Progress in Heterocyclic Chemistry: A critical review of the 2001 literature preceded by two chapters on current heterocyclic topics

PROGRESS IN HETEROCYCLIC CHEMISTRY Volume 14 Related Titles of Interest Books CARRUTHERS: Cycloaddition Reactions i...

Author: G.W. Gribble | Thomas L. Gilchrist

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PROGRESS IN

HETEROCYCLIC CHEMISTRY Volume 14

Related Titles of Interest Books

CARRUTHERS: Cycloaddition Reactions in Organic Synthesis CLARIDGE: High-Resolution NMR Techniques in Organic Chemistry FINET: Ligand Coupling Reactions with Heteroatomic Compounds GAWLEY & AUBI~" Principles of Asymmetric Synthesis HASSNER & STUMER: Organic Syntheses Based on Name Reactions KATRITZKY: Advances in Heterocyclic Chemistry KATRITZKY & POZHARSKII: Handbook of Heterocyclic Chemistry, 2 nd Edition LEVY & TANG: The Chemistry of C-Glycosides MATHEY: Phosphorus-Carbon Heterocyclic Chemistry: The Rise of a New Domain McKILLOP: Advanced Problems in Organic Reaction Mechanisms OBRECHT: Solid Supported Combinatorial and Parallel Synthesis of SmallMolecular-Weight Compound Libraries PELLETIER: Alkaloids; Chemical and Biological Perspectives SESSLER & WEGHORN: Expanded Contracted and Isomeric Porphyrins WONG & WHITESlDES: Enzymes in Synthetic Organic Chemistry Major Reference Works

BARTON, NAKANISHI, METH-COHN: Comprehensive Natural Products Chemistry BARTON & OLLIS: Comprehensive Organic Chemistry KATRITZKY & REES: Comprehensive Heterocyclic Chemistry I CD-Rom KATRITZKY, REES & SCRIVEN: Comprehensive Heterocyclic Chemistry II KATRITZKY, METH-COHN & REES: Comprehensive Organic Functional Group Transformations SAINSBURY: Rodd's Chemistry of Carbon Compounds TROST & FLEMING: Comprehensive Organic Synthesis Journals

BIOORGANIC & MEDICINAL CHEMISTRY BIOORGANIC & MEDICINAL CHEMISTRY LETTERS CARBOHYDRATE RESEARCH HETEROCYCLES (distributed by Elsevier) PHYTOCHEMISTRY TETRAHEDRON TETRAHEDRON: ASYMMETRY TETRAHEDRON LETTERS Full details of all Elsevier Science pubfications, and a free specimen copy of any Elsevier Science journal, are available on request at www. elsevier, com or from your nearest Elsevier Science office.

PROGRESS IN

HETEROCYCLIC CHEMISTRY Volume 14

A critical review of the 2001 literature preceded by two chapters on current heterocyclic topics Editors

GORDON W. GRIBBLE

Department of Chemistry, Dartmouth College, Hanover, New Hampshire, USA and

THOMAS L. GILCHRIST

Department of Chemistry, University of Liverpool, Liverpool, UK

2002

PERGAMON An Imprint of Elsevier Science A m s t e r d a m - B o s t o n - L o n d o n - N e w Y o r k - O x f o r d - Paris San D i e g o - San F r a n c i s c o - S i n g a p o r e - S y d n e y - T o k y o

ELSEVIER SCIENCE Ltd. The Boulevard, Langford Lane Kidlington, Oxford OX5 1GB, UK 9 2002 Elsevier Science Ltd. All rights reserved. This work and the individual contributions contained in it are protected under copyright by Elsevier Science Ltd, and the following terms and conditions apply to its use: Photocopying Single photocopies of single chapters may be made for personal use as allowed by national copyright laws. Permission of the Publisher and payment of a fee is required for all other photocopying, including multiple or systematic copying, copying for advertising or promotional purposes, resale, and all forms of document delivery. Special rates are available for educational institutions that wish to make photocopies for non-profit educational classroom use. Permissions may be sought directly from Elsevier Science via their homepage (http://www.elsevier.com) by selecting 'Customer Support' and then 'Obtaining Permissions'. Alternatively you can send an email to: [email protected] or fax: +44 1865 853333. In the USA, users may clear permissions and make payments through the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA; phone: (+1) (978) 7508400, fax: (+1) (978) 7504744, and in the UK through the Copyright Licensing Agency Rapid Clearance Service (CLARCS), 90 Tottenham Court Road, London W1P 0LP, UK; phone: (+44) 20 7631 5555; fax: (+44) 20 7631 5500. Other countries may have a local reprographic rights agency for payments. Derivative Works Tables of contents may be reproduced for internal circulation but permission of Elsevier Science is required for external resale or distribution of such material. Permission of the Publisher is required for all other derivative works, including compilations and translations. Electronic Storage or Usage Permission of the Publisher is required to store or use electronically any material contained in this work, including any chapter or part of a chapter. Except as outlined above, no part of this work may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without prior written permission of the Publisher. Address permissions requests to: Elsevier Science Global Rights Department, at the mail, fax and e-mail addresses noted above. Notice No responsibility is assumed by the Publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. Although all advertising material is expected to conform to ethical (medical) standards, inclusion in this publication does not constitute a guarantee or endorsement of the quality or value of such product or of the claims made of it by its manufacturer.

First edition 2002 Library of Congress Cataloging in Publication Data A catalog record from the Library of Congress has been applied for. British Library of Cataloguing in Publication Data A catalogue record from the British Library has been applied for.

ISBN: ISBN:

008 0 4 4 1 9 0 4 008 044191 2

Hardcover (ISHC members edition)

O The paper used in this publication meets the requirements of ANSI/NISO Z39.48-1992 (Permanence of Paper). Printed in The Netherlands

Contents

Foreword

vii

Editorial Advisory Board Members

viii

Chapter 1: Recent Progress in the Chemistry of Sulfur-Containing Indoles Jan Bergman and Tomasz Janosik, Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden and S6dert6rn University College, Huddinge, Sweden Chapter 2: Electrophile-induced 5-Endo Cyclizations David W. Knight, Cardiff University, Cardiff. UK

19

Chapter 3: T h r e e - M e m b e r e d Ring Systems Albert Padwa, Emory University, Atlanta, GA, USA and S. Shaun Murphree, Allegheny College, Meadville, PA, USA

52

Chapter 4: F o u r - M e m b e r e d Ring Systems L. K. Mehta and J. Parrick, Brunel UniversiO', Uxbridge, UK

75

Chapter 5: Five-Membered Ring Systems Part 1.

Thiophenes & Se, Te Analogs

90

Erin T. Pelkey, Hobart and William Smith Colleges, Geneva, NY, USA

Part 2.

Pyrroles and Benzo Derivatives

114

Daniel M. Ketcha, Wright State University, Dayton, 0tt, USA

Part 3.

Furans and Benzofurans

139

Xue-Long Hou, The Chinese Academy of Sciences, Shanghai, China, Zhen Yang,

College of Chemistry and Molecular Engineering, Peking University, Beijing, China and Henry N. C. Wong, The Chinese University of Hong Kong, China and The Chinese Academy of Sciences, Shanghai, China Part 4.

With More than One N Atom

180

Larry Yet, Albany Molecular Research, Inc., Albany, NE USA

Part 5.

With N & S (Se) Atoms

200

David J. Wilkins, Key Organics Ltd., Camel)Cord, UK and Paul A. Bradley,

Pfizer Global Research & Development, Sandwich, UK Part 6.

With O & S (Se, Te) Atoms

R. Alan Aitken and Stephen J. Costello, UniversiO, of St Andrews, UK

222

Part 7. With O & N Atoms Stefano Cicchi, Franca M. Cordero and Donatella Giomi, Universith di Firenze, Italy

235

C h a p t e r 6: S i x - M e m b e r e d Ring Systems Part 1. Pyridines and Benzo Derivatives D. Scott Coffey, Stanley P. Kolis and Scott A. May, Lilly Research Laboratories,

257

Indianapolis, IN, USA Part 2. Diazines and Benzo Derivatives Grace H. C. Woo and John K. Snyder, Boston UniversiO', Boston, MA, USA and Zhao-Kui Wan, Wyeth Research, Cambridge. MA, USA

279

Part 3. Triazines, Tetrazines and Fused Ring Polyaza Systems Carmen Ochoa and Pilaf Goya, ]nstituto de Quimica M~dica fCSIC), Madrid, Spain

310

Part 4. With O and/or S Atoms John D. Hepworth, James Robinson Ltd., Huddersfield, UK and B. Mark Heron,

332

University of Leeds, Leeds, UK C h a p t e r 7: Eight M e m b e r e d and Larger Rings George R. Newkome, The UniversiO' of Akron, Akron, OH, USA

356

Index

370

vii

Foreword This is the fourteenth annual volume of Progress in Heterocyclic Chemistry, which covers the literature published during 2001 on most of the important heterocyclic ring systems. References are incorporated into the text using the journal codes adopted by Comprehensive

Heterocyclic Chemistry, and are listed in full at the end of each chapter. This volume opens with two specialized reviews.

The first, by Jan Bergman and Tomasz Janosik, covers sulfur-

containing indoles. The second, by David Knight, discusses 5-endo-trig iodocyclizations. The remaining chapters examine the recent literature on the common heterocycles in order of increasing ring size and the heteroatoms present. membered rings does not appear in this volume.

Unfortunately, the chapter on seven

We are delighted to welcome a few new

contributors to this volume and we continue to be indebted to the veteran cadre of authors for their expert and conscientious coverage. In particular we thank Lina Mehta and John Parrick who are giving up their coverage of four membered ring systems after many years' contribution. We are also grateful to Adrian Shell and Eleanor Hunter of Elsevier Science for supervising the publication of the volume. We hope that our readers find this series to be a useful guide to modem heterocyclic chemistry. As always, we encourage both suggestions for improvements and ideas for review topics. Tom Gilchrist has decided to retire as co-editor of PHC with the present volume. John Joule of Manchester University will be the new co-editor starting with Volume 15. G.W.G. wishes to thank Tom for his outstanding service with the past six volumes of PHC. His many excellent suggestions, wise counsel, and hard work have greatly improved the appearance and content of PHC.

Tom Gilchrist Gordon W. Gribble

viii

Editorial Advisory Board Members Progress in Heterocyclic Chemistry 2001 - 2002

PROFESSORY. YAMAMOTO(CHAIRMAN)

Tokyo University, Sendal Japan

PROFESSOR D. P. CURRAN

University of Pittsburg, USA

PROFESSORA. DONDONI

University of Ferrara, Italy

PROFESSOR C.J. MOODY

University of Exeter, UK

PROFESSOR K. FUJI

Kyoto University, Japan PROFESSOR T.C. GALLAGHER

University of Bristol UK

PROFESSORA.D. HAMILTON

Yale University, C T, USA

PROFESSOR M. IHARA

Tohoku University Sendal Japan

PROFESSOR G.R. NEWKOME

University of Akron, OH, USA

PROFESSOR R. PRAGER

Flinders University South Australia

PROFESSOR R.R. SCHMIDT

University of Konstanz, Germany

PROFESSORS.M. WEINREB

Pennsylvania State University University Park, PA, USA

Information about membership and activities of the International Society of Heterocyclic Chemistry can be found on the World Wide Web at http://euch6f, chem. emo ry. ed u/hetsoc, html

Chapter 1

Recent Progress in the Chemistry of Sulfur-Containing Indoles Jan Bergman* and Tomasz Janosik

Department of Biosciences at Novum, Karolinska Institute, Novum Research Park, SE-141 57 Huddinge, Sweden, and SOdertOrn University College, SE-141 04 Huddinge, Sweden [email protected], fax: +46 8 608 1501

1.1

INTRODUCTION

The chemistry of sulfur-containing indoles has been explored since the early days of the 20 th century, and has continuously gained in importance, as it has led to the development of a multitude of compounds displaying interesting structural features and potent biological activity profiles. This review is restricted to indoles possessing sulfur at C-2, at C-3, and both C-2 and C-3, respectively, and will focus on chemical studies, although some selected biologically oriented papers will also be accounted for. The emphasis will be placed on the achievements made during the last decade, but some deeper retrospect will be provided in some cases. Reports encompassing sulfur containing indoles are also abundant in the patent literature, but will not be covered here, in favour of more readily accessible publications. 1.2

INDOLES POSSESSING SULFUR AT C-2

The indoline-2-thiones constitute a group of well-studied simple indoles containing sulfur at C-2. It was early established, that the parent compound 1 and its N-methyl derivative 2 are easily prepared form the corresponding oxindoles 3 or 4 by thionation with PnS10 <67CI(L)275, 69CPB550>. In a somewhat later paper, the electron impact induced fragmentation characteristics of these compounds were described <69CPB 1651>. Other early studies focussed on the thione-thiol tautomerism of 3-arylindoline-2-thiones <71CC836, 74CPB 1053>. The keto-enol/enolate interconversions of indoline-2-thiones and their oxa- or selena-analogues in aqueous media have also been investigated recently <99CJC1528>. Indoline-2-thiones have been prepared via lithiation of certain 2-substituted anilines followed by reaction with CS2 <94H(37)701, 95CJC336, 95JMC58>, or thiomethylation of 2-chloro-1methylindole-3-carbonyl amides, followed by demethylation <95JMC58>. Preparation of the parent indoline-2-thione (1) has also been accomplished by treatment of a 2-1ithiated indole with elemental sulfur <01T7185>. A modified method, involving a combination of P4S10 and NazCO3 in THF, has been developed to effect the thionation of oxindoles to indoline-2thiones <94JMC2033>, an approach which has also been applied later for the preparation of

J. Bergman and T..lanosik indoline-2-thiones during development of indole-N-nucleosides <00JMC2449>. It has also been demonstrated that indoline-2-thiones can serve as precursors for the preparation of 2aminoindoles <71T775>. The access to a wide variety of indoline-2-thiones permitted preparation of various disulfides with the general structure 5 for biological assessment <94JMC2033, 95JMC58>. A related 2,2'-bisindolylsulfide possessing N,N'dimethylaminoethyl groups has also been previously evaluated as a serotonin antagonist <84JHC1901>. An early review on the chemistry of indoline-2-1hiones is also available <72IJS(B)217>.

1R=H,X=S 2R=Me,X=S 3R=H,X=O 4R=Me,X=O

1 S 5

Moreover, indoline-2-thiones have been studied as partners in addition reactions with dimethyl acetylenedicarboxylate leading e.g. to the tricyclic system 6 <81JCS(P1)415>, and in [2+2] n photocycloadditions with alkenes producing alkylindoles <97HCA388>. The reaction of indoline-2-thione (1) with benzaldehyde in the presence of piperidine is quickly followed by a [4+2] rt cyclodimerization of the resulting benzylidene derivative to produce the spiro compound 7, the structure of which was determined by X-ray crystallography <93JCS(P1)1835>. Reduction of indoline-2-thiones with Raney-nickel, LiA1H4, or DIBAL has been shown to give indoles and/or indolines <90HCA1719>. Further synthetic applications involving indoline-2-thiones include S-alkylation with a chiral protected bromoalcohol derivative, followed by cyclization leading to tetrahydrothiopyrano[2,3b]indoles <90JCS(P1)813, 90JCS(P1)827>. Both papers include mechanistic and conformational studies. An X-ray study of the phosphine derivative 8 has also been reported <90AX843>. Both indoline-2-thiones 1 and 2 were also included in a study on acidity measurements of heterocyclic aromatic anions with 4n+2 n-electrons <91JOC4218>. A synthesis of the interesting thione 9 from N-methylisatin and diethylcarbamoyl chloride in the presence of AIC13 has been described <78H(11)139>. Interestingly, the related compound 10 has been reported to easily produce indigo via a 2,2"-coupling accompanied by extrusion of sulfur <03MI1, 25CB820>. In a recent application, indoline-2-thiones have been utilized for the synthesis of various indole and indolenine derivatives <01JHC105>. H

S~--/N'~ C02Et ~ O6

0 ~ S H

~ " ~ / -'N

H

S

H 7

8

9R=Me

IOR=H

Several naturally occurring indoles possessing sulfur at C-2 have been isolated, such as the phytoalexin sinalexin (11), which was identified as a product formed in white mustard (Sinapis alba) under elicitation by e.g. the blackspot fungal pathogen Alternaria brassicae <97P(46)833>. A recent synthetic study provided the first route to 11, also including an

Sulfur-Containing Indoles efficient preparation of the closely related cruciferous phytoalexin brassilexin (12), employing a Vilsmeier-Arnold-Haack formylation followed by workup with ammonia, starting from the indoline-2-thiones 13 and 1, respectively. Both 11 and 12 displayed powerful antifungal activity against various pathogens of cruciferous plants <010L 1213>. 1. POCI 3, DMF S

3.12, pyridine

R 13 R = OMe 1 R=H

R 11 R = O M e 12R=H

The natural product 12, originally isolated from Brassica juncea <88TL6447>, has also been synthesized previously by a bio-mimetic approach again starting from indoline-2-thione (1) <98CC1565>, utilising the observation that 12 is formed from 14, a metabolite of cyclobrassinin (15) <98CC67>. Other reports of related interest include studies on the metabolism of cyclobrassinin (15) by e.g. the root rot Rhizoctonia solani, a process which is believed to proceed via the intermediacy of brassicanal A (16) <99MI1>. This had previously been demonstrated to undergo biotransformation by the blackleg fungus Leptosphaeria maculans in a detoxification pathway leading to several related metabolites <96MI1>. Cyclobrassinin (15) has also been included in a synthetic study aiming at the preparation of related compounds via 3-aminomethylindole derivatives <98T3549>. The related sinalbins A (17) and B (18) have also been isolated from Sinapis alba aider treatment with elicitors, and the structures were confirmed by syntheses <00P(55)213>. The biosynthesis of brassicanal A (16) has been proposed to involve the intermediate 19, which could be trapped successfully with aniline <96JOC9053>. Interestingly, 19 has also been suggested as an intermediate in the reaction of 2-chloroindole-3-carboxaldehyde with thiourea, since trapping with iodoalkanes produced the corresponding 2-alkylthioindoles <99MI2>. Feeding experiments with tetradeuterated derivatives of brassinin (20) and cyclobrassinin (15) demonstrated that both these compounds are biosynthetic precursors to brassilexin (12) <98BMCL3037>. An additional study involving feeding with deuterated species showed that the indole glucosinolate glucobrassicin is not a precursor to brassinin (20), whereas the simple compound indole-3-acetaldoxime proved to be incorporated in the metabolism in turnip roots (B. rapa) <01CC1572>. Recently, a synthesis of cyclobrassinon (21) was accomplished in six steps starting from 2-chloroindole-3-carboxaldehyde, utilising a nucleophilic substitution reaction of sulfur at the indole C-2 as the crucial step <01 TL6961 >, and a similar strategy was also employed for the preparation of various analogues of 21 <01 TL9281 >. A comprehensive review covering many different aspects concerning sulfur-containing phytoalexins from cruciferous plants has also appeared recently <00P(53) 161 >.

~~_N / NH2

SMe

~

" e

S H 14

SMe

~"~,-/ -" N IR 15R=H

18 R = O M e

H 16

OMe 17

J. Bergman and T. Janosik

H 19

~ ' ~ -" N H

H 20

21

Numerous reports describing the introduction of S-alkyl or S-aryl substituents at C-2 of indole have appeared over the years, and a full coverage is beyond the scope of this review. However, some of the recent efforts merit some attention. Nucleophilic displacement of 2halo substituents on indoles has been used for the preparation of tyrosine kinase inhibitors having the general structure 5 <95JMC58, 97JHC1399>, and their diselena-analogues <97JMC413, 97JHC1399>. Direct nucleophilic attack of NaSMe on N-methoxyindoles has been reported to take place with concomitant loss of the methoxy group producing e.g. the alkylthioindole 22 <99H(51)1949>, and also the ester 23, or the aldehyde 24 <01H(54)425>. A similar reaction has been reported in the case o f 6-nitro- 1-methoxyindole <01H(55) 1151 >. Ring opening of a 1,2-dithiolane has been employed for the introduction of an S-alkyl moiety by reaction with 2-1ithiated N-methylindole <98HAC289>. 2-Alkylthioindoles have also been encountered during studies on the behaviour of some hydroxynitrilium ions <96T9509>, or on treatment of 4-(o-aminophenyl)-l,2,3-thiadiazole with tert-BuOK <00T3933>. Moreover, 2-arylthioindoles or 2-alkylthioindoles have also been derived from isonitrile alkyne species using free-radical mediated cascade processes <99TL6325, 00JOC6213>. In a study on the selective lithiation of N-(2,2-diethylbutanoyl)indoles (N-DEB indoles), an excellent yield of the DEB-protected indole 25 could be obtained after metalation of N-DEB-indole with sec-BuLi in the presence of potassium tert-butoxide, followed by quenching of the resulting anion with diphenyldisulfide <01T975>. A different route to 2alkylthioindoles or 2-arylthioindoles has been developed employing a non-reductive desulfenylation of suitable indole-2,3-bissulfides using TFA in the presence of a thiol as the trapping agent <93PS(74)391, 94JOC6372>. The reactivity patterns of alkyl radicals attached to the nitrogen atom of 2-phenylthioindole have been studied leading to the development of a useful synthesis of [1,2-a]indoles <97JCS(P1)3591>. Routes to sulfonylindoles such as 26 or 27 have been devised based on the addition of tosyl fluoride to lithiated indoles, and in a further extension, the sulfone 27 could be transformed to a 2-stannylindole via a radical displacement reaction <96Tl1329>. 2-(Toluenesulfonyl)indoles have also been used as substrates in radical induced preparation of [1,2-a]indoles <97TL6249, 00T465>, while 1,2bis(phenylsulfonyl)-indole (28) has been reported to participate in a conjugate addition with lithium dimethylcuprate to give 2-phenylsulfonyl-3-methylindole <97TL5603, 99TL7615>. A 2-methanesulfonylindole derivative has also been included in a quantitative structure-activity relationship (QSAR) study on indole based melatonin receptor ligands <01BMC1045>. R ~ N sMe

~NN

H 22 R = COMe

23 R = CO2Et 24 R = C H O

SPh

COC(Et)3 25

~

X IR

26 R = SO2Ph, X = Ts 27 R = H, X = Ts 28 R = X = SO2Ph

Sulfur-Containing bzdoles Apart from the numerous cruciferous metabolites mentioned above, a few other natural products having a sulfur atom attached to the indole C-2 have been described. Thus, the O,Sglycoside calanthoside 29, an assumed precursor of, for example, indirubin and isatin, was isolated from two oriental orchids, Calanthe discolor or C. liukiuensis, and was demonstrated to possess skin blood flow promoting effects <98CPB886, 01H(54)957>. The thieno[2,3b]indole 30 produced by a Streptomyces strain has been identified as a plant growth regulator <93MI1>. Interestingly, the parent thieno[2,3-b]indole (31) has been prepared from N-benzyl2-chloro-3-formylindole in a sequence involving nucleophilic displacement of the chlorine with methyl mercaptoacetate followed by cyclization and debenzylation to 32, which in turn underwent saponification, and a final decarboxylation <95JHC1641>. The synthesis of a derivative of the 2-(cysteinyl)tryptophan residue present in the cyclopeptide natural products phallotoxins from the toxic mushroom Amanita phalloides has been described <86T4503>. In connection with studies on thionation of bisindoles, the interesting thienoindole 33 was isolated and the structure was confirmed by X-ray crystallography <02JCS(P1)330>. HO

H

HO ~ " ' ~ O HO""~-'O H HO

X

S H

H 30 X = Cl, R = CONH2

S

S/S

HN

32 X = H, R = C02Me 29

High throughput screening (HTS) for protein tyrosine phosphatase inhibitors has led to the identification of the thiazolo[5,4-b]indole 34 as a precursor to active decomposition products, and both 34 and two N-acetyl derivatives thereof were also synthesized and studied in detail <01JHC569>. Several tricyclic systems such as the thieno[2,3-b]indol-3-one 35 or the lactam 36, and seven membered ring containing systems, e.g. 37, were isolated from cyclizations of 2- or 3-indolylthioalkanoic acid derivatives under various conditions <96JHC1695>. Annelation experiments on 2-(indol-3-yl)thiobenzoate produced, among other products the ring system 38. In a similar fashion, cyclization of other 2/3-arylthio- or 2/3heteroarylthioindoles led to the formation of e.g. 39, 40 and 41 <99JHC643>. An alternative efficient protocol for the synthesis of 38 starting from indole-3-carboxylic acid methyl ester, which was chlorinated at C-2 using NCS, followed by nucleophilic displacement of the chlorine with thiophenol, and a final cyclization with PPA, has recently been developed <02UP>. The tetracyclic compound 42 has also been prepared by cyclization of the precursor 43 in refluxing xylene, whereas the N-methylated derivative 44 was obtained via annelation of a related 3-acylindole. In addition, 44 was demonstrated to undergo rearrangement to the isomeric system 45 upon heating in p-xylene, via a spiro-cyclic intermediate <95JHC1477>. The interesting bisindole 46 was obtained as a side product during the preparation of the phytoalexin brassilexin (12) <01OL1213>.

J. Bergrnan and T. Janosik

0 ~ H 34

N

0

H 35n=1

39

R 38 R =H, Z=CH 40R=H,Z=N 44 R = M e , Z = C H

36

37n=3

H

Z

g(cH2)n

41Z=N

42 Z = CH

43

46

~

~

Et

,

Me

45

H

Additional fused systems, e.g. 47 have been prepared from isatin and suitable arylthiosemicarbazides using a two step procedure, and the products were screened for antifungal activity <99IJC(B)501>. Access to compounds such as 48, incorporating a large ring, has been gained by employing a new annelation based on the sulfoxide precursors 49 <98JOC9190>. Recent synthetic approaches towards pentathiepino[6,7-b]indoles have lead to the discovery that the tetrasulfides 50 or 51 are formed as side products under the influence of the basic reaction conditions on the main products, the pentathiepins <01T7185>. Interestingly, the parent compound 50 had probably been obtained already in 1938 from the melt of indole with sulfur <38RZC804>, the correct structure of 50 was however proposed later when the same reaction was performed in DMF, thus providing a useful preparative route <60JA2739>. Later studies have demonstrated that both 50 and 51 can also be prepared by heating the corresponding 3,3'-biindolyls with elemental sulfur in refluxing DMF <02JCS(P1)330>; however, the reverse reaction has more potential as it has been used as a route to 3,3'-biindolyls by desulfurization of 50 or 51 with Raney-nickel <94TL1977, 00EJO3093>. Compound 50 has also been demonstrated to display considerable antifungal properties, in particular against dermatophytes and the fungus BotIytis cinerea <81 FES856>.

-"N

0 47

48n=1or2

/ S~(CH2)n 0=~%.~ ~..~' 49n=1 or2

/S S R 50R=H 51 R = M e

Sulfur-Containing Indoles

The system 52 has been described in connection with studies on thioindigoid compounds. Thus, for instance, generation of the species 53 via reductive cleavage of 51 <94TL1977> was reported to furnish 52, as was the reaction of N-methylindoline-2-thione (2) with p-toluenesulfonyl azide <00EJO3093>; an experiment which was previously incorrectly claimed to produce the isoindigo derivative 54 <74JCS(P1)2384>. Compound 54 has also been claimed as the product of the thionation of N,N'-dimethylisoindigo (55) with Lawesson's reagent <84ZN(B)1614>; however, with the above mentioned results in hand, a reinvestigation would appear to be appropriate. Although the dithiin 56 was regarded as the product from the treatment of 50 with sodium borohydride <60JA2739>, later findings indicate that other species are more likely to be produced in this reaction, as the dialkyl derivative 57 could never be isolated during a series of experiments which instead gave the 12-membered system 52 <00EJO3093>. In this context it is also interesting to note that coupling of N-methylindoline-2-thione (2) with iodine in ethanol has been demonstrated to afford 58 <69CPB550>, the structure of which was later analysed by X-ray crystallography <00AX830>.

~ N

'Me

Me

Me N

Me

Me M e ~ , ~

Me

52

N

53

Me 54X=S 55X=O I

2 M+ Me N S e

R

-S 56 R = H 57 R = Me

1.3

H M~

H

58

INDOLES POSSESSING SULFUR AT C-3

Several different mild methods for the preparation of 3-alkylthioindoles or 3arylthioindoles have been developed during the last ten years, as some of the previous protocols e.g. Fischer indolization of suitable precursors does not tolerate the presence of additional sensitive functionalities. Thiomethylation of indoles at C-3 has been achieved using a sequence involving treatment of the indoles with methylmagnesium bromide, followed by transmetallation with zinc chloride, and finally introduction of dimethyldisulfide followed by workup with cysteine hydrochloride, providing decent yields of 3-methylthioindoles <93TL6245>. A useful and mild general route to 3-arylthioindoles has been developed employing the reaction of the indolyl anion with diaryldisulfides in DMF, thus avoiding the use of highly reactive arenesulfenyl chlorides <88S480>. Various 3-phenylthioindoles have been obtained from the corresponding indoles via the use of a quinone mono O,S-acetal as the sulfenylating agent in the presence of TMSOTf as the catalyst <97CC1387, 01JOC2434,

J. Bergman and T. Janosik

01TL1077>. Other developments in this area include a ferrocenesulfonation of indole <97ZOB1670>, sulfenylation of e.g. N-methylindole, 2,2'-biindolyl or 2-phenylindole using the complex of trifluoromethanesulfonic anhydride and dimethysulfide <00KGS171>, or the synthesis of various 3-alkylthioindoles by treatment of 2-methylindole with thiourea, and subsequent S-alkylation <85CCA331>. 3-Arylsulfonylindoles have been obtained by oxidation of the corresponding 3-arylthioindoles, and were further transformed into 3cyanoindoles <85TL1827>. 3-Arylthioindoles have been used for the synthesis of 2alkylindoles via a Wittig olefination of 3-phenylthioindole-2-carboxaldehyde followed by concomitant cleavage of the thioaryl group and hydrogenation of the alkene <93IJC(B)481>. Desulfenylation of 3-thioindoles has been reported to take place under non-reductive conditions using trifluoroacetic acid in the presence of thiosalicylic acid as the trapping agent <93TL2059>. The sequential treatment of an indole with SOC12 and Me2CHMgC1, followed by reduction of the intermediate sulfoxide with NaI/TFAA has also been used for a synthesis of a 3-alkylthioindole carrying additional substituents <96JHC1627>, while some related derivatives have been obtained via treatment of an indole with DMSO in the presence of gaseous hydrogen chloride, followed by heating in DMF <96JHC2025>. A high-yielding method for the thiocyanation of various aromatics, including indole, using ammonium thiocyanate and sodium perborate in acetic acid has recently been developed <01SC3041>. The construction of hexasubstituted benzenes, e.g. 59 containing the 3-mercaptoindole moiety, as preorganized ligands containing three <97JCS(D)1857>, or six <97CC1931> indole-3-thiolate functionalities for the preparation of Fe4S4 clusters has been reported, while the N-methyl-3-mercaptoindole core was present in a molybdenum containing complex obtained from the electrophilic attack of N-methylindole on the complex [(CpMo(,uS))2(S2CH2)]2(B F4)2 <00OM3507>.

/~HS~N.N.HS-a " ~ ~ SH

~

SH~

SH

59

Additional examples of reports on the preparation and/or use of 3-thioindoles include a synthesis of a series of heterocyclic sulfonylureas <96JHC763>, preparation of indole-3dithiocarbamates <97KGS1700>, and an investigation of the chemical and physical properties of indole-3-sulfonium ylides and related structures <80JOC780>. Various 3-(methylthio)oxindole derivatives have been described and were in some cases used in synthetic applications. The simple system 60 has been obtained during studies of the oxidation and fluorination of ot-phenylsulfanylacetamides with difluoroiodotoluene <00TL4467>, whereas a number of differently substituted derivatives, among others the tricyclic system 61 have been prepared using a modified Gassmann oxindole synthesis <96TL4631>. The sulfone of compound 60 was also isolated from a rhodium catalyzed cyclization of a diazoamide precursor <96T2489>. Additional 3-(methylthio)oxindoles have

Sulfur-Containing hzdoles been used as intermediates for the preparation of 6,7-dihydroxyoxindole, a precursor to a subunit of the alkaloid paraherquamide A <96JOC8696>, or in the development of new indole containing dopaminergic agents <98BMCL2675>. The tricyclic pyrrolo[3,2-e]indole core present in the antitumor antibiotic CC-1065 has been achieved via the intermediate 62 which was obtained from ethyl 5-aminoindolyl-2-carboxylate using an efficient reaction sequence <86TL2735>. A protocol for non-reductive desulfenylation of 3-(alkylthio)oxindoles employing a combination of p-toluenesulfonic acid and triphenylphosphine has been described <96SL663> as a complement to the reductive method employing metal hydrides <97CJC536, 97CJC542>. Further studies involving related 3-thioindoles encompass a reexamination of some reactions of 5-hydroxysulfoxides <97TL1337>, and the development of a method for the generation of bicyclic o-quinodimethanes <97T15957>. The interesting molecule 63 has been reported as a product from the reaction of the gem-dichloride 64 with potassium ethyl xanthate <68CB701>. The 3,3-bis(phenylthio)oxindole 65 has been identified as one of the products from a nitrosation experiment performed on N-methyl-3phenylthioindole <77JCS(P1)1024>. A highly regioselective monofluorination of substituted 3-(phenylthio)oxindoles has been reported recently, producing the corresponding 3-fluoro-3(phenylthio)oxindoles <97SL655>.

~~N~ , S~ P N hNHO SMeoEt02C ~ 1MeS~/ONH X0 ~PhSSPho Me 60

N H

61

63 X = S 64 X = CI 2

62

Me 65

Additional examples of indole derivatives possessing sulfur at C-3 have been obtained during solid-phase synthesis of N-hydroxyindoles <99TL5799>, and from reactions of sulfanyl radicals with azidoalkynes <97TL7913, 98EJO1219>. The interaction of a 3phenylthioindole derivative with calf thymus DNA has been investigated, including an X-ray crystallographic study <96JST(358)123>. The structurally interesting brominated natural product echinosulfone A 66 was isolated from the southern Australian marine sponge Echinodictyum <99JNP1246>. The cruciferous phytoalexin (S)-(-)-spirobrassinin 67 has been obtained via a preparation of the racemate, and subsequent derivatization with (S)-(-)-Iphenethyl isocyanate, thus providing a pair of chromatographically resolvable amides, which were finally cleaved with sodium methoxide to give (S)-(-)-67 and its enantiomer <01JOC3940>.

MeS

HOOC N/

I

66

~N H

@

0 H 67

Numerous indoles having sulfur attached to C-3 have been screened for biological effects over the years, and only some selected examples will be included in this short survey. Thus for example, a series of indoles 68 has been evaluated for leukotriene synthesis inhibitory activity <96BMCL1547, 97BMC507>, whereas some closely related structures

10

J. Bergman and T. Janosik

have been proven to be 5-1ipoxygenase activating protein (FLAP) inhibitors <99BMCL2391>. Likewise, tricyclic systems containing the core 69 have been prepared and were shown to be potent, orally active 5-1ipoxygenase inhibitors <93JMC2771>. Additional related 3-arylthioindoles, such as 70 have been shown to be potent endothelin antagonists <96BMCL1367>.

R~ R2

S-~

SAr 1

R3

CI/'~ 68

69Z=OorS cI

OOH

CH2Ar 2

70 /

During studies aiming at the development of novel calcium entry blockers, 3indolylsulfones of the general formula 71, where R 2 is an alkylamino functionality containing species, have been prepared and evaluated, and exhibited some promising activity <93JMC1425>. A group of sulfides, sulfoxides and sulfones (72) has been the subject of an investigation searching for new HIV-1 reverse transcriptase inhibitors, and one of the compounds in the sulfone series was found to display interesting activity <93JMC1291>. An indole-3-sulfide belonging to this class has also been subjected to metabolism studies in rhesus monkeys or rat liver microsomes <93MI2>. In yet another related study, several sulfones of type 72 with e.g. X - CI and R - 1/2-imidazolyl or 4-thiazolyl have been synthesized and underwent screening as potential inhibitors of HIV-1 reverse transcriptase <95BMCL491>. Some related 3-indolylsulfones have also been evaluated as potential platelet-activating factor antagonists <98JMC74>.

n,O

71

72 • = H or CI n = 0,1, or 2

During a mechanistic investigation of the incorporation of the selective melanoma seeker 2-thiouracil into growing melanins, several thiouracil-5,6-dihydroxyindole adducts, such as 73 could be isolated after incubation of 2-thiouracil with 5,6-dihydroxyindole in the presence of tyrosinase <96JMC5192>. A new class of orally active analgesic agents having the general structure 74 has been synthesized starting from suitable 4-mercaptopiperidine derivatives, and several of the derivatives were demonstrated to possess analgesic activities comparable to that of morphine <00BMCLS05>. A series of spirocyclic indoles 75 has been prepared by condensation of isatin with anilines, followed by cyclization with mercaptoacetic acid derivatives, and in some cases a final thionation with P4S~0, and were screened for antifungal, antibacterial and insecticidal activities <93MI3>. Related fluorinated compounds having a six-membered sulfur containing spiro ring have also been synthesized <97MI 1>.

Sulfur-Containing Indoles

sHN

O

73

11

o O s _R2 74

R2

75 X = O or S

The thienoindole 76 was included in an investigation focussing on the electrochemical synthesis and electrochromic properties of a series of closely related heteroaromatics and their copolymers <96SM(82)11 >, and has as well been included in studies aiming at understanding the photophysics of various trans-stilbene analogues <97CPH(216)179>, whereas two mechanistic studies have focussed on the electrochemical oligomerization of 76 <93SM(60) 105, 97SA(A)2153>. Other related studies in this area encompass an investigation on the influence of relative humidity on the electrical properties of polymerised 76 <95SM(73)131>, and the preparation of a co-polymer from 76 and dithienopyrrole <94SM(68)85>. Polymeric 76 has also been probed for electronic and ionic conductivity <93MCLC(229)167>, and has also been used for the construction of a solid state battery which also contained gold and magnesium <94MI1>. The pentacyclic molecule 77 has been reported as a product from a Fischer indolization reaction <97MI2>. Tetrahydrothiopyranoindoles such as 78 have been prepared by cyclization of imine precursors using the base system NaNH2-tert-BuONa <94Tl1903, 97JCS(P1)2857>, and were also demonstrated to undergo a ring opening process giving 2-alkylindoles under the influence of A1C13 and benzylthiol <97JCS(P 1)2857>. Studies on Pummerer-type annulations have led to the isolation of the tetracyclic sulfonium salt 79, which was subsequently transformed into a 3-phenylthioindole derivative <96TL5217>. X-

76

NO2

77

78

79

MeO2C

CO2Me

The questionable existence of thioindigoid compounds has been discussed over the years, as all efforts aiming at e.g. dithioindigo (80) have instead produced systems containing a 12-membered ring. Thus for instance attempts to prepare 80, or an N,N'-dimethyl derivative thereof by oxidation of the 2,2'-biindolyl readily available precursors 81 or 82 failed, instead producing compounds 83 and 84 <94AG808, 94AG(E)739, 00EJO3093>. Also noteworthy in this context is the existence of an early, still used protocol for the preparation of 3,3'indolyldisulfides, which includes treatment of indoles with thiourea and iodine, followed by strong alkali <50JA4320>, which was recently applied on 2,2'-biindolyls for an alternative generation of 81 and 82 <00EJO3093>.

12

J. Bergman and T. Janosik

R

R

A S

S

R

h

sXs Js

S

R

80

S-

2M §

81R=H 82 R = Me

h 83R=H 8 4 R = Me

However, a recent study clearly demonstrated that an air induced oxidation of 81 gives 83 exclusively, and that the spectral characteristics observed are caused by quick transformation of 83 into the conformer 85, which could also be prepared conveniently by heating 83 in DMSO. The molecular conformation of 85 was also rigorously proven using Xray crystallography. An independent one-step synthesis of 83 was also developed by heating 2,2'-biindolyl and elemental sulfur in xylenes. The existence of a third conformer with the suggested structure 86 was also detected, albeit only in solution, as it easily reverts back to 85 on attempted isolation. In addition, the elusive dithiin 87 was prepared by heating 85 in DMA, and the structure was confirmed by X-ray crystallography <02EJO1392>. A thermal process leading to the indole alkaloid arcyriaflavin A, possibly involving the in situ formation of the dithiin 87 has also been described <99TL3795>. A related approach involving the use of 3,4dibromomaleimide and PBu3 has also been reported, leading to the intermediate 88, which was demonstrated to undergo transformation to arcyriaflavin A via a ring contraction involving extrusion of sulfur <00TL9835>. The tetrathiocine 89 has been isolated from the reaction of N,N'-dimethyl-2,2'-biindolyl and $2C12 a t - 2 0 ~ while at -60 ~ compound 84 was isolated in low yield <94AG808, 94AG(E)739>. S

..-= E-

H N

S ----:

H N

S-S '

"

_

H

N

H 87

S 85

0

H

N

S 86

0

s,S-S.s Me Me 89

88

Sulfur-Containing Indoles

13

Treatment of isatin with the powerful thionating agent P4S10 in refluxing pyridine has previously been reported to give a low yield of pentathiepino[6,7-b]indole, while the main product from this reaction remained unidentified <94TL5279>. In a recent more detailed study, the first example of a thionated indigo derivative, monothioindigo (90) was isolated as one of the minor products from the same reaction, and the main product was assigned the structure 91, as an alkylation provided the salt 92, which underwent extensive spectroscopic studies. A similar outcome was observed on thionation of indigo under the same conditions, and 91 was obtained as the major product. In these experiments, small amounts of the fully thionated products 93 and 94 could also be observed <02JCS(P 1)330>.

~H

1.4

'1 0

90

91Z=O,

R=H 92Z=O, R=Et 9 3 Z = S, R = H 94Z=S, R=Et

INDOLES POSSESSING SULFUR AT BOTH C-2 AND C-3

Indoles having sulfur atoms attached to both C-2 and C-3 are relatively rare. Thus for instance, the indole 95 where both substituents are cysteine derived groups, has been identified as a side product during development of an acid induced rearrangement protocol for the transformation of 3-alkylthioindoles to 2-alkylthioindoles, a process which was at that time believed to proceed via an episulfonium species <86T4511>. Further studies on the rearrangement of compounds of type 95 have later demonstrated that a complex intermolecular mechanism is in operation <89CC63, 92JOC2694>. A second sulfenylation of the readily available indol-3-yl sulfides provides a protocol for the regioselective synthesis of mixed 2,3-di(alkyl/arylthio)indoles, a process which was suggested to occur via an intermediate 3,3-dithiaindolenine species <96JOC1573>, which could later be isolated when the second sulfenylation was performed in the presence of a base <97TL8473>. Indoles possessing alkylthio- or arylthio-functionalities at both C-2 and C-3 have also been demonstrated to undergo desulfenylation upon treatment in TFA in the presence of a trapping agent to provide 2-indolylsulfides <93PS(74)391, 94JOC6372>. A 2,3-di(methylthio)indole has also been isolated from a product mixture originating from a nucleophilic attack on 1methoxy-6-nitroindole with NaSMe in methanol <01H(55)1151>. The disulfone 96 was prepared by oxidation with H202 of the corresponding disulfide which was in turn obtained by sulfenylation of 1-methyl-3-methylthioindole with N-thiomethylmorpholine in the presence of trifluoroacetic acid. It was also demonstrated that the 2,3-diphenylthioindole 97 can be obtained by treatment of the corresponding N-protected indole with phenylsulfenyl chloride in the presence of pyridine <91JHC1025>. The dielectrophile 1,2-ethanedisulfenyl chloride has been employed for the synthesis various dithioethylene substituted aromatics, to provide among others, the indole derivative 98 <01SM(120)1061>. A more complex system containing the core of 98 was obtained from the reaction of the spirooxindole 99 with POC13 and DMF <96T7003>. The optically active brominated alkaloids itomanindoles A (100) and B (101) have been isolated from the red alga Laurencia brongniartii, wherewith the structure

14

J. Bergman and T. Janosik

of 100 was determined using X-ray crystallography <88TL6091>. Additional related natural products, for instance 102, were later derived from the same alga species <89T7301>. Some 3-alkylthioindoline-2-thiones have been generated and used for the preparation of a sulfur analogue of the leukotriene synthesis inhibitor MK886 <95CJC336>. SR 3

SO2Me

~1

SPh

Me

95

96

MeO 98

97

H

S02Ph

o

x 100 X = SOMe, Y = SMe 101 X = SMe, Y = SOMe 102 X = Y = SMe

99

Apart from 98, a few other fused systems are known. A rational approach to the interesting pentathiepino[6,7-b]indoles 103 and 104 has been devised based on the reactions of 2-1ithiated indoles with elemental sulfur <01T7185>. Compound 103 has previously been isolated in low yield from the thionation of isatin with P4S10 in refluxing pyridine <94TL5279>. A synthesis of the benzo[1,4]dithiino[2,3-b]indole 105 has been reported, and the mass spectroscopic data of the product were discussed in some detail <69JCS(C)2169>. Some additional fused systems, having the general structure 106 have also been prepared and studied <84AJC2479>. s~S's /S S R 103R=H 104 R = M e

S

S

.NR

S H

H

105

106

1.5 R E F E R E N C E S 03MI129 25CB820 38RZC804 50JA4320 60JA2739 67CI(L)275 68CB701 69CPB550 69CPB 1651 69JCS(C)2196 71CC836

T. Sandmeyer, Z Farben Text. Chem. 1903, 2, 129. L. Sander, Chem. Ber. 1925, 58, 820. L. Szperl, Rocz. Chem. 1938, 18, 804. R.G. Woodbridge III, G. Dougher, J. Am. Chem. Soc. 1950, 72, 4320. W. Carpenter, M.S. Grant, H.R. Snyder, J. Ant. Chem. Soc. 1960, 82, 2739. T. Hino, K. Yamada, S. Akoboshi, Clzem. hzd. (London) 1967, 275. A. Sch/3nberg, E. Frese, Chem. Ber. 1968, 101,701. T. Hino, K. Tsuneoka, M. Nakagawa, S. Akaboshi, Chem. Pharm. Bull. 1969, 17, 550. T. Hino, M. Nakagawa, K. Tsuneoka, S. Misawa, S. Akaboshi, Chem. Pharm. Bull. 1969, 17, 1651. N.P. Buu-Hoi, P. Jacquignon, L. Led6sert, A. Ricci, D. Balucani, J. Chem. Soc. (C) 1969, 2196. T. Hino, M. Nakagawa, T. Suzuki, S. Takeda, N. Kano, Y. Ishii, J. Chem. Soc., Chem. Commun. 1971. 836.

Sulfur-Containing Indoles

71T775 72IJS(B)217 74CPB 1053 74JCS(P1)2384 77JCS(P 1) 1024 78H(11)139 80JOC780 81FES856 81JCS(P1)415 84AJC2479 84JHC1901 84ZN(B)1614 85CCA331 85TL1827 86T4503 86T4511 86TL2735 88S480 88TL6091 88TL6447 89CC63 89T7301 90AX843 90HCA 1719 90JCS(P1)813 90JCS(P1)827 91JHC1025 91 JOC4218 92JOC2694 93IJC(B)481 93JCS(P1)1835 93JMC1291

93JMC1425 93JMC2771

93MCLC(229)167 93MI636 93MI598

93MI129 93PS(74)391 93SM(60)105 93TL2059

15

T. Hino, M. Nakagawa, T. Hashizume, N. Yamaji, Y. Miwa, K. Tsuneoka, S. Akaboshi, Tetrahedron 1971, 27, 775. T. Hino, Int. J. Sulfur Chem., Part B 1972, 7, 217. T. Hino, T. Suzuki, M. Nakagawa, Chem. Pharm. Bull. 1974, 22, 1053. A.S. Bailey, J.F. Seager, Z. Rashid, J. Chem. Soc., Perkin Trans. 1 1974, 2384. A.H. Jackson, D.N. Johnston, P.V.R. Shannon, J. Chem. Soc., Perkin Trans 1 1977, 1024. M. Ogata, H. Matsumoto, Heterocycles 1978, 11,139. K.-H. Park, G.D. Daves Jr., J. Org. Chem. 1980, 45, 780. L. Montanari, F. Pavanetto, M. Mazza, Farmaco Ed. Sci. 1981, 36, 856. R.M. Acheson, J.D. Wallis, J. Chem. Soc., Perkin Trans. 1 1981, 415. R.L.N. Harris, H.G. McFadden, Aust. J. Chem. 1984, 37, 2479. C.K. Chu, J.D. Wander, R.L. Tackett, W.B. Iturrian, J.P. Schmitz, G.E. Gamer, K. Chae, J. Heterocycl. Chem. 1984, 21, 1901. A.A. E1-Kateb, R. Shabana, F.H. Osman, Z. Naturforsch., Teil B 1984, 39, 1614. R. Bennett Jr., T. Shah, S. Quashie, E.S. Mooberry, Croat. Chem. Acta 1985, 58, 331. J. Garcia, R. Greenhouse, J.M. Muchowski, J.A. Ruiz, Tetrahedron Lett. 1985, 26, 1827. R. Plate, R.J.F. Nivard, H.C.J. Ottenheijm, Tetrahedron 1986, 42, 4503. R. Plate, H.C.J. Ottenheijm, Tetrahedron 1986, 427, 4511. M.A. Warpehoski, V.S. Bradford, Tetrahedron Lett. 1986, 27, 2735. J.G. Atkinson, P. Hamel, Y. Girard, Synthesis 1988, 480. J. Tanaka, T. Higa, G. Bernardinelli, C.W. Jefford, Tetrahedron Lett. 1988, 29, 6091. M. Devys, M. Barbier, I. Loiselet, T. Rouxel, A. Sarniguet, A. Kollmann, J.F. Bousquet, Tetrahedron Lett. 1988, 29, 6447. P. Hamel, Y. Girard, J.G. Atkinson, J. Chem. Soc., Chem. Commun. 1989, 63. J. Tanaka, T. Higa, G. Bemardinelli, C.W. Jefford, Tetrahedron 1989, 45, 7301. J. Ha~ek, K. Hum1, Acta. Crystallogr. 1990, C46, 843. T. Nishio, N. Okuda, C. Kashima, Helv. Chim. Acta 1990, 73, 1719. N. Ishizuka, J. Chem. Soc., Perkin Trans. 1 1990, 813. N. Ishizuka, M. Shiro, Y. Makisumi, J. Chem. Soc., Perkin Trans. 1 1990, 827. H.M. Gilow, C.S. Brown, J.N. Copeland, K.E. Kelly, J. Heterocycl. Chem. 1991, 28, 1025. F.G. Bordwell, H.E. Fried, J. Org. Chem., 1991, 56, 4218. P. Hamel, Y. Girard, J.G. Atkinson, J. Org. Chem. 1992, 57, 2694. E.V. Sadanandan, M. Vedachalam, P.C. Srinivasan, Indian J. Chem., Sect. B 1993, 32, 481. A.M. Thompson, M. Boyd, W.A. Denny, J. Chem Soc., Perkin Trans. 1 1993, 1835. T.M. Williams, T.M. Ciccarone, S.C. MacTough, C.S. Rooney, S.K. Balani, J.H. Condra, E.A. Emini, M.E. Goldman, W.J. Greenlee, L.R. Kauffman, J.A. O'Brien, V.V. Sardana, W.A. Schleif, A.D. Theoharides, P.S. Anderson, J. Med. Chem. 1993, 36, 1291. J. Gubin, H. de Vogelaer, H. Inion, C. Houben, J. Lucchetti, J. Mahaux, G. Rosseels, M. Peiren, M. Clinet, P. Polster, P. Chatelain, J. Med. Chem. 1993, 36, 1425. J.H. Hutchinson, D. Riendeau, C. Brideau, C. Chan, D. Delorme, D. Denis, J.-P. Falgueyret, R. Fortin, J. Guay, P. Hamel, T.R. Jones, D. Macdonald, C.S. McFarlane, H. Piechuta, J. Scheigetz, P. Tagari, M. Th6rien, Y. Girard, J. Med. Chem. 1993, 36, 2771. G. Casalbore-Miceli, G. Beggiato, G. Giro, F. Capuano, B. Scrosati, Mol. Cryst. Liq. Cryst. 1993, 229, 167. K. Kanbe, H. Naganawa, K.T. Nakamura, Y. Okami, T. Takeuchi, Biosci. Biotech. Biochem. 1993, 57, 636. S.K. Balani, M.E. Goldman, L.R. Kauffman, S.L. Varga, J.A. O'Brien, S.J. Smith, T.V. Olah, H.G. Ramjit, T.W. Schorn, S.M. Pitzenberger, T.M. Williams, C.S. Rooney, A.D. Theoharides, Drug. Metab. Disp. 1993, 21,598. A. Dandia, V. Kaur, P. Singh, Indian J. Pharm. Sci. 1993, 55, 129. P. Hamel, N. Zajac, Y. Girard, J.G. Atkinson, Phosphorus Sulfur Silicon 1993, 74, 391. G. Casalbore-Miceli, G. Beggiato, A. Geri, G. Zotti, S. Daolio, Synth. Met. 1993, 60, 105. P. Hamel, N. Zajac, J.G. Atkinson, Y. Girard, Tetrahedron Lett. 1993, 34, 2059.

