General and synthetic methods: A review of the literature published during 1984, Volume 9

General and Synthetic Methods ~

Volume 9

A Specialist Periodical Report

General and Synthetic Methods Volume 9

A Review of the Literature Pubtished in 19Wq*:+, I

'/

f >

"~

~

-.:y.<

a ,

Senior Reporter G. Pattenden, Department of Chemistry, University of Nottingham Reporters

3. Blagg, University of Oxford K. Cooper, Pfizer Central Research, Sandwich, Kent S. G. Davies, University of Oxford S. C. Eyley, Fisons p.l.c., Loughborough, Leicestershire C. R. A. Godfrey, ICI Plant Protection, Jealott's Hill, Berkshire P. F. Gordon, lCl Organics Division, Manchester L. An. 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, University of Nottingham G. M. Robertson, University of Nottingham P. Whittle, Pfizer Central Research, Sandwich, Kent

SOCIETY OF HEM1STRY

ISBN 0-85186-904-1 ISSN 0141-2140

Copyright @ 1987 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 Society of Chemistry

Published by The Royal Society of Chemistry, Burlington House, London, W 1V OBN Printed by J. W. Arrowsmith Ltd, Bristol, England

Introduction T h i s n i n t h R e p o r t on G e n e r a l and S y n t h e t i c Methods c o v e r s t h e l i t e r a t u r e from J a n u a r y t o December, 1984.

I t i s t h e f i r s t volume

i n t h i s s e r i e s t o be produced from camera-ready copy o f m a n u s c r i p t s . t o e n s u r e t h a t t h e R e p o r t s remain v i a b l e e c o n o m i c a l l y , a l l f u t u r e volumes i n t h e s e r i e s w i l l now b e produced i n t h i s manner. The b r o a d aims o f o u r s u r v e y o f ' G e n e r a l and S y n t h e t i c Methods' remain as s e t o u t i n e a r l i e r R e p o r t s , and t h i s r e p o r t i s similar i n s c o p e and f o r m a t t o t h e p r e v i o u s two volumes i n t h e s e r i e s . Throughout t h e i r c o v e r a g e , c o n t r i b u t o r s a l w a y s a t t e m p t t o r e l a t e d e s c r i p t i o n s of s t r a t e g y , d e s i g n and methods i n o r g a n i c s y n t h e s i s t o problems a s s o c i a t e d with n a t u r a l products chemistry. I n a d d i t i o n , t h e R e p o r t a l s o i n c l u d e s a c h a p t e r ( C h a p t e r 9 ) which summarises " H i g h l i g h t s i n T o t a l S y n t h e s i s o f N a t u r a l P r o d u c t s " published i n each calendar year. The r e c e n t i n t r o d u c t i o n o f t h e new r e v i e w j o u r n a l ' N a t u r a l P r o d u c t R e p o r t s ' , u n d e r t h e a u s p i c e s

o f t h e Royal S o c i e t y o f C h e m i s t r y , w i l l no d o u b t i n t e r e s t many o f o u r r e a d e r s , s i n c e t h e m a t e r i a l embodied i n i t b o t h augments and complements much o f t h a t which i s c o v e r e d i n ' G e n e r a l and S y n t h e t i c Methods

.

G.

Pattenden

Con tents Chapter 1

Saturated and Unsaturated Hydrocarbons

1

B y C .R . A . Godf rey

1 Saturated Hydrocarbons 2 Olefinic Hydrocarbons 3 Conjugated 1,3-Dienes 4 Non-conjugated Dienes 5 Allenic Hydrocarbons 6 Acetylenic Hydrocarbons 7 Enynes and Diynes 8 Polyenes

Chapter 2 1

2

3

4

Aldehydes and Ketones B y S.C. E y l e y Synthesis of Aldehydes and Ketones

Oxidative Methods Reductive Methods Methods Involving Umpolung Other Methods Cyclic Ketones Synthesis of Functionalized Aldehydes and Ketones Unsaturated Aldehydes and Ketones a-Substitued Aldehydes and Ketones Dicarbonyl Compounds Protection and Deprotection of Aldehydes and Ketones Reactions of Aldehydes and Ketones Reactions of Enolates Aldol Reactions Conjugate Addition Reactions

Chapter 3

Carboxylic Acids and Derivatives Knight 1 Carboxylic Acids General Synthesis Diacids Hydroxy-acids Keto-acids Unsaturated Aliphatic Acids Aromatic Acids Acid Chlorides and Anhydrides Decarboxylation Carboxylic Acid Group Protection

1 7 37 45 50 53 58 61 71 71 71 75 76 78 84 88 88 99 106 110 113 113 115 118 130

B y D.W.

2

Esters

Esterification General Synthesis Diesters Hydroxy-esters Keto-esters Unsaturated Esters Thioesters

130 130 132 134 136 137 140 141 141 144 144 144 146 149 152 157 165 174

...

Conf en f s

Vlll

3 Lactones Butyrolactones a-Methylenebutyrolactones Butenolides Tetronic Acids Phthalides Valerolactones Macro1ides 4 Amides Synthesis Thioamides Amide (Peptide) Bond Formation 5 Amino-acids General Synthesis Unsaturated Amino-acids Asymmetric Hydrogenation Amino-acid Protection Chapter 4 Alcohols, Halogeno-compounds, and Ethers By L .M. Harwood 1 Alcohols Preparation By Addition to Alkenes By Reduction of Carbonyl Compounds Chemoselective Carbonyl Reductions Stereoselective Carbonyl Reductions Asymmetric Carbonyl Reductions By Nucleophilic Additions Miscellaneous Methods Protection and Deprotection Reactions Oxidation Deoxygenation Miscellaneous Reactions 2 Halogeno-c ompounds Preparation From Alcohols By Addition to Unsaturated Substrates Interhalide Conversions Miscellaneous Methods Reactions 3 Ethers Preparation Reactions 4 Thiols 5 Thioethers 6 Crown Ethers, Thia-crown Ethers, and Related Structures Chapter 5 Amines, Nitriles, and Other Nitrogencontaining Functional Groups By S.G. L i s t e r 1 Amines Primary Amines Secondary Amines Tertiary Amines Dim i n e s 2 Enamines 3 Allylamines, Homoallylamines, and Alkynylamines

178 178 185 187 188 188 190 195 199 199 204 204 208 208 213 216 217 233 233 233 233 233 234 234 236 241 249 252 254 254 256 256 258 258 258 261 261 262 262 263 263 265 267 267 270 284 284 284 29 6 303 306 311 319

ix

Contents 4 5 6 7 8 9 10 11 12 13 14 15 16

Amino-alcohols Amino-carbonyl Compounds Amides and Thioamides Nitriles and Isocyanides Nitro- and Nitroso-compounds Hydrazines and Hydrazones Hydroxylamines and Hydroxamic Acids Imines, Iminium Salts, and Related Compounds Oximes Carbodi-imides Azides and Diazo-compounds Azo- and Azoxy-compounds Isocyanates, Thiocyanates, Isothiocyanates, and Selenocyanates 17 Nitrones 18 Nitrates and Nitrites

Organometallics in Synthesis By J. Blagg S.G. D a v i e s , a n d P . F . PART I: The Transition Elements By J. Blagg a n d S.G. Davies

6 PART 1

2

3 4

5 6

384 385 385 398

Chapter 6

1 2 3 4 5

324 337 339 346 357 369 370 372 375 377 377 383

Gordon

Introduction Reduction Oxidation Isomerizations and Rearrangements Carbon-Carbon Bond-forming Reactions via Organometallic Electrophiles via Organometallic Nucleophiles via Coupling Reactions via Carbonylation Reactions Miscellaneous Reactions 11: Main Group Elements By P.F. G o r d o n Group I Selective Lithiations Synthetic Equivalents Miscellaneous Group I1 Magne siurn Zinc and Mercury Group I11 Boron Aluminium Group IV Allylsilanes Vinylsilanes Silicon-based Reagents Miscellaneous Silicon Compounds Tin Group V Phosphorus Group VI Su1phur Se1enium

398 398 400 408 415 415 419 422 426 429

436 436 440 442 447 447 450 452 452 457 459 459 461 463 465 467 471 471 475 475 482

Contents

X

Chapter 7

S a t u r a t e d C a r b o c y c l i c Ring S y n t h e s i s

B y T.V. 1 2 3

4

5 6 7 Chapter 8

490

Lee

Three-membered R i n g s G e n e r a l Methods Four-membered R i n g s Five-membered R i n g s G e n e r a l Methods Fused Five-membered R i n g s N a t u r a l l y O c c u r r i n g Fused C y c l o p e n t a n o i d s Six-membered R i n g s Diels-Alder Reactions Intramolecular Diels-Alder Reactions O t h e r S y n t h e s e s o f Six-membered R i n g s P o l yene Cyc 1i z a t i o n s Seven-membered, Medium, and L a r g e R i n g s Ring-expansion Methods S p i r o - r i n g Compounds

490 490 49 2 494 494 499 505 508 508 510 514 521 524 527 53 1

S a t u r a t e d H e t e r o c y c l i c Ring S y n t h e s i s

536

B y K . C o o p e r and P.J. M i t t l e 1

5

Chapter 9

Oxygen-containing H e t r o c y c l e s Three- and Four-membered R i n g s Five-membered R i n g s Te t r a h y d r o f u r a n s Dihydrofurans Six-membered R i n g s Tetrahydropyrans Dihydropyrans [5.n]Spiroacetals Six-membered R i n g s C o n t a i n i n g More t h a n One Oxygen Seven- a n d Eight-membered R i n g s Sulphur-containing Hetrocycles R i n g s w i t h More t h a n One H e t e r o a t o m N i t r o g e n - and O x y g e n - c o n t a i n i n g R i n g s Three- and Four-membered R i n g s Five-membered Rings Six-membered and L a r g e r R i n g s Oxygen and S u l p h u r - , and N i t r o g e n and S u l p h u r - c o n t a i n i n g Rings Nitrogen-containing Heterocycles Three-membered R i n g s Four-membered R i n g s Fi v e -memb e r e d R i n g s Five-membered R i n g s C o n t a i n i n g More t h a n One Nitrogen Six-membered R i n g s C o n t a i n i n g One N i t r o g e n Six-membered R i n g s C o n t a i n i n g More t h a n One N i t rogen Medium-ring N i t r o g e n H e t e r o c y c l e s R i n g s C o n t a i n i n g One N i t r o g e n R i n g s C o n t a i n i n g Two N i t r o g e n s 6-Lactams, P e n i c i l l i n s , C e p h a l o s p o r i n s , and R e l a t e d Compounds

536 536 538 538 542 548 548 548 553

H i g h l i g h t s i n T o t a l S y n t h e s i s of N a t u r a l P r o d u c t s

633

B y K.E.B. 1 2

558 558 560 563 563 563 563 570 573 580 580 583 583 59 6 59 9 608 613 613 613 617

P a r k e s and G . P a t t e n d e n

Introduction Terpenes

633 633

xi

Contents 3 4 5 6 7 8 9 10 11

1 2 3 4

5 6 7 8 9 10 11 12 13 14

Steroids Anthracyclinones A1kalo ids Prostanoids Spiroacetals Lignans Polyols Macrolides and Ionophores Other Natural Products

642 642 647 655 658 658 661 666 671

Reviews on General and Synthetic Methods Conpiled by G. Pattenden and G.M. Robertson

679

Olefins Aldehydes and Ketones Nitrogen-containing Functional Groups Organometallics General Transition Elements Main Group Elements Carbocyc 1es Cycloaddition Reactions Heterocycles Prostaglandins Sugars Alkaloids Enzymic Reactions and Asymmetric Synthesis Photochemistry and Electrochemistry General Mi scellaneous

679 679 679 680 680 680 680 681 682 682 684 684 684 685 685 686 686

Author Index

688

1 Saturated and Unsaturated Hydrocarbons BY C. R. A. GODFREY

1 S a t u r a t e d Hydrocarbons A number of new m e t h o d s f o r t h e p r e p a r a t i o n o f a l k a n e s

via

r e d u c t i v e r e m o v a l o f f u n c t i o n a l g r o u p s were r e p o r t e d d u r i n g 1984.

All-e-[5.5.5.5Ifenestrane ( 2 1 , a hydrocarbon containing a fourc o - o r d i n a t e c a r b o n atom w i t h p l a n o i d c o n f i g u r a t i o n , h a s b e e n The f i n a l s t e p i n t h e s y n t h e s i s s y n t h e s i z e d by Keese a n d L u y t e n . ' i n v o l v e s a n u n u s u a l r e d u c t i v e d e c a r b o x y l a t i o n o f t h e l a c t o n e ( 1 ) on h e a t i n g t o 310 O C u n d e r h y d r o g e n i n t h e p r e s e n c e o f e x c e s s p a l l a d i u m on c a r b o n (Scheme 1 ) . The r a d i c a l c h a i n d e c a r b o x y l a t i o n o f N-hydroxypyridine-2-thione e s t e r s r e p o r t e d p r e v i o u s l y h a s now b e e n a p p l i e d t o N - p r o t e c t e d a - a m i n o - a c i d s a n d p e p t i d e s . 2 Under t h e mild r e a c t i o n c o n d i t i o n s developed f o r t h i s t r a n s f o r m a t i o n , i n d o l i c , h y d r o x y l i c , and p h e n o l i c s i d e - c h a i n f u n c t i o n s do n o t r e q u i r e p r o t e c t i o n (Scheme 2 ) . F u r t h e r m o r e , r e m o v a l o f s i d e - c h a i n carboxy-groups of g l u t a m i c and a s p a r t i c a c i d r e s i d u e s a p p e a r s t o be l e s s f a c i l e t h a n t h e a-amino-acid d e c a r b o x y l a t i o n . G u t t i e r r e z a n d Summerhays h a v e r e p o r t e d on t h e u s e o f t r i - n b u t y l t i n h y d r i d e for t h e s e l e c t i v e cleavage of unsymmetrical d i a l k y l s u l p h i d e s t o t h e corresponding a l k a n e s and t r i - n butylstannyl alkyl sulphide. A mild, s e l e c t i v e procedure for t h e r e d u c t i v e d e s e l e n i z a t i o n of s e l e n i d e s w i t h n i c k e l b o r i d e h a s a l s o b e e n d e s c r i b e d by B a c k . 4 The r e a g e n t , w h i c h i s r e a d i l y p r e p a r e d by t r e a t m e n t of n i c k e l c h l o r i d e h e x a h y d r a t e w i t h s o d i u m 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 v i n y l and a l k y l s e l e n i d e s t o t h e c o r r e s p o n d i n g h y d r o c a r b o n s , even i n t h e p r e s e n c e o f a l k e n e s and s u l p h i d e s (Scheme 3 ) . An i m p r o v e d method f o r t h e d e o x y g e n a t i o n o f t e r t i a r y a l c o h o l s b a s e d on t h e r a d i c a l c h e m i s t r y o f t h i o h y d r o x a m i c 2 - e s t e r s h a s b e e n d e v e l o p e d by B a r t o n a n d C r i c h (Scheme 4 ) . 5 The i n t e r m e d i a t e mixed o x a l a t e e s t e r ( 3 ) , formed i n s i t u , undergoes smooth decomposition a t 80 OC i n t h e p r e s e n c e o f a n e x c e s s o f t - b u t y l t h i o l a n d t r a c e s of b a s e t o a f f o r d t h e d e o x y g e n a t e d p r o d u c t ( 4 ) i n 90% y i e l d . The For References see page 66. 1

2

General and Synthetic Methods

H

H

Scheme 1

i-iii 96 *I.

____)

H H

?H

XO~N+ 0

i-iii a7 *I.

CO,H

Reagents: i, BuiOCOCI, OANMe;

W

ii,

*

QiEt3N;

iii, h V , But SH

OH

Scheme 2

NiCl

, Na8H4 91 .I.

P - NOZC6H4Se'0

Scheme 3

m

1: Saturated and Unsaturated Hydrocarbons

3

(3)

i

90 '1. overal I

Reagents: i , (COC1)2 ; ii, But SH, DMAP,

Qs

6- Na' Scheme 4

R J - ( 0

ilii

- HogR 0

OH

iii

R

(6)

(5)

liv

HOD

R

-

(8 1

'

0P

R

k

0

(7)

Reagents: i, L D A , Me3SiCI; ii, m-CICsH4C03H; iii,LiAIH4,AIClg; iv, 1m2CO;

v, NaBH3CN, [Pd(PPh3l41

Scheme 5

4

General and Synthetic Methods

key step in the novel 1-6 oxygen transposition sequence illustrated in Scheme 5 is the selective reduction of the cyclic carbonate (7) to the alcohol ( 8 ) using NaBH3CN-[Pd(PPh ) I-THF.‘ Attempted 3 4 reduction (LiAlH4-A1C1 ) of the intermediate hydroxy-ketone ( 5 ) 3 directly to the homoallylic alcohol (8) fails, giving instead the cis-diol (6) with high selectivity. Khalifa and Rieker have shown that the 3,5-di-t-butyl-l-phenyl4-oxo-cyclohexa-2,5-dienyl N-protecting group can be removed electrochemically. Under the reaction conditions, the Ebenzyloxycarbonyl group is stable. ortho-Selective dehalogenation of halogenobenzoic acids can be effected with The reagent is bis(pentafluoropheny1)ytterbium in THF at -78 o C . 8 prepared in situ from bis(pentafluoropheny1)mercury and elemental ytterbium. Iida and his co-workers have reported that the use of acetic acid as solvent, both for the preparation and reductive cleavage of steroidal ketone tosylhydrazones, significantly improves yields and reduces unwanted side reactions Several examples of asymmetric hydrogenation have appeared during the year. l o ’ ” Evans and Morissey have observed dramatic hydroxyl-directed stereochemical control of high-pressure (640 p.s.i.) hydrogenation in both cyclic and acyclic systems when the cationic rhodium complex [Rh(NBDf(DIPHOS-4)]BF4 is used as catalyst.’* As the examples in Scheme 6 show, excellent selectivity can be achieved even in extremely hindered cases such as in the reduction of the allylic alcohol (9). Homogeneous catalytic hydrogenation of the 3-methylenecyclohexanol ( 1 0 ) in the presence of the complex ( 1 1 ) is highly stereoselective, giving Reduction of predominantly trans-3-methylcyclohexanol . 2-methylenecyclohexanol and 2-methlenecyclohexanemethanol, however, under the same conditions, exhibits poor selectivity. Imamoto and his co-workers have successfully reduced a wide range of unsaturated substrates, including alkynes and alkenes, using the intermetallic hydride LaNi5H6 under nitrogen at atmospheric pressure. l 4 The hydride is readily prepared by hydrogenation of LiNi5, which unlike many conventional hydrogenation catalysts is unaffected by substrates containing an amino-group, halogen atom, o r thiophene ring. Sodium hypophosphite in the presence of palladium on charcoal has a l s o been examined as a convenient alternative to catalytic low-pressure hydrogenation. Finally, Baldwin et al. have introduced the use of trityl- and d i p h e n y l - 4 - p y r i d y l m e t h y l hydrazones ( 1 2 ) for reductive C-C bond

.’

5

1: Saturated and Unsaturated Hydrocarbons

12: 1

(10)

>98: 2

General and Synthetic Methods

6

H

X

d

N=N/

R2‘

Li

iii

X R’ 2

R

(12)

N=N’ x

5

.R

(13) l ii

(14) liv

R’ R2 Reagents: i

, McLi;

3 4 ii, R R

5

CO; iii, R - Y ; i v , RSH; v , PCL3

Scheme 7

T i c $ , LiAlH4

%o

5.8%

Scheme 8

*

tR5

I : Saturated and Unsaturated Hydrocarbons

7

formation from aldehydes and ketones (Scheme 7). l6 Thus, homolytic decomposition of the intermediate azo-compounds (13) and (14) in the presence of a suitable radical trap, such as ethanethiol, leads to the smooth formation of the corresponding alkanes. Furthermore, on treatment with phosphorus trichloride, the adducts (14) are converted into unsymmetrical tri- and tetra-substituted alkenes in moderate yield (24-60%). 2 Olefinic Hydrocarbons

Molecules containing highly strained olefinic bonds continue to be of great theoretical interest. Lenoir and his co-workers, f o r example, have studied the conformational behaviour of (E)-3,4diethyl-2,2,5,5-tetramethylhex-3-ene (15), available in good yield by reductive dimerization of t-butyl ethyl ketone using known methodology (Scheme 8). l7 In an extension of earlier work, Tobe's research group has synthesized a series of bicyclo[n.2.11 bridgehead alkenes of type (16; 2=4-6) substituted at the opposite bridgehead position with an acetoxy-group. l 8 Interestingly, vapour-phase pyrolysis of the alkene (16; n=6) at 400 O C leads 2 elimination of acetic acid to the novel bicyclo[6.2.11 bridgehead diene (17) in 50% yield. The use of low-valent titanium and tungsten for the formation of carbon-carbon bonds is now well established. However, the outcome of the reaction is often unpredictable, depending largely on which method is used for the preparation of the reagent. Reduced tungsten species effective in the reductive dimerization of aromatic carbonyl compounds have now been generated by controlled Aliphatic electroreduction of WC16 at a platinum electrode. substrates, however, give disappointing results. General methods for the asymmetric olefination of carbonyl compounds have been scarce in the literature until very recently. Now Hanessian and co-workers have developed the use of chiral bicyclic phosphanamides such as ( 1 8 ) and (19) for this purpose. 2 0 On deprotonation, these reagents react in a highly diastereofacial manner with substituted cyclohexanones to produce optically enriched (alkylcyclohexy1idene)ethanes. Some representative examples of this important development are illustrated in Scheme 9. Mild conditions for the Horner-Wadsworth-Emmons reaction have been described which are applicable to both base-sensitive aldehydes and The successful olefination of aldehyde (20) with phosphonates

."

General and Synthetic Methods

8

OAc

H (1 7 )

R-

S-

95: 5 ( S ,S 1- (19). KDA P

5 : 95

Me

Me

I

0 (Me 01,

c!

%

Scheme 9

OSiEt,

(21)

Reagent: i ,

wCHo , LiCL, PriZNEt

(20)

Scheme 1 0

9

1: Saturated and Unsaturated Hydrocarbons

t h e e a s i l y e p i m e r i z a b l e phosphonate ( 2 1 ) is p a r t i c u l a r l y noteworthy s i n c e s t a n d a r d c o n d i t i o n s (sodium h y d r i d e o r p o t a s s i u m t - b u t o x i d e ) l e a d p r e d o m i n a n t l y t o s e l f - c o n d e n s a t i o n o f t h e a l d e h y d e (Scheme 10). M e t h y l e n a t i o n o f a c i d i c k e t o n e s c a n be e f f e c t e d u n d e r m i l d c o n d i t i o n s u s i n g t h e o r g a n o t i t a n i u m r e a g e n t s ( 2 2 ) and ( 2 3 ) .22 Y i e l d s a r e g e n e r a l l y high even w i t h ketones such a s ( 2 4 ) and ( 2 5 ) which normally respond badly t o c o n v e n t i o n a l methods.

a,a-

D i s u b s t i t u t e d k e t o n e s , however, are c o n v e r t e d under t h e s e c o n d i t i o n s i n t o t h e corresponding t i t a n i u m e n o l a t e s , presumably f o r s t e r i c reasons. Hernandez and Larsen have f u r t h e r extended t h e i r

e a r l i e r work on t h e c h e m i s t r y of a - s i l y l e s t e r s t o i n c l u d e t h e s y n t h e s i s of b o t h t r i - and t e t r a - s u b s t i t u t e d

o l e f i n s (Scheme 1 1 ) . 2 3

A l t h o u g h o p e r a t i o n a l l y s i m p l e , t h e r e a c t i o n a p p e a r s t o be q u i t e s e n s i t i v e t o s t e r i c f a c t o r s and i s t h e r e f o r e of l i m i t e d s c o p e . S e v e r a l c o n c e p t u a l l y similar methods f o r t h e c o n s t r u c t i o n o f o l e f i n s b a s e d on t h e c h e m i s t r y o f a c y l s u l p h o n e s h a v e b e e n p u b l i s h e d . 24 2 5 9 2 6

Hendrickson and co-workers,

f o r example, have

e x p l o i t e d t h e u s e o f t h e r e a g e n t ( 2 6 ) w h i c h i s r e a d i l y p r e p a r e d by a c y l a t i o n o f t h e a n i o n o f d i m e t h y l s u l p h o n e (Scheme 1 2 ) . 2 4 A l t h o u g h t h e s e q u e n t i a l a l k y l a t i o n o f t h i s compound p r o c e e d s w i t h c o m p l e t e r e g i 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 i s p o o r , a n d as a consequence m i x t u r e s of i s o m e r i c p r o d u c t s are o b t a i n e d .

The

d e c o m p o s i t i o n of a p p r o p r i a t e l y s u b s t i t u t e d p h e n y l a z i r i d i n e h y d r a z o n e s a t 140-160

OC

leads t o t h e formation of t r i s u b s t i t u t e d

o l e f i n s i n good y i e l d . 2 7

The r e a c t i o n w o r k s w e l l e v e n f o r s t e r i c a l l y h i n d e r e d s u b s t r a t e s s u c h as ( 2 7 ) , t h u s a l l o w i n g t r a n s f o r m a t i o n s n o t p o s s i b l e u s i n g S h a p i r o o r Bamford-Stevens m e t h o d o l o g y (Scheme 1 3 ) .

=

The c o n v e r s i o n o f a c a r b o x y l i c a c i d i n t o t h e c o r r e s p o n d i n g n o r o l e f i n is p o s s i b l e

p h o t o l y s i s of t h e d e r i v e d a-diazomethyl

k e t o n e i n t h e p r e s e n c e o f i m i d a z o l e (Scheme 1 4 ) . 2 8

This procedure

h a s now b e e n a p p l i e d w i t h some s u c c e s s t o t h e d e g r a d a t i o n o f b i l e acid side-chains. The d i r e c t d e o x y g e n a t i o n o f e p o x i d e s t o a l k e n e s r e m a i n s a synthetically important transformation. M a r t i n a n d Ganem h a v e suggested t h a t t h e development of mild methods compatible w i t h complex f u n c t i o n a l i z e d systems might l e a d t o t h e u s e o f t h e epoxide blocking group.29

T o t h i s e n d , t h e y h a v e shown t h a t r h o d i u m ( I 1 )

c a r b o x y l a t e s a l t s c a t a l y s e t h e d e o x y g e n a t i o n of e p o x i d e s by d i m e t h y l d i a z o m a l o n a t e (Scheme 1 5 ) . The r e a c t i o n p r o c e e d s s m o o t h l y

General and Synthetic Methods

10

Reagents: i , R3MgX; i i ,

4

R M Scheme 11 R1

-

R2 I BCF3S02CH2S02CH3 % CF3S02C-S02CH

I

A4

(26)

A3

so

[ l

4 / v

R R C -CR

?I]

R -RR

3 4 Reagents: i , 2BunLi, RIX; i i , Bu"Li, R2X, i i i , Bu"Li, R X ; iv, R X

Scheme 1 2

160

O C

____)

9 2 .I.

Me a CN

(27) Scheme 1 3

Reagents: , i , (COCI)

2

ii. CHPNZ;i i i ,

fi N b , h v , THF

Scheme 14

M

e

1 4

2 3

C=CR R

11

1: Saturated and Unsaturated Hydrocarbons Ac 0

Reagent : i , (MeO2Cl2 CN2, Rh2(0Ac)4

Scheme 15

& -& pm;2

AcO

b,.

AcO

Scheme 1 6

A c0,

-

-CN

Si Me,

SiMe,

-

n'C5H11

AcO, N

0 i , ii

&n-c5H11

& _.. -CN

()n ,-c5H11

SiMe3

S iMe,

/

0

Reagents: i , NHzOH-HCI, NaOAc, i i , Ac20, Py, iii; Me3SiOTf(10 mol * I . ) ; iv, n-C

H MgX,

10 21

v, H30+

Scheme 17

/

n-C5H11

12

General and Synthetic Methods

under mild, neutral conditions without either alkene isomerization or cyclopropanation, but, with certain aldehydes, competing carbonyl insertion is observed. Recent results suggest that the previously reported conversion of epoxides into iodohydrins on treatment with the triphenylphosphine-iodine complex is in fact sensitive to the degree of substitution of the epoxide ring.30 Indeed, in the case of a variety of trisubstituted steroidal epoxides, deoxygenation to the corresponding olefin takes place preferentially and in high yield (Scheme 16). A mild synthesis of olefins from vicinal diols, applicable to the field of ribonucleotides, has been described by Robins et The reagent [(C H ) TiC121 is an effective catalyst in the 5 5 2 stereoselective reduction of vicinal dibromides with zinc in THF. 32 The actual reducing species are thought to be [(C H ) TiC1I2 and 5 5 2 [(C5H5)2TiC112ZnC12. The stereospecific syntheses of both the major and minor sex pheromones (28) and ( 2 9 ) of the Douglas fir tussock moth (Orgyia pseudotsugata), carried out by Itoh and co-workers, illustrate the potential of the silicon-directed Beckmann fragmentation for stereocontrolled olefin synthesis (Scheme 1 7 ) . ” y-Stannyl alcohols also undergo selective fragmentation on reaction with lead tetra-acetate in refluxing benzene to afford excellent yields of either (E)- or (Z)-keto-olefins according to the stereochemistry of the starting materials. 34 Noteworthy examples illustrating this point are outlined in Scheme 18. Similar 1,4-fragmentation has also been observed on treatment of y-stannyl alcohols with iodosylbenzene, boron trifluoride etherate, and DCC. 35 A new catalyst for the (L)-selective semihydrogenation of alkynes has been developed by Brunet and Caubere. 36 Disubstituted acetylenes undergo palladium-catalysed coupling with aryl iodides in the presence of both formic acid and a tertiary amine to afford trisubstituted olefins in high yield (Scheme 19) .37 Regioselectivity for unsymmetrically substituted substrates, however, is poor and mixtures of olefinic products are obtained. General methods for the deoxygenation of carbonyl compounds to olefins are clearly important in synthesis. A versatile two-step conversion reported this year involves the palladium-catalysed reduction of enol triflates using trialkylammonium formate. 38 Although the reduction step is quite efficient, overall yields are often depenent on the efficiency of the initial formation of the triflate, as demonstrated in Scheme 20. The controlled generation

13

1: Saturated and Unsaturated Hydrocarbons

i

-

95 @I.

eu

Reagent : Pb(OAc14, CcHg

Scheme 16

Scheme 19

AcO

Reagents : i , CCF3S0,),O,

a

AcO

;

&

i i , HC02H, Bun3N, [Pd(OAcI2 (PPh3l21

Scheme

20

General and Synthetic Methods

14

a n d c y c l i z a t i o n of v i n y l - l i t h i u m s p e c i e s c o n t a i n i n g p r i m a r y c h l o r i d e g r o u p s h a s b e e n u s e d a s a means o f p r e p a r i n g a v a r i e t y of alkylidene-cycloalkanes

.

( S c h e m e 21 ) 39

The h i g h r e g i o s e l e c t i v i t y

o b s e r v e d i n t h e s e s e q u e n c e s for t h e S h a p i r o r e a c t i o n i s w e l l precedented.

(1,2-Dialkoxyethylene)iron c o m p l e x e s of t y p e ( 3 0 ) f u n c t i o n a s cis- or t r a n s - v i n y l e n e d i c a t i o n e q u i v a l e n t s on r e a c t i o n with a hide range of carbon nucleophiles, including cuprates, 40 e n o l a t e s , a n d G r i g n a r d r e a g e n t s (Scheme 2 2 ) . specific

A s p a r t of a programme d i r e c t e d t o w a r d s t h e s y n t h e s i s o f a t o x i c

a l k a l o i d i s o l a t e d from t h e p o i s o n d a r t f r o g , I b u k a and co-workers have s t u d i e d t h e d e c a r b o x y l a t i v e r e d u c t i o n o f y-carbamoyloxy-a,Bunsaturated esters with l i t h i u m d i a l k y l c u p r a t e s . '

'

Application of

t h i s methodology t o t h e c y c l i c carbamate (31) l e d t o t h e f o r m a t i o n of t h e ( E ) - a l k e n e ( 3 2 ) which h a s been p r e v i o u s l y t r a n s f o r m e d i n t o

(+)-perhydrogephyrotoxin ( S c h e m e 2 3 ) . V a r i a n t s of t h e C l a i s e n [ 3 , 3 1 s i g m a t r o p i c r e a r r a n g e m e n t , i n particular Ireland's modification, continue t o play a central role i n s t r a t e g i e s aimed a t t h e s t e r e o c o n t r o l l e d s y n t h e s i s of complex molecules. A number o f new a p p l i c a t i o n s a n d m o d i f i c a t i o n s a r e worth noting. R e p o r t s on 1 , 4 - c h i r a l i t y t r a n s f e r v i a C l a i s e n r e a r r a n g e m e n t o f ( S ) - b u t - l - e n - 3 - y l p r o p a n o a t e 1 4 2 p a l l a d i u m ( 11) c a t a l y s i s , 43 and t h e c h e l a t i o n - c o n t r o l l e d

r e a r r a n g e m e n t of c e r t a i n

a l l y l i c g l y c o l a t e esters44 have been p u b l i s h e d .

Additionally

,

the

r e s e a r c h g r o u p s of K ~ r t ah n d~ F~u j i s a w a L 1 6 h a v e b o t h c a r r i e d o u t i n d e p e n d e n t s t u d i e s on t h e [ 3 , 3 1 s i g m a t r o p i c r e a r r a n g e m e n t o f B h y d r o x y - e s t e r d i a n i o n s and t h e i r d e r i v e d s i l y l k e t e n e a c e t a l s .

An

e x c e l l e n t example of t h e a p p l i c a t i o n of t h i s r e a c t i o n 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 i s p r o v i d e d by P a q u e t t e ' s s y n t h e s i s o f p r e c a p n e l l a d i e n e ( S c h e m e 2 4 ) .47 S i m i l a r l y , Knight and h i s co-workers have developed a s t e r e o s p e c i f i c r o u t e b a s e d on t h i s m e t h o d o l o g y t o t h e p e r h y d r o a z u l e n e s

(33) and ( 3 4 ) , p o t e n t i a l p r e c u r s o r s of t h e d i c t y o l f a m i l y of m a r i n e n a t u r a l products.48

A prerequisite for chiral synthesis

via

the

C l a i s e n rearrangement is t h a t t h e a l l y l i c system be d e r i v e d from a n e n a n t i o m e r i c a l l y p u r e s e c o n d a r y or t e r t i a r y a l c o h o l , s i n c e p r i m a r y a l l y l i c alcohols can lead only t o racemic diastereorneric products. I r e l a n d and Varney h a v e e x p l o r e d t h e c o n c e p t o f a c h i r a l p r i m a r y a l c o h o l e q u i v a l e n t , f o c u s s i n g t h e i r i n i t i a l a t t e n t i o n s on t h e p r o p i o n a t e s d e r i v e d from t h e o p t i c a l l y a c t i v e ( S ) - u - s i l y l c r o t y l a l c o h o l ( 35 ) a n d i t s e n a n t i o m e r ( S c h e m e 25 ) .49 R e a r r a n g e m e n t

15

1: Saturated and Unsaturated Hydrocarbons

(INN -0 2 i , ii

(CH 2 ) $1

(CH,),

Reagents: i, Bu"Li, - 7 8 OC; i i , 0 OC

Scheme 2 1

-./k" MeoYo"' OMe

+ FP

ii

L

e

oR'

~

FP+

FP+

OMe

(30)

1

I

iii, ii ,iv

R2

iii,ii, iv

R1

w

Reagents: i , R I M ; ii,HBF&EtZ0,-78'C;

MeowR R'

iii, RZMi iv; M e C N , A , o r N a I , a c c t o n e

Scheme 2 2

(10 MeZCuLi equiv. )

-9

C0,Me (31)

H H

Me02C

(32) Scheme 23

General and Synthetic Methods

16

Reagents: i , Tebbe, i i , 200

*C; i i i , TsNHNH2; iv, B u " L i , A ; v , RhCS, EtOH Scheme 2 4

(35)

f

I

iv-vii

I

(37) ReagMts : i, iv,

LDA, "HF, - 76 %;

Clipzjv,

-

ii, TBSCI, HMPA, 78OC -RTi

(39) iii , LHMDS, THF, -78

LiAIH4; vi, W r , KHi vii, 50'10 H8F4,MeCN,55 * C

Scheme

25

OC;

17

1: Saturated and Unsaturated Hydrocarbons

o c c u r s s u c c e s s f u l l y w i t h h i g h s e l e c t i v i t y t o g i v e e i t h e r o f t h e two p r o d u c t s ( 3 6 ) o r ( 3 7 ) d e p e n d i n g on t h e r e a c t i o n c o n d i t i o n s , S u b s e q u e n t m o d i f i c a t i o n and r e m o v a l o f t h e s i l i c o n g r o u p s protiodesilylation affords the corresponding monosubstituted o l e f i n s ( 3 8 ) and ( 3 9 ) , t h u s completing t h e p r o c e s s . Highly s u b s t i t u t e d a l l y 1 v i n y l e t h e r s such as ( 4 0 ) u n e x p e c t e d l y undergo b o t h t h e r m a l (135 O C ) and a n i o n i c v e r s i o n s o f t h e C l a i s e n rearrangement with t h e formation of products c o n t a i n i n g v i c i n a l q u a t e r n a r y c e n t r e s (Scheme 2 6 ) .50 W i l s o n a n d P r i c e h a v e d i s c o v e r e d t h a t d i a n i o n s d e r i v e d from a l l y l i c a c e t o a c e t a t e s r e a d i l y undergo t h e r e l a t e d ester e n o l a t e Carrol rearrangement a t temperatures below 65 0 C . 5 1

I n contrast t o t h e corresponding thermal

r e a r r a n g e m e n t , p r o d u c t s of C3,31 r e a r r a n g e m e n t a r e formed S u b s e q u e n t h e a t i n g a t 77 exclusively. d e c a r b o x y l a t i o n (Scheme 2 7 ) .

OC

results in

Methods f o r t h e h i g h l y r e g i o - a n d s t e r e o - s e l e c t i v e

formation of

e n o l a t e s and t h e i r d e r i v a t i v e s are i m p o r t a n t t a r g e t s i n o r g a n i c s y n t h e s i s which c o n t i n u e t o a t t r a c t a t t e n t i o n .

A w i d e l y u s e d two-

s t e p procedure f o r t h e s e l e c t i v e formation of k i n e t i c a l l y g e n e r a t e d s i l y l e n o l e t h e r s i n v o l v e s t h e s l o w a d d i t i o n o f c a r b o n y l compounds t o l i t h i u m d i - i s o p r o p y l a m i d e (LDA) a t -78 silylation.

OC

i n THF f o l l o w e d by

Corey a n d Gross h a v e now shown t h a t when d e p r o t o n a t i o n

i s c a r r i e d o u t w i t h LDA a t -78 O C i n t h e p r e s e n c e o f t r i m e t h y l s i l y l c h l o r i d e , r e g i o s e l e c t i v i t y i s m a r k e d l y i m p r o v e d (Scheme 2 8 ) . 5 2 The

u s e o f t h e more h i n d e r e d b a s e l i t h i u m t - o c t y l - t - b u t y l a m i d e

(LOBA)

i s e v e n more e f f e c t i v e , and i n a d d i t i o n g i v e s e x c e l l e n t c o n t r o l o f enolate stereochemistry.

A r e v e r s a l of s e l e c t i v i t y (Scheme 2 9 ) i s

o b s e r v e d i n t h e p r e s e n c e o f HMPA, h o w e v e r , a r e s u l t c l o s e l y p a r a l l e l e d by t h e work o f T u r n e r e t a l . on t h e p r e p a r a t i o n of t - b u t y l d i m e t h y l s i l y l e n o l e t h e r s .53 perchlorate-Hunig's

The u s e o f t r i e t h y l s i l y l

b a s e f o r t h e s y n t h e s i s o f (Z-)-g-silyl

ketene a c e t a l s w o r k s w e l l e v e n i n t h e case o f i s o p r o p y l a - b r o m o a c e t a t e , a compound w h i c h h a s r e s i s t e d p r e v i o u s l y r e p o r t e d m e t h o d s .54 The s u b s t i t u t e d z i r c o n i u m c a r b e n e c o m p l e x e s ( 4 1 ) a n d ( 4 2 ) r e a c t w i t h c y c l i c i m i d a t e s t o a f f o r d good y i e l d s o f e n o l e t h e r s (Scheme 3 0 ) . 5 5 The (E):(L) s e l e c t i v i t y c a n b e c o n t r o l l e d by t h e u s e o f a n N - - s u b s t i t u t e d i m i d a t e . W i l c o x a n d h i s c o - w o r k e r s h a v e made u s e o f Tebbe's reagent (22) f o r t h e d i r e c t methylenation of aldonolactones, a transformation with potential application t o the s y n t h e s i s of mycotoxins such as a u r o v e r t i n B and ~ i t r e o v i r i d i n . ~ ~ The f i r s t s y n t h e s i s o f e n o l e t h e r s f r o m a l d e h y d e s i n v o l v i n g a

General and Synthetic Methods

18

p - T 0 [ s 0 2 3 0 \R'

R*

\

i or ii

P-TOlSO,

R2

(401 Reagents: i , KH, LiCl; ii, 135 O C

Scheme 26

no 0

K'

0

Y

0

0

-

67 : 33

ii,iii

100: 0

Reagents: i , 170 OC, neat; ii, 2LDA; i i i , 7 7 O C

-

Scheme 2 7 OTM S

i

d

0 ii

iii

____)

OTM S

+

d

86

14

95

5

97.5

2.5

Reagents: i , LDA then TMSCI; ii, LDA, TMSCI; iii, LOBA, TMSCI

Scheme 2 8

i

*

T O T M S

+

OTMS

98

2

18

82

0 It ___)

Reagents : i , LOBA,TMSCI,THF, ii, LOBA, THF, HMPA, then TMSCL

Scheme 29

1: Saturated and Unsaturated Hydrocarbons

19

R

Cp Zr L'

75

R

0 OC

( 4 1 ) R = B u t , L = PPh3 ( 4 2 ) R = Bu", L = PPh, Scheme 3 0

iv 77 .lo

0 - O "

(44)

(45 )

SPh

Reagents : i , L i <

;

ii, C S 2 ; iii, M e I ; iv, HSnBun3

OMe

(43 1

Scheme 3 1

0 opph2 i'ii

II

iii, i v 86 *I.*

76 ' l o

0 Reagents : i , Ph3P, HCI; ii, NaOH; i i i , LDA; i v , &-)'WLi

Scheme 3 2

; V,

H+

General and Synthetic Methods

20

r a d i c a l p r o c e s s h a s b e e n p u b l i s h e d by V a t 6 1 e . 5 7 A t y p i c a l example i s shown i n Scheme 3 1 . T h u s , t r e a t m e n t o f c y c l o h e x a n e c a r b o x a l d e h y d e w i t h methoxyphenylthiomethyl-lithium ( 4 3 ) f o l l o w e d by q u e n c h i n g w i t h c a r b o n d i s u l p h i d e a n d m e t h y l i o d i d e a f f o r d s t h e xanthate (44).

Subsequent r e d u c t i o n with t r i - n - b u t y l t i n

hydride i n

r e f l u x i n g benzene g i v e s r i s e t o a 40:60 m i x t u r e of ( Z / E ) - e n o l e t h e r ( 4 5 ) i n good y i e l d . Although simple e n o l e t h e r s have been widely s y n t h e s i z e d u s i n g Wittig-type

c h e m i s t r y , a p p l i c a t i o n o f t h i s m e t h o d o l o g y t o more

c o m p l e x e x a m p l e s h a s b e e n l i m i t e d by t h e a v a i l a b i l i t y o f s u i t a b l y functionalized reagents.

Ley a n d L y g o h a v e now d e s c r i b e d a

v e r s a t i l e r o u t e t o s p i r o - a c e t a l s which i n v o l v e s t h e i n t e r m e d i a c y of e n o l e t h e r s g e n e r a t e d by t h e r e a c t i o n o f 2 - d i p h e n y l p h o s p h i n o x y c y c l i c e t h e r s w i t h a l d e h y d e s a n d l a c t o l s ( f o r e x a m p l e , Scheme 32).58

A conceptually related approach t o enol e t h e r s has a l s o

b e e n p u b l i s h e d by t h e r e s e a r c h g r o u p s o f M i o s k o w s k i a n d F a l k . 5 9 P h e n y l v i n y l s u l p h i d e s may b e e f f i c i e n t l y p r e p a r e d by t h e B e t a i n e i n t e r m e d i a t e s of

r e a c t i o n of t h i i r a n e s w i t h b e n z y n e . 6 0

t y p e ( 4 6 ) , g e n e r a t e d i n t h i s way, u n d e r g o a s t e r e o s p e c i f i c rearrangement i n s i t u t o afford the corresponding vinyl sulphides i n good y i e l d (64-90%) (Scheme 3 3 ) .

Kauffman a n d h i s c o - w o r k e r s

h a v e d e v e l o p e d a n a l t e r n a t i v e r o u t e t o t h i s c l a s s o f compound b a s e d on o r g a n o g e r m a n i u m c h e m i s t r y . a d d i t i o n of t h e a - l i t h i a t e d

Thus, f o r example, t h e product of

s p e c i e s (47) t o benzaldehyde undergoes

s e l e c t i v e r i n g - o p e n i n g on t r e a t m e n t w i t h t h i o p h e n o x i d e a n i o n t o give the alcohol (48). anti-elimination

Under t h e i n f l u e n c e o f p e r c h l o r i c a c i d a n

t o t h e corresponding phenylvinyl sulphide takes

p l a c e i n 34% o v e r a l l y i e l d ( S c h e m e 3 4 ) .

A f u r t h e r a p p l i c a t i o n of

t h e Peterson o l e f i n a t i o n r e a c t i o n t o t h e p r e p a r a t i o n of t h e s y n t h e t i c a l l y i m p o r t a n t v i n y l s u l p h o n e s h a s b e e n d e s c r i b e d .62 A number o f d i v e r s e new m e t h o d s f o r 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 were p u b l i s h e d d u r i n g t h e y e a r . arene-substituted

For e x a m p l e , h e t e r o -

v i n y l s i l a n e s s u c h as ( 4 9 ) a n d ( 5 0 ) h a v e b e e n

s y n t h e s i z e d by t h e t w o c o m p l e m e n t a r y r o u t e s o u t l i n e d i n Scheme 3 5 , b o t h o f which r e q u i r e p a l l a d i u m c a t a l y s i s . 63

Similarly substituted a l l y l s i l a n e s c a n b e p r e p a r e d i n a n a n a l o g o u s way. The G r i g n a r d r e a g e n t ( 5 1 ) d e r i v e d f r o m 6-bromo-1-trimethylsilylhex-I-yne s p o n t a n e o u s l y u n d e r g o e s 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 ( S c h e m e 3 6 ) . 64 Both h i g h r e g i o - and s t e r e o - s e l e c t i v i t y

are observed f o r t h i s

p r o c e s s , and s u b s e q u e n t a l k y l a t i o n r e s u l t s i n t h e f o r m a t i o n o f a r a n g e of t r i s u b s t i t u t e d v i n y l s i l a n e s o f t y p e ( 5 2 ) i n e x c e l l e n t

21

1: Saturated and Unsaturated Hydrocarbons

Scheme

Li

I

Ph3GeCHI (471

-

H ph

ii, iii

-

33

p p y H

H"

Ph

iv

#Ph

~

PhS

SPh

GePh3

Reagents : i , PhCHO; ii , PhSNa, MeOH ; iii, H20 ; iv, HCLO, , 20

Scheme 34

O

M

g Br

r B :

81'1.

Qy SiMe3

oBr

d

Si Me3

i 60 */a

Reagent : i, [ PdC12(dppb)l

S c h e m e 35

22

General and Synthetic Methods

Me,Si C

C(CH,), Br

-Me++o BrMg

Me3Si

ti3

CHFCHCH,

(52)

(51) Reagents : i , Mg , Et20 ; ii, CH2=CHCH2 Br

Scheme 36

Si MezPh

a

Reagents: i . PhMe2SiMgMe. Cul; ii,

E

Et

Scheme 37

i , ii

H

OH R e a g e n t s : i , BflLi.

CIP(O)(OEt),

; i i , PhMe,SiMgMe, CuI

S c h e m e 38

23

1: Saturated and Unsaturated Hydrocarbons

yield. A l l e n e s r e a c t w i t h PhMe2SiMgMe, ( P h M e 2 S i ) 2 Z n , o r PhMe2SiA1Et2 i n t h e p r e s e n c e of t r a n s i t i o n - m e t a l c a t a l y s t s t o g i v e m e t a l l a t e d v i n y l s i l a n e s as p r o d u c t s . 65

Subsequent treatment with

e l e c t r o p h i l e s i s o f t e n h i g h l y r e g i o s e l e c t i v e (Scheme 3 7 ) .

Related

r e a c t i o n s e q u e n c e s h a v e b e e n d e v e l o p e d i n d e p e n d e n t l y by O s h i m a a n d h i s c o - w o r k e r s (Scheme 3 8 ) . 6 6

T h e same r e s e a r c h g r o u p h a s a l s o

shown t h a t Bun2Mg.2Et A 1 i s a n e f f e c t i v e r e a g e n t f o r t h e 3 c a r b o a l u m i n a t i o n o f s i l y l a c e t y l e n e s . 67 Good y i e l d s of p h e n y l v i n y l s e l e n i d e s a r e o b t a i n e d on t r e a t m e n t of k e t o n i c hydrazones w i t h p h e n y l s e l e n e n y l bromide i n t h e p r e s e n c e o f a s t r o n g , h i n d e r e d g u a n i d i n e b a s e . 68

Some r e p r e s e n t a t i v e

e x a m p l e s a r e g i v e n i n Scheme 39. Improved c o n d i t i o n s ( a n h y d r o u s c h l o r a m i n e T - m e t h a n o l ) f o r t h e o x i d a t i v e conversion of a l l y l i c s e l e n i d e s i n t o a l l y l i c s u l p h o n a m i d e s , o r i g i n a l l y r e p o r t e d by S h a r p l e s s , h a v e b e e n The u s e o f

d e v e l o p e d by H o p k i n s a n d h i s c o - w o r k e r s ( S c h e m e 4 0 ) .69

m e t h a n o l as s o l v e n t a p p e a r s t o b e a d v a n t a g e o u s , w h i c h s u g g e s t s t h a t r a p i d c l e a v a g e of t h e N-Se bond o f t h e i n t e r m e d i a t e ( 5 3 ) may b e A l e s s h a z a r d o u s m o d i f i c a t i o n h a s b e e n d i s c l o s e d by t h e same a u t h o r s w h i c h i n v o l v e s t h e u s e o f t h e c h l o r o - s o d i o c a r b a m a t e r e a g e n t s ( 5 4 ) a n d ( 5 5 1 , g e n e r a t e d i n s i t u by t r e a t m e n t of t h e In this c o r r e s p o n d i n g c a r b a m a t e s w i t h N - c h l o r o s u c c i n i m i d e . 70 1 7

important.

w a y , a l l y l i c p h e n y l s e l e n i d e s may b e c o n v e r t e d u n d e r m i l d c o n d i t i o n s i n t o a l l y l i c a m i n e s , u s e f u l l y p r o t e c t e d as t h e i r

4-

b u t y l o x y c a r b o n y l (Boc) a n d c a r b o b e n z y l o x y ( C b z ) d e r i v a t i v e s , respectively.

The t h e r m a l 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 o f

a l l y l i c t r i c h l o r o a c e t i m i d a t e s h a s been u s e f u l l y e x p l o i t e d i n a f o u r - s t e p s y n t h e s i s of racemic v i n y l g l y c i n e f r o m t h e r e a d i l y a v a i l a b l e (Z)-but-2-ene-l,4-diol

( S c h e m e 4 1 ) .72

The o v e r a l l y i e l d

f o r t h i s p r o c e s s i s 26%. A new, 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 a l l y 1 a l c o h o l s o r t h e i r d e r i v a t i v e s involves t h e reduction of t h e r e a d i l y prepared

(56) with tri-n-butyltin hydride In contrast t o t h e r e a c t i o n of B - p h e n y l t h i o o r B - p h e n y l s u l p h o n y l b r o m i d e s w i t h tri-n-butyltin r a d i c a l s , t h e reduction proceeds stereoselectively, thereby implicating a concerted elimination process. Artemisia a l c o h o l ( 5 7 1 , w h i c h o c c u r s n a t u r a l l y i n b o t h y-phenylthio-B-nitro-alcohols

( S c h e m e 4 2 ) .73

Ester d e r i v a t i v e s r e a c t s i m i l a r l y .

e n a n t i o m e r i c forms, i s a n u n u s u a l m o n o t e r p e n e d e r i v e d f r o m t w o isoprene u n i t s joined i n non-head-to-tail fashion. A new m e t h o d f o r t h e a s y m m e t r i c s y n t h e s i s o f 3,3-dimethylalk-l-en-4-01~ of t h i s

24

General and Synthetic Methods

0

Reagents : i , N H Z N H Z

ii

SePh

, PhSeBr,

Bu'N=C(NMe2l2

Scheme 39

Reagent

;

i , Chloramine

- T,

MeOH

Scheme 40

25

1: Saturated and Unsaturated Hydrocarbons

Reagents: i , CC13CN, N a ( c a t . ) ; i i ,175-l8OoC; iii, H2Cr207, iv, 6N-HCI

Scheme 4 1

(56) Reagents: i , P h S H , 37.10 HCHO a q . , T M G j i i , ActO; iii, BunjSnH,AIBN(cat.)

Scheme 4 2

@2B

I

(581

(59)

Reagents: i , A C H O , -78 OC; i i , NaOH,H202

Scheme 4 3

26

General and Synthetic Methods

kind, including both enantiomers of (57), has emerged this year from the laboratories of Brown.74 Thus, for example, treatment of 3-methylbut-2-enal with the borane (58) derived from (-)-a-pinene, followed by oxidation of the resultant borinate (59) with alkaline hydrogen peroxide affords (-)-(57) in 85% yield (96% e.e.) (Scheme 43). The structurally related methallyldi-isopinocampheylborane (60) behaves similarly. 75 Silver(1)-mediated cyclization of secondary allenic alcohols takes place with high stereoselectivity to give predominantly cis2,6-disubstituted tetrahydropyrans .76 An application of this methodology to the synthesis of the civet constituent ( 6 1 ) is outlined in Scheme 44. The intramolecular SE2 reaction of racemic allylic silanes with aldehydes as a route to cyclopentenols is known to take place stereoselectively. Application to the enantiospecific synthesis of chiral cyclopentenols, however, is limited by the availability of appropriately substituted chiral substrates. Nakai's group has solved this problem in their synthesis of the chiral homoallylic alcohol (62) by effective use of the Claisen rearrangement shown in Scheme 45.77 On treatment with TiC14, the intermediate allyl silane derived in this way is converted into the alcohol (62) with 98% e.e. The same authors have undertaken a thorough examination of the [ 2 , 3 1 Wittig rearrangement as a means of achieving stereocontrol in acyclic systems .78-8 Related work in this area has also been carried out by Midland and Tsai.82 The chiral ( 2 ) allyl ethers (63)78 and (64)79 serve as useful precursors of an alarm pheromone (65) of the leaf-cutting ant (Atta texana) and 1 ephedrine (66), respectively, both sequences exhibiting high enantio- and erythro-selectivity (Scheme 46). A similar strategy h a s also been applied to the formal total synthesis of ( 2 ) oudemansin.80 Finally, the asymmetric [2,3] Wittig rearrangement shown in Scheme 47 involving a chiral enolate as the migrating terminus is clearly and important development of this methodology. 81 A study of the effects of hydroxyl, protected hydroxyl, and oxyanion substituents on the stereochemistry of the Horner-Wittig reaction has enabled Warren et al. selectively to synthesize either (E)- or ( 2 )-homoallylic and higher alcohols . 8 3 3-Methythioprop-2-enyl p-tolyl sulphone (67) is a convenient synthetic 2-formylethenyl carbanion and dianion equivalent, useful in the preparation of B-monosubstituted and B,B-disubstituted

27

1: Saturated and Unsaturated Hydrocarbons

(61 1

Reagents: i , AgNOg(1-2 equiv.)

Scheme 4 1

I

OH

OH

(R,E)

(R)

ii i

,SiMe3

MeD iv

HO'

Reagents: i , E t M g B r , M q S i C I 100

OCj

ii NaAIH(OCHZCH~OMe)2 iii,CH=CHOEt,Hg(0Ac)2,

iv,TiCIL(l.l t q ~ i v ) , - 7 8 ~ C

Scheme 4 5

Men i,ii

%

O Y e

steps

* MwHYMe HOAPh

Reagents: i , Bu"Li , i i , CsF, MeOH, H20; i i i ,

H2, Ra-Ni;iv, Cr03,H2S04

Scheme 46

General and Synthetic Methods

28

enals, respectively (Scheme 48) .84 Dialkylation occurs regiospecifically at the position adjacent to the sulphonyl group. Subsequent TiC14-assisted hydrolysis, however, leads to mixtures of both and (Z)-isomers elimination of tosic acid. Tsuji and Nagashima have reported on the use of t-butyl perbenzoate as hydrogen acceptor in the palladium-catalysed oxidative coupling of arenes with a,B-unsaturated aldehydes, ketones, and esters. 85 Several new approaches to the synthesis of enones have appeared, including two complementary methods based on a-methylenated acyl anion equivalents. The first of these, reported by Otera and coworkers, involves the use of o-methoxyallyl sulphides of type (68) which are available by Peterson olefination of the corresponding ketones (69) (Scheme 49) .86 Alkylation followed by oxidative deprotection then leads to the formation of enones substituted at the a-position in high overall yield. Alternatively, the lithioderivative (70) undergoes reaction with a wide range of electrophiles, including alkyl halides, ketones, and enones, thus providing access to a-unsubstituted enones .87 The synthesis of the himachalene skeleton is illustrative (Scheme 50). An efficient and flexible process for the homologation of ketones (71) to enones (72) has been developed by the research group of van Leusen (Scheme 5 1 ) . 8 8 The key step in this sequence involves the regiospecific a-alkylation of the derived unsaturated isocyanosulphones (73) which subsequently break down on treatment with mineral acid. Yields are generally good (51-93%). An important application of this methodology to the construction of the pharmacologically important hydroxyacetal side-chain from 170x0-steriods has also been reported. 89 Reductive carbonylation of terminal acetylenes takes place on reaction with aryl iodides and a stoicheiometric amount of Zn-Cu under an atmosphere of carbon monoxide.90 The presence of catalytic amounts of both [PdC12(PPh ) 1 and [Cp2TiC12] is 3 2 essential. Although mixtures of products are generally formed, aryl vinyl ketones usually predominate (Scheme 5 2 ) . Deprotonation of a-silyl ketones with either l-trimethylsilyhexyl-lithium or I-trimethylsilylethyl-lithium in THF is highly regio- and stereo-selective in favour of (E)-enolates directed towards the trimethylsilyl group. A reversal of selectivity is observed, however, when lithium hexamethyldisilazide is used as base. Subsequent condensation with aldehydes occurs readily at low temperatures and with high (E)-selectivity to afford optionally

(El-

I : Saturated and Unsaturated Hydrocarbons

29

+

2

z

2

M

e

78"10e.e. e r y t h r o : threo = 90 :10

\OMe iii,CHZNZ

Reagents: i , BunLi or L D A ; i i , 3 N H2S04

Scheme 47

MeS

w

S0;Tol

SO~TOI

..

MeS

a

(67)

I

1'

iii I i v

Reagents: i , R'X, N a H ; ii, R2X, N a H ; i i i , T i C I 4 , CuCI2,H2O

iv,K2C03; v,TiClb,H$

Scheme 48

OH

(691

I

OMe

I

ii,iii

*-

R1+R2

iv

0

f?'+R"P, OMe

Reagents: i , Me3SiCH2MgCI,0°Cjii, NaH,HMPAj i i i , Bu"Li, HMPA,R2X; i v , [ o l

Scheme 49

30

General and Synthetic Methods

CN Reagents:

i, P l - 1 5 4 , ~HMPA; ~ NMe2

(70)

ii, m-CIC6H4C03H;

iii, A , CaC03

Scheme 50

R

Reagents:

i, TosCHzNC; ii, K O d , $X

; iii, H30'

Scheme 51

Reagents

i, CO, [Pd ( PPh3I2 CIzl. Zn / C u ,[ Cp2TiC12J

Scheme 52

1: Saturated and Unsaturated Hydrocarbons

31

substituted enones, such as sponge constituent (74) (Scheme 53). Carboxylation of trialkylalkynylborates with carbon dioxide under pressure (25 kg cm-2) at 20 OC yields, on work-up, a , B unsaturated carboxylic acids in high yield .92 In an extension of their earlier work on the palladium-catalysed allylation of silyl enol ethers derived from aldehydes and ketones, Tsuji and his co-workers have now applied this chemistry to ketene silyl acetals with similar results.93 When the reaction is carried out in the absence of phosphine ligands, dehydrogenation occurs with the formation of a,B-unsaturated esters (69-79%) (Scheme 5 4 ) . Two Peterson-type approaches to a,B-unsaturated esters exhibiting moderate to high stereoselectivity have also been In the first of these, Larson et al. have examined the condensation of anions derived from a-silylalkanoate esters with aldehydes and ketones as a route to a-alkyl-a,B-unsaturated esters (Scheme 55) .94 Battiste's group has shown that olefination of 2-substituted cyclohexanones with metallotrimethylsilylacetates proceeds with marked -stereoselectivity .95 In contrast, the corresponding Horner-Emmons modification is virtually nonstereoselective except in the case of carvone oxide ( 7 5 ) , which surprisingly gives the (E)-isomer (76) in good yield (Scheme 56). Radicals derived from esters of N-hydroxy-2-thiopyridone may be trapped in situ with 2-ethoxycarbonyl-3-t-butylthioprop-l-ene to give good yields of the corresponding 2-ethoxycarbonylallyl derivatives (Scheme 57). 96 Lewis acid-catalysed cyclization of the adducts (79) produced on treatment of a-methylenated ketones (77) with a-lithio-amethoxymethylallene (78) affords a simple route to highly functionalized cyclopentenones (Scheme 58) .97 Clearly, a variety of substitution on the z - m e t h y l e n e group is tolerated without adversely affecting the yield of the final reduction (56-82%)). Pohmakotr has described a general method for the synthesis of 5substitutedg8 and 5-methylenecyclopent-2-enonesgg y& the intramolecular acylation of appropriately substituted a-sulphinyl carbanions. The synthesis of methylenomycin B shown in Scheme 59 is representative. In an alternative approach, functionalized cyclopentenones are formed as a result of a conjugate additioncycloacylation sequence on hex-2-yne- 1 ,6-dioic esters. l o o Thus, treatment of diesters of type (80) with either lithium dialkylcuprates or copper(1) iodide-Grignard complexes leads

(z)

32

General and Synthetic Methods

, ysiMe3 5%

TH i-iii

0

56%

iv, v 7

0

(74) Reagents: i, Me$XH2MgCI ; i i , H20; iii, [HRh(PPh$4];

L;

iv, Me3Si

v. Pr'CH2CHO

Scheme 53

Reagents:

i, TMSCI, base; ii. -OCo2R4,

P~(OAC)~

Scheme 54

.

I,

T C 0 2 " SiMePh;!

.. II

73'1.

COzEt

80:20 Reagents:

i, LDA,THF;

ii, PhCHO

Scheme 55

(75)

(76) 0

90

II

Reagents : i , (Et 012PCHN o CO 2Et

Scheme 56

10

1: Saturated and Unsaturated Hydrocarbons

33

AcO=

Reagents:

Ds ,

i,

B ~ ~ s / K C O Z E ~

I

ONa

Scheme 57

(77) X = H, Ph, SPh, or OTMS

Reagents:

i, Md)=C=: Li (78)

(791

ii, BF3.0Et2

Scheme 58

0

/Me

0

Me*>

. ...

:;k''Phph

Me

+

S'

Me

0

Reagents: i, ZLDA;

ii, NH4CI; iii. LDA, Me1

Scheme 59

+ Me+ Me

34

General and Synthetic Methods

spontaneously to the formation of cyclized products (Scheme 60). Protonation at low temperature, to give the intermediate ( 8 1 ) , followed by separate treatment with LDA gives higher yields. However, application of this two-step procedure to the unsubstituted ester (82) yields differently substituted cyclopentenones (Scheme 61). Finally in this section, several new metnods for the synthesis of alkylidene lactones and butenolides have been reported. Scheme 62 illustrates a new route to a-methylene-y-butyrolactones developed by Otera et al.’O1 The key step in this sequence is t h e high-yielding thioallylic rearrangement of a-methoxyallyl sulphides which occurs on heating in refluxing hexane in the presence of silica gel. Radical cyclization also appears t o be a useful approach to the synthesis of compounds of this type. Thus, cyclization of radicals derived from the appropriately substituted bromo-acetals (83) or (84) occurs stereoselectively t o give the corresponding tetrahydrofurans (85) and (86), which are then easily converted into a- and B - m e t h y l e n e - y - b u t y r o l a c t o n e s , respectively (Scheme 63).Io2 Bromo-acetals of type (83) are readily prepared by the reaction of butoxyallene with an excess of allylic alcohol in the presence of N-bromosuccinimide. A one-pot procedure for the (E)-selective preparation of spiro-a-ethylidene-y-butyrolactones (87), which involves treatment of the dianion of methyl tiglamide with cycloalkariones, has been reported by Ladlow and Pattenden (Scheme 64).ID3 In another report, sodium salts derived from a formyl-lactones have been shown to react with aldehydes to give mixtures of ( E ) - and (L)-a-alkylidene-y- and 6-lactones in good yield. O4 Utimoto and his co-workers have examined the palladium(I1)catalysed cyclization of 3-, 4 - , and 5-alkynoic acids to but-3-en4-olides1 pent-4-en-4-olides1 and hex-5-en-5-olides1 respectively. I o 5 Similar results have also been obtained in an independent study using yellow mercury(I1) oxide. Io6 The reaction of dianions derived from N-substituted-3-(phenylsulphonyl)propanamides with aldehydes and ketones constitutes a short and versatile approach to 5-alkyl-2(5H)-furanones. I o 7 The application of this method to the synthesis of optically active products using chiral amides further enhances its importance (Scheme 65). Finally, Tanis and Head have made use of the silylfurans ( 8 8 ) and ( 8 9 ) as butenolide anion equivalents. lo’ The derived Grignard reagents couple with alkyl halides to give the corresponding 3 - and

35

1: Saturated and Unsaturated Hydrocarbons

zlCO,,. '

Reagents:

i. m ) z C u L i ; ii, LDA

Scheme 60

0

(82)

Reagents: i, Pr'MgCI, C u l ; ii, LDA

Scheme 61

SPh But Me,Si

6

OMe

Rv

...

111,

iv

t

& + -s R p h '

0

Rcogcnts: i, SiOz, hexanc,

A ; ii. 30% H2SO4 ; iii. CrOg , H#Q, Schema 62

OH acetone;

iv, DBU

General and Synthetic Methods

36

Br Bu0

Reagents: i, ButgSnH, AIBN; ii, Jones oxidation

Scheme 63

.

Reagents: i, 2 BusLi; ii,

.

; iii, H + , A

Scheme 64

j i, ii

PhSOZ

H

‘IY7fiNx PhS@

Reagents: i, 2 BuLi; ii, C8H17CHO; iii, H+

Scheme 65

H

Ph

1: Saturated and Unsaturated Hydrocarbons

37

4-alkylsilylfurans (9. Scheme 66). Subsequent oxidation with peracetic acid then effectively unmasks the latent butenolides, thus providing a general route to 3- and 4-alkyl-2(5H)-furanones.

3 Conjugated 1,3-Dienes The research groups of bill up^'^^ and Staley' l o have independently reported the synthesis of methylenecyclopropene ( 9 0 1 , the simplest cross-conjugated cyclic hydrocarbon (Scheme 67). Characterization of this novel compound both spectroscopically and by means of chemical trapping experiments is possible only at low temperatures. As part of an approach to polycyclic compounds via sequential Diels-Alder reactions, Minami and co-workers have devised a new synthesis of 1,2-bisylidenecyclobutanes, which proceeds in good yield. Thus, treatment of benzaldehyde with the ylide (91 ) , generated in,situ from the phosphonium salt (92) and diethyl lithiophosphonate, leads to the formation of diene (93) in 70% yield (Scheme 68). Cinnamaldehyde reacts in a similar manner (43%). l,l-Diphenyl-4,4-bis(trifluoromethyl)butatriene undergoes a concerted thermal [ n2s + x2s] cycloaddition reaction with 1 , l dimethoxyethylene at 100-110 OC to produce the structurally related 1,2-bismethylenecyclobutane (95). Enamines such as (96 ) react in the same way even at temperatures as low as 20-100 O C (Scheme 69). The reaction of aromatic five-membered heterocycles with Grignard reagents, in the presence of nickel catalysts such as 1,3bis-(dipheny1phosphino)propanenickel dichloride, has proved to be a Although (z,Z)-buta- 1 ,3-dienes tend useful route to 1,3-dienes. to be formed preferentially the stereochemical outcome of the reaction is sometimes dependent on the nature of the Grignard reagent (3. Scheme 70). The allyltitanium species (97), prepared by sequential treatment of t-butyl-3-trimethylsilylprop-I-enyl sulphide (98) with t-butyllithium and titanium tetra-isopropoxide, undergoes condensation with aldehydes at -78 OC. l 5 Subsequent substitution of the t-butyl sulphide group takes place on treatment with Grignard reagents in the presence of a nickel catalyst to afford (E,Z)dienes, as illustrated in the synthesis of spilanthol (99), an insecticidal natural product isolated from Spilanthes oleranceae (Scheme 71). The development of several new synthons for terminal 1,3-dienes

'

38

General and Synthetic Methods

Reagents: i, Mg,THF;

ii,;'B -r

iii, MeC03H

Scheme 66

Reagents: i, K0But, ChromosorbW, RT, 20-30 mtorr; ii, KOBut,THF, -40

OC,

0.50 torr

Scheme 67

0

(91)

(92) 0 II Reagents: i, (EtO+PLi;

ii, PhCHO

Scheme 6%

Ph

">

RZ

- YC Ph

A

(94) R' = R 2 = OMe (96) R' = R Z = NMe, Scheme 69

\

R'

RZ

(95)

1: Saturated and Unsaturated Hydrocarbons

39

Bun

Ph Reagents: i, Bun MgBr. 1 , 3 -bis(diphenylphosphino)propanenickel dichloride;

ii, PhMgBr, bis(tripheny1phosphino) nickel dichloride

Scheme 70

ButS,p,SiMel

ButMe2Si0 ~

X

SBU'

(98) X = H

ii - v

(97) X = Ti(OR)3

\

CONHBu'

( 99)

ii. MeMg1, Ni(cat.1; iii, B g 4 N F ; iv, (COC1)2, DMSO, Et3N;

Reagents: i, ButMe2SiO-CHO; V,

PhjP=CHCONHBu'

Scheme 71 ..

..

II,III

Ph

%S -

i Me3

+

SiMe, /

OSiMe3

Reagents: i ,

P h w M g C I ; ii, H2, Lindlar; iii, SnC14;

iv,

(5 (102)

Scheme 72

Ph

/ -

40

General and Synthetic Methods

has been reported this year. Clive and Angoh, for example, have examined the vinylogous counterpart of the well known fragmentation of 8-hydroxysilanes (Scheme 72). l 6 Thus, the aldehyde ( 100), readily prepared from propargylsilane, reacts with Grignard reagents such as (101) or silyl enol ethers (102) to give the corresponding propargyl alcohols. Subsequent semi-hydrogenation over Lindlar catalyst, followed by treatment with SnCl,,, leads stereospecifically to (E)-1,3-dienes in good yields. An alternative approach to compounds of this type is provided by the work of Shechter and Hsiao, who have used (E)- and benzenesulphonyl-4-trimethylsilylbut-2-ene as a general (El-l-buta1,3-dienyl synthon.’I7 The application o f this method to a highly stereoselective synthesis of (E)-dodeca-9,11-dien-l-y1 acetate (103), a sex pheromone of the red bollworm moth, is illustrated in Scheme 73. Regiospecific alkylation at the 2-position of 2,5dihydro-3-methylthiophene 1,l-dioxide (104), followed by Lhermal extrusion of sulphur dioxide, forms the basis of a useful method for stereoselective introduction of a terminal isoprene unit (Scheme 74). l8 Similarly , 3-acetyl-2,5-dihydrothiophene 1 , I dioxide (105) has been shown to be a stable precursor of 2acetylbuta-l13-diene (106), a useful synthetic building block (Scheme 75). 119 In a continuation of their work on the synthesis of 1,3-dienes via the vinylogous Rambert-Backlund reaction of a,@-unsaturated bromomethylsulphones, Block and co-workers have observed good regioselectivity in the y-deprotonation of unsymmetrical substrates (Scheme 76). In the case of the (L)-isomer ( 1 0 7 ) , the regioselectivity may be reversed on changing the base from potassium to lithium t-butoxide, possibly as a result of Mild complexation of the lithium cation by the sulphonyl group conditions for the synthesis of 1,3-dienes via the palladiumcatalysed coupling o f enol triflates with a variety of functionalized olefins have been reported by Ortar et al. (Scheme 77). 12’ Similar methodology involving the coupling of enol triflates with organostannanes in the presence of [Pd(PPh ) 1 and 3 4 lithium chloride has been applied to a short stereospecific synthesis of pleraplysillin-I ( 108) (Scheme 78). 122 The palladium(0)-catalysed reaction of vinyl halides with allenes in the presence of sodium ethyl malonate leads to functionalized dienes, such as (log), in good yields (Scheme 79). 123 Aryl halides react similarly to afford styrenes. In

(z)-l-

1: Saturated and Unsaturated Hydrocarbons

41

M

e

3

/

SO2Ph

S

i

Br

3

S02Ph

Reagents: i, Br(CH2)8Br, HMPA, BuLi; ii, Bun4NF, 0 O C ;

iii, NaOAc, DMF, 120 “c

Scheme 73

Reagents: i, LiN(SiMeg)z,THF; i i ,

wB , r , A. ”‘ 111

Scheme 74

(106 1

(105) Scheme 75 S02CH2Br i. ____)

R

R

6 BrcH2sh II

R

R

(107 1

Reagents.

I,

KOBU’, ii, LiOBut

Scheme 76

42

General and Synthetic Methods

Reagents; i, P C O z M e , Pd(OAc12, W h 3 , Et3N

Scheme 77

i=/'"""'

LiCy

Reagents: i,

'''Q

, [Pd(PPh3I4], LiCl

Scheme 78

Scheme 79

TT -

Et02C

C02Et

Reagents: i, [RhCI(PPh3)3];

Et:x2E EtoP l i

ii, [Pd(PPh3)4]

Scheme 80

1: Saturated and Unsaturated Hydrocarbons

43

certain cases, stereoselectivity can be high. Smooth deoxygenation of 1,4-endoperoxides to 1,3-dienes occurs readily on treatment with low-valent titanium at room temperature. 124 Under the influence of palladium o r rhodium catalysts, 2-bromo1,6-dienes cyclize to give mixtures of conjugated five-membered bis-exocyclic dienes and six-membered mono-exocyclic dienes. 125 In contrast, 2-bromo-1,7-dienes cyclize regiospecifically to give sixmembered rings only. The selectivity appears to be strongly dependent on reaction conditions. Thus, in the case of diene (IIO), 5-exo-trig cyclization predominates when the reaction is carried out in the presence of [RhCl(PPh ) 1 , whereas [Pd(PPh3)4] 3 3 favours the formation of the 6-endo-trig product (Scheme 80). Diynes of type ( 1 1 1 ) undergo a unique stereoselective cyclization at -20 O C on treatment with d i c y c l o p e n t a d i e n y l t i t a n i u m dichloridem e t h y l d i p h e n y l p h o s p h i n e - s o d i u m amalgam (molar ratio 1:1:2) to afford on hydrolysis (E,E)-exocyclic dienes (112) in good yields (Scheme 81).126 The reaction works well for five-, six- and sevenmembered rings, but fails for eight-membered rings and for substrates containing terminal acetylene functions. Both 2,3-bis(trimethylstannyl)buta-l,3-diene (113) and the bis(trimethylstanny1)acetylene (114) have proved to be useful as synthetic equivalents of the 2,3-dianion of buta- 1 ,3-diene. 27 Thus, step-wise lithiation of (113) followed by reaction with electrophiles, o r electrophilic substitution of (114), permits the synthesis of a wide range of both symmetrical and unsymmetrical 2,3-disubstituted buta-1,3-dienes (Scheme 82). Sternbach's group has studied the reaction of fulvenes with various nucleophiles as a means of preparing substituted cyclopentadienes required as intramolecular Diels-Alder precursors (Scheme 83). 128 2-Fluorodienes can be readily prepared from 2-fluoroalk-2-enals using standard Wittig methodology. 12' Although product isomer ratios are similar to those observed with the corresponding nonfluorinated substrates, the observed reaction rates appear to be significantly retarded. An alternative entry to compounds of this type involves the concerted fragmentation of I-chloro-I-fluoro-2(trimethylsilyl)methylcyclopropanes. This reaction occurs smoothly on heating to 130-140 OC in diethylene glycol dimethyl ether in the presence of tetrabutylammonium fluoride o r chloride (Scheme 84). 30 B-Alk-l-enyl-9-borabicyclo~3.3.llnonanes undergo a highly stereoselective conjugate addition-elimination sequence on treatment with 4-methoxybut-3-en-2-one (115) at room temperature to

44

General and Synthetic Methods

Reagents: i , [CpzTiCIz], MePPhZ, Na/Hg

Scheme 01 SnMe:, Me3Sn

X

Me3Sn

Y

Ill

(113 1

'%Me3

(114) Scheme 82

Reagents: i,

0 I

EtZNH; ii, DIGAL, iii, LiAlHL

Scheme 83

ie

SiMe,

CI

I

Me

Reagents: i, Bu"~NF, 130

OC

Scheme 84

M

p

O A (115)

~

Scheme 85

45

1: Saturated and Unsaturated Hydrocarbons

furnish the corresponding (E,E)-dienes in quantitative yield. The preparation of (E1E)-trideca-3,5-dien-2-one (116) is illustrative (Scheme 8 5 ) . 1 3 ’ The availability of both enantiomers of the tricarbonyliron complex (117) in optically active form permits the synthesis of various functionalized (E1E)-1,4-diene complexes of known absolute configuration and with high optical purity ( > 9 5 % e.e). 1327133 Final decomplexation to unmask the free dienes is simply carried out by treatment with ceric ammonium nitrate in methanol at -15 O C . The palladium-catalysed amination of the phosphonate (118) followed by condensation with aldehydes and ketones affords a general route to the 5-aminopenta-Il3-diene moiety, a structural feature present in several naturally occurring compounds (Scheme 86).134 Although overall yields are good, mixtures of <2E14E)-and (2E14Z)-products are usually obtained in ratios of 2.5-3:l. Luengo and Koreeda have developed a highly stereoselective synthesis of both ( & ) - and (Z)-l-alkoxybuta-Il3-dienes which proceeds the syn- and anti-dehydrative decarboxylation of the readily separable erythro- and threo-hydroxy-acids (119) and (1201, respectively (Scheme 8 7 ) . 13* A facile route to the synthetically useful I-phosphoryl- and l-sulphonyl-1,3-dienes has been reported. 136 Finally, Danishefsky’s group has disclosed a synthesis of l-alkoxy-3-~(trimethylsilyl)oxy]buta-l13-dienes via the vinylogous transesterification process illustrated in Scheme 88.137 Dienes of this type, bearing chiral auxilliaries, are of particular interest since they may offer useful diastereofacial selectivity on reaction with dienophiles. 4 Non-coniuaated Dienes Several important new methods and modifications for the preparation of non-conjugated dienes have appeared during the year. The allylmetallation of alkynes, although potentially useful, has enjoyed limited success as a general route to 1,4-dienes1 mainly because of the occurrence of unwanted side reactions. Negishi and Miller have now reported that allyl- and benzyl-alanes react cleanly and efficiently with alkynes (but not I-silyl-I-alkynes) in the presence of catalytic amounts of [C12ZrCp 1 to give exclusively

”’

products of cis-carboalumination (Scheme 89). Generally , mixtures 75:25) of the two possible regioisomers are obtained. Subsequent treatment of the product mixture with 0 . 6 - 0 . 7

(z.

46

General and Synthetic Methods

Reagents: i, RzNH, lPd(PPt1~)~1. (cat . ) ; ii, KDA; iii, R1CHO

Scheme 06

C02R2

R3

. .. I, I I

___)

' HO"

G

R3R

4

R' 0

(119)

. ..

R'O

R3

I , II

__j

(120) Reagents: i, PhSOZCI, Py, 0

OC;

ii, 10

"C; iii, DMF, dineopentyl acetal, 0 "C Scheme 87

1: Saturated and Unsaturated Hydrocarbons

47

Me

Me

Aco?Me 0 TMSO Reagents: i, I-phenmenthol, PyTsOH: ii, TMSOTf, Et3N

Scheme 06

R’

+

Reagents: i ,

2 ; [ClzZrCp~I ( cat)

Scheme 89

Y

Y

LBr Y = COzR

(121) (122)

Y = PO(0R)z

(123)

Y = SiMe3

Reagents: i, Zn. THF, 4 5 - 50

OC,

(124)

ultrasound

Scheme 90

R’

R’

(125) (126) Scheme 91

48

General and Synthetic Methods

equivalents of iodine leads selectively to the formation of the isomerically pure I-iodopenta-l14-diene derivative in high overall yield (50-70%). Bromo-esters (121), phosphonates (122), and silanes (123) add regioselectively to terminal alkynes on treatment with zinc in THF at 45-50 OC to afford functionalized dienes of type (124), some of which are versatile heterocyclic precursors (Scheme 90). 39 40 The use of ultrasound appears to be beneficial. Jousseaume has shown that the acetylenic tin derivatives (125; R4 = C02Me or CN) undergo a [4+2] cycloaddition reaction with 1,3-dienes at 120 OC to give good yields of the novel tin-substituted cyclohexa-l,4-dienes The regioselectivity is essentially the same ( 126) (Scheme 9 1 ) . l 4 as that observed for methyl propiolate, thus indicating that the presence of the tributyltin group has little effect on the orientation of the cycloaddition.

A re-examination of the anodic oxidation of p-xylene in methanol-sodium methoxide has revealed the co-formation of the isomeric 3,6-dimethoxy-3,6-dimethylcyclohexa-1,4-dienes (127) and ( 1 2 8 ) (ratio 3:l) in 21% combined yield (Scheme 92).142 Unsymmetrically substituted (allyl)(allyl')palladium(II) complexes may be formed by the selective cross-coupling of (ally1)palladium chlorides with an allylic Grignard reagent in the presence of dioxane (Scheme 93). 143 Subsequent treatment with maleic anhydride leads via a reductive elimination process to 1,5dienes in which 'head-to-head' coupling predominates. Gassman and Singleton have studied the dimerization of 2,4-dimethylpenta-l,3diene (129) in an attempt to distinguish between aminium cation radical and protic acid catalysed Diels-Alder reactions (Scheme 94). 144 Under the influence o f tris(p-bromopheny1)aminium hexachloroantimonate alone, the diene (129) dimerizes to give the same product (130) as the acid-catalysed reaction. However, the additional presence of base leads to the formation of a new dimer (131), which is presumably formed solely via a cation radical mediated process. Electrochemical reduction of ally1 and benzyl bromides in the presence of [Cu(acac),l leads to improved yields of the corresponding coupled products. 145 The yields for the corresponding chlorides and iodides, however, are unaffected. Yamamoto et al. have shown that allyltrialkylstannanes undergo regioselective 'head-to-tail' coupling with allylic halides at room temperature when subjected to high pressures ( 10 kbar) . 146

1: Saturated and Unsaturated Hydrocarbons

-

49

Me?

-e

21 .I0

Q

Me Me

Me

Me

+

Q /

OMe Me OMe (128)

(127) Scheme 92

R = A c or SiMezBu'

Scheme 93

Reagents: i, Ar3vSbClG-,

-23 "C; ii, HBr; iii Ar3+"SbCl{,

Scheme 94

OMe

a, +25 "C

50

General and Synthetic Methods

Allyltrimethylsilanes react slowly at room temperature with Y alkenyl-7-butyrolactones and trimethyloxonium tetrafluoroborate to afford methyl (E)-alka-4,8-dienoates in high yield. 147 Both regioand stereo-selectivity are high, as illustrated by the synthesis of 8-sinensal (132), a component of a Chinese orange oil. In the case of (Z)-hex-4-enolide1 ring-opening takes place without allylic rearrangement to furnish methyl (Z)-nona-4,8-dienoate exclusively in 87% yield (Scheme 95). 5 Allenic Hydrocarbons Few methods exist f o r allene synthesis which involve the direct coupling of propargyl alcohols with organometallic reagents. Frequently, prior activation of the alcohol function is necessary, thereby adding extra isolation and purification steps into the synthesis. A versatile one-pot sequence has now been introduced which proceeds the intermediacy of the iminium species (1331, formed in situ by treatment of a propargyl alcohol with the reagent (134) (Scheme 96). The reaction works well for primary, secondary, and tertiary alkyl, as well as aryl Grignard reagents, and is highly chemo- and enantio-selective. Although yields are generally good, further improvements can be achieved by the addition of copper(1) iodide and H M P A . Corey and Boaz have developed a stereospecific synthesis of chiral 1,3-disubstituted bromoallenes. Thus, treatment of suitably substituted optically active propargyl alcohols with thionyl bromide, in the presence of propylene oxide leads, via an SN i f rearrangement of the intermediate bromosulphinate, to bromoallenes without loss of optical purity (Scheme 97). A number of functionalized allenes have been prepared by the retro-Diels-Alder cleavage of the corresponding anthracene adducts (e.g.Scheme 98). I5O 15’ Flash vacuum pyrolysis thus permits the synthesis of sensitive allenes, which can be isolated and characterized only at very low temperatures. l-Bromoalkynes (135) or 1,l-dibromoalkenes (136) bearing a single aromatic substituent react with two or three equivalents, respectively, of methylenetriphenylphosphorane to afford ylides of type (137) (Scheme 99). 152 Subsequent hydrolysis leads to the formation of monosubstituted allenes (138) in moderate overall yield (43-70%). The research groups of Yamada and Yoshida have shown that a wide variety of propargyl thionophosphates undergo a novel [3,31 sigmatropic

1: Saturated and Unsaturated Hydrocarbons

51

.1

ii, i i i

0 OMe

Scheme 95

(133)

+a CI

Reagents: i ,

(134) ; i i , R3MgX, CUI

Scheme 96

Reagents : i, SOBrZ,

Scheme 97

General and Synthetic Methods

52

CHO R e a g e n t s : i , CHz=CHMgCI;

i i , H20; iii,PCC; i v , 7OO0C

torr

Scheme 98

(135)

RL(Br Br

R e a g e n t s : i , 2 Ph3P=CH2

; i i , 3 Ph,P=CHzj

H20

Scheme 99 Si Et,

II C

II

cty

+

"*3

"(y

I

I

(139)

I

1

( 14 0 )

,

Reagents: i T i C I 4 ,

Ax Scheme 100

87 : 13

1: Saturated and Unsaturated Hydrocarbons

53

rearrangement under t h e i n f l u e n c e of p a l l a d i u m ( I 1 ) c a t a l y s i s t o afford allenyl thiolophosphates,

s p e c i f i c a l l y and i n h i g h y i e l d . 153

J o h n s o n ' s g r o u p a t S t a n f o r d c o n t i n u e s t o champion t h e u s e o f c h i r a l

acetal t e m p l a t e s i n asymmetric s y n t h e s i s .

Scheme 100 f e a t u r e s t h e

conversion of t h e o p t i c a l l y a c t i v e acetal (139) i n t o t h e a l l e n i c i n t e r m e d i a t e ( I 4 0 ) , a key s t e p i n t h e i r s t e r e o s e l e c t i v e a p p r o a c h t o m e d i c i n a l l y i m p o r t a n t V i t a m i n D m e t a b o l i t e s . 154 S e v e r a l e x a m p l e s o f s y n t h e t i c r o u t e s t o a l l e n e s c o n t a i n i n g aamino-acids have been p u b l i s h e d t h i s y e a r .

Many o f t h e s e compounds

h a v e b e e n shown t o p o s s e s s i n t e r e s t i n g b i o l o g i c a l a c t i v i t y .

Krantz

and h i s c o - w o r k e r s , 1 5 5 and i n d e p e n d e n t l y t h e g r o u p of Casara, 1 5 6 h a v e f u r t h e r d e v e l o p e d c o n d i t i o n s f o r t h e known c o n v e r s i o n of abenzamidopropargylic esters (141) t o a-allenic-a-amino-acids t h e i n t e r m e d i a t e 4 - a l l e n i c o x a z o l o n e s ( 1 4 2 ) (Scheme 1 0 1 ) . a u t h o r s h a v e a l s o made u s e o f a n o v e l aza-Cope

2 The same

rearrangement of

t h e a c y l i m i n i u m i o n ( 1 4 3 ) i n t h e s y n t h e s i s of y - a l l e n i c G A B A a n d r e l a t e d a n a l o g u e s (Scheme 1 0 2 ) . 157

A f u r t h e r a p p r o a c h t o compounds

o f t h i s t y p e i n v o l v i n g r e a c t i o n o f propargyltrimethylsilane w i t h wethoxylactams under t h e i n f l u e n c e of boron t r i f l u o r i d e e t h e r a t e h a s b e e n r e p o r t e d by H i e m s t r a e t a l . (Scheme F i n a l l y , a new a l l e n e t r a n s f e r r e a g e n t ( 1 4 4 ) h a s b e e n d e v e l o p e d by B a l d w i n e t a l . , w h i c h i s g e n e r a l l y a p p l i c a b l e t o t h e s y n t h e s i s o f m o n o s u b s t i t u t e d t e r m i n a l a l l e n e s . 15'

Standard protecting groups

a p p e a r t o be c o m p a t i b l e w i t h t h e m i l d c o n d i t i o n s o f t h e r e a c t i o n . The s t e r e o d e f i n e d s y n t h e s i s o f t h e u n u s u a l n a t u r a l l y o c c u r r i n g 2-aminohexa-4,5-dienoic

(5)-

a c i d ( 1 4 5 ) i s i l l u s t r a t i v e o f t h e method

(Scheme 1 0 4 ) .

6 Acetylenic Hydrocarbons D e p h o s p h o r y l a t i o n of (~)-lH-F-I-alkene-l-phosphonates ( 1 4 6 ) o c c u r s s m o o t h l y on t r e a t m e n t w i t h c a t a l y t i c a m o u n t s o f t e t r a b u t y l a m m o n i u m fluoride at 0 105).

OC

t o give terminal F-alkylacetylenes

( 1 4 7 ) (Scheme

T h i s is c l e a r l y an a t t r a c t i v e e n t r y i n t o t h i s e l u s i v e

c l a s s of compounds, s i n c e t h e s t a r t i n g p h o s p h o n a t e s ( 1 4 6 ) c a n b e o b t a i n e d i n two s t e p s from t h e r e a d i l y a v a i l a b l e a c i d c h l o r i d e s (148).

C o m a s s e t t o ' s g r o u p h a s examined t h e p y r o l y s i s of a - a c y l - a -

t h i o p h o s p h o r a n e s as a g e n e r a l r o u t e t o t h i o a l k y n e s , u s e f u l p r e c u r s o r s of b o t h t e r m i n a l a n d a l k y l d i s u b s t i t u t e d a l k y n e s (Scheme 1 0 6 ) . 1 6 1 The method h a s a l s o 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 t h e a n a l o g o u s s e l e n o a l k y n e s , b u t a p p e a r s t o be l i m i t e d i n t h i s case t o

General and Synthetic Methods

54

R2 NHCOPh

0 Ph

(141 1

(142) R2

I

R e a g e n t s : i , PPh3 , C C I 4 , Et3N; i i , MeOH,Et3N; i i i , E t j b B F 4 ; i v , l O 0 L H O A c j v,1.0N

,

NaOH MeOH

S c h e m e 101

IfR'

C

i i , iii

4

R e a g e n t s : i, H C O Z H j ii. H30*; iii, 20.1. HC1,80 'C

S c h e m e 102

-

1: Saturated and Unsaturated Hydrocarbons

&.

55

0

I

OEt

qc

+

c0,-

S i Me3

, BFj.OEt2

Reagents: i ,

i ii,

HCI, H20

Scheme 103

(145) Reagents:

A I,*

SnPh3(144),AIBNj i i , T F A , a n i s o l e

Scheme 104

R f C F 2 C O C I D-,

Rf

i, ii

HHfi0 ...

Ill

___j)

( 1 48 1

/p\

EtO

Rf-E-H (147)

OEt

R e a g e n t s : i, P(OEtI3 ii, B u L i , C u l ; iii, B u ~ N F ,0°C

Scheme 105

PPh, ‘SMe

0 Scheme 106

56

General and Synthetic Methods

p r o d u c t s b e a r i n g a r y l or e l e c t r o n - w i t h d r a w i n g s u b s t i t u t e n t s . 1 6 2 Lithium e t h y l o r t h o p r o p i o l a t e (149) h a s been i n t r o d u c e d as a convenient p r o p i o l a t e a n i o n e q u i v a l e n t . 163

The r e a g e n t

,

which can

be o b t a i n e d f r o m t h e p r o d u c t formed between t r i m e t h y l s i l y a c e t y l e n e and triethoxycarbenium t e t r a f l u o r o b o r a t e , butyl-lithium,

by t r e a t m e n t w i t h n-

reacts r e a d i l y w i t h a l d e h y d e s and k e t o n e s a t 0

OC.

Reaction w i t h a l k y l h a l i d e s , however, r e q u i r e s t h e p r e s e n c e of TMEDA or HMPT.

T r e a t m e n t o f p r o p a r g y l b r o m i d e w i t h two e q u i v a l e n t s

of lithium hexamethyldisilazide leads t o t h e formation of lithium

N,N-bis(trimethylsily1)aminomethylacetylide various electrophiles,

( 1 5 0 ) which r e a c t s w i t h

i n c l u d i n g a l k y l h a l i d e s and carbonyl

compounds, t o g i v e t h e c o r r e s p o n d i n g f u n c t i o n a l p r o t e c t e d 164 propargylic primary amines. The u s e o f b o r o n t r i f l u o r i d e e t h e r a t e t o m o d i f y t h e r e a c t i v i t y of a c e t y l i d e s i s an important r e c e n t development i n a c e t y l e n e chemistry.

On t h e b a s i s o f s p e c t r o s c o p i c s t u d i e s u s i n g I I B n . m . r . ,

Brown e t a l . h a v e now c o n c l u d e d t h a t t h e i n i t i a l p r o d u c t o f r e a c t i o n of l i t h i u m a c e t y l i d e s w i t h boron t r i f l u o r i d e e t h e r a t e is p r o b a b l y t h e l i t h i u m t r i f l u o r o b o r a t e complex ( 1 5 1 ) and n o t t h e t r i v a l e n t b o r o n s p e c i e s ( 1 5 2 ) p o s t u l a t e d e a r l i e r . 1 6 5 T h e same a u t h o r s h a v e a l s o shown t h a t t r e a t m e n t o f t h i s c o m b i n a t i o n of r e a g e n t s w i t h c a r b o x y l i c a n h y d r i d e s a t -78 OC g i v e s a , 6 - a c e t y l e n i c k e t o n e s i n good y i e l d ( 7 1 - 8 2 % ) .

Similarly, epoxy-alcohols derived

from ( E ) - a l l . y l i c a l c o h o l s r e a c t t o g i v e predominantly e r y t h r o a c e t y l e n i c I l 2 - d i o l s (153) a r i s i n g from p r e f e r e n t i a l a t t a c k a t t h e C-I

p o s i t i o n (Scheme 1 0 7 ) .

The r e g i o s e l e c t i v i t y i s p o o r ,

however, f o r epoxides d e r i v e d from t h e c o r r e s p o n d i n g ( L ) - a l l y l i c alcohols.

Akiba and co-workers

h a v e a l s o f o u n d t h a t b e t w e e n -78

OC

a n d room t e m p e r a t u r e a l k y n y l b o r a t e s o f t y p e ( 1 5 1 ) a d d s m o o t h l y t o a l d i m i n e s b e a r i n g a c i d i c a-hydrogens t o a f f o r d secondary p r o p a r g y l a m i n e s (Scheme 1 0 8 ) . 167

By way o f c o n t r a s t , n o a d d i t i o n

takes place with t h e corresponding lithium species. T r i m e t h y l g a l l i u m i s a n e f f e c t i v e c a t a l y s t (8-16 mol%) f o r t h e r i n g o p e n i n g o f e p o x i d e s by l - l i t h i o - l - a l k y n e s

(Scheme 1 0 9 ) . 168

The

r e a c t i o n proceeds under mild c o n d i t i o n s a t t a c k a t t h e less s u b s t i t u t e d carbon atom, and e p o x i d e t o k e t o n e i s o m e r i z a t i o n i s n o t observed. Higher r e g i o - and d i a s t e r e o - s e l e c t i v i t y

have been observed f o r

t h e r e a c t i o n b e t w e e n a l d e h y d e s a n d a l l e n i c z i n c r e a g e n t s t h a n for t h e c o r r e s p o n d i n g a l a n a t e s . 16'

threo-Homopropargylic

a l c o h o l s are

t h u s p r o d u c e d i n good y i e l d h a v i n g d i a s t e r e o m e r i c p u r i t i e s o f

1 : Saturated and Unsaturated Hydrocarbons

57

OEt

(149)

(150)

L i l RCSC-BF,

3

(151)

OH

-

n C10ti21+@

I

57%

*

OH (153)

i-iii

R--Reagents: i , BunLi

I____)

i i , B F 3 * 0 E t Z i iii , R ’ ~ N / ~ ’

Scheme 108

OH

Reagents : i ,

-

M q G a , 0°C

j

ii, M q S i -

‘Li,

S c h e m e 109

-Li

,Me3Ga, reflux

58

General and Synthetic Methods

96-99y0. Similarly, allenic silanes undergo reaction with aliphatic imines to give exclusively threo-adducts (Scheme 110). I7O Aromatic imines, however, exhibit poor selectivity.

7 Enynes and Diynes (El-Alkenyldialkylboranes, prepared by sequential treatment of 1 iodo-I-alkynes with dialkylboranes and Grignard reagents, successfully cross-couple with I-bromo-I-alkynes to afford isomerically pure conjugated enynes in good overall yield (Scheme I I I 1 . l7 The presence of catalytic amounts of alkaline [Cu(acac)2] is essential; alkaline [Pd(PPh ) 1 is ineffective. Ally1 bromides 3 4 undergo an analogous reaction to give 1,4-dienes as products. The combination [ ( q5-C Me ) TiCl2I -PriMgBr has been shown to be a highly 5 5 2 effective catalyst ( 2 m o l % ) for the linear dimerization of I-alkynes to give 2,4-disubstituted but-I-en-3-ynes (154) (Scheme The reaction proceeds under mild conditions and with a high degree of regioselectivity. Furthermore, by-product formation is negligible. The co-dimerization of I-alkynes is also possible under these conditions, but the regioselectivity of the process is dependent on the nature of the alkyne substituents. Another convenient synthesis of alk-I-en-3-ynes based on the chemistry of l-methoxybuta-1,2,3-trienyltrialkylborates (155) has been developed by Suzuki and co-workers (Schem-e 113).173 On warming to room temperature, species of this type rearrange to give the corresponding cumulenic borates (156). Subsequent protonation, o r treatment with aldehydes, leads to the formation in good yield of alk-I-en-3-ynes and ynols, respectively. Scheme 114 illustrates a novel approach to enynes the alkynyl sulphenylation of olefins. 174 Thus, the epi-sulphonium salt intermediate formed initially on treatment of cyclohexene with dimethyl(methy1thio)sulphonium tetrafluoroborate (157) undergoes ring-opening on reaction with the alkynylalanate to give exclusively the transproduct (158). Final elimination % either oxidation or alkylation of sulphur then furnishes the corresponding enyne (159). This sequence works well for mono-, di-, and tri-substituted olefins, and furthermore initial anti-Markovnikov addition is always observed. Holmes and co-workers have synthesized four diastereomeric ( ? ) trans-maneonenes and thereby established unambiguously that the naturally occurring trans-maneonene-B has the relative

1: Saturated and Unsaturated Hydrocarbons

M

= Ti(OPr'Ij,

59

L i , or AIEt3

Scheme 110

Reagents: i , R ~ B H j i i , P r M g X i i i i , B r - ~ - B u n , [ C u ( a c a c ) g I , H O -

Scheme 111

R

Reagents : i I [(

3'-

C + i e g ) 2 T i C I z l , Pr MgBr, 3 0 "C

Scheme 112

R-=
-4

">c=,=

iv

R2B 'OMe Reagents:

t ,

ZBuLi,-45'Cjii,

R3B,-78'Cjiii,

RT, i v , E*

Scheme 113

liii (156)

General and Synthetic Methods

60

Scheme 114

OH

OH (162) Reagents: i , TsOH

(163) ii, P C C

Scheme 115

'X

(R)-(166)

( 1 6 5 ) X = H , S i M e 3 , or Me Reagents: i

, BuLi

,

i,i H2, R a - N i , EtOH

Scheme 116

(164)

1: Saturated and Unsaturated Hydrocarbons

61

configuration at C-5 as depicted in structure (161).175 A key step in the synthesis is the (E)-selective LAH reduction of the diastereomeric diynols (160). The stereoselective reduction of diynols to (E)-enynols can also be carried out under mild conditions via DIBAH reduction of the corresponding lithium alkoxides at -78 O C . 176 Aerssens and Brandsma have examined the reduction of a wide range of both conjugated and non-conjugated triple bonds with activated zinc powder in absolute In the former case, (Z)-enynes are produced selectively and in greater than 70% isolated yields. Moreover, the reduction of heterosubstituted diynes is regiospecific, the triple bond nearest to the substituent being reduced preferentially. BicycloC7.1.0ldec-3-yn2-01 (162) rearranges under acid catalysis to afford cyclodec-3-en5-ynol (163) which has been oxidized to the corresponding ketone (164) with PCC (Scheme 115).178 The [ 2 , 3 ] Wittig rearrangement of enantiomerically enriched a-methylallyl propargyl ethers of type (165) to give the corresponding enynes (166) takes place with high (95-98%) (Elselectivity and a high degree (=.90%) of 1,4-chirality transfer (Scheme 116). Finally, (~)-l-iodo-2-chloroethylene reacts cleanly with alkynylzincs in the presence of 1-5 mol% [Pd(PPh ) 1 3 4 to afford I-chlorobut-I-en-3-yne derivatives in high yield (Scheme 117). I 8 O Subsequent treatment with sodamide in liquid ammonia generates the corresponding l-sodio-1,3-diynes which can then be quenched with various electrophiles.

8 Polvenes Several unusual polyenes of theoretical interest have been characterized during the year. F o r example, Sugihara et al. have succeeded in preparing both tetracycloC5.3.0.0.0ldeca-6,8,lO-triene (azulvalene) (167) and tricyclo~5.3.0.0]deca-3,6,8,lO-tetraene ('Dewar azulene') (168). 1 8 ' Both compounds readily isomerize to azulene on either thermolysis o r photoysis. Perfluorobicyclo~4.2.0~octa-2,4,7-triene (169), the bicyclic valence isomer of p e r f l u o r o c y c l o - o c t a t e t r a e n e (1701, has also recently succumbed to synthesis. 182 Surprisingly, the half-life ( 1 4 min at 0 O C ) for valence isomerization of (169) to ( 1 7 0 ) is identical to that measured previously for the parent hydrocarbon. Furthermore, photolysis ( > 2 2 0 nm) of both (169) and (170) leads to the formation of anti-tricyclo-octadiene (171), possibly suggesting the

General and Synthetic Methods

62

,

R e a g e n t s : i , BuLi ; ii , Z n C I Z iii I C H = CHCI,[ Pd(PPh3)4]( cat.); iv, NaNH2 ,NH3; v, E

Scheme 117

Scheme 118

(172) Reagents:i,LiAIH4;

ii,MsCl;iii L i B r ; i v , A 1 2 0 3 j v , B u L i ; v i , C I P O ( O E t ) 2 ; v i i , L i , N H ~

S c h e m e 119

+

63

1: Saturated and Unsaturated Hydrocarbons i n t e r m e d i a c y of ( 1 6 9 ) i n t h e p h o t o c h e m i s t r y of ( 1 7 0 ) . Scheme 119 shows t h e f i n a l s t a g e s i n t h e s y n t h e s i s o f 1 1 , 1 2 -

dimethylbicyclo[5.3.2ldodeca-I

,6, 1l-triene

( 1 7 2 ) (m.p.

36-38

OC),

a

f a s c i n a t i n g m o l e c u l e i n which t h e c o n j u g a t e d d o u b l e b o n d s a r e

E.

90' t o e a c h o t h e r . 183 D e s p i t e e a r l i e r p r e d i c t i o n s r e g a r d i n g t h e t h e r m a l s t a b i l i t y of t h e h i g h l y permanently f i x e d a t

u n s a t u r a t e d p r o p e l l a n e s ( 1 7 3 ) a n d ( 1 7 4 ) , t h e s e m o l e c u l e s h a v e now b e e n s y n t h e s i z e d by PaqLlette e t a l . a n d shown t o be r e m a r k a b l y s t a b l e . 184

I n d e e d , on h e a t i n g ( 1 7 4 ) a t 160

evidence f o r retro-Diels-Alder

OC

f o r 90 h , no

f r a g m e n t a t i o n was f o u n d .

p e n t a e n e ( 1 7 3 ) , h o w e v e r , p r o v e d t o b e more r e a c t i v e , s m o o t h l y a t 95

The

fragmenting

OC.

The s y n t h e s i s by Corey a n d E c k r i c h o f 5 , 6 - d e h y d r o a r a c h i d o n i c a c i d ( 1 7 5 ) , o u t l i n e d i n Scheme 1 2 0 , s e r v e s t o i l l u s t r a t e a new, s t e r e o s p e c i f i c r o u t e t o complex p o l y u n s a t u r a t e d f a t t y a c i d s o f t h i s The i m p o r t a n t f e a t u r e s o f t h i s method w o r t h n o t i n g a r e

-

t y p e 185

t h e c i s - c a r b o s t a n n y l a t i o n of a l k y n e s u s i n g t r i b u t y l t i n t r i f l a t e and t h e s u b s e q u e n t i t e r a t i v e c o u p l i n g b a s e d on t h e d i f u n c t i o n a l intermediate (176).

The key s t e p i n a v e r s a t i l e s y n t h e s i s o f

e n y n e s , d i y n e s , a n d p o l y e n e s d e v e l o p e d by O t e r a ' s r e s e a r c h g r o u p i s t h e f o r m a t i o n o f a c e t y l e n i c o r p o l y e n i c b o n d s w h i c h o c c u r s on t r e a t m e n t of u n s a t u r a t e d 6 - a c e t o x y - s u l p h o n e s

(or t h e corresponding

THP e t h e r s ) w i t h p o t a s s i u m t - b u t o x i d e . 186

The method h a s b e e n a p p l i e d , f o r e x a m p l e , t o t h e f o r m a l t o t a l s y n t h e s i s o f (&)muscone,

p a r t of w h i c h i s shown i n Scheme 121.

Thermolysis (200

OC,

sealed

t u b e ) of t h e divinylcyclopropane (177) l e a d s smoothly t o t h e f o r m a t i o n o f t h e two p r o d u c t s ( 1 7 8 ) a n d ( 1 7 9 ) ( r a t i o 4 : l ) i n e s s e n t i a l l y q u a n t i t a t i v e y i e l d (Scheme 1 2 2 ) . 187

Subsequent c o n t r o l l e d h y d r o g e n a t i o n ( L i n d l a r c a t a l y s t ) f o l l o w e d by m i l d

alkaline hydrolysis furnishes both arachidonic acids.

cis- a n d

trans-7,13-bridged

I-Chloro-(~,~)-l74-dienes of t y p e ( 1 8 1 1 , which

a r e r e a d i l y a v a i l a b l e by t h e t r e a t m e n t o f ( E ) - a l k e n y l a l a n e s ( 1 8 0 ) react with terminal alkynes i n t h e p r e s e n c e o f [ P d ( P P h 3 ) 4 ] ( 5 mol%)>,c o p p e r i o d i d e ( 1 5 mol%), a n d b u t y l a m i n e t o g i v e t h e d i e n y n e s ( 1 8 2 ) i n 80-90% y i e l d (Scheme 1 2 3 ) 188 T r i p l y u n s a t u r a t e d h y d r o c a r b o n s s u c h as ( 1 8 4 ) a n d ( 1 8 5 ) r e s u l t from t h e s t e r e o s p e c i f i c c r o s s - c o u p l i n g o f with (E)-dichloroethylene,

-

e n y n y l d i a l k y l b o r a n e s ( 1 8 3 ) w i t h a l l y 1 b r o m i d e s or l-bromo-la l k y n e s , r e s p e c t i v e l y (Scheme 1 2 4 )

.

89

Finally, the ylide derived

bromide f r o m l-(trans-2,3-dichloroprop-2-enyl)triphenylphosphonium r e a c t s w i t h a v a r i e t y o f a l d e h y d e s , k e t o n e s , a n d e n o n e s a t -30 OC

General and Synthetic Methods

64

(174 1

(173)

I. , I .I

9o010

'

Bu3Sn \_/C5Hll

1, .1 .1 ,

iv

bu35n

i i i , iv 184°/o

-COzH ... Ill

e

c

Reagents: i , ( C 5 H l l ) Z C u L i

5

H

1

1

j i i , Bu3SnOTfi i i i , B u L i

v

,VI

84'1.

i v , Bu3Sn
Scheme 120

Reagents : i I B u l i ;ii) Me3SiCHrCHCHO iii, Ac20,Py ; i v , K 0 9 u t , T HF, A

S c h e m e 121

C5H11

L A J

~

89 '10

1: Saturated and Unsaturated Hydrocarbons

65

2

(178)

+ -C02Me

(7”

(177)

(179) Scheme 112

Scheme 123

iv

(183) R e a g e n t s : i R’zBH;

(181)

‘R3

iilR3-=-Li,iii,WBr,

‘R3

[Cu~acac~~l,HO~~iv,R4-~-Erl~Cu~acac)21,H

Scheme 1 2 4

CI

+qJ

Ph3 P

CI

. ..

I, II

64’10

’ 1:l ( E / Z )mixture

66

General and Synthetic Methods

to afford air-sensitive chloro[3]cumulenes (e.g. Scheme 125). 1 9 0 Although yields are generally good, the reaction with unsymmetrical substrates is non-stereoselective giving (E)- and (Z)-isomers in equal proportions. References 1

2 3 4 5 6 7 8 9 10 11 12 13 i4 15 16 17 18 19 20

M.Luyton and R.Keese, Angew. Chem., Int. Ed. Engl., 1984, 9, 390. D.H.R.Barton, Y.Herv6, P.Potier, and J. Thierry, J. Chem. SOC., Chem. Commun., 1984, 1298. C.G.Gut ierrez and L. R.Summerhays, J. Org. Chem., 1984, 49, 5206. T.G.Back, J. Chem. S O C . , Chem. Commun., 1984, 1417. D.H.R.Barton and D.Crich, J. Chem. S O C . , Chem. Commun., 1984, 774. J-K-Sutherland and G.B.Tometzki, Tetrahedron Lett., 198 4, 881. M.H.Khalifa and R. Rieker. Tetrahedron Lett.. 1984. 2 5 . 1027. G.B.Deacon and P.I.MacKinnon, Tetrahedron Lett., i 9 8 4 ; 25, 783. T. Iida, T.Tamura, T.Matsumoto, and F. C. Chang, Synthesis, 1984, 957. M.Yatagai, T.Yamagishi, and M.Hida, Bull. Chem. SOC. 1984, 57, 823. K.Harada and M.Takasaki, Bull. Chem. SOC. JprI., 1984, 57, 823. D.A.Evans and M.M.Morrissey, J. Pim. Chem. S O C . , 1984, 106,3866. J.M.Brown and S.A.Hal1. Tetrahedron Lett.. 1984. 2 5 . 1393. - T.Imamoto, T.Mita, and M.Yokoyama, J. Chem. Soc., Chem. Commun., 1984, 163. R.Sala, G.Doria, and C.Passarotti, Tetrahedron Lett., 1984, 25, 4565. J. E.Baldwin, J. C.Bottaro, J.N.Kolhe, and R . M . Adlington, J. Chem. SOC., Chem. Commun., 1984, 22. D.Lenoir, D.Malwitz, and B.Meyer, Tetrahedron Lett., 1984, 25, 2965. Y.Tobe, Y.Fukuda, K-Kakiuchi, and Y.Odaira, J. Org. Chem., 1984, 9, 2012. M.Petit, A.Mortreux, and F.Petit, J. Chem. SOC., Chem. Commun., 1984, 341. S.Hanessian, D.Delorme, S.Beaudoin, and Y.Leblanc, J. Am. Chem. SOC., 1984,

z,

k.,

I

I

106, 5754. 21 22 23 24 25 26 27 28

M.A.Blanchette, W.Choy, J.T.Davis, A.P.Essenfeld, S.Masamune, W.R.Roush, and T.Sakai, Tetrahedron Lett., 1984, 25, 2183. L.Clawson, S.L.Buchwald, and R.H.G=bbs, Tetrahedron Lett., 1984, 25, 5733. D.Hern5ndez and G.L.Larson, J . Org. Chem., 1984, 9, 4285. J.B.Hendrickson, G.J.Boudreaux, and P.S.Palumbo, Tetrahedron Lett., 1984, 25, 4617. -

J.S.Grossert, J.Hoyle, D.L.Hooper, Tetrahedron, 1984, 5 , 1135. D.Scholz, Liebigs Ann. Chem., 1984, 98. F.Mohamadi and D.B.Collum, Tetrahedron Lett., 1984, 25, 271. R-Pellicciari, B.Natalini, S.Cochetti, and S.Santucci, Tetrahedron Lett., ~

1984. , 25. - , 3103. -

29 30 31

M.G.MaXin and B.Ganem, Tetrahedron Lett., 1984, 25, 251. Z.Paryzek and R.Wydra, Tetrahedron Lett., 1984, 25, 2601. M.J. Robins, F.Hansske, N.H.Low, and J. I.Park, Tetrahedron Lett., 1984,

25,

367. 32 33 34 35

S.G.Davies and S.E.Thomas, Synthesis, 1984, 1027. H.Nishiyama, K.Sakuta, and K,Itoh, Tetrahedron Lett., 1984, 25, 223. K.Nakatani and S.Isoe, Tetrahedron Lett., 1984, 25, 5335. M.Ochiai, T.Ukita, Y.Nagao, and E.Fujita, J. Chem. SOC., Chem. Commun.,

36 37 38 39

J.-J.Brunet and P.Caubere, J. Ore;. Chem., 1984, 9, 4058. S. Cacchi, M.Felici, and B. Pietroni, Tetrahedron Lett., 1984, 25, 31 37. S.Cacchi, E.Morera, and G.Ortar, Tetrahedron Lett., 1984, 2 5 , 7 8 2 1 . A.R.Chamberlin and S.H.Bloom, Tetrahedron Lett., 1984, 25, 4901. M.Marsi and M.Rosenblum, J. Am. Chem. SOC., 1984, 106,7264. T.Ibuka, G.-N.Chu, and F.Yoneda, Tetrahedron Lett., 1984, 25, 3247. M.Nagatsuma, F.Shirai, N.Sayo, and T.Nakai, Chem. Lett., 1984, 1393. M.Ohshima, M.Murakami, and T.Mukaiyama, Chem. Lett., 1984, 1535.

1984, 1007.

40

41 42 43

67

I : Saturated and Unsaturated Hydrocarbons 44 45 46 47

J.K.Cha and S.C.Lewis, Tetrahedron Lett., 1984, 25, 5263. M.J.Kurth and C.-M.Yu, Tetrahedron Lett., 1984, 25, 5003. T.Fujisawa, K.Tajima, M.Ito, and T.Sato, Chem. Lett., 1984, 1169. W.A.Kinney, M.J.Coghlan, and L.A.Paquette, J. Am. Chem. S O C . , 1984, ~

106,

6868. 48 49 50 51 52 53 54 55 56 57 58 59

60 61

M.J.Begley, A.G.Cameron, and D.W.Knight, J. Chem. S O C . , Chem. Commun., 1984, 827. R.E.Ireland and M.D.Varney, J. Am. Chem. S O C . , 1984, 106,3668. S.E.Denmark and M.A.Harmata, Tetrahedron Lett., 1984, 25, 1543. S.R.Wilson and M.F.Price, J. Org. Chem., 1984, 49, 722, E.J.Corey and A.W.Gross, Tetrahedron Lett., 198c 25, 495. J.Orban, J.V.Turner, and B-Twitchin, Tetrahedron Lett., 1984, 25, 5099 C.S.Wilcox and R.E.Babston, Tetrahedron Lett., 1984, 25, 699. S.M.Clift and J.Schwartz, J. Am. Chem. SOC.,1984, 106,8300. C.S.Wilcox, G.W.Long, and H.Suh, Tetrahedron Lett,., 1984, 25, 395. J.-M.Vat&le, Tetrahedron Lett., 1984, 5997. S.V.Ley and B.Lygo, Tetrahedron Lett., 1984, 25, 113. J.B. Ousset , C.Mioskowski , Y .-L. Yang, and J. R. Falk, Tetrahedron Lett., 1984, 25, 5903. J. Nakayama, S. Takeue, and M. Hoshino, Tetrahedron Lett., 1984, 25, 2679 T.Kauffmann, R.KOnig, R.Kriegesmann, and M.Wensing, Tetrahedron Lett., 1984, 25. ~- 641. D.G.Ager, J. Chem. SOC., Chem. Commun., 1984, 486. A.Minato, K.Suzuki, K.Tamao, and M.Kumada, Tetrahedron Lett., 1984, 25-, 83. S.Fujikura, M.Inoue, K.Utimoto, and H.Nozaki, Tetrahedron Lett., 1984, 25 1999. Y.Morizawa, H.Oda, K.Oshima, and H-Nozaki, Tetrahedron Lett., 1984, 25, 1163. Y.Okuda, Y.Morizawa, K.Oshima, and H.Nozaki, Tetrahedron Lett., 1984, 25, 2483. H.Hayami, K.Oshima, and H.Nozaki, Tetrahedron Lett., 1984, 25, 4433. D.H. R.Barton, G.Bashiardes, and J.-L.Fourrey, Tetrahedron Lett., 1984, 25, 1287. J. E.Fankhauser, R.M.Peevey, and P.B.Hopkins, Tetrahedron Lett., 1984, 25, 15. J.N. Fitzner, R.G.Shea, J. E.Fankhauser , and P.B.Hopkins, Synth. Commun., 605. 1984, R.G.Shea, J.N.Fitzner, J. E.Fankhauser, and P.B.Hopkins, J. Org. Chem., 1984, 49, 3647. D.M.Vyas, Y.Chiang, and T.W.Doyle, J. Org. Chem., 1984, 9, 2037. N.Ono, A.Kamimura, and A.Kaji, Tetrahedron Lett., 1984, 25, 5319. H.C.Brown and P.K.Jadhau, Tetrahedron Lett., 1984, 25, 1215. H. C.Brown, P.K.Jadhau, and P. T.Peruma1, Tetrahedron Lett., 1984, 25, 51 1 1 . T.Gallagher, J. Chem. SOC., Chem. Commun., 1984, 1554. K.Mikami, T.Maeda, N.Kishi, and T.Nakai, Tetrahedron Lett., 1984, 25, 5151. N.Sayo, K.Azuma, K.Mikami, and T.Nakai, Tetrahedron Lett., 1984, 25, 565. N.Sayo, E.Kitihara, and T.Nakai, Chem. Lett., 1984, 259. K.Mikami, K.Azuma, and T.Nakai, Tetrahedron, 1984, 5, 2303. K.Mikami, K.Fujimoto, T.Kasuga, and T.Nakai, Tetrahedron Lett., 1984, 25, 601 1. D.J.-S.Tsai and M.M.Midland, J. Org. Chem., 1984, 9, 1842. A.D.Buss, N-Greeves, D.Levin, P.Wallace, and S.Warren, Tetrahedron Lett., 1984, 25, 357. K.Ogura, T.Iihama, K.Takahashi, and H.Iida, Tetrahedron Lett., 1984, 25, 2671. J.Tsuji and H.Nagashima, Tetrahedron, 1984, 5, 2699. T.Mandai, M.Takeshita, M.Kawada, and J.Otera, Chem. Lett., 1984, 1259. P.Tuchinda, V-Prapansiri, W.Naengchomnong, and V.Reutraku1, Chem. Lett., 1984, 1427. J.Moska1 and A.M.van Leusen, Tetrahedron Lett., 1984, 25, 2585. D-van Leusen and A.M.van L e u s V L e t t . , 19=, 25, 2581. Y. Tamaru, H.Ochiai, and Z.Yoshida, Tetrahedron Lett., 1984, 25, 3861.

z,

>

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

87 88 89 90

7

111,

~

68

General and Synthetic Methods

91 92 93

I . M a t s u d a , H.Okada, S . S a t o , and Y.Izumi, T e t r a h e d r o n L e t t . , 1984, 2 5 , 3879. D.Min-Zhi, T.Yong-ti, and X.Wei-hua, T e t r a h e d r o n L e t t . , 1984, 2, -97. J. T s u j i , K . T a k a h a s h i , I.Minami, and I . S k i m i z u , T e t r a h e d r o n L e t t . , 1984, 4783. G.L.Larson, C.Fernandez d e K a i f e r , R.Seda, L.E.Torres, and J . R . Ramirez, J . Org. Chem., 1984, 3385. L . S t r e k o w s k i , M.Visnick, and M . A . B a t t i s t e , T e t r a h e d r o n L e t t ., 1984, 5603. D.H.R.Barton and D . C r i c h , T e t r a h e d r o n L e t t . , 1 9 8 4 , 25, 2787. M.A.Tius and D.P.Astrab, T e t r a h e d r o n L e t t . , 1984, 25, 1539. M. Pohmakotr and P. P h i n y o c h e e p , T e t r a h e d r o n L e t t , , 1984, 25, 2249. M.Pohmakotr and S.Chancharunee, T e t r a h e d r o n L e t t . , 1984, 25, 4141. M.T.Crimmins, S.W.Mascarella, and J.A.Deloach, J . Org. Chem., 1984, 3033. T-Mandai, K.Mori, K.Hasegawa, M.Kawada, and J . O t e r a , T e t r a h e d r o n L e t t . , 1984, 2, 5225. O.Moriya, M,Okawara, and Y.Ueno, Chem. L e t t . , 1984, 1437. 11. M.Ladlow and G . P a t t e n d e n , S y n t h . Commun., 1984, A.W.Murray and R.C.Reid, J . Chem. SOC., Chem. Commun., 1984, 132. C.Lambert, K.Utimoto, and H.Nozaki, T e t r a h e d r o n L e t t ., 1984, 25, 5323. A . J e l l a 1 , J . G r i m a l d i , and M . S a n t e l l i , T e t r a h e d r o n L e t t ., 1984, 2 5 , 3179. K.Tanaka, H.Wakita, H.Yoda, and A . K a j i , Chem. L e t t . , 1984, 1359: S.P.Tanis and D.B.Head, T e t r a h e d r o n L e t t . , 1984, 25, 4451. W . E . B i l l u p s , L . - J . L i n , and E.W.Casserly, J . Am. Chem. SOC., 1984, 3698. 3699. S.W.Staley and T.D.Norden, J . Am. Chem. S O C . , 1984, T.Minami, Y.Taniguchi, and 1 - H i r a o , J . Chem. S O C . , Chem. Commun., 1984, 1046. H . G o t t h a r d t and R.Jung, T e t r a h e d r o n L e t t . , 1984, 25, 4217. E.Wenkert, M.H.Leftin, and E . L . M i c h e l o t t i , J . Chem. SOC., Chem. Commun., 1984, 617. J . U k a i , Y.Ikeda, N.Ikeda, and H.Yamamoto, T e t r a h e d r o n L e t t . , 1984, 25, 5173. Y.Ikeda, J . U k a i , N.Ikeda, and H.Yamamoto, T e t r a h e d r o n L e t t . , 1984, 25, 5177 J . Chem. S O C . , Chem. Commun., 1984, 534. A.G.Angoh and D.L.J.Clive, C.-N.Hsiao and H . S c h e c h t e r , T e t r a h e d r o n L e t t . , 1984, 25, 1219. T.Chou, H.-H.Tso, and L.-J.Chang, J . Chem. S O C . , Chem. Commun., 1984, 1323. J.F.Honek, M.L.Mancini, and B . B e l l e a u , S y n t h . Commun., 1984, 483. E.Block, V . E s w a r a k r i s h n a n , and K.Gebreyes, T e t r a h e d r o n L e t t . , 1984, 5469. S . C a c c h i , E.Morera, and G . O r t a r , T e t r a h e d r o n L e t t . , 1984, 2271. W . J . S c o t t , G.T.Crisp, and J . K . S t i l l e , J . Am. Chem. S O C . , 1984, 1 0 6 , 4630. M.Ahmar, B.Cazes, and J . G o r e , T e t r a h e d r o n L e t t . , 1984, 25, 4505. R.Riguera, E.Qui
94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137

25,

2,

25,

s,

2,

106,

106,

2,

25,

25,

106, s,

9, 2, 9,

2,

9,

9,

69

1: Saturated and Unsaturated Hydrocarbons 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 18 1 182 183 184 185 186

J.A.Miller and E.Negishi, Tetrahedron Lett., 1984, 25, 5863. P.Knoche1 and J. F.Normant, Tetrahedron Lett., 1984, 25, 1475. P.Knoche1 and J.F.Normant, Tetrahedron Lett., 1984, 25, 4383. B.Jousseaume, J. Chem. SOC., Chem. Commun., 1984, 1452. F.Barba, A.Guirado, and I.Barba, J. Org. Chem., 1984, 49, 3022. A.Goliaszewski and J.Schwartz, J. Am. Chem. S O C . , 198117106, 5028. P.G.Gassman and D.A.Singleton, J. Am. Chem. SOC., 1984, 106, 7933. M.Tokuda, K.Satoh, and H.Suginome, Chem. Lett., 1984, 10% Y.Yamamoto, K.Maruyama, and K.Matsumoto, J. Chem. SOC., Chem. Commun., 1984. 548. T.Fujisawa, M.Kawashima, and S.Ando, Tetrahedron Lett., 1984, 25, 3213. T.Fujisawa, S.Iida, and T.Sato, Tetrahedron Lett., 1984, 25, 4007. E.J.Corey and N.W.Boaz, Tetrahedron Lett., 1984, 25, 3055: A.Hakiki, J.-L.Ripol1, and A.Thuillier, Tetrahedron Lett., 1984, 25, 3459. A.Hakiki, Z.Jabry, J.-L.Ripol1, and A.Thuilier, Tetrahedron Lett., 1984, 25, 3461. H.J.Bestmann and H.Frey, Synthesis, 1984, 243. Y.Yamada, G-Suzukamo, and H.Yoshioka, Tetrahedron Lett ., 1984, 25, 3599. W.S.Johnson, J.D.Elliott, and G.J.Hanson, J. Am. Chem. SOC., 1984, 106, 1138. A.L. Castelhano. D.H. Pliura. G . J. Tavlor ., K. C.Hsieh. and A.Krantz. J. Am. " Chem. SOC., 1984, 106,2734. P.Casara, K.Juno, and P.Bey, Tetrahedron Lett., 1984, 25, 1891. A.L.Castelhano and A.Krantz, J. Am. Chem. SOC., 1984, 1877. H.Hiemstra, H.P.Fortgens, and W.N.Speckamp, Tetrahedron Lett., 1984, 25, 31 15. J.E.Baldwin, R.M.Adlington, and A.Basak, J. Chem. SOC., Chem. Commun., 1984, 1284. T.Ishihara, T.Maekawa, and T.Ando, Tetrahedron Lett., 1984, 25, 1377. A.L.Braga, J.V.Cmasseto, and N.Petragnani, Tetrahedron Lett., 1984, 25, 1111. A.L.Braga, J.V.Comasseto, and N.Petragnani, Synthesis, 1984, 240. G.Boche and J.Bigalke, Tetrahedron Lett., 1984, 25, 955. R.J. P-Corriu, V. Huynh, and J. J .E.Moreau, Tetrahedron Lett., 1984, 25, 1887. H.C.Brown, V.S.Racherla, and S.M.Singh, Tetrahedron Lett., 1984, 25, 2411. M.Yamaauchi and 1-Hirao. J. Chem. SOC.. Chem. Commun.. 1984. 202. M.WadaS Y,Sakurai, and K.Akiba, Tetrahedron Lett., 1 9 8 4 , - 9 ; 1083. K.Utimoto, C.Lambert, Y.Fukuda, H.Shiragami, and H.Nozaki, Tetrahedron Lett., 1984, 25, 5423. G.Zweife1 and G.Hahn, J. Org. Chem., 1984, 4565. Y.Yamamoto, W.Ito, and K.Maruyama, J. Chem. SOC., Chem. Commun., 1984, 1004. M.Hoshi, Y.Masuda, Y.Nunokawa, and A.Arase, Chem. Lett., 1984, 1029. M.Akita, H.Yasuda, and A.Nakamura, Bull. Chem. SOC., Jpn., 1984, 57, 480. J.Koshino, T.Sugawara, and A.Suzuki, Synth. Commun., 1984, 14, 245. B.M.Trost and S.J.Martin, J. Am. Chem. SOC., 1984, 4263, A.B.Holmes, C.L.D. Jennings-White, and D.A.Kendrick, J. Chem. SOC , Chem. Commun.. , 1984. , 1594. ~R. E. Doolittle , Synthesis, 1984, 730. M.H.P.J.Aerssens and L.Brandsma, J. Chem. SOC., Chem. Commun., 1984, 735. R.Rieth, A.W&htler, and M.Hanack, Synthesis, 1984, 1010. N.Sayo, F.Shirai, and T.Nakai, Chem. Lett., 1984, 255.. E.Negishi, N.Okukado, S.F.Lovich, and F.-T.Luo, J. Org. Chem., 1984, 2629. Y.Sugihara, T.Sugimura, and I.Murata, J. Am. Chem. SOC., 1984, 7268. R.F.Waldron, A.C.Barefoot 111, and D.M.Lema1, J. Am. Chem. SOC., 1984, 106, 8301. W.vonE.Doering and J.C.Schmidhauser, J. Am. Chem. SOC., 1984, 106,5025. L.A.Paquette, H.Jendralla, and G.DeLucca, J. Am. Chem. SOC., 1984, 106, 15 18. E.J.Corey and T.M.Eckrich, Tetrahedron Lett., 1984, 25, 2419. T.Mandai, T. Yanagi, K. Araki, Y.Morisaki, M.Kawada, and J. Otera, J. Am. Chem. SOC., 1984, 106,3670. -I

106,

9,

106,

.

2,

106,

70 187 188 189 190

General and Synthetic Methods K.C.Nicolaou and S.Webber, J. Chem. SOC., Chem. Commun., 1984, 350. V.Ratovelomanana and G.Linstrumelle, Tetrahedron Lett., 1984, 25, 6001. A.Arase, M.Hoshi, and Y.Masuda, Chem. Lett., 1984, 2093. R.D.Arnold, J.E.Baldwin, and C.B.Ziegler, Jr., J. Chem. S O C . , Chem. Commun., 1984, 152.

Aldehydes and Ketones BY S. C. EYLEY

1 Synthesis of Aldehydes and Ketones

Oxidative Methods.- With the exception of derivatives of simple primary alcohols, alkyl allyl carbonates react with a palladium(0) catalyst in acetonitrile to form carbonyl compounds [equation ( 1 11. The absence of phosphine ligands is necessary, since in their presence oxldation is not observed, and the allyl ether is formed instead. A potential advantage of this method lies in the neutral reaction conditions employed. A number of reagents have been described for the oxidation of benzylic and allylic alcohols. Both classes are oxidized by potassium ferrate under phase-transfer catalysis2 and tetrakis(pyridine)silver dichromate, whilst benzylic alcohols are oxidized by bis(2,2'-bipyridyl)copper(II) and cetyltrimethylammonium permanganates.4'5 Ruthenium dioxide, as the dihydrate, in oxygen effects the oxidation of allylic alcohols to unsaturated carbonyl compounds. 6 In reactions forming aldehydes, the addition of 2,6-di-t-butyl-pcresol prevented significant autoxidation of the product. Barium ruthenate is a selective, heterogeneous oxidant for benzylic and allylic alcohols, whereas the catalytic potassium ruthenatepotassium persulphate system is effective for the conversion of secondary alcohols into ketones, primary alcohols being oxidized to the acid.7 The related ruthenium complexes [PPh4] [Ru02C13] and [RuO2(bipy)Cl2], which are soluble in organic media, oxidize both primary and secondary alcohols to the corresponding aldehydes and ketones. Whereas ruthenium tetraoxide is a powerful oxidant which tends to lack selectivity, osmium tetraoxide in diethyl ether has been found to oxidize primary alcohols selectively .8 Secondary alcohols can be oxidized by this reagent. Bipyridyl complexes of ruthenium(I1) catalyse the photo-oxidation of alcohols to carbonyl compounds in the presence of an amine base and a diazonium salt as a quenching agent for the generation of the oxidizing R u ' " species For References see page 123. 71

General and Synthetic Methods

72

from Ru".' The examples quoted were all benzylic alcohols. Platinum on titanium dioxide is reported to be an efficient sensitizer for the photo-oxidation of alcohols to aldehydes and Saturated secondary alcohols were dehydrogenated in ketones. poor yield, suggesting that the method has applicability for the selective oxidation of primary alcohols. A series of cerium reagents has been developed for the oxidation of alcohols. Bis [ trinitratocerium( IV >]chromate and dinitratocerium(1V) chromate dihydrate12 are reagents which are stable to storage, for the oxidation of benzylic alcohols. This transformation may also be performed by trisCtrinitratocerium(1V)I paraperiodate, a reagent which will also cleave 1,2-diols to the carbonyl compounds, and oxidize a-hydroxy-ketones t o 1,2Ceric trihydroxy hydroperoxide shows similar diketones reactions towards alcohols and a-hydroxy-ketones. A potential benefit is the ease with which the cerium residues from these reactions may be treated with hydrogen peroxide to regenerate the reagent in very high yield. Chromium(II1) o r cerium(1V) salts impregnated on perfluorinated resin-sulphonic acid supports may be used f o r the catalytic oxidation of alcohols by t-butyl hydroperoxide. l 5 The recovered catalyst retains its catalytic activity, washing with water being all that is required before re-use. This peroxide in the presence of benzyltrimethylammonium tetrabromo-oxomolybdate oxidizes 16 secondary alcohols to ketones and primary alcohols to esters. However, the commercially available ammonium molybdate in conjunction with hydrogen peroxide oxidizes secondary, but not primary, Of interest here is the observation that hindered alcohols react more quickly. Control of reaction pH can be important. The reagent combination is capable of epoxidizing olefins, but this is suppressed in the presence of potassium carbonate. Nitroxyls in the presence of oxygen and catalytic amounts of cuprous salts oxidize allylic and benzylic alcohols to the carbonyl compound. l8 In the presence of stoicheiometric quantities of cupric salts primary alcohols are also oxidized to the aldehyde. Competitive studies of oxidations of alcohols by chlorodimethylsulphonium chloride (generated from dimethyl sulphoxide and oxalyl chloride) have demonstrated that hindered alcohols and those The bearing electron-withdrawing groups are less reactive. I' process involves the fast formation of the initial alkoxysulphonium

'"

. ''

alcohol^.'^

73

2: Aldehydes and Ketones

R'

H R'=H

1

RZ-

,

R e a g e n t s : i 30'1.

iii

C02H

,

H202, KHF2 DMFj ii, 3 0 " / 0 H202,KHC03, MeOH, THF,60°C; iii,30°/o

H202? A c 2 0 , KHFz, DMF

Scheme 1

R'

"YPh

R 2 A S i-

Reagents

i , PhCOCHtCl, Et3N ; i i , h v , PhH, XSiRgj iii, Bu4N'F-,THF

Scheme 2

2

BunMgCI +

ZnC12

+ Bun2Zn

Pr" C O C I

Pdo

PrnCOBun

74

General and Synthetic Methods

ions which then may slowly equilibrate. The addition of the amine base rapidly forms the carbonyl compound from this intermediate. These findings may be of significance for the application of the oxidation method to complex substrates. A remarkable specificity interchange has been reported for oxidations with di-isopropyl sulphide and N-chlorosuccinimide. 2o At 0 OC primary alcohols are oxidized to aldehydes and secondary alcohols are unaffected, but at -78 OC the opposite selectivity is reported! No explanation was detailed. A review of electrochemistry in organic chemistry includes a discussion of the applicability of the method to the oxidation of alcohols . 2 1 Poly(viny1pyridinium bromide) is an effective electron carrier in the electrochemical benzylic oxidation of alkylbenzenes to ketones .22 In an interesting extension, enantiomer differentiation has been observed in the electrochemical oxidation of 2,2-dimethyl-I-phenylpropan-l-ol on poly(L-va1ine)-coated electrodes. 23 Studies of flavin mimics for the oxidation of organic compounds continue to make progress. Whilst truly synthetically competitive reactions are not yet common, high catalytic turnovers are being achieved for alcohols,24-26 amines,27 and nitro-compounds. 28 A review of the palladium-catalysed oxidation of olefins to ketones has appeared .29 Although the review concentrates on the oxidation of terminal double bonds to methyl ketones, the selective oxidation of internal olefins is surveyed. Control of pH is important in the uncatalysed oxidation of alkenyl(a1koxy)silanes by hydrogen peroxide (Scheme 1 ) .30 Chromium carbonyl catalyses the oxidation of cyclic allylic methylene groups to a,b-unsaturated ketones by t-butyl hydroperoxide. 31 Cyclohex-2-enones are oxidized to the cyclohexene-1,4-diones by a combination of phosphomolybdic acid, potassium dichromate, cupric sulphate, and air .32 Bi~(p-methoxyphenyl)-~~ and diphenyl- and d i m e t h ~ l - ~ ~ selenoxides have been described as reagents for the Kornblum oxidation of benzyl halides to benzaldehydes. Sulphides may be oxidized to ketones by photolysis of their phenacyl derivative, trapping the intermediate thiocarbonyl compound with a nitronate ester (Scheme 2).35 Primary and secondary amines are oxidized to imines, and hence carbonyl compounds, by arylsulphonyl peroxides under basic (potassium hydroxide) conditions at low temperatures. 36

2: Aldehydes and Ketones

75

Reductive Methods.- In contrast to thexylborane, thexylchloroboranedimethyl sulphide rapidly reduces aliphatic carboxylic acids to the aldehyde.37 Reaction times are of the order of minutes, whereas the reduction by thexylchloroborane uncomplexed to the sulphide is somewhat more sluggish. Aromatic acids were, as expected, reduced more slowly, and competition experiments indicated potential f o r selective reductions. A simple preparation of bis(N-methylpiperaziny1)aluminium hydride f r o m lithium aluminium hydride has been published. 38 The reagent may be stored as a standard solution in THF and is convenient for the reduction of acids to the aldehydes. Of particular note is the lack of conjugate addition to unsaturated acids, enabling the simple preparation of unsaturated aldehydes. Di-isobutylaluminium deuteride reduces esters to 1deuterioaldehydes 39 Reaction times and stoicheiometry are dependent on the nature of the substrate, aliphatic esters being reduced significantly more rapidly than derivatives of aromatic acids. Formylation of metallic derivatives continues to be an important method for the preparation of aldehydes. 2-Formylmorpholine has been described as a further formylating agent for Grignard reagent^.^' The importance of mild reaction conditions (temperatures between 0 and 20 OC) and the avoidance of excesses of the Grignard reagent have been highlighted when simple dialkylformamides are used for the introduction of the aldehydic carbon atom.41 Elevated temperatures are required for satisfactory rates of reaction between Grignard reagents and sodium o r lithium formates. 42 The benefits of catalysis of the reactions between acid chlorides and organozinc compounds include higher yields of ketones and better s e l e ~ t i v i t i e s . ~In ~ a reaction on a 1.7 mol scale, the use of 0.1 mol% palladium [as benzylchlorobis(tripheny1phosphine)palladium] gave a yield of 92% [equation ( 2 ) 1 . Catalysis of the reaction between acid chlorides and Grignard reagents by tris(acetylacetonate)iroii(III) also leads to good yields of ketones .44 In place of (acid chlorides, N-acylaziridines may be used to produce ketones from either organolithium o r Grignard reagents. 45 Studies of the influence of acylating agent (acid chlorides, anhydrides, and mixed cai-bonic anhydrides), solvents, and added ligands on the formation of ketones from organomanganous compounds

.

76

General and Synthetic Methods

have been reported.46 In general, yields of ketones are not significantly altered by the use of co-solvents in addition to the normal ether solvent, with the exception of amines (pyridine, tetramethylethylenediamine, and triethylamine), which do lead to very low yields. Methods Involving Umpo1ung.- Anions of a-silylsulphones are readily alkylated by primary alkyl halides, control being possible to afford unsymmetrical dialkyl derivatives (Scheme 3) .47 Reduction followed by the now familiar Pummerer rearrangement affords ketones in good yield. Methoxyphenylthiomethyl-lithium forms adducts with aldehydes which may be transformed into vinyl ethers by reduction of their xanthates (Scheme 4) .48 The anticipated hydrolysis completes the homologation. The reagent may be easily prepared by the acidcatalysed reaction of dimethoxymethane with thiophenol, circumventing the need to use the carcinogenic chloromethyl methyl ether.49 Further details of the formation of the d l reagents 1 methylthio- and I-phenylthio-vinyl-lithiums from the B-methoxyalkyl sulphides have been reported. 50 Lithium di-isopropylamide is the preferred base for their formation, reducing the amount of allylic deprotonation observed. The well-established use of Wittig-type reagents f o r the formation of enol ethers has been extended to derivatives of cyclic ethers. The products from condensation of 2 - p h o ~ p h i n o y l - ~ ’ and 2phosphonium salts5* have obvious potential for the construction of spiroacetals of importance in the field of, inter alia, insect pheromone synthesis, as exemplified by the rapid preparation of a pheromone of the olive fly (Scheme 5). Lithium chloride in conjunction with an amine base ( f o r example DBU) offers mild conditions for olefination of base-sensitive aldehydes by phosphonates. 53 a-Diphenylphosphinoyl amines may be used in HornerWittig type reactions to construct enamines [equation ( 3 ) l .54 a-Acyloxyphosphonium salts are obtained by the reaction of aldehydes with acid chlorides in the presence of triphenylphosphine.55 On heating, the derived anions rearrange to give a-diketones, but do react with aldehydes to give enol ethers, and hence ketones [equation ( 4 ) l . The anion from diethyl (2trimethylsilylethoxymethy1)phosphonate is alkylated by allylic and benzylic halides to give intermediates which on treatment with fluoride give ketones in moderate yield .56

2: Aldehydes and Ketones

R’

A

PhS

P h S -SiMe,

SiMe3

PhS

ii,ii i

/ / .. ...

A Si

PhS

02

Me3

R’

02

02

R1

-

v,vi

R’ifR2 0

PhS 02

Reagents: i,2.2eq.m-CtC6H4C03H,-23OC;ii,

BuLi , T H F ; i i i , R X ; i v , MejSiCI; v,DIBAL-H

or L i A I H 4 ; v i , oxidation

Scheme 3

SPh

Reagents : i

, P h S h , BF3 .EtZO ; ii, B u L i ; iii, RCHO; iv, CS2; v , Me] ; v i ,

H S n B u j ; vii,

hydrolysis

Scheme 4

Reagents: i

, Ph3PHBr

j

77

i i ] B u L i iii,OHC(CH2)30THP; i v , S i 0 2 , C H Z C I Z

Scheme 5

78

General and Synthetic Methods

Many protected cyanohydrins are in occasional use as nucleophilic acylating agents. For example, dimethylaminoacetonitrile has been used for syntheses of 7-cyclocitral ( 1 ) (Scheme 6 ) 5 7 and artemisia ketone , 5 8 sequences which may procede via quaternary ammonium intermediates. Cyano-carbonates are readily prepared by addition of an aqueous solution of a metal cyanide to a solution of the aldehyde, a chloroformate, and a catalytic amount of a phase-transfer reagent .59 At low temperature these derivatives form anions which are excellent acyl transfer agents for enones and acrylates [equation ( 5 1 1 . 6 0 A review of three-carbon homologating agents6 includes discussion of, inter alia, the use of allylic anions and propionaldehyde homoenolate62 equivalents for the preparation of aldehydes and ketones. Homoenolate equivalents are themselves the subject of a review.63 The stereochemistry of condensations of allylic carbarnate anions is beginning to be unravelled with the reports of syn-diastereoselectivity in reactions with carbonyl compounds [equation ( 6 ) 1. 64 The direct formation of a homoenolate equivalent by deprotonation of propiophenone silyl enol ether has been demonstrated [equation (711.65 The anion was successfully trapped by alkyl iodides. Chirality transfer has been demonstrated in the reactions of allylstannanes with aldehydes (Scheme 7) .66 Although the product enol ethers were cleaved to acid derivatives, the stereoselection is equally appropriate to the aldehydes which should be obtained on hydrolysis. Other Methods.- Electrophilic formylation of electron-rich arenes may be carried out in moderate yield by the bis-phenylthiocarbenium ion.67 The ion is generated by treatment of tris(pheny1thio)methane with dimethyl(methy1thio)sulphonium tetrafluoroborate, other thiophiles being far less efficient. This carbenium reagent appears to be significantly more reactive than the 1,3-dithienium salt. The use of acyl fluorides in conjunction with boron trifluoride gives rise to different isomer distributions in the acylation of condensed aromatic systems, when compared with acyl chlorides and aluminium chloride .68 This suggests, since the yields are also higher, that certain reassessments of substrate reactivity may be necessary. Mixed trifluoromethanesulphonic anhydrides are recommended for the cyclization of 3- and 4-arylalkanoic acids to

79

2: Aldehydes and Ketones

(1) Reagents: i , MeZNCHZCN,KzC03, D M F ; ii , A g N 0 3 , H 2 0 , E t z O , T H F

Scheme 6 CN Ph A C O O E t

General and Synthetic Methods

80

M ~ ~ B U ' S+~ O ~ i

EtMe2 AJ ' i , R1 ii,I HCI

ButLi

Ph

Ph

Higher

(71

ph

Rf

Lower R f

?"

OH ROH =HoQ

,

R e a g e n t s : i ROCH2CI j i i , PhCHO, heat

Scheme 7

CH2C12, BF3 * Et 2-7BoC* 0

w O S i M e 3

/

L O S i M e 2 P h

i*ii

y S i M e ,

OYoEt

1

i , iii ,iv

TR v

T

R

0

OYOEt R e a g e n t s : i , BuSLi,-78OCj i i , e O E t , H*; i i i , l i ( O P r i ) 4 ; i v , RCHO;v, H30+

Scheme 8

(8)

2: Aldehydes and Ketones

81

cyclic aryl ketones, an extension of the known use of these acid derivatives for intermolecular reactions. 69 Reactions of epoxides, including their rearrangements into carbonyl compounds , have been reviewed. 70 The rearrangement of vinylsilane epoxides induced by boron trifluoride etherate at low temperatures is stereospecific, an outcome of significance when considered in conjunction with the rich chemistry known for the product enol ethers [equation ( 8 ) 1 . Vinylsilanes can be prepared by the Peterson reaction, which has aiso been the subject of review.72 A modification of the Peterson reaction using a titanium -ate complex derived from (I-a1koxy)allyltrimethylsilane offers a method for the three-carbon elongation of aldehydes (Scheme 8).73 3-Substituted propanals are the products from another three-carbon extension, this time centred on the reactions of 3-methoxy- 1 -phenylthioprop-1 -ene (Scheme 9 ) .74 In the context of conversion of sulphur derivatives into carbonyl compounds, Pummerer rearrangement of sulphoxides by zinc iodidecatalysed reaction with ketene silyl acetals offers a very mild method for this transformation .75 The methoxymethyl enol ether derived from alkyl phenyl ketones is deprotonated specifically B- and cis- to oxygen.76 The resulting vinyl anion is very reactive towards common carbon electrophiles [equation ( 9 ) l . Palladium catalyses the coupling of enol phosphates with organoaluminium reagents .77 By incorporation of a sulphide into the ketone prior to enol phosphate formation, 1,2- and 1,3-carbonyl transpositions with alkylation are possible (Scheme 10). Trialkyltin chlorides catalyse the migration of a primary alkyl group to the adjacent acetylenic carbon in lithium 1 alkynyltrialkylborate complexes .78 On a standard work-up of the alkenylborane, the tin residue is lost, leading to the formation of 2-Alkyl-1,3,2-dithiaborolanes react with the ketone (Scheme 11). trichloromethyl-lithium to afford, after simple hydrolysis with aqueous sodium hydroxide, the aldehyde protected as the thioacetal (Scheme 12) .79 Of note here is the efficient use of a single alkyl residue. Displacement of a-pinene from isopinocamphenylboranes provides a convenient route to chiral boronic esters of high enantiomeric purity. 8 o By applying established reactions to these intermediates, asymmetric acyclic ketones may be prepared in high chemical and optical yields (Scheme 13). (~-l-Arnino-2-(silyloxymethyl)pyrrolidines have been described for the (h.p.1.c.) chromatographic resolution of aldehydes

General and Synthetic Methods

82

R e a g e n t s : i , N a H , T H F ; ii M e l j i i i , R M g X , ( N i C 1 2 ( d p p p ) ] i v , h y d r o l y s i s ; v, b a s e ; v i , E'

Scheme 9

0-OMe

Bu'Li

OnOMe

E+

0-OMe

-Ph%E H

H

H

R e a g e n t s : i , L i N P r ' 2 ; i i , P h S S P h ; i i i , N a H ; i v , C I P ( O ) ( O P h ) 2 ; v , Me3AI,[Pd(PPh3),+],

80 .C; v i , T i C l 4 , H 2 0 j v i i , P h S L i

Scheme 10

83

2: Aldehydes and Ketones

0

Reagents: i , 9-BBN;

ii

, RCECLi;

i i i , C I S n B u 3 ; iv, N a O H , H202

Scheme 11

,

Reagents : i BHBr 2. MeZS ; ii

, LiS(CH 212 S Li ; iii, LiCX3 ; i v , T H F ; v , NaOH , H 20 Scheme 12

1

iv, v

...

vi,vii

R

PR1

E t O O B p H

R e a g e n t s : i, BH3.Me2S; i i , c i s - b u t - 2-ene; iii, MeCHO; iv,LiAIH&;v, RCH=CH2; vi, LiCCl20Me; v i i , o x i d a t i o n

Scheme 13

84

General and Synthetic Methods

their diastereomeric hydrazones. a 1 Cyclic Ketones.- Acid-catalysed ring expansion of cyclopropyl derivatives remains a versatile method for the synthesis of cyclobutanones. A further reagent f o r the preparation of suitable substrates is l-lithio-l-ethoxycyclopropane, readily generated from the alkoxybromocyclopropane (Scheme 14).82 Ring expansions of 1 vinylcyclopropanols can be controlled to give either cyclobutyl or cyclopentyl compounds (Scheme 15). 83 Methods for the fusion of five-membered rings onto other rings have been reviewed. 84 Cyclopropenone acetals take part in cycloaddition reactions with electron-deficient alkenes to introduce a cyclopentane ring [equation (1011.85 The principle for an annulation to give exocyclic methylenecyclopentanones has been demonstrated by the reaction of a-bromoalkyl esters with the dianion of succinate esters,86 or the vinylogous diester dianions” (Scheme 1 6 ) . Considerable attention has been paid in the past to the stereoselective synthesis of 2,3-disubstituted cyclopentanones. An approach to the formation of cis-3,4-disubstituted cyclopentanones has been revealed in the rhodium-catalysed cyclization of suitable pent-4-enals [equation ( 1 1 11. 88 The stereoselectivity may be understood in terms of the migration of hydrogen in the sterically more favourable acylrhodium intermediate ( 2 ) where the alkyl groups are transoid. Functionalized cyclopentenones are also available by cyclization of alkoxyallene adducts of 2-trimethylsilyl derivatives of 8-keto-aldehydes [equation ( 12) 1. 89 Palladium(I1) complexes catalyse the cyclization of 1 ethynylprop-2-enyl acetates to cyclopenta-l14-dieny1 acetates, and hence to cyclopentenones by hydrolysis. Ally1 propargyl ethers give substituted cyclopentenones on treatment with hexacarbonyldicobalt [equation ( l 3 ) ] .” Bicyclic ketones are also the product of cyclization of radicals generated by deoxygenation of 2 cyanoalkylcyc loalkanols .9 2 Hex-5-enoyl cyanides undergo thermal cyclization 2 an ene reaction to afford cyanohydrins which give cyclohex-2-enones on hydrolysis [equation (14)] . 9 3 The presence of an alkyl substituent at C-5 appears to be necessary for the ene reaction to take place. Intramolecular palladium-catalysed allylation of B-keto-esters has been shown to retain chirality at the allylic carbon atom provided the cyclization is carried out on the sodium salt

2: Aldehydes and Ketones

EtOxOSiMe3

,

~

85

EtOXBr

.. ...

R e a g e n t s : i , P B r 3 ; ii, B U ' L i ; i i i , R1R2CO; i v , H B F 4 , H20

Scheme 14

i -v

v i , vii

'

OSiMe3

0siMe3

4

R

R e a g e n t s : i , Br2; i i , H 2 O ; i i i , M e O H , S O C I z ; i v , d i h y d r o p y r a n j v , L i A I H q ; vi,(COC1)2, DMSO; vii,(RO)ZPOCHLiR;

v i i i , E+; i x , pyH*OTs-;

Xc

M e ~ S i C l ; x i ,600 "C

S c h e m e 15

n

-

General and Synthetic Methods

86

Pr ' 0,C

C0,Pr'

0

Scheme 16

LRhCI(PPh3) 33

+

r

1

R2(111

2: Aldehydes and Ketones

87

-4

(141

R’R?’

;r

;I

%I

MeNH

H

ONa

I

Ph

R e a g e n t s : i , RSO$-I ; i i , M e O H , H * j i i i , b a s e ; i v , C H ~ N Z

Scheme 17

88

General and Synthetic Methods

The use of the salt instead of the neutral [equation (15)].94 species also leads to shorter reaction times. An approach to the synthesis of optically pure 3-substituted cycloalkanones has been described which centres on reactions of monoacetals of prochiral non-enolizable diones .95 Monoacetalization with a chiral diol allows resolution by separation of the resulting mixture of diastereomers. A range of reactions, including retro-Claisen condensations, are then appropriate for the ring cleavage to the chiral cycloalkanone (Scheme 17). Moderate enantioselectivity is also observed in the cleavage of the dione itself with chiral bases, for example sodium salts of a-aminoalcohols .96 Kinetic resolution has been observed in related Robinson-type annelations of certain racemic diketones catalysed by proline. 97 Rearrangement of 8-hydroxyselenides is the key step in an established method f o r the ring enlargement of cyclic ketones. Acid conditions must be avoided for the rearrangement as this can lead to olefin formation as a significant side-reaction, but thallous ethoxide in chloroform has now been developed as a reagent which acts both as a base and as a co-ordinating agent for selenium to induce the reaction (Scheme 18).98 Ring expansion of cyclic acyloins by three carbon atoms to Ij5-dicarbonyl compounds may be accomplished in few steps, as exemplified by an approach to a substructure of the taxane skeleton (Scheme 19) .99 Acetylenic oxyCope rearrangements may be used for the expansion of cyclohexanones to cyclodecadienones [equation (16)l. l o o An equivalent f o r the butadienyl carbenium ion has been described, generating a new route to terminal dienes with potential f o r the macro-expansion of ketones (Scheme 2 0 ) . 10 1 2 Synthesis of Functionalized Aldehydes and Ketones

Unsaturated Aldehydes and Ketones.- Ultrasonic irradiation has been reported to shorten reaction times and improve yields in the aldol dimerization of ketones catalysed by basic alumina. l o * Unlike reactions of dialkylamide bases, which show only moderate selectivity for deprotonation at the terminal carbon of alkyl trimethylsilylmethyl ketones, very high selectivity is observed for alkyl-lithium reagents. I o 3 Such enolates take part in rapid condensation reactions with aldehydes to form (E)-a,B-unsaturated ketones in an alternative to the Horner-Wadsworth-Emmons reaction.

89

2: Aldehydes and Ketones

R e a g e n t s : i, RSeCR'R*Li;

ii, T I O E t , C H C I 3 , 20 "C

S c h e m e 18

CI

+

-

I, I1

+

TMS

TMS

.

IV

TMSO

= Me3Si

TMSO

R e a g e n t s : i, Z n C l 2 ; v, NaIOk

ii, p y r i d i n e ; iii, EtALCl2, -78 'C,

2 h; iv, EtAlCL2,-78 "C, 0.5 h ;

S c h e m e 19

aR a *

NaH, M e 0 CH2CHzOMe

OH

0

(161

General and Synthetic Methods

90 LIO

i-iv

+A

+-Br

Si Me3

OHC'

n = 1,2,7 or 8 Reagents

I,

Mg,SiMe3CI,

11,

Bu"LI,

V I , SnCIb, CH2CL2; vii, IX,

III,

(CH20)x,

IV,

CHZ= CHCH=CHLi,

PCC, v, HZ, Pd-BaSOL, p y , v i i i , SiMe3C1, ( M e 3 S i I 2 N H ,

200 "C

S c h e m e 20

R' Si Me3

Reagents

I,

BrCH2SO2Br,

R'

hu, ethylene

oxide,

S c h e m e 21

11,

DBN

91

2: Aldehydes and Ketones

The p r e f e r r e d b a s e s were I-(trimethylsi1yl)alkyl-lithium r e a g e n t s a s t h e s e showed l o w e r t e n d e n c y t o a d d t o t h e s t a r t i n g k e t o n e g r o u p . a,b-Epoxysilanes react w i t h molybdenum(I1) a c e t a t e t o form t h e e n o l a t e r e g i o s p e c i f i c a l l y . lo'

I n t h e presence of benzaldehyde t h e

e n o l a t e r e a c t e d t o form t h e enone i n a n a l d o l - t y p e [ e q u a t i o n (17)l.

reaction

A p a r t i a l l y dehydrated commercially a v a i l a b l e

barium hydroxide p r e p a r a t i o n h a s been d e s c r i b e d f o r t h e condensation of a l k y l ketones with aromatic aldehydes. lo5 A d v a n t a g e s o f t h i s r e a g e n t i n c l u d e t h e s u p p r e s s i o n o f t h e m a j o r byp r o d u c t s d e r i v e d from C a n n i z z a r o r e a c t i o n s a n d s e l f - c o n d e n s a t i o n o f the ketone. Moderate y i e l d s o f a - a l k y l i d e n e k e t o n e s r e s u l t from b a s e t r e a t m e n t o f a - ( b r o m o a l k y l ) s u l p h o n y l k e t o n e s . Io6

The s u b s t r a t e s

a r e r e a d i l y f o r m e d from t h e e n o l s i l y l e t h e r a n d t h e s u l p h o n y l b r o m i d e (Scheme 2 1 ) . C a r b o n y l a t i o n of u n s a t u r a t e d h y d r o c a r b o n s h a s p r o v e d t o be a v e r s a t i l e r o u t e t o enones.

Palladium-catalysed carbonylation of

t e r m i n a l a l k y n e s and a r y l i o d i d e s i n t h e p r e s e n c e o f d i c y c l o p e n t a d i e n y l t i t a n i u m d i c h l o r i d e and a zinc-copper v i n y l k e t o n e s . Io7

couple a f f o r d s a r y l

Without t h e t i t a n o c e n e p r e s e n t r e a c t i o n

p r o c e e d e d , b u t was v e r y s l o w .

Alkyl acetylenes appeared t o give

c l e a n e r p r o d u c t s t h a n a r y l a l k y n e s . Cross-coupling of a l l y l h a l i d e s l o 8 and v i n y l i o d i d e s l o g w i t h carbon monoxide and v i n y l s t a n n a n e s g i v e s f l e x i b l e r o u t e s t o a l l y l v i n y l k e t o n e s and unsymmetrical d i v i n y l ketones r e s p e c t i v e l y .

Regiochemistries of

t h e d o u b l e b o n d s a r e r e t a i n e d i n t h e i n i t i a l p r o d u c t s , b u t it i s a d v i s e d t o keep r e a c t i o n s i n t h e d a r k t o minimize subsequent

2-

to

E-isomerization. I n an e x t e n s i o n t o an e s t a b l i s h e d enone s y n t h e s i s , n i t r o n a t e a n i o n s have been found t o add t o a l l e n e s and 1 , 3 - d i e n e s i n t h e presence of a c y l - c o b a l t

c a r b o n y l s t o a f f o r d enone d e r i v a t i v e s i n

m o d e r a t e y i e l d [ e q u a t i o n ( 1 8 ) 1. D i m e t h y l s u l p h o x i d e was p r e f e r r e d t o THF owing t o t h e much h i g h e r s o l u b i l i t y o f t h e nitronate anion i n t h i s solvent.

a - A c e t y l e n i c a l c o h o l s may b e

converted i n t o e n a l s through t h e intermediacy of v i n y l s u l p h i d e s s i n c e t h e a d d i t i o n o f t h i o p h e n o l t o such a l k y n e s h a s been found t o be h i g h l y r e g i o s e l e c t i v e .

H y d r o l y s i s c o u l d b e e f f e c t e d by s t e a m

d i s t i l l a t i o n f r o m a q u e o u s a c i d c o n t a i n i n g s u l p h o l a n e t o remove t h e nucleophilic thiophenol released i n the reaction.

Alternatively a

t w o - p h a s e s y s t e m u s i n g p e n t a n e t o e x t r a c t t h e t h i o p h e n o l a s i t was formed proved s a t i s f a c t o r y .

92

General and Synthetic Methods

-

R R e a g e n t s : i, MeNHOH;

I

iii

i;, CHZ= C H S i M e 3 ; ill, H F

Scheme 22

R’

X = S i M e , or Ac

\

0

R’

I solvent

Reagents :

i, Pd’L,;

ii, PdOL,,

LR

0WoCo2R

S c h e m e 23

= MeCN

2: Aldehydes and Ketones

93

Fuller details on the scope of and conditions for the cuprate addition to acetylenic acetals to form a18-unsaturated derivatives have appeared. 112 The cycloaddition of an aldehyde-derived nitrone to vinyltrimethylsilane is central to a new homologation of aldehydes to unsaturated aldehydes (Scheme 2 2 ) A detailed investigation of factors controlling the fates of allyl-palladium enolates (8-elimination, protonation, and allylation) has shown that nitrile solvents are preferred for the selectivity of 8-elimination to the enone. l 4 Surprisingly, it was also found that phosphines need not be present for this catalytic dehydrogenation of ketone derivatives (Scheme 23). Some aspects of selenium chemistry in the dehydrogenation of ketones to enones have been reviewed.'15 The direct oxidation of ally1 selenides to unsaturated ketones has been observed using two equivalents of mchloroperbenzoic acid (Scheme 24). 116 a-Methylene-cyclopentenones and -butanones may be constructed from chloro[(trimethylsilyl)methyllketene, which acts as an In one recent equivalent for methyleneketene (Scheme 25). "7 synthesis of methylenomycin B ( 3 ) , a sulphoxide was used for both ring closure and elimination to the exocyclic alkene, l 8 whereas in a second approach the exocyclic double bond equivalent was carried through the ring-forming reactions as the methylthiomethyl group (Scheme 26). Phosphonates related to the intermediates may also be transformed into a variety of acyclic enones. 120 Copper-catalysed additions of Grignard reagents to 2-(2,Zdiethoxyethy1)oxirane afford aldol acetals which are readily hydrolysed to enals [equation ( 19 ) 1 . 21 Amongst new synthetic equivalents to a-anions of enones are 1 bromo-2-ethoxycyclopropyl-lithium (Scheme 27) 2 2 and the bicyclic diketones ( 4 1 , which are easily prepared from their parent (Scheme 28) . 2 3 Methoxyallyl sulphides offer potential for the formation of amethylene ketones,124 or a variety of more highly substituted enone derivatives (Scheme 29). 125 4-Phenylthio-N,N-dimethylaminobutyronitrile is described for the preparation of vinyl ketones [equation ( 2 0 ) l . 126 Of broader scope is the allylic alkylation of the condensation products from ketones and tosylmethyl isocyanide, leading to a wide range of alkene substituents (Scheme 30). 127 The sequential alkylation of the anion from 3-methylthioprop-2-enyl 2-tolyl sulphone offers another

.

General and Synthetic Methods

94

A-

CI

_r"c

SePh

i- &SePh

R = (Me02C),CH, PhO, PhNAc Reagents :

i,

PhSeCl, C C I L ; ii, R-Na';

iii, 2 e q rn-C1C6H4CO3H

Scheme 24

-

RHR2 iv

M e,Si

0

R e a g e n t s : i, SOClz ; ti, N C S , SOCL2;

ii;, Et3N, R'CH=

S c h e m e 25

CI

CHR2; i v , B u L N + F -

-

2: Aldehydes and Ketones

NMePh

i-iii

L

~

M

e

P

h

II

OH

Reagents

I,

LiNPr'2;

v,

Mel, NaOH, H20-CH2C12,

VII,

x,

11,

HCIOL,

XI,

0

PhSCH2CH2COMe,

cNCH2SMe.HCI,

VIII,

0

*lPh

I V

SPh

95

lv

m-CLC6H4CO3H,

111,

BzN+Me3CL-, KZC03, (CH20),

2°/0NaOH, E t O H ,

XII,

VI,

,

NaIOL;

S c h e m e 26

IX,

IV,

3 e q LiNPr'2;

110 "C, 0 0 2 T o r r , (EtS)(EtSO)CMeLi, XIII,

NaHC03

General and Synthetic Methods

96

EtO

E t O Y R AcO

AcO R e a g e n t s : I, Bu"Li;

11,

RCHO;

(11,

KZC03, EtOH,

IV,

H30+;

v , NaBH3CN

S c h e m e 27

Reagents :

i, M e O N a , H S C H 2 C 0 2 M e ;

II,

K2C03,

Scheme 2 8

E+;

111,

a q . NaOH

97

2: Aldehydes and Ketones

. ..

R' &SPh

I , I1

R' OMe

PhS, R l A y R 2

PhS-R3

0 Me

-

IiVJ

-

OMe

OMe

I

it.p"

...

Ill

i v , vii

R3qR2

R'

0

OMe Reagents :

i, Me SiCH2MgCl; i;, NaH; iii, NaIOl;

iv, BunLi; v, R 2 X ; vi, S i O z ;

vii, R 4

S c h e m e 29

CN

CN

0

98

General and Synthetic Methods

I Reagents:

I,

p-MeC6HLS02CH2NC; i;, B u t O K ; iii, R 3 X ;

..

..,

II,

1II

i v , H30+

Scheme 30

Et3N, CHZClZ

R 2 = HorMe

(23)

* 0

99

2: Aldehydes and Ketones

method for the preparation of B,B-dialkylenals. 128 The conditions employed for the protonation of adducts of electrophiles with 3-alkoxyallenyl-lithium reagents are crucial for the geometry of the product enones, higher temperatures favouring 129 the (E)-isomer. l-Alkenyl-9-borabicyclo[3.3.l]nonanes react by conjugate addition-elimination with methoxy- and dialkylamino-vinyl ketones to give I-acyl dienes [equation (21 11. I3O A stable precursor of 2acetylbuta-1,3-diene is 3-acetyl-2,5-dihydrothiophene 1,l-dioxide, prepared in three steps from p-dithiane-2,5-diol. a-Sulphinyl ketones bearing a- and B-hydrogen atoms undergo an interesting elimination to a-phenylthio-a,B-unsaturated ketones on treatment with stannous triflate [equation (22)1, 132 and dehydrochlorination o f chloromethyl ketones derived from aminoacids has been observed to give methyl a-amino-a,@-enones [equation ( 2 3 1 . 133 Selective alkoxy-acylation of enynes is possible if the acetylene is protected as its hexacarbonyldicobalt complex (Scheme 31).134 The regioselectivity is a function of the stability of the intermediate carbenium ion. Oxidative fragmentation of r-trialkylstannyl alcohols with either lead tetra-acetate 35 or iodosylbenzene , boron trifluoride etherate , and dicyclohexylcarbodi-imide' 36 leads to keto-olef ins whose stereochemistry is determined by the geometry of the starting material [equation (2411. Carboxylic acid anhydrides appear to be the acylating agent of choice for the formation of a,B-acetylenic ketones from acetylenes via lithium alkynyl trifluoroborates. 137 Diethyl phenyl orthoformate has been shown to be far superior to the triethyl derivative for the formylation of acetylenic Grignard '39 reagents. &-Substituted Aldehydes and Ketones.- Ketone enolates can be oxidized to a-hydroxy-ketones using 2-sulphonyloxaziridines . " The direct oxidation of the ketone to the a-hydroxy-acetal may be carried out by reaction with 2-iodosylbenzoic acid in methanol. 141 Amino-groups are not oxidized by this reagent' nor by (diacetoxyliodobenzene, allowing the preparation of B-amino-derivatives. 142 A direct homologation of aldehydes to a-silyloxy-aldehydes by [(C0)5MnH]

and [(CO)5MnSiMe3]

(25 )I.

A new one-carbon homologation of ketones to a-hydroxy-

43

has been described [equation

100

General and Synthetic Methods

L

I

Co,(CO 16

1

ii, iii

Reagents : i, R'CZO'

BFG-; ii, R50H; iii, N a H C 0 3 ; i v , Fe (N03t3

S c h e m e 31

CHO

(CO),Mn-SiMe,

+

+

(CO1,MnH

RCHO

RY

(251

OSiMe3

HO R'

Reagents:

i,

CICH2SO2Ph, B u t O K ;

R, x , 2

i i , ButOK, H20

S c h e m e 32

CHO

2: Aldehydes and Ketones

101

aldehydes in two steps involves a Darzens condensation with chloromethyl phenyl sulphone followed by ring-opening of the epoxysulphone with hydroxide ion (Scheme 32). Further details have been published on the synthesis of chiral tertiary a-hydroxyaldehydes based on ketone homologation reactions of asymmetric 1 , 3 oxathiane anions. 1 4 5 ' a-Hydroxy-carbonyl compounds are the products from hydroxylation of vinylphosphonates by osmium A wide variety of tetraoxide and N-methylmorpholine !-oxide. substrates is available by standard carbonyl olefination reactions. Such olefinations may also be carried out using a phosphorane derived from lactic acid, enabling a chiral synthesis of a t acetoxy-a,B-unsaturated ketones (Scheme 33). 148 a'-Acetoxylation of cyclic enones may be carried out with dried manganese triacetate. 1 4 9 An interesting conversion of allylic alcohols into a-hydroxyketones uses the regiospecificity of iodination of an ally1 carbonate [equation (26)l. I5O Homoallylic alcohols give the Bhydroxy-ketone. Methods for the formation of sulphur-substituted carbonyl compounds continue to be developed, as such compounds have considerable use in organic synthesis. Sulphosilylation of carbonyl compounds, including both aldehydes and ketones, to form trimethylsilyl 2-oxosulphonates may easily be accomplished using trimethylsilyl chlorosulphonate. The very hydrolysis-sensitive a-oxosulphines have been prepared by the reaction of ketone silyl enol ethers with thionyl chloride.152 These compounds show an interesting cycloaddition with dienes to form highly substituted aketo-sulphoxides (Scheme 3 4 ) . S-Alkyl toluene-p-thiosulphonates are efficient electrophilic thiolating agents for (cyclic) ketone enolates. 1 5 3 Under aprotic conditions, thiolate anions may be used f o r the formation of asulphenylated aldehydes by displacement from a-chloro-aldehydes . 54 However, in the presence of water or methanol, a-hydroxy-aldehydes or acetals are also formed. The reaction may be applied to a , a dihalogeno-carbonyl compounds. Isopropenyl acetate causes a Pummerer-type reaction of phenyl vinyl sulphoxides to afford a-phenylthio-carbonyl compounds. The method offers a convenient route to phenylthioacetaldehyde. aSulphenyl-carbonyl compounds may be prepared by the treatment of a ,B-epoxy-sulphoxides with alkyl thiolates. 156 The method is not applicable to selenium derivatives, as the use of sodium

'

General and Synthetic Methods

102

?At

VAc

?Ac

I

R e a g e n t s . i, Ph3P = C H C 0 2 B u t

; ii, C F 3 C 0 2 H ;

111;

RCHO

S c h e m e 33

OSi Me3 I, II

J. iii

Reagents

I,

base,

it,

Me3SiCL ;

111,

S O C l z , 2,6- L u t i d i n e ,

S c h e m e 31

IV,

2,3-dimethylbutadiene

103

2: Aldehydes and Ketones

phenylselenide leads to dialkyl ketones by deselenenylation. A full paper has appeared discussing the preparation of a-(2pyridylselenol-carbonyl compounds and their oxidative elimination to a , 0-unsaturated derivatives. Oxidation by dimethyl sulphoxide-phosgene has been found to be the only high-yielding method for the preparation of a-amidoaldehydes from amido-alcohols in which the nitrogen is in a 0lactam ring. No significant racemization was observed. Attempts to prepare the aldehyde by direct reduction of the acid were not successful. a-Allyloxy-enamines undergo ready low-temperature Claisen rearrangement, offering another method for the preparation of aamino-aldehydes [equation ( 2 7 ) 1. 59 Conditions have been described for the reduction of acyl nitriles to a-amino-ketones. Zinc in acetic acidlacetic anhydride mixtures affords good yields of acetamidomethyl ketones, provided the carbonyl is not further conjugated. I6O The trifluoroacetyl group has been shown to be a satisfactory protecting group for nitrogen during Friedel-Crafts acylations of electron-rich arenes by a-amino-acid derivatives. This group also has a second advantage in that it allows simple 1-alkylation prior to hydrolytic removal. Arylazoalkenes react with aromatic amines in the presence of copper(I1) salts to give a-arylamino-hydrazones, a reaction which may be employed with anilines substituted by electron-withdrawing groups [equat ion (28)1 . Phase-transfer catalysis speeds the chromium(V1)-mediated oxidation of 2-nitro-alcohols as a route to a-nitro-ketones. ' 6 3 The substrates are products of the Henry nitro-aldol reaction. N-Chlorosuccinimide has been used for the direct chlorination of lithium ketone enolates. 16' The products may be treated with hydroxylamine to give a-chloro-ketoximes, which are precursors to nitrosoalkenes. The method is similar to one reported for the a'chlorination of u,B-unsaturated ketones which employs the kinetically derived lithium enolate. 16' In the presence of equimolar amounts of sodium iodide, N-chlorosuccinimide in acetone is a convenient source of the N-iodo-derivative, which readily converts enol silyl ethers into the a-iodo-ketone. '66 Alternative reagents for the chlorination of these substrates are sulphuryl chloride fluoride and sulphuryl chloride. 1 6 7 Newly described brominating agents for carbonyl compounds

'

"'

' '*

General and Synthetic Methods

104

R II N*N

-

ArNH2 cuc12

R’

RHN,

(28)

R1 NHAr

Ph2MeSi

Ph2MeSi

Ph2MeSi

liii

OMgBr

R1+

R1+

PhzMeSi

Ph2MeSi

R e a g e n t s : i, R M g X ;

ii, m o i s t E t 2 0 ; iii, C H z = C H M g B r

Scheme 35

0

RlYc0siMe3 + ----+R*MCJX

R2

S i Me3

Cl

Me3Si

(29)

I

R2

.1+R3

Me,S i CHRh(PPh3)Ll 0-0, 105°C

OH

W

*

R

1

4

0

R

3

(30)

2: Aldehydes and Ketones

105

i n c l u d e 4- ( d i m e t h y 1 a m i n o ) p y r i d i n e b r o m i d e p e r b r o m i d e 168 a n d t h e The c o m b i n a t i o n o f t - b u t y l b r o m i d e a n d d i m e t h y l s u l p h o x i d e . 16' l a t t e r system i s i n t e r e s t i n g f o r i t s a p p l i c a b i l i t y f o r t h e bromination of a l d e h y d e s , and t h e h i g h s p e c i f i c i t y f o r r e a c t i o n a t t h e more h i g h l y s u b s t i t u t e d a - c a r b o n i n u n s y m m e t r i c a l d i a l k y l ketones. A cross-linked

co-polymer of s t y r e n e and 4 - v i n y l p y r i d i n e h a s

been d e s c r i b e d as a v e h i c l e f o r h a l o g e n a t i n g a g e n t s f o r a c e t o p h e n o n e s and 1 , 2 - d i c a r b o n y l compounds. I 7 O

Chlorinations of

d i k e t o n e s by p o l y m e r s c o n t a i n i n g N - m e t h y l p y r i d i n i u m t e t r a chloroiodate residues resulted i n e f f i c i e n t formation of dihalide derivatives.

gem-

Low y i e l d s i n t h e b r o m i n a t i o n of s o d i u m

a c e t o a c e t a l d e h y d e have been a t t r i b u t e d t o t h e d e l e t e r i o u s e f f e c t o f a c i d r e l e a s e d i n t h e r e a c t i o n of e x c e s s bromine w i t h sodium f o r m a t e , a m a j o r i m p u r i t y i n t h e s u b s t r a t e f o r m e d by C l a i s e n condensation. 17'

A s o l u t i o n t o t h e p r o b l e m , and i m p r o v e d i s o l a t i o n

c o n d i t i o n s , f o l l o w from t h e u s e of n.m.r.

spectroscopy t o determine

f o r m a t e l e v e l s , a l l o w i n g t h e u s e of p r e c i s e l y one e q u i v a l e n t o f bromine. The r e a c t i o n o f o r g a n o m a n g a n e s e r e a g e n t s w i t h a c i d c h l o r i d e s h a s b e e n e x t e n d e d t o i n c l u d e t h e u s e of a - s u b s t i t u t e d a c i d d e r i v a t i v e s , a s a c o n v e n i e n t r o u t e t o h a l o g e n a t e d k e t o n e s . 172 G r i g n a r d r e a g e n t s c a n a l s o be u s e d p r o v i d e d r e a c t i o n t e m p e r a t u r e s a r e k e p t b e l o w -78 O C . 173 The p r e p a r a t i o n o f h a l o g e n o m e t h y l k e t o n e s f r o m halogenomethyl-lithium

r e a g e n t s i s hampered by t h e low s t a b i l i t y o f

t h i s t y p e of r e a g e n t .

However, t h e y c a n be made p r o v i d e d t h e y a r e

g e n e r a t e d by m e t a l l a t i o n o f t h e b r o m o h a l o g e n o m e t h a n e i n t h e p r e s e n c e o f one e q u i v a l e n t o f l i t h i u m b r o m i d e i n T H F - d i e t h y l p e n t a n e s o l u t i o n s a t low t e m p e r a t u r e ( - 1 1 0 e s t e r s g i v e s t h e h a l o g e n o m e t h y l k e t o n e . 174

OC).

ether-

Reaction with

Treatment of s t a n n o u s c h l o r i d e w i t h di-isobutylaluminium h y d r i d e g i v e s a r e a g e n t capable of dehalogenating a-bromo-ketones under mild c o n d i t i o n s . 175 The combination of aluminium c h l o r i d e and e t h a n e t h i o l c o n v e r t s a-halogeno-ketones i n t o t h e d i t h i o a c e t a l of t h e c o r r e s p o n d i n g d e h a l o g e n a t e d k e t o n e . 176 O f n o t e i s t h e a b i l i t y o f t h i s r e a g e n t s y s t e m t o r e d u c e away a n y h a l o g e n , f l u o r i n e included. Reaction of a - s i l y l - e s t e r s t h e substituted ketone.177

with excess Grignard reagent l e a d s t o

The k e t o n e i s p r o t e c t e d i n t h e r e a c t i o n

m i x t u r e by e n o l a t e f o r m a t i o n , w h i c h l e a d s t o a n i n t e r e s t i n g v a r i a t i o n with v i n y l i c Grignard r e a g e n t s , g i v i n g a l k e n y l

General and Synthetic Methods

106

d e r i v a t i v e s ( S c h e m e 3 5 ) . G r i g n a r d r e a g e n t s a l s o r e a c t w i t h achloroacylsilanes t o give a-silyl-ketones 78 G r i g n a r d r e a g e n t s

.

b e a r i n g B-hydrogen

’

atoms reduce t h e s u b s t r a t e t o t h e a - s i l y l -

a l d e h y d e , which t h e n reacts t o g i v e t h e a l c o h o l , b u t r e o x i d a t i o n t o t h e k e t o n e was r e p o r t e d t o be p o s s i b l e [ e q u a t i o n (29)l. S i l y l enol e t h e r s with s t e r i c a l l y hindered s i l y l groups have b e e n shown t o u n d e r g o a 1 , 3 r e a r r a n g e m e n t t o t h e a - s i l y l - k e t o n e t r e a t m e n t w i t h a c o m b i n a t i o n of n - b u t y l - l i t h i u m butoxide,

on

a n d p o t a s s i u m t-

w h e r e a s a 1 , 4 m i g r a t i o n of s i l i c o n i s o b s e r v e d o n

t r e a t m e n t of k e t o x i m e 0 - s i l y l e t h e r 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 180 t o give the a-silyl-ketoxime. H i g h t u r n o v e r s of a r h o d i u m c a t a l y s t h a v e b e e n o b s e r v e d i n t h e i s o m e r i z a t i o n of s i l y l a t e d a l l y 1 a l c o h o l s . 18’ e l i m i n a t e s a n y n e e d for a q u e o u s w o r k - u p

The m e t h o d

of t h e r e a c t i o n m i x t u r e

[ e q u a t i o n (3011. Regiospecifically monosubstituted a-deuteriated

alkyl ethyl

k e t o n e s h a v e b e e n p r e p a r e d by t h e ruthenium(II1)-catalysed isomerization of 0 - d e u t e r i a t e d

v i n y l c a r b i n o l s . 182

Competitive

r e a c t i o n s o c c u r r e d w i t h more h i g h l y s u b s t i t u t e d v i n y l i c g r o u p s , l i m i t i n g t h e s c o p e of t h e r e a c t i o n i n i t s p r e s e n t f o r m . D i c a r b o n y l Compounds.-

A s i m p l e method f o r t h e p r e p a r a t i o n o f

v o l a t i l e e s t e r s of g l y o x y l i c a c i d c e n t r e s on t h e a c i d - c a t a l y s e d e x c h a n g e of a l c o h o l b e t w e e n t h e a c e t a l e s t e r a n d g l y o x y l i c a c i d monohydrate, and t h e s u b s e q u e n t d e h y d r a t i o n of t h e h e m i a c e t a l h y d r a t e m i x t u r e w i t h phosphorus p e n t o x i d e . 183 The a b i l i t y t o p e r f o r m t h e d i r e c t o x i d a t i o n of e n o l i z a b l e k e t o n e s t o I l 2 - d i c a r b o n y l c o m p o u n d s i s o n e p r o p e r t y o f oxoammonium s a l t s [ e q u a t i o n ( 3 1 1 1 . 84

Other o x i d i z a b l e groups i n c l u d e amines ,

p h e n o l s , and p h o s p h i n e s . The t w o - c a r b o n h o m o l o g a t i o n o f a l d e h y d e s t o a - k e t o - e s t e r s a c h i e v e d by Horner-Emmons phosphonoglycolate

may b e

r e a c t i o n w i t h t h e a n i o n of a p r o t e c t e d

e s t e r [ e q u a t i o n (32)l. ’85

The t e t r a s u b s t i t u t e d

e t h y l e n e ( 5 ) i s a f u r t h e r t w o - c a r b o n u n i t f o r t h e p r e p a r a t i o n of a keto-esters

by a l k y l a t i o n w i t h t e r t i a r y a l k y l h a l i d e s , a n d a , 6 -

d i k e t o - e s t e r s by c o n j u g a t e a d d i t i o n t o u n s a t u r a t e d c a r b o n y l 186 compounds (Scheme 3 6 ) . D e r i v a t i v e s of s u b s t i t u t e d m a l o n a l d e h y d e s may b e p r e p a r e d by t h e d o u b l e f o r m y l a t i o n o f a c e t i c a c i d d i a n i o n s w i t h N,Ndimethylmethoxymethaniminium m e t h y l s u l p h a t e [ e q u a t i o n ( 3 3 ) l . 187 Where t h e s e c o n d f o r m y l a t i o n i s s l o w , for e x a m p l e w i t h a r y l a c e t i c

2: Aldehydes and Ketones

107

0 OCOR’

0

aR A c o 2 M e SR A C O z M r

0 RCHO + (Me0l2P

EtO

(321

OSiMe3

...

CO,E t

0 Et

OSi Me3

Iii

(5)

1.

IV,

ii

h 0

0

>/?

C02E t

c02et

0 R e a g e n t s : i, B u t C l , ZnC12; ii, MeOH, HCL;

111,

t)H R 1 R 2 C 0 , ZnC12; iv, cyclohexenone, ZnC12

Scheme 36

R CH 2C 0,H

iii, , Me2N=CH ZLiNPr’2 +

NMe2

‘02

+

‘<;Me2

(33)

108

General and Synthetic Methods

acids, chloromethaniminium salts were shown to be superior agents for the introduction of this substituent. Palladium salts are stoicheiometric reagents for the dehydrogenation of B-amino-ketones to enaminones. r88 a-Hydroxy-B-keto-esters have been prepared by the base-induced rearrangement of acyloxy-acetates [equation (34)l. Ethyl diazoacetate cyclopropanates silyl enol ethers of B dicarbonyl compounds. The ready acid-catalysed rearrangement of the adducts offers a simple method for the homologation of 1 , 3 - to 1,4-diketones. y-Keto-aldehydes may also be obtained from dichlorocyclopropyl ketones, 2 reaction with sodium methoxide followed by reduction of the product 2,2-dimethoxy-2,3dihydrofurans with lithium aluminium hydride (Scheme 37). 1 9 ’ By choice of the appropriate work-up conditions, the aldehyde may be isolated protected as the acetal. a-Keto-sulphoxides rearrange in the presence of silyl enol ethers and stannous triflate to give sulphenylated 1,Q-diketones In a similar manner , a-halogeno-ketones couple [equation ( 3 5 ) l . with tributyltin enolates under either palladium or ruthenium catalysis to give 1,4-diketones. Imino-derivatives of 1,4-diketones are available by the conjugate addition reaction of a,B-unsaturated carbonyl compounds with copper(1) aldimines, formed by the addition of alkyl-lithium reagents to isocyanides followed by metal exchange. Irradiation of phenyl alkyl ketones in the presence of chromium(V1) or manganese(V1) oxidants leads to the formation of 1,4-diketones. However, a dialkyl ketone, octan-2-one , gave mixtures of 1 , 4 - , 1 , 5 - , and 1,6-diketones. Sodium persulphate has been shown to oxidize aliphatic ketones to 1,4- and 1,5-diketones in the presence of ferrous ions.Ig6 Little selectivity was observed in the simple substrates used, but the reaction may find application in the remote oxidation of ketones of higher complexity. A convenient, if modest-yielding, route to 2-halogeno-1,5diketones lies in the Lewis acid-induced coupling of methoxyallyl alcohols with a-halogeno-silyl enol ethers. The products are precursors to diacylcyclopropanes [equation ( 3 6 1 1 . Orthoesters are acylating agents for silyl dienol ethers, giving unsaturated 1 , 5 diketones [equation ( 3 7 ) l . 198 1,6-Diketones result from conjugate addition of homoenolate equivalents to enones. Acylsilanes can act as precursors for the

2: Aldehydes and Ketones

109

(341

/

kii, v

L

R&OMe

O

OMe Reagents:

1,

NaOMe;

11,

LiAlH4;

;;I,

Me2CO; iv, 5"/. NaOH, H20;

v,

loo/" HCL, H20

S c h e m e 37

ArS

0

R2

R2

M e O p O H+ R'

x)+y~3 fi,o

X

R2

base_ o

BF3*E0 t2L

OSiMe,

R1

R3

h R'

o

(36)

R3

X = CL or Br

Z n C L2.EtZ0

+

R

O

-OSiMe3

n

(37)

110

General and Synthetic Methods

homoenolate through their reactions with vinylmagnesium bromide to form 3 - ( trimethylsilyoxy)allylmagnesium reagents (Scheme 3 8 ) .

3 Protection and Deprotection of Aldehydes and Ketones The conversion of aldehydes and ketones into acetals remains one of the most useful forms of protection for the carbonyl group. The heterogeneous catalyst aminopropylated silica gel hydrochloride has been described for the preparation of acetals under mild conditions. 2oo The catalyst is prepared by derivatizing silica gel with aminopropyltriethoxysilane and subsequent treatment with methanolic hydrogen chloride. Acetalization may also be achieved by the reaction with alkoxysilanes catalysed by iodotrimethylsilane. 2 0 1 Unsaturated aldehydes and ketones react with diols and halogeno-trimethylsilanes to give the 8 -halogeno-acetals .202 2,4,6-Collidinium toluene-p-sulphonate has been described as a catalyst for the selective ethylene acetalization of an C C , B unsaturated ketone in the presence of a saturated carbonyl group. *03 In the cyclic systems studied, the 2,6-lutidinium salt could also be used. The selective mono-acetalization of cyclohexane-l,4-dione may be performed easily in a hydrocarbonwater system for the effective extraction of the monoacetal into the organic solvent as it is formed. 204 Sulphuric acid is a suitable acid catalyst. Spirocyclic acetals are currently of considerable interest in organic synthesis. Cyclizations of alkenyl hydroxy-ketones have been shown to be induced by phenylselenophthalimide, in a reaction which promises to be generally useful [equation ( 3 8 ) l . 205 Unsymmetrical a-ketosilanes may be converted into the corresponding silyl enol ethers by treatment with catalytic quantitites of trimethylsilyl triflate. 206 An appropriate route to the substrates is offered by the acylation of trimethylsilylmethylcopper. t-Butyldimethylsilyl enol ethers may be formed under equilibrating conditions by treating the silyl chloride and the ketone with potassium h ~ d r i d e . ~ ' ~Amine bases and tbutyldimethylsilyl triflate will form the enol silyl ethers even from sterically hindered ketones .208 The deprotonation and trapping of cyclohexenones usually gives rise to cross-conjugated dienol ether derivatives. However, investigations of a zero-valent iron reagent,209 formed from iron(II1) chloride and methylmagnesium bromide, have shown its

2: Aldehydes and Ketones

R e a g e n t s : i, CH2 = CHMgX;

111

ii, H 2 0 ;

iii, Me3SiC

Scheme 30

0

CCu6Me2 ; iv, R2CH=CHCOR3

112

General and Synthetic Methods

potential for the formation of the isomeric derivatives under oxygen-free conditions from 3-alkylcyclohexenones .2 1 0 The reagent gives the endocyclic dienol silyl ether in the presence of trimethylsilyl chloride and triethylamine, whereas the same combination but with the addition of methylmagnesium bromide gives the exocyclic isomer. Acetals react with alkyl [t-butyl, B-(trimethylsilyl)ethyl] isocyanides and titanium tetrachloride to give cyanohydrin ethers in good yield.211 The use of trimethylsilyl cyanide for the formation of cyanohydrin trimethylsilyl ethers from ketones is well established. In the presence of electrogenerated acid, acetals may also be used as substrates.212 These products may be converted into a-aminonitriles by treatment with amines in alcoholic solution.*” 3 The combination of trimethylsilylmethyl azide and triphenylphosphine converts carbonyl compounds into N-C(trimethylsily1)m e t h y l l i m i n e ~ . ~a~,B-Unsaturated ~ aldehydes may be masked as 1 , 3 bis(dialkylamin0)-I-alkenes by treatment with trimethylsilyl derivatives of secondary amines . 2 1 5 Trimethylsilyl triflate is a useful catalyst for 0-substituted substrates. Tosylhydrazones may be prepared from a - and 8-keto-esters and tosylhydrazine in the presence of activated aluminium oxide. 2 1 6 Amberlyst-15 is established as a catalyst for the formation of acetals from carbonyl compounds. As might be expected, it may also be used for the efficient regeneration of the carbonyl group under very mild conditions.217 Cleavage may also be accomplished by dimethylboron and diphenylboron bromides. Regeneration of carbonyl compounds from dithioacetals can be effected by oxidation by triarylamine cation salts, either using stoicheiometric quantities, or under catalytic conditions using Ferric and electrochemical regeneration of the amine salt . 2 1 cupric chlorides supported on K-10 clay are alternative reagents for the cleavage of thioacetals, and are applicable to the formation of both aldehydes and ketones.220 The former reagent also regenerates the carbonyl compound from “-dimethylhydrazones ,221 a transformation also conveniently carried out by -m-chloroperbenzoi c acid at low temperature. 2 2 2 The known reductive cleavage of isoxazolines to 8-hydroxyketones has been extended to the regeneration of ketones from oximes at nearly neutral pH.223 The method uses Raney-nickel, boric acid, and hydrogen, in methanol containing acetone to

2: Aldehydes and Ketones

,113

s u p p r e s s r e d u c t i o n of t h e i n t e r m e d i a t e i m i n e .

Oximes, a n d oxime

e t h e r s and e s t e r s , a r e c o n v e r t e d i n t o k e t o n e s by i r r a d i a t i o n o r h e a t i n g i n t h e presence of i r o n c a r b o n y l s , a g a i n an e x t e n s i o n of i s o x a z o l i n e c h e m i s t r y [ e q u a t i o n ( 3 9 1 1 . 2 2 4 Net d e o x y g e n a t i o n o f o x i m e s by a m m o n o l y s i s o f t h e d e r i v e d n i t r i m i n e s o f f e r s a r o u t e t o s t e r i c a l l y h i n d e r e d i m i n e s . 225

T r i b u t y l p h o s p h i n e i n con j u n c t i o n

w i t h d i p h e n y l d i s u l p h i d e i s a l s o an e f f e c t i v e r e a g e n t combination f o r t h e r e d u c t i o n o f oximes t o i m i n e s .

226

4 R e a c t i o n s o f Aldehydes and Ketones Continuing a series of r e v i e w s , t h e c h e m i s t r y of c o n j u g a t e d e n a m i n e s h a s now been s u r v e y e d . 227

Reactions of Eno1ates.-

D i l i t h i o a c e t o a c e t a t e shows v e r y h i g h s e l e c t i v i t y f o r a l k y l a t i o n a t c a r b o n w i t h a l k y l h a l i d e s , a l t h o u g h t h e r e a c t i o n a p p e a r s t o be s l o w . 228 The r e a d y d e c a r b o x y l a t i o n on work-up a l l o w s t h i s d i a n i o n t o be c o n s i d e r e d a s an e q u i v a l e n t f o r a c e t o n e e n o l a t e . 'Complex b a s e s ' , m i x t u r e s o f s o d a m i d e and sodium a l k o x i d e s ( f r o m t e r t i a r y a l k a n o l s o r d i e t h y l e n e g l y c o l m o n o e t h e r s ) , d e p r o t o n a t e a v a r i e t y of c a r b o n y l compounds a n d t h e i r d e r i v a t i v e s ( f o r e x a m p l e i m i n e s a n d d i t h i o a c e t a l s ) , t o f o r m c a r b a n i o n s which a r e r e a d i l y a l k y l a t e d o r s u l p h e n y l a t e d . 229 O f p a r t i c u l a r i n t e r e s t seems t h e l a c k o f n e e d f o r low t e m p e r a t u r e s i n t h e m e t a l l a t i o n s t e p , u n l i k e t h e d e p r o t o n a t i o n by l i t h i u m amide b a s e s . D i r e c t l i t h i a t i o n o f i m i n e s t a k e s p l a c e a r o u n d room t e m p e r a t u r e w i t h l i t h i u m m e t a l a n d p h e n a n t h r e n e ' a s h y d r o g e n a c c e p t o r .230 A p o t e n t i a l a d v a n t a g e i s t h e a b s e n c e of a n y p r o t o n s o u r c e from a m e t a l l a t i n g b a s e . F u r t h e r e x a m p l e s h a v e a p p e a r e d showing d e t a i l s of t h e s c o p e a n d h i g h e f f i c i e n c y o f t h e a s y m m e t r i c s y n t h e s i s o f a c y c l i c k e t o n e s by 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 s of h y d r a z o n e s d e r i v e d f r o m ( z ) - l amino-2-methoxymethylpyrrolidine. 2 3 1 M e t h y l a t i o n s of e n o l a t e s o f 8 - s i l y l - s u b s t i t u t e d k e t o n e s h a v e b e e n shown t o be h i g h l y d i a s t e r e o s e l e c t i v e [ e q u a t i o n ( 4 0 ) l . 232 I n c o m p a r i n g p a l l a d i u m - a n d r h o d i u m - c a t a l y s e d a l l y l a t i o n s of d i c a r b o n y l compounds by a l l y 1 c a r b o n a t e s , r e g i o s e l e c t i v i t y d i f f e r e n c e s h a v e b e e n n o t e d , i n t h a t a l l y l i c i n v e r s i o n was n o t observed f o r d e r i v a t i v e s of t h e l a t t e r m e t a l [ e q u a t i o n ( 4 1 ) l . 233 0 - A l l y l - i s o u r e a s may be u s e d i n t h e r e l a t e d p a l l a d i u m - c a t a l y s e d a l k y l a t i o n of k e t o n e s [ e q u a t i o n ( 4 2 ) 1. 2 3 4 T r i a l k y l s t a n n y l e n o l a t e s , p r e p a r e d from l i t h i u m e n o l a t e s and s t a n n y l t r i f l u o r o a c e t a t e s , are e x c e l l e n t nucleophiles towards s i l y l -

114

General and Synthetic Methods

0

d

0

. . I II

A

and I

J

R e a g e n t s : i, L i N ( S i M e 3 ) p ; ii, R 3 S n O C O C F j , ... I I I , M e 3 S i q c o 2 B u n ; iv,

( R = Bun or M e ) ;

+PdLL

+ Pd L,I,

OAc

OA c

S c h e m e 39

2: Aldehydes and Ketones

115

substituted ally1 acetates in palladium-catalysed alkylations (Scheme 39).235 The nature of the alkyl group on tin has an important effect on the rate of reaction. Methyl derivatives react faster than the butyltin substrates. Neither polyalkylation nor desilylation were observed in these reactions. It was anticipated that non-silylated electrophiles would react even better with these enolates owing to reduced steric effects. Tributyltin enolates are alkylated by aryl and I-alkenyl bromides in the presence of dichlorobis(tri-2-toly1phosphine)palladium [equation (4311 .236 The regiochemistry of the initial enol acetate precursor is retained throughout the reaction. (1,2-Dialkoxyethylene)iron complexes are air-stable crystalline compounds which react with carbon nucleophiles to give neutral adducts (Scheme 40) .237 Protonation affords olefinic complexes which may undergo the sequence a second time, allowing the versatile synthesis of a range of alkenylated ketones. Geminal dialkylation of ketone enolates to give cyclopropyl ketones can be accomplished using vinyl selenoxides [equation (4411 .238 With Il3-dicarbonyl substrates , higher yields are usually attained with vinyl selenones. An alternative dialkylating agent for ketones is 2-chloroethyldimethylsulphonium iodide .239 a-Amidoalkylation of carbon compounds, including ketones, has been surveyed. 240 Introduction of the dimethylaminomethyl group by reaction of Eschenmoser's salt with t-butyldimethylsilyl enol ethers proceeds in high yield, silicon being retained in the product [equation ( 4 5 ) l . 2 4 1 Substrate structure has a major influence on whether or not double bond migration occurs. Mannich bases may also be prepared from lithium enolates and trichlorotitanium a-dialkylamino-alkoxides [equation (46)1 . 242 Diastereoselectivity was observed in these reactions, but the configurations were not determined. Simple Mannich reactions af bis(dimethy1amino)methane and ketones take place cleanly in methanol at room temperature at high (several kilobar) pressures. 243 Aldol Reactions.- Aluminium enolates may be prepared regiospecifically by reduction of a-halogeno-carbonyl compounds with diethylaluminium stannanes or plumbanes. 2441245 Such enolates are efficient components in aldol reactions, particularly in the presence of a catalytic amount of tetrakis(tripheny1phosphino)palladium (0)

General and Synthetic Methods

116

A r B r , [Pd C 1 2 { P ( o - t o L 13

M eO

12]

-

MeoYoMe 'FP

+FP

V

I, .k'pBFb; ii, E t O H ; vii, A, or NoI, Me2C0

Reagents:

iii,

Nu';

i v , HBFL;

S c h e m e 40

v, R T , 3 0 m i n ;

VI,

Nu2;

2: Aldehydes and Ketones

117

L

-

0S iMe 6 u'

+

=&Me,

phwMe I , I1

OSi Me2But

+NMe2

>

O X N H R'

UR2 IV

R1

Reagents :

I,

2 LiNPri2;

ii, SnC12; iii, RZCHO ;

S c h e m e 41

IV,

Ar

HfO'

(45)

General and Synthetic Methods

118

C o n t r o l o v e r r e g i o c h e m i c a l outcome i s p o s s i b l e i n a l d o l c o n d e n s a t i o n s o f a-trimethylsilyl-ketones by c o r r e c t s e l e c t i o n o f r e a c t i o n c o n d i t i o n s . 246

I n d u c e d by L e w i s a c i d s , for e x a m p l e

s t a n n i c c h l o r i d e or boron t r i f l u o r i d e e t h e r a t e , r e a c t i o n proceeds

a t t h e s i l y l - s u b s t i t u t e d c a r b o n , w h e r e a s d e p r o t o n a t i o n by l i t h i u m di-isopropylarnide a f f o r d s t h e o t h e r r e g i o i s o r n e r i c e n o l a t e , and t h e a l t e r n a t i v e a l d o l product i s formed. S t u d i e s t o compare t h e e s t a b l i s h e d s t e r e o s e l e c t i v i t y o f metal e n o l a t e r e a c t i o n s towards aldehydes with acid-catalysed a l d o l r e a c t i o n s of s i l y l e n o l e t h e r s of e t h y l k e t o n e s and a l d e h y d e s have i n d i c a t e d t h a t o n l y v e r y low l e v e l s o f d i a s t e r e o s e l e c t i v i t y s h o u l d be e x p e c t e d . 2 4 7 Only r e a c t i o n s o f t h e s i l y l e n o l e t h e r f r o m tb u t y l e t h y l k e t o n e showed s i g n i f i c a n t s e l e c t i o n . High e r y t h r o - o r = - s e l e c t i v i t y h a s b e e n r e p o r t e d for t h e c o n d e n s a t i o n between e t h y l k e t o n e s and a l d e h y d e s u s i n g phenyld i c h l ~ r o b o r a n ea~n d~ ~e t h y l e n e c h l o r o b ~ r o n a t ’e250 ~ ~’ 251 ~ in the presence of ethyldi-isopropylamine. S i m i l a r r e a c t i o n s have a l s o b e e n r e p o r t e d f o r e n o l b o r a t e s ,252 w h i l s t t r i a l k y l - t i n e n o l a t e s c a n e x h i b i t t h r e o - o r a n t i - s e l e c t i v i t y . 25 3 C h i r a l s t a n n o u s a z a e n o l a t e s d e r i v e d from n o r e p h e d r i n e t a k e p a r t i n r e a c t i o n s with aldehydes t o produce a l d o l p r o d u c t s w i t h high e n a n t i o s e l e c t i v i t y (Scheme 4 1 ) . 254 The e s t a b l i s h e d d i a s t e r e o s e l e c t i v e c r o s s - a l d o l r e a c t i o n s of d i v a l e n t t i n e n o l a t e s have been e x t e n d e d t o i n c l u d e e n a n t i o s e l e c t i o n by r u n n i n g t h e r e a c t i o n i n t h e p r e s e n c e o f c h i r a l a m i n e s [ e q u a t i o n ( 4 7 ) 1 .255 T r i t y l perchlorate, i n catalytic quantities, induces aldol-type r e a c t i o n s b e t w e e n s i l y l e n o l e t h e r s a n d a c e t a l s .256 D i a s t e r e o s e l e c t i v i t y may be i n d u c e d i n t h e L e w i s a c i d - c a t a l y s e d r e a c t i o n s of e n o l s i l y l e t h e r s w i t h 1 , 3 - d i o x o l a n - 4 - o n e s d e r i v e d from o p t i c a l l y a c t i v e m a n d e l i c a c i d .257 The c h i r a l a u x i l i a r y c o u l d be removed w i t h o u t r a c e m i z a t i o n o f t h e a l d o l p r o d u c t [ e q u a t i o n ( 4 8 ) l . Conjugate Addition Reactions.-

The c h e m i s t r y o f ‘ h i g h e r o r d e r ’

o r g a n o c u p r a t e r e a g e n t s h a s b e e n r e v i e w e d . 258

Amongst many s p e c i e s

a n d r e a c t i o n s , r e a g e n t s o f t h e f o r m R2Cu(CN)Li2 show v e r y h i g h s e l e c t i v i t i e s f o r conjugate addition reactions t o unsaturated c a r b o n y l compounds. 259

S u c h r e a c t i o n s a r e s t r o n g l y c a t a l y s e d by

t h e p r e s e n c e of b o r o n 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 .260 D i c y c l o h e x y l p h o s p h i d e h a s b e e n shown t o be a u s e f u l l i g a n d f o r t h e f o r m a t i o n a n d r e a c t i o n s of mixed c u p r a t e r e a g e n t s , g i v i n g i m p r o v e d t h e r m a l s t a b i l i t y a n d r e a c t i o n r a t e s . 2 6 1 N o t e was made t h a t i n

2: Aldehydes and Ketones

119

e.e. 80 %

RRo

Ox0 + Ph

H

Reagents :

I,

CH2=

CMeMgBr ;

I;,

Me1 - H M P A

S c h e m e L2

General and Synthetic Methods

120

r e a c t i o n s of dimethylcopper(1) l i t h i u m , t h e presence of l i t h i u m b r o m i d e c o u l d be a s s o c i a t e d w i t h h i g h e r i s o l a t e d y i e l d s of t h e product of a d d i t i o n t o cyclohex-2-enone.

T h i s may b e o f g e n e r a l

i n t e r e s t i n t h a t such r e a c t i o n s are o f t e n p a r t of m u l t i - s t e p s e q u e n c e s , f o r e x a m p l e i n t h e s y n t h e s i s of p r o s t a g l a n d i n intermediates

via

conjugate addition t o cyclopentenones, followed 262

by a l k y l a t i o n , a s t r a t e g y r e c e n t l y r e v i e w e d .

The p r e p a r a t i o n o f bis(trimethylsilyl)copper(I)

l i t h i u m h a s been

r e p o r t e d , a n d t h e r e a g e n t shown t o a d d i n c o n j u g a t e f a s h i o n t o enones.263

T h i s r e a g e n t t h u s becomes u s e f u l f o r t h e p r o t e c t i o n o f

s u c h d o u b l e b o n d s , a s on r e g e n e r a t i o n o f t h e e n o n e t h e s i l i c o n byp r o d u c t i s v e r y v o l a t i l e , a n d h e n c e e a s i l y removed. L e w i s a c i d s a r e c a t a l y s t s f o r t h e c o n j u g a t e a d d i t i o n of organocopper r e a g e n t s t o a c e t a l s d e r i v e d from u n s a t u r a t e d c a r b o n y l compounds. 2 6 4

A c e t a l s d e r i v e d from c h i r a l d i o l s l e a d t o i n d u c t i o n o f asymmetry i n t h e a d d i t i o n p r o d u c t s [ e q u a t i o n ( 4 9 ) l . 26 5

Stereochemical c o n t r o l is a l s o observed i n t h e r e a c t i o n of o r g a n o a l u m i n i u m r e a g e n t s w i t h s u c h a ~ e t a l s . ~The ~ ~ ~ c t~s ~ p r o’ d u o b t a i n e d from o r g a n o l i t h i u m r e a g e n t s d e p e n d s t r o n g l y on t h e n a t u r e 268 of t h e a c e t a l s u b s t r a t e a n d r e a c t i o n s o l v e n t . Asymmetric a d d i t i o n of a G r i g n a r d r e a g e n t t o a c h i r a l i m i n e d e r i v a t i v e of a n e n o n e , f o l l o w e d by a l k y l a t i o n , h a s b e e n employed i n t h e c h i r a l s y n t h e s i s of t h e s e s q u i t e r p e n e ( + ) - i v a l i n ( 6 ) (Scheme 4 2 ) . 2 6 9 C o n j u g a t e a d d i t i o n o f a h y d r o x y m e t h y l g r o u p t o e n o n e s may be a c h i e v e d i n d i r e c t l y by t h e c o p p e r - c a t a l y s e d a d d i t i o n o f

(allyldimethylsilyl)methylmagnesium c h l o r i d e f o l l o w e d by c o n v e r s i o n o f t h e s i l y l g r o u p i n t o a h y d r o x y l r e s i d u e (Scheme 4 3 ) . 2 7 0

The

known 1 , 4 - a d d i t i o n o f a l k y n y l b o r a n e s t o e n o n e s h a s b e e n employed

f o r t h e s y n t h e s i s of (Z)-undec-5-en-2-one, a pheromone f r o m t h e b o n t e b o k (Scheme 4 4 ) . 2 7 1 L i t h i u m e n o l a t e s a n d magnesium b i s e n o l a t e s undergo p r e f e r e n t i a l c o n j u g a t e a d d i t i o n t o enones, w h e r e a s h a l o g e n o m a g n e s i u m e n o l a t e s show i n c r e a s e d t e n d e n c y t o w a r d s 1,2-additi0n.~~~ The u s e o f o r g a n o z i n c r e a g e n t s f o r c o n j u g a t e a d d i t i o n t o h i n d e r e d e n o n e s h a s b e e n h i g h l i g h t e d by s y n t h e s e s of 8 - c u p a r e n o n e (7), u s i n g a s t r a t e g y w h i c h f a i l e d w i t h o r g a n o c o p p e r r e a g e n t s . 27 3 The p r e p a r a t i o n of t h e s e m e t a l d e r i v a t i v e s i s g r e a t l y f a c i l i t a t e d by a p p l i c a t i o n o f u l t r a s o u n d [ e q u a t i o n ( 5 0 ) l . 2 7 4 N i c k e l acetylacetonate is a necessary c a t a l y s t for conjugate a d d i t i o n r e a c t i o n s of t h e s e r e a g e n t s . Alkyl manganese(I1) r e a g e n t s have

2: Aldehydes and Ketones

121

Si Me

0

0

Reagents:

1,

CH2=

C H C H ~ S ~ M ~ ~ C H Z MCuI; ~ C Lii,,

KH?,

CF3C02H; iii, H202, NaHC03, MeOH

Scheme 43

-

I , I1

n-C5Hll - G - B q

n-C5Hl1-=

,p 1

111 - v

'.

Reagents:

I,

MeCOCH=CH2;

i;, HO(CH2)20H; iii, 9-BBN;

S c h e m e 44

0

0

R' = Me, R 2 =p-MeCsHh or R 2 = Me, R' =p-MeCcH,

iv, A c O H ;

v, HCL

General and Synthetic Methods

122

Scheme 45

I

d

QCONH2

H

Pr

(9)

(1 01

2: Aldehydes and Ketones

123

also been shown to add in conjugate fashion to c y c l o h e ~ e n o n e s . ~ ~ ~ Addition reactions of simple lithium reagents to enones often have a pronounced tendency to add by 1,2-attack. However, the lithium enolate of methyl trimethylsilylacetate undergoes clean 1,4addition to c y ~ l o p e n t e n o n e . ~The ~ ~ utility of the reaction was exemplified by a synthesis of methyl jasmonate. Similarly the anion formed from trimethylsilylacetonitrile reacts in conjugate fashion with a variety of unsaturated carbonyl compounds. 277 Michael additions of 1,3-dicarbonyl compounds to enones show some degree of enantioselection when catalysed by optically active bases, but greater selectivity is observed using cobalt(I1) complexes of chiral diamines. 278 However, the chiral induction is still particularly dependent on the structure of the dicarbonyl component. Asymmetric additions are much more efficient when chirality is built into the enone, as exemplified by the reactions of enantiomerically pure 2-(arylsulphinyl)cycloalk-2-enones. Disubstituted cyclopentanones are available in chiral form from the 2-tolylsulphinyl derivative, as demonstrated in an asymmetric synthesis of ( + -a-cuparenone (8 (Scheme 45). 279 Of interest is that by choice of reaction conditions the same enantiorner may be used to obtain either optical isomer of the product after desulphurization .280 Addition of Grignard reagents in the presence of zinc bromide gives the product from chelation control in the enone starting material, whereas the use of the very weakly Lewisacidic dialkylmagnesium reagent gives the product from the configuration where the sulphinyl and ketone dipoles are oriented away from each other [equation (5111. In the former case, diastereoselectivity in the initial addition is greater if g28 1 anisylsulphinyl derivatives are employed. The reaction of enones with 2-phenylbenzothiazoline and aluminium chloride results in the chemospecific reduction of the enone to the saturated carbonyl compound.282 The Lewis acid is necessary for reaction to take place. The same chemoselectivity is observed with the dihydropyridine (9) and silica gel,283 and with the related derivative ( 1 0 ) in the presence of a rhodium(1) catalyst. 284 References 1

2

3 4

5

J.Tsuji, 1-Minami, and I.Shimizu, Tetrahedron Lett ., 1984, 25, 2791. K.S.Kim, Y.K.Chang, S.K.Bae, and C.S.Hahn, Synthesis, 1984, 866. H-Firouzabadi, A.Sardarian, and H.Gharibi, Synth. Commun., 1984, 14, 89. H.Firouzabadi, A.R.Sardarian, M-Naderi, and B.Vessa1, TetrahedronTl984, 5001. R-Rathore, V.Bhushan, and S.Chandrasekaran, Chem. Lett., 1984, 2131.

