THIOPHENE AND ITS DERIVATIVES

Part One

Edited by

Salo Gronowitz University of Lund

Lund, Sweden

AN INTERSCIENCE@ PUBLICATION

JOHN WILEY AND SONS

NEW YORK 0 CHICHESTER 0 BRISBANE 0 TORONTO 0 SINGAPORE

-

This Page Intentionally Left Blank

THIOPHENE AND ITS DERIVATIVES

Part One

This is the Forty-Fourth Volume in the Series

THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS

T H E C H E M I S T R Y O F H E T E R O C Y C L I C C O M P O U N D S

A SERIES OF M O N O G R A P H S

A R N O L D W E I S S B E R G E R and E D W A R D C . T A Y L O R

Editors

THIOPHENE AND ITS DERIVATIVES

Part One

Edited by

Salo Gronowitz University of Lund

Lund, Sweden

AN INTERSCIENCE@ PUBLICATION

JOHN WILEY AND SONS

NEW YORK 0 CHICHESTER 0 BRISBANE 0 TORONTO 0 SINGAPORE

-

An Interscience@ Publication Copyright 0 1985 by John Wiley & Sons, Inc

All rights reserved. Published simultaneously in Canada.

Reproduction or translation of any part of this work beyond that permitted by Section 107 or 108 of the 1976 United States Copyright Act without the permission of the copyright owner is unlawful. Requests for permission or further information should be addressed to the Permissions Department, John Wiley & Sons, Inc.

Library of Congress Cataloging in Publication Data:

Main cntry under title:

Thiophene and its derivatives.

(The Chemistry of heterocyclic compounds ; v. 44) “An Interscience publication.” Includes index. 1. Thiophene. I. Gronowitz, Salo. 11. Series. QD403.T55 1985 547l.594 84-15356 ISBN 0-471-38120-9 (v. 1)

Contributors

L. I. BELEN’KII N. D. Zelinsky Institute of Organic

Chemistry Academy of Sciences of the USSR Moscow, USSR

P. H. BENDERS Laboratory of Organic Chemistry Twente University of Technology Enschede, The Netherlands

F. BOHLMANN Institut fu r Organische Chemie Tech n isch e Un iv ersitat Berlin, Federal Republic of Germany

G. D. GALPERN Institute of Petrochemical Synthesis Academy of Sciences of the USSR Moscow. USSR

YA. L. GOL’DFARB N. D. Zelinsky Institute of Organic

Chemistry Academy of Sciences of the USSR Moscow, USSR

SALO GRONOWITZ Division of Organic Chemistry 1 Chemical Center University of Lund Lund, Sweden

ANITA HENRIKSSON-ENFLO Institute of Theoretical Physics University of Stockholm Stockholm, Sweden

ALAIN LABLACHE-COMBIER Laboratoire de Chimie Organique

Physique

Universite des Sciences et Techniques

Villeneuve d Ascq, France de Lille

A. E. A. PORTER Chemistry Department University of Stirling Stirling, Scotland

JEFFERY B. PRESS Cardio vascular-CNS Research Section American Cyanamid Company Medical Research Division L ederle Laboratories Pearl River, New York. Presen t affiliation : Ortho Pharmaceutical Corporation Raritan, New Jersey

MAYNARD S. RAASCH Central Research and Development

Experimental Section I<. I. du Pont de Nemours and

Wilmington, Delaware

Department

Company

D. N . REINHOUDT Laboratory of Organic Chemistry Twente University of Technology Ensch ede, The Netherlands

W. P. TROMPENAARS Laboratory of Organic Chemistry Twente University of Technology Enschede, The Netherlands

C. ZDERO Institut fur Organische Chemie Techn ische Un ivers itat Berlin, Federal Republic of Germany

This Page Intentionally Left Blank

To the memory of

VICTOR MEYER

great chemist and teacher and founder of thiophene chemistry

This Page Intentionally Left Blank

The Chemistry of Heterocylic Compounds

The chemistry of heterocyclic compounds is one of the most complex branches of organic chemistry. It is equally interesting for its theoretical implications, for the diversity of its synthetic procedures, and for the physiological and industrial significance of heterocyclic compounds.