16 93TL6245 94AG808 94AG(E)739 94H(37)701 94JMC2033 94JOC6372 94MI 114 94SM(68)85 94T11903 94TL1977 94TL5279 95BMCL491

95CJC336 95JHC1477 95JHC 1641 95JMC58 95SM(73)131 96BMCL1367 96BMCL1547 96JHC763 96JHC1627 96JHC1695 96JHC2025 96JMC3723 96JMC5192 96JOC 1573 96JOC8696 96JOC9053 96JST(385)123 96MI3404 96SL663 96SM(82)11 96T2489 96T7003 96T9509 96T11329 96TL4631 96TL5217 97BMC507 97CC1387 97CC 1931 97CJC536

J. Bergman and T. Janosik C.C. Browder, M.O. Mitchell, R.L. Smith, G. el-Sulayman, Tetrahedron Lett. 1993, 34, 6245. W. Schroth, E. Hintzsche, M. Felicetti, R. Spitzner, J.-Sieler, R. Kempe, Angew. Chem. 1994, 106, 808. W. Schroth, E. Hintzsche, M. Felicetti, R. Spitzner, J. Sieler, R. Kempe, Angew. Chem., Int. Ed. Engl. 1994, 106, 739. G.W. Rewcastle and W.A. Denny, Heterocycles, 1994, 37, 701. G.W. Rewcastle, B.D. Palmer, E.M. Dobrusin, D.W. Fry, A.J. Kraker, W.A. Denny, J. Med. Chem. 1994, 37, 2033. P. Hamel, N. Zajac, J.G. Atkinson, Y. Girard, J. Org. Chem. 1994, 59, 6372. F. Capuano, G. Casalbore-Miceli, G. Giro, B. Scrosati, J. Appl. Electrochem. 1994, 24, 114. G. Casalbore-Miceli, G. Beggiato, G. Zotti, L. Favaretto, Synth. Met. 1994, 68, 85. C. Caubbre, P. Caubbre, S. Ianelli, M. Nardelli, B. Jamart-Gr6goire, Tetrahedron 1994, 50, 11903. W. Schroth, M. Felicetti, E. Hintzsche, R. Spitzner, M. Pink, Tetrahedron Lett. 1994, 35, 1977. J. Bergman, C. Sthlhandske, Tetrahedron Lett. 1994, 35, 5279. S.D. Young, M.C. Amblard, S.F. Britcher, V.E. Grey, L.O. Tran, W.C. Lumma, J.R. Huff, W.A. Schleif, E.E. Emini, J.A. O'Brien, D.J. Pettibone, Bioorg. Med. Chem. Lett. 1995, 5, 491. A. Cervantes, C.A. Contreras, A. Guzman, E.E. Vale, E. Velarde, S.L. Berthiaume, J. M. Muchowski, Can. J. Chem. 1995, 73, 336. D.K. Bates, Q.A. Habib, J. Heterocycl. Chem. 1995, 32, 1477. P.H. Olesen, J.B. Hansen, M. Engelstoft, J. Heterocycl. Chem. 1995, 32, 1641. B.D. Palmer, G.W. Rewcastle, A.M. Thompson, M. Boyd, H.D.H. Showalter, A.D. Sercel, D.W. Fry, A.J. Kraker, W.A. Denny, J. Med. Chem. 1995, 38, 58. M. Campos, G. Casalbore-Miceli, N. Camaioni, G, Chiodelli, Synth. Met. 1995, 73, 131. A.M. Bunker, J.J. Edmunds, K.A. Berryman, D.M. Walker, M.A. Flynn, K.M. Welch, A.M. Doherty, Bioorg. Med. Chem. Lett. 1996, 6, 1367. K.W. Woods, C.D.W. Brooks, R.K. Maki, K.E. Rodriques, J.F. Bouska, R.L. Bell, G.W. Carter, Bioorg. Med. Chem. Lett. 1996, 6, 1547. W. L6we, N. Matzanke, J. Heterocycl. Chem. 1996, 33, 763. P.C. Unangst, D.T. Connor, S.R. Miller, J. Heterocycl. Chem. 1996, 33, 1627. P. Hamel, L. Girard, J. Heterocycl. Chem. 1996, 33, 1695. P.C. Unangst, D.T. Connor, S.R. Miller, J. HeterocycL Chem. 1996, 33, 2025. K. Andersen, T. Liljefors, J. Hyttel, J. Perregaard, J. Med. Chem. 1996, 39, 3723. A. Napolitano, A. Palumbo, M. d'Ischia, G. Prota, J. Med. Chem. 1996, 39, 5192. P. Hamel, P. Pr6ville, J. Org. Chem. 1996, 61, 1573. B.M. Savall, W.W. McWhorter, J. Org. Chem. 1996, 61, 8696. K. Monde, A. Tanaka, M. Takasugi, J. Org. Chem. 1996, 61, 9053. J. Sivaraman, K. Subramanian, D. Velmurugan, E. Subramanian, J. Seetharaman, J. Mol. Struct. 1996, 385, 123. M.S.C. Pedras, A.Q. Khan, J. Agric. Food Chem. 1996, 44, 3404. T.J. Connolly, T. Durst, Synlett 1996, 663. G. Beggiato, G. Casalbore-Miceli, A. Geri, A. Berlin, G. Pagani, Synth. Met. 1996, 82, 11. S. Miah, A.M.Z. Slawin, C.J. Moody, S.M. Sheehan, J.P. Marino Jr., M.A. Semones, A. Padwa, I.C. Richards, Tetrahedron, 1996, 52, 2489. D. StC. Black, A.J. Ivory, N. Kumar, Tetrahedron 1996, 52, 7003. J.-M. Coustard, Tetrahedron 1996, 52, 9509. K. Aboutayab, S. Caddick, K. Jenkins, S. Joshi, S. Khan, Tetrahedron 1996, 52, 11329. S.W. Wright, L.D. McClure, D.L. Hageman, Tetrahedron Lett. 1996, 37, 4631. M. Amat, M.-L. Bennasar, S. Hadida, B.A. Sufi, E. Zulaica, J. Bosch, Tetrahedron Lett. 1996, 37, 5217. T. Kolasa, P. Bhatia, C.D.W. Brooks, K.I. Hulkower, J.B. Bouska, R.R. Harris, R.L. Bell, Bioorg. Med. Chem. 1997, 5, 507. M. Matsugi, K. Gotanda, K. Murata, Y. Kita, Chem. Commun. 1997, 1387. C. Walsdorff, W. Saak, D. Hase, S. Pohl, Chem. Commun. 1997, 1931. T.J. Connolly, T. Durst, Can. J. Chem. 1997, 75, 536.

Sulfur-Containing Indoles

97CJC542 97CPH(216)179 97HCA388 97KGS1700 97MI41 97MI5 97SL655 97JCS(D)1857 97JCS(P1)2857 97JCS(P1)3591 97JHC1399 97JMC413

97P(46)833 97SA(A)2153 97T15957 97TL1337 97TL5603 97TL6249 97TL7913 97TL8473 97ZOB 1670 98BMCL2675 98BMCL3037 98CC67 98CC1565 98CPB886 98EJO1219 98HAC289 98JMC74

98JOC9190 98T3549 99BMCL2391

99CJC1528 99H(51)1949 99IJC(B)501 99JHC643 99JNP1246 99MI1196 99MI1060 99TL3795 99TL5799 99TL6325

17

T.J. Connolly, T. Durst, Can. d. Chem. 1997, 75, 542. S. Dobrin, P. Kaszynski, S. Ikeda, J. Waluk, Chem. Phys. 1997, 216, 179. T. Nishio, M. Oka, Helv. Chim. Acta 1997, 80, 388. N.M. Przeval'skii, I.V. Magedov, V.N. Drozd, Khim. Geterosikl. Soedin. 1997, 1700. S.N. Bajpai, K.C. Joshi, R. Jam, Heterocycl. Commun. 1997, 3, 41. Y.I. Gao, F.J. Li, R.S. Jiang, S.C. Zhou, Chin. Chem. Lett. 1997, 8, 5. Y. Hou, S. Higashiya, T. Fuchigami, Synlett 1997, 655. C. Walsdorff, W. Saak, S. Pohl, J. Chem. Soc., Dalton Trans. 1997, 1857. C. Kuehm-Caub~re, I. Rodriguez, B. Pfeiffer, P. Renard, P. Caub~re, d. Chem. Soc., Perkin Trans. 1 1997, 2857. T. Uetake, M. Nishikawa, M. Tada, J. Chem. Soc., Perkin Trans. 1 1997, 3591. L. Sun, J.R. Rubin, A.J. Kraker, H.D.H. Showalter, d. Heterocycl. Chem. 1997, 34, 1399. H.D.H. Showalter, A.D. Sercel, B.M. Leja, C.D. Wolfangel, L.A. Ambroso, W.L. Elliott, D.W. Fry, A.J. Kraker, C.T. Howard, G.H. Lu, C.W. Moore, J.M. Nelson, B.J. Roberts, P.W. Vincent, W.A. Denny, A.M. Thompson, J. Med. Chem. 1997, 40, 413. M.S.C. Pedras, K.C. Smith, Phytochemistry 1997, 46, 833. G. Poggi, G. Casalbore Miceli, G. Beggiato, S.S. Emmi, Spectrochim. Acta, Part A 1997, 53, 2153. T.J. Connolly, T. Durst, Tetrahedron 1997, 53, 15957. T.J. Connolly, T. Durst, Tetrahedron Lett. 1997, 38, 1337. E.T. Pelkey, G.W. Gribble, Tetrahedron Lett. 1997, 38, 5603. S. Caddick, C.L. Shering, S.N. Wadman, Tetrahedron Lett. 1997, 38, 6249. P.C. Montevecchi, M.L. Navacchia, P. Spagnolo, Tetrahedron Lett. 1997, 38, 7913. P. Hamel, Tetrahedron Lett. 1997, 38, 8473. V.I. Boev, A.S. Bykanov, S.I. Alferova, A.I. Moskalenko, E.M. Krasnikova, Zh. Obshch. Khim. 1997, 67, 1670. R.E. Mewshaw, A. Verwijs, X. Shi, G.B. McGaughey, J.A. Nelson, H. Mazandarani, J.A. Brennan, K.L. Marquis, J. Coupet, T.H. Andree, Bioorg. Med. Chem. Lett. 1998, 8, 2657. M.S.C. Pedras, A. Loukaci, F.I. Okanga, Bioorg. Med. Chem. Lett. 1998, 8, 3037. M.S.C. Pedras, F.I. Okanga, Chem. Commun. 1998, 67. M.S.C. Pedras, F.I. Okanga, Chem. Commun. 1998, 1565. M. Yoshikawa, T. Murakami, A. Kishi, T. Sakurama, H. Matsuda, M. Nomura, H. Matsuda, M. Kubo, Chem. Pharm. Bull. 1998, 46, 886. P.C. Montevecchi, M.L. Navacchia, P. Spagnolo, Eur. J. Org. Chem. 1998, 1219. M. Tazaki, T. Hieda, H. Maeda, S. Nagahama, A. Jyo, Heteroatom Chem. 1998, 9, 289. M.L. Curtin, S.K. Davidsen, H.R. Heyman, R.B. Garland, G.S. Sheppard, A.S. Florjancic, L. Xu, G.M. Carrera Jr., D.H. Steinman, J.A. Trautmann, D.H. Albert, T.J. Magoc, P. Tapang, D.A. Rhein, R.G. Conway, G. Luo, J.F. Denissen, K.C. Marsh, D.W. Morgan, J.B. Summers, J. Med. Chem. 1998, 41, 74. D.K. Bates, M. Xia, J. Org. Chem. 1998, 63, 9190. P. Kutschy, M. Dzurilla, M. Takasugi, M. T6r6k, I. Achbergerov~, R. Homzov~i, M. R~icov~t, Tetrahedron 1998, 54, 3549. R. Frenette, J.H. Hutchinson, S. L6ger, M. Th6rien, C. Brideau, C.C. Chan, S. Charleson, D. Ethier, J. Guay, T.R. Jones, M. McAuliffe, H. Piechuta, D. Riendeau, P. Tagari, Y. Girard, Bioorg. Med. Chem. Lett. 1999, 9, 2391. A.J. Kresge, Q. Meng, Can. J. Chem. 1999, 77, 1528. M. Somei, M. Nakajou, T. Teramoto, A. Tanimoto, F. Yamada, Heterocycles, 1999, 51, 1949. Nizamuddin, M.H. Khan, S. Alauddin, R. Haque, Indian ,I. Chem. 1999, 38B, 501. P. Hamel, M. Girard, N.N. Tsou, J. Heterocycl. Chem. 1999, 36, 643. S.P.B. Ovenden, R.J. Capon, J. Nat. Prod. 1999, 62, 1246. M.S.C. Pedras, F.I. Okanga, J. Agric. Food Chem. 1999, 47, 1196. A.B. Tomchin, V.V. Marysheva, Russ. J. Org. Chem. 1999, 35, 1060. M.M.B. Marques, A.M. Lobo, S. Prabhakar, P.S. Branco, Tetrahedron Lett. 1999, 40, 3795. H. Stephensen, F. Zaragoza, Tetrahedron Lett. 1999, 40, 5799. J.D. Rainier, A.R. Kennedy, E. Chase, Tetrahedron Lett. 1999, 40, 6325.

18 99TL7615 00AX830 00BMCL805 00EJO3093 00JMC2449 00JOC6213 00KGS 171 00OM3507 00P(53)161 00P(55)213 00T465 00T3933 00T10159 00TL4467 00TL9835 01B MC 1045

01CC1572 01H(54)425 01H(54)957 01H(55)1151 01JHCI05 01JHC569 01JOC2434 01JOC3940 01OL1213 01SC3041 01SM(120)1061 01T975 01T7185 01TL1077 01TL5187 01 TL6961 01TL9281 02EJO1393

02JCS(P1)330 02T479 02UP

J. Bergman and T. Janosik E.T. Pelkey, T.C. Barden, G.W. Gribble, Tetrahedron Lett. 1999, 40, 7615. U. Baumeister, H. Hartung, R. Spitzner, M. Felicetti, W. Schroth, Acta Crystallogr. 2000, C56, 830. D. Potin, V. Parnet, J,-M. Teulon, F. Camborde, F. Caussade, J. Meignen, D. Provost, A. Cloarec, Bioorg. Med. Chem. Lett. 2000, 10, 805. W. Schroth, R. Spitzner, M. Felicetti, C. Wagner, C. Bruhn, Eur. J. Org. Chem. 2000, 3093. J.J. Chen, Y. Wei, J.C. Drach, L.B. Townsend, J. Med. Chem. 2000, 43, 2449. J.D. Rainier, A.R. Kennedy, J. Org. Chem. 2000, 65, 6213. N.E. Shevchenko, A.S. Karpov, E.P. Zakurdaev, V.G. Nenajdenko, E.S. Balenkova, Khim. Geterotsikl. Soedin 2000, 171. M. Rakowski DuBois, L.D. Vasquez, R.F. Cianccaelli, B.C. Noll, OrganometaUics 2000, 19, 3507. M.S.C. Pedras, F.I. Okanga, I.L. Zaharia, A.Q. Khan, Phytochemistry 2000, 53, 161. M.S.C. Pedras, I.L. Zaharia, Phytochemistry 2000, 55, 213. S. Caddick, C.L. Shering, N.S. Wadman, Tetrahedron 2000, 56, 465. M.A. Abramov, W. Dehaen, B D'hooge, M.L. Petrov, S. Smeets, S. Toppet, M. Voets, Tetrahedron 2000, 56, 3933. A. Padwa, A.G. Waterson, Tetrahedron 2000, 56, 10159. M.F. Greaney, W.B. Motherwell, Tetrahedron Lett. 2000, 41, 4467. M.M.B. Marques, M.M.M. Santos, A.M. Lobo, S. Prabhakar, Tetrahedron Lett. 2000, 41, 9835. M. Mor, G. Spadoni, B. Di Giacomo, G. Diamantini, A. Bedini, G. Tarzia, P.V. Plazzi, S. Rivara, R. Nonno, V. Lucini, M. Pannacci, F. Fraschini, B. Michaylov Stankov, Bioorg. Med. Chem. 2001, 9, 1045. M.S.C. Pedras, S. Montaut, Y. Xu, A.Q. Khan, A. Loukaci, Chem. Commun. 2001, 1572. M. Somei, A. Tanimoto, H. Orita, F. Yamada, T. Ohta, Heterocycles 2001, 54, 425. T. Murakami, A. Kishi, T. Sakurama, H. Matsuda, M. Yoshikawa, Heterocycles 2001, 54, 957. K. Yamada, T. Kawasaki, T. Fujita, M. Somei, Heterocycles 2001, 55, 1151. T. Nishio, O. Saku, H. Yamamoto, J. Heterocycl. Chem. 2001, 38, 105. J. Breinholt, C.B. Jeppesen, S. Branner, C.E. Olsen, N.P. Hundahl Moiler, B.H. Nielsen, H.S. Andersen, J. Heterocycl. Chem. 2001, 38, 569. M. Matsugi, K. Murata, K. Gotanda, H. Nambu, G. Anilkumar, K. Matsumoto, Y. Kita, J. Org. Chem. 2001, 66, 2434. M. Such2~, P. Kutschy, K. Monde, H. Goto, N. Harada, M. Takasugi, M. Dzurilla, E. Balentov~i, J. Org. Chem. 2001, 66, 3940. M.S.C. Pedras, I.L. Zaharia, Org. Lett. 2001, 3, 1213. V.K. Jadhav, R.R. Pal, P.P. Wadgaonkar, M.M. Salunkhe, Synth. Commun. 2001, 31, 3041. F. Allared, J. Blid, J. Hellberg, T. Remonen, M. Svensson, Synth. Met. 2001, 120, 1061. T. Fukuda, Y. Mine, M. Iwao, Tetrahedron 2001, 57, 975. G.W. Rewcastle, T. Janosik, J. Bergman, Tetrahedron 2001, 57, 7185. M. Matsugi, K. Murata, H. Nambu, Y. Kita, Tetrahedron Lett. 2001, 42, 1077. U. Hary, U. Roettig, M. Paal, Tetrahedron Lett. 2001, 42, 5187. M. Such)~, P. Kutschy, M. Dzurilla, V. Kovficik, A. Andreani, J. Alf01di, Tetrahedron Len. 2001, 42,6961. P. Kutschy, M. Such3~, A. Andreani, M. Dzurilla, M. Rossi, Tetrahedron Lett. 2001, 42, 9281. T. Janosik, J. Bergman, I. Romero, B. Stensland, C. Sthlhandske, M.M.B. Marques, M.M.M. Santos, A.M. Lobo, S. Prabhakar, M.F. Duarte, M.H. F16rencio, Eur. J. Org. Chem. 2002, 1392. T. Janosik, J. Bergman, B. Stensland, C. Sthlhandske, J. Chem. Soc., Perkin Trans. 1 2002, 330. T. Yamada, C. Iwamoto, N. Yamagaki, T. Yamanouchi, K. Minoura, T. Yamori, Y. Uehara, T. Andoh, K. Umemura, A. Numata, Tetrahedron 2002, 58, 479. J. Bergman, R. Engqvist, Unpublished results, 2002.

19

Chapter 2

Electrophile-induced 5-Endo Cyclizations David W. Knight

Chemistry Department, Cardiff University, P. O. Box 912, Cardiff CF10 3 TB, UK. knightdw@cf ac.uk

2.1

INTRODUCTION

The aim of this review is to provide an overview of overall 5-endo cyclizations of unsaturated alcohol, amine and thiol derivatives when induced by various electrophiles, predominantly iodine and selenides. An attempt to be reasonably comprehensive has been made but is not claimed! One of the fundamental tenets of Baldwin's rules of cyclization <76CC734, 76CC738> is that 5-endo-trig processes are particularly disfavoured <76CC736>. It therefore came as a surprise to discover, during our studies of iodolactonizations of (E)-3-silyloxyalk-5-enoic acids 1, that small amounts (ca. 5%) of the iodotetrahydrofurylacetic acids 4 were also formed <91JCS(P1)133; 91JCS(P1)1543; 96JCS(P1)1505>.

RI[• siR3

OSiR 3

(~

, , H

OH

1

R R 1 = alkyl

I ....

0

I

CO2H

I

2

3

4

This observation was accompanied by the finding that such iodolactonizations led largely to the trans-3,5-disubstituted valerolactones 3, presumably via chair conformation 2 wherein the silyloxy group is held in an axial position by hydrogen bonding with the carboxylic acid. We had expected to isolate predominantly the corresponding cis-isomers in view of the results obtained by Bartlett <84T2317> which suggested a distinct preference, not surprisingly, for the altemative chair conformation 5 wherein the 3-substituent is positioned equatorially.

16) RI~

~

H 5

,,O

"

~

cis-"3"

1

=

R1

~..-O"siR3 6

CO2H

4

20

D. W. Knight

Throughout these initial studies, we used the usual Bartlett conditions for iodolactonization consisting of three equivalents each of iodine and sodium hydrogen carbonate in aqueous acetonitrile <78JA3950; 84T2317; B-84MI001>. Returning to the minor tetrahydrofurans [4; R = n-alkyl], their richly-detailed 1H NMR spectra showed that these were essentially single diastereoisomers. What was unusual was that these appeared to have arisen by a 5-endo-trig cyclization, in contravention of one of the key features of Baldwin's rules <76CC736>. Re-drawing the acids 1 in conformation 6 shows how this cyclization could occur and hence merit the term 5-endo-trig. However, this apparent violation of an established set of rules raised doubts about this conclusion. In contrast, the phenyl-substituted (E)-hydroxy-acid 7 underwent cyclization under the "standard" iodolactonization conditions (see above) to give only iodotetrahydrofurans 8 and 9, in a ratio of 7:1, rather than the corresponding lactones.

ph__/~___k HO

12' NaHCO3 C02H

aq. MeCN

I

I

Ph'"

Ph'. . . . . . .

C02H 8

I C02H

9

We felt that this could a special case in which the phenyl group would stabilize an electron-deficient benzylic centre, hence favouring the 5-endo etherification at the expense of the 6-exo lactonization which would feature attack at the carbon 13- to the phenyl group. It may be relevant that the Kurth group <89JA3712> have found the differences between 5-exo iodolactonization and iodoetherification to be very small and hence the effect of the phenyl group may be sufficient to tip the balance in favour of the 5-endo cyclization. When we biased the cyclizations towards tetrahydrofuran formation by blocking the carboxylic acid group as the corresponding methyl ester, exposure of the alkyl-substituted hydroxy-ester 10 to the usual iodolactonization conditions led to a ca. 70% yield of a single iodotetrahydrofuran 11.

Et.~~~..,k HO 10

12' NaHC03 C02Me

aq. MeCN 11

C02Me

Subsequent results however showed that this was a special case. Thinking we had discovered a new route to tetrahydrofurans, we tried a similar cyclization of a simpler model, (E)-3-hexen-l-ol 12, under the same conditions. Sadly, however, this resulted in a return to the original ca. 5% yield of the hoped-for iodotetrahydrofuran 13 together with the iodohydrins 14 and 15, formed because, not surprisingly, competing and non-regioselective attack of water on the intermediate iodonium ion 16 occurs at a faster rate than the disfavoured 5-endo cyclization. Therefore, we reasoned that by using anhydrous acetonitrile, this competing pathway should be suppressed. This proved to be a correct deduction: exposure of (E)-3-hexen-l-ol to three equivalents each of iodine and sodium hydrogen carbonate in dry acetonitrile at 0~ gave an essentially quantitative yield of the iodotetrahydrofuran 13 in around 0.25h. This then set the stage for much of our subsequent work in this area.

21

Electrophile-induced 5-Endo Cyclizations

aq. MeCN

HO

HO

I

12, NaHCO3

I 9

Et'"

12

13[-5%]

14

15

~"OH

I

E ! ~ H-.OH HO

Et---~-~ HO

16

12' NaHC03 DRY MeCN

12

Et"' 13 [> 9 5 % 1

Almost inevitably, few discoveries are entirely novel. In 1978, Bartlett and Myerson <78JA3950> had observed a similar phenomenon when attempting to iodolactonize the hydroxy-ester 17. While the major product was indeed the expected butyrolactone 18 arising from ester dealkylation and 5-exo-trig cyclization, a minor product was the iodotetrahydrofuran 19, despite the fact that its formation required demethylation of the methyl ether. In line with this, the corresponding hydroxy-ester underwent selective 5-endo cyclization to give only the tetrahydrofuran 19. Little comment was made regarding formation of the latter and the stereochemistry was assigned on the basis that the least hindered product should be formed; an alternative formulation could be the 2,5-trans diastereomer 20.

/••Me

OMe

17

~e ,,,"

I

18

+

O02Me 19

....

20

Isolated examples of 5-endo cyclizations of alcohol 12 to give the iodotetrahydrofuran 13 using more sophisticated iodonium sources, namely sodium iodide, 18-crown-6 and mchloroperoxybenzoic acid in dichloromethane <84CC1070> or bis(sym-collidine)iodine(l) perchlorate <885862> have also been reported without additional comment. Also reported without any special mention was bromoetherification of compound 21 on a pathway towards biosynthetic intermediates of the macrolide protomycinolide IV <89TL4001>. No comment of the stereochemistry of the product 22 was made, understandably so, as the cyclization was carried out as a means to protect both the alcohol and alkene functions in precursor 21 which were later regenerated by reductive cycloreversion. In view of our model work described above, it is notable that use of an aqueous solvent has no deleterious effect and serves as an illustration of reading too much into model studies. As will be described below, the presence of additional substituents can have a profound effect on 5-endo cyclizations. The same tactic has been used to "protect" the alkene function of the homoallylic alcohol 23 <99JOC663>. Formation of the bromotetrahydrofuran 24 enabled subsequent oxidation to the carboxylic acid 26 to be carried out without complications, via the butyrolactone 25.

22

D. W. Knight

BnO

NBS aq. THF

HO

BnO

22

21

-" ""

--~OR

1

R

NBS CH2Cl2

Br~. , R'"~"""

23

2.2

RuO4

Br ...Zn ~..~-~'" R''~'~O/%O aq. EtOH

24

~CO2H R

25

26

5-ENDO-IODOCYCLIZATIONS OF H O M O A L L Y L I C ALCOHOLS

Having established an optimum set of conditions for 5-endo-trig iodocyclizations of homoallylic alcohols, we carried out model studies to ascertain the scope and limitations with regard to substitution patterns of both the alcohol and alkene functions <99JCS(PI)2143>. In summary, most types of (E)-homoallylic alcohols undergo smooth and stereoselective 5-endo cyclizations to give excellent yields of the iodotetrahydrofurans 27-31, 33 and 34. A typical procedure for carrying out such cyclizations is as follows. Sodium hydrogen carbonate (4.11g, 48.9 mmol) is added to an ice-cold solution of the homoallylic alcohol (16.3 retool) in dry acetonitrile (70 ml). Atter stirring for 5 minutes, solid iodine (12.42g, 48.9 mmol) is added in one portion and the resulting mixture stirred with the exclusion of light at 0~ with tlc monitoring. Once complete, the mixture is diluted with ether (100 ml) and treated with saturated aqueous sodium thiosulfate until the colour of the excess iodine was discharged. (On larger scales, sodium sulfite can be used to advantage, its greater solubility reducing the volume of water required). The resulting layers are separated and the aqueous layer extracted with ether (3 x 50 ml). The combined organic solutions are washed with water and brine then dried and evaporated. In the examples 27-31, the resulting residue is usually essentially pure iodotetrahydrofuran. Purified by silica gel chromatography and 1020% ether in pentane, the iodotetrahydrofurans are somewhat light-sensitive and are best stored below 0~ in the dark.

Et~'"Bu

~ '

Et 28

27

R 29; R = H; CH2CO2Et

I

MeO2C

"Bu 31

"Bu

MeO2C

30

I

---

S 32 [R = Ph(CH2)2] L

I

+

J

33

"R 34

As can be seen from the variety of model structures 27-31, which were all obtained in >80% isolated yields, both secondary [27] and tertiary [28] alcohols work well and

23

Electrophile-induced 5-Endo Cyclizations

cyclizations can be effected onto alkenes with one [27, 28] or two [29] distal substituents, c~Hydroxy-esters also work well [30], not surprising in view of the initial observation by Bartlett and Myerson <78JA3950> as well as [3-hydroxy-esters [11, 31] which gave marginally higher yields (ca. 5-10%) under the foregoing anhydrous conditions relative to the aqueous conditions outlined in the introduction. At a lower oxidation level, an aldehyde function in the form of a 1,3-dithiane residue, could also be incorporated without affecting the cyclization although, not surprisingly, partial hydrolysis occurred to give a good combined yield of the dithian-2-ylmethyl-3-iodo tetrahydrofuran 33 and the corresponding aldehyde 34. Presumably, the excess iodine attacks the sulfur of the dithiane to form an iodosulfonium species which collapses and is then hydrolysed by water produced during the cyclization. Isolated hydroxyl groups can also be incorporated but usually only when in a suitable position so as not to compete with the desired 5-endo cyclization. Thus, the symmetrical and unprotected ene-diol 35 gave an 87% isolated yield of the iodotetrahydrofuran 36 when exposed to the standard cyclization conditions. Whether or not this idea could be usefully extended to less symmetrical diols remains to be established. HO

c

I

OH

-35

HO

__ 36

37

..... 38

I

The veracity of Baldwin's rules is illustrated by the finding that 4-pentene-l,2-diols 37 cyclize exclusively by a 5-exo pathway when treated with iodine-sodium hydrogen carbonate to give only the ~-iodoalkyl tetrahydrofurans 38 <88JA4533, 86TL1237, 87JOC1680>. It is quite probable that other nucleophiles in general such as amines or carboxylic acids etc. will also usually compete successfully with 5-endo processes when positioned so as to undergo 5exo cyclization. This may also be true of competing 6-exo reactions although, as ever, highly substituted substrates may not obey this principle. Blocking an undesired competing pathway may not always be successful, as many alcohol protecting groups are easily lost during iodocyclizations; even methyl ethers can be cleaved (see the formation of tetrahydrofuran 19 above). Certainly, O-silyl and O-benzyl ethers are labile under these seemingly mild conditions <92TL3607; 81JA3963>. For example, the benzyl ether is easily cleaved in the protected triol 39 during a highly selective 5-exo cyclization to give the (+)-citreoviral precursor 40 <87JOC5067>. No competing 5-endo products arising from cleavage of the MOMO function were observed. We have compared the relative facility of protecting group cleavage in both 5-exo and 5-endo modes under the same conditions (see above) <01MI001>. In the 5-exo examples [41 to 42], the presence of protecting groups hardly slowed the cyclization. This was also true of the corresponding 5-endo cyclizations [43 to 13] which generally took about twice as long to reach completion relative to the 5-exo reactions. Hence, the use of protecting groups to block an undesired pathway must be approached with caution in this area. It is likely that, in general, rates of 5-exo cyclizations will be faster than 5-endo processes, even when the nucleophilic hydroxyl group in the former is blocked.

24

D. W. Knight

MOMO'O ~ ...... ~ ph____/O

~

--~

~ I

R

39

41

R=H'<15min; R = TBS --20 9 min; R = Bn "-20 min

42

1 Et

R,,O 40

~

43

R = TBS ' 40 min" R = Bn 40 9 min 13

A final example of this phenomenon from our own work serves as a warning <01MI001 >. We had planned to prepare the tetrahydrofurans 45 by 5-endo cyclization of the hydroxyester 44 in which the hydroxy group within the 1,3-diol array, which could potentially undergo competing 5-exo cyclization onto the alkene, was protected as a rather stable cyclic acetal which we anticipated should also prevent any approach of the acetal oxygen towards the activated alkene. We were unamused to find that the only product obtained 46 was indeed that arising from 5-exo cyclization, with complete loss of the 'protecting' group, hence spelling the end of this particular target synthesis!

•••[/O•co2 o./

Me

45

CO2Me ~. 44

......~ C O 2 M e I

OH

46

Another caution regarding protecting groups concerns the masking of carboxylic acid functions. Methyl esters are probably the best blocking groups, but even these can be lost, as such esters can participate in 5-exo iodocyclizations (see 18 above). It is therefore perhaps stating the obvious that both t-butyl and benzyl esters are less stable under such reaction conditions. Certainly our experience with esters 47 was that poorer yields of the iodotetrahydrofurans 48 were obtained due to loss of the ester groups during competing 6-exo cyclization. R

HO 47

CO2R1

~

R'"

R1 = But or Bn w.r.t. CO2R1 R1 = Me 48

At first sight, all of the foregoing comments are not consistent with the findings of Kang

Electrophile-induced 5-Endo Cyclizations

25

and Lee <93TL7579> who reported that iodocyclization of the furyl-substituted 4-pentene1,2-diol derivative 49 led, under optimized conditions, to the 2,5-cis-isomer 50. This seemingly contradictory result, wherein a 5-endo-trig cyclization occurs in preference to a 5exo process, can however be explained by participation of the furyl residue. Assuming the intermediacy of the iodonium species 51, rapid donation of the furan oxygen lone pair would provide the highly activated intermediate 52 which would then cyclize rapidly with loss of the triethylsilyl group to give the observed product 50. Hence, the competition at the cyclization step is arguably between 5-exo and 6-exo processes in which the former clearly wins out.

TBDPSO/~~~'~O

12,Et3N MeCN, O~

49

TBDPSO[~~O 5O

l TBDPs ~

,I

TBDPs~O,~

OTES

G1

Q

52

The origins of the different stereochemistry with respect to our foregoing examples (2,5cis rather than 2,5-trans) is probably associated with the bulk of the triethylsilyl group and is discussed below. Consistent with this is the finding that the corresponding free alcohols 53 undergo iodocyclization to give very largely the 2,5-trans isomers 54. The survival of the distal trityl group is remarkable and lends credence to the mechanism involving participation of the furan ring outlined above <93TL1955>. Such cyclizations are relatively slow at this low temperature and the highest stereoselectivities were realized in ether. I

RO

OH G3

Et20' _78oc

R

,,

R = TBDPS, Pri, Trt

54

A logical extension of this principle is to reduce it to its simplest form by replacing the activating furan with a vinyl ether function. The control inherent in this idea has been elegantly illustrated by Lipshutz and Tirado <94JOC8307> in the overall 5-endo cyclization of the polyfunctional substrate 55 which gives the five-membered cyclic acetal 56 almost exclusively. Similarly, a protected sugar derivative 57 can be generated in 75% isolated yield. Thus in reality probably undergoing 5-exo cyclizations, such sensitive substrates do however demand the use of rather special conditions which feature prior alkoxide formation and low temperature; direct treatment with iodine, I2-Ag+ or PhSeC1 was less effective.

26

D. W. Knight

BnO.....

o.

BnO'~l~"~ OH

Et20, -78~

I..... "0" "'OR BnO

55

0

O o ~O 57

56

.,~0

The same idea has been applied to the deconjugated aldol systems examined by Galatsis. Thus, exposure of the vinyl ether 58 to the 'standard' iodocyclization conditions gives the acetal 59, accompanied by the corresponding de-iodo derivative, which was presumably formed by acid-catalysed cyclizalion <95TL8179>. Stereoselection was higher at lower temperatures in acetonitrile. Presumably, the same mechanism is in operation in the useful bromine-induced cyclization of the [3-1actam 60 to give only the annulated derivative 61 <94TL6317>.

MeO. Me02C,~_ /~ ~>~0

H

" ~ .~ MeO,2C,,,___~1 ~

R O ~ H H

R ~ H 1"21_

/ "0" "OMe

58

59

PhS

60

0 Ph 62

~

C02Et

12,Et3N aq. acetone

0t

.,,,Br ~ EtO C02Et 61

PhS

0 "0" "SPh 63

Evidently, sulfur can participate in a similar fashion as in a new approach to furans <94TL7327>: iodocyclizations of the vinyl thioether 62 occur readily to give the thioacetal 63. Eliminations under various conditions then lead to substituted furans. Returning to our own model studies, one failure of the 5-endo method was when it was applied to the internally substituted homoallylic alcohol 64 which delivered none of the iodotetrahydrofuran 65. Mainly decomposition products were observed and it may be that the methodology is incapable of forming a tertiary iodide. Alternatively, the substrate 64 may be just too simple in the sense that it lacks a distal alkene substituent and hence 4-exo cyclization is favoured. This is certainly the case when using bis(sym-collidine)iodine(I) perchlorate in dichloromethane at -20~ when the alcohol 64 is converted instead into the oxetane 66 <88S862>. Similarly, 3-buten-l-ol is converted into a mixture of oxetane 67 and 3-iodotetrahydrofuran while the ot,ot-dimethyl derivative gives exclusively the oxetane 68. Further examples suggest this may be a feature of such distally unsubstituted 3-buten-l-ols. Thus, exposure of the hydroxy-esters 69 to iodine and sodium hydrogen carbonate in acetonitrile gives largely the oxetanes 70, accompanied sometimes by products epimeric at the iodomethyl substituted centre <94TL6611; 97JOC5048>.

Electrophile-induced 5-Endo Cyclizations

27

I

64

65

66

67

68

The balance between 4-exo and 5-endo iodocyclizations is evidently quite delicate in some cases. For example, in an extension of the forcgoing methodology, iodocyclization of the hydroxy-amides 71 under standard conditions gives slowly but exclusively the annulated tetrahydrofurans 72 and not the corresponding spiro-oxetanes, as reported in a preliminary communication <97JOC5048>. This example also shows that it is possible to obtain a tertiary iodide from this chemistry, negating a conclusion from our initial studies. Simpler chiral oxazolidinone derivatives having a single distal substituent on the alkene group also give tetrahydrofurans 73 with some loss of stereoselection at the ncw m-carbon while cyclizations onto simple vinyl groups give only iodomethyloxetanes [cf. 66] or mixtures of oxetanes and tetrahydrofurans, in the case of the corresponding methyl esters [94JOC6643>. HO

0

I

MeO2C~'R;~--MeO2C' / 2R, .'~/4_RO"' ~-~'R 'I R~~~j~Xc --"" ~ H 69

70

71

,OOXc R ~"/-'0 R I :"

~COXc

72

73

The tendency for more highly substituted homoallylic alcohols to cyclize by the 4-exo pathway has been further exemplified by Jung and Nichols <96T7776> who found that the divinyl carbinols 74 gave mainly the oxetanes 75, together with some isomers, along with the iodotetrahydrofurans 76 in ratios ranging from 3:1 to 10:1, when using iodine and silver(I) bis (sym-collidine) perchlorate in dichloromethane.

12, Ag(coll)2Cl04

Ar

%"

CH2Cl 2 74

+

I ,,,,,~ ~ A [3:1-.,10:1] r

I

75

76

A significant limitation of the 5-endo-trig iodocyclization method, at least with simple substrates, is the poor returns obtained from (Z)-homoallylic alcohols 77. Although the cyclizations retain excellent levels of stereoselection, giving only the all-cis diastereomers 78, yields are generally below 50% and the reactions arc evidently highly disfavoured, as complete consumption of starting material can take up to 72h at ambient temperature <99JCS(P1)2143>. Other products were iodohydrins, formed by attack of water on the intermediate iodonium species [cf. 16], the extreme lethargy of the 5-endo cyclizations in these cases providing plenty of opportunity for this. Water will inevitably be generated during the course of the cyclizations by neutralization of the by-product hydrogen iodide by the hydrogen carbonate. Addition of magnesium sulfate or use of other bases (e.g. potassium carbonate, magnesium oxide) which could remove this water had little or no effect. However, this limitation is not evident with more highly substituted (Z)-precursors as described below. One final and extraordinary result from our model studies was the finding

28

D. W. Knight

that iodocyclizations of the (Z)-3-hydroxy-5-alkenoates [79; R-alkyl] gave the hydroxytetrahydrofurans 80 <92TL6511 >.

OH Bu

R

77

Bu

Me02

c'~O

78

H~R

,.,OH R

Me02C

79

80

The origin of the hydroxy groups was at first a complete mystery. While this could in principle arise by Su2 displacement by hydroxide or carbonate of iodide from the expected all-cis iodotetrahydrofuran [cf. 78], this seemed most unlikely as such products were not observed in any other cyclizations and further, such substitutions turned out to be relatively difficult (see below). Further studies showed that the precursors 79 were rapidly converted into the corresponding iodohydrins which then slowly cyclized to give the observed products 80. That this occurred directly and not via the derivcd epoxide was proven by exposure of the latter to the reaction conditions, when no hydroxy-tetrahydrofuran 80 was formed. As the only difference in this type of substrate is the ester function, we suspect that this is involved in the iodohydrin formation, and thus provides an alternative pathway to the evidently disfavoured, direct 5-endo iodocyclization. An explanation is based on conformation 81, closely related to that deduced for the 6-exo iodolactonizations described above. Cyclization provides the stabilized carbocation 82 which is trapped by water to give the ortho ester 83. Regeneration of the ester function and ring opening then provides a single diastereomer of iodohydrin 84 which, when redrawn in conformation 85, shows how the final product 80 is formed. This final cyclization would also be assisted by hydrogen bonding within the 13hydroxyester array. R|

I

H,,

, OMe H 81

I

I

I

HQ

R !.[io2Me OH H,,

!~1 ~ OMe H 82

tL! ~ OMe H 83

84

I

;

H

C02Me

85

As much to prove the nature and stereochemistry of the products 80 as to demonstrate a use of this chemistry, we have applied it to a brief synthesis of D-(-)-muscarine 89, the enantiomer of a powerful acetylcholine agonist present in the fly agaric mushroom, Amanita muscara <94SL295>. Starting with dimethyl (S)-malate on cost grounds, known chemistry <90T4277; 83TL391; 01TL6947> provided the (Z)-unsaturated hydroxy-ester 86. Exposure of this to IJ]XlaHCO3 gave the expected hydroxytetrahydrofuran 87 in 84% yield. Alcohol protection, saponification and Barton-Hunsdiecker degradation <85T3901>, using iodoform as the radical trap, gave an excellent yield of the iodomethyl derivative 88. Finally, heating the iodide 88 with Me3N in ethanol gave muscarine iodide 89, identical with previously prepared material, hence proving the veracity of the structural assignment to the hydroxytetrahydrofurans 80.

Electrophile-induced 5-Endo Cyclizations HO ..... \ C02M e 86

29 HO.

TIPSO.

. . ..... . . . .

,

I C02Me

, I(D I

87

@ NMe3

88

89

Further proof of the intermediacy of the iodohydrins 85 in the formation of the hydroxytetrahydrofurans 80 came from two sources. Firstly, treatment with potassium carbonate led to formation of the corresponding epoxides. Secondly, by providing a second alkene function, suitably positioned to trap the iodohydrin hydroxyl by a 6-exo-trig iodocyclization, we have been able to intercept these species and hence define a new approach to substituted pyrans. Thus, treatment of the dienyl hydroxy-ester 90 with iodine and NaHCO3 resulted in the formation of pyrans 92 in the ratio of 3.2:1. Presumably, initial iodohydrin formation 91 is followed by a relatively non-stereoselective 6-exo cyclization. Further chemistry of such products has yet to be carried out, especially efforts to distinguish the two iodine atoms and to cyclize to give furopyran systems <01MI001>.

C02Me 90

R

C02Me 91

R

C02Me 92

Returning to the central iodotetrahydrofurans, a few comments on structure determination are appropriate. The three protons adjacent to heteroatoms (2-, 3- and 5-H) in a typical iodotetrahydrofuran 27 usually resonate around 5~ 4 in a richly detailed proton spectrum. However, a key feature of the 13C spectrum is the appearance of a methine resonance at around 30 ppm due to the CHI function, shifted to this unusual area by the heavy atom effect. Correlation spectra then provide a complete assignment of all other protons and, in particular, permit a definite distinction to be made between the iodotetrahydrofuran structure [e.g. 27] and the corresponding oxetane which would arise from a 4-exo-trig cyclization. Finally, the stereochemistry can be assigned using NOE measurements, in which the iodotetrahydrofurans are reasonably well behaved. Being five-membered rings, the use of coupling constants is at best questionable and at the worst dangerous, beyond comparisons between closely-related structures. An explanation of the observed stereochemistry in general features the chair-like conformation 93 in which 'E' and 'Z' represent substituents on (E)- or (Z)- alkenes. This is controlled by the equatorial position of the substituent 'R' on the sp 3 carbon adjacent to the alcohol function. Rearside positioning of the iodine then allows the expected overall antiaddition to the alkene. The necessary axial-like positioning of the substituent 'Z' in a Zalkene accounts for the much poorer yields of all-cis isomers [e.g. 78]. The cyclizations, despite being 5-endo-trig in nature, are therefore probably best regarded as not being exceptions to Baldwin's rules as they are electrophile- rather than nucleophile-driven and hence presumably feature a late transition state in which the partial C-I bond begins to break, thus creating an electron-deficient carbon centre which attracts the hydroxyl oxygen. The very high levels of stereoselection observed in iodocyclizations of (E)-homoallylic alcohols are also consistent with a relatively unfavoured cyclization which will, necessarily, be much more demanding in terms of transition state geometry. In contrast, highly favoured 5-exo-trig halocyclizations are often relatively non-stereoselcctive <87T3309; 93TA1711>. A similar

D. W. Knight

30

conformation 94 explains why the 13-hydroxy-esters [e.g. 10, 47] cyclize easily and are less prone to competing attack on the iodonium species by water, to give iodohydrins, as the hydroxyl function can hydrogen bond with the ester carbonyl and hence is activated with respect to O-H bond cleavage. A final, unexplained feature of these and many other iodocyclizations is the requirement for three cquivalents of iodine. Presumably, a polyiodine species is involved; the exact nature of this is, as yet, unclear. In any event, the conformation 93 provides a basis for synthetic design, if nothing else, and can also in principle be used to account for the outcomes of cyclizations of more highly substitutcd precursors. |

,~.Z

,I-

"..

| E

~0"' MeO

H

'

/

93

~ ~

Z

";,

E

~

I

"

,,E

OH Z

Z

'syn'

94

95

96

| OH Z

97

~,

I

......

Z

~nfi' 98

99

100

However, some doubt as to the validity of this conclusion arose from the work of Lipshutz and Barton <92JA1084> who suggested, for example, that iodocyclization of the anti-(E)- homoallylic alcohol [98; Z = H] led to an all-cis-iodotctrahydrofuran. The extraordinary feature of this reaction is that it requires overall syn-addition of iodine and the hydroxy group to the alkene, suggesting that the foregoing mechanistic conclusions could be incorrect. However, contemporaneous reports by Michelich <90JA8995; 92JA7318> quoted isolated examples together with some related selenocyclizations (see below) which raised doubts about the correctness of Lipshutz's conclusions; in some examples, rather different conditions (I2, AgO2CCF3) were used, although this contrast did not appear to affect the stereochemical outcome. The Lipshutz paper also contained useful data conccrning the nature of the solvent and base used for such iodocyclizations using molecular iodine. Thus, (much) slower rates were observed in THF, dichloromethane or chloroform, DMF, DMSO, methanol, ethyl acetate and acetone; acetonitrile was confirmed as the optimum solvent, at least for this type of 5-endo iodocyclization. Further, the cyclizations were completely inhibited by prior alkoxide formation using sodium hydride and by thc addition of soluble bases such as triethylamine or pyridine. This is very much in line with our own observations and confirms that heterogeneous bases especially NaHCO 3 or K ~ C O 3 have no deleterious effects on the cyclizations. The role of these would appear to be to remove the hydrogen iodide formed, and hence prevent attack by the latter on the product tetrahydrofurans, rather than any other more subtle function, as cyclizations in the absence of any base also work well, but usually deliver slightly lower yiclds. At this point, we were confused by the apparent divergence of Mihelich's and our results with those reported by Lipshutz and hence chose to re-examine this type of cyclization. Representative examples of the diastereoisomeric homoallylic alcohols 95 and 98 were unambiguously prepared by Yamaguchi-Hirao alkylation <83TL391; 01TL6947> of

Electrophile-induced 5-Endo Cyclizations

31

lithiohexyne using 2,3-epoxybutanes followed by (E)-(LiAIH4) or (Z)- (Lindlar) selective alkyne reduction. Under standard conditions (3 equivalents each of 12, NaHCO3 in dry MeCN), each of the four isomers of alcohols 95 and 98 delivered excellent isolated yields (>90%) of a single iodotetrahydrofuran, with the exception of the anti-(E)-isomer [98; Z = H], which gave ca 10% of a second isomeric tetrahydrofuran. Detailed NMR analysis showed that all products were iodotetrahydrofurans and, on the basis of NOE data, that Lipshutz's stereochemical assignments were erroneous; in every case, addition of iodine and hydroxyl occurred by the expected anti pathway <94TL7529>. Thus, cyclization of the two possible syn-homoallylic alcohols [95; (E)-isomer-E = Bu, Z = H; (Z)-isomer - E = H; Z = Bu] proceeded via the chair-like transition state 96 to deliver only the iodotetrahydrofurans 97. While this is clearly favoured as both substituents are positioned pseudoequatorially, the improvement in yield for cyclization of the syn-(Z)-isomer with respect to the simpler 13unsubstituted examples 78 described above (<50% to nearly quantitative) is remarkable considering this is due to the addition of a single, relatively small methyl substituent. The corresponding anti-isomers 98 have a choice as to which substituent is positioned pseudoaxially, given a similar chair-like transition state. These results show that it is the substituent adjacent to the hydroxyl which preferentially occupies this position in conformation 99, leading largely to iodotetrahydrofurans 100. Again, despite the necessarily destabilizing effect of a pseudoaxial group, its very presence improves both the speed and cleanliness of the cyclization of the anti-(Z)-isomer which gave a >95% isolated yield of the tetrahydrofuran [100; Z = Bu; E = H]. Thus, all such cyclizations gave largely or usually exclusively iodotetrahydrofurans with the 13-substituents on opposite faces of the new ring. Hopefully, these conclusions will be of use in synthetic design but will need to be treated with some caution in examples with substituents of dissimilar sizes. The origins of the erroneous stereochemical assignments reported by Lipshutz and Barton <92JA1084> appear to lie in misinterpretation of NOE data, all too easy in this area. We also found that N-iodosuccinimide (1.1 equivalent) in dry dichloromethane at ambient temperature could be used to carry out all cyclizations of the substituted homoallylic alcohols 95 and 98. However, these were much slower (5-12h vs 0.75-3h), less efficient (ca 70% vs >95%) and less selective in the case of the anti-isomers 98 than those using iodine <94TL7529>. In addition, and for the first time in our work, we isolated a small amounts (< 15%) of oxetanes arising from a competing 4-exo-trig pathway in some cases. Thus, in these examples at least, the use of NIS offers no advantages. These results contrast somewhat with those obtained from 5-endo cyclizations of 3alkene-l,2-diols, although the dissimilarities stem from the smaller size of hydroxy group relative to a methyl. Thus, iodocyclization of the anti-(Z)-enediol [101; Z = Bu; E = H] gives essentially only the hydroxy-tetrahydrofurans [103; Z = Bu; E = H]. In contrast, cyclizations of the corresponding (E)-isomers only show useful stereoselectivity when the size of the nucleophilic hydroxyl is increased by O-benzylation. Thus, derivative [101; E = Bu; Z = H; R ~ - Bn] gives a reasonable 70% yield of the THF [103; E = Bu; Z - H] presumably via conformation 102 in a 9:1 ratio with the minor isomer, epimeric at the 2- and 3-positions <00TL4447>. The related syn-(Z)-isomeric diols [104; R ' = HI showed essentially no diastereoselectivity during iodocyclization until, once again, the nucleophilic oxygen was benzylated [104; R~=Bn] when a ca. 6:1 ratio in favour of diastereoisomer [106; Z = Bu; E = H] was obtained. Hence, it would appear that now the smaller hydroxyl group occupies the less favourable pseudoaxial position 105, at least when R - Me or Ph. Despite not showing complete selectivity, formation of largely the "all-cis" isomer [106; Z = Bu; E - H] is remarkable, again from a seemingly less favourable (Z)-alkene in terms of transition state

32

D. W. Knight

stability, and is perhaps an indication that hydrogen bonding may also be playing a key role in these cyclizations. Finally, and slightly oddly, the syn-(E)-isomers [104; R = Me, Ph] gave similar 4-5:1 ratios in favour of diastereoisomer [106; E = Bu; Z = H] independent of whether the nucleophile was OH or O-benzyl. Again, intramolecular H-bonding may play a role (see below). HQ oz HO, .I

HO 'anti' 101

,IR H.E

~,,,

R

102

HO RO R ~ ~Z E ~

| Z R-'-R - R ' E,~I-

Z 103

HO

~

HO R. , ~

~yn' 104

105

,,E z

106

All of the foregoing reactions were carried out using the 'standard' conditions (3eq. 12 and NaHCO3 in MeCN, 0-20~ However, an application of the latter cyclization led us to a better set of conditions. We planned to use this as one of a number of possible options, based on the foregoing, in a brief preparation of the tetrahydrofuran 110, a part of the unusual boron-containing antibiotic Aplasmomycin. In the event, iodocyclization of the diol 107, prepared using highly selective AD-mix oxidation of the corresponding diene <94CR2483; 95T1345>, under standard conditions was slow (72 h) but did deliver a good yield of largely (ca 6:1) the desired iodotetrahydrofuran 109. However, by using two equivalents of iodine monobrornide in acetonitrile at -10~ for 16 h, an improved 14:1 ratio was obtained, from which the desired heterocycle 109 was obtained by fractional crystallization in 78% isolated yield with >95% ee <00TL4453>. A possible role for H-bonding in controlling the cyclization is shown in conformation 108. Subsequent deiodination, Mitsunobu inversion of the ring hydroxyl and saponification then gave the desired diol 110.

. . ~ __H _/OBz HQ

2.1Br, NaHCO3

II1,,.

H OH 107

MeCN, -10 ~

I

"l~,0 OBz H.O . . . . . H 108

109

OBz

110

OH

We have also completed a second and very short synthesis of (L)-(+)-muscarine using this stereochemically flexible methodology. Starting with the anti-adduct 111, formed by nonchelation controlled addition of an O-silyl propargyl alcohol to the corresponding (S)lactaldehyde <93SL217>, Lindlar reduction delivered the anti-(Z)-enediol 112, cyclization of which using iodine monobromide (2eq.; NaHCO3, MeCN,-10~ 5h) was highly selective (>93%) in favour of the iodotetrahydrofuran 113. The necessary O-desilylation nor the presence of a free alcohol thus engendered no deleterious effects. Hydrogenolysis of the C-I bond (10% Pd-C, Et3N, EtOAc, 12h) <99TL276> which, understandably was significantly more convenient than radical-based methods using a tin hydride, and deprotection then gave

Electrophile-induced 5-Endo Cyclizations

33

the diol 114, identical in all respects to an established precursor to L-(+)-muscarine [cf 89] <02MI002>. OR

HO~,,~ *'H "OTBs

-~

H O ,H ,.~

--H~~IH

111

112

Natural L-(+)isomer of muscarine [cf 891

OR [R = TBDPS]

! : I.

113

" HOH~~ H .

