Organosulfur Chemistry, Volume 1: Synthetic Aspects

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Organosulfur Chemistry Synthetic Aspects

Editorial Advisory Board Dr D Bethell, Department of Chemistry, University of Liverpool, Liverpool, UK

Professor SV Ley, Department of Chemistry, University of Cambridge, Cambridge, UK Professor LA Paquette, Department of Chemistry, Ohio State University, W 18th Avenue, Columbus, Ohio 43210, USA Professor G Solladi6, Ecole Europeenne des Hautes Etudes des Industries

Chimiques de Strasbourg, 1 rue Blaise Pascal, Boite Postale 296F, 67008 Strasbourg Cedex, France Professor RJK Taylor, Department of Chemistry, University of York, York, UK Professor BM Trost, Department of Chemistry, Stanford University, California 94305-5080, USA

Organosulfur Chemistry Synthetic Aspects

edited by

Philip Page

Department of Chemistry University of Liverpool Liverpool, UK

ACADEMIC PRESS

Harcourt Brace & Company

London San Diego New York Boston Sydney Tokyo Toronto

ACADEMIC PRESS LIMITED 24-28 Oval Road LONDON NW1 7DX

U.S. Edition Published by ACADEMIC PRESS INC. San Diego, CA92101

This book is printed on acid free paper

Copyright 9 1995 ACADEMIC PRESS LIMITED

All rights reserved No part of this book may be reproduced or transmitted in any form or by any means, electronic or mechanical including photocopying, recording, or any information storage and retrieval system without permission in writing from the publisher

A catalogue record for this book is available from the British Library

ISBN 0-12-543560-6

Cover illustration reproduced with permission from A History of Technology, Volume 2, 1956 edited by C. Singer et al., published by Oxford University Press.

Typeset by Mackreth Media Services, Hemel Hempstead Printed in Great Britain by Hartnolls Ltd, Bodmin, Cornwall

Contents vii

Contributors Preface

Optically Active p-keto Sulfoxides and Analogues in Asymmetric Synthesis Guy Solladi~ and M. Carmen Carreffo 1.1 1.2 1.3 1.4 1.5 1.6

Introduction Homochiral sulfoxide preparations: the Andersen approach Stereoselective reduction of p-keto suifoxides Application of the p-keto sulfoxide reduction to total synthesis Diels-Aider reactions of aikenyi sulfoxides as dienophiles Diels-Alder reactions of sulfinyldienes

Homolytic Processes at Sulfur

1

2 7 18 25 42

49

David Crich 2.1 2.2 2.2.1 2.2.2 2.2.3 2.3 2.3.1 2.3.2 2.3.3 2.3.4 2.3.5 2.4 2.4.1 2.4.2

Introduction Reactions of sulfur-centred radicals Thiyl radicals Sulfinyl radicals Sulfonyi radicals Generation of alkyi radicals from organosulfur groups From thiols From sulfides From alkyi aryl sulfides From suifones From thiocarbonyl groups Formation of carbon-sulfur bonds by reaction of carbon-centred radicals with sulfur functional groups SH2 at sulfur Addition to thiocarbonyl sulfur

Synthetic Transformations Involving Thiiranium Ion Intermediates

49 50 50 64 64 72 72 73 74 76 76 79 79 81

89

Christopher M. Rayner 3.1 3.2 3.3 3.4 3.4.1 3.4.2 3.4.3 3.4.4 3.4,5

Reviews General considerations Synthesisof thiiranium ions Reactionsof thiiranium ions Halide nucleophiles Carbon nucleophiles Oxygen nucleophiles Nitrogen nucleophiles Sulfur nucleophiles

89 90 93 94 94 97 112 118 124

3.4.6 3.5

Miscellaneous transformations Summary

Trends in the chemistry of 1,3-dithioacetals

125 127

133

William W. Wood 4.1 Introduction 4.2 Applications of 1,3-dithioacetals in biological effect molecules 4.2.1 1,3-Dithioacetals in pharmaceuticals 4.2.2 1,3-Dithioacetals in crop protection compounds 4.3 Synthesisof 1,3-dithioacetals 4.3.1 Synthesesof 1,3-dithioacetals and precursors from carbon disulfide 4.3.2 Synthesesfrom carbonyl compounds and dithiois under acid catalysis 4.3.3 Synthesesusing pre-activated thioacetalation reagents 4.3.4 Synthesesusing supported thioacetalization catalysts and reagents 4.3.5 Synthesesby other methods 4.4 Chemistry of 1,3-Dithioacetals 4.4.1 Chemistry of anions derived from 1,3-dithioacetals 4.4.2 Reactionsof lithiated 1,3-dithioacetals with organometailic complexes 4.4.3 Diastereoselective reactions about 1,3-dithioacetals 4.4.4 Radicalreactions of 1,3-dithioacetals 4.5 1,3-dithioacetal as a functional group 4.5.1 Regenerationof carbonyl compounds from 1,3-dithioacetais 4.5.2 Synthesisof dithiins from 1,3-dithioacetals 4.5.3 Reduction of 1,3-dithioacetals to methylene and reductive alkylation 4.5.4 Conversion of 1,3-dithioacetals to gem-difluorides 4.5.5 Conversion of 1,3-dithioacetals to compounds containing one C-S bond Conclusion

Chemistry of Thioaldehydes Renji Okazaki Introduction 5.1 Transient thioaldehydes 5.2 Generation by photoreactions 5.2.1 Generation by 1,5-sigmatropy of thiosulfinates and thioseleninates 5.2.2 Generation by 1,2-elimination reactions 5.2.3 Generation by thermolysis 5.2.4 Spectroscopic detection 5.2.5 Stable thioaldehydes 5.3 Synthesis 5.3.1 Physical, structural and spectroscopic properties 5.3.2 Reactions 5.3.3

133 134 136 138 143 144 146 157 163 170 171 171 173 177 186 191 191 202 208 209 216 217

225 225 226 227 229 231 236 240 242 243 244 246

Author index

259

Subject index

269

vii

List of Contributors M. Carmen Carrefio, Universidad Autonoma, Departmento de Quimica, 28049, Madrid, Spain.

David Crich, Department of Chemistry (M/C 111), University of Illinois at Chicago, Box 4348, Chicago, Illinois, U.S.A. Renji Okazaki, Department of Chemistry, School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113, Japan.

Christopher M. Rayner, Department of Chemistry, The University of Leeds, Leeds LS2 9JT, U.K. Guy Soiladi~, Ecole Europeenne des Hautes Etudes des Industries Chimiques, F-67008, Strasbourg, France. William W. Wood, Shell Research Ltd., Sittingbourne Research Centre, Sittingbourne, Kent ME9 8AG, U.K.

This Page Intentionally Left Blank

Preface Over the last few years, the impact of organosulfur chemistry, especially in the areas of heterocyclic chemistry, stereocontrolled processes and the production of nonracemic materials, has led to an explosion of interest in the field and a rapidly growing number of related publications. While a number of specialist publications continue to appear, there is a clear need for considered, forward looking reviews across the field. This book is the first of a new series intended to provide coverage of topics of current interest throughout the whole range of organic sulfur chemistry, including bio-organic and physical organic topics, in addition to synthetic ones. Each volume will contain several articles, each consisting of an in-depth self-contained review in a well-defined area. This first volume begins with a survey by Professor Guy Solladid of the preparation of chiral [3-ketosulfoxides and analogues and their applications as stereocontrol elements in organic synthesis, principally the stereocontrolled reduction of [3-ketosulfoxides, and the stereocontrolled Diels-Alder reaction of vinyl and dienyl sulfoxides. This is followed by a review of homolytic processes at sulfur by Professor David Crich, covering the reactions of sulfur centred radicals, the generation of alkyl radicals from organosulfur compound and carbon-sulfur bond formation by reactions of carbon centred radicals with sulfur functional groups. Synthetically useful reactions of thiiranium ion intermediates are discussed thoroughly by Dr Christopher Rayner, and recent developments in the preparation and chemistry of dithioacetals, including their applications in biological effect molecules, are reported in a detailed review by Dr William Wood. In the final chapter, Professor Renji Okazaki summarizes the generation, properties and chemistry of stable and transient thioaldehyes. Offers of articles for consideration for inclusion in future volumes will be appreciated and should be sent to the editor, who would also welcome any comments from readers on the present volume.

Philip Page

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CHAPTER 1

OPTICALLY ACTIVE 13-KETO SU LFOXI DES AN D ANALOGUES IN ASYMMETRIC SYNTHESIS Guy Solladi~ Ecole Europ~enne des Hautes Etudes des Industries Chimiques, F-67008, Strasbourg, France

and

M. Carmen Carrefio Universidad Aut6noma, Departamento de Quimica, 28049, Madrid, Spain

CONTENTS 1.1 Introduction 1.2 Homochiral suifoxide preparations: the Andersen approach 1.3 Stereoselective reduction of [3-keto sulfoxides 1.4 Application of the [3-keto sulfoxide reduction to total synthesis 1.5 Diels-Aider reactions of alkenyl sulfoxides as dienophiles 1.6 Diels-Alder reactions of suifinyldienes References

1.1

1 2 7 18 25 42 44

INTRODUCTION

During the last decade, organic sulfur compounds have become increasingly useful and important in organic synthesis. Sulfur, incorporated into an organic molecule, stabilizes negative charges on an adjacent carbon atom, a property which has been especially important in the development of new ways to form carbon-carbon bonds. With respect to sulfides and sulfones, the sulfoxide group is of special interest due to its chirality and to the presence of three different kinds of ligands from the steric and stereoelectronic points of view: the lone pair of electrons, the oxygen atom and two aryl or alkyl groups, which give a special efficiency to sulfoxides in asymmetric synthesis. Most of the reviews published on the application of the chiral sulfoxide group in asymmetric synthesis are based on the reactivity of e~-sulfinyl carbanions or Michael additions to vinylic sulfoxides [1-5]. This chapter is limited to asymmetric synthesis from [3-keto sulfoxides and analogues, largely excluding ~-sulfinyl carbanions. The Andersen method for homochiral sulfoxide preparation is reviewed in detail, as well as the asymmetric ORGANOSULFURCHEMISTRYCopyright 91995 Academic PressLtd. ISBN-0-12-543560-6.All rights of reproduction in any form reserved.

2

GuY SOLLADII~AND M. CARMEN CARREIXlO

reduction of [3-keto sulfoxides and Diels-Alder additions of vinylic [3-keto sulfoxides and analogues. Several applications for the total synthesis of natural products are also described.

1.2 HOMOCHIRAL SULFOXIDE PREPARATIONS: THE ANDERSEN APPROACH Until now, optically active sulfoxides have been obtained in many different ways: by optical resolution, asymmetric synthesis, kinetic resolution and stereospecific synthesis. Optical resolution has been achieved, since the pioneering work of Harrison et al [6], by means of an acidic or basic group present in the molecule. The total resolution of ethyl p-tolyl sulfoxide was also achieved in 1966, through the formation and separation of the diastereoisomeric complexes with trans-dichloroethylene platinum(II) containing optically active ~-phenylethylamine as a ligand [7]. The more recent work on optical resolution has been thoroughly reviewed by Mikolajczyk [8]. Asymmetric oxidations of sulfides with optically active peracids was first reported by Montanari [9] and Balenovic [10]. However, they reported a low optical purity, generally not higher than 10%. More recently, Kagan [11] reported that high enantioselectivities could be obtained with a modified Sharpless reagent [Ti(O-Pri)4/DET/ButOOH/H20]; ee values in the range 80-90% were obtained in the case of simple alkyl aryl sulfides. Enzymatic oxidation of sulfides also gives very good results in a few cases [8, 12]. This approach, as well as a new method starting from cyclic disulfides [13], will be reported by H. Kagan in this book. However, all these methods, which give good results with specific substrates, are not yet general enough. The great achievement of the stereochemistry of organosulfur compounds was the stereospecific synthesis of optically active sulfoxides, originally proposed by Gilman [14a], and developed later by Andersen [14b]. This approach to sulfoxides of high optical purity ~ still most important and widely used ~ is based on the reaction of the diastereoisomerically pure (-)-(S)menthyl-p-toluenesulfinate [21] (1) with Grignard reagents. (+)-(R)-Ethyl p-tolyl sulfoxide (2) was the first optically active sulfoxide obtained by this method [14b]. (Scheme 1.1). 0

II

.....,~ S .. p-Tol O m e n t h y l

0

II

EtMgI ~

(-)- (S)- ( 1 )

,,,,~,S " Et "

p-Tol

(+)- (R)- (2)

Scheme 1.1

The reaction proceeds with complete inversion of configuration at sulfur. This was demonstrated by chemical correlation [15-17] and optical rotary dispersion

OPTICALLY ACTIVE [3-KETO SULFOXIDES AND ANALOGUES IN ASYMMETRIC SYNTHESIS

3

studies [15, 17-20]. A Cotton effect was observed between 235 and 255 nm for alkyl aryl sulfoxides and near 200 nm for dialkyl sulfoxides, characteristic of the absolute configuration at sulfur. The absolute configuration of ( - ) - m e n t h y l p-toluenesulfinate was previously established [18] by correlation with ( - ) - menthyl (-)-p-iodobenzenesulfinate by X-ray diffraction analysis [20]. The Andersen sulfoxide synthesis is general in scope and can be applied to the synthesis of complex homochiral sulfoxides, as will be shown later. However, a major drawback in this reaction is the obtainment of optically pure ( - ) - ( S ) - m e n t h y l p-toluenesulfinate (1). In the numerous examples reported by Andersen [14b, 19, 22], Mislow et al. [18, 20, 23] and others [15, 16, 24], ( - ) - ( S ) - ( 1 ) was obtained from the reaction of 1-menthol with p-toluenesulfinyl chloride followed by fractional crystallization of the mixture of the two diastereoisomers. This esterification reaction showed no particular stereoselectivity, giving a 1:1 diastereoisomeric mixture. We have been able to improve this process and avoid the fractional crystallization of the diastereoisomers by using the acid-catalysed epimerization of sulfinates. Philipps [25] reported in 1925 that 1-menthyl l-ptoluenesulfinate underwent mutarotation very slowly. It was shown later [26] that this was the result of catalysis by p-toluenesulfinic acid and that this epimerization could indeed be catalysed by hydrogen chloride [28]. In 1964 it was shown [23] that o II Ar--S--R

HC1 -~ -.

@ Ar--S--R I

C1 [ Ar-- S--R

~

H20 -_ Ar--S--R II O

I

C1

C1

+ C12

Achiral Scheme 1.2

sulfoxides are also rapidly and cleanly racemized at room temperature by HC1 in organic solvents such as benzene, dioxan or THF. Kinetic studies and 180 labelling experiments on sulfoxides [28] and sulfinate esters [29] confirmed the mechanism proposed for such experiments (Scheme 1.2). O

O II

(i) SOCI2

II

At./S ~ONa

(ii) menthol-" pyridine

o

[I

HC1

"......'"'4S~Omenthyl hE

('-)- (S) 90% yield Ar = p-tolyl

<

O II

. , , 2 s "Omenthyl Ar

c1 At',,. J -~ ....... S, ~ Omenthyl ",

4,, I

Ar2S - Omenthy 1

o H20 II ~ -~ A,-"") S

.-/ e,

C1 crystallization acetone, HC 1 Scheme

+

1.3

o menthyl

(+)-(R)

4

GuY SOLLADII~ AND M. CARMEN CARRENO

Therefore, starting from the mixture of (R)- and (S)-menthyl p-toluenesulfinate, we have been able to equilibrate the two diastereoisomers in acidic medium and displace the equilibrium towards the less soluble isomer within a few days. In this way, a 90% yield was obtained [30]. This epimerization process can be performed on large quantities of product [31] (Scheme 1.3).

O ]1/@~ Ar,,,,,,2S 9. O O~i i/ It Ar,,,,,...jS P(OMe)2

/

O ") II . ......,,S Ar " ~

R2 R39b]~=CH3 [

42]~ (MeO)2P(O)CH2UX\

""

RMgX l14b, 31, 22] RCH2 MgX

-\

O II

R@ M g B r

Ae"7 S@ R

"-"

[38, 39a]

(6)

o

0

II ..~,S,,o_menthyl Ar (-)-(S)

; ......

LPhSCH2Li 137] O

R ""~....MgBr~..J/~ [40,41]

tt

At" .... S

H2,

R

RhC1(PPh3) 140, 411

O II Ae,,'2S \_--..~/ 9. (7)

C 2 sII 9

R

l C1 NCS, K2CO3 [341

0 It Ar"2S- ~'R

(8)

RCHO [ [421

9.

RI

SPh

(5)

CH3COzBut (pri)2NMgBr [351

~

O II Arl,,~,S " ~ / R

O II ,.... V Ar'~ 'S "" (3)

CO~.But

~.~ " ~ ~iCH2CONMe2 3 6 ]

O II "~/CONMe2 Ar'2S. (4)

Ar = p-tolyl

R

Scheme 1.4

The reaction of arenesulfinates with Grignard reagents is usually carried out in ethyl ether solution. However, in this solvent, chiral sulfoxides are formed in moderate or low yields, depending upon the structure of both the sulfinic ester and the Grignard reagent. Harpp [32] carried out detailed studies on this reaction and reported that the reaction conditions must be carefully selected, otherwise considerable quantities of impurities, which are difficult to separate, are formed. He also found that the use of lithium cuprates instead of Grignard reagents gives a cleaner conversion of sulfinates to sulfoxides but with moderate yields (16-59%). Mikolajczyk [33] reported later that chiral sulfoxides of greater chemical and optical purity are obtained in higher yields when the reaction of menthyl sulfinate

OPTICALLY ACTIVE [3-KETO SULFOXIDESAND ANALOGUES IN ASYMMETRICSYNTHESIS

5

with Grignard reagent is carried out in a benzene solution. However, the application of this reaction to large-scale experiments is not straightforward because of the difficult separation of menthol from the resulting sulfoxide, usually requiring purification by chromatography. We found [31] that the separation of menthol could be performed by an appropriate change of solvent and reported a large-scale procedure for the preparation of optically pure methyl p-tolylsulfoxide. A great variety of sulfoxides have been prepared by this method (Scheme 1.4). Besides alkyl and aryl p-tolyl sulfoxides, sulfinyl esters (3) can be easily obtained by condensation of the magnesium enolate of esters [35] as well as sulfinyl amides (4) from lithiated tertiary amides [36]. Lithiated anions a to sulfides also react cleanly with the menthyl sulfinate (1) to give the corresponding optically pure sulfinyl sulfides (5) [37]. Homochiral vinylic sulfoxides (6) in the (E) configuration were also prepared [38, 39a] from vinylic Grignard reagents and the menthyl sulfinate (1). Both (E)-(6) and (Z)-(7) were readily obtained in a stereocontrolled manner and in two steps from acetylenic Grignard reagents followed by hydride or catalytic reduction of the triple bond [40, 41]. Finally, (E)-vinylic sulfoxides (6) can also be obtained in two steps using the Wittig-Horner type condensation of optically active sulfinyl phosphonates on aldehydes [42]. We have also recently reported a method giving (E)-l,3-butadienyl sulfoxides by a condensation-elimination sequence from lithiated methyl p-tolyl sulfoxide and e~, [3-unsaturated aldehydes [39b]. Cyclic vinylic [3-keto sulfoxides (9), (10) were also prepared [43] in enantiomerically pure form by attack of the corresponding functionalized o

~~ffffff Br

(

o

n n = 1,2

o

(i) Mg

~ .........: NAt

(ii)

o II ..,,,,,,.~,S ~O-menthyl Ar (iii) SO4Cu acetone

(

n

(9) n -- 1 (10) n = 2 o

OTBS ~

"('t4~_

Li

(S)-(l)

,,

OT~3S~

II

S .

('t~_4 ~,,A~. (i) B F 4

0 o

(Ar = p-tolyl)

0 II S

"',,,111 9

\~

(11 ) n = 5, 6 Scheme 1.5

--

(ii) MeLi, CO2 (iii) H +

6

GuY SOLLADII~AND M. CARMENCARREt~O

organometallic reagent on menthyl p-toluenesulfinate (1) (Scheme 1.5). In spite of their structural similarity, sulfinyl alkenolides (11) [44] had to be synthesized by a different route, also based on the Andersen synthesis of an acyclic vinylic sulfoxide which is further transformed into the lactone (11). In a complementary fashion, Lewis acid catalysis has been used successfully in the reaction of cycloalkanone enol silyl ethers with sulfinate esters to [3-keto sulfoxides (12) in good enantiomeric purity (Scheme 1.6) [45]. O

0

OSiMe 3

0

~'BF3 ' Et20

.,,,,,~ S \ OMe +

Ar

)

n-5

0~ n=5,6,7 (12)

(Ar = p-tolyl)

' )-5

90- 95% yield, 86- 89% ee Scheme 1.6

However, in the article by Hiroi et al. [45], there is no mention of the diastereoisomeric ratio resulting from the reaction. We have shown later [46, 47] that it was possible to carry out the direct condensation of cycloalkanones with menthyl ptoluenesulfinate in the presence of diisopropyl aminomagnesium bromide to give the cyclic [3-keto sulfoxides (12) without any epimerization at sulfur. In the case of cyclohexanone, the yield was 75% of a 75:25 (S2Rs):(R2Rs) diastereoisomeric mixture (Scheme 1.7). Similar results were obtained from cycloheptanone: 68% of a 72:28 (S2Rs):(RzRs) diastereoisomeric mixture which can be readily isomerized o benzene

.

..O O

iPri2NMgBr.o menthy (ii)

O

9 1t111111""

($2 Rs)

yield % 24% 75% 68%

n

1 2 3

(R 2 Rs)

(SzRs) 75 75 72

( tl o

(i) LDA (ii)

O

n

S

Ar'd'

Ph ~N

+

(t-,~

O

II

9 iiiiiiit"~ S

~O-menthyl

Ar

(RzRs) 25 25 28 o S

...... Iii

9

n = 1, 72% yield n = 2, 73% yield n = 3, 83% yield

n

(Ar = p-tolyl) Scheme 1.7

""

OPTICALLY ACTIVE I~-KETO SULFOXIDESAND ANALOGUES IN ASYMMETRIC SYNTHESIS

7

to give the pure (S2Rs) isomer in the presence of sodium hydroxide. In the case of cyclopentanone, yields are poor because of the competitive self-condensation of the ketone. This inconvenience was circumvented by carrying out the condensation with N-phenylcycloalkylidene imines, which reacted in the presence of LDA with (1), giving after hydrolysis good yields of diastereoisomeric [3-ketosulfoxides in a virtually enantiomerically pure form [47]. Finally, we have shown very recently [48] that dianions of 1,3-diketones also react with menthyl p-tolylsulfinate (1) to give in high yields the corresponding sulfinyl-2, 4-diketones (13) (Scheme 1.8).

0 ~,.,,~

0

R

0

LDA, THF _-. O ~ C , 2 equiv .

R

0 |

_78o C R

II

9

iw,,

" J

S

O

Oii

S~A} ~

"

0

|

(1) R = CH 3 (2) R = Ph

OH

" O menthyl

p-Tol

~

(13) R = CH3, 90% yield R = Ph, 80% yield

( - ) - (S)

(Ar = p-tolyl)

Scheme 1.8

1.3

STEREOSELECTIVE REDUCTION OF [3-KETO SULFOXIDES

Since the pioneering work of Corey [49], who was the first to prepare racemic [3keto sulfoxides from the anion of dimethyl sulfoxide and esters, numerous racemic [3-keto sulfoxides have been synthesized and widely used in organic synthesis. However, Kunieda et al. [50] were the first to prepare (+)-(R)-o~-(ptolylsulfinyl)acetophenone from (+)-(R)-methyl p-tolyl sulfoxide and ethyl benzoate and to report its reaction with alkyl Grignard reagents, leading to a mixture of diastereoisomeric alcohols in a 7 : 3 ratio. Using this general synthetic procedure (Scheme 1.9), Annunziata and Cinquini [51] prepared several [3-keto sulfoxides and studied the stereoselectivity of the ketone reduction. O II ........ s ~ ffV

(i) LiNEt, CH3

O

O

(ii) RCO2Et

,

(+)-(R)

(+)-(R)-(14) R = Ph, Et, Pr t, Bu t 62 - 82% yield

Scheme 1.9 Another possible synthesis of chiral p-tolylsulfinyl methyl ketone was reported

8

GuY SOLLADII~ AND M. CARMEN CARRENO

by Schneider [52]" decarboxylation of optically active sulfinyl esters obtained from menthyl p-toluenesulfinate (1) and the dianion of methyl acetoacetate (Scheme 1.10). 0 11 ........' J ; ' S " Omenthyl + Ar (-)-(s)

0 H 3 ~ C R

0

CO2Me

0

........ SII

Nail, BuLi THF, _40oc

j~

A~.~ 9

C02Me R

(i) KOH, MeOH (ii) HC1, CH2C12 O

O

II

(Ar = p-tolyl)

(+)-(R) Scheme 1.10

The stereoselectivity of the reduction of [3-keto sulfoxides (14) was first investigated by Annunziata and Cinquini [51] with sodium borohydride and lithium aluminum hydride at - 7 0 ~ C. They determined the de by 1H nuclear magnetic resonance (NMR) without the identification of the main diastereoisomer. The results, reported in Table 1.1, show that the extent of asymmetric induction was in the range 60-70% with LiA1H4, and lower with NaBH4.

o

II

9

II.../k

0

o ,,

R

........ S 9

(14)

OH

(15)

(Ar = p-tolyl) Scheme 1.11

Were reinvestigated [53] this reduction process with many different reducing TABLE 1.1

Reduction of [3-keto sulfoxides (14) by NaBH4 and LiA1H4

de(%) R

LiAIH4

NaBH4

Ph Et Pri Bu t

60 68 66 63

20 58 50 40

OPTICALLYACTIVE[3-KETOSULFOXIDESAND ANALOGUESIN ASYMMETRICSYNTHESIS

9

agents. The diastereoselectivity was determined by NMR from the AB pattern displayed by the methylene protons oL to the sulfoxide group. The absolute configuration of the main diastereoisomer was determined by chemical correlation with known methyl carbinols after desulfurization (Scheme 1.12). 0

Me

R_< ~

OH

0

II S

.,,elll!

'~Ar

9

Ar

LDA ( Ar = p-tolyl )

OEt

H

/

(14)

..

..

(S,R)- (15)

(R,R)-(15)

J RlmeyNi

I RaneyNi

R"I'~CH3H OH

RH~~oHCH3 Scheme 1.12

As shown in Table 1.2, we, of course, obtained the same results as Annunziata with LiA1H4 and NaBH4. However, with diborane and diisobutylaluminum TABLE1.2

Reduction of [3-keto sulfoxides (14) at -78 ~ C

Reducing agent

Solvent

(R,R)-(15)/(S,R)-(15)

NaBH4 NaBH4 LiBH4 (Bun)4NBH4 LiAIH4 LiEt~BH

Et20/1-HF EtOH Et20/THF Et20/1-HF Et20/THF THF

69/31 80/20 81/19 85/1 5 84/16 80/20

Li(Bus)~BH Zn(BH4)2 Zn(BH4)2 Me2S,BH3

THF Et20/THF EtOH THF

66/34 66/34 60/40 53/47

B2H6,THF (Bu')2AI

THF THF

30/70 22/78

10

GuY SOLLADII~ AND M. CARMEN CARREIxlO

(DIBAL), we observed a reverse asymmetric induction with respect to LiA1H4. Sodium, lithium, tetrabutylammonium borohydride as well as LiA1H4 gave mainly the (R,R) diastereoisomer (about 60% de), which indicated that the cation was not playing an important role in the control of the stereochemistry. On the other hand, diborane and DIBAL gave mainly the (S,R) diastereoisomer (60% de with DIBAL). Other reducing agents such as lithium tri-s-butyl borohydride, zinc borohydride and the borane-methyl sulfide complex showed a lower ste reose le ctivity. Later on [54] we found that in many cases the diastereoselectivity was significantly increased by adding DIBAL at - 7 8 ~ C to the [3-keto sulfoxide solution (method B) instead of adding the [3-keto sulfoxide solution to DIBAL (method A) (Table 1.3). Moreover, we found [54], simultaneously with Kosugi et al. [55], that the addition of DIBAL to a [3-keto sulfoxide THF solution containing one equivalent of anhydrous zinc chloride at - 7 8 ~ C gave a reverse stereoselectivity with a very high de (Table 1.3). Therefore, these results show that it is possible to reduce [3-ketosulfoxides with the appropriate reducing agent (DIBAL) or (ZnC12/DIBAL), with a very high diastereoselectivity into the corresponding diastereoisomeric (R,R)- or (R,S)-f3hydroxy sulfoxides, which are extremely useful synthons in organic synthesis. Both enantiomers of methylcarbinols [53], allylic methyl carbinols [56], epoxides [54, 55] and lactones [55] were prepared following this methodology (Scheme 1.13). Disulfurization of [3-hydroxy sulfoxides was easily carried out with Raney nickel. However, in the presence of an ethylenic linkage the desulfurization has to be done with lithium in ethylamine, thus allowing a good synthesis of chiral allylic TABLE

1.3 Reduction of [3-ketosulfoxides (14) at -78 ~ C

R

Reducing agenta

(R,R)-(15)/(R,S)-(15)

Yield (%)

Ref.

Ph

DIBAL, A DIBAL, B LiAIH 4 DIBAL, ZnCI2 DIBAL, ZnCI2

20/80 >5/95 80/20 >95/5 >99/1

95 95 80 90 80

[54] [54] [54] [55] [55]

Ph(CH2)2

DIBAL, A DIBAL, B LiAIH4 DIBAL, ZnCI2 DIBAL, B DIBAL, ZnCI2 DIBAL, B DIBAL, ZnCI2 DIBAL,ZnCI2 DIBAL,ZnCI2 DIBAL, ZnC[ 2

13/87 7/93 88/12 >95/5 5/95 >95/5 5/95 >95/5 99/1 97/3 >99/1

98 95 90 95 95 92 95 95 78 93 80

[54] [54] [54] [54] [54] [54] [54] [54] [55] [55] [55]

n-CsH17 n-C13H27 ButO2C(CH2)3

ButO2C(CH2)2 C2H 5

A--method A, addition of the [3-ketosulfoxide solution to DIBAL; B--method B, addition of DIBAL to a [3-ketosulfoxide solution.

OPTICALLY ACTIVEP-KETO SULFOXIDES AND ANALOGUES IN ASYMMETRIC SYNTHESIS

0

0

11

OH

DIBAL

Raney Ni Me

R ( Ar = p-tolyl)

R = Et. Ph, n-C,H,,

(R,S)-(15) (i) LiAIH, (ii) Me,OBF, (iii) 5% HONa

ZnCI,, DIBAL

v

(9

R = Ph, n-C,H,,, n-C,,H,,

v 0

R (R.R)-(15)

(i) Zn, Me,SiCl, pyridine, THF (ii) Me,OBF, (iii) 5% NaOH

(i) Raney Ni ( i i ) p-TsOH

(R)

I

(ii) TsOH

Scheme 1.1 3

alcohols. For the epoxide preparation, the sulfoxide was reduced to sulfide either with LiAIH, [54] or Zn-Me,SiC1 [55], and ring closure was carried out in the presence of a base from the corresponding sulfonium salt. Optically active 4-substituted butenolides were also obtained from Phydroxysulfoxides [57].The synthesis of one enantiomer is shown in Scheme 1.14. After the reduction step, the alkylation was carried out on the dianion of the hydroxysulfone with sodium iodoacetate, and then the molecule was lactonized with a catalytic amount of p-toluenesulfonic acid and desulfonylated in presence of triethylamine. Chiral P-sulfinylcyclohexanones (16) also underwent a stereoselective reduction [58, 591. As shown in Scheme 1.15. reduction with DIBAL of (S2,R,)-(16a) gave sulfoxide (17), while the reduction of the other only the trans-(S,,S,,R,)-P-hydroxy diastereoisomer, (RZ,R,)-(16b). led only to the cis-(S,,R,,R,) isomer (17). With

12

GuY SOLLADII~AND M. CARMEN CARREIxlO

0

II

Me/S~

0 R9 - - ~ OEt

O

II

O

0

ZnC12, DIB AL

LDA

OH

s

80% vielc(

R

(R,R)

9

( Ar = p-tolyl )

R

m-CPB A, 95% yield (i) BuLi (ii) ICH2CO2Na (iii) TsOH (iv) Et3N 50% yield

v

OH

S02~~'x

R

R = Bu t C8H,7, CsH,,

Scheme 1.14

ZnC12/DIBAL, the diastereoselectivity was lower: 80% de from (16a) and 72% de from (16b). oo

o.

DIBAL S ~ Ar 'q DIBAL

$2, Rs)-(17) 80% de

Cis-(R1,

S~A r

/ / ~ ~ ~ S _ OH

"~//

trans-(S l, S 2, Rs)-(17)

(Sz, Rs)-(16a) (Ar = p-tolyl) DIBAL

~ ~

I

Ar trans-(R l, R 2, 8s)-(17) 72% de

O ~

I

Ar

(R2, Rs)-(16b)

~hr

S/ 9

IOH Ar

9

R 2, Rs)-(17) >95% de

C i s - ( S I,

Scheme 1.15

The stereoselectivity of these reductions was first explained [54, 59] by an intramolecular hydride transfer in the case of DIBAL and an intermolecular one from a zinc chloride-chelated 13-keto sulfoxide in the case of ZnC12/DIBAL reduction, both controlled by steric and stereoelectronic effects. However, recent results [60] have afforded important information about the reaction mechanism of the ZnClflDIBAL reduction. We found that only a catalytic amount (0.05-0.1 equivalent) of zinc chloride was necessary for the reaction. This result allowed us to postulate an intramolecular hydride transfer and not an intermolecular one, assuming that the DIBAL approach was C-1 directed as shown in Scheme 1.16. The ZnC12-chelated ~-keto sulfoxide adopts the favoured twisted confirmation C1 where the p-tolyl group is pseudo-equatorial, the absolute configuration at sulfur being (R). In the early stage of the reaction, the approach of

OPTICALLY ACTIVE [3-KETOSULFOXIDESAND ANALOGUESIN ASYMMETRICSYNTHESIS

O

:f

oo

O

p_Tol "~IS/~

v

//~

I

p-Tol ....

-R1 f/ _ _

/--

R

C1 /

.~

Zn

---

\

//R,-~ C,

""

13

O

~C1

/

DIBAL

I ZnCI2 R

p-Tol ......~, S ~ _

R~"

[

~,,

"o~'~R

---

~0 /

p-Tol

......... C1

"T S I ,,'::

/

I

C1

M l (R = Bu i)

H

............

/~

7--

~..,.~ /

/

C1

------- ,,0.......... Zn

\ s'4,. ,' / -:=

\

C1

!

/o\

\a ,,.............

p-Tol

R C~

Mr

Scheme 1.16

HAI(Bui)2 is then directed by complexation with the geometrically well-located chlorine atom, leading to a bimetallic bridged species where aluminum is dsp s hybridized. In this model of approach M1, the hydride is just in the right position to be transferred intramolecularly from the top, leading to the (R) configuration at C-2 as observed. In conformation C2, where the p-tolyl group has an unfavourable pseudo-axial position, the C-l-directed approach of Hal(Bui)2 is now greatly hindered by the p-tolyl group, which explains the small contribution of the R

R, ~ i \ o o

Ms

14

GuY SOLLADII~AND M. CARMEN CARRENO

corresponding approach M 2 to the stereoselectivity. The high asymmetric induction obtained with non-stoicheiometric amounts of ZnC12 suggest that, after the hydride transfer, ZnC12 is displaced from the resulting aluminum alkoxide and used to chelate another molecule of [3-ketosulfoxide. Considering again the Lewis acid character of A13+ in HAI(Bui)2, we now think that the DIBAL reduction of [3-ketosulfoxides also involves, in an early stage of the reaction, a chelated dsp3-hybridized aluminum as shown in model M3 (where the p-tolyl group has a favourable equatorial orientation). Model M3 leads through an intramolecular hydride transfer to the (S) configuration at C-2 as observed. The stereoselective reduction of chiral sulfinylcyclohexanone was used to prepare optically pure (R)- and (S)-4-hydroxy-2-cyclohexenone [61], an important building block for the synthesis of ML-236A and compactin. Reduction of the [3keto sulfoxide (18) with DIBAL gave only the trans-f3-hydroxy sulfoxide (19T) whereas the use of ZnClz/DIBAL led to a 70 : 30 mixture of (19C : 19T), the major cis epimer (19C) being isolated by crystallization. Acetal hydrolysis and pyrolytic elimination of the sulfoxide occurred on acidic silica gel (Scheme 1.17).

(" ~

O

~

0 ' (i) pri2NMgBr (S)-p-Tol-SO2menthyl ,

0

jr "0 DIBAL

O

~~OH ~ .,,,

,

(ii) chromatographic purification

70% yield (18)

95% yield (19T) l SiO2' HzSO4' 40% yield

(i) DIBAL/ZnC12 (ii) crystallisation OH

OH H

O

> 95% ee 0

41% yield SiO2, H2SO4

70% yield (19C)

(R)

H

9

OH

0

O

(63

ee > 95%

Scheme 1.17

Bravo et al. [62]-64] also reported that diastereoisomerically pure c~'-fluoro c~sulfinyl ketones could be reduced with DIBAL to the corresponding a'-fluoro oLsulfinyl alcohols with a high diastereoselectivity to give, after desulfurization, optically pure fluorohydrins. It is interesting that the stereoselectivity of the reduction was entirely directed by the chirality of the sulfoxide whatever the original configuration of the vicinal asymmetric carbon atom (Scheme 1.18). Under the reaction conditions no epimerization occurred at the fluorinated centre, so that a single and optically pure enantiomer was always obtained (de > 95%, yields > 90%). Guanti et al. [65, 66] observed the same high diastereoselectivity for the LiA1H4 reduction of oL-arylthio oL-sulfinyl ketones (Scheme 1.19), but in that case the asymmetric induction was dependent on the chirality of the asymmetric carbon atom.

OPTICALLY ACTIVE [~-KETO SULFOXIDESAND ANALOGUES IN ASYMMETRICSYNTHESIS

F

Ar S

/

Rl

"'"

":-.

F

DIBAL

R2

~

Ar

g

S

RI

-

o" "-.

(i) N a l I ( C F 3 C O ) 2 0 ,

R2

"

F

acetone, -40 ~C ~

Rl R2

(ii) Raney Ni

o.

15

o.

R1

H

H

CH3

H

Ph

CH 3

Ph

R2

H

CH 3

H

Ph

H

Ph

CH 3

Scheme 1.18

~

Ph/ y

OH

\Tol

9 P

"" Tol

\

STol (1R, 2R, 3S)

STol (2R, 3S)

|

0

LiA1H4

~ \Tol

OH .=- 0 /,-'" ph~,,,,~//,.S \ Tol

LiA1H 4

STol

STol (2S, 3S)

(1R, 2S, 3S)

Scheme

1.19

T h e chiral s u l f e n y l a t e d c e n t r e b e t w e e n the k e t o n e g r o u p a n d the sulfoxide is highly e p i m e r i z a b l e . O g u r a et al. [67] used this p r o p e r t y to r e p o r t a very high s t e r e o s e l e c t i v e r e d u c t i o n of a d i a s t e r e o i s o m e r i c m i x t u r e of [3-keto oL-sulfenyl sulfoxides with s o d i u m b o r o h y d r i d e in basic c o n d i t i o n s ( S c h e m e 1.20). This efficient e p i m e r i z a t i o n d u r i n g k e t o n e r e d u c t i o n is limited to sulfenyl s u b s t i t u e n t s on C-2. In the case of alkyl (Me, Et, Pr ~) or aryl s u b s t i t u e n t s , a d i a s t e r e o i s o m e r i c m i x t u r e was always o b t a i n e d u n d e r e p i m e r i z i n g basic c o n d i t i o n s [67]. O

O

""

OH

O

S ~ P

STol

P

Tol

68

9

NaBH 4, MeOH, NH 3 98

9

Scheme 1 . 2 0

.

STol

STol

Diastereoisomeric ratio NaBH4, MeOH

0

h-'x'-../s

S Tol

65 935

OH

,-:'"

32

/.-" ~Tol

16

GuY SOLLADII~AND M. CARMEN CARREI~O

7-Chloro [3-keto sulfoxides, readily prepared from methyl chloroacetate and (+)(R)-methyl p-tolyl sulfoxide, can be reduced to the corresponding [3-hydroxy sulfoxides in the (R, R) or (S, S) configuration with ZnC12/DIBAL or DIBAL alone [68] (Scheme 1.21). 7-Chloro [3-hydroxy sulfoxides can be easily transformed into optically pure oL-sulfinyl epoxides, precursors of chiral homoallylic [3-hydroxy sulfoxides, by reaction with cyanocuprates [68, 77]. LDA

CI/~

C ~ l ".~~

O sII~

CO2Me Me"

. " S ..~, "-'II o

o

ZnCI 2 DIBAL _78oC ~ C l / " i ' ~ ' ' ' ~ OH

90% yield

......

K2CO3 ~ CH3CN/H20

O m.p. 61~ 84% yield > 98% de BF3, Et20 -60~ 40 min

CI~--~ OH

,,At" :

75% yield, 85% de K2CO3, [ CH3CN]H20] 2:1 r

DIBAL At"

S~ II O

,,,Ar "2~a : ~] O

,,Ar ~ ~ [ ~ " O O m.p. 56~ 86% yield > 98% de

90% yield, 95% de

c,< ......... ~ 2 CuCNLi2 Ar

75% yield

OH

H

0

90% yield

OH

O

Scheme 1.21

Page [69, 70] reported recently that 2-acyl-2-alkyl-l,3-dithiane 1-oxides (20) undergo diastereoselective reduction upon treatment with DIBAL. The sense of

the diastereoselectivity is commonly reversed by the presence of zinc chloride. O - R

(s.L O -" R

O

{

-

O " R

OH

+{

,Ts

OH

s

(20), SYN R

Reagent

Yield (%)

Me

DIBAL

45

100

9

DIBAL/ZnCI2

75

1

9

7

DIBAL

95

100

9

0

DIBAL/ZnCI2

80

100

9

0

Pr ~

0

OPTICALLY ACTIVE -KETO SULFOXIDES AND ANALOGUES IN ASYMMETRIC SYNTHESIS

17

However, in a few cases the selectivity was found to have the same sense in both conditions. Yields are also noticeably lower in the absence of zinc chloride. A few typical examples are given in Scheme 1.22. o

o

l

R

O

O

t .

s

R

OH

l

%....s

R

OH

%...s

(20) anti R

Reagent

Yield (%)

Me

DIBAL DIBAL/ZnCI2 DIBAL DIBAL/ZnCI2 DIBAL DIBAL/ZnCLe

40 75 21 81 50 42

Pr ~ Et

0 100 0 100 10.5 36

: : : : : :

100 0 100 0 1 1

Scheme 1.22 [3,y-Diketosulfoxides are also reduced with a very high diastereoselectivity with D I B A L to the corresponding y-keto [3-hydroxy sulfoxides [71]. The y-ketone group being totally enolized, two equivalents of D I B A L must be used. The absolute configuration of the reduced product was determined by correlation with the corresponding anti-diol obtained by the well-established Evans' procedure (Scheme 1.23). (R)-13,y-diketo sulfoxides and (R)-13-keto sulfoxides are both reduced with D I B A L to give (RS)-[3-hydroxy sulfoxides. ~

OH l

0 l

R

0 S .........: '%At"

DIBAL

0 OH 0 I Q ~ , / I I S .........:

_~

2 equiv.

R

"%Ar

(S3,Rs) R Yield (%) de (%) Me 85 >95 Ph 80 >95 Me4NHB(OAc)3 0~

(R = CH3)

AcOH

OH

OH

OH Raney nickel

H

OH ~

0 II S

RT, 15 min

C

(-)-(R R)

'"'~ollllH 9

"~Ar 95% yield, 86% de

Scheme

1.23

18

GuY SOLLADII~ AND M. CARMEN CARREINO

1.4 APPLICATION OF THE 13-KETO SULFOXIDE REDUCTION TO TOTAL SYNTHESIS One of the great advantages of chiral sulfoxides in total synthesis is to allow the asymmetric induction step to occur in the very last part of the synthesis through the stereoselective [3-keto sulfoxide reduction. Furthermore, both configurations of the chiral hydroxylic centre can be prepared according to the reduction conditions (DIBAL or ZnC12/DIBAL), allowing the obtainment of both enantiomers of the target molecule. Iwata [72] reported an interesting example in the field of spiroketal compounds belonging to the insect pheromone family. Due to conformational aspects which bring the ketone function very close to the sulfoxide group, this 1,6-asymmetric induction is very similar to that observed by us with [3-keto sulfoxides, the diastereoselectivity being, however, lower (Scheme 1.24). Ar

Ar "'~'S =O

S--O

DIBAL

94% yield, 70% de (i) KH, THF (ii) RaneyNi ZnCI 2 ,

DIBAL ~

O

CH3 H

Ar '~'S

-- O

(i) KH, THF

/~.0~"-~,~.

(ii) RaneyNi

-H CH~

Scheme 1.24 Chelated models were proposed to explain the observed stereoselectivity (Scheme 1.24a): Ar

L

I

F =-

.....z l

Scheme 1.24a

OPTICALLY ACTIVE ~-KETO SULFOXIDESAND ANALOGUES IN ASYMMETRICSYNTHESIS

19

We have recently reported the asymmetric synthesis of two macrolides using the stereoselective reduction of S-keto sulfoxides. In the case of lasiodiplodin dimethyl ether (21), the total synthesis [73] was divided into two parts: first the synthesis of the achiral diester (22) and then the introduction of the chiral carbinol part via a [3keto sulfoxide functionality in the very last steps of the synthesis, allowing the preparation of both configurations of the macrolide (Scheme 1.25). Reduction of the [3-keto sulfoxide (23) with DIBAL in presence of zinc chloride yielded the (R, R)-[3-hydroxysulfoxide, while reduction with DIBAL alone afforded the (R, S) isomer. After desulfurization, both enantiomers of the seco-acid were cyclized using Gerlach's method.

OMe ~,._

j COzMe CQ2Me THF-78~

OMe [..~11 " ~ CO2Me

~

o

M

s:.

/ S11 ....., . LiCH2 ' ~ / - T o l

(22)

....

(+)-(R), 2.2 equlv.

~~DIBA L THE -78 ~ -80% yield

J OMe < , ' ~ ~ CO2Me

I

II

.

e

~

OMe

~,.,... ~

OH O

"

..,,;

9

S

S. p-Tol

M

\

p-Tol

>95% de

86% de (i) Ra Ni, EtOH, 53% yield (ii) KOH, A, 74% yield iii) Pyr2S2, Ph~EPhH, 49% yield

l

l(

OMe

I Z|ICI2' THE DIBAL, RT, 20 rain, 95% yield

eO~~~A~CO2Me OH O

p-Tol

(23), 85~ yield

J

M

.., ...". O o~k

(i) RaNi, EtOH, 70%yield (ii) KOH, A, 91% yield (iii) Pyr2S2, Ph~P,PhH, 66% yield

O O '"-'-.

OMe 0 O /

O

M (R)-(21)

(S)-(21)

Scheme 1.25

In the case of zearalenone dimethyl ether (24), our strategy [74] was to prepare first the chiral part (25) using a chiral sulfoxide auxiliary and the achiral sulfone ester (26). The hydroxyester (25) was obtained from the [3-ketosulfoxide (27), readily prepared from glutaric anhydride (Scheme 1.26). After coupling the sulfonyl anion (26) with the ester (25), desulfurization and carbonyl group protection, the cyclization to zearalenone dimethyl ether was carried out following the Masamune method.

20

GuY SOLLADIr AND M. CARMENCARREIXlO

(9 (i) II Oo~

LDA, -78~

/S,~'A~ to-60~

~

MeO O 2AC . ~ ~

(ii) CH2N2

O

i '~'Ar':

(27) 75% yield

ZnC 12, DIBAL,

THE -78~ (i) TBDMSCI, OTBDMS imidazole, DMF, RT 98% yield (ii) Raney Ni EtOH, RT 89% yield

OH

O

,iI

(25)

80% yield > 98% de OMe

OMe

~CO2Me (i) (Me3Si)3NLi, THE -78~ MeO~J~,,,,,,,SK,,,,~~SO21'-Tol (ii) '' OTBD~S (26)

C 0 2 ~ (25) -40 to 0~

OMe O | l O

M

e

m

MeO

(14)

SO2p_To 1 62% yield (i) Na/Hg,90% yield (ii) HS(CH2)3SH,BF3OEt2 78% yield (iii) KOH, 84% yield (iv)(PhO)zPOC1, Et3N, DMAR 60% yield (v) IMe, CaCO3, 84% yield

O

(24) (S)

Scheme 1.26 Allylic [3-hydroxysulfoxides were used to prepare polyhydroxylated natural products. The asymmetric synthesis of L-arabinitol was the first example [75]. In this case the allylic [3-keto sulfoxide (28) was first reduced with ZnC12/DIBAL and then the double bond hydroxylated with a high diastereoselectivity to give the corresponding triol (29), easily transformed by a Pummerer rearrangement into Lpenta-O-acetylarabinitol (Scheme 1.27). A similar strategy was used in the asymmetric synthesis of the macrolide aspicilin (30), which also contains a chiral vicinal triol moiety [76]. In this case the hydroxylation step was not carried out on the allylic [3-hydroxy sulfoxide but on the chiral allylic alcohol after desulfurization [76a] through a Pummerer rearrangement followed by reduction of the intermediate to the primary alcohol (Scheme 1.28). The overall yield was much better, due to a competitive oxidation of the sulfoxide to sulfone with osmium tetroxide, the main triol diastereoisomer being then easily purified by chromatography.

OPTICALLY ACTIVE [3-KETO SULFOXlDESAND ANALOGUES IN ASYMMETRIC SYNTHESIS

21

O II /

Me

S

.,,,11111| "

N)Ar

O

O II

.,,m! *

9 (R)-(28), 60% yield

LDA, THE 0~

I ZnCI2,DIBAL, THE -78~

OH -

B

OH

0

II

S

5% OsO 4 ....... 9

Me2N(0)

9

OH n

O II

~

B

OH (29) (S4,R3,R2,Rs) >90% de 70% yield

...m!

S 9

9

(R2,Rs), 95% de. yield

I Ac,O, AcONa (i) DIBAL, 0~ A S (ii) Ac20, pyridine II, \At (iii) Raney Ni OAc (iv) Ac20, pyridine

OAc OAc BnO _ x / ~I ~ OAc

c

OAc ~

OAc OAc

_~ OAc

L-Penta-O-acetylarabinitol Scheme 1.27

O

0 S .......: 9

OH

ZnC12/DIBAL

0II ...,mll

OBn

OBn

9

95% yield > 95% de

[~;~) MEMCI, Et(i-Pr)2N' 95% yield Ac20, AcONa, 99% yield t(iii) LiAIH4,0~ 92% yield 0v) Ac20, pyridine O

OBn

OMEM

O (31)

OAc

(i)

O s O 4 cat.

60% de

85% yield

71% yield in pure (31) OBn (ii) Me2C(OMe)2,TSOH' DME 98% yield Scheme 1.28

OMEM

OAc

22

GuY SOLLADII~AND M. CARMEN CARRENO

The second necessary synthon (32) was readily made from t-butyl (R)-8-oxo-9-ptolylsulfinylnonanoate by DIBAL reduction followed by Raney nickel desulfurization, protection of the hydroxyl group, ester reduction and, finally, transformation of the primary hydroxyl group into a phosphonium salt (Scheme 1.29). o II

fS

Me ~ ButO~C -

C02Me

(~ IPPh3

(32)

~

9

'~Ar

_ LDA, _78oc~88% yield

0 t-BuO2C

(i) Raney Ni 96% yield OTBDMS (ii) TBDMSCI 95% yield . (iii) LiAIH4, 97% yield ~ t-BuO2C (iv) PPh 3, imidazole, 12, 92% yield (v) PPh3, CH,CN, 87% yield

/

0 S~A~. ....

DIBAL

l OH_

Oii

S > 98% de

Scheme 1.29 The compound (31) was debenzylated, oxidized to the aldehyde and submitted to a Wittig reaction with the phosphonium salt (32) to give the (Z)-olefin in 64% yield (Scheme 1.30). Reduction of the double bond, saponification of the acetate, Swern oxidation followed by a Wittig-Horner reaction gave the seco-ester. After saponification of the ester and removal of the TBDMS group, the seco-acid was cyclized to (-)-aspicilin using 2,6-dichlorobenzoyl chloride under the conditions described by Zwanenburg. The oL-sulfinyl epoxide (33), which is prepared by reduction of ~/-chloro [3ketosulfoxide (Scheme 1.21), is a very important precursor of functionalized chiral homoallylic carbinols. It was applied to the synthesis of the C-11-C-20 fragment of leukotriene B4 [77] (Scheme 1.31), the sulfoxide group being easily transformed into an aldehyde by a Pummerer rearrangement. The epoxide (R, R)-(33) was reacted with (E)-cyanocuprate to give the homoallylic [3-hydroxy sulfoxide (R, R)(34) in 90% yield. After protecting the OH group with a TBDMS group, the molecule was submitted to a Pummerer rearrangement in acetic anhydride and the resulting acetate reduced with LiA1H4 in toluene. Finally, oxidation of the primary alcohol gave the target (R) homoallylic hydroxyaldehyde corresponding to the C-11-C-20 fragment of LTB4. We have already mentioned (Scheme 1.13) that [3-hydroxysulfides can be easily transformed into chiral epoxides. That result was applied to the synthesis of chiral syn- and anti-l,3-diols present in the C-1-C-12 unit of amphotericin B [78] (Scheme 1.32). The [3-keto sulfoxide (R)-(35) was reduced with ZnClz/DIBAL and transformed into the epoxide (S)-(36) by the method already described. Epoxide opening with dithiane followed by protection of the hydroxyl group led to the aldehyde (S)-(37). Condensation of 2-bromomagnesium 1,3-dithiane to aldehyde (37) gave in 70% yield only the (S, S) diastereoisomer (38), due to a chelationcontrolled 1,3-asymmetric induction. The compound (38) was then easily

( ( i ) Raney Ni (98%) yield c ( i i ) (COC1)2,DMSO

OBn

OAc

"4

Et,N 93% yield

0

0

0Ac

(31) (32). BunLi.64% yield

0

( i ) ff,f'D/cat.. 90% yield ( 1 1 ) LIOH, MeOH. 9 0 8 y~eld

-

w

(111)

OTBDMS

=\

.

OMEM

.

(a) (CO('1 l2 DMSO

OTBDMS

I

( i ) LiOH, 90% yield (ii) TBAF. 95% yield ( i i i ) 2,5-dichlorobenzoyl chloride Et,N. DMAP. 55% yield

85% yield

OH

C

BF,Et,O. HS(CHJ2SH, OMEM 74% yield

OH

(-)-Aspicilin (30)

Scheme 1.30 L-cIH,+

0 O h " . ,

s

...a

, ,o

:

& 0

s ....,,,,-

2CuCNl.i2

(7) Et,O, -60°C. niin

(K,R)-(33)

(K.K)-(34),> 95% cie 90% yield

1

( i ) TBDMSCI .i~nidazole DMF, 2SoC, 14h, 89% y~eld ( ~ i ) Ac,O, AcONa, A, 6h, 9.5% yield

OTBDMS

84% yield

OTBDMS

Toluene, -25"C, I h, 94% yield

Scheme 1.31

OTBDMS

24

GuY SOLLADII~AND M. CARMEN CARREI~IO

transformed into the aldehyde (39) with an anti-diol part, which can be completely isomerized in a basic medium under thermodynamic control to the aldehyde (40) with a syn-diol moiety. Finally, condensation of 2-chloromagnesium 1,3-dithiane with the aldehyde (40) gave only the syn adduct (41), as expected from chelation control.

BnO

~

(i) ButBr, CHC13 (ii)Et3OBFa, CH2CI2 O ~ 1 1 (iii) K2CO3 BnO "-" 90% yield

O

(S)-(36) (i) 2-1ithio-l,3-dithiane THF, -30~ 87% yield (ii) TBDMSCl,imidazole, DMF, 90% yield ~(iii) MeI, CaCO 3, CH3CN 90% yield

O

O O ZnC12 DIBAL, II I I S ............. 9 __. BnO..,l.l~ . S '~ ............." v v 'N~Ar" 70% yield (R,R), 94% de (R)-(35)

l

OTBDMS BnO ~

CHO (S)-(37)

S "X"S MgBr

THE -78~

B

n

OTBS OH O ~

s

(i) HE CH3CN (ii) MeC(OMe)CH2 CSA, CH~CI~ (iii)Ce(NH4)2(N~3)6~ BnO

(36) S~ 70% yield, > 98% de 1,3-Asymmetric induction

O~O

53% yield

CHO (39) anti K2CO3, MeOH, 80% yield

~ 1 7 6 s s "1

s....s

oXo CHO

90% yield (41) > 95% de OH

(40), syn

Scheme 1.32

OPTICALLY ACTIVE [3-KETO SULFOXlDESAND ANALOGUES IN ASYMMETRICSYNTHESIS

0 Ar,~,S ~

OH

0 ,, ZnC12'DIBAL

25

0

Ar,fi, S.

> 98% de 75% yield v i~) TMSC1, Zn 95% yield MeO3BF4 ~(iii) K2CO3

O

H

Li

s

S .--

69% yield

(S)-(42)

(i) TBDMSC182% yield (ii) Mel, CaCO3 o

OH

(iii) CSA, MeOH, THF, 67% yield

(-)-Yashibushiketol

Scheme 1.33 Another application of chiral epoxides obtained from [3-hydroxysulfoxides was the total synthesis of yashibushiketol having a chiral aldol functionality [79]. In this rather short asymmetric synthesis, the optically active epoxide (S)-(42) was opened by reaction with a substituted dithiane anion to give the corresponding chiral alcohol, which is easily transformed into (-)-yashibushiketol (Scheme 1.33). Both enantiomers of this natural product can be easily obtained from the epoxide enantiomers.

1.5

DIELS-ALDER REACTIONS OF ALKENYL SULFOXIDES AS DIENOPHILES The first reported Diels-Alder cycloaddition of oL,13-unsaturated sulfoxides was carried out with substrates containing a second activating substituent (-SO2R , - S O R , - C O 2 R ) which reacts with cyclopentadiene, giving a mixture of diastereoisomers [80]. Further studies showed that simpler vinyl sulfoxides could be used as acetylene synthons in cycloadditions due to the thermal lability of sulfoxides to yield olefins. This possibility was applied by Paquette et al. [81] to the synthesis of dibenzobarrelene (43), achieved in one step by reaction of phenyl vinyl sulfoxide with anthracene (Scheme 1.34).

26

GuY SOLLADII~AND M. CARMEN CARRENO

PhOS~

+

~

(43) Scheme 1.34

The first stereochemical study of the Diels-Alder reaction with alkenyl sulfoxides was carried out by Maignan and Raphael [82] on the cycloaddition between (R)-p-tolyl vinyl sulfoxide and cyclopentadiene, with discouraging results (Scheme 1.35). They showed the existence of four diastereoisomers whose endo or exo structures and absolute configurations were established by NMR and chemical correlation with dehydronorcamphor. The poor stereoselectivity observed ( e n d o / e x o 2 ;facial selectivity 2-4) is probably due to the lack of dienophile reactivity, which requires energetic reaction conditions favouring thermodynamic control of the process.

o

~,.. I Sx

o

Tol

115~ sealed tube, 15h

(6)

soro,

._

SOTol

"

SOTol

8%

SOTol

endo

exo

28%

42%

22%

Scheme 1.35

0 ToI,, II .,~,'S,,,,~ 9

+

0

/CH3 N\

~

ToI,, II :~'S~N,~/

CH 3

(6)

l

(i) MeLi (ii) CH3CHO

0I I

9o,,,:.~ :O

,:::rO3,~,.SO,,. '

0I I

To,,. ~ CH3-CHOH

(44)

Scheme 1.36

0 (i~ ~e~

(ii) N a O H

~o,,,

II

CH3-CHOH

OPTICALLY ACTIVE [~-KETO SULFOXIDESAND ANALOGUES IN ASYMMETRIC SYNTHESIS

27

With the aim of improving the reactivity of such chiral dienophiles, efforts focused on the design of ketones or acrylates bearing the chiral sulfinyl function on C-2 or C-3. The [3-keto-~-vinyl sulfoxide (44) was obtained in an enantiomerically pure form by further transformation of (R)-p-tolyl vinyl sulfoxide (6) (Scheme 1.36). The introduction of a tertiary amino group in the [3 position of (6), followed by addition to acetaldehyde, Hoffman elimination and subsequent Jones oxidation, allowed the isolation of the [3-keto-e~-vinyl sulfoxide [83] (44). Koizumi [84] prepared the sulfinylacrylate (46) by a method which involves the introduction of a phenylselenyl group into the oL-position of (R)-ethyl p-tolyl sulfoxide (2), thus enabling, in the last steps of the synthesis, the formation of a double bond. As shown in Scheme 1.37, carboxylation of the selenide (45), followed by esterification and MCPBA oxidation, afforded the sulfinylacrylate (46). O Tol ........~ (2)

(i) Bu'~Li

0 Tol ........

(ii) PhSeC1 (45) SePh (i) Bu"Li

(ii) C02

(iii) EtOH/DCC O Tot,, II :r .......S~

MCPBA

O ,-r,ol,,ell,,. II :r S ~ ]t

C

EtOzC

OzEt SePh

(46)

Scheme 1.37

The results obtained in reactions of the 1-acyl-l-alkenyl sulfoxides (44) [83] and (46) [84] with cyclopentadiene, collected in Table 1.4, showed that in thermal conditions ~x-sulfinyl vinyl ketone gave almost exclusively endo adducts, the facial selectivity being still low (entry 1). The stereoselectivity did not improve significantly in the case of the acrylate (46) (entry 2), but in the presence of ZnC12 (entry 3), the endo/exo ratio slightly changed while the facial selectivity increased significantly, now yielding the adducts with opposite configuration at the new chiral centres. The cyclic vinylic sulfoxides (9) and (10) are poor dienophiles, undergoing the Diels-Alder reaction with cyclopentadiene only in the presence of a Lewis acid [85]. Only two diastereoisomers (Table 1.5) were formed in this cycloaddition, revealing a great efficiency of the sulfinyl group in the control of the facial selectivity of the process. The resulting anomalous high exo/endo ratio with the aluminium catalyst was attributed to the steric hindrance of the sulfinyl substituent chelated to the catalyst (higher with EtA1C12), which makes the endo approach difficult.

28

GuY SOLLADII~AND M. CARMEN CARREI'TqO

TABLE 1.4

Diels-Alder reactions of 1-acyl l-alkenyl sulfoxides (44) and (46) with cyclopentadiene ROC,~SOTol (44) R =

CH 3

(46) R =

OEt

o o, ; so,.ro, COR

endo

(I) Entry

Dienophile

1

(46)

3

TABLE

(III)

Lewis acid

(44)

2

(46)

T

Time (h)

20oc

12

0~

3

RT

--

ZnCI2

SOTol

exo

(II)

(IV)

6

endo:

(I)/(ll)

exo: (nl,l/(iv)

40/60 64/11 2/77

0/0 32/2 2/19

1.5 Catalysed Diels-Alder reactions of (9) and (10) with cyclopentadiene

o

o

~4

r ~

] (CH2),,

2). Toluene,

+

(9) n = 1

exo

(10) n = 2

endo

Dienophile

Lewis acid

Time (h)

exo/endo

(9) (9) (10) (10)

AICI3 EtAICI2 AICI3 EtAICI2

5 1 10 2

58/62 60/40 68/32 83/1 7

Chiral acrylates with the sulfoxide on C-3 have been widely studied. The synthesis of such dienophiles was complicated by the possibility of c i s - t r a n s isomerism. Almost simultaneously, Maignan [86] and Koizumi [87] described a synthetic approach, based on the Andersen method, to the starting material which was further functionalized to give alkenyl sulfoxides. Thus, the Emmons-Horner reaction of the dialkyl p-tolylsulfinylmethanephosphonate (8) [88] with carbonyl compounds such as methyl glyoxylate or ethyl pyruvate gave (Rs)-3-p-tolylsulfinylacrylates (47) or (48) as a mixture of (E) and (Z) isomers (Scheme 1.38). Although both isomers could be separated by chromatography, the isolated yields were always poor.