A field of such importance and intrinsic difficulty should be made as readily accessible as possible, and the lack of a modern detailed and comprehensive presentation of heterocyclic chemistry is therefore keenly felt. It is the intention of the present series t o fil l this gap by expert presentations of the various branches of heterocyclic chemistry. The subdivisions have been designed t o cover the field in its entirety b y monographs which reflect the importance and the interrelations of the various compounds, and accommodate the specific interests of the authors.

In order to continue to make heterocyclic chemistry as readily accessible as possible new editions are planned for those areas where the respective volumes in the first edition have become obsolete by overwheliniiig progress. If, however, the changes are not too great so that the first editions can be brought up-to-date by supplementary volumes, supplements to the respective volumes will be published in the first edition.

Research Laboratories Eastman Kodak Company Rochester, New York

Princeton University Princeton, New Jersey

ARNOLD WEISSRERGER

EDWARD C. TAYLOR

ix

This Page Intentionally Left Blank

Preface

In 1952, in the first volume of The Chemistry of Heterocyclic Compounds, Howard D. Hartough described the state of research on the chemistry o f thiophene and its derivatives up t o 1950. Selenophene and tellurophene were also included in this monograph which, except for two chapters was written b y Hartough alone. When this book was written, the explosive development triggered b y the commercial process for thiophene from butane and sulfur, developed b y Socony-Vacuum Oil Company in the 1940’s, had just begun. The enornious aniount o f w o r k carried out on this important aromatic five-membered heterocycle since 1950 makes it of course impossible for one person t o cover all aspects, and a n able group o f special- ists were assembled from all over the world to treat the entire field. This makes some minor overlaps between chapters unavoidable, but I think it is important t o treat some topics from different angles of approach.

Because of the wealth of results and the rather large number of contributors, these volumes are not as strictly organized as some previous volumes in this series, bu t can be considered as a collection of topics on thiophene chemistry. Together, however, it is my hope that these chapters give as comprehensive a description as possible of the chemistry of thiophene and its monocyclic derivatives, based on the literature from 1950 t o 1982. References t o previous results, treated in Hartough’s book, are also given when necessary.

The chapters fall in two categories: (1) those that treat syntheses, properties, and reactions of thiophenes, and (2) those that treat systematically functionalized simple thiophenes, such as alkylthiophenes, halothiophenes, aminothiophenes, thiophenecarboxylic acids, and so on. The latter chapters, as is customary in the Wcissberger-Taylor series, contain tables of compounds with their physical proper- ties, which should be very useful for all synthetic chemists. Part 1 of these volumes contains only chapters in category (1) and starts with a treatise o n the preparation of thiophenes by ring-closure reactions and from other ring systems. It is followed by a chapter on theoretical calculations. Then, in two chapters, naturally occurring thiophenes in plants and in petroleum, shale oil, and coals are treated. The topic of the next chapter is the important field of pharmacologically active compounds. The synthetic use of thiophene derivatives for the synthesis of aliphatic compounds by desulfurization follows. Two chapters treat thiophenes modified a t the sulfur, namely thiophene-1,l-dioxides and thiophene-1-oxides, and S-alkylation of thiophenes. In the last three chapters, the discussion on different reactivities of thiophenes starts with radical reactions of thiophenes, cycloaddition reactions, and photochemical reactions.

In the latter parts of this monograph, chapters on derivatives such as alkyl- thiophenes, halothiophenes, nitrothiophenes, aminothiophenes, hydroxy- and alkoxythiophenes, thiophenethiols, thiophenesulfonic acids, metal derivatives, formyl and acyl derivatives, thiophenecarboxylic acids, thienylethenes and

xi

x ii Preface

-acetylenes, arylthiophenes, and bithienyls are intercalated with chapters o n physical and spectroscopical properties, electrophilic and nucleophilic substitution, and side-chain reactivity.

