Organosulfur Chemistry, Volume 1: Synthetic Aspects

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

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

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

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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

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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.

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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


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

,
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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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~'~

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

~



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 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: 98 :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


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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TRENDS IN THE CHEMISTRY OF

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1,3-DITHIOACETALS

223

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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

"- 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