40,

General and Synthetic Methods

124 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 48 49 50

51 52

3435. W.E.Billups, B.E.Arney, and L.-J.Lin, J. Org. Chem., 1984, 9, G .Grenn, W. P Griffith , D.M. Hol linshead , S.V .Ley, and M. Schr6der , J. Chem SOC., Perkin Trans. 1 , 1984, 681. A.M.Maione and A.Romeo, Synthesis, 1984, 955. H.Cano-Yelo and A.Deronzier, Tetrahedron Lett., 1984, 25, 5517. F .H.Hussein , G. Pat tenden, R. Rudham , and J. J .Russel 1 , Tetrahedron Lett. , 1984, 5, 3363. H.Firouzabadi, N.Iranpoor, H.Parham, and J.Toofan, Synth. Commun., 1984, 14, 631. H.Firouzabadi, N.Iranpoor, F.Kiaeezadeh, and J. Toofan, Synth. Commun., 1984, 14, 973. H-Firouzabadi, N.Iranpoor, G.Hajipoor, and J.Toofan, Synth. Commun., 1984, 14, 1033. H.Firouzabadi and N.Iranpoor, Synth. Commun., 1984, 875. S-Kanemoto, H.Saimoto, K.Oshima, and H-Nozaki, Tetrahedron Lett., 1984, 25, 3317. Y.Masuyama, M.Takahashi, and Y.Kurusu, Tetrahedron Lett., 1984, 25, 4417. B.M.Trost and Y.Masuyama, Tetrahedron Lett., 1984, 25, 173. M.F. Semmelhack, C. R .Schmid, D.A. CortCs , and C.S.Hou, J. Am. Chem. SOC. , 1984, 106,3374. M.Marx and T.T.Tidwel1, J . Org. Chem., 1984, 788. K.S.Kim, I.H.Cho, B.K.Yoo, Y.H.Song, and C.S.Hahn, J. Chem. SOC., Chem. Commun., 1984, 762. T.Shono, Tetrahedron, 1984, 5, 81 1 . J.-I.Yoshida, K.Ogura, and N.Kawabata, J. Org. Chem., 1984, 3419. T.Komori and T.Nonaka, Chem. Lett., 1984, 509. F.Yoneda, M.Koga, and T-Ibuka, Tetrahedron Lett., 1984, 25, 5345. S.Shinkai, H.Nakao, K.Ueda, and O.Manabe, Tetrahedron Lett., 1984, 25, 5295. S.Fukuzumi, S.Kuroda, and T.Tanaka, Chem. Lett., 1984, 1375. Y.Sakuma, T.Nagamatsu, Y.Hashiguchi, and F.Yoneda, Chem. Pharm. Bull., 1984, 32, 851. Y.Yano, M.Ohshima, S.Sutoh, and M.Nakazato, J. Chem. SOC., Chem. Commun., 1984, 1031. J.Tsuji, Synthesis, 1984, 369. K.Tamao, M.Kumada, and K.Maeda, Tetrahedron Lett., 1984, 25, 321. A.J.Pearson, Y.-S.Chen, S.-Y.Hsu, and T.Ray, Tetrahedron Lett., 1984, 25, 1235. V.J.Freer and P.Yates, Chem. Lett., 1984, 2031. K.Ariyoshi, Y.Aso, T.Otsubo, and F.Ogura, Chem. Lett., 1984, 891. L.Syper and J.MYochowski, Synthesis, 1984, 747. E.Vedejs and D.A.Perry, J . Org. Chem., 1984, 9, 573. R.V.Hoffman and A.Kumar, J. Org. Chem., 1984, 401 1 . H.C.Brown , J.S.Cha , B. Nazer, and N.M. Yoon, J. Am. Chem. Soc., 1984, 106, 8001, T.D.Hubert, D.P.Eyman, and D.F. Wiemer, J. Org. Chem., 1984, 2279. D.M.Kalvin and R.W.Woodward, Tetrahedron. , 1984, 40, 3387. G.A.Olah, L.Ohannesian, and M.Arvanaghi, J. Org. Chem., 1984, 49, 3856. G.A.Olah, G.K.S. Prakash, and M.Arvanaghi, Synthesis, 1984, 228. M.Bogavac, L.Arsenijevi6, S.Pavlov, and V.Arsenijevi6, Tetrahedron Lett., 1984, 25, 1843. R.A.Grey, J. Org. Chem., 1984, 2288. V.Fiandanese, G.Marchese, V.Martina, and L.Ronzini, Tetrahedron Lett., 1984, 25, 4805. S.Wattanasin and F.G.Kathawala, Tetrahedron Lett., 1984, 25, 81 1. G.Friour, A.Alexakis, G.Cahiez, and J.Normant, Tetrahedron, 1984, 40, 683. D.J.Ager, J. Chem. SOC., Chem. Commun., 1984, 486. J.-M.Vatele, Tetrahedron Lett., 1984, 25, 5997. V.H.Rawa1, M.Akiba, and M.P.Cava, Synth. Commun., 1984, 1129. T.Takeda, H.Furukawa, M.Fujimori, K.Suzuki, and T.Fujiwara, Bull. Chem. SOC., J p n . , 1984, 57, 1863. S.V.Ley and B.Lygo, Tetrahedron Lett., 1984, 25, 113. J.B.Ousset, C.Mioskowski, Y.-L.Yang, and J.R.Zlck, Tetrahedron Lett., 1984, 25, 5903.

.

.

c,

2,

5,

5,

2,

~

49,

2,

2: Aldehydes and Ketones 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 87

88 89 90 91 92 93 94 95

96 97 98 99 100

101 102 103 104

125

.

M.A.Blanchette, W.Choy, J.T.Davis, A.P.Essenfeld, S.Masamune, W. R Roush , and T.Sakai, Tetrahedron Lett., 1984, 25, 2183. N.L.J. M.Broekhof , P.Vanelburg, D.J. Hof f , and A.Vandergen, Rec:l.: J. R. Neth. Chem. SOC., 1984, 317. E.Anders and T-Gassner, Chem. Ber., 1984, 117, 1034. J.Binder and E.Zbira1, Tetrahedron Lett., 1984, 25, 4213. L.Stella, Tetrahedron Lett., 1984, 25, 3457. L.Stella and A.Amrollah-Mad jdabadi, Synth. Commun., 1984, 2, 1141. A.T.Au, Synth. Commun., 1984, 743. 749. A.T.Au, Synth. Commun., 1984, J.C.Stowel1, Chem. Rev., 1984, 84,409. J.C.Stowel1 and B.T.King, Synthesis, 1984, 278. D.Hoppe, Angew. Chem., Int. Ed. Engl., 1984, 3,932. D.Hoppe and F.Lichtenberg, Angew. Chem., Int. Ed. Engl., 1984 , 23, 239. G.Trimitsis, S.Beers, J. Ridella, M. Carlon, D. Cullin, J.High, and D.Brutts J. Chem. SOC., Chem. Commun., 1984, 1088. V. J. Jephcote, A. J.Pratt, and E.J. Thomas, J. Chem. SOC., Chem. Commun., 1984, 800. R.A.J.Smith and A.R.Bin Manas, Synthesis, 1984, 166. J.A.Hyatt and P.W.Raynolds, J. Org. Chem., 1984, 9, 384. B.Hulin and M.Koreeda, J. Org. Chem., 1984, 9, 2 0 7 . J.Gorzynski Smith, Synthesis, 1984, 629. 1.Fleming and T.W.Newton, J. Chem. SOC., Perkin Trans. 1 , 1984, 119. D.J.Ager, Synthesis, 1984, 384. A.Murai, A.Abiko, N.Shimada, and T.Masamune, Tetrahedron Lett., 1984, 25, 4951. H-Sugimura and H.Takei, Chem. Lett., 1984, 1505. Y.Kita, H.Yasuda, O.Tamura, F.Itoh, and Y.Tamura, Tetrahedron Lett., 1984, 25, 4681. P.G.McDouga1 and J.G.Rico, Tetrahedron Lett., 1984, 25, 5977. K.Takai, M.Sato, K.Oshima, and H.Nozaki, Bull. Chem. SOC. Jpn., 1984, 57, 108. K.K.Wang and K.-H. Chu, J. Org. Chem., 1984, 5175. H.C.Brown and T.Imai, J. Org. Chem., 1984, 892. H.C.Brown, P.K.Jadhav, and M.C.Desai, Tetrahedron, 1984, 40, 1325. D.Enders and W.Mies, J. Chem. SOC., Chem. Commun., 1984, 1221. R.C.Gadwod, Tetrahedron Lett., 1984, 3, 5851. J-Ollivier and J.Salan, Tetrahedron Lett., 1984, 25, 1269. M.Ramaiah, Synthesis, 1984, 529. D.L.Boger and C.E.Brotherton, J. Am. Chem. SOC., 1984, 805. K.Furuta, A.Misumi, A.Mori, N.Ikeda, and H.Yamamoto, Tetrahedron Lett., 1984, 25, 669. A.Misumi, K.Furuta, and H.Yamamoto, Tetrahedron Lett., 1984, 25, 671. K.Sakai, Y.Ishiguro, K.Funakoshi, K.Ueno, and H.Suemune, Tetrahedron Lett., 1984, 25, 961. M.A.Tius and D.P.Astrab, Tetrahedron Lett., 1984, 25, 1539. V.Rautenstrauch, J. Org. Chem., 1984, 950. D.C.Billington and D.Willison, Tetrahedron Lett ., 1984, 25, 4041. D.L.J.Clive, P.L.Beaulieu, and L.Set, J. Org. Chem., 1984, 9, 1313. D.El-Abed, A.Jella1, and M.Santelli, Tetrahedron Lett., 1984, 25, 1463. K.Yamamoto, El-Deguchi, Y.Ogimura, and J.Tsuji, Chem. Lett., 1984, 1657. 832. R.O.Duthaler and P.Maienfisch, Helv. Chim. Acta, 1984, 9, R.O.Duthaler and P.Maienfisch, Helv. Chim. Acta, 1984, 67,845. C.Agami, J.Levisalles, and H.Sevestre, J. Chem. SOC., Chem. Commun., 1984, 418. J.L.Laboureur and A.Krief, Tetrahedron Lett., 1984, 25, 2713. B.M.Trost and M.J.Fray, Tetrahedron Lett., 1984, 25, 4605. K.Thangaraj, P.C.Srinivasan, and S.Swaminathan, Synthesis, 1984, 1010 A.G.Angoh and D.L.J.Clive, J. Chem. SOC., Chem. Commun., 1984, 534. B.C.Barot, D.W.Sullins, and E.J.Eisenbraun, Synth. Commun., 1984, 14, 397. I.Matsuda, H.Okada, S.Sato, and Y.Izumi, Tetrahedron Lett., 1984, 25 , 3879. T.Hirao, Y.Fujihara, S.Tsuno, Y.Ohshiro, and T.Agawa, Chem. Lett. , 1984, 367.

m,

2, 2,

9

2, 2,

106,

5,

126

General and Synthetic Methods

105

J.V .Sinisterra, A.Garcia-Raso, J. A. Cabello, and J.M.Marinas, Synthesis, 1984, 502. E.Block, M.Aslam, R.Iyer, and J.Hutchinson, J. Org. Chem., 1984, 3664. Y.Tamaru, H.Ochiai, and Z.-I.Yoshida, Tetrahedron Lett., 1984, 2 5 , 3861. F.K.Sheffy, J.P.Godschalx, and J.K.Stille, J. Am. Chem. SOC., 1984, 106, 4833. W.F.Goure, M.E.Wright, P.D.Davis, S.S.Labadie, and J.K.Stille, J. Am. Chem. SOC., 1984, 106, 6417. L.S.Hegedus and R.J.Perry, J. Org. Chem., 1984, 9, 2570. M.Julia and C.Lefebvre, Tetrahedron Lett., 1984, 25, 189. A.Alexakis, A.Commer$on, C.Coulentianos, and J.F.Normant, Tetrahedron, 1984, 40, 715. P.DeShong and J. M.Leginus, J. Org. Chem., 1984, 49, 3421 . J. Tsuji, I.Minami, I.Shimizu, and H. Kataoka, Chem. Lett., 1984 , 1 133. D.Liotta, Acc. Chem. Res., 1984, 28. R.S.Brown, S.C.Eyley, and P.J.Parsons, J. Chem. SOC., Chem. Commun., 1984, 438. L.A.Paquette, R.S.Valpey, and G.D.Annis, J. Org. Chem., 1984, 9, 1317. P.Pohmakotr and S.Chancharunee, Tetrahedron Lett., 1984, 25, 4141. M.MikoYajczyk and P.BaYczewski, Synthesis, 1984, 691. J.Villikras and M.Rambaud, Synthesis, 1984, 406. R.Cloux and M.Schlosser, Helv. Chim. Acta, 1984, 3, 1470. Y.Morizawa, A.Kanakura, H.Yamamoto, T.Hiyama, and H.Nozaki, Bull. Chem. SOC. Jpn., 1984, 57, 1935. P.G.Baraldi, A.Barco, S.Benetti, G.P.Pollini, and V.Zanirato, Tetrahedron Lett., 1984, 2 5 , 4291. T.Mandai, M.Takeshita, M.Kawada, and J.Otera, Chem. Lett., 1984, 1259. T.Mandai , T.Moriyama, Y. Nakayama, K.Sugino, M.Kawada, and J. Otera, Tetrahedron Lett., 1984, 25, 5913. P-Tuchinda, V.Prapansiri, W.Naengchomnong, and V-Reutrakul, Chem. Lett., 1984. 1427. J.Moska1 and A.M.van Leusen, Tetrahedron Lett,, 1984, 25, 2585. K.Ogura, T.Iihama, K.Takahashi, and H.Iida, Tetrahedron Lett., 1984, 25, 2671. F.Derguini and G.Linstrumelle, Tetrahedron Lett ., 1984, 25, 5763. G.A.Molander, B.Singaram, and H.C.Brown, J. Org. Chem., 1984, 5024. J.F.Honek, M.L.Mancini, and B.Belleau, Synth. Commun., 1984, 2, 483. T. Akiyama, H. Iwakiri, M.Shimizu, and T.Mukaiyama, Chem. Lett., 1984, 1843. E.M.Gordon, J.Pluscec, N.G.Delany, S.Natarajan, and J.Sundeen, Tetrahedron Lett., 1984, 25, 3277. W. A.Smit , A.A.Schegolev, A. S.Gybin, G .S.Mikaelian, and R. Caple, Synthesis, 1984, 887. K.Nakatani and S.Isoe, Tetrahedron Lett., 1984, 25, 5335. M.Ochiai, T-Ukita, Y.Nagao, and E.Fujita, J. Chem. SOC., Chem. Commun., 1984, 1007. H. C.Brown, U.S.Racherla, and S.M.Singh, Tetrahedron Lett., 1984, 25, 241 1. L.Poncini, Liebigs Ann. Chem., 1984, 1529. L.Poncini, J. Org. Chem., 1984, 9, 2031. F.A.Davis, L.C.Vishwakarma, J.M.Billmers, and J. Finn, J. Org. Chem., 1984, 49, 3241. R.M.Moriarty and K.C.Hou, Tetrahedron Lett., 1984, 25, 691. R.M.Moriarty, O.Prakash, P.Karalis, and I.Prakash, Tetrahedron Lett., 1984, 2 5 , 4745. K.C.Brinkman and J.A.Gladysz, Organometallics, 1984, 3, 147. M.Adamczyk, E.K.Dolence, D.S.Watt, M. R.Christy , J.H.Reibenspies, and O.P.Anderson, J. Org. Chem., 1984, 49, 1378. J.E.Lynch and E.L.Elie1, J. Am. C h e K SOC., 1984, 2943. E.L.Elie1 and S.Morris-Natschke, J. Am. Chem. SOC., 1984, 106, 2937. W.Waszku6, T.Janecki, and R.Bodalski, Synthesis, 1984, 1025.( T.Hiyama, K.Kobayashi, and M.Fujita, Tetrahedron Lett., 1984, 2 5 , 4959 N.K.Dunlap, M.R.Sabo1, and D.S.Watt, Tetrahedron Lett., 1984, 25, 5839. G.Cardillo, M.Orena, G.Porzi, S.Sandri, and C.Tanasini, J. Org. Chem., 1984, 49, 701.

106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128

2,

-

2,

-

134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150

106,

2: Aldehydes and Ketones 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

177 178

179 180

181 182 183 184 185 186 187 188 189 190

191 192 193 194 195 196 197 198

127

K.Hofmann and G.Simchen, Liebigs Ann. Chem., 1984, 39. B.G.Lenz, H.Regeling, and B.Zwanenburg, Tetrahedron Lett., 1984, 25, 5947. D.Scholz, Liebigs Ann. Chem., 1984, 259. R.Verhd, N.De Kimpe, L.De Buyck, and N-Schamp, Synthesis, 1984, 46. O.De Lucchi, G.Marchioro, and G.Modena, J. Chem. SOC., Chem. Commun., 1984, 513. T.Satoh, Y.Kaneko, T.Kumagawa, T.Izawa, K.Sakata, and K. Yamakawa, Chem. Lett., 1984, 1957. A.Toshimitsu, H.Owada, K.Terao, S.Uemara, and M.Okano, J. Org. Chem., 1984, 49. - , 3796. R.Labia and C.Morin, Chem. Lett., 1984, 1007. J.Barluenga, F.Aznar, R.Liz, and M.Bayod, J. Chem. SOC., Chem. Commun., 1984, 1427. A.Pfaltz and S.Anwar, Tetrahedron Lett., 1984, 25, 2977. J.E.Nordlander, M.J.Payne, F.G.Njoroge, M.A.Balk, G.D.Laikos, and V.M.Vishwanath, J. Org. Chem., 1984, 9, 4107. 0-Attanasi, P.Filippone, P.Battistoni, and G.Fava, Synthesis, 1984, 422. G.Rosini, R.Ballini, P.Sorrenti, and M.Petrini, Synthesis, 1984, 607. S.E.Denmark and M.S.Dappen, J. Org. Chem., 1984, 9, 798. A.D.N.Vaz and G.Schoellmann, J. Org. Chem., 1984, 9, 1286. Y.D.Vankar and G.Kumarave1, Tetrahedron Lett., 1984, 25, 233. G.A.Olah, L.Ohannesian, M.Arvanaghi, and G.K.S.Prakash, J. Org. Chem., 1984, 49, 2032. A.Arrieta, I.Ganboa, and C.Palomo, Synth. Commun., 1984, 939. E.Armani, A.Dossena, R.Marchelli, and G.Casnati, Tetrahedron, 1984, 40, 2035. B.Sket and M.Zupan, Tetrahedron, 1984, 5, 2865. 566. C.A.Lipinski, T.E.Blizniak, and R.H.Craig, J. Org. Chem., 1984, 9, G. Friour , G. Cahiez, and J. F. Normant, Synthesis, 1984, 37. B.Fr6lisch and R-Flogaus, Synthesis, 1984, 734. R.Tarhouni, B.Kirschleger, M.Rambaud, and J.Villieras, Tetrahedron Lett., 1984, 25, 835. T.Oriyama and T.Mikaiyama, Chem. Lett., 1984, 2069. K.Fuji, M.Node, T.Kawabata, and M.Fujimoto, Chem. Lett., 1984, 1153. G.L.Larson, 1.Montes de L6pez-Ceper0, and L.E.Torres, Tetrahedron Lett., 1984, 25, 1673. T.Sato, K.Matsumoto, T.Abe, and I.Kuwajima, Bull. Chem. SOC. Jpn., 1984, 57. 2167. E.J.Corey and C.RGker, Tetrahedron Lett., 1984, 25, 4345. J.Mora and A.Costa, Tetrahedron Lett., 1984, 25, 3493. S.Sato, H.Okada, I.Matsuda, and Y.Izumi, Tetrahedron Lett., 1984, 25, 769. C.Georgoulis, J.M.Val&y, and G.Ville, Synth. Commun., 1984, 1043. J.M.Hook, Synth. Commun., 1984, 83. D.H.Hunter, D.H. R.Barton, and W.J-Motherwell, Tetrahedron Lett., 1984, 25, 603. D.Horne, J.Gaudino, and W.J.Thompson, Tetrahedron Lett., 1984, 25, 3529. M.T.Reetz, H-Heimbach, and K.Schwellnus, Tetrahedron Lett., 1984, 25, 51 1. R.Knorr, P.L6w, P.Hasse1, and H.Bronberger, J. Org. Chem., 1984, 49, 1288. S.-I.Murahashi, T.Tsumiyama, and Y.Mitsue, Chem. Lett., 1984, 1419, S.D.Lee, T.H.Chan, and K.S.Kwon, Tetrahedron Lett., 1984, 25, 3399. K.Saigo, H.Kurihara, H.Miura, A.Hongu, N.Kubota, H.Nohira, and M.Hasegah‘a, Synth. Commun., 1984, 787. O.G.Kulinkovich, I.G.Tischenko, and N.V.Masalov, Synthesis, 1984, 886. M.Shimizu, T.Akiyama, and T.Mukaiyama, Chem. Lett., 1984, 1531. M.Kosugi, I.Takano, M.Sakurai, H.Sano, and T.Migita, Chem. Lett., 1984, 1221. Y.Ito, H.Imai, T.Matsuura, and T.Saegusa, Tetrahedron Lett., 1984, 25, 3091. M.Mitani, M.Tamada, S . - I . Uehara, and K.Koyama, Tetrahedron Lett., 1984, 25, 2805. G. I.Nikishin , E. I.Troyansky , and M. I.Lazareva , Tetrahedron Lett., 1984, 25, 4987. P.Duhame1, J.-M.Poirier, and L.Hennequin, Tetrahedron Lett., 1984, 25, 1471. E.Akg6n and U.Pindur, Synthesis, 1984, 227.

14,

5,

5,

2,

128 199 20 0 20 1 202 20 3 204 20 5 206 20 7 20 8 209 210 21 1 212 213 21 4 21 5 216 21 7 218 219 220 22 1 222 223 224 225 226 227 228 229

232 233 234 235 236 237 238 239 240 24 1 242 243 24 4 24 5 246 24 7 248

General and Synthetic Methods J.Enda, T.Matsutani, and I.Kuwajima, Tetrahedron Lett., 1984, 25, 5307. F.Gasparrini, M.Giovannoli, D.Misiti, and G.Palmieri, Tetrahedron, 1984, 5, 1491. H.Sakurai, K.Sasaki, J.Hayashi, and A.Hosomi, J. Org. Chem., 1 9 8 4 , 9, 2808. G.Cil, Tetrahedron Lett., 1984, 25, 3805. T.J.Nitz and L.A.Paquette, Tetrahedron Lett., 1 9 8 4 , 2, 3047. J.H.Babler and K.P.Spina, Synth. Commun., 1984, 14,39. A.M.Doherty, S.V.Ley, B.Lygo, and D.J.Williams, J. Chem. SOC., Perkin Trans. 1 , 1984, 1371. Y.Yamamoto, K.Ohdoi, M.Nakatani, and K.Akiba, Chem. Lett., 1984, 1967. J.Orban, J.V.Turner, and B.Twitchin, Tetrahedron Lett ., 1 9 8 4 , 25, 5099. L.N.Mander and S.P.Sethi, Tetrahedron Lett ., 1984, 25, 5953. M.E.Krafft and R.A.Holton, J. Org. Chem., 1984, 3669. M.E.Krafft and R.A.Holton, J. Am. Chem. SOC., 1 9 8 4 , 106,7619. Y.Ito, H.Imai, K.Segoe, and T.Saegusa, .____ Chem. Lett., 1984, 937. S.Torii, T.Inokuchi, and T.Kobayashi, Chem. Lett., 1 9 8 4 , 897. K.Mai and G.Pati1, Tetrahedron Lett., 1 9 8 4 , 2, 4583. O.Tsuge, S.Kanemasa, and K.Matsuda, J. Org. Chem., 1 9 8 4 , 2688. J.C.Combret, J.L.Klein, and M.Mouslouhouddine, Synthesis, 1984, 493. P.Vinczer, L.Novak, and C.Szintay, Synth. Commun., 1984, 281. G.M.Coppola, Synthesis, 1984, 1021. Y.Guindon, C.Yoakim, and H.E.Morton, J. Org. Chem., 1984, 3912. M.Platen and E.Steckhan, Chem. Ber., 1984, 117,1679. M.Balogh, A.Corndlis, a n d , Tetrahedron Lett., 1984, 25, 3313. P.Laszlo and E.Polla, Tetrahedron Lett., 1984, 25, 3309. M.Duraisamy and H.M.Walborsky, J. Org. Chem., 1984, 9, 3410. D.P.Curran, J.F.Bril1, and D.M.Rakiewicz, J. Org. Chem., 1984, 49, 1654. M.Nitta, I.Sasaki, H.Miyano, a n d T.Kobayashi, Bull. SOC. Chim. Fr., Part 2 , 1984, 5 7 , 3357. F.S.Guzec a n d J.M.Russo, Synthesis, 1984, 479. D.H.R.Barton, W.B.Mothwwel1, E.S.Simon, and S.Z. Zard, J. Chem. SOC., Chem. Commun., 1984, 337. P.W.HickmoLt, Tetrahedron, 1984, 2989. R.A.Kjonaas and D.D.Pate1, Tetrahedron Lett., 1 9 8 4 , 5 , 5467. M.C.Carre, G.Ndebeka, A.Rionde1, P.Bourgasser, and P-Caubere, Tetrahedron Lett., 1984, 25, 1551. E.A.Mistryukov and I.K.Korshevetz, Synthesis, 1 9 8 4 , 947. D.Enders, H.H.Eichenauer , U.Baus, H.Schubert , and K.A.M.Kremer , Tetrahedron., 1984, "0, 1345. W.Bernhard, I.Fleming, and D.Waterson, J. Chem. SOC., Chem. Commun., 1 9 8 4 , 28. J.Tsuji, I.Minami, and I.Shimizu, Tetrahedron Lett., 1 9 8 4 , 25, 5157. Y.Inoue, M.Toyofuku, and H.Hashimoto, Chem. Lett., 1 9 8 4 , 1227. B.M.Trost and C.R.Self, J. Org. Chem., 1984, 9, 468. M.Kosugi, I.Hagiwara, T.Sumiya, and T.Migita, Bull. Chem. SOC. Jpn., 1 9 8 4 , 5 7 , 242. M.Marsi and M.Rosenblum, J. Am. Chem. SOC., 1984, 106,7264. R.Ando, T.Sugawara, M.Shimizu, and I.Kuwajima, Bull. Chem. SOC. Jpn., 1 9 8 4 , 5 7 , 2897. S.M.Ruder and R.C.Ronald, Tetrahedron Lett., 1984, 2, 5501. H.E.Zaugg, Synthesis, 1984, 85. M.Wada, Y.Nishihara, and K.Akiba, Tetrahedron Lett., 1 9 8 4 , 3,5405. D.Seebach, '2-Betschart,and M.Schiess, Helv. Chim. Acta, 1984, 67,1593. K.Matsumoto, S.Hashimoto, S.Otani, F.Amita, and J.Osugi, Synth. Commun., 1984, 1 4 , 585. N. Tsubziwa, S-Matsubara, Y.Morizawa , K. Oshima, and H. Nozaki , Tetrahedron Lett., 1984, 25, 2569. S.Matsubara, N.Tsuboniwa, Y.Morizawa, K.Oshima, and H.Nozaki, Bull. Chem. SOC. Jpn., 1984, 57, 3242. T.Inoue, T.Sato, and I.Kuwajima, J. Org. Chem., 1 9 8 4 , 9, 4671. C.H.Heathcock, K.T.Hug, and L.A.Flippin, Tetrahedron Lett., 1984, 25, 5973. H.Hamana, K.Sasakura, and T.Sugasawa, Chem. Lett., 1984, 1729. ~

2,

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2, 14, 2,

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fi,

-

~

2: Aldehydes and Ketones 249

129

C-Gennari, S.Cardani, L.Colombo, and C-Scolastico, Tetrahedron Lett., 1984, 25, 2283. C.Gennari,

L.Colombo, and G.Poli, Tetrahedron Lett., 1984, 25, 2279. C-Gennari, L. Colombo, C .Scolastico, and R. Todeschini , Tetrahedron , 1984, 2, 4051. 252 R.W.Hoffmann and K.Ditrich, Tetrahedron Lett., 1984, 2 5 , 1781. 253 S.S.Labadie and J.K.Stille, Tetrahedron, 1984, 5, 23%. 254 K.Narasaka, T.Miwa, H.Hayashi, and M.Ohta, Chem. Lett., 1984, 1399. 25 5 T.Mukaiyama, N.Iwasawa, R.W.Stevens, and T.Haga, Tetrahedron, 1984, 2, 1381. 256 T.Mukaiyama, S.Kobayashi, and M.Murakami, Chem. Lett., 1984, 1759. 2513. 257 S.H.Mashraqui and R.M.Kellogg, J. Org. Chem., 1984, 258 B.H.Lipshutz, R.S.Wilhelm, and J.A.Kozlowski, Tetrahedron, 1984, 5, 5005. 3938. 259 B.H.Lipshutz, R.S.Wilhelm, and J.A.Kozlowski, J. Org. Chem., 1984, 9, 260 B.H.Lipshutz, D.A.Parker, J.A.Kozlowski, and S.M.Nguyen, Tetrahedron Lett., 1984, 25, 5959. 1119. 26 1 S.H.Bertz and (3-Dabbagh,J. Org. Chem., 1984, 9, 26 2 R.Noyori and M.Suzuki, Angew. Chem., Int. Ed. Engl., 1984, 23, 847. 26 3 1.Fleming and T.W.Newton, J. Chem. SOC., Perkin Trans. 1 , 1984, 1805. 264 A.Ghribi, A-Alexakis, and J.F.Normant, Tetrahedron Lett., 1984, 25, 3079. 265 A.Ghribi, A.Alexakis, and J.F.Normant, Tetrahedron Lett., 1984, 25, 3083. 26 6 J.Fujiwara, Y.Fukutani, M.Hasegawa, K.Maruoka, and H.Yamamoto, J. Am. Chem. SOC., 1984, 106,5004. 267 Y.Fukutani, K.Maruoka, and H.Yamamoto, Tetrahedron Lett., 1984, 25, 5911. 268 C.Mioskowski, S.Manna, and J.R.Falck, Tetrahedron Lett., 1984, 25, 519. 269 K-Tomioka, F.Masumi, T.Yamashita, and K.Koga, Tetrahedron Lett., 1984, 25, 333. 270 K.Tamao and N.Ishida, Tetrahedron Lett., 1984, 25, 4249. 27 1 H.C.Brown, U.S.Racherla, and D.Basavaiah, Synthesis, 1984, 303. 272 J.Bertrand, L.Gorrichon, and P.Maroni, Tetrahedron, 1984, 40, 41 27. 273 A.E.Greene, J.-P. Lansard, J.-L .Luche, and C.Petrier , J. Org. Che!m., 1984, 4 9 , 931. 274 C.Petrier, J.-L.Luche, and C.Dupuy, Tetrahedron Lett., 1984, 25, 34613. 27 5 T.Kauffmann and M.Bisling, Tetrahedron Lett., 1984, 25, 293. 276 H-Nishiyama, K.Sakuta, and K.Itoh, Tetrahedron Lett., 1984, 25, 2487 277 K.Tomioka and K.Koga, Tetrahedron Lett., 1984, 25, 1599. 278 H.Brunner and B-Hammer, Angew. Chem., Int. Ed. Engl., 1984, 23, 312. 279 G.H.Posner, T.P.Kogan, and M.Hulce, Tetrahedron Lett., 1984, 25, 382 280 G.H.Posner and M-Hulce, Tetrahedron Lett., 1984, 25, 379. 28 1 G.H.Posner , L.L.Frye, and M.Hulce, Tetrahedron, 1984, 5, 1401 . 282 H.Chikashita, M.Miyazaki, and K.Itoh, Synthesis, 1984, 308. 28 3 K-Nakamura, M.Fujii, A.Ohno, and S.Oka, Tetrahedron Lett., 1984, 2 5 , 3983. 28 4 K-Nakamura, M.Fujii, A.Ohno, and S.Oka, Chem. Lett., 1984, 925. 250 25 1

9,

-

~

Carboxylic Acids and Derivatives BY D. W. KNIGHT

A considerable increase in publications relevant to this area has resulted in the inclusion of more references than normal, at the expense of some o f the usual detailed discussion. Even so, a completely comprehensive coverage is not claimed, and some selection has been necessary; this has been done hopefully not on the basis of the appalling Matthew effect.' A very brief mention of a paper is not meant to imply that the results contained therein are of a lower quality o r less useful. 1 Carboxylic Acids

General Synthesis.- A one-carbon homologation of olefins to carboxylic acids, which could be fairly generally applicable, is outlined in Scheme I.* Overall yields are good for relatively unhindered substrates; the lower returns from more substituted olefins can be somewhat offset by the stereoselectivity of the sequence. For example, l-methylcyclopentene can be converted into the trans-cyclopentanecarboxylic acid ( 1 ) in 44% isolated yield. As selective hydroboration by BHBr2.SMe2 of differently substituted olefins is also possible, unsaturated acids can be obtained by this ( 3 ) ; 58% yield]. method [e.g.( 2 ) Alkylations of anions derived from the u-(phosphory1)enamines (4) lead exclusively to the y-products ( 5 1 , which on acidic hydrolysis afford the acids (6) Overall yields are generally good, and further alkylations of the intermediates ( 5 ) are possible, leading to more highly substituted acids (6). Some uses have been found for the dianion ( 7 ) generated from dichloroacetic acid using LDA.4 Alkylations, only effective with allylic o r benzylic bromides, lead to dichloro-acids ( 8 ) while condensations with aldehydes give the Darzens-type products ( 9 1 , useful as precursors to B-chloro-a-keto-acids. Reactions with ketones are only successful at low temperatures, leading to the Darzens-type precursors, 2,2-dichloro-3-hydroxyalkanoic acids. The direct a-

-

.'

For References see page 221.

130

3: Carboxylic Acids and Derivatives

131

R e a g e n t s : i , BHBr2*SMc2, CHZCL2; i i , 2 L i S R 3 , p e n t a n c iii, LiCCI3,THF,-100

'C;

;

i v , 10M-H202,6M-NaOH

Scheme 1

cf

CO 2H

o " - r

CO2H

132

General and Synthetic Methods

iodination of simple alkanoic acids can be achieved using molecular iodine in the presence of CuCl and C U C ~ yields ~ ; ~ of the acids ( 10) are in the range 85-90% (see also ref. 1 4 ) . Alkenyl(a1koxy)silanes (12) are readily oxidized using H202One particular use of Ac20-KHF2 in DMF to carboxylic acids ( 1 3 ) . 6 this transformation is as the second step in a conversion of terminal acetylenes ( 1 1 ) into acids (13) by sequential hydrosilylation-oxidation. Overall, this 'one-pot' sequence represents a good alternative to the Zweifel-Backlund method for

-

effecting the transformation ( 1 1 ) (131, based on the hydroboration of silylacetylenes. Various oxo-complexes of ruthenium-(VI) and -(VII) have been shown to be valuable for the oxidation of a wide range of alcohols to the corresponding carboxylic acids .7 A ring-contraction method for the elaboration of cycloalkanea carboxylic acids (15) from cycloalkanones (14) has been detailed. This alternative to the Favorskii rearrangement involves a 1 , 3 dipolar cycloaddition of diphenyl phosphorazidate (see a l s o ref. 390) to the pyrrolidine-enamine of the ketone followed by loss of nitrogen, and hydrolysis of the resulting phosphorylated amidine [(CH20H)2-KOH-reflux!1. A useful method for obtaining extremely anhydrous carboxylates

(16; M = Li, Na, or K) is by reactions between esters or acid chlorides and trimethylsilanolates , MOSiMe 3'

Diacids.-References throughout this chapter attest to the rapidly increasing use of enzymes in enantioselective synthesis. Porcine liver esterase (PLE) has found particular application in the partial hydrolysis of prochiral aliphatic diesters to chiral monoesters. For example, the dialkyl malonate ( 1 7 ) is converted into the monoester (18) of 97% optical purity after crystallization. Unfortunately, other malonates are hydrolysed with rather lower selectivities. A number of groups" have found that PLE is also capable of the selective hydrolysis of meso-

cycloalkane-1,2-dicarboxylates to give monoesters ( 1 9 ) . In general, optical yields are extremely high with the exception of cyclopentanes, although which enantiomer is produced does depend on the ring size. The absolute configurations of the products do not restrict the utility of esters ( 1 9 ) , since selective group transformations can be readily performed, such as acid reduction (BH3), ester reduction (LIBH4) or selective isomerization to either

3: Carboxylic Acids and Derivatives

133

Ye

I

Go- (Yco2H (14)

(15)

- "" PLE

C02Et

C02Me

ciCozH ! C0,Me

H

(17)

(18)

(19)

General and Synthetic Methods

134

of the trans-isomers. Furthermore, such hydrolyses have been performed on scales of up to 1 0 0 g. Similarly, PLE or microorganisms can be used to prepare chiral mono-esterified glutarates (20);12 in these cases, the =-(S) ester group is hydrolysed. Further examples of a non-enzymatic approach to chiral glutarates have also been reported , l 3 in which a meso-glutaric acid is converted into a diamide using a chiral amine; nucleophilic attack onto such a derivative occurs enantioselectively, thus distinguishing between the two prochiral amide groups. Carboxylic acid dianions can be oxidatively coupled using iodine (0.5 equiv.) to give succinates (21) (58-90%), largely as the d,lisomers.14 By using excess iodine, a-iodo-acids can be obtained. The ozonolysis of cycloalkenes (22) to a,w-dicarboxylic acids (23) is not always a satisfactory method; stimulated by some seemingly erroneous reports in the Russian literature, Bailey et a1.I5 have suggested that such reactions are best performed in acetic acid-formic acid mixtures followed by further oxidation by oxygen. Hydroxy-acids.- Alkylations of the anion (24) derived from a camphor-based oxazoline followed by hydrolysis lead to the ( R ) - a hydroxy-acids (25) with enantiomeric enrichments (e.e.1 of 77-92%.16 Synthetic yields are variable, mainly due to problems at the final hydrolysis stage as is the case in the related work of Meyers et al.; optical yields in the present examples, however, are much higher. The or (S)-enantiomers of (25) can be obtained in moderate to good optical yields by reductions of 2-acyloxathianes (26), readily obtained from (+)-pulegone. Similarly, Grignard reactions with (261, followed by hydrolysis, lead to tertiary a-hydroxy-acids with over 90% e.e. ’7 9 324 A S ( - 1 -pulegone is also available, this approach offers good flexibility in the elaboration of enantiomers of ( 2 5 ) . Alkylations of menthyl esters of phenylglyoxylic acid with the ate complexes LiAlEt OR give rise 3 to a-hydroxy-acids with variable optical purities, the best being obtained when ‘ R ’ is very large. 18 Crossed aldol-type condensations between the bis(trimethylsily1) acetals ( 2 7 ) and aldehydes give hydroxy-acids (28) in high With monosubstituted acetals (27; R 1 = H) the reactions yields.” are stereoselective; when R2 is small, largely threo-B-hydroxyacids are produced whereas when R2 = But the erythro-isomers predominate. erythro-B-Hydroxy-acids can also be prepared by

(R)-

3: Carboxylic Acids and Derivatives

135

zH

R3&co

R' (27 1

(28)

R2

ph/yco2 Ph

(29)

136

General and Synthetic Methods

alkylations of iron acyl complexes or by aldol condensations between iron acetyl complexes and aldehydes,20 while a variety of stereoselective approaches to 8-hydroxy-acids involve degradations of isoxazolines obtained by 1,3-dipolar cycloadditions of various nitrile oxides to olefins .21 threo-8-Hydroxy-acids related to (28) are the major products from condensations between carboxylic acid dianions and aldehydes.22 The reactions were found to be cleaner when the dianions were generated using LDA prepared from amethylstyrene, lithium, and di-isopropylamine in ether-THF rather than the more usual BunLi-based method. Furthermore, the condensation of phenylacetic acid with benzaldehyde using the trilithio-derivative of (1~,2~)-2-amino-2-methyl-l-phenylpropane-l13diol as base gave the hydroxy-acid (29) in 85% e.e. Other chiral bases were less effective. An alternative approach to chiral 8hydroxy-acids involves condensations of the dianion (30), derived in three simple steps from methyl (&)-mandelate, with aldehydes. Base hydrolysis of the initial adducts leads to almost optically pure hydroxy-acids (31 ) , in the three simple examples quoted. 23 Keto-acids.- In a notable series of papers, Ramage et al. have exploited the enhanced electrophilicity of the carbonyl group in rarely used 1,3-dioxolan-4-ones in general syntheses of a-ketoacids24 and relatives, and of a variety of tetronic acid derivatives.293-295 The actual derivative used, (32), is easily prepared from aqueous glycolic acid and cyclohexanone using toluene-p-sulphonic acid as catalyst; conversion into the 5-ylidene homologues (33) is achieved by Wittig methodology (base-catalysed aldol condensations were not satisfactory). Hydrolysis using sodium hydroxide in aqueous THF leads to the a-keto-carboxylates (34) in high yield. The synthetic utility of y-keto-acids continues to encourage the development of novel routes to these compounds; various Michaeltype reactions form the basis of a number of new methods. Carboxylic acid dianions (36) (or ester enolates) add in this way to nitro-olefins (35) to provide a good range of substituted ketoacids (37) (or esters) in variable yields, after aqueous acid hydrolysis .25 Similarly substituted 7-keto-acids can also be obtained by TiC14-catalysed conjugate additions of silyl enol ethers derived from ketones to a,g-unsaturated acyl cyanides; An alternative strategy 2 7 yields are between 25 and 75%.26 involves SN2' reactions between Grignard reagents and the 6-

137

3: Carboxylic Acids and Derivatives

propiolactone (38). The intermediate vinyl halides (39) are best hydrolysed to the y-keto-acids using TiC14 in a mixed aqueous1 organic solvent, whereas base hydrolysis using aqueous sodium hydroxide leads to y-hydroxy-a,B-unsaturated acids. Variable yields of keto-acids (37) have also .been obtained by direct electrolysis of unsaturated ketones (40) in the presence of carbon dioxide. 28 Unsaturated Aliphatic Acids.- A high yielding, stereospecific route to (L)-a,B-unsaturated acids (43) involves carboxylation pressure of C 0 2 ) of lithium trialkylalkynylborates ( 4 1 ) (25 kg to give vinylboranes (42) followed by acid hydrolysis (AcOH) .29 Wastage of two of the initial alkyl groups ( R 1 ) is a drawback; one wonders whether the method could be applied to mixed alkylboranes derived from R2BH, and a terminal olefin, where the groups 'R' have low migratory aptitudes. A general entry to 6,y-unsaturated acids ( 4 7 ) is by thermal ene reactions between unactivated olefins (44) and diethyl oxomalonate (45), here acting as a synthetic equivalent of carbon dioxide. 30 The intermediate hydroxy-malonates (46) are best degraded using ceric ammonium nitrate in aqueous acetonitrile rather than the previously reported sodium periodate-based method. In general, dienes react at the less substituted olefin whereas in the presence of Lewis-acid catalysts the more substituted olefin is attacked. Overall, this efficient method should find many applications. Related ene reactions between olefins and chloral give rise to trichloroalk-4-en-2-ols(48). 31 These can also be converted into 8,y-unsaturated esters as well as into 2,4-dienoates and a-alkoxyor a-hydroxy-acids. A further example of the extraordinary effects that reaction conditions can have on the outcome of Ireland-Claisen rearrangements is the conversion of (2)-propionate (49) into the (2R73S)-acid (50) when LDA is used as base. However, when lithium hexamethyldisilazide is used, the corresponding (25,3S) enantiomer the (E)is formed almost e x c l ~ s i v e l y ,presumably ~~ lithioenolate. The major product from a similar rearrangement of the dianion (51) derived from (g)-but-2-enyl 3-hydroxybutanoate is the acid ( 5 2 1 , but when the dianion is bis-2-silylated before rearrangement the dominant product is the acid (53).33 The lowish yields detract somewhat from the value of this method; however, an added bonus is that a related rearrangement c(54) ( 5 5 ) l proceeds

-

General and Synthetic Methods

138

(361

(37)

0

'ic

-Y3 +-& 0

OH

(481

+si I

H

(491

__c

+Sil+P I

I

(50)

3: Carboxylic Acids and Derivatives

139

-

OH

A

TMSCl ___c

A (53)

TMSCl ___t

A

I

0 2 "

-R

CO,H

I

I

OH (55)

(56)

140

General and Synthetic Methods

w i t h a l m o s t c o m p l e t e t r a n s f e r of c h i r a l i t y i n 71% c h e m i c a l y i e l d 3 ' ( s e e a l s o r e f . 269). A g e n e r a l a p p r o a c h t o v i r t u a l l y i s o m e r i c a l l y p u r e (Z)-Q-alkenoic

a c i d s (56) c o n s i s t s o f SN2 a t t a c k by l i t h i u m d i a l k y l c u p r a t e s o n (L)-hex-4-enolide. P r o d u c t s a r i s i n g from S N 2 ' a t t a c k are a l s o f o r m e d ( 8 - 2 ~ % )( s~e ~ e a l s o r e f . 220). A r o m a t i c A c i d s . - The r e c e n t l y d e s c r i b e d b e n z y n e ( 5 7 1 , o b t a i n a b l e f r o m m-chlorophenyloxazoline, u n d e r g o e s r e g i o s e l e c t i v e a t t a c k by l i t h i o a l k y l n i t r i l e s t o give t h e 3-cyano-derivatives presumably

via

a benzocyclobutenimine;

r e f l u x ) t h e n l e a d s t o 3-cyanobenzoic

(58),

a c i d h y d r o l y s i s (4.5M-HC1, a c i d s (59) i n g e n e r a l l y g o o d

yields.36

The i n t e r m e d i a t e (58) c a n b e a l k y l a t e d t o p r o v i d e h i g h e r h o m o l o g u e s of (59). A v a r i e t y of arylmethanes can be o x i d i z e d t o t h e c o r r e s p o n d i n g

a r y l c a r b o x y l i c a c i d s u s i n g KOH a n d o x y g e n i n d i m e t h o x y e t h a n e c o n t a i n i n g c a t a l y t i c a m o u n t s o f 1 8 - c r o w n - 6 . 37

I n some c a s e s a t l e a s t , t h i s m e t h o d c o u l d p r o v e s u p e r i o r t o t h e u s u a l KMn04-based

approaches.

Aromatic h a l i d e s as w e l l as b e n z y l i c h a l i d e s c a n be

electrochemically carboxylated using s a c r i f i c i a l anodes t o g i v e good y i e l d s o f b e n z o i c a n d p h e n y l a c e t i c a c i d s ( 6 1 ) r e s p e c t i v e l y . 3 8 The anti-inflammatory

a c t i v i t i e s o f t h e l a t t e r compounds h a v e

r e s u l t e d i n t h e d e v e l o p m e n t o f many a p p r o a c h e s t o t h e m . a r e b a s e d on [1,21 a r y l s h i f t s C(60)

-t

A number

(61)l s t a r t i n g w i t h r e a d i l y

a v a i l a b l e a r y l k e t o n e s o r d e r i v a t i v e s , and most n o t a b l y i n r e c e n t l y y e a r s , t h e T a y l o r - M c K i l l o p method u s i n g t h a l l i u m ( I I 1 ) n i t r a t e . T h i s t o x i c r e a g e n t c a n b e r e p l a c e d by s i l v e r n i t r a t e i n c l o s e l y r e l a t e d r e a r r a n g e m e n t s o f t h e d i m e t h y l a c e t a l s of a - h a l o g e n o a l k y l

.

a r y l k e t o n e s ( a - h a l o g e n o a c e t o p h e n o n e s ) 39 T h e l a t t e r m e t h o d i s a l s o e f f e c t i v e i n t h e s y n t h e s i s of B - p y r r y l a c e t i c a c i d s o f u s e i n porphyrin synthesis

."

a-halogenoacetophenones

P r i o r c o n v e r s i o n o f t h e e t h y l e n e a c e t a l s of i n t o t h e c o r r e s p o n d i n g a-phenylseleno- or

a-phenyltelluro-derivatives f o l l o w e d by o x i d a t i o n u s i n g mc h l o r o p e r b e n z o i c a c i d i s y e t a n o t h e r way o f e f f e c t i n g t h e t r a n s f o r m a t i o n C(60) ( 6 1 )I ,41 w h i c h c a n a l s o b e c a r r i e d o u t d i r e c t l y by t r e a t m e n t of k e t o n e s ( 6 0 ; R = Me) w i t h d i a c e t o x y p h e n y l i o d i n e and t r i m e t h y l o r t h o f o r m a t e . The o r i g i n a l Taylor-McKillop method i s a l s o e f f e c t i v e i n r e a r r a n g e m e n t s of r e a d i l y a v a i l a b l e B - a r o y l p r o p i o n i c a c i d s (62) i n t o a - a r y l s u c c i n a t e s ( 6 3 ) a n d c a n b e f u r t h e r e x t e n d e d t o s y n t h e s e s of a - a r y l g l u t a r a t e s a n d - a d i p a t e s as w e l l a s a , a ' - d i a r y l - s u c c i n a t e s and

-

''

3: Carboxylic Acids and Derivatives

-adipates. 43 The use of aryl-lead(1V) tricarboxylates, ArPb(OAc)3,

141

in the

direct a r y l a t i ~ n l ~ ~ ’of B-dicarbonyl compounds has been extended to include mono-alkyl Meldrum’s acids; hydrolysis and decarboxylation leads to a-aryl-acids (61 ; R=H) .44 Kinetic resolution of acids (61) can be achieved by reaction of the corresponding anhydrides with optically active I-pyridylethanols; optical yields are 70-90%.45 Condensations of phenols with ninhydrin followed by degradation 46 give salicylic acids (64) in generally good overall yields. Although this method fails with phenols containing electronwithdrawing substituents, it otherwise represents a viable alternative to the classical Kolbe-Schmitt carboxylation of phenols. Bromomagnesium salts of phenols are efficiently acylated by oxalyl chloride in toluene at ambient temperature to give arylglyoxylic acids (65) in 44-70% isolated yields. 47 A new synthesis of 2-arylindole-3-carboxylic acids (67) is cyclizations of the readily available imines (66) .48 A [I , 5 1 dipolar mechanism is probably involved which relies on the presence of the free carboxylic acid to catalyse the dipole formation. The two dianionic species (68) and (69) can be readily obtained from the corresponding benzofurancarboxylic acids;49 the latter is a particularly useful intermediate, undergoing efficient couplings with a wide range of electrophiles. Acid Chlorides and Anhydrides.- Details of more efficient methods for the preparation of (E)-3-chloro- and 3-bromo-acryloyl chloride have been given in a paper containing some unfortunate misprint^.^' These compounds are useful as acetylene equivalents in Diels-Alder reactions.51 Trimethylsilylethoxyacetylene appears to be a better reagent than ethoxyacetylene for the synthesis of symmetrical acyclic o r cyclic anhydrides; yields are essentially quantitative. 52 Radical chain reactions between cyclohexyl- ( o r t-butyl-) mercuric chloride and maleic anhydrides ( 7 0 ) give largely the cis-disubstituted succinic anhydrides (71 1 .53 Presumably the method could be extended to other alkylmercury salts or even to other types of radical. Decarboxy1ation.- Arylacetic acids, ArCH2C02H, can be decarboxylated to the hydrocarbons, ArCH3, using oxygen and catalytic quantities of copper(1) salts. 54 The same system can

General and Synthetic Methods

142

a l s o be u s e d t o d e g r a d e a - h y d r o x y - a c i d s t o k e t o n e s [cf. r e f . 301. B a r t o n a n d c o - w o r k e r s h a v e c o n t i n u e d t h e i r s t u d i e s on t h e r a t i o n a l design of radical-mediated

decarboxylations.

a r e known t o p r o v i d e c a r b o n r a d i c a l s , R ' .

The e s t e r s ( 7 2 )

T h e s e c a n b e t r a p p e d by

d i a r y 1 d i s u l p h i d e s , d i s e l e n i d e s , or d i t e l l u r i d e s t o p r o v i d e a c c e p t a b l e y i e l d s (55-80%) o f t h e s u l p h i d e s , s e l e n i d e s , or t e l l u r i d e s ( 7 3 ) .55

S i m i l a r l y , s u c h r a d i c a l s when g e n e r a t e d f r o m

e s t e r s of 5-hydroxy-2-thiopyridone r e a c t w i t h o x y g e n i n t h e p r e s e n c e o f t - b u t y l t h i o l t o g i v e a l c o h o l s o r c a r b o n y l compounds d e p e n d i n g on t h e p r e c i s e m e t h o d u s e d . 56 T h e i n t e r m e d i a t e h y d r o p e r o x i d e s c a n , if d e s i r e d , b e i s o l a t e d i n h i g h y i e l d s . P r o t e c t e d a-amino-acids

Fa-

can s i m i l a r l y be d e c a r b o x y l a t e d e f f i c i e n t l y

t o g i v e t h e c o r r e s p o n d i n g a m i n e s .57 d e c a r b o x y l a t i o n of a-amino-acids

By c o n t r a s t , o x i d a t i v e

i n aqueous s o l u t i o n can be

c a t a l y s e d by t h e c o e n z y m e PQQ ( m e t h o x a t i n ) t o g i v e f a i r y i e l d s o f a l d e h y d e s and a c i d s ; f o r example p h e n y l a l a n i n e i s degraded t o a m i x t u r e o f p h e n y l a c e t a l d e h y d e a n d p h e n y l a c e t i c a c i d .58 I n a n e x t e n s i o n o f o b s e r v a t i o n s o r i g i n a l l y made by I w a s a k i

e t a l . , p h o t o l y s i s of a-diazomethyl k e t o n e s , r e a d i l y d e r i v e d from c a r b o x y l i c a c i d s ( 7 4 ) , i n t h e p r e s e n c e of i m i d a z o l e l e a d s t o t h e n o r - o l e f i n s ( 7 5 ) i n 35-54% y i e l d .59 V a r i o u s r e d u c e d D i e l s - A l d e r a d d u c t s (76)51 undergo a n o d i c d e c a r b o x y l a t i v e d e s i l y l a t i o n t o g i v e o l e f i n s (77);60 t h e m e t h o d i s a g o o d a l t e r n a t i v e t o a n o d i c b i s decarboxylation of r e l a t e d , Diels-Alder

derived, carbocycles.

61

O n e - c a r b o n d e g r a d a t i o n s of 3,3-disubstituted-2-oxocarboxylic a c i d s c a n b e a c h i e v e d by a n o d i c o x i d a t i o n t o g i v e ' n o n - K o l b e '

products,

methyl t r i a l k y l a c e t a t e s , t o g e t h e r w i t h t h e corresponding aldehydes, 62 i n s u i t a b l e cases. The C u r t i u s r e a r r a n g e m e n t i s o f t e n n o t s u i t a b l e f o r t h e s y n t h e s i s of primary amines because of d i f f i c u l t i e s encountered

ir,

t h e h y d r o l y s i s o f t h e f i n a l c a r b a m a t e s , when s e n s i t i v e s u b s t r a t e s are i n v o l v e d . A solution t o t h i s is t o t r a p the i n t e r m e d i a t e i s o c y a n a t e s u s i n g 2-trimethylsilylethanol; c l e a v a g e t o t h e f r e e a m i n e s i s t h e n a c h i e v e d by t r e a t m e n t w i t h t e t r a - n butylammonium f l u o r i d e .

T h e r e l a t e d HofmaRn d e g r a d a t i o n (RCGNH2

-

RNH2) c a n b e c a r r i e d o u t u s i n g s o d i u m b r o m i t e ( N a B r 0 2 ) a n d s o d i u m bromide i n aqueous sodium hydroxide.64 T h i s method i s n o t s u i t a b l e f o r l o n g c h a i n (>7 C) a l i p h a t i c a m i d e s o r d i a m i d e s . s u c h Hofmann d e g r a d a t i o n s c a n b e e f f e c t e d u s i n g

Alternatively,

[I,L-

bis(trif1uoroacetoxy)iodolbenzene u n d e r a c i d i c c o n d i t i o n s (pH 1-3).65 Retention of configuration a t t h e migrating group is

3: Carboxylic Acids and Derivatives

R4

143

0

C02 L i I

Li

(68)

O

C

O

(70)

R

(69)

-

O

A

,A0AN~'

R-X-Ar

X = S,Se or Te (71)

(72)

(73)

General and Synthetic Methods

144

o b s e r v e d and y i e l d s a r e i n t h e r a n g e 55-92%. R e l a t e d i o d o n i u m s p e c i e s d e r i v e d from 1205/12 c a n be u s e d t o o x i d a t i v e l y d e g r a d e p r o p i o l i c a c i d s (RC5CC02H) t o a c e t a l e s t e r s [RC(OMe)2C02Mel a l t h o u g h t h i s method w i l l be l i m i t e d t o s u b s t r a t e s w h i c h d o n o t c o n t a i n a d d i t i o n a l i o d i n e - s e n s i t i v e f u n c t i o n s .66

A 'double

H u n s d i e c k e r d e g r a d a t i o n c a n be u s e d t o p r e p a r e 1 , l dibromocyclopropane o r c y c l o b u t a n e from t h e c o r r e s p o n d i n g 1 , l dicarboxylic acids.67

T h i s should be of v a l u e i n t h e p r e p a r a t i o n

o f s i m p l e gem-dibromocyclopropanes w h i c h c a n n o t be e f f i c i e n t l y p r e p a r e d from o l e f i n s and d i b r o m o c a r b e n e . C a r b o x y l i c Acid Group P r o t e c t i o n . -

The 4 , 5 - d i p h e n y l o x a z o l e f u n c t i o n

c a n s e r v e as a masked e s t e r g r o u p , as shown by p r e v i o u s work by Wasserman e t a l .

A good d e m o n s t r a t i o n o f t h i s p r i n c i p l e i s i n t h e

s y n t h e s i s of t h e c h i r a l epoxy-ester

( 7 9 ) by S h a r p l e s s e p o x i d a t i o n

o f t h e o x a z o l e d e r i v a t i v e (78) f o l l o w e d by a c e t y l a t i o n a n d d e g r a d a t i o n o f t h e h e t e r o c y c l e by s e q u e n t i a l r e a c t i o n s w i t h s i n g l e t oxygen a n d t o s i c a c i d i n m e t h a n o l . 6 8

T h i s s e r v e s t o emphasize t h a t

a l t h o u g h t h i s m e t h o d o l o g y c l e a r l y h a s some s e v e r e l i m i t a t i o n s it c o u l d b e v e r y u s e f u l i n a p p r o p r i a t e cases. t-Butylthio-esters

c o u l d f i n d u s e as masked c a r b o x y l i c a c i d

f u n c t i o n s a s t h e y c a n be c l e a v e d u n d e r e s s e n t i a l l y n e u t r a l c o n d i t i o n s by e l e c t r o l y s i s i n a q u e o u s a c e t o n i t r i l e c o n t a i n i n g a bromide s a l t . 6 9

T h i s i s a s i m i l a r l y a t t r a c t i v e f e a t u r e of 4-

silylbut-2-en-1-01

e s t e r s ( 8 0 ) w h i c h c a n be d e g r a d e d t o s i l y l e s t e r s ( 8 1 ) s i m p l y by t r e a t m e n t w i t h a c a t a l y t i c amount o f [ P d ( P P h ) 1 i n m e t h y l e n e c h l o r i d e a t room t e m p e r a t u r e f o r 2 h.70 3 4 A d d i t i o n of a n a l c o h o l b e f o r e work-up p r o v i d e s t h e c o r r e s p o n d i n g a l k y l e s t e r s . The r e l a t e d 8-trimethylsilylethoxymethyl. (SEM) g r o u p h a s p r o v e d u s e f u l i n a s y n t h e s i s o f I-hydroxycyclopropanecarboxylic a c i d p h o s p h a t e . 7 1 Some o t h e r m e t h o d s for t h e t e m p o r a r y b l o c k i n g o f c a r b o x y - g r o u p s a r e d e s c r i b e d i n t h e l a t e r s e c t i o n on a - a m i n o - a c i d protection. 2 Esters

Esterificatio;.-

S t i l l more c o u p l i n g a g e n t s h a v e b e e n i n t r o d u c e d

f o r e s t e r formation, a l l seemingly capable of producing h i g h y i e l d s o f e s t e r s from e q u i m o l a r a m o u n t s o f a c i d s a n d a l c o h o l s , u s u a l l y under s l i g h t l y b a s i c c o n d i t i o n s . Examples i n c l u d e d i - 2 - p y r i d y l c a r b o n a t e ,72 w h i c h r e q u i r e s t h e p r e s e n c e o f 4 - d i m e t h y l a m i n o p y r i d i n e

3: Carboxylic Acids and Derivatives

145

(78)

(79)

R2

Me3Si0

A R’

C0,Me

Ac0 do;;ii

Me Si 0--

Me

R’

R’

(83)

(82)

(84)

1.‘. R

H

CN

CO,E t

R+

R3 (86)

(87)

(85)

General and Synthetic Methods

146

and is n o t s u i t a b l e f o r t h e e l a b o r a t i o n of h i g h l y h i n d e r e d esters,

N ,N - b i s ( 2 - o x o - 3 - o x a z o l i d i n y l ) p h o s p h o r d i a m i d i c c h l o r i d e , 73 w h i c h h a s p r e v i o u s l y been used t o p r e p a r e t h i o e s t e r s and l a c t o n e s , and 1 , l ' oxalyldi-imidazole

and t h e c o r r e s p o n d i n g 1 , 2 , 4 - t r i a z o l e and

1 , 2 , 3 , 4 - t e t r a z o l e . 74

R e l a t e d t o t h i s l a t t e r method i s t h e

E-

p r e p a r a t i o n o f s e n s i t i v e r e t i n o a t e s by r e a c t i o n s o f

r e t i ny l i m i d a z o l i um t o l u e n e -p-s u l p h o n a t e s w i t h a 1c o h o l s

.

R C O C l + CH20) f o r t h e p r e p a r a t i o n o f

Classical procedures (e.g.

c h l o r o m e t h y l esters o f s e n s i t i v e s u b s t r a t e s s u c h as B-lactam d e r i v a t i v e s have been found t o be u n s a t i s f a c t o r y .

Thus, a novel

p r o c e d u r e h a s b e e n d e v e l o p e d c o n s i s t i n g of c o u p l i n g t e t r a - n butylammonium c a r b o x y l a t e s w i t h c h l o r o m e t h y l c h l o r o s u l p h a t e ( C l S O CH C l ) ; y i e l d s o f e s t e r s a r e u s u a l l y a r o u n d 80%.76 3 2 H i g h l y h i n d e r e d e s t e r s c a n b e p r e p a r e d i n e x c e l l e n t y i e l d s by c o p p e r ( I 1 ) bromide promoted c o u p l i n g s o f 5 - 2 - p y r i d y l 2-pyridyl

t h i o e s t e r s or

esters w i t h a l c o h o l s ( 1.2 equiv. ) i n a c e t o n i t r i l e

.77

An

a l t e r n a t i v e methodr18 f o r t h e e l a b o r a t i o n o f t r i p h e n y l m e t h y l e s t e r s i n v o l v e s SiF4-mediated

c o u p l i n g of t r i m e t h y l s i l y l e s t e r s w i t h

t r i p h e n y l m e t h y l f l u o r i d e ; p o s s i b l y t h i s method c o u l d have o t h e r applications. A v a r i e t y of

0,N, a n d

2-nucleophiles

i n c l u d i n g sodium

c a r b o x y l a t e s or f r e e c a r b o x y l i c a c i d s c a n b e v e r y e f f i c i e n t l y a l k y l a t e d by p h D s p h o n i u m s a l t s , (RO) 3pMe.BF4-,

readily prepared

f r o m t h e c o r r e s p o n d i n g t r i a l k y l p h o s p h i t e s ( R = Me, E t , P r i , o c t y l ) and Meerwein's

salt.79

or 2-

The method c o u l d b e o f u s e w i t h

v a l u a b l e c a r b o x y l i c a c i d s where w a s t a g e o f two o f t h e a l k y l g r o u p s ,

R , i s o f no consequence.

M e t h y l e s t e r s c a n a l s o b e o b t a i n e d by

a l k y l a t i o n s o f a c i d s w i t h m e t h y l t r i c h l o r o a c e t a t e a t 90-150

OC

in

t h e p r e s e n c e o f p o t a s s i u m c a r b o n a t e a n d 1 8 - c r o w n - 6 ; 8o a n a d v a n t a g e h e r e c o u l d be t h a t t h e o t h e r p r o d u c t s o f t h e r e a c t i o n a r e c h l o r o f o r m and carbon d i o x i d e . General Synthesis.potentially useful

Two e x a m p l e s h a v e b e e n d e t a i l e d of a 'one-pot'

method f o r t h e c o n v e r s i o r , o f a l c o h o l s

(RCH20H) i r , t o t h e c o r r e s p o n d i n g t - b u t y l Cr03-pyridine

,

e s t e r s (RC02But), u s i n g

a c e t i c a n h y d r i d e , and t - b u t y l

r e a c t i o n probably proceeds

via

alcohol.81

aldehyde and hemi-acetal

The s t a g e s and

is n o t a p p l i c a b l e t o benzylic a l c o h o l s presumably because formation of t h e l a t t e r i s u n f a v o u r a b l e . E n o l a t e s d e r i v e d f r o m cyclopropanecarboxylates ( 8 2 ) a r e a l k y l a t e d t o g i v e mainly o r e x c l u s i v e l y t h e trans-products

(83) i n

3: Carboxylic Acids and Derivatives excellent yields.82

147

R i n g c l e a v a g e o f t h e s e compounds l e a d s t o

y-

k e t o - e s t e r s . 155 A l k y l a t i o n of e n o l a t e s (84) d e r i v e d from c h i r a l i m i d a t e e s t e r s l e a d s t o high or v i r t u a l l y complete asymmetric i n d u c t i o n ; subsequent e t h a n o l y s i s provides t h e a , a ’ - d i s u b s t i t u t e d

esters (85)

i n g e n e r a l l y e x c e l l e n t c h e m i c a l y i e l d s . 83 The a - c y a n o e n a m i n e ( 8 6 ; R = H ) , p r e p a r e d i n t h r e e s t e p s f r o m

N,N-diethylacrylamide, a t the y-position

undergoes p h a s e - t r a n s f e r mediated a l k y l a t i o n

t o p r o v i d e homologues (86; R = a l k y l ) w h i c h on

a c i d i c m e t h a n o l y s i s and d e s u l p h u r i z a t i o n l e a d t o e s t e r s ( 8 7 ) .

84

The s t a r t i n g e n a m i n e t h u s c a n be r e g a r d e d a s a h o m o e n o l a t e e q u i v a l e n t ; 235 by s u i t a b l e m a n i p u l a t i o n t h e i n i t i a l p r o d u c t s ( 8 6 ) c a n a l s o be c o n v e r t e d i n t o

a,B-

o r , i n some c a s e s w h e r e t h e d o u b l e

bond i s c o n j u g a t e d , B , y - u n s a t u r a t e d e s t e r s . V i a b l e r o u t e s t o a number of u s e f u l a - s u b s t i t u t e d e s t e r s ( 8 8 ) have been r e p o r t e d .

These i n c l u d e a - t r i b u t y l s t a n n y l d e r i v a t i v e s

( 8 8 a ) , r e a d i l y a v a i l a b l e from a l k y l a t i o n s o f e s t e r e n o l a t e s by t r i b u t y l s t a n n y l c h l o r i d e , 85 a n d t h e 2- (trimethylsilyloxysulphonyl) h o m o l o g u e s ( 8 8 b ) , 86 o b t a i n e d e i t h e r d i r e c t l y f r o m t h e s u b s t i t u t e d

e s t e r s ( 8 8 ; X = H , R 2 = SiMe ) o r f r o m t h e c o r r e s p o n d i n g k e t e n e 3 a c e t a l s by r e a c t i o n w i t h t r i m e t h y l s i l y l c h l o r o s u l p h o n a t e . A l k y l a t i o n of t h e e a s i l y p r e p a r e d , polymer-supported,

carbanion

d e r i v e d from methyl n i t r o a c e t a t e l e a d s t o t h e a - n i t r o - e s t e r s ( 8 8 ~ ) . The ~ ~c a r b a n i o n i c r e s i n i s s t a b l e e n o u g h t o p e r m i t prolonged s t o r a g e and hence can be r e g a r d e d a s an ‘ o f f t h e s h e l f ‘ c a r b a n i o n ! The c a r b a n i o n s a l s o a d d s m o o t h l y t o a c r y l a t e s t o provide a-nitroglutarates.

An a l t e r n a t i v e more d i f f i c u l t Michael.

a d d i t i o n , t h a t of secondary n i t r o a l k a n e s t o B-substituted-a,Bu n s a t u r a t e d e s t e r s when c a t a l y s e d by D B U , p r o v i d e s a c c e s s t o t h e isomeric 7-nitro-esters

(89).88 Con j u g a t e a d d i t i o n s o f t h e s i l y l -

c u p r a t e r e a g e n t s (PhMe2Si)MeCuLi a n d (Me S i ) 2 C u L i p r o c e e d w e l l w i t h

3

a number of M i c h a e l a c c e p t o r s i n c l u d i n g a , B - u n s a t u r a t e d e s t e r s , t h e

l a t t e r l e a d i n g t o 8 - s i l y l - e s t e r s (90).89 T h e s e d e r i v a t i v e s (90; R=Ph) c a n be r e a d i l y c o n v e r t e d i n t o t h e c o r r e s p o n d i n g B-hydroxyesters.

Michael a d d i t i o n s t o u n r e a c t i v e a c c e p t o r s i n g e n e r a l

c a n o f t e n b e a c h i e v e d by u s i n g h i g h e r - o r d e r

organocuprates; t h i s

a n d o t h e r a s p e c t s of t h e s e r e a g e n t s h a v e b e e n r e v i e w e d . ” An a l t e r n a t i v e method f o r e f f e c t i n g t h e D a r z e n s g l y c i d i c e s t e r s y n t h e s i s is t o u s e c h l o r o a c e t a t e s i n a c e t o n i t r i l e w i t h sodium h y d r i d e as b a s e . ” A modified p r o c e d u r e h a s been used t o p r e p a r e c h i r a l g l y c i d i c e s t e r s . Thus, c o n d e n s a t i o n s between t h e l i t h i u m

148

General and Synthetic Methods

RIJ

C02R

C02R2

(88)a; X = SnBun3

(89)

b; X = SOq.0SiMe3

c ; X = NO2

KO

)(\co,R~ R'

R2

3:"" R '

0

(91)

(90)

R R-Br

H

------Jc

RMe2Si

--+

RC02Bu"

-

yBr R+c02E1 Me3S

Me3Si

i

(96)

(95)

(94)

(93)

(92)

T -

R

Me 3SiT

S i Me OAc

OC02Me

(99)

(97)

1 51me3 R Me02C

'

v

R

C02Me (101)

2 R+ Me02C

SiMe3 C02Me (100)

149

3: Carboxylic Acids and Derivatives

e n o l a t e of i m i d a t e ( 9 1 ) i n t h e p r e s e n c e o f S n ( O T f ) 2 o r Bu2BOTf w i t h a l d e h y d e s f o l l o w e d by t r e a t m e n t w i t h l i t h i u m b e n z y l o x i d e g i v e s (E,E)-epoxy-esters adducts.

(92) i n e x c e l l e n t o p t i c a l y i e l d s , 9 2 v i a syn-

R e m a r k a b l y , when z i n c c h l o r i d e i s u s e d a s a c o m p l e x i n g

a g e n t , l a r g e l y t h e (S,S)-enantiomers of (92) are obtained. D u r i n g t h e p a s t few y e a r s , t h e a b i l i t y o f p a l l a d i u m a n d r e l a t e d t r a n s i t i o n m e t a l s t o c a t a l y s e carbon-carbon

bond f o r m a t i o n h a s

b l o s s o m e d f r o m r e l a t i v e o b s c u r i t y a n d many s u c h r e a c t i o n s a r e now g e n u i n e a l t e r n a t i v e s t o c l a s s i c a l methods. A f u r t h e r example of t h i s phenomenon i s t h e s u c c e s s f u l and g e n e r a l c a r b o n y l a t i o n o f a r y l , v i n y l , a n d a l i p h a t i c b r o m i d e s ( 9 3 ) by r e a c t i o n w i t h c a r b o n monoxide a n d t r i - n - b u t y l b o r a t e

a t 150 "C

i n t h e presence of

c a t a l y t i c a m o u n t s o f hexa-1,5-dienerhodium(I) c h l o r i d e d i m e r a n d [ P d ( P P h ) 4 ] , w h i c h p r o v i d e s t h e b u t y l e s t e r s ( 9 4 ) i n 42-93% yield." employed.

Lower t e m p e r a t u r e s

(e.g.90

OC

f o r 48 h ) c a n a l s o be

The r e a c t i o n s work b e s t w i t h B(OBunI3 a l t h o u g h t h i s

l i m i t a t i o n i s of l i t t l e consequence i f one simply r e q u i r e s a n e s t e r The same t r a n s f o r m a t i o n c ( 9 3 )

by o n e - c a r b o n h o m o l o g a t i o n .

-

(9411

can a l s o be e f f e c t e d u s i n g c a t a l y t i c q u a n t i t i e s of p e n t a c a r b o n y l i r o n i n t h e p r e s e n c e of potassium c a r b o n a t e and an a l c o h o l , a l t h o u g h i n t h i s case e t h e r s a r e a l s o f o r m e d by a l c o h o l y s i s of t h e h a l i d e . g 4

Diesters.- A major problem a s s o c i a t e d w i t h a l k y l a t i o n s u s i n g unsymmetrical a l l y 1 h a l i d e s is t h e i n e v i t a b l e p o s s i b i l i t y of c o m p e t i t i o n b e t w e e n t h e SN2 a n d S N 2 ' modes o f a t t a c k by t h e incoming n u c l e o p h i l e .

A s o l u t i o n t o t h i s i s t o u s e 3-

( t r i m e t h y l s i l y l ) a l l y l i c bromides

[x. (95)1,

which undergo

r e g i o s p e c i f i c SN2 r e a c t i o n s w i t h a v a r i e t y o f n u c l e o p h i l e s ( w i t h t h e e x c e p t i o n o f n - a l k y l c o p p e r s which react e x c l u s i v e l y i n t h e S N 2 ' mode) .95

Thus, r e a c t i o n with sodio-malonate provides d i e s t e r s (96)

i n which t h e s t e r e o c h e m i s t r y o f t h e a l l y l i c bromide i s p r e s e r v e d . The v i n y l s i l a n e f u n c t i o n i n ( 9 6 ) s h o u l d a l l o w c o n v e r s i o n o f t h e i n i t i a l p r o d u c t s i n t o many o t h e r d e r i v a t i v e s s u c h a s y - o r 6 - k e t o e s t e r s a n d many, m o r e - h i g h l y s u b s t i t u t e d , y , 6 - u n s a t u r a t e d e s t e r s . R e g i o s e l e c t i v i t y of a t t a c k i s a l s o a n i n h e r e n t p r o b l e m i n t h e t r a n s i t i o n metal-catalysed

c o u p l i n g s of a l l y l i c acetates and

r e l a t e d d e r i v a t i v e s w i t h m a l o n a t e s which have been e x t e n s i v e l y s t u d i e d by T r o s t ' s g r o u p . Based on MO p r e d i c t i o n s , i t h a s b e e n foundg6 t h a t d i e n y l c a r b o n a t e s ( 9 7 ) and r e l a t e d i s o m e r s undergo a t t a c k by m a l o n a t e s p r e d o m i n a n t l y a t t h e c e n t r a l c a r b o n i n

General and Synthetic Methods

150

t u n g s t e n - c a t a l y s e d r e a c t i o n s t o p r o v i d e access t o d i e s t e r s ( 9 8 ) . I n s i m i l a r v e i n , t h e u s e f u l b u i l d i n g b l o c k (99) u n d e r g o e s e f f i c i e n t molybdenum-catalysed

a d d i t i o n of malonates t o provide b i s - s i l a n e s

( 1 0 0 ) which u n d e r g o f l u o r i d e - i n d u c e d

( e s p e c i a l l y A r C H O ) t o g i v e an i n variable yields.”

(E/Z)

condensations with aldehydes mixture of t h e 1 , 3 - d i e n e s ( 1 0 1 )

The o r i g i n a l T r o s t method f o r t h e

c o n d e n s a t i o n o f m a l o n a t e s w i t h a l l y l i c a c e t a t e s c a n be c a r r i e d o u t u s i n g p a l l a d i u m c o m p l e x e s and b a s i c a l u m i n a o r KF-alumina;

a r e u s u a l l y c o m p a r a b l e .98

yields

Palladium(0)-catalysed addition of

sodio-malonate t o a - a l l e n i c a c e t a t e s (102) or phosphates occurs o v e r a l l l a r g e l y o r e x c l u s i v e l y i n an SN2 f a s h i o n t o g i v e r e a s o n a b l e y i e l d s (30-67%) of B - a l l e n i c m a l o n a t e s ( 1 0 3 )

.”

2-Substituted

K-

a l l y l p a l l a d i u m c o m p l e x e s c a n a l s o be g e n e r a t e d f r o m a r y l o r v i n y l h a l i d e s and a l l e n e s ; t h e s e r e a c t e f f i c i e n t l y w i t h s o d i o - m a l o n a t e

to

provide one-pot s y n t h e s e s of s t y r e n e s ( 1 0 4 ) or t h e buta-1,3-dienes (105),

p o t e n t i a l l y valuable a s Diels-Alder

the optically a c t i v e n-allylpalladium

dienes. loo

Coupling of

complex ( 1 0 6 ) w i t h s o d i o -

malonate occurs with v i r t u a l l y complete i n v e r s i o n t o g i v e d i e s t e r ( 1 0 7 ) . ’lo’ D i m e t h y l a m i n e r e a c t s s i m i l a r l y w h e r e a s G r i g n a r d

r e a g e n t s t e n d t o a d d f r o m t h e same s i d e as t h e p a l l a d i u m g r o u p , b u t w i t h somewhat l o w e r s e l e c t i v i t i e s .

The r e s t r i c t e d a v a i l a b i l i t y o f

c h i r a l c o m p l e x e s r e l a t e d t o ( 1 0 6 ) would seem t o b e t h e m a j o r drawback w i t h t h i s method.

S i m i l a r c h i r a l p r o d u c t s c a n a l s o be

o b t a i n e d by p a l l a d i u m - c a t a l y s e d r e a c t i o n s b e t w e e n o p t i c a l l y a c t i v e a l l y l i c s u l p h i n a t e s a n d s o d i o - m a l o n a t e ; o p t i c a l y i e l d s a r e up t o 45%, b u t a n y v a l u e i n t h e method i s d i m i n i s h e d by l a c k o f regioselectivity

.l o *

S y n t h e t i c a l l y u s e f u l a l k y l i d e n e m a l o n a t e s and a l k y l i d e n e d e r i v a t i v e s ( 1 0 8 ) o f Meldrum’s a c i d a r e o f t e n d i f f i c u l t t o o b t a i n i n h i g h y i e l d from t h e p a r e n t d i e s t e r s because f u r t h e r a d d i t i o n o c c u r s t o t h e s e powerful Michael a c c e p t o r s . T h i s problem can be c i r c u m v e n t e d i n t h e case of Meldrum’s a c i d ( a n d 1 , 3 - d i o n e s ) by f o r m a t i o n o f t h e c o r r e s p o n d i n g Mannich b a s e s u s i n g a n a l d e h y d e a n d pyrrolidine; acid hydrolysis then provides t h e 2-alkylidene d e r i v a t i v e s ( 108) i n e x c e l l e n t y i e l d s . I o 3 Michael a d d i t i o n s of Meldrum’s a c i d i t s e l f t o a c r y l a t e s a n d r e l a t i v e s c a n be c a r r i e d o u t Only t h e m o n o - a d d u c t s a r e 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 . lo‘ f o r m e d w h i c h c a n be f u r t h e r a l k y l a t e d , a t l e a s t w i t h m e t h y l i o d i d e

or benzyl c h l o r i d e , t o g i v e t h e d i s u b s t i t u t e d products (109). S u i t a b l e c o n d i t i o n s have been found whereby s i m p l e e t h y l e s t e r e n o l a t e s undergo Michael a d d i t i o n s t o a,B-unsaturated esters t o

3: Carboxylic Acids and Derivatives

151

R’

-

R 2 + - Y 0 * ‘R

R’

\hEt ”I” Me

(

c

C02Et

(105)

‘::TrR’

(106)

RO 2C

H . 5

Et 0 2 C

RO,C

Ph

P d C I 12

R2 (104)

-.

OH R’

H

-

ACO,nZ

H

OH CO2E t

General and Synthetic Methods

152

give generally excellent yields of the erythro-glutarates (110).105 By contrast, the corresponding t-butyl ester enolates give threoglutarates. A simple if non-stereoselective route to symmetrical 3-hydroxyglutarates ( 1 1 1 ) consists of Reformatsky reactions between 2-bromopropionates and ethyl formate which are only successful in the presence of a catalytic amount of trimethylsilyl chloride. 106 Hydroxy-esters.- 3-Phenyl-2-phenylsulphonyloxaziridine has been found to be an excellent reagent for the direct oxidation of ester (and ketone) enolates giving better yields of a-hydroxy-esters (at least in the case of phenylacetates) than does oxygen o r MoOPH. 107 Chiral a-hydroxy-esters (112) c a n be obtained with optical purities of up to 100% by reduction of the corresponding ketones using I3--(3pinanyl)-9-borabicyclo[3.3.l]nonane (Alpine-Borane). lo8 The recent development of a procedure for obtaining optically pure ( + ) - o r (-)-a-pinene will greatly enhance the utility of this method. An alternative approach to chiral hydroxy-esters (112; R 1 = RCH2) is by coupling of lithium dialkylcuprates, R2CuLi, with ethyl (R)-[or (~)]-3-bromo-2-hydroxypropanoate (1131, readily derived from the corresponding aspartic acid by sequential nitrous acid deamination Condensations between menthyl and Hunsdiecker degradation. l o g pyruvates and l-naphthol provide virtually optically pure a110 hydroxy-esters (112; R ’ = l-hydroxynaphth-2-yl). There are three basic strategies available for the synthesis of chiral 8-hydroxy-esters, namely enantioselective aldol condensations’ l 1 or reductions of 8-keto-esters using either chemical l 1 o r microbial methods. Baker s yeast has proven especially useful in this last respect and a number of significant examples have been added to the already extensive list. Thus, yeast reduction of a - s u l p h e n y l - 8 - k e t o - e s t e r s provides separable mixtures of optically pure threo- (114) and erythro- (115) 8hydroxy-esters, l 4 both of which can be desulphurized to give the corresponding (S)-B-hydroxy-esters. Similarly, reduction of 4p h e n y l s u l p h o n y l a c e t o a c e t a t e leads to hydroxy-ester (116) (98% 115 e.e.1, which on desulphurization affords (R)-3-hydroxybutanoate. As direct yeast reduction of methyl acetoacetate affords the corresponding (2)-enantiomer; this represents a good example of how bulky, removable substituents can be used to influence the course of these reductions in a synthetically useful way. Yeast reduction of tetrahydro-4-oxo-thiopyran-3-carboxylate gives the corresponding 4-hydroxy-derivative (117) (of 98% diastereoisomeric and c.85%

’

3: Carboxylic Acids and Derivatives

153

OH

OH

OH PhS02&C02Me

SR2

SR2

(115)

(114)

(118 1

(117)

HO H u 0 2 R

M

e

(120) a ; R = Me b; R Z E t

H HO L C 0 2 M e Me0,C

(121 1

(116)

(119)

HO HO &C02Me

(1 22 1

General and Synthetic Methods

154

e n a n t i o m e r i c p u r i t y ) , u s e f u l as a p r e c u r s o r t o a v a r i e t y o f c h i r a l b i f u n c t i o n a l compounds. R e d u c t i o n s o f 3 - k e t o g l u t a r a t e s a n d 3k e t o a d i p a t e s g i v e a r a n g e o f o p t i c a l y i e l d s d e p e n d e n t on t h e n a t u r e of t h e ester groupings. o b t a i n e d w i t h 84% e . e . ,

However, t h e h y d r o x y - e s t e r

(118) can be

a l t h o u g h t h e c h e m i c a l y i e l d i s r a t h e r low

I n g e n e r a l , it is q u i t e s t r a i g h t f o r w a r d t o c a r r y o u t

(26%).’17

t h e s e r e d u c t i o n s on p r e p a r a t i v e l y u s e f u l s c a l e s .

A f u r t h e r example

o f t h i s i s y e a s t r e d u c t i o n o f e t h y l 4,4,4-trichloroacetoacetate on a 50 g s c a l e t o g i v e t h e p o t e n t i a l l y u s e f u l b u i l d i n g b l o c k ( 1 1 9 )

w i t h 85% e . e . ,

i n c r e a s e d t o 98% on c r y s t a l l i z a t i o n .

l8

An

a l t e r n a t i v e s t r a t e g y f o r t h e p r e p a r a t i o n of t h e o p p o s i t e enantiomer t o t h a t p r o d u c e d i n y e a s t r e d u c t i o n s i s t o make u s e o f o t h e r m i c r o -

’’

organisms. E x a m p l e s of t h i s i n t h e p r e p a r a t i o n o f 8-hydroxye s t e r s a r e t h e u s e o f t h e r m o p h i l i c b a c t e r i a ’ ” a n d of Details have been Geotrichum candidum and A s p e r g i l l u s n i g e r . I 2 O g i v e n f o r t h e d e p o l y m e r i z a t i o n of t h e c o m m e r c i a l l y a v a i l a b l e mixed

PHB/PHV b i o p o l y m e r t o g i v e m e t h y l ( R ) - 3 - h y d r o x y - b u t a n o a t e and - v a l e r a t e

(120a)

(120b), the latter being a valuable addition t o t h e

c h i r a l pool. 21 Many e x a m p l e s a r e known o f t h e u s e f u l d i r e c t i n g e f f e c t t h a t c a n be d i s p l a y e d by h y d r o x y - g r o u p s .

A novel m a n i f e s t a t i o n of t h i s

i s i n t h e b o r a n e - m e t h y l sulphide-NaBH4

(cat.)

r e d u c t i o n of dimethyl

( 1 2 1 ) which is e n t i r e l y r e g i o s e l e c t i v e , g i v i n g y e t 122 a n o t h e r u s e f u l c h i r a l . s t a r t i n g m a t e r i a l ( 1 2 2 ) i n 88% y i e l d . (?)-malate

Asymmetric a l d o l c o n d e n s a t i o n s c a n be c a r r i e d o u t u s i n g t h e sulphinyl-acetimidate hydrolysis,

( 123). 1 2 3

8-hydroxy-esters

(2)-

After d e s u l p h u r i z a t i o n a n d a c i d i c

(124) a r e o b t a i n e d w i t h > 8 0 % e . e . , a s

e i t h e r t h e (El- o r ( 2 ) - e n a n t i o m e r d e p e n d i n g on t h e r e a c t i o n conditions.

The c h i r a l 0 - h y d r o x y - e s t e r

[ ( 2 ) - ( 1 2 4 ) ; (R = Me)] c a n be

c o n v e r t e d i n t o a d i a n i o n w h i c h on a l k y l a t i o n w i t h m e t h y l i o d i d e , o r a l l y 1 or benzyl bromide, g i v e s e x c l u s i v e l y t h e (2S,3S)-homologues ( 1 2 5 ) .124, Racemic ( S *S*)-hydroxy-esters (125) can a l s o be o b t a i n e d by a ‘ o n e - p o t ’ a l d o l - a l k y l a t i o n s e q u e n c e . Furthermore, yeast r e d u c t i o n of t h e k e t o - e s t e r s c o r r e s p o n d i n g t o ( 1 2 5 ) l e a d s t o m i x t u r e s of t h e (2RS,3S)-diastereoisomers of ( 1 2 5 ) w h i c h on f u r t h e r a l k y l a t i o n provide c h i r a l a , a - d i s u b s t i t u t e d B-hydroxy-esters. F u r t h e r m a n i p u l a t i o n s of t h e s e p r o d u c t s s e r v e t o e m p h a s i z e t h e potential inherent i n these transformations.

I n r e l a t e d work, t h e

s t e r e o c h e m i c a l outcome o f 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 l d e h y d e s a n d a v a r i e t y o f a - h y d r o x y - a c i d d e r i v a t i v e s h a s b e e n e x a m i n e d . 1 2 5 Some o f t h e b e s t r e s u l t s were o b t a i n e d u s i n g m e t h y l 2 - m e t h o x y p r o p a n o a t e

155

3: Carboxylic Acids and Derivatives

which g i v e s v i r t u a l l y pure d i h y d r o x y - d e r i v a t i v e s (126) i n c o n d e n s a t i o n s w i t h a - b r a n c h e d a l d e h y d e s . Some s i m i l a r l y i m p r e s s i v e r e s u l t s using highly s u b s t i t u t e d phenyl a c e t a t e s are a l s o reported i n t h i s u s e f u l summary p a p e r .

(Z)-Allylboronates (127) undergo

pressure-induced a l d o l condensations with ethyl pyruvate a t 6 kbar t o g i v e l a r g e l y t h e d i a s t e r e o i s o m e r ( 1 2 8 ) which u n u s u a l l y i s a l s o l a r g e l y a s i n g l e isomer w i t h r e s p e c t t o t h e t e t r a h y d r o p y r a n y l e t h e r centre.

The e x c i t i n g p o s s i b i l i t y p r e s e n t s i t s e l f t h a t , by u s i n g

c h i r a l THP d e r i v a t i v e s , o p t i c a l l y a c t i v e a , B - d i h y d r o x y - e s t e r s 126 r e l a t e d compounds c o u l d be o b t a i n e d . An a l t e r n a t i v e a n d u s u a l l y e f f i c i e n t way t o c a r r y o u t

and

Reformatsky r e a c t i o n s is t o use t h e e a s i l y prepared r e a g e n t s Bun3SnA1Et2 o r R PbA1Et2 ( R

3

Bun o r P h ) i n p l a c e o f z i n c . 1 2 7

B-

H y d r o x y - e s t e r s c a n a l s o be p r e p a r e d f r o m k e t e n e s i l y l a c e t a l s a n d a l d e h y d e s o r k e t o n e s u n d e r n e u t r a l c o n d i t i o n s s i m p l y by t h e Although y i e l d s are

.

a p p l i c a t i o n of high p r e s s u r e (10 k b a r ) 128

e x c e l l e n t , d i a s t e r e o s e l e c t i v i t i e s are g e n e r a l l y poor. 126

e s t e r s ( 9 0 ; R:Ph)89

B-silyl

c a n be c o n v e r t e d i n t o B - h y d r o x y - e s t e r s

by

s e q u e n t i a l p r o t i o d e s i l y l a t i o n o f t h e p h e n y l g r o u p (HBF ) a n d o x i d a t i o n ( M C P B A ) , w i t h r e t e n t i o n o f c o n f i g u r a t i o n . 12’ The p h e n y l d i m e t h y l s i l y l g r o u p i s t h e r e f o r e a p o t e n t i a l l y u s e f u l masked

For e x a m p l e , a - a l k y l a t i o n o f B - s i l y l e s t e r s i s p o s s i b l e w i t h o u t any problems of B-elimination which u s u a l l y a r i s e w i t h p r o t e c t e d h y d r o x y - g r o u p s ( L g . B-benzyloxyf o r m of a h y d r o x y f u n c t i o n .

esters).

A s t h e o r i g i n a l s i l y l e s t e r s c a n be o b t a i n e d i n a h i g h l y

d i a s t e r e o s e l e c t i v e manner, t h i s sequence, o v e r a l l , r e p r e s e n t s a n equivalent t o a diastereoselective aldol reaction. Treatment of epoxides

[e.g. ( 1 2 9 ) l

w i t h t r i a l k y l s i l a n e s and

c a r b o n monoxide ( 1 a t m ) 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 [Co2(CO)

1

l e a d s t o e x c e l l e n t y i e l d s of 1 , 3 - d i o l d e r i v a t i v e s

[e.g.

The r e a c t i o n i s a l s o a p p l i c a b l e t o g l y c i d i c e s t e r s ( t o g i v e a , y - d i h y d r o x y - e s t e r s ) a n d c a n be r e g a r d e d a s i n v o l v i f l g t h e (1301.

e q u i v a l e n t of t h e methanol-derived

carbar,ion ( l 3 l ) , and a s s u c h

d i s p l a y s t h e e x p e c t e d r e g i o - and s t e r e o - s e l e c t i v i t y

of a d d i t i o n .

Presumably, o l e f i n i c s u b s t r a t e s a r e not a p p r o p r i a t e . approach t o w-hydroxy-esters hydroxy-I-bromoalkynes hydrogenation. l 3

A useful i s by c o p p e r - c a t a l y s e d c o u p l i n g of w -

and w - e t h y n y l - c a r b o x y l i c

a c i d s f o l l o w e d by

T h i s v e r s i o n of t h e C a d i o t - C h o d k i e w i c z r e a c t i o r ,

i s p a r t i c u l a r l y s u i t a b l e f o r t h e s y n t h e s i s o f l o n g - c h a i n w-hydroxya c i d s and - e s t e r s .

General and Synthetic Methods

156

fl ,s..A ..1 OE

HO

NOMe

p-Tol

t

----

-

'X/COZMe

R

OSiR3

R,SiO A

C

O

(130)

(129)

0E t OSi Me3

(132)

Z

M

e

-CH,OSi R, (131 1

R' R 2

OSi Me,

O+

OH H

H

x C O Z E t

RCHo--

-tCozEt

H o v 0 0 2 E t

0

(133)

(134)

157

3: Carboxylic Acids and Derivatives Keto-esters.-

a-Hydroxy-esters

can be oxidized t o a-keto-esters

u n d e r m i l d c o n d i t i o n s by u s i n g t - b u t y l h y d r o p e r o x i d e w i t h a r u t h e n i u m c a t a l y s t s u c h as [RuC12(PPh ) Remarkably, t h e 3 3 method works i n t h e p r e p a r a t i o n o f B , y - u n s a t u r a t e d a - k e t o - e s t e r s ,

as e p o x i d a t i o n d o e s n o t compete.

The t e t r a - a l k o x y e t h y l e n e

(l32),

d e r i v e d f r o m d i e t h y l o x a l a t e , r e p r e s e n t s a s y n t h e t i c e q u i v a l e n t of the acyl anion (133) i n Lewis acid-catalysed reactions with c a r b o n y l s or t e r t i a r y h a l i d e s which l e a d t o a - k e t o - e s t e r s ( 1 3 4 ) The r e a g e n t g i v e s M i c h a e l a d d i t i o n p r o d u c t s

a f t e r h y d r o l y s i s . 133

with conjugated enones.

An a l t e r n a t i v e e q u i v a l e n t o f t h e a n i o n

( 133) is t h e phosphonate ( 135), derived from methyl g l y o x y l a t e .

34

Wadsworth-Emmons c o n d e n s a t i o n s w i t h a l d e h y d e s o c c u r c l e a n l y a n d w i t h o u t r a c e m i z a t i o n when p o s s i b l e t o g i v e t h e e n o l s ( 1 3 6 ) , w h i c h a r e d e p r o t e c t e d u s i n g z i n c d u s t . 35 Aromatic a-keto-esters

c a n b e o b t a i n e d by F r i e d e l - C r a f t s

r e a c t i o n s u s i n g dichloro(ethoxy)acetates

(138); y i e l d s can be

better than those obtained i n the conventional procedure with e t h o x a l y l c h l o r i d e . 136

P h e n y l p y r u v a t e s ( 139) can be o b t a i n e d from

some ( a l k y l b e n z e n e ) - C r ( C O ) 3 c o m p l e x e s by c o n d e n s a t i o n w i t h e t h y l o x a l a t e , u s i n g ButOK a s b a s e . 137

The r e a c t i o n c a n a l s o b e

s u c c e s s f u l l y a p p l i e d t o ( i n d e n e ) - C r ( C O ) ? and i n t e r e s t i n g l y , t h e p r o d u c t s e x i s t e n t i r e l y i n t h e e n o l f o r m i n t h e l a t t e r case o r i n S i m p l e p r e p a r a t i o n s of t h e s y n t h e t i c a l l y u s e f u l (139; R1 = H ) . monoacetals ( 1 4 0 ) of formylpyruvate esters have a l s o been d e s c r i b e d i n d e t a i l . 38 A new p r o c e d u r e f o r t h e p r e p a r a t i o n o f a c e t o a c e t a t e s ( 1 4 2 ) f r o m

d i k e t e n e ( 1 4 1 ) and a n a l c o h o l , i n which 4 - d i m e t h y l a m i n o p y r i d i n e i s u s e d as t h e c a t a l y t i c b a s e , a p p e a r s t o b e a d i s t i n c t i m p r o v e m e n t on t h e m e t h o d s d e s c r i b e d i n O r g a n i c S y n t h e s i s a n d e l s e w h e r e . 39 A l l y l i c a c e t o a c e t a t e s (143) prepared using t h i s procedure undergo Carroll-type rearrangements t o g i v e B-keto-acids

(144), after

conversion i n t o t h e corresponding acetoacetate dianions, under c o n d i t i o n s ( ~ 6 5O C ) w h i c h a r e much m i l d e r t h a n i s t h e case i n normal C a r r o l l r e a c t i o n s . C l a i s e n and Dieckmann c o n d e n s a t i o n s c a n be c a r r i e d o u t i n t h e p r e s e n c e of t h e t i t a n i u m ( 1 V ) b i s t r i f l a t e [ T i c 1 (OTf) 1 and 2 2 I s o l a t e d y i e l d s are i n t h e t r i e t h y l a m i n e at ambient temperature. r a n g e of 52-72% for t h i s p a r t i c u l a r l y m i l d p r o c e d u r e , w h i c h i s , however, n o t a p p l i c a b l e t o a-branched e s t e r s . Dieckmann c o n d e n s a t i o n s l e a d i n g t o f i v e - and six-membered r i n g s ( o n l y ) c a n a l s o b e a f f e c t e d r a p i d l y a n d c l e a n l y a t room t e m p e r a t u r e u s i n g a

General and Synthetic Methods

158

0-xco2R

C 0 2 Et

EtoXC02R CI CI

R2X

XR2

Cr (CO) (140) a; X '0,R'= R Z = Et

(139)

(136)

b; X = S, R2= -(CH2)r

- uoR Mo =eo ROH

0

(142)

(141 1

dCO2,,

A J O " R

W

R

'

R2

(144)

(146)

(145) n = l o r 2

'

L

O

A

CI OC02Me

0

R2

0

C02Me

C02Me C02Me

(152)

(153)

(151)

c

3: Carboxylic Acids and Derivatives

159

t o l u e n e suspension of c o l l o i d a l potassium, g e n e r a t e d ultrasonically. V a r i o u s v i n y l o g o u s Dieckmann c o n d e n s a t i o n s h a v e been e x a m i n e d a n d f o u n d t o obey B a l d w i n ' s r u l e s , t h u s p r o v i d i n g a n e x t e n s i o n of t h e s e v a l u a b l e p r e d i c t i v e p r i n c i p l e s . 142 An a l t e r n a t i v e t o t h e Dieckmann f o r t h e p r e p a r a t i o n o f c y c l i c B-ketoe s t e r s i s a l k o x y c a r b o n y l a t i o n of t h e p a r e n t c y c l o a l k a n o n e , u s u a l l y e m p l o y i n g d i e t h y l c a r b o n a t e and sodium h y d r i d e . W h i l e b e i n g much more g e n e r a l t h a n t h e Dieckmann i n t h e s e n s e t h a t i t i s a p p l i c a b l e t o most s i z e s o f c y c l o a l k a n o n e , t h i s method c a n be p r o b l e m a t i c i n examples i n v o l v i n g unsymmetrical or a,B-unsaturated k e t o n e s .

These

l i m i t a t i o n s c a n be l a r g e l y overcome i n t h e l a t t e r c a s e s by u s i n g

as t h e a c y l a t i n g F o r e x a m p l e , k i n e t i c e n o l a t e s d e r i v e d from a , B-

t h e much more r e a c t i v e d i e t h y l % c a r b o n a t e reagent.

u n s a t u r a t e d c y c l o a l k a n o n e s a t -78

OC

d e r i v a t i v e s ( 1 4 5 ) i n 35-78% y i e l d s .

c a n be c o n v e r t e d i n t o Under t h e s e c o n d i t i o n s ,

e n o l a t e s of s a t u r a t e d c y c l o a l k a n o n e s t e n d t o u n d e r g o ethoxycarbonylation.

0-

O x a z o l i n e d e r i v a t i v e s ( 1 4 6 ; R 1 = H ) c a n be

e f f i c i e n t l y mono-alkylated

t o g i v e oxazolines (146; R1 = a l k y l )

w h i c h c a n t h e n be h y d r o l y s e d t o t h e c o r r e s p o n d i n g 8 - k e t o - e s t e r s .

, 144

T h e s e d e r i v a t i v e s c o u l d be of u s e as p a r t i a l l y p r o t e c t e d B-ketoe s t e r s , a l t h o u g h t h e method i s l i m i t e d b e c a u s e t h e i n i t i a l oxazolines (146; R1

H ) a r e o b t a i n e d f r o m two e q u i v a l e n t s of a

n o n - e n o l i z a b l e a c i d c h l o r i d e , R2COC1. R h o d i u m - c a t a l y s e d a l k y l a t i o n s of 8 - k e t o - e s t e r s

(147) u s i n g

[RhH(PPh ) ] and Bun3P c a n be c a r r i e d o u t u n d e r n e u t r a l c o n d i t i o n s 3 4 ( i . e . no b a s e n e e d e d ) u s i n g a l l y l i c c a r b o n a t e s ( 1 4 8 ) ; t h e p r o d u c t s ( 1 4 9 ) a r e l a r g e l y o r e x c l u s i v e l y t h o s e of SN2 a t t a c k .

Following

on from work by T r o s t e t a l . a n d N e g i s h i e t a l . , S c h u d a a n d B e r n s t e i n have r e p o r t e F t h a t t h e r e a d i l y a v a i l a b l e a l l y l i c a c e t a t e ( 1 5 0 ) car, be u s e d i n P d ( O A c ) 2 - c a t a l y s e d a l k y l a t i o n s o f s o f t nucleophiles. T h u s , for e x a m p l e , r e a c t i o n w i t h amethoxycarbonylcyclopentanone f o l l o w e d by h y d r o l y s i s o f t h e v i n y l c h l o r i d e f u n c t i o n l e a d s t o t h e homologue ( 1 5 1 ) ; t h e a c e t a t e ( 1 5 0 ) c a n t h e r e f o r e be r e g a r d e d a s a n o t h e r e q u i v a l e n t o f t h e h y p o t h e t i c a l acetone C-cation. Two a p p r o a c h e s t o t h e u n s a t u r a t e d 8 - k e t o - e s t e r s ( 1 5 3 ) h a v e b e e n d e s c r i b e d i n f u l l , 1 4 7 e i t h e r by W i t t i g - H o r n e r r e a c t i o n s between phosphine o x i d e d i a n i o n s ( 1 5 2 ) and a l d e h y d e s o r k e t o n e s o r by d i r e c t a l k y l a t i o n o f t h e u n s a t u r a t e d k e t o - e s t e r s (153; R1 H) t h u s d e r i v e d , u s i n g NaOMe-A1203 a s b a s e . D i a n i o n s d e r i v e d from k e t o - e s t e r s ( 1 5 3 ) u n d e r g o f u r t h e r a l k y l a t i o n a t t h e y p o s i t i o n l e a d i n g t o deconjugated homologues.

General and Synthetic Methods

160

Full details have been given for the direct a - a r y l a t i ~ nof ~ ~ 13keto-esters by aryl-lead triacetates. 148 This method can be extended to vinylogous examples in which substituted B-keto-esters [e.g. (154)l are obtained from the parent compounds on reaction with distyrylmercury or a styrylstannane, and lead tetraPreliminary indications are that these reactions will acetate. probably be applicable to vinylmercuries and vinylstannanes in general and also to other 6-dicarbonyl compounds. Enders has summarized much of his group's work on the asymmetric synthesis of ketones using 'SAMP ' - and RAMP -hydrazones . 50 Of relevance to this section is the preparation of both enantiomers of the protected 3,6-dioxo-ester (155) with an e.e. of 95%, from ethyl (E)-4-bromo-3-ethoxycrotonate. Many other applications of this spectacularly successful methodology will doubtless be forthcoming. Chiral a-alkyl-B-keto-esters (157) have been obtained by metallation (LDA; toluene) and alkylation (by reactive halides only) of enamines (156), easily prepared from the parent B-ketoOptical yields vary between ester and (S)-valine t-butyl ester. 15' 44-100y0 and the sense of asymmetric induction can be varied by the addition of appropriate ligating solvents, HMPA leading to the opposite enantiomer when compared with T H F , dioxolane o r trimethylamine. Enantiomeric enrichments of up to 66% have been achieved in the preparation of keto-ester (158) by Michael addition of l-oxo-indanecarboxylate to methyl vinyl ketone in the presence of [C~(acac)~]and ( + ) - o r ( - ) - I ,2-diphenylethane-I ,2-diamine. 152 A novel and rather neat route to a-hydroxy-B-keto-esters (159) is by base-induced (LDA) rearrangement of a-acyloxyacetates, readily derived from an acid, RC02H, and ethyl bromoacetate. 153 Isolated yields are 52-65%; the initially formed a-alkoxides can be trapped in situ to provide the corresponding a-acetoxy or atrimethylsilyloxy analogues. The many applications of palladium-catalysed Wacker-type oxidations of olefins to ketones have been reviewed;'54 these include the conversions of a , B - and B,y-unsaturated esters into Band y-keto-esters respectively. An alternative, general route to y-keto-esters (161) consists of mild, fluoride-induced ring cleavage of 2-silyloxycyclopropanecarboxylates ( 160) ; 82 generally, yields are excellent even in cases of rather sensitive products. 155 Preliminary indications are that the method can also be applied to related silylcyclopropanes. Further alkylation at the a-position of (161) can be effected in situ during the ring opening but yields

'''

3: Carboxylic Acids and Derivatives

161

C02E t

M

C02Et

H

(154)

OEt

(155)

(156)

0

Q,,,,

C02Et

R

K

Rl

f OH

R2

4

(158)

(159)

(157)

C02Me (160)

(161) R 4 = a l k y l , a l l y l , PhSe, or SR5

(162)

SiMe,

dyEt>p OSiMe,

R

_t

R&

0

R&

C02Et

I

C02Et

SiMe, (1 63)

(16 4 )

(1 6 5 )

(166)

General and Synthetic Methods

162 a r e a l w a y s l e s s t h a n 60%. R3=H)

However, c l e a v a g e o f c y c l o p r o p a n e s ( 1 6 0 ;

w i t h bromine g i v e s t h e c o r r e s p o n d i n g a - b r o m o - d e r i v a t i v e s o f

keto-esters

( 1 6 1 ) w h i c h c a n s o m e t i m e s be i s o l a t e d .

Subsequent

e l i m i n a t i o n of H B r t h e n l e a d s t o t h e u n s a t u r a t e d homologues ( 1 6 2 ) . 56

S i m i l a r l y , TiC14-catalysed

r i n g opening of cyclopropanes

( 1 6 0 ) i n t h e p r e s e n c e of p h e n y l s e l e n e n y l c h l o r i d e o r

0-

nitrophenylsulphenyl chloride gives the potentially useful a-seleno

o r u - s u l p h e n y l d e r i v a t i v e s ( 1 6 1 ; R 4 = PhSe o r g-N02C6H4S).157 r i n g - c l e a v a g e r e a c t i o n a l s o c o n s t i t u t e s a key s t e p i n t h e

A

' r e d u c t i v e s u c c i n o y l a t i o n ' approach t o 6 - s u b s t i t u t e d y-keto-esters. T h u s , t h e t r a p p e d a c y l o i n ( 1 6 4 ) , d e r i v e d from d i e t h y l s u c c i n a t e , undergoes SnC14-catalysed a l d o l - t y p e

condensations with a c e t a l s

(163) leading d i r e c t l y t o the ring-cleavage useful, semi-protected y-keto-esters i n t o y-keto-esters

products (165).

These

c a n be i s o l a t e d o r c o n v e r t e d

( 1 6 6 ) d u r i n g work-up. 1 5 8 Yet a n o t h e r r o u t e t o

y - k e t o - e s t e r s which r e l i e s upon L e w i s a c i d - c a t a l y s e d r i n g c l e a v a g e o f a s i l y l o x y - c y c l o p r o p a n e i n v o l v e s an i n i t i a l r e a c t i o n between t h e mixed a c e t a l ( 1 6 7 ) o f c y c l o p r o p a n o n e a n d z i n c c h l o r i d e , w h i c h p r o d u c e s t h e z i n c h o m o e n o l a t e s ( 1 6 8 ) . 235 S u b s e q u e n t c o u p l i n g w i t h a n a c i d c h l o r i d e i n t h e p r e s e n c e of c u p r o u s i o d i d e a n d HMPA l e a d s t o simple

y

-keto-esters

( 169) i n high y i e l d .

Homoenolates ( 168)

a l s o add i n a Michael f a s h i o n t o e n o n e s , b u t o n l y i n t h e p r e s e n c e o f t h e Me S i c 1 f o r m e d d u r i n g t h e i r g e n e r a t i o n , t o g i v e t h e E - k e t o 3 ester d e r i v a t i v e s (170) i n high y i e l d s . I s o x a z o l i n e s ( 1 7 1 1 , o b t a i n e d by [ 1 , 3 ] - d i p o l a r c y c l o a d d i t i o n s between n i t r i l e o x i d e s and a c r o l e i n d i e t h y l a c e t a l , undergo t h e e x p e c t e d N-0 bond c l e a v a g e on r e d u c t i o n w i t h R a n e y - n i c k e l , l e a d i n g t o t h e useful hydroxy-acetals (172). However, on t r e a t m e n t w i t h HC1-EtOH, t h e s e undergo rearrangement w i t h s u r p r i s i n g f a c i l i t y t o g i v e t h e y-keto-esters (169; R 1 = E t ) i n very high yields.16' High e n a n t i o m e r i c e n r i c h m e n t s h a v e b e e n o b t a i n e d i n a l k y l a t i o n s o f b i c y c l i c l a c t a m s d e r i v e d from 3 - b e n z o y l p r o p i o n i c a c i d a n d valinol, leading t o

ci

,a-disubstituted

keto-esters

(L)-

( 173). 16'

U n f o r t u n a t e l y , t h e method i s n o t s u i t a b l e f o r t h e s y n t h e s i s o f t h e c o r r e s p o n d i n g mono-alkyl

d e r i v a t i v e s ( 173; R2=H)

owing t o e x t e n s i v e

r a c e m i z a t i o n d u r i n g t h e f i n a l a c i d h y d r o l y s i s of t h e lactams. Novel v e r s i o n s o f t h e M i c h a e l r e a c t i o n c o n t i n u e t o p r o v i d e new r o u t e s t o b o t h y - and 6 - k e t o - e s t e r s . N i t r o - o l e f i n s ( 1 7 4 ) a c t as e x c e l l e n t Michael a c c e p t o r s i n r e a c t i o n s w i t h k e t e n e s i l y l a c e t a l s ( 1 7 5 ) u n d e r t h e now f a m i l i a r c o n d i t i o n s c o n s i s t i n g o f T i C 1 4 - C H 2 C 1 2 a t -78

OC,

a l t h o u g h i n some c a s e s t h e f u r t h e r a d d i t i o n o f T i ( O P r 1 ) 4

3: Carboxylic Acids and Derivatives

163

i s b e n e f i c i a l . 162 H y d r o l y s i s of t h e r e s u l t i n g n i t r o - e s t e r s t o k e t o - e s t e r s (176) i s b e s t c a r r i e d o u t i n s i t u by a d d i n g DME-H20. A z o - a n i o n s (177) d e r i v e d from a l d e h y d e t - b u t y l h y d r a z o n e s u n d e r g o M i c h a e l r e a c t i o n s w i t h m e t h y l c r o t o n a t e t o g i v e a z o - e s t e r s (178; R 2 = M e ) ; s u b s e q u e n t i s o m e r i z a t i o n (TFA) a n d h y d r o l y s i s ( o x a l i c a c i d ) l e a d s t o t h e 7 - k e t o - e s t e r s (179) i n 50-60% o v e r a l l y i e l d s . 163 A l t e r n a t i v e l y , a z o - e s t e r s (178; R 2 = H ) c a n be o b t a i n e d d i r e c t l y f r o m t h e r m a l ene r e a c t i o n s between t h e t - b u t y l h y d r a z o n e s and methyl Similar e n e r e a c t i o n s of p h e n y l h y d r a z o n e s and m e t h y l acrylate. a c r y l a t e a l s o g i v e a z o - e s t e r s [cf.(178)1 w h i c h c a n be s u c c e s s f u l l y r e d u c e d u s i n g Adam's c a t a l y s t a n d h y d r o c h l o r i c a c i d t o h y d r o c h l o r i d e s a l t s of 7 - a m i n o - a c i d s . L e w i s acid-catalysed Michael a d d i t i o n s o f k e t e n e s i l y l a c e t a l s (175) t o e n o n e s (180), l e a d i n g t o & k e t o - e s t e r s , h a v e b e e n known f o r some time. A m o d i f i c a t i o n t o t h i s is t o c a t a l y s e t h e r e a c t i o n s with tris(dimethylamino1s u l p h o n i u m difluorotrimethylsiliconate (TASF), 1 6 4 w h i c h i s n o t o n l y

a good s o u r c e o f c o m p l e t e l y a n h y d r o u s f l u o r i d e b u t a l s o a l l o w s f o r t h e e a s y i s o l a t i o n o f t h e i n i t i a l s i l y l e n o l e t h e r s (181). I n some unhindered examples, such Michael a d d i t i o n s can be simply c a r r i e d o u t a t room t e m p e r a t u r e by u s i n g n i t r o m e t h a n e a s s o l v e n t i n t h e a b s e n c e of f l u o r i d e . (A previously reported fluoride-free alternative involves heating the reactants i n acetonitrile.) An e x c e p t i o n t o t h e u s u a l o b s e r v a t i o n t h a t l i t h i u m e n o l a t e s add mainly [1,2] t o e n o n e s i s t h e f i n d i n g t h a t m e t h y l l i t h i o t r i m e t h y l s i l y l a c e t a t e a d d s t o c y c l o p e n t e n o n e t o g i v e t h e M i c h a e l a d d u c t [cf.(l81; R=SiMe ) ] i n 85% y i e l d . 165 A s i m i l a r r e a c t i o n w i t h c y c l o h e x e n o n e 3 g i v e s m a i n l y t h e [ 1 , 2 ] a d d u c t . Howzver, s i m p l e l i t h i u m e n o l a t e s d e r i v e d from e s t e r s w i l l add i n a Michael f a s h i o n t o v e r y r e a c t i v e enones; such is t h e c a s e with t h e e x o c y c l i c a ' - e t h y l i d e n e c y c l o p e n t e n o n e (182). 166 A l k y l a t i o n o f t h e i n t e r m e d i a t e e n o l a t e s w i t h r e a c t i v e e l e c t r o p h i l e s ( E + > p r o v i d e s t h e homologues ( 183). L i t t l e or no a t t a c k a t t h e endo-enone f u n c t i o n i s o b s e r v e d . B a s e d on some p r e v i o u s r e p o r t s s c a t t e r e d t h r o u g h o u t t h e l i t e r a t u r e , C o a t e s a n d Hobbs h a v e d e v e l o p e d a g e n e r a l method f o r t h e i n t r o d u c t i o n o f a n a - a l k o x y a l l y l g r o u p i n t o 0 - d i c a r b o n y l compounds a n d r e l a t e d r e a d i l y e n o l i z a b l e s u b s t r a t e s . 167 The r e a c t i o n s s i m p l y i n v o l v e h e a t i n g t h e s u b s t r a t e and an a c e t a l of an a , B - e n a l , t o g e t h e r w i t h a t r a c e o f [ N i ( a c a c ) , l i n t h e case o f a 0 - k e t o - e s t e r . The p r o d u c t s [e.g. (184)l amount t o f o r m a l M i c h a e l a d d u c t s b u t may arise v i a 0 - a l k y l a t i o n and s u b s e q u e n t C l a i s e n rearrangement.

General and Synthetic Methods

164

-

R

OEt

R&

(177)

0

(169)

Ph

OH

(178)

(179)

+

C02Me

ii, 5"L NaOH

COZEt

C0,Me

3: Carboxylic Acids and Derivatives

165

Unsaturated Esters.- A full account has been given of the alkylation and subsequent base-induced ring cleavage of the 4oxothiolane anion ( 185) leading to acrylates ( 186). 1 6 8 The anion ( 1 8 5 ) can thus be regarded as the equivalent of the vinyl carbanion ( 187). A tandem Michael addition-Peterson olefinationlgO sequence starting with the a-silylacrylate ( 1 8 8 ) can be used to obtain highly substituted acrylates (189) in a 'one-pot' reaction. So far, the method has been found to be successful with PhMgBr, 2 lithiobutadiene, and lithio(methylsulphiny1)methyl sulphide but not with alkyl Grignard reagents. The useful skipped dienes (191) can be readily obtained by coupling bromomethyl methacrylate (190) with a terminal acetylene using zinc-zinc bromide in THF under ultrasonic agitation. I7O Sensitive functionalities such as trimethylsilyl ethers and diethyl acetals are tolerated. Carbon radicals, R', generated from an acid chloride, R C O C 1 , and Ehydroxy-2-thiopyridone as mentioned earlier,56 157 add to the methacrylate derivative (192) to give homologues (193) in 56-74% yield l7 O f particular significance is the finding that tertiary radicals react as efficiently as less substituted species. The synthesis of chiral a-(hydroxyalky1)acrylates (195) of 75% e.e. has been achieved, albeit in poor yield, by sequential condensation betweer, the magnesium enolate of chiral sulphoxide ( 194) and an aldehyde, followed by thermolysis. 172 The related threo-y-alkoxy homologues (196) have been prepared by highly diastereoselective condensations between esters of 0-alanine and C I alkoxy-aldehydes. 17' A Wadsworth-Emmons approach to substituted acrylates (193) consists simply of treating a-substituted phosphonates (197) with potassium carbonate and 30% aqueous formaldehyde. 174 An alternative method for the preparation of these useful phosphonates is by Wolff rearrangement of a-diazo-0-ketophosphonates, available f r o m esters following reaction with a lithiomethylphosphonate and diazo-group transfer using TsN 175 These latter authors use LDA3' THF at -15 OC followed by anhydrous formaldehyde to effect the Wadsworth-Emmons reaction leading to (193). Modified recipes also continue to be developed for Wadsworth-Emmons approaches to a , B unsaturated esters in general. Condensations of phosphonates (197; R = H ) with aldehydes can be effected using solid potassium carbonate in d i o ~ a n e 'o~r ~ lithium chloride and an amine such as DBU or diisopropylethylamine. 177 Both methods result in high ( E l selectivity; the latter method is especially designed for use with

166

General and Synthetic Methods

C0,Me

CO, Me

(188)

CO, B u t

(189)

(196)

(198)

CHO

(199) n = 0,1, or 2

P h S e w

(200)

(1 91 1

(190)

(197)

SCO),, A r

C02But

(2011

----

OMe R

Ho&cozBut

(202)

167

3: Carboxylic Acids and Derivatives base-sensitive

substrates.

When B u n L i i s u s e d a s b a s e , e n o l a t e s o f

p h o s p h o n a t e s (197; R=Me) c o n d e n s e w i t h a - b r a n c h e d a l d e h y d e s a t l o w t e m p e r a t u r e s t o g i v e s e l e c t i v e l y t h e ( Z ) - i s o m e r s o f e s t e r s ( 198; R ’

= Me). 178 P h o s p h i n e o x i d e s c o r r e s p o n d i n g t o (197; R=Me) by c o n t r a s t l e a d t o t h e ( E ) - i s o m e r s (198; R 1 = M e ) . Knoevenagel r e a c t i o n s between a l d e h y d e s and t h e s u l p h u r s u b s t i t u t e d a c e t a t e s (199) c a n b e c a t a l y s e d b y p i p e r i d i n e a n d i n g e n e r a l l e a d t o t h e (El-isomers acceptors.

(200) of t h e s e u s e f u l Michael

An u n u s u a l r o u t e t o u , B - u n s a t u r a t e d

esters (202) (201) w i t h

c o n s i s t s of s e q u e n t i a l treatment of t h e 8-selenenyl-enal

a l i t h i u m e n o l a t e of an ester, t p c h l o r o p e r b e n z o i c a c i d , and LiOHThe m e c h a n i s m i n v o l v e s t h e i n t e r m e d i a c y o f a 3 - m e t h o x y o x e t a n e a n d r e l i e s on t h e a b i l i t y o f a s e l e n o n y l g r o u p t o a c t b o t h as a n a c t i v a t o r o f d o u b l e bonds t o M i c h a e l a d d i t i o n s a n d as a good

MeOH. I8O

leaving group.

A nitro-group

is a l s o u s e f u l i n t h e l a t t e r r e s p e c t .

T h i s h a s b e e n e x p l o i t e d i n a new a p p r o a c h t o u n s a t u r a t e d e s t e r s c(204); n

0 and

a,B-

a s w e l l as

y,b-

2 r e s p e c t i v e l y ] by r e a c t i o n s

between t h e a l l y l i c nitro-compounds ( 2 0 3 ) and l i t h i u m d i a l k y l c u p r a t e s . 18’

Although only t r i e d with r a t h e r simple

s u b s t r a t e s , t h e method l o o k s t o h a v e a f a i r l y g e n e r a l a p p l i c a t i o n and l e a d s l a r g e l y t o t h e ( E ) - i s o m e r s .

Lewis acid-catalysed

a d d i t i o n s of a l l y l i c sulphides t o methyl p r o p i o l a t e g i v e t h e u s e f u l v i n y l s u l p h i d e s ( 2 0 5 ) whose s t e r e o c h e m i s t r y i s d e t e r m i n e d by t h e n a t u r e o f t h e L e w i s a c i d u s e d ; ZnC12 g i v e s v i r t u a l l y p u r e ( Z ) isomers while A1C13 g r e a t l y favours formation of t h e ( E ) isomers.

182

A m i l d and n o n - b a s i c method f o r t h e c o n s t r u c t i o n o f ( E ) - u , B -

u n s a t u r a t e d e s t e r s ( 198 ; R =H) p r o c e e d i n g

via

a r a d i c a l coupling(206) a n d a n a l k y l b r o m i d e , i n i t i a t e d by h e x a b u t y l d i t i n t h e r m o l y s i s , h a s b e e n e l i m i n a t i o n sequence involving e t h y l 8-stannylacrylate

e x e m p l i f i e d i n a s y n t h e s i s o f a c y c l o p e c t a n o i d i s o c y a n i d e .I 83 A l l y l i c h a l i d e s i n g e n e r a l undergo very e f f i c i e n t couplings with v i n y l t i n In these s p e c i e s [ e . g . (206)l u s i n g p a l l a d i u m c a t a l y s t s . 18‘ e x a m p l e s , t h e s t e r e o c h e m i c a l i n t e g r i t y o f t h e v i r , y l t i n d o u b l e bond

-

i s r e t a i n e d [ e . g . (207) (20811. O t h e r v a l u a b l e f e a t u r e s o f t h i s w i d e - r a n g i n g t e c h n i q u e a r e t h e t o l e r a n c e of a n u m b e r o f f w c t i o n a l g r o u p s ( e . g . O H , C N , C02R, a n d C H O ) w h i c h c a n b e p r e s e n t i n e i t h e r r e a c t a n t and t h e c o m p l e t e i n v e r s i o n of s t e r e o c h e m i s t r y w h i c h o c c u r s a t t h e h a l i d e carbon c(207) (20811. When c a r r i e d o u t i n t h e

-

p r e s e n c e o f c a r b o n m o n o x i d e , k e t o n e s a r e f o r m e d by i n s e r t i o n o f CO i n t o t h e n e w l y f o r m e d C-C b o n d . B e n z e n e a n d f u r a n s car, b e d i r e c t l y

General and Synthetic Methods

168

0

II

b

C02Me

(Et0)2PO

-

M e p Li

OCONHPh (218)

(219 1

(220)

169

3: Carboxylic Acids and Derivatives

c o u p l e d t o a c r y l a t e s t o g i v e u n s a t u r a t e d e s t e r s ( 2 0 9 ; A r = Ph or 2f u r y l ) u s i n g p a l l a d i u m s a l t s i n t h e p r e s e n c e of t - b u t y l p e r b e n z o a t e . 185 S i m i l a r r e a c t i o n s w i t h some m o n o s u b s t i t u t e d b e n z e n e s ( C 6 H 5 C 1 and C 6 H 5 C H 3 ) w e r e u n f o r t u n a t e l y nonregioselective.

P a l l a d i u m - c a t a l y s e d a l k y l a * - + i o n s of s i m p l e e n o l a t e s

by a l l y l i c a c e t a t e s a r e u s u a l l y u n s a t i s f a c t o r y owing t o t h e s l o w n e s s o f t h e r e a c t i o n , which t e n d s t o l e a d t o p o l y a l k y l a t i o n . However, by u s i n g e n o l s t a n n a n e s , g e n e r a t e d from l i t h i u m e n o l a t e s using t r i m e t h y l t i n t r i f l u o r o a c e t a t e , high-yielding mono-alkylations c a n be a c h i e v e d i n t h e c a s e o f a c e t a t e ( 2 1 0 ) , w h i c h r e a c t s u s u a l l y b u t n o t a l w a y s r e g i o s p e c i f i c a l l y a t t h e c a r b o n a- t o s i l i c o n , l e a d i n g t o u n s a t u r a t e d k e t o - e s t e r s ( 2 1 1 ) . 86 O r g a n o m e r c u r y compounds a r e o f t e n u s e f u l s u b s t r a t e s i n p a l l a d i u m - c a t a l y s e d p r o c e s s e s ; a good e x a m p l e of t h i s i s t h e p r e p a r a t i o n o f u n s a t u r a t e d

esters (198; R1

H ) by P d - c a t a l y s e d

c a r b o n y l a t i o n of v i n y l

m e r c u r i a l s o b t a i n e d f r o m t e r m i n a l a c e t y l e n e s by s e q u e n t i a l h y d r o b o r a t i o n and boron-mercury

exchange.

The l a c k of

(E)-

s t e r e o s e l e c t i v i t y which is sometimes o b s e r v e d , e s p e c i a l l y w i t h h i g h e r m o l e c u l a r w e i g h t a c e t y l e n e s , h a s now b e e n l a r g e l y o v e r c o m e by o p t i m i z a t i o n of t h e c o n d i t i o n s f o r B-Hg e x c h a n g e . 187 The v a l u a b l e method f o r c o n v e r t i n g 8 - k e t o - e s t e r s

(212) i n t o

via

sequence

unsaturated esters (214)

an a d d i t i o n - e l i m i n a t i o n

involving t h e corresponding enol-phosphates d e s c r i b e d i n f u l l . 188

( 2 1 3 ) h a s been

I n some a c y c l i c e x a m p l e s , m i x t u r e s o f MeMgCl

and MeCu h a v e been f o u n d t o g i v e h i g h e r s t e r e o s e l e c t i v i t i e s t h a n Me2CuLi i n t h e s e c o n d s t e p . 1 8 9 A l t h o u g h many e x a m p l e s of t h e u s e o f t h e P e t e r s o n r e a c t i o n ” ’

in

& , @ - u n s a t u r a t e d e s t e r s y n t h e s i s h a v e b e e n r e p o r t e d , t h e method a p p e a r s n o t t o have been extegded t o a - s u b s t i t u t e d homologues ( 2 1 6 ) until recently. lgl

The d i p h e n y l m e t h y l s i l y l e s t e r s ( 2 1 5 ) a r e u s e d

m a i n l y b e c a u s e t h e y c a n be o b t a i n e d by d i r e c t 5 - s i l y l a t i o n of t h e c o r r e s p o n d i n g e s t e r l i t h i u m e n o l a t e s ; t h e r e a c t i o n s show m o d e r a t e t o good ( Z ) - s e l e ~ t i v i t y land ~ ~ i n c o n t r a s t t o some o f t h e a n a l o g o u s W i t t i g - t y p e a p p r o a c h e s a r e a p p l i c a b l e t o b o t h a l d e h y d e s and ketones. The a v a i l a b i l i t y o f a , @ - u n s a t u r a t e d e s t e r s by a p l e t h o r a of m e t h o d s , some e x e m p l i f i e d a b o v e , means t h a t d e c o n j u g a t i o n t o t h e c o r r e s p o n d i n g B , y - u n s a t u r a t e d e s t e r s c a n be a n a t t r a c t i v e method f o r t h e p r e p a r a t i o n o f t h i s l a t t e r c l a s s o f compound.

However,

s t e r e o s e l e c t i v i t y i s a problem w i t h long-chain e s t e r s ; t h i s can be overcome by u s i n g crowded e s t e r s d e r i v e d f r o m 2 , 4 - d i m e t h y l p e n t a n - 3 -

170

General and Synthetic Methods

In the case of such an ester derived 01 and KN(SiMe3)2 as base. l g 3 from (El-dodecanoic acid, selectivity in favour of the (L)-isomer (217) can be as high as 97:3. Likewise, deconjugation of methyl (2E,4E)-dienoates, using LDA as base, leads to the (3E,5Z) deconjugated dienoates (218) with 72-80% stereochemical purities whereas similar treatment of the corresponding (2E,4Z)-dienoates gives the (3E,5E)-isomers of (218) with stereoselectivities of 8198%.194 Possibly these could be improved by using the foregoing methodology. An unprecedented ‘decarboxylative reduction’ of unsaturated carbamates [e.g. (219)l occurs on reaction with a lithium dialkylcuprate leading to 0,y-unsaturated esters [e.g. (22011 in excellent yields.lg5 The method can also be applied by acyclic analogues of (219) and to cyclic carbamates. A full account has been given of the palladium-catalysed decarboxylationcarbonylation process whereby allylic carbonates (221) can be converted into unsaturated esters (222). Yields are generally around 70% but much lower in examples where a secondary carbonate is used. Details have also been given of ar, appropriate precedure for the homologation of nerol o r geraniol into the homologous esters “223) and (E)-(223) respectively], without migration o r isomerization of the sensitive olefinic bond, by conversion into the corresponding sulphones, followed by carboxylation and desulphurization. y-Seleno-esters (224) can be obtained by Wadsworth-Emmons reactions using a-selenoaldehydes and, after oxidation to the corresponding selenoxides, undergo [2,3]sigmatropic rearrangements to provide a novel route to a-hydroxyB,y-unsaturated esters (225). y,b-Unsaturated (a-ally1)-esters (226) can be obtained in 64-91% yields by palladium-catalysed reactions between ketene silyl When such reactions are acetals and allylic carbonates (221 ) . lg9 carried out using a phosphine-free palladium catalyst [e.g. P~(OAC)~], unsubstituted a,b-unsaturated esters derived from the ketene acetal are produced; this could prove to be a useful twostep dehydrogenation procedure for esters. Yields are 70%. aNitro-derivatives (227) of esters (226) can be similarly obtained by palladium-catalysed couplings of a-nitroacetates to allyl carbonates (221) o r allyl phenyl esters.200 A full discussion has been given regarding vinylogous Wolff rearrangements of f3,y-unsaturated diazoketon-es (228) which wher, catalysed by copper salts in the presence of an alcohol, R30H, lead to the rearranged esters (229) accompanied by little or none of the

=.

3: Carboxylic Acids and Derivatives

171

R'

R2

R'

R2

NOq

(227)

(229 1

(228)

dR3 C02Me

CO,E t

( 2 31)

(230)

@CO2Me

R2

(232)

172

General and Synthetic Methods

simple Wolf f rearrangement products. 2o For use in planning syntheses, this process can be regarded overall as an alternative to ortho-ester or Ireland-type Claisen rearrangements. The former version of the Claisen rearrangement is somewhat limited because of the requirement of an acid catalyst, usually EtC02H, to trigger transetherification between the allylic alcohol and ortho-ester components. It has now been shown that this can be done using a palladium catalyst; hence such Claisen rearrangements can be effected under neutral conditions .202 In ger,eral, ketene silyl acetals derived from esters can only be successfully mono-alkylated under Lewis acid conditions by halides which can form a stabilized carbonium ion, such as secondary benzylic halides leading to, in the latter case, esters (230). 203 This methodology thus neatly complements the various anionic approaches to ester homologues which would almost certainly fail with secor,dary allylic or befizylic halides. An additional example of this principle is the preparation of the gem-dichloro-enoates (231; R1=R2iH) from ketene silyl acetals and secondary or tertiary

1,1,3-trihalogenopropene derivatives. This approach car, also be used to obtain 4-alkynoates from secondary propargyl chlorides .204 Efficient monoalkylations of methyl phenylacetates can be carried out using a base, generated by cathodic reduction of 2pyrrolidoce, to give homologues (232; R 1 Me, E t , or Pri) in 8 1 99% yield. 205 More conventional bases generally lead to mono- and dialkylated products. PheFylacetates (232; R1=H), as well as ber,zoates and crotonates, can be readily obtained in excellent yields by rhodium o r in some cases rhodium-palladium assisted carbonylations ( 1 atm C O , 75 OC) of benzylic, aryl, or styryl bromides respectively in the presence In many cases, it seems reasonable to of ar, aluminium alkoxide.2"6 expect that this method will supersede Grignard-based homologation procedures using carbon dioxide or chloroformates as electrophiles. Similar carbonylations (6.8 atm C O , 75 'C) of various heteroaromatic bromides using palladium catalysts have also been effected in usually excellent yields.207 Some rather unusual reactions have been reported in aromatic ester chemistry this year. For example, treatment of nitrobenzenes with enolates of chloroacetates yields p-nitrophenylacetates (233; R 1 = H , C 1 , F o r OPh) .208 Presumably a Meisenheimer complex is involved, but further than this the mecharism is m c l e a r . This w o r k is closely related to earlier results reported by Makosze

173

3: Carboxylic Acids and Derivatives

et al., who have now found that the same type of transformation can also be effected using a-phenylthioacetates 209 Perhaps surprisingly, the orselliniate anion (234) can be generated at -78 OC using LDA as base. Presumably reaction of (234) with the parent ester is suppressed because of steric hindrance. Anion (234) reacts efficiently with a number of simple electrophiles; with aldehydes dihydroisocoumarins are formed directly.210 A full account has been given of the remarkable modification of the Birch reduction in which benzoic acid esters can be successfully reduced to the dihydro-esters (235) by adding water 1.5 equiv.) before the metal; some mechanistic rationales are given. 21 1 Ethyl lithiopropynoate (236) is known to condense well with aldehydes and ketones at low temperatures. The useful intermediates (237) thus produced can serve as precursors to the ( 2 ) - (238) and (E)-unsaturated esters (239) after protection of the alcohol group (R2=THP, MEM or TBDMS); as yet direct reduction to the (E)-isomers is rather inefficient .21 However, in general the acetylide (236) does not afford good yields with other electrophiles owing to the typically low reactivity associated with acetylides, which necessitates the use of higher temperatures at which (236) tends to polymerize. This problem is overcome by making use of the analogous ortho-ester (240) which is formed from the corresponding TMS-acetylene using BunLi at 0 OC .21 Subsequent reactions with a range of electrophiles proceed unexceptionally at 0-20 OC; the ester group can be revealed simply by reaction with aqueous oxalic acid. Condensations between ester enolates and various polyhalogeno-olefins have been examined, resulting in the . )

(z.

development of routes to a number of useful acetylenic esters [e.g. (241; R = C l 1 Ph, SPh, or H)l.214 A detailed description of the preparation of allenic esters [e.g. (24211 from an acid chloride and a phosphorane has been given.215 Conjugated dienoates and trienoates (243; ;=I or 2) can be obtained in variable yields by palladium-catalysed coupling between acrylates and enol triflatesl2I6 in reactions which are closely similar to those with vinyl bromides. The regioselectivity of Reformatsky reactions between ethyl 4bromocrotonate and ketones or aldehydes has been found to be critically dependent on the nature of the zinc used and on the solvent. Thus the 'a-adducts' (244) are usually produced exclusively using a zinc-copper couple in ether while 7-adducts (245) are mainly formed using pure zinc in hydrocarbon solvents or

General and Synthetic Methods

174

i n THF.217 I s o l a t i o n o f t h e s e s e n s i t i v e p r o d u c t s i s o f t e n b e s t a c h i e v e d by i n s i t u a c e t y l a t i o n , w h i l e d e h y d r a t i o n l e a d s t o t h e i s o m e r i c d i e n o a t e s (246) and (247) r e s p e c t i v e l y .

Bromo-crotonates

c a n a l s o be d i m e r i z e d r e g i o s e l e c t i v e l y u s i n g z i n c i n DMSO t o g i v e t h e a l l - ( E-) - 2 , 6 - d i e n o a t e s

(248).2 1 8 I n c o r , t r a s t t o t h e u s u a l

R e f o r m a t s k y r e a g e n t s d e r i v e d from m e t h y l o r e t h y l b r o m o a c e t a t e s , which have a n e n o l a t e - t y p e s t r u c t u r e , t h o s e d e r i v e d from t - b u t y l ab r o m o - e s t e r s h a v e b e e n f o u n d t o b e 2 - m e t a l l a t e d . 219 T h e s e i n t e r m e d i a t e s c a n be e f f i c i e n t l y a l k y l a t e d by a l l y l i c b r o m i d e s (SN2') or a l k y l i o d i d e s i n c l u d i n g primary y-bromocrotonates, Meerwein's r e a g e n t , Me30+BF4-,

leading t o d i e s t e r s (249).

c a t a l y s e s t h e coupling of a l l y 1 s i l a n e s t o y - v i n y l b u t y r o l a c t o n e s , r e s u l t i n g i n a g e n e r a l approach t o (E)-nona-4,8-dienoates (250; = H o r Me). 220 The c o r r e s p o n d i n g ( Z ) - i s o m e r s c a n b e o b t a i n e d i n t h e same way, b u t u s i n g

(z)- h e ~ - Q - e n o l i d e ~a s~ s t a r t i n g

material.

Thioesters.-

Homologation o f a l d e h y d e s o r k e t o n e s u s i n g t h e r e a g e n t

(251) g i v e s g e n e r a l l y e x c e l l e n t y i e l d s of k e t e n e - g , S - a c e t a l s

(252).

T h e s e c a n be c o n v e r t e d i n t o t h e t h i o e s t e r s by d e m e t h y l a t i o n e i t h e r d i r e c t l y u s i n g LiSMe o r i n d i r e c t l y

via

the 2-silyl,

2-acetals using

Me S i I f o l l o w e d by a l u m i n a o r f l u o r i d e ; t h e l a t t e r p r o c e s s , i n 3 p r i n c i p l e , should a l l o w a n o t h e r s u b s t i t u e n t t o be i n c o r p o r a t e d i n t h e a - p o s i t i o n by a l k y l a t i o n o f t h e i n t e r m e d i a t e e n o l a t e .221 Nitro-olefins

( 2 5 4 ) a r e e a s i l y p r e p a r e d by 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 l d e h y d e s a n d p h e n y l t h i o n i t r o m e t h a n e , PhSCH NO

*

2; good M i c h a e l a c c e p t o r s w i t h a number of n u c l e o p h i l e s ( R

a n d act as

=

a l k o x i d e s , amide a n i o n s , s u l p h i n a t e s , o r m a l o n a t e ) t o p r o v i d e n i t r o n a t e s a l t s w h i c h on o z o n o l y s i s , i n s i t u , g i v e t h e t h i o e s t e r s

(255).222

The method c a n a l s o b e a d a p t e d t o p r o v i d e a - h y d r o x y A d d i t i o n o f o r g a n o m e t a l l i c s , RM ( M = M g X

t h i o e s t e r s ( 2 5 5 ; R2=OH).

o r L i ) , or h y d r i d e s ( R = H ) t o a - 0 x 0 - k e t e n e

thioacetals (256)

f o l l o w e d by d e g r a d a t i o n u s i n g HBF4 a n d / o r m e r c u r y s a l t s g i v e s t h e u n s a t u r a t e d t h i o e s t e r s (257).223 A s t h e s t a r t i n g m a t e r i a l s a r e 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 k e t o n e e n o l a t e s a n d CS2-MeI,

this

sequence i s , overall, a [1,3]-carbonyl t r a n s p o s i t i o n . A f u r t h e r e x a m p l e o f t h e a b i l i t y of p y r i d i n i u m c h l o r o c h r o m a t e a n d r e l a t e d o x i d a n t s t o c l e a v e f u r a n r i n g s i s i n r e a c t i o n s w i t h 2a l k y l t h i o f u r a n s (258) which g i v e u n s a t u r a t e d t h i o e s t e r s ( 2 5 9 ) i n i t i a l l y a s t h e ( Z ) - i s o m e r s w h i c h t h e n i s o m e r i z e t o t h e (E)-form on p r o l o n g e d r e a c t i o n . 224 A l d o l c o n d e n s a t i o n s o f b o r o n e n o l a t e s

3: Carboxylic Acids and Derivatives

(236)

175

(237)

(238)

(239)

CO,Me

R5 R 4 R2 T,.co2BUt

.

R (248)

SPh

(254)

(249)

w R6

C R3

O

2

R' (250)

M

e

General and Synthetic Methods

176

d e r i v e d from p h e n y l t h i o p r o p i o n a t e w i t h a l d e h y d e s g i v e a l m o s t p u r e

syn-O-hydroxy-thioesters ( 2 6 0 ) , r e g a r d l e s s of t h e e n o l a t e g e o m e t r y . 225 C o n d e n s a t i o n s w i t h c h i r a l a - s u b s t i t u t e d a l d e h y d e s give variable relative stereoselectivities.

0 - A l k y l t h i o e s t e r s ( 2 6 1 ) 2 2 6 c a n be e a s i l y 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 e s t e r s by 2 - s i l y l a t i o n

(LDA; TMSC1) 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 s u l p h i d e .227 The d i r e c t c o n v e r s i o n o f

e s t e r s , a c i d s , and a c i d c h l o r i d e s i n t o d i t h i o e s t e r s u s i n g L a w e s s o n ‘ s r e a g e n t 2 2 8 h a s b e e n amply d o c u m e n t e d i n r e c e n t y e a r s . However, r a t h e r h i g h t e m p e r a t u r e s a r e r e q u i r e d , w h i c h h a s l e d t o t h e d e v e l o p m e n t o f a number o f a n a l o g u e s of t h e o r i g i n a l r e a g e n t which are e f f e c t i v e a t lower t e m p e r a t u r e s , 2 2 9 and which can a l s o be u s e d t o p r e p a r e t h i o a m i d e s from a m i d e s a n d t h i o a m i d e b o n d s i n

pep tide^.^^'

A l t h o u g h a g e n e r a l r o u t e t o d i t h i o e s t e r s i s by

c o n d e n s a t i o n of o r g a n o m e t a l l i c s w i t h c a r b o n d i s u l p h i d e , 23 lithium species, RC(O)Li,

acyl-

g e n e r a t e d from R L i and carbon monoxide,

c o n d e n s e w i t h CS2 t o g i v e 2 - m e t h y l t h i o e s t e r s a f t e r m e t h y l a t i o n w i t h M e I ; 2 3 2 t h e r e a c t i o n s may i n v o l v e t h e i n t e r m e d i a c y o f a n a d i t h i o l a c t o n e s p e c i e s (see a l s o ref. 381).

[%.

N-Phenylthioimidoesters

( 2 6 2 1 1 , r e a d i l y o b t a i n e d from t h e a p p r o p r i a t e G r i g n a r d

r e a g e n t and p h e n y l i s o t h i o c y a n a t e , c a n be a l k y l a t e d e f f i c i e n t l y a t t h e a - p o s i t i o n u s i n g LDA-RX. sulphide gives dithioesters

Subsequent t r e a t m e n t w i t h hydrogen

[s. (263)l

whereas a c i d h y d r o l y s i s

l e a d s t o t h e c o r r e s p o n d i n g t h i o e s t e r s . 233

S i m i l a r a l k y l a t i o n s of

t h i o i m i n o e s t e r s i n which t h e r e a c t i n g c a r b a n i o n i s n o t a l l y l i c as i n (262) r e s u l t i n N-alkylation; using diar.ionic intermediates. hydroxy-dithioesters

t h i s l i m i t a t i o n c a n be o v e r c o m e by A probably g e n e r a l r o u t e t o B-

(264) i n v o l v e s c o n d e n s a t i o n s between methyl

d i t h i o a c e t a t e a n d a l d e h y d e s o r k e t o n e s , u s i n g NaH-THF a t - 2 0 o C . 2 3 4 T h i s i s somewhat more c o n v e n i e n t t h a n a p r e v i o u s l y r e p o r t e d method u s i n g LDA as b a s e , a n d d e l i v e r s t h e h y d r o x y - e s t e r s isolated yields.

(264) i n

E.

60%

C o n d i t i o n s have a l s o been e s t a b l i s h e d f o r t h e

dehydration o f esters (264) t o t h e corresponding a , B - u n s a t u r a t e d a n a l o g u e s , w h i c h a r e u s e f u l b o t h as d i e n e s a n d d i e n o p h i l e s i n Diels-Alder

r e a c t i o n s ; i n d e e d s u c h compounds r a p i d l y d i m e r i z e v i a a

[ 4 + 2 1 c y c l o a d d i t i o n when d e r i v e d f r o m e s t e r s (264) i n w h i c h R2 i s hydrogen.

R’Y

3: Carboxylic Acids and Derivatives

177

R’

0

R1

H H

R2

(2721

( 2 731

(274)

(275)

Generul and Synthetic Methods

178

3 Lactones Butyro1actones.- A versatile approach to butyrolactones is by condensations between h o m ~ e n o l a t e sand ~ ~ ~aldehydes or ketones. The first reported example of a syn-diastereoselective versior. of such a reaction is the condensation of butenyl carbamates (265) with aldehydes which leads largely to the (E)-=-isomers (266), following metallation (BunLi) and cation exchange (Bui2AlS03Me) .236 Conversion into the cis-disubstituted butyrolactones (267) proceeds with retention of configuration using known methodology. In related work, a highly enantioselective approach to 11- and 4,4disubstituted butyrolactones has been developed involving condensations of the cyclic urea (268) readily derived from (-)-ephedrine, with aldehydes or methyl ketones; subsequent degradation leads to optically pure butyrolactones ( 2 6 9 ; R2=H or Me) .237 Very high ( 3 9 3 % ) diastereoselectivity has beer, found in reactions between allenic zinc reagents and aldehydes, leading to the homopropargylic alcohols (270) . 2 3 8 Conversion to the translactones (271) is then achieved by silylation, hydroboration, ar.d oxidation of the acetylene function.6 The asymmetric reduction of propargyl ketones using Alpine-borane O8 leading to chiral propargyl alcohols (272) has been discussed at length.239 These valuable intermediates can serve as precursors to chiral a- ar,d 8-substituted butyrolactones as well as to butenolides or valerolactones, and can also be obtained by reductior,s of propargylic ketones using LiAlH,, modified by the addition of chiral binaphth01~~' or ephedrine derivatives. 24 Chiral dianionic species (273; R=H or Me) car, be obtained from readily available ' 12' subsequent carboxylation gives the chiral PHB; butyrolactones (274; R=H or Me). 242 Presumably this method could be exter,ded to more interesting products. The 'quercus' or 'oak' lactones C(275) and the corresponding trans-isomer] have beer. obtained by diastereoselective condensations between suitable allylic boronates and pentanal; this approach should be applicable to many homologues of (275) .243 Further examples of Lewis acid-catalysed ring closures of terpenoid acids to give annulated butyrolactones include alternative syntheses of the pheromones (+)-anastrephin (2'76) and epianastrephin (isomeric at C-4)244 and of the tobacco constituer:t (277) , directly from (5,E) -homofarnesic acid .245 The related butyrolactone (279) has been obtained using a novel oxidative

179

3: Carboxylic Acids and Derivatives

c l e a v a g e o f a n o l e f i n (278) u s i n g PCC o r , b e t t e r , ( b i p y H 2 ) A l t h o u g h c l e a r l y l i m i t e d t o t e r t i a r y a l c o h o l s a n d monoo l e f i n s , t h i s method s h o u l d f i n d o t h e r a p p l i c a t i o n s . Treatment of

CrOC15 . 2 4 6

cyclopropanecarboxylates

[e.g.(280)l

( M e 3 S i ) 2 S 0 4 l e a d s t o t h e *-fused

with the Lewis acid

b u t y r o l a c t o n e s (2811 .247

S i m i l a r l y , a-ethoxycarbonyl l a c t o n e s

[e.g.(28211

can be o b t a i n e d

f r o m vinylcyclopropane-1,l-dicarboxylates a n d f u s e d l a c t o n e s (283) f r o m bicyclo[3.1.01-butyrolactones. t h u s a p p e a r s t o be c o n s i d e r a b l e .

The p o t e n t i a l o f t h i s m e t h o d Further e x p l o r a t i o n s of

c y c l o a l k a d i e n y l t r a n s i t i o n metal c o m p l e x e s h a v e r e s u l t e d i r : s t e r e o s e l e c t i v e r o u t e s t o t h e u s e f u l s y n t h e t i c i n t e r m e d i a t e s (284; R

a-

or B - C 0 2 M e or H)248 a n d ( 2 8 ~ ) ; ~t h~e’ l a t t e r a i e o f

p a r t i c u l a r i n t e r e s t as t h e c o n t r o l of stereochemistry around a cycloheptane r i n g is something of a black a r t .

During s t u d i e s

aimed a t Q u a s s i n o i d t o t a l s y n t h e s i s , c a e s i u m f l u o r i d e h a s been u s e d t o e f f e c t 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 i n t h e e n o n e (286), I n t r a m o l e c u l a r Die 1s - A l d e r l e a d i n g t o t h e b u t y r o l a c t o n e (287).25 r e a c t i o n s u s i n g b u t e n o l i d e s as d i e n o p h i l e s h a v e been shown t o r e p r e s e n t v i a b l e and s t e r e o s p e c i f i c r o u t e s t o b u t y r o l a c t o n e d e r i v a t i v e s s u c h as (288).25 D e h y d r a t i o n o f k e t o - d i a c i d d e r i v a t i v e s (289), w h i c h a r e r e a d i l y a v a i l a b l e by a l k y l a t i o n s o f 8 - k e t o - e s t e r s

w i t h a-bromo-acids

(R2CHBrC02H), l e a d s t o t h e u n s a t u r a t e d l a c t o n e s ( 2 9 0 ) w h e r e a s r e a c t i o n w i t h a l l y l z i n c b r o m i d e g i v e s b u t y r o l a c t o n e s (291) .252 I t seems l i k e l y t h a t o t h e r t y p e s of b u t y r o l a c t o n e c o u l d b e o b t a i n e d from t h e s e p r e c u r s o r s . An i n c r e a s i n g i n t e r e s t h a s b e e n shown i n t h e s y n t h e s i s o f butyrolactones related t o carbohydrates.

A g e n e r a l b u t non-

s t e r e o s e l e c t i v e r o u t e t o h y d r o x y - b u t y r o l a c t o n e s (292) c o n s i s t s of L e w i s acid-mediated c y c l o a d d i t i o n s of u,b-epoxy-aldehydes or -ketones t o t h e ketene dimethyl acetal of propionic a c i d , followed by a c i d h y d r o l y s i s o f t h e r e s u l t i n g o ~ e t a n e . A~ n~u m ~ber o f r o u t e s t o a - a m i n o - b u t y r o l a c t o n e s C-. (29311, r e l a t i v e s o f a m i n o - s u g a r s , h a v e a l s o b e e n r e p o r t e d , many b a s e d on n u c l e o p h i l i c a d d i t i o n s t o t h e a c e t o n i d e o f ( L ) - g l y c e r a l d e h y d e . 254 T h e h o m o l o g o u s (5s)b e n z y l o x y m e t h y l d e r i v a t i v e o f g l y c e r a l d e h y d e , a p r o t e c t e d form of ( L ) - t h r e o s e , d e r i v e d from d i e t h y l ( R , R ) - t a r t r a t e , a t o t a l s y n t h e s i s of ( + ) - D e l e s s e r i n e

h a s been used i n

(294), t h e v i t a l s t e p b e i n g a

non-stereoselective condensation with a phenyl-lactic acid derivative.255 The compound e x i s t s i n s o l u t i o n a s a m i x t u r e o f (294) a n d t h e c o r r e s p o n d i n g b i c y c l i c h e m i a c e t a l . An e n t i r e l y

General and Synthetic Methods

180

Me II

( 2 84)

3: Carboxylic Acids and Derivatives

181

different approach to a-amino-butyrolactones, (2961, which is also applicable to a-amino-valerolactones, is by thermal ene reactions of N-sulphonylimines, [%. (295)1, generated in situ from the corresponding aldehydes and t o l u e n e - f l - s u l p h o n a m i d e . Such stereoselective ene reactions can also be carried out intermolecularly, leading to unsaturated a-amino-acid derivatives which can be iodolactonized to give annulated a-aminobutyrolactones [e.g.(297)1. 256 The utility of enzymes in enantiospecific syntheses has been amply demonstrated by results discussed in the diacid and 8hydroxy-ester sections of this chapter. Further examples of this are to be found in another report of the ability of horse liver alcohol d e h y d r ~ g e n a s e ~ to ~ ' catalyse oxidations of meso-diols to optically pure butyrolactones such as (298) .257 Various enzyme systems have also been found which can mono-hydrolyse prochiral meso-diacetates to chiral intermediates (299) ,258 ( 300) , 259 and (301 ) .259 As the two alcohol groups are now chemically distinguishable, standard methods can be used to prepare both enantiomers of many compounds from these single isomers. This is exemplified in the cases of the Corey lactone (302),258 the biotin precursor (303),259 and the precursor (304 )259 to the microbial autoregulator 'A-factor'. Both the related '(L)-L-factor' (305) and its (5S)-diastereoisomer have been synthesized from (D)-ribose employing Wittig reactions to introduce the required substituent chains. 260 Controlled base-induced epimerization at an appropriate stage was used to gain access to the (5S)-derivative. L-Factor (305) has also been prepared from 2,3,6-tri-2-acetyl-D-glucan; introduction of the alkyl side chain was achieved in this case by the coupling of a tosylate derivative with lithium di-nbutylcuprate, an example of a generally useful procedure for this A number of reports262 have emphasized type of homologation.26 the potential of cheap, commercially available D-ribonolactone ( 3 0 6 ) in the elaboration of chiral butyrolactones such as the 8 hydroxy-derivatives (307) and various naturally occurring a ylidenelactones ( 3 0 8 ) . When chiral sulphoxides are used in the previously reported route to butyrolactones from vinyl sulphoxides and chloroketenes, asymmetric induction is complete leading to optically pure a halogeno-butyrolactones [-. (30911; hopefully other examples will be forthcoming.263 Chiral sulphoxides also feature in an enantioselective approach to lignans (312) by asymmetric Michael

182

General and Synthetic Methods

(295)

(296)

( 2 98)

(297)

0 AcO & O H OAc

HO-

I

\

‘OAc

(301 1

(300)

(299)

I

I

I

I

II

I

3

4

9

0 BzN

H

N6z

H

HO

(304)

(303)

(302)

H

HO

n-C5Hll

(305)

(306)

(307)

(308)

3: Carboxylic Acids and Derivatives

183

addition of a benzylic Grignard to the butenolide (310) followed by Raney nickel desulphurization to give lactones (311). Subsequent trans-acylation then gives (312) of 95% optical purity in the one example quoted. 264 This method will very likely be applicable to many other related derivatives. Lignans belonging to the dioxabicyclo[3.3.0loctane family have been obtained diastereoselectively by using a novel intramolecular aldol reaction C(313) (314)l.265 Although yields are not spectacular, this brief approach is clearly ripe for further development. An alternative type of asymmetric Michael addition has been used to prepare a prostaglandin analogue [from (316)l by addition of a sulphonylcarbanion to chiral butenolide ( 3 1 5 ) , readily derived from oxide. Subsequent in situ trapping can be effected (S)-propylene using a propargyl iodide but unfortunately fails with other electrophiles such as allylic or alkyl halides. 26 6 Under suitable conditions, y16-unsaturated amides o r thioamides (317; X 0 o r S ) have been found to undergo highly stereoselective halogenolactonizations to give trans-disubstituted butyrolactones (318), in contrast to such reactions of the corresponding acids which usually show some *-selectivity. 2,3,4-Trisubstituted analogues can also be obtained stereoselectively in some cases .267 An alternative and high-yielding method for carrying out halogenolactonizations consists of brief treatment of the usual substrates with m-chloroperbenzoic acid, an excess of sodium iodide ( o r bromide), and catalytic amounts of 18-crown-6.268 As the peracid is rapidly consumed, possibly by formation of an acyl hypohalite, non-participating double bonds are not epoxidized; the method can also be used to prepare tetrahydrofurans and pyrans. A synthesis of (+)-blastmycinone (319)269 makes use of an asymmetric enolate Claisen rearrangement33 ' 34 while a further preparation of the racemic compound proceeds 2 nitrile oxide addition to an olefin followed by stereoselective alkylation of the resulting isoxazoline .270 Radical-mediated cyclizations have once again been featured in a number of novel approaches to butyrolactones. Cobalt(1)-initiated cyclizations of the vinyl ethers (320; R'=H or Me) lead to high yields of the ring-fused lactones (321), after oxidation using Jones reagent, presumably 2 [1,2]-elimination of C o - H from an intermediate cyclohexyl-cobalt complex. 27 Analogous cyclizations initiated by Bu"SnH give the corresponding saturated homologues . The ability of tin to participate in radical reactions has further

-

General and Synthetic Methods

184

R'

Ph--

0

R2

c

0

OSiMe,

(317 1

(320)

(319)

(318)

(321)

(322)

(323) H

OH

OH

185

3: Carboxylic Acids and Derivatives

been exploited in a general route to butyrolactones (323) by 1 stereorandom cycloadditions of stannyl a-iodo-esters (322; R =H or Me) to 0 1 e f i n s . ~ ~The ~ cyclization of alkynoic acids to ylidenebutyrolactones using mercury salts has been known for some time; such reactions can also be carried out efficiently using a palladium(I1) catalyst. 273 Stoicheiometric amounts of Pd(OAcI2 are required to effect a new alkoxycarbonylation-lactonization sequence [(324) (325)l which will be of use in the synthesis of various naphthoquinone antibiotics containing this type of fused pyran-7The reaction proceeds with stereoselectivities lactone system.274

-

z.

of 5 : l in favour of the *-fused isomer. Another type of double annelation is by treatment of B-keto-acids 1%. (326; X=CH2 or O ) ] with Mn30(0AcI7. 275 This method has considerable utility, being also applicable to cyclopentene derivatives and to acyclic precursors. As is usual in such cyclizations, all-*-products

[e.g. (32711 are produced. a-Methylenebutyro1actones.- There have been relatively few developments in this area recently. A rather lengthy approach to

-

lactones (330) involves a thioallylic rearrangement C(328) (329)l which is brought about using silica gel. The starting materials (328) are obtained by Peterson olefination of the corresponding ketones which are available from B-hydroxy-amides or -esters and PhSCH(Li)OMe. Completion of the sequence is carried out by acid hydrolysis (30% H 2 S 0 4 ) , Jones oxidation, and elimination of the elements of PhS02H using DBU. A chiral centre in the original B hydroxy-ester can be carried through unmolested. 276 Lactones (330; R2=H) have also been obtained by Bun3SnH-induced cyclizations of vinyl bromides (331)277 along similar lines to the route discussed in the foregoing section.271 The method is also applicable to the synthesis of B-methylenebutyrolactones. a-Alkylidenelactones (333) can be readily obtained by heating aldehydes with the sodium salt (332), obtained from butyrolactone itself and ethyl formate. 278 The final elimination step finds precedent in the conversion of a-acetyl-lactones into the corresponding a-methylene derivatives by condensation with formaldehyde. Spiro-(E)-ethylidene-lactones [e.g. (335)l are obtained in 40-55% yields in a 'one-pot' sequence beginning with condensations of the amide dianion (334) with cycloalkanones, followed by acid hydrolysis and lactonization. (pH 3, A , 14 h).279 Acrylate derivatives (336) react with dienes in the presence of

186

General and Synthetic Methods

(328)

(329)

(336)

R3 R 2 Q R 4 - ; y

(337)

R3

(330)

(338)

(339)

K4 R3

<----

SMe

R'

0

(331)

SMe

I--

R3 +R4 MeS

SMe

3: Carboxylic Acids and Derivatives

187

LiPdC13 to give a-chloromethylene-lactones [x. (337 I. 280 This type of reaction is applicable to the synthesis of many other types of heterocyclic systems by using vinyl mercury species containing various nucleophilic functions (C02H, OH, NHAc) at the a- o r f3position. A useful summary has been given of the synthesis of a methylenebutyrolactones and related compounds using organoiron 28 1 complexes. Buteno1ides.- Optically active butenolides (339) have been obtained from condensation between aldehydes and the homoenolate anions (338) ,235 in which chirality is present in either a sulphoxide282 o r amide283 function. As neither type of condensation proceeds with significant diastereoselectivity, the chiral substituents effectively act only as resolving agents. Further accounts have been given of the preparation of 4-alkyl- and 4,4-dialkylbutenolides by reactions of Grignard reagents with maleic anhydride Diels-Alder adducts followed by pyrolytic cycloreversion. 284 Keteniminium salts, prepared usually from the corresponding tertiary amide and (CF SO 0, react with acetylenes to give good 3 2 2 yields of the cyclobutenones (340; R4 = H o r R 3 ) which on regioselective Baeyer-Villiger oxidation are converted into the A full report has been given of conversions butenolides (341).285 of readily available a-oxo-ketene dithioacetals (342) into butenolides (341 ; R 2 = H ) by sequential epoxidation using dimethylsulphonium methylide to give dihydrofurans (3431, followed by acid hydrolysis. 286 The additional substitutent, R ’ , can be introduced by alkylations of 2-methylthiofurans obtained from (343) by mild acid treatment. The dihydrofurans (343) may also be useful as protected forms of the butenolides (341). A related method for the elaboration of ring-fused butenolides (347) consists of the condensation of a-thiomethylene-ketones [e.g. (344)l with phenylthiomethyl-lithium, leading to the aldehyde (345) which on oxidation and Pummerer rearrangment affords the furan (346); slow acid hydrolysis completes the sequence. 287 Presumably, it would be possible to alkylate the intermediate furan (346) as mentioned above to give 4-substituted homologues of butenolides (347). Silylfurans can also act as protected forms of butenolides. Thus, coupling of the Grignard reagent (348) with alkyl iodides using Li2CuC14 as promoter proceeds smoothly to give butenolides (349) following oxidation using buffered peracetic acid. 288 3-Substituted butenolides can be similarly obtained from the

188

General and Synthetic Methods

isomeric al-silyl furan; presumably more highly substituted furans could also be used. In further studies of the oxidation of 2-furylcarbinols, it has been found that tertiary derivatives can be converted to ylidenebutenolides (350) using PDC-DMF. 289 However, y.ields are only high when R ' R L = aryl. Oxidation of 4-substituted-(~)-but-2-ene-l,4-diols (351) with Fetizon's reagent occurs regioselectively at the primary alcohol group to give 4-substituted butenolides directly. 290 The intramolecular Diels-Alder reaction between oxazoles and acetylenic dienophiles, resulting in the formation of an annelated furan, has been successfully applied to a total synthesis of the natural butenolide paniculide A ( 352 .29 Tetronic Acids.- A classical route to tetronic acids in by intramolecular Claisen condensations of a-acetoxy-esters, which are best carried out using LDA as base. Even this fails sometimes, in which case LiN (SiMe may prove effective .292 Ramage et a1 . have 3 2 further exploited the useful chemistry inherent in dioxolanones (32) and the 5-ylidene derivatives (33)24 to include a variety of tetronic acid syntheses. In the simplest type, reaction between the dioxolanone (32) and 2.5 equivalents of a lithium ester enolate results in ring opening to give dianions (353) which cyclize on work-up to tetronic acids (354) in 35-6356 yield.293 Similar reactions of appropriate 5-ylidene derivatives [cf. (33)l have been used to prepare natural ylidenetetronic acids such as fungal pigments belonging to the p u l ~ i n o n eand ~ ~ ~pulvinic acid 294 families and the microbial metabolite multicolanic acid .295 During work towards a synthesis of the antibiotic chlorothricin, the 'tophalf' (358) has been obtained by condensation between dianion (355) and cyclohexanone (356); metallation of the derived carboxylic acid (357; R=H) can be carried out at the 2-position of the butenolide. Oxidation of the resulting anion and silylation then provides the a-hydroxytetronic acid derivative (358) .296 Phtha1ides.- A Diels-Alder approach to synthetically useful hydroxyphthalides (361) consists of cycloadditions between cyclohexa-1,3-dienes (359) and acetylenic ester (360) followed by hydrolysis of the initial adducts. Cyclohexa-l,4-dienes, obtained by Birch reductions of the corresponding aromatic compounds, can also be used in many instances when these undergo rapid thermal isomerization to conjugated dienes C359) under the reaction

3: Carboxylic Acids and Derivatives

189

R'

MgCl

SiMe3

5:02TBDMS

OTBDMS

( 356 1

(355)

(357)

(358)

RGdo C0,Et

R

@

+

EtoyOEt Ill

------)

I

C02Me

0

0

190

General and Synthetic Methods

conditions (160-170 OC) .297 o-Thallated benzoic acids can be coupled with electron-deficient olefins such as acrylates and acrylonitrile in the presence of PdC12 to give phthalides such as (362). In general, such reactions with other types of olefins result in the formation of i s o c o ~ m a r i n s(see ~ ~ ~ also refs. 375, 377, and 379). Valero1actones.- Many a,B-unsaturated valerolactones can be obtained from the corresponding 5,6-dihydropyrans by oxidation of the carbon a- to the ether oxygen using PCC. 299 Simple alkylsubstituted oxetanes (363) have been found to undergo ring opening on treatment with lithium enolates of esters o r amides in the presence of BF3.0Et2 to give valerolactones (364) after cyclization of the initially produced 6-hydroxy-esters. 300 The reactions reported are completely non-stereoselective. The ability of horse liver alcohol dehydrogenase to stereospecifically oxidize mesod i 0 1 s ~has ~ ~ been used to convert 1,5-diols (365) into optically pure bridged valerolactones (366; fi = 1 o r 2 ) on preparatively useful scales. 301 Unfortunately, the method fails when endocyclic unsaturation is present. Palladium-catalysed addition of malonate to the allylic acetate (367) occurs exclusively at the position remote to sulphur with retention of configuration leading to the cis-fused valerolactone (368) after standard manipulations. 302 This route is therefore complementary to an alternative approach to (368) involving Michael addition to the cyclohexenone corresponding to (367), which gives only the trans-isomer. The isomeric lactones (370) can also be obtained using a Michael addition to an enone (369) but in this case followed by enolate trapping with formaldehyde.303 This approach can also be applied to other ring sizes and to some acyclic enones; overall yields are variable. Modified, full details have been given of the brief synthesis of racemic mevalonolactone (372) from the Grignard adduct (371) via ozonolysis to the corresponding diacid, anhydride formation (the problematical step), and finally borohydride reduction.304 New routes to chiral mevalonolactones have as the key step the selective ring opening of the aforementioned anhydride by a chiral binaphthyldiamine derivative, 305 diastereoselective oxidation of a chiral butyrolactone derived from (S)-glutamic acid or gmannitol, '06 or asymmetric Sharpless epoxidation. 307 Enantiomeric enrichments claimed for the final products are 58%, l o o % , and 88% respectively; the last two routes provide both enantiomers.

z.

3: Carboxylic Acids and Derivatives

191

( 3 6 81

(367)

(371 1

(372)

*OBn OH

(369)

(373)

(374)

0

(375)

(376)

0 (377)

(370)

(378)

192

General and Synfhetic Methods

Once again synthesis of the Prelog-Djerassi (PD) lactone (373) has proven to be a popular way to illustrate the value of a number of new routes to valerolactones. For example, condensations between various meso-2,4-dimethylglutaric anhydride derivatives and ally1 silanes using TiC14 as catalyst have to be used to obtain the precursor (374).308 Greatest stereoselectivity was found in reactions o f the aldehydo-ester derived from the anhydride.312 A hydroformylation procedure has been developed for the conversion of homoallylic alcohols [e.g.(375)l into valerolactones [e.g. (376)l by treatment with CO/H2 mixtures at 350 p.s.i. and 100 O C , using Rh2(0Ac)4 as the catalyst.309 Yields, after oxidation of the initially formed lactols with PCC, are 380%. The ready availability of the starting homoallylic alcohols suggests many applications for this method. Kinetic lactonization, by acidification and rapid extraction, of the salt (377) gives essentially only the valerolactone (378). 'lo An explanation based

on the possible ground-state conformations could have predictive value for studies on related systems. An asymmetric synthesis o f the PD lactone (373) has been achieved in which the key steps are preparation of the optically pure alcohol (379) using a diastereoselective aldol condensation of a boron enolate derived from chiral imide o f the type developed by Evans et al. followed by oxidation and homologation to the pyran (380) and catalytic hydrogenation to the penultimate precursor (381 1 .31 A full account has been given o f the development o f aldol condensations between crotylstannanes and aldehydes which generally product PD lactone has thus been obtained erythro-homoallylic alcohols. 3 1 in a directly analogous way to that described above.308 The method has further been applied to a synthesis o f (-)-verrucarinolactone (382), the enantiomer of which has been obtained via an enantioselective [2,3]-Wittig rearrangement .31 Considerable interest continues in finding new routes to the lactone portion (383) of the hypocholesterolemic agents compactin and its 4-methyl homologue mevinolin. The (R,S)-enantiomer of a model lactone (383; R = CH2Ph) has been derived from (S)-malic acid314 while a related, optically active, precursor (383; R = O B z ) of compactin has been obtained3I5 from a chiral epoxy-alcohol, prepared by asymmetric Sharpless epoxidation. The synthesis of some chiral precursors to compactin has also culminated in the elaboration of an optically active model compound ( 3 8 3 ; R cyclohexylmethyl) .316 Finally, a diastereoselective approach

193

3: Carboxylic Acids and Derivatives

to lactones (383) has been developed in which cis-cyclohexane2,3,5-triol is used as the starting material. 3T Another group of popular targets for total synthesis are the pentalenolactones; a key step in an alternative approach to the E and F homologues consists of formation of the valerolactone function by carbenoid insertion into an unactivated tertiary C-H bond C(384) (385)1.318 In this work, preparation of the diazoester (384) by the established method from the corresponding alcohol, glyoxalyl chloride tosylhydrazone, and triethylamine proved unsatisfactory. Eventually, the ester was obtained from these precursors using silver cyanide in place of Et N, although 3 related work has shown that such reactions can be optimized by using N,N-dimethylaniline as base during the ester bond formation .3'9 5-Hexadecanolide (386), a pheromone of the oriental hornet, has been prepared in optically pure form from both (L)-glutamic acid3*' and (R)- or (S)-3-hydroxytetradecanoic acid,321 obtained by asymmetric reduction of the corresponding keto-ester. A related reduction, b u t of cyclohex-2-en-l-one7 is a key step in a synthesis of both enantiomers of the acetoxy homologue (387),322which has also been prepared diastereoselectively by a sequence which featues a novel approach to erythro-1,2-diols by reactions between epoxides of (g)-allylic alcohols and lithium acetylides, in the presence of BF3-Et20.323 A synthesis of the antibiotic (-1-malyngolide (388) and three of its stereoisomers has been achieved starting with asymmetric conjugate additions of phenylmagnesium bromide to N-crotonyl-ephedrines, 324 followed by application of the novel oxathiane chemistry mentioned above. l 7 Bartlett and his co-workers have summarized their useful studies of iodolactonizations and related reactions of both y ,6- and 6 ,€-unsaturated acids. 325 Good 1,2- and 1,3-induction is usually observed under thermodynamic control leading, for example, to a highly stereocontrolled route to the lactone (389). In typical style, Mori and co-workers have synthesized all four isomers of pestalotin (390), a gibberellin synergist, using either an asymmetric Sharpless epoxidation or (D)-(+)-glyceraldehyde acetonide to obtain the chiral precursors. 326 The natural enantiomer (390) has also been prepared from (R,&)-diethyl tartrate , 327 or 3 a highly diastereoselective europium( 111)catalysed Diels-Alder reaction [ ( 3 9 1 (392 11, 328 which has also been used to elaborate the closely related lactone kawain

-

-

General and Synthetic Methods

194

H

(3831

(382)

(384)

(385)

OSiMe3

MEMO

B Un

H

H

Ph

J 0

0

phu A

A

(394)

(393)

0

(395) %H

-

OTHP

*,

OH NHCO OTHP

cut L i

SiMe3

(396)

I 1

T e , OH

(397)

Si Me,

(398)

3: Carboxylic Acids and Derivatives

195

(393) .329 (+)-Cryptocaryalactone (394) and its (6S)-enantiomer have been obtained from the coupling of (35)-3-hydroxypent-4-en-la1 derivatives and the dianion of ethyl acetoacetate; the absolute configuration of the natural product was then established by c.d. measurements.330 A route to racemic asperlin (395) begins with an erythro-selective condensation of a propargyl alcohol derivative (396) with crotonaldehyde leading to the diol (397); subsequent homologation to the valerolactone, Mitsunobu inversion of the 5acetoxy function, and lastly epoxidation gives the natural product.331 Finally of note in this section is a total synthesis of (+)-actinobolin (398) in which an early key step is an asymmetric intramolecular Diels-Alder reaction using an (L)threonine-derived substituent for chiral control, followed by a rather lengthy sequence of functional group transformations. 3 3 2 Macro1ides.- An attractive new method for the preparation of macrolides (401) from o-hydroxy-acids is by prior formation in >95% yield of the isolatable enol esters (400) using the 'push-pull' acetylene (399) .333 Cyclization is effected in greater than 80% yield by the slow addition of these adducts to hot toluene containing a trace of camphorsulphonic acid o r magnesium bromideetherate; presumably the mechanism is related to other 'doubleactivation' methods (see ref. 348). Two additional features of this particular method are the absence of racemization at a chiral centre u- to the alcohol group and the relatively high concentrations at which it can be carried out (final dilution: E. 1 mmol per 20 ml of solvent). Two other new methods, using either active esters derived from a 1 , 2 - b e n z i ~ o t h i a z o l eor ~ ~the ~ bistrimethylsilyl derivatives of w-hydroxy-acids and Pr2BOTf ,335 although efficient will only be of interest to those with small amounts of substrate to lactonize as very high dilutions are required ( 1 mmol in 750 ml or 450 ml respectively). An unusual intramolecular Diels-Alder reaction C(402) (40311 occurs in 58% yield at 170 O C in dilute solution in xylene (1.6 x M) .336 As well as providing a useful entry into the anthracyclins, this suggests that other macrolide systems could perhaps be obtained in this way. A conceptually related approach to naphthoquinones (405) proceeds the cobalt complex (404), readily obtained from the corresponding benzocyclobutenedione, and has been used in a total synthesis of the natural quinone (?INanaomycin. 337

-

196

General and Synthetic Methods

0 n

Y

“Me2

(399)

...-.

”

(4011

(400)

O(CH2)60COCH=CH2

co-

CI

0-0

I

‘PPh3

0

0

197

3: Carboxylic Acids and Derivatives

Alternative types of ring expansion continue to be developed for the synthesis of macrolides. The cyclo-octanone derivative (406) has been converted into a 14-membered lactone (409) via a two-stage 'zip reaction, first to the undecanolide (407) using Bun4NF followed by reductive cleavage of the pendant olefin function to the corresponding alcohol (408) and a final acid-catalysed expansion. 338 Presumably, this method could be applied to other systems although the subtle balance between the various driving forces in these steps makes definite predictions difficult. A rather more general four-atom ring expansion method also begins with 2-nitrocycloalkanones which are first converted into the aldehydes (410). Subsequent reaction with [MeTi(OPri) 3 occurs 3 regioselectively at the aldehyde group leading to the cyclic hemiacetals (411), Grob-type fragmentation of which affords the expanded products (412).339 The unusual [3,3]-sigmatropic rearrangement which occurs when ally1 sulphides are treated with dichloroketene has been adapted to a general approach to large thiolactones by a four-carbon expansion and subsequently to macrolides (415) by a 'zip' reaction. Thus, treatment of a suitable vinylthiane (413) with dichloroketene leads smoothly to the thiolactones (414) which, after dechlorination and deprotection, undergo facile S 0 acyl transfer when treated with acid. 340 A number of natural macrolides have been the subject of synthetic work during 1984; however, lack of space dictates that neither their structures nor a discussion of the procedures can be given. Therefore there follows a listing of these compounds together with the key lactonization methods used. In some cases, the yields from these steps are at best moderate and extremely high dilution conditions are often required and therefore consultation of these papers is recommended for those planning such work. Lactonization of w-hydroxy-acids has been used to prepare the following: ( 3 2 , 6~)-ll-methylundecadienolide and the 12- and 13-membered homologues [2-chloro-l-methylpyridinium iodide (Mukaiyama's reagent )I, 341 the 16-membered Protomycinolide [mixed anhydride with 2,4,6-trichlorobenzoic acid (TCBAI-DMAP] , 342 (+)-Colletodiol [DEAD, Ph P ( M i t s ~ n o b u )or~ ~TCBA-DMAP], ~ 344 3 (+)-Conglobatin [TCBA-4-pyrrolidinopyridine], 345 ( - 1-Brefeldin A [Mukaiyama's reagent], 346 ( + 1-Brefeldin A [pyridinethiol ester347 o r the push-pull acetylene method33393481, (-)-Hybridalactone [bis (4-t-butyl-~-isopropylimidazol-2-yl)disulphide-Ph PI. 349

-

3

198

General and Synthetic Methods

(406 1

63

OR

(4131

(4071

(408)

Q!

OR 0 C l

(414)

(409)

(415)

3: Carboxylic Acids and Derivatives

199

( + )-3-Deoxyrosaranolide, 350 Baccharin B5, 35 and Roridin E35 were obtained by alternative macro-cyclizations using Horner-Emmons reactior,s. Interest in the synthesis of the related verrucarins continues to be intense. Approaches to model 18-membered lactones have included examples of the Mitsunobu procedure as well as lactone bond formation from w-hydroxy-thioesters using either NBS or Hg(02CCF ) 352 This work also features the use of a 3 2' cyclobutene function fused to the triolide ring which is open by

thermolysis to provide ring-expanded (E,L)-triolides corresponding to the natural products. The final macrolide linkage in Verrucarins B353 and J354 has been formed using a mixed-anhydride method. New routes to precursors of these compcunds, V e r r u c a r 0 1 ~ ~ ~ and Verrucarinic acid,356 will also be of interest to workers in this area. Two new lactonization procedures have been developed during total syntheses of examples of macrocyclic pyrrolizidine alkaloids. During a synthesis of the 12-membered (')-Integerriminel the final lactone bond was formed from the (methylsulphonyl) methyl ester (416 )357 whereas syntheses of ( + )-Fulvine and ( + )-Crispatine , both Il-membered pyrrolizidine dilactones, relied upon cyclizations of B-trimethylsilylethyl ester mesylates (417) .358 Both methods may well find other applications. 4 Amides Synthesis.- The useful dianion (418) can be readily derived from and can be alkylated or acylated to provide homologous amides or 6-keto-amides respectively in E. 50% isolated yield.359 An attraction of this reagent is the simple removal of the silyl protecting group on acidic work-up. Claisen rearrangements of enamines formed from propargyl alcohols (419) and amide acetals (420) can be readily carried out by uncatalysed reactions between the two starting materials in refluxing benzene, and lead to the allenic amides (421 ) in 54-88% yields.360

N-(trimethylsilyl)acetamide,

Furthermore, treatment of these initial products with alumina in hot benzene gives largely the (2E,4L)-dienamides (422), thus complementing the known base-catalysed isomerization (KOBut) of allenes (421), which affords the corresponding all-(:)-isomers. In an extension of previous studies, it has been found that vinyl boranes (424), obtained from terminal acetylenes (423) and boron tribromide, react with phenyl isocyanate to give unsaturated amides

General and Synthetic Methods

200

6r

Br

0 (423)

(424)

(426)

( 4 2 7)

0 H

(430)

-

(422 1

(425 )

( 4 2 8 ) n =1 o r 2

R2R3NH

(429)

0

___)

RANR2R3 (431)

20 1

3: Carboxylic Acids and Derivatives ( 4 2 5 ) i n 65-80% y i e l d s ; 3 6 1 isomer r a t i o s a r e d e p e n d e n t b o t h o n s u b s t i t u e n t s i z e a n d on r e a c t i o n t e m p e r a t u r e , a n d a r e u s u a l l y better than 4:l

i n f a v o u r of one isomer.

L a c t o n e s ( 4 2 6 ) c a n be

(z.

c o n v e r t e d i n t o u n s a t u r a t e d a m i d e s ( 4 2 7 ) s i m p l y by t h e r m o l y s i s 180 O C ) i n HMPA; y i e l d s , h o w e v e r , a r e r a t h e r v a r i a b l e . 3 6 2 Readily a v a i l a b l e 2 - o x a z o l i n e and 2 - o x a z i n e

d e r i v a t i v e s (428) can be r i n g -

o p e n e d i n h i g h y i e l d t o p r o v i d e s e c o n d a r y c a r b o x a m i d e s ( 4 2 9 1 , by t r e a t m e n t w i t h Me S i x w h e r e X C1, N 3 , S P h , o r S e P h . 3 6 3 The 3 r e a c t i o n s a r e u s u a l l y b e s t p e r f o r m e d i n r e f l u x i n g m e t h a n o l , when t h e r e a c t i n g s p e c i e s is p r o b a b l y ' H X ' ,

and w i l l be u s e f u l f o r t h e

s y n t h e s i s o f a w i d e v a r i e t y of a m i d e s c o n t a i n i n g s e n s i t i v e functionality. A u s e f u l m e t h o d f o r t h e e x c h a n g e of a m i d e g r o u p s , w h i c h d o e s n o t

r e q u i r e h y d r o l y s i s t o t h e c o r r e s p o n d i n g a c i d s , i s by N - n i t r o s a t i o n

o r !-nitration o f a s e c o n d a r y a m i d e ( 4 3 0 ) f o l l o w e d by d i s p l a c e m e n t o f t h e a c t i v a t e d a m i d e g r o u p by ammonia o r a s e c o n d a r y a m i n e t o ~ ~ of t h e reaction g i v e p r i m a r y o r t e r t i a r y a m i d e s ( 4 3 1 ) . ~ Most c o n d i t i o n s a p p e a r m i l d e n o u g h t o p e r m i t t h e i n c l u s i o n o f many t y p e s of functionality i n t h e substrates.

Two known r e a c t i o n s h a v e b e e n

combined t o p r o v i d e f o r t h e s y n t h e s i s o f t h e t e r m i n a l l y functionalized g-alkylamides

(434) from u n s u b s t i t u t e d amides (432)

However, t h i s method i s and a m o n o s u b s t i t u t e d o l e f i n (433).365 p r o b a b l y l i m i t e d t o mono- a n d s y m m e t r i c a l c y c l i c o l e f i n s a n d a m i d e s which do n o t c o n t a i n o t h e r o l e f i n i c f u n c t i o n s . Complete asymmetric i n d u c t i o n h a s been o b s e r v e d i n a l k y l a t i o n s (LDA; R3X) o f t h e c h i r a l p y r r o l i d i n e s ( 4 3 5 ) . 3 6 6

The i n i t i a l

p r o d u c t s c a n be h y d r o l y s e d t o t h e c o r r e s p o n d i n g c a r b o x y l i c a c i d s u s i n g 1M-HC1 w i t h no r a c e m i z a t i o n .

Such p y r r o l i d i n e s u b s t i t u e n t s

s i m i l a r l y d i r e c t a c y l a t i o n s t o p r o v i d e c h i r a l B-keto-amides R'

(436; = R4CO) w h i c h on z i n c b o r o h y d r i d e r e d u c t i o n a r e c o n v e r t e d i n t o

t h e c h i r a l B-hydroxy-amides o p t i c a l y i e l d s . 367

(437) i n e s s e n t i a l l y q u a n t i t a t i v e

An a l t e r n a t i v e a p p r o a c h t o c h i r a l B - h y d r o x y -

a m i d e s i s by c o n d e n s a t i o n s b e t w e e n t h e m a g n e s i u m e n o l a t e s o f c h i r a l a - s u l p h i n y l a c e t a m i d e s and a l d e h y d e s ; a f t e r d e s u l p h u r i z a t i o n , t h e e n a n t i o m e r i c e x c e s s e s o f t h e hydroxy-amides s i m p l e c a s e s . 368

Lewis acid-catalysed

d e r i v e d from ( S ) - p r o l i n e

a r e >95% i n t h r e e

a l l y l a t i o n s of a-keto-amides

have been used t o p r e p a r e c h i r a l a - a l l y l -

a - h y d r o x y - a r n i d e ~ ~a ~n d~ s i m p l e c h i r a l a - h y d r o x y - a m i d e s

have been

o b t a i n e d by h y d r o g e n a t i o n o f c h i r a l p y r u v a m i d e s d e r i v e d f r o m (21-am e t h y l b e n z a m i d e o r s i m i l a r a m i n e s ; 370 i n b o t h c a s e s e i t h e r t h e chemical or o p t i c a l y i e l d s are n o t s p e c t a c u l a r .

202

General and Synthetic Methods

An extensive and useful review of a-amidoalkylation at carbon by Mannich-type reactions has been published .371 Under the usual allylic bromination conditions, g-bromosuccinimide reacts with N,Ndimethylamides to give the succinimido-derivatives (438) generally in excellent yields; as expected, the corresponding IJ-bromomethylN-Bromo-amides (439 ) can be N-methylamides are intermediates. 3 7 2 obtained in generally excellent yields from the parent primary amides using aqueous sodium bromite in acetic acid.373 A generally applicable method for the homologation of amide N-alkyl g r o u p s is by metallation of the latter a- to nitrogen [cf. (44011. This type of reaction has been thoroughly reviewed374 and is perhaps more relevant to the section on amine synthesis as clearly the amide cannot contain protons a- to the carbonyl group. The development of novel metallated intermediates has also contributed significantly to benzamide chemistry, particularly in the work of Snieckus and co-workers. Two severe restrictions on the utility of ortho-lithiated tertiary benzarnides (441) is their failure to condense cleanly with allylic halides and aldehydes. These problems can be largely solved by transmetallation to the corresponding magnesium species thus allowing a general access to dihydroisocoumarins (442) and phthalides (443). 375 3-Aryl-3,4dihydroisocoumarins can also be prepared by condensations of the homologous toluamide anion (444) with aromatic aldehydes followed by base hydrolysis.376 The use of trimethylsilyl groups to block the more reactive site in these types of ortho-metallations has been extended to examples where removal of the silicon group generates a further useful anionic species. For example, treatment of the 2-silyl-benzamide (445) with C s F in DMF in the presence of an aromatic aldehyde (ArCHO), followed by acid hydrolysis, leads to the 3-arylphthalides (446),377 which are useful as precursors to anthraquinones following a known hydrogenolysis-cyclizationoxidation sequence. The silyl group in amides (445) can also be replaced by bromine ( B r 2 , CC14, 25 OC), thus providing an alternative and somewhat milder route to the phthalides (446) after rapid halogen-metal exchange using BunLi , and condensation with ArCHO. Amide metallation chemistry also provides a simple route to the 3-triflyl-benzamide ( 4 4 7 ) which is converted into the benzyne (448) on treatment with Bun4NF in acetonitrile at room temperature. 378 The benzyne (448) undergoes typical Diels-Alder reactions and regioselective attack by nucleophiles at the 3 position. Silyl g r o u p s are also effective in protecting an ortho-

3: Carboxylic Acids and Derivatives

203

/OMEM

LOR2 (435)

0

o.... .L i

0

RA N N 0

"9

RA N H B r

$NJ

1 R

0

(4401

(439)

(438 1

& aCON Et 2

HCI

\

(442)

(4411

4oK;Et2 Me0

R (443)

SiMe3

Me0

(444)

CONEt 2

(445) Me3Siv

SiMe 3

(446)

.

OTf

(447)

(448)

(449)

(450)

o

204

General and Synthetic Methods

methyl substitutent against metailation. Thus, double metallation and silylation of p-methoxy-2-toluamide gives the derivative ( 4 4 9 ) , which then undergoes metallation at the ortho-position; subsequent condensation with an aromatic aldehyde, desilylation (CSF-DMF-H O), and acid-catalysed cyclization also leads to phthalides (450). 3?9 Thioamides.- Enolates generated from unsaturated thioamides (451) by Michael addition of R 2 M condense stereoselectively with aldehydes to give largely or exclusively the threo-adducts (452), thereby providing a good alternative to direct condensations of thioamide enolates with aldehydes which tend to lead to erythroisomers or to mixtures of products, depending on the substituents present. 380 The acyl-lithium species RC(C0)Li mentioned earlier232 reacts cleanly with alkyl (but not phenyl) isothiocyanates to give Similarly , reactions with good yields of u-keto-thioamides. 38 isocyanates give the corresponding a-keto-amides. Condensations between methyl or phenyl isothiocyanate and the carbanion of EtP(0)(OEt)2 afford the Wittig-Horner substrates (453) which, after deprotonation using sodium hydride, react with aromatic aldehydes (or cinnamaldehyde) to give the unsaturated thioamides (4541, probably with the ( E ) - c ~ n f i g u r a t i o n . ~This ~~ first example of a successful Wittig-Horner reaction with a B-thioxo-phosphonate unfortunately fails with aliphatic aldehydes, although this is not too serious as aliphatic amides (454; ' A r ' = alkyl) can be prepared in other ways. (&)-S-Silylketene S,N-acetals (455) react with enones such as benzylidine acetophenone (PhCH:CHCOPh) in the presence of TiC1(OPr1)3 to give the [1,2]-adducts (456) with little o r no stereoselectivity in 47-84% yields.383 In some cases, [ I , 4 1 addition products are formed when titanium(1V) isopropoxide is used in place of TiC1(OPri) 3' Amide (Peptide) Bond Formation.- Some further modifications a n d extensions of existing coupling reagents have been reported this year. An improved preparation of the benzotriazolyl coupling reagent (457) has been reported .384 This method seems particularly attractive combining as it does the features of rapidity, efficiency, and mildness with an absence of racemization. The direct use of N-tritylamino-acid l-benzotriazolyl esters has been successfully applied to peptides such as leucine-enkephalin. 385 Similarly, related 3-acyl-1,3-thiazolidine-2-thiones undergo very efficient aminolysis with unprotected a-amino-acids in aqueous THF to give peptides in which no significant racemization h a s occurred

3: Carboxylic Acids and Derivatives

205

(451)

SSiMe, "&NMe2

(453)

-

(455)

+

HO

R2 NMe2

(456)

/ N+

n i 04-c'

(457)

(454)

(458)

I

oYNtP-C' 0 (459)

206

General and Synthetic Methods Furthermore, it is n o t n e c e s s a r y t o

i n e i t h e r component.386

p r o t e c t hydroxyl o r t h i o l groups i n t h e s e coupling r e a c t i o n s ; t h e r e f o r e t h i s m e t h o d c o u l d be e s p e c i a l l y u s e f u l i n some c a s e s , a s some awkward p r o t e c t i o n p r o b l e m s c a n b e a v o i d e d . 2-Acyl-lm e t h y l i m i d a z o l e s c a n a l s o be u t i l i z e d i n a m i d e s y n t h e s i s f o l l o w i n g conversion i n t o the corresponding 2 - s i l y l cyanohydrin, q u a t e r n i z a t i o n ( M e 2 S 0 4 , 70

OC)

of t h e r e m a i n i n g u n s u b s t i t u t e d

n i t r o g e n , and f i n a l l y r e a c t i o n w i t h an amine.

This sequence looks

t o be u n s u i t a b l e f o r p e p t i d e s y n t h e s i s , b u t i s u s e f u l f o r t h e p r e p a r a t i o n o f o t h e r a m i d e s as w e l l a s e s t e r s a n d t h i o e s t e r s a n d f o r the C-acylation

o f B - k e t o - e ~ t e r s . ~ A~ ~f u r t h e r a n a l o g u e o f

- c a r b o n y l d i - i m i d a i o l e , b a s e d on 2( 35)- b e n z o x a z o l e t h i o n e , h a s been r e p o r t e d ; t h e enhanced s t a b i l i t y o f t h e r e a g e n t t o m o i s t u r e

N

may b e a n a d v a n t a g e i n c e r t a i n c i r c u m s t a n c e s . 388 Amj.de,. a r e e f f i c i e n t l y o b t a i n e d f r o m e q u i m o l a r a m o u n t s o f a c a r b o x y l i c a c i d , a n a l k y l o r a r y l a z i d e , a n d t r i p h e n y l p h o s p h i n e , on h e a t i n g i n benzene.389

It is p e r h a p s s u r p r i s i n g t h a t t h i s

a p p l i c a t i o n of t h e S t a u d i n g e r r e a c t i o n h a s n o t been p r e v i o u s l y r e p o r t e d when s o many o t h e r p h o s p h o r u s - b a s e d m e t h o d s h a v e b e e n u s e d i n a m i d e bond f o r m a t i o n . One s u c h p h o s p h o r u s r e a g e n t , w h i c h h a s b e e n u s e d f o r r a c e m i z a t i o n - f r e e p e p t i d e s y n t h e s i s as w e l l a s i n a w i d e v a r i e t y o f o t h e r a p p l i c a t i o n s ( s e e , f o r e x a m p l e , r e f . 8) i s diphenyl phosphorazidate,

(Ph0),P(O)N3;

a d e t a i l e d procedure f o r The p h o s p h i n i c c h l o r i d e

i t s p r e p a r a t i o n h a s now b e e n p u b l i s h e d . 390

f u n c t i o n , R2P(0)C1, h a s p r o v e n t o be o f c o n s i d e r a b l e u t i l i t y i n p e p t i d e s y n t h e s i s by p r i o r f o r m a t i o n o f a m i x e d p h o s p h i n i c c a r b o x y l i c a n h y d r i d e f o l l o w e d by a m i n o l y s i s .

During a study of

v a r i o u s t y p e s o f p h o s p h i n i c c h l o r i d e , l-oxo-l-chlorophospholane

( 4 5 8 ) (CptC1) h a s b e e n f o u n d t o b e p a r t i c u l a r l y good i n t h i s r e s p e c t e s p e c i a l l y as t h e by-product phosphinic a c i d is r e a d i l y removed by a n a q u e o u s w a s h . 3 9 1 An i m p r o v e d r e c i p e h a s b e e n f o u n d f o r a m i d e bond f o r m a t i o n u s i n g t h e p h o s p h o r d i a m i d i c

chloride (459)

which a v o i d s premature r e a c t i o n w i t h t h e amine component, l e a d i n g t o u n r e a c t i v e p h o s p h ~ r o t r i a m i d e s . ~A~ ~f u l l a c c o u n t h a s b e e n g i v e n of t h e u t i l i t y of t h e s t r a i n e d s u l t o n e (460) i n p e p t i d e s y n t h e s i s . 3 9 3 The r e a c t i o n s p r o c e e d via a m i x e d a n h y d r i d e w h i c h r e a r r a n g e s t o t h e a c t i v a t e d e s t e r s (461) and c o u l d be p a r t i c u l a r l y u s e f u l f o r t h e s e l e c t i v e a c y l a t i o n of p r i m a r y a m i n e s i n t h e p r e s e n c e of u n p r o t e c t e d s e c o n d a r y amines. The u s e of D C C i n p e p t i d e bond f o r m a t i o n i s o f t e n a c c o m p a n i e d by e x t e n s i v e r a c e m i z a t i o n a l t h o u g h t h i s c a n b e m i n i m i z e d by v a r i o u s

207

3: Carboxylic Acids and Derivatives a d d i t i v e s s u c h as l - h y d r o x y b e n z o t r i a z o l e

(HOBt).

I t h a s now b e e n

f o u n d t h a t c o p p e r ( I 1 ) c h l o r i d e is a l s o v e r y e f f e c t i v e i n t h i s r e s p e c t . 394

The a d d i t i o n o f a 4 - d i a l k y l a m i n o p y r i d i n e

is v e r y

e f f e c t i v e i n t h e p r o m o t i o n o f DCC c o u p l i n g r e a c t i o n s b u t t h i s c a n a l s o r e s u l t i n some o r c o m p l e t e r a c e m i z a t i o n o f , f o r e x a m p l e , a c y l a m i n o - a c i d c o m p o n e n t s . 395 However , v a r i o u s u r e t h a n e

g-

derivatives survive rather better. V a r i o u s new p o l y s t y r e n e s u p p o r t e d 4 - a m i n o p y r i d i n e s h a v e b e e n d e s c r i b e d , some o f w h i c h d i s p l a y a g o o d c a t a l y t i c a c t i v i t y i n a m i d e bond f o r m a t i o n ; r a c e m i z a t i o n p r o b l e m s w e r e n o t e x a m i n e d . 396

F u r t h e r s t u d i e s have

b e e n r e p o r t e d on t h e u s e o f a D C C a n a l o g u e f o r t h e f o r m a t i o n o f s y m m e t r i c a l a n h y d r i d e s f r o m !-protected by-product

amino-acids,

i n which t h e

u r e a s c a n b e removed b y a n a q u e o u s a c i d wash l e a v i n g t h e

a n h y d r i d e s i n t a c t . 397 The s l u g g i s h c o u p l i n g r e a c t i o n s b e t w e e n Z - a m i n o - a c i d 1 - h y d r o x y s u c c i n i m i d a t e e s t e r s a n d galkoxycarbonylmethylamino-esters i s g r e a t l y a c c e l e r a t e d by t h e

la-

a p p l i c a t i o n of high p r e s s u r e (10 k b a r ) ; y i e l d s of t h e coupled p r o d u c t s ( 4 6 2 ) a r e s t i l l g e n e r a l l y p o o r b u t a g r e a t i m p r o v e m e n t on t h e r e a c t i o n s a t a t m o s p h e r i c p r e s s u r e which g i v e abysmal N-Hydroxysuccinimide esters have a l s o been used as key r e t u r n s . 398 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 of p e p t i d e s c o n t a i n i n g l-hydroxyg r o u p s .399 E x c e l l e n t y i e l d s o f some d i p e p t i d e s h a v e b e e n o b t a i n e d o n a p r e p a r a t i v e s c a l e by u s i n g t h e e n z y m e s t h e r m o l y ~ i na n~ d~ ~Q chymotrypsin. 400140

The m i l d n e s s o f t h e p r o c e d u r e s a n d t h e h i g h

o p t i c a l p u r i t y of t h e p r o d u c t s s u g g e s t t h a t many f u r t h e r developments w i l l be forthcoming i n t h i s a r e a . The e x t r e m e l a b i l i t y o f 9 - f l u o r e n y l m e t h y l

protecting groups i n

t h e p r e s e n c e of s e c o n d a r y a m i n e s , which h a s found c o n s i d e r a b l e a p p l i c a t i o n i n p e p t i d e e l a b o r a t i o n , h a s been used i n t h e d e s i g n o f

a new v e r s a t i l e a n c h o r i n g g r o u p f o r s o l i d - s t a t e p e p t i d e P r o t e c t e d p e p t i d e s c a n a l s o be r e m o v e d f r o m 2-[4s y n t h e s i s . ‘02 (hydroxymethyl)phenylacetoxy]propionyl r e s i n s u s i n g s i m i l a r conditions, the best reagents being the hindered non-nucleophilic b a s e s t e t r a m e t h y l g u a n i d i n e and DBU. 403 Bromoacetamide g r o u p s a r e s u i t a b l e f o r a t t a c h i n g t h e f i r s t amino-acid t o a p o l y a c r y l i c r e s i n v i a a n e s t e r l i n k a g e which c a n be c l e a v e d q u a n t i t a t i v e l y w i t h o u t Various r a c e m i z a t i o n u s i n g b o i l i n g 1N-sodium c a r b o n a t e . ‘04 b i f u n c t i o n a l compounds s u c h as 2 - ( 4 - c a r b o x y p h e n y l s u I p h o n y l ) e t h a n o l a r e v e r y u s e f u l f o r t h e a t t a c h m e n t of g r o w i n g p e p t i d e c h a i n s t o s u p p o r t s , b e i n g s u i t a b l y r o b u s t a n d c l e a v a b l e by a m i l d , b a s e -

208

General and Synthetic Methods

.

catalysed 8-elimination ‘05 Diphenylphosphinic mixed anhydrides have been shown to be very suitable for solid-state syntheses of pept ides in general. 406

5 Amino-acids General Synthesis .- A further development407 in the phase-transfer alkylations of Schiff bases (463) derived from a-amino-esters is the discovery that potassium carbonate is a sufficiently strong base for such reactions when carried out in refluxing acetonitrile, thus avoiding nucleophilic bases such as NaOH, the use of which can result in the occurrence of side reactions in some examples. Yields of the alkylated amino-acids (464) are usually in the order of 75% after deprotection; simple n-alkyl bromides as well as more reactive benzylic or allylic halides can be used as electrophiles. The diphenylmethylene Schiff base derived from aminoacetonitrile can be doubly alkylated, under PTC conditions using sodium hydroxide as base, by u,w-dibromides. In the cases of 1,2dibromoethane or 1,4-dibromobutane, the cyclic products (465; p. = 1 or 3 ) are formed in excellent yields; while other ring sizes or more substituted products have not been obtained by this method, the use of two equivalents of the Schiff base results in good yields of diaminodicarboxylic acids (466 1 , after hydrolysis. ‘08 Both stereoisomers of the chlorocyclopropanecarboxylic acids (467) have also been prepared but using diazomethane addition to a 4(chloromethylene )-oxazolone to form the three-membered ring. 409 Not surprisingly the major developments in this area, however, have been in the diastereoselective and enantioselective synthesis of amino-acids. Anions of Schiff bases derived from glycine can be converted into optically active alanine by methylation using a chiral methyl sulphate derived from (D)-glucose; the highest optical yields (up to 71%) were observed when the substituents at nitrogen were very large andlor were electron donating pExcellent enantiomeric enrichments have been Me2NC6H4). ‘lo observed in the transaminations of some u-keto-acids into a-aminoacids (alanine, nor-valine, tryptophan) using a pyridoxal co-enzyme model.411 Serine analogues (469) have been prepared by an extension of the ‘self-reproduction of chirality’ principle following condensations between the oxazolidine enolate (468) and a variety of electrophiles. As is pointed out in this paper, the products (469) are versatile intermediates for syntheses of the

(x.

3: Carboxylic Acids and Derivatives

Ar

(463 )

-

209

+ R3

NH3

R1 xco;

(464)

NH2 ( F C 0 2 H

(465)

Ho2c NH,

NH2

(466)

CHO

(4671

(468)

Scheme 2

(469)

General and Synthetic Methods

210

o p p o s i t e e n a n t i o m e r s or of o t h e r a-amino-acids. This principle has b e e n a m p l y d e m o n s t r a t e d by R a p o p o r t a n d c o - w o r k e r s 4 ’ who h a v e d e v e l o p e d r o u t e s t o a number o f D - a - a m i n o - a c i d s i n e x p e n s i v e 2-(phenylsulphony1)-L-serine;

starting with

the first s t e p is d i r e c t

conversion i n t o t h e corresponding p r o t e c t e d a-amino-ketones

by t h e

a d d i t i o n o f a n o r g a n o l i t h i u m o r G r i g n a r d r e a g e n t w h i c h is t h e n f o l l o w e d by v a r i o u s , r e l a t i v e l y s t r a i g h t f o r w a r d , t r a n s f o r m a t i o n s (Scheme 2 ) .

An a l t e r n a t i v e ‘ s e l f - r e p r o d u c t i o n ’ m e t h o d i n v o l v e s

a l k y l a t i o n of t h e r e a d i l y a v a i l a b l e o x a z o l i d i n o n e s ( 4 7 0 ) i n which t h e e l e c t r o p h i l e a p p r o a c h e s f r o m t h e o p p o s i t e f a c e of t h e b u l k y a r y l s u b s t i t u e n t t o g i v e t h e o p t i c a l l y p u r e homologues ( 4 7 1 ) a f t e r h y d r ~ l y s i s . ~ ’The ~ oxazin-2-ones (E)-(2-furyl)glycine

( 4 7 2 ) , r e a d i l y prepared from

and a c h i r a l a - h y d r o x y - a c i d ,

can be s i m i l a r l y

a l k y l a t e d s t e r e o s p e c i f i c a l l y on t h e l e s s h i n d e r e d f a c e , l e a d i n g t o PhCH2 o r Me). t h e furyl-glycine analogues (473; R The r e l a t e d b i s - l a c t i m e t h e r method h a s been f u r t h e r e x t e n d e d t o a n a s y m m e t r i c s y n t h e s i s of a - a l k y l - l e u c i n e s . 416 An i m p r o v e d p r o c e d u r e h a s b e e n developed417 f o r t h e p r e p a r a t i o n of t h e amino-dioxan

( 4 7 4 ) , which

h a s b e e n u s e d i n a s y m m e t r i c S t r e c k e r - t y p e s y n t h e s e s o f c h i r a l aa m i n o - and a - m e t h y l - a - a m i n o - a c i d s . h a s as t h e key s t e p a [3,31-

A novel r o u t e t o a-amino-acids

sigmatropic (acetimidate) rearrangement.

Thus, condensation of a n

a l l y l i c alcohol with trichloroacetonitrile leads t o the a c e t i m i d a t e s ( 4 7 5 ) which r e a r r a n g e t o t h e a l l y l i c amines ( 4 7 6 ) i n refluxing xylene.

S u b s e q u e n t o x i d a t i v e c l e a v a g e (RuC13; N a I 0 4 ) and

h y d r o l y s i s a f f o r d s t h e amino-acids yields418

(cf. r e f .

445).

( 4 7 7 ) i n 50-75% o v e r a l l

A r e v i e w of v a r i o u s a s p e c t s o f

electrochemistry i n s y n t h e s i s i n c l u d e s a d i s c u s s i o n of t h e c o n v e r s i o n of a-methoxycarbamates

i n t o a-amino-acid

derivatives.

The p o s s i b i l i t y o f o b s e r v i n g e n h a n c e d b i o l o g i c a l a c t i v i t i e s i n p e p t i d e s by i n t r o d u c i n g n o n - n a t r u a l

amino-acid

residues has

r e s u l t e d i n t h e development of an e x p e d i t i o u s s y n t h e s i s of t h e b i c y c l i c a n a l o g u e ( 4 7 8 ) o f p r o l i n e by c o u p l i n g a n e n a m i n e o f c y c l o p e n t a n o n e w i t h a p r o t e c t e d d e h y d r o a l a n i n e f o l l o w e d by c y c l i z a t i o n and f i n a l l y h y d r o g e n a t i o n . 420 n a t u r a l 2-carboxymethyl-amino-acids d e v e l o p e d . 42 1

threo-B-Hydroxy-a-amino-acids

F u r t h e r r o u t e s t o non-

(479) have a l s o been

(480) c a n b e o b t a i n e d by 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 o f t h e c o r r e s p o n d i n g f u l l y p r o t e c t e d B-ketoc o m p o u n d s . 4 2 2 D i a s t e r e o s e l e c t i v i t i e s a r e v e r y h i g h a n d much b e t t e r t h a n t h o s e o b t a i n e d i n d i r e c t a l d o l - t y p e a p p r o a c h e s t o a c i d s (480).

3: Carboxylic Acids and Derivatives

Ph'

21 1

,

NH;

NHCOCCl

I

CCI,

NH2

(474 1

(475)

(476)

(477)

OH

C0,Me

cVNH "1

OH

(4791

(478)

R2°2H

H,N L

(4801

(4821

+

(Me3SiI2NCH20Me 5 CH2NH2

R4

(483)

(484)

(485)

H H

(486)

(4871

(488) I

OH H

CO, H

H 2N

Ph*O2H

OH

(4901

(489)

General and Synthetic Methods

212

A s t e r e o c o n t r o l l e d a p p r o a c h t o c y c l i c y-hydroxy-a-amino-esters

( 4 8 1 ) h a s as t h e key s t e p an 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 a n an i t r o n e e s t e r t o a d i s t a l o l e f i n i c bond.423 A number o f u s e f u l p r o c e d u r e s f o r t h e r e s o l u t i o n o r a n a l y s i s o f

a-amino-acid

d e r i v a t i v e s have been r e p o r t e d t h i s y e a r .

o f a number o f r a c e m i c 5-acetyl-[a-'H]-a-amino-acids k i d n e y a c y l a s e g i v e s g e n e r a l l y e x c e l l e n t y i e l d s of

D-a-Amino-acids

a m i n o - a c i d s . 424

Treatment

with porcine

( L )- [ a - 2 H ] - a -

containing an aliphatic side-chain

(e.g. V a l , L e u , I l e ) c a n b e s e p a r a t e d f r o m r a c e m i c m i x t u r e s s i m p l y by t r e a t m e n t w i t h L - p h e n y l a l a n i n e A g e n e r a l method f o r a m i n o - a c i d

r e s o l u t i o n i s by c o n v e r s i o n o f a

r a c e m i c m i x t u r e of a - a m i n o - e s t e r s

(R,R,R)-

i n aqueous sodium h y d r o x i d e . 425 into the Schiff bases using

or (S,S,S)-2-hydroxypinan-2-one f o l l o w e d by c o l u m n

c h r o m a t o g r a p h y and h y d r o l y s i s .

O v e r a l l y i e l d s of o p t i c a l l y pure

p r o d u c t s a r e e x c e l l e n t , and f u r t h e r m o r e t h e method looks t o be v e r y g e n e r a l l y a p p l i c a b l e t o b o t h n a t u r a l and n o n - n a t u r a l a c i d s . 426

a-amino-

Another c h i r a l s t a t i o n a r y phase h a s been developed for d e r i v a t i v e s as w e l l a s amino-

t h e d i r e c t r e s o l u t i o n of a-amino-acid a l c o h o l s , a m i n e s , a n d a l c o h o l s . 427

T . 1. c .

a n a l y s i s of d a n s y l a m i n o - a c i d s c a n b e c a r r i e d o u t on r e v e r s e - p h a s e p l a t e s , p r e t r e a t e d w i t h a c o p p e r ( I 1 ) c o m p l e x o f N,N-di-n-propyl-4-alanine. 4 2 8 Enantiomers of a l l t h e n a t u r a l amino-acid w i t h t h e e x c e p t i o n of d a n s y l - p r o l i n e .

d e r i v a t i v e s are r e s o l v e d

Oxazolidine-2,5-dione

d e r i v a t i v e s , r e a d i l y o b t a i n e d from N-methyl-a-amino-acids

and

p h o s g e n e , c a n be r e s o l v e d by gas c h r o m a t o g r a p h y u s i n g a c h i r a l s t a t i o n a r y p h a s e ; t h i s m e t h o d l o o k s t o be p a r t i c u l a r l y u s e f u l f o r

small-scale,

q u a n t i t a t i v e work.429

Isoxazolidin-5-ones

( 4 8 2 ) c a n b e o b t a i n e d i n t w o s t e p s by

c o n j u g a t e a d d i t i o n s of N - s u b s t i t u t e d

hydroxylamines t o a,B-

u n s a t u r a t e d e s t e r s f o l l o w e d by c y c l i z a t i o n u s i n g L i N ( S i M e 3 I 2 ( o t h e r b a s e s w e r e i n e f f e c t i v e ) ; s u b s e q u e n t h y d r o g e n o l y s i s of ( 4 8 2 ; R 1 = 4 (483).430 The R g r o u p c a n

Bz) l e a d s d i r e c t l y t o B - a m i n o - a c i d s

a l s o be a d d e d l a t e r by a l k y l a t i o n o f t h e i n i t i a l a d d u c t s ( 4 8 2 ; R4=H); u n f o r t u n a t e l y ,

i n c o r p o r a t i o n of a c h i r a l s u b s t i t u e n t a t

n i t r o g e n d o e s n o t l e a d t o good c h i r a l i n d u c t i o n i n t h i s o t h e r w i s e r a t h e r g e n e r a l a p p r o a c h t o t3-amino-acids. 'disconnection'

An a l t e r n a t i v e

f o r t h e s y n t h e s i s of B-amino-acids

of t h e 2 , 3 - b o n d s ;

i s by c l e a v a g e

t h e f o r w a r d r e a c t i o n would t h e n i n v o l v e

a l k y l a t i o n of a n e s t e r e n o l a t e , or e q u i v a l e n t , w i t h a 'CH2NH2 s y n t h o n ( 4 8 5 ) . T h i s h a s b e e n a c h i e v e d by c o n d e n s i n g 2 - s i l y l e n o l a t e s w i t h t h e a m i n e ( 4 8 4 ) i n t h e p r e s e n c e of TMSOTf.431

ester Yields

3: Carboxylic Acids and Derivatives

213

a r e g e n e r a l l y b e t t e r t h a n 80% a n d t h e r e a c t i n g s p e c i e s i s p r o b a b l y a n i m i n i u m s a l t , (TMSI2fi:CH2, r e l a t e d t o E s c h e n m o s e r ' s s a l t . aM e t h o x y c a r b a m a t e s c a n be u s e d i n p l a c e o f r e a g e n t ( 4 8 4 ) i n s i m i l a r r e a c t i o n s w i t h 2 - s i l y l e s t e r e n o l a t e s . 4 3 2 A n o t h e r way t o f o r m t h e C ( 2 ) - C ( 3 ) bond i n B - a m i n o - a c i d s i s t o c o n d e n s e l i t h i u m e n o l a t e s o f e s t e r s w i t h t h e t i t a n i u m a l k o x i d e r e a g e n t s ( 4 8 6 ) ; 4 3 3 t h e method is a l s o u s e f u l f o r t h e p r e p a r a t i o n o f B-amino-ketones. The B-aminoa c i d ( 4 8 9 ) , a p r e c u r s o r of B e s t a t i n , h a s b e e n p r e p a r e d u s i n g a s t e r e o c o n t r o l l e d iodocyclocarbamation of t h e a l l y l a m i n e (4871, w h i c h g i v e s l a r g e l y t h e t r a n s - i s o m e r ( 4 8 8 ) .434 T h i s a p p r o a c h a p p e a r s t o have c o n s i d e r a b l e p o t e n t i a l f o r t h e e l a b o r a t i o n of a wide v a r i e t y of r e l a t e d s t r u c t u r e s . The a s y m m e t r i c S h a r p l e s s e p o x i d a t i o n of a l l y l i c a l c o h o l s h a s been extended t o h o m o a l l y l i c a l c o h o l s although o p t i c a l y i e l d s are u n f o r t u n a t e l y rather lower (23-55% .435 U s i n g t h i s m e t h o d , ( - )-y-amino-B-(R)-hydroxybutanoic a c i d (GABOB) ( 4 9 0 ) h a s b e e n s y n t h e s i z e d i n t h r e e s t e p s f r o m b u t - 3 e n - 1 - 0 1 ; t h e f i n a l p r o d u c t h a d a n e n a n t i o m e r i c e n r i c h m e n t of 49%. U n s a t u r a t e d Amino-acids.- F u l l d e t a i l s have been g i v e n o f t h e p r e p a r a t i o n of t h e p h o s p h o n a t e s ( 4 9 1 ) and t h e i r s u b s e q u e n t u s e i n t h e s y n t h e s i s o f d e h y d r o a m i n o - a c i d d e r i v a t i v e s ( 4 9 2 ) .436 I n g e n e r a l , such r e a c t i o n s are l i m i t e d t o non-conjugated a l i p h a t i c or a r o m a t i c a l d e h y d e s , a l t h o u g h i n t h e s e cases y i e l d s are e x c e l l e n t ( 7 0 - 9 0 % ) a n d , a l t h o u g h a v a r i e t y o f bases c a n b e e m p l o y e d , t h e r e a g e n t of c h o i c e is p o t a s s i u m t - b u t o x i d e i n d i c h l o r o m e t h a n e a t -70 O C , t h e u s e o f w h i c h u s u a l l y l e a d s t o a p r e d o m i n a n c e of t h e The u n s a t u r a t e d a m i n o - a c i d (L)-isomers i n t h e products (492). d e r i v a t i v e s ( 4 9 2 ) c a n a l s o be o b t a i n e d by c o n d e n s a t i o n s b e t w e e n a z l a c t o n e s d e r i v e d from N-acetyl- or N-benzoyl-glycine and a n a l d e h y d e , f o l l o w e d by a l c o h o l y s i s . 437- A l t h o u g h o n l y a r o m a t i c a l d e h y d e s a n d c i n n a m a l d e h y d e were u s e d , i m p l y i n g t h a t t h e m e t h o d may n o t be s u c c e s s f u l w i t h a l i p h a t i c a l d e h y d e s , t h i s a p p r o a c h d o e s work w i t h c y c l o h e x a n o n e 1 - p h e n y l i m i n e and c o u l d t h u s p e r h a p s be a p p l i e d t o o t h e r k e t o n e s , t h e r e b y p r o v i d i n g a way a r o u n d o n e o f t h e l i m i t a t i o n s o f t h e f o r e g o i n g Wadsworth-Emmons m e t h o d o l o g y . 436 Readily a v a i l a b l e a-azido-esters (493) can a l s o s e r v e as precursors t o d e h y d r o a m i n o - e s t e r s (492; R 1 = A c ) , f o l l o w i n g t r e a t m e n t w i t h a c e t i c a n h y d r i d e a n d a c a t a l y t i c a m o u n t of r h e n i u m h e p t a s u l p h i d e , Re2S7. 438 S i m i l a r l y , a , 8-unsaturated-a-azido-esters c a n b e t r a n s f o r m e d i n t o esters (492) u s i n g e i t h e r t h i s method or c a t h o d i c r e d u c t i o n . 439

General and Synthetic Methods

214

A d e r i v a t i v e (494) of t h e parent dehydroamino-acid,

d e h y d r o a l a n i n e , h a s b e e n s i m p l y o b t a i n e d by d e h y d r a t i o n o f t h e c o r r e s p o n d i n g S c h i f f b a s e of s e r i n e methyl e s t e r u s i n g 1 , l ' carbonyldi-imidazole. 440

I n c o n t r a s t t o other such N-arylidene

d e r i v a t i v e s , t h i s p a r t i c u l a r analogue is a r e l a t i v e l y s t a b l e s o l i d which s h o u l d prove t o be a u s e f u l s y n t h e t i c i n t e r m e d i a t e as it u n d e r g o e s f a c i l e M i c h a e l a d d i t i o n s and a l s o c o n t a i n s an e a s i l y removable 1-protecting group. acid derivatives

A n o v e l approach t o dehydroamino-

[e.g.( 4 9 6 ) l c o n s i s t s o f a d d i t i o n o f

p h o t o c h e m i c a l l y g e n e r a t e d s i n g l e t o x y g e n , i n t h e p r e s e n c e of t h e b a s e DBU,

t o t h e corresponding imidazoles (4951, i n a Diels-Alder

l i k e p r o c e s s w h i c h i s f o l l o w e d by b a s e - c a t a l y s e d

isomerization.