I wish to thank all the distinguished scientists who contributed chapters t o these volumes for their splendid cooperation and my secretary Ann Nordlund for her invaluable help. I am also indebted to Dr. Robert E. Carter for correcting my chapter and those of some of the other authors whose native tongue is not English.

SALO GRONOWITZ

Lund, Sweden August I984

Contents

I

I1

111

IV

V

VI

VII

VIII

IX

X

PREPARATION OF THIOPHENES BY RING-CLOSURE REACTIONS AND FROM OTHER RING SYSTEMS

SALO GRONOWITZ

THEORETICAL CALCULATIONS ON THIOPHENES

ANITA HENRIKSSON-ENFLO

NATURALLY OCCURRING THIOPHENES

F. BOHLMANN and C. Z L I I X ~

THIOPHENES OCCURRING IN PETROLEUM, SHALE OIL, AND COALS

G. D. GALPCRN

1

215

26 1

325

PHARMACOLOGICALLY ACTIVE COMPOUNDS AND OTHER THIOPHENE DERIVATIVES

JEIWRY B. PRESS

353

REDUCTION AND DESULFURIZATION OF THIOPHENE COMPOUNDS

L. I . BELEN’KII and YA. L. GOL’DPARH

THIOPHENE 1 ,]-DIOXIDES, SESQUIOXIDES AND 1 -OXIDES

MAYNARD s. RAASCH

REACTIONS AT SULPHUR

A. E. A. PORTER

RADICAL REACTIONS OF THIOPHENE

A. E. A. PORTER

CYCLOADDITION REACTIONS OF THIOPHENES, THIOPHENE-1 -OXIDES AND 1 ,I -DIOXIDES

P. M. BENDERS, D. N . REINHOUDT, and W . P. TROMPENAARS

457

57 1

629

651

67 1

xiii

xiv Contents

XI PHOTOCHEMICAL REACTIONS OF THIOPHENES

&AIN LABLACWE-COMBIER

AUTHOR INDEX

SUBJECT INDEX

745

771

819

THIOPHENE AND ITS DERIVATNES

Part One

7'his is the Forty-Fourth Volume in the Series

THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS

This Page Intentionally Left Blank

CHAPTER I

Preparation of Thiophenes by Ring-Closure Reactions and

from Other Ring Systems SALO GRONOWITZ

Division of Organic Chemistry I . Chemical Center. University of Lund. Lund. Sweden

I . Introduction . . . . . . . . . . . . . . . . . . . . I1 . Two-Component Methods . . . . . . . . . . . . . . . .

1 . C, + S Methods . . . . . . . . . . . . . . . . . . A . Thiophenes from Alkanes. Alkenes. and Alkadienes and

Sulfur-Con taining Reagents . . . . . . . . . . . . . . B . Thiophenes from the Rcaction of Diacetylenes and Related Compounds

with Hydrogen Sulfide . . . . . . . . . . . . . . . C . Thiophenes from the Reactions of 1.4.Dicarbony 1. and Related

Compounds with P,S,, . . . . . . . . . . . . . . . D . Thiophenes from the Reactions of 1.4.Dicarbony I. and Related

Compounds with Hydrogen Sulfide and IIydrogen Chloride . . . . . E . Thiophenes from 7-Keto Acids and Sulfurating Agents . . . . . . 1. . Thiophenes from the Reaction of Succinic Acid Salts with P,S,, and

Other Sulfurating Agents . . . . . . . . . . . . . . G. Thiophenes from Tetra- and Tricyanoethylencs and H, S . . . . . I I . Thiophenes Through the Willgerodt-Kindler Reaction . . . . . . I . Thiophenes by Various C, + S Methods . . . . . . . . . .

