General and synthetic methods

General and Synthetic Methods Volume 10 A Specialist Periodical Report General and Synthetic Methods Volume I 0 A R...

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General and Synthetic Methods Volume 10

A Specialist Periodical Report

General and Synthetic Methods Volume I 0

A Review of t h e Literature Published in 1985 Senior Reporter G. Pattenden, Department of Chemistry, University of Nottingham Reporters K. Carr, University of Nottingham K. Cooper, Pfizer Central Research, Sandwich, Kent D. J. Coveney, University of Nottingham S. G. Davies, University of Oxford T. Gallagher, University of Bath L. M. Harwood, University of Oxford D. W. Knight, University of Nottingham T. V. Lee, University of Bristol S. G. Lister, Wellcome Research Laboratories, Beckenham, Kent K. E. B. Parkes, Roche Products Limited, Welwyn Garden City, Herts. N. Simpkins, Queen Mary College, University of London P. J. Whittle, Pfizer Central Research, Sandwich, Kent

..*

-,

SOCIETY OF EMI STRY

"-a.

s"-

ISBN 0-85 186-9 14-9 ISSN 0141-2140 Copyright 0 1988 The Royal Society of Chemistry All Rights Reserved No part of this book may be reproduced or transmitted in any form or by any means-graphic, electronic, including photocopying, recording, taping or information storage and retrieval systems-without written permission from the Royal Sociery of Chemistry Published by The Royal Society of Chemistry, Burlington House, London, W 1V OBN Printed in England by Staples Printers Rochester Limited, Love Lane, Rochester, Kent.

Introduction This tenth Report on General and Synthetic Methods, and the second volume to be produced from camera-ready copy of manuscripts, covers the literature from January to December, 1985. The general aim of the Reports remains as set out in earlier volumes. Whilst our contributors strive to provide a critical and comprehensive summary and assessment of reactions and methods in synthetic organic chemistry which appear to be useful to the practitioner, this task has become increasingly onerous with time, as a consequence of the explosive and rapid development in the subject over the past decade or so. Nevertheless, these features, together with the theme of 'selectivity' i.e. chemo-, regio-, diastereo- and enantio-selectivity, in organic synthesis remain as our prime focus. We welcome any comments and suggestions for improving the coverage and presentation of future Reports in this series. G.

V

Pattenden

Contents

Chapter 1 Saturated and Unsaturated Hydrocarbons

1

B y N . Simpkins

1 1 11 13 17 21 24 26

1 Saturated Hydrocarbons 2 Olefins 3 Conjugated 1,3-Dienes 4 Non-conjugated Dienes 5 Allenes 6 Alkynes 7 Enynes and Diynes 8 Polyenes

32

Chapter 2 Aldehydes and Ketones By K . E . B .

Parkes

1 Synthesis of Aldehydes and Ketones Oxidative Methods Reductive Methods Methods Involving Umpolung Other Methods Cyclic Ketones 2 Synthesis of Functionalized Aldehydes and Ketones Unsaturated Aldehydes and Ketones a-Substituted Aldehydes and Ketones Dicarbonyl Compounds 3 Protection and Deprotection of Aldehydes and Ketones 4 Reactions of Aldehydes and Ketones Reactions of Enolates Aldol Reactions Conjugate Addition Reactions Chapter 3 Carboxylic Acids and Derivatives By D . W .

32 32 35 36 38 43 47 47 49 55 57 59 59 64 66 75

Knight

1 Carboxylic Acids General Synthesis Diacids Hydroxy-acids Keto-acids Unsaturated Acids Anhydrides Carboxylic Acid Protection Decarboxylation 2 Carboxylic Acid Esters Ester ification General Synthesis

vii

75 75 77 78 83 83 86 86 87 88 88 90

Contents

viii Diesters Hydroxy-esters Keto-esters Unsaturated Esters Aromatic Esters Acetylenic Esters Allenic Esters and Dienoates Thioesters 3 Lactones 0-Lactones Butyrolactones a-Methylenebutyrolactones Butenolides Tetronic Acids Phthalides Valerol actones Macrolides 4 Carboxylic Acid Amides General Synthesis Hydroxy-amides Keto-amides Unsaturated Amides Thio- and Seleno-amides 5 Amino-acids a-Amino-acids B-Amino-acids y -Amino-acids Unsaturated a-Amino-acids Carboxylic Acid Protection Amino Group Protection Thiol Group Protection Chapter 4 Alcohols, Halogeno-compounds, and Ethers By L . M .

93 96 101 109 117 120 120 122 124 124 124 135 136 140 142 142 146 150 150 151 153 153 156 156 156 165 167 167 169 169 172 187

Ha r w o o d

1 Alcohols Preparation by Addition to Alkenes Preparation by Reduction of Carbonyl Compounds Chemoselective Carbonyl Reductions Stereoselective Carbonyl Reductions Asymmetric Carbonyl Reductions Enzymic Asymmetric Carbonyl Reductions Preparation by Nucleophilic Addition General Methods of Preparation Protection and Deprotection Reactions of Alcohols Oxi da t ion Hydrogenation and Deoxygenation Miscellaneous Reactions 2 Halogeno-compounds Preparation from Alcohols Interhalide Conversions Miscellaneous Preparations React ions Dehalogenation Acylation and Coupling Reactions Miscellaneous Reactions 3 Ethers Preparation Reactions 4 Thiols and Thioethers

187 187 187 188 188 190 192 192 203 205 207 207 208 2 08 212 212 214 214 216 216 216 218 218 218 220 222

ix

Contents

Chapter 5 Amines, Nitriles, and Other Nitrogencontaining Functional Groups

230

B y S.G. L i s t e r 1 Amines Primary Amines Secondary Amines Tertiary Amines D iamines 2 Enamines 3 Allylamines, Homoallylamines, and Alkynylamines 4 Amino-alcohols and Related Compounds 5 Amino-carbonyl Compounds 6 Amino-esters 7 Amides, Thioamides, and Selenocarboxamides 8 Nitriles and Isocyanides 9 Nitro- and Nitroso-compounds 10 Hydrazines and Hydrazones 11 Hydroxylamines and Hydroxamic Acids 1 2 Imines, Iminium Salts, and Related Compounds 1 3 Oximes 1 4 Carbodi-imides 1 5 Azides and Diazo-compounds 1 6 Azo- and Azoxy-compounds 1 7 Isocyanates, Thiocyanates, Isothiocyanates, Selenocyanates, and Isoselenocyanates 1 8 Nitrones 1 9 Nitrates and Nitrites

Chapter 6 Organometallics in Synthesis B y S.G.

PART

230 230 235 240 241 242 245 249 2 64 264 265 275 284 294 294 295 300 301 301 304 304 307 307 320

Davies and T. Gallagher

I: The Transition Elements

320

B y S.G. Davies

1 Introduction 2 Reduction 3 Oxidation 4 Rearrangements and Isomerizations 5 Carbon-Carbon Bond Formation via Organometallic Electrophiles via Organometallic Nucleophiles via Coupling Reactions via Carbonylation Reactions 6 Miscellaneous Reactions PART 11: Main Group Elements

320 320 322 322 325 325 325 333 343 347 354

B y T . Gallagher 1 Group I Selective Lithiations Dianions and Alkenyl and Alkynyl Anions Sulphur-stabilized Anions 2 Group I1 Magnesium Zinc and Mercury

354 354 362 367 369 369 373

Contents

X

375 375 379 381 381 381 386 388 395 395 401 401 401 406

3 Group I 1 1

Boron Aluminium and Thallium 4 Group IV Si 1icon Allyl- and Vinyl-silanes Other Silicon-containing Reagents Tin and Lead 5 Group U Phosphorus Arsenic, Antimony, and Bismuth 6 Group V I Sulphur Selenium and Tellurium

416

Chapter 7 Saturated Carbocyclic Ring Synthesis By T . V . L e e

1 Three-membered Rings 2 Four-membered Rings 3 Five-membered Rings General Methods Fused Five-membered Rings Naturally Occurring Fused Cyclopentanoids 4 Six-membered Rings Diels-Alder Reactions Other Syntheses of Six-membered Rings Polyene Cyclizations 5 Seven-membered, Medium, and Large Rings 6 Ring Expansion Methods 7 Spiro-ring Compounds

416 4 18 418 4 18 424 434 437 437 440 443 446 446 450 457

Chapter 8 Saturated Heterocyclic Ring Synthesis By K . C o o p e r a n d P . J .

Whittle

1 Oxygen-containing Heterocycles Three- and Four-membered Rings Five-membered Rings Tetrahydrofurans Dihydrofurans Six-membered Rings Tetrahydropyrans Dihydropyrans [5.n]Spiroacetals Six-membered Rings with More than One Oxygen Seven- and Eight-membered Rings 2 Sulphur-containing Heterocycles 3 Heterocycles Containing More than One Heteroatom Nitrogen- and Oxygen-containing Rings Five-membered Rings Six- and Seven-membered Rings Nitrogen- and Sulphur-containing Rings Oxygen- and Sulphur-, and Nitrogen-, Oxygen-, and Sulphur-containing Rings 4 Nitrogen-containing Heterocycles

’

457 4 57 460 460 4 69 472 472 472 477 477 479 479 486 486 486 488 491 494 494

xi

Contents

Three- and Four-membered Rings Five-membered Rings Six-membered Rings Six-membered Rings Containing Two Nitrogens 5 8-Lactams, Penicillins, Cephalosporins, and Related Compounds Chapter 9 Highlights in Total Synthesis of Natural Products By K.E.B.

494 494 515 527 531 550

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

1 Terpenes 2 Steroids 3 Anthracyclinones and Naphthaquinones 4 Alkaloids 5 Prostaglandins and Thromboxanes 6 Spiroacetals 7 Sugars 8 Macrolides and Ionophores 9 Other Natural Products Reviews on General and Synthetic Methods Compiled by K . Carr, D . J .

596

C o v e n e y , and G . P a t t e n d e n

1 Olefins 2 Aldehydes and Ketones 3 Esters and Lactones 4 Fluoroorganic Compounds 5 Organometallics General Transition Elements Main Group Elements 6 Carbocyclic Ring Synthesis 7 Heterocycles 8 Natural Products 9 Enzymic Reactions and Asymmetric Synthesis 10 Oxidation 11 Reduction 12 Protective Groups 13 Radical Chemistry 14 General 15 Miscellaneous Author Index

550 557 557 564 574 578 581 583 585

596 59 6 59 6 596 597 597 59 7 598 599 599 600 600 601 601 602

602 602 603 604

1 Saturated and Unsaturated Hydrocarbons BY N. SlMPKlNS

A c a t a l y s t c o m p r i s i n g f u s e d i r o n p r o m o t e d b y V205 i s e x t r e m e l y

e f f i c i e n t i n t h e gas-phase hydrodeoxygenation o f ketones and a l c o h o l s a t r e l a t i v e l y low p r e s s u r e s .

'

Reductive decyanation o f a

v a r i e t y o f n i t r i l e s can be accomplished very cleanly using potassium metal i n c o m b i n a t i o n w i t h a crown e t h e r . 2

The u s e o f u l t r a -

s o u n d a l l o w s f o r s h o r t r e a c t i o n t i m e s i n t h e r e a c t i o n o f gemd i h a l o g e n o p r o p a n e s w i t h v a r i o u s metals t o form t h e u s u a l c a r b e n o i d derived products.'

The r e d u c t i o n o f C-C

m u l t i p l e bonds h a s been

found t o t a k e p l a c e i n t h e presence o f p l a t i n i z e d Ti02 under i l l u minated

condition^.^

A variety of unsaturated substrates react,

a l t h o u g h t h e r e a c t i o n times a r e q u i t e l o n g method f o r c o n j u g a t e r e d u c t i o n o f

(c. 26

a,B-unsaturated

h).

A useful

ketones and alde-

h y d e s i n v o l v e s r e a c t i o n w i t h d i p h e n y l s i l a n e c a t a l y s e d by Pdo i n c o m b i n a t i o n w i t h ZnC12.

E x c e l l e n t y i e l d s o f r e d u c e d compounds

were o b t a i n e d u s i n g t h i s m e t h o d , w h i c h d o e s n o t a f f e c t

a,B-

u n s a t u r a t e d n i t r i l e s o r esters (Scheme 1 ) . T h e u s e o f a trialkylaluminium-alkylidene i o d i d e m i x t u r e t o e f f e c t c y c l o p r o p a n a t i o n has been re-examined.

f o u n d t o w o r k w e l l when c o n d u c t e d i n C H 2 C 1 2 ,

T h e r e a c t i o n was and shows c o n t r a s t i n g

r e g i o s e l e c t i v i t y t o t h e Simmons-Smith r e a g e n t i n r e a c t i o n w i t h g e r a n i o l ( S c h e m e 2 1. A new m e t h o d w h i c h a l l o w s e n a n t i o s e l e c t i v e c y c l o p r o p a n a t i o n o f

u,b-unsaturated

esters.

aldehydes employs acetals d e r i v e d from t a r t r a t e

The method a p p e a r s o p e r a t i o n a l l y s t r a i g h t f o r w a r d a n d

g i v e s good y i e l d s and enantiomeric e x c e s s e s ( e . e . )

(Scheme 3 ) .

2 Olefins S o d i u m b o r o h y d r i d e c a n now b e u s e d f o r t h e r e d u c t i o n o f acetylenes, system.

b y e m p l o y i n g a NaBH4-PdCl2-po1yethylene

glycol-CH2C12

A v a r i e t y o f r e d u c e d p r o d u c t s were o b t a i n e d i n c l u d i n g

cis-

For References see p - 29

1

General and Synthetic Methods

2

Scheme 1

Bd3Al, CH,I,

76

1

EtzZn, C H , I ,

2

74

+

4 3

Scheme 2

k 88 Scheme 3

- 94%

e.e.

3

I : Saturated and Unsaturated Hydrocarbons o l e f i n s and f u l l y reduced materials. The u s e o f t r a n s i t i o n m e t a l c a t a l y s t s f o r d e h y d r o g e n a t i o n o f a l k a n e s h a s r e c e i v e d more a t t e n t i o n . [(Pri3P)21rH

5

The i r i d i u m complex

] exhibits unusual selectivity f o r t h i s type of

reaction i n t h a t methyl groups a r e attacked preferentially. S i m i l a r l y , a p h o t o l y t i c d e h y d r o g e n a t i o n r e a c t i o n was o b s e r v e d u s i n g

[IrH ( C F C O ) ( P R ) 1 , e v e n i n t h e a b s e n c e o f t h e u s u a l h y d r o g e n 2 3 2 3 2 acceptor t-butylethylene. The r e d u c t i v e r e m o v a l o f a l l y l i c o x y g e n a t e d f u n c t i o n s c a n b e carried out effectively using nickel boride.

Allylic alcohols

a n d t h e i r s i l y l e t h e r s r e a c t , a l t h o u g h t h e y r e q u i r e much l o n g e r r e a c t i o n times t h a n t h e c o r r e s p o n d i n g a c e t a t e s (Scheme

4).

Another

new d e o x y g e n a t i o n p r o c e d u r e c o n s t i t u t e s t h e l a t e s t c o n v e r s i o n o f epoxides i n t o t h e corresponding o l e f i n s , and u t i l i z e s a r y l s e l e n o carboxamides. l 2

The method i s s t e r e o s p e c i f i c ( r e t e n t i o n ) a l t h o u g h

i t r e q u i r e s t h e p r e s e n c e o f a s t r o n g a c i d ( C F C O H) a n d d o e s n o t

3

2

c o n v e r t more s t e r i c a l l y h i n d e r e d e p o x i d e s s u c h a s n o r b o r n e n e o x i d e . Luche h a s r e p o r t e d t h e r e a c t i o n o f c a r b o n y l compounds w i t h a l l y l i c h a l i d e s i n aqueous media.

The r e a c t i o n c a n b e p e r f o r m e d

u s i n g e i t h e r z i n c or t i n , a n d d i s p l a y s g o o d c h e m o s e l e c t i v i t y b e t ween a l d e h y d e s a n d k e t o n e s (Scheme 5 ) . Asymmetric c o u p l i n g o f a r y l G r i g n a r d s w i t h a l l y l i c p i v a l a t e s i s p o s s i b l e i n good e.e.

by u s e o f N i C l 2 [ ( S , S ) - c h i r a p h o s I

c a t a l y t i c ( 1 mol % ) a m o u n t s . l 4

i n only

Another a l l y l i c coupling r e a c t i o n

u s e s palladium t o mediate displacement o f a n acetoxy-group a l l y l i c g e m i n a l d i a c e t a t e by a s t a b i l i z e d n u c l e o p h i l e ,

frbm a n

x.

Scheme 6 .

Depending upon t h e s u b s t i t u e n t s p r e s e n t on t h e r e a c t i n g

partners,

t h e r e g i o s e l e c t i v i t y alters and a v a r i e t y of products can

be prepared.

A number o f a l l y l a t e d a n d r e l a t e d p r o d u c t s h a v i n g q u a t e r n a r y c a r b o n a t o m s may b e p r e p a r e d b y r a d i c a l c h e m i s t r y s t a r t i n g f r o m 16 t e r t i a r y alcohols. A l l y l s t a n n a n e s h a v e b e e n p r e p a r e d i n a r e g i o s e l e c t i v e f a s h i o n by

a selenoxide elimination r o u t e , l7 of hydrocarbons.”

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

T h e l a t t e r p r o c e d u r e when c o m b i n e d w i t h a

protodestannylation s t e p enables isomerization of various terpenes,

e.g. S c h e m e 7.

A number o f r e p o r t s h a v e f o c u s e d i n t e r e s t o n t h e s y n t h e s i s o f v a r i o u s a l l y l i c s u l p h u r compounds. A one-pot procedure f o r t h e p r e p a r a t i o n o f a l l y l i c s u l p h i d e s from t h e c o r r e s p o n d i n g a l c o h o l s i n v o l v e s i n i t i a l r e a r r a n g e m e n t of t h e x a n t h a t e f o l l o w e d by


4

7sH17

7aH17

Nickel boride, diglyrne, R T

*& R = COMe, 98% after 10 min R = SiMe3, 80% after 6 h Scheme 4

OH

92 -98"Io (one diastereomer 1

Scheme 5 C02Me

I Ph

C 0 2 Me

C02Me

10% P d k

T

O

OAC A '

R

Pyrolysis

Scheme 8

>CHCH2SPh

“”13

/

Me

PhSNa. HMPA

‘GHl3

‘

Ch eC i=CH,

( 2 ) 77”/0, E / Z mixture

0,” (1)

C6H13\

CMeCH=CH2

Ph0,S’

( 3 ) 96’10 Scheme 9

- R22Bg R3sxH R 3S

i

IC-CR’

I

Reagents

1,

RZZBH,THF,

11,

LL

R’

R3SMg6r, -5O’C

to RT,

R*, B

111,

R’

Bu”L1, 6 M NaOH(aq 1

Scheme 10

n

7

1 : Saturated and Unsaturated Hydrocarbons

RXH

[ Pd(PPh3)41 1 m o l '1.

R-C

m

EC-H

48 h, 60 - 7 0 'C

+

Me3Sn

SiMe,

Me3Si -SnMe, (neat)

I,

RC=CH

Reagent, CuCN

+

ii, H,O+

H

SiMe,Ph

RXH PhMe2Si

(5)

R = THPOCH,CH,

H

(6)

Reagent =(PhMe2Si)3ZnMgMe

100

:0

97 % yield

1

: 99

87V0 yield

Reagent = PhMe2SiZnButzLi

Scheme 11

i

-eC 111

QoH ' 6 P h

Ph3pY (7) H

Li

Reagents: i, ButLi, - 7 8 *C, then at 2 3 'C for 2.5 h; ii; Cyclopentene oxide (17 h, 23.C); PhCHO(6 h, 2 3

*C); iii, Fenchone, HMPA; ButOH Scheme 12


8

H Ph 3P =CH,

Ph3P=C/

‘Br

1

B ? L ~( 2 . 0 equiv.)

+ -

Ph,P-CH,

bLi

(7)

(9) Scheme 13

&OR

EtPPh3Br, K H M p

&OR

+

6

1

? T O R R =Ac R =CH,Ph

36 Scheme 14

Reagents

1,

BUnL1, Me3SnCH21,

11,

Bu4NF

Scheme 15

0

I : Saturated and Unsaturated Hydrocarbons

9

t o d i f f e r e n c e s e v i d e n t i n t h e r e a c t i o n c o n d i t i o n s u s e d by e a c h group and p a r t i c u l a r l y t h e temperatures used f o r t h e second metal-

l a tion. A v e r y d i r e c t e l e c t r o c h e m i c a l method f o r t h e p r e p a r a t i o n o f 1-

cycloalkenyltriphenylphosphonium s a l t s h a s b e e n r e p o r t e d , w h i c h uses simple c y c l i c alkenes and triphenylphosphine as s t a r t i n g

m a t e r i a l s . 36

Although y i e l d s a r e o n l y moderate, t h i s r o u t e should

p r o v e t h e method o f c h o i c e f o r p r e p a r a t i o n o f t h e s e v a l u a b l e i n t e r mediates.

S a l t - f r e e W i t t i g r e a c t i o n o f 2-oxygenated

e x h i b i t s good t o e x c e l l e n t Z - s e l e c t i v i t y nature of the 2-substituent

(Scheme

cyclohexanones

depending on t h e e x a c t '

14). 37

Amongst t h e a l t e r n a t i v e s t o p h o s p h o r u s - b a s e d dures, t h e use o f sulphones remains popular.

o l e f i n a t i o n proce-

Thus, f l u o r o m e t h y l

p h e n y l s u l p h o n e h a s b e e n u s e d t o p r e p a r e v i n y l f l u o r i d e s v i a afluoro- a,B-unsaturated

s u l p h o n e s , 38 a n d a n i m p r o v e m e n t o n a n

earlier methylenation procedure involves a l k y l a t i o n of sulphone a n i o n s w i t h R SnCH21 ( S c h e m e 1 5 1 . ~ '

Use o f R SnCH21 r a t h e r t h a n

3

3

its s i l i c o n analogue r e s u l t s i n a dramatic i n c r e a s e i n t h e rate of both t h e a l k y l a t i o n and fragmentation s t e p s .

T h e m e t h o d was a l s o

e x t e n d e d t o m e t h y l e n a t i o n o f n i t r i l e s a l t h o u g h somewhat h a r s h e r c o n d i t i o n s ( M e L i , -20

OC)

were r e q u i r e d f o r t h e s e c o n d f r a g m e n t a -

t i o n s t e p a s Bu4NF was f o u n d t o b e i n e f f e ~ t u a l . ~ ' S u l p h o n e s a r e a l s o u s e d i n a new m e t h o d f o r t h e s t e r e o s e l e c t i v e p r e p a r a t i o n o f a, 8 - u n s a t u r a t e d

amides. 41

T h e d i a n i o n o f t h e s u l p h o n e ( 10 1 was

s e q u e n t i a l l y a l k y l a t e d , a n d t h e n r e a c t e d w i t h NaBH4 t o f u r n i s h t h e d e s i r e d a m i d e s (Scheme 1 6 ) .

R e a c t i o n o f ( 1 0 ) w i t h e p o x i d e s was

a l s o p o s s i b l e , g i v i n g a d d u c t s w h i c h c o u l d b e c y c l i z e d u s i n g KOBut leading t o s u b s t i t u t e d dihydropyrans. U n s a t u r a t e d a m i d e s a n d e s t e r s a r e a l s o a v a i l a b l e by a n o v e l p a l l a d i u m - c a t a l y s e d c a r b o n y l a t i o n o f e n o l t r i f l a t e s . 42

T h i s method

g a v e u n i f o r m l y h i g h y i e l d s o n a number o f s t e r o i d a l s u b s t r a t e s ,

e.g. -

Scheme 17.

Wittig and P e t e r s o n methodologies have been used f o r t h e preparation of

a,8-unsaturated

t h i 0 e ~ t e r - sa~n d~ a - s i l y l - a, B-

u n s a t u r a t e d esters r e s p e c t i v e l y . 'lr

Selenoxide elimination i s well

e s t a b l i s h e d as a m i l d method f o r o l e f i n a t i o n , s e l e n i u m u s u a l l y being introduced i n t o t h e s u b s t r a t e molecule i n its divalent state. T h e u s e o f p h e n y l s e l e n i u m t r i c h l o r i d e now a l l o w s d i r e c t i n t r o d u c t i o n of t e r v a l e n t selenium and enables subsequent conversion i n t o t h e selenoxide and elimination without t h e use o f a n oxidant ( S c h e m e I 8 1. 4 5

Reduction o f t h e i n t e r m e d i a t e d i c h l o r o s e l e n i d e s t o

10


CONHPh

___) I

PhSO

R F C . O N H P h

___) 'I

R d C O N H P h

PhSO, (10)

Reagents

I,

BULI ( 2 equiv 1, THF, HMPA; R X ;

11,

NaBHL

Scheme 16

NEt, Scheme 17 CI

0 PhSeCL3

N a H CO 3(aq.1

Scheme 18

Reagents

1,

CH2Br2, NaHMDS,

11,

BJLi, MgBr2, PhSCH21, c a t a l y t i c L I ~ C U C ~oxidant-oxone, ~,

MCPBA, o r MoO5*HMPT*H2O,

111,

BuLi, THF, HMPT

Scheme 19

0

d

f3r-

LDA,

f i h h 3 ( 2 equiv 1, KOH

gF

8 u'o

Bu'O

Scheme 2 0

11

1 : Saturated and Unsaturated Hydrocarbons t h e c o r r e s p o n d i n g s e l e n i d e s was a l s o a c h i e v e d b y r e a c t i o n w i t h thiourea.

A n u m b e r o f p a p e r s h a v e a p p e a r e d d e t a i l i n g new d e v e l o p m e n t s o f

e x i s t i n g a n n u l a t i o n methods which y i e l d c y c l i c o l e f i n s . D a n h e i ~ e rh ~a s~ m o d i f i e d h i s s t e r e o c o n t r o l l e d [ 4 + 1 ] a n n u l a t i o n approach t o cyclopentene derivatives, t h a n o x y g e n s u b s t i t u t i o n a t C-3

t o accommodate c a r b o n r a t h e r

(Scheme 1 9 ) .

sequence is t h e carbanion-accelerated

The k e y s t e p i n t h e

vinylcyclopropane-

cyclopentene rearrangement which a p p e a r s q u i t e e f f i c i e n t . Unfortunately t h e r a t h e r poor y i e l d s i n t h e i n i t i a l s t e p s o f t h e sequence and t h e lengthy n a t u r e o f t h e o v e r a l l procedure d e t r a c t somewhat from i t s a p p e a l . p o t , three-component

P o s n e r h a s developed a c o n v e n i e n t one-

c o n s t r u c t i o n o f cyclohexenes which i n v o l v e s

two c o n s e c u t i v e M i c h a e l a d d i t i o n s f o l l o w e d by a r i n g c l o s u r e reaction,47

e.g. S c h e m e 2 0 .

Fragmentation reactions o f c y c l i c s u b s t r a t e s containing s i l i c o n

or t i n p r o v i d e a u s e f u l r o u t e i n t o f u n c t i o n a l i z e d a c y c l i c o l e f i n s . Wilson h a s developed t h e CeIV-mediated o x i d a t i v e fragmentation o f 7-hydroxy-silanes

which a f f o r d s f a i r y i e l d s o f

a l d e h y d e s or k e t o n e s . 48

Cyclic B-stannyl-oximes

when t r e a t e d w i t h l e a d t e t r a - a c e t a t e , ring-contracted study5'

p r o d u c t s (Scheme 21 )

6,~-unsaturated fragment s i m i l a r l y

leading to either acyclic or

."

Both t h i s and a n o t h e r

indicate t h a t such fragmentations occur with e f f i c i e n t

t r a n s l a t i o n o f stereochemistry i n t o t h e o l e f i n i c products.

A

cyclopropane-opening c a r b o n y l a t i o n r e a c t i o n g i v e s good y i e l d s o f Y,6-unsaturated

carboxylic acid derivatives

(Scheme 2 2 ) . 51

The

r e a c t i o n o f f e r s a method of r e g i o s e l e c t i v e c a r b o x y l a t i o n o f a n a l l y l i c a l c o h o l or h a l i d e [ t h e p r e c u r s o r s t o c y c l o p r o p a n e s ( I I ) ] , b u t h a s t h e d i s a d v a n t a g e o f u s i n g 3-6 e q u i v a l e n t s o f [ N i ( C O ) , l .

3 Conjugated 1,3-dienes Taylor has n i c e l y c o n t r o l l e d t h e double carbocupration r e a c t i o n o f organocuprates with acetylenes t o provide a general entry t o dienes,52

e.g. S c h e m e 2 3 .

w i t h a c e t y l e n e ( i n i t i a l l y a t -50

OC

a n d t h e n a t 0 OC) t h e r e a c t i o n

can b e quenched w i t h a v a r i e t y o f e l e c t r o p h i l e s

etc.)

t o g i v e t h e Z-,Z-products

Terminal conjugated

(E)

z,z-

After t r e a t m e n t o f t h e d i a l k y l c u p r a t e

(RX,

enones, C02,

stereospecifically.

d i e n e s a n d t r i e n e s a r e a v a i l a b l e by

SnC12-mediated r e a c t i o n o f a n a l d e h y d e w i t h l-bromo-3-iodop r o p a n e , 5 3 e.g. S c h e m e 2 4 . The p r o c e d u r e i s o p e r a t i o n a l l y s i m p l e ,


12

Ac +/

Pb (OA c l4 CH2CL2, -SO’C*

0-

6 Scheme 2 1

xb 9 0 % e.e.). a-Aryl ketones can be prepared by the reaction of arene diazonium salts with silyl enol ethers [equation (45)3 15', or alternatively per-phenylation of a ketone may be achieved by reaction of its enolate with triphenylbismuth carbonate [equation (46)] I6O. An equally suprising enolate reaction is

2: Aldehydes and Ketones

63

Reagents: i, Li, NH3 THF, -78OC; i i , BujSnCl; iii, R X , HMPA, - 5 O O C I

Scheme 26

Y = H,D, MtCO, M t o c O , ~8r , , Reagents: i , HgC$ ; ii , Y +

Schem 27


64

that between 1-bromoadamantane and the cobalt(I1) or zinc(I1) salts of 8-diketones to give a-adamantyl-B-diketones161 ; unfortunately the reaction appears to be of limited generality. Tsuji et al. have reported on the palladium catalysed allylation of keto-esters with allylic carbonates162. The alkylation of 8-keto sulphones can prove troublesome due to the high stability, and consequent low reactivity, of the anion and the steric demand of the sulphone group. In view of the fact that it is the desulphonated product that is generally required a one-pot desulphonation alkylation procedure should prove useful, and gives nearly double the yields obtained by a conventional two-pot procedure (Scheme 2 6 ) Although dienolates generally react with electrophiles at the a-position, good y-selectivity may be obtained by the use of tin(11) dienolates, which will also add specifically 1,4 to enones allowing the preparation of 1,7-diketones in high yield [equation ( 4 7 ) I 164. Conia et al. have reported an alternative to their thermal enol ene reaction of acetylenic ketones, which not only has the advantage of milder conditions but also allows additional functionality to be introduced (Scheme 27) Aldol Reactions. - Reports have appeared on the use of dimethylaluminium chloride166, and of a variety of trityl salts167, to catalyse the aldol reaction of silyl enol ethers with aldehydes, moderate to fair diastereoselectivities were observed. Probably the most widely used catalyst for this process is titanium tetrachloride and optimised conditions for the reaction, in particular the use of aqueous stannous chloride in the work-up, have been reported to lead to a dramatic increase in yields168. Lewis acids, such as boron trif luoride, are reported to catalyse the reaction of morpholine enamines with aldehydes to give aldol products with moderate threo ~electivity'~'. erythro-Aldols of high purity were obtained in good (50-87%) yield by the chromium(I1) chloride mediated reaction of an a-bromoketone with an aldehyde. Interestingly the authors suggest that chromium endlates are not involved in the reaction [equation (4811 170

.

Tin(I1) aza enolates have been used to prepare anti-aldol products with high e.e. The aza-enolates, which are prepared by the lithiation and transmetallation of the (-)-norephedrine-

65


(39)

Me

)Iyle

Me major

minor

Scheme 2 8

EtCHO 0

(49)

____c

0

OH B

9

ScPh

66


derived oxazoline (39), were found to react rapidly with aldehydes at room temperature to give, after hydrolytic work-up, the aldols in >92% e.e. and >86% d.e. (Scheme 28)171. Studies on the use of chiral a-sulphinyl hydrazones €or stereoselective aldol type condensations have been reported; in general the enantioselectivity found was poor, although in one example an e.e. of 88% was observed172.

The aldol type condensation of aldehydes with the a-position of enones can be achieved directly using tetrakis-triphenylphosphine rhodium hydride in the presence of some iso-propanol but no solvent. Yields of 18-79% were obtained [equation (49)] 173. The same transformation can be achieved less directly, but in better yield via a 6-seleno boron enolate although the reaction fails with 6,B-disubstituted enones (Scheme 29)174. The very mild conditions and high diastereoselectivity of the tin mediated crossed aldol reaction, which allow the formation of even a-bromoketone enolates, have been exploited in a convenient synthesis of = - a , O-epoxyaldehydes (Scheme 30) 175. Conjugate Addition Reactions.

-

A review of the very important

organocopper conjugate addition enolate trapping reactions has appeared176. One common enolate trapping reagent in these processes is trimethylsilyl chloride which is now not only found to be compatible with organo-cuprates below - 5 O O C but also to improve and accelerate their 1,4 addition reactions to give better yields of products containing a lower proportion of lf2-addition by-product than are obtained when the chlorosilane is not present in the reaction

With nickel

acetoacetonate catalysis organozinc reagents, which are readily prepared in toluene-THF by sonication of the appropriate organic halide with lithium and a zinc halide, add in a conjugate fashion to enones. The zinc reagents appear to have some advantages over their better known organocopper alternatives, in that they are stable at room temperature, will add well to BBdisubstituted enones, and are relatively inert to saturated ketones as well as much other common f~nctionality'~~. Several publications have appeared describing conjugate addition elimination processes of alkoxy-substituted enones179r180 ( i d Scheme 3 1 ) , and an extensive study of the reactions of organocuprates with a-oxoketene dithioacetals has

67

2: Aldehydes and Ketones TMsg T w & R O

-

H+Y

iii , iv

0

Reagents:

1,

Sn(OTf+, E t N s

O

I

RCHO; ii, Na2C03, MeOH;iil,NaBHq,

Scheme

30

1 Reagents: i , MeZCuLi; ii, R LI

Scheme

31

Reagents: i, PrMgBr; i i , NH4CI; iii, E#j*EtF, MeOH

Scheme

32

IV,

kI04

H


68

shown that careful choice of reagent and conditions allows quite high stereoselectivity to be achieved [equation ( 5 0 ) gproducts are normally favoured. The same Michael reaction, this time with alkyl magnesium bromides (but not iodides) provides the first step in a 1,3-carbonyl transposition (Scheme 32)182. The 1,4-addition of e n e t h i ~ l a t e s ' ~to ~ enones has been studied and found to give S-alkylated products with thioketone derived enethiolates, C-alkylated products with thioester derived enethiolates, but interestingly 1,2-addition with thioamide anions. The conjugate addition of nitroalkane anions184 and the phase-transfer catalysed addition of substituted acetonitriles to enones has also been described18'. Heathcock and his group have reported a series of studies on the stereoselectivities of the Michael additions of and ester187 enolates and of enol silanes188 to enones. The product ratios of the enolate additions were rationalised using an open transition state non-chelate) model, and may be summarised as follows: (i) 1,2/1,4 ratios depend on steric demand at the B position. (ii) ester enolates show a greater intrinsic propensity for 1,4 addition than do amide enolates, (iii) 5enolates show a greater preference for 1,2 addition than do

(u.

z-

enolates, (iv) 1,2 additions are more freely reversible with ester than with amide enolates, (v) amide enolates and Z-ester enolates showed anti-selectivity and El-ester enolates synselectivity . In the stannic chloride catalysed reactions of enol silanes with enones a preference for anti-addition is observed which is higher in the case of 2-enol silanes188. Similar results have been reported for the reaction with trityl perchlorate catalysis189. The goal of introducing a nucleophile to an enone 1,4 enantioselectively has been reported by the use of both chiral enones and chiral nucleophiles. The former strategy is exemplified by a synthesis of natural (-)-methyl jasmonate by the addition of an acetate enolate equivalent to a chiral sulphoxide [equation (5111 which gave material of >98% purity"'. Sulphoxide chirality in the nucleophile also allows the achievement of high e.e. (96%), as is shown by the addition of an allylic sulphoxide anion to cyclopentenone in a recent 191 synthesis of ( + ) -hirsutene [equation ( 5 2 ) 1 Halovinyl boranes, which are readily prepared by haloboration

.


69

0

Scheme

R=Hor

33

Me 0 -80°C

Mt

0

70


of terminal acetylenes, add readily in a conjugate fashion to enones to give 6-halo-yI6-unsaturated ketones in a convenient one pot procedure (Scheme 33) .Ig2 The 2-alkenyl substituted methyl-2-siloxycyclopropanecarboxylates (40) have been used as in situ precursors of the enones (41) which were trapped by a variety of acidic methylene compound in the presence of acid or fluoride. l g 3 Lastly, the subject of conjugate addition reactions cannot be left without mentioning a remarkable sequential triple Michael addition reaction which provides the key step in a recent, and very elegant, formal total synthesis of (5)-seychellene [equation (53)I .Ig4 References 1.

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-

69. 70.

71


72

71. 72. 73 * 74. 75. 76. 77.

78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88.

,

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89. 90. 91* 92. 93. 94. 95. 96. 97* 98. 99. 100.

101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111.

112. 113. 114. 115.

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73

116.

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117.

B.W.Metcalf, E.T.Jarvi,and J.P.Burkhart, Tetrahedron Lett., 1985,

118. 119. 120. 121. 122.

D.J.Buckley and M.A.McKervey, J. Chem. SOC., Perkin Trans. 1, 1985, 2193. D.Liotta, M.Saindane, C.Bamum, and G.Zima, Tetrahedron, 1985, 41, 4881. T.G.Back and R.G.Kerr, Tetrahedron, 1985, 41, 4759. L . E n p , Tetrahedron Lett., 1985, 26, 6 3 8 r J.M.Muchawski, R.Naef, and M.L.Maddox, Tetrahedron Lett., 1985, 26,

123. 124-

P.Sampson and D.F.Wiemer, J. Chem. Soc., Chem. Ccarmun., 1985, 1746. T.Satoh, T.Kumagawa, and K.Yamakawa, Bull. Chem. SOC. Jpn., 1985, 58,

125. 126. 127. 128.

T.Satoh, Y.Kaneko, K.Sakata, and K.Yamakawa, Chemistry Lett., 1985, 585. P.Bravo and G.Resnati, Tetrahedron Lett., 1985, 2, 5601. K.Akiba, H.Ohnari, and K.Ohkata, Chemistry Lett., 1985, 1577. M.B.Floyd, M.T.Du, P.F.Fabio, L.A.Jacob, and B.D.Johnson, J. Org. Chem.,

129. 130. 131. 132. 133. 134. 135. 136.

M.C.Carre and P.Caubere, Tetrahedron Lett., 1985, 26, 3103. H.H.Wasserman and J.L.Ives, J. Org. Chem., 1985, 5 %3573. F.Huet, Synthesis, 1985, 496. L.Hevesi and K.M.Nsunda, Tetrahedron Let.., 1985, 3, 6513. Y.Tanabe and T.Mukaiyama, Chemistry Lett., 1985, 673. O.G.Kulinkovich, I.G.Tischenko, and V.L.Sorokin, Synthesis, 1985, 1058. J.Jurczak and S.Piku1, Tetrahedron Lett., 1985, 26, 3039. L..Lorenc,L.Bondarenko, and M.L.Mihailovic, Tetrahedron Lett., 1985, 26,

137. 138.

C.Botteghi and F.Soccolini, Synthesis, 1985, 592. Y.Kamitori, M.Hojo, R.Masuda, and T.Yoshida, Tetrahedron Lett.. 1985,

406.

26,

2861.

5375 * 2849.

1985,

50,

5022.

389.

26,

4767.

139. 140.

J.R.Hwu and J.M.WetZe1, J. Org. Chem., 1985, 50, 3946. B.H.Lipshutz, D.Pollart, J.Monforte, and H.Kotsuki, Tetrahedron Lett.,

141.

D.Grave1, S.Murray, and G.Ladouceur, J.Chem.Soc., Chem. Carrermn., 1985,

142. 143. 144.

A.Mori and H.Yamamoto, J. Org. Chem., 1985, 50, 5444. H.E.Morton and Y-Guindon,J. Org. Chem., 1985, 50, 5379. L.M.Baigrie, D.Lenoir, H.R.Seikaly, and T.T.Tidwel1, J. Org. Chem., 1985,

1985, 26,705.

1828.

145. 146. 147. 148. 149. 150. 151. 152. 153.

50, 2105. -

L.M.Baigrie, H.R.Seiklay, and T.T.Tidwel1, J. Amer. Chem. Soc.,

107 , 5391. -

R.H%er, T-Laube,and D-Seebach,J. Amer. Chem. Soc., 1985,107, 5396. M.Kawanisi, Y.Itoh, T.Hieda, S.Kozha, T.Hitcsni, and K.Kobayashi, Chemistry Lett., 1985, 647. A.R.Chamberlin and S.H.Reich, J. Amer. Chem. SOC., 1985, 107,1440. D.W.Moreland and W.G.Dauben, J. Amer. Chm. Soc., 1985, 107,2264. R.W.Hoffmann, K.Ditrich, and S.Froech, Tetrahedron, 1985, 41, 5517. D-Seebachand M.A.Brook, Helv. Chim. Acta, 1985, 68, 319. R.W.Stevens and T.Mukaiyama, Chemistry Lett., 1985, 855. D.Seebach, A.K.Beck, J.Golifiski, J.N.Hay, and T.Laube, Helv. Chim. Acta, 1985,

154. 155.

1985,

68,

162.

R.Kober, K.Papadopulos, W.Miltz, D.Enders, W.Steglich, H.Reuter and H.Puff, Tetrahedron, 1985, 41, 1693. C.C.Silveira, J.V.Comasseto, and V.Catani, Synth. C m ., 1985, 5, 931.

156. 157. 158.

1.Fleming and J.J.Lewis, J. Chem. Sm., Chem. Ccmnun., 1985, 149. C.Stetin, B.De Jeso, and J.-C.Paer, J. Org. Chem., 1985, 50, 3863. M-Pfau,G.Revia1, A.Guingant, and J.d'Angelo, J. Amer. Chem. Soc., 1985,

107, -

273.