44 1

A s t h e i n i t i a l products (496) can be subsequently hydrogenated t o d e r i v a t i v e s o f 88-96% e . e .

g i v e c h i r a l amino-acid

u s i n g a rhodium

c a t a l y s t w i t h (E,R)-DIPAMP a s l i g a n d , t h i s a p p r o a c h c o u l d r e p r e s e n t a n e x c e l l e n t method f o r f u l l y p r o t e c t i n g a n a m i n o - a c i d

residue

during peptide synthesis. A b r o a d l y a p p l i c a b l e a n d e n a n t i o s e l e c t i v e r o u t e t o B,runsaturated-a-amino-acids ( 4 9 7 ) f e a t u r e s a n e x t e n s i o n o f S c h d l l k o p f ' s b i s - l a c t i m e t h e r methodology i n which t h e l a t t e r are condensed e i t h e r with an u-silyl-aldehyde or a thioketone; o p t i c a l y i e l d s a r e u s u a l l y h i g h . 442 Racemic a m i n o - a c i d s ( 4 9 7 ; R 3 = H ) c a n b e s i m p l y o b t a i n e d u s i n g a o n e - p o t s e q u e n c e b a s e d on t h e S t r e c k e r

r e a c t i o n , t h e key s t e p b e i n g t h e a d d i t i o n of t r i m e t h y l s i l y l c y a n i d e t o i m i n e s d e r i v e d f r o m a ,@ - u n s a t u r a t e d a l d e h y d e s .443 member o f t h i s g r o u p o f a m i n o - a c i d s ,

L-vinylglycine

R3 = H), can be r e a d i l y o b t a i n e d from L-glutamic

The s i m p l e s t

( 4 9 7 ; R 1 = R2 =

a c i d i n an

o p t i c a l l y p u r e s t a t e by e l i m i n a t i o n o f t h e e l e m e n t s o f f o r m i c a c i d from t h e p r o p i o n i c a c i d s i d e - c h a i n Cu ( OAc ) 2. 444

o f t h e l a t t e r u s i n g Pb(OAc)4-

Racemic v i n y l g l y c i n e h a s b e e n p r e p a r e d f r o m ( L ) - b u t -

2-ene-I , Q - d i o l , 445 t h e key s t e p b e i n g a [ 3 , 3 ] - s i g m a t r o p i c r e a r r a n g e m e n t of t h e t y p e m e n t i o n e d a b o v e i n a n o v e l s y n t h e s i s o f a-amino-acids

[(475)

-

(476)].418

T h e u t i l i t y of t h e r e l a t e d

Claisen rearrangement i n t h e s y n t h e s i s of a-allenyl-a-amino-acid d e r i v a t i v e s was d e s c r i b e d some n i n e y e a r s a g o b y S t e g l i c h a n d c o workers.

However,

t h e v a l u e of

t h i s m e t h o d was s e v e r e l y l i a i t e d

b y p r o b l e m s a t t h e f i n a l d e p r o t e c t i o n s t e p s ; t h e s e h a v e now b e e n o v e r c o m e , 4 4 6 a l l o w i n g t h e m e t h o d t o b e u s e d for t h e p r e p a r a t i o n of t h e free amino-acids

(498).

Homologous a l l e n i c a c i d s , s u c h as t h e

n a t u r a l l y o c c u r r i n g c o m p o u n d (S)-2-aminohexa-4,5-dienoic a c i d (500), c a n be o b t a i n e d i n good y i e l d s (55-60%) w i t h n o r a c e m i z a t i o n

3: Carboxylic Acids and Derivatives

215

0 ( MeO), FycozMe

R~CHO ~

R 2 y c o z M e

NHR'

NHR'

( 4 9 1 ) R'= Boc,Ac or CHO

(492)

YCoZMe

- RzYo N3

( 4 93 1

Bz

b

N

Ph (494)

(497)

(495 )

(496)

(498)

C02Et %NHTs Ar

(503)

H2NLC02H (504)

216

General and Synthetic Methods

[s.

by radical coupling reactions between an alkyl iodide (499)l and triphenylprop-2-ynylstannane, followed by deprotection. 447 A straightforward synthesis of 2-methylidene-2-aminopropanoates ( 5 0 3 ) is based on previous observations and simply involves heating ethyl acrylate (501) with an 1-tosylbenzaldimine (502) in the presence of DABCO. 448 Two new routes to y-allenic GABA (504) have been reported, both of which have 5-allenyl-2-pyrrolidinone as the penultimate compound, prepared either by BF3-catalysed coupling of propargy 1t r imethy Isi lane and 5-ethoxy-2 -pyr r o lid i n ~ n e or ~ ~by a novel example of an aza-Cope rearrangement. '5' Asymmetric Hydrogenation.- Useful discussions have been published on the design and efficiency of a variety of chiral rhodiumphosphine complexes in asymmetric hydrogenations of both !acyldehydro-u-amino-acids and dehydropeptides. 45 I A new addition to the ever-growing list of chiral ligands is (&,&)-g-benzoyl-3,4bis(dipheny1phosphino)pyrrolidine derived in eight steps from (+Itartaric acid. 4 5 2 This stable and rigid ligand, designated 'benzoylpyrphos', in combination with [ R h ( ~ o d ) ~ l B Fproduces ~ the which catalyses the novel complex [Rh(cod)(benzoylpyrphos)]BF4, hydrogenation of a-(acety1amino)cinnamic acid to give (S)-g-acetylphenylalanine with 99% e.e. More significantly, some preliminary experiments have revealed that re-usable catalysts derived from this complex and either Merrifield resin or silica gel can effect the same hydrogenation with >95% e.e., a selectivity which has not previously been achieved in heterogeneous catalysis. Some homogeneous rhodium(1) catalysts containing chiral diphosphine ligands based on 1,l'-binaphthyls have been found to give optical yields of up to 100% in hydrogenations of various a-(acy1amino)acrylic and -cinnamic acids. 453 Modifications of DIOP ligands by the introduction of aryl groups onto the dioxolane ring or by replacing one of the PPh2 groups by PAr2 can result in slightly higher optical yields when compared with the parent ligand, especially in hydrogenations of some dehydropeptides 454 A new diphosphinite ligand, ( 1 ~ , 3 ~ ) - b i s ( d i p h e n y l p h o s p h i n o x y ) 1,3-diphenylpropane, has been reported which, in conjunction with rhodium(I), effects asymmetric hydrogenations of some (Z-)-a(acy1amino)cinnamic acids in 79-84% optical yields.455 However, in general, currently available diphosphinite ligands are only useful in the asymmetric hydrogenation o f certain dehydrodipeptides .456 Optical yields of between 43 and 93% have been observed in

.

217

3: Carboxylic Acids and Derivatives

h e t e r o g e n e o u s h y d r o g e n a t i o n s of d e h y d r o a l a n i n e r e s i d u e s i n c h i r a l t r i p e p t i d e s c o n t a i n i n g a t e r m i n a l p r o l i n e r e s i d u e , u s i n g 5% Pd-C a s c a t a l y s t ; 4 5 7 p o s s i b l y t h i s i d e a c o u l d be e x t e n d e d t o o t h e r , r a t h e r rigid substrates. Amino-acid

Protection.-

An e s t a b l i s h e d t h r e e - s t e p

e s t e r i f i c a t i o n of a-amino-acids

method f o r t h e

c o n s i s t s of p r o t e c t i o n o f t h e amino

f u n c t i o n by e n a m i n e f o r m a t i o n u s i n g e t h y l a c e t o a c e t a t e f o l l o w e d by a l k y l a t i o n of t h e p o t a s s i u m s a l t of t h e c a r b o x y l i c a c i d g r o u p and finally acid hydrolysis.

T h i s o v e r a l l conversion can be performed

much more r a p i d l y a n d i n o n e p o t when a m i x t u r e o f d i m e t h y l Y i e l d s of esters are

s u l p h o x i d e and b e n z e n e is u s e d a s s o l v e n t . 4 5 8

i n t h e r a n g e 67-89% when a d i a l k y l s u l p h a t e o r b e n z y l i c h a l i d e i s u s e d as t h e a l k y l a t i n g r e a g e n t , a n d f u r t h e r m o r e t h e method i s v i r t u a l l y f r e e from r a c e m i z a t i o n drawbacks.

N-Protected

a-amino-

a c i d s can be simply converted i n t o t h e corresponding diphenylmethyl (Dpm) e s t e r s by d i r e c t r e a c t i o n w i t h Dpm d i p h e n y l p h o s p h a t e . 459 No r a c e m i z a t i o n o c c u r s and g i v e n a c h o i c e t h e r e a g e n t w i l l r e a c t p r e f e r e n t i a l l y w i t h t h e a l c o h o l g r o u p of a hydroxy-acid f o r e x a m p l e , t h e p r e p a r a t i o n o f lf-L-serine-g-Dpm pyridy1)ethoxycarbonyl

ether.

allowing, The 2-(2-

(2-Pyoc) f u n c t i o n h a s r e c e n t l y been

e s t a b l i s h e d as an i m p o r t a n t v a r i a n t o f e x i s t i n g m e t h o d s f o r aminogroup protection.

Perhaps predictably,

t h i s f u n c t i o n h a s a l s o been

f o u n d t o b e u s e f u l for t h e p r o t e c t i o n o f c a r b o x y l i c a c i d g r o u p s during peptide synthesis.460 formed u s i n g 2 - p y r i d y l e t h a n o l ,

The s o - c a l l e d DCC,

Pet-esters

(505) are

a n d e i t h e r H O B t o r DMAP a n d a r e

s t a b l e t o a c i d h y d r o l y s i s ( d e p r o t e c t i o n of t-butyl-based functions), t o hydrogenolysis

(removal of benzyl g r o u p s ) , and t o

a m i n e s ( r e m o v a l of Fmoc o r F M - e s t e r s ) . i n much t h e same way a s If-Pyoc

Pet-esters

can be c l e a v e d

g r o u p s by q u a t e r n i z a t i o n u s i n g

m e t h y l i o d i d e f o l l o w e d by t r e a t m e n t w i t h d i e t h y l a m i n e ; t h e r e f o r e t h i s t y p e o f p r o t e c t i n g g r o u p is n o t u s u a l l y c o m p a t i b l e w i t h e i t h e r h i s t i d i n e or methionine residues.

Both t h e p r o t e c t i o n and

d e p r o t e c t i o n s t e p s a r e e s s e n t i a l l y f r e e of r a c e m i z a t i o n .

The

r e l a t e d 2-(diphenylphosphino)ethyl ( D p p e ) g r o u p h a s s i m i l a r l y b e e n u s e d t o p r o t e c t c a r b o x y l i c a c i d f u n c t i o n s a n d o f f e r s much t h e same a d v a n t a g e s as P e t - g r o u p s . 4 6 1

An a l t e r n a t i v e t o t h e e x i s t i n g

(506) u s i n g mild r e d u c i n g a g e n t s i s e l e c t r o c h e m i c a l r e d u c t i o n u s i n g DMF a s s o l v e n t . 4 6 2 T h i s methods f o r t h e c l e a v a g e of (Maql-esters

f u n c t i o n is a l s o u s e f u l f o r N"-protection. a - A m i n o - e s t e r s c a n b e N - m e t h y l a t e d by p r i o r c o n v e r s i o n i n t o t h e

218

General and Synthetic Methods

S c h i f f b a s e or p r e f e r a b l y t h e a m i d i n e d e r i v a t i v e s ( 5 0 7 ) f o l l o w e d b y m e t h y l a t i o n u s i n g d i m e t h y l s u l p h a t e or MeOTf usual base-alkyl

,

and h y d r o l y s i s .463

reactions provide a useful a l t e r n a t i v e t o t h e

These Decker-type

h a l i d e m e t h o d a n d p r o c e e d i n 41-75% y i e l d s w i t h

l i t t l e o r no r a c e m i z a t i o n i f t h e c o n d i t i o n s a r e c a r e f u l l y controlled.

Free a-amino-acids

(508) can be d i r e c t l y alkylated

without racernization t o give only mono-alkylated

p r o d u c t s ( 5 0 9 ) by 464

t r e a t m e n t w i t h a n a l d e h y d e o r k e t o n e a n d NaBH CN i n m e t h a n o l .

3

T h i s r e d u c t i v e a l k y l a t i o n method, previously a p p l i e d t o t h e

is v e r y e f f i c i e n t and i t s g e n e r a l i t y a p p e a r s

s y n t h e s i s of t-amines,

t o b e l i m i t e d m a i n l y by t h e n e c e s s i t y t o a v o i d t h e p r e s e n c e o f o t h e r f u n c t i o n s which react w i t h cyanoborohydride.

Yet a n o t h e r s t a b l e , c r y s t a l l i n e r e a g e n t f o r t h e i n t r o d u c t i o n o f

Na-Boc g r o u p s i s t - b u t y l 2 - p y r i d y l c a r b o n a t e . 4 6 5 hydroxypyridine,

phosgene, and t - b u t y l

w i t h a-amino-acids

a t 20

OC

P r e p a r e d f r o m 2-

alcohol, t h e reagent reacts

i n 50% a q u e o u s DMF c o n t a i n i n g E t N t o

3

g i v e 8 5 - 9 9 % o f t h e NQ-Boc d e r i v a t i v e s w i t h o u t r a c e m i z a t i o n . d e s c r i p t i o n of t h e u t i l i t y o f t h e d i p h e n y l p h o s p h i n y l i n amino-group

p r o t e c t i o n h a s been g i v e n . 466

( 5 1 0 ) a r e o b t a i n e d from a - a m i n o - e s t e r s

f o l l o w e d by e s t e r h y d r o l y s i s .

A full

(Dpp) f u n c t i o n

NQ-Dpp-amino-acids

by t r e a t m e n t w i t h D p p C l

The f u n c t i o n i s s t a b l e t o b a s e a n d

h y d r o g e n o l y s i s b u t is e a s i l y removed u n d e r a v a r i e t y o f a c i d i c c o n d i t i o n s , t h e b e s t o f t e n b e i n g s i x e q u i v a l e n t s of h y d r o g e n c h l o r i d e i n methanol.

A s m e n t i o n e d a b o v e , 4 6 0 t h e 2-(2-

pyridy1)ethoxycarbonyl

(2-Pyoc) group is a l s o v a l u a b l e f o r t h e

p r o t e c t i o n of amino f u n c t i o n s ; t h e 4 - p y r i d y l a p p e a r t o o f f e r similar a d v a n t a g e s . 467

isomer (4-Pyoc) would

A disadvantage a s s o c i a t e d w i t h t h e use of p r o t e c t i n g groups which c a n be v e r y s e l e c t i v e l y c l e a v e d is t h a t t h e y are o f t e n r a t h e r b u l k y (3. Fmoc g r o u p s ) .

A f u n c t i o n a l i t y which does n o t s u f f e r

from t h i s p o t e n t i a l drawback i s t h e a l l y l o x y c a r b o n y l

(Aloe) group

w h i c h c a n b e r e a d i l y r e m o v e d by a l l y 1 t r a n s f e r t o dirnedone u s i n g [Pd(PPh )

same

1

a s c a t a l y s t . 468

A l l y 1 esters c a n be c l e a v e d i n t h e

t h e one obvious d i s a d v a n t a g e of t h e s e groups is t h e i r

i n c o m p a t i b i l i t y w i t h t h e h y d r o g e n o l y s i s c o n d i t i o n s u s e d t o remove benzyl-based protecting groups.

T h e m o r e c o m p l e x Ea-DB-t-Boc

f u n c t i o n [see ( 5 1 1 ) l is r e m a r k a b l y s t a b l e t o a c i d i c h y d r o l y s i s b u t c a n b e r e m o v e d s i m p l y b y w a r m i n g i n m e t h a n o l or e t h a n o l , 4 7 0 a n d h e n c e c o u l d p r o v e o f g r e a t u t i l i t y i n some c a s e s .

e s t e r i-NOPY-Gly-OSu

The a c t i v a t e d

( 5 1 2 ) i s u s e f u l for t h e i n t r o d u c t i o n o f

g l y c i n e r e s i d u e s i n t o p r o t e i n s or p o l y p e p t i d e s u n d e r a q u e o u s

3: Carboxylic Acids and Derivatives

219

3

R1$

0

NHR NHR~

0 (506 1

(505)

-

RYco2Me "Yo'"

R~COR

NH2

(508)

(507)

I HNPPh,

(510)

""y0x:: I

(511 1

(509)

General and Synthetic Methods

220

c o n d i t i o n s a n d f e a t u r e s t h e u s e of t h e i-NOPY a m i n o - p r o t e c t i n g g r o u p ( t h e N - c y c l o h e x y l homologue h a s b e e n r e p o r t e d p r e v i o u s l y ) w h i c h i s r e a d i l y r e m o v e d upon e x p o s u r e t o ammonium h y d r o x i d e . 4 7 1 Some new p r o c e d u r e s f o r t h e r e m o v a l o f known N " - p r o t e c t i n g g r o u p s have been developed. "Q-Z(OMe

)I

N-4-Methoxybenzyloxycarbonyl g r o u p s

c a n be removed u s i n g t o l u e n e - p - s u l p h o n i c

acid i n

a c e t o n i t r i l e ; t h e s o l v e n t a p p e a r s t o a c t as a s c a v e n g e r o f t h e b e n z y l i c c a t i o n s p r o d u c e d d u r i n g d e g r a d a t i o n . 472 A q u e o u s h y d r a z i n e a t pH 7-9 h a s b e e n shown t o b e v e r y e f f e c t i v e f o r t h e r e m o v a l o f (TNP) f u n c t i o n s . 4 7 3 H y d r a z i n e i s a l s o

Na-2,4,6-trinitrophenyl

o f t e n t h e r e a g e n t of c h o i c e f o r t h e c l e a v a g e of p h t h a l i m i d o g r o u p s u s i n g t h e Ing-Manske

procedure.

Racemization can be a drawback

w i t h t h i s method and so an e s s e n t i a l l y r a c e m i z a t i o n - f r e e

m e t h o d ,474

c o n s i s t i n g o f s e q u e n t i a l t r e a t m e n t of t h e p h t h a l i m i d e w i t h s o d i u m b o r o h y d r i d e i n propan-2-01

f o l l o w e d by a c e t i c a c i d , c o u l d l e a d t o

g r e a t e r u s e b e i n g made o f t h i s p r o t e c t i n g g r o u p i n p e p t i d e synthesis.

The r e c e n t l y i n t r o d u c e d c y c l o h e x a d i e n y l - b a s e d

p r o t e c t i n g g r o u p , N"-PChd,

amino

c a n be r e m o v e d by c a t h o d i c r e d u c t i o n i n

a c i d i c m e t h a n o l , a g a i n w i t h o u t r a c e m i z a t i o n . 475 A number o f r e a g e n t s h a v e b e e n i n t r o d u c e d f o r d e b l o c k i n g v a r i o u s

t y p e s of t h i o l p r o t e c t i n g g r o u p s i n c y s t i n e r e s i d u e s .

2-4-

(MBZL) g r o u p s a r e u s u a l l y c l e a v e d u s i n g s o d i u m i n A useful l i q u i d ammonia476 o r h y d r o g e n f l u o r i d e - a n i s o l e

Methoxybenzyl

.

a l t e r n a t i v e i s t o u s e t h e homogeneous e l e c t r o n t r a n s f e r r e a g e n t ,

tris(4-bromophenyl)ammoniumyl w h i c h p r o v i d e s t h e c o r r e s p o n d i n g c y s t i n e d i s u l p h i d e s i n E. 90% y i e l d s . 477 The Boc a n d Z g r o u p s a r e n o t a f f e c t e d by t h i s r e a g e n t .

2-Mpt

(dimethylphosphinothioyl)

p r o t e c t i n g g r o u p s c a n b e r e m o v e d u s i n g p o t a s s i u m f l u o r i d e a n d 18crown-6

i n a c e t ~ n i t r i l e - m e t h a n o lw~h~e~r e a s d i a c e t o x y p h e n y l i o d i n e

,

PhI(OAc)2, is c a p a b l e of o x i d a t i v e l y c l e a v i n g 2-triphenylrnethyl ( T r t ) , 2-diphenylmethyl

(Dpm), a n d 2 - a c e t a m i d o m e t h y l

(Acm)

f u n c t i o n s , i n e a c h case g i v i n g t h e o p t i c a l l y p u r e c y s t i n e i n 65-97% y i e l d s , a n d l e a v i n g N"-Boc a n d Z g r o u p s i n t a c t . 4 7 9 A new m e t h o d f o r m a s k i n g t h e i n d o l i c n i t r o g e n i n t r y p t o p h a n i s by c o n v e r s i o n t o t h e Nin-Boc d e r i v a t i v e by t r e a t m e n t w i t h Boc20-DMAP. 480 C a r e f u l a c i d i c c l e a v a g e i s p o s s i b l e i n t h e p r e s e n c e o f o t h e r Na-Boc g r o u p s . F i n a l l y , t h e t-butoxymethyl

group h a s been found t o be eminently 48 1

s u i t a b l e f o r b l o c k i n g t h e i m i d a z o l e NH f u n c t i o n i n h i s t i d i n e .

221

3: Carboxylic Acids and Derivatives References 1 2

3 4 5

6

7 8 9 10

F.Serratosa, Acc. Chem. Res., 1984, 17,2. H.C.Brown and T.Imai, J. Org. Chem., 1984, 9, 892. H.Ahlbrecht and W.Franung, Chem. Ber., 1984, 117, 1. P.Coutrot and A.E1 Gadi, Synthesis, 1984,.511 C.A.Horiuchi and J. Y.Satoh, Chem. Lett,, 1984, 1509 K.Tamao, M.Kumada, and K.Maeda, Tetrahedron Lett., 7984, 25, 321. G.Green, W.P.Griffith, D.M.Hollinshead, S.V.Ley, and M.Schroder , J Soc.Perkin Trans. 1 , 1984, 681. Y.Hamada and T.Shioiri, Org. Synth., 1984, 62, 191. E.D.Laganis and B.L.Chenard, Tetrahedron Lett., 1984, 25, 5831. M.Schneider, N.Enge1, and H.Boensmann, Angew. Chem., Int. Ed. Engl 23, 66. See also T.Kitazume, T.Sato, and N.Ishikawa, Chem. Lett.,

Chem .

1984,

984,

1811. 11

M.Schneider, N.Enge1, P.Honicke, G-Heinemann, and H.Gorisch, Angew. Chem., Int. Ed. Engl., 1984, 23, 67; M.Schneider, N-Engel, and pp.64,66; G.Sabbioni, M.L.Shea, and J.B.Jones, H-Boensmann, J. Chem. SOC., Chem. Commun., 1984, 236; S.Kobayashi, K.Kamiyama, T.Iimori, and M.Ohno, Tetrahedron Lett., 1984, 25, 2557; H.-J.Gais and K.L.Lukas, Angew. Chem., Int. Ed. Engl., 1984, CF142. C.J.Francis and J.B.Jones, J. Chem. S O C . , Chem. Commun., 1984,. 579: A.S.Gopalan and C.J.Sih, Tetrahedron Lett., 1984, 25, 5235. Y .Nagao, T. Inoue, E.Fujita, S.Tereda, and M.Shiro, Tetrahedron, 1984, 5, 1215. J.L.Belletire, E.G.Spletzer, and A.R.Pinhas, Tetrahedron Lett., 1984, 2, 5969. R.M.Habib, C.-Y.Chiang, and P.S.Bailey, J. Org. Chem., 1984, 9, 2780. T.R.Kelly and A.Arvanitis, Tetrahedron Lett., 1984, 25, 39. K.-Y.Ko, W. J.Frazee, and E.L.Elie1, Tetrahedron, 1984, 40, 1333; J,E.Lynch and E.L.Elie1, J. Am. Chem. SOC., 1984, 106,2943. A.Deberly, G.Boireau, and D.Abenhaim, Tetrahedron Lett., 1984, 25, 655. See also A.Solladie-Cavallo and J.Suffert, M.,p.1897. J.-E.Dubois and G.Axiotis, Tetrahedron Lett., 1984, 25, 2143; J.-E.Dubois, G-Axiotis, and E.Bertounesque, p.4655. S.G.Davies, I.M.Dordor, J.C.Walker, and P.Warner, Tetrahedron Lett., 1984, 25, 2709; S.G.Davies, I.M.Dordor, and P.Warner, J. Chem.. SOC., Chem. Commun., 1984, 956. D.P.Curran, S.A.Scanga, and C.J.Fenk, J. Org. Chem., 1984, 9, 3474. J.Mulzer, P.DeLasalle, A.Chucholowski, LJ-Blaschek,G.Bruntrup, I.Jibri1, and G .Huttner , Tetrahedron, 1984, 5, 221 1. M.Braun and R.Devant, Tetrahedron Lett., 1984, 25, 5031. R.Ramage, G.J.Griffiths, F.E.Shutt, and J.N.A. Sweeney, J. Chem. SOC., Perkin Trans. 1 , 1984, 1531. 2857. M.Miyashita, R.Yamaguchi, and A.Yoshikoshi, J. Org. Chem., 1984, 9, D.El-Abed, A.Jella1, and M.Santelli, Tetrahedron Lett., 1984, 25, 4503. M.Kawashima and T.Fujisawa, Chem. Lett., 1984, 1851. J.Harada, Y.Sakakibara, A.Kunai, and K.Sasaki, Bull. Chem. SOC. Jpn., 1984, 57, 611. D.Min-zhi, T.Yong-ti, and X.Wei-hua, Tetrahedron Lett., 1984, 25, 1797. M.F.Salomon, S.N.Pardo, and R.G.Salomon, J. Am. Chem. SOC., 1984, 106, 3797; J. Or . Chem., 1984, 2, 2446; G.Jenner, M.Papadopoulos, J.Jurczak,nd -trahedron Lett., 1984, 25, 5747; J.-F.Roudier and A.Foucaud, ibid, p.4375. J. P .Benner , G .B.Gill, S.J. Parrott , and 8.Wallace, J. Chem. SOC , Perkin Trans. 1 , 1984, 331. R.E.Ireland and M.D.Varney, J. Am. Chem. SOC., 1984, 106,3668. T.Fujisawa, K.Tajima, M.Ito, and T.Sato, Chem. Lett., 1984, 1169; M.J.Kurth and C.-M.Yu, Tetrahedron Lett., 1984, 25, 5003. T.Fujisawa, K.Tajima, and T.Sato, Chem. Lett., 1984, 1669; M.Nagatsuma, F.Shirai, N.Sayo, and T.Nakai, p.1393. See also J.K.Cha and S.C.Lewi, Tetrahedron Lett., 1984, 25, 5263.

u,

12 13 14 15

16 17 18

19 20

21 22

23 24 25 26 27

28 29 30

31 32 33 34

u.,

.

w.,

222 35 36 37 38 39

General and Synthetic Methods T-Fujisawa, K.Umezu, and M.Kawashima, Chem. Lett., 1984, 1795. A.I.Meyers and P.D.Panegrau, Tetrahedron Lett., 1984, 25, 2941. G.A.Artamkina, A.A.Grinfel'd, and I.P.Beletskaya, Tetrahedron Lett., 1984, 25, 4989. G.Silvestri, S.Gambino, G.Filardo, and A.Gulotta, Angew. Chem., Int. Ed. Engl., 1984, 23, 979. C.Giordano, G.Castaldi, and F.Uggeri, Angew. Chem., Int. Ed. Engl,, 1984, 23, 413. T.Wollmann and B.Franck, Angew. Chem., Int. Ed. Engl., 1984, 23, 226. S.Uemura, S.Fukuzawa, T.Yamauchi, K.Hattori, S.Mizutaki, and K.Tamaki, J. Chem. SOC., Chem. Commun., 1984, 426. Y.Tamura, Y.Shirouchi, and J.Haruta, Synthesis, 1984, 231. E.C.Taylor, R.A.Conley, A.H.Katz, and A.McKillop, op, J. Org. Chem., Chz., 1984, 3840. R.P.Kopinski, J.T.Pinhey, and B.A.Rowe, Aust. J. Chem., 1984, 37, 1245. For a review of the use of diaryliodonium salts in this transformation, see A.Varvoglis, Synthesis, 1984, 709. C.Riichardt, H.Gartner, and U.Salz, Angew. Chem., Int. Ed. Engl., 1984, 23, 162; U.Salz and C.Ruchardt, Chem. Ber., 1984, 3,3457. G.Schmitt, N.D.An, J.-P. Poupelin, J.Vebre1, and B. Laude, Synthesis, 1984, 758. F.Bigi, G.Casiraghi, G.Casnati, and G.Sartori, J. Chem. S O C . , Perkin Trans. 1 , 1984, 2655. R.Grigg and H.Q.N.Gunaratne, J. Chem. SOC. , Chem. Commun., 1984, 661. C.D.Buttery, D.W.Knight, and A.P.Nott, J. Chem. SOC., Perkin Trans. 1 , 1984, 2839. D.P.Stack and R.M.Coates, Synthesis, 1984, 434. For a review, see 0.DeLucchi and G.Modena, Tetrahedron, 1984, 5, 2585. Y.Kita, S.Akai, M.Yoshigi, Y-Nakajima, H.Yasuda, and Y.Tamura, Tetrahedron Lett., 1984, 6027. B.Giese and G.Kretzschmar, Chem. Ber., 1984, 117,3175. O.Toussaint, P.Capdevielle, and M.Maumy, Tetrahedron, 1984, 40, 3229; Tetrahedron Lett., 1984, 25, 3819. B.H.R.Barton, D.Bridon, and S.Z.Zard, Tetrahedron Lett., 1984, 25, 5777. D.H.R.Barton, D.Crich, and W.B.Motherwel1, J. Chem. SOC., Chem. Commun., 1984, 242. D.H.R.Barton, Y.Herv6, P.Potier, and J.Thierry, J. Chem. SOC., Chem. Commun., 1984, 1298. S.Itoh, N.Kato, Y.Ohshiro, and T.Agawa, Tetrahedron Lett., 1984, 25, 4753. R.Pellicciari, B.Natalini, S.Cecchitti, and S.Santucci, Tetrahedron Lett., 1984, 2, 3103. D.Hermeling and H.J.Schafer, Angew. Chem., Int. Ed. Engl., 1984, 23, 233; M.Huhtasaari , H. J.Schafer , and L.Becking, g . , p .980. For a review of the Kolbe reaction, see M.M.Baizer, Tetrahedron, 1984, 40, 935. Chem 1984, 9, 1732. N-Rabjohn, W.L.Cranor, and C.M.Schofield J Or T.L.Capson and C.D.Poulter, Tetrahedron t e e & : 3515. S.Kajigaeshi, T.Nakagawa, S.Fujisaki, A.Nishida, and M.Noguchi, Chem. Lett., 1984, 713. G.M.Loudon, A.S.Radhakrishna, M.R.Almond, J.K.Blodgett, and R.H.Boutin, J. Org. Chem., 1984, 4272; R.H.Boutin and G.M.Loudon, g., p.4277. M.J.Cohen and E.McNelis, J. Org. Chem., 1984, 5, 515. 983. C-Blankenship and L.A.Paquette, Synth. Commun., 1984, L.N.Pridgen, S.C.Shilcrat, and I.Lantos, Tetrahedron Lett., 1984, 25, 2835. M.Kimura, S.Matsubara, and Y.Sawaki, J. Chem. SOC., Chem. Commun., 1984, 1619. H-Mastalerz. J. Ora. Chem.., 1984. 49. 4092. E.W.Logusch; Tetrahedron Lett ., i984; 25, 4195. S.Kim, J.I.Lee, and Y.K.Ko, Tetrahedron Lett., 1984, 25, 4943. M.Ballester-Rodes and A.L.Palomo-Coll, Synth. Commun., 1984 9 14, 51 5. S.Murata, Bull. Chem. SOC. Jpn., 1984, 57, 3597. See also O X i t sun0bu , A.Takemasa, and R.Endo, Chem. Lett., 1984, 855. -'

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

c,

s,

2,

14,

,

223

3: Carboxylic Acids and Derivatives 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101

102 103 104 105 106 107

F.E.Carlon and R.W.Draper, Synth. Commun., 1984, 14, 725. E.Binderup and E.T.Hansen, Synth. Commun., 1984, 857. S.Kim and J.I.Lee, J. Org. Chem., 1984, 1712. S.Hashimoto, M.Hayashi, and R.Noyori, Bull. Chem. SOC. Jpn., 1984, 57, 1431. S.E.Fry and N.J.Pienta, J. Org. Chem., 1984, 2, 4877. J:M.Renga and P.-C.Wang, Synth. Commun., 1984, 11(, 77. E.J.Corey and B-Samuelsson, J. Org. Chem., 1984, 4735. See also Y.Masuyama, M.Takahashi, and Y.Kurusu, Tetrahedron Lett., 1984, 25, 4417. 1.Reichelt and H.-U.Reissig, Liebigs Ann. Chem., B. A.Feit , R .Elser, Y .Melamed , and I.Golc and L.K.Sydnes and S.Skare, Can. J. Chem., 1984, 62, i C.Gluchowski, T.Tiner-Harding, J.K.Smith, D.E.Berbreiter, and M.Newcomb, J. Org. Chem., 1984, 9, 2650. S.De Lombaert and L.Ghosez, Tetrahedron Lett., 1984, 25, 3475. A.Zapata and C.Acuna, Synth. Commun., 1984, 5, 27. K.Hofmann and G.Simchen, Liebigs Ann. Chem., 1984, 39. V.Fiandanese, F.Naso, and A.Scilimati, Tetrahedron Lett., 1984, 25, 1187. N.Ono, A.Kmimura, and A.Kaji, Synthesis, 1984, 226. 1.Fleming and T.W.Newton, J. Chem. S O C . , Perkin Trans. 1 , 1984, 1805; 1.Fleming and D.Waterson, p . 1809. B.H.Lipshutz, R.S.Wilhelm, and J.A.Kozlowski, Tetrahedron, 1984, 40, 5005 See also S.H.Bertz and G.Dabbagh, J. Org. Chem., 1984, 9, 1119. R.D.Pergola and P.DiBattista, Synth. Commun., 1984, 121. A-ABel-Magid, I.Lantos, and L.N.Pridgen, Tetrahedron Lett., 1984, 25, 327 3. K.E.Hashem, J.B.Woel1, and H.Alper, Tetrahedron Lett., 1984, 25, 4879; J.B.Woel1 and H.Alper, p.3791. G.C.Tustin and R.T.Hembre, J. Org. Chem., 1984, 49, 1761. J.Kang, W.Cho, and W.K.Lee, J. Org. Chem., 1984,-2, 1840. B.M.Trost and M.-H.Hung, J. Am. Chem. SOC., 1984, 106,6837. B.M.Trost and A.Brandi, J. Org. Chem., 1984, 9, 4811. D.Ferroud, J.P.Genet, and J.Muzart, Tetrahedron Lett., 1984, 25, 4379. D.Djahanbini, B.Cazes, and J.Gore, Tetrahedron Lett., 1984, 25, 203. M.Ahmar, B.Cazes, and J.Gore, Tetrahedron Lett., 1984, 25, 4505. T.Hayashi, M.Konishi, and M.Kumada, J. Chem. SOC., Chem. Commun., 1984, 1 07. K.Hiroi, R.Kitayama, and S.Sato, Chem. Lett., 1984, 929. B.R.Chhabra, M.L.Bolte, and W.D.Crow, Aust. J. Chem., 1984, 37, 1795. C.-C.Chan and X.Huang, Synthesis, 1984, 224. M.Yamaguchi, M.Tsukamoto, S.Tanaka, and I.Hirao, Tetrahedron Lett., 1984, 25, 5661; M.Yamaguchi, M.Tsukamoto, and I.Hirao, Chem. Lett., 1984, 375. J.K.Gawronski, Tetrahedron Lett., 1984, 25, 2605. F.A.Davis, L.C.Vishwakarma, J.M.Billmers, and J. Finn, J. Org. Chem., 1984 , 49. 3241. H.C.Brown, G.G.Pai, and P.K.Jadhav, J. Am. Chem. SOC., 1984, 1531. M.Larchev&que and Y.Petit, Tetrahedron Lett., 1984, 25, 3705. O.Piccolo, L.Filippini, L.Tinucci, E.Valoti, and A.Citterio, Helv. Chim. Acta, 1984, 9, 739; A.Citterio, M.Gandolfi, O.Piccolo, L-Filipptni, L.Tinucci, and E.Valoti, Synthesis, 1984, 760. M.T.Reetz, Angew. Chem., Int. Ed. Engl., 1984, 23, 556. T.Oishi and T.Nakata, Acc. Chem. Res., 1984, 17,338. C.J.Sih and C.-S.Chen, Angew. Chem., Int. Ed. Engl., 1984, 23, 570. T.Fujisawa, T.Itoh, and T.Sato, Tetrahedron Lett. , 1984, 25, 5083. K.Nakmura, K.Ushio, S.Oka, A.Ohno, and S.Yasui, Tetrahedron Lett., 1984, 25, 3979. R.W.Hoffmann, W.Ladner, and W.Helbig, Liebigs Ann. Chem., 1984, 1170. D.W.Brooks, N.Castro de Lee, and R.Peevey, Tetrahedron Lett., 1984, 25, 4623. D.Seebach , P. Renaud , W. B. Schweizer , M. F .Z&ger, and M.- J.Brienne , Helv. Chim. Acta, 1984, 9, 1843. D.Seebach, M.F.Ziiger, F.Giovannini, B.Sonnleitner, and A-Fiechter, Angew. Chem., Int. Ed. Engl., 1984, 23, 151.

2,

2,

u.,

111,

u.,

,~

108 109 110 111 112

113 114 115 116 117 118 119

E,

5,

General and Synthetic Methods

224 120

121 122 123 124 125

126 127

128 129

R.Bernardi, R.Cardillo, and D.Ghiringhelli, J. Chem. S O C . , Chem. Commun., 1984, 460. D.Seebach and M.F.ZUger, Tetrahedron Lett., 1984, g,2747. For an application, see K.Mori and H.Watanabe, Tetrahedron, 1984, 5, 299. S.Saito, T.Hasegawa, M.Inaba, R.Nishida, T.Fujii, S.Nomizu, and T.Moriwake, Chem. Lett., 1984, 1389. A.Bernardi, L.Colombo, C.Gennari, and L.Prati, Tetrahedron, 1984, 5, 3769. 1269. G.Frater, U.Muller, and W.Gunther, Tetrahedron, 1984, C.H.Heathcock, M.C.Pirrung, S.D.Young, J.P.Hagen, E.T.Jarvi, U.Badertscher, H.-P.Marki, and S.H.Montgomery, J. Am. Chem. S O C . , 1984, 106, 8161. R.Metternich and R.W.Hoffmann, Tetrahedron Lett., 1984, 25,4095. N .Tsuboniwa , S .Matsubara , Y .Mor izawa , K .Oshima , and H.Nozaki , Tetrahedron Lett., 1984, 25, 2569; Bull. Chem. S O C . Jpn., 1984, 57, 3242. K a m o t o , K-Maruyama, and K.Matsumoto, Tetrahedron Lett ., 1984, 25, ‘075. W.Bernhard, I.Fleming, and D.Waterson, J. Chem. S O C . , Chem. Commun., 1984, p.29 ; Y.Yamamoto and 28 ; I.Fleming, R .Henning, and H.Plaut , p. 904. K.Maruyama, S.Murai, T.Toki, S.Suzuki, and N.Sonoda, J. Am. Chem. SOC., 1984, 6093. D.Villemin, P.Cadiot, and M.Kuetegan, Synthesis, 1984, 230. M.Tanaka, T-Kobayashi, and T.Sakakura, Angew. Chem., Int. Ed. Engl., 1984, 697. 23, 518; M.Matsumoto and S.Ito, Synth. Commun., 1984, K T - R e e t z , H.Heimbach, and K.Schwellnus, Tetrahedron Lett., 1984, 25, 51 1. J.M.Hook, Synth. Commun., 1984, 83. D.Horne, J.Gaudino, and W.J.Thompson, Tetrahedron Lett., 1984, 3529. O.Itoh, T.Nagata, I.Nomura, T.Takanaga, T.Sugita, and K.Ichikawa, Bull. Chem. SOC. Jpn., 1984, 57, 810. B.Caro, J.-Y.LeBihan, J.-P.Guillot, S.Top and G.Jaohen, J. Chern. SOC., Chem. Commun., 1984, 602. J.Leroy and C.Wakselman, Synth. Commun., 1984, 14, 239. S.R.Wi1son and M.F.Price, J. Org. Chem., 1984, 722. Y.Tanabe and T.Mukaiyama, Chem. Lett., 1984, 1867. J.L.Luche, C.Petrier, and C.Dupuy, Tetrahedron Lett., 1984, 25, 753. M.Kodpinid and Y.Thebtaranonth, Tetrahedron Lett., 1984, 25, 2509. J.Hellou, J.F.Kingston, and A.G.Fallis, Synthesis, 1984, 1014. Y.Tohda, T.Kawashima, M.Ariga, R.Akiyama, H.Shudoh, and Y.Mori, Bull. Chem. SOC. Jpn., 1984, 57, 2329. J.Tsuji, I.Minami, and I.Shimizu, Tetrahedron Lett., 1984, 25, 51 57. 293. P.F.Schuda and B-Bernstein, Synth. Commun., 1984, J.A.M.van den Goorbergh and A.van der Gen, Recl.: J. Roy. Neth. Chem. S O C . , 1984, 2,90. R.P.Kozyrod and J.T.Pinhey, Org. Synth., 1984, 62, 24. M.G.Moloney and J.T.Pinhey, J. Chem. S O C . , Chem. Commun., 1984, 965. D.Enders, H-Eichenauer, U.Baus, H.Schubert, and K.A.M.Kremer, Tetrahedron, 1345. 1984, K.Tomioka, K.Ando, Y.Takemasa, and K.Koga, J. Am. Chem. SOC., 1984, 2718; Tetrahedron Lett., 1984, 25, 5677. H.Brunner and B.Hammer, Angew. Chem., Int. Ed. Engl., 1984, 23, 312. S.D.Lee, T.H.Chan, and K.S.Kwon, Tetrahedron Lett., 1984, 25, 3399. J.Tsuji, Synthesis, 1984, 369. E.Kunke1, I.Reichelt, and H.-U.Reissig, Liebigs Ann. Chem., 1984, 802; K-Saigo, H.Kurihara, H.Miura, A.Hongu, N.Kubota, H.Nohira, and M.Hasegawa, 787; 1.Reichelt and H.-U-Reissig, Liebigs Ann. Synth. Commun., 1984, Chem., 1984, 828. m i c h e l t and H.-U.Reissig, Liebigs Ann. Chem., 1984, 820. H.-U-Reissig and I.Reichelt, Tetrahedron Lett., 1984, 25, 5879. J. Shimada, K .Hashitnoto, B. H.Kim, E. Nakamura , and I.Kuwajima, J. Am. Chem. SOC., 1984, 1759. E.Nakamura and I.Kuwajima, J. Am. Chem. S O C . , 1984, 3368. K.K.Sharma and K.B.G.Torssel1, Tetrahedron, 1984, 40, 1085. A.I.Meyers, M.Harre, and R.Garland, J. Am. Chem. S G . , 1984, 1146. M-Miyashita, T.Yanami, T.Kumazawa, and A.Yoshikoshi, J. Am. Chem. S O C . , 2149. 1984,

s,

w.,

u,

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

106,

2,

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3,

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2,

c,

2,

2,

156 157 158 159

160 161 162

106,

106,

106,

106,

3: Carboxylic Acids and Derivatives 163

225

J.E.Baldwin, R.M.Adlington, J.C.Bottaro, A.U.Jain, J.N.Kolhe, M.W.D.Perrv. -. and I.M. Newington, J. ?hem: SOC., Chem. Commun., 1984, 1095. T.V.RajanBabu, J. Org. Chem., 1984, 2083. H.Nishiyama, K.Sakuta, and K.Itoh, Tetrahedron Lett ., 1 T.Siwapinyoyos and Y.Thebtaranonth, Tetrahedron Lett., R.M.Coates and S.J.Hobbs, J. Org. Chem., 1984, 3, 140. P. G.Baraldi, M.Guarneri, G.P. Pollini, D.Simoni, A.Barco, and S.Benet ti, J. Chem. SOC.. Perkin Trans. 1., 1984. 2501. 0-Tsuge, S.Kanemasa, and Y.Ninomiya, Chem. Lett., 1984, 1993. P.Knoche1 and J.F.Normant, Tetrahedron Lett., 1984, 25, 1475. D.H.R.Barton and D.Crich, Tetrahedron Lett., 1984, 3, 2787. C.Papageorgiou and C.Benezra, Tetrahedron Lett., 1984, 25, 1303. L.Banf i , A.Bernardi, L. Colombo, C.Gennari, and C.Scolastico, J. Org. Chem., 1984, 3, 3784. J.Villieras and M.Rambaud, Synthesis, 1984, 406; V.T.Ravikumar, S-Swaminathan, and K.Rajago-Tetrahedron Lett., 1984, 25, 6045. P.Callant, L.D’Haenens, E.Van der Eycken, and M.Vandewalle, Synth. Commun., 1984, 163. See also F.Barbot, E.Paraiso, and Ph.Miginiac, Tetrahedron Lett., 1984, 12, 4369. Z.Mouloungui, M.Delmas, and A.Gaset, Synth. Commun., 1984, 111, 701. M.A.Blanchette, W. Choy, J.T.Davis, A.P.Essenfeld, S.Masamune, W. R.Roush, and T.Sakai, Tetrahedron Lett., 1984, 25, 2183. G.Etemad-Moghadam and J.Seyden-Penne, Tetrahedron, 1984, 5, 51 53. R.Tanikaga, T.Tamura, Y.Nozaki, and A.Kaji, J. Chem. SOC., Chem. Commun., 1984, 87. M.Shimizu, R.Ando, and I.Kuwajima, J. Org. Chem., 1984, 1230. N.Ono, I.Hamamoto, and A.Kaji, J. Chem. SOC., Chem. Commun., 1984, 274. K-Hayakawa, Y.Kamikawaji, A.Wakita, and K.Kanematsu, J. Org, Chem., 1984, 49, 1985. J.E.Baldwin, D.R.Kelly, and G.B.Ziegler, J. Chem. Soc., Chem. Commun., 1984, 133. F.K.Sheffy, J.P.Godschalx, and J.K.Stille, J . Am. Chem. SOC., 1984, 106, 4833. J-Tsuji and H.Nagashima, Tetrahedron, 1984, 2699; T.Itahar-a and F.Ouseto, Synthesis, 1984, 488. 468. B.M.Trost and C.R.Self, J. Org. Chem., 1984, R.C.Larock and K.Narayanan, J. Org. Chem., 1984, 9, 3411. M.Alerdice, F.W.Sum, and L.Weiler, Org. Synth., 1984, 62, 14. M.Alerdice, C.Spino, and L.Weiler, Tetrahedron Lett., 1984, 25, 1643. See also F.L.Harris and L.Weiler, ibid., p.1333. For a review, see D.J.Ager, Synthesis, 1984, 384. G.L.Larson, C.Fernandez de Kaifer , R.Seda, L.E. Torres, and J. R. Ramirez, J. Org. Chem., 1984, 3385. L.Strekowski, M.Visnick, and M.A.Battiste, Tetrahedron Lett., 1984, 25, 5603. Y.Ikeda and H.Yamamoto, Tetrahedron Lett., 1984, 25, 5181. S.Tsuboi, A.Kuroda, T.Masuda, and A.Takeda, Chem. Lett., 1984, 1541. T.Ibuka, G.-N.Chu, and F.Yoneda, Tetrahedron Lett., 1980, 25, 3247. 1341. J.Tsuji, K.Sato, and H.Okumoto, J. Org. Chem., 1984, P.Gosselin, C.Maignan, and F.Rouessac, Synthesis, 1984, 876. P.Lerouge and C.Paulmier, Tetrahedron Lett ., 1984, 25, 1983; 1987. J.Tsuji, K.Takahashi, I.Minami, and I.Shimizu, Tetrahedron Lett., 1984, 25, 4783. J.P.Genet and D.Ferroud, Tetrahedron Lett., 1984, 25, 3579. A.B.Smith 111, B.H.Toder, and S.J.Branca, J. Am. Chem. S O C . , 1984, 106, 3995 ; A.B.Smith 111, B. H. Toder, R. E. Richmond, and S.J.Branca, ibid., p.4001 . M-Ohshima, M-Murakami, and T.Mukaiyama, Chem. Lett ., 1984, 1535. M.T.Reetz, P.Walz, F.Hubner, S.H.Huttenhain, H.Heimbach, and K.Schwellnus, Chem. Ber., 1984, 117,322. T.N.Wheeler, J. Org. Chem., 1984, 9, 706. T.Shono, S.Kashimura, and H.Nogusa, J. Org. Chem., 1984, 9, 2043. ’

164 165 166

167 168

9,

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169 170 171 172 173 174 175 176

177 178 179 180 181 182 183 184 185

186 187 188 189

190 191 192 193 194 195 196 197 198 199 200 20 1 202 203 204 205

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General and Synthetic Methods

226 206 20 7 20 8 20 9 21 0 21 1 21 2 21 3 21 4 21 5 21 6 21 7 21 8 21 9 220 221 222 223 224 225 226 227 228 229

232 233 234 235 23 6 237 238 239 240 24 1 242 24 3 24 4 24 5

H.Alper, S.Antebi, and J.B.Woel1, Angew. Chem., Int. Ed. Engl., 1984, 23, 732. R.A.Head and A.Ibbotson, Tetrahedron Lett., 1984, 25, 5939. G.P.Stahly, B.C.Stahly, -na Org. Chem., 1984, 49, 578. M.Makosza and J.Winiarski, J. Org. Chem., 1984, 3,1494. T.A.Carpenter , G.E. Evans , F.J. Leeper, J. Staunton, and M. R-Wilkinson, J. Chem. SOC., Perkin Trans. 1 , 1984, 1 0 4 3 ; F.J.Leeper and J.Staunton, ibid., p.1053. P.W.Rabideau, D.M.Wetze1, and D.M.Young, J. Org. Chem., 1 9 8 4 , 1544. H.-J.Gais, Angew. Chem., Int. Ed. Engl., 1 9 8 4 , 143. G.Boche and J.Bigalke, Tetrahedron Lett., 1984, 25, 955. A.S.Kende, P. Fludzinski, J.H.Hil1, W. Swenson, and J. Clardy , J. Am. Chem. SOC., 1984, 106,3551. R.W.Lang and H.-J.Hansen, Org. Synth., 1984, 62, 202. S.Cacchi, E.Morera, and G.Ortar, Tetrahedron Lett., 1984, 25, 2271. L.E.Rice, M.C.Boston, H.O.Finklea, B.J.Suder, J.O.Frazier, and T-Hudlicky, J. Org. Chem., 1984, 1845. F.Orsini and F.Pelizzoni, Synth. Commun., 1984, 169. F.Orsini, F.Pelizzoni, and G.Ricca, Tetrahedron, 1 9 8 4 , 5, 2781 ; F.Orsini 805. and F.Pelizzoni, Synth. Commun., 1984, T.Fujisawa, M.Kawashima, and S.Ando, Tetrahedron Lett., 1984, 2 5 , 3213. S.Hackett and T.Livinghouse, Tetrahedron Lett., 1 9 8 4 , 25, 3 5 3 9 7 B.J.Banks, A.G.M.Barrett, and M.A.Russel1, J. Chem. SOC., Chem. Commun., 1984, 670. R.K.Dieter, Y.J.Lin, and J.W.Dieter, J. Org. Chem., 1984, 9, 3183. R.Antonioletti, M-D'Auria, A.DeMico, G.Piancatelli, and A-Scettri, Synthesis, 1984, 280. C-Gennari, A.Bernardi, S.Cardani, and C.Scolastico, Tetrahedron, 1984, 40, 4059. J.S.Bradshaw and B. A.Jones, Chem. Rev., 1984, 17. E.J.Corey and S.W.Wright, Tetrahedron Lett., 1984, 25, 2639. I.Thomsen, K.Clausen, S.Scheibye, and S.-O.Lawesson, Org. Synth., 1984, 62, 158. B.Yde, N.M.Yousif, U.Pedersen, I.Thomsen, and S.-O.Lawesson, Tetrahedron, 1984, 40, 2 0 4 7 ; N.M.Yousif, U.Pedersen, B.Yde, and S.-O.Lawesson, p.2663; M.Yokoyama, Y.Hasegawa, H.Hatanake, Y.Kawazoe, and T.Imamoto, Synthesis, 1984, 827. K.Clausen, M.Thorsen, S.-O.Lawesson, and A.F.Spatola, J. Chem. SOC., Perkin Trans. 1 , 1984, 785. For a review of carbon disulphide chemistry see M.Yokoyama and T.Imamoto, Synthesis, 1984, 797. D.Seyferth and R.C.Hui, Tetrahedron Lett., 1984, 25, 2623. S.Masson, V.Mothes, and A.Thuillier, Tetrahedron, 1984, E, 1573. K.R.Lawson, A.Singleton, and G.H.Whitham, J. Chem. SOC., Perkin Trans. 1 , 1984. 859: 865. For a review, see D.Hoppe, Angew. Chem., Int. Ed. Engl., 1984, 3, 932. D.Hoppe and F.Lichtenberg, Angew. Chem., Int. Ed. Engl., 1984, 3, 239. H. Roder , G.Helmchen, E.-M.Peters, K.Peters, and H.-G.von Schnering, Angew. Chem., Int. Ed. Engl., 1984, 2, 898. G.Zweife1 and G.Hahn, J. Org. Chem., 1984, 9, 4565. M.M.Midland, A. Tramontano, A.Kazubski, R.S.Graham , D.J. S.Tsai, and D.B.Cardin, Tetrahedron, 1984, 4 0 , 1371. R.Noyori, I.Tomino, M.Yamada, and M.Nishizawa, J. Am. Chem. SOC., 1984, 106, 6717. J.P.Vigneron, R.M&ic, M.Larchev&que, A.Deba1, J. Y .Lallemand, G.Kunesch, P.Zagatti, and M.Gallois, Tetrahedron, 1984, 5, 3521. C.NAjera, M.Yus, and D-Seebach, Helv. Chim. Acta, 1 9 8 4 , 67,289. E.Moret and M.Schlosser, Tetrahedron Lett., 1984, 2 5 , 4491. See also G.Costisella, H.Gross and H.Schick, Tetrahedron, l g 4 , 40, 733. A.Saito, H.Matsushita, and H.Kaneko, Chem. Lett., 1984, 729. A.Saito, H.Matsushita, and H.Kaneko, Chem. Lett., 1984, 5 9 1 . See also H.Zamarlik, N.Gnonlonfoun, and F.Rouessac, Can. J. Chem., 1984, 62, 2326.

-

c,

2,

9,

2,

2,

84,

m.,

~

227

3: Carboxylic Acids and Derivatives 246 247 248 249 250 25 1

252 253 254

255 256 257 258 259 260 26 1 262

263 264

265 266 267

268 269 270 27 1 272 273 274 275 276

T.K.Chakraborty and S.Chandrasekaran, Tetrahedron Lett., 1984, 25, 2985. Y-Morizawa, T.Hiyama, K.Oshima, and H.Nozaki, Bull. Chem. SOC. Jpn., 1984, 57, 1123. A.J.Pearson and Md.N.I.Khan, J. Am. Chem. SOC., 1984, 106,1872; Tetrahedron Lett., 1984, 25, 3507. A.J.Pearson, S.L.Kole, and T.Ray, J. Am. Chem. SOC., 1984, 106, 6060. S.N.Suryawanshi and P.L.Fuchs, Tetrahedron Lett ., 1984, 5,y.See also p. 1859. S.N.Suryawanshi , C.J Swenson, W. L.Jorgensen , and P.L. Fuchs , M., S.D.Burke, D. R .Magnin, J. A. Oplinger , J. P .Baker, and A. Abdelmagid, Tetrahedron Lett., 25, 19. See also P.R.Jenkins, K.A.Menear, P.Barraclough, and M.S.Nobbs, -J. Chem. SOC., Chem. Commun., 1984, 1423; B.Fraser-Reid, p.1029. Z.Benko, R.Guiliano, K.M.Sun, and N.Taylor, g, F.Gaudemar-Bardone, M.Mladenova, and R.Couffigna1, Tetrahedron Lett., 1984, 25, 1047. J.W.Scheeren and J.Lange, Tetrahedron Lett., 1984, 25, 1609. J.-C.Depezay, A.Dur&ault, and T.Prange, TetrahedronLett., 1984, 25, 1459; Y.Hamada, A.Kawai, and T.Shioiri, H., pp.5409, 5413; for related work with (D)-ribono-1,4-lactones, see T.Shono, N.Kise, and T.Suzumoto, J. Am.Chem. SOC., 1984, 106,259, and J.Mulzer, M.Kappert, G.Huttner, and I.Jari1, Angew. Chem., Int. Ed. Engl., 1984, 23, 704. For a review of some approaches to a-aminobutyrolactones, see H.E.Zaugg, Synthesis, 1984, 85, 181. D.Seebach, M.Dust, R.Naef, and M.Banziger, Angew. Chem., Int. Ed. Engl., 1984, 23, 530. 5058. D.M.Tschaen, E.Turos, and S.M.Weinreb, J. Org. Chem., 1984, 9, G.S. Y. Ng, L.-C. Yuan, I.J. Jakovac, and J. B.Jones, -~ Tetrahedron, 1984, 40, 1235; J.B.Jones and C.J.Francis, Can. J. Chem., 1984, 62, 2578. K.Lauman and M.Schneider, Tetrahedron Lett., 1984, 25, 5875. Y.-F.Wang and C.J.Sih, Tetrahedron Lett., 1984, 25, 4999. R.D.Cooper, V.B. Jigajinni, and R.H.Wightman, Tetrahedron Lett., 1984, 25, 5215. J.-R.Pougny, Tetrahedron Lett., 1984, 25, 2363; L.Stamatatos, P.Siney, and J.-P.Pougny, Tetrahedron, 1984, 40, 173. S.-Y.Chen and M.M.Joulli6, J. Org. Chem., 1984, 2, 2168; G.Papageorgiou and C.Benezra, Tetrahedron Lett., 1984, 25, 6041; S.V.Attwood and A.G.M.Barrett, J. Chem. SOC., Perkin Trans. 1 , 1984, 1315. J.P.Marino and A.D.Perez, J. Am. Chem. SOC., 1984, 106,7643. G.N.Posner, T.P.Kogan, S.R.Haines, and L.L.Frye, Tetrahedron Lett., 1984, 25, 2627. For other studies of stegane-type lignan synthesis, see J.-P.Robin, R.Oha1, and E.Brown, Tetrahedron, 1984, 9, 3509, and K.Tomioka, p. 1303. T. Ishiguro, Y. Iitaka, and K .Koga, U., C.P.Til1 and D.A.Whiting, J. Chem. SOC., Chem. Commun., 1984, 590. For a related approach to symmetrical lignan dilactones, see L.Lozzi, A.Ricci, and M.Taddei, J. Org. Chem., 1984, 9, 3408. J-Nokami, T.Ono, Y.Kajitani, and S.Wakabayashi, Chem. Lett., 1984, 707. Y.Tamaru, M-Mizutani, Y.Furukawa, S.Kawamura, Z.Yoshida, K.Yanagi, and M.Minobe, J. Am. Chem. SOC., 1984, 106,1079; see also H.J.Gunther, E-Guntrum, and V.Jager, Liebigs Ann. Chem., 1984, 15, and G.Cardillo, M.Orena, G.Porzi, S.Sandri, and C-Tomashini, J. Org. Chem., 1984, 9, 701. M.Srebnik and R.Mechoulam, J. Chem. SOC., Chem. Commun., 1984, 1070. T.Fujisawa, H.Kohama, K.Tajima, and T.Sato, Tetrahedron Lett., 1984, 25, 51 55. A.P.Kozikowski and A.K.Ghosh, J. Org. Chem., 1984, 9, 2762. M.Ladlow and G.Pattenden, Tetrahedron Lett., 1984, 25, 4317. G.A.Kraus and K.Landgrebe, Tetrahedron Lett., 2984, 25, 3939. C.Lambert, K.Utimoto, and H.Nozaki, Tetrahedron Lett., 1984, 25, 5323. For examples of the mercury-catalysed method, see A.Jella1, J.Grimaldi, and M.Santelli, M.,p.3179. M.F.Semmelhack, C.Bodurow, and M.Baum, Tetrahedron Lett., 1984, 25, 3171. 5384. E.J. Corey and M.Kang, J. Am. Chem. SOC., 1984, T-Mandai, K.Mori, K.Hasegawa, M.Kawada, and J.Otera, Tetrahedron Lett., 1984, 5, 5225.

.

~

106,

228

General and Synthetic Methods

277 O.Moriya, M.Okawara, and Y.Ueno, Chem. Lett., 1984, 1437. 278 A.W.Murray and R.G.Reid, J. Chem. SOC., Chem. Commun., 1984, 132.

14,

11. 279 M.Ladlow and G.Pattenden, Synth. Commun., 1984, 280 R.C.Larock, L.W.Harrison, and M.H.Hsu, J. Org. Chem., 1984, 3662. 281 M. Rosenblum, A.Bucheister , T.C.T.Chang, M. Cohen, M.Marsi, S.B .Samuels, D.Scheck, N.Sofen, and J.C.Watkins, Pure Appl Chem., 1984, 56, 129. 282 P.Bravo, P.Carrera, G . Resnati, and C.Ticozzi, J. Chem. SOC., Chem. Commun., 1984, 19. 283 K.Tanaka, H.Wakita, H.Yda, and A.Kaji, Chem. Lett., 1984, 1359. 284 P-Canonne, M.Akssira, and G.Fytas, Tetrahedron, 1984, 40, 1809; P.Canonne and M.Akssira, Tetrahedron Lett., 1984, 25, 3453. 285 C.Schmit , S . Sahraoui-Taleb, E.Dif ferding, C.G .Dehasse-De Lombaert , and L.Ghosez, Tetrahedron Lett., 1984, 25, 5043. 286 R.Okazaki, Y.Negishi, and N.Inamoto, J. Org. Chem., 1984, 49, 3819. 287 A De Groot and B.J.M.Jansen, J. Org. Chem., 1984, 2043: 288 S.P.Tanis and D.B.Head, Tetrahedron Lett., 1984, 25, 4451. 289 R.Antonioletti, M.D'Auria, A.De Mico, G.Piancatelli, and A.Scettri, Tetrahedron, 1984, 40, 3805. 290 T.K.Chakraborty and S.Chandrasekaran, Tetrahedron Lett ., 1984, 25, 2891. 29 1 P. A.Jacobi, C.S. R.Kaczmarek, and U.E.Udodong, Tetrahedron Lett., 1984, 25, 4859. For approaches to paniculides B and C, see R.Baker, C.L.Gibson. . _ C.J.Swain, and D.J.Tapolczay, J. Chem. SOC., Chem. Commun., 1984, 619. See also P.A.Jacobi, T.A.Craig, D.G.Walker, B. A.Arrick, and R.F.Frechette, J. Am. Chem. SOC., 1984, 5585. 927. 29 2 S.Brandange, L.Flodrnan, and A.Norberg, J. Org. Chem., 1984, 29 3 R.Ramage, G.J.Griffiths, F.E.Shutt, and J.N.A.Sweeney, J. Chem. SOC., Perkin Trans. 1 , 1984, 1539. 294 R.Ramage, G.L.Griffiths, and J. N.A.Sweeney , J. Chem. SOC., Perkin Trans 1984. 1547. 295 R.Ramage and P.P.McCleery, J. Chem. SOC., Perkin Trans. 1 , 1984, 1555. 296 R.R.Schmidt and R.Hirsenkorn, Tetrahedron Lett., 1984, 25, 4357. See also R.R.Schmidt and R.Betz, Angew. Chem., Int. Ed. Engl., 1984, 23, 430. 297 J.Freskos, T.Cynkowski, and J.S.Swenton, J. Chem. SOC., Chem. Commun., 1984,

2,

2,

106,

2,

819. 298 299 300 301 302 303 304 305 306

R.C.Larock, S-Varaprath, H.H.Lau, and C.A.Fellows, J. Am. Chem. SGC., 1984, 106, 5274. m o n a d i e s , R.Di Fabio, and C.Bonini, J. Org. Chem., 1984, 9, 1647. M-Yamaguchi, K.Shibato, and I.Hirao, Tetrahedron Lett., 1984, 25, 1159. A.J.Bridges, P.S.Raman, G.S.Y.Ng, and J.B.Jones. J. Am. Chem. S O C . , 1984, 106, 1461. =.Godleski and E.B.Villhauer, J. Org. Chem., 1984, 2246. M.Kato, H.Saito, and A.Yoshikoshi, Chem. Lett., 1984, 213. E.Bardshiri, T.J.Simpson, A.I.Scott, and K-Shishido, J. Chem. SOC., Perkin Trans. 1 , 1984, 1765. Y-Kawakami, J-Hiratake, Y.Yamamoto, and J-Oda, J. Chem. S O C . , Chem. Commun., 1984, 779. S.Takeno, M.Morimoto, and K.Ogasawara, J. Chem. SOC., Chem. Commun., 1984, 82. F.Bonadies. G.Rossi. and C.Bonini. Tetrahedron Lett.. 1984. 215, 5431. C-Santelli-Rouvier, Tetrahedron Lett., 1984, 3, 4371. P.G.M.Wuts, M.L.Obrzut, and P. A.Thompson, , 1984, 25, 4051. T.R .Hoye, D. R.Peck, and T. A. Swanson, J. Am .-Chem 4, 106,2738. S.F .Martin and D. E.Guinn, TetrahedronY. Yamamoto, H. Yatagai , Y. Ishih Tetrahedron, 1984, 40, 2239. K - M i k a Z , K-Fujimoto, T.Kasuga, and T.Nakai, Tetrahedron Lett., 1984, 25, 601 1. M.Majewski, D.L.J.Clive, and P.C.Anderson, Tetrahedron Lett., 1984, 22, 2101, K-Prasad and O.RepiC, Tetrahedron Lett., 1984, 25, 3391. T-Rosen, M.J.Taschner, and C.H.Heathcock, J. O r F Chem., 1984, 9, 3994.

2,

I

31 3 314 315 316

-

,

229

3: Carboxylic Acids and Derivatives 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 36 1 362 363 364 365

K.Prasad and O.RepiE, Tetrahedron Lett., 1984, 25, 2435. See also K.Prasad p.4889. and O.RepiE, D.E.Cane and P.J.Thomas, J. Am. Chem. SOC., 1984, 106,5295. See also T.Ohtsuka, H-Shirahama, and T.Matsumoto, Chem. Lett., 1984, 1923. E.J.Corey and A.G.Myers, Tetrahedron Lett., 1984, 25, 3559. M.Larcheveque and J.Lalande, Tetrahedron, 1984, 5, 1061. T.Kikukawa and A.Tai, Chem. Lett., 1984, 1935. T.Sato, M.Watanabe, N.Honda, and T.Fujisawa, Chem. Lett., 1984, 1175. M-Yamaguchi and I.HJirao, J. Chem. SOC.,Chem. Commun., 1984, 202. See also 3693. M.J.Eis, J.E.Wrobe1, and B.Ganem, J. Am. Chem. SOC., 1984, T.Kogure and E.L.Elie1, J. Org. Chem., 1984, 9, 576. P.A.Bartlett, D.P.Richardson, and J.Myerson, Tetrahedron, 1984, 5, 2317. K.Mori, T.Otsuka, and M.Oda, Tetrahedron, 1984, 40, 2929. Y.Masaki, K.Nagata, Y.Serizawa, and K.Kaji, Tetrahedron Lett., 1984, 25, 95. M.M.Midland and R.S.Graham, J. Am. Chem. SOC., 1984, 106,4294. S.Castellino and J. J .Sims, Tetrahedron Lett., 1984, 25, 2307, 4059. H.H.Meyer, Liebigs Ann. Chem., 1984, 791, 977. H.Hiraoka, K.Furuta, N.Ikeda, and H.Yamamoto, Bull. Chem. SOC. Jpn., 1984, 57, 2777. KYoshioka, H.Nakai, and M.Ohno, J. Am. Chem. SOC., 1984, 106, 1133. See alsc R-Cordova and B.B.Snider, Tetrahedron Lett., 1984, 25, 2945. H.-J.Gais, Tetrahedron Lett., 1984, 25, 273. A.Ahmed, N.Taniguchi, H.Fukuda, H.Kinoshita, K.Inomata, and H.Kotake, Bull. Chem. SOC. Jpn., 1984, 57, 781. N.Taniguchi, H.Kinoshita, K.Inomata, and H.Kotake, Chem. Lett., 1984, 1347. J.Tamariz and P.Voge1, Angew. Chem., Int. Ed. Engl., 1984, 23, 74. M.S.South and L.S.Liebeskind, J. Am. Chem. SOC., 1984, 106,7181. T.Aono and M-Hesse, Helv. Chim. Acta, 1984, 2, 1448. See also N.Ono, H.Miyake, and A.Kaji, J. Org. Chem., 1984, 4997. K.Kostova and M.Hesse, Helv. Chim. Acta, 1984, 5, 1713. E.Vedejs and R.A.Buchanan, J. Org. Chem., 1984, 1840; E.Vedejs, Acc. Chem. Res., 1984, 17,358. 2332. J.F.Millar and A.C.Oehlschlager, J. Org. Chem., 1984, 9, M.Honda, T.Katsuki, and M.Yamaguchi, Tetrahedron Lett., 1984, 25, 3857. H.Tsutsui and O.Mitsunobu, Tetrahedron Lett., 1984, 25, 2159, 2163. P-Schnurrenberger, E-Hungerbuhler, and D.Seebach, Tetrahedron Lett., 1984, 25, 2209. YSchregenberger and D.Seebach, Tetrahedron Lett., 1984, 25, 5881. K.H.Marx, P.Raddatz, and E.Winterfeldt, Liebigs Ann. Chem., 1984, 474. T-Kitahara and K.Mori, Tetrahedron, 1984, 40, 2935. H.-J.Gais and T.Lied, Angew. Chem., Int. Ed. Engl., 1984, 23, 145. E.J.Corey and B.De, J. Am. Chem. SOC., 1984, 2735. W.C.Stil1 and V.J.Novack, J. Am. 'Chem. SOC., 1984, 1148. W.C.Stil1, C.Gennari, J.A.Noguez, and D.A.Pearson, J. Am. Chem. SOC., 1984, 106, 260. E i T r o s t and P.G.McDouga1, J. Org. Chem., 1984, 9, 458. W.R.Roush and T.A.Blizzard, J. Org. Chem., 1984, 49, 4332. W.R.Roush and T.A.Blizzard, J. Org. Chem., 1984, 1772. B.M.Trost, P.G.McDouga1, and K.J.Haller, J. Am. Chem. SOC., 1984, 106,383; D.B.Tulshian and B.Fraser-Reid, Tetrahedron, 1984, 40, 2083. P.Grossen, P.Herold, P.Mohr, and C.Tamm, Helv. Chim. Acta, 1984, 1625. K.Narasaka, T.Sakakura, T.Uchimaru, and D.Gu&din-Vuong, J. Am. Chem. SOC., 1984, 106, 2954. E.Vederand S.D.Larsen, J. Am. Chem. SOC., 1984, 106,3030. P.C.Kuzma, L.E.Brown, and T.M.Harris, J. Org. Chem., 1984, 2015. S.Tsuboi, Y.Nooda, and A.Takeda, J. Org. Chem., 1984, 1204. Y.Satoh, H-Serizawa, S.Hara, and A.Suzuki, Synth. Commun., 1984, 31 3. J.T.Gupton, D.Baran, and J.P.Idoux, Synth. Commun., 1984, 1001. S.Saito, H.Tamai, Y.Usui, M.Inaba, and T.Moriwake, Chem. Lett., 1984, 1 243. J.Garcia, J.GonzSlez, R.Segura, F. Urpi, and J.Vilar-rg. Chem., 1984, 49, 3322. J.Barl=nga, L.Ferrera, C.N6jera, and M.Yus, Synthesis, 1984, 831.

u.,

106,

9, 9,

106,

106,

5,

67,

9, 2, 2, 14,

230

General and Synthetic Methods

366 367 368

Y.Kawanami, Y.Ito, T.Kitagawa, Y.Taniguchi, T.Katsuki, and M.Yamaguchi, Tetrahedron Lett., 1984, 25, 857. Y.Ito, T.Katsuki, and M-Yamaguchi, Tetrahedron Lett., 1984, 25, 6015. R.Annunziata, M.Cinquini, F.Cozzi, F.Montanari, and A.Restelli, Tetrahedron,

369 370 37 1 372

K.Soai and M-Ishizaki, J. Chem. SOC., Chem. Commun., 1984, 1016. K.Harada and T.Munegumi, Bull. Chem. S O C . Jpn., 1984, 2,3203. H.E.Zaugg, Synthesis, 1984, 85 and 181. C-Caristi, A.Ferlazzo, and M.Gattuso, J. Chem. SOC., Perkin Trans. 1, 1984,

1984,

40,

3815.

281. 37 3 374 37 5 376 37 7 378 379 380

S.Kajigaeshi, T.Nakagawa, and S.Fujisaki, Chem. Lett., 1984, 2045. P.Beak, W.J.Zajde1, and D.B.Reitz, Chem, Rev., 1984, 471. M.P.Sibi, M.A.J.Miah, and V.Snieckus, J. Org. Chem., 1984, 737. M.Watanabe, M.Sahara, M.Kubo, S.Furukawa, R. J. Billedeau, and V. Snieckus, J. Org. Chem., 1984, 742. R.J.Mills and V.Snieckus, Tetrahedron Lett., 1984, 25, 483. K.Shankaran and V. Snieckus, Tetrahedron Lett., 1984, 25, 2827. R.J.Mills and V.Snieckus, Tetrahedron Lett., 1984, 25, 479. Y.Tamaru, T.Hioki, and Z.Yoshida, Tetrahedron Lett., 1984, 5793; Y.Tamaru, T.Hioki, S.Kawamura, H.Satomi, and Z.Yoshida, J. Am. Chem. SOC.,

84,

z,

1984, 38 1 382 38 3 38 4 38 5 386 387 38 8 389 390 39 1 392 39 3 39 4

2,

2,

106,3876.

D.Seyferth and R.C.Hui, Tetrahedron Lett., 1984, 2 5 , 5251. E.Schaumann and S.Fittkau, Tetrahedron Lett., 1 9 8 q 25, 2325. C.Goasdoue, N.Goasdoue, and M.Gaudemar, Tetrahedron Lett., 25, 537. V.Dourtoglou, B.Gross, V.Lambropoulou, and C-Zioudrou, Synthesis, 1984, 572. K.Barlos, D.Papaioannou, and C.Sanida, Liebigs Ann. Chem., 1984, 1308. Y.Nagao, T.Miyasaka, K.Seno, E.Fujita, D-Shibata, and E.Doi, J. Chem. SOC., Perkin Trans. 1, 1984, 2439. S.Ohta, S.Hayakawa, and M.Okamoto, Tetrahedron Lett., 1984, 25, 5681. M.Ueda, N-Kawaharasaki, and Y.Imai, Bull. Chem. SOC., Jpn., 1984, 57, 85. J-Garcia, F.Urpi, and J.Vilarrasa, Tetrahedron Lett., 1984, 25, 4841. T.Shioiri and S.Yamada, Org. Synth., 1984, g ,187. R.Ramage, C.P.Ashton, D.Hopton, and M.J .Parrott, Tetrahedron Lett., 1984,

25, 4825. J.Cabr-6 and A.L.Palomo, Synthesis, 1984, 413. F.Acher and M.Wakselman, J. Org. Chem., 1984, 4133. T.Miyazawa, T.Otomatsu, T.Yamada, and S.Kuwata, Tetrahedron Lett., 1984,

2,

25,

771.

39 5 396

J.P.Gamet, R-Jacquier, and J.Verducci, Tetrahedron, 1984, 40, 1995. F.Guendouz, R.Jacquier, and J.Verducci, Tetrahedron Lett., 1984, 25, 4521. See also B.J.Cohen, H.Karoly-Hafeli, and A.Patchornik, J. Org. Chem., 1984,

49, 922. 397 398 39 9

A-Paquet, F.M.F.Chen, and N.L. Benoiton, Can. J. Chem., 1984, 62, 1335. T.Yamada, Y.Manabe, T-Miyazawa, S.Kuwata, and A.Sera, J. Chem. SOC. , Chem. Commun., 1984, 1500. K-Shimizu, K.Nakayama, and M.Akiyama, Bull. Chem. SOC. Jpn., 1984, 57, 2456.

40 0 40 1 402 40 3 40 4 40 5 40 6 40 7 408

D.D.Petkov and I.B.Stoineva, Tetrahedron Lett., 1984, 25, 3751. Y.L.Khme1 'nitski, F.K.Dien, A.N.Semenov, K-Marinek, B.VeruoviE, and V. Kubhek , Tetrahedron, 1984, 5, 4425. M.Mutter and D.Bellof, Helv. Chim. Acta, 1984, 67,2009. D.B.Whitney , J. P. Tam, and R.B.Merrif ield, Tetrahedron, 1984, 4237. F.Baleux, J.Daunis, and R.Jacquier, Tetrahedron Lett., 1984, 25, 5893. R.Schwyzer, E.Felder, and P.Failli, Helv. Chim. Acta, 1984, 3, 1316. 1.J.Galpin and A.E.Robinson, Tetrahedron, 1984, 5, 627. M.J.O'Donnel1, K.Wojciechowski, L.Ghosez, M.Navarro, F.Sainte, and J.-P.Antoine, Synthesis, 1984, 313. M.J.O'Donnel1, W. A.Bruder, T.M. Eckrich, D.F.Shullenberger, and G.S.Staten, Synthesis, 1984, 127. J.M.Bland, C.H.Stammer, and K.L.Varghese, J. Org. Chem., 1984, 1634.

g,

2,

3: Carboxylic Acids and Derivatives 41 0 41 1 41 2

41 3 41 4 41 5 41 6 41 7 41 8 41 9 420 42 1 42 2 423 424 42 5 42 6 427 42 8 42 9 430 43 1 432 43 3 43 4 43 5 436 43 7 438 439 4 40 441 4 42 443 444 445 446 447 448 449 450

23 1

z, u.,

P.Duhame1, J.Jame1 Eddine, and J.-Y.Valnot, Tetrahedron Lett., 1984, 2355. See also R.Jacquier, R.Lazaro, H.Raniriseheno, and P-Viallefont, ibid., p . 5525, and N.Minowa, M.Hirayama, and S.Fukatsu, p.1147. S.C.Zimmerman and R.Breslow, J. Am. Chem. SOC., 1984, 106, 1490. See also Deschenaux and K.Bernauer, Helv. Chim. Acta, 1984, 67,373. D.Seebach and J.D.Aebi, Tetrahedron Lett., 1984, 25, 2545; D.Seebach and T.Weber, Helv. Chim. Acta, 1984, 67, 1650. P.J.Maurer, H-Takahata, and H.RapGort, J. Am. Chem. SOC., 1984, 106,1095. See also J.A.Bajgrowicz, A.E1 Hallaoui, R.Jacquier, C.Pigikre, and P.Viallefont , Tetrahedron Lett., 1984, 25, 2231 , 2759. S.Karady, J.S.Amato, and L.M.Weinstock, Tetrahedron Lett., 1984, 2 4337. U.Schollkopf and R.Scheuer, Liebigs Ann. Chem., 1984, 939. U.Schollkopf, U.Busse, R.Kilger, and P.Lehr, Synthesis, 1984, 271. See a1so D.S.Kemp and P.E.McNamara, J. Org. Chem., 1984, 9, 2286. 1.C.Nordin and J.A.Thomas, Tetrahedron Lett., 1984, 25, 5723. S-Takano,M-Akiyama, and K.Ogasawara, J. Chem. SOC., Chem. Commun. 1984. 770. T.Shono, Tetrahedron, 1984, 40, 81 1 . V.Teetz, R.Geiger, and H.Gau1, Tetrahedron Lett., 1984, 25, 4479; V.Teetz and H.Gau1, p. 4483. B.Garrigues, Tetrahedron, 1984, 5, 1151 ; T.Miyazawa, T.Yamada, and S.Kuwata, Bull. Chem. SOC. Jpn., 1984, 57, 3605. G.Guanti, L.Banfi, E.Narisano, and C.Scogstico, Tetrahedron Lett., 1984, 25, 4693. See also P.Garner, E., p. 5855. A.Toy and W.J.Thompson, Tetrahedron Lett., 1984, 25, 3533. H.Fujihara and R.L.Schowen, J. Org. Chem., 1984, 9, 2819. See also K.Tanimura, T.Kato, M.Waki, S.Lee, Y.Kodera, and N.Izumiya, Bull. Chem. SOC. Jpn., 1984, 57, 2193. T.Shiraiwa, A. Ikawa , K. Sakaguchi , and H.Kurokawa, Bull. Chem. SOC . Jpn., 1984, 57, 2234. J.A.Bajgrowicz, B-Cossec, C.Pigi&e, R-Jacquier, and P.Viallefont, Tetrahedron Lett., 1984, 25, 1789. W.H.Pirkle and M.H.Hyun, J. Org. Chem., 1984, 3043. S.Weinstein, Tetrahedron Lett., 1984, 25, 985; K.Gunther, J.Martens, and M-Schickedanz, Angew. Chem., Int. Ed. Engl., 1984, 23, 506. W.A.Konig, E-Steinbach, and K.Ernst, Angew. Chem., Int. Ed. Engl., 1984, 3, 527. J.E.Baldwin, L.M.Harwood, and M.J. Lombard, Tetrahedron, 1984, 5, 4363. K.Okano, T.Morimoto, and M.Sekiya, J. Chem. SOC., Chem. Commun., 1 984 , 883 T.Shono, K.Tsubata, and N-Okinaga, J. Org. Chem., 1984, 1056. D.Seebach, C.Betschart, and M.Schiess, Helv. Chim. Acta, 1984, 5, 1593. S.Kobayashi, T.Isobe, and M.Ohno, Tetrahedron Lett., 1984, 25, 507 9. B.E.Rossiter and K.B.Sharpless, J. Org. Chem., 1984, 9, 3707. U-Schmidt, A.Lieberknecht , and J.Wild, Synthesis, 1984, 53. P.K.Tripathy and A.K.Mukerjee, Synthesis, 1984, 418. F.Effenberger and T.Beisswenger, Chem. Ber., 1984, 117,1497, 1513 D.Knitte1, Monatsch. Chem., 1984, 5,1335. G.Wulff . w e d n a Chem., Int. Ed. Engl., 1984, 23, 380. B.H.Lipshutz and M.C.Morey, J. Am. Chem. SOC., 1984, 106,457. U.Schollkopf, J.Nozulak, and U.Groth, Tetrahedron, 1984, 110, 1409. W.J.Greenlee, J. Org. Chem., 1984, 49, 2632. S.Hanessian and S.P.Sahoo, Tetrahedron Lett., 1984, 25, 1425. D.M.Vyas, Y.Chiang, and T.W.Doyle, J. Org. Chem., 1984, 9, 2037. P.Casara, K.Jund, and P.Bey, Tetrahedron Lett., 1984, 25, 1891; A.L.Castelhano, D.H.Pliura, G.J.Taylor, K.C.Hsich, and A.Krantz, J. Am. Chem. SOC., 1984, 106, 2734. J.E.Baldwin, R.M.Adlingtorand A.Basak, J. Chem. SOC., Chem. Commun., 1984, 1284. P.Perlmutter and C.C.Teo, Tetrahedron Lett., 1984, 25, 5951. H.Hiemstra, H.P.Fortgens, and W.N.Speckamp, Tetrahedron Lett. , 1984, 25, 31 15. A.L.Castelhano and A.Krantz, J. Am. Chem. SOC., 1984, 106,1877.

-

u.,

2,

9,

c

232

General and Synthetic Methods

45 1

I.Ojima, Pure Appl. Chem., 1984, 56, 9 9 ; I.Ojima, N.Yoda, M.Yatabe, 1255. T.Yanaka, and T.Kogure, Tetrahedron, 1984, , 1984, 2 3 , 435. 'on, 1984, E, 1 2 4 5 ; -

452 453 454 45 5 456 457 458 459 460

46 1 462 46 3 464 46 5 46 6 46 7 468 469 470 47 1 472 47 3 47 4 47 5 476 47 7 478 479 480 48 1

c,

T.Yamaghishi, M.Yatagai, H.Hatakeyama, and M.Hida, Bull. Chem. SOC. Jpn., 1984, 57, 1897. J.Bakos, I.Toth, and B.Hei1, Tetrahedron Lett., 1984, 25, 4965. M.Yatagai, M.Zama, T.Yamagishi, and M.Hida, Bull. Chem. SOC. Jpn., 1 9 8 4 , 5 7 , 739 ; M.Yatagai , T. Yamaghishi, and M.Hida, ibid., p . 8 2 3 . M-Takasaki and K.Harada, Chem. Lett., 1 9 8 4 , 1 7 1 1 5 . A.M.Kotodziejczyk and M.Slebioda, Synthesis, 1984, 865. M.Kolovos and C.Froussios, Tetrahedron Lett., 1 9 8 4 , 5, 3909. H-Kessler, G.Becker , H.Kogler , and M.Wolf f, Tetrahedron Lett., 1 9 8 4 , 25, 3971 ; H.Kunz and M.Kneip, Angew. Chem., Int. Ed. Engl., 1984, 23, 7 1 6 ; f o r a description of the 4-pyridyl analogues, see A.R.Katritzky, G.R.Khan, and O.A.Schwarz, Tetrahedron Lett., 1984, 25, 1223. D.Chantreux, J.-P.Gamet, R.Jacquier, and J.Verducci, Tetrahedron, 1984, 40, 3087. R.L.Blankespoor, A.N.K.Lau, and L.L.Miller, J. Org. Chem., 1984, 9, 4441. M.J. O'Donnell, W . A.Bruder, B. W.Daugherty , D.Liu , and K .Wojciechowski, Tetrahedron Lett., 1984, 25, 3651. Y.Ohfune, N.Kurokawa, N.Higuchi, M.Saito, M.Hashimoto, and T.Tanaka, Chem. Lett., 1984, 441. S.Kim and J.I.Lee, Chem. Lett., 1984, 237. R.Ramage, D.Hopton, M.J.Parrott, G.W.Kenner, and G.A.Moore, J. Chem. SOC., Perkin Trans. 1 , 1984, 1 3 5 7 ; see also, Y.-F.Zhao, S.-K.Xi, A.-T-Song, and G.-J.Ji, J. Org. Chem., 1984, 49, 4549. H.Kunz and S.Birnbach, Tetrahedron Lett., 1984, 5, 3567. H.Kunz and C.Unverzagt, Angew. Chem., Int. Ed. Engl., 1 9 8 4 , 23, 436. H.Kunz and H.Waldmann, Angew. Chem., Int. Ed. Engl., 1 9 8 4 , 23, 71. L.A.Carpino, N.W.Rice, E.M.E.Mansour, and S.A.Triolo, J . Org. Chem., 1 9 8 4 , 4 9 , 836. P.L .Southwick, G .K.Chin, M.A.Koshute, J. R.Miller , K.E.Niemela, C.A. Siegel, R.T.Nolte, and W.E.Brown, J. Org. Chem., 1984, 49, 1130. H.Yamada. H.Tobiki, N.Tanno, H.Suzuki, K. Jimpo, S.Ueda, and T-Nakagome, Bull. Chem. SOC. Jpn., 1984, 57, 3333. S.Takahashi, T.Yamamura, M.Kamo, and K.Satake, Chem. Lett., 1 9 8 4 , 127 . J.O.Osby, M.G.Martin, and B.Ganem, Tetrahedron Lett., 1984, 5, 2093 M.H.Khalifa and R.Rieker, Tetrahedron Lett., 1984, 2 5 , 1027. For a review, see I.Schon, Chem. Rev., 1984, E, 2 8 7 . M.Platen and E.Steckhan, Liebigs Ann. Chem., 1984, 1563. M-Ueki and K.Shinozaki, Bull. Chem. SOC. Jpn., 1984, 57, 2156. M.G.Kolovos and P.Moutevelis-Minakakis, Tetrahedron Lett., 1984, 25, 4153. H.Franz&n, L.Grehn, and U.Ragnarsson, J. Chem. SOC. , Chem. Commun., 1984. 1699. R.Colombo, F.Colombo, and J.H.Jones, J. Chem. SOC., Chem. Commun., 1 9 8 4 , ?n ?

Alcohols, Halogeno-compounds, and Ethers BY L. M. HARWOOD

Reactions are listed according to the type of compound prepared wherever possible. For example ROH RC1 reactions are classified

-

as halide preparations and not alcohol reactions. Exceptions are those reactions which are considered to be protection or deprotection procedures. Within each class preparations are discussed before reactions. Cross-referencing to earlier Reports follows the established style. 1 Alcohols

Preparation.- By Addition to Alkenes. The hydroboration characteristics of lithium borohydride-ethyl acetate, sodium borohydride-titanium( 111) chloride, and the complex between sodium borohydride and dicyclopentadienyltitanium dichloride3 have been investigated. Aromatic olefins are reductively oxygenated to benzyl alcohols in good yield by molecular oxygen and tetraethylammonium borohydride in the presence of a cobalt(I1) catalyst. Hydroxyalkylation of olef ins has been achieved in moderate yield by heating olefins neat with hydroxyperoxydiazenes (care, explosive) in a sealed tube.5 Procedures for %-I ,2hydroxylation of alkenes have been reported using cetyltrimethylammonium permanganate in dichloromethane at room temperature, and mercury( 11) oxide-f luoroboric acid in water at 70 0C.7 Further work has been published regarding empirical rules to predict the stereochemistry of osmylation of allylic alcohols. a

By Reduction of Carbonyl Compounds. Sodium (dimethy1arnino)bor-ohydride and sodium(t-buty1amino)borohydride have been shown to be more powerful reducing agents than sodium borohydride, reducing esters to alcohols.' Reduction of ketones with borohydride has been found to be accelerated by carrying out the reaction in an emulsion. I " The alloy LaNi5 readily absorbs hydrogen and has been applied to the reduction of ketones; yields are high and the 233

For References s e e page 277.

234

General and Synthetic Methods

r e a c t i o n i s c a r r i e d o u t i n m e t h a n o l a t low t e m p e r a t u r e . ”

A

combination of l i t h i u m borohydride-Grignard reagent provides a c o n v e n i e n t means o f c o n v e r t i n g e s t e r s i n t o s e c o n d a r y a l c o h o l s i n y i e l d s t h a t compare w i t h s t a n d a r d m u l t i s t e p p r o c e d u r e s (Scheme I ) . ’ *

The s u c c e s s o f t h e p r o c e d u r e r e s u l t s f r o m t h e

r e d u c t i o n o f t h e i n i t i a l l y formed k e t o n e o c c u r r i n g a t a g r e a t e r r a t e than a d d i t i o n o f a second equivalent of t h e Grignard reagent. Chemoselective Carbonyl Reductions. S e l e c t i v e reduction of aldehydes i n t h e presence of s a t u r a t e d ketones h a s been demonstrated u s i n g sodium b o r o h y d r i d e i n d i m e t h y 1 , s u l p h o x i d e i n t h e p r e s e n c e of e i t h e r c e r i u m ( 111) c h l o r i d e o r c o b a l t ( 11) c h l o r i d e h y d r a t e s . system a l s o reduces a , ~ - u n s a t u r a t e d ketones.

This

Some s e l e c t i v i t y f o r

aldehyde over k e t o n e r e d u c t i o n h a s a l s o been found w i t h t i n f o r m a t e s i n d i g y l m e a t 160 oC.14a

The same a u t h o r s h a v e s h o w n t h a t

t h e y i e l d s a n d s e l e c t i v i t y a r e i m p r o v e d by t h e a d d i t i o n o f n - b u t a n o l , when r e a c t i o n o c c u r r e d a t 1 1 5 t i n r e a g e n t . 14b

OC

a n d was c a t a l y t i c i n

F o r e x p e d i e n c y h o w e v e r , o n e o r two e q u i v a l e n t s o f

t h e s t a n n a n e a r e recommended, t h e mechanism b e i n g t h a t o f t h e Merwein-Pondorf-Verley

couple under t h e s e conditions.

Borohydride

e x c h a n g e r e s i n i n m e t h a n o l a t room t e m p e r a t u r e s e l e c t i v e l y r e d u c e s a,B-unsaturated

c a r b o n y l compounds t o a l l y l i c a l c o h o l s w i t h o u t

a f f e c t i n g t h e d o u b l e bond.15

T h i s r e a g e n t i s more e f f i c i e n t t h a n

o t h e r s , a n d c a n b e r e m o v e d by f i l t r a t i o n a t t h e e n d o f t h e S e l e c t i v e r e d u c t i o n of e s t e r s i s p o s s i b l e u s i n g l i t h i u m b o r o h y d r i d e c a t a l y s e d by ~-methoxy-9-borabicyclo[3.3.llnonane, 1 6

reaction.

a n d a l s o s o d i u m b o r o h y d r i d e i n r e f l u x i n g t e t r a h y d r o f u r a n or t - b u t y l a l c o h o l t o which methanol i s s l o w l y added.”

Under t h e l a t t e r

c o n d i t i o n s c h l o r i d e s , c y a n i d e s , amides, and n i t r o and c a r b o x y l a t e groups are s t a b l e , t h e a d d i t i o n of methanol being t h e e s s e n t i a l 13-Keto-esters are c o n v e r t e d i n t o l , 3 - d i o l s f e a t u r e of t h e p r o c e s s . i n h i g h y i e l d u s i n g t h i s s y s t e m . 1 8 E s t e r s p o s s e s s i n g a n cr-hydroxygroup are s e l e c t i v e l y reduced with diborane-dimethyl

sulphide i n

t h e p r e s e n c e o f s o d i u m b o r o h y d r i d e c a t a l y s t ( e . g . Scheme 2 1 . S t e r e o s e l e c t i v e Carbonyl Reductions. Zinc borohydride i n e t h e r a t O C s e l e c t i v e l y r e d u c e s a-methyl-B-hydroxy-ketone d e r i v a t i v e s t o

0

g i v e a m i x t u r e i n which t h e e r y t h r o - p r o d u c t dominates.20 T h i s r e s u l t i s s u g g e s t e d t o b e t h e c o n s e q u e n c e of a c y c l i c c h e l a t e d t r a n s i t i o n s t a t e ( S c h e m e 3 ) . T h e same g r o u p h a s u s e d t h i s r e a g e n t t o reduce a-methyl-8-keto-esters w i t h t h e same s t e r e o c h e m i c a l

4: Alcohols, Halogeno-compounds, and Ethers

23 5

OH R1C02Et

-b

R1 A

R

2

Reagent: i; Lif3H4, R 2 MgCl ( 0 . 5 : 2.01, THF, -20-0

OC,

24 h

Scheme 1

Reagent : i, BH3Me2S, NaBH4 cat., THF, r . t , 1 h

Scheme 2

"'AH

i R

0

I

A

H

+

R1+H

OR2

HO

OR2

crythro major

Reagent : i , Zn(BH4I2, Et20,

o

O c

R2

possibly via :

/

H

Scheme 3

HO

OR2

236

General and Synthetic Methods

outcome in the synthesis of structures related to subunits in polyether antibiotics.21a 0-Hydroxy-ketones with a-substituents are similarly converted largely into the erythro configurated products by initial treatment with tri-n-butylphosphine followed by sodium borohydride at -100 OC (Scheme 4).22 In contrast, L-Selectride has been shown to convert a-methyl-u,B-unsaturated ketones into the threo-homoallylic alcohols, generally with 99% stereoselectivity (Scheme 5) . 2 3 L-Selectride has also been found to reduce ketones with an a-thioether substituent to largely the *-products whereas the same substrates frequently gave antiproducts when zinc borohydride was used (Scheme 6)?4 Lithium aluminium hydride reduces B,B-dimethylthio-a,~-unsaturatedketones to the a n t i - a l c ~ h o l s . ~The ~ stereospecific reduction of the double bond is explained by formation of a cyclic intermediate (Scheme 7). Other reducing agents which have been investigated include sodium hydrogen telluride (prepared in situ from tellurium-sodium borohydride) which chemoselectively reduces ~1 ,f3-epoxy-ketones to 8-hydroxy-ketones . 2 6 Potassium 9-thexyloxy-9boratabicyclo[3.3.1]nonane ( 1 ) has been shown to possess similar selectivity to L-selectride, and to be stable for long periods when stored under nitrogen in tetrahydrofuran. 27 A combination of sodium borohydride-tartaric acid has been shown to reduce cyclic In this instance the ketones mainly to the equatorial alcohols.28 reducing species is presumed to be an in situ generated acyloxyborohy&ide . Asymmetric Carbonyl Reductions. Enantioselective reducing agents in which a chiral moiety is combined with a reducing species continue to attract much attention. For borane-base reducing agents the chiral adducts have ranged from (2)-(-)-2-amino-3methyl- 1 , I -diphenylbutan-I -01 (2) ,29 polymer-bound 2-proline ( 3 ) , 30 and isopinocamphenylborane derivatives , 3 1 a 7 b but optical yields using these reagents rarely reach useful levels. Borane-ammonia complexes with chiral ethers are restricted in their application to aromatic ketones and again the optical yields are generally only moderate. 32 Conversely , optical yields approaching 100% are frequently obtained using B-(3-pinanyl)-9borabicyclo[3.3.l]nonane (cf.2 , 115; 2 , 156) with u-keto-t-butyl esters33 or propargylic ketones. 34 Reductions with this reagent are accelerated and the optical yields may be increased by application of high pressure (6 kbar) to the reaction.35 Changing

231

4: Alcohols, Halogeno-compounds, and Ethers

major Reagents : i * Bun3B, air, THF, r t , 2 h ; i i , NaBH4, -100

Scheme

OC,

6h

4

threo major usually about 99 : 1 Reagent: i. L-selectride, THF, -78

OC

Scheme 5

anti 5 ii, R3= Me

minor

R e a g e n t s : i, L - s e l e c t r i d e , THF; ii. Z n ( B H 4 I 2 , T H F

Scheme 6

major

General and Synthetic Methods

238

RJy

HO

H

i ,

SMe

Regents : i , LiALH4, THF, 0

C'

-

H

reflux

Scheme 7

q

H ONH2 H

& o c H * + @

I

Me

/x

(410;X = - B

c

b ; X =-AlCl;!

(3)

SMe

4: Alcohols, Halogeno-compounds, and Ethers

239

from 8-(~-lO-pinanyl)-9-boratobicyclo~3.3.1]nonane (4a) to the corresponding aluminium derivative ( 4 b ) permits a change in reductive Bnantioselectivity .36 Use of the aluminium reagent (4b), prepared in four steps from (-)-B-pinene, generally results in optical yields of about 80%.37 Several research groups continue to investigate the enantioselectivity of aluminium hydrides combined with 2,2'd i h y d r ~ x y b i p h e n y l s ~(5a) ~ and the related binaphthy13' (cf. 2, 143; 6 , 16 1 ) (5b) and biphenanthry14' ( 5 c ) derivatives. These reagents generally only show good enantioface selectivity with aromatic ketones. Other chiral partially decomposed lithium aluminium hydride reagents investigated included the protected a-Dglucofuranose complex ( 6 ) , which results in only moderate enantiomeric excesses of (S)-alcohols. A q in situ prepared reagent from lithium aluminium hydride/(lf172S)-(-)-E-methylephedrine/ 2-alkylaminopyridine (1:1:2) has been applied to the reduction of cyclic ketones with some success.42 Sharpless has developed a readily available chiral sulphamide for use as a chiral ligand in lithium aluminium hydride reductions ,43 and a reducing agent derived from di-isobutylaluminium hydride, tin(I1) chloride, and a proline-derived diamine has also been applied to ketone reductions with moderate optical yields. " N-Benzolycysteine has been used similarly as a chiral ligand with lithium borohydride, frequently giving high optical yields in the reduction of aromatic ketones.45 Microbial enantioselective reduction of ketones is growing in importance particularly as the extremely high optical yields are frequently being complemented by good chemical conversions. A review of the strategies of using intact cells or isolated enzymes has appeared during 1984.46 Ready availability is undoubtedly a feature in the popularity of Baker's yeast (Saccharomyces cerevisiae). Substrates have included a-sulphenyl-B-keto-esters (Scheme 8a) ,47 aryl ketones (Scheme 8b) ,48 and 4-thiacyclohexanone carboxylic esters (Scheme 8c) .49 A l l substrates gave good chemical and usually excellent yields. Reduction has been shown to occur on the re face of the prochiral ketones.47 Baker's yeast has been successfully used in cyclohexane-1,3-dione reductions to synthesize a zoapatanol precursor50 and in the preparation of chiral anthracyclinone intermediates. Other microbial systems used for enantioselective reductions of 8-keto-esters include Saccharomyces fermentati,52 Aspergillus niger , Geotrichum candidum,53 and the thermophilic bacterium

General and Synthetic Methods

240

OR (5)

c;

L =

qH

+02 R’

R3

i

-

I

,j l / c o z

- iii R

R3

SR2 R e a g e n t s : i , Yeast, a q glucose, I I , ~ - C L C ~ H ~ C O iii, ~ HAI/Hg ,

I

d

Reagent

: i , Yeast, a q . glucose

Reagent : i , Y e a s t , aq. sucrose, 30

Scheme

OC,

8

MeOH, 2 - 3 d a y s

a

4: Alcohols, Halogeno-compounds, and Ethers

The rmoanaerobium br ock ii

24 1

.

By Nucleophilic Additions. Investigations into stereoselective aldol condensations continue to be pursued vigorously and the by Reetz on the subject has been reviewed by H e a t h ~ o c k . ~Work ~ titanium(1V)-catalysed aldol addition to chiral a- and B-alkoxyaldehydes has been shown to yield mainly 'chelationlsyn' adducts (Scheme 9 ) . 5 6 This result, somewhat in conflict with earlier work of Heathcock, is considered to be due to initial precomplexation of the alkoxy-aldehyde at -78 OC as temperatures higher than -50 OC have been found to cause decomposition of the complex.57 Indeed Reetz has demonstrated the reversal of stereoselectivity with this system if boron trifluoride is used as the Lewis catalyst,58 although selectivities are lower than in the chelation-controlled titanium(1V) chloride process (Scheme 1 0 ) - Temperature-dependent stereoselectivity has also been noted in the aldol reaction of organotin reagents with aldehydes when threo-alcohols predominate at -78 OC and erythro at +45 0C.59 High erythro selectivity is observed using enolates obtained by generation with phenyldichloroborane and Hoenig ' s base,6 o and chiral boroazaenolates (7) derived from oxazolines have also been demonstrated to show stereoselectivity . a-Trimethylsilanes undergo regioselective aldol condensations depending on whether the enolate is generated with base or by using a Lewis acid (Scheme 1 1 ) .62 a-Methylene-8-hydroxy-esters may be stereoselectively prepared by reaction of the enolate of 8-dimethylaminopropanoates with aldehydes followed by quaternization and elimination (Scheme 1 2 ) . 6 3 The iron complexaluminium enolate (8) has been shown to undergo stereoselective condensation with aldehydes to give complexes which yield erythro8-hydroxy-acids upon further alkylation and oxidative decomplexation. 64 Chiral a-halogenoimidates have been utilized in a chiral aldol procedure favouring syn-adducts which in some cases, where the halide was bromide, could be converted into epoxides to constitute a chiral Darzens condensation (Scheme 1 3 ) .65 A wide range of metals has been investigated in the search for a means of allylating carbonyl compounds in a regio- and diastereo-selective manner. The Lewis acid-mediated reactions of crotyl-stannanes has been shown to occur at the y-position of the allylic unit to yield predominantly erythro-B-methyl-homoallyl alcohols regardless of initial crotyl stereochemistry 66 Allyl-stannanes likewise add to

.

General and Synthetic Methods

242

-

-

7

JC ! RO"

1,

"0

ii, iii

Ph

RO

RO

non-chelation/unti Reagents

i. T i C t 4 , - 7 8

RO chelation /anti

non -chelation/syn

OCj

, -78

ii,

Scheme

Reagents : i, BF3 gas, CHZCIz,

- 95

OC,

RO

OC;

c helation /syn

iii,H30+

9

5 min; ii.

,

4 0 T M S B "t

Scheme 10

- 95

OC,

1h

243

4: Alcohols, Halogeno-compounds, and Ethers

0

R’

R+’R2

i,ii

~

R3+ R2 OH

SiMe3

0

iii, i i 4

Reagents : i . BF3.Et20, SnC14 or TiCl,+, CH2Cl , - 7 8 O C , 1 h; ii, R3CHOi iii, L D A , THF,

- 78

OC,

15 min

Scheme 11

c

R2## H

R’O i

R’0

H

- iii R2

CHO

N

H

-co2R3 OH

co,

R~

+

R2 HO’

major

Me, N

Reagents : i , LDA , THF; ii, MeI, MeOH,

- 15 OC; i i i , DBU,

Scheme 12

a c e t o n e , r.t.

H

General and Synthetic Methods

244

Y

GR + yy R

I

i

X

i, ii, iii 4

0 Y

X = Br or C I Y =

L f-i

V R

+

X

syn (favoured)

iii,

RCHO,

- 20

iu anti

O K0" Reagents : i , L D A , E t 2 0 , THF; ii, Bu"2BOTf;

Y

OC

Scheme 13

[ dBR

R

245

4: Alcohols, Halogeno-compounds, and Ethers a-silyloxy-aldehydes erythro-Cram

under Lewis a c i d c a t a l y s i s t o g i v e l a r g e l y

p r o d u c t s . 67

Use o f

0:

-benzyloxy-aldehydes

similar c o n d i t i o n s f u r n i s h e s t h e threo-anti-Cram

stereoselectivity. y-position.68ay

under

products with high

C r o t y l d e r i v a t i v e s once a g a i n a t t a c k

via

the

A l l y l - s t a n n a n e s g e n e r a t e d i n s i t u from t h e

r e q u i s i t e b r o m i d e s a n d t i n powder a d d i n h i g h y i e l d t o c a r b o n y l c o m p o u n d s , 6 9 a n d s u c h a p r o c e s s h a s b e e n made c a t a l y t i c i n t i n by e l e c t r o c h e m i c a l l y r e g e n e r a t i n g t h e a l l y l - s t a n n a n e .70 Acetylenic a l c o h o l s h a v e a l s o b e e n p r e p a r e d by g e n e r a t i n g b i s a l l e n y l s t a n n y l d i b r o m i d e f r o m p r o p a r g y l b r o m i d e a n d t i n metal a n d r e a c t i n g t h i s with carbonyl

compound^.^'

y-(Alky1thio)allylboronates a d d t o t o give B-thioalkyl-homoallylic a l c o h o l s w i t h h i g h d i a s t e r e o s e l e c t i v i t y d e p e n d e n t upon t h e i n i t i a l

aldehydes a t t h e y-position

s t e r e o c h e m i s t r y of t h e a l l y l u n i t .72

Extremely high

e n a n t i o s e l e c t i v i t y i n t h e a l k y l a t i o n of aldehydes h a s been achieved u s i n g t h e a l l y l a t e d di-isopinocamphenylboranes ( 9 a ) a n d ( 9 b ) 7 3 a n d

B-allyldi-isocaranylborane

(

(cf.3 , 1 4 4 ; 5 ,

164;

6,

169).

T i t a n i u m r e a g e n t s d e r i v e d from a l l y l t h i o e s t e r s r e a c t w i t h aldehydes with high a - s e l e c t i v i t y due t o t h e t h i o e t h e r s u b s t i t u e n t .75

The d i a s t e r e o s e l e c t i v i t y f o r t h e

y

-adducts obtained

from t h e r e a c t i o n of c r o t y l t i t a n i u m r e a g e n t s t o a l d e h y d e s h a s been shown t o b e d e p e n d e n t upon L e w i s a c i d p r o m o t i o n . 7 6

I n the absence

of boron t r i f l u o r i d e t h e e r y t h r o - p r o d u c t s a r e favoured whereas t h e i n v e r s e r e s u l t i s o b t a i n e d i n t h e p r e s e n c e of boron t r i f l u o r i d e (Scheme 1 4 ) .

B i s a l l e n y l z i n c c h l o r i d e , g e n e r a t e d from a l l e n y l -

l i t h i u m , r e a c t s with aldehydes t o f u r n i s h homopropargylic alcohols77 similarly t o the allenyl-stannanes. at the y-position

Alkylation occurs

and, i n t h e case of y-alkylallenyl reagents,

t h r e o s e l e c t i v i t y is observed. Allyl-cerium r e a g e n t s add c l e a n l y t o c a r b o n y l g r o u p s a n d t h i s c o n v e r s i o n c a n b e s i m p l y c a r r i e d o u t by r e a c t i n g a l l y l i o d i d e w i t h c e r i u m amalgam i n t h e p r e s e n c e o f t h e k e t o n e .78

High a - r e g i o s e l e c t i v i t y

for t h e a l l y l n u c l e o p h i l i c

m o i e t y c a n be o b t a i n e d u s i n g t h e a l u m i n i u m o r b o r o n ' a t e ' c o m p l e x e s ( 1 1 ) . 7 9 A l l y l - s i l a n e s h a v e b e e n shown t o r e a c t w i t h h i g h 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 w i t h c h i r a l a- a n d B - b e n z y l o x y aldehydes under L e w i s a c i d c a t a l y s i s . 8 0 c o n t r o l l e d and u-benzyloxyaldehydes

The r e a c t i o n i s c h e l a t i o n

lead t o threo-diol

derivatives

w i t h h i g h s e l e c t i v i t y (Scheme 1 5 ) . P r o p a r g y l i c s i l a n e s r e a c t w i t h c a r b o n y l compounds i n t h e p r e s e n c e of 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 w i t h r e a r r a n g e m e n t t o produce a l l e n i c a l c o h o l s , u s u a l l y i n moderate y i e l d s . 8 1

Grignard

General and Synthetic Methods

246

r X = Cl, Br or I

\

Favoured

threo ii

~

erythro Favoured

R e a g e n t s : i, RCHO; ii, RCHO, BF3.Et20

Scheme 14.

threo 45

R e a g e n t : i , SnC14, CH2C12, - 78

OC

Scheme 15

erythro 1

4: Alcohols, Halogeno-compounds, and Ethers

247

reagents are reported to undergo stereoselective Cram-type addition to 2-alkyl-3-trimethylsilyl-3-unsaturated aldehydes in good yield These substrates react similarly with ketone and (Scheme 16) ester enolates.83 (1sopropoxydimethylsilyl)methylmagnesium chloride has been developed as a synthon for the hydroxymethyl anion.84 The advantage of this reagent over the similar di-isopropoxymethylsilyl derivative is that it will undergo conjugate additions as well as simple additions to carbonyl compounds. Another means of hydroxymethylating ketones involves the samarium iodide-mediated addition of chloromethylbenzyl ether followed by hydrogenolysis. 85 This method may also be applied to aldehydes although with these substrates pinacol coupling is frequently troublesome. a-Alkoxysilanes similarly add to carbonyl compounds in the presence of an equivalent o f caesium fluoride in dimethylformamide to furnish 1 , 2 diols after removal of the alcohol masking group.66 1,3-Diols may be prepared f r o m ally1 alcohols silylmethyl radical cyclization and oxidative cleavage of the cyclic silyl ether thus produced (Scheme 17).87 The anion generated from chlorome.thy1 phenyl sulphone has been shown to add to ketones to produce a,8-epoxy-sulphones, which on base treatment furnish a-hydroxy-aldehydes, resulting in homologation of ketones to a-hydroxy-aldehydes .88 Similar homologation may be achieved by nucleophilic addition of the anion derived from cyclic 1,3-oxathianes to aldehydes. The adduct may be converted directly into the homologated product or oxidized and realkylated by Cram addition of alkyl Grignard reagents (Scheme 18).89 This sequence has lent itself to the efficient asymmetric synthesis of various a-hydroxylated compounds using 1,3-oxathiane Alkylation of ketones with a-nitroderived from (+)-pulegone .” anions is usually inefficient when both the ketone and nitrocompound are sterically encumbered. However, it has been demonstrated that in some cases use of tetrabutylammonium fluoride and high pressure (9 kbar) renders such condensations efficient .” Nucleophilic cleavage of acetals continues to be developed as a means of generating chiral alcohols (Scheme 19). Combinations of Grignard reagents with titanium(1V) or organotitanium reagentsg3 are commonly used, but organoaluminium cleavageg4 and boron trif luoride-promoted cleavage with organocupratesg5 have also been reported. The readiness of epoxides to undergo nucleophilic cleavage has

General and Synthetic Methods

248

-

S iMe,

SiMe, OH

R'M~X

R'+cHo

R2

R1+

Scheme 16

SO" --L-0 I

-Lq h SiMe,

j iii

HO

6 r CH2SiMe2 Reagents : i, Me2SiCl(CH2Br), Et3N,CH2Cl2, r.t C6H6,

A ; iii, H202

;

OH

ii, Bun3SnH, AIBN (cat.)

or peracid, DMF, KF or KHFZ

Scheme 17

1 Reagents: i, BuLi; ii, R CHO; iii, OMSO,(CF,CO),O, VI

Et3N; iv, R2MgI;

V.

H20;

, N- chlorosuccinimide, AgN03

Scheme 18

y -L

R2

ii, iii

-> , OH

R' O X H0

Reagents: i, R2 Metal, Lewis acid; ii, Oxidation; iii, Base

Scheme 19

Rlx;

4: Alcohols, Halogeno-compounds, and Ethers

249

received further attention. Dilithium tetrabromonickelate(I1) has been used as a source of soft nucleophilic bromide to convert epoxid,es into b r ~ m o h y d r i n s . ~The ~ reaction is very sensitive to steric factors and hindered epoxides are unreactive. Opening of epoxides with lithium acetylides promoted by boron trifluoride is high-yielding and is regioselective with attack occurring at the least hindered carbon. 97 Alternatively a catalytic quantity of trimethylgallium has been shown to increase the yield of this r e a ~ t i o n . ’ ~ A trimethylsilyl cyanide-zinc iodide combination will cleave chiral a,B-epoxy-alcohols obtained by the Sharpless procedure to establish three contiguous chiral centres and furnish 3-substituted 1,2-diols.99 13 ,y-Epoxy-halides are cleanly converted into allylic alcohols using butyl-lithium o r sodium iodide-zinc An electrochemical epoxide cleavage procedure dust (Scheme 20). l o o has been developed,”’ and the chiral amide base (12) derived from (S)-2-(pyrrolidinomethyl)pyrrolidine has been used to obtain (S)-2cyclohexen-1-01 in 92% e.e. from cyclohexene epoxide. 102 Nucleophilic substitution of oxetanes, although less facile than that of epoxides, occurs readily with lithium alkyllo3 and acetylidelo4 reagents. The use of aminosilanes o r aminostannanes provides a two-step procedure for regiospecifically converting oxetanes into 3-amino-alcohols (Scheme 21). O 5 An intramolecular nucleophilic substitution of the oxetane system has been carried out by in situ generated benzyl anion (Scheme 22). 106 Regioselective ring opening of unsymmetrical cyclic ethers has been demonstrated using aluminium chloride-sodium iodide in acetonitrile. The yields are good and in all instances the alcohol with the highest degree of a-substitution is the major product.lo7 Miscellaneous Methods. Wittig [2,3]-sigmatropic rearrangements have been widely utilized to generate B-substituted homoallylic alcohols with a high degree of stereoselectivity, both relative and absolute. g-Crotyl ethers yield threo-alcohols O 8 and Z-crotyl ethers form erythro-products (Scheme 23). ’ 0 9 ’ ’lo 1,4-Chirality transfer has been demonstrated using chiral allylic propargyl ethers, chiral bisallylic ethers, and ethers in which the migrating terminus constitutes a chiral azaenolate ( 13). Organoaluminium-promoted aliphatic Claisen rearrangements have been used to prepare homoallylic alcohols via initial rearrangement of ally1 vinyl ethers followed by transfer of an alkyl group from the aluminium reagent to the aldehyde thus formed.

250

General and Synthetic Methods

i

HO"

R

SO"

X = Br, I or CL Reagents : i, Sharpless epoxidation procedure; ii BunLi, THF, I

or

Z n , NaI, MeOH, reflux

Scheme 2 0

- 23

OC

4: Alcohols, Halogeno-compounds, and Ethers

25 1

Ph

n = 1 , 2 , 3 or 4 Reagents: i, BunLi, HMPA, THF, - 7 8 to 0 OC

Scheme 2 2

I I

I

erythro

threo

Scheme 23

252

General and Synthetic Methods

a-Acyloxyacetates are rearranged in the presence of potassium carbonate into 2-hydroxy-3-keto-esters. a-Hydroxylation of this ketones has been demonstrated using 2-iodosylbenzoic acid ;I procedure is facilitated by the base solubility in alkali of the 2-iodobenzoic acid produced. The phenyldimethylsilyl group may be converted into a hydroxy-group via the fluorodimethylsilyl species by sequential treatment with fluoroboric acid and peracid. 177 a,8-Unsaturated aldehydes are precursors to a-functionalized a-hydroxyallenes a-phenylseleno-enals (Scheme 24). 118 Cohalogenation of olefins has been applied to the synthesis of allylic alcohols in which the double bond has undergone a 1,2transposition (Scheme 25). 119

Protection and Deprotection.- Various bases have been shown to be advantageous in the preparation of t-butyldimethylsilyl ethers. 1,1,3,3-Tetramethylguanidine (0.2 equvalents) has been shown to be more effective than triethylamine for primary and secondary alcohols’2o and di-isopropylamine in dichloromethane or DMF also In DMF permits protection of tertiary and hindered alcohols. 12’ the silylation of primary alcohols is exothermic using this reagent. t-Butylmethoxyphenylsilyl bromide has been developed as a less sterically demanding, acid-stable protecting group for primary, secondary, and tertiary alcohols when used in DMF with triethylamine. 122 Use of dichloromethane as solvent in the absence of base permits selective protection of primary alcohols and the ethers formed are more easily cleaved with fluoride than t-butyldimethylsilyl ethers. Japanese workers have developed the related 2-benzyloxyprop1 -ene123 and 2-benzyloxy-3-fluoroprop-I -enel 24 to protect alcohols

as acetals under neutral conditions with palladium catalysis. Deprotection is carried out by hydrogenolysis and the acetals derived from the fluoro-reagent are resistant to acid hydrolysis. 3,4-Dimethoxybenzyl ethers may be oxidatively cleaved more readily than the 4-methoxybenzyl ethers previously used. 125 Both of these ethers are more resistant to hydrogenolysis than benzyl ethers, permitting selective removal of the latter. 126 Benzyl ethers may be cleaved with triethylsilane, palladium(I1) chloride, and triethylamine at elevated temperatures if the presence of sensitive functionalities within the molecule renders catalytic or Birch reduction impossible. 127 Methoxymethyl ethers may be cleaved with trimethylsilyl bromide

253

4: Alcohols, Halogeno-compounds, and Ethers

R’

R1

\

i . ii

\

0

\\

qh

R’

Fc‘ R ’ R2

R2

HO

Reagents : i, Morpholinobenzeneselenamide, hexane r . t ; ii, S i 0 2 ; iii, RZCH=PPhg ~

THF, -30

OC;

iv, H202, CHZCl2, 20

OC;

V.

Et3N, THF, H20, A

Scheme 24

Reagents

;

i, NBS, R20H (RZ=PhCH2 or Me 1; ii,ButOK, 18 - c r o w n - 6, C6H6, r e f l u x

iii, N a , NH3 (R2=PhCH2), NaI, ButCOCl, K2CO3

(R2= Me)

Scheme 25

Reagents: i, E l e c t r o l y s i s , AcOH, AcONa; ii, K2CO3; aq. MeOH

Scheme 26

I

PhO

I

k O ] M e , I

I

I

I

Figure 1

i

General and Synthetic Methods

254

i n d i c h l o r o m e t h a n e a t 0 OC when e s t e r s a n d b e n z y l a n d t-butyldimethylsilyl

e t h e r s a r e s t a b l e . 28

Similarly,

m e t h o x y e t h o x y m e t h y l e t h e r s a r e d e p r o t e c t e d w i t h a c o m b i n a t i o n of t r i m e t h y l s i l y l c h l o r i d e - s o d i u m i o d i d e a t low t e m p e r a t u r e w i t h o u t a f f e c t i n g l a c t o n e s or e s t e r s .

C h l o r o m e t h y l m e t h y l e t h e r , now

d i f f i c u l t t o o b t a i n c o m m e r i c a l l y o w i n g t o i t s t o x i c i t y , may b e c o n v e n i e n t l y p r e p a r e d by a p r o c e d u r e i n w h i c h m e t h o x y a c e t i c a c i d i s

(cf.2 ,

refluxed with thionyl chloride

153) .I3'

Methyl thiomethyl

e t h e r s a r e c o n v e r t e d i n t o a c e t o x y m e t h y l e t h e r s by e l e c t r o l y s i s i n a c e t i c a c i d , a c e t a l s and t e t r a h y d r o p y r a n y l e t h e r s r e m a i n i n g i n t a c t under t h e s e c o n d i t i o n s .

The a c e t o x y i n t e r m e d i a t e s may b e

d e p r o t e c t e d w i t h o u t t h e n e c e s s i t y f o r i s o l a t i o n (Scheme 2 6 ) . T r i s ( m e t h y 1 t h i o ) 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 c l e a v e d w i t h mercury(I1) a c e t a t e i n aqueous a c e t o n i t r i l e . P e r f l u o r o a r y l e t h e r s may b e c l e a v e d u s i n g s o d i u m m e t h o x i d e i n DMF.

" Under t h e s e c o n d i t i o n s p h e n o l e t h e r s a r e s e l e c t i v e l y

deprotected over a l i p h a t i c ethers.

Boron t r i c h l o r i d e s e l e c t i v e l y

c l e a v e s h i n d e r e d a r y l m e t h y l e t h e r s . 34

This f e a t u r e is

r a t i o n a l i z e d as c o m p l e x a t i o n o f t h e b o r o n w i t h t h e e t h e r , which h a s been deformed o u t o f t h e p l a n e of t h e a r o m a t i c r i n g , h a v i n g i t s oxygen l o n e p a i r s more a v a i l a b l e .

The d e f i n i t i v e p a p e r o f e a r l i e r

work o n t h e 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 a n d d i p h e n y l b o r o n b r o m i d e

for m i l d e t h e r c l e a v a g e h a s a p p e a r e d d u r i n g I 9 8 4 . 35

Aluminium

i o d i d e h a s b e e n f o u n d t o show n o v e l c l e a v a g e b e h a v i o u r c o m p a r e d w i t h boron and s i l i c o n h a l i d e s ,

over a l k y l ethers (Figure 1)

.

selectively cleaving aryl ethers

36

Dimethylaluminium c h l o r i d e h a s

been found u s e f u l i n t h e s e l e c t i v e c l e a v a g e of t e t r a h y d r o p y r a n y l e t h e r s i n t h e p r e s e n c e o f t - b u t y l d i m e t h y l s i l y l e t h e r s . 37 P r o t e c t i o n g r o u p i n t e r c o n v e r s i o n h a s been r e p o r t e d whereby m e t h o x y m e t h y l e t h e r s may b e c o n v e r t e d i n t o t h i o e t h e r s w i t h d i ( i s o p r o p y 1 t h i o ) b o r o n b r o m i d e i n t h e p r e s e n c e of 2 e q u i v a l e n t s of 4-dimethylaminopyridine

a t -95

p y r i d i n e t h e a l c o h o l is obtained.

I n the absence of t h e Conversion i n t o t h e cyanomethyl

e t h e r may b e a c h i e v e d w i t h a n e x c e s s o f d i e t h y l a l u m i n i u m c y a n i d e i n toluene near reflux. Reactions.- Oxidation. O x i d a t i o n s of p r i m a r y a n d s e c o n d a r y a l c o h o l s t o aldehydes and k e t o n e s r e s p e c t i v e l y have been d e m o n s t r a t e d u s i n g bis(2,2'-pyridyl)copper(II)

p e r m a n g a n a t e . 139

P h o t o - o x i d a t i o n , c a t a l y s e d by p l a t i n i z e d t i t a n i u m ( I 1 ) o x i d e , h a s b e e n d e v e l o p e d a s a c o n v e n i e n t m e a n s of p r e p a r i n g a l d e h y d e s

255

4: Alcohols, Halogeno-compounds, and Ethers

a l t h o u g h o x i d a t i o n of s e c o n d a r y a l i p h a t i c a l c o h o l s i s l o w e r y i e l d i n g . I4O Crown e t h e r s h a v e b e e n a p p l i e d t o t h e h e t e r o g e n e o u s o x i d a t i o n o f secondary a l c o h o l s , a c c e l e r a t i n g and improving t h e y i e l d of chromium t r i o x i d e o x i d a t i o n s i n d i c h l o r o m e t h a n e . O x i d a t i o n of s e c o n d a r y a l c o h o l s h a s a l s o b e e n c a r r i e d o u t u n d e r n e u t r a l c o n d i t i o n s via t h e i r c a r b o n a t e s u n d e r p a l l a d i u m catalysis. Phase t r a n s f e r - c a t a l y s e d o x i d a t i o n o f 2-hydroxynitroalkanes yield

h a s been demonstrated t o occur i n high

and a-hydroxy-esters

and - n i t r i l e s

catalysed oxidation with t-butyl r e s p e c t i v e keto-products. 144

undergo ruthenium-

hydroperoxide t o furnish t h e

S p e c i f i c o x i d a t i o n s of b e n z y l i c and a l l y l i c a l c o h o l s h a v e been c a r r i e d o u t u s i n g a suspension o f barium r u t h e n a t e i n dichloromethane

a n d a l s o r u t h e n i u m d i o x i d e i n 1 ,2 - d i c h l o r o e t h a n e

under a n oxygen atmosphere.

A v a r i a t i o n of t h i s system u s e s

RuVI1 s p e c i e s , g e n e r a t e d by o x i d a t i o n o f r u t h e n i u m ( 111) c h l o r i d e w i t h p o t a s s i u m p e r s u l p h a t e ; i n t h i s case p r i m a r y a l c o h o l s a r e o x i d i z e d t o c a r b o x y l i c a c i d s . 146 A n o t h e r r e a g e n t s y s t e m w h i c h o x i d i z e s b e n z y l i c and a l l y l i c a l c o h o l s s e l e c t i v e l y is t e t r a k i s ( p y r i d i n e ) s i l v e r d i c h r o m a t e ' 47 a n d a t m o s p h e r i c o x y g e n , m e d i a t e d by c o p p e r ( I 1 ) a n d n i t r o s o n i u m i o n . 148 N o v e l r e a g e n t s f o r t h e highly s e l e c t i v e oxidation of benzylic alcohols include cetyltrimethylammonium permanganate, trihydroxyhydroperoxide chromate'

ceric

i n benzene, I5O b i s [ t r i n i t r a t o c e r i u m ( IV) I

and d i m e t h y l s e l e n o x i d e - p o t a s s i u m b e n z e n e s e l e n i t e . 152

Various r e a g e n t s have been developed t o c a r r y o u t s e l e c t i v e o x i d a t i o n s of s e c o n d a r y i n t h e p r e s e n c e o f primary a l c o h o l s . s t e p procedures have u t i l i z e d polymer-supported cerium( IV) r e a g e n t s molydbdate-hydrogen

,

One-

c h r o m i u m ( I I 1 ) or

r e g e n e r a t e d w i t h s o d i u m p e r b o r a t e , 15'

ammonium

p e r o x i d e , 154 a n d b e n z y l t r i m e t h y l a m m o n i u m

tetrabromo-oxomolybdate. 1 5 5

A three-step

procedure proceeds

s e l e c t i v e s i l y l a t i o n o f p r i m a r y a l c o h o l s f o l l o w e d by o x i d a t i o n o f secondary hydroxy-groups with pyridinium f l u o r o c h r o m a t e , which does n o t r e m o v e a c i d - l a b i l e s i l y l g r o u p s ( S c h e m e 27).156 A m e a n s o f c a r r y i n g o u t t h e a l t e r n a t i v e c o n v e r s i o n , G. primary i n p r e f e r e n c e t o s e c o n d a r y a l c o h o l o x i d a t i o n , i n v o l v e s t h e u s e of a n e q u i v a l e n t

o f osmium t e t r a o x i d e i n e t h e r - a c e t i c

a c i d a t room t e m p e r a t u r e . 157

I n t h e absence of primary hydroxy-groups, hydroxy-groups can be c l e a n l y o x i d i z e d .

however, secondary

O x i d a t i v e c l e a v a g e of b e n z y l i c d i o l s have been demonstrated u s i n g tris[trinitratocerium(IV)I

p a r a p e r i o d a t e . 158

256

General and Synthetic Methods

Deoxygenation. A review has been published which covers the preparation of olefins via deoxygenation of vicinal diols.159 A radical chain reaction deoxygenation procedure for tertiary alcohols has been developed based on the decomposition of the mixed oxalate ester with N-hydroxy-2-thiopyridine (Scheme 28). 160 Tertiary hydroxy-groups have also been reductively removed from &,@-unsaturated 6-hydroxy-ketones using a chlorotrimethylsilanesodium iodide combination as an alternative to zinc-acetic acid reductions16 (cf. 6, 179). Iodotrimethylsilane (presumably the active species in the previous case) has been used to effect selective removal of the tertiary hydroxy-group at C-17 of the dihydroxyacetone moiety of steroids. 16* Miscellaneous Reactions. The conversions of alcohols nucleophilic attack on oxyphosphonium intermediates have been reviewed. 163 Benzoyl triflate has been introduced as a reagent f o r benzoylating sterically hindered secondary and tertiary alcohols. 1 6 4 Alcohols may be converted into triflates and tosylates under neutral conditions using the sulphonyl pyridiniurn Tertiary, benzylic, and allylic alcohols may be reagents (14). converted into dialkyl selenides by reacting with the requisite alkyl selenides in refluxing 1,2-dichloromethane in the presence of zinc chloride. Alkanesulphuric acids have been prepared from alcohols via the 2-alkylthiobenzothiazoles in good overall yield (Scheme 29). Under Lewis acid catalysis, benzylic and tertiary alcohols have been converted into azides with hydrazoic acid. Quantitative dehydration of tertiary and benzylic cycloalkanols has been shown to be possible using 4h or 5A molecular sieves in benzene at room temperature, 69 and threo- 1 ,2-diols may be stereospecifically converted into Z-01-efins with phosphonium iodide followed by treatment with base. 17' An efficient method for inverting secondary alcohols uses an excess of caesium acetate in refluxing toluene together Kith 18crown-6. 17' In the absence of crown ether some olefinic products are also formed. Allylic alcohols have been found to undergo stereoselective y e - m e t a l l a t i o n with n-butyl-lithium in the presence of TMEDA. 172 The bisanionic products react with a wide variety of electrophiles (for long-chain alkyl halides a Cox' catalyst is required) with retention of configuration. Stereospecific migration of the alkenyl group of allylic alcohol derivatives via triethylaluminium-

4: Alcohols, Halogeno-compounds, and Ethers

257

Reagents : i, ButMeZSiCl, Et3N; ii, pyridinium fluorochromate, CHzCIZ, 2 5

iii, 6 u 4 N + F - , THF, 2 5

OC

OC

Scheme 27

o$- -+ 0

R&H

R3 0.

f Reagents:

i, ( C O C I ) ~ ; ii,& ((

I

OH

S Scheme 20

/-\

(14)

R =

or

CF3,

X = BFq-

General and Synthetic Methods

258

c a t a l y s e d p i n a c o l rearrangement h a s been developed t o p r o v i d e

a c c e s s t o o p t i c a l l y p u r e ( e . e . >99%) a-methyl-B,y-unsaturated k e t o n e s (Scheme 3 0 ) . 173 a ,B - U n s a t u r a t e d a l d e h y d e s are p r o d u c e d from p r o p a r g y l i c a l c o h o l s

via

a d d i t i o n of t h i o p h e n o l t o t h e

a c e t y l e n i c m o i e t y f o l l o w e d by h y d r o l y s i s o f t h e i n t e r m e d i a t e a d d u c t ( S c h e m e 31 ) . 17'

h a v e b e e n c o n v e r t e d i n t o B ,y -

Hex-5-en- I - y n - 3 - 0 1 s

u n s a t u r a t e d k e t o n e s by s i l v e r t r i f l a t e - c a t a l y s e d oxy-Cope r e a r r a n g e m e n t (Scheme 3 2 ) . 175

A one-step

h o m o a l l y l i c a l c o h o l s t o six-membered which u t i l i z e s r u t h e n i u m - c a t a l y s e d

homomologation o f

l a c t o n e s h a s been r e p o r t e d

hydroformylation under an

a t m o s p h e r e o f c a r b o n m o n o x i d e a n d h y d r o g e n a t 350 p . s. i . 76 2 - A c e t o x y b e n z o y l b r o m i d e , p r e p a r e d by t h e a c t i o n o f b r o m o s u c c i n i m i d e on 2 - a c e t o x y b e n z a l d e h y d e 1

E-

is a convenient reagent

f o r converting 1 , 2 - d i o l s i n t o epoxides i n a two-stage

procedure

via

t h e c o r r e s p o n d i n g a c e t y l a t e d b r o m o h y d r i n s w h i c h c o l l a p s e on b a s e t r e a t m e n t . 177 2

Halogeno-compounds

Preparation.-

From A l c o h o l s .

Various phosphine-derived

reagent

s y s t e m s h a v e b e e n shown t o c o n v e r t a l c o h o l s i n t o h a l i d e s .

Zinc azodicarboxylate-triphenylphosphine i n a n h y d r o u s THF c a u s e s m i l d SN2 r e a c t i o n and i s p a r t i c u l a r l y u s e f u l f o r o b t a i n i n g u n r e a r r a n g e d h a l i d e s from a l l y l i c a l c o h o l s . 178 O t h e r s y s t e m s developed include triphenylphosphine-methyl halide-4-methyl-Il2,4t r i a z o l i n e - 3 ,5 - d i o n e , triphenylphosphine-carbon t e t r a c h l o r i d e i m i d a z o l e , I8O and a p o l y m e r - s u p p o r t e d v a r i a n t . 18' Sterically h i n d e r e d c y c l o p r o p y l c a r b i n o l s may b e c o n v e r t e d i n t o t h e corresponding h a l i d e s , without formation of homoallylic cleavage p r o d u c t s , by t r e a t m e n t w i t h t r i p h e n y l p h o s p h i n e i n DMF f o l l o w e d by b r o m i n e o r by i n v e r s e a d d i t i o n t o a s t i r r e d s l u r r y o f 182 triphenylphosphine i n hexachloroacetone. D i r e c t conversions of a l c o h o l s i n t o c h l o r i d e s have been a c c o m p l i s h e d via a c l e a n S N 2 p r o c e s s u s i n g t h e i m i n i u m c h l o r i d e ( 1 5 ) . 1 8 3 C h l o r i d e s may a l s o b e o b t a i n e d u s i n g t o l u e n e - 2 - s u l p h o n y l The y i e l d s o f c h l o r i d e a r e chloride-dimethylaminopyridine. 18' g e n e r a l l y h i g h a n d s e n s i t i v e g r o u p s s u c h a s a c e t a l s , THP e t h e r s , and epoxides a r e u n a f f e c t e d . Regio- and s t e r e o - s e l e c t i v e c o n v e r s i o n of a l l y l i c a l c o h o l s i n t o h a l i d e s h a s b e e n a c h i e v e d t r e a t m e n t of t h e c o r r e s p o n d i n g a l l y l i c p h o s p h a t e s w i t h l i t h i u m h a l i d e s i n DMF a t room t e m p e r a t u r e . 185 The c o n d i t i o n s a r e m i l d

halide-diethyl

259

4: Alcohols, Halogeno-compounds, and Ethers

Reagents: i,

(ayF%,Bu3P, THF, ii. K M 4 . aq.AcOH; iii, NaBH4, MeOH Scheme 29

Reagents : i, €$A[,

CH2C12, -42

OC

Scheme 30

R‘

P OH

R2J&s,ph i’ii

*

iii

~

R2L

C

H

O

OH predominantly E

Reagents:

i, PhSH (0.25 q u i v added in 3 portions), 0 “c; i i , Recovery of excess alcohol, iii, H3O+

Scheme 31

Reagents

i, F3CS03Ag, og.THF, 20-60 C ‘,

1-48 h

Scheme 32

260

General and Synthetic Methods

Ph'

(15)

f

I I

SePh

iii, iv

+ ,Ph CL

Reagents :

i, PhSeCl , MeCN ; ii, CL2,CCl4 ; iii, Bun4NfCI-;

iv, H202

Scheme 33

Reagents : i, ( 4 8 ;

ii, MeOH;

iii, 12 ,NaOH, THF

3

Scheme 34

iii. i v

R 9

Reagents: i, NaOH a q . 5N; ii, I*, Etfl; iii, Br2,CH2CLZ, -25

Scheme 35

OC

; iv, N a m e , MeOH

261

4: Alcohols, Halogeno-compounds, and Ethers

enough t o c a u s e l i t t l e m i g r a t i o n a n d no g e o m e t r i c a l i s o m e r i z a t i o n

of t h e d o u b l e bond. By A d d i t i o n t o U n s a t u r a t e d S u b s t r a t e s .

A s a r e s u l t of a c o n v e n i e n t

method f o r i n s i t u g e n e r a t i o n o f D C 1 , u - d e u t e r i o - c h l o r i d e s o b t a i n e d r e a d i l y f r o m o l e f i n s . 186

may b e

The r e a g e n t i s g e n e r a t e d by

a d d i t i o n o f t i t a n i u m ( 1 V ) c h l o r i d e t o MeOD or D20 a t 5 OC. 1 , 2 - D i c h l o r i d e s h a v e b e e n p r e p a r e d by t h e a c t i o n o f m a n g a n e s e ( I I 1 ) c h l o r i d e s p e c i e s u p o n o l e f i n s . 187

Manganese(II1) a c e t a t e is

t r e a t e d w i t h e i t h e r c a l c i u m c h l o r i d e or a c e t y l c h l o r i d e i n r e f l u x i n g a c e t i c a c i d i n t h e presence of t h e o l e f i n . s o m e t i m e s r e s u l t s i n low y i e l d s f o r t h i s p r o c e s s . c h l o r i d e h a s been used i n a f o u r - s t e p

Elimination

Phenylselenyl

procedure f o r o v e r a l l

a d d i t i o n o f c h l o r i n e t o o l e f i n s , 1 8 8 a n d 4-(dimethylamino)pyridinium bromide perbromide i n a c e t i c a c i d r e a d i l y c o n v e r t s o l e f i n s i n t o 1,2-dibromides

(Scheme 3 3 ) .

B-Iodo-9BBN

i n r e f l u x i n g hexane has

b e e n shown t o r e a c t w i t h t e r m i n a l a l l e n e s t o g e n e r a t e 2 - i o d o - l a l k e n e s ; l g o B-bromo-9BBN procedure.

i s t o o u n r e a c t i v e t o be u s e d i n t h i s

l-Iodopenta-l,4-dienes

i o d i n a t i o n of penta-1,4-dienylboron

a r e t h e p r o d u c t s o b t a i n e d by derivatives,

themselves derived

from t r i a l l y l b o r a n e and t e r m i n a l a c e t y l e n e s (Scheme 3 4 ) .

Ene-

t y p e c h l o r i n a t i o n of t r i s u b s t i t u t e d o l e f i n s h a s b e e n d e m o n s t r a t e d t o occur with dichlorine oxide, furnishing t h e rearranged a l l y l i c chloride.

Both c h l o r i n e atoms of t h e r e a g e n t are u t i l i z e d and

t h e y i e l d s and r e g i o s e l e c t i v i t y are r e p o r t e d t o be h i g h . Interhalide Conversions.

Primary a l k y l c h l o r i d e s have been

c o n v e r t e d i n t o t h e i r c o r r e s p o n d i n g bromides w i t h sodium bromide i n DMF-methylene

bromide

” a n d a l s o via a p h a s e - t r a n s f e r v a r i a n t o f

t h e F i n k e l s t e i n r e a c t i o n using calcium bromide-tetra-nbutylammonium b r o m i d e .

94

I n t e r c o n v e r s i o n of primary a l k y l

b r o m i d e s a n d c h l o r i d e s i n t h e p r e s e n c e o f a q u a t e r n a r y ammonium

s a l t i s p o s s i b l e by r e f l u x i n g i n 1 , 2 - d i c h l o r o e t h a n e ( R B r R C 1 ) or R B r ) .Ig5 A l k y l f l u r o i d e s may b e o b t a i n e d by

p r o p y l bromide ( R C 1

-

--t

t h e a c t i o n o f q u a t e r n a r y ammonium f l u o r i d e s u p o n a l k y l h a l i d e s . T h i s p r o c e s s i s m o s t e f f i c i e n t when a n h y d r o u s t e t r a - n - b u t y l a m m o n i u m f l u o r i d e ( o b t a i n e d by h e a t i n g t h e c o m m e r c i a l l y a v a i l a b l e h y d r a t e t o 40 OC u n d e r h i g h v a c u u m ) i s u s e d 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 solvent.

262

General and Synthetic Methods

Miscellaneous Methods. Iodine in the presence of a mixture of copper(1) and copper(I1) chlorides will directly iodinate carboxylic acids at the a-position. Hexabromocyclopentadiene will readily brominate activated sites such as a-keto and benzylic positi~ns.’’~ Benzyl halides may be obtained from the corresponding aldehydes by treatment with an inorganic halide in the presence of chlorotrimethylsilane-I , I , 3,3-tetramethylsiloxane. This combination of reagents has been used to carry out reductive halogenation of terminal epoxides to give 2-halogenoalkanes . Procedures have been published f o r the synthesis of E-vinyl bromides and Z-vinyl iodides from ?-vinyl boronic esters (Scheme 3 5 ) .201 Aromatic compounds may be directly iodinated in the presence of mercury(I1) oxide-fluoroboric acid supported on silica. 202

”’

Reactions.- The use of polyvalent iodine compounds in organic synthesis has been the subject of a review.203 Monohalogenomethyllithium reagents, of potential synthetic utility, have been shown to be stabilized by the presence of an equivalent of lithium bromide and may thus be generated by the addition of s-butyllithium to the methylene dihalide-lithium bromide mixture at -110 0c.204 Reductive dehalogenation of 1,2-dibromides to olefins has been performed using titanium catalysts,2 0 5 sodium sulphide under phasetransfer conditions,206 potassium-graphite intercalate,*07 tin( 11) chloride-di-isobutylaluminium hydride ,208 and sodium dithionite under phase-transfer conditions. 209 In the latter instance threodibromides are shown to be converted selectively into E-olefins whereas erythro-dibromides gave mixtures. Monodebromination of 1,l-dibromides has been shown to be possible using sodium hydrogen A telluride whereas sodium borohydride was ineffective .20 procedure has been developed in which a,w-dibromides are converted into w-bromo-I-alkenes by adding HMPA slowly to the hot dibromide and allowing the product to distil out.211 The order of addition is crucial for avoiding bis-elimination. Reductive dehalogenation of ortho- and para-halogenophenols with excess aluminium chlorideethanethiol has been the subject of further investigation . 2 1 2 Carbonylation of unactivated bromides to esters has been carried out using trialkyl borates with carbon monoxide at atmospheric pressure with palladium(0) or rhodium(1) catalysis.213 The same research group has demonstrated that the use of aluminium alkoxides

263

4: Alcohols, Halogeno-compounds, and Ethers

i n s t e a d of b o r a t e e s t e r s u n d e r s i m i l a r c o n d i t i o n s c o n v e r t s b e n z y l and a r y l bromides i n t o t h e c o r r e s p o n d i n g c a r b o x y l i c e s t e r s .214 I n t h i s case hexa-1,5-dienylrhodium(I) c h l o r i d e d i m e r i s t h e p r e f e r r e d catalyst.

Cyanomethylation of a r y l bromides h a s been d e m o n s t r a t e d

t o o c c u r by p a l l a d i u m - c a t a l y s e d

reaction with

cyanomethyltributyltin. Palladium-catalysed cross-coupling of a l l y 1 h a l i d e s w i t h organostannanes r e s u l t s i n h i g h l y r e g i o - and s t e r e o - s e l e c t i v e r e a c t i o n . 216 I n a c o n t i n u a t i o n of t h i s work, v i n y l i o d i d e s have been found t o c o u p l e w i t h v i n y l t i n r e a g e n t s u n d e r CO a t m o s p h e r e a n d p a l l a d i u m ( I 1 ) c a t a l y s i s t o f u r n i s h u n s y m m e t r i c a l d i v i n y l k e t o n e s i n good y i e l d s u n d e r n e u t r a l a n d m i l d conditions.217

R e d u c t i o n o f n i c k e l h a l i d e s by l i t h i u m i n g l y m e

w i t h n a p h t h a l e n e as a n e l e c t r o n c a r r i e r f o r m s h i g h l y r e a c t i v e m e t a l l i c n i c k e l , Lihich w i l l c a u s e c o u p l i n g o f b e n z y l i c h a l i d e s . 2 1 8 S i l v e r n i t r a t e s u p p o r t e d on a l u m i n a c a u s e s t h e c o n v e r s i o n o f 5-halogenopent-2-enes 3 6 ) .‘I9

i n t o I-cyclopropyl

F o r t h e iodo-compound

e t h y l n i t r a t e (Scheme

simple percolation through t h e

r e a g e n t i s s u f f i c i e n t w h e r e a s t h e b r o m i d e r e q u i r e s s t i r r i n g a t room t e m p e r a t u r e and t h e c h l o r i d e is u n r e a c t i v e .

I n a similar p r o c e s s ,

s i l v e r acetate treatment of homoallylic i o d i d e s e f f i c i e n t l y y i e l d s c y c l o p r o p y l c a r b i n y l a c e t a t e s . 220 t o E-methylene-cycloakanes

w-Alkynyl

h a l i d e s may b e c y c l i z e d

Cr’I-induced

radical cyclization

i n a q u e o u s D M F - e t h y l e n e d i a m i n e , 221 when i o d i d e s g i v e b e t t e r y i e l d s than bromides.

In a four-step

s e q u e n c e (Scheme 3 7 ) 1 , l - d i b r o m o a l k -

I - e n e s may b e r e a c t e d w i t h a l d e h y d e s t o p r e p a r e a l l e n e s . 2 2 2 T e r t i a r y a l k y l e s t e r s a n d e t h e r s a r e t h e p r o d u c t s f o r m e d by r e a c t i n g t h e z i n c s a l t s o f c a r b o x y l i c a c i d s , p h e n o l s , or a l c o h o l s i n non-polar

s o l v e n t s and i n t h e p r e s e n c e o f b a s e w i t h t e r t i a r y

alkyl halides.223

The u s e of u l t r a s o u n d p e r m i t s t h e s y n t h e s i s o f

a z i d e s f r o m p r i m a r y h a l i d e s u s i n g a q u e o u s s o d i u m a z i d e . 224 3

Ethers

The r e d u c t i o n o f Preparation (see a l s o Alcohols - Protection).t h i o c a r b o x y l i c a c i d g-esters t o e t h e r s h a s b e e n r e v i e w e d . 225 A s t r a i g h t f o r w a r d m e a n s o f p r e p a r i n g a l i p h a t i c e t h e r s by t h e s t a n d a r d means o f r e a c t i n g a l k y l h a l i d e s w i t h a l k o x i d e s u s e s KOH-aliquat

336

i n t h e a b s e n c e of s o l v e n t t o g e n e r a t e t h e n u c l e o p h i l i c s p e c i e s ; 2 2 6 y i e l d s a r e e x c e l l e n t with primary a l c o h o l s .

Diphenylmethyl e t h e r s

may b e p r e p a r e d u s i n g d i p h e n y l m e t h y l d i p h e n y l p h o s p h a t e a s t h e a l k y l a t i n g a g e n t . 227 A l t h o u g h t h i s r e a g e n t a l s o c o n v e r t s a c i d s

General and Synthetic Methods

264

Y

R2=H, X = I , Y =NO2 b ; R1 = Me, R2 = H , X = B r , Y = NO2 C ; X = I, Y = OAc a ; R'=Me,

Reagents: i a, 30% AgN03/ At203 column , pentane eluant; i b, 30% ASfJO3/ A1203 suspended in neat halide, r. t . ;

ic,

AgOAc , C&,

r . t . , dark

Scheme 36

bc4

R'

R'

Reagent:

i, BunLi, THE

Br

-

R'

i -iv

-105 "C; ii, RZCHO, r.t. ; iii, (MeaSi)zNH, Me3SiC1, KOH, pyridine;

iv. ButLi

Scheme 37

Reagent:

i, SOSiMq(2 equiv.), Me351 (10 ml.*/.), CHzC12;

Scheme 38

ii, -SiMe3

4: Alcohols, Halogeno-compounds, and Ethers

265

into diphenylmethyl esters it reacts faster with alcohols and permits some degree of selectivity. Aryl bromides may be methoxymethylated using methoxymethyltributyltin in the presence of a palladium(I1) catalyst in HMPA.228 A salt-free synthesis of aryl ethers utilizes methyl trichloroacetate to act as a 'sponge' for the acid produced, liberating chloroform, carbon dioxide, and the methyl halide.229 The procedure is carried out at 150 OC and requires catalytic quantities of 18-crown-6. Carbonyl compounds can be converted into homoallyl ethers in a one-pot procedure via the reaction of the acetals with allyl-silane (Scheme 38).230 The use of sugar 7-lactones has been described as a convenient means of synthesis of chiral tetrahydrofurans. 23 Pentaethoxyphosphorane in dichloromethane at 0 O C has been found to cyclodehydrate butane-l,4-diols. Increasing the degree of 1,4substitution slows the reaction but yields are generally high. 232 In a stereocontrolled synthesis of trans-2,5-disubstituted tetrahydrofurans from 5-hydroxyalk-l-enes (Scheme 39) cyclization to the 3-bromotetrahydropyrans is followed by solvolysis using silver fluoroborate in aqueous acetone to furnish the desired products. 233 Tetrahydrofurans have also been obtained from benzylidene acetal derivatives of pentane-l,3,5-triols on treatment with N-bromosuccinimide in chloroform (Scheme 40). 234 Intramolecular alkoxypalladation-carbonylation of alk-l-en-6-01s has been shown to result in formation of 2,5-disubstituted tetrahydropyrans ,235 in which the =-products are favoured. Silver nitrate cyclization of allenic alcohols to tetrahydropyran derivatives has been independently reported by two groups.2367237 In the case of secondary alcohols the *-2,5disubstituted tetrahydropyrans are the major products. 237 Reactions (see also Alcohols - Deprotection).- Oxidative cleavage of primary alkyl ethers with p-nitroperbenzoic acid is reported to yield carboxylic acids,238 although, if one of the alkyl groups is secondary, a Baeyer-Villiger-type oxidation occurs. Tetrahydrofuran may be cleaved with sodium iodide-chloroglyoxalate esters in methyl cyanide to form 4-iodobutylglyoxalates .239 The reactivity of allylic ethers towards cleavage by alkyl-copper reagents has been shown to be markedly enhanced by the addition of boron t r i f l ~ o r i d e ~ ~ (see ' also cleavage of acetalsg5). Similarly, boron trifluoride etherate-assisted cleavage of oxetanes by alithiated esters and amides has been used in a synthesis of 6-

General and Synthetic Methods

266

I*.

%L+-++

Br

major

lii Reagents: i, 2,4,4,6-tetrabrornocyclohexo-2,5-dienone,

C H ~ C L Z ; ii, AgBFb, aq. acetone

Scheme 39

. ..

1

Reagents: i, N - Brornosuccinimide, CHC13, r. t .

Scheme 40

1

267

4: Alcohols, Halogeno-compounds, and Ethers

lactones. Superacid-catalysed oxygenation of a l i p h a t i c e t h e r s w i t h o z o n e r e s u l t s i n g o o d y i e l d s of o x o a l k y l e t h e r s by e l e c t r o p h i l i c i n s e r t i o n of p r o t o n a t e d ozone i n t o t e r t i a r y or secondary centres at the 6-position o x y g e n . 24 2

4

or f u r t h e r from t h e e t h e r

Thiols

S e l e c t i v e r e d u c t i o n o f d i s u l p h i d e s t o t h i o l s h a s b e e n shown t o b e po s s i b 1e w i t h p o t a s s i um t r i - i s o p r o p o x y b o r ohy d r i d e polystyryldiphenylphosphine

.2 4 4

a three-step

primary amines i n t o t h i o l s o v e r a l l y i e l d (Scheme 4 1 ) .

and

2-Mercaptobenzothiazole

converts

p r o c e s s i n u s u a l l y good

N-Sulphinylbenzenesulphonamide

u n d e r g o e s e n e r e a c t i o n s w i t h o l e f i n i c s u b s t r a t e s a t 0 OC t o y i e l d a d d u c t s w h i c h may b e r e d u c e d t o t h i 0 1 s . ~ ' ~ T h i s p r o c e d u r e h a s b e e n a p p l i e d t o t h e s e p a r a t i o n of o p t i c a l l y a c t i v e t h i o l s from t e r p e n e p r e c u r s o r s (Scheme 4 2 ) .

M e t h y l a r y l t h i o e t h e r s may b e c o n v e r t e d

i n t o the aromatic thiols

via

a m i l d one-pot p r o c e d u r e based upon

Pummerer r e a r r a n g e m e n t o f t h e i n t e r m e d i a t e s u l p h o x i d e s ( S c h e m e O v e r a l l y i e l d s f o r t h e p r o c e s s are h i g h and r e a c t i o n

43).24-6

c o n d i t i o n s a r e c o m p a t i b l e w i t h a w i d e v a r i e t y of f u n c t i o n a l i t i e s . Oxidation r e a g e n t s f o r t h i o l s t h a t have been r e p o r t e d d u r i n g t h e year include potassium superoxide f o r the conversion of aromatic t h i o l s i n t o d i s u l p h i d e s ,246 and b i s [ t r i n t r a t o c e r i u m ( I V )

1

c h r o m a t e . 247 An e f f i c i e n t s y n t h e s i s o f u n s y m m e t r i c a l d i s u l p h i d e s h a s b e e n r e p o r t e d which u t i l i z e s t h e r e a c t i o n of

alkylthiotriphenylphosphonium p e r c h l o r a t e s w i t h t h i o l s . 248 T h e phosphonium r e a g e n t s are p r e p a r e d e l e c t r o c h e m i c a l l y from t h e d i s u l p h i d e s and t r i p h e n y l p h o s p h i n e .

P y r i d y l e t h y l a t i o n has been

developed as a n o v e l t h i o l p r o t e c t i o n sequence .249

Michael

a d d i t i o n o f t h i o l s w i t h 2- o r 4 - v i n y l p y r i d i n e y i e l d s t h e a d d u c t s w h i c h may b e d e p r o t e c t e d by q u a t e r n i z a t i o n o f t h e p y r i d i n e a n d treatment of t h e i s o l a b l e methiodides w i t h potassium carbonate. Aryl v i n y l sulphones have been used t o p r o t e c t t h i o l s

via

a similar

M i c h a e l a d d i t i o n - b a s e e l i m i n a t i o n s e q u e n c e . 250 5

Thioethers

S u l p h i l i m i n e s and sulphoximines have been found t o be c o n v e r t e d i n t o t h i o e t h e r s by a q u e o u s p o t a s s i u m h y d r o x i d e - c h l o r o f o r m u n d e r

268

General and Synthetic Methods

-

R2

\cHs,-?’n tHNH2 4

R2

\

R

Reagents: i, ButONO,

R2

S

ii, iii

‘CHSH

~

/

R

a>>SH,

r.t.; it, Me2S04, 90 “C;

R’

iii, NH2NH2, EtOH

Scheme 41

Reagents: i, EtZO, 0 “c; ii.LiAIH4

Scheme 42

0Reagents: i, m-ClC6H4CO$,

CHCl3, 0°C;

\OTFA ti, Ca(OH)2 ;

Scheme 43

iii, (CF$O)20,

40

OC;

iv, Et3N, MeOH

4: Alcohols, Halogeno-compounds, and Ethers

269

phase-transfer conditions. 251 The same research group has demonstrated the reduction of sulphoxides and sulphilimines to thioethers by sodium borohydride in the presence of a catalytic quantity of meso-tetraphenylporphyrin metal complexes. 2 5 2 Deoxygenation of sulphoxides has been demonstrated using a series of boron bromide reagents at low temperature (Me2BBr, g B B N - B r , BBr3). 253 Decomposition of S-alkylthiouronium salts under anhydrous basic conditions provides a convenient way of generating the thiolates which can be reacted with alkyl halides to generate unsymmetrical thioethers. 254 Reduction of dithioacetals with pyridine-borane complex in trifluoroacetic acid provides an efficient means of preparing thioethers from carbonyl compounds .255 Excellent yields of phenyl vinyl sulphides are obtained from benzyne-induced ring opening of thiiranes ; 256 nickel (11 -catalysed coupling of 3-methoxy-I-phenylthioprop-I-ene with Grignard reagents provides an alternative approach. 257 In a stereoselective construction of allylic thioethers, divinylcuprates have been coupled with a-halogenothioethers in good yields .258 Aromatic di-, tri-, or tetra-halides under phase-transfer conditions react with thiolates .259 In unsymmetrical substrates substitution occurs predominantly at the halogen lacking para-substitution. Phenols undergo ortho-alkylthiolation on sequential treatment with aluminium powder followed by the requisite disulphide at elevated temperature. 260 Aromatic amines may be converted into thioethers by reaction of the diazonium salts with methythiocopper at 4 0C.261 In this procedure yields are usually good and the technique is reported to involve less risk of explosion than other methods. S-Alkyl-4-methylbenzenethiosulphonates have been shown to be useful reagents for the a-thiolation of cyclic ketones and hence introduction of unsaturation. 2 6 2 Thioacetylenes may be prepared by pyrolytic elimination of a - a c y l - a - t h i o p h o s p h o r a n e s ( 16) at 230 OC and reduced pressure. 2 6 3 The phosphoranes are obtained by reaction of alkylthiomethylenetriphenyl phosphorane with acyl halides at room temperature. The oxidation of sulphides has continued to attract much attention. Heterogeneous permanganate oxidation of thioethers using either potassium permanganate-copper(I1) sulphate or copper(I1) permanganate in refluxing hexane produces sulphones without attacking any double bonds in the substrate. 264 Work-up simply involves filtration from the reagent and evaporation of the solvent. Reagents used for converting thioethers into sulphoxides

General and Synthetic Methods

270

include a-azohydroperoxides in base,265 and hexamethylphosphoramidochromium(V1) oxide diperoxide. 266 Diarylbut not dialkyl-thioethers may be oxidized to sulphoxides by a twophase system of 20% aqueous sulphuric and nitric acids with nitromethane at room temperature. 267 Further application of the use of gold(II1) oxidation under phase-transfer catalysis is described by the same group in the selective mono-oxidation of dithia-alkanes to sulphoxides. 268 Selectivity for mono-oxidation decreases with increasing separation of the two thioether groups. Modifications of the Sharpless system for sulphoxidation include the substitution of vanadium and molybdenum catalysts for titanium( IV) i s o p r o p ~ x i d eand ~ ~ ~addition of water to the reaction mixture. 270 In general the enantiomeric excesses obtained are inferior to those obtained with the original reagent combination. Cyclodextrin-mediated chiral sulphoxidations similarly give disappointing ( 0 - 3 4 % ) enantiomeric excesses ,27 but microbial oxidation with Corynebacterium equi has been found frequently to result in high enantiomeric excess with conversions ranging from 7 to 1 0 0 ” / . 2 7 2 Allylic sulphides have been shown to add to propiolic esters under Lewis acid the El2 ratio of products being dependent upon the thioether and the Lewis acid used (Scheme 44). Vinyl sulphides may be reduced in good yield with triethylsilane promoted by titanium( IV) chloride. 2 7 4 Treatment of phenyl thioethers with a mixture of copper metal, copper(I1) acetate, and lithium acetate in acetic acid-acetic anhydride leads to substitution of the phenylthio-group to form acetates.275 A copper(1) species is believed to be operative.

6

Crown Ethers, Thia-Crown Ethers, and Related Structures

Owing to the large number of reports concerning cr-own ethers which have appeared during this year it is not possible to detail those prepared by standard methods but only those structures having a degree of novelty. The synthesis of a series of lithium-selective acyclic polyethers ( 1 7 ) has been described.276 Phase-transfer catalysis has been profitably applied to the construction of crown ethers containing benzoin subunits277 and aza-crown ethers. 278 The first syntheses of ‘ostrich molecules’ , a r e n e d i a ~ o n i u m ~’ 280 ~ ’ ( 18 and anilinium280 lariat crown ethers ( 1 9 ) , have been reported together with evidence for intramolecular sidearm-macrocycle interaction.

27 1

4: Alcohols, Halogeno-compounds, and Ethers

R = Ph R = cyclohexyl

Lewis acid = ZnCI;!: Lewis acid = AICI, :

3 90

:

97

:

10

92% 80°h

Reagents: i, HC3CC02Me, Lewis acid. CH2C12, r.t.

Scheme 44

+

-I-

272

General and Synthetic Methods

Other lariat crown ethers include those possessing an epoxy-group in the side chain281 and 'double armed' crown Polymer-supported crown ethers (20) have been prepared and have found use as phase-transfer catalysts for nucleophilic displacement reactions284 (cf. 2 , 137; 2 , 1 5 9 ) . Crown ethers containing novel subunits include tetraester dipyrazole crowns (21) , 2 8 5 lipophilic crown diacids (22),286 and a flavin crown ether mimic.287 Crowned morphine and isosmorphine analogues (23) have also been prepared. 288 Further examples of chiral crown ethers incorporating carb~hydrate~~ '290 ' (cf.2 , 1 4 0 ) and tartaric acid derived subunits291 have been reported, and name 'pagiand' (Greek n a y l a trap) being proposed for the latter. Optically active biphenanthryl crowns (24) have also been further i n ~ e s t i g a t e d ~ ' ~ and a related class of crown ethers in which a steric restraint is imposed by a three-blade propeller substituent ( 2 5 ) has been reported. 293 Novel photoresponsive crown ethers have been synthesized which consist of a polyether chain possessing two anthracene subunits which undergo cycloaddition to generate the crown ether (Scheme 45). 294 Further examples of photoresponsive azobenzene crown ether systems have been reported , 2 9 5 '296 of which an interesting variant generates an 'ostrich' crown ether on irradiation (Scheme 46) .297 The same research group has published further work on redox-switched crown ethers in which the macrocycle is constructed by disulphide formation (Scheme 47) .298 Additional reports of the synthesis of oxa-crown ethers containing a ferrocene nucleus299 ' 300 have been accompanied by a synthesis of the thiaand the ruthenocene thia-oxa-crown (26).302 crown analogues3' Chiral macrocyclic polysulphides (27) have been developed as ligands for nickel(I1)-catalysed C - C bond formation although the enantiomeric excesses in the products are The macrobicyclic polyethers ( 2 8 ) 304 and other bicyclic systems ( 2 9 ) 305 and (30I3O6 have been reported. The latter compounds act as V-shaped hosts for cis-diamine-transition metal complexes. Further spherand analogues have been reported (cf.i, T O ) , including structures (31) possessing additional functionality on the outer periphery307 and extended hemispherands (32) .308

4: Alcohols, Halogeno-compounds, and Ethers

273

274

General and Synthetic Methods

Y

Scheme 45

Scheme 46

275

4: Alcohols, Halogeno-compounds, and Ethers

qsH 9- p S-

sJQ

SH

ox

A

Red

Scheme 47

?

Ru

W ( 2 6 ) n = 2 , 3 , or 4

(28 1 n = lor2 n =Oorl

(27)

(29)

276

General and Synthetic Methods

x

= 0,

Q -0

-0

or -0

n 0-' 0-

0-

Me

X

(31)

R = Me or H

p

0

Me

(32) X = S , SO2, or

0 -t-

277

4: Alcohols, Halogeno-compounds, and Ethers 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

9,

4822. H.C.Brown, V.Somayaji, and S-Narisimhan, J. Org. Chem., 1984, H.S.Lee, K.Isagawa, H.Toyoda, and Y-Otsuji, Chem. Lett., 1984, 1433. H.S.Lee, K.Isagawa, and Y.Otsuji, Chem. Lett., 1984, 363. 1589. Okamoto and S.Oka, J. Org. Chem., 1984, E.Y. Osei-Twum, D.McCallion, A.S.Nazran, R.Panicucci, P. A.Risbood, and 336. J.Warkentin, J. Org. Chem., 1984, V.Bhushan, R.Rathore, and S.Chandrasekaran, Synthesis, 1984, 431. J.Barluenga, L.Alonso-Cires, J. P. Campos, and G.Asensio, Tetrahedron, 1984, 40, 2563. J.K. Cha, W.J.Christ, and Y-Kishi, Tetrahedron, 1984, 40, 2247. R.O.Hutchins, K.Learn, F.El-Telbany, and Y .P.Stercho, J. Org. Chem., 1984, 49, 2438. D.A.Jaeger, M.Darlene-Ward, and C.A.Martin, Tetrahedron, 1984, 5, 2691. T.Imamoto, T.Mita, and M.Yokoyama, J. Chem. SOC., Chem. Commun., 1984, 164. D.L.Cmins and J.J.Herrick, Tetrahedron Lett., 1984, 25, 1321. 1349. C.Adams, Synth. Commun., 1984, ( 5 ) J.D.Wuest and B.Zacharie, J.Org.Chem., 1984, 3,163. A. R.Sande, M.H.Jagadale, R.B.Mane, and M.M.Salunkhe, Tetrahedron Lett., 1984, 25, 3501. H. C.Brown and S.Narasimhan, J. Org. Chem., 1984, 3, 3891. K.Soai, H.Oyamada, M-Takase, and A.Ookawa, Bull. Chem. SOC. Jpn., 1984, 57, 1948. K-Soai and H.Oyamada, Synthesis, 1984, 605. S.Saito, T.Hasegawa, M.Inaba, R.Nishida, T. Fuji, S.Nomizu, and T.Moriwake, Chem. Lett., 1984, 1389. ( 5 ) T.Nakata, Y.Tani, M.Hatozaki, and T.Oishi, Chem. Pharm. Bull., 1984, 32, 1411. T.Nakata, M.Fukui, H.Ohtsuka, and T.Oishi, Tetrahedron, 1984, ‘lo, 2225; (b) T.Oishi and T.Nakata, Acc. Chem. Res., 1984, 17,338. K.Narasaka and F.-C.Pai, Tetrahedron, 1984, 5, 2233. K.Suzuki, E.Katayama, and G.Tsuchihashi, Tetrahedron Lett., 1984, 25, 2479. M.Shimagaki, T.Maeda, Y .Matsuzaki, I.Hori, T. Nakata, and T.Oishi, Tetrahedron Lett.. 1984. 25. 4775. . _ 3039. R.B.Gammil1, L.T.Be1 1, and S.A.Nash, J. Org. Chem., 1984, 9, A.Osuka. K.Taka-Oka. and H.Suzuki. Chem. Lett.. 1984. 271. H. C.Brown, J. S.Cha, and B. Nazer, J. Ora. Chem. - , 1984, 2073. C.Adams, Synth. Commun., 1984, 955. 555. S.Itsumo and K.Ito, J. Org. Chem., 1984, S.Itsumo, K. I t o , A. Hirao, and S-Nakahama, J. Chem. SOC., Perkin Trans. 1 , 1984, 2887. H.C.Brown and A.K.Manda1, J. Org. Chem., 1984, 2558; (b) N.M.Yeon, p.3646. G.P.Kim, and K.W.Kim, B .L A1 1wood , H .Sha hr iar i- Zavareh , J - F .Stod dart , and D .J .W illiam s , J. Chem. SOC., Chem. Commun., 1984, 1461. H.C.Brown, G.G.Pai, and P.K.Jadhav, J. Am. Chem. SOC., 1984, 106, 1531. M.M.Midland, A. Tramonto, A.Kazubski, R .S.Graham, D.J .S.Tsai, and D.B. Cardin, Tetrahedron, 1984, ‘lo, 1371 . M.M.Midland and J. I.McLoughlin, J. Org. Chem., 1984, 1316. 4101. M.M.Midland and J.I.McLoughlin, J. Org. Chem., 1984, 310. G.Giacomelli, L.Lardicci, and F.Palla, J. Org. Chem., 1984, H.Suda, S.Kano1, N.Umeda, M.Ikka, and M.Motoi, Chem. Lett., 1984, 89 9. R-Noyori, 1-Tomino, Y.Tanimoto, and M.Nishizawa, J. Am. Chem. SOC., 1984, 106,6709, 6717 K.Yamamoto, H.Fukuishima, and M-Nakazaki, J. Chem. SOC., Chem. Commun., 1984, 1490. S.R. Landor, Y.M.Chan, O.O.Sonola, and A.R.Tatchel1, J. Chem. SOC., Perkin Trans. 1 , 1984, 493. M.Kawasaki, Y.Suzuki, and S.Terashima, Chem. Lett., 1984, 239. 3861. J.M.Hawkins and K.B.Sharpless, J. Org. Chem., 1984, 9, T.Oriyama and T.M&aiyama, Chem. Lett., 1984, 2071.

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K.Soai, H.Oyamada, and T.Yamanoi, J. Chem. SOC., Chem. Commun., 1984, 1413; K.Soai, T.Yamanoi, and H.Oyamada, Chem. Lett., 1984, 251. C.J.Sih and C.-S.Chen, Angew. Chem., Int. Ed. Engl., 1984, 23, 570. T.Fujisawa, T.Itoh, and T.Sato, Tetrahedron Lett., 1984, 25, 5083. K.Nakamura, K.Ushio, S.Oka, and A.Ohuo, Tetrahedron Lett., 1984, 25, 3979. R.W.Hoffmann, W.Ladner, and W-Helbig, Liebigs Ann. Chem., 1984, 1170. D.W.Brooks, H-Mazdiyasni, and S.Chakrabarti, Tetrahedron Lett., 1984, 25, 1241. K.Tamoto and S.Terashima, Chem. Pharm. Bull., 1984, 32, 4328. H.Akita, A.Furuichi, H.Koshiji, K.Horikoshi, and T.Oishi, Chem. Pharm. Bull., 1984, 32, 1333, 1342, 1619. R.Bernardi, R.Cardillo, and D.Ghiringhelli, J. Chem. SOC., Chem. Commun., 1984, 460. D.Seebach, M.F.Zuger, F.Giovanni, B.Sonnleitner, and A.Fiechter, Angew. Chem., Int. Ed. Engl., 1984, 23, 151. C.H.Heathcock, Stud. Org. Chem. (Amsterdam), 1984, 177. M.T.Reetz, K-Kesseler, and A.Jung, Tetrahedron, 1984, 4327. M.T.Reetz, K.Kesseler, and A.Jung, Tetrahedron Lett., 1984, 25, 729. M.T.Reetz and K.Kesseler, J. Chem. SOC., Chem. Commun., 1984, 1079. S.S.Labadie and J.K.Stille, Tetrahedron, 1984, 2329. W.Hamana, K.Sasakura, and T.-hem. Lett., 1984, 1729. A.I.Meyers and Y.Yamamoto, Tetrahedron, 1984, 5, 2309. T.Inoue, T.Sato, and 1-Kuwajima, J. Org. Chem., 1984, 9, 4671. L.Banfi, A.Bernandi, L.Colombo, C.Gennari, and C.Scolastico, J. Org. Chem., 1984, 3784. S.G.Davies, I.M.Dordor, and P.Warner, J. Chem. SOC., Chem. Commun., 1984, 956. A.Abde1-Magid, I.Lantos, and L.N.Pridgen, Tetrahedron Lett., 1984, 25, 3273. Y.Yamamoto, H.Yatagai, Y.Ishihara, N.Maeda, and K.Maruyama, Tetrahedron, 1984, 40, 2239. G.E.Keck and E.P.Boden, Tetrahedron Lett., 1984, 25, 265. (5) G.E.Keck and E.P.Boden, Tetrahedron Lett., 1984, 25, 1879; (b) G.E.Keck p.1883. and D.E.Abbot, T.Mandai, J.Nokami, T.Yano, T.Yoshinaga, and J.Otera, J. Org. Chem., 1984, 49, 172. K.Uneyama, H.Matsuda, and S.Torii, Tetrahedron Lett., 1984, 25, 6017. J.Nokami, T.Tamaoka, T.Koguchi, and R.Okawara, Chem. Lett., 1984, 1939. R.W.Hoffmann and B.Kemper, Tetrahedron, 1984, 5, 2219. H.C.Brown and P.K.Jadhav, Tetrahedron Lett., 1984, 25, 1215, 51 1 1 . H.C.Brown and P.K.Jadhav., J. Org. Chem., 1984, 9, 4089. K. Furuta, Y. Ikeda, N.Meguriya, N.Ikeda, and H.Yamamoto, Bull. Chem. SOC. Jpn., 1984, 57, 2781. M.T.Reetz and M.Sauerwald, J. Org. Chem., 1984, 9, 2292. G.Zweife1 and G.Hahn, J. Org. Chem., 1984, 3, 4565. T.Imamoto, T.Kusumoto, Y.Tawarayama, Y.Sugiara, T.Mita, Y.Hatanaka, and M.Yokoyama, J. Org. Chem., 1984, 3904. Y.Yamamoto, H.Yatagi, Y.Saito, and K.Maruyama, J. Org. Chem., 1984, 9, 1096. C.H.Heathcock, S.Kiyooka, and T.A.Blumenkopf, J. Org. Chem., 1984, 49, 4214. J.Pornet, B.Randriananoelina, and L-Miginiac, Tetrahedron Lett., 1984, 651. (5) F.Sato, M.Kusakabe, and Y.Kobayashi, J. Chem. SOC., Chem. Commun., 1984, 1130; (b) F.Sato, Y.Takeda, H.Uchiyama, and Y.Kobayashi, p.1 132. F-Sato, M.Kasakabe, T.Kato, and Y.Kobayashi, J. Chem. SOC., Chem. Commun., 1984, 1331. K.Tamao and N.Ishida, Tetrahedron Lett., 1984, 25, 4245, 4249. T.Imamoto, T.Takeyama, and M.Yokoyama, Tetrahedron Lett ., 1984, 25, 3225. O.Tsuge, S.Kanemasa, H.Nagahama, and J.Tanaka, Chem. Lett., 1984, 1803. H-Nishiyama, K.Kitajima, M.Matsumoto, and K.Ito, J. Org. Chern., 1984, 9, 2298. M.Adamczyk, E.K.Dolence, D.S.Watt, M.R.Christy, J.H.Reibenspies, and 1378. Q.P.Anderson, J. Org. Chem., 1984, E.L.Elie1 and S.Morris-Natschke, J. Am. Chem. SOC., 1984, 106,2937.

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4: Alcohols, Halogeno-compounds, and Ethers

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E . L . E l i e 1 and J.E.Lynch, J . Am. Chem. SOC., 1984, 2943. K.Matsumoto, Angew. Chem., I n t . Ed. E n g l . , 1984, 23, 617. (5) S . D . L i n d e l 1 , J . D . E l l i o t , and W.S.Johnson, T e t r a h e d r o n L e t t . , 1984, 25, 3947 ; ( b ) W.S.Johnson, P.H. C r a c k e t t , J . D . E l l i o t t , J. J . J a g o @ z i n s k i , S.D.Lindel1, and S . N a t a r a j a n , T e t r a h e d r o n L e t t . , 1984, 25, 3951 ; (2) W.S.Johnson, J . D . E l l i o t , and G.J.Hanson, J . Am. Chem. S O C . , 1984, 1138. A.Mori, K.Maruoka, and H.Yamamoto, T e t r a h e d r o n L e t t . , 1984, 25, 4421. 93 J - F u j i w a r a , Y . F u k u t a n i , M.Hasegawa, K.Maruoka, and H.Yamarnoto, 94 J . Am. Chem. SOC., 1984, 5004. A . G h r i b i , A.Alexakis, and J.F.Normant, T e t r a h e d r o n L e t t . , 1984, 25, 3083. 95 R.D.Dawe, T.F.Molinski, and J . V . T u r n e r , T e t r a h e d r o n L e t t . , 1984, 25, 2061. 96 M.Yamaguchi and L . H i r a o , J . Chem. SOC., Chem. Commun., 1984, 202. 97 K.Utimoto, C.Lambert, Y.Fukuda, H.Shiragami, and H.Nozaki, 98 T e t r a h e d r o n L e t t . , 1984, 25, 5423. P.G.Gassman and R.S.Gremban, T e t r a h e d r o n L e t t . , 1984, 25, 3259. 99 100 K.C.Nicolau, M.E.Duggan, and T.Ludduwahetty, T e t r a h e d r o n L e t t . , 1984, 25, 2069. 101 K.Uneyama, N-Nisiyama, and S . T o r i i , T e t r a h e d r o n Lett., 1984, 25, 4137. 102 M . A s a m i , Chem. L e t t . , 1984, 829. 3693. 103 M . J . E i s , J.E.Wrobe1, and B.Ganem, J . Am. Chem. S O C . , 1984, 104 M.Yamaguchi, Y.Nobayashi, and I . H i r a o , T e t r a h e d r o n , 1984, 40. 4261. 105 A . P a p i n i , A . Ricci, M. Taddei , G.Seconi, and P. IIembech, J . ' C h e m . SOC., P e r k i n T r a n s . 1 , 1984, 2261. 106 M.Yamaguchi and I . H i r a o , T e t r a h e d r o n L e t t . , 1984, 25, 4589. 107 M.Note. T.Kaiimoto. K.Nishide. , IZ . F u j i t a , and K . F u j i , T e t r a h e d r o n L e t t . , 219. 1984, 108 K.Mikami, K.-1-Azuma, and T.Nakai, T e t r a h e d r o n , 1984, 2303. 2 5 , 565. ' e t r a h e d r o n L e t t . , 1984. 109 N.Sayo, K.Azuma, K.Mikami, and T.Nakai, 'I 110 D.J.-S.Tsai and M.M.Midland, J . Org. Chem., 1842. 111 N.Sayo, F . S h i r a i , and T.Nakai, Chem. L e t t . , 1984, 255. 1707. 112 J.A.Marshal1 and T.M.Jenson, J . Org. Chem., 1984, 113 K.Mikami, K . F u j i m o t o , T.Kasuga, and T.Nakai, T e t r a h e d r o n L e t t . , 1984, 25, 601 1 . 114 K - T a k a i , I . M o r i , K.Oshima, and H.Nozaki, B u l l . Chem. SOC. J p n . , 1984, 446. 115 S.D.Lee, T.H.Chan, and K.S.Kwon, T e t r a h e d r o n L e t t . , 1984, 25, 3399. 116 R.M.Moriarty and K.-C.Hou, T e t r a h e d r o n Le 117 I . F l e m i n g , R.Henning, and H . P l a n t , J . Chem. Sc 118 P-Lerouge and C.Paulmier, T e t r a h e d r o n L e t t . , 1 119 J . R c d r i g u e z , J . - P . D u l c e r r e , and M.Bertrand, T e t r a h e d r o n L e t t . , 1 9 8 4 , 2 5 , 527. 120 S.Kim and H.Chana. S"v n t h . Commun.. 1984. . 899. , 1 4, - 121 L.Lombardo, T e t r a h e d r o n L e t t . , 1984, 25, 227. 122 Y.Guindon, R . F o r t i n , C. Yoakim, and J . W . G i l l a r d , T e t r a h e d r o n L e t t . , 1984, 2, 471 7. 123 T.Mukaiyama, M.Ohshima, and M.Murakami, Chem. L e t t . , 1984, 265. 124 T.Mukaiyama, M.Ohshima, H-Nagaoka, and M.Murakami, Chem. L e t t . , 1984, 61 5. 125 Y. Oikawa, T . Tanaka, K . H o r i t a , T . Yoshioka, and 0. Yonemitsu, T e t r a h e d r o n L e t t . , 1984, 25, 5393. 126 Y.Oikawa, T.Tanaka, K . H o r i t a , and O.Yonemitsu, T e t r a h e d r o n L e t t . , 1984, 25, 5397. 127 Y.Watanabe, Y.Maki, K.Kikuchi, and H-Sugiyama, Chem. I n d . ( L o n d o n ) , 1984, 272. 128 S . H a n e s s i a n , D.Delorme, and Y.Dufresne, T e t r a h e d r o n L e t t . , 1984, 25, 2515. 129 J.H.Rigby and J . Z . W i l s o n , T e t r a h e d r o n L e t t . , 1984, 25, 1429. 130 M.Jones, S y n t h e s i s , 1984, 727. 131 T.Mandai, H.Yasunaga, M.Kawada, and J . O t e r a , Chem. L e t t . , 1984, 715. 227. 132 D.N.Sarma. N . C-Barua. and R.P .Sarma. Chem. I n d . ( L o n d o n ) . 1984. 133 M.Jarman &d R.McCague, J . Chem. S o ; . , Chem. Commun., 1984, 125. C.F.Carvalho and M.V.Sargent, J . Chem. SOC., Chem. Commun., 1984, 227. 134 3912. 135 Y-Guindon, C.Yaokim, and H.E.Morton, J . Org. Chem., 1984, 136 M.V.Bhatt and J.R.Babu, T e t r a h e d r o n L e t t . , 1984, 25, 3497. 90 91 92

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General and Synthetic Methods

137 Y.Ogawa and M.Shibasaki, Tetrahedron Lett., 1984, 2, 663. 138 E.J.Corey, D.H.Hua, and S.P.Seitz, Tetrahedron Lett., 1984, 25, 3. 139 H.Firouzabadi, A.R.Sardarian, M.Naderi, and B.Vessa1, Tetrahedron, 1984, 5, 5001. 140 F. H. Hussein , G. Pattenden, R. Rudham , and J. J .Russell, Tetrahedron Lett., 1984, 25, 3363. 141 I.Granboa, J.M.Aizpurua, and C.Palomo, J. Chem. Res. ( S ) , 1984, 92. 142 J.Tsuji, I.Minami, and I-Shimizu, Tetrahedron Lett., 1984, 5,2791. 143 G.Rosini, R.Ballini, P.Sorrenti, and M.Petrini, Synthesis, 1984, 607. 144 M.Tamaka, T.Kobayashi, and T.Sakakura, Angew. Chem., Int. Ed. Engl., 1984, 23, 518. 145 G.Green, W.P.Criffith, D.M.Hollinshead, S.V.Ley, and M.Schroder, J. Chern. S O C . , Perkin Trans. 1 , 1984, 681. 146 M.Matsumoto and N.Watanabe, J. Org. Chem., 1984, 9, 3435. 147 H.Firouzabadi, A.Sardarian, and H.Gharibi, Synth. Commun., 1984, 89. 148 M.F.Semmelhack, C.R.Schmid, D.A.Cortes, and C.S.Chou, J. Am. Chem. SOC., 1984, 106,3374. 149 R.Rathore, V.Bhushan, and S.Chandresakaran, Chem. Lett., 1984, 2131. 875. 150 H.Firouzabadi and N.Iranpoor, Synth. Commun., 1984, 631 ; 151 H.Firouzabadi, N.Iranpoor, and H.Parham, Synth. Commun., 1984, H.Firouzabadi, N.Iranpoor, F.Kiaeezadeh, and J. Toofan, p.973. 152 L.Syper and J.Mlochowski, Synthesis, 1984, 747. 153 S.Kanemoto, H.Saimoto, K.Oshima, and H.Nozaki, Tetrahedron Lett., 1984, 25, 3317. 154 B.M.Trost and Y.Masuyama, Tetrahedron Lett., 1984, 25, 173. 155 Y.Masuyama, M-Takahashi, and Y.Kurusu, Tetrahedron Lett., 1984, 25, 4417. 156 T.Nonaka, S.Kanemoto, K.Oshima, and H.Nozaki, Bull. Chem. SOC. Jpn., 1984, 57. 2019. 157 A.M.Maione and A.Rmeo, Synthesis, 1984, 955. 158 H. Firouzabadi , N. Iranpoor , G .Hajipoor , and J. Toofan, Synth. Commun . , 1984, 14, 1033. 159 E.Block, Org. Reactions, 1984, 30, 457. 160 D.H.R.Barton and D.Crich, J. Chem. SOC., Chem. Commun., 1984, 774. 161 D .N .Sarma , J. C.Sarma, N. C.Barua, and R .P.Sharma, J. Chem. SOC- , Chem. Commun., 1984, 813. 162 M.Numazawa, M-Nagaoka, and Y.Kunitama, J. Chem. S O C . , Chem. Comrnun., 1984, 31. 163 Ed. W.G.Dauben, Org. Reactions, 1983, 9, 1. 164 L.Brown and M.Koreeda, J. Org. Chem., 1984, 49, 3877. 165 E.Anders and A.Stankowiak, Synthesis, 1984, 1039. 166 M.Clarembeau and A.Krief, Tetrahedron Lett., 1984, 25, 3625. 167 Y.Ueno, A.Kojima, and M.Okawara, Chem. Lett., 1984, 2125. 168 A.Hassner, R.Fibiger, and D.Andisk, J. Org. Chem., 1984, 4237. 169 J. H.Markgraf, D.B .Burns, E .W.Greeno, K .J. Leonard, and M. D.Miller , Synth. Commun., 1984, 647. 170 J.N.Chatterjee, R.N.Majee, and S.N.Mukerjee, Indian J. Chem., Sect. B, 1984, 23, 733. 171 Y.Torisawa, H.Okabe, and S.Ikegami, Chem. Lett., 1984, 1555. 172 T.Cuvigny, M.Julia, and C.Rolando, J. Chem. SOC., Chem. Commun., 1984, 8. 173 K-Suzuki, E.Katayama, and G.Tsuchihashi, Tetrahedron Lett., 1984, 25, 1817. 174 M.Julia and C.Lefebvre, Tetrahedron Lett., 1984, 25, 189. 175 M.Bluthe, M.Malacria, and J.Gore, Tetrahedron Lett., 1984, 25, 2873. 176 P.G.M.Wuts, M.L.Obrzut, and P.A.Thompson, Tetrahedron Lett., 1984, 5, 4051. 177 K.S.Bhat, P.L.Joshi, and A.S.Rao, Synthesis, 1984, 142. 3027. 178 P.-T.Ho and N-Davies, J. Org. Chem., 1984, 179 T.Oshikawa and M.Yamashita, Bull. Chem. SOC. Jpn., 1984, 51, 2675. 180 R.J.Garegg, R.Johansson, and B.Samuelsson, Synthesis, 1984, 168. 181 P.Hodge and E-Khoshdel, J. Chem. SOC., Perkin Trans. 1 , 1984, 195. 182 R.T.Hrubiec and M.B.Smith, J. Org. Chem., 1984, 9, 432. 183 T.Fuyisawa, S.Iida, and T.Sato, Chem. Lett., 1984, 1173. 184 C.K.Hwang, W.S.Li, and K.C.Nicolau, Tetrahedron Lett., 1984, 25, 2295. 185 S.Araki, K.Ohmori, and Y.Butsugan, Synthesis, 198b, 841. 186 A.Hassner and R.F.Fibiger, Synthesis, 1984, 960.

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.

.

187 K D. Donnelly , W. E. F r i s t a d , B. J Gellerman , J . R . P e t e r s o n , and B. J . S e l l e , T e t r a h e d r o n L e t t . , 1984, 25, 607. 188 A.M.Morella and A.D.Ward, T e t r a h e d r o n L e t t . , 1984, 25, 1197. 189 A - A r r i e t a , I.Ganboa, and C-Palomo, S y n t h . Commun., 1984, 3, 939. 190 S.Hara, S.Takinami, S.Hyuga, and A.Suzuki, Chem. L e t t . , 1984. 345. I91 B. M. M i k a i l o v and L . I . L a v r i n o v i c h , J . Organomet. Chem ., 1984, 268, 5. 192 S . T o r i i , H.Tanaka, N.Tada, S.Nagao, and M.Sasaoka, Che'm. L e t t . , 1984, 877. 14,13. 193 J.H.Babler and K.P.Spina, S y n t h . Commun ., 1984, 194 M-Yonovich-Weiss and Y.Sa s s o n , S y n t h e s i s , 1984 , 34. 25 , 5949. 195 I . B i d d and M.C.Whiting, ' e t r a h e d r o n L e t t . , 1984 , 3216. 196 D.P. Cox, J. T e r p i n s k i , and W. Lawrynowicz, J . Org Chem., 1984, 2, 197 C.A.Horiuchi and J . Y.Sato h , Chem. L e t t . , 1984, 1 509. 198 S.Magen, J.Oren, and B.Fu c h s , T e t r a h e d r o n L e t t . , 1984, 25, 3369. 1103. 199 J.M.Aizpura and C.Palomo, T e t r a h e d r o n L e t t . , 19814 20 0 J . M. Aizpura and C. Palomo, T e t r a h e d r o n L e t t . , 19884 31 23. 20 1 H.C.Brown and V.Somayaji, S y n t h e s i s , 1984, 91 9. 20 2 J . B a r l u e n n a . P . J . C a m ~ o s . J.M.Gonzalez, and G.Asensio, J . Chem. SOC. , P e r k i n T r a n s . 1 , 1984, 2623. 20 3 A . V a r v o a l i s . S v n t h e s i s . 1084., 709. 20 4 R.Tarhouni, B . K i r s c h l e g e r , M.Rambaud, and J . V i l l i e r a s , T e t r a h e d r o n L e t t . , 1984, 25, 835. 20 5 S . G . D a z e s and S.E.Thomas, S y n t h e s i s , 1984, 1027. 20 6 D . L a n d i n i , L.Milesi, M.L.Quadri, and F . R o l l a , J . Org. Chem., 1984, 152. 377. 20 7 M.Rabinovitz and D-Tamarkin, S y n t h . Commun., 1984, 208 T.Oriyama and T.Mukaiyama, Chem. L e t t . , 1984, 2069. 20 9 T.Endo, Y.Saotome, and M.Okawara, J . Am. Chem. SOC., 1984, 106, 1124. 21 0 A.Osuka, K.Takechi, and H.Susuki, B u l l . Chem. SOC. J p n . , 1984, 57, 303. 21 1 G.A.Kraus and K-Landarebe., S"v n t h e s i s ., 1984. , 885. 21 2 M.Mode, T.Kawabata, K-Ohta, M.Fujimoto, E . F u j i t a , and K . F u j i , J . Org. Chem., 1984. A, 49. -1641. 21 3 K.E.Hashem, J.B.Woel1, and H.Alper, T e t r a h e d r o n L e t t . , 1984, 25, 4879. 21 4 H.Alper, S . A n t e b i , and J.B.Woel1, Angew. Chem., I n t . Ed. E n g l . , 1984, 23, 732. 21 5 M.Kosugi, M . I s h i g u r o , Y.Negishi, H.Sano, and T.Migita, Chem. L e t t . , 1984, 1511. 21 6 F.K.Sheffy, J . P . G o d s c h a l x , and J . K . S t i l l e , J . Am. Chem. SOC., 1984, 106, 4833. 21 7 W.F.Goure, M.W.Wright, P.D.Davis, S.S.Labadie, and J . K . S t i l l e , J. Am. Chem. SOC., 1984, 106,6419. 21 8 S . I n a b a , H.Matsumoto, and R.D.Rieke, J . Org. Chem., 1984, 2093. 21 9 R.T.Hrubiec and M.B.Smith, J . Chem. SOC., P e r k i n T r a n s . 1 , 1984, 107. 220 L . P r e v i t e r a , P.Monaco, and L.Margoni, T e t r a h e d r o n L e t t . , 1984, 25, 1293. 4244. 22 1 J.K.Crandal1 and W.J.Michaely, J . Org. Chem., 1984, 2, 222 R.Hassig, D.Seebach, and H.Siege1, Chem. B e r . , 1984, 117,1877. 223 B.Ravindranath and P . S r i n i v a s , T e t r a h e d r o n , 1984, K , 1623. 224 H . P r i e b a , Acta Chem. S c a n d . , S e r . B , 1984, 38, 895. 225 B.A.Jones and J.S.Bradshaw, Chem. Rev. , 1984, 811, 17. 226 J . B a r r y , G.Bran, G.Decodts, A.Loupy, P.Pigeon, and J . S a n s o u l e t , T e t r a h e d r o n , 1984, 5, 2945. 227 M.Kolovos and C - F r o u s s i o s , T e t r a h e d r o n L e t t ., 1984, 25, 3909. 228 M.Kosugi, T.Sumiya, T.Ogata, H.Sano, and T . M i g i t a , Chem. L e t t . , 1984, 1225. 229 J.M.Renga and P.-C.Wang, S y n t h . Commun., 1984, 69. 230 H . S a k u r i , K . S a s a k i , J . H a y a s h i , and A-Hosomi, J . Org. Chem., 1984, 9, 2808. 23 1 Y.Chapleur, J . Chem. SOC., Chem. Commun., 1984, 449. 2831. 232 B.D.Denney, D.Z.Denney, and J . J . G i g a n t i n o , J. Org. Chem., 1984, 23 3 P.C.Ting and P . A . B a r t l e t t , J . Am. Chem. SOC., 1984, 106,2668. 234 D.R.Williams, Y.Harigaya, J . I . M o o r e , and A.D'sa, J . Am. Chem. SOC., 1984, 1 0 6 , 2641. 23 5 M.F.Semmelhack and C.Bodurow, J . Am. Chem. SOC., 1984, 106,1496. P.Audin, A.Doutheau, J . G o r e , and J . - J . C h i l o t , B u l l . SOC. Chim. Fr., 1984, 23 6 297 , 307. 237 T . G a l l a g h e r , J . Chem. SOC., Chem. Commun., 1984, 1554.

.

Y

v

I

I

I

,

*

2,

14,

-

~

I

2,

2,

~

282

General and Synthetic Methods

238 23 9 240 24 1 24 2

H.-J.Schneider, A.Ahlhelm, and W.Muller, Chem. Ber., 1984, 117,3297. P.M.Geschwinder, S-Preftitsi, and H.M.R.Hoffman, Chem. Ber., 1984, 117,408. A.Ghribi, A.Alexakis, and J.F.Normant, Tetrahedron Lett., 1984, 2, 3079. M-Yamaguchi, K.Shibato, and I.Hirao, Tetrahedron Lett., 1984, 25, 1159. N. Youeda, T.Kiuchi, T.Kukuhara, A.Suzuki, and G.A. Olah, Chem. Lett., 1984,

24 3 24 4 245 246 247

H.C.Brown, B.Nazer, and J.S.Cha, Synthesis, 1984, 498. R.A.Amos and S.M.Fawcett, J. Org. Chem., 1984, 2637. A.Gadras, J.Dunoguks, R.Calas, and G.Deleris, J. Org. Chem., 1984, 442. G.Gank and M.I.H.Makin, Aust. J. Chem., 1984, 37, 2331. H.Firouzabadi, N.Iranpoor, H.Parham, A.Sardarian, and J.Toofan, Synth. Commun., 1984, 717. M.Masui, Y.Mizuki, K.Sakai, C.Ueda, and H.Ohmori, J. Chem. SOC., Chem. Commun., 1984, 843. A.R.Katritzky, G.R.Khan, and O.A.Schwarz, Tetrahedron Lett ., 1984, 2, 1223. Y.Kuroki and R.Lett, Tetrahedron Lett., 1984, 25, 197. N.Furukawa, K-Hoshino, T.Morishita, and S.Oae, Synthesis, 1984, 317. T.Nagato, T.Yoshimura, K.Fujimori, and S.Oae, Tetrahedron Lett., 1984, 25,

16 17.

248 249 250 25 1 252

2,

2,

14,

341. 253 254 25 5 256 257 258 259 260 26 1 26 2 263

Y.Guindon, J.G.Atkinson, and H.E.Morton, J. Org. Chem., F.A.Luzzio, Synth. Commun., 1984, 209. Y.Kikugawa, J. Chem. SOC., Perkin Trans. 1 , 1984, 609. J.Nakayama, S.Takeue, and M.Hoshino, Tetrahedron Lett., H-Sugimara and H.Takei, Chem. Lett., C.German, A.Alexakis, and J.F.Normant, Synthesis, 1984, D.J.Brunelle, J. Org. Chem., 1984, 1309. P.F.Ranken and B.G.McKinnie, Synthesis, 1984, 117. J.D.Baleja, Synthesis, 1984, 14,215. D.Scholz, Liebigs Ann. Chem., 1984, 259. A.L.Braga, J. V. Comasseto, and N.Petragnani , Tetrahedron

14,

4538.

1984

2679

7 43. 2,

1111.

264 265 26 6

1984

-

Lett -

N.A.Noureldin, W.B.McConnel1, and D.G.Lee, Can. J. Chem., 1984, 62, 2112. T.Tezuka, M.Iwaki, and Y.Haga, J. Chem. SOC., Chem. Commun., 1984, 325. R.Curci, S.Giannattasio, O.Sciacovelli, and L.Troisi, Tetrahedron, 1984,

5,

2763. 267

F .Gasparrini, M. Giovannoli, L.Maresca, G.Natile, and G.Palmieri, Synth.

268

Commun., 1984, 2, 1111. F.Gasparrini, M. Giovannoli, D.Misit i , G. Natile, and G-Palmieri, Tetrahedron,

269 270 27 1 27 2 27 3

F.DiFuria, G.Modena, and R-Seraglia, Synthesis, 1984, 325. P.Pitchen and H.B.Kagan, Tetrahedron Lett., 1984, 25, 1049. A.W. Czarnik, J. Or . Chem., 1984, 49, 924. H.Ohta, Y.Okamoto,gand G.Tsuchihashi, Chem. Lett., 1984, 205. K.Hayakawa, Y-Kamikawaji, A.Wakita, and K.Kanematsu, J. Org. Chem., 1984,

1984,

274 27 5 27 6 27 7 27 8

5, 165.

49, 1985. T.Takeda, T.Tsuchida, and T.Fujiwara, Chem. Lett., 1984, 1219. D.Uguen, Tetrahedron Lett., 1984, 25, 541. K.Hiratani, K.Taguchi, H.Sugihara, and K.Ito, Bull. Chem. SOC. Jpn., 1984,

57,

1976.

E.Blasius, R.A.Rausch, G.D.Andreetti, and J.Rebizant, Chem. Ber., 1984, 117, 1113. -

A.V .Bogatsky, N. G . Lukyanenko, S.S .Basok , and L .K .Ostrovskaya, Synthesis , 1984, 138.

279 280

J.R.Beedle and G.W.Goke1, Tetrahedron Lett., 1984, 25, 1681. J. R.Beadle, D.M.Dishong, R.K.Khanna, and C.W.Goke1, Tetrahedron, 1984,

"0,

3935. 28 1 28 2 28 3 28 4

B.B.Jarvis, V.M.Vrudhula, D.M.Dishong, and G.W.Goke1, J. Org. Chem., 1984,

49,

2423.

Y.Nakatsuji, T.Mori, and M.Okahara, Tetrahedron Lett., 1984, 25, 2171. M.Ouchi, Y.Inoue, K.Wada, and T.Hakushi, Chem. Lett., 1984, 1137. P.Hodge, E.Khoshde1, and J-Waterhouse, J. Chem. SOC., Perkin Trans. 1 , 1984, 911 F 1

4: Alcohols, Halogeno-compounds, and Ethers 285 286 287 28 8 289 290 29 1 29 2 29 3 29 4 29 5 29 6 297 29 8 29 9 30 0 30 1 302 30 3 304 30 5 30 6

J.Elguero, P.Navarro, and M.I.Rodriguez Franco, Chem. Lett., 1984, 425. T.M.Fyles, C.A.McGavin, and D.M.Whitfield, J. Org. Chem., 1984, 753. S.Shirikai, Y.Ishikawa, H.Shinkai, T.Tsuno, H.Makishima. K. Ueda, and O.Manabe, J . Am. Chem..Soc., 1984; 106, 1801. I.Fujii, K.Hayakawa, and K.Kanematsu, Tetrahedron Lett., 1984, 25, 3335. M.Pietraskiewicz and J. Jurczak, Tetrahedron, 1984, 40, 29 67. R.Aldag and G-Schroder, Liebigs Ann. Chem., 1984, 1036. A.V .Bogatsky , N.G.Lukyanenko, A.V .Lobach, N. Yu .Nazarova, and L.P.K Iarpenko, Synthesis, 1984, 139. K. Yamamoto, H. Fukushima, Y. Okamoto, K .Hatada, and M.Nakazaki , J. Chem. SOC., Chem. Commun., 1984, 1111. J.C.Lockhardt, M.B.McDonnel1, and W.Clegg, J. Chem. SOC., Chem. Commun., 1984, 365. J.-P.Desvergne, N.Bitit, and H.Bouas-Laurent, J. Chem. Res. ( S ) , 1984, 214. S.Shinkai, K.Shigematsu, Y.Honda, and O.Manabe, Bull. Chem. S O C . Jpn., 1984, 57, 2879. S.Shinkai, Y.Honda, K.Ueda, and O.Manabe, Bull. Chem. SOC. Jpn., 1984, 2, 2144. S.Shinkai, M.Ishihara, K.Ueda, and O.Manabe, J. Chem. SOC., Chem. Commun., 1984, 727. S.Shinkai, K.Inizuka, K.Hara, T.Sono, and O.Manabe, Bull. Chem. SOC. Jpn., 1984, 57, 2150. T.Izumi, T.Tezuka, S.Yusa, and A-Kasahara, Bull. Chem. SOC. Jpn., 1984, 2, 2435. B.Czech, A.Czech, S.I.Kang, and R.A.Bartsch, Chem. Lett., 1984, 37. M.Sato, S.Tanaka, S.Ebine, and S.Akabori, Bull. Chem. SOC. Jpn., 1984, 57, 1929. S.Akabori, Y.Habata, H.Muneguni, and M.Sato, Tetrahedron Lett., 1984, 25, 1991. M.Lemaure. J.Buter. B.K.Vriesema. and R.M.Kellon. J. Chem. SOC.. Chem. Commun., i 9 8 4 , 309: Y.Nakatsuji, T.Mori, and M.Okahara, J. Chem. SOC., Chem. Commun., 1984, 1045. D.G.Parsons, J. Chem. SOC., Perkin Trans. 1, 1984, 1193. D.R .Alston, A.M.Z. Swain, J. F .Stoddart, and D.J .Williams, Angew. Chem., Int . Ed. Ennl.. 1984. 21. 821. P.J.Dijkstra, J.Cxoerrigter, B.J.van Steene, H.J.den Hertog, and D.N.Reinhoudt, J. Chem. SOC., Chem. Commun., 1984, 1660. D.J.Cram, M.de Grandpre, C.B.Knobler, and K.N.Trueblood, J. Am. Chem. S O C . , 1984, 106,3286.

2,

v ,

~

307 30 8

283

~-

r .

1

~

I

- - I

-

Amines, Nitriles, and Other Nitrogen-containing Functional Groups BY S.

G. LISTER

1 Amines

Reductive methods are s t i l l amongst t h e most

P r i m a r y Amines.-

popular f o r t h e preparations of amines.

I n p a r t i c u l a r t h e ease o f

n i t r a t i o n o f many a r o m a t i c s y s t e m s a n d t h e g e n e r a l s y n t h e t i c v e r s a t i l i t y of a r y l nitro-compounds has continued to f a c i l i t a t e a n i l i n e f o r m a t i o n by a n i t r a t i o n - r e d u c t i o n

sequence.

Although well

d o c u m e n t e d , b o t h s t a g e s s t i l l r e c e i v e much a t t e n t i o n , w i t h t h e s e a r c h f o r s e l e c t i v e r e a g e n t s c a p a b l e of e f f e c t i n g t h e l a t t e r s t e p i n t h e presence of o t h e r f u n c t i o n a l i t y being of prime importance. R e d u c t i o n of n i t r o a r e n e s h a s b e e n a c h i e v e d w i t h s o d i u m borohydride - copper(1) chloride under conditions t h a t t o l e r a t e d an electron-donating

substituent i n the ortho-

relatively simple substrates.

SnC12.2H20

a n d p a r a - p o s i t i o n s of ( i n ethanol or ethyl

acetate) and t h e a n h y d r o u s s a l t ( i n e t h a n o l ) proved t o be e f f i c i e n t reductants for a wide v a r i e t y of n i t r o a r e n e s c o n t a i n i n g s e n s i t i v e s u b s t i t u e n t s.2

Y i e l d s , w h i c h were c o n s i s t e n t l y s u p e r i o r t o t h o s e

previously r e p o r t e d , appeared t o be independent o f both t h e n a t u r e and p o s i t i o n of t h e a r y l s u b s t i t u e n t s . More e s o t e r i c r e a g e n t s e f f e c t i n g n i t r o a r e n e r e d u c t i o n h a v e included the rare-earth

i n t e r m e t a l l i c a l l o y LaNi5 ( a s L a N i 5 H 6 )

although t h i s r e a g e n t w i l l be o f l i m i t e d u t i l i t y s i n c e it a l s o r e a d i l y reduces a l k e n e s , a l k y n e s , aldehydes, and ketones.

Castor

soap (derived from c a s t o r o i l and aqueous sodium hydroxide) a l s o s e r v e d i n t h e p r e p a r a t i o n of a n i l i n e s , b u t e x a m p l e s were l i m i t e d t o simple substrates

.4 B e n z e n e t e l l u r o l i n e t h a n o l - b e n z e n e - w a t e r

has

a l s o b e e n i d e n t i f i e d a s a n e f f i c i e n t r e a g e n t f o r t h e c o n v e r s i o n of n i t r o a r o m a t i c s i n t o a n i l i n e s (Scheme 1 ) .5 C a t a l y t i c systems f o r n i t r o a r e n e r e d u c t i o n s have been extensively studied.

Use of P d / C w i t h ammonium f o r m a t e a s a

c a t a l y t i c hydrogen-transfer

agent has l e d to t h e synthesis of both 6 i n m o d e r a t e t o good y i e l d s ,

primary a l k y l - and aryl-amines

e l e c t r o c a t a l y t i c reductions employing Devarda-copper e l e c t r o d e s i n For References see page 386.

284

285

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

PhTeSiMe3-f MeOH r(PhTeTcPh

+ H,PO,

%

Y PhTeTePh + NaBH4

L-

I

+PhTtTePh i-ArNH,

1

- - - ------ J

- _ - _ -

Reagents : i, C C I 4

I-ArNO,

[PhTeH]

r . t . , A r ; i i , THF

I

H 2 0 ; i i i , C6H6

, H20

,EtOH

Scheme 1

fyR X

G

N

0

2

-k

3

X

e

N

H

2

+

(YR

3 5-5

SH

SH

LAm

DHLAm

R = (CH2I4CONH 2 R e a g e n t : F e r r o u s a m m o n i u m s u l p h a t e , Na2C03

Scheme

,

NaHC03

2

OMe

OR

OR

OMe

R = CH2Ph, S02Ph , o r Me R e a g e n t : FeS04.7H20

OMe

OMe

R = M e or S0,Ph

, NH40H/H20 Scheme

3

286

General and Synthetic Methods

b a s i c media have allowed m i l d e r ( ' l o w e r a p p l i e d p o t e n t i a l s ' )

and

more s e l e c t i v e ( t h a n w i t h c o n v e n t i o n a l e l e c t r o d e s ) r e d u c t i o n s o f nitro-groups;

and a polymer-bound

s y s t e m8

a n t h r a n i l i c acid-PdC12

are a l l noteworthy amongst r e c e n t r e p o r t s . Homogeneous r e d u c t i o n o f n i t r o a r e n e s by t w o a z o b e n z e n e - P d " c a t a l y s t s i n DMF a l s o p r o v e d effective,

although m-dinitrobenzene

and p - n i t r o p h e n o l

be reduced t o t h e corresponding hydroxylamines.

could only

Presumably t h e s e

i n t e r m e d i a t e s were n o t r e d u c e d f u r t h e r o w i n g t o t h e i r p o o r a b i l i t y t o co-ordinate t h e metallic c e n t r e . Formic a c i d and t r i e t h y l a m i n e i n t h e p r e s e n c e of c a t a l y t i c a m o u n t s o f dichlorotris(triphenylphosphine)ruthenium(II) s u c c e s s f u l l y employed i n r e d u c t i o n o f c h l o r o - , methoxy-substituted

nitroaromatics. lo

methyl-,

have been and

Reactions proceeded even i n

t h e a b s e n c e o f s o l v e n t , b u t r a t e s were a c c e l e r a t e d w i t h e t h a n o l a s

s o l v e n t , w i t h b e n z e n e g i v i n g o p t i m u m r e d u c t i o n s i n t e r m s of r a t e and s e l e c t i v i t y .

However, u s i n g t h i s p r o c e d u r e 4 - n i t r o a c e t o p h e n o n e

yielded only the corresponding ethanol derivative.

Dihydrolipoamide-iron(I1) i n b u f f e r e d e t h a n o l p r o v e d t o b e a n o t h e r v e r s a t i l e s y s t e m g i v i n g good y i e l d s o f a n i l i n e s i n smallscale reductions.

''

Both o r t h o - and p a r a - e l e c t r o n - d o n a t i n g - w i t h d r a w i n g s u b s t i t u e n t s were t o l e r a t e d ( S c h e m e 2 ) .

and

Another i r o n ( I 1 ) s a l t (FeS04.7H20) h a s been u s e d t o p e r f o r m r e d u c t i o n s of 2 - n i t r o - t o 2-amino-cinnamic a c i d s i n a h i g h - y i e l d m o d i f i c a t i o n o f t h e P s c h o r r p h e n a t h r a c e n e s y n t h e s i s (Scheme 3 ) . l 2 M e t a l l i c i r o n i n a c e t i c a c i d h a s b e e n u s e d t o p r e p a r e 3-bromo-2-

v i n y l a n i l i n e from t h e c o r r e s p o n d i n g nitro-compound

as p a r t of a

s y n t h e t i c approach t o Ergot a l k a l o i d s . l 3 Another approach t o t h e s e compounds i n v o l v e d a t r i f l u o r o a c e t i c a c i d - m e d i a t e d a z a - C l a i s e n rearrangement of meta-substituted

a n i l i n e s t h a t afforded 2-allyl-3-

s u b s t i t u t e d a n i l i n e s c a p a b l e of f u r t h e r t r a n s f o r m a t i o n t o t h e p r e v i o u s l y d e s c r i b e d U h l e ' s k e t o n e ( 1 ) (Scheme 4 ) . l4 Although r e d u c t i o n s of nitro-compounds have been s t u d i e d i n d e t a i l , i t h a s o n l y r e c e n t l y b e e n shown t h a t s u c h r e d u c t i o n s c o u l d be c a r r i e d out i n t h e presence of an a l k y l n i t r i l e group.15 Thus, on a small s c a l e , t h e e x o t h e r m i c r e d u c t i o n o f a n i t r o - g r o u p achieved i n e x c e l l e n t y i e l d w i t h h y d r a z i n e and Raney-nickel

can be a t or

b e l o w room t e m p e r a t u r e . Nitrile r e d u c t i o n o n l y o c c u r s w i t h a large e x c e s s of h y d r a z i n e a t h i g h e r r e a c t i o n t e m p e r a t u r e s . I t was a l s o d i s c l o s e d t h a t on a l a r g e r s c a l e u s e o f p a l l a d i u m - o n - c a r b o n prevented over-reduction problems t h a t a r o s e from poor c o n t r o l of r e a c t i o n t e m p e r a t u r e i n t h e f i r s t s t e p (Scheme 5 ) .

287

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

CEN

E N

d-0

gn

NH

I

I

H

R

g0

I

I

H

H (1

1 U h l e ' s ketone

-?