2 . C, + CSC Methods . . . . . . . . . . . . . . . . . A . The Hinsberg Reaction . . . . . . . . . . . . . . . B . Thiophenes from a-Diketones and Wittig Reagents . . . . . . .

. . . . . . . . . . . . . . . . . A . The Gewald Reaction . . . . . . . . . . . . . . . B . Various Reactions . . . . . . . . . . . . . . . .

A . The Crompper Reaction . . . . . . . . . . . . . . . B . The Smutny. Rajappan. and Related Reactions . . . . . . . .

5 . C, + CS Methods . . . . . . . . . . . . . . . . . . A . The Fiesselmann Reaction . . . . . . . . . . . . . .

a . Introduction . . . . . . . . . . . . . . . . .

3 . C, S + C, Methods

4 . C, S + C Methods . . . . . . . . . . . . . . . . . .

C . The C, S + C Modification of the Fiesselmann Reaction . . . . . .

b . Thiophenes from Acetylenes and Alkyl Thioglycolates . . . . . c . Thiophenes from p-Keto Esters and Alkyl Thioglycolates . . . . d . Thiophcnes from a. @.Dihalo Esters or aHalo.. P.Unsaturated Esters

and Alkyl Thioglycolates . . . . . . . . . . . . .

2 4 4

4

11

15

21 25

27 27 28 30 34 34 42 42 42 5 9 66 66 78 84 88 88 88 89 91

9 1

2 Salo Gronowitz

e . Thiophenes from a, p.Dihalonitriles and pChloroacrylonitriles and Alkyl Thioglycolate . . . . . . . . . . . . . .

f . Thiophenes from p.Diketones, Ketoaldehydes and Related Compounds. and Thioglycolates . . . . . . . . . .

g . Thiophenes from 0-Halovinyl Aldehydes and Ketones with Thioglycolates . . . . . . . . . . . . . . .

h . Thiophenes from a-Bromovinylketones and Thioglycolates . . . i . Thiophenes from Reactions with Other a-Mercapto Derivatives . j . Various Ring-closure Reactions According to Fiesselmann . . .

€3 . Thiophenes from Various C, + CS Ring.Closures . . . . . . . I11 . Three- or More-Component Methods . . . . . . . . . . . .

C, + C, + S Methods . . . . . . . . . . . . . . . . 1 . A . Thiophenes from 2 Moles of Acetylenes and a Sulfur Reagent . . . B . Thiophenes from Two Moles of an Olefin and Sulfur Reagent . . . C . Thiophenes from Methyl Ketones and Sulfur Reagents . . . . . D . Various Reactions of C, + C, + S Type and Reactions Involving Large

Numbers of Compounds . . . . . . . . . . . . . . IV . One-Component Methods . . . . . . . . . . . . . . .

1 . Ring-Closure ofC.,-Scornpounds toThiophenes . . . . . . . 2 . RingClosure ofC,-S--C Compounds toThiophenes . . . . . . 3 . Ring-Closure of C,-S--C, Compounds . . . . . . . . . . .

V . Thiophenes from Tetra- and Dihydrothiophenes . . . . . . . . . 1 . Introduction . . . . . . . . . . . . . . . . . . 2 . Dehydrogenation of Simple Tetrahydro- and Dihydrothiophenes . . . 3 . Thiophenes from 3-Oxotetrahydrothiophenes . . 4 . Thiophenes from Dihydrothiophenes Obtained from

Vinylphosphonium Salts . . . . . . . . . 5 . Various Methods . . . . . . . . . . .

VI . Thiophenes from Other Heterocyclic Compounds . . 1 . Thiophenes from Four-Membered Rings . . . . 2 . Thiophenes from F'ive-Membered Rings . . . .

A . Thiophenes from k'urans . . . . . . . . B . Thiophenes from 1, 3.Oxathiolium Derivatives .

D . Thiophenes from 1, 3.Dithiole Derivatives . . . E . Thiophenes from Isothiazolium Salts . . . . F . Thiophenes from 1, 2.Dithiolium Derivatives . .