OR

OH

114

Bicyclic systems can also be formed efficiently and highly stereoselectively using 5-endotrig iodocyclizations <00JCS(P1)3469>. In the light of the foregoing transition state conformations, we were not too surprised to find that both (E)- and (Z)-trans-2alkenylcyclohexan-l-ols 115 underwent smooth cyclization to give only the perhydrobenzofurans [116; n = 1]. Understandably, due to the strain associated with a transring fusion, the corresponding 5/5 systems were not formed with similar facility: the (Z)isomer failed completely but we were able to isolate a 29% yield of the product 117 from the (E)-trans-alkenylcyclopentanol [115; n - 0; E = Bu; Z = H]. More uncertainty lay in cyclizations of the related cis-alkenyl cycloalkanols, where the two possible cyclization conformations [118 and 119] both appeared somewhat unfavourable, the latter seeming to have too large a distance between the reacting centres while the former's boat-like eclipsed structure looked unhelpful. In the event, the latter clearly operated in examples of (Z)alkenyl substituents which afforded excellent yields of only the diastereoisomers [120; E H] indicating, once again, that a late transition state is involved. The corresponding (E)isomers [119; Z = HI underwent less selective cyclizations: the cyclopentanol [119; n = 0] showed almost no selectivity while the homologous cyclohexanol [119; n = 1] gave largely the perhydrobenzofurans [120; Z = H] in a 5:1 ratio at 0~ improved to 10:1 by conducting the cyclization at-78~ when sufficient dichloromethane was added to the reaction mixture to prevent freezing of the acetonitrile. In line with the findings of Lipshutz mentioned above <92JA1084>, we also found that these cyclizations were completely suppressed when tertiary amines (Et3N , Hiinig's base) were used as proton scavengers, in place of bicarbonate. Although giving the same products, replacement of iodine with N-iodosuccinimide again resulted in slower and less efficient cyclizations. H I Z H I

(

E

=

(

Z

[n = 0,1]

....R

12I

115

H 117

116

Z (

OH Z 118

E

(

OH 119

( E

H

I

Z

=

[n=0,1]

H 120

A brief survey of the chemistry of the iodine group in the model iodotetrahydrofurans showed that, in general, SN2 displacements are not especially facile, hardly surprising as the iodide is both secondary and deactivated by the ring oxygen in a manifestation of the 13-halo-

D. W. Knight

34

ether effect. Displacement by azide usually was the most efficient. Thus, exposure of iodotetrahydrofuran 27 to sodium azide in DMF at 80~ for 2h gave the inverted azide 121 in 87% isolated yield <99JCS(P1)2143>. Subsequent hydrogenation in the presence of Boc anhydride <89TL837> then delivered a good yield of the protected amine 122. Stronger heating gave substantial amounts of the elimination product, the 2,5-dihydrofuran 123. Displacement by an oxygen nucleophile could be effected using caesium acetate in hot DMF <81JOC4321> to give acetate 124 in moderate yield; the use of potassium superoxide and 18-crown-6 also in DMF <75CC658> gave marginally better yields of the corresponding alcohol, typically 60-70% at most. A viable alternative to this <86JOC2230> was to encourage the iodine to leave using silver tetrafluoroborate in DMF which acted both as solvent and trapping agent. In view of the complete inversion observed and the good yields (ca 70-75%) of the formates [e.g. 125] isolated, this reaction shows the characteristics of an SN2 displacement rather than alternative mechanisms involving anchiomeric assistance from the ring oxygen, via a rather strained oxiranium species, which would result in retention of stereochemistry <00JCS(P1)3469>. Yields of the related sulfide 126 obtained using sodium thiophenolate in warm DMF were ca. 50%.

,,N3

.,NHBoc

,OAc

H .OCHO

Et~/--O-O-~' "Bu E t ~ " "Bu E t ~ ' "Bo Et~~O ""Bu : ~ ~ O H 121

122

123

124

Bu

,SPh

E t ~ ' "Bu

125

126

While carbanion formation is unlikely to be successful with [3-iodotetrahydrofurans, due to facile D-elimination of the ring oxygen, the corresponding carbon-centred radicals formed by homolysis of the carbon-iodine bond should be kinetically stable with respect to this. o

Rl~V-,,O/ .....~

80~ ~

O~:~ R

127

R 128

129

O

Et~Bu 130

131

132

Bu

We have demonstrated the synthetic potential of this principle using substrates 127 and 131 derived from the corresponding aldehydes [e.g. 34] using Wittig homologations <94CC2447>. Thus, treatment of the 2,5-trans-iodotetrahydrofurans 127 with triphenyltin hydride under standard conditions gave the radicals 128 which then underwent efficient cyclizations to give largely (ca. 3:1) the exo-2-oxabicyclo[2.2.1]heptanes 129 in excellent yields. Understandably, an analogue lacking the activating carbonyl in conjugation with the acceptor alkene function gave a lower but still respectable 59% yield of the derivative 130. Similarly, Barton-McCombie deoxygenation <75JCS(P1)1574> of the 2,5-cis-4-

Electrophile-induced 5-Endo Qvclizations

35

hydroxytetrahydrofuran 131 gave very largely the 3-endo-5-exo isomer 132 in 77% isolated yield. An alkylidene derivative related to ester 131 with methyl in place of the ester group failed to cyclize however, attesting to the importance of alkene activation in such examples.

2.3

Selenocyclization of Homoallylic alcohols

In contrast to iodocyclizations, 5-endo-trig selenocyclizations have been carried out under wider range of reaction conditions, often ones featuring assistance from a Lewis acid. The potential for 5-endo-trig selenoetherifications was established very early in the history of such selenium chemistry by the finding due to Nicolaou who showed that the cyclohexenyl ethanol 133 could be readily converted into the tertiary selenide 134 <81T4097>. Subsequently, Kang et. al. showed a more general pattern for this reaction, again using substrates [135; R = H] which rely on a pendant aryl group, in this case phenyl, to control cyclization at the 'inner' alcohol site, i.e. the reactions are effectively 5-exo processes. The survival of a tritylmethoxy group is again particularly revealing in this respect <90TL5917>. An optimized set of conditions features a combination of phenylselenenyl chloride and zinc bromide in 1,2-dimethoxyethane at -55~ which selectively delivers the trans products 136. Tin(IV) chloride is a good alternative Lewis acid. The same substrates 135, when converted into the O-triethylsilyl ethers [135; R = YES] deliver the corresponding 2,5-cis-isomers 137 when treated with PhSeC1 in acetonitrile in the presence of potassium carbonate at ambient temperature <91TL4015>. Presumably the formation of the 2,5-trans isomers 136 follows a conformation 138 similar to that (93) proposed for the related iodocyclizations outlined above whereas, by increasing the size of the nucleophilic centre by O-silylation, this type of conformation 139 is too crowded with respect to the alternative 140, despite its boat-like structure, which leads to the 2,5-cis isomers 137. In any event, the disparate conditions and reactants, together with the product structures will be useful in synthetic planning. .SePh

SePh

R 1.... 133

134

R Ph

R 1 - - X / - - - ~ ph OR [R1 = CH2OR 2]

Ph 136

~

R I " ~ ' ~ ' O / ~ Ph

135

137

~ R

Et3 Ph

H 138

,SePh

139

----- ~

R

SiEt3 O

H~H~,~ph 140

A definitive study of selenocyclizations of alkyl-substituted homoallylic alcohols was reported by Mihelich and Hite <92JA7318>. Employing N-(phenylseleno)phthalimide (NPSP) and p-toluenesulfonic acid as activator in dichloromethane at ambient temperature, both "syn"-(Z)-[95; E = H) and 'anti"-(Z)-[98; E - H] alkenols were found to give essentially single products [142; E = H] and [144; E = H] respectively in excellent yields. As with the related iodocyclizations, these results are consistent with chair-like transition state geometries 141 and 143; when a choice is necessary, the substituent remote to the alkene adopts the axial position. Under similar conditions, the corresponding (E)-isomers undergo less selective cyclizations: the 'syn-(E) [95; Z = H] precursor gives largely the 2,5-trans product [142; Z -

36

D. W. Knight

H] along with the alternative product of anti-addition while the 'anti-(E) [98; Z = H] reacts essentially stereorandomly in this sense. However, both ratios can be increased to >9:1 by using phenylselenenyl chloride in acetonitrile at -30~ Again, the major products are consistent with the intermediacy of (E)-isomers of the conformations 141 and 143. In summary, all additions occur in an anti fashion across the alkene as expected and all major isomers have the [3-substituents on opposite faces of the newly-formed ring. All such products can be efficiently converted into the corresponding trisubstituted tetrahydrofurans by deselenation using tin hydride and AIBN in hot benzene. A contemporaneous report of very similar cyclizations <92JA1084> contains a number of structural misassignments (see above). The relatively low levels of stereoselection in cyclizations of the foregoing examples of 'anti'-(E)-homoallylic alcohols can also be addressed by using the very bulky aryl selenide 145 <95JOC3572>; levels are increased to 49:1 using this novel reagent. \

Z E QH

~

"., E

.SePh "

=

,,E

Z

Z

'syn' 95

141

\

142 Z

...... ~ - E

=

.SePh ~E

......

'anti' 98

-..

"

OH Z

143

r

145

Z

144

A number of studies have also been carried out to assess the impact of potentially more interactive substituents on such selenocyclizations. Landais has suggested that steric effects are probably responsible for the predominant formation of diastereoisomers 147 from alkenols 146 <95TL2987; 95SLl191>. In contrast oxygen-based substituents engender formation of largely the alternative isomers 148, perhaps via a conformation wherein the substituent now occupies an axial position which allows coordination with the incoming selenium species. These latter compounds 148 are rare examples of major products in which the 13-substituents are syn to each other. Silicon groups may be used as similar control elements as in the selective generation of tetrahydrofuran 149 <97T4339>. This is consistent with a chair-like transition state [143-(E)-isomer] in which the substituent or-to the hydroxyl occupies an axial position and steric control by the large silicon group which, significantly, can be used as a hydroxyl surrogate, thereby complementing the formation of isomers 148. Low temperatures are essential in this case. The related 2-thienyl derivative 150 may be more suitable for the latter transformation into a hydroxy group following, in this case, radical generation and trapping using allyl bromide.

Electrophile-induced 5-Endo Cyclizations

37

S ,,~

R

R

OH

'---Ph

,SePh

R,

,SePh

Me2PhS~ePh.,

PhSeCI Ph

146

~" "0 ~ -Ph

Ph

147

R =OTIPS [3:1] NHPh [3:1] SPh [3:1] SO2Ph [-9:1]

148

150

149

OH [3:7] OEt [1:9] OCHzCF 3 [1:3] OPh [1:4]

Much the same pattern is observed when the substituent is a methoxycarbonyl group <99EJO9797>. Thus, selenocyclization of the erythro-[3-hydroxy-esters [151; R 1, R 2 - Me, Ph] gives largely (>9:1) the 2,5-trans-tetrahydrofurans 152 whereas similar reactions of the corresponding threo-isomers lead to the 2,5-cis isomers 153.

,..SeOS02 Me02C,"

Me02C. OH

R1

151

Me02C,.

.SePh

.SePh

R1....~ ' , , R

"R2

152

2

Me02/~ R1

153

R2 154

A particular feature of this study is the use of phenylselenenyl sulfate as the source of electrophilic selenium, generated from a combination of diphenyl diselenide and ammonium persulfate. In the presence of excess persulfate, the selenides [152 or 153] undergo smooth oxidation and elimination to give either trans- or cis-isomers of the useful 2,5-dihydrofurans 154, thereby considerably expanding the scope of this methodology which is also effective in 5-endo cyclizations of nitrogen-centred nucleophiles (see below). At a higher oxidation level, the same reagent combination is effective in the cyclization of enols of 13-keto-esters 155; once again, excess persulfate is used with the result that furans 156 are isolated directly in 50-91% yields <94SL373>. Understandably, precursor preparation is not especially efficient.

Me02C

Me02C~

/

BnO

OH OR

PhSe. BnO ~ -

R I - ~ R 0 155

2

~ R1/\of\R2 156

OR

-

[R = TBDPS] 157

158

The utility of this cyclization mode is illustrated in the recent synthesis of the antifungal macrolide pamamycin 607 whose structure contains three nonactic acid-like tetrahydrofuran residues. Selenocyclization of the (Z)-homoallylic alcohol derivative 157 was highly selective in favour of the 5-endo mode, despite the potential for a competing 6-exo cyclization, to give 50-60% isolated yields of the 2,5-cis-seleno-tetrahydrofuran 158 when PhSeCI or N-PSP was used as the source of selenium in the presence of 20 mol % tin(IV) chloride <01TL4969>.

D. W. Knight

38

A conceptually different approach to the asymmetric synthesis of tetrahydrofurans by selenocyclization is to employ a chiral, non-racemic selenium reagent. Although the majority of studies have focussed on 5-exo cyclizations, a few feature 5-endo modes and are restricted to homoallylic alcohols which do not already contain an asymmetric centre, as the latter should of course be capable of providing control without the requirement for a relatively sophisticated chiral selenium-based reagent. For example, cyclizations of the simple alkenols 159 give high levels of asymmetric induction (ca. 12:1) in the products [160; R = Bu' or Ph], but which are lower (ca 2:1) with a smaller substituent such as R = Et, using the chiral reagent 161 <95JOC4660>. The enantiomeric products 163 are obtained from the same precursors 159 using the selenenyl triflate 162a, obtained from the corresponding diselenide by sequential treatment with bromine and silver triflate <98EJO1361>. The observed diastereoselectivities are again variable [163; R - Ph (84%); R - Et (0%)] and reversed in favour of tetrahydrofuran 160 when R = Bu'. Such chemistry was not viable with (Z)-isomers of the alkenols 159. Similar results [163; R -- Ph (93:7); R = Et (4:1)] were obtained using the related sulfur-based chiral selenium reagent 162b <01TA1493> and the persulfate 164 <00TA4645>. In the latter case, the more substituted tetrahydrofuran 165 was obtained with 95:5 d.e.

"SeAr* OH 159

R

=

R2

160 R~..R

~s'/R

~

SeX /'J" ....OEt 161

~*SeAr*

eOTf a) R b) R == OH SMe 162

1 -

~/ -Seoso3H',,-~ 164

~

.,/R2 163

,,SeAr*

R1, R2 = H, Me 165

In contrast to the success of 5-endo-trig cyclizations using selenium-based electrophiles, related reactions with sulfenyl reagents are, as yet, not as successful. Intramolecular sulfenyl etherification in general using N-(phenylthio)morpholine requires an acid promoter such as triflic acid but works poorly with 3-butenol, unless TMSOTf is used when the phenylsulfenyl tetrahydrofuran 166 is formed in 47% yield <87CC1280>. In contrast, phenyl- or methylsulfenyl chlorides produce only the alkene addition product 167 <87TL523>. However, currently much the best way to establish the necessary episulfenium intermediates [e.g. 169] is to carry out an acid-catalysed dehydration of a vicinal hydroxy-sulfide [e.g. 168]. Subsequent cyclization is usually highly stereocontrolled as indicated by the final product structure 170. This area has been extensively developed by the groups of Warren and Williams and is the subject of a review by Warren in Angew. Chem. Int. Ed. Engl. to be published during 2002; hence this will not be discussed further here.

Electrophile-induced 5-Endo Cyclizations ,SPh

CI

",,,

. .OH

-, HO-J

OH 166

2.4

167

39

168

G

.... -

/"R

-

-

SPh

.

R

169

170

PYRROLIDINE FORMATION USING 5-ENDO-TRIG CYCLIZATIONS

Iodocyclizations The success of our studies and those of others in the elaboration of iodotetrahydrofurans using 5-endo-trig cyclizations led us to consider the viability of related chemistry using nitrogen as a nucleophile. Direct cyclizations of homoallylic amines appeared unlikely to be viable due to reactions between the free amine group and iodine; further, the stability of an unprotected 13-iodopyrrolidine seemed questionable. The ubiquitous carbamate function was rejected on the grounds that 6-exo cyclizations could compete, as has been observed in an isolated example of a selenocycIization of N-acetylbut-3-enamine <86JOC1724>. We therefore elected to examine iodocyclizations of homoallylic sulfonamides 172 which were readily obtained from the corresponding alcohols 171 by sequential Mitsunobu displacement using TsNHBoc <89TL5709> and acid-catalysed removal of the Boc group. Under the 'standard' conditions (3 equivalents 12 and NaHCO3, MeCN), smooth but non-stereoselective cyclization occurred; by changing the base to the stronger potassium carbonate, excellent yields of the 2,5-trans-iodopyrrolidines 173 were secured accompanied by only 5-7% of the corresponding 2,5-cis isomers 174 <01JCS(P 1) 1182>. I

RI~--~__R2

~_____~ R I ~ F - - ~ . _ R

OH

2

NHTS

171 R 1, R 2

=

alkyl, Ph

12, K2CO 3

MeCN, 0-20~

172

R1

12, MeCN

Ts

, I

',R 2

173

R1

Ts

R2

174

_I

This encouraged us to carry out the cyclizations in the absence of base which provided a significant bonus in that now only the 2,5-cis isomers 174 were obtained. Subsequent experiments confirmed that the trans-isomers 173 were the initially formed, kinetic products which could then undergo acid-catalysed isomerization to the more thermodynamically stable 2,5-eis-isomers 174, either by separate treatment with hydrogen iodide or by exposure to the latter when generated during cyclization in the absence of a base. Although not proven, it is assumed that this isomerization involves N-protonation, cycloreversion with loss of iodide and re-cyclization. The corresponding N-methanesulfonyl derivatives do not undergo this isomerization under similar conditions, for reasons which are not obvious. More highly substituted examples also underwent highly selective cyclizations under both sets of conditions leading to the tetrasubstituted pyrrolidines 175 and 176; isomerization was thus not occurring during these reactions.

~ , Ts 175

"Bu

'"

Ts 176

Bu

).... Bu H Ts 177

40

D. W. Knight

This can be understood by considering the "all-trans" structure of pyrrolidine 175 and the more thermodynamically stable 2,3-trans, 2,5-cis combination isomer 176, which features remove any benefit from isomerization. Formation of the latter isomer 176 also shows the same preference for a transition state conformation in which the substituent or-to the nucleophilic centre occupies the axial position [99 and 143]. Similar chemistry can also be used for the stereoselective generation of perhydroindoles [e.g. 177]. Once again, Baldwin's rules apply when there is competition between 5-exo- and 5-endotrig cyclizations. Thus, exposure of the amino alcohol derivative 178 to iodine in acetonitrile gives only the amino-tetrahydrofuran 180 via intermediate 179 and not the corresponding pyrrolidine <98TL8909>. However, when a furan ring is conjugated to the alkene 181, then pyrrolidine formation 182 does ensue, presumably by a rather different 5-exo process, as argued above in respect of the Kang tetrahydrofuran synthesis 50.

~ P r HO NHTS

TsHN

I

178

III

TsHN

(~)

/'~/"

Pr

HO"

180

OH 179

181

Ts " o r ~ 182

Pr

As exemplified above, the inclusion of more substituents can often assist cyclization. A further example of this concerns iodocyclizations involving monosubstituted alkenes which were found to be rather poor during our model studies <01JCS(P1)l182>. In contrast, the amino alcohol derivative 183 is converted very efficiently into the iodopyrrolidine 184 <99CC251>. The stereochemical outcome is consistent with the usual chair conformation 93; the use of a 9-phenylfluorenyl (Pf) group to block the nitrogen is a notable and potentially significant feature as sulfonamide hydrolysis is hardly trivial. In contrast, the related monosubstituted alkene 185 is converted into the benzoyloxypyrrolidine 186 using iodine in aqueous THF <88CC1527; 89H(29)1861>.

AcQ R

AcQ

, ,Na oo NHPf

THF, Et20 =

R

183

I Pf 184

_OBz BnO/ ..... NHBz

20~ 6h Bn

I" '"

185

186

This extraordinary observation suggests a more complex mechanism, initiated by a more favourable 6-exo cyclization: /I

H"O

HNT-~O

HN-~k.~. ! Ph

N-,~p h

41

Electrophile-induced 5-Endo Cyclizations

Se lenocy c liz a tions We have extended our studies of (E)-homoallylic sulfonamide cyclizations to include examples induced by electrophilic selenium. Throughout this initial work, we used phenylselenenyl chloride and discovered that although the cyclizations are efficient and rapid, a much wider range of conditions were necessary to achieve stereocontrol <99TL3267>. For example, the dialkyl substituted precursor 187 gave essentially only the 2,5-trans pyrrolidine 188 using PhSeC1 in dichloromethane at -78~ for lh. Under the same conditions, the phenyl substituted substrate 189 gave a mixture of products. However, the 2,5-trans kinetic product [188; Ph in place of C5Hll] was obtained by adding potassium carbonate as an acid quench and 5 mol% water followed by warming to ambient temperature. The corresponding 2,5-cis isomer 190 was secured by addition of a catalytic amount of 10M hydrochloric acid. Stereoselection in furyl-substituted examples [189; 2furyl in place of Phi required both the addition of base and careful temperature control. More recently, we have found that phenylselenenium bromide can provide both faster reaction and better stereocontrol in some cases.

_SePh

Et

NHTS C5H11 CH2CI2' _78oc

Et

Ts

187

'"CsH11

188

hSeC NHTS

,SePh

t

CH2CI2, Et cat. HCI

189

Ts

Ph

190

Oxidation using hydrogen peroxide (THF, 20~ lh) gave the 2,5-dihydropyrroles 191 in excellent yield without any isomerization of the remaining stereocentrcs. Overall, the pattern of stereoselection reflects that found in the foregoing iodocyclizations. In contrast to these findings, selenenation of the homoallylic benzylamines 192 mainly results in azetidine formation 193 via a 4-exo process <97TL1393>. Remarkably, however, when the same substrates 192 are treated with three equivalents of phenylselenenyl halide, the halopyrrolidines 194 are formed, apparently not by rearrangement of the azetidines 193.

.~~ R1 Ts

R2

191

R12.~~ ~ 1.5 eq PhSeBr R N H B n Na2C03,MeCN ~ 192

1 [---r"/'~SePh R 2"'71~IklBn

R ~ ~ R Bn

193

SePh

194

Imines can also act as the source of nucleophilic nitrogen in such cyclizations: exposure of the Schiff's base 195 to PhSeBr leads to the iminium salt 196, reduction of which gives the N-benzylpyrrolidine 197, not surprisingly with little stereocontrol <93CC916; 95CC2029>.

Ph N

Ph SePh

PhSeBr ._

P~SePh Bn

~Ph 195

NaBH4

h 196

197

42

D. W. Knight

O-Allylhydroxamic acids 198 show more complex behaviour when treated with electrophilic selenium, derived either from PhSeC1-AgOTf or phcnylselenenyl persulfate, PhSeOSO3H <95CC237>. At low temperature (-50~ cyclization involves the N-acetyl group in a 6-exo mode, leading to the 1,4,2-dioxazines 199. However, upon warming to ambient temperature, these presumed kinetic products revert to starting materials which then cyclize to the thermodynamically more stable N-acetylisoxazolidines 200. Clearly, this methodology has considerable potential. Similarly, the corresponding N-alkenyl acetylhydrazines lead to the 1,3,4-oxadiazines 201 at low temperatures, whereas at 20~ the pyrazolidines 202 are isolated <96T11841>. Stereocontrol is good in more highly substituted examples <96G635>.

0 / - - ~ R-50~ PhSe+ 0

R[~~ePh

OSePh N . ~, Ac

198

19g

"a

Rr~~ePh 201

2OO

HN.N ~sePh,, 'R 202

t O-Alkenol hydroxylamines 203 can also participate in 5-endo-trig cyclizations without the complication of competing 4-exo reaction, in contrast to the benzylamines 192. However, in these cases, the electrophile was generated from phenylselenenyl persulfate and triflic acid and the cyclization carried out in methanol at 20~ <95TL163>. Only the trans product 204 was formed, although a more highly substituted example showcd poor stereoselectivity. This drawback can be obviated by cyclizations of the corresponding O-alkenyl oximes 205, in similar fashion to that outlined above [195] which, after reduction, give very largely diastereoisomers 206 <95T1277; 95CC235>. Such cyclizations can also be carried out asymmetrically using thioether 162b <01TA3053; 95CC235>. Degradation of the final products gives amino alcohols [e.g. 207] of 86% ee. However, this does seem at present to be a case of a sophisticated reagent 162b being used to make a simple product 207.

,SePh "

"N 203

2.5

~_~SePh

204

205

H BnHN Ph

206

207

SULFUR AS THE N U C L E O P H I L E

Relatively little work has been reported in this area. Firstly, free thiols 208 cannot be used in conjunction with iodine as this will result in oxidation to the corresponding disulfides 209. An answer to this is to use S-benzyl derivatives [e.g. 210], a principle adopted in related 5exo cyclizations. An isolated example 211 serves to indicate the potential of this application of 5-endo-trig methodology <95JOC6468>. A problem associated with such initial products 211 is their inherent instability; oxidation to the S,S-dioxide was carried out prior to characterization. As yet, the stereochemical characteristics of such cyclizations remain unknown. An isolated example 213 suggests that such cyclizations could be viable when the

Electrophile-mduced 5-Endo Cyclizations

43

two reacting functions are attached to a ring 212 <94JOC5858>. Perhaps surprisingly, the cyclization is not stereoselective but interestingly does demonstrate that a thioacetal can be the source of the sulfur nucleophile without affecting the second thioether function.

V' /

208

RSSR

SBn

BnS

209

Br2

N 210

211

O

E S

R~ = H, SBn

212

H

Br

213

So far, the use of tellurium-based electrophiles has not proven useful for 5-endo-trig cyclizations. For example, exposure of the alkenol 214 to an aryltellurinic anhydride in hot acetic acid delivers only a 15% yield of the spiro-tetrahydrofuran 215, the major product 216 being that from addition to the alkene <89JOC4391>. TeAr OAc ~

+

214

~ ~ O H

215

TeAr

216

Thallium triacetate in aqueous acetic acid has also been used to carry out overall 5-endo cyclizations with terpenoid substrates [e.g. 217 and 219] to provide the ]3-hydroxytetrahydrofurans 218 and 220 respectively by a mechanism which may involve 4-exo cyclization to the corresponding oxetanes and rearrangement <86TL811; 94TL1497>. OH

II

o

_=

-

OAc

6H OH

217

218

219

220

Although not driven by an external electrophile, two further methods of tetrahydrofuran synthesis are worthy of note in the context of this review. Firstly, Mohr has developed a neat approach to [3-vinyltetrahydrofurans 223 in which an allylsilane function acts as the internal nucleophile in homoallylic alcohol 221 cyclizations, effectively by a 5-endo process involving an intermediate oxonium species 222 <93TL6251> Finally, it is interesting to note that, following initial findings by Normant, Craig has developed a useful synthesis of [3-sulfonyltetrahydrofurans 225 by 5-endo-trig cyclizations of the alkoxides 224 <99T13471>. Maybe these are indeed true exceptions to the rules!

44

D. W. Knight

SiMe3 R,.__/- -/~

SiMe3

R2CH(OR2)2 H+ ~

OH

RI~'~R

I~) O ~ R 2

221

223

222

,S02Ph

,,SO2Ph

224

2.6

2

225

5-ENDO-DIG CYCLIZATIONS

5-Endo-dig cyclizations are distinguished from the foregoing 5-endo-trig processes in two contrasting ways: firstly, these are favoured according to Baldwin's rules but, secondly, have enjoyed significantly less popularity. This surprising feature is despite early hints in the literature as to their viability. For example, mercuration of 3-alkyne-l,2-diols 226 under acidic conditions was reported to give good yields of 2,4-disubstituted furans 227 <55ZOB81; 77RZC249>. Perhaps the (formal) requirement of a 60 ~ approach angle between the nucleophilic centre and the acetylenic terminus is somewhat discouraging!

RI"~H

9m

R2

HgCI2

R1

OH 226

227

A more recent application of a similar cyclization is during a synthesis of (+)-preussin 230 in which a key step is mercury(II)-induced cyclization of the ynone 228 to give the ketodihydropyrrole 229 <94JOC4721>. There are a number of notable features of this reaction. Firstly, despite conjugation to the keto group, the alkyne remains sufficiently nucleophilic to interact with the electrophilic mercury, the intermediate ketone is stable to racemization and the N-Boc group does not interfere, presumably because the 5-endo-dig mode is favoured.

0 HH,,~, ~ ph/- \NHBoc 228

C9H19

i) Hg(OAc)2 MeNO2 ii) NaCI

O~HgCI HI, 229

~

~

HO.~,,H H/,.~ ~.,~H 230

In anticipation that iodofurans might also be prepared from alkyne-l,2-diols [cf 226] and that these would be amenable to homologation by a wide range of Pd- and Ni-catalysed coupling methods, we prepared a range of such precursors 231 using the highly selective b/shydroxylation of conjugated enynes first reported by the Sharpless group <92TL3833>.

Electrophile-induced 5-Endo Cyclizations

45

Exposure of these to iodine in acetonitrile or dichloromethane containing sodium hydrogen carbonate then delivered excellent yields of the [3-iodofurans 232 <96CC1007>. The presumed intermediates, 3-hydroxy-2,3-dihydrofurans, were not observed and probably underwent dehydration as formed. The synthetic utility of the iodofurans 232 was demonstrated by a largely very successful survey of various Pd(0)-catalysed reactions including Sonogashira and Stille couplings and carbonylations, along with more traditional halogen-metal exchange methods, all of which delivered the expected trisubstituted analogues 233. R2 \

HO

I

12 NaHCO 3 MeCN

OH 231

R1

R2

R1

R2

232

.

~,,,

R3

/I

R 1 / \ O / x R3

233

234

Practical alternatives involve precursor synthesis by acetylide addition to ct-hydroxy ketones or ct-hydroxy-esters; in the latter examples, two acetylene groups are added, one of which survives iodocyclization unscathed to give tetrasubstituted furans 234 <01TL5945>. Unfortunately, examples of simpler homopropargylic alcohols 235 have yet to be successfully cyclized: rather, iodine addition products 237 are obtained, and not the hopedfor dihydrofurans 236 <01MI002>. However, it is known that the related allenic alkoxides 238 do undergo iodocyclization leading to the iodofurans 240, via the 2,5-dihydrofurans 239 <87JOC2315>. This may in reality be an example of 5-exo-trig cyclization following participation of the methoxyl group (see above).

R1

..... OH 235

R2

/~<"

R2 236

~

C =.,,,

OMe

238

=

OMe 239

R R1

12

I

OH 237

240

A combination of the foregoing results led us to attempt similar chemistry with amine derivatives. In contrast to the foregoing unfruitful attempts to induce iodocyclization of homopropargylic alcohols 235, the related sulfonamides 241 underwent relatively slow but clean cyclization (I2, K2CO3, MeCN, 20~ 14h) to provide excellent yields of the iododihydropyrroles 242 <98CC2207>. Subsequent elimination of p-toluenesulfinic acid was easily carried out using DBU in DMF at 20~ to give excellent returns of the iodopyrroles 243 which already have a proven track record of being good partners in Pd(0)-catalysed couplings <95TL7043; 96TL3247>. An isolated example 244 indicates that the iododihydropyrroles 242 are also amenable to Sonogashira couplings, at least at ambient temperatures <98CC2207>. Preliminary results also indicate that the corresponding N-Boc derivatives undergo similarly smooth iodocyclizations. This methodology should prove useful for the synthesis of annulated pyrroles, exemplified

D. W. Knight

46

by a synthesis of the bicyclic core 246 of the antitumor antibiotic Roseophilin, by radicalmediated cyclization of the iodopyrrole 245 and oxidation <99TL6117>.

Ph MeO2C~

R

NHTs

= MeO2C

241

Ts

R

=- MeO2C

242

CO2Me 245

R

H

MeO2CN ' ~ / R Ts

243

244

ii) [O]

CO2Me

H

0

246

We have developed an even briefer version of this sequence: condensation between a 2alkynal 247 <98TL6427> and dianion 248 <98JOC4524> gives excellent yields of the amino alcohols 249 which undergo smooth iodocyclization to give largely the hydroxydihydropyrroles 250 together with iodopyrroles 251 in excellent combined yields <02MI001>. In view of the chemistry leading to the [3-iodofurans 232, isolation of the former was unexpected.

k,~_

R

Q 247 SnCl2

MeO2C--~

= MeO2c

Ts

HO ~ --

R MeO2C

NHTs

248

Ts

249

R

MeO2C

Ts

250

R

251

The idea of using sulfur as the nucleophile in related 5-endo-dig cyclizations has also been established in principle but only developed within the context of [3-1actam annulation. Once again (see above), if the trick of blocking the sulfur with a labile benzyl group to prevent oxidative thiol dimerization is used, decent yields of the dihydrothiophenes [253; R ~ = H] can be secured from the acetylenic precursors [252; R ~- H] <94JOC5858; 95JOC648>. Again, these proved to be rather sensitive and were characterized as the corresponding S,Sdioxides. Similarly, hydroxy sulfides [252; R ~ -- OH] can be converted into the isolable hydroxy-dihydrothiophenes [253; R ~ = OH]. An alternative strategy involves iodonium ioninduced ring expansion of episulfides 254 which proceeds via the S-iodo intermediates 255 which isomerize to the final products 256 <95JOC6484>.

~/~ --:- R2 12 R1SBn R ~ I . ~ R2 [R1 = H or OH] 252

253

~/S

R 254

I

~

SI

255

R

~i~ I

256

Two versions of this type of chemistry have been used for [3-1actam annulation. Firstly, the

Electrophile-induced 5-Endo Cyclizations

47

N-methylsulfenyl derivatives 257 undergo slow but efficient 5-endo-dig cyclizations to the vinyl iodides 258, which may be limited to arylethynyl derivatives <95JOC4980; 00T5571>. Alternatively, ct-sulfenyl-derivatives [259; R ~ = H] <98JOC8898> or the corresponding thioacetals [259; R 1 = SR 2] <95JOC5858> cyclize very efficiently simply by reaction with iodine in dichloromethane to give the penicillin analogues [260; R = H or SRZ]. The latter thioacetal cyclizations are related to 5-endo-trig versions mentioned above [cf. 213]. While attempted halogen-metal exchange of the iododihydrothiophenes 260 results in ring-opening even at low temperature, Stille couplings and Pd(0)-catalysed carbonylations are viable; unfortunately similar reactions of the isomeric isothiazoline 258 are not <98JOC8898>. /Ph .

R1

I

., ,, o/~N "SMe

12' CH2Cl2

40~

, "

~,.~r~

Ph

12' CH2CI2

R3

RN

[R1 = H or SR 2]

257

258

Ra

259

I 260

Although not electrophile-driven, it should be borne in mind that base-induced cyclizations of homopropargylic alcohols are useful methods. Thus, exposure of alcohol 261 to potassium t-butoxide in dimethyl sulfoxide delivers an excellent yield of the dihydrofuran 262 <89CC1371>. In much the same way, ortho-alkynyl anilines 263 can be converted into 2-substituted indoles 264 <00AG(E)2488>. R2

J

BnO/,,,.~ - / ' ~ H OH

KoBu'"" BnoJ..

DMSO

261

I}

H "" 262

INH 2

263

KOBut _--or CsOBu t NMP, 20~

R2

H 264

Similar base-catalysed isomerization of both a- and ]3-alkynylallylic alcohols and related allenic systems to give highly substituted furans have been extensively studied by Marshall and co-workers <93JOC3435>; arguably, a culmination of these studies is the identification of 10% silver nitrate on silica as an electrophilic catalytic trigger <95JOC5966; 9805263>. R 1- ~ HO 265

R2

10% AgNO 3 SiO2 [RI' R2 = alkyl]

R1

R2 266

......

C-~ OH 267

OR -

=

,,,,~

....

OR

268

Using this remarkably effective catalyst alkynyl allylic alcohol (e.g. 265) are converted into furans 266 very efficiently. Similarly, allenic alcohols (e.g. 267) can be converted into 2,5-dihydrofurans (e.g. 268) by this relative of a 5-endo-dig process <93JOC7180; 94JOC324>. At a higher oxidation level, conjugated allenic ketones 269 can be similarly cyclized, effectively by carbonyl hydration and a final dehydration to the furans 270 <92JOC3387; 94JOC7169>.

48

D. W. Knight

R'~"~C=// R1 0 " / ~ O

AgNO3

R'

CaCO3 aq. acetone

1

269

OMe H

270

~

Pd(ll) c'=

271

272

Of course, these latter routes do not incorporate the triggering electrophile (e.g. iodine) which lends itself to additional homologation. Beyond the scope of this review are the many palladium-catalysed cyclizations which are formally 5-endo-dig processes and which have been summarized elsewhere <00MI001>. However, the power of these methods both to trigger cyclization a n d to allow incorporation of an additional substituent post-cyclization in a catalytic manner can be spectacular as illustrated by conversion of the alkyne-diol derivatives 271 into the furans 272 <85T3655>. A final example serves to both highlight the potential for further developments of 5-endodig cyclizations and to encourage a search for novel electrophilic triggers: reaction of the alkynyl hydroxylamines 273 with zinc iodide and DMAP in dichloromethane delivers excellent yields of the isoxazolines 274 <000L2331>. It therefore seems very likely that 5endo cyclizations in general, those already developed and new versions to come, will make many useful contributions to synthetic organic methodology.

R1

<

R2

HO,'NBn 273

Znl2 DMAP,CH2CI2

R2

_---

RI'"~O/it Bn 274

Acknowledgements

Although mentioned in the references, I am delighted to have this opportunity to record my thanks to some exceptionally talented students who contributed so much to the 5-endo projects within my group. These are Frank Bennett, whose diligence first uncovered the reaction, Duncan Shaw, Jenny Barks and Andy Jones from the Nottingham group together with Sean Bew, Adele Redfem, Ann Evans, Simon Jones, Mafia Fagan and Oli Foot who showed that the chemistry worked in Wales as well as in England. Thanks are also due to the EPSRC, Rh6ne-Poulenc-Rorer, GSK and The Lilly Research Centre Ltd. for financial support and to Drs Garry Fenton, Gordon Weingarten and Jeremy Gilmore for advice and support. 2.7

REFERENCES

55Z0881 75CC658 75JCS(P1)1574 76CC734 76CC736 76CC738 77RZC249 78JA3950 81JA3963

A. Fabritsy, S. Goshchinskii, Zh. Obshch. Khim, 1955, 29, 881 [Chem. Abstr., 1959, 53, 21868]. E.J. Corey, K.C. Nicolaou, M. Shibasaki, J. Chem. Soc., Chem. Commun., 1975, 658. D.H.R. Barton, S.W. McCombie, J. Chem. Soc., Perkin Trans. 1, 1975, 1574. J.E. Baldwin, J. Chem. Soc., Chem. Commun. 1976, 734. J.E. Baldwin, J. Cutting, W. Dupont, L. Kruse, L. Silberman, R.C. Thomas, J. Chem. Soc., Chem. Commun., 1976, 736. J.E. Baldwin, J. Chem. Soc., Chem. Commun., 1976, 738. A. Fabrycy, Z. Wichert, Rocz. Chem., 1977, 51,249 [Chem. Abstr., 1977, 87, 68471]. P.A. Bartlett, J.A. Myerson, J. Am. Chem. Soc., 1978, 100, 3950. S.D. Rychnovsky,P.A. Bartlett, J. Am. Chem. Soc., 1981, 103, 3963.

Electrophile-induced 5-Endo Cyclizations 81JOC4321 81 T4097 83TL391 84CC1070 84MI001 84T2317 85T3655 85T3901 86JOC1724 86JOC2230 86TL811 86TL 1237 87CC1280 87JOC 1680 87JOC2315 87JOC5067 87T3309 87TL523 88CC 1527 88JA4533 88S862 89CC1371 89H(29)1861 89JA3712 89JOC4391 89TL837 89TL4001 89TL5709 90JA8995 90T4277 90TL5917 91JCS(P1)133 91JCS(P1)1543 91TL4015 92JA 1084 92JA7318 92JOC3387 92TL3607 92TL3833 92TL6511 93JOC3435 93JOC7180 93SL217 93TA1711 93TL1955 93TL6251 93TL7579 94CC2447 94CR2483

49

W.H. Kruizinga, B. Strijtveen, R.M. Kellogg, J. Org. Chem., 1981, 46, 4321. K.C. Nicolaou, Tetrahedron, 1981, 37, 4097. M. Yamaguchi, I. Hirao, Tetrahedron Lett., 1983, 24, 391. M. Srebnik, R. Mechoulam, J. Chem. Soc., Chem Commun.. 1984, 1070. P.A. Bartlett, Asymmetric Synthesis, Vol 3, ed. J.P. Morrison, Academic Press, New York, 1984, Ch.6. P.A. Bartlett, D.P. Richardson and J. Myerson, Tetrahedron, 1984, 40, 2317. Y. Wakabayashi, Y. Fukuda, H. Shiragami, K. Utomito, H. Nozaki, Tetrahedron, 1985, 41, 3655. D.H.R. Barton, D. Crich, W.B. Motherwell, Tetrahedron, 1985, 41, 3901. A. Toshimitsu, K. Terao, S. Vemura, J. Org. Chem., 1986, 51, 1724. P.A. Bartlett, P.C. Ting, d. Org. Chem., 1986, 51, 2230. H.M.C. Ferraz. T.J. Brocksom, Tetrahedron Lett., 1986, 27, 811. Y. Guindon, Y. St. Denis, S. Daigneault, H.E. Morton, Tetrahedron Lett., 1986, 27, 1237. P. Brownbridge, J. Chem. Soc., Chem. Commun., 1987, 1280 Y. Guindon, M. Therien, Y. Girard, C. Yoakim, J. Org. Chem., 1987, 52, 1680. H.J. Reich, R.E. Olson, J. Org. Chem., 1987, 52, 2315. D.R. Williams, F.H. White, J. Org. Chem., 1987, 52, 5067. T.L.B. Boivin, Tetrahedron, 1987, 43, 3309. S.M. Tuladhar, A.G. Fallis, Tetrahedron Lett., 1987, 28, 523. S. Takano, Y. Iwabuchi, K. Ogasawara, J. Chem. Soc., Chem. Commun., 1988, 1527. M. Labelle, H.E. Morton, Y. Guindon, J.P. Springer, J. Am. Chem. Soc., 1988, 110, 4533. R.D. Evans, J.W. Magee, J.H. Schauble, Synthesis, 1988, 862. S. Takano, Y. Iwabuchi, K. Ogasawara, J. Chem. Soc., Chem. Commun, 1989, 1371. S. Takano, Y. Iwabuchi, K. Ogasawara, Heterocycles, 1989, 29, 1861. M.J. Kurth, R.L. Beard, M. Olmstead, J.G. Macmillan, J. Am. Chem. Soc., 1989, 111, 3712. N. X. Hu, Y. Aso, T. Otsubo, F. Ogura, J. Org. Chem. 1989, 54, 4391. S. Saito, H, Nakajima, M. Inaba, T. Moriwake, Tetrahedron Lett., 1989, 30, 837. S. Takano, Y. Sekiguchi, Y. Shimazuki, K. Ogasawara, Tetrahedron Lett., 1989, 30, 4001. J.R. Henry, L.R. Marcin, M.C. McIntosh, P.M. Scola, G.D. Harris, jun., S.M. Weinreb, Tetrahedron Lett., 1989, 30, 5709. E.D. Mihelich, J. Am. Chem. Soc., 1990, 112, 8995. M. Larchev~que, S. Henrot, Tetrahedron, 1990, 46, 4277. S.H. Kang, T.S. Hwang, W.J. Kim, J.K. Lim, Tetrahedron Lett., 1990, 31, 5917. F. Bennett, D.W. Knight, G. Fenton, J. Chem. Soc., Perkin Trans. 1, 1991, 133. F. Bennett, D.W. Knight, G. Fenton, J. Chem. Soc., Perkins Trans 1, 1991, 1543. S.H. Kang, T.S. Hwang, W.J. Kim, J.K. Lim, Tetrahedron Lett., 1991, 32, 4015. B.H. Lipshutz and J.C. Barton, J. Am. Chem. Soc., 1992, 114, 1084. E.D. Mihelich, G.A. Hite, J. Am. Chem. Soc., 1992, 114, 7318. J.A. Marshall, W. J. Wang, J. Org. Chem., 1992, 57, 3387. H. Dehmlow, J. Mulzer, C. SeiIz, A.R. Strecker, A. Kohlmann, Tetrahedron Lett., 1992, 33, 3607. K. S. Jeong, P. Sj6, K.B. Sharpless, Tetrahedron Lett., 1992, 33, 3833. F. Bennett, S.B. Bedford, K.E. Bell, G. Fenton, D.W. Knight, D.E. Shaw, Tetrahedron Lett., 1992, 33, 6511. J.A. Marshall, W.J. DuBay, J. Org. Chem., 1993, 58, 3435. J.A. Marshall, K.G. Pinney, J. Org. Chem., 1993, 58, 7180. M. Alami, B. Crousse, G. Linstrumelle, L. Mambu, M. Larchev6que, Synlett, 1993, 217. J.-C. Harmange, B. Figadbre, Tetrahedron." Asymmetp3', 1993, 4, 1711. S.H. Kang, S.B. Lee, Tetrahedron Lett., 1993, 34, 1955. P. Mohr, Tetrahedron Lett., 1993, 34, 6251. S.H. Kang, S.B. Lee, Tetrahedron Lett., 1993, 34, 7579. D.E. Shaw, G. Fenton, D.W. Knight, J. Chem. Soc., Chem. Commun., 1994, 2447. H.C. Kolbh, M.S. VanNieuwenhze, K.B. Sharpless, Chem. Rev., 1994, 94, 2483.

50 94JOC324 94JOC4721 94JOC5858 94JOC6643 94JOC7169 94JOC8307 94SL295 94SL373 94TL 1497 94TL6317 94TL6611 94TL7327 94TL7529 95CC235 95CC237 95CC2029 95JOC3572 95JOC4660 95JOC4980 95JOC5966 95JOC6484 95JOC6468 95SLl191 95TI277 95T1345 95TL 163 95TL2987 95TL7043 95TL8179 96CC1007 96G635 96JCS(P 1) 1505 96T 11841 96TL3247 96TL7667 97JOC5048 97T4339 97TL1393 98CC916 98CC2207 98EJOC1361 98JOC4524 98JOC8898 98OS263 98TL6427 98TL8909 99CC251

D. W. Knight J.A. Marshall, B.C. Yu, J. Org. Chem., 1994, 59, 324. M. Overhand, S.M. Hecht, J. Org. Chem., 1994, 59, 4721. X.-F. Ren, E. Turos, J. Org. Chem, 1994, 59, 5858. P. Galatsis, S.D. Millan, G. Furguson, J. Org. Chem., 1994, 59, 6643. J.A. Marshall, G.S. Bartley, J. Org. Chem., 1994, 59, 7169. B.H. Lipshutz, R. Tirado, J. Org. Chem., 1994, 59, 8307. G. Fenton, D.W. Knight, D.E. Shaw, Synlett, 1994, 295. M. Tiecco, L. Testaferri, M. Tingoli, F. Marini, Synlett,, 1994, 373. H.M.C. Ferraz, C.M.R. Ribeiro, M.V.A. Grazini, T.J. Brocksom, U. Brocksom, Tetrahedron Lett., 1994, 35, 1497. O. Sakurai, M. Takahashi, T. Ogiku, M. Hayashi, H. Horikawa, T. lwasaki, Tetrahedron Lett., 1994, 35, 6317. P. Galatsis, D.J. Parks, Tetrahedron Lett., 1994, 35, 6611. G.V.J. daSilva, M.M.M. Pelisson, M.G. Constantino, Tetrahedron Lett., 1994, 35, 7327. J.M. Barks, D.W. Knight, C.J. Seaman, G.G. Weingarten, Tetrahedron Lett., 1994, 35, 7529. M. Tiecco, L. Testaferri, M. Tingoli, L. Bagnoli, J. Chem. Soc., Chem. Commun., 1995, 235. M. Tiecco, L. Testaferri, M. Tingoli, F. Marini, J. Chem. Soc., Chem. Commun., 1995, 237. D. DeSmaele, N. DeKimpe, J. Chem. Soc., Chem. Commun., 1995, 2029. B.H. Lipshutz, T. Gross, J. Org. Chem., 1995, 60, 3572. R. D6ziel, E. Malenfant, J. Org. Chem., 1995, 60, 4660. X. F. Ren, M.I. Konaklieva, E. Turos, J. Org Chem., 1995, 60, 4980. J.A. Marshall, C.A. Sehon, J. Org. Chem., 1995, 60, 5966. X. F. Ren, M.I. Konaklieva, E. Turos, L.M. Krajkowski, C.H. Lake, T.S. Janik, M.R. Churchill, J. Org. Chem., 1995, 60, 6484. X. F. Ren, E. Turos, C.H. Lake, M.R. Churchill, J. Org. Chem., 1995, 60, 6468. Y. Landais, D. Planchenault, Synlett., 1995, 1191. M. Tiecco, L. Testaferri, M. Tingoli, L. Bagoli, C. Santi, Tetrahedron, 1995, 51, 1277. H. Becker, M.A. Soler, K.B. Sharpless, Tetrahedron, 1995, 51, 1345. M. Tiecco, L. Testaferri, M. Tingoli, C. Santi, Tetrahedron lett., 1995, 36, 163. Y. Landais, P. Planchenault, V. Weber, Tetrahedron Lett., 1995, 36, 2987. J.J. Wang, A.I. Scott, Tetrahedron Lett., 1995, 36, 7043. P. Galatsis, J.J. Manwell, Tetrahedron Lett., 1995, 36, 8179. S.P. Bew, D.W. Knight, J. Chem. Soc., Chem. Commun., 1996, 1007. M. Tiecco, L. Testaferri, M. Tingoli, L. Bagnoli, F. Marini, C. Santi, A. Temperini, Gazz. Chim. Ital., 1996, 126, 635. S.B. Bedford, G. Fenton, D.W. Knight, D.E. Shaw, J. Chem. Soc., Perkin Trans. 1, 1996, 1505. M. Tiecco, L. Testaferri, F. Marini, Tetrahedron, 1996, 52, 11841. J.J. Wang, A.I. Scott, Tetrahedron Lett., 1996, 37, 3247. M.E. Jung, C.J. Nichols, Tetrahedron Lett., 1996, 37, 7667. P. Galatsis, S.D. Millan, G. Ferguson, J. Org. Chem., 1997, 62, 5048. O. Andrey, L. Ducry, Y. Landais, D. Planchenault, V. Weber. Tetrahedron 1997, 53, 4339. B. Berthe, F. Outurquin, C. Paulmier, Tetrahedron Lett., 1997, 38, 1393. N. DeKimpe, M. Moelens, J. Chem. Soc., Chem. Commun., 1993, 916. D.W. Knight, A.L. Redfern, J. Gilmore, Chem. Commun., 1998, 2207. G. Gragale, T. Wirth, Eur. J. Org. Chem., 1998, 1361. R. Grandel, U. Kazmaier, F. Rominger, J. Org. Chem., 1998, 63, 4524. X. F. Ren, M.I. Konaklieva, H. Shi, S. Dickey, D.V. Lim, J. Gonzalez, E. Turos, J. Org. Chem., 1998, 63, 8898. J.A. Marshall, C.A. Sehon, Org. Synth., 1998, 76, 263. M. Journet, D.W. Cai, L.M. DiMichele, R.D. Larsen, Tetrahedron Lett.,1998, 39, 6427. D.W. Knight, A.L. Redfern, J. Gilmore, Tetrahedron Lett., 1988, 39, 8909. W.S. Lee, K.C. Jang, J.H. Kim, K.H. Park, Chem. Commun., 1999, 251.

Electrophile-induced 5-Endo Cyclizations 99EJOC797 99JCS(P1)2143 99JOC663 99T13471 99TL2961 99TL3267 99TL6117 00AG(E)2488 00JCS(P 1)3469 00MI001 00OL2331 00T5571 00TA4645 00TL4447 00TL4453 01JCS(P1)1182 01MI001 01MI002 01TA1493 01TA3053 01TL4969 01TL5945 01TL6947 02MI001 02MI002

51

M. Tiecco, L. Testaferri, C. Sandi, Eur. J. Org. Chem., 1999, 797. S.B. Bedford, K.E. Bell, F. Bennett, C.J. Hayes, D.W. Knight, D.E. Shaw, J. Chem. Soc., Perkin Trans 1, 1999, 2143. M.E. Jung, U. Karama, R. Marquez, J. Org. Chem., 1999, 64, 663. D. Craig, N.J. Ikin, N. Matthews, A.M. Smith, Tetrahedron. 1999, 55, 13471. L. Lem6e, A. J6gou, A. Veyri6res, Tetrahedron Lett., 1999, 40, 2961. A.D. Jones, D.W. Knight, A.L. Redfem, J. Gilmore, Tetrahedron Lett., 1999, 40, 3267. M.A. Fagan, D.W. Knight, Tetrahedron Lett., 1999, 40, 6117. A.L. Rodriguez, C. Koradin, W. Dohle, P. Knochel, Angew. Chem., Int. Ed. Engl., 2000, 39, 2488. J.M. Barks, D.W. Knight, G.G. Weingarten, J. Chem. Soc., Perkin Trans. 1, 2000, 3469. J.J. Li, G.W. Gribble, 'Palladium in Heterocyclic Chemistry, Tetrahedron Organic Chemistry Series, Elsevier Science Ltd., Oxford, 2000. P. Aschwanden, D.E. Franz, E.M. Carreira, Org. Lett., 2000, 2, 2331. E. Turos, M.I. Konaklieva, X. F. Ren, H.C. Shi, J. Gonzalez, S. Dickey, D. Liu, Tetrahedron, 2000, 56, 5571. M. Tiecco, L. Testaferri, C. Santi, C. Tomassini, F. Marini, L. Bagnoli, A. Temperini, Tetrahedron: Asymmetry, 2000, 11, 4645. S.P. Bew, J.M. Barks, D.W. Knight, R.J. Middleton, Tetrahedron Lett., 2000, 41, 4447. S.P. Bew, D.W. Knight, R.J. Middleton, Tetrahedron Lett., 2000, 41, 4453. A.D. Jones, D.W. Knight, D.E. Hibbs, J. Chem. Soc., Perkin Trans 1, 2001, 1182. J.M. Barks, D.W. Knight, unpublished observations. A.B. Evans, D.W. Knight, unpublished observations. M. Tiecco, L. Testaferri, F. Marini, S. Stemativo, L. Bagnoli, C. Santi, A. Temperini, Tetrahedron." Asymmetry, 2001, 12, 1493. M. Tiecco, L. Testaferri, F. Marini, S. Sternativo, C. Santi, L. Bagnoli, A. Temperini, Tetrahedron: Asymm., 2001, 12, 3053. O. Germay, N. Kumar, E.J. Thomas, Tetrahedron Lett., 2001 42, 4969. G.M.M. E1-Taeb, A.B. Evans, S. Jones, D.W. Knight, Tetrahedron Lett., 2001, 42, 5945. A.B. Evans, D.W. Knight, Tetrahedron Lett., 2001, 42, 6947. J.J. Gridley, D.W. Knight, C.M. Sharland, J. Singkhonrat, paper in preparation. D.W. Knight, E.R. Staples, paper in preparation.