R = COZEt CHo

iv,v

R e a g e n t s : i , CF3COZH (1.5 e q u i v . ) ; i i , N a B H 4 , E t O H ; i i i, O 3 iv

, Ag20 , MeOH , H20 ; v ,

EtOH

, CHzClz , - 7 8

, HCI

Scheme 4

X = N or CH Reagents:

i , N2H4.H20, R a - n i c k e l ; ii, N H .H 0, P d / C ; 2 4 2

Scheme 5

iii, N H H 0 2 4' 2

OC ;

288

Generul and Synthetic Methods

-ortho-Substituted aminoaphthalenes have been synthesized in reasonable yields from the parent nitro-compounds by conjugate additions of suitable Grignard reagents followed by treatment of the adducts with phosphorus trichloride in THF. l 6 Conjugate reductions of nitro-olefins have also led to the synthesis of primary amines, l 7 the reductions being achieved with borane-THF plus a small amount of sodium borohydride. Electrochemical reductions of tertiary nitroalkanes have also been studied. 1 8 As well as the aforementioned report of nitrile reduction, the use of Raney-nickel-hydrogen in basic ethanol in a high-pressure conversion of dinitriles and aminonitriles into diamines and polyamines has been reported, as has been the selective reduction of acyl cyanides to a-amino-ketones with zinc and excess acetic anhydride in acetic acid.20 In the latter reduction, yields of amines from aryl and a,B-unsaturated nitriles were poor. Similarly, hydrogenolysis of nitriles to primary amines has found an application in the synthesis of N-methylputrescine and related homologues. 21 Azides are an extremely useful source of arnines, particularly in the carbohydrate area where nucleophilic azide anion can be introduced SN 2-type displacement of an active ester or sulphonate ester, or alternatively at an epoxide centre (see below 1 . Organotellurium reagents have featured prominently in the preparation of primary amines from nitro-compounds, and likewise sodium hydrogen telluride has found application in their preparation from azides.22 The reduction is also compatible with other sensitive functionality. Another report described reduction of the azido-aminoester (2) to the diamino-acid ( 3 ) with hydrogen sulphide in aqueous pyridine .23 Oximes, too, are a valuable source of amines by reduction. Lithium aluminium hydride reduction of substituted benzaldehyde oximes afforded benzylamines , 2 4 which were evaluated as antimycobacterial agents. Attempted hydrosilylation of oximes with diphenylsilane catalysed by either chlorotris(tripheny1phosphine)rhodium(1) or [Rh(COD)C1I2 in the presence of the chiral phosphine (-)-diop gave moderate yields of primary amines after acidic deprotection of the product diphenylsilylamines. However, product enantiomeric excesses were poor, with 14.4% the best figure obtained. 25

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

289

Treatment of aromatic and aliphatic ketone oximes with lithium aluminium h y d r i d e - 3 - ~ - c y c l o h e x y l m e t h y l - l 7 2 - ~ - c y c l o h e x y l i d i n e - 4 - a - D glucofuranose complex afforded 2-amines of up to 5 2 % optical 26 purity. Reduction of oximes has also been realized with sodium borohydride in the presence of transition-metal salts .27 Sodium borohydride-NiC12.6H20 effected reductions of unsaturated oximes to their saturated amine counterparts, whereas the use of Moo3 allowed reductions with preservation of the double bond. Differences in the stereochemistry of the two reductions were also noted. A method of in situ conversion of oximes into imines (by tributylphosphine-diphenyl disulphide), which can be trapped as amines (with sodium cyanoborohydride) o r as a-aminonitriles (with sodium cyanide-acetic acid) , has been reported. 28 Diphenyl disulphide appears to act catalytically in this process which can represent an overall reductive animation of ketones that works well even in cases of severe steric hindrance. A study concerned with the synthesis of analogues of anhydrotetracycline utilized a reduction of the 2-quinone monooxime 9-nitrosoanhydrotetracycline ( 5 ) by sodium dithionite in order to bring about specific 9-amination of anhydrotetracycline (4); the tetracycline (4) was prepared using standard methods.29 7 Aminoanhydrotetracycline ( 7 ) was also prepared, by coupling of (4) with diazotized sulphanilic acid and reduction of the so-formed azo dye with sodium dithionite. 2-Amino-4,6-dimethoxyindane has been prepared from 5 , 7 dimethoxyindan-2-one via hydrogenation of the a-oximino-ketone ( 8 ) . 3 0 Ketones are normally encountered as by-products in oximeto-amine transformations but it has recently been disclosed that inclusion of slight modifications of reaction conditions boric acid and excess acetone in the reaction mixture) lead to formation of ketones exclusively.' Related reductive aminations of ketones constitute another useful method for the preparation of amines. A recent development here has allowed enantioselective syntheses of $-substituted amines via metallation and alkylation of SAMP-hydrazones derived from the corresponding aldehydes (Scheme 6). 32 The amines were liberated from the product hydrazines by hydrogenolysis, the by-product of which, (S)-2-methoxymethylpyrrolidine, may be recycled by nitrosation and reduction. Asymmetric syntheses of 2-substituted cyclohexanamines from

(e.

'

290

General and Synthetic Methods

NHZ

NH Z

( 2 )

(3)

Me

R2

R’ HO

HO

( 4 )R’= R 2 = H

(5)

( 6 ) R ’ = NH, , R 2 = H ( 7 ) R’= H , R,=NH,

NOH

M eO

( 8 )

R2 e . e . 3 95’1.

;roMe + -v , V-I -

( R e c y c Iing)

SAM P

N”

R1J

( -N IL O M I ( S)

QOMe

H\”N

eMO‘

R1yJ

(S)

I

I V

2 2 yii” R2

,h

OMe

R d . e . 3 95*10 Reagents:

I,

LDA,

11,

R2X ;

III,

catecholborane;

Scheme

IV,

6

R a - N i , HI ; V , R O N O ; v i , LiALH4

29 1

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

r a c e m i c c y c l o h e x a m o n e s by m e a n s o f a t h r e e - s t e p r e d u c t i v e a m i n a t i o n Condensation of k e t o n e s w i t h

s e q u e n c e h a v e a l s o b e e n r e p o r t e d . 33

c h i r a l a u x i l i a r y a m i n e s g a v e i m i n e s w h i c h were h y d r o g e n a t e d w i t h Raney-nickel.

P r i m a r y a m i n e s w e r e s u b s e q u e n t l y o b t a i n e d by

c a t a l y t i c hydrogenolysis of t h e r e d u c t i o n products u s i n g palladiumon-charcoal

(Scheme 7 ) .

The p r o c e s s g a v e h i g h c h e m i c a l y i e l d s

under complete d i a s t e r e o m e r i c and very h i g h e n a n t i o m e r i c c o n t r o l . Enantiomeric excesses (determined using d i a s t e r e o m e r i c a c y l a t e d a m i n e s ) o f b e t w e e n 9 2 a n d 99% were c l a i m e d . R e d u c t i o n o f p,~'-dimethoxybenzhydryl i m i n e s o f s u b s t i t u t e d cyclohexanones with l i t h i u m t r i a l k y l b o r o h y d r i d e s a f f o r d e d p r o t e c t e d p r i m a r y a m i n e s w i t h a h i g h d e g r e e of s t e r e o s e l e c t i v i t y f o r a x i a l l y s u b s t i t u t e d p r o d u c t s . 34 P r i m a r y a m i n e s were o b t a i n e d a f t e r standard deprotection with formic acid. T r a n s f o r m a t i o n s o f h e t e r o c y c l i c k e t o n e s t o a m i n e s , w h i c h may f o r m a l l y be regarded as r e d u c t i v e a m i n a t i o n s , have a l s o been documented.

The m o s t n o t a b l e e x a m p l e s i n c l u d e a r e p o r t o f

s y n t h e s i s o f 4-aminoquinoline-2-carboxylates f r o m t h e c o r r e s p o n d i n g 4-0x0-derivatives

w i t h p-chlorophenoxysulphonyl i s o c y a n a t e

( S c h e m e 8 ) , 3 5 a n d o n e c o n c e r n i n g a g e n e r a l r o u t e t o 5- a n d 6s u b s t i t u t e d 4-amino-2-pyridones

f r o m 4-hydroxy-2-oxo-1,2-

d i h y d r o p y r i d i n e s e f f e c t e d by r e f l u x i n g i n b e n z y l a m i n e a n d s u b s e q u e n t h y d r o g e n o l y t i c d e b e n z y l a t i o n ( S c h e m e 8 ) . 36 The C u r t i u s r e a r r a n g e m e n t i s a c l a s s i c a l method u s e d t o o b t a i n amines from c a r b o x y l i c a c i d s .

A new v a r i a n t d e s c r i b e s t r a p p i n g t h e

i s o c y a n a t e formed i n t h e r e a c t i o n w i t h 2 - t r i m e t h y l s i l y l e t h a n o l

with

t h e a m i n e s l i b e r a t e d a f t e r d e s i l y l a t i o n 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 . 37

S i m i l a r l y , Hofmann d e g r a d a t i o n o f a m i d e s i s a l o n g -

e s t a b l i s h e d method o f amine p r e p a r a t i o n .

R e a s o n a b l e y i e l d s of

p r i m a r y amines c a n be o b t a i n e d u s i n g sodium b r o m i t e i n aqueous s o d i u m h y d r o x i d e t o b r i n g a b o u t t h e r e a r r a n g e m e r ~ t . ~I~t h a s a l s o b e e n d e m o n s t r a t e d t h a t L,I-bis(trif1uoroacetoxy)iodobenzene c a n a c h i e v e t h e same t r a n s f o r m a t i o n ( S c h e m e 9 ) .

The s c o p e of t h e

r e a c t i o n , 39 i n e f f e c t a n a c i d i c Hofmann r e a r r a n g e m e n t , k i n e t i c s a n d mechanism4'

and its

have been s t u d i e d .

E l e c t r o p h i l i c a m i n a t i o n o f o r g a n o m e t a l l i c r e a g e n t s i s a more recent general strategy. T o s y l a z i d e h a s p r e v i o u s l y been r e p o r t e d

a s a v i a b l e +NH2 s y n t h o n and h a s been f u r t h e r u t i l i z e d i n a s y n t h e s i s of anthramycin (11).

Key s t e p s of t h e s y n t h e s i s i n v o l v e d

p r e p a r a t i o n o f ( 1 0 ) by l i t h i a t i o n o f ( 9 ) f o l l o w e d by a d d i t i o n of t o s y l a z i d e , borohydride r e d u c t i o n , and p r o t e c t i o n , t h e s e s t e p s

292

General and Synthetic Methods

qR%p

H

QR

-k H2N-C-Ph I*

QR%

I

R

Me

0

N

NH.HC1

2 Me-CLH I Ph

Reagents:

I,

Ra-Ni,H2 ;ii,HCI,EtOH;

III,

I* Me-CI

NH,.H CI

H

Ph

H 2 , P d / C , EtOH

Scheme 7

.x

\

N H

I

k'

Reagents:

I,

C0,Me

x = c i a o - so,-

4-CLC6H40SO2NCO;

II

,HCL , E t O H ;

I I I , ~ ,N2;

iv,H2(1atm),Pd/C

Scheme 8

0

II

RCNH,

0

+

H,O

+

II

PhI(OCCF3),

MrCN

0

RNH;

p H 1-3

Scheme

9

+

PhI

II + CO, + ZC5CO + H'

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

293

being achieved in 72% overall yield (Scheme 1 0 ) . 4 1 An interesting report details conversion of a primary halide into a homologated primary amine via formation of a Grignard reagent and its reaction with a ~,IJ-bis(trimethylsilyl)aminomethyl ether obtained from sodium bis(trimethylsily1)amide and chloromethyl methyl ethers (Scheme 1 1 ) . 4 2 A similar study specified N-,~-bis(trimethylsilyl)methoxymethylamine, prepared from lithium hexamethyldisilazide and chloromethyl methyl ether, as the reagent of choice (Scheme 11).43 The mechanism of a related amination of organolithiums by alkoxyamines has also been studied in more detail. 44 An interesting and more novel example of amination of organometallics described use of the oxime tosylate derived from tetraphenylcyclopentadienone as the electrophilic species. lr5 After displacement of toluenesulphonate by the nucleophile the amine was liberated by exchange with hydroxylamine, thus establishing a 'catalytic ' cycle. The classical method for preparing primary amines from the corresponding alkyl halides without polyalkylation is the Gabriel synthesis. A new method of similar applicability facilitates alkylation of halides and sulphonates with the sodium salt of trifluoroacetamide and thus allows a much easier deprotection reaction.46 Primary amines are thus formed essentially free of secondary amines although some competing dehydrohalogenations were observed in the alkylations. In a similar vein, a one-pot, twostage deprotection of phthalimides leading to isolation of primary amines (and also amino-acids) in good yield has also been described. 47 As well as their utility in the synthesis of homologated amines from alkyl halides as described above, the potential of N,Nbis(trimethylsily1)amines (formed from sodium hexamethyldisilazide and alkyl halides or tosylates) to yield non-homologated primary amines directly by acidic hydrolysis was recognized and naturally exploited. 48 As well as by simple reductive methods nitriles can serve as a source of primary amino functionality in cyclizations where a nucleophilic centre can close onto a suitably disposed cyano-group. Such reactivity has been commonly employed in heterocyclic syntheses, e.g. Scheme 1 2 . 49-52 Michael additions to acrylonitriles also constitute a versatile method for amino-substituted heterocycles, with 5-aryl-3-amino-2-

General and Synthetic Methods

294

0

(11 1

T

-

0-0’

i- iv

Me&

Multistep

0-0’

Me&NH

C02But

7 2 ‘10

R e a g e n t s : i , ButLi ; i i , T s N 3

j

iii, NaBHq ; i v

,( B U ~ O ) ~ C O

S c h e m e 10

N a N ( S i Me3l 2

R2-0

- CH,-N(SiMe,),

4- R’MgBr

bR’-CH2-NN(SiMe3)z

ii i

R1CH2NH..$I

L

R = M e or C,H,3

[RMI RH

vi

RCH,N( S i Me3),

v ii

*

RCH2NH2

Y MzLi

or MgX

R e a g e n t s : I , R 2 0 C H 2 C l , HN(SiMe3I2 ; i i , E t z O , r . t . ,

Et20; v , L i , Mg8r2;

VI

12h ;

III

,HCI,H20,Et20;iv,Mg,

, ( M e 3 S ~ ) 2 N C H 2 0 M e ,t h e n aq. KOH;

or S i 0 2

S c h e m e 11

VII,

MeOH,p-TSA

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

Reagent : AlCL3

,P h C l S c h e m e 12

S c h e m e 13

L

(12)

R e a g e n t s : NHZOH.HCL

~

NaOH ; i i ) NH20H.HCL, N o

S c h e m e 14

295

296

General and Synthetic Methods

alkoxycarbonylthiophenes and 5-aryl-aminopyrazoles resulting from treatment of 8-chlorocinnamonitriles with esters of a mercaptoacetic (Scheme 13). Addition of has led to the cyclization of

acid53 and hydrazine hydrate5'

respectively , e.g.

hydroxylamine hydrochloride to 2-halogenonitriles synthesis of 3-amino-2,l-benzisoxazoles ( 1 3 ) upon the initial adducts (Scheme 14).55 Rearrangements of preformed heterocycles have also led to amino

substitution; for example the reduction of 4-cyanoisoxazoles afforded 5-amino-oxazoles ,56 whose preparation from 1 - a c y l - a aminonitriles has also been studied , 57 whilst base-induced rearrangement of (2-oxo-2-anilinoethyl)-Il2,4-oxadiazoles has afforded 3-(acylamino)-l-aryl-2-pyrazolin-5-ones, which can be easily deacylated to yield the corresponding primary amino derivatives .58 5-Amino-7(6H)-furazano[3 , 4-dlpyrimidinone can be obtained from a wide variety of 5 - a m i n o f u r a z a n o [ 3 , 4 - d l p y r i m i d i n e s after either basic or acidic ring cleavage, esterification, and recyclizat ion - 5 9 Addition-eliminations between malononitrile and heterocycles has served in the preparation of amino-cyano-substituted compounds. Thus, 2-amino-3-cyanopyridines have been made from 2(1Ij)pyrimidinones6' and 2-amino-3-cyan0-4-pyrones were synthesized from 1 , 3-oxazin-4-one-2-thiones .61 Hydrazine hydrate effected a novel amination of 6-aryl-3(25)pyridazinones in the 4-position. 6 2

Studies concerning the high-pressure liquid chromatographic separation of enantiomeric amines has revealed that primary amines could be separated using (~)-~-(3,5-dinitrobenzoyl)phenylglycine covalently bound to y -aminopropylsilanized silica.63 As well as a range of primary amines that included substituted cyclohexylamines, amino-alcohols and amino-acid derivatives could be separated. Another chiral stationary phase based on a-(6,7-dimethyl-lnaphthyl )isobutylamine was also developed . 6 4 E- ( 3 , 5 Dinitrobenzoy1)amines were resolved reasonably well (as were aminoalcohols, amides and amino-acids). The same report revealed that another stationary phase derived f r o m a-(l-naphthy1)ethylamine performed better for some amines, but generally less well for amino-acids. Secondary Amines.- Monoalkylation of primary amines is a key functional group transformation in organic synthesis and perhaps

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

297

the most obvious approach to the synthesis of secondary amines. However, there has been a long history of problems with overalkylation associated with the method which is, therefore, still investigated thoroughly. Ruthenium-catalysed 1-alkylations and N-benzylations of aminoarenes with alcohols have been reported, with excellent yields of secondary amines obtained when equimolar mixtures of amines and alcohols were employed with dichlorotris(tripheny1phosphine)ruthenium(I1) as the catalyst precursor.65 It was noted that use of an excess of alcohol gave predominant tertiary amine formation. Although monomethylation of primary arylamines via treatment of N-(alkoxymethy1)-N-arylamines with sodium borohydride (to reduce presumed arylmethyleneamine intermediates) in refluxing ethanol has been reported (Scheme 15) ,66 similar treatment of N-(alkoxymethy1)N-alkylamines failed to give monomethylated alkylamines. This problem was circumvented by effecting the reduction with lithium aluminium hydride in ether at -60 O C , under which conditions monomethylated amines were obtained essentially free of primary or N,N-dimethylated amines. In a subsequent paper, the same authors reported that ~-alkyl-~-(alkylthiomethyl)ammoniumchlorides afforded monomeric N-methylenealkylamines (stable at -60 OC) which could then be trapped with organometallic reagents, thus providing unsymmetrical secondary amines (Scheme 15 .67 A similar reaction of organolithiurn o r organomagnesium reagents with N-(cyanomethyl)or 1-(aminomethyl)-amine derivatives led to unsymmetrical secondary amine formation presumably via addition of the organometallic nucleophile to methyleneamine intermediates. 68 The selective methylation of primary amines has also been achieved, in a few examples, using methyltrialkoxyphosphonium tetrafluoroborates as the alkylating species.69 In another report, metathesis of primary amines to secondary amines was accomplished with d i c h l o r o b i s ( t r i p h e n y I p h o s p h o s p h i n e ) p l a t i n u m ( I I ) , but only in the presence of SnC12. 2H20. 7 0 Yields were variable, and particularly so for primary diamines. In bio-organic chemistry the study of polyamines has traditionally been an important area, and selective alkylations and acylations of the ubiquitous polyamines putrescine, spermidine, and spermine are thus of crucial importance. From the many strategies employed to achieve these goals a selective monoprotection (that would enable monoalkylation) occurred with benzyloxycarbonyl chloride provided that the reagent was added to the diamine with

298

General and Synthetic Methods

careful control of P H . ~ ’ A pH of between 3.5 and 4.5 is essential if diacylated products (formed at pH > 5 . 0 ) are to be avoided (Scheme 1 6 ) . Another approach leading to the synthesis of Emethylputrescine and its homologues involved alkylation of 4bromobutyronitrile with alkylbenzylamines followed by a hydrogenolysis to effect both reduction of the nitrile to primary amine as well its .debenzylation to yield the secondary amino function (Scheme 16).21 A third strategy utilized ltrifluoroacetyl-protected amino-acids which were converted through acyl halides to amides. This followed by alkylation and deprotection of the trifluoroacetamide moiety allowed the target compounds to be isolated after borane-dimethyl sulphide reduction of the amide as the final step (Scheme 16).72 Selective ~4-monoacylation of spermidine with hydroxycinnamoyl groups has been achieved from either 7-aminobutyric acid (Scheme 1 6 ) , 7 3 o r from , N 4 ,N8 -tri-t-butoxycarbonylspermidine via a known (see Volume 8, p.262) preferential 4 -deprotection with methyl-lithium andlor n-butyl-lithium in THF at -20 0C.73 A complementary approach to secondary amines is the dealkylation of tertiary amines. This more difficult transformation has been achieved N-oxides by formation of silyloxyammonium salts upon reaction with trialkyltrifluoromethanesulphonates. In the presence of a strong base these rearrange to a-silyloxyamines which react further with suitable electrophiles. Thus in the presence of an acyl halide acylated secondary amines can be isolated.74 Since Eoxide formation is nearly quantitative, overall yields for the process are high. A novel system employing a , B , y tetraphenylporphynatoiron(III), molecular oxygen, and sodium dithionite in which the iron(II1) species acts catalytically has been ~ t u d i e d . ’ ~ In the case of dealkylation of g-ethyl-gmethylaniline by this reaction both possible dealkylated products were obtained with the N-demethylated product predominating. A further dealkylative method required treatment of tertiary amines with a-chloroethyl chloroformate ( ACE-C1) in 1,2-dichloroethane . 7 6 The quaternized intermediate was not isolated, and the resultant acylated secondary amine was deprotected merely by heating in methanol. The method was applied to the development of improved syntheses of naltrexone and nalbuphine. As with primary amines, secondary amines may be prepared by reduction of imines. One example of reduction by an inter-metallic rare-earth alloy La5Ni6 (see above) was reported.

M1

x

299

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

R e a g e n t s : i I (CH20),

, NaOMe;

11,

NaBH4, then

1M-KOH ; i i i , ( a ) (CH20),

,(~)HcI

( 3 e q u I v . 1 , a n h y d r o u s E t 2 0 , ( c ) R2SH; i v , R 3 M ( 3 e q u i v . ) , E t 2 0 ; v , l M - K O H

S c h e m e 15

0

0 HzN(CH2),NH2

II

II

+ PhCH20-C-Cl

--LPhCHzO-C - NH(CH,),NH,

n =2-7 iii

I1

PhCH2NHR 4- B r C HZCHzCHzCN -b PhCHZNRCH2C3CH2CN+RNHCH2C3CH2CHzNH2.2HCl

-

R=Me,Et,Prn,

0 TFANH(CH,),CCI

It

iv

o r Bun

0

I

TFANH(CH,),CNR’R~ VI

0

R3

II

II

TFAN(CH,),,CNR’R~

,vi i

0

II

VI, V I I

R3iH,(CH2!,,+,iH

R1R2 2 Y-

R3NH(CHz),CNR’R2

a

0

H (CH&l

Boc NH (CH,),CON

-%B o c NH(C H,),CON

H (CH 2)3N

0 XI1

BocNH(CHZI4NH ( C H ~ ) ~ N H B O CaBocNH(CH,)3CONH(CH2)3NHBOC ( C H2)3NHBoc

CHSHCON xlll.l \/

R2+

YH2

)3NH3

CHXHCON \

- J $R

( C Hz 14NHBOC

R Reagents-

XlV,XV)

R

+

+

( C H&+NH3

2 CF3COO-

I , MeS03H, b r o m o c r e s o l g r e e n : ii,KZC03(1 e q u i v ) , K I (0.1equiv 1; vii,HCL; viii,K2C03; I V , R1R 2NH,py;R3XJK2CO3,MeZCO;vi,BH3.Me25;

111,

IX,

H,,Pd,C; NaH,

p h t h a l i r n i d e , N a I ; x , N2H4.H20;x~,(But0CO)Z0,NaZC03; XII, Na(CF3COZ)6H3;X I I I , 3-R’-4-

R2- 5 -R3C6HZCH=CHCOCI,CHZClZ ; X I v, MeOH, NH3 ; xv ,CF3C02H

S c h e m e 16

General and Synthetic Methods

3 00

Asymmetric r e d u c t i o n s w i t h l i t h i u m aluminium h y d r i d e complexes d e r i v e d f r o m 3-~-benzyl-l12-~-cyclohexylidine-~-D-g1ucofuranose g a v e r i s e t o o p t i c a l l y a c t i v e s e c o n d a r y amines a l b e i t i n low enantiomeric excess.”

The mechanism o f i m i n e r e d u c t i o n s , and i n

p a r t i c u l a r t h e case of 3 ,N-diphenylbutan-2-irninet

78 h a s b e e n

studied. R e d u c t i v e a m i n a t i o n o f c a r b o n y l c o m p o u n d s w i t h o u t i s o l a t i o n of i m i n e s is becoming a f r e q u e n t l y used s y n t h e t i c a l t e r n a t i v e t o t h e above methods.

Sodium hydrogen t e l l u r i d e e f f e c t s t h e

t r a n s f o r m a t i o n i n m o d e r a t e t o good y i e l d s

,79 w h i l s t b o r a n e - p y r i d i n e

h a s been proposed a s a v e r s a t i l e and c h e a p r e a g e n t f o r t h i s purpose, with t h e additional advantage t h a t t h e severe t o x i c i t y problems a s s o c i a t e d w i t h t h e popular r e a g e n t sodium c y a n o b o r o h y d r i d e a r e a v o i d e d . 8o

Borane-THF

h a s been s i m i l a r l y used

not only f o r t h e synthesis of simple a l i p h a t i c amines but a l s o f o r see-amino-alcohols

81

and sec-amino-phenols.

Imines have proven t o be e x c e l l e n t s u b s t r a t e s t o which o r g a n o m e t a l l i c n u c l e o p h i l e s may b e a d d e d .

They u n d e r g o t h r e o -

s e l e c t i v e a d d i t i o n of a l l e n y l s i l a n e s 8 2 a n d C r a m - s e l e c t i v e o f allyl-9-BBN

83 ( s e e S e c t i o n 3).

a-Hydrogen-containing

additions imines

a f f o r d e d good y i e l d s o f s e c o n d a r y a m i n e s a f t e r t r e a t m e n t w i t h b o r o n trifluoride-complexed Alkynyl-boranes

a l k y l c o p p e r r e a g e n t s (Scheme 1 7 ) .

84

( a n d -berates) a n a l o g o u s l y p r e p a r e d i n s i t u f r o m

l i t h i u m a c e t y l i d e a n d BF3.Et20 a l s o a d d w e l l t o a l d i m i n e s , y i e l d i n g R-aminoalkynes

( s e e S e c t i o n 3 ) .85

The r o l e o f o r g a n o b o r o n c h e m i s t r y i n t h e p r e p a r a t i o n o f s e c o n d a r y a m i n e s h a s been f u r t h e r e x t e n d e d by a r e p o r t t h a t reaction of trialkylboranes with N-chloroalkylamines can be u t i l i z e d t o synthesize a v a r i e t y of functionally s u b s t i t u t e d d i a l k y l a m i n e s i r , g r e a t e r t h a n 60% y i e l d

( S c h e m e 1 8 ) .86

Thus a n

o v e r a l l o l e f i n t o a m i n e t r a n s f o r m a t i o n was r e a l i z e d . Sulphonamidomercuration of o l e f i n s and subsequent r e d u c t i v e demercuration leading t o N-alkylsulphonamides

h a s b e e n s t u d i e d . 87

The r e a c t i o n of n i t r o g e n n u c l e o p h i l e s w i t h n - o l e f i n p a l l a d i u m ( I 1 ) c o m p l e x e s h a s been c o v e r e d a s p a r t of a l a r g e r r e v i e w d e a l i n g w i t h t h e t o p i c of p a l l a d i u m ( I 1 ) - a s s i s t e d r e a c t i o n s of mono-olefins.

88

Reductive aminations of ethynylpyridines with primary amines and s o d i u m c y a n o b o r o h y d r i d e h a v e a l s o b e e n d e m o n s t r a t e d .89 m e t h o d o l o g y was a l s o a p p l i e d t o t h e s y n t h e s i s o f some

The

B-(N,N-

dialky1amino)pyridines i n analogous r e a c t i o n s employing secondary amines.

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

301

S c h e m e 17

R’

+ R ~ ~ B - NI+-

~’p + CINHR’~ Reagents :

I,

I H

THF, NaHC03 ; 1 1 ~ 1 ‘100 HCL ;

III

, 3N-

~2

% R’R~NH

NaOH

S c h e m e 18

OTs

0=

H0’

‘

H

/J

HO

I

H I

____)

-

I

H

H

I1

1

-

8

I1

R’

R

4-

IJ H

R e a g e n t s : i ,(Me3SiI2NH ; i i , L e w i s a c i d , R’NHR‘

S c h e m e 19

Me2SiOH

General and Synthetic Methods

3 02 In a synthesis of aphidicolin

(15) a key s t e p r e q u i r e d

i n t r a m o l e c u l a r a l k y l a t i o n o f a n e n o l a t e d e r i v e d from ( 1 4 ) .

The

d e s i r e d d e p r o t o n a t i o n ( a t c a r b o n a ) was o n l y a c h i e v e d e f f e c t i v e l y when l i t h i u m d i - t - b u t y l a m i d e

was u s e d a s b a s e .

However, t h e amine

was o n l y p r e p a r e d w i t h d i f f i c u l t y a n d t h i s p r o m p t e d d e v e l o p m e n t of a g e n e r a l s y n t h e s i s of d i - t - a l k y l a m i n e ~ . ~ ~T h e s t a g e s of t h e

preparation are:

( i > oxidation of t-alkylamine

with peracetic acid

i n e t h y l a c e t a t e , ( i i ) conversion of t h e so-formed t - a l k y l n i t r o s o compound i n t o t h e c o r r e s p o n d i n g tri-t-alkylhydroxylamine by s u c c e s s i v e t r a p p i n g o f t w o t - a l k y l r a d i c a l s , a n d ( i i i ) r e d u c t i o n of t h e l a t t e r compound m e d i a t e d by s o d i u m n a p h t h a l i d e . The s y n t h e s i s o f u n s y m m e t r i c a l l y s u b s t i t u t e d l , 4 - d i a l k y l a m i n o s u b s t i t u t e d a r o m a t i c s y s t e m s h a s b e e n p r o m i n e n t i n t h e s e a r c h for antineoplastic agents. Photochemical methods have been used w i t h increasing success i n t h i s direction. I n one i n s t a n c e 1,4-

dimethoxyanthracene-9,lO-dione u n d e r w e n t p h o t o c h e m i c a l m o n o s u b s t i t u t i o n i n 30-51% y i e l d i n t h e p r e s e n c e of a p r i m a r y a m i n e , w i t h a s e c o n d a m i n e m o i e t y s u b s e q u e n t l y i n t r o d u c e d (28-92% y i e l d ) i n a thermal s u b ~ t i t u t i o n . ~ ’ Another e f f o r t developed a s u c c e s s f u l photochemical p r e p a r a t i o n o f 8-alkylamino-5-amino-3-

butylamino-2-cyano-l,4-naphthoquinones f r o m t h e p a r e n t 8u n s u b s t i t u t e d compound, and p r i m a r y a m i n e s . 9 2

Providing reactions

were c a r r i e d o u t under a n i n e r t atmosphere ( n i t r o g e n ) a h i g h l y 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 d e s i r e d compounds, a v o i d i n g t h e c o m p l e x p r o d u c t m i x t u r e s a n d l o w y i e l d s e n c o u n t e r e d when r e a c t i o n s took p l a c e i n t h e p r e s e n c e of oxygen, could be accomplished.

A

f u r t h e r report noted displacements of alkoxy s u b s t i t u e n t s para- t o a n i t r o - g r o u p by p r i m a r y a m i n e s i n t h e a b s e n c e o f o t h e r

reagent^.'^

I n t h e c a s e s s t u d i e d , r e p l a c e m e n t o f a p r i m a r y by a s e c o n d a r y a m i n e l e d t o t h e f o r m a t i o n o f p h e n o l s by d e a l k y l a t i o n . C o v a l e n t a m i n a t i o n o f l - a l k y l - a n d l-aryl-3-carbamoylpyridinium c h l o r i d e s w i t h l i q u i d ammonia h a s b e e n s t u d i e d , a n d t h e p o s i t i o n of s u b s t i t u t i o n f o u n d t o b e d e p e n d e n t on t h e n a t u r e of t h e n i t r o g e n s u b s t i t u e n t .g4

1- n - A l k y l

whereas l-branched

groups led t o exclusive 6-substitution,

a l k y l g r o u p s d i r e c t e d s u b s t i t u t i o n t o t h e C-4

a n d C-6 p o s i t i o n s w i t h p r o d u c t r a t i o s s h o w i n g d e p e n d e n c y o n t h e s i z e of t h e n i t r o g e n s u b s t i t u e n t . l - A r y l d e r i v a t i v e s were s u b s t i t u t e d o n l y a t C-2 a n d C-6, t h e r a t i o s of p r o d u c t s i n t h e s e cases b e i n g t e m p e r a t u r e dependent. I n t h e f i e l d of h e t e r o c y c l i c c h e m i s t r y a n e f f i c i e n t m e t h o d f o r a m i n a t i o n of h y d r o x y - N - h e t e r o c y c l e s h a s b e e n d e v e l o p e d . 9 5 The

303

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups method i n v o l v e s a o n e - s t e p ,

one-pot

silylation-amination

The a d d i t i o n - e l i m i n a t i o n o f a m i n e s t o 2 - s i l y l a t e d

procedure.

heterocycles with

l i b e r a t i o n of t r i m e t h y l s i l a n o l is L e w i s acid-catalysed

and a

p a r t i c u l a r l y e f f i c i e n t procedure i n t h e presence of excess h e x a m e t h y l d i s i l a n e which c o n v e r t s t h e s i l a n o l t h u s formed i n t o hexamethyldisiloxane. The m e t h o d w o r k s e q u a l l y w e l l u s i n g ammonia

o r a s e c o n d a r y a m i n e i n p l a c e of t h e p r i m a r y a m i n e (Scheme 1 9 ) . I n g e n e r a l , d i s p l a c e m e n t o f a l e a v i n g g r o u p by a p r i m a r y a m i n e is a s t r a t e g y t h a t works w e l l f o r t h e s y n t h e s i s of a h e t e r o c y c l i c secondary (and a l s o t e r t i a r y ) amines. T h i s p o i n t may b e e x e m p l i f i e d by t h e s y n t h e s i s o f 4 - a l k y l a m i n o f u r a n o n e s , 96 a n d t h e p r e p a r a t i o n o f 2-aminopyrazine l-oxides.97

from 4-alkoxy-2(5K)from 2-halogeno-

I t was a l s o f o u n d t h a t t r e a t m e n t o f 5-

a c e t y l o x a z o l e s w i t h p r i m a r y a m i n e s l e d t o t h e i s o l a t i o n o f I!-2-s-

alkylamino-5-acetylimidazoles 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 a m o u n t s o f 2 - a l k y l a m i n o - 4 - m e t hy 1 - 5 - h y d r o x y p y r i m i d i n e s . The u s e o f c o v a l e n t l y bound (g)-l-(3,5-dinitrobenzoyl)p h e n y l g l y c i n e a s a c h i r a l s t a t i o n a r y p h a s e for t h e s e p a r a t i o n o f e n a n t i o m e r i c amines h a s been extended t o i n c l u d e g-a-naphthoyl d e r i v a t i v e s o f c y c l i c s e c o n d a r y a m i n e s ,9 9 w h o s e 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 by a l k y l a t i o n s o f 1,2,3,4-tetrahydroisoquinolines h a s b e e n t h e s u b j e c t o f c o n t i n u e d s t u d y . 1oo-102 S t u d i e s o f r e l a t e d p y r r o l i d i n e , 1 0 3 ’ 1 0 4 p i p e r i d i n e , ’03-’05 a n d t e t r a h y d r o - g c a r b o l i n e l o 6 m e t a l l a t i o n s have been published. T e r t i a r y Amines.-

Reductive a l k y l a t i o n s of b o t h primary and

s e c o n d a r y amines c o n s t i t u t e f a c i l e r o u t e s t o t e r t i a r y amino derivatives.

The f o r m e r m e t h o d c a n b e i l l u s t r a t e d by t h e

d i m e t h y l a t i o n o f (6) a n d ( 7 ) w i t h f o r m a l d e h y d e a n d s o d i u m c y a n o b o r o h y d r i d e ,29 w h i l s t s o d i u m d i h y d r o g e n p h o s p h a t e i n c o n j u n c t i o n w i t h formaldehyde proved t o be a u s e f u l a l t e r n a t i v e r e a g e n t f o r N,X-dimethylation o f p r i m a r y and N-methylation o f secondary amines. Io7 The a l k y l a t i o n o f d i a r y 1 a n d a r o m a t i c secondary amines under phase-transfer

conditions with polyethylene

g l y c o l m e t h y l e t h e r i n p l a c e o f 18-crown-6 b e e n r e p o r t e d . 108

as c a t a l y s t h a s a l s o

An i n t e r e s t i n g r o u t e t o 1 - a l k y l - g - a r y l a n i l i n e s

b a s e d on

r e d u c t i v e a l k y l a t i o n o f a m i n e s w i t h c a r b o n y l compounds h a s b e e n d e v e l o p e d a f t e r h i g h y i e l d s o f t h e s e c o m p o u n d s were u n e x p e c t e d l y o b t a i n e d on c o n d e n s a t i o n o f c y c l o h e x a n e - 1 , 4 - d i o n e s and N,N-diaryl-amines

respectively

( S c h e m e 2 0 1. l o g

with 1-aralkyl-

General and Synthetic Methods

304

The n u m e r o u s t y p e s o f a - m e t a l l o a m i n e s y n t h o n s h a v e b e e n comprehensively reviewed and l i s t e d a c c o r d i n g t o t h e t y p e of activating substituent present. 'lo t e r t i a r y a l i p h a t i c N-methylamines a c t i v a t i o n , u s i n g Bu'Li-KOBut

,

It h a s a l s o been r e p o r t e d t h a t can be d e p r o t o n a t e d w i t h o u t

Formation o f t e r t i a r y amine g - o x i d e s fruitful.

'

and s u b s e q u e n t l y a l k y l a t e d . h a s also p r o v e d m o s t

a - S i l o x y a m i n e s d e r i v e d f r o m t h e m , by r e a c t i o n w i t h

t r i a l k y l s i l y l trifluoromethanesulphonates a n d r e a r r a n g e m e n t o f t h e r e s u l t a n t siloxyammonium s a l t s w i t h s t r o n g b a s e , n o t o n l y a f f o r d s e c o n d a r y a m i n e s by d e a l k y l a t i ~ nb~u t~ may a l s o b e s u b s t i t u t e d i n the a-position

by r e a c t i o n w i t h G r i g n a r d r e a g e n t s o r

t r i a l k y l a l u m i n i u m s i n m o d e r a t e t o good y i e l d s (Scheme 2 1 ) . ' I 2 In a d d i t i o n treatment of a-siloxyamines w i t h a l k y l h a l i d e s g i v e rise t o a-siloxyammonium

s a l t s capable of f l u o r i d e ion-induced

d e s i l y l a t i o n thereby a f f o r d i n g t r a n s a l k y l a t e d t e r t i a r y amines ( S c h e m e 21 1. 1 1 3 A l t h o u g h i t h a d b e e n p r e v i o u s l y shown t h a t q u a t e r n a r y p y r i d i n i u m salts could undergo r i n g f u s i o n , transamination,

and r e c y c l i z a t i o n

t o g i v e a r o m a t i c a m i n e s , t h e r e a c t i o n was p r o n e t o c o m p l i c a t i n g side reactions.

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 a b u l k y

E-

s u b s t i t u e n t f a v o u r s t r a n s a m i n a t i o n o f t h e a c y c l i c i n t e r m e d i a t e . l l' U s e f u l y i e l d s ( g r e a t e r t h a n 50% i n a l l c a s e s ) o f t e r t i a r y a m i n e s were o b t a i n e d by p r o l o n g e d ( 4 0 - 4 5 h ) h e a t i n g ( 1 8 0 - 2 0 0 O C ) o f 1 i s o p r o p y l p i c o l i n i u m i o d i d e w i t h a n amine and i t s s u l p h i t e s a l t i n One e x a m p l e o f s e c o n d a r y aqueous s o l u t i o n i n a s e a l e d ampoule. amine formation u s i n g t h i s t e c h n i q u e is c i t e d . A Lewis acid-mediated p r e n y l a t i o n of s e c o n d a r y amines u s i n g p r e n y l d i - i s o p r o p y l p h o s p h a t e may f i n d a p p l i c a t i o n i n c a s e s w h e r e s e l e c t i v i t y i s i m p o r t a n t . W i t h BF3.0Et2 o t h e r a m i n e s f a i l e d t o react, secondary amines g i v i n g reasonable y i e l d s of N-prenylated products. Diarylamines gave s i g n i f i c a n t l y higher y i e l d s than arylalkylamines, nitrogen-containing heterocycles affording n u c l e u s - p r e n y l a t e d p r o d u c t s . 115 Aminomethylations of a d e n i n e , c y t o s i n e , and guanine have been d e s c r i b e d . l 6 M o n o a l k y l a t e d p r o d u c t s were o n l y o b s e r v e d i n r e a c t i o n s of a d e n i n e w i t h aminomethylating a g e n t s d e r i v e d from r e l a t i v e l y non-basic amines used i n equimolar q u a n t i t i e s . Bisa l k y l a t e d p r o d u c t s were o b t a i n e d on r e a c t i o n s o f a d e n i n e w i t h a m i n o m e t h y l a t i n g a g e n t s d e r i v e d f r o m b a s i c a m i n e s , a n d were f o r m e d e x c l u s i v e l y i n r e a c t i o n s of c y t o s i n e and g u a n i n e r e g a r d l e s s o f b o t h

305

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

Scheme 2 0

R’

0-

\h/

R’2

R2HN\CH2R3

‘CH2R3

R’

RI +/

OSiMe2Buf

I

v

/ O S i Me2Buf

\

N-CH

R2/

‘R3

t

Me2Bu

,OSi

-0Tf

0F R’,

R’

CH(R3)-&-SiMe26u

L2 /‘id\R

x-

R

R’

\

ii

+

iv

2/

N-R

R

R4 N-CHC

N-E

R2/

R2’

R3

E = COR ( C 0 2 R J NO, or H 1 R e a g e n t s : i, B u t M e 2 S i O T f ; ii

MeLi ; iii

R X ; iv,Bun4NF; v , R4MgBr or R 2 I ; v i , R C O C I

S c h e m e 21

General and Synthetic Methods amine b a s i c i t y and r e a g e n t s t o i c h e i o m e t r y . Diamines.-

The s y n t h e s i s o f f o r m a m i n a l s on r e a c t i o n o f s e c o n d a r y

amines with formaldehyde is a l o n g - e s t a b l i s h e d

procedure.

Somewhat

s u r p r i s i n g l y , secondary amines reacted with bis(chloromethy1) e t h e r t o y i e l d methylenebisamines.

A mechanism i n v o l v i n g Grob

fragmentation t o dialkylaminomethyl chloromethyl e t h e r i n t e r m e d i a t e s was p r o p o s e d t o e x p l a i n t h e s e o b s e r v a t i o n s . F o r m a m i n a l s were a l s o p r e p a r e d f r o m s e c o n d a r y a m i n e s a n d d i c h l o r o m e t h a n e i n m e t h a n o l by c o n s e c u t i v e h i g h - p r e s s u r e Mensc h u t k i n r e a c t i o n s .

I n a d d i t i o n , a m i n a l s were o b t a i n e d f r o m

aminocarbenes, generated from phenylbromodiazirine, amines.

and s e c o n d a r y

'9

Hetero-Diels-Alder

r e a c t i o n s have played a n important p a r t i n

t h e synthesis of unsaturated v i c i n a l diamines.

Thus, bis(imides1

o f s u l p h u r d i o x i d e a c t e d as d i e n o p h i l e s i n r e a c t i o n s w i t h b o t h

(E,E)- a n d ( E , L ) - h e x a - 2 , 4 - d i e n e s . For e a c h p a i r o f 1 - a m i n o - 3 , 6 dihydro-2E-ll2-thiazines s o f o r m e d , s e p a r a t i o n o f S , C 6 - c i s - a n d S,C - t r a n s - i s o m e r s was a c h i e v e d c h r o m a t o g r a p h i c a l l y . Both isomers 6d e r i v e d from t h e ( E , g ) - d i e n e

c o u l d be c o n v e r t e d i n t o threo-N-

protected-3-ethylene-I,2-diaminesl w h e r e a s t h o s e a d d u c t s of t h e ( E , L ) - d i e n e were c o n v e r t e d i n t o t h e e r y t h r o - i s o m e r s . I 2 O These transformations required treatment of t h e S,C6-trans-isomers

with

p h e n y l m a g n e s i u m b r o m i d e f o l l o w e d by a d d i t i o n o f t r i m e t h y l p h o s p h i t e and r e a r r a n g e m e n t of t h e S , C 6 - c i s - i s o m e r s

t o Il2,5-thiadiazolidines

i n r e f l u x i n g b e n z e n e f o l l o w e d by t h e i r r e d u c t i o n w i t h s o d i u m b o r o h y d r i d e (Scheme 2 2 ) . Vicinal di-t-amines

have been p r e p a r e d i n up t o

54% y i e l d by a n

a m i n a t i v e r e d u c t i v e c o u p l i n g o f a r o m a t i c a l d e h y d e s i n d u c e d by

tris(dialkylamino)methylvanadium(IV).

T h e v a n a d i u m s p e c i e s was

p r e p a r e d i n s i t u e i t h e r b y t r e a t m e n t of chlorotris(dialky1amino)vanadium(1V) w i t h m e t h y l - l i t h i u m

or by s e q u e n t i a l a d d i t i o n s o f

l i t h i u m d i a l k y l a m i d e s ( 3 e q u i v a l e n t s ) and m e t h y l - l i t h i u m s o l u t i o n of vanadium t e t r a c h l o r i d e i n e t h e r - p e n t a n e . method f a c i l i t a t e s a one-pot

procedure s i n c e t h e aldehyde can be

added d i r e c t l y t o t h e r e a c t i o n m i x t u r e . m e c h a n i s m was p r o p o s e d

to a

The l a t t e r

A radical coupling

(Scheme 2 3 ) .

A p r e v i o u s l y r e p o r t e d m e t h o d o f v i c i n a l d i a m i n a t i o n of o l e f i n s

u s i n g cyanamide and N-bromosuccinimide been improved. 122 B-bromoalkylisourea

( s e e Volume 8 , p . 2 5 3 )

has

A k e y s t e p i n t h e s y n t h e s i s was c y c l i z a t i o n o f a

t o a n a z i r i d i n e [Scheme 2 4 ; ( 1 7 ) - ( 1 9 ) ] .

I t was

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

Me

307

Rfl-s,

YH R

H

NHR

Me

Me

RN-S Me R*

I

YHR Me

&

M

H Me

iii,(MeO$P;

V

e

NHR

I

R e a g e n t s : i, C 6 H 6 ; i i , P h M g B r ;

e

iv,PhH,A;v,NaBH4

Scheme 22

General and Synthetic Methods

308

[,,hANEt2] Me

,1

MeMlY(NEt,), -MeMw(NEt,), PhCHO

-I- O=M ( N E t 2 I 2

I NEt,

1l 2 PhF

P

h

NEt, Scheme 2 3

J

'tt'

I

Qc-c'2 H2N/

f

\NH2

(17) R = OEt (18) R : H

HNYN

R=H I"

R

R = O E t or H Reagents :

I ,

N H 2 C N , NBS ;

ii,

H2

, lo/,

Pd / C ;

III

, NaOMe

Scheme 2 4

f--

N

I

HNGCNR (IS)R=OEt or

H

; I V , 0 . 2 5 M - N a O H ; v , 5 0 " l o a q KOH

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

309

p o s t u l a t e d t h a t m i l d e r c o n d i t i o n s f o r t h e c y c l i z a t i o n and h y d r o l y s i s s t e p s would l e a d t o a more e f f i c i e n t p r o c e s s o v e r a l l . The f o r m a m i d i n e ( 1 8 ) was f o u n d t o b e a s u p e r i o r i n t e r m e d i a t e a n d was p r e p a r e d by t r e a t m e n t o f t h e b r o m o c y a n a m i d e ( 1 6 ) w i t h 1 % P d / C i n methanol-acetic acid. Sodium m e t h o x i d e t r e a t m e n t o f ( 1 8 ) a f f o r d e d t h e i m i d a z o l i n e which c o u l d t h e n be h y d r o l y s e d w i t h a q u e o u s b a s e ( S c h e m e 24).

I t was a l s o f o u n d t h a t h y d r o g e n a t i o n i n

t h e absence of acetic a c i d l e d t o t h e formation of t h e d e b r o m o f o r m a m i d i n e ( 2 0 ) which a f f o r d e d t h e r e l a t e d monoamines on t r e a t m e n t w i t h b a s e (Scheme 2 4 ) . Acid-catalysed

r i n g f r a g m e n t a t i o n s o f 2 - o x a z o l i n e s were f o u n d t o

y i e l d N-(2-aminoethyl)carboxamides

i n good t o e x c e l l e n t y i e l d s

p r o v i d i n g s e c o n d a r y o r h i n d e r e d p r i m a r y n u c l e o p h i l e s were employed.123

These amides were e a s i l y h y d r o l y s e d i n b a s i c or

a c i d i c m e d i a t o c o m p l e t e a s i m p l e s e l e c t i v e s y n t h e s i s of unsymmetrically substituted ethylenediamines.

cis-N,N,~',Nf-Tetramethyl-l,2-diaminocyclopentanewas

obtained

by r e d u c t i v e a m i n a t i o n o f 2-(dimethylamino)cyclopentanone

with

s o d i u m b o r o h y d r i d e . 12' P r o t e c t e d 1,3- and 1,4-diamines

r e s u l t e d from r e d u c t i o n s of

b i c y c l i c h y d r a z i n e s (Scheme 25). 125 B o t h a l i p h a t i c a n d o x y g e n a t e d c y c l i c d i a m i n e s were e l a b o r a t e d . 1,3-Diamines r e l e v a n t t o t h e s y n t h e s i s of c h l o r p r o m a z i n e a n a l o g u e s have been s y n t h e s i z e d i n a s o l i d - l i q u i d

(dimethy1amino)propylation o f s e c o n d a r y a m i n e s . 1 2 6

t w o - p h a s e N,NThe m e t h o d

u t i l i z e d sodium h y d r o x i d e / p o t a s s i u m c a r b o n a t e i n b e n z e n e w i t h 10 mol% o f t e t r a - n - b u t y l a m m o n i u m b i s u l p h a t e a s t h e c a t a l y s t . An a l t e r n a t i v 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 s u b s t i t u t e d putrescines

(cf. a b o v e )

u t i l i z e d degradation of 2-alkylpyrroles

w h i c h a f f o r d e d b i s - o x i m e s when t r e a t e d w i t h h y d r o x y l a m i n e h y d r o c h l o r i d e and sodium b i c a r b o n a t e i n e t h a n o l .

These were t h e n

r e d u c e d t o t h e d i a m i n e s by s o d i u m i n r e f l u x i n g e t h a n o l . a l k y l p y r r o l e s were u l t i m a t e l y d e r i v e d from p y r r o l e s

The 2Vilsmeier-

Haak a c y l a t i o n u s i n g I , I - d i m e t h y l a c y l a m i n e s (from s e c o n d a r y a m i n e s a n d a c y l h a l i d e s ) a n d s u b s e q u e n t r e d u c t i o n o f t h e r e s u l t a n t 2a c y l p y r r o l e s w i t h h y d r a z i n e and p o t a s s i u m h y d r o x i d e i n h o t e t h y l e n e g l y c o l . 27 A l k y n y l d i a m i n e s h a v e b e e n p r e p a r e d by a m i n o m e t h y l a t i o n o f 3128

arylaminobut-l-ynes.

General and Synthetic Methods

310

NHCO, E t

4

LNHC0,Et

c ) ) y

R2 &yC02E

COZE

NC0,Et

t

NC0,Et

- R'::

R2 z O H

-

R': O H , R ~ = H NHC02Et

N H CO, Et It

O = O

II

A HC0,Et

NHC0,Et

+R ' = R 2 =OH 2

1

R =OH,R = H e Reagents: i

, H2 ,P t 0 2 ;

i i , Na ,NH3

Scheme 25

0 II

O H II I

%Ph2P-C

Ph2P-CH,-Nn0

W

1

I

O -N

R-C-OLi

A

-

0

II

Ill

H

+Ph2P-C R'-

I

-NnO

I

C-OH ' 2

&Y

R e a g e n t s : i , Bu"Li ; i i ) R'R'CO;

iii, NH CL ; i v , K 0 6 u t 4

S c h e m e 26

R

-

311

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups 2 Enamines

A l t h o u g h m e t h o d s o f e n a m i n e s y n t h e s i s a r e l o n g e s t a b l i s h e d many of t h e more t r a d i t i o n a l p r e p a r a t i o n s a r e l i m i t e d i n t h a t t h e y are o n l y a p p l i c a b l e t o u n f u n c t i o n a l i z e d s y s t e m s , and also i n t h a t prolonged and o f t e n v i g o r o u s r e a c t i o n c o n d i t i o n s a r e r e q u i r e d .

Thus t h e

s e a r c h f o r new m e t h o d s f a c i l i t a t i n g p r e p a r a t i o n of f u n c t i o n a l i z e d enamines under mild c o n d i t i o n s continues. W i t t i g - t y p e methodology h a s proven v a l u a b l e i n a c h i e v i n g such

aims. M o r p h o l i n o - s u b s t i t u t e d H o r n e r - W i t t i g r e a g e n t s h a v e b e e n f o u n d t o r e a c t , i n good t o e x c e l l e n t y i e l d s , w i t h a r y l , a l i p h a t i c , and a , B - u n s a t u r a t e d a l d e h y d e s t o g i v e e n a m i n e s o f t h e c o r r e s p o n d i n g h o m o l o g a t e d a l d e h y d e s (Scheme 2 6 ) . 29 A n a l o g o u s l y , a- (N-

methylani1ino)methyldiphenylphosphine

o x i d e was f o u n d t o r e a c t w e l l

w i t h t h e s e s u b s t r a t e s and i n a d d i t i o n w i t h c y c l i c a n d a c y c l i c ketones.

Four d i f f e r i n g but complementary methods f o r p r e p a r i n g

t h e s e r e a g e n t s and t h e i r a - s u b s t i t u t e d

c o u n t e r p a r t s were

p r e s e n t e d ; 30 t h e s e w e r e b a s e d u p o n A r b u z o v r e a c t i o n s , M a n n i c h t y p e c o n d e n s a t i o n s o f d i p h e n y l p h o s p h i n e o x i d e w i t h formaldehyde and s e c o n d a r y a m i n e s , a d d i t i o n of d i p h e n y l p h o s p h i n e o x i d e t o e n a m i n e s , and f i n a l l y quenching of c a r b a n i o n s d e r i v e d from a - u n s u b s t i t u t e d

aminomethyldiphenylphosphine o x i d e s w i t h s u i t a b l e e l e c t r o p h i l e s . The a - s u b s t i t u t e d

reagents reacted w e l l with aromatic, aliphatic,

a n d a ,8 - u n s a t u r a t e d

a l d e h y d e s . 31 S i n c e t h e p r o d u c t h o m o l o g a t e d enamines can be converted i n t o t h e c o r r e s p o n d i n g c a r b o n y l d e r i v a t i v e s , t h e a p p l i c a t i o n of t h e a-unsubstituted

a n d a-

s u b s t i t u t e d d i p h e n y l p h o s p h i n e o x i d e s r e s p e c t i v e l y a s new f o r m y l a n d acyl-anion

equivalents is a l s o described.

I n r e c e n t y e a r s t i t a n i u m t e t r a c h l o r i d e h a s been used i n c r e a s i n g l y as a d e h y d r a t i n g a g e n t i n enamine s y n t h e s e s .

A

m o d i f i c a t i o n of t h e s t a n d a r d p r o c e d u r e , u s e of a p r e f o r m e d a m i n e T i C l 4 c o m p l e x , h a s b e e n r e p o r t e d as a g e n e r a l l y a p p l i c a b l e

( a l d e h y d e s , c y c l i c and a c y c l i c a l i p h a t i c k e t o n e s , and a r y l a l k y l k e t o n e s a l l b e i n g good s u b s t r a t e s ) m e t h o d , c l a i m e d t o b e t h e most Yields r a p i d m e t h o d of e n a m i n e s y n t h e s i s d e s c r i b e d t o d a t e . 1 3 2 were g e n e r a l l y v e r y g o o d , a l t h o u g h 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 r e q u i r e d l a r g e r a m o u n t s of t h e c o m p l e x a n d e x t e n d e d r e a c t i o n times (though s t i l l s h o r t e r than i n conventional procedures) f o r complete conversion.

The s c o p e of t h e m e t h o d was e x t e n d e d t o i n c l u d e

p r e p a r a t i o n o f e n a m i n e s from f u n c t i o n a l i z e d c a r b o n y l compounds. A r e l a t e d r e p o r t g i v e s d e t a i l s of i n v e s t i g a t i o n s of enamine

’’

General and Synthetic Methods

312

syntheses utilizing Lewis acids i n conjunction with various solid supports.134 The s u c c e s s of t h e r e a c t i o n was f o u n d t o b e h i g h l y d e p e n d e n t on r e a c t i o n t e m p e r a t u r e , t i m e , a n d t h e r a t i o s of t h e amine used t o t h e s o l v e n t , L e w i s a c i d , and s u p p o r t .

Best r e s u l t s

were o b t a i n e d f o r prolonged r e a c t i o n between bulky k e t o n e s and a l a r g e e x c e s s o f t h e a m i n e w i t h T i C 1 4 i n t h e p r e s e n c e of n e u t r a l o r a c i d i c alumina i n r e f l u x i n g hexane.

Y i e l d s were c o n s i s t e n t l y

higher i n t h e presence of t h e s u p p o r t , but evidence t o support t h e o c c u r r e n c e o f s i m u l t a n e o u s r e a c t i o n s on t h e s u p p o r t and i n s o l u t i o n

is presented. A h i g h l y e n a n t i o s e l e c t i v e i s o m e r i z a t i o n of p r o c h i r a l t e r t i a r y a l l y l a m i n e s c a t a l y s e d by c h i r a l d i p h o s p h i n e - r h o d i u m ( 1 ) h a s b e e n p u b l i s h e d . 135

complexes

Secondary a l l y l i c amines rearranged t o

imines under t h e r e a c t i o n c o n d i t i o n s .

A number of c a t a l y s t s ,

i n c l u d i n g a c h i r a l o n e s , were e x a m i n e d i n o r d e r t o d e t e r m i n e t h e e f f e c t o f t h e p h o s p h i n e l i g a n d s on t h e c o u r s e o f t h e r e a c t i o n . I t h a s a l s o been f o u n d t h a t s i m p l e e n a m i n e s c a n be g e n e r a t e d s i t u by o x i d a t i o n o f t r i a l k y l a m i n e s by i o d i n e . 1 3 6 i n t e r c e p t e d by c a t i o n s ;

in

T h e s e c o u l d be

t h e p r e s e n c e of a second e q u i v a l e n t ( o r

a n e x c e s s ) of I 2 t h e p r o d u c t s s o f o r m e d w e r e t r a n s f o r m e d i n t o iminium d y e s which c o u l d t h e n be h y d r o l y s e d back t o c a r b o n y l compounds.

A m e c h a n i s m was p r o p o s e d t o r a t i o n a l i z e t h e g e n e r a t i o n

of t h e e n a m i n e s (Scheme 2 7 ) . The s y n t h e s i s o f I - a c y l a t e d

and I - c a r b o x y l a t e d

enamine

d e r i v a t i v e s h a s c o n t i n u e d t o r e c e i v e much a t t e n t i o n . R e p r e s e n t a t i v e e x a m p l e s i n c l u d e t h e s y n t h e s i s o f a-amino-a,Bu n s a t u r a t e d k e t o n e s from c h l o r o m e t h y l k e t o n e s d e r i v e d from p r o t e c t e d a m i n o - a c i d ~ l a~n ~ d t h e p r e p a r a t i o n o f 2-acylamino-2a l k e n o i c a c i d s f r o m m i x e d a n h y d r i d e s o f e i t h e r g - a c e t y l - o r Eb e n z o y l - g l y c i n e . l 38 The l a t t e r p r e p a r a t i o n i n v o l v e d c y c l i z a t i o n of t h e m i x e d a n h y d r i d e s t o 5-oxo-4,5-dihydro-l,3-oxazoles f o l l o w e d by condensation of t h e heterocycles with ketones or ketimines. H y d r o l y s i s o f t h e u n s a t u r a t e d a z l a c t o n e s t h u s formed a f f o r d e d t h e d e s i r e d compounds. A n o v e l d e s i l y l a t i o n - r i n g f r a g m e n t a t i o n o f 1(trimethylsilylmethy1)aziridines c o n t a i n i n g a t l e a s t o n e a n i o n s t a b i l i z i n g c e n t r e , l e a d i n g t o t h e f o r m a t i o n of a-acylaminoe n a m i n e s , u s i n g CsF i n H20-HMPA h a s b e e n r e p o r t e d . 13’ The r e a c t i o n was f a c i l i t a t e d by c o n v e r s i o n o f a n o n - s t a b i l i z e d i n t o a s t a b i l i z e d a n i o n a n d t h e c o u r s e of t h e r e a c t i o n was d e p e n d e n t b o t h o n t h e number o f a n i o n - s t a b i l i z i n g g r o u p s a n d on t h e n a t u r e of t h e

3 13

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups quenching reagents. I n c o n t r a s t t o t h e n o r m a l mode o f a d d i t i o n o f n u c l e o p h i l e s ,

k.

a t t a c k a t t h e carbonyl centre with displacement of cyanide anion, t o b e n z o y l cyanide,bis(pentanedionato)nickel

was f o u n d t o d i r e c t

a t t a c k o f t h e C-2 c e n t r e o f 8 - d i c a r b o n y l c o m p o u n d s t o t h e c y a n o moiety.

S i m i l a r l y , t h e c o r r e s p o n d i n g z i n c (11) c o m p l e x

[Zn(acac),]

c a t a l y s e d a d d i t i o n o f C-2 i n v a r i o u s 8 - d i c a r b o n y l 141 systems t o cyanogen. D e s u l p h u r i z a t i o n o f 5 - a l k y l - q u a t e r n a r y c y a n i d e s h a s a f f o r d e d new s y n t h e s e s of l-cyanoenamines

i n moderate yields. 142

The method

i n v o l v e s s i m p l e t r e a t m e n t w i t h a n e x c e s s of m e t h y l i o d i d e f o l l o w e d (Scheme 2 8 ) .

by b a s i c work-up

Rhenium h e p t a s u l p h i d e h a s b e e n f o u n d t o c a t a l y s e c o n v e r s i o n s o f a-azidocarboxylic a c i d esters t o N-acetyl- and N,g-diacetyl-a,@-

e s t e r s via N 2 e l i m i n a t i o n . didehydro-a-amino-acid Good y i e l d s were a c h i e v e d t h r o u g h o u t a n d a d d i t i o n o f water b e f o r e w o r k - u p allowed e x c l u s i v e i s o l a t i o n of t h e monoacylated p r o d u c t s . R e d u c t i v e s i l y l a t i o n of a - s i l o x y - n i t r i l 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 a n d l i t h i u m i n THF a t 0 O C h a s b e e n e x a m i n e d a s a p o t e n t i a l r o u t e t o 1 N N-tris(trimethylsily1)enamines ( e n a m i n e s o f a c y l s i l a n e s )'-'" . Although t h e t r a n s f o r m a t i o n could be a c h i e v e d , y i e l d s w e r e p o o r owing t o a c o m p e t i n g r e a c t i o n l e a d i n g t o a-siloxysilane formation. D e p r o t o n a t i o n o f l - p h o s p h o r y l e n a m i n e s f o l l o w e d by s i l y l a t i o n o r a l k y l a t i o n h a s been found t o y i e l d homologous ( g ) - l phosphorylenamines capable of f u r t h e r h y d r o l y s i s t o C-3-alkylated carboxylic acids. always occurred

D e p r o t o n a t i o n s of compounds o f t h e t y p e ( 2 1 )

cis t o

t h e phosphoryl moiety with t h e r e s u l t a n t

a n i o n i s o m e r i z i n g r a p i d l y a b o u t t h e C-1-C-2

bond.

These h i g h l y

r e g i o - and s t e r e o - s e l e c t i v e d e p r o t o n a t i o n s a l l o w e d i n t r o d u c t i o n o f up t o t h r e e d i f f e r e n t a l k y l groups i n t o t h e molecule. M e t a l l a t e d y n a m i n e s were shown t o r e a c t n o r m a l l y w i t h m e t h y l e n e m a l o n o n i t r i l e and similar s y s t e m s t o g i v e 2-metallo-3aminobuta-1,3-diene (Scheme 29 )

.

2-Acylated

derivatives (metallated l-vinylenamines)

46 enamines t o o have been important s y n t h e t i c

i n t e r m e d i a t e s and a o n e - s t e p a l t e r n a t i v e t o a p r e v i o u s l y d e s c r i b e d improved two-step reported.

Blaise r e a c t i o n

( s e e Volume 8 , p . 2 6 6 ) h a s b e e n

The m e t h o d i n v o l v e s t r e a t m e n t o f e p o x i d e s d e r i v e d

f r o m (E)-ethylhex-3-enedioate c h l o r i d e i n aqueous e t h a n o l .

w i t h s o d i u m a z i d e a n d ammonium The r e s u l t a n t c y c l i c ( & ) - e n a m i n o -

General and Synthetic Methods

314

Et,N

+

+ I,

Et,NI

=

+

NEt3

NEt3

MeCH=NEt2 =CHFCHNEt2

1-

1-

Scheme 27

'

CN PhCH2-

CN

=*

C -N -0

PhCH=LNAo

U

1 -

SMe Scheme 2 8

M R3,

I

Ill I N R1/

R4

+

R5

Ill I

Ac c"Acc'

N

Rl/ \ R 2

\ 2

R

MeCN( 0

OC

3. _9

Acc'

N ' R'

Scheme

29

'

Acc' Acc'

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

315

e s t e r c a n b e i s o l a t e d p u r e i n 67% y i e l 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 f r o m t h e ( Z ) - i s o m e r and t h e n s u b s e q u e n t l y a l k y l a t e d on n i t r o g e n .

4-Dialkylaminobut-3-en-2-ones a r e r e c o g n i z e d a s i m p o r t a n t i n t e r m e d i a t e s i n h e t e r o c y c l i c s y n t h e s e s , and a f a c i l e , highy i e l d i n g p r e p a r a t i o n of t h e s e d e r i v a t i v e s by t r e a t m e n t o f 4,4dimethoxybutan-2-one p u b l i s h e d . 14'

with secondary amines i n methanol h a s been

A s an a l t e r n a t i v e , a d d i t i o n s of secondary (and

p r i m a r y ) a m i n e s t o B-alkoxy- a, B - e t h y l e n e - k e t o n e s A more i n t e r e s t i n g v a r i a n t ,

were d e s c r i b e d . 14'

h o w e v e r , i s t h e c o n v e r s i o n o f B-amino-

k e t o n e s t o t h e d e s i r e d enaminones u s i n g b i s ( a c e t o n i t r i 1 e ) d i c h l o r o p a l l a d i u m ( I 1 ) and t r i e t h y l a m i n e (Scheme 3 0 ) . I 5 O

This

p r o c e d u r e i s a t t r a c t i v e s i n c e t h e s t a r t i n g materials a r e e a s i l y a v a i l a b l e f r o m b o t h c a r b o n y l c o m p o u n d s by M a n n i c h r e a c t i o n s a n d t h e i r a,B-unsaturated

c o u n t e r p a r t s by M i c h a e l a d d i t i o n s .

However,

one d i s a d v a n t a g e i s t h a t t h e u s e of a s t o i c h e i o m e t r i c amount o f t h e complex i s r e q u i r e d . It h a s been d i s c o v e r e d t h a t n i t r i l i u m i o n s r e a c t w i t h enamines t o a f f o r d m i x t u r e s o f enamino-ketones and enaminimines i n good S i n c e t h e l a t t e r compounds a r e h y d r o l y s e d t o t h e f o r m e r

yield.15'

i n d i l u t e a c i d t h e p r o c e d u r e may w e l l f i n . d f u r t h e r a p p l i c a t i o n s . y-Amino-enamines

were a l i t t l e known c l a s s o f f u n c t i o n a l i z e d

e n a m i n e s u n t i l a r e c e n t d e s c r i p t i o n o f a f a c i l e s y n t h e s i s of t h e s e c o m p o u n d s by a d d i t i o n o f a t w o - f o l d e x c e s s o f trimethylsilyldialkylamines t o a - u n s u b s t i t u t e d t e m p e r a t u r e . 152 slowly.

In contrast a-substituted

a l d e h y d e s a t room

aldehydes reacted very

However, e l e v a t i o n o f r e a c t i o n t e m p e r a t u r e and a d d i t i o n of

c a t a l y t i c amounts of toluene-p-sulphonic y i e l d s i n r e a s o n a b l e r e a c t i o n times.

a c i d l e d t o improved

A f u r t h e r s t u d y showed t h a t

u s e o f o n l y o n e e q u i v a l e n t o f t h e s i l y l a t e d a m i n e s a f f o r d e d Ba m i n o t r i m e t h y l s i l y l e n o l e t h e r s , s i l y l e t h e r s o f B-aminok e t o n e s . 153

Aminomethylations of e n a m i n o - e s t e r s have a l s o been r e c o r d e d , t h e s e o c c u r r i n g a t t h e 2 - p o s i t i o n of primary and

s e c o n d a r y a m i n e - d e r i v e d 3 - a m i n o b u t - 2 - e n o a t e s . 15' 3-N,Ndialkylaminobut-2-enoates d i d n o t r e a c t a n a l o g o u s l y w i t h a l d e h y d e s a n d a m i n e s b u t were a m i n o m e t h y l a t e d a t C-4 w i t h N,Ndimethylmethyleneiminium c h l o r i d e i n a n h y d r o u s a c e t o n i t r i l e . In a r e l a t e d s t u d y , a l l t h r e e t y p e s o f 3-aminobut-2-enenitriles were f o u n d t o u n d e r g o a m i n o m e t h y l a t i o n a t C-2 u n d e r t h e s t a n d a r d c o n d i t i o n s . 155 (Dimethy1amino)allene h a s been s u c c e s s f u l l y r e a c t e d w i t h

316

General and Synthetic Methods

CI

R1

i-

[PdHCIL2]

'

L

L '

N

R

2

,

S c h e m e 30

CI

-

PO(OEt l2

ii

*

c

o

w

I iii

+ R'

I V

,v

PO(OEt),

R2N

R = M e or CH,Ph

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

317

aliphatic secondary amines, and the initial adducts rearranged with water or ammonium chloride or acidic alumina to give 3aminoenamines. 56 3-Alkoxy- and 3-Alkylthio-enamines were similarly obtained. 2-Alkylthio- and 2-alkoxy-enamines were synthesized from propargyl thioethers and ethers respectively following aminomercuration-demercuration sequences. 57 A previously reported preparation of enamino-sulphones had been restricted to the synthesis of N-unsubstituted examples. However, it was subsequently demonstrated that transaminations were possible, 158 and the conditions also applied to the synthesis of Ealkyl- and N-aryl-enamino-nitriles from 3-amino-2-ethylenenitrile derivatives. 2-Alkyl-3-aminoprop-2-enenitriles were prepared by a two-stage hydrogenolysis of 1,l-dicyanocyclopropanes which underwent the expected C-I-C-3 bond fission. 159 2-Alkylbenzothiazoles have been shown to undergo Claisen-type self-condensations to yield 2-(2-benzothiazolyl)enamines, on treatment with Grignard reagents. 160 0-(Enamino)-a,B-ethylene aldehydes have been obtained from gasphase pyrolyses of 5-(aminomethylene)-l,3-dioxane-4,6-diones. 161 Recent advances in the chemistry of conjugated enamines have been reviewed, 162 and two notable methods for their synthesis have appeared. The first reported details of 5-E,g-dialkylaminopental,+diene preparations in Wittig-like reactions utilizing l-amino4-phosphonobut-2-enes (as potassium rather than lithium salts) and aldehydes. 163 The organophosphorus reagents were prepared from 1,3-dienes by a three-step sequence involving palladium(I1) acetate-catalysed chloroacetoxylation, Arbuzov reaction, and tetrakis(tripheny1phosphine)palladium-catalysed allylic amination of the resultant l-acetoxy-~-phosphonobut-2-ene (Scheme 31). The second method was concerned with the synthesis of conjugated enamino-ketones 2 reaction of aralkyl ketone enolates with 1,5diazapentadienium (vinamidinium) salts, and in particular (22) (Scheme 32). 16' Ene-1,2-diamines have been produced on reaction of 1,2-di-imines with alkyl-lithiums, Grignard reagents, and trialkylaluminiums. 165 The use of higher reaction temperatures and non-polar solvents was found to favour formation of 2-alkylated products.

318

General and Synthetic Methods

I

I

Me

Me

i or

ii

n = 1 , 2 or 3 Reagents: i , NaH, N E t 3 ; ii, L D A , NEt3

Scheme 32

H\ R1/

c=c

/

R2 /Me CH2- N \ CHO

0 Reagents

I , E t 2 0 , -50 t o - 2 5

OC

;

[ I ,

HCONMe( CHIC\)

Scheme 33

;III,

N-chloromethylphthalimlde

3 19

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups 3 A l l y l a m i n e s , Homoallylamines, and Alkynylamines Organocopper r e a g e n t s have proven h i g h l y v a l u a b l e i n t h e p r e p a r a t i o n of a l l y l i c amines, p a r t i c u l a r l y t e r t i a r y a l l y l a m i n e s . C a r b o c u p r a t i o n of a l k y n e s t o a f f o r d a l k e n y l - c u p r a t e

and -copper

r e a g e n t s is a f r e q u e n t l y u t i l i z e d s y n t h e t i c o p e r a t i o n ; however, r e a c t i o n s of t h e s e n u c l e o p h i l i c s p e c i e s w i t h 1 - c h l o r o m e t h y l - 1 methylformamide and E - c h l o r o p h t h a l i m i d e

were u n r e c o r d e d .

These

r e a c t i o n s have r e c e n t l y been d e s c r i b e d , r e s u l t i n g i n good y i e l d s o f p r o t e c t e d primary and secondary a l l y l a m i n e s .

S i n c e t h e free amines

may b e l i b e r a t e d e a s i l y by s t a n d a r d d e p r o t e c t i o n t e c h n i q u e s a u s e f u l s y n t h e t i c p r o c e d u r e h a s e m e r g e d ( S c h e m e 3 3 ) . 1 6 6 The same a u t h o r s d i s c o v e r e d t h a t ( L ) - a l k e n y l c u p r a t e s and (El-alkenylaluminium r e a g e n t s added t o b o t h a m i n o - e t h e r s and a m i n o t h i o - e t h e r s t o yield

(L)-

or ( E l - t e r t i a r y a l l y l a m i n e s r e s p e c t i v e l y ;

these

p r e p a r a t i o n s gave good y i e l d s of amines w i t h 99.5-99.9% stereoisomeric purity. Organoselenium chemistry h a s f e a t u r e d prominently i n strategies f o r r e g i o - and s t e r e o - c o n t r o l l e d

f o r m a t i o n o f C-N

bonds, and h a s

t h u s found a p p l i c a t i o n s i n t h e f i e l d of a l l y l a m i n e s y n t h e s i s .

The

discovery t h a t anhydrous chloramine-T i n methanol e f f i c i e n t l y c o n v e r t s a l l y l i c phenyl s e l e n i d e s i n t o 1-allyl-toluene-

p - s u l p h o n a m i d e s h a s l e d t o t h e p r e p a r a t i o n o f a number o f allylamines.

The r e a c t i o n was a s s u m e d t o o c c u r

via

[2,3]-

sigmatropic rearrangement of an a l l y l i c selenimide i n t e r m e d i a t e , t h i s being c o n s i s t e n t w i t h t h e observed predominance of (L)-trisubstituted

(El-

over

a l l y l a m i n e s i n t h e cases s t u d i e d (Scheme 3 4 ) .

Use o f t h e a n h y d r o u s r e a g e n t i s e s s e n t i a l f o r t h e s u c c e s s o f t h e ' p r o c e s s and t h u s t h e h a z a r d s a s s o c i a t e d w i t h h a n d l i n g t h e r e a g e n t a n d a l s o t h e l i m i t e d number o f m i l d s u l p h o n a m i d e d e p r o t e c t i o n Subsequent s t u d i e s methods a v a i l a b l e l e f t s c o p e f o r improvement. d e m o n s t r a t e d t h a t t - b u t y l - a n d benzyl-N-chloro-1-sodiocarbamates c o u l d b e u s e d t o p r e p a r e t h e m o r e v e r s a t i l e t-Bocp r o t e c t e d a l l y l a m i n e s . 16'

a n d Cbz-

However, t h i s m o d i f i c a t i o n s u f f e r s i n

t h a t t h e r e a g e n t s are p o t e n t i a l l y u n s t a b l e .

Thus a f u r t h e r

r e f i n e m e n t was m a d e , a n d t h e p a r e n t c a r b a m a t e s , H u n i g ' s b a s e p l u s

N-chlorosuccinimide,

were a d d e d t o a m e t h a n o l i c s o l u t i o n o f t h e

appropriate selenide i n order to achieve the desired transformation (Scheme 3 4 ) . I 7 O The a b i l i t y of p a l l a d i u m c o m p l e x e s t o f u n c t i o n a l i z e a l l y l i c s u b s t r a t e s , i n c l u d i n g a l l y 1 nitro-compounds, is well recognized.

General and Synthetic Methods

320

+

[PhSeZ]

R

P = B o c or Cbz Reagents : i, anhydrous chloramine T (TsNClNa) ; ii, ButOCONCI-Na’;

iii, Bu~OCONHZ(2.5 equiv. )

P r ‘ NEt2, NCS

Scheme 3 4

ON 2 -

R

1

R

^-1 b

type c

RZN

‘

R= R’=R‘+H

Scheme 3 5

H

32 1

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups However, a l l y l i c n i t r o - d e r i v a t i v e s a r e s y n t h e t i c a l l y r a t h e r elusive. T h i s a p p a r e n t i n c o m p a t i b i l i t y , however, h a s been circumvented with t h e observation t h a t a d d i t i o n o f amines t o t h e

more r e a d i l y a v a i l a b l e n i t r o a l k e n e s i n t h e p r e s e n c e o f z e r o - v a l e n t palladium l e a d s t o t h e i s o l a t i o n of ( E ) - a l l y l i c amines r a t h e r t h a n t h e expected Michael adducts.

The f a c t s t h a t r e a c t i o n r a t e s showed

marked s o l v e n t d e p e n d e n c y and t h a t c e r t a i n a l l y l a m i n e s c o u l d b e d e r i v e d from more t h a n o n e r e g i o i s o m e r i c n i t r o a l k e n e s u g g e s t e d t h a t t h e n i t r o a l k e n e s were i s o m e r i z e d t o t h e a l l y l i s o m e r s by t h e a m i n e s b e f o r e a d d i t i o n , t h i s b e i n g f a v o u r e d by p o l a r s o l v e n t s . f o r m a t i o n o f common n - a l l y l - p a l l a d i u m

Thus t h e

intermediates before

n u c l e o p h i l i c a t t a c k by t h e a m i n e was u s e d t o e x p l a i n t h e o b s e r v e d r e g i o - and s t e r e o - s e l e c t i v e s u b s t i t u t i o n s . r e a c t i v i t y were i d e n t i f i e d ( S c h e m e 3 5 ) . 1 7 1 The s y n t h e s i s o f 2 - p h e n y l by p a l l a d i u m - p h o s p h i n e

T h r e e d i s t i n c t modes o f

or 2-alkenyl-substituted

complex-catalysed

allylamines

f u n c t i o n a l i z a t i o n of 1 , 2 -

d i e n e s h a s a l s o b e e n r e p o r t e d (Scheme 3 6 ) . 1 7 2 A z i r i d i n e f r a g m e n t a t i o n s a f f o r d i n g enamines have been d i s c u s s e d a b o v e . 39

D e t a i l s o f N-ethoxycarbonylaziridine t h e r m o l y s e s

y i e l d i n g a l l y l carbamates have a l s o appeared, 173 w i t h primary a l l y l a m i n e s o b t a i n e d f r o m t h e l a t t e r compounds f o l l o w i n g s t a n d a r d deprotections. One e x a m p l e of a n e n z y m i c c o n v e r s i o n o f a n a l l y l i c a m i n o - a c i d i n t o a n a l l y l a m i n e h a s a p p e a r e d . 17'

The t r a n s f o r m a t i o n of ( 2 4 )

i n t o ( 2 5 ) was e f f e c t e d by a r o m a t i c L - a m i n o - a c i d ( 2 4 ) p r e p a r e d from ( 2 3 )

via

decarboxylase with

a s t r a i g h t f o r w a r d d i s p l a c e m e n t (Scheme

37). The a d d i t i o n o f o r g a n o m e t a l l i c n u c l e o p h i l e s t o i m i n e s h a s b e e n a l l u d e d t o i n S e c t i o n 1, S e c o n d a r y Amines. i s o l a t e d a f t e r a d d i t i o n s of allyl-9-BBN

H o m o a l l y l a m i n e s c a n be

t o imines.

Very h i g h 1 , 2 -

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 some c a s e s a n d a s t e r e o e l e c t r o n i c e f f e c t was i n v o k e d t o e x p l a i n t h e e n h a n c e m e n t o f C r a m s e l e c t i v i t y ( S c h e m e 3 8 ) .82 , 8 3 A l l e n i c o r g a n o s i l a n e r e a g e n t s were f o u n d t o add t o i m i n e s w i t h t h r e o - s e l e c t i v i t y (Scheme 3 8 ) . 8 2 The p r o d u c t s i l y l a t e d h o m o a l k y n y l a m i n e s were e l a b o r a t e d i n t o h o m o a l l y l a m i n e s by d e s i l y l a t i o n a n d r e d u c t i o n .

N-Diallylalkyl-2-aminophenols

were o b t a i n e d u p o n t r e a t m e n t o f

b e n z o x a z o l e s w i t h a l l y l i c G r i g n a r d r e a g e n t s . 175 A s i m i l a r r e a c t i o n of benzothiazoles t o y i e l d disulphide-bridged bis(dihomoally1amine) d e r i v a t i v e s was a l s o r e p o r t e d . S y n t h e s i s o f a l l e n i c a m i n e s h a s become a n i m p o r t a n t a r e a o w i n g

General and Synthetic Methods

322

R2 R2X

A

[R'PdX]

___) ii

R32NCH2C( R )=CH R'

[A$]

+

j

2i R 32X

H

Pd(OACl2- L n

R32NCH2CR=CHR1 2 R3$ H 2 i R2PdX L n

p-

CH~=C=CHR'

3

2 R,NH

s.

2

*PldXLn

Reagents : i , P d ( O A ~ ) ~ ( 0 . 0 2equiv.),dppe(O.O5equiv.) 5 ; ii ,CH=C=CHd; 2

iii,R3 NH(2 equiv.) 2

S c h e m e 36

Reagents : i

L D A ; ii, NH3 DMSO; i i i , aq. H e r , propylene o x i d e ; i v , h o g

kidney AADC

0.1M- p h o s p h a t e b u f f e r , p y r i d o x a l p h o s p h a t e , HOCH2CH2SH, pH 7.2 I 37 O C

S c h e m e 37

323

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

erythro

threo

i i.J.iv

I

v

- ++

NHR PhX C O H

+mM

II 0

M= L i , Mg , 8 ,

Ph

P

h bH

OH

-2:l

Si ....

PhA c / H

+

m

B

a

L

P

k

i

i -I-h P

NH

AH

R'

R'

R'

up to

1oo:o

Reagents : i , ButLi (1.1 equiv.); ii,CITi(OPri)g or B(OMe)30r A I E t 3 ; iii, NaOMe,MeOH;iv,H2,

PdlBaSOq;v, PhCH20COCI,Na2C03; v i , T H F , -78OC,N2

c""'-yz

Scheme 3 8 +]sR14N,R2

RCECH RCEC-BF3Li

H

Ill

I

R R e a g e n t s : i , 6unLi (1 e q u i v . ) , THF, - 7 8 i i i , R'CHZCH=NR2, - 7 8

OC,

OC,

3 0 min

, Ar

; ii, BF3.0Et2, Et20,10 min,

l h t h e n r . t . , l h ; 1 0 ° / ~a q . NaOH

S c h e m e 39

i

324

General and Synthetic Methods

t o t h e p o t e n t i a l o f t h e s e compounds t o i n h i b i t p y r i d o x a l p h o s p h a t e d e p e n d e n t enzymes i r r e v e r s i b l y . attention.

T h u s t h e s u b j e c t h a s r e c e i v e d much

It h a s been found t h a t a l l e n y l a m i n e s c a n be s y n t h e s i z e d

f r o m a - e t h y n y l a m i n e s . 177 T h e l a t t e r c o m p o u n d s were t r e a t e d w i t h di-isopropylamine-formaldehyde p l u s c u p r o u s b r o m i d e i n d i o x a n e t o y i e l d t h e d e s i r e d compounds. N-t-Butoxycarbonyl esters of t h e corresponding a-allenyl-a-amino-acids

c o u l d a l s o be p r e p a r e d i n

t h i s w a y , b u t t h e a l l e n y l m o i e t y was f o u n d t o b e i n c o m p a t i b l e w i t h the deprotection conditions required.

An a l t e r n a t i v e p r o c e d u r e

esters o f a m i n o - a c i d s a f f o r d e d b e n z a m i d e s w h i c h were m o r e e a s i l y deprotected t o g i v e t h e desired a-allenyl amino-acids. Racemic b a s e d on t h e C l a i s e n r e a r r a n g e m e n t of N - b e n z o y l p r o p a r g y l i c

a l l e n y l d e r i v a t i v e s o f GABA, p u t r e s c i n e , and p h e n y l a l a n i n e t h u s f o r m e d were f o u n d t o b e i r r e v e r s i b l e t i m e - d e p e n d e n t

inhibitors of

m a m m a l i a n 4-aminobutyrate-2-oxoglutarate a m i n o t r a n s f e r a s e (GABA-TI, b a c t e r i a l o r n i t h i n e d e c a r b o x y l a s e , and b a c t e r i a l L-aromatic-aamino-acid

decarboxylase respectively.

Two s y n t h e s e s of a - a l l e n i c - G A B A , r e a r r a n g e m e n t , 17'

the other

via

one i n v o l v i n g a n o v e l aza-Cope

h y d r o l y s i s of 5 - a l l e n y l - 2 -

p y r r o l i d i n o n e p r e p a r e d by r e a c t i o n o f propargyltrimethylsilane w i t h

a y-ethoxylactam

i n t h e p r e s e n c e of a L e w i s a c i d (BF3.0Et,),

179

have a l s o appeared. A l k y n y l a m i n e s h a v e r e s u l t e d n o t o n l y f r o m t h e r e a c t i o n of a l l e n y l s i l a n e s with imines above, but a l s o from t h e a d d i t i o n of alkynyl-boranes

( a n d -berates) t o a l d i m i n e s c o n t a i n i n g a - h y d r o g e n s

( S c h e m e 39 1. 85

A s i m p l e p r o c e d u r e f o r t h e p r e p a r a t i o n o f l i t h i u m IJ,gbis(trimethylsilylaminornethy1)acetylide a n d t h e r e a c t i o n s o f t h i s compound w i t h v a r i o u s e l e c t r o p h i l e s h a v e b e e n described. I 8 O S i m i l a r l y , n o v e l s u b s t i t u t i o n s of s t a n n y l a t e d ynamines have been reported.

T h e r e a c t i o n s o f e i t h e r (3,4,4-trichlorobut-3-en-I-

y n y 1 ) a m i n e s o r (pentachlorobuta-l,3-dienyl)amines w i t h t w o or t h r e e e q u i v a l e n t s of n-butyl-lithium

t o a f f o r d l i t h i u m 4-aminobuta-1,3-

d i y n i d e s and t h e i r s u b s e q u e n t a d d i t i o n s t o e l e c t r o p h i l e s have been r e p o r t e d as a s y n t h e s i s of alka-I , 3 - d i y n y l ) a m i n e s . 4 Amino-alcohols The i m p o r t a n c e o f a m i n o d e o x y - s u g a r s

and h y d r o x y l a t e d amino-acids i n

n a t u r a l p r o d u c t c h e m i s t r y h a s e n s u r e d t h a t t h e s y n t h e s i s of c o m p o u n d s w i t h a m i n o - a l c o h o l f u n c t i o n a l i t y h a s r e m a i n e d a n a r e a of

325

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups competitive research.

S y n t h e t i c s t r a t e g i e s l e a d i n g t o amino-

a l c o h o l formation can be broadly c l a s s i f i e d i n t o t h o s e i n v o l v i n g SN2-like displacements

e.g. r e a c t i o n s

o f amino- o r a z i d e -

nucleophiles with sulphonates, halides, or epoxides, those i n v o l v i n g r e d u c t i v e m e t h o d s , and t h o s e i n v o l v i n g f r a g m e n t a t i o n o f N,O-heterocycles

w h i c h may b e f o r m e d a f t e r c y c l o a d d i t i o n s o r by

f u n c t i o n a l i z a t i o n o f b o t h a c y c l i c and c y c l i c a l l y 1 a l c o h o l s o r allylamines.

Trifluoromethanesulphonates h a v e p r o v e n p a r t i c u l a r l y u s e f u l i n t h e s y n t h e s i s of a m i n o d e o x y - s u g a r s s i n c e t h e y u n d e r g o s m o o t h S N 2 d i s p l a c e m e n t w i t h ammonia183 a n d a z i d e a n i o n . 1 8 4 R e d u c t i o n s o f a z i d e s f o r m e d i n t h i s way h a v e b e e n u t i l i z e d i n s y n t h e s e s of

u-

m a n n o s i d a s e i n h i b i t o r s t y p i f i e d by 1,4-dideoxy-I,4-imino-D-mannitol ( 2 6 ) 185 a n d 1,5-dideoxy-l,5-imino-D-mannitol ( 2 7 ) . 186 S y n t h e s e s o f D-ossamine

(28) and D-tolyposamine

( 2 9 ) were l i k e w i s e f a c i l i t a t e d

by r e d u c t i o n s of a z i d e s w h i c h were i n t r o d u c e d by d i s p l a c e m e n t s o f a n a l l y l i c s u l p h o n a t e and an a l l y l i c i o d i d e r e s p e c t i v e l y . 187 S i m i l a r l y , a d i s p l a c e m e n t of a s e c o n d a r y m e s y l a t e by a n a z i d e , a n d i t s s u b s e q u e n t r e d u c t i o n , formed key s t e p s i n a s y n t h e s i s of 188 swainsonine (30). A s t r a t e g y d i r e c t e d t o w a r d s t h e t o t a l s y n t h e s i s of (+Ic a s t a n o s p e r m i n e ( 3 1 ) a n d ( + ) - d e o x y n o j o r i m y c i n ( 3 2 ) was b a s e d on t h e 89 The a m i n o f u n c t i o n was

c y c l i z a t i o n of an amino-epoxide. introduced

via

t h e formation of a glycosylamine from a r e d u c i n g

s u g a r a n d b e n z y l a m i n e f o l l o w e d by r e d u c t i o n ( S c h e m e 40). Allylamino-,

anilino-,

a n d morpholino-glycosylamines h a v e b e e n

p r e p a r e d from g l y c o s y l f l u o r i d e s and t h e a p p r o p r i a t e amines under t h e i n f l u e n c e of a Lewis a c i d . ” ’

The a m i n e c o u l d a l s o b e r e p l a c e d

by a z i d e t o g i v e a p r e p a r a t i o n o f t h e c o r r e s p o n d i n g g l y c o s y l azides. R e d u c t i o n s of a m i n o c a r b o n y l c o m p o u n d s a n d t h e i r d e r i v a t i v e s h a v e c o n t i n u e d t o be o f i m p o r t a n c e i n a m i n o - a l c o h o l

syntheses.

E n a n t i o m e r s o f e t i l e f r i n e were p r o d u c e d by e n a n t i o s e l e c t i v e h y d r o g e n a t i o n s of an a-amino-ketone. u-Amino-ketones were a l s o demonstrated t o undergo d i a s t e r e o c o n t r o l l e d

reductions with

hydrosilanes, with excellent selectivities for erythro-like products observed.lg2

I t was f o u n d t h a t r e d u c t i o n o f s y n - 0 -

hydroxy-ketone-g-benzyloximes 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 p r o c e e d e d w i t h h i g h s e l e c t i v i t y for ~ - 1 , 3 - a m i n o - a l c o h o l s w h i l s t o n l y m o d e r a t e s t e r e o s e l e c t i o n was o b s e r v e d i n r e d u c t i o n s o f t h e anti-oxime isomers.

C o n d i t i o n s were modified i n o r d e r t o

General and Synthetic Methods

326

R =COCF3 or H

&/

R

CH,OH

&*oY OR

R=BnZlx R=H

+Hoe

Of3n

?H

R = CH(OH)CH,CO R = CO,H

H0 ' .

R: CHO

xiii

xi

R = CH(OH)CH~CO~B"~

"1

OH

OH

xvc H H0 '

O

~

H0 ' .

0

Reagents :

I,

BnNH2(10 e q u i v 1 ;

11,

LIALH~ ;

III

(CF3CO),O;

IV,

v , M s C I , p y , v i , Bun4NF; v 1 1 , N a O M e ; v i i i , N a B H 4 , H2

I

Pd I C ; X I , D M S O , o x a l y l c h l o r i d e , N E t 3 ; X I I ,

ix,chromatography,x, C H T C ( O L I ) O B U ~; XIII,

c h r o m a t o g r a p h y a n d h y d r o g e n o l y s i s (XI; xiv,TFA

Scheme 40

TBDMSCI, r m i d a z o l e ,

HZO,60 OCJ3h;xv,Dlbal-H

H

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

327

circumvent t h e need t o s e p a r a t e t h e oximes b e f o r e t h e i r r e d u c t i o n , a n d i t was f o u n d t h a t i n t h e p r e s e n c e o f s o d i u m m e t h o x i d e a n t i o x i r n e s were r e d u c e d t o syn-1 , 3 - a m i n o - a l c o h o l s a t -78 O C ( a s o p p o s e d t o 0 OC i n r e a c t i o n s 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 o n e ) w i t h 95.5% s e l e c t i v i t y , 2 a n a s s u m e d s i x - m e m b e r e d t r a n s i t i o n s t a t e i n w h i c h t h e s o d i u m c a t i o n was c h e l a t e d . l g 4 S i n c e t h e s y n - o x i m e s c o u l d n o t c h e l a t e Na+ n o r a t e e n h a n c e m e n t was o b s e r v e d a n d r e d u c t i o n s o c c u r r e d ( w i t h 95.5% s e l e c t i v i t y ) a t 0 OC e i t h e r i n t h e p r e s e n c e o r a b s e n c e o f sodium m e t h o x i d e (Scheme 4 1 ) . S t e r e o s e l e c t i v e c a t a l y t i c h y d r o g e n a t i o n s of a - h y d r o x y - k e t o x i m e s w i t h Pd/C w e r e o b s e r v e d t o g i v e e r y t h r o - l i k e a m i n o - a l c o h o l s i n a p p r o x i m a t e l y 80% d i a s t e r e o m e r i c e x c e s s i r r e s p e c t i v e of w h e t h e r t h e E- o r 2 - o x i m e was r e d u c e d . l g 5 The s y n / a n t i i s o m e r i z a t i o n o f t h e o x i m e s i n t h e p r e s e n c e o f t h e c a t a l y s t was t h e r e f o r e s t u d i e d i n connection with t h e observed s t e r e o s e l e c t i v i t i e s .

N-Protected amino-acid esters have i n t h e p a s t been reduced t o t h e c o r r e s p o n d i n g a m i n o - a l c o h o l s by s o d i u m b o r o h y d r i d e . An improved p r o c e d u r e f o r t h i s t r a n s f o r m a t i o n h a s been p u b l i s h e d which i n v o l v e s s l o w a d d i t i o n o f m e t h a n o l t o t h e r e a c t i o n m i x t u r e . 196 T h i s enabled t h e r e d u c t i o n t o be performed i n t h e p r e s e n c e o f o n l y a small e x c e s s of t h e h y d r i d e t r a n s f e r r e a g e n t . A l t h o u g h r e a c t i o n o f a - a m i n o - c a r b a n i o n s w i t h c a r b o n y l compounds would a p p e a r t o be a f e a s i b l e a p p r o a c h t o a m i n o - a l c o h o l s , i t s u s e h a s b e e n somewhat r e s t r i c t e d i n t h e p a s t . However t h e a l k a l o i d s macromerine ( 3 3 ) and s t o v a i n e ( 3 4 ) have r e c e n t l y been prepared from c a r b o n y l compounds and a - d i m e t h y l a m i n o m e t h y l - l i t h i u m , g e n e r a t e d by t r a n s m e t a l l a t i o n of t h e c o r r e s p o n d i n g t r i - n - b u t y l s t a n n a n e . S t a n n a n e s o f t h i s t y p e were p r e p a r e d by t r e a t m e n t o f ad i a l k y l a r n i n o r n e t h y l e t h e r s w i t h tri-n-butylstannylmagnesium c h l o r i d e i n e t h e r , t h e l a t t e r r e a g e n t s b e i n g p r e p a r e d by t h e a c t i o n o f i s o p r o p y l m a g n e s i u m c h l o r i d e on t r i - n - b u t y l s t a n n a n e , a g a i n i n d i e t h y l ether.

F r a g m e n t a t i o n s o f N , O - h e t e r o c y c l e s h a v e p r o v i d e d many a m i n o a l c o h o l d e r i v a t i v e s , and t h e s y n t h e s i s o f a - a m i n o - a l c o h o l s f r o m i s o x a z o l i n e s c o n s t i t u t e s p a r t of a larger t r e a t i s e of t h e u s e o f isoxazolines as intermediates i n n a t u r a l product syntheses. The u s e of 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 s h a s been a p p l i e d I n t h e case t o t h e s y n t h e s i s o f e r g o t a l k a l o i d s via i s o x a z o l i n e s . of p a l i c l a v i n e (35) t h e o l e f i n a l s o bore an a l l y l i c asymmetric c e n t r e which, disappointingly, gave only marginal d i a s t e r e o f a c i a l s e l e c t i o n i n t h e c y c l i z a t i o n s t e p (Scheme 4 2 ) .

328

General and Synthetic Methods

\

Y

Li+

+

AlH3 O B n I /

BUn

/OBn Na

BnO

b

+

L i A l H30Me

Reagents :

I ,

LiAIHL

, NaOMe ; i i I

\

N

LiAIH,OMe

aq. N a 2 S 0 4

S c h e m e 41

MeO

!- II Me

0- C

MeO&-!:-CHz-NMe2

(33)

Et

(34)

CH,-

NMe,

5: Am in es, Nitriles, and Other Nitrogen - conta ining Functiona1 Groups

R e a g e n t s : i , HZC=CHNOZ > C 6 H 6 ; i i , P h N C O , c a t . N E t 3

Scheme 4 2

329

General and Synthetic Methods

330

I s o x a z o l i n e s were a l s o e m p l o y e d i n t h e s y n t h e s i s o f a m i n o s u g a r s , w i t h 2-amin0-2~3-dideoxy-ribo-hexoses b e i n g p r e p a r e d f r o m 200 4-vinyl-l,3-dioxolanes and n i t r o a c e t a l d e h y d e a c e t a l s . AL-Isoxazolines have been proposed a s i n t e r m e d i a t e s i n a n a p p r o a c h t o Lankacidin s y n t h e s i s and a one-pot

C-4-carboxylation-

m e t h y l a t i o n p r o c e d u r e h a s been d e v e l o p e d f o r t h i s p u r p o s e . 201 Reductive fragmentations of i s o x a z o l i d i n e s ,

t o o , have played a

r o l e i n t h e s y n t h e s i s of compounds c o n t a i n i n g a m i n o - a l c o h o l m o i e t i e s , and e x a m p l e s o f s u c h r e a c t i o n s c a n b e f o u n d i n s y n t h e s e s of p t i l o c a u l i n (36Ir2O2 h i r s u t e n e

(38)

( 3 7 ) ( t h e amino f u n c t i o n

o f w h i c h was removed i n a s u b s e q u e n t Cope e l i m i n a t i o n ) , 2 0 3 a n d a204 hydroxy-a-amino-esters b a s e d on a l i c y c l i c s y s t e m s . A somewhat d i f f e r e n t u s e o f o x a z o l i d i n e s was t h e

E-

d e r i v a t i z a t i o n (primary t o secondary amine) o f amino-alcohols d e r i v e d from a - a m i n o - a c i d s . Reactions of t h e amino-alcohols w i t h a l d e h y d e s l e d t o t h e f o r m a t i o n of c h i r a l o x a z o l i d i n e s which were \ t h e n t r e a t e d w i t h benzylmagnesium c h l o r i d e t o a f f o r d h y d r o x y a l k y l a t e d p h e n y l e t h y l a m i n e h y d r o c h l o r i d e s ( s e e Volume 8 , p . 2 5 4 ) . 20 5 D e r i v a t i v e s o f t h e o x a z o l e r i n g system have a l s o been e x t e n s i v e l y used t o provide a c c e s s t o amino-alcohol

derivatives.

The o x a z o l e ( 3 9 ) was t r a n s f o r m e d t o t h e l a c t o n e ( 4 0 ) w h i c h a f t e r The 2-amino-3p r o t e c t i o n and h y d r o g e n a t i o n a f f o r d e d ( 4 1 ) .206

E-

was t h e n e l a b o r a t e d i n t o L - d a u n o s a m i n e ( 4 2 ) a n d d e r i v a t i v e ( 4 3 ) (Scheme 4 3 ) .207 2-0xazoline-4-phosphonates, p r e p a r e d f r o m diethylisocyanomethanephosphonates a n d c a r b o n y l c o m p o u n d s i n t h e p r e s e n c e of c u p r o u s o x i d e , w e r e f o u n d t o be h y d r o l y s e d t o l - a m i n o 2-hydroxyalkanephosphonic a c i d s ( m o l e c u l e s o f p o t e n t i a l b i o l o g i c a l i m p o r t a n c e ) or i n c e r t a i n c a s e s u n d e r m i l d e r c o n d i t i o n s t o d i e t h y l 1 -formylamino-2-hydroxyalkanephosphonates ( S c h e m e 4 4 ) . 2 0 8 hydroxy-lactone

a l s o i n t o a p r o t e c t e d L-vancosamine

H y d r o l y s i s of (411,5E)-4-buta-l,

3 - d i e n y l )-5-methyl-2-phenyl-AL-

o x a z o l i n e , u l t i m a t e l y d e r i v e d from L - t h r e o n i n e , benzoylated amino-alcohol

afforded an

0-

which formed an 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 a c t i n o b o l i n .209 I o d o c y c l i z a t i o n s of a l l y l i c t r i c h l o r o a c e t a m i d a t e s h a v e b e e n d e v e l o p e d i n t o a v e r s a t i l e s t r a t e g y for t h e s y n t h e s i s o f a m i n o -

*

a l c o h o l d e r i v a t i v e s ( s e e Volume 8 , p . 2 7 0 ) . Cyclizations n i t r o g e n l e a d t o 4-iodoalkyl-2-trichloromethyloxazolines w h i c h may be hydrolysed t o iodoamino-alcohols and t h e n d e i o d o n a t e d . Such m e t h o d o l o g y w i t h t h e c y c l i z a t i o n r e a c t i o n i n i t i a t e d by E-

331

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

M e - - R O

-ko Me, , e MeOCH,O

HO

O d N

1

2

(431R-Me0, R = H 1 2 R = H , R = Me

ii

NH,.HCI

HO

(41)

NHBoc

(42)

R e a g e n t s : i t 10°/o H C I I M e O H ; i i , ( B o c ) 2 0 , N a H C 0 3 ; i i i , H 2 , R h / A 1 2 0 3 , A c O E t

Scheme 1 3

0

NC

I O,IEt R ~ - C H - P\

+ 0E t

R2

R3'

\c=o

i ,

OEt

ii, iii

HO NH2

I I +R --C-C-PO,Hz 2

13 1 1

R R

R1=Hor Ph

0 HO

HN-CHO

I

I

Ph-CH-CH-P,,

,OEt

11

0

9

OEt

R2 R H

NH-CHO

0

Reagents: i , Cu20,C6Hg, KOBU~

A;

qMe,

ii, H C I , H * O ; ~ ~ ~ ,

H Schtme 44

EtOH; A

;

iv,H20,MeOH,b; v ,

332

General and Synthetic Methods

i o d o s u c c i n i m i d e , 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 methyl-a-l21 0

daunosaminide hydrochloride.

I t was a l s o d e m o n s t r a t e d t h a t t h e n o r m a l mode o f c y c l i z a t i o n o f a l l y l i c and h o m o a l l y l i c 2 - c a r b a m a t e s

( t o give d i o l s following

h y d r o l y s i s o f t h e h e t e r o c y c l e s ) c a n b e r e v e r s e d s i m p l y by u s i n g a n

N-sulphonylcarbamate, although t h e n a t u r e of t h e sulphonyl group d i d not appear t o a l t e r t h e d i a s t e r e o s e l e c t i v i t y

or t h e c h e m i c a l

y i e l d o f t h e c y c l i z a t i o n s . 21 A p r e v i o u s l y e s t a b l i s h e d p r o c e d u r e for t h e s y n t h e s i s o f

( s e e Volume 8 , p . 2 7 0 ) b a s e d on 'allylic-functionalization' m e t h o d s h a s b e e n o p t i m i z e d , a n d

protected aminocyclohexanediols cyclohex-2-en-1-01

converted i n t o f i v e protected derivatives

(44)-

( 4 8 ) o f t h e s e v e n p o s s i b l e 1 ,2 , 3 - a m i n o c y c l o h e x a n e d i o l s . 2 1 I o d o c y c l i z a t i o n s of c a r b o n i m i d a t e s , and t h e i r r e a r r a n g e m e n t s and s u b s e q u e n t c y c l i z a t i o n s of t h e r e s u l t a n t c a r b o n i m i d a t e s , b o t h l e a d i n g t o o x a z o l i d i n o n e f o r m a t i o n , c o n s t i t u t e d t h e two major

s t r a t e g i c o p e r a t i o n s (Scheme 4 5 ) . The l a t t e r s t r a t e g y o u t l i n e d a b o v e i n v o l v e d c y c l i z a t i o n of a d e r i v a t i z e d a l l y l i c amine t o an o x a z o l i d i n e .

Hydroxylations of

h e t e r o c y c l e f o r m a t i o n a n d h y d r o l y s i s a l s o seem t o

allylamines

form a g e n e r a l l y a p p l i c a b l e approach t o s t e r e o c o n t r o l l e d s y n t h e s i s of amino-alcohols.

cis-Hydroxyamino-sugars

have again provided an

a r r a y of a t t r a c t i v e t a r g e t s , and L-garosamine h a s been s y n t h e s i z e d v i a b o t h o x a z o l i n e and o x a z o l i d i n o n e i n t e r m e d i a t e s formed i n iodonium d i c o l l i d i n e p e r c h l o r a t e - i n d u c e d

cyclizations.

The

n i t r o g e n f u n c t i o n a l i t y was d e r i v e d f r o m a s u b s t i t u t i o n o f a n a l l y l i c e p o x i d e by a n a m i n e . * I 3

T h e l a t t e r r o u t e was f o u n d t o b e

more c o n v e n i e n t s i n c e N - m e t h y l a t i o n and r e d u c t i o n s t e p s , r e q u i r e d i n t h e f o r m e r r o u t e , were n o t n e e d e d , a n d t h u s a s y n t h e s i s o f e t h y l 214

h o l o c o s a m i n i d e was a c h i e v e d ( S c h e m e 4 6 ) . a-Acylamino-alcohols

h a v e b e e n made f r o m u n s a t u r a t e d a z l a c t o n e s

upon h y d r o g e n a t i o n . 215 [4+2]-Cycloadditions

have been u t i l i z e d e x t e n s i v e l y t o prepare

h e t e r o c y c l i c i n t e r m e d i a t e s from w h i c h a m i n o - a l c o h o l s obtained.

can be

The s y n t h e s e s o f t h r e o - and e r y t h r o - s p h i n g o s i n e s h a v e

been f u r t h e r described2'

and t h e g - s u l p h i n y l - t y p e

dienophiles

used i n t h e i r s y n t h e s e s have a l s o been employed i n a s y n t h e s i s o f 218 5-epi-desosamine (Scheme 4 7 ) . Acyl nitroso-compounds

have been u t i l i z e d as d i e n o p h i l e s i n

syntheses culminating i n t h e formation of amino-alcohol derivatives.

The s y n t h e s i s o f t a b t o x i n ( 5 0 )

via

(49)was a notable

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

333

N - Cycli z a t i on

SMe

( 4 4 ) R = H or Ac

liv

111c

o +

I

CH2Ph (46) Reagents :

I,

I

I

CHZPh

CH2Ph

(471

R = H or Ac

PhCHZNCS, N a H , Me1 ; 1 1 , 1 2 ;1 1 1 , Ag0COCF3

L-SeLectrlde;

vi,PhCH2N=C(OMe)CL,

I

MeN02 ;

IV,

PCC, CH2CLZ; v ,

KH; vii ,PhMe,n, v i i i , 0 ~ 0 ~ , N M M N O

Scheme 45

334

General and Synthetic Methods

1

2

R=R=H 3 R =H

EE

CH(0Et)Me

ix I

\

Me

AEE

OR

v, v i

X - I, R :EE X=H,R=EE l x i X-R=H 4 xii

V

i

OMe

OMe

+ ...

Me

; OH Me

Me

R:H

.. .

Xlll

ko.

MeNX

OEt

'=

Me

ry

rO T s

XVlll

+

Y

l x i v

X = C02Et 4

o . I

xvii Reagents:

I,

X = Y = I

L O MeN P O R 2 / OR' X

OE t

OEt

or EE

x= X =

X=Y=H

NH3 ; i i , PhCOCl , NaHC03 ; iii , EVE ,PPTS ; I V , i o d o n i u m dicollidineperchlorate

(1.Oequiv.); v , Bun3SnH; v i , Me1 , MeN02 ; v i i , NaBH4 ; v i i i , MeOH , HCI; ix,iodinium d i c o l l i d i n e p e r c h l o r a t e (1.0equiv.l; x , H 2

,1 0 O l 0

P d I C ; xi , PPTS,EtOH; xii,15"/0

a q . K O H ; x i i i , MeNH2 ,DMSO;xiv, ClC02Et, N E t 3 ; xv, iodonium dicollidine perchlorate (1.5 e q u i v . ) , d i o x a n e ; x v i , NaI,Me2CO; xvii,Bun3SnH,cat.(PhC0 1 ;xviii,5"/oaq.KOH; 22

xix,Ac20

Scheme 46

335

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

?H

M

e

2

N

Me

Me+

h

Me

6H

Me2N

OH OH Me riii

i, i i + H

Me

$OR Me

O ' 0k

Me

Me

\

R = H or CONH,

I

R e a g e n t s : i , P h M g E r ; i i , p i p e r i d i n e , E t O H ; iii,(HCHO),

,cat.p-TSA;iv,LiAIH4;

v i ,03,s i l i c a g e l

Scheme 4 7

CO CH2CI

I

NH

'

H02C H02Ce

0

0

v,TFA;

General and Synthetic Methods

336 e x a m p l e ( s e e Volume 8 , p . 2 7 6 ) .

A more d e t a i l e d a c c o u n t o f t h e

s y n t h e s i s h a s been p u b l i s h e d 1 2 1 gand i n a d d i t i o n r a c e m i c diaminodideoxy-lyxopyranoses have been p r e p a r e d a l o n g similar

lines.

220,

a-Chloronitroso-compounds h a v e a l s o b e e n e x a m i n e d a s d i e n o p h i l e s i n hetero-Diels-Alder

r e a c t i o n s and isomers o f diaminodideoxykonduritols p l u s a n a l o g u e s o f s t r e p t a m i n e h a v e b e e n s y n t h e s i z e d 2 t h e i r c y c l i z a t i o n s w i t h trans-6-azido-cyclohexaI l 3 - d i e n - 5 - o l . 221 The p o t e n t i a l f o r u t i l i z i n g a - c h l o r o n i t r o s o compounds c o n t a i n i n g c h i r a l a u x i l i a r i e s i n a s y m m e t r i c h e t e r o - D i e l s Alder r e a c t i o n s l e a d i n g t o t h e s y n t h e s i s of e n a n t i o m e r i c a l l y pure a m i n o c y c l o h e x e n o l s h a s a l s o b e e n e v a l u a t e d 2 2 2 , 223 i n some d e t a i l . The u s e o f a - a m i n o - a c i d s a s c h i r a l e d u c t s f o r t h e s y n t h e s i s o f h y d r o x y l a t e d D-a-amino a c i d s via a m i n o - a l c o h o l i n t e r m e d i a t e s h a s b e e n d e s c r i b e d . 224 Lithium e n o l a t e s of N,N-dibenzylglycinate

have f e a t u r e d i n t h e

s y n t h e s i s o f a-amino-B-hydroxy-acids. 225 T h e e n o l a t e c o u l d b e a c y l a t e d w i t h a c y l h a l i d e s a t low t e m p e r a t u r e s o r r e a c t e d w i t h However, t h e l a t t e r r e a c t i o n s were n o t p a r t i c u l a r l y d i a s t e r e o s e l e c t i v e , a n d r e d u c t i o n s of t h e a m i n o d i c a r b o n y l compounds r e s u l t i n g f r o m t h e a c y l a t i o n s w i t h e x c e s s

aldehydes i n a l d o l condensations.

N a B H 4 i n a q u e o u s e t h a n o l b u f f e r e d by ammonium c h l o r i d e ( w i t h o u t w h i c h t h e r e d u c t i o n s d i d n o t o c c u r ) f o l l o w e d by d e p r o t e c t i o n s l e d t o t h e d e s i r e d hydroxylated amino-acids threo:erythr-o

w i t h much b e t t e r

s e l e c t i v i t i e s ( r a t i o s i n t h e r a n g e 89:ll t o 9 9 : l w e r e

cited). A three-step

s y n t h e s i s o f (-1-a-amino-B-hydroxybutyric a c i d

(GABOB) i n 6 6 % o v e r a l l y i e l d a n d i n 49% e n a n t i o m e r i c e x c e s s h a s b e e n d i s c l o s e d . 226 The s e q u e n c e i n v o l v e d a s y m m e t r i c e p o x i d a t i o n o f a homoallylic a l c o h o l , o x i d a t i o n of t h e epoxy-alcohol t o t h e c o r r e s p o n d i n g epoxy-acid, and f i n a l l y o p e n i n g o f t h e e p o x i d e w i t h a n e x c e s s o f c o n c e n t r a t e d ammonium h y d r o x i d e . R e a c t i o n o f (2gl2S-)-2,3-(cyclohexylidenedioxy)butanenitri1e [prepared from e i t h e r L - ( + ) - t a r t r a t e o r ( S ) - l a c t a t e ] w i t h t h e magnesium e n o l a t e o f t - b u t y l a c e t a t e g a v e a ( L ) - B - a m i n o a c r y l a t e a d d u c t , w h i c h was u l t i m a t e l y c o n v e r t e d i n t o N - b e n z o y l - L - d a u n o s a m i n e by c o n s e q u e n t i v e a c e t y l a t i o n , s t e r e o s e l e c t i v e h y d r o g e n a t i o n , a c i d i c h y d r o l y s i s , p r o t e c t i o n , l a c t o n i z a t i o n , and dibal-H reduction.227 R e v e r s i b l e o x y a m i n o p a l l a d a t i o n s o f a l k e n e s 2 2 8 and a d d i t i o n s o f b e n z e n e s u l p h e n e a n i l i d e s t o olef i n s 2 2 9 have a l s o been s t u d i e d .

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

337

5 Amino-carbonyl Compounds

Syntheses of a-amino-aldehydes in electrocyclic rearrangements have been reported. Propargyl allyl ethers may be aminomercurateddemercurated to yield 8-allyloxy-enamines, Claisen rearrangement of which occurs almost quantitatively to afford 2-aminopent-4-enals (Scheme 48).230 When the allyl moiety formed part of an aromatic system, however, products were found to arise from [1,3]-(as opposed to [3,31-)sigmatropic rearrangements. Amino-ketones have been prepared in a number of ways. gTrifluoroacetyl-a-amino-acid chlorides have been employed in Friedel-Crafts acylations of arenes (reduction of the products to aralkylamines was also reported ,231 and high-pressure Mannich reactions have effected dimethylaminomethylation of ketones with bis (dimethylamino )methane. 232 Ketone t-butyldimethylsilyl enolates have been successfully added to Eschenmoser's salt, dimethyl(methy1ene)ammonium iodide,with retention of the protecting group to give silyl enol ethers of Mannich bases.233 Diastereoselective syntheses of novel examples of this type of compound have been achieved through the use of organotitanium reagents. Thus titanates of g,g-hemiacetals (trichlorotitanium dialkylamino-alkoxides) were used to convert lithium enolates into 8-dialkylamino-ketones and -esters. 234 The organotitanium species were generated either from lithium alkoxides and titanium tetrachloride o r from addition of trichlorodialkylamino-titanium to aldehydes (Scheme 49). Novel 2-amino-3-cyanophenyl ketones were obtained from cycloaddition-eliminations of vinyl ketones and 2-amino-3cyanofurans (Scheme 5 0 ) . 235 These compounds were employed as precursors to potential anticonvulsant quinazolines and 1,4benzodiazepines that had previously been synthetically inaccessible. 2 - A l k y l a m i n o b e n z o p h e n o n e s have been prepared from both 3-aryl2,I-benzisoxazolinium salts236 and the parent 3-aryl-2,l2b e n ~ i s o x a z o l i n e sthrough ~~~ the agency of iodotrimethylsilane Amino-3-acetyl-4-phenylpyridines have been prepared from 4-amino-lazabutadienes via reaction with diketene and rearrangement of the resultant dihydropyrimidines 238 Amino-esters have been isolated from thermal inter- and intramolecular E-sulphonylimine ene reactions, which favoured formation of products from endo transition states in most cases,239 in couplings of ethyl acrylate to N-(toluene-E-sulphonyl)imines catalysed by 1,4-diazabicycl0[2.2.2loctane,~~~and in dye-

.

.

General and Synthetic Methods

338

h2 I

R2 S c h e m e 40

Scheme 4 9

Scheme 50

339

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups 24 1 s e n s i t i z e d photo-oxygenations of 4(1H)-quinolones. B-Amino-acid e s t e r s c a n be p r e p a r e d by a m i n o m e t h y l a t i o n s o f s i 1y 1k e t e n e a c e t a 1s w i t h a-me

a n d E, EThe l a t t e r p r i m a r y

t h o x y c a r bama t e s 2 4

b i s ( t r i m e t h y l s i l y l )methoxymethylamine. 243

a m i n o m e t h y l a t i n g a g e n t was a l s o f o u n d t o r e a c t w i t h s i l y l - s u l p h i d e s and - p h o s p h i t e s t o g i v e aminomethyl-sulphides 24 4 respectively.

and -phosphonates

6 Amides a n d T h i o a m i d e s F o r m a m i d e s h a v e b e e n p r e p a r e d f r o m s e c o n d a r y a m i n e s on a t t e m p t e d silylation with t-butyldimethylsilyl

chloride-triethylamine-N,N-4-

d i m e t h y l a m i n o p y r i d i n e i n DMF, 2 4 5 a n d by d i e t h y l z i n c - c a t a l y s e d c a r b o n y l a t i o n of a m i n e s . 2 4 6 proceed

via

The f o r m e r r e a c t i o n was p r e s u m e d t o

t h e Vilsmeier-type

reagent (51).

be used as a m i d o a l k y l a t i o n r e a g e n t s , and

Formamides c a n a l s o

n o t a b l y I-formyl-5-

methoxyproline methyl ester, generated e l e c t r o c h e m i c a l l y from t h e d e s m e t h o x y d e r i v a t i v e , was f u n c t i o n a l i z e d i n t h e 5 - p o s i t i o n by N-Arylarylcarboxamides r e a c t i o n w i t h n u c l e o p h i l e s .247 -

and amides

o f weak c a r b o x y l i c a c i d s h a v e t r a d i t i o n a l l y b e e n r e g a r d e d a s d i f f i c u l t t o p r e p a r e , and as a r e s u l t numerous n o v e l r e a g e n t systems, e s p e c i a l l y methods f o r carboxy-group d e v i s e d i n o r d e r t o circumvent t h e problem. such systems are still a c t i v e l y sought.

a c t i v a t i o n , have been However, v a r i a n t s o f

Many o f t h e s e r e a g e n t s a r e

b a s e d on some a s p e c t o f o r g a n o p h o s p h o r u s c h e m i s t r y .

and i t h a s been

shown t h a t a m i d e s c a n b e made f r o m e q u i m o l a r q u a n t i t i e s o f c a r b o x y l i c a c i d s , a z i d e s , and t r i p h e n y l p h o s p h i n e i n r e f l u x i n g benzene.

The r e a c t i o n o c c u r s t h r o u g h p r o t o n a t i o n o f t h e i n i t i a l l y

formed phosphazenes ( S t a u d i n g e r r e a c t i o n between t h e a z i d e and p h o s p h i n e ) by t h e a c i d f o l l o w e d by a d d i t i o n of c a r b o x y l a t e a n i o n t o t h e phosphonium s p e c i e s and r e a r r a n g e m e n t w i t h e l i m i n a t i o n o f t r i p h e n y l p h o s p h i n e o x i d e (Scheme 5 1 ) . 2 4 8

N,N-Carbonyldi-imidazole i s a commonly u s e d r e a g e n t f o r a c t i v a t i o n of c a r b o x y - g r o u p s t o w a r d s n u c l e o p h i l i c a t t a c k a n d i t s u s e h a s b e e n a p p l i e d t o t h e s e l e c t i v e a c y l a t i o n of p r i m a r y a m i n o g r o u p s i n s p e r m i d i n e and o t h e r l i n e a r t r i a m i n e s . 249

N ,ECarbonyldi[2(3~)-benzoxazolethionel h a s b e e n d e v e l o p e d a s a r e a g e n t w i t h similar a p p l i c a b i l i t y , namely s y n t h e s i s o f a m i d e s , e s t e r s , p e p t i d e s , and polyamides. 250

N - M e t h y l a t i o n of trimethylsilyl-cyanohydrins o f 2 - a c y l - l K i m i d a z o l e s h a s a f f o r d e d i n t e r m e d i a t e s from which amides c a n be

340

General and Synthetic Methods

o b t a i n e d i n good y i e l d .

Thus s e q u e n t i a l t r e a t m e n t of t h e

acylimidazole with trimethylsilyl cyanide, n-butyl-lithium, d i m e t h y l s u l p h a t e , a n d a n a m i n e a f f o r d e d a m i d e ~ . ~ ~An’ a c y l n i t r i l e was t e n t a t i v e l y p r o p o s e d a s t h e r e a c t i v e i n t e r m e d i a t e o f t h e p r o c e s s (Scheme 5 2 ) . S e l e c t i v e one-pot

a c y l a t i o n s of benzylic amines i n t h e presence

of a n i l i n e s were made p o s s i b l e by u t i l i z a t i o n o f 3 , 6 - d i e t h y l - 2 h y d r o x y p y r a z i n e as a n a c y l t r a n s f e r r e a g e n t ( S c h e m e 5 3 ) .252 I n g e n e r a l t h e o r d e r f o r e a s e o f a c y l a t i o n was p r i m a r y > s e c o n d a r y a l i p h a t i c amine = primary > s e c o n d a r y a r y l amine. Amides c a n b e p r e p a r e d f r o m a v a r i e t y o f o t h e r n i t r o g e n -

For i n s t a n c e , a m i d e s w e r e p r e p a r e d

containing functional groups.

f r o m n i t r i l e s by r e a c t i o n w i t h c y c l i c h y d r o x y l a m i n e s t y p i f i e d by 4-

benzyloxy-l-hydroxy-2,2,6,6-tetramethylpiperidine, 253 f r o m k e t o x i m e s u s i n g !,I-carbonyldi-imidazole

i n c o n j u n c t i o n w i t h a l l y 1 bromide o r

o t h e r a c t i v e h a l i d e s , 254 f r o m a 2-amino-3-phenylcarbamoylazirene on r e a c t i o n w i t h a c y l h a l i d e s 255 i n p l a t i n u m - p h o s p h i n e c a t a l y s e d , Lewis acid-mediated

c o m p o u n d s , 256 a n d by r e a c t i o n o f N - n i t r o s o a l k y l a m i d e s w i t h a m i n e s .257

complex-

reductive Ij-acylations

of n i t r o -

a n d Ij-nitro-!-

In the last reaction arylamines

reacted poorly with the N-nitrosocarboxamides,

whereas t h e N-nitro-

compounds r e a c t e d w e l l . The a d d i t i o n o f a m i n e s t o p h o t o c h e m i c a l l y g e n e r a t e d k e t e n e s h a s a l s o b e e n e x a m i n e d .258

N-Bromoamides

have been i s o l a t e d a f t e r t r e a t m e n t w i t h aqueous

sodium b r o m i t e i n a c e t i c t h e p r e p a r a t i o n o f a m i n e s . 35

as w e l l a s b e i n g i n t e r m e d i a t e s i n o r t h o - A l k y l a t i o n of a c e t a n i l i d e s w i t h

a l k y l h a l i d e s and p a l l a d i u m acetate has a l s o been a c h i e v e d .260 H e t e r o c y c l e s h a v e a l s o b e e n u s e d a s s o u r c e s of a m i d e s . a-Aminoa c i d a m i d e s h a v e b e e n o b t a i n e d f r o m a c i d i c h y d r o l y s e s o f 4i m i d a z o l i d i n o n e s a n d f r o m 4 - i m i n o - o x a z e t i d i n e s . 261 P h o t o o x y g e n a t i o n o f 1 , 2 , 4 - t r i s u b s t i t u t e d i m i d a z o l e s w i t h s i n g l e t oxygen i n t h e p r e s e n c e o f DBU and a s e n s i t i z e r l e d t o t h e f o r m a t i o n o f i m i n e - d i a m i d e s i s o l a t e d a f t e r p u r i f i c a t i o n by c h r o m a t o g r a p h y , w h i c h f o l l o w i n g i s o m e r i z a t i o n t o enamine-diamides afforded a-acetylamino-acid w e r e o b t a i n e d f r o m !-protected

a m i d e s . 26

a-

amino-acids

and h y d r o g e n a t i o n

Acy l a m i n o - a c i d amid e s by s e q u e n t i a l t r e a t m e n t

with Ij-methylmorpholine, i s o b u t y l c h l o r o f o r m a t e , and c o n c e n t r a t e d a q u e o u s a m ~ n i a . a~- A~m i~n o - a c i d a m i d e s a l s o r e s u l t e d f r o m r e a c t i o n s o f s e c o n d a r y a m i n e s w i t h t r i c h l o r o e t h y l e n e e f f e c t e d by aqueous sodium h y d r o x i d e and s m a l l amounts of b e n z y l t r i e t h y l a m m o n i u m c h l o r i d e a t 70 0C.264

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

RCO L.H N,R'

Ph,P J

341

i

+) *Ph,P=NR1

J. J. + Ph,PO

(+ N,)

S c h e m e 51

-

Me

Reagents :

Me

I ,

-

T M S C N , c a t . BunLi ; M e 2 S 0 4 , 70 " C ; i i i ,

Scheme 5 2

Scheme 53

Me

Me SOL

R'NH,

0

OC

1

RCONHR'

General and Synthetic Methods

342

Amides o f u n s a t u r a t e d a c i d s h a v e a l s o b e e n much s o u g h t a f t e r , and b e n z y l i c a c r y l o y l a m i n a t i o n s have been a c h i e v e d u t i l i z i n g f e r r i c p e r c h l o r a t e n o n a h y d r a t e and a c e t i c a c i d t o c o n v e r t a r e n e s and a c r y l o n i t r i l e i n t o a r y l a c r y l a m i d e s i n moderate y i e l d s . 265

3-

Dimethylphosphonoacetyl-l,~-thiazolidine-2-thione(DMPATT) was u s e d t o prepare a,B-unsaturated

amides i n moderate t o good y i e l d s

r e a c t i o n w i t h a m i n e s f o l l o w e d by W i t t i g - H o r n e r a l d e h y d e s a n d k e t o n e s ( S c h e m e 5 4 ) . 266

via

coupling with

I n t h e f o r m a t i o n of

a l i p h a t i c amides t h e coupling s t e p favoured formation of 5 - o l e f i n s . a m i d e s h a v e b e e n o b t a i n e d a f t e r r e a c t i o n s of

a,13,7,6-Unsaturated

p r o p a r g y l a l c o h o l s and acetals of l - a c e t y l - p y r r o l i d i n e -piperidine.

and

I s o m e r i z a t i o n of t h e r e s u l t a n t 8 - a l l e n y l a m i d e s

2 ( E ) , 4 ( & ) - d i e n a m i d e s was p r o m o t e d by t h e 2 (E ) , 4 ( E-) - i s o m e r s

to

t h e formation of

with potassium-t-butoxide

having a l r e a d y been

e s t a b l i s h e d (Scheme 5 5 ) . A number o f dihydropyran-5-carboxamides r e s u l t e d from t r e a t m e n t of d i h y d r o p y r a n s w i t h t o s y l i s o c y a n a t e i n THF. 2 6 8 Olefin-substituted several instances.

enamides have a l s o been s y n t h e s i z e d i n

N-Acetyl-

and N,N-diacetyl-a,B-didehydro-a-

a m i n o - a c i d a m i d e s r e s u l t e d f r o m t r e a t m e n t of a - a z i d o c a r b o x a m i d e s w i t h rhenium c a t a l y s t s i n a c e t i c a n h y d r i d e ,269 and l-phenyl-8a m i d e s were o b t a i n e d

bromo-a,B-unsaturated

via

bromoboration of

t e r m i n a l a l k y 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 8bromoalkenyl-boranes

with phenyl isocyanate.

The

E:L r a t i o s

of

p r o d u c t s d e r i v e d from a l i p h a t i c a l k y n e s appeared t o be dependent upon t h e t e m p e r a t u r e a t w h i c h t h e p h e n y l i s o c y a n a t e was a d d e d . Temperatures of 23

OC

a n d -78

Z-B-bromo-a,B-unsaturated

OC

f a v o u r e d t h e f o r m a t i o n of

E-

and

a m i d e s r e s p e c t i v e l y ( S c h e m e 5 6 ) .270

Alkyl-3-arylazo-2-halogenobut-3-enamides were f o r m e d by r i n g o p e n i n g s of l-aryl-4,4-dihalogeno-3-methylpyrazoline-5-ones w i t h a m i n e s a n d ammonia. 27 y,b-Unsaturated

*

a m i d e s h a v e r e s u l t e d f r o m c y c l i z a t i o n s of t h e

c o r r e s p o n d i n g epoxy-amide

e n o l a t e s f o l l o w e d by d e h y d r a t i o n , t h i s

sequence being exemplified with p r e p a r a t i o n s of p y r e t h r o i d a m i d e s , 2 7 2 and i n moderate y i e l d s f o l l o w i n g t r e a t m e n t of

l,N-

dimethylamino-4-alkanoic a c i d l a c t o n e s w i t h HMPA a t h i g h temperatures.273

S i m i l a r r i n g o p e n i n g s o f 6- and E - l a c t o n e s

were

noted i n the latter report. Ynamines h a v e b e e n f o u n d t o r e a c t w i t h s i l y l a l d o k e t e n e s i n t h e n o r m a l [2+21 s e n s e t o g i v e y - s i l y l a t e d a l l e n e c a r b o x a m i d e s , w h i c h c a n t h e n b e t r a n s f o r m e d i n t o y - s i l y l y n a m i d e s . 274

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

343

’ yellow ’

‘colourless ’ Reagents:

i, DCC- D M A P ; ii, R’R’NH;

iii , N A H , T H F ; i v , R 3 R 4 C 0

Scheme 5 4

OH

\ii

iii/

-

R e a g e n t s : i , MeC(OEt)2NdCH2),

; i i , ALZ03 ; iii , KOBut

Scheme 55

-

Br RCECH

R e a g e n t s : i , BBr3 ; ii

\ RIC =c\

, PhNCO

ii,iii

H

/CONHPh 7=c\ +

Br

\ R

; iii, H20

Scheme 5 6

H

H

Br\

/

R

‘CONHPh

General and Synthetic Methods

344

Michael a d d i t i o n s t o a ,B-unsaturated amides have s e r v e d t o 2-Carbamylethylphosphonous e x t e n d t h e s c o p e of amide s y n t h e s i s . a c i d was p r e p a r e d b y a d d i t i o n o f h y p o p h o s p h o r o u s a c i d t o a c r y l a m i d e ( m e t h a c r y l a m i d e a n d c r o t o n y l a m i d e r e a c t e d p o o r l y ) , 275 N - p r o t e c t e d 2-carbalkoxyaminothioethers were f o r m e d i n m o d e r a t e t o g o o d y i e l d s by a d d i t i o n s t o l - B o c - p r o t e c t e d d e h y d r o - a - a m i n o - a c i d s , 276 a d d i t i o n o f sodium b e n z e n e s u l p h i n a t e

t o N,N-diethylacrylamide

afforded the

s u l p h o n e a m i d e ( 5 2 1 , w h i c h was a l s o c o n v e r t e d i n t o t h e c o r r e s p o n d i n g t h i o a m i d e ( 5 3 ) w i t h P 4 S , 0 ,277 a n d ( L ) - B - a r y l s e l e n o a,B-ethylene

c a r b o x a m i d e s were o b t a i n e d i n g o o d y i e l d s u p o n

a d d i t i o n s o f s e l e n o l s t o a l k y n a m i d e s . 278 The s y n t h e s i s o f o x y g e n a t e d a m i d e s m u s t a l s o b e c o n s i d e r e d t o b e a n i m p o r t a n t area.

a-Oxoamides

have been s y n t h e s i z e d i n good

y i e l d s by t r e a t m e n t o f a l k y l - l i t h i u m s 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 i s o c y a n a t e . 279

a - O x o t h i o a m i d e s were s i m i l a r l y p r e p a r e d i n t h e analogous reactions with isothiocyanates. Addition of

Grignard r e a g e n t s t o e t h y l oxamate a l s o a f f o r d e d a-0x0-amides. I n t e r m e d i a t e s i n t h i s p r e p a r a t i o n c o u l d a l s o b e c o n v e r t e d i n t o ah y d r o x y - a m i d e s by h e a t i n g i n t o l u e n e ( S c h e m e 5 7 ) .280 Asymmetric s y n t h e s i s o f B - h y d r o x y a c e t a m i d e s

h a s b e e n r e a l i z e d by

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 e n a n t i o m e r i c a l l y p u r e as u l p h i n y l a c e t a m i d e s a n d a l d e h y d e s f o l l o w e d by r e d u c t i v e E n a n t i o m e r i c e x c e s s e s of u p t o

d e s u l p h u r i z a t i o n o f t h e a d d u c t s . 281

47% were o b t a i n e d .

B-Keto-carboxamides

have been 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 a d d i n g t h e d i a n i o n d e r i v e d f r o m

l-

(trimethylsily1)acetamide t o e s t e r s a n d 1-methoxy-N-methylbenzamide ( a l k y l a t i o n s w i t h a l k y l h a l i d e s and h y d r o x y a l k y l a t i o n s w i t h a l d e h y d e s were a l s o d e m o n s t r a t e d ) , 2 8 2 a n d f r o m t h e r m a l r e a c t i o n s o f

2,2-dimethyl-2~,4~-1,3-dioxin-4-ones with amines, these occurring i n t e r m e d i a c y of a l ~ y l k e t e n e s . ~ ~ ~ The a d d i t i o n s o f N-halogeno-N-alkylamides a n d N-halogeno-!-

via the

acylamides (N-halogenoimides) t o o l e f i n i c s u b s t r a t e s under 284 photochemical c o n d i t i o n s have been s t u d i e d and compared. Amidomercuation-demercurations o f o l e f i n s h a v e b e e n d o c u m e n t e d ( s e e Volume 8 , p . 2 8 2 ) a n d a n e x t e n s i o n t o t h e p r o c e d u r e h a s b e e n made by performing t h e demercuration of t h e a-amidomercurial

in the

presence of an e l e c t r o n - d e f i c i e n t o l e f i n . T h i s l e a d s t o 1,4d i f u n c t i o n a l i z e d p r o d u c t s i n r e a s o n a b l e y i e l d s ( S c h e m e 58). 2 8 5 Recent advances i n a-amidoalkylation

reactions at carbon centres

h a v e b e e n r e v i e w e d , 286’287 a n d a new a m i d o a l k y l a t i o n r e a c t i o n h a s b e e n a c c o m p l i s h e d by c o n d e n s a t i o n of c a r b a n i o n s w i t h c y c l o - 1 , 3 -

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

345

X

II

0 (52) X = O

(53) x = s

OMget NHMgBr

EtO

RMg8r

-% R

R

50 f

0

Jiii OMgBr

“ . ,

NHMg8r

R

IK

&

NH,

R

0

0

R = C,alkyl ; n = 2 , 4 , 6 - 1 0 R e a g e n t s : i , EtOCOCONH,;

i i , H20 ; iii, PhMe

Scheme 57

R’

0 1

4-

R-CH=CH-R2 Reagents : i

~

R3-C-NH,

Hg(NO3I2 ; i i , H,C=CHX

-*

I

, II

R

3

11

- C-

NH-

RZ

I I CH-CH-CH,CH,X

NaBH4

Scheme 5 8

S

S

S R-P’

ii s \s’H

(55) X = H ( 5 6 ) X=OMe

(54) R :MeOC6H4-p (57)R= MeS ( 5 8) R = Ph SC6H4-p

\P-R

s (59)R = MeOC6H,.-p (60)R = PhOC,H,-p

General and Synthetic Methods

346 o x o i m m i n i u m s a l t s . 288

High-yielding

p r e p a r a t i o n s o f new

3-(

1-

acylaminobenzyl)-2-oxo-2~-1 - b e n z o p y r a n s were a l s o d i s c l o s e d . 2 8 9 S y n t h e s i s of amido m o i e t i e s w i t h i n h e t e r o c y c l i c n u c l e i h a v e been a c h i e v e d by a d i v e r s i t y o f m e t h o d s . Representative examples i n c l u d e s y n t h e s e s of 4-carbamyl-1,2,3-triazoles b y r e c y c l i z a t i o n o f 5 - h y d r o x y - 1 ,2,3-triazole-4-aldimines,290 p r e p a r a t i o n s o f (Ns u b s t i t u t e d carboxamido)methylene d e r i v a t i v e s of 1,2,5-oxathiazole a n d 1 , 2 , 3 - t h i a d i a z o l e b y t r e a t m e n t o f 2-substituted-5-aryl-3(2H)i s o t h i a z o l o n e s w i t h hydroxylamine and a r y l h y d r a z i n e s r e s p e c t i v e l y , 291 p l u s p r e p a r a t i o n s o f s y m m e t r i c a l and mixed

imidazole-4,5-dicarboxamides f r o m t h e p a r e n t d i a c i d . 2 9 2 Some t h i o f o r m a m i d e s h a v e b e e n made b y t r e a t m e n t o f f o r m a m i d i n e s w i t h h y d r o g e n s u l p h i d e i n DMF b e l o w 0 0C.293 T h i o n a t i o n of a m i d e s c o n s t i t u t e s a v e r y p o p u l a r m e t h o d f o r 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 .

A number of improved v a r i a n t s of

Lawesson's r e a g e n t ( 5 4 ) have been r e p o r t e d .

( 5 5 ) a n d ( 5 6 ) were

shown t o c o n v e r t a m i d e s i n t o t h i o a m i d e s a t room t e m p e r a t u r e i n

THF,294 a n d ( 5 8 ) - ( 6 0 ) were f o u n d t o e f f e c t s i m i l a r t r a n s f o r m a t i o n s w i t h e x t r e m e l y s h o r t ( l e s s t h a n f i v e m i n u t e s ) r e a c t i o n t i m e s . 295 a,b-Unsaturated

t h i o a m i d e s h a v e b e e n p r e p a r e d by W i t t i g - H o r n e r

c o u p l i n g o f p h o s p h o n a t e a n i o n s , a r i s i n g from d e p r o t o n a t i o n of ( 6 1 1 , w i t h a l d e h y d e s (Scheme 5 9 ) .296 S y n t h e s e s o f a-alkyl-B-hydroxyalkyl-thioamides achieved via threo-selective

have been

a l d o l c o n d e n s a t i o n s of t h i o a m i d e

e n o l a t e s , d e r i v e d b y M i c h a e l a d d i t i o n s o f o r g a n o l i t h i u m or organomagnesium r e a g e n t s t o c r o t o n o t h i o a m i d e , s o r b o t h i o a m i d e , c i n n a m o t h i o a m i d e , w i t h a l d e h y d e s .297 7 2 9 8

and

Michael a d d i t i o n s of

9BBN a n d d i b a l - H were a l s o a c c o m p l i s h e d b u t t h e y l e d t o condensations t h a t proceeded with poorer e r y t h r o - s e l e c t i v i t y . A new s y n t h e s i s of m o n o t h i o d i a c y l a m i n e s h a s b e e n d e s c r i b e d , 299

a n d N-thioacylthionocarbamic a c i d e s t e r s h a v e b e e n s y n t h e s i z e d from b o t h i m i n o c h l o r i d e s a n d potassium-2-alkylxanthates a n d s u l p h e n y l h a l i d e s a n d t h i o n o c a r b a m i c a c i d e s t e r s . 300

7 Nitriles and Isocyanides S y n t h e s i s o f n i t r i l e s by d e h y d r a t i o n o f 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

i s commonplace.

C a r b o x a m i d e s h a v e b e e n d e h y d r a t e d by s u p p o r t e d

p h o s p h o r u s p e n t o x i d e , 30

a n d by m i x t u r e s o f c a r b o n y l d i - i m i d a z o l e

conjunction with an excess of an a c t i v e halide.254 Thioamides and a l d e h y d e s c a n a l s o f u r n i s h n i t r i l e s i n m o d i f i e d

in

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

0

0

Et02P,

’

(Et012P,-

,CH2 Me

Me

’.

CH

-

347

0 ( E t 0 l 2 P ~ S -

-

Me

NR

J

iii

J

Reagents : i, 6u”Li ; ii, RNCS(0.5equiv.); iiiI H30+; i v , N a H ; v , R’CHO

Scheme 5 9

-2e

t

B r - 4 Br+’; N a + +

MeONa

+ 1’zH2

RCH2NHzARCH2NHBr-1’,RCH=NH

,

Indirect Electro- oxidation

-!+ RCH=NBr !!+

a::;Reagents : i ‘ B r ”

I

b a s e ; ii, b a s e

Scheme 60

RC=N

General and Synthetic Methods

348 Willgerodt-Kindler

r e a c t i o n s u s i n g e l e m e n t a l s u l p h u r , sodium

n i t r i t e , a n d l i q u i d ammonia.302 A l d o x i m e s may be d e h y d r a t e d t o n i t r i l e s a n d s u c h r e a c t i o n s h a v e b e e n n o t e d on t h e i r t r e a t m e n t w i t h t r i - n - b u t y l p h o s p h i n e - d i p h e n y l d i s u l p h i d e , 28 a n d w i t h d i m e t h y l ( s u c c i n i m i d y 1 ) s u l p h o n i u m c h l o r i d e t r i e t h y l a m i n e . 303 N i t r i l e s h a v e been o b s e r v e d as p r o d u c t s a r i s i n g from f l a s h p y r o l y s e s o f i s o c y a n i d e s , 304 a n d h a v e b e e n o b t a i n e d ion-mediated

electro-oxidation

halonium

o f a m i n e s ( S c h e m e 6 0 ) . 305

Acyclic

d i n i t r i l e s w e r e p r o d u c e d by f r a g m e n t a t i o n o f c y c l i c ? , 2 - d i a m i n e s using the l a t t e r procedure. A novel s y n t h e s i s of a l k y l n i t r i l e s from t e r m i n a l a l k e n e s

r e s u l t e d f r o m f o r m a t i o n o f t r i a l k y l b o r a n e s f o l l o w e d by a d d i t i o n o f a l a r g e e x c e s s o f sodium c y a n i d e p l u s s t o i c h e i o m e t r i c q u a n t i t i e s of l e a d t e t r a - a c e t a t e . 306 Y i e l d s were p o o r i n c a s e s s t u d i e d i n i t i a l l y , a l t h o u g h c o n s i d e r a b l e improvements r e s u l t e d from u s e of

9-BBN a s t h e h y d r o b o r a t i n g a g e n t . The e f f i c i e n c y o f d i p h e n y l a l k y l s u l p h o n i u m s a l t s i n a l k y l a t i o n s o f c y a n i d e a n i o n and p h e n y l a c e t o n i t r i l e

h a s b e e n e v a l u a t e d . 307

P r i m a r y n i t r i l e s w e r e p r o d u c e d i n good y i e l d s , and m o n o a l k y l a t i o n s of phenylacetonitrile

were achieved i n h i g h y i e l d s w i t h o n l y t r a c e s

of contaminating dialkylated products detected. E l e c t r o p h i l i c t h a l l a t i o n o f a r e n e s f o l l o w e d by n u c l e o p h i l i c d i s p l a c e m e n t o f t h e t h a l l i u m m o i e t y h a s a l l o w e d a number of f l e x i b l e a r e n e f u n c t i o n a l i z a t i o n methods t o be developed.

Cuprous

cyanide treatment of a r y l t h a l l i u m b i s ( t r i f 1 u o r o a c e t a t e s ) r e s u l t e d i n t h e f o r m a t i o n o f a r y l n i t r i l e s i n good y i e l d s . 3 0 8 The r e a c t i o n i s a n a l o g o u s t o t h e Rosenmund-von B r a u n r e a c t i o n o f h a l o g e n o a r e n e s w i t h Cu'CN

a n d t h e p r o c e s s was f a c i l i t a t e d by u s e o f t h e

e l e c t r o n e g a t i v e t r i f l u o r o a c e t a t e l i g a n d s which i n c r e a s e d t h e o x i d a t i o n p o t e n t i a l o f t h e metal.

Both 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 a r e n e s could be converted i n t o t h e c o r r e s p o n d i n g n i t r i l e s , and t h e u s e of a c e t o n i t r i l e a s s o l v e n t a i d e d r e g e n e r a t i o n o f Cu'

by s t a b i l i z i n g i t t h r o u g h c o m p l e x a t i o n .

An e l e g a n t s y n t h e s i s o f 2 - a l k y l - 3 - c y a n o - b e n z o i c a c i d s or -benzaldehydes involved a d d i t i o n of a-metallated a l k y l n i t r i l e s t o t h e b e n z y n e d e r i v e d f r o m 2-(~-chlorophenyl)-4,4-dimetyl-1,3o x a z o l i n e . 309 C h e l a t i o n of t h e l i t h i u m c a t i o n promoted a d d i t i o n t o the ortho-position,

and t h e s e i n i t i a l a d d u c t s t h e n c y c l i z e d t o

benzocyclobutenimines which s u b s e q u e n t l y fragmented t o g i v e b e n z y l i c a n i o n s o f t y p e ( 6 2 ) (Scheme 6 1 ) . T h e s e c o u l d t h e n be

349

5: Arnines, Nitriles, and Other Nitrogen-containing Functional Groups

1

X

0x2

0x2

I

Li

&R CN

CN

CN

(6 2)

X=COtMe or CHO

1

iii

X

R'

0x2

X=CO,Me or CHO Reagents i , RCH(Li)CN; i i , E t O H ; i i i , R ' X

S c h e m e 61 MeSCN

iJ.

Bu3P(CN)SMe

Bu,P+SMe

Ar CHOW-

I

CN

it

CN I

pFiHAr

p\

@--tAr 4

Bu,P=O Reagents

'

I)

Bu3P ;

11,

Bu3Pf0CHAr

I

c-

ArCHO

CN

"

SMe

S Me

+ ArCH2CN + ArCOSMe Scheme 62

-

R1

350

General and Synthetic Methods

a l k y l a t e d , o r p r o t o n a t e d , p r i o r t o d e p r o t e c t i o n o f t h e o x a z o l i n e by either hydrolysis or reduction. A r o m a t i c a l d e h y d e s may a l s o be t r a n s f o r m e d i n t o a r y l n i t r i l e s following treatment with t r i m e t h y l s i l y l a z i d e i n t h e presence of

via collapse

z i n c c h l o r i d e ,310’ 31

of t h e t r i m e t h y l s i l y l

azidohydrin to a benzylic nitrenium ion. The s y n t h e s i s o f a r y l a c e t o n i t r i l e s i s a n a r e a w h i c h h a s n o r m a l l y received considerable attention.

Palladium-catalysed

reactions of

c y a n o m e t h y l t r i b u t y l t i n with a r y l bromides a f f o r d e d moderate y i e l d s of a r y l a c e t o n i t r i l e s , e x c e p t i n c a s e s o f a r y l b r o m i d e s w h i c h c o n t a i n e d s t r o n g l y e l e c t r o n - w i t h d r a w i n g s u b s t i t u e n t s . 312 A r y l a c e t o n i t r i l e s have a l s o been o b t a i n e d from k e t o n e s f o r m a t i o n o f c y a n o p h o s p h a t e s f o l l o w e d by h y d r o g e n a t i o n , 31 t r e a t m e n t of a r y l a l d e h y d e s w i t h t r i - n - b u t y l p h o s p h i n e

a n d by

and methyl

thiocyanate i n a novel disproportionation reaction t h a t also afforded S-methylthiobenzoates

(Scheme 6 2 ) . 3 1

A r y l m a l o n o n i t r i l e s were f o r m e d i n p a l l a d i u m - c a t a l y s e d

couplings

o f t h e sodium s a l t of m a l o n o n i t r i l e t o a r y l h a l i d e s . 3 1 5

E-a

,B-Unsaturated

n i t r i l e s have been s y n t h e s i z e d w i t h h i g h

s t e r e o s e l e c t i v i t y using Wittig-Horner

r e a c t i o n s employing

diphenyl(cyanomethy1 Iphosphine oxides.316 cited.

a,B-Unsaturated

E:L

r a t i o s o f > 9 5 : 5 were

n i t r i l e s were a l s o o b t a i n e d i n r e a c t i o n s

u t i l i z i n g d i e t h y l p h o s p h o r o c y a n i d a t e i n t h e p r e s e n c e of l i t h i u m cyanide3’ alk-2-ene

( i n t e r m e d i a t e cyanophosphates were c o n v e r t e d i n t o 2-aryln i t r i l e s by b o r o n t r i f l u o r i d e e t h e r a t e ) , f r o m

trisubstituted olefins

via

ene-type

c h l o r i n a t i o n s , 318 a n d i n

h e t e r o g e n e o u s Knoevenagel c o n d e n s a t i o n s o f b o t h a l d e h y d e s and k e t o n e s w i t h m a l o n o n i t r i l e o r e t h y l c y a n o a c e t a t e c a t a l y s e d by T y p e I a n d Type I V c y a n o l i p i d s b o t h c o n t a i n A1P04-A1203.319 a l l y l i c n i t r i l e m o i e t i e s a n d t h e s e c o m p o u n d s were 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 a , B - u n s a t u r a t e d a l d e h y d e s by t r e a t m e n t w i t h p o t a s s i u m c y a n i d e , a c y l h a l i d e s , a n d 18-crown-6 Palladium-catalysed

i n t o l u e n e (Scheme 6 3 1.320

a l k y l a t i o n s of a l l y 1 a c e t a t e s w i t h e t h y l

c y a n o a c e t a t e h a v e a l s o b e e n s t u d i e d , a n d m i x t u r e s o f mono- a n d d i h o m o a l l y l n i t r i l e s p r o d u c e d .321

The g e n e r a l u t i l i t y o f n i t r i l e s 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 was a p t l y d e m o n s t r a t e d by t h e s y n t h e s i s of b o n g k r e k i c a c i d ( 6 7 ) i n w h c i h t h e a - c y a n o - k e t o n e ( 6 3 ) was c o n v e r t e d i n t o t h e a l k y n y l n i t r i l e ( 6 5 ) by way of t h e e n o l t r i f l a t e (64) and t h e n c e i n t o t h e L-a,B-unsaturated

n i t r i l e ( 6 6 ) upon

a d d i t i o n of d i m e t h y l c o p p e r l i t h i u m a t l o w t e m p e r a t u r e i n THF ( S c h e m e 6 4 ) 322

.

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

k C H 0

&

,xo2cR -

R = 2 Me(CH,),CH=CH(CH,),

2 - Mc(CH2),CH=CH(CHz)l,,

CN

c17H33co2 ~

351

,

,C,H3,C,HB9 or C5H,,

0 2 c c 1 7 H 3 3

CN Reagents: i, RCOCI,KCN,18-crown-6; ii, P B r 3 ( 0 . 5 e q u i v . ) ; iii, C1fLJ02Na(2

equiv.),Bu*NBT

4

(0.1equiv.),ultrasound,iv,Mn02,C6H14v,C H COCI,KCN, 18-crown-6 17 33

Scheme 63

I

iii

+ ’ OMe

c

;

c

Me /

=

TIPS’

Me

COZH (66)

(67) Reagents: i , NaH, T f 2 0 ( 1 . 5 e q u i v . ) ;

11,

N a H , DMSO ; iii, MeZCuL I

Scheme 64

CN

352

General and Synthetic Methods

I t was shown t h a t t h e r e a c t i v e i n t e r m e d i a t e h e x y n y l c y a n o k e t e n e c o u l d b e g e n e r a t e d by p y r o l y s i s o f 2,5-diazido-3,6-dihexynyl-l,4-

b e n z o q u i n o n e i n b e n z e n e , a n d t h a t i n t h e p r e s e n c e of a n e x c e s s o f a l c o h o l s a l k y l 8-alkoxy-a-cyano-a,B-ethylenecarboxylates

were

formed.323

R e a c t i o n s of t h e k e t e n e w i t h imines gave cyanos u b s t i t u t e d 8 - o r y - l a c t a m s d e p e n d i n g on t h e s t r u c t u r e of t h e imine. The c h e m i s t r y of o x y g e n a t e d n i t r i l e s i s a l s o a n i m p o r t a n t a r e a ,

a n d t h e c h e m i s t r y o f 3 - o x o a l k a n e n i t r i l e s h a s b e e n r e v i e w e d 324

Methoxy-2-(benzenesulphonyl)propenenitriles

r e a c t i o n s of o r t h o e s t e r s with benzenesulphonyl from c a r b o x y l i c a c i d c h l o r i d e s

3-

h a v e b e e n s y n t h e s i z e d by a c e t o n i t r i l e and

a-cyano-B-keto-sulphones.

325

W i t h i n t h i s a r e a t h e s y n t h e s i s of h y d r o x y a l k y l a t e d n i t r i l e s i s a more s p e c i a l i z e d i n t e r e s t .

2-(l-Hydroxyalkyl)acrylonitriles

were

s y n t h e s i z e d from s a t u r a t e d a l i p h a t i c a l d e h y d e s and a c r y l o n i t r i l e i n a r e a c t i o n c o c a t a l y s e d by t r i - n - b u t y l p h o s p h i n e t r i e t h y l a l u m i n i u m ( S c h e m e 65). 326 r e s u l t e d from base-mediated

and

7-Hydroxyalkene n i t r i l e s

r e a c t i o n s of a-(phenylsulphiny1)-

a c e t o n i t r i l e w i t h a l d e h y d e s a n d k e t o n e s . 327 The s u l p h o n e - t h i o a m i d e

( 5 3 ) was m e t h y l a t e d w i t h d i m e t h y l

s u l p h a t e and t h e n t r e a t e d w i t h p o t a s s i u m c y a n i d e t o a f f o r d t h e a -

cyano-y-phenylsulphonylenamine (68) . 3 2 8 A d d i t i o n s o f sodium s a l t s o f a r y l a c e t o n i t r i l e s t o 1 , l bis(methylthio)-2-phenylsulphonylethene g a v e r e a s o n a b l e y i e l d s of E-3-(methylthio)vinyl n i t r i l e s with near t o t a l s t e r e o s e l e c t i v i t y .329 The a c t i o n of c y a n o t r i m e t h y l a m m o n i u m m e t h y l i d e on d i a l k y l t r i t h i o c a r b o n a t e s a f f o r d e d 3,3bis(alky1thio)acrylonitriles by e l i m i n a t i o n of s u l p h u r f r o m 2,2d i t h i o a l k y l - 3 - c y a n o - e p i s u l p h i d e i n t e r m e d i a t e s .330 6 - K e t o - a c y l c y a n i d e s r e s u l t e d from r e a c t i o n s b e t w e e n e n o x y s i l a n e s a n d a , @ - u n s a t u r a t e d a c y l c y a n i d e s , 331 t h e f o r m e r compounds t h e n b e i n g c o n v e r t e d i n t o 6 - k e t o - c a r b o x y l i c a c i d s . S u b s t a n t i a l i n t e r e s t h a s b e e n shown i n t h e s y n t h e s i s o f af u n c t i o n a l i z e d n i t r i l e s and a v a r i e t y of s u c h d e r i v a t i v e s h a v e been A f a c i l e s y n t h e s i s o f a - a m i n o - n i t r i l e s was d e v e l o p e d , synthesized. w i t h t r e a t m e n t of s i l y l a t e d c y a n o h y d r i n s by a m i n e s o r ammonia g i v i n g g o o d t o e x c e l l e n t y i e l d s of t h e d e s i r e d compounds?32 A s y m m e t r i c s y n t h e s i s of t h e s e c o m p o u n d s i n h i g h o p t i c a l p u r i t y was a l s o p o s s i b l e when c h i r a l a m i n e s were e m p l o y e d , a l t h o u g h c h e m i c a l y i e l d s were somewhat d e c r e a s e d i n t h e s e i n s t a n c e s . 333 A p a r t f r o m t h e a p p l i c a t i o n o f t h e s e compounds t o t h e s y n t h e s i s of a-amino-

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

Y3P

Et3AI BU&H,CHCN

( Y = Bu,

+ CH2=CHZ

Y36CH2eHZ

+

Eu3PCH2CHCN --j Bu,bCH2CCN

I

I

RCH-0-

Z = CN)

+ CHFCCN I

RCH-OH

Scheme 65

HC

NCN

Ph

‘N=C< Ph

E E O Hy M e

-

EEOYc;

CHO

HO

(70)

(71)

TMS

TMS

#k%

Me

3 53

C02Mc

0 Me

0

RCH-OH

+

ByP

General and Synthetic Methods

3 54

a c i d s , c h i r a l a m i n o - n i t r i l e s d e r i v e d from a l d e h y d e s c a n b e m e t a l l a t e d and added t o a l d e h y d e s t o y i e l d , a f t e r d e p r o t e c t i o n , hydroxy-ketones

i n u p t o 9 7 % e n a n t i o m e r i c e x c e s s . 334

Q-

Reaction of

N,g-dimethylaminoacetonitrile w i t h l - b r o m o m e t h y l - 3 , 3 dim,ethylcyclohexene

a l k y l a t i o n and r e a r r a n g e m e n t f a c i l i t a t e d

t h e synthesis of y-cyclocitral nitrate-induced

i n w h i c h t h e l a s t s t e p was a s i l v e r

deprotection i n water-diethyl

e t h e r - T H F . 335

a ,B-

were p r e p a r e d from t h e a p p r o p r i a t e

Unsaturated a-amino-nitriles

a l d e h y d e s by t r e a t m e n t o f t h e i r i m i n e s w i t h t r i m e t h y l s i l y l c y a n i d e . 336

F u r t h e r h y d r o l y s i s a f f o r d e d a ,8 - u n s a t u r a t e d

amino-

acids. Acylated y-amino-nitriles

were o b t a i n e d f r o m a - a m i d o e t h y l a t i o n s

o f s i m p l e n i t r i l e s w i t h 1 - a c y l a z i r i d i n e s . 337 Cyclic a-imino-nitriles

c a n b e o b t a i n e d by r e a c t i o n o f ( 6 9 ) w i t h

1 ,G-dibromoalkanes under phase-transfer

c o n d i t i o n s . 338

@-Nitro-

n i t r i l e s , p r e p a r e d by r e a c t i o n o f n i t r o a l k a n e c a r b a n i o n s w i t h potassium cyanide i n t h e presence of t r i p o t a s s i u m h e x a c y a n o f e r r a t e ( I I I ) , were f o u n d t o r e a c t r e a d i l y w i t h a n i o n s o f o t h e r nitro-compounds

t o yield the corresponding B-nitro-nitriles

i n g o o d t o e x c e l l e n t y i e l d s . 339 The p r e p a r a t i o n o f c y a n o h y d r i n s a n d f u n c t i o n a l i z e d d e r i v a t i v e s t h e r e o f i s a n o t h e r area which r e c e i v e s c o n s i d e r a b l e a t t e n t i o n .

The

c y a n o h y d r i n ( 7 1 ) was p r e p a r e d f r o m a l d e h y d e ( 7 0 ) by a n e x c h a n g e r e a c t i o n w i t h a c e t o n e c y a n o h y d r i n , i n a s y n t h e s i s of g-benzoyl-Lacosamine from e t h y l ( S ) - l a ~ t a t e , T ~ h~e ~r o l e o f t h e c h o i c e o f c a t a l y s t i n r e a c t i o n s of c y a n o t r i m e t h y l s i l a n e h a s a l r e a d y been n o t e d ( s e e Volume 8 , S e c t i o n 7 ) a n d t h i s p o i n t h a s b e e n f u r t h e r e x e m p l i f i e d by t h e p r e p a r a t i o n o f b o t h ( 7 2 ) a n d

(73) f r o m m e t h y l

2,4-dioxopentanoate using, respectively, cyanotrimethylsilane alone and c y a n o t r i m e t h y l s i l a n e p l u s z i n c i o d i d e . New examples of t h e cyanation-cleavage

34’ of c h i r a l acetals have

been r e p o r t e d , 3 4 2 o n e s u c h r e a c t i o n l e a d i n g t o an 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 o f p y r e t h r o i d i n s e c t i c i d e s (Scheme 6 6 ) . o-Methoxy-nitriles

h a v e b e e n p r e p a r e d f r o m d i m e t h y l a c e t a l s by

t r e a t m e n t w i t h b o t h c y a n o t r i m e t h y l s i l a n e i n t h e p r e s e n c e of

e l e c t r o g e n e r a t e d a c i d , 3 4 3 a n d t- b u t y l i s o c y a n i d e - t i t a n i u m t e t r a c h l o r i d e , 344 w h i l s t a - a l k y l - t h i o n i t r i l e s were p r e p a r e d by c y a n a t i o n of d i t h i o a c e t a l 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 a n d 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 (Scheme 6 7 ) .345

The l a t t e r c l a s s

o f compounds have a l s o been p r e p a r e d from a r y l a l d e h y d e s and a r y l t h i o c y a n a t e s u s i n g t r i b u t y l p h o s p h i n e ( S c h e m e 6 7 ) , 346 a n d h a v e f o u n d

355

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

R

X

Nu

p - elimination

.

97-

PhO

I

0

&cN PhO

acidic or method

ii

HO

basic) HO

PhO &CN

~

;0

H' OR

--LA

I

H

iii6"

iv

R =H

,

R =

Reagents : i , TMSCN, T i C I G ; ii, PCCJCH2CL2 ; iii

, p-TSA.H20

H20 ; i v , R C O C l

Scheme 66

R2 1

R2

1

R -C - 0 M e

I

+

1

Me3SiCN

1

4-

R -C-CN

I

OMe

Me3SiOMe

OMe

Ri/oMe + * R<

Bu'NC

R

'OMe

SR

CN

R

RxsR +

R2

,OMe

TI C 1 4

Me3SiCN

Sn C14

RxR

R2 Scheme 67

CN

General and Synthetic Methods

356

an a p p l i c a t i o n i n a s y n t h e s i s of g e r m a c r e n e s which i n v o l v e d a c y c l i z a t i o n of d e p r o t o n a t e d a c y c l i c s u b s t i t u t e d ( p h e n y l t h i o l a c e t o n i t r i l e d e r i v a t i v e s . 347 Cyanomethyl e t h e r s c a n be p r e p a r e d from t r a n s f o r m a t i o n s of t h e c o r r e s p o n d i n g MEM e t h e r s b r o u g h t a b o u t by d i e t h y l a l u m i n i u m The f o r m a t i o n o f c y a n o c a r b o n a t e s a n d t h e i r u s e a s l a t e n t a c y l c a r b a n i o n s h a v e a l s o b e e n r e c o r d e d . 349

cyanide.348

a-Halogeno-nitriles compounds

via

h a v e b e e n made from a r o m a t i c c a r b o n y l

t h e i r s i l y l a t e d cyanohydrins.

T r e a t m e n t of t h e l a t t e r w i t h d i e t h y l a m i n o s u l p h u r t r i f l u o r i d e y i e l d i n g af l u o r o a c e t o n i t r i l e s , 350 w h e r e a s a n a l o g o u s r e a c t i o n s w i t h t i t a n i u m t e t r a c h l o r i d e a f f o r d e d a - c h l o r o - n i t r i l e s . 351 D i r e c t i n t r o d u c t i o n o f c y a n o - g r o u p s i n t o t h e C-2 p o s i t i o n o f q u i n o l i n e s a n d t h e C-I p o s i t i o n o f i s o q u i n o l i n e s h a s b e e n f a c i l i t a t e d by u s e o f t h e i n h e r e n t i n s t a b i l i t y o f N - t o l u e n e - p s u l p h o n y l R e i s s e r t c o m p o u n d s f o r m e d by t h e a c t i o n o f p o t a s s i u m Monoc y a n i d e , t o s y l c h l o r i d e , and DBU i n a b i p h a s i c s y s t e m . 3 5 2 R e i s s e r t compound f o r m a t i o n a t t h e 1 , Z - a n d 3 , 4 - p o s i t i o n s o f t h e q u i n a z o l i n e system h a s a l s o been documented,353 a s h a s t h e u s e of c y a n o t r i m e t h y l s i l a n e i n t h e f o r m a t i o n o f Reissert c o m p o u n d s f r o m f i v e - m e m b e r e d r i n g h e t e r o c y c l e s . 354 The r e a r r a n g e m e n t of E- b e n z y l - 2 - c y a n o - A3-pi p e r i d e i n e s t o t h e c o r r e s p o n d i n g b4-compounds on a l u m i n a s u r f a c e s h a s b e e n e x p l o i t e d i n t h e development of a g e n e r a l r o u t e of 2 , 6 - d i s u b s t i t u t e d p i p e r i d i n e a l k a l o i d s . 3 5 5 9 356 I n t h e a r e a of h e t e r o c y c l i c s y n t h e s i s i n g e n e r a l , cyanation r e a c t i o n s have been w i d e s p r e a d . S y n t h e s i s of 20c y a n o i s o b a c t e r i o c h l o r i n s , 357 2-aryl-4,5-dicyano-imidazoles a n d - i m i d a z o l i n e s ( f r o m d i a m i n o m a l e o n i t r i l e 1, 358 m e t h y l ( 2 chlorothienyl)-2-cyanoacetate, 359 2- a n d 3 - c y a n o p y r r o l e s , 360 c y a n o i n d o l e s , 360 a n d l-alkoxy-2-cyanopyrrolidines, 36 h a v e a l l b e e n reported , along with p r e p a r a t i o n s of halogenated cyanaminomethylene-piperidines a n d - p i p e r i d i n e s . 36z N-Alkyl-N' cyano-El-4-pyridylguanidines h a v e b e e n p r e p a r e d f r o m 4p y r i d y l d i t h i o c a r b a m i c a c i d via e i t h e r E-alkyl-N'-pyridylthioureas o r 4 - p y r i d y l c y a n a m i n o t h i o c a r b a m i c a c i d s . 363 4 - P h e n y l - 4 , 6 , 7 , 8 , 9,lOhexahydrothieno-2,3-&~~1,4]oxazonine 8 - c a r b o n i t r i l e a n d t h e analogous 4-pheny1-6,7,8,9,10,11-hexahydro-4~-thieno~2,~-~1C1,51oxazecine-9-carbonitrile were 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 c y a n o g e n b r o m i d e - i n d u c e d r i n g e x p a n s i o n o f t h e a p p r o p r i a t e w( t e t r a h y d r o t h i e n o [ 3,2-2] p y r i d y 1> a 1k a n - 1 - 0 1 s .364

-

357

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups G l y c o s y l c y a n i d e s have r e s u l t e d from r e a c t i o n s of g l y c o s y l f l u o r i d e s w i t h cyanotrimethylsilane-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 365 d i m e t h y l a l u m i n i u m c y a n i d e , 365 a n d f r o m a d d i t i o n o f diethylaluminium cyanide t o 3-2-acylated

g l y c a l s . 366

Cyano-

c o n t a i n i n g C - g l y c o s i d e s were s i m i l a r l y p r e p a r e d from g l y c o s y l f l u o r i d e s u s i n g e i t h e r trimethylsilylacetonitrile-boron

trifluoride-

d i e t h y l e t h e r a t e o r a c r y l o n i t r i l e p l u s magnesium b r o m i d e - d i e t h y l e t h e r a t e , t r i - n - b u t y l s t a n n a n e , a n d A I B N . 365 T h e s e m e t h o d s a r e i l l u s t r a t e d i n Scheme 6 8 . S y n t h e s e s o f t- b u t y l d i m e t h y l s i l y l c y a n i d e 3 6

and t h e

c o r r e s p o n d i n g i s o c y a n i d e , 368 t r i f l u o r o a c e t o n i t r i l e o x i d e , 369 c h l o r o c y a n o k e t e n e , 370 a n d

l-( c y a n o m e t h y l me than amid ate^^^

have a l l

appeared. On r e a c t i o n o f (74) w i t h e x c e s s c y a n o t r i m e t h y l s i l a n e a n d z i n c iodide i n refluxing dichloromethane,

t h e corresponding 1 , 2 - ~ - 2 , 3 -

anti-1,2-bistrimethylsilyloxy-~-isocyano-compound ( 7 5 )

was

o b t a i n e d , and t h e n c o n v e r t e d i n t o (1~*,2~*,3~*)-3-aminocyclohexane1 ,2 - d i o l

( S c h e m e 6 9 1 . 372 K e t o n e s may be c o n v e r t e d i n t o I-isocyano-I-tosyl-I-alkenes by

t h e a c t i o n of t o s y l m e t h y l i s o c y a n i d e , and t h e n t o t h e c o r r e s p o n d i n g

3-isocyano-3-tosyl-I-alkenes by t r e a t m e n t w i t h p o t a s s i u m t - b u t o x i d e a n d a n a l k y l a t i n g a g e n t . 373 into a,b-unsaturated

C o n v e r s i o n o f t h e l a t t e r compounds

k e t o n e s was a l s o d e s c r i b e d .

L i t h i a t e d 4-

methyloxazoles can be converted i n t o e i t h e r t h e 8trimethylsilyloxy-

or t h e B - a c e t o x y - a c e t o n i t r i l e s

( 7 6 ) . 374

*

f r a g m e n t a t i o n o f t h e o x a z o l i n e ( 7 7 ) l e d t o t h e f o r m a t i o n of t h e 8 -

hydroxyformamido-derivative

( 7 8 ) w h i c h was t o s y l a t e d a n d t r e a t e d

w i t h D B U t o g i v e t h e u n s a t u r a t e d i s o c y a n i d e ( 7 9 ) by i s o m e r i z a t i o n of t h e d i e n e . The i s o c y a n i d e ( 7 9 ) was t h e n e l a b o r a t e d i n t o t h e f u n g a l i s o c y a n i d e a n t i b i o t i c ( 8 0 ) ( S c h e m e 7 0 ) .375 2 , 3 - E p o x y - 2 i s o c y a n o a l k a n o a t e s w e r e s y n t h e s i z e d by t r e a t m e n t o f m e t h y l ai s o c y a n o a c r y l a t e s w i t h e i t h e r H202 i n a q u e o u s s o d i u m h y d r o x i d e or

m-CPBA

a n d s o d i u m m e t h o x i d e i n m e t h a n o l .376

P r e p a r a t i o n of

( a r y l s u l p h o n a m i d o ) m e t h y l i s o c y a n i d e s h a s a l s o b e e n r e p o r t e d . 377 8 N i t r o - and Nitroso-compounds The i m p o r t a n c e o f n i t r o - c o m p o u n d s

as s y n t h e t i c intermediates is

r e f l e c t e d b o t h i n t h e d i v e r s i t y o f s u c h compounds p r e p a r e d , and i n t h e v a r i e t y o f a p p l i c a t i o n s of t h e s e d e r i v a t i v e s h a v e f o u n d . The n i t r a t i o n o f a r e n e s i s a c l a s s i c a l p r o c e d u r e w h i c h s t i l l f i n d s much

General and Synthetic Methods

3 58

2oT i or ii (R=CN) or

iii ( R = c H ~ c Nor ) iv* O C H , ~ ~( R2CH2CH2CN)

PhCH PhCHzO'

OCH2Ph

R2

R'

R3

OCH,Ph

R4

H M e OAc H (3cc-OAc) H Me H OAc ( 3 a - O A c ) CHzOAc H H OAc ( 3 p - O A c ) H H H OAC ( 3 a - o ~ ~ ) Reagents

I,

Me2AICN(1 Z e q u i v ) ,

11

I

M e 3 S i C N ( 2 0 e q u t v ) , B ~ . 0 E t 2 ( 0 . 2 e q u l v),iii,Me3S~C

YN

( 2 . 0 e q u i v 1, EF O E t (0.2 e q u i v 1, i v , H,C=CHCN ( 1 0 e q u l v ) , M g B r . O E t i S e q u i v 1, 3' 2 B u n 3 S n H ( 2 . O e q u i v ) , A I B N ( 0 . l e q u t v 1, PhMe,v, EtALCN ( 1 5 - 3 0 e q u l v )

Scheme 68

(75)

Reagents.

I,

T M S C N ( 4 e q u i v 1 , 1 5 mol 'lo a n h y d r o u s Z n 1 2 ;

MeOH

Scheme 69

11,

K F ( 5 e q u i v );

111,

HCI,

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

359

(76) R': R 2 = Ph R'= Me, R2- H P : Ac or TMS

C02Et

SnBu3

+

NHCHO

(77)

COZEt

JNC&

iiii

LC

C02Et

03SC6H4Me-p

CO 2 Et

&OH

C02Et

NHCHO

$;"

dNCdNC v ii

+

(79)

Reagents

I

, N B S (1.0 equi v 1 ; IiJBun3SnSnBun3 (0.03 e q u IV.

NMe3(5- 1 0 e q u i v ) ; v , D R U ( 1 . 5 - 1 0 e q u i v VII

~

NC

(80)

); iii,T

HF, H20 ; I v, TsCL ( 2.2 equiv 1,

) ; v i , [ * H 6 ] b e n z e n e J 12(0.3 m o \ ' L ) ;

1M- L i O H

S c h e m e 70

General and Synthetic Methods

360

use. Nitronium t e t r a f l u o r o b o r a t e is an e s t a b l i s h e d a g e n t f o r t h e n i t r a t i o n o f a r e n e s a n d a new m e t h o d o f g e n e r a t i n g t h e r e a g e n t e l e c t r o c h e m i c a l l y i n s i t u i n a c e t o n i t r i l e h a s r e c e n t l y been p u b l i s h e d .378

In addition t o t h e preparation of nitro-aromatics

yields superior t o those previously obtained,

a-nitro-ketones

produced from e n o l s i l y l e t h e r s , v i c i n a l n i t r o - a m i d e s

in

were

prepared from

o l e f i n s , and m i x t u r e s o f 1 , 2 - and 1 , Q - n i t r o a c e t a m i d e s p r e p a r e d f r o m 1,3-dienes

(Scheme 7 1 ) . Rates o f n i t r a t i o n o f p o l y c y c l i c a r o m a t i c h y d r o c a r b o n s u s i n g n i t r o g e n d i o x i d e i n s o l u t i o n have been measured and e v i d e n c e s u p p o r t i n g an e l e c t r o n - t r a n s f e r n i t r a t i o n mechanism h a s been d i s c u s s e d . 379 N i t r a t i o n o f p h e n o l s by u s e o f c l a y - s u p p o r t e d f e r r i c n i t r a t e h a s b e e n s t u d i e d , 3 8 0 a n d t h e u s e of c e r i c ammonium n i t r a t e t o e f f e c t n i t r a t i o n of n a p h t h y l e s t e r s w i t h o u t h y d r o l y s i s h a s been reported.381

Good y i e l d s o f 2- a n d 5 - n i t r o - I - n a p h t h y l

nitro-2-naphthyl

a c e t a t e plus I-nitro-2-naphthyl

acetates

8-

b e n z o a t e were

obtained with t h e latter procedure. A range of unsymmetrically s u b s t i t u t e d b i p h e n y l s h a s b e e n s y n t h e s i z e d i n v e r y h i g h y i e l d by a n i n t e r e s t i n g c o u p l i n g of a r y l b o r o n i c a c i d s w i t h a r y l bromides, c a t a l y s e d by z e r o v a l e n t p a l l a d i u m c o m p l e x e s . 382

The n i t r o

s u b s t i t u e n t was t o l e r a t e d i n b o t h s u b s t r a t e s i n a r e a c t i o n w h o s e y i e l d s were i n s e n s i t i v e t o s t e r i c c o n s t r a i n t s (Scheme 7 2 ) . Nitro-substituted

a r y l h y d r o x y l a m i n e s and a l k o x y a m i n e s h a v e been

o z o n i z e d t o y i e l d p o l y n i t r o b e n z e n e s . 383

The h y d r o x y l a m i n e s w e r e

prepared from t h e c o r r e s p o n d i n g b r o m o n i t r o a r e n e s .

In addition,

p o l y n i t r o a n i l i n e s were o x i d i z e d t o t h e f u l l y n i t r a t e d d e r i v a t i v e s by p e r o x y d i s u l p h u r i c a c i d g e n e r a t e d i n s i t u f r o m s u l p h u r t r i o x i d e and o z o n e .

The r a t e o f n u c l e o p h i l i c a r o m a t i c s u b s t i t u t i o n o f

a c t i v a t e d a r e n e s by NO2-

( a n d a l s o o t h e r n u c l e o p h i l e s ) was f o u n d t o

be a c c e l e r a t e d i n t h e p r e s e n c e o f c e r t a i n m a c r o c y c l i c p o l y a m i n e s . 384

The a p p l i c a t i o n o f i p s o - n i t r a t i o n

t o the

p r e p a r a t i o n o f nitrocyclohexa-2,4-dienones h a s c o n t i n u e d t o b e s t u d i e d . 385 386 F u n c t i o n a l i z a t i o n of n i t r o a r e n e s h a s s e r v e d t o w i d e n t h e r a n g e o f t h e s e compounds p r e p a r e d . Additions of Grignard r e a g e n t s t o a r e n e s f o l l o w e d by o x i d a t i o n o f a r y l n i t r o n a t e a d d u c t s b a c k t o nitroarenes (along with preparations of t h e corresponding a r y l nitroso-compounds

by t r e a t m e n t o f t h e a d d u c t s w i t h a c i d ) h a v e b e e n

t h e s u b j e c t of a review.387 A s e r i e s of r e l a t e d p a p e r s c o n c e r n i n g v a r i o u s n u c l e o p h i l i c s u b s t i t u t i o n s of hydrogen p a r a t o a n i t r o - g r o u p i n a r e n e s has been

-

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

NHCOMe

361

NHCOMe

R e a g e n t : i , NOZBF4

, L i BF4 , P t , 50

mA

-2

cm

Scheme 71

Scheme 72

X = leaving g r o u p

, Y-carbanion

s t a b i l i z i n g group

a

, S P h , M e , P r ' Ph , CI f r o m : SPh , C I , S R , Me,NCS,, MeS , P h O , F , Br , I Y f r o m : SPh , S0,Ph S R , C N , C02Me, CO,Bu* ,morpholino R from: H

X

S c h e m e 73

R = substituent

General and Synthetic Methods

362

published. Reactions of chloromethyl phenyl sulphone w i t h nitrocyclohexadienonitronate a n i o n s , 38a p l u s a d d i t i o n s o f a n i o n s d e r i v e d f r o m a l d e h y d e d i t h i o a c e t a l s , 389 a n i o n s o f a - s u b s t i t u t e d n i t r i l e s and e s t e r s 3 ” ( l e a d i n g t o d i r e c t a - c y a n o a l k y l a t i o n a n d aalkoxycarbonylalkylation), a-halogenoalkyl phenyl sulphone a n i o n , 391 ’ 392 a n d t h e a n i o n of p h e n y l t r i t h i o o r t h ~ f o r m a t e ~ ~ ~ ( l e a d i n g t o n u c l e o p h i l i c f o r m y l a t i o n ) w e r e a l l r e p o r t e d (Scheme

73). A m u l t i s t e p r o u t e t o nitro-compounds

f r o m e i t h e r p r i m a r y or

secondary h a l i d e s o r s u l p h o n a t e s h a s been developed i n c o n n e c t i o n with a s y n t h e s i s of tunicamycin.

The m e t h o d i n v o l v e d S N 2

d i s p l a c e m e n t by a z i d e , a n d f o r m a t i o n o f a p h o s p h i n e - i m i n e

followed

by o z o n o l y s i s ( r e q u i r i n g t h r e e e q u i v a l e n t s o f o z o n e ) a t l o w t e m p e r a t u r e . 394

The f o r m a t i o n o f c a r b o n y l c o m p o u n d s a s s i d e

p r o d u c t s i s f a v o u r e d by t h e p r e s e n c e o f a n a - p h e n y l

substituent i n

t h e a z i d e (Scheme 7 4 ) . Reduction of a,b-unsaturated

nitro-compounds

a l s o s e r v e s as an

e f f e c t i v e method f o r t h e p r e p a r a t i o n o f n i t r o a l k a n e d e r i v a t i v e s . B-Phenyl-substituted n i t r o e t h a n e s h a v e b e e n p r e p a r e d by n i t r o olefin reductions using trialkylborohydrides o f n i t r o n a t e s a l t s on s i l i c a

f o l l o w e d by h y d r o l y s i s

by u s e o f sodum b o r o h y d r i d e i n

m e t h a n o l , 396 a n d w i t h 3 , 5 - d i e t h o x y c a r b o n y l - 2

6-dimethyl-I ,4-

d i h y d r o p y r i d i n e - s i l i c a g e l . 397 The C - a l k y l a t i o n o f n i t r o a l k a n e c a r b a n i o n s w i t h I - a l k y l - 2 - t butyl-4-phenyl-(and

2,4-diphenyl-)5,6-dihydrobenzo-[~]-quinoliniurn

c a t i o n s h a s b e e n r e p o r t e d .398

More s p e c i a l i z e d s t u d i e s h a v e

i n c l u d e d s y n t h e s i s o f 1 , 4 - d i n i t r o c u b a n e , 399 p l u s a n e x a m i n a t i o n o f t h e e f f e c t s of sodium n i t r i t e - a c e t i c

a c i d on b o t h a- a n d 8 -

- 400

pinene The p r e p a r a t i o n o f a , b - u n s a t u r a t e d r e p o r t e d on s e v e r a l o c c a s i o n s .

nitro-compounds

h a s been

D i r e c t n i t r a t i o n s of o l e f i n s have

b e e n a c h i e v e d i n t e r a l i a by u s e o f n i t r i c a c i d - a c e t i c ( l e a d i n g t o n i t r a t i o n of an enol-lactone

anhydride

i n t e r m e d i a t e i n an

C/D r i n g s y n t h o n s ) 1401 a n d w i t h cisbis(acetonitri1e)dinitro-(or chloronitro-)palladium(II) u n d e r s t r i c t l y anhydrous c o n d i t i o n s . 4 0 2 N i t r o - o l e f i n s have a l s o r e s u l t e d f r o m t h e c o n d e n s a t i o n o f n i t r o m e t h a n e w i t h some s a l i c y l a l d e h y d e s i n t h e p r e s e n c e of d i m e t h y l a m m o n i u m c h l o r i d e a n d p o t a s s i u m f l u o r i d e i n The a d d i t i o n o f a c e t y l n i t r a t e t o c y c l i c relfuxing toluene.396 o l e f i n s was a l s o i n v e s t i g a t e d . H o w e v e r , 1 , 2 - a d d i t i o n was f o u n d t o be a m i n o r pathway w i t h 1 , 3 - and l y 4 - a d d i t i o n p r o d u c t s

approach t o 1 I-keto-steroid

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

R’N3

+R P

+ R’NO,

dN=PR;%

3 63

+

R;P=O

+ N2

/O

R*CH~N’ ‘0-

J. +R33p0 R’CH=N-OOH

-

RZCH~N=O

+ 2 0, R’CHO

fog+ 0

OC HZC C 1,

-To

K)(= N, X=

‘ I

i’

NO2

R e a g e n t s : i , CHZC12, 3 5 O C ; i i , 0 3 ( 3 . 3 - 4 e q u i v . )

Scheme 74

yx

Y

RX

+

0

NaCo(CO14

Y

4, (CO

II + CO -+ RC-CoKO),

=

KO),

0

R

J.

B-

A4yR 0

Scheme 75

General and Synthetic Methods

364

p r e d o m i n a t i n g . 403 H o m o a l l y l i c n i t r o - d e r i v a t i v e s w e r e o b t a i n e d on s u b s t i t u t i o n o f a l l y l p h e n y l e t h e r s and a l l y l c a r b o n a t e s w i t h n i t r o a c e t a t e s c a t a l y s e d by p a l l a d i u m c o m p l e x e s , p a r t i c u l a r l y [Pd ( d d p e ),I

, 404

and

w e r e a l s o o b t a i n e d f r o m a l l y l a c e t a t e s u s i n g [ P d ( d b a ) 2 1 - P h P and 3 [Pd ( d p p e ) , I , 323 a l t h o u g h i n t h e l a t t e r r e p o r t a - d i a l l y l a t e d n i t r o a c e t a t e s were sometimes o b s e r v e d . The s y n t h e t i c u t i l i t y o f n i t r o e t h e n e s a s M i c h a e l a c c e p t o r s i s w e l l known a n d h a s b e e n e x e m p l i f i e d

i n t h e s y n t h e s i s o f 6-oxo-PGE1,

a n d 6 - 0 x o - P G F 2 , , ~ ~ a~n d a l s o i n a n o v e l c y c l o p e n t e n o n e a n n u l a t i o n . 406 2 ' - N i t r o p r o p - 2 I - e n y l - 2 , 2 - d i m e t h y l p r o p a n o a t e r e p o r t e d t o b e a v e r s a t i l e n i t r o a l l y l a t i n g r e a g e n t . '07

was

The Henry r e a c t i o n was a l l u d e d t o a b o v e i n c o n n e c t i o n w i t h t h e s y n t h e s i s of n i t r o a l k e n e s

nitroaldol products. This useful r e a c t i o n h a s b e e n a c c o m p l i s h e d u n d e r h i g h - p r e s s u r e c o n d i t i o n s , 408 a n d a l s o u n d e r s o l v e n t - f r e e c o n d i t i o n s on s i l i c a g e l . 4 0 9

Products

of t h e l a t t e r method w e r e o x i d i z e d t o l i n e a r a - n i t r o - k e t o n e s

chromium r e a g e n t s u n d e r p h a s e - t r a n s f e r

using

c o n d i o n s .409

E-Nitro-B,y-enones have been s y n t h e s i z e d , i n moderate y i e l d s from 1 , 3 - d i e n e s and a l k y l n i t r o n a t e s under t h e i n f l u e n c e of ( n - a l l y l ) c o b a l t complexes.410

T h i s r e a c t i o n was f o u n d t o b e h i g h l y

sensitive t o s t e r i c constraints with severely hindered substrates g i v i n g r i s e t o p r o d u c t s a r i s i n g from competing dienone f o r m a t i o n (Scheme 7 5 ) .

A l l e n e s were found t o undergo similar r e a c t i o n

a f f o r d i n g 2-[1-(2-nitroethyl)len-2-ones.

2-(2-Nitroethyl)-1,3-dioxolane

was r e p o r t e d t o b e a u s e f u l 3-

oxopropyl a n i o n synthon i n t h e s y n t h e s i s of jasmonoid and p r o s t a n o i d compounds i n t e r m e d i a t e s . 41 1

via

nitro-alcohol

and n i t r o - k e t o n e

I n a similar v e i n t o t h e hydrogen s u b s t i t u t i o n s noted above, s i l y l e n o l e t h e r s a n d s i l y l k e t e n e a c e t a l s were f o u n d t o r e a c t w i t h n i t r o a r e n e s i n the presence of a f l u o r i d e i o n s o u r c e , f o r example

tris(dimethy1amino)sulphonium

difluorotrimethylsiliconate, t o g i v e

a - n i t r o a r y l c a r b o n y l c o m p o u n d s on 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 a d d u c t s w i t h b r o m i n e ,41 w h i l s t 2 - c h l o r o p r o p i o n a t e s w e r e shown t o g i v e good y i e l d s o f 2-(4-nitroaryl)-propionates i n t h e p r e s e n c e o f b a s e . 413 The s y n t h e s i s o f n i t r o - s u b s t i t u t e d c5.4.0. O2

.O3? l o .05'91undecane-8

,1 l - d i o n e s

pentacyclowas r e p o r t e d . 4 1 4

a - N i t r o - c a r b o x y l a t e s w e r e 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 achloro-a-nitro-compounds by t r e a t m e n t w i t h t r i p h e n y l p h o s p h i n e . 4 1 5 S i m i l a r l y , t h e =,a-dichloro-a-nitro-derivatives c o u l d b e

365

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups s e l e c t i v e l y dehalogenated t o g i v e t h e a-chloro-a-nitro-esters. l-Nitro-3-ethylene-l,1,5-trichlorides w e r e o b t a i n e d u p o n c u p r o u s chloride-assisted d i e n e s . 416

a d d i t i o n s of trichloronitromethane a c r o s s 1,3-

A number o f o t h e r h e t e r o a t o m - s u b s t i t u t e d

been r e p o r t e d .

nitro-compounds

have

A d d i t i o n s of t h i o p h e n o l and formaldehyde t o n i t r o -

o l e f i n s w e r e f o u n d t o be c a t a l y s e d by t e t r a m e t h y l g u a n i d i n e ,

and

f o l l o w i n g a c y l a t i o n I-acyloxymethyl-I-nitro-2-phenylthioalkanes were o b t a i n e d .417

T h e s e s u b s t r a t e s were u t i l i z e d i n s y n t h e s e s o f

a l l y l i c actates since tri-n-butyltin

hydride reduction led t o

r e g i o s e l e c t i v e d e n i t r a t i o n and d e s u l p h u r i z a t i o n .

1-Nitroalkane

p h o s p h o n a t e s w e r e o b t a i n e d upon o x i d a t i o n o f t h e c o r r e s p o n d i n g p h o p h o n o x i m e s w i t h F-CPBA

i n d i c h l o r o m e t h a n e . ‘I8

A Henry-type

r e a c t i o n o f p h e n y l t h i o m e t h a n e w i t h some a l d e h y d e s a f f o r d e d a l d o l p r o d u c t s w h i c h g a v e r i s e t o I-nitro-I-phenylthioalkenes o n t r e a t m e n t w i t h m e t h a n e s u l p h o n y l c h l o r i d e . ‘Ig

T h e s e p r o v e d t o be

e x c e l l e n t s u b s t r a t e s f o r Michael s u b s t i t u t i o n s w i t h n u c l e o p h i l e s , t h e s e r e a c t i o n s l e a d i n g u l t i m a t e l y t o t h e f o r m a t i o n of a -

substituted-2-phenyl-thioesters.

I-Aryl

(and a l k y l ) - l - e t h y l t h i o - 2 -

n i t r o - o l e f i n s c a n be p r e p a r e d from a - n i t r o - k e t o n e s the c o r r e s p o n d i n g d i e t h y l t h i o a c e t a l s by t r e a t m e n t w i t h e t h a n e t h i o l i n t h e p r e s e n c e of e i t h e r z i n c c h l o r i d e o r 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 . 420

A d d i t i o n of b e n z e n e s e l e n y l bromide t o v i n y l s i l a n e s i n

t h e p r e s e n c e of H g C 1 2 i n THF a t -78

OC

f o l l o w e d by a d d i t i o n o f

s i l v e r n i t r a t e i n a c e t o n i t r i l e l e d t o t h e i s o l a t i o n o f 1-

selenophenyl-I-trimethylsilyl-2-nitroalkanes.

O x i d a t i o n of

s e l e n i u m a n d s y n - e l i m i n a t i o n o f t h e s e l e n o x i d e f u r n i s h e d 2n i t r o v i n y l s i l a n e s w h i c h were s t u d i e d f u r t h e r i n r e l a t i o n t o t h e i r p o t e n t i a l as D i e l s - A l d e r d i e n o p h i l e s . 42 1 The i n t r o d u c t i o n o f a n i t r o - g r o u p i n t o h e t e r o c y c l i c n u c l e i c o n t i n u e s t o be a matter o f i n t e r e s t .

was p r e p a r e d f r o m 2 - a m i n o - 4 - n i t r o a n i l i n e

The n i t r o b e n z i m i d a z o l e ( 8 1 ) by r e a c t i o n w i t h

N,l-

dimethylchloroformiminium c h l o r i d e i n t o l u e n e , 4 2 2 w i t h r e l a t e d , n i t r o i n d a z o l e s b e i n g 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 2a l k y l n i t r o d i a z o n i u m s a l t s , p o t a s s i u m a c e t a t e a n d 18-crown-6 i n c h l o r o f o r m . 423 I n g e n e r a l i n d a z o l e s b e a r i n g e l e c t r o n - d o n a t i n g o r - w i t h d r a w i n g s u b s t i t u e n t s c o u l d b e p r e p a r e d by t h i s m e t h o d . A n u m b e r of 2 - n i t r o b e n z o f u r a n s

have been s y n t h e s i z e d .

One r o u t e

t o t h e s e compounds i n v o l v e d m e t a l l a t i o n of 3 - a l k y l - I - b e n z o f u r a n s

at

with t-butyl-lithium, transmetallation with trimethylchlorotin, 424 and s u b s e q u e n t r e a c t i o n w i t h t e t r a n i t r o m e t h a n e (Scheme 7 6 ) , C-2

General and Synthetic Methods

3 66

+ R3

BrCH,NO,

i v or 7

3

R4

R4

R e a g e n t s : i, 6utLi (1.lequiv.);

NO2

R

OH

ii,Me3SnCL,(1.1equiv.);

K Z C 0 3 ( 2 . 3 e q u i v . ) , Me2C0, 2 5 O C

iii, C ( N O 2 ) 4 , D M S O ; iv,

; v, K2C03(2.5 e q u i v . ) , OMSO

Scheme 76

5: Amines, Nirriles, and Other Nitrogen-containing Functional Groups

367

while another l e a d i n g t o a wider range of 3-unsubstituted-2nitrobenzo[b]furans required only treatment of t h e appropriate s a l i c y l a d e h y d e d e r i v a t i v e s w i t h p o t a s s i u m c a r b o n a t e i n DMSO (Scheme 7 6 1. 425 The n i t r a t i o n of m e t h y l 2 - f u r o a t e w i t h a c e t y l n i t r a t e h a s b e e n s t u d i e d i n d e t a i l and t h e s t r u c t u r e s of s i x i s o l a t e d i n t e r m e d i a t e a d d u c t s w e r e c h a r a c t e r i z e d .426

N i t r a t i o n i n t h e c a r b o z o l e series

h a s a l s o b e e n s t u d i e d . 427 Novel n i t r o p y r a z i n e s were s y n t h e s i z e d as hypoxic c e l l r a d i o s e n s i t i z e r s ,428 a n d 3 - n i t r o - 5 - a c y l p y r i d i n e s p r e p a r e d by c o n d e n s a t i o n o f n i t r o m a l o n a l d e h y d e w i t h e n a m i n o n e s . 429 The l a t t e r r e p o r t a l s o p r e s e n t e d e v i d e n c e f o r t h e i n t e r m e d i a c y of 3 - c h l o r o - 2 nitroacrolein i n the preparation.

A one-pot

u n s u b s t i t u t e d 3-nitro-2H-chromenes

involving refluxing

s y n t h e s i s of 2-

s a l i c y l a l d e h y d e s w i t h n i t r o e t h a n o l and di-n-butylammonium i n i s o p e n t y l a c e t a t e h a s been d e s c r i b e d (Scheme 7 7 ) . 4 3 0

chloride 6- and 7-

Methoxy-2-aryl-3-nitro-2H-chromenes (3-nitroflavenes) have a l s o been r e p o r t e d , being s y n t h e s i z e d from t h e a p p r o p r i a t e m e t h o x y s a l i c y l a l d e h y d e s and w - n i t r o s t y r e n e s i n t h e p r e s e n c e o f t r i e t h y l a m i n e , 431 t h i s forming p a r t of a n o v e l methoxyflavonol synthesis.

N i t r o g e n d i o x i d e h a s been observed t o n i t r a t e

m e t a l l o p o r p h y r i n s i r r e v e r s i b l y , a n d t h e s i t e of n i t r a t i o n f o u n d t o b e d e p e n d e n t on t h e c o - o r d i n a t e d

Copper ( 1 1 1 , n i c k e l ( I I ) ,

a n d p a l l a d i u m ( I 1 ) c o m p l e x e s were n i t r a t e d a t t h e p o r p h y r i n B p y r r o l i c p o s i t i o n w h e r e a s m i x t u r e s o f p r o d u c t s , i n w h i c h t h e meson i t r a t e d compounds p r e d o m i n a t e d ,

were o b t a i n e d f r o m t h e

m a g n e s i u m ( I I ) , z i n c ( I I ) , c o b a l t ( I I ) , and c h l o r o i r o n ( I I 1 ) porphyrins. The g e n e r a l u t i l i t y o f d e o x y n i t r o - s u g a r s b e on t h e i n c r e a s e .

i n synthesis appears t o

The p r e p a r a t i o n o f I - C - n i t r o g l y c o s y l

chlorides

f r o m p a r t i a l l y p r o t e c t e d 4- o r 5 - h y d r o x y - s u g a r NaOCl under p h a s e - t r a n s f e r

oximes w i t h aqueous c o n d i t i o n s h a s b e e n d e s c r i b e d , 433 a l o n g

w i t h d e t a i l s c o n c e r n i n g s u b s t i t u t i o n s o f t h e s e c o m p o u n d s by w e a k l y b a s i c c a r b a n i o n s . 434 C h a i n e l o n g a t i o n o f t h e d e o x y - n i t r o r i b o s e d e r i v a t i v e ( 8 2 ) by M i c h a e l a d d i t i o n t o t h e v i n y l p h o s p h o n a t e ( 8 3 ) l e d u l t i m a t e l y t o a s y n t h e s i s o f d i e t h y l phosphashikimate ( 8 4 ) . 435 An a t t e m p t e d s y n t h e s i s of ( 8 4 ) 2 p r e p a r a t i o n o f ( 8 5 1 , h o w e v e r , f a i l e d s i n c e t h e l a t t e r compound c o u l d n o t b e p r e p a r e d . However, p r e p a r a t i o n of a s i m i l a r a - n i t r o - a - b u t y r o l a c t o n e

was d e s c r i b e d . 436 N-Nitro-compounds

d e r i v a t i v e (86)

h a v e been p r e p a r e d on a number o f o c c a s i o n s .

General and Synthetic Methods

368

NO2 CH=O

I

'

CH2 f3un22NCH2 Cl-

+ I

CH2

R3

R4

OH

'W"

R3

I

R4

OH

S c h e m e 77

T r O g N o 2

a

HyPOIEtl

HO'

O

x

0

(83)

OH OH

(841

(82)

-.$

H 02C

NO2

(86)

O2NR

0

4 (85 1

369

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

a - A c e t o x y n i t r a m i n e s h a v e b e e n s y n t h e s i z e d , 437 a n d r e l a t e d l - a c o x y c o n v e r t e d i n t o 1 - a l k o x y - I - n i t r a m i n e s .438 N i t r a t i o n o f

N-nitramines

-N-alkyl-2-benzolyhydroxylamines d e r i v a t i v e s . 439

a f f o r d e d t h e c o r r e s p o n d i n g !-nitro-

The s y n t h e s i s o f c y c l i c 1 , 3 - d i n i t r a m i n e s h a s a l s o

b e e n r e p o r t e d . 440 Treatment of N - c h l o r o d i a l k y l a m i n e s w i t h sodium n i t r a t e a f f o r d e d i n o v e r 90% y i e l d , 4 4 1 a n d , f u r t h e r m o r e , i t was

N-nitrosamines

d i s c o v e r e d t h a t s e c o n d a r y a m i n e s c o u l d be c l e a n l y c o n v e r t e d i n t o n i t r o s a m i n e s i n high y i e l d under phase-transfer s o d i u m n i t r i t e a n d N - c h l o r o s u c c i n i m i d e . 442

E-

conditions using

I n a d d i t i o n , sodium

n i t r i t e was u s e d t o c o n v e r t N , N - d i a l k y l s u l p h a m o y l c h l o r i d e s i n t o t h e c o r r e s p o n d i n $ 1 - n i t r o s a m i n 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 s . 443 The s y n t h e s i s o f p h e n o l i c a l k y l b e n z y l n i t r o s a m i n e s h a s b e e n reported.

444

Reaction of n i t r o s y l c h l o r i d e with imines afforded N-alkyl-I-

chloro-N-nitrosoalkylamines w h i c h c o u l d b e s u b s t i t u t e d by c a r b o x y l a t e a n i o n s . 445 a-Chloroketoximes nitrosoalkenes,

were e v a l u a t e d as p r e c u r s o r s o f

s i n c e t h e s e compounds h a v e been p o s t u l a t e d a s d i e n e

"'

Ncomponents of i n t r a m o l e c u l a r Diels-Alder-type r e a c t i o n . N i t r o s o - d i p e p t i d e s h a v e b e e n s y n t h e s i z e d , 447 a n d l a r g e - s c a l e preparations of t h e carcinogens E-nitrosodiethanolamine

a n d a-

ureidodimethylnitrosamine h a v e b e e n r e p o r t e d . 448 Thionitroso-compounds were r e p o r t e d t o a r i s e from t r e a t m e n t of some s t e r i c a l l y h i n d e r e d E - n i t r o s a m i d e s and f r o m b e n z i s o t h i a z o l e r i n g

w i t h L a w e s s o n ' s r e a g e n t , 449

fragmentation^.^^'

Thiophene

y l i d e s w e r e shown t o r e a c t r e a d i l y w i t h e l e c t r o n - r i c h t o y i e l d a d d u c t s f o r m e d by e x t r u s i o n o f a c y l thionitroso-compounds

S,g-

dienophiles

and s u l p h o n y l -

which were r e a d i l y t r a p p e d as t h e i r

corresponding Diels-Alder

or e n e - r e a c t i o n a d d u c t s .45

N i t r o s y l s a l t s have been g e n e r a t e d i n anhydrous c h l o r i n a t e d hydrocarbons

via

c l e a v a g e of a l k y l n i t r i t e s w i t h t r i m e t h y l s i l y l

h a l i d e s2. 5 - 2

9 Hydrazines and Hydrazones H y d r a z i n e s h a v e b e e n p r e p a r e d from azo-compounds

by t h e a c t i o n of

p h e n y l t e l l u r o l ( g e n e r a t e d i n s i t u from phenyl-lithium

and m e t a l l i c . t e l l u r i u m i n THF) i n t h e p r e s e n c e o f t r i f l u o r o a c e t i c a c i d . 4 5 3 (Amines c o u l d a l s o b e p r e p a r e d from n i t r o - c o m p o u n d s u s i n g t h e r e a g e n t , and t h e r e a g e n t s p e c i f i c i t y compared w i t h t h a t o f h y d r o g e n

General and Synthetic Methods

370

N i t r o s a m i n e s w e r e c o n v e r t e d i n t o h y d r a z i n e s on

telluride.)

r e a c t i o n i n a q u e o u s s o l u t i o n w i t h t i t a n i u m t r i c h l o r i d e , f o l l o w e d by t r e a t m e n t w i t h p o t a s s i u m h y d r o x i d e . 454

P r e p a r a t i o n s of c a r b o x y l i c

a c i d h y d r a z i d e s have a l s o been r e p o r t e d .455 Cupric chloride-catalysed

a d d i t i o n s of a r y l a m i n e s t o

a r y l a z o a l k e n e s l e d t o t h e f o r m a t i o n of some 2a r y l a m i n o h y d r a z o n e s . 456

An i n d e p e n d e n t

s y n - and a n t i - p h e n y l h y d r a z o n e s d e p e n d e n t . 457

s t u d y showed t h a t r a t i o s o f

o b t a i n e d i n t h i s manner were s o l v e n t

Improved c o n d i t i o n s f o r t h e p r e p a r a t i o n and

r e d u c t i v e c l e a v a g e o f s t e r o i d a l k e t o n e t o s y l h y d r a z o n e s , by s i m p l e m o d i f i c a t i o n s of l i t e r a t u r e m e t h o d s , were r e p o r t e d . 458 S y n t h e s e s of t h i o a c y l h y d r a z ~ n e s a~n~d ~ s y m m e t r i c a l h y d r a z o n y l ~ u l p h i d e s ~ h~a 'v e b e e n p u b l i s h e d . A s y m m e t r i c s y n t h e s e s i n v o l v i n g m e t a l l a t i o n of c h i r a l h y d r a z o n e s h a v e been mentioned above;32 t h e u s e of s u c h r e a c t i o n s i n enantioselective a-alkylations 46 1

of a c y c l i c k e t o n e s h a s been f u r t h e r

described.

10 H y d r o x y l a m i n e s a n d H y d r o x a m i c

Acids

Hydroxylamines have been o b t a i n e d from a c y l nitro-compounds

by

t r e a t m e n t w i t h e x c e s s h y d r a z i n e h y d r a t e and s m a l l amounts o f Raney N i c k e l W-4

i n ethanol-dichloromethane

(1:l)

at 0

OC.

462

Unstable

hydroxylamines were c o n v e r t e d i n s i t u i n t o t h e i r r e s p e c t i v e benzoylhydroxamic a c i d s . P h e n o x y a m i n e s w e r e p r e p a r e d by t h e a c t i o n of s o d i u m h y d r i d e a n d on p h e n o l s i n a n e x c h a n g e r e a c t i o n . 4 6 3

2,4-dinitrophenoxyamine

Y i e l d s w e r e s e n s i t i v e t o t h e pKa of t h e p h e n o l i n a m a n n e r consistent with a competitive bimolecular decomposition involving the reagent.

2,4-Dinitro-

a n d 2,4,6-trinitro-chlorobenzenes were

shown t o r e a c t w i t h a l k o x y a m i n e h y d r o c h l o r i d e s , or f r e e 464 t r i t y l o x y a m i n e , t o y i e l d 2-alkyl-PJ-arylhydroxylamines.

0-Benzoylhydroxylamines have been i s o l a t e d f o l l o w i n g t r e a t m e n t of p r i m a r y a m i n e s a l t s w i t h p o t a s s i u m c a r b o n a t e and d i b e n z o y l p e r o x i d e . 465

The p r e p a r a t i o n of h y d r o x a m i c e s t e r - c h l o r i d e s

h a s been r e p o r t e d

a n d t h e r e a c t i o n s of t h e s e s p e c i e s w i t h v a r i o u s n u c l e o p h i l e s h a v e b e e n e x a m i n e d . 466

The s y n t h e s i s of t h i o h y d r o x a m i c a c i d s h a s

evolved i n t o an i m p o r t a n t area owing t o t h e i r a b i l i t y t o c h e l a t e m e t a l i o n s a n d t h e d i v e r s i t y of r e a c t i o n s w h i c h t h e y u n d e r g o . Conversion of hydroxamic a c i d s i n t o t h e i r 2 - a c e t a t e s ,

f o l l o w e d by

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

37 1

OH C-CI

R e a g e n t s : i , NaHC03 L a w e s s o n 's

+

CHZCLZ or

I

HN-R-

CHCL3 ; ii, A c C I , NaHC03

reagent ; i v , NaOH

Scheme 7 8

I

4 Arnolecular sieves;iii,

372

General and Synthetic Methods

t h i a t i o n w i t h Lawesson's r e a g e n t and d e a c e t y l a t i o n , allowed d e v e l o p m e n t of a c o n v e n i e n t s y n t h e t i c m e t h o d f o r t h e s e c o m p o u n d s (Scheme 7 8 ) . 4 6 7 11 Imines,

I m i n i u m S a l t s , a n d R e l a t e d Compounds

D i r e c t l i t h i a t i o n of i m i n e s i n t h e p r e s e n c e o f p h e n a n t h r e n e a s a h y d r o g e n a c c e p t o r h a s been d e m o n s t r a t e d , 468 and a l k y l a t i o n s o f t h e r e s u l t a n t a n i o n s have been d e s c r i b e d . P e r h a p s t h e most i m p o r t a n t r o u t e s t o i m i n e s a r e t h e i r p r e p a r a t i o n s f r o m c a r b o n y l compounds a n d t h e i r d e r i v a t i v e s .

An

&

s i t u oxime t o i m i n e r e d u c t i o n u s i n g t r i - n - b u t y l p h o s p h i n e - d i p h e n y l d i s u l p h i d e h a s b e e n a l l u d e d t o a b o v e 2 8 a n d t h e same r e a g e n t s w e r e f o u n d t o r e d u c e n i t r o a l k a n e s t o i m i n e s some o f w h i c h c o u l d b e t r a p p e d i n t r a m o l e c u l a r l y t o y i e l d p y r r o l e s . 469 4 , 5 - D i h y d r o - 2 -

methyl-5-methyleneaminofuran-3-carboxylates were s y n t h e s i z e d f r o m a c e t o a c e t a t e s and n i t r o - o l e f i n s

(Michael a d d i t i o n ) p l u s a c t i v e

m e t h y l e n e c o m p o u n d s .470 An i n t e r e s t i n g m u l t i s t e p c o n v e r s i o n o f h i n d e r e d k e t o n e s i n t o imines h a s been d i s c l o s e d .

Formation of t h e ketoxime from t h e

c a r b o n y l compounds was f o l l o w e d by t r e a t m e n t w i t h n i t r o s y l c h l o r i d e The l a t t e r compound c o u l d

t o yield t h e corresponding N-nitrimine.

b e t r e a t e d w i t h ammonia t o y i e l d t h e i m i n e ( S c h e m e 7 9 ) . 4 7 1 Imines r e s u l t e d from r e a c t i o n s of carbodi-imides

and t u n g s t e n -

c a r b e n e complexes i n a m e t a t h e s i s r e a c t i o n i n v o l v i n g four-membered r i n g i n t e r m e d i a t e s .472 The i m p o r t a n c e o f p h o s p h i n e - i m i n e s

h a s b e e n i n c r e a s e d by t h e i r

u s e i n t h e a f o r e m e n t i o n e d s y n t h e s i s of n i t r o - c o m p o n d s . 394 s y n t h e s i s of phosphine t o s y l i m i n e s h a s been s t u d i e d .

The

Thus f o r

e x a m p l e t r i p h e n y l p h o s p h i n e was a d d e d t o a s o l u t i o n of t e t r a b u t y l a m m o n i u m 1-chlorotoluene-p-sulphonamide ( p r e p a r e d from chloramine-T t r i h y d r a t e and tetrabutylammonium c h l o r i d e ) i n methylene c h l o r i d e t o g i v e (N-toluene-p-sulphonyl-P,P,Pt r i p h e n y l p h o s p h i n e i m i d e . 473-

Related methods l e a d i n g t o

t o s y l i m i n o p h o s p h o r i c a c i d esters and t o s y l s u l p h i n i l i m i n e s (from t h i o e t h e r s ) were a l s o d e s c r i b e d .

[(Trimethylsilyl)methylliminotriphenylphosphorane, p r e p a r e d i n s i t u f r o m [(trimethylsilyl)methyl]azide and t r i p h e n y l p h o s p h i n e , g a v e r i s e t o ( t r i m e t h y l s i l y 1 ) m e t h y l i m i n e s on r e a c t i o n w i t h c a r b o n y l c o m p o u n d s i n a one-pot

procedure.474

lithio-species

Copper(1) a l d i m i n e s g e n e r a t e d from t h e

( p r e p a r e d by a d d i t i o n o f

an

alkyl-lithium

t o an

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

R\ C=N

R\

O ,H

C=N

R’

R’

+ / 0N ‘O

-

373

R’

\0

H,N-NO,

R\ ,C=NH

-k

&--

R Reagents : i , N O C l , T H F ; ii, NH,

R\

N,O,

C=N R’

,T H F Schema 79

/

Ph

Ph

+ A?-CH=N-A?

Ph C HZr;Et3Cc

I

Ar2-NH-CH-CH-N=C,

PhCHZ-N=ch I, S c h e m e 80

Br2 , C s F

R\

RCZN

-t CSBr,

,C=N

F

‘or

S c h e m e 81

ph

0

Ph

374

General and Synthetic Methods

i s o c y a n i d e ) added c o n j u g a t i v e l y t o ~ , B - u n s a t u r a t e d c a r b o n y l compounds t o g i v e 4 - i m i n o - k e t o n e s .475 T h e s e c o u l d be f u r t h e r elaborated i n t o 1,4-diketones.

1 - I m i n o a l k y l i m i d a z o l e s were

obtained i n a novel r e a c t i o n of cuprous imidazolide with n i t r i l e s and a l k y l h a l i d e s .476 Reactions of phenyl g l y o x a l with primary amines has allowed t h e s y n t h e s i s o f some m o n o i m i n e s . 4 7 7

N-Cyanamines a n d N-,N'-dicyanoquinone

d i - i m i n e s have been

r e p o r t e d , 478 a s h a v e g - c y a n ~ r n e t h y l m e t h a n i m i d a t e a~n~d~ r e l a t e d F a c i l e s y n t h e s e s of s u b s t i t u t e d N-methylenecarboxanides

and

alkyl-N-methylenecarbamates h a v e b e e n a c h i e v e d by r e a c t i o n o f t r i m e t h y l s i l y l i m i n e s w i t h t h e a p p r o p r i a t e a c y l c h l o r i d e s or chloroformates.