74

159. 160. 161. 162. 163. 164. 165. 166. 167.

T-Sakakura,M.Hara, and M.Tanaka, J. Chem. SOC., Chem. Camnun ., 1985, 1545. D.H.R.Barton, J.-C.Blazejewski, B.Charpiot, J-P.Finet, W.B. Motherwell, M.T.B.Papoula, and S.P.Stanforth, J. Chem. SOC., Perkin Trans 1, 1985, 2667. A-Gonzdlez,F.Giiel1, J.Marquet, and M.Moreno-mas, Tetrahedron Lett., 1985, 3735. J.Tsuji, I.Shimizu, I.Minami, Y.Ohashi, T.Sugiura, and K.Takahashi, J. Org. Chem., 1985, 50, 1523. M.J.Kurth and M.J.O'Brien, J. Org. Chem., 1985, 50, 3846. R.W.Stevens and T.Mukaiyama, Chemistry Lett., 1985, 851. J-Drouin,M-A.Boaventura and J.-M.Conia, J. Amer. C h . Soc., 1985, 107, 1726. Y.Naruse, J.Ukai, N.Ikeda and H.Yamamoto, Chemistry Lett., 1985, 1451. S.Kobayashi, M.Murakami, and T.Mukaiyama, Chemistry L e t t . , 1985, 1535; T.Mukiayama and H.Iwakiri, Chemistry Lett., 1985, 1363; and T.Mukaiyama, S.Koyayashi, and M.Murakami, Chemistry Lett.,1985, 447. B.A.B.Kohler, Synth. Camnun., 1985, 15,39. O.Takazawa, K.Kcqami, and K-Hayashi,Bull. Chem. SOC. Jpn., 1985, 58, 2427J.-E.Dubois, G.Axiotis, and E.Bertounesque, Tetrahedron Lett., 1985, 26, 4371. K.Narasaka and T.Miwa, Chemistry Lett., 1985, 1217. R.Annunziata, F.Cozzi, M.Ciriquini, L.Col&, C.Gennari, G.Poli, and C.Scolastico, J. Chem. Soc., Perkin Trans. 1, 1985, 251. S.Sato, I.Matsuda, Y.Izumi, Chemistry Lett., 1985, 1875. W.R.Leonard and T.Livinghouse, J. Org. Chem., 1985, 50, 730. T.Mukaiyama,T.Yura, and N-Iwasawa,Chemistry Lett., 1985, 809. R.J.K.Taylor, Synthesis, 1985, 364. E.J. Corey and N.W. Boaz, Tetrahedron Lett., 1985, 26, 6019. C.Petrier, J.C.de Souza Barbosa, C.Dupuy, and J.-L.Luche, J.Org.Chem., and J-L.Luche, 1985, 50, 5761; and J.C. de Souza Barbosa, C.P&rier Tetrahedron Lett., 1985, 26, 829. C.W.Spangler, R.P.K.Tan, R.S.Gibson, and R.K.Mdoy, S y n t h . Comnun., 1985, 15, 371. J.-C.Depezay and M.Saniere, Tetrahedron, 1985, 41, 1869. R.K.Dieter, L.A.Silks, J.R.Fishpaugh, and M.E.Kastner, J. Amer. Chem. S o c . , 1985, 107, 4679. Eingh, M.L.Purkayastha, H.Ila, and H.Junjappa, J. Chem. S o c . , Perkin Trans. 1, 1985, 1289. P.Metzner and R.Rakotonirina, Tetrahedron, 1985, 41, 1289. N.Ono, A.Kamimura, H.Miyake, T,Harmmto, and A.Kaji, J. Org. Chem., 1985, 50, 3692. M.Cossentini and J.Seyden-Penne, Synth. Cmun., 1985, 15,689. C.H.Heathcock, M.A.Henderson, D.A.Oare, and M.A.Sanner, J. Org. Chem., 1985, 3019. C.H.Heathcock, and D.A.Oare, J. Org. Chem., 1985, 50, 3022. C.H.Heathcock, M.H.Norman, and D.W.Uehling, J. Amer. Chem. SOC., 1985, 107, 2797. S.Kobayashi, M.Murakami, and T-Mukaiyama,Chemistry Lett., 1985, 953. G.H.Posner and EAsirvathx-,,J. Org. Chem., 1985, 50, 2589. D.H.Hua, G.Sinai-Zingde,and S.Venkatarm,J. Amer. Chem. Soc., 1985, 107, 4088. Y.Satoh, H.Serizawa, S.Hara, and A-Suzuki,J. Amer. Chem. Soc., 1985, 107, 5225. E.L.Grimn, R.Zschiesche, and H.-U.Reissig, J. Org. Chem., 1985, 50, 5543. H.Hagiwara, A.Okano, and H.Uda, J. Chem. Soc., Chem. Ccmrmn., 1985, 1047. ~

168. 169. 170. 171. 172. 173. 174. 175. 176. 177. 178. 179. 180. 181. 182. 183. 184. 185. 186. 187. 188. 189. 190. 191. 192. 193. 194.

so,

3 Carboxylic Acids and Derivatives BY D. W. KNIGHT 1

Carboxvlic Acids

General Synthesis.- The principle of steric shielding has been applied by a number of research groups'

to the elaboration of

3-substituted carboxylic acids, with enantiomeric enrichments of 94-98%: one of the variants of these asymmetric Michael additions is outlined in Scheme 1. Overall yields are generally excellent, the chiral auxiliary can easily be recovered, and the sense of the chirality in the final product can in principle be varied simply by changing the order of introduction of the two substituents, given that both organo-copper species are available. An entirely different approach to chiral carboxylic acids is based on asymmetric hydroboration using monoisocamphenylborane ( I ~ C B H ~ )For . ~ example, reaction between IpcBH2 and 1-methylcyclopentene (1) (Scheme 2) gives borane (2) which is converted into the dioxaborinate (3) in three steps. Alkylation at boron using LiCH(0Me)SPh and Hg(I1)-induced alkyl migration then leads to the one-carbon homologue (4) which is finally converted into the acid (5) by a two-step oxidation sequence ( H 2 0 2 , aldehyde.

pH 8, then chromic acid)

2 the

corresponding

The length and complexity of this sequence are

somewhat ameliorated by high chemical yields and the excellent optical purity ( > 9 9 % ) of the final product. The radical chain decarboxylation method (see below) has been adapted to a one-carbon homologation procedure for carboxylic acids by trapping the intermediate carbon radicals with electron-deficient olefins, specifically nitro-olefins or vinyl

'.

sulphones (Scheme 3) This 'one down-two up' procedure is efficient enough for it to be considered as an alternative to the Arndt-Eistert method, especially in large-scale operations with acids which do not contain functionalities which are incompatible with a free-radical intermediate. A wide variety of organic halides can be carboxylated electrochemically using a magnesium anode and an atmospheric pressure of C 0 2 : the process overall has a mechanism reminiscent of the carboxylation bf 75

For References see p. 173


76

i,

R ~ C U . B F ~B

P~P D

i i , NaOH-H20

HO,C

Scheme 1

(3)

I

Li2M). Many other types of prochiral ketones are also reduced with excellent asymmetric inductions although 6-keto-esters may not be particularly suitable substrates as ethyl acetoacetate is reduced to ethyl 3-hydroxybutanoate with an enantiomeric excess of only

3: Carboxylic Acids and Derivatives

COzEt

R C0,Et

(103)

OTMS

97

98


55%.

a-Keto-esters can also be reduced asymmetrically using

di-isobutylaluminium hydride modified by the addition of SnC12 and a chiral pyrrolidine, although in these examples, optical yields are variable.

Asymmetric induction has also been

achieved in reactions between achiral reagents and a-keto-esters derived from a chiral alcohol.

For example, some simple

a-keto-esters obtained from chromium complexes of chiral secondary benzyl alcohols can be reduced with up to 90% e.e., lo7 whereas tetra-alkylaluminates (LiAlR ) transfer an alkyl group to 4 (-)-menthy1 phenylglyoxylate to give the tertiary alcohols (109) in ca. 70% e.e. A combination of (-)-menthy1 pyruvate and a Lewis acid (RA1C12 or TiC14) modified by the addition of (-)-menthol reacts with various phenols to give hydroxy-esters (110), in some cases with remarkably high stereoselectivities (up to 96%). log Extremely high selectivities have also been obtained in oxidations of sterically shielded enolates [cf.structure (107) and Scheme 11 by MoOPH

110

or Pb(OAc)4111 (of the derived 0-silyl-enolates), leading to a-hydroxy- and a-acetoxy-esters respectively. Both methods should be widely applicable. A generally efficient route to the a,B-dialkoxy-esters (111)

-

is by condensations between carbonyls

(R1R2co)and of methyl a-alkoxyacetates, catalysed by zinc Unfortunately little or no stereoselectivity is

0-silyl-enolates

chloride.

observed (see also ref.115) . Condensations of the dithiolane or dithiane enolates (112) with a-methyl-aldehydes lead to a-hydroxy-esters ( 1 1 3 ) (major isomer) with good to excellent stereoselectivities. These initial, rather sensitive adducts can be smoothly desulphurized using NiC12-NaBH4-H2 to give esters (114) in high yields. Heathcock's group has amply demonstrated the potential of the stereoselective aldol-type condensations which they have developed in syntheses of the C-1 to C-7 synthon (115) of Erythronolide and of the branched sugar Cladinose (116) T h e latter work features a highly stereoselective route to

trihydroxy-ester derivatives (117) by condensations between 0-si1yl -en01ates of a-methoxypropanoatesl

-

( 5 )-2-benzyloxypropanol

and

.

A detailed recipe has been given for the reduction'of ethyl acetoacetate to ethyl-(S)-3-hydroxybutanoate (118) by Baker's yeast. Various forms of immobilized Baker's yeast can also be used,ll7 resulting in improved optical yields in some cases.


n

99

n CO,E t

C0,Et OH

-

Rj r C 0 , E t OH

Bz? OMe d

AoAOH

C

0

,

R

OH (117)

OH

“FO2

H&;2Et

N3

0

(1 2 0 )

(119)

RH$C ,O

Me

TBDMSO+

-.H

OH

C02Me

100


Dense polyurethane matrices are particularly useful in this respect and furthermore often give rise to the opposite enantiomer to that obtained using untreated yeast. Normal Baker's yeast can also be used to prepare cyclic B-hydroxy-esters [e.g. (119)1 and the 4-azido-esters (120) in high optical yields from the corresponding B-keto-esters; the latter examples are in direct contrast to the corresponding 4-halogeno-derivatives which are reduced largely to the opposite enantiomers. Purely chemical routes to a variety of chiral B-hydroxy-esters include reductions of 8-keto-esters by LiBH 4 modified by the addition of a cysteine derivative'120 and kinetic resolutions of a-(hydroxyalky1)acrylates by asymmetric hydrogenation using biphosphine-rhodium catalysts.12' Similar products (121) to those obtained in this latter approach can also be prepared by Mukaiyama-type aldol condensations using an ephedrine derivative to supply the asymmetry.1 2 2 A similar condensation of 2-O-benzyl-3-0-(t-butyldimethylsilyl)-glyceraldehyde derived from mannitol and the 2-silyl-enolate of methyl acetate leads almost exclusively to trihydroxy-ester (122)123 whereas B , y dihydroxy-esters, also largely or exclusively as the syn-isomers, result from condensations of sulphur-substituted silyl-enolates and a-alkoxy-aldehydes.124 An alternative but related route to the (achiral) anti-isomers (121) involves condensations of aldehydes and ketones, activated by a Lewis acid, with 'enolates' of transition metal-carbene complexes.1 2 5 It may be that the initial products [e.g. (123)l will be particularly useful in some circumstances as the ester function is present in a 'protected' form. The diazo-esters (124), prepared by condensations between aldehydes or ketones and ethyl (lithio)diazoacetate, can be converted into B-hydroxy-esters (125) by hydrogenation using 5% This simple homologation method is thus Pd/C in methanol.126 clearly limited to substrates which do not contain exposed olefinic bonds or sulphur functions. Similar homologations can also be carried out using anionic chain reactions induced by electroreduction of an a-halogeno-ester in the presence of an aldehyde.12' Two new methods €or the conversion of a,$-unsaturated esters into a-substituted-B-hydroxy-esters have been developed, both of

which can be used to prepare both possible diastereoisomers.


101

One method is based on conjugate additions of PhMe2Si groups to enoates (126; R2+H) leading largely to the e - a d d u c t s (127) which can be converted (HBF4 then MCPBA) into the corresponding 8-hydroxy-esters (128; R3=H) with the retention of stereochemistry.128 Alternatively, additions of the same nucleophile to simpler enoates (126; R2#H) followed by alkylation (by R2X) of the resulting enolates gives almost entirely anti-isomers of esters (127), precursors of the The second approach involves anti-hydroxy-esters (130; R3=H) . oxymercuration of esters (126) to give methoxy-esters (128a) which undergo demercuration by propane-1,3-dithiol with retention, or by NaBHq with inversion, to give mainly esters 3 129 ( 1 2 8 ; R =Me) or (128b; R3=Me) respectively. Dianionic Claisen rearrangements of 8-hydroxy-esters (129) give largely the substituted esters ( 1 3 0 1 , although only in moderate yields (z.4 0 % ) . Despite this, the method is brief and should find many applications, as such highly functionalized esters can be used as precursors to a wide variety of compounds. The homoenolate of methyl propanoate can be obtained by treatment of the readily available tin derivative ( 1 3 1 ) with TiC14; subsequent condensations with aldehydes or ketones lead to y-hydroxy-esters (132) (isolated as the derived butyrolactones The corresponding zinc homoenolate has also when Rl, R2#Ar) .I3' been generated, but in a rather different way, ring opening of a mixed acetal of cyclopropanone using a zinc halide catalyst.1 3 2 High yields of r-hydroxy-esters (132) are produced following 'homo-Reformatsky' condensations of this species with aldehydes or ketones (see also Ref. 1 5 7 ) . High levels of [1,3]-stereocontrol have been observed in hydrogenations of homoallylic alcohols [e.g. ( 1 3 3 ) -s (134)l using various rhodium and iridium catalysts.13rJudging from the examples quoted, this method will be applicable to a wide range of important structural types. Keto-esters. - Wasserman and have given full details of their method for the conversion of esters into a-keto-esters ( 1 3 6 ) by dye-sensitized photo-oxygenation of enamino-esters (135) which can be easily obtained from the parent esters using a variety of methods. Overall yields are excellent in this relatively mild procedure which can also be used to obtain a-keto derivatives of lactones, lactams, ketones, and amides. The


102

C02E1

-

R'

C0,Et

-

SiMe2Ph

dTco2Me

C02Me R2

N2

J (1280)

( 1 28b)

R

Uo

(128)

OH L

C

d (129)

(130)

(131)

(132)

O Me


103

unsaturated keto-esters (137) are reduced regioselectivity to This observation has esters or other 1,4-dihydropyridines.135 preparative significance as other more conventional reductants show entirely different selectivities.

A general route to a,@-diketo-esters (141) consists of condensations between acyl chlorides and the oxalic acid derivative (139).136 The intermediate, partly protected adducts (140) can be isolated if required: the bis-acetal (139) is thus another equivalent of the unknown acyl anion (142). A practical electrochemical procedure for the preparation of the acetal (143), a masked form of unstable methyl formylacetate, 137 from methyl acrylate has been reported. Various homologues having a substituent at C-2 can also be obtained in this way. Disubstituted homologues of formylacetate itself can be prepared in moderate yields

by condensations of ketene silyl acetals

(144) with g-t-butylformimidoyl cyanide (ButN=CHCN).13* Acetals (144) can also be used as precursors to B-keto-esters in general by alkylations with dithiane-derived salts (145).

Yields of

the protected 8-keto-esters (146) are in the range 22-94%. A classical method for the elaboration of acetoacetates is by the addition of alcohols to diketene.

This unpleasant reagent can

be avoided by using the inexpensive dioxinone (147) (diketene-acetone adduct) which on heating above E. 120 "C decomposes to acetone and acetylketene (148); in situ trapping by an alcohol affords acetoacetates (149) in excellent yields.

140

6-Keto-thioesters and amides can also be obtained using this method.

An alternative route to acetoacetates (149) involves

transesterification of methyl acetoacetates with primary or secondary alcohols using 4-dimethylaminopyridine as catalyst.

141

This method can also be applied to methyl esters of homologous 6-keto-esters, but fails if the latter are disubstituted at C-2. The excellent procedure for preparing B-keto-esters by acylations of Meldrum's acid with acid chlorides has been described in detail. 142 The same type of approach to 6-keto-esters (152) can be carried out in one step by condensation of methyl or ethyl esters (150) with t-butyl lithio-acetate ( 1 5 1 ) . High yields of keto-esters are obtained only in the presence of an additional equivalent of a base such as LiOBut, which ensures that the product is fully enolized as it is formed, and thus protected 143 from further attack by the enolate (151).


104

Eto$OEt

-

0

OTMS

zncl-,' RCOCl RIIXtOiEt EtO

OTMS

C0,Et

-If

0

OTMS

0

5

OMe &C02Me

I

3 X sB F i

I

R R'HoTMs

R~

Me0

OMe

(145)

(143)

OLi

0

+

-

0

LlOBUt

AOBU'

R

Co2Et

CO, But

CO, Me


105

The arylation of B-keto-esters to give, for example, the cyclopentanone derivative (153) using aryl-lead triacetates has been shown to be compatible with a range of aryl substituents (e.g. F, OMe, NO2). 144 The lead species are best generated in situ from diarylmercuries and P ~ ( O A C ) ~ . Enolates of 0-keto-esters can be similarly phenylated by various bismuth(V) compounds to give the same type of product.145 8-Keto-esters can also be efficiently allylated without the addition of a base by treatment with an allylic carbonate and a Pd(0) ~ a t a 1 y s t . l ~ ~ For example, ester (154) can be obtained in 98% yield from methyl 2-methyl-3-oxopentanoate using diallyl carbonate in THF at 30 "C, in only 10 min. Some cyclic O-keto-esters have been alkylated enantioselectively by optically active sulphonium salts; however, as yet yields, both chemical and optical, are poor.147 Further studies148 have revealed that enamines derived from cyclic B-keto-esters, especially six-membered examples, undergo regioselective alkylations at the y-position to give the derivatives (155) in good to excellent yields, with the usual restriction that only reactive electrophiles (allylic, benzylic halides, acrolein, MVK) couple efficiently with enamines. The strongly basic conditions required in the dianionic or Dieckmann routes to esters (155) are thus avoided, which allows the alkylations to be carried out in the presence of various base-sensitive ring substituents (e.g. OAc). Enolates of a-phenylthiocrotonates undergo regioselective C-acylation when treated with an acid chloride or anhydride to give B-keto-esters (156) in which a [1,3]-SPh shift to give esters (157) can be induced by heating with AIBN-PhSH.149 These latter products can be desulphurized, resulting in a reasonably efficient route to a-alkylidene-0-keto-esters. A sulphur extrusion reaction is the basis of yet another approach to 8-keto-esters.150 Thus, tretment of 0-acylthio-esters (157a) with LiNR2 at -78°C followed by warming to room temperature leads directly to 8-keto-esters (157b) in 54-93% yield. The'oxygen analogue of this rearrangement (i.e. starting with ester (157a) with 0 in place of S ) is already established as a route to a-hydroxy-0-keto-esters. The latter derivatives can also be obtained from the silyl enol ethers of 0-keto-esters by oxidation with 2-chloroperbenzoic acid. lS1 Conjugate additions of thioacetals (159) to a,B-unsaturated esters (158) followed by alkylation using iodomethane leads

106


exclusively tothe syn-isomers (1601, useful as precursors to ~

keto-esters. 152

y-

In direct parallel to Fleming's

observations, 128 similar additions to the a-methyl hom'ologues of esters (158) followed by quenching with acetic acid give only the corresponding g i - i s o m e r s (161).

Acyl radicals generated from

aldehydes show a distinct preference for additions to electron-deficient olefins. This fact has been employed in the development of a novel cyclization procedure leading to the Y keto-ester derivatives (162) (Scheme 12)152 The highest yield obtained during this trial study of a potentially very useful reaction type was 57%. Following on from previous work, R e i s ~ i ghas ~ ~discovered ~ that cyclopropane carboxylates (163) smoothly rearrange to silyl enol ethers (164) when treated with small amounts of iodotrimethylsilane.

The initial products can be further

homologated to B,B-disubstituted-Y-keto-esters by condensations with electrophiles. A full account has been given of related work in which vinyl cyclopropanecarboxylates (163; R'=vinyl) undergo nucleophilic additions to give heterosubstituted y -

A completely different approach toy-keto-esters proceeds y & Michael additions of carboxylic acid dianions to an a-anilino-acrylonitrile followed by alkylation of the resulting anion and finally acidic hydrolysis (Scheme 13) .156

Overall

yields are in the range 47-79%; the method is also useful in the synthesis of y-keto-amides. An alternative anion-based route to keto-esters utilizes the homoenolate (166) as the intermediate which undergoes smooth acylation by a wide variety of acid chlorides. 157

The h ~ m o e n o l a t e l ~is ~ 'obtained ~~~ from the

corresponding iodoester using Zn-Cu couple, and it seems likely that the method can be used to prepare more highly substituted keto-esters although such reactions have not yet been reported. In the same way, the bis-homoenolate (167) can also be generated and used to make 6-keto-esters (168). Overall yields are excellent. Michael additions of ketene silyl acetals (169) to enones using Mukaiyama-type conditions result in the almost exclusive The stereochemical formation of the syn-isomers (170).lS8 outcome of these condensations is not dependent on the ketene geometry, whereas in related reactions of the lithium enolates of

y-


(1531

0

107

(154)

(155)

-

RZ

L I NR2

R'

( 1 56)

C0,Et

CO, Me

R2

( 1 57a)

(157b)

-

(157)

SMe

MeS

i, R Z x L i

R1/+C02Me

ii, Me1 ( 1 59)

R2&C02Me MeS MeS

(1 5 8 )

C0,Me MeS MeS

(1611

(1 6 0 )

- &(

COzMe

&OzMe

?If

0

0 (162) Scheme 12

I


108

-

Scheme 13

IZn

C02Et

,R

OBu' (1 69)

4

(170)

&--A c 0,M e


109

t-butyl propanoate with enones, this is the key factor, as the (Z)-enolate gives the anti-adducts whereas the (El-enolate leads to only the =-isomers.l5' The chiral enamine (171) participates in a Michael reaction with methyl acrylate to give the 6-keto-ester (172) with >95% enantiomeric enrichrnent.l6' This isolated example which echoes the hydrazone work of Enders ('SAMP' and 'RAMP') no doubt illustrates a more widely applicable principle. Closely related organotin enamines afford the same product (172) with acrylates but usually in poorer chemical and A first example of an asymmetric additive optical yields. 16' Pummerer rearrangement, (173) (174), an uncommon reaction in its racemic form, is featured in a new route to the 6-keto-esterI (-)-methyl jasmonate (175), having 20% enantiomeric purity

-

s.

(Scheme 13) Organomanganese reagents are relatively unreactive species and so are useful for the synthesis of many types of keto-esters via couplings with acid chlorides derived from diacid monoesters 1i.e. ClCO(CH ) C02Etl.163 2 r !

Unsaturated Esters. - Following on from a recent report that the ionization of triethyl phosphonoacetate can be promoted by lithium chloride to such an extent that only DBU or Hunig's base is required, Rathke and N ~ w a k lhave ~ ~ discovered that even triethylamine is sufficiently basic when either lithium or The resulting enolate magnesium bromide is present. 164 condenses rapidly with a variety of aldehydes and cyclohexanone (but not methyl ketones) at ambient temperature to provide generally excellent yields of a,B-unsaturated esters. An alternative way in which the use of strong bases can be avoided in such reactions is to employ various phase-transfer conditions; examples reported this year include barium hydroxide, 165 potassium carbonate, 166' 167 and potassium fluoride on alumina. 16* A notable feature associated with some of these methods is that high yields of a,B-unsaturated esters are obtained even with rather sensitive aldehydes substituted by unprotected hydroxy-, nitro-, or keto-groups. Exceptionally sensitive aldehydes which may even defy isolation can be generated and trapped in situ by carrying out a Swern oxidation of the corresponding alcohol at -78 "C and then adding a stabilized phosphorane [e.g. (17611 (Scheme 1 5 ) Remarkably high yields can be obtained; in the example shown, the extremely reactive a-keto-aldehyde is trapped

110

General and Synthetic Methods c

Scheme 15

+

+

Ph3P=C=C=0

R~OH

Scheme 16

~

o

" "B""

R

c'

R

-4co, d

____jt

Et

OSiMe3

"ZEt

~

''+ / OEt R2

d C 0 , E t

:C ,cI

3R'

R3

OSi Me3

CI

R,+oEt

A R2

Scheme 17

~

'+

R3 /

R2

C02Me

"


111

to give the keto-crotonate (177) in 90% isolated yield (E:Z =85:5). A 'three component' synthesis of a,@-unsaturated esters is outlined in Scheme 16. 170 This unusual method is simple to perform (equimolar amounts of each component are heated together in toluene), affords generally high yields (81-94%) and presumably proceeds & y the phosphorane (176, Me=R 2 1 . Examples of the synthesis of macrolides (179) from a-hydroxy-aldehydes (178; "=8 or 10) (60-65% yields) and of the Diels-Alder adduct (180) by a four-component reaction, in which the additional reactant is 2,3-dimethylbutadieneI suggest that the method could be of considerable utility. Although Wittig reagents [e.g. (176)l condense efficiently with acrolein, the corresponding, cheaper, phosphonates give low yields of penta-2,4-dienoates (182). This difficulty can be circumvented by substituting 3-chloropropanal for acrolein; the initial adducts (181) undergo smooth and rapid elimination of the elements of HC1 when treated

s.

80% ~ i e 1 d s . l ~ ~ with DBN to give esters (182) in Ruthenium-catalysed co-dimerization of a terminal acetylene (183) with hexadienoate (184) gives, regioselectively, the formal Michael adduct (185) in 86% yield. 172 Unfortunately, similar reactions with pentadienoates lead to mixtures of 2-en- and 4-en-6-ynoates but presumably the method could be extended to higher homologues. A one-carbon homologation method (Scheme 17) for the conversion of esters into a,@-unsaturated esters has as the key step the addition of chloro-carbenes to silyl ketene acetals.173 Yields overall are generally excellent and largely ( E ) - or (Z)-isomers can be obtained with R 3 =H by controlling the stereochemistry of the ketene acetal. However, the remainder of the substrate must be inert to attack by chloro-carbenes which will clearly limit the utility of this method. Reformatsky reactions of oxoketene acetals (187) derived from aryl ketones (186) followed by dehydration and hydrolysis or just dehydration (I2) afford propene-lI3-dicarboxylates (188) or their partly 174 protected derivatives (189) respectively. A useful and efficient one-carbon homologation method for the conversion of ketones (190) into a,$-unsaturated esters (191) involves Pd(0)-catalysed carbonylation of enol triflates derived from ketones (190).175 The regioselective generation of these intermediates seems to be the only potential problem associated with this method.

(&)-Vinylsilanes

(192) can also be

converted into esters (1911, via the derived vinyliodonium

112


SMe

Ar

Et0,C W

S

M

e

OH

\

€to$

+YSMe Ar

SMe

(189)

R’-X (193)

+

rf /

C02Me

R

(194)

4

R’rco (195)

113

3: Carboxylic Acids and Derivatives 176 salts. A useful polystyrene-bound palladium catalyst has been

developed for use in Heck-type coupling reactions [(193)-+ (195); R 1=Aryll The same overall transformation can be carried out by the addition of alkylradicals, generated from alkyl bromides (193; X=Br) , to B-stannyl acrylates (194; R2=Bu!$n) followed by elimination of the stannyl group.178 Respectable yields (43-79%) have been obtained with a variety of useful substrates suggesting that this experimentally simple method could find wide application. Peterson olefination reactions between lactones (196) and a-silylacetates have been used to obtain isomeric mixtures of the ylidene acetates (197). Yields are variable and best for six-membered lactones. The nitrogen analogues of heterocycles (197) can be prepared by the direct coupling of -N-alkyl-lactams with lithium t-butyl acetate,180 and a specific route to tetrahydro-2-furylidene acetates involves BF -catalysed reactions between epoxides and acetoacetate dianions.381 Baldwin et a1.182 have provided some useful information about the relationships between reaction conditions and substrate structure in conjugative isomerizations of $,v-unsaturated esters to the corresponding a,B-unsaturated isomers. A new asymmetric synthesis of cyclohexylidene esters (198) relies on the presence of a chiral sulphoxide function which allows the diastereoisomeric a-sulphinylester precursors to be separated and the facile introduction of the double bond by thermolytic 183 elimination of the sulphinyl group. Routes to useful functionalized a,8-unsaturated esters reported this year include a Peterson-type approach to the a-trimethylsilyl esters (199)184 and Lewis acid-catalysed condensations between acetylene (200) and aldehydes (or ketones) which efficiently produce the allylsilanes (201)185 (see also ref. 188). a-Thioesters (203) can be obtained by 'elminiative deoxygenation', using TMS triflate and a weak base, from the The Peterson reaction readily available sulphoxides (202) 18'

.

has been used in the same sense as in the preparation of a-silyl esters (199) to obtain a-stannyl esters ( 2 0 4 ) from aldehydes One value of (RCHO) and a-stannyl-a-trimethylsilylacetate. 187 the esters (204) is as precursors to the useful vinyl anions ( 2 0 5 ) into which they are converted following tin-lithium exchange using n-butyl-lithium.

A summary of the various


114

Y

Si Mej

+CO,,d

R

MegSi

-*

,OE

t

R (199)

(198)

(200)

T I CI4

R

n = 0 , l or2

*

CO,R

(204)

(205)

(206)

Hoe< AC02Me

R A c o p e

(209)

(208)

(207)


115

equivalents of acrylate anions (205) has been given in a full paper by Hoffmann and Rabe in which is described the preparation of hydroxy-acrylates (206) by DABCO-catalysed condensations of aldehydes with methyl acrylate. 188 On treatment with N-halogenosuccinimides and Me2S, esters (206) are converted into allylic halides (207) stereoselectively, while reduction (LiBEt H) of the derived acetates leads to 3 (E)-a-methyl-a,B-unsaturated esters (208) via SN2' addition of hydride. An alternative phosphonate-based approach to silyl esters (201) is also described in this paper. Ene-type reactions between substituted a,@-unsaturated esters and singlet oxygen proceed with good to excellent regioselectivity of attack at the allylic position geminal to the ester group, leading largely to hydroperoxides 1e.g. ( 2 0 9 ) I .18' The g-silyl-enolate of methyl a-thiopropionate condenses with a-benzyloxy-aldehydes to give very largely the --isomers (210) after oxidation and elimination of the thio function. Weedon et al. have given a full account of their work on the photo-deconjugation of a,6- to a, y-unsaturated esters. 19' The more conventional method for effecting this transformation enolization and protonation has been used to obtain the useful

(z)-vinyl-stannanes

(211) from the corresponding

Likewise (2)-isomers of the latter can be converted exclusively into the (El-isomers of stannanes (211). Treatment of (cyclic) y -acetoxy-

( E )-a, a-unsaturated isomers.

a,B-unsaturated esters (212) with Bu 2CuLi generates copper enolate species which undergo smooth alkylations by primary halides to give esters (213), thus providing a useful Phenyl method for combined deconjugation and homologation.lg3 vinyl sulphoxide has been used as a vinyl cation equivalent in the conversion of enolates [e.g. (21411 into ethenyl homologues (215); yields for the two steps are in the order of 50% when this somewhat limited method is successful.lg4 Cyclopropane derivatives (216) can be converted into v , b unsaturated esters (217) by reaction with nickel carbonyl and an alcohol (R20H);lg5 yields of the esters are in the range 20-80%. The method can also be used to form amides by using an amine rather than an alcohol, but the returns are generally inferior. A common method €or the preparation of v , d unsaturated esters is to use one of the modifications of the Claisen rearrangement. One limitation of the Ireland version,


116

BtO RA

C0,Et

A! O

2

M

(V

e

OAc

OH

IRX

BuzCuLi,

a

Cope

Ph

(214)

--A

C02Me

Ph

(213)

(215 )

CI E t OA

o

h

O

M

e


117

in which g-silyl-enolates are used, is the problem associated with competing elimination at the enolization step when the allylic ester contains a a-leaving group such as an alkoxide. This can be overcome by premixing the base (often LDA) and the silylating agent (TMSCl or TBDMSC1) before addition of the When a Claisen intermediate contains two allylic ester. lg6 alcohol residues, the less substituted component participates in the rearrangement; thus acetal (218) affords very largely the dienoate (219).lg7 Conjugate additions of vinylalanes, in the presence of a palladium catalyst, to orthoester (220) is an alternative route to yI6-unsaturated esters (221).lg8 Palladium is also used as a catalyst in the coupling of ketone enolate (222) with the allylic nitro-compound (223); the product (224) is obtained in 60% yield largely as the (E)-isomer.lg9 It seems likely that this type of reaction will be applicable to many other substrates. Rather unexpectedly, lead tetra-acetate has been found to effect a highly stereoselective %-bond cleavage of cyclopropanes (225) to give w-unsaturated esters (226) in good yie Ids.2oo In examples where the methyl and silyloxy groups are anti, the sole products are the (;)-isomers of esters (226). Full details have been given of a useful two-carbon degradation procedure for the conversion of unsaturated esters (e.g. methylundec-10-enoate) into w-unsaturated esters (e.g. methylnon-8-enoate), by treatment of alkoxy hydroperoxides produced by ozonolysis of the starting olefin with iron(I1) and copper ( 11 salts . O

-

Aromatic Esters. A relatively simple route to 4-hydroxybenzoates (228) has been developed during work directed towards Avermectin syntheses and consists of sequential addition-elimination of 1,3-diketone dianions (227) to (;)-3-bromopropenoate followed by mild base treatment; overall yields vary between 23 and 34% but are probably in excess of those of alternative routes to such compounds.202 In another approach to aromatic esters from aliphatic precursors Kang and Chan203 have discovered that the silyl crotonate (229) unexpectedly reacts with carbonyl electrophiles at the y-position leading to 9-hydroxybenzoates [e.g. (23011. Yields are around 60%. Related chemistry has been used to prepare the acetoacetate derivative (231)-204

Benzylic ethers (232) can be

118


OSi Me3 I

OH

(227)

(228) R' = H, n-alkyl, Ph, or a l k e n y l

R2 = H or M e

3: Carbonylic Acids and Derivatives

119

converted into the corresponding esters (233), sometimes in excellent yields, by photo-oxygenation in the presence of titanium dioxide.205 The analgesic properties of various phenylacetic acids continue to stimultae the development of new routes to compounds of this type. Aryl bromides can be converted directly into phenylacetates by palladium-catalysed coupling with ethyl 206 a-(tri-n-butylstanny1)acetate in the presence of zinc bromide. Aryl iodides can also be directly coupled to the potassium enolate of a-cyanoacetate using a palladium catalyst to give In a rather different a-cyano-phenylacetates in fair yields.207 approach, nitroarenes (234) have been found to undergo fluoride-induced couplings with ketene silyl acetals leading to phenylacetates (235) after oxidation of the intermediate dihydroarene.208 An alternative strategy €or the preparation of phenylacetates is by carbonylation of benzylic halides. The dimer of chloro(hexa-1,5-diene)rhodium is an especially useful catalyst for such processes while the source of the alkoxide residue can be a titanium or zirconium a l k ~ x i d e , ~ ”a dialkyl ether,210 or a borate ester.211 The presence of iodide as a promoter is essential in the latter two recipes which afford generally excellent yields of a-aryl-alkanoates. Benzyl mercaptans can also be converted into a-arylacetates by carbonylation using [Co2( C O ) 8] as catalyst2I2 but high temperatures and pressures are necessary, in contrast to the foregoing methods using benzylic halides. Nevertheless, reasonable yields (25-83%) can be obtained. Various substituted phenylacetates can be prepared by phase-transfer catalysed Michael additions of t-butyl 213 phenylacetate to acceptors such as cinnamates or chalcone. The rearrangement of a-bromoacetophenones, or acetals thereof, by a [1,2laryl shift to a-arylacetates is somewhat limited because of the requirement of toxic and expensive thallium or silver salts asreagents. This limitation can be overcome by using zinc bromide2I4 (except when no other a-substituents are present in the acetophenone, when simple replacement of Br by OMe occurs), or simply by heating the substrates as their acetals in ethylene glycol containing sodium acetate or a similar weak base at 125 OC for 8-32 h.215 As isolated yields are >80%, this

z.

would appear to be the method of choice for effecting this transformation.


120 Acetylenic Esters.

-

When the allene (236) is metallated using

BunLiin a 1:l mixture of ether and hexane, the intermediate dilithio species can .be sequenially alkylated by primary, benzylic, or allylic halides and ethyl chloroformate to give acetylenic esters (237) in high yield uncontaminated by the corresponding allenic isomers.216 5-Aminoisoxazoles (238) containing an electron-withdrawing substituent at the 4-position undergo ring cleavage upon diazotization using NaN02 in aqueous Yields of products such as the acetylenic ester acetic acid. 217 (239) are variable but there could be some potential in using this type of isoxazole as a masked acetylene in complex syntheses. Efficient syntheses of the hex- and hept-2-yn-dioates (240) have been described in which the acetylene function is generated by pyrolysis of the corresponding a-keto-phosphoranes derived from Wittig reactions between succinic or glutaric anhydrides and Ph3PCHC02Et.218 When the copper acetylide derived from ethyl propynoate is coupled with propargylic bromides, an unusual rearrangement takes place to give excellent yields of 3,5-diynoates (241).219 By contrast, similar couplings with primary allylic bromides lead to 5-en-2-ynoates (242) accompanied by small amounts of the SN2' products. Allenic Esters and Dienoates. - The Wittig approach to allenes from phosphoranes and ketenes or equivalents thereof has been extended to include both 2,4,5-trienoates (243) and the as yet Although yields are unreported 2,3,5-isomers (244).220 sometimes rather low, even in such cases this method probably is and will be the most expedient route to these classes of compounds. a-Allenic esters [cf. (244)l can also be obtained directly from carboxylic acids and phosphoranes by activating the former-with 2-chloro-1-methylpyridinium iodide; [ 3 ] - CUmUlene carboxylates can also be obtained using this method. 221 A range of (Z,Z)-dienes _ including dienoic acids (245) are readily obtainably by an extension of the Normant reaction in which lithium dialkylcuprates undergo double incorporation of acetylene to give a dienylcuprate which can be trapped by a variety of reactive electrophiles including C 0 2 [+(245)1, enones, allylic halides, or methyl propynoate, the latter leading to trienoates (246).222 Stereochemical mixtures of 2,4-dienoates can be efficiently obtained by Pd(OAc)2-catalysed


R'

121

R2

(240)n = 0 or 1, R ' - 4 = H, Me, Ph

(241 1

(242)

C0,Et

0

tu

CO, Et

Ho&

(248)

(2491

122


coupling of vinyl iodides with methyl acrylate, under phase-transfer conditions.223

Much the same couplings can also

be carried out using vinyl triflates.224 2,4-Dienoates can prepared in high yields by Wiftig-typereactions between aldehydes 225 or ketones and arsonium ylides. 7-Aryl-hepta-2,4,6-trienoates (247) have been formed from cinnamaldehydes by coupling with acetylketene dithioacetals followed by NaBH4 reduction and hydrolysis using BF3 in methanol; Vinylogous Reformatsky reagents overall yields are 50-60%.226 derived from u-bromocrotonates undergo highly selective and condition-dependent reactions with enones. For example, cyclohexenone is converted to the '2-a' adduct (248) using 'polar' conditions (Zn/Cu, HOAc in ether) whereas with zinc in THF only the '4-Y' isomer (249) is formed.227 Thioesters.- A useful review of thionation reactions in general using Lawesson's reagent has been published;228 2,4-dialkyl analogues of the reagent can be used to convert carboxylic acids directly into s t h i ~ e s t e r s . ~ ~ ' It has been claimed that the best way to make thioacids is by treatment of an acid chloride with hydrogen sulphide in dichloromethane containing Disulphides have been found to dimethylthioformamide.230 undergo cobalt-catalysed carbonylations to give thioesters; however, at present, the method is only really useful for the preparation of symmetrical aromatic thioesters (ArCOSAr)231 (cf. ref. 212). High diastereofacial selection has been found in condensations between a-methyl-aldehydes (250) and the dithioacetate enolate (251); the =-isomers (252) predominate in these and homologous condensations using the lithium enolate of ethyl dithiopropionate, which give largely diastereoisomers (253).2 3 2 2,3-syn-3,4-anti- or 2,3-anti-3,4-syn-isomers of 6-hydroxy'thioesters related to adducts (253) can be obtained by various Lewis acid catalysed condensations of thioester silyl The thio analogue ketene acetals with a-methyl-aldehydes. 233 (254) of the well known phosphorane from bromoacetate can be prepared in much the same manner as the latter and reacts smoothly with aldehydes to give the unsaturated thioesters (255). The proportion of trans-isomer formed is usually greater than is the case with the oxygen analogue and furthermore (Z)+(E) isomerization of such unsaturated thioesters can be effected by

123


CS,Et

OH

CS2Me

R4 R3

0

Ph P

3

RKS-SeAr

R'

0 RKSeAr

(2631

(264) R1-5

= Hor a l k y l

(2651

124


treatment with a catalytic amount of 4- (dimethylamino)pyridine. 2 3 4 Related phosphonates have also been synthesized and these will prove useful in the preparation Lithium of a,@-unsaturated thiono- and dithio-esters.235 enolates of both thiono- and dithio-esters are soft nucleophiles judging by their propensity to give very largely the 1,4(Michael) adducts with enones. 236 Lithium enolates of dithioesters can be converted into unsaturated esters (256) by coupling with activated derivatives of allylic alcohols; the sequence most likely involves 2-alkenylation followed by a thio-Claisen rearrangement237 (see also Beslin and Vallee in ref. 232). Se-Aryl-selenoesters (258) are available by desulphurization of the sulphenoselenoates ( 2 5 7 ) , obtained from RCO.SBr and a diary1 diselenide or a thiocarboxylate salt and ArSeBr. 238 Methyl selenoesters can be simply obtained by treating alkyl esters with the aluminium-based reagent Me2AlSeMe at 0-20 " C , 239 and a rather neat method has been developed for obtaining phenyl selenoesters from (hindered) carboxylic acids.240 3

Lactones

8-Lactones. - In model studies directed towards a synthesis of the naturally occurring B-lactone Anisatin, it has been found that oxetanes [e.g. (259)l can be oxidized to the corresponding @-lactones (260) ( a s a 1:l mixture of diastereomers) using ruthenium tetroxide, albeit in low yield (25-30%),241 Butyrolactones. - Butane-1,4-diol can be oxidized to butyrolactone itself using a 1-oxopiperidinium salt. 242

One further example suggests that the reagent reacts preferentially with primary alcohols and thus could be useful for the synthesis of a variety of higher homologues of butyrolactone. I n an ~ ~ ~found exploitation of earlier work, G r i m and R e i ~ s i ghave that the readily available silyloxycyclopropanecarboxylates (261) can be converted into butyrolactones (262) in excellent yields by treatment with potassium borohydride in methanol. 4-Methoxycarbonyl derivatives (264) can be obtained by ti related, fluoride-induced cleavage of cyclopropanes (263) followed by oxidation of the resulting lactol. 244 2,2,-Dichlorocyclopropane-l-propanoic

acids undergo direct


125

conversion into the vinylbutyrolactones (265) on treatment with hot 1% aqueous sulphuric acid: yields are variable (8-90%).245 Further examples of an alternative approach to butyrolactones (262) using carbamate-derived homoenolates have been reported in The allylsulphoxide carbanion (266) adds in a detail.246 Michael fashion to but-2-en-4-olide to give largely one diastereoisomer (267) accompanied only by the C - 1 ' ( * ) epimer.247 Presumably, therefore, optically active @-substituted butyrolactones could be obtained by starting with a chiral sulphoxide. Related conjugate additions to a-ethylidenebutyrolactones followed by trapping of the resulting enolate using ally1 bromide are also highly diastereoselective 248 leading to, for example, butyrolactones (268). a-Methylene-6-hydroxybutyrolactones such as compound (269) can be obtained by stereoselective condensations of 6-amino-acid esters with aldehydes followed by elimination. These useful products undergo highly selective reductions or bis-hydroxylation [to give (270) for example], although conjugate additions to the exposed enone system are not particularly attractive in terms of either stereoselection or yield; such reactions are probably best performed on the acyclic precursors to these lactones.249 5-Alkenylbutenolides (271) can be readily obtained from the corresponding but-2-en-4-olides by kinetic enolization and protonation at low temperature and serve as dienes in Diels-Alder Most of the reactions reactions leading to adducts (272).250 are carried out in water at ambient temperature and under these conditions the method seems limited largely to geminally activated dienophiles such as the example shown. Intramolecular Diels-Alder approaches to 3,4-annulated butyrolactones [(273) and Highly substituted [(274)] have also been reported.251 butyrolactones [e.g. (27711 can be prepared from pyrone esters (275) by a sequential intra- and inter-molecular Diels-Alder sequence.252 The isolable intermediates (276) may well be useful in a number of other reactions. Systematic studies253 have shown that intramolecular [2+21 cycloadditions of unsaturated ketenes or ketiminium salts (278) constitute a simple and reasonably general approach to cyclobutanones (279), which are useful as precursors to butyrolactones following Baeyer-Villiger oxidation. The potential of this method is clearly shown by the efficient formation of the bicyclo[5.2.0]nonane

(280) and of the

126


HO

OTry

OTry

(271)

(270)

(269)

*YCozEt H20, 20°C

P

Et

h

S

O

A

___)

- co2

(275)

RJ &o

(276)

(277)

b0

127


w a

L y\=c=x

H

H

(279)

(278)

Y = CH, or 0

eaun F3c0

0

0

(282)

(283)

02 c.