52

Chapter 3 Three-Membered Ring Systems Albert Padwa

Emopy University, Atlanta, GA, USA [email protected] S. Shaun Murphree

Allegheny College, Meadville, PA, USA [email protected]

3.1

INTRODUCTION

The chemistry of three-membered rings continues to be as exciting as ever. Owing to the enormous synthetic utility of these compounds, existing methodology centered about three membered rings has been improved and expanded in scope, while novel and promising techniques have also been reported. The goal of the present chapter is to provide a sampling of the current literature from a synthetic chemist's point of view, with an eye towards new understanding of existing methods, as well as new applications and techniques. The organization of the chapter is similar to that of previous years.

3.2

EPOXIDES

3.2.1

Preparation of Epoxides

In general, epoxides can be prepared through one of two broadly defined methods: introduction of an oxygen atom to an existing alkene (approach " a " ) , or by modification of a carbonyl substrate (approach "b"), whereby the former approach is the more familiar.

R•: •R3 R2 R4

approach a

R1 ~2~RR3 4

approach

1~ R R2

Many interesting reports on the epoxidation of alkenes have appeared in the literature, particularly involving asymmetric methods. In this regard, the chiral salen catalysts (1 and 2) developed by Jacobsen and Katsuki <01COC663> find frequent use, and convenient methods for their industrial preparation continue to be reported. For example, Jacobsen's catalyst (1, R1 = R2 = t-Bu; X = C1) is now available in 75% overall yield from commercially available starting materials <01SC2913>.

53

Three-Membered Ring Systems

R2

R2

1

2

While complexes of this type represent a powerful and general approach to the catalytic asymmetric epoxidation of non-functionalized alkenes, enantioselectivities are generally somewhat lower for trans-alkenes. Gilheany and co-workers <01OL663> have attempted to overcome this limitation by the use of stoichiometric chromium complexes. For example, treatment of trans-[3-methyl styrene (3) with a full equivalent of salen catalyst (2, R1 = trifluoromethyl, R2 - H, X -- NO3) with triphenylphospine oxide as an auxiliary ligand led to the formation of epoxide 4 in 92% ee, albeit in ca. 50% yield. The low yield is presumed to result from the formation of a ~-oxo Cr(IV) dimer in situ. Their systematic study of the effect of aromatic substituents on enantioselectivities <01OL3435> is consistent with an oblique approach of the substrate to a nonplanar (stepped) oxidized catalyst (Figure 1).

Me

PhS

R,R-2 CH3CN

3

"Me

P

~_.~OFigur e 1

4

i

i

|

The topic of approach angle--and even the conformation of the active species--is a controversial one. However, recent hybrid density functional calculations <0lAG(E)2073> support the idea that N-oxides, frequently used as additives to enhance reactivity and selectivity, operate by coordinating in the axial position and inducing a conformational change to a highly reactive non-planar species. Furthermore, Adam <01JOC5796> invokes the oblique approach to the oxygen via the path between the cyclohexyl and aromatic moieties (the "Katsuki trajectory"), albeit from a more planar reactive species, to rationalize the observed enantioselectivities in the kinetic resolution of aryl substituted allylic alcohols (Figure 2). , P c- nexyl-"---I~ln--'-A r

than

c- h e x y l - - M ~

Figure 2 A fascinating "triphase" catalyst has been developed this past year for catalytic epoxidation of allylic alcohols. The combination of phosphotungstic acid with an amphiphilic poly(N-isopropylacrylamide)-derived polymer provides a macroporous complex 5, which functions as a recoverable catalyst in aqueous conditions. Thus, treatment of allylic alcohol 6 with 0.003 mol% catalyst 5 and 2 equiv of hydrogen peroxide in aqueous medium resulted in the formation of the corresponding epoxide 7 in 96% yield. The catalyst exhibits

54

A. Padwa and S.S. Murphree

a very high turnover rate (35,000), is easily recoverable by filtration, and is reusable. In fact, twice recovered catalyst provided a 97% yield of epoxide in subsequent reactions <01OL1837>. In a similar vein of using organic-inorganic hybrids, titanium-silsesquioxane catalysts have been prepared by the complexation of titanium to incompletely condensed silsesquioxanes. The activity of the catalyst was found to be highly dependent upon the nature of the monosilane precursor <01AC(E)740>.

. ~ -' ~\ ~ amphiphilic / .~_ ~copolymer /~"'(~~,.~

H3PW12040

P

5

H

30%H202 P r.t.

6

7 (96%)

macroporouscatalyst5 Another known catalyst for the epoxidation of allylic alcohols, methyltrioxorhenium (8), has been studied using a hybrid density function method to explore the most reasonable mechanism for the epoxidation of allyl alcohol (9). These studies suggest that a bis(peroxo)rhenium complex is the active species, which goes through a spiro-type transition state (Figure 3) with hydrogen bonding to the attacking peroxo fragment from the allylic alcohol -OH group. The role of hydration from the solvent (water) in this transition state is still ambiguous <01JA2365>.

O.

Je-~O O:~Me O

,~xv,.O H 9

8

~

H202

O : R . < ! I::::H u:. \

-vO H

Me/

10

"CH2

Figure 3 |

A very simple and general method for the non-acidic epoxidation of alkenes has been reported using manganese(II) salts and hydrogen peroxide as the terminal oxidant. Thus, when the styrene derivative 11 was treated with 1 mol% of MnSO4 and 10 equiv of H202 in a DMF/bicarbonate buffer medium, the corresponding epoxide 12 was produced in 94% yield. In contrast to the corresponding rhenium-catalyzed reactions, these conditions were used to selectively epoxidize an internal double bond in the presence of a terminal olefin <01JA2933>.

H 11

NaHCO3,DMF

~

H 12

A fluorous medium has been utilized for alkene epoxidation employing the dioxirane derived from the fluoroketone 14, which is also effective in catalytic quantities with Oxone as the terminal oxidant. For example, treatment of trans-4-decene (13) with 5 mol% of ketone 14 and 1.5 equiv of Oxone in a bicarbonate buffered water/hexafluoroisopropanol (HFIP) medium led to the quantitative formation of the corresponding epoxide 15 <01TL4463>.

55

Three-Membered Ring Systems

C F 3 ~ C e F 13 14 Oxone/NaHCO: HFIP / water

13

~

0

0

(96%)

15

Progress continues to be made in the area of novel asymmetric methods. For example, the [1,4]diazepanone 16 has been shown to promote asymmetric epoxidation with modest enantioselectivities in the presence of Oxone and a mild base. The active oxygen transfer species is believed to be the chiral dioxirane 17, which adopts a twisted conformation and imposes a facial bias via the phenylsulfonyl groups. Yields are relatively low (< 50%), presumably due to Baeyer-Villiger degradation of the chiral auxiliary (16 "-) 18). This process can be retarded by replacing the phenylsulfonyl moieties with trifluoromethyl sulfonyl groups; curiously enough, however, this also leads to a decrease in ee's <01H615>.

0

PhO2S_4N~~_SO2Ph~ PB

_ Oxone

m

PhO2S-N--'~ -sO2Ph . . . . ~

Ph

P5

17

Ph 16

PhO2,_q I .-~'SO2Ph

PI~

Ph 18

Chiral iminium salts are also effective at promoting chiral epoxidation of simple olefins, although the aryl iminium species typically used give rise to very low ee's, presumably because of the planar topography imposed by the aromatic ring. However, a broader palette of these catalysts can be generated in situ from chiral amines and aldehydes under slightly acidic conditions (Scheme 1), and then convcrted to oxaziridinium salts in the presence of Oxone. The latter species serve as a catalytic oxygen transfer reagents via a fairly straightforward experimental protocol. Thc yields and enantiomeric excesses are highly variable and substrate-dependent, but can be quite good, as illustrated by the epoxidation of trans-stilbene (20) with the oxaziridinium salt derived from chiraI amine 19 and 3,3dimethylbutanal (21) <01OL2587>.

0

~N j I HA

KHS04

\e,~

~::)

Scheme 1

56

A. Padwa and S.S. Murphree

-

Oxone/ NaHC03

0

FI~ "~Ph

~ P*h

19

~~j~

20

H

21

93%yield 65%ee

22

Page and co-workers <01JOC6926> have boosted enantioselectivities of the more traditional aryl iminium catalysts by including alcohol, ether, and acetal functionalities on the nitrogen substituent. Thus, the phenyldihydronaphthalene 24 was converted to the corresponding epoxide in 64% yield and 49% ee using the iminium catalyst 23. The relatively high enantioselectivity of the dioxane-derived catalyst (compared to other nonfunctionalized aromatic iminiums) has been rationalized on the basis of a high conformational rigidity imposed by a stabilizing interaction between the oxygen atom lone pairs and the electron-deficient carbon atom of the iminium moiety, as shown in Figure 4. Ph

Ph

Na2CO3 23

24

25

"~"/ /

ii

Figure 4

Simple alkenes can also provide non-racemic cpoxides via a two-step sequence of asymmetric dihydroxylation (AD) and Mitsunobu cyclodehydration of the intermediate diol. For example, the styrene derivative 26 was converted to the corresponding (S)-epoxide in excellent yield and enantiomeric excess by standard AD conditions, followed by a combination of tricyclohexylphosphine [ ( ~ H l l ) 3 P } and diisopropyl azodicarboxylate (DIAD). The best optical yields were obtained with electron-poor alkenes, presumably due to the stabilization of the secondary alkoxide intermediate (Scheme 2) <01OL2513>.

OH AD-mix-a 97% ee

CF

F3

(C6Hll)3 P, DIAD 96% ee

F3C

F3

F 3c

F3

27

26 retention-~--

,,,OH

\+/

r

/P....O~,~O

A~

28 ~

\+./"O"-*vAr I f~'~_ ~ .u

/1~

~

inversion

Ar Scheme 2

Electron-deficient alkenes generally undergo epoxidation through mechanisms distinct from their electron-rich counterparts, and the reaction conditions necessary for their selective conversion are also the subject of investigation. Toward this end, progress is being made in terms of simplicity, improved reactivily, and higher enantioselectivities. For example, a chiral ytterbium complex formed from Yb(O-iPr)3 and 6,6'-diphenyl-BINOL (31) catalyzed the asymmetric epoxidation of chalcone (29) in 91% yield and 97% ee <01TL6919>. A

57

Three-Membered Ring Systems

similar, but much more rapid reaction is represented by the lanthanoid-BINOLtriphenylarsine complex 32, which provides complete epoxidation in three minutes <01JA2725>. The enantioselective epoxidation of enones can also be carried out using 1 mol% of a Cinchona alkaloid-derived quaternary ammonium phase-transfer catalyst (33) with sodium hypochlorite as the terminal oxidant <01TL1343>. ~

9 O O

Ph

P

P ~ P h

29

30

Catalyst

Results

91% yield 97% ee 8 hours

, Yb(Oi-Pr)3

31

••L -

~f

/

O O~--"AsPh3

95% yield 97% ee 3 minutes

~a--Oi-Pr

32

98% yield 86% ee 12- 24 h

+ NaOCI (phase transfer)

Also under the rubric of reaction acceleration, the carboxylic acid imidazolides 34 were found to undergo epoxidation 12 times faster than the corresponding esters, using lanthanoid catalysts of type 32. The resultant epoxy peroxyesters (35) could be converted to alkyl esters 36 under mild conditions <01JA9474>. 32

0

Me O H

,,,O O

TBHP 34

~

Ph

35

OIt - B u

36

Asymmetric epoxidation of tetralone-derived enones can be accomplished using the immobilized synthetic peptide poly-L-leucine (i-PLL), urea-peroxide, and DBU in a medium 'of isopropyl acetate. Yields are variable and substrate-dependent, but can be quite good, as

58

A. Padwa and S.S. Murphree

illustrated by the epoxidation of nitrophenylmethylene tetralone 37, which proceeds in 85% yield and 96% ee <01TL3471>. o

o urea_H20~" DBU

NO2

NO2

37

38

Another broad category of epoxide synthesis is based not on olefins, but on carbonyl compounds, in which the carbonyl oxygen ends up in the epoxide ring. One of the most straightforward manifestations of this approach is the conversion of benzaldehyde (39) to styrene oxide (41) by treatment with diiodomethane and methyllithium at 0~ This reaction is reported to proceed through lithium-halogen exchangc followed by carbonyl addition, to give the intermediate iodoalkoxide 40, which undergoes rapid ring closure to furnish the observed product <01T8983>. O

CH212 Me"------~ ~

H 39

40

41

In a similar vein, N-protected aminoepoxides (44) have been prepared from otbromoketones (42) in excellent yields through initial reduction to the isolable bromohydrin 43, followed by carbonate-promoted cyclization <01JOC 5790>. 0 R

Br

-

LiAIH(Ot-Bu)3 EIOH

ProtNH

~

R

~

OH

K2CO3 b. MeOH

Br

ProtNH

42

43

,,.~0

R

ProtNH 44

The use of sulfur ylides allows for the introduction of other carbon fragments besides the methylene group, and if the sulfur-bearing species is chiral, this methodology can be used for the enantioselective epoxidation of aldehydes. For example, the chiral sulfide 45, derived from valinon, has been used catalytically to generate sulfur ylides upon treatment with diazoalkanes, which in turn convert aldehydes to the corresponding scalemic epoxides. For example, benzaldehyde (39) provides trans-stilbcne oxide (46) in 90% ee <01T4629>. This methodology can also be carried out in a completely catalytic fashion (Scheme 3), whereby the generation of diazoalkanes occurs in situ, thus obviating the need to isolate these hazardous intermediates. The [2.2.1] bicyclic sulfide 47, prepared in four steps from camphorsulfonyl chloride, provides for high yields and ee's. In this case, the enantioselectivity is a result of the rigidity of the bicyclic system, combined with a face selectivity imposed by the bulky camphor moiety, which disfavors attack from the Si face <01AG(E) 1430>. P

H 39

p 46

59

Three-Membered Ring Systems Results

Conditions

~

N---BOc

, N2CHPh / Rh2(OAc)4

16% yield; 90% ee

45

82% yield; 94% ee

, Na+[PhCH=N-N-Ts] / Rh2(OAc)4

47

ph~H

Y

| R'2S-C HR

(

R'2S

=

4

RCH N2

N2

Scheme 3

An alternative approach to the ylide methodology, appealing in its simplicity, has been developed by Metzner and co-workers <01JOC5620>. In this protocol, the sulfur ylide is generated in situ by the reaction of chiral sulfide 48 with, for example, benzyl bromide, which provides the ylide after deprotonation with NaOH. In this way, furaldehyde (49) was converted to furyl epoxide 51 in a one-pot reaction in 89% yield and 93% ee.

Et~,'"

Et 48

+

CHO 49

+

PhCH2Br

t-BuOH / H~:,O

""

Ph

50

51 The addition of simple carbenes and carbenoids onto carbonyl groups represents another

viable approach to epoxides, and this method can be used to access interesting functionality on the heterocyclic ring. For example, the donor-acceptor rhodium carbenoids derived from aryldiazoacetates 52 add across the carbonyl moiety of ct,[3-unsaturated aldehydes, such as trans-crotonaldehyde (53), to give vinyl epoxides (e.g., 54) in good to excellent yield. No asymmetric induction was observed when chiral rhodium amide catalysts were used <01TL6803>. Using an analogous approach, the first isolated 2,2-dialkoxyoxirane (58) was

60

A. Padwa and S.S. Murphree

prepared by the reaction of cyclohexanone with the dimethoxycarbene 56, which was generated by the thermolysis of the oxadiazoline 55 <01CJC 110>.

O CO2Me + MeA'~U" H

P

53

52

MeO OMe N~

57

H O .Ph "~C O2Me

M

54

O [~

_N2 ~~. (MeO)2C. - acetone

55

3.2.2

Rh2(OAc)4

.~,.

MeO ~~] MeO

56

58

Reactions of Epoxides

Perhaps the most familiar reaction of epoxides is their propensity to undergo ring-opening with various nucleophiles. In this arena, most current developments center about selectivity, whether regiochemical or stereochemical in nature. With respect to the former, an interesting regioselective conversion of epoxides to chlorohydrins has been reported, in which a monosubstituted oxirane (e.g., 59) undergoes ring-opening with bis(chlorodibutyl)tin oxide in 2chloroethanol to give the less substituted chlorohydrins (e.g., 60) in generally good to excellent yield <01SL65>.

hv ~ P

(Bu2SnCI)20 OH D,. Phv,J,,,,,,/Ci CICH2CH2OH

59

93%

60

Cyclic meso-epoxides, such as cyclopentene oxide (64), can be induced to undergo alkylative ring-opening in the presence of trialkylaluminum reagents under catalysis using Nheterocyclic carbenes (62). These unusual catalysts are derived from the deprotonation of imidazolinium salts (61), and serve as phosphine mimics in terms of electron-pair donation behavior to form aluminum complexes of the type 63 <01 OL2229>.

~ii-Pr/~ i-Pr R~Np r ~ 9

KH,.

A~-N~N-Ar ..

Et3AI~

L'/~+N Ar Ar--,,~k.IE-

9

62 61

63

52eq. .mol%Et3A . . . 62L 64

E.t~C) H 65

77%

Three-Membered Ring Systems

61

Jacobsen and Ready <01JA2687> have reported on the development of a highly active cyclic oligosalen catalyst (66), which is remarkably effective in promoting the asymmetric ring opening of epoxides by water and alcohols. For example, exposure of the notoriously recalcitrant substrate cyclohexene oxide (67) to water in methylene chloride/acetonitrile and 1.5 mol% of catalyst 66 led to smooth conversion to the chiral diol 68 in 98% yield and 94% ee. This catalyst is also effective in the kinetic resolution of epoxides with alcohols (i.e., 69 "-) 71) <01 JA2687>.

cI

CI

O

66 (1.5 mol%)

O

-"

67

O

OH

CI

66,

68

B[~~

o

CI

98% yield 94% ee

CH3CN / CH2CI2 H20

69

R = t-Bu, n = 1 - 5

66 (0.5 mo I%) ~" A~.,,,,,,O CH3CN ~>~ n-Bu

O,~

99% yield n-Bu > 99% ee

71

7O

Also from Jacobsen's lab comes a clever application of chiral recognition to drive regioselective and stereospecific ring opening of epoxides. When an optically pure nonsymmetrical 1,2-disubstituted epoxide (e.g., 72) is treated with a chiral (salen)chromium(III) azide complex, only one approach results in a chiral "match", thus azide is delivered selectively to one position. Using this protocol, (1S,2S)-norpseudoephedrine (74) was synthesized in three steps with 42% overall yield and > 99% ee <01SL 1013>.

/O~ Ph'. . . . ' Me

(salen)Cr(lll) T MSO _..(.Me LAH TMS N3 ~ ~ ~ P 3

72

73

HOhf_._j.Me P

H2 74

Of course, the nucleophilic ring-opening can also occur in an intramolecular fashion, as demonstrated by the Payne rearrangement of the epoxyalcohol 75 to form the corresponding secondary alcohol (76). Dess-Martin oxidation of the latter provided expoxyketone 77 formally derived from j3-disubstituted enones, which are difficult to access directly in an enantioselective fashion <01JCS(P 1) 1109>.

Ph'.-~..', H p h H O~ i-Pr 75

NaOH t-BuOH

H,. . . . . P OH 76

i-Pr Ph

Dess-Martin H,. . . . . . . i-Pr )" P ~ P h 0 77

In contrast, similar systems underwent semi-pinacol rearrangement promoted by rare earth triflates. Thus, treatment of epoxyalcohol 78 with 20 tool% of ytterbium triflate in methylene chloride cleanly produced the hydroxyketone 79 in 99% yield a~er three hours. Attempts to

62

A. Padwa and S.S. Murphree

reduce the catalyst loading resulted in much longer reaction times and appearance of byproducts <01JCS(P1)1253>.

MHpO..~

Me

Yb(OTf)3 ~ CH2CI2

e M

o

78

OH ~ Me . F'h

79 Aryl epoxides undergo rearrangements to aldehydes and ketones in the presence of Lewis acid catalysts. For example, the cyclopentene oxide derivative 80 opens up to the more stable benzylic carbocation, which then provides the cyclopentanone derivative 82 via 1,2-methyl migration in 93% yield <01T815>. A similar rearrangement (83 --) 84) has been shown to occur using bismuth triflate, which has the advantages of low toxicity and moisture tolerance <01TL8129>. MeO

9 O~~_J

B

OBF E t3.. . 2

Me~

OPNB

~

eO

--~,.

OPNO

CH2CI2

80

~F~

82

81

O Bi(OTf)3xH20~ Ph,,, , , ~ CH2CI2 "I H Ph

Ph~~H H" "Ph 83

92%

84

In their studies in the realm of Lewis acid-promoted carbocyclizations, Petterson and Frejd <01JCS(P1)789> observed a high-yielding rearrangement of the tetrasubstituted epoxide 85 to the ketone 86 as a competing pathway. The migratory aptitude of the siloxymethyl moiety could be suppressed by changing to a trimethylsilylethoxymethyl (SEM) protecting group.

\

e

TBDMSO ,,,(k -,~'----K,.! :O ~OTBDMS 85

BF3.OEt2 78%

/ CO2Me

2.----.---

TBDMSO'" <

~ OTBDMS

86

A variety of interesting cycloaddition strategies involving epoxides have been reported. For instance, the epoxypropargyltungsten species 87, prepared from the corresponding propargyl chloride and NaCpW(CO)3, undergoes Lewis acid catalyzed [3+3]-cycloaddition to yield the bicyclic product 89. The proposed mechanism for this reaction involves a tungsten-TI2-allene cation (88) produced by exo-attack of the epoxide, followed by secondary ring closure onto the terminal allene carbon. These cyclizations proceed with high diastereoand enantioselectivity <01JA7427>.

63

Three-Membered Ring Systems W* W/ '

\0

-

' ~ Et

BF3OEt2~ ~

9

W

F3B87

_,,.

..,,Io

t

Et

88

89

An allene precursor is also at the heart of a [4+3] cycloaddition protocol yielding bicyclic ketones 93. Thus, allenamide 90, equipped with an oxazolidinone chiral auxiliary, is epoxidized using DMD to give the vinylidene epoxide intermediate 91. This species undergoes epoxide ring-opening to give a stabilized oxallyl cation 92, which can be trapped with furan to give the endo cycloadduct (93). The best diastereoselectivity in these reactions is observed when two equivalents of ZnCI2 were added <01JA7174>. O

O

Ph

O ..

Ph

90

_

Ph

[4+31

92

91

93,

77%

Another broad class of reactions might be viewed as heterocyclic interconversions, as they transform the epoxide ring system into another heterocyclic entity. For example, the epoxyaldehydes 95, derived from the oxidation of the corresponding epoxyalcohols 94, are converted to 4-hydroxy-4,5-dihydroisoxazole 2-oxides 96 upon treatment with ethyl nitroacetate and imidazole. These N-oxides can be deoxygenated with trimethyl phosphite to give heterocycles (97) corresponding to the formal addition of nitrile oxides onto vinyl ethers <01OL727>. ..i"~ R2" R1

OH 94

BAIB ~,TEMPO

I

R~". R1 0

H

95 O2Nf~CO2Et imidazole

O-N R3 R1,R3~J~~ CO2Et

%,OO-N R 3 RR~co2Et R_OH~"~! OH P(OMe)3 R2~'] ~, OH OH 97 96 Epoxides can also be converted to 1,3-dioxolanes by treatment with acetone in the presence of catalytic amounts of bismuth(III) salts, with yields ranging from 87-99%. For example, the epoxy allyl ether 98 provided the dioxolane 99 in 97% yield using bismuth triflate as the catalyst <01SC3411>. When simple epoxides are treated with bis(triphenylphosphine)-iminium cobalt tetracarbonyl (PPN-Co(CO)4) under Lewis acid catalysis, a carbonyl insertion reaction provides 13-1actones regioselectively in good to high yields. The carbonylation occurs selectively at the unsubstituted position, and the reaction is

64

A. Padwa and S.S. Murphree

tolerant of other functionality within the molecule. Thus, the alkenyl epoxide 100 is converted to the lactone 101 in 87% yield <01JOC5424>.

~0~~.~

Bi(OTf)3 acetone ~

~,,,,/O

98

99

......PPN-Co(CO)4BF3.0Et2 100

0 101

Tetrahydropyran derivatives 104 can be generated through a novel indium trichloride mediated cross-cyclization of aryl epoxides (102) and homoallyl alcohols (103). The mechanism (Scheme 4) is believed to proceed through an initial indium-induced epoxide ring opening followed by alkyl migration to give an oxygen-stabilized carbocation. Nucleophilic capture by the alcohol and subsequent electrophilic cyclization lead to the observed products <01 TL793 >. CI

102

103

•?/•

CI2

104

(~)

iI~C12

I n ~ ~

iIi cI 2

~9 ~....../cr

cl

Scheme 4

The Ishii group <00TL3389> reported an interesting samarium iodide promoted reaction of epoxides (e.g., 105) with imines (e.g., 106) to form oxazolidincs (e.g., 107). The mechanism proceeds through a radical pathway. The radical chemistry of epoxides has been the subject of a recent review <01TI>. Bn i

+ 105

.Bn 9 106

THF 107

65

Three-Membered Ring Systems

Vinyl epoxides exhibit reactivity distinct from their unfunctionalized counterparts. One such mode of reaction can be described as a vinylogous ring-opening, in which addition onto the olefinic moiety results in double-bond migration and concomitant fracture of the heterocycle. This activity has been used to advantage in some novel coupling protocols. For example, vinyl epoxide 108 undergoes palladium(0) mediated cross-coupling with vinyl stannane 109, which proceeds through initial formation of an (q3-allyl)palladium complex (Figure 5). Subsequent Pd/Sn transmetalation leads to the cross coupled product 110 in 93% yield <01JOC589>. A similar arylation of vinyl epoxides can be accomplished using bismuth reagents. Thus, treatment of methyl vinyl oxirane 111 with triphenylbismuthine (112) in the presence of palladium(II) chloride gave rise to the allylic alcohol 113 as a mixture of E/Z isomers in 91% yield <01 SC2365>. Me

+ M e O 2 ~ . . S n B u 3 Pd(MeCN)2CI2 Me02C.~ ~ ~ . t O H Me02C II DMF Me02C ~

108

109

+

110

ph3Bi

111

PdCI2 ~ ~

~~,,jOH

112

113

Of course, epoxides can also undergo many modes of chemistry in which the heterocyclic ring remains intact. One such example is the addition of lithiated oxazolinyl epoxides (114) onto carbonyl compounds, providing a synthesis of trisubstituted oxiranes (116). In this case the oxazolinyl group not only confers stability to the lithiate, but also provides an opportunity to introduce chiral auxiliaries <01JOC3049>. HO

Li~ ,p-Tol N~]....~70..,H "~~0

+

~

0 Ph~Ph

114

P h ~ Ph ,p-Tol

"~0"

115

3.3

AZIRIDINES

3.3.1

Preparation of Aziridines

" ' ~ ""'H

> 95% yield

116

In analogy with epoxides, most preparative syntheses of aziridines fall into one of two major categories: the [C + C=N] approach or the [N + C=C] strategy (Scheme 5). Also in keeping with their oxygen counterparts, continually more activity is reported in the area of asymmetric synthesis of aziridines.

--N

+

II

[N + C=C]~

.....

I

A,

-'-

[C + C=N]

Scheme 5: Two major approaches to aziridine synthesis

§

,,c,,

66

A. Padwa and S.S. Murphree

In the area of imine functionalization, aziridines can be synthesized enantioselectively from imines and alkyl halides using a camphor-derived chiral sulfide mediator (117) in a onepot procedure via the imino Corey-Chaykovsky reaction. Thus, benzyl bromide (118) and tosyl imine 119 provide aziridine 120 in practically quantitative yield as a 3:1 mixture of E/Z isomers and in 92% ee (E isomer). An electron-withdrawing substituent on the imine nitrogen is necessary to activate the system for nucleophilic attack <01TL5451 >.

Et p-Tol

~

- "

H

" Me

P~Br

+ PI1/...~N/T s

118

119

Ts ~

117),,. Ph,~,H

K2C03 MeCN

H

Ph

120

117

Aggarwal and coworkers have applied their sulfur ylide methodology to aziridines with some success. Thus, the ylides derived from chiral sulfide 47 and rhodium carbenoids (generated in situ) provide chiral aziridines (e.g., 123) from imine precursors (e.g., 121). The protecting group on the imine nitrogen plays a large role in yield and diastereomeric ratios, and to a lesser extent on the enantioselectivity. The BOC group gives the best trans/cis ratio, but the lowest overall yield. The opposite is true for the SES group. Enantiomeric excesses range from 89 - 9 8 % <01AG(E)1433>. The SES group also turns out to be the best choice when the sulfide 124 is used as the chiral auxiliary. Solvent and substrate structure also influence the selectivity <01JCS(P1) 1635>.

Na+ -

+ pI~~,-N..Ts 47

121

47

- Rh(OAc)4 BnEt3NCI

122

124

12,5

126

BOC - -

CH2CI2

Ptf"L-&"'Ph

33% yield 89% ee

123

SES I

84% yield 95% ee

127

124

For the alternative approach, namely aziridination of alkenes, an examination of the recent literature reveals two frequently employed nitrene donors, [N-(p-tolylsulfonyl)imino)]phenyliodinane (PhI=Ts, 128) and bromamine T (129). The latter reactions can be catalyzed by palladium(II) reagents (i.e., 130 ") 131) <01JCS(CC)405>, or with a variety of more common transition metals with the assistance of microwave radiation (i.e., 132 ") 133) <01JOC30>.

67

Three-Membered Ring Systems

0

128

._/C02Me

129

129

Pd(MeCN)2CI2

130

02Me

60%

131

129

duCa2 132

Ts

81%

~" 133

Similarly, the nitrene transfer reaction from 128 is facilitated by a variety of catalysts, including MTO (136) <01JCS(CC)235>, the tri(pyrazolyl)borate-copper(1) complex 137 <01OL1423>, and tetrakis(acetonitrile)copper(I) hexafluorophosphate (138) <01JA7707>. In the latter case, the reaction can be carried out using a sultbnamide and the primary oxidant, iodosylbenzene, whereby the actual nitrene transfer reagent 128 is presumed to be formed in situ. In all cases, acetonitrile appears to be the solvent of choice. An interesting asymmetric variant of this methodology has been reported, which employs an immobilized catalyst of Cu 2+ ion-exchanged into zeolite H-Y (CuHY) modified by the chiral bis(oxazoline) 139. Using nitrene donor 128, this catalyst system led to the chiral aziridination of styrene (134) in 70% yield and 77% ee, a marked improvement of enantioselectivity compared to the same reaction using the homogeneous catalyst Cu(OTf)2 (28% ee). The optical yield could be further increased by using the p-nitrophenyl variant of the nitrene donor, PhI=NNs (82% ee) <01JCS(P2)1714>.

68

A. Padwa and S.S. Murphree Catalyst

Yield

Me

I

O=~e=O

28%

O 136

~~B'CuCl ~NJ~ 13T

/ms -

128 ,,

co nd ition s

(see right)

134

90%

Cu (CH 3CN)4PF6

135

138

75%

(128) generated in situ from Phl=O and RSO 2NH2)

Ph

Ph

139

70% (77% ee)

Other approaches to chiral aziridines have been reported. For example, treatment of cycloheptadiene (141)with the leucine-derived (S)-3-acetoxyamino-2-(3-hydroxy-2,2dimethylpropyl)quinazolin-4(3H)-one (140) in the presence of titanium(IV) t-butoxide ~ ) in methylene chloride leads to formation of the chiral aziridine 142, in which the chiral auxiliary (Q) is in the exo position, as the only isolated product in 29% yield <JCS(P1)1518>. Q I

,_

Q

1,o,

141

_.__.._--_.---~

CH2CI2

142

The aziridination of electron-deficient alkenes can be carried out under slightly different conditions. The reaction between primary amines 143 and 2-bromo-2-(cycloalkylidene)acetates 144 in alcohol under high pressure provides spiroaziridines 145 in good yields and diastereomeric excesses. The reaction is general for most primary amines, except for those that are weakly nucleophilic or sterically bulky <01EJOC2569>. Enamides (e.g., 147) can be

Three-Membered Ring Systems

69

converted to corresponding aziridinylamides 148 with excellent enantioselectivity using the chiral diaziridine 146 <01CL984>. 2

2 n

R3-NH2

+

143

Br"

11 kbar MeoH ~

~02R1

)n

R

144

02R1

145

H N

P,

146

P 1

~

147

BuLi ~

Ph/ ~

-~

76% yield

98% ee

148

Aziridines can also be formed by the ring closure of appropriately substituted amines. For example, treatment of N-aryl-13-amino alcohols (149) with p-toluenesulfonyl chloride under phase transfer conditions provides N-aryl aziridines (150) in 80-90% yield <01SCl105>. Enantiomerically pure aziridines can be prepared in a similar fashion, starting with optically pure amino alcohols derived from the enantioselective reduction of ct-amino ketones. Thus, treatment of the amino alcohol 151 with DEAD and Ph3P in THF led to the formation of aziridine 152 in 92% yield and 99% ee <01JCS(P1)1916>. The chiral chloroimine 153 could be converted to the optically pure aziridine 155 via diastereoselective reduction with sodium cyanoborohydride to produce the intermediate amide anion, which cyclizes to form 155 in 90% yield and > 98% ee <01JOC2764>. Finally, the oxidation of 13-amido selenides 156 with MCPBA, followed by treatment of the corresponding selenones with potassium tbutoxide gives N-acylaziridines in good to excellent yields <01JCS(P1)944>.

70

A. Padwa and S.S. Murphree

p-TsCI Bu4NHs04 NaOH

a

N

R

149

150

OH H ph/~.N~]~10_t_Bu

DEAD PPh3 TH~ '~"

Ph,,, ~N'~I/'O-t-Bu O

O 151

92% yield 99% ee

152

Bn

Bn

-

Na BH3CN r.t.

Bn 90% yield > 98% ee

153

154

155

0 MCBPA

m

P h S e ~ N - C OR1 R2

156

3.3.2

R3

COR1 I~1

t-BuOK R2

157

R3

158

Reactions of Aziridines

Like epoxides, aziridines engage in facile ring-opening reactions with a variety of nucleophiles, and this represents an entry into many functionalized amines. For example, the 3-trifluoromethylaziridine-2-carboxylate 159 undergoes efficient nucleophilic attack by chloride or thiols under acidic conditions to provide the protected amino esters 160 and 161, respectively, in high yield and as a single diastereomer <01SL679>.

EIHBn ,- ~ C 0 2 E t

C/3

:

HCI r.t. 95%

CF3~ ~ Bn

160

gn I

pty"~ph 162

.AC02Et

_E,IHBn BnSH c ,,~,,,~02Et CF3S03 H'- C-3 : 98% SBn

159

p-TolSH ZnCI2 CH2CI2

161

p-TolS

in13

~~,

NHBz 163

164

165

NHTs

71

Three-Membered Ring Systems

The latter reaction can also be promoted by zinc chloride, as exemplified by the conversion of aziridine 162 to amino sulfide 163 <JCS(P1)1314>. As for halide-mediated ring opening, indium trihalides are competent reagents in promoting this transformation, as demonstrated by the clean conversion of N-tosylaziridine 164 to the iodo amine derivative 165 <01SL1417>. Hydroxylamines react with non-symmetrical aziridines under Lewis acidic conditions to give products of nucleophilic attack at the less substituted site. Thus, treatment of methyl aziridine 166 with N-t-butylhydroxylamine (167) with 20 mol% boron trifluoride etherate provides the diamine derivative 168 in 77% yield <01TL8243>. Fluoride ion is a powerful catalyst for the reaction of aziridines with the weakly nucleophilic ptoluenesulfonamide, a phenomenon which has been applied with advantage toward the preparation of protected diamino diol 170, a precursor to the aminocyclotol substructure <01TL6433>.

H

Ts

OH ~HTs

BF3.0Et2

167

166

168

Br

Ts/

Br

="

DMSO

TsHN

: F4HTs

169

170

Some interesting advances have been made in the area of ring-opening by carbon-centered nucleophiles, an area of obvious practical impact. For example, aziridines react smoothly with arenes in the presence of a catalytic amount of indium triflate at ambient temperature to give the corresponding 13-aryl amines (e.g., 173) in good to excellent yields <01TL8067>. The aziridine 174 was opened up in a stereocontrolled fashion by the chiral enolate prepared by deprotonation of 175, itself derived from (S,S)-(+)-pseudoephedrine, and provides the yaminoamide 176 in 87% yield <01JOC5801>.

Ph /

Ts

\

p t ~ "-'~

-F

MeO~

I

O

Me O ~ ~ ~ l N M eO

OH

175

HTs

173

172

ms i N 174

In(OTf)3 CH2CI2

MeO

171

i_Pr~ - X

"

LDA LiCI

TsNH " I OH i - P ~ ? P 176

72

A. Padwa and S.S. Murphree

Finally, aziridines can undergo a variety of conversions which provide new heterocyclic species, as exemplified by the microwave-assisted ring expansion of N-acetyl 3'-aziridines (177) to oxazolines 178 <01T2807, 01EJOC3545>, the formation of pyrrolines 180 in the presence of acrylonitrile and solid sodium hydroxide <01T6993>, and thermal ring-opening to a 1,3-dipole followed by capture with electron-rich alkenes to provide substituted pyrrolidines 183 <01TL6087>. Some radical variants include the intramolecular 5-endo cyclization of 3-(2-methyleneaziridin-l-yl)propyl radicals 185 to methylenepiperidine derivatives 186 <01OL2383>, and the rearrangement of the aziridinyl radical 188 to the azahomoallyl radical 189, which undergoes [3+2] cyclization with olefins to give the iodopyrrolidines 190 <0lAG(E)3865>. MeO

"-,.~,"

~N,~

0

Zn(OTf)2 1,.. m ic rowave

0 177

ms

pl.f,,J-_~

178

NaOH

~k

N

CN

~ ph/L~

171

Ph

179

180

ms 182

R

181

171

Ts 183

Ph,,,. ~ S

l

eP h

N

Bu3SnH

N

AIBN ~

H 185

184

ms

z-k..~l 187

(n-Bu3Sn) 2

186

Ts I

N 188

--~

Ts N.,"'-,,,~7 189

R

Ts

I R 190

Three-Membered Ring Systems

3.4

REFERENCES

00TL3389 0lAG(E)740 0lAG(E)1430 01AG(E)1433 0lAG(E)2073 0lAG(E)2255 0lAG(E)3865 01CC235 01CC405 01CC966 01CJC110 01CL984 01COC663 01EJOC1959 01EJOC2569 01EJOC3545 01H(54)615 01HCA662 01JA2365 01JA2687 01JA2725 01JA2933 01JA6947 01JA7174 01JA7427 01JA7705 01JA9474 01JCS(P1)789 01JCS(P1)944 01JCS(P1)ll09 01JCS(P1)1253 01JCS(P1)1314 01JCS(P1)1518 01JCS(P1)1635 01JCS(P1)1916 01JCS(P2)1714 01JOC30 01JOC589 01JOC1867 01JOC2764 01JOC3049 01JOC4022 01JOC5424 01JOC5620 01JOC5790 01JOC5796 01JOC5801

73

T. Nishitani; H. Shiraishi,; S. Sakaguchi; Y. Ishii, Tetrahedron Lett. 2000, 41,3389. P.P. Pescarmona, J.C. van der Waal, I.E. Maxwell, T. Maschmeyer, Angew. Chem. bzt. Ed. 2001, 40, 740. V. K. Aggarwal, E. Alonso, G. Itynd, K. M.Lydon, M. J. Palmer, M. Porcelloni, J.R. Studley,Angew. Chem. htt. Ed. 2001, 40, 1430. V. K. Aggarwal, E. Alonso, G. Fang, M. Ferrara, G. Hynd, M. Porcelloni, Angew. Chem. Int. Ed. 2001, 40, 1433. J. EI-Bahraoui, O. Wiest, D. Feichtinger, D.A. Plattner, Angew. Chem. hit. Ed. 2001, 40, 2073. S.E. Denmark, T. Wynn, B.G. Jellerichs,Angew. Chem. Int. Ed. 2001, 40, 2255. O. Kitagawa, Y. Yamada, H. Fujiwara, T. Taguchi Angew. Chem. hit. Ed. 2001, 40, 3865. H.-J. Jeon, S .T. NguyenJ. Chem. Soc., Chem. Commun. 2001, 235. A.M.M. Antunes, S.J.L. Marto, P.S. Branco, S. Prabhaka~ A.M. Lobo, J. Chem. Soc., Chem. Commun. 2001, 405. M.A. Graham, A.H. Wadsworth, M. Thomton-Pett, C.M. Raymer, J. Chem. Soc., Chem. Cornmun. 2001, 966. M. Dawid, P.C. Veneri, J. Warkentin, Cart. J. Chem. 2001, 110. H. Ishihara, Y.N. Ito, T. Katsuki, Chem. Lett. 2001, 984. T. Katsuki, Curt. Org. Chem. 2001,5,663. W. Adam, R.M. Bargon,Eur. J. Org. Chem. 2001, 1959. A. Rulev, J. Maddaluno, Eur. J. Org. Chem. 2001, 2569. G. Cardillo, L. Gentilucci, G.P. Mohr,Eur. J. Org. Chem. 2001, 3545. K. Matsumoto, K. Tomioka, Heterocycles, 2001, 54,615. B. Miiller, P. Nury, Ilelv. Chim. Acta 2001,84,662. C. Di Valentin, R. Gandolfi, P. Gisdakis, N. R6sch,J. Ant. Chem. Soc. 2001,123, 2365. J. M. Ready, E.N. Jacobsen,./. Ant. Chem. Soc. 2001,123, 2687. T. Nemoto, T. Ohshima, K. Yamaguchi, M. Shibasaki,J. Am. Chem. Soc. 2001,123, 2725. B.S. Lane, K. Burgess,J. Ant. Chem. Soc. 2001,123, 2933. M. Shimizu, T. Fujimoto, H. Minezaki, T. Hata, T. Itiyama,J. Am. Chem. Soc. 2001,123, 6947. H. Xiong, R.P. Hsung, C.R. Berry, C. Rameshkumarfl. Am. Chem. Soc. 2001,123, 7174. R.J. Madhushaw, C.-L.Li, K.-tt. Shen, C.-C. Hu, R.-S. Liu,J. Am. Chem. Soc. 2001,123, 7427. K. Hada, T. Watanabe, T. Isobe, T. lshikawa,l. Am. Chem. Soc. 2001, 123, 7705. T. Nemoto, T. Ohshima, M. Shibasaki, J. Am. Chem. Soc. 2001,123, 9474. L. Petter'son, T. Frejd,J. Chem. Soc.,Perkm Trans. 1 2001, 789. V.R. Ward, M.A. Cooper, A.D. Ward,J. Chem. Soc., Perkin Trans. 1 2001, 944. J.F. Bickley, A.T. Gilhnore, S .M. Roberts, J. Skidmore, A. Steiner, J. Chem. Soc., Perkin Trans. 1,2001, 1109. J.F. Bickley, B. Hauer, P.C.A. Pena, S.M. Roberts, J. Skidmore,.L Chem. Soc., Perkin Trans. 1 2001, 1253. J. Wu, X.-L. Hou, L.-X. Dai,J. Chem. Soc., Perkin Trans. 1 2001, 1314. R.S. Atkinson, C.K. Meades, J. Chem. Soc.,Perkin Trans. I 2001, 1518. V.K. Aggarwal, M. Ferrara, C.J. O'Brien, A. Thompson, R.V.H. Jones, R. Fieldhouse, J. Chem. Soc., Perkin Trans. 1 2001, 1635. A.M. Kawamoto, M. Wills, J. Chem. Soc.,Perkin Trans. 1, 2001, 1916. S. Taylor, J. Gullick, P. McMorn, D. Bethell, P.C.B. Page, F.E. ttancock, F. King, G d. Hutchings, J. Chem. Soc., Perkin Trans. 22001, 1714. B.M. Chanda, R. Vyas, A.V. Bedekar,J. Org. Chem. 2001, 66, 30. A.M. Castafio, M. M6ndez, M. Ruano, A.M.Echavarren, J. Org. Chem. 2001, 66,589. H. Ohno, H. Hamaguchi, T. Tanaka,.l. Org. Chem. 2001, 66, 1867. J.M. Concell6n, P.L. Bernad, E. Riego,J. Org. Chem. 2001, 66, 2764. A. Abbotto, V. Capriati, L. Degennaro, S. Florio, R.Luisi, M. Pierrot, A. Salomone, J. Org. Chem. 2001, 66, 3049. O. P~mies, JE. B~ickvall,J. Org. Chem. 2001, 66, 4022. J.T. Lee, PJ. Thomas, H. Alper,J. Org. Chem. 2001, 66, 5424. J. Zanardi, C. Leriverend, D. Aubert, K. Julienne, P. Metzner, J. Org. Chem. 2001, 66, 5620. R.V. Hoffman, W. S. Weiner, N. Maslouh, J. Org. Chem. 2001, 66, 5790. W. Adam, H.-U. I]umpf, K.J. Roschmann, C.R. Saha-M611er, J. Org. Chem. 2001, 66, 5796. J.L. Vicario, D. Bad/a, L. Cafillo, J. Org. Chem. 2001, 66, 5801.

74 01JOC6926 01OL663 01OL727 01OLl153 01OL1423 01OL1837 01OL2229 01OI,2269 01OL2383 01OL2455 01OL2513 01OL2587 01OL3435 01SCl105 01SC2365 01SC2913 01SC3411 01SL65 01SL679 01SL1013 01SL1335 01SL1417 01SL1608 01T1 01T71 01T815 01T2807 01T4623 01T4629 01T6993 01T8983 01TL333 01TL793 01TL943 01TL1343 01TL2141 01TL2185 01TL2739 01TL3741 01TL4463 01TL5451 01TL5789 01TI.,6087 01TL6433 01TL6803 01TI~919 01TL8067 01TL8129 01TL8243

A. Padwa and S.S. Murphree P.C.B. Page, G.A. Rassias, D. Barros, A. Ardakani, B. Buckley, D. Bethell, T.A.D. Smith, A.M.Z. Slawin, J. Org. Chem. 2001, 66, 6926. A.M. Daly, M.F. Renehan, D.G. Gilheany, Org. Lett. 2001, 3,663. E. Marotta, L.M. Micheloni, N. Scardovi, P. Righi, Org. Lett. 2001, 3,727. M. Bandini, P.G. Cozzi, P. Melchiorre, S. Morganti, A. Urnani-Ronchi, Org. Lett. 2001, 3, 1153. S.T. Handy, M. Czopp, Org. Lett. 2001,3, 1423. Y.M.A. Yamada, M. Ishinohe, H. Takahashi, Shiro Ikegami, Org. Lett. 2001, 3, 1837. H. Zhou, E.J. Campbell, S.T. Nguyen, Org. Lett. 2001,3, 2229. H. Ohno, H. Hamaguchi, T. Tanaka, Org. Lett. 2001, 3, 2269. N. PrEvost, M. Shipman, Org. Lett. 2001, 3, 2383. M. Dawid, G. Mlostofi, J. Warkentin, Org. Lett. 2001,3, 2455. S.A. Wei~man, K. Rossen, P.J. Reider,Org. Lett. 2001,3, 2513. M.-K. Wong, L.-M. IIo, Y.-S. Zheng, C.-Y. Iio, D. Yang, Org. Lett. 2001, 3, 2587. C.P. O'Mahony, E.M. McGarrigle, M.F. Renchan, K.M. Ryan, N.J. Kerrigan, C. Bousquet, D.G. Gilhcany, Org. Lett. 2001,3, 3435. K. Sriraghavan, V.T. Ramakrishnan, Synth. Commun. 2001,31, 1105. S.-K. Kang, H.-C. Ryu, Y.-T. Hong, M.-S. Kim, S .-W. Lee, J.-tI. Jung, Synth. Cornmum. 2001, 31,2365. I. Capanee, H. Mikuldas, V. Vinkovic, Synth. Contrnttn. 2001, 31, 2913. I. Mohammadpoor-Baltork, A.R. Khosropour, II. Aliyan, Synth. Cornrnun. 2001, 31,3411. C.J. Salomon, Synlett 2001, 65. B. Crousse, S. Narizuka, D. Bonnet-Delpon, J.-P. BdguE, Synlett 2001, 679. B. D. Brandes, E. N. Jacobsen, Synlett 2001, 1013. D. Diez, R.F. Moro, W. Lumcr,"ks,L. Rodriguez, I.S. Marcos, P. Basabe, R. Escarcena, J.G. Urones, Synlett 2001, 1335. J.S. Yadav, B.V. Subba Reddy, G. Mahesh Kumar, Synlett 2001, 1417. J.S. Yadav, A. Bandyopadhyay, B.V.S. Reddy, Synlett 2001, 1608. J.J. Li, Tetrahedron 2001, 57, 1. P. Garner, O. Dogan, W.J. Youngs, V.O. Kcnnedy, J. Protasicwicz, R. Zaniewski, Tetrahedron 2001, 57, 71. Y. Kita, A. Fun, kawa, J. Futamura, K. ltiguchi, K. Ueda, tt. Fujioka, Tetrahedron 2001, 57, 815. G. Cardillo, L. Gentilucci, M. Gianotti, A. Tolomelli, Tetrahedron 2001, 57, 2807. G. Del Signore, S. Fioravanti, L. Pellacani, P.A.Tardella, Tetrahedron 2001,57, 4623. V.T. Myllym~ii, M.K. Lindvall, A.M.P. Koskinen, Tetrahedron, 2001, 57, 4629. K.A. Kumar, K.M.L. Rai, K.B. Umesha, Tetrahedron 2001, 57, 6993. J.M. Concell6n, H. Cuervo, R. Fern~indez-Fano, Tetrahedron 2001, 57, 8983. E.N. Prabhakaran, J.P. Nandy, S. Shukla, J. lqbal, Tetrahedron Lett. 2001, 42,333. J. Li, C.-J. Li, Tetrahedron Lett. 2001, 42,793. S. Kim, M.S. Jung, C. ti. Cho, C.H. Schiesset; Tetrahedron Lett. 2001, 42,943. B. Lygo, D.C.M. To, Tetrahedron Lett. 2001, 42, 1343. Y.Q. Tu, S.K. Ren, Y.X.Jia, B .M. Wang, A.S .C. Chan, M.C.K. Choi, Tetrahedron Lett. 2001, 42, 2141. A. Fazio, M.A. Loreto, P.A. Tardella, Tetrahedron Lett. 2001, 42, 2185. M. Freccero, R. Gandolfi, M. Sarzi-Amad~, A. Rasteili, Tetrahedron Lett. 2001, 42, 2739. P.A. Bentley, J.F. Bickley, S .M. Roberts, A. Steiner, Tetrahedron Lett. 2001, 42, 3741. J. Legros, B. Crousse, J. Bourdon, D. Bonnet-Deipon, J.-P. BdguE, Tetrahedron Lett. 2001, 42, 4463. T. Saito, M. Sakairi, D. Akiba, Tetrahedron Lett. 2001,42, 5451. B. Chao, D.C. Dittmer, Tetrahedron Lett. 2001, 42, 5789. I. Ungureanu, P. Klotz, A. Schoenfclder, A. Mann,Tetrahedron Lett. 2001, 42, 6087. B.J. Paul, E. ttobbs, P. Buccino, T. Hudlicky, Tetrahedron Lett. 2001, 42, 6433. H.M.L. Davies, J. DeMeese, Tetrahedron Lett. 2001, 42, 6803. R. Chen, C. Qian, J.G. de Vries, Tetrahedron Lett. 2001,42, 6919. J.S. Yadav, B.V. Subba Reddy, R. Srinivasa Rao, G. Vcerendhar, K. Nagaiah, Tetrahedron Lett. 2001, 42, 8067. K.A. Bhatia, K.J. F_ash, N.M. Leonard, M.C. Oswald, R.S.Mohsn, Tetrahedron Lett. 2001, 42, 8129. I.A. O'Neil, J.C. Woolley, J.M. Southern, H. Hobbs, Tetrahedron Lett. 2001, 42, 8243.

75

Chapter 4

Four-Membered Ring Systems L. K. Mehta and J. Parrick

Brunel University, Uxbridge, UB8 3PH, UK [email protected] and [email protected]

4.1

INTRODUCTION

This chapter is subdivided into sections mainly as in previous volumes but with the exception that there is no section on ring systems containing two different heteroatoms due to the dearth of publications in this area. Recent developments in the chemistry of saturated heterocycles have been reviewed <00JCS(P 1)2862>.

4.2

AZETIDINES

An efficient two-step synthesis of 1-benzylazetidine 2 (R l= Ph, R 2 = H) uses benzaldehyde and 3-bromopropylamine to obtain the intermediate 1 which is cyclised with sodium borohydride in methanol <01SC565>. The same reagent causes the cyclisation of readily accessible alkylidene- and arylidene-2,2,3-tribromopropylamines 3 to give the ketal 2 (R ~= Ar or alkyl, R 2 - OMe), a useful intermediate for the formation of 1-substituted azetidin-3ones <01 TL2373>.

PhCH=N(CH2)3Br

,,

RR2

=

N

~

R1CH=NBr/~~Br

R1) 2

Br

3

OH R1COCHR2NMeR 3

.....

hv_

R 2/

5

The photocyclisation of N-protected-N-methylaminoketones 4 gives azetidin-3-ols $ but the yield and diastereoselectivity depend upon the substituents <00MI245>.

76 Selective reduction of the hydroxy ester group of the aspartate 6 (R ~= CO2Me, R 2 = H, Pf = 9-phenylfluorenyl) by borane-dimethyl sulfide complex in the presence of sodium borohydride gave 6 (R ~ = CH2OH, R 2 = H). After conversion of the alcohol groups to mesylate esters, treatment with base gave the azetidine 7, which is easily deprotected to give an intermediate potentially useful in the synthesis of analogues of the quinonoid anticancer drug, mitomycin <00JOC6780>.

OR2 R1. - ~ 7 C02Me

MesO.,

CO2Me

NHPf

Pf

6

7

A one step procedure to 3-aminoazetidines 9 by ring expansion of 1-arylsulfonyl-2(halomethyl)aziridines 8 (X = Br or C1) with aliphatic amines has been described but the yields were low <00TL 10295>.