3 . Thiophenes from Six-Membered Heterocycles . . A . Thiophenes from Rings with One Heteroatom . B . Thiophenes from Rings with Two IIcteroatoms .

b . Thiophenesfrom Other Rings . . . . . References . . . . . . . . . . . . . . .

C . Thiophenes from Thiazolium Derivatives . . .

G . Thiophenes from Thiadiazoles . . . . . .

a . Thiophenes from 1, 4-Dithiins . . . . .

I . INTRODUCTION

. .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

99

103

110 117 120 124 125 127 127 127

. 128

. 131

132 . 132

132 . 141

144 148

. 148 148 152

168 168 170 170 170 170 171 176 179 181

. 182

. 184

. 185 185 188

. 188

. 193

. 193

In this chapter. ring-closure reactions leading to various thiophene derivatives are discussed. as well as the use of di- and tetrahydrothiophenes and other heterocyclic

Introduction 3

compounds for the preparation of thiophenes. The aromatic nature of thiophene leads to the easy formation of the ring system under many different and sometimes unexpected conditions.

The various preparative methods can be systematized according to the number of compounds reacting in the ring-closure, as demonstrated by Meth-Cohn.' The different possibilities are indicated in Scheme 1 ; the transformations with solid lines are known.

The division is of course artificial, and it is a matter of taste whether certain related methods should be treated under C2 + C2 + S, C2S + Cz, or C4 + S. This is the case with the very versatile Gewald reaction, different modifications of which would fall in one of these classes. To provide a uniform treatment, they are all discussed under the CzS + C2 approach. Furthermore, the transformation of other rings into thiophenes is treated in a separate section and is not divided according to Scheme 1 .

Four-Component Methods

c c

S 4. c c

Five-Component Methods

One-Component Methods

Scheme 1

4 Salo Gronowitz

From the synthetic point of view, the two-component methods are by far the most important. The classical thiophene syntheses from disodium succinate and P4Sl0 and the Paal-Knorr synthesis from 1,4-dicarbonyl compounds and P4S10 fall under this heading. The modern commercial routes to thiophene from almost any four carbon units and a source of sulfur over a suitable catalyst at high temperature, and modern laboratory methods using diacetylenes and H,S/HCl, are other examples of the C4 + S approach. The old Hinsberg reaction is a very useful example of the Cz i- CSC technique. Modern methods like the Fiesselmann reaction, consisting of the condensation of thioglycolic esters with acetylenecarboxylic esters or other substrates with the same oxidation level, illustrates the C3 + CS procedure. The reaction of a-mercaptoketones with activated acetonitriles, constituting the original version of the Gewald reaction, illustrates the CzS + Cz approach. These two- component reactions are, therefore, treated first, followed by three- and one- component reactions.

It is an almost impossible task to include examples of all the reactions leading to thiophene derivatives. It is, however, my hope that the coverage of the principal routes to thiophenes is as complete as possible.

11. TWO-COMPONENT METHODS

1. C4 + S Methods

A . Thiophenes from Alkanes, Alkenes, and Alkadienes and Sulfur-Containing Reagents

The discovery and development of the modern thiophene synthesis from butane, butadiene, or butenes with sulfur at Socony-Vacuum Oil Company in the early 1940's was described in detail in Hartough's monograph.' The reaction was carried out at 565°C and contact times between the hydrocarbon and sulfur vapor were about 2 sec. The most useful by-product of this reaction was 3- th i~pheneth io l~ and a product believed to be 3,4-thiolanedithione but later shown to be 5-methyl-1,2- dithi01-3-thione.~ Numerous patents describe the preparation of thiophene from butane, butenes, or butadiene and hydrogen sulfide using an A1203-Cr203 catalyst at about 600"C.5-'7 The reactions of C6-hydrocarbons led to the formation of thiophene and 2- and 3-rnethylthi0phene.'~~ Various catalyst compositions for this process have been described.'s-z' A study of the mechanism of the thiophene synthesis from n-butane and hydrogen sulfide over an alumina-lanthania-chromia- potassium oxide catalyst, using 14C labeled intermediates, showed that the conver- sion of butane into butenes and butadiene took place during thiophene synthesis. In addition, this stepwise dehydrogenation is not the only possible route for thiophene formation, since both butane and butenes can react directly with hydro- gen sulfide on the catalyst surface." The use of piperylene23-25 or pentadienesZ6' 27