N-

480

A d d i t i o n s o f N-diphenylmethylenebenzylamine t o S c h i f f b a s e s l e d t o f o r m a t i o n o f 1,2-diarylethane-1,2-diamine d e r i v a t i v e s ( S c h e m e

8 0 ) .481 A new i m i n a t i o n p r o c e d u r e f o r g - a l k y l - p y r i d i n i u m a n d -quinolinium salts h a s been p r e s e n t e d , t h i s i n v o l v i n g o x i d a t i o n o f t h e a p p r o p r i a t e s u b s t r a t e s with potassium permanganate i n l i q u i d ammonia. 482 R e p o r t s c o n c e r n i n g a n u m b e r o f o t h e r h e t e r o a t o m s u b s t i t u t e d imines have appeared. B e n z i m i d o y l c h l o r i d e s and d i a l k y l phosphites afforded benzimidoyl phosphites i n t h e presence of t r i e t h y l a m i n e h y d r o c h l o r i d e . On h e a t i n g i n v a c u o t h e s e compounds r e a r r a n g e d t o t h e c o r r e s p o n d i n g b e n z i m i d o y l a n d - s u l p h o x i d e s were p h o s p h o n a t e s . 483 a - I m i n o - s u l p h e n a t e s o b t a i n e d via e l e c t r o p h i l i c a l k y l a t i o n o f t h i o a m i d e - 2 - o x i d e s ( a m i n o s u l p h i n e s ) . 484 An e f f i c i e n t s y n t h e s i s o f N - b r o m o p e r h a l o g e n o I-alkanimines h a s been d e s c r i b e d . The m e t h o d i n v o l v e d a d d i t i o n o f p e r f l u o r o a l k y l n i t r i l e s and bromine t o a c t i v a t e d caesium f l u o r i d e (Scheme 81 ) .485 The b r o m o i m i n e s c o u l d b e p h o t o l y s e d t o y i e l d perfluoroalkyl azines. Sulphenimines ( t h i o - o x i m e s ) have been s y n t h e s i z e d e l e c t r o c h e m i c a l l y i n a m a g n e s i u m b r o m i d e - p r o m o t e d r e a c t i o n o f aa m i n o - a l k a n o a t e s w i t h d i a l k y l o r d i a r y 1 s u l p h i d e s . 486 (2Silyloxyalky1)dialkylphosphine s i l y l i m i n e s w e r e p r e p a r e d f r o m o x i r a n e s and N , N - d i s i l y l p h o s p h i n o u s a c i d a m i d e s i n t h e p r e s e n c e o f N - S u b s t i t u t e d and N - u n s u b s t i t u t e d s u l p h o x i m e s z i n c bromide. were o b t a i n e d on t r e a t m e n t o f s u l p h i l i m i n e s w i t h p o t a s s i u m s u p e r o x i d e a n d 18-crown-6 i n d i c h l o r o m e t h a n e . 4 8 8 I t h a s b e e n shown t h a t , u n d e r c e r t a i n c o n d i t i o n s , c h i r a l 1 , 2 -

"'

375

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups d i m i n e s ( d i a z a d i e n e s ) d e r i v e d from amines w i t h s e c o n d a r y or t e r t i a r y a - c a r b o n s c a n b e s y n t h e s i z e d .489 S y n t h e s i s o f 1 , 3 d i c h l o r o - 1 ,5-diazapenta-l , 4 - d i e n e s , 4 g 0 1 , 2 - h y d r o x y i m i n o i m i n e s ( o b t a i n e d by d i r e c t n i t r o s a t i o n o f B-thio-8-amino-a,B-unsaturated k e t o n e s w i t h n i t r o s y l c h l o r i d e ) ,49

and N,"-bis(2-

h y d r o x y b e n z y l i d e n e ) a r y l m e t h a n e d i a m i r ~ e sh~a ~ v e~ a l l b e e n r e p o r t e d . B e t a i n e s r e s u l t e d f r o m a l k y l a t i o n s o f i m i n e s b e a r i n g a n ahydroxy-group with a l k y l or a l l y 1 i o d i d e s . 493 12 Oximes

The f o r m a t i o n o f a n o x i m e i s a c l a s s i c a l m e a n s o f d e r i v a t i z i n g a c a r b o n y l compound.

I t h a s r e c e n t l y b e e n shown t h a t m e t h o d s f o r

s u c h t r a n s f o r m a t i o n c a n be a p p l i e d t o a - k e t o - c a r b o x y l a t e An e x a m p l e was t h e s y n t h e s i s o f a - a l k o x i m i n o - c a r b o x y l i c moderate y i e l d s from a - k e t o - t h i o l i c alkoxyamines. 4g4

systems. acids in

a c i d e s t e r s and

The method was a p p l i e d t o t h e s y n t h e s i s of

a m i n o p y r i d i n e - c o n t a i n i n g B-lactams. C a t a l y t i c n i t r o s a t i o n o f s t y r e n e d e r i v a t i v e s may become a u s e f u l m e t h o d for t h e s y n t h e s i s of o x i m e s a f t e r t h e r e p o r t t h a t t h e c a t a l y s t [ C O ( D M G H ) ~ ( ~ ~ p) rCo ~ m ]o t e d r e g i o s e l e c t i v e h y d r o n i t r o s a t i o n o f s t y r e n e i t s e l f t o g i v e a c e t o p h e n o n e ~ x i m e . ~ 'O~x i m e s h a v e a l s o b e e n o b t a i n e d i n g o o d y i e l d s from a c t i v e m e t h y l e n e c o m p o u n d s by t r e a t m e n t with. s i l v e r n i t r a t e - t h i o n y l

c h l o r i d e ( S c h e m e 8 2 1. 4 9 6

M e t a l l a t i o n s o f o x i m e s , and i n p a r t i c u l a r a l d o x i m e s , h a v e b e e n t h e s u b j e c t of s e v e r a l s t u d i e s , a n d i t was d i s c l o s e d t h a t d e p r o t o n a t i o n o f a l d o x i m e s c a n be a c h i e v e d and t h e r e s u l t i n g a n i o n s a l k y l a t e d i n h i g h y i e l d .497

Anions g e n e r a t e d from t r i a l k y l s i l y l

e t h e r s of methyl ketoximes were found t o undergo r e a r r a n g e m e n t w i t h 1,4-migration

of t h e s i l y l m o i e t y , t h i s b e i n g r e v e r s e d i n a t h e r m a l

1 , Q - m i g r a t i o n of s i l i c o n from c a r b o n t o oxygen

.498

I n t h e s t e r o i d s e r i e s , 6 - n i t r o - o l e f i n d e r i v a t i v e s underwent f a c i l e r e a c t i o n s w i t h ammonia, m e t h a n o l , and z i n c t o a f f o r d e x c l u s i v e l y t h e o x i m e s o f t h e c o r r e s p o n d i n g 6 - k e t o - s t e r o i d s .499

It

was a l r e a d y known t h a t c o n j u g a t e a d d i t i o n o f G r i g n a r d r e a g e n t s t o

nitroarenes afforded I-alkylnitronates into alkylated nitro16).

t h a t c o u l d be t r a n s f o r m e d

and n i t r o s o - a r e n e s

( s e e , f o r example, r e f .

T r e a t m e n t o f s u c h n i t r o n a t e a d d u c t s d e r i v e d f r o m l-methoxy-4-

nitronaphthalene with hexamethylphosphoric t r i a m i d e l e d t o t h e i s o l a t i o n of 2 - a l k y l - 4 - m e t h o x y - l - ( 2 H ) - n a p h t h a l e n o n e ammonium c h l o r i d e work-up

oximes w i t h an

a n d f o r m a t i o n o f l-alkyl-2,3-dihydro-l,4-

376

General and Synthetic Methods

Et02CCH2C02Et

-h E tO,CCH(

PhCH20COCH2C02CHfh

NO,)CO,Et

NOH PhCH,OCOCCO,CH II ,Ph

R e a g e n t s : i 1 CF SO C L ( l . O e q u i v . 1 , A g N 0 3 ( 1 . 1 e q u i v . ) , K O B u t (1.0 e q u i v . ) ;

3

2

ii,SOClz

( l . O e q u i v . ) , AgN03 (1.1 e q u i v . )

Scheme 82

OMe

4- RMgX

-b

OMe

OMc

N

/OH

0 Reagents : i , THF; i i , P ( N M e 3 ) 3

Scheme 8 3

377

5: Am in es, Nitriles, and 0t her Nitrogen -conta ining Fun ctiona1 Groups naphthoquinone-I-oximes

i f a work-up

c h l o r i d e was u s e d ( S c h e m e 8 3 ) .

with methanolic hydrogen

16

P y r r o l e d e r i v a t i v e s r e a c t e d with benzenesulphonyl c a r b o n i t r i l e o x i d e g e n e r a t e d i n s i t u t o g i v e 2- a n d 3 - s u l p h o n y l o x i m e s

without

i s o l a b l e oxazoline i n t e r m e d i a t e s , whereas f u r a n r e a c t e d t o g i v e an o x a z o l i n e from w h i c h t h e c o r r e s p o n d i n g 2 - s u l p h o n y l o x i m e was obtained after a ~ i d i f i c a t i o n . ~ " 3-Substituted indoles afforded t h e corresponding 2-sulphonyloximes,

w h i l s t 3-sulphonyl

o x i m e s were

obtained otherwise.

N-Aroyl-N-t-butylhydroxylamines a f f o r d e d 0chlorosulphonylbenzohydroximoyl c h l o r i d e s on t r e a t m e n t w i t h t h i o n y l chloride.

F u r t h e r t r e a t m e n t with e t h a n o l a f f o r d e d benzohydroximoyl

chlorides.501

I-Imidazoyl(hydroximino)acetate was u n e x p e c t e d l y

i s o l a t e d as t h e major p r o d u c t of a r e a c t i o n between 3-ethoxy-2-

.

n i t r o p r o p e n o a t e and i m i d a z o l e 502 G l y o x i m e s were o b t a i n e d f r o m 4 - a c y l - n 2 - o x a z o l - 5 - o n e s

acyl-4-halogeno-A2-oxazol-5-ones

via

4-

by s e q u e n t i a l 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 s u l p h u r y l c h l o r i d e , h y d r o g e n c h l o r i d e i n

acetic a c i d , sodium b i c a r b o n a t e , and f i n a l l y hydroxylamine h y d r o c h l o r i d e . 503 a - C h l o r o s i l y l k e t o x i m e s h a v e b e e n u s e d a s n i t r o s o a l k e n e p r e c u r s o r s .504 13 Carbodi-imides M i x t u r e s of t w o c a r b o d i - i m i d e s a f f o r d e d u n s y m m e t r i c a l d i - i m i d e s by a m e t a t h e s i s i n v o l v i n g t h e c a r b e n e complex p e n t a c a r b o n y l ( i s o p r o p y 1 i s 0 c y a n i d e ) t u n g s t e n (Scheme 8 4 ) . 4 7 2 The r e a c t i o n o f [(trimethylsilyl)methyl]iminotriphenylphosphorane with e i t h e r i s o c y a n a t e s o r i s o t h i o c y a n a t e s y i e l d e d t h e (Scheme c o r r e s p o n d i n g N'-[(trimethylsilyl)methyl]carbodi-imides 85).474 14 A z i d e s and Diazo-compounds The a b i l i t y o f a z i d e a n i o n t o a c t as a n u c l e o p h i l e i n d i s p l a c e m e n t r e a c t i o n s o f e p o x i d e s , s u l p h o n a t e s , and o t h e r a c t i v a t e d e s t e r s h a s ensured t h a t its use i n t h e s y n t h e s i s of amino-sugars a l c o h o l s h a s been prominent ( s e e a b o v e ) .

and amino-

That a z i d e anion i s

p a r t i c u l a r l y s u i t a b l e f o r displacement of secondary t r i f l a t e s i n b o t h f u r a n o i d a n d p y r a n o i d s u g a r s was e x e m p l i f i e d by s y n t h e s e s o f l-~-methyl-3-azido-2,3-dideoxy-b-ribofuranose, 5 0 5 a n d 1 , 6 - a n h y d r o -

General and Synthetic Methods

378

4- C,H,,N=C

(CO &W=C =NPr

(

=NC 6Hll

I c 0 I5W-coNPr

I

I

//C-N, ‘6”llN

C6Hll

ti

-I- C6H,,N=C= N P r ’

(CO)5W=C=NC6Hl,

ti

+ Pr I N = C =

hN ‘6*11 (CO,,W-C’ I I 4C-N Pr ‘N ‘Pr i

N Pr’

1.r (CO15W=C =N Pr ’

+

C6H,,N=C=NPr1

Scheme 84

Me3SiCH, N, -tPh,P

+Me3SiCH2N=PP h,

-

Me3Si CH,N=C=N

R

R = Ph, c y c l o h e x y l , or E t Reagents : i , R N C O ; i i , R N C S

g$8& Scheme 85

y&EzMe \

N CO2Et

(87)

‘

N

‘ C02Et

(88)

N

\

H

N

H

(major 1 Clavicipitic a c i d (minor)

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

379

2-azido-2-deoxy- B-D-glucopyranose derivatives. 506

Use of tosylazide as the ‘+NH2I synthon for the electrophilic amination of arenes and organometallics has been mentioned , 4 1 and treatment of the substituted malonate derivative (87) with sodium hydride and tosylazide in sequence led to the azide ( 8 8 ) , this being a key intermediate in an approach to clavicipitic acids.507 An overall synthesis of primary azides from terminal alkenes resulted from treatment of trialkylboranes with lead tetra-acetate and azidotrimethylsilane (cf. ref. 306) .508 Although hydrazoic acid is normally considered to be unreactive towards alkenes, it has been demonstrated that Lewis acids, particularly titanium tetrachloride, promote addition of the acid to phenylethylenes or 1,1-disubstituted ethylenes but not to monosubstituted 01efins.~” Under these new conditions enoxysilanes gave I-silyloxyazides. It was also found that tertiary ally1 and benzyl alcohols also afforded azides in the presence of titanium tetrachloride, whilst primary alcohols did not. Treatment of a-hydroxyacetophenone dimethyl acetals with azidotrimethylsilane and tin tetrachloride has led to the isolation of both 1-alkoxy-2-silyloxyazides and tetrazoles (&. isolation of intermediate azides was not achieved), the product obtained being dependent on the nature of the aryl substituent (Scheme 86).510 Clay-supported ferric nitrate has been used to convert hydrazines to azides , the latter compounds also being elaborated into iminophosphoranes . 5 1 2 A good deal of research has been directed towards the synthesis of unsaturated azides. Propargylic azides have been synthesized from the corresponding bromides 2 direct displacement with azide anion, and also by addition of the anion to the unsubstituted terminus of allenyl iodide .51 Ultrasonication has facilitated synthesis of propargyl azide, azidoacetonitrile, and primary allylic azides from the corresponding activated halides and aqueous sodium a ~ i d e . ~ ’ These ~ conditions were applied to the synthesis of azido-butadienes via displacement of propargylic bromides with azide anion followed by migration of azides to the vinylic position via an allylic rearrangement (Scheme 87). 5 1 5 Bimolecular nucleophilic substitution of halogenonitroarenes by azide anion was shown to be catalysed by a macrocyclic ammonium salt (cf. ref. 384) .516 2- and 4-Azido-4H-2-chromenes were prepared by addition of excess sodium azide to benzopyrylium salts.517 Ferrier-type

General and Synthetic Methods

380

OMe

I

X=H x-CI

OMt

I

C

- CH,OH

X X=Me or OMe TMSN3- S n C I 4

,":N

1

CH ,OH

X

Scheme 8 6

BrCH,-CEC-

CH, B r

4' [ N3CH2-

4N~CH,-C~C-CH,N,

C,C-CH,Brl

Reagents : i , NaN,

, EtOH

; ii,

C6H6 ; i i i , NaN3 MeOH; i v , TMGN, Scheme 87

sulpholane

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

381

carbocyclization of azido hex-5-enopyranosides of D-arabino configuration led to chiral cyclohexane precursors of a m i n o ~ y c l i t o l s . ~In ~ ~ a second study of such reactions, attempted carbocyclization of 3-azido-4-~-benzoyl-2,4,6-trideoxy-B-D-erythrohex-5-enopyranoside led to a cyclohexenone (89) elimination of the elements of hydrazoic acid .51 The a-D-threo-isomer reacted without such elimination (Scheme 88). Addition of p-tosyl azide and various other aryl azides to nbutyl-lithium-treated THF at low temperature was found to result in the formation of diazomethane. The enolate of acetaldehyde (resulting from cycloreversion of THF in the presence of n-butyllithium) was identified as the agent responsible for initiation of the azide decomposition. 520 2,2,2-Trifluorodiazoethane was prepared and used as a protecting reagent for sulphonic acids since, unlike other diazo-compounds, it did not react with carboxylic acids to form esters.521 The reagent was prepared by direct nitrosation of 2,2,2-trifluoroethylamine followed by washing the ethereal solution of the reagent with aqueous citric acid to remove unreacted started amine. 7-Substituted l-diazo-2-norbornanones were synthesized on chromatography of the monotosylhydrazones, derived from the corresponding a-diketones, on basic alumina. 522 The discovery that a-diazoacetates can be transformed into the corresponding silylenol ethers on reaction with trialkylsilyl trifluoromethanesulphonates facilitated an approach to chiral thienamycin analogue precursors (Scheme 89 .523 Efficient preparations of a-diazo-0-ketophosphonates and adiazophosphonoacetates have been described,524 and their intramolecular cyclopropanation reactions studied. The former compounds also underwent photo-induced Wolff rearrangements to yield substituted phosphonoacetates 525 Electrophilic diazolalkane substitution of (diazomethyllphosphoryl compounds with pyrylium tetrafluoroborate afforded 4diazo(phosphony1 )methyl-4g-pyrans. 526 Thermolysis of 3,3diazidotetrahydroquinoline-2,4-diones afforded 3diazidotetrahydroquinoline-2,4-diones 527 Alkyl nitrites and tralkylsilyl halides can be used to generate nitrosyl halides which can react with N,N-bis(trimethylsilyl)amines to generate diazonium salts with the exclusion of a nucleophile from the reaction mixture (since the by-product of the reaction is hexamethyldisiloxane). This method was termed

.

.

General and Synthetic Methods

382

elimination

OH

OH

RO--Q--OMe Ok

-&

N, R = PhCO or

+

P h C H zRO O..o

Bz 0

PhC HzOO

OAc N3

R e a g e n t s . I , Me3SiS02CF3, E t 3 N ;

1 1 )

PhCHzo.:Q RO, X

PhCH20’

Scheme 89

N3

X=H,R=H

Bu~M~~SIO E tT3 ~ N ;, i i i , ZnC12,

OAc

IV,

1N-NaOH

5: Amines, Nitriles, and Other Nitrogen-containing Functiona 1 Groups

383

'azodesilylation I . 528 15 Azo- and Azoxy-compounds Azo-compounds were reported to result from oxidations of arylamines with bis(2,2'-bipyridyl )copper(II) ~ermanganate.~~' Both 2- and pdiaminobenzenes and 0- and p-aminophenols were oxidized by potassium superoxide to yield diaminoazobenzenes and dihydroxyazobenzenes respectively. 530 Hydrazines may also be converted into azo-compounds. Alkyl- and aryl-hydrazines were oxidized with 2-(trifluoromethy1)benzenesulphonyl peroxide and then treated with base to afford azocompounds which yield products typical of the expected degradation pathways.531 Ethylenediamine has been examined as a potential agent for the reduction of nitroarenes to azo-compounds. At 150 OC meta- and para-substituted nitroarenes afforded symmetrical azo-compounds in good yield, although the corresponding ortho-isomers were inert. 5 32 On the other hand 0- and p-nitroanilines were not reduced whereas the meta-isomer was, affording a mixture of 3,3'-diaminoazobenzene and 1,3-diaminobenzene. 2- and p-Halogenonitrobenzenes were substituted by the reagent. Nitrobenzene was reduced with hexamethyldisilane and a catalytic quantity of tetrabutylammonium fluoride in THF to give azobenzene in 84% yield.533 In an analogous reaction azoxybenzene gave azobenzene in 95% yield. ortho-Substituted nitrobenzenes gave the corresponding azoxycompounds under these conditions, with the exception of 0nitrobenzaldehyde, bulky ortho-substituents preventing further reduction of the azoxy- to azo-compounds. 4-Nitropyridine !-oxide afforded the azoxy-compound (90) which precipitated from the reaction solvent ~,~-dimethylimidazoline-2-one,in 52% yield, plus the azo-compounds (91) and (92) which were recovered in 26% and 12% yields respectively from the mother liquors. Reduction of 4nitropyridines to azo-compounds (or to amines) by lithium aluminium hydride was also described.534 The reaction products that were obtained were dependent on the nature of the pyridine substituents. Substituted 21-hydroxyacetophenone-4-bromophenylhydrazones were readily oxygenated in the presence of Co(Sa1pr) in ethanol to give good yields of 2- (4-bromophenylazo )-I , 3-benzodioxoles. 535 A mechanistic rationale was offered in explanation of the formation of azo-compounds in sodium hydride-induced decompositions of ethyl-

General and Synthetic Methods

384

N- (2-azidoaryl )carbonates. 536 16 Isocyanates, Thiocyanates, Isothiocyanates, and Selenocyanates Isocyanates have been obtained from perfluoroaklyl hydroxamic acids of I-silyloxy-I-silyloximes derived from the former compounds by treatment with hexamethyldisilazane in acetonitrile .537 Hindered aryl isocyanates may be prepared in exchange reactions between hindered anilines and phenyl isocyanate. 538 a-Arylazo-isocyanates and -isothiocyanates were obtained after the respective oxidations of 2,5,5-trisubstituted 1,2,4-triazolidin-3-ones and -3-thiones with potassium permanganate .539

via pyrolysis -

Reactions of (93) with alkyl halides in the presence of potassium carbonate afforded alkyl thiocyanates. 540 Benzylic thiocyanates were obtained on reaction of the corresponding nitrates with potassium thiocyanate. 54 The benzylic nitrates were formed by the action of ceric ammonium nitrate on methyl benzenes, followed by neutralization of excess nitric acid with potassium carbonate. Hydroxide, cyano, azide, and piperidine nucleophiles were used in place of thiocyanate to afford a useful method for benzylic functionalization. As a reagent system isothiocyanatotributyltin-iodine was found to be superior to potassium thiocyanate-iodine f o r the preparation of v&-iodothiocyanates from olefins .542 The tin reagent was prepared from chlorotributylstannane and potassium thiocyanate. An aryl silane was substituted with thiocyanate by means of thiocyanogen and aluminium chloride. 543 Thiocyanate-subst itur;ed pyridines and pyridinopyrimidines have also been reported .544 As well as hindered isocyanates, hindered aryl isothiocyanates have been prepared in a metathesis between hindered amines and aryl isothiocyanates .545 Glycosyl isothiocyanates have been prepared from anomeric halides and potassium thiocyanate in a polar aprotic solvent in the presence of a tetralkylammonium salt .546 The reaction of cycloalkanones with silicon tetraisothiocyanate in the presence of zinc isothiocyanate or bis(trimethylsilyl!sulphate/tri-n-butyltin fluoride afforded I-cycloalkenyl isothiocyanates in good yield under mild conditions.547 Chloro(pheny1thio)methyltrimethylsilane reacted with lead

385

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups t h i o c y a n a t e t o a f f o r d phenylthio(trimethylsily1)methyl

i s o t h i o c y a n a t e w h i c h was u s e d t o p r e p a r e o x a z o l e s on r e a c t i o n w i t h a r y l aldehydes i n t h e presence of f l u o r i d e ion.54g

3-(3- a n d 4-Methylselenopheny1)alanines were p r e p a r e d by a d d i t i o n o f m e t h y l G r i g n a r d t o acetamido(cyanoselenobenzy1)m a l o n a t e s f o l l o w e d by h y d r o l y s i s .549

The l a t t e r c o m p o u n d s were

f o r m e d by d i a z o t i z a t i o n o f t h e a p p r o p r i a t e a r o m a t i c a m i n e s f o l l o w e d by d e c o m p o s i t i o n o f t h e i n t e r m e d i a t e s i n t h e p r e s e n c e o f a q u e o u s selenocyanate salts.

17 N i t r o n e s N i t r o n e s h a v e b e e n o b t a i n e d from s e c o n d a r y a m i n e s i n o n e s t e p by s o d i u m t u n g s t a t e o x i d a t i o n w i t h h y d r o g e n p e r o x i d e .5501551 ZN i t r o n e s w e r e s y n t h e s i z e d u n d e r m i l d c o n d i t i o n s by a d d i t i o n o f alkoxyamines t o aldehydes i n t h e p r e s e n c e of sodium b i c a r b o n a t e and

C-Aryl-N-( I - c a r b o x y a l k y l ) - n i t r o n e s were o r by c o n d e n s a t i o n o f a - h y d r o x y i m i n o - c a r b o x y l i c a c i d s w i t h a r o m a t i c a l d e h y d e s .553 N-

calcium c h l o r i d e . 552

p r e p a r e d by a l k y l a t i o n of a r o m a t i c 2 - a l d o x i m e s

Carbamoyl-nitrones

w e r e p r e p a r e d by l o w - t e m p e r a t u r e

addition of

i s o c y a n a t e s t o a l d o x i m e s . 554 The r e a r r a n g e m e n t s of 2-chloro-2-nitrosofenchane a n d 2 - c h l o r o - 2 nitrosocamphane t o c h l o r o n i t r o n e s have been r e c o r d e d , 555 and r e c e n t s y n t h e t i c a p p l i c a t i o n s of n i t r o n e s have been reviewed.556

18 N i t r a t e s a n d N i t r i t e s A s w e l l a s t h e a f o r e m e n t i o n e d r e p o r t o f b e n z y l i c n i t r a t i o n by c e r i c

ammonium n i t r a t e , 54

photochemical r e a c t i o n of t o l u e n e s with ceric

ammonium n i t r a t e i n a c e t o n i t r i l e h a s b e e n r e p o r t e d t o e f f e c t t h e same t r a n s f o r m a t i o n i n g o o d y i e l d s u n d e r m i l d c o n d i t i o n s . 557 Both t h i o n y l c h l o r i d e - n i t r a t e

a n d t h i o n y l n i t r a t e were e f f e c t i v e

r e a g e n t s f o r t h e n i t r a t i o n of p h e n o l s and a l c o h o l s .

The f i r s t

r e a g e n t proved s u i t a b l e f o r n i t r a t i o n of primary a l c o h o l s i n c a r b o h y d r a t e m o l e c u l e s , w h e r e a s t h e s e c o n d r e a g e n t was s u f f i c i e n t l y r e a c t i v e t o n i t r a t e secondary hydroxy-groups primary.

i n addition t o

T h u s s e l e c t i v e n i t r a t i o n s o f r i b o n u c l e o s i d e s were

f a c i l i t a t e d .496 A c h r o m a t o g r a p h i c medium c o n s i s t i n g of 30% s i l v e r n i t r a t e -

n e u t r a l a l u m i n a p r o v e d a means f o r c o n v e r t i n g 5 - h a l o g e n o p e n t - 2 - e n e s i n t o 1 - c y c l o p r o p y l e t h y l n i t r a t e . 558

3 86

General and Synthetic Methods References

1

2 3 4 5

6

7 8 9 I0

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 48

A.Ono, M.Hiroi, and K.Shimazaki, Chem. Ind., 1984, 75. F.D.Bellamy, and K.Ou, Tetrahedron Lett., 1984, 25, 839. T.Imamoto, T.Mita, and M.Yokoyama, J. Chem. SOC., Chem. Commun., 1984, 163. S-Ranganathan, R.Kumar, and V.Maniktala, Tetrahedron, 1984, 40, 1167. N.Ohira, Y.Aso, T.Otsubo, and F.Ogura, Chem. Lett., 1984, 853. S.Rm and R.E.Ehrenkaufer, Tetrahedron Lett., 1984, 25, 3415. G.Belot, S.Desjardins, and J.Lessard, Tetrahedron Lett., 1984, 25, 5347. E.Baralt and N.Holy, J. Org. Chem., 1984, 2626. P.K.Santra and C.R.Saha, Chem. Ind., 1984, 713. Y.Watanabe, T.Ohta, Y.Tsuji, T.Hiyoshi, and Y.Tsuji, Bull. Chem. SOC., Jpn., 1984, 57, 2440. 1434. M.Kijima, Y.Nmbu, T.Endo, and M.Okawara, J. Org. Chem., 1984, R.I.Duclos,Jr., J.S.Tung, and H.Rapoport, J. Org. Chem., 1984, 5243. 2657. P.J.Harrington and L.S.Hegedus, J. Org. Chem., 1984, S.J.Danishefsky and G.B.Phillips, Tetrahedron Lett., 1984, 25, 3159. B.M.Adger and R.G.Young, Tetrahedron Lett., 1984, 25, 5219. C.Bartoli, M.BOSCO, G.Cantagelli, and R.Dalpozzo, Tetrahedron, 1984, 40, 3437. M.S.Mourad, R.S.Varma, and G.W.Kabalka, Synth. Commun., 1984, 1099. H.Ohmori, S.Furusako, M.Kashu, C.Ueda, and M.Masui, Chem. Pharm. Bull., 1984, 32, 3345. R.J.Bergeron and J.R.Garlich, Synthesis, 1984, 782. A.Pfaltz and S.Anwar, Tetrahedron Lett., 1984, 25, 2977. D.O.Alonso Garrido, G.Buldain, and B.Frydman, J. Org. Chem., 1984, 2021. H.Suzuki and K.Takaoka, Chem. Lett., 1984, 1733. B.T.Golding and C.Howes, J. Chem. Res. ( S ) , 1984, 1. W. R-Meindl, E.von Angerer, H.Schonenberger, and G. Ruckdeschel, J. Med. Chem., 1984, 3, 1 1 1 1 . H.Brunner and R.Becker, Angew. Chem., Int. Ed. Engl., 1984, 3,222. S. R.Landor , Y .M.Chan, O.O.Sonola, and A. R.Tatchell, J. Chern. SOC., Perkin Trans. 1 , 1984, 493. J.Ipaktschi, Chem. Ber., 1984, 117,856. D.H. R .Barton, W.B.Motherwel1, E.S.Simon, and S.Z.Zard, J. Chem. Soc., Chern. Commun., 1984, 337. M.D.Menachery and M.P.Cava, Can. J. Chem., 1984, 62, 2583. J.G.Cannon, J.P.Pease, R.L.Hamer, M.Iihan, R.K.Bhatnagar, and J.P.Long, J. Med. Chem., 1984, 3, 186. D.P.Curran, J.F.Bri.11, and D.M.Rakiewicz, J. Org. Chem., 1984, 9, 1654. D.Enders and H.Schubert, Angew. Chem., Int. Ed. Engl., 1984, 23, 365. G.Knupp and A.W.Frahm, Chem. Ber., 1984, l l J ,2076. R.O.Hutchins and W.-Y.Su, Tetrahedron Lett., 1984, 25, 695. R.G.McR.Wright, Synthesis, 1984, 1058. N.C.Hung and E.Bisagni, Synthesis, 1984, 765. T.L.Capson and C.D.Poulter, Tetrahedron Lett., 1984, 25, 3515. S.Kajigaeshi, T-Nakagawa, S.Fujisaki, A.Nishida, and M.Noguchi, Chem. Lett., 1984, 713. G.M.Loudon, A.S. Radakrishna, M. R.Almond, J.K.Blodgett, and R.H.Boutin, 4272. J. Org. Chem., 1984, 9, R.H.Boutin and G.M.Loudon, J. Org. Chem., 1984, 2, 4277. J.N.Reed and V-Snieckus, Tetrahedron Lett., 1984, 25, 5505. H.J.Bestmann and G.Wolfe1, Angew. Chem., Int. Ed. Engl., 1984, 23, 53. T.Morimoto , T.Takahashi, and M. Sekiya , J. Chem . SOC , Chem. Commun . , 1984, 794. P.Beak, A.Basha, and B.Kokko, J. Am. Chem. SOC., 1984, 106, 1511. R.A.Hagopian, M.J.Thieren, and J.R.Murdoch, J. Am. C h e m x o c . , 1984, 5733. P.A.Harland, P.Hodge, W.Maughan, and E.Wildsmith, Synthesis, 1984, 941. J.O.Osby, M.G.Martin, and B.Ganem, Tetrahedron Lett., 1984, 25, 2093. H.J.Bestmann and G.Wolfe1, Chem. Ber., 1984, I J , 1250.

9,

9,

2, 2,

c,

2,

-

.

106,

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups 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 84 85 86 87 88 89 90 91 92

387

K.Gewald, O.Calderon, H-Schafer, and U.Hain, Liebigs Ann, Chem., 1984, 1390. S.F.Campbel1, J.O.Hardstone, and M.J. Palmer, Tetrahedron Lett., 1984, 25, 4813. N.Calo, N.Desideri, F.Manna, and M.L.Stein, Gazz. Chim. Ital., 1984, 211. K.Gewald and U.Hain, Synthesis, 1984, 62. H.Hartmann and J.Liebscher, Synthesis, 1984, 275. H.Hartmann and J.Liebscher, Synthesis, 1984, 276. J.Wrube1 and R.Mayer, Z. Chem., 1984, 2, 245. A.Alberola, A.M.Gonzalez, M.A.Laguna, and F.J. Pulido, J. Org. Chem., 1984, 49, 3423. P.Verschave, J.Vekemans, and G.Hoornaert, Tetrahedron, 1984, 5, 2395. C.-K-Kim, P.A.Zielinski, and C.A.Maggiulli, J. Org. Chem., 1984, 9, 5247. P.H.Boyle and R.J.Lockhart, Tetrahedron, 1984, 5, 879. A-Katoh, Y.(Xnote, and C-Kashima, Chem. Pharm. Bull., 1984, 32, 2942. Y.Yamamoto and Y.Morita, Chem. Pharm. Bull., 1984, 32, 2 9 5 7 7 B.Singh, Heterocycles, 1984, 22, 1801. W.H.Pirkle and C.J.Welch, J. Org. Chem., 1984, 138. W.H.Pirkle and M.H.Hyun, J. Org. Chem., 1984, 3043. Y-Watanabe, Y.Tsuji, H.Ige, Y.Oshugi, and T.Ohta, J. Org. Chem., 1984, 9, 3359. J-Barluenga, A.M.Bayon, and G.Asensio, J. Chem. SOC., Chem. Commun., 1984, 1334. J.Barluenga, A.M.Bayon, and G.Asensio, J. Chem. SOC., Chem. Commun., 1984, 427. L.E.Overman and R.M.Burk. Tetrahedron Lett.. 1984. 25. 1615. -S.E.Fry and N.J. Pienta, i. Org. Chem., 1984: 68%; Y.Tsuji, J.Shida, R.Takeuchi, and Y.Watanabe, Chem. Lett., 1984, 889. G.J.Atwel1 and W.A.Denny, Synthesis, 1984, 1032. J.E.Nordlander, M.J.Payne, M.A.Balk, J.L.Gress, F.D.Harris, J.S.Lane, R.F.Lewe, S.E.Marshal1, D.Nagy, and D.J.Rachlin, J. Org. Chem., 1984, 133. R.Sundaramoorthi, C.Marazano, J.-L.Fourrey, and B.C.Das, Tetrahedron Lett., 1984, 25, 3191. R.Okazaki and N.Tokitoh, J. Chem. Soc., Chem. Commun., 1984, 192. T.Santa, N.Miyata, and M.Hirobe, Chem. Pharm. B u l l . , 1984, 32, 1252. R.A.Olof son, J.T.Martz, J.-P. Senet , M.Piteau, and T-Malfroot, J. Org. Chem., 1984, 2081. S.R.Landor, O.O.Sonola, and A.R.Tatchel1, Bull. Chem. SOC. Jpn., 1984, 57, 1658. C Alvarez-Ibarra , 0.Ar jona , R. Perez ,- Ossorio , A. Perez-Rubalcaba , M.L.Quiroga, and F.Valdes, J. Chem. Res. ( S ) , 1984, 224. M.Yamashita, M.Kadokura, and R.Suemitsu, Bull. Chem. Sac. Jpn., 1984, 57, 3359. A.Pelter, R.M.Rosser and S.Mills, J. Chem. SOC., Perkin Trans. 1 , 1984, 717. H.R.Morales, M.Perez-Juarez, L.Cuellar, L.Mendoza, H.Fernandez, and R.Contreras, Synth. Commun., 1984, 2, 1213. Y.Yamamoto, W.Ito, and K.Maruyama, J. Chem. SOC., Chem. Commun., 1984, 1004. Y.Yamamoto, T.Komatsu, and K.Maruyama, J. Am. Chem. SOC., 1984, 106,5031. M.Wada, Y.Sakurai, and K.-y.Akiba, Tetrahedron Lett., 1984, 25, 1079. M.Wada, Y-Sakurai, and K.-y.Akiba, Tetrahedron Lett., 1984, 2, 1083. G.W .Kabalka, G.W .McCollum, and S.A.Kunda, J. Org. Chem., 1984, 9, 1656. J.Barluenga, C. Jimenez, C.Najera, and M. Yus, J. Chem. SOC., Perkin Trans. 1, 1984, 721. L.S.Hegedus, Tetrahedron, 1984, 5, 2415. T.Sakamoto, H.Nagata, Y.Kondo, K.Sato, and H. Yamanaka, Chem. Pharm. B u l l . , 1984, 32, 4866. E.J.Corey and A.W.Gross, Tetrahedron Lett., 1984, 25, 491. A.P.Krapcho, K.J.Shaw, J.J.Landi,Jr., and D.J.Phinney, J. Org. Chem., 1984, 49, 5253. M.Matsuoka, K.Takagi, H.Tajima, K.Ueda, and T.Kitao, J. Chem. SOC., Perkin Trans. 1 , 1984, 1297.

114,

2, 9,

5,

9,

2,

.

-

General and Synthetic Methods

388 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

128 129 130 131 132 133 134 135 136 137 138

14,

J.F.Pilichowski and J.C.Gramain, Synth. Commun., 1984, 1247. S.A.G.F.Angelino, A.van Veldhuizen, D.J.Buurman, and H.C.van der Plas, Tetrahedron, 1984, 5, 433. H-Vorbruggen and K.Krolikiewicz, Chem. Ber., 1984, 117, 1523. M.Y.Shandala, M.T.Ayoub, and M.J.Mohammad, J. Heterocycl. Chem., 1984, 21, 1753. M.V.Jovanovic, Heterocycles, 1984, 22, 1105. J.L.LaMattina and C.J.Mularski, Tetrahedron Lett ., 1984, 25, 2957. W.H.Pirkle, C.J.Welch, G.S.Mahler, A. I.Meyers, L.M. Fuentes, and M.Boes, J. Org. Chem., 1984, 2504. D.Seebach and M.A.Syfrig, Angew. Chem., Int. Ed. Engl., 1984, 23, 248. A.I.Meyers, L.M.Fuentes, and Y.Kubota, Tetrahedron, 1984, 1361. A.I.Meyers, M.Boes and D.A.Dickman, Angew. Chem., Int. Ed. Engl., 1984, 3, 458. P.D.Edwards and A.I.Meyers, Tetrahedron Lett., 1984, 25, 939. A.I.Meyers, P.D.Edwards, W.F.Rieker, and T.R.Bailey, J. Am. Chem. SOC., 1984, 106,3270. P.Beak and W.J.Zajde1, J. Am. Chem. SOC., 1984, 1010. A.I.Meyet-s and M.F.Loewe, Tetrahedron Lett., 1984, 25, 2641. H.Loibner, A.Pruckner, and A.Stutz, Tetrahedron Lett., 1984, 5, 2535. R.S.Davison, A.M.Pate1, and A-Safdar, J. Chem. Res. (S), 1984, 88. K.Haga, M.Oohashi, and R.Kaneko, Bull. Chem. SOC. Jpn., 1984, 57, 1586. P.Beak, W.J.Zajde1, and D.B.Reitz, Chem. Rew., 1984, 84, 471. H.Ahlbrecht and H.Dollinger, Tetrahedron Lett., 1984,-2, 1353. N.Tokitoh and R.Okazaki, Tetrahedron Lett., 1984, 2, 4677. N.Tokitoh and R.Okazaki, Chem. Lett., 1984, 1937. R.S.Sagitullin, B.A.Lugovik, G.P.Shkil', and I.M.Zhelyaeva, Khim. Geterotsikl. Soedin., 1984, 417. S-Araki, S.-i.Manabe, and Y.Batsugan, Bull. Chem. SOC. Jpn., 1984, 57, 1433. K.B.Sloan and K.G.Siver, Tetrahedron, 1984, 5, 3997. M.Iovu and M.Iqba1, Rev. Roum. Chem., 1984, 9, 333. K.Matsumoto, S.Hashimoto, Y.Ikemi, and S.Otani, Heterocycles, 1984, 22, 1417. R.A.Moss, D.P.Cox, and H.Tomioka, Tetrahedron Lett., 1984, 25, 1023. H.Natsugari, R.R.Whittle, and S.M.Weinreb, J. Am. Chem. SOC., 1984, 106, 7867. R.Imwinkelried and D.Seebach, Helv. Chim. Acta, 1984, 67, 1496. S.-H.Jung and H.Kohn, Tetrahedron Lett., 1984, 25, 399M.J.Fazio, J. Org. Chem., 1984, 4889. J.M.Mellor and N.M.Smith, J. Chem. SOC., Perkin Trans. 1 , 1984, 2927. G.Fraenke1 and P-Pramanik, J. Org. Chem., 1984, 1316. S.J.Schmolka and H.Zimmer, Synthesis, 1984, 29. D.O.Alonso Garrido, G.Buldian, and B.Frydman, J. O r K . Chem., 1984, 2619. S.F.Malysheva, B.A.Trofimov, E.P.Vyalykh, L.V.Shertstyannikova, and M.V.Sigalov, Zh. Org. Khim., 1984, 20, 968. N.L.J.M.Broekhof and A.van der Gen, Recl.: J. R. Neth. Chem. SOC., 1984, 103, 305. E.J.M.Broekhof, P.van Elburg, and A.van der Gen, Recl.: J. R. Neth. Chem. SOC., 1984, 103,312. N.L.J.M.Broekhof, P.van Elburg, D.J.Hoff and A.van der Gen, Recl.: J. R. Neth. Chern. SOC., 1984, 103,317. R.Carlson and A.Nilsson, Acta Chem. Scand., Ser. B, 1984, 38, 49. A.Nilsson and R.Carlson, Acta Chem. Scand., Ser. B, 1984, 38, 523. S.-S.P.Chou and C.-W.Chu, 3. Chin. Chem. SOC., 1984, 31, 351. K. Tani , T. Yamagata, S.Akutagawa , H-Kumobayashi, T. Taketomi, H. Takaya , A.Miyashita, R.Noyori, and S.Otsuka, J. Am. Chem. SOC., 1984, 106,5208. D.H.Wadsworth, M. R.Detty, B. J .Murray, C.H .Weidnet-, and N. F.Haley , J. Org. Chem., 1984, 49, 2676. E.M.Gordon, J.Pluscec, N.G.Delaney, S.Natarajan, and J.Sundeen, Tetrahedron Lett., 1984, 25, 3277. P.K.Tripathy and A.K.Mukerjee, Synthesis, 1984, 418.

2,

g,

2,

9,

2,

2,

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups 139 140 141 142 143 144 145 146 147 148 149

O.Tsuge, S.Kanemasa, H.Suga, and K-Matsuda, Heterocycles, 1984, 22, 1955. M.Basato, B.Corain, M.Cofler, A.C.Veronese, and G.Zanotti, J. Chem. SOC., Chem. Commun., 1984, 1593. M. Basato , B. Corain , A. C .Veronese , F D Angeli , G .Valle , and G. Zanotti, 4696. J. Org. Chem., 1984, S.A.Okecha, Chem. Ind., 1984, 414. F-Effenberger and T.Beisswenger, Chem. Ber., 1984, 117,1497. J.-P.Picard, A.Aziz-Elyusufi, R.Calas, J.DunoguCs, and N.Duffaut.

9,

154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184

.

G.Himbert and W.Brunn. Chem. Ber.. D.E.Orr, Synthesis, 198C.A.Maggiulli and P.-W.Tang, Org. Prep. Proced. Int., 1984, 16, 31. N.K.Markova, Yu. A. Zaichenko, A. E. Tsil 'ko, and I.A.Mar etina, Zh. Org. Khim., 1984. 20. 962. S.-I.MFahashi, T.Tsumiyama, and Y.Mitsue, Chem. Lett ., 1984, 1419. D.Badoux and R.Fuks, Bull. SOC. Chem. Belg., 1984, 2, 1009. J.C.Combret, J.-L.Klein, and M.Mouslouhouddine, Synthesis, 1984, 493. J.C.Combret, J.-L.Klein, and M.Mouslouhouddine, Tetrahedron Lett ., 1984, 25, 3449. H.Mohrle and H.W.Reinhardt, Arch. Pharm. (Weinheim, Ger.), 1984, 317, 1017. H.Mohrle and H.W.Reinhardt, Pharmazie., 1984, 2, 384. W.Klop, P.A.A.Klusener, and L.Brandsma, Recl. : J. R. Neth. Chem. SOC., 1984, 103, 27. J-Barluenga, F.Aznar, and R.Liz, Synthesis, 1984, 304. T.Yamamoto and M.Muraoka, Org. Prep. Proced. Int., 1984, 130. N.Neumann and P.Boldt, Chem. Ber., 1984, 117,1935. F.Babudri, F.Ciminale, and S.Florio, Tetrahedron Lett., 1984, 3, 205'1 H.J.Gordon, J.C.Martin, and H.McNab, J. Chem. SOC., Perkin Trans, 1 , 1984. 21 29. P.W.Hickmott, Tetrahedron, 1984, 5, 2989. M. Nikaido , R. Aslanian , F. Scavo , P. Helquist , B. Akermark , and J.-E.Backvall , J. Org. Chem., 1984, 2, 4738. V.Nair and T.S.Jahnke, Synthesis, 1984, 424. L.Stamp and H.tom Dieck, J. Organometal. Chem., 1984, 277, 297. C.Germon, A.Alexakis, and J.F.Normant, Synthesis, 1984, 40. C.Germon, A.Alexakis, and J.F.Normant, Bull. SOC. Chim. Fr., 1984, 11, 377. J.E.Fankhauser , R.M.Peevey, and P.B.Hopkins, Tetrahedron Lett., 1984, 2, 15. J. N.Fitzner , R.G.Shea, J. E.Fankhauser , and P. B. Hopkins, Synth. Commun., 1984, 605. R.G.Shea, J. N-Fitzner, J. E.Fankhauser , and P.B.Hopkins, J. Org. Chem., 1984, 49, 3647. R.Tamura, K-Hayashi, Y.Kai, and D.Oda, Tetrahedron Lett., 1984, 215, 4437. 1.Shimizu and J.Tsuji, Chem. Lett., 1984, 233. A.Laurent, P.Mison, A.Nafti, R.B.Cheikh, and R.Chaabouni, J. Chem. Res. ( S ) , 1984, 354. I.A.McDonald, J. M.Lacoste, P.Bey, J.Wagner , M.Zreika, and M.G .Palfreyman, J. Am. Chem. S O C . , 1984, 106,3354. S.Florio, E.Epifani, G.Ingrosso, and R-Sgarra, Tetrahedron, 1984, 5, 5089. F.Babudri, G.Bartoli, F.Ciminale, S.Florio, and C.Ingrosso, Tetrahedron Lett., 1984, 25, 2047. P.Casara, K.Jund, and P.Bey, Tetrahedron Lett., 1984, 25, 1891. A.L.Castelhano and A.Krantz, J. Am. Chem. SOC., 1984, 106,1877. H.Hiemstra, H.P.Fortgens, and W.N.Speckamp, Tetrahedron Lett., 1984, 25, 31 15. R.J. P. Corriu, V. Huynh, and J. E.Moreau, Tetrahedron Lett., 1984, 2, 1887. G.Himbert and M.Feuste1, J. Chem. Res. (S), 1984, 240. M.Feuste1 and G.Himbert, Liebigs Ann. Chem., 1984, 586. A.Malik, N.Afza, M.ROOSZ, and W.Voelter, J. Chem. SOC., Chem. Commun., 1984, 1530. G.W.J.Fleet, M.J.Gough, and P.W.Smith, Tetrahedron Lett., 1984, 25, 1853. I

150 151 152 153

389

,

16,

.

fi,

-

-

General and Synthetic Methods

390

185 G.W.J.Fleet, P.W.Smith, S.V.Evans, and L.E.Fellows, J. Chem. SOC., Chem, Commun . , 1984, 1240. 186 G.W. J. Fleet, M. J. Gough, and T.K.M.Shing , Tetrahedron Lett., 1984, 25, 4029. 187 A.Malik, N.Afza, and W.Voelter, Liebigs Ann. Chern., 1984, 636. 188 N. Yasuda, H. Tsut sumi , and T.Takaya, Chem . Lett. , 1984, 1201 . 189 R.C.Bernotas and B.Ganem, Tetrahedron Lett ., 1984, 25, 165. 190 K. C.Nicolaou, A.Chucholowski, R.E.Dolle, and J. L.Randal1, J. Chem. SOC., Chem. Commun., 1984, 1155. 19 1 H.Knorr, R.Reich1, W.Traunecker, F-Knappen, and K.Brandt, Arzneim.-Forsch., 1984, 34(II), 1709. 192 M.Fujita and T.Hiyama, J. Am. Chem. SOC., 1984, 106,4629. 193 K.Narasaka and Y.Ukaji, Chem. Lett., 1984, 147. 194 K.Narasaka, S.Yamazaki, and Y.Ukaji, Chem. Lett., 1984, 2065. 195 K.Harada, and S.Shiono, Bull. Chem. SOC. Jpn., 1984, 57, 1040. 196 K.Soai, H.Oyamada, and M.Takase, Bull. Chem. SOC. Jpn., 1984, 57, 2327. 197 J.-P.Quintard, B-Ellissondo, and B-Jousseaume, Synthesis, 1984, 495. 198 A.P.Kozikowski, Acc. Chem. Res., 1984, 17, 410. 40.. 199 A.P.Kozikowski, Y-Y .Chen. B. C.Wann. - . and 2.-B.Xu. Tetrahedron., 1984. , 2345. 200 V.Jager and R.Schohe, Tetrahedron, 1984, fi, 2199. 201 M.J.Fray and E.J.Thomas, Tetrahedron, 1984, 5, 673. 202 W.R.Roush and A.E.Walts, J. Am. Chern. SOC., 1984, *,721. 203 R.L.Funk and G.L.Bolton, J. Org. Chem., 1984, 2,5021. 204 A.Toy and W.J.Thompson, Tetrahedron Lett., 1984, 25, 3533. 205 H-Takahashi, Y.Chida, T.Suzuki, H.Onishi, and S.Yanaura, Chem. Pharm. Bull., 1984, g , 2714. 206 Y.Hamada, A.Kawai, and T.Shioiri, Tetrahedron Lett ., 1984, 25, 5409. 207 Y.Hamada, A.Kawai, and T.Shioiri, Tetrahedron Lett., 1984, 25, 5413. 208 U.Sch6llkopf and T.Winte1, Synthesis, 1984, 1033. 209 M.Yoshioka, H.Nakai, and M.Ohno, J. Am. Chem. S O C . , 1984, 106, 1133. 21 0 G.Cardillo, M.Orena, S.Sandri, and C.Tornasini, J. Org. Chem., 1984, 3951 21 1 M-Hirama, M.Iwashita, Y.Yamazaki, and S.Ito, Tetrahedron Lett., 1984, 25, 4963. 212 S-Knapp and D.V.Pate1, J. Org. Chem., 1984, 2, 5072. 21 3 H.W.Pauls and B.Fraser-Reid , Can. J. Chem., 1984, 62, 1532. 21.4 M.Georges, D-Mackay, and B.Fraser-Reid, Can. J. Chem., 1984, 62, 1539. 21 5 R.B.Bates and K.D.Janda, Synthesis, 1984, 310. 21 6 S.M.Weinreb, R.S.Garigipati, and J.A.Gainor, Heterocycles, 1984, 21, 309. 21 7 R.S.Garigipati, A.J.Freyer, R.R.Whittle, and S.M.Weinreb, J. Am. Chem. SOC., 1984, 106,7861. 21 8 S.W.Remiszewski, R.R.Whittle, and S.M.Weinreb, J. Org. Chem., 1984, 2, 3242. 219 J.Baldwin, P. D.Bailey, G.Gallacher , M.Otsuka, K.A.Singleton, P.M.Wallace, K.Prout, and W.M.Wolf, Tetrahedron, 1984, 5, 3695. 220 A.Defoin, C.Schmidlin, and J.Streith, Tetrahedron Lett., 1984, 25, 4515. 221 G.Kresze, M.M.Weiss, and W.Ditte1, Liebigs Ann. Chem., 1984, 203. 222 M.Sabuni, G.Kresze, and H.Braun, Tetrahedron Lett ., 1984, 25, 5377. 223 H.Felber, G.Kresze, H.Braun, and A.Vasella, Tetrahedron Lett., 1984, 25, 5381. 224 P.J.Maurer, H.Takahata, and H.Rapoport, J. Am. Chem. SOC., 1984, 106,1095. 225 G.Guanti, L.Banfi, E-Narisano, and C.Scolastio, Tetrahedron Lett., 1984, 25, 4693. 226 B.E.Rossiter and K.B.Sharpless, J. Org. Chem., 1984, 2, 3707. 227 T.Hiyama, K.Nishide, and K.Kobayashi, Chem. Lett., 1984, 361. 228 J.-E.Backval1 and E.E.Bjorkman, Acta Chem. Scand., Ser. B, 1984, 38, 91. 229 L.Benati, P.C.Montevecchi, and P.Spagnolo, Tetrahedron Lett., 1984, 3, 2309. 230 J.Barluenga, F.Aznar, R.Liz, and M.Bayod, J. Chem. SOC., Chem. Commun., 1984, 1427. J. E. Nordlander , M.J .Payne , F. G . N joroge , M.A . Balk, G. D. Laikos , and V.M.Vishwanath, J. Org. Chem., 1984, 9, 4107.

-

c,

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups 232 23 3 234 235 236 237 238 23 9 240 24 1 242 243 24 4 24 5 24 6 24 7 248 249 250 25 1 252 25 3 254 25 5 256 257 258 259 260 26 1 26 2 26 3 264 26 5 26 6 267 268 269 270 27 1 27 2 27 3 274 27 5 276 27 7 278 279 280 28 1 28 2

391

K.Matsumoto, S.Hashimoto, S.Otani, F.Amita, and J. Osugi, Synth. Commun., 1984, 14, 585. M.Wada,Y.Nishihara, and K.-y.Akiba, Tetrahedron Lett ., 1984, 25, 5405. D.Seebach, C.Betschart, and M.Schiess, Helv. Chim. Acta, 1984, 5, 1593. A.A.Fatmi, N.A.Vaidya, W.B.Iturrian, and C.D.Blanton,Jr., J. Med. Chem., 1984, 27 772. D . K o ~ w G ,R.C.Boruah, and J.S.Sandhu, Ind. J. Chem., Sect. B, 1984, 23, 975. D.Konwar, R.Boruah, J.S.Sandhu, and J.N.Baruah, Synth. Commun., 1984, 1053. J.Barluenga, M.Tmas, and V.Gotor, J. Chem. Res. ( S ) , 1984, 154. D.M.Tschaen, E.Turos, and S.M.Weinreb, J. Org. Chem., 1984, 9, 5058. P.Perlmutter and C.C.Teo, Tetrahedron Lett ., 1984, 5951. B.Staksun and C.S.Foote, S. Afr. J. Chem., 1984, 37, 182. T.Shono, K.Tsubata, and N.Okinaga, J. Org. Chem., 1984, 1056. K.Okano, T.Morimoto, and M.Sekiya, J. Chem. SOC., Chem. Commun., 1984, 883. T.Morimoto, K.Okano, and M.Sekiya, J. Chem. SOC., Chem. Commun., 1984, 1055. S.W.Djuric, J. Org. Chem., 1984, 1311. Y.Yoshida, S.Asano, and S.Inoue, Chem. Lett., 1984, 1073. M.Malmberg and K.Nyberg, Acta Chem. Scand., Ser. B, 1984, 2, 85. J.Garcia, F.Urpi, and J.Vilarrasa, Tetrahedron Lett., 1984, 5, 4841. A.V.Joshua and J.R.Scott, Tetrahedron Lett., 1984, 25, 5725. M-Ueda, N.Kawaharasaki, and Y.Imai, Bull. Chem. SOC. Jpn., 1984, 57, 85. S.Ohta, S.Hayakawa, and M.Okamoto, Tetrahedron Lett., 1984, 25, 5681. A.Ohta, Y.Inagawa, Y.Okuwaki, and M.Shimazaki, Heterocycles, 1984, 22, 2369. T.Miyazawa, T.Endo, M.Okawara, Synthesis, 1984, 1034. T.Kamijo, H.Harada, and K.Izuka, Chem. Pharm. Bull., 1984, 32, 2560. A.V.Eremeev, I.P.Piskunova, and R.S.Elkinson, Khim. Geterotsikl. Soedin., 1984, 1286. Y.Watanabe, Y.Tsuji, T.Kondo, and I?-Takeuchi,J. Org. Chem., 1984, 4451. J.Garcia, J-Gonzalez, R.Sequra, F.Urpi , and J.Vilarrassa, J. Org. Chem., 1984, 9, 3322. A.G.Schultz and Y.S.Kulkarni, J. Org. Chem., 1984, 9, 5202. S.Kajigaeshi, T.Nakagawa, and S.Fujisaki, Chem. Lett., 1984, 2045. S.J.Tremont and H.U. Rahman, J. Am. Chem. SOC., 1984, 106,5759. D.Moderhack, M.Lorke, and D.Schomburg, Liebigs Ann. Chem., 1984, 1685. B.H.Lipshutz and M.C.Morey, J. Am. Chem. SOC., 1984, 457. B.Rzeszotarska, M.Makowski, and Z.Kubica, Org. Prep. Proced. Int., 1984, 136. J.Pielchowski and R.Popielarz, Tetrahedron, 1984, 5, 2671. E.Kotani and S.Tobinga, Chem. Pharm. Bull., 1984, 32, 4281. Y .Nagao, Y.Hagiwara, S.Yamada, M.Ochiai, and E.Fujita, Chem. Pharm. Bull., 1984, 32. 4686. S.Tsub=, Y.Nooda, and A.Takeda, J. Org. Chem., 1984, 1204. J.H.Chan and S.S.Hal1, J. Org. Chem., - 1'984, 195. T.Beisswinger and F.Effenberger , Chem. Ber., 1984, 117,1513. Y.Satoh, H-Serizawa, S.Hara, and A.Suzuki, Synth. Commun., 1984, 313. K.Kirschke, G.Lutze, and E.Schmitz, J. Prakt. Chem., 1984, 326, 367. M.Majewski and V.Snieckus, J. Org. Chem., 2682. - 19811, J.T. Gupton, D.Baran, and J.-P. Idoux , Synth. Commun., 1984, 1001. G.Himbert and L.Henn, Liebigs Ann. Chem.. 19811, 1358. L.A.Cates and V.S.Li, Phosphoru: 3 Sulfur, 1984, 21, 187. G.A.Flynn and D.W.Bright, Tetrahedron Lett., 1984, 25, 2655. S.De Lombaert and L.Ghosez, Tetrahed ron Lett., 1 9 8 4 7 2 5 , 3475. L.A.Tsoi , A.K.Patsaev, V. Zh.Ushanov, and L.V .VyaznikoGtsev, Zh. Org. Khim., 1984, 2 0 , 2081. D.Seyf&h and R.C.Hui, Tetrahedron Lett., 1984, 25, 5251. V.V.Kashinskii, A.A.Burba, R.I.Zu1' Karnaev, and I.I.Lapkin, Zh. Obsch. Khim., 1984, 2767. R.Annunziata, M.Cinquini, F.Cozzi, F.Montanari, and A-Restelli, Tetrahedron, 1984, 2, 3815. P.C.Kuzma, L.E.Brown, and T.M.Harris, J. Org. Chem., 1984, 2015.

14,

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2,

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2,

106,

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General and Synthetic Methods

392 283 284 285 286 287 288 289 290 29 1 292 293 294 295 296 297 298 299 300 30 1 302 303 304 305 306 307 308 309 31 0 31 1 31 2 31 3

31 5 31 6 317 31 8 31 9 320 321 322 323 324 325

M.Sato, H.Ogasawara, S.Komatsu, and T.Sato, Chem. Pharm. Bull., 1984, 32, 3848. J.Lessard, Y.Couture, M.Mondon, and D.Touchard, Can. J. Chem., 1984, 62, 105. J.Barluenga, L.Ferrera, C.Najera, and M.Yus, Synthesis, 1984, 831. H.E.Zaugg, Synthesis, 1984, 85. H.E.Zaugg, Synthesis, 1984, 181. M.Dreme, S.Brune1, P.Le Perchec, J.Garapon, and B.Sillion, Tetrahedron, 1984, 40, 4947. A.BojiKva and C.Ivanov, Synthesis, 1984, 489. P.H.Olesen, F.E.Nielsen, E.B.Pedersen, and J.Becher, J. Heterocycl. Chem., 1984, 2, 1603. A.Tsolomiti8 and C.Sandris, J. Heterocycl. Chem., 1984, 2, 1679. N.Yasuda, Synth. Commun., 1984, 2, 251. K.-H.Ongania, Y.Schwarzenbrunner, and K.Humer, Monatsh. Chem., 1984, 115, 215. M. Yokoyama , Y.Hasegawa, H. Hatanaka, Y. Kawazoe , T. Imamota , Synthesis, 1984, 827. B. Yde, N.M.Youssif , Y .Pedersen, 1.Thomsen , and S.-O.Lawesson, Tetrahedron, 1984, 5, 2047. E.Schaumann and S.Fittkau, Tetrahedron Lett ., 1984, 25, 235. Y.Tamaru, T.Hioki, and Z.Yoshida, Tetrahedron Lett., 1984, 25, 5793. Y.Tamaru, M.Okada, O.Kitao, and 2. 5797. Y .-i Lin, M. N.Jennings , D.R. Sliskovic , T. L. Fields, and S.A. Lang , Jr ., Synthesis, 194, 946. G.Barnikow and A.A.Martin, Z. Chem., 1984, 2, 438. D.A.Kaiser, P.T.Kaye, L.Pillay, and G.H.P.Roos, Synth. Commun., 1984, 883. R.Sato, K.Itoh, K.Itoh, H.Nishina, T.Goto, and M.Saito, Chem. Lett., 1984, 1913. N.K.A. Dalgard, K.E.Larsen, and K.B. G-Torssell, Acta Chem. Scand., Ser . B, 1984, 38, 423. M.Meier and C.Ruchardt, Tetrahedron Lett., 1984, 25, 3441. T.Shono, Y.Matsumura, and K.Inoue, J. Am. Chem. SOC., 1984, 106,6075. Y .Masuda, M.Hoshi, T. Yamada, and A.Arase, J. Chem. S O C . , Chem. Commun., 1984, 398. B.Badet, M.Julia, and C.Lefebvre, Bull. S O C . Chim. Fr., 1984, 11, 431. E.C.Taylor, A.H.Katz, and A-McKillop, Tetrahedron Lett., 1984, 25, 5473. A.I.Meyer-s and P.D.Pansegrau, Tetrahedron Lett. , 1984, 25, 2941. K.Nishiyama and A.Watanabe, Chem. Lett., 1984, 773. K-Nishiyama and A.Watanabe, Chem. Lett., 1984, 455. M.Kosugi , M. Ishiguro , Y. Negishi, H. Sano, and T.Migita, Chem. Lett., 1984, 151 1. S.Harusawa, S-Nakamura, S.Yagi, T-Kurihawa, Y.Hamada, and T.Shioiri, Synth. Commun., 1984, 14,1365. M.Yokoyama, H.Ohtaki, M.Karauchi, K.Hoshi, E-Yanagisawa, A.Suzuki, and T.Imamoto, J. Chem. SOC., Perkin Trans. 1 , 1984, 2635. M.Uno, K.Seto, and S.Takahashi, J. Chem. SOC., Chem. Commun., 1984, 932. G.Etemad-Moghadam and J.Seyden-Penne, Synth. Commun., 1984, 565. S.Harusawa, R.Yoneda, T.Kurihawa, Y.Hamada, and T.Shiori, Tetrahedron Lett., 1984, 25, 427. S.Suzuki, Y.Fujita, and T.Nishida, Synth. Commun., 1984, 817. J.A.Cabello, J.M.Campello , A.Garcia, D.Luna, and J.M.Marinas, J. Org. Chem., 1984, 49, 5195. M.NishEawa, K.Adachi, and Y.Hayashi, J. Chem. SOC., Chem. Commun., 1984, 1637. D.Ferroud, J.P.Genet, and J.Muzart, Tetrahedron Lett., 1984, 25, 4379. E.J.Corey and A.Tramontano, J. Am. Chem. SOC., 1984, 106,462, N.V.Nguyen and H.W.Moore, J. Chem. SOC., Chem. Commun., 1984, 1066. M. H. Elnagdi, M. R.H.Elmoghayar , and C. E. H.Elgemeie , Synthesis, 1984, 1 M.A.Perez, J.L.Soto, F.Guzman, A.Daiz, and H.Alcala, Synthesis, 1984, 1045.

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2,

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5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups 326 327 32 8 32 9 330 331 332 333 334 335 336 337 338 339 340 34 1 342 34 3 34 4 345 346 347 34 8 349 350 35 1 352 35 3 354 35 5 356 357 358 359 360 36 1 362 36 3 364 36 5 36 6 367 368 369 370 37 1 372 373

393

T.Imagawa, K.Uemura, Z-Nagai, and M.Kawanisi, Synth. Commun., 1984, 2, 1267. T.Ono, T-Tamaoka, Y.Yuasa, T.Matsuda, J.Nokami, and S.Wakabayashi, J. Am. Chem. SOC. , 1984 , lob, 7890. S.De Lombaert and L.Ghosez, Tetrahedron Lett., 1984, 25, 3475. M.Yokoyama, K.Tsuji, and T.Imamoto, Bull. Chem. SOC., Jpn., 1984, 57, 295 S.S.Bhattacharjee, H.Ila, and H.Junjappa, Synthesis, 1984, 249. D.El-Abed, A.Jella1, and M.Santelli, Tetrahedron Lett., 1984, 25, 4503. K.Mai and G.Pati1, Tetrahedron Lett.-, K.Mai and G.Pati1, Synth. Commun., 1984, 1299. D.Enders and H.Lotter, Nouv. J. Chim., 1984, 8, 747. L.Stella, Tetrahedron Lett., 1984, 25, 3457. 2632. W.J.Greenlee, J. Org. Chem., 1984, A-Woderer. P.Assithianakis. W.Wiessert., D.Soeth. . , and H.Stamm. Chem. Bet-.. 1984, 117;3348. M.J.O'Donnel1, W.A.Bruder, T.M.Eckrich, D.F.Shullenberger, and G.S.Staten Synthesis, 1984, 127. N.Kornblum, H.K.Singh, and S.D.Boyd, J. Org. Chem., 1984, 358. T.Hiyama, K.Nishide, and K-Kobayashi, Tetrahedron Lett., 1984, 25, 569. L.H.Foley, Synth. Commun., 1984, 1291. V.M.F.Choi, J.D.Elliot, and W.S.Johnson, Tetrahedron Lett., 1984, 25, 591. S.Torii, T.Inokuchi, and T.Kobayashi, Chem. Lett., 1984, 897. Y.Ito, H.Imai, K.Segoe, and T.Saegusa, Chem. Lett., 1984, 937. M.T.Reetz and H.Muller-Starke, Tetrahedron Lett., 1984, 25, 3301. M.Yokoyama, M.Kurauchi, K.Hoshi, F.Yanagisawa, A.Suzuki, and T.Imamoto, J. Chem. SOC., Perkin Trans. 1 , 1984, 2635. T-Kitahara and K.Mori, J. Org. Chem., 1984, 9, 3281. E.J.Corey, D.H.Hua, and S.P.Seitz, Tetrahedron Lett., 1984, 25, 3. A.T.Au, Synth. Commun., 1984, 743. M.E.Le Tourneau and J.R.McCarthy, Tetrahedron Lett., 1984, 25, 5227. S.-i.Kiyooka, R.Fujiyama, and K.Kawaguchi, Chem. Lett., 1984, 1979. D.L.Boger, C.E.Brotherton, J.S.Panek, and D.Yohannes, J. Org. Chem., 1984, 49 , 4056. J.Kant, F.D.Popp, B.L.Joshi, and B.C.Uff, Chem. Ind., 1984, 415. B.C.Uff, S.L.A.A.Chen, Y.-P.Ho, F.D.Popp, and J.Kant, J. Chem. SOC.,Chem. Commun., 1984, 1245. M.Bonin, J.R.Rorne~-o,D.S.Grierson, and H.-P.Husson, J. Org. Chem., 1984, 5, 2392. R.J.Sundberg, D.S.Grierson, and H.-P.Husson, J. Org. Chem., 1984, 2400. D.M.Arnott, A.R.Battersby, P.J.Harrison, G.B.Henderson, and Z.-C.Sheng, J. Chem. SOC. , Chem. Commun., 1984, 525. O.Moriya, H-Minamide, and Y.Urata, Synthesis, 1984, 1057. P.W.Raynolds, J. Heterocycl. Chem., 1984, 2, 1231. P.A.Wade and M.K.Pillay, Gazz. Chim. Ital., 1984, 239. S.Shatzmiller, E.Shalom, and E.Bahar, J. Chem. SOC., Chem. Commun. 1984 , 1522. A-Kreutzberger and E-Kreutzberger, Arch. Pharm. (Weinheim, Ger.) , 1984, 317, 417. E.T.Hansen and H.J.Petersen, Synth. Commun., 1984, 1275. J.B.Bremmer, E.J.Browne, V.Chohan, and B.F.Yates, Can. J. Chem., 1984, 37, 1043. K.C.Nicolaou, R.E.Dolle, A.Chucholowski, and J.L.Randal1, J. Chem. SOC., Chem. Commun., 1984, 1153. D.S.Grierson, M.Bonin, H.-P.Husson, C.Monneret, and J.-C.Florent, Tetrahedron Lett. , 1984, 25, 4645. J.R.Hwu, J.C.Lazar, and P.F.Corless, Synthesis, 1984, 1020. R.Smith and T.Livinghouse, Synth. Commun., 1984, 639. W.J.Middleton, J. Org. Chem., 1984, 9, 919. P.L.Fishbein and H.W.Moore, J. Org. Chem., 1984, 5, 2190. R.S.Hosmane, F.N.Burnett, and M.S.Albert, J. Org. Chem., 1984, 9, 1212. P.G.Gassman and R.S.Cremban, Tetrahedron Lett., 1984, 25, 3259. J.Moska1 and A.M.van Leusen, Tetrahedron Lett., 1984, 25, 2585.

14,

5,

5,

2,

2,

5,

114,

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14,

2,

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394

General and Synthetic Methods

374 375

A. Dond ini , T.Dall 'Occo, G. Fantin, M. Fogagnolo , A .Medic i, and P. Pedr ini , J. Chem. SOC., Chem. Commun., 1984, 258. J.E.Baldwin, D.R.Kelly, and C.B.Ziegler, J. Chem. SOC.,Chem. Commun., 1984,

376 377

1.Hoppe and U.Schollkopf, Liebigs Ann. Chem., 1984, 608. D.van Leusen and A.M.van Leusen, Recl.: J. R. Neth. Chem. SOC., 1984,

133. 41.

103,

378 379

A.J.Bloom, M.Fleischmann, and J.M.Mellor, Tetrahedron Lett., 1984, 25, 4971. W.A.Pryor, G.J.Gleicher, J.P.Cosgrove, and D.F.Church, J. Org. Chem., 1984,

380

TCornelis, P.Laszlo, and P.Pennetrau, Bull. SOC. Chim. Belg., 1984,

49, 5189.

2,

961.

381 382 383

H.Mohindra Chawla, and R.S.Mitta1, Ind. J. Chem., Sect. B, 1984, 23, 899. R.B.Miller and S.Dugar, Organometallics, 1984, 3 , 1261. R.L.Atkins, A.T.Nielsen, C.Bergens, and W.S.Wilson, J. Org. Chem., 1984,

2,

503. 384 385

F.P.Schmidtchen, Chem. Ber., 1984, 117, 1287. G.C.Cross, A.Fischer, G.N.Henderson,d T.A.Smyth, Can. J. Chem., 1984,

g,

1446. 386 387 38 8 389 390 39 1

G. C. Cross A.Fischer, and G.N.Henderson, Can. J. Chem., 1984, 6 2 , 280 3. G .Bart01i Acc. Chem. Res.., 1984. 1 7 . 109. M. Makosza and S-Ludwiczak, J. Org. Chem., 1984, 4562. M.Makosza and J.Winiarski, J. Org. Chem., 1984, 5273. M.Makosza and J.Winiarski, J. Org. Chem., 1984, 1494. M .Mak osza J.Golinski, J.Baran, and D.Dziewonska-Baran, Chem. Lett., 1984,

392 39 3 394 395 396 397 398 39 9

M.Makosza, J.Golinski, and J.Baran, J. Org. Chem., 1984, 1488. M.Makosza and J.Winiarski, Chem. Lett., 1984, 1623. E.J.Corey, B.Samuelsson, and F.A.Luzzio, J. Am. Chem. SOC., 1984, 106,3682. R.S.Varma and G.W.Kabalka, Synth. Commun., 1984, 1093. D.Dauzonne and R.Royer, Synthesis, 1984, 1054. K-Nakamura, M.Fujii, A.Ohno, and S.Oka, Tetrahedron Lett., 1984, 25, 3983. A.R.Katritzky, M.A.Kashmiri, and D.K.Wittmann, Tetrahedron, 1984, 1501. P.E.Eaton, B.K.R.Shankar, G.D.Price, J.H.Pluth, E.E.Gilbert, J.Alster, and O.Sandus, J. Org. Chem., 1984, 9, 185. C.G.Fransisco, R.Friere, R.Hernandez, D.Melian, J.A.Salazar, and E.Suarez, J. Chem. SOC.,Perkin Trans. 1 , 1984, 459. G.Stork, G.Clark, and T.Weller, Tetrahedron Lett., 1984, 25, 5367. M.A.Andrews, T.C.-T.Chang, C.-W.F. Cheng, and K.P .Kelly, Organometallics,

I

_ I

9, 9, 2,

1619.

400 40 1 402

2,

s,

1984, 40 3 404 405 406 407 408 409 410 41 1

415 416

3,

1779.

A.A.Borisenko, A.V.Nikulin, S.Wolfe, N.S.Zefirov, and N.V.Zyk, J. Am. Chem.

SOC., 1984, %, 1074.

J.P.Genet and D.Ferroud, Tetrahedron Lett., 1984, 25, 3579. T.Tanaka, A.Hazato, K.Bannai, N-Okamura, S.Sugiura, K.Manabe, S.Kurozumi, M.Suzuki, and R.Noyori, Tetrahedron Lett., 1984, ? 4947. j , Y.Nakashita, T.Watanabe, E.Benkert, A.Lorenzi-Riatsch, and M.Hesse, Helv. Chim. Acta, 1984, 67,1204. D.Seebach and P.Knoche1, Helv. Chim. Acta, 1984, 6 7 , 261. K.Matsumoto, Angew. Chem. , Int. Ed. Engl., 1984, 23, 617. G-Rossini, R.Ballini, P.Sorrenti, and M.Pet rini, Synthesis, 1984 607. L.S.Hegedus and R.J.Perry, J. Org. Chem., 1 984, 49, 2570. G-Rossini, R. Ballini, M.Petrini, and P.Sor renti , Tetrahedron, 19 8 4 , 2, 3809.

412 413 414

2,

2,

T.V.Rajan Babu and T.Fukunaga, J. Org. Chem., 1984, 4571. G.P.Stahly, B.C.Stahly, and K.C.Lilje, J. Org. Chem., 1984, 578. A.P.Marchand, S.C.Suri, A.D.Earlywine, D.R.Powel1, and C.van der Helm, J. Org. Chem., 1984, 3,670. I.V.Martynov, L.V.Postnova, R.Kh.Bikkineev, and A.I.Yurtanov, Zh. Org. Khim., 1984, 20, 1724. W S t a r t s e v , L.M.Zubritskij, and A.A.Petrov, Zh. Org. Khim., 1984, 20, 2475.

417

N.Ono, A.Kamimura, and A.Kaji, Tetrahedron Lett., 1984,

25,

2,

5319.

5: Amines, Nilriles, and Other Nitrogen-containing Functional Groups 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 45 1 452 453 454 455 456 457 458 459 460 46 1 462 463 464

395

J.Zon, Synthesis, 1984, 661. B. J .Banks, A.G.M.Barrett, and M.A.Russel1, J. Chem. SOC.,Chem. Commun., 1984, 670. M.Node, T.Kawabuta, M-Fujimoto, and K.Fuji, Synthesis, 1984. T.Hayama, S-Tomoda, Y.Takeuchi, and Y-Nomura, J. Org. Chem., 1984, 9, 3235. B.Stanovnik, O.Bajt, B.Belcic, B.Koren, M.Prhavc, A.Stimac, and M.Tisler, Heterocycles, 1984, 1545. R.A.Bartsch and I.-W.Yang, J. Heterocycl. Chem., 1984, 21, 1063. J.Einhorn, P.Demersman, and R.Royer, Synthesis, 1984, 978. Y.Ohishi, Y.Doi, and T.Nakanishi, Chem. Pharm. Bull., 1984, 32, 4260. V.M.Kolb, S.D.Darling, D.F.Koster, and C.Y.Meyers, J. Org. Chem., 1984, 3, 1636. J.B.Kyzio1 and Z.Daskiewicz, Tetrahedron, 1984, 5, 1857. G.D.Hartman, R.D.Hartmann, J.E.Schwering, W.S.Saari, E.L.Engelhardt, N.R.Jones, P.Wardman, M.E.Watts, and M.Woodcock, J. Med. Chem., 1984, 3, 1634. J.M.Hoffmann, B.T.Phillips, and D.W.Cochran, J. Org. Chem., 1984, 9, 193. D.Dauzonne and R.Royer, Synthesis, 1984, 348. T.Sudhakar Rao, S.Deshpande, H.H.Mathur, and G.K.Trivedi, Heterocycles, 1984, 22, 1943. M.M.Catalano, M. J. Crossley, M.M.Harding, and L.G.King, J. Chem. SOC., Chem. Commun., 1984, 1535. R.Meuwly and A.Vasella, Helv. Chim. Acta, 1984, 67,1568. B.Aebischer, R.Meuwly, and A.Vasella, Helv. Chim. Acta, 1984, 2236. S.Mirza and A.Vasella, Helv. Chim. Acta, 1984, 67,1562. K.Kastova and M.Hesse, Helv. Chim. Acta, 1984, 67,1725. W.Plesch and M.Wiessler, Liebigs Ann. Chem., 1984, 1494. T.C.Adams,Jr., W.M.Koppes, and H.G.Adolph, Synthesis, 1984, 1029. E.H.White, J-Reefer, R.H.Erickson, and P.M.Dzadzic, J. Org. Chem., 1984, 4872. R.L.Willer and R.L.Atkins, J. Org. Chem., 1984, 9, 5147. M-Nakajima, J.C.Warner, and J.-P.Anselme J. Chem. SOC., Chem. Commun., 1984, 451. M.Nakajima, J.C.Warner, and J.-P.Anselme, Tetrahedron Lett., 1984, 25, 2619. J.C.Warner, M.Nakajima, and J.-P.Anselme, Bull. SOC. Chim. Belg., 1984, 93, 91 9. P.J.Bowman, B.R.Brown, M.A.Chapman, and P.M.Doyle, J. Chem. Res. ( S ) , 1984, 72. E.Muller, R-Kettler, and M.Weissler, Liebigs Ann. Chem., 1984, 1468. S.E.Denmark and M.S.Dappen, J. Org. Chem., 1984, 9, 798. B.C.Challis, J.R.Milligan, and R.C.Mitchel1, J. Chem. SOC., Chem. Commun., 1984, 1050. T.P.Johnston and G.S.McCaleb, Synthesis, 1984, 31 1. K.A.Jorgensen, A-B.Ghattas, and S.-O.Lawesson, Bull. SOC. Chim. Fr., 1984, 11, 204. M.F.Jouda and C.W.Rees, J. Chem. SOC., Chem. Commun., 1984, 374. 0.Meth-Cohn and G.van Vuuren, J. Chem. SOC., Chem. Commun., 1984, 1144. R.WeiB and K-G.Wagner, Chem. Ber., 1984, 117,1973. 1119. M.Akiba and M.P.Cava, Synth. Commun., 1984, G.Lunn, E.B.Sansome, and L.K.Keefer, J. Org. Chem., 1984, 9, 3470. C.I. Chiriac, Rev. Roum. Chem., 1984, 2, 219. 0.Attanasi and P.Fillipone, Synthesis, 1984, 422. S.Bozini, S.Gratton, and A.Risaliti, Tetrahedron, 1984, 5263. T.Iida, T.Tamura, T.Matsumoto, and F.C.Chang, Synthesis, 1984, 957. K.N.Zelenin, V.V.Alekseev, and V.A.Krustalev, Zh. Org. Khim., 1984, 20, 169. M.Tirant and T.D.Smith, Synthesis, 1984, 833. D.Enders, H-Eichenauer, U.Baus, H.Schubert, and K.A.M.Kermer, Tetrahedron, 1984, 5, 1345. N.R.Ayyangar, K.C.Brahme, U.R.Kalkote, and K.V.Srinivasan, Synthesis, 1984, 938. A.J.Castellir-10 and H.Rapoport, J. Org. Chem., 1984, 2, 1348. G.Stancinc and A.T.Balaban, Org. Prep Proced. Int., 1984, 5, 401.

c,

67,

2,

~

14,

~

s,

396

General and Synthetic Methods

465 46 6

M.Psiorz and G.Zinner, Synthesis, 1984, 217. B.N.Misra, A.S.Singha, G.S.Chauhan, and R.P.Sharma, Ind. J. Chem., Sect. B,

467 46 8 469

S.Prabhakar, A.M.Lobo, M.A.Santos, and H.S.Rzepa, Synthesis, 1984, 829. E.A.Mistryukov, I.K.Korshevets, Synthesis, 1984, 947. D.H.R.Barton, W.B.Motherwel1, and S.Z.Zard, Tetrahedron Lett., 1984, 25,

1984,

23,

728.

3707. 470 47 1 472 473 474 475 476 47 7 478 47 9 480 48 1 482 48 3 484 48 5 486

F.Boberg, K.-H.Garburg, K.-J.Gorlich, E.Pipereit, and M.Ruhr, Liebigs Ann. Chem., 1984, 911. F.S.Guziec, Jr . , and

J. M. Russo, Synthesis, 1984, 479. K.Weiss and P.Kind1, Angew. Chem., Int. Ed. Engl., 1984, 23, 629. T-Yamamoto, D.Yoshida, J.Hojyo, and H.Terauchi, Bull. Chem. SOC. Jpn., 1984,

57,

(S)., -

1984, 144.

3341.

O.Tsuge, S.Kanemasa, and K.Matsuda, J. Org. Chem., 1984, 9, 2688. Y.Ito, H.Imai, T.Matsuura, and T.Saegusa, Tetrahedron Lett., 1984, 2, 3091. C.E.Castro, R.S.Wade, and J.Fukuto, J. Heterocycl. Chem., 1984, 2, 1905. B.Alcaide, G.Escobar, R.Perez-Ossorio, J.Plumet, and D.Sanz, J. Chem. Res. A.Aumuller and S.Hunig, Angew. Chem., Int. Ed. Engl., 1984, 23, 447. R.S.Hosmane, Tetrahedron Lett., 1984, 25, 363. R.Kupfer, S.Meier, and E.-U.Wurtwein, Synthesis, 1984, 688. V.Dryanska, C.Ivanov, and R.Krusteva, Synthesis, 1984, 1038. H.C.van der Plas and D.J.Buurman, Tetrahedron Lett., 1984, 25, 3763. D.M.Malenko, L.A.Repina, and A.D.Sinitsa, Zh. Obshch. Khim., 1984, E, 2154. B.G.Lenz and B.Zwanenburg, Recl.: J. R . Neth. Chem. SOC., 1984, 3, 342. B.A.O'Brien and D.D.DesMarteau, J. Org. Chem., 1984, 49, 1469. S.Torii, H.Tanaka, S-i.Hamano, N.Tada, J.Nokama, and KSasaoka, Chem. Lett., 1984, 1823.

2,

487 48 8 489 490 49 1 492 49 3 494

J.D.Bunyak, N.M.Graff, and K.P.Jadhay, J. Org. Chem., 1984, 1828 K.Akutagawa, N.Furukawa, and S.Oae, Bull. Chem. SOC. Jpn., 1984, 57 , 1104. H.tom Dieck and J.Dietrich, Chem. Ber., 1984, 117,694. J.Barluenga, M.Tomas, J.F.Lopez-Ortiz, and V.Gotor, Synthesis, 1984, 935 A.Rahman, H.Ila, and H.Junjappa, J. Chem. SOC., Chem. Commun., 1984, 430, T.Takajo, S.Kambe, and W.Ando, Synthesis, 1984, 256. F.Akiyama, J. Chem. SOC., Chem. Commun., 1984, 59. J.Goto, K-Sakane, Y.Nakai, T.Teraji, and T.Kamiya, J. Antibiotics, 1 984, 37,

495 496

T.Okamoto and S.Oka, J. Chem. SOC., Chem. Commun., 1984, 289. G.H.Hakimelahi , H. Sharni , H.Zari

s

532.

497 498 49 9

114,

500 50 1 502 503 50 4 50 5 50 6

P.W.Wade and M.K.Pillay, Cazz. Chim. Ital., 1984, 239. Y.Uchida and S.Kozuka, Bull. Chem. SOC. Jpn., 1984, 57, 2011. G.D.Hartmann and R.D.Hartmann, J . Heterocycl. Chem., 1984, 2, 1907. S.I.Zavyalov and G.I.Ezhovo, Izv. Akad. Nauk SSSR, Ser. Khim., 1984, 161. 4741. S.E.Denmark, M.S.Dappen, and J.A.Sternberg, J. Org. Chem., 1984, 9, N.B.Dyatkina and A.V.Azhayev, Synthesis, 1984, 961. M.Kloosterman, M.P.de Nijs, and J.H.van Boom, Recl.: J. R. Neth. ChemI . SOC.,

507 50 8 509 510 51 1 512 51 3 514 51 5 51 6

A.P.Kozikowski and M.N.Greco, J. Org. Chem., 1984, 2310. Y.Masuda, M.Hoshi, and A.Arase, ,.1984, 57, 1026. A-Hassner, R.Fibiger, and D-Andisik, J. Org. Chem., 1984, 49, 4237. R.Moriarty, K.-C.Hou, and R.-S.Miller, Synthesis, 1984, 6 8 3 . P.Laszlo and E.Polla, Tetrahedron Lett., 1984, 25, 3701. P.Laszlo and E.Polla, Tetrahedron Lett., 1984, 4651. H-Priebe, a= Chem. Scand., Ser. B, 1984, 2,623. H-Priebe, Acta Chem. Scand., Ser. B , 1984, 38, 895. H.Priebe, Angew. Chem., Int. Ed. Engl., 1 9 8 q 3 , 736. F.P.Schmidtchen, Chem. Ber., 1984, 117,725.

1984,

3, 243.

2,

25,

397

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups 51 7 51 8

P.-L.Desbene and J-C.Cherton, Tetrahedron, 1984, 40, 3567. F.Chretien and Y.Chapleur, J. Chem. SOC.,Chem. Commun., 1984, 1286.

I.Pelyvas, F.Sztaricskai, and R.Bognar, J. Chem. SOC., Chem. Commun., 1984, 104. 520 F-Babudri, L.di Nunno, S.Florio, and S.Valzano, Tetrahedron, 1984, 5, 1731. 52 1 C.O.Meese, Synthesis, 1984, 1041. 52 2 P.Yates and J.D.Kronis, Can. J. Chem., 1984, 62, 1751. 52 3 Y.Ueda, G-Roberge, and V.Vinet, Can. J. Chem., 1984, 62, 2936. 155. 524 P-Callant, L-D'Haenens, and M.Vandewalle, Synth. Commun., 1984, 52 5 P.Callant, L.D'Haenens, E.Van der Eycken, and M.Vandewalle, Synth. Commun., 1984, 163. Chem. Ber., 1984, 117,2233. 52 6 M.Regitz and S.G.Khbeis, 52 7 T.Kappe, G.Lang, and E.Pongratz, J. Chem. SOC., Chem. Commun., 1984, 338. 528 R.WeiB, K.-G.Wagner and M.Herte1, Chem. Ber., 1984, 117, 1965. 52 9 H.Firouzabadi, A.R.Sardarian, M.Naderi, and B.Vessa1, Tetrahedron, 1984, 5001. 530 G-Crank and M.I.H.Makin, Aust. J. Chem., 1984, 37, 845. 4014. 53 1 R.V.Hoffman and A.KUmar, J. Org. Chem., 1984, 1215. 532 T.F.Chung, Y.M.Wu, and C.H.Cheng, J. Org. Chem., 1984, 53 3 H.Vorbruggen and K.Krolikiewicz, Tetrahedron Lett., 1984, 25, 1259. 534 J-Urbanski and L.Wrobe1, Pol. J. Chem., 1984, 58, 899. 53 5 A-Nishinaga, S-Yamazaki, and T.Matsuura, Tetrahedron Lett., 1984, 25, 5805 536 R.K.Smalley and A.W.Stocker, Tetrahedron Lett., 1984, 25, 1389. 49. 4541. 537 W.J.Middleton. J. Orn. " Chem.. 1984. . Z. Nat.urforsch., 1984, 1593. 538 N.S.Habib and A.Riel ker, ,&s 1984, 315. 539 J. G .Schantl, P.Hebeisen, and L.Minach, Synthe: 540 Y.Yamamoto and Y.Morita, Chem. Pharm. Bull.,. 1984, 32, 2957. 283. 54 1 A.Dalla Cort. and L.Mandolini, Gi322. Chim. Ital., 1984, 542 P.P.WoodRate, S.J.Janssen, P.S.Rutled Ige, S.D.Woodgate, and R ..C.Cambie , Synthesis, 1984, 1017. 54 3 W.C.Christophe1 and L.L.Miller, J. Org. Chem., 1984, 9, 5198. el, and M.H.Elnagdi, S y n t h s.is, 54 4 519

2,

2,

fi,

2,

1

-

z - z

2,

s,

3,

54 5 546 547 548 549 5 50 551 5 52 5 53 554 555 5 56 5 57 5 58

N.S.Habib and A.Rieker, Synthesis, 1984, 825. M.J.Camarasa, P.Fernandez-Resa, M.T.Garcia-Lopez, F.G.de las Heras, P.P.Mendez-Castrillion, and A.S.Felix, Synthesis, 1984, 509. I.Mori, K.Oshima, and H.Nozaki, Tetrahedron Lett., 1984, 25, 4683. I.Yamamoto, K.Okuda, S.Nagai, J.Motoyoshiya, H.Gotoh, and K.Matsuzaki, J. Chem. SOC., Perkin Trans. 1, 1984, 435. C.A.Loeschorn, C.J.Kelly, R.N.Hanson, and M.A.Davis, Tetrahedron Lett., 1984, 25, 3387. H.Mitsui, S.-i .Zenki, T.Shiota and S.-i. Murahashi , J. Chem. SOC., Chem. Commun., 1984, 874. S.-i.Murahashi, H.Mitsui, and S.-i.Zenki, Heterocycles, 1984, 2, 483. P.DeShong and J.M.Leginus, J. Org. Chem., 1984, 2, 3421. W.Kliege1 and J.Graumann, Liebigs Ann. Chem., 1984, 1545. V.P.Tashchi, A.F.Rukasov, T.I.Orlova, A.P.Ivanov, O.A.Tashchi, Yu.A.Baskakov, and Yu.G.Putsykin, Zh. Org. Chim., 1984, 20, 988. J.Lub and Th.J.de Boer, Recl.: J. R . Neth. Chem. SOC., 1984, 103,328. N.Balasubramanian, Org. Prep.Proced. Int., 1984, 25. E.Baciocchi, C.Rol, G.V.Sebastiani, and B.Serena, Tetrahedron Lett., 1984, 25, 1945. R.Hrubiec and M.B.Smith, J. Chem. SOC., Perkin Trans. 1 , 1984, 107.

16,

Organometallics in Synthesis BY J. BLAGG, S. G. DAVIES, AND P. F. GORDON

The Transition Elements by J. Blagg and S. G. Davies

PART I: 1

Introduction

The format of this report is similar to that of previous years, and as last year the section covering carbon-carbon bond-forming reactions has been subdivided. A book highlighting some practical aspects of the spplications of transition metals for organic synthesis has appeared, as have several useful reviews covering various aspects of the applications of transition metals to organic synthesis. Topics which have been reviewed include the oxidation of olefins to ketones catalysed by palladium, transition-metal-catalysed Cope and Claisen rearrangements, palladium-assisted reactions of mono-olef ins,4 carbene complexes in organic synthesis, copper-assisted coupling and substitution reactions, and cobalt-mediated [2+2+21 'cycloadditions .7 2

Reduction

Further examples of the use of cationic rhodium and iridium catalysts to achieve hydroxyl directed hydrogenations of allylic, homoallylic, and bis-homoallylic alcohols have been reported. Hydrogenation of 3-methylenecyclohexanol ( 0 . 1 M ) at 1 atm H2 pressure with [ (Ph2P (CH2)4PPh2)Rh(norbornadiene) I+BPh4- as catalyst (2 mol%) has been shown to give trans-3-methylcyclohexanol with Very little greater than 98% stereoselectivity (Scheme 1 ) stereocontrol was observed on similar reductions of 2-methylenecyclohexanol and 2-methylenecyclohexanemethanol. The use of the BPh4 salt suppresses competing isomerization 1" eact ions Some optimization of the conditions for these stereoselective hydrogenations and a comparison between the catalysts

.*

For References see page 433.

398

399

6: Organometallics in Synthesis

OH

OH

>> 9 8

OH OIO

<< 2

OIO

Ph2 Reagents: i, C ~ ~ R h + ~ ~ ~ a 1 , H 2 ( 120°C a t m ) , Ph2

Scheme 1

6 -..6 i

95%. selectivity 290: 1

65 Ole, selectivity 12: 1 Reagents: i , [Rh]' cat.. H2 ( 6 4 0 p.s.i.) ; ii, 5 O/. [Rh ]+,H2(800p.s.i.)

Scheme 2

General and Synthetic Methods

400

[(Ph2P(CH2)4PPh2)Rh(norbornadiene) ]+BF4- a n d [ ( 1 , 5 - c y c l o In octadiene)Ir(pyridine)(P(C6Hl )3)]+PF6- h a s b e e n d e s c r i b e d . ' g e n e r a l , u n d e r t h e same r e a c t i o n c o n d i t i o n s , t h e r h o d i u m c a t a l y s t g i v e s b e t t e r s t e r e o s e l e c t i v i t i e s and works moderately well even w i t h e x t r e m e l y h i n d e r e d t r i - and t e t r a - s u b s t i t u t e d

a l l y l i c alcohols

f o r which t h e i r i d i u m c a t a l y s t is i n e r t (Scheme 2 ) . S t e r e o s e l e c t i v i t i e s for t h e rhodium-catalysed

r e a c t i o n s are

i m p r o v e d d r a m a t i c a l l y on r a i s i n g t h e h y d r o g e n p r e s s u r e f r o m 1 5 p.s.i.

t o 64-800 p . s . i .

o r by l o w e r i n g t h e a m o u n t o f t h e c a t a l y s t

f r o m 20 t o 2 . 5 mol%. The u s e o f f o r m a t e i n t h e p r e s e n c e o f p a l l a d i u m c a t a l y s t s t o r e d u c e t e r m i n a l a l l y l i c compounds t o o l e f i n s h a s b e e n i m p r o v e d s u c h t h a t w i t h (Bun) P as t h e l i g a n d , v e r y h i g h s e l e c t i v i t y f o r I - o l e f i n

3

f o r m a t i o n i s o b s e r v e d (Scheme 3 ) . l o The s c o p e o f p a l l a d i u m - c a t a l y s e d

formate r e d u c t i o n s h a s been

e x t e n d e d t o s t e r o i d a l e n o l t r i f l a t e s ( S c h e m e 4). [(C5H5)2TiC121 c a t a l y s e s t h e z i n c r e d u c t i o n o f 1 , 2 - d i b r o m i d e s t o t h e corresponding o l e f i n s .

More c o n v e n i e n t l y , t h e r e d u c i n g a g e n t

(Scheme 5 ) . R e d u c t i o n o f 1 , 2 5 5 2 d i b r o m i d e s i n t e t r a h y d r o f u r a n is v e r y r a p i d and t h e s t a r t i n g [(C

H ) TiC1I2ZnCl2 i s p r e f e r r e d

The method is e x t r e m e l y reagent [(C H ) TiC121 is recoverable. 5 5 2 m i l d a n d y i e l d s a r e b e t t e r t h a n , o r c o m p a r a b l e t o , t h o s e of o t h e r 12 more e x t r e m e r e d u c i n g s y s t e m s . The r e d u c t i v e d i m e r i z a t i o n o f d i y n e s t o g i v e c o n j u g a t e d d i e n e s c a n b e a c h i e v e d w i t h a t i t a n i u m r e a g e n t f o r m e d by s o d i u m amalgam r e d u c t i o n of [ ( C H ) T i C l 2 1 . l 3 The r e a c t i o n i s s t e r e o s e l e c t i v e , 5 5 2 g i v i n g o n l y E,E-dialkylidenecycloalkanes. The r e a c t i o n g i v e s g o o d y i e l d s f o r f i v e - a n d six-membered

r i n g s , low y i e l d s f o r s e v e n -

membered, and f a i l s f o r eight-membered

r i n g s (Scheme 6 ) -

I n t h e presence of [Rh2(0Ac)Q] as c a t a l y s t d i m e t h y l d i a z o m a l o n a t e c l e a n l y and s t e r e o s p e c i f i c a l l y d e o x y g e n a t e s e p o x i d e s 14 t o t h e c o r r e s p o n d i n g a l k e n e s u n d e r n e u t r a l c o n d i t i o n s (Scheme 7 ) .

3

Oxidation

A number o f a n a l o g u e s o f K h e l l i n h a v e become a v a i l a b l e t h r o u g h t w o

c o m p l e m e n t a r y o x i d a t i o n s u s i n g O s 0 4 - N a I 0 4 a n d Wacker c o n d i t i o n s

.

,02) ( S c h e m e 8 ) u,B-Unsaturated e s t e r s are o x i d i z e d t o 8 - k e t o - e s t e r s

( P d C 1 2 , CuCl

on

t r e a t m e n t w i t h ButOOH i n a q u e o u s A c O H i n t h e p r e s e n c e o f p a l l a d i u m s a l t s as c a t a l y s t s . T h i s o x i d a t i o n h a s been u t i l i z e d i n t h e

6: Organometallics in Synthesis

-R

X

or

R

40

-

R&

A9

X = OAc, OPh, OCO,Me, or C l ii

*

mOH

Reagents : i , PdC$, Bun3P or [ Pd2(dba)3.CHC13], Bun3P, NH4HC02 ii,[ Pd(dba)3.CHCl: Bun3F, NH4HC02

Scheme 3

OTf 85 'lo

Reagents : i , HCOZH, Bun3N, [ P ~ ( O A C ) ~ ( P P ~ ~ ) ~ ]

Scheme 4

402

General and Synthetic Methods

h

B

r

& ..

q/J

70 'lo

Br

Br

Reagents: i [~(C5HS)zTiCl),ZnClz]; ii,[(C5H5)zTiCIz 1, Zn ,THF I

Scheme 5

~ = 3 ( 6 0 " / 0 ) , 4 ( 8 0 % ) , 0 r5( 2 7 % )

79O l O

Reagents:i,[(C5H5)ZTiClZ],Na/Hg,Ph2PMe;i i , H + ( D + )

Scheme 6

iii,H+; i v . A

403

6: Organornetallies in Synthesis

+

a

OMe

82%

OMe

Scheme 7

t HO i w . i

OMe

OMe

73 ' l o

Khell in

Reagents: i.OsO4,NaIO4. THF,5O0C; ii,PdCLZ,CuCL,02(30p.s.i.),MeOH, 7 O o C , 2h

Scheme 8

General and Synthetic Methods

404

synthesis of 6-epithienamycin (Scheme 9). 16 The oxidation of several ene diols under Wacker conditions gives bicyclic acetals. This methodology has been applied to various insect pheromones. The oxidations are performed with PdC12 in the presence of excess cuc12’7 or catalytic amounts of Cucl2 in air 18 as reoxidant for the palladium. Scheme 10 illustrates the and endosynthesis of the bark beetle phermomones brevicomin. 18 Various procedures for the dehydrogenation of primary and secondary alcohols to the corresponding aldehydes and ketones have been reported (Scheme 11). Ru02-02 behaves similarly to Mn02 in the aerobic oxidation of allyl alcohols to a,~-unsaturated aldehydes. l9 [ (Ph3P)3RuC12] in the presence of aqueous ButOOH or H 202 oxidizes secondary alcohols to ketones , 2 0 catechols to 1,2benzoquinones,2 o and a-hydroxy-esters to a-keto-esters .21 Overoxidation to give carboxylic acids can occur in the case of primary alcohols. Na2PdC14 selectively cyclopalladates the 4a-methyl group of the oxime of lanost-8-en-3-one. The resulting palladium complex can be converted into the corresponding monodeuteriated compound with NaBD4 (78%) or oxidized to the 4a-iodomethyl compound with I2 in CHC13 (40%) (Scheme 12).22 The Sharpless asymmetric epoxidation system [Ti(OPr1)4, diethyl tartrate, ButOOH] which gives good enantiomeric control for allyl alcohols, gives lower enantiomeric excesses (23-55%) in the case of homoallylic alcohols. 2 3 The asymmetric epoxidation of allyl alcohols with ButOOH in the presence of Ti(OPri)4 and tartramide ( 2 :1 ratio) gives the opposite enantioselectivity to the Ti(OPr1I4 and tartrate esters ( 2 :1 ) system.24 Expected enantioselection is observed if the ratio of Ti(OPr1)4 to tartramide is 2:2.4 (Scheme 13) 24 Modification of the Sharpless epoxidation system CTi(OPr1)4, diethyl tartrate, ButOOH] by the addition of I equivalent of water gives a reagent that will enantioselectively oxidize sulphides to sulphoxides (Scheme 14 ) .25 Molybdenum(V1) oxodiperoxo-complexes in the presence of chiral lactamides enantioselectively epoxidize the tetracyclic olefin shown in Scheme 15.26 Of note is the fact that no allylic hydroxyl function is present, a prerequisite for Sharpless asymmetric epoxidation. ButOOH in the presence of [MO(CO)~] proved more effective for

z-

.

405

6: Organometallics in Synthesis

Scheme 9

-

ex0 Brevicomin Scheme 10

Reagents: i , RuOZ,Oz,ii ,[(Ph3P)3RuC121,ButOOH; iii,HZOZ

Scheme 11

406

General and Synthetic Methods

Pd' Cl'

\PPh3

S c h e m e 12

Ph

OH

OH

Ph

0 2 % e.e.

Ph 96% e.e.

NHCHZPh

Ho+ HO-'

0 (1)

NHCHZPh

6: Organometallics in Synthesis

407

95% yield, 9 3 % e.e. Reagents : i, Ti(0Pr I 14, H t O ,

Scheme 14

OR

OR

0

R = COCMe3

1

0 "C [(S)-piperidinelactamidel MOOS

53% e.e.

Scheme 15

HO

HO

85 Y o

Scheme 16

General and Synthetic Methods

408

t h e e p o x i d a t i o n o f t h e h o m o a l l y l i c a l c o h o l shown i n Scheme 16 t h a n e i t h e r ButOOH-~VO(acac)21 o r MCPBA.27 The r e a c t i o n was r e g i o - a n d stereo-selective. I n c o n t r a s t , ButOOH i n t h e p r e s e n c e o f [ C r ( C O ) 6 ] o l e f i n s i n a c e t o n i t r i l e t o e n o n e s (Scheme 1 7 ) .28

w i l l oxidize Secondary

a l c o h o l s are n o t a f f e c t e d . The f i r s t e x a m p l e o f t h e u s e o f d i l u t e a q u e o u s H202 t o e p o x i d i z e o l e f i n s has appeared. e p o x i d i z e d w i t h 35% H 0

T e r m i n a l o l e f i n s c a n be s e l e c t i v e l y i n t h e presence of an hydroxyplatinum

c a t a l y s t (Scheme 1 8 ) . 2 9 2 The mechanism p r o b a b l y i n v o l v e s n u c l e o p h i l i c a t t a c k o f HOO- on c o - o r d i n a t e d o l e f i n . 1,3-Dienes are converted i n t o 1,4-diacetoxy-2-alkenes

on

t r e a t m e n t w i t h c a t a l y t i c a m o u n t s of Pd(OAcI2 i n t h e p r e s e n c e o f

p-benzoquinone

and l i t h i u m s a l t s .

Very h i g h r e g i o s e l e c t i v i t i e s ( 9 5 -

100%) f o r 1 , 4 - a d d i t i o n a r e o b s e r v e d i n m o s t c a s e s .

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 i s d e p e n d e n t on t h e l i t h i u m s a l t s p r e s e n t (Scheme 1 9 ) . 30 1 , 3 - D i e n e s a r e o x i d i z e d t o 1 - a c e t o x y - 4 -

trifluoroacetoxy-2-alkenes by Pd(OAc)2 i n A c O H c o n t a i n i n g CF CO H 3 2 and Li02CCF 31 O v e r a l l t r a n s - a d d i t i o n i s o b s e r v e d f o r c y c l o h e x a 3' is preferred f o r cyclohepta-1,41,3-diene whereas =-addition diene.

The p r o d u c t s c o n t a i n s e l e c t i v e l y p r o t e c t e d h y d r o x y - g r o u p s

a s e v i d e n c e d by t h e r e a d y h y d r o l y s i s o f t h e t r i f l u o r o a c e t a t e m o i e t y (Scheme 1 9 ) . The a l l y l i c o x i d a t i o n o f o l e f i n s t o a l l y l i c a c e t a t e s c a n b e a c h i e v e d w i t h c a t a l y t i c a m o u n t s o f Pd(02CCF3)2 w i t h o n e e q u i v a l e n t of E-benzoquinone

as o x i d a n t i n a c e t i c a c i d .

The t e r m i n a l m e t h y l

group of g e r a n y l a c e t o n e can be o x i d i z e d s e l e c t i v e l y b u t u n f o r t u n a t e l y t h i s o x i d a t i o n i s n o t v e r y r e g i o s e l e c t i v e (Scheme 20)

.32 The s t e r e o c h e m i c a l outcome o f t h e Os04 o x i d a t i o n o f a l l y l i c

a l c o h o l s , e s t e r s , and e t h e r s h a s been p r e d i c t e d w i t h numerous e x a m p l e s b e i n g s u p p l i e d . 33 The r e l a t i v e s t e r e o c h e m i s t r y b e t w e e n the pre-existing hydroxy-group

4

oxygen f u n c t i o n a n d t h e a d j a c e n t newly i n t r o d u c e d

o f t h e m a j o r p r o d u c t i s a l w a y s e r y t h r o (Scheme 2 1 ) .

I s o m e r i z a t i o n s and Rearrangements

A s p a r t o f a f o r m a l s y n t h e s i s o f (+)-perhydrohistrionicotoxin,

s t o i c h e i o m e t r i c q u a n t i t i e s o f RhC13 i n r e f l u x i n g e t h a n o l w e r e n e c e s s a r y t o e f f e c t t h e endo- t o =-double shown i n Scheme 2 2 . 3 4

bond r e a r r a n g e m e n t

409

6: Organometallics in Synthesis

COzMe

C0,Me ?H

OH

Reagents : i,[Cr(C0)6 I,MeCN, ButOOH

Scheme 17

Scheme 18

0

AcO

--OzCCF,

iv

*

AcO

-0-OH

( > 92 '10 trans 1

Reagents : i , L i OAc ,LiCl ,P d ( O A C ) ~ p, - benzoquinone; ii ,LiOAc ,Pd ( OAc)Z, p

- benzoquinonei iii , Pd(OAc)z,

AcOH ,CF3C03H, CF3COzLi; iv, NaZC03

Scheme 19

General and Synthetic Methods

410

0 1

+

OAc

OAc Reagents : i , Pd(OtCCF3)t, p

- benzoquinone Scheme 2 0

OSiPhzBut I

+

OSiPhzBut

8:l

I

OH

OH

Scheme 21

RhC13 ___)

EtOH

Ph

Scheme 2 2

411

6: Organometallics in Synthesis

A formal synthesis of (+)-deplancheine utilizes iron complexes in two key steps. Butadiene-2-carboxylic acid is stabilized against intramolecular Diels-Alder reactions by complexation to CFe(C0) 1 and [Fe2(CO)gl induces a stereoselective double bond shift .33 In the latter rearrangement several other reagents were found to be non-stereoselective (Scheme 23). The chiral isomerization catalyst [Rh( binap) codl+C104-; binap = 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl, isomerizes allylamines to enamines. In the case of 3-alkyl-3-methyl-allylamines efficient conversions can be achieved together with high stereoselectivities (Scheme 24). 36 Several examples of the l,3-shift of allyl acetates have been reported. E,Z-4-Acetoxyhepta-2,5-diene rearranges under the influence of [(Ph P) Pdl to E,E-l-acetoxyhepta-2,4-diene, but under 3 4 [(MeCN)2PdC12] catalysis the product is E,Z-l-acetoxyhepta-2,4diene (Scheme 25). 37 Diastereomeric mixtures of 2-substituted-Ivinylcyclohexyl acetates are rearranged stereoselectively to 2substituted-E-B-acetoxyethylidenecyclohexanes with [(MeCN)2PdC121 as catalyst (Scheme 25) 38 The allyl group has found use as a mild and selectively removable protecting group in the synthesis of labile 0g l u ~ o p e p t i d e s . ~As ~ shown in Scheme 26 deprotection of the allyl protected xylosyl tripeptide ester can be quantitatively achieved using [(Ph P) Pdl. Alternatively, carboxylic acids can be 3 4 protected as their (4-trimethylsilyl)but-2-enyl esters. Removal of this protecting group is effected by addition of [(Ph P) Pd] to 3 4 yield trimethylsilyl esters which are readily hydrolysed (Scheme 26) .40 Thiazetidines of the type shown below also undergo a 1,3-allyl rearrangement to give the corresponding thiazines (Scheme 27). This rearrangement is catalysed by [(Ph P ) RhC11. 41 3 3 A catalytic amount of [(Ph P) Pd] causes the rearrangement of 3 4 the carbohydrate-derived vinyl epoxide shown below to a 3 : l mixture of E- and Z-a,B-unsaturated aldehydes (Scheme 28).42 A review of some prostaglandin syntheses includes several examples of palladium-catalysed rearrangements of vinyl epoxides and also of transition metal-catalysed reactions of endoperoxides 43 y,b-Unsaturated aldehydes rearrange to cyclopentanones upon treatment with [(Ph3P)3RhC1] (Scheme 29). 44 [(PhCN)2PdC121 catalyses the cyclization of 3-, 4-, and 5-alkynoic acids to 3-buten-4-olides, 4-penten-4-olides, and 5-

.

.

General and Synthetic Methods

412

[ Fe2(C0

P 77%

Scheme 2 3

[Rh((+)- binap )(cod)]+

96% e.e.

Scheme 2 1

Scheme 2 5

413

Organometallics in Synthesis

Z-Set -Ala -Ala

@?

BnO

- 0/=

Z-Ser -Ala -Ala-OH

BnO

OBn

I

OBn Z = benzyloxycarbony 1 6 n = benzyl

R

SiMe,

+ R C C O + OSiMe3

'

RCOzH Scheme 26

80 - 98%

Pdo

414

General and Synthetic Methods

Scheme 2 9

RC

= c -CH,CO,H

t(PhCNlzPdCl~]

HC

C- CHZCH,CH,COzH

HC

C

R -CHzCHCOzH

40 - 95 'lo

Et3N

PdCIz, MeCN

43 %

Et3N

[(PhCN)+'dCIZ

I

Et3N

63 - 100 '10

Scheme 3 0

9 5 '10 Scheme 31

415

6: Organometallics in Synthesis hexen-5-olides

r e s p e c t i v e l y (Scheme 3 0 ) .45

5 Carbon-Carbon Bond-forming R e a c t i o n s v i a Organometallic Electrophi1es.v i n y l acetate, N-phenylhydroxamic

I n t h e p r e s e n c e of L i 2 P d C 1 4 a n d a c i d s g i v e N-phenyl-2-

vinylhydroxamines which r e a r r a n g e t o N-acyl-indoles 2-Substituted buta-1,3-dienyl

(Scheme 3 1 ) .

46

c o m p o u n d s may b e p r e p a r e d i n h i g h

i s o m e r i c p u r i t y by a [ P d ( P P h ) I - E t 3 N c a t a l y s e d e l i m i n a t i o n 3 4 r e a c t i o n on m e t h y l v i n y l c a r b i n o l a c e t a t e s (Scheme 3 2 ) . " A l l y l c a r b o n a t e s may b e u s e d i n a v a r i e t y o f t r a n s i t i o n metalc a t a l y s e d s - a l l y l a t i o n r e a c t i o n s (Scheme 3 3 ) .

No a d d e d b a s e i s

r e q u i r e d s i n c e one e q u i v a l e n t o f a l k o x i d e is l i b e r a t e d from t h e a l l y l c a r b o n a t e . C a r b o n n u c l e o p h i l e s may b e a l l y l a t e d i n t h e presence of [RhH(PPh3)4(PB~n3)1. O f p a r t i c u l a r n o t e is t h e very r e g i o s e l e c t i v e S N 2 r a t h e r t h a n S N 2 ' s u b s t i t u t i o n of s e c o n d a r y a l l y l c a r b o n a t e s . 48 P a l l a d i u m p h o s p h i n e c o m p l e x e s c a t a l y s e t h e a l l y l a t i o n of k e t e n e t r i m e t h y l s i l y l a c e t a l s t o g i v e a - a l l y 1 e s t e r s . With p h o s p h i n e - f r e e formed .4g

palladium c a t a l y s t s a,@-unsaturated e s t e r s are

Nitroacetic esters g-allylate with a l l y l carbonates,

phenyl e t h e r s , and a c e t a t e s i n t h e p r e s e n c e o f t h e c a t a l y s t [ P d ( d p p e I 2 1 .50 The p a l l a d i u m - c a t a l y s e d

1,4-addition of nucleophiles t o vinyl

epoxides provides a regio-

and s t e r e o - s e l e c t i v e method f o r t h e

i n t r o d u c t i o n o f s t e r o i d s i d e c h a i n s (Scheme 3 4 ) .51 V i n y l s u l p h i d e a l l y l i c acetates r e a c t w i t h sodium d i m e t h y l m a l o n 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 [ P d ( d ~ p e ) ~w]i t h c l e a n r e g i o - and s t e r e o - s p e c i f i c s u b s t i t u t i o n o f t h e a c e t a t e moiety a n d r e t e n t i o n o f c o n f i g u r a t i o n , making s u c h compounds u s e f u l e q u i v a l e n t s o f e n o n e s i n M i c h a e l a d d i t i o n s ( S c h e m e 3 5 .52 A l l y l a c e t a t e s may b e c o n v e r t e d i n t o a l l y l s t a n n a n e s u s i n g This represents an o v e r a l l inversion of ) 1. 3 4 t h e e l e c t r o p h i l i c c h a r a c t e r of a l l y acetates t o t h e n u c l e o p h i l i c c h a r a c t e r of a l l y l s t a n n a n e s , w h i c h a r e i n a c c e s s i b l e b y o t h e r [Et2A1SnBu3]-[Pd(PPh

r o u t e s b u t c a n b e r e a d i l y p r e p a r e d i n t h i s way ( S c h e m e 3 6 ) .53 Whereas a - n i t r o - o l e f i n s

undergo Michael a d d i t i o n s w i t h secondary

a m i n e s , i n t h e p r e s e n c e of [Pd(PPh ) 1 a l l y l a m i n e s are formed 3 4 ( S c h e m e 3 7 ) 54 T h e m e c h a n i s m p r e s u m a b l y i n v o l v e s i n i t i a l

.

isomerization t o 3-nitro-olefins

f o l l o w e d by f o r m a t i o n of n 3 - a l l y l

p a l l a d i u m i n t e r m e d i a t e s w i t h l o s s of n i t r a t e . 1,3- a n d 1 , 4 - D i e n e s r e a c t w i t h LiPdC13 a n d o r g a n o m e r c u r i a l s

416

General and Synthetic Methods

I OAc

66 */a , 9 8 % isomeric purity

Scheme 32

vR +

CH,(CO,Me),

OC02Me

-

~ C H ( C 0 2 M e ) z R

-

71 86 %

R

-C02Me \

4 "

C02Me

R

-

70 8 0 ° / o

I

X = OAc , OPh ,or OC02Et Reagents : i , [ R h H I ,1OO'C, 2h; ii,Pd(OAc)Z,H.$=CHCHzOC02Me,MeCN; HZC = CHCH20C02Me, dio~ane,[Pd~(dba)~(CHCL$l, dppe; iv, [ P ~ ( ~ P P ~ ) ~ I

Scheme 33

iii,

6: Organometallics in Synthesis

417

OH

0

86 ' l a

(3) Reagents : i , [ P d 3 ( T B A A I 3 ( C H C L 3 ) ] , ii,CH?(CO?Me)? ( 2 ) ; iii, (3)

Scheme 3 4

Jc

(y

PhS

&m

-

PhS

OAc OSiButMez

PhS 78 Ole

i

OSiButMez

0 Reagents : i , 'CH(C0zMe)2,

[Pd(dp~e)~]

Scheme 35

PhS

41 8

General and Synthetic Methods

X=Oi

86%

X = NAc; 74'10

Scheme 38

R

R

R

iii4

I.

R e a g e n t s : i , - C H ( C 0 z M e ) 2 ~i i , 1 2 ; i i i , 0 3 ; i v , M e 2 S

Scheme 39

0

419

6: Organometallics in Synthesis

q3-allyl intermediates, bearing heteroatoms to give, heteroannulated products (Scheme 38) .55 Cyclohexadiene molybdenum cations react stereospecifically with stabilized carbanions to give q3-allyl intermediates which may be converted into either substituted allylic iodides or lactones on oxidation with iodine (Scheme 3 9 ) . 5 6 A similar type of reactivity is observed for tricarbonyl (cycloheptatriene )manganese cations .57 An enantiospecific synthesis of (-)-Gabaculine has been achieved via an optically active tricarbonyl(cyclohexadieny1)iron cation (Scheme 40) .58 The increased stabilization of benzylic carbanions and the regiospecific ortho-lithiation of anisole derivatives co-ordinated to tricarbonylchromium have been employed f o r the synthesis of Il-deoxydaunomycinone from tricarbonyl(3,4-dihydro-5methoxynaphthalene) chromium (Scheme 4 1 ) 59 Manganese acetate [Mn O(0Ac) 1 in acetic acid converts 3 7 unsaturated B-keto-acids into polycyclic y-lactones (Scheme 42) .60

.

via Organometallic Nucleophi1es.- Alkyl-lithium or Grignard reagents with Mn12 give organomanganese iodides which with acyl chlorides give the corresponding ketones ( 5 0 - 1 0 0 % ) . The yields of ketones in these reactions are comparable to o r superior to yields obtained with alternative organometallic reagents, 3 . C d R 2 . 6 1 RCuBF3 (generated in situ from RMgX, CuI, and BF OEt2) on 3 treatment with aldimines generates secondary amines in good yield (60-80%) even if the aldimine contains a-hydrogens. 6 2 Easily enolizable ketones give tertiary alcohols in good yield (70-97%) with organocerium reagents (RCeC12) prepared from alkyl-lithiums and anhydrous CeCl 6 3 3' One alkoxy-group of an acetal of ethyl orthoformate can be substituted with RCuBF3 reagents (Scheme 43) . 6 4 Chiral acetals are cleaved by R2CuLi-BF3 stereoselectively to give secondary alcohols with up to 100% e.e. (Scheme 4 3 ) . 6 5 Whereas 3,4,4-trimethylcyclopentenone is resistant to coppermediated conjugate additions, [Ni(acac),l catalyses the conjugate addition of (p-tolyl)2Zn to give cuparenone in 67% yield (Scheme 44). 65 Chiral oxazolidines derived from trans-cinnamaldehyde undergo conjugate addition with Me2CuLi to give after hydrolysis 3-phenylbutanal with 80Y0 e. e. (Scheme 45 ) .67 Enolates derived from the iron acetyl complex

General and Synthetic Methods

420

Reagents : i , ( 4 ) ; ii, BuLi,

-78°C ; iii,(5); i v , oxidation

Scheme 41

6: Organornetallics in Synthesis

42 1

M n 30(OAc ,)

*

'q; ,

HO

Scheme 42

HC(OEt13

RCUBF~

H

80 - 92 '10

-Mex: Ph

100 Scheme 4 3

d(-4--& /

0

[~i(acac)~l

(k1-P -Cuparenone Scheme 44

80 O/O yield Scheme 45

e.e.

422

General and Synthetic Methods

[ ( C H )Fe(CO)(PPh3)COMel u n d e r g o a v a r i e t y o f e f f i c i e n t c a r b o n 5 5 carbon bond-forming r e a c t i o n s i n c l u d i n g a l k y l a t i o n and Reformatsky

a n d a l d o l - t y p e r e a c t i o n s . 68

Highly s t e r e o s e l e c t i v e a l d o l r e a c t i o n s c a n be a c h i e v e d , w i t h t h e d i a s t e r e o s e l e c t i v e p r e f e r e n c e d e p e n d i n g on t h e c o u n t e r i o n .69 7 7 0

F u r t h e r s t e r e o s e l e c t i v e e l a b o r a t i o n of t h e

a l d o l p r o d u c t s y i e l d s erythro-8-hydroxy-&-methyl a c i d s on These i r o n a c y l e n o l a t e s a l s o add

d e c o m p l e x a t i o n (Scheme46).69’

with high s t e r e o s e l e c t i v i t y t o imines t o y i e l d , after (Scheme 4 7 ) .72

decomplexation, 8-lactams

E n o l e t h e r s d e r i v e d from i r o n a c y l c o m p l e x e s a l s o u n d e r g o s t e r e o s e l e c t i v e a l k y l a t i o n r e a c t i o n s 7 3 and t h i s h a s been a p p l i e d t o t h e s t e r e o s e l e c t i v e f o r m a t i o n o f q u a t e r n a r y c a r b o n c e n t r e s (Scheme 48).74

A s e r i e s of r u l e s g o v e r n i n g asymmetric s y n t h e s i s u s i n g t h e

)I h a s b e e n p r e s e n t e d . 7 5 3 Whereas t h e Tebbe r e a g e n t [ ( C H ) T i ( C H 2 ) C 1 A 1 M e 2 1 i s r e s t r i c t e d 5 5 2 t o methylene t r a n s f e r t o carbonyl groups t h e z i r m n i u m analogue can

c h i r a l a u x i l i a r y [(C5H5)Fe(CO)(PPh

t o l e r a t e s u b s t i t u t e n t s (Scheme 4 9 ) .76 On p h o t o l y s i s [alkyl(meth~xy)carbenelCr(CO)~ c o m p l e x e s r e a c t with imines t o g e n e r a t e 8-lactams

i n g o o a y i e l d s (Scheme 5 0 ) . 7 7

Unfortunately t h e r e a c t i o n n e c e s s i t a t e s an a l k y l group a p p e a r i n g i n the +position

of t h e 8 - l a c t a m .

v i a Coupling Reactions.palladium-catalysed

V i n y l h a l i d e s a r e w e l l known t o u n d e r g o

coupling with nucleophiles.

This reaction has

been extended t o i n c l u d e v i n y l t r i f l a t e s which i n t h e p r e s e n c e of [ P d ( P P d 3 ) 4 1 c a t a l y s t c o u p l e w i t h o r g a n o s t a n n a n e s .78 G i v e n t h e e a s e o f f o r m a t i o n o f v i n y l t r i f l a t e s from r e g i o s p e c i f i c a l l y d e r i v e d e n o l a t e s t h i s p r o m i s e s t o be a v e r y p o w e r f u l m e t h o d .

.

P l e r a p l y s i l l i n - 1 h a s b e e n s y n t h e s i z e d by t h i s method (Scheme 5 1 ) 78 The c o u p l i n g o f v i n y l h a l i d e s w i t h o l e f i n s h a s a l s o b e e n e x t e n d e d t o vinyl triflates.79 A r o m a t i c m e t h o x y m e t h y l a t i o n c a n b e a c h i e v e d via t h e p a l l d i u m 80 c a t a l y s e d c o u p l i n g o f Bu SnCH20Me w i t h a r y l b r o m i d e s ( 6 0 - 7 0 % ) .

3

[NiC12(dppe)l c a t a l y s e s t h e coupling of chlorobenzenes w i t h G r i g n a r d r e a g e n t s (Scheme 5 2 ) .81 The f i r s t s u b s t i t u t i o n o f 1 , 3 , 5 t r i c h l o r o b e n z e n e i s much f a s t e r t h a n s u b s e q u e n t o n e s t h u s a l l o w i n g t h e i n t r o d u c t i o n of d i s s i m i l a r a l k y l groups. E n o l a t e s d e r i v e d from 8 - d i c a r b o n y l compounds r e a c t w i t h 2 - i o d o a n i l i n e and CuI t o g i v e , i n a o n e - p o t r e a c t i o n , 2 , 3 d i s u b s t i t u t e d i n d o l e s ( 6 0 - 8 0 % ) .82 T r i b u t y l t i n e n o l a t e s , g e n e r a t e d i n s i t u f r o m e n o l a c e t a t e s a n d Bu SnOMe, c a n b e c o u p l e d w i t h a r y l

3

423

6: Organometallics in Synthesis

iv ,v

H i#/'

selectivity

> 100 : 1 HO

Li +

q; H

Me

7 erythro

PPh,

selectivity

< 12 : 1

Reagents : i , Et2AICL ; ii ,RCHO iii,SnCl,+ ; iv, 2 Bu L i ; v , Me1

Scheme 46

PPh3

M+ = L i + or Et2Al

R ' = a r y l or a l k y l R ~ Ph = or PhCH;!

Scheme 4 7

.Me Ph3P

Reagents : i , Me1

;

ii, base ; iii , E t I i iv,-OH, Br2

Scheme 4 8

0

=be

General and Synthetic Methods

424

7 72 - 76 '1.

R

Ph

R

Lo+

-71--J 80' 1m%

L = PPh3 or PPhMe2 Reagents : i , PhCHO ii

Scheme 49

QoTf

+

Bu3SnR

(Pd(PPh3)h I

QR

R = vinyl, Bu , a l l y l , or Me3SiC

Cl

80 - 100%

Ec

R1

Cl

44 - 73 '10

42 - 50%

-

R' ,R2 = n alkyls Scheme

52

6: Organometallics in Synthesis

425

SI; BU3

Aryl

5 4*I*

86 %

Reagents : i , Bu3SnOMe ; ii , Aryl Br, K ( o - t 0 1 y l ) ~ P ) ~ P d C L ~iiil ,AcOC(Bd) iv,

@OAc , Bu3SnOMe

;v

=CH2 ;

, [ Pd 1

S c h e m e 53

RCGCH

i-iii

1 ' ' [ R C r C - C G C - 1 A RC=C-CrCE iv

R-=

-

-

73 91 @lo

67 09 '10

E = H, Me3Si,or Reagents: i , BuLi; ii ,ZnCLz ;iii,[Pd(PPh3)41,1CH=CHCIi

Scheme 5 4

i v , NaNH2; v , E+

Me

General and Synthetic Methods

426

[{(o-

a n d v i n y l b r o m i d e s i n t h e p r e s e n c e of c a t a l y t i c a m o u n t s of t o l y l ) P ) PdC121 (Scheme 5 3 ) . 8 3 Y i e l d s a r e good (70-94%) i f 3 2 e l e c t r o n - d o n a t i n g s u b s t i t u e n t s a r e p r e s e n t on t h e a r e n e r i n g b u t t h e r e a c t i o n f a i l s i n t h e p r e s e n c e of e l e c t r o n - w i t h d r a w i n g o n e s (e.g.

C N , Ac, N O 2 ) .

The s y n t h e s i s o f c o n j u g a t e d d i y n e s i s r e a d i l y a c h i e v e d palladium-catalysed

via

c o u p l i n g of t e r m i n a l a c e t y l i d e s w i t h 2 - i o d o - l -

c h l o r o e t h y l e n e f o l l o w e d by t r e a t m e n t w i t h NaNH2 (Scheme 5 4 ) .84 The d i r e c t c o u p l i n g of h a l o g e n o a l k y n e s w i t h a c e t y l i d e s g i v e s m i x t u r e s of homo- a n d c r o s s - c o u p l e d

products.

The p a l l a d i u m - c a t a l y s e d c y c l i z a t i o n of 3 - b r o m o - 2 - v i n y l a n i l i n e toluene-2-sulphonamide

p r o v i d e s a good r o u t e t o t h e o t h e r w i s e

d i f f i c u l t t o p r e p a r e 4-bromoindoles

(Scheme 5 5 ) .85

Subsequent

i n t r o d u c t i o n of c a r b o n s u b s t i t u e n t s i n t o t h e 3- a n d 4 - p o s i t i o n s proved p o s s i b l e w i t h p a l l a d i u m - c a t a l y s e d

coupling reactions.

1 , 2 , 4 - T r i a z i n e s c a n b e p r o d u c e d by t h e [ F e 2 ( C O ) g l - ~ a t a l y s e d c o u p l i n g o f a d i p o n i t r i l e s a n d a l k y l n i t r i l e s (Scheme 5 6 ) .86 b a s i c a l l y similar t y p e of r e a c t i o n p y r i d o x i n e been p r e p a r e d

via

In a hydrochloride has

a [ C ~ ( C ~ H ~ ) ~ ] - c a t a l ycsoeudp l i n g o f d i y n e s w i t h

a c e t o n i t r i l e a s t h e k e y s t e p (Scheme 5 6 ) . 8 7 The u s e o f [ ( P h P ) CoC11 t o c o u p l e b e n z o c y c l o b u t e n e d i o n e s 3 3 i n t r a m o l e c u l a r l y w i t h a c e t y l e n e s h a s b e e n s u c c e s s f u l l y employed i n 88 a s y n t h e s i s o f nanaomycin A (Scheme 5 7 ) . [ ( s 5 - C g H g ) F e ( C 0 ) 2 ( ~ 1 - C 5 H ~ ) lu n d e r g o e s D i e l s - A l d e r r e a c t i o n s

w i t h a v a r i e t y of a c t i v a t e d o l e f i n s i n c l u d i n g a c r y l o n i t r i l e and t h u s provides a s y n t h e t i c equivalent t o methyl cyclopenta-1,3d i e n e - 5 - c a r b o x y l a t e (Scheme 5 8 ) . 89

v i a Carbonylation Reactions.-

The r e a c t i o n o f chromium

vinyl(meth0xy)carbene complexes w i t h a c e t y l e n e s t o achieve b e n z a n n u l a t i o n h a s 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 a number o f s y n t h e t i c a l l y u s e f u l i n t e r m e d i a t e s (Scheme 5 9 ) . The o x i d a t i v e decomplexation c o n d i t i o n s used as t h e f i n a l s t e p i n t h e s e benzannulations determine products.90

t h e o x i d a t i o n state of t h e i s o l a t e d

I n one approach t o a n t h r a c y c l i n e s y n t h e s i s a

t e t r a c y c l i c t r i o n e h a s b e e n p r e p a r e d via t h i s m e t h o d o l o g y . Chromium a c e t y l e n i c ( m e t h o x y ) c a r b e n e c o m p l e x e s u n d e r g o tandem

Diels-Alder-benzannulation r e a c t i o n s .92 employed u n d e r m i l d c o n d i t i o n s .

A v a r i e t y of d i e n e s can be T h i s t y p e of tandem r e a c t i o n h a s

a l s o b e e n a p p l i e d t o a n t h r a c y c l i n e s y n t h e s i s . Where t h e b e n z a n n u l a t i o n r e a c t i o n is b l o c k e d by a l k y l s u b s t i t u e n t s ,

6: Organometallics in Synthesis

427

R Br

I

Ts

TS

ii

Br

1

iv

Br

f

Br I

Ts

TS

4

Br vi

81'lo

I

I

TS

50%

TS

Reagents : i,IPdCIz(MeCN)211 ii, HzC=CHR, [ P d I P ( o - t ~ i y l ) ~ } ~ iii,HgCl2, I; HCLo4 ( c a t . ) ; iv, H2C = CHCOZMe, Pd '(cat.)

; v,

HZC=CHCHzCI, Pd ' ( c a t . )

; vi

,

-

[PdIP(o tolyl)3 l4 1 ( c a t . )

Scheme 5 5

42

f "I111

111

I

I

- 71%

-Me3si ++ + O H' '

[(C MeCN SH~I~COI

SiMe3

SiMe3 SiMe3

73 OIO Scheme 5 6

H

CI-

pyridoxine HCl

General and Synthetic Methods

428

C02H

0

Nanaomycin A Scheme 57

Me02C\

9 ocj=e

,&CO2Me

MeOH,CO -IP,

C02Me

OC 8 5 '10 Scheme 5 8

429

6: Organometallics in Synthesis c y c l o h e x a d i e n o n e s a r e formed . 9 3 The i n t r a m o l e c u l a r v e r s i o n of t h e Pauson-Khand

r e a c t i o n , where

c y c l o p e n t e n o n e s a r e f o r m e d by c a r b o n y l a t i v e c y c l i z a t i o n of e n y n e s , 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 3-oxabicyclo[3.3.0loct-6-en-7o n e s g 4 a n d t o a n g u l a r l y f u s e d t r i q u i n a n e s y s t e m s (Scheme 6 0 ) .95 The i n t e r m o l e c u l a r Pauson-Khand r e a c t i o n h a s b e e n u s e d i n a p p r o a c h e s t o t h e s y n t h e s e s of p r o s t a g l a n d i n a n a l o g u e s (Scheme 6 1 ) ,96 a n d t h e c a r b o n y l a t i v e c y c l i z a t i o n o f 1 , I l - d i e n e s u s i n g [CO,(CO)~]

h a s b e e n employed i n t h e s y n t h e s i s of a - c u p a r e n o n e

.

(Scheme 62) 97 C y c l i c e t h e r s , o x i r a n e s , o x e t a n e s , and t e t r a h y d r o f u r a n s a r e o p e n e d by [(CO)5MnSiMe31; c a r b o n y l a t i o n a n d r e d u c t i o n w i t h [(CO) MnH] s u b s e q u e n t l y y i e l d s B - , 7 - , a n d 6 - s i l y l o x y - a l d e h y d e s 5 r e s p e c t i v e l y (Scheme 63) .98 A l d e h y d e s a r e c o n v e r t e d by t h e same methodology i n t o a a - s i l y l o x y - a l d e h y d e s . C y c l o b u t a n o n e s may be r i n g - e x p a n d e d

i n excellent yield t o give

d i s i l y l o x y c y c l o p e n t e n e s u s i n g c a t a l y t i c a m o u n t s of [ C O , ( C O ) ~ I i n t h e p r e s e n c e o f PPh3,

C O , and HSiEt2Me (Scheme 6 4 ) . ”

6 Miscellaneous Reactions I-Ethynyl-I-propenyl

a c e t a t e s a r e cyclized t o cyclopeqt-2-enones

u n d e r t h e i n f l u e n c e of [(MeCN)2PdC12] a s c a t a l y s t (Scheme 6 5 ) .

100

430

General and Synthetic Methodr

Fe0g(yJE -

OH

Et

___) 65iii'1.

0

ii

1

64%

Et

*Et

OMe

NH Tri sy 1

N

V

-viii

___)

0

1

OH

** OMe Scheme 59: continued on next page

OMe

43 1

5: Organometallics in Synthesis

- qR xiii, xiv

( C o J C r a

45

(

- 75 %

> 90%

trans 1

OMe

R=Ph,Me3Si,Bun, or Me Reagents : i,EtC =CEt

,45OC, 2 4 h i i i , F e m ; iii,Ce=,H20;

iv,CeH,MeOHiv,BuLii

[Cr(CO)6]i vii, NMe4Br; viii, MeS03F , i x , Me3SiOh;x, xi,450Ci xii,Fem,xiii , R C E C H ; x i v , 02

xl;",

Me3SiCl;

/ \

Scheme 59

Scheme 6 0

Scheme 61

$ $ NaNH2 Me I

0

>90

OIO

Scheme 6 2

vi,

0

56 *lo

General and Synthetic Methods

I32

ii

RCHO

R

y;"o

Reagents: i , [(CO)5MnSiMegl, CO; ii, [(C0)5MnH]

Scheme 63 ,OSiE tpMe 88 '10

i

O @

c

100 %

Reagents: i .HSiEtzMe, CO(50atm),[Co2(C0)~l,PPh3

Scheme 6 4

0 48 - 89 ' l o R$)R'

[(MeCN j2 PdCl 1 B

&

Scheme 65

89%

433

6: Organometallics in Synthesis 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

H.M.Colquhoun, J . H o l t o n , D.J.Thompson, and M.V.Twigg, "New Pathways f o r O r g a n i c S y n t h e s i s " , Plenum P r e s s , New York, 1984. J . T s u j i , S y n t h e s is , 1984, 369. R.P.Lutz, Chem. R e v . , 1984, 84, 205; L.E.Overman, Angew. Chem., I n t . Ed. E n g l . , 1984, 23, 579. L.S.Hegedus, T e t r a h e d r o n , 1984, 2415. K.H.Dotz, Angew. Chem. , I n t . Ed. E n g l . , 1984, 23, 587. E . E r d i k , T e t r a h e d r o n , 1984, 40, 641; J . L i n d l e y , N., p.1433; B.H.Lipshutz R.S.Wilhelm and J . A . K o z l o w s k C p.5 i005. K . P . C . V o l l h a r d t , Angew. Chem., I n t . Ed. ICngl., 1984, 23, 539. J.M.Brown and S.A.Hal1, T e t r a h e d r o n L e t t . , 1984, 25, 1393. D.A.Evans and M.M.Morrissey, J . Am. Chem. SOC., 1984, 3866; T e t r a h e d r o n L e t t . ., 1984. , 4617J. T s u j i , I . S h i m i z u , and I.Minami, Chem. L e t t . , 1984, 1017. S. C a c c h i , E.Morera, and G.Ortar, T e t r a h e d r o n L e t t . , 1984, 25, 4821. S. G.Davies and S.E.Thomas, S y n t h e s i s , 1984, 1027. W. A.Nugent and J . C . C a l a b r e s e , J . Am. Chem. SOC., 1984, 106, 6422. M. G - M a r t i n and B.Ganem, T e t r a h e d r o n L e t t . , 1984, 25, 2 5 1 . R . B.Gammil1 and S.A.Nash, T e t r a h e d r o n L e t t . , 1984, 25, 2953. A . K n i e r z i n g e r and A.Vasella, J . Chem. S O C . , Chem. Commun., 1984, 9. B. K o n g k a t h i p and N.Kongkathip, T e t r a h e d r o n L e t t . , 1984, 25, 2175. N.T.Byrom, R.Grigg, B.Kongkathip, G.Reimer, and A.R.Wade, J . Chem. S O C . , P e r k i n T r a n s . 1 , 1984, 1643. M-Matsumoto and N-Watanabe, J . Org. Chem., 1984, 3435. Y . T s u j i , T.Ohta, T . I d o , H.Minbu, and Y.Watanabe, J . Organomet. Chem., 1984,

40,

u.,

106,

9,

270,

333.

M.Tanaka, T.Kobayashi,

23,

and T . S a k a k u r a , Angew. Chem., I n t . Ed. E n g l . ,

1984,

518.

K.Carr and J . K . S u t h e r l a n d , J . Chem. SOC., Chem. Commun., 1984, 1227. B . E . R o s s i t e r and K . B . S h a r p l e s s , J . Org. Chem., 1984, 3707. L.D.L.Lu, R.A.Johnson, M.G.Finn, and K . B . S h a r p l e s s , J . Org. Chem., 1984,

3,

2

728. 25 26

P . P i t c h e n and H.B.Kagan, T e t r a h e d r o n L e t t . , 1984, 25, 1049. E . B r o s e r , K.Krohn, K . H i n t z e r , and V . S c h u r i g , T e t r a h e d r o n L e t t . ,

1984,

2463. 27 28

2,

106,383.

B.M.Trost, P.G.McDouga1, and K.J.Haller, J . Am. Chem. SOC., 1984, A . J . P e a r s o n , Y.-S.Chen, S.-Y.Hsu, and T.Ray, T e t r a h e d r o n L e t t . , 1984,

25,

1235. 29 30 31 32 33 34 35

G.Struku1 and R.A.Michelin, J . Chem. SOC., Chem. Commun., 1984, 1538. J . E . B a c k v a l 1 , S.E.Bystrom, and R.E.Nordberg, J . Org. Chem., 1984, 4619. J . E . B a c k v a l 1 , J . V a g b e r g , and R.Nordberg, T e t r a h e d r o n L e t t . , 1984, 25, 2717. J.E.McMurry and P.Kocovsky, T e t r a h e d r o n L e t t . , 1984, 4187. J.K.Cha, W . J . C h r i s t , and Y . K i s h i , T e t r a h e d r o n , 1984, 2247. A.B .Holmes, K . R u s s e l l , E.S. S t e r n , M. E. S t u b b s , and N.K.Wellard, T e t r a h e d r o n L e t t . , 1984, 25, 4163. G-Lesma, G.Palmisano, and S . T o l l a r i , J . Chem. SOC., P e r k i n T r a n s . 1 , 1984,

9,

z, 2,

1593.

36 37

.

1984, 38 39 40 41

42 43

.

.

.

.

.

K Tan i , T Yamagat a , S Akut ag awa , H Kumobay a s h i , T Taket omi , H Takay a , A . M i y a s h i t a , R.Noyori, and S . O t u k a , J . Am. Chem. S O C . , 1984, 5208. E.Curzon, B.T.Golding, C . P i e r p o i n t , and B.W.Waters, J . Organomet. Chem.,

262,

106,

263.

Y.Tamaru, Y.Yamada, H . O c h i a i , E.Nakajo, and Z . Y o s h i d a , T e t r a h e d r o n , 1984 9 40. 1 7 9 1 .

71

-

H . M a s t a l e r z , J . Org. Chem., 19' N.K.Capps, G.M.Davies, and D.W. Young, T e t r a h e d r o n L e t t . , 1984, 2 5 , 4157. S.Achab, J . P . C o s s o n , and B.C.Das, J . Chem. SOC., Chem. Commun., 1984, 10140. R.Noyori and M.Suzuki, Angew. Chem., I n t . Ed. E n g l . , 1984, 23, 847.

General and Synthetic Methods

434 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

K . S a k a i , Y.Ishigut-o, K.Funakoshi, K.Ueno, and H.Suemune, T e t r a h e d r o n L e t t ., 1984, 25, 961. C.Lambert, K.Utimoto, and H.Nozaki, T e t r a h e d r o n L e t t . , 1984, 25, 5323. P . M a r t i n , Helv. Chim. Acta, 1984, 1647. A . C a p r i t a , F . B o n a c c o r s i , and R.Rossi, T e t r a h e d r o n L e t t . , 1984, 2 5 , 5193. 5157. J . T s u j i , I.Minami, and I . S h i m i z u , T e t r a h e d r o n L e t t . , 1984, J . T s u j i , K.Takahashi, I.Minami, and I . S h i m i z u , T e t r a h e d r o n L e t t . , 1984, 4783. J.P.Genet and D.Ferroud, T e t r a h e d r o n L e t t . , 1984, 2, 3579; D.Ferroud, J . P . G e n e t , and J . M u z a r t , p.4379. T . T a k a h a s h i , A.Ootake, and J . T s u j i , T e t r a h e d r o n Lett., 1984, 25, 1921. 2246, S.A.Godleski and E . B . V i l l h a u e r , J . Org. Chem., 1984, 6835. B.M.Trost and J.W.Herndon, J . Am. Chem. S O C . , 1984, R.Tamura, K.Hayashi, Y.Kai, and D.Oda, T e t r a h e d r o n L e t t . , 1984, 2 5 , 4437. F62. R.C.Larock, L.W.Harrison, and M.H.Hsu, J . Org. Chem., 1984, 1872 ; T e t r a h e d r o n A.J.Pearson and M.N.I.Khan, J . Am. Chem. SOC., 1984, 1984, 25, - 3507. A . J . P e a r s o n , P.Bruhn, and I . C . R i c h a r d s , T e t r a h e d r o n L e t t . , 1984, 387 B.M.R.Bandara, A.J.Birch, a n d L . F . K e l l y , J . Org. Chem., 1984, 2496. M.Uemura, T.Minami, and Y.Hayashi, J . Chem. SOC., Chem. Commun., 1984, 1 193. E.J.Corey and M. Kang, J . Am. Chem. SOC., 1984, 5384. G . F r i o u r , G . C a h i e z , and J . F.Normant , S y n t h e s i s , 1984, 37. M.Wada, Y.Sakurai, and K.Akiba, T e t r a h e d r o n L e t t . , 1984, 25, 1079. T.Imamoto, Y . S u g i u r a , and N.Takiyama, T e t r a h e d r o n L e t t . , 1984, 25, 4233. A . G h r i b i , A - A l e x a k i s , and J.F.Normant, T e t r a h e d r o n L e t t . , 1984, 3075 A . G h r i b i , A - A l e x a k i s , and J.F.Normant, T e t r a h e d r o n L e t t . , 1984, 3083 A.E.Greene, J.P.Lansard, J.-L.Luche, and C . P e t r i e r , J . Org. Chem., 1984, 931. J . B e r l a n , Y.Besace, D . P r a t , and G . P o u r c e l o t , J . Organomet. Chem., 1984, 399. N.Aktogu, H . F e l k i n , G . J . B a i r d , S . G . D a v i e s , and 0-Wat ts , J . Organomet. Chem., 49. 1984, S.G.Davies, I.M.Dordor, and P.Warner, J . Chem. SOC., Chem. Commun., 1984, 956. L . S . L i e b e s k i n d and M.E.Welker, T e t r a h e d r o n L e t t . , 1984, 25, 4341. S.G.Davies, I.M.Dordor, J. C.Walker, and P.Warner , T e t r a h e d r o n L e t t . , 1984, 2 5 , 2709. 1743; K.Broadley and S.G.Davies, T e t r a h e d r o n L e t t . , 1984, L . S . L i e b e s k i n d , M.E.Welker, and V.Goedken, J . Am. Chem. SOC., 1984, 441. G . J . B a i r d , S.G.Davies, R.H.Jones, K . P r o u t , and P.Warner, J . Chem. SOC* , Chem. Commun., 1984, 745. P . J . C u r t i s and S.G.Davies, J. Chem. S O C . , Chem. Commun., 1984, 747. S.G.Davies and J . I . S e e m a n , T e t r a h e d r i3n L e t t . , 1984, 25, 1845. S.M.Clift and J . S c h w a r t z , J . Am. Chem. SOC., 1984, 106, 8300. L.S. Hegedus, M. A. McGuire, L .M. S c h u l t !ze. C.Yi.iun. . and 0.P.Anderson , J . Am. Chem. SOC.. 1984. 106. 2680. W.J.Scott, G.T.Crisp, and J . K . S t i l l e , J . Am. Chem. SOC., 1984, %, 4630. 2271. S . C a c c h i , E.Morera, and G-Ortar, T e t r a h e d r o n L e t t . , 1984, M.Kosugi, T.Sumiya, T.Ogata, H.Sano, and T . M i g i t a , Chem. L e t t . , 1984, 1225. K.C.Eapen, S.S.Dua, and C.Tamborski, J . Org. Chem., 1984, 4 9 , 478. H.Suzuki, S.V.Thiruvikraman, and A.Osuka, S y n t h e s i s , 1 9 8 4 , 7 1 6 . M.Kosugi, I.Hagiwara, T . S m i y a , and T . M i g i t a , B u l l . Chem. S O C . , J p n . , 1984, 5 7 , 242. E . N e g i s h i , N-Okukado, S . F . L o v i c h , and F.T.Luo, J . Org. Chem., 1984, 2629. 2657. P . J . H a r r i n g t o n and L.S.Hegedus, J . Org. Chem., 1984, E.R.F.Gesing, U.Groth, and K.P. C - V o l l h a r d t , S y n t h e s i s , 1984, 351. R.E.Geiger , M.Lalonde, H . S t o l l e r , and K . S c h l e i c h , Helv. Chim. A c t a , 1984, 6 7 , 1274. 4181. M.S.South and L . S . L i e b e s k i n d , J . Am. Chem. SOC., 1984,

3,

25,

w.,

9, 106,

78 80 81 82 83 84

85 86

87 88

106,

g.,

2,

25,

2,

106,

25, 25,

264,

262,

-

25,

106, -

,

I

79

2,

-

- 7

25,

-

9,

9,

-

106,

6: Organometallics in Synthesis

43 5

M.E.Wright , J. F.Hoover , G.O.Nelson, C.P.Scott, and R.S.Gfass, J. Org. Chem., 1984, 2, 3059; R.S.Glass and W.W.McConnel1, Organometallics. 1984, 3, 1630. -. 90 W.D.Wulff, K.-S.Chan, and P.-C.Tang, J. Org. Chem., 1981+,49, 229 3. . 1984, 106, 4 3 4 7 W.D.Wulff and P.-C.Tang, J. Am. Chem. SOC.. 91 W.D.Wulff and D.C.Yang, J. Am. C-hem. SOC., 1984, 106,7565. 92 P.-C.Tang and W.D.WUlff, J. Am. Chem. SOC., 1984, 106, 1132. 93 D.C.Billington and D-Willison, T'etrahedron Lett ., 1984, 25, 4041. 94 M.J.Knudsen and N.E.Schore, J. Org. Chem. - 198-4, 5 0 2 c 95 L .Daalman , R. F. Newton, P. L .Pauson, R.,G.Taylor, and A.Wadsworth, 3 . Chem. 96 Res. ( S ), 1984, 344 ; L.Daalman, R.F.Newton, P.L .Pauson, and A-Wadsworth, ib_ i_d- .-. n.246.- P.Eilbracht, E.Balss, and M.Acker, Tetrahedron Lett., 1984, 25, 1131. 97 K.C.Brinkman and J. A-Gladysz, Organometallics, 1984, 3, 147: 98 N.Chatani, H-Furukawa, T.Kato, S.Murai, and N.Smoda, J. Am. Chem. SOC., 99 1984, 106,430. 100 V.Rautenstrauch, J. Org. Chem., 1984, 2, 950. 89

2,

-

I

r - +

General and Synthetic Methods

436 PART 11:

Main Group E l e m e n t s by P. F . Gordon 1

Group I

S e l e c t i v e L i t h i a t i o n s . - S n i e c k u s and h i s co-workers have c o n t i n u e d t h e i r a c t i v e r e s e a r c h on s p e c i f i c o r t h o - l i t h i a t i o n r e a c t i o n s i n b e n z e n e compounds. Much o f t h i s work i s now t a r g e t t e d t o w a r d s p r e p a r i n g n a t u r a l p r o d u c t s , and t h i s y e a r h a s s e e n e x t e n s i v e u s e made o f t h e a m i d e g r o u p (CONEt2) a n d t o a l e s s e r e x t e n t t h e carbamate and e t h e r g r o u p s t o p r o v i d e t h e n e c e s s a r y d i r e c t i n g i n f l u e n c e . For example t h e benzamides ( l a , b ) a r e c o n v e r t e d i n t o t h e s i l y l protected 2-toluamides (2a,b) i n a sequence t h a t involves t h r e e separate l i t h i a t i o n reactions; t h e first is an orthol i t h i a t i o n and t h e second and t h i r d are used t o i n t r o d u c e t h e protecting s i l y l groups. ortho-Lithiation of t h e toluamides (2a,b) and r e a c t i o n w i t h t h e c o r r e s p o n d i n g a r y l a l d e h y d e t h e n l e a d s t o p h t h a l i d e s ( 3 ) , f r o m w h i c h t h e a n t h r a q u i n o n e s (4) a n d ( 5 ) c a n b e o b t a i n e d by c o n v e n t i o n a l f u n c t i o n a l g r o u p t r a n s f o r m a t i o n s . '2 A similar s e q u e n c e l e a d s from t h e benzamide ( 6 ) t o e r y t h r o l a c c i n t e t r a m e t h y l e t h e r ( 7 ) . 'b P a r t i c u l a r l y n o t e w o r t h y i n t h i s l a t t e r

case is t h a t r e a c t i o n w i t h t h e a r y l a l d e h y d e a c t u a l l y o c c u r s w i t h t h e i n t e r m e d i a t e g e n e r a t e d by f l u o r i d e - i n d u c e d d e s i l y l a t i o n o f t h e benzamide ( 8 ) r a t h e r t h a n d i r e c t l y from t h e o r t h o - l i t h i a t e d b e n z a m i d e , as was t h e c a s e f o r (4) a n d ( 5 ) . L i k e w i s e , t h e t r i s u b s t i t u t e d benzamide ( 9 ) is o b t a i n e d a f t e r o r t h o - l i t h i a t i o n and a l k y l a t i o n , and is f u r t h e r l i t h i a t e d and r e a c t e d w i t h a r y l a l d e h y d e s t o p r o v i d e isocoumarins ( 1 0 1 , p r e c u r s o r s t o h y d r a g e n o l and p h y l l o d u l c i n . '2 An e l e g a n t s y n t h e s i s of a n t h r a m y c i n p r e c u r s o r ( 1 1 ) u s e s t h e methylmethoxy e t h e r and carbamate g r o u p s i n c o n s e c u t i v e o p e r a t i o n s . T h u s , t h e e t h e r - c a r b a m a t e ( 1 2 ; R = NHC02But) i s p r o d u c e d f r o m t h e e t h e r (12; R = H ) , and t h e carbamate so i n t r o d u c e d i s t h e n used t o d i r e c t t h e n e x t ortho-lithiation/trapping r e a c t i o n s t o g i v e t h e t e t r a s u b s t i t u t e d benzene ( I ? , ) , which is c o n v e r t e d e a s i l y i n t o

(ll).ld Another popular o r t h o - d i r e c t i n g group is t h e o x a z o l i n e r i n g s y s t e m . Scheme 1 i l l u s t r a t e s i t s a p p l i c a t i o n t o t h e s y n t h e s i s o f 3-cyano-2-alkyl-benzoic acids (and a l d e h y d e s ) and i n v o l v e s a tandem a d d i t i o n rearrangement. Y i e l d s are u s u a l l y good a n d s u b s t i t u e n t s I R a n d R may b e v a r i e d b e t w e e n h y d r o g e n , a l k y l , a n d a r o m a t i c groups. For References see page 485,

437

6: Organometallics in Synthesis

8 pE:3 CONEt,

CONEt,

R

R &o AT

R

( 2 ) a; R = H

(1) a; R = H

b;R =OMe

(3)

b;R=OMe

R

0 (4)R = H

0 (5) R=OMe

OMe (6)

General and Synthetic Method:

43 8

Asymmetric s y n t h e s i s i n v o l v i n g l i t h i u m r e a g e n t s c o n t i n u e s t o b e a p o p u l a r and i m p o r t a n t t o p i c f o r r e s e a r c h . I n t h i s c o n t e x t , c h i r a l sulphoxide groups have achieved prominence as c h i r a l a u x i l i a r i e s and t h i s y e a r h a s s e e n s e v e r a l more e x a m p l e s o f t h e i r use.

I n t h e s y n t h e s i s of o p t i c a l l y p u r e f u r a n o n e s ( 1 4 a , b ) t h e

l i t h i a t e d s u l p h o x i d e ( 1 5 ) a c t s as a c h i r a l homoenolate a n i o n e q u i v a l e n t by a d d i n g t o a l d e h y d e s t o g i v e d i a s t e r e o i s o m e r i c

B-sulphoxide-y-lactones,which c a n b e s e p a r a t e d a n d p y r o l y s e d t o A t r u e asymmetric induction is observed w i t h c h i r a l l i t h i a t e d s u l p h o x i d e s (16), w h i c h y i e l d B - h y d r o x y k e t o n e s ( 1 7 ) and ( 1 8 ) upon r e a c t i o n w i t h a l k y l a t i n g a g e n t s and give the furanones.3

a l d e h y d e s , r e s p e c t i v e l y , and a f t e r r e d u c t i v e unmasking.

429b

A point worth n o t i n g f o r workers i n t h i s g e n e r a l f i e l d is t h a t i n

t h e a d d i t i o n o f l i t h i a t e d a r y l m e t h y l s u l p h o x i d e s (ArSOCH2Li) t o c a r b o n y l c o m p o u n d s t h e u s e of a n o r t h o - p y r i d y l s u b s t i t u t e d s u l p h o x i d e g r o u p d r a m a t i c a l l y i n c r e a s e s t h e l e v e l of a s y m m e t r i c i n d u c t i o n o v e r t h a t found w i t h t h e more u s u a l p - t o l y l group.

substituted

T h i s i n t e r e s t i n g r e s u l t may w e l l h a v e w i d e r a p p l i c a t i o n s .

P y r r o l i d i n e s , e.g.

( 1 9 ) and (201, a l s o prove t o be e x c e l l e n t

c h i r a l a u x i l i a r i e s i n t h e asymmetric a - a l k y l a t i o n and - a c e t y l a t i o n of l i t h i a t e d carboxamides ( 2 1 ) where e n a n t i o m e r i c e x c e s s e s ( e . e . ' s ) g r e a t e r t h a n 95% h a v e b e e n a c h i e v e d . 6 *

Furthermore, t h e acylated

d e r i v a t i v e s can be reduced s t e r e o s e l e c t i v e l y w i t h z i n c b o r o h y d r i d e t o g i v e t h e corresponding c h i r a l 8-hydroxy-ketone;

the overall

s e q u e n c e is t h e r e f o r e a u s e f u l a l t e r n a t i v e t o t h e a l d o l r e a c t i o n . L i k e w i s e , l i t h i a t e d c h i r a l i m i d a t e esters ( 2 2 ) are a l k y l a t e d a t t h e a-position

t o yield a,B-disubstituted

c a r b o x y l i c a c i d s w i t h good

t o e x c e l l e n t e . e , ' ~ . ~I n c o n t r a s t , i n

the a-alkylation of the

i m i n e of g l y c i n e ( 2 3 ) t h e c h i r a l g r o u p r e s i d e s i n t h e a l k y l a t i n g agents (RX*). However, t h e s t r u c t u r e o f t h e i m i n e p l a y s a n i m p o r t a n t r o l e s i n c e a m a r k e d i n c r e a s e i n t h e l e v e l of a s y m m e t r i c i n d u c t i o n is o b s e r v e d where R 1 i s p - d i m e t h y l a m i n o p h e n y l and R2 h a s 8 adamantyl. C h i r a l o x a z o l i n e s a r e y e t a n o t h e r e f f i c i e n t c h i r a l a u x i l i a r y and

a high steric requirement,

x.

h a v e b e e n u s e d t h i s y e a r by M e y e r s e t a l . i n c o n v e r t i n g 1 - a n d 2 - n a p h t h y l o x a z o l i n e s i n t o 1 , 1 , 2 - t r i s u b s t i t u t e d and 1 , 2 , 2 t r i s u b s t i t u t e d 1,2-dihydronaphthalenes, ( 2 4 ) a n d ( 2 5 ) , The o v e r a l l respectively, with high enantioselectivity

.-

p r o c e s s i n v o l v e s t h e n u c l e o p h i l i c a d d i t i o n of v a r i o u s o r g a n o l i t h i u m r e a g e n t s ( R L i ) t o a c h i r a l n a p h t h y l o x a z o l i n e f o l l o w e d by a t r a p p i n g o f t h e i n t e r m e d i a t e a z a - e n o l a t e w i t h e l e c t r o p h i l e s (E'). A mild

6: Organometallics in Synthesis

439

0x2

R’

X

R’

X = CHO or C 0 2 E t Reagents : i , RCH(CN)Li; ii, E t O H ; iii , H’or

[HI ; i v ,

RIX

Scheme 1

(17) R4 = Ar,

R5 = H

(18) R4 = a l k y i , R 5 = OH

(19) R = Me

(20)R = MOM

General and Synthetic Methods

440

h i g h - y i e l d i n g procedure f o r unmasking t h e o x a z o l i n e moiety t o g i v e a n a l d e h y d e i s r e p o r t e d i n t h e same p a p e r . A s j u s t seen, c h i r a l a u x i l i a r i e s a r e extremely important agents i n m e d i a t i n g a s y m m e t r i c i n d u c t i o n , s o new o r i m p r o v e d r o u t e s t o them a r e a l w a y s welcome. I n t h i s context c h i r a l binaphthyls (26; X , Y = B r , I ) c a n be mono- o r d i - l i t h i a t e d t o g i v e ( 2 6 ; X Li, Y = B r , I ) and ( 2 6 ; X = Y = L i ) , r e s p e c t i v e l y ; b o t h s p e c i e s are c o n f i g u r a t i o n a l l y s t a b l e b e l o w -44 O C a n d h a v e b e e n r e a c t e d f u r t h e r t o g i v e b i d e n t a t e l i g a n d s u s e f u l i n a s y m m e t r i c s y n t h e s e s , s u c h as 10 hydrogenations, V a l i n e and t h e c y c l i c u r e a ( 2 7 ; R H ) ) have a l s o been used as c h i r a l a u x i l i a r i e s . V a l i n e reacts t o form t h e i s o q u i n o l i n e ( 2 8 ) , which can be l i t h i a t e d and t h e n a l k y l a t e d t o y i e l d , a f t e r

e.

deprotection, isoquinolines (291, with enantiomeric excesses g r e a t e r t h a n 9374.’’ This r e a c t i o n has obvious a p p l i c a t i o n s i n a l k a l o i d s y n t h e s e s . On t h e o t h e r h a n d , t h e u r e a ( 2 7 ; R = H ) , p r e p a r e d f r o m e p h e d r i n i u m c h l o r i d e a n d u r e a , p r o v i d e s access t o o p t i c a l l y p u r e y - l a c t o n e s ( 3 0 ) via t h e s e q u e n c e : a l l y l a t i o n t o ( 2 7 ; R = CH2CH=CH2),

m e t a l l a t i o n and quenching w i t h e l e c t r o p h i l e s t o f o r m a l c o h o l s ( 2 7 ; R = CH=CHC(OH)R1R2), a n d f i n a l l y h y d r o l y s i s a n d o x i d a t i o n t o ( 3 0 ) . l 2 The u r e a i s p r o p o s e d t o f u n c t i o n a s a d i r e c t i n g g r o u p by s e l e c t i v e l y c o - o r d i n a t i n g w i t h t h e metal p r i o r t o q u e n c h i n g w i t h t h e e l e c t r o p h i l e . An u n p r e c e d e n t e d l y h i g h s t e r e o s e l e c t i v i t y i s o b s e r v e d d u r i n g t h e a l d o l - t y p e c o n d e n s a t i o n o f B-dimethylaminopropionates (R1R2CO)

(Me2NCH2CH2C02R) w i t h o r - a l k o x y - a l d e h y d e s , y i e l d i n g a n t i - o r methylene-8-hydroxy-y-alkoxy-esters ( 3 1 ) l 3 Best s e l e c t i v i t i e s ( 2 4 : l ) a r e f o u n d w i t h e t h e r a s s o l v e n t a n d when t h e r e a c t i o n i s c a r r i e d out under e q u i l i b r a t i n g c o n d i t i o n s .

.

S y n t h e t i c Equivalents.- 3-Alkoxyallenyl-lithium r e a g e n t s , 3. ( 3 2 1 , f u n c t i o n as B - a c y l v i n y l a n i o n e q u i v a l e n t s , r e a c t i n g w i t h e l e c t r o p h i l e s (RX, C 0 2 , Me S i C 1 , Me2S2) t o f o r m t h e o r , B - u n s a t u r a t e d 3 d e r i v a t i v e s ( 3 3 ) . 1 4 T h i s u s e f u l r e a c t i o n h a s been used i n a s h o r t s y n t h e s i s of t h e m a c r o l i d e a n t i b i o t i c p y r e n o p h o r i n . The a c y l a n i o n e q u i v a l e n t ( 3 4 ; R 1 = R 2 = H ) c a n be e a s i l y c o n v e r t e d i n t o t h e d i a l k y l a t e d compound ( 3 4 ; R 1 , R 2 = a l k y l ) f r o m w h i c h k e t o n e s (R1R2CO) c a n be o b t a i n e d a f t e r r e d u c t i o n a n d a s i l a A l t e r n a t i v e l y , ( 3 4 ; R2 = H ) c a n be Pummerer r e a r r a n g e m e n t . 1 5 l i t h i a t e d and r e a c t e d w i t h k e t o n e s (R3R4CO) t o g i v e t h e s y n t h e t i c a l l y u s e f u l v i n y l s u l p h o n e s ( 3 5 ) . Y i e l d s are i n t h e r a n g e

441

6: Organometallics in Synthesis

R

R

w;; H

(27)

(30)

(29)

Me0

E’

“+C02ROH

R’ R2 Ph02S X S i M e )

R Ph02S

Li

>=<“,:

R K ( S P h

(35)

(34)

0

R)$fR’

OMe

0

(36)

(37)

MeeButSiO -Li

R

AJphso2 NEt,

(30)

(39)

442

General and Synthetic Methods

20-87% with poorer yields tending to occur where the starting ketone is cyclic. With a very similar strategy novel acyl anion equivalents (36) are alkylated (R'X) at the allylic carbon to yield a-methylenated ketones (37) in good yield after unmasking. l6 The same methoxyallyl sulphides (36) also feature in the synthesis of more highly substituted a,~-unsaturatedketones (Scheme 2) by adopting a slightly different approach, and can therefore be classed as homoenolate dianion equivalents, an illustration of the 1'7 versatility of these simple compounds." The metallated compounds (38) and (39) also function as homoenolate anion equivalents. Compounds (38) are generated from the corresponding silyl enol ether with strong base and then react with electrophiles to provide 6-substituted ketones in good yield. l8 In contrast , the homoenolate anion equivalent (39) can be generated under the mildly basic conditions of phase-transfer catalysis and can be alkylated to yield sulphonyl esters The sulphonyl esters are [PhS02CH(R)CH2C02Me] after hydrolysis. useful intermediates in their own right since, in the same paper, their conversion into homologated esters (RCH2CH2C02Me) and also to acrylates (RCH=CHC02Me) is described. Lithium benzodithioles (40) are shown to be new carboxyl carbanion equivalents.20 They can be generated readily either by deprotonation of 2-methylthio-1,3-benzodithioles or by thiophilic addition of methyl-lithium to 2-phenylenetrithiocarbamates. The anions (40) so generated can be trapped by alkylating agents and also undergo an unexpected carbophilic addition reaction with cyclic trithiocarbonates to yield unsymmetrical hexathio-orthooxalates ( 4 1 ) , which are difficult to prepare by conventional methods. The interest in these latter molecules presumably arises from their application, after suitable modification, to the field of electronics. Miscellaneous.- The synthetic utility of lithiated hydrazones is well recognized, and Scheme 3 illustrates a crop of useful transformations which involve their intermediacy and further underline their flexibility and versatility. 21a,b In a similar context, lithiated allenes, e.g. (421, can be seen to be versatile intermediates for the preparation of highly substituted 2,5-dihydro-oxoles .22 In all cases the first step is electrophilic addition of a ketone o r an aldehyde to the lithium salt, and the various oxoles are then produced by suitable

443

6: Organometallics in Synthesis

(36)

i

R k

R .

1

ii

r,

PhS+,

SPh OMe

OMe

1

iii

R

R

Reagents : i , L D A , RIX ; ii , s i 0 2 ; iii , LDA, R2X ; i v , NaI04

Scheme 2

L

R'

R2

R2

X = CN or C02Me

OH

Y R', R2# H/

/

\

v ii

VI

\

vi

I

NHPh Reagents : i , R 3 R 4 C 0 , P C l 3 , i i , R 3 R 4 C 0 , R S H i iii, ff4CH=CHX;

HOAc

; vii

, P d / C ; v i i i , TFA

Scheme 3

iv, EtSH ; v , P t O Z ; v i , Zn,

General and Synthetic Methods

44

+

phSKLi R’

ARl

Me

Me

(421

Br

Me

SPh

/

\

R 22C0

1

Me

-

PhS

H+, R’

P

=H

o

HA H+R’-Me R’ Me

R’

Li

I

.

0

SPh

6: Organometallics in Synthesis

445

synthetic manipulation of the intermediate allenes (43) as shown. Addition of aldehydes and ketones to lithium carbanion is a well known and extremely useful reaction for the construction of carboncarbon bonds. Indeed several examples of this reaction have already been mentioned; however, two more which fall into this general category are concerned with homologation of an aldehyde or ketone by one or three carbon atoms. Thus, the lithium salt (44) is a readily accessible and convenient reagent for the homologation of aldehydes and ketones (R1R2CO) by one carbon to keteneacetals [R1R2C=C(SPh)OMe] .23 These latter intermediates are readily converted into ketene 2-silyl-2-acetals, thioesters, and carboxamid s. The lithiated compound (45) also reacts with aldehydes (RICH01 to give three-carbon homologated ketones (46) in which the carbonyl group has effectively undergone a 1,2t r a n s p ~ s i t i o n . ~The ~ key to this transformation is a new modification of the Peterson reaction in which (45) is first treated with titanium(1V) isopropoxide, then the aldehyde, and finally hydrolysed. A very useful one-carbon homologation provides access to aldehydes starting from an organolithium reagent and the new formylating reagent N-formylmorpholine .25 The yields are generally good and the formylating reagent may also be used with Grignard reagents. Several papers have recently appeared concerned with the nucleophilic attack of carbanions upon nitrophenyl and nitropyridine rings according to equation ( 1 ) The carbanions are generated from alkyl nitriles, esters, sulphones, and sulphonamides, and bear an a-chloro- or a-(thio)alkoxy-group. Several simple generalizations can be made about the reaction: the carbanions add at positions ortho- or para- to the nitro-group and lose the a-chloro- or a-(thio)alkoxy-group from the attacking species and a proton from the ring. Electron-donating and -accepting groups do not impede the reaction although nitrophenols do not participate at all and, interestingly, nucleophilic replacement of hydrogen proceeds faster than the corresponding substitution of halogens at the ortho- or para-positions. A more conventional reaction is the intramolecular nucleophilic attack of lithiated phenyl compounds upon a,b-unsaturated sulphones used in the construction of polycyclic system^.^' The method is sufficiently versatile as to allow several fused rings to be created in a one-pot reaction as shown by the example in equation

.26a-e

(2)

-

446

General and Synthetic Methods

X = C l , O R , or SR Y = SOZR S02NR'R2, C02R

~r

CN

6: Organometallics in Synthesis

44'

I - L i t h i o - I - a l k y n e s a r e known t o f o r m r e a d i l y b e c a u s e o f t h e a c i d i t y of t h e t e r m i n a l a l k y n e p r o t o n , a n d w i l l t h e n a d d t o e p o x i d e s i n h i g h y i e l d a n d u n d e r m i l d c o n d i t i o n s ( r . t . 1 t o g i v e 3a l k y n - 1-01s. 28 as catalyst.

It is, however, necessary t o use t r i m e t h y l g a l l i u m F o r l e s s r e a d i l y f o r m e d metal s a l t s s o d i u m a m i d e -

a l k o x i d e complex b a s e s h a v e b e e n p r o p o s e d f o r t h e e f f i c i e n t deprotonati6n of imines, aldehydes,

1 , 3 - d i t h i a n e s , and

d i t h i o a c e t a l s , and have a l s o been used i n m e t h y l s u l p h e n y l a t i o n o f ketones

.*'

R e a c t i o n c o n d i t i o n s i n v o l v i n g t h e s e b a s e s are m i l d ,

y i e l d s a r e v e r y a c c e p t a b l e , a n d t h e i r low c o s t m u s t r a t e as a m a j o r advantage.

Finally, a report has appeared d e t a i l i n g t h e e f f i c i e n t

d e p r o t o n a t i o n o f a l d e h y d e o x i m e s t o t h e i r d i a n i o n s ( a t -78 s u b s e q u e n t a l k y l a t i o n r e a c t i o n s . 30

OC)

and

T h i s p a p e r t h e r e f o r e r e f u t e s ar:

e a r l i e r p a p e r on t h e s u b j e c t . 2 Group I1 Magnesium.-

The a b i l i t y o f magnesium c a t i o n s t o c o - o r d i n a t e w i t h

l i g a n d s p a r a l l e l s t h a t of l i t h i u m , and s o it i s n o t s u r p r i s i n g t o f i n d t h a t magnesium r e a g e n t s w i l l u n d e r g o many o f t h e h i g h l y s p e c i f i c r e a c t i o n s f a c i l i t a t e d by o r g a n o l i t h i u m s .

I n f a c t many o f

t h e c h i r a l a u x i l i a r i e s used w i t h l i t h i u m r e a g e n t s f o r c h i r a l i n d u c t i o n r e a c t i o n s also p r o v e e x t r e m e l y e f f e c t i v e f o r magnesium reagents.

T h i s can be i l l u s t r a t e d i n t h e s y n t h e s i s of p o t e n t i a l l y

a l l e r g e n i c c h i r a l a-(hydroxyalky1)-acrylates s u l p h o x i d e s ( 4 8 ) .31

( 4 7 ) from c h i r a l

Deprotonation of the sulphoxides (48) with

t - b u t y l m a g n e s i u m b r o m i d e f o l l o w e d by r e a c t i o n w i t h a l d e h y d e s (RCH2CHO)

l e a d s t o an i n t e r m e d i a t e which g i v e s t h e a c r y l a t e s ( 4 7 )

by t h e r m a l e l i m i n a t i o n o f t h e s u l p h o x i d e g r o u p . e x c e s s e s g r e a t e r t h a n 75% a r e a c h i e v a b l e , a n d t h e

Enantiomeric

(El- o r CS)-

i s o m e r s a r e formed a c c o r d i n g t o t h e c o n f i g u r a t i o n a t t h e s t a r t i n g c h i r a l sulphoxide group. P r o l i n o l d e r i v a t i v e s are a n o t h e r f a m i l i a r and h i g h l y e f f i c i e n t c l a s s of c h i r a l a u x i l i a r y , and have been used t h i s y e a r f o r t h e p r e p a r a t i o n o f a m i n e s (49) from e n a m i n o n i t r i l e s ( 5 0 ) a n d G r i g n a r d r e a g e n t s , R2MgBr. 32 The e n a m i n o n i t r i l e s ( 5 0 ) a r e f o r m e d i n h i g h y i e l d f r o m (S)-(+)-2-methoxymethylpyrrolidine, H C N , a n d t h e 1 c o r r e s p o n d i n g a l d e h y d e s (R C H O ) , a n d r e a c t i o n w i t h t h e G r i g n a r d r e a g e n t s t h e n o c c u r s t o g i v e a m i n e s i n 80% d i a s t e r e o i s o m e r i c A h i g h l y d i a 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 8-hydroxy-acids excesses. ( 5 1 ) a l s o p r o c e e d s by way o f a magnesium i n t e r m e d i a t e , ( 5 2 ) . 3 3

General and Synthetic Methods

448

However, u n l i k e t h e p r e v i o u s r e a c t i o n t h e organomagnesium s a l t i s o b t a i n e d by a Li-Mg e x c h a n g e u s i n g MgBr2 r a t h e r t h a n by d i r e c t magnesiation.

The a c i d s ( 5 1 ) a r e t h e n o b t a i n e d b y r e a c t i o n o f ( 5 2 )

w i t h a l d e h y d e s (R’CHO) a n d t h e c h i r a l a u x i l i a r y [Ph*CH(OH)CH20HI therefore recoverable.

A Li-Mg

is

e x c h a n g e (MgBr2) i s a l s o u s e d i n

g e n e r a t i n g t h e i s o q u i n o l i n e ( 5 3 ; X = MgBr) w h i c h g i v e s e s s e n t i a l l y one diastereoisomer o f t h e hydroxyalkylated CH(0H)Rl w i t h a l d e h y d e s (RCH0).34

isoquinolines

[53; X =

A s with the last reaction the

c h a n g e t o t h e m a g n e s i u m compound i s a c c o m p a n i e d b y a n i n c r e a s e i n s e l e c t i v i t y over t h a t found w i t h t h e c o r r e s p o n d i n g o r g a n o l i t h i u m . The k e y s t e p i n t h e f i r s t a s y m m e t r i c t o t a l s y n t h e s i s o f t h e antileukaemic s e s q u i t e r p e n e ( + ) - i v a l i n is t h e h i g h l y asymmetric (1,4)-addition

of isopropenyl Grignard reagent t o t h e c h i r a l imine

( 5 4 ) . 35 Once a g a i n , t h e h i g h e n a n t i o s p e c i f i c i t y o b s e r v e d c a n b e e x p l a i n e d by a s s u m i n g p r i o r c o - o r d i n a t i o n o f t h e i m i n e g r o u p w i t h m a g n e s i u m , t h u s l e a d i n g t o s t e r e o s p e c i f i c ( 1 , 4 ) - a t t a c k by t h e c a r b a n i o n . A s i m i l a r h i g h l y e n a n t i o s p e c i f i c r e a c t i o n o c c u r s when Grignard r e a g e n t s add ( 1 , 2 ) t o 2 - a c y l - l , 3 - o x a t h i a n e s c h i r a l hydroxy-aldehydes

(55) t o give

( 5 6 ) i n >90% e . e . a f t e r u n m a s k i n g o f t h e

o x a t h i a n e . 365 The same p a p e r d e s c r i b e s t h e p r e p a r a t i o n o f o x a t h i a n e s ( 5 5 ) from (+)-pulegone and t h e c o n v e r s i o n o f t h e hydroxy-aldehydes

i n t o t h e hydroxy-acids

and g l y c o l s .

I n a second

r e l a t e d p a p e r optimum c o n d i t i o n s f o r t h e a d d i t i o n o f G r i g n a r d r e a g e n t s t o o x a t h i a n e s ( 5 7 ) a r e r e p o r t e d t o y i e l d > 9 5 % of o n e diastereoisomer of t h e adduct.

362

P u b l i c a t i o n s i n t h e m a g n e s i u m a r e a h a v e by no m e a n s b e e n confined t o c h i r a l induction reactions.

Indeed s e v e r a l papers have

been concerned w i t h t h e p r e p a r a t i o n of s u b s t i t u t e d k e t o n e s from c a r b o x y l i c a c i d esters, c h l o r i d e s , and amides.

For e x a m p l e ,

a - s i l y l - e s t e r s react w i t h an e x c e s s of G r i g n a r d r e a g e n t t o g i v e a - s i l y l - k e t o n e s i n g o o d y i e l d s , 37 a n d d i c h l o r o m e t h y l k e t o n e s [C12CHC( O)R2] a r e o b t a i n e d i n f a i r l y a c c e p t a b l e y i e l d s by r e a c t i o n of a,a-dichloroacetyl (R2MgX). 38

c h l o r i d e (C12CHCOC1) w i t h G r i g n a r d r e a g e n t s

Another p a p e r d e s c r i b e s a similar though h i g h e r

y i e l d i n g c o u p l i n g between a c y l c h l o r i d e s and Grignard r e a g e n t s t o g i v e both a l i p h a t i c and a r o m a t i c k e t o n e s ; t h e key t o the h i g h y i e l d s i s , i n p a r t , d u e t o t h e u s e o f a n i r o n ~ a t a l y s t . ~ ’H i g h y i e l d s are a l s o a t t a i n a b l e i n t h e a d d i t i o n of Grignard reagents (RMgX) t o N , N - d i m e t h y l f o r m a m i d e ,

a c e t a m i d e , and dimethylbenzamide

40

g i v i n g a l d e h y d e s , e t h y l k e t o n e s , and phenones, r e s p e c t i v e l y . T h i s is c o n t r a r y t o e a r l i e r r e p o r t s o f s u c h r e a c t i o n s and t h e

44

6: Organometallics in Synthesis

OH

0

II

Tol--- S-CHZfnCL

..A

(58)

(60) Me

I

ySiCH2MgCI

I

Me

R

A

ye

R'

0

Scheme 4

Reagents : i, EtOH , H';

ii , NaBH4 ; iii, ti+

450

General and Synthetic Methods

authors point out the importance of carrying out the reaction under mild conditions (0-20 O C ) whilst avoiding an excess of the Grignard reagent. Aromatic and unsaturated aldehydes are also obtained in high yield after the addition of Grignard reagents to lithium o r sodium formate. 41 A new Grignard reagent ( Pr10Me2SiCH2MgC1) for hydroxymethylating ketones and aldehydes provides access to glycols in a simple twostep reaction. 422 After addition of the Grignard reagent to the carbonyl group the silicon-carbon bond is oxidatively cleaved to provide the second glycolic hydroxy-group. The same authors have used another hydroxymethyl anion synthon to convert a,@-unsaturated ketones to y-hydroxy-ketones as shown in Scheme 4. 42 2 Equation (3) shows a novel primary amino-protected Grignard reagent useful for the preparation of 2-substituted pyrrolidines .43 Zinc and Mercury.- Organozinc reagents generally find less use in organic synthesis than the corresponding organomagnesium reagents, and certainly their use in stereocontrolled syntheses has been less explored. Nevertheless, the following illustrates the potential for enantioselective syntheses involving organozincs. In the addition of diethylzinc to benzaldehyde a catalytic quantity of a chiral 2-amino-l-alcohol ensures an almost quantitative yield of optically active l-phenylpropan-1-01 (50% e.e.) ,44 and in the addition of sulphoxides ( 5 8 ) to the same aldehyde even higher diastereoselectivity (>80%) is observed in the formation of the corresponding alcohols .45 Continuing in the same vein, the allenic zinc reagents (59) add in a regio- and stereo-selective manner to aldehydes, giving threohomopropargylic alcohols (60) in a remarkable 96-99% diastereoisomeric purity. 46 In contrast, high erythro-selectivity is observed in the addition of allylic zinc reagents to aldehydes (61) and, after further synthetic manipulation, the lactones (62) are formed in good yield.47 Cyclopropanations involving zinc reagents are probably the most widely practised reactions in the zinc field, and so new examples further extending the usefulness of this reaction are always worthy of mention. This is so for a novel synthesis of cyclopropanecarboxylic acid ester (63) by an unprecedented cyclopropanation of ketene alkyl silyl acetals (64) with bromoformdiethylzinc. 48 On the other hand, destruction of the cyclopropane ring in (65)

45 1

6: Organometallics in Synthesis

R'MoRz OSiMe,

Zn

(65) (66)

(67) SPh

R'CH=CHR2

+

1

-

0

i,ii

R3CONH2

R3C-NH

X = CN, COMe, or C02Me Reagents : i, HgN03 ; ii, CH2CHX , NaBH4

Scheme 5 R'X-CH,

R'YCH-:-Me

-C=CH

Y-CCCR ( 7 2 ) X = O,S,or C02 Y =-,co

HgCl

(73)

General and Synthetic Methods

452

by zinc chloride leads to the zinc homoenolate (66) which then undergoes conjugative addition to a,@-unsaturated ketones, with copper catalysis, giving 6-oxo-esters, and can also be 5-acylated yielding 4-oxo-esters .49 Similarly, transition-metal catalysis [Ni(acac)21 promotes conjugate audition of dimethylzinc to the cyclopentenone (67) to give (*)-B-cuparenone, a reaction not possible with lithium-copper and magnesium-copper reagents. 50 In a quite different reaction dimethylzinc has again been used for the introduction of a methyl group, this time by displacing a phenylthio-group in the cyclic system (68) to give the corresponding =-dimethyl compound (69), a transformation not achieved with various other common organometallic reagents. Amino- and amido-mercurations have received particular attention in the past few years and continue to provide useful routes to synthetically valuable compounds. This is demonstrated by publications which describe the tandem amidomercuration-reductive alkylation of alkenes (Scheme 5 ) , 5 2 and the catalytic aminomercuration of propargyl ethers and thioethers (70) to provide B-oxy- and B-thio-enamines (71) in yields varying between 20 and 8 0 7 0 . ~ Similarly ~ the acetylenic linkage in aryl acetylenes (72) is attacked by oxygen o r sulphur, yielding mercurated heterocycles (73) in fair to good yields.54 The mercury reagent used to effect the ring closure is the conventional combination of mercuric acetate-acetic acid and, in the same paper, the further conversion of appropriately substituted (73) to the coumarin and commestan ring systems (by carbonylation) is described. Vinyl mercurials are available by an improved stereospecific approach via hydroboration-mercuration of acetylenes, and have then been converted into predominantly trans-a,@-unsaturated esters by selectivity is also observed in the novel ~ a r b o n y l a t i o n . ~High ~ reaction of acetyl hypofluorite with aromatic mercury compounds to furnish fluoroaromatics in which the fluorine enters exclusively at the position vacated by the mercury. 56

3 Group I11 Boron.- Several papers have appeared relating to asymmetric hydroborations, and therefore further extend the scope of this important reaction. In the reduction of a-keto-esters to a-hydroxy-esters optical purities of up to 100% are achieved when B- ( 3-pinanyl)-9-BBN (74) is the reducing agent. 57 Not

6: Organornetallics in Synthesis

453

s u r p r i s i n g l y , t h e b e s t o p t i c a l p u r i t i e s a r e o b t a i n e d when t h e t b u t y l esters a r e used r a t h e r than l e s s s t e r i c a l l y hindered e s t e r s . I t is n o t necessary t o s t a r t with a c h i r a l boron r e a g e n t t o e f f e c t a n a s y m m e t r i c i n d u c t i o n , as shown i n t h e r e d u c t i o n o f a r o m a t i c k e t o n e s by ammonia-borane.58 I n t h i s c a s e c h i r a l crown e s t e r s a r e a d d e d t o y i e l d a complex which t h e n f u r n i s h e s t h e c o r r e s p o n d i n g c h i r a l secondary a l c o h o l s with enantiomeric excesses i n t h e range 20-67%. H i g h e r e . e . ' s ( 7 6 - 9 0 % ) a r e o b s e r v e d when l i t h i u m b o r o h y d r i d e is combined w i t h N , N ' - d i b e n z o y l c y s t i n e t o r e d u c e a r o m a t i c a n d a , B - u n s a t u r a t e d k e t o n e s .59 High chemical y i e l d s a r e a l s o observed Asymmetric r e a c t i o n s i n v o l v i n g b o r o n r e a g e n t s a r e n o t r e s t r i c t e d j u s t t o r e d u c t i o n s , b u t can be a p p l i e d t o t h e c o n s t r u c t i o n of carbon-carbon bonds. T h u s , t h e c h i r a l b o r o n a t e ( 7 5 ) a d d s t o ak e t o - e s t e r s and a l d e h y d e s t o y i e l d c h i r a l a l c o h o l s ( 7 6 ) w i t h a d i a s t e r e o s e l e c t i o n o f 1 4 : 1 . 6o I n t e r e s t i n g l y , t h e a s y m m e t r i c i n d u c t i o n o r i g i n a t e s f r o m a c h i r a l c e n t r e i n t h e THP p r o t e c t i n g g r o u p . A s i m i l a r a p p r o a c h i s u s e d w i t h t h e THP p r o t e c t e d b o r o n a t e ( 7 7 ) t o s e c u r e t h e asymmetry i n a s y n t h e s i s of (-I-%brevicomin. 61 In a d d i t i o n t o t h e a l l y l a t i o n r e a c t i o n j u s t d e s c r i b e d a r e t h e foliowing three enantiospecif i c a l l y l a t i o n s , confirming t h e s y n t h e t i c u t i l i t y of boron r e a g e n t s f o r such r e a c t i o n . For example, t h e c h i r a l boronate ( 7 8 ) a l l y l a t e s aldehydes (RCHO) e n a n t i o s e l e c t i v e l y t o g i v e a l c o h o l s ( 7 9 ) with e . e . ' s of g r e a t e r t h a n 90%. 6 2 g-Allyldi-isocaranylborane i s a l s o a n e x t r e m e l y e f f e c t i v e a l l y l a t i n g agent, reacting with aldehydes t o give c h i r a l h o m o a l l y l i c a l c o h o l s i n good c h e m i c a l y i e l d a n d w i t h e n a n t i o m e r i c p u r i t i e s i n t h e r a n g e 86-99%.635 The r e l a t e d b o r a n e s ( 8 0 a , b ) i s o p r e n y l a t e and m e t h a l l y l a t e a l d e h y d e s , r e s p e c t i v e l y , 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 i n t e r m e d i a t e s , one of which h a s been used i n a n e f f i c i e n t s y n t h e s i s of ( + ) a n d ( - ) - a r t e m i s i a a l c o h o l ( 8 1 1 .63* Brown and h i s c o - w o r k e r s h a v e p u b l i s h e d s e v e r a l more p a p e r s on stereoselective reactions involving boranes. I n one paper a g e n e r a l s y n t h e s i s o f E-6-alkeno-1-01s ( i m p o r t a n t s u b - u n i t s i n some p h e r o m o n e s ) i s p r e s e n t e d a c c o r d i n g t o t h e s e q u e n c e shown i n Scheme 6 . The p r o c e d u r e o f f e r s s i g n i f i c a n t a d v a n t a g e s o v e r p r e v i o u s l y p u b l i s h e d methods, e s p e c i a l l y i n view o f t h e h i g h s t e r e o s p e c i f i c i t y and t h e f a c t t h a t t h e e n t i r e sequence can be c o n d u c t e d as a ' o n e - p o t ' r e a c t i o n . 64 S e v e r a l a d v a n t a g e s accrue- from u s i n g t h e potassium b o r a t o

General and Synthetic Methods

54

( 8 0 ) a; R' = Me, R 2 = R 3 = H

b; R' = H , R 2 = R 3 = M e OMe

I

Scheme 6

6: Organornetallics in Synthesis

455

r e d u c i n g a g e n t ( 8 2 ) on k e t o n e s , i n c l u d i n g q u a n t i t a t i v e c o n v e r s i o n , e a s y r e c o v e r y of t h e p r o d u c t s , and h i g h s t e r e o s e l e c t i v i t y r e s u l t i n g , n o t s u r p r i s i n g l y , from a t t a c k o f t h e r e a g e n t a t t h e l e a s t h i n d e r e d f a c t of t h e k e t o n e .65 A r e m a r k a b l y s t e r e o s e l e c t i v e r e a c t i o n is a l s o observed i n t h e r e d u c t i o n of t h e hydroxy-ketone ( 8 3 ) i n f a v o u r o f t h e i s o m e r ( 8 4 ) .66 The r e a g e n t of c h o i c e i n t h i s c a s e is l i t h i u m t r i e t h y l b o r o h y d r i d e w h i c h g i v e s 100% s e l e c t i v i t y a n d 88% c h e m i c a l y i e l d o f ( 8 4 ) , i n a c h e l a t i o n - c o n t r o l l e d r e a c t i o n . T h i s is i n s t a r k c o n t r a s t w i t h o t h e r metal b o r o h y d r i d e s and a l u m i n i u m h y d r i d e s w h i c h show l i t t l e o r no s e l e c t i v i t y . R e p l a c e m e n t of a h y d r i d e i n b o r o h y d r i d e by a n e l e c t r o n - d o n a t i n g a l k y l a m i n o - g r o u p g r e a t l y e n h a n c e s i t s r e d u c i n g a b i l i t y . 67 T h u s , s o d i u m ( d i m e t h y l a m i n o ) - a n d (t-buty1amino)-borohydrides n o t o n l y r e d u c e a l d e h y d e s and k e t o n e s b u t a l s o e s t e r s ( t o a l c o h o l s ) , p r i m a r y amides ( t o a m i n e s ) , and t e r t i a r y amides t o amines o r a l c o h o l s , d e p e n d i n g on t h e s t e r i c b u l k o f t h e a l k y l s u b s t i t u e n t s on n i t r o g e n . However, s e c o n d a r y a m i d e s a r e u n a f f e c t e d , t h u s a l l o w i n g s e l e c t i v e r e d u c t i o n of primary and t e r t i a r y amides i n t h e p r e s e n c e o f secondary amides. Many o f t h e r e a c t i o n s j u s t d i s c u s s e d i n v o l v e a d d i t i o n s t o o r r e d u c t i o n s o f c a r b o n y l compounds; h o w e v e r , b o r o n r e a g e n t s c a n a l s o be u s e d i n t h e s y n t h e s i s o f k e t o n e s a s shown by a g e n e r a l h i g h l y e f f i c i e n t s y n t h e s i s o f 1 , 4 - , 1,5- a n d 1 , 6 - d i k e t 0 n e s . ~ ~ The method

i s e x e m p l i f i e d i n Scheme 7. C o n j u g a t e d d i e n o n e s , 3 .( 8 5 1 , a r e f o r m e d i n e s s e n t i a l l y q u a n t i t a t i v e y i e l d s by r e a c t i o n of v i n y l b o r a n e s ( 8 6 ) w i t h a t room t e m p e r a t u r e c o m m e r c i a l l y a v a i l a b l e 4-methoxybut-3-en-2-one i n e t h e r . 6 9 _Z a , B - U n s a t u r a t e d a c i d s c a n a l s o b e p r e p a r e d i n good y i e l d via o r g a n o b o r a n e s and i n o n e p a p e r p u b l i s h e d t h i s y e a r a r o u t e via a l k y n y l - b o r a t e s i s d e ~ c r i b e d . ~ ’ T h u s , t h e b o r a t e ( 8 7 ) i s c a r b o n y l a t e d and a c i d i f i e d t o y i e l d t h e u n s a t u r a t e d a c i d ( 8 8 ) . S i m i l a r b o r a t e i n t e r m e d i a t e s , j&. ( 8 9 ) , c a n b e u s e d t o p r e p a r e u , B - a c e t y l e n i c k e t o n e s ( 9 0 ) , ’5 a n d 8 - a m i n o a c e t y l e n e s ( 9 1 ) 71bby t h e i r r e a c t i o n w i t h a n h y d r i d e s [(R’CO),Ol a n d a l d i m i n e s (R1CH=NR2), respectively. S i m p l e d i a l k y l a m i n e s ( R 1 R 2 N H ) c a n a l s o b e p r e p a r e d by r e a c t i o n of an organoborane (RI3B) w i t h N-chloroalkylamines ( R 2 N H C 1 ) , g i v i n g y i e l d s v a r y i n g b e t w e e n 50% a n d V a r i a b l e y i e l d s are a l s o found i n a r y l cross-coupling r e a c t i o n s b o r a t e complexes ( s e e Scheme 8 ) . 7 3 U n s y m m e t r i c a l b i a r y l s (Ar1-Ar2) a r e f o r m e d a s shown i n t h e s e q u e n c e b e l o w , a n d t h e method p r o v e s t o b e p a r t i c u l a r l y

General and Synthetic Methods

456

RC 3 C-

BF3

RC

C-COR’

R1

6: Organometallics in Synthesis

457

e f f e c t i v e f o r c o u p l i n g f u r y 1 a n d t h i e n y l r i n g s t o each o t h e r a n d t o b e n z e n o i d r i n g s u n d e r m i l d c o n d i t i o n s . However, p o o r y i e l d s a r e o b t a i n e d when t h e c r o s s - c o u p l i n g r e a c t i o n b e t w e e n two s u b s t i t u t e d benzene r i n g s is attempted. Aluminium.- Not s u r p r i s i n g l y s e v e r a l p a r a l l e l s c a n b e d r a w n b e t w e e n t h e c h e m i s t r y of o r g a n o b o r o n and o r g a n o a l u m i n i u m compounds. One s u c h a r e a i s i n e n a n t i o s e l e c t i v e r e d u c t i o n s where b o t h b o r o n a n d a l u m i n i u m r e a g e n t s h a v e p r o v e n u t i l i t y . Once a g a i n , s e v e r a l p a p e r s have been p u b l i s h e d d e s c r i b i n g asymmetric r e d u c t i o n s w i t h aluminium r e a g e n t s . For i n s t a n c e , t h e aluminium c h l o r i d e ( 9 2 ) reduces k e t o n e s t o t h e c o r r e s p o n d i n g c a r b i n o l s i n h i g h chemical y i e l d a n d under m i l d c o n d i t i o n s . 74 Furthermore, t h e e n a n t i o m e r i c e x c e s s e s a c h i e v e d c a n be a s h i g h as 85%, a l t h o u g h t h e s t r u c t u r e of t h e k e t o n e p l a y s an i m p o r t a n t r o l e i n d e t e r m i n i n g t h e l e v e l of a s y m m e t r i c r e d u c t i o n . C h i r a l a l u m i n i u m r e a g e n t s , %. ( 9 3 ) 7 5 a n d ( 9 4 ) 7 6 , show h i g h e n a n t i o f a c i a l s e l e c t i v i t y when r e d u c i n g k e t o n e s t o t h e corresponding a l c o h o l s . I n t e r e s t i n g l y , t h e ligand used t o p r e p a r e ( 9 3 ) c a n be p r e p a r e d i n 98% o p t i c a l p u r i t y by t h e c o p p e r p r o m o t e d c o u p l i n g o f p h e n a n t h r o l ( 9 5 ) i f (!)-1,2-diphenylethylamine i s u s e d as c o - r e a c t a n t . More s i m p l y , by m o d i f y i n g l i t h i u m aluminium hydride w i t h t h e chiral sulphamide l i g a n d (96) a r e a g e n t i s o b t a i n e d w h i c h a l s o r e d u c e s k e t o n e s a s y m m e t r i c a l l y .77 I n w o r k d e s c r i b e d by T s u c h i h a s h i a n d c o - w o r k e r s on r e d u c t i v e pinacol-type rearrangements, t h e c h i r a l i t y resides n o t i n t h e aluminium r e a g e n t b u t i n t h e k e t o n e s u b s t r a t e . Thus, Dibal i n combination w i t h triethylaluminium or diethylaluminium c h l o r i d e reduces a-chiral ketones (97) t o c h i r a l a l c o h o l s ( 9 8 ) , involving a c o m p l e t e l y s t e r e o s p e c i f i c 1 , 2 - a l k y l m i g r a t i o n .782 u - C h i r a l k e t o n e s ( 9 9 ) a r e p r e p a r e d i n a n a n a l o g o u s manner s t a r t i n g f r o m c h i r a l d i o l s ( 1 0 0 ) and u s i n g t r i e t h y l a l u m i n i u m o r d i e t h y l a l u m i n i u m c h l o r i d e t o i n i t i a t e t h e r e a r r a n g e m e n t .78b,c I n t h i s l a t t e r r e a c t i o n a l k e n y l g r o u p s have a l s o been s t u d i e d a n d , n o t u n e x p e c t e d l y , are found t o migrate i n p r e f e r e n c e t o a l k y l g r o u p s . I n t h e r e a c t i o n of t r i a l k y l a l u m i n i u m w i t h t h e c h i r a l a c e t a l s ( 101 ; R 2 = a l k y l ) , a n a l k y l g r o u p f r o m t h e a l u m i n i u m r e a g e n t a d d s t o t h e d o u b l e bond w i t h c l e a v a g e o f t h e a c e t a l t o p r o v i d e c h i r a l 13s u b s t i t u t e d k e t o n e s ( 1 0 2 ) , a f t e r h y d r o l y s i ~ . ~ ~The Z choice of t h e t a r t a r i c a c i d d i a m i d e is c r u c i a l i f h i g h e n a n t i o m e r i c e x c e s s e s a r e t o b e o b t a i n e d . I n a c l o s e l y r e l a t e d r e a c t i o n , a s u r p r i s i n g degree of r e g i o - a n d s t e r e o - c h e m i c a l c o n t r o l i s o b s e r v e d f o r t h e a d d i t i o n

General and Synthetic Methods

458

Arl-

Ar2

-

Ar'

\ /

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459

6: Organometallics in Synthesis

o f a l k y l a l u m i n i u m s t o a c e t a l s ( 101 ; R 2 = H ) .792 I n 1 , 2 dichloroethane conjugate addition predominates, yielding aldehydes (1031, whereas i n chloroform a t t a c k o c c u r s a t t h e a - p o s i t i o n t o give a l l y l i c alcohols (104). S e v e r a l cases o f c a r b o n - c a r b o n bond f o r m a t i o n h a v e a l r e a d y b e e n e x e m p l i f i e d , and a f u r t h e r example which i l l u s t r a t e s t h e u s e f u l n e s 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 i n s u c h c o n s t r u c t i o n s i s g i v e n by t h e s t e r e o s e l e c t i v e r e a c t i o n of a l k e n y l a l a n e s

.

d i c h l o r o e t h y l e n e s 8o

(105) with

E-

The p r o d u c t s a r e l - c h l o r o - E , g - l , 3 - d i e n e s

( 1 0 6 ) , a n d t h e method h a s been u s e d t o p r e p a r e m e t h y l ae l e o s t e a r a t e , an i n s e c t f e e d i n g d e t e r r e n t . alanes (R3Al)

I n t h e r e a c t i o n of

w i t h hydroxylamines ( 107) t o form n i t r o g e n

h e t e r o c y c l e s ( 1 0 8 ) a c a r b o n - c a r b o n bond a n d a c a r b o n - n i t r o g e n bond

are formed i n one s t e p . 8 1 regiospecificity,

The r e a c t i o n i s n o t a b l e f o r i t s marked

w i t h no 1 - a l k y l a t i o n p r o d u c t s d e t e c t a b l e , a n d , i n

c o n t r a s t t o p r e v i o u s l y r e p o r t e d Beckmann r e a r r a n g e m e n t s o f oxime s u l p h o n a t e s , i t p r e s e n t s a method f o r s t e r e o s e l e c t i v e i n t r o d u c t i o n o f a c a r b o n - c a r b o n bond a t t h e a - p o s i t i o n

of amines.

F i n a l l y , t h e aluminium h y d r i d e (109) i s a u s e f u l r e a g e n t f o r t h e r e d u c t i o n of a c i d c h l o r i d e s d i r e c t l y t o aldehydes i n high y i e l d .

A

p a p e r now d e t a i l s a method f o r i t s p r e p a r a t i o n f r o m l i t h i u m a l u m i n i u m h y d r i d e w h i c h i s f a r more c o n v e n i e n t t h a n t h e p r e v i o u s l y 82

p u b l i s h e d r o u t e from aluminium h y d r i d e . 4

Group I V

Allylsi1anes.-

Allylsilanes are outstandingly useful intermediates

i n o r g a n i c s y n t h e s i s and e s p e c i a l l y i n t h e c o n s t r u c t i o n o f c a r b o n carbon bonds.

The t r e n d i n r e c e n t y e a r s h a s b e e n t o w a r d s u s i n g

t h e s e i n t e r m e d i a t e s i n asymmetric s y n t h e s e s , and t h i s y e a r proves t o b e no e x c e p t i o n .

For i n s t a n c e , t h e c h i r a l a l l y l - s i l a n e

(110)

h a s b e e n r e a r r a n g e d t o e i t h e r of two i s o m e r s d e p e n d i n g upon t h e n a t u r e o f t h e b a s e u s e d ; c a r b o x y l i c a c i d ( 1 1 1 ) i s o b t a i n e d i f LHMDS

i s added t o ( I I O ) , whereas c a r b o x y l i c a c i d ( 1 1 2 ) i s formed a f t e r t r e a t m e n t w i t h LDA.83

The same p a p e r a l s o d e s c r i b e s t h e r e d u c t i o n

of both a c i d s t o t h e corresponding a l c o h o l s . A nucleophilic Lewis acid-catalysed addition of a l l y l s i l a n e s t o a - c h i r a l a- a n d 6 - a l k o x y - a l d e h y d e s

(113) a l s o proceeds i n a highly

d i a s t e r e o s e l e c t i v e f a s h i o n t o y i e l d d i o l s ( 1 1 4 ) .84a,b I n t h e s e c o n d p a ~ e r d~ e~t aki l s o f t h e c o n d i t i o n s n e c e s s a r y f o r e f f i c e n t r e a c t i o n a r e p r e s e n t e d which c l e a r s up a n a p p a r e n t d i s c r e p a n c y

General and Synthetic Methods

460

R

,+CHO

(103)

R’

CI

Ph

( 106 1

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+

I

? I

Me

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(107 1

Me

Me HO2c\j\//\Ji i

w

I

1

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H

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Me

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H

X

(112)

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(113) X = OR or CHzOR

H R

( 114 1

46 1

6: Organometallics in Synthesis

n o t e d by o t h e r w o r k e r s i n a p r e v i o u s p u b l i c a t i o n . A n o t h e r L e w i s a c i d [TiC14-Ti(OPr)41 c a t a l y s e d a d d i t i o n of a l l y l s i l a n e s p r o v i d e s e r y t h r o - c o m p o u n d s ( 1 1 5 ) f r o m p r o t e c t e d a l d e h y d e s ( 1 1 6 ) .85 The a d d i t i o n i s t h e r e f o r e l,3-syn s e l e c t i v e , b u t u n f o r t u n a t e l y t h e s e l e c t i v i t y is r a t h e r low, 2 . 8 : l . The same t i t a n i u m c a t a l y s t p r o m o t e s t h e c l e a v a g e o f c h i r a l a c e t a l s ( 1 1 7 ) by a l l y l s i l a n e s (118), giving homoallylic alcohols (119) with higher e.e.’s, i.e. 8 6 >go%, upon t r e a t m e n t w i t h p y r i d i n i u m c h l o r o c h r o m a t e a n d KOH. Titanium c h l o r i d e a l s o c a t a l y s e s t h e r e a c t i o n of t h e a l l y l s i l a n e ( I Z O ) , a l t h o u g h t h i s time t h e r e a c t i o n i s an i n t r a m o l e c u l a r one and l e a d s t o t h e c y c l i z e d p r o d u c t ( 1 2 1 ) .87 S t r i k i n g l y , t h e e n a n t i o m e r i c p u r i t y o f t h e p r o d u c t i s e s s e n t i a l l y t h e same as t h a t of t h e c h i r a l a l c o h o l (122) used t o p r e p a r e a l l y l s i l a n e ( 1 2 0 ) . Asymmetric i n d u c t i o n s i n v o l v i n g a l l y l s i l a n e s c a n a l s o b e e x e c u t e ( u s i n g c h i r a l a u x i l i a r i e s , a f e a t u r e o f t h e c h e m i s t r y o f Group I a n d I1 o r g a n o m e t a l l i c s . I n common w i t h G r o u p s I a n d I1 t h e p r o l i n e g r o u p i s f o u n d t o b e a n e f f i c i e n t a u x i l i a r y , a s shown i n t h e a d d i t i o n o f a l l y s i l a n e t o a-keto-amides d e r i v e d from S - p r o l i n e e s t e r s . The p r o d u c t s o f r e a c t i o n a r e t h e h o m o a l l y l i c a l c o h o l s ( l 2 3 ) , w h i c h a r e f o r m e d i n good d i a s t e r e o i s o m e r i c e x c e s s a n d i n

88

a c c e p t a b l e chemical y i e l d . (E)-4,8-Alkadienoates (124) a r e formed i n a h i g h l y r e g i o - and s t e r e o - s e l e c t i v e r i n g o p e n i n g o f 7-alkenyl-7-butyroketones ( 1 2 5 ) u s i n g a combination o f a l l y l s i l a n e s and trimethyloxonium tetrafluoroborate t o effect the ring cleavage Yields vary b e t w e e n 74 a n d 100% a n d t h e s y n t h e t i c u t i l i t y o f t h e r e a c t i o n h a s been demonstrated i n t h e s y n t h e s i s of B-sinsenal. I n a n o t h e r new d i e n e s y n t h e s i s t h e a l l y l s i l a n e (126) is t h e key r e a g e n t and r e a c t s w i t h a l d e h y d e s via i t s t i t a n i u m s a l t t o g i v e c o n j u g a t e d 1 , 3 - d i e n e s (127).”* The method f o r m s t h e k e y s t e p i n t h e s y n t h e s i s o f s e v e r a l n a t u r a l a c y c l i c p o l y e n e s , 3 .s p i l a n t h o l . V i n y l s i 1 a n e s . - V i n y l s i l a n e s a r e a n o t h e r g r o u p of s y n t h e t i c a l l y v a l u a b l e o r g a n o s i l i c o n compounds a n d s i g n i f i c a n t c o n t r i b u t i o n s c o n t i n u e t o b e made i n t h i s i m p o r t a n t f i e l d o f c h e m i s t r y . For e x a m p l e , a d d i t i o n of n u c l e o p h i l e s t o t h e a l d e h y d e g r o u p i n t h e r e a d i l y o b t a i n a b l e v i n y l s i l a n e s (128) occurs d i e s t e r e o s e l e c t i v e l y i n f a v o u r of t h e s y n - h o m o a l l y l i c a l c o h o l s ( 1 2 9 ) .” Removal o f t h e bulky s i l y l group then y i e l d s t h e corresponding 3,4-=-aldols; f u r t h e r m o r e , o x i d a t i o n and r e d u c t i o n of ( 1 2 9 ) l e a d s t o t h e o p p o s i t e ( a n t i ) isomer, a l s o i n high yield. The method t h e r e f o r e p r o v i d e s a

General and Synthetic Methods

462

Me

R'

R4 R5 R2

'

0

0

OR

OH

( 131 1

(130) n = 1 or 2; m + n = 3

M e 3 S i y S i M e 3

I

TMS

E

OAc

E

I

(132 1

iI

R

y

E E

Scheme 9

"

'

E = C02Me

463

6: Organometallics in Synthesis

.

means f o r c o n t r o l l i n g t h e 3 , 4 - s t e r e o c h e m i s t r y o f a l d o l s ’a,b A clear example of s i l i c o n e x e r t i n g a n e f f e c t i n c h i r a l s e l e c t i o n i s g i v e n by t h e v i n y l s i l a n e s ( 1 3 0 ) w h i c h p r o v i d e access t o c h i r a l a l c o h o l s ( 1 3 1 ) i n m o d e r a t e e . e . rs.92

The s e q u e n c e

l e a d i n g from ( 1 3 0 ) t o (131) i n v o l v e s a d d i t i o n of an o r g a n o l i t h i u m (RLi), coupling with halide (R’X), silicon-carbon

a n d o x i d a t i v e c l e a v a g e of t h e

bond.

E- a n d Z - V i n y l s i l a n e s (RHC=CHSiMe a l s o lend themselves t o 3 h i g h l y s t e r e o s p e c i f i c o l e f i n a t i o n s , a s e v i d e n c e d by t h e i r r e a c t i o n

w i t h phenyl p a l l a d i u m a c e t a t e l e a d i n g t o s t y r e n e s i n which t h e s t e r e o c h e m i s t r y a t t h e d o u b l e bond i s c o m p l e t e l y i n v e r t e d .93

The

v i n y l s i l a n e ( 1 3 2 ) is a l s o a n e f f i c i e n t o l e f i n a t i n g r e a g e n t a s shown by t h e s e q u e n c e d e s c r i b e d i n Scheme 9 . 9 4 P a r t i c u l a r l y i n t e r e s t i n g i s t h e u s e o f t h e two s i l y l g r o u p s ; t h e f i r s t i s u s e d f o r t h e n u c l e o p h i l i c a t t a c k on t h e p r o t e c t e d a l d e h y d e a n d t h e s e c o n d f o r v i c i n a l e l i m i n a t i o n , both s t e p s i n a s i n g l e operation.

N e w a n d i m p r o v e d r o u t e s t o v i n y l s i l a n e s a r e a l w a y s t o b e welcomed a n d Scheme 10 shows t h r e e s y n t h e s e s s t a r t i n g f r o m s i l y l a t e d alkyne~.’~=

A q u i t e d i f f e r e n t approach l e a d s t o t h e

s y n t h e t i c a l l y u s e f u l v i n y l s i l a n e s ( 1 3 3 ) .96

Sulphoxide ( 134) is u s e d a s s t a r t i n g m a t e r i a l and t h e i n t e r m e d i a t e s ( 1 3 3 ) a r e g e n e r a t e d i n h i g h y i e l d u s i n g LDA f o l l o w e d by t r i m e t h y l s i l y l c h l o r i d e . S i l i c o n r e a g e n t s are c a p a b l e of promoting a wide v a r i e t y o f u s e f u l c h e m i c a l t r a n s f o r m a t i o n s . I n many cases t h e y a r e used as p r o t e c t i n g g r o u p s , and i n t h i s c o n t e x t t h e s i l y l bromide ( 1 3 5 ) proves an e x t r e m e l y u s e f u l p r o t e c t i n g group f o r p r i m a r y , s e c o n d a r y , a n d t e r t i a r y a l c o h o l s .97 P r o t e c t i o n i s Silicon-based Reagents.-

e f f e c t e d by t r e a t i n g t h e a l c o h o l w i t h ( 1 3 5 ) i n DMF i n t h e p r e s e n c e o f t r i e t h y l a m i n e and d e p r o t e c t i o n o c c u r s a f t e r t r e a t m e n t w i t h fluoride.

A u s e f u l f e a t u r e of t h i s p r o t e c t i n g g r o u p i s t h a t it c a n

be cleaved i n t h e presence of o t h e r s i l y l e t h e r s .

Apart from t h e i r

u s e a s p r o t e c t i n g g r o u p s o r g a n o s i l i c o n r e a g e n t s w i l l a l s o unmask p r o t e c t e d a l c o h o l s a s shown i n t h e c l e a v a g e o f m e t h o x y m e t h y l (MOM) a n d m e t h o x y e t h o x y m e t h y l (MEM) e t h e r s by t r i m e t h y l s i l y b r o m i d e a n d i ~ d i d e . ’ ~ QThe c o n d i t i o n s a r e s o m i l d ( 0 t o -78 O C ) a n d s e l e c t i v e , t h a t MOM and MEM e t h e r s c a n be c l e a v e d i n t h e p r e s e n c e o f m e t h y l a n d b e n z y l e t h e r s , g&.