Xv.~N

__ SOzAr

ArSO2NH" RNH2 ~ ~N~_R

8

9

2-Phenyl-N-tosylazetidine 10 is a formal 1,4-dipole precursor and addition to activated or non-activated alkenes occurs. For instance, methylenecyclobutane reacts with 10 to give the spiro compound 11 <01 CC958>. Ph Ph [

"Tos lO

I Tos 11

1-Benzylazetidine derivatives bearing 2,4-bis(hydroxymethyl), 2-acetoxymethyl-4hydroxy-methyl and 2,4-bis(acetoxymethyl) substituents have been obtained with high ee using lipase from porcine pancreas immobilised on celite. The absolute stereochemistry was established for these compounds <01TA605>. A substantial body of work on the chemistry of substituted 2-azabicyclo[2.2.0]hexanes (e.g. 14) has been reported. The basic ring system is readily accessible by photochemical intramolecular cyclisation of 1,2-dihydropyridine 12 followed by reduction of the olefin 13 <00T9227>. Stereochemical inversion occurs on benzylic bromination of 15 (R ~ - Ar, R 2 = H) with NBS to give 15 (R ~ - Br, R 2 = At). <00T9233>. Brominated derivatives of the 2azabicyclo[2.2.0]hexane ring system are also formed by addition of bromine to an olefin (e.g. 13) but this process is complicated by a bromine mediated rearrangement to yield 2azabicyclo[2.1.1 ]hexanes <01JOC 1805>. Bromohydrin derivatives of the 2-azabicyclo[2.2.0]hexane system can be obtained either from the epoxide of the olefin or by the action of NBS in aqueous DMSO, but in the latter case with concomitant formation of the rearranged nucleus <01JOC 1811 >.

77

H2OH ~ h~v I

4.3

R1 "CO2Me ~ ~ _ N..-CO2Me N 3 steps~ ~~-.jNH R2

~ OH

02Me

OAr 13

14

15

OXETANES AND OXETANONES

Reviews of the Paterno-Btichi photocycloaddition reaction for the synthesis of mono- and bi-cyclic oxetanes <00SL 1699> and the stereoselective synthesis of oxetanones are available <00PAC1721>. The Paterno-Btichi reaction of the aromatic ketone 16 and either chiral or achiral allylic compounds 17 may give rise to the regio-isomers 18 and 19, and each of these may be present in diastereoisomeric forms. The presence of a hydroxyl group in the allylic reactant 17 (R 3 -OH) produces both a strong regio- and stereo-selective effect favouring the formation of 18 <01S1203>. R3 R3

O

+

16

R

R4

_____.

17

R4

! Ph

+

phil oj

8

19

Other workers searching for regio- and diastereo-selectivity have used silyl O, Se-ketene acetals 20 and aromatic aldehydes 21. When the mixture of reactants was irradiated with light of wavelength greater than 320 nm, the major product was the trans isomer of 22. However, when light of wavelength greater than 400 nm was used in a reaction sensitised by 9,10-diphenylanthracene, the other regioisomer 23 was formed <01S1243>.

OTBDMS Ar\ --.~Ar o ~ S Me2C:C(SeR)(OTBDMS)+ ArCHO eR + oI 20

21

22

SeR OTBDMS 23

--

2-Hydroxymethyloxetanes 25 have been obtained stereoselectively from suitably substituted oxiranyl ethers 24 by the action of a mixture of LDA and potassium tert-butoxide. The relative stereochemistry of R ~ and the hydroxymethyl group is determined by the stereochemistry in 24 but the relative stereochemistry of R 2 and the alcohol group is produced in the reaction and was found always to be trans <01 JOC3201>. High yields of 2-oxetanyl hydroperoxides 27 are provided by thermal rearrangement of substituted alkoxyfuran endoperoxides 26 via a neighbouring group participation mechanism. The ring opening of the hydroperoxide 27 (R t = R 2 = Et, Ar = Ph) by the action of diethyl sulfide provides the keto ester 28 quantitatively and stereoselectively <01JOC4732>.

78 0 0

~

R I

1 .

~ HO

O~f.R 2

24

25

R 1

R1

R2

HOO

Ar

R2

A

0

OMe

1"-

O~O 26

Et Et CO2Me

Ph

27

O

CO2Me

28

Other reactions of oxetanes reported include the asymmetric ring expansion of 2substituted oxetanes in an enantioselectively catalysed reaction with diazoacetic esters to give 2,3-disubstituted tetrahydrofurans <01T2621>, and the Lewis acid promoted reactions of 2methoxy-2-siloxyoxetane with allylsilane <00MI651 >. Dirhodium complex catalysed formation of 2-oxetanone from isopropyl phenyldiazoacetate 29 has been found to give good yield of 30 but with only moderate ee. The formation of oxetanones by insertion into the one tertiary C-H bond with very little reaction at the six primary C-H bonds of the isopropyl group is striking. Interestingly, only the ]'-lactone is formed when a tertiary C-H bond is available in the ],-position. Several dirhodium complexes and dirhodium acetate were effective in forming [3-1actones from other phenyldiazoacetates <01 SL967>.

0 Me Ph~o.,/~Me N2

29

O'~o~/Ph

30

The addition of trimethylsilylketene to an ot-ketoester in the presence of a C2-symmetric bis(oxazoline)-Cu(II) complex affords 4-substituted 2-oxetanone 4-carboxylates in high yield and with 83-91% ee. These [3-1actones react with soft nucleophiles to give acyclic [3substituted carboxylic acids <010L2125>. Carbonylation of simple and functionalised oxiranes (e.g. 31) occurs in the presence of bis(triphenylphosphine)iminium cobalt tetracarbonyl, [(C6Hs)3P].,NCo(CO)4, and boron trifluoride etherate to give J3-1actones (e.g. 32). Carbonylation occurs selectively at the unsubstituted C-O bond and stereochemistry is retained. In contrast, the carbonylation of aziridine with CO in the presence of cobalt octacarbonyl causes inversion of configuration <01JOC5424>. Interestingly, the new iminium catalyst also caused inversion of configuration when applied to the carbonylation of aziridines, so raising the question of the significant mechanistic difference between the carbonylation of the two heterocycles <00H2379>.

79 o

/\

,,R .... R

"-

31

32

The Wynberg [3-lactone synthesis, which requires the use of a ketene generator and an activated aldehyde (e.g. 33) has been investigated and improved. It has been found that an external source of ketene is not a necessity because in situ generation of ketene from acetyl chloride by quinidine and Hfinig's base provides ]3-1actones from suitably activated aldehydes in good yield and high ee (e.g. 94 % for 34) <00JOC7248>.

PhC I / ' ~ CHO+ AcCI CI

base

PhH2C-,~/0

c,->~cI

33

34

The same group of workers has proceeded to develop an intramolecular version of the reaction. The aldehyde acids (35, n - 1 or 2) on treatment with Mukaiyama's reagent, 2chloro-l-methylpyridinium iodide, and triethylamine afforded the cis substituted bicyclic lactones (36, n = 1 or 2). The authors have adduced evidence in support of a nucleophilecatalysed aldol lactonisation (NCAL) reaction mechanism rather than the alternative thermal [2+2] cycloaddition. They have also found that the intramolecular reaction, like the intermolecular process, is subject to asymmetric catalysis. When an optically active base such as O-acetylquinidine was present in the reaction mixture, the bicyclic lactones were produced with high ee <01JA7945>. H

/CO2H R~CHO 35

4.4

R

/0 O~

,,.._

36 H

DITHIETES, DITHIETANES, THIETES AND [3-SULTAMS

A review, which includes the chemistry of 1,2-dithietes and 1,2-dithietanes, is available <00AHC221>. The dithiete 37 is one of three products obtained after chromatography when diadamantylacetylene reacts with S2Cl 2 <00TL8349>. The cycloaddition reaction of the ynamine 38 with an aryl isothiocyanate affords the 2Hthietamine 39 in high yield when the ynamine is stable <01SL361>. Thietanylureas are available from thietanyl 3-isocyanate <00MI565>.

80

O S~S

O SS NR2

R

R

37

ArN

38

39

The chemistry of [3-1actams, 13-sultams and ]3-phospholactams has been compared and the potential of the last two as mechanism based inhibitors of bacterial and mammalian proteases discussed <00T5631 >.

4.5

SILICON, PHOSPHORUS AND SELENIUM HETEROCYCLES

A review of the effects of substituents on the reactivity of the silicon-carbon bond in silacyclobutanes and silacyclobutenes when probed by laser flash photolysis has appeared <01ACR 129>. Zirconocene-induced bicyclisation of the diacetylene 40 yielded 41, which was a starting material for the synthesis of 42 and 43 by reaction with acetylene dicarboxylate and benzyne, respectively <00CL 1082>. Me2Si ~

I][

iMe 2

Me2Si-- SiMe 2 MeO

I~11

MeO

OMe MeO 40

Me2Si-- SiMe 2

OMe 41

--

Me02C

Me2Si-- SiMe 2 OMe MeO

OMe

C02Me 42

43

The reaction of the cyclic sulfates 44 of symmetrical anti-l,3-diols and 1,2-bis(phosphino)ethane yielded 1,2-bis(phosphetano)ethane 45 <01JOM 162>.

~---p

"'"~R

p

L f~

.-"

-l 45

R

Diphosphine 46 undergoes valence isomerism at 120 ~ to give mainly the Dewar-l,3diphosphine 47 <01S463>. Selone 48 undergoes addition to benzyne to afford the first isolated benzoselenete derivative 49 <01JA7166>.

81 TMS. p / P u B u t

But~~

P

,

Bu t

46

47

Se 48

49

Synthesis of the first stable spiro selenarane 50 has been achieved and its pyrolysis provides the oxirane 51 by elimination of elemental selenium. This behaviour is in contrast to that found for the analogous phosphorus and silicon compounds <01 CC463>. CF 3

, L _ Se--q"" PhS'" I ~

O-~CF 3

50

4.6

_

A

2

/\/0 ~ PhS"

CF3 CF3

+ Se

CF3

MONOCYCLIC 2-AZETIDINONES (I3-LACTAMS)

Reviews of [3-1actam chemistry include the use of enolate chemistry in asymmetric synthesis <00RHA33>, the utility of 4-formyl-13-1actams as synthons in stereocontrolled syntheses <01CSR226> and the use of [3-1actams in the synthesis of complex nucleoside antibiotics and macrocyclic peptides <00PAC 1763>. The stereochemistry of products obtained from the Staudinger reaction and the mechanism by which they are formed continue to be topics of interest. The cycloaddition of ketenes and N-silylimines has been subjected to density-functional theory studies. This shows that the first reaction is nucleophilic addition of the iminic nitrogen atom to the sp-hybridised carbon atom of the ketene with migration of the silyl group to the oxygen atom so yielding the Osilyl intermediates, in agreement with the experimental observations. The second process consists of a conrotatory thermal electrocyclisation and a silatropic rearrangement to give the N-silylated ]3-1actam. However, N-silylimines have a lower activation barrier to isomerisation than that for the formation of the N-C bond, which explains the poor stereocontrol found in these reactions <00JOC8458>. In general, the level of asymmetric induction achieved with imines derived from achiral aldehydes and chiral amines is lower than that observed when a chiral aldehyde or chiral ketene is used. Nevertheless, threonine-derived imines 52 give the cis-[3-1actams 53 with diastereoselectivity which increases as the size of the protecting group on the hydroxyl group increases <00SC3685>.

82 Me02C

Me02C 1

CI

M ~ N ~ CO2Me CICH2COCI-TEA _ TBDMSO ? ~ O TBD O

52

Me

Me

53

:"CO2Me

Acyloxy- or alkyloxy-acetyl chlorides in the presence of triethylamine and the imine 54 (R 1 = R 2 = H) yielded the cis-~-lactam as expected. However, when the imine 54 (W = polycyclic aromatic, R 2 = monocyclic aromatic) was used the product was the trans isomer <00TL6551 >. Staudinger reactions have been used to obtain [3-1actams as substituents on quinones (e.g. 55) <01TL1503> and as spiro compounds (e.g. 56) <00IJC(B)304>. The N,N-dialkylhydrazone 57 was used to obtain 58, which was N-deprotected in high yield with magnesium monoperoxyphthalate in methanol to give the 1,4-unsubstituted [3-1actam <00AG(E)2893>.

O

CI

H H

R2 N~R1

~

O

C~

N

N, II CH2

O

. ~ N'Ar N "O Me

55

54

If

56

PhCH20xjz__._ . MeO Et NI ~//---Et

OMe \~'Et et

57

58

Reaction of the hydrobenzamide 59, formed from the aromatic aldehyde and aqueous ammonia, with azidoacetyl chloride and base yielded 60, which on being stirred with silica gel was converted to 61 in good yield. An experimental system was developed for the recycling of the mother liquors remaining after the isolation of the hydrobenzamide. 3Hydroxy-4-phenyl-[3-1actam is available by this route and is a synthon for the C-13 side chain of taxol and its analogues. Ammonium chloride enriched ~SN is readily available and it is therefore possible to label the [3-1actams using the 'green' chemistry developed <01 MI493>.

% pAr

R1

N--CHAr / ARCH\ Nm CHAr 59

)_,

O

N

Ar

~ N .~ Ar H 60

R1% pAr /~1 NH O 61

Two alternatives to an acid chloride and base as the starting material in these reactions are the use of trichloroacetonitrile-triphenylphosphine reagent on the acid <00SC4177> or the

83 action of propane phosphonic acid anhydride on glycine 'Dane salt' (the condensation product of glycine sodium salt with methyl acetoacetate).<00SC3737>. Perhaps the most obvious approach to 13-1actams is by cyclisation of an appropriate amino acid. Reagents used recently to cause amide formation include phenylphosphonic dichloride <01T1883> and a mixture of triethylamine, 2,2'-dipyridyl sulfide and triphenyl phosphine (Ohno's reagent) <00JOC8372>. Other approaches from acyclic precursors are through the formation of the 1,4- or 3,4bonds of the lactam. The former can be achieved by nucleophilic attack of the amide nitrogen on an activated carbon atom. A suitable [3-substituent in the amide is a hydroxyl group and cyclisation can be accomplished by the action of carbon tetrachloride-triphenylphosphine in the presence of a base <00T5719>, by use of the Mitsunobu reaction conditions <01TL1247>, or by formation of the mesylate and subsequent treatment with base to activate the amide. Investigation of this last process with amide 62 has shown that both 63 and 64 are formed in the ratio of 1:50, respectively <00TL8539>. MesO

O

~

NH ~ ~ , But

TBDPSO

1)ButOK HO 2)TBAF =

O

~

62

N 1

Bu t -F

~ O HO N ~ ,,But

~'"

63

64

Resin bound hydroxylamine has been converted to the amides of[3-hydroxy acids 65. These amides can be cyclised by the Mitsunobu procedure, the amino substituent deprotected and a peptide chain assembled to give 66. The lactam can then be cleaved from the resin by reduction with samarium iodide <01OL337>.

HO. O"" O" H ' ~

R2

R2

NHpeptide

Q'~'O" N

NHR'

O 65

O 66

Formation of the 3,4-bond of the lactam from threonine derivative 67 uses the acidity of the methine group <01TA89>. Similarly, 68 contains an activated methine carbon atom and cyclisation under basic conditions provides a simple route to 3-unsubstituted-4-alkyl-2azetidinone 4-carboxylic acids 69 <01JOC3538>.

AcO .-

/.

CO#e R

67

CI/~,.~N~R 3 O 68

ste s

00 .

O

69

Chiral bisoxazolines, a chiral diaminoether and an aminodiether have been used to catalyse the asymmetric condensation of lithium enolates with imines to provide enantioselectivity in the formation of 3,3-dimethyl-4-substituted-2-azetidinones <00CPB1577,00MI125>.

84 Lithium enolates from the already formed [3-1actam 70 undergo [1,2]- and ortho [2,3]-Wittig rearrangements to afford routes to 71 and 72, respectively <01 OL2529>. Me

T.

Ph

OH Ph

F3c

OH

....

, .....

RN--~

70 O

RN-~

71 O

L=#_ 9

72 O

Bromoenamides 73 undergo a 4-exo-bromine atom transfer radical cyclisation to the lactams 74 in the presence of copper(I) bromide-tripyridylamine complex <01TL4409>. It would be advantageous if the use of reagents containing toxic metals could be avoided in the manufacture of pharmaceuticals. In an attempt to develop 'cleaner' radical cyclisation procedures, the action of di-tert-butyl peroxide on 1-carbamoyl-1-methylhexa-2,5-dienes (e.g. 75) has been investigated. The radical formed breaks down by loss of toluene (rather than the alternative route by loss of a methyl radical) to give the aminoacyl radical 76, which yields the lactam 77 (34%) and the formamide 78 <00CC2327>.

phH2C\ N./..,.~.~ ~ BO'~-

Me Mle __

M ~ ~ :~O

/ Br O/~ --NR 74

I 71~

75

\ O/,~'---- V Ph

-

76

77

v

Ph

0, ~ N ~ P h 78

N,N-Dialkylarylglyoxylamide 79 carrying an ionic chiral auxiliary can be photochemically converted in the solid state and with high enantioselectivity to 80. When the crystals are suspended in hexane, the process can be performed on a 500 mg scale <01S1253>. OH

+

N 79

4.7

co/

Ph

HaN~,,Me

H

hv _ __

....

-'~

CeH4CO2Me-4

o

80

BI- AND TRI-CYCLIC [3-LACTAMS

Structural aspects of carbapenem antibiotics have been reviewed <01 H497>. Photochemical cyclisation of N-methylacryloylthiobenzanilide 81 in the solid state gave 82 <01T6713>.

85 R1

S

R

o

Ph

Ph

R3

R1 /

R3

~R2 "~ O

81

82

Carbapenems having a conjugated diene system are obtained from suitably 1,4disubstituted 13-1actams 83 by use of a ruthenium complex catalyst. The unsaturated system can be of use in the formation of tricyclic nuclei <00OL3245, 01 TL2461 >. Thioesters 84 have been cyclised by triethyl phosphite to carbapenems with heteroarylthio substituents <01SC587>. A novel carbapenem 85 shows broad spectrum activity against gram-positive organisms (including MRSA type) <01 CPB476>. R2

I O

H H [

,

N ~ R

S

HO| .H H

Me

r

s

,

O O~,.CO2PN B

83

84

CO2H

85

Allyl protecting groups are advantageous in the synthesis of penicillin N and isopenicillin N <00T7601>. Further investigations and evaluation of the azomethine ylide strategy for bicyclic 13-1actamsynthesis have been reported <01JCS(P 1) 1281 >. The bicycles 87 (R = OMe or N-phthalimido) are obtained by the action of iodine on compounds 86, which are reported to possess potent antimicrobial activity <00T5571 >. H_ H_

H _':' H ':'

i-

O//

Ph

"SMe 86

R

O

9

/

"

'

R~ Ph

87

Br H ~ ~/S

H H R " ....

"

"

, ~ N

O

88

CO2R2

CO2R2 89

Stereoselective reduction of 6-bromopenicillins 88 by tributylphosphine in methanol afforded 89 through formation of an intermediate phosphonium [3-1actam enolate species and subsequent diastereoselective protonation <00OL2889>. The synthesis of (6S)-cephalosporins from 6-aminopenicillanic acid derivatives 90 has been achieved by two routes. The Morin penam sulfoxide-cephem rearrangement was shown to be a practical method for the preparation of cephalosporins 91 with unnatural configurations <00T6053>. Cephalosporins form the host lattice and naphthalene derivatives are the guest molecules when complexes form. 2-Naphthol can be used to extract cephalosporins selectively from aqueous solutions by complex formation <01JCS(P2)633>. 2,7-Dialkylidenecephalosporin sulfones 92 are reported to be potent class C lactamase inhibitors <00T5709> and other cephalosporin sulfones show human elastase inhibiting abilities <00CHE1232, 01EJM185>. Many novel cephalosporins have been reported as a

86 result of the search for antibiotics active against MRSA bacteria <00T5657, 00JAN1045, 00BMC2781, 01JAN257, 01JAN364, 01BMCL137, 01BMCL797>. _

O PhthalN !+ ",.. . . . . S

PhthalN ,,

o.~N~

,,,S.,,h ~--~N'~

O~

H

~

R

O

".~ S CH2

O/~-- N "~-"%" Me

CO2R 91

90 co2m

O

"

92

CO2H

Nucleophilic and radical chemistry of benzyl selenides has been used in the preparation of 93 and 94 <01TL4737>. Baylis-Hillman adduct 95 undergoes chemo- and stereo-controlled divergent radical cyclisation to give highly functionalised medium-sized rings fused to a 13-1actam 96 <01JOC1612>.

OAc

SeCHzPh

O.~___#H

2 steps

O~ N ' ' v ' ' ' ' ~ ' / '

Se Bu3SnH~- o ~ N ' ~

93

94

OH H H " Ac

OH PhO I

~,...~,. Ac

oJ-

PhO

\

0-

95

96

\

SnPh3

A review of tricyclic 13-1actams has appeared <00MII5>. Several methods have been employed to obtain tficyclic lactams including the [2+2] cyc]oaddition of indene and an isocyanate <00TA4179>, the Wittig cyclJsation of suitably ],4-disubstJtuted 13-lactams <00T5649>, base induced intramolecular reaction of the 13-lactam nitrogen atom at an activated carbon atom to yield, for instance, 97 <01TA979>, and the [2+4] cycloaddition of dimethyl acetylenedicarboxylate with bicyclJc 13-lactam dienes (e.g. 98) to give (e.g. 99) <0]TL2461>. H H

O'

i

97

H

TBDMSO

H

O

TBDMSO

98

O'/'/-- I~''''/

CO2Me

99

More unusual structures have been obtained by photolysis of the bicyclic pyridone 100 to yield 101 <00JCS(P1)4373>, and the radical cyclisation of 1-substituted-4-methylenecyclopropyl-[3-1actams to afford 102 <00TL 10347>.

CH2OEs ~N~M e O 100CO2Et

H r-~m~sOEt O--~N~'~Me CO2Et 101

TBSO

87

102

R

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88 00T5649

S. Bondi, A. Pecunioso, F. Busi, S. A. Contini, D. Donati, M. Maffeis, D. A. Pizzi, L. Rossi, T. Rossi, F. M. Sabbatini, Tetrahedron 2000, 56, 5649. 00T5657 A.N. Pae, J. E. Lee, B. H. Kim, J. H. Cha, H. Y. Kim, Y. S. Cho, K. Choi, H. Y. Koh, E. Lee, J. H. Kim, Tetrahedron 2000, 56, 5657. 00T5709 J.D. Buynak, V. R. Doppalapudi, M. Frotan, R. Kumar, A. Chambers, Tetrahedron 2000, 56, 5709. 00T5719 A. Bulychev, J. R. Bellettini, M. O'Brien, P. J. Crocker, J.-P.. Samama, M. J. Miller, S. Mobashery, Tetrahedron 2000, 56, 5719. 00T6053 T. Fekner, J. E. Baldwin, R. M. Adlington, T. W. Jones, C. K. Prout, C. J. Schofield, Tetrahedron 2000, 56, 6053. 00T7601 R . M . Lau, J. T. H. van Eupen, D. Schipper, G. I. Tesser, J. Verweij, E. de Vroom, Tetrahedron 2000, 56, 7601. 00T9227 G.R. Krow, J. Yuan, Y. Fang, M. D. Meyer, D. J. Anderson, J. E. Campbell, P. J. Carroll, Tetrahedron, 2000, 56, 9227. 00T9233 G.R. Krow, J. Yuan, Q. Huang, M. D. Meyer, D. J. Anderson, J. E. Campbell, P. J. Carroll, Tetrahedron 2000, 56, 9233. 00TA4179 F. Fulop, M. Palko, J. Kaman, L. Lazar, R. Sillanpaa, Tetrahedron. Asymmeoy 2000, 11, 4179. 00TL6551 B.K. Banik, F. F. Becker, Tetrahedron Lett. 2000, 41, 6551. 00TL8349 J. Nakayama, K. Takahashi, T. Watanabe, Y. Sugihara, A. Ishii, Tetrahedron Lett. 2000, 41, 8349. 00TL8539 O. Kitagawa, M. Fujita, M. Kohriyama, M. Hasegawa, T. Taguchi, Tetrahedron Lett. 2000, 41, 8539. 00TL10295 M. Karikomi, N. De Kimpe, Tetrahedron Lett. 2000, 41, 10295. 00TL10347 D.J. Penfold, K. Pike, A. George, M. Anson, J. Kitteringham, J. D. Kilburn, Tetrahedron Lett. 2000, 41, 10347. 01ACR129 T.L. Morkin, W. J. Leigh, Acc. Chem. Res. 2001, 34, 129. 01BMCL137 A. Cho, T. W. Glinka, M. Ludwikow, A. T. Fan, M. Wang, S. J. Hecker, Bioorg. Med. Chem. Lett. 2001, 11, 137. 01BMCL797 D.M. Springer, B.-Y. Luh, J. J. Bronson, Bioorg. Med. Chem. Lett. 2001, 11,797. 01CC463 F. Ohno, T. Kawashima, R. Okazaki, J. Chem. Soc., Chem. Commun. 2001, 463. 01CC958 I. Ungureanu, P. Klotz, A. Schoenfelder, A. Mann, J. Chem. Soc., Chem. Commun. 2001, 958. 01CPB476 H. Imamura, A. Shimizu, H. Sato, Y. Sugimoto, S. Sakuraba, K. Yamada, H. Morishima, Chem. Pharm. Bull. 2001, 49, 476. 01CSR226 B. Alcaide, P. Almendros, Chem. Soc. Rev. 2001, 30, 226. 01EJM185 A. Balsamo, G. Cercignani, D. Gentili, A. Lapucci, M. Macchia, E. Orlandini, S. Rapposelli, A. Rossello, Eur. J. Ailed. Chem. 2001, 36, 185. 01H497 M. Sunagawa, A Sasaki, Heterocycles 2001, 54, 497. 01JA7166 K. Okurna, A. Okada, Y. Koga, Y. Yokomori, J. Am. Chem. Soc. 2001, 123, 7166. 01JA7945 G.S. Cortez, R. L. Tennyson, D. Romo, J. Am. Chem. Soc. 2001, 123, 7945. 01JAN257 T. Ishikawa, K. Kamiyama, Y. Nakayama, Y. Iizawa, K. Okonogi, A. Miyake, J. Antibiot. 2001, 54, 257. 01JAN364 T. Ishikawa, Y. Nakayama, M. Tomimoto, S.-I. Niwa, K. Kamiyama, S. Hashiguchi, Y. Iizawa, K. Okonogi, A. Miyake, J. Antibiot. 2001, 54, 364. 01JCS(P1)1281 G.A. Brown, S. R. Martel, R. Wisedale, J. P. H. Charmant, N. J. Hales, C. W. G. Fishwick, T. Gallagher, ,I. Chem. Soc., Perkin Trans. 1 2001, 1281. 01JCS(P2)633 G . J . Kemperman, R. de Gelder, F. T. Dornmerholt, P. C. Raemakers-Franken, A. J. H. Klunder, B. Zwanenburg, J. Chem. Soc., Perkin Trans. 2 2001, 633. 01JOC1612 B. Alcaide, P. Almendros, C. Aragoncillo, J. Org. Chem. 2001, 66, 1612. 01JOC1805 G.R. Krow, Y. B. Lee, W. S. Lester, N. Liu, J. Yaun, J. Duo, S. B. Herzon, Y. Nguyen, D. Zacharias, J. Org. Chem. 2001, 66, 1805. 01JOC1811 G.R. Krow, W. S. Lester, Y. J. Liu Nian, A. Hiller, J. Duo, S. B. Herzon, Y. Nguyen, K. Cannon, J. Org. Chem. 2001, 66, 1811. 01JOC3201 A. Mordini, S. Bindi, A. Capperucci, D. Nistri, G. Reginato, M. Valacchi, J. Org. Chem. 2001, 66, 3201. 01JOC3538 G. Gerona-Navarro, M. A. Bonache, R. Herranz, M. T. Garcia-Lopez, R. Gonzalez-Muniz, J. Org. Chem. 2001, 66, 3538.

89 01JOC4732 01JOC5424 01JOM162 01MI493 01OL337 01OL2125 01OL2529 01S463 01S1203 01S1243 01S1253 01SC565 01SC587 01SL361 01SL967 01T1883 01T2621 01T6713 01TA89 01TA605 01 TA979 01TL1247 01TL 1503 01TL2373 01TL2461 01 TL4409 01TL4737

M. R. Iesce, F. Cermola, F. De Lorenzo, I. Orabona, M. L. Graziano, ft. Org. Chem. 2001, 66, 4732. J. T. Lee, P. I. Thomas, H. Alper, J. Org. Chem. 2001, 66, 5424. A. Marinetti, S. Juo, J.-P. Genet, L. Ricard, J. Organomet. Chem. 2001, 624, 162. S. H. Park, S. Y. Lee, A. K. Bose, Bull. Korean Chem. Soc. 2001, 22, 493. M. M. Meloni, M. Taddei, Org. Lett. 2001, 3, 337. D. A. Evans, J. M. Janey, Org. Lett., 2001, 3, 2125. A. Garbi, L. Allain, F. Chorki, M. Ourevitch, B. Crousse, D. Bonnet-Delpon, T. Nakai, J.-P. Begue, Org. Lett. 2001, 3, 2529. M. A. Hofmann, H. Heydt, M. Regitz, Synthesis, 2001, 463. W. Adam, V. R. Stegmann, Synthesis, 2001, 1203. M. Abe, K. Tachibana, K. Fujimoto, M. Nojima, Synthesis 2001, 1243. J. R. Scheffer, K. Wang, Synthesis 2001, 1253. G. Lai, Synth. Commun. 2001, 31, 565. P. Bitha, Y.-I. Lin, Synth. Commun. 2001, 31,587. C. Y. Yoo, E. B. Choi, C. S. Pak, S)'nlett 2001, 361. M. P. Doyle, E. J. May, Synlett 2001, 967. J. Escalante, M. A. Gonzalez-Tototzin, J. Avina, O. Munoz- Muniz, E. Juaristi, Tetrahedron 2001, 57, 1883. M. M.-C. Lo, G. C. Fu, Tetrahedron 2001, 57, 2621. M. Sakamoto, M. Takahashi, T. Mino, T. Fujita, Tetrahedron 2001, 57, 6713. Z. Santa, L. Parkanyi, I. Nemeth, J. Nagy, J. Nyitrai, Tetrahedron. Asymmeoy 2001, 12, 89. G. Guanti, R. Riva, Tetrahedron." Asymmeoy 2001, 12, 605. K. Borsuk, K. Suwinska, M. Chmielewski, Tetrahedron. A~ymmeoy 2001, 12, 979. C. T. Brain, A. Chen, A. Nelson, N. Tanikkul, E. J. Thomas, Tetrahedron Lett. 2001, 42, 1247. B. Alcaide, P. Almendros, N. R. Salgado, Tetrahedron Lett. 2001, 42, 1503. D. De Smaele, Y. Dejaegher, G. Duvey, N. De Kimpe, Tetrahedron Lett. 2001, 42, 2373. R. Duboc, C. Henaut, M. Savignac, J.-P. Genet, N. Bhatnagar, Tetrahedron Lett. 2001, 42, 2461. A. J. Clark, G. M. Battle, A. Bridge, Tetrahedron Lett. 2001, 42, 4409. M. W. Carland, R. L. Martin, C. H. Schiesser, Tetrahedron Lett. 2001, 42, 4737

90

Chapter 5.1

Five-Membered Ring Systems" Thiophenes & Se, Te Analogs Erin T. Pelkey Hobart and William Smith Colleges, Geneva, NY, USA [email protected]

5.1.1 INTRODUCTION The chemistry and syntheses of thiophenes, benzo[b]thiophenes, and related selenium and tellurium ring systems that has been reported during the past year (Jan-Dec 2001) is the primary focus of this review. Many aspects of thiophene chemistry have been reviewed during the past year <01AM545, 01JHC809, 01OM1259>, and general reviews of heterocyclic chemistry <01JCS(P1)2491, 01JCS(PI)2885> and sulfur compounds <01JCS(P1)335> have also included sections on thiophenes. 5.1.2 THIOPHENE RING SYNTHESIS One strategy for preparing new thiophene-containing materials involves adding Lawesson's reagent or P4S,0 to 1,4-dicarbonyl compounds. This reaction has been reported for making 2-arylthiophenes under microwave conditions <01JOC7925>, 1,3-dithiole-fused terthiophenes <01SM115>, dithiophenes <01H(55) 1487>, alkoxythiophenes <01JOC7283>, biphenylthiophenes <01JMAC3068>, and thieno[2,3-d]thiazoles <01S413>. A novel sulfurbridged heterocycle, trithiapentalene 2, was prepared by thiolation of keto dienamine 1 with Lawesson's reagent or P4S,0 <01SL1129>. The addition of disodium trithiocarbonate to quinoxaline 3 unexpectedly led to the fused thiophene, thieno[2,3-b]quinoxaline 4, rather than the expected fused 1,3-dithiole (formed by replacement of the dibromide) <01JCS(P1)154>. The reaction between acrylic acids and thionyl chloride led to 3chlorobenzo[b]thiophene-2-carbonyl chlorides <01H(55)741> including a benzo[2,1-b:4,5b']dithiophene <01 SC2997>. reagent or P4S10 Me2N

0 1

Br

N

NMe2 2

Ph Na2CS3__

~N

N

N

3

4

h

Intramolecular condensation reactions of activated thiol compounds (e.g., ct-thioglycolate derivatives) have been utilized to prepare fused thiophene compounds. For example, treatment of imine 5 with methyl thioglycolate gave the nucleophilic aromatic substitution

91

Five-Membered Ring Systems." 171iophenes& Se, Te Analogs

product 6 which underwent an intramolecular condensation followed by aromatization to give 4,6-dinitrobenzo[b]thiophene 7 <01HC283>. Similar intramolecular condensation reactions were utilized to prepare thieno[2,3-blthiophenes <01JHCl167>, thieno[2,3-c]pyridines <01JMC988>, 5-nitrobenzo[b]thiophenes <01JHC1025>, thiophene-3-carboxylates <01JOC2493>, benzo[b]thiophenequinones <01H(55)2423>, and complex thiophene-2carboxamides <01T7213>. An improved synthesis of thiophene-3-carboxaldehyde involved the condensation of thioacetaldehyde dimer with acrolein followed by aromatization with sulfuryl chloride <01SC1527>. A novel synthesis of 5-oxa-ll-thia-benzo[b]fluoren-10-one (11) was reported involving the combination of thiosalicylate 8 with ot-bromoacetophenone 9 <01TL8429>. The reaction most likely proceeds via an intermolecular alkylation to 10, intramolecular cyclization, and an ipso substitution. An interesting rearrangement leading to dihydrothienocoumarin 15 occurred upon treatment of chromene 12 with ethyl glycolate <01TLSl17, 01TL5121>. The initial conjugate addition of the thiol onto enone 12 apparently gives tricyclic intermediate 13 which undergoes a ring opening to give phenol 14 followed by an intramolecular lactonization to 15.

NO2~I'Ph 1 K2003,MeCN .,~N02 /NHPh NO2p "~S "~N HSACO2Me 2:[0] . L IL s O2N 02 K2CO3,MeCNO2N ~CO2M: 02N" ~ "S" 'CO2Me ~6'Ph

5

6

~CO2Et ~ "SH Br

Cs2CO3 F CO2EtF, .. "] DMF l ~ 1 O~ ~ ~ 1

4-

8

7

.....

O

i,

9

~

~ S 11 O OF3

~""~O""'CF3 Et3N 12

L "
~ O H C02Et 14

15

The Gewald reaction consists of a three component condensation between an activated nitrile, ketone or aldehyde, and sulfur and has been utilized to prepare a variety of aminothiophenes <01SC3113>. One of the first (if not the first) de novo syntheses of the thiophene ring on the solid-phase involved a Gewald reaction <01TL7181>. Thus, treatment of resin-bound nitrile 16 with cyclohexanone and sulfur gave intermediate aminothiophene 17. Acetylation and cleavage of the resin cleanly provided tetrahydrobenzo[b]thiophene 18. The condensation of the dimer of c~-mercaptoacetaldehyde and sulfone 19 proceeded to give 2-aminothiophene 20 <01BMCl123>. Modified Gewald conditions (condensation of thioglycolates with unsaturated nitriles) have been utilized to prepare 3aminobenzo[b]thiophenes <01TL8539>, 2-aminothiophenes <01JCS(P1)144>, and 3aminothiophenes <01BMCL9, 01BMCL915, 01BMCL2205>. An approach to 2-amino-45-

92

E.T. Pelkey

dihydrothiophenes involved the reaction of sulfur ylides with arylidenecyano-thioacetamides <01SC1647>. The condensation of benzotriazole 21 with phenyl isothiocyanate followed by heterocyclization gave 2-aminothiophene 22 <01JOC2850>. Related sequences involving isothiocyanates have been reported in the connection with the synthesis of thieno[2,3b]pyrroles <01SL1731> and 2-aminothiophenes <01TL4687>. The double condensation of 1,3-dichloroacetone (23) with thioacrylamide 24 gave bis(2-amino-5-thienyl)ketone 25 which was utilized as a building block for the preparation of novel thiophene-containing analogues (e.g., 26)of Crystal Violet dyes <0lAG(E)3008>.

o

>o

,,,c.~~

morpholine, S8

S

EtOH

16

HS " ~ NCvSO2Ph

H

o,L: ,Acc,c,,~c,~o,A

.~

17

.SO2Ph

o

DBU

NH2

19

20

O

21

S

CH2CI2

ln-~ I

lZn'

S

~O

NHPh 22

_ Me2

O

CH3CN Me2N

18

(Bt = benzotriazole)

NMe2

CI CI +Me2N 23 24

2. TFA, H20

Me2

: Me~lC I O ~

NMe2

25

Lewis acid-catalyzed cyclizations have been utilized to prepare novel fused thiophene derivatives. Treatment of benzo[b]thiophene 27 with zinc chloride led to the formation of thieno[2,3-b]benzothiophene 28 <01JCS(P1)2483>. Side chain functionalization of 28 was accomplished using benzotriazole chemistry. This type of cyclization reaction was also utilized to prepare additional fused thiophenes including naphtho[1,2-b]thiophenes, naphtho[2,1-b]thiophenes, and thieno[2,3-b]thiophenes. An intramolecular Friedel-Crafts acylation of mercaptan 29 gave thioindoxyl 30 which was further elaborated into novel hemithioindigo derivatives 31 <01JOC2966>. Similar intramolecular cyclization reactions were utilized to prepare 2,3-diarylbenzo[b]thiophenes <01HC271> and novel thiophenecontaining diphosphane ligands <01S2327>.

O~B S~

t

ZnCI2, PhH ~ (Bt = benzotriazole)

27

28

1. SOCI2 B r , ~ - - ~ O.~OH 2..AICI3 . B r ~ O "S / 29

Z ~-Bt S S

== R.,.~

.,.~~O,.[~,.OCeH 13 S

30

31

93

Five-Membered Ring Systems." Thiophenes & Se, Te Analogs

Electrophile-mediated (Br2, NBS, I2, PhSeCI,p-NO2C6H4SCI) cyclizations of mercaptans (ArSMe) onto adjacent alkynes gives 3-substituted benzo[b]thiophenes which can be further elaborated <01TL6011>. Iodocyclization of mercaptan 32 gave 3-iodobenzo[b]thiophene 33 which underwent a Negishi coupling with organozinc chloride 34 to give 2,3diarylbenzo[b]thiophene 35 <01OL651>. This reaction sequence was also applied to the synthesis of 2,3-diarylthiophenes (analogues of Combretastatin A-4) <01BMCL2341>. The flash vacuum pyrolysis of alkynes leading to benzo[b]thiophene resulted in a multi-step cascade reaction leading to a 7-(2-benzothienyl)benzofuran <01SL228>.

(,~'~r/OMe / / / J/J.~

OMe ~ /OMe CIZnl/~M e

,

MeOAL~~SB r~'Y/'~ n 12' - 0H20 I M e o ~ s ~ P d ( P p h 4 3 2 ) C, ~i 32

33

~

OMe ~OMe

MeO~S~

"OM e

-'~OMe

35

""P"

"OMe

The cycloaddition between C60 and the thiocarbonyl ylide derived from 36 gave tetrahydrothiophene-C60 adduct 37 <01TL1737>. The cycloaddition between 1,4naphthoquinone (38) and thiazolidine 39 gave dihydrothieno[2,3-b]naphtho-4,9-dione 40 <01TL5755>. Heating trisulfide oxide 42 in the presence of myrcene (41) leads to cycloadduct 43 via transfer of sulfur monoxide to the diene. Dehydration of 43 with trifluoroacetic anhydride (Pummerer reaction) gave thiophene 44 <01OL3565>. COaEt

O

"'O

II C6o,heat /S~ Me3Si SiMe3

O

36

37

38

39

S

Ag2CO3,DBU

O2Et 40

o

41

II 42

0 43

44

5.1.3 THIOPHENE RING SUBSTITUTION The elaboration of unsubstituted o~-positions of the thiophene ring system continue to be reported using electrophilic aromatic substitution reactions including bromination with NBS <01CC1274, 01EJO3437, 01JAIl600, 01JCS(P1)740, 01MM7331>, bromination with Br2 <01CC1628, 01H(55)171>, chlorination with NCS <01OL2129>, and iodination with NIS/CH3CO2H <01JHC923, 01SL634>. A thorough investigation of the bromination of fluorothiophene 45 yielded regioselective methods for the preparation of dibromothiophene

94

E. 7". Pe/kev

47 (10 equiv. Br2, FeBr3) or 4-bromothiophene 48 (1.5 equiv. Br:, AICl 3, FEB%) depending on the reaction conditions <01TL8797>. The benzylation of silylated thiophenes proceeded with retention of the silyl group in the presence of proton sponge <01 OL1629, 010L 1633>. Tert-butylation of electron deficient thiophenes was reported by photolysis with tertbutylmercury(II) chloride <01JCS(P1)2035>. Under high dilution conditions, two dialkoxythiophenes 49 were linked together to give bis(thiophene) 50 via a double Mannich reaction <01JCS(P1)2595>. The Friedel-Crafts acylation of 5-substituted benzo[b]thiophenes was studied with a variety of acylating agents <01JHC1025>.

~

F

bromination F Br. F Br ~conditions, ~ . + .,~ CO2Me Br CO2Me Br O2Me +

45

46

~

47

MeNH2,formaldehyde,H2O

F CO2Me 48

~ ' ~ N Me .~

49

50

Sulfur oxidation of the thiophene ring to either thiophene-l-oxides or thiophene-l,1dioxides modifies the chemistry of thiophene ring <01CM4112, 0102487>. A new method for preparing electron deficient thiophene-l,l-dioxides utilized trifluoroperacetic acid as the oxidant <01TL4397>. The conversion of thiophene-l-oxide 51 to the corresponding Nunsubstituted thiophene-l-imide 54 was reported using a three-step procedure <01TL8461>. The preparation of the first heterocyclic sulfanenitrile (containing an S-N triple bond) was reported with a dibenzothiophene <01TL5041>.

t-Bu t-Bu ~ ~TFAA'. B~ .

.

t-Bu

TFA

O

NBoc

51

52

II

t-Bu

t-Bu II

CF3002C)

t-Bu

~

t-Bu~t-Bu

NaOH

NH2

NH

53

54

II

Nucleophilic aromatic substitution of the thiophene ring has been reported in the presence of different electron withdrawing groups. The reaction of 5-bromo-2thiophenecarboxaldehyde with various heteroatom nucleophiles provided thiophene-based building blocks for the preparation of PAI-1 (plasminogen activator inhibitor-I) inhibitors <01BMCL2589>. Treatment of 3-bromo-2-nitrobenzo[b]thiophene (55) with aniline (56) in the presence of a base gave a mixture of 57 and an unexpected rearrangement product 58 <01T8903>. The effect of solvent and base on this reaction was investigated and the redox potential of compounds related to 57 was reported separately <01T1857>. Treatment of 2fluoro-3-trifluoromethylthiophene 59 with the sodium salt of benzyl alcohol gave the substitution product 60 which upon heating underwent [1,3]- and [1,5]-benzyl group migrations to give 2(3H)-thiophenone 61 and 2(5H)-thiophenone 62, respectively <01M929, 01TL1657>.

95

Five-Membered Ring Systems: Thiophenes & Se, Te Analogs

/ Br

base , ~,_

+

55

N

56

57

CF 3 Ph

F

+ 58

CF 3 Nail, THF

Ph

59

CF3 ''~

O~Ph

CF 3 + Ph

Ph

60

61

62

A general method for preparing a-substituted thiophenes involves ot-lithiation followed by quenching with various electrophiles including BusSn-Cl <01EJO1249>, TMS-CI <01BMCL1027>, C1CO2Et <01TL5955>, PPh2C1 <01JA9963, 01JCS(P1)3352, 01S2327>, and PhSeSePh <01JCS(P1)37>. Lithiation of dithieno[3,2-b:2',3'-d]thiophene (63) followed by treatment with chromium hexacarbonyl and quenching with triethyloxonium tetrafluoroborate gave mono-carbene complex 64 and the corresponding bis-carbene complex <01EJI233, 01JOM280>. The selective c~-metallation of a 3-substituted thiophene was achieved using a magnesium amide base. Treatment of thiophene 65 with the magnesium amide derived from diisopropylamine and butylmagnesium chloride followed by quenching with benzaldehyde gave thiophene 66 as the only product <01JCS(P1)442>. The [3substitution of the thiophene ring can be achieved by directed ortho metallation. Directed metallation of benzo[b]thiophene 67 with sec-butyllithium followed by transmetallation and allylation gave 3-allylbenzo[b]thiophene 68. Acid-catalyzed cyclization of 68 gave benzothieno[2,3-c]pyran-9-one 69, a model compound related to the anti-fungal agent semivioxanthin <01TL5955>. 1. n-BuLl, TMEDA 2. Cr(CO) 6 S..~/S 3. (Et30)BF 4 ~ 0

.... 63

:~

-

~t

64

OMe ~ ~ ' ~ C

CO2Et 1. i-Pr2NMgCI CO2Et 2. PhCHO ~ H

~__~Cr (CO)5

1. sec-BuLi, CuBr-Me2S 2. allyl bromide

Ph

65

OMe

OMe

ONEt2 67

68

69

0

Halogen-metal exchange has been utilized to prepare a variety of highly functionalized thiophene derivatives <01H(55)1475, 01JA9963, 01OL2379>. Selective halogen-metal exchange of dibromide 70 with n-butyllithium followed by quenching with isopropanol gave 71 <01OL2129>. A second halogen-metal exchange reaction of 71 followed by quenching with tributyltin chloride gave stannane 72 which was utilized as a building block for the structurally interesting tubular sexithiophene 73. A sequential, double halogen-metal exchange of dibromide 74 with n-butyllithium followed by treatment with N-

96

E.T. Pelkey

fluorobenzenesulfonimide gave 3,4-difluorothiophene 75 <01JA4643>. The latter was utilized as a building block for the preparation of perfluorinated sexithiophene 76, a potential n-type organic semiconductor. cI cI cI Br-~,/,S,,~,CI Br~S vCI Bu3SnvSvCI S s \\ff~-~/1.n-BuU ~/1.n-BuLi ~ . 2. i-PrOH / ~ 2. Bu3SnCI / ~ steps Br ' CI" x3" "CI" "S"

CI

70

71

72

cI

i

ci

cI 73

Br -~-

Br

1. n-BuLi E F 2. (PhSO2)2NF "~---~

steps _- F

E

T M S / \ s / \ T M S (repeat2x) TMS/~s~TM S 74

F

E

F

75

F

F F

E F

F F

F F

76

The organometallic cross-coupling of metallated thiophenes is highly utilized for the preparation of complex thiophenes. Examples of metallated thiophenes that have been reported in cross coupling reactions include thiophene-2-borates <01T4559>, thiophene-3borates <01AM1871, 01SMll3>, thiophene-2-iodonium derivatives <01SC1021>, thiophene-2-1ead derivatives <01SC1035, 01SC1059>, thiophene-2-stannanes <0lAG(E)3372, 01AM133, 01CM2234, 01JA7917, 01JAIl600, 01JOC6109, 01SC1027, 01TL3311>, and thiophene-2-zincates <01CC1060, 01EJO3437, 01MM7241>. An iterative, combinatorial approach to oligothiophenes utilized a palladium catalyzed coupling reaction between a thiophene-2-borate and solid-phase bound 2-iodothiophene as a key step <0lAG(E)4680>. Structurally unique thiophene-containing cyclophanes have been prepared utilizing palladium chemistry <01TL6869>. A palladium-catalyzed coupling of 2-thienylzinc chloride (77) with 1,8-diiodonaphthalene (78) gave bis(thiophene) 79 which was dimerized in two steps to cyclophane 80 and other complex materials depending on the reaction conditions. A novel synthesis of acetylenic thiophenes involved a palladium-catalyzed coupling reaction of 2-(butyltelluro)thiophene (81) <01TL7921>. Lithiation of thiophene followed by treatment with tellurium metal and butyl bromide gave 81 which was coupled to propargyl alcohol giving 2-alkynylthiophene 82.

I

~ZnCI 77

78

I

steps ,,

Pd(PPh3)4

,R

(dimerization) 79

8O

97

Five-Membered Ring Systems." Thiophenes & Se, Te Analogs

l 9

,..

2. Te(O) 3. n-BuBr

,

81

TeBu PdCI2,Et3N, CH30H

~)H

82

The organometallic cross-coupling reaction of halogenated thiophenes is an important method for the preparation of functionalized thiophenes. Examples of halogenated thiophenes utilized in organometallic cross coupling reactions include 2-bromothiophenes <01CC1060, 01TL8797>, 3-bromothiophenes <01CC1628>, 3-iodobenzo[b]thiophenes <01OL651>, and 2,5-diiodothiophenes <0104360, 01TL8619>. A new ligand system (cyclopentane-based tetraphosphine) has been investigated in the coupling of boronic acids with 3-bromothiophene <01CC325>. Sonogashira-type coupling reactions involving 2bromothiophenes <01BCJ889, 01BCJ1789, 01OL885, 01TL3311> and 2-iodothiophenes <01SM125> have been utilized for the preparation of complex acetylenic thiophenes. The preparation of aminothiophene via palladium-catalyzed amination reactions has been studied <01CC1628, 01JOC9067>. The regioselective functionalization of 2,3-dibromothiophene (83) has been optimized based on the observation that initial oxidative addition of palladium(0) is favored at C2 over C3 <01T7871>. For example, treatment of 83 under Suzuki coupling conditions [vinyl boronic acid 84, Pd(PPh3)4, and K2CO3] gave vinylthiophene 85 and only a trace of the corresponding disubstituted product. The preparation of fused thiophene ring system related to the biologically active indolocarbazoles, benzo[b]thieno[2,3-a]pyrrolo[3,4-c]carbazole 89, has been reported <01JHC591>. A Stille coupling between indole-2-stannane 86 and 2-bromobenzo[b]thiophene (87) gave 2-(2benzothienyl)indole (88) which was converted into 89. Finally, a novel tandem cyclizationanion capture reaction involving 2-iodotosylaniline (90), allene, 2-iodothiophene (91), and phenylboronic acid gave indoline 92 in a one pot reaction<01TL8677>.

Br 83

(HO)2B~oH84

Br

gr

. . . . . . . Pd(PPh3)4, K2C03,dioxane

85

H

C•SR C02H

Pd(PPh3)2CI2

gu 3

86

[N 9O

H }s

H

H 88

pd(PPh3)4

U II

-K2C03,toluen; 91

~Pdl

89

S

B(OH)2

~I~~N ~ 92 Ts

E.T. Pelkey

98

The preparation of vinyl-substituted thiophenes has been reported utilizing Wittig reactions <01SC1361, 01SM79, 01TL1309, 01TL1507, 01TL8733>. A novel application of benzotriazole chemistry has been reported in connection with the preparation of vinyl thiophenes <01JCS(P1)2483>. The benzotriazole moiety serves to lower the acidity of adjacent protons and also makes a good leaving group. Lithiation of fused thiophene 93 followed by treatment with benzyl chloride gave fused thiophene 94. Elimination of benzotriazole from 94 then gave vinyl thiophene 95. A novel synthetic approach to Zileuton (ABT-077) (97) involved an acid-catalyzed substitution of hydroxyalkyl-substituted thiophenes <01SC3081>. Treatment of benzo[b]thiophene 96 with N-hydroxyurea in the presence of HC1 gave 97. The preparation of 1,1-difluoroalkylthiophenes was accomplished in good yield by a novel fluorodesulfurization reaction <01T5757>. Treatment of 1,3dithiolane 98 with N-iodosuccinimide (NIS) and pyridine poly(hydrogen fluoride) (PPHF) gave difluoride 99.

Bt

1. n-BuLl 2. PhCH2CI

s)J

93

94

HNHNH2 96

HCI

HO..N,,~ 0 97

NH2

t-BuC)K 95

0

OH

Bt

Br

~ 98

NIS 34H9 P P H F .~~C4H - Br S F L__/

F

99

5.1.4 RING ANNELATION ON THIOPHENE The electron-rich thiophene ring system can be transformed into fused thiophenes by acidmediated intramolecular annelation reactions. Treatment of thiophene 100 with methacrylic acid in the presence of polyphosphoric acid (PPA) gave fused thiophene 101 <01JA4763>. Reduction of the ketone followed by an acid-catalyzed elimination gave cyclopentadienefused thiophene 102 which was utilized as a building block for the synthesis of silyl-bridged metallocenes (e.g., 103). The intramolecular cyclization of a thiophene ring (n-nucleophile) onto a pendant acyliminium ion gave the benzo[f]thieno[2,3-c]azepine ring system <01H(55)1519>. Similar cyclizations with thiophene carbinols gave complex polycyclic thiophene heterocycles <01H(54)275, 01JHC35, 01T4939>. Interestingly, treatment of dithiophene 104 with oxalyl chloride gave fused thiophene 105 in higher yield in the absence of a Lewis acid catalyst <01JAl1899>. 105 was utilized as a building block for the preparation of helicene 106. Photocyclization reactions of 3-chlorothiophenes have been utilized to prepare a variety of thiophene-containing polycyclic aromatic hydrocarbons. Recently, the preparation of the novel ring system, naphtho[2',l':4,5]thieno[2,3-c]naphtho[2,1-f]quinoline, has been reported using a photocyclization reaction <01JHC137>.