OPTICALLY ACTIVE [3-KETO SULFOXIDESAND ANALOGUES IN ASYMMETRICSYNTHESIS

O

Tol, .... ~ :4 V

O

Tol, ....

B

~OR 1 ~OR 1

o

(8)

"

29

O II

i0 2

R

R2

R 2 ~'CO2R3

RI= Me, Et (47) R 2 = H,

R 3 =

(48) R 2 = Me,

Me

R 3 =

Et

Scheme 1.38

Compounds (47) and 48) underwent cycloaddition with cyclopentadiene from both the e n d o and e x o approaches under thermal conditions [86, 87] (Table 1.6) with a high facial diastereoselectivity. Nevertheless, the more substituted dienophile (48) showed a lower reactivity and stereoselectivity. TABLE

1.6 Diels-Alder reactions of 3-sulfinylacrylates (47) and (48) with cyclopentadiene

R1

RI ~SOT~ ..

SOTol

R1

endo

(I) Dienophile (Z)-(47) RI=H, R2=CO2Me (Z)-(48) RI=Me, R2=CO2Et (E)-(48) RI=CO2Et, R2=Me

exo

(II) Reaction conditions Toluene, 4~ 60 h Sealed tube, 90~ 3 h Sealed tube, 90~ 6 h

(III)

(I) 93 63 63

endo

exo

(11)

(111)

0 2 15

7 35 22

Although the reaction proceeds with low e n d o / e x o diastereoselectivity, the adducts resulting from (Z)-(48) were used in the asymmetric synthesis of santalene-type sesquiterpenes [89]. However, the applicability of this methodology remained limited to the highly reactive cyclopentadiene. In order to improve the dienophile reactivity, the introduction of strong electron-withdrawing substituents on the sulfinyl function was investigated. A study on 3-(2-pyridylsulfinyl)acrylates [90] (49), carried out on the racemic series, showed an enhancement of the dienophile reactivity in such a way that cycloaddition proceeded even with furan, which is known to be a poorly reactive diene (Table 1.7). As shown in Table 1.7, the increasing electron-withdrawing ability of the pyridine ring, due to the NO2 or CF3 substituent at the C-3 position, resulted in a considerable increase in dienophile reactivity and the diastereoselectivity of the process.

30

GuY SOLLADII~ AND M. CARMEN CARREIXlO

TABLE1.7 Diels-Alder reactions of 3-(2-pyridylsulfinyl)acrylates(49) with furan x

0

~s~'O~co2Et

~

0

~CO2Et ,S..

.

o,

"~CO2Et N.~

x

(49)

endo

Dienophile X=H X=NO 2

X=CF3

T 50~ 50~ RT

exo

Time

Yield (%)

de (%)

Yield (%)

de (%)

6 days 6 days 7 days

49 56 84

10 >98 84

13 16 7

86 >98 86

The application of these reactions in asymmetric synthesis required the synthesis of enantiomerically pure 3-(2-pyridylsulfinyl)acrylates (49). Chiral alkenyl sulfoxides with a variety of substituents on the sulfur atom can be prepared by oxidation of optically active alkenyl sulfides. Thus, (Rs)- and (Ss)-menthyl 3-(2pyridylsulfinyl)acrylates (51) [91] have been obtained, as shown in Scheme 1.39, by MCPBA oxidation of the (Z)-sulfenylacrylate (50) resulting from the addition of 2-mercaptopyridine to (+)-menthyl propiolate. The asymmetric induction of the oxidation step is low (a 50:50 mixture of the two possible diastereoisomeric sulfoxides (51) was formed), but fractional crystallization allowed the isolation of optically pure (Ss) and (Rs) epimers. The method has been extended to 3trifluoromethylpyridyl sulfinylacrylates (52) [92].

~x C02menthyl

/~ s

SH X / . ~ N ,.- ~

os/~x C02menthyl

C02menthyl

(50)

MCPBA

r--

X

N

(51) X = H (52) X = CF 3

Scheme 1.39

Diels-Alder reactions of (51) with furan led to a high diastereoselectivity in the presence of Et2C1A1 [91] (Table 1.8). The absolute configuration of the new chiral centres generated in the endo cycloaddition was established by reducing the endo cycloadducts obtained from (Ss)- and (Rs)-(51) epimers to the enantiomeric sulfenyl alcohols (+)-(53) and (-)(53) (Scheme 1.40). The results indicate that the sulfinyl group and not the methyl moiety controls the stereoselectivity of the cycloaddition.

OPTICALLY ACTIVE ~-KETO SULFOXIDESAND ANALOGUES IN ASYMMETRICSYNTHESIS

TABLE1.8

31

Catalysed Diels-Alder reactions (51) with furan and cyclopentadiene

~ S ~0

~~/

~CO2menthyl EhAICI~

(51) X

H

X

~CO2menthyl SOPy

endo

(I)

x

...~~

/~~ ff~SOPy CO2menthyl

x SOPy , - / ~ CO2menthyl C 0 2 m e n t h y l / ~ ' ~ SOPy 8.~0

(II)

(111)

(IV) endo

Dienophile

Diene

(5)-51 (Rs)-51 (5)-51 (R)-51

X=O X=O X=CH, X=CH:

T RT RT -78~ -78~

0

Time

Yield (%)

(I)/(11)

Yield (%)

(III)/(IV)

7 days 7 days 3h 3h

44 49 96 93

93/7 8/92 100/0 0/100

25 31

96/4 3/97

0

~

(i) TiCl~ 02 menthyl ...... S .

6

( S s)-(l )

PY

exo

0

g

0 ,~

(ii) LiA?H 4

OH S.

Py

HO

(i) TiCI3 4(ii) LiAIH 4 menthyl O

S

py"

(+) - (53)

(-)-(53)

S ......

py'b

(R s ) -(II)

Scheme 1.40

The furan endo adduct resulting from (Ss)-(51) allowed the asymmetric synthesis of some key compounds for the preparation of nucleosides. Even better results were obtained in the reactions of (Ss)- and (Rs) (51) with cyclopentadiene in the presence of Et2C1A1 [94] (see Table 1.8). The endo adducts obtained as the only products in each case were later used as starting materials for the enantioconvergent synthesis of some carbocyclic nucleosides [94]. The stereoselective cycloaddition of the sulfinylacrylate (Ss)-(52) was applied to the total synthesis of the cancerostatic agent glyoxilase I inhibitor [92] (57), as shown in Scheme 1.41. Reaction of (Ss)-(52) with 2-methoxyfuran took place under thermal and mild conditions to give the endo adduct (54) almost exclusively. Oxidation by OsO4 of the compound (54) followed by acetalization afforded the exo-diol derivative (55), whose reduction with TiC1B-LiA1H4 yielded the primary alcohol (56). Esterification of (56) and subsequent MCPBA oxidation yielded a 1:1 mixture of diastereoisomeric sulfoxides, which upon acidic treatment afforded enantiomerically pure (57).

32

GuY SOLLADII~AND M. CARMEN CARREIXlO

FaCx~CO2menthyl ~.0,~/ ~ O_C H 3 o,.S.....,

toluene. 0~ 6 days

(Ss)-(52)

~~

H3

(i) Me3NO, OsO4c a t . O2menthyl (ii) MeO "OMe. SOAr / vN

(54)

p-TsOH

+.O O,, ,,OCH3 O~..~ C 02 menthyl SOAr (55)

l

(i) TiCI3 (ii) LiAIH4

0 HO" " ] I

0

+O

O, ..OCH3

(i) ( ~ C O ) 2 0 . p y

+O

O...OCH 3

(ii) MCPBA

-20 ~C

SAr

OH

OH

(56)

(-)-(57)

Scheme 1.41

The facial diastereoselectivity observed in these processes has been explained by steric factors, assuming that the more stable conformation of vinyl sulfoxides determines the diene approach from the less hindered side of the dienophilic double bond, syn to the lone pair on sulfur [87]. The stability of the rotamers depends on the structure of the sulfoxide and on the reaction conditions. In the absence of a Lewis acid, 1-acyl vinyl sulfoxides adopt predominantly the s-cis conformation C3 indicated in Scheme 1.42, where dipolar repulsion between the C=O and S=O bonds is minimized [95]. In the presence of a chelating Lewis acid, the most stable conformation is C4 with an s-trans arrangement of S=O and C=C bonds [84, 85]. In the case of (Z)-3-sulfinylacrylates or (E) derivatives with an additional substituent on C-2, the s-trans conformation C5 is favoured due to steric and dipolar effects. The endo or exo approach of diene to these conformations is most favourable from the less hindered face of the dienophilic double bond, indicated by the arrows in Scheme 1.42. The attack from the top or bottom face on C3 and C4 afforded the adducts with the opposite configuration at the new asymmetrical centres. In the absence of structural features or experimental conditions favouring one conformation, the coexistence of both s-cis and s-trans rotamers leads to a low diastereoselectivity in the Diels-Alder cycloaddition, as in the case of vinyl p-tolyl sulfoxide [82]. A different mechanistic approach based on frontier molecular orbitals has been proposed by Kahn and Herhe [96], who suggested a stereoelectronic approach control of nucleophilic diene to the less electron-rich face of the sulfinyl dienophile (syn to the bulky p-tolyl group) which mainly adopts the s-cis conformation. Nevertheless, this hypothesis could only explain some of the experimental results.

OPTICALLY ACTIVE [3-KETO SULFOXIDESAND ANALOGUES IN ASYMMETRICSYNTHESIS

O Ar

o"

..

, "'S '~ O

R

C~

C4

s-trans

O II _s~,,,: (11 Ar

'?"

o II S.~A:r

R

s-cts

II

,M,

33

H

II~

COeR

ROzC

C5

O II /~s~,,,: Ar R

C5 s-trans

Scheme 1.42

Other compounds successfully used in asymmetric Diels-Alder cycloadditions are the sulfinyl dienophiles (61), reported by De Lucchi [97, 98] and available in both (Rs) and (Ss) configurations. The (Rs) substrates were obtained by oxidation of sulfides, taking advantage of a chiral auxiliary such as 10-mercaptoisoborneol (58), which is able to induce a high diastereoselectivity in the oxidation step, a good method to obtain alkenyl sulfoxides bearing an hydroxyl group. Michael addition of (58) to electron-poor acetylenes (59a,b) occurs exclusively trans, giving the (Z) isomers (60a,b) of sulfonyl-activated acetylenes (Scheme 1.43). In the case of the propiolate (59c), the pure (Z) isomer (60c) is formed in the presence of EtgN, and the (E)-alkene is the main product when Michael addition is carried out in the presence of 1,4-diazabicyclo[2,2,2]octane (DABCO). The self-induced chiral oxidation of vinyl sulfides (60) takes place with MCPBA in dry CH2C1 e in a highly X OH +

iiI

r--

OH

~-CH2CIa

OH

Y (58)

(59)

(a) (b) (c) (d)

(60)

X

X = PhSO2, Y = H X = p-C1PhSO2, Y= H X = CO2Me, Y = H X = Y = CO2Me Scheme 1.43

(61)

X

34

GuY SOLLADII~AND M. CARMENCARREt~O

stereoselective manner (up to 80% de of (Rs) epimer) due to the directing effect of the substrate hydroxy group through an incipient hydrogen bonding between this OH and the peracid. A similar strategy was used to obtain the sulfinylmaleate (61d) [99, 100] starting from dimethyl acetylene dicarboxylate (59d). Nevertheless, the conjugate addition of (59d) is not so highly stereoselective, producing a mixture of (E) (80%) and (Z) (20%) isomers. Diastereoisomers (Ss)-(61) were crystallized from the resulting oxidation mixture in acetone [98]. Compounds (61a--c) reacted with cyclopentadiene to give exclusively endo adducts (62) [98] (Scheme 1.44). The rigid conformation represented for (Rs)(61a-c), with a hydrogen bond between the OH of the isoborneol moiety and the sulfinylic oxygen, accounts for the high diastereoselectivity observed. In such a conformation the endo approach of the diene is favoured from the less hindered face of the dienophile that is the re face with respect to the sulfoxide. Compounds (Ss)-(61a-c) afforded similar good results, giving access to the opposite configuration at the newly generated chiral centres. (E) isomers gave a mixture of diastereoisomers.

: ~

H

x" J ,

z--

CH2CI2or CHCI3 0~

c

,,,R* :+S'~ 0 X (62)

(Rs)-(61) X = PhSO 2 (b) X = p - C 1 P h S O 2 (c) X = M e C O 2 (a)

Scheme 1.44

When the sulfoxide group of (Z)-(Rs)-(61a-c) is oxidized to sulfone, the cycloaddition affords a mixture of diastereoisomers. This finding shows that the diastereoselectivity of the process is governed by the sulfoxide, and the presence of a chiral ligand on the sulfur substituent is not alone able to control the diene approach. This point was confirmed by using a bornyl substituent (endo-hydroxy) on the (Rs)-sulfoxide instead of the isobornyl group (exo-hydroxy). The reaction between methyl (Z)-(Rs)-3-(2-endo-hydroxy-lO-bornyl)sulfinylacrylate and cyclopentadiene gave only the endo adduct (62) (R* = bornyl), showing that the orientation of the hydroxy group does not play an important role. The use of sulfinyl maleates, (61d) [99] (see Scheme 1.43) and (63) [101] (Scheme 1.45), as chiral equivalents of acetylene dicarboxylate in Diels-Alder reactions has also been described. The synthesis of (63), recently published, is based on the transformation of t-butyl 2-p-tolylsulfinylacetate (3) through a Knoevenagel condensation with glyoxylic acid [101].

OPTICALLY ACTIVE [B-KETO SULFOXIDES AND ANALOGUES IN ASYMMETRIC SYNTHESIS

O Toll~.~~

CO2But

9

0 Toln.....

(i) OCH-CO2H/Et~N, pyrrolidine, DMF ;

.r

35

~ 1 ~ CO2But

"

(ii) NaHCO3/MeI, DMF

CO2Me

(3)

(63)

Scheme 1.45

Cycloaddition of (61d) and (63) with cyclopentadiene in the presence of zinc halides (Table 1.9) afforded mainly the endo adducts (65-I) and (66-II), respectively, with the opposite configuration at the new stereocentres because of the different absolute configuration of the sulfur atom in dienophiles (Rs)-(61d) and (Ss)-(63). The monoester (Ss)-(64) gave a complex reaction mixture in the presence of ZnBr2, while in the absence of the Lewis acid a drastic change in the stereoselectivity, which is now opposite to that obtained with the diester (Ss)-(63) and in favour of the diastereoisomer (67-I), was observed. TABLE

1.9 Diels-Alder reactions of sulfinylmaleates cyclopentadiene

o

k

R~S~

CO2R1

~

~CO2

~

~L~'~~

CH2CI~

S~'R~4

"1' Co2R1 + CO2R2 endo

R2

(61d), (63) and (64) with

....j 4 ~

(I)

Dienophile (61d) R I = R2= Me, R~= ", R4 = 10-isobornyl (63) R I = B u t, R2= Me, R~= p-Tol, R4 = " (64) R I = B u t , R 2 = H , R-~ = p-Tol, R4 = "

~ ~ R ~ CO2R"I

+

exo

adducts

(II)

Lewis acid

ZnCI2

endo

(65-1) 94

ZnCI2 (66-1) 6 (67-1) 91

exo

(65-11) 0 (66-11) 89 (67-11) 9

6 5 7

Transformation of adducts (65-I) [99] and (66-II) [101] in both enantiomers of the monoester (69) confirmed the configurational assignments and demonstrated the utility of sulfinylmaleates as chiral acetylene dicarboxylate equivalents. As shown in (Scheme 1.46), partial demethylation of (65-I) and further benzylation afforded (68), which upon treatment with DBU, followed by cishydroxylation, diol protection and debenzylation yielded the optically active half ester (-)-(69), which has been used as a chiral starting material in the synthesis of carbocyclic nucleosides [99]. The compound (+)-(69) was obtained in a similar way by basic elimination of the sulfinyl group from (66-II), followed by cis-hydroxylation and diol protection

[1011.

36

GuY SOLLADII~ AND M. CARMEN CARRENO

~ C O

SOR*

~

(i) A1Br3, Me2S

2Me CO2Me

SOR*

O2Bn CO2Me

(ii) BrBn, Nail 18-crown-6

(65-1) R* = 10-isobornyl

(68)

DBU, Phil

(i) OsO4, Me3NO (ii) MeO OMe ,/~ , p-TsOn

O~r--CO2H

~---CO2Bn

_..,,

CO2Me

(iii) 5%, Pd cat., cyclohexa-1,3 diene

(-) -(69)

CO2Me

Scheme 1.46

Enantiomerically pure sulfinylmaleimides (70), recently prepared using a selfinduced chiral oxidation procedure [103], turned out to be powerful dienophiles, reacting with cyclopentadiene and furan under very mild conditions in the presence of ZnC12 [102]. The cycloaddition with cyclopentadiene is highly endo-selective (Table 1.10), with also a high facial diastereoselectivity (up to 80% de). The results obtained with furan are dependent on the temperature: the exo/endo ratio increases with the temperature while the diastereofacial selectivity decreases. TABLE 1.10

furan

Catalysed Diels-Alder reactions of maleimide (70) with cyclopentadiene and X

L2

..-

OH

X

X

S~

SOR"

X

ZnCl2 Bn

(70)

o

Diene X = CH2 X = O X = O

(II)

n

'/

"

Bn endo

(1)

O

T

endo (I)/(11)

exo (lll)/(IV)

-78 ~ C 0~ C RT

97/3 29/0 0/0

0/0 0/71 45/55

O

so,,

exo

(III)

X

(IV)

37

OPTICALLY ACTIVE [3-KETO SULFOXIDESAND ANALOGUES IN ASYMMETRICSYNTHESIS

These facts reinforce the above-mentioned directing effect of sulfoxides in Diels-Alder cycloadditions when the dienophiles react through a rigid conformation: the s - t r a n s in the presence of Zn 2§ and the s-cis when there is an intermolecular hydrogen-bonded dienophile, such as the monoester (64) [103].

.>.....7oi o

"Zn/

T~ J

O" Rl........... :f ~

%

"0

"R2

r

ButO

S

~r~,

'~..COR~ s-cis

s-trans (61d), (63) and (70)

(64)

There are few reports concerning cycloadditions between sulfinyl dienophiles and acyclic dienes. The regiochemistry of these reactions between 3-sulfinylacrylic derivatives (71) and highly polarized dienes, such as Danishefsky's diene, appeared to be directed by the ester group [104]. The easy elimination of sulfenic acid in the resulting adducts prevents any stereochemical determination, but could be exploited for the synthesis of prefenic acid derivatives or phenols (Scheme 1.47).

R~ R1

e

F|

CO2M

SOPh TMSO" "~

,/'~CO2Mel /~,~~SOPh/

t~

/

reflux

LTMSO

f

LR1

..J

(71)

O2Me HO"

~

"Me -'~

R = H, R I = Me HCI

OMe I R

TMSO ~ x , ~

--R 1

R = Me, R ~= H "-HCI

Me

~ _ . ~ .,f~"~ CO2Me O-"

~

Scheme 1.47

The regiochemical course of these cycloadditions has also been studied by Boeckman [105] on 2- and 3-phenylsulfinyljuglones (72) and (73). The regiochemistry of reactions between these quinones and isoprene, a poorly polarized diene, is that expected on the basis of the dienophilic double bond

38

GuY SOLLADIr AND M. CARMEN CARREI~IO

polarization by the sulfoxide, even for compound (72), where the 5-hydroxy substituent exerted the opposite polarization (Table 1.11). A significant improvement in the regioselectivity was observed by using BF3"OEt2 as a catalyst as a consequence of the complexation of the carbonyl group syn to the sulfoxide. TABLE 1.11

and isoprene

Regiochemical course of cycloadditions between sulfinyljuglones (72) and (73)

R1 R2

+

OH O

OH O

OH O (II)

(I) Lewis acid (72) RI = S O P h , R 2 = H R1 = SOPh, R2 = H (73) RI = H , R 2 = S O P h R~ = H, R2 SOPh

(I)/(11) 1/2.0 1/5.4 2.9/1 4.3/1

BF3-OEt2 BF3"OEt2

=

These studies and other reports on 2-phenylsulfinyl-l,4-naphthoquinone [106] showed that these systems represent a synthetic equivalent of the unknown naphthynoquinone, by simultaneous pyrolytic elimination of the sulfinyl group in the resulting adducts (Scheme 1.48). CH3

O

CH3

Ac

O SOMe ~ O

0

O

OCH3

Scheme 1.48

We have recently reported the first synthesis of homochiral sulfinylquinones [107-109] and the dienophilic behaviour of the simplest member of the series [107]. Two alternative methods were employed to obtain (S)-2-p-

39

OPTICALLY ACTIVE [3-KETO SULFOXlDESAND ANALOGUES IN ASYMMETRICSYNTHESIS

tolylsulfinylbenzoquinone bisketal (75) (Scheme 1.49), which upon deketalization afforded the enantiomerically pure sulfinylbenzoquinone (77). The compound (75) could be prepared by Andersen's synthesis both from bromobenzoquinone bisketal (74), and from 1,4-dimethoxy-2-bromobenzene through the sulfoxide (76), which was electrochemically oxidized to (75). This anodic oxidation has to be performed at constant current in a single cell using 2% methanolic potassium hydroxide to avoid the overoxidation of the sulfur function. The synthesis has been extended to other benzo and naphthoquinone derivatives [108] in high chemical and optical yields.

OCH 3

(OCH3)2

Br

(i)

_ y

78% yield OCH3

(OCH3h (74)

70% yield ~-.,,~

" ~ 62% yield

(OCH3)2

~~,~SOTol p-TsOH ~-

OCH3

acetonet, 85% yield, 98% ee

(i)/'/(OCH3)2

.OCH3

75%(ii)( 7"- ~5 ) SyO Ti ~ e 89% l dleiyd OCH3

~

SOTol

(77)

OCH3 (76)

(i) (~),KOH/MeOH; (ii)Bu"Li,(S)-p-TolSO2menthyl Scheme 1.49

The aromatic carbanion necessary for the nucleophilic substitution on (Ss)menthyl p-toluenesulfinate (1) can also be obtained by ortho metallation of 1,4dimethoxybenzene with BuLi at 0~ Thus, starting from symmetrical 1,4dimethoxy aromatic derivatives, the synthesis of enantiomerically pure sulfinylquinones has been achieved in only two steps, as shown in Scheme 1.50 for (S)-2-p-tolylsulfinyl-l,4-naphthoquinone [108]. Oxidation of the substituted aromatic ring with cerium ammonium nitrate (CAN) afforded enantiomerically pure sulfinylquinones. OCH3 ~

OCH3 ~ S O T o l

(i) ButLi,RT, 1 h ......

(ii)

OCH3

I~

0 SOTol

CAN ~

(S)-pTolSO2menthyl -78 ~C, 2 h, 71% yield

86% yield OCH3

Scheme 1.50

O

40

GuY SOLLADII~ AND M. CARMEN CARREIqO

Diels-Alder reactions of (Ss)-2-p-tolylsulfinyl-p-benzoquinone (77) with acyclic dienes gave, as expected, the corresponding naphthoquinones by aromatization of the unstable adducts (Scheme 1.51), even when cycloadditions were carried out at low temperature [107]. R1 ~ R2

O

Tol 1

O

R2 R3

o

R'-.,

O

RI = OTMS,R2- R3:- H RI = OCH 3, R 2 = H, Rs = OTMS

(771

Scheme 1.51

Surprisingly, cycloaddition of (77) with cyclopentadiene took place on the C5-C6 dienophilic double bond with a high endo and diastereofacial selectivity that could be inverted by choosing the experimental conditions (Table 1.12). TABLE 1.12 Catalysed Diels-Alder reactions of the sulfinylbenzoquinone (77) with cyclopentadiene.

~

o

SOTol

G

.

.

H

~:

o

Eu(fod)3 BF3.OEt 2

To, ~

""

"

(78) Lewis acid

O"

! H

'b

(77)

.o

+

(79) Yield (%)

(78)

(79)

91 10

9 90

In the presence of Eu(fod)3, the adduct (78) is mainly formed, whereas with BF3.OEt 2 the major adduct is (79). The models of approach given below account for the stereochemical results. When the chelating Lewis acid Eu(fod)3 is present, sulfinyl quinone (77) adopts the s-trans chelated conformation, which favours the diene approach, even on the remote C5-C6 bond from the bottom face. In the presence of BF3.OEt2, the s-cis conformation, which directs the diene approach from the top side, is favoured. This is the first sulfinyl dienophile known where the chiral auxiliary is acting from a remote point.

OPTICALLY ACTIVE [3-KETO SULFOXIDESAND ANALOGUES IN ASYMMETRICSYNTHESIS

,Eu(f~)3 d

41

F3B,

b

"0

~Tol

S~, I 'ol

S ~ O. . . . BF3

,<

t" o

o,

%

%

"gu(fod)3

"BF3

s-trans

s-cis

Kagan [110] has recently reported the use of chiral alkoxysulfonium salts derived from the corresponding sulfoxides as dienophiles. The most striking result concerns the reaction of ethoxy-p-tolylvinylsulfonium tetrafluoroborate (80) with cyclopentadiene, giving only the compound which results from the endo approach (Scheme 1.52). oEt

Tol

I ~

:~ 'S-+

0

BF4-

-78~

II

NaOH 0

~

SOTol

(80) Scheme 1.52

If we compare this result with the similar reaction with p-tolyl vinyl sulfoxide, where a mixture of four diastereomers is formed in a sealed tube [24], we observe a dramatic increase in both reactivity, probably due to the stronger activating ability of the salt, and stereoselectivity. The sulfinyl group has also allowed the design of chiral ketene equivalents such as (81) [111] and (82) [112] (Scheme 1.53). Their cycloadditions with cyclopentadiene occur with a moderate stereoselectivity, enabling the synthesis of ( - ) n o r b o r n e n o n e (83) in 54% ee from (81), and both enantiomers of (83) from the separable 70 : 30 mixture of adducts obtained by using (82) as the dienophile.

o

O ,~::=::=

~

- _ _ ..~ Tol

:"11 O (81)

o

:,,. II Tol "" S ~

SOTol

(-)-(83)

o

SOTol ~

+

(82)

SOTol

(+)-(83)

Scheme 1.53

42

GuY SOLLADIEAND M. CARMEN CARREIXlO

1.6

DIELS-ALDER REACTIONS OF SULFINYLDIENES

In contrast to the efforts devoted to the study of dienophiles bearing a sulfoxide, only a few examples of sulfinyldiene cycloadditions are known. Evans [113] was the first to report a Diels-Alder reaction between 1-butadienyl phenyl sulfoxide (84) and an electron-rich dienophile (85) (Scheme 1.54). The adduct (86) resulted from the preferred endo approach, and upon treatment with hydrated sodium sulfide suffered a [2,3] sigmatropic rearrangement of the allylic sulfoxide to give an amino alcohol showing intramolecular hydrogen bonding, which allowed the establishment of a syn relationship between the hydroxy and nitrogen functions. The reactivity of the sulfinyldiene as compared with a common electron-deficient diene like methyl pentadienoate is slightly lower.

+

[4+2] ~ I CH3

S\ O~"

(85)

HO%,(

NaES. 9H20, MeOH

" N PhOS I CH 3

Ph

(a4)

[2,3] ~

") N e CH3

(86)

Scheme 1.54

This pioneering work was followed by a study on the racemic pyrone sulfoxide (87), which undergoes inverse-electron-demand cycloadditions with dienophiles (88), (89) and (90) under different experimental conditions [114, 115], as shown in Scheme 1.55. O

TolOS

.vA . -0

, ~/R1

O o ~O- "

-R E

~

~

RI

HO""

(88) R ! = R 2 = OMe (25~ (89) R ! = H, R 2 = OEt (ZnBr 2) (90) R I = H, R 2 = SPh (6.8 kbar) (87)

CO2Me

OMEM (91)

(92)

Scheme 1.55

The reactions give rise, regiospecifically and stereospecifically, to polyfunctionalized synthons with fixed stereochemistry. The derivative (91), resulting from the reaction of phenyl vinyl thioether (90), could be transformed into the precursor of chorismic acid (92). Unfortunately, enantiomerically pure (87) could only be obtained in small quantities by a method that is not easily

OPTICALLY ACTIVE [3-KETO SULFOXIDESAND ANALOGUES IN ASYMMETRICSYNTHESIS

43

reproducible [114]. Thus, the applicability of these reactions is limited to racemic series. A completely e x o stereoselective intramolecular Diels-Alder (IMDA) reaction of the vinyl allenic sulfoxide (94) has allowed the enantioselective synthesis of (+)sterpurene, a [4,5,6]tricyclic sesquiterpene which can be prepared from the sulfoxide (95) [116]. The enantiomerically pure diene propargylic alcohol (93) upon treatment with phenylsulfenyl chloride afforded the compound (94), through the reaction sequence indicated in Scheme 1.56. Both the [2,3] and [4+2] intramolecular processes occur with complete enantion ..,OH

H DSPh

-7

PhSCI, E t 3 N

(93)

SOPh -~- . . . .

~

~

H (+)-Sterpurene

IMDA

-"

//

(95)

"~

(94)

Scheme 1.56

and diastereoselectivity, showing the transfer of central to axial and axial to central chirality. In this synthesis, sulfur chirality does not play a central role. Overman and co-workers [117] have investigated the Diels-Alder reactivity of diheterosubstituted dienes. The sulfinyldiene carbamate (96) exhibits excellent Diels-Alder reactivity with electron-deficient dienophiles, high e n d o selectivity and high regioselectivity controlled by the acylamino substituent (Scheme 1.57). NHCOzBn

O

NHCO2Bn

Ph

25~ 3 days

+

~

85% yield 0,~ S,,

(5'

,,,,COPh

SOPh

Ph

(96) Scheme 1.57

44

GuY SOLLADII~AND M. CARMEN CARREI~IO

There are few data concerning the face selectivity of cycloadditions with sulfinyldienes. The only study available referred to conformationally rigid systems (97) [118] (Scheme 1.58). Their reactions with N-phenylmaleimide gave the endo adducts (98) resulting from addition anti to the sulfinylic oxygen, through the transition state depicted here, where both electrostatic and steric destabilizing

~ ~ !

+

o

~N

--Ph

toluene

o

~

-

0

S ,~

N"%O

Ph

(97)

(98)

X = CH2, R I = H X=O, RI=H X =O, R1 =CH 3

Scheme 1.58 interactions between the carbonyl groups of the dienophile and the sulfoxide oxygen are minimized. //O ,

N-Ph

, ,

/

"~0 t I i,"

X

0

0

REFERENCES 1. (a) G. Solladi6, Synthesis 185 (1981). (b) S. Colonna, R. Annunziata and M. Cinquini, Phosphorus Sulfur, 10, 197 (1981). 2. G. Solladi6, in: Asymmetric Synthesis (J. D. Morrison, ed), p. 184, Academic Press, New York (1983). 3. (a) M. Cinquini, F. Cozzi and F. Montanari, in: Organic Sulfur Chemistry (F. Bernardi, I. G. Csizmadia and A. Mangini, eds), pp. 305-407, Elsevier, Amsterdam (1985). (b) G. Solladi6, in: Perspectives in the Organic Chemistry of Sulfur (B. Zwanenburg and A. J. H. Klunder, eds), pp. 293-314, Elsevier, Amsterdam (1987). (c) G. H. Posner, in: The Perspectives in the Organic Chemistry of Sulfur (B. Zwanenburg and A. J. H. Klunder, eds), pp. 145-152, Elsevier, Amsterdam (1987). 4. (a) G. Posner, in: The Chemistry of Sulfones and Sulfoxides (S. Patai, Z. Rappoport and C. J. M. Stirling, eds), pp. 823-849, Wiley, New York (1988). (b) G. H. Posner, in: Asymmetric Synthesis (J. D. Morrison, ed.), vol. 2, p. 225, Academic Press, New York (1983). 5. (a) G. Solladi6, in: Comprehensive Organic Synthesis (B. Trost, ed.), vol. 6, pp. 133-170, Pergamon Press, Oxford (1991). (b) G. Solladi6, in: Houben Weyl, Stereoselective Synthesis (H. G. Padeken, ed.), vol. 22, Georg Thieme, Stuttgart (in press). 6. P.W.B. Harrison, J. Kenyon and H. Phillips, J. Chem Soc., 128, 2079 (1926).

OPTICALLY ACTIVE ~-KETO SULFOXIDESAND ANALOGUES IN ASYMMETRICSYNTHESIS

7. 8. 9. 10. 11. 12.

13. 14. 15. 16. 17. 18. 19. 20. 21.

22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41.

45

A.C. Cope and E. Caress, J. Am. Chem. Soc., 88, 1711 (1966). J. Drabowicz, P. Kielbasinski and M. Mikolajczyk, in: The Chemistry of Sulfones and Sulfoxides (S. Patai, Z. Rappoport and C. J. M. Stirling, eds), p. 233, Wiley, New York (1988). A. Macconi, F. Montanari, M. Secci and M. Tramontini, Tetrahedron Lett., 607 (1961); U. Folli, D. Iarossi, F. Montanari and G. Torre, J. Chem. Soc. C, 1317 (1968). K. Balenovic, N. Bregant, D. Francetic, Tetrahedron Lett., 20 (1960). (a) P. Pitchen, F. Dunach, M. N. Deshmukh and H. B. Kagan, J. Am. Chem. Soc., 106, 8188, (1984). (b) E. Dunach and H. B. Kagan, Nouv. J. Chim., 9, 1 (1985). (a) B. J. Auret, D. R. Boyd, H. B. Henbest and S. Ross, J. Chem. Soc. C, 2371 (1968). (b) E. Abushanab, D. Reed, F. Suzuki and C. J. Sih, Tetrahedron Lett., 3415 (1978). (c) S. Colonna, M. Gaggero, L. Casella, G. Carrea and P. Pasta, Tetrahedron: Asym. 3,95(1992). H.B. Kagan and F. Rebibre, Synlet, 643 (1990). (a) H. Gilman, J. Robinson and N. H. Beaber, J. Am. Chem. Soc., 48, 2715 (1926). (b) K. K. Andersen, Tetrahedron Lett., 93 (1962). M. Axelrod, P. Bickart, J. Jacobus, M. M. Green and K. Mislow, J. Am. Chem. Soc., 90, 4835 (1968). M. Nishio and K. Nishihata, J. Chem. Soc., Chem. Commun., 1485 (1970). S. Juge and H. B. Kagan, Tetrahedron Lett., 2733 (1975). This article gives a general method for determining the absolute configuration of sulfoxides. K. Mislow, M. M. Green, P. Laur, J. P. Melillo, T. Simmons and A. L. Ternay, J. Am. Chem. Soc., 87, 1958 (1965). K.K. Andersen, W. Garfield, N. E. Papanikolaou, J. W. Foley aod R. I. Perkins, J. Am. Chem. Soc., 86, 5637 (1964). K. Mislow, A. Ternay and J. T. Melillo, J. Am. Chem. Soc., 85, 2329 (1963). An ambiguity arises in the configuration designation of sulfinate esters because the prefixes (R) and (S) are reversed according to whether the S-O bond is regarded as a single or a double bond. We followed a previously established custom and considered for nomenclature purposes the S-O bond as a single bond. K.K. Andersen, J. Org. Chem., 29, 1953 (1964). K. Mislow, T. Simmons, J. T. Melillo and A. L. Ternay, J. Am. Chem. Soc., 8@ 1452 (1964). C.J.M. Stirling, J. Chem. Soc., 5741 (1963). H. Philipps, J. Chem. Soc., 127, 2552 (1925). K. Ziegler and A. Wenz, Juzstus Liebigs Ann. Chem., 511, 109 (1934). H.F. Herbrandson and R. T. Dickerson, J. Am. Chem. Soc., 81, 4102 (1959). M. Cioni and E. Ciuffarin, J. Chem. Res. S, 270, 272, 274 (1978). J. Drabowicz and S. Oae, Tetrahedron, 34, 63 (1978). C. Mioskowski and G. Solladi6, Tetrahedron, 36, 227 (1980). G. Solladi6, J Hutt and A. Gigardin, Synthesis, 173 (1987). D . N . Harpp, S. M. Vines, J. P. Montillier and T. H. Chan, J. Org. Chem., 41, 3987 (1976). J. Drabowicz, B. Bujnicki and M. M. Mikolajczyk, J. Org. Chem., 47, 3325 (1982). T. Satoh, T. Oohara, Y. Ueda and K. Yamakawa, Tetrahedron Lett., 29, 313 (1988). The reaction proceeds with inversion of configuration at sulfur. C. Mioskowski and G. Solladi6, Tetrahedron Lett., 3341 (1975). R. Annunziata, M. Cinquini, S. Colonna and F. Cozzi, J. Chem. Soc. Perkin I, 614 (1981). L. Colombo, G. Gennari and E. Narisano, Tetrahedron Lett., 3861 (1978). D.J. Abott, S. Colonna and C. J. M. Stirling, J. Chem. Soc. Chem. Commun., 471 (1971). (a) G. H. Posner and P. W. Tang, J. Org. Chem., 43, 4131 (1978). (b) G. Solladi6, P. Ruiz, F. Colobert, C. Hamadouchi, M. C. Carrefio and J. L. Garcia Ruano, Synthesis, 1011 (1991). H. Kosugi, M. Kitaoka, K. Tagami and H. Uda, Chem. Lett., 85 (1985). H. Kosugi, M. Kitaoka, K. Tagami, A. Takahashi and H. Uda, J. Org. Chem., 52, 1078 (1987).

46

GuY SOLLADIr AND M. CARMEN CARRENO

M. Mikolajczyk, W. Midura, S. Grejszczak, A. Zatorski and A. Chejczynska, J. Org. Chem., 43, 473 (1973). 43. M. Hulce, J. P. Mallamo, L. L. Frye, T. P. Kogan and G. H. Posner, Org. Synth., 64, 196(1985). 44. (a) G. H. Posner, T. P. Kogan, S. R. Haines and L. L. Frye, Tetrahedron Lett., 25, 2627 (1984). (b) G. H. Posner, M. Weitzberg, T. G. Hainell, E. Asirvathan, H. CunLeng and I. Clardy, Tetrahedron, 42, 4919 (1986). 45. K. Hiroi and N. Matsuyama, Chem. Lett., 65 (1986). 46. M.C. Carrefio, J. L. Garcia Ruano and A. Rubio, Tetrahedron Lett., 28, 4861 (1987). 4 7 . . M. C. Carrefio, J. L. Garcia Ruano, C. Pedregal and A. Rubio, J. Chem. Soc. Perkin Trans. I, 1335 (1989). 48. G. Solladi6 and N. Ghiatou, Tetrahedron Asymmetry, 3, 33 (1991). 49. E.J. Corey and M. Chaykowski, J. Am. Chem. Soc., 84, 866 (1962) and 87, 1345 (1965). 50. N. Kunieda, J. Nokami and M. Kinoshita, Chem. Lett., 369 (1974). 51. R. Annunziata, M. Cinquini and F. Cozzi, J. Chem. Soc. Perkin Trans. I, 1687 (1979). 52. F. Schneider and R. Simon, Synthesis, 582 (1986). 53. G. Solladi6, C. Greck, G. Demailly and A. Solladi6-Cavallo, Tetrahedron Lett., 23, 5047 (1982). 54. G. Solladi6, G. Demailly and C. Greck, Tetrahedron Lett., 26, 435 (1985). 55. H. Kosugi, H. Konta and H. Uda, J. Chem. Soc. Chem. Commun., 211 (1985). 56. G. Solladi6, G. Demailly and C. Greck, J. Org. Chem., 50, 1552 (1985). 57. G. Solladi6, C. Fr6chou, G. Demailly and C. Greck, J. Org. Chem., 51, 1912 (1986). 58. M.C. Carrefio, J. L. Garcia Ruano and A. Rubio, Tetrahedron Lett., 28, 4861 (1987). 59. M.C. Carrefio, J. L. Garcia Ruano, A. M. Martin, C. Pedregal, J. H. Rodriguez, A. Rubio, J. Sanchez and G. Solladi6, J. Org. Chem., 55, 2120 (1990). 60. A. Solladi6-Cavallo, J. Suffert, A. Adib and G. Solladi6, Tetrahedron Lett., 31, 6649 (1990). 61. M. C. Carrefio, J L. Garcia Ruano, M. Garrido, M. P. Ruiz and G. Solladi~, Tetrahedron Lett., 31, 6653 (1990). 62. P. Bravo, E. Piovosi and G. Resnati, Synthesis, 579 (1986). 63. P. Bravo and G. Resnati, Tetrahedron Lett., 28, 4865 (1987). 64. P. Bravo, E. Piovosi, G. Resnati and G. Fronza, J. Org. Chem., 54, 5171 (1989). 65. G. Guanti, E. Narisano, L. Banff and C. Scolastico, Tetrahedron Lett., 24, 817 (1983). 66. G. Guanti, E. Narisano, F. Pero, L. Banff and C. Scolastico, J. Chem. Soc. Perkin Trans. I, 189 (1984). 67. K. Ogura, M. Fujita, T. Inaba, K. Takahashi and H. Iida, Tetrahedron Lett., 24, 503 (1983). 68. G. Solladi6, C. Hamdouchi and M. Vincente, Tetrahedron Lett., 29, 5929 (1988). 69. P.C.B. Page, E. S. Namwindwa, S. S. Klair and D. Westwood, Synlett, 457 (1990). 70. P.C.B. Page, J. C. Prodger, Synlett, 460 (1990). 71. G. Solladi6 and N. Ghiatou, Tetrahedron Lett., 33, 1605 (1991). 72. C. Iwata, Y. Moritani, K. Sugiyama, M. Fujita and T. Imanishi, Tetrahedron Lett., 28, 2255 (1987). 73. G. Solladi6, A. Rubio, M. C. Carrefio and J. L. Garcia Ruano, Tetrahedron Asymmetry, 1, 187 (1990). 74. G. Solladi6, M. C. Maestro, A. Rubio, C. Pedregal, M. C. Carrefio and J. L. Garcia Ruano, J. Org. Chem., 56, 2317 (1991). 75. (a) G. Solladi6, J. Hutt and C. Frechou, Tetrahedron Lett., 28, 61 (1987). (b) G. Solladi6, C. Frechou, J. Hutt and G. Demailly, Bull. Soc. Chim. France, 827 (1987). 76. (a) G. Solladi6, I. Fernandez and M. C. Maestro, Tetrahedron Lett. 32, 509 (1991). (b) G. Solladi6, I. Fernandez and M. C. Maestro, Tetrahedron: Asymmetry, 2, 801 (1991). 77. G. Solladi6, C. Hamadouchi and C. Ziani-Cherif, Tetrahedron: Asymmetry, 2, 457 (1991). 78. G. Solladi6 and J. Hutt, Tetrahedron Lett., 28, 797 (1987). 79. G. Solladi6 and C. Ziani-Cherif, Tetrahedron Lett., 33, 931 (1992). 80. (a) H. H. Ghersett, G. Maccagnani, F. Montanari and F. Taddei, J. Chem. Soc., 3718 (1963). (b) H. Hogeveen, G. Maccagnani and F. Montanari, J. Chem. Soc. C., 1585 (1966). 42.

OPTICALLY ACTIVE ~-KETO SULFOXlDESAND ANALOGUES IN ASYMMETRICSYNTHESIS

81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118.

47

L . A . Paquette, R. E. Moerck, B. Harirchian and P. D. Magnus, J. Am. Chem. Soc., 100, 1597 (1978). C. Maignan and R. A. Raphael, Tetrahedron, 39, 3245 (1983). C. Maignan, A. Guessous, F. Rouessac, Tetrahedron Lett. 27, 2603 (1986). Y. Arai, S. Kuwayama, Y. Takeuchi and T. Koizumi, Tetrahedron Lett., 26, 6205 (1985). I. Alonso, J. C. Carretero and J. L. Garcia Ruano, Tetrahedron Lett., 38, 3853 (1989). C. Maignan, A. Guessous, F. Rouessac, Tetrahedron Lett., 25, 1727 (1984). T. Koizumi, I. Haskamada and E. Yoshii, Tetrahedron Len., 25, 87 (1984). M. Mikolajczyk, W. Midura, S. Grejszczak, A. Zatorski and A. Chejcznska, J. Org. Chem., 43, 473 (1978). (a) Y. Arai, H. Yamamoto and T. Koizumi, Chem. Lett. 1225 (1986). (b) Y. Arai, H. Yamamoto and T. Koizumi, Bull. Chem. Soc. Japan, 61, 467 (1988). H. Takayama, K. Hayashi, Y. Takeuchi and T. Koizumi, Heterocycles, 24, 2137 (1986). H. Takayama, A. Iyobe and T. Koizumi, J. Chem. Soc. Chem. Commun., 771 (1986). H. Takayama, K. Hayashi and T. Koizumi, Tetrahedron Lett., 27, 5509 (1986). H. Takayama, A. Iyobe and T. Koizumi, Chem. Pharm. Bull., 35, 433 (1987). Y. Arai, Y. Hayashi, M. Yamamoto, M. Takayama and T. Koizumi, J. Chem. Soc. Perkin Trans. I, 3133 (1988). T. Koizumi, Y. Arai and H. Takayama, Tetrahedron Lett., 28, 3689 (1987). S.D. Kahn and W. J. Herhe, Tetrahedron Lett., 27, 6041 (1986). O. De Lucchi, V. Lucchini, G. Valle and G. Modena, J. Chem. Soc. Chem. Commun., 878 (1985). O. De Lucchi, V. Lucchini, C. Marchioro, G. Valle and G. Modena, J. Org. Chem., 51, 1457 (1986). Y. Arai, K. Hayashi and T. Koizumi, Tetrahedron Lett., 29, 6143 (1988). Y. Arai, M. Matsui and T. Koizumi, Synthesis, 320 (1990). I. Alonso, J. C. Carretero and J. L. Garcia Ruano, Tetrahedron Len., 32, 947 (1991). Y. Arai, M. Matsui and T. Koizumi, J. Org. Chem., 56, 1983 (1991). I. Alonso, B. Cid, J. C. Carretero and J. L. Garcia Ruano, Tetrahedron: Asymmetrv, 2, 1193 (1991). S. Danishefsky, R. Sing and T. Harayama, J. Am. Chem. Soc., 99, 5810 (1977). R . K . Boeckman Jr, T. M. Dolak and K. O. Culos, J. Am. Chem. Soc., 100, 7098 (1978). G . A . Kraus and S. H. Woo, J. Org. Chem., 52, 114 (1986). (a) M. C. Carrefio, J. L. Garcia Ruano and A. Urbano, Tetrahedron Lett., 30, 4003 (1989). M.C. Carrefio, J. L. Garcia Ruano, J. M. Mata and A. Urbano, Tetrahedron, 47, 605 (1990). M.C. Carrefio, J. L. Garcia Ruano and A. Urbano, Synthesis, 651 (1992). B. Ronan and H. B. Kagan, Tetrahedron: Asymmetry, 2, 75 (1991). Y. Arai, S. Kuwayama, Y. Takeuchi and T. Koizumi, Synthetic Commun., 16, 233 (1986). C. Maignan and F. Belkasmioui, Tetrahedron Leu., 29, 2823 (1988). D. A. Evans, C. A. Bryan and C. L. Sims, J. Am. Chem. Soc., 94, 2891 (1972). G. H. Posner and W. Harrison, J. Chem. Soc. Chem. Commun., 1786 (1985). G. H. Posner, A. Haces, C. M. Kinter and W. Harrison, J. Org. Chem., 52, 4836 (1987). (a) R. A. Gibbs and W. H. Okamura, J. Am. Chem. Soc., 110, 4062 (1988). (b) R. A. Gibbs, K. Bartels, R. N. K. Lee and W. H. Okamura, J. Am. Chem. Soc., 11, 3717 (1989). L. E. Overman, C. B. Petty, T. Ban and G. T. Huang, J. Am. Chem. Soc., 105, 6335 (1983). (a) M. J. Fisher and L. E. Overman, Z Org. Chem., 53,2630 (1988). (b) M. J. Fisher, W. J. Hehre, S. D. Kahn and L. E. Overman, J A m . Chem. Soc., 110, 4625 (1988).

This Page Intentionally Left Blank

CHAPTER2

H O M O L Y T I C PROCESSES AT SULFUR David Crich Department of Chemistry (M/C 111), University of Illinois at Chicago, Box 4348, Chicago, Illinois, USA

ContEnts 2.1 2.2

2.3

2.4

Introduction Reactions of sulfur-centred radicals

49 50

Generation of alkyl radicals from organosuifur groups

72

2.2.1 2.2.2 2.2.3

Thiyi radicals Sulfinyl radicals Sulfonyl radicals

2.3.1 2.3.2 2.3.3 2.3.4 2.3.5

From From From From From

2.4.1 2.4.2

SH2 at sulfur Addition to thiocarbonyl sulfur

thiols sulfides

alkyl aryl sulfides suifones thiocarbonyl groups

Formation of carbon-sulfur bonds by reaction of carboncentred radicals with sulfur functional groups

Acknowledgements References

2.1

5O 64 64 72 73 74 76 76

79

79 81

83 83

INTRODUCTION

The history of the homolytic chemistry of sulfur functional groups is both long and detailed and includes some of the earliest free radical processes studied. This richness is a function of the diversity of sulfur functional groups that readily undergo homolytic reactions to provide sulfur, or carbon, centred radicals, and of the availability and stability of many of these classes of compounds. The intention of this chapter is not to survey in detail this extensive and long-standing chemistry, aspects of which have formed the subject matter of many book chapters and review articles, but rather to provide, by means of literature examples, a guide to the use of homolytic reactions at sulfur in synthesis. The bible of the modern free radical chemist Free Radicals, edited by Kochi, is a rich source of information, ORGANOSULFURCHEMISTRYCopyright 91995 Academic Press Ltd. ISBN-0-12-543560-6. All rights of reproduction in any form reserved.

50

DAVID CRICH

particularly of the more physical organic aspects, and should be consulted avidly by anyone intending to venture into this area [1]. A very readable, brief, descriptive overview of sulfur-centred radicals in synthesis is found in a monograph by Davies and Parrott [2], and excellent coverage of sulfur-containing radicals in general and of thiyl radical chemistry in particular is given in book chapters by Block [3] and Kellogg [4], respectively.

2.2

REACTIONS OF SULFUR-CENTRED RADICALS

2.2.1

Thiyl Radicals

Thiyl radicals can be generated, either photochemically or thermally, from a number of organosulfur groups [3, 4]. However, the use of thiyl radicals in synthesis requires that the precursor be compatible with as wide a range of functional groups as possible and be capable of providing a smooth, controlled flow of radicals. When these constraints are taken into consideration, the range of precursors is narrowed somewhat such that hydrogen abstraction from thiols and homolytic substitution at disulfides and related functions are by far the most common methods. The current success and popularity of free radical chain reactions in carbon-carbon bond-forming reactions owes much to the extensive compilations of data available on the rates of uni- and bimolecular radical processes. With the expectation that the reader will find it useful, some rates for key reactions of thiyl radicals are give in Table 2.1 together with some more familiar radical processes for comparison. The preparative chemistry of thiyl radicals is dominated by the addition to carbon-carbon multiple bonds with concomitant formation of carbon-centred TABLE2.1

Rates of some bimolecular processes involving thiyl radicals

Radical

Trap

ButS 9 Ph2CH~CH2 ButS 9 (C3Hs)2C~CH2 ButS 9 CH3(CH2)~CH CH2 ButS 9 Et3B ButS 9 (EtO)3P PhS. PhCH ~ C H 2 PhS. CH302CC(CH3)----CH2 CH2~CH(CH2)3CH2. PhSSPh CH3(CH2)6CH2. O-Acyl thiohydroxamate Bun. PhSH CH3(CH2)~CH2. CH302CCH~CH2 Alkyl radicals 1,1,3,3-Tetramethylisoindoxyl Bu". Bu3SnH

k (M-1S -1) 9.9 2.4 2 1.3 3.1 2.7 5.4 7.6 1.9 1.36 4.6 ca1 2.4

• • • • • • • • • • • • •

108 108 106 108 108 107 106 104 106 108 10 ~ 109 106

T (K)

Ref.

298 298 298 298 298 298 298 298 313 298 273 273-353 300

[5] [5] [5] [5] [5] [6] [6] [7] [8] [9] [10] [11] [12]

HOMOLYTIC PROCESSESAT SULFUR

51

radicals (Scheme 2.1).

RS"

RS"

/ \

+

+

~

'

Scheme 2.1 The anti-Markownikoff addition of thiols and thiolacids to alkenes, recognized in 1905 by Posner [13], and explained in terms of a radical mechanism in 1938 by Kharasch [14] has been extensively studied and is the subject of an article in Organic Reactions [15]. Selected examples of the addition of the S-H function to alkenes are given in Schemes 2.2 [16], 2.3 [17], 2.4 [18], 2.5 [19], 2.6 [20], 2.7 [21], 2.8 [22] and 2.9 [23]. From the examples presented, here and in Organic Reactions, it can be seen that thiyl radicals add to most types of alkene and alkyne and that these reactions are apparently much less susceptible to steric hindrance in the alkene than are the corresponding reactions of alkyl radicals [24]. Thiyl radicals are generally considered to be electrophilic and so to add most rapidly to electronrich alkenes. However, they are evidently much less selective than alkyl radicals in this respect and the overall picture is complicated by the reversible nature of the addition reaction and the thermodynamic stability of many of the products. As such, values for the rates, absolute and relative, of thiyl radical addition to alkenes and alkynes have to be viewed with caution. A recent example, from the Murphy group, serves to introduce the addition of thiyl radicals to alkenes as a trigger for further radical rearrangement reactions Peroxide CH3SH

+

CH3CH = C H C H O

~-~ CH3SCH(CH3)CH2CH O

67%

Scheme 2.2 93% EtSH

+

A(

CH2~CHOEt

~

EtSCH2CH2OEt

Scheme 2.3 77% + CH3COSH SCOCH 3

Scheme 2.4 O II (EtO)2P~sH

+

50% CH3OCCHmCHCO2CH3 ~ Scheme 2.5

0 II (EtO)2P-.SCH(CO2CH3)CH2CO2CH3

52

DAVID CRICH

EtSH +

EtSC~CCO2Et

h~ + AIBN -~ 58%

EtSCH----C(SEt)CO2Et

Scheme 2.6 ~ : ~

O

AIBN

+ H2S

J

64%

Scheme 2.7 ~ "

+ MeSH

Et20, 63% -no initiator

SMe

Scheme 2.8 AcO~Q A c O . . . ~ . . ~ ~ SH + OAc

A..

AIBN

AcO A

~

80%

S OAc

.eL

Scheme 2.9

(Scheme 2.10). It is noteworthy in this example that opening of the epoxyalkyl radical is faster than 13 elimination and also that the chain is propagated by the benzoyl radical [25]. O O

BUSH, AIBN ,

Ph

A

O

SBu

-

PhAH

Scheme 2.10

From the standpoint of organic synthesis, the most attractive feature of these addition reactions, apart from the formation of carbon-sulfur bonds, is the use of the intermediate [3-thioalkyl radicals in the subsequent formation of new bonds to carbon, whether by inter- or intramolecular processes. The successful use of [3thioalkyl radicals (and [3-thiovinyl radicals) generated in this manner in synthesis is a function of many variables. These variables stem from the numerous alternative pathways for the evolution of the [3-thioalkyl radical and are frequently a function of the precursor, such as hydrogen atom abstraction from a molecule of thiol or attack on the S-S bond of a disulfide molecule. However, the most important, and omnipresent, competing pathway is the back-reaction, namely the rapid and efficient [3 elimination of a thiyl radical. This is independent of the radical precursor. The rate of elimination of the n-butylthiyl radical from [3-butylthioalkyl radicals has been estimated by Wagner to be 2.7 • 105 s -~ at 25 ~ C [26], which is very close to the rate of the 5-hexenyl rearrangement (2.3 • 105 s -1) [27] at the same temperature. Arenethiyl radicals are eliminated even more rapidly. Fortunately, this apparently problematic process turns out to be extremely useful

HOMOLYTIC PROCESSESAT SULFUR

53

in practice, as will become clear in the course of this chapter. The intramolecular addition of thiyl radicals to alkenes and alkynes (that is, cyclization of unsaturated thiyl radicals) is, like the intermolecular reaction, complicated by the reversibility of the fundamental step. As such, mixtures of exo and endo mode cyclization products are observed and the ratio of products is found to change with temperature and concentration. Furthermore, even under conditions where the addition is not reversible, lower exo/endo selectivity than for the prototypical 5-hexenyl cyclization is to be expected due to the longer C-S bond length. Early attempts at the formation of sulfur heterocycles by radical addition of hydrogen sulfide to ot,~o-dienes appear to have been particularly susceptible to problems of regioselectivity. Nevertheless, the following examples, taken from the work of Surzur and co-workers [28, 29] demonstrate the viability of thiyl radical cyclizations under appropriate conditions (Schemes 2.11 and 2.12) [30].

~

SH 70% Scheme 2.11 Ph

hi) ~ P h

75% Scheme 2.12

An interesting example of efficient cyclization in the 6-endo mode was described by Maki for the photolysis of a penicillin sulfoxide-derived disulfide (Scheme 2.13) [31]. It is interesting to note, in this example, that the cyclized radical did not combine with the benzoxazole-thiyl radical but rather suffered hydrogen atom abstraction.

PhCH2CONH~---~S

.••O•

~

PHCH2CONHhu

S

PHCH2CONH +

O

CH3CN

60%

COEMe

S

O 15%

~

CO2Me

+ 2-mercaptobenzoxazole, 58% Scheme 2.13

Further interesting examples of predominant ring closure in the 6-endo mode have been described by Surzur (Scheme 2.14) [32]. In this particular study the thiyl radicals were generated by photolysis of allyl and benzyl sulfides. The results were interpreted in terms of a reversible cyclization leading, eventually, to the more thermodynamically stabilized radical with subsequent quenching by the allyl or benzyl radical. That the reaction was not concerted nor a radical cage mechanism, was demonstrated by crossover experiments.

54

DAVID CRICH

~

hx)

~

P h ~

ph)

+

PhCH2CH2Ph

50%

46%

Scheme 2.14 A recent example from the Heimgartner group serves to illustrate the nonapplicability of Baldwin's rules to second row elements such as sulfur (Scheme 2.15) [331.

I•S•

Ph'~

AIBN, hexanes,A ~

--~~N Ph

s.

Scheme 2.15 In contrast to the addition of thiols, the successful addition of disulfides to alkenes is rare, owing to effective competition of 13 elimination with attack of the [3-thioalkyl radical on the disulfide (Scheme 2.16). A very attractive solution to this problem has recently been described by Ogawa [34]. This ingenious piece of work simply employs one equivalent of the more reactive diphenyl diselenide such that the adduct radical is trapped before elimination (Scheme 2.17).

RS-

RS) \

RSSR

Scheme 2.16

PhSSPh + PhSeSePh h~, 74%

~ ~ S P h SePh

Scheme 2.17 The reversible addition of thiyl radicals, in conjunction with disulfides as a poor trap, to alkenes has been exploited most often as a means of isomerization of alkenes to their more stable configuration (Schemes 2.18 and 2.19) [35, 36]. As with all radical reactions, the addition of thiols and disulfides to alkenes must be carried out in the absence of oxygen to avoid quenching of intermediate radicals. However, this side-reaction can be turned to advantage. The reaction of thiols with alkenes in the presence of molecular oxygen is used as a means of entry

PhSSPh,h~)

50% Scheme 2.18

HOMOLYTIC PROCESSESAT SULFUR

H

55

PhSSPh, hv y

100%

Scheme 2.19

into [3-hydroperoxysulfides and thence, by reduction, to [3-hydroxysulfides or, by rearrangement, to [3-hydroxysulfides (Scheme 2.20) [37, 38]. In practice, the reduction can be achieved in situ by an excess of thiol or with a phosphine. Ph.~

Pr"SH, 0 2

~

Ph

89%

~

OH

SPr" 0

Scheme 2.20

The addition of thiyl radicals to alkenes and alkynes with trapping of the adduct radical by carbon monoxide leading, after chain transfer, to 3-alkylthioaldehydes has been described, albeit in low yield (Scheme 2.21) [39]. It is possible in view of the recent publications of Ryu on the reaction of alkyl halides with CO in the presence of tin hydrides [40] that this process could be improved. 125~C, 3000 atm EtSH +

H C - C H + CO

17%

EtSCH=CHCHO

Scheme 2.21

Most of the more preparatively interesting thiyl radical additions to alkenes involve rearrangements of the initial adduct radical with simple examples involving heterocycle formation. An interesting synthesis of 1,3-dithiolanes involves AIBNinitiated addition of dithio acids to alkenes (Scheme 2.22) [41]. This reaction, in which the thiocarbonyl group serves as a trap for the initial adduct radical, has been extended to encompass the use of dienes [42]. The addition of thiyl radicals to alkenes bearing a thiocarbonyl group in the 5 position also results in heterocycle formation by attack of the adduct radical on the thiocarbonyl group (Scheme 2.23) [431. A further simple heterocycle synthesis is known as selenothiolactonization. This process (Scheme 2.24), described by Toru and evidently related to the disulfide/diselenide addition of Scheme 2.17, involves the AIBN-initiated rearrangement of unsaturated S-acyl phenylselenosulfides [44]. Presumably, a chain reaction is involved whereby the acylthiyl radicals cyclize in the 5-exo mode S

Pr' "-'~SH

+

PhCH--CH2

AIBN

,sin Pr' --CHs. ~

Ph

85%, c i s ' t r ans = 1'1

Scheme 2.22

56

DAVID CRICH X

X

,s.

-,r-z

AIBN R Scheme 2.23

followed by attack of the ring closed radical on the S-Se bond of a further molecule of precursor. The requisite S-acyl phenylselenosulfides are readily prepared by reaction of N-phenylselenophthalimide with thiol acids.

~ ~ ~ t-- COSSePh ....S

AIBN, 80~

+

~/~

SePh

79%

11%

....S

""SePh

Scheme 2.24

There are surprisingly few examples of 5-hexenyl rearrangements initiated by thiyl radical addition to 1,5-dienes and related substances; in the very extensive review by Stacey and Harris [15], there are none. This lacuna can probably be attributed to difficulties arising from rapid 13 elimination and efficient hydrogen abstraction before ring closure. Nevertheless, Kuehne has defined conditions under which dimethyl diallylmalonate can be induced to cyclize using both thiols and disulfides (Scheme 2.25) [45]. However, it is possible that in these particular examples, cyclization occurs in preference to [3 elimination due to the obvious accelerating 'Thorpe-Ingold' effect of the two ester groups.

EtS"-~ / /" ~'~''~ Me02C C 0 2 M e ~

MeO2C~CO2Me

CF3SSCF3,h'o ~

CF3S~

~

#~SCF3

48%

X

Me02C- "C02M e Scheme 2.25

More recently, Broka has demonstrated that slow addition of thiophenol to a refluxing solution of an appropriate enyne in benzene or toluene, or better, 2,2,5,5-tetramethyltetrahydrofuran (TMTHF) was effective in promoting cyclization [46]. The isolated products were the result of thiyl radical addition to the unsubstituted terminus of the alkyne, 5-exo cyclization of the vinyl radical, ring

HOMOLYTICPROCESSES ATSULFUR

57

expansion as detailed by Beckwith and Stork [47], and chain transfer (Scheme 2.26).