In contrast, trimethysilyl

b r o m i d e a n d i o d i d e , i n c o m b i n a t i o n w i t h 1,l-tetramethyldisiloxane, reduce aromatic aldehydes d i r e c t l y t o the corresponding benzyl h a l i d e s ; f u r t h e r m o r e , s u b s t i t u e n t s s u c h as t h e n i t r o - g r o u p

remain

464

General and Synthetic Methods

R' vii,viii

i

( ref. 95c 1

R'C

R'= H

cx

-

q

7

SiMe,

R

z

X = SiMe3 (ref. 9 5 0 )

-

x s i M x i RlHSiMe3 (ref. 9 5 6 )

Et x' X1= C l , B r D o rI Reagents :

I ,

OIBAL ; i i , MeLi ,iii, CuI, ( E t O I 3 P iv, R2X ; v , E t 2 A l C l ; v i , NXS

vii, MeAICI2; viii , H20

Scheme 10

OMe PhSCHZCHR

I - But

Ph- Si

I

(1341

Br ( 135)

0

(136) x = OAc OBz ,NMe, ,OTHP, NHCOZMe, or NHS02Ph

ArYoY 0

9

I

( 137 1

(138 1

465

6: Organometallics in Synthesis u n a f f e c t e d . 99 H y d r o s i l a n e s w i l l r e d u c e c h i r a l 2 - a l k o x y - a n d 2 - a m i n o - k e t o n e s ( 1 3 5 ) t o t h e c o r r e s p o n d i n g 1 , 2 - d i o l s a n d 2-amino-

a l c o h o l s r e s p e c t i v e l y . l o o I f TBAF i s u s e d a s c o - r e a g e n t i n t h e r e d u c t i o n t h e n t h e o p t i c a l l y a c t i v e 1 , 2 - d i o l s and amino-alcohols are formed t h r e o - s e l e c t i v e l y ; however, t h e s e l e c t i v i t y is c o m p l e t e l y r e v e r s e d when t h e r e d u c t i o n i s c a r r i e d o u t i n t h e a b s e n c e o f TBAF u n d e r a c i d i c c o n d i t i o n s s i n c e e r y t h r o - p r o d u c t s a r e o b t a i n e d i n good y i e l d . T r i m e t h y l s i l y l c y a n i d e (TMSCN) i s a n o t h e r p o p u l a r s i l i c o n r e a g e n t and h a s been used t o c l e a v e t h e c h i r a l acetals ( 1 3 7 ) (TiC14 c a t a l y s t ) g i v i n g c y a n o h y d r i n s ( 1 3 8 ) . l o ’ The c h i r a l c y a p o h y d r i n s s o f o r m e d a r e u s e f u l as 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 p y r e t h r o i d insecticides. M i s c e l l a n e o u s S i l i c o n Compounds.-

Scheme 1 1 shows some o f t h e

i n t e r e s t i n g c h e m i s t r y c a r r i e d o u t by P a q u e t t e a n d c o - w o r k e r s i n t h e f i e l d of silylcyclopropanes, a f i e l d t h a t has received increasing a t t e n t i o n o v e r t h e p a s t few y e a r s . The same w o r k e r s h a v e u s e d t h e k e t o n e ( 1 3 9 1 , p r e p a r e d by d e h y d r o h a l o g e n a t i o n of t h e a - c h l o r o - a c i d c h l o r i d e , i n r e g i o - and stereo-controlled addition reactions t o cyclopentadienes, s i l y l enol e t h e r s , a n d v i n y l e t h e r s t o g i v e c y c l o b u t a n o n e s , 3 .( 1 4 0 ) , w h i c h c a n be f u r t h e r e l a b o r a t e d t o a-methylenecyclobutanones ( 14 1 ) I o 3

.

The i n t e r m e d i a t e s ( 1 4 0 ) c a n a l s o be r i n g - e x p a n d e d (CH2N2) t o a-methylenecyclopentanones ( 1 4 2 ) . Propargylic silanes, ( 1 4 3 ) , h a v e b e e n s y n t h e s i z e d l o 4 f i from m e t h y l a l k y n e s (RCIC-Me) a n d t h e n u s e f u l l y employed i n t h e s y n t h e s i s o f a l l y l i c s i l a n e s ( 144), by h y d r o a l u m i n a t i o n o r h y d r o b o r a t i o n , 104b and 1 , 3 - d i e n e s ( 1 4 5 ) . The l a t t e r a r e p r e p a r e d f r o m t h e a l d e h y d e ( 1 4 3 ; R = C H O ) by a d d i t i o n o f G r i g n a r d r e a g e n t s (R’MgX)

s.

f o l l o w e d by e l i m i n a t i o n o f Me SiOH. 3 An a s y m m e t r i c s y n t h e s i s i n v o l v i n g c h i r a l a c e t a l t e m p l a t e s h a s been n o t e d above; a f u r t h e r example of t h i s u s e f u l s t r a t e g y i s a p p a r e n t i n t h e h i g h l y d i a s t e r e o s e l e c t i v e c l e a v a g e of a c e t a l s ( 1 4 6 ) u s i n g a - s i l y l - k e t o n e s as n u c l e o p h i l e . I o 5 C h i r a l B - a l k o x y - k e t o n e s ( 1 4 7 ) a r e formed which a r e e a s i l y e l a b o r a t e d t o t h e c o r r e s p o n d i n g a l d o l p r o d u c t s ; t h i s sequence h a s been used i n a s y n t h e s i s of (25,4R)-2,4-dihydroxyoct-7-ene, a k e y i n t e r m e d i a t e i n t h e B a r t l e t t nonactic acid synthesis. F i n a l l y i n t h i s s e c t i o n , t h e f o l l o w i n g two p a p e r s f u r t h e r i l l u s t r a t e t h e v e r s a t i l i t y o f o r g a n o s i l i c o n compounds i n s y n t h e s i s .

General and Synthetic Methods

466

OH

seY R C N or CO2Me

Me

Me

R =CHO

I SiMe

Me 5

T

r

e

s

0 Reagents : i , LDA ; ii , Br(CH2)2Br ; iii , LDA ( r e f . 102 a ) ; i v , Mg , CHZO ,CH2 12

,

0 EtZnI(ref.i026);v,R1R2COjv i , ~ ~ ( r e f . 1 0 2 bv ) ~j M s o ~ M e 0 OEt

Tic[&, MeLi( ref, 102 a

i

v i i i Y e e M e ( ref. 102 c 1

S c h e m e 11

0

Me3Si

RO (139)

R -C

C -CH2SiMe3 (143 1

R2

Lf-SiMe3 (144)

\ -

R'

(145)

467

6: Organometallics in Synthesis

In the first, a procedure is described for converting the phenyldimethylsilyl group into an alcohol in two steps (protodesilylation and oxidation), thus revealing Bphenyldimethylsilyl-ketones as masked aldols , Io6 and the second paper claims the amine (148) as a useful synthetic equivalent for +CH2NH2. O7 Grignard reagents ( RMgX) and organolithiums ( RLi) react with (148) to give amines (RCH2NH2) in high yield after deprotection.

Tin.-

Not surprisingly the chemistry of organostannanes resembles that of organosilicons, particularly in their propensity to participate in selective reactions. F o r exarple, the Eallylstannanes (149) react stereoselectively with benzaldehyde to give (35,4S)-enol ethers (1501, and in the same way the (?)-isomer of (149) gives the (3R,4R)-isomer of (150). Io8 Presumably further work will extend the scope of this reaction. In contrast, in the diastereoselective addition of crotyltri-n-butylstannane to aalkoxy-aldehydes (151) the chirality resides in the aldehyde. Here, excellent diastereofacial selectivity is shown with either erythro- or tlireo-isomers being obtained depending upon the nature of the Lewis acid used and the order in which the reagents are mixed.lo9a-d Perhaps the most striking result is that observed when titanium tetrachloride is the Lewis acid. If crotylstannane is added to a mixture of alkoxy-aldehyde and TiC14, then erythro selectivity results, whereas when the aldehyde is added to the crotylstannane and TiC14 precisely the opposite stereochemistry is obtained, i.e. threo. In another paper catalysis is avoided completely in the head-to-tail coupling of allylstannanes (152) with allylic halides (153) to provide adducts (154). 'lo However, instead of using a catalyst high pressures are used to facilitate the react ion. Vinylstannanes have also figured in a number of useful transformations this year, as detailed below. However, before these are discussed Scheme 12 describes a convenient synthesis of vinylstannanes from terminal alkynes. Interestingly two isomeric stannanes can be produced simply by varying the stannylating reagent; copper-catalysed stannylmagnesiation provides access to the trans-vinylstannane whereas palladium-catalysed stannyl-zincation favours the methylenestannane, in certain cases. Palladium-catalysed cross-couplings of vinylstannanes with vinyl halides, ally1 halides, and vinyl triflates have been studied

'

General and Synthetic Methods

468

R

H

R+fk0 Me (151)

(149)

R'

R\ Bun3Sn

f=CH2

-

RCECH

Scheme 12

-

R

\c=c \SnBun3

6: Organometallics in Synthesis

469

’

e x t e n s i v e l y by t h e S t i l l e g r o u p . I 2 a - d T h u s , v i n y l i o d i d e s c r o s s c o u p l e w i t h v i n y l s t a n n a n e s i n t h e p r e s e n c e o f c a r b o n monoxide t o g i v e unsymmetrical d i v i n y l ketones (155) i n y i e l d s v a r y i n g between 40 a n d 93% i n t h e t w e n t y - f i v e e x a m p l e s a t t e m p t e d . a w i d e v a r i e t y o f v i n y l i o d i d e s were f o u n d t o p a r t i c i p a t e i n t h e r e a c t i o n , r a n g i n g from a l k y l - and a r y l - v i n y l i o d i d e s t o a l i c y c l e s c o n t a i n i n g t h e v i n y l i o d i d e s u b u n i t . V i n y l - a n d a r y l - t i n compounds a l s o c o u p l e w i t h a l l y l h a l i d e s i n t h e p r e s e n c e of c a r b o n monoxide t o yield the corresponding vinyl ketones i n high yield. Coupling a t the a l l y l h a l i d e occurs with i n v e r s i o n of c o n f i g u r a t i o n a t t h e carbon b e a r i n g t h e halogen, with r e t e n t i o n of geometry a t t h e d o u b l e bond, and r e g i o s e l e c t i v e l y a t t h e l e a s t h i n d e r e d carbon i n t h e a l l y l i c framework. Vinyl t r i f l a t e s react w i t h a l k y l - , v i n y l - , a l l y l - and a r y l - s t a n n a n e s , once a g a i n i n t h e p r e s e n c e of carbon monoxide, y i e l d i n g t h e c o r r e s p o n d i n g v i n y l k e t o n e s , a r e a c t i o n u s e d i n t h e s y n t h e s i s o f ( + ) - A 9 ( 1 2 ) - C a p n e l l e n e . l2C t h e a b s e n c e o f c a r b o n monoxide t h e c o u p l i n g r e a c t i o n s p r o c e e d w i t h e q u a l e f f i c i e n c y t o f u r n i s h t h e corresponding hydrocarbons such as P l e r a p l y s i l l i n I. 1 1 2 2 V i n y l s t a n n a n e s f i g u r e as key r e a g e n t s i n a s t e r e o s p e c i f i c , i t e r a t i v e and n o n - a c e t y l e n i c r o u t e t o 5 , 6 - d i h y d r o a r a c h i d o n i c a c i d a s d e p i c t e d i n Scheme 13. l 3 h a s u s e d a s i m i l a r v i n y l s t a n n a n e , ( 1 5 6 ) , as s t a r t i n g m a t e r i a l i n a g e n e r a l s y n t h e s i s of c h i r a l 1 , 2 - d i s u b s t i t u t e d c y c l o p r o p a n e s ( 1 5 7 ) , v i a t h e i n t e r m e d i a c y o f t h e s t a n n y l c y c l o p r o p a n e ( 1 5 8 ) . 114 Smooth c o u p l i n g o f t h e s t a n n a n e ( 1 5 9 ) w i t h a l k y l r a d i c a l s g e n e r a t e d f r o m a l k y l b r o m i d e s or i o d i d e s l e a d s t o t e r m i n a l a l l e n e s ( 1 6 0 ) ; t h i s new r e a c t i o n h a s b e e n a p p l i e d t o a s i m p l e a n d s t e r e o s p e c i f i c s y n t h e s i s of t h e n a t u r a l l y o c c u r r i n g a l l e n i c a c i d (?)-2-arninohexa-4,5-dienoic acid. S t a n n y l a l l e n e s ( 16 1 ) c a n a l s o be f o r m e d from a l k y n e s , e.g. ( 1 6 2 1 , by t r e a t m e n t w i t h b u t y l l i t h i u m , t h e n w i t h t r i p h e n y l t i n c h l o r i d e , and f i n a l l y w i t h a n organocopper reagent ( R C ~ ) S t e r e o s p e c i f i c r i n g opening of y-hydroxyalkylstannanes is a c c o m p l i s h e d by a d d i t i o n o f l e a d t e t r a - a c e t a t e t o y i e l d (El- a n d (2)-keto-olefins (163) according t o t h e stereochemistry of t h e s t a r t i n g materials. ’ I 7 bis(trimethylstannyl)buta-l,3-diene ( 1 6 4 ) w h i c h a c t s as a v e r s a t i l e synthon f o r t h e 2,3-dianion of buta-1,3-diene; s e l e c t i v e r e m o v a l of o n e o r b o t h g r o u p s is p o s s i b l e a n d r e a c t i o n w i t h e l e c t r o p h i l e s s u c h as h a l o g e n o s i l a n e s , d i s u l p h i d e s , s e l e n i u m , a l k y l

.

470

General and Synthetic Methods

Bug Sn

/--=\/oA~

B ’ 3 s n ~ C 5 H 1 1

+

\Bu3sn

= (J & ,l.,

/--7/OAc

SnBu,

Scheme 13

H-w.H R

B”3snLr0 (156)

R1

(157 1

R’

R’ A ( C H z ) , , / . \ V R 2

R2

( 1 6 3 ) n = 2 or 3

I

(162 1

K

O

H

(158 1

0

I

HCSC-C-CCI

Bu3Sn

SnMeg

47 1

6: Organometallics in Synthesis h a l i d e s , a l d e h y d e s , and ketones can t h e n occur.

5

118

Group V

Phosphorus.-

Not s u r p r i s i n g l y t h e m a j o r i t y o f t h e p u b l i c a t i o n s i n

t h e f i e l d o f o r g a n o p h o s p h o r u s r e a g e n t s d e a l w i t h some a s p e c t o r o t h e r of t h e W i t t i g r e a c t i o n , o r one of i t s m o d i f i c a t i o n s . For i n s t a n c e , a c o n v e n t i o n a l W i t t i g r e a c t i o n u s i n g t h e phosphonium s a l t (165) t o react w i t h k e t o n e s (R2R3CO) chloro-3-cumulenes

provides easy a c c e s s t o

(166), albeit i n rather variable yield;

w h e r e a s a l d e h y d e s and a l k y l / a r y l k e t o n e s g i v e m o d e s t t o good y i e l d s of t h e cumulenes, a,B-unsaturated t o g i v e r a t h e r poor y i e l d s . r e a c t s with a-diketones

k e t o n e s and a - k e t o - e s t e r s

appear

The v i n y l phosphonium s a l t ( 1 6 7 )

(168) t o y i e l d c y c l o p e n t e n o n e s ( 1 6 9 ) , which

can be f u r t h e r e l a b o r a t e d t o dihydrojasmone, dihydrojasmololone, a n d known p r e c u r s o r s t o m e t h y l e n o m y c i n A a n d B.120 On t h e o t h e r hand t h e s i m p l e r W i t t i g r e a g e n t ( P h P-CHC02Et) o f f e r s a r a t h e r

3 -

s u r p r i s i n g e n t r y t o isocoumarins (170)

via

its r e a c t i o n with ortho-

b e n z o y l b e n z o i c a c i d s 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 of t h e 12 1 intermediate keto-ylides (171). A r o m a t i c a l d e h y d e s ( A r C H O ) r e a c t w i t h t h e phosphonium s a l t s ( 1 7 2 ) t o y i e l d a l k a n o n e s (ArCH2COR1) i n a r e a c t i o n w h i c h i s effectively a reductive 2-acylation

of a r o m a t i c aldehydes. 122

L i k e w i s e , a l d e h y d e s ( R C H O ) c a n be h o m o l o g a t e d t o a - k e t o - e s t e r s by t h e c r y s t a l l i n e p r o t e c t e d p h o s p h o n o g l y c o l a t e and v i n y l o g o u s k e t o - e s t e r s (174) are formed i n a q u i t e

(RCH2COC02Me)

(173)

a n a l o g o u s p r o c e s s from t h e phosphono-ester

(175) and a l d e h y d e s

a sequence used i n t h e s y n t h e s i s of pyrenophorin antibiotic, (R'CHO),

S e v e r a l of t h e o r g a n o p h o s p h o r u s r e a g e n t s j u s t m e n t i o n e d h a v e b e e n u s e d i n s y n t h e s e s of n a t u r a l p r o d u c t s .

C o n t i n u i n g on t h i s

theme, t h e phosphinoxy c y c l i c e t h e r s (176) have been coupled w i t h a l d e h y d e s and l a c t o l s , and a f t e r an a c i d - c a t a l y s e d c y c l i z a t i o n T h i s g e n e r a l r o u t e h a s been used i n

y i e l d s p i r o a c e t a l s (177).125

t h e s y n t h e s i s of two i n s e c t p h e r o m o n e s p o s s e s s i n g t h e i m p o r t a n t spiroacetal substructure. formed

Another h e t e r o c y c l e ,

e.g.

(178), is a l s o

via

t h e agency o f organophosphorus r e a g e n t s s t a r t i n g from t h e b i s - p h o s p h o n a t e ( 1 7 9 ) . 1 2 6 By r e a c t i n g t h e b i s - p h o s p h o n a t e w i t h a l d e h y d e s (RCHO), t h e a z a d i e n e ( 1 8 0 ) i s o b t a i n e d w h i c h u n d e r g o e s a n intramolecular Diels-Alder r e a c t i o n , t h u s forming t h e i n d o l i z i n e r i n g s y s t e m ( 1 7 8 ) . The same p a p e r d e s c r i b e s f u r t h e r e l a b o r a t i o n s

General and Synthetic Methods

=(:

PPh3

(167)

U

(168)

Ar (170)

0

0

II

II

R OC02CMezCC 13

I

A

C O (174)

z

R

(Ro) OTHP

(175 1

473

6: Organometallics in Synthesis

of t h i s s y s t e m u t i l i z i n g t h e v i n y l p h o s p h o n a t e as a n a c t i v e c e n t r e . The b i s - p h o s p h o n a t e

CH2[P(0)(OEt)2]2 a l s o r e a c t s w i t h a l d e h y d e s

and k e t o n e s y i e l d i n g a , B-unsaturated

p h o s p h o n a t e s R1R2C=CP(0)( O E t )

2

which can be f u r t h e r c o n v e r t e d i n t o a-hydroxy-aldehydes R1R2C(OH)CH0 by o s m y l a t i o n a n d h y d r o l y s i s . 127 C h e m i c a l y i e l d s v a r y b e t w e e n good a n d e x c e l l e n t i n t h e e x a m p l e s a t t e m p t e d , a n d v a r i o u s g r o u p s c a n be t o l e r a t e d as R 1 a n d R 2 .

Most o f t h e p a p e r s j u s t d e s c r i b e d r e l y upon t h e u s e of s t r o n g b a s e s i n o r d e r t o g e n e r a t e t h e c a r b a n i o n a- t o t h e p h o s p h o r u s s p e c i e s .

However, a v e r y m i l d

o l e f i n a t i o n p r o c e d u r e h a s b e e n p u b l i s h e d w h i c h r e l i e s upon l i t h i u m c h l o r i d e and a n a l k y l a m i n e t o g e n e r a t e t h e a n i o n .

Thus, t h e

p h o s p h o n a t e ( 1 8 1 ) i s i d e a l l y s e t - u p f o r c o - o r d i n a t i o n , see ( 1 8 2 1 , w i t h t h e l i t h i u m c o u n t e r - i o n , and c o n s e q u e n t l y t h e f a c i l i t y f o r removing t h e a-proton

i s g r e a t l y enhanced such t h a t amines w i l l

The p r o c e d u r e i s p a r t i c u l a r l y s u i t e d t o t h e u s e o f b a s e - s e n s i t i v e a l d e h y d e s a n d i n t h i s c o n t e x t t h e method s u f f i c e as base.128

proves f a r superior t o those using conventional bases. The c h i r a l p h o s p h o n a m i d e s ( 1 8 3 ) a n d ( 1 8 4 ) e x h i b i t r e m a r k a b l e 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 i n asymmetric o l e f i n a t i o n s and alkylations.

I n t h e i r r e a c t i o n with s u b s t i t u t e d cyclohexanones

o p t i c a l p u r i t i e s o f >70% of‘ t h e c o r r e s p o n d i n g o l e f i n s a r e o b t a i n e d . For example, 4-methylcyclohexanone g i v e s (R)-cyclohexene (185) i n

69% o p t i c a l p u r i t y .

A somewhat more u n u s u a l r e a c t i o n o f

p h o s p h o n a t e s l e a d s t o t h e s y n t h e s i s o f mono- a n d 1 , 4 - d i - c a r b o n y l compounds as d e p i c t e d i n Scheme l 4 . I 3 *

The k e y s t e p i n t h e r o u t e i s t h e oxygenation of phosphonate c a r b a n i o n s which i s accomplished

s i m p l y by p a s s i n g a stream o f oxygen t h r o u g h t h e r e a c t i o n m i x t u r e . Using t h i s n o v e l s y n t h e s i s of 1 , 4 - d i k e t o n e s dihydrojasmone, a l l e t h r o n e , and methylenomycin B have been p r e p a r e d . A n o t h e r n o v e l s y n t h e s i s , t h i s time o f t e r m i n a l f l u o r o a l k y l a c e t y l e n e s ( 1 8 6 1 , i s e f f e c t e d by d e p h o s p h o r y l a t i n g t h e v i n y l p h o s p h o n a t e s ( 1 8 7 ) w i t h c a t a l y t i c q u a n t i t i e s o f TBAF. 13’

In t h e f o u r e x a m p l e s a t t e m p t e d y i e l d s v a r y b e t w e e n 75% a n d 90% a n d t h e

r e a c t i o n occurs under mild conditions. The p h o s p h o l e n e (188) i s p r e p a r e d s i m p l y from P C 1 and a c h i r a l d i o l a n d i s t h e n o b t a i n e d a f t e r a n o x i d a t i o n s t e p . 3 3 2 The r e a g e n t p r o v e s t o be a new c h i r a l d e r i v a t i z i n g a g e n t and h a s been used s u c c e s s f u l l y w i t h v a r i o u s alcohols.

General and Synthetic Methods

474

Li,

0.-

II

0 I

1

i , iii

Reagents : i, Bu”Li

ii, RCH2X iii ,O2

iv , H 2 0 , TsOH

;V ,

NaOH, EtOH

Scheme 14

R,C

CH

(186 1

Rf\ F

P O (OEt 12 (188

475

6: Organornetallies in Synthesis

6 Group V I Sulphur.-

T h e v e r s a t i l i t y of o r g a n o s u l p h u r r e a g e n t s i s w e l l known

and o v e r t h e p a s t decade a high l e v e l of a c t i v i t y h a s been a p p a r e n t in this field.

T h i s i n t e r e s t c o n t i n u e s u n a b a t e d as e v i d e n c e d by

t h i s y e a r ' s l i t e r a t u r e b o t h i n volume and c o n t e n t .

For i n s t a n c e ,

J u l i a a n d h i s c o - w o r k e r s h a v e p u b l i s h e d a new m e t h o d f o r t h e conversion of propargyl alcohols [RIRC(OH)C=CHI u n s a t u r a t e d a l d e h y d e s CR1R2CH=CHCHO]. 1 3 3

into

a,B-

Phenylthiophenol

f a c i l i t a t e s the conversion, reacting with the propargyl alcohol d i r e c t l y t o f u r n i s h v i n y l s u l p h i d e s ( 1 8 9 ) from which t h e a l d e h y d e s Another v i n y l s u l p h i d e , ( 1 9 0 ) , is

a r e o b t a i n e d by h y d r o l y s i s .

formed from a l d e h y d e s and p h e n y l t h i o n i t r o m e t h a n e , a n d t h e n r e a c t s w i t h n u c l e o p h i l e s (Nu) t o g i v e , on s u b s e q u e n t o z o n o l y s i s , In a quite

a - s u b s t i t u t e d t h i o e s t e r s (191 ) i n r e a s o n a b l e y i e l d . 134

d i f f e r e n t r e a c t i o n v i n y l s u l p h i d e s (192) react w i t h k e t e n e s t o g i v e [ 2 + 2 ] a d d i t i o n p r o d u c t s f r o m w h i c h b u t e n e d i o n e s may b e e a s i l y e l a b o r a t e d (Scheme 15).135

S i n c e t h e v i n y l s u l p h i d e s c a n be

d e r i v e d from k e t o n e s t h e o v e r a l l p r o c e s s c o r r e s p o n d s t o a s i m p l e f o u r - s t e p c o n v e r s i o n of c y c l i c a n d a c y c l i c k e t o n e s t o cyclobutenediones.

a sulphide

I n t h e n o v e l s y n t h e s i s of a-methylene-y-butyroketones

p l a y s a k e y r o l e i n t h e c o n s t r u c t i o n o f t h e r i n g s y s t e m a s shown i n Scheme 1 6 . 1 3 6

Important a s p e c t s of t h i s r o u t e are t h e facile

t h i o a l l y l i c r e a r r a n g e m e n t i n d u c e d by s i l i c a a n d t h e e a s y i n t r o d u c t i o n o f t h e c a r b o n - c a r b o n d o u b l e bond by e l i m i n a t i o n o f t h e sulphur. The d o u b l e bond i n

cis- a n d

t r a n s - a l k e n e s is a l s o i n t r o d u c e d

d u r i n g e l i m i n a t i o n o f a s u l p h u r moiety from (193) and (194).1372

SJJ-

and a n t i - a l c o h o l s

A key f e a t u r e o f t h i s p a r t i c u l a r s y n t h e s i s i s

t h e h i g h l y s t e r e o s e l e c t i v e manner i n which ( 1 9 3 ) and ( 1 9 4 ) a r e Reduction with l - s e l e c t r i d e g i v e s t h e

o b t a i n e d from k e t o n e s ( 1 9 5 ) . =-configuration,

e x c e p t when R

'

is cyclohexyl, whereas r e d u c t i o n provided t h a t R2 i s

with z i n c borohydride g i v e s t h e a n t i - a l c o h o l , methyl.

The same p a p e r a l s o d e s c r i b e s t h e c o n v e r s i o n o f ( 1 9 3 ) a n d

(194) i n t o the corresponding

cis- a n d

trans-epoxides.

T h e same

authors d e t a i l an alternative highly stereoselective route t o t r a n s - e p o x i d e s which i n v o l v e s m e t h y l a t i o n of k e t o n e s (1951, r e d u c t i o n t o t h e 8 - h y d r o x y s u l p h o n i u m s a l t ( 1 9 6 ) , f o l l o w e d by b a s e t r e a t m e n t t o y i e l d t h e t r a n s - e p o x i d e . 137b S u l p h o n i u m s a l t s h a v e

a l s o b e e n u s e d i n t h e s y n t h e s i s of s p i r o a n n e l a t e d c y c l i c k e t o n e s

476

General and Synthetic Methods

R I X H s p h

RYCOSPh

R JNo2

Nu

R2

SPh C l

R1j--&L;yJ; ; ; E o

YSPh -

R2 (192 1

R2

0

0

SPh

Scheme 15

OH

0 Reagents : i , SiOz ii , H 2 S 0 4 j iii, Cr03,H2S04

i

i v , DBu

S c h e m e 16

6: Organornetallies in Synthesis

477

( 197). 138 The c y c o p r o p a n e r i n g i s i n t r o d u c e d by t h e s u l p h o n i u m s a l t (C1CH2CH2$Me2) i n o n e s t e p . H a r d l y a y e a r g o e s by w i t h o u t some r e f e r e n c e t o k e t e n e d i t h i o a c e t a l s and t h i s y e a r proves no e x c e p t i o n . I n one r e p o r t t h e s y n t h e s i s of d i a s t e r e o m e r i c a l l y p u r e t h r e o - a l c o h o l s

(198) b y a n o v e l r e g i o - a n d s t e r e o - s p e c i f i c r e d u c t i o n o f d i t h i o a c e t a l s ( 199) 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 i s d e t a i l e d . 13’ S e l e c t i v i t y i s t h o u g h t t o o c c u r f r o m a n i n t e r m e d i a t e s u c h as ( 2 0 0 ) . I n c o n t r a s t d i t h i o a c e t a l s (201) u n d e r g o c a t i o n - i n d u c e d c y c l i z a t i o n t o c o m p o u n d s (202), t h u s a l l o w i n g e f f i c i e n t c o n s t r u c t i o n of pyrrolizidine, s y s t e m s . 140

i n d o l i z i d i n e , and q u i n o l i z i d i n e a l k a l o i d r i n g

I n t h e c o n v e r s i o n o f p u l e g o n e t o (~)-5-methylcyclohex-2-en-lones ( 2 0 3 ) , u s e f u 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 of lycopodium a l k a l o i d s , a p r o c e d u r e h a s been developed which d o e s n o t i n v o l v e t h e i n t e r m e d i a c y o f t h e c y c l o h e x a n o n e (204), t h e r e b y a v o i d i n g t h e p r o b l e m s p r e v i o u s l y e n c o u n t e r e d i n c o n v e r t i n g (204) i n t o (203). The k e y s t e p i n t h e r o u t e is t h e r e a c t i o n o f s o d i u m p h e n y l t h i o l a t e w i t h t h e e p o x i d e (205), o b t a i n e d d i r e c t l y f r o m p u l e g o n e , t o y i e l d e n o l a t e ( 2 0 6 ) which is t h e n c o n v e r t e d s i m p l y i n t o t h e c y c l o h e x e n o n e s ( 2 0 3 ) by c o n v e n t i o n a l m e t h o d s . The p h o s p h o r u s - s u l p h u r new o x y g e n - s u l p h u r

compound ( 2 0 7 ) h a s b e e n d e v e l o p e d a s a

exchange r e a g e n t and i t is claimed t h a t t h e

r e a g e n t is e a s i l y p r e p a r e d and r e q u i r e s o n l y f a i r l y g e n t l e r e a c t i o n c o n d i t i o n s u n l i k e many commonly u s e d 0-S e x c h a n g e r e a g e n t s . 142 The s y n t h e t i c u t i l i t y o f s u l p h o x i d e s h a s a l r e a d y b e e n n o t e d i n G r o u p s I a n d I1 w i t h r e s p e c t t o t h e i r a - c a r b a n i o n s i n chiral induction reactions.

and e s p e c i a l l y

However, s u l p h o x i d e s h a v e w i d e r

a p p l i c a t i o n s as e v i d e n c e d by t h e f o l l o w i n g p a p e r s .

Before these

p a p e r s are d i s c u s s e d , however, it is worth n o t i n g a n e l e c t r o c h e m i c a l o x i d a t i o n of s u l p h i d e s t o y i e l d c h i r a l s u l p h o x i d e s . The e s s e n t i a l e l e m e n t o f t h e s y n t h e s i s i s t h e u s e o f p l a t i n u m e l e c t r o d e s coated doubly w i t h p o l y p y r r o l e and poly-(L-valine) i n t h e c a s e of t - b u t y l possible.

,

and

p h e n y l s u l p h o x i d e o p t i c a l y i e l d s o f 93% a r e

Unfortunately the o p t i c a l y i e l d appears t o drop

d r a m a t i c a l l y when l e s s b u l k y a l k y l g r o u p s a r e u s e d . Complete e n a n t i o s p e c i f i c i t y i s f o u n d t o o c c u r when c h i r a l s u l p h o x i d e s (208) r e a c t w i t h a c i d c h l o r i d e ( C l CHCOC1) i n t h e p r e s e n c e o f z i n c t o Another l a c t o n e h a s been prepared g i v e c h i r a l l a c t o n e s (209). by a d i f f e r e n t a p p r o a c h as e x e m p l i f i e d i n Scheme 1 7 . l ~O~n c e formed t h e l a c t o n e c a n be used i n t h e h i g h l y e n a n t i o c o n t r o l l e d

General and Synthetic Methods

47 8

R' ( 200 1

(199 1

( 198 1

0 (202 1 ONa

0

Me H

H

(203 1

H

(204 1

s

I

H

(205 1

(206 1

s

( 2 0 8 ) R,R=H,O or O)

( 2 0 7 ) X = H or OMe

'

bS

L

O

(209)

0

H

0 Tol---

II Tol---ir*H 0 .

Scheme 17

OH

6: Organometallics in Synthesis

479

s y n t h e s i s o f 3-substituted-4-butenolides, 3 .( - ) - p o d o r h i z o n , M i c h a e l a d d i t i o n t o t h e d o u b l e bond.

via

Another i n t e r e s t i n g c h i r a l i n d u c t i o n i n v o l v i n g a c h i r a l sulphoxide is demonstrated i n t h e p r e p a r a t i o n of c h i r a l c y c l o h e x y l i d e n e bromomethanes ( 2 1 0 ) from t h e s u l p h o x i d e ( 2 1 1 ) . 146 The r e a c t i o n o c c u r s i n two s t e p s ; t h e f i r s t i s a s t e r e o s p e c i f i c bromination and t h e second a s t e r e o s p e c i f i c p y r o l y t i c e l i m i n a t i o n of t h e sulphoxide moiety.

High a s y m m e t r i c i n d u c t i o n i s a l s o s e e n

i n t h e r e a c t i o n of c h i r a l B-oxosulphoxides corresponding sulphoxido-alcohols,

(212) t o t h e

w h i c h c a n b e r e a d i l y unmasked t o On t h e o t h e r h a n d , B -

y i e l d c h i r a l a-hydroxy-aldehydes.

o x o s u l p h o x i d e ( 2 1 3 ) r e a c t s w i t h a l d i m i n e s p r o v i d i n g access t o B-

lactams ( 2 1 4 ) i n m o d e r a t e y i e l d a n d i n c e r t a i n c a s e s i n v e r y h i g h d i a s t e r e o i s o m e r i c e x c e s s e s . 148

A less conventional use f o r the s u l p h o x i d e g r o u p is a p p a r e n t i n t h e s u l p h o x i d e - m e d i a t e d i n t r a m o l e c u l a r h y d r o x y l a t i o n o f a r e m o t e d o u b l e bond i n a n a c y c l i c s y s t e m ; f o r e x a m p l e c h i r a l s u l p h o x i d e ( 2 1 5 a , b ) r e a c t s w i t h osmium

t e t r a o x i d e t o form t h e d i a c e t y l a t e d s u l p h o n e ( 2 1 6 a , b ) i n good ~ i e 1 d . l ~ ’ A v e r y similar s t r a t e g y , b u t t h i s time u s i n g a s u l p h o x i m i n e , i s d e p i c t e d i n Scheme 18 a n d i s c l a i m e d t o b e t h e

f i r s t time a s y n t h e s i s o f c h i r a l 2,3-dihydroxycyclohexanones h a s been r e p o r t e d . S u l p h o n e s , i n common w i t h s u l p h o x i d e s , h a v e d e v e l o p e d i n t o extremely v e r s a t i l e s y n t h e t i c r e a g e n t s .

Several papers t h i s year

r e l a t e t o t h e p r e p a r a t i o n a n d / o r u s e of u n s a t u r a t e d s u l p h o n e s . Thus, t h e v i n y l s u l p h o n e s (217) are produced e f f i c i e n t l y from a l k e n e s by t r e a t m e n t w i t h m e r c u r i c c h l o r i d e and s o d i u m a r e n e s u l p h i n a t e f o l l o w e d by b a s e - c a t a l y s e d

eliminative

demercuration. I5O A second paper d e t a i l s t h e p r e p a r a t i o n of c o n j u g a t e d d i e n e s ( 2 1 8 ) by a d d i t i o n o f b r o m o m e t h a n e s u l p h o n y l bromide t o a l k e n e s t o g i v e v i n y l s u l p h o n e s ( 2 1 9 ) which r e a r r a n g e t o ( 2 1 8 ) upon t r e a t m e n t w i t h b a s e . 1 5 ’ S i g n i f i c a n t l y , t h e e l i m i n a t i o n o c c u r s i n a syn f a s h i o n p r o m o t e d by p r i o r c o m p l e x a t i o n b e t w e e n t h e l i t h i u m c a t i o n o f t h e b a s e and t h e s u l p h o n e g r o u p . B i s a r y l s u l p h o n y l a l k e n e s have been a f o c u s of a t t e n t i o n f o r a number o f y e a r s a n d t h i s y e a r h a s s e e n s e v e r a l g r o u p s e x t e n d i n g f u r t h e r t h e uses for these reagents. and e n o l a t e s t o 1 , l - b i s - s u l p h o n y l

Michael a d d i t i o n o f enamines

alkene (220) leads t o adducts

( 2 2 1 ) w h i c h c a n be d e s u l p h o n y l a t e d r e a d i l y t o t h e f o r m a l e t h y l e n e a d d u c t s ; ( 2 2 0 ) t h e r e f o r e a c t s a s a n e t h y l e n e 1 , 2 - d i p o l e . 152* The 1 , 2 - r e g i o i s o m e r s o f ( 2 2 0 1 , ( 2 2 2 1 , h a v e b e e n employed as

e.

General and Synthetic Methods

480

0

0

t

To\S-COzR

TO[

t

- S--'

X Y

NHAC

(216) a; X = O A c , Y = H

b; Y = : O A C , X = H

0

cl

0

Ho%,-j$ -

I

[ ] MeNH Ph!LEH2

Reagents: i, BuLi; ii,

Ph

- IIS - C,H2

iv

+-

A

HO,''r

-/

._,iii, 0 s O 4 ; iv, heat ;

Scheme 18

HO'

48 1

6: Organometallics in Synthesis

Pho2sYso2Ph ( 221 1

( 220 1

(222 1

0

Scheme 19

Rxso2R \ SO 2R

\

AcO

R'

( 226 1

I

OAc

( 227 1

\

COZR

General and Synthetic Methods

482

d i e n o p h i l e s i n c y c l o a d d i t i o n r e a c t i o n s . 1 5 3 B o t h t h e (E)- a n d (Z-)i s o m e r s are e a s i l y a v a i l a b l e from d i c h l o r o e t h y l e n e and are s t a b l e , h i g h l y r e a c t i v e i n t h e c y c l o a d d i t i o n r e a c t i o n , and undergo e a s y d e s u l p h o n a t i o n , t h u s a c t i n g as a c e t y l e n e e q u i v a l e n t s . The s u l p h o n e s ( 2 2 3 ; R H) a n d ( 2 2 4 ) a r e b o t h d e s c r i b e d a s I l l dipole synthons.

I n t h e f i r s t c a s e t h e s u l p h o n e ( 2 2 3 ; R = H) c a n

b e a l k y l a t e d by e l e c t r o p h i l e s (R'X) g i v i n g s u l p h o n e s ( 2 2 3 ; R = R ) . 15'2

,

i n c l u d i n g Michael a c c e p t o r s , The s u l p h o n e s ( 2 2 3 ; R

R1)

may t h e n b e unmasked t o e s t e r s (R1CO2Me) or a l t e r n a t i v e l y c y c l i z e d t o alkanones (2251, i n t h o s e c a s e s where t h e o r i g i n a l e l e c t r o p h i l e 1

(R X) i s a n a r y l a l k y l h a l i d e . The s e c o n d d i p o l e s y n t h o n ( 2 2 4 ) a l s o l e n d s i t s e l f t o t h e c o n s t r u c t i o n of m u l t i - r i n g

s y s t e m s a s shown i n

T h~i s 2g e n e r a l s t r a t e g y h a s b e e n a p p l i e d t o t h e Scheme 1 9 . ~ ~ c o n s t r u c t i o n of two-,

three-

and four-condensed

r i n g systems which

may a l s o c o n t a i n h e t e r o a t o m s . A v e r y u s e f u l one c a r b o n homologation which c o n v e r t s k e t o n e s

i n t o a-hydroxy-aldehydes

u s e s a phenyl sulphone, s p e c i f i c a l l y 5 5 T h i s new s e q u e n c e i n v o l v e s D a r z e n s

chloromethylphenyl sulphone

.

c o n d e n s a t i o n o f k e t o n e s w i t h t h e c h l o r o m e t h y l s u l p h o n e f o l l o w e d by r i n g o p e n i n g of t h e i n t e r m e d i a t e a , f 3 - e p o x y - s u l p h o n e s provide t h e a-hydroxyaldehyde.

t o finally

Finally i n t h i s section, a novel

s y n t h e s i s of a c e t y l e n e s and p o l y e n e s r e l i e s upon a d e s u l p h o n y l a t i o n o f a - a c e t o x y s u l p h o n y l compounds ( 2 2 6 ) . 1 5 6 I f t h e c a r b o n - c a r b o n bond i s p r e s e n t i n a n u n s a t u r a t e d s y s t e m t h e n a n a c e t y l e n i c l i n k a g e i s i n s e r t e d concomitant w i t h t h e removal of t h e a c e t o x y and

sulphone groups.

I n c o n t r a s t two d o u b l e b o n d s a r e i n s e r t e d i n

systems c o n t a i n i n g a t l e a s t one o t h e r carbon-carbon

s i n g l e bond,

e.g. (227). S e l e n i u m . - The i n t r o d u c t i o n o f s e l e n i u m i n t o m o l e c u l e s i s a p a r t i c u l a r l y u s e f u l r e a c t i o n s i n c e once p r e s e n t a selenium group may b e e l i m i n a t e d w i t h t h e i n t r o d u c t i o n o f u s e f u l f u n c t i o n a l i t y . Scheme 20 i l l u s t r a t e s some o f t h e p a p e r s p u b l i s h e d c o n c e r n e d w i t h this topic.

A n o t h e r two p a p e r s r e l a t e t o t h e s y n t h e s i s of phenylvinylselenides. [R 'CH2C(R)

I n the f i r s t , ketonehydrazones

= N N H 2 1 r e a c t w i t h t-butyltetramethylguanidine-

p h e n y l s e l e n i d e t o g i v e g o o d y i e l d s of t h e s e l e n i d e s ( 2 2 8 1 , I 6 O a n d i n t h e s e c o n d morpholinobenzene-selenamide (MBSe) i s u s e d t o introduce t h e phenylselenyl group i n t o a , b - u n s a t u r a t e d aldehydes The l a t t e r c a n t h e n be g i v i n g s e l e n i u m compounds ( 2 2 9 ) . 1 6 '

483

6: Organometallics in Synthesis converted i n t o various usefully substituted dienes (230). Alcohols w i l l react w i t h a l k y l or a r y l s e l e n o l s t o g i v e 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 , a l t h o u g h t h e n a t u r e of t h e a l c o h o l u l t i m a t e l y d e t e r m i n e s t h e e f f i c i e n c y o f t h e c o n v e r s i o n . 16* T e r t i a r y a l k y l , b e n z y l , and a l l y l a l c o h o l s a l l work w e l l b u t t h e method i s u n s u c c e s s f u l f o r p r i m a r y a n d s e c o n d a r y a l c o h o l s .

A l l y 1 methyl s e l e n i d e s are r e p o r t e d t o be v a l u a b l e p r e c u r s o r s t o a l l y l - l i t h i u m s a n d a - m e t a l l a t e d a l l y l s e l e n i d e s (Scheme 21 1. 1 6 3 High y i e l d s o f t h e a l l y l - l i t h i u m s a r e g e n e r a t e d by c l e a v a g e o f t h e c a r b o n - s e l e n i u m bond w i t h a l k y l - l i t h i u m trapped with electrophiles.

r e a g e n t s , and c a n t h e n be

I n c o n t r a s t , u s e of amide b a s e s

r e s u l t s i n deprotonation t o the a-metallated a l l y l selenides r a t h e r t h a n C-Se bond c l e a v a g e .

The m e t a l l a t e d d e r i v a t i v e s s o f o r m e d

r e a c t w i t h e l e c t r o p h i l e s , 3.a l d e h y d e s , i n h i g h y i e l d a n d a r e claimed t o possess s e v e r a l advantages over t h e corresponding t i n and l e a d d e r i v a t i v e s ;

e.g.,s e l e n i d e

b y - p r o d u c t s a r e removed more

e a s i l y , r e a c t i o n s a r e homogeneous, a n d t h e s t a r t i n g a l l y l s e l e n i d e s are readily available.

P r o t e c t e d a l l y l i c amines (231) are a l s o

f o r m e d i n h i g h y i e l d s from a l l y l i c s e l e n i d e s s i m p l y by t r e a t m e n t w i t h t h e chloramine ( P N C 1 . N a ) . 164 The l a s t few r e a c t i o n s i l l u s t r a t e some o f t h e a d v a n t a g e s i n u s i n g s e l e n i u m r e a g e n t s : t h e i r a v a i l a b i l i t y a n d t h e ease w i t h w h i c h selenium is l o s t concomitant with a u s e f u l f u n c t i o n a l i z a t i o n .

This

i s i l l u s t r a t e d f u r t h e r by a new p r e p a r a t i v e r o u t e t o 2 - a r y l p r o p a n o i c a c i d s from p r o t e c t e d a-seleno-

(and t e l l u r o - ) e t h y l

ketones

and

i n a new r e a c t i o n of a - p h e n y l s e l e n y l - k e t o n e s

(232) w i t h mercury

p e r c h l o r a t e t o f u r n i s h a , a-dimethoxy-ketones

( 2 3 3 ) . 166

This latter

r e a c t i o n h a s b e e n u s e d a s a key s t e p i n t h e s y n t h e s i s o f a n erythrinan alkaloid, erysotrine. A l k y l - a n d a r y l - s e l e n i d e g r o u p s a r e a l s o l o s t r e a d i l y f r o m 8hydroxyselenides, thereby stereoselectively generating t h e corresponding epoxide. e t h o x i d e . 167

The r e a g e n t o f c h o i c e h e r e i s t h a l l i u m ( 1 )

A d i f f e r e n t facet of selenium r e a c t i v i t y is e v i d e n t

i n t h e o x i d a t i o n o f halogenomethylarenes and a l c o h o l s t o a l d e h y d e s u s i n g d i m e t h y l s e l e n o x i d e and p o t a s s i u m b e n z e n e s e l e n i t e .

The

y i e l d s a r e g e n e r a l l y good w i t h v a r i o u s o t h e r f u n c t i o n a l i t i e s u n a f f e c t e d by t h e s e l e n i u m r e a g e n t s , 3.N O 2 , C N , O R , SR, a l k y l , double bonds; furthermore t h e s p e n t r e a g e n t can be r e g e n e r a t e d w i t h hydrogen peroxide.

484

General and Synthetic Methods

RSeR’

i.ii R = Ph N2H4 c NaOH

RSe-SeR

iii

RSe’

RSeMe3 CHz(SeR l2

/ lvi

CH(SeR)3

‘

SeR

Reagents : i,

@ - GR,

Vi,

R

ii, RIX ( r e f . 157); iii, MeCl ; iv, CHzCL2

hX

;v

, CHCL3 ( r e f . 158)

( X = B r o r C l ) ; vii, R / - 7 X ( X = C i o r B r ) ( r e f . l 5 9 )

Scheme 20

\

CHO ‘X

(228)

(229)

(230 1

Scheme 21

R

R

ASePh

OMe

485

6: Organometallics in Synthesis References 1

s.,

(5)R.J.Mills and V.Snieckus, Tetrahedron Lett., 1984, 25, 479; (b) p .483 ; (c) M.Watanabe, M-Sahara, M.Kubo, S.Furukawa, R.J .Billedeau, and em.

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

1984, 19. (a) M.Cinquini, F.Cozzi, and A.Gilardi, J. Chem. SOC., Chem. Commun., 1984, p.1253. 591 ; (b) R.Annunziata, M.Cinquini, F.Cozzi, and A.Restelli, G.Demailly, C.Greck, and G.Solladie, Tetrahedron Lett., 1984, 25, 41 73. Y.Kawanami, Y.Ito, T.Kitagawa, Y.Taniguchi, T.Katsuki, and M-Yamaguchi, Tetrahedron Lett., 1984, 25, 857; (b-) Y.Ito, T.Katsuki, and M.Yamaguchi, ibid., p.6015. C.Gluchowski , T .Tiner-Harding, J.K. Smith, D. E-Bergbreiter, and M. Newcomb, J. Org. Chem., 1984, 49, 2650. P.Duhame1, J.J.Eddine,and J.-Y.Valnot, Tetrahedron Lett., 1984, 25, 2355. (5)B.A.Barner and A.I.Meyers, J. Am. Chem. SOC., 1984, 106,1 8 6 5 7 (b) A.I.Meyers, and D.Hoyer, Tetrahedron Lett., 1984, 3667. K.J.Brown, M.S.Berry, K.C.Waterman, D.Lingenfelter, and J. R.Murdoch, J. Am. Chem. SOC., 1984, 106, 4717. A.I.Meyers, M.Boes, and DTDickman, Angew. Chem., Int. Ed. Engl., 1984, 23, 458. H.Rcder, G.Helmchen, E.-M.Peters, K.Peters, and H.-G.von Schnering, Angew. Chem., Int. Ed. Engl., 1984, 23, 898. L.Banfi, A-Bernardi, L.Colombo, C.Gennari, and C.Scolastico, J. Org. Chem., 3784. 1984, F.Derguini and G.Linstrumelle, Tetrahedron Lett., 1984, 25, 5763. D.J.Ager, J. Chem. Soc., Chem. Commun., 1984, 486. T.Mandai, M.Takeshita, M.Kawada, and J.Otera, Chem. Lett., 1984, 1259. T.Mandai , T.Noriyama, Y.Nakayama, K .Sugino, M.Kawada, and J. Otera, Tetrahedron Lett., 1984, 25, 5913. G.Trimitsis, S.Beers, J.Ridella, M.Carlon, D.Cullin, J.High, and D.Brutts, J. Chem. SOC., Chem. Commun., 1984, 1088. S.de Lombaert and L.Ghosez, Tetrahedron Lett., 1984, 25, 3475. C.A.Brown, R.D.Miller, C.M.Lindsay, K.Smith, Tetrahedron Lett., 1984, 25, 991. (5) J.E.Baldwin, R.M.Adlington, J.C.Bottaro, A.U.Jain, J.N.Kolhe, M.W.D.Perry, and I.M.Newington, J. Chem. SOC., Chem. Commun., 1984, 1095; (b) J.E.Baldwin, J.C.Bottai-o, J.N.Kolhe, and R.M.Adlington, ibid., p.22. ATJ.Bridges and R.D.Thomas, J. Chem. SOC., Chem. Commun., 1 9 r 6 9 4 . S.Hackett and T.Livinghouse, Tetrahedron Lett., 1984, 25, 3539. A.Murai, A.Abiko, N.Shimada, and T.Masamune, Tetrahedron Lett., 1984, 25, 4951 G.A.Olah, L.Ohannesian, and M.Arvanaghi, J. Org. Chem., 1984, 2, 3856. (5)G.P.Stahly, B.C.Stahly, and K.C.Lilje, J. Org. Chem., 1984, 9, 578; (b) M.Makosza and J.Winiarski, H,p.1494; (2) M.Makosza and S-Ludwiczak, ibid., p.4562; (&) M.Makosza, J.Golinski, and J.Baran, p.1488; M.Makosza, B.Chylinska, and B.Mudryk, Liebigs Ann. Chem., 1984, 8. P.R.Hamann, J.E.Toth, and P.L.Fuchs, J. Org. Chem., 1984, 9, 3865. K.Utimoto, C.Lambert, Y.Fukuda, H-Shiragami, and H.Nozaki, Tetrahedron 1984, 25, 5423. M. C. Carre, G .Ndebeka, A. Riondel , P.Bourgasser, and P. Caubere, Tetrahedron E.,1984, 25, 1551. R.E.Gawley and T-Nagy, Tetrahedron Lett., 198b, 25, 263. C-Papageorgiou and C.Benezra, Tetrahedron Lett., 1984, 3,1303. N.Maigrot, J.-P-Mazaleyrat, and Z.Welvart, J. Chem. SOC.,Chem. Commun., 1984, 40. M.Braun and R.Devant, Tetrahedron Lett., 1984, 25, 5031.

z.,

(a)

z,

2,

-

(e) 27 28 29 30 31 32 33

s.,

x.,

General and Synthetic Methods

486

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

D.Seebach and M.A.Syfrig, Angew. Chem., Int. Ed. Engl., 1984, 23, 248. K.Tomioka, F.Masumi, T-Yamashita, and K.Koga, Tetrahedron Lett., 1984, 25, 333. ( 5 ) J.E.Lynch and E.L.Elie1, J. Am. Chem. SOC., 1984, 106,2943; (b) E.L.Elie1 and S.Morris-Natschke, p.2937. G.L.Larson, I.M.De Lopez-Cepero, and L.E.Torres, Tetrahedron Lett., 1984, 25. 1673. B.Fohlisch and R.Flogaus, Synthesis, 1984, 734. V-Fiandanese, G.Marchese, V.Martina, and L.Ronzini, Tetrahedron Lett., 1984, 25, 1843. G.A.Olah, G.K.Surya Aakash, and M. Arvanaghi, Synthesis, 1984, 228. M.Bogavac, L.Arsenijevic, S.Pavlov, and V.Arsenijevic, Tetrahedron Lett ., 1984, 25, 1843. ( 5 ) K.Tamao and N.Ishida, Tetrahedron Lett., 1984, 2, 4245; (b) p -4249. 5271. F.Z.Basha and F.De Bernardis, Tetrahedron Lett., 1984, N.Oguni and T.Omi, Tetrahedron Lett., 1984, 25, 2823. M.Braun and W.Hild, Chem. Ber., 1984, 117,413. G.Zweife1 and G-Hahn, J. Org. Chem., 1984, 9, 4565. J.Mulzer, M.Kappert, G.Huttner, and I.Jibri1, Angew. Chem., Int. Ed. Engl., 1980, 3, 704. G.Rousseau and N.Slougui, J. Am. Chem. SOC., 1984, 106,7283. E.Nakamura and I.Kuwajima, J. Am. Chem. S O C . , 1984, 106,3368. A.E.Greene, J.-P.Lansard, J.-L.Luche, and C.Petrier , J. Org. Chem., 1984, 49, 931. A.P.Kozikowski, M.N.Greco, and J.P.Springer, J. Am. Chem. S O C . , 1984, 106, 6873. J.Barluenga, L-Ferrera, C.Najera, and M.Yus, Synthesis, 1984, 831. J.Barluenga, F.Aznar, and R.Liz, Synthesis, 1984, 304. R.C.Larock and L.N.Harrison, J. Am. Chem. S O C . , 1984, 4218. R.C.Larock and K.Narayanan, J. Org. Chem., 1984, 49, 341 1. G.W.M.Visser, B.W.V.Halteren, J.D.M.Herscheid, G.A.Brinkman, and A.Hoekstra J. Chem. SOC., Chem. Commun., 1984, 655. H.C.Brown, G.G.Pai, and P.K.Jadhav, J. Am. Chem. S O C . , 1984, 106,1531. B.L.Allwood , H.Shahriari-Zavareh, J. F.Stoddart, and D.J. Williams, J. Chem. SOC., Chem. Commun., 1984, 1461. K.Soai, H.Oyamada, and T.Yamanoi, J. Chem. SOC., Chem. Comrnun., 1984, 413. R.Metternich and R.W.Hoffman, Tetrahedron Lett., 1984, 25, 4095. P.G.M.Wuts and S.S.Bigelow, J. Chem. SOC., Chem. Commun., 1984, 736. R.W .Hoffman and B.Landmann, Angew. Chem., Int . Ed. Engl., 1984, 23, 4.37. (a) H.C.Brown and P.K.Jadhav, J. Org. Chem., 1984, 49, 4089; (2) H.C. Brown. PTK.Jadhav, and P.T.Peruma1, Tetrahedron Lett ., 1984, 2, 51 1 1 ; (5)H.C.Brown and P.K.Jadhav, p.1215. H.C.Brown, D.Basavaiah, and S.M.Singh, Synthesis, 1984, 920. H.C.Brown, J.S.Cha, and B.Nazer, J. Org. Chem., 1984, 3, 2073. R.Baker, P.D.Ravenscroft, and C.J.Swain, J. Chem. S O C . , Chem. Commun. , 1984

e.,

u.,

z,

m,

64 65 66

r, I,

14-

67 68 69 70

71 72 73 74 75 76

R.O.Hutchins, K.Learn, F.El-Telbany, and Y .P.Stercho, J. Org. Chem., 1984, 49, 2438. H.C.Brown, U.S. Racherla, and S.M.Singh, Synthesis, 1984, 922. 5024. G.A.Molander, B.Singaram, and H.C.Brown, J. Org. Chem., 1984, 2, D.Min-zhi, T-Yong-ti, X.Wei-hua, Tetrahedron Lett., 1984, 25, 1797. ( 5 ) H.C.Brown, U.S.Racherla, and S.M.Singh, Tetrahedron Lett., 1984, 25, 2411; (b) M.Wada, Y.Sakurai, and K.Akiba, p.1083. G.W.Kabalka, G.W.McCollum, and S.A.Kunda, J. Org. Chem., 1984, 49, 1656. A.Pelter, H.Williamson, and G.M.Davies, Tetrahedron Lett., 1984725, 453. G.Ciacomelli, L.Lardicci, and F.Palla, J. Org. Chem., 1984, 9, 310. K.Yamamoto, H.Fukushima, and M.Nakazaki, J. Chem. Soc., Chem. Commun., 1984 1490. R.Noyori, I.Tomino, Y.Tanimoto, and M.Nishizawa, J. Am. Chem. S O C . , 1984, 106, 6709. -

u.,

6: Organometallics in Synthesis 77 78 79 80 81 82 83 84 85 86

487

J.M.Hawkins and K.B.Sharpless, J. Org. Chem., 1984, 2, 3861. (2) K.Suzuki, E.Katayama, T.Matsumoto, and G.Tsuchihashi, Tetrahedron Lett., p.1817; 1984, 25, 3715; (5) K.Suzuki, E.Katayama, and G.Tsuchihashi, (c) G.Tsuchihasi, K.Tomooka, and K.Suzuki, p.4253. Y.Fukutani, K.Maruoka, and H.Yamamoto, Tetrahedron Lett. , 1984, 2, 591 1 ; (b) J.Fujiwara, Y.Fukutani, M.Hasegawa, K.Marouka, and H.Yamamoto, J. Am. Them. SOC., 1984, 106, 5004. V.Ratovelomanana and G.Lizrumelle, Tetrahedron Lett., 1984, 25, 6001. J-Fujiwara, H.Sano, K.Maruoka, and H.Yamamoto, Tetrahedron Lett., 1984, 25, 2367. T.D.Hubert, D.P.Eyman, and D.F.Wiemer, ,..J 1984, 3,2279. R.E.Ireland and M.D.Varney, J. Am. Chem. SOC., 1984, 3668. (5) M.T.Reetz and K.Kesseler, J. Chem. SOC., Chem. Commun., 1984, 1079; (b) M.T.Reetz, K-Kesseler, and A.Jung, Tetrahedron Lett., 1984, 25, 729. S.Kiyooka, H-Sasaoka, R-Fujiyama, and C.H.Heathcock, Tetrahedron Lett., 5, 1984, 5331. W.S.Johnson, P.H.Crackett, J. D.Elliott, J. J.Jagodzinski, S.D.Lindel1, and on Lett., 1984, 25, 3951.

s.,

m.,

(a)

106,

87 88 89 90 91 92 93 94 95 96 97

hrahedron Lett,, 1984, 25, 131 ; J . Org. Chem., 1984, 49, 7 2 5 ; and I Kuwajima I, J. Chem. SOC., Chem. Commun., 1984, 1589. 3. Tetrahedron Lett,, 1984, 25, 5351. tnd J.W.Gillard, Tetrahedron Lett

98

(5) J.H.Rigby and J.Z.Wilson, Tetrahedron Lett., 1984,

,

i-j R .B. Miller and M.I.Al-Hasson,

.

w.,

J. Endla 1984 , 25 I

25, 1429;

(b) S.Hanessian, D.Delorme, and Y.Dufresne, p.2515. J.M.Aizpurua and C.Palomo, Tetrahedron Lett;., 1984, 25, 1103. M.Fujita and T.Hiyama, J. Am. Chem. SOC., 1984, 4629. V.M.F.Choi, J.D.Elliott, and W.S.Johnson, Tetrahedron Lett., 1984, 25, 591. ( 5 ) G.J.Wells, T.-H.Yan, and L.A.Paquette, J. Org. Chem., 1984, 2, 3604; (b) L.A.Paquette, C.Blankeship, and G.J.Wells, J. Am. Chem. SOC., 1984, 106, 6442; (5) L.A.Paquette, T.-H.Yan, and G.J.Wells, J. Org. Chem., 1984, 3610. 103 L.A.Paquette, R.S.Valpey, and G.D.Anuis, J. Org. Chem., 1984, 2, 1317. 104 (2) S.Rajagopalan and G.Zweife1, Synthesis, 1984, 1 1 1 ; (b-) p.113; (2) A.G.Angoh and D.L.J.Clive, J. Chem. SOC., Chem. Commun., 1984, 534. 105 W. S. Johnson , C-Edington, J. D.Elliott, and I.R.Silverman, J. Am. Chem. SOC , 1984, 106,7588. 106 I.Fleming, R.Henning, and H.Plaut, J. Chem. Sac. , Chem. Commun., 1984, 29. 107 T.Morimoto, T.Takahashi, and M.Sekiya, J. Chem. SOC., Chem. Commun., 1984, 794. 108 V.J.Jephcote, A.J.Pratt, and E.J.Thomas, J. Chem. SOC., Chem. Commun., 1984,

99 100 101 102

106,

G.,

.

800.

109

(5) G.E.Keck and E.P.Boden, Tetrahedron Lett., 1984, 25, 1879; (5) G.E.Keck and D.E.Abbott, p.1883; (2) G.E.Keck, D.E.Abbott, E.P.Boden, and E.J.Enholm, p.3927; G.E.Keck and E.P.Boden, N,p.265. Y.Yamamoto, K.Maruyama, and K.Matsmoto, J. Chem. SOC., Chem. Commun., 1984, 548. J. Hibino , S-Matsubara, Y. Morizawa, K. Oshima , and H. Nozaki , Tetrahedron Lett., 1894, 25, 2151.

s., (c)

w.,

110 111

General and Synthetic Methods

488 112

(a) W.F.Goure, M.E.Wright, P.D.Davis, S.S.Labadie, and J.K.Stille, J. Am. CFem. SOC.,1984, 106,6417; (2) F.K.Sheffy, J.P.Godschalz, and J.K.Stille, ibid., p.4833; ( 2 ) G.T.Crisp, W.J.Scott, and J.K.Stille, M,p.7500; (d) p.4630. E.J.Corey and T.M.Eckrich, Tetrahedron Lett., 1984, 25, 2419. E.J.Corey and T.M.Eckrich, Tetrahedron Lett., 1984, 25, 2415. J.E.Baldwin, R.M.Adlington, and A.Basak, J. Chem. SOC., Chem. Commun., 1984, 1284. K.Ruitenberg and P.Vermeer, Tetrahedron Lett., 1984, 25, 3019. K.Nakatani and S.Isoe, Tetrahedron Lett., 1984, 25, 5335. H.J.Reich, K.E.Yelm, .grO.JO-na Chem., 1984, 2, 3438. R.D.Arnold, J. E.Baldwin, and C.B.Ziegler , Jr , J. Chem. Soc., Chem. Commun., 1984, 152. A.G.Cameron, A.T.Hewson, and M.I.Osammor, Tetrahedron Lett., 1984, 25, 2267. P.Babin and J.Dunoguds, Tetrahedron Lett.-, E.Anders and T.Gassner, Chem. Ber., 1984, 117, 10%. D.Horne, J.Gaudino, and W.J.Thompson, Tetrahedron Lett., 1984, 25, 3529. W.Dumont, C.Vermeyen, and A.Krief, Tetrahedron Lett., 1984, 25, 2883. S.V.Ley and B.Lygo, Tetrahedron Lett., 1984, 25, 113. M.A.Whitesel1 and E.P.Kyba, Tetrahedron Lett., 1984, 25, 21 19. N.Waszkuc, T.Janecki, and R.Bodalski, Synthesis, 1984, 1025. M.A.Blanchette, W. Chov, J. T.Davis, A.P.Essenfeld, S.Masamune, W.R.Roush, and T.Sakai, Tetrahedron iett., 1984, .%, 2183. S.Hanessian, D.Delorme, S.Beaudoin, and Y.Leblanc, J. Am. Chem. SOC., 1984, 106, 5754. M.Mikolajczyk, W.Midura, and S.Grzejszczak, Tetrahedron Lett ., 1984, 25, 2489. T.Ishihara, T.Maekawa, and T.Ando, Tetrahedron Lett., 1984, 25, 1377. R.C.Anderson and M.J.Shapit-o, J. Org. Chem., 1984, 2, 1304. M.Julia and C.Lefebvre, Tetrahedron Lett., 1984, 25, 189. B.J.Banks, A.G.M.Barrett, and M.A.Russel1, J. Chem. SOC., Chem. Commun., 1984, 670. L.S.Liebeskind and S.L.Baysdon, Tetrahedron Lett., 1984, 25, 1747. T.Mandai, K.Mori, K.Hasegawa, M.Kawada, and J.Otera, Tetrahedron Lett., 1984, 25, 5225. (a) M.Shimagaki, T.Maeda, Y.Matsuzaki, I.Hori, T.Nakata, and T.Oishi, TFtrahedron-Lett., 1984, 25, 4775; (b) M.Shimagaki, Y.Matsuzaki, I.Hori, T.Nakata, and T.Oishi, p.4779. S.M.Ruder and R.C.Ronald, Tetrahedron Lett., 1984, 25, 5501. R.B.Garnmil1, L.T.Bel1, and S.A.Nash, J. Org. Chem., 1984, 2, 3039. A.R.Chamberlin, H.D.Nguyen, and J.Y.L.Chung, J. Org. Chem., 1984, 49, 1682. D.Caine, K.Procter, and R.A.Cassel1, J. Org. Chem., 1984, 9, 2647, M.Yokoyama, Y.Hasegawa, H.Hatanaka, Y-Kawazoe, and T.Imamoto, Synthesis, 1984, 827. T.Komori and T.Nonaka, J. Am . Chem. SOC., 1984, 106,2656. J.P.Marino and A.D.Perez, J. Am. Chem. SOC., 1984, 106,7643. G.H.Posner, T.P.Kogan, S.R.Haines, and L.L.Frye, Tetrahedron Lett., 1984, 25, 2627. G.Solladie and R.G.Zimmermann, Tetrahedron Lett., 1984, 25, 5769. G.Guanti, E.Narisano, F.Pero, L.Banfi, and C.Scolastico, J. Chem. SOC., Perkin Trans. 1 , 1984, 189. G.Guanti, L.Banfi, E.Narisano, and S.Thea, J. Chem. SOC., Chem. Commun., 1984, 861. ( 5 ) F.M.Hauser and S.R.Ellenberger, J. C. Clardy, and L.S.Bass, J. Am. Chem. SOC., 1984, 106,2458; (b) C.R.Johnson and M.R.Barbachyn, p.2459. W.Sas, J. Chem. SOC., Chem. Commun., 1984, 862. E.Block, V.Eswarakrishnan, and K.Gebreyes, Tetrahedron Lett., 1984, 25, 5469. (5) O.D.Lucchi, L.Pasquato, and G.Modena, Tetrahedron Lett., 1984, 25, 3643; (b) ibid., p.3647. O.D.LucFhi,Lucchini, L.Pasquato, and G.Modena, J. Org. Chem., 1984, 596.

u.,

113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130

135 136 137

.

s,

138 139 140 141 142 143 144 145 146 147 148 144 15a 151 152 153

-

-

c.,

z,

6: Organometallics in Synthesis

154 155 156 157 158 159 160 161 162 163 164 165 166

(a) B.M.Trost

106,

and P.Quayle, J. Am. Chem. SOC., 1984, 2469; and M.R.Ghadiri, =., p.7260. M.Adamczyk, E.K.Dolence, D.S.Watt, M. R. Christy, J.H.Reibenspies, and O.P.Anderson, J. Org. Chem., 1984, 1378. T..Mandai, T.Yanagi, K.Araki, Y.Morisaki, M.Kawada, and J.Otera, J. Am. Chem. SOC., 1984, 3670. J.V.Weber, P.Faller, G.Kirsch, and M.Schneider, Synthesis, 1984, 1044. L.Syper and J.Mlochowski, Synthesis, 1984, 439. M.Tieco, L.Testaferri, M.Tingoli, D.Chianelli, and M.Montanucci, Tetrahedron Lett., 1984, 25, 4975. D.H.R.Barton, G.Bashiardes, and J.-L-Fourrey, Tetrahedron Lett., 1984, 25, 1287. P.Lerouge and C-Paulmier, Tetrahedron Lett., 1984, 25, 1987. M.Clarembeau and A.Krief, Tetrahedron Lett ., 1984, 5, 3625. M.Clarembeau and A.Krief, Tetrahedron Lett ., 1984, 25, 3629. R.G.Shea, J.N.Fitzner, J.E.Fankhauser, and P.B.Hopkins, J. Org. Chem., 1984, 49, 3647. S.Uemura, S. Fukuzawa, T. Yamauchi , K.Hattori, S.Mizutaki , and K. Tamaki , J. Chem. SOC., Chem. Commun., 1984, 426. Y.Tsuda, S.Hosoi , A .Nakai, T.Ohshirna, Y. Sakai , and F.Kiuchi , J. Chem. SOC , Chern. Commun.. 1984. 1216. J.L.Laboureur, W.Dumont, and A.Krief, Tetrahedron Lett., 1984, 25, 4569. L.Syper and J.Mlochowski, Synthesis, 1984, 747.

(b) B.M.Trost

9,

106,

.

,

167 168

489

-

I

7 Saturated Carbocyclic Ring Synthesis BY T. V. LEE

1 Three-membered

Rings

G e n e r a l Methods.- A c o m p l e t e a c c o u n t o f t h e u s e of v i n y l s e l e n o x i d e s s u c h as ( 1 ) i n t h e s y n t h e s i s of c y c l o p r o p y l c a r b o n y l c o m p o u n d s by r e a c t i o n w i t h e n o l a t e a n i o n s may e n c o u r a g e t h e u s e o f D e t a i l e d s t u d i e s of t h e s t a b i l i z e d t h i s method i n s y n t h e s i s .

'

s u l p h u r y l i d e ( 2 ) i n c y c l o p r o p a n a t i o n s had l e d t o c l e a r e r i n s i g h t i n t o 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 ,

and 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 bis-dichlorocyclopropanation o f some b u t a - l , 4 - d i e n e s h a s b e e n d e ~ c r i b e d . ~C y c l o p r o p a n e s c a n a l s o b e p r e p a r e d by t h e

r e a c t i o n of k e t e n e s i l y l a c e t a l s ( 3 ) a n d b r o m o f o r m - d i e t h y l z i n c .

4

C a r b e n e a d d i t i o n s t o a l k e n e s are s t i l l t h e most p o p u l a r means o f s y n t h e s i z i n g c y c l o p r o p a n e s , a n d o n e new way o f g e n e r a t i n g chlorophenylcarbene

is by t h e r m o l y s i s of 3 - c h l o r o - 3 -

via

phenyldiazirine,

i n a r e a c t i o n proposed t o go

i n t e r m e d i a t e s .5

F u r t h e r m o r e , perhalogenovinylcarbenes s u c h a s ( 4 )

ylide

h a v e b e e n u s e d t o p r e p a r e halogenovinylcyclopropanes. O b s e r v a t i o n s on t h e e f f e c t o f o l e f i n c o - o r d i n a t i o n

6

on t h e

r e g i o s e l e c t i v i t y o f c y c l o p r o p a n a t i o n s may p r o v e of u s e i n s y n t h e s i ~ a, s~ c o u l d a m o d i f i e d p r o c e d u r e t o e n h a n c e t h e y i e l d o f t h e i n t r a m o l e c u l a r c y c l o p r o p a n a t i o n of u n s a t u r a t e d d i a z o a c e t i c e s t e r s . 8 A s t u d y o f t h e i n t r a m o l e c u l a r o p e n i n g o f t h e o x e t a n e (5) h a s l e d t o a new s y n t h e s i s of t h r e e - m e m b e r e d r i n g s a s w e l l a s f i v e The c y c l o a d d i t i o n r e a c t i o n o f t h e and six-membered r i n g s . ' a-chlorosulphide

( 6 ) w i t h 1 , 3 - d i e n e s i n a [2+41 r e a c t i o n l e a d s ,

a f t e r b a s e t r e a t m e n t , t o t h e y l i d e ( 7 ) , which r e a r r a n g e s t o t h e s y n t h e t i c a l l y u s e f u l v i n y l c y c l o p r o p a n e s ( 8 ) i n 71% y i e l d ( S c h e m e 1 ) . l o H o m o a l l y l i c i o d i d e s h a v e b e e n shown t o f o r m c y c l o p r o p y l c a r b i n y l a c e t a t e s upon t r e a t m e n t w i t h s i l v e r a c e t a t e ,

11

and t h e p r e v i o u s l y r e p o r t e d l i m i t a t i o n s upon t h e u s e o f y - s t a n n y l a l c o h o l s t o form c y c l o p r o p a n e s c a n b e o v e r c o m e by u s i n g t h i o n y l 12

chloride t o achieve cyclization. F u r t h e r d e t a i l s on t h e p r e p a r a t i o n a n d r e a c t i o n s of For References see page 531.

490

7: Saturated Carbocyclic Ring Synthesis

49 I

0-

w 2 e IP h

,S=CHCOzEt \

SMe

(6)

(7)

Reagents: i, SnCI4; ii, Et3N

Scheme 7

ld (9)

(10)

General and Synthetic Methods

492

f u n c t i o n a l i z e d l-(trimethylsily1)-substituted cyclopropanes have a p p e a r e d , l 3 i n c l u d i n g t h e i r u s e as p o s s i b l e 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 s p i r o c y c l i c s e s q u i t e r p e n e s . l4 intramolecular '[2+1]'

By m e a n s of a n

c y c l o a d d i t i o n of l a r g e - r i n g

cycloalkenes the

"perannulanes" ( 9 ) and ( 10) have been p r e p a r e d . l 5

L e s s w o r k on n a t u r a l c y c l o p r o p a n e s h a s b e e n r e p o r t e d t h i s y e a r a l t h o u g h a new conversion of (+)-3-carene

i n t o chrysanthemic a c i d h a s been

described. 2 Four-membered R i n g s The f a c t o r s c o n t r o l l i n g t h e r i n g c l o s u r e o f t h e i n t e r m e d i a t e d i r a d i c a l s formed i n t h e r e a c t i o n o f a l l e n e s w i t h d i e t h y l f u n i a r a t e and d i e t h y l m a l e a t e h a v e been s t u d i e d .

I t would a p p e a r t h a t t h e

t h r e e c o m p e t i t i v e p r o c e s s e s of r i n g c l o s u r e t o c y c l o b u t a n e s , i n t e r n a l r o t a t i o n , a n d r a d i c a l c l e a v a g e a r e b e s t e x p l a i n e d i n terms o f t h e p r e f e r r e d c o n f o r m a t i o n s of t h e d i r a d i c a l i n t e r m e d i a t e s . l 7

A

f u l l y d e t a i l e d , and l o n g o v e r d u e , a c c o u n t of t h e u s e of t h e a n i o n o f ( 1 1 ) r e a c t i n g w i t h a , w - d i h a l i d e s t o f o r m c y c l o b u t a n o n e s may b e of use.18

The k e t e n e ( 1 2 ) h a s b e e n p r e p a r e d and u s e d i n

c y c l o a d d i t i o n s t o form cyclobutanones which p o s s e s s h i g h l y u s e f u l additional functionality,

and f u l l d e t a i l s of t h e p r e p a r a t i o n and

u s e o f c h l o r o c y a n o k e t e n e s h o u l d also b e o f g e n e r a l i n t e r e s t . 2 0 M e c h a n i s t i c c o n s i d e r a t i o n s on t h e r e a c t i o n s o f a l k e n y l metal d e r i v a t i v e s , e.g.

(13)

--t

(141, should enhance t h e s y n t h e t i c u t i l i t y

of t h e s e r e a c t i o n s .21 T h e r e h a s b e e n a n i n c r e a s e d i n t e r e s t i n i n t r a m o l e c u l a r [2+21 p h o t o c y c l i z a t i o n s d u r i n g t h e y e a r , and one r e p o r t h i g h l i g h t s a n o v e l p r o c e s s o f t h i s t y p e w h i c h u t i l i z e s a copper(1) s a l t a s a c a t a l y s t . T h u s , a s s e e n i n Scheme 2 , c o p p e r ( 1 ) t r i f l u o r o m e t h a n e sulphonate c a t a l y s e s t h e conversion of t h e t r i e n e (15) i n t o t h e bicyclo[3.2.0]-system (161, i n a process not observed f o r d i r e c t or t r i p l e t s e n s i t i z e d i r r a d i a t i o n . H o w e v e r , t h e low y i e l d s of ( 1 6 ) and t h e f o r m a t i o n o f ( 1 7 ) as a b y - p r o d u c t do l i m i t t h e s y n t h e t i c u t i l i t y of t h e p r o c e s s . 2 2

A d e t a i l e d study of t h e intramolecular

[ 2 + 2 ] p h o t o p r o d u c t s o f some v i n y l o g o u s i m i d e s h a s a p p e a r e d 2 3 a n d t h e s e r e a c t i o n s h a v e b e e n a p p l i e d t o a s y n t h e s i s of p a r t o f t h e t a x a n e c a r b o n s k e l e t o n . 24 F u l l p a p e r s o f p r e v i o u s c o m m u n i c a t i o n s on work u s i n g i n t r a m o l e c u l a r [ 2 + 2 ] p h o t o c y c l i z a t i o n s i n c l u d e i t s u s e i n t h e p r e p a r a t i o n o f ( 1 8 ) , 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 26 ( + ) - h i b i s c o n e C 2 5 a n d i n a s y n t h e s i s of perhydrohistrionicotoxin.

493

7: Saturated Carbocyclic Ring Synthesis

,

SMe H C '$Me

I

7=*

Si Me3

0(11

CL

1

(12)

(14) 84'10

(13)

Scheme 2

H

General and Synthetic Methods

494

The known photolytic cyclization of keto-esters such as (19) has been used in the synthesis of a derivative of [4.4.4.51fene~tone,~~ and the often used strategy of intramolecular [2+21 photocycloaddition-cyclobutane fragmentation has been put to good use in a synthesis of ('1-pentalenic acid. 28 It has been shown that phenyl-substituted 1,3-diketones can lead, upon photolysis, to substituted cyclobutanones (Scheme 3), albeit as the major product of a complex mixture.29 Comprehensive experimental details on the photoannulation of an enone to an alkene should be invaluable,30 as will full and authenticated details on the copper(1)-catalysed p h o t o c y ~ l i z a t i o n . ~ ~ An interesting thermal [2+21 cycloaddition of the butatriene (20) and an alkene has been shown to occur exclusively at the central double bond of the cumulated t ~ - i e n e . ~An~ improved procedure for generating and using I-lithiocyclopropanes to synthesize c y c l o b ~ t a n o n e smay ~ ~ be useful, as may be a full account of the preparation of a transfused cyclobutanone .34

3 Five-membered Rings General Methods.- A review of nitrile oxide cycloadditions in carbocyclic synthesis will be of interest. Radical cyclizations continue to be studied, and it has now been shown that w-allenyl halides (21) undergo tin hydride induced cyclizations to form mainly five-membered rings. " The same research group has also reported upon the chromium(I1) reductive cyclization of w-alkynyl halides. 37 Intramolecular versions of the well known reactions of allyl- and vinyl-silanes are becoming increasingly popular, and have been applied in cyclopentanoid synthesis. The most exciting development in this area is the use of the optically active allylsilane (221, prepared via a Claisen rearrangement, to synthesize an optically active cyclopentane (Scheme 4) .38 Additionally, a new route to mainly *-fused cyclopentanes involves a Lewis acid-induced cyclization of the epoxy allylsilane (23). 39 Furthermore, intramolecular cyclization of the alkylsilane (24) allows the ready formation of cyclopentanones and constitutes an interesting addition to organosilicon chemistry. However, current methods for preparing (24) limit the react ion somewhat. 40 A new route to vicinal cyclopentanediones has been described, and a simple two-step conversions of diallyl adipate

''

495

7: Saturated Carbocyclic Ring Synthesis

Me..ySiMe3

i

OH

H 0' H

(22) Reagents: i, I $ C = C H O E ~ , H ~ ( O A C ) ~i i;, TiCI4

Scheme 4 SiMe,

General and Synthetic Methods

496

i n t o 2 - m e t h y l c y c l o p e n t e n o n e s h o u l d make t h e l a t t e r v e r y r e a d i l y a v a i l a b l e . 42 A s h o r t s e r i e s o f p a p e r s on new a n n u l a t i o n r e a c t i o n s u t i l i z e s

a c o n c e p t u a l l y s i m p l e a p p r o a c h (Scheme 5 ; E = e l e c t r o n - w i t h d r a w i n g

g r o u p s ) t o r i n g f o r m a t i o n , whereby s t a b i l i z e d d i a n i o n s c y c l i z e o n t o m o l e c u l e s b e a r i n g two e l e c t r o p h i l i c c e n t r e s .

Thus, t h e doubly

c h a r g e d s u c c i n a t e a n i o n ( 2 5 ) c o n d e n s e s w i t h t h e a-bromomethyl a c r y l a t e ( 2 6 ) t o form ( 2 7 ) , 4 3 w h e r e a s u s e of t h e v i n y l o g o u s d i a n i o n

(28) has l e d t o t h e s y n t h e s i s of sarkomycin and t h e p r o s t a g l a d i n s .44 A d d i t i o n a l l y , a g e n e r a l approach t o a n n u l a t i o n is o f f e r e d by t h e d i a n i o n o f t h e b i s o x a z o l i n e ( 2 9 1 , w h i c h i s equivalent t o t h e a , a f - d i a n i o n of s u c c i n i c a c i d r e a c t i n g with a , w - d i h a l i d e s . 45 There is an i n c r e a s i n g i n t e r e s t i n t h e chemistry of 3-substituted

c y c l o p e n t e n e s and t h i s h a s r e s u l t e d i n an improved

s y n t h e s i s o f cyclopentene-3-carboxylic a c i d ( 3 0 ) by t h e known r e a c t i o n of d i m e t h y l malonate and ~ - 1 , 4 - d i c h l o r o b u t - 2 - e n e b u t u s i n g new

condition^.^^

Additionally, t h e first d i r e c t s y n t h e s i s

o f o p t i c a l l y a c t i v e 3 - m e t h y l c y c l o p e n t e n e h a s b e e n d e s c r i b e d . 47 T h i s work i n v o l v e d t h e u s e o f t h e R a m b e r g - ' B a c k l u n d r e a c t i o n w h i c h h a s a l s o been used i n a f a c i l e s y n t h e s i s of t h e c y c l o p e n t - 3 - e n o n e 48

derivatives (31).

a - S u l p h i n y l c a r b a n i o n s a r e much u s e d i n s y n t h e s i s a n d h a v e now been a p p l i e d t o t h e p r e p a r a t i o n of cyclopent-2-enones.

Thus

t r e a t m e n t of t h e s u l p h o x i d e ( 3 2 ) w i t h b a s e g a v e t h e c y c l i z e d p r o d u c t ( 3 3 ) which r e a d i l y e l i m i n a t e s p h e n y l s u l p h i n i c a c i d . 49 w-Iodo-a, & u n s a t u r a t e d

e s t e r s undergo an intramolecular conjugate

a d d i t i o n r e a c t i o n upon r a p i d l i t h i u m - h a l o g e n

e x c h a n g e as shown f o r

( 3 4 ) 5 0 and a c e t y l e n i c d i e s t e r s c a n a l s o be u s e d t o s y n t h e s i z e h i g h l y f u n c t i o n a l i z e d and u s e f u l c y c l o p e n t a n e s i n a c o n j u g a t e a d d i t i o n - i n t r a m o l e c u l a r a c y l a t i o n s e q u e n c e a s s h o w n i n S c h e m e 6. Another a n i o n i c 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 r o u t e is t h e c o n v e r s i o n of ( 3 5 ) i n t o ( 3 6 ) , w h i c h i s a k e y s t e p i n a s y n t h e s i s o f ( + ) - b r e f e l d i n A w h i c h h a s now b e e n r e p o r t e d i n f u l l . 5 2 Cyclopentanes were t h e unexpected p r o d u c t of t h e r e a c t i o n of t h e bis-enamine ( 3 7 ) w i t h n i t r o - o l e f i n s t o form t h e i s o m e r i c c y c l o p e n t e n e s ( 3 8 ) a n d ( 3 9 ) .53 More a p p l i c a t i o n s o f t h e u s e o f vinylphosphonium s a l t s t o prepare cyclopentanoid n a t u r a l products h a v e b e e n d e s c r i b e d , 54 a n d f u r t h e r s t u d i e s on t h e r e g i o s e l e c t i v i t y o f t h e c y c l i z a t i o n o f w-halogeno-a,@-epoxyhexanes a r e o f i n t e r e s t .55

497

<

7: Saturated Carbocyclic Ring Synthesis

QEE

X

Y - C02Pri

P~~o,C

$"'

&co*pri

Br

co2Pri

(28) Scheme 5

(29)

f

HO2C-

CO H

Reagents: i, B r v B r ; ii,H2S0kIEtOH

C02H

I

(30) 7 0 % Reagents: i, LiH, DMF; ii, KOH; iii, H30'

n

n +O (31)

General and Synthetic Methods

498

-0

CO2 But

BunLi

-100

(34)

*c

82

"/a

Reagents: i, PriMgCI,Cu*1; i i , Lithium di-isopropylamide

Scheme 6

TosO

MEMO--

MEMO' (35)

(36)

7: Saturated Carbocyclic Ring Synthesis

499

Although the intramolecular carbometallation of an acetylene group (40) is known, the reaction is not stereospecific. However, incorporation of a trimethylsilyl group (41) (Scheme 7) into the acetylene gives total stereochemical control and allows the reaction to be performed under mild conditions, so making this process synthetically useful. 56 Furthermore , by use of the Shapiro process to generate a vinyl-lithium it has proved possible to obtain intramolecularly cyclized products as exemplified by the synthesis of (42).57 5-Substituted cyclopent-2-enones can be prepared as shown in Scheme 8 by reaction of a suitably substituted acid chloride (43) and an alkyne in a process which can also lead to spirocompounds .58 Cyclodimerization of dimethyl methylenesuccinate (44) with dichloroethylaluminium also forms highly functionalized cyclopentanones , 59 and boron trifluoride-induced cyclization of a,B-epoxy-artemesia ketone afforded a 1:l mixture of the ketols (45) and (46).60 Transition metal-catalysed processes have made an important contribution to the synthesis of five-membered rings, and some new examples have been reported. 3,4-Disubstituted pent-4-enals such as (47) are cyclized to the highly useful cis-3,4-disubstituted cyclopentanones (48) using a rhodium catalyst in 88% yield,61 and 2-methylcyclopent-2-enone can be prepared in a novel fashion by the palladium-catalysed cyclization of I-ethenyl-2-propenyl acetate (49).62 The first application of the reaction of allyliron complexes and electron-deficient alkenes to give cyclopentanes is ~ methylenecyclopentane in a synthesis of ( * ) - s a r k ~ m y c i n . ~The annulation using the cuprate (50) has now been applied to a synthesis of (+I-pentalenene.64 An elegant study of the vinylogous Dieckmann condensation has demonstrated that such cyclizations follow Baldwin's guidelines for ring closure,65 and a comprehensive account of' the synthesis of pentenomycin from D-quinic acid has been reported.66 Fused Five-membered Rings.- A general but relatively long annulation procedure is illustrated in Scheme 9 by the preparation of (52) in which the key step is the transmetallationintramolecular cyclization of (51) which proceeded in 92% yield. 67 Lanthanides are being increasingly used in synthesis, and have now been utilized for the otherwise difficult cyclization of the iodoA useful new route to cyclopentenones involves base ketone (53).68

500

General and Synthetic Methods

R C E C ( CH2),Br

RFo""" RP

Br Mg M g *

( 4 0 )R = H ( 4 1 ) R = SiMe,

/

97

"I0

Scheme 7

LC[ [ L c ja BulLi

Tr i s N H N /

+

L i2 Cu CI4

(42)66'10

CI

0

Reagents: i, HC=CH;

0

ii,ALClg

Scheme 8

CH2C02Me CH2=C'

,OC' (44)

Me

EiAlC12

* Me0 2

Me

7: Saturated Carbocyclic Ring Synthesis

501

0

OCOMe

0 (48)

(47)

(49)

(50) CI

(51)

(52)

Reagents: i , N ~ H , ( C F ~ S O Z ) ~ii,OPhSCuSnMe3; ; iii, lithium di-isopropylamide, CI(CH2)3I; iv, DIBAI-H; v,MeZButSiCl, vi,MeLi

Scheme 9

H (53)

axNo.

n

n

60 ' h

n

NaOH, Bun4NB;

Hi)

(54)

(55)

(561

502

General and Synthetic Methods

t r e a t m e n t o f t h e n i t r o k e t o n e ( 5 4 ) t o f u r n i s h t h e e n o n e ( 5 5 ) . The mechanism f o r t h i s t r a n s f o r m a t i o n p r e s u m a b l y i n v o l v e s r e a c t i o n via t h e i n t e r m e d i a t e ( 5 6 ) w h i c h upon c o n v e r s i o n i n t o a 1 , h - d i k e t o n e

condition^.^'

c y c l i z e s under t h e b a s i c r e a c t i o n A novel high y i e l d i n g c y c l o p e n t a n n u l a t i o n h a s b e e n r e p o r t e d w h i c h d e p e n d s upon a c a t i o n i c c y c l i z a t i o n of t h e a l l e n o l a l d e h y d e ( 5 7 ) when t r e a t e d w i t h boron t r i f l u o r i d e .

Such a s i m p l e s y n t h e s i s of h i g h l y

f u n c t i o n a l i z e d c y c l o p e n t a n e s w i l l undoubtedly be of u s e and one can presume t h a t t h e p r o d u c t i s d e r i v e d from a s i m p l e a l d o l - t y p e c o n d e n s a t i o n o f t h e e n o l e t h e r a n d t h e a l d e h y d e (58), f o l l o w e d by d e h y d r a t i o n a n d c l e a v a g e of t h e e t h e r .70 Some h i g h l y f u n c t i o n a l i z e d c y c l o p e n t a n o n e s , o f g r e a t p o t e n t i a l i n s y n t h e s i s , have been d e s c r i b e d .

A s shown i n Scheme 10

c o n d e n s a t i o n of methyl hex-2-enoate

with dimethyl o x a l a t e gave a

cyclopent-3-en-1,2-dione d e r i v a t i v e ( 5 9 ) . T h i s , owing t o i t s i n a b i l i t y t o e n o l i z e t o ( 6 0 1 , would be e x p e c t e d t o be u n s t a b l e , a n d it d o e s i n f a c t d i m e r i z e t o ( 6 1 ) . A p l a u s i b l e m e c h a n i s m , i n v o l v i n g two v i n y l o g o u s d o u b l e C l a i s e n c o n d e n s a t i o n s , f o r f o r m a t i o n o f t h e d i m e r i s shown.

The d i m e r i s a p p a r e n t l y i n e q u i l i b r i u m w i t h t h e

monomer ( 5 9 ) , and u s e c a n be made o f t h i s t o a c h i e v e r e a c t i o n s of t h i s potentially useful species.

T h u s , t r e a t m e n t of ( 6 1 ) w i t h t h e

a n i o n of d i m e t h y l malonate gave t h e k e t o - e n o l

(62) possessing t h e

s t e r e o c h e m i s t r y shown. 7 1 The c o n d e n s a t i o n o f d i m e t h y l 3 - k e t o g l u t a r a t e

and a

1 , 2 - d i c a r b o n y l compound i s a w e l l known f a c i l e r o u t e t o + - f u s e d bicyclo[3.3.0]octanes

a n d i t h a s now b e e n shown t h a t t h e p r e v i o u s l y

p o s t u l a t e d hydroxyenone ( 6 3 ) i s a g e n u i n e i n t e r m e d i a t e i n t h i s process.72

Use o f a n e n a n t i o s e l e c t i v e d o u b l e M i c h a e l a d d i t i o n h a s

p e r m i t t e d t h e p r e p a r a t i o n o f t h e h y d r i n d a n e (64).73 F u r t h e r work on t h e L e w i s a c i d - c a t a l y s e d t o p r e p a r e c y c l o p e n t e n e s h a s b e e n r e p o r t e d . 74

c y c l i z a t i o n of ( 6 5 ) Functionalized

c y c l o p e n t a n e s c a n a l s o be p r e p a r e d by a tandem C l a i s e n - e n e r e a r r a n g e m e n t , e . g . ( 6 6 ) g i v i n g ( 6 7 ) and ( 6 8 ) i n a 1 : l r a t i o (Scheme 1 1 ) .

I n t h e s e r e a c t i o n s lower t e m p e r a t u r e s a l l o w a

complementary oxy-ene r e a c t i o n t o o c c u r , i n d i c a t i n g t h e c r i t i c a l n a t u r e of t h e r e a c t i o n c o n d i t i o n s i n t h e s e p r o c e s s e s . 7 5 However, t h e s e t y p e s o f e n e r e a c t i o n c a n be r e g i o c h e m i c a l l y c o n t r o l l e d by i n c o r p o r a t i o n of a t r i m e t h y l s i l y l g r o u p i n t o t h e m o l e c u l e as shown by t h e c o n v e r s i o n s of ( 6 9 ) a n d ( 7 0 ) i n t o ( 7 1 ) a n d (72).76 The f o r m a l t h e r m a l 1 , 3 - d i p o l a r c y c l o a d d i t i o n of c y c l o p r o p e n o n e a c e t a l 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 is a u s e f u l a d d i t i o n t o t h e

503

7: Saturated Carbocyclic Ring Synthesis

P

...

OSiMe,

3

t

POH t

(57)

(58)

MeOReagents: i ,

Li

-C=;

i i , Bu:NF;

iii,BFg

C0,Me

-‘*zMe

MeOK (

~

Me02C)2

Et

+e 0

--

CO M

0

C02 Me

0

OH C02Me

MeQ2CVCo2 Me C02 Me Et P

O

H

11

General and Synthetic Methods

504

~ -0 3

0

0

'

C

d'

+

I

6

II

~H,CHO

/

300

OC,

S

H I

I I

CH, CO, Et

CHZCOZEt

(69) R = H (70) R = SiMe3

(71)

~H~CHO

&ti I

1

C H2 C 02Et

(72)

R = H ( 7 1 ) : (72) = 3 : l R = SiMe, ( 7 1 ) : (72) = 1OO:O S c h e m e 11

dk

CO2 Me

t

(741

(75)

7: Saturated Carbocyclic Ring Synthesis

505

e f f o r t s t o d e v e l o p t h i s much s o u g h t a f t e r C3+21 c y c l o a d d i t i o n reaction.

I t would a p p e a r (Scheme 1 2 ) t h a t t h e s t r a i n e d a l k e n e

( 7 3 ) a d d s t o a n a c t i v a t e d d o u b l e bond a n d t h e r e s u l t i n g c y c l o p r o p y l carbenium i o n ( 7 4 ) c o l l a p s e s t o an a l l y l c a t i o n which forms t h e I n a r e l a t e d study

observed products (75) i n reasonable yields.77

t h e a c e t a l ( 7 3 ) was shown t o b e h a v e a s a 1 , l - d i p o l e l e a d i n g t o c y c l o p r o p a n e f o r m a t i o n .78 O t h e r work on [3+21 c y c l o a d d i t i o n s h a s demonstrated t h a t a , B - u n s a t u r a t e d k e t o n e s and t h e a l l y l c a r b o n a t e ( 7 6 ) r e a c t w i t h a p a l l a d i u m c a t a l y s t t o g i v e good y i e l d s of h i g h l y f u n c t i o n a l i z e d cyclopentanones .79 I n t e r e s t i n b o t h o r g a n o - i r o n c h e m i s t r y and h y d r o a z u l e n e s y n t h e s i s c o n t i n u e s , a n d t h e two h a v e been combined i n a o n e - s t e p of t h e hydroazulane s k e l e t o n .

synthesis

Thus, r e a c t i o n of t h e t r o p o n e

t r i c a r b o n y l i r o n ( 7 7 ) w i t h t r i m e t h y l s i l y l trifluoromethanesulphonate gives t h e tropylium salt (78).

Regiospecific reaction of t h i s with

a n a l l y l i r o n complex g i v e s a good y i e l d o f t h e h y d r o a z u l e n e ( 7 9 1 , i n a p r o c e s s w h i c h s h o u l d be a p p l i c a b l e t o t h e s y n t h e s i s o f t h e guianolides.80

An i t e r a t i v e c y c l o p e n t a n e a n n u l a t i o n of 81

a , B - u n s a t u r a t e d k e t o n e s i s a l s o w o r t h y of n o t e . Radical-induced

I

c y c l i z a t i o n s a r e h i g h l y t o p i c a l and have been

u s e d i n a p r e p a r a t i o n o f a n g u l a r l y f u s e d c y c l o p e n t a n o i d s by a p h o t o l y s i s of t h e enone ( 8 0 ) t o form a 3 : l m i x t u r e of t h e k e t o n e s 82 ( 8 1 ) and ( 8 2 ) . N a t u r a l l y O c c u r r i n g Fused C y c 1 o p e n t a n o i d s . - The i n t e r e s t i n g c y c l i z a t i o n of t h e d i m e t h a n e s u l p h o n a t e ( 8 3 ) h a s l e d t o a new r o u t e t o t h e c a r b o ~ y c l i n s . ~An~ a r e a of c u r r e n t i n t e r e s t i n more t h a n one l a b o r a t o r y i s t h e c o b a l t - p r o m o t e d i n t r a m o l e c u l a r c y c l o p e n t e n o n e s y n t h e s i s , a n d t h i s h a s now been u s e d t o p r e p a r e t h e a n g u l a r l y fused t r i q u i n o n e s k e l e t o n ( 8 4 ) , a l b e i t i n poor y i e l d ; 8 4 however, a s u p e r i o r s y n t h e s i s of t h e same c a r b o n s k e l e t o n i s d e s c r i b e d i n f u r t h e r work on t r a n s a n n u l a r c y c l i z a t i o n s w h i c h h a s l e d t o a s y n t h e s i s of ( + ) - p e n t a l e n e n e i n w h i c h t h e c y c l i z a t i o n of ( 8 5 ) a n d ( 8 6 ) is t h e key s t e p . 8 5 An a n a l o g o u s c y c l i z q t i o n o f t h e d i e n e ( 8 7 ) 86 h a s a l s o been d e s c r i b e d . A s t u d y of t h e f l a s h vacuum p y r o l y s i s of t h e p e n t a c y c l e ( 8 8 ) h a s b e e n r e p o r t e d i n c l u d i n g t h e c o n v e r s i o n of ( 8 8 ) i n t o t h e t r i q u i n o n e ( 8 9 ) .87

Bicyclo[3.3.0]octenones

c o n t i n u e t o b e of g r e a t

u t i l i t y i n s y n t h e s i s as e x e m p l i f i e d by 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 q u a d r o n e 8 8 a n d a s y n t h e s i s of ( + ) - c e d r e n e .89 known a - a l k y n o n e

The p r e v i o u s l y c y c l i z a t i o n t o form c y c l o p e n t e n o n e s h a s been

506

General and Synthetic Methods

CN

- -@

NCd-LocozEt 0 (

Reagents: it TMSOS02CF3; ii, F

76)

p

65 “ l o

v

& & h v ,

+

@

(80)

0t

MsO

MeSY:\/Li T H PO’’

Li

4-

Me$+-, ~

T H PO”

OSi Buf P

507

7: Saturated Carbocyclic Ring Synthesis

A

L

(88)

( 8 9)

/cyp - \dH /’!

Me

Y‘

LIi

MeNHOH EtONa

I

;r

H (91)

(90)

(921

0 (93)

-5-1

(94)

+

[ti Ph

Ph

508

General and Synthetic Method3

a p p l i e d t o a s y n t h e s i s o f ( ‘ ) - c l o ~ e n e . ~ ~The u s e o f t r i c y c l o o c t a n o n e s 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 well e s t a b l i s h e d and t h i s y e a r a v a r i a t i o n i n t h i s s t r a t e g y h a s l e d t o a new s y n t h e s i s o f (*)-corioling1

a n d two o t h e r g r o u p s h a v e now p r o v i d e d f u l l d e t a i l s

o f t h e i r s y n t h e s e s of ( * ) - c o r i o l i n . 9 2 1 9 3

The ‘ d o n o r - a c c e p t o r

’

a n n u l a t i o n r e a g e n t (90) h a s b e e n u s e d f o r t h e s y n t h e s i s o f (+)-A9(

1 2 ) - c a p n e l l a n e , 9 4 a n d i n a new s y n t h e s i s of (+ ) - h i r s u t e n e

the nitrone-olefin

cycloaddition, i.e. as t h e k e y r e a c t i o n . 9 5 4 Six-membered Diels-Alder

( 9 1 ) t o (921, h a s been used

Rings

Reactions.-

Although n o t y e t a p p l i e d t o t h e s y n t h e s i s

o f c y c l o h e x e n e s i t i s w o r t h n o t i n g t h a t f u r t h e r w o r k on a s y m m e t r i c Diels-Alder

r e a c t i o n s u s i n g c h i r a l a u x i l l a r i e s s u c h as ( 9 3 ) and ( 9 4

h a s b e e n r e p ~ r t e d , ~a n~d -t h~ i ~s w h o l e a r e a of work h a s b e e n reviewed. loo

Another approach t o c o n t r o l l i n g a b s o l u t e

s t e r e o c h e m i s t r y i n t h e s e r e a c t i o n s is t h e u s e of c h i r a l carboxamide

( 9 5 ) as shown.”’

D e t a i l e d k i n e t i c s t u d i e s of t h e Diels-Alder

r e a c t i o n have l e d t o t h e c o n c l u s i o n t h a t a l t h o u g h t h e r e a c t i o n s a r e c o n c e r t e d , i . e . t h e y occur i n a s i n g l e k i n e t i c s t e p , they are n o t synchronous, i.e. t h e v a r i o u s changes i n bonding have n o t 102 p r o g r e s s e d t o similar e x t e n t s i n t h e t r a n s i t i o n s t a t e . The r e a c t i o n of s t y r e n e s a n d e l e c t r o n - r i c h a l k e n e s w i t h d i e n e s under c a t i o n - r a d i c a l t h e Diels-Alder

c y c l o a d d i t i o n c o n d i t i o n s forms a mixture of

a d d u c t (96) a n d t h e c y c l o b u t a n e (97), w i t h t h e

latter predominating.

The a d d u c t (97) c a n b e r e a d i l y c o n v e r t e d

i n t o t h e formal Diels-Alder Diels-Alder

adduct (98). Io3

reaction of a cross-conjugated

A diene transmissive

t r i e n e c o n s i s t s o f two

c o n s e c u t i v e c y c l o a d d i t i o n s , t h e f i r s t one of which p r o v i d e s a d i e n e f u n c t i o n a l i t y for t h e second. F u r t h e r work on t h i s c o n c e p t h a s b e e n r e p o r t e d i n a p r o c e s s t h a t i s c h a r a c t e r i z e d by t h e r e a c t i o n o f t h e t r i e n e (99).’04-’06

F u l l a c c o u n t s o f some o f t h i s work h a v e

a l s o a p p e a r e d . 107’108 The d i e n e ( 1 0 0 ) i s t h e k e y c o m p o n e n t i n a c o n c e p t u a l l y n o v e l approach t o m u l t i p l e f u s e d r i n g s y s t e m s , whereby t h e i n i t i a l a d d u c t u n d e r g o e s a [3+21 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 t o form f o u r f u s e d r i n g s ( o n e b e i n g a h e t e r o c y c l e ) a f t e r r e d u c t i o n o f t h e m o r e r e a c t i v e e n o n e d o u b l e bond (Scheme 1 3 ) . l o g The s i l v e r c o m p l e x ( 1 0 1 ) o f a t r a n s - c y c l o h e p t e n e p r o b a b l y c o n s t i t u t e s o n e of t h e m o s t i n t e r e s t i n g d i e n o p h i l e s i n t r o d u c e d t h i s

7: Saturated Carbocyclic Ring Synthesis

509

rC' ii, iii

(96) R = CH2CHZCI (98) R = H

(98

(97)

Reagents: i, Ar3N?; ii, BunLi,iii, KH

-i Me3Si0

OSiMe,

(99)

S i Me3

iMe3

Me3Si0

'0 Reagents: i, (0

(100)

ii, iii

C02Me

Reagents: i, CgHg, 25

OC;

ii, L-selectride,-78

OC;

iii, PhN=C=O,

Scheme 13

Et3N

General and Synthetic Methods

510

year. It undergoes cycloaddition with d i e n e s at ambient t e m p e r a t u r e i n a p r o c e s s w h i c h p r o b a b l y i s c a t a l y s e d by t h e s i l v e r salt.’”

F u l l d e t a i l s o f t h e u s e o f ( 1 0 2 1 , as a n e q u i v a l e n t t o

a c e t y l e n e , as a d i e n o p h i l e s h o u l d be u s e f u l , ’ ”

a n d some D i e l s -

A l d e r r e a c t i o n s of 1,l-bis(benzenesulphony1)ethene

(103) have been

described. A new p r e p a r a t i o n o f E , E - e x o c y c l i c d i e n e s , e . g .

(1041, w i l l

e n h a n c e t h e i r u s e i n s y n t h e s i s as d e m o n s t r a t e d by t h e s y n t h e s i s o f ( 1 0 5 ) (Scheme 1 4 ) . ’ 1 3

A d d i t i o n a l l y t h e d i e n e ( 1 0 6 ) h a s been used

i n a new a p p r o a c h t o s t e r i o d C - r i n g s y n t h e s i s . ’ I 4

A novel general

r o u t e t o d i e n e s s u c h as ( 1 0 7 ) w i l l b e i n v a l u a b l e , l 5 w h i l s t t h e d i e n a m i n e ( 1 0 8 ) h a s b e e n u s e d as a d i e n e f o r t h e f i r s t t i m e . l l 6 Aqueous D i e l s - A l d e r r e a c t i o n s a r e c u r r e n t l y i n v o g u e , and s u c h and ( 1 1 0 ) 1 1 8 h a v e b e e n d e s c r i b e d

r e a c t i o n s of t h e d i e n e s

w i t h t h e l a t t e r b e i n g u s e d i n a f o r m a l s y n t h e s i s of v e r n o l e p i n . r e a c t i o n s h a v e now b e e n shown t o b e c a t a l y s e d by F e 111-

Diels-Alder doped c l a y s .

Intramolecular Diels-Alder

Reactions.- This strategy continues t o

b e a n o t a b l e f e a t u r e o f t h e c u r r e n t l i t e r a t u r e , w i t h many c o m p o u n d s succumbing t o s y n t h e s i s

via

t h i s powerful methodology.

A rather

n e a t a p p l i c a t i o n o f t h i s p r o c e d u r e is t h e c y c l i z a t i o n o f t h e t r i e n e ( 1 1 1 ) ( p r e p a r e d i n s i t u ) as t h e k e y s t e p i n a s h o r t s y n t h e s i s o f ( + ) - o e s t r o n e . I2’-Of

a d d i t i o n a l i n t e r e s t is t h e c y c l i z a t i o n of t h e

t r i e n e (112) which h a s been used t o s y n t h e s i z e t h e t a x a n e s k e l e t o n (113).121

The s a m e g r o u p h a s u s e d t h e m e t h o d t o c o n v e r t t h e t r i e n e

(114) i n t o ( 1 1 5 ) , an intermediate towards t h e s y n t h e s i s of ( ? ) forskolin.122

I n a t y p i c a l l y e l e g a n t l y conceived p i e c e of work, it

h a s b e e n shown t h a t a t a n d e m alkylation-cycloaddition c a n l e a d t o t r a n s i t i o n metal t e m p l a t e s . Thus as shown i n Scheme 1 5 , a l k y l a t i o n o f t h e a l l y l i c a c e t a t e ( 1 1 6 ) f o r m s a

polycyclic systems

t r i e n e which upon t h e r m o l y s i s g i v e s a D i e l s - A l d e r

adduct ( 117).

A f u r t h e r new a p p l i c a t i o n i s i n t h e c o n v e r s i o n o f t h e t r i e n e ( 1 1 8 )

i n t o t h e bicyclo[6.4.0]dodecane

system. 124

This constitutes a

timely r e p o r t s i n c e t h e development of r o u t e s t o cyclo-octanones is c u r r e n t l y o f p a r a m o u n t i m p o r t a n c e i n many l a b o r a t o r i e s . The intramolecular Diels-Alder

r e a c t i o n of t h e t r i e n e (119) is worth

n o t i n g , n o t o n l y as a p o t e n t i a l r o u t e t o t r i c h o t h e c a n e s , b u t s i n c e , f o r i t t o p r o c e e d as o b s e r v e d , it must do so l i k e t r a n s i t i o n s t a t e ( 1 2 0 ) . 125

via

An a l t e r n a t i v 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

an unusual boat-

approach t o

7: Saturated Carbocyclic Ring Synthesis

511

PhSo21 (,,,P, (102)

(103)

(1 04)

(105)

Reagents: i, [Cp2T iCI 21,MePP hZ,Na -Hg (1 : 1 :2) ; ii, H30+; i i i ,

0

S c h e m e 14

Q!y

Me0

C 02-Na

+

TM S

(106) (109)

R =OMo

(110)

R = H

General and Synthetic Methodr

512

I

C02Me

OAc

(116)

H (117)

S c h e m e 15

7: Saturated Carbocyclic Ring Synthesis

0

513

0

.Me

General and Synthetic Methods

514

compactin h a s been r e p o r t e d which i n v o l v e s t h e c y l o a d d i t i o n of t h e t r i e n e ( 1 2 1 ) a t 165 OC t o form ( 1 2 2 ) and ( 1 2 3 ) i n a r a t i o o f 4 : l . Compound ( 1 2 2 ) was t h e n c o n v e r t e d i n t o ( + ) - c o m p a c t i n i n f i v e s t e p s . 1 2 6 T h e r m o l y s i s of t h e d i e n y l a - m e t h a c r y t h i o i m i d a t e s ( 1 2 4 ) g i v e s a p r o d u c t w h i c h c a n b e u t i l i z e d t o p r e p a r e *-fused h y d r i n d a n o n e s . 127

The c y c l o a d d i t i o n of a l l y 1 c a t i o n s t o 1 , 3 - d i e n e s

i n a formal Diels-Alder intramolecular reaction.

r e a c t i o n has been extended t o t h e Thus, t r e a t i n g t h e thermally u n r e a c t i v e

u n a c t i v a t e d p o l y e n e ( 1 2 5 ) w i t h a n a m i n e s a l t g a v e a 42% y i e l d o f t h e hydrindane ( 126). t h e Z-diene

Intramolecular Diels-Alder

reaction of

( 1 2 7 ) o c c u r s w i t h a v e r y h i g h d e g r e e of s e l e c t i v i t y a n d

i s t h e key r e a c t i o n i n t h e f i r s t s y n t h e s i s o f ( + ) - o c t i n o b o l i n , 1 2 9 a n d c h i r a l triene-N-acyloxazolidones u n d e r g o c y c l i z a t i o n w i t h e x c e l l e n t 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 , a s s h o w n by t h e r e a c t i o n o f ( 1 2 8 ) . I3O

Two new v a r i a t i o n s on t h e i n t r a m o l e c u l a r p r o c e s s a r e t h e

u s e of t h e c o n j u g a t e d a l d e h y d e ( 1 2 9 ) a s a d i e n o p h i l e t o p r e p a r e t h e chlorothricolide intermediate ( 130),

and t h e u s e o f t h e e n o n e

s i l o x y a l l e n e ( 1 3 1 ) t o g i v e access t o t h e e r e m o p h i l a n e and eudesmane sesquiterpenes. O t h e r S y n t h e s e s o f Six-membered R i n g s . -

A previously reported

c y c l o p e n t a n n u l a 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 h o m o l o g o u s s i x membered r i n g s y n t h e s i s , u t i l i z i n g r e a g e n t s e q u i v a l e n t t o t h e s y n t h o n ( 1 3 2 ) a s shown i n Scheme 1 6 . 1 3 3

I n t r a m o l e c u l a r v e r s i o n s of

t h e s t a n d a r d r e a c t i o n s of s i l i c o n r e a g e n t s a r e c u r r e n t l y h i g h l y p o p u l a r and o n e e x c e p t i o n a l example i s t h e c y c l i z a t i o n o f t h e e n o n e ( 1 3 3 ) w i t h a Lewis a c i d .

T h i s r e a c t i o n i n v o l v e s a two f o l d

d i a s t e r e o s e l e c t i o n w h i c h c a n b e made u s e o f i n c l e r o d a n e s y n t h e s i s . 1 3 4 T h e s e l e c t i v i t y a t C-7 i s s u g g e s t e d t o o c c u r

via

the

c h a i r t r a n s i t i o n s t a t e ( 1 3 4 ) , which i n v o l v e s no u n f a v o u r a b l e i n t e r a c t i o n s w h e r e a s c o n t r o l o f C-6 i s e x p l a i n e d by p r e f e r e n t i a l Two r e s e a r c h g r o u p s h a v e i n d e p e n d e n t l y

f o l d i n g of t h e a l l y l s i l a n e .

a c h i e v e d a p r e p a r a t i o n of t r a n s - f u s e d

h y d r i n d a n e s by a n

i n t r a m o l e c u l a r v i n y l s i l a n e a c y l a t i o n o f ( 1 3 5 ) t o g i v e ( 1 3 6 ) . 35 ' 36 T h e same t a r g e t h a s b e e n p r e p a r e d i n a n o p t i c a l l y p u r e f o r m s t a r t i n g f r o m c a m p h o r , 1 3 7 a n d by u s i n g a n o v e l a s y m m e t r i c c o n j u g a t e a d d i t i o n r e a c t i o n t h e same aim h a s b e e n a c h i e v e d . Scheme 17 a d d i t i o n o f ( 1 3 7 )

(R

or

2)

Thus as s e e n i n

t o 2-methylcyclopent-2-enone

g a v e ( 1 3 8 ) w h i c h was c o n v e r t e d i n t o ( 1 3 9 ) by s t a n d a r d procedures. An i n t e r e s t i n g new s i x - m e m b e r e d r i n g a n n u l a t i o n c e n t r e s u p o n a

515

7: Saturated Carbocyclic Ring Synthesis

a,

0 O\yX MezALCL

b H

CHO

(129)

(130)

+

A

General and Synthetic Methods

516

65 'lo cis : t r a n s , 1 2

(132)

Reagents: i , MeLi; ii, MgBr2; iii,CulBr:SMe2; iv,

0 ;v, NH4CL; vi, KH

Scheme 16

(133)

MeONa

SiMe3

I

0

O

X

J H3

517

7: Saturated Carbocyclic Ring Synthesis

n o v e l p r e p a r a t i o n o f 1 , 5 - d i k e t o n e s , formed f r o m t h e r e a c t i o n of 0s i l y l a t e d e n o l a t e s and v i n y l o g o u s h e m i a c e t a l s ( 140). A s shown i n Scheme 1 8 , t h e d i e n o l e t h e r ( 1 4 1 ) u n d e r g o e s a s u r p r i s i n g l y s t e r e o s e l e c t i v e r e a c t i o n with t h e iodoenolsilane (142) i n a r e a c t i o n which is presumed t o go v i a t h e a l l y l i c c a t i o n ( 1 4 3 ) t o 140 form a n a n n u l a t e d p r o d u c t . I n an i m p o r t a n t a d d i t i o n t o an e x i s t i n g p r o c e s s it h a s been shown t h a t t h e p r o l i n e - c a t a l y s e d

a s y m m e t r i c a n n u l a t i o n of d i k e t o n e s

c a n be a p p l i e d t o racemic d i k e t o n e s w i t h k i n e t i c r e s o l u t i o n occurring.

C y c l i z a t i o n of t h e d i k e t o n e (144) w i t h ( ? ) - p r o l i n e

t h e enone (?)-(I451

and ( g ) - ( 1 4 4 ) .

gave

However, a n o p p o s i t e

e n a n t i o s e l e c t i o n i s o b s e r v e d w i t h t h e d i k e t o n e ( 1 4 6 ) b e a r i n g no m e t h y l g r o u p 1 4 ' i n a p r o c e s s which a p p e a r s t o be g o v e r n e d by a

si-enantioface

selectivity.

Mechanistic s t u d i e s have added

f u r t h e r i n s i g h t s i n t o t h e mechanism of t h i s p r o c e s s a n d w i l l u n d o u b t e d l y be o f u s e . 1 4 3 The d e m o n s t r a t i o n t h a t s u l p h o n e s c a n b e h a v e a s 1 , l - d i p o l e s ( 1 4 7 ) h a s l e d t o a new six-membered r i n g s y n t h e s i s , w h e r e b y t r e a t m e n t of t h e s u l p h o n e ( 1 4 8 ) w i t h a l u m i n i u m c h l o r i d e g i v e s a good y i e l d o f t h e c y c l i z e d p r o d u c t . 1 4 4 I t i s p o s s i b l e t h a t t h i s f i n d i n g w i l l l e a d t o an expansion of sulphone c h e m i s t r y i n synthesis.

A s i m p l e means of p r e p a r i n g some c o m p l e x c a r b o n y l

s k e l e t o n s i s d e m o n s t r a t e d by t h e u s e o f t h e i n t r a m o l e c u l a r d o u b l e Michael r e a c t i o n of t h e u n s a t u r a t e d k e t o - e s t e r

(149).

Treatment

w i t h b a s e a t low t e m p e r a t u r e g a v e a m o d e s t y i e l d ( 4 5 % ) o f t h e ketone (150).

The 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 c a n be e x p l a i n e d

by a p r o c e s s o c c u r r i n g

( 1 5 1 ) i n w h i c h t h e two o x y g e n s a r e

complexed t o a l i t h i u m c a t i o n .

T h i s method h a s a l s o b e e n 146

a p p l i e d t o t h e s y n t h e s i s of i s o a t i s i r e n e t y p e compounds.

F u r t h e r work on t h e s t e r e o c h e m i s t r y of a p r e v i o u s l y r e p o r t e d [2+2+21 a n n u l a t i o n w a r r a n t s a t t e n t i o n . 1 4 7 Two i n t r a m o l e c u l a r a l d o l t y p e r e a c t i o n s h a v e b e e n u s e d t o g r e a t e f f e c t i n a s s e m b l i n g t h e e s s e n t i a l c a r b o n s k e l e t o n of t h e pentacyclic quassinoids. Hence, t r e a t m e n t of ( 1 5 2 ) w i t h mild b a s e (Scheme 1 9 ) g a v e t h e a l c o h o l ( 1 5 3 ) w h i c h c a n be r e a d i l y c y c l i z e d t o t h e k e t o l ( 1 5 4 ) i n a n o v e r a l l y i e l d o f 83%.148 A c o m b i n a t i o n o f Diels-Alder

r e a c t i o n and sulphone-mediated

intramolecular

c y c l i z a t i o n h a s l e d t o t h e p r e p a r a t i o n o f ( 1 5 6 1 , via ( 1 5 5 ) a s shown i n Scheme 2 0 . The k e t o - e s t e r ( 1 5 6 ) i s a key i n t e r m e d i a t e i n a new s y n t h e s i s of dihydrocompactin. I n t r a m o l e c u l a r a l l y l a t i o n of t h e k e t o n e ( 1 5 7 ) c a n be a c h i e v e d

General and Synthetic Methods

518

R e a g e n t s ; Me3SiCL; ii,CH(OMe)a,SnCI4;

iii,AcOH,PhCHzCHZNHZ

Scheme 1 7

S c h e m e 18

(144) R = Me (146) R = H

R

R

Reagents; Bu"Li; ii, 2MeI; iii,ALClg

5 19

7: Saturated Carbocyclic Ring Synthesis

H (1 5 0 )

(149)

(151)

&lEt CH (CNIC02Et

I

I

NaHC03)

CHO

&'

'C02Et

I I

A

A

Scheme 19

OH

General and Synthetic Methods

520

0 S-0

L

W

h

+?

--a:.f Lo

”

3 3 3 - (

COpMe

SOpPh

’

=d H

(156) ,8OoC;ii,2LiN(TMS)2,-78OC,S

days; iii,CH2N2;

Scheme 2 0

H

1

,0SiMe2But

w -6 N

OMe

CsF

Me

tie

(158)

Me

J

iv, AL/Hg; v,NaOMe

7: Saturated Carbocyclic Ring Synthesis

521

u s i n g m e t a l l i c t i n and a l u m i n i u m . I 5 O

An i n t r i g u i n g i n t r a m o l e c u l a r

v e r s i o n o f t h e known [4+21 a d d i t i o n r e a c t i o n o f n i t r o s o a l k e n e s h a s T h u s , f l u o r i d e a n i o n t r e a t m e n t of t h e s i l y l a t e d n i t r o a l k e n e ( 1 5 8 ) a f f o r d s t h e d e c a l i n ( 1 5 9 ) i n m o d e r a t e y i e l d . 151 been demonstrated.

An 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 u s i n g k e t o n e s as e n o p h i l e s h a s b e e n d e v e l o p e d and i 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 of ( 1 6 0 ) i n t o

.

( 1 6 1 ) 15*

U n f o r t u n a t e l y t h i s p r o c e s s is l i m i t e d t o t h e s y n t h e s i s

o f six-membered r i n g s .

A d d i t i o n a l l y t h e c y c l i z a t i o n of ( 1 6 2 ) t o

( 1 6 3 ) c o n s t i t u t e s a n o v e l e n e r e a c t i o n . 153

A f u r t h e r development

i n t h i s a r e a i s t h e t h e r m o l y s i s of t h e a l k e n y l a c y l n i t r i l e ( 1 6 4 ) ( p r e p a r e d a s shown) t o form 3,5-dimethylcyclohex-2-en-one. 15' This r e a c t i o n h a s been a p p l i e d t o a wide r a n g e o f s u b s t r a t e s a n d p r o v i d e s a new g e n e r a l r o u t e t o h i g h l y s u b s t i t u t e d c y c l o h e x e n o n e s . F u r t h e r s t u d i e s on t h e p a l l a d i u m - c a t a l y s e d

c y c l i z a t i o n of

a l l y 1 c a r b o n a t e s h a v e shown t h a t t h e c h i r a l c a r b o n a t e ( 1 6 5 ) c y c l i z e s t o g i v e a racemic product.

I n c o n t r a s t t h e d e r i v e d sodium

a n i o n ( 1 6 6 ) c y c l i z e s w i t h c o m p l e t e r e t e n t i o n o f c h i r a l i t y . 155

It

a p p e a r s t h a t i n t h e f i r s t case p r o t o n r e m o v a l , w h i c h i s n e c e s s a r y

for c y c l i z a t i o n and i s b r o u g h t a b o u t by i n s i t u g e n e r a t e d m e t h o x i d e a n i o n , o c c u r s more s l o w l y t h a n r a c e m i z a t i o n of t h e i n t e r m e d i a t e x - a l l y 1 complex.

However, i n t h e s e c o n d c a s e , w i t h ( 1 6 6 ) , p r o t o n

r e m o v a l h a s a l r e a d y been a c h i e v e d p r i o r t o r e a c t i o n .

2-Tetralones

c a n be o b t a i n e d by t h e r h o d i u m ( I 1 ) - c a t a l y s e d a-diazo-ketones

c y c l i z a t i o n of t h e d e r i v e d from 3 - a r y l p r o p i o n i c a c i d s . 156

There h a s been an e x t e n s i o n t o t h e cobalt-mediated enediyne c y c l i z a t i o n which p e r m i t s t h e u s e of t e t r a s u b s t i t u t e d a l k e n e s a s

, full [2+2+2] a n n u l a t i o n h a v e a p p e a r e d . 158

d e m o n s t r a t e d by t h e r e a c t i o n o f ( 1 6 7 ) . 157 A d d i t i o n a l l y d e t a i l s of a cobalt-mediated

C y c l o h e x a d i e n o n e s c a n now be p r e p a r e d by a n n u l a t i o n o f c a r b e n e c o m p l e x e s s u c h as ( 1 6 8 ) and a c e t y l e n e i n f a i r ~ i e 1 d s . l ~ A ~s h o r t s y n t h e s i S o f ( + ) - m e t h y l s h i k i m a t e f r o m f u r a n and q e t h y l a c r y l a t e h a s b e e n d e s c r i b e d 1 6 ' a n d a ' s y m p o s i a - i n - p r i n t ' on r e c e n t a s p e c t s o f a n t h r a c y c l i n o n e c h e m i s t r y s h o u l d be o f i n t e r e s t t o many synthetic chemists. Polyene Cyc1izations.-

E l e g a n t work i n t h i s a r e a h a s c o n t i n u e d t o

a p p e a r , s u c h as t h e c y c l i z a t i o n of ( 1 6 9 ) t o ( 1 7 0 ) w h i c h was u s e d t o confirm t h e s t r u c t u r e of ( k ) - k a r a t a v i c a c i d , t h e f i r s t seco-drimane s e s q u i t e r p e n e . 16*

I n a r e a c t i o n which is r e m i n i s c e n t of t h e

b i o s y n t h e t i c r o u t e t o t h e p a l l e s c e n s i n s , t h e a l c o h o l ( 1 7 1 ) h a s been shown t o c y c l i z e u s i n g e i t h e r i o d o t r i m e t h y l s i l a n e o r t i n ( 1 V )

General and Synthetic Methods

522

.Q

C02Me

'Me

I

CozMe

EtAlCl2

'

Q=co2Me

A

(162)

(163)

0 J . J J . TiCI,, - NC -

+ 0

Me

S i Me3

(164)

+ HCN

eMe0

0

CO, Me

OC02Me

I'do

c

racemization

7: Saturated Carbocyclic Ring Synthesis

Reagents: i, Hg(0S02CF3)2,PhNMeZ; ii, NaCL(aq.)

523

General and Synthetic Methods

524

c h l o r i d e t o g i v e t h e f u r a n ( 1 7 2 ) a s t h e m a j o r p r o d u c t . 163 A s p a r t of a c o n t i n u i n g s t u d y of t h e u t i l i t y of a c e t a l t e m p l a t e s i n a s y m m e t r i c s y n t h e s i s t h e e n y n e ( 1 7 3 ) was c y c l i z e d t o g i v e two p r o d u c t s , t h e m a j o r one of 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 t h e p r e p a r a t i o n o f v i t a m i n D m e t a b o l i t e s . 164 acid-catalysed cyclization

Furthermore L e w i s

o f p o l y e n e c a r b o x y l i c a c i d s s u c h as

( 1 7 4 ) i s a go’od way o f f o r m i n g t r a n s - f u s e d

y-lactones fused t o a

six-membered r i n g as d e m o n s t r a t e d by a f a c i l e s y n t h e s i s o f ( + ) - a n a s t r e p h i n ( 1 7 5 ) and ( + ) - e p i a n a s t r e p h i n ( 1 7 6 ) . 6 5 C y c l i z a t i o n o f ( 1 7 7 ) p r o c e e d s r e a d i l y u s i n g t h e complex of m e r c u r y ( I 1 )

trifluoromethanesulphonate-N,N-dimethylaniline t o give (178) l e a d i n g t o a s y n t h e s i s of (*)-orand y - p o l y p o d a t e t r a e n e . 1 6 6 An a n a l o g o u s s t r a t e g y h a s l e d t o a s y n t h e s i s of (?)-orand y-onoceradienedione

.1 6 7

Brominative c y c l i z a t i o n of polyenes h a s

b e e n shown t o b e a h i g h l y s e l e c t i v e p r o c e s s by u s e o f 2,4,4,6tetrabromocyclohexa-2,5-dienone i n a c e t o n i t r i l e . I 68

5 Seven-membered, Medium and L a r g e R i n g s A r e v i e w on t h e u s e o f a l l y 1 c a t i o n s i n t h e s y n t h e s i s of

seven-membered

r i n g s s h o u l d be o f i n t e r e s t . 1 6 ’

I n an approach t o

t h e p s e u d o g u a i a n o l i d e s t h e 1 , 5 - d i e n e ( 1 9 7 ) was h y d r o b o r a t e d , w h i c h

was f o l l o w e d by m e t h a n o l y s i s t o t h e m e t h o x y b o r o c y c l a n e w h i c h was r e a d i l y c o n v e r t e d i n t o ( 1 8 0 ) (Scheme 2 1 ) . ’7’ A novel application of t h e e n o l a t e - C l a i s e n r e a r r a n g e m e n t h a s l e d t o a v e r y f a c i l e s y n t h e s i s of a d i c t o y l d i t e r p e n e p r e c u r s o r . T h u s , a s shown i n Scheme 22 k e t e n e a c e t a l f o r m a t i o n a n d t h e r m o l y s i s o f ( 1 8 1 ) g i v e s i n 64% y i e l d t h e s e l e c t i v e l y p r o t e c t e d d i k e t o n e d e r i v a t i v e ( 1 8 2 ) . 1 7 ’ H i g h l y f u n c t i o n a l i z e d c y c l o h e p t a n e s h a v e b e e n o b t a i n e d by f r a g m e n t a t i o n o f v a r i o u s b i c y c l o C 4 . 2 . 1 I n o n a n e ~ ’a ~n d~ 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 an e p o x y a l l y l s i l a n e h a s a l s o been a p p l i e d t o t h e s y n t h e s i s of k a r a h a n a e n o l (183). 173 It h a s been shown t h a t r e a c t i o n o f t h e e n o l e t h e r ( 1 8 4 ) w i t h t r i isobutylaluminium r e s u l t s i n f o r m a t i o n of t h e c y c l o h e p t a n o l ( 1 8 5 ) . 174 I n t e r e s t i n t h e s y n t h e s i s of eight-membered r i n g s is b u r g e o n i n g , a n d i n a n e x t e n s i o n of p r e v i o u s work t h e C l a i s e n r e a r r a n g e m e n t o f 6-alkenyl-2-methylenetetrahydropyrans s u c h a s ( 1 8 6 ) h a s b e e n u s e d t o p r e p a r e c y c l o - o c t a n o n e s . 175 I t i s w o r t h n o t i n g t h a t a r e v i e w on c a t a l y s i s of t h e Cope a n d C l a i s e n r e a r r a n g e m e n t s h a s b e e n p u b l i s h e d a n d s h o u l d p r o v e u s e f u l . 176

As

7: Saturated Carbocyclic Ring Synthesis

525

87 : 1 3

(1 73)

( % & . , i_iii

(179)

qJ (180)

Reagents: i , ClBH2:SMe2; ii, MeOH; iii, -CC120Me

S c h e m e 21

526

General and Synthetic Methods

(181)

(182)

Reagents: i, lithium di-isopropylamide; ii, Me2ButSiCl; iii,PhMe,reflux

Scheme 2 2

HO

4T (183)

(1 84)

(1 85)

175 O C

a

H

0

H

( 18 6 )

42

- q3 RuO2, Na104

0

Scheme 23

7: Saturated Carbocyclic Ring Synthesis

527

i l l u s t r a t e d i n Scheme 2 3 , f r a g m e n t a t i o n o f t h e t r i c y c l i c a l k e n e (1987) p r o v i d e s a s y n t h e s i s of ( ' ) - p r e c a p n e l l a d i e n e . 177 Ring e x p a n s i o n of t h e k e t o n e ( 1 8 8 ) i n t o t h e c y c l o - o c t a d i o n e ( 1 8 9 ) h a s g i v e n a c c e s s t o t h e c a r b o n s k e l e t o n of f u s i c o c c i n F u l l d e t a i l s of t h e s y n t h e s i s of c y c l o u n d e c a n e c a r b o x y l i c a c i d by a r i n g c o n t r a c t i o n of c y c l o d o d e c a n o n e may be of u s e , 17'

as

u n d o u b t e d l y w i l l be d e t a i l e d k i n e t i c s t u d i e s on t h e r o l e of t h e r i n g s t r a i n i n t h e c y c l i z a t i o n of d i e t h y l (w-bromoalky1)malonates. From t h e s e it would a p p e a r t h a t f o r seven-membered

and l a r g e r r i n g s t h e t r a n s i t i o n s t a t e s t r a i n

e n e r g i e s p a r a l l e l c y c l o a l k a n e s t r a i n e n e r g i e s , which i s n o t t h e

case f o r s m a l l e r r i n g s . Cyclodeca-3,5-dienones

a r e now a v a i l a b l e

via

an a c e t y l e n i c

oxy-Cope r e a r r a n g e m e n t o f ( 1 9 0 ) a n d ( 1 9 1 ) 1 8 1 a n d t h e s y n t h e s i s of some c y c l o a l k e n y n o n e s , e . g . ( 1 9 2 ) , h a s b e e n d e s c r i b e d . 182

6 R i n g - e x p a n s i o n Methods F u l l d e t a i l s on t h e p r e v i o u s l y r e p o r t e d e x p a n s i o n o f c y c l i c ketones t o 1,2-ketothioacetals t h e r i n g enlargement of

h a v e a p p e a r e d , 183 and more work on

8 - h y d r o x y s e l e n i d e s t o k e t o n e s now

recommends t h a t t h e b a s e of c h o i c e f o r t h i s i s t h a l l i u m e t h o x i d e i n c h l o r o f o r m , w h i c h s h o u l d a p p e a l t o t h e more a d v e n t u r o u s s y n t h e t i c

.

c h e m i s t 184

I n a f o r m a l t o t a l s y n t h e s i s of ( + ) - m o d h e p h e n e t h e

e p o x y c y c l o b u t a n e ( 1 9 3 ) h a s been r i n g e x p a n d e d t o t h e c y c l o p e n t a n o n e (194) i n a chelate-controlled

p r o c e s s . 185

The d e v e l o p m e n t o f t h e

y n a l ( 1 9 5 ) a s a n e q u i v a l e n t t o t h e b u t a d i e n y l c a r b e n i u m i o n (Scheme 2 4 ) h a s l e d t o t h e p r e p a r a t i o n o f ( 1 9 6 ) , w h i c h upon t h e r m o l y s i s f o r m s t h e r i n g e x p a n d e d p r o d u c t ( 1 9 7 ) . 186 three-carbon

A s s e e n i n Scheme 25 a

i n t e r c a l a t i o n r e a c t i o n of t h e b i s - f u n c t i o n a l r e a g e n t

(198) h a s been developed i n t o a s h o r t r o u t e t o t h e p a r t i a l s k e l e t o n of t h e taxane system (199).187

The c a t a l y t i c i n c o r p o r a t i o n of

c a r b o n monoxide i n t o a c a r b o n y l g r o u p c o n s t i t u t e s a new r i n g e x p a n s i o n p r o c e s s of w i d e a p p l i c a b i l i t y .

F o r i n s t a n c e r e a c t i o n of

t h e cyclobutanone (200) with a h y d r o s i l a n e , carbon

monoxide, and a

c a t a l y t i c amount of c o b a l t c a r b o n y l f o r m s t h e d i s i l o x y c y c l o p e n t e n e ( 2 0 1 ) i n 73% y i e l d . 188

General and Synthetic Methods

528

Reagents: i,MeLi; ii,ZnCl2; iii, H2,Pd/BaSO,+; iv, SnCl4; v,-Li;vi,

Scheme 2 4

MqSiCL; v i i : 200OC

529

7: Saturated Carbocyclic Ring Synthesis

MQSiO (198)

...

(199) iii Reagents: i,ZnCI2; ii,EtZALCI; iii,NaI04

Scheme 2 5

OSiMeE t g

( ZOO)

Reagents; i , HSiEt2Me,[Co2(C0)8I,PPh3,-100O C

(201)

?!Yo

General and Synthetic Methods

530

(202)

(204) 93"l.

(203) Reagents; i, Me3SiOS02CF3; ii, &;ph2-BC;

iii, LiNEtz; iv, Me3SiCI

Scheme 2 6

&NMq

*c

____) -100

rnNM C02Me

C02Me

(209)

(210)

7: Saturated Carbocyclic Ring Synthesis

53 1

7 S p i r o - r i n g Compounds An i n t r i g u i n g new s y n t h e s i s o f s p i r o - c y c l o b u t a n o n e s h a s b e e n d e v e l o p e d (Scheme 2 6 ) . T h i s r e l i e s upon t h e a b i l i t y o f a c y c l o p r o p y l r i n g t o s t a b i l i z e an a d j a c e n t p o s i t i v e c h a r g e , t h u s a l l o w i n g t h e r e a c t i o n of ( 2 0 2 ) w i t h e l e c t r o p h i l e s ( e . g . a c e t a l s ) t o p r o c e e d e f f i c i e n t l y . An i n t e r e s t i n g i n t r a m o l e c u l a r v e r i s o n o f t h i s i s shown i n t h e c o n v e r s i o n of ( 2 0 3 ) i n t o ( 2 0 4 ) . A n o v e l [C4+C2] coupling r e a c t i o n has led t o t h e s y n t h e s i s of t h e spiroC2.3lhexanes. Thus t h e f i r s t i n t e r m o l e c u l a r r e a c t i o n o f a c y c l o b u t y l i d e n e ( 2 0 5 ) h a s b e e n shown t o f o r m low y i e l d s o f t h e spirohexames (206 ) . S p i r o [ l l 1 5 ] d e c a n o n e s a r e f o r m e d by t h e 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 n a l l y l s i l a n e a n d a n e n o n e . The r e a c t i o n shown f o r ( 2 0 7 ) i s d i a s t e r e o s e l e c t i v e , f a v o u r i n g f o r m a t i o n o f ( 3 0 8 ) a n d o n l y p r o c e e d i n g w i t h dichloroethyl-aluminium. l9 The same s y s t e m c a n b e p r e p a r e d f r o m t h e d i e n a m i n e ( 2 0 9 1 , w h i c h f o r m s (210) as shown.lg2 A s h o r t s e r i e s o f p a p e r s on t h e t o t a l s y n t h e s i s o f v a r i o u s s p i r o v e t i v a n e s such as ( + ) - h i n e s o l , ( + ) - s o l a v e t i v a n e , ( + ) - l u b i m i n , and ( + ) - o x y l u b i m i n c o n s t i t u t e s a n i m p r e s s i v e e f f o r t i n t h i s area o f s y n t h e t i c e n d e a v o u r . 193 References 1

R.Ando, T.Sugaware, M-Shimizu, and 1-Kuwajima, Bull. Chem. SOC. J p n . ,

57, 2897. 2

3 4 5 6 7 8 9 10 11 12

13 14 15

16 17 18 19 20 21

1984,

9, 106,

R.W.Curley,Jr. and H.F.DeLuca, J . Org. Chem., 1984, 1944. M.A.Hashern, P.Weyerstah1, and B.S.Green, T e t r a h e d r o n , 1984, 110, 203. G.Rousseau and N.Slougu, J . Am. C h e m . S O C . , 1984, 7283. M.P.Doyle, J . W . T e r p s t r a , and C.H.Winter, T e t r a h e d r o n L e t t . , 1984, 25, 901. W.Cothling, S - K e y a n i y a n , and A.de M e i j e r e , T e t r a h e d r o n L e t t . , 1984, 25, 4101, 4105. M.P.Doyle, L.C.Wang, and K.-L.Yoh, T e t r a h e d r o n L e t t . , 1984, 25, 4087. E.J.Corey and A.G.Meyers, T e t r a h e d r o n L e t t . , 1984, 25, 3559. M-Yamaguchi and I . H i r a o , T e t r a h e d r o n L e t t . , 1984, 25, 4549. H . I s h i b a s h i , Y . K i t a n o , H.Nakatani, M. Ckado, M. I k e d a , M. Ckura, and Y .Tamura, T e t r a h e d r o n L e t t . , 1984, 25, 4231. L . P r e v i t e r a , P.Monaco, and L.Mangoni, T e t r a h e d r o n L e t t . , 1984, 25, 1293. J.F.Kadow and C.R.Johnson, T e t r a h e d r o n L e t t . , 1984, 25, 5255. G.J.Wells, T.-H.Yan, and L.A.Paquette, J . Org. Chem., 1984, 3604. 3610. L.A.Paquette, T.-H.Yan, and G.J.Wells, J. Org. Chem., 1984, J.A.Marshal1, J . C . P e t e r s o n , and L.Lebioda, J . Am. Chem. S O C . , 1984, 6006. R . B . M i t r a , B.G.Mahumulkar, and G.H.Kulkarni, S y n t h e s i s , 1984, 428. 152. D.J.Pasto and S.H.Yang, J. Am. Chem. SOC., 1984, K. Ogura, M. Yamashita, M.Suzuki , S. Furukawa, and G. T - T s u c h i h a s h i , B u l l . Chem. SOC. J p n . , 1984, 57, 1637. L.A.Paquette, R.S.Valpey, and C.D.Annis, J. Org. Chem., 1984, 1317. P.F.Fishbein and H.W.Moore, J . Org. Chem., 1984, 49, 2190. Am. Chem. SOC., 1984, L.D.Boardman, V.Bagheri, H.Sawada, and E.Negishi,J. 106, 6105.

9, 9,

106,

9,

-

106,

General and Synthetic Methods

532 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 48 49

50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68

2,

K . A v a s t h i , S . R . R a y c h a u d h u r i , and R.G.Salomon, J . Org. Chem., 1984, 4322. C.S.Swindel1, S.J.de Solms, and J . P . S p r i n g e r , T e t r a h e d r o n L e t t . I 1984, 2, 3797. C.S.Swindel1 and S . J . d e Solms, T e t r a h e d r o n L e t t , , 1984, 25, 3801. E.R.Koft and A.B.Smith 111, J . Am. Chem. S O C . , 1984, 2115. 832. E.R.Koft and A.B.Smith 111, J . Org. Chem., 1984, J . Chem. SOC. Chem. Commun., 1984, 293. V.B.Rao, S . W o l f f , and W.C.Agosta, 2076. M.T.Crimmins and J . A . DeLoach, J . Org. Chem., 1984, M.Yoshioka, T . S u z u k i , and M.Oka, B u l l . R.L.Cargil1, J . R . D a l t o n , G.H.Morton, and W.E.Caldwel1, Org. S y n t h . , 1984, 6 2 , 118. R.G.Salomon and S.Ghosh, Org. S y n t h . , 1984, 125. 4217. H . G o t t h a r d t and R.Jung, T e t r a h e d r o n L e t t . , 1984, R.C.Gadwocd, T e t r a h e d r o n L e t t . , 1984, 5851. G.R.Lenz, J . Chem. S O C . , P e r k i n T r a n s . 1 , 1984, 2397. 410. P.Kozikowski, Acc. Chem. Res., 1984, 2125. M.Apparu and J.K.Crandal1, J . Org. Chem., 1984, J . K C r a n d a l l and W. J Michaely , K.Mikami, T.Maeda, N . K i s h i , an 5151. T.S.Tan, A . N .Mather, G . P r o c t e r , and A . H . Davidson, J . Chem. S O C . , Chem. Commun., 1984, 585. 1140. H.Urabe and I.Kuwajima, J . Org. Chem., 1984, M.S.Newman, J . Org. Chem., 1984, 4 9 , 397. J . T s u j i , M.Nisar, I . S h i m i z o , and T M i n a m i , S y n t h e s i s , 1984, 1009. K . F u n i t a , A.Misumi, A-Mori, N . I k e d a , and H.Yamamoto, T e t r a h e d r o n L e t t . , 1984, 2 5 , 669. 671. A . M i s u Z , K . F u n i t a , and H.Yamamoto, T e t r a h e d r o n L e t t . , 1984, K . F u r u t a , N . I k e d a , and H.Yamamoto, T e t r a h e d r o n L e t t . , 1984, 25, 675. J.-P.Depres and A.E.Greene, J . Org. Chem., 1984, 928. 434. H.R.Sliwka and H.-J.Hensen, Helv. Chim. Acta, 1 9 8 4 , H.Matsumaya, Y.Miyazawa, Y.Takei, and M.Kobayashi, Chem. L e t t . , 1984, 833. M.Pohmakotr and P . P h i n y o c h e e p , T e t r a h e d r o n L e t t . , 1984, 25, 2249. F.P.Cooke, J r . , J . Org. Chem., 1984, 1144. M.T.Crimmins, S.W.Mascarella, and J.A.De Loach, J . Org. Chem., 1984, 3033. T . K i t a h a r a and K.Mori, T e t r a h e d r o n , 1984, 2935. D.Pocar, P.Trimarco, R . D e s t r o , E - O r t o t e r a , and M - B a l l a b i o , T e t r a h e d r o n , 1984, 40, 3579. A.G .Camyron, A.T.Hewson, and M. I . Osammar , T e t r a h e d r o n L e t t - , 1984, 2, 2267. J.H.Babler and W.E.Bauta, T e t r a h e d r o n L e t t . , 1984, 25, 4323. S . F u j i k u r a , M.Inoue, K.Utimoto, and N.Nozoki, T e t r a h e d r o n L e t t . , 1984, 1999. - .. A.R.Chamberlin and S.H.Blocun, T e t r a h e d r o n L e t t . , 1984, 25, 4901. 73. M.Karpf, Helv. Chim. Acta, 1984, K.Yamaguchi, K.Yokota, and Y.Takada, Chem. L e t t . , 1984, 543. 2435. E.Tsankova, V.Enev, and S.Simova, T e t r a h e d r o n , 1984, K.Sakai, Y . I s h i g u r o , K.Funakoshi, K.Veno, and H.Suemene, T e t r a h e d r o n L e t t . , 1984,, 2 5 .. 961. V . R a u t G s t r a u c h , J . Org. Chem., 1984, 950. R.Baker, R.B.Keen, M.D.Morris, and R.W.Turner, J. Chem. SOC., Chem. Commun. 1984, 987. E . P i e r s and V . K a r u n a r a t r e , J . Chem. S O C . , Chem. Commun., 1984, 959. M.Kodpinid and Y . T h e b t a r a n o n t h , T e t r a h e d r o n L e t t . , 1984, 2509. M.Hetmanski, N . P u r c e l 1 , R.J. S t o o d l e y , and M.N.Palfreyman, J . Chem. S o c . , P e r k i n T r a n s . 1 , 1984, 2089. E . P i e r s and H.L.A.Tse, T e t r a h e d r o n L e t t . , 1984, 2 5 , 3155. G.A.Molander and J . B . E t t e r , T e t r a h e d r o n L e t t . , 1 g 4 , 25, 3281.

106, 9, 9,

-

62,

25, 17,

.

25,

9,

.

9,

2,

9,

5,

9,

9,

40,

z,

3,

5,

9,

9,

7: Saturated Carbocyclic Ring Synthesis 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101

102 103 104 105 106 107 108 109 110 111 112 113 114

533

Y.Nakashita, T.Watanabe, E.Benkert, A.Lorenzi-Riatsch, and M.Hesse, Helv. Chim. Acta, 1984, 5, 1204. M.A.Trus and D.P.Astrab, Tetrahedron Lett., 1984, 25, 1539. R.T.Brown, R.P.Blackstock, and M-Wingfield, Tetrahedron Lett., 2 5 , 1831. G.Kubiak, J.M.Cook, and U.Weiss, J. Org. Chem., 1984, 561. T.Takahashi, H-Okumoto, and J.Tsuji, Tetrahedron Lett., 1984, 25, 1925. B.B.Snider and C.P.Cartaya-Marin, J. Org. Chem., 1984, 1537 F.E.Ziegler and J.J.Mence1, Tetrahedron Lett., 1984, 25, 123. F.E.Ziegler and K.Mikami, Tetrahedron Lett., 1984, 25, 127. D.L.Bolger and C.E.Brotherton, J. Am. Chem. SOC., 1984, 805. D.L.Bolger and C.E.Brotherton, Tetrahedron Lett., 1984, 25, 561 1 . 1-Shimizu, Y.Ohashi, and J.Tsuji, Tetrahedron Lett., 1984, 25, 5183. J.C.Watkins and M.Rosenblum, Tetrahedron Lett., 1984, 25, 2097. M.Dorsch, V.Jager, and W.Sponlein, Angew. Chem., Int. Ed. Engl., 1984, 23, 798. Y.Tobe, I.Iseki, K.Kakiuchi, and Y.C!daira, Tetrahedron Lett., 1984, 25, 3895. Y.Torisawa, H.Okabe, and S-Ikegami, J. Chem. SOC., Chem. Commun., 1984, 1602. M.J.Knudsen and N.E.Schor-e. J. Orn. Chem.., 1984., 49. - . 5025. - G.Pattenden and S.J.Teague, Tetravhedron Lett., 1 9 m , 25, 3021. G.Mehta and K.S.Rao, Tetrahedron Lett., 1984, 25, 3481. G.Mehta, R.K.S.Rao, A.P.Marchand, and R.Kaya, J. Org. Chem., 1984, 3848. K.Cooper and G.Pattenden, J. Chem. S O C . , Perkin Trans. 1 , 1984, 799. M.Horton and G.Pattenden, J. Chem. SOC., Perkin Trans. 1 , 1984, 811. J.Ackroyd, M.Karpf, and A.S.Dreiding, Helv. Chim. Acta, 1984, 67, 1963. M.Demuth, P-Ritterskamp, and K.Schaffner, Helv. Chim. Acta, 1 9 m , 2023. T.Itao, N.Tomiyoshi, K.Nakamura, S.Azuma, M.Izawa, F.Murayama, M.Yanagiya, H.Shimara, and T.Matsumoto, Tetrahedron, 1984, 5 , 241. P.F.Schuda and M.R.Heimann, Tetrahedron, 1984, 5, 2365. E.Piers and V.Karunaratne, Can J. Chem., 1984, 62, 629. R.L.Funk and G.L.Botton, J. Org. Chem., 1984, 5021. W-Oppolzer and C.Chapuis, Tetrahedron Lett., 1984, 25, 5383. W.Oppolzer, (2-Chapuis,and G.Bernardinelli, Tetrahedron Lett., 1984, 2, 5885. W. Oppolzer , M.J .Kelly, and G .Bernardinelli, Tetrahedron Lett., 1984, 25, 5889. W.Oppolzer, C.Chapuis, and G.Bernardinelli, Helv. Chim. Acta, 1984, 67, 1397. W.Oppolzer, Angew. Chem., Int. Ed. Engl., 1984, 23, 876. D.A.Evans, K.T.Chapman, and J.Bisaha, J. Am. Chem. SOC., 19184, 2,426 1 . 203. M.J.S.Dewar and A.B.Piernin, J. Am. Chem. SOC., 1984, R.A.Pabon, D.J.Bellville, and N.L.Bauld, J. Am. Chem. SOC., 1984, 2730. 0 . Tsuge , S.Kanemasa, H. Sakoh , and E .Wada , Chem. Lett., 1984, 273 S.Kanemasa, H.Sakoh, E.Wada, and O.Tsuge, Chem. Lett., 1984, 277 O.Tsuge, S.Kanernasa, H.Sakoh, and E .Wada, Chem. Lett., 1984, 469 0.Tsuge, S.Kanemasa, H. Sakoh , and E .Wada, Bull. Chem. SOC. Jpn., 3221. 0.Tsuge, S.Kanemasa, E .Wada , and H.Sakoh , Bull. Chem. SOC. Jpn., 1984, 57, 3234. A.P .Kozikowski, K.Hiraga, J. P .Springer, B. C.Wang, and Z.-B.Xu, J. Amer Chem. SOC., 1984, 106,1845. H.Jendrella and B.Spur, J. Chem. SOC., Chem. Commun., 1984, 887. O.DeLucchi, V.Lucchini, L.Pasquato, and G.Mcdena, J. Org. Chem., 1984, 49, 596. Y.K.Rao and M.Nagarajan, Synthesis, 1984, 757. W.A.Nugent and J.C.Calabrese, J. Amer. Chem. SOC., 1984, 106,6422. N.S.Narasimhan and C.P.Bapat, J. Chem. SOC., Perkin Trans. 1 , 1984, 1435.

9, 2,

106,

~

5,

67,

9,

106,

106,

.

General and Synthetic Methods

534 115

S.Danishefsky,

M.Bednarski,

T . I z a w a , and C.Maring, J . Org. Chem.,

2,

1984,

2290. 116 117 118 119 120 121

123

R.L.Snowden, T e t r a h e d r o n L e t t . , 1984, 2 5 , 3835. P.A.Grieco, K.Yoshida, and Z . H e , T e t r a G d r o n L e t t . , 1984, 25, 5715. K.Yoshida and P.A.Grieco, J . Org. Chem., 1984, 49, 5257. P . L a s z l o and J . L u c h e t t i , T e t r a h e d r o n L e t t . , 1 9 8 4 , 25, 1567 and 2147. M.E.Jung and K.M.Halweg, T e t r a h e d r o n L e t t . , 1984, 25, 2121. P.A.Brown, P.R.Jenkins, J . F a w c e t t , and D.R.Russel1, J . Chem. S O C . , Chem. Commun., 1984, 253. P. R . J e n k i n s , K.A.Menear , P . B a r r a c l o u g h , and M.S.Nobbs, J . Chem. S O C . , Chem. Commun.. 1984. 1423. B.M.Trost, M.Lautens, M.-H.Hung, and C.S.Carmichae1, J . Am. Chem. S O C . ,

124 125 126 127

K.S&a&d D.A.Smith, T e t r a h e d r o n L e t t . , 1984, 2081. M.Koreeda and J . I . L u e n g o , J . Org. Chem., 1984, 4 9 , 2079. R.L.Funk, C.J.Massman, and W . E . Z e l l e r , T e t r a h e d r o n L e t t . , 1984, 2, 1655. Y.Tamura, O . I s h i g e , S.Kawamura, and Z . Y o s h i d i , T e t r a h e d r o n L e t t . , 1984, 25,

122

1984. 106. 7641.

25,

3583.

128

106,6085 and M.Yoshioka, H.Nakai, and M.Ohno, J . Am. Chem. S O C . , 1984, 106,1133. D.A.Evans, K.T.Chapman, and J . B i s a h a , T e t r a h e d r o n L e t t . , 1984, 25, 40 7 1 . J.A.Marshal1, J . E . A u d i a , and J . G r o t e , J . Org. Chem., 1984, 2, 5277. H.J.Reich and E . K . E i s e n h a r t , J . Org. Chem., 1984, 4 9 , 5282. E . P i e r s and B.W.A.Yeung, J . Org. Chem., 1984, 2, G67. P.G.Gassman and D.A.Singleton,

J . Am. Chem. S O C . , 1 9 8 4 ,

7993.

129 130 131 132 133 134 135 136 137

25,

T.Tokoroyama, M.Tsukamoto, and M . I i o , T e t r a h e d r o n L e t t . , 1984, 50 6 7 . S.E.Denmark and J.P.Germas, T e t r a h e d r o n L e t t . , 1984, 1231. K-Kukuzaki, E-Nakamura, and 1 - K u w i j i m a , T e t r a h e d r o n L e t t . , 1984, 25, 3591. J . H.Hutchinson, T.Money, and S . E . P i p e r , J . Chem. S o c . , Chem. Commun., 1984,

25,

455. 138

K.Yamamoto, M - I i j a m a , Y-Ogimura, and J. T s u j i , T e t r a h e d r o n L e t t . ,

2813.

1984,

25,

25,

139 140 141

P.Duhame1, J . - M - P o i r i e r , and G.Tave1, T e t r a h e d r o n L e t t . , 1984, 43. G.A.Kraus and P . G o t t s c h a l k , J . Org. Chem., 1984, 1153. C.Agami, J . L e v i s a l l e , and H - S e v e s t r e , J . Chem. S O C . , Chem. Commun., 1984,

142 143

C-Agami and H . S e v e s t r e , J . Chem. S O C . , Chem. Commun., 1984, 1385. C.Agami, F - M e y n i e r , C.Pochot, J.Guilhem and C . P a s c a r d , T e t r a h e d r o n , 1984,

~

3,

418.

144 145

4 0 , 1031. -

z,

B.M.Trost and M.R.Ghadiri, J . Am. Chem. S O C . , 1984, 7260. M . I h a r a , M.Toyota, K.Fukumoto, and T . K a m e t a r i , T e t r a h e d r o n L e t t . ,

21 67. 146

M . I h a r a , H-Toyota, K.Furumoto, and T . K a m e t a r i , T e t r a h e d r o n L e t t . ,

1984, 25 , 1984, 25,

3235. 147

S.Danishefsky,

1984,

9, 1319.

P . H a r r i s o n , M . S i l v e s t r i , and B . S e g m u l l e r , J . Org. Chem.,

106,

148 149 150 151 152 153 154 155 156

D.G.Batt, N.Takumura, and B.Ganem, J . Am. Chem. S O C . , 1984, 3353. Y.-L-Yang, S.Manna, and J . R . S l a c k , J . Am. Chem. S o c . , 1 9 8 4 , 1 0 6 , 3811. J.Nokami, S.Wakabayoshi, and R.Okawara, Chem. L e t t , , 1984, 8 6 9 . S.E.Denmark, M.S.Dappen, and J . A . S t e r n b e r g , J . Org. Chem., 1984, 474.1 A.C.Jackson, B.E.Goldman, and B.B.Snider, J . Org. Chem., 1984, 3988. B.B.Snider and G . B . P h i l l i p s , J . Org. Chem., 1984, 183. D.El-Abed, A . J e l l a 1 , and M . S a n t e l l i , T e t r a h e d r o n L e t t . , 1984, 25, 1463. K.Yamamoto, R.Deguchi, Y.Ogimura, and J . T s u j i , Chem. L e t t . , 1984, 1657. M. A-McKervey, S.M. T u l a d h a r , and H . F. Twohig, J . Chem. SOC., Chem. Commun. 1

157 158 159 160

M.Malacria and K . P . C . V o l l h a r d t , J . Org. Chem., 1984, 49, 5010. E.D.Stenberg and K . P . C . V o l l h a r d t , J. Org. Chem., 1 9 8 4 r 4 9 , 1564 and 1574. P.-C.Tang and W.D.Wolff, J . Am. Chem. S o c . , 1984, 1 0 6 , 1 1 3 2 . M . M . Campbell, A.D.Kaye, M.Sainsbury , and R . Yavarzadeh, T e t r a h e d r o n , 1984,

2,

9, . 3,

1984, 129.

4 0 , 2461. -

7: Saturated Carbocyclic Ring Synthesis 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193

535

T.R.Kelly (Ed.), Tetrahedron, 1984, 110, No.22. M.Nishizawa, H-Takenaka, and Y.Hayashi, Tetrahedron Lett., 1984, 25, 437. V.C.Pandey, P.Sarmah, and R.P.Sharma, Tetrahedron, 1984, 110, 3739W.S.Johnson, J.D.Elliott, and G.J.Hanson, J. Am. Chem. SOC., 1984, 106, 1138. P.A.Saito, H.Matsushita, and H.Kaneko, Chem. Lett., 1984, 729. M.Nishizawa, H.Nishide, and Y.Hayashi, J. Chem. SOC., Chem. Commun., 1984, 467. M-Nishizawa, H.Nishide, and Y-Hayashi, Tetrahedron Lett., 1984, 2, 5071. T.Kato, M.Machizuki, T.Hirano, S.Fujiwara, and T.Uyehara, J. Chem. SOC., Chem. Commun., 1984, 1077. H.H.R.Hoffman, Angew. Chem., Int. Ed. Engl., 1984, 2 3 , 1. J.W.S.Stevenson and T.A.Bryson, Chem. Lett., 1984, 5. M.J .Begley , A. G. Cameron, and D.W. Knight, J. Chem. SOC , Chem . Commun., 1984, 827. R.Huston, M.Rev. - . and A.S.Dreidinn. Helv. Chim. Acta. 1984., 6 7. ., 1507. -- D.Wang and T.-H.Chan, J. Chem. S O C . , Chem. Commun., 1984, 1273. I.Mori, K-Takai, K-Oshima, and H.Nozaki, Tetrahedron, 1984, 40, 4013. W.A.Kinney, M.J.Coghlan, and L . A . P a q u e t t T A m . Chem. Soc: 1984, 106, 6860. R.P.Lutz, Chem. Rev., 1984, 205. G.Mehta and A.N.Murtly, J. Chem. SOC., Chem. Commun., 1984, 1058. D.H.Grayson and J.R.H.Wilson, J. Chem. SOC., Chem. Commun., 1984, 1695. Y.Hamada and T.Shioiri, Org. Synth., 1984, 62, 191. M.A.Casadei, C.Cralli, and L.Mandolini, J. Am. Chem. SOC., 19 8 4 , 106, 1051. K.Thangaraj, P.C.Srinivasan, and S-Swaminathan, Synthesis, 1984, 1010. R.Rieth, A.WZchtler, and M.Hanack, Synthesis, 1984, 1010. S.Knapp, A. F. Trope, M. S.Theodore, N-Hirata, and J. J .Barchi, J. Org. Chem, 1984, 608. J.L.Laboureur and A.Krief, Tetrahedron Lett., 1984, 25, 2713. Y.Tobe, S.Yamashita, T.Yamashita, K.Kakiuchi, and Y.Odaira, J. Chem. SOC. Chem. Commun., 1984, 1259. A.G.Angoh and D.L.J. Clive, J. Chem. SOC., Chem. Commun., 1984, 534. B. M. Trost and M.J. Fray, Tetrahedron Lett., 1984, 25, 4605. N.Chatani, H.Furukawa, T.Kato, and S.Murai, J. Am. Chem. SOC., 1984, 106, 430. B.M.Trost and A.Brandi, J. Amer. Chem. SOC.. 1984. 106. 5041. U.H .Brinker and M.Boxberger , I-.-"knnew. Chem., Int. Ed . x g l -., 1984, 23, 974. D.Schinzer, Angew. Chem., I n t x . Engl., 1984, 23, 308. V.Nair and T.S.Jahnke, Tetr ahedron Lett., 1984, 25, 3547 A.Murai, S.Sato, and T.Masamurie., Bull. Chem. SOC. J m . . 1984, 57,, 2276, 2282, 2286, 2291.

-

.

I,

~

~

84,

9,

.

I

Saturated Heterocyclic Ring Synthesis BY K. COOPER AND P. J. WHllTLE

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

'Comprehensive H e t e r o c y c l i c

C h e m i s t r y ' , a n e i g h t volume work w h i c h c o v e r s t h e s t r u c t u r e , r e a c t i o n s , s y n t h e s i s , and u s e s o f h e t e r o c y c l i c compounds.

'

1 Oxygen-containing H e t e r o c y c l e s

T h r e e - a n d Four-membered R i n g s . -

S t e r e o s e l e c t i v i t y i n epoxide-

f o r m i n g r e a c t i o n s h a s d o m i n a t e d t h e l i t e r a t u r e on e p o x i d e s t h i s year.

For example L a n t o s ' group h a s p u b l i s h e d a m o d i f i c a t i o n o f tht

D a r z e n s c o n d e n s a t i o n whereby c h i r a l a - h a l o g e n o i m i d a t e s r e a c t w i t h aldehydes t o give t h e 1,2-halohydrins i n t o t h e a,B-epoxy-esters

(2).

( I ) , which a r e t h e n c o n v e r t e d

Boron e n o l a t e s g a v e t h e b e s t

asymmetric i n d u c t i o n b u t only moderate chemical y i e l d s (50-60%).

2

O p t i c a l l y p u r e B-ethanolamines, which a r e e a s i l y p r e p a r e d from amino-acids,

give c h i r a l epoxides with high e.e.

w i t h d i c h l o r o c a r b e n e (Scheme 1 ) . 3 poly-a-amino-acids

( > 9 5 % ) on r e a c t i o n

F u r t h e r d e t a i l s on t h e u s e o f

i n asymmetric e p o x i d a t i o n have a l s o appeared.

Krief's group h a s demonstrated t h a t t h e B-hydroxy-selenides

4

and

- s u l p h i d e s ( 3 ) g i v e e p o x i d e s w i t h c o m p l e t e i n v e r s i o n of c o n f i g u r a t i o n a t t h e selenium/sulphur-bearing c a r b o n .

The r e a c t i o n

i s t h o u g h t t o p r o c e e d by d i c h l o r o c a r b e n e a d d i 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 m e n t . 5 Ruthenium o x i d e i s g e n e r a l l y c o n s i d e r e d t o be a vigorous oxidant.

However, i t s r e a c t i v i t y i s m o d e r a t e d by

complexation with b i p y r i d y l such t h a t o l e f i n s a r e converted i n t o syn-epoxides, -

a l b e i t i n v a r i a b l e y i e l d (10-83%), r a t h e r t h a n 6

c l e a v e d t o k e t o n e s o r c a r b o x y l i c a c i d s ( s e e Scheme 2 ) . The a - a z o h y d r o p e r o x i d e s

(4) e p o x i d i z e o l e f i n s i n good y i e l d s

(58-84%) u n d e r b a s i c c o n d i t i o n s , r e t a i n i n g t h e g e o m e t r y of t h e d o u b l e bond. Acyclic hydroxyvinyl-selenones

undergo a s u b s t i t u t i o n r e a c t i o n

w i t h a l k o x i d e s f o l l o w e d by a n i n t r a m o l e c u l a r s u b s t i t u t i o n t o g i v e 3-alkoxyoxetanes. The p h e n y l s e l e n o n e a c t s a s b o t h a M i c h a e l a c c e p t o r and a l e a v i n g g r o u p ( s e e Scheme 3 ) . 8 B i a c e t y l r e a c t s w i t h For References see page 626

536

537

8: Saturated Heterocyclic Ring Synthesis

r 3

Enotizat ion RCHO

O 0Y

N0 Y

X

f i ; RtLiOBn ?J -20 OC ___)

O Y 0

J

Scheme

R'

0KNb-A 0

1

R3 RuCi3, bpy, NaI04 CHZCL2, H 2 0

R2

0 Scheme 2

0

'R

538

General and Synthetic Methods

1,l-diacetoxyethene to give the oxetanes ( 5 ) o r (6) depending on the reaction conditions. The first full characterization of the parent 1,2-dioxetane (7) has now been published; the dioxetane was prepared by base-induced cyclization of l-bromo-2-hydroperoxyethane, and shown to have a half-life of 1.1 min." Five-membered Rings.- Tetrahydrofurans. The groups of Williams and Bartlett have continued their studies into the stereospecific formation of tetrahydrofurans. In pursuit of the total synthesis of polyether antibiotics, Barlett's group has developed a stereocontrolled synthesis of trans-2,5-disubstituted tetrahydrofurans. The method uses initial six-membered ring formation, where stereocontrol is much better, followed by ring contraction to give, for example, the tetrahydrofuran (8). An attempted extension to the trisubstituted tetrahydrofuran ( 9 ) , a model for the antibiotic monensin, gave only moderate selectivity. Williams et al. have shown that on oxidation, benzylidene acetals bearing a neighbouring hydroxy-group cyclize to give tetrahydrofurans (Scheme 4) a backside attack on the intermediate dioxolenium ion in high yield (45-80%) and high stereospecificity. l 2 Williams' group has also demonstrated two complementary modes of cyclization of B,y-unsaturated alcohols induced by electrophilic attack. Thus, the dihydroxy-olefins (10) close to give the 2,3,4-trisubstituted tetrahydrofurans ( 1 1 ) with high stereoselectivity, whereas the epoxides derived from the olefins cyclize to give tetrahydrofurans (12) of the opposite s tereochemis try. An intramolecular epoxide opening also features in a synthesis of the tricyclic system of the nargenicin antibiotics. The bicyclic keto-epoxide ( 1 3 ) , when treated with methyl Grignard, 14 closes exclusively to the tetrahydrofuran (14) in 79% yield. A general method for the construction of the ethano bridge of the quassinoid group of natural products has been reported whereby simply heating the bromo-ketones (15) gives the required tetrahydrofuran products. l 5 A simple, new procedure for the useful halogenoetherificationllactonization reaction involving the treatment of the appropriate olefin with MCPBA in the presence of 18-crown-6 and a halogen salt has been published, giving good to excellent yields ( 5 5 - 9 5 % ) , l 6 and another direct synthesis of tetrahydrofuranones

539

8: Saturated Heterocyclic Ring Synthesis

R - Metal

Arse--YR OH

1

m - CIC6HkC03H

-

A r SeO

MeOH, H20

i OH

NaOH

Scheme 3

OEt polar solvent

EtO

OEt

Et

solvent

0

TBCO

OEt

Me02C

Me02C

Me0

ML

0

Meo+

(9)

H

H

(8) TBCO = Te t rabromocyc Lohexadienone

General and Synthetic Methods

540

R3

R3

// R2

0

0 &'R3

R3

Scheme 4

OH

120' PhSeCl

HO

& X

(10)

(11)

HO

OH

541

8: Saturated Heterocyclic Ring Synthesis

MeMgBr _____)

OMOM

OMOM

0

(13)

(14)

(16)

R e a g e n t s : i,Bu"Li;

ii,

LR1;

R2

RZ

R

(17)

iii, R2R3CO; iv, M s C l

R4C02H,-e 5'1. KOH, MeOH (Pt)

*

,$lR

)/R3

0

+

*R4 (19)

General and Synthetic Methods

542

( 1 7 ) features t h e b i s - a l k y l a t i o n of 1 , 3 - d i t h i a n e . The p r o d u c t ( 1 6 ) i s t h e n c y c l i z e d by i n t r a m o l e c u l a r a l k y l a t i o n a f t e r c o n v e r s i o n i n t o a mono-mesylate. '7

The a l l y l o x y c a r b o x y l i c a c i d s ( 1 8 ) , p r e p a r e d by M i c h a e l a d d i t i o n of a l l y l a l c o h o l s t o a,B-unsaturated

n i t r i l e s and s u b s e q u e n t

h y d r o l y s i s , undergo r a d i c a l c y c l i z a t i o n t o t e t r a h y d r o f u r a n s under Kolbe e l e c t r o l y s i s c o n d i t i o n s .

The r e a c t i o n i s t h o u g h t t o p r o c e e d

by i n i t i a l d e c a r b o x y l a t i o n t o g i v e a n a l k y l r a d i c a l w h i c h i s t h e n c a p t u r e d by t h e d o u b l e bond.

The r e s u l t i n g r a d i c a l t h e n c o m b i n e s

w i t h t h e r a d i c a l ( 1 9 ) , g e n e r a t e d from d e c a r b o x y l a t i o n o f t h e c o - a c i d . 18 The oxochromenes ( 2 0 ) r e a c t w i t h h a l o g e n o - a l c o h o l s a n d b a s e t o g i v e 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 i n t e r m e d i a t e s which t h e n decarbonylate t o give the products (21). S e v e r a l t y p e s of c y c l o a d d i t i o n r e a c t i o n s have been used t o construct tetrahydrofurans t h i s year.

Alkyne h e x a c a r b o n y l d i c o b a l t

c o m p l e x e s a r e known t o u n d e r g o 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 o l e f i n s t o g i v e cyclopentanones.

The 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 o f oxabicyclo[3.3.0]octenones

( 2 3 ) by t h e i n t r a m o l e c u l a r

r e a c t i o n of propargyl a l l y l e t h e r s ( 2 2 ) w i t h c o b a l t carbonyl.*' Sammes' g r o u p h a s p u b l i s h e d a f u r t h e r e x a m p l e o f t h e oxidopyrilium ylide chemistry i n the preparation of a benzopyrilium y l i d e and i t s c y c l o a d d i t i o n w i t h d i p o l a r o p h i l e s t o g i v e t r i c y c l e s (24) containing tetrahydrofurans.21 C a r b o n y l y l i d e s g e n e r a t e d by i r r a d i a t i o n of s t i l b e n e o x i d e s h a v e b e e n shown t o be s y n t h e t i c a l l y u s e f u l , g i v i n g good y i e l d s o f t e t r a h y d r o f u r a n s ( 2 5 ) w i t h h i g h s t e r e o s p e c i f i c i t y , and d i h y d r o f u r a n s (26) with poor s t e r e o s p e c i f i c i t y .

22

D i h y d r o f u r a n s . The d i r e c t s y n t h e s i s o f 2 , 3 - d i h y d r o f u r a n s , e . g . ( 2 7 ) , by tandem M i c h a e l a d d i t i o n / i n t r a m o l e c u l a r s u b s t i t u t i o n o f bromomalonic e s t e r t o m e t h y l e n e m a l o n i c a l d e h y d e s p r o c e e d s u n d e r phase-transfer

c o n d i t i o n s i n 51-75% y i e l d s . 2 3

Michael a d d i t i o n

a l s o f e a t u r e s i n t h e s y n t h e s i s of t h e d i h y d r o f u r a n s ( 2 9 ) , w h e r e a c e t o a c e t a t e s add t o t h e n i t r o - o l e f i n s

(28).

The a d d u c t s t h e n

r e a c t w i t h a m o l e c u l e o f a n a c t i v e m e t h y l e n e compound g i v i n g t h e methyleneaminodihydrofurans ( 2 9 ) . 24 Vinyl e t h e r - i r o n complexes have p r e v i o u s l y been used as v i n y l cation synthons.

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 t h e r e l a t e d

1,2-dialkoxyethylene-iron c o m p l e x e s ( 3 0 ) b e h a v e a s v i n y l e n e dication equivalents.

On r e a c t i o n w i t h l i t h i o k e t o n e e n o l a t e s a n d

543

8: Saturated Heterocyclic Ring Synthesis

OH

- do+ 0-

QR2

A

R1

OAc

(24)

+ _____)

kr

or A

__I____)

H

rR Ar

=-C02 Me

M e O2 C-

hL)

H

A

Me02C

lo+

(26)

C02Me

General and Synthetic Methods

544

Eto2C

Et 0

K2C03.DMF, BnN+Et3CL-

Y

R y C H 0

C0,Et

2

Et02C

C

H

HL Et 0

2

C

Et0,C

Br

(27)

CHO

R i c

R3

co2R~

+

R’

0

I

0-

(28) 4

5

R ,R = C 0 2 R , CN, COR

EtoYoEt +

+

FP

( 3 0 ) Fp = q5- CcjH5Fe(C0)2

R2

U Ho

-

R2 R% ’p OH

1

i, L-Selectride HBF4

ii,

545

8: Saturated Heterocyclic Ring Synthesis s u b s e q u e n t r e d u c t i o n o r m e t h y l - l i t h i u m a d d i t i o n f o l l o w e d by HBF4 e t h e r a t e t r e a t m e n t , t h e d i h y d r o f u r a n complexes a r e formed. D e c o m p l e x a t i o n w i t h i o d i n e l e a d s t o t h e d i h y d r o f u r a n s ( 3 1 ) .25

The

r e a c t i o n o f 2,2-dibromo-l,3-diketones w i t h o l e f i n s i n t h e p r e s e n c e o f c o p p e r powder g i v e s d i h y d r o f u r a n s ( 3 2 ) i n v a r i a b l e y i e l d f o r m a l d i p o l a r c y c l o a d d i t i o n .26 The d i h y d r o - 3 ( 2 E ) - f u r a n o n e

via

a

r i n g s y s t e m , which o c c u r s i n s e v e r a l

n a t u r a l p r o d u c t s , h a s c o n t i n u e d t o s t i m u l a t e i n t e r e s t amongst organic chemists.

The s t r a t e g y u s u a l l y e m p l o y e d f o r t h e s y n t h e s i s

of t h i s r i n g system is t h e acid-catalysed cyclization-dehydration o f a'-hydroxy-1,3-diketones, a n d t h u s many m e t h o d s c o n c e n t r a t e on

t h e s y n t h e s i s of t h e precursor diketones.

5-Substituted-3-

i s o x a z o l e c a r b o x y l a t e s s e r v e as d i k e t o n e e q u i v a l e n t s , b e i n g r e a d i l y c o n v e r t e d i n t o t h e v i n y l o g o u s a m i d e s ( 3 3 ) as o u t l i n e d i n Scheme 5. C y c l i z a t i o n o f t h e a m i d e s w i t h a t l e a s t o n e y-hydrogen

gives the

furanones (34) whereas t h e t e r t i a r y amides g i v e t h e i r n i n o f u r a n s ( 3 5 ) .27

A f u l l r e p o r t on R a p h a e l ' s s y n t h e s i s o f

w h i c h a l s o u s e s a c i d - c a t a l y s e d c y c l i z a t i o n of 28 v i n y l o g o u s amides, h a s been p u b l i s h e d . furan-3(2E)-ones,

T h e i n t r a m o l e c u l a r Wadsworth-Emmons

condensation of

B-ketophosphonates w i t h e s t e r c a r b o n y l s h a s been used i n a n i n t e r e s t i n g s y n t h e s i s o f t h e f u r a n o n e ( 3 6 .29

The c o n d i t i o n s a r e

c r u c i a l t o t h e success of t h e r e a c t i o n ; potassium carbonate and dicyclohexyl-18-crown-6

i n toluene give the required product,

w h e r e a s sodium h y d r i d e i n d i m e t h o x y e t h a n e g i v e s t h e r e a r r a n g e d furanone (37). S u b s t i t u t e d but-2-ene-1,4-diols

usually dehydrate t o give

u n s a t u r a t e d c a r b o n y l compounds u n d e r a c i d i c c o n d i t i o n s . 2-trirnethylsilyl

However, a

substituent d i v e r t s the dehydration reaction t o

g i v e t h e 2 , 5 - d i h y d r o f u r a n s ( 3 9 ) . 30

The r e q u i s i t e d i o l s a r e r e a d i l y

p r e p a r e d by h y d r o m a g n e s i a t i o n o f t h e t r i m e t h y l s i l y l p r o p a r g y l a l c o h o l ( 3 8 ) a n d c o n d e n s a t i o n of t h e i n t e r m e d i a t e w i t h a l d e h y d e s o r ketones.

The l i t h i o - a l l e n e s ( 4 0 ) r e a c t w i t h k e t o n e s t o g i v e

a d d u c t s which react w i t h e l e c t r o p h i l e s t o g i v e a r a n g e of h i g h l y substituted 2,5-dihydrofurans The o r t h o - m e t a l l a t i o n

( 4 1 ) .31

of a m i d e s h a s b e e n u s e d e x t e n s i v e l y i n

i n t e r m o l e c u l a r r e a c t i o n s and more r e c e n t l y i n t h e i n t r a m o l e c u l a r sense.

S n i e c k u s a n d S h a n k a r a n h a v e shown t h a t t h e e p o x y - a m i d e s

(42) cyclize

t h e ortho-metallated

intermediate t o furnish the

d i h y d r o b e n z o f u r a n s ( 4 3 ) i n m o d e r a t e y i e l d (32-68%) ,32 and i n a similar t y p e o f r e a c t i o n t h e l i t h i o d e r i v a t i v e s ( 4 4 ) a d d i n a

General and Synthetic Methods

5 46

NH2 OH. HC I

R'

-Eto2cYYR1 N-0

COZ Et

N-0

R' (34)

R3&R1 R2

7

d:

H

R2,R3f

R'

NH2

0

(33)

(35)

Scheme 5

";

+" 0

P (OE t),

K2C03 7 18 - c r o w n 6, toluene

Na H

v

-

DME

(36)

(37)

Me3Si-

=

7 OH

(38)

,

i, Bu'MgBr,[Cp2TiCL21 ii,

"b

me351

Me3Si R1*oH

BFjOEt2>

-

R ~ R ~ C O

R2

OH

R2

547

8: Saturated Heterocyclic Ring Synthesis

(40)

(41) E+= H+, Br+, I+, or PhSe'

R2

i. Bu"Li _____)

ii,NH4Cl aq.

Bu'02S

Buto2sT!+ (44)

(45)

_____) Amberlyst 15

X

\

R2 OH

(46)

toluene, 80 "C

.-O/'$RZ

548

General and Synthetic Methods

Michael s e n s e t o t h e v i n y l sulphone moiety t o g i v e t h e dihydrobenzofurans (45).

2,2-Dialkyldihydrobenzofurans, most commonly p r e p a r e d by t h e C l a i s e n r e a r r a n g e m e n t , a r e much more r e a d i l y s y n t h e s i z e d by t h e a c i d - c a t a l y s e d d e h y d r a t i o n o f t h e h y d r o x y b e n z y l a l c o h o l s ( 4 6 ) . 34 A m b e r l y s t 15 i s t h e a c i d c a t a l y s t u s e d a n d y i e l d s a r e e x c e l l e n t

Six-membered R i n g s . - T e t r a h y d r o p y r a n s . The c y c l i z a t i o n o f s i m p l e a l l e n i c a l c o h o l s t o g i v e monosubstituted t e t r a h y d r o p y r a n s has been e x t e n d e d t o t h e s y n t h e s i s o f more complex t e t r a h y d r o p y r a n s by two r e s e a r c h g r o u p s . 35 36 e i t h e r s i l v e r or mercury salts and, i n a d d i t i o n t o t h e high r e g i o s p e c i f i c i t y , h i g h s t e r e o s p e c i f i c i t y i s o b s e r v e d i n many c a s e s . Thus, t h e secondary a l l e n i c a l c o h o l s ( 4 7 ) c y c l i z e t o g i v e predominantly =-2,6-disubstituted p r o d u c t s ( 4 8 ) , and s u b s t i t u t e d a l l e n e s (49) g i v e t h e E - o l e f i n i c tetrahydropyrans (50) a s t h e major isomers. U . V . i r r a d i a t i o n o f y - a l l y l o x y - c a r b o n y l compounds a f f o r d s t h e t e t r a h y d r o p y r a n s ( 5 1 ) via i n t r a m o l e c u l a r € - h y d r o g e n a b s t r a c t i o n a n d r a d i c a l c o m b i n a t i o n . It 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 t o have a f u l l y s u b s t i t u t e d y - p o s i t i o n o t h e r w i s e N o r r i s h Type I1 r e a c t i o n becomes t h e m a j o r pathway.37

D i h y d r o p y r a n s . A f u l l p a p e r on t h e p r e p a r a t i o n of d i h y d r o p y r a n s a n n e l a t e d t o c y c l o p e n t a d i e n e s h a s now b e e n p u b l i s h e d , e x t e n d i n g t h e scope and d e m o n s t r a t i n g t h e i r u s e i n t h e s y n t h e s i s of i r i d o i d s and seco-iridoids. Danishefsky’s continued i n t e r e s t i n t h e hetero-Diels-Alder r e a c t i o n has r e s u l t e d i n t h e p u b l i c a t i o n of s e v e r a l p a p e r s d e t a i l i n g f u r t h e r advances i n t h e f i e l d . Thus, formaldehyde itself h a s b e e n shown t o b e a n e f f e c t i v e d i e n o p h i l e g i v i n g m o d e r a t e y i e l d s o f t h e d i h y d r o p y r o n e s ( 5 2 ) , w h i c h i n c l u d e s t h e p r e v i o u s l y unknown p a r e n t member ( 5 2 ; R ’ = R 2 = H) .39 f u n c t i o n a l i t y h a s a l s o been i n v e s t i g a t e d d e m o n s t r a t i n g t h a t , w i t h a 3-trimethylsilyloxy-group i n t h e d i e n e , t h e c y c l o c o n d e n s a t i o n i s successful with 1-silyloxy-I-alkyl, I - a l k y l , and 1 , l - d i m e t h o x y s u b s t i t u e n t s ( s e e Scheme 6 ) . 4 0 t h a t l,l-dimethoxy-3-trimethylsilyloxydiene i s a s u i t a b l e p a r t n e r i n t h e hetero-Diels-Alder r e a c t i o n . The d e g r e e o f s t e r e o c o n t r o l i n t h e c y c l o a d d i t i o n h a s a l s o b e e n

8: Saturated Heterocyclic Ring Synthesis

549

(48)

(47)

I

(49)

“y

OMe

+

Me3Si0

/s H

(50)

ZnCL2

H R’

R’

(52)

Me,SiO t

R

2

+ R4CH0

-oG [Eu(fod)31

R4

R3

R3

Scheme 6

R’ = OMe or a1kyl R 2 = OMe or OSiMe, R3= Me or H R4=Ph or hexyl

550

General and Synthetic Methods

a d d r e s s e d by D a n i s h e f s k y ' s g r o u p . They h a v e f o u n d t h a t magnesium b r o m i d e d i r e c t s t h e r e a c t i o n by c h e l a t i o n c o n t r o l g i v i n g e x c l u s i v e l y t r a n s - d i h y d r o p y r o n e s w i t h a-alkoxy-aldehydes and 8 - a l k o x y - a l d e h y d e s ( s e e Scheme 7 ) . 4 2 t i t a n i u m t e t r a c h l o r i d e g i v e s t h e c i s - d i h y d r o p y r o n e s via a n a l d o l process. L e w i s a c i d c a t a l y s i s h a s a l s o proved u s e f u l i n t h e i n v e r s e hetero-Diels-Alder r e a c t i o n such t h a t s u b s t i t u t e d a c r o l e i n s react with enol e t h e r s t o f u r n i s h t h e dihydropyrans (53) i n moderate y i e l d s (30-80%) .43 h a s 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/E r i n g system (54) of t h e heteroyohimbine a l k o l o i d s . I n an approach broadly similar t o t h a t published p r e v i o u s l y , b u t w i t h an extended s c o p e , a c e t a l s d e r i v e d from e t h y l v i n y l e t h e r ,

l-chloromethoxy-2-methoxymethane,and 3 , 4 - d i h y d r o p y r a n w i t h y-unsaturated a l c o h o l s c y c l i z e under t i t a n i u m t e t r a c h l o r i d e c a t a l y s i s t o g i v e d i h y d r o p y r a n s i n g e n e r a l l y h i g h y i e l d ( 6 5 - 9 8 % ) as o u t l i n e d i n Scheme 8 . The e n o l a t e C l a i s e n r e a r r a n g e m e n t h a s b e e n u s e d e x t e n s i v e l y i n t h e s y n t h e s i s o f s t e r e o c h e m i c a l l y d e f i n e d s y s t e m s and t h i s y e a r a n i n t e r e s t i n g u s e of t h e rearrangement i n t h e s y n t h e s i s of dihydropyrans has been published. Thus t h e d i o x a n p r e c u r s o r s ( 5 5 ) a r e t r a n s f o r m e d t o t h e d i h y d r o p y r a n s ( 5 6 ) i n good y i e l d ( > 5 2 % ) w i t h high stereospecificity. The d i h y d r o p y r o n e s ( 5 7 ) a r e s y n t h e s i z e d from c y c l o h e x a n e d i o n e s by i n i t i a l e n o l i c 2 - a c y l a t i o n f o l l o w e d by F r i e s r e a r r a n g e m e n t u s i n g t i t a n i u m t e t r a c h l o r i d e as t h e c a t a l y s t . 47 The p r o d u c t s a r e e a s i l y c o n v e r t e d i n t o t h e b e n z o p y r o n e s ( 5 8 ) , n o t e a s i l y p r e p a r e d by o t h e r m e t h o d s . Benzo-3-pyrones ( 6 0 ) a r e u s u a l l y p r e p a r e d f r o m o r t h o d i s u b s t i t u t e d benzene d e r i v a t i v e s , which t h e m s e l v e s are o f t e n d i f f i c u l t t o p r e p a r e . Saba h a s a p p l i e d t h e i n t r a m o l e c u l a r k e t o c a r b e n e a d d i t i o n t o p r e p a r e t h e b e n z o p y r o n e s ( 6 0 ) f r o m t h e much more a c c e s s i b l e a c i d c h l o r i d e s ( 5 9 ) i n h i g h y i e l d ( > 7 3 % ) . A l t h o u g h t h e M i t s u n o b u r e a c t i o n i s known t o work w e l l f o r t h e c o u p l i n g o f p h e n o l s and a l c o h o l s , t h e i n t r a m o l e c u l a r v a r i a n t h a s o n l y j u s t been p u b l i s h e d and p r o v i d e s a f a s t and e f f i c i e n t s y n t h e s i s of b o t h b e n z o d i h y d r o f u r a n s a n d b e n z o d i h y d r o p y r a n s ( s e e Scheme 9 ) .lr9 The b e n z o d i h y d r o p y r a n a - t o c o p h e r o l h a s b e e n synthesized enantiospecifically using the c h i r a l sulphoxide (61) t o s e t up t h e a s y m m e t r i c c e n t r e a n d t h e method s h o u l d b e a p p l i c a b l e t o a w i d e r a n g e o f b e n z o p y r a n s 50

.

8: Saturated Heterocyclic Ring Synthesis

TkH

0

OCH2Ph- Hi, i i

551

OCHZPh iii, iv

.J$H

0& K H 2

R

Ph

R

/ v,vi

Q"

A=

$Me;

B=

OCH2Ph

0

Et

Me3Si0

lM

Me3Si0

Reagents :i,A,MgBr2; ii ,AcOH; i i i , MgBr2, B,THF; iv, Et3N, MeOH; v, A,TiC14, CHZC12; v, TFA

Scheme 7

q0 +

H R'

R2

(&. (--$ f Ph

CPh

A

H

0

(541

552

General and Synthetic Methods

R2

R2

R3 OSiMe3]

# /

co, Me

(59)

(60)

Phg P,DEAD

OH Scheme 9

553

8: Saturated Heterocyclic Ring Synthesis G e n e r a l methods f o r t h e s y n t h e s e s of benzopyrans and 3 - n i t r o b e n z o p y r a n s have a l s o been p u b l i s h e d , f e a t u r i n g i n t h e f o r m e r case c y c l i z a t i o n o f s u b s t i t u t e d p h e n o l s w i t h t h e halogenopropionaldehyde a c e t a l ( 6 2 ) , 5 1 and c y c l i z a t i o n o f

o-hydroxybenzaldehydes ( 6 3 ) w i t h 2 - n i t r o e t h a n o l case.52

2-H-Pyrans,

i n the latter

w h i c h a r e a much l e s s w e l l known c l a s s o f

compounds, a r e r e a d i l y 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

alkylthiodiphenylcyclopropenium s a l t s a n d 1 , 3 - d i k e t o n e s , g i v i n g products (64) with 2-alkylthio s u b ~ t i t u e n t s . ~ ~ [ 5 , n l S p i r o a c e t a l s . The i n t e r e s t i n s p i r o a c e t a l s y n t h e s i s h a s c o n t i n u e d u n a b a t e d a n d t h u s o n l y a few o f t h e many p u b l i c a t i o n s i n t h i s f i e l d h a v e b e e n r e v i e w e d , f e a t u r i n g m e t h o d s o f a more g e n e r a l nature. F u l l d e t a i l s of t h e organoselenium-mediated

s y n t h e s i s of

s p i r o a c e t a l s d e v e l o p e d by Ley e t a l . h a v e b e e n p u b l i s h e d 5 4 a n d t h e i n t r a m o l e c u l a r Michael a d d i t i o n of an hydroxy-group t o an u n s a t u r a t e d s u l p h o x i d e g r o u p h a s b e e n shown t o g i v e s p i r o a c e t a l s with a high degree of stereocontrol, providing t h e

2-

or E-isomers

r e s p e c t i v e l y f r o m t h e s u l p h o x i d e s ( 6 5 ) a n d ( 6 6 ) .55 The g e n e r a l i t y o f t h e a d d i t i o n o f d i h y d r o p y r a n - c u p r a t e s t o e p o x i d e s and s u b s e q u e n t c y c l i z a t i o n t o g i v e s p i r o a c e t a l s 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 K o c i e n s k i ' s g r o u p i n a s y n t h e s i s o f T a l a r o m y c i n B ( s e e Scheme 1 0 ) , 5 6 a n d Amouroux h a s shown t h a t t h e corresponding lithio-dihydropyran protected iodo-alcohols

i s e f f i c i e n t l y a l k y l a t e d by t h e

( 6 7 ) t o g i v e d i h y d r o p y r a n a l c o h o l s which

then c y c l i z e under a c i d i c c o n d i t i o n s t o g i v e t h e

.

s p i r o a c e t a l s ( 6 8 ) 57 Another p o t e n t i a l l y very g e n e r a l s y n t h e s i s of s p i r o a c e t a l s i s b a s e d on t h e H o r n e r - W i t t i g r e a c t i o n . 58

The d i p h e n y l p h o s p h i n o x y

c y c l i c e t h e r s ( 6 9 ) , p r e p a r e d from t h e c o r r e s p o n d i n g c y c l i c e n o l e t h e r s , c o u p l e w i t h a l d e h y d e s or l a c t o l s t o g i v e a m i x t u r e o f i s o m e r i c p r o d u c t s which c y c l i z e under a c i d c a t a l y s i s t o g i v e t h e spiroacetals (70) i n generally high yield. F i n a l l y , on t h e a s p e c t o f new g e n e r a l m e t h o d s K o c i e n s k i a n d S t r e e t h a v e e x t e n d e d t h e i n t r a m o l e c u l a r Mukaiyama r e a c t i o 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 , i n v o l v i n g t h e a d d i t i o n o f a n e n o l e t h e r t o a d i o x o n i u m i o n w h i c h i s g e n e r a t e d by t h e r e a c t i o n o f a spirocyclic ortholactone with a Lewis acid.59

The method h a s b e e n

e x e m p l i f i e d by t h e s y n t h e s i s of t h e s p i r o a c e t a l p o r t i o n ( 7 1 ) of Milbemycin 8 3 .

General and Synthetic Methods

554

I

i ,B U " ~ N F

ii, NaOMe. MeOH

0

Y'

R2xYoH i, KH, THF

ii. Bun4NI, (62)

R3

pTs-OH

R'

R~

R3

\

8: Saturated Heterocyclic Ring Synthesis

555

Ph

\

I

i, p-TsOH, MeOH

i, p-TsOH,MeOH

ii, KH, THF

ii, KH, THF

PhS ,O

PhSO

556

General and Synthetic Methods

+ 0

OH

.1

aq. HCl

4

H0

Scheme 10

Q

L

i

+

557

8: Saturated Heterocyclic Ring Synthesis

Me,SiO

ll OH

(72)

(74)

(73)

R'

DCA, hu _____)

02,MeCN

R*

* ' Y O H

R e a g e n t s : i , m-CLC6H4CO3H;

H+

i i , H+, HC(OMeI3, Me2CO; iii, KOH, DMSO

Scheme 11

(75)

General and Synthetic Method5

558

The v a s t m a j o r i t y o f p u b l i c a t i o n s on s p i r o a c e t a l s y n t h e s i s h a v e u t i l i z e d k e t o - d i o l c y c l i z a t i o n s as t h e k e y r i n g - f o r m i n g s t e p a n d consequently have n o t been covered.

H o w e v e r , m e n t i o n m u s t b e made

o f M o r i ' s g r o u p who h a v e made a n o t a b l e c o n t r i b u t i o n t o s p i r o a c e t a l c h e m i s t r y i n t h e i r s y n t h e s e s o f all t h e i s o m e r s o f t h e i n s e c t pheromones ( 7 2 ) , ( 7 3 1 , ( 7 4 ) , and ( 7 5 ) i n o p t i c a l l y p u r e form. S i x - m e m b e r e d R i n g s C o n t a i n i n g More t h a n One O x y g e n . o b s e r v a t i o n t h a t DCA-sensitized o f I,l=di-(p-anisyl)ethylene R1 = R2

p-MeOC6H4)

electron-transfer

g i v e s t h e 1,2-dioxane

60-62

The i s o l a t e d

photo-oxygenation

(76;

h a s now b e e n e x t e n d e d t o a g e n e r a l

s y n t h e s i s of s y m m e t r i c a l 1 , 2 - d i o x a n e s .

The y i e l d s a r e g e n e r a l l y

v e r y h i g h ( > 7 5 % e x c e p t when R 1 = R2 = P h ) , a n d t h e f o r m a t i o n o f s i d e products is negligible.63 Acid-catalysed

d i m e r i z a t i o n of a - h y d r o x y - d i m e t h y l a c e t a l s ,

on t h e

o t h e r hand, a f f o r d s 1 , 4 - d i o x a n e s ( 7 7 ) i n h i g h y i e l d and h i g h p u r i t y where t h e r e q u i r e d d i o x a n e c r y s t a l l i z e s d i r e c t l y from t h e r e a c t i o n medium.64

F u l l d e t a i l s on t h e s y n t h e s i s o f 1 , 4 - d i o x a n e

analogues

of zoapatanol, previously only published i n t h e patent l i t e r a t u r e , h a v e now a p p e a r e d w h e r e b y y , b - u n s a t u r a t e d and c y c l i z e

via

ketones a r e epoxidized

t e t r a h y d r o f u r a n s as shown i n Scheme 1 1 . 6 5

J e f f o r d ' s g r o u p h a s c o n t i n u e d work o n t h e s y n t h e s i s o f 1 , 2 , 4 trioxanes.

The g e n e r a l m e t h o d o l o g y u s e d by t h e g r o u p i n v o l v e s t h e

t r a p p i n g of 8-hydroperoxy

c a t i o n s or z w i t t e r i o n i c p e r o x i d e s w i t h

a l d e h y d e s , and s e v e r a l e x t e n s i o n s t o t h e method h a v e b e e n p u b l i s h e d t h i s year.

Thus, t h e dye-sensitized

photo-oxygenation

of t h e

i n d o l e ( 7 8 ) i n t h e p r e s e n c e of a l d e h y d e s g i v e s t h e t r i o x a n e s ( 7 9 ) as t h e major p r o d u c t s , 6 6 t h e y i e l d s of t r i o x a n e s from t h e r e a c t i o n o f e n d o p e r o x i d e s ( 8 0 ) w i t h a l d e h y d e s a r e much i m p r o v e d i f

t r i m e t h y l s i l y l trifluoromethanesulphonate i s u s e d a s t h e a c i d c a t a l y s t , 6 7 a n d t h e c y c l i c a l l y l i c h y d r o p e r o x i d e (81 ) r e a c t s w i t h a l d e h y d e s t o g i v e t r i o x a n e s . 68 Both symmetrical and unsymmetrical s p i r o o r t h o c a r b o n a t e s a r e r e a d i l y p r e p a r e d from t e t r a m e t h y l o r t h o c a r b o n a t e by r e a c t i o n w i t h two e q u i v a l e n t s of d i o l s t o g i v e t h e s y m m e t r i c a l o r t h o c a r b o n a t e s ( 8 2 ) , o r by r e a c t i o n w i t h p r o p a n e - 1 , 3 - d i o l t o g i v e t h e 1 , 3 - d i o x a n e ( 8 3 ) which t h e n a f f o r d s t h e u n s y m m e t r i c a l o r t h o c a r b o n a t e s ( 8 4 ) on r e a c t i o n w i t h a l k a n e d i o l s .69 S e v e n - a n d E i g h t - m e m b e r e d R i n g s . - T h e r e h a v e b e e n v e r y few new c o n t r i b u t i o n s i n t h i s area. C a r l e s s and Fekarurhobo, i n an

8: Saturated Heterocyclic Ring Synthesis

559

Me

’

02

R’R’CO

*

I

Me

Me Me OOH

H

Me (79

(78)

@

QI..p

____, RCHO

R2

General and Synthetic Methods

560

a p p r o a c h t o a n a n a l o g u e o f t h e e l u s i v e t h r o m b o x a n e A 2 , h a v e shown t h a t v i n y l o x y c a r b o n y l compounds u n d e r g o i n t r a m o l e c u l a r photocycloaddition t o the 2,7-dioxabicylo[4.1.1 ]octanes (85)

which

s u b s e q u e n t l y r i n g - o p e n i n t h e p r e s e n c e of a c i d i c m e t h a n o l t o g i v e

.

t h e seven-membered r i n g s ( 8 6 ) 7 0 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 of l a u r e n c i n , a m a r i n e n a t u r a l p r o d u c t , S c h r e i b e r and K e l l y h a v e d e v e l o p e d a g e n e r a l method whereby, under c e r t a i n c o n d i t i o n s , a l k y n y l - l i t h i u m s add t o 6 - l a c t o n e s t o g i v e t h e eight-membered r i n g s ( 8 7 ) . 7 1

The s u c c e s s of

t h e r e a c t i o n g r e a t l y d e p e n d s b o t h on t h e n a t u r e o f t h e a l k y n y l l i t h i u m a n d t h e s u b s t i t u t i o n p a t t e r n of t h e l a c t o n e . 2 Sulphur-containing Heterocycles

Ring e x p a n s i o n s and r e a r r a n g e m e n t s h a v e f e a t u r e d h e a v i l y i n s u l p h u r h e t e r o c y c l e s y n t h e s i s t h i s y e a r , and so i t is f i t t i n g t h a t a p r i m e e x p o n e n t i n t h i s area o f c h e m i s t r y , V e d e j s , h a s p u b l i s h e d a r e v i e w on s u l p h u r - m e d i a t e d r i n g e x p a n s i o n s i n t o t a l s y n t h e s i s . 72 The a l l e n e e p i s u l p h i d e ( 8 8 ) r e a c t s w i t h v a r i o u s e l e c t r o p h i l e s t o 2-Lithio-

g i v e a r a n g e of s u l p h u r h e t e r o c y c l e s ( s e e S c h e m e 1 2 ) . 7 3

1 , 3 - d i t h i a n e s h a v e b e e n u s e d e x t e n s i v e l y a s Umpolung r e a g e n t s i n t h e l i t e r a t u r e , but t h e deprotonation of 2 , 2 - d i s u b s t i t u t e d dithianes has received l i t t l e attention.

1,3-

I k e h i r a and Tanimoto have

shown t h a t t h e d i t h i a n e s ( 8 9 ) u n d e r g o W i t t i g r e a r r a n g e m e n t on t r e a t m e n t w i t h LDA t o g i v e t h e 2 , 2 - d i s u b s t i t u t e d tetrahydrothiophene-3-thiols ( 9 0 ) . 7 4 1,3-Dithianes (91; n = 3 ) rearrange i n a d i f f e r e n t s e n s e , under t h e influence of phenyl selenenyl c h l o r i d e t o g i v e dihydro-l,4d i t h i e p i n e s , and t h e r e a c t i o n a l s o works f o r 1 , 3 - d i t h i o l a n e s ( 9 1 ; n 2 ) t o g i v e d i h y d r o - I , Q - d i t h i i n ~ . ~R i~n g e x p a n s i o n o f t h e v i n y l d i t h i o a c e t a l s ( 9 2 1 , i n i t i a t e d by c a r b e n e a d d i t i o n t o s u l p h u r , provides t h e first e n t r y t o t h e betweenanenes (93)

alkoxycarbonyl-stabilized

via

y l i d e s . 76

The s c o p e o f t h e r e a c t i o n o f t h e m e r c a p t o c a p r o a t e ( 9 4 ) w i t h o l e f i n s a n d a c e t y l e n e s h a s now b e e n c l a r i f i e d i n a p u b l i c a t i o n f r o m Anklam a n d M a r g a r e t h a .

T h u s i r r a d i a t i o n of ( 9 4 ) i n t h e p r e s e n c e o f

o l e f i n s or a c e t y l e n e s l e a d s t o t h i o l a n e s (95) or dihydrothiophenes ( 9 6 ) r e s p e c t i v e l y i n v a r i a b l e y i e l d . 77 Most o f t h e r e m a i n i n g m e t h o d s have u s e d v a r i a t i o n s on t h e theme of cycloaddition chemistry i n t h e c o n s t r u c t i o n of sulphur heterocycles. Y o s h i d a ' s g r o u p h a s shown t h a t

561

8: Saturated Heterocyclic Ring Synthesis

-

hu

McOH, H+

w CgH6

R’

R’

R’

0

+ R O2

R ’ = H, Me, or SMe;

R = H or Me

R2= H, CH,OMe, or CH(OEt12

+

/4

R’

R2

Scheme 12

-

nR

General and Synthetic Methods

562

R3X

4 2 s R1

R2

(89)

k 2 S R 3 R’

R2

(90)

I

ROH hu

HS

[2,3] shift

AcozR (94)

563

8: Saturated Heterocvclic Ring Synthesis

N-methyldithiophthalimide

is an e x c e l l e n t d i e n o p h i l e g i v i n g

h i g h y i e l d s of d i h y d r o t h i o p y r a n s w i t h h i g h r e g i o s e l e c t i v i t y and m o d e r a t e s t e r e o s e l e c t i v i t y ( s e e Scheme 1 3 1 , 78 a n d 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 o f a , @ - u n s a t u r a t e d d i t h i o e s t e r s , a s t h e 41[ component, w i t h d i e n o p h i l e s g i v e s t h e a d d u c t s ( 9 7 ) i n v a r i a b l e y i e l d (20-100%) .79 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 of t h e d i e n y l

a - m e t h a c r y l t h i o i m i d a t e s h a s been s t u d i e d under a v a r i e t y of c o n d i t i o n s g i v i n g t h e b i c y c l i c r i n g system ( 9 8 ) and ( 9 9 ) i n generally high yield.

The r e a c t i o n s p r o c e e d r a p i d l y w h e r e n = 0 ,

more s l o w l y w h e r e n = 1 , and n o t a t a l l w h e r e n = 2 , a n d t h e exop r o d u c t s a r e f o r m e d i n s l i g h t p r e f e r e n c e o v e r t h e e n d o - a d d u c t 7s .

0

Hantke and G o t t h a r d t have d i s c l o s e d t h e s y n t h e s i s of t h e

dithiabicyclo~4.2.1~nonenones( 1 0 1 ) v i a a 1 , 3 - d i p o l a r c y c l o a d d i t i o n of t h e m e s o i o n i c compounds ( 1 0 0 ) w i t h 1 , 3 - d i e n e s .

This is the

f i r s t r e p o r t o f s u c h a r e a c t i o n a n d t h e y i e l d s a r e m o d e r a t e t o good 81 (34-8 1 % ) . F i n a l l y i n t h i s s e c t i o n , G r o s s e r t e t a l . h a v e shown t h a t i n t r a m o l e c u l a r a l k y l a t i o n of t h e keto-sulphone

halide (102) leads

t o t h e c y c l i c s u l p h o n e ( 1 0 3 ) a n d t h a t t h e method s h o u l d b e w i d e l y a p p l i c a b l e . 82 3 R i n g s w i t h More t h a n One H e t e r o a t o m NitrogenRings.

and Oxygen-containing Rings.-

T h r e e - a n d Four-membered

C h i r a l s u l p h a m y l o x a z i r i d i n e s h a v e b e e n s y n t h e s i z e d by t h e

o x i d a t i o n of t h e o p t i c a l l y a c t i v e s u l p h a m i d e s ( 1 0 4 ) w i t h MCPBA and t h e y have been used as e n a n t i o s e l e c t i v e s u l p h i d e o x i d a t i o n reagents.83

The o x i d a t i o n o f t h e a z a d i e n e s (105) w i t h MCPBA l e a d s

t o t h e v i n y l o x a z i r i d i n e s ( 1 0 6 ) w h i c h a r e good b u i l d i n g b l o c k s f o r t h e s y n t h e s i s o f v a r i o u s h e t e r o c y c l e s , a s o u t l i n e d i n Scheme 14. 8 4

1,3,4-Dioxazine-2,5-diones a r e known t o u n d e r g o e x p u l s i o n o f C 0 2 a n d G e f f k e n h a s p u b l i s h e d a new e n t r y

t o give 1,2-oxazetidinones,

i n t o t h e p r e c u r s o r s by t r e a t m e n t o f t h e g l y c o l o h y d r o x a m i c a c i d s with carbonyl diimidazole.

The d i o x a z i n e d i o n e s ( 1 0 7 ) t h e n r e a r r a n g e

e i t h e r i n s i t u or after i s o l a t i o n , t o g i v e t h e oxazetidinones (108) i n h i g h y i e l d (86-97%). 85

F i v e membered R i n g s . The u s e o f n i t r i l e o x i d e s a n d n i t r o n e s i n t h e 1,3-dipolar cycloaddition r e a c t i o n t o g i v e i s o x a z o l i n e s or i s o x a z o l e s h a s b e e n e v e r p o p u l a r , a n d s e v e r a l new m e t h o d s f o r t h e

5 64

General and Synthetic Methods R’

+

@ M :e

R’

S R2

Scheme 13

POCI3.pyridine

R2

S

R3

R4

R’ R2

(97)

i-iii

Ph

Reagents;

i, NaH, THF; ii, Bu”Li; hi, Br(CH2)3CI; iv, NaI, Me2C0

8: Saturated Heterocyclic Ring Synthesis

565

major product

PhCH2COCI

R’

phN/

R’

\y/R2

phNro Scheme 14

566

General and Synthetic Methods

g e n e r a t i o n of t h e r e a c t i v e i n t e r m e d i a t e s h a v e b e e n p u b l i s h e d . F o r example, c h l o r i n a t i o n of aldoximes with N-chlorosuccinimide r a t h e r t h a n c h l o r i n e f o l l o w e d by t r e a t m e n t w i t h t r i e t h y l a m i n e l e a d s t o n i t r i l e o x i d e s c l e a n l y a n d r a p i d l y , 86 a n d p r i m a r y n i t r o - c o m p o u n d s a r e c o n v e r t e d i n t o n i t r i l e o x i d e s by d e h y d r a t i o n w i t h a c a t a l y t i c amount o f t o l u e n e - p - s u l p h o n i c a c i d . 8 7 The o x a z i r i d i n e ( 1 0 9 )

r e a r r a n g e s i n t h e p r e s e n c e of s i l i c a t o g i v e t h e n i t r o n e ( 1 1 0 ) which u n d e r g o e s t h e n o r m a l c y c l o a d d i t i o n r e a c t i o n s . 88 Kozikowski’s group has i n v e s t i g a t e d t h e d i a s t e r e o s e l e c t i v i t y of n i t r o n e c y c l o a d d i t i o n when t h e o l e f i n i s c h i r a l , a n d h a s shown t h a t t h e --product p r e d o m i n a t e s , p r e s u m a b l y by t h e d i r e c t i n g e f f e c t o f t h e o x y g e n . 8 9 The h i g h e s t s e l e c t i v i t i e s a r e s e e n w i t h t h e i s o p r o p y l i d e n e a c e t a l ( 1 1 1 ) (Scheme 1 5 ) . T e t r a h y d r o p y r a n y l n i t r o n e ( 1 1 2 ) i s r e a d i l y g e n e r a t e d from t h e oxime o f 5 - h y d r o x y p e n t e n a l a n d paraformaldehyde and p r o v i d e s a u s e f u l e n t r y i n t o t h e tetrahydropyranyl-protected i s o x a z o l i d i n e s ( 1 1 3 ) N i t r o n a t e s undergo 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 o l e f i n s t o g i v e n i t r i l e o x i d e a d d u c t s ( 1 1 4 ) ,’I a n d t h e n i t r i l e o x i d e s ( 1 1 5 ) h a v e b e e n shown t o add t o a z o m e t h i n e s t o g i v e t h e o x a d i a z o l e s ( 1 1 6 ) i n

.”

m o d e r a t e y i e l d (35-60%) . 9 2 P o l y c y c l e f o r m a t i o n h a s been u s e d many t i m e s f o r t h e s y n t h e s i s of c o m p l e x n a t u r a l p r o d u c t s , e m p l o y i n g v a r i o u s methodologies. Kozikowski e t a l . have demonstrated t h a t t h e d i e n e nitro-compound ( 1 1 7 ) i s a u s e f u l p o l y c y c l e r e a g e n t i n v o l v i n g t h e intermediacy of a n i t r i l e o x i d e s p e c i e s (see Scheme 1 6 ) 93 The f a t e o f a l d e h y d e a n d k e t o n e o x i m e s i n c y c l o a d d i t i o n r e a c t i o n s h a s n o t b e e n e x t e n s i v e l y s t u d i e d up u n t i l now, b u t G r i g g

.

h a s d o n e a s y s t e m a t i c s t u d y of t h i s r e a c t i o n and h a s m o d i f i e d a n d e x t e n d e d t h e r e s u l t s of p r e v i o u s i s o l a t e d p u b l i c a t i o n s . 9 4 H i s g r o u p h a s f o u n d t h a t a l l p o s s i b l e r e g i o - a n d s t e r e o - i s o m e r s of t h e 2 : l a d u c t s (118) are formed. I n c o n t r a s t t o t h e c y c l o a d d i t i o n approach t o five-membered n i t r o g e n - and o x y g e n - c o n t a i n i n g r i n g f o r m a t i o n t h e r e h a v e b e e n muck fewer a l t e r n a t i v e s t r a t e g i e s published t h i s y e a r . A o n e - p o t c o n v e r s i o n of k e t o n e s i n t o t h e o x a z o l i n o n e s ( 1 1 9 ) has b e e n r e p o r t e d a n d i s a c c o m p l i s h e d by t h e a d d i t i o n of a r y l t h i o l s t c e t h y l c y a n o f o r m a t e i n t h e p r e s e n c e o f TiC14 a n d t r i e t h y l a m i n e , f o l l o w e d by a d d i t i o n o f t h e k e t o n e s . Although t h e y i e l d s are n o t

h i g h (15-40%) t h e s i m p l i c i t y of t h e method makes it an a t t r a c t i v e o n e . 95 A l l y l i c a l c o h o l s are r e a d i l y c o n v e r t e d i n t o a c y l a m i n o e t h y l ethei

8: Saturated Heterocyclic Ring Synthesis

567

-/i.a - -$I silica gel

PhNCO

0-

(1091

(110)

C02Me

CO 2 Me

major

Scheme 15

Qb4HOI-i

I

0-

minor

General and Synthetic Methods

568

-

R2 -R3

+

RCH =N02R'

x3

R

(114)

R = PhS02, COZEt, PhCO, or MeCO

+

, ; ' -hP

0-

AJ-N-A,~

---+

EtOH, 0

OC

Ar

'Ar

CI

\

N%cN H

Y H

H

Scheme 16

-

X I

-

xI

X

8: Saturated Heterocyclic Ring Synthesis

NCic"

ArSH ______)

OEt

EtZNH, Tic14

569

ArskO R~R~CO

HN

BF3' E t 2 0

OEt

R'

R2

( 119)

Hop R

E

____)

0 (122)

R

R ' y f

AYE air

E = electrophile

R1+

0

HN R3

570

General and Synthetic Methods

derivatives (120) and cyclization to oxazolidines is known to proceed with halogen electrophiles, usually giving predominantly cis-oxazolidines. Harding et al. have shown that a mercuric ioninitiated cyclization gives the trans-oxazolidines (121) as the major products.96 In a similar vein cyclization of propargyl amine derivatives (122) with electrophiles gives selectively the dihydrooxazoles (123) rather than the corresponding six-membered ring (124) .97 During an investigation into the reactions of diketones with amines directed toward pyridine synthesis, Tashiro et al. observed the unusual oxidative cyclization of the enamines (125) to the dioxotetrahydrofuro[3,2-b]pyrroles (126) albeit in modest yield (3-60%) .98 Six-membered and Larger Rings. Nitroso-compounds are useful intermediates for the synthesis of heterocycles Diels-Alder reaction, and several new facets of this reaction type have emerged this year. Thus, the enantiomerically pure a-chloronitrosocompounds (127) and (129) react with cyclohexadiene to give the adducts (128) and (130) in 69% chemical yield and >95% optical yield. 99 ’ l o o Regiochemistry rather than stereochemistry has been investigated in a publication from Boger and Patel. They have shown that acyl nitroso-compounds give predominantly the paraadducts (l3l), in contrast to aryl nitroso-compounds. 10 1 Nitrosoalkenes participate in the intermolecular Diels-Alder reaction as the 4n component, but there are severe restrictions to the applications of the reaction. However the intramolecular variant of the reaction proceeds in much better yield and with high stereoselectivity. For example, the nitrosoalkene (133), generated in situ from the chloro-oxime (132) by slow release of fluoride ion, gives the adduct (134) as the predominant (5:1 ) isomer. lo* The Diels-Alder reaction of triethyl azomethinetricarboxylate with electron-rich dienophiles such as enol ethers or styrenes gives dihydro-I ,3-oxazines (135) in good yields (61-98%), Io3 whereas dihydro-l,4-benzoxazines (136) are prepared in a one-pot procedure from ortho-amino-phenols and chloroacetyl chloride. O4 The opening of epoxides with 1-hydroxycarbamate gives the corresponding methoxycarbonylaminoxy-alcohols which can then be transformed into either 1,4,2-tetrahydrodioxazine-3-ones (137) o r 2-methoxycarbonyl-I ,4,2-tetrahydrodioxazines ( 1381, I o 5 and the previously unknown 1,2,4-oxadiazin-6-ones (139) are readily

8: Saturated Heterocyclic Ring Synthesis

(129)

571

(130 1

(131)

+

+Si- I

General and Synthetic Methods

572

EtOzC,

C02Et

,CO2Et

EtO

R

G

o

+

H

- Ra:&

cl(),c'

TEBA NaHC03,CHC13

NH2

H

R'

R2 R1~o,~KO".