H o 2 c q o (284)

(285)

(286)

128


aflatoxin-type system (281), obtained after oxidation of the initial cyclobutanone. Further developments of a route to chiral butyrolactones based on Claisen rearrangements have resulted in highly selective syntheses of lactones (282) and the less stable (3S)-epimer, derived in five steps from compound (282). 2 5 4 Chiral butyrolactones Ie.g. (283)] can be obtained by Kolbe homologation of the corresponding optically active B-hydroxy-acid using monomethyl malonate followed by enolization 255 and trapping. Complete details have been given for the conversion of (L)-glutamic acid into the useful (5)-butyrolactone acid (284). 2 5 6 Remarkably, protonation of disodium 4-hydroxypimelate by (2)-camphorsulphonic acid (in EtOH at -78 "C) followed by lactonization gives a quantitative yield of the homologous The (R)-enantiomer can butyrolactone acid (285) in 9 4 % e.e. 257 be obtained by reduction (LiA1H4), lactonization, and Jones oxidation with slight loss of optical activity. By contrast, a standard resolution procedure using brucine has been employed to obtain the (5)-azidobutyrolactone (286), a useful precursor to 258 (L)-homoserine analogues. In work directed towards the elaboration of sesquiterpene lactones from sugars, Fraser-Reid's group has succeeded in preparing lactone (287) from glucose.259 The butyrolactone residue is subsequently homologated to a cyclohexanone function. The useful chiral starting material (288), a precursor of Lauraceae lactones, can be obtained from (D)-glucal triacetate.260 (D)-1soascorbic acid (erythorbic acid) can be easily converted into yet another useful, chiral butyrolactone 2 Racemic epoxylactones (290; R1 or R =HI can derivative (289).261 be obtained from the corresponding a-methylene derivatives by direct epoxidation using MCPBA at 80 "C in the presence of a radical inhibitor (nucleophilic methods failed), and disubstituted examples [ e. g. (290; R1=Me, R2=Ph) I can be obtained 262

from B-bromobutyrolactone by a Darzens condensation. Hydrolysis of the meso-diacetates (291; n=1-4) using porcine pancreatic lipase followed by oxidation uniformly gives the lactones (292) with very high optical purities. Yields vary between 56 and 82% overall on scales of up to 2 g of Similarly, rigid meso-dimethyl esters undergo substrate.263 highly selective hydrolyses of only one ester group by PLE leading to tricyclic butyrolactones [e.g. (293)I after

3: Carboxylic Acids and Derivatives reduction.264

129

An alternative approach to chiral bicyclic

butyrolactones (e.g. (292; 2 = 4 ) ] is by the oxidation Of meso-diols using horse liver alcohol dehydrogenase; full details of a suitable procedure have been given although an alternative 265 A set of conditions has also been published recently. variety of enzyme preparations as well as whole-cell systems have been found which can reduce bicyclo[3.2.0lhept-2-en-6-ones to the corresponding alcohols in high optical yields: among other cases, the products can be employed as butyro- and valero-lactone precursors.2 6 6 A further application of Baker's yeast reductions is in the conversion of a-ketothioacetals into optically pure a-hydroxy-derivatives (294; R=alkyl); the utility of these intermediates is shown by a conversion of dithian 267 [ (294); R=(CH2)30H] into the natural butyrolactones (295) (see also ref. 272). Optically pure (+)-eldanolide (296) has been obtained from (Sl-ethyl lactate by a route which features a novel pinacol rearrangement268 and the racemic compound has been prepared using some novel ketenethioacetal chemistry in which a synthetic equivalent of 8-lithioacrylate (297) is generated.269 Racemic pyrocin (298) can be prepared from monomethyl maleate in a 'one-pot' procedure which involves the sequential addition of MeMgI followed by a copper-catalysed Michael addition of 2-methylprop-1-enylmagnesium bromide to the resulting ethylenic Syntheses of the Paniculide B and C precursor carboxylate.270 (299)271 and of all four of the L-factors (295)267 rely on the attack of dilithioacetate on an epoxide to establish the lactone ring, a reaction more notable for its excellent regio- and stereo-selective properties than ,or its efficiency. Full details have been given for the preparation of

stereo isomer^^^^

-

(D) (-1 -pantoy1 lactone (300) by asymmetric hydrogenation of the corresponding keto-lactone; the initial e.e. of 78-84% is improved to 98.5% by two crystallizations.273

(+I-Blastmycinone (301) has been prepared in three different ways; two related methods involve high [1,2]-asymmetric induction in condensations using chiral a-substituted aldehydes as electrophiles which lead initially to the 6-hydroxy-ester 1302) 274 or vinylsilane (303).275 An alternative approach proceeds via an asymmetric [2,31 Wittig rearrangement which initially provides acetylene (3041,276 while ( - 1 -blastmycinone has been obtained from the chiral butenolide (305) by selective

130


(291)

(292)

(294)

(293)

(296)

(295)

yr., SiMej

Bun

(3041

( 305)


131

trans epoxidation, conversion into the corresponding (3-hydroxybutyrolactone, and finally a-alkylation.277

The

synthetic methodology illustrated by these diverse approaches seems likely to find other applications in this and related areas. The useful prostaglandin precursor (308) has been prepared by de Mayo-type photo-addition of diol (306) to the dioxinone (307) followed by heating in water; the simplicity and brevity of this 278 procedure easily compensate for the moderate 30% yield. Closely related prostaglandin precursors have also been prepared from iridoids,2 7 9 norbornadiene,280 and via an iodolactonization procedure which features a pH-dependent O+O

acyl transfer.281

Butyrolactones [e.g. (309)l obtained from but-2-en-4-olide by an established conjugate addition-trapping sequence can be This cyclized to give useful lignan precursors [e.g. (310)I .282 approach has resulted in a synthesis of desoxyisopodophyllotoxin [(310); H in place of PhSl whereas desoxypodophyllotoxin has been obtained by trapping an 2-quinodimethane, generated from an O-silylmethylbenzyl

alcohol, with maleic anhydride followed by some relatively straightforward manipulations. 283 A full account has been given of a radical-based route to

butyrolactones (312) involving the addition of radicals derived from a-iodo-stannyl esters (311) to 0 1 e f i n s . ~ ~ ~ Some intramolecular versions of the reaction are also described in this paper which in addition contains a useful summary of recent radical chemistry aimed at lactone synthesis. A novel intramolecular radical cyclization onto a tetronic acid [(313)+ (314)l is a key feature in the first total synthesis of

alliacolide [B-epoxy-(314)1 . 285

5-Substituted butyrolactones

(315) can be prepared by heating simple methyl esters with t-bu tyl perpent-4-enoate286 and 5-hydroxymethy1 derivatives of butyrolactones can be similarly obtained from ally1 t-butyl peroxide. 287

This recent upsurge of interest in radical chemistry

is perhaps responsible for the resurrection of a method for the elaboration of butyrolactones (318) from olefins (316) and carboxylic acids (317) using manganese(II1) acetate. Rates are enhanced if the acid substituent 'XI is electron withdrawing, X=So2Ph, NO2, P(0) (OEt)21 although some such functionalities [x. lead to gross mixtures of products. However, when X=C1, CN, CH2C1, or C02Me, butyrolactones (318) are produced (yields are ofken between 50 and 6 0 % ) which can be further manipulated to


132

OH

(307)

(306)

PhS

(308)

PhS

-

5

'I

T FA

0

Me0 \ OMe OMe

OMe

(310)

(309)

R1

nBu3

I -CO,S

-

R2

AIBN,

R2tko (312)

(311)

0

R'

0-


133

(321) X = Br, I or SePh

(328)

(329)

(330)

(331)

134


give a-methylene- or a , 8-unsaturated lactones. 288

The method can

also be extended to intramolecular examples and to the elaboration

of bis-spiro-lactones. Major drawbacks with thisapproach can be a lack of regio- and stereo-selectivity and sometimes poor yields coupled with the requirement for substrate stability to hot acetic acid. A simple route to spiro-lactones (320) is by oxidation of the readily available precursors (319) using Cr03 in HOAc-Ac20.289 This one-carbon degradation probably proceeds via the chromate monoester and can also be used to prepare spiro-valerolactones; yields for the simple examples quoted are 42-80%.

Halogenolactones [e.g. (321)l have been found to

undergo smooth coupling with allylic sulphide (322) to give only 'SH2' products (323) by photolysis in the presence of Perhaps surprisingly, yields are quite respectable (Bu3Sn)2. 2 9 0 (33-74%; non-stereoselective) in view of the potential for side reactions; furthermore this method complements the related allylstannane chemistry which cannot be used to introduce a prenyl group. Simple allylstannanes as well as acetonyltributyltin can also be coupled efficiently with a-halogenobutyrolactones in the presence of a palladium(I1) catalyst to provide a useful homologation procedure which is unfortunately limited at present to these two types of 291 organotin. Further work by Alper's group has revealed that hydrocarboxylation of unsaturated alcohols [e.g. (324)I or allylic alcohols using an established set of conditions [PdC12, CuC12, HC1, CO, O2 (1 atm each), 20 " C I leads directly to butyrolactones [e.g. (325)l under sufficiently mild conditions that the method should be applicable to more complex substrates.292 Under different conditions (HOAc, NaOAc, CO, CuC12] palladium chloride catalyses a double cyclization of 3-hydroxypent-4-enoic acids (326) to give, stereoselectively, the his-lactones (327).293 The first step of this reasonably efficient procedure (39-84%) resembles a halogenolactonization. Similarly, pent-4-ene-1,3-diols can be converted into tetrahydrofurans (328);294 alternatively, treatment of 3-hydroxpent-4-enamide derivatives with MCPBA leads to good yields of hydroxybutyrolactones but with variable Dimethyl (methylthio)sulphonium stereoselectivities.2 9 5 fluoroborate (DMTSF) has been found to be an effective reagent for sulphenyl-lactonization, giving comparable yields of

135


5-methylsulphenylmethylbutyrolactones from y,b-unsaturated acids

relative to the coresponding halogeno- or seleno-lactonization unsaturated esters (330) are obtainable in high processes.296 yield by ene-type reactions btween thioacetate(329) and mono-olefins; subsequent saponification and selenolactonization provides the butyrolactones (331), useful as precursors to butenolides G . following sequential oxidative elimination of Selenolactonization of 4-ynoic the seleno- and thio-groups.2 9 7 acids to give v-phenylselenomethylidene-butyrolactones proceeds 298 smoothly using N-.phenylselenophthalimide (N-PSP). Simple 8-acyl-butyrolactones (333; R=Ph or Me) are formed in good yields by TiC14-induced condensations of enol ethers (332) with aldehydes or ketones. This non-stereoselective method can be extended to the elaboration of spiro-butyrolactones (from cyclic ketones) and to v-acylated valerolactones by using The excellent one-carbon homologues of enol ethers (332).299 control of both regio- and stereo-chemistry in reactions between nucleophiles and cyclohexadiene-molybdenum complexes is further exemplified by brief syntheses of various fused butyrolactones [e-g. (334)1 . 300 Further work on condensations of lithium enolates of acyliron complexes, in this case with but-2-ene epoxides,has revealed various stereochemical preferences which may well be of value in designing stereoselective syntheses of 2,3,4-trisubstituted butyrolactones.301

-

a-Methylenebutyrolactones. A useful systematic review of An a-methylenebutyrolactone synthesis has been published.302 improved preparation of the allyl-silane (335), useful as a precursor to a-methylenebutyrolactones by Lewis acid catalysed condensations with ketones or acetals, has been developed.303

A

closely related route to these lactones is by Reformatsky reactions between ethyl a-bromomethylacrylate [i.e. (335) but Br in place of SiMe3] and aldehydes or ketones; these are best carried out in a solution of THF and saturated aqueous ammonium chloride.304 Chiral lactones (336) have been prepared in high optical yields using bromomethylacrylate as the electrophile in condensations with chiral sulphoxides;305 similar optical yields of lactones (336) can also be obtained from condensations between aldehydes and chiral 2-(stannylmethy1)propenamides [cf. (335): Deconjugative alkylation of Bu3Sn in place of Me3Si; amidel. 306 cyclohexylidene acetate (337) by PhSeCH2Br followed by

136


lactonization and elimination provides a new route to lactone 307 (338) which could well find use in much more complex systems. A novel synthesis of (5)-avenaciolide (341) centres on the stereospecific elaboration of the anti-ester (339) by an enolate Claisen rearrangement of the corresponding (g)-allylic glycolate and a highly stereoselective selenolactonization of the derived lactone (340).308 The synthesis of higher homologues, the a-alkylidene-butyrolactones (344), continues to attract interest. A new route proceeds by hydrocyanation of B-hydroxyalkyne derivatives (342) using HCN or acetone cyanohydrin and a The addition is highly regioselective nickel (0) catalyst.309 only when R1 is large (or HI, but in such cases acid hydrolysis of the predominant cyano-alkene (343) gives only the (E)-ylidene-lactones (344). a-Alkylidene substituents can be introduced directly into butyrolactones by a Peterson-type olefination following C-silylation of the unsubstituted lactone (LDA, MePh2SiC1), re-enolization, and condensation with an aldehyde or ketone.310 Often, only the (E) -isomers are obtained from aldehydes: the method appears quite general and can also be applied to a-silylvalerolactones. Essentially the same transformation can be effected by TiC14-catalysed condensations between 2-silyl-enolates of a-trimethylsilylbutyrolactones and aldehydes; in appropriate examples, high Cram diastereo311 selectivities are observed. A deconjugative alkylation procedure has been used to contruct B-methylenebutyrolactones and employed in a total synthesis of 312 the natural product bakkenolide A.

-

Butenolides. An expedient large-scale procedure for the preparation of the parent member of this group, but-a-en-4-olide, by Baeyer-Villiger-type oxidation of furfural using H202-HC02H, has been reported. 313 Hydroxybutenolides (346) are available by regiospecific singlet oxygenation of 2-silylfurans (345).3 1 4 The presence of the readily incorporated silicon function is beneficial to each stage of the reaction sequence. Alternatively, 5-substituted silylfurans (347)I readily obtainable using new carbanion methodology, can be easily oxidized to butenolides (348) using peracetic acid and then The isomerized to the conjugated isomers if desired.315 related but-3-en-4-olides (349) can be prepared in two steps from


137

4

ii, p - T S A

0

(332)

(333)

S i Me3

9 CO, E t

0

RHQ

COzH

(33 5 )

(342)

(336)

(337)

(343)

-----’ H Q ? 0 (338)

(340


138

a 6-keto-ester by sequential alkylation with an a-bromo-acid and careful intramolecular dehydration; coupling of the intermediate keto-esters with simple allylzinc reagents provides the butyrolactones (350), formally Michael adducts of the butenolides (349).316 The easily prepared sulphinyl carbonates (351) undergo smooth intramolecular cyclization upon treatment with LDA; subsequent pyrolytic elimination provides the butenolides (352) in generally This method should find many applications excellent yields.317 and can also be used to prepare the corresponding valerolactone derivatives as well as the saturated analogues by desulphurization using A1-Hg.

4-Amino-butenolides (354) have

been obtained by a related cyclization from the cyanohydrin derivatives (3531, or by an acid-catalysed closure of 318 3-amino-alk-2-enoates derived from protected cyanohydrins. Direct lithiation of a-methoxyacrylic acid (or derived secondary amides) using ButLi produces the vinyl-lithium species (355) which condenses with aliphatic aldehydes to give methoxy-butenolides (356); the rapidity and simplicity of the method compensates for the rather low yields.319 The related mono-anion (357) can be generated from 3-bromoacrolein diethyl acetal by hydrogen-lithium exchange (BunLi, THF, -78 "C) and condenses with ketones to give bromobutenolides (358; X=Br) following mild acid treatment and oxidation of the intermediate Overall yields are high and the initial lactol using Mn02. 320 lactones can be further elaborated to give the corresponding debromo-derivatives (358; X=H) by reduction with Bu3SnH. An alternative method for constructing butenolide substituents of cardenolides features palladium-catalysed couplings of enol triflates derived from steroidal 17-ones and protected 4-hydroxybutenoatesI 321 and a synthesis of digitoxigenin also relies on the use of palladium catalysis, in this case to effect an allylic epoxide rearrangement and concomitant cyclization 322 [ (359)--3(360) 1 . A double carbonylation of styrene oxide using [ C O ~ ( C O ) ~ ] , NaOH, and a phase-transfer catalyst affords a 65% yield of the butenolide (361); further work is needed to define fully the Allenic acids or potential of this simple and mild method.323 esters can be cyclized in variable yields to butenolides ( 3 5 8 ; X=Br, I, H, HgOAc, SPh, or SePh) by a mechanism similar to halogeno- or seleno-lactonization. 324 Ring-fused butenolides.


139

*

CO, Et

CO,Et

R2

PhS=O

(351 1

(3521

L i y o M e

RCHO,

RQOMe

C0,L i

0

Br

X

R’

Li%*Et OEt (357)

-

R

2

(358)

q

140


have been obtained from phenyl esters of allenic acids by intramolecular Diels-Alder reactions in which, unusually, the 325 aryl ring acts as the diene component. Rhodium(1) hydride complexes are known to be capable of effecting a variety of olefin isomerizations; a further example of this phenomenon is the facile and efficient conversion of a-alkylidene-butyrolactones into butenolides.326 Notable natural product syntheses in this area include an improved route to the seed germination stimulant strigol, in which the butenolide unit is introduced by 9-alkylation using 4-bromo-2-methylbutenolide [ (362)+ (363)I , 327 and a synthesis of 8,9-deoxyalliacol B (3651, in which lactonization was effected by acid treatment of the allylic alcohol (364).328 Finally, some methods €or preparing various 2,3-dideoxy-ascorbic acid derivatives, which could be useful synthetic intermediates, have been described in detail. 329 Tetronic Acids. - An attractive new route to tetronic acids (368) consists simply of a Blaise reaction between protected cyanohydrins (366) and Reformatsky reagents derived from bromo-esters (367).330 Yields are generally good (40-72%), although they are much lower when cyanohydrins derived from ketones are used. Rather unexpectedly, deprotonation of 4-ethylidenetetronic acid 2-methyl ether using LDA at -78 "C in THF leads directly to the vinyl anion (369) and thence to 2-substituted homologues.331 Extension of the 2'-position can be achieved by Wittig reactions of the phosphonium salt (370) derived from the parent ethylidenetetronic acid by NBS bromination and quaternization with PPh3. The former metallation method has been applied to the elaboration of structures [e.g. (371)1 proposed for the aspertetronin group of microbial metabolites; however, the non-identity of the natural and synthetic compounds led to the deduction that the natural 332 compounds are actually the 5-methoxyfuran-3(2g)-one isomers. The novel phosphonium salt (372) has been used in a non-stereoselective synthesis of members of the pulvinone group (373). This brief and useful method, which produces (E)-pulvinones for the first time, is complemented by an alternative approach to these compounds using a Dieckmann-type condensation of diester (374) to establish the tetronic acid ring, and which produces only the (Z)-isomers of acids (373).333


141

PhJo

d rl,

2

(359)

(360)

Go-

Ph

&OH

0 0

OMe

+rLi 0

(369)

OMe

1


142

Phthalides. - In chemistry related to the foregoing work the phthalide phosphonates (375) have been shown to be useful precursors to ylidene-pthalides (376).334

The initial isomeric

mixture can be converted into solely the (Z)-isomer by base hydrolysis (KOH-H20, 100 "C) followed by re-closure (Et3N, C1C02Me). The phosphonates are derived from the corresponding phthalaldehydic acids and hence no regioselectivity problems arise. Decarboxylation of phthalide-3-carboxylic acid salts by thermolysis at 145 "C in the presence of aromatic aldehydes gives variable yields of the ylidene-phthalide precursors (377);335 the the phthalide anion, which can reaction probably proceeds JJ& also be generated from phthalide itself using a strong base. A variety of routes to substituted hydroxy-phthalides (378) have been developed which mostly rely on diverse types of metallations of benzene derivatives although a Diels-Alder approach from cyclohexadienes (379) and acetylene (380) The products (378) are useful represents a good alternative.3 3 6 as precursors of the corresponding 3-cyanophthalides. Under appropriate conditions 3-methoxy- and 3-nitro-phthalic anhydrides undergo almost regiospecific attack at the 'metal carbonyl by aryl Grignard reagents, thus providing a route to 337 3-aryl-3-hydroxyphthalides. Valerolactones. - Enantioselective reduction using Baker's yeast, a method most often associated with chiral 8-hydroxy-ester has also been applied to generation of the preparation, 116-119 useful diol (381) from the corresponding propanone (90% yield, 78% e.e.); the potential utility of the diol is demonstrated by its conversion into both enantiomers of the hornet pheromone 5-hexadecanolide (382), following conversion into the Alternative thio-epoxide and subsequent cuprate additions. 338 approaches to chiral 5-hexadecanolide (382) also include methodology which could be applicable to other asymmetric syntheses. Thus, Mori and Otsuka have prepared both enantiomers by resolution of 2-chloroacetylaminotridecanoic acid using Aspergillus amino acylase which hydrolyses only the (S)-acetyl enantiomer, 339 and other Japanese workers340 have developed a procedure for chelation-controlled reduction of chiral 8-keto-sulphoxides by Dibal-H and applied the method to the elaboration of both butyrolactones and valerolactones, such as the pheromone (382).

A synthesis of the acetoxy-valerolactone

143


(371) 0-

OH

(372)

(373)

(374)

R'C H O

R'R+@

____)

*

0

0

Ar

(375)

(376)

(377)

(378)

1

C0,Me

COzMe


144

(383) in racemic form relies upon a stereoselective iodine(II1)-induced fragmentation of a 3-stannylycyclohexanol (384)+ (385)1 .341 isomer to generate an (E) - -en-5-enal precursor New routes to the related lactone Malyngolide (386) have also been reported; the (-)-enantiomer has been obtained from D-mannose,342a the ( + ) -enantiomer using an asymmetric Sharpless epoxidation,34223 and simple hydrogenation of the corresponding 2,3-dehydro-derivative obtained 2 a crossed-aldol condensation delivers (2) - (386) with high s t e r e o ~ e l e c t i v i t y . ~The ~~~ carpenter bee pheromone (389) has been prepared by Pd-catalysed 1,4-acetoxychlorination of (g,Z)-hexa-2,4-diene; the single diastereoisomer (387) of the acetoxychloride thus produced is then homologated to the sulphone (388) by Pd-catalysed attack of the corresponding lithiated sulphone, with retention of stereochemistry.343 By starting with (g,g)-hexa-2,4-dieneI the same sequence leads to trans-(389). That ever-popular traget, the Prelog-Djerassi lactone (390), has once again provided the motivation to develop new and useful methodology. Various allyl-stannanes condense with meso- or (5)-dimethylglutaric hemialdehyde with high anti-Cram and Cram selectivities respectively to provide a rapid route to the lactone (390) and

potentially many related structures.344 An alternative approach is based on allyl-silane chemistry and features some fascinating and potentially valuable methods for stereocontrol in acyclic Routes to optically pure material include examples systems .3 4 5 based on enantioselective aldol-type condensations346 and [2,31 sigmatropic (Wittig) rearrangements347 (see also ref. 353) . An essentially enantiospecific route to another popular valerolactone target, the terpene precursor mevalonolactone (392), has been developed based on Eliel's chiral benzoxathiane chemistry; the key intermediate is the (Rl-nitrile (391) which is - (392).348 The subsequently converted into both ( 5 ) and (2)

-

ability of the natural products c ~ m p a c t i nand ~ ~ mevinolin ~

to

suppress terpenoid biosynthesis by mimicking mevalonolactone (392) has continued to stimulate research into new routes to the key structural feature, the valerolactones (393). A general route to optically active lactones (393) begins with isoascorbic acid,350 whereas an alternative proceeds y & nucleophilic attack onto a (3R, 6~)-5,6-epoxy-3-alkoxyhexanoates derived ultimately Compactin analogues (393) have also from ( 5 )-malic acid. 351 been obtained from (D)-glucose in a brief sequence which relies


145

zoAc (387)

(388)

(389)

146


heavily on Wittig olefinations.352 The synthetic potential of Lewis acid catalysed cycloadditions of aldehydes [e.g. (39411 and 'activated' dienes [e.g. (395)l has been amply demonstrated by Danishefsky's group353 in, for example, a further preparation of the Prelog-Djerassi lactone (390) via pyran (396). This methodology has also been elegantly applied to the synthesis of various sugars and amino-carbohydrates: the mechanism is either Diels-Alder or aldol-like depending upon the Lewis acid used. An alternative Diels-Alder approach to valerolactones consists of cycloadditions between dienes and ketomalonates (mesoxalates) followed by degradation of the geminal diester function; the method is thus the equivalent of using carbon dioxide as the dienophile and has been illustrated this year in a synthesis of (2)-Ambreinolide (397).354 The rather congested nature of the diene required the use of high pressure ( 2 0 kbar; 55 "C) to force the cycloaddition to proceed. Yet another Diels-Alder route to pyrans and hence valerolactones is to employ a,D-unsaturated carbonyls as the diene components. A good illustration of this method is a highly enantioselective synthesis of tricyclic lactones (398)

using a benzylidene-oxazepanedione easily derived from ( + ) - or (-)-ephedrine as the diene component.3 5 5 One example, [(399)-+ (400) + (401)], indicates that palladium-catalysed cyclizations

of 2-silyl-enolates (399) of butenyl esters could be developed into a viable route to many more highly substituted v a l e r o l a ~ t o n e s . ~An ~ ~alternative way to form the C-3 to C-4 bond in valerolactones by an intramolecular Claisen condensation has been illustrated.357 Given the choice, as in 4-alkenoic acids, iodolactonization will generally afford five- rather than six-membered lactones. However, bromolactonization of these systems tends to favour valerolactone formation, especially when the 3-position is s~bstituted.~~' Macrolides. - The Steglich esterification procedure (DCC-DMAP) can be applied to the macrolactonization of w-hydroxy-acids if, in addition, an excess of the hydrochloride salt of DMAP is present, presumably to assist in the proton-transfer steps and However, slow thus prevent the formation of N-acylureas. 359 addition and relatively dilute conditions

(z.35 ml

of solvent

per m o l ) are still required and yields tail off distinctly when medium-sized rings are formed: 16- and 17-rnembered, 9 5 % yield,


147

OMe

Ph

OSiMe3

Ph

(397)

(399)

(3981


148

l3-memberedI 32% yield. Full details have been given for the Gerlach macrolactonization method which uses silver-ion promoted cyclization of w-hydroxy-pyridylthioesters.360 However, the main emphasis in this area recently with respect to the development of new methodology has been on macrolide formation by C-C rather than C-0 coupling. Intramolecular displacement of a methylthio-group by an allyl-stannane function, initiated by dimethyl(methy1thio)sulphonium fluoroborate (DMTSF), under high dilution conditions (0.01M) has been used to prepare 14- and 15-membered examples [e.g. (402)-(403) ] in 46-48% yields.361 An added bonus inherent in this procedure is that the thioacetal function is also a key element in the elaboration of the precursor (402).

Thiol groups are also crucial in a

related method consisting of EtAlCl 2-promoted condensations of a-chlorosulphides with an allyl-silane function [e.g. (404)(405)l. Significantly this method affords medium-sized lactones (8-11 membered), which are the most difficult to prepare, in

relatively good yields (34-55%) without recourse to high-dilution 362 conditions. A neat fragmentation approach to 14-membered lactones consists of ozonolysis of decalins [e.g. (406)] containing an hydroxypropyl substituent which traps the intermediate carbonyl oxide to give the isolable hydroperoxide (407), which is subsequently cleaved using Cu(OAcI2-Fe SO4 to give the macrolide Oxygenation as in [e.g. (408)1, in good overall yield. 36' substrate (406) may well be a minimum requirement for the success of this methodology. In a somewhat related route, phoracantholide I (decan-9-olide) has been prepared by 364 alkoxy-radical mediated ring cleavage of a bicyclic lactol. The rather unusual natural macrolide pyrenolide B (411) has been prepared by a route which features an oxidative cleavage [(409)-+ (410)l at the key lactonization stage as well as protection of the reactive enedione function as a Diels-Alder adduct. 365 Attempts to form medium-sized macrolides from w hydroxy-f3-keto-thioesters using a Masamune-type procedure results instead in the formation of bis-macrolides (diolides) in reasonable yields.366 This observation is a timely one as there has been considerable interest in the synthesis of natural diolides.

Both pyrenophorin (412) and the structurally similar

colletallol have been prepared by formation of the corresponding saturated diolides, using diethyl phosphorochloridate as coupling


(402)

149

(403)

SiMc,

PhS

H


150

agent, followed by introduction of the two olefinic bonds (PhSeBr-LDA, oxidative elimination) thus avoiding any problems of Michael addition to the enoate functions.367

The latter steps are unfortunately not particularly efficient (<SO% yields). An alternative approach to nor-pyrenophorin and related macrolides

containing u-hydroxy- or v-keto-enoate functions consists of a combination of Bestman's macrolactonization procedure170 using

W-

hydroxy-aldehydes and ketenylidenetriphenylphosphorane and selenium dioxide oxidations either in dry dioxan, which leads to the v-keto-derivatives, or in dioxan-3% water which affords the Optically active corresponding Y-hydroxy-compounds.368 (-)-grahamimycin A1 ( 4 1 3 ) has been prepared by a relatively brief sequence in which the potentially awkward vicinal dione function is masked until the last stage as an acetylene group: sadly this final oxidation step was very inefficient.369 Another success has been a synthesis of (+)-l1,ll'-di-2-methylelaiophylidene, a diolide which, although possessing a C2 symmetry axis, is still a relatively fearsome target.370 Various simpler analogues of the dilactonic necine alkaloids have been obtained using the Corey-Nicolaou (pyridine-thiol ester) method to form the final lactonic bond,371 and some progress has been made towards the synthesis of pyridomycin, an unusual diolide lactam. 372

Finally,

a useful review of the total synthesis of macrolide antibiotics has been published.373 The macrolactonization of w-hydroxy-acids can sometimes be significantly assisted by restricting the mobility of the connecting chain. An extreme example of this is the efficient (74% yield) lactonization of (~)-ll-hydroxyundec-6-en-4,8-diynoic acid to give the macrolide (414) simply by treatment with p-TSA

in hot benzene; perhydrogenation then gave 11-undecanolide (85%) .374 Finally, Hesse has reported a further ring expansion method for converting cycloalkanones into macrolides by the overall 'insertion' of (CH2)2CH(Me)0.375 4

Carboxylic Acid Amides

General Synthesis. - Unsaturated secondary amides [ ( 4 1 5 ) and ( 4 1 6 ) l have been found to undergo largely anti-Michael additions The when treated with an excess of an alkyl-lithium.3 7 6

initially formed CON(Li)Me function is probably the key factor in triggering these very unusual reactions.

The N-tosyl-amides


151

(417) are particularly suitable €or the preparation of substituted amides 2 a conventional Michael reaction with alkyl-lithium or -magnesium species in the presence of copper salts.377 As such conjugate additions can be achieved in other ways, probably the main interest of this method is the possibilities offered by the N-tosyl-amide group €or facile transformations into other functionalities. TWO new methodsfor the conversion of carboxylic acids into primary amides may be of use in some circumstances. Acyl azides are reduced to the corresponding amides by potassium tetracarbonylhydridoferrate [KHFe(C0)41 in ethanol at -40 "C under an atmosphere of carbon monoxide378 and acid chlorides are directly converted into primary amides (50-92% yields) upon treatment with 2-3 equivalents of hexamethyldisilazane in This latter method methylene chloride at room temperature.379 could be particularly useful with sensitive substrates. The overall conversion of alkyl halides (418) into N-substituted acetamides (420) can be achieved by sequential N-alkylation of 2-methyl-2-oxazoline, ring cleavage of the resulting salt using NaSePh and oxidative elimination to give the N-vinyl derivative (419) and finally de-vinylation by oxymercuration-demercuration.380 The method is only practical for reactive halides (allylic or benylic). Primary amides can be specifically N-alkylated by primary alkyl halides using a mixture of potassium hydroxide and alumina as p r ~ m o t e r ~ ~ l a n d N-allylated under neutral conditions by treatment with 2-allylisourea (derived from DCC and an allylic alcohol) and a A new route to enamides (423) and palladium (0)complex.382 dienamides proceeds & y initial formation of sulphones (422) from a secondary amide (421) using formaldehyde and PhS02H followed by deprotonation (LDA), alkylation and base-induced elimination.383 Of course, the substituent 'R1' cannot contain a proton a- to the amide carbonyl; in the examples quoted, R1=Ph or OEt. Hydroxy-amides. - Wittig rearrangement of acetamide (424) [LDA, - 8 5 " C ] provides almost exclusively the erythro-a-hydroxy-amide (425). The likely transition-state geometry suggests that the presence of vinylic substituents larger than methyl should at least maintain this level of selectivity during rearrangement. Unfortunately similar reactions of chiral amides derived from prolinol result in only moderate asymmetric induction.3 8 4

152


(417) R3MgX, Cul

R = P h o r MejSi

(418)

0

,IKI,, (4211

R’ !

R’

R2 = Ph or M e 3 S i


153

a-Hydroxy-amides can also be obtained from ring opening of a-hydroxy-acid acetonides by direct nucleophilic atack by amines; a study of the scope and limitations of this moderately useful method has been reported.385 O-Keto-amides (426) are available by asymmetric acylations of the corresponding amide enolate and on reduction with zinc borohydride provide

syn-2-alkyl-3-hydroxy-amides; however, the corresponding anti-isomers (427) which are the less common products in this type of chemistry, are obtained upon reduction of keto-amides Reductions of (426) using potassium triethylborohydride.386 B-keto-amides and esters in general by this reagent are anti-selective to a greater or lesser degree. Either 2-or anti-selectivity is observed in reductions of a-alkyl-0-keto-amides [cf. (42611 by PhMe2SiH depending upon the additive (either F- or )'H present. 387 This latter method looks especially useful as it is not particularly dependent on the nature of the amide substituents, and is generally extremely stereoselective. Keto-amides. - A detailed mechanistic study has been carried out on the useful palladium-catalysed double carbonylation of aryl halides leading to a-keto-amides which further establishes optimum conditions for the reaction.388 Another detailed study, this time of kinetic Michael additions of amide enolates to enones has resulted in the determination of various conditions for effecting such reactions with high diastereoselectivities, thus providing a useful route to substituted 6-keto-amides.389 Unsaturated Amides.

-

In further examples of conjugate additions

to unsaturated amides, various stannyl copper species have been found to add to acetylenic amides (428) to give either (El- (429) or (Z)-@-stannyl amides, depending on the reaction conditions. The intermediate enolates can be trapped by reactive Another group of electrophiles to provide higher homologues.390 useful synthetic intermediates are the a-chloroacrylamides (430) which can be obtained from simple saturated amides by chlorination of the derived a-chloro-enamines followed by A1C13-induced dehydrochlorination.391 The method is also applicable to the preparation of the corresponding thioamides and amidines. A full account has been given of B ' - l i t h i a t i o n ~of ~~~ unsaturated amides (431); yields of the trapped products (432)

154

General and Synthetic Methods 0

OwNMe2

NMe2

&NMe2

R'

R1+c, R

M e3Sn

(428)

( 4 3 01

(429)

CONE1,

CONE12

Li

(434)

R

E'2NK0 0

(437)

( 4 3 6 ) R = H or CI

(435)

I I -

(438)

(439)

(440)

0

II

d-

CO, R h ( l ) , HNR2R3

0 (441)

( 4 4 21

155

3: Carboxylic Acids and Derivatives are moderate to excellent.392

Over the past few years a number of research groups, especially that lead by Snieckus, have demonstrated that a wide range of substituted aromatics can be obtained by lithiations of aromatic amides. The novel dianionic species (433)-(435) can be obtained by metal-halogen exchange or direct metal-hydrogen exchange in the latter case. Reasonable yields of the expected disubstituted homologues are obtained on trapping with simple electrophiles.393 Upon warming, the dianion (435) undergoes a bis-anionic Fries rearrangement to give 2,5-dihydroxyterephthalamide; a combination of this rearrangement and the foregoing chemistry, but using stepwise metallations, has been used to prepare the isocoumarins 394 (436), precursors of the natural toxins ochratoxin A and B. Similarly, heterocyclic amides can be bis-metallated;395 the dianion (437) can be coupled with different electrophiles, the first attacking the more reactive 3-positionf although perhaps predictably yields of 2,3,5-unsymmetrically substitutedthiophenes are only moderate. The ability of amide groups in general to direct metallation to the usually less reactive 3-position in 396 these types of heterocycles has been summarized. The sulphone-stabilized dianion (438) undergoes efficient condensations with aldehydes to provide diols (439) after overall replacement of PhS02 by OH using selenium chemistry; the dianion can therefore be regarded as the equivalent of anion (440).397 Allylic phosphates (441) can be smoothly carbonylated using a rhodium carbonyl catalyst under strictly defined conditions; when a primary or secondary amine is present, B,v-unsaturated amides This could certainly (442) are obtained in good yields.398 prove to be a method of choice for at least small-scale homologations to such unsaturated amides.

A standard route to

y,b-unsaturated amides is the amide acetal version of the Claisen rearrangement, for which new and potentially useful conditions More have been described in a preliminary report. 399 conventional amide acetal rearrangements of chiral allenic alcohols can result in high asymmetric inductions to give Diethoxyallenes dienamides [e.g. (443)] in good yields.400 (444) can be derived from malonic acid diamides, and react with malonyl dichloride to give allenic dicarboxamides (445) in 401 variable yields.


156

-

Thio- and Seleno-amides. Thioamides can be obtained in good yields by reactions between tj-methyl-nitrones derived from aldehydes and 1 I 1 '-thiocarbonyldiimidazole or related species. 402 This method could therefore also be valuable as an overall oxidation procedure although the conditions (80 "C, 8 h) probably preclude the possibility of having olefinic bonds in the An substrate due to competing [ 1 , 3 1 dipolar cycloadditions. alternative oxidative method for thioamide preparation is based on a very mild version of the Willgerodt-Kindler reaction in which primary alkyl chlorides (446) or a corresponding tertiary amine carrying an additional electron-withdrawing function (IRI) react with morpholine and elemental sulphur at room temperature in DMF to give amides (447) in generally respectable yields, exemplifying the special reactivities associated with 'captodative' compounds such as halides (446). 4 0 3 A further application of chiral sulphoxides is in an asymmetric synthesis of C-hydroxy-thioamides (448) with 40-90% e.e. from aldol condensations using optically pure p- to 1y 1su 1 phiny 1 -rJ ,g-dime thy 1 thioacetamide . [The absolute configuration of the products (448) varies with the nature of substituent 'R'.] Achiral 8-amino-thioamides (449) are available by condensations of 5-silyl-enolates of thioamides with aldimines in the presence of a Lewis acid.405 A seemingly straightforward method to prepare aromatic selenoamides (451) is to react the corresponding nitrile (450) with elemental selenium in aqueous THF containing Et3N under 5 Presumably the key reagent is atm of carbon monoxide.406 hydrogen selenide formed in a water-gas shift reaction: the method is unfortunately much less efficient when applied to aliphatic nitriles. Thioamides can be very efficiently desulphurized to afford the corresponding amides by treatment with 2-nitrobenzenesulphonyl chloride and potassium superoxide at -30 " C in acetonitrile.407 5

Amino-acids

a-Amino-acids. - Further examples of Sch6llkopf's bis-lactim ether approach to a-amino-acids serve to emphasize the value of the methodology. Condensation of the key intermediate (452; R'=H or Me) with epoxides in the presence of BF3.0Et2 provides the protected homoserines (453) after appropriate manipulations

157


(4451

(444)

R

( 4 4 6 ) R = NC or Ac

NHR~ s

R

1

(447)

NMe,

(448)

Se

vN Me2

(449)


158

of the initial products.

