. ( 5 ) 521; ( 7 ) 30 W i l d , .T. ( 3 ) 455 Wildeman, J . ( 5 ) 387 W i l e y , M . R . ( 3 ) 290 Willer, R.L. ( 5 ) 5 0 1 W i l l i a m s , D . J . ( 3 ) 366 Williams, D.L.H. ( 5 ) 447 Williams, D.R. ( 7 ) 1 0 7 ; ( 9 ) 33, 76 Williams, J.M. (1) 9 6 ; (3) 73 W i l l i a m s , L.M. ( 4 ) 209 W i l l i a m s , P.D. ( 7 ) 110 W i l l i a m s , P.H. ( 5 ) 132 Williams, T.M. ( 3 ) 448; ( 5 ) 18 W i l s o n , C.G. ( 3 ) 465 W i l s o n , E.R. ( 5 ) 5 0 6 Wilson, J.D. ( 5 ) 543; ( 8 ) 99 W i l s o n , K.D. ( 3 ) 392; ( 5 ) 2 4 4 , 406 W i l s o n , S.K. ( 1 ) 4 8 ; ( 6 i i ) 121 W i n d e r s , J . A . ( 3 ) 266, 269 W i n k l e r , T. (8) 117 Witczak, Z . J . ( 5 ) 540 W o e l l , J . B . ( 3 ) 209-211; ( 4 ) 174, 175 Wolanin, D.J. ( 9 ) 1 4 W o l f e , J . F . ( 8 ) 180 W o l f f , S. ( 6 i i ) 6 8 ; (8) 43 Wong, C.-H. (3) 1 6 , 265 Wong, G.S.K. ( 8 ) 1 5 6 , 157
Wong, H. ( 5 ) 7 3 Wong, J.K. (1) 9 2 Wong, S. ( 3 ) 342 Wonnacott, A. ( 4 ) 46; ( 6 i i ) 49 Woo, P.W.K. ( 5 ) 204 Woodard, R. ( 3 ) 435 Woods, M.F. ( 5 ) 3 5 Worakun, T. (1) 6 2 ; ( 4 ) 180; ( 6 i ) 52 Wovkulich, P.M. ( 9 ) 6 6 Wozniak, J . ( 3 ) 57 W U , T.-C. ( 7 ) 106 Wu, Y.M. ( 5 ) 528 wu, ( 5 ) 499 Wurthwein, E.-U. ( 5 ) 484 W u l f f , W.D. ( 3 ) 1 2 5 ; ( 9 ) 25 Wunsch, E. (3) 474 Wustrow, D . J . ( 3 ) 3 5 5 ; ( 8 ) 39 Wyberg, H. ( 3 ) 116 Wyler, H . ( 8 ) 208 Wyss, H . ( 8 ) 230
z.4.
X i a n , Y.T. ( 3 ) 6 1 x u , L. ( 1 ) 3 X U , W.-H. (3) 26 Y a g i , M. ( 3 ) 88 Yahata, N. ( 2 ) 41; ( 6 i i ) 190 Yajima, H. ( 3 ) 481 Yakirnovi.ch, S . I . ( 5 ) 449 Yakura, T. ( 2 ) 107 Yakushijin, K. ( 9 ) 46 Yamada, H. ( 5 ) 460 Yamada, K . (1) 6 0 ; ( 2 ) 18; ( 6 i ) 46 Yamada, M. ( 3 ) 429 Yamada, S. (3) 3 6 4 , 367 Yamada, T. ( 8 ) 142 Yamada, Y. ( 8 ) 1 2 7 , 162 Yamagata, J. ( 6 i ) 22 Yamagata, K . ( 5 ) 5 2 , 3 8 3 ; ( 8 ) 41 Yamagata, T. ( 5 ) 115 Yamagata, Y. ( 5 ) 1 1 5 ; ( 6 i ) 22 Yamaguchi, H. ( 1 ) 7 9 , 80; ( 4 ) 198; ( 6 i i ) 113; ( 8 ) 52 Yamaguchi, M. ( 3 ) 13 1 0 4 , 180, 181, 386 ( 6 i i ) 114; ( 7 ) 45; 21 Yamaguchi, R . ( 6 i i ) 36 Yamaguchi, S. ( 4 ) 24 ( 5 ) 3 1 4 , 315