TMTHF, A, 70%

Scheme 2.26

The addition of thiyl radicals to cyclic polyenes with a subsequent trans-annular carbon-carbon bond-forming reaction is also known, as for example in the cyclization of germacrene to the valencene skeleton with thiophenol described by Sutherland (Scheme 2.27) [48]. The rapid trapping of the initial [3-thioalkyl radical by such favourable trans-annular cyclizations means that disulfides may be efficiently used as sources of thiyl radicals. A further example, in which otacoradiene was cyclized in an essentially quantitative yield with dimethyl disulfide, was reported by Kuehne (Scheme 2.28) [45]. PhS

PhSH, hu 34%

Scheme 2.27

MeSSMe

h~

~ S M e .........~

SMe

Scheme 2.28

The normally rapid [3 elimination of thiyl radicals from [3-thioalkyl radicals has been turned to advantage in the formation of carbon-carbon bonds by intermolecular radical addition to electron-deficient alkenes. In this type of reaction, telomerization, by attack of the adduct radical on a further molecule of alkene, is a serious, and often limiting, competing factor. When electron-deficient allylic sulfides are used, in place of simple electron-deficient alkenes, the adduct radical undergoes rapid [3-elimination, resulting in the formation of clean, polymerfree, products. The Barton group has developed two such alkenes for use in conjunction with their O-acyl thiohydroxamate method for radical generation (Scheme 2.29). Both reagents have been used in the preparation of the 25hydroxysteroid side-chain from the corresponding cholanic acids [49]. Keck has also reported on a protocol in which methallyl phenyl sulfides were used in conjunction with alkyl halides and hexabutyldistannane in an

58

DAVIDCRICH H

S OCI

~._

O- Na*

'C02Et

OAc

,,,,,,

{

74%

. .v

rCO2Et

SBu t

NO2

S

77% Scheme 2.29

intermolecular carbon-carbon bond-forming reaction involving [3-elimination of a thiyl radical as a key propagation step (Scheme 2.30) [50]. In intramolecular versions of this process it is possible to generate the attacking radical by means of the more usual alkyl or aryl halide/tributyltin hydride couple (Scheme 2.31) [51]. o

P~O

0

ISPh

Ph

~ N~l

(Bu3Sn) 2, h~

~ 68%, cis " t r a n s = 2.6:1

Scheme 2.30

..SPh Bu3SnH, 91%

PhCH20~N

PhCH20

PhSO2

I

~'~~N

PhSO2

Scheme 2.31

The unwritten implication, in the latter example, is that the eliminated thiyl radical efficiently abstracts hydrogen from the stannane to regenerate the chainpropagating stannyl radical: PhS. + Bu3SnH

PhSH + Bu3Sn"

The most significant advance in recent years in the preparative chemistry of thiol radicals has been their use to trigger cyclopropylmethyl-3-butenyl-type rearrangements. A number of interesting variations on this theme have appeared, but the first example was described almost 20 years ago by Gompper (Scheme

HOMOLYTIC PROCESSESAT SULFUR

59

2.32) [52]. Rather interestingly, the reaction sequence appears to include a rare 4endo- (or exo-) trig process. Unfortunately, no yields were given for this unusual rearrangement.

9Ptl

Scheme 2.32

In the last few years, several groups have taken ingenious advantage of the rapid 13-elimination of thiyl radicals as a final step in various cyclopropylmethyl-3butenyl-type rearrangements. These sequences were also initiated by the addition of a thiyl radical to a multiple bond and require only a catalytic quantity of a disulfide. These processes may involve only intramolecular carbon-carbon bondforming steps as in the work of Oshima (Scheme 2.33) [53], or may include an intermolecular radical carbon-carbon bond-forming step as in that of Feldman (Schemes 2.34 and 2.35) [54]. The possibility of using electron-rich alkenes in the latter sequence is noteworthy. Alkynes may also be used in the Feldman procedure (Scheme 2.36) [55]. A further interesting variant uses molecular oxygen, instead of a carbon-carbon multiple bond, to provide the requisite atoms for the cyclization step [56, 57]. The vast majority of examples described in this chapter use the couple PhSeSePh/O2/AIBN, but it is stated that all aromatic disulfides and diselenides

s, 73,

-

Scheme 2.33

ButO2C~

ButO~C (PhS)2,AIBN ~k

53%

r

4.4

Bu'O:2C %CO2But +

CO2But

~

1.9

U

ButO2C% ~ ~ +

1.2

Scheme 2.34

~CO2But

1 0 '~176

t

60

DAVID CRICH EtO

+

o ,o

(PhS) 2, A I B N

0

I

--

oyo "~-'"~

"

+

+

ou "*

O 5.5

n

,..,

~176

0yo

*"

~

O 4.4

O 1.0

Scheme 2.35

ButOzCV~-'7~+---

PhSSPh,50%

__ SO2Ph

~ ~ Bu'02C

-SO2Ph

SO2Ph

+ ~ / ButO2C" " 1

1.9

Scheme 2.36

performed equally well. A serial bisoxygenation could be achieved with diphenyl disulfide but not with the corresponding diselenide (Scheme 2.37). o--O

P h ~

PhSSPh,48%AIBN hag,

O-O +

1

o..O

0-0

1.4 Scheme 2.37

Following a report by Hiraguri and Endo [58] on the fragmentation, with expulsion of benzophenone, of 2,2-diphenyl-l,3-dioxolan-4-yl radicals leading to the formation of oL-keto radicals, Feldman has reported a further variant on his strategy, enabling the formation of cyclohexanones (Scheme 2.38) [59].

/~

~O

Ph

PhSSPh,A I B N + ~N,CO2 ~ BU'A,h~, 51%

O

+ Ph2CO cis

9trans

=

1.8

" 1

CO2But Scheme 2.38

An alternative thiyl radical-catalysed annelation sequence, which combines methylene cyclopropanes with electron-rich alkenes, has been reported by Singleton and Church (Scheme 2.39) [60]. Consideration of the mechanism of this

HOMOLYTIC PROCESSESAT SULFUR

~OBUlcis"trans

BuSSBu, h~

~'OBu'

+

81%

~S02Ph

61

= 56 " 44

PhSO2' f

Scheme 2.39

~C02Me

I

BuSSBu

+

htL 73%

~C02Me

60 940 mixture

MeO2C MeO2C

Scheme 2.40

reaction led these authors to propose that increasing the steric bulk of the thiyl radical catalyst would increase the t r a n s : cis ratio of the annelated products [61]. This proved to be the case: replacement of dibutyl disulfide by dimesityl disulfide in the above example gave a t r a n s : cis ratio of 69: 31. With other alkenes the ratio was as high as 92 : 8. Recent examples from Singleton's laboratory have replaced the sulfonyl groups by one, or two, carbomethoxy groups (Scheme 2.40) [62]. In recent years, thiyl radicals, together with a range of other electrophilic and nucleophilic radicals, have been shown to attack at the bridgehead carbon atom in [1.1.1]propellane, resulting in cleavage of the central bond and formation of the [1.1.1]bicyclopentane nucleus (Scheme 2.41) [63]. This sequence effectively amounts to bimolecular homolytic substitution (SH2) at saturated carbon, a process for which there is only a relatively limited number of examples. The absolute rate constant for the key step, reaction of the benzenethiyl radical with [1.1.1]propellane, has been measured by laser flash photolysis. A lower limit of k = 2• -1 was set [64]. It was suggested at the same time that the reaction is reversible, and there is some experimental support for this idea [65]. RSSR

A

-

Scheme 2.41

The process has been extended to [2.1.1]propellanes in a spectacular cascade arrangement (Scheme 2.42) [66] and even to a [3.1.1]propellane encapsulated in an adamantane skeleton (Scheme 2.43) [67]. CO2Me

CO2Me PhSH, AIBN 80 ~ 57%

CO2Me

PhS

Scheme 2.42

CO2Me

62

DAVID CRICH

PhSSPh

PhS

C606,RT,99% Scheme 2.43

Thiols are very efficient sources of hydrogen atoms for the quenching of alkyl radicals. Indeed, alkyl radicals abstract hydrogen from aromatic thiols more rapidly than from the common synthetic reagent tributyltin hydride (see Table 2.1). Nowhere is this propensity for the donation of hydrogen atoms more apparent than in nature, where hydrogen abstraction from glutathione serves as a repair mechanism for radiation damage [68]. Evidently, in synthesis the most obvious examples are the addition of thiols across multiple bonds discussed above, but thiols have also served as hydrogen atom donors in so-called dissolving metal reductions. The most notable examples are in chromous acetate reductions. In the two examples given here (Schemes 2.44 [69] and 2.45 [70]), the inclusion of a powerful hydrogen atom source to prevent over-reduction of the intermediate alkyl radical to the corresponding carbanion, and consequent elimination, was crucial to the success of the reaction. I

O ~ O

Cr(OAc) 2,DMSO

H

EtSH,88% O Scheme 2.44 o

O ~

BUSH,74% Scheme 2.45

Thiyl radicals are electrophilic, and, in the absence of effective competing reactions, themselves abstract hydrogen atoms from activated C - H bonds. Thus, thiols have been used to catalyse the decarbonylation of aldehydes [71]. Thiyl radicals derived from disulfides have been used to promote dehydrogenation of allylic and benzylic hydrocarbons, as in the formation of guaiazulene from terpenoids (Scheme 2.46) [72]. For a more detailed coverage of the hydrogenabstracting capabilities, the reader is referred to the chapter by Kellogg [4]. With a view to replacing the use of tributyltin hydride in the reduction of alkyl halides with that of the less noxious tri(isopropyl)silane, Roberts has introduced

HOMOLYTIC PROCESSESAT SULFUR

63

PhSSPh, ha9 - 30%

Scheme

2.46

the notion of polarity reversal catalysis by thiols (Scheme 2.47) [73]. The simple use of the silane alone is essentially precluded by the inefficiency of the reaction of alkyl radicals with silanes to give alkanes and silyl radicals. In the Roberts protocol a catalytic amount of thiol serves to quench the alkyl radical. The resulting electrophilic thiyl radical then abstracts, efficiently, the relatively electron-rich silane hydrogen. The protocol has been extended to include the Barton-McCombie reaction (Scheme 2.48) [74].

R--Hal + ,siipr3 R. + R'S" + R--Hal

~

H--SR' H--Siipr3 +

R.

~ ~

Scheme

SCH3

R'SH

.SR' ,siipr3

HalmSiipr3

2.47

Pr'~SiH. 140~

0

catalytic R'SH

Scheme

+ +

R--H +

H--Siipr3

'9~

HalmSiipr3

+

R--H

O 60%

~

2.48

An interesting variant on this theme has been introduced by the Ottawa/Bordeaux radicals group. In this process, tris(trimethylsilyl)silylmercaptan serves as a source of hydrogen atom. After hydrogen abstraction the so-formed thiyl radical undergoes what might be described as a radical thio-Brook-type rearrangement to give a silyl radical capable of propagating a chain by halogen abstraction from alkyl halides (Scheme 2.49) [75]. TMS t

+R.

SH

-RH

TMS - - S i - T M S ~ T M S I

TMS

TMS

I

t

-S i-TM S - O - ~ TMS- Si. i i

S.

+RX

S-TMS

Scheme

2.49

TMS I

----T M S - Si-X -R. I

S--TMS

64

2.2.2

DAVID CRICH

Sulfinyl Radicals

In contrast to thiyl and sulfonyl radicals, sulfinyl radicals have been little exploited in preparative organic chemistry [76]. The reaction of most potential interest for the synthetic organic chemist, the addition of sulfinyl radicals to multiple bonds with trapping of the adduct radical, does not appear to have been recorded. There is, however, limited evidence for the addition of sulfinyl radicals to styrenes in the form of a report by Iino, who observed the scrambling of stereochemistry of cis-f3deuteriostyrene in the presence of methyl and p-tolylsulfinyl radicals, generated by the pyrolysis of the corresponding benzhydryl sulfoxides [77]. The major obstacle to the exploitation of this addition reaction in synthesis appears to be the extreme rapidity of the reverse reaction: elimination of sulfinyl radicals from [3-sulfinylalkyl radicals. The relative rates of elimination of BUS., BuS(O)., and BuS(O2). at 25 ~ C have been estimated by Wagner to be a 1:475 : 2.9 and the relative rates of elimination of BuS(O). and PhS(O). to be 1:8.3 [26]. These relative rates of elimination are confirmed by the more qualitative work of Ueno [78]. However, perhaps the most striking illustration of the rapidity of the elimination of [3-sulfinyl radicals was reported by Boothe et al. [79]. These workers observed that treatment of each of the four possible diastereoisomers of 2-bromo-3-phenylsulfinylbutane with tributyltin hydride resulted in stereoselective 2-butene formation, the implication being that the elimination of the phenylsulfinyl radical competes effectively with rotation of the 2,3-bond in the intermediate radical. Clearly, the addition of sulfinyl radicals to alkenes will only be of use, in a preparative sense, with very efficient radical traps.

2.2.3

Sulfonyl Radicals

Like thiyl radicals, sulfonyl radicals are generally considered to be electrophilic in nature. This characteristic was put on a superficially firm footing by Corr6a, who noticed that the rate of addition of the tosyl radical to various ring-substituted styrenes increased regularly with the electron-donating character of the substituents [80]. The relative rates of addition of the phenylsulfonyl radical to several alkenes have been measured by Takahara, who found that they vary in the proportions acrylonitrile : methyl acrylate : styrene : e~-methyl styrene = 0.006 : 0.012 : 1 : 3.21 [81]. These relative rates appear to support the electrophilic nature of the phenylsulfonyl radical but, again as with thiyl radicals, could also represent differing rates of the back reaction and/or stability of the adduct radicals. The situation is further complicated by the very recent work of Corr~a, who found that, in competition experiments tosyl iodide added, with seemingly equal facility to acrylate esters and vinyl ethers [82]. Evidently the situation is complex and is governed not only by the electrophilicity of the sulfonyl radical and relative rates of addition and elimination but also by the stabilities of the adduct radicals and their ability to abstract halogen from arenesulfonyl halides. This latter factor probably results in apparently different reactivities for the same alkene, depending on the sulfonyl halide (chloride, bromide or iodide) used.

HOMOLYTIC PROCESSESAT SULFUR

65

As with sulfinyl radicals, Chatgilialoglu has recently presented an overview of the physical organic chemistry of sulfonyl radicals, and the reader is referred to this article, and references therein, for information on this aspect of sulfonyl radical chemistry [83]. The preparative chemistry of sulfonyl [169] radicals is closely analogous to that of thiyl radicals, and is dominated by their reversible addition to carbon-carbon multiple bonds. The major difference between preparative thiyl and sulfonyl radical chemistry lies in the greater range of precursors available for use in radical chain reactions. Thus, radical chain reactions involving thiyl radicals are largely dominated by the use of thiols and disulfides. As such there are effectively only two propagation steps to choose from (R. + R'SH -~ RH + R'S. and R. + R'SSR' --* RSR' + R'S.) with vastly differing rates. Chain reactions with sulfonyl radicals usually involve sulfonyl halides and pseudohalides as radical precursors, and hence the propagation step R. + R'SO2 x --~ RX+R'SO2.. The increased subtlety of sulfonyl halide chemistry therefore comes from the ability to vary the halide and so the rate of the propagation step. As such, the adduct radical derived from sulfonyl addition to a multiple bond may be permitted to undergo, or indeed be prevented from undergoing, a further rearrangement by an appropriate choice of sulfonyl halide. The relative rates of halogen abstraction from sulfonyl halides by alkyl radicals are I>Br>C1, with fluorides being inactive. The relative rates of abstraction of iodine, bromine and chlorine by the phenyl radical from the corresponding ptoluenesulfonyl halides was found by Correa to be 602 : 192 : 1 [84]. The intermolecular addition of sulfonyl halides to alkenes, alkynes and allenes has been extensively studied and reported on in the literature [85]. A number of early examples are to be found in the article by Stacey and Harris in Organic Reactions [15], and several further illustrative examples are given in Schemes 2.50 [86], 2.51 [87], 2.52 [88], 2.53 [89], 2.54 [90], 2.55 [91], 2.56 [92], 2.57 [93] and 2.58 [94].

PhS02CI + h ~ O ' ~ MeO"

AIBN,hx) .~

~'0~ MeO~

S02Ph CI

Scheme 2.50 0

~--SO2C1

CUC12,95%_._~_g . ~ . , , . " ~ / +

Scheme 2.51

--~S02C1

67% Scheme 2.52

'C1

66

DAVID CRICH

MeSO2Br+

__. ---

MeOf

jOMe

59%

Me SO2 M e O ~ O M e

Br

Scheme 2.53

---•SO21

+

Ph

80%

~.--'-Ph

Scheme 2.54 PhS02C1 TMS ~

TMS

~ CuC1, cat., 80%

~TMS PhSO2" (E)/(Z ) = 82 : 8

Scheme 2.55

Q

PhSO2I

SO2Ph

I

CuC12, 78%

trans: cis = 1:15

Scheme 2.56 IOEt ~""1

t~

OEt

CHEC12 68%

"

I t~

~'~CHO

Scheme 2.57

BrCH2SO2Br~ CH2CI2, h~, 96%

~ ~ 7 ~/SO2CH2Br+ Br

Br~

SO2CH2Br

1 9I

Scheme 2.58

Sulfonyl chalcogenides also add to alkenes and alkynes by a radical chain reaction. Thus, it was demonstrated in 1974 that toluenesulfonyl thiocyanate reacted, inter alia, with cyclohexene to give a, presumably, trans adduct in good yield [95]. However, it was not until the more recent discovery of the reaction of phenylselenosulfonates with carbon-carbon multiple bonds that the usefulness of such processes was realized (Schemes 2.59 [97], 2.60 [98], 2.61 [99] and 2.62 [100]). By reasonable analogy with the abstraction of bromine atoms and phenylseleno groups from the corresponding alkyl derivatives with stannyl radicals [96], it can safely be assumed that phenylselenosulfonates have comparable reactivity to

HOMOLYTICPROCESSES ATSULFUR

O

67

L~,,. sOztOlyl

PhSeSO2tolyl, 80%

~"SePh Scheme 2.59 PhSeSO2Ph, CHCI3, A, 66%

~

Scheme 2.60

SO~Ph

SePh

PhSeSO2toly1

tolyl~~L'~ph

y

h~, CC14,91% Scheme 2.61

HOv"~~

PhSeSO2Ph

~

HO~'~---"/SO2Phphs/

CHC13, AIBN, A, 88% Scheme 2.62 sulfonyl bromides in radical chain reactions. Toluenesulfonyl cyanide also adds cleanly to alkenes with A I B N initiation [101]. This process (Scheme 2.63) is especially useful as it includes the addition of a single functionalized carbon atom, and is to be contrasted with the use of thiols and carbon monoxide (Scheme 2.21).

O

T~

~

NC....~

SO2TolyI

AIBN, 60 eC, 68%

Scheme 2.63 Sulfonyl radicals are also known to take place in homolytic allylic substitution reactions with alkenes carrying radical leaving groups. This area has been R'~[Co] H ~ R~ R"

~[Co]

~

RSO2C1

SO2R R ' ~

=

RSO2C1 ..... RSOzC1

RSO2~~ R

RSO2 I

+ [Co]C1

t

-------

R"

[Co] = bis(dimethylglyoximato)pyridinecobalt(IIl) Scheme 2.64

+ [ColC1

+[Co]C1

68

DAVID CRICH

MeCH=CHCH2SnBu3

Me~CH2

Pr"SO2CI 46%

prnSO2'

Scheme 2.65

---/ SnBu3

MeOEC

PhSO2C1

_ _ / SO2Ph

h~, 68%

MeO2C (E)/(Z)=50" 1

Scheme 2.66

comprehensively studied by Johnson's group for cobaloximes (Scheme 2.64) [102] and by Russell's group for allyl and vinyl stannanes (Schemes 2.65 and 2.66) [103, 104]. There have been surprisingly few studies on the cyclization of sulfonyl radicals onto alkenes. However, work in this area has been recently reported by Walton, who noted that the AIBN-initiated cyclization of pentenesulfonyl chloride resulted, at 150 ~ C, in the unique formation of the e n d o mode product, albeit in low yield [105]. At 75 ~ C, the ratio of e n d o : e x o mode products was approximately 8 : 1 (Scheme 2.67). This variation of e n d o : e x o ratio with temperature is obviously strongly suggestive of a reversible cyclization. It is highly likely that if a more efficient trap ~ the sulfonyl iodide ~ were used that a much higher proportion of the five-membered ring would be observed. C1

~]S 02CI

AIBN' CuC12 "o "-75C

Z ~.......]Sg2 12

CI"A~Vj d9 "~0

+ 9

88

Scheme 2.67

The ready [3-elimination of sulfonyl radicals has been exploited by a number of workers. In particular, Ueno has developed the AIBN-initiated reaction of tributyltin hydride with allylic sulfones as a means of entry into allylic stannanes, important reagents in modern organic synthesis (Scheme 2.68) [106]. Padwa has used allylic sulfones in radical carbon-carbon bond formations (Scheme 2.69) [107]. As with thiyl radicals, the most attractive applications of the ready and reversible addition of sulfonyl radicals to carbon-carbon multiple bonds arise when the adduct radical undergoes a skeletal rearrangement, prior to chain

Bu3SnH, AIBN 80~ C, 71% Scheme 2.68

~

~ ~ ' ' ' ' I SnBu3 71%

HOMOLYTIC PROCESSESAT SULFUR

Br~CO2

9

69

ha0

+

S

SO2Ph

SO2Ph

88%

Br

Scheme 2.69

transfer. Early advantage of this type of process was taken by Whitham (Scheme 2.70), who caused a number of olefinic, or acetylenic, allylic sulfones to suffer rearrangement with formation of the cyclopentane nucleus [108]. A number of other cyclizations induced by the addition of sulfonyl radicals to non-conjugated dienes are outlined in Schemes 2.71 [109], 2.72 [110], 2.73 [111], 2.74 [111] and 2.75 [111]. The example in Scheme 2.75 is especially interesting in so far as the electrophilic sulfonyl radical is seen to have undergone selective addition to the more electrondeficient of the two possible alkenes. This unanticipated regioselectivity is probably best interpreted in terms of a rapid and reversible addition to each of the two alkenes with trapping of the adduct which leads to the more rapid cyclization. CC14' (PhCO2)2

2Ar

H

A, 74% O ~

SO2Ar Scheme 2.70

tolylSO2Br

~

"

"-

~O2tolyl ~

B

r

Scheme 2.71

tolylSO2Br fi~, 70%

b

AcO=-=x tolylSO2--~- ~.~.0 = 1:7

exo : endo

Scheme 2.72

tolylSO2C1 M

e

~ tolylSO2__~Cl

89%

aStereochemistrv not defined. Scheme 2.73

MeO2C~CO2MI.3 91"

70

DAVID CRICH

tolylSO2

tolylSO2Cl M

81%

e

"-

~ -1.4 91~ , .. _/N__ _ MeO2C CO/Me

"Stereochemistry not defined. Scheme 2.74

: O

tolylSOZo~"-

t~ --

Nt Bn

64%

C1 4:1 .

I

Bn

aStereochemistry not defined. Scheme 2.75

This phenomenon has also been observed by Surzur's group (Scheme 2.76) [112], and promises to be general with a further example using an allylic sulfone in a tandem process coming from Chuang (Scheme 2.77) [113]. Interestingly, however, and in contrast to the cyclization of N-allylacrylamide, CorrSa has recently drawn attention to the failure of the allyl acrylates to cyclize with tosyl iodide [82]. Chuang (Scheme 2.78) [114] and Uguen [115], have also recorded some interesting examples of the sulfonyl radical as a leaving group in a manganese triacetateinduced tandem addition/cyclization procedure. The addition of sulfonyl radicals to 1,5-cyclooctadiene has also been studied with a view to the isolation of trans-annularly cyclized products. Kice found that with the phenylselenosulfates, approximately 1:1 mixtures of simple adducts and trans-annularly cyclized products were obtained (Scheme 2.79) [97]. More recently, Surzur has studied the same phenomenon with tosyl halides [116]. The increased yield of trans-annularly cyclized product, observed by these workers, with the ...C02Me MeO2Q ~ : tolylSO2Brt o l y l S O 2 ~ . ~ B r + _ _~x__

EtOeC CO2Et

67%

"

"~___ EtO2C CO2Et 52 9 __

~,.~~C ~0

MeO2C tolylSO2

,-- ,-, ur

2Et

48

Scheme 2.76 RO2C~SOetolyl 53% aStereochemistr7 not defined.

Scheme 2.77

MeO2~CI _ax tolylSO2" " ~ N/'~~R -~ 1.1:1 a MeO2C CO2Me

HOMOLYTIC PROCESSESAT SULFUR

SOe~c2t~ ~co + M

71

r C6I't13 Mn(OAc)3'A90*c, cOH,CU(OAc)235%

2c

2Me

13

Scheme 2.78

chloride nicely illustrates the slower rate of chain transfer as compared to the bromide. Other trans-annular cyclizations with tosyl cyanide and an allylic sulfone have been described by Fang [117], and Chuang [113], respectively, with higher yields of the trans-annular product again arising from slower propagation (Scheme 2.79).

N SePh

~SOEX

C)

~

H SO2Ar

/-X

X=PhSe X - C1 X - Br X = CN

39% 0% 44%

34% 44% 16% 78%

B ~

X=

// COzR

49%

Scheme 2.79

Motherwell [118] and Back [119] have independently shown that the cyclopropylmethyl butenyl rearrangement (and its acetylenic equivalent) can be initiated by reaction of vinyl cyclopropanes with tosyl iodide and phenylselenosulfates, respectively (Schemes 2.80 and 2.81). A further interesting rearrangement, reported by Corr6a [120], involves ring closure by homolytic displacement of a sulfonyl radical from a sulfonate or thiosulfonate by an alkyl radical, which in turn was generated by addition of a sulfonyl radical to an alkene (Scheme 2.82). Finally, in this section, attention is

tolylSO2 tolylSO2I, 59%

..._

I

Scheme 2.80

~

t~

~'~~'~SO2tolyl + P h S e ~ . PhSe 48% 23% Scheme 2.81

=='t~SO2tolyl

72

DAVID CRICH

~N~

"SO2tOlyl

._ t o l y l S 0 2 - ~

CC14, A (PhCO2)2

X = O, 100%; X = S, 90%

Scheme 2.82 tolylS021

tolylS02~

[Co] CH2C12,A, 80%

1:1

tolylSO2I /r

CH2C12, A, 80%

tolylSO2

[Co] [Co] - Bis(dimethylglyoximato)pyridinecobalt III

Scheme 2.83

drawn to the work of Johnson [102], whereby sulfonyl radicals add to unsaturated cobaloximines resulting in the formation of carbocycles by intramolecular SH2 of the adduct radical on the carbon-cobalt bond (Scheme 2.83).

2.3 GENERATION OF ALKYL RADICALS FROM ORGANOSULFUR GROUPS 2.3.1

From Thiols

By far the most efficient method for the generation of alkyl radicals from alkanethiols is by treatment with a phosphine or phosphite. A radical chain reaction ensues and the alkyl radical is trapped by hydrogen atom transfer from the thiol (Scheme 2.84) [121]. Although this method of alkyl radical generation was used in 1964 for the generation and study of the 5-hexenyl radical [122], it does not appear to have been used in synthesis other than for the desulfurization of thiols. A closely related method involves treatment of disulfides with phosphines leading to sulfide formation (Scheme 2.85) [121]. The desulfurization of thiols with tin hydrides has been described [123]. This method, which requires two equivalents of stannane, appears to offer few advantages over the phosphine method, especially in the light of the difficulties RS.

+

PX 3

~

RS'-*PX3

RS--*PX 3

~

R* +

R.

~

RH

+ RSH

Scheme 2.84

S=PX 3 + RSo

HOMOLYTIC PROCESSESAT 5ULFUR

RS.

+

PX 3

RS--.PX 3 R.

+

RSSR

73

~

RS-- "PX3

~

R.

~

+

S=PX 3

RSR

RS.

+

Scheme 2.85 frequently encountered in the removal of tin residues from reaction products (Scheme 2.86).

SH

E t O 2 C ~ ~

'~

Bu3SnH, AIBN EtO2C~~ 80 ~

~'~

89%

Scheme 2.86

2.3.2

From Sulfides

Corey and Block have studied the photolytic extrusion of sulfur from sulfides in the presence of a phosphine [124]. This process, which is most efficient for allylic, benzylic or strained sulfides, is thought to occur by homolytic cleavage of a sulfur-carbon bond, leading to a radical pair, followed by transfer of sulfur from the thiyl radical to the phosphine, and ultimately coupling of two alkyl radicals (Scheme 2.87). This procedure has been successfully applied in the preparation of cyclophanes (Schemes 2.88 [125] and 2.89 [126]), and is covered more extensively by Block in his treatise on organosulfur chemistry [3]. h'u

R--S--R RS~ +

R"

~

R'-S.

+ R.

+ PX 3 - S=PX 3

R.

+

Ro

-~

R--R

H

H 46% PhCH2SCH2Ph

46%

PhCH2CHzPh

59%

Scheme 2.87

(MeO)3P

k__s_f-

h'o, 85%

Scheme 2.88

\

/

74

DAVID CRICH

(EtO)3P

h~, 37%

iP

S Scheme 2.89

2.3.3

From Alkyl Aryl Sulfides

The cleavage of alkyl aryl sulfides with stannanes is not an efficient reaction unless a stabilized radical is generated. A number of examples of this latter kind are known, and the method has been used in conjunction with radical cyclizations in synthesis (Schemes 2.90 [127], 2.91 [128], 2.92 [129], 2.93 [130], 2.94 [131], 2.95 [132], 2.96 [133], 2.97 [134] and 2.98 [135]). An important example, reported by Ikeda, demonstrates however, that similarly activated chlorine atoms are abstracted more rapidly than the methylthio group (Scheme 2.98). Dithioacetals may be reduced with excess stannane to the corresponding

A

/SPh

Bu3SnH,97%

Scheme 2.90

BnO---~ BB nO ~Q nO ~SMe

Bu3SnH,87%

BnO OMe

BnO---~ BnO'----v.....L,Q BnO,.~~OMe

a :fl = 1:12 BnO i~i Scheme 2.91

0 NH

NH

HO

Bu3SnH,62%

ors

HO

EtO

Me Scheme 2.92

HOMOLYTIC PROCESSESAT SULFUR

75

Stolyl

Bu3SnH E\ t~O ,~y , t,2_' C BN~~r.O ~. ~E\ O

toluene, A, 87%

EtO

O

Scheme 2.93

~N APh CO2Me I CO2Me

CO2Me 60% COEMe " t r a n s = 35 "65

CO2Me CO2Me 30%

I

cis

I

Scheme 2.94

I s

O

~ ~ ...,OH+

Bu3SnH (no yield reported)