Chiral inductions are usually very

high, as are kinetic resolutions when the anion (452; R'=Me) is 408 treated with two equivalents of a racemic epoxide. Hydrolysis of amino-esters (453) leads to

a-amino-butyrolactones (454).

Intermediate (452) has also been used to prepare chiral tryptophan and its a-methyl homologue409 as well as the chiral between (452; derivative (455) of a - m e t h ~ l a l a n i n e . ~Reactions ~~ R'=H) and a-chloroketones lead to the novel epoxy-a-amino-acids (456; R=Ph or Me); only the (3R)-enantiomer is obtained although 411 little stereoselection occurs at the epoxide carbon. Nucleophilic attack of azide provides the potentially useful azide derivative (457). High asymmetric inductions occur in condensations of the lithium carbanion (452; I ? ' = H ) or the corresponding titanium derivative with glyceraldehydes or (z)-lactaldehyde to give optically pure hydroxy amino-acids [e.g. Use of the titanium species also improves the

(458)3 .412

diastereofacial selectivity in condensations of bis-lactim ethers with simple aldehydes as exemplified in a synthesis of (D)- (2g,32)- t h r e ~ n i n e . ~ lA~ useful variant of this method is to homologate the chloro-derivative (459), obtained from (452; R1=H) and hexachloroethane, surprisingly as the &-isomer, addition of soft nucleophiles.

by the

For example, reaction with

sodio-malonates followed by degradation leads to the A powerful 8-carboxyaspartic acid (Asa) derivative (460).414 alternative to the foregoing Schb'llkopf method for asymmetric syntheses of a-alkylated homologues of a-amino-acids is the Seebach approach in which an a-amino-acid is converted into an oxazolidinone (461) or imidazolidinone by condensation with pivalaldehyde and cyclization; subsequent enolization and electrophilic attack anti to the bulky t-butyl group provides, after hydrolysis, essentially optically pure homologues (462). Whereas the oxazolidinones are formed as largely the &-isomers (461),415 the corresponding irnidaz~lidinones~'~ are produced mainly as trans-isomers, hence allowing the preparation of either enantiomer of the desired homologue. In contrast, alkylations of a nickel complex derived from the Schiff's base of (L)-alanine and (~)-2-~-(~-benzylprolyl)aminobenzaldehyde proceed with poor diastereoselectivities; however, separation of the two products is claimed to be straightforward and hence both enantiomers

of

the a-methyl-a-amino-acids (462; R=Me) can be obtained from one reaction417 (see also ref. 439).

A potentially general route to


159

RZ \

MEMO R2

R’

Me0

(453 1

(4521

(454)

H7Hco2H

R

O

N-3 (456)

(457)

0,Me N

-----’ RO,C

H%NX:Ye

Me0

CO, R

H

(459)

(460)

R\/\/C 0,

H

(4611

(462)

t

‘

OH

hH2

(663)

160


(racemic) dihydroxyamino-acids (463), aldol condensations between aldehydes and the tin(I1) enediolate derived from furylglyoxal, has been exemplified by a synthesis of methyl (D)-glucosaminate (463; R=2,2-dimethyl-1,3-dioxolan-4-yl). 418 A new route to racemic a-amino-acids in general consists of an overall a-amination of simple carboxylic acid esters in a relative of the Japp-Klingermann reaction, a method which is usually only successful with active methylene compounds such.as malonates. Thus, 2-silyl-enolates of esters (464) condense with benzenediazonium tetrafluoroborate to give, after isomerization, the hydrazono-derivatives (465), precursors of the a-amino-esters (466), following hydrogenolysis. Perhaps surprisingly,

one

treatment of methyl hippurate (467) with equivalent of LDA followed by alkylation gives the C-alkylated products (468) in No 2-alkylated products were observed. 52-61% yields.420 Presumably dipole stabilization by the adjacent amido carbonyl group is the key to this reaction, which is certainly more economical than related methods in which the dianion of the ester (467) or even the trianion of hippuric acid itself have been used to effect the same overall homologation. N-Alkylation of a-amino-acids without racemization can often be difficult, so a new procedure for the 2-ethylation of N-Boc-a-amino-acids by dianion formation followed by addition of Et30BF4 will be of interest.421 The N-ethyl derivatives (469) are isolated in 70% yields with no racemization. Most of the general methods for preparing a-amino-acids are based around the intermediacy of a C-nucleophilic amino-acid equivalent. A departure from this pattern is the observation that the acetoxy function of the readily available glycine derivative (470) can be displaced by a range of nucleophiles including neutral alcohols and thiophenols but not amines or phenols. 4 2 2 More exciting is the finding that the acetate (470) undergoes similar reactions with organocopper species423 and o r g a n o b ~ r a n e sto ~ ~ provide ~ a whole range of a-amino-acids (after facile imine hydrolysis) with substituents such as aromatic,

z.

heteroaromatic [e.g. (472)I , 427 secondary and tertiary groups [e.g. (473)], which are difficult or impossible to incorporate by the more conventional anion chemistry. The future utility of this glycine cation (471) equivalent thus seems considerable. Nucleophiles potentially can attack a-imino-esters at three sites: the ester group, the imine carbon, or the imine nitrogen.


161

Allyl-BBN derivatives have been found specifically to attack the imine carbon in ester (474)to provide some examples of u , b unsaturated a-amino-acids; thus a-imino-esters (474) can also act as synthetic equivalents of the cation (471).425 When the imine is derived from optically pure 1-cyclohexylethylamine, very high asymmetric induction is observed. Similarly, enamines [e.g. (47511 attack the imine carbon in the related ester (475) 426 to give a-amino-esters [e.g. (47711 after acidic hydrolysis. When the ester group is (+)-menthyl, chiral induction is complete. The principle of asymmetric steric shielding has been used to control hydrocyanation of Schiff's bases formed between thienylcarboxaldehydes and a chiral dioxan; hydrolysis of the resulting amino-nitriles leads to optically active The highly activated imine (478), and thienylglycines (472).427 the related compound derived from chloral, behave as powerful enophiles in reactions with simple alkenes at ambient temperature with no additional catalyst leading to ally1 glycine derivatives (479) in 49-90% yields.428 A 8-cyclodextrin derivative has been used to effect reductive amination of some a-keto-esters to give 429 almost pure enantiomers of the expected a-amino-acids. Although this B6 enzyme mimic is as yet inefficient and small-scale, further developments will surely follow in this exciting area. A full account has been given430 of the rather unexpectedly efficient couplings of tosyl or halogeno derivatives (480) of serine and homoserine with organocuprates which can be used to prepare a wide range of optically pure a-amino-acids. As these reactions are free of racemization, an elimination-addition mechanism is ruled out; however, organocuprates [RMgX + CuIl do add efficiently to the serine elimination product, methyl 2-amidoacrylate, to give reasonable yields o f racemic Trapping the intermediate enolates with D + or a-amino-acids.431 Me1 provides further homologues. A rather unusual approach to chiral a-amino-acids begins with the chiral and very sensitive seleno-aldehyde (481), derived from ethyl (2)-lactate, which is homologated to the olefins (482) using a (Z)-selective Wittig reaction; these are subjected to an established [2,31 sigmatropic rearrangement to give allylamines (483) which are finally degraded to amino-acids (484) using ozonolysis and Jones Of particular note is that this method leads to oxidation.432 (D)-enantiomers (78-84% e.e.) but begins with the much cheaper

162

General and Synthetic Methods NH I,

LDA,TMSCI

H2 Pd IC

R-CO~M~

(465)

(464)

Ph

~

(4661

Ph

-

AN”

L0 DA RX

L 0 2 M e

Ph NAP,

(470)

(474)

R AC02Me

NH2

t‘C02H

(471)

(475)

d

;

O

2

(472)

(476)

H

JC02H

(473)


163

(S)-enantiomer of ethyl lactate and should therefore find some applications, within the obvious constraints of the methodology (see also ref. 458). The continuing interest in the role of aminocyclopropanecarboxylic acids in ethylene biosynthesis has resulted in the development of large scale routes to deuterium-labelled coronamic acid analogues [e.g. (485) and (48611 and methods for the optical resolution of such compounds433 (see also ref. 435) . Two natural cyclopropanes [(487) and (488)l have been successfully synthesized starting from allylic acetate ( 4 8 9 ) which undergoes smooth Pd-catalysed [3,3] sigmatropic rearrangement to give the isomeric acetate (490); cyclopropanation [CH2N2-Pd (cat.)1 then leads to the amido-ester (4911, the final precursor of both compounds.434 Four-, five-, and six-membered alicyclic amino-acids (493) can be obtained in ca. 50% overall yields by alkylations of the isocyanoacetate (492) with 1,~-dibromidesfollowed by mild hydrolysis; the effects of substituents have not been examined. 435 A wide range of.optically pure 6-substituted-a-amino-acids (495) have been obtained from 2 - 2 or 5-Boc-serine by formation of the corresponding @-lactone (494) using Mitsunobu conditions followed by nucleophilic attack by arange of soft heteroatomic Two useful starting materials, the reagents.436 B-hydroxy-amino-acid derivatives (496) and (4971, have been derived from tartaric acid by epoxide formation, azide ring opening, and reduction; as both L- and D-tartaric acid are freely available so are both enantiomers of these useful materials. 437 A reasonably general though rather poor-yielding route to 6-hydroxy-a-amino-acids is by aldol condensations between aldehydes and 2-silyl-enolates of N,N-dibenzylglycinates; the major isomer is usually t h r e ~ . However, ~ ~ ~ chiral, threo-B-hydroxy-a-amino-acids can be obtained in high yields by similar aldol condensations but with the nucleophilic component being a nickel complex of a chiral Schiff ' s base4I7 of g~ycine.~~'

A potentially widely applicable route to chiral 8-aminoalanines has been exemplified in a neat synthesis of ( L ) -quisqualic acid (498) from ( L ) -serine. 440 Eantiomerically pure a,y-diamino-acids have been obtained by Michael reactions between nitro-olefins and a 1,3-oxazoline-4-carboxylate derived from ( S ) - t h r e ~ n i n e . ~ This ~ ~ work could form the basis of a


164

NHZ C0,H ( 4 8 2)

(481)

Me & H 3

H+LOi

H

D (485)

H

(486)

YHBoc

N H Boc

NHBoc

H

I I

I

H

OAc (489)

(490)

(491)

qHR

90 " l o R e a g e n t s : i;[Coif(CO)8

3 ; ii, CF3C02H, N a B H 4 ; iii, F e ( N O 3 I 3 . 9 H 2 0

Scheme

5

I

6 5 - 99"Io

R = a r y i or vinyl OH H

i, ii

Ph' N 2 O H

PhXCN

a

H

A

R e a g e n t s : i , B u t O O H , [ ( P h 3 P I 3 R u C L 2 ] ; ii,

Scheme

65 "lo

H N 2 o H

6

[CI-(CO)61

B ~ ~ O ~ H

HO

HO Scheme

9 9 "I0

7

324


I , V , 11-IV

HO

Ac 0

69"lo OAc Reagents:

I,

Na2PdC14 ,NaOAc

i i , p y r ; iii, P b ( O A c I 4

Scheme

iv, NaBH4

;

L

N

E

v, Ac20

8

[ R h ( R- bina p ) (C 0 D) 3

&NEtz

;

-

'

____t

t

t

5 -99 "lo e.e. Scheme

9

Scheme

10

6: Organometallics in Synthesis

325

the co-catalyst trifluoroacetic acid (Scheme 1 1 ) ;24 whereas the corresponding thermal reactions require 170-250 OC , the catalysed isomerizations occur at 50-100 OC. I-Vinylcyclobutanols undergo ring expansion to 2-methylcyclopent-2-enones in the presence of catalytic amounts of [ ( PhCN l2PdCl2I and an excess of benzoquinone (Scheme 12). 25

Allylic acetates couple with dimethyl propargylmalonate anion in the presence of [(Ph P) Pdl to give Il6-enynes. In the presence of 3 4 [(g-toly13)P12Pd(OAc)2 these 1,6-enynes isomerize to Il4-dienes unless the l14-diene product would contain a trisubstituted olefin in which case Il3-dienes are obtained (Scheme 13) .26 1 ,3-Dienes are also obtained when the enyne contains an allylic oxygen substituent .27

5 Carbon-Carbon Bond Formation via Organometallic Electrophi1es.- 4,6-Isopropylidene-3-(trifluoroacety1)-D-glucal reacts with stabilized carbanions in the presence of catalytic amounts of bis(dibenzy1ideneacetone)Pd [(dba) Pdl and bis(dipheny1phosphino)ethane (dppe) to give the 2 corresponding B -C-glycosides (Scheme 14 1. 28 Aryl ketones may be converted into the corresponding benzylic compounds arenetricarbonylchromium chemistry

gem-dimethyl

(Scheme 15 1 . 29 Controlled polyfunctionalization of cycloheptene can be achieved via nucleophilic addition and subsequent decomplexation of cycloheptadiene molybdenum cationic complexes (Scheme 16). 30 via Organometallic Nucleophi1e.s.- Simple 2,3-dialkylated thian-4ones have been prepared using tandem organocopper conjugate addition-enolate alkylation reactions of 3-methoxycarbonyl-5,6dihydrothiin-4-one (Scheme 17). 3 1 This methodology has been applied to the synthesis of thiathromboxane analogues. 3-Substituted lithium cyclopentenolates, which are readily available via a conjugate addition of organocopper reagents to cyclopentenone, react with Z-allylic acetates in the presence of an excess of BEt3 and catalytic amounts of [(Ph P) Pd] to give trans2,3-disubstituted cyclopentanones (Scheme 18).33 Stereoselective Michael additions of organocopper reagents to the trans-crotonyl ester of the chiral auxiliary 10-sulphonamidoisonorborneol generates, after hydrolysis, B-substituted carboxylic

326


a 2 elo

90 "lo

Reagent:

i , [ (PPh314Pd

I , c F 3 C 0 2 ~( c a t . ) Scheme

11

6 7 "lo

58 ' 1 0

Reagent

1,

[ ( P h C N ) 2 P d C 1 2 1( c a t 1, p - b e n z o q u i n o n e

Scheme

R

q

12

Meo2ccA -

i

OAc

Me0,C

-

R R+ OAc

OSi M e But

R

MeO,C Meozc=R

50 - 80 "lo

M eO,C

R

-q

91"lo

\os Reagents:

I,

[(Ph3PI1,Pd1, (Me02C12C(Na)CH2C = C H

Scheme

13

;

ii,


327

I , II

6 3 "lo Reagents

I,[

56 "lo

OCOCF, P d ( d b a I 2 J ,d p p e ,

11.

KCH (C02Me)2,

Scheme

111,

K+-

14

Cr (CO) 3

Cr KO), R e a g e n t s : i , [ C r (CO) 1; i i , M e L i ; iii, Me3AI , T i c [ & 6

Scheme

;

iv,

O2

15

c-V--

( J 4 c H ~ z p h

76 " l o

CH2C0, H Mo(C0) ,Cp R e a g e n t s : i , [ M o ( C 0 ) 6 ] , MeCN ; ii, LiC5H5 v, Na2HP04 ; v i , K O H ; vii, I 2

;

Scheme

/

C02Me

Mo(CO),Cp

iii, P h 3 C + B F i ; i v , NaCH (SO2Ph)CO2Me,

16

328


0

bco2Me i - iii

I

4 9 "lo

iv

0

0

- GM v,vi,iii,vii

6 S i Me 2 B d

OH

88 "lo Reagents:

i , B u C u S M e 2 ; ii, CH2=CHCH2Br; iii, L i I , DMF, H 2 0 ; iv. Me2SCuCH=CHCH (OSiMe2But)C5HIli vi, Z-BrCH2CH=CH(CH2)3C02Me

Scheme 0

v, N a H

;

vii, a q . HF

;

17

OLi

0

88 OIo

90"10

R e a g e n t s : i , Li2Cu(CH= CH2I2CN; ii, Me3SiCl; iii, B u L i ; i v , 2 B E t 3 ; V,

Z-ACOCH2CH=CHEt

, [ ( Ph3P),+Pd

Scheme

R e a g e n t s : i, R C u ( R

= Pr, B u , v i n y l

3

18

or 2 - p r o p e n y l 1 ; ii, NaOH

Scheme

19


329 ^ ^

acids with high optical purity (Scheme 1 9 ) . ” 3-Alkyl-2,3-epoxy-acids undergo epoxide ring opening with lithium organocuprates (Scheme 20). 34 The regioselectivity is dependent on the epoxide geometry; cis-epoxides open at C-3 preferentially whereas trans-epoxides open at C-2. Organocuprates convert 4-acetoxy-2-azetidinone into 4-substituted-2-azetidinone (Scheme 21 ) .35 Stereoselective reactions of acyl ligands attached to the iron chiral auxiliary [(C H )Fe(CO)(PPh )] have been reported. Thus, 5 5 3 the aluminium enolate derived from the iron acetyl complex [(C H )Fe(CO)(PPh )COMe] functions a s a chiral acetate enolate 5 5 3 equivalent. Decomplexation of the resultant 0-hydroxyacyl complexes yields B-hydroxy-acids o r -esters (Scheme 22) . 3 6 The aluminium and copper enolates derived from [(C5H5)Fe(CO)(PPh )COEtl are 3 chiral propionate enolate equivalents which on reaction with aldehydes provide stereoselective syntheses of threo- and erythro-amethyl-0-hydroxy-acids respectively (Scheme 23). 37 The chiral copper propionate enolate complex also undergoes stereoselective addi.tions to symmetrical ketones. 3a a,B-Unsaturated acyl complexes of [(C H )Fe(CO),l undergo 5 5 Michael addition reactions with amines to give B-amino-acyl complexes which on oxidative decomplexation yield 0-lactams (Scheme 2 4 1 . ~ ~ The cis-crotonyl complex of [ ( C H )Fe(CO)(PPh ) ] undergoes 5 5 3 exclusive deprotonation with BuLi to form a dienolate which undergoes stereoselective a-methylation. 40 In contrast the transcrotonyl complex undergoes stereoselective tandem Michael additions and subsequent alkylation reactions where both the nucleophile and electrophile add to the same face of the trans-crotonyl ligand the case where the nucleophile is lithium (Scheme ~ 5 ) ~ In ~ ’ benzylamide decomplexation of the methylated products gives the cis-3,4-dimethyl-B-lactam. 41 In the presence of Et2A1C1 the lithium enolate derived from the iron acetyl complex [(C H )Fe(CO)(PPh 5 5 3 )COMe] discriminates between

the enantiomers of monosubstituted epoxides, e.g. propylene oxide, to provide essenti.ally only one product (Scheme Z6).42 The resultant y-hydroxy-acyl complex may be decomplexed to y-lactones. Tricarbonyl-N-methyltetrahydroisoquinolinechromium undergoes stereo- and regio-selective 4-exo-deprotonation and subsequent electrophilic additions to generate the corresponding 4-exo-derivatives which after decomplexation yield 4-alkyl-, 4-phenyl-, and 4-

330


OH

Eu2CuLi n-C7H15

0

O -H

+

Bu

OH 12

OH

:

1

0

Bu

0

Bu2CuL i 88

"lo

OH

OH

BU

0

: 11

1 Scheme

20

GOA C fiR R~CULI

0'

0

R = a l k y l , v i n y l , a r y l , etc.

Scheme

0

-

21

0

i - iv

H

>loo Reagents : i , BuLi

;

ii, E t 2 A l C I

;

iii, R C H O

Scheme

: 1 ;

i v , B r 2 , MeOH

22

80 - 98%


33 1

0

0

0

C

-

C

i,iv, iii

GFe* 0

R

OH

0

OH

lv

lv

Me I

HO,Ci/"

OH

OH

R e a g e n t s : i , BuLi

;

ii, E t 2 A I C I ; i i i , R C H O ;

Scheme

0

Reagents: i , NaFp

iv, C u C N ; v ,

23

0

0

;

ii, P h C H 2 N H 2 ; iii, B r 2 , E t 3 N

Scheme

24

Br2, H20

332


.

..

I , II

0

C

I, II

ii, iii

0 C

""

iv ____)

78 "I,

Reagents:

i, B u L i

;

ii, M e 1

;

iii, L i N H C H 2 P h

Scheme

0 C

Reagents:

pbPh

0

;

iv,

Br2, CS2

25

0 C

i, B u L i

;

ii. p r o p y l e n e o x i d e , E t 2 A I C I

Scheme

26

;

iii, B r 2


333

hyd r ox y-N-me t hy 1tetrahyd roi soquinol i nes ( Scheme 27 ) . The pro-! hydrogen of tricarbonyl-(+)-N,N-dimethylamphetaminechromium can be stereospecifically substituted, 2 sequential treatment with BuLi and an electrophile, with retention of configuration to give, for example, N-methylpseudoephedrine after 44 complexation (Scheme 2 8 ) . via Coupling Reactions.- The organocopper derivative generated by lithiation of tricarbonylfluorobenzenechromium and transmetallation with the cuprous bromide-dimethyl sulphide complex couples with the vinyl bromide 2-bromo-l-trimethylsiloxyprop-2-ene. Subsequent desilylation of the product results in spontaneous cyclization, promoted by the tricarbonylchromium moiety, to tricarbonyl-3methylene-2,3-dihydrobenzofuranchromium (Scheme 29). 45 Decomplexation yields 3-methylbenzofuran. The regio- and stereo-specific synthesis o f conjugated dienes can be achieved 2 the palladium-catalysed coupling of alkenylboranes and vinyl bromides (Scheme 30). 46 The stereochemistry of the intermediate alkenyl boranes and of the vinyl bromides is maintained. The nickel-catalysed substitution of aryl methylthiol groups for alkyl groups has been extended to aromatic heterocycles. Treatment of 4-methylthiopyridines with Grignard reagents in the presence of bisphosphinenickel dichloride catalyst generates the corresponding 4-alkylpyridines (Scheme 31 1 .47 6-(Methylthio)purines are converted into the corresponding 6-alkyl- and 6-aryl-purines by nickel-catalysed coupling with Grignard reagents (Scheme 32). 48 The reaction is also applicable to purine nucleosides. The coupling of trimethylaluminium and terminal acetylenes promoted by [(C H ) ZrC12] has been successfully employed in a carbo5 5 2 hydrate-based synthesis of the goldinonolactone intermediate in the total synthesis of the antibiotics aurodox and efrotomycin (Scheme 3 3 ) *49 Conjugated 5,Z-dienes may be prepared readily by carbocupration of acetylenes (Scheme 34) .50 This methodology has been employed in the synthesis of a novel orange-worm pheromone.50 Vinyl triflates couple with Michael acceptors in the presence of triethylamine and palladium catalysts (Scheme 3 5 ) .51 The reaction conditions are mild enough so that even acrolein gives good yields without significant polymerization. The intra- and inter-molecular reductive self-coupling of vinyl bromides may be achieved using a catalytic amount of palladium

3 34


I

1

ii, iii

KO),

E = Reagents

Me, E t , PhCH,, I ,

Ph or OH

[ C r (C0l6 1, ii, B U L I

IV.

,

- 65'10

15

iii, E+[ Me1 , E t I ,PhCH2Br,(PhF)Cr(CO)3,0r MoOPHl,

0 2 , hW

Scheme

m''

27

m''

1

/'

/

/'

Cr

(+>

KO13

I

.. ...

11, I l l

E I

-

E I

iv

Cr E = D , M e or OH

Y - met hyl pse u doe phedr i ne),

R e a g e n t s : i , [ C r ( C 0 I 6 3 ; ii, B u L i ; iii, E + ( C D 3 0 D , Me1 or M o O P H ) ; i v , 0,. hv

Scheme

28


335

a-a CuSMe2

I. ll

/

'.!-'

Cr (CO13

'd-)

F

/

F

Cr

;

7 5 OO I

Cr (CO),

90 "lo R e a g e n t s : i , B u L i ; ii, C u B r . S M e 2

Cr

(COl3

(CO),

iii, CH2=C(Br)CH20SIMe3;

Scheme

IV,

B u 4 N F ; v, 0

29

42 - 0 9 "lo

R'

R , R 1 = alkyl or Ph Scheme

8 9 "10

30

49

- 93'10

2


336

SMe

Ph

b

+

R

I

RMgX

Ph

86 - 89"Io Ph&Ph

R = Me, P h , B u n , or C,H, Reagent :

i , c a t . [ ( P h 3 P I 2 N i C l 2 J or [ { P h 2 P ( C H 2 ) 3 P P h 2 ] N i C 1 2 ]

Scheme

Reagent: RMgX

,

31

cat. [ { P h 2 P ( C H 2 ) 3 P P h d N i C l , 1

Scheme

32

I ____)

Reagent :

i

,

A1 Me3, [ ( C 5 H 5 I 2 Z r C12 1

Scheme

- m2CuLi

4HC=CH

Bu2CuLi

33

Bu

Scheme

Me

Me1

34

Bu

71 "lo


D

O

T

f

+

337

- rZ

tZ

Z = C02Me (91 'lo), COMe ( 8 9 O l 0 ) CN (99Ol0) or CHO (86'10)

C0,Me +

/;COzMe

b +I;,,,,. OTf

92 '10

~

.

~

&COzMe a4 'lo

R e a g e n t : E t 3 N , c a t . [ ( P h 3 P ) 2 P d C 1 2 1 , 75OC, D M F

Scheme

35

9 5 "lo Et02C

Reagent :

C0,Et

i , c a t . Pd ( O A c I Z

Et0,C

,

PPh3, KZCO3

Scheme

36

C0,Et


338

acetate in the presence of stoicheiometric amounts of triarylphosphines (Scheme 36) .52 Double bond isomerization is not observed under these conditions. Terminal acetylenes are oxidatively coupled to diynes by chloroacetone in the presence of catalytic amounts of [(Ph P ) Pd] 3 4 and CuI (Scheme 37).53 Heck arylation of 1,5-dienes leads to cyclized products (Scheme

38) .54 Similar cyclizations are observed for. 1 ,5-enynes. 1,6- and 1,7-Enynes react with ‘Cp2Zr‘ to give zirconabicyclic intermediates which yield bicyclic pentenones with carbon monoxide, di-iodides with iodine, and vinyl derivatives with protons (Scheme 39) .55 The palladium-catalysed [3+2] ring annulation reaction has been directed towards a synthesis of a loganin aglucon fragment.56

Thus

palladium-catalysed cycloaddition of a substituted 2-[(trimethylsilyl)methyl]allyl carboxylate with cyclopentenone generates the required substitution pattern for loganin (Scheme 40). The palladium catalysed [3+2] cycloaddition reaction has been extended to aldehydes and imines. One method employs the Lewis acid-catalysed to the addition of 2-[(acetoxymethyl)-3-allyl]tributylstannane aldehyde o r imine fol-lowed by palladium-catalysed cyclization (Scheme 41) .57 Under the appropriate conditions the whole process can be catalysed by palladium (Scheme 42).58 Of note in this latter reaction is the lack of cycloaddition to the double bond of a,B-unsaturated aldehydes. The complex pentacarbonyl-(2-furylmethoxycarbene)chromium couples with alkoxyacetylenes to generate benzofurans (Scheme 43).59 met hod

The total synthesis of Khellin has been achieved by this

.

In the *presence of the [(Ph P) Pd] catalyst organoaluminiurn 3 4 60 reagents convert acyl chlorides into ketones (Scheme 44). Grignard reagents in the presence of nickel catalysts couple with S-phenyl

carbanochloridothioate to give the corresponding 2-phenyl carbanothioates. These in turn couple with Grignard reagents in

the presence of iron catalysts to give symmetrical or unsymmetrical ketones (Scheme 45). 61 Unsymmetrical a-diketones are readily accessible by the [(Ph P) PdC12]-catalysed cross coupling of acyltributyltin reagents 3 2 62 with acyl chlorides (Scheme 46). The rhodium-catalysed C-H bond insertion reaction of a-diazo-Bketo-esters has been shown t o proceed with retention of configura-


339

i

2 RCECH

R C r C - C G CR

___1_1)

50- 94"/0

R = a r y l or a l k y l Reagent :

i , [ ( Ph3PIL Pd 1, C u I , CICH, COMe , E t 3 N

37

Scheme

phsozc

5 0%

P h S O Z d

I

PhSO,

PhSO;!

CI PhSO, PhSO, Reagent : i,

PhSO, P h H g C l , CuC12, c a t . P d C I Z

Scheme

38

&:

55-65"/0

(

-

Si Me3

Si Me3

r=siMe3 I

CH,),

Ill

61 - 70'10

\=

6 3 "lo

Reagents'

I .

Cp,ZrCI,,

Mg,

HgCIZ,

Scheme

li, CO;

39

III,

I,

; IV,

H+


340

111

I Pd:

' L Reagents:

1 iii,

i , P d ( O A c ) p , P P h 3 ; it, B u " L i ;

@.

40

Scheme

Ph'

PhNH

N/ph

+

r " " c L p h J & A c

Ph SnBu,

81 "10 R e a g e n t s : i , BF O E t 2 ; ii, P d ( O A c I 2 , P P h 3 / B u L i , DBU 3'

Scheme

41

0

AH

Ph

I

+

P

A

C

100"10

____)

Ph

SnBu3

8 0"In

Reagent : i, Pd(OAc)2, PPh3

Scheme

42


34 1

OAC OSiMe2Bu'

I

OMe

OEt

OMe

4 3 OIO Reagent :

i , Ac20, NEt3

, THF, 6 5 O C ,

1Oh

Scheme

-k

)$Cl

43

-

Et3AI

( P h 3P

Pd ]

Ph

J$Et

'

68%

Ph Scheme

0

0 I

CI

44

___)

R'

A

SPh

85 - 9 6 'lo

0

-

R'

AR2

58

- 99 'lo

0 86'10 overall yield


342

41

- 65

'/e

R 1 , R 2 = a l k y l or a r y l Scheme

46

(+)

Scheme

47

-OSiMe2Bu'

Reagents :

i , [ C O ~ ( C O ) ~ Ii ;i , C O , 1 6 O o C , 3 d

Scheme

- a-cuparenone

48

H


343

tion. This reaction has been employed in an enantiospecific synthesis of (+)-a-cuparenone which involves the enantiospecific generation of a quaternary carbon centre (Scheme 4 7 ) . 6 3 via Carbonylation Reactions.- The Pauson-Khand reaction has been used to effect the synthesis of the perhydrotriquinacene skeleton by a bis-annulation process (Scheme 48).64 In certain cases the Pauson-Khand reaction to prepare bicyclo[3.3.0]octenones proceeds stereoselectively (Scheme 49) .65 Carbonylation of allylic and hornoallylic alcohols catalysed by PdCl gives y-butyrolactones in moderate yield .66 Unfortunately 2 little stereoselectivity is observed (Scheme 50) .67 3-Hydroxyalkenes possessing a nucleophilic group on C-5 cyclize, via palladium-catalysed addition of the nucleophile to the alkene and subsequent carbonylative lactonization to the 3-hydroxy-group, to give bicyclic c3.3.01 systems. This general process has been used to prepare bicyclic bis-lactones ,68 &-3-hydroxypyrrolidine2 ac e t ic ac id 1ac tone , and cis-3-h yd r ox y te tr a h yd r ofu r an -2- ac e t ic acid lactones (Scheme 51 ) .70 Enol triflates are carbonylated to the corresponding a , B unsaturated esters and amides under the influence of palladium

-

-

catalysis (Scheme 52) .71 2-Bromoallylamines are similarly converted into a-methylene-6-lactams (Scheme 53) .72 This latter 8 lactam synthesis has been applied to the ( f ) - 3 - a r n i n o n o c a r d i c i n i c acid .73 l-Iodo-1,4- and -1,5-dienes undergo two successive carbonylation reactions to generate substituted cyclopentenones and cyclohexenones respectively (Scheme 54) .74 Protected glucosyl bromides react with NaMn(C0) via an SN2 5process with inversion of configuration to give the corresponding glycosyl pentacarbonylmanganese complexes. These undergo a variety of carbonylative coupling reactions to give C-glycosides (Scheme 5 5 ) .75 Allylic and homoallylic alcohols undergo amidocarbonylation in the presence of two catalysts: [HRh(PPh3)3(CO)] to isomerize to the corresponding aldehydes and [CO~(CO)~] to achieve the amidocarbonylation of the aldehydes (Scheme 5 6 ) .76 Epoxides undergo a similar reaction in the presence of C C O ~ ( C O ) ~ ]and a Lewis acid such as Ti(OPr1I4, the latter presumably causing rearrangement of the e oxide to the aldehyde required for amidocarbonylation (Scheme 5 7 ) -7 %


344

SiMe3

)FSiMe3 I

I

7 8 'lo

,

iH

OMOM

Reagent :

i

I

OMOM

, [ C O ~ ( C O 1) ,~ CO , 115 OC ,

36 h

Scheme

49

>- a-

HO

0-

1

2'

R e a g e n t : i , C O , C u C 1 2 , 0 2 , H C I , c a t . PdCI2

Scheme

50 Pr"

H

I ______)

88 Ole

0,-0

ti

dH

brn

H I

Z

90OIO

I ______)

Ph

Reagent :

i,

c a t . PdC12, CuC12

, NdOAc , CO Scheme

51

80 'lo

345


0

i _____i.)

X=OorNH

-

75 '10

Tf 0 Reagents :

I ,

CO , R X H , c a t . Pd (OAc12, PPh3 ; ii, CO , MeOH , c a t . Pd (OAc12, PPh 3

Scheme

52

wo

Br I _____)

NH Ph Reagent

1

6 7O l e

LN-Ph

i , C O , 6un3N, c a t . P d ( O A c I 2 , PPh3

Scheme

/J

53

I

C6H13

8*' 73 OIO

'6*

Reagent : i , CO, MeOH

, c a t . [ ( P h 3 P I 2 PdCI2 1

Scheme

ILL

13

346


M e 0 7

M

e

0

9 C02Me

Me0

Me0 OMe

Br

63 "lo

Mn (CO),

Me0

-

Me0

C0,Me

OMe

OMe

\

47

"10

M e 0 4 Me0 OMe

69 ' 1 0 Reagents :

I ,

N a M n (CO),

;

ii , CO, M e O H ; iii, CHZ= C H C 0 2 M e , 6 kbar

%OH

OH

+A

i v , hV,MeCN

;

Scheme

55

+

o

c

i

63 "lo

NH2

0

+

A,,, +

R e a g e n t : i , [ H R h ( PPh313CO

co

'

NHCOMe

5 5 OIO

AC02H

I , Co2(C0)8lI H2 Scheme

0

/Ao+ A

Ph

;

H30+

v, HCECCO2Me, 6 kbar, vi,

+

co

"2

R e a g e n t : i , [ C O ~ ( C O I) ,~ [ T i ( O P r ' I 4

56

-

I , H2

Scheme

57

NHCOMe Ph

92 OIO


347

6 Miscellaneous Reactions Ethylene glycol derived acetals are hydrolysed under mild conditions in the presence of [(MeCN)2PdC121 (Scheme 58) ;77 this deprotection can be performed in the presence of various alcohol protecting groups. Allyl esters are stable to acids and bases and can be cleaved under very mild conditions using [(PPh RhCl] or 3 3 This acid protection methodo[(Ph P ) Pd] catalysts (Scheme 59).78 3 4 logy has been used in the synthesis of a g l y ~ o p e n t a p e p t i d e . ~ ~ Owing to its ready removal under mild conditions by brief treatment with [(Ph P) Pdl in the presence of amines the allyl group provides 3 4 a useful protecting group for an internucleotide bond (Scheme 60).79 The phospho(II1)triesters are prepared from (allyl)OP(NMe2)2. The allyl group is quite stable under conditions needed to deprotect other oxygen substituents such as ButMe2Si, and p-MeOC6H4Ph2C. Amides can be N-allylated with a 2-allylisourea in the presence of [Pd(dbaI21 as catalyst (Scheme 61).80 Allyl acetates and chlorides undergo substitution with retention of configuration with sodium toluene-p-sulphonamide in the presence of catalytic amounts of [ (Ph3P)4Pd] (Scheme 62) .81 In combination with known methods for the cleavage of the toluene-p-sulphonyl group this represents a good method for generating primary allylamines. Oximes may be O-arylated using halogenoarene tricarbonylchromium complexes (Scheme 63). 82 Aromatic amines are converted into carbamate esters on treatment with an alcohol and CO ( 1 atm) in the presence of 02, CuC12, and catalytic amounts of PdC12 (Scheme 64).83 Vinyl epoxides react with C 0 2 in the presence of a palladium(0) catalyst, generated in situ from Pd(OH2)2, P(OPr1)3, and BuLi, to give the corresponding vinyl carbamates (Scheme 65) .84 The epoxide stereochemistry is retained and this methodology corresponds overall to a cis-dihydroxylation process. Selective methylation of an aldehyde in the presence of a ketone occurs with CH212-Zn-Ti(OPr1)4. The reverse selectivity is observed if the keto-aldehyde is pretreated with Ti(NEt,)4 prior to CH212-Zn-TiC14 (Scheme 66). 85

348


n

i

L

0

&OR

OR

R = H , M E M , SiPh,Bu'

or THP

R e a g e n t : i , MeZCO , 2 0 OC , c a t . [ ( MeCN 1, PdCI, 1

Scheme

58

NHBoc

NHBoc

i A c o @ H d C 002 H

AcO v H + c o * w

AcO

AcO NHAc

NHAc

R e a g e n t : i , E t O H , H 2 0 , 7OoC, c a t . [ ( P h 3 P I 3 R h C r ] or [ ( P P h 3 ) 4 P d J

Scheme

59

1

PhzCO

Q

i

0

4

_.__)

OMe Th = t h y m i d i n e

Ph$O

Q OMe

B = thymidine or a d e n o s i n e

Scheme

1

0-P-0

OSiBu'Me,

60

'J-,si~u~,e~

I

OH >95

'10


349

+'
-9O t o 0 "C,

CO, M e

II

, MeOH, HCI ; III , LiCHBr2

f o l i o w e d by B I J ~ L I

Scheme 15

LI

Reagents : i , RMgX

, THF

then

Li, - 15 "C ; ii, E ', t h e n H t

S c h e m e 16

then

& Organometallics in Synthesis

367

k e t o d i a n i o n s i s a r e a c t i o n o f some g e n e r a l i t y . V a r i o u s s t e r e o chemical and m e c h a n i s t i c a s p e c t s o f t h e p r o c e s s have been i n v e s t i g a t e d , and t h i s m i l d p r o c e d u r e has been used a s a key s t e p i n t h e s y n t h e s i s o f t h e a n t i f u n g a l a n t i b i o t i c o u d e m a n s i n (Scheme 1 5 ) . O f p a r t i c u l a r i n t e r e s t is t h e h o m o l o g a t i o n of (563 and ( 5 7 ) w i t h complete r e t e n t i o n o f a l k e n e geometry.39 2-Chloropropenal has been c o n v e r t e d i n t o t h e d i a n i o n ( 5 8 ) and used t o s y n t h e s i z e v a r i o u s l y s u b s t i t u t e d a l l y l i c a l c o h o l s (Scheme 1 6 ) . 4 0 ' T h e s e i n t e r m e d i a t e d i a n i o n s ( 5 8 ) show n o t e n d e n c y t o u n d e r go B - e l i m i n a t i o n t o a l l e n e s , a l t h o u g h u n d e r a p p r o p r i a t e c o n d i t i o n s 41 t h i s r e a c t i o n may b e o b s e r v e d . The d i r e c t C - l i t h i a t i o n o f 2 - m e t h o x y p r o p e n o i c a c i d ( 5 9 ; X = O H ) w i t h ButLi a t -100 O C r e s u l t s i n t h e f o r m a t i o n o f t h e d i a n i o n ( 6 0 ; X = O L i 1, a n d t h e c o r r e s p o n d i n g m o n o a l k y l a m i n e s ( 5 9 ; X = N H P r ') u n d e r g o a s i m i l a r t r a n s f o r m a t i o n . 42 The c h e m i s t r y o f l i t h i a t e d c y c l i c e n o l e t h e r s c o n t i n u e s t o be a pr-oductive f i e l d . M e t a l l a t i o n o f l , 4 - d i o x e n e leads t o t h e therma l l y s t a b l e 2 - l i t h i o - d e r i v a t i v e ( 6 1 ) . T h i s s p e c i e s h a s been used t o e f f e c t a two-carbon homologation of a l d e h y d e s and k e t o n e s t o g i v e a-hydroxy- a n d Q , U ' - d i h y d r o x y - k e t o n e s (Scheme 1 7 ) .43 A v e r y c o n v e n i e n t p r e p a r a t i o n of 2 - l i t h i o b u t a - 1 , 3 - d i e n e has been A l l e n e i s well d e s c r i b e d , s t a r t i n g from 2-chlorobuta-I ,3-diene.44 known t o u n d e r g o m o n o l i t h i a t i o n b u t t r e a t m e n t w i t h a n e x c e s s o f BunLi g e n e r a t e s a s p e c i e s ( C H L i ) t h a t i s a h i g h l y e f f e c t i v e 3 2 2 The p r e c i s e s t r u c operational equivalent of a propargyl dianion. t u r e o f t h i s s p e c i e s , i s n o t known b u t i t r e a c t s w i t h a l k y l h a l i d e s t o g i v e a l k y n e s i n good y i e l d (Scheme 1 8 ) a n d n o n e o f t h e i s o m e r i c a l l e n e a d d u c t s have been o b s e r v e d .45 S u l p h u r - s t a b i l i z e d A n i o n s . - As i n p r e v i o u s y e a r s a number o f carba n i o n r e a c t i o n s h a v e r e l i e d on t h e s t a b i l i z i n g e f f e c t o f a s u l p h u r s u b s t i t u e n t a- t o t h e a n i o n c e n t r e . 1 - A l k y l c a r b a z o l e s ( 6 2 ; X = a l k y l ) , f o r e x a m p l e , a r e known t o u n d e r g o C - I l i t h i a t i o n , b u t i n c o n t r a s t t h e FJ-(phenylthio)methyl d e r i v a t i v e (62; X = SPh) c l e a n l y metallates a d j a c e n t t o s u l p h u r and t h i s f e a t u r e h a s been used t o p r e p a r e a v a r i e t y o f % - s u b s t i t u t e d c a r b a ~ o l e s . ~S u~ l p h u r - d i r e c t e d m e t a l l a t i o n of t h e s i l y l a t e d f u r a n s ( 6 3 ) a n d ( 6 4 ) i s a f a c i l e p r o c e s s , a n d t h e r e s u l t i n g a n i o n s may be r e g a r d e d a s s y n t h e t i c a l l y e q u i v a l e n t t o t h e b u t e n o l i d e n u c l e o p h i l e ( 6 5 1. 4 7 Sulphones are e s p e c i a l l y powerful a n i o n s t a b i l i z i n g subs t i t u e n t s . B o t h a- a n d B - 5 - p y r a n o s i d e s h a v e b e e n o b t a i n e d f r o m 2-


368

Meo+x

Meo<x (591

Reagents

I,

B I J ~ L I,THF, - 3 0 "C;

11,

(60)

RCOR';

111,

; ' H

IV,

L i A I H l ; v , rn-chloroperoxybenzoic

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

Scheme 17

CH2,jC=CH,

*

[C3H2Li2]

II

R

n . R e a g e n t s : i, Bu L i ( 3 . 5 e q u i v . l ; i i , R X ( R = a l k y l or a l l y [ )

S c h e m e 18

q

a-

TMSO+SPh

0

T MSO

SPh

(63)

SPh ( 641

(65)

6: Organometallics in Synthesis deoxy-D-glycopyranosyl

369 p h e n y l s u l p h o n e ( 6 6 ) ‘(Scheme 1 9 ) .