Author Index Yamaguchi, Y. ( 7 ) 138 Yamakawa, K. ( 2 ) 5 3 , 1 2 4 , 1 2 5 ; ( 5 ) 211 Yarnarnoto, A. ( 3 ) 388; ( 4 ) 176 Yarnarnoto, H. (1) 6 , 7 ; ( 2 ) 142 166; ( 5 ) 8 5 , 507; ( 6 i i ) 9 0 , 9 1 ; ( 7 ) 3, 9 , 1 4 0 ; ( 8 ) 181 Yamamoto, I . ( 3 ) 4 8 1 ; ( 8 ) 46 Yamamoto, J. ( 2 ) 1 2 Yamarnoto, K. ( 3 ) 1 0 2 , 311; ( 4 ) 15 Yarnamoto, T. ( 3 ) 388; ( 4 ) 1 7 6 ; ( 5 ) 124 Yamarnoto, Y. ( 2 ) 8 ; ( 3 ) 8 5 , 8 7 , 3 4 4 , 425; ( 4 ) 1 2 2 ; ( 5 ) 81, 8 2 ; ( 6 i i ) 84 Yarnamura, S ( 9 ) 4 4 , 7 3 , 7 7 , 78 Yamana, Y. Yamanoi, T. 27 Yamasaki, Y 357 Y a m a s h i t a , A. ( 6 i ) 5 9 ; ( 9 ) 24 Y a m a s h i t a , H. ( 3 ) 101; ( 4 ) 77 Yarnashita, J . ( 4 ) 1 6 7 Y a m a s h i t a , T. ( 2 ) 8 8 ; ( 5 ) 40; ( 9 ) 3 Y a m a s h i t a , Y. ( 5 ) 329 Yamataka, H. (1) 4 Yamato, M. ( 3 ) 274; ( 4 ) 68 Yamazaki, M. ( 5 ) 2 0 , 5 2 ; (8) 41 Yamazaki, Y. ( 3 ) 450; ( 5 ) 162, 1 6 3 Yamoto, M. (3) 124 Y a n a g i d a , S. (5) 7 1 Y a n a g i h a r a , H. ( 3 ) 388 Yanagisawa, A. ( 9 ) 50 Y a n a g i y a , M. ( 5 ) 226 Y a n a i , T. (1) 2 1 ; ( 4 ) 217; ( 5 ) 3 9 3 Yang, C.-C. ( 5 ) 100 Yang, J. ( 6 i i ) 162 Yang, Y. ( 2 ) 9 2 Yanuck, M.D. ( 7 ) 67 Yaounc, J.J. (5) 456 Yasuda, A . ( 3 ) 315; ( 6 i i ) 47
635 Yasuda, H. ( 3 ) 1 2 3 ; ( 6 i ) 7 Yasuda, M. ( 5 ) 4 0 Y a t e s , J . B . (3) 290 Yatsenko, A.E. (1) 1 Yazawa, H. ( 3 ) 4 7 1 Ye, W. ( 6 i i ) 152 Y e a t e s , C. ( 8 ) 6 9 ; ( 9 ) 5 4 , 55 Yi, K.Y. ( 3 ) 468; ( 4 ) 1 6 6 ; ( 5 ) 502 Y i j u n , C. ( 8 ) 218 Y i n g r u i , L. (1) 9 Yoakim, C. (3) 351 Yoda, H. (1) 41; ( 3 ) 3 0 6 , 397; ( 5 ) 236, 237; ( 6 i i ) 5 6 ; ( 8 ) 56 Yokoyama, C.T. ( 8 ) 127 Yokoyarna, T. ( 8 ) 9 Yokoyama, Y. ( 6 i i ) 140 Y o n a s h i r o , M. ( 3 ) 307 Yoneda, F. ( 3 ) 1 9 3 Yoneda, N. ( 3 ) 4 2 ; ( 4 ) 1 3 2 , 150 Yoneda, R. ( 5 ) 307 Yonemitsu, 0. ( 3 ) 1 4 2 ; ( 8 ) 29 Y o n e t a , A . ( 4 ) 214 Yonezawa, Y . ( 5 ) 274 Yorozu, K . (8) 1 4 3 Y