0

aR2 HON H

+

J

R2

R'+O

0

HO

I

R3

)=o H

-

+

Y N"2

H'OMe

4 R2

0,N/C02Me

(138)

+

OMe

R' x ~ A ~ 3

O Y0 N H

Ar-C=N-O

R3

or

Co2E'

0

573

8: Saturated Heterocyclic Ring Synthesis s y n t h e s i z e d by t h e n u c l e o p h i l i c a d d i t i o n of a - a m i n o - a c i d s n i t r i l e o x i d e s . 106

to

T h e dihydro-1,3,4-oxadiazepine h e t e r o c y c l i c r i n g s y s t e m i s s i m i l a r l y r a r e , a n d now a n e a s y a n d g e n e r a l s y n t h e s i s h a s b e e n published.

The m e t h o d e n t a i l s t h e a d d i t i o n o f h y d r a z i n e a n d

carboxylic a c i d s t o e i t h e r t h e propenones (140) or t h e d e r i v a t i v e s ( 1 4 1 ) or ( 1 4 2 ) g i v i n g t h e p r o d u c t s ( 1 4 3 ) i n m o d e r a t e y i e l d (30-72%) and i n a s i n g l e s t e p . Io7 The e i g h t - m e m b e r e d r i n g ( 1 4 5 1 , a dihydro-1,2,6-oxadiazocine, h a s b e e n p r e p a r e d by t r e a t m e n t o f t h e (chloroacety1amino)propiophenone o x i m e s ( 1 4 4 ; R = CH2Ph) w i t h s o d i u m h y d r o x i d e , w h e r e a s t h e corresponding desbenzyl derivatives dimerize t o give the sixteenmembered r i n g c o m p o u n d s ( 1 4 6 ) u n d e r t h e same r e a c t i o n 108 conditions. Oxygen a n d S u l p h u r - , a n d N i t r o g e n a n d S u l p h u r - c o n t a i n i n g R i n g s . Bromomethanesulphonyl bromide, r e c e n t l y developed f o r t h e s y n t h e s i s of d i e n e s , h a s now b e e n u s e d f o r t h e p r e p a r a t i o n o f 1 , 3 - o x a t h i o l e 3 , 3 - d i o x i d e s (147) from t r i m e t h y l s i l y l e n o l e t h e r s i n t h e p r e s e n c e o f e t h y l e n e o x i d e f o l l o w e d by t r e a t m e n t w i t h D B N . 109 K o s k i m i e s h a s r e p o r t e d on t h e s y n t h e s i s o f 1 , 4 - o x a t h i a n - 2 - o n e s by a v a r i e t y of m e t h o d s ( s e e Scheme 1 7 ) , a n d h a s a l s o i n v e s t i g a t e d t h e i r s t a b i l i t y demonstrating t h a t t h e oxathianones are less s t a b l e than t h e corresponding v a l e r o l a c t o n e s . l o I n an extension t o a p r e v i o u s s t u d y Abramovitch e t a l . h a v e s y n t h e s i z e d seven-membered sultams using t h e s o l u t i o n p y r o l y s i s of arylpropanesulphonyl azides.”’

The b e s t y i e l d s a r e o b t a i n e d u s i n g t h e r a t h e r e x o t i c

s o l v e n t F r e o n 113. T h i s y e a r h a s s e e n a n i n c r e a s e i n t h e n u m b e r of p u b l i c a t i o n s on t h e s y n t h e s i s o f s u l p h u r - and n i t r o g e n - c o n t a i n i n g r i n g s and t h e methods can be c l a s s i f i e d i n t o s e v e r a l g e n e r a l themes. V a r i a t i o n s on i n t r a m o l e c u l a r d i s p l a c e m e n t r e a c t i o n s h a v e b e e n t h e m o s t common m e t h o d r e p o r t e d ; f o r e x a m p l e , t h e t r e a t m e n t o f t h e i s o t h i o c y a n a t o a l l y l c h l o r i d e s (149) w i t h e i t h e r a l c o h o l s or amines g i v e s t h e 1 , 3 - t h i a z i n e s ( 1 5 0 ) o r ( 1 4 8 ) by i n i t i a l a d d i t i o n t o t h e i s o t h i o c y a n a t e f o l l o w e d by d i s p l a c e m e n t o f c h l o r i n e . T h e arylazomethylenephosphoranes ( 1 5 1 ) r e a c t w i t h c a r b o n disulphi.de t o g i v e t h i a d i a z o l i n e t h i o n e s i n g e n e r a l l y high y i e l d ( > 7 0 % ) , via t h e i n t e r m e d i a t e ( 1 5 2 ) w h i c h t h e n d i s p l a c e s triphenylphosphine. dihydro-oxothiadiazine

A p r e v i o u s r e p o r t of t h e s y n t h e s i s of t h e

( 1 5 3 ) h a s now b e e n shown t o b e i n c o r r e c t ,

5 74

General and Synthetic Methoc:

0 (140)

‘b R1woH R1woco NHz NH2

*

R*CO*H

ij (141 1

(143)

0

(142)

NaOH c

R1

(144)

R

0

R1%N

=

CH2Ph

-

8: Saturated Heterocyclic Ring Synthesis

>-;

OSiMe

R’

R2

+

BrCH2S02Br

“\s\

575

o ~ ~ c H 2 BDBNr

A

A (147)

Br

Scheme 17

576

General and Synthetic Methods

L

(152 1

N-N

ArNHN-

7 rs

N-N

I

Ar

C02H

(153)

(155)

(154)

R’

I

PhCH2 S-CH(CH 2)n- NX

I (Olm

I

(156)

rn=

Oor2

n =

Oorl Scheme 18

PhCHzSCH(CH2InN =CHPh

I

R’ (157

LDA

Ph

H

__j

KC

(153

577

8: Saturated Heterocyclic Ring Synthesis

t h e a c t u a l p r o d u c t s b e i n g t h e t h i a z o l i d i n o n e s ( 1 5 4 ) . The t h i a d i a z i n e s ( 1 5 3 ) c a n , h o w e v e r , b e p r e p a r e d by t h e i n t r a m o l e c u l a r c o u p l i n g of t h e a c i d s ( 1 5 5 ) w i t h DCC.

Intramolecular

s u b s t i t u t i o n o f a v a r i e t y of d e r i v a t i v e s o f ( 1 5 6 ) w i t h LDA g i v e s t h e c o r r e s p o n d i n g t h i a z o l i d i n e s , t h i o m o r p h o l i n e s , and d i h y d r o b e n z o t h i a z i n e s i n v a r i a b l e y i e l d (24-100%) a s d e s c r i b e d i n Scheme I 8 . ’ l 5

The r e a c t i o n i s a l s o s u c c e s s f u l f o r 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 t o t h e enamine ( 1 5 7 ) . Intramolecular a d d i t i o n a l s o f e a t u r e s i n t h r e e o t h e r methods reported t h i s year. Thus, t h e r e a c t i o n of amines with carbon d i s u l p h i d e and p r o p a r g y l bromide a f f o r d s t h e a d d u c t s (158),, which t h e n c y c l i z e t o g i v e 3,6-dihydro-1,3-thiazine-2-thiones ( 1 5 9 ) , whereas t h e propargylamines (160) r e a c t with carbon d i s u l p h i d e i n t h e p r e s e n c e of b a s e t o g i v e t h e 3,4-dihydro-1,3-thiazine-2116 thiones. The a c e t y l e n i c d e r i v a t i v e s ( 1 6 1 ) r e a c t w i t h h e t e r o c y c l e s t o g i v e t h e fused h e t e r o c y c l i c r i n g systems (162) containing an exocyclic methylene i n poor t o moderate y i e l d t h e a c e t y l e n i c moiety.

l7

via

i n t r a m o l e c u l a r a m i n a t i o n of

F u r t h e r s t u d i e s on t h e r a d i c a l

h e t e r o c y c l i z a t i o n of N - a l l y l - 2 - a m i n o t h i o l s

t o g i v e m i x t u r e s of

t h i o m o r p h o l i n e s a n d t h i a z o l i d i n e s h a v e shown t h a t t h e m o r e s u b s t i t u t e d t h e d o u b l e bond t h e h i g h e r t h e r a t i o o f t h i o m o r p h o l i n e 118

t o t h i a z o l i d i n e (Scheme 1 9 ) .

The 2 , 3 - s i g m a t r o p i c r e a r r a n g e m e n t of N - y l i d e s , N - i m i d e s ,

and i s well p r e c e d e n t e d , b u t i n c o n t r a s t 2-imide r e a r r a n g e m e n t s had n o t been r e p o r t e d . S a s h i d a and Tsuchiya have

S-ylides

f i l l e d t h a t g a p w i t h t h e r i n g e x p a n s i o n of t h e 2 - v i n y l t h i a c y c l o a l k e n e N-imides

(163) t o give 1,2-thiazocycles i n

The a n i l i n e d e r i v a t i v e s ( 1 6 4 ) u n d e r g o a n i n t r i g u i n g v a r i a n t of t h e 2,3-sigmatropic rearrangement involving

60-70% y i e l d .

f o r m a t i o n o f t h e a z a - s u l p h o n i u m i n t e r m e d i a t e s ( 1 6 5 ) g e n e r a t e d by t r e a t m e n t of ( 1 6 4 ) w i t h N - c h l o r o s u c c i n i m i d e . I 2 O On a t t e m p t i n g t o p r e p a r e a d i - i m i d e

from t h e t h i o u r e a ( 1 6 6 a )

B e r n a u e r e t a l . i s o l a t e d t h e r e a r r a n g e m e n t p r o d u c t ( 1 6 7 a ) . 12’ F u r t h e r i n v e s t i g a t i o n l e d t o t h e d i s c o v e r y of t h e g e n e r a l r e a c t i o n where t h e t h i o u r e a s ( 1 6 6 ) and ( 1 6 8 ) r e a r r a n g e t o g i v e t h e

cis- a n d

trans-dihydrothiazolothiazoles ( 1 6 7 ) a n d ( 1 6 9 ) w h e r e t h e r a t i o s A s i m p l e s y n t h e s i s of t h e depend on t h e c o n d i t i o n s used. 2,3-dihydrobenzisothiazoles ( 1 7 0 ) , r e l a t i v e s of t h e s a c c h a r i n r i n g s y s t e m , i s a c c o m p l i s h e d by t h e r e a r r a n g e m e n t o f b e n z o t h i e t e s i n t h e p r e s e n c e of a m i n e i n r e f l u x i n g t o l u e n e . 1 2 2

It is e s s e n t i a l t o have

578

General and Synthetic Methods

R e a g e n t s : i, NaOH; ii, piperidine, or

Triton B, or HgS04, H2S04

i, Et3N

RNH7 + csz

ii, HCL, H20

N

* S

Y = Br Or OTS

R3

I

RadiCQ I

Scheme 19

8: Saturated Heterocyclic Ring Synthesis

579

0 S-N

Ts n =4 140 OC

+ S

-

+

I

(168) Me

H

;I (169)

General and Synthetic Methods

580

a n e x c e s s of t h e a m i n e , o t h e r w i s e s i d e p r o d u c t s a r e p r o d u c e d i n significant quantities. W e i n r e b ' s g r o u p h a s p u b l i s h e d f u r t h e r work on t h e D i e l s - A l d e r r e a t i o n s o f s u l p h u r d i o x i d e b l s i m i d e s w i t h d i e n e s , 1 2 3 12'

and t h e

i r r a d i a t i o n o f t h e e n a m i d e s ( 1 7 1 ) i n h e x a n e f u r n i s h e s good y i e l d s (75-80%) of t h e 5 , 5 - d i s u b s t i t u t e d

t h i a z o l i n e s ( 1 7 2 ) .125

4 Nitrogen-containing Heterocycles Three-membered

Rings.-

Two d e h y d r a t i v e p r o c e d u r e s f o r t h e s y n t h e s i s

o f a z i r i d i n e s from 2 - 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 , u s i n g e i t h e r d i p h o s p h o r u s t e t r a i o d i d e 1 2 6 o r triphenylphosphine-diethyl a z o d i c a r b o x y l a t e (Scheme 2 0 ) . 1 2 7

C y c l i z a t i o n occurs under mild

c o n d i t i o n s and y i e l d s a r e g e n e r a l l y g o o d , a l t h o u g h t h e l a t t e r method o n l y w o r k s w e l l i f t h e r e i s a t l e a s t o n e s u b s t i t u e n t a t t a c h e d t o e i t h e r o f t h e two c a r b o n a t o m s b e t w e e n oxygen and n i t r o g e n i n t h e precursor amino-alcohols.

2-Phenylsulphinylaziridines ( 1 7 5 ) h a v e b e e n p r e p a r e d by t h e a d d i t i o n of a-halogenosulphinyl c a r b a n i o n s ( 1 7 3 ) t o i m i n e s ( 1 7 4 ) . 128

The same r e s e a r c h g r o u p h a s a l s o d e s c r i b e d t h e

p r e p a r a t i o n o f 2-phenylsulphonylaziridines ( 1 7 6 ) by a n a n a l o g o u s p r o c e d u r e . 12' Two r e l a t e d m e t h o d s f o r t h e p r e p a r a t i o n of a z i r i d i n e s by r i n g c l o s u r e of a - c h l o r o - E - l i t h i o s p e c i e s h a v e a l s o a p p e a r e d : Mauz4 h a s r e p o r t e d t h e s y n t h e s i s of aza-I-bicyclobutanes

( 1 7 9 ) by r e a c t i o n o f

a z i r i n e s ( 1 7 7 ) w i t h gem-chloro-(alky1)allyl-lithium r e a g e n t s ( 1 7 8 ) , '30 a n d De Kimpe e t a l . h a v e p r e p a r e d a z i r i d i n e s ( 1 8 1 ) by a d d i t i o n o f m e t h y l - l i t h i u m t o a - c h l o r o i m i n e s

(1801,

a l t h o u g h t h e homologated i m i n e s ( 1 8 2 ) are a l s o produced i n t h i s r e a c t i o n by a c o m p e t i n g h y d r i d e s h i f t o r 1 , 2 - e l i m i n a t i o n mechanism.

'

2- and 5-N,N,N-trimethylhydrazonium i o d i d e s ( 1 8 3 ) h a v e been reduced t o s a t u r a t e d or a,B-unsaturated

a z i r i d i n e s ( 1 8 4 ) and ( 1 8 5 )

r e s p e c t i v e l y by sodium bisC2-methoxyethoxylaluminium h y d r i d e : ( 1 8 4 )

o r ( 1 8 5 ) c a n be p r o d u c e d s e l e c t i v e l y d e p e n d i n g upon r e a c t i o n c o n d i t i o n s , a n d y i e l d s a r e g e n e r a l l y h i g h e r t h a n t h o s e o b t a i n e d by r e d u c t i o n of t h e c o r r e s p o n d i n g o x i m e s . 3 2 E t h o x y c a r b o n y l n i t r e n e , w h i c h i s g e n e r a t e d by a - e l i m i n a t i o n f r o m

4-nitrobenzenesulphonyloxyurethane (NBSU), a d d s t o a l l y 1 e t h e r s ( 1 8 6 ) t o p r o d u c e a z i r i d i n e s ( 1 8 7 ) i n good y i e l d b e f o r e c h r o m a t o g r a p h y : no C-H i n s e r t i o n p r o d u c t s w e r e d e t e c t e d . 33

581

8: Saturated Heterocyclic Ring Synthesis

Ar

AyR H

(172)

(171 1

R1

R1

,COZEt N

1

II

1

, Ph3P

& /R -3

D

45

R4

R2, R3, R4 not all H

- 75 *I*

-

59 90 Scheme 20

0

11

N

1

Ar2

(0)"

II

-

(175) 42 100%

+

PhsYLi x (173)

R2

*b SOZPh

N 1

Ar

(176) 72

- 100

'/a

582

General and Synthetic Methods

H

-

Ph

H -90

2

OC

.-*THF

+ (R-CCFCH-CH,)Li (178) (177)

-

J

i, -90 'C, -40

Ph

OC

i i , H20

H 2*

R1

CH=CH,

(179) 10

R1 '$2R

H

-

- 46

O/o

R1

I

R1

MeLi

Ether

R2fN\ Me

+ Me

R2JMe

Me

Me C I

(180)

I-

(181) 40 - 7 5 'I0

(182) 25

- 50 '10

+

P 4 e 3 N

H Na (MeOCH2 C H2 0 I 2 A l H2 >

"

h

H R

3

R2

(183)

R'

(184) 2

4-

z

d

R3

- 95

"10

R

3 R3

(185) 0

- 98.10

583

8: Saturated Heterocyclic Ring Synthesis

Four-membered R i n g s . - N e w p r o c e d u r e s f o r t h e c y c l i z a t i o n of 3 - a m i n o p r o p a n o l s t o a z e t i d i n e s h a v e b e e n r e p o r t e d , b a s e d upon t h e M i t s u n o b u r e a c t i o n ; 134 N - b e n z y l a z e t i d i n e

( 1 9 0 ) , f o r e x a m p l e , c a n be

p r e p a r e d from a c i d s a l t s of t h e a m i n o - a l c o h o l

(188) i n good y i e l d .

Under t h e same c o n d i t i o n s t h e f r e e b a s e ( 1 8 8 ) r e a c t s t o g i v e o n l y t h e hydrazide (189). The N - t o l y l a z e t i d i n e

(192) h a s been p r e p a r e d from p - t o l u i d i n e

( 1 9 1 ) i n e x c e l l e n t y i e l d by a s i m p l e a l k y l a t i o n p r o c e d u r e w h i c h may h a v e g e n e r a l a p p l i c a t i o n . 135

Five-membered

Rings.-

Two r e v i e w s r e l e v a n t t o t h e s y n t h e s i s o f

five-membered n i t r o g e n h e t e r o c y c l e s have appeared t h i s y e a r : r i n g f o r m a t i o n by r e a c t i o n o f n i t r o g e n n u c l e o p h i l e s w i t h x - o l e f i n palladium complexes h a s been d e s c r i b e d i n a r e v i e w of p a l l a d i u m ( 1 1 ) - a s s i s t e d r e a c t i o n s o f mono-olef i n s ,

" and

a review

of' 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 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 i n c l u d e s r e f e r e n c e t o t h e s y n t h e s i s of f i v e - and s i x membered N - h e t e r o c y c l i c s y s t e m s . 37

'

The f o r m a t i o n o f s u b s t i t u t e d p y r r o l i d i n e s by 1 , 3 - d i p o l a r c y c l o a d d i t i o n of azomethine y l i d e s t o o l e f i n s c o n t i n u e s t o be a very popular a r e a f o r study.

Grigg e t a l . have published f u r t h e r

d e t a i l s , a n d some b a c k g r o u n d d i s c u s s i o n , on t h e g e n e r a t i o n o f s t a b i l i z e d 1 , 3 - d i p o l a r s p e c i e s f r o m i m i n e s o f a m i n o - a c i d e s t e r s by a 1,2-H s h i f t and s u b s e q u e n t t r a p p i n g w i t h o l e f i n s . 138 promoted c y c l o a d d i t i o n o f !-(phenylthiomethy1)amino-acid

A new b a s e -

esters

( 1 9 3 ) and o l e f i n s ( 1 9 4 ) t o p r o d u c e p y r r o l i d i n e s ( 1 9 5 ) h a s b e e n d e s c r i b e d by Imai e t a l . I 3 '

The r e a c t i o n p r e s u m a b l y p r o c e e d s

via

t h e i n t e r m e d i a c y of a 1 , 3 - d i p o l e a l t h o u g h r e g i o - and s t e r e o s e l e c t i v i t y a r e g e n e r a l l y low.

The same g r o u p h a s a l s o d e s c r i b e d

t h e p r e p a r a t i o n of 2 , 2 , 4 - s u b s t i t u t e d

pyrrolidines with high

r e g i o s e l e c t i v i t y by two c o m p l e m e n t a r y 1 , 3 - c y c l o a d d i t i o n p r o c e d u r e s , s t a r t i n g f r o m t h e trimethylsilylmethyLamine d e r i v a t i v e ( 1 9 6 ) (Scheme 2 1 ) . I 4 O S e v e r a l new m e t h o d s f o r t h e g e n e r a t i o n and t r a p p i n g of nons t a b i l i z e d a z o m e t h i n e y l i d e s b a s e d upon a l k y l a t i o n - d e s i l y l a t i o n sequences have been d e s c r i b e d .

N-(Trimethylsilylmethyl)aminomethyl

e t h e r s ( 1 9 7 ) a r e e a s i l y p r e p a r e d and f u n c t i o n a s e x c e l l e n t azomethine y l i d e p r e c u r s o r s t o produce, a f t e r t r a p p i n g w i t h electron-deficient

olefins (198), the substituted pyrrolidines

( 1 9 9 ) s t e r e o s p e c i f i c a l l y and i n h i g h y i e l d . I n two u s e f u l e x t e n s i o n s o f known m e t h o d o l o g y , 1 , 3 - d i p o l a r s p e c i e s h a v e a l s o b e e n

General and Synthetic Methods

584

X' hPii , + - l 4? - - ) HO

HO

I N t i

Ph

Ph

v

v

X-

X=BFL, 51 ' l o X =Br, 40 'lo

(189)

(190 1

Reagents: i, Et02CN=NC02Et,

M

e

o

N

H

Ph3P; i i , HX

Z + Et<

OTs OTs

HMPA, A NaHC03

E t < N o M e

(191)

/

M\e..

(192) 99.6 ' l o

C H,CO, Me CHZSPh

(193)

\ C ,=C,

/

(194)

N a H , HMPA / DME

a C1 O z M e Me

-

(195) 47 84 ' l o

\

,C=C,

/

= HZC=CHCOzMe, PhCH=CHCOzMe, PhCH=C(C02Me)2

581

8: Saturated Heterocyclic Ring Synthesis

\

iii

1

Ph

R = H or SiMe3

I

90

- 100 '/*

R e a g e n t s : i, BuLN+F- c a t , j ii, CH2=CHX; iii, CF3C02H c a t . or CF3S03SiMe3 c a t .

Scheme 21

R'

I

Me,SiCH,NCH,

CF3S03SiMe3

OR2

MegSiI / CsF

(197) (199) 47-91 q/'

586

General and Synthetic Methods

generated from N-(benzylidene)trimethylsilylmethylamine (200) and trapped with electron-def icient olef ins to give 1 J _ - a l k ~ l - 'o~r~ N - u n s ~ b s t i t u t e d l pyrrolidines ~~ as mixtures of diastereomers in generally good yields (Scheme 22). Full details have also appeared from Padwa et al. of the generation of azomethine ylides from immonium salts of amides, thioamides, and vinylogous amides by caesium fluoride-induced desilylation, and their subsequent reaction with added dipolarophiles to produce five-membered nitrogen heterocycles. 144 N-Substituted and a,a-disubstituted amino-acids have been shown to react with carbonyl compounds to generate 1,3-dipolar species which can be trapped both inter- and intra-molecularly to produce bridgehead nitrogen and spirocyclic products in good yield. 145"46 This novel decarboxylative transamination reaction is illustrated by the preparation of cycloadducts (204) from the reaction of pyridine-3-carbaldehyde (201) and the carbocyclic amino-acids (202) in the presence of N-phenylmaleimide ( 2 0 3 ) . A similar reaction has also been described by Wang et al. as the key step in a stereospecific synthesis of (2)-lycorane (2051, and further details have appeared of the synthesis and intramolecular Zycloaddition of related stabilized iminium ylides formed by A full report reaction of aldehydes with sarcosine ethyl ester. 14' 3 f the synthesis of substituted pyrrolines from the reaction of Dhotogenerated vinyl cations with azide anion has also appeared. 1 4 9 3i- and tricyclic pyrrolidines (207) have been prepared by a 'opper(I)-catalysed photobicyclization of N,N-diallylcarbamates (206). I 5 ' The corresponding N-formyl and N-acetyl derivatives were inert under the reaction conditions. The intramolecular Diels-Alders reaction of 1,2-diazines has Ieen applied to a general synthesis of substituted indolines :208),15' and a new route to pseudotropine (210), and other tropane ilkaloids, involving a [4+2] cycloaddition of nitroso-compound :209) followed by intramolecular SN2 displacement has been lescribed by Iida et al. (Scheme 23). 152 Reinhoudt and his group have published further details of the synthesis of five- and six-membered benzo-fused nitrogen ieterocycles by thermal rearrangment of substituted 2-vinyl-Qlialkylanilines, 153 and have extended the scope of this reaction to .nclude the preparation of hydroxymethyl-substituted ,etrahydropyrrolo[l ,2-a]indoles. 15' The formation of N-heterocycles by acid-catalysed cyclization of

8: Saturated Heterocyclic Ring Synthesis

587

/ 'c=c(

f

/

*

HMPA, r.t., H20 ( 1 eq.) AcOH ( 1 eq.)

t $ PI h H 6 5 100 *la

-

/

/

>=C,

PhCH=NCH2SiMe3

\

(200)

\

>C=C,',

RX

HMPA, 80

OC

= electron -deficient olef in

, I

R 45 -02

RX = alkyl halides or tosylates

Scheme 22 Ph

qCHO

I

(203)

0 0

N

I

Ph

+

DMF, 90

(201)

(202) n

OC

= 1 or 2 (204) n = 1, 6 0 % n = 2, 5 0 *Ir

PhCHzNHCH2CO2 H HN ( SiMe3 1 2 , Toluene

'

P& 0

L(

f

Ph 2 5 *I*

*la

588

General and Synthetic Methods

m N C 0 , E t

(207) 50 -76 'lo

( 206 1

R2

R2

A _____)

150 -250 OC

I

I

C0,Me

C0,Me

(208) 72 - 92 '1.

R' OCOPh

OH N-H

(209)

Cl'

C 1-

I

H

R' =OCOPh, R2= H 79 R' = H,R2=OCOPh

il

iii, iv

72O l e OCOPh

I v, v i

to,

-

Et

R e a g e n t s : i, CCL4, EtOH (3:2),-20 'C, 2 weeks; i i , H z , P d / C , MeOH; iii, EtOCOCl, a q . N a 2 C 0 3 , CHCL3, 0

OC

--+r.t.;

iv, SOCLz, Py, CHCL3, 0 OC

HMPA, 0 - 5 OCi vi, L i A l H 4 , THF, r e f l u x

Scheme 23

r e f l u x ; v,

ButOK,

benzene -

8: Saturated Heterocyclic Ring Synthesis

5 89

-N - a c y l i m i n i u m

i o n s a n d r e l a t e d s p e c i e s c o n t i n u e s t o be a s u b j e c t o f i n t e r e s t t o s e v e r a l groups. P r o c t o r and c o - w o r k e r s h a v e p u b l i s h e d d e t a i l e d s t u d i e s of t h e u s e of chloroalkenylamines i n t h e s y n t h e s i s o f 5,.5- a n d 5 , 6 - f u s e d n i t r o g e n h e t e ’ r o c y c l e s a n d shown t h a t t h e reaction has useful but limited application. Thus, c y c l i z a t i o n of h y d r o x y l a c t a m ( 2 1 1 ) g a v e t h e a c e t y l p y r r o l i z i d i n e ( 2 1 2 1 , a l b e i t i n low y i e l d . A f u l l r e p o r t h a s a l s o appeared of t h e c a t i o n i c cyclization of ketene d i t h i o a c e t a l s t o provide a general synthesis of p y r r o l i z i d i n e , i n d o l i z i d i n e , and q u i n o l i z i d i n e a l k a l o i d r i n g s y s t e m s . 156

Two r o u t e s t o t h e p y r r o l i z i d i n e a l k a l o i d s ( + ) - t r a c h e l a n t h a m i d i n e (213) and ( f ) - i s o r e t r o n e c a n o l (214) have been r e p o r t e d , b o t h based upon a n o d i c a - m e t h o x y l a t i o n a s t h e k e y s t e p (Scheme 2 4 ) . 1 5 7 , 1 5 8 S e v e r a l o t h e r c a t i o n i c c y c l i z a t i o n r o u t e s t o five-membered n i t r o g e n h e t e r o c y c l e s h a v e b e e n r e p o r t e d t h i s y e a r . Gawley e t a l . have published a f u l l account of t h e s y n t h e s i s of a l k y l i d e n e A I-pyrrolines

by a c i d - c a t a l y s e d c y c l i z a t i o n o f f u n c t i o n a l i z e d a l k e n y l oximes , 59 and Rapoport and co-workers have d e s c r i b e d f u r t h e r a p p l i c 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 Mannich r e a c t i o n t o t h e s y n t h e s i s o f a z a - b i c y c l o a l k a n e s . 160 Barluenga e t a l . have r e p o r t e d d e t a i l e d m e c h a n i s t i c and s y n t h e t i c s t u d i e s o f t h e s y n t h e s i s o f N-aryl-azabicyclononanes by a n aminomercuration procedure s t a r t i n g from c i s , c i s - c y c l o - o c t a - l , 5 diene16 and have a l s o d e s c r i b e d t h e 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 cis-2,5-dimethyl-~-tosylpyrrolidine ( 2 1 7 ) by sulphonamidomercuration-demercuration o f d i e n e s ( 2 1 5 ) o r ( 2 1 6 ) .

A g e n e r a l s y n t h e s i s o f ~-tosyl-2-halogenomethyl-3-

h y d r o x y p y r r o l i d i n e s ( 2 1 9 ) h a s a l s o b e e n r e p o r t e d , b a s e d upon a h a l o g e n o s u l p h a m i d a t i o n p r o c e d u r e s t a r t i n g from s u l p h o n a m i d e s (218).163 d e g r e e o f s t e r e o s e l e c t i v i t y and works f o r s e v e r a l examples where c y c l i z a t i o n o f t h e a n a l o g o u s a m i d e s or c a r b a m a t e s was t o t a l l y unsuccessful. I n a similar t y p e o f c a t i o n i c c y c l i z a t i o n p r o c e d u r e T o s h i m i t s u e t a l . h a v e shown t h a t o r g a n o s e l e n i u m - b a s e d c y c l i z a t i o n p r o c e d u r e s c a n b e a p p l i e d t o t h e s y n t h e s i s o f y - a n d 6-lactams from a l k e n a m i d e ~ . ’ ~Lactams ~ (222) and (2231, f o r example, are produced i n e x c e l l e n t y i e l d a s m i x t u r e s of s t e r e o i s o m e r s f r o m p r e c u r s o r s (220) and ( 2 2 1 ) . I s o i n d o l i n i m i n e s ( 2 2 5 ) h a v e b e e n p r e p a r e d i n good y i e l d by t h e i n s e r t i o n o f i s o c y a n i d e s i n t o t h e m e t a l - c a r b o n bond of t h e o r t h o p a l l a d a t e d primary benzylamine complex ( 2 2 4 ) .

General and Synthetic Methods

590

3 5 '1. combined yield

.1

Cl

conc. H2SO4

(211)

(212) 60 ' h

A

- 2e

C02 Me

0

CO, Me

I

iii, i v

ovrall yield 60 *lo

(213)

I

- 2e

CO;,C Hz Ph

@:&Me

t

(214) v i - i x , iv

I COZCHZ Ph overall yield 14°/0

CO,CH,Ph

CO, Me

Reagents : i, MeOH; ii, ALCL3; iii, DMSO, LiCl, r e f l u x ; i v , LiAlH4; v , Me02CCH2CH(C02Me)2,TiC14i vi, NaOH, then HCL; vii, AcOH, H20,

A; viii, EtOH, H2S04; i x , H 2 / R a - N i , E t O H

Scheme 24

8: Saturated Heterocyclic Ring Synthesis

59 I

t J

or

(216)

TS

(217) 80°/"

Hoe:: R'

N B S , N I S , or

R3'

& l

X '.R2

12, NaHC03

I

(218)

is X = Br or I (219) 5 3 - 100 "lo cis : trans ratio 3 9 : 1

NHBu"

-w PhSeCl

PhSe

MeCN r . t . 1 h

0

0

(220) R = H

(222) R =H,

R = Me

(221)

87%

(223) R = Me, 94

L

(224)

0 HC--

Pdo

R = Ph or CMe3

+

j' I'

592

General and Synthetic Method.!

Several examples of the synthesis of nitrogen heterocycles by cyclization involving 2- or N-alkylation o r -acylation steps have appeared this year. Pinnick and co-workers have reported a new and general synthesis of 4-alkoxy- n3-pyrrolin-2-ones (227) and tetramic acids (228) by treatment of 4-bromo-3-alkoxybut-2-enoates (226) with primary amines o r ammonia. 166 A useful method for the preparation of 2-substituted pyrrolidines (230) based upon the novel Grignard reagent (229) has appeared, 167 and a high-yield synthesis of 2-(diphenylphosphinoyl)pyrrolidines (231) has also been reported, thus providing easy access to heterocyclic enamines (232) by subsequent Horner-Wittig reaction. 168 Meyers and co-workers, in a continuation of their studies on the reaction of a-amino-carbanions generated from formamidines, have described a three-step synthesis of l-azabicycloalkanes (234) The involving alkylation of cuprates (233) as the key step. same group has also reported the preparation of fused five- and six-membered nitrogen heterocycles by regioselective C-I alkylatior of 6-carboline formamidine. I 7 O Overman and Burke have shown that the cyclic imines (237) can be produced in good yield by reaction of the nitriles (235) o r (236) with di-isobutylaluminium hydride, 17' and have used this reaction in a synthesis of the Amaryllidaceae alkaloid (+)-epielwesine. 172 Four interesting ring expansion o r contraction routes to fivemembered nitrogen heterocycles have been reported. Alper et al. have described a novel and stereospecific synthesis of imides (240) from azirines (238) and carbanions (239), mediated by hexacarbonylmolybdenum. 173 A possible mechanism for the conversior is shown. Yamamoto and co-workers have reported a novel variant of their rearrangement-alkylation route to nitrogen-containing heterocycles from oxime sulphonates and organoaluminium reagents. Ring expansion of hydroxylamine carbonates (241) leads to heterocycles (242) regiospecifically and in high yield. 174 An advantage of this method compared with that based upon rearrangement of oxime sulphonates is that it offers the possibility of an asymmetric synthesis of a-alkylated amines by incorporation of chiral functionality into the N-substituent. Thus, in a preliminary experiment, the cyclic carbonate (243), derived from phenylglycine, was converted into piperidine (244) with some degree of diastereoselectivity. A new route to the hexahydropyrrolidino[2,3-dlcarbazole system

593

8: Saturated Heterocyclic Ring Synthesis

0

R2 OR'

I I

*

(226)

CNR3 conc H2SO4

Br CH C=CH CO, R' R3NH2

R'O

04 N R 3

R2

(227) 42

- 74

\ / +MgBr

0A N N M 'OMe e

>

CHzCL2

+

Si

-rNCs) / \

(229)

0

II

+ Ph2PCL

'lo

-

R

i, EtOH,HCL

HN

ii, NaBH4 iii, H +

( 2 3 0 ) 48 -71%

R'

I

Ph,PCH,N(CH,),Cl

R10N-O

R2

( 2 2 8 ) R2=H,R3=PhCH2, 9 2 "lo

4 -70 OC THF

A' (231) 80

- 90%

( 2 3 2 ) 5 7 -87%

n = l or 2

(233)

( 2 3 4 ) 32 - 90 '10 overall

General and Synthetic Method5

594

HAL BU '2 -70 OC 4 r . t .

.1

NaF, H 2 0

(237) n = 1 or 2

54 - 8 6 '1.

H

(238)

(240)27-68 ' l o

t

t

0

11

R3\ ,C-OEt CH

i

n

I

R, T - - - M O ( C O ) ~

R2

H

595

8: Saturated Heterocyclic Ring Synthesis

C T I I

Ph

0-25OC

r N \ 0 C O 2 Et

Ph (241) n = 1-3,5, or 9

Me,Al .-

6I "lo

PhJj OH

(243)

R = E t or Me

(244)22% diastereomeric excess

J CF' 4

0-q ROzC

C02R

Scheme 25

CO2R

596

General and Synthetic Methods

(245) has been described, based upon the rearrangement sequence shown in Scheme 25,175 and the A3-pyrrolines (247) and (248), useful precursors for 4-amino-4-deoxy-D,L-ribose derivatives, have been prepared by base-catalysed ring contraction of tetrahydropyridazine (246). 176 Tseng et al. have reported the preparation of 2-pyrrolidinones (250) by the cyclization of N-allylhalogenoacetamides (249) in the presence of ferrous salts, presumably via a free-radical mechanism, 177 and hart and co-workers have published full details of their studies of the generation and intramolecular addition of a-acylamino radicals to olefins and allenes to give pyrrolizidinones and indolizidinones. 178 The same group has a l s o published two syntheses of isoretronecanol (214) using this methodology. 17’ 3-Pyrrol-2-ones (254) and (255) are formed by reaction of N,Ndialkylpyruvamides (251) with diethyl (diazomethy1)phosphonate (2521, via the alkylidene carbene (253). 8o Although combined yields of (254) and (255) are acceptable, these products are always accompanied by significant amounts of the but-2-ynamides (256) and the reaction is probably only useful synthetically in cases where the pyruvamide is symmetrically substituted. Five-membered Rings Containing More than One Nitrogen.- Further details have appeared of the synthesis of the imidazo[1,2-a]indolespirolactone ring system of the tryptoquivalines by oxidative double cyclization, 18’ with specific application to the total synthesis of (+)-tryptoquivaline. 182 Pyrazoline derivatives (259) have been prepared in good yield by reaction of the dianion of acetophenone N-ethoxycarbonylhydrazone (257) with a-chloroketones (258), 183 and tetrahydropyrazolo[l ,5-a]pyridine derivatives (261) have been produced in generally good yields by cycloaddition of I-aminopyridinium salts (260) with electron-deficient olefins in the presence of base. 184 Two novel heterocyclic systems containing five-membered rings with three nitrogens have been reported. Huth et al. have prepared the triazolo[1,2-al-triazole-l,3-diones (264) by reaction of substituted oxazoles (262) with PTAD (263), 185 and several derivatives of the tetrahydro-l~-pyrrolo[1,2-b]~1,2,4]triazole2(3H)-thione ring system (268) have been prepared in low yield by a double cyclization reaction of thiosemicarbazides (265) with 186 y-chlorobutyrophenones (266), 2 the thiosemicarbazone (267).

597

8: Saturated Heterocyclic Ring Synthesis

“C

_____) THF, LDA, -45 2 . 2 eq.

+

@r02Et

tE2;$(

NHC02Et

NHCO2Et

(2461

.UX

Y

I

Fe C Lz

R2-C-X CH=CH, o A N / C H ZI

____)

0

diglyme, A

I

R1

(250) 30 - 83.10 R’ = allyl,Ph or 3 -CF,C,H4

x

= C l or Br Y = CL,Br or H R * = H or ci

(249)

0.

0

II

MeC-fi-NyRZ

(EtOZPCHN2

(R1

(252)

O

,y“’

Me $R’

0

+

+ MR ? I$e‘

0

R3

43 - 6 3 “lo

R

General and Synthetic Methods

598

EtO2CNH

CO2Et

\

i, 2

Bu”Li, -78

ii, R’COCHCLR’

Ph A M e

N-N’

*C, THF

>

(258)

Ph

iii,H+

( 2 5 9 ) 39 - 6 2 O l 0

(257)

MeCN, H20

Ph

Ph

I

R2

NH* H

B F ~

(261) R1= H or C02Et

(260)

R2=CN or C02Et

-

30 92 ‘lo

4

N

Ar dioxane ____)

0

R

(263)

( 2 6 4 ) 20

R’

R2

O

- 60 ‘lo R2

R’

I

I PA

+ A

H~NNCSNHR’

+ A t CO (CH,),CL

(266)

(267)

-

( 2 6 8 ) 10 46 ‘lo

599

8: Saturated Heterocyclic Ring Synthesis R e a c t i o n o f n i t r i l i u m s a l t s ( 2 6 9 ) w i t h a z i d e s ( 2 7 0 ) g i v e s good y i e l d s of (271).

1,4,5-alkyl-

or -aryl-substituted

tetrazolium salts

R e d u c t i o n o r a l k y l a t i o n of t h e s e s a l t s l e a d s t o f o r m a t i o n

of t h e c o r r e s p o n d i n g t r i - o r t e t r a - s u b s t i t u t e d

tetrazolines

(272) Six-membered

R i n g s C o n t a i n i n g One N i t r o g e n . -

R e v i e w s on t h e

s y n t h e s i s and p r o p e r t i e s of h i n d e r e d ( 2 , 2 , 6 , 6 - t e t r a a l k y l ) p i p e r i d i n e s 88 a n d s y n t h e t i c a p p l i c a t i o n s o f t h e m o d i f i e d P o l o n o v s k i r e a c t i o n as an approach t o s u b s t i t u t e d p i p e r i d i n e s h a v e a p p e a r e d t h i s y e a r . The s y n t h e s i s o f t e t r a h y d r o p y r i d i n i u m

s a l t s and t h e i r a p p l i c a t i o n t o a l k a l o i d s y n t h e s e s h a s a l s o been reviewed. Several novel cycloaddition or electrocyclization routes t o sixmembered n i t r o g e n h e t e r o c y c l e s h a v e b e e n r e p o r t e d .

Ihara et al.

have d e s c r i b e d a novel s y n t h e s i s of b e n z o [ a ] q u i n o l i z i d i n e s an intramolecular Diels-Alder u n s a t u r a t e d amides ( 2 7 3 ) .

'''

( 2 7 4 ) by

r e a c t i o n , s t a r t i n g from t h e a,@-

stereoisomers i n moderate y i e l d s , p o s s i b l y

a transition state

i n v o l v i n g z i n c c h e l a t i o n w i t h t h e e s t e r and amide oxygens. Indole[a]quinolizidines

c a n a l s o b e p r e p a r e d by a s i m i l a r r e a c t i o n

sequence. T e t r a h y d r o q u i n o l i n e d e r i v a t i v e s (278) and ( 2 7 9 ) have been p r e p a r e d i n low y i e l d by a L e w i s a c i d - c a t a l y s e d

[4+21 c y c l o a d d i t i o n

r e a c t i o n of o l e f i n s ( 2 7 5 ) o r ( 2 7 6 ) w i t h i m i n e ( 2 7 7 ) , I g 2 a n d W e i n r e b and co-workers have p u b l i s h e d a t o t a l s y n t h e s i s of t h e s p e r m i d i n e a l k a l o i d a n h y d r o c a n n a b i s a t i v e n e by a p p l i c a t i o n o f t h e i r i n t r a m o l e c u l a r imino-Diels-Alder

methodology.

1 , 2 - D i h y d r o i s o q u i n o l i n e ( 2 8 1 ) h a s b e e n p r e p a r e d by a n o v e l procedure involving an intramolecular c y c l o a d d i t i o n of a z i d e (280) f o l l o w e d by a r h o d i u m - c a t a l y s e d

carbene insertion-ring

expansion

s t e p . 'g4 A new a p p r o a c h t o t h e s y n t h e s i s of N-acyl-1,2-dihydropyridines ( 2 8 4 ) h a s b e e n r e p o r t e d by Wyle a n d F o w l e r , b a s e d upon e l e c t r o c y c l i z a t i o n of I - a z a t r i e n e s ( 2 8 3 ) , which are formed i n s i t u by f l a s h vacuum p y r o l y s i s o f 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 ( 2 8 2 ) . 195 A new r o u t e t o t h e a l k a l o i d d e r i v a t i v e N - b e n z o y l m e r o q u i n e n e m e t h y l

e s t e r ( 2 8 7 ) h a s a l s o b e e n d e s c r i b e d , u s i n g as t h e k e y s t e p a s t e r e o s p e c i f i c C l a i s e n rearrangement of t h e E - s i l y l k e t e n e acetal d e r i v e d from a z a l a c t o n e ( 2 8 5 ) t o c o n s t r u c t t h e d e s i r e d d i s u b s t i t u t e d p i p e r i d i n e r i n g system (286).

cis-

General and Synthetic Methods

600

R1Cd-R2

R3N3 (270)

R’

R’

A

R2-N

\

N-N

A’

NaBH4 ( R 4 = H )

N-R3

R4MgX or R4Li

I

(R~*H)

A(271 1

(269)

R4

’ RLN\N=N N-R3 i

(272) 40- 90 ‘/o

Me0 Me0

(273) NEt3

Me0

Me0

Me0

Me0

J Me0 N ,=

M e 0W

Et 0 2 C

y

O

?/\

R’

I? ( 2 7 4 ) 41-5Z0/o

BF3.Et20

&0r2 /

R1o + PhCH=NPh

*-

A

R20

(277)

\

‘

Me

Ph

H A

(278) R 1 , R 2 = Me, 30%

(279) R1+R2= CH2, 16 ‘1.

8: Saturated Heterocyclic Ring Synthesis

601

CO Et +tN-

r

CO, Et

(281)

53%

-

OCO, Me

L?K"

A

0

R

(282)

(2841 3 2 -58 '/o

-

r

63

1

H% O Y R

7

1

RAO

LDA.1.2 eq.

But MqSiCl, 1.2 eq. T H E - 7 0 C'

*

PhAO (285)

Q

4

L

Ph

(286) 93"h

(287)

602

General and Synthetic Methods

Cyclization of N-acyliminium ions as a route to six-membered nitrogen heterocycles continues to be explored by several groups. Thus, Kano et al. have prepared the tetrahydropyrimidoisoquinoline derivative (289) and related compounds from ureas (288) in good yieldIg7 and Liao et al. have applied similar procedures to the synthesis of annelated hydantoins and 2-imidazolidinones. 198' A convenient entry into the quinolizidine and benzoquinolizidine ring systems h a s also been described, based upon anodic a methoxylation of the N-heterocycle precursors and subsequent 200 intramolecular Lewis acid-catalysed cyclization. Overman and his group have published a full report of the enantioselective total synthesis of pumiliotoxins B and 251D via stereospecif ic iminium ion-vinylsilane cyclizations ,20 and the indole alkaloid (-)-hobartine (291) has been prepared in good yield via a stereoselective biomimetic cyclization of imine (290) .202 Three useful modifications to existing procedures for the synthesis of tetrahydroisoquinolines and related heterocycles by electrophilic cyclization onto an aromatic system have been reported. The methylthio-group has been found to be a useful activating group for six different cyclization routes to the isoquinoline ring system and has the advantage over the methoxygroup that it can be readily removed after cyclization by nickel boride-induced desulphurization. Tetrahydroisoquinolines (292) and (293), for example, can be prepared in moderate yield under conditions where reaction does not occur in the absence of activating groups. 2 0 3 Pictet-Spengler condensation using activated alkynes has been shown to be a useful alternative to the standard reaction using carbonyl compounds: the 1,2,3,4-tetrahydro-~-carbolines (296) are produced in excellent yield from reaction of tryptamines (294) with electron-deficient alkynes (295) .204 The use of carbonyl partners in the reaction gave poor and irreproducible yields. Some simple tetrahydroisoquinolines have also been prepared in good yield by the reaction of arylethylamines with paraformaldehyde and formic acid at 40 O C , conditions which are milder than those normally employed in Pictet-Spengler cyclizations. 205 1,2-Dihydro-B-carbolin-4(3~)-ones (298) have been produced in good yield an acid-catalysed rearrangement of aminonitriles (297) .206 Carruthers et al. have synthesized 2,6-dialkylpiperidines (302) by intramolecular amidomercuration of carbamate (299), followed by

8: Saturated Heterocyclic Ring Synthesis

603

0

I1

RCH,CH, NHCNH

Et02C

(288)

R Me0

(289) 63%

(290)

M

e

s

p

N

f'

R

CF3C02H or HCL

(291)

64'/0

Mesq - qN R

R

(292) R=Ph, 75% ( 2 9 3 ) R = H, 51 "/o

General and Synthetic Methods

604

R4

I

R5 L

(295)

A

R’

(296) 76 -99.5’10

H2S04

~

O ‘c, 15 min ‘R2

I

A1

(298) 41-88’10

t NH

I

R’

H’,

H20

8: Saturated Heterocyclic Ring Synthesis

605

reductive trapping of the intermediate organomercurial (300) with electron-deficient olefins (301). 207 Yields are variable, however, and the products are formed as mixtures of‘ diastereomers. The trans-5-hydroxy-2-propylpiperidine (?)-pseudoconhydrine (303) has also been synthesized by an intramolecular amidomercuration procedure, followed by a ring-expansion sequence (Scheme 26) .208 Mercuric chloride-catalysed reaction of the propargyl ethers (304) with N-methylaniline (305) leads to formation of 1,4-dihydroquinolines (306), possibly via the mechanism shown. 209 An example of the formation of a nitrogen heterocycle by platinum-mediated ortho-functionalization of benzylamine has been described: 165 reaction of the platinum complex (307) with ethyl iodoacetate gives 3-0X0-1,2,3,4-tetrahydroisoquinoline (308) as the major product. Abe et al. have reported that cis-6-alkyl-2-methylpiperidines (310) can be prepared simply and in high yield by reductive aminocyclization of alkane-2,6-diones (309). 210 The products are formed as single isomers in all cases, making this a very useful synthetic method for compounds of this type. Marsden and MacLean have reported full details of the synthesis of the protoberberine ring system by condensation of cyclic imines with phthalide anions2’’ and have applied the same methodology to the synthesis of thiaprotoberberines.212 Meyers and his group have described procedures for the enantioselective alkylation of chiral formamidine derivatives of 1,2,3,4-tetrahydroisoquinolinesto produce I-alkyl-I ,2,3,4-tetrahydroisoq~inolines.~~~ The intramolecular version of this reaction leads to an enantioselective synthesis of benzoquinolizine (311) in good yield and extends the group’s other published work on the synthesis of fused six-membered nitrogen heterocycles by the same general intramolecular alkylative procedure. 16’ ’ 70 A convenient synthesis of 3,4-dihydrocarbostyrils (313) has been reported, based upon reduction-cyclization of the readily available o-nitrocinnamates (312) ,214 and 3,4-dihydropyridinones (315) have been prepared by the reaction of l-azabuta-1,3-dienes (314) with ethyl bromoacetate under Reformatsky reaction conditions. No products derived from 1,2-addition to the azadiene were detected. 215 Finally, two natural product syntheses involving formation of six-membered N-heterocyclic systems have been reported. Holmes

General and Synthetic Methods

606

C02Me (299)

COz Me ( 300)

(302) X =CN,COZEt, or COC7H15 25 -75.1,

(303) 56.1. overall

Scheme 26

8: Saturated Heterocyclic Ring Synthesis

+

ROCH2CECH

607

PhNHMe

(304)

(305)

(306 1 4 6 - 89%

Ph\ N / M e

I

R0CHz-- C -CH2-C-Me

II

N+ \Ph

’

Me

I

11 Ph\+/Me NH

ROCHz-C=CH

I

Me

N N , ~

t

CHzOR

I

-C-Me

I

- PhNHMe ____)

j

G$20R I

CH20R

CHrOR

Me

1

i, HCI ii, NazC03

608

General and Synthetic Methods

et al. have prepared the spiro-amino-ketone (316) as an intermediate in their formal synthesis of (')-perhydrohistrionicotoxin,216 and the 1 6 ~ -and 1613- epimers of (~)-3-hydroxy-16,17-butanomorphinan (317) have been prepared by a novel route involving the intramolecular alkylation-ring expansion sequence shown in Scheme 27. 217 Six-membered Rings Containing More than One Nitrogen.- Two research groups have described new routes to the tetrahydropyridazine ring system by [4+2] cycloaddition reactions. Two papers by Hunig and co-workers describe Diels-Alder reactions with inverse electron demand, where the protonated azines (318) serve as electrondeficient dienes and react with electron-rich olefins (319) to give heterocycles of general type ( 320 ) . ' For example , reaction of the trimer of dihydropyridazine (321) with cyclopentadiene gives the adduct (322) in good yield. Nelson et al. have invsstigated the potential of protonated azo-compounds (323) in the Diels-Alder reaction and found that these species can be trapped with dienes to yield stable adducts (324) in good yield. 220 Under the same conditions the unprotonated diazenes fail to react with cyclohexadiene. The hexahydropyrrole[l,2-~]quinazoline derivative (326) has been prepared by Reinhoudt and co-workers by thermal isomerization of imine (325). 221 A similar process also afforded a tetrahydropyrrolo[l,2-a]benzothiazine derivative by cyclization of the thiocarbonyl analogue of imine (325). Reaction of 6-sulphinyl or f3-sulphenyl enones (327) with di-imines (328) provides a simple route to Il2-dihydropyrimidine derivatives (329), albeit in only moderate yield.222 A one-step, biomimetic synthesis of the dihydropyrimidinone unit of syncarpurez (332) has been accomplished from syncarpic acid (330) and the l-carboxamido- A'-pyrrolinium ion (331 1 , formed in situ from citrulline by treatment with N-bromosuccinimide .223 The 2,3,8-triazabicyclo[3,3,llnon-3-ene (335), a new heterocyclic system, has been synthesized in good yield by basecatalysed isomerization of tetrahydropyridine (333) to the enamine (334) and subsequent intramolecular cyclization of the hydrazone derivative. 224 An interesting synthetic route to novel annelated 1,2,4triazines has been reported. Reaction of 2-(l-hydroxyalkyl)indole derivatives (336) with the Mitsunobu reagent DEAD-

8: Saturated Heterocyclic Ring Synthesis

609 H

NaBbCN, NH4Br MeCOCH2CH2CHzCOR

MeOH, r . t .

(3091

(310) 71-91'ir

Ph

H

S-(311) 70°/090'1.

e.e.

R'mcHo

R2

NO2

+ Ph,P =C

A

__j

Ph H

/ R3

(312 1

'C02Et

PhCH=CH-CH=NAr

(314)

+

BrCHZCqEt

(313) 45- 94% overall

- &* Zn dust, PhH

A

1

Ar

(315) 16-90%

General and Synthetic Methods

610

2

Z = PhCH20CO

(316)

H

iv

M eO

1,

Meo+

v, v i

HO

Reagents: i( (CF3CO)zO; ii, m-CIC&C03H,

iii, NaBH4 ; iv, PBr3; v, H 2 , PtOZ

Scheme 27

:

v i , BBr3

61I

8: Saturated Heterocyclic Ring Synthesis

I

BF4-

H

( 3 2 3 ) n = 1 or 2

C=NAr Me

(324) n = 2 , 97O1,

-118OC q Sdays TM e

H

I

H

CF3 (32 5)

0 R'

0

II -CCH=

II

C( R2 ) SR3

or

CF3

( 3 2 6 ) 66%

H N

R1

h;% phP R4

Ph ( 328)

*

PhH, 130 "c, 12 h,

Ph+Ph

sealed take

A4

(327)

( 3 2 9 ) 23

- 48'10

General and Synthetic Methods

612

0 (330)

Me

I

(331)

Me

KO H

(334)

a

Ph

H'

I

(335)

6770

613

8: Saturated Heterocyclic Ring Synthesis triphenylphosphine results in cyclization to give the 1,2-dihydro[1,2,4]triazino[4,5-a~indole-2-carboxylates

(337). 225

These can be converted into the corresponding 4-0x0-derivatives (338) by acid treatment. Pyrrolo[1,2-d][1,2,4]-triazines can also be prepared in the same way. Medium-ring Nitrogen Heterocycles.- Rings Containing One Nitrogen. 3,4,5,6-Tetrahydroazepino[4,5-b]indoles (341) have been prepared via a novel thermolysis route from vinyl azides (339). A possible mechanism is shown in Scheme 28: in some cases the intermediate enamines (340) could be isolated and shown to cyclize to azepinoindoles (341). 226 Preliminary results indicate that this cyclization is only successful if R~ = H. A convenient one-step synthesis of benzazepines (343) by anodic cyclization of enaminones (342) has been described ,227 and Ssnchez et al. have reported a total synthesis of lycoramine which features a further application of their modified Tscherniac-Einhorn amidoalkylation procedure to form the requisite tetrahydrobenzazepine

-

Two interesting ring expansion reactions have been used in the synthesis of medium-ring azaheterocycles. The 0x0-lactams (345) have been prepared by an iron(I1)-catalysed radical cleavage of oxaziridines (344),229 and photolysis of pyrrolo[2,1-a]isoquinolinium salt derivatives (346) gave the hexahydrobenzazonine derivatives (347) in moderate yield .230 A biomimetic synthesis of the dibenz[d,f]azonine alkaloids neodihydrothebaine (349) and bractazonine (350) from thebaine (348) has also been reported.231 Rings Containing Two Nitrogens. Dihydrodiazepines (353) have been prepared in excellent yield by cycloaddition of diazoalkanes (352) to diazobicyclohexene (351) followed by nitrogen elimination and thermal ring expansion .232 A ring-expansion sequence has also been used to prepare tetrahydro-1,2-diazepine derivatives (355) by treatment of isoxazoloC3,4-dlpyridazin-7(6~)-ones (354) with base.233 Kellog and co-workers have applied their caesium carbonate-DMF macrocyclization procedure to the synthesis of a range of azamacrocycles of general structure (357) from bis-tosylamide derivatives (356) .234 High-dilution conditions are not required, and the tosyl groups are readily removed with sodium amalgam.

614

General and Synthetic Method:

DMF

A

( 339)

R' =

(3411

CH20Me

R 3 = H, 60'1.

R2= H

R 3 = Me, 5'10

R3 = H or Me

(340 1

It

COZEt [1 61H

b

Q-+==f3

Scheme 28

MeOH, NaC104

elec tro I ysis

Me0

( 3 4 3 ) X = CH2, 4Oo/e X=-CH2CMe2 -, 43'1'

OH

0

OH

(345)

=3-6 30 - 42 '10 n

615

8: Saturated Heterocyclic Ring Synthesis Me

i

i , h W 2 5 0 nm), R20H ii, basification

Me0

Me0

( 3 4 6 ) R = H, D, or Me R = H or Me

Meoq -0

1

reduct ion

Me0

1

reduction

M eO

HO

Me0 OMe

(350)

(349)

616

General and Synthetic Methods

a”Eo+,y R

R( 3Z5C2N)Z ,

N E ‘

‘E =H, Me, or Ph

(351) R E =COzMe

N

E‘

cl

(353) 80 - 95’10 Ph

-

(355 1 50 72.18

TsNH (chain lo NHTs

i , CszCO3, DMF

11,

Br(chan)b&

Ts

I

(chain la

(chain)b

(356

1 Ts

(357) a = 5 or 10 b = 4- 6,10, or 16 2 5 - 95’10

8: Saturated Heterocyclic Ring Synthesis

617

Reaction of diphenyl-l,2,4,5-tetrazine (358) with the enolate or enamine derived from cyclobutanone provides a simple route t o 1,2diazocines (359) via a cycloaddition-ring expansion mechanism. 235

5 B-Lactams, Penicillins, Cephalosporins, and Related Compounds

A review on the stereospecific construction of chiral B-lactams has appeared .236 The 8-lactam (364) has been prepared via a novel route involving stereoselective formation of the B-amino-acyl complex (363) from the enolate (361) of iron acetyl complex (360) and imine (362). Addition occurs from the least hindered face of (361) to give (363) with >98% stereoselectivity. 237 Ley and co-workers have continued their studies of the use of n-allyltricarbonyliron lactone complexes in 8-lactam synthesis by applying the method to a formal total synthesis of ( + ) - t h i e n a m ~ c i n . ~Full ~ ~ details have also appeared of the synthesis of 8-lactams by reaction of chromium carbene complexes with imines. 239 A novel high-yielding synthesis of thietane-fused 8-lactams (366) has been reported via a photochemical intramolecular [2+21 cycloaddition of N-(thiobenzoy1)methacrylamides (365). 240 Standard desulphurization and oxidation chemistry can be carried out on products (366) to give B-lactams (367) and (368), respectively. Kaneko and co-workers have described a useful route to monocyclic 24 1 substituted 8-lactams by photoisomerization of pyridones (369). Although this method is well known, cleavage of bicyclic B-lactams (370) generally involves ozonolytic cleavage of the C-5=C-6 double bond. 4-(2'-Hydroxyethyl)azetidinones (372) have now been prepared by an alternative cleavage procedure involving reduction of (370) followed by a retro-aldol reaction. A procedure for isolating (371 ) ( R 1 ,R2,R3 = H) has also been described.242 Padwa et al. have published full details of the synthesis of B-lactams by photochemical o r thermal ring contraction of isoxazolidines. 243 Optically pure B-lactams (375) have been obtained by a highpressure [2+21 cycloaddition reaction of toluene-4-sulphonyl isocyanate (374) with glycals (373). 244 This reaction has been investigated by several groups in the past but is relatively unsuccessful at normal pressure. In this case, the reaction is

General and Synthetic Methods

618

Ph

' Ph

Ph (359)

(358)

X =OH, 40'1. X = NEt,,SO'/r Reagents: i , MeO',

MeOH, A; ii, HNEt2,

A

H

Q '.!/ I o c q y o PPh3 (360)

(361)

I

I '

orCAN CuCl2

Ei;r$NHPh

'Ph (364)

H

Ph

619

8: Saturated Heterocyclic Ring Synthesis

Me

Me ( 3 6 6 ) 55-96’1.

(365)

m -CIkH4C03H R = CH2Ph

Me

(368)

(369)

( 3 7 2 ) 6 4 - 8 0 % overall

L

(371 1

R3

J&+

R3

R* 10 k b a r

+

__i,

r . t . ether

R’

(373)

R’ Q-Ts 0

(374) ( 37 5 )

60 -77 *la

620

General and Synthetic Methods

r e g i o - and s t e r e o - s p e c i f i c : t h e C-3 a c e t o x y - g r o u p ,

t h e isocyanate always adds t r a n s - t o

and y i e l d s a r e g o o d .

S e v e r a l p o t e n t i a l l y u s e f u l v a r i a t i o n s of t h e s t a n d a r d a c i d c h l o r i d e - i m i n e r o u t e t o B-lactams have been r e p o r t e d t h i s y e a r . 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 h a s b e e n shown t o b e a n e f f i c i e n t c a r b o x y l g r o u p a c t i v a t o r i n t h e s y n t h e s i s of m e t h o x y c a r b o n y l v i n y l amino-8-lactams

f r o m Dane s a l t s a n d i m i n e ~ a n d~ i~n ~a s i m i l a r w a y ,

p h e n y l (N-me thyl-N-pheny l p h o s p h o r a m i d o c h l o r i d a t e ,2 4

s a c c h a r i n , 247

and N ,N-dimethylchlorosulphitemethaniminium c h l o r i d e 2 4 8 h a v e b e e n used i n mild one-pot s y n t h e s e s of s u b s t i t u t e d B-lactams. C a r d e l l i n i e t a l . have confirmed t h a t 4-alkoxy-B-lactams

can be

p r e p a r e d from i m i d a t e s and a c i d c h l o r i d e s , i n t h e p r e s e n c e o f t r i e t h ~ l a m i n e , ~ a~n’d a f u l l r e p o r t h a s a p p e a r e d of t h e s y n t h e s i s o f s u b s t i t u t e d B-lactams by r e a c t i o n o f c h i r a l i m i n e s w i t h ac h l o r o i m i n i u m c h l o r i d e s . 250 Bose e t a l . h a v e 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 s t u d i e s o f t h e s y n t h e s i s o f 8 - l a c t a m s from a - a m i n o - 8 - h y d r o x y - a c i d derivatives 2 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 - t y p e r e a c t i o n , 2 5 1 a n d t h e Merck g r o u p h a s u s e d t h e same c y c l i z a t i o n method i n t h e s y n t h e s i s o f

N-( tetrazol-5-y1)azetidinone d e r i v a t i v e s . 2 5 2 ’ 253

F u r t h e r examples

o f t h i s l a t t e r c l a s s o f compounds h a v e a l s o b e e n p r e p a r e d by t h e a d d i t i o n o f g l y c i n e e n o l a t e s t o N-(tetrazol-5-yl)imines, f o l l o w e d by ~ y c l i z a t i o n . ~ ~ ~ S u b s t i t u t e d monocyclic 8-lactams have been p r e p a r e d from 8-amino-acids

i n good y i e l d by u s i n g 2-chloro-l-methylpyridinium

i o d i d e a s t h e c o n d e n s i n g r e a g e n t 2 5 5 a n d Shono e t a l . h a v e r e p o r t e d

a g e n e r a l s y n t h e s i s o f B - l a c t a m s ( 3 7 8 ) by r e a c t i o n o f u-methoxylated

carbamates (376) with ketene methyl t r i m e t h y l s i l y l

a c e t a l s ( 3 7 7 ) . 256 A l d o l - t y p e r e a c t i o n s h a v e b e e n u t i l i z e d i n s e v e r a l B-lactam syntheses t h i s year.

Reaction of ketene bis(trimethylsily1)

a c e t a l s ( 3 7 9 ) w i t h i m i n e s ( 3 8 0 ) g a v e p r o d u c t s ( 3 8 1 ) i n good y i e l d and under mild c o n d i t i o n s , w i t h no f o r m a t i o n of t h e c o r r e s p o n d i n g B - a m i n o - a c i d s . 257

T h r e e g r o u p s h a v e r e p o r t e d on t h e u s e o f

d i a n i o n s of 3-hydroxybutyrates produce B-lactams of N - t r i m e t h y l s i l y l co-workers

(Scheme 2 9 ) .

i n the reaction with imines t o A s p a r t o f a s t u d y of t h e r e a c t i o n

i m i n e s w i t h a r a n g e o f e s t e r e n o l a t e s , Hart a n d

f o u n d t h a t B-lactams c o u l d b e p r o d u c e d by r e a c t i o n o f

t h e d i e n o l a t e ( 3 8 2 ) w i t h t h e i m i n e ( 3 8 3 ) b u t w i t h low s t e r e o c o n t r o l : p r o d u c t s ( 3 8 4 ) - ( 3 8 7 ) a r e formed as a p a r t i a l l y s e p a r a b l e m i x t u r e , a l t h o u g h *-isomer ( 3 8 4 ) i s formed a s t h e major

62 1

8: Saturated Heterocyclic Ring Synthesis

Me0 (376 1

i, HBr,AcOH TiCl4

+

R'

CH2C12, -70 'C*r.t.

R5 R%siMe3

ii RMgBr

(378) 11-69% overal

OMe

R'xos Me3 OSiMe,

R2

+

R3CH=NR4 (380)

(379)

xR4

R3 Tic14 CHzCI2, r.t.

'

R'

R2

(381)

Me S i C

OLi

0k N \ R 2

-

60

- 75'10

C C H=NSi M e 3

OLi

(382 1

HMPA( ph-\ 1.5 eta.) THF, -20

OC

+r.t.,

6h

43 *lo; trans

(388 1 Scheme 29

s*

95%

General and Synthetic Methods

622

p r o d u c t . 258 The s a m e r e a c t i o n h a s b e e n c a r r i e d o u t by C h i b a e t a l . I n c o n t r a s t , reaction of w i t h e s s e n t i a l l y t h e same r e s u l t . 2 5 9 d i e n o l a t e ( 3 8 2 ) w i t h b e n z y l i d e n e a n i l i n e u n d e r t h e c o n d i t i o n s shown gives trans-azetidinone

.

( 3 8 8 ) w i t h 95% d i a s t e r e o s e l e c t i v i t y 2 6 0

In

a s i m i l a r t y p e of r e a c t i o n , u l t r a s o u n d h a s b e e n f o u n d t o p r o m o t e

the reaction of ethyl bromoacetate with imines (389) t o give

B-lactams

( 3 9 0 ) i n e x c e l l e n t y i e l d . 26

The spiro-epoxy-azetidinones ( 3 9 2 ) h a v e b e e n p r e p a r e d i n g o o d y i e l d from b i s ( chloromethy1)propionamides

(39 1 ) ,262 and crown

e t h e r s h a v e b e e n shown t o b e e x c e l l e n t p h a s e - t r a n s f e r t h e s y n t h e s i s of (3-lactams

catalysts for

f r o m N-aryl-B-bromopropionamides . 2 6 3

Two n o v e l s y n t h e s e s of t h e c a r b a p e n a m s k e l e t o n h a v e a p p e a r e d . P r o d u c t s ( 3 9 5 ) a n d ( 3 9 6 ) a r e p r o d u c e d i n l o w y i e l d by a new b a s e c a t a l y s e d c y c l o a d d i t i o n r e a c t i o n of t h e i o d o m e t h y l a z e t i d i n o n e s (393) with 2-thiosubstituted

dimethyl fumarate d e r i v a t i v e s (394)

a n d Wasserman h a s a p p l i e d a new p h o t o - o x i d a t i v e

264

c l e a v a g e method o f

g e n e r a t i n g v i c i n a l t r i c a r b o n y l systems t o s y n t h e s e s of t h e carbapenam ( 3 9 7 ) and t h e carbacepham ( 3 9 8 ) (Scheme 3 0 ) . 265,266 The Merck g r o u p h a s r e p o r t e d t h e s y n t h e s i s o f 3-methylphosphonylthienamycin a n d r e l a t e d 3-phosphonyl-carbapenems v i a a r h o d i u m - c a t a l y s e d i n s e r t i o n r e a c t i o n of t h e a p p r o p r i a t e a - d i a z o p h o s p h o n a t e p r e c u r s o r s , 267 a n d F a r m i t a l i a w o r k e r s h a v e p r e p a r e d c a r b a p e n e m ( 4 0 0 ) a n d p e n e m s ( 4 0 2 ) by r e d u c t i v e c o u p l i n g o f t h e monocyclic d i c a r b o n y l - a z e t i d i n o n e s (399) and ( 4 0 1 ) , r e s p e c t i v e l y . 268-270 The l - p h o s p h a c e p h a l o s p o r i n r i n g s y s t e m h a s b e e n s y n t h e s i z e d f o r t h e f i r s t t i m e by a r o u t e i n v o l v i n g t h e i n t r a m o l e c u l a r W i t t i g r e a c t i o n shown i n Scheme 31. F i n a l p r o d u c t s ( 4 0 3 ) a n d ( 4 0 4 ) were T h e same g r o u p h a s a l s o d e v o i d of a n t i b a c t e r i a l a c t i v i t y . 2 7 1 d e s c r i b e d t h e s y n t h e s i s of o p t i c a l l y a c t i v e 7 - s u b s t i t u t e d 1- p h o s p h a c e p h a l o s p o r i n s by s i m i l a r p r o c e d u r e s . 2 7 2 T h i o p e n a m d e r i v a t i v e s ( 4 0 7 ) a n d ( 4 0 8 ) 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 of alkynyl s i l y l s u l p h i d e (405) with d i h y d r o t h i a z o l e s ( 4 0 6 ) a~n d~ ~a f u l l r e p o r t o f t h e s y n t h e s i s of y-lactam a n a l o g u e s 274

of p e n i c i l l a n i c a n d c a r b a p e n i c i l l a n i c a c i d s h a s a p p e a r e d .

623

8: Saturated Heterocyclic Ring Synthesis

Br-CH2

KArl

+

I

N

COtEt

sonication Zn, 1121 dioxane, 25 "C

0

'A?

CH2CI

I

R2C02-

KOH

C-CONHR'

___)

O

THF

CHzCI 1

(391)

(392 )

SR2

Me02C

(394)

i (R2=Ph) or ii (R2=Me)

C02Me

R' = H ,

(396)

27'10 OSiMe2Bu'

, 15*/.

Reagents : i, KH, 10-crown-6,

70 - 80%

/4c02Me

+

(395)

Y N\R1

THF; ii , PhZCHK, 18-crown-6, THF

General and Synthetic Method3

624

R’.H/-

H

H

I

i,HF, Py

ii, 3

A molecular sieves

..R’

TMSl

0

0

Cop R2

CO ZR

(397) n = 1 , R’ = E t , R‘ = PNB, 120/~overall (398) n = 2 , R ’ = H, R 2 = B u t , Scheme 30

But Me2Si 0

But M e2Si 0 P(OEt13,A

CO2 PNB

cO2 PNB

8: Saturated Heterocyclic Ring Synthesis

625

CO2R

C02R

+ C02R

1

i, AIC13, anisole ii, NaHC03

i ii

tE$+J

$ J b . -

0

0 C02Na

C02 Na

(403)

(404)

Scheme 31

Bu' - CEC-S-SiMe3

+

[ n$:;] But

(405) 2 OC, 7 days without solvent ~

yut

sonic,"'io~L>*dPR*

SSiMea

1

R'

(406)

R2

R'

(407)R' ,R = H, 80% ( 4 0 8 ) R' = COiMe, R 2 = Me, 55%

General and Synthetic Methodr

626 References 1.

'Comprehensive H e t e r o c y c l i c Chemistry I , e d . A . R . K a t r i t z k y and C.W.Rees, Pergamon , O x f o r d , 1984. A.Abde1-Magid, I . L a n t o s , and L.N.Prigden, T e t r a h e d r o n L e t t . , 1984, 3273. L . C a s t e d o , J.L.Castr-o, and R . R i g u e r a , T e t r a h e d r o n L e t t . , 1984, 1205. S . B a n f i , S . C o l o n n a , H . M o l i n a r i , S . J u l i a , and J . G u i x e r , T e t r a h e d r o n , 1984, 40, 5207. J . L . L a b o u r e u r , W.Dumont, and A . K r i e f , T e t r a h e d r o n L e t t . , 1984, 2, 4569. G . B a l a v o i n e , C . E s k a n a z i , F - M e u n i e r , and H . R i v i e r e , T e t r a h e d r o n L e t t . , 1984 2 5 , 3187. T.Tezuka and M.IwaKi, H e t e r o c y c l e s , 1984, 22, 7 2 5 ; J . Chem. S O C . , P e r k i n T r a n s . 1 , 1984, 2507. M.Shimizu, R.Ando, and I.Kuwajirna, J . Org. Chern., 1984, 1230. 817. J . M a t t a y , J . G e r s d o r f , and U.Freudenberg, T e t r a h e d r o n L e t t . , 1984, W.Adam and hl.J.Baader, W w . Chem., I n t . Ed. E n g l . , 1 9 8 4 , 23, 166. 2668. P.C.Ting and P . A . B a r t l e t t , J . Am. Chem. S O C . , 1984, D.R.Williams, Y.Harigaya, J.L.Moore, and A.D'sa, J . Am. Chem. S O C . , 1984, 1 0 6 , 2641. D.R.Williams, J . G r o t e , and Y - H a r i g a y a , T e t r a h e d r o n L e t t . , 1984, 5231. 2843. J . K a l l m e r t o n , T e t r a h e d r o n L e t t . , 1984, K.Kanai , R . E . Z e l l e , H.-L .Sham, P. A.Grieco, and P. C a l l a n t , J . Org Chem., 3867. 1984, M.Srebnik and R.Mechoulam, J . Chem. S O C . , Chem. Commun., 1984, 1070. B. Tarnchompoo and Y. T h e b t a r a n o n t h , T e t r a h e d r o n L e t t . , 1984, 5567. M . H u h t a s a a r i , H . J . S c h a f e r , and L - B e c k i n g , Angew. Chem., I n t . Ed. E n g l . , 1 9 8 4 , 2 3 , 980. P . J . C b G m i n s and T.W.Wallace, J . Chem. S O C . , Chem. Commun., 1984, 1698. 4041. D . C . B i l l i n g t o n and D . W i l l i s o n , T e t r a h e d r o n L e t t . , 1984, P.G.Sammes and R.J.Whitby, J . Chem. S O C . , Chem. Commun., 1984, 702. P.J.Clawson, P.M.Lmn, and D.A.Whiting, J . Chem. SOC., Chem. Commun., 1984 134. Z . Arnold, V . K r a l , G.V.Kryshta1, and L . A . Yanovskaya, S y n t h e s i s , 1984, 974. F.Boberg, K.-H.Garburg, K . - J . G o r l i c h , E - P i p e r e i t , and M.Ruhr, L i e b i g s Ann. Chem., 1984, 911. 7264. M.Marsi and M.Rosenblum, J . Am. Chem. S O C . , 1984, J . Y o s h i d a , S.Yano, T.Ozawa, and N.Kawabata, T e t r a h e d r o n L e t t . , 1984, 25, 2817. P G .Bar a l d i , A .Barco , S Bennet t i , S .Manf r e d i n i , G P Pol l i n i , and D S i m o n i , T e t r a h e d r o n L e t t . , 1984, 4313. R.F.W.Jackson and R.A.Raphae1, J . Chem. SOC., P e r k i n T r a n s . 1 , 1984 , 535. G . J . D r t i n a , P.Sampson, and D.F.Wiemer, T e t r a h e d r o n L e t t . , 1984, 25, 4467. F . S a t o , H.Kanbara, and Y.Tanaka, T e t r a h e d r o n L e t t . , 1984, 2, 5063. A . J . B r i d g e s and R.D.Thomas, J . Chem. S O C . , Chem. Commun., 1984, 694 5022. K.Shankaran and V . S n i e c k u s , J . Org. Chem., 1984, 3865. P.R.Hamann, J . E . T o t h , and P.L.Fuchs, J . Org. Chem., 1984, A - A r d u i n i , A . P o c h i n i , and R.Ungaro, S y n t h e s i s , 1984, 950. T - G a l l a g h e r , J . Chem. S o c . , Chem. Commun., 1984, 1554. P.Audin, A-Dotheau, and J . G o r e , B u l l . S O C . Chim. F r . , P a r t 2 , 1984, 297. 594 3 . H . A . J . C a r l e s s and G.K.Fekarurhobo, T e t r a h e d r o n L e t t . , 1984, J . P . A l a z a r d , J . L . B r a y e r , A - T i x i d r e , a n d C.Tha1, T e t r a h e d r o n , 1984, 40, 695 S.Danishefsky and R.R.Webb 11, J . Org. Chem., 1984, 1955. S. Danishef s k y , D. F.Harvey , G . Q u a l l i c h , and B. J . Uang, J . Org. Chem., 4 9 , 392. S . C a s t e l l i n o and J . J . S i m s , T e t r a h e d r o n L e t t . , 1984, 25, 4059. S . D a n i s h e f s k y , W. H.Pearson, and D.F.Harvey , J . Am. Chem. SOC., 1984 2455. S - D a n i s h e f s k y and M.Bednarski, T e t r a h e d r o n L e t t . , 1984, 25, 721. S.F.Martin and B.Benage, T e t r a h e d r o n L e t t . , 1984, 25, 4863. W.H.Bunnelle, D.W.Seamon, D.L.Mohler, T.F.Bal1, and D.W.Thompson, T e t r a h e d r o n L e t t . , 1984, 25, 2653. S.D.Burke, D.M.Armistead, and F . J . S c h o e n e n , J . Org. Chem., 1 9 8 4 , 4320.

5,

2.

25,

3.

4. 5. 6. 7

9,

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.

5,

106,

-

5,

25,

.

9,

25,

25,

.

106,

.

..

25,

5,

.

9,

3,

~

2,

2,

8: Saturated Heterocyclic Ring Synthesis 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. 84. 85. 86. 87.

88. 89. 90. 91.

621

A.Arnoldi, Synthesis, 1984, 856. A.Saba, Synthesis, 1984, 268. P.A.Aristoff, A.W.Harrison, and A.M.Huber, Tetrahedron Lett., 1984, 25, 3955. G.Solladie and S.Moine, J. Am. Chem. SOC., 1984, 106,6097. P.F.Shuda and J.L.Phillips, J. Heterocycl. Chem., 1984, 21, 669. D.Dauzonne and R.Royer, Synthesis, 1984, 348. H.Yoshida, M.Nakajima, T.Ogata, and K.Matsumoto, Bull. Chem. SOC. Jpn., 1984, 57, 734. A.M.Doherty, S.V.Ley, B.Lygo, and D.J.Williams, J. Chem. SOC., Perkin Trans. 1 , 1984, 1371. C.Iwata, K.Hattori, S.Uchida, and T.Imanishi, Tetrahedron Lett., 1984, 5, 2995. P.Kocienski and C.Yeates, J. Chem. SOC., Chem. Commun., 1984, 151. R.Amouroux, Heterocycles, 1984, 22, 1489. S.V.Ley and B.Lygo, Tetrahedron Lett ., 1984, 25, 113. P.Kocienski and S.D.A.Street, J. Chem. SOC., Chem. Commun., 1984, 571. K.Mori and H.Watanabe, Tetrahedron Lett., 1984, 25, 6025. K.Mori, T.Uematsu, H.Watanabe, K.Yanagi, and M.Minobe, Tetrahedron Lett., 1984, 25, 3875. K.Mori and M.Ikunaka, Tetrahedron, 1984, 110, 3471. K.Gollnick and A.Schnatterer, Tetrahedron Lett., 1984, 25, 2735. 4581. R.M.Moriarty and K.-C.Hou, J. Org. Chem., 1984, 9, Z.G.Hajos, M.P.Wachter, H.M.Werblood, and R.E.Adams, J. Org. Chem., 1984, 49, 2600. C.W. Jefford, D.Jaggi , J. Boukouvalas, S.Kohmoto, and G .Bernardinelli, Helv. Chim. Acta, 1984, 67,1104. C.W. Jefford, J.Boukouvalas, and S.Kohmoto, J. Chem. SOC , Chem. Commun., 1984, 523. C.W.Jefford, D.Jaggi, S.Kohmoto, J.Boukouvalas, and G.Bernardinelli, Helv. Chim. Acta, 1984, 67,2254. T.Endo and M.Okawara, Synthesis, 1984, 837. H.A.J.Carless and G.K.Fekarurhobo, J. Chem. SOC., Chem. Commun., 1984, 667. S.L.Schreiber and S.E.Kelly, Tetrahedron Lett., 1984, 25, 1757. E.Vedejs, Acc. Chem. Res., 1984, 17,358. W.Ando, T.Furuhata, Y.Hanyu, and T.Takata, Tetrahedron Lett., 1984, 25, 401 1. H.Ikehira and S.Tanimoto, Bull. Chem. SOC. Jpn., 1984, 57, 2474. C.G.Francisco, R-Freire, R-Hernandez, J.A.Salazar, and E.Suarez, Tetrahedron Lett., 1984, 2, 1621. A.Nickon, A.Rodriguez, V.Shirhatti, and R.Ganguly, Tetrahedron Lett., 1984, 25, 3555. E-Anklam and P.Margaretha, Helv. Chim. Acta, 1984, 2, 2198. Y-Tamaru, H.Satomi, O.Kitao, and Z-Yoshida, Tetrahedron Lett., 1984, 25, 2561. K.R.Lawson, A.Singleton, and G.H.Whitham, J. Chem. SOC., Perkin Trans. 1 , 1984, 859. Y.Tamaru, 0-Ishige, S.Kawamura, and Z.Yoshida, Tetrahedron Lett., 1984, 25, 3583 K.Hantke and H.Gotthardt, J. Chem. SOC., Chem. Commun., 1984, 1682. J.S.Grossert, J.Hoyle, and D.L.Hooper, Tetrahedron, 1984, 40, 1135. F.A.Davis, J.P.AcAuley,Jr., and M.E.Haraka1, J. Org. Chem., 1984, 2,1465. Y.Ohshir-o, M.Komatsu, M. Uesaka, and T.Agawa, Heterocycles, 1984, 22, 549. D.Geffken, Liebigs Ann. Chem., 1984, 894. K.E.Larsen and K.B.G.Torssel1, Tetrahedron, 1984, 40, 2985. T.Schimizu, Y.Hayashi, and K.Teramura, Bull. Chem. SOC., Jpn., 7984, 57, 2531. S.P.Ashburn and R.M.Coates, J. Org. Chem., 1984, 2, 3127. A.P.Kozikowski and A.K.Ghosh, J. Org. Chem., 1984, 2, 2762. S.Mzengeza and R.A.Whitney, J. Chem. SOC., Chem. Commun., 1984, 606. P.A.Wade, N.V.Amin, H.-K.Yen, D.T.Price, and G.F.Huhn, J. Org. Chem., 1984, 49, 4595.

.

-

-

628 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.

General and Synthetic Methods

14,

K.K.Singa1, Synth. Commun., 1984, 1047. A.P .Kozikowski, K.Hiraga, J. P.Springer , B. C.Wang, and Z.-B.Xu, J. Am. Chem. SOC., 1984, 106,1845. R.Grigg, M. Jordan, A. Tangthongkum, F .W .B.Einstein, and T.Jones, J. Chem. SOC., Perkin Trans. 1 , 1984, 47. P.Wipf and H.Heimgartner, Tetrahedron Lett., 1984, 25, 5127. K.E.Harding, R.Stephens, and D.R.Hollingsworth, Tetrahedron Lett., 1984, 2 4631. C.Capozzi, C.Caristi, and M.Gattuso, J. Chem. SOC., Perkin Trans. 1 , 1984, 255. S.Mataka, K.Uehara, K.Takahishi, and M.Tashiro, Synthesis, 1984, 663. M.Sabuni, G.Kresze, and H.Braun, Tetrahedron Lett ., 1984, 3,5377. H.Felber, G.Kresze, H.Braun, and A-Vasella, Tetrahedron Lett., 1984, 25, 5381. 4098. D.L.Boger and M.Pate1, J. Org. Chem., 1984, S.E.Denmark, M.S.Dappen, and J.A.Sternberg, J. Org. Chem., 1984, 9, 4741. H.K.Hal1, Jr. and D.L.Miniutti, Tetrahedron Lett., 1984, 25, 943. X.Huang and C.-C.Chan, Synthesis, 1984, 851. A.Fruchier , V. Moragues, C.Petrus, and F.Petrus, Bull. SOC Chim. Fr , Part 2, 1984, 173. A.Q.Hussein, M.M. El- Abadelah, and W.S.Sabri, J. Heterocycl. Chem., 1984, 21 455. G.Cignarella and D.Barlocco, Synthesis, 1984, 342. H.Cnichte1, J.-U.Wahner, and K.Hirte, Liebigs Ann. Chem., 1984, 1696. E.Block, M.Aslam, R.Iyer, and J.Hutchinsin, J. Org. Chem. , 1984, 9, 3664 J.K.Koskimies, Acta Chem. Scand., Ser. B, 1984, 2,101. R.A.Abramovitch, A.O.Kress, S.P .McManus, and M. R.Smith, J Org. Chem., 1984, 9, 3114. K.Schulze, C.Richter, F.Richter, E.Mrozek, R.Weisheit, and F.Anchenbac J. Prakt. Chem., 1984, 326, 101. A. Alemagna, P. D.Buttero, E. Licandro, S-Maiorana, and R .Trave, Tetrahedron, 1984, 5, 971. Y.Matsubara, S.Yamada, M.Yoshihara, and T-Maeshima, Chem. Pharm. Bull ., 1984, 32, 1590. Y.Ishikawa, Y.Terao, K.Suzuki, N.Shikano, and M.Sekiya, Chem. Pharm. Bull. 1984, 32, 438. W.Hanefeld, Arch. Pharm. (Weinheim, Ger.), 1984, 317, 297. T.Sasaki and I.Shimizu, Heterocycles, 1984, 22, 1225. M.P.Crozet, M.Kaafarani, and J.-M.Surzur, Bull. SOC. Chim. F r . , Part 2, 1984, 390. H.Tashida and T.Tsuchiya, Heterocycles, 1984, 22, 1303. S.Sato, K.Tomita, H.Fujita, and Y.Sato, Heterocycles, 1984, 22, 1045. J.Borgulya, J.J.Daly, P.Schonholzer, and K.Bernauer, Helv. Chim. Acta, 1983, 3, 1827. K.Kanakarajan and H.Meier, Angew. Chem., Int. Ed. Engl., 1984, 3,244. H.Natsugari, R.R.Whittle, and S.M.Weinreb, J. Am. Chem. SOC., 1984, 106,

9,

.

.

.

-

7867. R.S.Garigipati, A.J.Freyer, R.R.Whittle, and M.Weinreb, J. Am. Chem. SOC., 1984, 106,7861. 125. A.Couture, R.Dubiez, and A.Lablache-Combier, J. Org. Chem., 1984, 714. 126. H.Suzuki and H.Tani, Chem. Lett., 1984, 2129. 127. J.R.Pfister, Synthesis, 1984, 969. 128. C.Mahido1, V.Reutraku1, V.Prapansiri, and C.Panyachotipun, Chem. Lett., 1984, 969. 129. V.Reutraku1, V.Prapansiri, and C.Panyachotipun, Tetrahedron Lett., 1984, 25. 1949. -_ - 130. B.Mauzk, Tetrahedron Lett., 1984, 25, 843. 131. N.DeKimpe, B.DeCorte, R.Verhe, L.DeBuyck, and N.Schamp, Tetrahedron Lett., 1984, 25, 1095. 132. Y.Girazt, M.Decouzon, and M.Azzaro, Tetrahedron Lett., 1984, 25, 2763. 133. M.A.Loreto, L.Pellacani, P.A.Tardella, and E.Toniato, Tetrahedron Lett., 1984, 25, 4271. 124.

2,

I

~

8: Saturated Heterocyclic Ring Synthesis 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. 175. 176. 177.

629

P.G.Sammes and S.Smith, J. Chem. SOC., Perkin Trans. 1 , 1984, 2415. E.Juaristi and J.D.Reyna, Tetrahedron Lett., 1984, 25, 3521. L.S.Hegedus, Tetrahedron, A.G.Fallis, Can. J. Chem., 1984,-g, 183. R-Grigg, H.Q.N.Gunaratne, and J.Kemp, J. Chem. SOC., Perkin Trans. 1 , 1 984, 41. N.Imai, Y.Terao, K.Achiwa, and M.Sekiya, Tetrahedron Lett., 1984, 25, 1 579. K.Achiwa, N.Imai, T.Motoyama, and M.Sekiya, Chem. Lett., 1984, 2 0 4 r A.Hosomi, Y.Sakata, and H.Sakurai, Chem. Lett., 1984, 1117. K.Achiwa, N.Imai, T.Inaoka, and M.Sekiya, Chem. Pharm. Bull., 1984, 32, 2878. O.Tsuge, S.Kanemasa, A.Hatada, and K-Matsuda, Chem. Lett., 1984, 801. A.Padwa, G-Haffmanns, and M.Tomas, J. Org. Chem., 1984, 9, 3314. R.Grigg and S.Thianpatanagu1, J. Chem. SOC., Chem. Commun., 1984, 180. R.Grigg, M.F .Aly , V. Sridharan, and S.Thianpatanagu1, J. Chem. SOC . , Chem. Commun., 1984, 182. C.-L.J.Wang, W.C.Ripka, and P.N.Confalone, Tetrahedron Lett., 1984, 25, 4613. P.N.Confalone and E.M.Huie, J. Am. Chem. SOC., 1984, 106,7175. T.Kitamura, S.Kobayashi, and H.Taniguchi, J. Org. Chem., 1984, 9, 4755. R.G.Salomon, S.Ghosh, S.R.Raychaudhuri, and T.S.Miranti, Tetrahedron Lett., 1984, 25, 3167. D.L.Boger and R.S.Coleman, J. Org. Chem., 1984, 49, 2240. H.Iida, Y.Watanabe, and C.Kibayashi, Tetrahedron Lett., 1984, 25, 5091. W.Verboom, D.N.Reinhoudt, R.Visser, and S.Harkema, J. Org. Chem., 1984, 9, 269. W.C.Dijksman, W.Verboom, D.N.Reinhoudt, C.G.Hale, S.Harkema, and G.J.van Hummel, Tetrahedron Lett., 1984, 25, 2025. A.W.Lochead, G.Proctor, and M.P.L.Caton, J. Chem. SOC., Perkin Trans. 1 , 1984, 2477. 1682. A.R.Chamberlin, H.D.Nguyen, and J.Y.L.Chung, J. Org. Chem., 1984, Z.Blum, M.EkstrOm, and L.-G-Wistrand, Acta Chem. Scand., Ser. B, 1984, 38, 297. T.Shono, Y .Matsumura, K.Uchida, K. Tsubata, and A.Makino, J. Org. Chem., 1984, 3, 300. 1946. R.E.Gawley and E.J.Termine, J. Org. Chem., 1984, 9, J.S.Petersen, S.Tateberg-Kaulen, and H.Rapoport, J. Org. Chem., 1984, 2948. J.Barluenga, J.Pdrez-Prieto, A.M.Bay6nt and G.Asensio, Tetrahedron, 1984, 40, 1199. J.Barluenga, C.Jimknez, C.Ndjera, and M.Yus, J. Chem. SOC.,Perkin Trans. 1 1984, 721. Y.Tamaru, S.Kawamura, K.Tanaka, and Z.Yoshida, Tetrahedron Lett., 1984, 25, 1063. A.Toshimitsu, K.Terao, and S.Uemura, Tetrahedron Lett., 1984, 25, 5917. R.D.O'Sullivan and A.W.Parkins, J. Chem. SOC., Chem. Commun., 1984, 1165. K.S.Kochhar, H.J.Carson, K.A.Clouser, J.W.Elling, L.A.Gramens, J.L.Parry, H.L .Sherman, K .Braat, and H.W. Pinnick, Tetrahedron Lett., 1984, 25, 1871 F.Z.Basha and J.F.DeBernardis, Tetrahedron Lett., 1984, 25, 5271. B.H.Bakker, D.S.T.A-Lim, and A.van der Gen, Tetrahedron Lett., 1984, 4259. P.D.Edwards and A.I.Meyers, Tetrahedron Lett., 1984, 25, 939. A.I.Meyers and M.F.Loewe, Tetrahedron Lett., 1984, 25, 2641. L.E.Overman and R.M.Burk, Tetrahedron Lett., 1984, 25, 5737. L.E.Overman and R.M.Burk, Tetrahedron Lett., 1984, 25, 5739. H.Alper, C.P.Mahatantila, F.W.B.Einstein, and A.C.Willis, J. Am. Chem. SOC 1984, 106,2708. J.Fujiwara, H.Sano, K.Maruoka, and H.Yamamoto, Tetrahedron Lett. , 1984, 3 , 2367. J.Vercauteren, G-Massiot, and J.Levy, J. Org. Chem., 1984, 9, 3230. A.K.Forrest and R.R.Schmidt, Tetrahedron Lett., 1984, 25, 1769. 1027. C.K.Tseng, E.G.Teach, and F.W.Simons, Synth. Commun., 1984,

2,

9,

.

z,

111,

630 178.

General and Synthetic Methoc D.A.Burnett, J.-K.Choi, D.J.Hart, and Y.-M.Tsai, J. Am. Chem. SOC., 1984, 106, 8201. D.J.Hart and

Y.-M.Tsai, J. Am. Chem. SOC., 1984, 106,8209. 179. 180. J.C.Gilbert and B.K.Blackburn, Tetrahedron Lett., 1984, 25, 4067. 181. M.Nakagawa, M.Sodeoka, K.Yamaguchi, and T.Hino, Chem. Pharm. Bull., 1984, 32, 1373. 182. TNakagawa, M.Ito, Y.Hasegawa, S.Akashi, and T.Hino, Tetrahedron Lett., 1984, 25, 3865. 183. N.Matsumura, A.Kunugihara, and S-Yoneda, Tetrahedron Lett., 1984, 25, 452( 184. H.Beltrami and J.Mallen, Tetrahedron, 1984, “0, 1683. 185. A.Huth, D.Rosenberg, I.Schumann, and K.Thielert, Liebigs Ann. Chem., 1984 641. 186. W.D.Jones, Jr , J .M.Kane, and A.D.Sill, J. Heterocycl. Chem., 1984, 11,88( 187. B.Carboni and R.CarriC, Tetrahedron, 1984, “0, 41 15. 188. M.Dagonneau, E.S.Kagan, V.I.Mikhailov, E.G.Rozantsev, and V.D.Sholle, Synthesis, 1984, 895. 189. M.Lounasmaa and A.Koskinen, Heterocycles, 1984, 22, 1591. 190. R.V.Stevens, Acc. Chem. Res., 1984, 2, 289. 191. M-Ihara, T-Kirihara, A.Kawaguchi, K-Fukumotu,and T-Kaqetani, Tetrahedrc Lett., 1984, 12,4541. 192. T.Kametani, H.Takeda, Y-Suzuki, and T.Honda, Heterocycles, 1984, 22, 275. 193. T.R.Bailey, R.S.Garigipati, J.A.Morton, and S.M.Weinreb, J. Am. Chem. Soc 1985, 106,3240. 194. J.-J.Young and C.-K.Sha, Heterocycles, 1984, 22, 2571. 4025. 195. M.J.Wyles and F.W.Fowler, J. Org. Chem., 1984, 9, 196. R.L.Funk and J.D.Munger, Jr., J. Org. Chem., 1984, 9, 4319. 197. S.Kano, Y.Yuasa, and S.Shibuya, Synthesis, 1984, 1071. 198. 2.-K.Liao and H-Kohn, J. Org. Chem., 1984, 2, 3812. 4745. 199. Z.-K.Liao and H.Kohn, J. Org. Chern., 1984, 200. P. D.Palasz, J.H.P .Utley, and J. D.Hardstone, Acta Chem. Scand., Ser. B, 1984. 38. 281. 201. L.E.OvFman, K.L.Bel1, and F.Ito, J. Am. Chem. SOC., 1984, 106,4192. 202. T.Darbre, C.Nussbaumer, and H.-J.Borschberg, Helv. Chim. Acta, 1984, 3, 1040. 203. M.R.Euerby and R.D.Waigh, J. Chem. SOC., Chem. Commun., 1984, 127. 204. J.Vercauteren, C.Lavaud, J.Lkvy, and G.Massiot, J. Org. Chem., 1984, 2278. 205. S. Ruchirawat, M. Chaisupakitsin,N.Patranuwatana,J. L .Cashaw, and V. E. Davis, Synth. Commun., 1984, 1221. 206. C.Mackay and R.D.Waigh, Heterocycles, 1984, 22, 687. 207. W-Carruthers, M.J.Williams, and M.T.Cox, J. Chem. SOC., Chem. Commun., 1984, 1235. 208. K.E.Harding and S.R.Burks, J. Org. Chern., 1984, 40. 209. J.Barluenga, F.Aznar, and R.Liz, Synthesis, 1984, 304. 210. K.Abe, H.Okumura, T.Tsugoshi, and N.Nakamura, Synthesis, 1984, 597. 211. R.Marsden and D.B.MacLean, Can. J. Chem., 1984, 62, 1392. 212. R.Marsden, D.B.MacLean, and L.Fodor, Can. J. Chem., 1984, 62, 2682. 213. A.I.Meyers, L.M.Fuentes, and Y-Kubota, Tetrahedron, 1984, g,1361. 214. R.S.Mali and V.J.Yadav, Synthesis, 1984, 862. 215. K.Krishan, A.Singh, B.Singh, and S.Kumar, Synth. Commun., 1984, 14,219. 216. A.B.Holmes, K.Russel1, E.S.Stern, M.E.Stubbs, and N.K.Wellard,

.

2,

I

-

,

5,

2,

2,

217. 218. K.Beck, A.HZhn, S.Hunig, and F. 219. S.Hunig and F.Prokschy, Chem. Ber., 1984, 117,534. 220. S.F.Nelsen, S.C.Blackstock, and T.B.Frigo, ,J. Am. Chem. SOC., 1984, 106, 3366. 221. W.Verboom, M.R.J.Hamzink, D.N.Reinhoudt, and R.Visser, Tetrahedron Lett ., 1904, 25, 4309. 222. T.Nishio, T.Tokunaga, and Y.Cknote, Synth. Commun., 1984, E, 363. 223. K.T.Okamoto and J.Clardy, Tetrahedron Lett., 1984, 25, 2937. 224. J.Bosch, M.Rubiralta, N.Valls, and A.Diez, Heterocycles, 1984, 22, 1137. 225. H.Bottcher and B.Arzt, Angew. Chem., Int. Ed. Engl., 1984, 518.

s,

8: Saturated Heterocyclic Ring Synthesis 226. 227. 228. 229. 230. 231. 232. 233. 234. 235. 236. 237. 238. 239. 240. 241. 242. 243. 244. 245. 246. 247. 248. 249. 250. 251. 252. 253. 254. 255. 256. 257. 258. 259. 260. 261. 262. 263. 264. 265. 266. 267. 268. 269. 270. 271. 272.

63 1

C.J.Moody and J.G.Ward, J. Chem. SOC., Perkin Trans. 1 , 1984, 2895. W.Eilenbet-g and H.J.Schafer, Tetrahedron Lett., 1984, 25, 5023. I.H.S&chez, J.J.Soria, F.L.L6pez, M.I.Larraza, and H.J.Flores, J. Org. Chem., 1984, 3, 157. D.St.C.Black and L.M.Johnstone, Aust. J. Chem., 1984, 37, 599. J.B.Bremner and K.N.Winzenberg, Aust. J. Chem., 1984, 1203. H.G.Theuns, G.F.La Vos, M.C. ten Noever de Brauw, and C.A.Salemink, Tetrahedron Lett., 1984, 25, 4161. H.D.Martin, H.Hochstetter, and A.Steige1, Tetrahedron Lett., 1984, 25, 297. V. D.Piaz , G. Ciciant i , A. Constanzo, G. Auzzi , and S. Chimichi, Heterocycles, 1984, g,1741. B.K.Vriesema, J.Buter, and R.M.Kellogg, J. Org. Chem., 1984, 110. M.J.Haddadin, B.J .Agha, and M.S.Salka, Tetrahedron Lett., 1984, 25, 2577. R.Labia and C.Morin, J. Antibiotics, 1984, 37, 1103. K.Broadley and S.G.Davies, Tetrahedron Lett., 1984, 25, 1743. S.T.Hodgson, D.M.Hollinshead, and S.V.Ley, J. Chem. S O C . , Chem. Commun., 1984, 494. L.S.Hegedus, M.A.McGuire, L.M.Schultze, C.Yijun, and O.P.Anderson, J. Am. Chem. SOC., 1984, 106,2680. M.Sakamoto, Y.Cmote, and H-Aoyama, J. Org. Chem., 1984, 396. C.Kaneko, T.Naito, and A.Saito, Tetrahedron Lett., 1984, 25, 1591. N.Katagiri, M.Sato, T-Naito, M.Muto, T.Sakamoto, S.Saikawa, and C.Kaneko, 5665. Tetrahedron Lett., 1984, 2, A.Padwa, K.F.Koehler, and A.Rodriguez, J. Org. Chem., 1984, 282. M. Chmielewski, Z.Kaluza , C .Be1 zecki , P .Salanski , and J Jurc zak , Tetrahedron Lett., 1984, 3,4797. J.M.Aizpurua, I.Ganboa, F.P. Cossio, A-Gonzalez, A.Arrieta, and C.Palomo, Tetrahedron Lett., 1984, 3,3905. D.R.Shridhar, B.Ram, V.L.Narayana, A.K.Awasthi, and G.J.Reddy, Synthesis, 1984, 846. M-Miyake, N-Tokutake, and M.Kirisawa, Synth. Comrnun., 1984, 2, 353. A.Arrieta, J.M.Aizpurua, and C.Palomo, Tetrahedron Lett ., 1984, 25, 3365. M.Cardellini, F.Claudi, and F.M.Moracci, Synthesis, 1984, 1070. E.Rogalska and C.Belzecki, J. Org. Chem., 1984, 3, 1397. A.K.Bose, M.S.Manhas, D.P.Sahu, and V.R.Hegde, Can. J. Chem., 1984, 62, 2498. A-Andrus, B.Partridge, J.V.Heck, and B.G.Christensen, Tetrahedron Lett., 1984, 25, 911. A.Andrus, B.Partridge, J.V.Heck, B.G.Christensen, and J.P.Springer, Heterocycles, 1984, 22, 1713. M-Klich and G-Teutsch, Tetrahedron Lett., 1984, 25, 3849. H.Huang, N-Iwasawa, and T.Mukaiyama, Chem. Lett., 1984, 1465. T.Shono, K.Tsubata, and N.Okinaga, J. Org. Chem., 1984, 1056. J.E.Dubois and G.Axiotis, Tetrahedron Lett., 1984, 25, 2143. D.-C.Ha, D.J.Hart, and T.-K.Yang, J. Am. Chem. SOC., 1984, 106,4819. T.Chiba, M.Nagatsuma, and T.Nakai, Chem. Lett., 1984, 1927. G.I.Georg, Tetrahedron Lett., 1984, 25, 3779. A.K.Bose, K.Gupta, and M.S.Manhas, J. Chem. SOC., Chem. Commun., 1984, 86. S.Sebti and A.Foucaud, Tetrahedron, 1984, 40, 3223. B.G.Fleming and M.J.Meegan, J. Pharm. Pharmacol., 1984, 36, suppl., 9OP. K-Fujimoto, Y.Iwano, and K.Hirai, Tetrahedron Lett., 1984, 25, 1151. H.H.Wasserman and W.T.Han, Tetrahedron Lett., 1984, 25, 3747. H.H.Wasserrnan and W.T.Han, Tetrahedron Lett., 1984, 25, 3743. A.Andrus, B.G.Christensen, and J.V.Heck, Tetrahedron Lett., 1984, 25, 595. C.Battistini, C.Scarafile, M.Foglio, and G.Francheschi, Tetrahedron Lett., 1984, 25, 2395. E.Perrone, M.Alpegiani, A.Bedeschi, F.Giudici, and G.Francheschi, Tetrahedron Lett., 1984, 25, 2399, M.Alpegiani, A.Bedeschi, E.Perrone, and G.Francheschi, Tetrahedron Lett., 1984, 25, 4171. H.Satoh and T.Tsuji, Tetrahedron Lett., 1984, 25, 1733. H.Satoh and T.Tsuji, Tetrahedron Lett., 1984, 25, 1737.

x,

9,

2,

.

2,

9,

632 273. 274.

General and Synthetic Methods E-Schaumann, W.-R.FBrster, and A-Adiwidjaja, Angew. Chem., Int. Ed. Engl., 1984, 23, 439. J.E.Baldwin, M.F.Chan, G.Callacher, M.Otsuka, P.Monk, and K.Prout, Tetrahedron, 1984, 5, 4513.

Highlights in Total Synthesis of Natural Products BY K. E. B. PARKES AND G. PATTENDEN

1 Introduction This Report is similar in selectivity and subjectivity to the previous chapters in the series.

2 Terpenes The pentalenane family of angularly fused triquinane antibiotic metabolites produced by Streptomycetes has attracted the attentions of a number of synthetic chemists over the past few years. During 1984, the authors' research group outlined a stereocontrolled synthesis of (?I-pentalenene (6) which was based on an intramolecular photocycloaddition-cyclobutane fragmentation, 2. (1) ( 2 ) ; (3) (4), to set up the central bicycloC6.3.01undecadiene intermediate ( 5 ) for transannulation to (6) in the presence of boron trifluoride. A second new synthesis of ( ? ) pentalenene (6) featured a recently developed methylenecyclopentane

-

-

'

annulation process, from ( 7 ) , and using 4-chloro-2-trimethylstannyl2 but-l-ene, to provide the tricyclic intermediate ( 8 ) (Scheme 1 ) . The scope for the intramolecular photocycloaddition-cyclobutane fragmentation approach to ring synthesis, mentioned above, has also been exemplified in a new synthesis of (t)-pentalenic acid ( 1 1 ) (Scheme 2 ) , where the key step involved reductive cleavage of the tricyclic adduct (10) produced from irradiation of the dienone ( 9 ) . 3 Shirahama and Matsumoto's research group4 has extended their elegant investigations of the biomimetic in vitro conversions of humulene ( 1 2 ) to provide neat syntheses of a number of natural pentalenolactones, 3.(13b), and Cane et a1.5 have highlighted the use of an intramolecular carbene insertion sequence to elaborate the 6-lactone ring in their synthesis of ( 2 ) pentalenolactones E (14) and F (13a). An interesting synthesis of (+)-modhephene ( 1 7 1 , the first carbocyclic [3.3.3]propellane isolated from Nature, has employed a For References see page 676.

633

General and Synthetic Methods

634

; ii,

0 3 ; iii, Me02CCH=PPh3;

Scheme 2

i v , h v , 366nm; v, L i , N H 3

9: Highlights in Total Synthesis of Natural Products

635

(13) a; R = H b; R = OH

(12)

a

& H?

___) MeNHOH E tONa

H

H

H

H

(18) steps

$

OH

H

636

General and Synthetic Methods

chelation-controlled r e g i o s e l e c t i v e epoxide-carbonyl

i.e. (15)

-

(16),

rearrangement,

as a key s t e p . 6

A l t h o u g h a n u m b e r of s y n t h e s e s o f t h e l i n e a r - f u s e d

triquinanes

h i r s u t e n e ( 2 0 ) a n d c o r i o l i n ( 1 9 ) h a v e now b e e n p u b l i s h e d ,7 a n i n t e r e s t i n g new a p p r o a c h t o h i r s u t e n e h a s e m p l o y e d a n a t t r a c t i v e intramolecular nitrone-olefin

cycloaddition reaction using the

easily accessible ketone (18).

8

P a q u e t t e and S t e v e n s have p u b l i s h e d f u l l d e t a i l s of t h e i r s y n t h e s i s of t h e m a r i n e m e t a b o l i t e c a p n e l l e n e ( 2 3 ) , which f e a t u r e s

a Nazarov c y c l i z a t i o n ,

G. (21)

-

( 2 2 ) , 9 and two a l t e r n a t i v e

s y n t h e s e s of t h i s i n t e r e s t i n g m e t a b o l i t e , b o t h h i g h l i g h t i n g some u s e f u l stannane chemistry, have been d e s c r i b e d - l o

The n o v e l a n d

u n u s u a l f u s e d 5-8 r i n g h y d r o c a r b o n p r e c a p n e l l a d i e n e ( 2 5 ) i s believed t o be t h e b i o g e n e t i c precursor of capnellene ( 2 3 ) i n marine c o r a l .

F i r s t s y n t h e s i z e d i n 1 9 8 0 , t h i s r i n g s y s t e m h a s now

b e e n e l a b o r a t e d by t h e r e s e a r c h g r o u p s o f M e h t a ” Paquette. l2

and of

Whereas Mehta and Murty have u s e d t h e t r i q u i n a n e ( 2 4

as a c e n t r a l i n t e r m e d i a t e i n t h e i r s y n t h e s i s , P a q u e t t e e t a l . employed t h e C l a i s e n r e a r r a n g e m e n t of (27) t o precapnelladiene. Cope r e a r r a n g m e n t ,

(26) t o produce t h e precursor

Another rearrangement,

t h a t is t h e oxy-

h a s been used i n an i n t e r e s t i n g manner t o

p r o d u c e t h e 5-8 r i n g f u s e d s y s t e m ( 2 9 ) from ( 2 8 ) i n a t o t a l s y n t h e s i s of ( 2 ) - p o i t e d i o l

( 3 0 ) found i n r e d seaweed L a u r e n c i a

p o i t e i . ’3 The e n g a g i n g s e s q u i t e r p e n e q u a d r o n e ( 3 5 ) h a s now b e e n synthesized i n c h i r a l non-racemic acid-catalysed

form u s i n g a s t r a t e g y b a s e d on

rearrangement of t h e propellane (34 )

.

The

p r o p e l l a n e ( 3 4 ) i s e a s i l y a v a i l a b l e from t h e b i c y c l i c e n o n e ( 3 1 ) following photocycloaddition of isobutene, t o ( 3 2 ) , reduction t o ( 3 3 1 , m e s y l a t i o n , and l a c t o n i z a t i o n .

(+)-Quadrone, the enantiomer

o f t h e n a t u r a l p r o d u c t , was p r o d u c e d f r o m a r e s o l v e d s a m p l e o f ( 3 3 ) using S-(+)-g-acetylmandelic

acid.

Additional work, i n c l u d i n g t h e

f u l l d e t a i l s of B u r k e ‘ s s y n t h e s i s , on a p p r o a c h e s t o w a r d s q u a d r o n e and r e l a t i v e s , h a s a l s o been p u b l i s h e d . l5 T h e b i t t e r p r i n c i p l e s o f q u a s s i a wood Q u a s s i a a m a r a , known as quassinoids,

possess potent cytotoxic properties.

With t h e i r high11

oxygenated t e t r a c y c l i c c a r b o n s k e l e t o n s and d e n s e s t e r e o c h e m i c a l d e t a i l , t h e s e f e a t u r e s h a v e c o m b i n e d t o make t h e q u a s s i n o i d s p a r t i c u l a r l y challenging molecules f o r synthesis.

During 1984,

Grieco e t a1.I6 d e s c r i b e d a t o t a l s y n t h e s i s of q u a s s i n ( 3 8 ) , t h e m a j o r c o n s t i t u e n t o f q u a s s i a wood, w h i c h f e a t u r e d t h e L e w i s a c i d -

9: Highlights in Total Synthesis of Natural Products

637

steps

H (22)

(21)

H

Ru02

+ Na104 '

(23)

@ steps

0

H

(25)

(24)

200

*c

steps

+

(25)

I

(2 6)

(27)

50 *C ___)

' A

G

O

H

4 h

steps

.OH

General and Synthetic Methods

638

I

I

C02Me

J

(31)

NaBH4

C0,Me

(32)

=-!

C0,Et

(36)

/

Scheme 3

(37)

OMe

9: Highlights in Total Synthesis of Natural Products

c a t a l y s e d i n t e r m o l e c u l a r Diels-Alder

639 r e a c t i o n between t h e

d i e n o p h i l e ( 3 6 ) and e t h y l E-4-methylhexa

- 3,5-dienoate

( 3 7 ) (Scheme

3). G i b b e r e l l i c a c i d ( 3 9 1 , t h e phytohormone which p l a y s a c e n t r a l r o l e i n t h e r e g u l a t i o n o f p l a n t g r o w t h , f i r s t succumbed t o t o t a l

s y n t h e s i s i n 1978. T h i s c h a l l e n g i n g t a r g e t , however, s t i l l a t t r a c t s a t t e n t i o n from s y n t h e t i c c h e m i s t s throughout t h e world. D u r i n g 1 9 8 4 , Mander a n d h i s g r o u p ” u n d e r p i n n e d t h e i r n o v e l a n d o u t s t a n d i n g c o n t r i b u t i o n s i n t h i s area with an a d d i t i o n a l s y n t h e s i s o f g i b b e r e l l i c a c i d which h i g h l i g h t e d t h e i m p o r t a n c e o f ( a ) i n t r a m o l e c u l a r a l k y l a t i o n o f r - s y s t e m s by p r o t o n a t e d d i a z o m e t h y l k e t o n e s , and ( b ) r e d u c t i v e a l k y l a t i o n of a r o m a t i c s u b s t r a t e s , i n g e n e r a l s y n t h e s i s (Scheme 4 ) . The b i c y c l i c h y d r o c a r b o n t r i c h o d i e n e ( 4 2 1 , b i o g e n e t i c p r e c u r s o r t o t h e biologically a c t i v e trichothecanes, is a deceptively simple s y n t h e t i c t a r g e t , c o n t a i n i n g a s i t d o e s two a d j a c e n t c h i r a l quaternary centres. Two e f f e c t i v e s o l u t i o n s t o t h i s p r o b l e m h a v e now b e e n d e s c r i b e d . T h e s e s o l u t i o n s a r e b a s e d on f r a g m e n t a t i o n o f t h e p o t a s s i u m s a l t d e r i v e d from ( 4 0 ) , 1 8 a n d on Beckmann

f r a g m e n t a t i o n f r o m t h e oxime of t h e k e t o n e ( 4 1 ) p r o d u c e d by a Nazarov r e a c t i o n (Scheme 5 ) . A n e a t s y n t h e s i s of p e r i p l a n o n e B ( 4 5 ) , t h e p o t e n t s e x a t t r a c t a n t and s e x e x c i t a n t pheromone of t h e American c o c k r o a c h P e r i p l a n e t a a m e r i c a n a , h a s b e e n a c h i e v e d by S c h r e i b e r a n d S a n t a n i (Scheme 6 ) . 2 0 I n t h i s r o u t e t h e 10-membered r i n g i n t h e p h e r o m o n e was e l a b o r a t e d a n a n i o n - a c c e l e r a t e d oxy-Cope r e a r r a n g e m e n t , i . e . (43) ( 4 4 ) , 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 o p e n i n g o f t h e resulting cyclobutene. The t a x a n e f a m i l y o f b i o l o g i c a l l y a c t i v e m e t a b o l i t e s , f i r s t i s o l a t e d f r o m t h e common Yew t r e e , i n c o r p o r a t e a n o v e l a n d u n u s u a l f u s e d 6 , 8 , 6 - r i n g s y s t e m [ s e e ( 4 8 ) l . H o l t o n 2 ’ h a s now shown t h a t +

t r e a t m e n t of t h e epoxide ( 4 6 ) , d e r i v e d i n f o u r s t e p s from commercial p a t c h o u l i a l c o h o l , w i t h dimethyl s u l p h i d e r e s u l t s i n s m o o t h f r a g m e n t a t i o n t o t h e f u s e d 6 , 8 - r i n g p o r t i o n of t h e t a x a n e s i n essentially quantitative yield. E l a b o r a t i o n of ( 4 7 ) t o t h e c o m p l e t e t a x a n e r i n g s y s t e m ( 4 8 ) was t h e n a c c o m p l i s h e d by a l k y l a t i o n f o l l o w e d by a l d o l i z a t i o n ( S c h e m e 7 ) .

General and Synthetic Methods

540

i

10,c

Li 0

OMe

OMe

Me0 i

OL i

C0,Me

i WCOR -M (PPA)

steps

Me0

ITFA 0

I

COzMe

C0,Me

NZ

0 Me0R

O

COzMe

C

O

R

HOW

O

CO,H

0

Scheme 4

0-

0-H

Scheme 5

H

641

9: Highlights in Total Synthesis of Natural Products

1

175

(45) Scheme 6

J RO'0 -

H

OH

H' 0

H (47)

(48) Scheme 7

'C

General and Synthetic Methods

642

3 Steroids S t e r n b e r g and V o l l h a r d t h a v e 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 work on t h e s y n t h e s i s of s t e r o i d s b a s e d on c o b a l t - m e d i a t e d

[2+2+21 c y c l o a d d i t i o n r e a c t i o n s . 2 2 ( 4 9 ) t o e x c e s s [CpCo(CO),]

T h u s , e x p o s u r e of t h e e n e d i y n e

i n boiling iso-octane gave the red

c r y s t a l l i n e c o b a l t c o m p l e x ( 5 0 ) i n 65% y i e l d . d e m e t a l l a t i o n of

Oxidative

( 5 0 ) t h e n p r o v i d e d t h e a r y l d i e n e ( 5 1 ) w h i c h was

c o n v e r t e d i n t o t h e known k e t o n e ( 5 2 ) u s e d e a r l i e r i n a s y n t h e s i s o f oestrone. I n a f u r t h e r a p p l i c a t i o n of t h e p o l y e n e c y c l i z a t i o n a p p r o a c h t o s t e r o i d s y n t h e s i s , i t h a s b e e n shown t h a t a n e n o l a c e t a t e c a n f u n c t i o n as a u s e f u l t e r m i n a t o r ;

t h u s , treatment of t h e epoxy-enol

a c e t a t e ( 5 3 ) w i t h a L e w i s a c i d , f o l l o w e d by m a n i p u l a t i o n o f t h e i n t e r m e d i a t e ( 5 4 ) , produced t h e androst-4-en-3

-one - 1 , 1 7 - c a r b o x y l i c

a c i d ( 5 5 1 i n 11% y i e l d .23 4 Anthracyclinones S n i e c k u s and h i s c o l l e a g u e s have c o n t i n u e d t h e i r development o f t h e arylamide ortho-lithiation

s t r a t e g y with s y n t h e s e s of e r y t h r o l a c c i n

t e t r a m e t h y l e t h e r ( 6 0 a ) , 2 4 and d e s o x y e r y t h r o l a c c i n t r i m e t h y l e t h e r I n b o t h of t h e s e s y n t h e s e s , t h e r e a d y b e n z y l i c l i t h i a t i o n

(60b).25

o f t h e A-ring

a r y l m e t h y l had t o b e p r e v e n t e d s o a s t o a l l o w t h e

r e q u i r e d a r y l l i t h i a t i o n f o r p h t h a l i d e f o r m a t i o n by c o n d e n s a t i o n w i t h 3,5-dimethoxybenzaldehyde, (59b).

e. (56a)

-

( 5 9 a ) and (56b)

-

Two s t r a t e g i e s f o r o v e r c o m i n g t h i s d i f f i c u l t y were

developed.

I n t h e former s y n t h e s i s extremely r a p i d halogen-metal

e x c h a n g e o f ( 5 7 ) , o b t a i n e d by s i l y l a t i o n , m e t h y l a t i o n , a n d b r o m o d e s i l y t i o n of t h e b e n z a m i d e lithium.

I n t h e s y n t h e s i s of

b l o c k e d by b i s - s i l y l a t i o n

(56a) gave t h e r e q u i r e d a r y l -

( 6 0 b ) , b e n z y l i c l i t h i a t i o n was

as (581, w i t h t h e b l o c k i n g groups b e i n g

r e m o v e d by t r e a t m e n t w i t h c a e s i u m f l u o r i d e . The e n o r m o u s p o w e r o f t h e D i e l s - A l d e r

r e a c t i o n is w e l l

i l l u s t r a t e d t h i s y e a r w i t h a s y n t h e s i s o f v i n e o m y c i n B2 a g l y c o n e methyl e t h e r (61).26

I n t h i s s y n t h e s i s , both of t h e phenol r i n g s

a n d t h e p y r a n c o m p o n e n t o f t h e n a t u r a l p r o d u c t were c o n s t r u c t e d by Diels-Alder

r e a c t i o n s (Scheme 8 ) .

The n a p h t h o q u i n o n e a n t i b i o t i c

(*)-nanaomycin

A ( 6 6 ) h a s been

prepared using the i n t e r e s t i n g intramolecular phthaloylcobalt acetylene insertion-reductive elimination sequence ( 6 2 ) ( 6 3 ) .27

-

643

9: Hightights in Total Synthesis of Natural Products

n

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9: Highlights in Total Synthesis of Natural Products

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646

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647

9: Highlights in Total Synthesis of Natural Products Z i n c r e d u c t i o n of ( 6 3 ) t h e n g a v e t h e p r e s u m e d i n t e r m e d i a t e (64) a 6 - e n d o t r i g c y c l i z a t i o n , a n d o x i d a t i v e work-up l e d t o t h e p y r a n o n a p h t h o q u i n o n e ( 6 5 ) w h i c h was c o n v e r t e d i n t o t h e n a t u r a l product (66). T h i s y e a r , 1 9 8 4 , a l s o saw t h e p u b l i c a t i o n of a T e t r a h e d r o n Symposium-in-Print

on ' R e c e n t A s p e c t s o f A n t h r a c y c l i n o n e

which g a v e a v a l u a b l e and d e t a i l e d p i c t u r e of t h e s t a t e 28 of contemporary anthracyclinone chemistry.

Chemistry',

5 Alkaloids Cycloaddition reactions, p a r t i c u l a r l y those involving 1,3-dipoles, h a v e been u s e d e x t e n s i v e l y i n a l k a l o i d s y n t h e s i s i n 1984. E s p e c i a l l y a t t r a c t i v e was a o n e - p o t s y n t h e s i s of t h e i s o - i n d o l e ( T O ) , an a n t i m i c r o b i a l m e t a b o l i t e i s o l a t e d f r o m a Mexican s p o n g e . I n t h i s s y n t h e s i s t r e a t m e n t of t h e amine ( 6 7 ) w i t h s i l v e r f l u o r i d e formed a n azo-methine y l i d e i n t e r m e d i a t e ( 6 8 ) , which underwent [ 3 + 2 ] c y c l o a d d i t i o n w i t h 2-methoxy-3-methylbenzoquinone t o g i v e (69).

The q u i n o n e ( 6 9 ) was t h e n o x i d i z e d i n s i t u t o t h e n a t u r a l

p r o d u c t by e x c e s s s i l v e r f l u o r i d e

.*'

Confalone's r e s e a r c h group has reported t h e i r a p p l i c a t i o n o f an i n t r a m o l e c u l a r iminium y l i d e - o l e f i n s y n t h e s i s of ( + I - a - l y c o r a n e

( 7 4 ) .30

[3+21 c y c l o a d d i t i o n f o r t h e In this synthesis the ylide

( 7 2 ) , w h i c h was g e n e r a t e d by h e a t i n g t h e a l d e h y d e ( 7 1 ) w i t h

g-

b e n z y l g l y c i n o i n t h e p r e s e n c e of b a s e , u n d e r w e n t c y c l i z a t i o n d i r e c t l y t o y i e l d ( 7 3 ) w h i c h was t h e n c o n v e r t e d i n t o ( + ) - a - l y c o r a n e ( 7 4 ) by d e p r o t e c t i o n a n d P i c t e t - S p e n g l e r

cyclization.

T h e same

r e s e a r c h g r o u p h a s a l s o used t h i s methodology f o r t h e s y n t h e s i s o f t h e Sceletium a l k a l o i d A4 (76)

via

the aldehyde (75).31

Rebek e t a l . h a v e now p u b l i s h e d t h e f u l l d e t a i l s o f t h e i r s y n t h e s i s o f m i t o s e n e ( 8 0 ) , i n which a key s t e p i n v o l v e d t h e u s e of iminium y l i d e s i n a Huisgen p y r r o l e s y n t h e s i s t o form t h e p y r r o l i z i d i n e r i n g system of t h e n a t u r a l product,

-

G. (77)

-

(78)

(79).32 I n t e r e s t i n g u s e h a s b e e n made d u r i n g 1984 o f o t h e r [ 3 + 2 1

c y c l o a d d i t i o n s , such as those o f n i t r o n e s i n a s y n t h e s i s of inatoxin-a

(861, t h e ' v e r y f a s t d e a t h f a c t o r ' i s o l a t e d f r o m t h e

blue-green

a l g a e A n a b a e n a f l o s - a q u a e . 33

In t h i s synthesis the

a d d u c t ( 8 3 ) o f t h e n i t r o n e ( 8 1 ) w i t h t h e d i e n o l ( 8 2 ) was, a f t e r o x i d a t i o n of t h e a l c o h o l , t r e a t e d w i t h m - c h l o r o p e r b e n z o i c a c i d t o g e n e r a t e a new n i t r o n e (84), w h i c h u n d e r w e n t a n i n t r a m o l e c u l a r

648

General and Synthetic Methods

Ph

(71)

(72)

\Ph

(73)

(74)

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OAc

649

9: Highlights in Total Synthesis of Natural Products

(81)

(82)

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d

(91)

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650

General and Synthetic Methods

c y c l o a d d i t i o n t o form ( 8 5 1 , c o n t a i n i n g t h e r i n g system of t h e alkaloid. The s y n t h e s i s was f i n i s h e d i n f o u r f u r t h e r s t e p s . N i t r o n e s have a l s o played a key r o l e i n a remarkably g e n e r a l approach t o t h e p h e n a n t h r o i n d o l i z i d i n e and p h e n a n t h r o q u i n o l i z i d i n e alkaloids.34

The a p p r o a c h i s t y p i f i e d by t h e s y n t h e s e s o f

j u l a n d i n e ( 8 9 ) and ( ' ) - c r y p t o p l e u r i n e quinolizidine

( 9 0 ) c o u l d be p r e p a r e d

(92).

(2)-

Thus, t h e d i a r y 1

by a l d o l c y c l i z a t i o n o f t h e

acylated piperidine

( 8 8 ) d e r i v e d from t h e n i t r o n e c y c l o - a d d u c t

(87).

(90) then gave ( f ) - j u l a n d i n e ( 8 9 ) , o r

Reduction of

a l t e r n a t i v e l y , p h o t o l y s i s i n t h e p r e s e n c e of i o d i n e g a v e t h e a r y l coupling product (91)

which c o u l d be r e d u c e d t o t h e a n t i - t u m o u r

agent (5)-cryptopleurine

(92).

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

used n i t r o n e s i n a n e a t s y n t h e s i s of ( + ) - l a s u b i n e I ( 9 5 ) . 3 5

Here

t h e a d d i t i o n of hydrogen c h l o r i d e t o t h e n i t r o n e adduct (931, f o l l o w e d d i r e c t l y by r e d u c t i v e c l e a v a g e o f t h e n i t r o g e n o x y g e n bond leads

(94) t o t h e natural product.

An a p p r o a c h t o c l a v i c i p i t i c a c i d (99), a n e r g o t a l k a l o i d d e r a i l m e n t p r o d u c t , i s a l s o b e l i e v e d t o p r o c e e d by a [ 3 + 2 1 c y c l o a d d i t i o n r e a c t i o n . 36

o-dichlorobenzene

a t I90

Thus, t h e r m o l y s i s of t h e a z i d e ( 9 6 ) i n OC

g a v e (97) c o n t a i n i n g t h e r e q u i r e d

via ( 9 8 ) a s p r e s u m e d i n t e r m e d i a t e . via a n i t r e n e was d i s c o u n t e d on t h e b a s i :

natural product r i n g system, The a l t e r n a t i v e m e c h a n i s m

o f t h e s o l v e n t e f f e c t s o b s e r v e d , and a l s o t h e l a c k o f b y - p r o d u c t s . Amongst c y c l o a d d i t i o n r e a c t i o n s , t h e D i e l s - A l d e r

reaction has

l o n g been a f a v o u r e d s t r a t e g y , and t h i s y e a r t h e r e a c t i o n h a s p r o v i d e d a s h o r t s y n t h e s i s o f e l l i p t i c e n e ( 1 0 2 ) by t h e r e a c t i o n o f p y r i d y n e w i t h t h e i n d o l o p y r a n o n e ( 1 0 0 ) .37

Unfortunately

,

no

r e g i o s e l e c t i v i t y was o b s e r v e d , a n d t h e p r o d u c t h a d t o b e s e p a r a t e d from an e q u a l q u a n t i t y of i s o - e l l i p t i c e n e ( 1 0 1 ) . A n o t h e r , l o n g e r s y n t h e s i s b a s e d on a c l o s e l y r e l a t e d d i s c o n n e c t i o n h a s a l s o b e e n p u b l i s h e d , b u t a g a i n no r e g i o s e l e c t i v i t y was o b s e r v e d . 38 A hetero-diene

Diels-Alder

r e a c t i o n h a s been used i n an

i n t e r e s t i n g s y n t h e s i s o f t h e known p r e c u r s o r ( 1 0 5 ) o f t h e heteroyohombine a l k a l o i d s t e t r a h y d r o a l s t o n i n e (106b).39

( 1 0 6 a ) and akummiginf

Thus, t h e r m o l y s i s of t h e e n a l (103) i n r e f l u x i n g x y l e n e

g a v e t h e d i h y d r o p y r a n ( 1 0 4 ) i n 73% y i e l d . Friedel-Crafts

R e d u c t i o n , f o l l o w e d by

t y p e m e t h o x y c a r b o n y l a t i o n and d e b e n z y l a t i o n , t h e n

g a v e t h e known i n t e r m e d i a t e ( 1 0 5 ) . W e i n r e b e t a l . h a v e now a p p l i e d t h e i r i m i n o Diels-Alder

reactior

t o t h e c o n s t r u c t i o n of t h e t e t r a h y d r o p y r i d i n e m o i e t y o f t h e s p e r m i d i n e a l k a l o i d (f)-anhydrocannabisativine ( 1 1 0 ) . 4 0 T h u s ,

65 1

9: Highlights in Total Synthesis of Natural Products

CO,E t

I

cop (96)

CO, E t

I

CO, E t

I

H

+

I

General and Synthetic Methods

652

I

(108)

steps

&o

9: Highlights in Total Synthesis of Natural Products

653

a c e t y l a t i o n of t h e c r u d e p r o d u c t f r o m t h e r e a c t i o n of m e t h y l g l y o x y l a t e w i t h t h e c a r b a m a t e ( 1 0 7 ) g a v e ( 1 0 8 ) , w h i c h on h e a t i n g i n t h e p r e s e n c e o f H u n i g ' s b a s e a t 215 a c i d and underwent a Diels-Alder

OC

f o r 3 h both l o s t a c e t i c

reaction t o (109).

Hydrolysis of

t h e c a r b a m a t e , a n d e l a b o r a t i o n o f t h e m a c r o l i d e , w h i c h was c l o s e d a t t h e amine n i t r o g e n , completed t h e s y n t h e s i s .

Use h a s b e e n made o f a n a s y m m e t r i c [ 2 , 3 1 s i g m a t r o p i c r e a r r a n g e m e n t o f a n ammonium y l i d e i n a s y n t h e s i s o f t h e m i l l i p e d e In t h i s synthesis the i n s e c t r e p e l l a n t (+)-polyzonimine ( 1 14).41 t e r t i a r y a m i n e ( I l l ) , d e r i v e d f r o m L - b e n z y l p r o l i n o l , was f i r s t c o n v e r t e d i n t o t h e ammonium s a l t ( 1 1 2 ) by t r e a t m e n t w i t h cyanomethyl benzenesulphonate. potassium t-butoxide,

Formation of t h e y l i d e w i t h

rearrangement, and i n s i t u h y d r o l y s i s of t h e

r e s u l t i n g cyano-amine w i t h c o p p e r ( I 1 ) c a t a l y s i s t h e n g a v e t h e c h i r a l a l d e h y d e ( l l 3 ) , w h i c h was c o n v e r t e d i n t o ( + ) - p o l y z o n i m i n e . The p r o d u c t was f o u n d t o h a v e t h e same s e n s e of r o t a t i o n a s t h e n a t u r a l p r o d u c t , a l t h o u g h t h e a b s o l u t e c o n f i g u r a t i o n i s n o t known. ortho-Lithiation

methodology h a s proved a powerful r o u t e t o

d e n s e l y f u n c t i o n a l i z e d aromatic and hetero-aromatic

systems.

S n i e c k u s e t al.42 h a v e now f o u n d t h a t t h e m e t h o x y m e t h y l e t h e r ( 1 1 5 ) may b e a m i n a t e d

via

e q u i v a l e n t TsN3.

the lithio-derivative

by u s i n g t h e fiH2

The p r o d u c t w a s t h e n c o n v e r t e d i n t o t h e c a r b a m a t e

( 1 1 6 ) , which c o u l d i t s e l f be l i t h i a t e d a n d l e d t o t h e a c i d ( 1 1 7 ) after treatment with carbon dioxide. This acid then provided a p i v o t a l i n t e r m e d i a t e i n t h e i r s y n t h e s i s o f ( 1 1 8 ) , a known p r e c u r s o r o f t h e anti-tumoural a l k a l o i d anthramycin (119). L i t h i a t i o n h a s a l s o b e e n u s e d i n a s y n t h e s i s o f b e r n i n m y c i n i c a c i d ( 1 2 3 ) ~T ~ h u ~s , t r e a t m e n t of t h e p y r i d i n e d e r i v a t i v e ( 1 2 0 ) w i t h e x c e s s b u t y l l i t h i u m f o l l o w e d by MeOCH2NCS g a v e ( 1 2 1 ) , t h e r e b y s i m u l t a n e o u s l y f u n c t i o n a l i z i n g t h e p y r i d i n e n u c l e u s and i n t r o d u c i n g an amide p r o t e c t i n g group.

Treatment of (121) w i t h e t h y l bromopyruvate t h e n g a v e t h e b i s t h i a z o l e ( 1 2 2 ) , w h i c h was c a r r i e d on t o b e r n i n m y c i n i c a c i d (123) i n a f u r t h e r t h r e e s t e p s . The p y r r o l i d i n e a l k a l o i d s c o n t i n u e t o b e a n a r e a o f c o n s i d e r a b l e a c t i v i t y , a l t h o u g h much o f t h e work i s a l o n g w e l l t r o d d e n p a t h s . H o w e v e r , a 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 ( 1 2 6 ) ,44 by a f r e e r a d i c a l cyclization of the succinimide-derived

s u l p h i d e ( 1 2 4 ) by

t r e a t m e n t w i t h t r i b u t y l t i n h y d r i d e i n i t i a t e d by A I B N , i s noteworthy.

The c y c l i z a t i o n g i v e s ( 1 2 5 ) a s t h e m a j o r p r o d u c t

i s o m e r , w i t h o n l y small q u a n t i t i e s o f t h e d i a s t e r e o m e r a n d p r o d u c t s of r e d u c t i o n a n d e n d o - c y c l i z a t i o n b e i n g f o u n d .

General and Synthetic Methods

654

0 (118)

(119)

HN

NHBU'

0 (1 20 1

0 (121)

C02 E t /

0

OH

0

(123)

(122)

OAc

OAc

b

HO

steps

0

(124)

(125)

(126)

9: Highlights in Total Synthesis of Natural Products

655

Holmes a n d c o - w o r k e r s h a v e p u b l i s h e d a n e a t s y n t h e s i s o f t h e known perhydrohistrionicotoxin p r e c u r s o r ( 130 ) 4 5 f r o m t h e a d d u c t of nitrosyl chloride with octalin (127). of t h e Boc-protected

I n t h e key s t e p , o z o n o l y s i s

a m i n e ( 1 2 8 1 , f o l l o w e d by r e d u c t i v e w o r k - u p

with methyl s u l p h i d e , gave t h e n a t u r a l product r i n g system as t h e enamine ( 1 2 9 ) .

The b e n z y l d e r i v a t i v e ( 1 3 0 ) was t h e n o b t a i n e d i n A general entry t o another group of f r o g

s i x further steps.

t o x i n s , t h e p u m i l i o t o x i n s h a s a l s o been p u b l i s h e d .46 T h i s s y n t h e s i s h i n g e s on a s t e r e o s p e c i f i c i m i n i u m i o n - v i n y l s i l a n e cyclization,

(131)

(132).

+

The s i d e c h a i n was t h e n e l a b o r a t e d

u s i n g Wittig methodology l e a d i n g t o p u m i l i o t o x i n B ( 1 3 3 ) . A r e g i o s e l e c t i v e Polonovski rearrangement has provided

s t e p i n a s y n t h e s i s of ( - 1 - c h e r y l l i n e

t h e key

( 1 3 7 ) . ~ T~ h u s , t r e a t m e n t o f

t h e c h i r a l a m i n e o x i d e ( 1 3 5 1 , d e r i v e d by c y c l i z a t i o n , r e s o l u t i o n , and o x i d a t i o n of t h e d i b e n z y l amine ( 1 3 4 ) , w i t h p o t a s s i u m tb u t o x i d e and q u e n c h i n g w i t h e t h y l c h l o r o f o r m a t e g a v e ( 1 3 6 ) i n a n 8 : l m i x t u r e w i t h t h e product of c l e a v a g e o f t h e a l t e r n a t i v e b e n z y l i c C-N

bond.

Deformylation, carbamate r e d u c t i o n , and

d e p r o t e c t i o n then gave (-1-cherylline

( 1 3 7 ) i n 46% o v e r a l l y i e l d .

The n o v e l b i c y c l i c s t r u c t u r e o f t h e now c o m m e r c i a l l y c u l t u r e d a n t i b i o t i c bicyclomycin

(140) continues t o a t t r a c t a t t e n t i o n .

In

o n e i n t e r e s t i n g r o u t e t h e e t h e r b r i d g e was i n t r o d u c e d by nucleophilic attack a t electrophilic centres i n a dioxopiperazine r i n g g e n e r a t e d by t r e a t m e n t o f t h e p y r i d i n e t h i o l d e r i v a t i v e s ( 1 3 8 ) 48

and ( 1 3 9 ) w i t h s i l v e r t r i f l a t e .

L a s t l y , i n t h i s s e c t i o n , Inoue's group has r e p o r t e d an i m p r e s s i v e s y n t h e s i s of ( f ) - s u r u g a t o x i n

(141 ) .4g

6 Prostanoids The i s o l a t i o n o f t h e e n d o p e r o x i d e s P G G 2 a n d P G H 2 ,

some t e n y e a r s

ago, has given support t o the idea t h a t t h e prostaglandins are b i o s y n t h e s i z e d f r o m C 2 0 - p o l y u n s a t u r a t e d f a t t y a c i d s by a f r e e r a d i c a l process involving i n t e r m e d i a t e s of t h e t y p e (1421, ( 1 4 3 ) , and ( 1 4 4 ) .

Now C o r e y a n d h i s c o - w o r k e r s

h a v e mimicked t h i s

s e q u e n c e i n t h e l a b o r a t o r y t o p r o v i d e a new, s u b t l e r o u t e t o t h e s y n t h e s i s o f PGs. 50

Thus, t r e a t m e n t of t h e h y d r o p e r o x i d e ( 145)

w i t h m e r c u r y ( I 1 ) c h l o r o a c e t a t e l e d t o t h e endo-peroxide ( 1 4 6 ) which c o u l d b e c o n v e r t e d i n t o a m i x t u r e o f t h e a d v a n c e d PG p r e c u r s o r s (147) and (1481, f o l l o w i n g r e d u c t i o n w i t h t r i p h e n y l p h o s p h i n e and transacetalization i n t h e presence of pyridine tosylate.

656

General and Synthetic Methods

(131) Ph

A

(132)

,

HO

Me (133) Me0

OMe

H

-0 Ph

Ph

Ph (135)

(134)

CHO

&ph

-

6 I

Me0

3 steps

,OC'

Et

HO E

N

Ph (1 36)

(1 37)

,

Me

9: Highlights in Total Synthesis of Natural Products

657

(138)

(139)

42

HO

H

0

H o e M e

OH

Br


(141)

(140)

f

0--

R’

TR’ I(-

0- -

-

0--

0-y-%R2

,

R2

R2 (143)

(142)

HOO

R

(145)

(144)

General and Synthetic Methods

658

I n f u r t h e r s t u d i e s of t h e s y n t h e s i s o f p r i m a r y PGs, M a r i n o

e t al.51 have e s t a b l i s h e d t h a t t h e t r i m e t h y l s i l y l e n o l e t h e r (149 d e r i v e d f r o m c y c l o p e n t a d i e n e m o n o e p o x i d e c a n a c c e s s b o t h PGE1 a n d P G F l , by a s e r i e s o f t a n d e m 1 , 4 - a d d i t i o n 9).

of cyanocuprates

(Scheme

Furthermore, t h e intramolecular n i t r i l e oxide cycloaddition

reaction,

+.

(150)

-

(151)

-

( 1 5 2 1 , c a n be used t o good e f f e c t t o

p r o v i d e a d v a n c e d p r e c u r s o r s t o PGF2. 5 2 F u l l d e t a i l s o f e a r l i e r p u b l i s h e d w o r k o n t h e s y n t h e s e s o f PGD2 m e t h y l e s t e r a n d PG12 m e t h y l e s t e r h a v e now b e e n r e v e a l e d . 5 3 The c l a v u l o n e s ,

e.g. ( 1 5 3 ) , a r e a new f a m i l y o f m a r i n e

e i c o s a n o i d s , which b e a r a s u p e r f i c i a l resemblance t o p r o s t a g l a n d i n s , i s o l a t e d from C l a v u l a r i a v i r i d i s .

Two g r o u p s o f

r e s e a r c h e r s h a v e now p u b l i s h e d t h e i r i n d e p e n d e n t s y n t h e s e s o f c l a v u l o n e s , and t h e s a l i e n t f e a t u r e s of t h e r o u t e s are summarized i n Scheme 1 0 . 54

7 SDiroacetals A s y n t h e s i s o f t h e t a l a r o m y c i n s , w h i c h a r e n o v e l t o x i n s p r o d u c e d by

t h e f u n g u s T a l a r o m y c e s s t r i p i t a t a s , was f i r s t p u b l i s h e d b y S c h r e i b e r a n d Sommer i n 1 9 8 3 .

D u r i n g 1 9 8 4 , n o l e s s t h a n f o u r new

s y n t h e s e s o f t h e s e i n t e r e s t i n g m e t a b o l i t e s were d e s c r i b e d .

Whereas

Kozikowski e t al.55 used t h e i s o x a z o l i n e ( 1 5 6 ) as a key i n t e r m e d i a t e i n t h e i r s y n t h e s i s , Kay a n d v i a an intramolecular c a t i o n - o l e f i n

~

bar tho lo me^^^

cyclization step,

proceeded

y&.

-

(158)

( 1 5 9 ) , t o s e t u p t h e 4-hydroxytetrahydropyran p r e c u r s o r ( 1 5 9 ) t o talaromycin B (157).

The n u c l e o p h i l i c c l e a v a g e of t h e o x i r a n e

( 1 6 0 ) by t h e o r g a n o c u p r a t e d e r i v e d f r o m 6 - l i t h i o - 3 - e t h ~ l - 3 ~ 4 dihydro-2H-pyran

( 1 6 1 ) was t h e k e y s t e p i n a n o t h e r s y n t h e s i s o f

( 1 5 7 1 , ~a n~d S m i t h a n d T h o m p s o n ’ s r o u t e t o t h e ( - 1 - t a l a r o m y c i n s b a s e d o n G r i g n a r d a d d i t i o n of

was

( 1 6 3 ) t o t h e l a c t o n e ( 1 6 2 ) . 58

P h y l l a n t h o c i n ( 1 6 6 ) is t h e a g l y c o n e of t h e a n t i l e u k a e m i c glycoside (+)-phyllanthoside,

a n d t h e m o l e c u l e was f i r s t

s y n t h e s i z e d b y M c G u i r k a n d C 0 1 l u m . ~ ~N o w W i l l i a m s e t a 1 . 6 0 h a v e described an a l t e r n a t i v e s y n t h e s i s of

(166) s t a r t i n g from tartaric

a c i d , which u s e s ( 1 6 4 ) and ( 1 6 5 ) as c e n t r a l i n t e r m e d i a t e s .

8 Lignans The h i g h b i o l o g i c a l a c t i v i t y o f many n a t u r a l l y o c c u r r i n g l i g n a n s h a s p r o d u c e d i n c r e a s e d i n t e r e s t i n t h e s y n t h e s i s of t h i s c l a s s o f

9: Highlights in Total Synthesis of Natural Products

659

-

OSiEt,

PGE,

ii, KF buffer

(149)

OH

Scheme 9

N-0

H

N-0

I

I steps

j. OR

0

OH

I

C,H..

I

c, I

W

OH

OAc

Scheme 10

660

General and Synthetic Methods

&Y

+

0

1571

(160)

(yo I’ +

BrMg

(1 63)

(162)

BnO

OMEM

‘OH

H

66 1

9: Highlights in Total Synthesis of Natural Products

natural product. The a n t i l e u k a e m i c ( + I - s t e g a n a c i n ( 1 7 1 ) h a s b e e n t h e s u b j e c t of a n i n t e r e s t i n g 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 i n w h i c h Michael a d d i t i o n t o , and a l k y l a t i o n o f , a c h i r a l b u t e n o l i d e , are t h e key s t e p s . 6 1

Thus, a d d i t i o n of t h e l i t h i o - a r y l d i t h i a n e

t o the (-)-glutamic specifically.

(168)

acid derived butenolide (167) gave (169)

A f t e r r e d u c t i v e d e s u l p h u r i z a t i o n and d e t r i t y l a t i o n

t h e s u b s t i t u t e d l a c t o n e ( 1 6 9 ) was b e n z y l a t e d t o g i v e ( 1 7 0 ) , t h e e l e c t r o p h i l e a p p r o a c h i n g f r o m t h e now l e s s h i n d e r e d a - f a c e o f t h e molecule.

F u n c t i o n a l g r o u p m a n i p u l a t i o n of t h e l a c t o n e r i n g ,

f o l l o w e d by t h a l l i u m - m e d i a t e d

a r y l c o u p l i n g and b e n z y l i c o x i d a t i o n ,

then completed t h e s y n t h e s i s . Another approach t o ( + ) - s t e g a n a c i n ( 1 7 1 ) and t h e r e l a t e d ( * ) s t e g a n o n e ( 1 7 6 ) a l s o depended o n a t h a l l i u m - m e d i a t e d b u t t h i s time c l o s i n g a seven-membered

ring,

a r y l coupling,

G. (172)

-

(1731,

w h i c h was s u b s e q u e n t l y e x p a n d e d t o t h e r e q u i r e d d i b e n z o c y c l o - o c t a n e ( 1 7 5 ) by s o l v o l y s i s o f t h e c y c l o p r o p a n e c a r b i n o l ( 1 7 4 1 , t h e r e b y also introducing the required benzylic oxidation. The i n t e r m e d i a t e ( 1 7 5 ) was t h e n c a r r i e d t h r o u g h t o ( + ) - s t e g a n o n e f i v e s t e p s . 62

(176) i n a f u r t h e r

A p o t e n t i a l l y g e n e r a l r o u t e t o t h e 2,6-diarylmonoepoxy

l i g n a n o l i d e s involved t h e s y n t h e t i c a l l y l i t t l e used manganese(II1)mediated r a d i c a l a d d i t i o n of a c e t i c a c i d t o an o l e f i n (177) l e a d i n g t o (178) -63

A c e t a t e h y d r o l y s i s , f o l l o w e d by f o r m a t i o n o f t h e m i x e d

a c e t a l and s i l y l a t i o n , t h e n gave t h e s i l y l e n o l e t h e r ( 1 7 9 ) , which c o u l d b e c y c l i z e d by t r e a t m e n t w i t h t i t a n i u m t e t r a c h l o r i d e t o g i v e a diarylmonoepoxylignanolide ( 1 8 0 ) w i t h s p e c i f i c a l l y t h e n a t u r a l

cis-geometry. A l s o of n o t e h a s b e e n t h e s y n t h e s i s of t h e known p r e c u r s o r ( 1 8 1 ) o f t h e c y t o t o x i c n e o l i g n a n (+)-megaphone 64 f r o m 3,4,5-trimethoxybenzaldehyde.

(182) i n fourteen s t e p s

9 Polyols A s in previous years,

t h e need f o r a n t h r a c y c l i n o n e - d e r i v e d amino-

s u g a r 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 g e n u i t y , a n d t h i s y e a r t h e p r e p a r a t i o n of t h e s e s u g a r s from non-carbohydrate received particular attention. L-daunosamine

precursors has

I n 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 of

( 1 8 7 ) l a c t i c a c i d ( 1 8 3 ) was u s e d a s t h e b a s i c c h i r a l T h u s , p r o t e c t i o n of t h e l a c t i c a c i d hydroxy-

b u i l d i n g block.65

g r o u p as t h e M E M e t h e r , f o l l o w e d by diphenylphosphorazide-mediated condensations with methyl isocyanoacetate gave t h e oxazoline ( 1 8 4 ) ,

General and Synthetic Methods

662

OMe

(169)

r O

,OH OMe OMe

(170)

(171)

rc!

f-0

C02Me

C02Me

OMe

OMe

CH,OH

OMe

(1 72 1

/-O

(175)

OMe

(176)

9: Highlights in Total Synthesis of Natural Products

663

Ph'

(177)

(178)

(179)

(181)

(182)

Me

Me

HO

(180)

<

Meo-o-k..--$To C0,Me

CO,H

O L

H

I N

HO

NH,HCL

NHCOPh &C02Me \

(188)

(189)

0

/

NHCOPh (190)

NHCOPh

(191)

(193)

(1 9 2 )

General and Synthetic Methods

664

w h i c h was b o t h l a c t o n i z e d a n d h y d r o l y s e d on t r e a t m e n t w i t h a q u e o u s acid t o give the amino-tetronate (185). Sequential reduction of t h e d o u b l e bond i n ( 1 8 5 ) , a m i n e p r o t e c t i o n , a n d c a r b o n y l g r o u p r e d u c t i o n t h e n g a v e t h e l a c t o l ( 1 8 6 ) , which c o u l d be r i n g e x p a n d e d by r e a c t i o n w i t h methoxymethylenetriphenylphosphorane t o g i v e , a f t e r d e p r o t e c t i o n , L-daunosamine

(187).

N-Benzoyldaunosamine ( 1 9 2 ) h a s a l s o been p r e p a r e d i n o p t i c a l l y a c t i v e f o r m by a r o u t e i n w h i c h t h e a z e t i d e n o n e ( 1 8 8 ) , p r e p a r e d

from p e n t a d i e n e a n d c h l o r o s u l p h o n y l i s o c y a n a t e , p r o v i d e d a p i v o t a l i n t e r m e d i a t e . 6 6 H y d r o l y s i s a n d p r o t e c t i o n of ( 1 8 8 ) g a v e ( 1 8 9 ) w h i c h c o u l d b e r e s o l v e d by m e a n s o f e i t h e r i t s d i b e n z o y l t a r t r a t e o r

p-bromotartranilate

salts.

The r e s o l v e d a m i d e - e s t e r

h y d r o x y l a t e d w i t h t r i m e t h y l a m i n e ;-oxide

was t h e n

a n d c a t a l y t i c osmium

t e t r a o x i d e t o g i v e a m i x t u r e of t h e l a c t o n e s ( 1 9 0 ) and ( 1 9 1 ) . P r o t e c t i o n o f t h e f r e e a l c o h o l g r o u p s i n ( 1 9 0 ) a n d (1911, f o l l o w e d by DIBAL r e d u c t i o n t o t h e c o r r e s p o n d i n g l a c t o l , a n d a m m o n o l y s i s t h e n gave from ( 1 9 0 ) Ls-N-benzoyldaunosamine

( 1 9 2 ) , and f r o m ( 1 9 1 ) i t s 5-epimer ( 1 9 3 ) . A s y n t h e s i s o f 5 - e p i - d e o s a m i n e ( 1 9 7 ) h i n g e s on a n i n t r a m o l e c u l a r N-sulphinyl d i e n o p h i l e Diels-Alder r e a c t i o n as t h e key s t e p . 67 Thus, t r e a t m e n t of t h e c a r b a m a t e ( 1 9 4 ) w i t h t h i o n y l c h l o r i d e g a v e t h e s i n g l e D i e l s - A l d e r a d d u c t ( 1 9 5 ) i n 80% y i e l d . Phenylmagnesium b r o m i d e c l e a v e d t h e s u l p h u r - n i t r o g e n bond i n ( 1 9 5 ) t o f o r m a n a l l y l i c s u l p h o x i d e , w h i c h on w a r m i n g i n t h e p r e s e n c e o f p i p e r i d i n e g a v e , by m e a n s o f a s u l p h o x i d e - s u l p h e n a t e r e a r r a n g e m e n t , t h e carbamate a l c o h o l (196). The s y n t h e s i s was t h e n c o m p l e t e d by Em e t h y l a t i o n and o z o n o l y s i s . Rodrigo and h i s co-workers have p u b l i s h e d a remarkably s h o r t s y n t h e s i s o f ( + ) - s h i k i m i c a c i d ( 2 0 1 .68 T r e a t m e n t o f t h e D i e l s Alder a d d u c t ( 1 9 8 ) d e r i v e d from f u r a n a n d a c r y l o n i t r i l e w i t h LDA, and p r o t e c t i o n of t h e r e s u l t i n g a l c o h o l as i t s t - b u t y l d i m e t h y l s i l y l e t h e r , f i r s t g a v e ( 1 9 9 ) . c i s - H y d r o x y l a t i o n o f ( 1 9 9 ) w i t h osmium t e t r a o x i d e p r o c e e d e d from t h e l e s s h i n d e r e d f a c e o f t h e more e l e c t r o n - r i c h d o u b l e bond t o g i v e ( 2 0 0 ) . H y d r o l y s i s o f t h e n i t r i l e group i n (200) and d e s i l y l a t i o n completed t h e s y n t h e s i s . A c l o s e l y analogous approach t o (*)-methyl s h i k i m a t e h a s a l s o been p u b l i s h e d .69 Disodium p r e p h e n a t e ( 2 0 4 ) p r o v i d e s an e x t r e m e l y c h a l l e n g i n g s y n t h e t i c target owing t o t h e e a s e w i t h which d e h y d r a t i v e A d e c a r b o x y l a t i o n o c c u r s under even m i l d l y a c i d i c c o n d i t i o n s . r e c e n t s y n t h e s i s o v e r c o m e s t h i s d i f f i c u l t y by u s i n g a n y l i d e n e

665

9: Highlights in Total Synthesis of Natural Products

M

e

N OHw

2

H

Me (194)

(195)

(1 97)

( 1 96)

CO, H

H 0”

OH (1 98)

(199)

(200)

(201)

C0,Me A

c

O

W

C0,Me

0 p COzNa

ij

o::q (204)

(203)

(202) (OAc

II/

<Me2But

OSiMe,Bu‘ (205)

CHo (206)

OSiMe2Bu‘ @OAC

/O

OSiMe,Bu‘

OH

(207)

ooAc & MeO2c,

,N-C0,Me

MeOZC

\ /N

/

&oAc

\

x

‘OAc

AC

OAc

OH

(208)

COzMe

OAc

NHMe Meox;@H

.‘OH

HO’ NH,

General and Synthetic Methods

666 dioxolan-4-one

a s a l a t e n t p y r u v a t e w h i c h may b e d e p r o t e c t e d by

treatment with alkali."

Thus, t h e Diels-Alder

acetoxy-3-trimethylsilyloxybutadiene work-up

t h e dienone (203).

r e a c t i o n of 1 -

with (202) gives a f t e r acidic

R e d u c t i o n o f t h e k e t o n e w i t h 9-

b o r a b i c y c l o n o n a n e , f o l l o w e d by s e p a r a t i o n o f t h e d i a s t e r e o m e r s a n d t r e a t m e n t w i t h m e t h a n o l i c sodium h y d r o x i d e , disodium prephenate

then yielded

(*)-

(204).

The c y c l o h e x a n e p o r t i o n o f t h e a n t i f u n g a l c y c l i t o l ( ? ) eupenoxide ( 2 0 8 ) h a s been p r e p a r e d , s t a r t i n g w i t h t h e D i e l s - A l d e r r e a c t i o n of a n a c e t y l e n i c a l d e h y d e ( 2 0 6 ) w i t h t h e b i s - s i l y l o x y diene (205) t o give the cyclohexadiene d a y s a t 115 0C.71 t-butyl

(207) i n 68% y i e l d a f t e r 4

T h e s y n t h e s i s was c o m p l e t e d by e p o x i d a t i o n w i t h

hydroperoxide catalysed with p-nitroperoxybenzoic

Wittig chain extension, iodine-catalysed

acid,

photochemical

e q u i l i b r i a t i o n o f t h e d o u b l e bond t o t r a n s , and f i n a l l y d e p r o t e c t i o n t o g i v e (k)-euponoxide

(208).

An u n u s u a l p h o t o c h e m i c a l l y p r o m o t e d D i e l s - A l d e r

r e a c t i o n was

u s e d t o f o r m t h e ~ - I l 4 - d i a m i n o c y c l o h e x a n ef u n c t i o n a l i t y o f t h e aminoglycoside a n t i b i o t i c aglycone (+)-fortarnine

( 2 1 2 ) .72

Thus,

i r r a d i a t i o n of a c y c l o h e x a n e s o l u t i o n of e q u i m o l a r q u a n t i t i e s o f t h e c y c l o h e x a d i e n e ( 2 0 9 ) and d i m e t h y l a z o d i c a r b o x y l a t e a t 46-50 f o r 24 h g a v e , a f t e r c h r o m a t o g r a p h y , (210).

OC

a 75% y i e l d o f t h e b i c y c l e

H y d r o x y l a t i o n w i t h osmium t e t r a o x i d e i n p y r i d i n e o c c u r r e d

from t h e l e s s h i n d e r e d a-face t o g i v e ( 2 1 1 ) , which c o n t a i n s t h e appropriately substituted cyclohexane r i n g of t h e n a t u r a l product o n l y r e q u i r i n g some f u n c t i o n a l g r o u p m a n i p u l a t i o n t o c o m p l e t e t h e synthesis. 10 M a c r o l i d e s a n d I o n o p h o r e s

The n o v e l e i c o s a n o i d h y b r i d a l a c t o n e ( 2 2 0 ) h a s b e e n p r e p a r e d f r o m t h e r e a d i l y a v a i l a b l e c h i r a l b i c y c l e (2131, thereby confirming t h e a b s o l u t e s t r u c t u r e p r o p o s e d on b i o s y n t h e t i c a n d c o m p u t a t i o n a l grounds.73

Thus, a d d i t i o n of t h e l i t h i u m r e a g e n t d e r i v e d from t h e

cyclopropylstannane

( 2 1 5 ) t o t h e b i c y c l o h e p t e n o n e ( 2 1 4 ) w h i c h was

p r e p a r e d by f o r m y l a t i o n a n d t o s y l a t o n o f hydroxy-tosylate

t r e a t m e n t w i t h tetra-n-butylammonium acetylene (217).

(213), f i r s t gave t h e

( 2 1 6 ) w h i c h u n d e r w e n t a Grob f r a g m e n t a t i o n on f l u o r i d e t o produce t h e

R e d u c t i o n , S h a r p l e s s e p o x i d a t i o n , t-

b u t y l d i m e t h y l s i l y l p r o t e c t i o n , and c o u p l i n g w i t h t h e i o d o - a l l e n e OBO e s t e r ( 2 1 8 ) , f o l l o w e d by L i n d l a r h y d r o g e n a t i o n , t h e n g a v e t h e

9: Highlights in Total Synthesis of Natural Products

667

(217)

9

0 '

H-6°H

H--

H

i

L

(220)

(219)

CO, Me

bH

0 (221)

(222)

____)

HO

*HO

H

C02Me

OH

C02Me

HO

(224)

(226)

668

General and Synthetic Methods

diene (219). The synthesis was completed by deprotection and macrolactonization by the double activation method with bis-(4-tbutyl-~-isopropylimidazo-2-yl) disulphide/triphenylphosphine to give hybridalactone with the same rotation and spectroscopic properties as the natural material. An interesting synthesis of nonactin (227), described by Bartlett et a1.,74 uses an enantiodivergent approach to the ( + ) and (-)-nonactic acid subunits required. Thus, the key carbonate (222), which is available in six steps from the alcohol (221), could be cyclized by treatment with potassium hydride to give (223) or by methanolysis followed by acid-catalysed hydration to its epimer (224). Hydrogenation of either (223) or (224) in the presence of a 5% rhodium on alumina catalyst occurred from the face opposite to the hydroxypropyl group to give (+)-nonactic acid (225) acid (226), respectively. Linkage of these and (-)-8-epi-nonactic two compounds to form a dimer was achieved by the reaction of the potassium salt of (225) with the mesylate of (2261, thereby simultaneously achieving the required inversion of the 8-position of the (-)-unit. Hydrolysis of the methyl ester functionality, followed by macrolactonizationldimerization by formation of the mixed anhydride with diphenyl phosphorochloridate, and refluxing it in benzene in the presence of D M A P then gave nonactin (227). Isobel and co-workers have extended their approach to the important maytansine antitumour macrolactams with syntheses of ( * ) maysine (228) and (+)-I-methylmaysenine (229) ,75 and have also developed the strategy so as to allow the synthesis of chiral ( - ) maytansinol (233) .76 Thus, the key intermediate (232) was prepared by Wittig coupling of the right-hand aryl fragment (230) with the D-mannose-derived aldehyde (23l), which was then converted into (-)-maytansin01 ( 2 3 3 ) in a further eleven steps. Full details of the synthesis of the macrocyclic pyrrolizidine alkaloid (+I-intergerrimine (237) by Narasaka's group have now been published.77 The synthesis hinged on the use of a methylthiomethyl ester as an activatable protecting group. Thus, the seco-compound

(236) could be prepared by the reaction of the lithium alkoxide of the retronecine silyl ether (235) with the protected intergerrinecic anhydride (234). The t-butyldimethylsilyl group was then removed by treatment with tetra-n-butylammonium fluoride, and the ester group activated by oxidation of the sulphide to sulphone. Closure of the macrolide was then initiated by formation of the lithium alkoxide by reaction with n-butyl-lithium, which

9: Highlights in Total Synthesis of Natural Products

669

Me0

),2

(229)

( MeO

MeO

CI

“CO,Me

OSiMe, But

OMe

0/

/

OMe OMe (231)

( 2 30)

Me0

OMe

(232)

(233)

/

PPh,

General and Synthetic Methods

670

L \

“)2O

‘COICH2SMe

.

.

N

(234)

(235) Me

I

0s Mez Bu

Me

0siMe2But

(237)

9: Highlights in Total Synthesis of NaturaZ Products

67 1

l a c t o n i z e d b y e x p u l s i o n of f o r m a l d e h y d e a n d m e t h y l s u l p h i n a t e anion. The f u l l p a p e r d e s c r i b i n g L e y ' s s y n t h e s i s o f t h e i o n o p h o r e

' h a s now b e e n p u b l i s h e d , 78 a s w e l l a s d e t a i l s of Roush's approach t o indanomycin methyl e s t e r a n t i b i o t i c X - I 4547A ( ' i n d a n o m y c i n

( 2 4 3 1 , w h i c h was b a s e d on i n t r a m o l e c u l a r D i e l s - A l d e r t h e p e n t a e n e ( 2 4 2 ) .79

Thus, potassium t-butoxide

reaction of

initiated

condensation of t h e phosphinate (238) w i t h t h e pyran aldehyde ( 2 3 9 1 , p r e p a r e d by d e g r a d a t i o n o f t h e n a t u r a l p r o d u c t , g a v e a f t e r Swern o x i d a t i o n t h e a l d e h y d e ( 2 4 0 ) .

Reaction of (2401-with t h e

pyrrolic Wittig reagent (241) then gave,

via

the unisolated

p e n t a e n e ( 2 4 2 ) , a 51% y i e l d o f i n d a n o m y c i n m e t h y l e s t e r , w h i c h h a s p r e v i o u s l y been c o n v e r t e d i n t o indanomycin. S e v e r a l r e s e a r c h g r o u p s have a c c e p t e d t h e c h a l l e n g e of s y n t h e s i z i n g macrocyclic t r i c h o t h e c a n o i d s from v e r r u c a r o l

(2481, a

t a s k which poses t h e formidable problems of ( a ) c o r r e c t i n t r o d u c t i o n of t h e remote c h i r a l c e n t r e s , prone E,Z-muconate

( b ) t h e isornerization-

m o i e t y , a n d ( c ) t h e e v e n t u a l c l o s u r e o f a n 18-

membered m a c r o l i d e r i n g .

These s y n t h e s e s , of r o r i d i n E ( 2 4 4 ) ,

b a c c h a r i n B5 ( 2 4 5 ) , 8 0 v e r r u c a r i n J ( 2 4 6 ) , 8 1 a n d v e r r u c a r i n B ( 2 4 7 ) ,82 a l l reward c a r e f u l s t u d y .

Also d e s e r v i n g of more t h a n

c u r s o r y a t t e n t i o n i s a s y n t h e s i s of t h e s p e r m i d i n e s i d e r o p h o r e p a r a b a c t i n ( 2 4 9 ) .83 11 Other Natural Products

Two g r o u p s o f r e s e a r c h e r s h a v e d e s c r i b e d a c o n c e p t u a l l y n o v e l

a p p r o a c h t o t h e 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 v i t a m i n D c o m p o u n d s ,

e.g.

( 2 5 1 ) , w h i c h i s b a s e d on u s e o f t h e c h i r a l b i c y c l o [ 3 . 1 . 0 1 -

h e x a n e d e r i v a t i v e ( 2 5 0 ) .84 1 8 5 Tirandarnycin

( 2 5 5 ) i s a n a n t i b i o t i c c h a r a c t e r i z e d by t h e

presence of a 3-dienoyltetramic

a c i d m o i e t y , l i n k e d by a p o l y e n e

s e g m e n t t o a f u n c t i o n a l i z e d 2,9-dioxabicyclo[3.3.l]nonane ring s y s t e m . ' D u r i n g 1 9 8 4 , t h e r e s e a r c h g r o u p s of M a r t i n 8 6 a n d Z i e g l e r 8 7 have d e s c r i b e d approaches t o t h e a c i d p r e c u r s o r (254) of t i r a n d a m y c i n b a s e d on s i m i l a r f u r a n p r e c u r s o r s a s k e y i n t e r m e d i a t e s , v&.

( 2 5 2 ) and ( 2 5 3 ) .

F u r a n s h a v e a l s o f e a t u r e d as s t a r t i n g m a t e r i a l s i n w h a t c a n b e described as Paterno-Buchi photocycloaddition approaches t o a v e n a c i o l i d e ( 2 6 1 ) a n d a s t e l t o x i n ( 2 6 6 ) d e s c r i b e d by S c h r e i b e r a n d co-workers. Thus, p h o t o c y c l o a d d i t i o n of nonanal t o f u r a n f i r s t l e d

672

General and Synthetic Methods

A

HO

HO

(244)

H

H

Lodo

0

(245)

$J ?i-y/ 0L

‘0

H

O

673

9: Highlights in Total Synthesis of Natural Products \

Jfj+

H

-

I

HO

/

F.J" H

(2501

p - TSA

Li

(252)

General and Synthetic Methods

674

H

(256)

(257)

H

17

$BH17

m$eHl7

bMe (259)

260

(258)

I 17

(261) Reagents: i, HCI; ii,

A MgBr;

i i i , Me,COIP-TSA, L

i v , PCC; v, 0,: vi, mcpba J

675

9: Highlights in Total Synthesis of Natural Products

1

&

OH I

(271 1

NC

General and Synthetic Methods

676

t o t h e o x e t a n e ( 2 5 6 ) i n n e a r q u a n t i t a t i v e y i e l d , w h i c h was s m o o t h l y transposed t o the t r i o 1 (257).

Conversion of (257) i n t o t h e b i s -

l a c t o n e ( 2 6 0 ) was t h e n a c c o m p l i s h e d 2 t h e i n t e r m e d i a t e s ( 2 5 8 ) a n d ( 2 5 9 ) , and m e t h y l e n a t i o n o f ( 2 6 0 ) f i n a l l y p r o d u c e d ( * ) - a v e n a c i o l i d e ( 2 6 1 ) .88 S i m i l a r l y , t h e a d v a n c e d p r e c u r s o r ( 2 6 4 t o t h e m y c o t o x i n a s t e l t o x i n ( 2 6 6 ) was e l a b o r a t e d , via ( 2 6 5 1 , s t a r t i n g f r o m o x e t a n e (263) r e s u l t i n g from Paterno-Buchi

p h o t o c y c l o a d d i t i o n between 3 , 4 -

d i m e t h y l f u r a n a n d t h e a l d e h y d e ( 2 6 2 ) .89 The t r i s u b s t i t u t e d f u r a n r i n g p o r t i o n i n t h e f u r a n o s e s q u i t e r p e n e g n i d i d i o n e ( 2 6 8 ) p r o d u c e d by G n i d i a l a t i f o l i a , h a s b e e n e l a b o r a t e d

via thermolysis

of a c e t y l e n i c o x a z o l e i n t e r m e d i a t e s ,

G. ( 2 6 7 1 ,

a n d Ramage e t a l . h a v e h i g h l i g h t e d t h e u s e of d i o x o l a n o n e i n t e r m e d i a t e s , v&.

( 2 6 9 ) , i n n e a t s y n t h e s e s of p u l v i n o n e s ,

t e t r o n i c a c i d s , and p u l v i n i c a c i d s

e.g. ( 2 7 0 ) . ”

O t h e r i n t e r e s t i n g n a t u r a l p r o d u c t s whose s y n t h e s e s h a v e been a c h i e v e d d u r i n g t h e p e r i o d of t h e R e p o r t i n c l u d e t a b t o x i n ( 2 7 1 ) , t h e e x o t o x i n from Pseudomonas t a b a c i , 9 2 b o n g k r e k i c a c i d ( 2 7 2 ) , a t o x i n p r o d u c e d by P . c o c o v e n e n a n s , 93 t h e i s o c y a n i d e ( 2 7 3 ) p r o d u c e d ,, a n d some n o v e l c h l o r i n s o f p a r t i c u l a r r e l e v a n c e by T r i c h o d e r m a , t o b i o s y n t h e t i c r e s e a r c h on V i t a m i n

’’ n

References 1 2 3 4 5 6

7

G.Pattenden and S.J.Teague, Tetrahedron Lett., 1984, 25, 3021. E.Piers and V.Karunaratne, J. Chem. S O C . , Chem. CommuK, 1984, 959. M.T.Crimmins and J.A.DeLoach, __.____ J. Org. Chem., 1984, 9, 2076. T.Ohtsuka, H.Shiraharna, and T.Matsurnoto, Chem. Lett., 1984, 1923. D.E.Cane and P.J.Thomas, J. Am. Chem. SOC., 1984, 106,5295. Y.Tobe, S.Yamashita, T.Yamashita, K.Kakiuchi, and Y.Odaira, J. Chem. SOC., Chem. Commun., 1984, 1259. For synthesis during 1984 see : B. A .Dawson, A. K. Ghosh, J. L.Jurila, A.J.Ragauskas, and J.B.Stothers, Can. J. Chem., 1984, 62, 2521; M.Demuth, P.Ritterskamp, and K.Schaffner, Helv. Chim. Acta, 1984, 2, 2023; T.Ito, N .Tomiyoshi, K-Nkamura, S. Azuma, M. Izawa, F.Nuruyama, M. Yanagiya, H.Shiraharna, and T.Matsumoto, Tetrahedron, 1984, 5, 241 ; P.F.Schuda and M.Heimann, p.2365. R.L.Funk and G.L.Bolton, J. Org. Chem., 1984, 5022. L.A.Paquette and K.E.Stevens, Can. J. Chern., 1984, 62, 2415. 629; G.T.Crisp, E.Piers and V.Karunaratne, Can. J. Chem., 1984, W.J.Scott, and J.K.Stille, J. Am. Chem. SOC., 1984, 106,7500. G.Mehta and A.N.Murty, J. Chem. SOC., Chem. Commun., 1984, 1058. W.A.Kinney, M.J.Coghlan, and L . A . P a m C h e m . SOC., 1984, 106, 6868. R.C.Gadwood, R.M.Lett, and J.E.Wissinger, J. Am. Chem. SOC., 1984, 106, 3869. A.B.Smith I11 and J.Konopelski, J. Org. Chem., 1984, 2, 4094. S. D.Burke, C.W.Murtiashaw, J. O.Saunders, J. A-Oplinger, and M.S.Dike, J. Am. Chern. SOC., 1984, 106,4558; K.Kon, K.Ito, and S.Isoe, Tetrahedron Lett., 1984, 5, 3739; K.Kakiuchi, T.Nakao, M.Takeda, Y.Tobe, and Y.Waira, p.557.

u.,

8 9 10

11 12

13 14 15

x.,

s, e,

9: Highlights in Total Synthesis of Natural Products 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 48 49 50 51 52 53

3539.

-

.em., 1984 49, 1574. :hem. Commun , 1984, 721. n Lett., 1984, 2, 483. ledron Lett., 1984, 25, 479. [.Quallich. J. Am. Chem. SOC., 1984

55 56 57 58 59 60 61

.

1

106,

,106,

M.S.South and L.S.Liebeskind, J. Am. Chem. SOC., 1984, 4181. Tetrahedron, 1984, 110, No.22. K.A.Parker, I.D.Cohen, A.Padwa, and W.Dent, Tetrahedron Lett., 1984, 2, 4917. C.-L.J.Wang, W. C. Ripka, and P.N. Confalone, Tetrahedron Lett., 1984, 25, 4613. P.N.Confalone and E.M.Huie, J. Am. Chem. SOC., 1984, 106,7175. J. Rebek, S. H. Shaber , Y .-K.Shue, J. -C.Gehret , and S.Zimmerman, J. Org. Chem., 1984, 9, 5164. J.J.Tufariello, H.Meckler, and K.P.A.Senaratne, J. Am. Chem. SOC., 1984, 106, 7979. H.Lida, Y.Watanabe, M.Tanaka, and C-Kibayashi, J. Org. Chem., 1984, 2, 2412. H.Lida, M.Tanaka, and C.Kibayashi, J. Org. Chem., 1984, 49, 1901. A.P.Kozikowski and M.N.Greco, J. Org. Chem., 1984, 5, 2 E 0 . C.May and C.J.Moody, J. Chem. SOC., Chem. Commun., 1984, 926. G.W.Gribble, M.G.Saulnier, M.P.Sibi, and J.A.Obaza-Nutaitis, J. Org. Chem., 1984, 9, 4518. S.F.Martin and B.Benage, Tetrahedron Lett., 1984, 2, 4863. T.R.Bailey, R.S.Garigipati, J.A.Morton, and S.M.Weinreb, J. Am. Chem. SOC., 1984, 106,3240. T.Sugahara, Y.Komatsu, and S.Takano, J. Chem. SOC., Chem. Commun., 1984, 214. J.N.Reed and V.Snieckus, Tetrahedron Lett., 1984, 25, 5505. T.R.Kelly, A.Echavarren, N.S.Chandrakumar, and Y.Koksa1, Tetrahedron Lett., 1984, 25, 2127. D.J.Hart and Y.-M.Tsai, J. Am. Chem. SOC., 1984, 106,8209. A.B.Holmes, K . Russell, E. S.Stern, M. E.Stubbs, and N.K.Wellard, Tetrahedron Lett., 1984, 25, 4163. L.E.Overman, K.L.Bel1, and F.Ito, J. Am. Chem. S O C . , 1984, 106, 4192. T.Nomoto, N.Nasui, and H.Takayama, J. Chem. SOC., Chem. Corn=., 1984, 1646. R.M.Williams, R.W.Armstrong and J.-S.Dung, J. Am. Chem. SOC., 1984, 106, 5748. S.Inoue, K.Okado, and H.Tanino, Tetrahedron Lett., 1984, 25, 4407. E.J.Corey, K.Shimaji, and C.Shih, J. Am. Chem. SOC., 1984, 106,6425. J.P.Marino, €'t.F.de la Pradilla, and E.Laborde, J. Org. Chem., 1984, 2, 5279. A.P.Kozikowski and P.D.Stein, J. Org. Chem., 1984, 5, 2301. A.G.Cameron, A.T.Hewson, and A.H.Wadsworth, J. Chem. SOC., Perkin Trans. 1984, 2337; A.D.Baxter, S.M.Roberts, B.J.Wakefield, G.T.Woolley, and R.F.Newton, 1984, 675. E.J.Corey and M.M.Mehrotra, J. Am. Chem. S O C . , 1984, 106,3384' ; H.Nslgaok T.Miyakoshi, and Y-Yamada, Tetrahedron Lett., 1984, 25, 3621. A.P.Kozikowski and J.G.Scripko, J. Am. Chem. SOC., 1984, 106, 353. I.T.Kay and D.Bartholomew, Tetrahedron Lett., 1984, 25, 2035. P.Kocienski and C.Yeates, J. Chem. SOC., Chem. Commun., 1984, 151. A.B.Smith I11 and A.S. Thompson, J. Org. Chem. , 1984, 9, 1471. See: P.R.McCuirk and D.B. Collum, J. Org. Chem.. 1984. 49. 843. D.R.Williams and S.-Y.Sit, J. Am. Chem. Sc K. Tomioka, T. Ishiguro, Y.Litaka,

-

u.,

54

677

General and Synthetic Methods

678 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 87

88 89 90

91 92 93 94 95

P.Magnus, J-Schultz, and T.Gallagher, J. Chem. SOC., Chem. Commun., 1984, 1179. C.P.Til1 and D.A.Whiting, J. Chem. SOC., Chem. Commun., 1984, 590. T.Matsumoto, S.Imai, S.Usui, A.Suetsugu, S.Kawatsu, and T.Yamaguchi, Chem. Lett., 1984, 67. Y.Hamada, A.Kawai, and T.Shioiri, Tetrahedron Lett., 1984, 25, 5409. F.M.Hauser, R.P.Rhee, and S.R.Ellenberger, J. Org. Chem., 1984, 2236. S.W.Remiszewski, R.R.Whittle, and S.M.Weinreb, J. Org. Chem., 1984, 9, 3243. D.Rajapaksa, B.A.Keay, and R.Rodrigo, Can. J. Chem., 1984, 62, 826. M. M. Campbell, A. D.Kaye , M. Sainsbury , and R. Yavar zadeh , Tetrahedron, 1984, 40, 2470. R.Ramage and A.M.MacLeod, J. Chem. SOC., Chem. Commun., 1984, 1008. R.K.Duke and R.W.Rickards, J. Org. Chem., 1984, 1898. C.H.Kuo and N.L.Wendler, Tetrahedron Lett., 1984, 25, 2291. E.J.Corey and B.De, J. Am. Chem. SOC., 1984, 106,2735. P.A.Bartlett, J.D.Meadows, and E.Otlow, J. Am. Chem. SOC., 1984, 106,5304. M.Kitamura, M.Isobe, Y.Ichikawa, and T.Goto, J. Org. Chem., 1984, 3517. M.Kitamara, M.Isobe, Y.Ichikawa, and T.Goto, J. Am. Chem. SOC., 1984, 106, 3252 K.Narasaka, T.Sakakura, T.Uchimaru, and D.Guedin-Vuong, J. Am. Chem. SOC., 1984, 106,2954. M.P. Edwards, S.V. Ley, S.G . Lister, B. D .Palmer, and D.J. Williams, 3503. J. Org. Chem., 1984, W.F.Roush, S.M.Peseckis, and A.E,Watts, J. Org. Chem., 1984, 9, 3429. W.C.Stil1, C.Gennari, J.A.Noguez, and D.A.Pearson, J. Am. Chem. S O C . , 1984, 106. 260. W.R.Roush and T.A.Blizzard, J. Org. Chem., 1984, 9, 1772. W.R.Roush and T.A.Blizzard, J. Org. Chem., 1984, 4332. Y .Nagao, T.Miyasaka, Y .Hagiwara, and E.Fujita, J. Chem. SOC., Perkin Trans. 1 , 1984, 183. H.Nemoto, X-M.Wu, H.Kurobe, M.Ihara, W.Fukumoto and T.Kametani, Tetrahedron Lett., 1984, 25, 3095. S.R.Wilson, M.S.Haque, A.M.Venkatesan and P.A.Zucker, Tetrahedron Lett., 1984, 25, 3151. S.F.Martin, C.Gluchowski, C.L. Campbell and R. C. Chapman, J. Org. Chem., 1984, 49, 2513. F.E.Ziegler and R.T.Wester, Tetrahedron Lett., 1984, 25, 617. S.L.Schreiber and A.H.Hoveyda, J. Am. Chem. S O C . , 1984, 106,7200. S.L.Schreiber and K.Satake, J. Am. Chem. S O C . , 1984, 106,4186. P.A.Jacobi and H.G.Selnick, J. Am. Chem. S O C . , 1984, 106,3041. R-Ramage, G.J.Griffiths, F.E.Shutt, and J.N.A.Sweeney, J. Chem. SOC., Perkin Trans. 1 , 1984, 1539; R.Ramage, G.J.Griffiths and J.N.A.Sweeney, ibid., 1984, 1547; R.Ramage and P.P.McCleery, g., 1984, 1555. J. E.Baldwin, P.D.Bailey, G-Gallacher, M.Otsuka, K.A.Singleton, P.M.Wallace, K.Prout and W.M.Wolf, Tetrahedron, 1984, 5, 3695. E.J.Corey and A.Tramoutano, J. Am. Chem. SOC., 1984, 462. J.E.Baldwin, D.R.Kelly and C.B.Ziegler, J. Chem. SOC., Chem. Commun., 1984, 133. A.R.Battersby and L.A.Reiter, J. Chem. SOC., Perkin Trans. 1 , 1984, 2743.

2,

2,

2,

2,

2,

106,

Reviews on General and Synthetic Methods COMPILED BY G. PATTENDEN AND G. M. ROBERTSON D u r i n g 1 9 8 4 t h e R o y a l S o c i e t y of C h e m i s t r y l a u n c h e d i t s new publication Natural Product Reports

.....

a journal of c r i t i c a l

r e v i e w s which is i n t e n d e d t o f o s t e r p r o g r e s s i n t h e s t u d y of n a t u r a l p r o d u c t s by p r o v i d i n g r e v i e w s o f t h e l i t e r a t u r e t h a t h a s b e e n p u b l i s h e d on t h e t o p i c s o f t h e g e n e r a l c h e m i s t r y a n d biosynthesis of alkaloids, terpenoids, O-heterocyclic,

.......

s t e r o i d s , f a t t y a c i d s , and

a l i p h a t i c , a r o m a t i c , and a l i c y c l i c n a t u r a l p r o d u c t s

These r e v i e w s c o n t a i n a n abundance of u s e f u l g e n e r a l and

s y n t h e t i c m e t h o d s , a n d a r e commended t o a l l s e r i o u s o r g a n i c chemists.

1 Olefins ' A l l e n e s i n O r g a n i c S y n t h e s i s ' , H.F. S c h u s t e r a n d G . M . C o p p o l a , W i l e y , New Y o r k ,

D.J. 1984,

D.J.

Pasto,

1984.

'Recent Development i n A l l e n e C h e m i s t r y ' , T e t r a h e d r o n ,

5,2 8 0 5 . Ager,

'The P e t e r s o n R e a c t i o n ' ,

Synthesis,

1984, 384.

2 Aldehvdes and Ketones

J. Tsuji,

' 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 P a l l a d i u m - C a t a l y s e d

Oxidation of Olefins t o Ketones', Synthesis,

A.

Alexakis, C. Chuit, M.

N.

J a b r i , P. Mangeney,

Commerqon-Bourgain,

and J . F .

Normant,

P u r e Appl.

Chem.,

1984,

3 Nitronen-containinn

P . B e a k , W.J.

Z a j d e l , and D.B.

J.P.

Foulon,

'Organocopper Reagents f o r

t h e S y n t h e s i s of S a t u r a t e d a n d a , R - E t h y l e n i c Ketones',

1984, 369.

Aldehydes and

56, 9 1 .

F u n c t i o n a l GrouDs Reitz,

' M e t a l a t i o n and

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 o f Amine D e r i v a t i v e s A d j a c e n t t o Nitrogen:

& - M e t a l l o Amine S y n t h e t i c E q u i v a l e n t s ' ,

679

Chem. R e v . ,

1984,

General and Synthetic Methods

680

84, 471. T.R. Govindachari, P. Chimasamy, S. Rajeswari, S . Chandrasekaran, M.S. Premila, S. Natarajan, K. Natarajan, and B.R. Pail 'Some Recent Work on Schiff Bases, Imines and Iminium Salts in Synthetic Heterocyclic Chemistry - A Review', Heterocycles, 1984, 22, 585. H.E. Zaugg, 'a-Amidoalkylation at Carbon: Recent Advances - Parts 1 and 2', Synthesis, 1984, 85, 181. V.G. Granik, 'Advances in the Chemistry of Enamines', Russ. Chem. Rev., 1984, 53, 383. P.W. Hickmott, 'Recent Advances in the Chemistry of Conjugated Enamines', Tetrahedron, 1984, 110, 2989. A.R. Katritzky and C.M.Marson, 'Pyrilium Mediated Transformations of Primary Amino Groups into Other Functional Groups', Angew. Chem. Int. Ed. Engl., 1984, 23, 420. 'Azides and Nitrenes. Reactivity and Utility', ed. E.F.V. Scriven, Academic Press, Orlando, FL, 1984. M.H. Elnagdi, M.R.H. Elmoghayar, and G.E.H. Elgemeie, 'The Chemistry of 3-0xoalkanenitriles', Synthesis, 1984, 1 . 4 Orzanometallics General N.R. Natale, 'Lanthanides in Organic Synthesis', Org. Prep. Proc. Int., 1983, 5, 387. L.E. Overman, 'Mercury(I1)- and Palladium(I1)-Catalyzed [3,31Sigmatropic Rearrangements', Angew. Chem., Int. Ed. Engl., 1984,

23, 579.

Transition Elements 'New Pathways for Organic Synthesis: Practical Applications of Transition Metals', H.M. Colquhoun, J. Holton, D . J . Thompson, and M.V. Twigg, Plenum Press, New York, 1984. B.H. Lipshutz, R.S. Wilhelm, and J.A.Kozlowski, 'The Chemistry of Higher Order Organocuprates', Tetrahedron, 1984, 40, 5005. L . S . Hegedus, 'Palladium(I1)-Assisted Reactions of Mono-Olefins', Tetrahedron, 1984, 40, 2415. Main Group Elements E. Erdik, 'Copper(1) Catalyzed Reactions of Organolithiums and Grignard Reagents', Tetrahedron, 1984, 641. R.O. Hutchins, K. Learn, B. Nazer, D. Pytlewski, and A. Pelter,

5,

6

Reviews on General and Synthetic Methods 'Amine B o r a n e s a s S e l e c t i v e R e d u c i n g a n d H y d r o b o r a t i n g A g e n t s ' , Org. P r e p . P r o c .

Int.,

N e g i s h i a n d M.J.

E.-I.

16,335.

1984,

I d a c a v a g e , ' F o r m a t i o n of C a r b o n - C a r b o n a n d

C a r b o n - H e t e r o a t o m Bonds v i a O r g a n o b o r a n e s a n d O r g a n o b o r a t e s ' , Org. React.,

33,

1985,

G . Z w e i f e 1 and J . A .

1.

Miller, ' S y n t h e s i s Using Alkyne-Derived

a n d A l k y n y l a l u m i n i u m Compounds', Org. React.,

1985,

Alkenyl

32, 375.

' S i l i c o n Compounds: R e g i s t e r a n d R e v i e w ' , P e t r a r c h S y s t e m s I n c . , B r i s t o l , PA, 1984. Akhrem, N.M.

I.S.

C h i s t o v a l o v a , a n d M.E.

Vol'pin,

'The S p l i t t i n g o

Bond by Compounds of P l a t i n u m a n d P a l l a d i u m ' ,

t h e Silicon-Carbon R u s s . Chem. Rev.,

1983,

52,

542.

'Tin Reagents f o r Organic S y n t h e s i s ' , Aldrichim.

G.S.

Bristow,

Acta, A.A.

1 9 8 4 , 17,75. P e t r o v , A . V . D o g a d i n a , B.I. I o n i n , V . A .

A.A.

Leonov,

G a r i b i n a , and

'The Arbuzov R e a r r a n g e m e n t w i t h P a r t i c i p a t i o n o f

H a l o g e n o a c e t y l e n e s a s a Method o f S y n t h e s i s of E t h y n y l p h o s p h o n a t e s a n d O t h e r O r g a n o p h o s p h o r u s Compounds', R u s s . C k e m . R e v . , 1030. 'Selenium i n N a t u r a l Product S y n t h e s i s ' , K.C. P e t a i s i s , CIS I n c . ,

N.A.

D. L i o t t a ,

17, -

1983,

52,

Nicolaou and

P h i l a d e l p h i a , 1984.

'New O r g a n o s e l e n i u m M e t h o d o l o g y ' , Acc. Chem. Res.,

1984,

28. 5 Carbocycles

M.

Ramaiah, ' C y c l o p e n t a a n n e l l a t i o n R e a c t i o n s i n O r g a n i c S y n t h e s i s ' ,

S y n t h e s i s , 1984, 529. T . H u d l i c k y , T.M.

Kutchom, a n d S.M. N a q v i ,

L.A.

Paquette,

'The Vinylcyclopropane-

1985, 3 3 , 247. ' R e c e n t S y n t h e t i c Development i n P o l y q u i n a n e

Cyclopentene Rearrangement',

C h e m i s t r y ' , Top. C u r r . Chem.,

Org. R e a c t . , 1984,

9, 1.

L.A. P a q u e t t e , ' S y n t h e t i c R o u t e s t o C y c l o p e n t a n o i d - F u s e d U n n a t u r a l a n d N a t u r a l P r o d u c t s ' , A l d r i c h i m . A c t a , 1 9 8 4 , 17,43. H.M.Fi.

Hoffmann, 'The C y c l o a d d i t i o n of A l l y 1 C a t i o n s t o 1 , 3 - D i e n e s :

G e n e r a l Methods f o r t h e S y n t h e s i s of Seven-Membered Angew. Chem., S.F.

I n t . Ed. E n g l . ,

K a r a e v , Sh.V.

1984,

Goraeva, and A.M.

Carbocycles,

3,1. S l a d k o v , ' P r o g a r g y l Compounds

i n t h e S y n t h e s i s o f C a r b o c y c l e s a n d H e t e r o c y c l e s ' , R u s s . Chem.

Rev.,

z,

1984, 492. J . L i n d l e y , 'Copper A s s i s t e d N u c l e o p h i l i c S u b s t i t u t i o n of A r y l

General and Synthetic Methods

682

Halogen', Tetrahedron, 1984, 40, 1433. 'Recent Aspects of Anthracyclinone Chemistry', ed. T.R. Kelly, Tetrahedron, 1984, 40, 4537. 6 Cycloaddition Reactions 'Natural Product Synthesis Through Pericyclic Reactions', G.Desimoni, G.Tacconi, A. Barco, and G.P. Pollini, ACS, New York, 1983. E. Ciganek, 'The Intramolecular Diels-Alder Reaction', Org. React., 1984, 32, 1. 'Intramolecular Diels-Alder and Alder Ene Reactions', D.F. Taber, Springer Verlag, New York, 1984. A.I. Konovalov, 'The Reactivity of Addends in the Diene Synthesis Reactions', Russ. Chem. Rev., 1983, 52, 1064. W. Oppozler, 'Asymmetric Diels-Alder and Ene Reactions in Organic Synthesis', Angew. Chem., Int. Ed. Engl., 1984, 23, 876. A.P. Kozikowski, 'The Isoxazoline Route to the Molecules of Nature', Ace. Chem. Res., 1984, 17,410. 'Il3-Dipolar Cycloaddition Chemistry', ed. A. Padwa, Wiley, New York, 1984. 0 . DeLucchi and G. Modena, 'Acetylene Equivalents in Cycloaddition Reactions', Tetrahedron, 1984, 2585. T. Tsuji and S. Nishida, 'Thermal Ring-Opening Cycloadditions of Cyclopropyl Derivatives with Activated Olefins' , Ace. Chem. Res., 1984, 17,56.

s,

7 Heterocycles R.J. Gallo, M. Makosza, H-J-M. D O U , and P. Hassanaly, 'Applications of Phase Transfer Catalysis in Heterocyclic Chemistry', Adv. Heterocycl. Chem., 1984, 36, 176. E.A.A. Hafez, N.M. Abed, M.R.H. Elmoghayer, and A.G.A. El-Agamey, 'Hydrazines and Hydrazine Derivatives in Heterocyclic Synthesis' , Heterocycles, 1984, 22, 1821. N.S. Narasimhan and R.S. Mali, 'Syntheses of Heterocyclic Compounds Involving Aromatic Lithiation Reactions in the Key Step', Synthesis, 1983, 957. Y. Ohshiro and T. Hirao, 'Heterocycles Synthesis by Metal Carbonyl Induced Cyclization Reaction', Heterocycles, 1984, 22, 859. J.Gorzynski Smith, 'Synthetically Useful Reactions of Epoxides',

Reviews on General and Synthetic Methods

683

Synthesis, 1984, 629. W. Ried and B. Heinz, 'Four-membered Rings Containing One Sulphur Atom', Adv. Heterocycl. Chem., 1984, 35, 200. M.P. Sammes and A.R. Katritzky, 'The 2kJ-Imidazoles', Adv. Heterocycl. Chem., 1984, 35, 376. M.P. Sammes and A . R . Katritzky, 'The 4H-Imidazoles', Adv. Heterocycl. Chem., 1984, 35, 414. M.P. Sammes and A.R. Katritzky, 'The 3H-Pyrazolesf, Adv. Heterocycl. Chem., 1983, 34, 2. Adv. Heterocycl M.P. Sammes and A.R. Katritzky, 'The 4H-Pyrazoles', Chem., 1983, 34, 54. V.A. Pankratov, Ts.M. Frenkel and A.M.Fainleib, '2-0xazolidinones', Russ. Chem. Rev., 1983, 52, 576. W. Sliwa, 'The Chemistry of Furazams', Heterocycles, 1984, 22, 1571. J. Kuthan, 'Pyrans, Thiopyrans and Selenopyrans', Adv. Heterocycl. Chem., 1983, 34, 146. G . Jones and D.R. Sliskovic, 'The Chemistry of the Triazolopyridines', Adv. Heterocycl. Chem., 1983, 34, 80. J.I. Seeman, 'Recent Studies in Nicotine Chemistry. Conformational Analysis, Chemical Reactivity Studies and Theoretical Modelling', Heterocycles, 1984, 22, 165. C.R. Hardy, 'The Chemistry of Pyrazolopyridines', Adv. Heterocycl. Chem., 1984, 36, 345. L.A. Summers, 'The Bipyridines', Adv. Heterocycl. C+., 1984, 35, 282. M.J. Hearn and F. Levy, 'Recent Progress in the Synthesis and Reactions of 1,2,3- and 1,2,4-Triazines1, Org. Prep. Proc. Int., 1984, 16, 199. 'Azepines - Part 2', J.W.H. Watthey, J. Stanton, and N.P. Peet, Wiley-Interscience, New York, 1984. R.D. Clark and D.B. Repke, 'The Leingruber-Batcho Indole Synthesis', Heterocycles, 1984, 22, 195. M. Lounasmaa and A. Koskinen, 'Modified Polonovski Reaction, A Versatile Synthetic Tool', Heterocycles, 1984, 22, 1591. J.A Joule, 'Recent Advances in the Chemistry of gE-Carbazoles', Adv. Heterocycl. Chem., 1984, 35, 84. M.J.E. Hewlins, A.-M. Oliveira-Campos, and P.V.R. Shannon, 'Synthetic Approaches to Ellipticenes and Other Derivatives and Analogues of 6H-Pyrido[4,3-blcarbazole', Synthesis, 1984, 289. W.K. Fife and E.R. Scriven, 'Cyanation in the Pyridine Series:

General and Synthetic Methods

684

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 R e i s s e r t - H e n z e Reactions', M.V.

H e t e r o c y c l e s , 1984,

S a r g e n t and P.O.

Chem.,

1984,

Stransky,

s, 2 .

and R e l a t e d

22, 2375. ' D i b e n z o f u r a n s ' , Adv. H e t e r o c y c l .

8 Prostaglandins S.M.F.

L a i and P.W.

Manley,

' P r o s t a g l a n d i n s , Thromboxanes,

L e u k o t r i e n e s , a n d R e l a t e d A r a c h i d o n i c A c i d M e t a b o l i t e s ' , Nat. P r o d .

Rep.,

1 9 8 4 , _I, 409. R . N o y o r i a n d M . S u z u k i , ' P r o s t a g l a n d i n S y n t h e s e s by Three-Component C o u p l i n g ' , Angew. Chem., I n t . Ed. E n g l . , 1 9 8 4 , 23, 8 4 7 . D o m b r o v s k i , D . Yu. F o n s k i i , a n d V . A . M i r o n o v , ' T h e S y n t h e s i s

V.A.

o f P r o s t a g l a n d i n s from C y c l o p e n t a n e D e r i v a t i v e s ' , R u s s . Chem. R e v . , 1 9 8 4 , 53, 401. R.F. Newton, S.M.

R o b e r t s , and R . J . K .

Taylor,

' S t r a t e g i e s Employed

i n t h e S y n t h e s i s of P r o s t a c y c l i n s and T h r o m b o x a n e s ' , S y n t h e s i s , 1 9 8 4 , 449.

T.D.

Inch,

' F o r m a t i o n of C o n v e n i e n t C h i r a l I n t e r m e d i a t e s from

C a r b o h y d r a t e s and T h e i r Use i n S y n t h e s i s ' , T e t r a h e d r o n , 1 9 8 4 ,

40,

3161. J. Yoshimura,

' S y n t h e s i s of B r a n c h e d - C h a i n S u g a r s ' , Adv. C a r b o h y d .

z,

Chem. Biochem., 1 9 8 4 , 69. P . J . G a r e g g , 'Some A s p e c t s of R e g i o - ,

Stereo-,

and Chemo-Selective

R e a c t i o n s i n C a r b o h y d r a t e C h e m i s t r y ' , P u r e A p p l . Chem.,

1984,

56,

845. 10 A l k a l o i d s

(See a l s o u n d e r H e t e r o c y c l e s ) P . Magnus, T. G a l l a g h e r , P . Brown, a n d P . P a p p a l a r d o ,

'The I n d o l e -

2 , 3 - q u i n o d i m e t h a n e S t r a t e g y f o r t h e S y n t h e s i s of I n d o l e A l k a l o i d s ' ,

Acc. Chem. Res., 1 9 8 4 ,

17,35.

Bennasar, ' E l a b o r a t i o n of t h e E t h y l i d e n e S u b s t i t u e n t i n t h e S y n t h e s i s of I n d o l e A l k a l o i d s ' , H e t e r o c y c l e s ,

J . Bosch a n d M.L.

20, 247'1. S a x t o n , ' R e c e n t P r o g r e s s i n t h e C h e m i s t r y of I n d o l e A l k a l o i d s a n d Mould M e t a b o l i t e s ' , N a t . P r o d . R e p . , 1 9 8 4 , _I, 20. 1983,

J.E.

685

Reviews on General and Synthetic Methods T . F u j i i and M .

Ohba, ' I p e c a c A l k a l o i d s a n d 13-Carboline C o n g e n e r s ' , i n 'The A l k a l o i d s , C h e m i s t r y and P h a r m a c o l o g y , Volume 2 2 ' , e d .

A.

B r o s s i , Academic P r e s s , N e w Y o r k , 1983. and M. S u l t a n a , ' S y n t h e t i c A p p r o a c h e s t o t h e

Atta-ur-Rahman

22,

H u n t e r i a A l k a l o i d s ' , H e t e r o c y c l e s , 1984,

841.

1 1 Enzymic R e a c t i o n s a n d Asymmetric S y n t h e s i s J.R.

Knowles,

'Enzyme C a t a l y s i s : L e s s o n s f r o m S t e r e o c h e m i s t r y ' ,

P u r e A p p l . Chem., I. Tabushi,

1984,

110,

T e t r a h e d r o n , 1984, V.

56, 1005.

' D e s i g n and S y n t h e s i s of A r t i f i c i a l E n z y m e s ' , 269.

S v e d a a n d I.U. G a l a e v , 'Enzymic C o n v e r s i o n of Racemates i n t o

Aminoacid E n a n t i o m e r s ' , R u s s . Chem. R e v . , C.J.

S i h a n d C.S.Chen,

1983,

52,

1203.

-

' M i c r o b i a l Asymmetric C a t a l y s i s

E n a n t i o s e l e c t i v e R e d u c t i o n of K e t o n e s ' , Angew. Chem., I n t . Ed. E n g l . ,

1984,

23,

570.

' S y n t h e s i s o f C h i r a l Non-Racemic Tetrahedron,

1984,

40,

Compounds',

ed. A . I .

Meyers,

1215.

' C o n t r o l of A c y c l i c S t e r e o c h e m i s t r y ' , e d . T . Mukaiyama, Tetrahedron, 1984, M.T.

Reetz,

110,

2197.

' C h e l a t i o n or N o n - C h e l a t i o n C o n t r o l i n A d d i t i o n

R e a c t i o n s of C h i r a l a- and 8-Alkoxy C a r b o n y l Compounds', Angew. Chem., I n t . Ed. E n g l . , I. O j i m a ,

1984,

23, 5 5 6 .

'Homogeneous Asymmetric C a t a l y s i s by Means of C h i r a l

Rhodium C o m p l e x e s ' , P u r e A p p l . Chem., T . O i s h i and T . N a k a t a ,

1984,

56, 9 9 .

'An I n t r o d u c t i o n o f C h i r a l C e n t r e s i n t o

A c y c l i c S y s t e m s B a s e d on S t e r e o s e l e c t i v e K e t o n e R e d u c t i o n ' , Acc. Chem. Res.,

1984,

17,338.

'Asymmetric S y n t h e s i s , Volume 4.

The C h i r a l C a r b o n P o o l a n d C h i r a l

S u l p h u r , N i t r o g e n , Phosphorus, and S i l i c o n C e n t r e s ' ,

e d . J.D.

M o r r i s o n a n d J.W. S c o t t , Academic P r e s s , N e w Y o r k , 1 9 8 4 . R.M.

K e l l o g g , ' C h i r a l Macrocycles as Reagents and C a t a l y s t s ' ,

Angew. Chem.,

I n t . Ed. E n g l . ,

1984,

23,

782.

L a b i a a n d C . M o r i n , ' S t e r e o s p e c i f i c C o n s t r u c t i o n s of C h i r a l B Lactams', J . A n t i b i o t . , 1 9 8 4 , 37, 1 1 0 3 . R.

12 P h o t o c h e m i s t r y a n d E l e c t r o c h e m i s t r y A . A l b i n i a n d M . A l p e g i a n i , 'The P h o t o c h e m i s t r y o f N-Oxide 43. F u n c t i o n ' , Chem. R e v . , 1 9 8 4 ,

84,

General and Synthetic Methods

686

R.S. D a v i d s o n , J . W .

Goodwin, a n d G .

Kemp,

'The Photochemistry of

Org. C h e m . ,

A r y l H a l i d e s a n d R e l a t e d C o m p o u n d s ' , Adv. P h y s .

1984,

20. Liu and A.E.

R.S.H.

Asato,

S t e r e o i s o m e r s of Vitamin A ' , M.M.

Baizer,

'Photochemistry and S y n t h e s i s of Tetrahedron,

40,

1984,

1931.

' R e c e n t D e v e l o p m e n t s i n O r g a n i c S y n t h e s i s by

s,9 3 5 .

E l e c t r o l y s i s ' , T e t r a h e d r o n , 1984,

T. Shono, ' E l e c t r o o r g a n i c Chemistry i n Organic S y n t h e s i s ' ,

40,

T e t r a h e d r o n , 1984,

811.

11 General

' S t r a t e g i e s and T a c t i c s i n Organic S y n t h e s i s ' , Acadmic P r e s s , N e w Y o r k ,

ed. T. L i n d b e r g ,

1984.

P . D e s l o n g c h a m p s , ' T h e C o n c e p t of S t r a t e g y i n O r g a n i c S y n t h e s i s ' , A l d r i c h i m . Acta,

-

'Selectivity

1984,

17,5 9 .

A Goal f o r S y n t h e t i c E f f i c i e n c y , ed. W.

B.M.

T r o s t , Verlag C h e m i e , B a s e l ,

H.W.

Pinnick,

Proc. I n t . ,

'Potassium Hydride i n Organic S y n t h e s i s ' ,

1983,

H u d l i c k y , E l l i s Horwood L t d . ,

1984.

'Comprehensive Carbanion C h e m i s t r y , P a r t B: C a r b o n Bond F o r m i n g R e a c t i o n s ' , E l s e v i e r , New York, U.E.

Wiersum,

ed-. E .

1984.

' P r e p a r a t i v e Flash-Vacuum

Vollhardt,

S e l e c t i v i t y i n Carbon-

Buncel and T. D u r s t , Thermolysis.

o f P y r o l y t i c S y n t h e s i s ' , A l d r i c h i m . Acta, K.P.C.

Org. P r e p .

15, 1 9 9 .

'Reduction i n Organic Chemistry', M. Chichester,

Bartmann and

1983.

'Cobalt-Mediated

1984,

The R e v i v a l

17,3 1 .

[2+2+2]-Cycloadditions:

M a t u r i n g S y n t h e t i c S t r a t e g y ' , Angew.

Chem.,

Int.

Ed. E n g l . ,

A 1984,

2 3 , 539. E. V e d e j s ,

'Sulphur-Mediated

Acc. Chem. R e s . ,

1984,

Ring Expansions i n T o t a l S y n t h e s i s ' ,

17,3 5 8 .

14 M i s c e l l a n e o u s ' T h e T o t a l S y n t h e s i s of N a t u r a l P r o d u c t s , Volume 6 ' , e d . J.ApSimon,

Wiley, New York,

'Friedel-Crafts

1984.

Alkylation Chemistry',

A.A.

K h a l a f , Marcel Dekker I n c . ,

J.E.

Baldwin and P.

Porphyrins',

Perlmutter,

T o p . C u r r . Chem.,

R.M.

New Y o r k , 'Bridged,

1984,

R o b e r t s and 1984. Capped a n d Fenced

121,1 8 1 .

687

Reviews on General and Synthetic Methods 'Reactive Molecules', 1984.

C. Wentrup, W i l e y - I n t e r s c i e n c e ,

K a t r i t z k y and G . Musumara,

A.R.

New York,

'New I n s i g h t s i n t o A l i p h a t i c

N u c l e o p h i l i c S u b s t i t u t i o n R e a c t i o n s from t h e Use of P y r i d i n e s a s L e a v i n g G r o u p s ' , Chem. SOC. R e v . ,

1984,

13,3 7 .

D B t z , ' C a r b e n e C o m p l e x e s i n O r g a n i c S y n t h e s i s ' , Angew. Chem.,

K.H.

I n t . Ed. E n g l . , Stowell,

J.C.

1984,

23,

587.

'Three-Carbon

H o m o l o g a t i n g A g e n t s ' , Chem.

Rev.,

1984,

84 , 409. K.

Miillen,

1984, M.

' R e d u c t i o n a n d O x i d a t i o n o f A n n u l e n e s ' , Chem. R e v . ,

84,6 0 3 .

Yokoyama a n d T . I m a m o t o ,

Disulphide', Synthesis, R.P.

Lutz,

Chem. R e v . , E.V.

'Organic R e a c t i o n s of Carbon

1984, 797.

' C a t a l y s i s o f t h e Cope a n d C l a i s e n R e a r r a n g e m e n t s ' , 1984,

2,205.

Merkushev, 'Advances i n t h e S y n t h e s i s of Aromatic Iodo-

Compounds',

R u s s . Chem. R e v . ,

1984,

53, 3 4 3 .

' R e a c t i v e I n t e r m e d i a t e s , Volume 3 ' , e d . M .

.

J o n e s Jr. a n d

R.A.

M o s s , W i l e y - I n t e r s c i e n c e , New Y o r k , 1 9 8 4 . ' T h e O r g a n i c C h e m i s t r y o f Drug S y n t h e s i s , Volume 3 ' , D . L e d n i c e r and L.A.

M i t s c h e r , Wiley, New York, 1984.

' R e c e n t A s p e c t s of t h e C h e m i s t r y of N u c l e o s i d e s , N u c l e o t i d e s , a n d

s,

Reese, T e t r a h e d r o n , 1 9 8 4 , 1. ' S y n t h e s i s and Reduction of T h i o c a r b o x y l i c O - E s t e r s ' , Chem. R e v . , 1 9 8 4 , &, 1 7 . P.G. J o n e s , ' C r y s t a l S t r u c t u r e D e t e r m i n a t i o n : A C r i t i c a l V i e w ' , Chem. S O C . R e v . , 1 9 8 4 , 13, 1 5 7 .

N u c l e i c A c i d s ' , ed. C.B. B.A.

J o n e s and J.S.

A. Varvoglis, Synthesis, T.S.

Bradshaw,

' P o l y v a l e n t I o d i n e Compounds i n O r g a n i c S y n t h e s i s ' ,

1984, 709.

Santhanakrishnan,

T e t r a h e d r o n , 1984,

40,

' B i o h y d r o x y l a t i o n o f T e r p e n e s i n Mammals, 3597.