= = =

OH

~ ~ ~

1

1

Scheme 2.95

O ~"~,,,_. SnBu 3

HN) O

71%

/~SPh

O

HNJI'O

Scheme 2.96

TMS

S.N~

OAc

TMS~ A c

Bu3SnH,71%

(E) :(Z) = 1 : 3.7 "-

0 Scheme 2.97

~..~SMe

RN

Bu3SnH

O R N ' J ~ SMe + \ (N 68% Scheme 2.98

o

~SMe RN~ 1 6 %

~ O

76

DAVID CRICH

~~~

1Bu3SnI"I'AIB I_ < ~ S ~ s H

4Bu3SnH, ~N~~~'~,,,~ ~

64%

76%

Scheme 2.99 methylene group, or alternatively, with one equivalent of stannane, the reaction may be stopped after cleavage of the first, more-reactive, bond (Scheme 2.99) [136].

2.3.4

From Sulfones

Sulfonyl radicals undergo slow loss of sulfur dioxide to give alkyl radicals (Scheme 2.100). This process is not normally sufficiently rapid to be a problem in sulfonyl radical chemistry, or a preparatively useful entry into alkyl radicals unless high temperatures are employed or the radical to be formed is stabilized. The thermal extrusion of sulfur dioxide from dibenzyl sulfones, thought to occur by homolytic scission of a carbon-sulfur bond, followed by extrusion of SO2 and eventual radical coupling, has found application in the preparation of cyclophanes (Scheme 2.101) [1371.

R--SO2"

~

R. + SO2

Scheme 2.100

o~

o~

470~ 94% Scheme 2.101

2.3.5

From Thiocarbonyl Groups

The thiocarbonyl group (RR'C .S) exhibits very extensive free radical [138] and photochemistry [139], both of which have been thoroughly reviewed elsewhere. A number of free radicals, and in particular stannyl radicals, add to the thiocarbonyl sulfur atom with generation of oL-thioalkyl radicals. In the simplest cases, this adduct radical can be quenched by addition to an appropriately placed unsaturation, as in Schemes 2.102 [140], 2.103 [141], 2.104 [142] and 2.105 [143].

HOMOLYTIC PROCESSESAT 5ULFUR

77

Bu3SnH SMe S

~

Scheme 2.102

f-~N Ph3SnH >80%

Ph

Ph

Scheme 2.103

N-Me

t SMeI Ph

Bu3SnH

N---/

Ph

60% Scheme 2.104

S~--SMe Ph

Bu3SnH 77%

s

( ~ ~

~

Ph

Scheme 2.105

In certain cases, such as cyclic carbonates and related compounds, the thiocarbonyl group may also be reduced to a methylene group provided the reaction is conducted under conditions when fragmentation of the intermediate radical is suppressed (Scheme 2.106) [144]. Unfortunately, if complete reduction is required, these methods seemingly have little to recommend them over the use of Raney nickel. Ac

EtO2C'~ ~ S 0

0

Ph~~_Os~ S

EtO2C,,

Bu3SnH

75%

O

O

Ph~/O_~s

Bu3SnH ~__,

OEt

, OEt OEt

Scheme 2.106

Ac

78

DAVID CRICH

Two strategically placed thiocarbonyl groups may also be induced to undergo coupling under reductive conditions as in the Nicolaou approach to oxapolycyclic frameworks (Scheme 2.107) [145].

" 0

S

SMe

H *0

i) Na § naphthalenide

.-" O

~ O

ii) MeI, 80%

Scheme 2.107

However, by far the most common uses of thiocarbonyl groups in radical chemistry are the methods developed by Barton's group for the generation of alkyl radicals from alcohols [146] and from carboxylic acids [147]. In the BartonMcCombie reaction process, a secondary or primary alcohol [148] is converted into a thiocarbonyl ester, which in turn undergoes a radical chain reaction with tributyltin hydride, resulting in formation of the deoxygenated product. The propagation steps are outlined in Scheme 2.108.

S R..O,,~X

+ Bu3Sn.

s~SnBu 3 R..O.~ x

~

S ~'SnBu3 R..O.~X Ro + HSnBu 3

s.SnBu 3 "

~ ~

R. + RH

+

O~

x

oSnBu3

Scheme 2.108

In this general mechanistic scheme, the group X may be a phenyl, SMe or 1-imidazolyl group as first described by Barton and McCombie [146]. The group X may also be an OPh group as in the Robins [149] modification, or an O C 6 F 5 group as recently advised by Barton [150]. For tertiary alcohols, for reasons of stability of the thiocarbonyl esters, the only X group yet to prove successful is H, that is, the thioformate ester [152]. Significantly, from the point of view of the homolytic chemistry of sulfur compounds, thiocarbamates (X = NR"2) are completely unreactive towards stannyl radicals, indicative of a strong contribution of the thioimidate canonical form [138]. Exceptions to this rule are apparently the thioamides of aryl acids (Scheme 2.104). For a long time it was thought that thiocarbonyl esters were unreactive towards other radicals than the stannyl radicals. However, it has recently been discovered that silyl radicals, and hence silanes, are also appropriate provided that they are carefully chosen to enable facile hydrogen abstraction by the alkyl radical from the silane [152], or used in conjunction with a catalytic quantity of thiol as suggested by Roberts (Schemes

79

HOMOLYTIC PROCESSESAT SULFUR

2.47 and 2.48). Diphenylsilane, as recommended by Barton, appears to give clean, high-yielding reactions and hence to be a good replacement for the tin hydrides. There is a very large number of examples of the Barton-McCombie deoxygenation reaction in the literature, and of its use for the generation of alkyl radicals in rearrangements and in carbonmcarbon bond-forming reactions. The reader is referred to a comprehensive review [138] on this reaction for entries into the primary literature. The thiocarbonyl bond in thiohydroxamate derivatives of carboxylic acids is reactive towards a much wider range of radicals than is that in thiocarbonyl esters. This provides a very attractive source of carboxyl radicals, and so, by rapid decarboxylation, of alkyl radicals [147]. A general mechanism may be written as in Scheme 2.109.

+X~

~N~S

( sx

I

~R

RCO2~ R.

+

X--Y

~-~

R~ + R--Y

+ RCO2o

CO 2

+

Y.

Scheme 2.109 The enormous versatility of this reaction stems from the large variety of reagents X-Y that take part in this chain reaction. Thus, use of thiols and stannanes results in the formation of noralkanes whilst the use of perhalomethanes results in the formation of Hunsdiecker products. Activated allylic sulfides result in the formation of carbon-carbon bonds (Scheme 2.29) [49]. As with the thiocarbonyl esters, the number and diversity of examples are far too wide to be covered here, and the reader is referred to the authoritative review of the area [138].

2.4

FORMATION OF CARBON-SULFUR BONDS BY REACTION OF CARBON-CENTRED RADICALS WITH SULFUR FUNCTIONAL GROUPS 2.4.1

SH2 at Sulfur

Carbon-centred radicals attack a number of divalent (and tetravalent) sulfur species RSX with displacement of a radical X. in what is formally an SH2 reaction (Scheme 2.110). In this process X may be a stabilized carbon radical (benzyl), a sulfonyl radical, an acyl radical or a thiyl radical [153]. From a preparative point of view, this reaction is most frequently practised with disulfides. Diaryl disulfides have weaker bonds than dialkyl disulfides and are

80

DAVID CRICH

R'o

+

~-

R--S--X

R'--S--R

+ X.

Scheme 2.110

therefore more reactive. Intermolecular examples of this type of reaction are to be found in Schemes 2.25, 2.28, 2.41 and 2.43 and an intramolecular example in Scheme 2.82. More recent examples may be found in the work of Pattenden (Scheme 2.111) with radicals generated from cobaloximes [154], and in the work of Barton using the O-acyl thiohydroxamate method (Scheme 2.112) [155].

R,~~Co(salophen)py 0

+ PhSSPh

A, h~

RCH2SPh

R is phenyl or vinyl Scheme 2.111

CH3(CH2)14CO2--N~

+ PhSSPh

h~

S

CH3(CH2)14SPh + [[ ~] 82% KN ~ S S P h

Scheme 2.112

A recent example, from Tada and co-workers, points to the efficiency of thioesters as radical traps, to the extent that they compete effectively with O-acyl thiohydroxamates (Scheme 2.113) [156]. The same authors have also applied an intramolecular extension of their method to the formation of thionolactones from thiolesters (Scheme 2.114) [157]. The initial radical is generated from the corresponding cobaloxime or from the bromide. The method is apparently successful for the formation of four- and five- membered rings but not of valerolactones. It is noteworthy that the expelled radical in these processes is either an acyl radical or an alkyl radical.

SN~ Me 0 I MeO2CC_CH2 I[ OMe

Ph2CHCOSPh h~

~--

Me t MeO2CC-CH2SPh Me

Scheme 2.113 0

0

Scheme 2.114

The intramolecular SH2 reactions of carbon radicals at sulfur accept a wide variety of leaving groups, and some examples are given in Schemes 2.82 and 2.114.

HOMOLYTIC PROCESSESAT SULFUR

81

The process has been most extensively studied for o-alkylthioethylaryl radicals (Scheme 2.115) [158], where it is found that the exocyclic bond is always cleaved with the concomitant formation of the five-membered heterocycle. This regioselectivity is understood in terms of a concerted mechanism with a backside attack on sulfur. In this efficient ring closure the leaving group R- may even be such reactive species as the methyl and phenyl radicals. The absolute rate constants for the displacements of R. from RSCH2CH2CH2CH 2. have been recently determined by Franz, and some examples are given in Scheme 2.116 [159]. For the related reaction with sulfoxides, Beckwith has demonstrated, by the use of optically active sulfoxides of known configuration, that the mechanism is indeed a concerted one (Scheme 2.117) [160].

+ Ro

Scheme 2.115 S--R

k(298 K)

~

~___jS +Ro

R PhCH,* But. Pr".

k 3.91 x 10~ 2.74 X 10 2 18.2

Scheme 2.116 o-

)+S

o-

-~

§ >

Scheme 2.117

2.4.2

Addition to Thiocarbonyl Sulfur

The intermolecular addition of carbon-centred radicals to thiocarbonyl esters is a little studied process. This gap must arise in part from the difficulties of generating the requisite radicals in the presence of the thiocarbonyl ester without destroying it in the process. Nevertheless, Cristol has reported that trichloromethyl radicals apparently do not fragment xanthate esters. This lack of reaction was attributed to the probable reversibility of the addition step [161]. Much more recently, Minisci has demonstrated that the higher-energy phenyl radicals, in which the addition

82

DAVID CRICH

would not be reversible or at least many orders of magnitude slower, does indeed add to, and fragment, thiocarbonyl esters (Scheme 2.118) [162]. A rate constant of k > 10SM-~S-~ in chlorobenzene at reflux is estimated for the addition step. This is an important development of the Barton-McCombie reaction in so far as it enables radical generation from the thiocarbonyl esters in the absence of reducing agents and so vastly expands the range of potential radical traps. Zard has also described the addition of alkyl radicals to S-acyl xanthate esters [163].

s @O.,~SMe+

0

!

§

+(PhC02)2 130~

0

PhS

H

92%

SMe

)

Scheme 2.118

Intramolecular addition of alkyl radicals to thiocarbonyl groups is a little more common, and two examples of this process are given in Schemes 2.22 and 2.23 and a more involved example in Scheme 2.119 [164]. Ph

Ph

o-I-o

Y0 - /0 MeS

Bu3SnH, A

Ph

,r-O. ....o,(Ph

80%

SMe Scheme 2.119

As alluded to in Section 2 . 5 , the thiocarbonyl group in O-acyl thiohydroxamates is reactive towards a much wider range of radicals than thiocarbonyl esters. This range of radicals includes all classes of alkyl radicals ranging from the highly electrophilic perfluoroalkyl radicals through to nucleophilic radicals such as c~-alkoxy radicals [165, 138]. Basically, two methods have been used to generate alkyl radicals for trapping by addition to O-acyl thiohydroxamates. In the first, the O-acyl thiohydroxamate is simply decomposed, photochemically or thermally, by a radical chain reaction, to give the product of decarboxylative rearrangement [147, 166]. An example of this type, including a 5hexenyl rearrangement, is given in Scheme 2.120 [167]. In the second variant, the initial nucleophilic radical, formed on decarboxylation, adds to an electrondeficient alkene, forming a relatively electrophilic radical which then propagates the chain by addition to the thiocarbonyl group [166]. The example of Scheme 2.121 serves to illustrate the application of these types of reaction to organic synthesis [168]. More examples of both types can be found in a recent review of this area [138].

83

HOMOLYTIC PROCESSESAT SULFUR

CO 2 h~

s.c y

~

82%

Scheme 2.120 s

o

.

o

Scheme 2.121 ACKNOWLEDGEMENTS I wish to express my sincere gratitude to Professors Jean-Marie Surzur and Paul Tordo, and their colleagues Dr Mich6le P. Bertrand, Dr Michel P. Crozet, Dr JeanPierre Finet, Dr Robert Nougier and Dr Lucien Stella, for their warm hospitality and many stimulating discussions during the tenure of a visiting professorship at the University of Aix-Marseille III, when the majority of this chapter was written.

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86

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87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121.

DAVID CRICH

Y. Takahara, M. Iino and M. Matsuda, Bull. Chem. Soc., Japan, 49, 2268 (1976). A.C. Serra, C. M. M. S. Corr~a and M. C. do Vale, Tetrahedron, 47, 9463 (1991). C. Chatgilialoglu in: The Chemistry of Sulphones and Sulphoxides (S. Patai, Z. Rapoport and C. J. M. Stirling, eds), ch. 24, p. 1089, Wiley, Chichester (1988). C . M . M . S . Corr~a and M. A. B. C. S. Oliveira, J. Chem. Soc., Perkin Trans. 2, 711 (1983). For overviews on this area, see: ref. 83, K. Schank, in The Chemistry of Sulphones and Sulphoxides (S. Patai, Z. Rapoport and C. J. M. Stirling, eds), ch. 7, p. 189, Wiley, Chichester (1988). A.V. Kalaina, M. A. Vasil'eva and T. I. Bychkova, Zh. Org. Khim., 15, 268 (1979) (Chem. Abstr., 91, 5004) (1979); M. A. Vasil'eva, T. I. Bychkova, D. F. Kusharev, T. I. Rozova, and A. V. Kalabina, Zh. Org. Khim., 13, 283 (1977) (Chem. Abstr. 87, 5551)(1977). J.A. Sinnreich and M. Asscher, J. Chem. Soc., Perkin Trans. 1, 1545 (1972). W.E. Truce, C. T. Goralski, L. W. Christensen and R. H. Bavry, J. Org. Chem., 35, 4217 (1970). W. B011, Ann. Chem., 1665 (1979). W.E. Truce and G. C. Wolf, J. Chem. Soc., Chem. Commun., 150 (1969). J-P. Pillot, J. Dunog~es and R. Calas, Synthesis, 469 (1977). L.K. Liu, Y. Chi and K-Y Jen, J. Org. Chem., 45, 406 (1980). C. Nfijera, B. Bald6 and M. Yus, J. Chem. Soc., Perkin Trans. 1, 1029 (1988). E. Block, M. Aslam, V. Eswarakrishnan, K. Gebreyes, J. Hutchinson, R. Lyer, J-A1. Laffitte and A. Wall, J. Am. Chem. Soc., 108, 4568 (1986). G.C. Wolf, J. Org. Chem., 39, 3454 (1974). A.L.J. Beckwith and P. E. Pigou, Aust. J. Chem., 39, 77, 1151 (1986). R.A. Grancarz and J. L. Kice, J. Org. Chem., 46, 4899 (1981). T.G. Back and S. Collins, J. Org. Chem., 46, 3249 (1981). Y-H. Kang and J. L. Kice, J. Org. Chem., 49, 1507 (1984). T.G. Back, S. Collins and R. G. Kerr, J. Org. Chem., 48, 3077 (1988). J-M. Fang adn M-Y. Chen, Tetrahedron Lett., 28, 2853 (1987). M.D. Johnson, Acc. Chem. Res., 16, 343 (1983). G.A. Russell and L. L. Herold, J. Org. Chem., 50, 1037 (1985). G.A. Russell and P. Ngoviwatchai, Tetrahedron Lett., 26, 4975 (1985). P.N. Culshaw and J. C. Walton, Tetrahedron Lett., 31, 6433 (1990). Y. Ueno, S. Aoki and M. Okawara, J. Am. Chem. Soc., 101, 5414 (1979). A. Padwa, S. S. Murphee and P. E. Yeske, Tetrahedron Lett., 31, 2983 (1990). T . A . K . Smith and G. Whitham, J. Chem. Soc., Perkin Trans. 1,313,319 (1989). V.K. Gubernatorov, B. E. Kogai and V. A. Sokolenko, Izv. Akad. Nauk. SSSR, Ser. Khim., 8, 1874 (1983); V. K. Guvernatorov, B. E. Kogai, E. D. Korniels and V. A. Sokolenko, Zh. Org. Khim., 19, 2209 (1983). R. Nougier, C. Lesueur, I. De Riggi, M. P. Bertrand and A. Virgili, Tetrahedron Lett., 31, 3541 (1990). C-P. Chuang and T. H. J. Ngoi, Tetrahedron Lett., 30, 6369 (1989). I. de Riggi, S. Gastaldi, J.-M. Surzur, M.P. Bertrand and A. Virgili, J. Org. Chem. 57, 6118(1992). C-P. Chuang, Syn. Lett., 527 (1990). C-P. Chuang, Syn. Lett., 829 (1991). P. Breuilles and D. Uguen, Tetrahedron, 44, 7119 (1988). I. De Riggi, J-M. Surzur and M. P. Bertrand, Tetrahedron Lett., 31, 357 (1988). J.M. Fang and M-Y. Chen, Tetrahedron Lett., 28, 2853 (1987). A.D. Morris, M. C. de C. Alpoim, W. B. Motherwell and D. M. O'Shea, Tetrahedron Lett., 29, 4173 (1988). T.G. Back and K. R. Muralidharan, J. Org. Chem., 54, 121 (1989). A.C. Serra and C. M. M. S. Corr~a, Tetrahedron Lett., 32, 6653 (1991). F.W. Hoffmann, R. J. Ess, T. C. Simmons and R. S. Hanzel, J. Am. Chem. Soc., 78, 6414 (1956); C. Walling and R. Rabinowitz, J. Am. Chem. Soc., 81, 1243 (1959).

HOMOLYTIC PROCESSESAT SULFUR

122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. 149. 150. 151. 152. 153.

154.

155. 156.

87

C. Walling and M. Schmidt Pearson, J. Am. Chem. Soc., 86, 2262 (1964). M. Pang and E. I. Becker, J. Org. Chem., 29, 1948 (1964); G. A. Krafft and P. T. Meinke, Tetrahedron Lett., 26, 135 (1985). E.J. Corey and E. Block, J. Org. Chem., 34, 1233 (1969). V. Boekelhide, I. D. Reingold and M. Tuttle, J. Chem. Soc., Chem. Commun., 406 (1973). M.W. Haenel, fetrahedron Lett., 3053 (1974). J.D. Buynak and S. C. Chu, J. Org. Chem., 50, 4245 (1985). D. Kahne, D. Yang, J. J. Lira, R. Miller and E. Papuaga, J. Am. Chem. Soc., 110, 8716 (1988). B.V. Joshi and C. B. Reese, Tetrahedron Lett., 31, 7483 (1990). J.P. Marino, E. Laborde and R. S. Paley, J. Am. Chem. Soc., ll0, 966 (1988); also see: D. P. Curran, C. P. Jaspersee and M. J. Tottleben, Y. Org. Chem., 56, 7169 (1991). P.M. Esch, H. Hiemstra ahd W. N. Speckamp, Tetrahedron Lett., 31, 759 (1990). V. Yadav and A. G. Fallis, Can. J. Chem., 65, 779 (1991): see also: T. L. Fevig, R. L. Elliott and D. P. Curran, J. Am. Chem. Soc., ll0, 5064 (1988). S. Kano, T. YokomatsuandS. Shibuya, Y. Org. Chem.,54,513(1989). J-K. Choi and D. J. Hart, Tetrahedron, 41~ 3959 (1985). H. Ishibashi, T. Sato, M. Irie, S. Harada and M. Ikeda, Chem. Lett., 795 (1987); T. Sato, Y. Wada, M. Nishimoto, H. Ishibashi and M. Ikeda, Y. Chem. Soc., Perkin Trans. ], 879 (1989). C.G. Gutierrez, R. A. Stringham, T. Nitasaka and K. G. Glassock, Y. Org. Chem., 45, 3393 (1980). D.T. Longone, S. H. Kusefoglu adn J. A. Gladysz, J. Org. Chem., 42, 2787 (1977). For a review see: D. Crich and L. Quintero, Chem. Rev., 89, 1413 (1989). For a review see: J. D. Coyle, Tetrahedron, 41, 5393 (1985). S. Iwasa, M. Yamamoto, S. Kohmoto and K. Yamada, J. Chem. Soc., Perkin Trans. 1, 1173 (1991). A . G . Angoh and D. L. J. Clive, J. Chem. Soc., Chem. Commun., 980 (1985). M.D. Bachi and D. Denemark, J. Am. Chem. Soc., 111, 1886 (1989). M. Yamamoto, T. Uruma, S. Iwasa, S. Kohmoto ahd K. Yamada, J. Chem. Soc., Chem. Commun., 1265 (1989): M. D. Bachi and E. Bosch, J. Org. Chem., 54, 1234 (1989). D.R. Williams and J. L. Moore, Tetrahedron Lett., 24, 339 (1983). K.C. Nicolauo, C-K. Hwang, B. E. Marron, S. A. De Frees, E. A. Couladouros, Y. Abe, P. J. Carroll and J. P. Snyder, J. Am. Chem. Soc., 112, 3040 (1990). D . H . R . Barton and S. W. McCombie, J. Chem. Soc., Perkin Trans. 1, 1574 (1975). D . H . R . Barton, D. Crich and W. B. Motherwell, Tetrahedron, 41, 3901 (1985). D . H . R . Barton, W. B. Motherwell and A. Stange, Synthesis, 743 (1981). M.J. Robins, J. S. Wilson and F. Hansske, J. Am. Chem. Soc., 105, 4059 (1983). D . H . R . Barton adn J. Cs Jaszberenyi, Tetrahedron Lett., 30, 2619 (1989). D. H. R. Barton, W. Hartwig, R. S. Hay-Motherwell, W. B. Motherwell and A. Stange, Tetrahedron Lett., 2019 (1982). D . H . R . Barton, D. O. Jang and J. Cs Jaszberenyi, Tetrahedron Lett., 31, 4681 (1990). For extensive discussions of the scope and mechanism of SH2 at sulfur, see: K. U. Ingold and B. P. Roberts Free Radical Substitution Reactions, Bimolecular Homolytic Substitutions (Stt2 Reactions) at Saturated Multivalent Atoms, Wiley, ch. 7, p. 200, Wiley, New York (1971); J. A. Kampmeier, R. B. Jordan, M. S. Liu, H. Yamanaka and D. J. Bishop in: Organic Free Radicals (N. A. Pryor, ed), American Chemical Society, Washington, DC (1978) ref. 1b. V. F. Patel and G. Pattenden, J. Chem. Soc., Perkin Trans. 1, 2703 (1990); D. V. Coveney, V. F. Patel, G. Pattenden and D. M. Thompson, J. Chem. Soc., Perkin Trans. 1, 2721 (1990); V. F. Patel, G. Pattenden and D. M. Thompson, J. Chem. Soc., Perkin Trans. 1, 2729 (1990). D . H . R . Barton, D. Bridon and S. Z. Zard, Heterocycles, 25, 449 (1987). M. Tada, T. Uebake and M. Matsumoto, J. Chem. Soc., Chem. Commun., 1408 (1990).

88

157. 158. 159. 160. 161. 162. 163. 164. 165. 166. 167. 168. 169.

DAVID CRICH

M. Tada, M. Matsumoto and T. Nukamura, Chem. Lett., 199 (1988). For a good discussion of this process, see ref. 153. J.A. Franz, D. H. Roberts and K. F. Ferris, J. Org. Chem., 52, 2256 (1987). A . L . J . Beckwith and D. R. Boate, J. Chem. Soc., Chem. Commun., 189 (1986). S.J. Cristol and D. G. Seapy, J. Org. Chem., 47, 132 (1982). F. Coppa, F. Fontana, F. Minisci, G. Pianese, P. Tortoreto and L. Zhao, Tetrahedron Lett., 33, 687 (1992). P. Delduc, C. Tailhan and S. Z. Zard, J. Chem. Soc., Chem. Commun., 308 (1988); F. Mestre, C. Tailhan and S. Z. Zard, Heterocycles, 28, 171 (1989); J. E. Forbes, C. Tailhan and S. Z. Zard, Tetrahedron Lett., 31, 2565 (1990). A . V . Rama Rao, K. A. Reddy, M. K. Gurjar and A. C. Kunwar, J. Chem. Soc., Chem. Commun., 1273 (1988). D . H . R . Barton, B. Lacher and S. Z. Zard, Tetrahedron, 42, 2325 (1986). D . H . R . Barton, D. Crich and P. Potier, Tetrahedron Lett., 26, 5943 (1985). D . H . R . Barton, D. Crich and G. Kretzschmar, J. Chem. Soc., Perkin Trans. 1, 39 (1986). K. Sumi, R. Di Fabio and S. Hanessian, Tetrahedron Lett., 33, 749 (1992). During the period this book was in publication an excellent review on sulfonyl radical chemistry has appeared. M. P. Bertrand, Organic Prep. Proc. Int. 26, 257 (1994).

CHAPTER3

SYNTHETIC TRANSFORMATIONS I N V O L V I N G T H I I R A N I U M ION INTERMEDIATES Christopher M. Rayner Department of Chemistry, The University of Leeds, Leeds, LS2 9JT, UK

CONTENTS 3.1 3.2 3.3 3.4

Reviews General considerations Synthesisofthiiranium ions Reactionsof thiiranium ions 3.4.1 3.4.2 3.4.3 3.4.4 3.4.5 3.4.6

Halide nucleophiles Carbon nucleophiles Oxygen nucleophiles Nitrogen nucleophiles Sulfur nucleophiles Miscellaneous transformations

3.5 Summary Acknowledgements References

3.1

89 90 93 94

94 97 112 118 124 125

127 128 128

REVIEWS

A number of earlier reviews exist in the literature on thiiranium ions and related topics. For example, the chapter on thiiranes and thiirenes in Comprehensive Heterocyclic Chemistry also includes some chemistry of thiiranium ions. [1] The chemistry of cyclic sulfonium salts including thiiranium ions has been reviewed. [2] Thiiranium ions are also included in a review of reactive sulfonium salts. [3] There is an excellent recent review on the chemistry of sulfenyl halides and sulfenamides. [4] There are also some less extensive reviews in this area [5-7]. The major emphasis of this review is on synthetically useful reactions where thiiranium ion intermediates are believed to be involved, covering the literature published since 1985 although a number of earlier papers are included for completeness. The following two sections are designed to give a brief introduction into the general chemistry of thiiranium ions and related species. More detailed discussions are available and should be consulted when necessary [1-7]. ORGANOSULFURCHEMISTRYCopyright O 1995 Academic Press Ltd. ISBN-0-12-543560-6. All rights of reproduction in any form reserved.

90

3.2

CHRISTOPHERM. RAYNER

GENERAL C O N S I D E R A T I O N S

Thiiranium ions (episulfonium ions) (1) are synthetically useful and mechanistically interesting functional groups [1-7]. They are, however, relatively unstable and are often generated in situ and used without isolation. In some cases they are only tentatively suggested as intermediates; however, a number of simple thiiranium salts have been isolated and characterized, for example (2) [8].

R S+ / \

Ph CH3 / 3 . ~ c,+ CH SbCI6-

X

(1)

(2)

The nucleophilic ring opening reaction is the most important transformation of these species, leading to the formation of functionalized sulfides. Relief of ring strain and neutralization of the positive sulfur atom upon ring opening means that they are particularly electrophilic species and as a result will react with relatively unreactive nucleophiles (e.g. silyl enol ethers) with a high degree of efficiency and often stereospecificity. The latter is probably one of the most important factors in that it allows for stereochemical control at two adjacent chiral centres. This results from SN2-type ring opening of the thiiranium ion (3) in an analogous way to the related oxiranes and thiiranes. Thiiranium ions can be considered as equivalent to carbenium ions stabilized by a ~-thio group. In cases where a stabilized carbenium ion can be formed, loss of stereospecificity is observed due to non-selective addition to the carbenium ion (4) by an SNl-type mechanism (Scheme 3.1). In cases where stabilized carbe nium ions are be intermediates, Markovnikov regioselectivity is usually observed (Scheme 3.2). For example, the arylpropene (5) which has a 4-methoxy group to stabilize the benzylic carbenium ion (7), shows total Markovnikov regioselectivity, but as a planar carbenium ion intermediate is involved there is a loss of stereochemical integrity in the products.

R I

S+ R,,,,.7~,,R4

.. Nu...- .

R2v (3) "R3

R2

R's R24'

RS R3 R , , , , . . ~ , R4

NM"

~.~

(4)~._R~ Scheme 3.1

RS

Nu

R4

R I , ~ R3 R2"

Nu

SYNTHETIC TRANSFORMATIONS INVOLVING THIIRANIUM ION INTERMEDIATES

91

CI SAr SAr ArSCI CH3~H + CH3 C HH +3 ~H ~ H R-~ C H 3 RCsH RC6H4~ RCsH4 CI cI Ar = 2,4-dinitrobenzene SAr threo

threo

anti-Markovnikov Markovnikov 70% 0% (5) R = 4-MeO 30% 70% (6) R=3-NO2 I .. + /SAr"

erythro

Markovnikov 30% 0%

(7) Scheme 3.2

If, however, the arylpropene (6) is used, where a 3-nitro substituent replaces the 4-methoxy group disfavouring an open carbenium ion intermediate, then stereochemical integrity is retained but anti-Markovnikov regioselectivity dominates [9]. The regiochemistry of the ring-opening reaction also depends on the reaction conditions (vide infra), and the nature of the thiiranium ion. In many reactions, thiiranium ions are not isolated but are often postulated as intermediates to explain observed reactivity and stereoselectivity. The actual nature of such species is not as simple as one might initially expect [10] and is still the subject of some controversy [11]. This is due to the potential for the formation of sulfurane-type complexes (8) analogous to the large number of known sulfuranes [12]. The thiiranium ions and sulfuranes are extreme structures, and intermediate ion pairs (9) should also be considered as potential intermediates in the reaction [13]. R

"S S

X

R,s~\X/\

/\

(9)

(8)

Sulfuranes derived from thiiranium ions have been detected in a number of cases, for example the addition of chloride ion to the thiiranium ion (10) results in the formation of the sulfurane (11) (Scheme 3.3) [14]. Gas phase molecular orbital calculations indicate that sulfuranes are > 90 kcal mo1-1 more stable than the

(

~

S+-Me TNBS-

Ph4As+CI-

(

~

CD3NO2

(10) TNBS- =trinitrobenzenesulphonate Scheme 3.3

(11)

/CI S~Me

92

CHRISTOPHERM. RAYNER

corresponding thiiranium ions [15, 16] The trigonal-bipyramidal structure of sulfuranes is illustrated by the recent examples (12) and (13) [17]. The three-membered rings are believed to bridge an equatorial and apical position, and the most electronegative substituent is also usually apical. This is also consistant with a number of structures proposed for the related selenurane intermediates (14) [18].

CH

CH3

:"'S

CH,-"

F

:""

CH3

(12)

CH3

CH,")

p-Tol

F

(13)

. _ :

e

C, (14)

One would expect there to be a significant difference in the reactivity of thiiranium ions and sulfuranes [10]. Thiiranium ions are essentially charged structures and would be expected to have the characteristics of cationic species, for example undergoing cationic rearrangements (as side-reactions in appropriate cases) and giving Markovnikov-type regioselectivity in the ring-opening reactions. Sulfuranes, however, are essentially uncharged, and the cationic character would be very much reduced [12]. Hence a decrease in Markovnikov regioselectivity would be expected with steric effects now playing a more important role. Such differences in reactivity originally led to controversy in the literature as to the exact properties of thiiranium salts. The addition of phenylsulfenyl chloride to alkenes (likely to go via a sulfurane or tight ion pair) shows antiMarkovnikov selectivity [10, 19] (e.g. (15) and (16)) whereas the preformed thiiranium ion (17) reacting with acetate shows mainly Markovnikov selectivity (Scheme 3.4) [10, 20]. R

PhS%

Ph

c,,-" ",

§

SbF6

(17)

AcO

SPh CH3-" v

CI

c,

+

CH3.." v

(15) R = H

3

:

1

(16) R = M e

5

:

1

SPh CH3-'- v

OAc

SPh

OAc

+

R..g-.v.SPh

CH 3

(18) R = H

28

:

72

(19) R = M e

5

:

95

Scheme 3.4

This complementary selectivity is potentially a very useful property of thiiranium ions and sulfuranes if it can be controlled. In addition to the factors

SYNTHETIC TRANSFORMATIONS INVOLVING THIIRANIUM ION INTERMEDIATES

93

mentioned above, variables such as solvent polarity (liquid sulfur dioxide or hexane), anionic counterion (CI-, C104-), temperature, and even added salts (LiC104) have all been shown to have an effect on the reaction [10]. In this review, thiiranium ions will be assumed as intermediates rather than the corresponding sulfurane or ion pair unless otherwise stated, although it should be appreciated that this may not always be the case.

3.3

SYNTHESIS

OF THIlRANIUM IONS

As previously mentioned, thiiranium ions are usually not isolated because of their instability, but are generated in situ. There are two synthetically useful approaches for their preparation [1-7]. The first involves the sulfenylation of an alkene with an electrophilic sulfur species. A considerable number of reagents for this have been developed over the years, and particularly important examples are dimethyl(methylthio)sulfonium tetrafluoroborate (20) [21, 22], and the related trifluoromethanesulfonate [23], methyl(bismethylthio)sulfonium hexachloroantimonate (21) [3, 7], sulfenyl halides (22a) [4], sulfenamides (22b) [4, 24, 25], sulfenate esters (22c) [5], and disulfides (22d) [26, 27]. The general principle is illustrated in Scheme 3.5. It is important to note that unless carbenium ion intermediates are involved, the reactions (24)4(25) and (24)4(26) are stereospecific, and are thus potentially very useful. Thus, addition of a sulfenylating agent (22) to an alkene (23) gives the thiiranium ion (24), which may be opened by the counterion (X) to give the CHa--S+-CH3 S

CH3--S-S+-CH3 S

BF4

SbCI 6-

i

CH 3

I

CH 3

(20)

RSX (22)

+

R1

R4 (23)

(21)

catalyst

R1

,R x-]

S+ R4/

R

R3

(24)

I

(22a) X = Cl, Br (22c) X = OCH 3 (22d) X = SCH 3

R1

S ~R

R2.~~

"R4

NI u

"R3

(26) Scheme 3.5

_

R1

S "R )~ (25)

Nu-

(22b) X = N(CH3) 2

X

"R 3

94

CHRISTOPHER M. RAYNER

substituted sulfide (25). If the counterion is chosen such that it is not nucleophilic (e.g. tetrafluoroborate or hexachloroantimonate) then it is possible to add an additional nucleophilic reagent to form the sulfide (26). Frequently there is an equilibrium between (24) and (25) such that small concentrations of the thiiranium ion will be present in solution (by neighbouring group participation [28, 29]) and will react with an added nucleophile (usually irreversibly) to form the sulfide (26). The alternative method for the generation of thiiranium ions is directly related to that above in that it involves the preparation and isolation of sulfides of the type (25) (X = C1, OR, etc.), either via a thiiranium salt or using some other method. These are then converted into the thiiranium ions, often in the presence of a catalyst (e.g. TMSOTf[5], H+[25], or SBC1515]), which may be opened by nucleophiles in the usual way. It is also possible to prepare thiiranium salts by alkylation of thiirane [2]; however, this reaction is not particularly useful synthetically and so is not discussed here. It is beyond the scope of this chapter to list all the known methods for the preparation of thiiranium ions, although many of the more useful are described in the following sections. More detailed discussions can be found in earlier reviews [1-7].

3.4 REACTIONS OF THIIRANIUM IONS The following sections will describe the reactions of thiiranium ions with various classes of nucleophile including halide, carbon, oxygen, nitrogen and sulfur. Particular emphasis is placed on reactions which are of potential synthetic use.

3.4.1 Halide nucleophiles This is probably the most common reaction of thiiranium ions and, in general, results from the addition of sulfenyl halides to alkenes. This reaction, particularly in the case of sulfenyl chlorides, has been extensively reviewed [2-4, 6] and is discussed briefly in Section 3.2. Frequently the adducts of sulfenyl halides and alkenes are used as intermediates in which further transformations substitute the halide with another nucleophile. These examples are not included here, but are discussed in the relevant sections below depending on the type of nucleophile introduced.

3.4.1.1 Bromide and fluoride [3-Bromo sulfides are readily converted into thiiranium ions [20] by a neighbouring group participation mechanism and are usually unstable [30]. An example is the dibromo sulfide (29) used in the preparation of 3-bromo-2-butylsulfonyl-l-propene (31), a versatile multicoupling reagent for use in synthesis (Scheme 3.6) [31].

SYNTHETICTRANSFORMATIONSINVOLVINGTHIIRANIUMION INTERMEDIATES

95

Treatment of the allylsulfide (27) with bromine generates the thiiranium salt (28) as a yellow precipitate. On warming, this forms the unstable dibromo sulfide (29), which is oxidized immediately to the sulfone (30) in an 87% overall yield. Elimination using sodium acetate then gives (31) in an 80% yield.

Br2.CCI4 -20"C

Br'v~

(27)

_

(28)

Br( 2 ' ~ ~ 9 ) Br

j 2.4equiv. MCPBA

r ~25oc. Et20

Br",v~,,,./Br

(31)

(30)

80% yield

87% overall

Scheme 3.6

Thiiranium bromide salts have been used in the synthesis of thiiranes (scheme 3.7). Treatment of bis(trimethylsilyl) sulfide with bromine generates trimethylsilylsulfenyl bromide [7a] which will then add to 1,2-disubstituted alkenes to form a thiiranium bromide. Rather than attacking the carbon atom of the thiiranium ion, the bromide counterion then attacks the trimethylsilyl group, resulting in formation of the thiiranes in moderate yields.

Br2~ [ Me3Si--S-Br l

MeaSi--S-SiMe 3

R4 S

R3

-Me3SiBr

R1/Y~R 2 ~30% yield overall

+

MeaSiBr

SiMe3 R4 S§ R 3 R

1 ~ 2 Br- R

Scheme 3.7

[3-Fluoro sulfides may be prepared by addition of the elements of phenylsulfenyl fluoride across the carbon-carbon double bond. This can be achieved by addition of a sulfenylating agent to an alkene in the presence of fluoride ions, (Scheme 3.8, Equations 1 and 2) [32, 33]. In general, overall t r a n s addition is observed, with a preference for Markovnikov selectivity although mixtures can be obtained in some

96

CHRISTOPHERM. RAYNER

cases, particularly terminal alkenes. Alternatively, the reagent NEt3.3HF will stereospecifically convert [3-chloro sulfides, prepared in the usual way, into the corresponding fluorinated compounds (Scheme 3.8, Equation 3) [34]. Me2S+SMe,BF4F --- Ph. , , ~ . CH3 NEt3~ CH2CI2, 25~ SMe 90% yield

ph~CH3

PhSCI, AgF

F

CH3CN, 90"/o yield

..,CI

(1)

(2)

~....SMe

NEt3.3HF ~..,F

SPh

(3) SPh

Scheme 3.8 [3-Hydroxy sulphides have also been converted into the corresponding [3-fluoro sulfides using diethylaminosulfur trifluoride (DAST) (Scheme 3.9). In this case the reaction proceeds with 1,2-migration of the thiophenyl group, a common observation with certain substrates when thiiranium ions are intermediates. Activation of the alcohol (32) followed by ring closure gives the thiiranium ion (33), which is then opened by fluoride, forming the glycosyl fluoride (34) with full regio and stereochemical control [35]. Such compounds have been used for the stereocontrolled synthesis of glycosidic bonds in 2-deoxy sugars and are discussed in more detail in Section 3.3.

TBDP s

" M

(32)

OH OTBDMS

Et2NSF3 .._

TBD

CH2(~12'0~C-

T B D P S O ~ . . . O~.~_F MeO'" " ~ ""SPh (34) OTBDMS

PSO~ M

.(3

,,SPh

SF2NEt2 OTBDMS

1 _.

F

_

T B D P S O ~ . , . O"~"~[(S§-Ph MeO"" " ~ " (33) OTBDMS

88% yield

Scheme 3.9 [3-Fluoro sulfides have been shown to be converted into stable fluoroepisulfuranes on standing in solvent at room temperature (Scheme 3.10).

SYNTHETICTRANSFORMATIONS INVOLVINGTHIIRANIUMIONINTERMEDIATES

97

This has interesting mechanistic significance in that sulfuranes are postulated as intermediates in some reactions of thiiranium ions (see Section 3.2) and their characterization provides further evidence for this. The [3-fluoro sulfide (35) converts on standing into the fluorosulfuranes (36) and (37) as an inseparable mixture of diastereoisomers epimeric at sulfur. These are considered to be thermodynamic products due to the strength of the S - F bond [17].

Me

..-" CH2CI20rCHCI3 :,,,..~Me 3-7 days. 25~ Me...- ~ F

MeS

Me~..,,M e F (35)

(36)

Me

+

.-" Me,, ]qN. ,Me :~..~;_x~ F (37)

Scheme 3.10

3.4.2 Carbon

nucleophiles

The formation of carbon-carbon bonds is one of the most important synthetic reactions. This is particularly true if some degree of stereochemical control is possible. Thiiranium ions are powerful electrophiles and react with weak carbon nucleophiles such as allyl silanes, aromatic rings, and silyl enol ethers, usually with a considerable degree of stereochemical control. Such reactions are thus potentially very important synthetically and are discussed in some detail in this section.

3.4.2.1 Silyl enol ethers and related compounds The ring opening of thiiranium ions with silyl enol ethers and related compounds is one of the most useful and most thoroughly investigated reactions of these reactive intermediates. In general, adducts of sulfenyl chlorides and alkenes are treated with Lewis acids to give the thiiranium ion intermediates, which can be opened by a silyl enol ether to give y-thio-substituted carbonyl compounds with full trans selectivity and Markovnikov regioselectivity (Scheme 3.11) [36, 37].

Ri

"~ J

RSCI

Z

S CI

OSiR 13

Lewis~ acid

Ri

[> ] ~R2 S~..,~t,~ S+.R

R2

Scheme 3.11

As typically illustrative examples, treatment of the chlorosulfide (38) ( A r - pchlorophenyl) with titanium tetrachloride followed by the trimethylsilyl enol ether

98

CHRISTOPHERM. RAYNER

of cyclohexanone (method A) gives the ketone (39) in a 73% yield (Scheme 3.12). An alternative procedure uses silver tetrafluoroborate rather than TIC14 with isolation of the intermediate thiiranium ion (40) (method B); however, this leads to a significantly reduced yield (54%) [36].

O "~SAr

(i). TiCl4,-30~

CI (38)

(ii) ~ o S i a e

SAr

=

3

Method A AgBF4 methodB

"••S

~~--OSiMe 3

+

BF4 Ar

(40)

~SAr CI

(41)

Method A or B ., = OSiMe3

~

o

Method A" Method B:

D

SAr

60% 5%

o SAr

+ + +

10% 15%

Scheme 3.12 Use of method A is generally superior to method B, particularly for substrates prone to carbenium ion rearrangements such as the cyclopropylchlorosulfide (41), which undergoes relatively efficient addition with a silyl enol ether using method A, but with method B gives a poor yield of the desired adduct along with significant amounts of rearrangement product. Trimethylsilyl ketene acetals are also useful nucleophiles for reaction with thiiranium ions (Scheme 3.13) [37]. In this case ZnBr2 can be used as the Lewis acid catalyst forming ~/-phenylthio esters. Trimethylsilyl ketene acetals are preferred as equivalents of substituted acetate nucleophiles, whereas tbutyldimethylsilyl ketene acetals are preferred as equivalents for acetate itself. In general, retention of stereochemistry at the reacting centre is observed along with Markovnikov regioselectivity. Vinylic thiiranium ions may also undergo ring opening with various silyl enol ether derivatives. In this case, SN2-type ring opening (c~ attack), or SN2' allylic displacement (~/ attack) are both possible (Scheme 3.14). In general, c~ attack appears to be favoured for these types of substrates [38], and overall retention of stereochemistry is observed at the substituted carbon atom (Equation (5)), which is excellent evidence for the intermediacy of a thiiranium ion.

SYNTHETICTRANSFORMATIONSINVOLVINGTHIIRANIUMION INTERMEDIATES

_,~..

OTBDMS

SPh

~9O M e

~/"CI

99

L _ , ~ . . Spg

~

.~/....,,.,,fll~OMe

ZnBr2, CH2CI2, 20~C, 77% yield OSiMe3

~

.~~P

""'~OEt

OEt Me 7nN2, CH2CI2, 20 ~C, 95% yield

I

Me

Scheme 3.13 (i) 10% TMSOTf CH2CI2,-78~ RT = (ii) OTMS

~ S P h OAc

"~~~~SPh

"~OMe

MeO

(i) 10% TMSOTf CH2CI2, -78~

_

~

But

(ii) OTMS

"~

'~Bu

t

91 9 o~.yattack 78% yield

(4)

100 0 (:x, ',(9 attack 67% yield

(5)

Scheme 3.14

The reaction of a sulfenyl chloride with a vinyl ether usually results in t r a n s addition [39-42], although sometimes non-stereospecificity can be observed (Scheme 3.15). Markovnikov selectivity is almost invariably obtained, and this reaction is similar to the addition to the stabilized carbenium ion (7) discussed above in Section 3.2 [40, 43].

R" X ~

R'SCI .._ r

X=O, S

R , ' X ~+ CI-

R" X ~

~D'S~

CI

SR' ~

II

'

x.

(or

CI ..._ R" v Nu)

] c,

R" ~ ' ~ ' ~ S R ' =Cl] (or Nu)

. _CI

SR'

R.x. Cl

SR'

Scheme 3.15

The reaction of chloro sulfide adducts of vinyl ethers with silyl enol ethers and related compounds has been investigated (Table 3.1) [41]. In general, overall t r a n s

1O0

CHRISTOPHERM. RAYNER TABLE3.1 Reaction of silyl enol ethers with e~-alkoxythiiranium ions

Entry

Substrate MethodNucleophile

L EtO~ CI

S,r

sPh

Major product

OT, S

A

MeO"~SArcI C

Et E t ~ Me/,~~OTMS SPh O OEt OTMS

~

O

C.

O

MeO"~"'~SAr CI

OTMS ~~.,~

[41]

63

[36]

52

_

[41]

93

[44]

90

[44]

70

[44]

= 1:4

0

E

59

OMe

threo : erythro

6

R~.

OMe

~,SAr

threo : ervthro

OTMS

Yield (%)

= 4:1

O OMe ~ S A r threo : erythro

= 1:7.3

Reagents: A, ZnBr2,20~ b, Ticl4, -78~ C, TiCI4,20~ D, ZnCI2,20~ E, EMSOTf, -40~ Ar = p- chlorophenyl. addition is observed when chloro sulfides are treated with a silyl enol ether in the presence of a Lewis acid, although in the case of tetrahydrofuran systems, significant amounts of the cis isomers are produced. In all cases, full Markovnikov selectivity is observed. It is interesting to note that a wide variety of Lewis acids has been used for this reaction, in some cases (e.g. with prochiral silyl enol ethers and acyclic chloro sulfides (entries 4 and 5)) giving complementary stereoselectivity. This may be due, at least in part, to different degrees of thiiranium ion or open carbonium ion intermediates present in the reaction. This reaction has been used in as a key step in the synthesis of (-)-monic acid C (42) [45]. Addition of a sulfenyl chloride to the dihydropyran (43) followed by addition of zinc bromide and 2-[(trimethylsilyl)oxy]propene can give the two

SYNTHETICTRANSFORMATIONSINVOLVINGTHIIRANIUM ION INTERMEDIATES

101

carboxylic acid derivatives (44) and (45), the formation of which is rationalized in Scheme 3.16 by sequential formation of two different thiiranium ions, the first undergoing ring opening in the normal way, the second (46) undergoing nucleophilic attack at sulfur, resulting in formation of an alkene and 1-(phenylthio)propan-2-one. A 1:1 mixture of (44) and (45) was obtained using phenylsulfenyl chloride (86% yield); however, the more sterically demanding triphenylmethanesulfenyl chloride gave a 3:1 mixture in favour of the desired isomer (44) in a 97% yield, probably as a result of increased facial selectivity for the initial sulfenylation reaction. o

"%0

(i) ArSCI, ZnBr 2, CH2CI2 ._-

(43)

OH

-

(ii) OH2--C(Me)OSIMe3

O~'-O

rMe3SiO O Br-'l ..SAr Me3SiBr [ ..~l~+Aro ] OSiMe 3

OH

..,,.J...~.~OH 0

Me3SiO

Me3SiO~o

...,___

"%

(42)

O

+ ~"'~

(44)

(45)

Scheme3.16 A similar reaction can also be carried out with dienol silyl ethers, some examples of which are shown in Table 3.2 [41, 44]. As before, cyclic systems give good control of stereochemistry at the chiral centres originating from the thiiranium ion, with Markovnikov selectivity. There is also a preference for ~/-substitution of the silyl enol ether, particularly if a bulky ester group (CHPr~2, entry 1) is used. The corresponding methyl ester results in formation of an approximately 2:1 mixture of the ~/and e~ isomers [41]. The nucleophilic trapping of c~-heterothiiranium ions generated by neighbouring group displacement has also been investigated for silyl enol ether derivatives. In the case of ~-alkoxythiiranium ions, this allows the use of two possible acetal precursors of types (47) and (48) as shown in Scheme 3.17. The trapping of thiiranium ions generated from substrates of type (47) with silyl

I OR" " "~SPh_OR, Lewis= R'I"~ ~OR'] Lewis R@OR, R.J~ acid Ph~ . J acid OR' SPh (47)

(48)

Scheme3.17

102

CHRISTOPHERM. RAYNER TABLE3.2 Reaction of dienol silyl ethers with thiiranium ions

Entry

Substrate

Method

L~_

Nucleophile

SPh

1

~ A

"0" "CI

~OTMS

7

2 MeO'~"i"~'SAr B B u n "o y ~ "sAr CI

r~

Yield (%) Ref.

O OCHP?2

O~SAr

TMSO

C

,~SPh

K'..O,')'",,~ . ~ ~

o~

~

CI

3

OCHPr'2

Major product(s)

OMe

~"'~'~OTMS

O H C ~ S A r OBu~

82

[41]

75

[44]

60

[44]

Reagents: A, ZnBr2, 20~ B, SnCI4,-78~ C, TiCI4, 20~ Ar = p- chlorophenyl.

enol ethers are shown in Table 3.3 [46]. These reactions are presumed to go via the thiiranium ion (49) to account for the observed stereoselectivity (Scheme 3.18). It is particularly significant that when R ~ is bulky (Ph, pri), steric interactions would be expected to destabilize (49) and may thus favour the open carbonium ion (50), which would show reduced syn/anti selectivity as is observed (entry 3) [46, 42]. The reason why this particular thiiranium ion should be favoured is unclear, although it is known that thiiranium TABLE

3.3 Reaction of silyl enol ethers with (47)

SR2 R1

SR2

SR2 j[,,,.~ Nu R1 OMe

nucleophile OMe "TMSOTf(5 rnol%), MeCN OMe

RI~

OMe syn

ant/ Entry

Substrate

~

SPh

Nucleophile OTMS

OMe

"~

~

Product SPh

But

Nu

But

OMe O

anti:syn

Yield(%)

92"8

92

89" 11

97

59 " 41

80

OMe SPh

~ O M e OMe SMe t ~ e Ph OM OMe

OTMS ~But

SPh

~

But

OMe 0 OTMS ,~ But

~ Ph

SMe B

u

OMe O

t

SYNTHETICTRANSFORMATIONSINVOLVINGTHIIRANIUMION INTERMEDIATES

103

ions with the sulfur substituent trans to carbon substituents are more easily formed than cis isomers [47]. R2

H iIRH, ~, , . . ~~'OM = L

fmul

R1 - Pr' or Ph_

(49)

+.,,~H

L R (50) ~ N u ]

R1 = Me or / vinyl 1Nu

Nu SR2

SR2 RI,~

RI~

Nu

Nu OMe

OMe

Scheme 3.18 The nucleophilic trapping of thiiranium ions derived from substrates of type (48) with silyl enol ethers has also been investigated (Scheme 3.19). Treatment with a Lewis acid generates the thiiranium ion as indicated previously (Scheme 3.17). For activated systems (benzylic or allylic), acetate is a good enough leaving group (OR") for this process: however, for less reactive systems it is necessary to use the corresponding mesylate. The thiiranium ion so formed can then be trapped using a silyl enol ether. In this case, 1,2-migration of the phenylthio group is observed due to the Markovnikov selectivity of the ring opening [48].

OTMS

OAc

ph~

OMe SPh

OSO2Me

SnCI4,-78~ CH2CI2, 64% yield OTMS

SPh Ph

OMe O SPh

n . C e H 1 3 ~ r ~OMe SnCI4,-78~ CH2Cl2_ n ' C 6 H 1 3 ~ SPh

59% yield

OMe O

(Relative stereochemistry not given)

Scheme 3.19 Alkyl enol ethers have also been used in this type of reaction but to a lesser degree than the silyl enol ethers [49]. In this case, because the alkyl group has a much smaller tendency to leave than a silyl group, then the initial product of ring opening is a sulfonium salt (51), which itself can then be treated with a variety of different nucleophiles including Grignard reagents [49], alcohols [50, 51] and

104

CHRISTOPHERM. RAYNER

]

TABLE3.4 Reaction of alkyl enol ethers with thiiranium ions R

(i)I"iC14,-70~ CH2C13

RO~Sp'T~

R~'~OMe a"

Entry 1

Substrate

MeO,.,~ CI

Sp'ToI ~ ' O M e

MeO',,~',Sp.To I CI MeO',,~~Sp.To I CI ,~. Sp-Tol ""CI 5

Enol ether

L - ' ~ . . Sp'T~ "'CI

~"OMe ~'OMe "~OMe

~",,OM e

"

I"~'S.'o,

L

MeO

Nu

el

R' I

p-Tol TiC153

Nucleophile ~MgCI MeOH

Me

p-Tol

Product

P"T~

R" R.

MeO

OMe

MeO

n

OMe

p -TolS v,,j,,,,,.~OMe

MeO Bu4N'BH4 p - T o l S" v -'Lv ~ O-- M e PhCH2MgBr

Yield (%) Ref. 69 a

[49]

95

[50]

60

[50]

78 ~

[49]

69t',

[51]

Sp-Tol H20

r

CHO

2 anti'syn t,Single diastereoisomer.

a5~

hydride [50] (Table 3.4). In some cases considerable stereoselectivity can be achieved (entry 4). Interestingly, allenol ethers are also suitable substitutes for enol ethers in this reaction (entry 5).

3.4.2.2 Allyl silanes and related compounds In addition to silyl enol ethers, thiiranium ions also react with allyl silane and allyl stannane derivatives, with the introduction of an allyl group to form ~-unsaturated sulfides [38, 41, 52]. A number of typical examples are shown in Table 3.5. In general the allyl silane is introduced with overall retention of stereochemistry at the substituted centre and Markovnikov regioselectivity is preferred. For vinylic thiiranium ions, substitution is observed at the allylic (cx) position (entry 3). For suitable substrates, 1,2-phenylthio migration can be observed (entries 2 and 5). oL-Alkoxythiiranium ions or their equivalents have also been shown to react with allyl silane and stannane derivatives (Table 3.6). The results (entries 1 and 2) indicate that if the thiiranium ion is relatively unstable (entry 2, cf. Scheme 3.18)

SYNTHETIC TRANSFORMATIONSINVOLVING THIIRANIUM ION INTERMEDIATES

TABLE 3.5 Entry

Reaction of allyl trimethyl silane with thiiranium ions

Substrate

Method

Me-~_ SPh A

MeI"',,CI CIv~ph

•••"•SPh OAc

M e . ~ SPh

Yield (%)

Ref.

92

[41]

A

Ph P h S ~

74

[41]

B

~-.,,,T....,,~ s ph ~ (a)

59

[38]

65

[52]

79

[52]

SPh

(b)

Product

Me I ' ...., ~

SPh

~

105

SPh

iPh

C

NO2

(c) Ph

SPh D

PhS

NO2

| Ph

v

Notes: (a) 91 : 9 a : 7.(b) 34 : 66 anti : s y n ; (c) 25 : 75 anti : syn. Reagents: All reaction use allyl trimethy!silane under the following conditions: A, ZnBr2, MeNO2, 20~ B, TMSOTf (10 mol%), CH2CI2,-78~ C, TiCI4 CH2CI2,RT; D, AICI3, CH2CI2, RT.

the less nucleophilic allyl silanes react via the open ~-methoxy carbenium ion intermediate (Scheme 3.15) whereas for allyl stannanes the stereoselectivity observed is consistent with a thiiranium ion intermediate [42]. Entries 3 and 4 provide interesting examples of other related reactions, both of which occur with good stereoselectivity to create an additional chiral centre in the product. Cyclization reactions of thiiranium ions with adjacent alkenes have been shown to lead to six-membered ring formation (Scheme 3.20) even when the usually more favourable five-membered ring formation is also possible [53]. Treatment of the chlorosulfide (51) derived from myrcene with tin tetrachloride (0.2 equivalent)

II

cl SnCI4, CH2CI2._ 48-58% yield- PhS

PhS

(sl)

(52) Scheme 3.20

106

CHRISTOPHERM. RAYNER TABLE 3.6

Entry 1

Reaction of allyl trimethyl silane and allyl trimethyl stannane with c~-heterothiiranium ions

Substrate OAc .=

ph~

OMe

Nucleophile

p h ~

OMe

~XMe3 OMe

~vXMe3 OMe

SMe

X = Si, 20" 80 X =Sn, 4" 96

72 89

[42]

X=Si, 21 "79

69

79'21

57

[46]

6'94

80

[42]

X=Sn, 86" 14 79

[42]

SMe

3a.. ~ O M e

~,,.,,,tSiMe 3

OMe

OMe SPh

OAc ph@

Yield (%) Ref.

SPh

SPh

4

anti:syn

SPh

SPh OAc 2

Major product

sPh

~',,,,v,,SnMe3

SPh

SPh

Reagents: TMSOTf, CH2CI2,-78to 20 ~ "Reactiorl carried out in MeCN at -40 ~C.

gives the cyclized product (52) with up to 85:15 (E):(Z) selectivity in 48-58% yields. Related cyclizations have also been reported for polyenes by selective sulfenylation of the external double bond and a series of cyclization steps by an adjacent double bond and aromatic ring terminator (Scheme 3.21). In this example, a sulfenate ester and Lewis acid (boron trifluoride) are used to initiate the cyclization [54]. OMe

~

I ~

OMe

OMe

OMe

PhSOMe.BF3 MEN02, 230~C_

Scheme 3.21

This type of chemistry has been used in an approach to the synthesis of the tricyclic ketoditerpene totarolone (53), involving a thiiranium ion-initiated biomimetic polyene cyclization (Scheme 3.22) [54]. Treatment of the enol acetate (54) with methylbenzene sulfenate and boron trifluoride yields the cyclized adduct (55) in a 53% yield. Interestingly, if TMSOTf is used to initiate the cyclization,

only the monocyclic compound (56) is isolated, which if treated with BF, or BF,.MeOH fails to cyclize to (55), suggesting that (56) is not an intermediate in the polyene cyclization, and that a cascade mechanism is more likely.

$

~

-78" C

~

phs@

1

(54)

~

~

(55)

PhSOMe, TMSOTf

PhS

(53)

Scheme 3.22

3.4.2.3 Aromatic rings Thiiranium ions will add to aromatic rings in an intramolecular electrophilic substitution-type reaction. Use of p-nitro sulfides as thiiranium ion precursors under Lewis acidic conditions in general results in formation of six-membered rings even when competing five-membered ring formation is possible (Scheme 3.23) [54.55].

PhS

SnC14,CH2C12,RTb 80% yield

Me0

Scheme 3.23

The addition of a sulfenium ion (PhS+) equivalent t o alkenes with a suitably positioned benzene ring also results in cyclization by electrophilic aromatic

~

108

CHRISTOPHERM. RAYNER

substitution (Scheme 4.24). The sulfenium ion equivalent in this case is generated by the addition of methyl benzenesulfenate and a Lewis acid, in particular TMSOTf and boron trifluoride. Both non-activated (57) and activated (58) aromatic rings participate in the reaction, and six-membered ring formation occurs even when this results in anti-Markovnikov addition to the alkene. In no cases were products containing seven-membered rings detected [55].

N

PhSOMe, BFs, MeNO~ 47% yield

N

(57)

/---o O,

h

/---o

"~--"'1

PhSOMe,BF3,MeNO,~ 0 ' 75% yield

Me

-

SPh

(58)

Scheme 3.24

3.4.2.4 Ring expansion reactions The high reactivity and cationic character of thiiranium ions means in certain cases that cationic rearrangments are observed [60, 36, 56]. This is potentially useful in ring expansion reactions (Scheme 3.25). Thus, treatment of a t-butyldimethylsilyl ether of a tertiary allylic alcohol with phenylsufenyl chloride followed by silver tetrafluoroborate generates the thiiranium ion, which on warming above 0~ selectively undergoes a 1,2-migration of the most substituted carbon atom to give the ring-expanded product. This reaction is successful for the preparation of fiveto seven-membered rings.

TBDM

(i) PhSCI,-78 ~ C, CH2CI.2

(ii) AgBF4,MEN02

(ill) wa~ng

-

0

SPh

(6)

58% yield

(i) PhSCI, -78 ~ C, CH2CI2 But

~

B

"(ii)AgBF4,MEN02

DMS (ill)warming 84% yield

Scheme 3.25

= BUt ~

O

(7) SPh

SYNTHETIC TRANSFORMATIONS[NVOLVING THIIRANIUM ION INTERMEDIATES

109

3 . 4 . 2 . 5 0 r g a n o m e t a l l i c reagents Carbosulfenylation of alkenes can be carried out in a number of ways using organometallic reagents. Treatment of alkenes with DMTSF (20) followed by a metal acetylide results in overall alkynylsulfenylation of an alkene (Scheme 3.26). Interestingly in this case, predominant anti-Markovnikov regioselectivity is observed, even for trisubstituted alkenes; however, high trans selectivity indicates that thiiranium ion-like intermediates are still involved in the reaction. The use of functionalized alkynes as nucleophiles, for example propargylic alcohol derivatives, and the high degree of stereo- and regioselectivity make this reaction potentially very useful synthetically [57]. I , . .

Li C5HI I = (,,,,,,~Me Et3AI, DMTSF, L J CI(CH2)2CI, THF, RT, ~ ' " ~ 86% yield ~"~"-CsH 1 Li . C5Hll Et2AICI, DMTSF, ~ CsHll I ~ ' ~ SMe ~'~(CH2~C02Me CI(CH2)2CI,THF, 0~C, ~"~',,.,,."~CH2~CO2Me 54~ yield

O

TBDMSO"~"~.. Et3AI, DMTSF, CI(CH2)2CI, THF, 40~ 72% yietd

SMe ~

....,~-,,~ ~"~......OTBDMS

Scheme 3.26 [3-Chloro sulfides have also been shown to react with suitable organometallic reagents under Lewis acidic conditions. Addition of phenylsulfenyl chloride to an alkene followed by addition of titanium tetrachloride and dimethylzinc generates MeTiC14-, which will react with a chloro sulfide to replace the chloride with a methyl group with overall retention of stereochemistry, presumably via a thiiranium ion (Scheme 3.27). In contrast to the earlier example (Scheme 3.26), high Markovnikov selectivity is observed (Equation (8), Scheme 3.27) along with complete trans stereoselectivity [58]. It is important to note that although quite good yields of products are obtained in these reactions, some nucleophilic attack at sulfur can occur, to regenerate the alkene and thioanisole. This side-reaction can be almost totally suppressed by using a more bulky sulfide (e.g. 2,4,6triisopropylsulfenyl chloride, Equation (9)), which shields the sulfur atom from external nucleophiles. In addition to the titanium-derived reagents, trialkylaluminum reagents are also efficent in this reaction (Equation (10)). The regio- and stereochemistry for addition to o~-chiral alkenes have also been investigated using these types of reactions (Scheme 3.28) [58, 59]. In the case of the cyclohexene (59) the major product is (60) with > 99% apparent diastereofacial selectivity observed for the initial sulfenylation and 85% regioselectivity for the

110

CHRISTOPHERM. RAYNER

[ ~ M e / i ) , PhSCI,CH2C~ [ ~ e (ii) Me2Zn,TiCI4 (i) ArSCI,CH2Cl2 (~) M~Zn, nc~

-

PhSCl, CH2Cl2

((il'iAIEt3

-

Me

59'/o yield

(8)

=~e Ar = Ph, 68% yield Ar = 2,4,6-triisopropyl Ar phenyl,82% yield

(9)

SPh 95 : 5 regioselectivity

i•••t Ph

85% yield

(10)

Scheme 3.27

ring-opening reaction, although competing nucleophilic attack at sulfur may mean that actual selectivities may not be quite this high [59].

SPh =..._

(ii) Me2Zn,"ricl4

(59)

"l'tCIs

(60)

Me

61% yield

Scheme 3.28 Allylic alcohol derivatives also show interesting stereo- and regiocontrol in this reaction (Scheme 3.29). Facial selectivity for the sulfenylation reaction is highly sensitive to the protecting group on the oxygen atom. Thus, with the methyl ether, the product resulting from the thiiranium ion (61) is almost exclusively formed (99: 1), although, as before, nucleophilic attack at sulfur as a side-reaction may make this figure misleading. Stabilization of the positive sulfur atom in (61) by the adjacent oxygen atom similar to the sulfurane or ion pair stabilization discussed in Section 4.2 is possible and may account for the selectivity. Larger groups on the

,,,'L~'~

(ii) Me2Zn, "1"iCI4-

i

SPh i.

(61)

TBDMSO

(i) PhSCI (ii) ae2Zn,TlCl4 =

50% yiekJ

TBD

PM~ ] (62)

Scheme 3.29

SPh

7(P/o yield

SYNTHETIC TRANSFORMATIONS INVOLVING THIIRANIUM ION INTERMEDIATES

111

oxygen atom disfavour (61) because of increased steric hindrance either preventing coordination to the sulfur atom, or directing the sulfenylating reagent to the opposite face of the alkene. Thus the corresponding t-butyldimethylsilyl ether gives mainly products resulting from the thiiranium ion (62), albeit with poorer selectivity (63:37 ratio), Similar stabilization of the thiiranium ion (62) by the adjacent oxygen atom is possible; however, it would also result in unfavourable steric interactions between the three-membered ring and the carbinol methyl group [58, 59]. Full regiocontrol is observed, with opening occurring at the site distant from the oxygen functionality as would be expected on steric and electronic grounds.

3.4.2.6 Cyanide Thiiranium ions can be treated with cyanide ion to form the expected products (Scheme 3.30). The reaction with acetonitrile is discussed in Section 4.4. If the thiiranium ion is generated using DMTSF (20), then anti-Markovnikov selectivity is favoured; however, if the less reactive trimethylsilyl cyanide is used rather than metal cyanides then Markovnikov selectivity can predominate [22].

(i) DMTSF, MeCN..__ r,~SMe (ii) KCN ~"'CN 99% yield

[~~

v

!i) DMTSF, CH2CI2... (ii) TMSCN 72% yield

[ ~

r

[~

92 8 regioselectivity

CN 69 31 9 regioselectivity SMe

SMe (i) DMTSF, MEN02 ,,"'~~CH2)eCO2Me iii)NaCN, HBF4, MeOH --" N C v , J~CH2)sCO2Me 81% yield Scheme 3.30 Thiiranium ions derived from [3-nitrosulfides also react with trimethylsilyl cyanide (Scheme 3.31). Again with this reagent, predominant Markovnikov regioselectivity is observed, along with stereospecificity consistent with a thiiranium ion intermediate, and thiophenyl migration where appropriate [52].

~~,

SPh

SnCl4,TMSCN No,,

NO2 Ph SPh

0oc to

64% yield

SnCI4,TMSCN CH2Cl2,0~ to RT, 73% yield

"••'SPh CN

CN Ph SPh

Scheme 3.31

73"27 regioselectivity

single regioisomer - 8 : 92

anti : syn

112

CHRISTOPHERM. RAYNER

3.4.3 Oxygen nucleophiles The ring opening of thiiranium ions with oxygen nucleophiles leads to the formation of [3-hydroxy or alkoxy sulphides and related compounds. This reaction has found particular use in the synthesis of cyclic ethers and lactones by intramolecular cyclization reactions of an oxygen functionality onto a thiiranium ion. The intermolecular reaction has also found considerable application, for example in controlling the configuration at anomeric centres in sugar chemistry.

3.4.3.1 Alcohols The oxysulfenylation of alkenes can be achieved in a number of ways. One of the simplest is the addition of sulfenyl chloride and then displacement of the reactive chloride ion with a suitable oxygen nucleophile. Examples of this are shown in Scheme 3.32. In general, Markovnikov regioselectivity is observed although there are exceptions (Equation (12)). A similar conversion can be effected by using an alkene with DMTSF (211) in the presence of water and a suitable base (Scheme 3.33). Markovnikov-type selectivity is observed predominantly; however, for terminal alkenes an almost 1:1 mixture of regioisomeric products is observed [22].

- ~

PhSCI,Et20 " ~ , , " 96% yield -

,_. SPh

KOH (aq.) ,Ci 70% yield-

H PhCO-N,. O {i) MeSCI O y , ~ (ii) MeOH, AgBF4 ., 96% yield CO2CHPh2 O

O

H PhCO-N,,.

O

CH2CI2~ .78oc,

~CI

(12)

(13) t631 COCH2Ph

COCH2Ph PhSCI

(11~

0

O,~"'~ .'~'.,,...,OMe [621 ' CO2CHPh2

~ CH2CI2, 87%yield

Nv~ L-"

.., SPh

OH [61]

NaOH --'- ~ H SPh dioxane orwetAg20 Scheme3.32

SPh [64]

(14)

SYNTHETIC TRANSFORMATIONS INVOLVING THIIRANIUM ION INTERMEDIATES

DMTSF, NaHC03= H20, MeCN, 93% yield O DMTSF,NaHCO3=_ H20, MeCN,

[~..,~~)H Me O

83% yield MeS

113

O

+

79 21 9 HO

e

Scheme 3.33 Thiiranium ion intermediates have been used to control the stereochemistry at the anomeric centres of sugars (Scheme 3.34). In some cases where thiiranium ions may be intermediates, there is evidence for other diastereoselective influences controlling the selectivity, and so other effects must also be considered [65-67]. The sulfenyl fluorides (63) and (64), prepared as described in Section 4.1.2 (Scheme 3.9) can be coupled with alcohols selectively to give the oL or [3 anomer, with addition anti to the thiophenyl group always taking place [35].

TBDPso~O~~

"F

ROH, SnCI2, E,20,-15~

"~'SPh 4 A molecular sieves, 93% yield OMe (63)

TBDMSO" " ~

TBDPso~O"I"~"O?| '''OMe~'--~'t~O~ .....

k9, . . , , , ~

A c O ," ' , , . . , , ' - ' . , , - - -

TBDMSO" " ~ ~SPi~-OMe

"T" uAc OAc

TBDPSO~_.. O~.... F

ROH, SnCI2, Et20,-15~ TBDPSO "" . ..... ~.,,J ...... A c O ,'- ' - , . . , - ' - . . , , . - TBDMSO" " ~ "'SPh-"T u,~c TBDMSO"" " ~ "'~176 4 ,~ molecular sieves, 92% yield OMe OAc OMe (64)

ROH =

HO~~..0....,,,,OMe AIO,.,'VL~-..,,OAc OAc Scheme 3.34

The thiiranium ion may also be prepared by addition of a reactive sulfonium salt to a glucal, and can then be trapped using a suitable nucleophile (Scheme 3.35). Both the methyl- and phenylsulfonium salts are successful for this reaction: however, the latter give higher [3 selectivity. Although alcohols are successful for this reaction, it is sometimes necessary to use more nucleophilic stannyl ethers to improve efficiency [66]. Sulfenate esters have also been used as glycosyl acceptors and add to sugar-

114

CHRISTOPHERM. RAYNER

..OBn B n O ~ a BnO"-.--.-~.~~

+

BnO SR ~ OSnBu3 BnO ~~] RSS+(SR'R'SbCI6 B n O ~ a a Bn ~ CHaCI2 = B n O ' ~ ~ S N ~OPh + B n O . ~ OPh R=Me, I]'a= 1 1.60% 9 yield R = Ph, 13.o~= 3 1, 9 56% yield

Scheme 3.35 derived vinyl ethers with almost total anti stereoselectivity (Scheme 3.36) [68]. Facial selectivity for the addition to the double bond is moderate but can be improved by judicious choice of protecting groups, nucleophile and reaction conditions.

~

?~

R

O

R'OSPh

=SOT,_ toluene, -15~

~

---"

~ "

O_...~~1.O ~

"

oR o.'

+ %

o,

OR' (x 13 9 = 81 19, 9 81% yield

R= Bn, R'=

~o~ BnOI OMe Scheme 3.36

This has been used in a model approach to the synthesis of the aureolic antibiotic olivomycin using the 2-naphthylsulfenate ester of 2-hydroxytetralone (Scheme 3.37) [69].

OBR 0=< )

..OBn BI~O~o'---~~~ + I [ ~ ~ o , , S , , , , ] ~ o

~

TMSOTf CH2CI2,_20o~-, B n O ~ O, 78% yield BnO~~~O Snaphthyl Raney Ni EtOH, A 67% yield OBn

~no~O

Scheme 3.37

~

SYNTHETIC TRANSFORMATIONS INVOLVING THIIRANIUM ION INTERMEDIATES

115

One of the most investigated oxysulfenylation reactions is the intramolecular etherification reaction of an unsaturated alcohol initiated by an electrophilic sulfur species adding to the alkene, and cyclization onto the resulting thiiranium ion (Scheme 3.38). This has been extensively investigated using a number of different approaches, e.g. addition of a sulfenyl halide in the presence of a tertiary amine base (Equation (15)) [70]. Attempted cyclization of ~/-hydroxyalkenes fails to produce the oxetane using this method, and simple addition of PhSC1 is observed. In the absence of base only addition of PhSC1 is observed with no cyclization. Initiation using sulfonium salts (Equations (16)-(18)) can be an excellent reaction [71-73]; however, because of their high reactivity, some sidereactions (e.g. electrophilic aromatic substitution) have been observed [72]. The acid-catalysed addition of sulfenamides (Equation (19)) [25, 74] and sulfenate esters (Equation (20)) [75-77] have also been reported. The latter method is somewhat less efficient than using phenylsulphenyl chloride and base whereas the former is particularly efficient and has been used for the preparation of large-ring ethers.

~,~,,,~OH ~~~.,,~OH

RSCI, EtPr'2N MeCN','RT ~ MeS§

R

'

MeS§

~ Ho

SR

R = Ph, Me

-

-"- R

~ S M e 1:1 mixture

~ S M e

MeS+(SMe)Me-BF4-

MeS \ O /

. . i l t

~,,,,,,,~OH ~,,,.~OSPh

/--"k PhS-N O \ / _~ ~ , , i S p CF3SO3H BF 3 or

SiO2~ ~ S P h

h

[70]

(15)

[71]

(16)

[72]

(17)

[73]

(18)

[25,74]

(19)

[75,77]

(20)

Scheme 3.38

Similar types of cyclization have also been carried out on substrates not necessarily derived from alkenes. A particularly extensive series of investigations [78-86] involving f3-hydroxy sulphides has led to a number of useful guidelines for the reactivity and cyclization of thiiranium ions derived from such precursors (Scheme 3.39), which can be summarized as follows:

116

CHRISTOPHERM. RAYNER Ph I S§ %

5-exo-tet 5-exo-tet 6-endo-tet

FIGURE3.1 Cyclization occurs onto the more substituted end of the thiiranium ion intermediate (Equation (21)) [86]. This is because any partial positive charge in the transition state can be better supported at more substituted centres, allowing for longer partial bonds which allow a less stringent alignment of the reacting centres (OH, C and S*) away from the usual 180 ~ which would normally be very difficult to adopt in this type of cyclization reaction. This appears to be the dominant factor in determining regioselectivity in the ringopening reaction. The alternative tetrahydrofuran product would result from attack at a secondary carbon atom, for which a tighter transition state would be required. (ii) The 5-exo-tet cyclization process is preferred to the hybrid 5-exo/6-endo-tet cyclization (Figure 3.1), in accordance with Baldwin's rules [87]. Fivemembered ring formation is preferred over six-membered, all other things being equal (Equations (22) and (23)) [78, 80]. (i)

PhS....-V

=

C CH2CI2

HO HO

PhS _.

TsOH

OH

HO

~ CH2CI 2

0

OSitBuPh2

i

f - '~.SPh - ~, " OH

+

SPh

-

OH

HO

H O ~ ' ~ ~ ~ HQ PhS ..- x s H O v @ ~ j ~ O

V

~

(22)

PhS

SPh +

PhSq " HO~ PhS

NO

91 99

HO HO~~~~~J~~

..SPh

OH

(23)

61 "14 TsOH

PhS

0H2012"- H O / " " ~ ~10 anti, 94%

V

H TsOH

r

~ +

OH

PhS Scheme

3.39

91 9

(24)

syn, 0%

SPh

~

CH cl; HO

OH

PhS ~ O

(25)

SYNTHETIC TRANSFORMATIONSINVOLVING THIIRANIUM ION INTERMEDIATES

11 7

(iii) There is a preference for developing anti rather than syn stereochemistry in the cyclization products (Equation 24) [79]. (iv) The Thorpe-Ingold effect favours formation of the more substituted ring (Equation (25))[78]. Of the last three points, the Thorpe-Ingold effect is the most important, followed by developing stereochemistry and Baldwin's rules (almost equal precedent). Generally, the final result is a combination of all these factors, which can be biased to give almost exclusively one product. Other cyclizations of [3-hydroxy sulphides have also been reported (Scheme 3.40) [88, 89]. Use of strong alkylating agents (dimethyl sulfate, methyl triflate, methyl iodide and trimethyloxonium tetrafluoroborate) allows cyclization with dehydration (Equation (26)) [88]. Cyclization can also be preceded by in situ reduction of a sulfoxide to give the sulfide, which then cyclizes with dehydration under the reaction conditions (Equation (27) and (28)). In addition to alcohols, ethers can also be used to trap the thiiranium ion intermediate, with subsequent cleavage of the resultant oxonium salt to give a tetrahydrofuran (Equation (28)) [881. .."

OH ""

OH SPh -. OH

~

Ph

Ph /

CH2CI2, C, Me 90% yield CH3COBr __

S§

'~0-

CH2CI2.0 ~ C, Me 77% yield

CICOCOCI, NaL MeCN, 22 ~C, 78% yield

.,,,SPh 9

Ph

M~~~_.~~SPh

v

HOph,,S~,o.

MeO

Me,, "..

Me2S04

MoS "'"Ph

H

Me

(26)

(27)

(28)

.... e

Scheme 3.40

3.4.3.2 Carboxylic acid derivatives The reaction of a thiiranium ion with a carboxylate nucleophile is a good method for the preparation of ester derivatives of [3-hydroxy sulfides. One of the easiest methods for this involves the carboxysulfenylation of an alkene. This may be carried out via a [3-chloro sulfide, or directly by a number of other methods summarized in Scheme 3.41. Extensive use of this reaction has been made intramolecularly using unsaturated acids which can be cyclized to form lactones (Scheme 3.42) [96-104]. This includes the use of some unusual sulfenyl chlorides (Equation (36) and (37)) [98-100]. This type of lactonization has also been carried out on substrates where the thiiranium ion is generated from a [3-hydroxy sulfide (Equation (38)) [101,102].

118 Ph

CHRISTOPHERM. RAYNER H

O O

H

li) MeSCI

~

= (ii) NaOAc, AeOH-~O2CHPh2 DMF, 65 ~

86% yield

~,~CN

(CFCO)O,cc,, 70%

\

86% yield

[67] (30)

/"'SMe

[/~.

yield

Mn(OAc)3, PhSSPh CF3CO2H, =

[62] (29)

~~..,OAc

[i) MeSBr, AgBF4 (ii) Me4NOAc,AcOH95% yield MeS(O)SMe

~-SMe

CO2CHPh2

. _

Q

""r~

O O.,.,'~N i . . , J . ~ O A c

SMe

[90,91] (31)

"OCOCF SPh

CF3CO2vJ~CN

+

77:23

OCOCF3 PhSv'L",./CN

[92-95] (32)

Scheme 3.41 Other carboxylic acid derivatives have also been used, in particular amides which undergo O-alkylation on cyclization (Scheme 3.43) [105,106].

3.4.3.3 Other oxygen nucleophiles One other important oxygen nucleophile is dimethyl sulfoxide (DMSO) [22]. This reagent, in conjunction with DMTSF (20), directly gives 13-ketosulfides from alkenes via a thiiranium ion which is opened by DMSO with predominant Markovnikov regioselectivity to form a sulfoxonium salt. This eliminates on treatment with base to give the expected product in a process related to the Swern oxidation (Scheme 3.44) [107].

3.4.4 Nitrogen nucleophiles The ring opening of thiiranium ions with nitrogen nucleophiles leads to the formation of [3-amino sulfides and related compounds. The reaction may be carried out in both inter- and intramolecular fashion.

3.4.4.1 Amines and their derivatives The azasulfenylation reaction of alkenes using DMTSF (20) and an appropriate nitrogen nucleophile results in overall t r a n s addition, as would be expected if a thiiranium ion is an intermediate, although other intermediates in the reaction, such as dimethyl sulfide adducts, are also no doubt present [21]. The reaction is particularly powerful in that regioselectivity can be controlled by judicious choice

SYNTHETICTRANSFORMATIONSINVOLVINGTHIIRANIUMION INTERMEDIATES

~

OH

(i) PhSCI, CH2CI2 S , # ~ " ~ O - Ph " O (ii) EtN~Pr2 84% yield

CO2H

(i) DMTSF, MeCN ~O~ (ii) EtNipr2 60% yield MeS~~ O

1] 9

[70,75]

(33)

[73]

(34)

[103,104]

(35)

r

CO2H

0

(i) NEt3' CH2CI2'25~ (ii) PhSCI,-78~ 70% yield

O~~ SPh

CI,~ , . . ~..~jCO2Me

n- C14H29~ J ~ . , i ~ . i " ~ C O 2 H

S. ~ ~e". CO2Me

I H~NHCOCF3 H NHCOC9 n-C14H29'" Y "~ NEt3, CH2CI2, O,~ [99] 30-40% yield O

(36)

1:1 mixture of anti isomers CO2H MeO2CCH2CH2SCI'NEt3, CH2CI2,-78~ 69% yield

~"

s~CO2

Me

[loo]

(37)

[101,102]

(38)

O

O HO -.- SPh

TsOH (7 equiv.) Me

~

.,,SPh

CH2CI2,~, 80% yield

Me

Scheme 3.42

A

H

N.,,~Ph O H N ~ , , Ph

(i) MeS+(SMe)SMe.SbCI6-, CH2CI2 (ii) H20, base ~ 96% yield

~N~r,,p O H

MeS§ CH2CI2, 60% yield Scheme 3.43

h SMe

Ph

sS C,, -

120

CHRISTOPHERM. RAYNER

- ~ ~ C H2)sCO2Me

,,,

(i) DMTSF, MeNO2

IIO

~SMe

(ii) DMSO, EtNPri2,--- MeSv~cH2)sCO2Me + O ' ~ '''~cH2)eCO2Me 84% yield H 2.5 to 4.1:1 -'=9 (ii) DMSO, HgO, EtN Pr'2

71% yield

Scheme 3.44 Nu

DMTSF ~ CH2CI2, nucleophile

(66)

(65)

nucleophile

Nu

NH3

NH2

85 : 15

84

Me3SiN3

N3

5:95

82

Ratio (65):(66) Yield (%))

Scheme 3.45 of nucleophile and substrate (Scheme 3.45). Relatively good nucleophiles (e.g. pyrrolidine, ammonia and sodium azide) tend to give anti-Markovnikov selectivity whereas poorer nucleophiles (trimethylisilyl azide) favour Markovnikov selectivity. [3-Hydroxysulphides when treated with BF3"OEt2 in the presence of sulfonamides give [3-sulfonamido sulfides, which are precursors of N-sulfonyl aziridines (Scheme 3.46). The hydroxyl group is replaced by the sulfonamide, with overall retention of configuration due to the participation of the arylthio group [108].

HO sAr i p . p . S..l

TsNH'~"~SAr ~

ph,~

Ts

Ph 70% yield

Scheme 3.46 In a related reaction, [3-hydroxy sulfides under strongly acidic conditions form thiiranium ions which can be trapped by acetonitrile solvent with Markovnikov selectivity in a Ritter-type reaction (Scheme 3.47). The presence of water as a cosolvent allows hydrolysis of the intermediate nitrilium ion to give the related acetamide. Again the hydroxyl group has been replaced by an amide, with overall retention of stereochemistry [109]. This Ritter-type reaction has been observed in a number of cases of reactions of thiiranium ions. For example, anodic oxidation of a disulfide in the presence of an alkene in acetonitrile solvent gives acetamido sulfides [110, 111]. If the acid-catalysed addition of phenyl sulfenamides is carried out in nitrile

SYNTHETIC TRANSFORMATIONSINVOLVING THIIRANIUM ION INTERMEDIATES

o

n-C,oH2,' ~ ' V ' s P h

PhS

+ n-C,oH2,' ~ ' V ' O H

c so

I c0

MeCN.H20" LCF3SO3

1 21

,l

Phi

l In

NHCOMe n.CloH21~,,~,tSPh = 81% yield

CH3 .C10H21~',~SPh

Scheme 3.47 solvents (MeCN, PriCN, PhCN), then amidines are the major products (Scheme 3.48) [112]. If however, dichloromethane is used as the solvent then the more usual [3-amino sulfides are found, albeit in only moderate yields.

0

(67) Pr'CN, CF3SO3H =

r i ' ~ sPh L v , J..,,N:=~'Pr

L)

(67), CH2CI2 CF3SO3H ~ ~ . . SPh 44% yield

C N-SPh (67)

Scheme 3.48 Sulfenanilides have also been shown to add to alkenes using BF3-OEt 2 as a catalyst (Scheme 3.49, Equation (89)). Fair to good yields are obtained with t r a n s stereospecificity and predominant Markovnikov regioselectivity [113]. Similarly, sulfenamides add to alkenes in the presence of either BF3"OMe2 or Me30+.BF4 -, to give [3-aminosulfides (Equation (40)) [24]. 2,3-Epoxy sulfides, which may be readily accessed in an enantiomerically pure

N02"-~

1-hexene, NHSPh BF3"OEt2=- "~v"~~SPhNHAr + " / V ' ~ ~ N H A r s P h C6H6, 77:23 91% yield

MeSNMe2, Me30+- BF4" ~,],~SMe MEN02, 0~ CI ~ ~O/.,,,NMe2 75% yield Scheme 3.4 9

(39)

(40)

122

CHRISTOPHERM. RAYNER

form by the Sharpless asymmetric epoxidation [114], isomerize under Lewis acidic conditions to the corresponding 3-hydroxy-l,2-thiiranium ions, which have been trapped with various nitrogen nucleophiles. This leads to the synthesis of sulfides containing a high degree of functionality in enantiomerically and diastereoisomerically pure form (Scheme 3.50) [115].

,,O_

(i) TMSOTf, CH2CI2, -78 oC

HO

(ii) 2- t rim'ethylsilyloxy pyridine) -78 ~C~RT (iii) K2CO3, MeOH '81% yield

0 N SPh

Scheme 3.50

[3-Chloro sulfides, formed by the addition of sulfenyl chlorides to alkenes, are readily converted into the corresponding [3-amino sulfides (Scheme 3.51). For example, addition of methanesulfenyl chloride to methyl acrylate produces a mixture of the two regioisomeric [3-chloro sulfides (68) and (69). Treatment of a mixture of these with aqueous sodium azide under phase transfer conditions regioselectively produces the 2-azido ester via a common thiiranium ion intermediate [116]. MeSCI, CH2CI2._ ~"-CO2M e -65"C 85% yield

CI

SMe

MeS',~CO2M

+ C I , v ~ C02Me 83:17 (69)

e

(68)

NAN3, H20~ Aliquat 336 NH2 MeSv~cO2Me

H2S, H20 ~,pyddine

N3

MeS~co2M e 96% yield

58% yield Scheme 3.51

Similar effects have also been observed for acryloyl proline esters (Scheme 3.52) [117], and bornyl propenoates (Scheme 3.53) [118]. It would appear in these cases that chloride is displaced by azide with net inversion of the stereochemistry even though overall retention through sulfur participation has been reported in related systems [119]. Thiiranium ions have been implicated as intermediates for the control of stereochemistry at anomeric centres in nucleoside derivatives (Scheme 3.54), although other explanations for the observed selectivity have also been suggested [35]. Thus, treatment of the acetate (70) with SnC14 followed by addition of a silylated nucleoside base precursor gives predominantly the [3-anomer, possibly

SYNTHETIC TRANSFORMATIONSINVOLVING THIIRANIUM ION INTERMEDIATES

"~C02Et 0

123

~~,,C02Et PhSCl ~C02Et TiCl4, CI CH2CI2' .0'~ ,CI + 0 .95oC, 65" 35 71% yield SPh ((i)NAN3,PTC ii) H2S,pyridine ~C02Et 0

N3

Scheme 3.52

H

PhSCI

~cO

"~N"ph

. - ~ NHPh ~,,~SPh ~ azide

0 Scheme 3.53

due to the intermediacy of the thiiranium ion (71) [120, 121]. An alternative explanation for such stereoselectivity invokes a bulky SnC14-sulfide complex (72) which shields the OLface from the incoming nucleophile. Reaction of unsaturated amine derivatives with sulfenylating agents has been used for the preparation of four-, five- and six-membered nitrogen heterocycles. For example, sulfonamides cyclize onto thiiranium ions generated by addition of MeS+(SMe)SMe.SbC16 - to an alkene (Scheme 3.55, Equation (41)) [122], or by Lewis acid-catalysed dehydration of [3-hydroxy-g-sulfonamido sulfides (Equation (42)) [123]. Alternatively, unsaturated amines, initially protected as their hydrochloride salts, form the expected [3-chloro sulfide adducts when treated with phenylsulfenyl chloride. These adducts cyclize to give the nitrogen heterocycles when neutralized with potassium carbonate (Equation (43)) [124]. Finally, [3-1actam derivatives may be prepared in good yields by addition of phenylsulfenyl chloride

124

CHRISTOPHERM. RAYNER

Bu'Ph2SiO"~O,~oA c !

SPh

(70)

u'Ph2SiO

SnCl, = CI(CH2)2Cl 0~C

"~0,~

LAcOSnCl4 ('/1)

S*"PhJ

Butph2SiO...~

0

t

Bu Ph2SiO....~

(72) Ph

(NH

N'~"O

-'~,,Oy I

o~:l]=3" 97

SPh Scheme 3.54 to acrylamides followed by base and phase transfer catalysed cyclization (Equation (44)) [125].

3.4.5 Sulfur nucleophiles The formation of 1,2-bis(thioethers) by the ring opening of thiiranium ions by sulfur nucleophiles has been reported. Treatment of an alkene with a disulfide (MeSSMe or PhSSPh), usually in the presence of a catalytic amount of BF3"OEt2, ms I

Mes',sMe,sMe-s c,, CH2CI2, 0~C OH PhS =. ~

C

NHTs

BnO

I O ~ NHBn

TMSOTf CH2CI2, -78~ to RT

SMe

~v § ~

(i) PhSCI, CH2CI2 _ BnO (ii) K2C03, Nal, MeCN-

SPh _(i) PhSCl' C H 2 C-.-I20~ N (ii) KOH, Bu4NBr, H=~D,CeH6 "Bn Scheme 3.55

SPh

[122]

(41)

[123]

(42)

[124]

(43)

[125]

(44)

SYNTHETICTRANSFORMATIONSINVOLVINGTHIIRANIUM ION INTERMEDIATES

125

results in overall t r a n s addition of the disulfide, although yields using this procedure can be poor, particularly for terminal alkenes (Scheme 3.56, Equation (45)) [27]. The reaction is, however, successful for dienes, where 1,4-addition of the disulfide is observed. Similarly, activation of disulfides using iodosylbenzene activated by trifluoromethylsulfonic acid also results in overall t r a n s addition of disulfide, and is successful for terminal alkenes (Equation (46)) [26].

O

SMe

MeSSMe'BF3"OMe2 ~ ~ .,. . MEN02, CH2CI2

~"~'SMe

81%yield PhSSPh

(45)

~

PhlO-CF3SO3H(0.1equiv.) 92%yield

.~'v~,~~

SPh

Sp h

(46)

Scheme 3.56 The addition of thioethers to thiiranium ions generates reactive sulfonium salts. These are believed to be intermediates when alkenes are treated with DMTSF (20), with dimethyl sulfide acting as a leaving group allowing introduction of a nucleophile either by direct displacement or via the regenerated thiiranium ion (Scheme 3.57) [21, 24].

R~

BF4- Me"

DMTSF

[

es

nucleophile._ MeS RSJ,~iNu

It Scheme 3.57

This type of reaction has also been reported intramolecularly for formation of a five-membered ring sulfonium salt which undergoes elimination to give the final product with overall dehydration (Scheme 3.58) [126].

3.4.6 Miscellaneous transformations A number of miscellaneous reactions of thiiranium ions are described here, including reactions with hydride and phosphine nucleophiles and rearrangements.

126

CHRISTOPHERM. RAYNER

SOCI2, NEt3 CCI4, 0~C

PhS SPh

FH Me

1

"Phi

SPh']

SPh SPh 82% yield

Scheme 3.58

3.4. 6.1 Hydride Thiiranium ions generated from [3-nitro sulfides under Lewis acidic conditions can be efficiently reduced [52] with triethylsilane with predominant Markovnikov selectivity in good yield, and thiophenyl migration where appropriate (Scheme 3.59).

~NO SPh

Et3SiH 2 AICI3, CH2CI~ ~ I ' ~ S P h H 77% yield

Scheme 3.59

3.4.6.2 Phosphines Treatment of alkenes with DMTSF (20) followed by triphenylphosphine generates [3-thiophosphonium salts, which eliminate to give the corresponding vinyl phosphonium salts on addition of base (Scheme 3.60) [23].

(i) DMTSF, CH2CI2,O~

--~ ,,SMe BF4

(ii) PPh3

~.,~,.~ p+Ph3

DBU ~

~BF4-

p+ph3

86% yield Scheme 3.60

3.4.6.3 Eliminations [3-Hydroxy sulphides can form thiiranium ions which readily eliminate with ring opening and loss of proton to form an allylic sulfide (Scheme 3.61). It is essential that the proton is in an antiperiplanar orientation relative to the breaking C-S bond for efficient elimination to occur [127-130].

127

SYNTHETIC TRANSFORMATIONS INVOLVING THIIRANIUM ION INTERMEDIATES

I lnrsoj .sPh

.SPh

*-Ph

OH C6H6,TsOH=A LH`"

"H* ~

97-100% yield

Scheme 3.61

3.4.6.4 Rearrangements Thiiranium ions have a high degree of cationic character, which in some cases can lead them to rearrange. An example involves the ring expansion of the thiiranium ion derived from trans-di(t-butyl)ethylene. This gives a thietanium ion (73), which opens to give the alkene (74) (Scheme 3.62) [131].

s,,e

I

I

Bu,,,~/Bu'

M e SbOls" S+-SMe

co~cl~

~

-

But

[ Me'

, uSbC,,e,

Bu

.

=

sbcl,-]

"~SqMMe e] +

Me"

Bu' ~

MeS

(73)

Me

M~

(74)

3.62

Scheme

The adducts of thiiranes with benzyne rearrange to give a vinyl sulfide in synthetically useful yields (Scheme 3.63). The mechanism of this reaction may involve the betaine (75) or alternatively may be a concerted process [132].

'::'X-/'=' S

+

[~1

R

R

_-

__

_

R ,:, \---/

PhS/

ffs) Scheme

3.63

3.5 SUMMARY In this review I have concentrated on what I believe to be the most important synthetic transformations involving thiiranium ion intermediates. A wide variety of functionalized sulfides can be accessed through them, often with stereochemical

128

CHRISTOPHERM. RAYNER

and regiochemical control. I hope this review will encourage their further use in synthesis.

ACKNOWLEDGEMENTS I wish to thank my research group for their continued hard work and support, and Dr Neil Pegg (Glaxo Group Research) and Dr David Miller (SmithKline Beecham Pharmaceuticals) for useful discussions.

REFERENCES 1. D.C. Dittmer, Comprehensive Heterocyclic Chemistry (A.R. Katritzky and C.W. Rees, eds), vol. 7, ch. 5.06, Pergamon Press, Oxford (1984). 2. D.C. Dittmer and B.H. Patwardhan, The Chemistry of the Sulphonium Group (S. Patai, ed.), ch. 13, Wiley, Chichester (1981). 3. G. Capozzi and G. Modena, Organic Sulfur Chemistry (F. Bernardi, I.G. Csizmadia and A. Mangini, eds.), ch. 5, Elsevier, Amsterdam (1985). 4. G. Capozzi, G. Modena and L. Pasquato, The Chemistry of Sulphenic Acids and their Derivatives (S. Patai, ed.), ch. 10, Wiley, Chichester (1990). 5. D.R. Hogg, The Chemistry of Sulphenic Acids and their Derivatives (S. Patai, ed.), ch. 9, Wiley, Chichester (1990). 6. (a) F. Capozzi, G. Capozzi and S. Menichetti, Reviews on Heteroatom Chemistry (S. Oae, ed.), vol 1, p. 178, Myu, Tokyo (1988). (b) Y.G. Gololobov and N.I. Gusar, Sulphenyl Chlorides, Nauka, Moscow, (1989). 7. (a) G. Capozzi, Pure Applied Chem., 59, 989 (1987). (b) W.A. Smit, Cationoid Reagents and Intermediates in Electrophilic Additions to Carbon-Carbon double and Triple Bonds, Soviet Sci. Rev. B, 7, 144, Harwood Academic Press, Amsterdam, (1985). 8. M. Oki, W. Nakanishi, M. Fukunaga, G.D. Smith, W.L. Duax and Y. Osawa, Chem. Lett., 1277 (1975). 9. G.H. Schmid and V.J. Nowlan, Can. J. Chem., 54, 695 (1976). 10. W.A. Smit, N.S. Zefirov, I.V. Bodrikov and M.Z. Krimer, Acc. Chem. Res., 12, 280 (1979). 11. G.H. Schmid, M. Strukelj, S. Dalipi and D. Ryan, J. Org. Chem., 52, 2403 (1987). 12. R.A. Hayes and J.C. Martin, Organic Sulfur Chemistry (F. Bernardi, I.G. Csizmadia and A. Mangini, eds), ch. 8, Elsevier, Amsterdam (1985). 13. For a more detailed discussion of this point, see ref. 4, pp. 423-436. 14. D.C. Owsley, G.K. Helmkamp and M.F. Rettig, J. Am. Chem. Soc., 91, 5239 (1969). 15. V.M. Csizmadia, Applications of M.O. Theory in Organic Chemistry (I.G. Csizmadia, ed), ch. 2, p. 80, Elsevier, New York (1977). 16. V.M. Csizmadia, G.H. Schmid, P.G. Mesey and I.G. Csizmadia, J. Chem. Soc., Perkin Trans. 2, 1019 (1977). 17. J.C. Carretero, J.L. Garcia Ruano and J.H. Rodriguez, Tetrahedron Lett., 28, 4593 (1987). 18. G.H. Schmid and D.C. Garratt, Can. J. Chem., 52, 1027 (1974). 19. G.H. Schmid, C.L. Dean and D. Garratt, Can. J. Chem., 54, 1253 (1976). 20. W.A. Smit, A.S. Gybin, V.S. Bogadanov, M.Z. Krimer and E.A. Vorobieva, Tetrahedron Lett., 1085 (1978).

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129

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65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107.

CHRISTOPHERM. RAYNER

W.R. Roush and X.F. Lin, J. Org. Chem., 56, 5740 (1991). S. Ramesh, N. Kaili, G. Grewel and R.W. Francke, J. Org. Chem., 55, 5 (1990). R. Preuss and R.R. Schmidt, Synthesis, 694 (1988). Y. Ito and T. Ogawa, Tetrahedron Lett., 28, 2723 (1987). S. Ramesh and R.W. Franck, J. Chem. Soc., Chem. Commun., 960 (1989). S.M. Tuladhar and A.G. Fallis, Tetrahedron Lett., 28, 523 (1987). G. Capozzi, S. Menichetti, M. Nicastro and M. Taddei, Heterocycles, 29, 1703 (1989). G. Capozzi, V. Lucchini, F. Marcuzzi and G. Modena, J. Chem. Soc., Perkin Trans. 1, 3106(1981). G.J. O'Malley and M.P. Cava, Tetrahedron Lett., 26, 6159 (1985). P.L. Lopez-Tudanca, K. Jones and P. Brownridge, Tetrahedron Left., 32, 2261 (1991). S.M. Tuladhar and A.G. Fallis, Can. J. Chem., 65, 1833 (1987). W.L. Brown and A.G. Fallis, Can. J. Chem., 65, 1828 (1987). O. Arjona, R. Fernandez de la Pradilla, R.A. Perez, J. Plumet and A. Viso, Tetrahedron Lett., 28, 5549 (1987). S. McIntyre, F.H. Sansbury and S. Warren, Tetrahedron Lett., 32, 5409 (1991). F.H. Sansbury and S. Warren, Tetrahedron Left., 33, 539 (1992). S. McIntyre and S. Warren, Tetrahedron Left., 31, 3457 (1990). V.K. Aggarwal, I. Coldham, S. McIntyre and S. Warren, J. Chem. Soc., Perkin Trans. 1,451 (1991). V.K. Aggarwal and S. Warren, Tetrahedron Lett., 28, 1925 (1987). V.K. Aggarwal, I. Coldham, S. McIntyre, F.H. Sansbury, M.-J. Villa and S. Warren, Tetrahedron Leu., 29, 4885 (1988). D. Hall, A.-F. Sevin and S. Warren, Tetrahedron Left., 32, 7123 (1991). K. Chibale and S. Warren, Tetrahedron Left., 32, 6645 (1991). F.H. Sansbury and S. Warren, Tetrahadron Lett., 32, 3425 (1991). J.E. Baldwin, J. Chem. Soc., Chem. Commun., 734, 736, 738 (1976). D.R. Williams and J.G. Phillips, Tetrahedron, 42, 3013 (1986). D.R. Williams, J.G. Phillips and B.A. Barner, J. Am. Chem. Soc., 103, 7398 (1981). T. Morishita, N. Furukawa and S. Oae, Tetrahedron, 37, 2539 (1981). N. Furukawa, T. Morishita, T. Akasaka and S. Oae, Tetrahedron Lett., 3973 (1979). Z.K.M. Abd E1 Samii, M.I. A1 Ashmawy and J.M. Mellor, J. Chem. Soc., Perkin Trans. I, 2523 (1988). Z.K.M. Abd E1 Samii, M.I. A1 Ashmawy and J.M. Mellor, J. Chem. Soc., Perkin Trans. I, 2509 (1988). Z.K.M. Abd E1 Samii, M.I. A1 Ashmawy and J.M. Mellor, J. Chem. Soc., Perkin Trans. 1, 2517 (1988). Z.K.M. Abd E1 Samii, M.I. A1 Ashmawy and J.M. Mellor, Tetrahedron Lett., 28, 1949 (1987). R. Kimura, A. Ichihara and S. Sakamura, Synthesis, 516 (1979). J.L. Acena, O. Arjona, R. Fernandez de la Pradilla, J. Plumet and A. Viso, J. Org. Chem., 57, 1945 (1992). A.Y. Sizov, V.V. Linev, N.V. Kondrashov, A.V. Kolomiets and A.V. Fokin, Izv. Akad, Nauk SSSR, Ser. Khim., 1, 150 (1990). R.N. Young, W. Coombs, Y. Guindon, J. Rokach, D. Ethier and R. Hall, Tetrahedron Lett., 22, 4933 (1981). M.R. Huckstep, R.J.K. Taylor and M.P.L. Canton, Tetrahedron Lett., 27, 5919 (1986). I. Coldham, E.W. Collington, P. Hallet and S. Warren, Tetrahedron Lett., 29, 5321 (a988). V.K. Aggarwal and S. Warren, Tetrahedron Lett., 27, 101 (1986). K.C. Nicolaou, S.P. Seitz, W.J. Sipio and J.F. Blount, J. Am. Chem. Soc., 101, 3884 (1979). K.C. Nicolaou and Z. Lysenko, J. Chem. Soc., Chem. Commun., 293 (1977). G. Capozzi, R. Ottana, G. Romeo, and G. Valle, J. Chem. Res. S, 200 (1986). G. Capozzi, R. Ottana and G. Romeo, Heterocycles, 26, 39 (1987). B.M. Trost and M. Fray, Tetrahedron Lett., 29, 2163 (1988).

SYNTHETIC TRANSFORMATIONS INVOLVING THIIRANIUM ION INTERMEDIATES

108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132.

1 31

A. Toshimitsu, H. Abe, C. Hirosawa and S. Tanimoto, J. Chem. Soc., Chem. Commun., 284 (1992). A. Toshimitsu, C. Hirosawa and S. Tanimoto, Tetrahedron Lett., 32, 4317 (1991). J.M. Mellor and D.L. Bruzco de Milano, J. Chem. Soc., Perkin Trans. 2, 1069 (1986). A. Bewick, D.E. Coe, J.M. Mellor and D.J. Walton, J. Chem. Soc., Chem. Commun., 51 (19801. P. Brownridge, Tetrahedron Lett., 25, 3759 (1984). L. Benati, P.C. Montevecchi and P. Spagnolo, Tetrahedron, 42, 1145 (1986). C.M. Rayner and A.D. Westell, Tetrahedron Lett., 33, 2409 (1992). D.M. Gill, N.A. Pegg and C.M. Rayner, J. Chem. Soc., Perkin Trans. 1, 1371 (1993). F. Effenburger, T. Beisswenger and F. Dannehauer, Chem. Ber., 121, 2209 (1988). F. Effenburger and H. Isak, Chem. Ber., 122, 545 (1989). F. Effenburger, T. Beissenger and H. Isak, Tetrahedron Lett., 26, 4335 (1985). W. Dumont and A. Krief, J. Chem. Soc., Chem. Commun., 673 (1980). H. Kawakami, T. Ebata, K. Koseki, H. Matsushita, Y. Naoi and K. Itoh, Chemistry Lett., 1459 (1990). L.J. Wilson and D. Liotta, Tetrahedron Lett., 31, 1815 (1990). G. Capozzi, R. Ottana and G. Romeo, Heterocycles, 24, 583 (1986). I. Coldham and S. Warren, Tetrahedron Lett., 30, 5937 (1989). T. Ohsawa, M. Ihara and K. Fukumoto, J. Org. Chem., 48, 3644 (1983). M. Ihara, Y. Haga, M. Yonekura, T. Ohsawa, K. Fukumoto and T. Kametani, J. Amer. Chem. Soc., 105, 7345 (1983). S. Warren and M.-J. Villa, Tetrahedron Lett., 30, 5933 (1989). M. Hannaby and S. Warren, Tetrahedron Lett., 26, 3133 (1985). M. Hannaby and S. Warren, J. Chem. Soc., Perkin Trans. 1,303 (1989). P. Brownbridge and S. Warren, J. Chem. Soc., Perkin Trans. 1, 2272 (1977). P. Brownbridge and S. Warren, J. Chem. Soc., Perkin Trans. 1, 1131 (1977). V. Lucchini, G. Modena and L. Pasquato, J. Am. Chem. Soc., 110, 6900 (1988). J. Nakayama, S. Takeue and M. Hoshino, Tetrahedron Lett., 25, 2679 (1984).

This Page Intentionally Left Blank

CHAPTER 4

TRENDS IN THE CHEMISTRY OF 1,3DITHIOACETALS* William W. Woods Shell Research Ltd, Sittingbourne Research Centre, Sittingbourne, Kent, ME9 8A G, UK ++.American Cyanamid Company, Agricultural Research Division, PO Box 400, Princeton, NJ 08543-0400, USA

CONTENTS 4.1 4.2 4.3

4.4

4.5

Introduction Applications of 1,3-dithioacetals in biological effect molecules

133 134

Synthesisof 1,3-dithioacetals

143

Chemistry of 1,3-dithioacetals

171

1,3-Dithioacetal as a functional group

191

4.2.1 4.2.2

1,3-Dithioacetals in pharmaceuticals 1,3-Dithioacetals in crop protection compounds

4.3.1 4.3.2 4.3.3 4.3.4 4.3.5

Synthesesof 1,3-dithioacetals and precursors from carbon disulfide Synthesesfrom carbonyl compounds and dithiols under acid catalysis Syntheses using pre-activated thioacetalation reagents Syntheses using supported thioacetalation catalysts and reagents Syntheses by other methods

4.4.1 4.4.2 4.4.3 4.4.4

Chemistry of anions derived from 1,3-dithioacetals Reactions of lithiated 1,3-dithioacetals with organometallic complexes Diastereoselective reactions about 1,3-dithioacetals Radical reactions of 1,3-dithioacetals

4.5.1 4.5.2 4.5.3 4.5.4 4.5.5

Regeneration of carbonyl compounds from 1,3-dithioacetals Synthesis of dithiins from 1,3-dithioacetals Reduction of 1,3-dithioacetals to methylene and reductive alkylation Conversion of 1,3-dithioacetals to gem-difluorides Conversion of 1,3-dithioacetais to compounds containing one C-S bond

Conclusion References

4.1

136 138 144 146 157 163 170

171 173 177 186

191 202 208 209 216

217 219

INTRODUCTION

The concept of "umpolung" and its best known example, the 1,3-dithiane acyl anion equivalent, have played an important role in the development of synthetic organic chemistry. 1,3-Dithioacetals have remained high on the synthetic chemists' *This review is dedicated to the chemists of OCR and SCP, Sittingbourne Research Centre, 1988-1993. ORGANOSULEURCHEMISTRYCopyright 91995 Academic Press Ltd. ISBN-0-12-543560-6. All rights of reproduction in any form reserved.

134

WILLIAM W. WOOD

methodology agenda, resulting in many developments of novel chemical processes, and, more recently, in the exploration of stereoselective reactions involving this unit. The chemistry of 1,3-dithioacetals also serves as a good example of the divergence of interests between academic chemists and their industrial counterparts. This is, I believe, a growing trend. On the one hand most of the chemistry in this area emerging from academic laboratories is concerned with the 2-position, following, probably unconsciously, the original ideas of "umpolung." On the other side of the laboratory bench, industrial researchers in pharmaceutical and crop protection companies have followed the structural demands of biological activity, which have led them away from chemistry at the 2-position towards chiral 1,3-dithioacetals, dithiolanes and dithianes substituted throughout the ring. Sadly, much of the excellent chemistry of this type is buried in patent claims and is seldom reported in the open literature. It is one of the objectives of this review to highlight some of this unusual and exciting chemistry. The primary objective of this review is, however, to report on trends in the chemistry of 1,3-dithioacetals over the last 5 years. I have not tried to present a comprehensive survey of all the chemistry of 1,3-dithioacetals, but rather to look at recent developments in the area and, where necessary, to place some historical perspective on these. The principal reason for this decision, apart from the enormity of the task, lay in the large number of excellent reviews on this topic which have appeared elsewhere. For those whose interests lie in particular aspects of dithioacetal chemistry, a listing of pertinent reviews has been tabulated (Table 4.1). I have also deliberately not covered ketene dithioacetal chemistry since this appears to warrant a separate treatment. The first part of the review deals with applications of 1,3-dithioacetals in pharmaceuticals and crop protection agents, dwelling mainly on structure, since this may be of value to academic chemists seeking new challenges in the area, but also reporting on some of the synthetic routes used. Secondly, syntheses of 1,3dithioacetals are considered, as there has been a great deal of work published recently in this area, particularly on the use of supported reagents. The third part of the review examines some of the manipulative chemistry of 1,3-dithioacetals, concentrating on the particular areas that have received attention over the last 5 years.

4.2 APPLICATIONSOF 1,3-DITHIOACETALS IN BIOLOGICAL EFFECT MOLECULES 1,3-Dithioacetals have become part of the regular armoury of pharmaceutical and crop protection chemistry and have been used in a number of roles, for example as isosteres for cyclohexane and cyclopentane rings, as "super" t-butyl groups and as pivots for stereogenicity. The group also appears in biologically active natural products. Recent examples from pharmaceutical and crop protection chemistry will be dealt with separately.