Reductive

c l e a v a g e of t h e s u l p h o n e g e n e r a t e s a n u c l e o p h i l e t h a t r e a c t s w i t h e l e c t r o p h i l e s t o g i v e t h e a-C-pyranoside alkylation of t h e sulphone-stabilized c l e a v a g e l e a d s t o t h e 8-5-pyranoside

(67).

Alternatively,

anion before reductive ( 6 8 ) . 48

S p i r o a c e t a l s have

b e e n o b t a i n e d f r o m ( 6 9 ) by a l k y l a t i o n w i t h o - a l k o x y a l k y l h a l i d e s f o l i o w e d by a m i l d a c i d ~ o r k - u p , ~ ’a n d t h e u s e o f c y c l i c s u l p h o n e s ( 7 0 ) a s s y n t h e t i c e q u i v a l e n t s of t h e c o r r e s p o n d i n g b u t a d i e n y l a n i o n s ( 7 1 ) h a s been e x p l o i t e d i n t h e s y n t h e s i s of p o l y c y c l i c c a r b o c y c l e s . 50

2-Lithio-2-phenylsulphonylpropane

(72) acts as an alkylidene

t r a n s f e r a g e n t t o w a r d s e l e c t r o p h i l i c a l k e n e s (Scheme 2 0 ) .51

A new h o m o e n o l a t e e q u i v a l e n t h a s b e e n d e v e l o p e d b a s e d on t h e s u l p h o n e -

s t a b i l i z e d a l k o x y c y c l o p r o p y l a n i o n ( 7 3 ) .52 D i a n i o n s b a s e d on s u l p h o n e s a r e a l s o u s e f u l s y n t h e t i c t o o l s . T h u s , t h e [(phenylsulphonyl)methylene]dilithium s p e c i e s (74) undergoes a series of u s e f u l t r a n s f o r m a t i o n s w i t h b i f u n c t i o n a l subs t r a t e s ( S c h e m e 21 and t h e d i a n i o n ( 7 5 ) , d e r i v e d from a - t r i f y l s u l p h o n e s , h a s b e e n u t i l i z e d i n a g e n e r a l s y n t h e s i s of 2 , 3 - d i s u b s t i t u t e d c y c l o p e n t e n o n e s by e x p l o i t i n g t h e d i f f e r e n t i a l r e a c t i v i t y o f t h e two a n i o n i c s i t e s i n ( 7 5 ) . 5 4 The s u b s t i t u t e d k e t e n e S , S - d i t h i o a c e t a l ( 7 6 ) h a s been d e v e l o p e d as a 6 - l i t h i o a c r y l a t e e q u i v a l e n t (Scheme 2 2 ) . D e p r o t o n a t i o n of (76) l e a d s t o an a l l y l i c a n i o n ( 7 7 ) t h a t reacts w i t h a wide range of e l e c t o p h i l e s t o g i v e t h e ? ‘ - s u b s t i t u t e d a d d u c t ( 7 8 ) , a s t h e o n l y observed product. Hydrolysis of t h e ketene t h i o a c e t a l then r e l e a s e s t h e c a r b o x y l r e s i d u e , and t h i s a c t i v a t e s t h e system towards e l i m i n a t i o n of t h i o p h e n o l , t h e r e b y unmasking t h e a c r y l a t e unit.55 D i a n i o n ( 7 9 ) may a l s o b e r e g a r d e d a s a m o d i f i e d B - l i t h i o b u t t h e c h e m i s t r y of t h i s s p e c i e s i s d i v e r s e . Not o n l y h a v e 8 - s u b s t i t u t e d a , 8 - u n s a t u r a t e d a m i d e s b e e n s y n t h e s i z e d , b u t t h e same r e a g e n t r e a c t s , f o r e x a m p l e , w i t h e p o x i d e s t o g i v e u l t i m a t e l y dihydropyrans; t h e s p e c i e s (79) is t h e r e f o r e perh a p s more a c c u r a t e l y r e p r e s e n t e d a s e q u i v a l e n t t o t h e d i p o l a r s p e c i e s ( 8 0 ) .56 acrylate equivalent,

Magnesium.-

An e f f i c i e n t o n e - p o t

synthesis of 2-terphenyls

h a s been

reported t h a t involves t h e reaction of an a r y l Grignard reagent ~ l a t t e r component is (ArMgBr w i t h a t e t r a h a l ~ g e n o a r e n e . ~The

370


RO‘

Y I

OR (67)

RO‘

OR ( 6 6 ) R = Si Me2But

Y” RO’ OR (681 Reagents : 1 , L i t h i u m n a p h t h a l i d e , - 7 8 ‘C;

I ~ , E + ( R c H o R, X ,

D~o),

LDA

S c h e m e 19

R1

R

(69)

MeY

71)

Rk52M

OL i 2

Me

X Reagents:

I,

C02Me

( X = H or C02Me

1, THF ;

11

, MeOH , ref l u x

Scheme 20

Me

37 1


SO, P h

(73) P h S 0 2 u

b

Li

Li

(743

Y -%

S02Ph

HoV

ti

Ph S OzMe n . R e a g e n t s : i , B u L I ( 2 e q u i v . ) ii, C I / V c '

; ii i,

0

&"

0

h~~ ; iv

S c h e m e 21

CFISOzy i L , , , OS

Li (75)

I PhS

PhS

SPh

Li+ (771

(761 (771

=

--cop ..

.

4-

PhSYYSPh E

Reagents : i , L D A , T H F ;

11,

E +;

iii,

SPh

(78) DBU

R'OH, HgC12 or CF3COZH; i v ,

Scheme 2 2


372

I SO, Ph

SO, Ph

Li

1791

R CONHPhRdCONHPh

(801 Reagents : i , Bu"L1

,

H M P A , T H F ; i i , R X , t h e n N a B H L , iii, R / B ,

t h e n KOBut

Scheme 2 3 Mg Br /

-*

-

-

Ph@--Ph

p h - - @ - - - P h

I Mg Br

Br

Z

= H 54 "/o I ( Z = I J 50"/aI

( 82 I ( Z

(811

I

Me

, Ill

Me

Br

60 " / a Reagents :

I ,

PhMgBr

( Lequlv.),

THF;

11,

H 3 0 f or I 2 ;

Scheme 2L

III,

H30+


373

e q u i v a l e n t t o a d i - a r y n e , and b o t h s y m m e t r i c a l and unsymmetrical p o l y a r y l s h a v e b e e n p r e p a r e d (Scheme 2 4 ) . The i n i t i a l p r o d u c t , t h e bis-organomagnesium

( 8 1 1 , c a n be s i m p l y p r o t o n a t e d on work-up t o

g i v e ( 8 2 ; Z = HI, o r q u e n c h e d w i t h a n o t h e r e l e c t r o p h i l e , iodine, t o give (82; Z = I).

x.

Obviously o t h e r e l e c t r o p h i l e s could

be u s e d a n d t h i s m e t h o d o f f e r s c o n s i d e r a b l e p o t e n t i a l .

The

r e a c t i o n o f n i t r o a r e n e s w i t h G r i g n a r d r e a g e n t s t o g i v e o r t h o - and para-substituted

n i t r o a r e n e s h a s a l s o b e e n s t u d i e d a n d t h e s c o p e of

t h i s s u b s t i t u t i o n r e a c t i o n , i n terms o f t h e r a n g e o f f u n c t i o n a l g r o u p s t h a t may b e t o l e r a t e d , h a s b e e n d e t e r m i n e d . 58 A l l y l i c a c e t a t e s undergo an asymmetric coupling w i t h ArMgX,

in

t h e presence of a c h i r a l n i c k e l ( I 1 ) c a t a l y s t , t o g i v e (83) i n up t o 89% e n a n t i o m e r i c e x c e s s ( S c h e m e 2 5 ) .59

Bromomagnesium a l k y l a m i d e s

( 8 4 ) , p r e p a r e d from a d i a l k y l a m i n e a n d EtMgBr, r e a c t w i t h e p o x i d e s 60 u n d e r m i l d c o n d i t i o n s t o g i v e 6 - a m i n o a l c o h o l s ( 8 5 ) i n good y i e l d . P r e s u m a b l y c h e l a t i o n of m a g n e s i u m t o t h e e p o x i d e p l a y s a n i m p o r t a n t part in t h i s reaction. Although sulphones have developed a c e n t r a l r o l e i n s y n t h e t i c c h e m i s t r y , t h e removal of t h i s r e s i d u e , a f t e r , f o r example, an a l k y l a t i o n s t e p , can be problematic. Sodium amalgam i s f r e q u e n t l y used, but t h e t o x i c i t y of t h i s r e a g e n t can be a l i m i t i n g f a c t o r . I t h a s now b e e n r e p o r t e d t h a t m a g n e s i u m i n m e t h a n o l i s a n e f f e c t i v e a l t e r n a t i v e r e a g e n t f o r r e d u c t i v e d e s u l p h o n y l a t i o n . 61 Zinc and Mercury.-

There h a s n o t been a great d e a l of a c t i v i t y i n R e f o r m a t s k y r e a g e n t s r e a c t w i t h 0-

t h e organozinc area t h i s y e a r .

s i l y l a t e d c y a n o h y d r i n s t o p r o v i d e t e t r o n i c a c i d s i n good y i e l d s (Scheme 2 6 ) . 6 2 U l t r a s o n i c t e c h n i q u e s h a v e p r o v e d u s e f u l i n t h e p r e p a r a t i o n o f d i o r g a n o - z i n c s (R2Zn) ( f r o m t h e c o r r e s p o n d i n g h a l i d e and Z n ) , a n d t h e p o i n t i s made t h a t R2Zn, w h i c h c l e a n l y u n d e r g o c o n j u g a t e a d d i t i o n t o enones, are well worth c o n s i d e r i n g as an a l t e r n a t i v e t o c u p r a t e - b a s e d methodology .63 U l t r a s o u n d a l s o p r o m o t e s t h e r e a c t i o n o f R2R3C=CHCH2ZnBr t o g i v e homoallylic a l c o h o l s . 64

w i t h aldehydes and k e t o n e s

A new r e d u c i n g a g e n t , made u p o f a m i x t u r e o f N a B H 4 a n d ZnC12 i n a r a t i o of 2 : 1 , h a s b e e n r e p o r t e d t o r e d u c e a v a r i e t y o f c a r b o n y l -

c o n t a i n i n g compounds.65

However, a n h y d r i d e s , a c i d s , e s t e r s , a n d

amides a r e i n e r t , a l t h o u g h a l d e h y d e s and k e t o n e s c a n be deoxyg e n a t e d by r e a c t i o n b e t w e e n t h e r e d u c i n g s y s t e m a n d t h e c o r r e s ponding t o s y l hydrazones. S t e r e o c h e m i c a l c o n t r o l h a s d e v e l o p e d a s a major theme i n s o l v o -

3 74


R’-fR’ O

Ar L

I

R

2

Y Me 0

(83) Reagents :

I,

A r M g B r , N1C1~L(S’S)-ChiraphosJ

Scheme 2 5

&Rl

R,NMgBr

(84)

OH ( 85)

HO

--+ Rkosi

R2

Reagent:

I,

CN M e 3

Z n / C u , B r C H CO E t , t h e n H 3 0 t 2 2

Scheme 2 6

&

Me

R

R

l

R

OR’

bR’

0

Me &M

R1

Me

( 9 2 1 R: R ’ = a l k y l , H , o r

R aryl

(931


375

m e r c u r a t i o n r e a c t i o n s t h i s y e a r , and t h e i m p o r t a n c e of a neighbouring group i n t h e alkoxymercuration of a c y c l i c a l l y l i c a l c o h o l s has been e s t a b l i s h e d . 6 6

Reaction of t h e f r e e hydroxyl (86; X = H )

leads, after demercuration, t o t h e erythro-adduct

( 8 7 ) , b u t u s e of

( 8 6 ; X = O C O M e o r OCOPh) r e s u l t s i n a p r e d o m i n a n c e o f t h e t h r e o adduct (88; X

O C O M e o r OCOPh).

D e m e r c u r a t i o n of a - m e r c u r o c a r b o x y l a t e s

( 8 9 ) can be c a r r i e d o u t

s e l e c t i v e l y t o g i v e e i t h e r of t h e d i a s t e r e o m e r i c B-hydroxy-esters ( 9 0 ) or ( g l ) , d e p e n d i n g on t h e c o n d i t i o n s u s e d . 6 7 of

NaBH4 r e d u c t i o n

(89) r e s u l t s i n n e t i n v e r s i o n l e a d i n g t o ( g o ) , but propane-1,3-

d i t h i o l removes mercury w i t h r e t e n t i o n of c o n f i g u r a t i o n t o g i v e (91 ). A l l e n i c ketones ( 9 2 ) undergo a c l e a n c y c l i z a t i o n i n t h e presence of Hg(OCOMeI2 i n a c e t i c a c i d t o g i v e 3 ( 2 H ) - f u r a n o n e s 68 in excellent yield.

(93) directly

F u n c t i o n a l i z e d c a r b o c y c l e s may b e s y n t h e s i z e d by t h e c y c l i z a t i o n of t h e s i l y l e n o l e t h e r of a n a c e t y l e n i c k e t o n e (Scheme 2 7 ) . 69 F u r t h e r m o r e t h e p r o d u c t of c y c l i z a t i o n , a Z--vinylmercurial

(95),

undergoes e l e c t r o p h i l i c s u b s t i t u t i o n w i t h r e t e n t i o n of a l k e n e geometry.

C y c l i z a t i o n of

( 9 4 ) t h r o u g h c a r b o n r a t h e r t h a n oxygen i s an

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

Enol e t h e r s (96;

fl. = 3 or 4) c y c l i z e t o g i v e ( 9 7 ; ; 3 or

4) i n g o o d y i e l d . P h o t o l y s i s o f RHgC1, i n c l u d i n g t h o s e d e r i v e d by a l k o x y m e r c u r a t o n of

l-alkenes,

i n t h e presence of p y r i d i n e l e a d s t o t h e c o r r e s -

p o n d i n g 2- a n d 4 - a l k y l - p y r i d i n e s

by a f r e e - r a d i c a l

process.”

B e a r i n g i n mind t h e v a l u e of H g ( I 1 ) i n t h e e l e c t r o p h i l i c c h e m i s t r y of a l k e n e s , a l k y n e s t i o n s o f t h e C-Hg

e. (see

b e l o w ) , a n y new m a n i p u l a -

bond a t t r a c t i n t e r e s t .

A l t h o u g h a number o f

t r a n s f o r m a t i o n s of t h i s b o n d a r e a v a i l a b l e t h e d i r e c t c o n v e r s i o n of RCH2-CH2HgX

i n t o RCH=CH2 i s a t p r e s e n t a l o w - y i e l d i n g

process.

A

s o l u t i o n t o t h i s p r o b l e m h a s b e e n p r o p o s e d and r e l i e s on t h e e f f i c i e n t c o n v e r s i o n of C-HgC1

i n t o C-SePh

(Scheme 2 8 ) .7

3 G r o u p I11 Boron.-

The c h e m i s t r y o f o r g a n o b o r a n e s h a s s e e n s i g n i f i c a n t

developments a c r o s s a r a n g e of d i f f e r e n t f r o n t s .

A s with zinc,

u l t r a s o u n d h a s had a n i m p a c t i n t h e b o r o n a r e a .

Alkyl and a r y l

h a l i d e s r e a c t w i t h BF3.Et20 g i v e organoboranes.72

a n d Mg u n d e r u l t r a s o n i c c o n d i t i o n s t o

The r e a c t i o n s a r e r a p i d a n d a l l o w access t o


376

Reagents :

5""1

HgCL2 CH2C12 ; 1 1 ) N - b r o m o s u c c i n i m i d e ;

i J

+

*

III

I

MeCOCL; i v , CO, MeOH

S c h e m e 27

Reagents :

I

I

Ph2Se2, PhH , hV ;

11

,

NaI04

S c h e m e 28

J+ OR (99)

*

.+*.

R1

L

0 I

OR2

OR2

( 1 00)

( 1 011

"


377

p r o d u c t s s u c h a s t r i a r y l b o r a n e s , t h a t a r e n o t a v a i l a b l e by d i r e c t hydroboration. Ultrasound can a l s o d r a m a t i c a l l y enhance t h e rate A s e r i e s o f commonly u s e d h y d r o -

o f h y d r o b o r a t i o n of a l k e n e s . 7 3

b o r a t i n g a g e n t s h a s been examined i n t h i s c o n t e x t . new s y n t h e s i s of g-alkyl-9-BBN

An e f f i c i e n t

d e r i v a t i v e s ( 9 8 ) h a s been p u b l i s h e d ,

a n d i n v o l v e s r e a c t i o n o f 9-BBN w i t h a homo- o r h e t e r o - c u p r a t e . 7 4 A t t e n t i o n h a s a l s o been paid t h i s y e a r t o t h e h y d r o b o r a t i o n of heteroatom-substituted

alkenes.

hydroboraion-oxidation

of s u b s t i t u t e d e n o l e t h e r s ( 9 9 ) h a s b e e n

studied.

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

syn ( 1 0 0 ) r a t h e r t h a n a n t i ( 1 0 1 ) p r o d u c t s a r e o b t a i n e d ,

but t h e underlying s t r u c t u r a l f e a t u r e s c o n t r o l l i n g t h e s t e r e o c h e m i c a l o u t c o m e of t h e a d d i t i o n a r e n o t y e t f u l l y u n d e r ~ t o o d . ~A ~ c o m p r e h e n s i v e s t u d y o f t h e h y d r o b o r a t i o n of t h e h e t e r o c y c l i c a l k e n e s ( 1 0 2 ; X = 0 , S , o r N R ; p. = 1 , 2 , o r 3 ) h a s b e e n p u b l i s h e d , and t h e s e r e a c t i o n s show g o o d s y n t h e t i c p r ~ m i s e . ’ ~ P r o b a b l y t h e most i m p o r t a n t a s p e c t of b o r o n c h e m i s t r y t h i s y e a r concerns i t s use i n t h e c o n t r o l of a b s o l u t e stereochemistry. Masamune h a s d e s c r i b e d t h e s y n t h e s i s o f t h e ( R , R ) - b o r o l a n e

well as t h e

a l k e n e s , r e a c t w i t h ( 1 0 3 ) t o g i v e a d d u c t s of h i g h

1,l-disubstituted optical purity.

T h i s r e a g e n t i s c l a i m e d t o be s u p e r i o r t o t h e more

t r a d i t i o n a l terpene-derived (Q)-(103)

(103) as

A wide range of a l k e n e s , a l t h o u g h n o t

o r g a n o b o r a n e s and t h e a v a i l a b i l i t y o f

is a l s o s i g n i f i c a n t .

Once a v a i l a b l e , o p t i c a l l y p u r e

o r g a n o b o r a n e s c a n b e m a n i p u l a t e d i n v a r i o u s w a y s a n d nebi m e t h o d o logy h a s appeared.

Boronic esters ( 1 0 4 ) undergo homologation t o

t h e a-methoxyalkyl

d e r i v a t i v e (105) which is t h e n o x i d i z e d t o g i v e

t h e a l d e h y d e ( 1 0 6 ) .78

Successvie homologations,

( 1 0 8 1 , may b e a c h i e v e d u s i n g t h e o n e - c a r b o n

( 104) t o

u n i t LiCHC12,

by r e d u c t i o n w i t h p o t a s s i u m t r i - i s o p r o p o x y b o r o h y d r i d e (Scheme 2 9 ) . 7 9

or

( 107 )

followed

(KIPBH)

B o t h p r o c e d u r e s a r e a p p l i c a b l e t o a n u m b e r of

boronic esters r e l a t e d t o (104). A l l y l i c boranes g e n e r a l l y undergo r a p i d a l l y l i c rearrangement, but hydroboration of cyclohexa-1,3-diene pinocamphenylborane

with

( + I - or (-)-a-iso-

(Ipc2BH) g i v e s t h e f i r s t example of an o p t i -

c a l l y a c t i v e a l l y l i c b o r a n e ( 1 0 9 ) t h a t is s t a b l e t o w a r d s r e a r r a n g e ment a n d t h e r e f o r e r a c e m i z a t i o n . 8 0

A l l y 1 b o r a n e s are good n u c l e o p h i l e s towards a l d e h y d e s , and t h e s t e r e o c h e m i c a l a s p e c t s of t h i s

r e a c t i o n have f e a t u r e d prominently t h i s year. and L - c r o t y l b o r o n a t e s , dialkoxy-aldehydes,

E-(110)

and L - ( l l O ) ,

The r e a c t i v i t y o f

E-

t o w a r d s c h i r a l a,B-

e.g. ( 1 1 1 ; R = H o r Me) h a s b e e n s t u d i e d .

With

b o t h a l d e h y d e s 2-(110) reacts i n a h i g h l y s t e r e o s e l e c t i v e f a s h i o n ,


378

"ec'

CHO

299

>,99O/. Reagents :

I)

LIC=

[Pd( PPh3kl

*

Me

M bSi Me3 SnMe3

>--c

Me

SiMe3Me3

(1L7)

( 1 491 Reagents:

I ,

Me3SiSn B u n 3 ( 1 4 8 1 , c a t a l y t i c K C N , 1 8 - c r o w n - 6 ;

Scheme L5

R’

(150)

R’

S c h e m e 46

I I

;F-

391

6: Organornetallics in Synthesis

-

Bun3Sn A l E t2

(151)

R

( 6un3Sn1,Zn

Bun3SnMgMe

(1521

(153)

SnBun3

x

f15L1

(1551

Me3Sn(SPh1CuL i

Me3SnCu. Me, S

(157)

( 156)

RYcoNMe R-

= - -c

If \

\ NMe,

Me3Sn E - ( I 58)

)-7CONMe2

Me3Sn

Z- (158)

e2

RHcoNM

M e3S n

"

Cu "

392


isomeric stannane (155; X SnBun3). Enol triflates (155; X = OSO CF 1 are also precursors of vinyl stannanes (155; X = SnBu" 2 3 3)' The nucleophilic addition of the (trimethylstanny1)cuprates (156) and ( 1 5 7 ) to propiolamides can be controlled to give E-(158) or 2-(158) selectively (Scheme 47). Tetrasubstituted vinylstannanes may be obtained by alkylation of the initial product of addition, a vinylcopper species (159). 128 An efficient synthesis of 2-(tri-n-butylstannyl)buta-l,3-diene (1601, an established precursor of 2-lithiobuta-l,3-diene, has been developed. 129 The Diels-Alder reactions of (160) also offer considerable potential since the cycloadduct retains a vinyltin moiety. a-Substituted allylstannanes (161) have been obtained from 8 stannyl esters using a selenoxide elimination as the key step (Scheme 48). 3 0 In the case of secondary selenides such as ( 1621, the orientation of elimination is dependent on the nature of R 3 , but homoallylic stannanes (163) tend to predominate. Allylstannanes (161) were also shown to be stable towards allylic rearrangement. One of the most interesting chemical transformations described this year involves the stereospecific oxidative fragmentation of the B-stannyl oximes (164) and (165).131 The products of the cleavages are nitrones which can be trapped in an intramolecular fashion to give AL-isoxazolines. Bifunctional stannanes (166) and (167) have played a central role in a number of recent annulation sequences (Scheme 50). Lee et al. have used (166) in a one-pot annulation of cyclic ketones, 32 and bicyclic 1 ,3-dienes ( 168) have been prepared by Piers using, as a key step, the Pd(0)-catalysed coupling of an en01 triflate and a vinylstannane. 33 Another bifunctional stannane (169) has been developed by Trost for use in a two-step [ 3 + 2 1 addition of C = X (X = 0 or N R ) (Scheme 51). Imines derived from ketones do not apparently undergo this C3+21 addition, but aldehydes, ketones, and aldimines may all be used successfully. 34 Allylstannane (770) reacts with aldimines, in the presence of TiC14 or B F 3 , to give homoallylic amines. 135 In the case of the butenyl derivative (171) the stereoselectivity of the addition is very sensitive to the reaction conditions used. The allylstannane (170) also reacts with N - - ( a l k o x y c a r b o n y l ) p y r i d i n i u m salts to give the 2-allylated adducts with a much higher regioselectivity than that observed with the corresponding Grignard reagents


393

(161) R ' , R 2 = Me, Ph, or H

R3nMe SnR3 S e A r

SnR3

(162) Reagents: i , L i A I H L ;

11,

(163)

2-N02C6HLSeCI, Bun3P,

ill,

MCPBA

Scheme 4 8

Ho,

hMe N

f ,

+ ,

G

0-

M

e

N-0

+ I,

&Me

SnBu"3 ( 1 64)

6 +/

Ho,

&Me

i,

0-

1 1 )

Sn~u"3 (1651 Reagents

:

Pb(OAc14

I

- 60 C'

; 1 1 , NaHC03, 20aC

Scheme L9 OH

Me0 Me0

k

SnMe3

[ 166)

0 Me

(1 67)

(1681

Scheme 50


394

A

c

O

A Sn6un3

( 1 69)

\ R Reagents:

I,

RRICO, BF3. E t 2 0 , t h e n P d ( O A d 2 , Ph3P; ii, RCI-i=NR2, BF3. Et20,then Pd[OAc)*,

Ph3P

Scheme 51

R

wS n B u n 3 (170) R = H (171 1 R =

(1721

Me

R1

R'

R

>S02Ph

-&

> R

R1 4

4

R

>CN

Reagents: i , BunL! , ( 1 7 2 1 , t h e n 6 u n L N F ; 1 1 , L D A , ( 1 7 2 ) , t h e nM e L i . L i B r

I

R' B u 3 S n /+ A -K 0

R e a g e n t : i , [Pd(Ph3P),C12]

Scheme 5 3 Sn CI 2

I

RCHO

Scheme 5 4

6: Organometallics in Synthesis ( CH2=CHCH2MgBr).

395

36

(1odomethyl)tri-n-butylstannane (172) is a useful reagent for the methylenation of moderately hindered sulphones and nitriles (Scheme 52). 137 This reagent is considerably more reactive than the corresponding silane. Palladium(I1)-catalysed cross-coupling reactions involving stannanes have continued to be developed. a-Halogeno-esters and -1actones couple with allylstannanes and a-stannyl-ketones in good yield (Scheme 53 1 . 138 Symmetrical and unsymmetrical a-diketones are available from coupling of acyl halides and acylstannanes. 39 These types of coupling procedures, though useful, may be limited by the availability of the requisite stannane. A promising solution to this problem involves reaction of readily available allylic acetates with aryl halides in the presence of hexa-n-butyldistannane (Bun3SnSnBun3).140 This avoids the need to prepare the previously used substrate, the arylstannane, and it will be interesting to see whether this technique becomes applicable to processes such as those shown in Scheme 53. Stannous chloride, in conjunction with l-bromo-3-iodopropene1 has been used to convert aldehydes directly into conjugated dienes, in fair to good yield (Scheme 54). a,B-Unsaturated aldehydes have also been used to obtain trienes. 141 Two new organolead reagents (173) and (174) have been described. Both anions are good nucleophiles, reacting with a wide range of electrophiles to give adducts incorporating one or two Ph Pb 3 residues respectively. 142 5 Group V Phosphorus.- As in previous years the chemistry of the Wittig reaction and related processes has been the subject of a large proportion of the publications in this area. Various stereochemical aspects of the Wittig reaction have been described. a Oxygenated cyclohexanones and 2,3-epoxycyclohexane react with Ph P-CHMe to give the L-ethylidene derivatives in a highly stereo3 selective fashion (Scheme 55) under both Li-base and Li-free con-

'

ditions. 43 The presence of anionic nucleophilic groups in the side-chain of triphenylphosphonium ylides (175; X OH, C02H, or is known to influence dramatically the stereochemistry of a l k e n e s formed by the Wittig reaction. This phenomenon has been NH2)

the subject of a detailed study, and although the effect is most

396


Ph, P b C H2Li

(

(173)

Ph,Pbl,CHLi (17-L)

Ph P=CHMe

&OR

" ? T O R

R = a l k y l or SIR'

3

Ph3P=CH Me

"b0

Scheme 5 5

I

HO

Reagents

qCHO' II

: i , (EtO)2POCH2C02Et,K 2 C 0 3 , H20; i i , KOH

Scheme 56

Ph,P+ OH

BF


397

p r o n o u n c e d w i t h a r y l a l d e h y d e s , i t i s a l s o h i g h l y d e p e n d e n t on t h e d e g r e e o f s e p a r a t i o n of t h e y l i d e and t h e n u c l e o p h i l i c r e s i d u e 144 X. Generally t h e c o n d i t i o n s r e q u i r e d t o c a r r y o u t t h e Horner-Wittig r e a c t i o n are n o t compatible with s e n s i t i v e f u n c t i o n a l groups such

as hydroxy-, n i t r o - , mally be p r o t e c t e d .

and keto-aldehydes; t h e s e r e s i d u e s must norHowever, t h e u s e o f a h e t e r o g e n e o u s b a s e s u c h

as K 2 C 0 3 i n e i t h e r a q u e o u s o r o r g a n i c m e d i a a l l o w s t h e c o n d e n s a t i o n of t h e s e s e n s i t i v e s u b s t r a t e s w i t h a c t i v a t e d phosphorates t o t a k e place directly. The s y n t h e s i s o f ' R o y a l J e l l y ' a c i d f r o m 8 h y d r o x y o c t a n a l a p t l y i l l u s t r a t e s t h e method (Scheme 5 6 ) . 145 S c h l o s s e r h a s d e s c r i b e d v a r i o u s a p p l i c a t i o n s of h i s ' i n s t a n t y l i d e ' m e t h o d o l o g y . 1 4 6 T h i s r e l i e s on t h e c o n v e n i e n t u s e o f a p r e m i x e d b a s e (NaNH2) a n d p h o s p h o n i u m s a l t t h a t a r e s t a b l e i n t h e absence of a solvent. A number o f s u c h c o m b i n a t i o n s a r e c o m m e r c i a l l y a v a i l a b l e and y l i d e f o r m a t i o n t a k e s p l a c e ' i n s t a n t l y '

on

dissolution. P r o b l e m s h a v e , h o w e v e r , b e e n e n c o u n t e r e d when u s i n g phosphonium s a l t s s u c h a s ( 1 7 6 ) t h a t c o n t a i n ' k i n e t i c a l l y a c i d i c ' protons. The ' i n s t a n t y l i d e ' m i x t u r e s w e r e f o u n d t o b e u n s t a b l e b u t t h i s was r e s o l v e d by p r e - c o a t i n g t h e p a r t i c l e s o f N a N H 2 w i t h p a r a f f i n ; t h e s e new m i x t u r e s a r e now s t a b l e u n t i l a s o l v e n t i s a d d e d , a n d t h e b a s e becomes a v a i l a b l e . The s y n t h e s i s a n d r e a c t i v i t y o f t h e a - l i t h i o - y l i d e g e n e r a t e d some c o n t r o v e r s y t h i s y e a r ( S c h e m e 5 7 ) .

(178) has

This reagent,

f i r s t d e s c r i b e d by C o r e y , was g e n e r a t e d by d e p r o t o n a t i o n o f t h e y l i d e ( 1 7 7 ) w i t h BuSLi o r B u t L i . I n r e s p o n s e t o a p u b l i c a t i o n from S c h l o s s e r , 47 t h e H a r v a r d g r o u p h a s now p u b l i s h e d f u l l e x p e r i m e n t a l d e t a i l s t o support t h e i r earlier report. Almost s i m u l t a n e o u s l y t h e L a u s a n n e g r o u p h a s r e F , c r t e d o n t h e i r own work i n t h e a r e a . 1 4 9 They claim t h a t r e a c t i o n o f ( 1 7 7 ) w i t h BuSLi o r B u t L i d o e s n o t g i v e (178) but instead t h e ortho-lithiated s u p p o r t e d by 'H n . m . r .

species (179).

T h i s was

s t u d i e s , a n d a d d i t i o n o f Me1 t o ( 1 7 9 ) g a v e

(180). On w a r m i n g , ( 1 7 9 ) d e c o m p o s e d t o g i v e a d i b e n z o p h o s p h a t e a n d b e n z e n e ; t h i s e x p e r i m e n t e l i m i n a t e d t h e p o s s i b i l i t y of a t h e r m a l c o n v e r s i o n o f ( 1 7 9 ) t o ( 1 7 8 ) t h a t h a d b e e n s u g g e s t e d by C o r e y . The a - l i t h i o - y l i d e ( 1 7 8 ) was p r e p a r e d b y t h e L a u s a n n e g r o u p by b r o m i n e l i t h i u m exchange i n v o l v i n g (181).

Clearly t h i s situation has not

been f u l l y r e s o l v e d .

New m e t h o d s f o r t h e s y n t h e s i s o f p h o s p h o r u s - c o n t a i n i n g compounds T h e P-Ph bond i n PhPR2 may b e have also been developed. r e d u c t i v e l y c l e a v e d ( L i , THF, u l t r a s o u n d ) t o p r o v i d e t h e d i s u b s t i -


398

Ph,P=CH2

BU’L~ or ButLi 7 ( r e f . 1L8)

*-~ButLi

Ph3P-\

Ph 3 ,P

7 Br

Li

(1771

I1781

(181 1

( 1 801

( 1 791 Scheme 57

R

1831

(

(1821 0

0

0

Li ( 1841

0

0

II

(1851

4

0

0

II

+

Ph-P-CH-C-0 2

n

PhcP4CH2C02H

t

t

(1861

( 1 881

(1871 Scheme 5 8 yo2

(1891

+

0

CIO, R e a g e n t s : i P h 3 P J 2 .6

- lutidinium

(1901

perchlorate ; ii NaOH , E t O H , H20

Scheme 5 9

II

PhtPaMe

(1911


399

t u t e d phosphide anion (R2PLi), which i s u s e f u l f o r t h e s y n t h e s i s of t e r t i a r y p h o s p h i n e s . 50 A r y l p h o s p h o n a t e s (182) a r e p r e p a r e d i n g o o d y i e l d from a n a r e n e and e i t h e r a t r i - o r d i - a l k y l

cal oxidant respectively.

p h o s p h i t e , u s i n g a n i o n i c or a c h e m i -

The s c o p e of t h i s p r o c e s s h a s been

e x t e n d e d a n d v a r i o u s c h e m i c a l o x i d a n t s h a v e b e e n e v a l u a t e d . 15’ A s i m p l e s y n t h e s i s o f dialkylalkoxycarbomethanephosphonates ( 1 8 3 )

h a s been a c h i e v e d u s i n g p h a s e - t r a n s f e r

c a t a l y s i s ,152 and v i n y l -

p h o s p h o n a t e s ( 1 8 5 ) h a v e b e e n p r e p a r e d by r e a c t i o n o f a n a l k y l i d e n e d i p h o s p h o n a t e a n i o n ( 1 8 4 ) w i t h a n a l d e h y d e or k e t o n e . 1 5 3

Access t o o p t i c a l l y p u r e p h o s p h i n e o x i d e s i s i m p o r t a n t f o r t h e preparation of c h i r a l bidentate l i g a n d s t h a t have found a p p l i c a t i o n i n asymmetric hydrogenation.

T e r t i a r y phosphine oxides are avail-

a b l e i n high enantiomeric excess using menthyl 2-phosphinylacetate ( 1 86) ( S c h e m e 5 8 1. 154

The two d i a s t e r e o i s o m e r s c o r r e s p o n d i n g t o

( 1 8 6 ) a r e s e p a r a t e d by f r a c t i o n a l c r y s t a l l i z a t i o n ( o n e i s o m e r i s shown).

Hydrolysis t o (187) and decarboxylation g i v e s (188) which

c a n t h e n be used a s a b a s i c b u i l d i n g b l o c k f o r t h e s y n t h e s i s of more complex d e r i v a t i v e s .

(~)-(-)-~-(3,5-Dinitrobenzoyl)-a-

p h e n y l e t h y l a m i n e (189) h a s b e e n d e v e l o p e d f o r u s e a s a c h i r a l s h i f t r e a g e n t for t h e a n a l y s i s o f c h i r a l p h o s p h i n e o x i d e s . 155

This

reagent h a s previously been used t o analyse c h i r a l sulphoxides. Alkenylphosphonium s a l t s and a l k e n y l p h o s p h i n e o x i d e s are b o t h o f u s e i n t h e s y n t h e s i s of c a r b o c y c l i c a n d h e t e r o c y c l i c s y s t e m s , a n d new r o u t e s t o t h e s e d e r i v a t i v e s a r e o f v a l u e .

Cycloalkenes react

with triphenylphosphine using constant current electrolysis t o give

l-cycloalkenylphosphonium s a l t s (190) ( S c h e m e 59). 156 T h e p r o c e d u r e i s s i m p l e a n d t h e c o r r e s p o n d i n g p h o s p h i n e o x i d e s (191) a r e a v a i l a b l e by h y d r o l y s i s .

Vinyltriphenylphosphonium b r o m i d e (VTB) (192) h a s b e e n u s e d b y Posner i n an e f f i c i e n t one-pot,

three-component

[2+2+2] a n n u l a t i o n

p r o c e s s , coined t h e M I M I R C (Michael-Michael Ring C l o s u r e ) r e a c t i o n (Scheme 6

0

~ G’e n e~r a l~l y b o r o n or l i t h i u m e n o l a t e s a r e u s e d , a n d

t h e r e a c t i o n , i n terms o f t h e c a r b o n y l c o m p o n e n t , i s q u i t e g e n e r a l , though aldehyde e n o l a t e s tend t o g i v e lower y i e l d s . products,

e.g. (193) a n d

The a n n u l a t e d

( 1 9 4 ) , were c o n v e r t e d i n t o t h e c o r r e s -

ponding phosphine o x i d e s f o r easier handling. F u l l d e t a i l s o f t h e s t e r e o s p e c i f i c s y n t h e s i s of y , 6 - u n s a t u r a t e d a c e t a l s h a v e b e e n p u b 1 i ~ h e d . l ~T~h e s u c c e s s o f t h i s m e t h o d l i e s i n t h e e f f i c i e n t s y n t h e s i s o f e i t h e r t h e t h r e o - or e r y t h r o - B - h y d r o x y phosphine o x i d e s (195) and (1961, t h e fragmentation of which g i v e s


400

A PPh,Br(192)

0

II If (y-JPPh3 ,

+

.I .. ll

m

P

P

h

(193)

\iL (-=+

Ill,($

PPh,

PPh,

II

0

(19Ll R e a g e n t s : i, LIBU~,BH t h e n (192)

2 equiv ;

II

L I NPr12 , t h e n (1921, Zequiv., iii ,KOH

Scheme 6 0

0

P-l

0

OH

II

0

I 1

, ? & - y ! 2P h

A'

Me

R'

(200)

( 201)

R'

2

401


E-

the corresponding and L-alkenes r e s p e c t i v e l y . The e p o x i d a t i o n o f a l l y l i c p h o s p h i n e o x i d e s ( 1 9 7 ) w i t h p e r a c i d h a s b e e n shown t o be h i g h l y s t e r e o s e l e c t i v e t o g i v e ( 1 9 8 1 , w h i c h u n d e r g o e s n u c l e o p h i l i c r i n g o p e n i n g , l e a d i n g t o s y n t h e t i c a l l y u s e f u l B-hydroxyphosphine oxides. I n t h e case o f ( 1 9 9 ) and (2001, t h e e p o x i d a t i o n s a r e c o n t r o l l e d by t h e a l l y l i c h y d r o x y l f u n c t i o n t o g i v e ( 2 0 1 ) a n d (202).

159

Polymer-bound

r e a g e n t s h a v e become p o p u l a r l a t e l y , a n d d i e t h o x y diphenylpolystyrylphosphorane h a s b e e n u s e d f o r t h e c y c l i c d e h y d r a t i o n o f d i o l s . I 6 O An u n b o u n d v e r s i o n o f t h i s r e a g e n t i s a l s o . available. A r s e n i c , Antimony, and Bismuth.-

(Dipheny1arsino)methyl-lithium or tin-lithium exchange from (204) o r (205) r e s p e c t i v e l y . 16' Interestingly the r e a c t i v i t y o f ( 2 0 3 ) d e p e n d s on t h e method o f p r e p a r a t i o n u s e d , a l t h o u g h t h e r e a s o n s f o r t h i s a r e n o t known. A stereoselective s y n t h e s i s o f & - a , B - u n s a t u r a t e d a l d e h y d e s h a s b e e n a c h i e v e d by r e a c t i n g a l d e h y d e s w i t h t h e a r s o n i u m s a l t (206) i n t h e p r e s e n c e o f a weak b a s e . 1 6 2 T h e y l i d e d e r i v e d f r o m (206) s h o w s a r e a s o n a b l e d e g r e e of c h e m o s e l e c t i v i t y , r e a c t i n g w i t h a l d e h y d e s i n t h e p r e s e n c e A combination of aluminium c h l o r i d e and d i p h e n y l of ketones. s t i b i n e (Ph2SbH) r e d u c e s a l d e h y d e s a n d k e t o n e s t o g i v e a l c o h o l s . Enones undergo con j u g a t e r e d u c t i o n u n d e r t h e s e c o n d i t i o n s . " The c o n v e r s i o n of c a r b o x y l i c a c i d s , v i a t h e c o r r e s p o n d i n g t h i o hydroxamic e s t e r (2071, i n t o n o r - a l c o h o l s ( R O H ) has been a c h i e v e d 164 i n h i g h y i e l d u s i n g ( P h S ) S b i n t h e p r e s e n c e of O2 a n d H20; ( 2 0 3 ) h a s b e e n p r e p a r e d by e i t h e r h a l o g e n - l i t h i u m

3

(PhS) Sb p r o v i d e s a s o u r c e of p h e n y l t h i y l r a d i c a l s ( P h S ' ) , t h e

3

r a d i c a l chain carrier. A l l y l i c h a l i d e s r e a c t w i t h a l d e h y d e s and metallic bismuth t o g i v e good y i e l d s o f h o m o a l l y l i c a l c o h o l s (Scheme 6 1 ) . 165

6 Group V I Sulphur.-

A s i n p r e v i o u s y e a r s a l a r g e component o f t h e s u l p h u r

chemistry reported has involved t h e reactions of sulphur-stabilized c a r b a n i o n s , a n area t h a t h a s been c o v e r e d i n S e c t i o n 1 .