Two-Component Methods 5

in the reaction with hydrogen sulfide gave 2-methylthiophene, which was also obtained through the noncatalytic reaction of Cs-straight-chain hydrocarbons with sulfur.28 From isoprene and hydrogen sulfide over a KzO-promoted AI-Cr catalyst, 3-methylthiophene was ~ repa red , ’~ and from 2,3-dimethylbutadiene, 3,4-dimethyl- thiophene was obtained. 3-Ethylthiophene3’ has been prepared from the 2-ethyl- butanol fraction from butanol manufacture by reaction with H2S over the catalyst mentioned a b ~ v e . ~ ~ , ~ ’ Another alternative for the synthesis of thiophene is the reaction of C4-hydrocarbons with sulfur dioxide over suitable catalyst^.^^-^^ 3-Vinylthiophene was obtained from the reaction of 3-methylpentane and sulfur dioxide.43

The influence of transition metal oxides on the catalytic activity of aluminum oxide in this reaction has been evaluated.@ The equilibrium yields of thiophene in the reaction of C4-hydrocarbons with sulfur dioxide or hydrogen sulfide were determined, and thermodynamic calculations on the synthesis of thiophene from butane, butenes, butadiene, and sulfur dioxide or hydrogen sulfide were carried out .45 From 2,3-dimethyl-2-butene and 2,3-dimethylF1,4-butadiene, 3,4-dimethyl- thiophene was obtained.46 A review by Ryashentseva et al. on catalytic methods for obtaining thiophene and alkylthiophenes from CYC6 hydrocarbons and from various organosulfur corn pound^^^^^^ indicates that the reaction with hydrogen sulfide is the most promising one.49 Sulfur atoms, S (‘D) atoms obtained from the gas-phase photodissociation of COS, reacted with 1,3-butadiene to give vinyl t hiacy clo pr o pane and t hio phene . 5 0

Thiophene has been prepared by passing C4-molecules, such as butane, butene, n-butanol, or crotonaldehyde, together with carbon disulfide over a promoted chromium-aluminum oxide catalyst at about 500°C and with short contact times (5-8 s~c) . ’*- ’~ With crotonaldehyde and butanol, yields of 78 and 42% of thiophene were obtained. From Cs-C7 molecules, alkylthiophenes were obtained. Thus, 2-pcntanol gave 70% of 2-methylthiophene, 1- and 3-hexanol yielded predominantly 2-ethylthiophene, 2-hexanol provided a 68% yield of 2,5-dimethylthiophene, and 2-heptanol gave an 84% yield of 2-ethyl-5-methylthiophene. 2-Pentanone was used for the preparation of 2-methylthiophene (80%) and 2-hexanone for the synthesis of 2,5-dimethylthi0phene.’~ (2-Butyne-1,4-diol and butane-1,4-diol derived from it have also been used for the preparation of thiophene by reaction with H Z S ~ ’ ’ ’ ~ or sulfurs7 over Alz03-CrZ03 catalysts at high temperature.)