TABLE4.1 Reviews of 1,3-dithioacetal chemistry

1

G. Boche, Angew. Chem., 101(3), 286-306 (1989).

Structure of lithium compounds of sulfones, sulfoximides, sulfoxides, thioethers and 1,3-dithioanes The attractive and repulsive gauche effects Conformation analysis of four- to six-membered cyclanes and heterocyclic analogues Conformation analysis in saturated heterocyclic compounds

E. Juaristi, J. Chem. Educ., 56(7), 438-441 (1979). K. Pihlaja, Kem.-Kemi, 1(8), 492-496 (1974). E. L. Eliel, Accounts Chem. Res., 3(1 ), 1-8 (1970). 2

Synthetic uses of the 1,3-dithiane grouping from 1977-1988 Five-membered ring systems: with oxygen and sulfur Application of 1,3-dithianes as intermediate compounds of reversed polarity of carbonyl in synthesis Chiral sulfoxidation by biotransformation of organic sulfides A short route to chiral sulfoxides using titanium-mediated asymmetric odidations Applications of the 1,3-dithiane procedure for the synthesis of branched-chain carbohydrates Asymmetric synthesis. Highly stereoselective reactions of organosulfur compounds Umpolong (dipole inversion) of carbonyl reactivity Nucleophilic acylation with 2-lithium-1,3-dithianes and 2l ith ium- 1,3,5-trith ianes

Structural aspects

Synthetic aspects P. C. B. Page, M. B. Van Neil, J. C. Prodger, Tetrahedron, 45(24),7643 (1989). J. G. Keay, Prog. Heterocycl. Chem., 1, 1 78-185 (1989). A. Hu and Z. Zeng, Huaxue Shiji, 11(6), 351-357 (1989)

i m-1 m

H-L. Holland, Chem. Rev., 88(5), 473-485 (1988). H. B. Kagan, E. Dunach, C. Nemecek, P. Pitchen, O. Samuel and Z. H. Zhao, Pure Appl. Chem., 57(12), 1911-1916 (1985). H. Paulsen, V. Sinnwell and J. Thiem, Methods Carbohydr. Chem., 8, 1 8 5 - 1 9 4 (1980). E. L. Eliel, Tetrahedron, 30(12), 1503-1513 (1974). D. Seebach and M. Kolb, Chem. Ind. (London), 687-692 (1974). D. Seebach, Synthesis, 1 7-36 (1969). Applications

New liquid crystal materials with sulfur atoms incorporated in the principal structure Liquid Crystalline 1,3-diheterocyclic alkanes

-1m-1

Y. Haramoto and H. Kamogawa, Rev. Inorg. Chem., 9(1),65-100 (1987). C. Tschierske and H. Zaschke, Wiss. Z. -Martin-Luther-Univ. HalleWittenberg. Math.-Naturwiss. Reike, 38(3), 3-14 (1989).

-<

9

| m "1-

r'~ > r'-

9

136

WILLIAMW. WOOD

4.2.1

1,3-Dithioacetals in Pharmaceuticals

The chemical versatility of the 1,3-dithioacetal unit has led to its incorporation into a number of projects in several different areas of medicinal chemistry. While some of these studies have been extensively reported in the open literature, the story of verlukast being such a case (vide infra), some appear only in patents and are consequently difficult to piece together. What follows is not intended as an exhaustive account of the uses of thioacetals in pharmaceutical chemistry, since some of the uses are rather trivial. Instead, some of the more recent chemically interesting examples will be examined. Antimuscarinic agents such as oxybutynin (Fig. 4.1) act as potent calcium channel blockers, as do the related compounds verapamil and tiapamil, the latter itself an oxidized 1,3-dithiane. A new class of compounds related to these has been recently reported by the Nova Pharmaceutical Corporation [1]. In one of these, a 1,3-dithiane moiety replaces the cyclohexanes of oxybutynin while the other group bears a closer resemblance to tiapanil itself. The synthesis of these compounds illustrates the two most frequently used reactions in dithiane chemistry (Scheme 4.1). The routes involved either Lewis

C

OS

I

NEt2 M

Oxybutynin

OMe

OMe OMe

Verapimil

M~

~OMe OMe

Tiapimil

Nna

Figure 4.1 Nova oxybutynin analogues

TRENDS IN THE CHEMISTRYOF 1,3-DITHIOACETALS

S

SH SH ~. BF3.OEt2 "

S\ / S Ph

+

r/

137

S

~NR'R

,-..Z><" J ~T

2

(CH2)n

88

(i) n-BunLi

/(CH2) OHC ~"~~NR~R 2

(ii) TMSCI

r

S J

~

S

~

NR~

/ (CH2)n OTMS

Scheme 4.1 acid catalysed thioacetalization or formation of a dithianyl anion and addition of this to a carbonyl compound. Many of the familiar classes of pharmaceutical have been varied by the addition of dithiane and dithiolane groups. It is no surprise that a dithiolane ring has been added to the cephalosporin structure [2], with a view to enhancing activity (Fig. 4.2). Similar structural appendages have been added to xanthine derivatives OH

5 oH

N/O~co2 N.~~NH

o

H

s

..S.

O

I

I Figure 4.2

138

WILLIAM W. WOOD OH C4~

S~C02H S~CONMe2

0 Leukotriene

D4

Mk-0571(verlukast)

Figure4.3 patented for the treatment of respiratory disorders [3]. In both of these groups of compounds the thioacetal moiety was introduced by conventional dithioacetal chemistry from the aldehyde. In recent years, some of the most impressive chemistry in the 1,3-dithioacetal area has been devoted to the synthesis of antagonists of leukotrienes D 4 and B 4. The structural relationship between the natural substrate for the receptor and the synthetic antagonist is readily apparent (Fig. 4.3), as is the importance of the chirality at the thioacetal carbon. A range of different antagonists derived from dithioacetals have been designed and prepared, and considerable effort has been devoted to the synthesis of some of these compounds in optically active form. As part of this effort, a general method for the preparation of optically pure 1,3dithioacetals was developed (Scheme 4.2) [4]. Central to this method, was the formation of an alkylthioacylthioacetal from an optically pure thioacid. The resulting pair of diastereoisomers could be separated by physical means. Treatment with sodium methoxide resulted in the cleavage of the thioester bond, and addition of methyl acrylate gave the optically pure thioacetal without racemization via the corresponding thioaldehyde. An alternative synthesis involved an enzymatic kinetic resolution of a prochiral thioacetal [5]. This gave an optically pure thioacetal which could be readily converted into either enantiomer of verlukast (Scheme 4.3).

4.2.2

1,3-Dithioacetals in Crop Protection Compounds

As in the chemistry of pharmaceuticals, the 1,3-dithioacetal moiety has appeared frequently over recent years in patents and in papers in the open literature, dealing with novel crop protection compounds. In at least two major classes of insecticide, for example, cyclic 1,3-dithioacetals form the central feature of the active compound, as opposed to representing merely a space-filling adjunct. However, the role of 1,3-dithioacetals as 'super t-butyl groups' should not be underestimated. In one of the more active areas of dithiane chemistry from the insecticide field, the dithiane derivative has served as both a synthetic precursor to the parent

TRENDSIN THE CHEMISTRYOF 1,3-DITHIOACETALS

139

O

O y@/CHO

,OMe " Ph HSR, catalyst

S

HS

~

"

/~Separate diastereoisomers (ii) Nu:, R'X

SR

Y

S?"OMe O

O MeO\,.~/CHO

,,OMe

y~~t~S RPh

SR'

HS

.,l

,,,OMe

Ph HS/~./CONMe2

M e O w @ r

S Ph

L'~OONMe2 Separate

(ii) NaOMe,-78~ ~ c o ~ e s~CO2

Me

MeO~s~CONMe~

Enantiomer1" yield83%,[c~]D-3.2 ~ Enantiomer2" yield78%,[oL]o+3.6~ Scheme 4.2

compound of the series, and as an important analogue of that parent in its own right. Nereistoxin (Fig. 4.4), isolated from the marine annelid Lumbriconereis hewropoda, has long been of interest as an insecticide [6], due to its broad spectrum of activity. The compound is thought to act at the nicotinic acetylcholine receptor. Charatoxin, a structurally related 1,2-dithioacetal obtained from the aptly named skunkweed alga, shows similar properties and activity [7]. Bensultap, a third member of this class, used against Lepidoptera and Coleoptera, has demonstrated the viability of this group as commercial products [8]. Similar structures are found in the bark of the Brazilian shrub tree, Cassipourea guanesis, which contains guinesines A, B and C stereoisomers of 4-hydroxy-3-(1-

140

WILLIAM W. WOOD

s~CO~e

I Pseudomonas lipase _s~ c ~

90% yield > 98% ee

o

(i) DCC: M e 2 /

, Me2NH'HCI

(ii) LiOH

__s/~/co ~

s~OONMe2

(S)-Vedukast

(R)-Vedukast

Scheme 4.3 NMe2

S--S Nereistoxin

NMe2

SMe

S--S Charatoxin

OH

Guinesines A,B, and C

Figure 4.4

PhO2SS

SSO2Ph

Bensultap

TRENDSIN THECHEMISTRYOF1,3-DITHIOACETALS

] 41

~

EtO OEt S

s>

r

I NaBH

Scheme

4.4

methylpyrrolidin-2-yl)-l,2-dithiolane [9]. The 3,4-disubstitution pattern of the guinesines presents a considerable synthetic challenge, which was overcome in a recent synthesis by Takeda's group using an intermediate 1,3-dithiane. Thus, condensation of 3-keto-l,3-dithiane with 1methyl-2,2-ethoxypyrrolidine (Scheme 4.4), gave the required substitution pattern in the product, which was reduced with borohydride to give a mixture of diastereoisomers. This compound was converted into the guinesines in a series of further steps. However, the importance of this synthesis lies less on the achieve-

Pr'S ~--SSO2Ph

NC'7"~CO2Et

~-.--SS02Ph

~..._~

"CO~t

I Et2NH

./-s~.,c. PrS'--~__s/~O

CZ?J,c, o

0

Scheme

4.5

Pr'S

/--s~ ,,cN ~-~

TM

142

WILLIAM W. WOOD

ment of the target and more in the demonstration of a method for the ready synthesis of 3,4-disubstituted dithianes. As indicated previously, 1,3-dithianes have been of importance as active analogues in this class [10]. Once again, substitution away from the readily functionalizable 2-position has been of importance, in targets such as the 2,2,5trisubstituted analogue (Scheme 4.5). In this case the 1,2,3-trithio precursor already carried what would eventually form the 5-S-isopropyl group (Scheme 4.5). Condensation of this compound with ethyl cyanoformate gave a 1,3-dithiane, which readily decarboxylated. A final condensation with an appropriate carbamoyl chloride gave the target. The so-called 'cage' ~/-aminobutyric acid (GABA) antagonists are another important area of insecticide chemistry in which 1,3-dithioacetals are the basis for biological activity [11]. The structural parentage of this class lies in the phosphoroorthoester, which was discovered to be a potent toxin acting at the GABA site [12]. This was developed by Casida at Berkeley and the Wellcome group into the bicyclo-octane cages, which showed high insecticidal activity, particularly against the house-fly, Musca domestica [13]. A recent development in this area has been the 'opening' of the cage, and the replacement of the remaining oxygen atoms with sulfur, leading to 1,3-dithianes [14], and 1,3-dithiolanes [15]. The fully sulfurated bicyclo-octane cages have also been prepared [16]. Typical compounds of the open-cage type are the dithianes and dithiolanes shown (Fig. 4.5).

3 CN

CN

Figure 4.5 The syntheses of these compounds amply illustrates the dearth of efficient routes to multiply substituted dithianes, although the situation is somewhat better for dithiolanes (vide infra). The final step in the synthesis of dithiane analogues is usually condensation of an aldehyde or ketone with a 1,3-dithiol, for which a host of methods are available. However synthesis of the dithiol precursor relies exclusively on rather tedious malonate chemistry as illustrated (Scheme 4.6). Thus, to prepare 2-t-butyl-l,3-propanedithiol, a six-step synthesis is required. Even simple alkylsubstituted propane 1,3-dithiols require long, inefficient syntheses. Although the majority of 1,3-dithioacetal chemistry in the crop protection field has been concentrated in pest control, further examples of highly substituted 1,3dithiolanes may be found amongst the herbicide patent literature [17]. A recent example of the importance of substitution at the 4-, 5- (and 6-) positions of

TRENDSIN THECHEMISTRYOF 1,3-DITHIOACETALS

~ ==O

143

O2Et

~ k~,=~ CO2Et

CO2Et

~CO2Et

I MoM Br LAH

/C,02Et

KSAc

~SAc

~C02Et

I TsCI

/

I LAH

\

/

fSH

Scheme4.6 dithianes and dithiolanes involved phthalimide bleaching herbicides patented by BASF. This patent, in which several hundred compounds were exemplified, clearly indicates the commercial importance of routes to this type of compound.

4.3

SYNTHESIS OF lp3-DITHIOACETALS

Since the first syntheses of thioacetals in the early steroid work of the 1940s and 1950s, there has been considerable interest in novel reagents and catalysts for the conversion of carbonyl compounds into 1,3-dithioacetals. This interest has been maintained to the present day with the introduction of several Lewis acid and supported catalysts. Chemoselectivity between different types of carbonyl compounds can be achieved with many of these reagents--the normal order of reactivity being aliphatic aldehyde > aliphatic ketone > aromatic or ~,[3unsaturated aldehyde > aromatic or ~,[3-unsaturated ketone. Reagent systems may be categorized into three types~catalytic systems, pre-activated reagents and supported reagents~and will be discussed under these headings. However, before considering these topics, an alternative approach to dithioacetals using the chemistry of carbon disulfide will be considered.

144

WILLIAM W. WOOD

4.3.1 Syntheses of 1,3-Dithioacetals and Precursors from Carbon Disulfide As chemists have become interested in the applications of 1,3-dithiolanes and 1,3dithianes bearing substituents on the 4-, 5- (and 6-) carbon atoms, so access to 1,2and 1,3-dithiols bearing a range of substituents has become important. The classical approach, of displacing a leaving group (typically a bromide or a sulfonate ester) with two molecules of a sulfur nucleophile, has found extensive use, but more elegant methods have been discovered. The most significant reagent in this area has been carbon disulfide, which has the potential for supplying both sulfur atoms of the target compounds. One of the seminal processes in this area has been the synthesis of 1,3-dithiol-2thiones, useful precursors to 1,2-dithiols, by treatment of oxiranes with carbon disulfide and a base (Scheme 4.7) [18]. This procedure gives excellent yields of 1,3dithiolan-2-ones bearing a range of substituents. On an industrial scale the reaction may be carried out by treating the epoxide with carbon disulfide in hexane in the presence of triethylamine in an autoclave (Scheme 4.8) [19,20]. The mechanism of the reaction under these conditions follows a slightly different path to the laboratory-scale procedure [21,22]. S,S-Dialkyltrithiocarbonates may be prepared in a similar process (Scheme 4.9) [23], as can S,S-dialkyldithiocarbonates [24]. Carbon disulfide may also be used to supply both sulfur atoms and C-2 of 1,3dithioacetals by reaction with the anion of an active methylene compound, followed by alkylation with an alkyl halide, to give acyclic dithioketene acetals, or with an ~,~o-dibromoalkane to give the cyclic analogues (Scheme 4.10) [25-27]. A range of active methylene compounds may serve as precursors for this process. CS2, EtOH, EtONa

"••8•

S S LAH

~

SH SH

Scheme 4.7 C6H13~10

CS2, Hexane Et3N, 800 MPa 20 h

C6H13

C6H13~1~.~ S...~ \\S

S

71%

Scheme 4.8

+

I

06H13-

.S 0

5%

12%

TRENDS IN THE CHEMISTRYOF 1,3-DITHIOACETALS

2RX

+

S

Bun4NHSO4

CS2

1 45

,~

33% aq.NaOH

R = C1-C4alkyl, PhCH2

Ius

Yields >90%

Scheme 4.9

MeCN

(i) LDA

r

(ii) CS2

US

RS

2 RX

RS

CN

CN

O (i) CS2 (ii)RX,

RSR

KF/alumina

O R

(i) CS2, K2CO3, DMF

R

r

O

(ii) (CH2Br)2

Scheme 4.10 Br[~NH

2

NaH, CS2

~Br

~ 2 O

O

SNa

1 Br/'~Br

Scheme 4.11

Similar reactions with heteroatom nucleophiles are possible (Scheme 4.11). This area has been thoroughly reviewed recently in Tetrahedron (see Table 4.1). An alternative reagent for the synthesis of 1,3-dithioalkyl-2-thiones is sodium trithiocarbonate (Scheme 4.12). This reagent has been used to prepare both 1,3dithiolan-2-thiones and 1,3-dithian-2-thiones [28], but has the disadvantage that it is not readily available from commercial sources.

146

WILLIAM W. WOOD R~

~

X

R2"" ~'X

+ 2Na2C~3

PTC

+ 2Na2CS3

PTC ~-

R2

R2

Scheme4.12 1,3-Dithiolan-2-thiones and 1,3-dithian-2-thiones may both be readily reduced to 1,2- and 1,3-dithiols on treatment with lithium aluminum hydride in ether at room temperature [18]. More vigorous conditions lead to over-reduction. Both 1,2- and 1,3-dithiols of the type available from this reduction have been of particular importance in some of the application areas described above. Dithiols may also be obtained by aminolysis of thiones [29,30]. The 2-thione unit may also be removed or functionalized directly without cleavage of the C-S bond by treatment with organometallic reagents. In this way simple dithianes and diverse alkyl trithiocarbonates may be prepared (Scheme 4.13) [31].

~(!).EtMgBr, RT

uLi, -78~

ii)

~ ( i ) n_BunLi~i~ RT (ii)MeBr

~~

EtBr

!i) n-BuLi, -78~ C

Scheme4.13 4.3.2

Synthesesfrom Carbonyl Compounds and Dithiols under

Acid Catalysis

Most of the traditional methods for the conversion of carbonyl compounds into 1,3-dithioacetals originated in steroid chemistry, where the use of the thioacetal as

TRENDSIN THE CHEMISTRY OF 1 ,3-DITHIOACETALS TABLE4.2 Dithioacetalization with aluminum trichloride

Substrate

Product

Yield (%)

148

WILLIAM W. WOOD

TABLE4.2 Dithioacetalization with aluminum trichloride Substrate

(cont.)

Product

Yield (%) 86

55

94

o

93

SEt

94

02N

02N

81 ~

C

H

O

SPh

~ C i - I C

42

~"SPh

90

o

o

~ o

a protecting group was first developed. These methods normally involved an acid combined with a mechanical or chemical dehydrating agent, although the latter is not always necessary if the acid catalyst has dehydrating properties and is used in an appropriate stoicheiometry. These methods, summarized by Fieser in 1954 [32], included zinc chloride and sodium sulphate [33,34], hydrogen chloride in ether [35,36], p-toluenesulfonic acid under Dean-Stark conditions [37,38], and boron

TRENDS IN THE CHEMISTRY OF 1,3-DITHIOACETALS

1 49

trifluoride etherate in a variety of solvents [32]. Most of these reagents are also effective under thioacetal exchange conditions of various types [38]. A variety of Lewis acid thioacetalization catalysts have been examined over recent years. Of these, aluminum trichloride, which is both a catalyst and a dehydrating agent, appears to be the most active, allowing the ready conversion of aryl and diaryl ketones into cyclic and acyclic dithioacetals in good yield (Table 4.2) [39]. However, this reagent is unsuitable for more sensitive substrates, giving low yields in reaction with carbonyl compounds bearing ot protons and leading to the formation of vinyl sulfides where these substrates are readily enolizable (Scheme 4.14). Tetrachlorosilane is also a powerful catalyst and dehydrating agent, converting aldehydes and aliphatic ketones into 1,3-dithioacetals (Table 4.3) [40]. This reagent appears to be less active than aluminum trichloride, since it does not convert aromatic ketones and allows some selectivity between aldehydes and aliphatic ketones (Scheme 4.16), yet causes elimination to vinyl sulfides for some aliphatic ketones. Trimethylsilyl chloride also acts as a catalyst for the reaction (Table 4.4)[411 . Tellurium tetrachloride, as reported in a recent publication [42], shares many of the properties of tetrachlorosilane (Table 4.5), showing selectivity between aldehydes and aliphatic ketones, but not reacting with aromatic ketones (Scheme 4.16). However, a-protons remain unaffected even in readily enolizable ketones, in contrast to the silyl chloride. This reagent has also been used to catalyse thioacetal exchange reactions. Lanthanum trichloride has also been used as a catalyst for the reaction [43]. In this case the hydrated metal salt is entirely unreactive, but the commercially available anhydrous material is effective in catalysing the thioacetalation of aldehydes and aliphatic ketones. The authors ascribed the effectiveness of the anhydrous salt to its dehydrating power. The reagent does not catalyse the reaction with aromatic or hindered ketones effectively (Table 4.6). However, of all the Lewis acids of the metal chloride type that have been used as catalysts for thioacetalation, titanium tetrachloride appears to be the most versatile, acting as a catalyst and a dehydrating agent [44]. This reagent can be used to convert almost all types of aldehyde and ketone into cyclic or acyclic thioacetals, without adverse side-reactions (Table 4.7). Unfortunately, the chemoselectivity of the reagent has not been thoroughly examined. Some of the most remarkable achievements in chemoselectivity in this area have involved magnesium bromide in ether (Table 4.8) [45]. This reagent converts aldehydes and aliphatic ketones, but not aromatic ketones, into thioacetals, as do

,,,AIC,',3'CH2CICH#I PhSH

(E)/(Z) =45/55 90% yield

Scheme 4.14

150

WILLIAM W. WOOD

TABLE4.3 Dithioacetalation with tetrachlorosilane o

R,~R

$i014

C1"!2~2

Substrate

Product

Yield (%)

PhCHO

PhCH(SBn)2

98 95

PhCHO

PhCHO

92

S

p-NO2PhCHO

p-NO2PhCH(SBn)2

72

p-CIPhCHO

p-CIPhCH(SBn)2

85

o-CIPhCHO

o-CIPhCH(SBn)2

75

p-CIPhCHO

p-MeOPhCHO p-NO2PhCHO

trans-PhCH ~ C H C H O

89

S

p-MeOPhCH(SBn)2

99 87

s

S

85

89

@'~CNO

TRENDS IN THE CHEMISTRYOF I ,3-DITHIOACETALS

1 51

TABLE4.3 Dithioacetalation with tetrachlorosilane (cont.) Substrate

Product

Yield (%) 90

~

C

H

O

o

69

Ph2C~O

~

<5 <5

O

O PhCHO +

HS SH ..._ CH2CI2, SiCI4

Ph

0%

99%

pF~ ~S 98%

~

C

99% H

O

+

2%

0%

+

+ Ph" ~ 0%

sF q s

99%

0%

d o 88%

76%

7%

O ph.,.-'~,,/-CHO 27%

+

P,~~

{ ~ 59%

70'/o

+ 28%

Percentages= ratiosof carbonylcompoundsandthioacetalscalculatedseparatelyafterthe completionof the reaction

Scheme 4.15

152

WILLIAM W. WOOD

TABLE 4.4 Dithioacetalization with trimethylsilyl chloride

O

RS

TMSCI, CHC!3

Substrate

Product

~

SR'

R~R Yield (%)

.O

SEt

82

O

.SEt

40 (+55% vinyl sulfide)

100

0

100

0 v

/~ O

/OEt

"OEt

100

PhS/v~~.OEt

O

0

SEt

95

92 .-

v

"NHPh

other reagents described above. However, acetals are particularly sensitive to magnesium bromide and are readily converted to thioacetals in exchange reactions with mono- or dithiols (Scheme 4.17). This sensitivity even extends to acetals of aromatic ketones which can be converted into thioacetals in the presence of aliphatic ketones with complete chemoselectivity, thus effectively reversing the

TRENDS IN THE CHEMISTRY OF I ,3-DITHIOACETALS

153

TABLE 4.5 Dithioacetalization with tellurium tetrachloride

o

Substrate

Product

Yield (%)

PhCHO PhCHO

PhCH(SEt)2

99 97

s~

PhCHO

93

4-MeCoH4CHO 4-HOC6H4CHO 4-HOCoH4CHO

4-CIC6H4CHO PhCH--CHCHO PhCH~CHCHO

4-MeC6H4CH(SEt)2 4-HOCoH.CH(SEt)2

o.0

s

4-CIC6H4CH(SEt)2 PhCH ~CHCH(SEt)2

~

C7 Cr O

SEt

sE,

99 87 99

84

94

o

o~:~,

95 99 88

COC~3

COON3

Et$

80

154

WILLIAM W. WOOD

TABLE4.5 Dithioacetalization with tellurium tetrachloride Substrate

(cont.)

Product

eoe~

Yield (%)

eoe~

80

96

normal chemoselectivity sequence. Another metal chloride-based catalytic system, cobalt chloridetrimethylchlorosilane, allows dithioacetalization of particularly sensitive substrates such as ~-chloromethylacetals, which readily form 1,4-dithiins (vide infra) under other conditions. A range of such substrates can be converted in good yields (Table 4.9)[46]. O

HSCH2CH2SH TeCI4, C2H4CI2, RT 76%

Conditions as above 68%

MeO_

PhXH

OMe

Conditions as above

X

99%

Scheme 4.16

TRENDSIN THECHEMISTRYOF 1,3-DITHIOACETALS

155

TABLE 4.6 Dithioacetalization with lanthanum trichloride

R....~R Entry

LaCi3'CH2CI2r,-~ Substrate

1 2 3 4 5 6 7 8 9 10 11 12 13

SR~,~RS Yield of dithiolane (%)

Octanal Cyclohexanecarboxaldehyde 3-Phenylpropionaldehyde Benzaldehyde 4-( D i meth yl am ino)benz aldeh yde 4-N itrobenzaldehyde 2-Furaldehyde 2-Heptanone Cyclopentanone Cyclohexanone Acetophenone Benzophenone Camphor

66 75 65 85 55 60 90 91 93 90 25 <10

One other catalyst should also appear in this section: the trimethyl ester of polyphosphoric acid, reported as a combined catalyst and dehydrating agent in 1987 [47]. However, this does not appear to have any particular advantages over

R~, OR R2XOR

R3 R'vSR ~===O RSH,MgBr2 = 2/2~ R4 R SR

R3 R4~O

Yield (%)

PhCH(OMe)2 But~ 0

~

.•O• ,,,-

CH3(CH2)COCH3

93

92

CH3(CH2)COCH3

87

93

91

92

0

92

89

0

89

91

CH3(CH2)COCH3

0 ~

Scheme 4.17

156

WILLIAMW.WOOD

TABLE4.7 Dithioacetalization with titanium tetrachloride

R~ ~

TiCI4

Starting material

Product

Yield (%)

Me(CH2)sCHO

Me(CH2)sCH(SEt)2

95

Me(CH2)~CHO

s..... Me(CH2)5"-'~S.,,~

95

SEt

PhCHO

95

C~

IJ~SEt

4-MeOC6H4CHO

SEt

M e ~

SEt 98

O

O -o

C~

99

Cx~il

?~i,

98

98

O

90

O

96

TRENDS IN THE CHEMISTRYOF 1,3-DITHIOACETALS

TABLE4.7 Dithioacetalization with titanium tetrachloride Starting material

(cont.)

Product

Yield (%)

O

90

98

O

~,j,

157

CO2Et

E I ~ ~ . ~ C O a Et

other reagents and gives vinyl sulfides in reaction with enolizable ketones.

4.3.3

Synthesesusing Pre-activated Thioacetalization Reagents

The conventional methods for conversion of carbonyl compounds into 1,3dithioacetals generally require strong BrOnsted or Lewis acids, leading, in some circumstances, to synthetic difficulties with acid sensitive substrates. Thioacetalization can be achieved under neutral conditions if the reagent used is pre-activated by formation of a weak S-heteroatom bond. Three types of such reagents have been developed involving boron, silicon or tin intermediates. The underlying principal behind most of the pre-activated reagents is the formation of an intermediate containing B ~ S or Si ~ S bonds, which are less thermodynamically stable than B O or S i - O bonds. Thus, when the activated reagent is challenged with a carbonyl compound or an acetal, the consequent reaction follows a thermodynamically downhill path with the formation of relatively strong C S and B O or S i - O bonds. In the single example of a tin thioacetalization reagent this general principle does not apply, and a further activating reagent is required.

4.3.3.1

Pre-activated thioacetalization reagents containing boron

The earliest reported pre-activated thioacetalization reagents were prepared from NaBH4

+

3S

THF

#

NaBH2S3

RSH

R[.k~IR + B203 R R

R'COR"

(RS)3B + H2 + RSSR + NaS3H

Scheme4.18

158

WILLIAMW. WOOD

TABLE 4.8

Acetal-thioacetal exchange with magnesium bromide

R ~ OR'

R OR'

R" +

MgBr2,Et20~ RSH

)=o

R"

Substrate

Product

OMe

OMe

SPh

~ S

R"""-x/SR" " R"/\SR"

R~O Yield(%) 94

90

92

~ ' ~ ~''''''v~OMe OMe ~/~~OMe

~'~ SPh

93

~~'/~~SPh 88

97

sodium borohydride [48,49]. Thus (Scheme 4.18), treatment of sodium borohydride with elemental sulfur gives a sulfurated borohydride which reacts with three equivalents of an alkyl thiol to form an alkyl orthothioborate. This, in turn, reacts with aldehydes or ketones in benzene or petroleum ether to give high yields of 1,3-dithioacetals. The reagent appears to be general, thioacetalizing all types of aldehyde and ketone, and, since the reaction medium is neutral, most functional groups are unaffected by the reaction conditions. The tricoordinate nature of the alkylthioborate ester intermediate inevitably results in its unsuitability for the preparation of cyclic thioacetals. Approximately

TRENDSINTHECHEMISTRY OF1,3-DITHIOACETALS

159

TABLE 4.9 Dithioacetalization with cobalt chloride-trimethylsilyl chloride

CI Substrate OMe t~OMe

OMe OMe

CoCI3.TMSC I HS SH Product ,r-

SI~S"S" S~

o::

i P ~ s "S~ Yield (%) 80

85

79

/~~j

~

92

OMe OMe OMe

S

87

S

70

OMe

CI OMe 1

OMe

77

OMe

C! OMe

Cl $ I " ~

Ct s '

91

1 60

WILLIAM W. WOOD

Ck,Si /

~

HS

SH

r ~ s , ./

~

RBCI2 (R = Ph or CI) R1

.~R2

R2

CHCI3

B---

Scheme 4.19

10 years after the initial reports described above, the preparation of 1,3-dithiolanes using 1,3,2-dithiaborolanes was reported [50]. The requisite dithioborolanes were prepared by treating a 1,3-dithia-2-silacyclopentane with either boron trichloride or phenyl borondichloride [51,52]. The silyl reagent itself was obtained from dichlorodimethylsilane (Scheme 4.19). 2-Chloro-l,3,2-dithiaborolane is a highly reactive thioacetalization reagent, capable of converting even hindered or diarylketones into 1,3-dithiolanes very rapidly, but showing no chemoselectivity. On the other hand, 2-phenyl-l,3,2-dithiaborolane does not convert aryl ketones and is mild enough for use on sensitive substrates (Table 4.10). A more recent development in this area has been the description of a method for converting carboxylic acids directly into 1,3-dithianes using the 1,3,2dithiaborinane-dimethyl sulfide complex and stannous chloride or boron trifluoride etherate (Scheme 4.21) [53]. The reagent is simply prepared by mixing the borane-dimethyl sulfide complex with propane-l,3-dithiol. Substitution of ethane-l,2-dithiol for the latter allows the preparation of dithiolanes [54]. In this reaction either tin(I[) chloride or boron trifluoride etherate is required, other Lewis acids being ineffective as catalysts. The reagent converts hindered and aromatic ketones, and does not interact with other functional groups, such as double bonds, which have been reported to be susceptible to hydroboration by this type of reagent (Table 4.11) [55]. Me2.BH3 +

THF HS

Me2S

RCO2H,

THF

Scheme 4.20

SnCI 2

TRENDSIN THECHEMISTRYOF 1,3-DITHIOACETALS

161

TABI.E 4.10 Dithioacetalization with dithiaborolanes

Ph'"E0

R1

i/~_o

or

R

(1)

S.-....

Substrate

Reagent

PhCHO

1

Product

~

Yield (%)

98

<7 0

1

98

o

1

27

1

98

o

2

99

o

2

Cr Cr

~ " - ' ~

99

4.3.3.2 Pre-activated thioacetalization reagents containing silicon A reagent similar to that used to prepare some boron-containing thioacetalization reagents, 2,2-dimethyl-2-sila-l,3-dithiane, may itself be used as a thioacetalization reagent [56]. This reagent reacts in a highly chemoselective manner, converting

162

WILLIAM W. WOOD

TABLE4.11 Dithioacetalization with the 1,3,2-dithiaborinane-dimethyl sulfide complex

,/-,, sH

~ . _ S / \SMe 2 +

s~

RCOOH

Cx:

THF

Entry

R

Yield (%)

1 2 3 4 5 6 7 8 9 10 11 12 13

PhCH2 CH3(CH2) 6 Pr~ Cyclohexyl 1-Adamantanyl Ph p-CIPh p-MeOPh Br(CH2)10 MeO2C(CH2h Et2NCO(CH2)8 CH2 CH(CH2)8 CH2 CHCH2

84 90 81 82 80 77 71 75 82 83 59 72 75

only aldehydes and aldehyde-derived acetals into 1,3-dithianes under boron trifluoride etherate catalysis (Table 4.12). The origins of the use of sila-sulfur reagents for thioacetalization lie in earlier work, in which the conversion of a range of aldehydes and ketones into cyclic and acyclic 1,3-dithioacetals was described under catalysis by zinc iodide, aluminum trichloride or anhydrous hydrogen chloride using simple sila-sulfur reagents [57]. 2,2-Dimethyl-2-sila-l,3-dithiane TABLE 4.12

Dithioacetalization with 2,2-dimethyl-2-sila-l,3-dithiane C~SiMe 2

Entry

RCHOor RCH(OMe)2~ BF3.0Et2 -

RCHO or RCH(OMe)2 MeCHO prnCHO BunCHO Pr~CHO PhCHO ButCHO Piperonal

EtCH(OMe)2 MeCH(OMe)CH2CH(OMe)2

~\CHR ~S /

R

Yield (%)

Me Prn Bu n Pri Ph Bu t ~ >

99 98 99 98 98 99 94

Et MeCH(OMe)CH2

95 94

~

] 63

TRENDS IN THE CHEMISTRY OF 1,3-DITHIOACETALS

shows a high degree of chemoselectivity, but cannot be used on oL,[3-unsaturated aldehydes due to a competing Michael addition reaction.

4.3.3.3

Pre-activated thioacetalization reagents containing tin

Unlike the examples described above, the Sn-S bond is stronger than the Sn-O bond and so 2-stanna-l,3-dithianes require the presence of an activating reagent to be used to form 1,3-dithianes. Nevertheless these materials are highly chemoselective thioacetalization reagents which do not affect acid-sensitive functional groups (Table 4.13). Using such a reagent it is possible to differentiate between aliphatic and aromatic aldehydes and acetals [58]. A general reactivity sequence was found to be aromatic acetal > aliphatic aldehyde > aromatic aldehyde > aliphatic acetal. This reaction sequence was rationalized on the basis of two different reaction mechanisms with acetals reacting via ot-alkoxy carbocations and aldehydes by coordination of the carbonyl oxygen to tin.

4.3.4 SynthesesUsing Supported Thioacetalization Catalysts and Reagents The advantages of polymer or mineral supported reagents in organic synthesis are well known and require no rehearsal here. As in many other areas of chemistry, supported reagents have found considerable use in thioacetalization. Most of the TABLE 4.13

Dithioacetalization with 2-stanna-l,3-dithiane

c

SN

SnBu2

+

RCHO or RCH(OR')2

Entry

RCHO or RCH(OR)2

1 2 3 4 5 6 7 8 9 10 11

n-C4HgCHO CH3CH~CHCHO PhCHO Furfural AcO(CH2)~CHO THPO(CH2)~CHO TBDMSO(CH2)sCHO Butph2SiO(CH2)~CHO n-C3HTCH ~CHCH(OMe)2 n-C4HgCH(OMe)2

(

Bu2Sn(OTf) 2

Yield (%) n-C4Hg CH3CH - - C H Ph Furan AcO(CH2)s THPO(CH2)5 TBDMSO(CH2)5 Butph2SiO(CH2)5 n-C3HTCH - - C H n-C4H9 Ph

99 93 100 100 79 77 92 94 81 92 79

164

WILLIAMW. WOOD

TABLE4.14 Formation of dithiolanes with Nation H a 1

R2'N'~'~/z~'-'

Nation~~H, Phil, he~.

R1

R2

Yield %

CO2Et PhCH2 Me Me Ph Ph Ph

100 79 100 96 92 100 80 85

~(CH2)5~

91

~(CH2)s~ Me PhCH2 Ph 4-MeOmPh Ph 4-CI--Ph 4-Me-Ph

TABLE4.15 Formation of dithiolanes with sulfonated charcoal al

R2~~ O

~,~

Sulfonatedcharcoal,Phil

Substrate

Yield (%)

Cyclopentanone Cyclopentanone 2-Octanone 2-Methylcyclohexanone 4-Methylcyclohexanone Acetophenone Benzaldehyde p-Nitrobenzaldehyde

98 96 96 91 93 97 93 97

supported reagents that have been used to prepare 1,3-dithioacetals have consisted of BrCnsted acids on various supports. Lewis acid-supported catalysts have also been reported. Nation-H, the perfluorinated resisulfonic acid manufactured by Du Pont, is one of the most active supported thioacetalization catalysts, converting a range of ketones (and probably aldehydes) into 1,3-dithiolanes, regardless of structure (Table 4.14) [59]. A related reagent, prepared by sulfonating active charcoal with fuming sulfuric acid, may also be used to catalyse the same reaction with a similar

165

TRENDS IN THE CHEMISTRYOF ] ,3-DITHIOACETALS

TABLE 4.16 Formation of dithiolanes with Amberlyst-15 Amberlyst-15,CHCis R2

USH

R2

Substrate

Yield (%)

Cyclopentanone Cyclopentanone 2-Naphthaldehyde CliO

95 87 94

Adamantanone n-Nonaldehyde Pivaldehyde

98 93 88 98

92

cx5 o

Acetophenone

~

83

OHO

I O0

MeC~ ~Me

O

C.~C:

Amberlyst15 . CHCI3, RT

.

93%

0%

O

C -~CHO

+

A

Z~

,O

Conditions as above

96%

Scheme 4.21

0%

166

WILLIAM W . WOOD

TABLE 4.17 Competition experiments on formation of dithiolanes using montmorillonite KSF

p/ 2

montmoriUon'deKSF

Substrate I

Substrate 2

Substrate 1

R Product I

Substrate 2

PhCHO

o

+

R

Product 2

Relative yield Product 1 Product 2 100

0

PhCHO

48

52

PhCHO

73

27

o 2 ~ GHO

PhCHO

Me(CH2)2CHO

100

0

PhCHO

MeO~~OHO MeO"%e

100

0

52

48

PhCHO

100

0

PhCHO

100

0

PhCHO

100

0

C?"

100

0

OlVle

Me(CH2)sCHO

o

o

TRENDS IN THE CHEMISTRY OF

TABLE 4.17

1,3-DITHIOACETALS

167

Competition experiments on formation of dithiolanes using montmorillonite

KSF (cont.)

Substrate 1

Substrate 2

"~

o

-~

Relative yield Product 1 Product 2 IOO

0

95

5

IOO

O

IOO

O

o

level of activity (Table 4.15) [60]. Amberlyst-15, another supported sulfonic acid reagent, also catalyses the formation of dithiolanes (Table 4.16), in this case showing some chemoselectivity between aldehydes and ketones (Scheme 4.21) [61]. Acidic clays provide an alternative supported acid catalyst for thioacetalization. Montmorillonite KSF, one of the most acidic clay catalysts manufactured by Sud Chemie, is used as a solid BrOnsted acid. Used in toluene with azeotropic removal of water, dithiolanes, dithianes and acyclic 1,3-dithioacetals are formed from a variety of aldehydes and ketones [62]. This reagent can also be used without solvent and shows chemoselectivity between aromatic aldehydes and ketones and between aromatic and aliphatic aldehydes, as demonstrated by competition experiments (Table 4.17) [63]. More recently, bentonite earth catalysts have been found which catalyse the formation of dithiolanes in one seventh the concentration of montmorillonite" KSF [64]. Finally, silica gel-supported catalysts are effective catalysts for thioacetalization. The earlier of these catalysts, formed from thionyl chloride [65] or sulfuryl chloride [66] and silica gel, is a chemoselective reagent, discriminating between aldehydes and ketones (Table 4.18). The latter react more slowly than aldehydes, allowing selectivity, but can be thioacetalized in high yield. The second of these reagents, formed from iron(IxI) chloride dispersed on silica gel, allows the rapid formation of dithiolanes from alkyl, aryl and cycloalkyl aldehydes and ketones and ethanedithiol [67]. In both cases the reported yields are high. An H-Y zeolite reagent (Si/A1 = 2.43) has also been used to catalyse thioacetalizations, showing high reactivity and converting sterically hindered ketones (Table 4.19) [68].

168

WILLIAM W . WOOD

TABLE4.18 Formation of dithiolanes with thionyl chloride on silica

RX ,n

R1

~==O

_ HSCH2(CI"I2)nCH2SH

R2

S ( 3 ~ - -SiO2

R2

R1

R2

n

CH3(CH2)s_ Ph(CH3)CH--

H

0

99

H

0

100

H2C~CH(CH2)8_

H

0

100

Ph

H

0

100

PhCH ~ C H - -

H

0

97

CH3CH ~ C H - -

H

0

100

CH~(CH2)s_

H

1

99

Ph

H

1

97

H

1

100

H

0

99

H

0

98

H

0

93

H

0

88

H

0

91

H

0

98

PhCH

CH--

4-CI - - Ph--

4-MeO

Ph--

2-NO2 - - Ph-4-HO

4-M%N w 4-HO2C Ph--

Ph--

Ph--

Ph--

PhCh2 Ph--

Yield (%)

CH 3 ~

0

91

PhCH2 m

0

93

Ph ~ m (CH2)s ~

0

31

0

100

TABLE 4.19 Formation of dithiolanes form carbonyl compounds by H-Y Zeolite

Substrate

Yield (%)

n-Heptanal

93

Crotonaldehyde

90

Benzaldehyde

94

2-Furfuraldehyde

94

2-Octanone

95

Cyclopentanone

92

Cyclohexanone

90

Acetophenone

93

Benzophenone

91

(-)-Menthone

93

(_)-Camphor

90

c~-Tetralone

96

TRENDS IN THE CHEMISTRY OF 1,3-DITHIOACETALS ~'~SSO2Ph MeS'~~SSO2Ph

O

COPh +

169

base

MeS

CN

~~) . lequiv.mCPBA

~----S" CN

/mS

CN

/~S-~s~CONM"

~~.mC~ \ ~ /---\~ O

//

Scheme 4.22 HS--- 1

Pr3B or AIBN

HS--(-J ) n

MeOH

R = Pr, Bu, C(Me)2OH, CH2CI; R' - H, Pr; n = 1, 2

HS••

Ph

PhCI-12"-~S~ ,)n

Pr3B or AIBN In

MeOH

Scheme 4.23 O

SH alumina

R1

Rz

Pr' Ph 4-MeO--Ph 3,4-(MeO)2--Ph Pr' Ph

or"h

SH

H H H H CH2OCH3 CH2OCH3

Scheme 4.24

R

I

Yield (%) 70 82 85 80 80 75

~

2

170

WILLIAM W. WOOD

s

RCHBr2,Zn,TiCI4 TMEDA F--

Yield (%) Me Bu n

72

PhCH 2

87

c-C6Hll

86

76

Scheme 4.25 P~SH + CH212

PtCI2(dppm) ~ MeOH,Na2CO3

"~

S,,,,,v~ 66%

HS'~SH

+ CH212

PtCI2(dppm) MeOH,Na2CO#

I ~ S",,,v.,,~ 70%

Scheme 4.26 4.3.5

Syntheses by other Methods

There have been only a few recent examples of synthetic methods leading to 1,3dithioacetals which do not involve acid-catalysed reactions of dithiols and carbonyl compounds or their equivalents. Among this select group some truly unusual chemistry has appeared. From the area of agrochemical research, synthesis of bensultap analogues (vide supra) has been achieved by condensation of an active methylene compound with a dithiolsulfonate (Scheme 4.22) [69,70]. This paper also reported oxidation of 4-thioether-l,3-dithianes with mCPBA, which gave interesting indications of the order of reactivity of the sulfur atoms in this type of system. Another unusual route to cyclic dithianes involves radical reactions of acetylenes and 1,3-dithiols in the presence of tripropylborane or AIBN [71]. Disubstituted acetylenes lead to 1,4-dithianes while 1,3-dithianes or dithiolanes are formed when the acetylene bears only one substituent (Scheme 4.23). The authors make no speculation on the mechanism of this reaction, but the process must clearly involve initial bromination of the acetylene. In a related general approach, [3-ketodithianes have been prepared by addition of 1,3-propanedithiol to an acetylene catalysed by alumina (Scheme 4.24) [72]. Two other recent examples in this category both involve reaction of alkyl 1,1dihalides. A variation of the Tebbe alkylidenation reaction of esters allows a similar process for 1,3-dithian-2-ones (Scheme 4.25)) [73], while a palladiumcatalysed reaction, aimed primarily at the synthesis of alkyl thioethers, can also

TRENDS IN THE CHEMISTRY OF 1,3-DITHIOACETALS

I 71

lead to cyclic or acyclic 1,3-dithioacetals (Scheme 4.26) [74,75]. Both of these processes are limited by the lack of commercially available starting materials. Finally, an exchange procedure has been reported involving trimethylsilyltriflate as a catalyst under anhydrous conditions, which makes use of the relative stabilities of thioacetals derived from aldehydes and ketones. Thus, a dithioacetal in the presence of a more reactive aldehyde undergoes an exchange reaction, regenerating the parent carbonyl compound. The system may be used, therefore, either as a selective deprotection or thioacetalization regime [76].

4.4 4.4.1

CHEMISTRY OF

lp3-DITHIOACETALS

Chemistry of Anions Derived from 1,3-Dithioacetals

The chemistry of anions prepared from 1,3-dithioacetals has been studied extensively for many years. Much of this work has been summarized in a recent review [77]. It is not intended to cover this ground again here, and consequently this section will deal only with one facet of the chemistry of 1,3-dithioacetal anions which has received significant attention in the last 5 years: the chemistry of 2-acyl1,3-dithianylanions. The chemistry of anions derived from alkenyl-l,3-dithianes has also received some attention, but this topic is more appropriately covered in conjunction with a consideration of the chemistry of ketene-dithioacetals.

4.4.1.1 Chemistryof 2-acyl-l,3-dithianylanions 2-Acyl-l,3-dithianes have been known for many years, and have generally been HO

R~

R~R 2 HS(CH2)nSH BF3"OEt2, CH2Cl 2

O 40% H2SO4

THF (

R2

Scheme 4.27

172

WILLIAM W. WOOD

Et3AI

~-

r~ s,~s

RCOCi

r

S

S

LiAIEt3

Li

Scheme 4.28

prepared by acylation of a 2-1ithio-l,3-dithiane with an appropriate acylating agent (acid chloride, ester or amide), as reported in one of the seminal papers in this area [78]. There is, however, an older, less efficient method starting from carboxylic acids [79,80]. More recently, a syntheses from dihydro-l,4-dioxin (Scheme 4.27) and a variant on the Seebach and Corey method have appeared (Scheme 4.28) [81.82]. In the latter example, none of the tertiary alcohols which can be formed by reaction of two equivalents of the 2-1ithiodithiane and one of the acid chloride were detected, although in some cases the dithiane ring opened. The chemistry of 2-acyl-l,3-dithianes reported recently has concentrated on two broad areas: the synthesis of spiro derivatives and further studies of alkylation and acylation chemistry of the species. In this latter area it was shown by Scholastico and co-workers that 2-acyl-l,3-dithianes could be alkylated, provided that the acyl group was not too bulky [83]. It was also noted in this study that lithiodithianes were unreactive and the use of more reactive potassium dithianes led to some competing O-alkylation. It was shown in 1979 that 1,3-dithiane-2carboxylic acid could be alkylated at carbon in high yield using L D A - T H F (Scheme 4.29) [84]. Alkylation of 2-formyl-l,3-dithianes has also been demonstrated [85].

LDA

CO2H

BF

C'l Scheme 4.29

TRENDS IN THE CHEMISTRYOF 1,3-DITHIOACETALS

1 73

4.4.2 Reactionsof Lithiated 1,3-Dithioacetals with Organometallic Complexes The intense interest in the synthetic chemistry of organometallic complexes, which has developed in recent years has led to the application of these reagents in many different areas of chemistry. 1,3-Dithioacetals have been no exception to this trend. The majority of the reports on the organometallic chemistry of 1,3dithioacetals have been concerned with organochromium complexes. There have, however, also been some reports of reactions of 1,3-dithioacetals with organomanganese and organoiron complexes. These three aspects will now be considered in turn.

4.4.2.1 Organochromium complexes and 1,3-dithioacetals Two types of organochromium complex of 1,3-dithiane have been reported, differing in the point of attachment of the metal. Treatment of CrOs(THF) with dithiane gives a product in which chromium is bonded to sulfur [86]. These complexes show somewhat different reactivity to the uncoordinated analogues. For example, lithiation of the pentacarbonyl complex followed by treatment with carbon disulfide and alkylation gives the bis-substituted product which is stabilized by the chromium atom (Scheme 4.31) [87,88]. The alternative type of complex, in which the metal is bonded to C-2, can be obtained by reaction of chromium carbonyl coordinated trichloromethyl isocyanide with 1,2-alkyldithiols, but little chemistry of these complexes has been reported [89]. The majority of the reported organochromium chemistry of 1,3-dithioacetals has been concerned with the reactions of lithiated thioacetals with arene chromium complexes, rather than with organochromium complexes of 1,3-dithioacetals. The chemistry reported has normally formed part of larger studies of the reactions of arene chromium complexes with nucleophiles in general. In the absence of a leaving group, nucleophiles add to these complexes, which can then be oxidized, protonated or acylated (Scheme 4.31) [90]. If a leaving group is present, the (OC)5Cr~

~ S~.S

(i) BuLi

.~

(ii) CS2

l (oc)3c[~ss==~```T x,x.~___s/>

(i) BuLi (ii) CS2 (iii) BF4.OEt3

S~.,/ / S E t ~

SEt

Scheme4.30

174

WILLIAM W . W O O D

(,)

,Cr(CO)3

C'q s..,T~S Li

r% H+

" !~

e Cr(CO)3

S.

S 0 ..,..'LR

Scheme 4.31 reaction takes a different course leading to substitution. However, the regiochemistry of the reaction may vary, resulting in ipso, cine or tele substitution. Rose-Munch and co-workers have made an extensive study of the nucleophilic substitution reactions of chromium complexes of various chlorotoluenes and chloroxylenes. The products from these reactions vary according to the reaction conditions and the nature of the nucleophile. The results from several studies are summarized in Table 4.20. As can be seen from the table, the effect of variation of nucleophile is quite dramatic (entries 3 and 4, and 5 and 6). A range of leaving groups appears to be tolerated. The mechanism of the reaction is thought to involve an initial reversible addition of the lithiated dithiane to the complex, thus the outcome of the reaction probably depends on the relative stabilities of the intermediate adducts. Although there have been some X-ray and nuclear magnetic resonance studies of the precursor complexes which show an equilibrium between eclipsed and anti-eclipsed conformations, depending on the substitution pattern of the aromatic ring, there has been no correlation between these studies and the outcome of the substitution reactions. This type of chemistry has also been extended to 1,2-dihydrocyclobutabenzene, indane and 1,2,3,4-tetrahydronaphthalene rings systems [95].

4.4.2.2

1,3-Dithioacetals and complexes of other metals

As seen above, there have been no systematic studies of the reactions of

TRENDSIN THECHEMISTRYOF 1,3-DITHIOACETALS

1 75

TABLE4.20 Substitution patterns of products from nucleophilic attack on organochromium complexes Substrate

Nucleophile % cine % tele-meta % tele-para

S Or(OO) 3

(00)3

~r

10

12

50

[91]

0

58

0

0

[91]

18

0

0

70

[91]

13

30

0

20

[91]

0

0

79

0

[92]

0

62

0

0

[93]

0

86

0

0

[94]

S

phSX~i

Cl r(CO)s

IS

"~~

s

s

PhXLi

F

~'~c~oo)3

PI'~~Cr(O_,O)s

0 PhXLi

S

)3

Cyclohexadiene Ref.

U

s

$

PhXLi dithioacetals with organometallic species. There have, however, been some sporadic reports which should be noted in an area which will undoubtedly grow. Iron tricarbonyl complexes of 2-butadienyl-l,3-dithianes have been prepared, and the reactions of the derived anions studied [96]. Three butadiene complexes (Scheme 4.32) were prepared by conventional chemistry of the pre-coordinated aldehyde. The metal could be removed in high yield. This compound could not be

176

WILLIAMW. WOOD

OHS

C

Fe(CO)3

Fe(CO)3

BF3.Et20,AcOH " ~ ,

TMS2NLi

-78j ~0~Ct o

MeOH

Ha0/ /

S~.

FelCO)3

e(cO)3 Fe(("

S

)3

Scheme 4.32

C

(i) HMPA,THF,-78~ u

Mn(CO)3

Mn(CO)4

(ii) H § CO

Scheme 4.33

prepared directly from the uncoordinated aldehyde. On treatment with lithium hexamethyldisilazide, an anion was generated which showed a remarkable dichotomy in reaction with electrophiles: alkyl halides reacted exclusively at the C2 position of the dithiane, while aldehydes reacted at the ~ position of the butadiene moiety. There has also been a report of nucleophilic attack of a lithiated dithiane on an organomanganese complex. In this instance a single product was obtained (Scheme 4.33), in which the xlS-pentadienyl complex was converted to a ~, ~q3-complex [97]. This chemistry can also be applied to cyclohexadienyl systems (Scheme 4.34) [98].

s.../s

02 ~

e

Mn(CO)3

Mn(CO)a Scheme 4.34

TRENDS IN THE CHEMISTRY OF

4.4.3

1,3-DITHIOACETALS

I 77

Diastereoselective Reactions about 1,3-Dithioacetals

The 1,3-dithiane unit has been used extensively in synthesis to provide a rigid template which controls the stereochemical course of reactions on attached ligands. The addition to its rigid conformational preferences, the dithiane ring also provides chelating heteroatoms which can form rigid chelated structures in combination with side-chain heteroatoms. Control has been demonstrated on o~, [3 and 7 positions, although in the latter case, control normally arises by transfer from the oL position. In this area a considerable amount of the work has involved microbial reductions of ketodithianes, often as extensions of studies on reductions of keto-esters. The discussion of this section will be divided according to the location of the asymmetric centre with respect to the dithiane ring.

4.4.3.1

Stereoselection at the c~p o s i t i o n

Stereoselection at the oLposition has been achieved by reduction of or nucleophilic addition to oL-ketodithianes. In chemical systems this has usually involved chelation of the side-chain to one of the sulfur atoms of the dithiane ring.

4.4.3.1.1 Microbial reductions Although the first report on the enzymatic reduction of e~-ketodithianes was probably due to Sih in 1982 [99], the first systematic study did not appear until 1985 [100]. Reduction of dithianes (Table 4.21) formally derived from pyruvaldehyde with baker's yeast, gave high yields and high enantiomeric excesses (> 96%). Yields were lower in more highly substituted cases, although equally high enantiomeric excesses were obtained. A similar procedure was later applied to various protected glyceraldehyde derivatives, prepared according to Scheme 4.35 [101]. In this case, yields were generally lower than in the previous example, although enantiomeric excesses remained high (Table 4.22). In both of these cases TABLE 4.21 Reduction of o~-ketodithianes with baker's yeast 0

OH R'

R

HO--

:

Fr

Baker's Yeast

RS ~ " ~ S

R'

Yield (%)

ee (%)

Configuration

Me

H

84

> 96

(33

Et

H

71

>96

(33

Pr n

H

92

> 96

Bu n

H

71

>96

(33 (s)

H

74

> 96

(33

Me

50

>96

31

>96

(33 (R)

(CH,)~ -Me Me

S

--CH2CH --

CH2

1 78

WILLIAM W. WOOD

O R-~N j

O

SvS e

I

OMe

Scheme 4.35 TABLE4.22 Reduction of c~-keto dithianes with baker's yeast.

O

OH Baker's'Yeast ~

R S.--J

R

Yield (%)

ee(%)

CH2OBzl CH20(4-MeO-- Ph) CH2OCH2OMe CH2OTBS Me Et n-Hexyl CF3

50 27 82 <10 73 52 36 96

i>95 t> 98 i> 95 /> 95 i>95 i> 95 67

reductions generally followed Prelog's rule, giving (S) products. A range of other microbial systems have been examined as reducing systems for related structures (Table 4.23), giving high yields and good enantiomeric excesses [102].

4.4.3.1.2 Reduction using chiral reagents Enzymatic reductions of this type are generally limited to the production of only one enantiomer, often in long reaction times. Chiral reducing reagents, such as the oxazaborolidines developed by Corey [103], are available in both enantiomeric forms, allowing the preparation of both enantiomers of the product. When applied to the reduction of e~-ketodithianes, excellent yields of reduced products were obtained in high enantiomeric excess [104]. Clearly in this case the dithiane unit, together with its pendant alkyl group, represents the 'large' group and so additional functionality at the 2-position causes no fall in selectivity. It is therefore of no surprise that when the 'small' group is enlarged (methyl to ethyl), the selectivity falls away (Table 4.24). 4.4.3.1.3 Reaction of asymmetric dithianes An alternative source of stereochemical bias in non-enzymatic reactions of dithianes can be provided by oxidation of one of the two sulfur atoms of the dithiane (Scheme 4.36). Separate treatment of the two diastereoisomers with

TRENDS IN THE CHEMISTRY OF 1,3-DITHIOACETALS

1 79

TABLE 4.23 Reduction of c~-ketodithianes with various organisms

OEt

OEt o

o

OH

0

OEt 0

0

Substrate

(1) R = Me (1) R = Me (2) R = Et (2) R = Me (1) R = H (1) R = H TABLE

OEt

Organism

Yield (%)

Candida albicans Torulasporadelbrueckii Torulasporadelbrueckii Torulasporadelbrueckii Torulasporadelbrueckii Saccharomycescerevisiae

ee (%)

Absolute stereochemistry

38

85

(R)

50

61

(R)

100

92

(R)

95

85

(R)

58

95

(S)

78

95

(S)

4.24 Reduction of c~-ketodithianes with chiral oxazaborolidines. 1.0

/R'

Ph. ,,

o R

Ph

~

R'

~H R'

ee (%)

Me

Me

94

Pr

Me

93

PhCH2

Me

96

Ph

Me

90

Ph

Et

60

TBSOCH2

Me

-(CH2)4-

95

>96

methylmagnesium iodide in T H F at - 7 8 ~ gives high diastereoselectivity [105]. In both cases, the results from the reaction can be rationalized on the basis of Cramtype transition states, as shown for one example. Although beyond the scope of this review, some related work of Frye and Eliel provides an excellent theoretical overview of this type of reaction [106]. It is also possible to obtain chiral induction at the ot position from relatively remote chiral centres, albeit at a modest level of selectivity (Scheme 4.37) [107].

180

WILLIAM W. WOOD (i) BunLi

Swem

(ii)~CHO

..OH

0

,/J(i)

NalO4,MeOH,H20

(ii) Separate

0 e

0

MeMgl,-78~ THF

\?.

Exclusively

(~)

0e

0

I MeMgl,-78~ THF Oe

15:1

excess

Mg~.~3G ",,~

/0--% Mg

Scheme 4.36

4.4.3.2

Stereoselection at the ~ position

4.4.3.2.1 Microbialreductions A number of [3-ketodithianes have been examined as substrates for reduction by baker's yeast and by other microbial reductions. In these reductions the dithiane moiety must represent the 'large' group in the substrate and the other half of the ketone must be sterically much less demanding otherwise low enantiomeric excesses are obtained, as was found in the case of the n-octyl ester (Scheme 4.38), which gave a 14% excess of the unexpected (according to Prelog's rule) product [108]. In contrast, the methyl ester gave a much higher enantiomeric excess. However, the chemical yields from these reductions were low, partly due to decarboxylation of the substrate. Reduction of 2-dithianylacetone, however, gives a high yield and enantiomeric excess (Scheme 4.39) of the (S) product on reduction with baker's yeast [109]. The

TRENDSINTHECHEMISTRY OF1,3-DITHIOACETALS

o

~

181

2-1ithio-dithiane

~

s,v

I BuU,THF

RCHO

R

Yield of adduct (%)

Diastereoisomeric ratio

Ph PhCH2CH2 CH3(CH2)~ Me Pr'

14 55 46 43 55

1:1.9 1:1.5 1:1.3 1:1.5 1:1.8

Scheme 4.37

Baker's OH Yeast~R02C.. vLv

S'/~

OH

Z "S'J + R O 2 ~ s / ' J

S"/~

R

Yield (%)

(ee)

(%)

Yield (%)

Me Et n-Octyl K

16 14 15 3

(74) (50) (21 ) (86)

(S) (S) (R) (S)

26 13 21 8

Scheme 4.38

enantiomer is also available from reduction of the same substrate with growing cultures of Aspergillus niger or Geotrichum candidum [110].

4.4.3.2.2 Alkylation of asymmetric dithianes As discussed previously, asymmetric ec-ketodithiane-S-oxides can be readily prepared. Under appropriate conditions, compounds of this type can be alkylated with high diastereoisomeric excesses [111]. The high selectivity can be rationalized in accordance with a chelated chair transition state, giving a high steric bias

182

WILLIAM W. WOOD OH

S"'~

.A..A.s) Reducing organism

Absolute stereochemistry

ee(%)

Baker's yeast Streptomyces spp. Aspergillus niger Geotrichum candidum

(5) (R) (R) (R)

>99 99 90 90

Scheme 4.39 0

(9

Is

(9 I_i--. f "0 e

Base

I Mel

o

o~

le

(Stereochemical assignment assumed by analogy)

Scheme 4.40

towards the observed product (Scheme diastereoisomeric ratios between 2"1 and 1"1.

4.4.3.3

4.40).

Other

examples

gave

Stereoselection at the ~l position

Conjugate addition to appropriate substrates has been examined as a method of achieving stereocontrol at a ~/carbon atom (Scheme 4.41) [112], using an oxidized sulfur atom as an asymmetric control element. Moderate levels of stereocontrol were obtained (maximum 10.5:1). However, the distance between the site of addition at the chelated control element clearly limits the potential for this type of approach.

4.4.3.4

Stereoselection at the ~ and f3 positions

Almost all of the recent examples of the preparation of dithianes bearing asymmetric centres at the oLand 13positions have arisen through steric control from

Scheme 4.41

the p position. The exception to this general trend involved reduction of an asubstituted 6-ketodithiane and separation of the resulting diastereoisomeric mixture. 4.4.3.4.1 Microbial rrd~lctions In an example of apparent asymmetric reduction at both the a and P positions, reduction of a propandione system (Scheme 4.42) occurs in a stepwise fashion, giving a (lS,2S) product. The P stereocentre provides significant steric bias in the second reduction. as demonstrated by the fact that the intermediate hydroxyketone could be isolated and reduced with DIBAL to give a (1R.2S) product [ I 121. An alternative strategy for the preparation of dithianes with chiral centres at both the a and P positions involved diastereoselective reduction of a-

4 7

Baker's Yeast

0

/

DIBAL

78% ee

Scheme 4.42

0

\

baker's Yeast

97% ee

184

WILLIAMW. WOOD Baker'sYeast ~ ~

S

s

C02Me >98%ee

C02Me

~~.,~0

S/~"I #

OH

Baker'sYeast

+~ 96:4

OH S / ~

>99%e e

_OH

S

S"'~

~02Me >99%e e

)

OH S / ~

2:8

>99%e e

Scheme 4.43

substituted [3-ketodithianes (Scheme 4.43). Where the oL substituent was methyl, moderate diastereoselectivity was obtained in the reduction, but the individual isomers were obtained with high enantiomeric excesses. However, when the oL substituent was a carboxylic ester, a remarkable degree of diastereoselectivity was obtained, again with a high enantiomeric excess [114]. 4. 4.3.4.2 Induction from the [3position As indicated above, chiral induction from the [3 position can give a high degree of stereocontrol at the oLcentre. In two related examples, the orientation of addition of a nucleophile to a n sp 2 centre located oL to a dithiane moiety was controlled by an asymmetric centre in the [3 position. Optically active dithianes derived from (S)lactate and bearing a range of O-protecting groups were treated with several different organometallic reagents, giving mixtures of syn and anti products. The selectivity of the reaction (Scheme 4.44) could be controlled by appropriate choice of the protecting group and alkylating reagent. In general, alkyllithium-cerium reagents in ether gave syn selectivity, while titanium and magnesium reagents favoured the anti product. In the best examples, the syn product could be obtained almost exclusively using a MEM protecting group and alkyllithium, while a TBDMS group and a titanium reagent gave the anti product with moderate selectivity. The general syn selectivity was explained by invoking chelation between one of the dithiane sulfur atoms and either the carbonyl or the protected hydroxyl group. Two models of the transition state, depending on the chelating abilities of the protected hydroxyl group, were proposed, both leading to syn attack from the less hindered face. The stereochemical outcome of both models was the same [115]. Both syn and anti products could be obtained by related chemistry from the same research group (Scheme 4.45) [116]. Treatment of an isopropylidene derivative of (S)-lactate with two equivalents of alkyllithium gave a ketenedithioacetal by elimination of acetone. On reaction with a third equivalent of alkyllithium, syn products were obtained exclusively. By contrast, the anti products were obtained if the alkyl group was already present in the substrate and the intermediate ketene-dithioacetals were reduced with lithium aluminum hydride. These results were explained by a non-chelation-controlled addition, where the alternative transition state brings the methyl group close to the dithiane ring.

TRENDS IN THE CHEMISTRYOF 1,3-DITHIOACETALS RO

TBDMS

MEM

S""'~

R'M

RO

S"""~

RO

R'

Solvent

Yield (%)

MeLi MeCeCl2 MeMgBr MeTi(OPri)~ Pr~Li priCeCl2 MeLi MeCeCI2 MeMgBr-ZnCI2 priLi

Et20 THF THF CH2CI 2 Et20 THF Et20 THF Et20 Et20 THF Et20 THF THF Et20 THF THF

40 67 86 40 74 65 81 20 37 11 30 95 27 75 36 83 26

Pr'CeCI2 MeLi MeLi MeMgBr priLi

PhCH 2

priCeCI2 MeMgBr

H

H

1 85 S"""~

syn anti 9 80:20 94:6 35:65 19:81 97:3 97:3 94:6 79:21 55:45 > 98:<2 > 98 :<2 99:1 75:25 37:63 83:17 86:14 68:32

H

H

"S "M"

Scheme 4.44

4.4.3.5

Stereoselective at the ot and y positions

Examples of stereoselection at both the oL and y positions are comparatively unusual and have generally arisen by 1,3-asymmetric induction. This was the case for a recent enzymatic reduction (Scheme 4.46) carried out as part of a synthesis of FK506 [117].

4.4.3.6

Stereoselection at both ot positions

1,3-asymmetric induction across a dithiane group at the 2-position has been examined. Syn selectivity was obtained by addition of a lithiated dithiane to aldehydes (maximum selectivity 9:4:1) (Scheme 4.47) [118]. In contrast, the corresponding anti products can be obtained by adding a nucleophile to an aldehyde. The highest selectivity in these examples was found with alkyltitanium

186

WILLIAM W. WOOD

o_ o

OLi

S""~

OH

S"/'~

H

OLi

@sJ

S''~

OH

R

S"~

R

R = Me, Et, Bu", P?, Ph Li~o/M~R'

_OH

S"~

R=H,M=U R = alkyl, a = H3AI

Scheme 4.45 A 0

-yy

/CO2 Bu'

baker's yeast :'-

=

_

:_

OH

=

CO2But

Scheme 4.46 reagents [119]. The higher selectivity found in the latter sequence presumably arises from the tighter, chelated transition state.

4.4.4

Radical reactions of 1,3-dithioacetals

In recent years, one of the fastest growing areas of synthetic organic chemistry has been that involving the generation and subsequent reaction of radicals [120,121]. Not surprisingly, this level of interest has been reflected in studies on 1,3dithioacetals. The significant feature of these recent papers has been the progression away from simple reductive dithioacetalization towards more complex and more synthetically useful chemistry, based on the reactions of the intermediate o~heteroatom stabilized radical. The origin of much of the chemistry in this area lies in the observation by Gutierrez et al. that 1,3-dithiolanes could be effectively reduced to alkanes, bis(tri-

TRENDSIN THE CHEMISTRY OF 1 ,3-DITHIOACETALS

187

Scheme 4.47

n-butyltin) sulfide and ethane using four equivalents of tributyltin hydride and a radical initiator (AIBN) [122]. In these studies it was also noted that the reduction was usually of a stepwise nature and could be halted after the first or second steps by limiting the availability of tin hydride (Scheme 4.48). The sequence observed can be satisfactorily explained by considering the relative stabilities of the intermediate radicals. The radical leading to ethane is primary, and therefore less stable than that leading to cyclohexane, which is secondary. The initial product arises from a tertiary radical. which is further stabilized by the presence of an a

8I

..

1 equiv. Bu", SnH

A,BN 3 equiv. Bu", SnH, \Bun3

f-

.

;*;

SnH, AIBN

Scheme 4.48

188

WILLIAM W. WOOD

2 equiv.Bu~

S~SSnBu3

AIBN

Phil

~;nBu3 I silicagel

Scheme 4.49

~~S

Phil

Bu%SnH,AIBN,

,~SSnBu3

, r

Scheme 4.50

/OCH2CH2SH

Bur'3snH,AIBN,Phil~

~0

OH

BCI3"/OCOCH2SH

Bu"aSnH,AIBN,Phil*-

OH

base

Scheme 4.51

heteroatom. The intermediates have been used in the synthesis of tetradentate organosulfur ligands (Scheme 4.49), by the same authors [123]. The most significant feature of Gutierrez' work was the recognition that the first-formed radical was relatively stable and nucleophilic in nature, due to its location adjacent to a heteroatom, and, as a consequence, that other radical reactions, in particular intramolecular cyclization, might be faster than radical

TRENDSINTHECHEMISTRY OF] ,3-DITHIOACETALS

~ ~

SPh '~~SPh

Bu'3SnH,AIBN,Phil

~SPh c i s trans

Scheme 4.52

HSi(TMS)3,.~ AIBN,PhCH'3 ~

189

=35 65 ,.SSi(TMS)2

S

Scheme 4.53 quenching. This possibility was realized by Fallis (Scheme 4.50) [124,125]. Thus, treatment of a dithiolane with Bu3SnH and AIBN led to a substituted cyclopentane in high yield as a 2:1 mixture of cis and trans diastereoisomers. The same reaction can also be applied to 1,3-oxathiolanes, leading initially to an ether. However, in this instance, the product can be further transformed into the free alcohol by boron trichloride ether cleavage. Similarly, and perhaps more usefully, 1,3-oxathiolane-5-ones react in a similar manner and the resulting esters can be more easily cleaved (Scheme 4.51) [126,127]. The relative selectivities of desulfurization by tin hydride of 1,3-dithianes, oxathiolanes and thiazoldines have been studied in a more detailed report [128]. A similar reaction can also be performed with acyclic dithioacetals, leading to the cyclopentane thioethers, in this case in an approximately 1:2 cis:trans ratio (Scheme 4.52) [129]. As an alternative to tributyltin hydride, the less toxic reagent tri(trimethylsilyl)silane can be used to generate a similar type of intermediate (Scheme 4.53) [130]. Radical generation from dithiolanes using tributyltin hydride leads to cleavage of a carbon-sulfur bond and opening of the dithiolane ring. Hydrogen abstraction could, however, result in retention of the dithiolane ring and a radical stabilized by two e~ heteroatoms. Such a process would have obvious advantages since the intermediate would be a synthetic equivalent of the acyl radical. Early studies indicated that such a process would be possible using the t-butoxy radical as an initiator [131 ]. The practical realization of this type of process has been reported very recently, leading to the synthesis of spirocyclic systems (Scheme 4.54), generating the required radical precursor with photo-excited benzophenone [132]. In this case the reaction was favoured by allowing the nucleophilic sulfur-stabilized radical to react with an electron-deficient alkene. It was demonstrated that sulfur was the better radical-stabilizing heteroatom (over O and N) and that benzene was the preferred solvent. Other ketonic initiators failed. While most of the chemistry in this area has concentrated on radical cyclizations,

CO2Et ~S

)~

S/~'~S hvbenz~176 300am)

"-'~

Scheme 4.54

~

CO2Et

190

WILLIAM W. WOOD

r~

r~

SYB'u/

-e-

SnBu3

r~

S S " ~

~

S

9

-"Me3Si 0

o

-SnBu3

r~

SvS

~,A.ph OTMS

S

~

S

-eOI'MS

Ph

Ph

S 0"I"MS

Ph

Scheme 4.55 TABLE 4.25 Radical alkylations of dithianyl stannane

+Olefin nBuz R

Olefin

H

orbs

MeCN,molecu,lar sieves ..~

Oxidant

Product

OSIMe2Ph

A

H

o'r~

B

H

~L,,.p h

B

H

~',.,.v,,SnPh3

Yield (%) 87

A

~ H

Product

r

CAN (A) or [FeCp?.]PF6 (B)

C% p

r

OTiS

B

Ph

OTMS

B

85

54

56

67

B

Me

i

cja.,

64

92

TRENDS IN THE CHEMISTRYOF 1,3-DITHIOACETALS

191

it is possible to generate a 1,3-dithioacetal radical and allow this to react with an appropriate olefin in a biomolecular reaction [133]. It was found that treatment of 2-tributylstannyl-l,3-dithiane with ceric ammonium nitrate led to a radical species, probably by way of a cation radical (Scheme 4.55). These radicals coupled with silyl enol ether or olefins (Table 4.25).

1,3-DITHIOACETALAS A

4.5

FUNCTIONAL GROUP

In addition to serving as an activator for diverse chemical reactions, as described above, the 1,3-dithioacetal group can also be considered as a functional group which can undergo relatively simple, functional group manipulations. The most well known of these are those relating to protecting group chemistry, but the group can also serve, for example, as a methylene or difluoromethylene equivalent. These functional group manipulations will be considered in the following discussion.

4.5.1

Regeneration of Carbonyl Compounds from Dithioacetals

The role of 1,3-dithioacetals as protecting groups has inevitably generated a large number of methods for regenerating the parent carbonyl compounds under mild conditions and in high yield. Thioacetals of both aldehydes and ketones are stable to a wide range of conditions and can be converted back to the parent carbonyl in high yield. Methods for this regeneration are described in the well-known texts on protecting group methodology [134]. With very few exceptions, cleavage of dithioacetals to regenerate the carbonyl groups follow the same general mechanism (Scheme 4.56). In this process the central carbon atom is rendered susceptible to aqueous hydrolysis by formation of

K X-Y/~

R

x

.. S

~ R

R

R"

~|

yE)

Sq

X

\

~

"S~

XS ~P-

R ~)

R

-H +

S

)

~" R

~176

=X--Y

OH

+

HtO',H

XS~ s x

Scheme4.56

. c vSMe /

\O'"J~/\SelVle

O !. N H2SO4

.~ -

d

Scheme4.57

0 R

HO ....

192

WILLIAM W. WOOD

a full or partial positive charge at sulfur. The variety and varying efficacies of reagents used for this process arise from the range of reagents which undergo nucleophilic attack by sulfur and their relative thiophilicities. Activation of sulfur towards hydrolysis as illustrated above is demonstrated by the susceptibility of oxidized dithioacetals towards acid hydrolysis. Thus, an oxidized dithioacetal may be cleaved with a mild acid (Scheme 4.57), whereas an unoxidized analogue would be inert to such conditions. [135].

4.5.1.1 Regeneration with metal salts As shown in Table 4.26, metal salts, particularly those of mercury, silver, copper and thallium, have been used for many years to catalyse the hydrolysis of dithioacetals. These reactions follow the general hydrolysis mechanism (Scheme 4.58), requiring acid for the hydrolysis step. In addition to the above, antimony pentachloride has also been reported to bring about the hydrolysis of dithioacetals [136]. However, this reagent is thought to act by a single-electron transfer (SET) mechanism (Scheme 4.59). High yields of carbonyl compounds were obtained by

(f-'~X/Hg--'~" R

HgX

S

R

Xe

~)~:--.~

- - RX

OH

R'

S'~

-

HgX2 SHgx

R R"

H~Ox H Scheme 4.58

Lj

+

SbCl 5

SET

~

t

+

SbCI5-,

I SET

+

+

sF•R'S+

1 LJ

S

R'

s~ 9

+ SbCI4" + CI-

S+

L;

H20 Scheme 4.59

P~R'

+

SbCI 5.

TRENDS IN THE CHEMISTRY OF

TABLE

1,3-DITHIOACETALS

193

4.26 Metal-catalysed hydrolysis of 1,3-dithioacetals

Entry

Metal

1

Hg

2

Hg

3

Hg

4

Hg

5

Hg

6

Hg

7

Hg

8

Hg

9 10

Hg Hg

11

Cu

12

Cu

13

Ag

14

TI

15

TI

16

TI

17

Ce

18

Ce

19

Ni

Conditions

Reference

E. Fujita, Y. Nagao and K. Kaneko, Chem. Pharm. Bull., 26, 3743 (1978). HgO-BF3, H20, THF E. Vedejs and P. L. Fuchs, J. Org. Chem., 36, 366 (1971 ). HgO, HBF4 (35% aq), THF I. Degani, R. Fochi and V. Regondi, Synthesis, 51 (1981 ). HgCI2, H20 B. Tarnchompoo and Y. Theblaranoth, Tetrahedron Lett., 25, 5567 (1984). HgO, HgCI2, MeOH, H20 D. Seebach, B. W. Erickson and G. Singh, J. Org. Chem., 31, 4303 (1966). HgCI2, acetone, H20 S.M. Weinreb and R. R. Staib, Tetrahedron, 38, 3087 (1982). HgCI2, CaCO3, MeCN, H20 A. I. Meyers et al., J. Am. Chem. Soc., 105, 5015 (1983). HgO, Hg(OAc)2, THF, M.D. Rozwadowska and D. Mateeka, H20, CH2CI2 Tetrahedron, 44, 1221 (1988). Hg(OAc)2, H20 G.P. Pollini et al., Ed. Sci., 23, 405 (1968). HgCI2, CdCO3, MeCN, H20 R. Rosen, M. J. Taschner, J. A. Thomas and C. H. Heathcock, J. Org. Chem., 50, 1190 (1985). CuCI2, CuO, acetone P. Stutz and P. A. Stadler, Org. Synth., 8, 56 (1977). CuCI2, acetone H. Redlich and W. Francke, Angew Chem. Int. Ed. Engl., 23, 519 (1984). AgNO~, EtOH, H20 C.A. Reece, J. O. Rodin, R. G. Brownlee, W. G. Duncan and R. M. Silverstein, Tetrahedron, 24, 4249 (1968). TI(NO3)3, MeOH E. Fujita, Y. Nagao and K. Kaneko, Chem. Pharm. Bull., 26, 3743 (1978). TI(OCOCF3)3, THF T.-L. Ho and C. M. Wong, Can. J. Chem., 50, 3740 (1972). TI(OCOCF3)3, THF T.-L. Ho, R. J. Hill and C. M. Wong, Heterocycles, 27, 1719 (1988). Ce(NH4)2(NO3)6, MeCN, T.-L. Ho, H. C. Ho and C. M. Wong, J. Chem. H20 Soc., Chem. Commun., 751 (1977). Ce(NH4)2)NO)6, NaBH4, A.J. Cristau, B. Chabaud, H. Cristol, J. Org. MeCN, H20 Chem., 49, 2023 (1984). Tris(2,2-bipyridyl)Ni(CIO4)~, M. Murase, E. Kotani and S. Tobinaga, Chem. H20 Pharm. Bull., 34 (1986). Hg(CIO4)2, MeOH-CHCI3

this process, in some instances with contamination from 1,2-dithiolane-S-oxides. Perhaps the most significant advance in this area over recent years has been the introduction of supported metal salts as hydrolysis reagents, which give considerable advantages in terms of the ease of work-up and yield over the conventional methodologies--factors of importance in protecting group chemistry. Silica gel, used widely as a support for other types of reagent, has been used to

194

WILLIAM W. WOOD o

H

0

CuSO4 on silica gel, Phil

---

H

O

Scheme 4.60 Ph .S---'k H ~ ..__,~ S

Clayfen (A) Claycop (B)

PhCHO A: 100% B: 100%

Ph

SEt

Clayfen (A)

Ph

SEt

Claycop (B)

Ph

O A: 99% B: 99%

Clayfen (A)

.-"--

O

Claycop (B) A: 98% B: 98%

Scheme 4.61

support copper sulphate and copper chloride (Scheme 4.60) [137,138]. A selection of examples were examined, giving high yields of carbonyl compounds. Ferric nitrate on K-10 bentonite clay ('Clayfen') and copper nitrate, also on K-10 clay ('Clayco') are also efficient catalysts for the regeneration reaction (Scheme 4.61) [139], probably acting as an NO+-releasing agents since other chemistry of these supported reagents indicates this type of reactivity and recent reports indicate that dithioacetals can be cleaved by release of NO + (vide infra).

4.5.1.2

Cleavage by halogens, NBS, NCS and related reagents

Halogens have been known for many years to bring about cleavage of dithioacetals. For example, hydrolysis with bromine was reported in 1928 by Chivers and Smiles [140]. Other sources of halogens may also be employed for similar processes (Scheme 4.62) [141]. Similarly, NBS and NCS are known to cause oxidation at sulfur and thus can be used to initiate hydrolysis of dithioacetals. This method for hydrolysis was developed by Corey and Erickson, as a milder

Scheme 4.62

TRENDS IN THE CHEMISTRY OF ] ,3-DITHIOACETALS

195

B2 i

NBS

R

R %-...~

a ,/

Scheme 4.63 0 TMS-i

+

R~R '

I

/S~....

~

I le 1.~S~

+ TMSOTMS

e~e~

r

R"

R r

!e

I--"

R,,~

0

21e

+

2Me2S

"R'

+ I-S-CH2CH2-S-I + Me2S

Scheme 4.64

regeneration procedure than mercuric chloride [142]. These reactions may involve oxidation of sulfur to sulfoxide prior to hydrolysis, but it seems more likely that hydrolysis of the intermediate, halogen-activated, dithioacetal occurs (Scheme 4.63). Corey and Erickson found that NBS and NCS were particularly effective in the presence of a silver(I) salt.

4.5.1.3 Cleavage by activated DMSO As might be expected from the above, activated DMSO provides an effective means of regenerating carbonyls from dithioacetals. A number of activating agents have been used for this process (Table 4.27). The reactions probably follow the mechanism illustrated for trimethylsilyl iodide, although differentiation between this and the simple halogen mechanism could prove difficult (Scheme 4.64).

4.5.1.4 Cleavage by alkylation at sulfur Alkylation at sulfur to form a sulfonium salt activates dithioacetals towards hydrolysis (Table 4.28). In its simplest form, this procedure employs methyl iodide as the alkylating agent, sometimes in the presence of a base, but other more complex alkylating agents such as trialkyloxonium tetrafluoroborates have also been used to activate the dithioacetal (Scheme 4.65). Methylfluorosulfonate may

196

WILLIAM W. WOOD

TABLE4.27 Hydrolysis of 1,3-dithioacetals by activated DMSO Entry

Activating agent

Conditions/ comments

Reference

1

TMSBr

TMSBr, DMSO, CCI4

2

TMSI

3

HCI

4

SbCIs

5

ButBr (or I)

TMSI, DMSO, CCI4 (Faster than TMSBr) HCI, DMSO, H20, CH2CI2 SbCIs, DMSO, CH2CI2 (For acid-sensitive substrates) ButBr, DMSO

G. A. Olah, S. C. Narang and A. K. Mehrotra, Synthesis, 965 (1982).

6

Me2S*MeBF4 Me3S*BF4-,CH2CI2

7

Me2SBr2

Me2SBr2,CH2CI2

8

12

12, DMSO

Ibid.

M. Prato, U. Quintily, G. Scorraro and A. Sluraro, Synthesis, 679 (1982).

Ibid.

G. A. Olah, A. K. Mehrotra, S. C. Narang, Synthesis, 151 (1982). B. M. Trost and E. Murayama, J. Am. Chem. Soc., 103, 6529 (1981 ). G. A. Olah, Y. D. Vankar, M. Arvanaghi and G. K. S. Prakash, Synthesis, 720 (1979). J. B. Chattopadhaya and A. V. Rama Rao, Tetrahedron Lett., 3735 (1973).

TABLE 4.28 Hydrolysis of 1,3-dithioacetals by alkylation at sulfur

Entry

Alkylating agent

Conditions/ comments

Reference

1

Mel

Mel, MeOH, H20

2

Mei

Mei, MeCN, H20

3

Mel

4

Et30§

-

5

Et30§

-

6

MeSO3F

Mel, CaCO3, MeCN, H20 Et30§ -, CuSO, or NaOH Et30§ -, CH2CI2, H20 MeSO3F,CH2CI2

M. Fetizon and M. Jurion, J. Chem. Soc., Chem. Commun., 382 (1972). S. Takano, S. Hatahayama and K. Ogarasawa, J. Chem. Soc., Chem. Commun., 68 (1977). Y. Mori and M. Suzuki, Tetrahedron Lett., 30, 4383 (1989). T. Oishi, K. Kamemoto and Y. Ban, Tetrahedron Lett., 1085 (1972). I. Stahl, Synthesis, 135 (1981 ).

s

s

Et30+BF4

.._

T.-L. Ho and C. M. Wong, Synthesis, 561 (1972).

Et~,.,/~"~e~ Et

pha~~. 2BF4Scheme 4 . 6 5

10% NaOH ._

o I J i

or 3% CuS04-Ph

i

TRENDSIN THECHEMISTRYOF1,3-DITHIOACETALS

197

TABLE 4.29 Hydrolysis of dithiolanes with nitronium and nitrosonium salts (Yields (%))

Substrate

NO+HSO4 -

NaNOJTFA

NaNO3

NO2 +BF4-

67

81

66

96

82

98

92

98

74

91

71

<. 95

also be used as an extremely effective alkylating agent, but its toxicity and reactivity make it undesirable.

4.5.1.5 Cleavageby nitrogeneous activating agents Nitrogeneous electrophiles in all four possible oxidation states can activate dithioacetals towards hydrolysis. In a very thorough examination of this area, Olah and co-workers explored several different sources of nitronium and nitrosonium salts, and found that nitronium tetrafluoroborate gave the best yields (Table 4.29) [142a]. Nitration of aromatic systems did not occur under the conditions examined.

/~ /sEt Br---~_, /~~SEt

Br~----'~?CHO isoamylnitrite ~ ' ~

SEt CH3(CH2)8-~ SEt

74% CH3(CH2)8CHO <5%

Scheme 4.66

198

WILLIAMW. WOOD H2NOSOt~~ I R// S~kk~ or |a'

L

S:---/

N/H2 ArSO20 e

NH2 !

NH2

2ArSO2Oe

H20 R a"

Scheme 4.67

A similar process was examined by JCrgensen and co-workers, and compared with hydrolysis using t-butyl hypochlorite in carbon tetrachloride [142b]. Yields from this and the reagents described above varied considerably with substrate, but the nitration procedure gave better yields. Nitrosation with isoamyl nitrate also leads to hydrolysis, showing good chemoselectivity, hydrolysing aryl dithioacetals more quickly than alkyl analogues (Scheme 4.66) [143]. Dithioacetals may also be aminated with suitable reagents such as chloramine T [144] or O-mesitylene sulfonylhydroxylamine [145]. This hydrolysis presumably occurs by way of an amine salt (Scheme 4.67).

4.5.1.6

Cleavage by activation with iodosobenzene derivatives

Hypervalent iodine reagents activate dithioacetals towards hydrolysis, presumably by nucleophilic attack of sulfur at iodine. The reaction with iodosobenzene ditrifluoroacetate was developed by Stork and Zhao and was shown to be compatible with a wide range of functional groups, including nitriles, esters and double bonds. The reagent was shown effectively to hydrolyse dithianes formed from aldehydes and ketones (Scheme 4.68). In alcoholic solvents, an exchange reaction leads to acetals (Scheme 4.69) [146]. Hydrolysis of dithioacetals by iodosylbenzene was examined by Barton, Motherwell and co-workers, in an earlier report [147]. A dithioacetalization with concommitant aldol cyclization has also been reported using the same reagent (Scheme 4.70) [148].

4.5.1.7

Photolytic and electrolytic procedures

Early work on the photolytic removal of dithioacetal groups suggested such procedures but showed little promise for general application, requiring specialized equipment and with limitations on scale. A report from Takahashi et al. indicated that such reactions were possible using ultraviolet light and benzophenone as a sensitizer, giving moderate to good yields of ketones, although the range of examples was limited (Scheme 4.71) [149]. Later reports described similar results

TRENDSIN THECHEMISTRYOF 1,3-DITHIOACETALS S/ R'

(CF3CO2)21Ph

R

Me0H H~ (9-3)

"R'

Reaction time (min)

Substrate

199

Yield (%)

s ~/'~ ~-.-(CH2)4CO2Me ",---S

91

C

85

%(CH2)sOAc

92

s 86

Scheme 4.68

O PhS~~~'~~

sEt

(CF3CO2)21Ph ~ MeOH

0 PhS~~,/Ome Ome

Scheme 4.69

OTBS

EtO~I

OTBS_OBn (CF3CO2)21Ph -20~C, MeCN,aq. work-up 67%

Scheme 4.70

hexane,02,hv

b' R

Scheme 4.71

[150,151]. More recently, the restrictions described above have been overcome, and a method by which dithioacetals can be cleaved with visible light and on a large scale has been reported (Table 4.30) [152]. In this process, methylene green acts as a sensitizer in an oxygen-free system. For larger scales (up to 100g), a mixture of dyes (methylene green, rose bengal and anthraquinone) were used to

200

WILLIAM W. WOOD

TABLE4.30 Photolytic hydrolysis of 1,3-dithioacetals

[X•

R

o

..,L.=

methylenegreen,visiblehv MECH"H20,1:1

)n

n=0orl

Entry

Substrate

Product

Yield (%)

O

91

ph.,..~Me 97

o

2

PI~Ph 93

O Ph~ 4

5

,.Ph

p h ~ ~

pl1~~M

P ~ P h O

95

O

94

H

e

Ph~Me 91

0 6

H(~~Me

7

H ~ M e

NMe

95

NMe

O

8

91

86

9 MeO~

10

o

o

90

TRENDSIN THE CHEMISTRYOF 1,3-DITHIOACETALS

e RXi -2e ~

R

e

R'

H20

201 OH

...-

H+

e

H20, -H"

S(CH2,t 3s,

R

7=o

a ~'

Scheme 4.72

increase the efficiency of the system and to shorten reaction times. The reaction is thought to occur through an SET mechanism (videsupra) [153]. Several authors have reported electrolytic hydrolysis of dithioacetals. In the earliest of these reports, by Porter and Utley [154], dithianes were readily cleaved in moderate yield, but dithiolanes were not. A mechanism (Scheme 4.72) was proposed to explain these results, in which the strained intermediate could not be formed from a dithiolane. A recent study indicated that acyclic dithiolacetals appear to be susceptible to electrolytic cleavage, although the examples were primarily diphenyl dithioacetals [155].

4.5.1.8 Cleavage by acid hydrolysis Direct acid hydrolysis of unactivated dithioacetals generally requires forcing \

s~------o

B u t O ~ M

MeO

o

e

HCIO4,H2oMeCN,.._.,_B u t O ~ ~ , ~ , .10,0,%, , , , , . ~ O

/----~ ~ ~

MeO

0

HCI,AcOH

0 CI

MeO

MeO

O SMe

,,

Me

SMe

81~

0 SMe

TsOH,acetone

~SMe cI Scheme 4.73

88%

202

WILLIAMW. WOOD Ar

S~

MeZ~S.~

AF

Ar ~.S--..~

LDA

e

LDA

;)

Ar

Ar

Scheme 4.74 conditions, but oxidized dithioacetals [156] and derivatives activated by benzylic [157], allylic [158] or similar groups [159] may be conveniently cleaved by this method (Scheme 4.73). Periodic acid has been used to cleave unactivated dithiolanes in steroid chemistry. Acetal hydrolysis is also possible using Amberlyst15, with paraformaldehyde as an exchange reagent, in a system which appears to be fairly widely applicable [160].

4.5.1.9 Cleavage with base As indicated above, almost all dithioacetal hydrolysis procedures involve activation at sulfur, prior to nucleophilic attack at the dithioacetal carbon atom. An exception to this general mechanism is found for arylalkyl dithiolanes, which may be hydrolysed on treatment with LDA through abstraction of a proton from C-4 of the dithiolane ring (Scheme 4.74) [161]. However, this procedure is limited to arylalkyl (particularly methyl) derivatives.

4.5.2

Synthesesof Dithiins from 1,3-Dithioacetals

There has, over recent years, been a consistent interest in the rearrangement of cyclic-l,3-dithioacetals to dithiins. These reactions may be grouped according to the mechanism of the rearrangement (Scheme 4.75). The first type of mechanism requires the presence of an c~ leaving group, while in the second, activation occurs by prior oxidation of one of the sulfur atoms to the sulfoxide. In the last mechanism, a similar type of activation occurs, but the 'activated' intermediate is not isolated.

TRENDS IN THE CHEMISTRY OF 1,3-DITHIOACETALS

~

Mechanism A: a-leaving group

Mechanism B: sulfoxide

o| I

Xe

,

(S H

HO

H

203

s

S

-H +

(sZR

,.._

R

Mechanism C: sulfur activation R R'

R

S

S

R'

R

e

X

S

Y

-HY s

i

Y

Scheme 4.75

4.5.2.1

Rearrangements involving e~ leaving groups

One of the most recent developments in this area has involved the rearrangement of oL-hydroxydithianes under the influence of Lewis acids (Scheme 4.76) [162]. Examination of a range of Lewis acids led to the identification of trimethylsilyltrifluoromethylsulfonate (TMSOTf) as the most effective activator for the initial elimination. The authors also examined some of the further chemistry of the product 5,6-dihydro-l,4-dithiins. This reaction is, in fact, a variant of an earlier report in which the leaving group was a sulfonate ester (Scheme 4.77) [163]. Similar processes also occur directly in the reaction of e~-bromoketones with ethanedithiol (Scheme 4.78) [164], and can be used to prepare 1,4-oxathiins [165]. When the leaving group is appropriately placed, medium-ring compounds can also be prepared by this type of chemistry (Scheme 4.79) [166].

204

WILLIAM W. WOOD HO S ~

TMSOTf,Et20 molecularsieves

U5 R

R'

R'

Scheme 4.76

A SH

S

,~OTMS Scheme 4.77

E:: Br

0

E:".

Br

I KOBuVDMSO

Scheme 4.78

4.5.2.2 Rearrangementsof dithiolane sulfoxides It has been known for some time that dithiolane sulfoxides undergo a thermal [2,3] sigmatropic shift leading, after loss of one molecule of water, to a 5,6-dihydro-l,4dithiin (Scheme 4.80) [167]. The reaction also occurs under acidic conditions [168]. Both thermal and acid-catalysed reactions have been reported for oxathiolanes and thiazines [169,170].

4.5.2.3 Rearrangementof dithiolanes with halogens The reactions of dithiolanes and dithianes with halogens have been extensively studied, originally with a view to the development of methods for the regeneration of carbonyl compounds from these protecting groups. Indeed, dithiolanes derived from diaryl ketones can be deprotected on reaction with any of the halogens [171]. However, this reaction proceeds in an entirely different direction when the

TRENDS IN THE CHEMISTRY OF 1,3-DITHIOACETALS

~.~,n

oMF,Pr'2EtN

S/--'~n~

"

:;.-1

205

s/-~s

A

Entry

B

n

m

X

Ring size

Product

Ph

1

2

CI

8

(Z)-A

71

Ph

2

2

CI

9

(Z)-A

62

Ph

1

3

Br

9

(Z)-A

72

Ph

2

3

Br

10

A,(E) : (Z) = 6.7:1

98

Ph

1

4

Br

10

(Z)-A

54

Ph

2

4

Br

11

A,(E) :(Z) = 2-4:1

57

Me

1

2

CI

8

(Z)-A

84

R

Me

2

2

CI

9

Yield (%)

B

4

A,B

8O

(E) : (Z) : exo

1:3:6

Scheme 4.79 eO

H .... OM

e

H

O 100o

T

HO

~G~

FI

H20 Scheme 4.80

dithiolane is formed from a ketone containing a primary or secondary alkyl group. In these cases the product is a 5,6-dihydro-l,4-dithiin (Table 4.31) [172]. The mechanisms of the deprotection and rearrangement reactions follow the same initial steps (Scheme 4.81), since the intermediate may react further to regenerate the original ketone, if neither R or R' carry any oL protons. The alternative route, leading to the dithiin, occurs when elimination from the ot carbon atom is possible. Similar reactions also occur on treatment of 1,3-oxathiolanes with chlorine [173,174]. Other chlorinating reagents bring about similar ring expansions. Sulfuryl chloride, acting on the 1,3-dithiolane of cyclohexanone, brings about a

206

WILLIAM W. WOOD

TABLE4.31 Conversion of dithiolanes to dithiins by halogen

~I~R

R'

CHCI3, CCI4, 25-88%

Halogen

R

Me

gr 2 Br2 Br2 Br2 Br2 Br2 Br2 CI2 CI2

S

S

!

Me

n-Pentyl H

Me

But Bu n Ph

Prn Ph H

-CH2CH2CH2-

-CH2CH2CH2CH(Me)-

Ph

-CH(Me)CH2CH(Me)CH2-

X2 ~

~ Xe S. eS--X

H20 (if no a-protons)

HR . ' ~

R'

O R

R'

R..~ H

I

-HX

Scheme 4.81

ring expansion, followed by chlorination of the resulting dithiin, leading eventually to an oL-ketone (Scheme 4.82) [175]. The same reaction can be realized with greater reproducibility using a 1,3-oxathiolane. This oL-ketonation sequence is clearly substrate-dependent, since, in a recent study on a range of 1,3-oxathiolanes, products arising from oL-ketonation were not observed [176]. Thionyl chloride also brings about dithiolane ring expansions to dithiins, and also, more generally, [1,3]phenylthio migrations of 1,3-dithiophenylthioacetals [177].

TRENDSIN THE CHEMISTRYOF 1,3-DITHIOACETALS

207

I S02Ci2

.....~-~ s

c~~ OH2

Scheme 4.82

Se S

0

NaNTMS2 ~

c 2Me

C02Me

U5 O

Scheme 4.83

A variety of other reagents have been used to bring about rearrangement of 1,3dithiolanes to 1,4-dithiins, including phenylselenyl chloride [178,179]. Nchlorocarbamates [180] and titanium tetrachloride [181], all through the intermediacy of the sulfenyl chloride. Recently a ring expansion reaction of

208

WILLIAM W. WOOD

dithianes has been reported to occur through a deprotonation reaction (Scheme 4.g3). This represents a comparatively unusual anionic mechanism for this type of ring expansion [182].

4.5.3

Reduction of 1,3-Dithioacetals to Methylene Groups and

Reductive Alkylation

The reduction of 1,3-dithioacetals to methylene or methyl groups is one of the classical functional group interconversions in synthetic organic chemistry. Although many methods have been developed by which the transformation may be carried out, there is still a need for mild desulfurization methods. Raney nickel has been used for many years for this purpose [183], as has sodium in liquid ammonia, and lithium in ethylamine [184,185]. A Wolff-Kishner reduction may also be carried out using basic hydrazine hydrate [186]. Reduction of benzylic and allylic dithioacetals is particularly facile and has been reviewed recently [187]. There has been considerable interest in complex nickel-containing reducing agents in recent years, including applications to desulfurization generally and of dithioacetals in particular. It has been shown that the reagent produced from nickelocene and lithium aluminum hydride is a reducing agent for sulfur species, including 1,3-dithioacetals, although yields are low and only a limited number of examples were presented (Scheme 4.84) [188]. A similar reagent can be produced from nickel bromide, triphenylphosphine and lithium aluminium hydride (Scheme 4.85) [189]. The complex reducing agents developed by Caubere and co-workers have also been applied to desulfurization of 1,3-dithioacetals with some success. In this case the reduction has been demonstrated on a wider range of examples, illustrating the synthetic utility of the reaction (Table 4.32) [190]. A relatively

NO2

nickelocene,

THF

LAH

L./

40% S Conditions

as above

Scheme4.84

42%

NiBr2"DME'LAHPh3P,r-

Scheme4.85

84%

TRENDS IN THE CHEMISTRYOF 1,3-DITHIOACETALS

209

TABLE4.32 Reduction of dithioacetals with complex nickel reducing agents Entry

I

Substrate

C6H,3~ / , S ~ Me"

"S-==/

X %

2

CsH~ Me

'S..-J

06Hl~

SIEt

Me

SEt

X

~'~1

06HI

Reagent

Solvent

Product

Yield (%)

NiCRA

THF

C8H18

92

C6H13 S"-- v

>99

10"2"I

NiCRA-bpy

4"2"1 "2

DME

M/ N iCRA 521

TH F

C8H18

> 99

NiCRA 5 "2 " 1

THF

C8H18

92

NiCRA

THF

NiCRA

THF

Me" "S~I 5

.

96

/ 6

Nail, tAmONa, and nickel acetate in ratio x : y: z. NiCRA, NiCRA-bpy Nail, AmONa, and nickel acetate and 2,2'-bipyridyl in ratio x : y:z

96

: t.

simple nickel reducing agent, formed from nickel chloride and sodium borohydride, may also be used to reduce dithioacetals [191]. This procedure has been applied to ~,[3-unsaturated ethylene dithioketals (Scheme 4.86) [192], and to other situations (Scheme 4.87) [193], giving high yields of reduced products without the formation of olefins reported earlier and with superior yields when compared with Raney nickel. In related chemistry above, a number of novel functional group interconversions have been developed involving nickel-catalysed reductive cross-coupling of dithioacetals and Grignard reagents. Early work in this area has been reviewed [194,195]. Several nickel catalysts may be used in these reactions (Table 4.33), leading to styrenes, 1,4- and 1,3-dienes, and a range of other products (Scheme 4.88) [196-201]. The variety of chemistry recently reported in this area suggests that the full potential of this type of chemistry has yet to be realized.

4.5.4 The

Conversion of 1,3-Dithioacetals to

gem-Difluorides

gem-difluoride group is a popular isosteric replacement in a variety of

210

WILLIAM W. WOOD

s

=H :: -

H

OAc

NiCI2, NaBH4 DMF

OAc

90% (85%)

7

NiCI2, NaBH4 DMF

85% (80%)

NiCI2, NaBH4 AcO

S

~"

DMF

s

AcO 90% (90%)

NiCI2, NaBH4 r

DMF

90% (80%)

NiCI2, NaBH4 DMF

50% (45%) (Figures in parenthesis= yieldsobtained by reductionwith Raneynickel) Scheme 4.86

biological situations, yet methods for preparing this group are comparatively rare, generally involving reaction of ketones with vigorous reagents such as DAST or selenium tetrafluoride. In a seminal paper, published in 1986, Sondej and Z S ~ s + , ~ ~ , ~S' / ~ S NiC'2"- P h ~ Ph" T "C02Et Ph C02EtNaBH4 OH OH OH

C02Et

+ Ph~CO2E .i IDH

Overall yield: 94% Scheme 4 . 8 7

t

TRENDSIN THECHEMISTRYOF 1,3-DITHIOACETALS

21 1

TABLE4.33 Interconversion of a dithioacetal with various catalysts

<

~

)

MeMg,,catalyst

Entry

Catalyst

mol %

Reactiontime (h)

Yield (%)

1 2 3 4

NiCI2(PPh3)2 NiBr2.DME NiCI2(dppe) NiCI2(dppp)

6 6 4 5

18 16 60 60

70 68 37 51

Katzenellenbogen reported an elegant study on the conversion of 1,3-dithiolanes into gem-difluorides, which demonstrated that the two-step process--carbonyl to dithiolane to gem-difluoride--was reliable, mild and efficient (Table 4.34) [202]. It should be noted, however, that the first report of this conversion was a single example (Scheme 4.89), published in 1976 by Kollonitsch et al. [203] in a paper describing a general cleavage of the C-S bond by elemental fluorine in trifluoromethyl hypofluorite, or liquid hydrogen fluoride with Nchlorosuccinimide. TABLE4.34 Conversion of carbonyls to gem-difluorides ~R'

BF3"2HOAc DBH= 1,3-dibromo-5,5-dimethylhydantoin

Entry

1

Starting material

~

Dithiolane yield (%)

Difluoro yield (%)

97

80

2

N v v v ~

80

86

3

~

70

75

98

7O

95

61

95

65

r162 4

'

~

k,) 5 6

~

x_./ ",,_./

Scheme 4.88

As with many of the other reactions described in this review, it is thought that fluorination of dithioacetals is initiated by activation at sulfur, in this case by the bromonium ion (Scheme 4.90). Fluoride then reacts with the sulfur-stabilized carbocation. 1,3-Dibromo-5,5-dimethyl hydantion, and N-iodo-, N-bromo- and N-

TRENDSIN THE CHEMISTRYOF 1,3-DITHIOACETALS

21 3

CF3OF,HF 50% Scheme 4.89

pBr

- ~S.~,~.~-- Br F|

BrS/~Br F-

Br~s'~ Br~A..~~F

1 F~.F Scheme 4.90

chlorosuccinimide all initiate the reaction with pyridine-hydrogen fluoride in dichloromethane. DBH proved the most effective activator in a 1:1 ratio with the dithiolane. A range of aromatic and aliphatic substrates was converted to gem-difluorides in 60-85% yield. In one instance, bromination of the aromatic ring also occurred, but this could be avoided by replacing DBH with NIS. A variant has been reported which allows the preparation of gem-difluoro compounds from dithiolanes bearing acid-sensitive groups (Table 4.35) [204]. Although this methodology provides a much needed alternative to the conventional methods of fluorination, the conditions under which the reaction is carried out can lead to competing processes due to the generality of the activation step. Thus Jazberenyi and co-workers observed that aromatic dithiolanes derived from arylalkyl ketones cannot be gern-difluorinated because a rapid rearrangement to a 1,4-dithiin (vide supra) is also induced by bromine (Scheme 4.91) [205]. More recently, Motherwell and Wilkinson reported that 4-methyliodobenzene difluoride (prepared as shown in Scheme 4.92) was an effective reagent for converting benzophenone dithioacetals to gem-difluorides (Table 4.36), presumably by activation though a sulfur-iodine bond [206]. Yields for other types of dithioacetals (three examples only) were lower. It has also been reported that anodic gem-difluorination of dithioacetals provides an alternative, safe method for the conversion in the absence of oxidizing agents (Table 4.37)[207].

214

WILLIAMW. WOOD

TABLE4.35

Conversion of dithioacetals to

R/~S~ R2 )n Entry

gem-difluorides

Bu~ " reagent, -78~ to > RT,9 h

Starting Material

n-C3H~,~~

n'C3H7~ n-C4HgO-.~

~

~

n-C4HgO~~

R1 F R~XF Reagent

Yield (%)

DBH

84

DBH

61

NIS

62

DBH

81

NBS

89

DBH

84

NIS

84

NBS

67

NIS

94

NIS

82

Hex

MeO"

10

~

.AyQr -

215

TRENDS IN THE CHEMISTRY OF ] ,3-DITHIOACETALS

TABLE4.35

Conversion of dithioacetals to

gem-difluorides (cont)

Entry

Starting Material

Reagent

Yield (%)

11

~

NIS

82

DBH

81

~

NIS

47

~s.,...~

DBH

74

NBS

72

DBH

90

NBS

86

NBH

82

NIS

92

12