There h a s ,

h o w e v e r , b e e n a g o o d d e a l of a c t i v i t y i n t h e s y n t h e s i s a n d r e a c t i o n s o f o r g a n o s u l p h u r compounds.

Two i n t e r e s t i n g f r a g m e n t a t i o n s o f a - t r i m e t h y l s i l y l s u l p h i d e s h a v e b e e n u s e d t o g e n e r a t e t h i o c a r b o n y l y l i d e ( 2 0 8 ) 166 a n d t h i o a l d e h y d e s


402

+

Ph, A s C H, X

Ph3AsCH2CH0 Br-

(2031X = L i

( 206)

(2041X = I (205) X = SnBun3

Me

O II RCH,’

h

‘0’NyS S

(2071 OH

R = a \ k y l or a r y l

S c h e m e 61

Br

J

( 208)

(209)

Scheme 6 3

6: Organometailics in Synthesis (209)

403

both u s e f u l i n t h e synthesis of sulphur heterocycles

(Scheme 6 2 ) . A g e n e r a l method f o r t h e a c e t a m i d o s u l p h e n y l a t i o n o f a l k e n e s i s

b a s e d on t h e a n o d i c , o r m e t a l - i o n p h i d e s (Scheme 6 3 ) . 168

promoted, o x i d a t i o n of d i s u l -

Both B-aminosulphides

s u l p h i d e s a r e a v a i l a b l e by t h i s m e t h o d .

and B-acetamido-

High d i a s t e r e o s e l e c t i v i t y

( u p t o 97%) h a s been observed i n t h e low-temperature

a d d i t i o n of

b e n z e n e s u l p h o n y l c h l o r i d e t o t h e b o r n y l a c r y l a t e s ( 2 1 0 ) and ( 2 1 1 ) . The a b s o l u t e c o n f i g u r a t i o n s o f t h e a d d u c t s ( 2 1 2 ) h a v e been established.

Dimethyl(methythi0 )sulphonium t e t r a f l u o r o b o r a t e

,

a

c o n v e n i e n t s o u r c e o f MeS+, h a s f o u n d a p p l i c a t i o n i n t h e s y n t h e s i s of l a c t o n e s and c y c l i c ethers'"

a n d h a s been u s e d t o e f f e c t macro-

c y c l i c r i n g c l o s u r e s . '7' A number o f r e a r r a n g e m e n t s i n v o l v i n g s u l p h u r h a v e b e e n r e p o r t e d . A novel a n n u l a t i o n of a-alkylthiomethylene ketones t o cyclohexenones

(Scheme 6 4 ) i n v o l v e s a s u l p h u r - a s s i s t e d

r i n g o p e n i n g and s u b s e q u e n t

r e c l o s u r e o f a c y c l o b u t a n o n e 2-trimethylsilylcyanohydrin. 7 2 R e a r r a n g e m e n t o f 2,2-bis(phenylthio)ethanols

( 2 1 3 ) c a n be con-

t r o l l e d i n a number o f s y n t h e t i c a l l y u s e f u l w a y s , f u l l d e t a i l s o f w h i c h a r e now a v a i l a b l e . 1 7 3 A r a n g e o f f u n c t i o n a l i z e d c y c l o p e n t e n e s a r e a v a i l a b l e by m a n i -

p u l a t i o n of b i c y c l i c s u l t e n e s ( 2 1 5 ) (Scheme 6 5 ) .

These r e l a t i v e l y

r a r e h e t e r o c y c l e s a r e o b t a i n e d by s t e r e o s p e c i f i c r e a r r a n g e m e n t o f t h e c y c l o a d d u c t s ( o n e isomer i s shown) o b t a i n e d from a l k a n e t h i a l o x i d e s ( 2 1 4 ) and c y c l o p e n t a d i e n e . 174

2-

Asymmetric s y n t h e s i s b a s e d on c h i r a l s u l p h o x i d e s i s a r a p i d l y developing f i e l d .

Two s y n t h e s e s o f

(-)-methyl

jasmonate have been

accomplished s t a r t i n g from t h e c h i r a l a l k e n y l s u l p h o x i d e ( 2 1 6 ; A r 4-MeC6H4).

The k e y i n t e r m e d i a t e ( 2 1 7 ) i s a r r i v e d a t by e i t h e r a

c o n j u g a t e a d d i t i o n o f a n a - l i t h i ~ a c e t a t e ' t~o~ ( 2 1 6 ) or by a p p l i c a t i o n of t h e

' a d d i t i v e Pummerer'

rearrangement.

I n v i e w o f t h e i r i m p o r t a n c e i n a s y m m e t r i c s y n t h e s i s new r o u t e s have been developed t o c h i r a l s u l p h o x i d e s and r e l a t e d s p e c i e s . S u l p h i n a t e s , u s e f u l as p r e c u r s o r s of c h i r a l s u l p h o x i d e s , have been p r e p a r e d i n 40-70% e n a n t i o m e r i c e x c e s s a n d t h e s y n t h e s i s a n d d i e n o p h i l i c p r o p e r t i e s of t h e i s o m e r i c s u l p h i n y l a c r y l a t e s ( 2 1 8 ) a n d ( 2 1 9 ) ( A r = 4-MeC6H4) h a v e b e e n d e s c r i b e d .

(E)-Vinyl s u l -

phoxides have been prepared i n h i g h o p t i c a l p u r i t y v i a l-alkynyl s u l p h o x i d e s (Scheme 6 6 ) . 1 7 '

The f i n a l s t e r , o f t h i s s e q u e n c e i s

i n t e r e s t i n g , an unusual trans-hydroalumination observed.

of the alkyne being


404

0 Reagents:

I ,

1- L r t h i o - 1 -

m e t h o x y c y c l o p r o p a n e , t h e n HBFL ; i i I M e g S i C N , Z n I , t h e n F -

Scheme 6 4

HO (2131

\sR, -

0-

q R

f H

Scheme 65

7


405

..

(2171

R-=-

-

0-

0-

MgCl

-*

( 218)

0-

R

-*

R - = - S - -+ -:/

-

(2191

A+/'S.

\

**:

Ar Ar

R e a g e n t s : i, (S)-(-)-menthyi - p - t o l u e n e s u l p h i n a t e ;

it,

.& '

Scheme 6 6

H& ;

s3

B u ~ A L H t, h e n H 2 0

4

502ph

PhOzS (221 1

X i 220)

R

( 2 2 2 R : a l k y l or a r y l )

PhSO2

Gck (2231

Reagents : i

, ButOCl

(2241

( 22 51

; i i , P(NMeZl3 t h e n NHLPF6 ; ii , n u c l e o p h i l e f N u - )

Scheme 67


406

norbornadienes relies

An a s y m m e t r i c s y n t h e s i s o f 2 - s u b s t i t u t e d

on t h e d i a s t e r e o s e l e c t i v e c y c l o a d d i t i o n o f c y c l o p e n t a d i e n e t o t h e These activated alkenyl sulphoxides (220; X CO Me or S 0 2 P h ) . I8O 2 d i e n o p h i l e s w e r e o b t a i n e d by a s e l f - i n d u c e d c h i r a l o x i d a t i o n o f t h e corresponding sulphide. Although a l k e n y l s u l p h o x i d e s are w e l l e s t a b l i s h e d as Diels-Alder dienophiles,

t h i s year h a s s e e n t h e f i r s t e f f e c t i v e u s e o f a s u l 4-MeC H ) a s a c h i r a l e n o p h i l e i n a n 6 4 181

phinyl diene (221; A r

i n v e r s e e l e c t r o n demand c y c l o a d d i t i o n r e a c t i o n .

The r e a c t i v i t y o f a n u m b e r o f o t h e r d i e n e s a n d d i e n o p h i l e s carrying sulphur s u b s t i t u e n t s i n a range of oxidation l e v e l s has a l s o been examined.

E x a m p l e s i n c l u d e ( 2 2 2 ) , 1 8 2 ( 2 2 3 1 , 1 8 3 ( 2 2 4 ) , 18‘

and s u l p h o n a t e ( 2 2 5 ) 1 8 5 h a s b e e n shown t o b e c o n s i d e r a b l y more r e a c t i v e than phenyl v i n y l sulphone towards f u r a n . Two r e s e a r c h g r o u p s h a v e r e p o r t e d o n t h e e f f i c i e n t 1 , 3 asymmetric r e d u c t i o n of c h i r a l B-keto-sulphoxides

w i t h Bui2A1H.

C o m p l e m e n t a r y s t e r e o s e l e c t i v i t y may b e o b t a i n e d i f r e d u c t i o n i s 186 c a r r i e d o u t under c o n d i t i o n s of c h e l a t i o n c o n t r o l . The f i r s t e x a m p l e o f d i r e c t n u c l e o p h i l i c s u b s t i t u t i o n o f a t h i o l from a n a s y m m e t r i c c a r b o n c e n t r e , w i t h i n v e r s i o n of c o n f i g u r a t i o n , h a s b e e n c l a i m e d ( S c h e m e 6 7 ) . 187

A c t i v a t i o n of t h e t h i o l i s

r e a d i l y a c h i e v e d , and a range of heteroatom and carbon n u c l e o p h i l e s h a s been u t i l i z e d .

3-Bromo-2-(t-butylsulphonyl)prop-l-ene

(226) is an extremely

f l e x i b l e r e a g e n t t h a t s h o w s a b r o a d s p e c t r u m o f r e a c t i v i t y . 188

Two

p r i n c i p a l p a t h w a y s ( a ) and ( b ) , (Scheme 6 8 ) h a v e b e e n e s t a b l i s h e d a n d t h e r e a c t i v i t y o f ( 2 2 6 ) may b e r e p r e s e n t e d a s t h e d i p o l a r e q u i v a l e n t s ( 2 2 7 ) and (228) c o r r e s p o n d i n g t o pathways ( a ) and ( b ) respectively

.

Cyclic sulphones (229) undergo a r e g i o s e l e c t i v e cleavage with u l t r a s o n i c a l l y d i s p e r s e d potassium t o g i v e , after a l k y l a t i n g t h e r e s u l t i n g s u l p h i n a t e with an a l k y l h a l i d e ( R ’ X ) , phone ( 2 3 0 ) . 189

the acyclic sul-

The p o t e n t i a l o f s u l p h o n e s , o f t h e t y p e d e s c r i b e d a b o v e , h a s b e e n e x t e n d e d w i t h new m e t h o d s b e i n g d e v e l o p e d f o r t h e c o n v e r s i o n

of s u l p h o n e s i n t o k e t o n e s . ” ’

Finally,

s e v e r a l new m e t h o d s f o r t h e

r e d u c t i o n of s u l p h o x i d e s have been r e p o r t e d . Selenium and Tellurium.-

T h i s a r e a h a s s e e n c o n t i n u e d p r o g r e s s this

y e a r a n d , i n a d d i t i o n t o new d e v e l o p m e n t s i n s e l e n i u m c h e m i s t r y , t h e s y n t h e t i c u t i l i t y o f t e l l u r i u m i s now b e g i n n i n g t o e s t a b l i s h

407


Nu’

Nu2=RS-,

(228)

Do-.

R 2 C u L i ; E ’ = R C H O , R,CO,

Reagents: i , Nu’ then N u * ;

ill

RCN

E’,Zn,then Nu1

S c h e m e 68

i SO, R1

QR (2291

R

(230) P h S 0 e - N m

Me2A l SeMe

6’

( 2 3 11

(2321

R

R (2331

R

(234)

Reagents : i , PhSeH , H’ ; i i , B u ’ ~ A I H t h e n PhSeH , BF3.Et20

Scheme 6 9 Ph Se SeR’

R

R

iUR’ SCPh

II

( 2 3 5 ) R1= a l k y \ or aryl (236)

0


408

itself. One o f t h e m o s t s i g n i f i c a n t c o n t r i b u t i o n s h a s b e e n t h e p u b l i c a t i o n of a Tetrahedron ’Symposia i n P r i n t ‘ l a r g e l y devoted t o selenium chemistry.

T h i s volume c o v e r s a wide r a n g e o f t o p i c s , b u t

only t h o s e w i t h a s y n t h e t i c b i a s can be d i s c u s s e d here. chemistry of t h e v e r s a t i l e selenenylating agents methaneselenolate (231

The

dimethylaluminium

9 2 a n d N-phenylselenophthalimide ( 2 3 2 ) 1 9 3

h a s been covered and u s e f u l overviews o f t h e s y n t h e s i s and reactiv i t y o f ~ e l e n o a c e t a l s ~a’n~d 2-phenylselenenylenones’ 95 h a v e a l s o been i n c l u d e d . cx-Selenyl e t h e r s ( 2 3 4 ) a r e c o n v e n i e n t l y p r e p a r e d f r o m e i t h e r a l a c t o l ( 2 3 3 ) o r a l a c t o n e l g 6 (Scheme 6 9 ) a n d u n d e r g o , n o t s u r prisingly, a facile oxidative elimination t o give enol ethers. Diazomethane undergoes a c o p p e r - c a t a l y s e d i n s e r t i o n i n t o t h e a c y l S e bond o f s e l e n o e s t e r s t o g i v e c x - ( a l k y l (235). of

or aryl-se1eno)ketones

A l t h o u g h m e t h y l k e t o n e s h a v e b e e n o b t a i n e d by r e d u c t i o n

(2351, t h e c h e m i s t r y o f t h e s e systems h a s y e t t o be f u l l y

exploited. D i r e c t s e l e n a t i o n o f C-C n-bonds i s a n i m p o r t a n t s y n t h e t i c A l k e n e s r e a c t w i t h 2-benzoylphenylselenosulphide

process.

(PhCOSSePh), i n t h e p r e s e n c e o f A I B N , t o g i v e t h e a d d u c t s ( 2 3 6 ) . 199 Allenes a l s o undergo f r e e - r a d i c a l

s e l e n o s u l p h o n a t i o n w i t h PhSeS02Ph

t o g i v e t h e a l l y l i c s e l e n i d e s ( 2 3 7 ) (Scheme 7 0 ) . 2 0 0

These adducts

h a v e f o u n d a p p l i c a t i o n i n t h e s y n t h e s i s o f a u s e f u l c l a s s of a l l y l i c a l c o h o l s [see a l s o ( 2 2 6 1 , Scheme 6 8 1 . The r e g i o s e l e c t i v e s y n t h e s i s o f t h e r e l a t e d n i t r o a l l y l i c a l c o h o l s ( 2 3 8 ) ,201 a n o t h e r g r o u p o f u s e f u l m u l t i p l e c o u p l i n g r e a g e n t s , i s a l s o shown, and involves t h e addition of a selenyl residue t o a nitroalkene. A tandem a l d o l c o n d e n s a t i o n - r a d i c a l

c y c l i z a t i o n a p p r o a c h (Scheme

7 1 ) t o c a r b o c y c l i c s y n t h e s i s r e l i e s on a n i n i t i a l c o n j u g a t e a d d i t i o n of a n a r y l s e l e n i d e t o an enone.202

T h i s can be achieved

u s i n g e i t h e r PhSeA1Me2 o r [ P h S e T i ( O P r i I 4 ] L i a n d t h e r e s u l t i n g e n o -

late then undergoes a l d o l condensation.

Use o f a n a p p r o p r i a t e

c a r b o n y l c o m p o n e n t c o m b i n e d w i t h h o m o l y t i c c l e a v a g e of t h e C-Se bond p r o v i d e s a p a t h w a y t o a s e r i e s o f b i c y c l i c c a r b o c y c l e s . The c h e m i s t r y o f s e l e n o x i d e s h a s a l s o s e e n some a d v a n c e s t h i s year.

The f i r s t c a s e o f a n a s y m m e t r i c o x i d a t i o n o f a n a c h i r a l

s e l e n i d e , u s i n g a c h i r a l 2 - s u l p h o n y l o x a z i r i d i n e 7 h a s been reported.203

T h i s r e a c t i o n i s n o t as e f f i c i e n t a s t h e c o r r e s -

ponding s u l p h i d e t o s u l p h o x i d e c o n v e r s i o n , and e n a n t i o m e r i c e x c e s s e s o f l e s s t h a n 10% h a v e b e e n o b t a i n e d .

Peracid oxidation

o f a l k y l p h e n y l s e l e n i d e s ( R S e P h ) i n t h e p r e s e n c e of a l c o h o l s


409

OH

SePh

(2371 F

R

1

CF3CO0Ph f i NSe o2

MeOH

CF3 C02 A g

I

RG R'

H202

R

R

R'

NO2

(2381 S c h e m e 70 OH

Me

b

1 [ O

f i R

Me

Mk

Me Me

R R e a g e n t s : i , PhSeALMeZ or [phSeTi(OPri)l]Li

, t h e n RCH=CH-CH2CHO;

ii, Bun3SnH, A

S c h e m e 71 R A N / R ' H

t

-

R3N-O R3N

kTeH ),

I

OH

NaTeH Rdo*

NIB

~

R

Scheme 7 2

Ar2Te C I,

P h T e S i Me3

(2391

(

240) Ar = Ph or L- MeOC,H,

Me


410

(R 'OH) g i v e s g o o d y i e l d s o f d i a l k y l e t h e r s , R O R

'.

B-Elimination

c a n be s u p p r e s s e d and a l k y l phenyl t e l l u r i d e s undergo a similar 204 transformation. Phenylselenenic anhydride, (PhSe0)20, and phenylselenenic a c i d , PhSe02H, a r e b o t h shown t o e f f e c t t h e m i l d o x i d a t i o n o f i n d o l i n e s t o i n d o l e s . 205 T h e c h e m i s t r y o f t e l l u r i u m h a s b e e n r e v i e w e d 2 0 6 a n d new u s e s o f NaTeH h a v e b e e n d e m o n s t r a t e d ( S c h e m e 7 2 ) . opening t o give B-telluroalcohols,

Epoxides undergo r i n g

w h i c h may b e f u r t h e r r e d u c e d .

Q u a t e r n a r y ammonium s a l t s a r e a l s o c l e a v e d b y t h i s r e a g e n t . 207 NaTeH a l s o r e d u c e s i m i n i u m a n d p y r i d i n i u m s a l t s 1 2 0 8 a s w e l l a s n i t r o n e s and amine

oxide^.^"

Disodium t e l l u r i d e , Na2Te, r e d u c t i v e l y d e h a l o g e n a t e s 1 , 2 dibromoalkanes t o g i v e a l k e n e s i n e x c e l l e n t y i e l d .210

An

a t t r a c t i v e f e a t u r e of t h i s method i s t h a t o n l y a c a t a l y t i c q u a n t i t y of t e l l u r i u m is required.

Phenyltellurotrimethylsilane ( 2 3 9 ) i s a r e a d i l y a c c e s s i b l e r e a g e n t , a n d i n terms of i t s r e a c t i v i t y t o w a r d s e s t e r s , l a c t o n e s , 21 1 e p o x i d e s , a n d e t h e r s , i s e q u i v a l e n t t o NaTePh. The o x i d a t i o n o f a l k y l p h e n y l t e l l u r i d e s w i t h p e r a c i d i n t h e p r e s e n c e of a l c o h o l s , t o g i v e d i a l k y l e t h e r s , h a s been mentioned. Oxidative elimination of these substrates t o give alkenes can a l s o I n some c a s e s s t a b l e T e ( 1 V ) i n t e r m e d i a t e s c a n be

be o b s e r v e d . 212

i s o l a t e d , b u t t h e s e u s u a l l y undergo e l i m i n a t i o n a t h i g h (200-250 OC)

temperatures. The 2 , 3 - s i g m a t r o p i c

rearrangement chemistry of sulphoxides and

s e l e n o x i d e s i s w e l l known, and a l t h o u g h r e a r r a n g e m e n t s i n v o l v i n g t e l l u r o x i d e s have o n l y r e c e n t l y been examined2

their reactivity

p a r a l l e l s t h a t o f t h e b e t t e r known G r o u p V I e l e m e n t s .

Finally,

v i n y l and a r y l t e l l u r i d e s undergo a n i n t e r e s t i n g P d ( I 1 ) - c a t a l y s e d c a r b o n y l a t i o n t o g i v e a c r y l i c and benzoic a c i d d e r i v a t i v e s

.

r e s p e c t i v e l y *I4 b i a r y l s . 21 4

U n d e r t h e same c o n d i t i o n s , ( 2 4 0 ) r e a c t s t o g i v e

References 1

R.C.Gadwood

,

M.R.Rubino, S. C.Nagarajan, and S.T.Miche1, J. Org. Chem., 1985,

5 0 , 3255. 2

3 4

2

A.Duchene, D.Monko-Mpegna, and J.-P-Quintard, Bull. SOC. Chim. France, 1985, 787. 1093. M. C 2 6 , 364 3 . M. P 1 9 8 5 , 6, 3433. T.R 1985, 1 1 2 4 ; F.L 1939. F.L

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13

14 15

411

D.Hoppe, R.Hanko, A-Bronneke, F.Lichtenberg, and E.van Hulson, Chem. Ber., 1985. 118. 2822. (a) Y.meus-Koos, L.P.de Jong, H.D.Verkruijsse, S.Julia and L.Brandsm a , Synthesis, 1985, 958 ; (b) P.A.A.Klusener, HIH.Hommes, H.D.Verkrui jsse, and L.Brandsma, J. Chem. SOC., Chem. Commun., 1985, 1677. T.Kauffmann and K.R.Gaydou1, Tetrahedron Lett., 1985, 26, 4067, 4071. L.M.Baigrie, D. Lenoir , H. R. Seikaly , and T. T. Tidwell, J. Org. Chem., 1985, 50. 2105. R.Haner, T.Laube, and D.Seebach , J. Am. Chem. S O C . , 1985, 107,5396. B.M.Trost and M.G.Saulnier, Tetrahedron I,ett., 1985, 26, 223. A.J.Carpenter and D.J.Chadwick, J. Chem. SOC., Perkin Trans. 1 , 1985, 173. P.Pate1 and J.A.Joule, J. Chem. S O C . ., Chfm . Commun., 1985, 102 1 . A.M.B.S.R.C.S.Costa, F.M.Dean, PI.A.Jones, and R.S.Varma,

16

17

A.I.Meyers, P.D.Edwards, T. R.Bs 50. 1019. -

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

7

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w.,

z,


412

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

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4,

80 81 82 83 84 85 86

87 88 89 90 91 92 93 94

6: Organometallics in Synthesis 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

413

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w.,

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414

c,

137 138 139 140 141 142 143 144 145 146 147 148 I49 150

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161 162 163 164 165 166 167 168

169

170 171 172 173

174 175 176

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118,

26,

41,

26,

w., 26,

26,


415

177 J-Drabowicz, S . Legedz,and M.Mikolajczyk, J. Chem. 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

206 207 208 209 210

211 212

213 214

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26,

285, 3,

x., 26, 5,

2,

5,

26,

26, 26,

26,

m.,

2, 5, 2,

5, 26, 5, 26,

5,

5,

26, 18,

26,

26, 26,

7 Saturated Carbocyclic Ring Synthesis BY T. V. LEE

1 Three-membered Rings

The appearance of a 'Symposium-in-Print' on aspects of carbene chemistry is obviously relevant to those interested in cyclopropane chemistry . Sonication reactions are becoming increasingly popular and now permit the use of dibromomethane and a zinc-copper couple for cyclopropanation .2 By using a trialkylaluminium compound and methylene iodide in dichloromethane a new cyclopropanation of alkenes has been achieved in a reaction thought to go via the species ( 1 1 . Two research groups have independently reported studies on the l,4-addition of dihalogenocarbenes to 1,3-dienes in which cyclopropanes are major It has been shown that metal-halogen exchange of the vinyl iodide (2) results in rapid formation of cyclopropene derivatives . 6 1- (Pheny1thio)cyclopropylsilanes are highly useful synthetic reagents and can now be prepared by the addition of a sulphur-stabilized anion to the vinylsilane (3) .7 An intramolecular cyclopropanation an iron carbene intermediate has been described which gives access to fused three-membered rings. 8 The previously developed coupling of the dianions of diesters with 1,w-dihalides has now been made into an efficient asymmetric process by the use of menthyl esters (Scheme I ) . ' Interestingly the use of a homochiral acetal such as (4) allows a diastereoselective cyclopropane-forming reaction to be performed in a reaction which could be widely applicable in natural product synthesis. l o 2-Lithio-2-phenylsulphonylpropane ( 5 ) acts as an alkylidene transfer reagent in reactions with a,B-unsaturated esters to allow the facile preparation of gem-dimethylcyelopropanecarboxylic acids. Furthermore, 1 -aminocyclopropanecarboxylates can be obtained by the addition of diazomethane to the oxazolone ( 6 ) . 12 The addition of 2-nitropropane tp a-cyanoacrylates, under the influence of base, proceeds to give the acid component of the

416

For References see p. 453

7: Saturated Carbocyclic Ring Synthesis

IC H,-A

417

I\/ R

ph

-78 BU'Li *C

R

I

CH,CI

-

bSPh

1

+

ii

SPh

Si Me3

(3)

SiMe3

h

S

P

h

CO, R R02Cw

C0,R R = I - menthyl

Scheme 1

mfH2

H

C V ,

___)

'CH,OCH,Ph H2Ph

(4)

Zn-Cu

'CH ZOCH ,P h OL -cyctopropyl :

p - cyclopropyl

9:l


418

pyrethroids. l 3 synthesized

Additionally (+)-cis-chrysanthemic acid has been a well planned use of the alicyclic Claisen

rearrangement as shown by the conversion of (7) into (8), in a route developed independently by two groups. ' 2 Four-membered Rings

This area is dominated by [2+2] cycloadditions in their various guises. Thus a new, and useful route to cyclobutane-l,3-dione involves the dimerization of t-butoxyethyne (9), which is thought to go formation of ketene from (9) followed by a [2+2] cycloaddition to the adduct (lo), which can then be hydrolysed.i6 Contrary to previous reports, the cyclobutane derivative ( 1 1 ) is the major product of the high-pressure reaction of a ketene acetal and acrolein.17 A range of chiral auxiliaries used in Diels-Alder reactions have been used in efforts to achieve induction in the ketene cycloaddition of the enol ether (12), with the sultam (13) giving the best degree of induction of 90% diastereoisomeric excess.18 Similar studies on esters such as (14)19 and enols such as (15)20 have also been reported, although in these cases the degree of induction is only modest. [2+21 Cycloadditions are the latest reactions to be extensively studied in an intramolecular manner, although this variant has been known for many years. The reactions are very facile, giving access to a range of bicyclic frameworks possessing a cyclobutane. 21-24 Interestingly the reaction has also been shown for the intramolecular reaction of allenes and c y c l o h e x e n o n e ~ ,26 ~~ (')-Lineatin has been synthesized by using the [2+2] cycloaddition of dichloroketene to a cyclic ally1 ether,27 and finally some interesting mechanistic studies have shown that the reaction

of t-butylcyanoketene and silyl enol ethers is a non-concerted process. 28

3 Five-membered Rings General Methods.- The current high level of activity in using radical ring closure reactions to form cyclopentanes will engender great interest in a set of force-field calculations which correlate the rate and stereochemical outcome of such cyclizations with the transition-state strain energies.29 A good example of the use of the reaction is in a new route to hydroxylated cyclopentanes from


419

Me

SOzPh )(Li

Ph (5)

-

(6)

-

C F, C 0, H

Sealed tube

B~O-CGC-H

30 'C, 86 h

BU'O

H,

/OMe +

Me

A C H O

12lkbar

420


c‘Kc‘

.,.B

+

C

II0

/

\

R*6

(12)

P

‘Me

R*o)Q

R*O, C

0

( 1 4)

(1 5)

C0,Et

,Bun3SnH -* AIBN

HO

52

HO

..

I

.

11, I

___.)

q

=

-0

‘CHo

Scheme 2

O

H


42 1

t h e c a r b o h y d r a t e - d e r i v e d b r o m i d e ( 1 6 ) .30 A s s h o w n i n Scheme 2 t h e known p h o t o c h e m i c a l s y n t h e s i s o f t h e i r i d o i d s k e l e t o n h a s b e e n resulting in a

applied t o t h e preparation of (2)-speciorin, r e v i s i o n of i t s s t r u c t u r e . ” The vinylcyclopropane-cyclopentene

r e a r r a n g e m e n t h a s b e e n popu-

l a r f o r c y c l o p e n t e n e f o r m a t i o n o v e r a number o f y e a r s , a n d h a s now been modified t o permit a c a r b a n i o n - a c c e l e r a t e d v e r s i o n t o be d e v e l o p e d w h i c h o f f e r s p r o m i s e i n i t s f u t u r e u s e (Scheme 3 ) . 3 2 A new c y c l o p e n t e n o n e s y n t h e s i s h a s b e e n d e s c r i b e d w h i c h u s e s t h e Ramberg-Backlund r e a c t i o n o f t h e s u l p h o n e ( 1 8 1 , which i s d e r i v e d

from t h e a-trif lyl-sulphone

( 17 )

.

( S c h e m e 4 ) 33

A p r e v i o u s l y known

r o u t e t o cyclopentenones is % t h e conversion o f 2-hydroxyalkylf u r a n s , w h i c h h a s now b e e n e x t e n d e d t o t h e s y n t h e s i s o f a c y c l o p e n t e n o n e b e a r i n g a p h o s p h o n a t e g r o u p . 34 It h a s been demonstrated t h a t f o r less e l e c t r o p h i l i c c a r b o n y l d e r i v a t i v e s t h e metal-halogen exchange of i o d i d e s such as ( 1 9 ) can r e s u l t i n good y i e l d s o f c y c l i z a t i o n p r o d u c t s . 3 5 Better results a r e o b t a i n e d h o w e v e r by u s i n g t h e G r i g n a r d r e a g e n t d e r i v e d from t h e

bromide ( 2 0 ) , which undergoes s t e r e o s p e c i f i c i n t r a m o l e c u l a r a d d i t i o n t o t h e a l k e n y l s i l a n e t o a f f o r d t h e c y c l o p e n t a n e ( 2 1 ) .36 I n c o n t r a s t , some r e g i o c h e m i c a l s t u d i e s o f w - l i t h i o - e p o x i d e s s u c h a s ( 2 2 ) show t h a t c y c l i z a t i o n t o a f i v e - o r s i x - m e m b e r e d r i n g depends upon t h e a d d i t i v e s used d u r i n g g e n e r a t i o n o f t h e l i t h i u m species. A d d i t i o n o f a c o p p e r ( 1 ) s a l t f a v o u r s six-membered r i n g f o r m a t i o n , p r e s u m a b l y via a n o r g a n o c o p p e r i n t e r m e d i a t e , whereas a d d i t i o n of a L e w i s a c i d a c t i v a t e s t h e o x i r a n e t o o p e n i n g a t t h e s e c o n d a r y p o s i t i o n s o g i v i n g a f i v e - m e m b e r e d r i n g . 37 An e a r l i e r r e p o r t on t h e s t e r e o c h e m i c a l c o n s e q u e n c e s o f a r h o d i u m - c a t a l y s e d i n t r a m o l e c u l a r C-H i n s e r t i o n o f t h e B - k e t o - e s t e r (23),

l e a d i n g t o an e n a n t i o s e l e c t i v e s y n t h e s i s o f a-cuparenone,

has

now b e e n d e s c r i b e d i n f u l l . 3 8

F u r t h e r m o r e , owing t o t h e r e q u i r e -

ment t h a t t h i s r e a c t i o n o c c u r s

% a chair-like transition state,

t h e r e a c t i o n o f ( 2 4 ) p r o c e e d s d i a s t e r e o s e l e c t i v e l y t o form a 2,4d i s u b s t i t u t e d c y c l o p e n t a n e d e r i v a t i v e . 39 [3+21 A n n u l a t i o n s a r e c u r r e n t l y r e c e i v i n g much a t t e n t i o n , w i t h many g r o u p s r e s o r t i n g t o allyl-palladium

complexes t o a c h i e v e t h i s .

For e x a m p l e t h e

z w i t t e r i o n i c n - a l l y l p a l l a d i u m complex ( 2 6 ) can be g e n e r a t e d from t h e v i n y l c y c l o p r o p a n e ( 2 5 ) and t h e n r e a c t e d w i t h a Michael adduct t o f o r m a c y c l o p e n t a n e , a s o n e w o u l d e x p e c t by a n a l o g y w i t h previous studies.40 By a v a r i a t i o n i n t h e s u b s t r a t e i n t h e i n t e r n a l t r a p p i n g o f a n-ally1 complex, t h e c y c l i z a t i o n of t h e a l l e n i c

422


I

&CHz

SO2 Ph

____)

9 7% Reagents.

I>

Bu"LI,

THF-HMPA,

- 7 8 t o -30 ' C

Scheme 3

I, II

C F , S O , v S02Me Me

( 1 7)

(18) Reagents

i , BuLi(3 equiv.), i i , M e 1 (excess); iii, BuLi (2 equiv.) i v , A C H O ; v, Mn02; v i , K2C O3

Scheme 4

( 2 2)


423

I

Ph

Ph

(24)

(23) Reagents. i, MeS0,N3, Et,N; ii, [Rh,(OAc),]

Me0,C

pdO

Me02C

MeOzC

T+Az MeOzC

>a/=, - M e 0 2 C

MeOzC

Pd

CO, M e PhI

+ Me

+

=C54%) a n d w i t h h i g h e . e . s

(>96%).'

Both enantiomers of t h e

a u x i l i a r y are a v a i l a b l e , enabling both isomers t o be prepared. R e d u c t i o n of t h e c h i r a l B - k e t o - s u l p h o x i d e s

(3) can be adjusted t o

g i v e e i t h e r i s o m e r of t h e B - h y d r o x y - s u l p h o x i d e

which can then be

c y c l i z e d t o g i v e t h e r e q u i r e d e p o x i d e s (4) a n d ( 5 ) a s s h o w n i n Scheme

As w i t h O p p o l z e r ' s m e t h o d t h e y i e l d s a r e g o o d (>60%) e x c e l l e n t (>95%).

and t h e e.e.s

W i t h o u t d o u b t t h e most g e n e r a l method f o r t h e s y n t h e s i s o f c h i r a l e p o x i d e s t o d a t e i s t h a t of S h a r p l e s s a n d c o - w o r k e r s s u c h t h a t t h e s t e r e o c h e m i c a l o u t c o m e o f t h e e p o x i d a t i o n of t h e a l l y l i c a l c o h o l ( 6 ) h o l d s t r u e a l m o s t n o matter t h e n a t u r e o f R 1 t o R

4.

However, r e c e n t s t u d i e s h a v e shown t h a t i f t - b u t y l g r o u p s a r e incorporated a t e i t h e r t h e c a r b i n o l carbon or a t t h e B-Z-position t h e n t h e e . e . s o f t h e a - h y d r o x y - e p o x i d e s a r e much r e d ~ c e d . ~T h e s y n t h e s i s of a - k e t o - e p o x i d e s b y t h e D a r z e n s c o n d e n s a t i o n i s w e l l k n o w n , b u t t h i s y e a r h a s s e e n t h e f i r s t e x a m p l e of c h i r a l , a q u e o u s catalysed Darzens condensation t o g i v e t h e epoxy-ketones ( 7 ) a l b e i t i n o n l y m o d e r a t e o p t i c a l a n d c h e m i c a l y i e l d s ( 2 - 6 2 % a n d 5-43% r e s p e c t i v e l y 1.

4

S e v e r a l new o r m o d i f i e d g e n e r a l s y n t h e s e s of e p o x i d e s h a v e a l s o appeared t h i s year.

For e x a m p l e M o s s e t a n d Gree h a v e f o u n d t h a t

trimethylsulphonium methylsulphonate 457

(8) is a highly reactive For References see p. 544

458


R X/O

7-J 0

i, L D A , T M S C l ii, N B S or NCS

/

2

O

d

X

Halogen

0

I

i , Ca ( BH4$

ii, NaOMe

R

\ti 0

0

I

0

Reagents : i , D I B A L ;

I

i i , D I B A L , Z n C l 2 ; i i i , L i A I H 4 ; i v , Me30+BF,-;

Scheme

1

v, NaOH

459

8: Saturated Heterocyclic Ring Synthesis

R’

R’

Ti(OR14,

R2

-

4

(+IDET,

R3

R3

TBHP

R4

X =

0 - , rn-,

or p-NO2 or 0 - C I

(7)

Y = Br or CL

+

Me+. CH3S04-

(8)

S’

Reagents:

i, L i C H 2 S M e

ii, Me1

;

iii, K + B u t O - , THF

Scheme

2

460


ketone epoxidizing reagent undre biphasic reaction conditions and indeed needs no phase-transfer ~ a t a l y s t . ~Also, yields in the Corey procedure for epoxidation of cyclic a,B-unsaturated ketones are much improved by carrying out the procedure in three discrete steps with some modification to the conditions (see Scheme 2). 6 The conversion of a ketonic carbonyl into a functionalized epoxide presents much more of a synthetic challenge, and a useful method for doing just that has been published by Cookson and Crumbie. Thus, addition of ally1 Grignard reagents to the ketones (9) affords the homoallylic alcohols (lo), which are converted into the epoxides ( 1 1 ) by treatment with NBS followed by cyclization with NaH.7 Kirschenbaum and Sharpless have shown that by altering the conditions of the Payne method for tungstate-catalysed epoxidation of a,B-unsaturated acids the yields are greatly improved and the scope of the reaction is increased. It was also concluded from this study that a-alkyl and B-cis-alkyl substitution of the acid is rate enhancing.' F u l l details of the incorporation of vanadium(1) and molybdenum(I1) complexes onto polymer, and their subsequent use as epoxidation reagents, have appeared, and the development of polymer-supported dioxyphosphorane as a cyclodehydration reagent (giving epoxides from 1,2-diols) from the previously known diethoxytriphenylphosphorane has been published. Finally on epoxides, contrary to their original publication, Bloch et al. have found that potassium hydrogen sulphate alone is capable of epoxidizing alkenes, giving yields of 62-94%. 1 1 The system developed by Edwards and Curci to generate dimethyldioxirane in situ has been modified by Murray and Jeyaraman to allow the distillation of a number of dioxiranes ( 1 2 ) as solutions, thus allowing spectroscopic characterization and a study o f their chemical properties. 12 2-0xabicyclo[2.2.0]hexanes (14) are formed in high yield ( 8 0 -

90%) by the cycloaddition of aldehydes with the cyclobutadiene (13) at room temperature in pentane. ' 3 Five-membered Rings.- Tetrahydrofurans. The halogenoetherification procedure and related reactions have been extensively used for the formation of tetrahydrofurans and in recent years attention has turned to the stereochemical outcome o f the reaction and to the use of more complex starting materials. This year has been no exception. F o r example, the pentene-l,3-diols (15) cyclize under


46 1

R'

i, N B S

*

ii, 1 5 - c r o w n - 5 , NaH,THF

R2

R'&= R2

R3

0-0

CO28U'

EL

+

(13)

RCHO

-

C02Bu'

*R

(14)R = Me, Ph or CI,C

R

m-

OH

OH

-J

462


carefully controlled iodoetherication conditions to give predominately the &-isomers (16) (usually better than 5:l) in excellent yield (73-99%),14 and Davies et al. have reported the bromineassisted epoxide ring expansion of epoxy-olefins (Scheme 3 ) . 15 The stereocontrol of the previously reported bromoetherification of 4-alkenols to give trans-tetrahydrofurans (17) can be improved

by using thallium salts as the electrophile,16 and the mixture of lead(1V) acetate and either NaI or ZnBr2 is a useful addition to the armoury of halogenoetherification reagents giving high yields ( > 75%)

. 17

The addition of phenylselenenyl chloride to the dienes (18) leads to the cyclic ethers ( 19) in variable yield, l 8 addition of dimethyl(thiomethy1)sulphonium alkenes also leads to ether formation.

and the

fluoroborate to hydroxy-

For example, the oxa-

bicyclo[3.3.0]octane (21) is formed on treatment of the hydroxyalkene (20), the reaction presumably proceeding through an episulphonium intermediate. The similar ring closure onto an epoxide has been further developed by Nicolaou's group into a potentially general 'zip'-type reaction to give a string of tetrahydrofurans such that treatment of the triepoxide (22) with a base gives the bis-tetrahydrofuran

(23) in >go% yield.20 Ring expansion of epoxides by the addition of the dianion of ethyl acetoacetate under Lewis acid conditions followed by cyclization generates a-methylenetetrahydrofurans (24) in generally good yield," whereas ring expansion of the cyclopropane esters (25) by addition of their corresponding enolates to ketones followed by fluoride treatment gives the lactols (26) which are readily converted into tetrahydrofurans. 22 The vinylsulphones (27) undergo an intramolecular Michael reaction in the presence of a catalytic amount of potassium hydride giving tetrahydrofurans in high yield (>81%),23 and the diols (28) can be cyclized to the corresponding tetrahydro-furans or -pyrans by simply heating at 220

OC

in the presence of 0.3 mole equivalents

of H M P A .24 Reactions which proceed through radical intermediates are gaining in popularity mainly because of the higher degree of con-

*

trol that can now be achieved, and several more examples of tetrahydrofuran synthesis

radicals have been published this year.