A method developed by Voronkov and coworkers especially for the synthesis of aryl-substituted thiophenes. consisted of heating alkenes and alkanes with at least four carbons in a straight chain with sulfur at 200-270”C58 (Table 1). Usually, no solvent is used, although o-dichlorobenzene has been utilized in some cases.59 Hydrogen sulfide is evolved, and the yields are often very low. When lower tempera- tures are used, the formation of mixtures of tetra- and dihydrothiophenes has been observed, as in the reaction of 2,6-dimethyl-octa-2,6-diene and sulfur at 140”C.67 Much higher yields are obtained when 1,3-butadienes are used, and excellent yields (90-95%) have been reported for 2,5-diaryl- and 3,4-diarylthiophenes in the reaction of 1,4- and 2,3-diarylbutadienes with sulfur at about 200°C68 (Scheme 2). 1.3-Dienes with various functional groups, such as carbethoxy, cyano, and carbon

m v,

0 *

re" V

4 W

I-

c/

3: u

",

4 V V

,

re" u 0

re u

m

3 CI

re V

0

N 3

0 0 0 0 m m m o N N N N

I l l 1 o o o v , o ~ m m N N 3 d

10

N I

0

N

,-. d

0 v, N

I 0 U N

0 N c1

v,

N d

0

N I

0 0 N

3 v, m N

I v,

OI 4

0

N i

0 0 N

6

z

0 0 1 0 0 N N

a

2s Y O

* 3: u

10 m N

I 0

N ,-

n I

G

3:o u

0 N N I

0

N 3

ci

3: u

i: I:' ?-U ,"

0

z U

3:- 0

0 N N

0

N 3

0

3: 8 U

C-

n u z II u Y

V= y n n

z z u o

0 O N

W W

3

4: N

\ /

+O

7

8 Salo Gronowitz

I I I I S ’ Ar QAr’

CH-CH

ArCH CHAr’

Ar Ar S

2

Ar = CsH5, CsH4CH3-p, C6H40CH3-p

Scheme 2

groups, can also be used in this reaction. In the reaction of a,y-diethylenic ketones, both thiophenes and 1,2-dithioles are formed 71, 72 (Scheme 3). With nit rile^,^" 70

Gewald-type reactions occur (see p. 42).

RCH=CH--CH=CHCOR’

0

+ R & L R I

Scheme 3

Tetrachlorothiophene has been prepared by heating highly chlorinated C4-type compounds with sulfur at temperatures between 150 and 300°C.73’74 The most convenient method for the synthesis of tetrachlorothiophene is the reaction of hexachlorobutadiene and sulfur at 205-240” C (Table 2).

The reaction of 2,3-diphenylbutadiene with bromine, followed by reaction of the mixture of dibromobutenes with sodium polysulfide in DMF, gave 3,4-diphenyl- thiophene as a dominant product, in addition to cyclic disulfides and tetra sulfide^.^' A convenient method for the synthesis of 3,4-di-f-butylthiophene consists of the reaction of 2,3-di-t-butylbutadiene, prepared by the copper-catalyzed reaction of t-butylmagnesium chloride with 1,4-dichloro-but-2-yne, with SC12 in CH2C12 .76

A synthesis of the important penicillin side-chain, 3-thiophenemalonic acid, is shown in Scheme 4.77-78”

Scheme 4

TA

BL

E 2

. R

EA

CT

ION

S O

F 1

,3-A

LK

AD

IEN

ES

WIT

H S

UL

FU

R T

O G

IVE

::Q:l S

ubst

rate

T

empe

ratu

re

Thi

ophe

ne

Yie

ld

Ref

eren

ce

H3C

C, W

,CH

=CH

--C

H=C

H,

CH

, I

CH

,=C

--C

=CH

\D

I

C,H

,CH

=CI-

I--C

H=C

HC

OC

€l

C,H

,CW

=CH

-€H

=C€I

CO

C,H

C

,H ,

CI-

I=C

H-C

H=C

HC

OC

,HO

CH

3-

p

-

21 2-

21 7

210

205-

240

220

220

220

220

270

270

270

36

CH

3 28

8.3

Me

Ph

25

CI

c1

C1

C1

81

CO

CH

, C

OC

,H,

p-C

H,O

C,H

,CO

C

,H,C

O

C,€

I,C

O

C,H

,CO

CO

CI-

I ,

160

160

58

60

161

72

12

1

2

12

71

p-C

H,O

C,H

, 4.