~~~.~~?~

13

C

14 15 16 17

~

~

n-O3H

i~

n-C3H7

.s~.~

~

n-C4HgO

n-C4HgO- ~ ~ s ~

18

19

2O

o

/~

O

NBH, 1,3-dibromo-5,5-dimethylhydantion;NIS, N-iodosuccinimide; NBS, N-bromosuccinimide.

53

216

WILLIAM W. WOOD

MeO,~.S r s.~ ~o Br+w~ source (wi t h or HF/py

L__/

"~BH, HFp /y M e O ~ F " "F

Scheme 4.91

CI~~1/ /CI

F~I/F aq.HF,HgO ~ Scheme 4.92

4.5.5 Conversion of 1,3-Dithioacetals to Compounds Containing one C-S Bond Procedures leading to the cleavage of one of the two C-S bonds in 1,3dithioacetals have been known for some time. Although most of these procedures are reductive in nature, oL-hydroxy dithioacetals undergo partial hydrolysis to give oL-thioketones (Scheme 4.93) without overall reduction [208,209]. Some simple reductive reactions are also well known, involving sodium borohydride, with [210] or without [211] nickel (Scheme 4.94), some under free radical conditions (vide supra). A similar reaction also occurs with sodium telluride [212] or P214 [213] and under electrolytic conditions [214]. Methods by which dithioacetals may be reductively alkylated have been explored concentrating on the use of lithium naphthalenide [215,216]. Although lithium naphthalenide is effective, naphthalene, which is produced as a by-product, can be difficult to remove. As an alternative, more convenient reagent, lithium 1(dimethylamine)naphthalenide (LDMAN) provides the same reactivity as the parent anion, but allows the by-product to be removed by a simple acid wash (Scheme 4.95) [217,218]. The main application of both reagents has been in the preparation of substrates for a subsequent Peterson olefination; electrophiles other than trimethylsilyl chloride may be used. Butyllithium has also been reported to form anions from ketone-derived dithioacetals, which have been allowed to react with a range of electrophiles (Scheme 4.96) [219,220].

TRENDSIN THE CHEMISTRY OF 1 ,3-DITHIOACETALS

21 7

TABLE 4.36 gem-Difluorination of diarylthioketals using 4-methyliodobenzene difluoride Product

Substrate

Yield (%)

TsOH

Scheme 4.93

As may be gauged from the activity in the area, the chemistry of 1,3-dithioacetals remains of considerable interest to organic chemists in many areas of endeavour.

218

WILLIAMW. WOOD

TABLE 4.37 Anodic diflourination of dithioacetals of ketones

O

PhSH ,= 131~3:0Et2 "-

R~R'

Ph~~Ph

'

-2e.._ F Et3N'HF/DME~

F

R

R'

Overall yield (%)

Ph p-CI-Ph p-F-Ph p-F-Ph p-Me-Ph p-MeO-Ph p-MeO-Ph n-Pentyl

Ph p-CI-Ph p-F-Ph Ph p-Me-Ph p-Me-Ph p-MeO-Ph n-Pentyl

44 58 79 70 31 31 30 23 15 20 7 57

-(CH2)11-

Ph p-MeO-Ph p-NO2-Ph

PhS .SPh phs

Ph

H H H

NaBH4, NiCI2

0

PhP j ' ~ P h

71%

O

SMe

N~

SMe

NaBH4

~/~N~N ~SMe

I

I

85% Scheme 4.94

PhS,,~SPh

LDMAN,TMSCI

PhS~!i( 95%

LDMAN, Mel LDMAN = lithium1-(dimethylamino)naphthalenide Scheme 4.95

PhS,~Me 81%

TRENDS IN THE CHEMISTRY OF 1,3-DITHIOACETALS

PhS .SPh

p,.Yx,,

P; Ph

21 9

OH

Bu~ PhCHO

95%

BunLi, Mel

7 phS~ph 97%

Scheme 4.96 However, it is also apparent that methods for the preparation of these compounds are many and varied, as are methods for hydrolysis to the parent carbonyl compounds. Two broad applications of 1,3-dithioacetals may be expected to grow in the coming years: the use of substituted, cyclic dithioacetals in bio-active applications and synthetic methods to these comounds, and the application of new reactions by which 1,3-dithioacetals may be converted directly into other functional groups. In these two areas there is still, clearly, much to be done.