The radical produced on reductive removal of nitro-groups can be captured by a remote double or triple bond to give the tetrahydro-


463

+

Scheme

3

f l O H R

X = OAc, OH OMe, ONO, or NHAc R

M e C N / H,0

*

P h S e d L S e P h

0


464

Pr',NE

t,

MeCN, DMTMF

(201

0

0

4

H

Meo2c& ,

'

,

O X 0

O X 0

(22)

(23)

O S i Me3

OSi Me, I,

LDA

R~

C0,Me

C0,Me

(26)

(25)

n R2 \

R' ) \ 7 \ 0 R4

,

o

R3 /

BF3.Et ,O, -78

4

O°C

-

465


KH

TH F

k2

Rl+---so2+

R2

HMPA v

2 2 0 OC

Bu3SnH

Scheme

4


466

f u r a n s (29)7 2 5 a n d t h e r e a c t i o n c a n a l s o b e c a r r i e d o u t i n a n i n t r a m o l e c u l a r s e n s e a s o u t l i n e d i n S c h e m e 4.26 The t r e a t m e n t of a l k y l h a l i d e s w i t h a l l y l t r i a l k y l s t a n n a n e s t o g i v e a l l y l i c compounds h a s been combined w i t h a r a d i c a l c y c l i z a t i o n reaction so that treatment of the vinyl ethers (30) with a l l y l t r i n-butylstannane

gives t h e a l l y l a t e d tetrahydrofurans.27

Although

y i e l d s a r e o n l y m o d e r a t e (25-48%) t h e r e a c t i o n h a s t h e a d v a n t a g e o f being c a r r i e d out i n one pot. Many o f t h e r a d i c a l r e a c t i o n s u s e t r i - n - b u t y l t i n reagent of choice, but t h e tin-derived t o remove.

hydride as t h e

residues are o f t e n d i f f i c u l t

T o r i i e t a l . h a v e s h o w n t h a t c o b a l o x i m e I , g e n e r a t e d by

e l e c t r o c h e m i c a l means, can r e p l a c e t h e t i n h y d r i d e and c o n v e r t s t h e ethers (31) i n t o t h e corresponding tetrahydrofuran derivatives i n 28 without g i v i n g any p u r i f i c a t i o n problems.

g o o d y i e l d (35-877;)

The DDQ o x i d a t i o n o f t h e m e t h o x y s t y r e n e a l c o h o l s ( 3 2 ) g i v e s a mixture of tetrahydrofurans

,

(33) and (34) i n which (33) pre-

oxidation of acetals a t room t e m p e r a t u r e g i v e s o r t h o c a r b o n a t e s , when t h e same r e a c t i o n i s

d o m i n a t e s ,29 a n d

whereas Baeyer-Villager

c a r r i e d o u t a t r e f l u x t h e c y c l i c e t h e r s ( 3 5 ) are formed i n v a r i a b l e y i e l d (6-63%). 3 0 Two r e a c t i o n s f o r m e r l y u s e d w i d e l y i n t h e f o r m a t i o n o f c a r b o c y c l e s h a v e now b e e n s u c c e s s f u l l y e x t e n d e d t o t h e s y n t h e s i s o f heterocyclic systems.

Thus t h e i n t r a m o l e c u l a r c y c l o a d d i t i o n o f t h e

o l e f i n i c alkoxyketenes (36) leads t o cyclobutanone annulated h e t e r o c y c l e s ( 3 7 ) , w h e r e b e t t e r y i e l d s a r e o b t a i n e d by u s i n g t h e ketene g e n e r a t e d from t h e a c i d c h l o r i d e r a t h e r t h a n from t h e k e t e n i m i n i u m i n t e r ~ n e d i a t e . ~ ’A l s o , L i t t l e ’ s 1 , 3 - d i y l c y c l o a d d i t i o n r e a c t i o n h a s b e e n shown t o work w i t h h e t e r o a t o m - c o n t a i n i n g

x-

systems, such as carbonyl groups, t o afford mixtures of regioi s o m e r i c h e t e r o c y c l e s ( S c h e m e 5) . 3 2 T h e trichloromethyl-3-bromoalkanes ( 3 8 ) a l s o a d d t o c a r b o n y l groups i n a formal [3+2]-type

cycloaddition r e a c t i o n under electro-

l y t i c c o n d i t i o n s where t h e intermediate i s thought t o be t h e d i c h l o r o m e t h y l a n i o n ( 3 9 ) .33

Trost has extended t h e scope of h i s

[3+2] c y c l o a d d i t i o n r e a c t i o n t o i n c l u d e t h e s y n t h e s i s o f t e t r a hydrofurans.

He f o u n d t h a t t h e s t a n n y l a c e t a t e ( 4 0 ) r a t h e r t h a n

t h e corresponding s i l y l acetate g i v e s high y i e l d s of t h e t e t r a h y d r o f u r a n s ( 4 1 ) w i t h b o t h e x c e l l e n t d i a s t e r e o - a n d chemos e l e c t i v i t y u n d e r p a l l a d i u m c a t a l y s i s . 34

I n t r a m o l e c u l a r palladiurn-

c a t a l y s e d o x y c a r b o n y l a t i o n o f t h e p e n t e n e d i o l s ( 4 2 ) a t room t e m p e r a t u r e l e a d s t o t h e t e t r a h y d r o f u r a n a n n u l a t e d l a c t o n e s ( 4 3 ) , 35


467

B u 5n 3

-

L

A1 BN

(30)

Br Co( I )

R2 R3 R4 R5

R2 R3 R4

R5

R’ 0

(33)

(34)


468

Scheme

+

5

3 moloI0 Pd(OAcI2

RCHO 15 moloI0 Ph3P

-J3 R

(411

(40) R 2 R3 R 4

R+’

OH

OH

R (43 1

0

0

469


where t h e carbonyl i n s e r t i o n proceeds w i t h high s t e r e o s e l e c t i v i t y and i n h i g h y i e l d . The i n t r a m o l e c u l a r i n s e r t i o n o f a c a r b e n e g e n e r a t e d from t h e diazo 8-keto-ester

( 4 4 ) g i v e s t h e p r e v i o u s l y unknown t e t r a h y d r o -

f u r a n ( 4 5 ) a l t h o u g h t h e r e a c t i o n h a s b e e n e x t e n s i v e l y u s e d f o r N-H

insertion^,^^

and t h e r i n g e x p a n s i o n o f o x e t a n e s by c a r b e n e i n s e r t i o n t o g i v e t e t r a h y d r o f u r a n s a s t h e main p r o d u c t has been r e p o r t e d by two g r o u p s o f w o r k e r s . 3 7

The g e n e r a t i o n o f o x a c a r b e n e s

b y u - c l e a v a g e of c y c l o b u t a n o n e s a n d s u b s e q u e n t c a p t u r e by a r e m o t e hydroxy-group had p r e v i o u s l y b e e n o n l y o f m e c h a n i s t i c i n t e r e s t , b u t t h e r e a c t i o n h a s now b e e n s h o w n t o h a v e s y n t h e t i c p o t e n t i a l , f u r n i s h i n g t h e b i c y c l i c a c e t a l s ( 4 6 ) i n m o d e r a t e y i e l d ( 4 5 - 7 0 % ) .38 F i n a l l y , when t h e a l l y 1 e n o l e t h e r s ( 4 7 ) a r e t r e a t e d w i t h Pd(OAcI2 i n a c e t o n i t r i l e t h e t e t r a h y d r o f u r a n s ( 4 8 ) a r e t h e exclusive products rather than the alternative Claisen products w h i c h a r e f o r m e d b y s i m p l y h e a t i n g t h e e n o l e t h e r s . 39 Dihydrofurans. T h e i n t r a m o l e c u l a r c y c l i z a t i o n of a p h e n y l s u l p h o n y l v i n y l a n i o n o n t o a n epoxide leads t o t h e d i h y d r o f u r a n s ( 4 9 ) i n average y i e l d (50-72%), where t h e v i n y l sulphone moiety is e a s i l y c o n v e r t e d i n t o o t h e r f u n c t i o n a l g r o u p s . 40 The i n t e r m o l e c u l a r a d d i t i o n o f m a l o n o n i t r i l e t o e p o x i d e s or c h l o r o - a l c o h o l s 41 p r e s e n c e of e t h o x i d e g i v e s t h e d i h y d r o f u r a n s ( 5 0 ) .

in the

H y d r o b o r a t i o n of t h e B - a c e t y l e n i c a l c o h o l s ( 5 1 ) f o l l o w e d b y basic peroxide oxidation leads t o t h e tetrahydrofuranols (52), which are r e a d i l y c o n v e r t e d i n t o t h e d i h y d r o f u r a n s ( 5 3 ) i n y i e l d s

of u p t o 9 5 % , 4 2 w h e r e a s m e r c u r i c a c e t a t e h y d r a t i o n o f t h e a l l e n i c k e t o n e s ( 5 4 ) a f f o r d s h i g h y i e l d s of t h e d i h y d r o f u r a n o n e s ( 5 5 ) p r o v i d i n g a n o t h e r s y n t h e s i s o f b u l l a t e n o n e .43 A l l e n y l - s i l a n e s a r e known t o r e a c t w i t h e l e c t r o n - d e f i c i e n t o l e f i n s t o g i v e c y c l o p e n t e n e s a n d t h i s r e a c t i o n h a s now b e e n e x t e n d e d t o t h e s y n t h e s i s o f t h e dihydrofurans (56) where t h e aldehyde c a r b o n y l i s a c t i n g a s a h e t e r ~ a l l e n o p h i l e . ~T~h e b u l k y s i l y l g r o u p

is e s s e n t i a l f o r t h e s u c c e s s of t h e r e a c t i o n . 1 , 3 - D i c a r b o n y l compounds h a v e f e a t u r e d i n s e v e r a l a p p r o a c h e s t o d i h y d r o f u r a n s u n d e r a v a r i e t y of r e a c t i o n c o n d i t i o n s . palladium-catalysed

The

reaction of propargyl carbonates with ethyl

a c e t o a c e t a t e g e n e r a t e s 4-methylene-4,5-dihydrofurans ( 5 7 ) i n h i g h y i e l d (79-94%) i n n e u t r a l media b u t t h e u s e o f B - d i k e t o n e s l e a d s t o f u r a n s . 45 E t h y l a c e t o a c e t a t e a d d s t o CL - c h l o r o v i n y l - s u l p h o n e s ( 5 8 under b a s i c c o n d i t i o n s to a f f o r d t h e dihydrofurans (59) and t h e


470

hv

Me0,C *OH

Me02C

R’

R2 R’

SO2Ph

S0,Ph

(49)

OH

R3

R3


47 1

kcaR2 R’

(54)

R1

+

-

R3CH0

v

R’

R3

SiMeZBut R2

(56)

R2 OC02Me +

u

C0,Me

0

2

M

e

[Pd2(dba)33 CHC13

PhSO;!

Ar

0

&x

C02Et

PhSO,

(59)

(58)

0

AR2-

R3 *CH(COMeI2

R’

[ Mn ( a ~ a c ) ~ ]

(60)

R2 (61)

R2 BugSnH w

( 6 2 ) X = N o r COMe


472 r e a c t i o n is thought t o proceed

i n i t i a l Michael addition

f o l l o w e d by i n t r a m o l e c u l a r 2 - a l k y l a t i o n . 4 6

The d i k e t o r a d i c a l ( 6 0 )

is claimed t o be t h e r e a c t i v e s p e c i e s i n t h e s y n t h e s i s o f t h e d i h y d r o f u r a n s ( 6 1 ) f r o m o l e f i n s by h e a t i n g w i t h t h e m a n g a n e s e complex of a c e t o a c e t o n e i n a c e t i c a c i d a t

re flu^.^^

L i t t l e a t t e n t i o n h a s b e e n p a i d t o t h e c a p t u r e of a r y l r a d i c a l s b u t an example o f d i h y d r o b e n z o f u r a n s y n t h e s i s p u b l i s h e d t h i s y e a r uses just this reaction.

Thus t h e a r y l h a l i d e s ( 6 2 ) c y c l i z e i n t h e

presence of t i n hydride t o g i v e dihydrobenzo- and dihydro-pyrido48 f u r a r i s i n good y i e l d s (52-88%). The i n t e r m o l e c u l a r c y c l o a d d i t i o n of o r t h o q u i n o n e d i a z i d e s t o vinyl e t h e r s t o give t h e dihydrobenzofurans (63) proceeds i n moderate y i e l d

(46-55%)

,"

whilst t h e dihydrobenzofurancyclo-

b u t a n o n e s a r e g e n e r a t e d i n h i g h y i e l d by t h e i n t r a m o l e c u l a r k e t e n e / o l e f i n [ 2 + 2 ] c y c l o a d d i t i o n o f t h e e t h e r s ( 6 4 ) .50 inverse electron-demanding

Diels-Alder

The

r e a c t i o n of t e t r a z i n e s h a s

a l s o been a p p l i e d i n an i n t r a m o l e c u l a r s e n s e t o g i v e t h e d i h y d r o p y r i d a z i n o f u r a n s (65) i n v a r i a b l e y i e l d . 5 1 Six-membered

Rings.-

t h e hydroxy-silanes

Tetrahydropyrans.

O x i d a t i v e c y c l i z a t i o n of

( 6 6 ) c a n b e a c c o m p l i s h e d by t r e a t m e n t w i t h

i o d o s y l b e n z e n e and a L e w i s a c i d a f f o r d i n g t h e t e t r a h y d r o p y r a n s

(67)

i n m o d e r a t e y i e l d ( 3 8 - 6 8 % ) . 52 The a c e t a l s ( 6 8 ) a r e r e a d i l y c o n v e r t e d i n t o t h e t e t r a h y d r o p y r a n s ( 6 9 ) on r e a c t i o n w i t h TiC14.53

T h e r e a c t i o n p r o c e e d s by l o s s o f

a l k o x i d e , g e n e r a t i n g a n oxonium s p e c i e s , which s u b s e q u e n t l y c y c l i z e s g i v i n g almost e x c l u s i v e l y e q u a t o r i a l s u b s t i t u t i o n where possible. The p o l y e t h e r n a t u r a l p r o d u c t s have p r o v i d e d a n e x c e l l e n t t e s t i n g g r o u n d for o x y g e n h e t e r o c y c l i c s y n t h e s i s , a n d h a v e a l s o i n s p i r e d many new m e t h o d s .

N i c o l a o u ' s g r o u p h a s shown t h a t i n

c o n t r a s t t o t h e u s u a l mode o f c y c l i z a t i o n o n t o a n e p o x i d e , t h e r e a c t i o n c a n b e made t o g o e n d o , g i v i n g t e t r a h y d r o p y r a n s Scheme 6 ) .54

(see

T h i s i s b r o u g h t a b o u t by s t a b i l i z i n g t h e d e v e l o p i n g

p o s i t i v e c h a r g e a t t h e d e s i r e d c e n t r e and h a s been a p p l i e d t o t h e s y n t h e s i s o f t h e ABC r i n g s y s t e m o f b r e v e t o x i n B .

Kozikowski and

Ghash h a v e d e v e l o p e d a s t e r e o s e l e c t i v e p y r a n o a n n u l a t i o n method s p e c i f i c a l l y designed f o r p o l y e t h e r s y n t h e s i s which is o u t l i n e d i n Scheme 7.55 Dihydropyrans.

The h y d r o x y a l k e n e s ( 7 1 ) f o r m e d by a d d i t i o n o f t h e


473

R’

d-”‘ oY

R~

(cocI)z ____)

Et3N

COzH

(64)

SMe

A

PhIO, _____t

B F3. E t *O ,

OH

dioxane

R

(66)

(67)

R

R

(68)

(69)


474

R

Br

H

Br

Scheme

Me02C,

*m

HO'

H 0

6

n

(yJ*-

WSPh m"sp Scheme

7

JHF

475

8: Saturated Heterocyclic Ring Synthesis ( 7 0 ) t o e p o x i d e s c y c l i z e t o t h e d i h y d r o p y r a n s ( 7 2 ) on

anion of

treatment with potassium t-butoxide.

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

i n i t i a l i n t r a m o l e c u l a r M i c h a e l a d d i t i o n f o l l o w e d bv e l i m i n a t i o n o f s u l p h i n i c a c i d a n d y i e l d s a r e g o o d ( 6 5 - 7 3 % ) . 56

Dihydropyranones

(7'1) a r e s y n t h e s i z e d by t h e r e a c t i o n o f t h e a n i o n of r e a c t i o n i s t h o u g h t t o go

via

1,3-dicarbonyl

( 7 3 1 , 57 a n d h e r e t h e

c o m p o u n d s w i t h t h e a ,CI - d i h a l o g e n o - k e t o n e s

nucleophilic addition of t h e diketo-

e n o l a t e t o t h e Favorski i n t e r m e d i a t e from

(73).

F u r t h e r s t u d i e s on t h e h e t e r o - D i e l s - A l d e r

r e a c t i o n by

D a n i s h e f s k y ' s g r o u p have f o c u s e d on t h e s t e r e o c h e m i s t r y o f t h e r e a c t i o n and t h e e x a c t mechanism i n v o l v e d .

Thus c y c l i z a t i o n o f

d i e n e s w i t h a l d e h y d e s i n t h e p r e s e n c e o f BF3.Et20 t e n d s t o g i v e cis-dihydropyranones

(76)

(75) i n toluene whereas trans-dihydropyranones

predominate i n CH2C12.18

However, t h e s e c o n d i t i o n s (BF3 i n

C H C1 ) p u s h t h e m e c h a n i s m t o w a r d a s t e p w i s e s i l o x o n i u m a l d o l - t y p e 2 2 cycladdition. T h e u s e o f ZnC12 i n THF, o n t h e o t h e r h a n d , i s

thought t o b i a s t h e hetero-Diels-Alder n a n t l y t r a n s - p r o d u c t s . 59

r e a c t i o n and g i v e s predomi-

a-Alkoxy-aldehydes

a l s o undergo t h e

r e a c t i o n , and are a l s o s u b j e c t t o c h a n g i n g mechanism u n d e r d i f ferent catalysis.

For e x a m p l e , t h e a d d i t i o n o f t h e d i e n e ( 7 7 ) t o

t h e aldehyde (78) goes

9c h e l a t i o n

c o n t r o l and hetero-Diels-Alder

( 7 9 ) u s i n g MgBr2 i n THF, w h e r e a s u s i n g

t o g i v e t h e &-product

BF3.Et20 a s c a t a l y s t d r i v e s t h e r e a c t i o n t o a Mukaiyama-type mechanism and m i x t u r e s o f i s o m e r s are o b t a i n e d . 6 0

The w e a l t h of

k n o w l e d g e t h a t D a n i s h e f s k y ' s team h a s b u i l t u p a r o u n d t h i s r e a c t i o n h a s l e d t o t h e s u c c e s s f u l u s e o f t h e methodology i n t h e s y n t h e s i s o f t h e s u b u n i t s of monensin and tirandamycin. The h e t e r o - D i e l s - A l d e r

reaction of

hydes normally requires high pressures

61

I-methoxybutadiene with alde-

(>I5 k b a r ) , a n d t h e u s e o f

L e w i s a c i d c a t a l y s t s s u c h as ZnC12 a n d B F 3 . E t t i o n of t h e d i e n e . [Eu(fod)

3

1

0 causes polymeriza2 However, by u s i n g t h e m i l d L e w i s a c i d s s u c h a s

p r e s s u r e s o f o n l y 10 k b a r a r e n e c e s s a r y .

A f u l l s t u d y on t h e hetero-Diels-Alder

62

reaction using

U , B -

u n s a t u r a t e d c a r b o n y l compounds as t h e d i e n e c o m p o n e n t h a s b e e n p u b l i s h e d , 6 3 a n d i n a n e x t e n s i o n t o t h e m e t h o d o l o g y t h e same a u t h o r s , S c h m i d t a n d Maier, h a v e shown t h a t a p h e n y l t h i o s u b s t i t u e n t is t o l e r a t e d on t h e d i e n e and t h a t i n c o r p o r a t i o n of a n a s y m m e t r i c a u x i l i a r y l e a d s t o d i a s t e r e o s e l e c t i v e r e a c t i o n s (Scheme 64

8).

Enamine-aldehydes

( 8 0 ) can a l s o s e r v e

i n t h e hetero-Diels-Alder

as t h e diene equivalent

r e a c t i o n w i t h v i n y l e t h e r s and y i e l d s o f

476


(73)

(74)

(75)

koTMs + H Q 6 . Et H

TMSO

(77)

(78)

+ Et$

Et$

He' H OB u (79)

Scheme

8

(76)

H0**

H

OBu

477


t h e d i h y d r o p y r a n s (81) are u s u a l l y good .65 V i n y l e t h e r s w i l l a l s o a d d t o o r t h o q u i n o n e m e t h i d e s ( s e e S c h e m e 9) a n d t h i s r e a c t i o n h a s b e e n s y s t e m a t i c a l l y s t u d i e d by A r d u i n i e t a l . , p r o p o s e s e v e r a l g u i d e l i n e s .66

l e a d i n g them t o

Thus t h e c o n f o r m a t i o n a l e q u i l i b r i u m

i s d e t e r m i n e d by t h e p s e u d o e q u a t o r i a l p r e f e r e n c e o f t h e 4 - a l k y l E c o n f i g u r a t i o n , and

g r o u p , t h e orthoquinone methides react i n t h e

t h e r e a c t i o n is u s u a l l y endo w i t h r e s p e c t t o t h e ethoxy-group. [5.n]Spiroacetals.

The s u r g e o f i n t e r e s t i n t o t h e s y n t h e s i s of

s p i r o a c e t a l s a p p e a r s t o have no end b u t a l t h o u g h t h e r e have been many p u b l i c a t i o n s i n t h e a r e a t h e r e a r e v e r y f e w new a p p r o a c h e s t o t h e r i n g system.

For e x a m p l e B r i n k e r e t a l . h a v e shown t h a t t h e

c y c l o p r o p y l c a r b e n e g e n e r a t e d from MeLi t r e a t m e n t o f ( 8 2 ) a f f o r d s t h e s p i r o a c e t a l ( 8 3 ) w h o s e c y c l o p r o p a n e r i n g i s r e a d i l y c l e a v e d by h y d r o g e n o l y s i s , 67 a n d c h i r a l s y n t h e s i s o f t h e s p i r o a c e t a l s ( 8 5 ) a n d

( 8 6 ) c a n b e a c h i e v e d by i n t r a m o l e c u l a r M i c h a e l r e a c t i o n o f t h e c h i r a l s u l p h o x i d e (84) a n d e i t h e r r e d u c t i v e r e m o v a l o f t h e s u l p h o x i d e g r o u p o r e p i m e r i z a t i o n f o l l o w e d by r e d u c t i o n t o g i v e t h e o t h e r e n a n t i o m e r . 68 The b u l k o f t h e o t h e r p u b l i c a t i o n s a r e r e p o r t s o f t o t a l s y n t h e s e s , s u c h a s t h a t o f m i l b e m y c i n B 3 by K o c i e n s k i ' s g r o u p , 69 and t h e e r y t h r o n o l i d e A d e r i v a t i v e by Deslongchamps 170 o r p a r t i a l s y n t h e s e s s u c h as t h e s y n t h e s i s o f t h e n o r t h e r n h e m i s p h e r e o f t h e m i l b e m y c i n s by L e y ' s g r o u p .7 S i x - m e m b e r e d R i n g s w i t h More t h a n One O x y g e n .

Without doubt t h e

g r e a t e s t a c c o m p l i s h m e n t i n t h i s area h a s been t h e t o t a l s y n t h e s i s o f t h e l o n g s o u g h t a f t e r a n d e v a s i v e TXA2 by t h e r e s e a r c h g r o u p o f T h e m e t h o d e m p l o y e d was t o c o n s t r u c t t h e s e n s i t i v e o x e t a n e r i n g by a n i n t r a m o l e c u l a r M i t s u n o b u r e a c t i o n o n t h e i n t e r m e d i a t e (871, where t h e Br a c t s as a s t a b i l i z i n g g r o u p .

Reductive

r e m o v a l o f t h e B r g r o u p f o l l o w e d by l a c t o n e c l e a v a g e g a v e s y n t h e t i c m a t e r i a l w h i c h i s i n d i s t i n g u i s h a b l e f r o m n a t u r a l TXA2, b u t t h e a u t h o r s add t h a t t h i s is

not

c o n c l u s i v e proof t h a t S a m u e l s s o n ' s

s t r u c t u r e i s TXA2. The method u s e d s h o u l d p r o v e g e n e r a l as model s t u d i e s g a v e a TXA2 a n a l o g u e . 7 3 The s t e r e o c h e m i c a l outcome and s c o p e o f t h e s i n g l e t oxygen a d d i t i o n t o d i e n e s t o g i v e endoperoxides (88) h a s been s t u d i e d and t h e order of r e a c t i v i t y is t r i s u b s t i t u t e d > 2-substituted s t i t u t e d .74

> disub-

478


qoH - qo +

\

R'

R

Scheme

MeLi

HZPd

(83)

NoH/THF ____)

9

R R3 *lJo

479


Seven- and Eight-membered Rings.- A new total synthesis of zoapatanol has been published which uses as the key step an acidcatalysed intramolecular epoxide opening reaction (see Scheme Model studies predicted that S n C l l l would give the best ratio of seven-membered to six-membered ring ether formation. The unusual [(20+2n)+2n]

cycloaddition reaction has been used to

prepare the oxabicyclo[3.2.l]octane (90) where homofuran (89) is acting as the ( 2 ~ + 2 n )component,76 and finally Mann’s group has reported a synthesis of the 2,6-dioxatricyclo[3.3.1 .03’7]nonanes ( 9 1 ) by a Combination of oxoallyl and iodoetherification chemistry. 77

2 Sulwhur-containing Heterocvcles

Sections on the synthesis of sulphur-containing heterocycles have appeared in three review articles published this year. The reviews are on organothiophosphorus compounds ,78 the thionation reactions of Lawesson‘s reagent,79 and the photochemistry of thiocarbonyl compounds. 80 The use of lasers in photochemistry is far from common, but Bertaina et al. have found that pulsing a mixture of s8 and cyclohexene with laser at 266 nm affords cyclohexane episulphide.

81

Whether this hails the start of a general method depends on whether the yield (E. 1%) can be improved and the scope extended; further studies are underway. In variant of the previously olefins to thioamides has amides (92) are converted yield. 8 2

a more familiar vein the intramolecular reported [2+21 photocycloaddition of been published where the alkenyl thiointo the tricycles (93) in 31-82%

Rao and Ramamurthy have studied the intermolecular [ 2+2]

cycloaddition of olefins to thienones (94).

The stereochemistry

and regiochemistry of the products have been determined and then rationalized on the basis of molecular orbital coefficients. 83 The thiol group has not seen regular use as a terminating group in polyene cyclization, but now Saito et a l , have shown that it behaves quite satisfactorily giving tetrahydrothiophene annulated polycycles (Scheme 1 1 ) in good yield and with a high degree of

84

stereocontrol. A new and potentially very useful method for the synthesis of substituted tetrahydrothiophenes by the addition of the thioThe ylide is carbonyl ylide (96) to olefins has been disclosed.85 generated by thermal extrusion of Me SiBr from the bromide ( 9 5 ) ,

3


480

OH

TXA2

R5

H oB )ou

1

zoa p at ano I Scheme

x,. -

R’

+

(89)

R’

10

R2

R2

(90)

48 1


OH

(94)

R

/r'

X = C N or C02Me, R = Ph or Me

R

Scheme

11


482

and t h e s u b s e q u e n t c y c l o a d d i t i o n s p r o c e e d i n h i g h y i e l d (>91”/0. T h e McMurray c o u p l i n g o f k e t o n e s h a s p r o v e d t o b e a v e r y u s e f u l m e t h o d o f c a r b o c y c l i c s y n t h e s i s a n d t h i s h a s now b e e n e x t e n d e d t o the synthesis of sulphur heterocycles.

Thus t r e a t m e n t o f t h e

( 9 7 ) w i t h l o w - v a l e n t T i ( f r o m T i C 1 4 a n d Z n ) a t low t e m p e r a t u r e g i v e s t h e 3,4-dihydroxytetrahydrothiophenes ( 9 8 ) i n

diketo-sulphides

good t o e x c e l l e n t y i e l d (50-93%).86

If t h e r e a c t i o n i s c a r r i e d o u t

a t r o o m t e m p e r a t u r e or a b o v e t h e n t h e d i h y d r o x y i n t e r m e d i a t e s cannot be i s o l a t e d and only t h e dihydrothiophenes are i s o l a t e d (Scheme 1 2 ) .87,88

A general synthesis of t h e thiophene-Z(3H)-thione

r i n g system

h a s b e e n d e s c r i b e d w h e r e t h e d i a n i o n s o f e i t h e r a l l e n e s or a l k y n e s

a r e t r e a t e d s u c c e s s i v e l y w i t h CS2, a n e l e c t r o p h i l e , a n d t h e n acid.89

The whole s e q u e n c e i s c a r r i e d o u t i n o n e p o t a n d t h e

y i e l d s of t h e r e q u i r e d p r o d u c t s

(99) a r e b e t w e e n 45 a n d 81%.

The i n t r a m o l e c u l a r a z a - D i e l s - A l d e r

reaction of 2-alkynyl-

t r i a z i n e s a f f o r d s dihydrobenzothiophenes ( 100)

and f u l l d e t a i l s

of t h e g e n e r a t i o n o f e t h y l a n d m e t h y l t h i o x o a c e t a t e s and t h e i r u s e i n t h e hetero-Diels-Alder

r e a c t i o n h a v e a l s o a p p e a r e d .”

Trimethyl-

s i l y l e n o l a t e s react w i t h t h i o n y l c h l o r i d e t o g i v e B-oxosulphinyl c h l o r i d e s ( 1 0 1 ) w h i c h r a p i d l y e l i m i n a t e HC1, g e n e r a t i n g aoxosulphines; these then p a r t i c i p a t e i n hetero-Diels-Alder r e a c t i o n s w i t h d i e n e s t o g i v e dihydrothiophene ?-oxides

(102) i n

v a r i a b l e y i e l d , 9 0 and t h e p a r e n t s u l p h i n e ( 1 0 4 ) c a n be g e n e r a t e d by fluoride treatment of

(103) a n d t h i s a l s o u n d e r g o e s C4+23 c y c l o -

addition reactions.93

S i m i l a r l y t h e sulphenes ( 105) a l s o g i v e

hetero-Diels-Alder

adducts.

The f l u o r i d e - i n d u c e d

B-elimination

of

t h e d i s u l p h i d e s ( 1 0 6 ) is a m i l d method f o r g e n e r a t i o n o f t h i o a l d e h y d e s w h i c h are s u b s e q u e n t l y c a p t u r e d by c y c l o p e n t a d i e n e t o g i v e predominantly endo-products

( 1 0 7 ) .94

The a - c h l o r o s u l p h i d e s

( 108),

when t r e a t e d w i t h S n C 1 4 g e n e r a t e p h e n y l t h i o n i u m c a t i o n s w h i c h u n d e r g o [4+21 c y c l o a d d i t i o n r e a c t i o n s w i t h s t y r e n e t o g i v e d i h y d r o b e n z o t h i o p y r a n s i n v a r i a b l e y i e l d s . 95 with trans-stilbene

The r e a c t i o n a l s o s u c c e e d s

a s t h e 2x c o m p o n e n t a n d h a s b e e n a p p l i e d i n t r a -

molecularly. If t h e n o r m a l c o n d i t i o n s f o r t h e W i t t i g r e a c t i o n a r e u s e d t o

p r e p a r e t h e d i h y d r o t h i o p y r a n s (110) from t h e phosphonium s a l t (109) and a-thioketones, of isomers.

then the reaction e i t h e r fails or gives mixtures

H o w e v e r , by p e r f o r m i n g t h e r e a c t i o n i n a s t e p w i s e

manner t h e r e q u i r e d d i h y d r o t h i o p y r a n s (110) are formed i n approxim a t e l y 50% y i e l d

.96 D e p r o t o n a t i o n o f t h e d i e n e s u l p h o x i d e s

( 11 1 )


Me 3Si,,

483

-

S iMe,

S Br

(96)

(95)

Ph . .. 0

X=Y=CO,Me,CN,

0

y/

0

X

0

o

r

~

N

~

o

u

y

SiMe3

TiCI4/ Zn _______)

T H F , O°C

(97)

(98)

Scheme

12

R’ R’

R’ R2+= Li

- Li

i, C S 2

T-Fiii, H ~ O +

R2-j-J S ’ S

E


484

R?0siMe3

+

-

SOCI,

R2

F-

Me3SiCH2SOCI (103)

(Me3SiCHS02 I2O

I

CH,=S=O

(104)

Cs F

>-%

vR SCO),

RCH=S=O

R

(105)

Ph Ph A SnC14

-

oclx,


485

0

’ “3

OE t

--

4

+PPh3

I i, Bu”Li

ii, E+

A3

01j$ R’

(112)

(1111

RF2)n

R2

OH

(114)

(1131

$3 ‘2’5

OH

Scheme 13

Toduene

R2

486


affords the dihydrothiopyrans (112) only when R is aryl or ally1.97 The yields are moderate (32-68%) and the reaction is thought to proceed

via

a concerted disrotatory electrocyclization.

In an attempt to dehydrate the B-hydroxy-dithianes (113) using P205 only the ring-expanded products (114) were isolated, and this has been developed into a general ring expansion method which also works for the a-hydroxy-dithiane (115) (Scheme 13) .98

3 Heterocycles Containing More than One Heteroatom Nitrogen- and Oxygen-containing Rings.- Five-membered Rings. Nitrone cycloaddition chemistry continues to dominate the literature on the synthesis of isoxazolidines.

More attention is now

being paid to the stereochemical outcome of the reaction o f both the intra- and inter-molecular varieties of the reaction.

For example

the preference for fused o r bridged products from the intramolecular reaction of nitrones (116) depends on the substitution pattern of the olefin moiety where bridged products are preferred, H , when the fused products predominate.99 1-Benzyl-Cunless R alkyl- and ~ - b & n z y l - C - - B - a l k o x y a l k y l - n i t r o n e s

add to methyl croto-

nate to give predominantly 3,5-trans-products ( 1 1 7 1 , whereas

E-

benzyl-C-a-alkoxyalkyl-nitrones add to give the 3,5-%-products ( 1 18) as the major isomer. l o o The use of nitrones in cycloaddition reactions has been reviewed,”’ and two new methods for the generation of nitrones have been developed by LeBel’s group. The first involves 1alkylation of c-trimethylsilyl-oximes,I o 2 and the second uses an interesting Grob-type fragmentation of the decahydroquinoline (119) (Scheme 14). I o 3 The commonly used reactive intermediates for isoxazoline synthesis are nitrile oxides, and two new ways of generating these have appeared this year. Thus alkyl carbonocyanidate N-oxides are generated by thermolysis of nitromalonates,Io4 and the furoxan (120) reversibly generates the nitrile oxide (121) at high temperature; the latter sequence allows stoicheiometric amounts of the olefin and nitrile oxide to be used in the reaction f o r the first time, giving high yields of the isoxazolines ( 122). O5 Most methods for the formation of oxazolines from b-hydroxyamines and -acids call for vigorous conditions often leading to polymeric side-products. However Roush and Pate1 have found that treatment of the easily obtained hydroxy-amides (123) with


P h O k f i R

I

0-

4-

*cO,Me

487

-

0-N U

-

+ *

I 1

I

C02Me

C0,Me (117)

Scheme

(120)

R

4" GR (11 8)

14

(122 1


488

DEADIPh P a f f o r d s t h e o x a z o l i n e s u n d e r v e r y m i l d c o n d i t i o n s , ' I o 6 3 M e y e r s a n d H o y e r h a v e s h o w n t h a t t h e Ph P / C C 1 4 / E t N m e t h o d f o r

and

3

3

o x a z o l i n e s y n t h e s i s from a c i d s and a m i n o - a l c o h o l s p r o c e e d s w i t h i n v e r s i o n a t t h e c a r b i n o l c e n t r e , c o n t r a r y t o w h a t was p r e v i o u s l y thought.lo7

O x a z o l i n e s c a n a l s o b e s y n t h e s i z e d b y t h e ZnC12-

catalysed cycloaddition of a,B-unsaturated t o i s o c y a n i d e s (Scheme 1 5 ) . Io8

and aromatic a l d e h y d e s

Y i e l d s are g e n e r a l l y good and a

CuClIEt N c a t a l y s t c a n also be u s e d ; i n f a c t t h i s is t h e c a t a l y s t

3

o f c h o i c e for t h e c y c l o a d d i t i o n r e a c t i o n w i t h a l i p h a t i c a l d e h y d e s .

Dimethyl N--ethoxycarbonylmethyliminodithiocarbonate

adds t o benz-

a l d e h y d e s t o g i v e o x a z o l i n e s ( 1 2 4 ) i n 52-96% y i e l d i n t h e p r e s e n c e o f p o t a s s i u m t - b u t o x i d e , log and t h e a u t h o r s claim t h a t t h e r e a g e n t s h o u l d be o f g e n e r a l a p p l i c a b i l i t y f o r t h e a d d i t i o n o f a C-N=C

unit

t o unsaturated systems. The c y c l o a d d i t i o n r e a c t i o n between e p o x i d e s and i s o c y a n a t e s h a s b e e n c a r r i e d o u t u n d e r n u m e r o u s c o n d i t i o n s , most o f w h i c h r e q u i r e e i t h e r e l e v a t e d t e m p e r a t u r e s or p o l a r s o l v e n t s , b u t t h e u s e o f L e w i s b a s e c a t a l y s t m i x t u r e s , s u c h as Bu2Sn12/Ph P , a l l o w s t h e

3

r e a c t i o n t o be conducted under mild c o n d i t i o n s and even works w i t h carbodi-imides t o g i v e imino-oxazolidines

(Scheme 1 6 ) . ' l o

The

d i a n i o n ( 1 2 5 ) h a s been f o u n d t o be a u s e f u l i n t e r m e d i a t e f o r t h e f o r m a t i o n o f a r a n g e o f h e t e r o c y c l e s s u c h as o x a z o l i n e t h i o n e s , o x a z o l i n o n e s , o x a z o c i n e s , and o x a z o n i n e s ( s e e Scheme 1 7 ) . S i x - and Seven-membered R i n g s .

F u l l d e t a i l s of t h e r e g i o s e l e c t i -

v i t y of t h e intramolecular hetero-Diels-Alder

reaction of acyl

n i t r o s o compounds and n i t r o s o f o r m a t e s h a v e been p u b l i s h e d

,

and

n i t r o s o i n t e r m e d i a t e s a l s o f e a t u r e i n two p u b l i c a t i o n s f r o m K i r b y ' s g r o u p on [ 4 + 2 1 c y c l o a d d i t i o n r e a c t i o n s t o g i v e o x a z i n e d e r i v a t i v e s . T h u s o x i d a t i o n o f h y d r o x a m i c a c i d s i n t h e p r e s e n c e of d i e n e s g i v e s t h e oxazines (126),

and f u l l d e t a i l s of t h e o x i d a t i o n of

K-

h y d r o x y - u r e a s i n t h e p r e s e n c e of d i e n e s t o g i v e o x a z i n e s ( 1 2 7 ) h a v e T h e f i r s t e x a m p l e of a n a z a d i e n e [ 4 + 2 ] c y c l o a d d i t i o n r e a c t i o n t o a l d e h y d e s a s t h e 2 r c o m p o n e n t h a s b e e n r e p o r t e d . 115

appeared. 'I4

T h e p r o d u c t s a r e 5,6-dihydro-2~-1,3-oxazines( 1 2 8 ) from p r e d o m i n a n t l y endo r e a c t i o n and y i e l d s are h i g h (70-95%). The r e a c t i o n o f e p o x i d e s w i t h i s o c y a n a t e s is well known, b u t

l e s s w e l l known i s t h e r e a c t i o n o f o x e t a n e s w i t h i s o c y a n a t e s . H o w e v e r , t h e m o d i f i e d r e a c t i o n c o n d i t i o n s r e p o r t e d for e p o x i d e a d d i t i o n have been found t o promote t h e oxetane v a r i a n t t o a f f o r d t h e oxazin-2-ones (129) i n good y i e l d (58-87%). ' I 6 The s y n t h e s i s


-

0

Ph3P/ DEAD

R’+;KR2

“il

OH

O f N R2

(123)

Erk, C02Et

ZnCl2

+

RY-fco2E N ’0-

or CuCIIEt3N

RCHO

15

Scheme

H

--+

Et02C

EtozcVNKSMe S

v

/

i , K+

N q s M e

BU~O-

ii, ArCHO

COZEt (124)

R’

R’

R’

Lewis b a s e

Lewis base R ~= N c = NR*

0 0 Scheme

16

SMe


490

-

Ph

R

NR

i, R N H 2

ii,NalEt20

cs2

Ph

Scheme

Ph

17

0 (126)

0

II

0 (127 1 R’

R2

+

- 3 0

R3CH0

R

v R~

1 R2

(128)

+

Bu25n12

R*--N=C=O

N\

Ph3P0

0 (129)

R2


49 1

of the previously unknown 2-amino-6K-I13-oxazin-6-one ring system has been reported by the base-mediated addition of 0-cyano-esters to N-cyano-imines and subsequent ring closure (see Scheme 1 8 ) , 47 and the 0-allenic oximes ( 1 3 0 ) cyclize to give 4,7-dihydro-1,2oxazepines

via

a silver-mediated process. 118

Nitrogen- and Sulphur-containing Rings.- In contrast to 8-lactams1 0-sultams have been little studied and most approaches have used

[2+21 cycloaddition as the obvious strategy. However, two research groups have independently developed similar approaches which get away from the cycloaddition methodology, and which involve intramolecular sulphonylation as the key ring-forming step. Champseix et al. have shown that both 0-amino-thiols and 0-aminosulphonic acids can be converted to the 0-ammoniumsulphonyl chlorides (131) which cyclize in the presence o f base to the 0 sultams (1321, and that amines add to vinyl sulphonyl fluoride also to give B-sultams.ll9

On the other hand Meyle et al. have found

that amines add to the vinylsulphonate (133), and the resultant product can be cyclized by conversion into the sulphonyl chloride and subsequent ring closure. Thiazolidine-2-thiones can be prepared with complete control over stereochemistry from the olefins (134).

Addition of iodoiso-

cyanate to the olefins in MeOH generates the known 8-iodocarbamates (135) which on treatment with potassium ethylxanthate followed by base give the thiazolidine (136).

The opposite stereoisomer (138)

is formed by addition of the xanthate to the aziridine (137) formed from base treatment of (135). ’I2’

A new method for the formation of the dihydro-l13-thiazines (140) from the thioureas (139) using BF3.Et20 in refluxing chloroform has been reported,122 and a new approach to the synthesis o f the dihydro-1,4-thiazines (143) has also been disclosed. This entails the reaction o f a - a l k y l t h i o - 0 - d i c a r b o n y l compounds (141) with 0-amino-halides as a one step procedure or the reaction of (141) with the more readily available 6-amino-alcohols (142) and subsequent ring closure by mesylation then displacement. 23 The fact that attempted 2-alkylation of dihydrobenzothiazoles (144) leads to the 2-alkylated amines has been used to advantage in the synthesis of dihydrobenzothiazines.