Author Index In this index the number given in parenthesis is the Chapter number of the citation and this is followed by the reference number or numbers of the relevant citations within that chapter

Abbot, D.E. ( 4 ) 68; (6ii) 109 Abdel-Magid, A. ( 3 ) 92, 251; ( 4 ) 65; ( 8 ) 2 Abdelrazek, F.M. ( 5 ) 544 Abe, K. ( 8 ) 210 Abe, T. ( 2 ) 178 Abenhaim, D. (3) 18 Abermark, B. ( 5 ) 163 Abiko, A. ( 2 ) 73; (6ii) 24 Abramovitch, R.A. ( 8 ) 111 Achab, S. (6i) 42 Acher, F. ( 3 ) 393 Achiwa, K . ( 8 ) 139, 140, 142 Acker, M. (6i) 97 Ackroyd, J. ( 7 ) 90 Acuna, C. ( 3 ) 85 Adachi, K . (5) 320 Adam, W. ( 8 ) 10 Adamczyk, M. ( 2 ) 144; ( 4 ) 8 8 ; (6ii) 155 Adams, C. ( 4 ) 13, 28 Adams, R.E. ( 8 ) 65 Adams, T.C. ( 5 ) 438 Adger, B.M. ( 5 ) 15 Adiwidjaja, A. ( 8 ) 273 Adlington, R.M. (1) 16, 159; ( 3 ) 163, 447; (6ii) 21, 115 Adolph, H.G. ( 5 ) 438 Aebi, J.D. ( 3 ) 412 Aerssens, M.H.P.J. (1) 177 Afza, N . ( 5 ) 183, 187 Agami, C. ( 2 ) 97; ( 7 ) 141-143 Agawa, T. ( 2 ) 104; ( 3 ) 58; ( 8 ) 84 Ager, D.J. ( 1 ) 62; ( 2 ) 47, 72; ( 3 ) 190; (6ii)

Alexakis, A. (2) 46, 112, 264, 265; ( 4 ) 95, 240, 258; ( 5 ) 166, 167; (6i) 6 4 , 65 Al-Hasson, M.I. (6ii) 95 A-Lim, D.S.T. ( 8 ) 168 Allwood, B.L. ( 4 ) 32; 100 (6ii) 58 Ahmed, A. ( 3 ) 334 Almond, M.R. ( 3 ) 65; ( 5 ) Aizpurua, J.M. ( 4 ) 141; 39 (6ii) 99; ( 8 ) 245, 248 Alonso-Cires, L. ( 4 ) 7 Akabori, S. ( 4 ) 301, 302 Alonso Garrido, D.O. ( 5 ) Akai, S. ( 3 ) 52 21, 127 Akashi, S. ( 8 ) 182 Alpegiani, M. ( 8 ) 269, Akermark, B. (1) 134, 136 2 70 Akguen, E. ( 2 ) 198 Alper, H. ( 3 ) 9 3 , 206; Akiba, K . (1) 167; ( 2 ) ( 4 ) 213, 214; ( 8 ) 173 206, 241; ( 5 ) 8 4 , 8 5 , Alster, J. ( 5 ) 399 233; (6i) 62; (6ii) 71 Alston, D.R. ( 4 ) 306 Akiba, M. ( 2 ) 49; ( 5 ) 453 Alvarez-Ibarra, C. ( 5 ) 78 Akita, H, ( 4 ) 52 Aly, M.F. ( 8 ) 146 Akita, M. ( 1 ) 172 Amato, J . S . ( 3 ) 414 Akiyama, F. ( 5 ) 493 Amin, N.V. ( 8 ) 91 Akiyama, M. ( 3 ) 399, 418 Amita, F. ( 2 ) 243; ( 5 ) Akiyama, R. ( 3 ) 144 232 Akiyama, T. ( 2 ) 132, 192 Amos, R.A. ( 4 ) 244 Akssira, M. ( 3 ) 284 Amouroux, R. ( 8 ) 57 Aktogu, N . (6i) 68 Amrollah-Madjdabadi, A. Akutagawa, K. ( 5 ) 488 (2) 58 An, N.D. ( 3 ) 46 Akutagawa, S . ( 5 ) 135; Anchenbach, F. ( 8 ) 112 (6i) 36 Alasz, P.D. ( 8 ) 200 Anders, E. ( 2 ) 55; ( 4 ) Alazard, J.P. ( 8 ) 38 165; (6ii) 122 Alberola, A. ( 5 ) 56 Anderson, O.P. ( 2 ) 144; Albert, M.S. ( 5 ) 371 (6i) 77; (6ii) 155; Alcaide, B. ( 5 ) 477 ( 8 ) 239 Alcala, H. ( 5 ) 325 Anderson, P.C. ( 3 ) 314 Aldag, R . ( 4 ) 290 Anderson, Q.P. ( 4 ) 88 Alekseev, V.V. ( 5 ) 459 Anderson, R.C. (6ii) 132 Alemagna, A. ( 8 ) 113 Andisik, D. ( 4 ) 168; ( 5 ) Alerdice, M. ( 3 ) 188, 509 Ando, K. ( 3 ) 151 189 15 Agha, B.J. ( 8 ) 235 Agosta, W.C. ( 7 ) 27 Ahlbrecht, H. ( 3 ) 3 ; ( 5 ) 111, 145 Ahlhelm, A. ( 4 ) 238 Ahmar, M. ( 1 ) 123; ( 3 )

688

Author Index Ando, R . (2) 238; (3) 180; (7) 1; (8) 8 Ando, S. (1) 147; (3) 220; (6ii) 89 Ando, T. (1) 160; (6ii) 131 Ando, W. (5) 492; (8) 73 Andreetti, G.D. (4) 277 Andrews, M.A. (5) 402 Andrus, A. (8) 252, 253, 267 Angelino, S.A.G.F. (5) 94 Angoh, A.G. (1) 116; (2) 101; (6ii) 104; (7) 186 Anklam, E. (8) 77 Annis, G.D. (2) 117; (6ii) 103; (7) 19 Annunziata, R. (3) 368; (5) 281; (6ii) 4 Anselme, J-P. (5) 441-443 Antebi, S. (3) 206; (4) 214 Antoine, J.-P. (3) 407 Antonioletti, R. (3) 224, 289 Anwar, S. (2) 160; (5) 20 Aono, T. (3) 338 Aoyama, H. (8) 240 Apparu, M. (7) 36 Araki, K. (1) 186; (6ii) 156 Araki, S. (4) 185; (5) 115 Arase, A. (1) 171, 189; (5) 306, 508 Arduini, A. (8) 34 Ariga, M. (3) 144 Aristoff, P.A. (8) 49 Ariyoshi, K. ( 2 ) 33 Arjona, 0. (5) 78 Armani, E. (2) 169 Armistead, D.M. (8) 46 Armstrong, R.W. (9) 48 Arney, B.E. (2) 6 Arnold, R.D. (1) 190; (6ii) 119 Arnold, Z. ( 8 ) 23 Arnoldi, A. (8) 47 Arnott, D.M. (5) 357 Arrick, B.A. (3) 291 Arrieta, A. (2) 168; (4) 189; (8) 245, 248 Arsenijevic, L. (2) 42; (6ii) 41 Arsenijevic, V. (2) 42; (6ii) 41 Artamkina, G.A. (3) 37 Arvanaghi, M. (2) 40, 41, 167; (6ii) 25, 40 Arvanitis, A. (3) 16 Arzt, J.G. (8) 225 Asami, M. (4) 102

689

Asano, S. (5) 246 Asensio, G. (4) 7, 202; ( 5 ) 66, 67; (8) 161 Ashburn, S.P. (8) 88 Ashton, C.P. ( 3 ) 391 Aslam, M. (2) 106; (8) 109 Aslanian, R. (1) 134, 136; (5) 163 Aso, Y. (2) 33; (5) 5 Assithianakis, P. (5) 337 Astrab, D.P. (1) 97; (2) 89; (7) 70 Atkins, R.L. (5) 383, 440 Atkinson, J.G. (4) 253 Attanasi, 0. (2) 162; (5) 456 Attwood, S.V. (3) 262 Atwell, G.J. (5) 71 Au, A.T. (2) 59, 60; (5) 349 Audia, J.E. ( 7 ) 131 Audin, P. (4) 236; (8) 36 Aumuller, A. (5) 478 Auzzi, G. (8) 233 Avasthi, K. (7) 22 Awasthi, A.K. (8) 246 Axiotis, G. (3) 19; (8) 257 Ayoub, M.T. (5) 96 Ayyangar, N.R. (5) 462 Azhayev, A.V. (5) 505 Azipura, J.M. (4) 199, 200 Aziz-Elyusufi, A. (5) 144 Aznar, F. (2) 159; (5) 157, 230; (6ii) 53; (8) 209 Azuma, K. (1) 78, 80, (4) 108, 109 Azuma, S. (7) 92; (9) 7 Azzaro, M. (8) 132

Bailey, P.D. ( 5 ) 219; (9) 92 Bailey, P.S. (3) 15 Bailey, T.R. (5) 104; (8) 193; (9) 40 Baird, G.J. (6i) 68, 73 Baizer, M.M. (3) 61 Bajgrowicz, J.A. (3) 413, 426 Bajt, 0. (5) 422 Baker, J.P. (3) 251 Baker, R. (3) 291; (6ii) 66; (7) 63 Bakker, B.H. (8) 168 Bakos, J. (3) 455 Balaban, A.T. (5) 464 Balasubramanian, N. (5) 556 Balavoine, G. (8) 6 Bakzewski, P. (2) 119 Baldwin, J.E. (1) 16, 159, 190; (3) 163, 183, 430, 447; (5) 219, 375; (6ii) 21, 115, 119 (8) 274; (9) 92, 94 Baleja, J.D. (4) 261 Baleux, F. (3) 404 Balk, M.A. (2) 161; 5) 72, 231 Ball, T.F. (8) 45 Ballabio, M. (7) 53 Ballester-Rodes, M. (3) 73 Ballini, R. (2) 163; (4) 143; (5) 409, 411 Balogh, M. (2) 220 Balss, E. (6i) 97 Bandara, B.M.R. (6i) 58 Banfi, L. (3) 173, 422; (4) 63; (5) 225; (6ii) 13, 147, 148 Banfi, S. (8) 4 Banks, B.J. (3) 222; (5) 419; (6ii) 134 Baader, W.J. (8) 10 Bannai, K. (5) 405 Babin, P. (6ii) 121 Banziger, M. (3) 255 Babler, J.H. (2) 204; Bapat, C.P. (7) 114 (4) 193; (7) 55 Baraldi, P.G. (2) 123; Babston, R.E. (1) 54 (3) 168; (8) 27 Babu, J.R. (4) 136 Babudri, F. (5) 160, 176, Baralt, E. (5) 8 Baran, D. (3) 362; (5) 520 273 Baciocchi, E. (5) 557 Baran, J. (5) 391, 392; Back, T.G. (1) 4 (6ii) 26 Badertscher, U. (3) 125 Barba, F. (1) 142 Badet, B. (5) 307 Barba, I. (1) 142 Badoux, D. (5) 151 Barbachyn, M.R. (6ii) 149 Bae, S.K. (2) 2 Backvall, J.-E. (1) 134, Barbot, F. (3) 175 136; (5) 163, 228; (6i) Barchi, J.J. (7) 183 30, 31 Barco, A. (2) 123; (3) Bagheri, V. (7) 21 168; (8) 27 Bardshiri, E. (3) 304 Bahar, E. (5) 361

General and Synthetic Methods

690

Barefoot, A.C. I11 (1) 182 Barlocco, D. (8) 107 Barlos, K. (3) 385 Barluenga, J . (2) 159; (3) 365; (4) 7, 202; (5) 66, 67, 87, 157, 230, 238, 285, 490; (6ii) 52, 53; (8) 161, 162, 209 Barner, B . A . (6ii) 9 Barnikow, G. (5) 300 Barot, B.C. (2) 102 Barraclough, P. (3) 251; (7) 122 Barrett, A . G . M . (3) 222, 262; (5) 419; (6ii) 134 Barry, J. (4) 226 Bartholornew, D. (9) 56 Bartlett, P.A. (3) 325; (4) 233; (8) 11; (9) 74 Bartoli, G . (5) 16, 176, 387 Barton, D.H.R. (1) 2, 5, 68, 96; (2) 184, 226; (3) 55-57, 171; (4) 160; (5) 28, 469; (6ii) 160 Bartsch, R.A. (4) 300; (5) 423 Barua, N.C. (4) 132, 161 Basak, A . (1) 159; (3) 447; (6ii) 115 Basato, M. (5) 140, 141 Basavaiah, D. (2) 271; (6ii) 64 Basha, A . (5) 44 Basha, F.Z. (6ii) 43; (8) 167 Bashiardes, G. (1) 68; (6ii) 160 Basok, S.S. (4) 278 Bass, L.S. (6ii) 149 Batalini, B. (3) 59 Bates, R.B. (5) 215 Batsugan, Y. (5) 115 Batt, D.G. (7) 148 Battersby, A.R. (5) 357; (9) 95 Battiste, M.A. (1) 95; (3) 192 Battistini, C. (8) 268 Battistoni, P. (2) 162 Bauld, N.L. (7) 103 Baum, M. (3) 274 Baus, U. (2) 231; (3) 150; (5) 461 Bauta, W.E. (7) 55 Baxter, A.D. (9) 53 Bayod, M. (2) 159; (5) 230 Bay6n, A.M. (5) 66, 67;

(8) 161 Baysdon, S.L. (6ii) 135 Beadle, J.R. (4) 279, 280 Beak, P. (3) 374; (5) 44, 105, 110 Beaudoin, S. (1) 20; (6ii) 129 Beaulieu, P.L. (2) 92 Becher, J. (5) 290 Beck, K . (8) 218 Becker, G . (3) 460 Becker, R. (5) 25 Becking, L. (3) 60; (8) 18 Bedeschi, A . (8) 269, 270 Bednarski, M. (1) 137; (7) 115; (8) 43 Beers, S. (2) 65; (6ii) 18 Begley, M.J. (1) 48; (7) 171 Beisswenger, T. (3) 438; (5) 143, 269 Belcic, B. (5) 422 Beletskaya, I.P. (3) 37 Bell, K.L. (8) 201; (9) 46 Bell, L.T. (4) 25; (6ii) 139 Bellamy, F.D. (5) 2 Belleau, B. (1) 119; (2) 131; (8) 217 Belletire, J . L . (3) 14 Bellof, D. (3) 402 Bellville, D.J. (7) 103 Belot, G. (5) 7 Beltrarni, H. (8) 184 Belzecki, C. (8) 244, 250 Benage, B. (8) 44; (9) 39 Benati, L. (5) 229 Benetti, S. (2) 123; (3) 168; (8) 27 Benezra, C. (3) 172, 262; (6ii) 31 Benkert, E. (5) 406; (7) 69 Benko, Z. (3) 251 Benner, J.P. (3) 31 Benoiton, N.L. (3) 397 Bergbreiter, D.E. (3) 83; (6ii) 7 Bergens, C. (5) 383 Bergeron, R.J. (5) 19 Berlan, J. (6i) 67 Bernardi, A. (3) 123; (3) 173, 225; (6ii) 13 Bernardi, R. (3) 120; (4) 53, 63 Bernardinelli, G . (7) 9799; (8) 66, 68 Bernauer, K . (3) 411; (8) 121

Bernhard, W. (2) 232; (3) 129 Bernotas, R.C. (5) 189 Bernstein, B. (3) 146 Berry, M.S. (6ii) 10 Bertounesque, E. (3) 19 Bertrand, J. (2) 272 Bertrand, M. (4) 119 Bertz, S.H. (2) 261; (3) 90 Besace, Y. (6i) 67 Bestmann, H.J. (1) 152; (5) 42, (5) 48 Betschart, C. (2) 242; (3) 433; (5) 234 Betz, R. (3) 296 Bey, P. (1) 156; (3) 446; (5) 174, 177 Bhat, K.S. (4) 177 Bhatnagar, R . K . (5) 30 Bhatt, M.V. (4) 136 Bhattacharjee, S.S. (5) 330 Bhushan, V. (2) 5; (4) 6, 149 Bidd, I. (4) 195 Bigalke, J. (1) 163; (3) 213 Bigelow, S.S. (6ii) 61 Bigi, F. (3) 47 Bikkineev, R.Kh. (5) 415 Billedeau, R.J. (3) 376; (6ii) 1 Billington, D.C. (2) 91; (6i) 94; (8) 20 Billmers, J.M. (2) 140; (3) 107 Billups, W.E. (1) 109; (2) 6 Bilzniak, T.E. (2) 171 Binder, J. (2) 56 Binderup , E. (3) 76 Bin Manas, A . R . (2) 67 Birch, A.J. (6i) 58 Birnbach, S. (3) 467 Bisagni, E. (5) 36 Bisaha, J. (7) 101, 130 Bisling, M. (2) 275 Bitit, N. (4) 294 Bjorkman, E.E. (5) 228 Black, D.St.C. (8) 229 Blackburn, B.K. (8) 180 Blackstock, S.C. (8) 220 Blackstock R.P. (7) 71 Blanchette, M.A. (1) 21; (2) 53; (3) 177; (6ii) 128 Bland, J.M. (3) 409 Blankenship, C. (3) 67; (6ii) 102 Blankespoor, R.L. (3) 462 Blanton, C.D. Jr. (5) 235

69 1

Author Index Blaschek, U. (3) 23 Blasius, E. (4) 277 Blizzard, T . A . (3) 353, 354; (9) 81, 82 Block, E. (1) 120; (2) 106; (4) 159; (6ii) 151; (8) 109 Blodgett, J . K . (3) 65; (5) 39 Bloom, A.J. (5) 378 Bloom, S . H . (1) 39; (7) 57 Blum, Z. (8) 157 Blumenkopf, T . A . (4) 80 Bluther, M. (4) 175 Boardman, L.D. (7) 21 Boaz, N.W. (1) 149 Boberg, F. (5) 470; (8) 24 Boche, G . (1) 163; (3) 213 Bodalski, R. (2) 147; (6ii) 127 Boden, E.P. (4) 67, 68; (6ii) 109 Bodurow, C. (3) 274 Bohnke, H. (3) 440 Boensmann, H. (3) 10 Boerrigter, J.C. (4) 307 Boes, M. (5) 99, 102; (6ii) 11 Bottcher, H. (8) 225 Bogatsky, A.V. (4) 278, 291 Bogavac, M. (2) 42 (6ii)

41 Boger, D.L. (2) 85; (5) 352; (7) 77, 78; (8) 101, 151 Bognar, R. (5) 519 Boireau, G. (3) 18 Bojilova, A. (5) 289 Boldt, P. (5) 159 Bolte, M.L. (3) 103 Bolton, G . L . (5) 203; (9) 8 Bonadies, F. (3) 299, 307 Bonin, M. (5) 355, 366 Bonini, C. (3) 299, 307 Borgulya, J. (8) 121 Borisenko, A.A. (5) 403 Borschberg, H.-J. (8) 202 Boruah, J . N . (5) 237 Boruah, R.C. (5) 236, 237 Bosch, J. (8) 224 BOSCO, M. (5) 16 Bose, A.K. (8) 251, 261 Boston, M.C. (3) 217 Bottaro, J.C. (1) 16; (3) 163; (6ii) 21 Botton, G.L. (7) 95 Bouas-Laurent, H . (4) 294

Boudreaux, G.J. (1) 24 Boukouvalas, J . (8) 66-68 Bourgasser, P. (2) 229; (6ii) 29 Boutin, R.H. (3) 65; (5) 39, 40 Bowman, P.J. (5) 444 Boxberger, M. (7) 190 Boyd, S . D . (5) 339 Boyle, P . H . (5) 59 Bozini, S. (5) 457 Braat, K. (8) 166 Bradshaw, J . S . (3) 226; (4) 225 Braga, A.L. (1) 161, 162; (4) 263 Brahme, K.C. (5) 462 Bran, G. (4) 226 Branca, S.J. (3) 201 Brandange, S. (3) 292 Brandi, A. (3) 97; (6ii) 94; (7) 189 Brandsma, L. (1) 177; (5) 156 Brandt, K. (5) 191 Braun, H . (5) 222, 223; (8) 99, 100 Braun, M. (3) 23; (6ii) 33, 45 Bravo, P. (3) 282; (6ii) 3 Brayer, J . L . (8) 38 Bremmer, J.B. (5) 364; (8) 230 Breslow, R. (3) 411 Bridges, A . J . (3) 301; (6ii) 22; (8) 31 Bridon, D. (3) 55 Brienne, M.-J. (3) 118 Bright, D.W. (5) 276 Brill, J . F . (2) 223; (5) 31 Brinker, U.H. (7) 190 Brinkman, G.A. (6ii) 56 Brinkman, K.C. (2) 143; (6i) 98 Broadley, K. (6i) 72; (8) 237 Broekhof, N . L . J . M . (2) 54; (5) 129-131 Bronberger, H. (2) 187 Brooks, D.W. (3) 117; (4) 50 Broser, E. (6i) 26 Brotherton, C.E. (2) 85; (5) 352; (7) 77, 78 Brown, B.R. (5) 444 Brown, C . A . (6ii) 20 Brown, E. (3) 264 Brown, H.C. (1) 74, 75, 131, 165; (2) 37, 79, 80, 130, 137, 271; (3)

2, 108; (4) 1, 16, 27 31, 33, 73, 74, 201, 243; (6ii) 57, 63-65, 68, 69, 71 Brown, J . M . (1) 13; (6i) 8 Brown, K.J. (6ii) 10 Brown, L . (4) 164 Brown, L.E. (3) 359 (5) 282 Brown, P.A. (7) 121 Brown, R.S. (2) 116 Brown, R.T. (7) 71 Brown, S.E. (3) 471 Browne, E . J . (5) 364 Bruder, W.A. (3) 408, 463; (5) 338 Bruhn, P. (6i) 57 Brunel, S. (5) 288 Brunelle, D.J. (4) 259 Brunet, J.-J. (1) 36 Brunn, W. (5) 146 Brunner, H. (2) 278; (3) 152; (5) 25 Bruntrup, G. (3) 23 Brutts, D. (2) 65; (6ii) 18 Bryson, T . A . (7) 170 Buchanan, R.A. (3) 340 Bucheister, A. (3) 281 Buchwald, S.L. (1) 22 Budurow, C. (4) 235 Buldian, G. (5) 21, 127 Bunnelle, W.H. (8) 45 Bunyak, J.D. (5) 487 Burba, A.A. (5) 280 Burdi, D . F . (1) 128 Burk, R.M. (5) 68; (8) 171, 172 Burke, S.D. (3) 251; (8) 46; (9) 15 Burks, S.R. (8) 208 Burnett, D.A. (8) 178 Burnett, F . N . (5) 371 Burns, D.B. (4) 169 Buskakov, Yu.A. (5) 554 Buss, A.D. (1) 83 Busse, U. (3) 416 Buter, J. (4) 303; (8) 234 Butsugan, Y. (4) 185 Buttero, P . D . (8) 113 Buttery, C.D. (3) 49 Buurman, D.J. (5) 94, 482 Byrom, N.T. (6i) 18 Bystrom, S.E. (6i) 30 Cabello, J . A . (2) 105; (5) 319 CabrC, J . (3) 392 Cacchi, S . (1) 37, 38, 121; (3) 216; (6i) 11,

General and Synthetic Methods

692

79 Cadiot, P. (3) 131 Cahiez, G. (2) 46, 172; (6i) 61 Caine, D. (6ii) 141 Calabrese, J.C. (1) 126; (6i) 13; (7) 113 Calas, R. (4) 245; (5) 144 Calderon, 0. (5) 49 Caldwell, W.E. (7) 30 Callant, P. ( 3 ) 175; (5) 524, 525; (8) 15 Calo, N. (5) 51 Camarasa, M.J. (5) 546 Cambie, R.C. (5) 542; (6ii) 120; (7) 54, 171; (9) 53 Cameron, A.G. (1) 48 Campbell, C.L. (9) 86 Campbell, M.M. (7) 160; (9) 69 Campbell, S.F. (5) 50 Campello, J.M. (5) 319 Campos, J.P. (4) 7, 202 Cane, D.E. (3) 318; (9) 5 Cannon, J.G. (5) 30 Canonne, P. (3) 284 Cano-Yelo, H. (2) 9 Cantagelli, G. (5) 16 Capdevielle, P. (3) 54 Caple, R. (2) 134 Capozzi, G. (8) 97 Capps, N.K. (6i) 41 Caprita, A. (6i) 47 Capson, T.L. (3) 63; (5) 37 Carboni, B. (8) 187 Cardani, S. (2) 249; (3) 225 Cardellini, M. (8) 249 Cardillo, G. (2) 150; (3) 267; (5) 210 Cardillo, R. (3) 120; (4) 53 Cardin, D.B. (3) 239; (4) 34 Cargill, R.L. (7) 30 Caristi, C. (3) 372; (8) 97 Carless, H.A.J. (8) 37, 70 Carlon, F.E. (3) 75 Carlon, M. (2) 65; (6ii) 18 Carlson, R. (5) 132, 133 Carmichael, C.S. (7) 123 Caro, B. (3) 137 Carpenter, T.A. (3) 210 Carpino, L.A. (3) 470 Carr, K. (6i) 22 Carre, M.C. (2) 229;

(6ii) 29 Carrera, P. (3) 282; (6ii) 3 CarriC, R. (1) 132, 133; (8) 187 Carruthers, W. (8) 207 Carson, H.J. (8) 166 Cartaya-Marin, C.P. (7) 74 Carvalho, C.F. (4) 134 Casadei, M.A. (7) 180 Casara, P. (1) 156; (3) 446; (5) 177 Cashaw, J.L. (8) 205 Casiraghi, G . (3) 47 Casnati, G. (2) 169; (3) 47 Cassell, R.A. (6ii) 141 Casserly, E.W. (1) 109 Castedo, L. (1) 124; (8) 3 Castelhano, A.L. (1) 155, 157; (3) 446, 450; (5) 178 Castellino, A.J. (5) 463 Castellino, S. (3) 329; ( 8 ) 41 Castro, C.E. (5) 476 Castro, J.L. (8) 3 Castro de Lee, N. (3) 117 Catalano, M.M. (5) 432 Cates, L.A. (5) 275 Caton, M.P.L. ( 8 ) 155 Caubere, P. (1) 36; (2) 229; (6ii) 29 Cava, M.P. (2) 49; (5) 29, 453 Cazes, B. (1) 123; (3) 99, 100 Cecchitti, S. (3) 59 Cha, J.K. (1) 44; (.3) 34; (4) 8; (6i) 33 Cha, J.S. (2) 37; (4) 27, 243; (6ii) 65 Chaabouni, R. (5) 173 Chaisupakitsin, M. (8) 205 Chakrabarti, S. (4) 50 Chakraborty, T.K. (3) 246, 290 Challis, B.C. (5) 447 Chamberlin, A.R. (1) 39; (6ii) 140; (7) 57; (8) 156 Chan, C.-C. (3) 104 (8) 104 Chan, J.H. (5) 268 Chan, K.-S. (6i) 90 Chan, M.F. (8) 274 Chan, T.H. (2) 189; ( 3 ) 153; (4) 115; (7) 173 Chan, Y.M. (4) 41; 5) 26

Chancharunee, S. (1) 99; (2) 118 Chandrakumar, N.S. (9) 43 Chandrasekaran, S. (2) 5; (3) 246, 290; (4) 6, 149 Chang, F.C. (1) 9; (5) 458 Chang, H. (4) 120 Chang, L.-J. (1) 118 Chang, T.C.T. (3) 281; (5) 402 Chang, Y.K. (2) 2 Chantreux, D. (3) 461 Chapleur, Y. (4) 231; (5) 518 Chapman, K.T. (7) 101, 130 Chapman, M.A. (5) 444 Chapman, R.C. (9) 86 Chapuis, C. 96, 97, 99 Chatani, N . (6i) 99; (7) 188 Chatterjee, J.N. (4) 170 Chauhan, G . S . (5) 466 Cheikh, R.B. (5) 173 Chen, C.-S. (3) 113; (4) 46 Chen, F.M.F. (3) 397 Chen, S.L.A.A. (5) 354 Chen, S.-Y. (3) 262 Chen, Y.-S. (2) 31; (6i) 28 Chen, Y.-Y. (5) 199 Chenard, B.L. (3) 9 Cheng, C.H. (5) 532 Cheng, C.-W.F. (5) 402 Cherton, J.-C (5) 517 Chhabra, B.R. (3) 103 Chianelli, D. (6ii) 159 Chiang, C.-Y. (3) 15 Chiang, Y. (1 72; (3) 445 Chiba, T. (8) 259 Chida, Y. (5) 205 Chikashita, H (2) 282 Chilot, J.-J. (4) 236 Chimichi, S. (8) 233 Chin, G.K. (3) 471 Chiriac, C.I. (5) 455 Chmielewski, M. (8) 244 Cho, I.H. (2) 20 Cho, W. (3) 95 Chohan, V. (5) 364 Choi, J.-K. (8) 178 Choi, V.M.F. (5) 342; (6ii) 101 Chou, C.S. (4) 148 Chou, S.-S.P. (5) 134 Chou, T. (1) 118 Chow, W. (2) 53 Choy, W. (1) 21; (3) 177;

693

Author Index (6ii) 128 Chretien, F. (5) 518 Christ, W.J. (4) 8; (6i) 33 Christensen, B.G. (8) 252, 253, 267 Christophel, W.C. (5) 543 Christy, M.R. (2) 144; (4) 88; (6ii) 155 Chu, C.-W. (5) 134 Chu, G.-N. (1) 41; (3) 195 Chu, K.-H. (2) 78 Chucholowski, A. (3) 22; (5) 190, 365 Chung, J.Y.L. (6ii) 140; (8) 156 Chung, T.F. (5) 532 Church, D.F. ( 5 ) 379 Chylinska, B. (6ii) 26 Cicianti, G. (8) 233 Cignarella, G. (8) 107 Ciminale, F. (5) 160, 176 Cinquini, M. (3) 368; (5) 281; (6ii) 4 Citterio, A. (3) 110 Clardy, J. (3) 214; (8) 223; (6ii) 149 Clarembeau, M. (4) 166; (6ii) 162, 163 Clark, G. (5) 401 Claudi, F. (8) 249 Clausen, K. (3) 228, 230 Clawson, L. (1) 22 Clawson, P.J. (8) 22 Clegg, W. (4) 293 Clement, K.S. (9) 19 Clift, S.M. (1) 55; (6i) 76 Clive, D.L.J. (1) 116; (2) 92, 101; (3) 314; (6ii) 104; (7) 186 Clouser, K.A. (8) 166 Cloux, R. (2) 121 Coates, R.M. (3) 50, 167; (8) 88 Cochetti, S. (1) 28 Cochran, D.W. (5) 429 Cofler, M. (5) 140 Coghlan, M.J. (1) 47; (7) 175; (9) 12 Cohen, B.J. (3) 396 Cohen, I.D. (9) 29 Cohen, M. (3) 281 Cohen, M.J. (3) 66 Coleman, R.S. (8) 151 Collum, D.B. (1) 27; (9) 59 Colombo, F. (3) 481 Colombo, L. (2) 249-251; (3) 123, 173; (4) 63; (6ii) 13

Colombo, R. (3) 481 Colonna, S. (8) 4 Colquhoun, H.M. (6i) 1 Comasseto, J.V. (1) 161, 162; (4) 263 Combret, J.C. (2) 215; (5) 152, 153 Comins, D.L. ( 4 ) 12 CommerCon, A . (2) 112 Confalone, P.N. (8) 147, 148; (9) 30, 31 Conley, R.A. (3) 43 Constanzo, A. (8) 233 Contreras, R. (5) 81 Cook, J.M. (7) 72 Cooke, M.P. Jr. (7) 50 Cooper, K. ( 7 ) 88 Cooper, R.D. (3) 260 Coppola, G.M. (2) 217 Corain, B. (5) 140, 141 Cordova, R. (3) 332 Corey, E.J. (1) 52, 149, 185; (2) 179; (3) 81, 227, 275, 319, 349; (4) 138; (5) 90, 322, 348, 394; (6i) 60; (6ii) 113, 114; (7) 8; (9) 50, 54, 73, 93 Corless, P.F. (5) 367 Cornelis, A. (2) 220; (5) 380 Corriu, R.J.P. (1) 164; (5) 180 Cortes, D.A. (2) 18; (4) 148 Cosgrove, J.P. (5) 379 Cossec, B. (3) 426 Cossio, F.P. (8) 245 Cosson, J.P. (6i) 42 Costa, A. (2) 180; (5) 498 Costisella, G . (3) 243 Cottens, S. (1) 129, 130 Couffignal, R. (3) 252 Coulentianos, C. (2) 112 Coutrot, P. (3) 4 Couture, A . (8) 125 Couture, Y. (5) 284 Cox, D.P. (4) 196; (5) 119 Cox, M.T. (8) 207 Cozzi, F. (3) 368; (5) 281; (6ii) 4 Crackett, P.H. (4) 92; (6ii) 86 Craig, R.H. (2) 171 Craig, T.A. (3) 291 Cralli, C. (7) 180 Cram, D.J. (4) 308 Crandall, J.K. (4) 221; (7) 36, 37 Crank, G. (5) 530

Cranor, W.L. (3) 62 Cremmins, P.J. (8) 19 Crich, D. ( I ) 5, 96; (3) 56, 171; ( 4 ) 160 Crimmins, M.T. (1) 100; (7) 28, 51; (9) 3 Crisp, G.T. (1) 122; (6i) 78; (6ii) 112; (9) 10 Cross, G.C. (5) 385, 386 Crossley, M.J. (5) 432 Crow, W.D. (3) 103 Crozet, M.P. (8) 118 Cuellar, L. (5) 81 Cullin, D. (2) 65: (6i 18 Curci, R. ( 4 ) 266 Curley, R.W. Jr. (7) 2 Curran, D.P. (2) 223; 3) 21; (5) 31 Curtis, P.J. (6i) 74 Curzon, E. (6i) 37 Cuvigny, T. (4) 172 Cynkowski, T. (3) 297 Czarnik, A.W. (4) 271 Czech, A. (4) 300 Czech, B. (4) 300 Daalman, L. (6i) 96 Dabbagh, G. (2) 261; (3) 90 Dagonneau, M. (8) 188 Dahan, R. (1) 130 Daiz, A. (5) 325 Dalgard, N.K.A. (5) 303 Dalla Cort, A. (5) 541 Dall'occo, T. (5) 374 Dalpozzo, R. (5) 16 Dalton, J.R. (7) 30 Daly, J.J. (8) 121 D'Angeli, F. (5) 141 Danishefsky, S. (1) 137; (5) 14; (7) 115, 147; (8) 39, 40, 42, 43; (9) 26 Dappen, M.S. (2) 164; (5) 446, 504; (7) 151; (8) 102 Darbre, T. (8) 202 Darlene-Ward, M. (4) 10 Darling, S.D. (5) 426 Das, B.C. (5) 73; (6i) 42 Daskiewicz, Z. (5) 427 Dauben, W.G. ( 4 ) 163 Daugherty, B.W. (3) 463 Daunis, J. ( 3 ) 404 D'Auria, M. (3) 224, 289 Dauzonne, D. (5) 396, 430; (8) 52 Davidson, A.H. (7) 39 Davies, G.M. (6i) 41; (6ii) 73

General and Synthetic Methods

694 Davies, N. ( 4 ) 178 Davies, S.G. (1) 3 2 ; ( 3 ) 2 0 ; ( 4 ) 6 4 , 205; (6i) 1 2 , 6 8 , 6 9 , 71-75; ( 8 ) 237 Davis, F . A . ( 2 ) 140; ( 3 ) 107; ( 8 ) 8 3 Davis, J.T. ( 1 ) 21; ( 2 ) 5 3 ; ( 3 ) 1 7 7 ; (6ii) 128 Davis, M.A. ( 5 ) 549 Davis, P.D. ( 2 ) 109; ( 4 ) 217; (6ii) 112 Davis, V.E. ( 8 ) 205 Davison, R.S. ( 5 ) 108 Dawe, R.D. ( 4 ) 96 . Dawson, B.A. ( 9 ) 7 De, B. ( 3 ) 349; ( 9 ) 7 3 Deacon, G.B. ( 1 ) 8 Debal, A . ( 3 ) 241 Deberly, A . ( 3 ) 18 De Bernadis, F. (6ii) 4 3 DeBernardis, J . F . ( 8 ) 167 de Boer, Th.J. ( 5 ) 555 De Buyck, L. ( 2 ) 154; ( 8 ) 131 Decodts, G . ( 4 ) 226 DeCorte, B . ( 8 ) 131 Decouzon, M. ( 8 ) 132 Defoin, A. ( 5 ) 220 de Grandpre, M. ( 4 ) 308 De Groot, A . ( 3 ) 287 Deguchi, R. ( 2 ) 9 4 ; ( 7 ) 155 Dehasse-De Lombaert, C.G. ( 3 ) 285 De Kimpe, N. ( 2 ) 154; ( 8 ) 131 Delaney, N . G . ( 2 ) 133; ( 5 ) 137 de la Pradilla, R.F. ( 9 ) 51 DeLasalle, P. ( 3 ) 22 de las Heras, F . G . ( 5 ) 546 Deleris, G. ( 4 ) 245 Delmas, M. ( 3 ) 176 DeLoach, J . A . (1) 1 0 0 ; ( 7 ) 28, 51; ( 9 ) 3 De Lombaert, S . ( 3 ) 8 4 ; ( 5 ) 2 7 7 , 328; (6ii) 19 De Lopez-Cepero, I.M. (6ii) 37 Delorme, D. (1) 2 0 ; ( 4 ) 128; (6ii) 9 8 , 129 DeLuca, H.F. ( 7 ) 2 DeLucca, G. ( 1 ) 184 DeLucchi, 0 . ( 2 ) 1 5 5 ; ( 3 ) 51; ( 7 ) 111 Dernailly, G. (6ii) 5 Dembech, P. ( 4 ) 105 de Meijere, A. ( 7 ) 6 Demersman, P. ( 5 ) 424

DeMico, A. ( 3 ) 2 2 4 , 289 Demuth, M. ( 7 ) 9 1 ; ( 9 ) 7 den Hertog, H.J. ( 4 ) 307 de Nijs, M.P. ( 5 ) 506 Denmark, S.E. (1) SO; ( 2 ) 164; ( 5 ) 4 4 6 , 504; ( 7 ) 1 3 5 , 151; ( 8 ) 102 Denney, B.D. ( 4 ) 232 Denney, D.Z. ( 4 ) 232 Denny, W.A. ( 5 ) 7 1 Dent, W. ( 9 ) 29 Depezay, J . - C . ( 3 ) 254 Depres, J.-P. ( 7 ) 46 Derguini, F. ( 2 ) 129 (6ii) 14 Deronzier, A. ( 2 ) 9 Desai, M.C. ( 2 ) 80 Desbene, P.-L. ( 5 ) 5 7 Deschenaux, R . ( 3 ) 4 1 DeShong, P. ( 2 ) 113; ( 5 ) 552 Deshpande, S . ( 5 ) 431 Desideri, N. ( 5 ) 51 Desjardins, S . ( 5 ) 7 DesMarteau, D.D. ( 5 ) 485 de Solms, S.J. ( 7 ) 2 3 , 24 Destro, R. ( 7 ) 53 Desvergne, J.-P. ( 4 ) 294 Detty, M.R. ( 5 ) 136 Devant, R. ( 3 ) 2 3 ; (6ii) 33 Dewar, M.J.S. ( 7 ) 102 D'Haenens, L. ( 3 ) 1 7 5 ; ( 5 ) 5 2 4 , 525 DiBattista, P. ( 3 ) 91 Dickman, D.A. ( 5 ) 1 0 2 ; (6ii) 11 Dien, F.K. ( 3 ) 401 Dieter, J.W. ( 3 ) 223 Dieter, R.K. ( 3 ) 223 Dietrich, J. ( 5 ) 489 Diez, A. ( 8 ) 224 Di Fabio, R. ( 3 ) 299 Differding, E. ( 3 ) 285 DiFuria, F. ( 4 ) 269 Dijksman, W.C. ( 8 ) 154 Dijkstra, P.J. ( 4 ) 307 Dike, M.S. ( 9 ) 15 DiMaio, J . ( 8 ) 217 di Nunno, L. ( 5 ) 520 Dishong, D.M. ( 4 ) 2 8 0 , 28 1 Ditrich, K. ( 2 ) 252 Dittel, W. ( 5 ) 221 Djahanbini, D. ( 3 ) 99 Djuric, S.W. ( 5 ) 245 Doering, W.von E. ( 1 ) 183 Doherty, A.M. ( 2 ) 2 0 5 ; ( 8 ) 54 Doi, E. ( 3 ) 386 Doi, Y. ( 5 ) 425 Dolence, E.K. ( 2 ) 144;

( 4 ) 8 8 ; (6ii) 155 Dolle, R.E. ( 5 ) 1 9 0 , 365 Dollinger, H. ( 5 ) 111 Dondini, A. ( 5 ) 374 Donnelly, K.D. ( 4 ) 187 Doolittle, R.E. (1) 176 Dordor, I.M. ( 3 ) 20; ( 4 ) 6 4 ; (6i) 6 9 , 7 1 Doria, G . ( 1 ) 15 Dorsch, M. ( 7 ) 81 Dossena, A . ( 2 ) 169 Dotheau, A. ( 8 ) 36 Dotz, K.H. (6i) 5 Dourtoglou, V. ( 3 ) 384 Doutheau, A. ( 4 ) 236 Doyle, M.P. ( 7 ) 5 , 7 Doyle, P.M. ( 5 ) 444 Doyle, T.W. (1) 7 2 ; ( 3 ) 445 Draper, R.W. ( 3 ) 7 5 Dreiding, A . S . (7) 9 0 , 172 Dreme, M. ( 5 ) 288 Drtina, G.J. ( 8 ) 29 Dryanska, V. ( 5 ) 481 D'sa, A . ( 4 ) 2 3 4 ; ( 8 ) 12 Dua, S.S.(6i) 81 Dubiez, R. ( 8 ) 125 Dubois, J.-E. ( 3 ) 1 9 ; ( 8 ) 257 Duclos, R.I. ( 5 ) 12 Duffaut, N . ( 5 ) 144 Dufresne, Y. ( 4 ) 1 2 8 ; (6ii) 98 Dugar, S . ( 5 ) 382 Duggan, M.E. ( 4 ) 100 Duhamel, P. ( 2 ) 1 9 7 ; ( 3 ) 4 1 0 ; (6ii) 8 ; ( 7 ) 139 Duke, R.K. ( 9 ) 71 Dulcerre, J.-P. ( 4 ) 119 Dumont, W. (6ii) 1 2 4 , 167; ( 8 ) 5 Dung, J.-S. ( 9 ) 48 Dunlap, N.K. ( 2 ) 149 Dunogues, J. ( 4 ) 2 4 5 ; ( 5 ) 144; (6ii) 121 Dupuy, C. ( 2 ) 2 7 4 ; ( 3 ) 141 Duraisamy, M. ( 2 ) 222 Durkault, A. ( 3 ) 254 Dust, M. ( 3 ) 255 Duthaler, R.O. ( 2 ) 9 5 , 96 Dyatkina, N.B. ( 5 ) 505 Dzadzic, P.M. ( 5 ) 439 Dziewonska-Baran, D. ( 5 ) 391

Eapen, K.C. (6i) 81 Earlywine, A.D. ( 5 ) 414 Eaton, P.E. ( 5 ) 399 Ebine, S . ( 4 ) 301 Echavarren, A. ( 9 ) 4 3

Author Index Eckrich, T.M. (1) 185; (3) 408; (5) 338; (6ii) 113, 114 Eddine, J.J. (3) 410; (6ii) 8 Edington, C. (6ii) 105 Edwards, M.P. (9) 78 Edwards, P.D. (5) 103, 104; (8) 169 Effenberger, F. (3) 438; (5) 143, 269 Ehrenkaufer, R.E. (5) 6 Eichenauer, H. (2) 231; (3) 150; (5) 461 Eilbracht, P. (6i) 97 Einhorn, J. (5) 424 Einstein, F.W.B. (8) 94, 173 Eis, M.J. (3) 323; (4) 103 Eisenbraun, E.J. (2) 102 Eisenhart, E.K. (7) 132 Ekstrom, M . (8) 157 El-Abadelah, M.M. (8) 106 El-Abed, D. (2) 93; (3) 26; (5) 331; (7) 154 El Gadi, A. (3) 4 Elgemeie, G.E.H. (5) 324 Elguero, J. (4) 285 El Hallaoui, A. (3) 413 Eliel, E.L. (2) 145, 146; (3) 17, 324; (4) 89, 90; (6ii) 36 Elkinson, R.S. (5) 255 Ellenberger, S.R. (6ii) 149; ( 9 ) 66 Elling, J.W. (8) 166 Elliott, J.D. (1) 154; (4) 92; (5) 342 (6ii) 86, 101, 105; (7) 164 Ellissondo, B . (5) 197 Elmoghayar, M.R.H. (5) 324 Elnagdi, M.H. (5) 324, 544 Elser, R. (3) 82 El-Telbany, F. (4) 9; (6ii) 67 Enda, J. (2) 199; (6ii) 95 Enders, D. (2) 81, 231; (3) 150; (5) 32, 334, 461 Endo, R. (3) 74 Endo, T. (4) 209; (5) 11, 253; (8) 69 Enev, V. (7) 60 Engel, N. (3) 10, 11 Engelhardt, E.L. (5) 428 Enholm, E.J. (6ii) 109 Epifani, E. (5) 175 E r d i k , E. ( 6 i ) 6

695

Eremeev, A.V. (5) 255 (5) 321, 404; (6i) 50 Erickson, R.H. (5) 439 Feustel, M. (5) 181, 182 Fiandanese, V. (2) 44; Ernst, K. (3) 429 Escobar, G. (5) 477 (3) 87; (6ii) 39 Eskanazi, C. (8) 6 Fibiger, R. (4) 168, 186; Essenfeld, A.P. (1) 21; (5) 509 (2) 53; ( 3 ) 177; (6ii) Fiechter, A. (3) 119; (4) 128 54 Eswarakrishnan, V. (1) Fields, T.L. (5) 299 120; (6ii) 151 Filiponne, P. (2) 162; Etemad-Moghadam, G. (3) (5) 456 Filippini, L. (3) 110 178; (5) 316 Finklea, H.O. (3) 217 Etter, J.B. (7) 68 Finn, J. (2) 140; (3) 107 Euerby, M.R. (8) 203 Evans, D.A. (1) 12; (6i) Finn, M.G. (6i) 24 Firouzabadi, H. (2) 3, 4, 9; (7) 101; (7) 130 11-14, 139, 147, 150, Evans, G.E. (3) 210 151, 158, 247; (5) 529 Evans, S.V. (5) 184 Eyley, S.C. (2) 116 Fischer, A. (5) 385, 386 Eyman, D.P. (2) 38; (6ii) Fishbein, P.F. (7) 20 Fishbein, P.L. (5) 370 82 Ezhovo, G.I. (5) 503 Fittkau, S. (3) 382; (5) 296 Fitzner, J.N. (1) 70, 71; Failli, P. (3) 405 (5) 169, 170; (6ii) 164 Fleet, G.W.J. (5) 184-186 Falck, J.R. (1) 59; (2) 52, 268 Fleischmann, M. (5) 378 Faller, P. (6ii) 157 Fleming, B.G. (8) 263 Fleming, I. (2) 71, 232, Fallis, A.G. (3) 143; (8) 137 263; (3) 89, 129; (4) 117; (6ii) 106 Fankhauser, J.E. (1) Flippin, L.A. ( 2 ) 247 69-71; (5) 168-170; Flodman, L. (3) 292 (6ii) 164 Flogaus, R. (2) 173; Fantin, G. (5) 374 (6ii) 38 Farnung, W. (5) 145 Fatmi, A.A. (5) 235 Florent, J.-C. (5) 366 Fava, G. (2) 162 Flores, H.J. (8) 228 Florio, S. (5) 160, 175, Fawcett, J. (7) 121 Fawcett, S.M. (4) 244 176, 520 Fludzinski, P. (3) 214 Fazio, M.J. (5) 123 Flynn, G.A. (5) 276 Feit, B . A . (3) 82 Fekarurhobo, G.K. (8) 37, Fodor, L. (8) 212 Forster, W.-R. (8) 273 70 Fogagnolo, M. (5) 374 Felber, H. (5) 223; (8) Foglio, M. (8) 268 100 Fohlisch, B. (6ii) 38 Felder, E. (3) 405 Felici, M. (1) 37 Foley, L.H. (5) 341 Felix, A.S. (5) 546 Foote, C.S. (5) 241 Felkin, H. (6i) 68 Forrest, A.K. (8) 176 Fellows, C.A. (3) 298 Fortgens, H.P. (1) 158; Fellows, L.E. (5) 185 (3) 449; (5) 179 Fortin, R. (4) 122; (6ii) Fenk, C.J. (3) 21 Ferlazzo, A. (3) 372 97 Fernandez, H. (5) 81 Foucaud, A. (3) 30; (8) Fernandez de Kaifer, C. 262 (1) 94; (3) 191 Fourrey, J.-L. (1) 68; Fernandez-Resa, P. (5) (6ii) 160 Fowler, F.W. (8) 195 546 Ferrera, L. (3) 365; (5) Fraenkel, G. (5) 125 285; (6ii) 52 Frahm, A.W. (5) 33 Ferrino, S. (9) 15 Francheschi, G. (8) 268, Ferroud, D. (3) 98, 200; 270

General and Synthetic Method3

696 Francis, C.J. (3) 12, 257 Francisco, C.G. (5) 400; (8) 75 Franck, B. (3) 40 Franung, W. (3) 3 Franzh, H. (3) 480 Fraser-Reid, B. (3) 251, 355; (5) 213, 214 Frater, G. (3) 124 Fray, M.J. (2) 99; (5) 201; (7) 187 Frazee, W.J. (3) 17 Frazier, J . O . ( 3 ) 217 Frechette, R.F. (3) 291 Freer, V.J. (2) 32 Freire, R. (8) 75 Freskos, J . (3) 297 Freudenberg, U. (8) 9 Frey, H. (1) 152 Freyer, A.J. (5) 217; (8) 124 Friere, R. (5) 400 Frigo, T.B. (8) 220 Friour, G. (2) 46, 172; ( 6 i ) 61 Fristad, W.E. (4) 187 Froelisch, B. (2) 173 Froussios, C. (3) 459; (4) 227 Fruchier, A . (8) 105 Fry, S.E. (3) 79; (5) 69 Frydman, B. ( 5 ) 21, 127 Frye, L.L. (2) 281; (3) 264; (6ii) 145 Fuchs, B. (4) 198 Fuchs, P.L. (3) 250; (6ii) 27; (8) 33 Fuentes, L.M. (5) 99, 101; (8) 213 Fuji, K. (2) 176; (4) 107, 212; (5) 420 Fuji, T. (4) 19 Fujihara, H. (3) 424 Fujihara, Y. (2) 104 Fujii, I. (4) 288 Fujii, M. (2) 283, 284; (5) 397 Fujii, T. (3) 122 Fujikura, S. (1) 64; (7) 56 Fujimori, K. (4) 252 Fujirnori, M. (2) 50 Fujimoto, K. (1) 81; (3) 313; (4) 113; (8) 264 Fujimoto, M. (2) 176; (4) 212; (5) 420 Fujisaki, S. ( 3 ) 64, 373; (5) 38 Fujisawa, T. (1) 46,147, 148; (3) 27, 33-35, 114, 220, 269, 322; (4) (4) 47, 183; (6ii) 89

Fujita, E. (1) 35; (2) 136; (3) 13, 386; (4) 107, 212; (5) 266; (9) 83 Fujita, H. (8) 120 Fujita, M. (2) 148; (5) 192; (6ii) 100 Fujita, Y. (5) 318 Fujiwara, J. (2) 266; (4) 94; (6ii) 79, 81; (8) 174 Fujiwara, S. (7) 168 Fujiwara, T. (2) 50; (4) 274 Fujiyama, R. (5) 351; (6ii) 85 Fukatsu, S. (3) 410 Fuks, R. (5) 151 Fukuda, H. (3) 334 Fukuda, Y. (1) 18, 168; (4) 98; (6ii) 28 Fukui, M. (4) 21 Fukuishima, H, (4) 40 Fukurnoto, K. (7) 145, 146; (8) 191 Fukumoto, W. (9) 84 Fukunaga, T. (5) 412 Fukushima, H. (4) 292; (6ii) 75 Fukutani, Y. (2) 266, 267; (4) 94; (6ii) 79 Fukuto, J . (5) 476 Fukuzawa, S. (3) 41; (6ii) 165 Fukuzumi, S. (2) 26 Funakoshi, K. (2) 88; (6i) 44; (7) 61 Funita, K. (7) 43, 44 Funk, R.L. (5) 203; (7) 95, 126; (8) 196; (9) 8 Furuhata, T. (8) 73 Furuichi, A . (4) 52 Furukawa, H. (2) 50; (6i) 99; (7) 188 Furukawa, N. (4) 251; (5) 488 Furukawa, S. (3) 376; (6ii) 1; (7) 18 Furukawa, Y. (3) 267 Furusako, S. (5) 18 Furuta, K. (2) 86, 87; (3) 331; (4) 75; (7) 45 Fyles, T.M. (4) 286 Fytas, G. (3) 284

(8) 274; (9) 92 Gallagher, T. (1) 76; (4) 237; (8) 35; (9) 62 Gallois, M. (3) 241 Galpin, I.J. (3) 406 Gambino, S. (3) 38 Garnet, J.-P. (3) 395, 461 Gammill, R.B. (4) 25; (6i) 15; (6ii) 139 Ganboa, 1. (2) 168; (4) 189; (8) 245 Gandolfi, M. (3) 110 Gandras, A . (4) 245 Ganem, B. (1) 29; ( 3 ) 323, 474; (4) 103 (5) 47, 189; (6i) 14; (7) 148 Ganguly, R. (8) 76 Gank, G. (4) 246 Garapon, J. (5) 288 Garburg, K.-H. (5) 470 Garcia, A. (5) 319 Garcia, J. (3) 364, 389; (5) 248, 257 Garcia-Lopez, M.T. (5) 546 Garcia-Raso, A . (2) 105 Garegg, R.J. (4) 180 Garigipati, R.S. (5) 216, 217; (8) 124, 193; (9) 40 Garland, R. (3) 161 Garlich, J.R. (5) 19 Garner, P. (3) 422 Garrigues, B. (3) 421 Gartner, H. (3) 45 Gaset, A . (3) 176 Gasparrini, F. (2) 200; (4) 267, 268 Gassman, P.G. (1) 144; (4) 99; (5) 372; (7) 128 Gassner, T. (2) 55; (6ii) 122 Gastaldi, G. (3) 39 Gattuso, M. (3) 372; (8) 97 Gaudemar, M. (3) 383 Gaudemar-Bardone, F. (3) 252 Gaudino, J . (2) 185; (3) 135; (6ii) 123 Gaul, H. (3) 420 Gawley, R.E. (5) 497; (6ii) 30; (8) 159 Gawronski, J.K. (3) 106 Gadwood, R.C. (2) 82; (7) Gebreyes, K. (1) 120; (6ii) 151 33; (9) 13 Gainor, J.A. (5) 216 Geffken, D. (8) 85 Gais, H.-J. (3) 11, 212, Gehret, J.-C. (9) 32 333, 348 Geiger, R.E. (3) 420; Gallacher, G. (5) 219; (6i) 87

697

Author Index Gellerman, B.J. (4) 187 Genet, J.P. (3) 98, 200; (5) 321, 404; (6i) 50 Gennari, C. (2) 249-251; (3) 123, 173, 225, 351; (4) 63; (6ii) 13; (9) 80 Georg, G.I. (8) 260 Georges, M. (5) 214 Georgulis, C. (2) 182 German, C. (4) 258 Germas, J.P. (7) 135 Germon, C. (5) 166, 167 Gersdorf, J. (8) 9 Geschwinder, P.M. (4) 239 Gesing, E.R.F. (6i) 86 Gewald, K. (5) 49, 52 Ghadiri, M.R. (6ii) 154; (7) 144 Gharibi, H. (2) 3; (4) 147 Ghattas, A.-B. (5) 449 Ghiringhelli, D. (3) 120; (4) 53 Ghosez, L. (3) 84, 285, 407; (5) 277, 328; (6ii) 19 Ghosh, A.K. (3) 270; (8) 89; (9) 7 Ghosh, S. (7) 31; (8) 150 Ghribi, A. (2) 264, 265; 95, 240; (6i) 64, 65 Giancomelli, G. (4) 37; (6ii) 74 Giannattasio, S. (4) 266 Gibson, C.L. (3) 291 Giese, B. (3) 53 Gigantino, J.J. (4) 232 Gil, G. (2) 202 Gilardi, A. (6ii) 4 Gilardo, G. (3) 38 Gilbert, E.E. (5) 399 Gilbert, J.C. (8) 180 Gill, G.B. (3) 31 Gillard, J.W. (4) 122; (6ii) 97 Giordano, C. (3) 39 Giovanni, F. (4) 54 Giovannini, F. (3) 119 Giovannoli, M. (2) 200; (4) 267, 268 Girault, Y. (8) 132 Gladysz, J.A. (2) 143; (6i) 98 Glass, R.S. (6i) 89 Gleicher, G . J . (5) 379 Gluchowski, C. (3) 83; (6ii) 7; (9) 86 Gnichtel, G. (8) 108 Gnonlonfoun, N. (3) 245 Goasdoue, C. (3) 383 Goasdoue, N . (3) 383

Godleski, S.A. (3) 302; (6i) 52 Godschalx, J.P. (2) 108; (3) 184; (4) 216; (6ii) 112 Goedken, V. (6i) 72 Gokel, G.W. (4) 279-281 Goldberg, I. (3) 82 Golding, B.T. (5) 23; (6i) 37 Goldman, B.E. (7) 152 Goliaszewski, A. (1) 143 Golinski, J. (5) 391, 392; (6ii) 26 Gollnick, K. (8) 63 GonzAlez, A. (8) 245 Gonzhlez, A.M. (5) 56 Gondlez, J. (3) 364; (5) 257 Gonzdlez, J.M. (4) 202 Gopalan, A.S. ( ) 12 Gordan. H.J. (5) 161 Gordon; E.M. (2) 133; (5) 137 Gore, J. (1) 123; (3) 99, 100; (4) 175, 236; (8) 36 Gorish, H. (3) 11 Gorlich, K.-J. (5) 470; ( 8 ) 24 Gorrichon, L. (2) 272 Gorzynski Smith, J. (2) 70 Gosselin, P. (3) 197 Gothling, W. (7) 6 Goto, J. (5) 494 Goto, T. (9) 75, 76 Gotoh, H. (5) 548 Gotor, V. (5) 238, 490 Gotthardt, H. (1) 112; (7) 32; (8) 81 Gottschalk, P. (7) 140 Gough, M.J. (5) 184, 186 Goure, W.F. (2) 109; (4) 217; (6ii) 112 Graburg, K.-H. (8) 24 Graff, N.M. (5) 487 Graham, R.S. (3) 239, 328; ( 4 ) 34 Gramain, J.C. (5) 93 Gramens, L.A. (8) 166 Granboa, I. (4) 141 Gratton, S. (5) 457 Graumann, J. (5) 553 Grayson, D.H. (7) 178 Greck, C. (6ii) 5 Greco, M.N. (5) 507; (6ii) 51; (9) 36 Grge, R . (1) 132, 133 Green, B.S. (7) 3 Green, G. (3) 7; (4) 145 Greene, A.E. (2) 273;

(6i) 66; (6ii) 50; (7) 46 Greenlee, W.J. (3) 443; (5) 336 Greeno, E.W. ( 4 ) 169 Greeves, N . (1) 83 Grehn, L. (3) 480 Gremban, R.S. (4) 99; (5) 372 Grenn, G. (2) 7 Gress, J.L. (5) 72 Grey, R.A. (2) 43 Gribble, G.W. (9) 38 Grieco, P.A. (7) 117, 118; (8) 15; (9) 16 Grierson, D.S. (5) 355, 356, 366 Griffith, W.P. (2) 7; (3) 7; (4) 145 Griffiths, G . J . (3) 24; (9) 91 Griffiths, G.L. (3) . _ 293, 294 Grigg, R. (1) 125; (3) 48; (6i) 18; (8) 94, 138, 145, 146 Grimaldi, J. (1) 106; (3) 273 Grinfel'd, A.A. (3) 37 Gross, A.W. (1) 52; (5) 90 Gross, B. (3) 384 Gross, H. (3) 243 Grossen, P. (3) 356 Grossert, J.S. (1) 25; (8) 82 Grote, J. (7) 131; (8) 13 Groth, U. (3) 442; (6i) 86 Grubbs, R.H. (1) 22 Grzejszczak, S. (6ii) 130 Guanti, G. (3) 422; (5) 225, (6ii) 147, 148 Guarneri, M. (3) 168 Gukdin-Vuong, D. (3) 357; (9) 77 Guendouz, F. (3) 396 Guilhem, J. (7) 143 Guiliano, R. (3) 251 Guillot, J.-P. (3) 137 Guindon, Y. (2) 218; (4) 122, 135, 253; (6ii) 97 Guinn, D.E. (3) 311 Guirado, A . (1) 142 Guixer, J. (8) 4 Gulotta, A . (3) 38 Gunaratne, H.Q.N. (3) 48; (8) 138 Gunther, H.J. (3) 267 Gunther, K. (3) 428 Gunther, W. ( 3 ) 124

698

General and Synthetic Method

Han, W.T. ( 8 ) 2 6 5 , 266 Guntrum, E. (3) 267 Hanack, M. (1) 1 7 8 ; ( 7 ) G u p t a , K. ( 8 ) 261 182 Gupton, J . T . ( 3 ) 3 6 2 ; ( 5 ) Hanefeld, W. ( 8 ) 116 273 H a n e s s i a n , S. (1) 2 0 ; G u t i e r r e z , C.G. (1) 3 G u z i e c , F.S. ( 2 ) 225; (5) (3) 4 4 4 ; ( 4 ) 1 2 8 ; ( 6 i i ) 98, 1 2 9 47 1 Hansen, E.T. ( 3 ) 7 6 ; Guzman, F. ( 5 ) 325 ( 5 ) 363 G y b i n , A.S. ( 2 ) 134 Hansen, H.-J. ( 3 ) 215 Hanson, G . J . ( I ) 1 5 4 ; ( 4 ) 9 2 ; ( 7 ) 164 Ha, D.-C. (8) 258 Hanson, R.N. ( 5 ) 549 H a b a t a , Y. ( 4 ) 302 Hansske, F. (1) 31 Habib, N.S. ( 5 ) 5 3 8 , 5 4 5 Habib, R. ( 3 ) 1 5 ; ( 5 ) 499 Hanyu, Y. (8) 7 3 Haque, M.S. ( 9 ) 8 5 H a c k e t t , S. (3) 221; H a r a , K. ( 4 ) 298 ( 6 i i ) 23 Haddadin, M.J. ( 8 ) 235 Hara, S . ( 3 ) 361; ( 4 ) 190; ( 5 ) 270 Haffmanns, G . (8) 1 4 4 Haga, K . ( 5 ) 109 H a r a d a , J. ( 3 ) 28 H a r a d a , K . (1) 11; (3) Haga, T. ( 2 ) 255 3 7 0 , 457; ( 5 ) 195 Haga, Y. ( 4 ) 265 H a r a k a l , M.E. (8) 83 Hagen, J.P. ( 3 ) 1 2 5 Hagiwara, I. ( 2 ) 236; H a r d i n g , K.E. ( 8 ) 9 6 , 208; ( 9 ) 1 9 ( 6 i ) 83 Hagiwara, Y. ( 5 ) 266; ( 9 ) H a r d i n g , M.M. ( 5 ) 432 Hardstone, J . O . ( 5 ) 50; 83 Hagopian, R . A . ( 5 ) 4 5 ( 8 ) 200 H a r i g a y a , Y. ( 4 ) 2 3 4 ; Hahn, C.S. ( 2 ) 2 , 20 (8) 1 2 , 13 Hahn, G . ( 1 ) 169; (3) Harkema, S. ( 8 ) 1 5 3 , 154 238; ( 4 ) 7 7 ; ( 6 i i ) 4 6 H a i n , U. ( 5 ) 4 9 , 52 H a r l a n d , P.A. ( 5 ) 4 6 H a i n e s , S.R. ( 3 ) 264; Harmata, M.A. (1) 5 0 ( 6 i i ) 145 H a r r e , M. ( 3 ) 1 6 1 H arrington, P.J. (5) 13; H a j i p o o r , C. ( 2 ) 1 3 ; ( 4 ) (6i) 85 158 H a j o s , Z.G. ( 8 ) 6 5 Harris, F.D. ( 5 ) 72 H a k i k i , A . (1) 1 5 0 , 151 H a r r i s , F.L. ( 3 ) 189 H a r r i s , T.M. (3) 3 5 9 ; ( 5 ) H a k i m e l a h i , G.H. ( 5 ) 496 H a k u s h i , T. ( 4 ) 283 282 H a r r i s o n , A.W. (8) 4 9 H a l e , C.G. ( 8 ) 1 5 4 H a r r i s o n , L.N. ( 6 i i ) 54 H a l e y , N.F. ( 5 ) 136 H a r r i s o n , L.W. ( 3 ) 280; H a l l , H . K . J r . ( 8 ) 103 H a l l , S.A. ( 1 ) 1 3 ; ( 6 i ) 8 ( 6 i ) 55 H a l l , S.S. ( 5 ) 268 H a r r i s o n , P. ( 5 ) 437; ( 7 ) 147 H a l l e r , K.J. ( 3 ) 3 5 5 ; H a r t , D . J . (8) 1 7 8 , 179, ( 6 i ) 27 H a l t e r e n , B.W.V. ( 6 i i ) 5 6 258; ( 9 ) 4 4 Hartmann, G . D . ( 5 ) 4 2 8 , Halweg, K.M. ( 7 ) 1 2 0 Hamada, Y. ( 3 ) 8 , 254; 502 ( 5 ) 2 0 6 , 207, 3 1 3 , 3 1 7 ; Hartmann, H. ( 5 ) 5 3 , 5 4 Hartmann, R.D. ( 5 ) 4 2 8 , ( 9 ) 65 502 Hamamoto, I. ( 3 ) 181 Harusawa, S. ( 5 ) 313, 317 Hamana, H. ( 2 ) 248 Hamana, W . ( 4 ) 6 0 H a r u t a , J . (3) 42 Hamann, P.R. ( 6 i i ) 2 7 ; Harvey, D.F. ( 8 ) 4 0 , 42 Harwood, L.M. (3) 430 ( 8 ) 33 Hamano, S . - i . ( 5 ) 486 Hasegawa, K . ( 1 ) 101; ( 3 ) Hamer, R . L . ( 5 ) 30 276; ( 6 i i ) 136 Hammer, B. ( 2 ) 278; ( 3 ) Hasegawa, M. ( 2 ) 1 9 0 , 152 266; (3) 155; ( 4 ) 94; Hamzink, M . R . J . ( 8 ) 221 ( 6 i i ) 79

Hasegawa, T. ( 3 ) 1 2 2 ; ( 4 ) 19 Hasegawa, Y. (3) 229; ( 5 ) 294; ( 6 i i ) 1 4 2 ; ( 8 ) 182 Hashem, K.E. (3) 9 3 ; ( 4 ) 213 Hashem, M . A . ( 7 ) 3 H a s h i g u c h i , Y. ( 2 ) 27 Hashimoto, H. ( 2 ) 234; (3) 4 5 3 Hashimoto, K. ( 3 ) 158 Hashimoto, M. ( 3 ) 464 Hashimoto, S. ( 2 ) 243; (3) 78; 5) 118, 232 Hassel, P. ( 2 ) 1 8 7 H a s s i g , R. ( 4 ) 222; ( 6 i i ) 96 H a s s n e r , A ( 4 ) 1 6 8 , 186; ( 5 ) 509 H a t a d a , A. ( 8 ) 1 4 3 H a t a d a , K . ( 4 ) 292 Hatakeyama, H. ( 3 ) 454 H a t a n a k a , H. ( 5 ) 2 9 4 ; ( 6 i i ) 142 H a t a n a k a , Y. ( 4 ) 78 H a t a n a k e , H. (3) 229 H a t o z a k i , M. ( 4 ) 20 H a t t o r i , K . (3) 41; ( 6 i i ) 165; (8) 55 H a u s e r , F.M. ( 6 i i ) 1 4 9 ; (9) 66 Hawkins, J.M. ( 4 ) 4 3 ; ( 6 i i ) 77 Hayakawa, K . ( 3 ) 182; ( 4 ) 273; ( 4 ) 288 Hayakawa, S. ( 3 ) 387; ( 5 ) 251 Hayama, T. ( 5 ) 4 2 1 Hayami, H . (1) 6 7 H a y a s h i , H. ( 2 ) 254 H a y a s h i , J . ( 2 ) 201; ( 4 ) 230 Hayashi, K. (5) 171; ( 6 i ) 54 H a y a s h i , M. ( 3 ) 7 8 H a y a s h i , T. (3) 101 H a y a s h i , Y. ( 5 ) 320; ( 6 i ) 59; ( 7 ) 162, 166, 167; (8) 87 H a z a t o , A . ( 5 ) 405 He, Z. ( 7 ) 117 Head, D.B. (1) 108; ( 3 ) 288 Head, R . A . ( 3 ) 207 H e a t h c o c k , C.H. ( 2 ) 247; ( 3 ) 1 2 5 , 316; ( 4 ) 5 5 , 80; (6ii) 85 H e b e i s e n , P. (5) 539 Heck, J . V . ( 8 ) 252, 2 5 3 ; (8) 267 Hegde, V . R . ( 8 ) 251 Hegedus, L.S. ( 2 ) 1 1 0 ;

Author Index (5) 13, 88, 410; (6i) 4, 77, 85; (8) 136, 239 Heil, B. (3) 455 Heimann, M. (7) 93; (9) 7 Heimbach, H. (2) 186; (3) 133, 203 Heimgartner, H. (8) 95 Heinemann, G . (3) 11 Helbig, W. (3) 116; (4) 49 Hellou, J. (3) 143 Helmchen, G. (3) 237; (6ii) 12 Helquist, P. (1) 134, 136; (5) 163 Hembre, R.T. (3) 94 Henderson, G.B. (5) 357 Hendeson, G.N. (5) 385, 386 Hendrickson, J.B. (1) 24 Henn, L. (5) 274 Hennequin, L. (2) 197 Henning, R . (3) 129; (4) 117; (6ii) 106 Hensen, H.-J. (7) 47 Hermeling, D. (3) 60 Hernsndez, D. (1) 23 Hernhdez, R. (5) 400; (8) 75 Herndon, J.W. (6i) 53 Herold, P. (3) 356 Herrick, J.J. ( 4 ) 12 Herscheid, J.D.M. (6ii) 56 Hertel, M. (5) 528 Her&, Y. (1) 2; (3) 57 Hesse, M. (3) 338, 339; (5) 406, 436; (7) 69 Hetmanski, M. (7) 66 Hewson, A.T. (6ii) 120; ( 7 ) 54; (9) 53 Hibino, J . (6ii) 111 Hickmott, P.W. (2) 227; (5) 162 Hida, M. (1) 10; (3) 454, 456 Hiemstra, H. (1) 158; (3) 449; (5) 179 High, J . (2) 65; (6ii) 18 Higuchi, N. (3) 464 Hild, W. (6ii) 45 Hill, J.H. (3) 214 Himbert, G . (5) 146, 181, 182, 274 Hino, T. (8) 181, 182 Hintzer, K. (6i) 26 Hioki, T. (3) 380; (5) 297 Hiraga, K. (7) 109; (8) 93 Hirai, K. (8) 264

699 Hirama, M. (5) 211 Hirano, T. (7) 168 Hirao, A . ( 4 ) 30 Hirao, I. (1) 111, 166; (3) 105, 300, 323; (4) 241; (7) 9 Hirao, L. (4) 97, 104, 106 Hirao, T. (2) 104 Hiraoka, H. (3) 331 Hirata, N . (7) 183 Hiratake, J. (3) 305 Hiratani, K. (4) 276 Hirayama, M. (3) 410 Hirobe, M. (5) 75 Hiroi, K. (3) 102 Hirsenkorn, R. (3) 296 Hirte, K. (8) 108 Hiyama, T. (2) 122; (2) 148; (3) 247; (5) 192, 227; (6ii) 100 Hiym, T. (5) 340 Hiyoshi, T. (5) 10 Ho, P.-T. ( 4 ) 178 Ho, Y.-P. (5) 354 Hobbs, S.J. ( 3 ) 167 Hodge, P. (4) 181, 284; ( 5 ) 46 Hodgson, S.T. (8) 238 Hochstetter, H. (8) 232 Hohn, A. (8) 218 Hoekstra, A . (6ii) 56 Hoff, D.J. (2) 54; (5) 131 Hoffman, H.M.R. (4) 239; (7) 169 Hoffman, R.V. (2) 36; (5) 531 Hoffmann, J . M . (5) 429 Hoffmann, R.W. (2) 252; (3) 116, 126; (4) 49, 72; (6ii) 60, 62 Hofmann, K . (2) 151; (3) 86 Hojyo, J. (5) 473 Hollinshead, D.M. (2) 7; (3) 7; (4) 145; (8) 238 Hollinsworth, D.R. (8) 96 Holmes, A . B . (1) 175; (6i) 34; (8) 216; (9) 45 Holton, R . A . (2) 209, 210; (9) 21 Holy, N . (5) 8 Honda, M. (3) 342 Honda, N. (3) 322 Honda, T. ( 8 ) 192 Honda, Y. (4) 295, 296 Honek, J.F. (1) 119; (2) 131 Hongu, A . (2) 190; (3) 155

Honicke, P. (3) 11 Hook, J.M. (2) 183; (3) 134; (9) 17 Hooper, D.L. (1) 25; (8) 82 Hoornaert, G . (5) 57 Hoover, J . F . (6i) 89 Hopkins, P.B. (1) 69-71; (5) 168-170; (6ii) 164 Hoppe, D. (2) 63, 64; (3) 235, 236 Hoppe, I. (5) 376 Hopton, D. (3) 391; 466 Hori, I. (4) 24; (6ii) 137 Horiguchi, C.A. (3) 5; (4) 197 Horikoshi, K. (4) 52 Horita, K. (4) 125, 126 Horne, D. (2) 185; (3) 135; (6ii) 123 Horton, M. (7) 89 Hoshi, K. (5) 314, 346 Hoshi, M. (1) 171, 189; (5) 306, 508 Hoshino, K. (4) 251 Hoshino, M. (1) 60; (4) 256 Hosmane, R.S. (5) 371, 479 Hosoi, S. (6ii) 166 Hosomi, A. (2) 201; (4) 230; (8) 141 Hou, C.S. (2) 18 HOU, K.4. (2) 141; (4) 116; (5) 510; (8) 64 Hoveyda, A . H . (9) 88 Howes, C. (5) 23 Hoye, T.R. (3) 310 Hoyer, D. (6ii) 9 Hoyle, J. (1) 25; (8) 82 Hrada, H. (5) 254 Hrubiec, R.T. (4) 182, 219; (5) 558 Hsiao, C.-N. (1) 117 Hsieh, K.C. (1) 155; (3)

446 Hsu, M.H. (3) 280; (6i) 55 Hsu, S.-Y. (2) 31; (6i) 28 Hua, D.H. (4) 138; (5) 348 Huang, H. (8) 255 Huang, X. (3) 104; (8) 104 Huber, A.M. (8) 49 Hubert, T.D. (2) 38; (6ii) 82 Hubner, F. (3) 203 Hudlicky, T. (3) 217 Hunig, S. (5) 478;

General and Synthetic Methods

700

(8) 218, 219 Hug, K.T. (2) 247 Hughes, J . W . (1) 128 Huhn, G.F. (8) 91 Huhtasaari, M. (3) 60; (8) 18 Hui, R.C. (3) 232, 381; (5) 279 Huie, E.M. (8) 148; (9) 31 Hulce, M. (2) 279-281 Hulin, B. (2) 69 Humer, K . (5) 293 Hung, M.-H. (3) 96; (7) 123 Hung, N.C. (5) 36 Hungerbuhler, E. (3) 344 Hunter, D.H. (2) 184 Husain, M. (5) 499 Hussain, A.Q. (8) 106 Hussein, F.H. (2) 10; (4) 140 Husson, H.-P. (5) 355, 356, 366 Huston, R . (7) 172 Hutchins, R.O. (4) 9; (5) 34; (6ii) 67 Hutchinson, 3 . (2) 106; (7) 137; (8) 109 Huth, A . (8) 185 Huttenhain, S.H. ( 3 ) 203 Huttner, G. (3) 22, 254; (6ii) 47 Huynh, V . (1) 164; (5) 180 Hwang, C.K. (4) 184 Hwu, J.R. (5) 367; (9) 23 Hyatt, J.A. (2) 68 Hyuga, S. (4) 190 Hyun, M.H. (3) 427; (5)

64 Ibbotson, A . (3) 207 Ibrahim, N.S. ( 5 ) 544 Ibuka, T. (1) 41; ( 2 ) 24; (3) 195 Ichikawa, K . (3) 136 Ichikawa, Y. (9) 75, 76 Ido, T. (6i) 20 Idoux, J.-P. (3) 362; (5) 273 Ige, H. (5) 65 Ihara, M. (7) 145, 146; (8) 191; (9) 84 Iida, H. (1) 84; (2) 128; (8) 152 Iida, S. (1) 148; (4) 183 Iida, T. (1) 9; (5) 458 Iihama, T. (1) 84; (2) 128 Iihan, M. (5) 30

Iijama, M. (7) 138 Iitaka, Y. (3) 264 Ikawa, A . (3) 425 Ikeda, M. ( 7 ) 10 Ikeda, N. (1) 114, 115; (2) 86; ( 3 ) 331; (4) 75; (6ii) 90; (7) 43, 45 Ikeda, Y. (1) 114, 115; (3) 193; (4) 75; (6ii) 90 Ikegami, S. (4) 171; (7) 83 Ikehira, H. (8) 74 Ikemi, Y. (5) 118 Ikenaga, K. (6ii) 93 Ikka, M. (4) 38 Ikunaka, M. (8) 62 Ila, H. (5) 330, 491 Imagawam T. (5) 326 Imai, H. (2) 194, 211; (5) 344, 475 Imai, N. (8) 139, 140, 142 Imai, S. (9) 64 Imai, T. (2) 79; (3) 2 Imai, Y. (3) 388; (5) 250 Imamoto, T. (1) 14; (3) 229, 231; (4) 11, 78, 85; (5) 3, 294, 314, 329, 346; (6i) 63; (6ii) 142 Imanishi, T. (8) 55 Imwinkelried, R. (5) 121 Inaba, M . (3) 122, 363; (4) 19 Inaba, S. (4) 218 Inagawa, Y. (5) 252 Inamoto, N. (3) 286 Inaoka, T. (8) 142 Ingrosso, G. (5) 175, 176 Inizuka, K. (4) 298 Inokuchi, T. ( 2 ) 212; (5) 343 Inomata, K. (3) 334, 335 Inoue, K. (5) 305 Inoue, M. (1) 64; (7) 56 Inoue, S. (5) 246; (9) 49 Inoue, T. ( 2 ) 246; (3) 13; (4) 62 Inoue, Y. (2) 234; (4) 283 Iovu, M . (5) 117 Ipaktschi, J . (5) 27 Iqbal, M. (5) 117 Iranpoor, N. (2) 11-14; (4) 150, 151, 158, 247 Ireland, R.E. (1) 49; (3) 32; (6ii) 83 Isagawa, K. (4) 2, 3 Iseki, I. (7) 82 Ishibashi, H. (7) 10

Ishida, N. (2) 270; (4) 84; (6ii) 42 Ishige, 0 . (7) 127; (8) 80 Ishiguro, M. (4) 215; (5) 312 Ishiguro, T. (3) 264; (9) 61 Ishiguro, Y. (2) 88; ( 6 i ) 44; (7) 61 Ishihara, M. (4) 297 Ishihara, T. (1) 160; (6ii) 131 Ishihara, Y. (3) 312; (4) 66 Ishikawa, N. (3) 10 Ishikawa, Y. (4) 287; (8) 115 Ishizaki, M. ( 3 ) 369; (6ii) 88 Isobe, M. (9) 75, 76 Isobe, T. (3) 434 Isoe, S. (1) 34; (2) 135; (6ii) 117; (9) 15 Itahara, T. (3) 185 Itao, T. (7) 92 Ito, F. (8) 201; (9) 46 Ito, K. (4) 29, 30, 87, 276; (9) 15 Ito, M. (1) 46; (3) 33; (8) 182 I t o , S. (3) 132; (5) 211 Ito, W. (1) 170; (5) 82 Ito, Y. (2) 194; (2) 211; (3) 366, 367; (5) 344, 475; (6ii) 6 Itoh, F. (2) 75 Itoh, K. (1) 33; (2) 276, 282; (3) 165; (5) 302 Itoh, 0. (3) 136 Itoh, S. (3) 58 Itoh, T. (3) 114; ( 4 ) 47 Itsumo, S. (4) 29, 30 Iturrian, W.B. (5) 235 Ivanov, A . P . (5) 554 Ivanov, C. (5) 289, 481 Iwaki, M. (4) 265; (8) 7 Iwakiri, H. (2) 132 Iwano, Y. (8) 264 Iwasawa, N. (2) 255; (8) 255

Iwashita, M . (5) 211 Iwata, C. (8) 55 Iyer, R. ( 2 ) 106; (8) 109 Izawa, M. (7) 92; (9) 7 Izawa, T. (1) 137; (2) 156; (7) 115 Izuka, K. (5) 254 Izumi, T. (4) 299 Izumi, Y. (1) 91; (2) 103, 181 Izumiya, N. (3) 424

Author Index

70

Johnson, W.S. (1) 1 5 4 ; Jabry, Z. (1) 151 ( 4 ) 9 2 ; ( 5 ) 342; (6ii) Jackson, A.C. ( 7 ) 152 8 6 , 101, 105; ( 7 ) 164 Jackson, R.F.W. ( 8 ) 28 Jacobi, P.A. ( 3 ) 291; ( 9 ) Johnston, T.P. ( 5 ) 448 Johnstone, L.M. ( 8 ) 229 90 Jones, B.A. ( 3 ) 226; ( 4 ) Jacquier, R. ( 3 ) 395, 396, 404, 410, 413, 426, 461 Jadhav, P.K. ( 1 ) 7 4 , 7 5 ; ( 2 ) 8 0 ; ( 3 ) 108; ( 4 ) 3 3 , 7 3 , 7 4 ; (6ii) 5 7 , 63 Jadhay, K.P. ( 5 ) 487 Jaeger, D.A. ( 4 ) 10 Jagadale, M.H. ( 4 ) 15 Jager, V. ( 3 ) 267; ( 5 ) 200; ( 7 ) 81 Jaggi, D. ( 8 ) 6 6 , 68 Jagodzinski, J.J. ( 4 ) 9 2 ; (6ii) 86 Jahnke, T.S. ( 5 ) 1 6 4 ; ( 7 ) 192 Jain, A.U. ( 3 ) 1 6 3 ; (6ii) 21 Jakovac, I.J. ( 3 ) 257 Janda, K.D. ( 5 ) 215 Janecki, T. ( 2 ) 1 4 7 ; (6ii) 127 Jansen, B.J.M. ( 3 ) 287 Janssen, S.J. ( 5 ) 542 Jaohen, G . ( 3 ) 137 Jaril, I. ( 3 ) 254 Jarman, M. ( 4 ) 133 Jarvi, E.T. ( 3 ) 125 Jarvis, B.B. ( 4 ) 281 Jefford, C.W. ( 8 ) 66-68 Jellal, A. (1) 1 0 6 ; ( 2 ) 9 3 ; ( 3 ) 2 6 , 273; ( 7 ) 154 Jellal, S. ( 5 ) 331 Jendralla, H. (1) 184; ( 7 ) 110 Jenkins, P.R. ( 3 ) 251; ( 7 ) 1 2 1 , 122 Jenner, G. ( 3 ) 30 Jennings, M.N. ( 5 ) 299

Jennings-White, C.L.D. (1) 175 Jenson, T.M. ( 4 ) 112 Jephcote, V.J. ( 2 ) 6 6 ; (6ii) 108 Ji, G.-J. ( 3 ) 466 Jibril, 1. ( 3 ) 2 2 ; (6ii) 47

Jigajinni, V.B. ( 3 ) 260 Jimhez, C. ( 5 ) 8 7 ; ( 8 ) 162

Jimpo, K. ( 3 ) 472 Johansson, R. ( 4 ) 180 Johnson, C.R. (6ii) 1 4 9 ; ( 7 ) 12

Johnson, R.A. ( 6 i ) 24

225

Jones, J.B. ( 3 ) 1 1 , 1 2 , 257, 301, 481 Jones, M. ( 4 ) 130 Jones, N.R. ( 5 ) 428 Jones, R.H. ( 6 i ) 73 Jones, T. ( 8 ) 94 Jones, W.D. ( 8 ) 186 Jordan, M. ( 8 ) 94 Jorgensen, K.A. ( 5 ) 449 Jorgensen, W.L. ( 3 ) 250 Joshi, B.L. ( 5 ) 353, 354 Joshi, P.L. ( 4 ) 177 Joshua, A.V. ( 5 ) 249 Jouda, M.F. ( 5 ) 450 Joulli6, M.M. ( 3 ) 262 Jousseaume, B. ( 1 ) 1 4 1 ; ( 5 ) 197 Jovanovic, M.V. ( 5 ) 97 Juaristi, E. ( 8 ) 135 Julia, M. ( 2 ) 1 1 1 ; ( 4 ) 172, 174; ( 5 ) 307; (6ii) 133 Julia, S. ( 8 ) 4 Jund, K. ( 3 ) 446; ( 5 ) 177 Jung, A. ( 4 ) 5 6 , 5 7 ; (6ii) 84 Jung, M.E. ( 7 ) 120 Jung, R. ( 1 ) 1 1 2 ; ( 7 ) 32 Jung, S.-H. ( 5 ) 122 Junjappa, H. ( 5 ) 330, 491 Juno, K. ( 1 ) 156 Jurczak, J. ( 3 ) 3 0 ; ( 4 ) 289; ( 8 ) 244 Jurila, J.L. ( 9 ) 7

8 2 , 185 ( 9 ) 6 , 15

Kalkote, U.R. ( 5 ) 462 Kallmerton, J. ( 8 ) 14 Kaluza, Z. ( 8 ) 244 Kalvin, D.M. ( 2 ) 39 Kambe, S . ( 5 ) 492 Kametani, T. ( 7 ) 145, 146; ( 8 ) 191, 192; ( 9 ) 84

Kamikawaji, Y. ( 3 ) 1 8 2 ; ( 4 ) 273

Kamimura, A. ( 1 ) 7 3 ; ( 3 ) 8 8 ; ( 5 ) 417

Kamiya, T. ( 5 ) 494 Kamiyama, K. ( 3 ) 11 Kamo, M. ( 3 ) 473 Kanai, K. ( 8 ) 15 Kanakarajan, K. ( 8 ) 122 Kanakura, A. ( 2 ) 122 Kanatani, R. (6ii) 92 Kanbara, H. ( 8 ) 30 Kandeel, Z.E.-S. ( 5 ) 544 Kane, J.M. ( 8 ) 186 Kaneko, C. ( 8 ) 241, 242 Kaneko, H. ( 3 ) 244, 245; ( 7 ) 165

Kaneko, R. ( 5 ) 109 Kaneko, Y. ( 2 ) 156 Kanemasa, S . ( 2 ) 214; ( 3 )

169; ( 4 ) 8 6 ; ( 5 ) 139, 474; ( 7 ) 104-108; ( 8 ) 143 Kanematsu, K. ( 3 ) 1 8 2 ; ( 4 ) 273, 288 Kanemoto, K. ( 4 ) 1 5 3 , 156 Kanemoto, S . ( 2 ) 15 Kang, J. ( 3 ) 95 Kang, M. ( 3 ) 275; ( 6 i ) 60 Kang, S.I. ( 4 ) 300 Kano, S . ( 4 ) 3 8 ; ( 8 ) 197 Kant, J. ( 5 ) 353 Kantke, K. ( 8 ) 81 Kaafarani, M. ( 8 ) 118 Kappe, T. ( 5 ) 527 Kabalka, G.W. ( 5 ) 1 7 , 8 6 , Kappert, M. ( 3 ) 254; 395; (6ii) 72 (6ii) 47 Kaczmarek, C.S.R. ( 3 ) 291 Karady, S. ( 3 ) 414 Kadokura, M. ( 5 ) 79 Karalis, P. ( 2 ) 142 Karauchi, M. ( 5 ) 314 Kadow, J.F. ( 7 ) 12 Karoly-Hafeli, H. ( 3 ) 396 Kagan, E.S. ( 8 ) 188 Kagan, H.B. ( 4 ) 270; (6i) Karpenko, L.P. ( 4 ) 291 Karpf, M. ( 7 ) 5 8 , 90 25 Kai, Y. ( 5 ) 171; ( 6 i ) 54 Karunaratne, V. ( 7 ) 6 4 , 9 4 ; ( 9 ) 2 , 10 Kaiser, D.A. ( 5 ) 301 Kaji, A. ( 1 ) 7 3 , 107; ( 3 ) Kasahara, A. ( 4 ) 299 179, 181, 283, 338; ( 5 ) Kasakabe, M. ( 4 ) 8 2 , 83 Kashima, C. ( 5 ) 60 417 Kashimura, S . ( 3 ) 205 Kaji, K. ( 3 ) 327 Kajigaeshi, S. ( 3 ) 6 4 , Kashinskii, V.V. ( 5 ) 280 373; ( 5 ) 3 8 , 259 Kashmiri, M.A. ( 5 ) 398 Kajimoto, T. ( 4 ) 107 Kashu, M. ( 5 ) 18 Kajitani, Y. ( 3 ) 266 Kastova, K. ( 5 ) 436 Kakiuchi, K. ( 1 ) 1 8 ; ( 7 ) Kasuga, T. ( 1 ) 8 1 ; ( 3 )

General and Synthetic Methods

702

313; (4) 113 Katagiri, N. (8) 242 Katajima, K. (4) 87 Kataoka, H. (2) 114 Katayama, E. (4) 23, 173; (6ii) 78 Kathawala, F.G. (2) 45 Kato, M. (3) 303 Kato, N. (3) 58 Kato, T. (3) 424; (4) 83; (6i) 99; (6ii) 91; (7) 168, 188 Katoh, A . (5) 60 Katritzky, A . R . ( 3 ) 460; (4) 249; (5) 398 Katsuki, T. (3) 342, 366, 367; (6ii) 6 Katz, A.H. (3) 43; (5) 308 Kauffmann, T. (1) 61; (2) 275 Kawabata, N. (2) 22; (8) 26 Kawabata, T. (2) 176; (4) 212; (5) 420 Kawada, M. (1) 86, 101, 186; (2) 124; (3) 276; (4) 131; (6ii) 16, 17, 136, 156 Kawaguchi, A . (8) 191 Kawaguchi, K. (5) 351 Kawaharasaki, N. (3) 388; (5) 250 Kawai, A . (3) 254; (5) 206, 207; (9) 65 Kawajima, I. (6ii) 49, 95 Kawakami, Y. (3) 305 Kawamura, S. (3) 267, 380; (7) 127; (8) 80, 163 Kawanami, Y. (3) 366; (6ii) 6 Kawanisi, M. (5) 326 Kawasaki, M. (4) 42 Kawashima, M. (1) 147; (3) 27, 35, 220; (6ii) 89 Kawashima, T. (3) 144 Kawatsu, S. (9) 64 Kawazoe, Y. (3) 229; (5) 294; (6ii) 142 Kay, I.T. (9) 56 Kaya, R. ( 7 ) 87 Kaye, A.D. (7) 160; (9) 69 Kaye, P.T. (5) 301 Kazubski, A. (3) 239; (4) 34 Keay, B.A. (9) 68 Keck, G.E. (4) 67, 68; (6ii) 109 Keefer, L.K. (5) 454 '

Keen, K.B. (7) 63 Keese, R . ( 1 ) 1 Kellogg, R.M. (2) 257; (4) 303; (8) 234 Kelly, C.J. (5) 549 Kelly, D.R. (3) 183; (5) 375; (9) 94 Kelly, K.P. (5) 402 Kelly, L.F. (6i) 58 Kelly, M.J. (7) 98 Kelly, S.E. (8) 71 Kelly, T.R. (3) 16; (7) 161; (9) 43 Kemp, D.S. (3) 416 Kemp, J. (8) 138 Kemper, B. (4) 72 Kende, A.S. (3) 214 Kendrick, D.A. (1) 175 Kenner, G.W. (3) 466 Kermer, K.A.M. (5) 461 Kessabi, J. (1) 133 Kesseler, K. (4) 56-58; (6ii) 84 Kessler, H. (3) 460 Kettler, R. (5) 445 Keyaniyan, S. (7) 6 Khalafi-Nezhad, A . (5) 496 Khalifa, M.H. (1) 7; (3) 475 Khan, G.R. (3) 460; (4) 249 Khan, M.N.I. (3) 248; (6i) 56 Khan, N.H. (5) 499 Khanna, R.K. (4) 280 Khbeis, S.G. (5) 526 Khmel'nitski, Y.L. (3) 401 Khoshdel, E. (4) 181, 284 Kiaeezadeh, F. (2) 12; (4) 151 Kibayashi, C. (8) 152; (9) 34, 35 Kijima, M. (5) 11 Kikuchi, K. (4) 127 Kikugawa, Y. (4) 255 Kikukawa, K. (6ii) 93 Kilger, R. (3) 416 Kim, B.H. (3) 158 Kim, C.-K. (5) 58 Kim, G.P. (4) 31 Kim, K.S. (2) 2, 20 Kim, K.W. (4) 31 Kim, S. (3) 72, 77, 465; (4) 120 Kimura, M. ( 3 ) 69 Kindl, P. (5) 472 King, B.T. ( 2 ) 62 King, L.C. (5) 432 Kingston, J.F. (3) 143 Kinney, W.A. (1) 47; (7)

175; (9) 12 Kinoshita, H. (3) 334, 335 Kirihara, T. (8) 191 Kirisawa, M. (8) 247 Kirsch, G . (6ii) 157 Kirschke, K. (5) 271 Kirschleger, B. (2) 174; (4) 204 Kise, N . (3) 254 Kishi, N. (1) 77; (6ii) 87; (7) 38 Kishi, Y. (4) 8; (6i) 33 Kita, Y. (2) 75; (3) 52 Kitagawa, T. (3) 366; (6ii) 6 Kitahara, T. (3) 347; (5) 347; (7) 52 Kitamura, M. (9) 75, 76 Kitamura, T. (8) 149 Kitano, Y. (7) 10 Kitao, 0. (5) 298; (8) 78 Kitao, T. ( 5 ) 92 Kitayama, R. (3) 102 Kitazume, T (3) 10 Kitihara, E. (1) 79 Kiuchi, F. (6ii) 166 Kiuchi, T. (4) 242 Kiyooka, S. (4) 80; (5) 351; (6ii) 85 Kji, A . (3) 88 Kjonaas, R.A. (2) 228 Klein, J.-L. (2) 215; (5) 152, 153 Klich, M. (8) 254 Kliegel, W. (5) 553 Kloosterman, M. (5) 506 Klop, W. (5) 156 Klusener, P.A.A. (5) 156 Kmijo, T. (5) 254 Knapp, S. (5) 212; (7) 183 Knappen, F. (5) 191 Kneip, M. (3) 460 Knierzinger, A. (6i) 16 Knight, D.W. (1) 48; (3) 49; (7) 171 Knittel, D. (3) 439 Knobler, C.B. (4) 308 Knochel, P. (1) 139, 140; ( 3 ) 170; (5) 407 Knorr, H. (5) 191 Knorr, R. (2) 187 Knudsen, M.J. (6i) 95; (7) 84 Knupp, G. (5) 33 KO, K.-Y. (3) 17 KO, Y.K. (3) 72 Kobayashi, K. (2) 148; (5) 227, 340 Kobayashi, M. (7) 48 Kobayashi, S. (2) 256;

703

Author Index (3) 11, 434; (8) 149 Kobayashi, T. (2) 212, 224; (3) 132; (4) 144; (5) 343; (6i) 21 Kobayashi, Y. (4) 82, 83; (6ii) 91 Kochhar, K.S. (8) 166 Kocienski, P. (8) 56, 59; (9) 57 Kocovsky, P. (6i) 32 Kodera, Y. (3) 424 Kodpinid, M. (3) 142; (7) 65 Koehler, K.F. (8) 243 Koenblum, N. (5) 339 Konig, R. (1) 61 Konig, W.A. (3) 429 Koft, E . R . (7) 25, 26 Koga, K. (2) 269, 277; (3) 151, 264; (6ii) 35; (9) 61 Koga, M. (2) 24 Kogan, T.P. (2) 279; (3) 264; (6ii) 145 Kogler, H. (3) 460 Koguchi, T. (4) 71 Kogure, T. (3) 324, 451 Kohama, H. (3) 269 Kohle, J.N. (1) 16; (6ii) 21 Kohmoto, S. (8) 66-68 Kohn, H. (5) 122; (8) 198, 199 Kojima, A. (4) 167 Kokko, B. (5) 44 Koksal, Y. (9) 43 Kolb, V.M. (5) 426 Kole, S.L. (3) 249 Kolhe, J.N. (3) 163 Kolovos, M. (3) 459, 479; (4) 227 Komatsu, M. (8) 84 Komatsu, S. (5) 283 Komatsu, T. (5) 83 Komatsu, Y. (9) 41 Komori, T. (2) 23; (6ii) 143 Kon, K. (9) 15 Kondo, K. (1) 129 Kondo, T. (5) 256 Kondo, Y. (5) 89 Kongkathip, B. (6i) 17, 18 Kongkathip, N. (6i) 17 Konishi, M. (3) 101 Konopelski, J. (9) 14 Konwar, D. (5) 236, 237 Kopinski, R.P. (3) 44 Koppes, W.M. (5) 438 Koreeda, M. (1) 135; (2) 69; (7) 125 Koren, B. (5) 422

Korshevets, I.K. (2) 230; (5) 468 Koshiji, H. (4) 52 Koshino, J. (1) 173 Koshute, M.A. (3) 471 Koskimies, J.K. (8) 110 Koskinen, A. (8) 189 Koste, D.F. (5) 426 Kostova, K. (3) 339 Kosugi, M. ( 2 ) 193, 236; (4) 215, 228; (5) 312; (6i) 80, 83 Kotake, H. (3) 334, 335 Kotani, E. (5) 265 Kotodjiejczyk, A.M. 3) 458 Koyama, K. (2) 195 Kozikowski, A.P. (3) 270; (5) 198, 199, 507; (6ii) 51; (7) 35, 09; (8) 89, 93; (9) 36 (9) 52, 55 Kozlowski, J.A. (2) 258260; (3) 90; (6i) 6 Kozluk, T. (3) 30 Kozuka, S . (5) 501 Kozyrod, R.P. (3) 148 Krafft, M.E. (2) 209, 210 Kral, V. (8) 23 Krantz, A. (1) 155, 157; (3) 446, 450; (5) 178 Krapcho, A.P. (5) 91 Kraus, G.A. (3) 272; (4) 211; (7) 140 Kremer, K.A.M. (2) 231; (3) 150 Kress, A.O. (8) 111 Kresze, G. (5) 221-223; (8) 99, 100 Kretzschmar, G. (3) 53 Kreutzberger, A. (5) 362 Kreutzberger, E. (5) 362 Krief, A. (2) 98; (4) 166; (6ii) 124, 162, 163, 167; (7) 184; (8) 5 Kriegesmann, R. (1) 61 Krishnan, K. (8) 215 Krohn, K. (6i) 26 Krolikiewicz, K. (5) 95, 533 Kronis, J.D. (5) 522 Krustalev, V.A. (5) 459 Krusteva, R. (5) 481 Kryshtal, G . V . (8) 23 Kubhek, V. (3) 401 Kubiak, G. (7) 72 Kubica, Z. (5) 263 Kubo, M. (3) 376; (6ii) 1 Kubota, N. (2) 190; (3) 155 Kubota, Y. (5) 101; (8)

213 Kuetegan, M. (3) 131 Kukuhara, T. (4) 242 Kukuzaki, K. (7) 136 Kulinkovich, O.G. (2) 191 Kulkarni, G.H. (7) 16 Kulkarni, Y.S. (5) 258 Kumada, M. (1) 63; (2) 30; (3) 101; (3) 6; (6ii) 92 Kumagawa, T. (2) 156 Kumar, A. (2) 36; (5) 531 Kumar, R. (5) 4 Kumar, S. (8) 215 Kumaravel, G. (2) 166 Kumazawa, T. (3) 162 Kumobayashi, H. (5) 135; (6i) 36 Kunai, A . (3) 28 Kunda, S.A. (5) 86; (6ii) 72 Kunesch, G. (3) 241 Kunitama, Y. (4) 162 Kunkel, E. (3) 155 Kunugihara, A. (8) 183 Kunz, H. (3) 460, 467469; (6i) 39 Kuo, C.H. (9) 72 Kupfer, R. (5) 480 Kurauchi, M. (5) 346 Kurihara, H. (2) 190; (3) 155 Kurihawa, T. (5) 313, 317 Kurobe, H. (9) 84 Kuroda, A. (3) 194 Kuroda, S. (2) 26 Kurokawa, H. (3) 425 Kurokawa, N. (3) 464 Kuroki, Y. (4) 250 Kurozumi, S. (5) 405 Kurth, M . J . (1) 45; (3) 33 Kurusu, Y. (2) 16; (3) 81; (4) 155 Kusakabe, M. (6ii) 91 Kusumoto, T. (4) 78 Kuwajima, I. (2) 178, 199, 238, 246; (3) 158, 159, 180; (4) 62; (7) 1 , 40 136; (8) 8 Kuwata, S. (3) 394, 398, 421 Kuzma, P.C. (3) 359; (5) 282 Kwon, K.S. (2) 189; (3) 153; (4) 115 Kyba, E.P. (6ii) 126 Kyziol, J . B . (5) 427 Laabassi, M. (1) 132 Labadie, S.S. (2) 109, 253; (4) 59, 217; (6ii)

7 04

General and Synthetic Methods

Lau, H . H . (3) 298 Laude, B. (3) 46 Lauman, K. (3) 258 Laurent, A. (5) 173 Lautens, M. (7) 123 Lavaud, C. (8) 204 La Vos, G.F. (8) 231 Lavrinovich, L.I. (4) 191 Lawesson, S.-0. (3) 228230; (5) 295, 449 Lawrynowicz, W. (4) 196 Lawson, K.R. (3) 234; (8) 79 Lazar, J . G . (5) 367 49 Laganis, E . D . (3) 9 Lazareva, M.I. (2) 196 Lazaro, R. (3) 410 Laguna, M.A. (5) 56 Laikos, G.D. (2) 161; (5) Learn, K. (4) 9; (6ii) 67 LeBihan, J.-Y. (3) 137 231 Lalande, J. (3) 320 Lebioda, L. (7) 15 Lallernand, J.Y. (3) 241 Leblanc, Y. (1) 20; (6ii) Lalonde, M. (6i) 87 129 Lee, D.G. r4) 264 LaMattina, J.L. (5) 98 Lee, H . S . (4) 2, 3 Lamaure, M. (4) 303 Lambert, C . (1) 105, 168; Lee, J . I . (3) 72, 77, 465 Lee, S. (3) 424 (3) 273; (4) 98; (6i) 45; (6ii) 28 Lee, S . D . (2) 189; (3) Lambropoulou, V. (3) 384 153; (4) 115 Landgrebe, K. (3) 272; Lee, W.K. (3) 95 (4) 211 Leeper, F . J . (3) 210 Lefebvre, C . (2) 111; (4) Landi, J . J . (5) 91 Landini, D. (4) 206 174; (5) 307; (6ii) 133 Landmann, B. (6ii) 62 Leftin, M.H. (1) 113 Landor, S.R. (4) 41; (5) Leginus, J.M. (2) 113; 26; (5) 77 (5) 552 Lehr, P. (3) 416 Lane, J . S . (5) 72 Le Lourneau, M.E. (5) 350 Lang, G . (5) 527 Lemal, D.M. (1) 182 Lang, R.W. (3) 215 Lenoir, D. (1) 17 Lang, S . A . Jr. (5) 299 Lenz, B.G. (2) 152; (5) Lange, J. (3) 253 Lansard, J . - P . (2) 273; 484 Lenz, G . R . (7) 34 (6i) 66; (6ii) 50 Leonard, K . J . (4) 169 Lantos, I. (3) 92; (4) Leopold, E . J . (9) 23 65; (8) 2 Le Perchec, P. (5) 288 Lapkin, 1.1. (5) 280 Larchevdque, M. (3) 109, Lerouge, P. (3) 198; (4) 118; (6ii) 161 241, 320 Leroy, J . (3) 138 Lardicci, L. (4) 37; (6ii) 74 Lesma, G. (6i) 35 Lessard, J. (5) 7, 284 Larock, R.C. (3) 187, 280, 298; (6i) 55; Lett, R. (4) 250; (9) 13 Levin, D. (1) 83 (6ii) 54, 55 Larraza, M . I . (8) 228 Levisalles, J. (2) 97; Larsen, K.E. (5) 303; (8) (7) 141 L&y, J . (8) 175, 204 86 Larsen, S.D. (3) 358 Lewe, R.F. (5) 72 Larson, G.L. (1) 23, 94; Lewis, S . C . (1) 44; (3) 34 (2) 177; (3) 191; (6ii) Ley, S.V. (1) 58; (2) 7, 37 Laszlo, P. (2) 220, 221; 51, 205; (3) 7; (4) (5) 380, 511, 512; (7) 145; (6ii) 125; (8) 54, 119 58, 238; (9) 78 Li, V.S. (5) 275 Lau, A.N.K. (3) 462

Li, W.S. (4) 184 Liao, Z.-K. (8) 198, 199 Licandro, E. (8) 113 Lichtenberg, F. (2) 64; (3) 236 Lida, (9) 34, 35 Lieberknecht, A. (3) 436 Liebeskind, L.S. (3) 337; (6i) 70, 72, 88; (6ii) 135; (9) 27 Liebscher, J. (5) 53, 54 Lied, T. (3) 348 Lilje, K . C . (3) 208; (5) 413; (6ii) 26 Lin, L.-J. (1) 109; (2) 6 Lin, Y.-i. (5) 299 Lin, Y.J. (3) 223 Lindell, S . D . (4) 92; (6ii) 86 Lindley, J. (6i) 6 Lindsay, C.M. (6ii) 20 Lingenfelter, D. (6ii) 10 Linstrumelle, G . (1) 188; ( 2 ) 129; (6ii) 14, 80 Liotta, D . (2) 115 Lipinski, C . A . (2) 171 Lipshutz, B . H . (2) 258260; (3) 90, 441; (5) 262; (6i) 6 Lister, S . G . (9) 78 Litaka, Y. (9) 61 Liu, D. (3) 463 Livinghouse, T. (3) 221; (5) 368; (6ii) 23 Liz, R . (2) 159; ( 5 ) 157, 230; (6ii) 53; (8) 209 Lobach, A.V. (4) 291 Lobo, A.M. (5) 467 Lochead, A.W. (8) 15.5 Lockhardt, J . C . (4) 293 Lockhart, R.J. (5) 59 Loeschorn, C.A. (5) 549 Loew, P . (2) 187 Loewe, M.F. (5) 106; (8) 170 Logusch, E.W. (3) 71 Loibner, H . (5) 107 Lombard, M . J . ( 3 ) 430 Lombardo, L. (4) 121 Long, G.W. (1) 56 Long, J . P . (5) 30 Lopez, F.L. (8) 228 Lopez-Ortiz, J.F. (5) 490 Lorenzi-Riatsch, A. (5) 406; (7) 69 Loreto, M . A . (8) 133 Lorke, M. (5) 261 Lotter, H. (5) 334 Loudon, G.M. (3) 65; (5) 39, 40 Lounasmaa, M. (8) 189 Loupy, A . (4) 226

112 Labia, R. (2) 158; (8) 236 Lablache-Combier, A. (8) 125 Laborde, E. (9) 51 Laboureur, J.L. (2) 98; (6ii) 167; (7) 184; (8) 5 Lacoste, J.M. (5) 174 Ladlow, M. (1) 103; (3) 271, 279 Ladner, W. (3) 116; (4)

705

Author Index Lourrey, J.-L. (5) 73 Lovich, S.F. (1) 180; (6i) 84 Low, N.H. (1) 31 Lozzi, L. (3) 265 Lu, L.D.L. (6i) 24 Lub, J. (5) 555 Lucchi, O.D. (6ii) 152, 153 Lucchini, V. (6ii) 153; (7) 111 Luche, J.-L. (2) 273, 274; (3) 141; (6i) 66; (6ii) 50 Luchetti, J. (7) 119 Ludduwahetty, T. (4) 100 Ludwiczak, S. (5) 388; (6ii) 26 Luengo, J.I. (1) 135; (7) 125 Lugovik, B.A. (5) 114 Lukas, K.L. (3) 11 Lukyanenko, N.G. (4) 278, 291 Luna, D. (5) 319 Lunn, G. (5) 454 Lunn, P.M. (8) 22 Luo, F.-T. (1) 180; (6i) 84 Lutz, R.P. (6i) 3; (7) 176 Lutze, G. (5) 271 Luyton, M. (1) 1 Luzzio, F.A. (4) 254 Lygo, B. (1) 58; (2) 51, 205; (6ii) 125; (8) 54, 58 Lynch, J.E. (2) 145; (3) 17; (4) 90; (6ii) 36 McAuley, J.P. (8) 83 McCague, R. ( 4 ) 133 McCaleb, G.S. (5) 448 McCallion, D. (4) 5 McCarthy, J.R. (5) 350 McCleery, P.P. (3) 295; (9) 91 McCollum, G.W. (5) 86; (6ii) 72 McConnell, W.B. (4) 264 McConnell, W.W. (6i) 89 McDonald, I.A. (5) 174 McDonnell, M.B. (4) 293 McDougal, P.G. (2) 76; (3) 352, 355; (6i) 27 McGavin, C.A. (4) 286 McGuire, M.A. (6i) 77; (8) 239 McGuirk, P.R. (9) 59 Machizuki, M. (7) 168 Mackay, C. (8) 206 Mackay, D. (5) 214

McKervey, M.A. (7) 156 McKillop, A. (3) 43; (5) 308 McKinnie, B.G. (4) 260 MacKinnon, P.I. '(1) 8 MacLean, D B. (8) 211, 212 MacLeod, A M. (9) 70 McLoughlin J.I. (4) 35, 36 McManus, S P. (8) 111 McMurry, J E. (6i) 32 McNab, H. 5) 161 McNamara, P.E. (3) 416 McNelis, E. (3) 66 Maeda, K. (2) 30; (3) 6 Maeda, N. (3) 312; (4) 66 Maeda, T. (1) 77; (4) 24; (6ii) 87, 137; (7) 38 Maekawa, T. (1) 160; (6ii) 131 Maeshima, T. (8) 114 Magen, S. (4) 198 Maggiulli, C.A. (5) 58, 148 Magnin, D.R. (3) 251 Magnus, P. (9) 62 Mahatantila, C.P. (8) 173 Mahidol, C. (8) 128 Mahler, G.S. (5) 99 Mahumulkar, B.G. (7) 16 Mai, K. (2) 213; (5) 332, 333 Maienfisch, P. (2) 95, 96 Maignan, C. ( 3 ) 197 Maigrot, N. (6ii) 32 Maione, A.M. (2) 8; (4) 157 Maiorana, S. (8) 113 Majee, R.N. (4) 170 Majera, C. (5) 87 Majewski, M. (3) 314; (5) 272 Maki, Y. (4) 127 Makin, M.I.H. (4) 246; (5) 530 Makino, A. (8) 158 Makishima, H. (4) 287 Makosza, M. (3) 209; (5) 388-393; (6ii) 26 Makowski, M. (5) 263 Malacria, M. (4) 175; (7) 157 Malenko, D.M. (5) 483 Malfroot, T. (5) 76 Mali, R.S. (8) 214 Malik, A. (5) 183, 187 Mallen, J. (8) 184 Malmberg, M. (5) 247 Malwitz, D. (1) 17 Malysheva, S.F. (5) 128 Manabe, K. (5) 405

Manabe, 0. (2) 25; (4) 287; (4) 295-298 Manabe, S.-i. (5) 115 Manabe, Y. (3) 398 Mancini, M.L. (1) 119; (2) 131 Mandai, T. (1) 86, 101, 186; (2) 124, 125; (3) 276; (4) 69, 131; (6ii) 16, 17, 136, 156 Mandal, A.K. (4) 31 Mander, L.N. (2) 208; (9) 17 Mandolini, L. (5) 541; (7) 180 Mane, R.B. (4) 15 Manfredini, S. (8) 27 Mangoni, L. (7) 11 Manhas, M.S. (8) 251, 261 Manna, F. (5) 51 Manna, S. ( 2 ) 268; (7) 149 Mansour, E.M.E. (3) 470 Marazano, C. (5) 73 Marchand, A.P. (5) 414 Marchelli, R. (2) 169 Marchese, G. (2) 44; (6ii) 39 Marchioro, G. (2) 155 Maresca, L. (4) 267 Maretina, I.A. (5) 149 Margaretha, P. (8) 77 Margoni, L. (4) 220 Marinas, J.M. (2) 105; (5) 319 Marinek, K. (3) 401 Maring, C. (1) 137; (7) 115 Marino, J.P. (3) 263; (6ii) 144; (9) 51 Markgraf, J.H. (4) 169 Marki, H.-P. (3) 125 Markova, N.K. (5) 149 Maroni, P. (2) 272 Marshall, J.A. (4) 112; (7) 15, 131 Marshall, S.E. (5) 72 Marsi, M. (1) 40; (2) 237; (3) 281; (8) 25 Martelli, J. (1) 133 Martens, J. (3) 428 Martin, A.A. (5) 300 Martin, C.A. (4) 10 Martin, H.D. (8) 232 Martin, J.C. ( 5 ) 161 Martin, M.G. (1) 29; (3) Martin, M.G. 474; (5) 47; (6i) 14 Martin, P. (6i) 46 Martin, S.F. (3) 311; (8) 44; (9) 39 Martin, S.J. (1) 174

706 Martina, V. (2) 44; (6ii) 39 Martynov, I.V. (5) 415 Martz, J . T . (5) 76 Maruoka, K . (2) 266, 267; (4) 93, 94; (6ii) 79, 81; (8) 174 Maruyama, K. (1) 146, 170; ( 3 ) 128, 129; (4) 66, 79; (5) 82, 83; (6ii) 110 Maruyama, N . (3) 312 Marx, K.H. (3) 346 Marx, M. (2) 19 Masaki, Y. (3) 327 Masalov, N.V. ( 2 ) 191 Masamune, S. (1) 21; (2) 53; (3) 177; (6ii) 128 Masamune, T. (2) 73; (6ii) 24; (7) 193 Mascarella, S.W. (1) 100; (7) 51 Masden, R. (8) 211, 212 Mashraqui, S.H. (2) 257 Massiot, G. (8) 175, 204 Massman, C.J. (7) 126 Masson, S. (3) 233 Mastalerz, H. (3) 70; (6i) 40 Masuda, T. (3) 194 Masuda, Y. (1) 171, 189; (5) 306, 508 Masui, M. (4) 248; (5) 18 Masumi, F. (2) 269; (6ii) 35 Masuyama, Y. (2) 16, 17; (3) 81; (4) 154, 155 Mataka, S. (8) 98 Mather, A . N . (7) 39 Mathur, H.H. (5) 431 Matin, S.F. (9) 86 Matsubara, S. (2) 244, 245; (3) 69, 127; (6ii) 111 Matsubara, Y. (8) 114 Matsuda, H. (4) 70 Matsuda, I. (1) 91; (2) 103, 181 Matsuda, K. (2) 214; (5) 139, 474; (8) 143 Matsuda, T. (5) 327; (6ii) 93 Matsumaya, H. (7) 48 Matsumoto, H. (4) 218 Matsumoto, K. (1) 146; (2) 178, 243; (3) 128; (4) 91; (5) 118, 232, 408; (6ii) 110; (8) 53 Matsumoto, M . (3) 132; (4) 87, 146; (6i) 19 Matsumoto, T. (1) 9; (5) 458; (6ii) 78; (7) 92;

General and Synthetic Methods

(9) 4, 7, 64 Matsumura, N. (8) 183 Matsumura, Y. (5) 305; (8) 158 Matsuoka, M. (5) 92 Matsushita, H. (3) 244, 245; (7) 165 Matsutani, T. (2) 199 Matsuura, T. (2) 194; (5) 475, 535 Matsuzaki, K. (5) 548 Matsuzaki, Y. (4) 24; (6ii) 137 Mattay, J. (8) 9 Maughan, W. (5) 46 Maumy, M. (3) 54 Maurer, P . J . (3) 413; (5) 224 Mauzk, B. (8) 130 May, C. (9) 37 Mayer, B. (1) 17 Mayer, H.H. (3) 330 Mayer, R. (5) 55 Mazaleyrat, J.-P. (6ii) 32 Mazdiyasni, H. (4) 50 Meadows, J.D. (9) 74 Mechoulam, R. (3) 268; (8) 16 Meckler, H. (9) 33 Medici, A . (5) 374 Meegan, M.J. (8) 263 Meese, C.O. (5) 521 Meguriya, N. (4) 75 Mehrotra, M.M. (9) 54 Mehta, G. (7) 86, 87, 177; (9) 11 Meier, H. (8) 122 Meier, M. (5) 304 Meier, S. (5) 480 Meindl, W.R. (5) 24 Melamed, Y. (3) 82 Melian, D. (5) 400 Mellor, J.M. (5) 124; 378 Menachery, M.D. (5) 29 Mencel, J.J. (7) 75 Mendez-Castrillion, P.P. (5) 546 Mendoza, L. (5) 81 Menear, K . A . (3) 251; (7) 122 Meric, R. (3) 241 Merrifield, R.B. (3) 403 Meth-Cohn, 0. (5) 451 Metternich, R. (3) 126; (6ii) 60 Meunier, F. (8) 6 Meuwly, R. (5) 433, 434 Meyers, A . G . (7) 8 Meyers, A . l . (3) 36, 161; (4) 61; (5) 99, 101104, 106, 309; (6ii) 2,

9, 11; (8) 169, 170; (8) 213 Meyers, C.Y. (5) 426 Miah, M.A.J. (3) 375 Michaely, W.J. (4) 221; ( 7 ) 37 Michelin, R . A . (6i) 29 Michelotti, E.L. (1) 113 Middleton, W.J. (5) 369; 537 Midland, M.M. (1) 82; (3) 239, 328; (4) 34-36, 110 Midura, W. (6ii) 130 Mies, W. (2) 81 Miginiac, L. (4) 81 Miginiac, Ph. (3) 175 Migita, T. (2) 193, 236; (4) 215, 228; (5) 312; (6i) 80, 83 Mikaelian, G.S. (2) 134 Mikailov, B.M. (4) 191 Mikaiyama, T. (2) 175 Mikami, K. (1) 77, 78, 80, 81; (3) 313; (4) 108, 109, 113; (6ii) 87, 95; (7) 38, 76 Mikhailov, V . I . (8) 188 Mikofajczyk, M. (2) 119; (6ii) 130 Milesi, L. (4) 206 Millar, J.F. (3) 341 Miller, J . A . (1) 138 Miller, L J . R . (3) 471 Miller, L.L. (3) 462; (5) 543 Miller, M.D. (4) 169 Miller, R.B. (5) 382; (6ii) 95, 96 Miller, R.D. (6ii) 20 Miller, R.-S. (5) 510 Milligan, J.R. (5) 447 Mills, R.J. (3) 377, 379; (6ii) 1; (9) 24, 25 Mills, S. (5) 80 Minach, L. (5) 539 Minami, I. (1) 93; (2) 1 , 114, 233; (3) 145, 199; (4) 142; (6i) 10, 48, 49; (7) 42 Minami, T. (1) 111; (6i) 59 Minamide, H. (5) 358 Minato, A . (1) 63 Minbu, H. (6i) 20 Miniutti, D.L. (8) 103 Minobc, M. (3) 267; (8) 61 Minowa, N. (3) 410 Min-Zhi, D. (1) 92; (3) 29; (6ii) 70 Mioskowski, C. (1) 59;

Author Index (2) 52, 268 Miranti, T.S. (8) 150 Mirza, S. (5) 435 Misiti, D. (2) 200; (4) 268 Mison, P. (5) 173 Misra, B.N. (5) 466 Mistryukov, E.A. (2) 230; (5) 468 Misurni, A. (2) 86, 87; (7) 43, 44 Mita, T. (1) 14; (4) 11, 78; (5) 3 Mitani, M. (2) 195 Mitchell, R.C. (5) 447 Mitra, R.B. (7) 16 Mitsue, Y. (2) 188; (5) 150 Mitsui, H. (5) 550, 551 Mitsunobu, 0. (3) 74, 343 Mittal, R.S. (5) 381 Miura, H. (2) 190; (3) 155 Miwa, T. (2) 254 Miyake, H. (3) 338 Miyake, M. (8) 247 Miyakoshi, T. (9) 54 Miyano, H. (2) 224 Miyano, S. (3) 453 Miyasaka, T. (3) 386; (9) 83 Miyashita, A. (3) 453; (5) 135; (6i) 36 Miyashita, M. (3) 25, 162 Miyata, N . (5) 75 Miyazaki, M. (2) 282 Miyazawa, T. (3) 394, 398, 421; (5) 253 Miyazawa, Y. (7) 48 Mizuki, Y. (4) 248 Mizutaki, S. (3) 41; (6ii) 165 Mizutani, M. (3) 267 Mladenova, M. (3) 252 MTochowski, J. (2) 34; (4) 152; (6ii) 158, 168 Mode, M. (4) 212 Modena, G. (2) 155; (3) 51; (4) 269; (6ii) 152, 153; (7) 111 Moderhack, D. (5) 261 Mohamadi,, F. (1) 27 Mohammad, M.J. (5) 96 Mohindra Chawla, H. (5) 381 Mohler, D L. (8) 45 Mohr, P. 3) 356 Mohrle, H (5) 154, 155 Moine, S. (8) 50 Molander , G.A. (1) 131; (2) 130 (6ii) 69; (7) 68

70' Molinari, H. (8) 4 Molinski, T.F. (4) 96 Moloney, M.G. (3) 149 Monaco, P. (4) 220; (7) 11 Mondon, M. (5) 284 Money, T. (7) 137 Monk, P. (8) 274 Monneret, C. (5) 366 Montanari, F. (3) 368; (5) 281 Montanucci, M. (6ii) 159 Montes de Lopez-Cepero, I (2) 177 Montevecchi, P.C. (5) 229 Montgomery, S.H. (3) 125 Moody, C.J. (8) 226; (9) 37 Moore, G . A . (3) 466 Moore, H.W. (5) 323, 370; (7) 20 Moore, J.I. (4) 234 Moore, J.L. (8) 12 Mora, J. (2) 180; (5) 498 Moracci, F.M. (8) 249 Moragues, V. (8) 105 Morales, H.R. (5) 81 Moreau, J.E. (1) 164; (5) 180 Moreeda, M. (4) 164 Morella, A.M. ( 4 ) 188 Morera, E. (1) 38, 121; (3) 216; (6i) 11, 79 Moret, E. (3) 243 Morey, M.C. (3) 441; (5) 262 Mori, A. (2) 86; (3) 453; (4) 93; (7) 43 Mori, I. (4) 114; (5) 547; (7) 174 Mori, K. (1) 101; (3) 121, 276, 326, 347; (5) 347; (6ii) 136; (7) 52; (8) 60-62 Mori, T. (4) 282, 304 Mori, Y. ( 3 ) 144 Moriarty, R.M. (2) 141, 142; (4) 116; (5) 510;

277; (5) 358 Moriyama, T. (2) 125 Morizawa, Y. (1) 65, 66; (2) 122, 244, 245; (3) 127, 247; (6ii) 111 Morris, M.D. (7) 63 Morris-Natschke, S. (2) 146; (4) 89; (6ii) 36 Morrissey, M.M. (1) 12; (6i) 9 Morton, G.H. (7) 30 Morton, H.E. (2) 218; (4) 135, 253 Morton, J.A. (8) 193; (9)

40

Mortreux, A. (1) 19 Moskal, J. (1) 88; (2) 127; (5) 373 Moss, R.A. (5) 119 Mosset, P. (1) 132, 133 Motherwell, W.B. (3) 56; (5) 28, 469 Motherwell, W.J. (2) 184, 226 Mothes, V. (3) 233 Motoi, M. (4) 38 Motoyama, T. (8) 140 Motoyoshiya, J. (5) 548 Mouloungui, Z. (3) 176 Mourad, M.S. (5) 17 Mouslouhouddine, M. (2) 215; (5) 152, 153 Moutevelis-Minakakis,P. (3) 479 Mrchand, A.P. (7) 87 Mrozek, E. (8) 112 Mudryk, B. (6ii) 26 Mukaiyama, T. (1) 43; (2) 132, 192, 255, 256; (3) 140, 202; (4) 44, 123, 124, 208 Mukerjee, A.K. (3) 437; (5) 138 Mukerjee, S.N. (4) 170 Mularski, C . J . (5) 98 Muller, E. (5) 445 Muller, U . (3) 124 Muller, W. (4) 238 Muller-Starke, H. (5) 345 (8) 64 Morimoto, M. (3) 306 Mulzer, J. (3) 22, 254; Morimoto, T. (3) 431; (5) (6ii) 47 243, 244; ( 5 ) 43; (6ii) Munegumi, T. (3) 370 107 Muneguni, H. (4) 302 Morin, -C. (2) 158; (8) Munger, J.D. (8) 196 236 Murahashi, S.-I. (2) 188; Morisaki, Y. (1) 186; (5) 150, 550, 551 (6ii) 156 Murai, A. (2) 73; (6ii) Morishita, T. (4) 251 24; (7) 193 Morita, Y. (5) 61, 540 Murai, S. (3) 130; (6i) Moriwake, T. (3) 122, 99; (7) 188 Murakami, M. (1) 43; (2) 363; (4) 19 Moriya, 0. (1) 102; ( 3 ) 256; (3) 202; (4) 123,

General and Synthetic Methods

708 124 Muraoka, M. (5) 158 Murata, I. (1) 181 Murata, S. (3) 74 Murayama, F. (7) 92 Murdoch, J.R. (5) 45; (6ii) 10 Murray, A.W. (1) 104; (3) 278 Murray, B.J. (5) 136 Murtiashaw, C.W. (9) 15 Murty, A.N. (7) 177; (9) 11 Muruyama, F. ( 9 ) 7 Muto, M. (8) 242 Mutter, M. (3) 402 Muzart, J . (3) 98; (5) 321; (6i) 50 Myers, A . G . (3) 319 Myerson, J . (3) 325 Mynier, F. (7) 143 Mzengeza, S. (8) 90 Naderi, M. (2) 4; (4) 139; (5) 529 Naef, R. ( 3 ) 255 Naengchomnong, W. (1) 87; (2) 126 Nafti, A . (5) 173 Nagahama, H. (4) 86 Nagai, S. (5) 548 Nagai, 2. (5) 326 Nagamatsu, T. (2) 27 Nagao, S. (4) 192 Nagao, Y . (1) 35; (2) 136; (3) 13, 386; (5) 266; (9) 83 Nagaoka, H. (4) 124; (9) 54 Nagaoka, M. (4) 162 Nagarajan, M. (7) 112 Nagashima, H. (1) 85; (3) 185 Nagata, H. (5) 89 Nagata, K. (3) 327 Nagata, T. (3) 136 Nagato, T. (4) 252 Nagatsuma, M. (1) 42; (8) 259 Nagel, U. (3) 452 Nagy, D. (5) 72 Nagy, T. (5) 497; (6ii) 30 Nair, V . (5) 164; (7) 192 Naito, T. (8) 241, 242 Najera, C. (3) 242, 365; (5) 285; (6ii) 52; (8) 162 Nakagawa, M. (8) 181, 182 Nakagawa, T. (3) 64, 373; (5) 38, 259 Nakagome, T. (3) 472

Nakahama, S. (4) 30 Nakai, A. (6ii) 166 Nakai, H. (3) 332; (5) 209; (7) 129 Nakai, T. (1) 42, 77-81, 179; (3) 34, 313; (4) 108, 109, 111, 113; (6ii) 87; (7) 38; (8) 259 Nakai, Y. (5) 494 Nakajima, M. (5) 441-443; (8) 53 Nakajima, Y . (3) 52 Nakajo, E. (6i) 38 Nakarnura, A . (1) 172 Nakamura, E. (3) 158, 159; (6ii) 49; (7) 136 Nakamura, K. (2) 283, 284; (3) 115; (4) 48; (5) 397; (7) 92; (9) 7 Nakamura, N. (8) 210 Nakamura, S. (5) 313 Nakanishi, T. (5) 425 Nakao, H. (2) 25 Nakao, T. (9) 15 Nakashita, Y. (5) 406; (7) 69 Nakata, T. (3) 112; (4) 20, 21, 24; (6ii) 137 Nakatani, H. (7) 10 Nakatani, K. (1) 34; (2) 135 Nakatani, K. (6ii) 117 Nakatani, M. (2) 206 Nakatsuji, Y . (4) 282, 304 Nakayama, J. (1) 60; (4) 256 Nakayama, K. (3) 399 Nakayama, Y . (2) 125; (6ii) 17 Nakazaki, M. (4) 292; (6ii) 75 Nakazato, M. (2) 28 Nakazawa, M. (4) 40 Nambu, Y . (5) 11 Namizu, S. (4) 19 Narasaka, K. (2) 254; (3) 357; (4) 22; (5) 193, 194; (9) 7 7 Narasimhan, N.S. (7) 114 Narasimhan, S. (4) 1, 16 Narayana, V . L . (8) 246 Narayanan, K. (3) 187; (6ii) 55 Nardlander, J . E . (2) 161 Narisano, E. (3) 422; (5) 225; (6ii) 147, 148 Nash, S.A. (4) 25; (6i) 15; (6ii) 139 Naso, F. (3) 87 Nasui, N. (9) 47

Natalini, B. (1) 28 Natarajan, S. (2) 133; (4) 92; (5) 137; (6ii) 86 Natile, G . ( 4 ) 267, 268 Natsugari, H. (5) 120; (8) 123 Navarro, M. (3) 407 Navarro, P. (4) 285 Nawa, M. (3) 453 Nazarova, N.Yu. (4) 291 Nazer, B. (2) 37; (4) 27, 243; (6ii) 65 Nazran, A.S. (4) 5 Ndebeka, G. (2) 229; (6ii) 29 Negishi, E. (1) 138; 180; (6i) 84; (7) 21 Negishi, Y . (3) 286; (4) 215; (5) 312 Nelsen, S.F. (8) 220 Nelson, G.O. (6i) 89 Nemoto, H. (9) 84 Neumann, N. (5) 159 Newcomb, M. (3).83; (6ii) 7 Newington, I.M. (3) 163; (6ii) 21 Newman, M.S. (7) 41 Newton, R.F. (6i) 96; (9) 53 Newton, T.W. (2) 71, 263; (3) 89 Ng, G . S . Y . (3) 257, 301 Ngatsuma, M. (3) 34 Nguyen, H.D. (6ii) 140; (8) 156 Nguyen, N.V. (5) 323 Nguyen, S.M. (2) 260 Nickon, A. (8) 76 Nicolaou, K.C. (1) 187; (4) 100, 184; (5) 190, 365 Nielsen, A . T . (5) 383 Nielsen, F.E. (5) 290 Niemela, K.E. (3) 471 Nikaido, M. (1) 134; (5) 163 Nikishin, G . I . (2) 196 Nikukawa, T. (3) 321 Nikulin, A . V . (5) 403 Nilsson, A . (5) 132, 133 Ninomiya, Y. ( 3 ) 169 Nisar, M. (7) 42 Nishida, A . (3) 64; (5) 3% Nishida, R. (3) 122; (4) 19 Nishida, T. (5) 318 Nishide, H. ( 7 ) 166, 167 Nishide, K. (4) 107; (5) 227, 340

709

Author Index Nishihara, Y. (2) 241; (5) 233 Nishina, H. (5) 302 Nishinaga, A . (5) 535 Nishio, T. (8) 222 Nishiyama, H. (1) 33; (2) 276; (3) 165; (4) 87 Nishiyama, K. (5) 310, 311 Nishizawa, M. (3) 240; (4) 39; (5) 320; (6ii) 76; (7) 162, 166, 167 Nisiyama, N. (4) 101 Nitta, M. (2) 224 Nitz, T . J . (2) 203 Njoroge, F.G. (2) 161: (5) 231 Nobayashi, Y. (4) 104 Nobbs, M.S. (3) 251; (7) 122 Node, M. (2) 176; (5) 420 Noguchi, M. (3) 64; (5) 38 Noguez, J.A. (3) 351; (9) 80 Nogusa, H. (3) 205 Nohira, H. (2) 190; (3) 155 Nokama, J. (5) 486 Nokami, J . (3) 266; (4) 69, 71; (5) 327; (7) 150 Nolte, R.T. (3) 471 Nomizu, S. (3) 122 Nomoto, T. (9) 47 Nomura, I. (3) 136 Nomura, Y. (5) 421 Nonaka, T. (2) 23; (4) 156; (6ii) 143 Nooda, Y. (3) 360; (5) 267 Norberg, A . (3) 292 Nordberg, R. (6i) 30, 31 Norden, T.D. (1) 110 Nordin, I.C. (3) 417 Nordlander, J . E . (5) 72, 231 Noriyama, T. (6ii) 17 Normant, J.F. (1) 139, 140; (2) 46, 112, 172, 264, 265; (3) 170; (4) 95, 240, 258; (5) 166, 167; (6i) 61, 64, 65 Note, M. (4) 107 Nott, A.P. (3) 49 Noureldin, N . A . (4) 264 Novack, V . J . (3) 350 Novak, L. (2) 216 Noyori, R. (2) 262; (3) 78, 240, 453; (4)'39; (5) 135, 405; (6i) 36, 43; (6ii) 76

Nozaki, H. (1) 64-67, 105, 168; (2) 15, 77, 122, 244, 245; (3) 127, 247, 273; (4) 98, 114, 153, 156; (5) 547; (6i) 45; (6ii) 28, 111; (7) 174 Nozaki, Y. (3) 179 Nozoki, N. (7) 56 Nozulak, J . (3) 442 Nugent, W.A. (1) 126; (6i) 13; (7) 113 Numazawa, M. (4) 162 Nunokawa, Y. (1) 171 Nussbaumer, C. (8) 202 Nyberg, K. (5) 247 Nystrom, J.-E. (1) 136

Ohmori, K. (4) 185 Ohno, A . (2) 283, 284; (3) 115; (5) 397 Ohno, M. (3) 332, 434; (5) 209; (7) 129 Ohshima, M. (1) 43; (2) 28; (4) 123, 124 Ohshima, T. (6ii) 166 Ohshiro, Y. (2) 104; (3) 58 Ohta, A . (5) 252 Ohta, H. (4) 272 Ohta, K. (4) 212 Ohta, M. (2) 254 Ohta, S. (3) 387; (5) 251 Ohta, T. (5) 10, 65; (6i) 20 Ohtaki, H. (5) 314 Ohtsuka, H. (4) 21 Oae, S. (4) 251, 252; (5) Ohtsuka, T. (3) 318; (9) 4 488 Obaza-Nutaitis, J.A. (9) Ohuo, A . (4) 48 38 Oikawa, Y. (4) 125, 126 O'Brien, B . A . (5) 485 Oishi, T. (3) 112; (4) 20, 21, 24, 52; (6ii) Obrzut, M.L. (3) 309; (4) 137 176 Ochiai, H. (1) 90; (2) Ojima, I. (3) 451 Oka, M. (7) 29 107; (6i) 38 Oka, S. (2) 283, 284; (3) Ochiai, M. (1) 35; (2) 136; (5) 266 115; (4) 4, 48; (5) Oda, D. (5) 171; (6i) 54 397, 495 Oda, H. (1) 65 Okabe, H . (4) 171; (7) 83 Oda, J . (3) 305 Okada, H. ( 1 ) 91; (2) 103, 181 Oda, M. (3) 326 Odaira, Y. (1) 18; (7) Okada, M. (5) 298 82, 185; (9) 6, 15 Okado, K. (9) 49 O'Donnell, M.J. (3) 407, Okado, M. (7) 10 408, 463; (5) 338 Okahara, M. (4) 282, 304 Oehlschlager, A.C. (3) Okamoto, J. (4) 4 341 Okamoto, K.T. (8) 223 Ogasawa, H. (5) 283 Okamoto, M. (3) 387; (5) 251 Ogasawara, K. (3) 306, 418 Okamoto, T. (5) 495 Ogata, T. (4) 228; (6i) Okamoto, Y. (4) 272, 292 Okamura, N. (5) 405 80; ( 8 ) 53 Ogawa, Y. (4) 137 Okano, K. (3) 431; (5) 243, 244 Ogimura, Y. (2) 94; (7) 138, 155 Okano, M. (2) 157 Oguni, N. (6ii) 44 Okawara, M. (1) 102; (3) Ogura, F. (2) 33; (5) 5 277; (4) 167, 209; (5) 11, 253; (8) 69 Ogura, K. (1) 84; (2) 22, 128; (7) 18 Okawara, R. (4) 71; (7) Ohal, R. (3) 264 150 Ohannesian, L. (2) 40, Okazaki, R. (3) 286; (5) 167; (6ii) 25 74, 112, 113 Ohashi, Y. (7) 79 Okecha, S.A. ( 5 ) 142 Ohdoi, K. (2) 206 Okinaga, N. (3) 432; (5) Ohfune, Y. (3) 464 242; (8) 256 Ohira, N. (5) 5 Okuda, K. (5) 548 Ohishi, Y. (5) 425 Okuda, Y. (1) 66 Ohmori, H. (4) 248; (5) Okukado, N. (1) 180; (6i) 84 18

General and Synthetic Methods

710 Okumoto, H. (3) 196, (7) 73 Okumura, H. (8) 210 Okura, M. (7) 10 Okuwaki, Y. (5) 252 Olah, G.A. (2) 40, 41, 167; (4) 242; (6ii) 25, 40 Olesen, P.H. (5) 290 Ollivier, J. (2) 83 Olofson, R . A . (5) 76 Omi, T. (6ii) 44 Omote, Y. (5) 60; (8) 222, 240 Ongania, K.-H. (5) 293 Onishi, H. (5) 205 Ono, A . (5) 1 Ono, N . (1) 73; (3) 88, 181, 338; (5) 417 Ono, T. (3) 266; (5) 327 Oohashi, M. (5) 109 Ookawa, A. (4) 17 Ootake, A . (6i) 51 Oplinger, J.A. (3) 251; (9) 15 Oppolzer, W. (7) 96-100 Orban, J . (1) 53; (2) 207 Oren, J. (4) 198 Orena, M. (2) 150; (3) 267; (5) 210 Oriyama, T. (2) 175; ( 4 ) 44, 208 Orlova, T.I. (5) 554 Orr, D.E. (5) 147 Orsini, F. (3) 218, 219 Ortar, G. (1) 38, 121: (3) 216; (6i) 11, 79 Ortotera, E. (7) 53 Osammar, M . I . (6ii) 120; (7) 54 Osby, J.O. (3) 474; (5) 47 Osei-Twum, E . Y . (4) 5 Oshikawa, T. (4) 179 Oshima, K. (1) 65-67; (2) 15, 77, 244, 245; (3) 127, 247; (4) 114, 153, 156, 547; (6ii) 111; (7) 174 Oshima, M. (3) 202 Oshiro, Y . (8) 84 Oshugi, Y . (5) 65 Ostrovskaya, L.K. (4) 278 Osugi, J. (2) 243; (5) 232 Osuka, A . (4) 26, 210; (6i) 82 O'Sullivan, R.D. (8) 165 Otani, S. (2) 243; (5) 118, 232 Otera, J. (1) 86, 101, 186; (2) 124; (3) 276;

(4) 69, 131; (6ii) 16, 17, 136, 156 Otlow, E. (9) 74 Otornatsu, T. (3) 394 Otsubo, T. (2) 33; (5) 5 Otsuji, Y. (4) 2, 3 Otsuka, M . (5) 219; (8) 274; (9) 92 Otsuka, S. (5) 135; (6i) 36 Otsuka, T. (3) 326 Ou, K. (5) 2 Ouchi, M. (4) 283 Ouseto, F. (3) 185 Ousset, J.B. (1) 59; (2) 52 Overman, L . E . (5) 68; (6i) 3; (8) 171, 172, 201; (9) 46 Owada, H. (2) 157 Oyamada, H. (4) 17, 18, 45; (5) 196; (6ii) 59 Ozawa, T. (8) 26

67; (6ii) 102, 103; (7) 13, 14, 19, 175; (9) 9, 12 Paraiso, E. (3) 175 Pardo, S.N. (3) 30 Parham, H. (2) 11; (4) 151, 247 Park, J.I. (1) 31 Parker, D.A. (2) 260 Parker, K.A. (9) 29 Parkins, A.W. (8) 165 Parrott, M . J . (3) 391, ,

466

Parrott, S . J . (3) 31 Parry, J.L. (8) 166 Parsons, D.G. (4) 305 Parsons, P.J. (2) 116 Partridge, B. (8) 252, 253 Paryzek, Z. (1) 30 Pasquato, L. (6ii) 152, 153; (7) 111 Passarotti, C. (1) 15 Pasto, D.J. (7) 17 Patchornik, A . (3) 396 Patel, A . M . (5) 108 Pabon, R . A . (7) 103 Padwa, A . (8) 144, 243; Patel, D.D. (2) 228 Patel, D.V. (5) 212 (9) 29 Pai, F.-C. (4) 22 Patel, M. (8) 101 Pai, G.G. (3) 108; (4) Patil, G. (2) 213; (5) 33; (6ii) 57 332, 333 Palfreyman, M.G. (5) 174 Patranuwatana, N . (8) 205 Palfreyman, M.N. (7) 66 Patsaev, A . K . (5) 278 Palla, F. (4) 37; (6ii) Pattenden, G. (1) 103; 74 (2) 10; (3) 271, 279; (4) 140; (7) 85, 88, Palmer, B.D. (9) 78 89; (9) 1 Palmer, M.J. (5) 50 Palmieri, G. (2) 200; (4) Paulmier, C. ( 3 ) 198; (4) 267, 268 118; (6ii) 161 Palmisano, G. (6i) 35 Pauls, H.W. (5) 213 Palorno, A . L . (3) 392 Pauson, P.L. (6i) 96 Palomo, C. (2) 168; (4) Pavlov, S. (2) 42; (6ii) 141, 189, 199, 200; 41 (6ii) 99; (8) 245, 248 Payne, M.J. (2) 161; (5) Palomo-Coll, A.L. (3) 73 72, 231 Palumbo, P.S. (1) 24 Pearson, A . J . (2) 31; (3) Pandey, V.C. (7) 163 248, 249; (6i) 28, 56, Panegrau, P.D. (3) 36 57 Pearson, D . A . (3) 351; Panek, J.S. (5) 352 Panicucci, R . (4) 5 (9) 80 Pansegrau, P.D. (5) 309; Pearson, W.H. (8) 42 Pease, J.P. (5) 30 (6ii) 2 Panyachotipun, C. (8) Peck, D.R. (3) 310 128, 129 Pedersen, E.B. (5) 290 Pedersen, U. (3) 229 Papadopoulos, M. (3) 30 Papageorgiou, C. (3) 172, Pedersen, Y . (5) 295 Pedrini, P. ( 5 ) 374 262; (6ii) 31 Papaioannou, D. (3) 385 Peevey, R.M. (1) 69; ( 3 ) Papini, A. (4) 105 117; (5) 168 Paquet, A. (3) 397 Pelizzoni, F. (3) 218, Paquette, L . A . (1) 47, 219 184; (2) 117, 203; (3) Pellacani, L. (8) 133

711

Author Index Pellicciari, R. (1) 28; (3) 59 Pelter, A . (5) 80; (6ii) 73 Pelyvas, I. (5) 519 Pennetrau, P. (5) 380 Perez, A.D. (3) 263; (6ii) 144 Perez, M.A. (5) 325 Perez-Juarez, M. (5) 81 Perez-Ossorio, R. (5) 78, 477 P&-ez-Prieto,J. (8) 161 Perez-Rubalcaba, A. (5) 78 Pergola, R.D. (3) 91 Perlmutter, P. (3) 448; (5) 240 Pero, F. (6ii) 147 Perrone, E. (8) 269, 270 Perry, D.A. (2) 35 Perry, M.W.D. (3) 163; (6ii) 21 Perry, R.J. (2) 110; (5) 410 Perumal, P.T. (1) 75; (6ii) 63 Pesecki-s,S.M. (9) 79 Peters, E.-M. (3) 237; (6ii) 12 Peters, K . (3) 237; (6ii) 12 Petersen, H.J. (5) 363 Petersen, J.S. (8) 160 Peterson, J.C. (7) 15 Peterson, J.R. (4) 187 Petit, F. (1) 19 Petit, M. (1) 19 Petit, Y. (3) 109 Petkov, D.D. (3) 400 Petragnani, N. (1) 161, 162; (4) 263 Petrier, C. (2) 273, 274; (3) 141; (6i) 66; (6ii) 50 Petrini, M. (2) 163; (4) 143; (5) 409, 411 Petrov, A.A. (5) 416 Petrus, C. (8) 105 Petrus, F. (8) 105 Pfaltz, A. (2) 160; (5) 20 Pfister, J.R. (8) 127 Phillips, B.T. (5) 429 Phillips, G.B. (5) 14; (7) 153 Phillips, J.L. (8) 51 Phinney, D.J. (5) 91 Phinyocheep, P. (1) 98; (7) 49 Piancatelli, G. (3) 224, 289

Pornet, J. (4) 81 Porzi, G. (2) 150; (3) 267 Posner, G.H. (2) 279-281; (3) 264; (6ii) 145 Postnova, L.V. (5) 415 Potier, P. (1) 2; (3) 57 Pougny, J.-P. (3) 261 Poulter, C.D. (3) 63; (5) 37 Poupelin, J.-P. (3) 46 Pourcelot, G. (6i) 67 Powell, D.R.'(5) 414 Prabhakar, S. (5) 467 Prakash, G.K.S. (2) 41, 167 Prakash, I. (2) 142 Prakash, 0. (2) 142 Pramanik, P. (5) 125 Prange, T. (3) 254 Prapansiri, V. (1) 87; (2) 126; (8) 128, 129 Prasad, K. (3) 315, 317 Prat, D. (6i) 67 Prati, L. (3) 123 Pratt, A.J. (2) 66; (6ii) 108 Preftitsi, F. (4) 239 Previtera, L. (4) 220; (7) 11 Prhavc, M. (5) 422 Price, D.T. (8) 91 Price, G.D. (5) 399 Price, M.F. (1) 51; (3) 139 Pridgen, L.N. (3) 68, 92; (4) 65; (8) 2 Prieba, H. (4) 224; (5) 513-515 Procter, G. (7) 39; (8) 155 446 Procter, K. (6ii) 141 Plumet, J. (5) 477 Prokschy, F. (8) 218, 219 Pluscec, J. (2) 133; (5) 137 Prout, K. (5) 219; (6i) Pluth, J.H. (5) 399 73; (8) 274; (9) 92 Pruckner, A . (5) 107 Pocar, D. (7) 53 Pryor, W.A. (5) 379 Pochini, A. (8) 34 Psiorz, M. (5) 465 Pochot, C. (7) 143 Pohmakotr, M. (1) 98, 99; Pulido, F.J. (5) 56 Purcell, N . (7) 66 (7) 49 Putsykin, Yu.G. (5) 554 Pohmakotr, P. (2) 118 Poirier, J.-M. (2) 197; Quadri, M.L. (4) 206 (7) 139 Poli, G. (2) 250 Quallich, G. (8) 40; (9) 26 Polla, E. (2) 221; (5) Quayle, P. (6ii) 154 511, 512 QuiAoB, E. (1) 124 Pollini, G.P. (2) 123; Quintard, J.-P. (5) 197 (3) 168; (8) 27 Poncini, L. (2) 138, 139 Quiroga, M.L. (5) 78 Pongratz, E. (5) 527 Rabideau, P.W. (3) 211 Popielarz, R. (5) 264 Rabinovitz, M. (4) 207 Popp, F.D. (5) 353, 354

Piaz, V.D. (8) 233 Picard, J.-P. (5) 144 Piccolo, 0. (3) 110 Pielchowski, J. (5) 264 Pienta, N.J. (3) 79; (5) 69 Piernin, A.B. (7) 102 Pierpoint, C. (6i) 37 Piers, E. (7) 64, 67, 94, 133; (9) 2, 10 Pietraskiewicz, M. (4) 289 Pietroni, B. (1) 37 Pigeon, P. (4) 226 Pigikre, C. (3) 413, 426 Pilichowski, J.F. (5) 93 Pillay, L. (5) 301 Pillay, M.K. (5) 360, 500 Pindur, U . (2) 198 Pinhas, A.R. (3) 14 Pinhey, J.T. (3) 44, 148, 149 Pinnick, H.W. (8) 166 Piper, S.E. (7) 137 Pipereit, E. (5) 470; (8) 24 Pirkle, W.H. (3) 427; (5) 63, 64, 99 Pirrung, M.C. (3) 125 Piskunova, I.P. (5) Pitchen, P. (4) 270 25 Piteau, M. (5) 76 Plant, H. (4) 117 Platen, M. (2) 219; 477 Plaut, H. (3) 129; 106 Plesch. W. (5) 437 Pliura; D.H: (1) 155; (3)

General and Synthetic Methods

712 Rabjohn, N . ( 3 ) 62 Racherla, U.S. (1) 165; ( 2 ) 137, 271; ( 6 i i ) 6 8 , 71 R a c h l i n , D . J . ( 5 ) 72 Raddatz, P. ( 3 ) 346 Radhakrishna, A.S. ( 3 ) 65; ( 5 ) 39 Ragauskas, A.J. ( 9 ) 7 Ragnarsson, U. ( 3 ) 480 Rahman, A. ( 5 ) 491 Rahman, H.U. ( 5 ) 260 Rajagopalan, K. ( 3 ) 174 Rajagopalan, S. ( 6 i i ) 104 Rajan Babu, T.V. ( 3 ) 164; ( 5 ) 412 Rajapaksa, D. ( 9 ) 6 8 Rakiewicz, D.M. ( 2 ) 223; (5) 31 Ram, B. ( 8 ) 246 R a m , S. ( 5 ) 6 Ramage, R . ( 3 ) 2 4 , 293295, 391, 466; ( 9 ) 7 0 , 91 Ramaiah, M. ( 2 ) 8 4 Raman, P.S. ( 3 ) 301 Rambaud, M. ( 2 ) 120, 174; ( 3 ) 174; ( 4 ) 204 Ramirez, J.R. ( 1 ) 94; ( 3 ) 191 R a n d a l l , J . L . ( 5 ) 190, 365 R a n d r i a n a n o e l i n a , B. ( 4 ) 81 Ranganathan, S . ( 5 ) 4 R a n i r i s e h e n o , H . ( 3 ) 410 Ranken, P.F. ( 4 ) 260 Rao, A.S. ( 4 ) 177 Rao, R.K.S. ( 7 ) 8 6 , 87 Rao, V.B. ( 7 ) 27 Rao, Y . K . ( 7 ) 112 Raphael, R.A. ( 8 ) 28 Rapoport, H. ( 3 ) 413; ( 5 ) 1 2 , 224, 463; (8) 160 Rathore, R. ( 2 ) 5; (4) 6 , 149 Ratovelomanana, V. (1) 188; ( 6 i i ) 80 Rausch, R . A . ( 4 ) 277 Rautenstrauch, V. ( 2 ) 90; ( 6 i ) 100; ( 7 ) 62 R a v e n s c r o f t , P.D. ( 6 i i ) 66 Ravikumar, V.T. ( 3 ) 174 R a v i n d r a n a t h , B. ( 4 ) 223 Rawal, V.H. ( 2 ) 49 Ray, T. ( 2 ) 31; ( 3 ) 249; ( 6 i ) 28 Raychaudhuri, S.R. ( 7 ) 22; ( 8 ) 150 Raynolds, P.W. ( 2 ) 68; ( 5 ) 359

Rebek, J . ( 9 ) 32 R e b i z a n t , J. ( 4 ) 277 Reddy, G . J . ( 8 ) 246 Reed, J.N. ( 5 ) 41; ( 6 i i ) 1; ( 9 ) 423 R e e f e r , J. ( 5 ) 439 Rees, C.W. ( 5 ) 450 R e e t z , M.T. ( 2 ) 186; ( 3 ) 111, 133, 203; ( 4 ) 565 8 , 76; ( 5 ) 345; ( 6 i i ) 84 R e g e l i n g , H. ( 2 ) 152 R e g i t z , M. ( 5 ) 526 Reibenspies, J.H. ( 2 ) 144; ( 4 ) 8 8 ; ( 6 i i ) 155 Reich, H.J. (1) 127; ( 6 i i ) 118; ( 7 ) 132 R e i c h , I.L. (1) 127; ( 6 i i ) 118 R e i c h e l t , I. ( 3 ) 8 2 , 155157 R e i c h l , R. ( 5 ) 191 R e i d , R.G. (1) 104; ( 3 ) 278 Reimer, G. ( 6 i ) 18 Rein, T. ( 1 ) 136 R e i n h a r d t , H.W. ( 5 ) 154, 155 Reinhoudt, D . N . ( 4 ) 307; ( 8 ) 153, 154, 221 R e i s s i g , H.-U. ( 3 ) 8 2 , 155-157 Reiter, L.A. ( 9 ) 95 R e i t z , D.B. ( 3 ) 374; ( 5 ) 110 Remiszewski, S.W. ( 5 ) 218; ( 9 ) 67 Renaud, P. ( 3 ) 118 Renga, J.M. ( 3 ) 8 0 ; ( 4 ) 229 RepiE, 0. ( 3 ) 315, 317 Repina, L.A. ( 5 ) 483 R e s n a t i , G . ( 3 ) 282; (6ii) 3 R e s t e l l i , A . ( 3 ) 368; ( 5 ) 281; ( 6 i i ) 4 R e u t r a k u l , V . (1) 8 7 ; ( 2 ) 126; ( 8 ) 1 2 8 , 129 Rey, M. ( 7 ) 172 Reyna, J.D. (8) 135 Rhee, R.P. ( 9 ) 66 Ricca, G . ( 3 ) 219 R i c c i , A. ( 3 ) 265; ( 4 )

105 Rice, L.E. ( 3 ) 217 R i c e , N.W. ( 3 ) 470 R i c h a r d s , I . C . ( 6 i ) 57 Richardson, D.P. ( 3 ) 325 Richmond, R.E. ( 3 ) 201 R i c h t e r , C. ( 8 ) 112 R i c h t e r , F. ( 8 ) 112

R i c k a r d s , R.W. ( 9 ) 71 R i c o , J . G . ( 2 ) 76 R i d e l l a , J. ( 2 ) 6 5 ; ( 6 i i ) 18 R i e k e , R.D. ( 4 ) 218 R i e k e r , A. ( 5 ) 538, 545 R i e k e r , R. (1) 7 ; ( 3 ) 475 R i e k e r , W.F. ( 5 ) 104 R i e t h , R . ( 1 ) 178; ( 7 ) 182 Rigby, J . H . ( 4 ) 129; ( 6 i i ) 98 R i g u e r a , R. (1) 124; (8) 3 R i o n d e l , A. ( 2 ) 229; ( 6 i i ) 29 Ripka, W.C. (8) 147; ( 9 ) 30 R i p o l l , J.-L. (1) 1 5 0 , 151 R i s a l i t i , A. ( 5 ) 457 Risbood, P.A. ( 4 ) 5 R i t t e r s k a m p , P. ( 7 ) 9 1 ; (9) 7 R i v i e r e , H. ( 8 ) 6 Roberge, G . ( 5 ) 523 R o b e r t s , S.M. ( 9 ) 5 3 Robin, J . - P . ( 3 ) 264 Robins, M.J. ( 1 ) 31 Robinson, A.E. ( 3 ) 406 Roder, H. ( 3 ) 237; ( 6 i i ) 12 Rodrigo, R. ( 9 ) 6 8 Rodriguez, A. ( 8 ) 7 6 , 243 Rodriguez, J. ( 4 ) 119 Rodriguez F r a n c o , M.I. ( 4 ) 285 Rogalska, E. ( 8 ) 250 R o l , C. ( 5 ) 557 Rolando, C. ( 4 ) 172 R o l l a , F. ( 4 ) 206 Romeo, A. ( 2 ) 8 ; ( 4 ) 157 Romero, J . R . ( 5 ) 355 Ronald, R.C. ( 2 ) 239; ( 6 i i ) 138 R o n z i n i , L. ( 2 ) 4 4 ; ( 6 i i ) 39 ROOS, G.H.P. ( 5 ) 301 ROOSZ, M. ( 5 ) 183 Rosen, T. ( 3 ) 316 Rosenberg, D. (8) 185 Rosenblum, M . (1) 40; ( 2 ) 237; ( 3 ) 281; ( 7 ) 8 0 ; ( 8 ) 25 R o s i n i , G. ( 2 ) 163; ( 4 ) 143 R o s s e r , R.M. ( 5 ) 8 0 R o s s i , G . ( 3 ) 307 R o s s i n i , G. ( 5 ) 409, 411 R o s s i t e r , B.E. ( 3 ) 435; (5) 226; ( 6 i ) 23 Roudier, J.-F. ( 3 ) 30 Rouessac, F. ( 3 ) 197, 245

Author Index Roush, W.R. (1) 21; (2) 53; (3) 177, 353, 354; (5) 202; (6ii) 128; (9) 79, 81, 82 Rousseau, G. (6ii) 48; (7) 4 Rowe, B.A. (3) 44 Royer, R. (5) 396, 424, 430; (8) 52 Rozantsev, E.G. (8) 188 Rubiralta, M. (8) 224 Ruchirawat, S. (8) 205 Ruckdeschel, G. (5) 24 Ruder, S . M . (2) 239; (6ii) 138 Rudham, R. (2) 10; (4) 140 Riichardt, C. (3) 45; (5) 304 Rueker, C. (2) 179 Ruhr, M. (5) 470; (8) 24 Ruitenberg, K . (6ii) 116 Rusakov, A . F . (5) 554 Russell, D.R. (7) 121 Russell, J.J. (2) 10; ( 4 )

Saito, A . (3) 244, 245; (8) 241 Saito, H. (3) 303 Saito, M. (3) 464; (5) 302 Saito, P . A . (7) 165 Saito, S. (3) 122, 363; (4) 19 Saito, Y. (4) 79 Sakaguchi, K . (3) 425 Sakai, K . (2) 88; (4) 248; (6i) 44; (7) 61 Sakai, T. ( 1 ) 21; (2) 53; (3) 177; (6ii) 128, 166 Sakakibara, Y. (3) 28 Sakakura, T. ( 3 ) 132, 357; (4) 144; (6i) 21; (9) 77 Sakamoto, M. (8) 240 Sakamoto, T. ( 5 ) 89; (8) 242 Sakan, K. (7) 124 Sakane, K. (5) 494 Sakata, K. (2) 156 Sakata, Y. (8) 141 Sakoh, K. (7) 104-108 140 Russell, K. (6i) 34; (8) Sakuma, Y. (2) 27 Sakurai, H. (2) 201; (4) 216; (9) 45 Russell, M . A . (3) 222; 230; (8) 141 (5) 419; (6ii) 134 Sakurai, M. (2) 193 RUSSO, J . M . (5) 471 Sakurai, Y. (1) 167; (5) Rutledge, P.S. (5) 542 84, 85; (6i) 62; (6ii) 71 Rzepa, H.S. (5) 467 Rzeszotarska, B. (5) 263 Sakuta, K. (1) 33; (2). 276; (3) 165 Sala, R. (1) 15 Saari, W.S. (5) 428 Saba, A . (8) 48 Salaen, J . (2) 83 Sabbioni, G. (3) 11 Salanski, P. (8) 244 Sabol, M.R. (2) 149 Salazar, J . A . (5) 400; Sabri, W.S. (8) 106 (8) 75 Salemink, C . A . (8) 231 Sabuni, M. (5) 222; (8) Salka, M.S. (8) 235 99 Saegusa, T. (2) 194, 211; Salomon, M.F. (3) 30 (5) 344, 475 Salomon, R.G. (3) 30; (7) Safdar, A . (5) 108 22, 31; (8) 150 Salunkhe, M.M. (4) 15 Sagasawa, T. (2) 248 Sagitullin, R.S. (5) 114 Salz, U. (3) 45 Saha, C.R. (5) 9 Sammes, P.G. (8) 21, 134 Sahara, M. (3) 376; (6ii) Sampson, P. (8) 29 1 Samuels, S.B. (3) 281 Samuelsson, B. (3) 81; Sahoo, S.P. (3) 444 Sahraoui-Taleb, S. (3) (4) 180; (5) 394 Ssnchez, I . H . (8) 228 285 Sahu, D.P. (8) 251 Sande, A.R. (4) 15 Saigo, K. (2) 190; (3) Sandhu, J.S. (5) 236, 237 Sandri, S. (2) 150; (3) 155 Saikawa, S. (8) 242 267; (5) 210 Saimoto, H. (2) 15; (4) Sandris, C. (5) 291 153 Sandus, 0. (5) 399 Sainsbury, M. (7) 160; Sanida, C. (3) 385 Sano, H. (2) 193; (4) (9) 67 Sainte, F. (3) 407 215, 228; (5) 312; (6i)

713 80; (6ii) 81; (8) 174 Sansome, E.B. (5) 454 Sansoulet, J. (4) 226 Santa, T. (5) 75 Santelli, M. (1) 106; (2) 93; (3) 26, 273; (5) 331; (7) 154 Santelli-Rouvier, C. (3) 308 Santini, C. (9) 20 Santos, M . A . (5) 467 Santra, P.K. (5) 9 Santucci, S. ( 1 ) 28; (3) 59 Sanz, D. (5) 477 Saotome, Y. (4) 209 Sardarian, A . (2) 3, 4; (4) 247; (5) 529 Sargent, M.V. ( 4 ) 134 Sarma, D.N. (4) 132, 161 Sarma, J.C. (4) 161 Sarma, R.P. (4) 132 Sarmah, P. (7) 163 Sartori, G . (3) 47 Sas, W. (6ii) 150 Sasaki, I. (2) 224 Sasaki, K. (2) 201; (3) 28; (4) 230 Sasaki, T. (8) 117 Sasakura, K . (2) 248; (4) 60 Sasaoka, H. (6ii) 85 Sasaoka, M. (4) 192; (5) 486 Sasson, Y. (4) 194 Satake, K . (3) 473; (9) 89 Sato, F . (4) 82, 83; (6ii) 91; (8) 30 Sato, K. (3) 196; (5) 89 Sato, M. ( 2 ) 77; (4) 301303; (5) 283; (8) 242 Sato, R. ( 5 ) 302 Sato, S. (1) 91; (2) 103, 181; (3) 102; (7) 193; (8) 120 Sato, T. (1) 46, 148; (2) 178, 246; (3) 10, 33, 34, 114, 269, 322; (4) 47, 62, 183; (5) 283 Sato, Y. (8) 120 Satoh, H. (8) 271, 272 Satoh, J . Y . (3) 5; (4) 197 Satoh, K . (1) 145 Satoh, T. (2) 156 Satoh, Y. (3) 361; (5) 270 Satomi, H. (3) 380; (8) 78 Sauerwald, M. (4) 76 Saulnier, M.G. (9) 38

General and Synthetic Methods

714

Saunders, J.O. (9) 15 Sawada, H. (7) 21 Sawaki, Y. (3) 69 Sayo, N. (1) 42, 78, 79, 179; (3) 34; (4) 109, 111 Scanga, S. A. (3) 21 Scarafile, C. (8) 268 Scavo, F. (1) 134; (5) 163 Scettri, A. (3) 224, 289 Schafer, H.J. (5) 49; (8) 18, 227 Schaffner, K. (7) 91; (9)

153; (4) 262 Schomburg, D. (5) 261 Schon, I. (3) 476 Schonenberger, H. (5) 24 Schonholzer, P. (8) 121 Schore, N.E. (6i) 95; (7)

84

Schowen, R.L. (3) 424 Schregenberger, C. (3) 345 Schreiber, S.L. (8) 71; (9) 20, 87, 88 Schroder, G. (4) 290 Schroeder, M. (2) 7; (3) 7 7; (4) 145 Schafter, H.J. (3) 60 Schubert, H. (2) 231; (3) Schamp, N. (2) 154; (8) 150; (5) 32, 461 131 Schuda, P.F. (3) 146; (7) Schantl, J.G. (5) 539 93; (9) 7 Schaumann, E. (3) 382; Schultz, A.G. (5) 258 Schultz, J. (9) 62 (5) 296; (8) 273 Schultze, L.M. (6i) 77; Schechter, H. (1) 117 Scheck, D. (3) 281 (8) 239 Schulze, K. (8) 112 Scheeren, J.W. (3) 253 Schegolev, A.A. (2) 134 Schumann, I. (8) 185 Scheibye, S. (3) 228 Schurig, V. (6i) 26 Scheuer, R . (3) 415 Schwartz, J. (1) 55, 143; (6i) 76 Schick, H . (3) 243 Schickedanz, M. (3) 428 Schwartzenbrunner, Y. (5) 293 Schiess, M. (2) 242; (3) Schwarz, O.A. (3) 460; 433; (5) 234 Schinzer, D. (7) 191 (4) 249 Schleich, K. (6i) 87 Schweizer, W.B. (3) 118 Schlosser, M. (1) 129, Schwellnus, K. (2) 186; (3) 133, 203 130; (2) 121; (3) 243 Schmid, C . R . (2) 18; (4) Schwering, J.E. (5) 428 148 Schwyzer, R. (3) 405 Sciacovelli, 0. (4) 266 Schrnidhauser, J.C. (1) Scilirnata, A. (3) 87 183 Schmidlin, C. (5) 220 Scolastico, C. (2) 249, 251; (3) 173, 225, 422; Schmidt, R . R . (3) 296; (4) 63; (5) 225; (6ii) (8) 176 Schmidt, U . (3) 436 13, 147 Scott, A.I. (3) 304 Schmidtchen, F.P. (5) Scott, C.P. ( 6 i ) 89 384, 516 Schmit, C. (3) 285 Scott, J . R . (5) 249 Schmitt, G. (3) 46 Scott, W.J. ( I ) 122; (6i) Schmitz, E. (5) 271 78; (6ii) 112; (9) 10 Schmolka, S.J. (5) 126 Scripko, J.G. (9) 55 Seamon, D.W. (8) 45 Schnatterer, A. (8) 63 Schneider, H.-J. (4) 238 Sebastiani, G.V. (5) 557 Schneider, M. (3) 10, 11, Sebti, S. (8) 262 Seconi, G. (4) 105 258; (6ii) 157 Seda, R . (1) 94; (3) 191 Schnurrenberger, P . (3) 344 Seebach, D. (2) 242; (3) 118, 119, 121, 242, Schollkopf, U. (3) 415, 255; 344, 345 412, 416, 442; (5) 208, 376 433; (4) 54, 222; (5) Schoellmann, G. (2) 165 100, 121, 234, 407; Schoenen, F.J. (8) 46 Schofield, C.M. (3) 62 (6ii) 34 Seeman, J.I. (6i) 75 Schohe, R. (5) 200 Segmuller, B. (7) 147 Scholz, D. (1) 26; (2)

Segoe, K. (2) 211; (5) 344 Segura, R. (3) 364 Seitz, S.P. (4) 138; (5) 348 Sekiya, M. (3) 431; (5) 43, 243, 244; (6ii) 107; (8) 115, 139, 140, 142 Self, C.R. (2) 235; (3) 186 Selle, B.J. (4) 187 Selnick, H.G. (9) 90 Semenov, A . N . (3) 401 Semmelhack, M.F. (2) 18; (3) 274; (4) 148, 235 Senaratne, K.P.A. (9) 33 Senet, J.-P. (5) 76 Seno, K. (3) 386 Sequa, R. (5) 257 Sera, A. (3) 398 Seraglia, R. (4) 269 Serena, B. (5) 557 Serizawa, H . (3) 361; (5) 270 Serizawa, Y. (3) 327 Serratosa, F. (3) 1 Set, L. (2) 92 Sethi, S.P. (2) 208 Seto, K. (5) 315 Sevestre, H. (2) 97; (7) 141, 142 Seyden-Penne, J. (3) 178; (5) 316 Seyferth, D. (3) 232, 381; (5) 279 Sgarra, R . (5) 175 Sha, C.-K. (8) 194 Shaber, S.H. (9) 32 Shahriari-Zavareh, H. (4) 32; (6ii) 58 Shalom, E. (5) 361 Sham, H.-L. (8) 15 Shandala, M.Y. (5) 96 Shankar, B.K.R. (5) 399 Shankaran, K. (3) 378; (8) 32 Shapiro, M . J . (6ii) 132 Shargi, H. (5) 496 Sharma, K.K. (3) 160 Sharma, R.P. (4) 161; (5) 466; (7) 163 Sharpless, K.B. (3) 435; (4) 43; (5) 226; (6i) 23, 24; (6ii) 77 Shatzmiller, S. (5) 361 Shaw, K.J. (5) 91 Shea, M.L. (3) 11 Shea, R.G. (1) 70, 71; (5) 169, 170; (6ii) 164 Sheffy, F.K. (2) 108; (3) 184; (4) 216; (6ii) 112

Author Index Sheng, Z.-C. (5) 357 Sherman, H.L. ( 8 ) 166 Shertstyannikova, L . V . ( 5 ) 128

Shibasaki, M. ( 4 ) 137 Shibata, D. ( 3 ) 386 Shibato, K. ( 3 ) 300; ( 4 ) 241

Shibuya, S. ( 8 ) 197 Shida, J. ( 5 ) 70 Shigematsu, K. ( 4 ) 295 Shih, C . ( 9 ) 50 Shikano, N. ( 8 ) 115 Shilcrat, S . C . ( 3 ) 68 Shimada, J. ( 3 ) 158 Shimada, N. ( 2 ) 7 3 ; (6ii) 24

Shimagaki, M. ( 4 ) 2 4 ; (6ii) 137 Shimaji, K. ( 9 ) 50 Shimara, H. ( 7 ) 92 Shimazaki, K. ( 5 ) 1 Shimazaki, M. ( 5 ) 252 Shimizu, I. ( 1 ) 9 3 ; ( 2 ) 1 , 114, 233; ( 3 ) 145, 199; ( 4 ) 142; ( 5 ) 1 7 2 ; ( 6 i ) 1 0 , 48, 49; ( 7 ) 4 2 , 7 9 ; ( 8 ) 117 Shimizu, K. ( 3 ) 399 Shimizu, M. ( 2 ) 132, 192, 238; ( 3 ) 180; ( 7 ) 1 ; (8) 8 Shimizu, T. ( 8 ) 87 Shing, T.K.M. ( 5 ) 186 Shinkai, H. ( 4 ) 287 Shinkai, s. ( 2 ) 2 5 ; ( 4 ) 295-298 Shinozaki, K. ( 3 ) 478 Shioiri, T. ( 3 ) 8 , 254; ( 5 ) 206, 207, 313, 317; ( 9 ) 65 Shiono, S. ( 5 ) 195 Shiori, T. ( 3 ) 390; ( 7 ) 179 Shiota, T. ( 5 ) 550 Shiragami, H . ( 1 ) 1 6 8 ; ( 4 ) 9 8 ; (6ii) 28 Shirahama, H. ( 3 ) 318; (9) 4, 7 Shirai, F. ( 1 ) 4 2 , 179; ( 3 ) 3 4 ; ( 4 ) 111 Shiraiwa, T. ( 3 ) 425 Shirhatti, V. ( 8 ) 76 Shirikai, S . ( 4 ) 287 Shiro, M. ( 3 ) 13 Shirouchi, Y. ( 3 ) 42 Shishido, K. ( 3 ) 304 Shkil', G . P . ( 5 ) 114 Sholle, V.D. ( 8 ) 188 Shono, T. ( 2 ) 21; ( 3 ) 205, 254.. 419.. 432:, ( 5 ) 242; 305; ( 8 ) 158, 256'

715 Shridhar, D.R. ( 8 ) 246 Shuda, P.F. ( 8 ) 51 Shudoh, H. ( 3 ) 144 Shue, Y.-K. ( 9 ) 32 Shullenberger, D . F . ( 3 ) 408; ( 5 ) 338

Shutt, F.E. ( 3 ) 2 4 , 293; ( 9 ) 91

Sibi, M.P. ( 3 ) 375; ( 9 ) 38

Siegel, C.A. ( 3 ) 471 Siegel, H. ( 4 ) 222 Sigalov, M.V. ( 5 ) 128 Sih, C . J . ( 3 ) 1 2 , 113, 259; ( 4 ) 46

Sill, A.D. ( 8 ) 186 Sillion, B. ( 5 ) 288 Silverman, I.R. (6ii) 105 Silvestri, G. ( 3 ) 38 Silvestri, M. ( 7 ) 147 Simchen, G . ( 2 ) 1 5 1 ; ( 3 ) 86

Simon, E.S.

( 2 ) 226; ( 5 )

28

Simoni, D. ( 3 ) 1 6 8 ; ( 8 ) 27

Simons, F.W. ( 8 ) 177 Simova, S. ( 7 ) 60 Simpson, T . J . ( 3 ) 304 Sims, J.J. ( 3 ) 329; ( 8 ) 41

Siney, P. ( 3 ) 261 Singal, K.K. ( 8 ) 92 Singaram, B. ( 1 ) 131; ( 2 ) 130; (6ii) 69 Singh, A. ( 8 ) 215 Singh, B. ( 5 ) 6 2 ; ( 8 ) 215 Singh, H.K. ( 5 ) 339 Singh, S.M. ( 1 ) 165; ( 2 ) 137; (6ii) 6 4 , 6 8 , 71 Singha, A.A. ( 5 ) 466 Singleton, A. ( 3 ) 234; ( 8 ) 79

Singleton, D.A.

( 1 ) 144;

( 7 ) 128

Singleton, K.A.

( 5 ) 219;

( 9 ) 92

Sinisterra, J . V . ( 2 ) 105 Sinitsa, A.D. ( 5 ) 483 Sit, S.-Y. ( 9 ) 60 Siver, K.G. (5) 116 Siwapinyoyos, T. ( 3 ) 166 Skare, S . ( 3 ) 82 Sket, B. ( 2 ) 170 Slack, J . R . ( 7 ) 149 Slebioda, M. ( 3 ) 458 Sliskovic, D . R . ( 5 ) 299 Sliwka, H . R . ( 7 ) 47 Sloan, K.B. ( 5 ) 116 Slougui, N. (6ii) 4 8 ; ( 7 ) 4

Smalley, R . K .

( 5 ) 536

Smit, W.A. ( 2 ) 134 Smith, A.B. ( 3 ) 201; ( 7 ) 2 5 , 2 6 ; ( 9 ) 1 4 , 58 ( 7 ) 124 ( 3 ) 8 3 ; (6ii) 7 Smith, K. (6ii) 20 Smith, M.B. ( 4 ) 182, 219; ( 5 ) 558 Smith, M.R. (8) 111 Smith, N.M. ( 5 ) 124 Smith, P.W. ( 5 ) 184, 185 Smith, R . ( 5 ) 368 Smith, R . A . J . ( 2 ) 67 Smith, S . ( 8 ) 134 Smith, T.D. ( 5 ) 460 Smyth, T . A . ( 5 ) 385 Snider, B.B. ( 3 ) 332; ( 7 ) 7 4 , 152, 153 Snieckus, V. ( 3 ) 375-379; ( 5 ) 4 1 , 272; (6ii) 1 ; ( 8 ) 3 2 ; ( 9 ) 2 4 , 2 5 , 42 Snowden, R.L. ( 7 ) 116 ( 9 ) 18 Soai, K . ( 3 ) 369; ( 4 ) 1 7 , 1 8 , 45; ( 5 ) 196; (6ii) 5 9 , 88 Sodeoka, M. ( 8 ) 181 Sofen, N. ( 3 ) 281 Solladie, G . (6ii) 5 , 146; ( 8 ) 50 Solladie-Cavallo, A. ( 3 ) 18 Somayaji, V. ( 4 ) 1 , 201 Song, A.-T. ( 3 ) 466 Song, Y.H. ( 2 ) 20 Sonnay, P. ( 9 ) 18 Sonnleitner, B. ( 3 ) 1 1 9 ; ( 4 ) 54 Sono, T. ( 4 ) 298 Sonoda, N. ( 3 ) 1 3 0 ; (6i) 99 Sonola, 0.0. ( 4 ) 4 1 ; ( 5 ) 2 6 ; 77 Soria, J . J . ( 8 ) 228 Sorrenti, P. ( 2 ) 1 6 3 ; ( 4 ) 143; ( 5 ) 409, 411 Soto, J.L. ( 5 ) 325 Souchi, T. ( 3 ) 453 South, M.S. ( 3 ) 337; ( 6 i ) 8 8 ; ( 9 ) 27 Southwick, P.L. ( 3 ) 471 Spagnolo, P. ( 5 ) 229 Spatola, A . F . ( 3 ) 230 Speckamp, W . N . ( 1 ) 158; ( 3 ) 449; ( 5 ) 179 Speth, D. ( 5 ) 337 Spina, K.P. ( 2 ) 204; ( 4 ) 193 Spino, C . ( 3 ) 189 Spletzer, E.G. ( 3 ) 14 Sponlein, W. ( 7 ) 81

Smith, D.A. Smith, J . K .

General and Synthetic Methods

716 Springer, J.P. ( 6 i i ) 51; ( 7 ) 2 3 , 109; ( 8 ) 9 3 , 253 S p u r , B. ( 7 ) 110 S r e b n i k , M. ( 3 ) 268; ( 8 )

16 S r i d h a r a n , V. ( 8 ) 146 S r i n i v a s , P. ( 4 ) 223 S r i n i v a s a n , K.V. ( 5 ) 462 S r i n i v a s a n , P.C. ( 2 ) 1 0 0 ; ( 7 ) 181 S t a c k , D.P. ( 3 ) 50 S t a h l y , B.C. ( 3 ) 2 0 8 ; ( 6 i i ) 26 S t a h l y , G.P. ( 3 ) 208; ( 5 ) 4 1 3 ; ( 6 i i ) 26 S t a k s u n , B. ( 5 ) 241 S t a l e y , S.W. ( 1 ) 110 S t a m a t a t o s , L. ( 3 ) 261 Stamm, H. ( 5 ) 337 Stammer, C.H. ( 3 ) 409 Stamp, L. ( 5 ) 165 S t a n c i n c , G . ( 5 ) 464 S t a n k o w i a k , A. ( 4 ) 165 S t a n o v n i k , B. ( 5 ) 422 S t a r t s e v , V.V. ( 5 ) 416 S t a t e n , G.S. ( 3 ) 4 0 8 ; 338 S t a u n t o n , J. ( 3 ) 210 S t e c k h a n , E. ( 2 ) 219; 477 S t e e l , L. ( 2 ) 5 7 , 58 S t e i g e l , A . ( 8 ) 232 S t e i n , M.L. ( 5 ) 51 S t e i n , P.D. ( 9 ) 52 S t e i n b a c h , E. ( 3 ) 429 S t e l l a . L. ( 5 ) 335 S t e n b e r g , E:D: ( 7 ) 158 S t e n b e r g , J.A. ( 7 ) 151 S t e p h e n s , R . ( 8 ) 96 S t e r c h o , Y.P. ( 4 ) 9 ; ( 6 i i ) 67 S t e r n , E.S. (6i) 3 4 ; ( 8 ) 216; ( 9 ) 45 S t e r n b a c h , D.D. (1) 128 S t e r n b e r g , E.D. ( 9 ) 22 Sternberg, J . A . ( 5 ) 504; ( 8 ) 102 S t e v e n s , K.E. ( 9 ) 9 S t e v e n s , R . V . ( 8 ) 190 S t e v e n s , R.W. ( 2 ) 255 S t e v e n s o n , J.W.S. ( 7 ) 170 S t e v e n s o n , P. ( 1 ) 125 S t i l l , W.C. ( 3 ) 3 5 0 , 3 5 1 ; ( 9 ) 80 S t i l l e , J.K. (1) 1 2 2 ; ( 2 ) 108, 109, 253; ( 3 ) 184; ( 4 ) 5 9 , 216, 217; ( 6 i ) 7 8 ; ( 6 i i ) 1 1 2 ; ( 9 ) 10 S t i m c , A . ( 5 ) 422 S t o c k e r , A.W. ( 5 ) 536 S t o d d a r t , J.F. ( 4 ) 32,

3 0 6 ; ( 6 i i ) 58 S t o i n e v a , I . B . ( 3 ) 400 S t o l l e r , H. ( 6 i ) 87 S t o o d l e y , R . J . ( 7 ) 66 S t o r k , G. ( 5 ) 401 S t o t h e r s , J.B. ( 9 ) 7 S t o w e l l , J . C . ( 2 ) 6 1 , 62 S t r e e t , S.D.A. ( 8 ) 59 S t r e i t h , J . ( 5 ) 220 S t r e k o w s k i , L. ( 1 ) 9 5 ; ( 3 ) 192 S t r u k u l , G. ( 6 i ) 29 S t u b b s , M.E. ( 6 i ) 3 4 ; ( 8 ) 216; ( 9 ) 45 S t u t z , A. ( 5 ) 107 s u , w.-Y. ( 5 ) 34 S u a r e z , E. ( 5 ) 4 0 0 ; ( 8 ) 75 S u d a , H. ( 4 ) 38 S u d e r , B.J. ( 3 ) 217 Sudhakar Rao, T. ( 5 ) 431 Suernitsu, R. ( 5 ) 79 Suemune, H . ( 2 ) 8 8 ; ( 6 i ) 44; ( 7 ) 61 S u e t s u g u , A. ( 9 ) 6 4 S u f f e r t , J. ( 3 ) 18 S u g a , H. ( 5 ) 139 S u g a h a r a , T. ( 9 ) 41 Sugasawa, T. ( 4 ) 6 0 Sugawara, T. ( 1 ) 1 7 3 ; ( 2 ) 238; ( 7 ) 1 S u g i a r a , Y. ( 4 ) 7 8 S u g i h a r a , H. ( 4 ) 276 S u g i h a r a , Y. ( 1 ) 181 S u g i m a r a , H . ( 4 ) 257 Sugimura, H. ( 2 ) 7 4 Sugimura, T. ( 1 ) 181 S u g i n o , K. ( 2 ) 1 2 5 ; ( 6 i i ) 17 Suginome, H. (1) 145 S u g i t a , T. ( 3 ) 136 S u g i u r a , S. ( 5 ) 405 S u g i u r a , Y. ( 6 i ) 63 Sugiyama, H. ( 4 ) 127 Suh, H. ( 1 ) 56 S u l l i n s , D.W. ( 2 ) 102 Sum, F.W. ( 3 ) 188 Sumiya, T. ( 2 ) 236; ( 4 ) 228; ( 6 i ) 8 0 , 83 Summerhays, L.R. ( 1 ) 3 Sun, K.M. ( 3 ) 251 S u n d a r a r n o o r t h i , R . ( 5 ) 73 S u n d b e r g , R . J . ( 5 ) 356 Sundeen, J. ( 2 ) 133; ( 5 ) 137 S u r i , S.C. ( 5 ) 414 S u r y a Aakash, G . K . ( 6 i i ) 40 S u r y a w a n s h i , S.N. ( 3 ) 250 S u r z u r , J.-M. ( 8 ) 118 S u s u k i . H. ( 4 ) 210 S u s u k i ; Y. ( 4 j 42

Sutherland, J.K. ( 1 ) 6 ; ( 6 i ) 22 S u t o h , S. ( 2 ) 28 Suzukamo, G. ( 1 ) 153 S u z u k i , A. ( 1 ) 1 7 3 ; (3) 361; ( 4 ) 1 9 0 , 2 4 2 ; ( 5 ) 270, 3 1 4 , 346 S u z u k i , H . ( 3 ) 472; ( 4 ) 26; ( 5 ) 22; ( 6 i ) 8 2 ; ( 8 ) 126 S u z u k i , K . ( 1 ) 63; ( 2 ) 50; ( 4 ) 23, 173; ( 6 i i ) 7 8 ; ( 8 ) 115 S u z u k i , M. ( 2 ) 262; ( 5 ) 4 0 5 ; ( 6 i ) 4 3 ; ( 7 ) 18 S u z u k i , S . ( 3 ) 130; ( 5 ) 318 S u z u k i , T. ( 5 ) 205; ( 7 ) 29 S u z u k i , Y. ( 8 ) 192 Suzumoto, T. ( 3 ) 254 Swain, A.M.Z. ( 4 ) 306 Swain, C.J. ( 3 ) 291; ( 6 i i ) 66 Swaminathan, S. ( 2 ) 100; ( 3 ) 1 7 4 ; ( 7 ) 181 Swanson, T.A. ( 3 ) 310 Sweeney, J.N.A. ( 3 ) 2 4 , 293, 2 9 4 ; ( 9 ) 91 Swenson, C . J . ( 3 ) 250 Swenson, W . ( 3 ) 214 Swenton, J.S. ( 3 ) 297 S w i n d e l l , C . S . ( 7 ) 2 3 , 24 S y d n e s s , L.K. ( 3 ) 82 S y f r i g , M . A . ( 5 ) 100; ( 6 i i ) 34 S y p e r , L. ( 2 ) 3 4 ; ( 4 ) 1 5 2 ; ( 6 i i ) 158, 168 S z a n t a y , C. ( 2 ) 216 S z t a r i c s h a i , F. ( 5 ) 519 Tada, N. ( 4 ) 1 9 2 ; ( 5 ) 486 T a d d e i , M. ( 3 ) 2 6 5 ; ( 4 ) 105 T a g u c h i , K . ( 4 ) 276 T a i , A. ( 3 ) 321 T a j i m a , H. ( 5 ) 92 T a j i m a , K . (1) 4 6 ; ( 3 ) 3 3 , 3 4 , 269 Takada, Y. ( 7 ) 59 T a k a g i , K . ( 5 ) 92 T a k a h a s h i , H. ( 5 ) 205 Takahashi, K. ( 1 ) 8 4 , 9 3 ; ( 2 ) 128; ( 3 ) 199; ( 6 i ) 4 9 ; ( 8 ) 98 T a k a h a s h i , M. ( 2 ) 1 6 ; ( 3 ) 8 1 ; ( 4 ) 155 Takahashi, S. ( 3 ) 473; f 5 ) 315 T a k a h a s h i , T. ( 5 ) 4 3 ; ( 6 i ) 51; ( 6 i i ) 107; ( 7 ) 73

717

Author Index Takahata, H. (3) 413; (5) 224 Takai, K. (2) 77; (4) 114; (7) 174 Takajo, T. (5) 492 Takanaga, T. (3) 136 Takano, I. (2) 193 Takano, S. (3) 418; (9) 41 Takaoka, K. (4) 26; (5) 22 Takasaki, M. (1) 11; (3) 457 Takase, M. (4) 17; (5) 196 Takata, T. (8) 73 Takaya, H. (3) 453; (5) 135; (6i) 36 Takaya, T. (5) 188 Takayama, H. (9) 47 . Takechi, K. (4) 210 Takeda, A. (3) 194, 360; (5) 267 Takeda, H. (8) 192 Takeda, M. (9) 15 Takeda, T. (2) 50; (4) 274 Takeda, Y. (4) 82 Takei, H. (2) 74; (4) 257 Takei, Y. (7) 48 Takemasa, A. (3) 74 Takemasa, Y. (3) 151 Takenaka, H. (7) 162 Takeno, S. (3) 306 Takeshita, M. (1) 86; (2) 124; (6ii) 16 Taketomi, T. (5) 135; (6i) 36 Takeuchi, R . (5) 70, 256 Takeuchi, Y. (5) 421 Takeue, S. (1) 60; (4) 256 Takeyama, T. (4) 85 Takinami, S. (4) 190 Takiyama, N. (6i) 63 Takumura, N. (7) 148 Tam, J . P . (3) 403 Tamada, M. (2) 195 Tamai, H. (3) 363 Tamaka, M. (4) 144 Tamaki, K. (3) 41; (6ii) 165 Tamao, K. (1) 63; (2) 30, 270; (2) 30; (3) 6; (4) 84; (6ii) 42 Tamaoka, T. (4) 71; (5) 327 Tamariz, J. ( 3 ) 336 Tamarkin, D. (4) 207 Tamaru, Y. (1) 90; (2) 107; (3) 267, 380; (5) 297, 298; (6i) 38; (8)

78, 80, 163 Tamborski, C. (6i) 81 Tameo, K. (6ii) 92 Tamm, C. (3) 356 Tamoto, K. (4) 51 Tamura, 0. (2) 75; (5) 171; (6i) 54 Tamura, T. (1) 9; (3) 179; (5) 458 Tamura, Y. (2) 75; (3) 42, 52; (7) 10, 127 Tan, T.S. (7) 39 Tanabe, Y. (3) 140 Tanaka, H. (4) 192; (5) 486 Tanaka, J. (4) 86 Tanaka, K. (1) 107; (3) 283; (8) 163 Tanaka, M. (3) 132; (6i) 21; (9) 34, 35 Tanaka, S. (3) 105; (4) 301 Tanaka, T. (2) 26; (3) 464; (4) 125, 126; (5) 405 Tanaka, Y. (8) 30 Tang, P.-C. (6i) 90, 91, 93; (7) 159 Tangthongkurn, A. (8) 94 Tani, H. (8) 126 Tani, K. (5) 135; (6i) 36 Tani, Y. (4) 20 Taniguchi, H. (8) 149 Taniguchi, N. (3) 334, 335 Taniguchi, Y. (1) 111; (3) 366; (6ii) 6 Tanikaga, R. (3) 179 Tanimoto, S. (8) 74 Tanimoto, Y. (4) 39; (6ii) 76 Tanimura, K. (3) 424 Tanino, H. (9) 49 Tanis, S.P. (1) 108; (3) 288 Tanno, N. (3) 472 Tapolczay, D . J . (3) 291 Tardella, P.A. (8) 133 Tarhouni, R . (2) 174; ( 4 ) 204 Tarnchompoo, B. (8) 17 Taschi, O.A. (5) 554 Taschi, V.P. (5) 554 Taschner, M . J . (3) 316 Tashida,- H . (8)-119 Tashiro, M. (8) 98 Tatchell, A.R. ( 4 ) 41 (5) 26, 77 Tawarayama, Y. (4) 78 Taylor, D . J . (3) 446 Taylor, E.C. (3) 43; 5) 308

Taylor, G . J . (1) 155 Taylor, N. (3) 251 Teach, E . G . (8) 177 Teague, S . J . (7) 85; (9) 1 Teetz, V. (3) 420 ten Noever de Brauw, M.C. (8) 231 Teo, C . C . (3) 448; (5) 240 Teraji, T. (5) 494 Teramura, K. (8) 87 Terao, K. (2) 157; (8) 164 Terao, Y. (8) 115, 139 Terashima, S. (4) 42, 51 Terauchi, H. (5) 473 Tereda, S. (3) 13 Termine, E.J. (8) 159 Terpinski, J. (4) 196 Terpstra, J.W. (7) 5 Testaferri, L. (6ii) 159 Teung, B.W.A. (7) 13 Teutsch, G. (8) 254 Tezuka, T. (4) 265, 299; (8) 7 Thal, C. (8) 38 Thangaraj, K. (2) 100; (7) 181 Thea, S. (6ii) 148 Thebtaranonth, Y. (3) 142, 166; (7) 65; (8) 17 Theddore, M . S . (7) 183 Theuns, H.G. (8) 231 Thianpatanagul, S. (8) 145, 146 Thielert, K. (8) 185 Thieren, M . J . (5) 45 Thierry, J. (1) 2; (3) 57 Thiruvikraman, S.V. (6i) 82 Thomas, E.J. (2) 66; (5) 201; (6ii) 108 Thomas, J . A . ( 3 ) 417 Thomas, P.J. (3) 318; (9) 5 Thomas, R . D . (6ii) 22; ( 8 ) 31 Thomas, S.E. (1) 32; (4) 205; (6i) 12 Thompson, A.S. (9) 58 Thompson, D.W. (8) 45 Thompson, P.A. (3) 309; (4) 176 Thompson, W . J . (2) 185; (3) 135, 423; (5) 204; (6ii) 123 Thomsen, I. (3) 228, 229; (5) 295 Thorsen, M. (3) 230 Thuillier, A. (1) 150,

General and Synthetic Methods

718

151; (3) 233 Ticozzi, C. (3) 282; (6ii) 3 Tidwell, T.T. (2) 19 Tieco, M. (6ii) 159 Till, C.P. (3) 265; (9) 63 Timori, T. (3) 11 Tiner-Harding, T. (3) 83; (6ii) 7 Ting, P.C. (4) 233; (8) 11 Tingoli, M. (6ii) 159 Tinucci, L. (3) 110 Tirant, M. (5) 460 Tischenko, I.G. (2) 191 Tisler, M. ( 5 ) 422 Tius, M . A . (1) 97; (2) 89 Tixidre, A. (8) 38 Tobe, Y. (1) 18; (7) 82, 185; (9) 6, 15 Tobiki, H. (3) 472 Tobinga, S. (5) 265 Toder, B.H. (3) 201 Todeschini, R. (2) 251 Toteberg-Kaulen, S. (8) 160 Tohda, Y. (3) 144 Toki, T. (3) 130 Tokitoh, N . (5) 74, 112, 113 Tokoroyama, T. (7) 134 Tokuda, M. (1) 145 Tokunaga, T. (8) 222 Tokutake, N . (8) 247 Tollari, S. (6i) 35 Tomas, M. (5) 238, 490; (8) 144 Tomasini, C. (2) 150; (3) 267; (5) 210 tom Dieck, H. (5) 165,

489 Tometzki, G.B. (1) 6 Tomino, I. (3) 240; (4) 39; (6ii) 76 Tomioka, H. (5) 119 Tomioka, K. (2) 269, 277; (3) 151, 264; (6ii) 35; (9) 61 Tomita, K. (8) 120 Tomiyoshi, N. (7) 92; (9) 7 Tomoda, S. (5) 421 Tomooka, K. (6ii) 78 Tong-ti, T. (3) 29 Toniato, E. (8) 133 Toofan, J. (2) 11-13; (4) 151, 158, 247 Top, S. (3) 137 Torii, S. (2) 212; (4) 70, 101, 192; (5) 343,

486

Torisawa, Y. (4) 171; (7) 83 Torres, L.E. (1) 94; (2) 177; (3) 191; (6ii) 37 Torssell, K.B.G. (3) 160; (5) 303; (8) 86 Toshimitsu, A . (2) 157; (8) 164 Toth, I. (3) 455 Toth, J.E. (6ii) 27; (8) 33 Touchard, D. (5) 284 Toussaint, 0. ( 3 ) 54 Toy, A . (3) 423; (5) 204 Toyoda, H. (4) 2 Toyofuku, M. (2) 234 Toyota, H. (7) 145, 146 Trai, D.J.S. (4) 34 Tramontano, A . (3) 239; (4) 34; (5) 322; (9) 93 Traunecker, W. (5) 191 Trave, R. (8) 113 Tremont, S.J. (5) 260 Trimarco, P. (7) 53 Trimitsis, G. (2) 65; (6ii) 18 Triolo, S.A. (3) 470 Tripathy, P.K. (3) 437; (5) 138 Trivedi, G.K. (5) 431 Trofimov, B.A. (5) 128 Troisi, L. (4) 266 Trope, A . F . (7) 183 Trost, B.M. (1) 174; (2) 17, 99, 235; (3) 96, 97, 186, 352, 355; (4) 154; (6i) 27, 53; (6ii) 94, 154; (7) 123, 144, 187, 189 Troyansky, E.I. (2) 196 Trueblood, K.N. (4) 308 Trus, M.A. (7) 70 Tsai, D.J.-S. (1) 82; (3) 239; (4) 110 Tsai, Y.-M. (8) 178, 179; (9) 44 Tsankova, E. (7) 60 Tschaen, D.M. (3) 256; (5) 239 Tse, H . L . A . (7) 67 Tseng, C.K. (8) 177 Tsil'ko, A . E . (5) 149 TSO, H.-H. (1) 118 T s o i , L . A . (5) 278 Tsolomitis, A. (5) 291 Tsubata, K. (3) 432; (5) 242; (8) 158, 256 Tsuboi, S. (3) 194, 360; (5) 267 Tsuboniwa, N . (2) 244, 245; ( 3 ) 127 Tsuchida, T. (4) 274

Tsuchihashi, G. (4) 23, 173, 272; (6ii) 78; (7) 18 Tsuchiya, T. (8) 119 Tsuda, Y. (6ii) 166 Tsuge, 0. (2) 214; (3) 169; (4) 86; (5) 139, 474; (7) 104-108; (8) 143 Tsugoshi, T. (8) 210 Tsuji, J. (1) 85, 93; (2) 1, 29, 94, 114, 233; (3) 145, 154, 185, 196, 199; (4) 142; (5) 172; (6i) 2, 10, 20, 48, 49, 51; (7) 42, 73, 79, 138, 155 Tsuji, K. (5) 329 Tsuji, T. (8) 271, 272 Tsuji, Y . (5) 10, 65, 70, 256 Tsukamoto, M. (3) 105; (7) 134 Tsumiyama, T. (2) 188; (5) 150 Tsuno, S. (2) 104 Tsuno, T. (4) 287 Tsutsui, H. (3) 343 Tsutsumi, H. (5) 188 Tuchinda, P. (1) 87; (2) 126 Tufariello, J.J. (9) 33 Tuladhar, S.M. (7) 156 Tulshian, D.B. ( 3 ) 355 Tung, J.S. (5) 12 Turner, J.V. (1) 53; (2) 207; (4) 96 Turners, R.W. (7) 63 Turos, E. (3) 256; (5) 239 Tustin, G.C. (3) 94 Tvel, G. (7) 139 Twang, P.-W. (5) 148 Twitchin, B. (1) 53; (2) 207 Twohig, H.F. (7) 156 Uang, B.J. ( 8 ) 40; (9) 26 Uchida, K. (8) 158 Uchida, S. (8) 55 Uchida, Y. (5) 501 Uchimaru, T. (3) 357; (9) 77 Uchiyama, H. (4) 82 Udodong, U.E. (3) 291 Ueda, C. (4) 248; (5) 18 Ueda, K. (2) 25; (4) 287, 296, 297; (5) 92 Ueda, M. (3) 388; (5) 250 Ueda, S. (3) 472 Ueda, Y. (5) 523 Uehara, K. (8) 98

719

Author Index Uehara, S . - I . (2) 195 Ueki, M. (3) 478 Uemara, S. (2) 157 Uematsu, T. .(8) 61 Uemura, K. (5) 326 Uemura, M. (6i) 59 Uemura, S. (3) 41; (6ii) 165; (8) 164 Ueno, K. (2) 88; (6i) 44 Ueno, Y. (1) 102; (3) 277; (4) 167 Uesaka, M. (8) 84 Uff, B.C. (5) 353, 354 Uggeri, F. (3) 39 Uguen, D. (4) 275 Ukai, J , (1) 114, 115; (6ii) 90 Ukaji, Y. (5) 193, 194 Ukita, T. (1) 35; (2) 136 Umeda, N. (4) 38 Umezu, K. (3) 35 Uneyama, K . (4) 70, 101 Ungaro, R . (8) 34 Uno, M. (5) 315 Unverzagt, C. (3) 467 Urabe, H. (7) 40 Urata, Y. (5) 358 Urbanski, J. (5) 534 Urech, R . (9) 17 Urpi, F. (3) 364, 389; (5) 248, 257 Ushanov, V.Zh. (5) 278 Ushio, K. (3) 115; (4) 48 Usui, S. (9) 64 Usui, Y. (3) 363 Utimoto, K . (1) 64, 105, 168; (3) 273; (4) 98; (6i) 45; (6ii) 28; (7) 56 Utley, J.H.P. (8) 200 Uyehara, T. (7) 168 Vagberg, J. (6i) 31 Vaidya, N.A. (5) 235 Valdes, F. (5) 78 Valery, J . M . (2) 182 Valle, G. (5) 141 Valls, N. (8) 224 Valnot, J.-Y. (3) 410; (6ii) 8 Valoti, E. (3) 110 Valpey, R . S . (2) 117; (6ii) 103; (7) 19 Valzano, S. (5) 520 van Boom, J.H. (5) 506 van den Goorbergh, J.A.M. (3) 147 Van der Eycken, E. (3) 175; (5) 525 van der Gen, A. (2) 54; (3) 147; (5) 129-131;

(8) 168 van der Helm, D. (5) 414 van der Plas, H.C. (5) 94, 482 Vandewalle, M. (3) 175; (5) 524, 525 Van Elburg, P. (2) 54; (5) 130, 131 van Hummel, G.J. (8) 154 Vankar, Y.D. (2) 166 van Leusen, A.M. (1) 88, 89; ( 2 ) 127; (5) 373, 377 van Leusen, D. (1) 89; (5) 377 van Steene, B.J. (4) 307 van Veldhuizen, A. (5) 94 van Vuuren, G. (5) 451 Varaprath, S. (3) 298 Varghese, K.L. (3) 409 Varma, R.S. (5) 17, 395 Varney, M.D. (1) 49; (3) 32; (6ii) 83 Varvoglis, A. (3) 44; (4) 203 Vasella, A. (5) 223, 433, 435; (6i) 16; (8) 100 Vatale, J.-M. (1) 57; (2)

Vinczer, P. (2) 216 Vinet, V. (5) 523 Vishwakarma, L.C. (2) 140; (3) 107 Vishwanath, V.M. (2) 161; (5) 231 Visnick, M. (1) 95; (3) 192 Visser, G.W.M. (6ii) 56 Visser, R . (8) 153, 221 Voelter, W. (5) 183, 187 Vogel, P. (3) 336 Vollhardt, K.P.C. (6i) 7, 86; (7) 157, 158; (9) 22 von Angerer, E. (5) 24 von Schnering, H.-G. (3) 237; (6ii) 12 Vorbruggen, H. (5) 95, 533 Vriesema, B.K. (4) 303; (8) 234 Vrudhula, V.M. (4) 281 Vyalykh, E.P. (5) 128 Vyas, D.M. (1) 72; (3) 445 Vyaznikovetsev, L.V. ( 5 ) 278

48 Vaz, A.D.N. (2) 165 Vebrel, J. (3) 46 Vedejs, E. (2) 35; (3) 340, 358; (8) 72 Vekemans, J . (5) 57 Venkatesan, A.M. (9) 85 Veno, K. (7) 61 Verboom, W. (8) 153, 154, 221 Vercauteren, J. (8) 175, 204 Verhe, R. (2) 154; (8) 131 Vermeer, P. (6ii) 116 Vermeyen, C. (6ii) 124 Veronese, A.C. (5) 140, 141 Verschave, P. (5) 57 VeruoviE, B. (3) 401 Vessal, B. (2) 4; (4) 139; (5) 529 Viallefont, P. (3) 410, 413, 426 Vidari, G. (9) 16 Vigneron, J.P. (3) 241 Vilarrasa, J . (3) 364, 389; (5) 248, 257 Ville, G . (2) 182 Villemin, D. (3) 131 Villhauer, E.B. (3) 302; (6i) 52 Villieras, J . (2) 120, 174; (3) 174; (4) 204

Wachter, M.P. (8) 65 Wachtler, A . (1) 178; (7) 182 Wada, E. (7) 104-108 Wada, F. (6ii) 93 Wada, K. (4) 283 Wada, M. (1) 167; (2) 241; (5) 84, 85, 233; (6i) 62; (6ii) 71 Wade, A.R. (6i) 18 Wade, P . A . (5) 360; (8) 91 Wade, P.W. (5) 500 Wade, R . S . (5) 476 Wadsworth, A. (6i) 96; (9) 53 Wadsworth, D.H. (5) 136 Wagner, J. (5) 174 Wagner, K.-G. (5) 452, 528 Waher, J.-U. (8) 108 Waigh, R.D. (8) 203, 206 Wakabayashi, S. (3) 266; (5) 327; (7) 150 Wakefield, B.J. (9) 53 Waki, M. (3) 424 Wakita, A. (3) 182; (4) 273 Wakita, H. (1) 107; (3) 283 Wakselman, C. (3) 138 Wakselman, M. ( 3 ) 393

General and Synthetic Methods

720

Walborsky, H.M. (2) 222 Waldmann, H. (3) 467; (6i) 39 Waldron, R.F. (1) 182 Walker, D.G. (3) 291 Walker, J.C. (3) 20; (6i) 71 Wallace, B. (3) 31 Wallace, P.M. (1) 83; (5) 219; (9) 92 Wallace, T.W. (8) 19 Walts, A.E. (5) 202 Walz, P. (3) 203 Wang, B.C. (5) 199; (7) 109; (8) 93 Wang, C.-L.J. (8) 147; (9) 30 Wang, D. (7) 173 Wang, K.K. (2) 78 Wang, L.C. (7) 7 Wang, P.-C. (3) 80; (4) 229 Wang, Y.-F. (3) 259 Ward, A.D. (4) 188 Ward, J.G. (8) 226 Wardman, P. (5) 428 Warkentin, J. ( 4 ) 5 Warner, J.C. 441-443 Warner, P. (3) 20; (4) 64; (6i) 69, 71, 73 Warren, S. (1) 83 Wasserman, H.H. (8) 265, 266 Waszkuc, N. (6ii) 127 Waszkuc, W. (2) 147 Watanabe, A . (5) 310, 311 Watanabe, H. (3) 121; (8) 60, 61 Watanabe, M. (3) 322, 376; (6ii) 1 Watanabe, N. (4) 146; (6i) 19 Watanabe, T. (5) 406; ( 7 ) 69 Watanabe, Y. (4) 127; (5) 10, 65, 70, 256; (6i) 20; (8) 152; (9) 34 Waterhouse, J. (4) 284 Waterman, K.C. (6ii) 10 Waters, B. (6i) 37 Waterson, D. (2) 232; (3) 89, 129 Watkins, J.C. (3) 281; ( 7 ) 80 Watt, D.S. (2) 144, 149; (4) 88; (6ii) 155 Wattanasin, S. (2) 45 Watts, A.E. (9) 79 Watts, M.E. (5) 428 Watts, 0. (6i) 68 Webb, R.R. I1 (8) 39 Webber, S. (1) 187

Weber, J.V. (6ii) 157 Weber, T. (3) 412 Weidner, C.H. (5) 136 Wei-hua, X. (1) 92; ( 3 ) 29; (6ii) 70 Weiler, L. (3) 188, 189 Weinreb, S.M. (3) 256; (5) 120, 216-218, 239; (8) 123, 124, 193; (9) 40, 67 Weinstein, S. (3) 428 Weinstock, L.M. (3) 414 Weisheit, R. (8) 112 Weiss, K. (5) 472 Weiss, M.M. (5) 221, Weiss, R. (5) 452, 528 Weiss, U. (7) 72 Weissler, M. (5) 445 Welch, C.J. (5) 63, 99 Welker, M.E. (6i) 70, 72 Wellard, N.K. (6i) 34; (8) 216; (9) 45 Weller, T. (5) 401 Wells, G.J. (6ii) 102; (7) 13, 14 Welvart, Z. (6ii) 32 Wendler, N.L. (9) 72 Wenkert, E. (1) 113 Wensing, M. (1) 61 Werblood, H.M. (8) 65 Wester, R.T. (9) 87 Wetzel, D.M. (3) 211 Weyerstahl, P. (7) 3 Wheeler, T.N. ( 3 ) 204 Whitby, R.J. (8) 21 White, E.H. (5) 439 Whitesell, M.A. (6ii) 126 Whitfield, D.M. (4) 286 Whitham, G.H. (3) 234; (8) 79 Whiting, D.A. (3) 265; (8) 22; (9) 63 Whiting, M.C. ( 4 ) 195 Whitney, D.B. (3) 403 Whitney, R.A. (8) 90; (5) 120 Whittle, R.R. (5) 217, 218; (8) 123, 124; (9) 67 Wiemer, D.F. ( 2 ) 38; (6ii) 82; (8) 29 Wiessert, W. (5) 337 Wiessler, M. (5) 437 Wightman, R.H. (3) 260 Wilcox, C.S. (1) 54, 56 Wild, J. (3) 436 Wildsmith, E. (5) 46 Wilenberg, W. (8) 227 Wilhelm, R.S. (2) 258, 259; (3) 90; (6i) 6 Wilkinson, M.R. (3) 210 Willer, R.L. (5) 440

Williams, D.J. (2) 205; (4) 32, 306; (6ii) 58; (8) 54; (9) 78 Williams, D.R. (4) 234; (8) 12, 13; (9) 60 Williams, M.J. (8) 207 Williams, R.M. (9) 48 Williamson, H. (6ii) 73 Willis, A.C. (8) 173 Willison, D. (2) 91; (6i) 94; (8) 20 Wilson, J.R.H. (7) 178 Wilson; J.Z. ( 4 j i29; (6ii) 98 Wilson, S.R. (1) 51; 3) 139; (9) 85 Wilson, W.S. (5) 383 Wingfield, M. (7) 71 Winiarski, J. (3) 209 (5) 389, 390, 393; (6ii) 26 Wintel, T. (5) 208 Winter, C.H. (7) 5 Winterfeldt, E. (3) 346 Winzenberg, K.N. (8) 230 Wipf, P. (8) 95 Wissinger, J.E. (9) 13 Wistrand, L.-G. (8) 157 Wittmann, D.K. (5) 398 Woderer, A . (5) 337 Woell, J.B. (3) 93, 206; (4) 213, 214 Wojciechowski, K. (3) 407, 463 Wolf, W.M. (5) 219; (9) 92 Wolfe, S. ( 5 ) 403 Wolfel, G . (5) 42, 48 Wolff, M. (3) 460 Wolff, S. (7) 27 Wolff, W.D. (7) 159 Wollmann, T. (3) 40 Woodcock, M. (5) 428 Woodgate, P.P. (5) 542 Woodgate, S.D. (5) 542 Woodward, R.W. (2) 39 Woolley, G.T. (9) 53 Worakun, T. (1) 125 Wright, M.E. (2) 109; (6i) 89; (6ii) 112 Wright, M.W. (4) 217 Wright, R.G.McR. (5) 35 Wright, S.W. (3) 227 Wrobel, J.E. (3) 323; (4) 103 Wrobel, L. (5) 534 Wrubel, J. (5) 55 WU, X.-M. ( 9 ) 84 Wu, Y.M. (5) 532 Wuest, J.D. (4) 14 Wulff, G. ( 3 ) 440 Wulff, W.D. (6i) 90-93

Author Index 6 Wurtwein, E.-U. (5) -480 Wuts, P . G . M . (3) 309; (4) Yamauchi, T. (3) 41; (6ii) 165 176; (6ii) 61 Yamazaki, S. (5) 194; 535 Wydra, R. (1) 30 Yamazaki, Y. (5) 211 Wyles, M . J . (8) 195 Yan, T.-H. (6ii) 102; (7) 13, 14 Yanagi, K. (3) 267; (8) Xi, S.-K. (3) 466 61 XU, Z.-B. (5) 199; (7) Yanagi, T. (1) 186; (6ii) 109; (8) 93 156 Yanagisawa, E . (5) 314; 346 Yadav, V.J. (8) 214 Yanagiya, M . (7) 92; (9) Yagi, S. (5) 313 7 Yamada, H. (3) 472 Yanaka, T. (3) 451 Yamada, M . (3) 240 Yanami, T. (3) 162 Yamada, S. (3) 390; (5) Yanaura, S. (5) 205 266; (8) 114 Yamada, T. (3) 394, 398, Yang, D.C. (6i) 92 Yang, 1.-W. (5) 423 421; (5) 306 Yamada, Y. (1) 153; (6i) Yang, S.H. (7) 17 Yang, T.-K. (8) 258 38; (7) 179; (9) 54 Yang, Y.-L. (1) 59; (2) Yamagata, T. (5) 135; 52; (7) 149 (6i) 36 Yamagishi, T. (1) 10; (3) Yano, S. (8) 26 Yano, T. (4) 69 454, 456 Yamaguchi, K. (7) 59; (8) Yano, Y. (2) 28 Yanovskaya, L . A . (8) 23 181 Yasuda, H. (1) 1?2; (2) Yamaguchi, M . (1) 166; 75; (3) 52 (3) 105, 300, 323, 342, 366, 367; (4) 97, 104, Yasuda, N . (5) 188, 292 106, 241; (6ii) 6; (7) Yasui, S. (3) 115 Yasunaga, H. (4) 131 9 Yatabe, M. (3) 451 Yamaguchi, R. (3) 25 Yatagai, H. (3) 312; (4) Yamaguchi, T. (9) 64 Yamakawa, K. (2) 156 66, 79 Yatagai, M. (1) 10; (3) Yamamoto, H. (1) 114, 454, 456 115; (2) 86, 87, 122, 266, 267; (3) 193, 331; Yates, B.F. (5) 364 Yates, P . (2) 32; (5) 522 (4) 75, 93, 94; (6ii) 79, 81, 90; ( 7 ) 43-45; Yavarzadeh, R. (7) 160; (8) 174 (9) 69 Yde, B. (3) 229; (5) 295 Yamamoto, I. (5) 548 Yamamoto, K. (2) 94; (4) Yeates, C. (8) 56; (9) 57 40, 292; (6ii) 75; (7) Yelm, K.E. (1)-127; (6ii) 118 138, 155 Yamamoto, T. (5) 158, 473 Yen, H.-K. (8) 91 Yamamoto, Y. (1) 146, Yeon, N . M . (4) 31 170; (2) 206; (3) 128, Yijun, C. (6i) 77; (8) 129, 305, 312; (4) 61, 239 66, 79; (5) 61, 82, 83, Yoakim, C. ( 2 ) 218; (4) 540; (6ii) 110 122, 135; (6ii) 97 Yamamura, T. (3) 473 Yoda, H. (1) 107; (3) 283 Yoda, N . (3) 451 Yamanaka, H. (5) 89 Yamanoi, T. (4) 45; (6ii) Yoh, K.-L. (7) 7 Yohannes, D. (5) 352 59 Yokota, K. (7) 59 Yamashita, M . (4) 179; Yokoyama, M . (1) 14; (3) (5) 79; (7) 18 Yamashita, S. (7) 185; 229, 231; (4) 11, 78; 85; (5) 3, 294, 314, (9) 6 329, 346; (6ii) 142 Yamashita, T. (2) 269; (6ii) 35; (7) 185; (9) Yoneda, F. (1) 41; (2)

72 1 24, 27; (3) 195 Yoneda, R. (5) 317 Yoneda, S. (8) 183 Yonemitsu, 0 . (4) 125, 126 Yong-ti, T. (1) 92; (6ii) 70 Yonovich-Weiss, M. ( 4 ) 194 Yoo, B.K. (2) 20 Yoon, N.M. (2) 37 Yoshida, D. (5) 473 Yoshida, H. (8) 53 Yoshida, J. (8) 26 Yoshida, J.-I. (2) 22 Yoshida, K. (7) 117, 118 Yoshida, Y. (5) 246 Yoshida, Z. (1) 90; (2) 107; (3) 267, 380; (5) 297, 298; (6i) 38; (7) 127; (8) 78, 80, 163 Yoshigi, M . (3) 52 Yoshihara, M. (8) 114 Yoshikoshi, A. (3) 25, 162, 303 Yoshimura, T. (4) 252 Yoshinaga, T. (4) 69 Yoshioka, H. (1) 153; (3) 332; (5) 209; (7) 29, 129 Yoshioka, T. (4) 125 Youeda, N . (4) 242 Young, D.M. (3) 211 Young, D.W. (6i) 41 Young, J.-J. (8) 194 Young, R.G. (5) 15 Young, S.D. (3) 125 Yousif, N . M . (3) 229; (5) 295 Yu, C.-M. (1) 45; (3) 33 Yuan, L.-C. (3) 257 Yuasa, Y. (5) 327; (8) 197 Yurtanov, A.I. (5) 415 Yus, M . (3) 242, 365; (5) 87, 285; (6ii) 52; (8) 162 Yusa, S. (4) 299 Zacharie, B. (4) 14 Zagatti, P. (3) 241 Zaichenko, Yu.A. ( 5 ) 149 Zajdel, W.J. (3) 374; (5) 105, 110 Zama, M. (3) 456 Zamarlik, H. (3) 245 Zanirato, V. (2) 123 Zanotti, G . (5) 140, 141 Zapata, A . (3) 85 Zard, S.Z. (2) 226; (3) 55; (5) 28, 469

722

General and Synthetic Methods

Zarrinmayeh, H. (5) 496 (3) 183; ( 5 ) 375; ( 6 i i ) 119; ( 9 ) 94 Zaugg, H.E. ( 2 ) 240; ( 3 ) Z i e g l e r , F.E. ( 6 i i ) 95; 254, 371; ( 5 ) 286, 287 ( 7 ) 75, 76; ( 9 ) 8 7 Zavyalov, S . I . (5) 503 Z i e l i n s k i , P.A. (5) 58 Z b i r a l , E. ( 2 ) 56 Zimmer, H. ( 5 ) 126 Z e f i r o v , N.S. ( 5 ) 403 Zimmerman, S.C. (3) 411; Z e l e n i n , K.N. (5) 459 Z e l l e , R.E. ( 8 ) 15 ( 9 ) 32 Zimmerrnann, R . G . ( 6 i i ) Z e l l e r , 'W.E. ( 7 ) 126 146 Zenki, S . - i . ( 5 ) 550, 551 Z i n n e r , G. ( 5 ) 465 Zhao, Y.-F. ( 3 ) 466 Zioudrou, C. (3) 384 Zhelyaeva, I . M . ( 5 ) 114 Zon, J. (5) 415 Z i e g l e r , C.B. (1) 190;

Z r e i k a , M. ( 5 ) 174 Z u b r i t s k i j , L.M. ( 5 ) 416 Zucker, P.A. ( 9 ) 85 Ziiger, M.F. ( 3 ) 1 1 8 , 119, 121; ( 4 ) 54 Zul'Karnaev, R . I . ( 5 ) 280 Zupan, M. (2) 170 Zwanenburg, B. ( 2 ) 152; ( 5 ) 484 Z w e i f e l , G. ( 1 ) 169; (3) 238; ( 4 ) 77; ( 6 i i ) 4 6 , 104 Zyk, N.V. ( 5 ) 403