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CHAPTER5

CHEMISTRY OF THIOALDEHYDES Renji Okazaki The University of Tokyo, Tokyo, Japan

Contents 5.1 5.2

Introduction Transient thioaldehydes 5.2.1 Generation by photoreactions 5.2.2 Generation by 1,5-sigmatropy of thiosulfinates and thioseleninates 5.2.3 Generation by 1,2-elimination reactions 5.2.4 Generation by thermolysis 5.2.5 Spectroscopic detection 5.3 Stable t h i o a l d e h y d e s 5.3.1 Synthesis 5.3.2 Physical, structural and spectroscopic properties 5.3.3 Reactions References

225 226 227 229 231 236 240 242 243 244 246 255

5.1 INTRODUCTION Compounds C=C, C=N, and C=O double bonds play a very important role in organic chemistry. By contrast, those having a C=X double bond where X is an element of the third row in the periodical table (i.e. X=Si, P, S, etc.) are highly unstable, and their chemical properties have been studied only recently. The quantitative estimation of the instability of these double bonds has become possible recently using ab initio quantum mechanical calculations, and some pertinent results are shown in Table 5.1 [1-3]. They indicate that the -rr bond energies of H2C=XHn decrease to a great extent (about 30---40 kcal mol -~) when X changes from the second to the third row elements, and furthermore the v bond energies become even smaller when X is an element of the fourth or higher row. For example, the v bond energy of H2C-Se is lower by 11.4 kcal mol -~ compared to HzC=S. For the stabilization of these unstable bonds, two methodologies are conceivable. One is to stabilize the C=X bond by the attachment of an electrondonating or -withdrawing substituent on C and/or X, or complexation with ORGANOSULFURCHEMISTRYCopyright 91995 Academic Press Ltd. ISBN-0-12-543560-6. All rights of reproduction in any form reserved.

226

RENJI OKAZAKI

TABLE5.1

"rr bond energies (Err, kcal mo1-1) of H2C=XHn

H2C=XH n

Schleyer [1 ] Err

Aa

H2C=BH H2C=AIH H2C=CH2 H2C=SiH2

53.7 9.4 69.6 36.1

44.3

H2C=NH H2C=PH H2C=O H2C=S H2C=Se H2C=Te

80.8 49.4 93.4 55.7

31.4

33.5

37.7

Schmidt [2] Err

Aa

65 38 63 43 77 52

27

Nagase [3] E~

Aa

20 25

94.0 56.1 44.7 34.1

37.9 11.4 10.6

aThe difference in Err between nth and (n+l)th row in the same group.

transition metals, which reduces the double bond character. The other is to stabilize the reactive C - X bond by protecting it with sterically bulky groups which prevent oligomerization or reactions with other reagents (e.g. oxygen and water). The former method is stabilization of the ground state and is referred to as 'thermodynamic stabilization', while the latter method is stabilization resulting from the increase of the transition state energy and is referred to as 'kinetic stabilization' (or 'steric protection'). Kinetic stabilization is obviously superior to thermodynamic stabilization since the latter necessarily perturbs the intrinsic nature of the C - X double bonds. For example, the chemistry of thioketones has been studied by taking advantage of kinetic stabilization [4]. Thioaldehydes, however, are very difficult to synthesize because they have a hydrogen atom on the sp 2 carbon which can function neither as an electronically perturbing substituent nor as a sterically demanding group. Therefore, most of the thioaldehydes so far studied are those existing as reactive, transient intermediates, although recently some examples of stable species have been described. In this chapter, thioaldehydes are classified as transient and stable, and their chemistry is described in this order. Thermodynamically stabilized thioaldehydes are outside the scope of this review [5,6].

5.2 TRANSIENTTHIOALDEHYDES Simple thioaldehydes are so reactive and have such short life-times that their reactions are usually carried out with the thioaldehydes generated in situ in the presence of trapping reagents. Most of these reactions are cycloadditions (the Diels-Alder reaction and 1,3-dipolar cycloaddition).

CHEMISTRYOF THIOALDEHYDES

227

5.2.1 Generation by Photoreactions

5.2.1.1 Photoreactions of ~-keto sulfides Vedejs [7] has carried out an extensive study on transient simple thioaldehydes by taking advantage of the Norrish type II photoreaction of [3-keto sulfides (1), known to generate thiocarbonyl compounds. The [3-keto sulfides (1) can be prepared by three reactions types (Equations (1)-(3)), starting from a thiol (RCHzSH), vinyl ketone (CHz=CHCOCH3) or halide (RCH2C1). Et3N

PhCOCH2CI + RCH2SH CH2=CHCOCH3 + PhCOCH2SH

+

PhCOCH2SCH2R (1)

=

PhCOCH2SH

PhCH2CI

=

(1)

(1)

(2)

(1)

(3)

Scheme 5.1 The thioaldehydes (2) generated in the presence of the dienes (3) such as cyclopentadiene, 2,3-dimethyl-l,3-butadiene, piperylene (RI=RZ=CH3), alkoxydienes (RI=H, R2-OMe), and Danishefsky's diene (RI=OMe, R2=OSiMezBut), give the Diels-Alder adducts (4) and (5) in good yields. The regiochemistry of the adducts is determined by the electronic nature of R, the electron-withdrawing (R=CN, COPh, etc.) and electron-donating groups (R=Ph, SiMe3, H, t-Bu, etc.) affording mainly (5) and (4), respectively. The regioselectivity may be explained by molecular orbital considerations, a higher (or equal) LUMO coefficent on the sulfur atom compared with that on the carbon atom of RCHS being favourable for the formation of (5) [7b, 7e, 7f, 8]. The adducts (4) and (5) thus obtained are useful synthetic intermediates and subject to a variety of functional transformations. For example, this methodology 92 RI__//__~ (3) Ph

Ph/~O

H

(2) "2

91

RS.~R (4)

2

R1

(5) Scheme 5.2

228

RENJI OKAZAKI OTBS

SiMe 3

("

OTBS

...r

phr---L,N ~=O

hv CH2SCH2COPh

I

Bz

C-,'/-",S I0

~~,~.-...l......f' ~ OAc OTBS

0 Ph

I

H

(6)

Scheme 5.3 is successfully applied to the total synthesis of cytochalasin (6) [7d]. The thioaldehydes (2) also react with the highly reactive 1,3-dipolar reagent (7) to give the adducts (8) in high yield. Since the reactions of (8) with fluoride ion gives the aldehydes RCHO in good yield, this provides a useful transformation of RCHzSH, RCHzC1 and CH3COCH=CH2 into RCHO [7c]. OTBS RCHS

\

+

~ N

i N

/OTBS

\o

R

(7)

(8)

TBS = SiMe2But

Scheme 5.4

5.2.1.2 Other photoreactions The photoisomerization of thiophene derivatives is reported to proceed via a thioaldehyde intermediate which is trapped as an imine in the presence of a primary amine [9]. hv R

. ~

= R

/H C %S

I

R1NH2 R=H

'R = Ph Ph

Scheme 5.5

~-CH=NR 1

1

CHEMISTRY OF THIOALDEHYDES

229

The irradiation of thietane in the presence of cyclopentadiene affords a Diels-Alder adduct of thioformaldehyde in quantitative yield [7a, 10].

hv

H2C=CH 2 +

H2C=S

Scheme 5.6

5.2.2 Generation by 1,5-Sigmatropy of Thiosulfinates and Thioseleninates Baldwin et al. [11] developed an efficient method for the generation of thioldehydes by taking advantage of the thermal decomposition of thiosulfinates discovered by Block et al. [12]. Thus, the thermolysis of (9) in the presence of anthracene affords the Diels-Alder adduct (10) almost quantitatively. Since the sulfenic acid (11) generated undergoes condensation to give the starting thiosulfinate again, the thiosulfinate is eventually transformed into two molecules of thiobenzaldehyde. Thiobenzaldehyde thus generated also reacts with 2,3dimethyl-l,3-butadiene and 9,10-dimethylanthracene. Thioacetaldehyde can also be generated from EtSS(O)Et by this method. Interestingly, the adduct (10) can behave as an efficient precursor of thiobenzaldehyde. Thus, in the presence of 2,3dimethyl-l,3-butadiene, the thermolysis of (10) gives a Diels-Alder adduct.

'

S ~ ~ ' ~ H Ph

Ph ~

PhCH3

H

100 "C, 1 h

I

PhCH2SOH

+

PhCHS

(11)

(9) anthracene 97%

10) Ph

(10)

+

~ //

98-99 ~

\,,

1h

PhCH 3

"-<'-s II

I

Ph

Scheme 5.7 Thioaldehydes generated by this method can also undergo intramolecular cycloaddition and ene reaction.

230

RENJIOKAZAKI ~

S" S

~

40%

/

PhCH3

H + H

H H

1

"

1 Ph H

[ ~ PhCHS +

~Ph

95-99~ 2h PhCH3 37%

19%

Scheme 5.8

In their study on selenenic acids, Reich et al. [13] found that a thioseleninate can also be a good precursor of thioaldehyde. While the reaction of the selenenic amide (12) with 2-methyl-2-propanethiol gives the thioseleninate (13a), the reaction with oL-toluenethiol does not afford (13b) but, in the presence of cyclopentadiene, gives the adduct (14) in high yield, suggesting that (13b) is O

ButSH

O

~>~NHMe ~-Se--S~Bu t O

PhCH2SH

(12) \ o

~ (13a)

N ~ ~.,... Me S

(13b)

0

~Se

NHMe OH

+

PhCHS

O

O ~ S

N-Me

(14) Ph Scheme 5.9

.~ Ph

CHEMISTRY OF THIOALDEHYDES

231

generated but undergoes a fast 1,5-sigmatropic rearrangement leading to the formation of thiobenzaldehydes indicating the weakness of the S--Se bond. The fast sigmatropy of (13b) at room temperature is in sharp contrast to the reaction of (13a), which requires 100~

5.2.3 Generation by 1,2-Elimination Reactions There are several known routes to thioaldehydes by 1,2-elimination reactions or their variants. M I R--C--S--L I H

R ---

\

H

/

C--S

M = H, SIR3; L = CI, NR2, S(O)nR

Scheme 5.10

Kirby reported that the thioaldehyde (17), generated by the reaction of the sulfenyl chloride (16), prepared by chlorination of the thiol (15) with NCS, with

ECH2SH

NCS

= ECH2SCI

(15)

NEt3

(16)

= [E-CHS] (17)

~ l i t ~ E = CO2Et (18)

E

%,..

(20) MeO

MeO

/ . ~

E'"I

H

~

N

* Me

(17)

MeO

(21) (19)

i

H

E R (22) R - H (23) R -- Me R

S

Scheme 5.11

232

RENJI OKAZAKI

triethylamine, was trapped by 2,3-dimethyl-l,3-butadiene to give the Diels-Alder adduct (18) [14]. The reaction in the presence of thebaine (19) afforded the adduct (20) in a 67% yield, but refluxing of a toluene solution of (20) gave the isomer (21). This indicates that (20) and (21) are kinetic and thermodynamic products, respectively, and there is an equilibrium between (17)/(19) and (20)/(21). The thioaldehyde (17) also reacts with anthracene and 9,10-dimethylanthracene to give (22) and (23), respectively, and the reaction of (22) and (23) with (19) in refluxing toluene gave (21) in good yield, indicating that (22) and (23) are good precursors of (17). The reaction of (22) with [3-pinene gives (24) and (25), which are ene reaction products of the thioaldehyde (17). SH (17)

=

v I

110~C, 4h E = CO2Et

(24) 73%

(25) 21%

Scheme 5.12

An imide group can also be a leaving group in this 1,2-elimination reaction. Thus, the reaction of the sulfenamide (26) with triethylamine gives (18) in the presence of 2,3-dimethyl-l,3-butadiene [15].

O

NEt3 - - - - - - - - ~ (17) RT

ECH2S-N~ O

Z

(18) 78%

(26)

Scheme 5.13

1,2-Elimination of the Bunte salt (2"/) and the related thiosulfinate (28) also affords thioaldehydes which can be trapped by cyclopentadiene to give (29) and (30) [16]. These reactions are superior to those using (16) and (26) in that the PhNHCO, PhCO, NC and 4-NOzC6H4groups can also be used as the group R. Calcium chloride is used as the trapping agent for the hyposulfate ion and sulfinic acid in these reactions. Since Kirby's method is based on 1,2-elimination by a base, the group R in the thioaldehyde RCHS must be electron-withdrawing. Kraft [17] reported a useful method for 1,2-elimination giving thioaldehydes which overcomes this drawback. Kraft's method is based on fluoride-promoted elimination of trimethylsilyl and thiolate groups, which proceeds under mild conditions. In the reaction with cyclopentadiene as a trap, the endo products (29) are always the major ones. Since

CHEMISTRY OF THIOALDEHYDES

RCH2SY

233

RCHS

CaCI2"2H20

+

H

R

R

(27) Y = SO3Na (28) Y = SO2Tol

H

(29)

(30)

Scheme 5.1 4

the precursors (31) are prepared by either Equation (4) or (5) using lithium reagents, the group R in (31) cannot contain a moiety which reacts with lithium reagents. In this respect, Kraft's and Kirby's methods are complementary. SiMe3 .~

(i) BuLi Ar'~SH

R~

0

(ii)TMSCI

SH (ii)ArSCI

Ar'

SiMe2P h /~ (i) MeLi H =- R SAc ~ (ii) TsCI (iii) KSAc (ii)ArSCI

CsF-THF, RT

\ S - - S A r or Bu4NF-THF, 0~

S--SAr

(4)

SiMe2P h R~ S -- SAr

(i) PhMe2SiLi

SiMe2R' R/

Ar'

SiMe 3

(i) Nail

(5)

S

R.~'~H

+

ArS

_

(31),

R = H, Me, Et, Pr n, Pr i 58-94%

(29)

+ (30)

Ph, PhCH2, c-hexyl R ' = Me or Ph

Ar - 4-CICsH4 or 2-NO2CsH4

Scheme 5.15

Segi found that the reaction of aldehydes with bis(trimethylsilyl) sulfide in the presence of a catalytic amount of butyllithium directly gives thioaldehydes which

RCHO

+ (Me3Si)2S

cat. BuLi

RCHS

~

(29) + (30)

R = Ph, 2-thienyl, Pr i, Bu t

+ (Me3Si)2S

R

BuLi

~-

R

(32)

H

R

(33) Scheme 5.1 6

234

RENJI OKAZAKI

are trapped by dienes [18a]. The thioaldehydes were considered to be formed by 1,2-elimination of Me3SiOLi from an intermediary lithium compound (RCH(SSiMe3)(OLi)). Aldehydes containing a diene moiety (32) can undergo an intramolecular Diels-Alder reaction to give the bicyclic thiane derivatives (33)

[18bl.

A similar reaction using COC12-6H20 as a catalyst also affords a thioaldehyde, which is trapped by 2,3-dimethyl-l,3-butadiene [19].

COCI2.6H20

RCHO

~

RCHS

(Me3Si)2S

R

Scheme 5.17

A similar reaction using hydrogen sulfide as a sulfurization reagent has been reported, but an intermediary thioaldehyde cannot be trapped in this reaction because of basic reaction conditions which transform the thioaldehyde into an enthiolate [20]. H2S, Me3SiCI

RR'CHCHO

:B

..'c.c.s

- - -

Nail

RR'CHCH(SH)OSiMe3

CsHsN R

H

R'

S

R"X

DMF

R

H

R'

SR"-

Scheme 5.18

Generation of thioaldehydes from some ylids can also be regarded as a 1,2elimination reaction. Treatment of the sulfonium salts (34) with a base (e.g. prizEtN, PrizNLi (LDA), Nail) gives thioaldehydes which are trapped by 1,3-dipolar reagents such as nitrile

.B

R

"

~

--S "c /

H Me

(34)

',~

R' SMe

Me

MesCNO

R

'~C=S / H

R +

.

s

"o..N

R -" Me, But, Ph, CH~---CH2 Ph

"Ph o.~N..

Ph

Scheme 5.19

Mes = 2,4,6-Me3C6H2

CHEMISTRYOF THIOALDEHYDES S

Ph3P=CHR (35)

+ PhCH/ ~CH2 or (35)

S8

235

PhCH3 or Phil reflux

RCH=CHR R

R

"C=S / H j R,2NH

R-C-NR'2 II S (36)

Ph

R = COOMe, COOEt, COMe, CN, Ph

~S~n

S

H

H NR'2 (37) R' = CH2Ph

(38) n=2

(39)

n =3

Scheme 5.20

oxide and nitrone [21]. Okuma found that the reaction of the stable ylids (35) with episulfide or sulphur gives olefins via thioaldehydes. In the presence of dienes, Diels-Alder cycloadducts are obtained [22]. Cyclic polysulfides such as 5H-1,2,3,4-benzotetrathiepin (38) and 6H-1,2,3,4,5-benzopentathiocin (39) can also be used as the source of sulfur in these reactions [23]. The reaction of the phosphorus ylides (35) with sulfur in the presence of a secondary amine affords the thioamides (36), the formation of which was explained in terms of the reaction of an intermediary thioaldehyde with the amine. When the thioaldehyde has oLhydrogen(s), the product is an enamine (37) instead of a thioamide [24].

RNH%. .~S--~-2

RNH, HSvH ~ .... i

o__NHR, HO

a ...... N.I"'HR, (40) dithiothreitol

RN~~H ..... CHS NHR'

OH

s.

_.--"7" NaBD4

RNH%.H _ _ L/HD ....1

O~---NHR' (41)

Scheme 5.21

;'-CO2H

236

RENJI OKAZAKI

Reductive cleavage of (40) with dithiothreitol gives intermediate thioaldehyde, as evidenced by the formation of the deuteriated thiol (41) in the reduction with NaBD4 [25].

5.2.4 Generation by Thermolysis Heating a solution of the monosubstituted trithianes (42) gives a mixture of parent and di- and trisubstituted trithianes. This transformation is explained by the dissociation of (42) into the thioaldehydes (43) and (44) followed by their recombination [26].

R

s-~s LsJ

[ .c.s (43)

(42)

§ 2.2c-s ] (44) R

SAS

LsJ

s.J-..s Ls.J

R

s.~.s

Scheme 5.22 Thermolysis of the vinylic sulfide (45) induces a retroene reaction to afford thioacetaldehyde, which is isolated as its trimer [27].

s.J] (45)

Scheme 5.23 Thermolysis of the [3-1actam (46), giving (47), proceeds via the thioaldehydes (48), which undergo intramolecular cyclization as their enethiols (49). The presence of (48) is evidenced by the formation of the thiols (50) in the reaction in the presence of NaBH3CN [28]. The transformation of (51) to (53) is also explicable in terms of an erie reaction of an intermediary thioaldehyde (52) [29]. Flash vaccum pyrolysis of 1,4-oxathiins (54) gives the c~-keto thioaldehydes (55), which undergo elimination of carbon monoxide at higher temperatures to give thioaldehyde [30].

CHEMISTRY OF THIOALDEHYDES

237

.OPh

OPh

= 1~//H //~

u

N\/~

I

H/~..,,,R ' "

(46)

(47)

OPh

OPh O

HN\

HN"\

2S

/

l

J NHR ""

-_.-

O

O|J

HN%..--"

SH

o;

NHR

SH

H" '" R'

(50)

(49)

(48)

/

Scheme 5.24 Ft

_SH

H" .........

H

H CO2CH3

A

CO2CH3

(52)

(51) Ft

H

H,""~'"'SH

O...~ N ~ C O 2 C H

3

(53)

Scheme 5.25

Recently, the very unstable, dark-pink trifluorothioacetaldehyde (57) has been prepared by flash vacuum pyrolysis of (56). Even in the solid state at -196~ (57) decomposes to a polymer [31]. Diallyl sulfide (58) undergoes thermal retroene decomposition in solution, giving thioacrolein (59), which can be trapped with dienophiles. Interestingly, diallyl sulfoxide (60) also gives (59) under milder conditions [32]. The reaction mechanism for the formation of (59) from (60) is proposed to proceed via the thiolsulfinate (61) (see Section 5.2.2) [33]. As indicated above, the reactions of thioaldehydes with dienes are often reversible, and some adducts, especially those with anthracene and cyclopentadiene, can be good precursors of thioaldehydes.

238

RENJIOKAZAKi S

750-850~

H

S

900-1000~

RCH=S

(55)

(54)

Scheme 5.26 750~

CF3

CF3CH--S .....

H "S.-A

(57)

02

(56)

Scheme 5.27

CH2= CHE

200~ C,... ~ . , . . . ~ S

Hc/j

E = CO2Et

H

(58)

(59)

~'~~ O

lO3"C" ~-.~s. s/-,..~ 0

(6o)

(61)

Scheme 5.28

The adducts (22) and (23) obtained by Kirby's method each give a cycloadduct with an added diene when heated (100-110~ in toluene [12, 14]. Adducts with cyclopentadiene are also converted into cycloadducts upon heating with an external diene [16]. The thermal reaction of the anthracene adduct (22) with the tetrazine (62) gives the pyrazole (63) via the cycloadduct (64) with thiobenzaldehyde. This constitutes (22) +

(~

E

79%-

R

[~CO2E

PhCH3

E = CO2Et

E R = Me; 82% R = P h; 48%

Z ~ A r + Ar = 4-NO2CsH4

t

80~C, 48 h

~ ' ~

06H6

Ar 78%

Scheme 5.29

CHEMISTRY OF THIOALDEHYDES

239

N

N ~1... N (22)

I

+

N

II

~

N~.T/N Z

N- ~

(62)

Z

-N 2

~.~H Ph

N S I ~ N Ph Z

~

(64)

Z ~N NI

H S

-S Ph

~

Z

N

Z = CF 3

Ph

Z

Z

(63)

Scheme 5.30

a new synthetic route to a pyrazole skeleton [34]. The bicyclic sulfur heterocycle (66), which is obtained from the enamine (65) and sulfur dichloride, is a good precursor of a thioaldehyde, giving a cycloadduct with 2,3-dimethyl-l,3-butadiene [35]. CcI3 2

ci3c

~ H2N

E

+

SCI 2

PhCl

=

RT

.~..N ~ CI3C

O

(65)

+

H

Z

(66)

PhCI, 80 ~C

O

~

33%

~

II

/

E

(66) 40%

E = CO2Et

Scheme 5.31

Thioaldehydes generated by the retro Diels-Alder reaction are also used for the reaction with azadienes and 1,3-dipolar reagents as well as for intramolecular ene reactions. The reactions of the 5-alkoxyoxazole (67) with thioaldehydes generated from cyclopentadiene adducts gives the 3-thiazoline (68) [36]. The pyrazolidinium ylid (69) reacts with thioaldehydes to give the 1,3-dipolar cycloadduct (70) [37]. Thermolyses of the cyclopentadiene adduct (71) and the anthracene adduct (73) afford the intramolecular ene reaction products (72) and (74), respectively [38]. Ph

~N_.~

(67)

BOCN

OMe Me

I. O

A

+ R

+

S Ph

CO2Me (66)

-~ BOCN CO2R

(69)

Me

/ O

CO2R (70)

Scheme 5.32

S

240

RENJI OKAZAKI

(71)

(72)

o

O

H

O

H

2

R = CH2CH=C(CH3) 2 (73)

(74)

Scheme 5.33 The 1,3-dipolar cycloadduct (75) also undergoes cycloreversion to regenerate a thioaldehyde [21].

? - V P. Xo~N'ph

~ =

(TS)

I ~

39~176

Scheme 5.34

5.2.5 Spectroscopic Detection In addition to chemical trapping as mentioned above, some transient thioaldehydes can be detected by spectroscopic methods. The detection of thioformaldehyde by electronic spectroscopy in the products of the flash photolysis of dimethyl disulfide was probably the first spectroscopic observation of the thioaldehyde [39]. The structure of the thioformaldehyde generated by the thermolysis of dimethyl disulfide or 1,3,5-trithiane was determined by microwave spectroscopy. From the change in the intensity of the microwave spectra, the half-life of thioformaldehyde was found to be 5-6 min, even under a reduced pressure of 10 -2 mmHg [40]. H

\\1.096 2(6) A

7 ~ C ,-~;-ff~A ..................... S ,,o.,6(6)o(%~ H

Scheme 5.35 Since the discovery of thioformaldehyde in interstellar space [41], extensive

CHEMISTRYOF THIOALDEHYDES

241

studies on the various spectra of thioaldehydes have been reported [42]. The infrared (IR), electronic and photoelectron spectra will be described here. The C=S stretching vibration of thioformaldehyde was assigned to an absorption at 1063 cm -1 on the basis of an IR study on a species generated in a matrix at 14 K [43]. Thioacetoaldehyde (76) can be prepared by matrix photolysis of ethanesulfenyl chloride (77) or thiirane (78), or by flash vacuum pyrolysis (FVP) of allyl ethyl sulfide (79), and its formation detected by IR spectroscopy [44]. CH3CH2SCi (77) 36h6"~nn m~. Me-C (76)

/\

//

S

A R = CH3

-CH2 S/',-._J"CH ;~ -CH3CH=CH2R H (~H2

xH

CH2--CH 2

"

H

(79)

R = Me

(80) R = CH=CH2 (81) R=Ph

(78)

Scheme 5.36

FVP of the allyl sulfides (80) and (81) has also been used for the measurement of the electronic spectra of thioacrolein (59) and thiobenzaldehyde, respectively, their n-~r* absorptions in matrices at 77 K occurring at 580 and 575 nm, respectively. The IR spectra indicate that thiobenzaldehyde is stable at 77 K but gradually decomposes above 110 K, while (59) decomposes slowly even at 77 K [45]. Mass spectroscopy has also been used for the detection of thioaldehydes. FVP or the vacuum gas-solid reaction (VGSR) of the thiols (82) and (83) and the sulfenyl chloride (84) gave thioformaldehyde, (76) and thioformyl cyanide (85), respectively, each detected by mass spectroscopy [46].

HSCH2CN

FVP

~

(82)

HSCH(Me)CN (83) HSCH2CN

H \ / C--S + HCN H

FVP Me-;c_. s ~. VGSR H (K2CO3 or CaO) (76) NCS

CISCH2CN (84)

HCN

VGSR

NC\

K2CO3

H

/C=S (85)

Scheme 5.37

Another important spectroscopic method for the detection of thioaldehydes is

RENJIOKAZAKI

242

photoelectron spectroscopy. Thioformaldehyde, (76), (59), thiobenzaldehyde, (85) and thioxoethanal (86) can be detected by this method. Thioformyl cyanide (85) was generated by FVP of allyl cyanomethyl sulfide (retroene reaction) and of the Diels-Alder adduct with cyclopentadiene, while (86) was generated by FVP of 2,3dihydro-l,4-oxathiin (87) [47].

O

H

(87)

O

(86)

Scheme 5.38 Thioformaldehyde can be produced from a large variety of acyclic and cyclic sulfur compounds [48]. H3CSCI,H3CSCN,H3CSCH2CH---CH:,,(CH3S)2 S--S

S

NC

S

S O

Scheme 5.39

5.3 STABLE THIOALDEHYDES Compounds having a thioformyl group are usually highly unstable and reactive. The thioamide (88), the thioesters (89) and (90), and their vinylogous and analogues (91) are, however, known to exist as isolable, stable species as a result of the mesomeric effect, which decreases the double bond nature of the C-S bond and hence the instability of the molecule. Heterocyclic thioaldehydes of this type, such as (92) [49] and (93) [50], were synthesized as early as the 1960s, and many examples are now known [4-6]. Aliphatic and aromatic thioaldehydes without such mesomeric stabilization had, however, been considered not to exist as stable species until the first examples of a stable aromatic (94) [51] and a aliphatic thioaldehyde (95) [52] were reported in 1982 and 1983, respectively. The thioaldehyde (95) is stable only in solution, but when the t-butyl group on the thioformyl carbon is changed into a bulkier tris(trimethylsilyl)methyl group, the thioaldehyde (96) is obtained as stable pink crystals [53]. The use of bulky substituents also enables the isolation of the stable thioaldehydes (97) [54] and (98) [55]. In this section, the synthesis, structure and reactivity of these stable thioaldehydes are described.

CHEMISTRYOF THIOALDEHYDES

243

H

H

(88) X = NR2

../ X

// C--S" X%

(89)

X=OR

(90)

X = SR

\

\

C--J-S

H\

H

XC--(C__.C)n--X

#

/

C=C-(C:C)r,_I--C=X +

S"

(91) Me02C

Me Et

Me

~/~'~ O

CHS

MeO2C(CH2)2C

CHS (93)

(92)

Scheme 5.40 H"c//S

CH3 '

"

H

CH3 (9S)

(94) R

"CH--

R/

\H

(97) (a) R,R=Bu t

H S H \ c ~ H ,.,.. Me3Si~~lMe3 Me3Si [ ~ "SiMe 3

[.....SiMe3 (98a)

SiMe3 H

I

/

,%

Me3Si--C--

SiMe 3 (96)

H,, .,~S Me3SL C >" H Me3Si~SiMe3 H/ I ~ . ~ 'SiMe3 ,,SiMe3 (98b)

(b) R , R = ~

Scheme 5.41 5.3.1 Synthesis

The first stable thioaldehyde (94) could be synthesized by either path A or path B, as shown in Scheme 5.42 [51]. The aliphatic thioaldehyde (96) was synthesized by reactions similar to those of path A in Scheme 5.42 [53], while (95) was prepared by the thermolysis of the polymer (100), obtained in turn from the photolysis of the [3-keto sulfide (99) (see section 5.2.1.1) [52]. Aliphatic thioaldehydes (97a,b) having an oLhydrogen may be synthesized by the reaction of the thioketenes (101) with a 'Cp2Zr' equivalent, prepared from Cp2ZrC12 and n-butyllithium, followed by acidolysis [54]. It is noteworthy that

244

RENJI OKAZAKI S ArBr

BuLi

II

H - C - O E t , 56%

_- ArLi

path A

O II

ArCHO

NH2NH2

(94)

Im = - N / ' ~ ~N

S2CI2/NEt3, 40% or Im2S2, 60%

path B

H-C-OEt

ArCHS

ARCH= NNH=

Scheme 5.42 TSiH

MeLi

~ TSiLi

PhCOCH2SCH2Bu t

HC(~--~--S)OEt 43%

hv

50%

(96) [ ButCHS]n

+

PhCOCH 3

(100)

(99) > 250~

TSi = (Me3Si)3C

TSiCHS

ButCHS

(95)

Scheme 5.43 there is no tautomeric interconversion between (97) and the corresponding enethiols (102) in view of the well-established pronounced tendency of enethiolization of a thiocarbonyl compound with an ~ hydrogen [4].

R"C=C=S R/

(101)

(i) CP2ZrCI2/BuLi (ii),2 equiv. HCI

R ,.//S R--C--,., I \H H

(97)

+

R\ /SH /C=C\ R H

(102)

Scheme 5.44 The synthesis of (98) is based on a novel approach to a thiocarbonyl compound, that is, desulfurization of the cyclic polysulfides (103) [56] and (104) by triphenylphosphine [55]. Interestingly, the two stable rotational isomers (98a) and (98b) were isolated, the structures of which were established by X ray crystallographic analysis (vide infra) [55].

5.3.2 Physical, Structural and Spectroscopic Properties Aliphatic thioaldehydes are usually pink, and may be crystalline, (96), or oils, (97a,b), at room temperature, while aromatic thioaldehydes are purple, (94), dark blue, (98a), or green, (98b), and crystalline. All these compounds are stable to air at ambient temperature.

CHEMISTRY OF THIOALDEHYDES

TbCH=N 2

Tb

58 A,

29%

\ / C H/\

245

S--. S

S/

\S i S S\ S~s /

3 equiv. Ph3P

Tb

64%

H

S--S S--S

\ /

S

(104)

(103~

(103)

\/ C /\

7 equiv. Ph3P Path A

Tbs \ /

4 equiv. Ph3P (104) Path B

Path A: Path B:

Tba C=S

+

H

\

/ C--S

(98a)

(98b)

72% 65%

17% 17%

R

Tb s =

Tb a =

:

R=SiMe 3

Scheme 5.45

The structures of the aromatic thioaldehydes (94) [57], (98a) [55], and (98b) [55] have been established by X ray crystallography, and their ORTEP drawings are shown in Figures 5.1-5.3. The C=S bond lengths are 1.598, 1.586 and 1.602 A in (94) (98a) and (98b), respectively, which are a little shorter than those for thiobenzophenone derivatives [58]. The thioformyl group of (94) is almost perpendicular (89.1 ~ to the aromatic ring due to the steric repulsion by the two o-t-butyl groups, while the dihedral angles between the thioformyl plane and the aromatic ring in (98a) and (98b) are 48.69 ~ and 10.64 ~, respectively, suggesting less congestion around the thioformyl group in (98) than in (94). The dipole moment of (94) suggests that its formyl group is also perpendicular to the benzene ring in solution [59]. Difference NOE 1H nuclear magnetic resonance (NMR) spectra suggest that the structures of (98a) and (98b) in solution are also similar to those in the crystalline state [55]. The spectroscopic data (1H/13C NMR, UV/visible, IR) for (94)-(98) are summarized in Table 2. The resonance of the thioformyl proton appearing at low field (g=11.5-13.0) indicates a higher anisotropy of the thioformyl group than the formyl group, whose proton resonates usually around g=9-10. The visible absorptions ( n ~ r * ) of aromatic thioaldehydes appear at longer wavelength than those of aliphatic ones, as is observed for thioketones. Among the aromatic thioaldehydes, the absorption maximum for (98b) appears at the longest wavelength, while that for (94) appears at the shortest wavelength. This is in keeping with the change in the angle between the thioformyl group and the aromatic ring observed by crystallographic analysis. Since (98b) has the smallest angle, the maximum conjugative interaction between the C=S bond and the aromatic ring is possible and hence the longest absorption can be expected.

Figure 5.1 ORTEP drawing of thioaldehyde (94) A

Figure 5.3 ORTEP drawing of thioaldehyde (98b)

TABLE 5.2

Spectral data of the stable thioaldehydes (94)-(98)

-

RCHS

--

-

' H NMR/(G) H-C

=S)

--

I

hexane. bln acetonitrile.
-

VIS/(nm) (n+n*)

IR/(cm '1 (C=S)

RENJIOKAZAKI

248

/4"1

Me3Si\

Me3Si/C=C \ SSiMe3=

(96)

hv

(105) +

Me3Si\ /H /C=C\ MesSi SiMe3 (106) 33%

66%

(105)

Scheme 5.46

(94)

A- 200~C, 14 h, Cells, 97%

AorB

B" Hg lamp, CsH6,91% (107)

Scheme 5.47

5.3.3 Reactions

5.3.3.1 Thermal and photochemical reactions The thioaldehyde (95) is stable only in a dilute solution (chloroform or benzene), the pink color of (95) surviving for 16-20 h at 20~ However, concentration of the solution results in polymerization [52]. Although (96) is stable at room temperature, it undergoes a thia-Brook-type rearrangement to give (105) quantitatively upon heating in toluene, with a half-life of 16 h at 70~ The photolysis of (96) also affords (105), along with (106) [53]. The thioaldehyde (94) is very stable. It can be stored at room temperature for a long time (several years) without any appreciable change. It is stable even after refluxing in degassed benzene for a long period in the absence of oxygen, but undergoes an interesting cyclization upon heating at about 200~ to give a quantative yield of (107) [60]. This cyclization most likely proceeds through a radical mechanism in view of the facile cyclization to the same benzothiane (107) in the reaction with radicals (vide infra). The photolysis of (94) also gives (107). The thioaldehyde (98) undergoes reversible thermal isomerization between (98a) and (98b), (98a) being more stable than (98b) with AH ~ = 0.27 kcal mol -~ and AS ~ = -1.77 cal tool -~ K - [55].

5.3.3.2 Cycloaddition reactions 2,2-Dimethylpropanethial (95) undergoes cycloadditions with dienes and 1,3dipolar reagents as do the transient thioaldehydes described in section 5.2.1 [52].

Bu,

O--N O~oMe H§

_ ~ R = p-MeOC6H4 (95) O" I+

MeCH=N-OTBS

But

S O--N

ButZ

...S/

Scheme 5.48

R OTBS

CHEMISTRY OF THIOALDEHYDES

249

The reaction of (95) with diphenylketene gives the 2:1 adduct (108) [52]. O Bu'CHS

+

Ph2C=C=O

,, Bu t

(95)

(108)

Scheme 5.49

Even the very sterically congested thioaldehyde (94) can react with 2,3dimethyl-l,3-butadiene, to give the cycloadduct (10) along with the thermolysis product (107) [61].

ArCHS

160~

(94)

+

Ar

(107) 35%

(109) 26%

Scheme 5.50

The thioaldehyde (94) also undergoes 1,3-dipolar cycloaddition diphenylnitrileimine to afford the [2+3] cycloadduct (110) [61].

with

Ph

ArCHS

+

PhCCI--NNHPh

S-~-~N

NEt 3

(94)

Ar'

N.,

Ph

(110) 34%

Scheme 5.51

Interestingly, however, the reaction with mesitonitrile oxide gives the aldehyde (111) and mesityl isothiocyanate instead of the expected cycloadduct (112), suggesting a lack of stability of the intermediary oxathiazoline (112), probably due to the steric repulsion between the two bulky aryl substituents in (112) [61]. Huisgen has reported a similar cycloreversion of oxathiazolines [62]. Mes

RT

ArCHS

(94)

+

MesCNO

THF

S

Ar

.~

N

~_(~

~

ArCHO

+

(111) 79%

MesNCS 76~

(112)

Scheme 5.52

The photochemical reaction of (94) with allenes gives the thietanes (113) in high yields [63].

250

RENJI OKAZAKI

ArCHS (94)

+

H H )C=C=C~ H X

/7~

=

X = OMe, SMe, Ph, etc.

A••

H C=C" "H

"~

X"

H

(113)

Scheme 5.53

Thioketones are known to react with diazo compounds, usually to afford thiadiazolines by 1,3-dipolar cycloaddition. The reaction of 2,2-dimethylpropanethial (95) with ethyl diazoacetate gives the 1,3-dithiolane (114) and the thiol (115) [52]. The formation of these products is explained in terms of the intermediacy of the 1,3-dipolar cycloadducts (116) and (117), respectively.

ButCHS

N2CHCO2Et

Bu~S,,~CO2E~

(95)

N--N

s/N'~N

But~O2Et (117)

(116) ~(95)

S-~ Bu t

C02Et

But-C=CH--CO2Et ,

SH

S Bu t

(114)

(115)

Scheme 5.54

The reaction of the stable thiobenzaldehyde (94) with dialkyl or diaryldiazo compounds, however, leads to the formation of the episulfide (118) and the benzothiane (107) [64]. The reaction proceeds more readily in the presence of a CuC1 catalyst to give only (118).

ArCHS

+

R2CN2 ~

S / \ CR2 ARCH-

(94)

+ (107)

(118)

Scheme 5.55

The formation of (107) in this reaction is best interpreted in terms of a catalytic cyclization of the anion radical (119) induced by single-electron transfer from the diazo compounds as shown in Scheme 5.56.

CHEMISTRY OF THIOALDEHYDES

ArCHS

+

R2CN2

~

(ArCHS);

(94)

+

251

(F~CN2)+

(119)

ArCHS

(107)

(119)

Scheme 5.56

The reaction with diazomethane gives more complex products with the 2:1 adduct (120) being the major product [65].

Ar,,,. ArCHS

+ CH2N2

(94)

RT THF

S

S + ARCH/ \CH2

LS~

Ar

+ Ar_C// \

S

Me

(120) 38% CH 2 +

II

SMe

I

Ar-C--S--C--Ar

I

+

H

Ar--C

//CH2

+

\SMe

ArCH=CH2

Scheme 5.57

5.3.3.3 Reactions with nucleophiles Since thiocarbonyl compounds have both relatively high HOMO and low LUMO energy levels, they have high reactivities towards both nucleophiles and electrophiles. The thioaldehydes (94) react with the amino compounds RNH2 (R=H, Bu n, NH2, OH) to give the corresponding imines under much milder conditions than the corresponding aldehyde (111) [61]. For example, the reaction of (94) with hydrazine is complete within 10 min at 0~ while that of (111) demands heating at 180~ for 4 days in ethylene glycol even in the presence of an acid catalyst, suggesting extremely high reactivity of the thioformyl functionality. ArCHS

RNH 2

ArCH=NR

n

R = H, Bu, NH2, OH

(94)

Scheme 5.58

In connection with the reactions of amines, it is interesting that the reaction of (94) with a catalytic amount of triphenylphosphine gives the benzothiane (107) [61]. This reaction is also considered to proceed by a catalytic radical mechanism

252

RENJI OKAZAK!

involving single-electron transfer from the phosphine, as shown in Scheme 5.56 for the reaction with diazo compounds. Thioketones are known to react with organometallic compounds such as organolithium and Grignard reagents, giving rise to both carbophilic and thiophilic products. The thioaldehyde (95) behaves similarly; the reaction with phenyllithium gives a thiophilic product, whereas that with butyllithium affords both carbophilic and reduction products [52]. ButCH2SP h

PhLi

(95)

(i) BuLi (ii) Mel ~

ButCH(SMe)Bu

30%

+

ButCH2SMe

70%

17%

Scheme 5.59

Interestingly, the main product of the reaction with (96) is olefin (106), which contains no sulfur. In the reaction with t-butyllithium, thiophilic and reduction products are also formed. The formation of (106) can be explained in terms of a mechanism involving a thiophilic attack giving (121), followed by rearrangement to (122) [53]. MeLi

Me3Si \ /H /C=C x Me3Si SiMe 3

,.

95% (96)

(106)

BuLit

+ (MeSi)3CCH2SBu t +

(106) 34%

(MeSi)3CCH2SH

10%

25%

Scheme 5.60 (96) , RLi ~

H (Me3Si)3C_(~_S R

c--~=

.

H (Me3Si)2(~_(~-SR I

(121)

(122)

~

(106)

SiMe 3

Scheme 5.61 The aromatic thioaldehyde (94) reacts in a more complex manner, giving five types of products depending on the conditions [65]. The formation of all these products can be explained through the intermediacy of the anion radical (119). The formation of the dithiol (123) is especially interesting since it is produced by dimerization of (119), which represents the first example of dimerization of thioketyl radicals. (94)

RM

H I

Ar-C-SH I

H I

+ Ar-C-SR I

R

H I

+ Ar-C-SR

H

i

R

H I

I

HS

(123)

(107)

Scheme 5.62

H I

+ A r - C - - C/ - A r SH

CHEMISTRY OF THIOALDEHYDES

253

Reaction of (94) with trimethylsilyllithium gives the carbophilic product (124), which was converted into the first stable selenoaldehyde (125) [67]. H

H

I

Ar-C-SiMe

H

t

3

~ Ar-C-SiMe

SPh

SH

(124)

3 ~

I

Ar-C-SiMe

SCN

3

~-

/

Ar--C

H

"XSe

(125)

Scheme 5.63

The anion radical (119) is also formed by single-electron transfer from the ethoxide ion under irradiation, and has been detected by electron spin resonance (ESR) spectroscopy [68]; (119) reacts further under irradiation to give the diarylethane (126) and the sulfide (127) as the main final products via the intermediate radicals Ar(~HCHzAr and Ar(~H2, as evidenced by ESR [69]. The analysis of the ESR spectrum of (119) indicates that its thioformyl group is also perpendicular to the aromatic ring, as is observed for (94) itself in the solid state.

(94)

EtOH/EtOK

hv

-~ ArCH2CH2Ar

+

(126) 12%

(ArCH2)2S

+ (107)

+

ArCH 3

(127) 37%

Scheme 5.64

Anion radicals of thioaldehyde can also be generated by photolysis of thiols in alkaline solution [70]. The thioaldehyde (95) reacts with a phosphorus ylid to give a thiirane [52]. H (95)

+

Ph3P=CH(CH2)2Ph

",,..

Ph'',/% S

Bu t

...,,

Scheme 5.65

Reduction of the thioaldehydes (94)-(98) with NaBH4 or LiAIH4 leads to the corresponding thiols [52-55, 61].

5.3.3.4 Reactions with electrophiles Oxidation of both the aliphatic thioaldehydes (95) and (97a) and the aromatic thioaldehydes (94) and (98) with m-chloroperbenzoic acid (MCPBA) gives the corresponding sulfines [52, 54, 55, 61]. Reaction of (96) with MCPBA is complex, no identifiable product being formed. The (E)-sulfine (128) is a kinetic product, which is isomerized by base into the thermodynamic product (Z)-(128) [61].

254

RENJIOKAZAKI mCPBA

(941,

Ar\ /C=S\ H "O

Ar\ //O / C=S H

+

(E)-(128)87%

(Z)-(128)6%

Scheme 5.66

Oxidation of (94) with dimethyldioxirane (129) at a low temperature (-78~ gives a quantitative yield of (128), the (E)/(Z) ratio being 20:1. Further oxidation of (E)-(128) with (129) does not proceed, whereas that of (Z)-(128) gives the interesting products (130) and (131) [71]. Although the mechanism of this oxidation is not clear, it probably proceeds through intramolecular cycloaddition of the highly reactive sulfene (132). Similar cyclization of a transient vinylsulfene has been reported by King [72].

% (Z)--(128)

,

-~

+

(129)

(130) 9%

(131) 29%

" ~ (Z)-(128)

(129)

//O ] I ~- ArCH--SNo

--

(132)

--

J-1

O II S (129)

(130)

(131)

Scheme 5.67

Meerwein's reagent reacts with (94) to give the corresponding aldehyde (111) and the dimethylacetal (133), most likely via the carbenium ion (134) [61]. H20 (94) Me3OBF4 .

.

.

.

.

.

.

(111)

ArCH=;MeBF2 (134)

- ArCHO + MeSH

MeSH

= ArCH(SMe)2 (133)

Scheme 5.68

5.3.3.5 Reactions with radicals Thioketones react with radicals at the sulfur atom to give persistent carbon radicals (135) as the initial products, which can be detected by ESR spectroscopy (spin-

CHEMISTRY OF THIOALDEHYDES

255

trapping technique) [73]. Reaction of thiobenzophenone with the 1-cyano-1methylethyl radical generated from azoisobutyronitrile gives a C,S double adduct of the radical [74]. R R2C=S

+

_

R'.

\o / C--S--R'

R

(135)

Scheme 5.69

Interestingly, however, the reaction of the thioaldehyde (94) with the 1-cyano-lmethylethyl radical affords the benzothiane (107), the same product as that of the thermal and photochemical reactions of (94) [61]. The mechanism for the formation of (107) in this reaction is considered to begin with an attack of the radical at the sulfur atom. Since the 1-cyano-l-methylethyl radical is relatively stable, it is expelled from the intermediate radical (136), thus making this cyclization a catalytic process. The cyclization is essentially the same as that shown in Scheme 5.56. In the reaction with a less stable radical such as the t-butyl radical, which is generated by photolysis of azodi-t-butyl, normal radical addition products such as (137)-(139) are formed in addition to (107). As is often observed in highly congested aryl compounds, the Dewar benzene (138) is a secondary photoproduct of (139).

H (94)

R I S

R I S~

R I.

R~

R. = Me2(CN)Co

(136)

+ H-C--

H-C--S

T (137)

(138)

(139)

Scheme 5.70 Finally, the thioaldehydes (94) and (96) are good spin traps. In the reaction with radicals centred at elements from groups 14-16, they give the persistent radicals (140) and (141), which can be detected by ESR spectroscopy [74]. Ar

\.

H

/

Tsi

C--SR

\.

H

(140)

/

C--SR

(141)

Scheme 5.71

256

RENJIOKAZAKI

REFERENCES 1. 2. 3. 4. 5. 6.

7.

8. 9. 10. 11. 12. 13. 14.

15. 16. 17. 18. 19. 20. 21. 22.

23. 24.

P. von R. Schleyer and D. Kost, J. Am. Chem. Soc., 110, 2105 (1988). M.W. Schmidt, P.N. Troung and M.S. Gordon, J. Am. Chem. Soc., 109, 5217 (1987). Calculated with HF/DZ (d,p). S. Nagase, private communication. F. Duus, in: Comprehensive Organic Chemistry (D.H.R. Barton and W.D. Ollis, eds), vol. 3, p. 373, Pergamon Press, New York (1979). (a) R. Okazaki, Kagaku no Ryoiki, 37, 178 (1983). (b) V.A. Usov, L.V. Timokhina and M.G. Voronkov, Sulfur Rep. 12, 95, (1992). See also ref. 4. For previous reviews on thioaldehydes, see: (a) J. Voss, in: Houben-Weyl, Methoden der Organischen Chemie, (D. Klamann, ed.), vol. 11, p. 188, George Thieme, Stuttgart (1985). (b) R. Okazaki, Yuki Gosei Kagaku Kyokai Shi, 46, 1149 (1988). (c) W.M. McGregor and D.C. Sherrington, Chem. Soc. Rev., 199 (1993). See also ref. 5. (a) E. Vedejs, T.H. Eberlein and D.L. Varie, J. Am. Chem. Soc., 104, 1445 (1982). (b) E. Vedejs, D.A. Perry, K.N. Houk and N.G. Rondan, J. Am. Chem. Soc., 105, 6999 (1983). (c) E. Vedejs and D.A. Perry, J. Org. Chem., 49, 573 (1984). (d) E. Vedejs and J.G. Reid, J. Am. Chem. Soc., 106, 4617 (1984). (e) E. Vedejs, T.H. Eberlein, D.J. Mazur, C.K. McClure, D.A. Perry, R. Rugeri, E. Schwartz, J.S. Stults, D.L. Varie, R.G. Wilde and S. Wittenberger, J. Org. Chem., 51, 1556 (1986). (f) E. Vedejs, J.S. Stults and R.G. Wilde, J. Am. Chem. Soc., 110, 5452 (1988). V.P. Rao, J. Chandrasekhar and V. Ramamurthy, J. Chem. Soc., Perkin Trans. 2, 627 (1988). (a) A. Couture and A. Lablache-Combier, Chem. Commun., 524 (1969). (b) H. Hiraoka, J. Phys. Chem., 74, 574 (1970). E. Vedejs, M.J. Armost, J.M. Colphin, and J. Eustache, J. Org. Chem., 4S, 2601 (1980). J.E. Baldwin and R.C.G. Lopez, J. Chem. Soc., Chem. Commun., 1029 (1982); Tetrahedron, 39, 1487 (1983). E. Block and J. O'Conner, J. Am. Chem. Soc., 96, 3929 (1974); E. Block, S. Ahmad, M.K. Jain, R.W. Crecely, R. Apitz-Castro and M.R. Cruz, J. Am. Chem. Soc., 106, 8295 (1984). H.J. Reich and C.P. Jasperse, J. Am. Chem. Soc., 109, 5549 (1987). (a) A.W. Lochead and D.C. McDougall, J. Chem. Soc., Chem. Commun., 423 (1983). (b) A.W. Lochead and D.C. McDougall, J. Chem. Soc., Perkin Trans. 1, 1541 (1985). (c) G.W. Kirby and A. D. Schare, J. Chem. Soc., Perkin Trans. 1, 2329 (1991). G.W. Kirby and A.W. Lochead, J. Chem. Soc., Chem. Commun., 1325 (1983). (a) G.W. Kirby, A.W. Lochead and G.N. Shedrake, J. Chem. Soc., Chem. Commun., 1469 (1984). (b) G.W. Kirby, A.W. Lochead and G.N. Shedrake, J. Chem. Soc., Chem. Commun., 922 (1984). G.A. Krafft and P.T. Meinke, Tetrahedron Lett., 26, 1947 (1985). (a) M.Segi, T. Nakajima, S. Suga, S. Murai, I. Ryu, A. Ogawa and N. Sonoda, J. Am. Chem. Soc., 110, 1976 (1988). (b) M. Segi, M. Takahashi, T. Nakajima and S. Suga, Synthetic Commun., 19, 2431 (1989). A. Ricci, A. Degl'Innocenti, A. Capperucci and G. Reginato, J. Org. Chem., $4, 20 (1989). D.N. Harpp, T. Aida and T.H. Chan, Tetrahedron Lett., 26, 1795 (1985). E. Schaumann and G. Riihter, Tetrahedron Lett., 26, 5265 (1985). (a) K. Okuma, Y. Yamasaki, T. Komiya, Y. Kodera and H. Ohta, Chem. Lett., 357 (1987). (b) K. Okuma, Y. Tachibana, J. Sakata, T. Komiya, I. Kaneko, Y. Komiya, Y. Yamasaki, S. Yamamoto and H. Ohta, BulL Chem. Soc. Jpn, 61, 4323 (1988). R. Sato and S. Sato, Synthesis, 785 (1991). (a) K. Okuma, Y. Komiya and H. Ohta, Chem. Lett., 1145 (1988). (b) Idem, BulL Chem. Soc. Jpn, 64, 2402 (1991).

CHEMISTRY OF THIOALDEHYDES

25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42.

43. 44. 45. 46. 47.

48.

49. 50. 51. 52. 53. 54.

257

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258

55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73.

74. 75.

RENJI OKAZAKI

N. Takeda, N. Tokitoh and R. Okazaki, J. Am. Chem. Soc., 116, 7907 (1994). N. Tokitoh, N. Takeda, T. Imakubo, M. Goto and R. Okazaki, Chem. Lett., 1599 (1992). F. Iwasaki, private communication. L.J.M. Manojlonic and I.G. Edmunds, Acta Cryst. 18, 543 (1965). H. Lumbroso, J. Curd, R. Okazaki, A. Ishii and N. Inamoto, Z. Naturforsch., 40a, 1157 (1985). R. Okazaki, A. Ishii, N. Fukuda, H. Oyama and N. Inamoto, Tetrahedron Lett., 25, 849 (1984). S. Watanabe, A. Ishii, N. Fukuda, H. Oyama, T. Yamamoto, Y. Hagino, T. Kawashima and R. Okazaki, in preparation. R. Huisgen and W. Mack, Chem. Ber., 105, 2815 (1972). G. Hofsta, J. Kamphuis and H.J.T. Bos, Tetrahedron Lett., 25, 873 (1984). T. Kawashima, S. Watanabe and R. Okazaki, Chem. Lett., 1603 (1992). S. Watanabe, T. Kawashima and R. Okazaki, BulL Chem. Soc. Jpn., in press. R. Okazaki, N. Fukuda, H. Oyama and N. Inamoto, Chem. Lett., 101 (1984). R. Okazaki, N. Kumon and N. Inamoto, J. Am. Chem. Soc., 111, 5949 (1989). D. Casarini, L. Lunazzi and G. Placucci, J. Org. Chem., 53, 1582 (1988). M.A. Cremonini, L. Lunazzi, G. Placucci, N. Kumon, A. Ishii, T. Kawashima and R. Okazaki, J. Chem. Soc., Perkin Trans. 2, 1045 (1991). (a) A.G. Davis and A.G. Neville, J. Chem. Soc., Perkin Trans. 2, 171 (1992). (b) M.A. Cremonini, L. Lunazzi and G. Placucci, J. Org. Chem., 58, 3805 (1993). S. Watanabe, T. Kawashima and R. Okazaki, in preparation. J.F. King, P. de Mayo, C.L. McIntosh, K. Piers and D.J.H. Smith, Can. J. Chem., 48, 3704 (1970). (a) J.C. Scaiano and K.U. Ingold, J. Am. Chem. Soc., 98, 4727 (1976). (b) A. Alberti, F.P. Colonna and G.F. Pedulli, Tetrahedron, 36, 3043 (1980). (c) B.B. Adeleke, K.S. Chen and J.K.S. Wan, J. Organomet. Chem., 208, 317 (1981). (d) A. Alberti, F.P. Colonna, M. Guerra, B.F. Bonini, G. Mazzanti, Z. Dinya and G.F. Pedulli, J. Organomet. Chem., 221, 47 (1981). (e) W.G. McGimpsey, M.C. Depew and J.K.S. Wan, Phosphorus Sulphur, 21, 135 (1984). (f) A. Alberti, B.F. Bonini and G.F. Pedulli, Tetrahedron Lett., 28, 3737 (1987). (g) A. Alberti, M. Benaglia, M.C. Depew, W.G. McGimpsey, G.F. Pedulli and J.K.S. Wan, Tetrahedron, 44, 3693 (1988). G. Tsuchihashi, M. Yamauchi and A. Ohno, Bull. Chem. Soc. Jpn, 43, 968 (1970). A. Alberti, M. Benaglia, B.F. Bonini and G.F. Pedulli, J. Chem. Soc., Faraday Trans. 1, 84, 3347 (1988) and references cited therein.