6 71

GI3

5 1.

3 71

TA

BL

E 2

. C

onti

nued

Sub

stra

te

Tem

pera

ture

T

hiop

hene

Y

ield

R

efer

ence

(“

C)

( %)

R,

R,

R4

Rs

‘<‘O

CH

3

270

CO

CH

,

250

CO

C6H

5

230

CO

CH

,

p-C

H,0

C61

1,

2.7

C6

H5

2.

5

71

71

C6

H5

2.

1 7

1

a a-(Dithiol-1,2-ylidene-3)ketones wer

e al

so f

orm

ed.

A t

otal

of

1.2%

of

ethy

l 2-p-methoxyphenyl-5-thiophenecarboxylate

was

als

o fo

rmed

.

Two-Component Methods 11

B. Thiophenes from the Reaction o f Diacetylenes and Related Compounds with Hydrogen Sulfide

A convenient method for the synthesis of 2,5-disubstituted thiophenes is the reaction of conjugated diacetylenes with hydrogen sulfide in aqueous methanol, ethanol, or acetone at pH 9-10 and temperatures between 20 and 80°C.79-81 It was shown recently that thiophene itself can be obtained in 94% yield, when diacetylene and hydrated sodium sulfide are reacted with potassium hydroxide in DMS08’” (Scheme 5). In some cases, glutathione or cystein was used as the source for hydro-

R’-CX--CX-R + H 2 S - R l / \ 0 Scheme 5

gen sulfide.’59 The diacetylene/H2S reaction has been used for the synthesis of naturally occurring t h i ~ p h e n e s . ~ ’ ” ~ No systematic investigation of the influence of substituents on the rate of ring-closure has been carried out. It has been found, however, that di-(dialky1amino)diacetylenes ring-close very slowly, and a reaction time of 30-35 h at 80°C had to be used, whereas dialkoxymethyldiacetylenes ring-closed in 0.5 h.84 In some cases, when the reaction was slow, refluxing butyl alcohol was used as solvent. Some interesting observations on the regiospecificity of the reaction have been made with unsymmetrical triacetylenes (Scheme 6).

3 I SH

4

Scheme 6

Thus, 1 gave only the phenyl thienylacetylene 2 and no phenylthiophene (3). Compound 4 was obtained as a by-product, indicating that the first intermediate is an enethiol upon addition of hydrosulfide to a triple bond.85 Similarly, it is claimed that 5 gives only 6 and no 7 (Scheme 7), (Table 3). A series of mono- and diglycosyl thiophenes has been synthesized recently by the reaction of mono- and diglycosylbutadiynes with sodium hydrosulfide.wa

7

Scheme 7

TABLE 3. THIOPHENES THROUGH THE REACTION BETWEEN DIACETYLENES AND HYDROGEN SULFIDE

R , Yield (%) Reference

H H

CH 3

c 2 H 5

C 6 H S

COOH

(C-C) ,C, H , CECC , H

C6H5

2 - h b 3-PYC

C6HS

2-Tha C, H, -2-Th

C 6 H 5

C6H ,CH(OH) C, H ,CII(OH) (CH ,),CH(OH) C,H5(CH3)C(OH)

A

C, H s-2-Th-

'6"5

C,H,CO

CH,CH,CH,

CH,CH,CH, CH 3C=C

n c' 'z-NWo C 6 H S

CH=C€l-CH ,OH t

CH 3

t

t CH=CHC€12011

CH=CHCOOH HCECHCOOH

20 51 70 65 85 52 83 I 5 56 66 40 68 1 4 74 33 64 14 37 27

55

32

24 60

54

69

36 4 2d

80 80 80 80

80 ,79 80

8 0 , 7 9 8 0 , 1 9

82 82 82 82 82 82 82 82 82 82 82

82

82

82 82

82

82

82 82