Thus alkylation of (144)

with an a-halogeno-ester, -ketone, or -nitrile affords the dihydrobenzothiazines (145) initial 2-alkylation followed by 124 cyclization onto the imine in generally g o o d yield (41-93%).


492

,YNCN X

+

-

N ~ O R ~

(,OZR’ CN

R’OH

HCIIEt20 -R’CI

0

Scheme

18

R’ Ag’, CHC13

I,

RNH2

Ph ___)

RNh 0 , C l

RNN


493

n

0 R' R

R3

')=I(

Me

INCO ___)

MeOH

R4

1

(134)

"

EtO%'

(135)

S

R 2 R4

"G-R3

KS

OEt

sKNH S (138)

(136)

(137)

BF3.Et20

+ R'

N R'

R3

(140)


494

The benzothiadiazine oxides (148) are formed by an unusual [4+21 cycloaddition reaction between the sulphinyl anilines (146) and the SchiPf bases (147) where the sulphinyl aniline is serving as the diene unit.125

The reaction fails for N-alkyl Schiff bases.

Oxygen- and Sulphur-, and Nitrogen-, Oxygen-, and Sulphurcontaining Rings. Chiral Il3-oxathianes have been shown to be 'usefiil reagents for the synthesis of optically pure hydroxyaldehydes, and DeLucchi et al. have developed a new approach to chiral oxathianes using a photochemically induced ring closure of 126 the vinyl sulphides (149) and (150) (Scheme 19). Cyclohexane monothioacetals rearrange in the presence of CuBr2 in diglyme to give the Zl3-dihydrobenzoxathiines (151) in moderate yield (35-68% 1 . No mechanistic rationale is offered. Nitrosoalkenes act as heterodienes in cycloaddition reactions with thiocarbonyl compounds to afford the first examples of the 4KI l ~ , 2 - o x a t h i a z i nring e system (152) in high yields (60-99%) and the low-temperature cycloaddition o f dioxadithiazine tetroxides to olefins gives mixtures of 8-sultams (153) and the 1,4,5-oxathiazin4,4-dioxides (154) depending on the substitution pattern. 129 4 Nitronen-containinn Heterocvcles Three- and Four-membered Rings.-

A convenient synthesis of sub-

stituted aziridines (157) has been described which utilizes a Darzens-type reaction between diarylimines (155) and isopropyl dichloroacetate (156). I3O The reaction is limited to aromatic imines ( R ' and ' R

= aryl) but is capable of easy scale-up and is

stereospecific, although the stereochemistry of the aziridines (157) has yet to be determined.

The first example of a spiroFormation of the

aziridine of type (160) has been reported.13'

iodoazide (159) from the alkene (1581, followed by immediate reduction,gave the spiro-aziridine (160) as an unstable oil which was characterized as the N-methoxycarbonyl derivative (161). 2-Cyano-3,3-dimethylazetidines (164) have been prepared by a novel procedure which involves nucleophilic addition of cyanide to B-chloroimines (162) followed by intramolecular alkylation of the anion (163) to give products in excellent yields. 132 Five-membered Rings.- The trend of previous years has continued in the 1985 literature with the synthesis of five-membered rings


X = Br or CI Y = C O P h , C0,Et

N=S=O

495

or CN

+

R3 k N R 5 R4 (147 1

(146)

L&o"

2 z

h'J.

SH

&

OH

3

S

(149)

(150)

X

X = PhSO,,

-

H

C I 0-S O 2 . or M e 0 2 C

S c h e m e 19

(X


496

R'

"x;"'

CuBr2, D

R3 @ $R

d i g l y m e , llO°C

R3

R4

R4

(151)

x%

Br

-

NOH

(152)

R R'

R2

R3

R4

R~C= H NR'

-k

.

CHC12C02Pr'

' 0

Y

R

-

Ct R'-CH-C N

(156)

(155)

I

Pr'OK/Pr'OH

I

R2

(157)

& (158)

-

I C I , NaN3

LiAIH4

______)

MeCN,-40°C

\

(1 59)

& \

(160) R = H (161) R = C0,Me


497

containing one nitrogen now constituting by far the most popular area for study in nitrogen heterocyclic synthesis. Two reviews have appeared. Giese has included several examples of the formation of oxygen and nitrogen heterocycles in his review of synthetic applications of radical C-C bond formation via organotin and organomercury intermediates’” and Speckamp and Hiemstra have produced a comprehensive review of the synthesis of nitrogen heterocycles by intramolecular cyclization of 1-acyliminium intermediates. 34 The intense interest in the formation of five-membered nitrogen heterocycles by a 1 , 3-dipolar cycloaddition of ah azomethine ylide, or related species, and an alkene or alkyne has been maintained this year. The majority of synthetic effort continues to be

’

directed towards the mild generation of non-stabilized azomethine ylides, in particular by desilylation procedures. The groups of Vede js, 35 Achiwa, 36 Livinghouse , 37 and Padwa’ 38 have all published full accounts of their earlier work in this area and the latter group has also reported the first examples of diastereoselective azomethine ylide cycloadditions. 39 In this preliminary study the best diastereoselectivity obtained was in the cycloaddition between the azomethine ylides formed from precursor Ecyanomethyl-N-trimethylsilylmethylamines (165) and (1661, and the electron-deficient alkene (167). Pyrrolidines (168) and (169) are produced in good yields as a 4:l mixture of diastereomers and undoubtedly this ratio will be improved when a larger range of substituents and dipolarophiles is investigated.

x-

Two reports from Achiwa and co-workers illustrate well the ease with which non-stabilized azomethine ylides can now be generated and trapped to give pyrrolidines or 2,5-dihydropyrroles. 5-BenzylN-(methoxymethyl)trimethylsilylmethylamine (170) reacts in the presence of a catalytic amount of trifluoroacetic acid and the appropriate dipolarophile at room temperature to give generally excellent yields of products (172) or (173)140 and the 3- or 3 , 4 substituted 2-acylpyrrolidines (175) are produced, also in high yields, by the reaction sequence shown in Scheme 20. The advantages of this method are that the triazine (174) is stable to long storage and a range of acyl halides can be utilized in the reaction, although yields are best with acyl fluorides. This type o f cycloaddition methodology also lends itself very conveniently to the synthesis of 1 - and 2-pyrrolines simply by incorporation of a potential leaving group in the azomethine ylide precursor. Thus,


498

(165) R = H

(167)

(166) R = OMe

(168) R = H, 30% (169) R = OMe,20%

X

-1 CF3C02H(cat.)

Me ,SiCH2N- CHzOMe

I

CH,Ph

CH2CI2, r .t

I CH2Ph

CC H ,;H 2i,Z

.,

(172)

XCH=CHY .____._)

C!.H,Ph]

or

xc=

CY

X

Y

3h

(170)

(171)

1 CH,Ph

X = COZMe (173) H,Ph or COZMe

Y =

I

COPh

SiMe3

(175) R1= C02Me or CN

(174)

R2- R4= H, C0,Me br Ph Scheme

20


499

pyrrolines (178) can be prepared conveniently and in good yields by the reaction of the thioimidate (176) with alkenes (177).142 Other 2-substituted pyrrolines are also potentially available this method starting from the appropriate substituted thioimidate. In an alternative procedure cycloaddition of the N-protonated azomethine ylide tautomer of benzylideneaminoacetonitrile (179) adds to substituted alkenes to give, after base- or thermally-induced 1 ,2-elimination , 1 - or 2-pyrrolines ; for example, ( 182) and (183) are produced in moderate yield from precursors (180) and

''

(181). Full details have appeared of the generation of the nonstabilized ylide (184) by treatment of trimethylamine N-oxide with L D A , and subsequent trapping with alkenes to give pyrrolidines (185).144 The great advantage of this ylide compared with those such as (171) that are generated by desilylation procedures is that (184) is sufficiently reactive to undergo cycloaddition with unactivated alkenes. Extension of this methodology to the cyclic N-oxides (186) and (187) provides a novel procedure for constructing the pyrrolizidine and indolizidine systems (188) and (189) in a stereospecific or highly stereoselective manner. 145,146 Thus (192) is formed stereospecifically and in high yield by reaction of (190) with cyclopentene (191). Product yields are lower for the pyrrolidine N-oxide (186) compared with the piperidine N-oxide (187) and in trapping reactions with monosubstituted alkenes regioselectivity is generally low but, nevertheless, this method of generating cyclic non-stabilized ylides does allow ready access to quite complex bi- and tri-cyclic nitrogen systems in synthetically useful yields. The related azabicyclic enaminones (195) have been prepared by electrocyclization of the conjugated azomethine ylide (194), formed by FVP of the Meldrum's acid derivatives (193).147 Grigg and co-workers have published full details of their studies on the synthesis of substituted pyrrolidines and dihydropyrroles by intramolecular cycloaddition of imines of amino-acid esters with alkenes or alkynes. 14' In a similar type of reaction, intermolecular trapping of ylides (197) with electron-deficient alkenes has been shown to provide a general route to pyrrolidines of type (198).149 The ylide (197) is generated in situ by reaction of benzaldehyde with the appropriate amino-acid ester (196). Cycloaddition generally occurs with only low stereoselectvity but this is compensated by the high yields obtainable in a one-pot procedure and the potential versatility of the reaction.


SMe

+

H20, HMPA

XCH=CHY

( c i s or truns 1

(176)

Ph

H

H

n

PhCN=NCH,CN

(179)

X

(178) X = COMe or C02Me Y = H , M e or Ph

(1 77)

andlor

Me Me

Me

(180)

(181 1

$; 0’

I+ Me-N-

LDA

Me

I

‘0

Me

Me

(1 8 2 )

(183)

- [-;I.]

Me

7

0’

‘0

N,.

R

w

I

R

R

0-

(185) R = a l k y l

(184)

an

LDA

R

R

____)

T HF, O°C

Me’

‘0-

(186) n = 1 (187) n = 2

R = H or Ph or RR=(CH2), (188) n = 1 (109)n= 2


50 1

i, L D A

ii.

0 (191)

-1-

92"lo

L.j - %

n

Me

(192)

0

0

(194)

(195)

PhCHO

HN

I

- CHC0,R3 I

R'

R2

(196)

A

\CN 02Me

-+N/\COzMe

R*CH=CHR;

L

I

,

R' (199) R = a

O

M

e or PhCH,

vyo I

CH2Ph (202)

COZMe

k'

(200)

(201)

FVP

&o

I

H O CH,Ph

(203 1

502


Aziridines containing two stabilizing substituents are known to undergo thermal ring opening and subsequent trapping with reactive dipolarophiles to give five-membered nitrogen heterocycles. De Shong and co-workers have now shown that this reaction is synthetically viable with only one stabilizing substituent. I5O Aziridines (199) undergo a thermally induced ring opening to azomethine ylides (200) which can be trapped intermolecularly by a range of alkenes to give pyrrolidines (201). Products are formed generally with high regio- and stereo-selectivity but, as expected, yields are

dependent upon the electronic character of the dipolarophile: alkenes substituted with electron-withdrawing or -donating groups react in good yields but unactivated aikenes do not form cycloadducts under intermolecular conditions.

In the intramolecular

version of the reaction, however, cycloadducts can be obtained under FVP conditions even with unactivated alkenes to form bicyclic systems in moderate to good yields. For example, the adduct (203) is formed in good yield, as a single stereoisomer, from the precursor aziridine (202). A similar study of the intramolecular trapping of azomeLhine ylides generated by thermal ring opening of This group has aziridines has been reported by Weckert et a1.I5' shown that the hydroindole system (205) can be generated efficiently in a thermally induced ring opening and cycloaddition process

from 2-aikenoylaziridines (204). The possibility that fused pyrrolines (207) may be generally available by a route involving intramolecular cycloaddition and subsequent ring expansion of dienic azides (206) has been explored by two groups, with essentially the same result (Scheme 21). 152,153

via radical or 'b' in the intermediate vinylaziridine (208) but yields are moderate at best and the major product is the monocyclic pyrroline (209), formed by a 1,5-homodienyl rearrangement. The route therefore could provide a useful access to the pyrrolizidine framework if conditions could be identified which would allow more controlled and efficient breakdown of (208). The synthesis of substitute pyrrolines by ring expansion of vinyl aziridine derivatives has also been accomplished in a palladium-catalysed reaction. N-Tosyl-2-vinyl five- and sixmembered nitrogen heterocycles (213) are obtained in generally high yields under mild conditions from precursor dienyl nitrogen heterocycles (212) in the presence of a catalytic amount of The complete diene unit is required for the [Pd(PPh3I4l. 15' Tetrahydropyrrolizines (210) and (211) can be formed scission of either bond


503

-

R2 3R+R

#’

N

Rm

Ph

H

I

Me

(205)

(204)

&-[&I-&

I H O Me

C02Et

C0,Et

C02Et

(209)

(208)

C02E t ( 211 1

(210) Scheme

21

R’

y-;N(Tos

d

R’

34_ [Pd(PPh 1 1 DMSO, 50y

N

- TOS

R2

(212) n = 0 or 1

(213)

504


reaction t o proceed: vinyl-substituted heterocycles do not g i v e ring-expanded products. a-Methylene-pyrrolines (216) have been produced i n a d i f f e r e n t kind o f palladium-catalysed

r i n g expansion

p r o c e s s , by a [ 3 + 2 1 c y c l o a d d i t i o n of m e t h y l e n e c y c l c p r o p a n e s ( 2 1 4 ) w i t h k e t e n i m i n e (215).

Y i e l d s are e x c e l l e n t f o r t h e two

examples reported. Rapoport and co-workers

have reported a g e n e r a l s y n t h e s i s of

n i t r o g e n , o x y g e n , and s u l p h u r h e t e r o c y c l e s ( 2 1 8 ) by rhodiumc a t a l y s e d i n t r a m o l e c u l a r N-H, diazo-!3 - k e t o - e s t e r

0-H,

or S-H i n s e r t i o n r e a c t i o n s . o f a -

p r e c u r s o r s ( 2 1 7 ) .36

T h i s r e a c t i o n i s well

d o c u m e n t e d as a n e f f i c i e n t r o u t e t o B-lactams b u t t h i s g r o u p h a s now s h o w n t h a t t h e r e a c t i o n w o r k s w e l l f o r t h e s y n t h e s i s o f f i v e and six-membered

n i t r o g e n h e t e r o c y c l e s (Scheme 2 2 ) .

f a i l s f o r seven-membered n i t r o g e n h e t e r o c y c l e s :

The r e a c t i o n

i n t h i s c a s e C-H

i n s e r t i o n t o g i v e a c y c l o p e n t a n o n e i s t h e p r e f e r r e d r e a c t i o n mode. I n common w i t h t h e g e n e r a l i n c r e a s i n g i n t e r e s t i n s y n t h e t i c applications of free-radical

cyclizations, t h i s year has seen a

h i g h l e v e l o f i n t e r e s t i n t h e s y n t h e s i s o f n i t r o g e n h e t e r o c y c l e s by such processes.

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

r a n g e o f N-benzenesulphonyl-pyrrolidines ( 2 2 0 ) a n d - p i p e r i d i n e s

(221) via a c a r b o n r a d i c a l c y c l i z a t i o n , s t a r t i n g f r o m b r o m o a l l y l o r d i a l l y l - s u b s t i t u t e d s u l p h o n a m i d e s ( 2 1 9 ) 1 5 6 1 5 7 For e x a m p l e s where R3=H,

1,5-cyclization occurs e x c l u s i v e l y and i n high y i e l d

(>85%) e v e n when t h e a l k e n e i s d i s u b s t i t u t e d , b u t i n t h e c a s e o f v i n y l r a d i c a l c y c l i z a t i o n s ( 2 2 0 ) or ( 2 2 1 ) may b e o b t a i n e d d e p e n d i n g upon t h e a l k e n e s u b s t i t u t i o n p a t t e r n .

Hart a n d c o - w o r k e r s h a v e

published f u l l d e t a i l s of t h e i r earlier s t u d i e s on t h e a d d i t i o n o f acylamino-radicals

t o alkynes t o g i v e p y r r o l i z i d i n o n e s and

i n d o l i z i d i n o n e s . 158

I n a similar type of c y c l i z a t i o n t h e a l l y l -

s t a n n a n e (223) h a s been used as a r a d i c a l t r a p t o g i v e t h e v i n y l pyrrolizidinone (2241, an intermediate i n t h e synthesis o f (?)i s o r e t r o n e c a n o l ( 2 2 5 ) i n m o d e r a t e (45"/0) y i e l d b u t w i t h h i g h stereoselectivity (11.3:l).

The p y r r o l i z i d i n o n e ( 2 2 4 ) c a n a l s o

b e o b t a i n e d more e f f i c i e n t l y a n d w i t h g r e a t e r s t e r e o s e l e c t i v i t y

( 7 4 : l ) d i r e c t l y from (222)

via

a 'two-electron'

cyclization.

The

key s t e p i n an a l t e r n a t i v e s y n t h e s i s o f i s o r e t r o n e c a n o l (225) i n v o l v e s a photoinduced r a d i c a l c y c l i z a t i o n of t h e a-keto-ester ( 2 2 6 ) t o g i v e t h e b i c y c l i c p r o d u c t ( 2 2 7 ) i n good y i e l d . I6O

The

e n o l form of (226) is n o t photoreducible. The s y n t h e s i s o f y - l a c t o n e s

by o x i d a t i v e a d d i t i o n o f a c e t i c a c i d

t o a l k e n e s i n t h e p r e s e n c e of Mn(OAcI3 h a s b e e n d o c u m e n t e d f o r some


505

(217)

(218)

I

I

Z

2 n

= 1-3

n = 1, n n

100'/0

= 2 , 100°/o = 3, 67'L \

Scheme

BugSnH

I

k1

jXshl

R3

AIBN

-

22

506


0

OH

(222)

SPh

Q-

0

2

(224)

i, MsCl , NEt3

Reagents

(225)

SnBu3

;

ii, ( P h S I 2 , Bu"3P

iii, hv

--

Me hv ButOH

W

(225)

II

0

(227)

(226)

R'

M n ( OAc 1 _____)

R2

CON H

HN

CONH,

AcOH

0

507

8: Saturated Heterocyclic Ring SyMhesis

time b u t a n example o f a n a p p l i c a t i o n o f t h i s p r o c e s s t o t h e s y n t h e s i s o f y - l a c t a m s h a s now a p p e a r e d . 16' a ,r3 - U n s a t u r a t e d y -1actams ( 2 2 9 ) c a n b e p r e p a r e d by r e a c t i o n o f s u b s t i t u t e d a l k e n e s ( 2 2 8 ) w i t h malonamide,

probably

via

a c a r b o n r a d i c a l c y c l i z a t i o n mechanism.

Y i e l d s are v a r i a b l e , however, and t h e corresponding y - l a c t o n e s are u s u a l l y a l s o o b t a i n e d b u t t h e s e d i s a d v a n t a g e s may b e o f f s e t i n s o m e a p p l i c a t i o n s by t h e s i m p l i c i t y o f t h e e x p e r i m e n t a l p r o c e d u r e . Two r o u t e s t o t h e p y r r o l i d i n e s y s t e m i n v o l v i n g t h e g e n e r a t i o n o f nitrogen-centred

r a d i c a l s have appeared. N - M e t h y l - e - 2 , 5 -

d i s u b s t i t u t e d p y r r o l i d i n e s ( 2 3 2 ) may b e o b t a i n e d i n m o d e r a t e y i e l d s by c y c l i z a t i o n o f a m i n y l r a d i c a l s ( 2 3 l ) , g e n e r a t e d by a n o d i c o x i d a t i o n of l i t h i u m alkenylamides (230). 162 i s o m e r s were n o t d e t e c t e d . sulphonyl-pyrrolidines

The c o r r e s p o n d i n g t r a n s -

I n t h e s e c o n d s t u d y , N-methane-

( 2 3 4 ) h a v e b e e n p r e p a r e d s i m p l y b u t i n low

y i e l d s by o x i d a t i v e c y c l i z a t i o n o f N - m e t h a n e s u l p h o n a m i d e s (233)

16'

2-substituted

The N - s u b s t i t u e n t

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

pyrrolidines (235).

L i t t l e e t a l . have extended t h e scope of t h e i r intermolecular d i y l t r a p p i n g r e a c t i o n t o i n c l u d e a range o f d i y l o p h i l e s which i n c o r p o r a t e h e t e r o a t ~ m s . ~T h~ u s , t h e b i -

and t r i - c y c l i c

nitrogen

h e t e r o c y c l e s ( 2 3 8 ) a n d ( 2 3 9 ) are p r o d u c e d by t h e r m o l y s i s of t h e d i a z e n e ( 2 3 6 ) i n t h e p r e s e n c e of t h e i m i n e ( 2 3 7 ) . however,

Yields are low,

a n d s o f a r t h i s is t h e o n l y r e a c t i o n e x a m p l e b u t t h e

p r o d u c t s ( 2 3 8 ) and (239) are u n u s u a l s t r u c t u r e s and t h e method c o u l d h a v e some s p e c i a l i z e d u t i l i t y . R e p o r t s on t h r e e u s e f u l t r a n s i t i o n metal c a t a l y s e d c y c l i z a t i o n r o u t e s t o nitrogen heterocycles have appeared t h i s year.

In an

e x t e n s i o n o f t h e i r e a r l i e r work on t h e s y n t h e s i s of t r i c h l o r i n a t e d y-butyrolactams

by c o p p e r - o r r u t h e n i u m - c a t a l y s e d

E-

cyclization of

a l l y l - t r i c h l o r o a c e t a m i d e s , I t o h a n d c o - w o r k e r s h a v e now s h o w n t h a t t h e method p r o v i d e s a n e f f i c i e n t r o u t e t o b i c y c l i c l a c t a m s . 165 Products (240) are g e n e r a l l y obtained i n e x c e l l e n t y i e l d s , and r e d u c t i v e d e c h l o r i n a t i o n t o g i v e (241) i s e a s i l y accomplished.

The

c y c l i z a t i o n i s h i g h l y s t e r e o s e l e c t i v e i n t h a t o n l y *-fused

Full d e t a i l s h a v e a l s o a p p e a r e d from M o r i p r o d u c t s are o b t a i n e d . e t a l . of t h e i r s y n t h e s i s o f f i v e - a n d s i x - m e m b e r e d n i t r o g e n h e t e r o c y c l e s by p a l l a d i u m - c a t a l y s e d a c e t a m i d e s . 166

c y c l i z a t i o n of N - a l l y l - i o d o -

The p y r r o l i d i n e l a c t o n e s ( 2 4 3 ) a r e formed i n good

y i e l d s by p a l l a d i u m - c a t a l y s e d

i n t r a m o l e c u l a r a m i n o c a r b o n y l a t i o n of

3-hydroxypent-4-enylamides ( 2 4 2 ) . 1 6 7 T h e r e a c t i o n i s h i g h l y s t e r e o s e l e c t i v e f o r f o r m a t i o n o f *-isomers a n d i n most c a s e s


508

Me

R(CH2)4NHS02Me

Me

Me

(230)

(231 1

Na2S208, CuC12

dNS02Me

HBr P h O H

(233 1

THF,ref lux PhN=CHPh

(237)

Aph

+

@NPh

H

Ph

Ph

(236)

R2 C u C l , MeCN D

or t R U C L ~ ( P P ~ ~ ) ~ I

I

R’ n = 1 o r 2

R’

(240)X = C I

I

Bu

nH

(241) X = H

509


equivalent results are obtained for both nitrogen substituents. Two other useful procedures for the generation of nitrogen heterocycles attack of a nitrogen nucleophile on an alkene unit have appeared. An ‘iodolactamization’ procedure has been reported which allows efficient conversion of substituted pentenamides into iodolactams. The key step is conversion of the starting carboxamide into the corresponding N,O-bis(trimethylsilyl) derivative prior to treatment with iodine. Thus, iodolactam (245) can be prepared from the 4-pentamide (244) in good yield: direct iodocyclization of (244) gives only the iodolactone (2461, as does the N-monosilylated derivative of (244). A new synthesis of cyclic nitrones (248) and (249) has been reported based upon Ag(1)catalysed cyclization of allenic oximes (247) (249) is too unstable to isolate but both (248) and (249) can be trapped in fair yields with a range of alkenes to afford cycloadducts (250). Danishefsky and his group have described a route to the aziridino-mitosenes which involves as one of the key steps a stereospecific double cyclization of (251) to (252) using gphenylselenophthalimide . 7 0 The formation of nitrogen heterocycles by N-acyliminium ion cyclizations and related processes continues to be a subject of interest to many groups. Several interesting new developments have appeared this year, mainly from Speckamp and co-workers who remain major contributors in this area. In addition to a review of nitrogen heterocycle formation by cyclization of N-acyliminium interm e d i a t e ~ ’full ~ ~ details have appeared of the group‘s earlier work on silicon-directed N-acyliminium cyclizations to produce pyrrolizidine, indolizidine, or quinolizidine ring systems. l 7 This methodology has now been extended to the synthesis of monocyclic systems ( 2 5 4 ) from ethoxyamide precursors (253). 172’173 For cyclization of propargyl-silanes, products are formed generally in good yields as mixtures of amide rotamers. When formic acid is used as solvent cyclization yields can sometimes be low owing to competing hydrolysis but this side reaction can be completely suppressed by using Et2A1C1 as Lewis acid. Allylsilanes also cyclize efficiently, in this case to give products generally as mixtures of cisand trans-isomers, although the pyrrolidine (255) is formed stereo-

’

specifically in 8 1% yield. 1 7 3 Overman and co-workers continue to report new applications of their tandem cationic aza-Cope rearrangement-Mannich cyclization route to nitrogen heterocyclic systems. Perhaps the nicest illus-


5 10

PdCI,. C u C l , CO, AcOH /AcONa ‘

I

R

X

(242)X = C 0 2 M e or S02ToI R = H,

Me

or

(243)

Ph

0

0

OSiMe, Me S i O T f

NH2

i ’ ‘2lTHF

3 E t 3N

~

i i , aq. Na2S03

I

(244)

(245)

0

I (246)

AgBF4,0 5- 1 equiv

OH

(247)n = 1 or 2

0(248)n = 1 (249)n = 2

(250)


NPSP

Me

NH2 \

r*T$1 51 1

-

OAc

OBn

SePh

Me

OMe

-- H

OMe Br

Br

(251)

J SePh

Me OMe

Me ,Si

\

----

-7 OEt

(CH2

HC02H or 1c

Et2AICI

O A R

(253) n = 1 o r 2 R = Me or OEt

(254)


5 12

t r a t i o n o f t h e s y n t h e t i c u t i l i t y of s u c h p r o c e s s e s i s t h e s y n t h e s i s of t h e h e x a h y d r o - l ~ - p y r r o l e [ 2 ~ 3 - d ] c a r b a z o l e (257).

This complex

h e t e r o c y c l i c system is formed i n q u a n t i t a t i v e y i e l d from t h e p r e c u r s o r (256) under mild c o n d i t i o n s and w i t h complete s t e r e o c o n t r o l . 174

Two r o u t e s t o f i v e - m e m b e r e d

n i t r o g e n h e t e r o c y c l e s from imines

v i a a [ 3 + 2 ] c o n s t r u c t i o n mode h a v e b e e n r e p o r t e d . -

Trost et al.

have used t h e b i f u n c t i o n a l reagent (258) t o prepare 2 - s u b s t i t u t e d

4-methylene-pyrrolidines

i n a s t e r e o c o n t r o l l e d m a n n e r . 34

(261

the first s t e p t h e allylstannane u n i t of

In

(258) adds cleanly t o

imines (259) i n t h e presence of boron t r i f l u o r i d e t o g i v e t h e intermediate adducts (260).

Palladium-catalysed

cyclization of

(260) then a f f o r d s (261) i n e x c e l l e n t y i e l d s d e s p i t e t h e unfavourable nature of the 5-endo-trig

geometry f o r r i n g closure.

In the

second r e p o r t , t h e p y r r o l i d i n e ( 2 6 2 ) h a s been p r e p a r e d i n two steps, again

via

a 5-endo-trig

cyclization.23

Only one example o f

t h i s r e a c t i o n as a r o u t e t o s u b s t i t u t e d p y r r o l i d i n e s h a s so f a r been r e p o r t e d , however, and t h e r e f o r e i t s g e n e r a l i t y r e m a i n s uncertain. P y r r o l i d i n e s (263) have been prepared

2an

unusual cyclization

mode, i n what c o n s t i t u t e s t h e f i r s t e x a m p l e s o f a n a n t i - M i c h a e l a d d i t i o n o f a c a r b a n i o n t o an a c e t y l e n i c amide.lc15

Amide s t a b i l i -

z a t i o n o f t h e d e v e l o p i n g a n i o n would r e q u i r e t h e f o r m a t i o n o f a n a l l e n e u n i t i n t h e six-membered r i n g and t h e s t r a i n a s s o c i a t e d w i t h t h i s p r o c e s s t h e r e f o r e m a k e s a n i o n s t a b i l i z a t i o n by t h e p h e n y l g r o u p a more f a v o u r a b l e p r o p o s i t i o n . Meyers and co-workers

have continued t h e i r s t u d i e s t o e x p l o i t

t h e synthetic p o t e n t i a l of a-lithio-formamidines d e s c r i b e d a n e f f i c i e n t s y n t h e s i s of 2 - a r y l p y r r o l i d i n e s and - p i p e r i d i n e s

(266).

a n d h a v e now

or 2 - h e t e r o a r y l -

Alkylation of formamidines

(264) g i v e s i n t e r m e d i a t e s (265) which c y c l i z e i n s i t u after cleavage of t h e amidine u n i t .

The a z a - W i t t i g r e a c t i o n h a s been

u t i l i z e d i n a general synthesis of heterocyclic vinylogous uret h a n e s and a m i d e s ( 2 6 8 ) . 177

Staudinger reaction of azides (267)

with triphenylphosphine gives t h e corresponding phosphinimines which c y c l i z e i n h i g h y i e l d t o g i v e p r o d u c t s ( 2 6 8 ) .

Eight-membered

r i n g s c a n a l s o b e f o r m e d by t h i s p r o c e d u r e b u t i n t w o s t e p s : t h e a z i d e is f i r s t reduced t o t h e primary amine which c y c l i z e s o v e r f i v e d a y s a t room t e m p e r a t u r e t o g i v e ( 2 6 8 ; Hindered l-aryl-pyrrolidines p r e p a r e d by a g a s - p h a s e ,

n=4),i n

and - p i p e r i d i n e s

38% y i e l d .

(271) have been

alumina-mediated r e a c t i o n of primary aro-


513

'1 HC02H ______)

Ph

A O E t

O A O E t

/Ph

Ph

/OSiBu'Me2

hV 300 nm)

Ph

PhC02 Ar

+ NH

++

PhCO,

' NH Ar

Ar

/

hydrolysis

Ar

(307)


525

MeOH

R’ = H o r a l k y l , Y =OMe or

R’

+Y

y2 95'1. e.e.1

/\

H

Z

0

N1

w

r

-

--

p

H

OCHzPh

(369)(3s : 3 R =10:1)

NccH2N OCH,Ph

(368)


5 34

imines is a well documented procedure but interesting new developments continue to appear. Overman has described a very useful method for the synthesis of 4-unsubstituted B-lactams (367) which makes use of his recently disclosed method for generating unsubstiN-(cyanomethyl)-amines.221 tuted imines from Treatment of the lithium enolate of' substituted esters (365) with !-(cyanomethyl)amiries (366) gives, in one step, B-lactams (367). A wide range of substituted esters are amenable to this procedure, including Eprotected a-amino-esters, and if the starting cyanoamine (366) is non-racemic the method provides a concise route to enantiomerically pure 3-amino- and 3-acylarnino-B-lactams.

The monocyclic B-lactam

(3691, for example, is formed from the (S)-cyanoamine (368) in 65% yield and 1O:l diastereoselectivity. Reaction of the dianion of ethyl (S)-b-hydroxybutyrate (371) with a range of imines continues to be employed by several groups as a route to 3-('l-hydroxyethyl)-2-azetidinones.

In a continuation

of their preliminary studies published last year, Hart et al. have now reported that reaction of the dianion of (371) with the imine (370) affords' a mixture of 6-lactams (372) and (373) which serve as useful precursors to the carbapenem system.222 Thus , 4-acetoxy-3(1-hydroxyethy1)azetidinone

(374), an intermediate in the synthesis

of thienamycin (3751, is available in good yield from (372) and

(373) via a straightforward reaction sequence. Essentially the same procedures have been employed by Cainelli et al. in their (376), except synthesis of the 3-[(~)-l-hydroxyethyl1azetidinone that inversion of the side-chain hydroxy-group from S to R configuration is undertaken at an earlier stage.223 The generality of the ester-imine cyclization route to 3-(l-hydroxyethyl)-2-azetidinones has been investigated by Georg and co-workers who have studied the reaction of the dianion of racemic ethyl-3-hydroxybutyrate (378) with non-enolizable N-arylaldimines (377).224 The trans-3-[(S)-l-hydroxyethyl]azetidinones (379) are generally formed as major products, although product ratios are dependent both upon the nature of the N-substituent and the precise reaction conditions. The presence of HEPA and higher reaction temperatures leads to cis-trans isomerization of the B-lactams. As an alternative procedure to the reaction of N-trimethylsilylimines with ester enolates Colvin et al. have now reported that silyl ketene acetals can be employed in a one-pot synthesis of &unsubstituted B-lactams. 225 Reaction of the ketene acetal ( 3 8 0 ) with the imine (381) in the presence of Zn12, and t-butyl alcohol


535

w T I

OSi+

1

i,LDA,-7045'C

-

N Si Me3

(370)

zlyph

I '

OH

C0,Et

ii, ButMe2SiCi,

*

I

OSi+ : I H H

'sit

NEt 3

Si+

I

(371)

I

(372) 16%

(373) 27'10

,i

i ,03 ii,Jones o x i d a t i o n iii, P b ( O A c I 4

OSi

+

I

(375)

I (376 1

R

MeCH(OLi)CH=C(OEt)(OLi)

(378)

*

xR 9+%" QHti

+

H

OH

OH

THF or HMPA

Ar

(377)

0 50 -95

\

Ar

Ole

0

\

Ar

5-5Oo/o

O

\ Ar 15 - 8 0 %

536


a s a weak p r o t o n s o u r c e , g i v e s B - a m i n o - e s t e r s cyclized i n s i t u t o N-unsubstituted

o f t h e r e a c t i o n m i x t u r e p r i o r t o work-up

w i t h MeMgBr.

t r a n s s e l e c t i v i t y is g e n e r a l l y observed. a d d i t i o n r o u t e t o t h e B-lactam

(382) which can be

a z e t i d i n o n e s ( 3 8 3 ) by t r e a t m e n t Moderate

The k e t e n e - i m i n e

cyclo-

system has been extensively s t u d i e d

o v e r r e c e n t y e a r s a n d s y n t h e t i c e f f o r t s a r e now m a i n l y d i r e c t e d towards t h e establishment of asymmetric r o u t e s t o s u b s t i t u t e d a z e t i d i n o n e s by t h i s p r o c e d u r e . chiral oxazolidinones B-lactarns

E v a n s e t al. h a v e s h o w n t h a t t h e

(384) react with N-benzylimines

(385) t o give

(386) i n g o o d y i e l d s a n d w i t h a h i g h d e g r e e o f s t e r e o -

c h e m i c a l c o n t r o l . 226

The c h i r a l o x a z o l i d i n o n e a u x i l i a r y c a n b e

e a s i l y r e m o v e d by a d i s s o l v i n g metal r e d u c t i o n t o f u r n i s h e n a n t i o merically pure azetidinones (387).

T h e same g r o u p h a s a p p l i e d t h i s

procedure t o t h e first enantioselective synthesis of t h e carbac e p h a l o s p o r i n n u c l e u s ( 3 8 9 ) from t h e c h i r a l o x a z o l i d i n o n e ( 3 8 8 ) by making u s e o f t h e a b i l i t y o f d i h y d r o a n i s o l e s t o act as B-keto-ester e q u i v a l e n t s ( S c h e m e 2 7 ) . 277

O p t i c a l l y a c t i v s cis-B-lactams

c a n b e p r e p a r e d i n m o d e r a t e y i e l d s from ' D a n e ' i m i n e ( 3 9 1 ) d e r i v e d from D - t h r e o n i n e . 228

(392)

salt (390) and t h e

The bulky t r i p h e n y l s i l y l

s u b s t i t u e n t is t h e b a s i s of t h e high d i a s t e r e o f a c i a l s e l e c t i v i t y of addition t o t h e imine (391).

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

a z e t i d i n o n e s h a s b e e n r e p o r t e d by P a l o m o a n d c o - w o r k e r s . 229 T r i m e t h y l s i l y l o x y a c e t i c a c i d s ( 3 9 3 ) h a v e been found t o react w i t h i m i n e s (394) i n t h e p r e s e n c e o f p h e n y l p h o s p h o r o d i c h l o r i d a t e a n d triethylamine t o give products (395) directly, thus obviating the n e e d for a n a d d i t i o n a l h y d r o x y - g r o u p sequence.

protection-deprotection

I n c a s e s w h e r e R=H i n ( 3 9 3 1 , m a j o r p r o d u c t s g e n e r a l l y

have cis-stereochemistry. F o u r i n t e r e s t i n g new p r o c e d u r e s f o r f o r m a t i o n o f m o n o c y c l i c B -

lactams

via N-C(4) or C(3)-C(4)

c l o s u r e have been r e p o r t e d .

Hanessian et a l . have demonstrated t h a t t h e imidazolylsulphonate g r o u p is a n e f f i c i e n t l e a v i n g g r o u p i n t h e r i n g c l o s u r e of s u b s t i t u t e d L-serine

d e r i v a t i v e s ( 3 9 6 ) t o g i v e B-lactams

x-

( 3 9 7 ) .230

C y c l i z a t i o n i n t h i s case p r o c e e d s w i t h o u t r a c e m i z a t i o n , e l i m i n a t i o n , or a z i r i d i n e f o r m a t i o n b u t f o r t h e c o r r e s p o n d i n g L t h r e o n i n e d e r i v a t i v e s a z i r i d i n e formation is t h e predominant pathway.

Miller a n d c o - w o r k e r s

observation t h a t B ,y-unsaturated

have a p p l i e d Ganem's earlier N-tosyl-amides

undergo bromine-

i n d u c e d o x i d a t i v e c y c l i z a t i o n t o t h e p r e p a r a t i o n of !-acyloxy-8-

l a c t a m s ( 3 9 9 1 from h y d r o x a m a t e s ( 3 9 8 ) . 2 3 1

The N-hydroxy-B-lactam

( 4 0 0 ) is a v a i l a b l e by t h i s p r o c e d u r e i n e x c e l l e n t o v e r a l l y i e l d .


HoMe +

R’ R2

R3CH=NSiMe3-

537

wH

R’ ZnIZ (1 equiv.)

R3

-----,

R* OSiMe3

MeOzC

R’

BJOHR

Z

u

R3 H

(1 equiv.)

Me02C

N-Znj

I

SiMe,

’

NH,

(382 1

J

MeMgEr

(

0 H % ( y 0-f N p R H

R

Ph

0

\ CH ,Ph

(384)

(385)

Ph

0 H

+

NCH,Ph

0

k0 9 N FH .

ph

H# R

NCH,Ph

0

( 3 8 6 ) 92-97

H

3 equiv.)

H

8-3

HZNwR (387)


538

(388) H

H

mo

BocH N

BocHN

!

vii,viii

0

CO,CH,

so Ph F 2r 3 c

OCH,Ph

/

J J

J

PhO

Scheme

ECHZ

I

27

E t OCOC I

+

OSiPh,

COZCH, Ph

COZCH, Ph

(390)

(391)

(392) Me

CO, C H Ph

539


i, RZCH= NR3, (394) PhOP(0)C121NEt3 ii,

H,O

OS0,-

N GN

RHNYoH - RHNY IrnSOpIm,

NaH/DME

0

0

OMe

OMe

RHN

0 OMe

(398)

(399)

(4001

540


A novel route to 3-acetylazetidinone-2,2-dicarboxylates (402) has been reported, based upon the reaction of aminomalonates (401) with diketene and subsequent cyclization using sodium ethoxide and iodine (Scheme 28).232 Protection of the acetyl group as the ethylene acetal, followed by partial decarboxylation and some straightforward synthetic manipulation provides access to the potentially useful intermediate (403). The phenyl thiolesters (406) are useful intermediates for carbapenem synthesis and are usually prepared from the corresponding 4-acetoxyazetidinones. Maruyama et al. have now reported an alternative synthesis of (406) which involves as the key step cyclization of the phenylthiopropargyl epoxide (404) to the 3,4-trans-azetidinone (405; R=H): no cisproduct is produced. 233 An interesting ring-contraction route to

N-substituted 8-lactams which may have relevance to penicillin biosynthesis has been reported by Procter and co-workers .234 Photolytic or thermolytic cleavage of the N-0 bond of tetrahydro1,2-oxazine-3,6-diones (4071, followed by decarboxylation, gives intermediate 1,4-diradicals (408) which close to form B-lactams (409), albeit in poor yields. Diradical intermediates analogous to (408) may be formed in the biosynthesis of isopenicillin N from tripeptide precursors. In a similar vein, Easton has published full details of the synthesis of 8-lactams by ring contraction o f isothiazolidinones, a reaction which may also be relevant to penicillin biosynthesis although via a mechanism involving ionic intermediates .235 Monocyclic 8-lactams (411), containing a sulphur substituent at C(4) can be formed in variable yields from thioimides (410) via a photochemical Norrish Type I1 mechanism involving y-hydrogen abstraction by the thiocarbonyl group.236 Ueda et al. have reported the first successful attempt to trap an unsaturated azetidinone (412) as a Diels-Alder adduct. 237 Reaction of 4-acetoxy-2-azetidinone (413) with siloxydienes (414), in the presence of zinc chloride, gives the displacement product (416) as the major component but low yields of cycloaddition products (415) are also obtained, making this a novel one-step synthesis of the carbacephalosporin framework from a monocyclic azetidinone precursor. Two other routes to the carbacepham system involving cyclization of monocyclic azetidinone intermediates have also appeared, Beckwith et al. have described a radical-induced ring closure of 4-phenylthioazetidinones (417) to afford cyclized products (418) and (419).238 No other cyclization products were


54 1

OH )(/COzEt

Scheme

&

General and synthetic methods

General and synthetic methods

General and synthetic methods., Volume 3