AUTHOR

! N DEX

Abaham, E. P., 236 Abd EI Samii, Z. K. M., Abe, H., 120 Abe, Y., 78, 146 Abel, E. W., 160 Abott, D. J., 5 Abramovitch, R., 53 Abushanab, E., 2 Acad, C. R., 53 Acena, J. L., 117 Adama, T. C., 136 Adams, V., 108 Adeleke, B. B., 254 Adib, A., 12 Adlington, R. M., 236 Ager, D. J., 216 Aggarwai, V. K., 115, 117 Ahmad, A., 229,238 Aida, T., 234 Airmar, N., 53 Akasaka, T., A1 Ashmawy, M. I., Alberti, A., 254, 255 Alexander, R. P., 99, 101, 104 Alexis, C. P., 189 Allen, R. P., 63 Allman, R., 239 Alnajjar, M. S., Alonso, I., 27, 32, 34-36 Alpoim, M. C. de C., 71 Alvernhe, G., 95, 96 Amato, J. S., 138 Arian, H., 137 Anderson, B. C., 51 Anderson, K. K., 2, 3 Anderson, S. W., 139 Ando, W., 242, 243,253 Angoh, A. G., 76 Anker, D., 95, 96 Annunziata, R., 1, 5, 7, 8 Anthoni, U., 139 Aoki, S., 68 Apitz-Castro~ R., 229, 238 Arai, N., 191 Arai, Y., 26, 29, 31-35, 41 Arens, J. F., 51 Arjona, O., 115, 117 Armitage, D. A., 160 Arya, P., 189 Asirvathan, E., 6 Aslam, M., 65 Asmus, K-D., 62

Asscher, M., 65 Auret, B. J., 2 Auvray, P., 94 Axelrod, M., 2, 3

Bachi, M. D., 62, 76 Back, T. G., 66, 71 Bairamova, F. A., Bakshi, R. K., 178 Bald6, B., 65 Baldwin, J. E., 116, 229, 236 Balenovic, K., 2 Ballini, R., 202 Balogh, M., 194 Ban, T., 43 Banff, L., 14, 177 Barbeaux, P., 216 Bargar, T. M., 144 Barner, B. A., 117 Barrett, K. E. J., 62 Barton, D. H. R., 57, 62, 78-80, 82, 198, 209 Barua, N. C., 209 Bastein, G., 53 Basu, N. K., 62 Bavry, R. H., 65 Bazbouz, A., 194, 197 Beaber, N. H., 2 Beck, G., 173 Beck, H. J., 236 Becker, E. I., 72 Becker, S. I., 208 Beckwith, A. L. J., 57, 59, 66, 81,189 Beckwith, A. L.,J., 189 Beissenger, T., 122 Beisswenger, T., 122 Belkasmioui, F., 41 Bellesia, F., 154 Bellet, E. M., 142 Belman, S., 237 Ben Alloum, A., 144 Benaglia, M., 254, 255 Benati, L., 121 Beratta, M. G., 172 Bergan, J. J., 138 Berman, J. D., 62 Bernardi, F., 91, 92 Bernardi, R., 181 Bernardinelli, G., 174

Bertrand, M. P., 69, 70 Bessette, F., 158 Bestmann, H. J., 172 Bestmann, J. J., 172 Bewick, A., 120 Bhar, S., 170 Bickart, P., 2, 3 Bishop, D. J., 79 Bland, J. M., 94 Blatcher, P., 206, 216 Block, E., 50, 65, 73, 229, 237, 238, 242 Blount, J. F., 117, 172 Boar, R. B., 209 Boate, D. R., 81 Bock, H., 242 Bodrikov, I. V., 91-93 Boeckman Jr, R. K., 36 Boekelhide, V., 73 Bogadanov, V. S., 92, 94 Boger, D. L., 58 B~511,W., 65 Boni, M., 154 Bonini, B. F., 254, 255 Bonnema, J., 51 Boothe, T. E., 64 Bordwell, F. G., 51 Bos, H. J. T., 249 Bosch, E., 76 Bourdon, F., 242 Boyd, D. R., 2 Brault, J., 158 Bravo, P., 14 Bregant, N., 2 Breuilles, P., 70 Bridon, D., 80 Brocka, C. A., 56 Brown, E. D., 57 Brown, M. P., 171 Brown, R. D., 51,240 Brown, W. L., 115 Brownridge, P., 93, 94, 115, 121,126 Brumby, S., 189 Bruzco de Milano, D. L., 120 Bryan, C. A., 41 Bujnicki, B., 4 Bunz, U., 61 Bush, R. P., 160 Buynak, J. D., 74 Bychova, T. I., 65 Byers, J. H., 58

260

Calas, R., 65 Callear, A. B., 240 Canton, M. P. L., 117 Capozzi, F., 89, 90, 93, 94 Capozzi, G., 89, 90, 93, 94, 95,115, 118 Capperucci, A., 234 Cappozzi, G., 118, 123 Caputo, R., 204, 205 Carballeira, N., 108 Cardillo, R., 181 Caress, E., 2 Carrefio, M. C., 5-7, 11, 12, 14, 18, 37-39 Carretero, J. C., 27, 32, 3436, 92, 97 Carroll, P.J., 78 Carter, J. P., 136 Casarini, D., 253 Caserio, M. C., 93, 121,125 Casida, J. E., 142 Caubere, P., 208 Cava, M. P., 115 Celmer, W. D., 202 Cervantes, H., 167 Chakraborti, R., 170 Chalmers, A. A., 173 Chan, M-C., 208 Chan, T. C., 189 Chan, T. H., 4, 148, 234 Chan, W. H., 144 Chandrasekhar, J., 227 Chang, F-C., 189 Chatgilialoglu, C., 58, 62, 64, 65 Chavan, S. P., 171 Chaykowski, M., 7 Chefczynska, A., 5 Chejcznska, A., 28 Chen, C. H., 204 Chen, K. S., 254 Chen, M-Y., 67, 71 Cheng, K-M., 208 Cheng, W-L., 209 Chi, Y., 65 Chibale, K., 115 Chikashita, H., 180, 184 Chino, K., 58 Chivers, J. C. A., 194 Choi, E. B., 144 Choi, J. K., 74, 205 Choi, S. S. -M., 239 Christensen, L. W., 65 Christie, M. A., 236 Christl, H., 61 Christophersen, C., 139

AUTHOR INDEX

Chu, S. C., 74 Chuang, C-P., 69-71 Chucholowski, A., 96, 113, 122 Church, K. M., 60, 61 Cid, B., 36 Cinquini, M., 1, 5, 7, 8 Cioni, M., 3 Ciuffarin, E., 3 Clardy, I., 6 Classcock, K. G., 187 Clayton, T., 147 Clive, D. L. J., 76 Coe, D. E., 120 Cohen, S. F., 62 Cohen, T., 216 Coldham, I., 115, 117, 123 Cole, L. M., 142 Collington, E. W., 117 Collins, S., 66 Colobert, F., 5 Colombo, L., 5, 172 Colonna, F. P., 254 Colonna, S., 1, 2, 5 Conner, J., 240 Coombs, W., 117 Cope, A. C., 2 Coppa, F., 82 Corey, E. J., 7, 54, 73,172, 198, 236 Corey, E. R., 242 Cornelis, A., 64, 194 Correa, I. D., 95 Corr~a, C. M. M. S., 64, 65, 70, 71 Couladouros, E. A., 78 Couture, A., 228 Coveney, D. V., 80 Cox, A. P., 240 Coyle, J. D., 76 Cozzi, F., 1, 5, 7, 8 Cramer, E., 108 Crecely, R. W., 229, 238 Creemer, L. C., 144 Cremonini, M. A., 253 Crich, D., 57, 76, 78, 79, 82 Crimmin, M. J., 236 Cristau, H-J., 194, 197 Cristol, S. J., 81 Crossley, N. S., 208 Crowe, B. F., 202 Crozet, M. P., 53 Crozet, P., 53 Cruz, M. R., 229, 238 Csizmadia, I. G., 91, 92 Csizmadia, V. M., 91

Cuervo, R., 216 Culos, K. O., 36 Culshaw, P. N., 68 Cun-Leng, H., 6 Cur6, J., 245 Curran, D. P., 74, 186 Dalipi, S., 91 Damon, R. E., 56, 57 Daniewski, W. M., 216 Danishefsky, S., 36 Dannehauer, F., 122 Daroszewski, J., 63 Davies, A. G., 50 Davies, D. I., 50 Davis, A. G., 253 De Frees, S. A., 78 De Lucchi, O., 33, 34 De Mayo, P., 241,254 De Riggi, E., 70 De Riggi, I., 69, 70 De Vercelli, S., 138 De Voss, J. J., 203 Dean, C. L., 92, 103 Degani, I., 208 Degl'Innocenti, A., 234 Degueil, M., 63 Delduc, P., 82 Demailly, G., 8, 10-12, 19 Demchuk, D. V., 170 Denemark, D., 76 DeNinno, M. P., 178 Denis, J. M., 241,242 Depew, M. C., 254 Desmukh M. N., 2 Desobry, V., 173 Dev, S., 148 Di Fabio, R., 82 Dickerson, R. T., Dickson, D. R., 240 Dingwall, J. C., 242 Dinya, Z., 254 Dittmer, C., 203 Dittmer, D. C., 89, 90, 93, 94 DiTullio, D., 177 Dixon, R. N., 241 Djerassi, C., 147, 148 Do Vale, M. C., 64, 70 Dodson, R. M., 147 Doherty, L. H., 240 Dolak, T. M., 36 Dolson, M. G., 239 Dombroski, M. A., 209 Donatelli, B. A., 204

AUTHOR [NDEX

Drabowicz, J., 2, 3, 4 Duax, W. L., 90 Dumont, W., 122 Dunach, E., 2 Dunach, F., 2 Dunogfies, J., 65 Dupont, A. C., 136 Dupuy, C., 53 Durman, J., 216 Duus, F., 226, 242, 244 Ebata, T., 123 Eberlein, T. H., 227 Edmunds, I. G., 245 Edstrom, E. D., 106-108 Effenburger, F., 122 Eicken, K., 142 E1-Wassimy, E. T. M., 198 Eliel, E. L., 179, 216 Elliot, R. L., 74 Elliott, J., 216 Elliott, M., 142 Emerson, D. W., Endo, T., 60 Engebrecht, J. R., 100 Entwistle, I. D., 208 Epling, G. A., 199, 201 Epstein, J. W., 62 Erickson, B. W., 198 Esch, P. M., 74 Ess, R. J., 72 Eswarakrishnan, V., 65 Ethier, D., 117 Evans, D. A., 41,162 Fabricant, B., 241 Fallis, A. G., 74, 115,189 Fang, J-M., 67, 71 Fang, L., 203 Farmer, S. G., 136 Fehlhammer, W. P., 173 Feldman, K. S., 59, 60 Fernandez de la Pradilla, R., 115, 117 Fernandez, I., 19 Fernandez-Monreal, M. C., 216 Ferreri, C., 204, 205 Ferris, K. F., 81 Fetizon, M., 172, 208 Fevig, T. L., 74 Field, L. D., 236 Fields, S., 239 Fieser, L. F., 147, 149

Fijita, E., 198 Fisher, C. L., 93, 125 Fisher, M. J., 43 Flesia, E., 53 Flippin, L. A., 209 F16gel, U., 241 Fochi, R., 208 Fokin, A. V., 117 Foley, J. W., 3 Folli, U., 2 Fontana, F., 82 Forbes, J. E., 82 Fort, Y., 208 Foster, R. E., 55 Fouessac, F., 26 Fourikis, N., 240 Francetic, D., 2 Francisco, C. G., 207 Franck, R. W., 114 Franck-Neumann, M., 175 Francke, R. W., 113 Franz, J. A., 81 Franzone, J. S., 138 Fraund, S., 61 Fray, M., 118 Frdchou, C., 11, 19 Freire, R., 207 Frenkel, A. D., 142 Fronza, G., 14 Frye, L. L., 5, 6 Frye, S. V., 179 Fuchigama, T., 213 Fueno, T., 99 Fugami, K., 59 Fuji, K., 198 Fujii, S., 198 Fujimura, O., 170 Fujisawa, T., 177, 184 Fujita, M., 15, 17 Fukuda, N., 242, 243,246, 248-255 Fukumoto, K., 123, 124 Fukunaga, M., 90 Furth, P. S., 203 Garfield, W., 3 Garcia Ruano, J. L., 5-7, 11, 12, 14, 18, 27, 32, 3439, 92, 97 Garcia, M., 216 Garlaschelli, L., 148 Garratt, D. G., 92, 99, 103 Garret, D. C., 99 Garrido, M., 14 Gaumont, A. C., 241

261

Gauthier, J. Y., 138 Gebreyes, K., 65 Gennari, C., 172 Gennari, G., 5 Georgian, V., 208 Ghelfi, F., 154 Ghersett, H. H., 25 Ghiatou, N., 7, 16 Ghiringhelli, D., 180 Gibbs, R. A., 42 Giese, B., 51,186 Gigardin, A., 4, 5 Giles, H. G., 241 Gill, D. M., 122 Gilman, H., 2 Gladysz, J. A., 76 Glassock, K. G., 76 Godfrey, P. D., 240 Gokyu, K., 184 Gololobov, Y. G., 89, 90, 93, 94 Gommper, R., 59 Goralski, C. T., 65 Gordon, M. S., 225 Gorman, M., 147, 148 Goto, M., 244 Goulaouic, P., 172, 208 Grabowski, J. J., 138 Gracian, F., 242 Grancarz, R. A., 66, 70 Greck, C., 8, 10-12 Green, M. M., 2, 3 Greene, J. L., 64 Greene, T. W., 191 Grejszczak, S., 5 Gresier, J-C., 55 Grewel, G., 113 Griesbaum, K., 51, 56, 65 Griller, D., 189 Grimm, K. G., 162 Grisoni, S., 237 Grivet, C., 174 Gros, E. G., 194 Grzejszczak, S., 28 Gu, R. L., 185 Guanti, G., 14, 177 Gubernatorov, V. K., 69 Gubisch, N., 208 Guenot, P., 242 Guerra, M., 254 Guessous, A., 26, 28, 29 Guillemin, J. C., 242 Guindon, Y., 117 Gupta, B. C. B., Gurjar, M. K., 82 Gusar, N. I., 89, 90, 93, 94

262

Gutierrez, C. G., 76, 187, 188, 189 Guzewska, M. E., 136 Gybin, A. S., 92, 94 Haces, A., 42 Haenel, M. W., 73 Haga, Y., 124 Hagino, Y., 248-251,253255 Hahn, H. G., 204 Hainell, T. G., 6 Haines, S. R., 6 Hakamada, I., 28, 29, 31 Hall, D., 115 Hall, R., 117 Hallet, P., 117 Hamaguchi, K., 137 Hamanaka, E., 54 Hamdouchi, C., 5, 16, 20 Hammadi, M., 167 Haner, D. A., 241 Hanessian, S., 82 Hanna, I., 172, 208 Hannaby, M., 126 Hansske, F., 78 Hanzel, R. S., 72 Hara, R., 137 Harada, S., 74 Harayama, T., 36 Harding, M. M., 171 Harirchian, B., 25 Harpp, D. N., 4, 234 Harris, E. F. P., 62 Harris, J. F., 51, 56, 65 Harrison, P. W. B., 2 Harrison, W., 42 Harrisson, R., 208 Hart, D. J., 74 Hartwig, W., Hasegawa, E., 192, 199 Hasegawa, M., 55, 98, 102, 104, 203 Hashimoto, K., 105 Hashimoto, T., 104, 111, 126 Hashimoto, Y., 98, 102, 104, 139, 203 Haufe, G., 95, 96 Hauptmann, H., 147 Hawkins, D. W., 209 Hayashi, K., 29-31, 33-35 Hayashi, S., 144, 146 Hayes, R. A., 91, 92 Hehre, W. J., 43

AUTHOR INDEX

Heimgartner, H., 54 Heitz, M-P., 175 Helmchen, G., 202 Helmkamp, G. K., 91 Henbest, H. B., 2, 208 Henneberger, H., 61 Herhe, W. J., 33 Hernandez, R., 207 Herold, L. L., 68 Herrmann, J. L., 202 Hershberg, E. B., 147 Herzberg-Minzly, Y., 62 Hess, B. A. Jr., 241 Hesse, R. H., 62 Hewett, W. A., 51 Hiemstra, H., 74 Hirabayashi, T., 242 Hiraguri, Y., 60 Hiraoka, H., 228 Hirashima, 144 Hiroi, K., 6 Hirosawa, C., 120 Hiyama, T., 213 Ho, K. M., 208 Hobbs, S. J., 160 Hoffmann, F. W., 72 Hofsta, G., 249 Hogeveen, H., 25 Hogg, D. R., 89, 90, 93, 94 Hojo, M., 167 Honda, Y., 185,186 Hori, M., 204 Hoshino, M., 127 Hoshino, O., 199 Houchigai, H., 98, 104 Houk, K. N., 227 Howe, R. K., 239 Huang, G. T., 43 Hubbard, S. D., 240 Huckstep, M. R., 117 Hughes, D. L., 138 Huisgen, R., 249 Hulce, M., 5 Hunag, J., 189 Hursthouse, M. B., 182, 183 Hutchins, R. R., 216 Hutchinson, J., 65 Hutt, J., 4, 5, 19, 21 Huval, C. C., 61 Hwang, C-K., 78 Iarossi, D., 2 Ibarra, C. A., 216 Ibragimov, M. A., 97, 98, 101,108

Ichihara, A., 117 Ichikawa, K., 198 Ihara, M., 123, 124 Iida, H., 15 Iino, M., 64 Ikeda, M., 74, 198 Ikehira, H., 202, 216 Imai, Y., 154 Imakubo, T., 244 Imanishi, T., 17 Inaba, T.,15 Inamasu, T., 148, 207 Inamoto, N., 242, 243, 245, 246, 252, 253 Ingold, K. U., 52, 79, 254 Inners, R. R., 64 Inoue, M., 103 Irie, M., 74 Isak, H., 122 Ishibashi, H., 74 Ishii, A., 242, 243, 245,246, 248-255 Ishiyama, M., 146 Isii, R., 178 Ito, H., 146 Ito, T., 114 Itoh, K., 123, 180, 184 Itoh, T., 177 Iwasa, I., 76 Iwasa, S., 76 Iwasaki, F., 245 Iwata, C., 17 Iyer, R., 237 Iyobe, A., 30 Jacobsen, N., 139 Jacobus, J., 2, 3 Jacox, M. E., 241 J ain, M. K., 229, 238 Jang, D. O., 78 Jasperse, C. P., 230 Jaspersee, C. P., 74 Jaszberenyi, J. Cs., 78, 213 Jayatilake, G. S., 236 Jeko, J., 213 Jen, K-Y., 65 Jenkins, P. R., 179 Jenny, C., 54 Johansson, J. G., 202 Johns, J. W. C., 241 Johnson, D. R., 240 Johnson, M. D., 68, 72 Johnston, L. J., 61 Jones, K., 115 Jones, W. E., 51

AUTHOR INDEX

Jordan, R. B., 79 Jorgenson, K. A., 198 Joseph-Nathan, P., 167 Joshi, B. V., 74 Juge, S., 2, 3 Jung, M., 236 Jungheim, L. N., 239 Kabe, Y., 242, 243,253 Kachur, J. F., 136 Kagan, H. B., 2, 3, 40 Kahn, S. D., 33, 43 Kahne, D., 74 Kaili, N., 113 Kaji, K., 105 Kajiwara, M. N., 178 Kakimoto, M-A., 154 Kalabina, A. V., 65 Kalaina, A. V., 65 Kamara, M., 192 Kamata, M., 199 Kambe, N., 55 Kametani, T., 124 Kamidado, T., 170 Kamikado, T., 142 Kamimura, A., 104, 111, 126 Kamitori, Y., 167 Kamphuis, J., 249 Kampmeier, J. A., 79 Kanefusa, T., 55 Kaneko, I., 235 Kang, Y-H., 66 Kano, S., 74 Kaomiya, Y., 235 Kaplin, L., 50 Kaszynski, P., 61 Kataoka, T., 204 Kataoka, Y., 170 Kato, H., 240 Kato, R., 184 Kato, Y., 199 Katritzky, A. R., 89, 90, 93, 94 Katzenellenbogen, J. A., 211 Kawachi, Y., 198 Kawakami, H., 123 Kawashima, T., 248-251, 253-255 Kawazoi, Y., 207 Keck, G. E., 58 Kellogg, R. M., 50, 62 Kenda, B., 216 Kenyon, J., 2

Kerr, R. G., 66 Kharasch, M. S., 55 Kharash, M. S., 51 Kharash, N., 51, 56, 65 Kice, J. L., 50, 66, 70 Kielbasinski, P., 2 Kim, J. K., 93, 121,125 Kim, S., 108, 148, 160 Kimoto, H., 102 Kimura, R., 117 Kimura, S., 184 Kimura, T., 167 King, J. F., 254 Kinoshita, M., 7 Kinter, C. M., 42 Kipnis, K., 147 Kirby, G. W., 232, 238, 239 Kirchoff, W. H., 240 Kirwan, J. N., 63 Kitamura, T., 93, 125 Kitaoka, M., 5 Kitchen, J., 236 Kiyoshima, Y., 146 Klair, S. S., 16, 171 Knochel, P., 94 Kobara, S., 103 Kobayashi, T., 163 Kochi, J. K., 50 Kodera, Y., 235 Koe, B. K., 202 Kogai, B. E., 69 Kogan, T. P., 5, 6 Kohmoto, S., 76 Koide, T.,137 Koike, T., 93, 126 Koizumi, T., 26, 28-35, 41 Kojima, E., 177 Kokami, J., 7 Kollonitsch, J., 211 Kolomiets, A. V., 117 Komiya, T., 235 Komoti, O., 146 Kondrashov, N. V., 117 Kono, Y., 170 Konoike, T., Konta, H., 10, 11 Korniels, B. E., 69 Koseki, K., 123 Kost, D., 225 Kosugi, H., 5, 10, 11 Kotake, H., 194 Krafft, G. A., 232 Kraus, G. A., 37 Kresteleva, I. V., 172 Kretzschmar, G., 82 Krief, A., 122, 216

263

Krieger, D., 241 Krimer, M. Z., 91-94 Kroto, H. W., 241 Kruger, G. J., 173 Ku, B., 148 Kudo, K., 102 Kuehne, M. E., 56, 57 Kugo, K., 98, 104 Kumar, P., 167 Kumar, V., 148 Kumon, N., 252, 253 Kundig, E. P., 173, 174 Kunieda, N., 7 Kunwar, A. C., 82 Kuroboshi, M., 213 Kuroda, C., 100 Kurumaya, K., 178 Kusano, K., 55 Kusefoglu, S. H., 76 Kusharev, D. F., 65 Kusick, B. C., 55 Kuwayama, S., 26, 32, 41 Labiad, B., 167 Lablache-Combier, A., 228 Laborde, E., 74 Lach, D., 59 Lachance, A., 158 Lacher, B., 82 Lacombe, J. M., 51 Ladduwahetty, T., 96, 113, 122 Laffitte, J-A1., 65 Lafon, C., 242 Laidig, K., 61 Lam, C. H., 208 Landsberg, B. M., 241 Larchar, A. W., 55 Larkin, J. P., 142 Laszio, P., 194 Laur, P., 3 Laurent, A., 95 Lawesson, S. O., 198 Lazareva, M. I., 101 Lee, A. W.,M., 144 Lee, L. F., 239 Lee, R. N. K., 42 Lee, W. S., 204, 205 Lelancette, J. M., 158 Lesage, M., 189 Lesueur, C., 69 Levesque, G., 55 Ley, S. V., 206 Lijewski, L., 178 Lim, J. J., 74

264

Lim, S. T., 160 Lin, X. F., 113 Lindstrom, M. J., 52, 64 Linev, V. V., 117 Liotta, D., 123 Lipscomb, R. D., 55 Litvinov, I. A., Liu, L. K., 65 Liu, M. S., 79 Livinghouse, T., 106-108 Lochead, A. W., 232, 238 Lombard, A., 173 Longone, D. T., 76 Lopez, R. C. G., 229 Lopez-Tudanca, P. L., 115 Lossener, K., 189 Lossing, F. P., 237 Lotz, S., 173 Lowenthal, H. J. E., 62 Lu, M. C., 236 Lucchini, V., 33, 34, 115, 127 Lucero, M. J., 61 Luh, T-Y., 208, 209 Lumbroso, H., 245 Lunazzi, L., 253 Lusztyk, J., 63 Lutsenko, A. I., 103, 104 Lyer, R., 65 Lyle, R. E., 94 Lysenko, Z., 117

Maccagnani, G., 25 Macconi, A., 2 Mack, W., 249 Mackie, R. K., 242 Macleod, J. M., 240 Macy, T. S., 176 Madsen, J. O., 139 Maekawa, A., 55 Maestro, M. C., 18, 19 Maginn, S. J., 171 Magnus, P. D., 25 Mahajan, M. P., 239 Mahjoub, A., 55 Maida, T., 137 Maignan, C., 26, 28, 29, 33, 41 Maillard, B., 63 Maire, G., 241 Majerski, Z., 61 Maki, Y., 53 Mallamo, J. P., 5 Manabe, Y., 142, 170 Mangini, A., 91, 92

AUTHOR INDEX

Manojlonic, L. J. M., 245 Mantell, G. J., 55 Marang, S. C., 164 Marburg, S., 211 Marchioro, C., 33, 34 Marcuzzi, F., 115 Marino, J. P., 74 Marron, B. E., 78 Marshall, J. A., 203 Martin, A. M., 11, 12 Martin, J. C., 91, 92 Martin, S. J., 93, 109, 111, 112, 118 Martina, D., 175 Marty, R. A., 241 Masaki, Y., 105 Masuda, R., 167 Masumoto, K., 148 Mata, J. M., 37, 38 Mathew, J., 172 Matsuda, M., 64 Matsui, M., 33, 35 Matsuomoto, M., 80 Matsushita, H., 123 Matsuyama, N., 6 Matsuyuki, J-I., 93, 125 Mattay, J., 203 Matz, J. R., 216 Mayo, F. R., 51 Mazid, M., 182, 183 Mazur, D. J., 227 Mazzanti, G., 254 McClure, C. K., 227 McCombie, S. W., 78 McDaniel, K. F., 176 McDougall, D. C.,232, 238 McElroy, A. B., 216 McGarry, P. F., 61 McGhie, J. F., 209 McGimpsey, W. G., 254 McGregor, W. M., 242 McHenry, B. M., 216 McIntosh, C. L., 254 McIntyre, S., 115-117 McKenzie, S., 242 McMahon Jr, W. A., 94 Mei, N-W., 209 Meidor, D., 164 Meinke, P. T., 232 Melillo, J. P., 3 Melillo, J. T., 3 Melknikov, N. N., 51 Mellor, J. M., 120 Menger, F. M., 94 Menichetti, S., 89, 90, 93, 94, 115

Mesey, P. G., 91 Mestre, F., 82 Meyers, C. Y., 51, 56, 65 Michl, J., 61 Midura, W., 5, 28 Mikolajczyk, M. M., 2, 4, 5, 28 Miller, R., 74 Miller, R. F., 59 Milligan, D. E., 241 Minisci, F., 82 Mioskowski, C., 4, 5 Miranda, E. I., 161 Miranda, R., 167 Mislow, K., 2, 3 Mitsudera, H., 140, 142, 170 Miura, K., 59 Miyano, T., 64 Mizuno, T., 144 Mlinaric-Majerski, K., 61 Moad, G., Modena, G., 33, 34, 89, 90, 93, 93, 115, 127 Moerck, R. E., 25 Mohmand, S., 242 Mohr, R., 239 Montanara, F., 1 Montanari, F., 2, 25 Montevecchi, P. C., 121 Montillier, J. P., 4 Mook, R., 57 Moore, J. L., 77 Morand, P., 194, 197 Morehouse, F. S., 62 Mori, M., 146 Morita, E., 185 Moritani, Y., 17 Morizur, J. P., 62 Morris, A. D., 71 Morton, D. R., 160 Morton, J. A., 206 Motherwell, W. B., 71, 78, 79, 82, 213 Motozawa, T., 184 Muenter, J. S., 241 Mulley, S., 171 Murai, S., 234 Muralidharan, K. R., 71 Murata, Y., 194 Murphee, S. S., 68 Murphy, J. A., 52 Muxfeldt, H., 202 Nagano, N.,137 Nagase, S., 225

AUTHOR INDEX

Nage, M., 239 Nfijera, C., 65 Nakahita, M., 184 Nakai, E-I., 137 Nakajima, T., 234 Nakamura, C. Y., 198 Nakanishi, W., 90 Nakayama, J., 127 Nam, K. D., 204, 205 Namba, H., 189 Namwindwa, E. S., 16 Naoi, Y., 123 Narasaka, K., 191 Narisamo, E., 5 Narisano, E., 14, 177 Navarro, C., 63 Nesbitt, S. L., 162 Nevalainen, V., 206 Neville, A. G., 253 Newman, M. S., 208 N g, C. T., 208 N goi, T. H. J., 69 Ngoviwatchai, P., 68 Ni, Z-J., 209 Nicastro, M., 115 Nicolau, K. C., 78, 96, 113, 117, 122, 172 Nikishin, G. I., 170 Nishida, A., 189 Nishida, M., 189 Nishiguchi, I., 144 Nishihata, K., 2, 3 Nishimoto, M., 74 Nishio, M., 2, 3 Nitasaka, T., 76, 187 Normant, J. F., 94 Nougier, R., 53, 69 Nowlan, V. J., 91 Noyori, R., 192 Nozaki, H., 99, 102, 103, 105 Nudenberg, W., 55 Nukamura, T., 80 Numata, M., 140 O'Conner, J., 229, 238 O'Malley, G. J., 115 O'Neil, S., 189 O'Shea, D. M., 57, 71 Oae, S., 3, 189 Obayashi, R., 54 Ogawa, A., 54, 234 Ogawa, T., 114, 216 Ogura, K., 15 Oh, D. Y., 148

Ohkawa, K., 180 Ohno, A., 254 Ohsawa, T., 123, 124 Ohshiro, K., 185 Ohta, H., 93, 126, 235 Ohtaki, T., 242, 243,253 Oida, T., 202, 216 Oka, T., 240 Okada, Y., 140 Okaichi, T., 139 Okamura, W. H., 42 Okano, M., 202 Okauchi, T., 191 Okawara, M., 58, 64, 68 Okazaki, R., 242-246, 248255 Oki, M., 90 Okuma, K., 93, 126, 235 Okushi, T., 144 Okuyama, T., 99 Olah, G. A., 164 Oliveira, M. A. B. C. S., 64, 65 Oliveto, E. P., 147 Olson, W. B., 241 Ong, B. S., 148 Ono, N., 104, 126 Ornfelt, J., 147 Osawa, Y., 90 Oshima, K., 59 Osimov, B., 103 Oswald, A. A., 51, 55, 56, 65 Otera, J., 99, 102, 103, 105, 163 Otogawa, H., 192 Ottana, R., 118, 123 Outurquin, F., 55 Overheu, W., 239 Overman, L. E., 43 Owsley, D. C., 91 Oyama, H., 242, 243, 246, 248-255 Padmanabhan, S., 216 Padwa, A., 68 Page, P. C. B., 16, 171,179, 181-183,206 Pagnoni, U. M., 154 Pak, C. S., 144 Paley, R. S., 74 Palmer, C. J., 142 Palumbo, G., 204, 205 Pandey, B., 167 Pang, M., 72

265

Papanikolaou, N. E., 3 Papuaga, E., 74 Paquette, L. A.,25 Park, J. H., 108, 148 Park, O. S., 205 Park, S. U., Parkin, D., 142 Parrot, M. J., 50 Pasquato, L., 89, 90, 93, 94, 127 Patai, S., 64, 65 Patel, S. K., 97, 98 Patel, V. F., 80 Paterson, C. W., 52 Paterson, I., 97-99, 101, 104 Patney, H. K., 167 Pattenden, G., 80 Patwardhan, B. H., 89, 90, 93, 94 Paul, V., 62 Pavia, A. A., 51 Pechet, M. M., 62 Pedregal, C., 6, 7, 11, 12, 18 Pedulli, G. F., 254, 255 Pedulli, G. G., 255 Pegg, N. A., 122 Penn, E. R., 242 Perez, R. A, 115 Perkins, L. M., 211 Perkins, R. I., 3 Perner, R. J., 178 Perni, R. B., 167 Pero, F., 14 Perry, D. A., 227, 228, 242, 243,246, 248, 249, 251, 253 Peters, E-M., 108 Peters, K., 108 Peters, R. H., 202 Petrini, M., 202 Petty, C. B., 43 Pfister-Guilluzo, G., 242 Phillips, H., 2, 3 Phillips, J. G., 117 Pianese, G., 82 Piers, K., 254 Pigou, P. E., 66 Pillot, J-P, 65 Piovosi, E., 14 Pirder, A. R., 51 Pitchen, P., 2 Placucci, G., 253 Plumet, J., 115, 117 Polborn, K., 61 Poohjala, E., 206 Porter, Q. N., 201

266

Posner, G. H., 1, 5, 6, 42 Posner, G., 1 Posner, T., 51 Potier, P., 82 Poutsma, M. L., 50 Powell, F. X., 240 Prange, T., 208 Preuss, R., 113 Priestley, E. S., 61 Prilezhaeva, E. N., 51 Prodger, J. C., 16, 171,182, 183 Pulman, D. A., 142 Purrington, S. T., 95 Quintero, L., 76, 78, 79, 82 Rabinowitz, R., 72 Rakotomanomania, N., 51 Rakvin, B., 61 Rama Rao, A. V., 82 Ramamurthy, V., 227 Ramesh, S., 113, 114 Randall, J. L., 96, 113, 122 Ranu, B. C., 170 Rao, V. P., 227 Raphael, R. A., 26, 33 Rapoport, Z., 64, 65 Raubenheimer, H. G., 173 Ravindranathan, T., 171 Rayner, C. M.,, 122 Rebidre, F., 2 Reddy, K. A., 82 Reddy, R. S., 167 Reed, A. T., 51 Reed, D., 2 Rees, C. W., 89, 90, 93, 94 Reese, C. B., 74 Reetz, M. T., 109-111 Reginato, G., 234 Reich, H. J., 230 Reichert, D. E. C., 56 Reid, D. H., 242 Reid, J. G., 227, 228 Reider, P. J., 138 Reingold, I. D., 73 Reisenauer, H. P., 241 Renken, T. L., 242 Resnati, G., 14 Rettig, M. F., 91 Ribes, J. C., 240 Ricci, A., 234 Riegel, B., 147 Ripoli, J. L., 236, 242

AUTHOR INDEX

Roberts, B. P., 50, 62, 63, 79 Roberts, D. H., 81 Roberts, F. E., 216 Robins, M. J., 78 Robinson, J., 2 Rodriguez, H. J., 11, 12 Rodriguez, J. H., 92, 97 Roebke, H., 203 Roell, B. C., 176 Rokach, J., 117 Rolls, J. W., 147 Romanelli, A. L., 59 Romeo, G., 118, 123 Romo, J., 147 Ronan, B., 40 Rondan, N. G., 227 Rosenkranz, G., 147 Ross, S., 2 Rouessac, F., 28, 29 Roush, W. R., 113 Rozova, T. I., 65 Rubinstein, H., 203 Rubio, A., 6, 7, 11, 12, 18 Ruckle, R. E., 59 Rueb, L., 142 Rugeri, R., 227 Rt~hter, G., 235,240 Ruiz, M. P., 14, 216 R uiz, P., 5 Russell, G. A., 68 Ryan, D., 91 Ryu, I., 55,234 Rzeszotarski, W. J., 136 Saha, C., 237 Saigo, K., 98, 102, 104, 203 Sakai, M., 139 Sakamura, S., 117 Sakata, J., 235 Sako, M., 53 Sakuma, K., 105 Salazar, J. A., 207 Salem, G. F., 164 Saluzzo, C., 95, 96 Sam, T. W., 57 Samson, C., 189 Samuel, C. J., Sansbury, F. H., 115-117 Sarmah, P., 209 Sasatani, H., 104, 111,126 Satao, T., 74 Sato, M., 137 Sato, R., 145, 146, 235 Sato, S., 235

Sato, T., 99, 102, 103, 105, 145, 163, 177, 184 Satoh, H., 198 Satoh, J. Y., 198 Sauer, J. C., 55 Sawaki, S., 199 Scaiano, J. C., 52, 61,254 Schaad, L. J., 241 Schank, K., 65 Schare, A. D., 232, 238 Schaumann, E., 235,240 Schleyer, P. von. R., 225 Schmid, G. H., 91, 92, 103 Schmidt Pearson, M., 72 Schmidt, K., 189 Schmidt, M. W., 225 Schmidt, R. R., 113 Schneider, F., 8 Schnerign, H. Georg von, 108 Scholastico, C., 172 Schuler, B., 237 Schultz-von-Itter, N., 201, 216 Schwartz, E., 227 Scolastico, C., 14 Scolastico, S., 14 Seapy, D. G., 81 Secci, M., 2 Sedon, J. H., 52, 64 Seebach, D., 172, 236 Segawa, T., 146 Segi, M., 234 Seitz, G., 239 Seitz, S. P., 117, 172 Seitz, T., 109, 111 Selim, M. M. R., 179 Semkow, A., 242 Senio, A., 242 Seri, T., 154 Serra, A. C., 64, 70, 71 Sevin, A. -F., 115 Shancez, J., 11, 12 Shapiro, E. S., 51 Sharma, R. P., 209 Shedrake, G. N., 232, 238 Shelvin, P. B., 64 Shepherd, T. A., 239 Sherbine, J. P., 216 Sherman, W. V., 62 Sherrington, D. C., 242 Sherwin, P. F., 242 Shibata, M., 93, 118, 125 Shibata, S., 178 Shibata, T., 93, 111,112, 118

AUTHOR INDEX

Shibuya, I., 144 Shibuya, S., 74 Shigemasa, Y., 216 Shim, S. C., 160 Shimizu, H, 204 Shin, C-L., 189 Shostakovskii, M. F., 51 Shvestsova-Shilovskaya, K. D.,51 Sidel'korkayo, F., 51 Sih, C. J., 2, 177, 185 Simmons, T. C., 72 Simmons, T., 3 Simon, R., 8 Simpson, R. E., 59 Sims, C. g., 41 Sinclair, M. W., 240 Sing, R., 36 Singh, A. P., 167 Singleton, D. A., 60, 61 Sinnreich, J. A., 65 Sipio, W. J., 117, 172 Sizov, A. Y., 117 Slawin, A. M. Z., 179, 181 Smiles, S., 194 Smit, W. A., 89-94, 97, 98, 101,103, 104, 108 Smith, C. S., 171 Smith, D. J. H., 254 Smith, G. D., 90 Smith, I. H., 142 Smith, T. A. K., 69 Smoliakova, I. P., 103, 104 Snyder, J. P., 78 Soderquist, J. A., 161 Sokolenko, V. A., 69 Solladi6, G., 1,4, 5, 7, 8, 1012, 14, 16, 18-21, 25 Solladid-Cavallo, A., 8, 10, 12 Solouki, B., 242 Sommons, D. P., 173 Sonada, N., 55 Sondej, S. C., 211 Sonoda, N., 54, 234 Spagnolo, P., 121 Speckamp, W. N., 74 Spivak, A. Y., 172 Stacey, F. W., 51, 56, 65 Stange, A., 78 Stanley, J. H., 62 Stanmer, C. H., 94 Steckhan, E., 201,216 Stingham, R. A., 187 Stirling, C. J. M.. 3, 5, 64, 65

Stork, G., 57, 198 Stringham, R. A., 76 Strukelj, M., 91 Stults, B. R., 239 Stults, J. S., 227 Suarez, E., 207 Suffert, J., 12 Suffolk, R. J., 241 Suga, S., 234 Sugawara, A., 145 Sugawara, R., 146 Sugiyama, K., 17 Suhara, Y., 144 Sui, Z., 203 Sumi, K., 82 Sumoto, K., 198 Sundermeyer, W., 237 Surzur, J-M., 53, 70 Sutherland, J. K., 57 Suzuki, F., 2 Suzuki, H., 207,216 Suzuki, M., 192 Suzuki, T., 242, 243,253 Szeimes, G., 61 Tabak, G., 55 Tachibana, Y., 235 Tada, M., 80 Taddei, F., 25 Taddei, M., 115 Tagami, K., 5 Taguchi, T., 207 Taguchi, Y., 144, 146 Tailhan, C., 82 Takahara, Y., 64 Takahashi, A., 5 Takahashi, K., 15 Takahashi, M., 234 Takahashi, T. T., 198 Takai, K., 170 Takaishi, Y., 177 Takatori, K., 178 Takayama, H., 29-32 Takayama, M., 31 Takeda, N., 242, 244, 245, 248, 253 Takeuchi, Y., 26, 29, 32, 41 Takeue, S., 127 Tamura, R., 207 Tamura, Y., 198 Tanabe, M., 202 Tanaka, H., 54, 146 Tang, P. W., 5 Tani, H., 148, 207 Tanimoto, S., 120, 202, 216

267

Taninguchi, H., 93, 125 Taylor, R. J. K., 117 Tejwani, R. B., 171 Ternay, A. L., 3 Theramongkol, P., 100 Therien, M., 138 Thompson, D. M., 80 Thraisrivongs, S., 160 Thullier, A., 55 Tidwell, T. T., 103 Timar, T., 213 Timokhina, L. V., 242 Togo, H., 57, 79 Tokitoh, N., 242, 244, 245, 248, 253 Toll, B. R., 202 Tolstikob, G. A., 172 Torre, A., 57 Torre, G., 2 Torreilles, P., 194, 197 Tortoreto, P., 82 Toru, T., 55 Toshimitsu, A., 120 Tottleben, M. J., 74 Toyoshima, K., 99 Tramontini, M., 2 Tran, P. B., 207 Trost, B. M., 93, 109, 111, 112, 118, 125 Troung, P. N., 225 Troyanskii, E. I., 170 Truce, E. W., 65,216 Truesdale, L. K., 162 Trujillo, D. A., 94 Tsai, Y-M., 189 Tsuchihashi, G., 185, 186, 254 Tuladhar, S. M., 115 Tuttle, M., 73 Tzeng, T-L., 209 Uda, H., 5, 10, 11 Udarov, B. G., Uebake, T., 80 U eda, H., 204 Uenishi, J., 198 Ueno, Y., 58, 64, 68 Uguen, D., 70 Umezawa, B., 199 Uneme, H., 140, 142, 170 Uneyama, K., 189 Unterweger, W. D., 202 Urbano, A., 37-39 Uribe, J. M., 189 Uruma, T., 76

268

Usov, V. A., 242 Utimoto, K., 59, 170 Utley, J. H. P., 201

Vajna de Pava, O., 181 Valle, G., 33, 34, 118 Valle6, Y., 236, 242 Van Niel, M. V., 171 Van, A., 173 Vanderesse, R., 208 Varghese, J. P., 171 Varie, D. L., 227 Vasil'eva, M. A., 65 Vaughan, W. S., 176 Vedejs, E.,72, 227, 228, 239 242, 243,246, 248, 249, 251,253 Veksli, Z., 61 Vicente, M., 16 Vidari, G., 148 Viljoen, H. W., 173 Viljoen, J. C., 173 Villa, M. J., 115, 125 Villemin, D., 144, 167 Vines, S. M., 4 Virgili, A., 69 Viso, A., 115, 117 Vodden, A., 241 Vong, A. K. K., 60 Vorobieva, E. A., 92 Voronkov, M. G., 242 Voss, J., 242 Vyrypaeis, E. M., 172

Wada, Y., 74 Waddell, S. T., 61 Wade, K., 242 Wagner, E. R., 144 Wagner, H. U., 61 Wagner, P. J., 52, 64 Wagner, R. D., 59 Wakabayashi, S., 198 Walborsky, H. M., 208 Wall, A., 65 Wallace, T. J., 55 Walling, C., 72 Walton, D. J., 120

AUTHOR INDEX

Walton, J. C., 68 Wan, J. K. S., 254 Wang, B. S. L., 208 Wang, M. C., 209 Wang, Q., 199, 201 Warren, S., 115-117, 123, 125, 126, 206, 216 Watanabe, S., 248-251,253255 Waters, W. A., 62, 64 Wazneh, L., 241,242 Webster, R. G., 241,242 Weisenfeld, R. B., 216 Weitzberg, M., 6 Wenger, E., 173,174 Wenz, A., 3 Westell, A. D., 122 Westphalen, K. P., 142 Westwood, D., 16, 179, 181 Weygand, F., 172 White, J. D., 100 White, R. L., 236 Whitham, G., 69 Wiberg, K. B., 61 Wilde, R. G., 227, 242, 243, 246, 248, 249, 251,253 Wilkinson, J. A., 213 Willcott, M. R., 64 Willey, P. R., 216 Williams, A. F., 174 Williams, D. J., 179, 181 Williams, D. R., 77, 117 Williams, J. R., 207 Willis, C. R., 62, 63 Wilson, G. E., 205 Wilson, J. S., 78 Wilson, L. J., 123 Wilson, S. R., 172 Wipf, P., 54 Witiak, D. T., 236 Wittenberger, S., 227 Wolf, G. C., 65, 66 Wong, H. C.,144 Wong, K-T., 209 Woo, S. H., 37 Wood, W. W., 208 Woodward, R. B., 242 Wooster, N. F., 52 Wrest, J. D., 160 Wuerthele, M., 203 Wuerzer, B., 142

Wysocki, R. J., 58

Yadav, V. K., 74, 189 Yam, T. M., 208 Yamada, K., 76 Yamaguchi, T., 144 Yamakawa, K., Yamamoto, H., 29 Yamamoto, M., 31, 76 Yamamoto, S., 93, 126, 235 Yamamoto, T., 248-251, 253-255 Yamanaka, H., 79 Yamasaki, Y., 235 Yamauchi, M., 254 Yanagiya, K.,144 Yand, Y. L., 177 Yang, D., 74 Yashuhiro, W., 198 Yasumoto, M., 144 Yeske, P. E., 68 Yoden, T., 137 Yokomatsu, T., 74 Yokoto, M., 137 Yokoyama, H., 54 Yokoyama, K., 54 Yonekura, M., 124 Yonemitsu, O., 189 Yoshida, E., 163 Yoshida, T., 167 Yoshii, E., 28, 29, 31 Yoshino, H., 207 Yoshiyama, T., 213 Youn, I. K., 144 Young, R. N., 117, 138 Yuan, T-M., 209 Yus, M., 65 Zaman, S. S., 209 Zard, S. Z., 57, 79, 80, 82 Zatorski, A., 5, 28 Zefirov, N. S., 91-93 Zhao, K., 198 Zhao, L., 82 Zhao, S. H., 237 Ziani-Cherif, C., 16, 20, 25 Ziegler, K., 3

SUBJECT INDEX Acetamido sulfides formation of, 120 Acetate reductions, 62 Acetylenic allylic sulfones, 69 oL-Acoradiene cyclization of, 57 Acrylate esters, 64 Acryloyl proline esters, 122 Acyclic dithioacetals formation of, 149 reaction of, 189 S-Acyl phenylselenosulphides preparation of, 56 rearrangement of, 55 2-Acyl-l,3-dithianylanions chemistry of, 171 1-Acyl-l-alkenyl sulfoxides reactions of, 26 2-Acyl-2-alkyl-1,3-dithiane 1-oxides diastereoselective reduction of, 16 Aldehydes decarbonylation of, 62 Alkenylsulfenylation of alkenes, 109 Alkenyl sulfoxides Diels-Alder reactions of, 25-41 Alkoxy sulphides formation of, 112 Alkoxydienes, 227 oL-Alkoxythiiranium ions: reaction with allyl silanes, 104 with stannane drivs., 104 Alkyl enol ethers reaction of, 103 Alkyl halides reactions of, 55, 57, 62 Alkyl radicals addition to S-acyl xanthate esters, 82 genaration from alcohols, 78 from alkyl Aryl sulfides, 74-76 from carboxylic acids, 78 from sulfides, 73-74 from sulfones, 76 from thiocarbonyl groups, 76-79 from thiols, 72-73 Alkyl thioethers synthesis of, 170 3-Alkylthioaldehydes formation of, 55 Alkylthiocylthioacetals formation of, 138 Alkyltrithiocarbonates preparation of 146

Allyl acrylates, 70 Allyl cyanomethyl sulfide, 242 Allyl ethyl sulfide flash vacuum pyrolysis of, 241 Allyl silanes reaction with thiiranium ions, 104, 105 Allyl stannanes, 68, 104 N-Allylacrylamide cyclization of, 70 Allylic hydrocarbons dehydrogenation of, 62 Allylic methyl carbinols preparation of, 10 Allylic sulfides formation of, 126 reaction of, 79 Allylic sulfones, 68 Aluminium trichloride, 149, 162 Alykllithium-cerium reagents, 184 Amberlyst-15, 167 dithiolation using, 202 Amidines, 121 [3-Amino sulfides formation of, 118, 121,122 ~/-Aminobutyric acid, 142 Andersen synthesis, 2-7 of acyclic vinylic sulfoxide, 6 Anoralkanes formation of, 79 Antagonists preparation of, 138 Anthracene reactions of, 229, 232, 237, 238 Anthraquinone, 199 Antimony pentachloride, 192 Antimuscarinic agents, 136 L-Arabinitol asymmetric synthesis of, 19 Arenesulfinates Grignard reaction of, 4 Arenethiyl radicals, 52 Aryl dithioacetals hydrolysis of, 198 Arylalkyl dithiolanes hydrolysis of, 202 ~-Arylthio ~-sulfinyl ketones reduction of, 14 Aspergillus niger, 181 (-)-Aspicilin formation of, 20 Azadienes reaction of, 239 Azoisobutylronitrile, 254

270

SUBJECTINDEX

Baker's yeast, 177, 180 Baldwin's rules, 54 Barton-McCombie reaction, 63 Benzhydryl sulfoxides pyrolysis of, 64 6H-1,2,3,4,5-Benzopentathiocin, 235 Benzophenone, 189 Benzophenone dithioacetals, 198 convertion to gem-difluorides, 213 5H-1,2,3,4-Benzotetratiepin, 235 Benzylic hydrocarbons dehydrogenation of, 62 Bimolecular homolytic substitution, 61 Biomimetic polyene cyclisation, 106 1,2-Bis (t hioeth e rs) formation of, 124 Bis(tri-n-butylin) sulfide formation of, 187 Bis(trimethylsilyl)sulfide, 95 reaction with aldehydes, 233 Bornyl propenoates, 122 ( Z )-(Rs)-3-( 2-endo-h y droxy- l O-Born ylsulfinylacrylate Diels-Alder reaction of, 34 Boron trichloride, 160, 189 Boron trifluoride etherate, 106, 108, 149, 160, 162 [3-Bromo sulfides, 94 3-Bromo-2-butylsulfonyl-l-propene preparation of, 94 N-Bromo-succinimide reaction of, 213 Bromobenzoquinone bisketal, 37 e~-Bromoketones reaction of, 203 2-Bromomagnesium-l,3-dithiane condensation of, 21 2-Butadienyl-l,3-dithianes preparation of, 175 reactions of, 175 t-Butyl 2-p-tolylsulfinylacetate Knoevengel condensation of, 34 t-Butyl hypochlorite, 198 2-t-Butyl-l,3-propanedithiol synthesis of, 142 1-Butyldienyl phenyl sulfoxide Diels-Alder reaction of, 41 t-Butyldimethylsilyl ether, 111 t-Butyldimethylsilyl ketene acetals, 98 Butyllithium, 216, 233,243, 251

Carbaloximes, 80 Carbocycles formation of, 72

Carbocyclic nucleosides synthesis of, 35 Carbon disulfide, 143, 144, 173 Carbon tetrachloride, 198 Carbon-centred radicals reaction of, 79 Carbon-sulfur bonds formation of, 79-82 Carboxysulfenylation of alkenes, 109, 117 Cerium ammonium nitrate, 38, 191 Charatoxin, 139 Chloramine T TM as aminating agent, 198 ~-Chloro 13-keto sulfoxides preparation of, 16 reduction of, 20 sulfinyl epoxides from, 16 ~-Chloro sulfides, 96, 100, 109, 122 N-Chloro-succinimide reaction of, 213 N-Chlorocarbamates, 207 2-Chloromagnesium-l,3-dithiane condensation of, 21 m-Chloroperoxybenzoic acid, 253 N-Chlorosuccinimide, 211 Chlorotoluenes reactions of, 174 Chloroxylenes reactions of, 174 Cholanic acids, 57 Cobalt chloride-trimethylchlorosilane, 154 Coleoptera, 139 Cotton effect, 3 Cyanide reaction with thiiranium ions, 111 Cyanocuprates reaction of, 16, 20 Cyclic carbonates, 77 Cyclic disulfides enzymatic oxidation of, 2 Cyclic ethers synthesis of, 112 Cyclic polyenes, 57 Cyclic- 1,3-dithio acet als rearrangement to dithiins, 202 Cycloalkanone enol silyl ethers condensation of, 6 Cyclohexanones formation of, 60 1,5-Cyclooctadiene, 70 Cyclopentadiene, 25, 26, 227,230, 232, 237 Cyclophanes preparation of, 73 Cyclopropylmethylbutenyl rearrangement of, 71

SUBJECTINDEX

2 71

DABCO (see 1,4-diazabicyclo[2,2,2] octane) Danishefsky's diene, 36, 227 DAST (see diethylaminosulfur trifluoride) Dehydronorcamphor, 26 Dephenylketene, 248 cis-[3-Deuteriostyrene, 64 Dialkyl disulfides, 79 S,S-Dialkyltrithiocarbonates preparation of, 144 Dially sulfide thermal decomposition of, 237 Dially sulfoxide, 237 Diaryl disulfides, 79 Diathianyl anion formation of, 137 1,4-Diazabicyclo[2,2,2]octane, 33 Diazomethane, 250 Dibenzobarrelene synthesis of, 25 Dibenzyl sulfones, 76 Diborane reduction of, 8 Dibromo sulfides, 94 1,3-Dibromo-5,5-dimethyl hydantion, 212 Dibutyl disulfide, 61 2,6-Dichlorobenzoyl chloride, 20 Dichlorodimethylsilane, 160 1,3-Dienes formation of, 209 1,4-Dienes formation of, 209 Diethylaminosulfur trifluoride, 96

Dimethyl disulfide, 57,240 Dimethyl sulfate, 117 Dimethyl sulfoxide, 118 Dimethyl(methylthio)sulfonium tetrafluoroborate, 93 2,3-Dimethyl-l,3-butadiene, 227, 229, 232, 234, 239, 248 2,2-Dimethyl-2-sila-l,3-dithiane as thioacetalation reagent, 161,162 9,10-Dimethylanthracene, 229, 232 2,2-Dimethylpropanethial, 248, 249 Dimethylzinc, 109 Diphenyl diselenide, 54 Diphenyl dithioacetals, 201 Diphenylnitrileimine, 249 Diphenylsilane, 79 Diselenides, 59 Disulfides 79, 93 aromatic, 59 Disulfides addition to alkenes, 54 1,3-Dithioacetals, 113-219 applications of, 134-143 as functional groups, 191-219 chemistry of, 171-191 synthesis of, 143-171 1,3,2-Dithiaborolanes, 160 1,3-Dithian-2-thiones formation of, 144, 145 1,3-Dithiane-2-carboxylic acid, 172 Dithianes applications of, 144 desulfurization of, 189 hydrolysis of, 198 reactions of, 204 reduction of, 177 2-Dithianylacetone reduction of, 180

formation of, 209, 213 2,3-Dihydro-l,4-oxathin, 242 1,2-Dihydrocyclobutabenzene, 174 Dihydropyrans reaction with sulfenyl chlorides, 100 Diisobutylaluminium reduction of, 9 Diisopropyl aminomagnesium bromide, 6 1,3-Diketones dianions of, 7 [3,~/-Diketosulfoxides reduction of, 16 Dimesityl disulfide, 61 1,4-Dimethoxy-2-bromobenzene, 38 Dimethoxydioxirane, 253 Dimethyl acetylene dicarboxylate, 33 Dimethyl diallylmalonate, 56

formation of, 154 syntheses of, 202 Dithio acids addition to alkenes, 55 Dithioacetals applications of, 134, 191,202 fluorination of, 212 formation of, 144, 146, 149 hydrolysis of, 192, 194, 198 in crop protection compounds, 138 in pharmaceuticals, 136 preparation of, 138 radical reactions of, 186 Dithioketene acetals formation of, 144 1,3-Dithiolan-2-ones formation of, 144, 145

Cytochalasin synthesis of, 228

gem-Difluorides

1,4-Dithiins

272

Dithiolane sulfoxides rearrangements of, 193, 204 Dithiolanes applications of, 134, 144 formation of, 167 reactions of, 186, 204 1,3-Dithiophenylthioacetals reactions of, 206 Dithiothreitol, 236 Episulfide reaction with stable ylids, 235 Episulfonium ions (see thiiranium ions) Epoxides preparation of, 10 2,3-Epoxy sulfides formation of, 121 Ethane-l,2-dithiol, 160 Ethanesulfenyl chloride matrix photolysis of, 241 Ethoxy-p -tolylvinylsulfonium tetrafluoroborate, 40 Ethyl cyanoformate, 142 Ethyl diazoacetate, 249 Ethyl p-tolylsulfoxide preparation of, 2 total resolution of, 2 Ethyl pyruvate, 28 Ethylene dithioketals reduction of, 209 Ethylene glycol, 251 [3-Fluoro sulfides preparation of, 95 Fluorosulfuranes formation of, 97 2-Formyl-l,3-dithianes alkylation of, 172 Geotrichum candidum, 181 Germacrene cyclization of, 57 Glutaric anhydride, 18 Glutathione hydrogen abstraction from, 62 Glyoxylase I total synthesis of, 31 Glyoxylic acid, 34 Guaiazulene formation of, 62 Hexabutyldistannane, 57 5-Hexenyl rearrangements, 56

SUBJECTINDEX

Hoffman elimination, 26 Homolytic allylic substitution reactions, 67 Hunsdiecker products formation of, 79 Hydrogen chloride, 148 Hydrogen sulfide, 53, 234 [3-Hydroperoxysulfides formation of, 55 oL-Hydroxy dithioacetals hydrolysis of, 216 [~-Hydroxy sulphides cyclisation of, 117 formation of, 96, 112, 117 reactions of, 115, 126 4-Hydroxy-2-cyclohexenone preparation of, 14 [3-Hydroxy-~-sulfonamido sulfides, 123 2-Hydroxy-tetralone, 114 c~-Hydroxydithianes rearrangement of, 203 13-Hydroxysulfides reactions of, 55,120 13-Hydroxysulfoxides desulfurization of, 10 formation of, 10 Indane, 174 N-Iodo-succinimide reaction of, 213 Iodosobenzene difluoroacetate reaction of, 198 Iodosylbenzene, 125, 198 Isomyl nitrate hydrolysis using, 198 Jones oxidation, 26 Ketenedithioacetals formation of, 184 ~-Keto sulfoxides reduction of, 1, 2, 7-16 a-Keto radicals formation of, 60 [3-Keto sulfides preparation of, 227 3-Keto-l,3-dithiane condensation of, 141 Ketoditerpene totarolone synthesis of, 106 a-Ketodithiane-S-oxides preparation of, 181 Ketodithianes reductions of, 177, 178, 180

SUBJECT[NDEX

Ketone reduction stereoselectivity of, 7 Kinetic stabilization, 226

(S)-Lactate reaction of, 184 Lactones preparation of, 10 synthesis of, 112 Lanthanum trichloride, 149 Lasiodiplodin dimethyl ether total synthesis of, 18 LDMAN (see lithium 1-(dimethylamine) naphthalenide) Lepidoptera, 139 Leuktrienes antagonists of, 138 Lithium 1-(dimethylamine)naphthalenide, 216 Lithium aluminium hydride, 146 Lithium cuprates use of, 4 Lithium hexamethyldisilazide, 176 Lithium Naphthalenide use of, 216 Lumbiconereis heteropoda, 139

Macrolide aspicilin asymmetric synthesis of, 19 Macrolides asymmetric synthesis of, 18 Magnesium bromide, 152 Manganese triacetate, 70 Markovnikov regioselectivity, 90, 99 Masamune method, 19 1-Menthol reaction with p-toluenesulfinyl chloride, 3 Menthyl 3-(2-pyridylsultinyl)acrylates formation of, 30 Menthyl p-Toluenesulfinate absolute configuration of, 3, 8 Grignard reaction of, 2 (+)-Menthyl propiolate, 30 10-Mercaptoisoborneol, 33 2-Mercaptopyridine, 30 Mercuric chloride, 195 Mesityl isothiocyanate, 249 O-Mesitylene sulfony!hydroxylamine, 198 Mesomeric effect, 242 Methallyl phenyl sulfides, 57 Methanesulfenyl chloride, 122 2-Methoxyfuran, 31

273

Methyl acrylate, 122, 138 Methyl benzenesulfenate reaction of, 108 Methyl glyoxylate, 28 Methyl iodide, 117, 195 Methyl p-tolylsulfoxide optically pure preparation of, 5 Methyl sulfinate Grignard reaction of, 4 Methyl triflate, 117 Methyl(bismethylthio)sulfonium hexachloroantimonate, 93 1-Methyl-2,2-ethoxypyrrolidine, 141 2-Methyl-2-propanethiol, 230 Methylbenzene sulfenate, 106 Methylcarbinols preparation of, 10 Methylene green, 199 Methylfluorosulfonate, 195 4-Methyliodobenzene difluoride, 213 Methylmagnesium iodide, 179 Methylsulfonium salts, 113 Michael additions on vinylic sulfoxides, 1 Microbial reductions, 183 Molecular oxygen, 59 Montmorillonite KSF, 167 Myrcene, 105 Nation-H, 164 Nereistoxin, 139 Nickel bromide, 208 Nickelocene as reducing agent, 208 [3-Nitro sulfides as thiiranium ion precursors, 107 Nitronium Tetrafluorborate, 197 [3-Nitrosulfides reaction with trimethylsilylcyanide, 111 (-)Norbornenone formation of, 41 Olefinic allylic sulfones rearrangement of, 69 Olivomycin synthesis of, 114 Organochromium complexes, 173 Organoiron complexes reactions of, 173 Organomanganese complexes reactions of, 173 Organometallic reagents, 109 Osmium tetroxide, 19

274

SUBJECTINDEX

1,4-Oxathiins preparation of, 203 Oxathiolanes desulfurization of, 189 reactions of,189, 205,206 Oxybutylnin as calcium channel blockers, 136 Oxygen nucleophiles, 112 Oxysulfonation of alkenes, 112 Paraformaldehyde as exchange reagent, 202 Penicillin sulfoxide photolysis of, 53 1-Penta-O-acetylarabinitol formation of, 19 Pentenesulfonyl chloride cyclization of, 68 Perhalomethanes use of, 79 Phenyl borondichloride, 160 Phenyl sulfenamides reaction of, 120 Phenyl vinyl sulfoxide reaction with anthracene, 25 N-Phenylcycloalkylidene imines, 7 N-Phenylmaleimide, 43 N-Phenylselenophthalimide reaction with thiol acids, 56 Phenylselenosulfates reaction of, 66, 70 Phenylsulfenyl chloride, 92, 101,108, 109, 123, 207 2-Phenylsulfinyl-l,4-naphthoquinone, 37 2-Phenylsulfinylj uglones in cycloaddition reactions, 36 Phenylsulfonium salts, 113 Phenylsulphenyl chloride, 115 Phosphine, 73 Phosphorus ylids reaction of, 235 Phthalimide bleaching herbicides, 143 [3-Pinene, 232 Piperylene, 227 Polarity reversal catalysis by thiols, 63 Potassium dithianes, 172 Prefenic acid derivs synthesis of, 36 1-(phenylthio)Propan-2-one, 101 Propane-l,3-dithiol, 160 Pyridine-hydrogen fluoride reactions of, 213 3-(2-Pyridylsulfinyl)acrylates, 29 Pyruvaldehyde, 177

Radiation damage repair mechanism for, 62 Raney nickel, 10, 19, 208, 209 Rose bengal, 199 Selenenic acids, 230 Selenic amide, 230 Selenium tetrafluoride, 210 Selenoaldehyde, 252 Selenothiolactonization, 55 Sesquiterpenes asymmetric synthesis of, 29 Sila-sulfur reagents for thioacetalation, 162 Silver tetrafluoroborate, 98, 108 Silyl enol ethers, 97, 100, 103 Skunkweed algae, 139 Sodium methoxide, 138 Sodium trithiocarbonate, 145 Spiro derivatives synthesis of, 172 Spirocyclic systems synthesis of, 189 2-Stanna-l,3-dithianes, 163 Stannanes, 72, 74, 79 Steric protection (see kinetic stabilization) (+)-Sterpurene enantioselective synthesis of, 42 Styrenes formation of, 209 Sulfenamides, 93, 115, 121 Sulfenanilides addition to alkenes, 121 Sulfenate esters, 93, 113, 115 Sulfenyl chlorides, 99, 100, 112, 117, 112, 207, 231 Sulfenyl halides, 93, 94 Sulfides asymmetric oxidations of, 2 enzymatic oxidation of, 2 formation of, 72 Sulfinates epimerization of, 3 Sulfinic acid, 232 Sulfinyl alkenolides synthesis of, 6 oL-Sulfinyl carbanions reactivity of, 1 Sulfinyl dienophiles Diels-Alder cycloaddition of, 33 Sulfinyl esters decarboxylation of, 8 Sulfinyl maleates in Diels-Alder reactions, 34, 35 Sulfinyl radicals

SUBJECTINDEX

addition to styrenes, 64 Sulfinyl-2,4-diketones formation of, 7 (Z)-3-Sulfinylacrylates, 32 Sulfin ylcycloh e x an on es stereoselective reduction of, 11, 14 Sulfinyldienes Diels-Alder reactions of, 41-44 Sulfinylquinones synthesis of, 38 [3-Sulfonamido sulfides formation of, 120 Sulfonium salts formation of, 103 Sulfonyl chalcogenides addition to alkenes, 66 Sulfonyl radicals 64-72 addition: to dienes, 70 cyclization of, 68 to unsaturated cobaloximines, 72 Sulfoxides preparation of, 1,4 Sulfur dichloride, 239 Sulfur dioxide thermal extrusion of, 76 Sulfur heterocycles formation of, 53 Sulfur nucleophiles, 124 Sulfur-centered radicals reactions of, 50 Sulfur extrusion from sulfides, 73 Sulfuranes, 91 reactivity of, 92 structure of, 92 Sulfuryl chloride, 167,205 Sulphonyl Radicals, 64, 65 Sulphur reaction with stable ylides, 235 Tellurium tetrachloride, 149 Terpenoids, 62 Tetrachlorosilane, 149 Tetradentate organosulfur ligands synthesis of, 188 1,2,3,4-Tetrahydronaphthalene, 174 2,2,5,5-Tetramethyltetrahydrofuran, 56 Thebaine, 232 Thermodynamic stabilization, 226 Thiadiazolidines, 249 Thiazolidines desulfurization of, 189 Thietanes formation of, 249 irradiation of, 29

Thiirane, 241,253 Thiiranium ions 89-128 nucleophilic attack on, 94-125 ring opening of, 90 synthesis of, 93, 94 Thioacetalation, 137, 149 Thioacetaldehyde, 229 Thioacetals formation of, 152 Thioacetoaldehyde preparation of, 241 Thioacrolein electronic spectra of, 241 formation of, 237 Thioaldehydes, 225-255 generation by 1,2-elimination reactions, 231 by 1,5-sigmatropy of thiosulfinates, 229-231 by photoreactions, 227-229 by thermolysis, 236-240 isolation of, 242 properties of 244-246 reactions of 246-255 spectroscopic detection of, 240-242 synthesis of, 243-244 [3-Thioalkyl radicals, 52 Thioamides formation of, 235 Thioanisole generation of, 109 Thiobenzaldehyde electronic spectra of, 241,242 formation of, 231 reactions of, 229, 238 stability of, 241 Thiobenzophenone, 254 Thiocarbamates, 78 Thiocarbonyl esters fragmentation of, 82 from alcohols, 78 Thiocarbonyl groups uses of, 78 Thiocarbonyl sulfur, 81 Thiocarbonyls enthiolization of, 244 Thioesters as radical traps, 80 4-Thioether-l,3-dithianes, 170 Thioformaldehyde detection of, 242 formation of, 241,242 Thioformyl cyanide formation of, 241,242 Thioketones, 226, 243 Thioketyl radicals

275

276

SUBJECTINDEX

dimerization of, 252 Thiolacids addition to alkenes, 51 Thiolesters, 80 Thiols addition to alkenes, 51 desulfurization of, 72 photolysis of, 253 reactions of, 56 Thiones aminolysis of, 146 Thionolactones formation of, 80 Thionyl chloride, 167,205 Thiophene photoisomerization of, 288 [3-Thiophosphonium salts generation of, 126 Thioseleninates 1,5-sigmatropy of, 229, 230 Thiosulfinates, 232 1,5-sigmatropy of, 229 as precursor of thioaldehyde, 230 Thiyl radicals 50-63 addition to cyclic polyenes, 57 [3-elimination of, 52, 57 cyclisation of, 53 generation of, 53 Thorpe-Ingold effect, 117 Thriphenylphosphine, 244 Thrithanes reacton of, 236 Tiapamil, 136 Tiiranes synthesis of, 95 Tin (II) chloride, 160 Tin hydride desulfurization by, 72, 189 Tin tetrachloride, 105 Titanium tetrachloride, 97, 109, 149, 207 p-Toluenesulfinic acid catalysis by, 3 Toluenesulfonyl cyanide addition to alkenes, 67 Toluenesulfonyl thiocyanate, 66 p-Toluenesulophonic acid, 148 (R)-p-Tolyl vinyl sulfoxide, 26 p-Tolylsulfinyl methyl ketone synthesis of, 7 (Ss)-2-p-Tolylsulfinyl-p-benzoquinone Diels-Alder reactions of, 39 (Rs)-3-p-Tolylsulfinylacrylates formation of, 28 (S)-2-p-Tolylsulfinylbenzoquinone bisketal formation of, 37 diketalization of, 37

Tosyl cyanide, 71 Tosyl iodide, 64, 70 Tosyl radicals addition to alkenes, 64, 70 Tri(isopropyl)silane, 62 Trialkyloxonium tetrafluoroborates as alkylating agents, 195 Tributyl hydride, 64 2-Tributylstannyl-l-l,3-dithiane, 191 Tributyltin hydride, 62, 68 Trichloromethyl isocyanide, 173 Trichloromethyl radicals, 81 Triethylamine, 232 Trifluoromethanesulfonate, 93 3-Trifluoromethyl hypofluorite, 211 Trifluoromethylpyridylsulfinylacrylates oxidation of, 30 Trifluoromethylsulfonic acid, 125 Trifluorothioacetaldehyde preparation of, 237 Triformaldehyde half-life of, 240 2,4,6-Triisopropylsulfenyl chloride reaction of, 109 Trimethyloxonium tetrafluoroborate, 117 Trimethylsilyl cyanide, 111 Trimethylsilyl enol ether, 97 Trimethylsilyl iodide, 195 Trimethylsilyl ketene acetals as nucleophiles, 98 2-[(Trimethylsilyl)oxy]propene, 100 Trimethylsilyllithium, 252 Trimethylsilylsulfenyl bromide formation of, 95 Trimethylsilyltrifluoromethylsulfonate, 203 Triphenylphosphine, 126, 208, 251 Tris(trimethylsilyl)silylmercaptan, 63 1,3,5-Trithiane, 240 Umpolung, 133 Verapamil, 136 Vinyl cyclopropanes reaction with tosyl iodide, 71 with phenylselenosulfates, 71 Vinyl ethers, 64, 99 Vinyl p-tolyl sulfoxide Diels-Alder cycloaddition of, 33 Vinyl stannanes, 68 Vinyl sulfides formation of, 149 Vinyl sulfoxides as acetylene synthons, 25

SUBJECTINDEX

Vinylic sulfide thermolysis of, 236 Vinylic sulfoxides Michael additions on, 1 preparation of, 5

Yashibushiketol total synthesis of, 25 Ylids, 234 Zearalenone dimethyl ether preparation of, 18

Wittig-Horner condensation of sulfinyl phosphonates, 5

277

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