9

99

Five-Membered Ring Systems." Thiophenes & Se, Te Analogs

0

HO2C.~ ..Me 9 ,

,

Ph 1.LIAIH4 2.p-TsOH

~

Me Me2S]ZrCI2

k

=

Me

PPA

100

101

0 + CIh'CI 0

102

1,2-dichloroethane O ~ (nocatalyst) "-

=

103

~

PC

"Me

OC12H25 O9~0~~ ('/ ~ "~ OC12H25 O 0 1 2 H25

o~--{@_ s

105

104

"1/

106 O012H25

Cycloaddition reactions of thiophencs have been utilized to prepare a variety of complex heterocycles. The regioselectivity of [3+2] cycloaddition of nitrile oxides with 2,5disubstituted thiophene-l,l-dioxides (dipolarophile) has been investigated< 0102487>. The cycloaddition of thiophene-l,l-dioxide 107 with in situ generated acetonitrile oxide gave a single regioisomeric product, isoxazoline 1 0 8 . Thiophencs act as dienophiles in cycloaddition reactions with masked o-benzoquinones <01TL7851>. Oxidation of phenol 109 with diacetoxyiodobenzene (DAIB) generated masked o-benzoquinone 110 which underwent a cycloaddition reaction in the presence of 2-methylthiophene (111) to give bicyclic cycloadduct 112. The high pressure cycloaddition of 2-vinylbenzo[b]thiophene (113) (diene) with 3-nitro-2-cyclohexone (114) gave cycloadduct 115 which upon treatment with base gave fused benzo[b]thiophene 116 <01T4959>. The hetero Diels-Alder reaction between 4,7-dioxobenzo[b]thiophenes and the crotonaldehyde N,N-dimethylhydrazone has been reported in the synthesis of benzothieno[4,5,6-ij][2,7]naphthyridine-7-ones (thiophene analogues of the antitumor natural product, kuanoniamine A) <01JCS(P1)2237>.

GeMe3

.~. Me3Ge

(~) ~) Me--C--N-O

~o

Me~~ !1\;" Me3Ge~S-~--C)

107

NC"~~ 109

108

e DAIB'MeOH, I NC~~~'~Me lOMe

+

O2N

114

111

NC/~TMe 0 112

110

0

S 113

Me.. _..S

O2N/' 9 kbar

115

~

O 116

E.T. Pelkey

100

The photochromism (photoinduced reversible transformation) of a variety of 1,2dithienylethene derivatives (e.g., 117 ~ 118 <01JA753>) and closely related compounds has been heavily investigated by a number of research groups including Irie <01CC363, 01CC711, 01CEJ3466, 01CL366, 01CL436, 01CL702, 01JA9896, 01JOC3913, 01JOC5419, 01JOC6164, 01JOC8799, 01T4559>, Branda <01AG(E)1752, 01JA1784, 01JA7447>, Feringa <01CC759>, Fan <01CC1744>, and Liebeskind <01JA7703>. Potential applications of these important photolabile systems include data storage and molecular switches. Alternate switching mechanisms have been investigated with a quinone-based system which could be converted from the open form to the closed form with either a Bronsted or Lewis acid <01JA7703>. E F F

F

F

E F

F

hvuv hvvls

117 (open state)

118 (closed state)

Treatment of 119 with tributyltin hydride and AIBN generated radical intermediate 120 which underwent a 6-endo radical cyclization giving 121 <01JCS(P1)37>. The regiochemical outcome of the radical cyclization was dependent on the substitution pattern of the alkene. Finally, an attempted photocyclization of 1,3-dithiole 122 to the thiophene linked analogue (2/2') proceeded instead to give thieno[3,2-c]dithiine 123 presumably via a novel cyclization/fragmentation/cyclization mechanism <01 OL3573>. Boc Me

Boc Me

Boc

gu3SnH, AIBN 119

"Br

toluene, heat

S...~

Me 6-endo

120

hv

:

121

S ~'" S

122

123

5.1.5 THIOPHENE INTERMEDIATES IN SYNTHESIS

Thiophenes can be utilized as synthetic scaffolds for the preparation of non-thiophene materials as the sulfur moiety can be removed by reduction (desulfurization) or extrusion (loss of SO2). The extrusion of sulfur dioxide from 3-sulfolenes (2,5-dihydrothiophene 1,1dioxides) gives dienes (butadienes or o-quinodimethanes) which can be utilized in

101

Five-Membered Ring Systems: Thiophenes & Se, Te Analogs

cycloaddition chemistry. A review article detailing synthetic routes to dendralenes (acyclic cross-conjugated polyenes) including the utilization of 3-sulfolene chemistry has appeared <0lAG(E)705>. An example of a 3-sulfolene which has been prepared for use as a diene equivalent was thieno[3,4-c]pyridine 124 <01T4203>. The preparation of a tetrahydroisoindole 125, a building block for the preparation of fused porphyrins, utilized a cycloaddition reaction of 3-phenylsulfonyl-3-sulfolene with dimethyl maleate as a key step <01CC261>. Thermalization of thieno[3,4-c]pyrrole 126 in the presence of C6o gave pyrrolefused fullerene 127 <01SL296>, a potential building block for the preparation of fullerenesubstituted porphyrins. Finally, a [4+4] cyclodimerization reaction involving 3,4-di(tertbutyl)thiophene- 1-oxide has been reported <01 CL758>.

C l ~

sO MeO2C'r''"h~ H

060

O~~ N - M e

heat

o 's

CI 124

125

CO2t-Bu

-

-

126CO2Et

1

O2Et

27

The combination of thiophene cycloaddition chemistry along with the generation of reactive dienes by extrusion of sulfur dioxide was utilized to prepare tetramine scaffold 133 <01HCA22>. The Diels-Alder cycloaddition of benzo[c]thiophene (128) with imidazol-2one 129 gave cycloadduct 130 which was oxidized to the sulfone 131. Heating 131 generated the corresponding o-quinodimethane moiety which underwent a second cycloaddition with 129 to give 132. o

129

S 128

Ac Ac ~ ,~N 129,heat O steps H2N NH2 . ~~, , ~ . , /N==O,.-.--~. NAc Ac AcN~ " ' ~ N ~ O ~ H2N"/-~~NH2 130 X = S

131 X=SO2~ H202

132

Ac

133

The reductive extrusion of sulfur from thiophene derivatives has been utilized to prepare a variety of materials. A recent example involved the reduction of thiophene 134 with Raney Ni which gave a mixture of enamide lactam 135 and lactam 136 <01JCS(P1)2774>.

MeMei j ~ P h ~ 134

RaneyNi,H2 MeOH j --,," Ph

Me ~

.0

135

~ + Ph

Me,

.0

136

The Lewis acid-catalyzed addition of vinylogous TBS-ether 137 to aldehyde 138 gave thiobutenolide 139 which was transformed into the thiol-substituted carbafuranose 140 via a cyclization/ring opening sequence <01JOC8070>. The ring opening reaction of 3-

102

E. T. Pelkey

nitrothiophenes and 3,4-dinitrothiophenes by addition of amines giving functionalized acyclic alkene products has been further investigated <01 T8159, 01 T9025>.

TBSO /~/S S ~'

+

137

~0 0

w~

138

,H

0 BF3-Et2O / ~ ~

o

"'~

o

OH ~ S H . .

steps " : -'-

""oH

....~~

\13

. o "~

140

~.

9

5.1.6 BIOLOGICALLY IMPORTANT THIOPHENE DERIVATIVES

The biosynthetic origin of the natural product, dithiophene 141, has been studied in root culture of Tagetespatula <01P875>. The results suggested a long-chain fatty acid precursor (with the thiophene ring being derived from the addition of H2S across a diene), although a cyclic polyketide precursor was not completely ruled out. A large variety of biologically important thiophene-containing compounds have been synthesized and evaluated. One of the more common scaffolds utilized in medicinal chemistry is the benzo[b]thiophene moiety, and examples of which include serine protease inhibitor 142 <01BMCL1801> and potential tubulin binding agents that are structurally related to combretastatin A-4 (e.g., 35) <01OL651>. Additional modes of action that have been investigated with benzo[b]thiophene derivatives include estrogen receptor modulation <01BMCL3129> and 5 - H T 6 receptor antagonism <01BMCL2843>. Fused benzo[b]thiophenes that have been prepared that are potentially biologically active include thieno[3,2-b]carbazole 143 <01JHC749> (structurally related to anti-cancer agent ellipticine) and indolocarbazole analogue 89 <01JHC591>. The synthesis has been reported of the potentially carcinogenic metabolite, 3,4-dihydroxy-3,4-dihydrophenanthro[3,2-b][1]benzothiophene <01JCS(P1)1018>, and closely related dihydroxylated polycyclic arenes <01JCS(P1)1264>. Me CH 2 '-141

/~H

CI ~ ~%j~.s.~NH

142

0

H

H o

~'%'>"

Me

~'~ "S" "Me 143

Me

A variety of fused biologically important thiophene analogues have been synthesized and/or evaluated, and examples of which include anti-tubulin agent 144 <01BMCL2205>, human cytochrome P450 inhibitor (ticlopidine) <01B 12112>, nitric oxide synthase inhibitors (thieno[2,3-c]pyridines) <01BMCL1027>, ohD receptor antagonists (thieno[2,3-d]pyrimidine2,4-diones) <01BMCLlll9>, E-selective and ICAM-1 expression inhibitors (thieno[2,3d]pyrimidines <01JMC988> and thieno[2,3-c]pyridines <01JMC3469>), HMG-CoA reductase inhibitors (thieno[2,3-b]pyridines) <01BMCL1285>, and anti-HIV agents (benzo[2,1-b:4,5-b']dithiophenes<01SC2997>). The preparation of additional ring systems that have been reported include pyrido[2',3':4,5]thieno[2,3-c]pyridazines <01T5413>, thieno[2,3-b][1,4]thiazines <01H(55)255>, and many other complex thiophene-containing

103

Five-Membered Ring Systems: Thiophenes & Se, Te Analogs

heterocycles <01JHC383, 01JHC419, 01JHC507, 01JHC743, 01JHC973, 01S2119, 01SL1953> including those previously mentioned in this review. The preparation of thienoquinoxalines has been reviewed <01JHC809>. Analogues of biologically active natural products have been prepared including thiophene derivatives of podophyllotoxin <01 T3963> and prodigiosin <01CBC60>. MeO

OH Br // \\

O2N,~~

144

145

H2N , ~ o I /

O

H

-~"-'N~ B o

r

H O

~ 146

H HN'~"~/~T~ O

A variety of biologically important simple (non-fused) thiophenes have been synthesized and/or evaluated, and examples of which include artificial nucleosides <01BMCL2221>, antitumor agent 145 <01JMC74>, tubulin binding agents <01BMCL2341>, avl33antagonist 146 <01BMCL2011>, anti-HIV agents <01BMCl123, 01H(55)2085, 01TL6629>, 5-HTIA receptor antagonists <01JMC418>, P38 kinase inhibitors <01BMCL9>, urokinase inhibitors <01BMCL915, 01BMCL1379>, Raf kinase inhibitors <01BMCL2775>, PAL1 inhibitors <01BMCL2589>, ~ adrenoceptor agonists <01JMC863>, topoisomerase II inhibitors <01CBC559>, subnanomolar inhibitors of human carbonic anhydrase II <0lAG(E)389>, endolethin antagonists <01BMC255, 01JMC1211>, novel phototoxic agents <01SC3747>, trypanocidal agents <01BMC1025>, and antibacterial agents <01BMCL2061, 01BMCL2675>. Finally, the synthesis and/or evaluation of various tetrahydrothiophenes have been reported including antibiotics <01T4999>, glycosidase inhibitors <01BMCL1137, 01JOC2312>, and anti-HIV agents <01BMCL599, 01BMCL1049>. 5.1.7 NON-POLYMERIC THIOPHENE MATERIALS The unique electronic and physical properties of thiophenes make it a useful component of a variety of novel materials including spectroscopic probes, organic dyes, organic light emitting diodes, and molecular devices. Thiophene derivatives functionalized with push-pull substitution have been prepared and evaluated as novel chromophores for second order nonlinear optical (NLO) materials including dithiophenes (e.g., 147) <01TL1507>, pyrrolethiophenes <01TL1309>, and pyrrole-imidazoles <01TL805>. Ferrocene moities (e.g., 148) <01EJO2671> have also been investigated as moderate electron donors in donor-thiopheneacceptor complexes <01CC49, 01JOM426, 01JOM435>. A novel class of bimetallic complexes (e.g., 149) containing both iron and chromium has been synthesized <01TL3311>. A structurally unique class of star-shaped molecules has been prepared which contain a thiophene core and ferrocene moities substituted around the periphery linked via alkynyl spacers <01JOM139>. Finally, the preparation of thiophenes conjugated to fullerenes (e.g., 127 <01SL296> and 37 <01TL1737>) has been reported in association with self-assembled monolayers <01 CC913> and photoinduced charge transfer <01 AM 1871, 01 TL6877>. Me ~

0

0 CN

O 147 ~

O

N(S

Fe

~

148

O1(OO)3

149

0)3

104

E. T. Pelkey

The preparation and/or evaluation (electron transfer properties) of thiophene-containing porphyrins and structurally related higher order macrocyclic materials have been reported including tetrathiaoctaphyrin (!)<01CEJ5099, 01JA8620>, trithiahexaphyrins <01TL3391>, dithiasapphyrins <01 OL1933>, dithiaporphyrins <01JCS(P 1) 1644>, Schiff-base macrocycles (e.g., 150) <01TL1969>, N-confused thiaporphyrins <01JOC153>, tetrathiafulvenesubstituted [22]annulenes <01HCA2220>, thiophene-containing calix[n]pyrroles <01T7323>, and dithiophene-substituted phthalocyanines <01JOC6109>. Additional types of novel thiophene-containing macrocycles and annulenes that have been prepared and/or evaluated include thiophene cage complex 151 <01CC529>, dithiophene-containing porphyrin cage complex (fluoride anion recognition) <0lAG(E)3372>, macrocyclic Mannich bases (e.g., 152) <01JCS(P1)1398>, thiophene-containing calixarenes <01JHC293>, dithiophene-substituted calixarenes <01CEJ3354>, thiophene-containing crown thioether 153 <01POL2517>, thiophene-containing cyclophanes <01JOC713, 01OL885> (e.g., 80) <01TL6869>, trithiophene-diacetylene macrocycles <01AM243>, and tubular sexithiophene 73 <01OL2129>. Thiohelicenes, helical shaped aromatic macrocycles containing fused thiophene tings, have been prepared and/or evaluated including helicene 106 <01JA11899>, [5]thiahelicenes (chiral recognition) <01 CC2692, 01CHIR 722>, [7]thiahelicenes (photochromism) <01JA7447>, and [n]thiahelicenes (n=5,7,9,11) <01CM3906, 01SM79>. A theoretical study concerning the feasibility of thiophene-containing heterobuckybowls appeared <01JOC6523>.

ts/-"s_ ---.

M

H

HN

S 151)

=~

Me/ ~

s 151

152

'Me 153

Thiophenes are important components of a variety of additional materials including novel phosphine ligands for transition metal chemistry <01JCS(P1)3352, 01JOC5940, 01S2327>, violene/cyanine hybrids <01EJO 1393>, carboxamide-based molecular recognition templates <01T7213>, novel fluorophores <01OL2469>, dithiothiophene nickel <01EJI3127, 01SM699> and gold <01CEJ511> complexes (conductors), and star-shaped molecules (liquid crystals) <01JMAC 1634> 5.1.8 THIOPHENE OLIGOMERS AND POLYMERS The thiophene ring is an important component of many novel oligomeric and polymeric materials. The synthesis of monodisperse thiophene oligomers continues to be an important field of study and selected examples include trithiophenes <01CL 1022, 01 CM634, 01SM 115, 01TL8733>, pentathiophenes <01MM7331, 01SM58 l>, sexithiophene 76 <01JA4643>), llmers <01T3785>, and 48-mer (!) 154 <01BCJ979>. The preparation of long monodisperse

105

Five-Membered Ring Systems." Thiophenes & Se, Te Analogs

oligothiophenes has also been reviewed <01BCJ1789>. A solid-phase approach to well defined tetrathiophenes has been reported <0lAG(E)4680, 01SM121>. The preparation of oligothiophenes with novel substitution patterns has been reported including those with chiral side chains <01OL2379>, amine groups <01SM67>, thiols groups <01EJI821>, alkylthiol groups <01JHC649>, phosphines (platinum complexes) <01JA9963>, fused adamantyl groups <01CM1665>, and fused silole groups <0104800>. A detailed study of the acidcatalyzed oligomerization of 2-hydroxymethylthiophenes has appeared <01MM26>. Oligothiophenes have been prepared with different groups located on one or both ends including those conjugated to cyclophanes <01AM133>, porphyrins <01BCJ889>, polybenzyl ether dendrons <01JA6916>, ferrocenes <01BCJ1737>, chromene groups <01SM23, 01SM1463>, Ru(II) complexes <01JA2503>, perfluoroalkyl groups <01CM4868>, tris(thiol) groups (self-assembled monolayers) <01CC1830>, fluorenes <01JA9214>, isothiocyanates (fluorescent markers) <01JAIl600>, diarylamines (glasses) <01OL1673>, and fullerenes <01AM1871, 01CC913, 01TL6877>. Mixed thiophene cooligomers have been prepared and/or evaluated including those containing chiral binaphthyl groups <01CC1060>, naphthyl groups <01SM425>, 1,4-phenyl groups <01JHC923>, fluorene groups <01MM2288>, spirofluorenyl groups <01JCS(P1)740>, phosphole groups <01CEJ4222>, thiazole groups <01 CM4868>, and tungsten-capped calixarenes <01JA7917>.

C8H17

/

S

C8H17 S

C8H17

~,

C8H17 S

C81q17

S

154

\ S

C8H17

C8H.17 S

//6

C8H17

Two reviews of polythiophenes have appeared which cover their impact on microelectronics <01AG(E)1037> and polythiophene-transition metal hybrids <01AM545>. Polythiophenes have been evaluated as novel materials in a variety of fields including for novel electronic devices <01AM1775, 01CC815, 01CM2234, 01EJO3437, 01MM1810, 01MM2232, 01MM5746, 01NAT189, 01SM153>, optical devices <01AM1871, 01CC1216, 01JMAC718, 01JMAC3082, 01MM7241, 01SMl13, 01SM191>, DNA molecular recognition <01TL155>, biosensors <01AM1555, 01SM289>, organic films <01CM526>, stereoselective synthesis <01TL867, 01TL3073>, and chemical lithography <01CC1274>. New approaches to the synthesis of polythiophenes have been reported <01TL5327, 01TL8653>. Finally, the functionalization of polythiophenes on an electrode surface has been reported <01AM1249>. 5.1.9 SELENOPHENES AND TELLUROPHENES

A small number of reports on the chemistry of selenophenes and tellurophenes appeared during the past year. The preparation of 3,4-ethylenedioxyselenophene (155) involved a condensation/decarboxylation approach <01OL4283>. A new preparation of benzo[b]seleno3(2H)-ones (e.g., 156)was accomplished utilizing a condenation reaction between 2(chloroseleno)benzoyl chloride and diethyl malonate <01CL826, 01TL4899>. The synthesis and chemistry of the novel bicyclic ring system selenabicyclo[3.1.0]hexene 157 has been explored <01H(55)465>. Polymer systems containing selenophene units have been prepared

106

E.T. Pelkey

and characterized <01JAPS2019>. Finally, the preparation of porphyrin-related macrocycles containing selenophene rings <01JA8620, 01JOC153, 01TL3391> and tellurophene rings < 0 l A G ( E ) 4 4 6 6 > have been reported.

,O~~/S

--0~ 155

e

~

l

.~0

II-J/CO2Et

N

~Se-"~,CO2Et 156

157

5.1.10 REFERENCES 0lAG(E)389 0lAG(E)705 01AG(E)1037 01AG(E)1752 0lAG(E)3008 01AG(E)3372 0lAG(E)4466 0lAG(E)4680 01AM133 01AM243 01AM545 01AM1249 01AM1555 01AM1775 01AM1871 01B12112 01BCJ889 01BCJ979 01BCJ1737 01BCJ1789 01BMC255 01BMC1025 01BMCl123 01BMCL9

01BMCL599 01BMCL915

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F i v e - M e m b e r e d Ring Systems: Thiophenes d,: Se, Te Analogs

01BMCL1027 01BMCL1049 01BMCL1119 01BMCLll37 01BMCL1285 01BMCL1379

01BMCL1801 01BMCL2011

01BMCL2061

01BMCL2205 01BMCL2221 01BMCL2341 01BMCL2589 01BMCL2675 01BMCL2775

01BMCL2843

01BMCL3129 01CBC60 01CBC559 01CC49 01CC261 01CC325 01CC363 01CC529 01CC711 01CC759 01CC815 01CC913 01CC1060

107

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108 01CC1216 01CC1274 01CC1628 01CC1744 01CC1830 01CC2692 01CEJ511 01CEJ3354 01CEJ3466 01CEJ4222 01CEJ5099 01CHIR722 01CL366 01CIA36 01CL702 01CL758 01CL826 01CL1022 01CM526 01CM634 01CM1665 01CM2234 01CM3906 01CM4112 01CM4868 01EJI233 01EJI821 01EJI3127 01EJO1249 01EJO1393 01EJO2671

01EJO3437 01H(54)275 01H(55)171 01H(55)255 01H(55)465 01H(55)741 01H(55)1475 01H(55)1487 01H(55)1519 01H(55)2085

E.T. Pelkey

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Five-Membered Ring Systems: 17ziophenes & Se, Te Analogs

01H(55)2423

109

Kobayashi, K.; Yoneda, K.; Uchida, M.; Matsuoka, H.; Morikawa, O.; Konishi, H. Heterocycles 2001, 55, 2423.

01HC271 01HC283 01HCA22 01HCA2220 01JA753 01JA1784 01JA2503 01JA4643 01JA4763 01JA6916 01JA7447 01JA7703 01JA7917 01JA8620 01JA9214 01JA9896 01JA9963 01JAl1600 01JAl1899 01JAPS2019 01JCS(P1)37 01JCS(P1)144 01JCS(P1)154 01JCS(P1)335 01JCS(P1)442 01JCS(P1)740 01JCS(P1)1018 01JCS(P1)1264 01JCS(P1)1398 01JCS(P1)1644 01JCS(P1)2035 01JCS(P1)2237 01JCS(P1)2483 01JCS(Pl)2491 01JCS(P1)2595 01JCS(P1)2774 01JCS(P1)2885 01JCS(P1)3352 01JHC35 01JHC137 01JHC293

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110 01JHC383 01JHC419 01JHC507 01JHC591 01JHC649 01JHC743 01JHC749 01JHC809 01JHC923 01JHC973 01JHC1025 01JHCl167 01JMAC718 01JMAC1634 01JMAC3068 01JMAC3082 01JMC74 01JMC418

01JMC863 01JMC988

01JMC1211

01JMC3469

01JOC153 01JOC713 01JOC2312 01JOC2493 01JOC2850 01JOC2966 01JOC3913 01JOC5419 01JOC5940 01JOC6109 01JOC6164 01JOC6523 01JOC7283 01JOC7925 01JOC8070 01JOC8799 01JOC9067 01JOM139 01JOM280 01JOM426

E.T. Pelkey

Sekhar, B. C.; Ramana, D. V.; Ramadas, S. RJ. tteterocycl. Chem. 2001,38,383. Giitschow, M.; Powers, J. C..L Heterocycl. Chem. 2001, 38,419. Demirayak, S .; Mohsen, U. A..1. tteterocycl. Chem. 2001,38,507. Hudkins, R. L.; Johnson, N. W.J. Heterocycl. Chem. 2001,38,591. Michalitsch, R.; EIKassmi, A.; Yassar, A.; Gamier, F.J. tIeterocycl. Chem. 2001, 38,649. Chowdhury, A. Z. M. S.; Shibata, Y.J. tleterocycl. Chem.2001,38,743. Ferreira, I. C. F. R.; Queiroz, M.-J. R. P.J. lteterocycl. Chem. 2001,38,749. Moustafa, O. S .; Yarnada, Y..L lteterocycl. Chem. 2001, 38,809. Hotta, S.J. lleterocycl. Chem. 2001,38, 923. Modica, M.; Santagati, M.; Santagati, A. J. lleterocycl. Chem. 2001,38, 973. P6rez-Silanes, S.; Martinez, -. E., J.; Oficialdegui, A. M .; Villenueva, H.; Orris, L.; Monge, A. J. Heterocycl. Chem. 2001,38, 1025. Cornel, A.; Kitsch, G.J. Heterocycl. Chem. 2001, 38, 1167. Embert, F.; L6re-Porte, J.-P.; Moreau, J. J. E.; Serein-Spirau, F.; Righi, A.; Sauvajol, J.-L.J. Mater. Chem. 2001,11,718. Geng, Y.; Fechtenk6tter, A.; Miillen, K.J. Mater. Chem. 2001,11, 1634. Kiryanov, A. A.; Sampson, P.; Seed, A. J.J. Mater. Chem. 2001, 11,3068. Ding, A.-L.; Pei, J.; Lai, Y.-H.; Huang, W.I. Mater. Chem. 2001, 11,3082. Botch, R. F.; Liu, J.; Joswig, C.; Baggs, R. B.; Dexter, D. L.; Mangold, G. L.I. Med. Chem. 2001, 44, 74. Martinez-Esparza, J.; Oficialdegui, A. M.; P6rez-Silanes, S.; I Ieras, A.; Orris, L.; Palop, J.-A.; Lasheras, B.; Roca, J.; Mourelle, M.; Bosch, A.; Del Castillo, J.-C.; Tordera, R.; Del Rio, J.; Monge, A. J. Med. Chem. 2001, 44,418. Boyd, R. E.; Rasmussen, C. R.; Press, J. B.; Raffa, R. B.; Codd, E. E.; Connelly, C. D.; Li, Q. S.; Martinez, R. P.; Lewis, M. A.; Almond, I I. R.; Rei~, A. B.J. Med. Chem. 2001, 44,863. Stewart, A. O.; Bhatia, P. A.; McCarty, C. M.; Patel, M. V.; Staeger, M. A.; Arendsen, D. L.; Gunawardana, I. W.; Melcher, L. M.; Zhu, G.-D.; Boyd, S. A.; Fry, D. G.; Cool, B. L.;Kifle, L.; Lartey, K.; Marsh, K. C.; Kempf-Grote, A. J.; Kilgannon, P.; Wisdom, W.; Meyer, J.; Gallatin, W. M.; Okasinski, G. F.J. Med. Chem. 2001, 44,988. Wu, C.; Decker, E. R.; Blok, N.; Li, J.; Bourgoyne, A. R.; Bui, H.; Keller, K. M.; Knowles, V.; Li, W.; Stavros, F. D.; Ilolland, G. W.; Brock, T. A.; Dixon, R. A. F.I. Med. Chern. 2001, 44, 1211. Zhu, G.-D.; Arendsen, D. L.; Gunawardana, I. W.; Boyd, S. A.; Stewart, A. O.; Fry, D. G.; Cool, B. L.; Kifle, L.; Schaefer, V.; Meuth, J.; Marsh, K. C.; Kempf-Grote, A. J.; Kilgannon, P.; Gallatin, W. M.; Okasinski, G. F.J. Med. Chem. 2001, 44, 3469. Pushpan, S. K.; Srinivasan, A.; Anand, V. G.; Chandrashekar, T. K.; Subramanian, A.; Roy, R.; Sugiura, K.-i.; Sakata, Y.J. Org. Chem. 2001, 66, 153. Godbert, N.; Batsanov, A. S.; Bryce, M. R.; tloward, J. A. K.J. Org. Chem. 2001, 66,713. Ghavami, A.; Johnston, B. D.; Pinto, B. M.J. Org. Chem. 2001, 66, 2312. Fevig, T. L.; Phillips, W. G.; Lau, P. HJ. Org. Chem. 2001, 66, 2493. Katritzky, A. R.; Wang, X.; Denisenko, A..I. Org. Chem. 2001, 66, 2850. Eggers, K.; Fyles, T. M.; Montoya-Pelaez, P. J.J. Org. Chem. 2001,66, 2966. Osuka, A.; Fujikane, D.; Shimnori, H.; Kobatakc, S.; Irie, M.J. Org. Chem. 2001, 66, 3913. Yagi, K.; Soong, C. F.; Irie, M..I. Org. Chem. 2001, 66, 5419. Benincori, T.; Gladiali, S .; Rizzo, S.; Sannicol6, F.J. Org. Chem. 2001, 66, 5940. Muto, T.; Temma, T.; Kimura, M.; ttanabusa, K.; Shirai, II..1. Org. Chem. 2001, 66, 6109. Yamada, T.; Muto, K.; Kobatake, S.; Irie, M.J. Org. Chem. 2001, 66, 6164. Priyakumar, U. D.; Sastry, G. N.J. Org. Chem. 2001, 66, 6523. Sonpatki, V. M.; Herbert, M. R.; Sandvoss, L. M.; Seed, A. J..l. Org. Client. 2001, 66, 7283. Kiryanov, A. A.; Sampson, P.; Seed, A. J.J. Org. Chem.2001, 66, 7925. Rassu, G.; Auzzas, L.; Pinna, L.; Zambrano, V.; Battistini, L.; Zanardi, F.; Marzocchi, L.; Acquotti, D.; Casiraghi, G.J. Org. Chem. 2001, 66, 8070. Matsuda, K.; Matsuo, M.; Irie, M.J. Org. Chem. 2001, 66, 8799. Ogawa, K.; Radke, K. R.; Rothstein, S. D.; Rasmussen, S. C.J. Org. Chem. 2001, 66, 9067. Thomas, K. R. J., Lin, J. TJ. Organornet. Chem. 2001, 637-639, 139. Landman, M.; G6rls, H.; Lotz, S.J. Organomet. Chem. 2001, 617-618,280. Stankovic, E.; Toma, S.; Van Boxel, R.; Asselberghs, I.; Persoons, A.J. Organornet. Chem. 2001, 637-639,426.

Five-Membered Ring Systems: Thiophenes & Se, Te Analogs 01JOM435 01M929 01MM26 01MM1810 01MM2232 01MM2288 01MM5746 01MM7241 01MM7331 01NAT189 0102487 0104360 010480O 01OL651 01OL885 01OL1629 01OL1633 01OL1673 01OL1933 01OL2129 01OL2379 01OL2469 01OL3565 01OL3573 01OL4283 01OM1259 01P875 01POL2517 01S413 01S2119 01S2327 01SC1021 01SC1027 01SC1035 01SC1059 01SC1361 01SC1527 01SC1647 01SC2997 01SC3081 01SC3113 01SC3747 01SL228 01SL296 01SL634 01SLl129 01SL1731 01SL1953

111

Hudson, R. D. A.; Asselberghs, I.; Clays, K.; Cuffe, L. P.; Gallagher, J. F.; Manning, A. R.; Persoons, A.; Wostyn, K.J. Organornet. Chem. 2001, 637-639, 435. Burger, K.; Fuchs, A.; Hennig, L.; Helmreich, B.; Greif, D. Monatsh. Chem. 2001, 132,929. Stagnaro, P.; Costa, G .; Gandini, A. Macromolecules 2001,34, 26. Meng, H.; Wudl, F. Macromolecules 2001,34, 1810. Skabara, P. J.; Serebryakov, I. M.; Perepichka, I. F.; Sariciftci, N. S.; Neugebauer, H.; Cravino, A. Macromolecules 2001,34, 2232. Bellet6te, M.; Morin, J.-F.; Beaupr6, S.; Ranger, M.; Leclcrc, M.; Durocher, G. Macromolecules 2001, 34, 2288. Lee, K.; Sotzing, G. A. Macromolecules 2001,34, 5746. Pei, J.; Yu, W.-L.; Ni, J.; Lai, Y.-II.; Iluang, W.; tteeger, A. J.Macromolecules 2001, 34, 7241. Miyata, M.; Matsumi, N.; Chujo, Y. Macromolecules 2001,34, 7331. Sch6n, J. H.; Dodabalapur, A.: Bao, Z.; Kioc, C.; Schenker, P.; Batlogg, B. Nature 2001, 410, 189. Lukevics, E.; Arsenyan, P.; Belyakov, S.; Popelis, J.; Pudova, O. Organometallics 2001, 20, 2487. Altamura, P.; Giardina, G.; SterTo, C. L.; Russo, M. V. Organometallics 2001, 20, 4360. Ohshita, J.; Kai, H.; Takata, A.; Iida, T.; Kunai, A.; Ohta, N.; Komaguchi, K.; Shiotani, M.; Adachi, A.; Sakamaki, K.; Okita, K. Organometallics 2001, 20, 4800. Flynn, B. L.; Verdier-Pinard, P.; llamel, E. Org. Lett. 2001,3,651. Marsella, M. J.; Wang, Z.-Q.; Reid, R. J.; Yoon, K. Org. Lett. 2001,3,885. Herrlich, M.; Itampel, N.; Mayr, H. Org. Lett. 2001,3, 1629. Herrlich, M.; Mayr, II.; Faust, R. Org. Lett. 2001,3, 1633. Hartmann, H.; Gerstner, P.; Rohde, D. Org. Lett. 2001, 3, 1673. Sprutta, N.; Latos-Grazynski, L. Org. Lett. 2001,3, 1933. Marsella, M. J.; Yoon, K.; Tham, F. S. Org. Lett. 2001, 3, 2129. Sakurai, S.-i.; Goto, H.; Yashima, E. Org. Lett. 2001, 3, 2379. Hwang, G. T.; Son, H. S.; Ku, J. K.; Kim, B. H. Org. Lett. 2001,3, 2469. Grainger, R. S.; Procopio, A.; Steed, J. W. Org.Lett. 2001,3, 3565. Celli, A. M.; Donati, D.; Ponticelli, F.; Roberts-Bleming, S. J.; Kalaji, M.; Murphy, P. J. Org. Lett. 2001,3, 3573. Aqad, E.; Lakshmikantham, M. V.; Cava, M. P. Org. Lett. 2001,3, 4283. Angelici, R. J. Organometallics 2001,20, 1259. Margl, L.; Eisenreich, W.; Adam, P.; Bacher, A.; Zenk, M. H. Phytochemist~y 2001,58, 875. Meliani, H.; Vifias, C.; Teixidor, F.; Sillanp~i~i, R.; Kivek~is, R. Polyhedron 2001, 20, 2517. Omar, M. T.; E1-Aasar, N. K.; Saied, K. F. Synthesis 2001, 413. Prasad, M. R.; Rao, A. R. R.; Rao, P. S.; Rajan, K. S. Synthesis 2001, 2119. Sannicol6, F.; Benincori, T.; Rizzo, S.; Gladiali, S.; Pulacchini, S.; Zotti, G.Synthesis 2001, 2327. Kang, S.-K.; Ryu, H.-C.; Kim, J.-W. Synth. Commun. 2001, 31, 1021. Kang, S.-K.; Ryu, H.-C.; Lee, S .-W. Synth. Contrnun. 2001, 31, 1027. Kang, S.-K.; Ryu, H.-C.; Choi, S.-C. Synth. Cornmun. 2001, 31, 1035. Kang, S.-K.; Ryu, H.-C.; Lee, S .-H. Synth. Commun. 2001, 31, 1059. Zhang, C.; Harper, A. W.; Dalton, L. R. Synth. Cornrnun. 2001, 31,1361. Huckabee, B. K.; Stuk, T. L. Synth. Contrnltn. 2001,31, 1527. Dawood, K. M. Synth. Commun. 2001, 31, 1647. Pavlicic, D.; Karminski-Zamola, G. Synth. Contrnun. 2001,31, 2997. Copp, R. R.; Fohey, B. T.; Lannoye, G. Synth. Contmun. 2001,31,3081. Rajagopal, R.; Jyothi, T. M.; Daniel, T.; Srinivasan, K. V.; Rao, B. S. Synth. Commun. 2001, 31,3113. Singh, S. P.; Naithani, R.; Aggarwal, R.; Prakash, O. Synth. Commun. 2001, 31,3747. Aitken, R. A.; Garnett, A. N. Synlett 2001, 228. Ishida, H.; Itoh, K.; Ito, S.; Ono, N.; Ohno, M. Synlett 2001, 296. Boas, U.; Dhanabalan, A.; Greve, D. R.; Meijer, E. W. Synlett 2001, 634. Zhang, W.; Henry, Y. Synlett 2001, 1129. Sommen, G.; Cornel, A.; Kirsch, G. Synlett 2001, 1731. Zaleska, B.; Ciez, D.; Lech, J. Synlett 2001, 1953.

112 01SM23 01SM67 01SM79 01SMl13 01SMl15 01SM121 01SM125 01SM153 01SM191 01SM289 01SM425 01SM581 01SM699 01SM1463 01T1737 01T1857 01T3785 01T3963 01T4203 01T4559 01T4939 01T4959 01T4999 01T5413 01T5757 01T7213 01T7323 01T7871 01T8159 01T8903 01T9025 01TL155 01TLS05 01TL867 01TL1309 01TL1507 01TL1657 01TL1969 01TL3073 01TL3311

E. T. Pelkey

Yassar, A.; Rebi6re-Galy, N.; Frigoli, M.; Moustrou, C.; Samat, A.; Gugliemetti, R.; Jaafari, A. Synth Met. 2001, 124, 23. Tanaka, S.; Yamashita, Y. Synth Met. 2001,119, 67. Caronna, T.; Sinisi, R.; Cateilani, M.; Luzzati, S.; Abbate, S.; Longhi, G. Synth Met. 2001, 119, 79. Svensson, M.; Theander, M.; Ingan~is, O.; Andersson, M. R. Synth Met. 2001, 119, 113. Pozo-Gonzalo, C.; Roberts, D. M.; Skabara, P. J. Synth. Met. 2001, 119, 115. Briehn, C. A.; B~iuerle, P. Synth Met. 2001,119, 121. Fuhrmann, G.; Kr6mer, J.; Btiucrle, P. Synth Met. 2001, 119, 125. Berlin, A.; Schiavon, G.; Zecchin, S.; 7~tti, G. Synth Met. 2001, 119, 153. Endo, T.; Rikukawa, M.: Sanui, K. Synth Met. 2001,119, 191. Sch~iferling, M.; B~iuerlc, P. Synth Met. 2001, 119, 289. Sankaran, B.; Alexander, M. D.; Tan, I~.-S. Synth Met. 2001, 123,425. Gigli, G.; Anni, M.; Thcandcr, M.; Cingolani, R.; Barbarella, G.; Favaretto, L.; Ingan~is, O. Synth Met. 2001, 119,581. Belo, D.; Alves, II.; Lopes, E. B.; Gama, V.; Henriques, R. T.; Duarte, M. T.; Almeida, M.; Perez-Benitez, A.; Rovira, C.; Veciana, J. Synth Met. 2001, 120,699. Yassar, A.; Rebi6re-Galy, N.; Frigoli, M.; Moustrou, C.; Samat, A.; Gugliemetti, R. Synth Met. 2001,121, 1463. Ishida, H.; Itoh, K.; Ohno, M. Tetrahedron 2001,57, 1737. Cosimelli, D.; Costanzo, F.; Tonelli, D.; Lamartina, L.; Sarvfi, M. C.; Seeber, R. Tetrahedron 2001, 57, 1857. Kr6mer, J.; B~iuerle, P. Tetrahedron 2001, 57, 3785. Ramos, A. C" Pel~iez, R.; L6pez, J. L.; Cabalero, E" Medarde, M.; San Feliciano, A. Tetrahedron 2001, 57, 3963. Carly, P. R.; Govaerts, T. C.; Cappelle, S. L.; Compernolle, F.; Itoornaert, G. J. Tetrahedron 2001,57, 4203. Uchida, K.; Matsuoka, T.; Kobatake, S.; Yamaguchi, T.; Irie, M. Tetrahedron 2001,57, 4559. Pigeon, P.; Mamouni, A.; Sikoraiova, J.; Marchalin, S.; Decroix, B. Tetrahedron 2001, 57, 4939. Marrocchi, A.; Minuti, L.; Taticchi, A.; Scheeren, H. W.Tetrahedron 2001, 57, 4959. Martyres, D. H.; Baldwin, J. E.; Adlington, R. M.; Lee, V.; Probert, M. R.; Watkin, D. J. Tetrahedron 2001, 57, 4999. Alvarez-Sarandds, R.; Peinador, C.; Quintela, J. M.Tetrahedron 2001, 57, 5413. Kiryanov, A. A.; Seed, A. J.; Sampson, P. Tetrahedron 2001, 57, 5757. Ray, J. K.; Gupta, S .; Pan, D.; Kar, G. K. Tetrahedron 2001, 57, 7213. Nagarajan, A.; Ka, J.-W.; Lee, C.-H. Tetrahedron 2001, 57, 7323. Pereira, R.; Iglesias, B.; de Lera, A. R. Tetrahedron 2001,57, 7871. Dell'Erba, C.; Gabellini, A.; Novi, M.; Petrillo, G.; Tavani, C.; Cosimelli, B.; Spinelli, D. Tetrahedron 2001, 57, 8159. Cosimelli, B.; Lamartina, L.; Spinelli, D. Tetrahedron 2001, 57, 8903. Dell'Erba, C.; Gabellini, A.; Mugnoli, A" Novi, M" Petrillo, G.; Tavani, C. Tetrahedron 2001, 57, 9025. Ewbank, P. C.; Nuding, G.; Suenaga, H.; McCullough, R. D., Shinkai, S. Tetrahedron Lett. 2001, 42,155. Santos, J.; Mintz, E. A.; Zehnder, O.; Bosshard, C.; Bu, X. R.; Giinter, P. Tetrahedron Lett. 2001, 42,805. Pelion, P.; Deltel, E.; Pilard, J.-F. Tetrahedron Lett. 2001, 42,867. Chou, S.-S. P.; Yeh, Y.-II. TetrahedronLett. 2001, 42, 1309. Raimundo, J.-M.; Blanchard, P.; Fr6re, P.; Mercier, N.; Ledoux-Rak, I.; Hierle, R.; Roncali, J. Tetrahedron Lett. 2001, 42, 1507. Burger, K.; Fuchs, A.; Hennig, L.; Hehnreich, B.Tetrahedron Lett. 2001, 42, 1657. Won, D.-H.; Lee, C.-H. Tetrahedron Lett. 2001, 42, 1969. L6re-Porte, J.-P.; Moreau, J. J. E.; Serein-Spirau, F.; Wakim, S. Tetrahedron Lett. 2001, 42, 3073. Tranchier, J.-P.; Chavignon, R.; Prim, D.; Auffrant, A.; Planas, J. G.; Rose-Munch, F.; Rose, E.; Stephenson, G. R. Tetrahedron Lett. 2001, 42, 3311.

F i v e - M e m b e r e d Ring Systems." Thiophenes & Se, Te Analogs

01TL3391

113

Pushpan, S. K.; Anand, V. G.; Venkatraman, S .; Srinivasan, A .; Gupta, A. K.; Chandrashekar, T. K. Tetrahedron Lett. 2001, 42, 3391.

01TL4397 01TL4687 01TL4899 01TL5041 01TL5117 01TL5121 01TL5327 01TL5755 01TL5955 01TL6011 01TL6629 01TL6869 01TL6877 01TL7181 01TL7851 01TL7921 01TL8429 01TL8461 01TL8539 01TL8619 01TL8653 01TL8677 01TL8733 01TL8797

Nenajdenko, V. G.; Gavryushin, A. E.; Balenkova, E. S. Tetrahedron Lett. 2001, 42, 4397. Brandsma, L.; Spek, A. L.; Trofimov, B. A.; Tarasova, O. A.; Nedolya, N. A.; Afonin, A. V.; Zinshenko, S. V. Tetrahedron Lett. 2001, 42, 4687. Kloc, K.; Mlochowski, J. Tetrahedron Lett. 2001, 42, 4899. Fujii, T.; Itoh, A.; Itamata, K.; Yoshimura, T. Tetrahedron Lett. 2001, 42, 5041. Sosnovskikh, V. Y.; Usachev, B. I.; Sevenard, D. V.; Lork, E.; R6schenthaler, G.-V. Tetrahedron Lett. 2001, 42, 5117. Sosnovskikh, V. Y.; Usachev, B. I. TetrahedronLett. 2001, 42, 5121. Xu, J.; Ng, S. C.; Chang, H. S. O. TetrahedronLett. 2001,42, 5327. Gomez-Monterrey, I. M.; Campiglia, P.; Mazzoni, O.; Novellino, E.; Diurno, M. V. Tetrahedron Lett. 2001, 42, 5755. Kamila, S.; Mukherjee, C.; De, A. Tetrahedron Lett. 2001, 42, 5955. Larock, R. C.; Yue, D. Tetrahedron Lett. 2001,42,6011. Venkatachalam, T. K.; Sudbeck, E. A.; Uckun, F. M. ]'etrahedron Lett. 2001, 42, 6629. Iyoda, M.; Nakao, K.; Kondo, T.; Kuwatani, Y.; Yoshida, M.; Matsuyama, II.; Fukami, K.; Nagase, S. Tetrahedron Lett. 2001, 42, 6869. Obara, Y.; Takimiya, K.; Aso, Y.; Otsubo, T. l"etrahedron Lett. 2001, 42, 6877. Castanedo, G. M.; Sutherlin, D. P. Tetrahedron Lett. 2001, 42, 7181. Lai, C.-H.; Rao, P. D.; Liao, C.-C. Tetrahedron Lett. 2001, 42,7851. Zeni, G.; Nogueira, C. W.; Panatieri, R. B.; Silva, D. O.; Menezes, P. H.; Braga, A. L.; Silveira, C. C.; Stefani, H. A.; Rocha, J. B. T. TetrahedronLett. 2001, 42, 7921. Collini, M. D.; Miller, C. P. Tetrahedron Lett. 2001, 42, 8429. Otani, T.; Sugihara, Y.; Ishii, A.; Nakayama, J. Tetrahedron Lett. 2001, 41,8461. Shevelev, S. A.; Dalinger, I. L.; Cherkasova, T. I. Tetrahedron Lett. 2001, 42, 8539. Kr~imer, C. S.; Zeitler, K.; Mtiller, T. J. J. Tetrahedron Lett. 2001, 42, 8619. Yamamoto, T.; Nurulla, I.; Ushiro, A. Tetrahedron Lett. 2001, 42, 8653. Grigg, R.; Mariani, E.; Sridharan, V. Tetrahedron Lett. 2001, 42, 8677. Collis, G. E.; Burrell, A. K.; Officer, D. L. TetrahedronLett. 2001, 42, 8733. Kiryanov, A. A.; Seed, A. J.; Sampson, P. Tetrahedron Lett. 2001, 42, 8797.

114

Chapter 5.2 Five Membered Ring Systems: Pyrroles and Benzo Derivatives Daniel M. Ketcha

Wright State University, Dayton, OH, USA daniel.ketcha @wri ght.edu

5.2.1

INTRODUCTION

Reviews published during the reporting period of this chapter include a publication by Makosza detailing the use of vicarious nucleophilic substitution of hydrogen as a tool for the synthesis of indole and quinoline derivatives <01H(54)445>. There also appeared a review of simple indole alkaloids and those with a nonrearranged monoterpenoid unit <01NPR66>.

5.2.2

SYNTHESIS OF PYRROLES

The Paal-Knorr (P-K) pyrrole synthesis involving the reaction of primary amines with 1,4-dicarbonyl compounds had previously been demonstrated using microwave irradiation <99TL3957>. Most recently, a novel domino type application of this expedient was reported wherein (E)-l,4-diaryl-2-butene-l,4-diones 1 are treated with ammonium formate (or alkylammonium formates) in the presence of palladium on carbon leading to formation of the corresponding pyrroles 2 <01TL6595>. In this one-pot sequence, the ammonium formate serves the dual roles of hydrogen source for reduction of the double bond and as well as the amine component for reductive amination-cyclization. This reaction can be conveniently carried out in refluxing methanol (30-60 min) or in polyethylene glycol (PEG-200) as solvent in a microwave oven (0.5-2 min). The use of the acidic clay montmorillonite KSF for promotion of the P-K reaction of a wide variety of amines with 1,4-dicarbonyl compounds in dichloromethane at room temperature was also reported <01H(55) 1019>. Another interesting application of the P-K reaction involved the use of substituted 3-aminopyrroles as the amine component to prepare 1-heteroarylpyrroles as novel DNA interactive agents <01T10147>. Additionally, this reaction process was employed in the first synthesis of a conformationally restricted 2,2'-bipyrrole <01S67>, a class of compounds that can represent highly luminescent materials <01CC721>. Finally, Mueller described a novel one-pot, three-step, four-component pyrrole synthesis via a coupling-isomerization-Stetter-P-K sequence of an electron poor aryl halide, a terminal propargyl alcohol, an aldehyde, and a primary amine <01 OL3297>. A r ~ A I O I 1

O r

+

+ R N H 3 HCOO

Pd/C (10%), PEG-200 microwave (200 W) or MeOH reflux

=

Ar"'X~N'P""Ar R 2

D.M. Ketcha

115

Murahashi described a new pyrrole synthesis involving a rhodium complex-catalyzed reaction of isonitriles (e.g., 3) with 1,3-dicarbonyl compounds 4 to afford the pyrroles 5 <01OL421>. This process is believed to proceed by chemoselective activation of the oc-C-H bond of the isonitrile even in the presence of the more acidic dicarbonyl derivative.

R2

CN~CO2Et

+

RI~.]~ 0

3

4

R3

Rh4(C0)12 cat.

0

R3

R1

C02Et

H 5

Lagu <01TL6027> reported an improvement on the Cushman pyrrole synthesis <96JOC4999> which utilizes aldol products formed by the reaction of (N-Boc)-o~-amino aldehydes and ketones. Reasoning that the modest yields observed in the original procedure were likely due to polymerization of the pyrroles under the acidic conditions employed for removal of the tert-butoxycarbonyl group, Lagu employed o~-(N,N-dibenzyl)amino aldehydes 6 which upon treatment with the lithium enolates of various ketones produced the aldol products 7 in high yields. Standard hydrogenation conditions led to deprotection of the benzyl group and cyclization to afford the corresponding pyrroles 8 in improved yields.

o

o

RI" ]~ " H [...N.~ Ph Ph

R3

OH 0

R3 ~ . ~ R 2 LDA, THE,-78~

6

R'~ , . . ~

R2

f N . . h R"

/

Ph

/

7

H2

~.~

Pd-black

R'

L

Ph

8

R2 Ph

Namy reported a novel pyrrole synthesis involving initial samarium diiodide reduction of an oc-iminoketone 9 to provide an o~-aminoketone which upon reaction with a second ketone 10 undergoes further imine formation and inlramolecular cyclization to furnish the pyrrole derivatives 11 <01T4881>. Ph\ R2 /

Ph ph.~N ~

0

+

1) 2 equiv. Sml2, THF

0 .~.~./R 2 R1

9

Ph" N "

2) HCI 1M

10

R' 11

In a process similar to Ishii's previously developed samarium catalyzed multicomponent process <98JOC6234>, Ranu describes an efficient three-component coupling of oc,13unsaturated aldehydes or ketones 12, an amine 13 and a nitroalkane 14 on the surface of silica gel or alumina without any solvent under microwave irradiation affording the polysubstituted pyrroles 15 <01T4767>.

0

R1

R I " ~ R 2 R3 + R4NH2 + R5~N02 12

13

14

Si02 MW

R2

. ~

R5

1~4 15

R3

116

Five-Membered Rings." Pyrroles and Benzo Derivatives

In another three-component process, Nair successfully trapped the intermediate 18 formed between isocyanides 16 and dimethyl acetylenedicarboxylate (DMAD, 17) with Ntosylimines 19 to afford amino substituted pyrroles 20 <01JOC4427>.

CO2Me

~

-N-Ct

CO2Me N.%...Ar CO2Me Ts~ 19

" ~ N

+

CO2Me 17

16

MeO2C

CO2Me r

~ 20

18

]'s

A straightforward procedure for the preparation of 2,4-dicarbonylated pyrroles was devised involving addition of primary amines 21 to methyl propiolate (22) to provide the ~5enaminoesters 23 which undergo bromocyclization to the substituted pyrroles 24 upon treatment with N-bromosuccinimide (NBS)in dichloromethane at 0~ <01SL1440>. /CO2Me O

a1

CO2Me

Ill

ph'~NH2 21

MeOH -,. reflux, 72h

R3

{

NBS R2

CH2CI2

-

23

MeO2C

2

24

Dieter previously described a versatile pyrrole synthesis involving initial Beak deprotonation of tert-butoxycarbonyl (Boc) amines 25 followed by addition CuCN to afford ~-aminoalkylcuprates <00OL2283>. Such cuprates undergo addition with propargyl substrates to yield N-Boc-protected amino allenes 26 which can be deprotected with trimethylsilyltriflate (TMSOTf) to afford free ~-amino allenes 27. These substrates can either undergo direct intramolecular cyclization to 3-pyrrolines in the presence of silver nitrate, or a palladium-catalyzed tandem cyclization-aryl coupling reaction in the presence of aryl iodides to afford the 3-arylpyrroles 28 <01OL3855>. R

R1

1. sec-BuLi

R

R~

R

. . . . .

LN# 13oc 25

2. CuCN-2LiCl OMs 3. R2~R~--~-~ 3 -78 to 25~

N TMSOTf Boc C CH2CI2 I~.R3 -30 to 25~ 26

R2

R~

Pd(PPh3)4 DMF, K2CO3, 70~ [J...R3 Arl 27

Ar

RI~'-~

In an alternate example of a palladium-catalyzed route to pyrroles, Gabriele found that (Z)-(2-en-4-ynyl)amines 29 bearing an internal double bond undergo smooth cycloisomerization to pyrroles 30 in the presence of catalytic amounts of PdCI2 in conjunction with KC1 <01TL1339>. Gore described a somewhat similar intramolecular approach involving the anionic cyclization of ~-allenylhydrazines affording 3-pyrrolines <01T1939>. R2 R3 R2 R3 PdCI2/KCI ~ R 4

DMA, 25-100~ R

29

R4

Iql 30

R3

D.M. Ketcha

117

Gevorgyan describes a novel copper-assisted cycloisomerization of alkynyl imines 31 to 2,5-disubstituted pyrroles 32 as well as fused systems containing a pyrrole ring <01JA2074>. It was found that utilization of easily deprotectable N-substituents such as trityl or 3(ethylbutyryl) (EB) groups allows for facile access to N-unsubstituted pyrroles.