o s h i d a , J. ( 6 i i ) 110 Y o s h i d a , T. ( 2 ) 1 3 8 ; ( 4 ) 24 Y o s h i d a , Z. ( 2 ) 3 0 , 31; ( 3 ) 1 5 7 , 293, 2 9 4 ; ( 4 ) 1 3 4 , 170, 195; ( 6 i ) 687 0 ; ( 8 ) 1 4 , 35, 167 Y o s h i k o s h i , A. ( 3 ) 241 Yoshimura, H . ( 9 ) 6 4 Yoshimura, J . ( 9 ) 6 5 Y o s h i n a g a , Y. ( 4 ) 7 8 Y o s h i o k a , H. ( 4 ) 1 4 8 Y o s h i o k a , M. ( 6 i i ) 136 Y o s h i o k a , T. ( 3 ) 1 4 2 ; ( 5 ) 4 5 9 , 460 Young, S.D. ( 3 ) 1 1 4 Youngdahl, K . ( 4 ) 7 Y u , C.-M. ( 3 ) 130 Yu, L.-C. ( 2 ) 80; ( 4 ) 1 4 2 ; ( 7 ) 157 Yu, T. (1) 3 Yuan, J.-J. ( 6 i i ) 150 Yuasa, Y. ( 8 ) 1 9 3 Yue, S. ( 7 ) 9 9 Yuen, P.-W. ( 9 ) 3 9 Yukawa, T. ( 8 ) 2 8
Yura, T. ( 2 ) 175; ( 3 ) 1 0 Yus, M. (1) 7 2 ; ( 4 ) 5 , 1 5 2 ; ( 5 ) 4 9 5 , 4 9 6 , 552; ( 6 i ) 20, 2 1 ; ( 6 i i ) 4 0 , 41 Yuzawa, Y . ( 5 ) 4 8 3
Z a h a l k a , H . A . ( 5 ) 72 Z a i k i n , V.G. (1) 1 Zaloom, J. ( 5 ) 228 Zarnir, L. ( 3 ) 204 Z a n i , P . ( 8 ) 128 Z a n i r a t o , P. ( 5 ) 381 Zanon, P. (5) 405 Z a n z i r a t o , V . ( 5 ) 326 Z a p a t a , A. ( 3 ) 187 Z a r d , S.Z. ( 3 ) 3 , 5 4 , 5 5 , 5 7 ; ( 4 ) 8 7 ; (5) 4 3 8 ; ( 6 i i ) 164 Z a s k , A . ( 9 ) 25 Z a u e r , K . ( 5 ) 46 Zawadzki, S . ( 4 ) 186; ( 5 ) 33 Z e c c h i , G. ( 6 i i ) 184 Z e e , S.-H. ( 6 i i ) 7 6 Z e f i r o v , N.S. ( 4 ) 135 Z e l e n i n , K . N . ( 5 ) 449 Z e l l e r , K.-P. ( 3 ) 1 4 3 Zhang, S. ( 3 ) 225 Z h d a n k i n , V . V . ( 4 ) 135 Zheng, J. ( 3 ) 225 Z i e g l e r , F.E. ( 3 ) 254; ( 7 ) 112 Z i g n a , A.M. ( 3 ) 61 Zima, G. ( 2 ) 119; ( 6 i i ) 195 Z i m i n , M.G. ( 5 ) 1 2 9 Zimmermann, J. ( 3 ) 370 Zimmermann, R. ( 3 ) 183 Z i n n e r , G. ( 5 ) 388 Z i n s m e i s t e r , K . ( 5 ) 433 Zjawiony, J. ( 5 ) 60 Z o l l e r , U. ( 8 ) 125 Z r e i k a , M. ( 5 ) 142 Z s c h i e s c h e , R. ( 2 ) 193; (3) 155 Z u b i e t a , J. ( 6 i i ) 174 Z u c k e r , P.A. (1) 4 8 ; ( 6 i i ) 121 Z u g a r , M.F. ( 3 ) 116 Zwane, I . ( 6 i i ) 7 4 Zwanenburg, B. (8) 9 2 Zwierzak, A . ( 4 ) 186; ( 5 ) 33