R2 ~..~. R~~

R3

31

Cul (30 mol%)

N"

R1

R2

Et3N/DMA (1:7), 110~

~2 32

An interesting synthesis of 2,3-difunctionalized 4-nitropyrroles 36 was developed employing 2-methyl-4-nitrosoisoxazolin-5(2H)-one (33) as the synthetic equivalent of a 1,3dipolar nitroenamine upon loss of CO2 <01JOC7535>. A one-pot synthesis of pyrroles can be achieved by reaction of 33 with sodium enolates 34 yielding 35 which can then undergo ring closure with ammonium chloride. NO2 N.O~ Me~

0

10~ 2h + ~ ONa 0 2." rt, 3h R1 R2 pyridine

33

34

H4C,

02N

EtOH

R1

I Me

02N.~ HO

R1

Me

0

36

35

Uno has devised a sequence to ~-frec pyrroles with perfluorinated groups at the 13positions based on the Barton-Zard synthesis <01S2255>. In this approach, the vinyl sulfones 37 were treated with ethyl isocyanoacetate in the presence of base to yield the pyrrole-2carboxylates 38. Reduction of 38 with lithium aluminum hydride gave the corresponding 2hydroxymethyl- pyrroles which were directly oxidized with manganese dioxide to afford the pyrrole-2-carboxaldehydes 39. Decarbonylation to the o~-free pyrroles 40 was achieved by refluxing with activated charcoal in mesitylene. Another interesting use of the Barton-Zard approach was made by Vicente for the synthesis of carboranylpyrroles bearing carborane cages in the 3- and/or 4-position of the pyrrole ring <01TL7759>. R2

R1

37 S02R

t-BuOK

R2

Et02 C 38

R1 2. MnO 2

H

R~

R2

OHC

R2

A 39

H 4O

H

Tosylmethyl isocyanide (TosMIC) was employed in a key step for the synthesis of bicyclic heterocycles from L-glutamic acid <01H(55)2099>, while benzyl isocyanoacetate was utilized for reaction with o~-acetoxynitro compound 41 to yield the pyrrole 42, an intermediate in the synthesis of (+)-deoxypyrrololine, a putative cross-link of bone collagen <01JOCll>. N(Boc)2

OAc

t _ B u O 2 C ~ 41

NO2

CNCH2CO2Bn

CO2Bu-t N(B~

DBU, THF

N_(Boc)2

N_(Boc)2

t-BuO2C~CO2Bu-t 42

"N" "C02Bn H

118

Five-Membered Rings: Pyrroles and Benzo Derivatives

Fillipone reported a solid phase synthesis of pyrroles from 1,2-diaza-l,3-butadienes 43 and 13-ketoamides 44 in the presence of copper(II) dichloride <01T5855>. It is envisaged that Michael-type addition of the activated methylene on the 1,2-diazaheterodiene moiety is followed by an intramolecular addition of the nitrogen atom of the C=N group to the carbonyl in ~5-position yielding the pyrroles 45.

Magnus devised a novel approach to the construction of pyrroles from amides enroute to the total synthesis of rhizinilam <01T8647>. Thus, conversion of amide 46 to the thiophenyl imino ether 47 followed by treatment with 2-nitrocinnamyl bromide (48) and DBU led to the pyrrole 49.

HNo~

HNo~

~ B r 1"/"-,.~"~NO2 48

1" PCI5 ~ 2. PhSH/Et3N= PhS 47

v

N "~-

2. DBU,0~

Grigg described a sequential palladium/ruthenium-catalyzed three-component process for the synthesis of heterocycles including 3-pyrrolines <01TL8673>. This procedure involves allenylation of aryl/heteroaryl iodides to generate (rt-allyl) palladium species which are intercepted by nitrogen nucleophiles (e.g., 50) to afford the 1,6-dienes 51 which are then subjected to ring-closing metathesis (RCM) to afford the arylated 3-pyrrolines 52. Dowden reported a similar olefin metathesis route to 3-pyrrolines using a recyclable, polymer supported alkylideneruthenium complex <01 CC37>.

[~~

.1

5.2.3

+ --,,---

S Pd(0) + HN/ = SO2Ph 50 I

,

RCM

SO2Ph

SO2Ph

51

52

I

I

REACTIONS OF PYRROLES

Gmeiner introduced the diethoxymethyl (DEM) substituent as a useful protecting group for pyrroles beating electron withdrawing groups 53 <01S2281>. N-Protection can be easily accomplished by heating the heterocycles in trimethyl orthoformate while deprotection can be achieved by treatment of the DEM-pyrroles 54 with trifluoroacetic acid in acetonitrile. DEM protection proved suitable for a variety of regioselective transformations such as directed ortho-metallation affording the c~-substituted derivatives 55. Additionally, halogenations upon the C-2 substituted derivatives occur at the C-4 position, from which Pdcatalyzed coupling procedures enable the introduction of a variety of carbon substituents at that [3-site. Interestingly, Reese has shown that reaction of orthoesters with pyrrole and chloroacetic acid leads to moderate yields of tri(pyrrolyl-2-yl)alkanes <01TL5545>.

D.M. Ketcha HC(OEt)3' reflux EWG 53

1. TFA, CH3CN, rt 2.2N NaOH, It

'

H

119

~ EWG 54

Base DEM

~-~

Electrophile

EWG

DEM

55

E

In terms of novel methodologies for C-2 functionalization, it was found that pyrrole could be converted to pyrrole-2-carboxylate in supercritical CO2 using cells of Bacillus megaterium PYR 2910 <01CC2194>. Meanwhile, MacMillan demonstrated the first enantioselective organocatalytic Friedel-Crafts alkylation of pyrroles (e.g., 56) generating 13-pyrrolyl carbonyls 59 via coniugate addition to oq3-unsaturated aldehydes 57 in the presence of chiral imidazolidinone 58 <01JA4370>.

+ Me

R ~ O 57

56

HXBn

O.

,Me N ,\Me ,/~Ue H

~O

58

Me R 59

20 tool% in THF/H20

Trofimov reported the C-vinylation of 1-vinylpyrroles 60 with electrophilic acetylenes such as benzoylacetylene (61) upon grinding the reagents with silica gel at room temperature to afford (E)-(2-benzoylvinyl)- 1-vinylpyrroles 62 <01S 1878>. a2

a1

(SiO2)n_mH20

+

J

o 60

61

62

Silica-supported Lewis acids [Si(M)] in conjunction with microwave irradiation were employed for the Michael addition of pyrrole (63) with a-acetamidoacrylate (64) as a route to pyrrolyl alanine derivatives 65 <01T5421>.

+

~0020H3

I

NHCOCH3

MW Si(M)

~,~

~,..O20H3

"N'I v

H

"NHCOCH3

H

63

64

65

Lanthanide based Lewis acids continue to play pivotal roles in expediting electrophilic substitution reactions of both pyrroles and indoles (vide infi'a). To the point, pyrroles (e.g., 63) have been found to undergo efficient conjugate addition with elcctron deficient olefins 66 in the presence of a catalytic amount of indium trichloride to afford the Michael adducts 67 <01TL8063>.

I H

63

+

~ R O 66

InCl3 (10 m~176176 0H2012, rt

R H

67

O

Additionally, Y(OTf)3 was found effective in catalyzing a novel Mannich reaction between N-alkoxycarbonylpyrroles 68 (R = EtO2C-, Me3CO2C-), formaldehyde and primary

120

Five-Membered Rings." Pyrroles and Benzo Derivatives

amine hydrochlorides 69 to produce monoalkylation products 70 in aqueous media <01TL461>.

+

i

R 68

O H..C.,H + R'--NH2 9

Y(OTf)3 (10 mol%) . . . H20/THF (10:1)

II

~N~H . .

-

I~

69

N

70

Tietze described a novel twofold Heck reaction of vinylpyrroles 71 with diiodobenzenes 72 as a convenient approach to the synthesis of linear pyrrole oligomers connected by divinylbenzene units 73 <01CEJ368,01SL337>. In work by others, sulfonyl substituted pyrrole-containing chromophores with a C=C ~: bridge to an aromatic ring possessing an amino function were prepared for use as second-order nonlinear optics materials <01TL1309>.

R

R

'~--

+

I

Boc 71

I

~

R ~

Pd~

R

R

~ "~

72

73

R

Boc

The importance of radical processes in the chemistry of pyrroles and indoles remain vital in expanding the repertoire of reaction processes available to these heterocycles. For example, Allin and Mclnally have devised a novel approach to [1,2-a l-fused pyrroles 76 via intramolecular acyl radical cyclization of N-(o~-acyl)-radicals 75 generated from acyl-selenide precursors 74 <01TL7887>. This reaction can be conducted even in the absence of CO and has also been shown feasible on electron rich pyrrole rings.

CHO

CHO

CHO

0

74

~ n

SePh AIBN

75~n ~

9

76

In terms of C-3 substitution reactions, the regioselective borylation of 1-triisopropylsilylpyrrole (77) was achieved providing a valuable reagent for cross-coupling reactions <01OL2831>. Thus, reaction of 77 with the rhodium precatalyst shown in the presence of pinacolborane affords the C-3 substituted derivative 78.

BPin

trans- R h (O l) (PiPr3) (N2 )

i SiPr3 77

HBPin

~ i SiPr3 78

Dolphin developed an efficient preparation of 3,3'-dipyrrolylsulfides 80 by the reaction of 3-unsubstituted pyrroles 79 with sulfur dichloride at low temperature <01S40>. Such dipyrrolyl species are anticipated to represent useful ligands for construction of supramolecular assemblies.

D.M. Ketcha

121

SCI__.s R1

R3

H i

CH2CI 2

R1

79

H

R3..----'-~N,>~-- R 1

i

I~1

80

Davies has further exploited his previously reported approach to the tropane skeleton related to cocaine based on the rhodium catalyzed decomposition of the vinyldiazomethane 81 in the presence of N-Boc-pyrrole (82) <01BMCL487>. Reduction of the non-conjugated double bond followed by N-deprotection and N-alkylation provided substrate 83 which was susceptible to conjugate addition of nucleophiles such as 84 in the presence of CuBr to afford 3-13-aryl tropanes which exhibited potent binding affinity for both the dopamine and serotonin transporters. Additionally, this author described the synthesis of various methyl heteroaryldiazoacetate analogues of 81, one of which possessed an indole function, for use in catalytic asymmetric cyclopropanations <()1JOC6595>.

N2

0 ~OEt

R1 ~ Rh2(OOct)4 N" 0 NBoc then[H] ~ ~ O E t

81

82

R4 R3

BrMg

83

84

Much attention has been focused on the Diels-Alder (D-A) reaction of pyrroles, and Node examined the endo/exo selectivities of cycloadditions of N-protected pyrroles 85 with allene1,3-dicarboxylates 86 under Lewis acid assisted and thermal reaction conditions <01TL9237>. It appears that a novel attractive effect operates between the N-protective group of the pyrrole and the ester group so as to favor the exo orientation in the adducts 87 by a mechanism more effective than the Alder orbital effect. The recognition-induced control and acceleration of a pyrrole D-A reaction was achieved through hydrogen bonding interactions involving an aminopyridine substituted N-benzoylpyrrole and a maleimide possessing a pendant carboxylic acid <01TL2377>. Additionally, the pyrrole D-A reaction was utilized as a key step in the synthesis of epibatidine derivatives displaying antinociceptive effects <01JMC2229>, while the reactions of masked o-benzoquinones with pyrroles were also examined <01TL5481>.

+

Ni

R'

5.2.4

H 85

. .F

N

H

86

87

C02R

SYNTHESIS OF INDOLES

The classical Bischler indole synthesis involving the reaction of using ~-haloketones and anilines was employed by researchers at Wyeth-Ayerst for the synthesis of 2-aryl-5hydroxyindole estrogens for potential use in hormone replacement therapy for the treatment of osteoporosis <01JMC1654>. A conceptually similar Bischler-type indole synthesis was described involving the reaction of anilines 88 with propargyl alcohols 89 in the presence of a ruthenium carbonyl/additive mixture <01TL3865>. This one-pot reaction consists of three steps: a) hydroamination of the alkyne triple bond; b) hydrogen migration of the resulting

122

Five-Membered Rings." Pyrroles and Benzo Derivatives

amino alcohol to an aminoketone (Bischler-type intermediate), and; c) cyclization to the indoles 90 <01TL3865>. HO

R2

R1

additive NH2

+

140~

88

RI

solventless

.... ~ ~ , , , . N ..~,,,,.R2

89

90

H

Previously, Cho and Shim disclosed an efficient protocol for the preparation of indoles via the ruthenium-catalyzed reaction of anilines and trialkanolammonium chlorides in an aqueous medium (H20-dioxane) at 180~ in the presence of triphenylphosphine and tin(II)chloride <00TL1811>. These authors now provide full details for this procedure and propose a reaction pathway involving alkanol group transfer from alkanolamines to anilines <01T3321>. The use of an "environmentally safer" solvent, namely chloroaluminate ionic liquids (1butylpyridinium chloride-A1Cl3), was reported as being effective for the Fischer indole synthesis <01S370>. The Buchwald-Hartwig Fischer indole synthesis involving Pd-catalyzed preparation of N-arylbenzophenone hydrazones was utilized by Gmeiner for the synthesis of indoloparacyclophanes <01AG(E)1283>. Naito developed a variant of the Fischer indole synthesis involving formation and thermal cyclization of N-trifluoroacetyl enehydtazines, wherein the requisite [3,3]-sigmatropic rearrangement is found to proceed even under nonacidic conditions. This author now discloses a one-pot protocol involving molecular sieve catalyzed condensation of the hydrazines 91 with enolizable ketones to afford the hydrazones 92, followed by formation of the enehydrazines 93 with trifluoroacetic anhydride (TFAA) in the presence of triethylamine. Finally, thermal cyclization in refluxing solvent (usually aromatic) leads to high yields of the desired indoles 94 <01S1635>. R3 R 2 ~ % v ~ ~ N ~N H2 91

R3

ketone

TFAA =

MS 4A, ~

i~ 1

92

N'N

Et3N

~'

0~

~ ~M'N'N"cOCF3

93

~,

-

94

~,

Bonjoch has just begun to explore a novel intramolecular annulation of 2-haloanilines with pendant ketones 95 which can lead to indolic products 96 by either of two different and competitive cyclization pathways, namely, enolate arylation or addition of the organometallic intermediate to the ketone carbonyl group <01 CC1888>. 'N

PdCI2(PPh3)2 ~9 ~

95

s Bn

O

Cs2CO 3, toluene sealed tube 110~

[ ~ ~ / 96

J

Bn

The Sonogashira coupling of terminal alkynes with 2-haloaniline derivatives followed by cyclization under metal- or base-promoted conditions has been a popular procedure for the preparation of indoles. Kabalka now reports a solventless, microwave-enhanced coupling reaction of aromatic iodides with terminal alkynes on potassium fluoride doped alumina in the presence of palladium powder, cuprous iodide, and triphenylphosphine <01T8017>. When applied to the case of o-iodoanilines 97 (Y = H, COCH3, COCF3, SO2CH3), this

R4

123

D.M. Ketcha

coupling occurs with concomitant deprotection and cyclization to generate indole products 98 especially when additional Pd(II) is employed. Cook employed this type of heteroannulation reaction using an internal alkyne derived from the Schollkopf chiral auxiliary for the preparation of optically active tryptophans <01JOC4525>. Alternatively, Dai reported the first use of 2-aminophenols in this process wherein the corresponding N-acylated triflates underwent iodide accelerated Sonogashira coupling using Pd(0)/Cu(I) in the presence of nBu4NI followed by a base-catalyzed cyclization-deprotection sequence to yield indoles products <01TL5275>.

[ ~ ' ~ 'N 97

+ HY

Pd-CuI-PPh3/KF-AI203 Solventless,MW

R-C-=CH

[ ~ ~ R

H

98

Flynn reports a single step, multi-component coupling approach to indoles and benzofurans involving initial deprotonation of a mixture of the N-acyl precursor 99 (or phenol) and the terminal alkyne with MeMgC1 to give the corresponding magnesium amide anion 100 and magnesium acetylide <01CC1501>. Addition of Pd(PPh3)2CI2 (3 tool%), dilution with DMSO and a suitable coupling partner (R3Y: e.g., vinyl- or arylhalide, allylic acetate) then gives the heteroannulatively coupled product 101.

R1~~ ;

+ i 2 MeUgC,(2eq)

HAc II

R I ~

Pa(PPh3)2CI2

R2

N_MgCI

99

Ac/

ml~ '~"R3

R3y DMSO

N~R2H

1 O0

101

Back utilized an interesting variant of the Heck reaction involving the palladiumcatalyzed heteroannulation of o-iodoanilines 102 with dienyl sulfones 103 to afford 2sulfonylindolines 104 <01JOC8599>. These indolines could be oxidized to the corresponding indoles with DDQ, whereupon D-A reaction of the resulting 2-vinylindoles with dienophiles led to a convenient route to carbazoles.

R..~~

+ H

102

I~1

Pd(OAc)2 U"

Ts

R3 103

R

DMF_H20

104

R~

Ts

R3

In nearly simultaneous publications, Mori <01OL1913> and P.A. Evans <01OL3269> disclosed procedures for the enantiospecific allylic amination of N-(arylsulfonyl)anilines providing allylic sulfonamides which could be converted to indolines. In the former approach, palladium-catalyzed cyclization of the allylic sulfonamides 105 led to a mixture of the corresponding indolines 106 and 107. Mori then utilized this type of indolization process in total syntheses of the Strychnos alkaloids (-)-dehydrotubifoline and (-)-tubifoline.

..OTBDMS N r

105

/OTBDMS

mo..

ligan_d(10 mol %) ,~ Ag2C03' 90Oc

OTBDMS +

106

TsH

107

N

TsH

124

Five-Membered Rings: Pyrroles and Benzo Derivatives

Belier disclosed additional details concerning a novel approach to the synthesis of indoles via reaction of aliphatic and aromatic amines with 2- and 3-chlorostyrenes 108 in the presence of potassium tert-butoxide to give N-substituted 2,3-dihydroindoles 109 <01JOC1403>. Dehydrogenation with 10% Pd/C and stoichiometric amounts of ammonium formate provides the corresponding indoles 110. The avoidance of palladium catalysts for the stylization step and the amenability of aryl chlorides to C-N coupling in this process make it an attractive alternative to Buchwald-Hartwig amination protocols

R1

R1

KOt-Bu + R2-NH2n~~-e--" tolue X 108

~N

135~

109

R1

J

Pd/C HCO2NH4 120~

i~2

110

!@

Johnston demonstrated the applicability of a conceptually novel process for aryl amination using free radical intermediates for the preparation of indoles <0lOLl009>. In this approach, ketimines derived from o-bromophenethylamines 111 cyclize via a reductive 5-exo radical process to N-substituted indolines 112 when treated with n-Bu3SnH and a radical initiator.

~ H

R1

111

q2 2

R1

1. Ph(R3)CO 2. n-Bu3SnH,AIBN 06H6,80~

R2 ph.~R3 112

Grigg reports further advancements in palladium-catalyzed cyclization-anion capture cascades which typically replace the [3-elimination step of a Heck reaction with a group or atom transfer <01T10335>. In one variant, after cyclization of iodo alkene 113 and subsequent carbon monoxide insertion, termination of this queuing process with hydride reagents, organostannes <01T1361>, or as illustrated below with NaBPh4, yields the termolecular adduct 114 <01T1347>.

[~i.

~

11:3

SO2Ph

I

Pd(O) CO(1 atm),NaBPh4

~

~

0 I

114

SO2Ph

Additionally, in what is termed a "zipper" cascade process, palladium-catalyzed reaction of 2-iodo-N-tosylaniline (115), allene and 2-iodothiophene (116) provided the intermediate 117, which after cyclization was treated with boronic acids as capture reagents to provide the indolines 118 <01TL8677>. A similar approach was employed for the synthesis of spiro- and fused heterocycles <01CC964>.

115

,,,

Ts

116

e,__70oo

s

117

118

Ts

D.M. Ketcha

125

Previously, Zhang reported a solid-phase approach to indoles involving the palladiumcatalyzed heteroannulation of 2-iodoanilines with terminal alkynes. Unlike the analogous reaction with internal alkynes, activation of the amine in this case was required and to that end the authors employed a resin-based traceless sulfonyl linker to serve the dual purposes of facilitating the indole cyclization and anchoring the substrate to the polymer <00OL89>. Schultz employed this traceless sulfonamide linker strategy in a cleverly designed combinatorial synthesis of 2,3,5-trisubstituted indoles <01OL3827>. Thus, reaction of commercially available PS-TsC1 (poylstyrene sulfonyl chloride, Argonaut Technologies) resin 119 with 4-bromo-2-iodoaniline (120) afforded the resin-bound sulfonamide 121. Initial attempts to selectively introduce substituents at C-2 using conditions previously reported by Zhang (i.e., 70~ led to reaction at both the 2-iodo and 4-bromo groups. However, conducting the reaction at room temperature provided the desired cyclized product 122. The indole C-3 position was then modified by Friedel-Crafts acylation yielding 123, which could then undergo Suzuki (or Sonogashira) coupling to afford the C-5 functionalized derivatives 124. Finally, saponification of the resin-bound indole with base provided N-unsubstituted indoles, or alternatively, the resulting nitrogen anion could be capped with alkyl halides to provide the indole scaffold 125 with four points of diversity.

Not to be outdone, Zhang described an alternate solid-phase approach to diverse indoles featuring sequential palladium-mediated indole ring construction, regioselective halogenation, and Suzuki coupling <01TL4751>. Thus, resin bound o-iodoaniline 126 underwent regioselective heteroannulation with trimethylsilylalkyne to provide the 2(trimethylsilyl)-3-alkylindole 127 predominantly. The silyl group was then converted to the corresponding 2-iodo species 128 upon reaction with N-iodosuccinimide (NIS). An alkyl group can then be introduced onto the indole nitrogen thereby creating another point of diversity yielding 129. Finally, Suzuki coupling to provide the 2-aryl derivatives followed by cleavage from resin led to the indoles 130. Zhang also reported the solid-phase synthesis of indole-based peptide mimetics as thrombin receptor (PAR-l) antagonists <01BMCL2105>.

126

Five-Membered Rings." Pyrroles attd Benzo Derivatives

The Fukuyama indole synthesis involves the intramolecular radical cyclization of 2alkenylisocyanides, the availability of which often limits the utility of this process. In order to access a wider variety of such substrates, the author prepared the versatile HomerWadsworth-Emmons reagent 131 using the Pudovik reaction <01SL1403>. Reaction of 131 with a variety of aldehydes thus provides a convenient and general route to diverse alkenyl precursors 132. Additionally, instead of the standard radical conditions using tri-n-butyltin hydride, Fukuyama now finds that excess thiols are quite effective for inducing cyclization, whereupon desulfurization of the indoles 133 can be effected with Raney-Ni if desired.

. . . . THF,-78~ .... [~NcPO(OEt)2 LDA, ~ RCHO,-78~ tort 131 132

R R'SH,AIBN CH3CN,100~

~ 133

~R N SR' H

Nettekoven has devised an interesting combinatorial approach to diverse libraries of indole derivatives <01BMCL2169>. In this approach, 2-aminobenzonitriles 134 are treated with acid chlorides affording the amides 135 which upon treatment with various o~bromoketones yield the corresponding indoles 136. Taking advantage of the "libraries from libraries" concept, the original library could be subjected to selective amide hydrolysis to produce a companion library of N-H indole derivatives.

C~N R1 ~

NH2

0 R4"~O C#N /NH Br'v'[L" R3 ~ / ~ N , ~ R 3 R2COCl I~o~HR DCM, pyridine~R 6s2003, DMF R thenR4COCl R2..~O0 136 135 2

134

5.2.5

REACTIONS OF INDOLES

Moody described the development of a new N-protecting group for indoles, namely the 2phenylsulfonylethyl moiety <01TL135>. This group can be introduced using 2-chloroethyl phenylsulfone and deprotected using potassium tert-butoxide in DMF. N-Alkylation of heterocyclic compounds bearing an acidic hydrogen atom attached to the nitrogen including pyrroles, indoles and carbazoles can be accomplished with alkyl halides in acetonitrile using cesium fluoride/celite as a solid base <01T9951 >. An environmentally benign method for the N-methylation of indole using dimethyl carbonate in refluxing DMF in the presence of K2CO3 was reported and used successfully in a 300 gal reactor for the N-methylation of 6nitroindole <01OPRD604>. Previously, it had been demonstrated that indoles 137 could be efficiently N-arylated via the palladium-catalyzed coupling of aryl halides 138 using Pdz(dba)3 in the presence of biaryl(dialkyl)phosphine ligands <00OL1403> or using the Pd(OAc)2/P(t-Bu)3 system <00TL481>. To complement these processes, Buchwald now describes application of the venerable Goldberg reaction for the N-arylation of a variety of heterocycles as well as the copper-catalyzed amidation of aryl and heteroaryl halides <01JA7727>. Thus, the combination of air stable CuI and racemic trans-l,2-cyclohexanediamine (140) in the presence of K3PO4, K2CO3, CszCO~, or NaOt-Bu comprises an extremely efficient catalyst for the N-arylation of indoles 139 (including 2-aryl and 7-alkyl derivatives) as well as pyrrole and carbazole.

127

D.M. Ketcha

137

N"

+

R2 138

10 mol%ligand 2.1 equiv K3PO4 110~ 24 h, dioxane

139

N

H2N

R2

NH2

140

In terms of interesting examples of C-2 substitution reactions, C-2 lithiation of indole and 1-methylindole followed by treatment of the resulting anions with elemental sulfur leads to formation of pentathiepino[6,7-b]indoles <01T7185>. Additionally, upon treatment with excess butyllithium, 2-iodoindole (141) undergoes both deprotonation at nitrogen and lithium-halogen exchange to generate 1,2-dilithioindole (142) <01SC947>. Once formed, the dianion 142 reacts with electrophiles of moderate reactivity selectively at the more basic carbon site to afford mainly C-2 substituted indoles 143.

~ N 141

LI I

H

BuLi (xs)

=-

~

E+ Li ihen H20=

142

~NLE

I

Li

143

I

H

In furtherance of studies on the synthetic utility of 2,3-dihaloindoles, Gribble reports a facile preparation of 2,3-diiodo-N-methylindole (144) from 2-iodoindole (141). Furthermore, upon halogen-metal exchange, a relatively stable 2,3-dilithio species 145 can be generated and undergo subsequent reactions with various electrophiles such as DMF, C1CO2Me, CO2, and phthalic anhydride <01 TL2949>.

141

I~ I"KOH'I2.= ~ N N I 2. Mel i n.-Bu4NHS04 144 H

i

I~ I ,-guLi = ~ I THF,-78~

Me

145

i ~ L` N Li i Me

In contrast to the facile rearrangement of 3-1ithio-l-(phenylsulfonyl)indoles to the more stable C-2 isomer, 3-1ithio species bearing bulky N-trialkylsilyl protecting groups are resistant to this undesired lithium atom migration and represent versatile synthetic intermediates with a variety of applications. Amat describes the synthesis and utilization of such species prepared by a sequence involving regioselective C-3 bromination of 4-, 5- and 6-methoxy substituted 1-(trialkylsilyl)indoles 146. The resulting C-3 bromo derivatives 147 then undergo halogenmetal exchange to provide the corresponding 3-1ithioindoles 148 <01S267>. The reactions of these robust lithio species with a number of electrophiles were examined as was their transmetallation with ZnC12 to afford the 3-indolylzinc chlorides which were demonstrated to undergo Pd(0)-catalyzed cross-coupling reactions with 2-halopyridines.

jBr N" I 146 SiR3

N" I 147 SiR3

HC.,i THF, -78~ ~

N" I 148 SiR3

Amazingly, Iwao reports that 1-(triisopropylsilyl)indole can be directly lithiated at the C3 position with tert-BuLi-TMEDA in hexane at 0~ <01TL7621>. Furthermore, this author also describes an unusual C-3 lithiation of indoles 149 beating the 2,2-diethylbutanolyl

128

Five-Membered Rings." Pyrroles and Be,zo Derivatives

(DEB) protecting group <01T975>. Although the DEB group normally directs lithiation to the C-7 position under kinetically controlled conditions (sec-BuLi, TMEDA, -78~ via a complex-induced proximity effect involving coordination of the lithiating species to the DEB-carbonyl, it was reasoned that use of a coordinatively saturated ligand might suppress such an effect and allow instead for C-3 lithiation. Indeed, use of 1.5 equiv, of sec-BuLi in the presence of the tridentate ligand N,N,N',N",N"-pentamethyldiethylenetriamine (PMDTA) at-78~ effects regioselective C-3 deprotonation which after quenching with electrophiles affords the C-3 substituted indoles 150. Moreover, using the superbasic system sec-BuLi-tertBuOK, lithiation is found to occur exclusively at the C-2 position via abstraction of the most acidic proton. 1. sec-Buki, PMDTA, hexane ~ E -78~ 1 h 2. electrophile, -78Oc, 1 h I I 149 DEB 150 DEB Indolylborates 152 (R = Me, Boc, OMe), available via regioselective C-2 lithiation of indoles 151, undergo palladium-catalyzed carbonylative cross-coupling with prop-2-ynyl carbonates to afford cyclopenta[b]indole derivatives 153 <01H(55)1063)>. • X

2 . BEta 151

I

R

t3

L 152 R

0COOMe PdLn, CO THF, 60~

153

Iq

0

Bennasar utilized the Shapiro reaction of the indolic trisilylhydrazones followed by quenching the intermediate vinyl anions with Me3SnC1 to yield the 1-(2indolyl)vinylstannanes 154 <01 T10125 >. Such vinylstannanes were demonstrated to undergo Sn-Cu transmetallation to produce higher order vinylcopper derivatives capable of reaction with N-alkyl-3-acylpyridinium salts 155 mainly at the (~-position affording the dihydropyridines 156. Interestingly, the observed a-regioselectivity could be partially or totally reversed when the corresponding organomagnesium reagents were utilized. a SnMe3 154

IVle

"

+

@x

N 155

Me2Cu(CN)Li2 . Y

156

I~le

"

I~

Bennasar also demonstrated the generation and intermolecular reaction of 2-indolylacyl radicals derived from the corresponding phenyl selenoesters 157 with a variety of alkene acceptors under reductive conditions (e.g., n-Bu3SnH/AIBN) affording 1,4-dicarbonyl compounds bearing the 2-acylindole moiety <01OL1697>. To further exploit the synthetic possibilities of 2-indolylacyl radicals, the author has devised a novel cascade annulation process utilizing n-Bu6Sn2/hv wherein the addition reaction of the 2-indolylacyl radical with suitable electron-deficient alkenes affords a new radical species 158 which can undergo intramolecular cyclization to afford the cyclopenta[b]indole nucleus 159 <01JOC7547>.

D.M. Ketcha

129

Z ,.SePh n-Bu6Sn2, hv 157

Me

C6H6

O

N

158 Me

Z O

-

---

"

159

IVle

O

Gribble described a novel radical cyclization of 2-bromoindole-3-carboxamides 160 to provide a synthesis of hexahydropyrrolo[3,4-b]indotes <01CC805>. It is believed that the reaction involves the sequence (1) generation of the expected indole C-2 radical, (2) 1,5-H atom abstraction to give the c~-amidoyl radical, (3), 5-endo-trig cyclization to the indole C-2 position, and (4) hydrogen abstraction to give indoline 161. O O

BUA~nNH toluene,A

160 Me

16~1 N

)n

Meanwhile, Jones described a somewhat similar tandem radical sequence upon the substrate 162 as a facile entry to the tetracycle 163 possessing the ABCE-rings characteristic of the Aspidosperma and Strychnos alkaloids <01 CC209>.

~N~,...CN 162 IMe

0

s-iBu'm-xylene ; 163 Me

l~e

Thermolysis of the 1-~-azidoalkylindoles 164, bearing an electron attracting substituent at C-3 ( - C H O , - C O M e , - C O z M e , - C N ) is found to provide the tricyclic 2-aminoindoles 165. This process is believed to proceed by initial intramolecular 1,3-dipolar cycloaddition of the azido moiety onto the indole 2,3-double bond to produce an intermediate triazoline which upon heating at 180~ in a sealed metal reactor undergoes loss of nitrogen to yield the fused ring products <01TL5351>.

PhBr, 180~ ,.

N '"

NH

('In

Historically, Friedel-Crafts acylations of N-unsubstituted indoles were found to provide a mixture of 3-acyl- and 1,3-diacylindoles. Last year, Yoshino disclosed a novel method for the regioselective C-3 acylation of N-unsubstituted indoles with acyl chlorides in the presence of dialkylaluminum chlorides in a process that obviated the need for prior N-protection <00OL1485>. Intriguingly, despite the known susceptibility of indoles towards acidcatalyzed dimerization processes, Yoshino nevertheless pretreated the indoles 166 with the Lewis acid prior to addition of the acid chlorides, an artifice that in some way may account for the observed selectivity for the desired 3-acyl derivatives 167. Ottoni confirms the effectiveness of this sequence and also notes the importance of added nitromethane as cosolvent <01OL1005>.

130

Five-Mernbered Rings." Pyrroles and Benzo Derivatives

O

X ~ 166

Et2AICI or Me2AICl

R'COCI

X ~ ~

I

H

167

~ " R' I~1

Moreover, Nakatsuka previously reported the formation of the unusual 1,6-diacyl substitution patten of indoles upon Friedel-Crafts acylation <94TL2699>. Noting that theoretical calculations indicate that the most reactive positions of 1-acylindoles should be C3 and C4, Ottoni hypothesized that upon premixing, 1-acylindoles form an A1C13-carbonyl complex 168, whereupon such an intermediate constitutes a de facto "meta" director favoring substitution at C-6 <01TL1467>. In fact, upon addition of l-acetylindole to a stirred suspension of aluminum chloride in dichloromethane followed by addition of the acylating agent, good yields of the 1,6-diacylated indoles 169 were indeed obtained.

Ci I . !/CIi HsCI~"-O.A/,'--C

RCOCl or (RCO)2; AICI3, CH2CI2

R O

H3C/-~O

168

169

Yadav reports the efficient conjugate addition of indoles 170 with ~,13-unsaturated compounds 171 in the presence of indium chloride yielding the 3-alkylindoles 172 <01S2165>. This reaction has been shown to be general for a variety of electron-deficient olefins and the products are free of any side products like dimers or trimers normally observed under the influence of strong acids. Alternatively, Jung utilized ytterbium triflate for the Michael addition of N-methylindole to mesityl oxide <01TL6835>. Furthermore, a microwave-assisted Michael reaction of 3-(2'-nitrovinyl)indole with indoles on TLC-grade silica gel affording bis(indolyl)nitroethanes was also reported <01TL3913>. O +

H

rt

R

O

170

H

171

172

In a reaction more characteristic of the reactivity of indoles under acidic conditions, Yadav finds that lithium perchlorate efficiently catalyzes the reaction of indoles 173 with aldehydes and ketones 174 to afford bis(indolyl)methanes 175 <01S783>. In a somewhat similar fashion, the coupling of indoles with 4-pyridinecarboxaldehyde produced 3-indolyl-4pyridinyl methanols which could be reductively deoxygenated with Et3SiH/'I'FA to provide a facile preparation of 3-(4-pyridinyl)methylindoles <01TL7333>. Meanwhile, Chakrabaty published a review on the synthesis and biological activity of diindolylalkanes <01H(55)2431>. R R1 o c,o.

X

173

H

+ R.-~ R1 174

CH3CN, r.t.

H

175

H

D.M. Ketcha

131

An interesting example of the Petasis reaction was employed as a highly stereoselective synthesis of indolyl N-substituted glycines by the reaction of indolyl-3-boronic acids <01TL2545>. Thus, reaction of N-tosyl-3-indolylboronic acids 176 with (R)-o~-methylbenzylamine (177) and glyoxylic acid (178) provides the indolyl N-substituted glycines 179 in optically pure form. Ph

HNA..

O P h . . ~ .~CO2H + + H NH2

R 176

t

Ts

177

R

rt, 12 h

N I

179

178

Ts

Kerr has devised a novel [3 + 2] cyclopentannulation of indoles bearing an alkyl substituent in the 3-position <01JOC4704>. In this protocol, 3-alkylindoles 180 are treated with 1,1-cyclopropanediesters 181 in the presence of ytterbium triflate at elevated temperatures or ultrahigh pressures to afford intermediates 182, which unable to undergo rearomatization instead undergo an annulative process via attack of the malonate ion onto the resultant indolenium ions to afford the fused-ring derivatives 183.

1

+

R~>~

R2

180

R4 CO2R

Yb(OTf)3 =-

181

R 1 R4

_ CO2R_

CO2R

43

CO2R

182

_

~N.~'\R 2 ~3

183

N CO2R ~3 R CO2R

In continuation of previous studies <00T10133> on the cycloaddition reactions of 2-and 3-nitroindoles, Gribble reports that such species (e.g., N-tosyl-3-nitroindole, 184) undergo Diels-Alder reaction with Danishefsky's diene 185 to give the expected 2- or 3hydroxycarbazoles 186 with apparent complete regioselectivity <01TL4783>. Meanwhile, Mancini <01JOC3906> and Piettre <01OL515> examined the behavior of 1-tosyl-3substituted indoles (e.g., 3-CHO, 3-acetyl, and 3-nitro) with conjugated dienes including Danishefsky's diene under thermal and/or high-pressure conditions. While cycloaddition could be achieved under either condition, reactions done under high pressure could be effected without thermal extrusion of nitrous acid and the accompanying aromatization. OMe ..~ 1. Toluene, A _-

184

N J Ts

+

OTMS 185

2. HCl, THF

OH 186

Ts

Larock prepared a variety of 13- and ;/-carbolines 188 by the palladium-catalyzed iminoannulation of internal alkynes with the tert-butylimines of N-substituted 3-iodoindole2-carboxaldehydes 187 as well as 2-haloindole-3-carboxaldehydes <01OL3083>. When unsymmetrical alkynes are employed, mixtures of regioisomers are observed in most cases. The optimal conditions at present employ 0.25 mmol of imine, 2 equiv of alkyne, 5 mol % of Pd(OAc)2, 5 tool % of PPh3, and 1 equiv of n-Bu3N as base in 5 mL of DMF at 100~ The reaction is envisaged as proceeding through oxidative addition of the indole halide to Pd(0) producing an organopalladium intermediate which then inserts the acetylene, producing a vinylic palladium intermediate which reacts with the neighboring imine substituent to form a

132

Five-Membered Rings: Pyrroles and Benzo Derivatives

seven-membered palladacyclic ammonium salt. Subsequent reductive elimination produces a tert-butylcarbonium salt and regenerates Pd(0). R1 + R1 - N I

187

R2

cat. Pd(0) .~

NtBu

/k....~N

base

N

R

188

I

R

Concurrent with this disclosure, Rossi reports a similar protocol wherein 2-acyl-1(phenylsulfonyl)-3-iodoindoles 189 undergo room temperature palladium-catalyzed coupling with terminal alkynes to afford the corresponding 3-alkynylindoles 190 <01S2477>. Subsequent treatment with ammonia in methanol leads to formation of the 13-carbolines 191 through sequential addition/elimination/cycloamination reactions accompanied by loss of the N-phenylsulfonyl group. a 1

N PhO2S

R O

PO(OAc)2,DPPF = TEA, DMF, rt

N I

PhO2S

.R

MeOH -"

N I

O

H

190

189

R

191

A variety of interesting cyclization processes have been reported for the construction of tricyclic indoles, for instance Nagata utilized an intramolecular radical cyclization of a 3bromoindole having an appended 4-alkenyl substituent for the preparation of NMDA-glycine antagonists <01JOC3474>. Kerr reported a convenient preparation of 4-iodoindoles via regioselective chloromercuration and subsequent iodination of a series of N-ptoluenesulfonylindoles bearing a variety of substituents at the 3-position <01TL983>. The synthetic potential of such easily accessed iodinated derivatives was demonstrated visa visa sequential cross-coupling sequence using dihaloindole 192 in a Stille coupling to produce 193 which then underwent a Heck reaction yielding 194. Methylenation of the ketone carbonyl produced a diene which upon intramolecular Diels-Alder reaction yielded a tetracyclic precursor to the hapalindole family of alkaloids. In fact, Kerr achieved a total synthesis of hapalindole Q by a route involving the intermolecular Diels-Alder of 3-vinylindole derivatives <01OL3189>. Additionally, this same author devised a new, indirect route to 5methoxyindoles via Diels-Alder reactions of quinone imine ketals <01 OL3325>.

I Br_ Pd(PPh3)4/BHA "

toluene, 90~ 192

I Ts

~'~J""SnBu3

~j B r

Pd(OAc)2/PPh3 DMSO, Et3N, O 90~

N" ~ 193 Ts

N" ~

194

Ts

A palladium-catalyzed intramolecular cyclization of a 4-bromo-l-tosylindole with a pendant alkynyl group attached to C-3 was utilized for the preparation of the tricyclic skeleton of 195 <01TL1635>. This key intermediate was subjected to ring closing metathesis (RCM) to give the tetracyclic ergoline ring system 196 using the Schrock catalyst 197. A Suzuki coupling of a 4-bromoindole derivative was employed by Nicolaou for construction of the complete aromatic core of the diazonamide alkaloids <0 lAG(E)4705>.

133

D.M. Ketcha

Phil,

i-Pr'~

N~

,5

95

6

i-Pr

(F3C)2MeCO,,dN (F3C)2MeCO\'M~CHC(Me")2Ph 197

Dodd investigated the ortho-metallation reactions of 5-carboxamide derivatives of indoles and indolines employing the N,N-dimethylsulfamoyl protecting group <01H(55)2289>. In the case of indoles, the authors first protected the C-2 position with a TMS-group to preclude abstraction of the acidic C-2 proton. Reaction of the amide with sec-BuLi followed by electrophile quench led to the C-4 substituted products. Interestingly, lithiation of the corresponding indoline derivative 198 also provided the C-4 substitution product 199, wherein the ortho-directing effect of the carboxamide was favored over abstraction of the benzylic protons at C-3. If the first electrophile added to the C-4 position is trimethylsilyl chloride, a subsequent ortho-lithiation can now be directed to the C-6 position providing 200.

o

o 9

198

I

SO2

2. E+

=

N(CH3) 2

E

O

N I

199

so2

2'. TMSCI (E = TMS)

N(CH3) 2

"

TMS

H

~

TMSI - ' J ~ ~ N , so2 200

N(CH3) 2

The Pictet-Spengler (P-S) reaction was employed in both solution- and solid-phase syntheses of the multi-drug resistance (MDR) reversing agent, fumitremorgin C (VI'C). Common to both approaches was the hitherto unreported use of an ml3-unsaturated aldehyde in the P-S cyclization process. In the solid-phase variant, Koomen prepared a library of fumitremorgin-type indolyl diketopiperazines via initial reaction of hydroxyethyl polystyrene bound L-tryptophan 201 with 3-methylcrotonaldehyde in pure trimethyl orthoformate to afford imine 202 <01BMCL29>. Reaction of 202 with Fmoc-chloride generated a highly reactive N-acyliminium ion which underwent P-S cyclization to afford the corresponding tetrahydro-13-carboline 203 bearing the unsaturated sidechain of v r c . Removal of the Fmoc group followed by attachment of Fmoc-proline produced the amide 204 which upon treatment with piperidine effected deprotection of the proline nitrogen and concomitant cyclizative cleavage from the resin to yield the diketopiperazine 205. In the solution phase variant, Bailey effected P-S cyclization directly from the imine by treatment with Fmoc-ProC1 <01TL113>.

N" 201

-HC(OMe)3 "

Fmoc-Cl~ 202 " ~

pyr.

~'J

203

oc

134

Five-Membered Rings." Pyrroles and Benzo Derivatives

0

O

--"1 piperidine _ ~_ 2. Frnoc-Pro-OH

piperidine

moc

In terms of the oxidation-reduction chemistry of indoles, perhaps the most interesting finding involved the report of a new and mild dehydrogenation reagent for conversion of indolines 206 to indoles 208 using trichloroisocyanuric acid (207, TCCA) in combination with DBU <01TL5385>. After workup with sodium hydrogen sulfite to destroy remaining oxidant, it was possible to obtain indole in almost quantitative yield. Remarkably, this mild oxidizing system is also suitable for indolines bearing electron donating- or electron withdrawing substituents. O

CI\N'~N"CI X 206

5.2.6

N.,~ H

+

DBU

O...~,,,.N.,~O ~

X

CI 207

H 208

P Y R R O L E AND INDOLE ALKALOIDS

In terms of pyrrole natural products, Tius reported an enantiospecific total synthesis of roseophilin by means of an asymmetric cyclopentannelation which served to establish the stereochemistry of this natural product as 22R,23R <01JA8509>. In another structureproving synthesis, Mort ascertained the absolute configuration of (-)-axinellamine A, a metabolite of the marine sponge Axinella sp. <01EJO503>. Liebscher reported the synthesis of the marine natural product phorbazole C possessing a chlorinated pyrrole-, an oxazole- and a phenol ring <01T4867>. Kock described the isolation of novel bromopyrrole alkaloids from the Caribbean sponge Stylissa caribica <01JNP1345> and Agelas sventres <01JNP1593>, while four new bioactive bromopyrrole-derived alkaloids were isolated from the marine sponge Axinella brevistyla collected in western Japan <01JNP1576>. Fresneda and Molina detailed a convergent approach to midpacamide and dispacamide, two pyrrole-imidazole alkaloids of the "oroidin group" isolated from marine sponges of the genus Agelas <01TL851>. Focusing on the ambivalent reactivity of 2-aminoimidazole precursors, a plausible biogenetic mechanism was advanced which accounts for the formation all polycyclic pyrrole-imidazole marine alkaloids isolated from sponges of various genera <01EJO237>. Finally, although not formally a pyrrole, an enantioselective synthesis of epibatidine employing a highly selective asymmetric hereto Diels-Alder reaction was reported by Evans <01OL3009>. O

. \'~~'C02H HO

~

O"

_

~-

v

"OH 209

D.M. Ketcha

135

In terms of indole alkaloids, the most noteworthy synthetic effort involved Harran's synthesis of the structures formerly proposed for the complex alkaloids diazonamide A and B <0lAG(E)4765>, leading to his proposing revised structures for both <0lAG(E)4770>. As regards these target molecules, Magnus utilized a photo-Fries rearrangement for the synthesis of the diazonamide macrocycle <01TL7193>, while Nicolaou employed a Suzuki coupling of a 4-bromoindole derivative for construction of the aromatic core of this target <0lAG(E)4705>. At present then, the most architecturally challenging indole alkaloid remains nodulisporic acid (209), towards which Smith reported construction of western hemisphere <01OL3967> and eastern hemisphere subtargets <01OL3971>. While on the topic of challenging targets, Danishefsky published an interesting retrospective commentary on his work on the himastatin problem <01CEJ41>. Martin described a biogenetically inspired approach to the Strychnos alkaloids akuammicine and strychnine featuring a vinylogous Mannich addition and an intramolecular hetero Diels-Alder reaction <01JA8003>. Magnus reported syntheses of the cyano-substituted Kopsia indole alkaloids demethoxypauciflorine B, pauciflorine B from 11,12-demethoxylahadine B and lahadinine B, respectively, via a peroxycarbinolamine fragmcntation reaction <01TL993>. Pearson meanwhile reported the total synthesis of the Kopsia lapidilecta alkaloid lapidilectine B <01JA6724>. Employing chiral auxiliaries for secodine-type intramolccular Diels-Alder reactions, Kuehne reported enantioselectivc syntheses of coronaridine and 18methoxycoronaridine <01T2085>. Cook reported an enantiospecific total synthesis of the sarpagine/macroline indole alkaloid trinervine <01OL4023> and utilized an oxy-anion Cope rearrangement in syntheses of alkaloid G and ajmaline <01OL345>. The asymmetric synthesis and stereochemical assignment of the marine indole alkaloid chelonin B was reported <01TL7671>. Jokela described the first total of the indole alkaloid tangutorine, the only known natural product containing the benz[/]indolo[2,3-a]quinolizidine ring system <01TL6593>. Bringmann reported the first total synthesis of the Murraya alkaloid murrastifoline-F, an unsymmetric, N,C-bonded heterobiarylic biscarbazole <01JA2703>. An azomethine ylide cycloaddition route was employed in the total synthesis of the oxindole alkaloid (-)-horsfiline possessing the spiro(indole-pyrrolidine) ring motif found in many pharmacologically relevant alkaloids such as vincristine and spirotryprostatins <01JOC8447>. Meanwhile, Hart dcscribed the synthesis of the spirocyclic oxindole entalantrypinone, the enantiomer of a natural product produced by the fungus Penicillium thymicola <01JA5892>. Because of their potential as anticancer and antiangiogenesis agents, indolo[2,3-a]carbazoles related to staurosporine and rebeccamycin have attracted much synthetic attention. In this past year, new protocols for the oxidative coupling of the bisindolylmaleimide precursors to these alkaloids were reported involving the use of phenyliodine(III) (bis)trifluoroacetate <01TL3271> as well as a Wackcr-type catalytic system using atmospheric oxygen as the stoichiometric oxidant <01TL8935>. Meanwhile, Brana described the synthesis and antiproliferative effects of a novel class of bisindolylmaleimides <01BMCL2701>.

5.2.7

REFERENCES

94TL2699 96JOC4999 98JOC6234 99TL3957 00OL89 00OL1403 00OL1485

S. Nakatsuka, K. Teranishi, T. Goto, Tetrahedron Lett. 1994, 35, 2699. M. Cushman, P. Nagafuji,.l. Org. Chem. 1996, 61,4999. H. Shiraishi, T. Nishitani, S. Sakaguchi, Y. Ishii,J. Org. Chem. 1998, 63, 6234. T.N. Danks, Tetrahedron Lett. 1999, 40, 3957. H.-C. Zhang, H. Ye, A.F. Moretto, K.K. Brumfield,B.E. Maryanoff, Org. Lett. 2000, 2, 89 D.W. Old, M.C. Harris, S .L. Buchwald, Org. Lett. 2000, 2, 1403. T. Okauchi, M. Itonaga, T. Minami, T. Owa, K. Kitoh, H. Yoshino, Org. Lett. 2000, 2, 1485.

136 00OL2283 00T10133 00TL481 00TL1811 0lAG(E)1283 0lAG(E)4705 0lAG(E)4765 0lAG(E)4770 01BMCL29 01BMCL487 01BMCL2105 01BMCL2169 01BMCL2701 01CC37 01CC209 01CC721 01CC805 01CC964 01CC1594 01CC1888 01CC2194 01CEJ41 01CEJ368 01CEJ2896 01EJO237 01EJO503 01H(54)445 01H(55)1019 01H(55)1063 01H(55)2099 01H(55)2289 01H(55)2431 01JA2074 01JA2703 01JA4370 01JA5892 01JA6724 01JA7727 01JA8003 01JA8509 01JMC1654

01JMC2229 01JNP1345 01JNP1576 01JNP1593 01JOCll 01JOC1403

F i v e - M e m b e r e d Rings." Pyrroles and Benzo Derivatives

R.K. Dieter, H. Yu, Org. Lett. 2000, 2, 2283. G.W. Gribble, E.T. Pelkey, W.M. Simon, H.A. Trujillo, Tetrahedron 2000, 56, 10133. M. Watanabe, M. Nishiyama, T. Yamamoto, Y. Koie,Tetrahedron Lett. 2000, 41,481. C.S. Cho, J.H. Kim, S .C. Shim, Tetrahedron Lett. 2000, 41, 1811. B. Ortner, R. Waibel, P. Gmeiner,Angew. Chem. hit. I'd. 2001,40, 1283. K.C. Nicolaou, X. Huang, N. Giuseppone, P.B. Rao, M. Bella, M.V. Reddy, S .A. Snyder, Angew. Chem. btt. Ed. 2001, 40, 4705. J. Li, S. Jeong, L. F_sser, P.G. Harran,Angew. Chem. hit. Ed. 2001, 40, 4765. J. Li, A.W.G. Burgett, L.Esser, C. Amezcua, P.G. Harran, Angew. Chem. hzt. Ed. 2001,40, 4770. A. van Loevezijn, J.D. Allen, A.H. Schinkel, G.-J. Koomen, Bioorg. Med. Chem. Lett. 2001, 11,29. H.M.L. Davies, P. Ren, N. Kong, T. Sexton, S.R. Childers, Bioorg. Med. Chem. Lett. 2001, 11,487. H.-C. Zhang, D.F. McComsey, K.B. White, M.F. Addo, P. Andrade-Gordon, C.K. Derian, D. Oksenberg, B.E. Maryanoff, Bioorg. Med. Chem. Lett. 2001, 11, 2105. M. Nettekoven, Bioorg. Med. Chem. Lett. 2001,/1,2169. M.F. Brana, L. Anorbe, G. Tarrason, F. Mitjans, J. Piulats, Bioorg. Med. Chem. Lett. 2001,11, 2701. J. Dowden, J. Savovic, Chem. Contrnun. 2001, 37. S.T. Hilton, T.C.T. Ho, G. Pljevaljcic, M. Schulte, K. Jones, Chem. Contrnun. 2001, 209. C.-M. Che, C.-W. Wan, W.-Z.Lin, W.-Y. Yu, Z.-Y.Zhou, W.-Y. Lai, S.-T. Lee, Chem. Commun. 2001, 721. G.W. Gribble, tI.L. Fraser, J.C. Badenock, Chem. Cornmun. 2001, 805. R. Grigg, I. Koppen, M. Rasparini, V. Sridharan, Chem. Commun. 2001, 964. J.H. Chaplin, B.L. Flynn, Chem. Cornmun. 2001, 1594. D. Sole, L. Vallverdu, E. Peidro, J. Bonjoch, Chem. Commun. 2001, 1888. T. Matsuda, Y. Ohashi, T. Harada, R. Yanagihara, T.Nagasawa, K. Nakamura, Chem. Commun. 2001, 2194. T.M. Kamenecka, S .J. Danishefsky, Chem. Eur. .1. 2001, 7, 41. L.F. Tietze, G. Kettschau, U. Iteuschert, G. Nordmann, Chem. Eur..1. 2001, 7, 368. F.J. Fananas, A. Granados, R. Sanz, J.M. Ignacio, J. Barluenga, Chem. Eur..1. 2001, 7, 2896. A.AI Mourabit, P. Potier, Eur. J. Org. Chem. 2001, 237. M. Seki, K. Mori, Eur. J. Org. Chem. 2001, 503. M. Makosza, K. Wojciechowski, Heterocycles 2001, 54, 445. S. Samajdar, F.F. Becket, B.K. Banik, Heterocycles2001,55, 1019. M. Ishikura, H. Uchiyama, N. Matsuzaki,Heterocycles 2001, 55, 1063. B.A. Frieman, C.W. Bock, K.L. Bhat, Heterocycles 2001, 55, 2099. J.-F. Rousseau, R.H. Dodd, Heterocycles 2001, 55, 2289. M. Chakrabarty, R. Basak, Y. I-tarigaya, tteterocycles 2001,55, 2431. A.V. Kel'in, A.W. Sromek, V. Gevorgyan, J. Am. Chem. Soc. 2001,123, 2074. G. Bringmann, S. Tasler, H. Endress, J. Kraus, K. Messer, M. Wohilarth, W. Lobin, J. Am. Chem. Soc. 2001, 123, 2703. N.A. Paras, D.W.C. MacMillan,J. Ant. Chera. Soc. 2001, 123, 4370. D.J. Hart, N.A. Magomedov,J. Am. Chem. Soc. 2001, 123, 5892. W.H. Pearson, Y. Mi, I.Y. Lee, P. Stoy,/. Ant. Chem. Soc. 2001, 123, 6724. A. Klapars, J.C. Antilla, X. Huang, S.L. Buchwald,,l. Am. Chem. Soc. 2001,123, 7727. M. Ito, C.W. Clark, M. Mortimore, J.B. Goh, S.F. Martin,J. Ant. Chem. Soc. 2001,123, 8003. P.E. Harrington, M.A. Tius, J. Am. Chem. Soc. 2001, 123, 8509. C.P. Miller, M.D. Collini, B.D. Tran, H.A. Harris, Y.P. Kharode, J.T. Marzolf, R.A. Moran, R.A. Henderson, R.tI.W. Bender, R.J. Unwalla, L.M. Greenberger, J.P. Yardley, M.A. AbouGharbia, C.R. Lyttle, B.S. Kormn, J. Med. Chem. 2001, 44, 1654. F.I. Carroll, F. Liang, I I.A. Navarro, L.E. Brieaddy, P. Abraham, M.I. Damaj, B .R. Martin, J. Med. Chem. 2001, 44, 2229. M. Assmann, R.W.M. van Soest, M. Kock,.l. Nat. Prod., 2001, 64, 1345. S. Tsukamoto, K. Tane, T. Ohta, S. Matsunaga, N. Fusetani, R.W.M. van Soest, J. Nat. Prod., 2001, 64, 1576. M. Assmann, S. Zea, M. Kock,J. Nat. Prod., 2001, 64, 1593. M. Adamczyk, D.D. Johnson, R.E. Reddy,.l. Org. Chern. 2001, 66, 11. M. Belier, C. Breindl, T.tI. Riermeier, A. Tillack, J. Org. Chem. 2001, 66, 1403.

D.M. Ketcha 01JOC3474 01JOC3906 01JOC4427 01JOC4525 01JOC4704 01JOC6595 01JOC7535 01JOC7547 01JOC8447 01JOC8599 01NPR66 01OL345 01OL421 01OL515 01OL1005 01OL1009 01OL1697 01OL1913 01OL2831 01OL3009 01OL3083 01OL3189 01OL3269 01OL3297 01OL3325 01OL3827 01OL3855 01OL3967 01OL3971 01OL4023 01OPRD604 01S40 01S67 01S267 01S370 01S783 01S1635 01S1878 01S2165 01S2255 01S2281 01S2477 01SC947 01SL337 01SL1403 01SL1440 01T975 01T1347 01T1361 01T1939 01T2085 01T3321 01T4767

137

S. Katayama, N. Ae, R. Nagata,.L Org. Chem. 2001,66, 3474. B. Biolatto, M. Kneeteman, E. Paredes, P.M.E. Mancini,.l. Org. Chem. 2001, 66, 3906. V. Nair, A.U. Vinod, C. Rajesh, J. Org. Chem. 2001, 66, 4427. C. Ma, X. Liu, J. Flippen-Anderson, S. Yu, J.M. Cook, J. Org. Chem. 2001, 66, 4525. D.B. England, T.D.O. Kuss, R.G. Keddy, M.A. Kerr,.l. Org. Chem. 2001,66, 4704. H.M.L. Davies, RJ. Townsend,J. Org. Chem. 2001, 66, 6595. N. Nishiwaki, M. Nakanishi, T. I lida, Y. Miwa, M. Tamura, K. Hori, Y. Tohda, M. Ariga, J. Org. Chern. 2001, 66, 7535. M.-L. Bennasar, T. Roca, R. Griera, J. Bosch, J. Org. Chem 2001, 66, 7547. G. Cravotto, G.B. Giovenzana, T. Pilati, M.Sisti, G. Palmisano, J. Org. Chem. 2001, 66, 8447. T.G. Back, R.J. BetheI1, M. Parvez, J.A. Taylor,./. Org. Chem. 2001, 66, 8599. S. tlibino, T. Choshi,Nat. Prod. Rep. 2001, 18, 66. T. Wang, Q. Xu, P. Yu, X. Liu, J.M. Cook, Org. Lett. 2001,3,345. H. Takaya, S. Kojima, S.-I. Murahashi, Org. Lett. 2001,3,421. I. Chataigner, E. Hess, L. Toupet, S.R. Pieltre, Org. Lett. 2001, 3,515. O. Ottoni, A.V.F. Neder, A.K.B. Dias, R.P.A. Cruz, L.B. Aquino, Org. Lett. 2001, 3, 1005. J.N. Johnston, M.A. Plotkin, R. Viswanathan, E.N. Prabhakaran, Org. Lett. 2001, 3, 1009. M.-L. Bennasar, T. Roca, R. Griera, J. Bosch, Org. Lett. 2001,3, 1697. M. Mori, M. Nakanishi, D. Kajishima, Y. Sato,Org. Lett. 2001,3, 1913. M.K. Tse, J.-Y. Cho, M.R. Smith, III, Org. Lett. 2001,3, 2831. D.A. Evans, K.A. Scheidl, C.W. Downey, Org. Lett. 2001, 3, 3009. H. Zhang, R.C. Larock, Org. Lett. 2001, 3, 3083. A.C. Kinsman, M.A. Kerr, Org. Lett. 2001,3, 3189. P.A. Evans, J.E. Robinson, K.K. Moffetl, Org. Lett. 20111, 3, 3269. R.U. Braun, K. Zeitler, T.J.J. Muller, Org. Lett. 2001, 3, 3297. S .C. Banfield, D.B. England, M .A. Kerr, Org. Lett. 2001,3, 3325. T.Y.H. Wu, S. Ding, N.S. Gray, P.G. Schul~, Org. Lett. 2001,3, 3827. R.K. Dieter, H. Yu, Org. Lett. 2001, 3, 3855. A.B. Smith, III, H. Ishiyama, Y.S. Cho, K. Ohmoto,Org. Lett. 2001,3, 3967. A.B. Smith, III, Y.S. Cho, H. Ishiyama, Org. Lett. 2001, 3, 3971. X. Liu, J.M. Cook, Org. Lett. 2001,3, 4023. X. Jiang, A. Tiwari, M. Thompson, Z. Chen, T.P. Clea~, T.B.K. Lee, Org. Proc. Res. Dev. 2001, 5,604. Q. Chen, D. Dolphin, Synthesis 2001, 40. M. Broring, S. Link, Synthesis 2001, 67. M. Amat, F. Seffar, N. Llor, J. Bosch, Synthesis 2001, 267. G.L. Rebeiro, B .M. Khadilkar, Synthesis 2001, 370. J.S. Yadav, B.V. Subba Reddy, Ch.V.S.R. Murthy, G.M. Kumar, Ch. Madan, Synthesis 2001, 783. O. Miyata, Y. Kimura, T. Naito, Synthesis 2001, 1635. B.A. Trofimov, Z.V. Stepanova, L.N. Sobenina, A.I. Mikhaleva, I.A. Ushakov, V.N. Elokhina, Synthesis 2001, 1878. J.S. Yadav, S. Abraham, B.V.S. Reddy, G. Sabilha, Synthesis 2001, 2165. H. Uno, K. Inoue, T. Inoue, Y. Fumoto, N. Ono, Synthesis 2001, 2255. M. Bergauer, P. Gmeiner, Synthesis 2001, 2281. G. Abbiati, E.M. Beccalli, A. Marchesini, E. Rossi, Synthesis 2001, 2477. J.M. Herbert, M. Maggiani, Synth. Commun. 2001, 31,947. L.F. Tietze, G. Nordman, Synlett 2001, 337. H. Tokuyama, M. Watanabe, Y. ttayashi, T. Kurokawa, G. Peng, T. Fukuyama, Synlett 2001, 1403. C. Agami, L. Dechoux, S. Hebbe, Synlett 2001, 1440. T. Fukuda, Y. Mine, M. Iwao, Tetrahedron 2001, 57, 975. S. Brown, S. Clarkson, R. Grigg, W.A. Thomas, V. Sridharan, D.M. Wilson, Tetrahedron 2001, 57, 1347. U. Anwar, A. Casaschi, R. Grigg, J.M. Sansano, Tetrahedron 2001, 57, 1361. V. Breuil-Desvergnes, J. Gore, Tetrahedron 2001, 57, 1939. M.E. Kuehne, T.E. Wilson, U.K. Bandarage, W. Dai, Q. Yu, Tetrahedron 2001, 57, 2085. C.S. Cho, J.H. Kim, T.-J. Kim, S.C. Shhn, Tetrahedron 2001,57, 3321. B.C. Ranu, A. Hajra, Tetrahedron 2001, 57, 4767.

138 01T4867 01T4881 01T5421 01T5855 01T7185 01T8017 01T8647 01T9951 01T10125 01T10147 01T10335 01TL113 01TL135 01TL461 01TL851 01TL983 01TL993 01TL1309 01TL1339 01TL1467 01TL1635 01TL2377 01TL2545 01TL2949 01TL3271 01TL3865 01TL3913 01TL4751 01TL4783 01TL5275 01TL5351 01TL5385 01TL5481 01TL5545 01TL6027 01TL6593 01TL6595 01TL6835 01TL7193 01TL7333 01TL7621 01TL7671 01TL7759 01TL7887 01TL8063 01TL8673 01TL8677 01TL8935 01TL9237

Five-Memb ered Rings." Pyrroles a nd B enzo Deriva rives

A. Radspieler, J. Liebscher, Tetrahedron 2001, 57, 4867. S. Farcas, J.-L. Namy, Tetrahedron 2001,57, 4881. A. de la Hoz, A. Diaz-Ortiz, M.V. Gomez, J.A. Mayoral, A. Moreno, A.M. Sanchez-Migallon, E. Vazquez, Tetrahedron 2001, 57, 5421. O.A. Attanasi, L. De Crescentini, P. Filippone, F. Mantellini, L.F. Tietze, Tetrahedron 2001, 57, 5855. G.W. Rewcastle, T. Janosik, J. Bergman,Tetrahedron 2001, 57, 7185. G.W. Kabalka, L. Wang, R.M. Pagni, Tetrahedron 2001,57, 8017. P. Magnus, T. Rainey, Tetrahedron 2001, 57, 8647. S. Hayat, Atta-ur-Rahman, M.I. Choudhary, K.M. Khan, W. Schumann, E. Bayer, Tetrahedron 2001, 57, 9951. M.-L. Bennasar, C. Juan, T. Roca, M. Monerris, J. Bosch,Tetrahedron 2001, 57, 10125. F. Mingoia, Tetrahedron 2001,57, 10147. R. Grigg, W.S. MacLachlan, D.T. MacPherson, V. Sridharan, S. Suganthan, Tetrahedron 2001, 57, 10335. P.D. Bailey, P.J. Cochranc, K. Lorenz, I.D. Collier, D.P J. Pearson, G.M. Rosair, Tetrahedron Lett. 2001, 42, 113. K.E. Bashford, A.L. Cooper, P.D. Kane, C.J. Moody, Tetrahedron Lett. 2001, 42,135. C. 7~ang, J. Dong, T. Cheng, R. Li, TetrahedronLett. 2001, 42,461. P.M. Fresneda, P. Molina, M.A. Sanz, Tetrahedron Lett. 2001, 42,851. M.A. Brown, M.A. Kerr, Tetrahedron Lett. 2001,42,983. P. Magnus, L.A. ttobson, N. Wcstlund, V. Lynch, Tetrahedron Lett. 2001, 42,993. S.-S.P. Chou, Y.-It. Yeh, Tetrahedron Lett. 2001, 42, 1309. B. Gabriele, G. Salerno, A. Fazio, M.R. Bossio, Tetrahedron Lett. 2001, 42, 1339. R.P.A. Cruz, O. Ottoni, C.A.M. Abella, I,.B. Aquino, Tetrahedron Lett. 2001, 42, 1467. K.L. Lee, J. B. Goh, S .F. Martin, Tetrahedron Lett. 2001, 42, 1635. R. Bennes, M.S. Babiloni, W. Hayes, D. Philp, Tetrahedron Lett. 2001,42, 2377. B. Jiang, C.-G. Yang, X.-t I. Gu, Tetrahedron Lett. 2001, 42, 2545. Y. Liu, G.W. Gribble, Tetrahedron Lett. 2001,42, 2949. M.M. Faul, KaX. Sullivan, Tetrahedron Lett. 2001, 42, 3271. M. Tokunaga, M. Ota, M. Haga, Y. Wakatsuki, Tetrahedron Lett. 2001, 42, 3865. M. Chakrabarty, R. Basak, N. Ghosh, Tetrahedron Lett. 2001, 42, 3913. H.-C. Zhang, II. Ye, K.B. White, B .E. Maryanoff, Tetrahedron Lett. 2001, 42, 4751. T.L.S. Kishbaugh, G.W. Gribble, Tetrahedron Lett. 2001, 42, 4783. W.-M. Dai, D.-S. Guo, L.-P. Sun, Tetrahedron Lett. 2001, 42, 5275. M.A. de la Mora, E. Cuevas, J.M. Muchowski, R. Cruz-Almanza, Tetrahedron Lett. 2001, 42, 5351. U. Tilstam, M. Itarre, T. Heckrodt, H. Weinmann, Tetrahedron Lett. 2001, 42, 5385. M.-F. Hsieh, R.K. Peddinti, C.-C. Liao, Tetrahedron Lett. 2001, 42, 5481. C.B. Reese, H. Yan, Tetrahedron Lett. 2001, 42, 5545. B. Lagu, M. Pan, M.P. Wachtcr, Tetrahedron Lett. 2001, 42, 6027. T. Putkonen, A. Tolvanen, R. Jokela, Tetrahedron Lett. 2001, 42, 6593. H. S. Prakash Rao, S. Jothilingam, Tetrahedron Lett. 2001, 42, 6595. M.E. Jung, F. Slowinski, Tetrahedron Lett. 2001,42, 6835. P. Magnus, C. Lescop, Tetrahedron Lett. 2001,42, 7193. P. Zhou, Y. Li, K.L. Meagher, R.G. Mewshaw, B .L. Harrison, Tetrahedron Lett. 2001,42, 7333. M. Matsuzono, T. Fukuda, M. Iwao, Tetrahedron Lett. 2001, 42, 7621. N.J. Lawrence, S.M. Bushell, Tetrahedron Lett. 2001, 42, 7671. S. Chayer, L. Jaquinod, K.M. Smith, M.G.It. Vicente, Tetrahedron Lett. 2001, 42, 7759. S.M. Allin, W.R.S. Barton, W.R. Bowman, T. Mclnally, Tetrahedron Lett. 2001, 42, 7887. J.S. Yadav, S. Abraham, B.V. Subba Reddy, G. Sabitha, Tetrahedron Lett. 2001, 42, 8063. H. A. Dondas, G. Balme, B. Clique, R. Grigg, A. Hodgeson, J. Morris, V. Sridharan, Tetrahedron Lett. 2001, 42, 8673. R. Grigg, E. Mariani, V. Sridharan, Tetrahedron Lett. 2001,42, 8677. J. Wang, M. Rosingana, D.J. Watson, E.D. Dowdy, R.P. Discordia, N. Soundarajan, W.-S. Li, Tetrahedron Lett. 2001, 42, 8935. K. Nishide, S. Ichihashi, II. Kimura, T. Katoh, M. Node, Tetrahedron Lett. 2001, 42, 9237.

139

Chapter 5.3 Five-Membered Ring Systems: Furans and Benzofurans

Xue-Long Hou Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis and State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, 354 Feng Lin Road, Shanghai 200032, China. xlhou @pub.sioc. ac. cn Zhen Yang

College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China. zyang @chem.pku, edu. cn Henry N.C. Wong

Department of Chemistry, Institute of Chinese Medicine and Central Laboratory of the Institute of Molecular Technology for Drug Discovery and Synthesis,? The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China. hncw ong @cuhk. edu.hk and Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, 354 Feng Lin Road, Shanghai 200032, China. hncwong @pub.sioc.ac.cn

t An Area of Excellence of the University Grants Committee (Hong Kong).

5.3.1

INTRODUCTION

The authors of the present chapter intend to review articles involving the more interesting applications and syntheses of furans, benzofurans and their derivatives that were published in 2001. Furan-containing marine natural products have been reviewed recently <01EJO633>. A large number of naturally occurring molecules that contain 3-substituted furan skeletons were isolated and identified in 2001. For example, from the sponge Sarcotragus sp. five new furanosesterterpene tetronic acids named sarcotin A-E were obtained via bioactivity-guided fractionation <01JNP1301> Four new furanosesquiterpenes, merrekentrones A, B, C and D were isolated from the roots and rootstocks of Merremia kentrocaulos. Their structures were substantiated on the basis of spectroscopic data <01JNP1471>. Two new sesquiterpenoid polyol esters 1 and 2 were isolated from the root bark of Celastrus angulatus by bioassay-guided fractionation.

X.-L. Hou, Z Yang and H.N.C. Wong

140

They were found to exhibit insecticidal activity against the larval of Mythimna separata <01JNP364>. Potamogetonyde and potamogetonol, two new furanoid labdane diterpenes, were obtained from the CH2C12 extract of Potamogeton malaianus. They were active against KB and BC cell lines but showed only weak antimycobacterial activity against Mycobacterium tuberculosis H37Ra <01JNP385>. Two more new labdane diterpenes, cacofurans A and B were isolated from a sponge Cacospongia sp. <01JNP 1468>.

AcO'~

OBz

.rr--O

RO

R -

.,~

HO ~.v O A c ~ 1

HO "-'" 0Ac'k," 2 AcO Potamogetonyde R = CHO Cacofuran A R = Ac Potamogetonol R = CH2OH Cacofuran B R = H

Three rearranged phragmalin-type limonoids, khayanolides A, B and C were isolated as insect antifeedant from the Et20 extract of the stem bark of Khaya senegalensis <01Tl19>. From the same source khayanone, 2-hydroxyseneganolide and 1-O-acetylkhayanolide A were also obtained <01JNP1261>. The CHCI3 extract of the bark of Aphanamixis polystachya yielded another new limonoid 3 <01IJC(B)536>. Two new tetranortriterpenoids 7isovaleroylcycloseverinolide and 7-isovaleroylcyclopiatalantin were obtained from the root bark of Severinia buxifolia collected in Hainan, China <01JNP1040>. Three other novel tetranortriterpenoids methyl 6-hydroxy- 1113-acetoxy- 12o~-(2-methylpropanoyloxy)-3,7-dioxo1413,1513-epoxy-l,5-meliacadien-29-oate, methyl 6,11[3-dihydroxy-12ot-(2-methylpropanoyloxy)-3,7-dioxo-1413,1513-epoxy-l,5-meliacadien-29-oate and methyl 6-hydroxy-1 ll3-acetoxy12ot-(2-methylbutanoyloxy)-3,7-dioxo- 1413,1513-epoxy-1,5-meliacadien-29-oate were isolated from the roots of Trichilia pallida, and their anitfeedant activities were tested against larvae of four species of Lepidoptera <01JNP 1117> Five new sesquiterpenes 4-8 were provided from the crude extract of fresh and undamaged fruiting bodies of Collybia maculata <01T2791>. O

0

HO

U

0 HO" ~ ~

I

4

R=H

CO2Me

5

R = COC6H 5

6

R = COCH 3

0

0

0 7

R = COC6H 5

8

Three modified clerodanes 9, 10 and 11 were extracted from Dodonaea viscosa. These compounds have been proposed as hypothetical intermediates in the biosynthesis of diterpenes containing bicyclo[5.4.0]undecane or bicyclo[5.3.0]decane ring systems <01T2981>. Three furoclerodanes, namely 12-epi-Teukotschyn, teughrebin and 12-epi-

Five-Membered Ring Systems: Furansand Benzofurans

141

teughrebin were isolated from the aerial parts of Teucrium "maghrebinum" (Teucrium polium subspecies still unidentified) <01EJO1669>. The aerial parts of Salvia gesneraeflora (Labiatae) provided a new neoclerodane 7a-acetoxy-7,8a-dihydrogensnerofolin B whose structure was established by spectroscopic methods as well as structural correlation with the known gensnerofolin B <01H(55)505>. Salvinorin C, a new neoclerodane diterpene, was isolated from the bioactive fraction of the hallucinogenic Mexican mint Salvia divinorum <01OL3935>. Two new limonoids polygonumin A and B 12 were obtained for the first time from the whole plant of Polygonum orientale L <01IJC(B)644>. Deoxyobacunone, a new limonoid, was obtained from the root bark of Harrisonia abyssinica collected in Nigeria <01JNP1434>. Three more limonoids haperforins C2, F and G were isolated from a sample of Harrisonia perforata leaves collected in Central Vietnam, and their structures were determined by X-ray diffraction analyses <01JNP634>.

,~"-o

H OH

R~~ i~

~

~'H~

o

~

H

/7"o

/2~o

" o

H ,

.."~

'o

H

o

MeO2C

~'=.,

~=.

10 RI=OH,R 2=H

11

~~o.

~co>

Y co_ ~co,,.~ 2 , ..../

0"

7o~-acetoxy-7,8~-L) dihydrogensnerofolin B

bl~"

~"

~co>

12-epi-Teukotschyn Teughrebin 12-epi-Teughrebin

@.o I cts

0

CO2Me SalvinorinC

O~ ~

_trans

~"O 12

A bioassay-guided study on the seeds of Caesalpinia minax led to the identification of five new cassane furanoditerpenes called caesalmin C, D, E, F and G that possess 2,3disubstituted furan skeletons <01JNP1266>. Recently, a 2,4-disubstituted furan called algoafuran was also obtained from extracts of the endemic nudibranch Leminda millecra collected in Algoa Bay, South Africa <01JNPl183>. Naturally occurring 2,5-disubstituted furans have also been identified from marine sponges. Thus, from a Chinese marine sponge Plakortis simplex were isolated three new furan derivatives 13, 14 and 15. Biological studies revealed that 14 exhibited cytotoxic activity against COLO-250 and KB-16 cells <01JNP324>. A new 2,5-disubstituted furan, namely acetyl Sumiki's acid was obtained via bioassay-guided fractionation of organic extracts of Cladosporium herbarum, isolated from the marine sponge Callyspongia aerizusa, and was found to be antimicrobially active against Bacillus subtilis and Staphylococcus aureus <01JNP527>. Phytochemical analysis of the rhizomes of Curcuma aromatica Salisb. (Zingiberaceae) led to the identification of a sesquiterpene zederone which possesses a 2,3,4-trisubstituted furan framework, and was found to show moderate antifeedant activity against 4th instar larva Spilartica obliqua <01IJC(B)87>. Another naturally occurring 2,3,4-trisubstituted furan radulifolin C was

142

X.-L. Hou, Z Yang and H.N.C. Wong

obtained from the roots of Psacalium radulifolium that is a member of the matarique complex of medicinal plants <01JNP432>.

R 1 0 ~ R 2 Algoafuran

AcO"~~CO2H

13 R 1 = CH3, R2 = CH2(CH2)14CH3 Acetyl Sumiki's acid 14 R 1 = H, R2 = CH2(CH2)14CH3 15 R 1 = CH3, R2 = CH2(CH2)6CH(CH2CH2CHO)(CH2)3CH 3

From the Dominican marine sponges Plakortis halichondrioides and Plakinastrella onkodes were isolated two natural 2,3,5-trisubstituted furans, namely ghinvillic acids A and B, respectively <01JNP281>. A search on the gum exudates of Commiphora myrrha led to the identification of two sesquiterpenoids named rel-1S,2S-epoxy-4R-furanogermacr-lO(15)en-6-one and rel-2R-methyl-5S-acetoxy-4R-furanogermacr- 1(10)Z-en-6-one <01JNP1460>. Tetrahydrofuran skeletons are also abundant in naturally occurring molecules. For example, furoplocamioids A-C, three novel polyhalogenated furanoid monoterpenes were obtained from Plocamium cartilagineum <01JNP1383>. Tetillapyrone and nortetillapyrone were isolated and characterized from the extract of the marine sponge Tetilla japonica from the Bay of Thailand <01JNP1056>. Two new cytotoxic annonaceous acetogenin, namely annomolin and annocherimolin were found from an EtOH extract of the seeds of Annona cherimolia <01JNP502>. Other new annonaceous acetogenins that were also isolated from the seeds of Annona muricata include seven in vitro cytotoxic muricins A--G whose structures are exemplified by muricin A as shown below <01JNP925>. From the Mediterranean tunicate Stolonica socialis was isolated and characterized a minor component 16 which showed potent inhibitory activity on mitochondrial electron transfer. A new minor carotenoid 17 was isolated from the oyster Crassostrea gigas <01JNP578>. Recently, a new squalene-derived epoxy tri-tetrahydrofuran diol 18 was isolated from the endemic Jamaican plant Spathelia glabrescens <01 TL7379>. MeO2C H

9o i l

OH

17

18

A new grindelic acid derivative called 19-hydroxygrindelic acid was isolated from the aerial parts of Grindelia integrifolia <01JNP1365>. From the bark and seeds of Colophospermum mopane was also obtained two new grindelic acid derivative, namely dihydrogrindelic acid and dihydrogrindelaldehyde <01P(57)537>. From the BuOH- and

Five-Membered Ring Systems: Furansand Benzofurans

143

CHC13-soluble fractions of the whole plant of Daphne oleoides (Thymelaeaceae), a new lignoid glycoside 19, and two dimeric phenylpropanoids 20 and 21 were isolated and their structures were elucidated by spectroscopic methods including 2D NMR spectroscopy <01HCA157>. Three new furofuran lignans named neocuscutosides A, B and C 22 were obtained from the EtOH extract of the dried seeds of Cuscuta chinensis. Again, their structures were established by chemical and spectroscopic methods <01CHJC282>. A spirodienone structure was observed by NMR spectroscopy as one of the important structures present in spruce and aspen lignins <01 CC2744>.

OMe

M e O ~

O

,,,.~., ' H { ~ OH OMe

~,co~

~ HO

OMe

,.~.

i',

.,.

~

~9

,,.

'

OMe HO" y

OMe

OMe 20

HO" y

OMe 21

HO

,HOO OH

~O~,o~....,o~,,

{ ~ O H Et

~,~~ o--~OH

Ho

H

~~

'~

o_~]

He

o

H

Four new metabolites called aglacins A-D were isolated from the MeOH extract of the stem bark of Aglaia cordata. The absolute structure of aglacin A was determined by spectroscopic means <01JNP1521>. Massarilactone A was obtained from cultures of the freshwater aquatic fungus Massarina tunicata and its absolute configuration was determined <01TL975>. A new dihydrogarofuran alkaloid 23 was yielded from the antimicrobially active EtOH extracts of Maytenus heterophylla <01P(58)475>. Three new diterpenoids pachyclavulariaenones A , B and C were isolated from the soft coral Pachyclavularia violacea. The structure of pachyclavulariaenone C was confirmed by an X-ray crystallographic study <01TL2333>. A new excitatory amino acid neodysiherbaine A was a minor constituent of the aqueous extract from the marine sponge Dysidea herbacea and its structure was unmistakably established by a total synthesis <01OL1479>. A reinvestigation of Euphorbia decipiens with a modified extraction method yielded the new myrsinane-type diterpene ester 24 <01HCA1980>. From the petroleum-ether extract of the dried aerial parts of Hypericum papuanum was isolated furonewuinone A <01HCA3380>.

O

--'O

BzO OAc

o. ,,,.~~ I .o~,c

MassarilactoneA

23

ONic + -O2C

"~

OH

~-.''o~

O ~.

,,~OH

NeodysiherbaineA

~

BzO&OAc 24

X.-L. Hou, Z. Yang and H.N.C. Wong

144

From the MeOH extract of Azadirachta indica leaves were isolated two new tetracyclic triterpenoids named melianol and desfurano-desacetylnimbin-17-one <01T10281>. Two new glycosides called atratoglaucosides A and B were obtained from the roots of Cynanchum atratum, and their structures were elucidated by chemical and spectroscopic evidence <01JNP608>. Furanodictine A and B, two amino sugar analogs produced by cellular slime mold Dictyostelium discoideum were isolated and found to exhibit neuronal differentiation activities <01JOC6982>. Three new 19-membered macrolides, amphidinolides T2, T3 and T4 were isolated from two strains of marine dinoflagellates of the genus Amphidinium. Their structures were elucidated by spectroscopic results. The absolute configurations of these compounds and amphidinolide T1 were further confirmed by comparison of the NMR data of their C1-C12 segments with those of the synthetic models <01JOC134>. The same research team also reported the absolute stereochemistry of amphidinolide C <01OL1363>. Two new quinoid diterpenes with nor-abietane skeleton, namely ll3-hydroxycryptotanshinone andloxocryptotanshinone were isolated from roots of the Iranian medicinal plant Perovskia abrotanoides <01JNP1398>. A bioassay-guided fractionation of Machaerium multiflorum gave a novel (+)-trans-hexahydrodibenzopyran named machaeriol B <01JNP1322>. Dehydroxymethylailanthoidol was isolated from the leaves of Litsea acutivena <01JNP1502>. From the stems of Derris malaccensis a new rotenoi 12a-hydroxyelliptone was isolated and its structure was substantiated by spectroscopic and chemical methods <01H(55)1121>. Four new 2-arylbenzofurans with isoprenoid units, namely mulberrofurans W, X, Y and Z were obtained from Chinese Morus mongolica. They all exhibited higher cytotoxicity against human oral tumor cell lines (HSG-2 and HSG) than against normal human gingival fibroblasts (HGF) <01JNP181>. The constituents in the cultured fruit body of Dictyostelium medium was investigated, whose MeOH extract gave two new aromatic dibenzofurans named dictyomedins A and B. Biological tests of these compounds showed that they delayed the differentiation of Dictyostelium discoideum cells <01TL61>. 0

HO

Ph

25

0:~26"0" "0

__~27"0" "0

OH

f

O

HO "

O

28

HO"

-O" " O

-R

O" 29 R = CH2CH(OH3)2 30 R = CHGH3GH2CH3 31 R = CH2CH2CH 3

H

O

o

39

Eight new 4-phenylfurancoumarins 25-32 were isolated form the stem bark and the fruits of Calophyllum dispar, whose structures were established by spectroscopy. Furanocoumarins 27, 29 and 30 were found to exhibit significant cytotoxic activity against KB cells <01JNP563 >.

145

Five-Membered Ring Systems: Furans and Benzofurans

Five more furanocoumarins, namely 5-methoxy-3-(3-methylbut-2-enyl)psoralen, 5,8dimethoxy-3-(3-methylbut-2-enyl)psoralen, 6-methoxy-5-(3-methylbut-2-enyl)angelicin, dorstegin and 2-(p-hydroxybenzyl)-6-methoxybenzofuran were obtained from Dorstenia gigas <01P(56)611>. Two new quinoline alkaloids, 2-acetylevolitrine and 2-acetylpteleine were identified from the root bark of Melicope semecarpifolia by means of spectroscopic analyses <01JNPl143>. Two novel biflavonoids, isolophirone C and dihydrolophirone C were obtained from the stem bark of the Cameroonian medicinal plant Ochna afzelii <01P(57)579>. From the core of Hibiscus cannabinus were isolated two phenolic constituents whose structures were proved to be boehmenan H and boehmenan K <01P(56759>. The structures of three isoflavonoids from Erythrina suberosa var. glabrescences called erysubins C-E were elucidated on the basis of spectroscopic analyses <01J(56769>. Two other new isoflavonoids eryvarins D and E were obtained from the roots of Erythrina variegata (Leguminosae) <01H(55)2341>. The EtOH extract of the whole plant of Justicia neesii gave tiruneesiin after chromatography <01IJC(B)596>. Suggested to be biogenerated from polyporic acid, a unique benzofuran named suillusin was yielded from the methanolic extract of the fruiting body of the mushroom Suillus granulatus <01JNP1230>. The novel resveratrol trimer caraphenol A was obtained from the roots of Caragana sinica and its structure and stereochemistry were elucidated by spectroscopic data <01T4849>. An oligostilbene called (+)-viniferol A was also isolated from the stem of Vitis vinifera "Kyohou" cultivated in the Wakayama Prefecture in Japan <01T2711>. Another four new stilbene oligomeric glucosides named gnemonoside A, B, C and C were isolated from the stem of Gnetum gnemonoides (BRONGN) <01H(55)2123>. From the acetone extract of the stem bark of Vatica rassak, two new oligostilbenoids, vaticanol E and vaticanol F, as well as three new O-glucosyl oligostilbenoids, vaticasides A, B and C were isolated. Their relative configurations were established on the basis of spectroscopic studies <01H(55)557>. The same research group also identified five new dihydrofuran stilbenoids, namely hemsleyanols C and D, hemsleyanosides E and F, and (-)ampelopsin H from the stem bark of Shorea hemsleyanan (Dipterocarpaceas). Again, only their relative configurations were determined <01H(55)729>. Rocagloic acid, a cytotoxic compound, was isolated from the leaves of Aglaia elliptifolia <01JNP92>. A structurally related compound 33 was also obtained from the twigs of Aglaia oligophylla collected in Vietnam <01JNP415>. Two unusual diarylheptanoid derivatives, neocalyxins A and B were identified from the EtOH extract of the seeds of Alpinia blepharocalyx <01JNP208>.

MeO

r...-Q 0-~/'

~~0~ Me :OH .,

OMe

OMe HO i ~

0

2H

Rocagloicacid

OMe

33

Ganbajunin B, a dibenzofuran molecule, was isolated from the fruiting bodies of the Basidiomycete Thelephora ganbajun Zang <01HCA3342>. A new ellagitannin, phyllanemblinin A, was obtained from Phyllanthus emblica <01JNP1527>.

5.3.2

REACTIONS

146

X.-L. Hou, Z Yang and H.N.C. Wong

5.3.2.1 Furans The intramolecular [4+3] cycloaddition reaction towards seven-membered rings involving furans and allylic cations have been reviewed <01ACR595>. A review on the use of 2siloxyfurans as butenolide precursors has appeared <01T3221>. Organometallic compounds of furans and their benzoannulated derivatives have also been summarized <01AHCI>. Because of the resilient properties of furans, their cycloaddition, especially Diels-Alder reaction and [4+3] cycloaddition reaction have attracted much attention in 2001. A combination of cycloaddition reactions with subsequent transformations is widely adopted as useful strategies in the construction of complex molecules. For example, the synthesis of the cyclohexane subunit of baconipyrones A and B did make use of a oxanorbornetic derivative as the starting material, which in turn was obtained from a Diels-Alder reaction involving furan <0lOLl07>. The Diels-Alder adduct of furan with acrylic acid was also used to construct the all diastereomeric stereotetrads (polypropionate fragments) <01JOC2400>. Diels-Alder reactions of furoindoles with halopyridynes provided the key intermediates in the synthesis of ellipticine alkaloids. In this synthesis, the presence of a chloro atom at C-2 of the pyridine ring was found to improve the yields as well as the regioselectivities of the cycloaddition <01EJO4543>. Reaction of 2-glycosylfuran with benzyne followed by an acidcatalyzed rearrangement of the product provided the aromatic part of C-aryl glycosides <01JA6937>. Benzyl aryl ether dendrons and dendrimers containing thermally reversible furan-maleimide Diels-Alder adducts were prepared up to the third generation <01 OL2681>. Silica-supported Lewis acids as catalysts under microwave irradiation promoted the DielsAlder reaction of 2- and 2,5-substituted furans with dienophiles and a subsequent oxygen extrusion reaction provided substituted benzene derivatives in a regiospecific manner <01SL753>. When silica-supported Lewis acids were used in the absence of microwave irradiation, normal Diels-Alder adducts were obtained instead <01EJO2891>. Gold-catalyzed intramolecular [4+2] cycloaddition of furans with alkynyl substituents led to the formation of phenol derivatives. A mechanistic study showed that a transposition of the oxygen from the carbon atoms of furan to the former terminal carbon of the alkynes seemed to occur through an intramolecular mode and the epoxide depicted below was presumably an intermediate <01 OL3769>.

/

Ts

--

CH3CN 92%

=

Ts

NTs

OH

If an ester group was introduced into the terminal position of the alkyne illustrated below, a rapid intramolecular Diels-Alder reaction took place smoothly in the absence of any catalyst and the corresponding cycloaddition adducts were obtained <01TL3171>.

~

Ph/,,~ ~

1. Nail,

Mel

2. MeLi CICO2Me

Ph~~OMe "r" /COOMeC6H5Me~ . , N ,P~ ~O~'/~ 5509 :AC OMe (3steps) C 0 2 M ~ -

A similar intramolecular cycloaddition was also studied by using N-allyl-N-(2furylmethyl)amides as a starting material. As a result, a highly functionalized pyrrolizidine

147

Five-Membered Ring Systems: Furans and Benzofurans

ring was generated. The reaction was controlled not only by the size of the amide appendage but also by the electronegativity of the amide <01EJO 1845>. 3-Methylthiofuran reacted with a variety of 2-substituted cycloalkenones to afford the corresponding Diels-Alder adducts with high regio- and stereoselectivities <01EJO2869>. Diels-Alder reactions of substituted furfurylamines and citraconic anhydride gave a mixture of regioisomers instead. The regioselectivity of the reaction was controlled by the reaction condition as well as by the substituent on the furan ring. Reactions conducted at room temperature gave more kinetically controlled product whereas at high temperature thermodynamically controlled product was predominant. Moreover, it was also found that the kinetic product rearranged to the thermodynamic product. The only exception is 3-methylthio-2-furfurylamine, which gave only the kinetic product <01T3165>.

OOH +

06H6 ~-

BnHN

'--NBn 0

~..-.~COOH ~

0

Kinetic Product ThermodynamicProduct Room Temperature 85 15 65 ~ 15 85 An intramolecular [4+2] cycloaddition of furanyl carbamates bearing tethered alkenyl groups furnished the corresponding oxabicyclic adducts, which underwent further nitrogenassisted ring opening reaction followed by deprotonation of the resulting zwitterion to give rearranged ketones having the hexahydroindolinone skeleton presented in many alkaloids <01JOC1716> <01JOC3119>. OMe OMe OMe

OMe

MeO,.~

" i s s oc =-

CO2Et

78%

~O2Et

C02Et

C02Et

Furan was also used as a dienophile in an intramolecular [4+2] cycloaddition reaction with o-quinodimethane to provide a tetracyclic adduct as the only product <01SL 1123>.

o% MeO/ ~

~'O

o-Dichlorobenzene = reflux 75% MeO~ ~..~f ~ I

H

O

2,2'-Methyldifuran reacted with 1,1,3-trichloroacetone through a double [4+3] cycloaddition to lead to the corresponding t h r e o and m e s o adduct, the latter being a starting material for the synthesis of all members of pentadecane -1,3,5,7,9,11,13,15-octols <01TA4935> <01JOC7869>. A similar [4+3] cycloaddition of 2,5-di(tBuMe2SiOCH2)furan and 1,1,3-trichloroacetone was used by Cha in a formal synthesis of (+)-phorbol

148

X.-L. Hou, Z. Yang and H.N.C. Wong

<01JA5590>. Reaction of a suitably functionalized furan with 1,1,3-trichloroacetone via [4+3] cycloaddition gave the corresponding adduct, which was employed as a key intermediate in the synthesis of tropoloisoquinoline called imerubrine <01JA3243>. Readily available cyclopropanone hemiacetals functioned closely as an oxyallyl derived from l,l,3trichloroacetone and smoothly reacted with furans through the inter- and intramolecular [4+3] cycloaddition modes, producing the corresponding adducts <01OL2891>. An intramolecular [4+3] cycloaddition of trimethylsilylmethyl substituted furan derivatives gave rise to the adducts with a high level of diastereoselectivity <01TL 149>. The computational examination (B3LYP/6-3 I+G*//HF/6-3 I+G*+ZPVE) of an intramolecular [4+3] cycloaddition reaction suggested that the simple diastereoselectivity observed was a result of a stepwise process. The likelihood of reversibility in at least one of the pathways was also examined <01 OL3663>. 4-Cyano-3-trifluoromethyl-substituted vinyldiazomethanes reacted with furans in the presence of rhodium(II) acetate to provide [4+3] cycloaddition products. The reaction was presumed to follow a tandem cyclopropanation-Cope rearrangement mechanism. The substituent at 4-position was found to greatly influence the product distribution. Reaction of 4-carbonyl substituted vinyldiazomethanes with furans resulted in cyclopropenes in addition to the usual [4+3] annulation product <01T7337>. An intermolecular [4+3] cycloaddition reaction of furans with cyclic oxyallyls was also adopted in the synthesis of a bicyclo[6,3,0]undecane skeleton <01TL6019>. Photooxidation of 3-acetyl-5-aryl-2methylfurans gave endoperoxides, which transformed to the corresponding 1,4-diones and aroylepoxides, respectively, depending upon the reaction conditions <01T6003>. Singlet oxygen oxidation of 5-methoxyfurans also provided endoperoxides, which were converted to isolable functionalized 2-oxetanyl hydroperoxides as illustrated below <01JOC4732>. Ho

OMe Ph" \ 0 / "OMe

0-0

02Me 88% (90% pure)

0 Trace

02Me

Reaction of furfuryl alcohol derivatives with 30% hydrogen peroxide in the presence of a catalytic amount of p-toluenesulfonic acid afforded stable furfurylhydroperoxides, which were purified by column chromatography on silica gel. Further oxidation of these furfurylhydroperoxides furnished pyranone peroxides in high yields. Both furfurylhydroperoxides and pyranone peroxides were used as oxidants in an asymmetric oxidation of sulfides and the reduction products alcohols were recovered and recycled <01TL4577>. Self-sensitized photooxygenation of 3,4-dialkoxyfurans with molecular oxygen and U V - o r sunlight at room temperature led to vitamin C derivatives in good to excellent yields. 3,4-Dialkoxyfurans were able to function as efficient oxygen scavengers without producing super-oxides <01JOC7067>. Silyloxyfurans have still been widely used as starting materials in organic synthesis. A new and highly efficient catalyst based on bis(oxazoline) or pyridine-bis(oxazoline) was developed to catalyze the stereoselective Mukaiyama-Michael reaction of a silyloxyfuran and (E)-3-crotonyl-l,3-oxazolidin-2-one <01T10203>. It was discovered that reaction of 5methyl-2-silyloxyfuran with arylacetaldehydes took place at the 3- and/or 5-positions <01T9597>. The reaction of 5-silyloxyfuran with a chiral aldehyde gave a vinylogous aldol product with different stereoselectivity <01TL2801> and high stereoselectivity <01JOC8070>. The intermolecular vinylogous Mannich reaction of 2-methyl-5-

Five-Membered Ring Systems: Furans and Benzofurans

149

silyloxyfuran with cyclic iminium ions of differing ring size was carried out <01TL6995>. The reaction was applied to the synthesis of (_)-securinine. A stereoselective addition of 2allyl-5-silyloxyfuran to an iminium ion generated in situ from N-Boc-2-ethoxypiperidine furnished a butenolide-containing intermediate <01OL703>. Intramolecular vinylogous Mannich reaction of 5-silyloxyfuran derivatives provided ring closure products, which were utilized as key intermediates in the total synthesis of the Ergot alkaloids rugulovasines A and B <01JA5918>. The Achmatowicz reaction of furfuryl derivatives was employed by several groups for the synthesis of functionalized ct,13-unsaturated 6-1actones from a-hydroxymethyl furfuryls <01T5161, 01TL7401>. This type of reaction was also applied successfully to the synthesis of 6-amino-6-deoxysugars and deoxymannojirimycin by starting from protected ctaminomethyl furfuryl alcohol (illustrated below) and ct-hydroxymethyl furfurylamine, respectively. The use of mCPBA increased the yield in the oxidation reaction of furfurylamine, whereas a ring opening product and a pyridine derivative were obtained in addition to 55% yield of the Achmatowicz reaction product when NBS was used <01OLA01, 01OL3899>. A general, two-directional synthesis of a C-(1-*6)-linked disaccharide was realized by using the oxidative ring expansion product of the enantiomerically enriched (R,R)- 1,4-di(furan-2-yl)butane- 1,4-diol as a key intermediate <01 CC695>.

_~NHCbz NBS

~O

"THF2H%20-HO OH

= " NHCbz

OH HO~,~OH = pivO" "N" "~ H NHCbz

2-Substituted furans were converted into 4-oxo-2-alkenoic acids by using convenient procedures. In this manner, macrosphelides A, B, C and F were synthesized successfully from a furyl alcohol as illustrated below <01TL2817, 01JOC2011 >. O_~

,~

I. NBS

0

Acet~ ~ 2.NaCIO~ = OPMB MeCH=CMe2 OPMB

CO2H

0~0 = //- - O~o MOMO~,,. O MacrosphelideB

Birch reductive alkylation reaction of chiral derivatives of 3-trimethylsilyl-2-furoic acid afforded 2,5-dihydrofuran derivatives. The presence of a trimethylsilyl group at the 3position resulted in high levels of stereoselectivity. The trimethylsilyl group was either removed or retained for further functional group transformation <01TL5841>. A Birch reductive alkylation procedure was also applied to the synthesis of medium ring ethers. Thus, annulated furans reacted with lithium in liquid NH3 and MeI to give the corresponding dihydrofuran derivatives, which underwent an oxidative cleavage reaction to produce an eight-membered cyclic ether. A nine-membered cyclic ether was also obtained in a similar manner <01 OL861 >.

150

X.-L. Hou, Z Yang and H.N.C. Wong

liq. NH3 CO2Pr

03 =

=

2. Mel 64%

CO2Pr

.,,,OH

85% HO~,,'N~._O./~ CO2Pr

The fluorine atom adjacent to a trifluoromethyl group in the furan ring shown below could be replaced under mild conditions by various nucleophiles. Consequently, the reaction of 2fluoro-3-trifluoromethylfuran with allyl alcohol followed by a Claisen rearrangement led to the formation of trifluoromethyl substituted butenolides <01TL 1657>.

/j,,,.~OH ArI~O~F

Nail

Ar

O

Ar

2,5-Disubstituted and 2,3,5-trisubstituted furans were converted to 5-acylisothiazoles in one step by utilizing ethyl carbamate, thionyl chloride and pyridine as reagents <01JCS(P1)1304>. Photolysis of 2-furfuryldiazomethanes was used to prepare acylsilanes and acylstannanes. The reaction afforded the products in (Z)-forms through a HoffmannShechter rearrangement of furfurylidenes <01EJO269>.

=- Me3Sn Me3Sn" "O" ~ ..N "N /Ts 10- 6 mbar H

Na +

N2

N2 = Me3Sn

H

Metal catalyzed polymerization of 2,5-dibromo-3-octylfuran afforded poly(3-octylfuran) with three regioregularities whose properties were studied <01JA2537>. Rhenium complexes of 4,5-rl2-furan underwent reaction with methanol catalyzed by acid to give 2-methoxy-2,3dihydrofuran complexes as diastereomeric mixtures. The results showed enhanced reactivity with carbon electrophiles at the 13-carbon of furan and provided a new entry towards furan functionalization <01JA8967>. Ozone oxidation of chiral 2,2,2-trifluoro-l-furan-2-ylethanone afforded chiral 2,2,2-trifluoro-l-furan-2-yl-ethylamine in high yield <01TA2309>. 2-Acylfurans reacted with ammonia at 150 ~ in a sealed vessel provided 3-hydroxypyridines in moderate yields <01JCS(P1)1853>. Microwave- and ultrasound-assisted oxidation of 3substituted furans by employing NBS to furnish a-substituted-ml3-unsaturated butyrolactones was also reported <01TL6577>. Metal catalyzed cyclopropanation reaction of methyl 2furoate was used in the preparation of trisubstituted butyrolactones <01OL1315>. When the substituent on the furan ring was methoxy or trimethylsilyloxy, the reaction of ethyl diazoacetate and aryl a-diazocarbonyl compounds with furans in the presence of a metal catalyst afforded ring opening products as illustrated below <01T7303>.

MeO

PhCOCHN2 Rh2(OAc)479% -"-

MeO

O

~~O

Five-Membered Ring Systems: Furans and Benzofurans

151

5.3.2.2 Di- and Tetrahydrofurans Oxygen atoms in the tetrahydrofuran rings embedded in inositol-based tris(spirotetrahydrofuranyl)ionophores were useful as chelation sites towards selective alkali metal ion binding and as a result rodlike supramolecular ionic polymer frameworks were prepared and analyzed in this study <01JA4974>. The temperature and viscosity dependence of the spin-directed stereoselectivity of the Patern6--Btichi photocycloaddition reactions between 2,3-dihydrofuran and benzaldehyde were studied <0lAG(E)4684>.

~

~+ H

-- K2Pd(SCN)4 = ~ N ~ 80~ 16hr 83%

Asymmetric Heck coupling reaction was achieved in 96% ee and 93% ee respectively between 2,3-dihydrofuran and phenyl triflate or a vinyl triflate employing novel chiral P,N ligands synthesized from (1S)-(+)-ketopinic acid <0lOLl61> as well as BOC-protected trans-4-hydroxy-L-proline <01JOC7240>. Palladium catalyzed addition of secondary amines to 2,3-dihydrofuran was also accomplished from which c~-aminotetrahydrofurans were obtained as shown below <01T5445>. Stereoselective formation of 2-substituted tetrahydrofurans was also realized from Lewis acid-promoted reactions between wlactols and silyl enol ethers <01EJO1169>. Optically active 2,3-disubstituted tetrahydrofurans were also realized for 2,3-dihydrofurans with chiral sulfoxides at C-3 as stereochemical controllers in an intramolecular Heck reaction <01CEJ3890>. Mechanistic and computational studies were carried out on intermolecular asymmetric Heck reactions <01HCA3043>. 2,3-Dihydrofuran was employed as a dienophile in the regio- and stereoselective inverse electron demand Diels-Alder reactions with masked o-benzoquinones derived from 2methoxyphenols <01T297>. A LiBF4-catalyzed imino Diels-Alder reaction was also performed on 2,3-dihydrofuran in Yadav's synthesis of furanoquinolines <01S1065>. The same condition was again employed in the cyclization of o-hydroxybenzaldimines with 2,3dihydrofuran from which a class of new furanobenzopyran derivatives was obtained in good yields with high diastereoselectivity <01TL6381>. An example of the formation of a furanoquinoline is shown below. ..Ph

EtO

H

+

PhNH

r.t., 3 h

88%

EtO

H

Phenylaziridines went through a 1,3-dipolar cycloaddition with 2,3-dihydrofuran in the presence of a catalytic amount of Sc(OTf)3 to give the corresponding pyrrolidine derivatives with good regioselectivity <01TL9089>. 2,3-Dihydrofuran also underwent a dysprosium(III) catalyzed 2:1 coupling reaction with substituted anilines to lead to the formation of hexahydrofuran[3,2-c]quinolines <01TL7935>. A three-component coupling between alkenyllithium, cyclopentenone and 2,3-dihydrofuran employing aluminum tris(2,6diphenylphenoxide) (ATPH) led to a mixture of trans- and cis-jasmonates. Tetrahydrofuran was also used in place of 2,3-dihydrofuran, leading instead to hydroxybutyl side chains <0lAG(E)3613>. A mechanism involving acid-catalyzed ring opening and recyclization was proposed for the formation of naphthalenes from 3-acetyl-5,5-diaryl-2-methyl-4,5dihydrofurans as depicted below <01TL3351>.

152

X.-L. Hou, Z. Yang amt H.N.C. Wong

Phil'

Ph

o

Me

O

conc HC, 100~

O-H

r

Me

94%

Me

8h

P

Ph

2,5-Dihydrofuran frameworks are also useful precursors in organic synthesis because the double bonds can be cleaved oxidatively to form pyran nuclei. Thus, 8-oxabicyclo[3.2.1]oct6-en-3-one and racemic 2,2-dimethyl-8-oxabicyclo[3.2.1 ]oct-6-en-3-one were transformed in multi-step routes to chiral precursors for the construction of the C1-C16 segment of the bryostatins <01OL929>. Medium ring heterocycles can also be realized through an oxidative cleavage of the double bond of a 2,5-dihydrofuran as depicted <01OL861>.

1. EDCI, DMAP, ~., ,sCO2H

i'PrOH-CH2CI2' 2.03, CH2CI2, -78~r't" 3. Me2S 66%

=

~O/,,,~/CO O

O

2ipr

A direct opening at the bridgehead of oxabicyclo[3.2.1]octenes with silyl ketene acetals in 4.0-5.0 M LiCIO4 gave highly functionalized cycloheptadienes. This reaction has been employed to the construction of the C19-C27 segment of rifamycin S <01OL481>. Enantiomers of tricyclic furan products were prepared accordingly via pivotal Diels-Alder reactions of the optically active 2,5-dihydrofurans as exemplified below <01OL1295>.

oBn

Ph

O

O

Me

CsH5Me 80~ 92%

O -

O H PhN

Bn 1.H2, Pd-C H Me

O H

POC

. . . . 82%

O H PhN

O

OAc

O H

Rhodium-catalyzed asymmetric ring--opening reactions of 1,4-epoxy- 1,4dihydronaphthalene with nucleophiles resulted in the formation of 1,2-dihydronaphthalenes. An example is illustrated below <01JA7170>.

.•ptBu2 Fe

PPh2

5 mol% [Rh(COD)CI]2 (2 mol%) (PhCH2)2NH (5 equiv.) Bu4NI (5 equiv.) CSA (1 equiv.) THF 91%

PhCH2., N"" PhCH2 OH 88%

ee

Unusual palladium-catalyzed trichlorosilane-promoted deoxygenative dimerization of 1,4epoxy-l,4-dihydroarenes was observed by Cheng, who prepared several diaryls in good to excellent yields. The mechanism is believed to involve a novel palladium-catalyzed

153

Five-Membered Ring Systems: Furans and Benzofurans

hydrosilylative dimerization with subsequent elimination of HOSiC13 and water <01OL811>. Cheng also reported a nickel-catalyzed highly regio- and stereoselective cyclization reaction involving 1,4-epoxy-l,4-dihydroarenes and alkyl propiolates, from which benzocoumarin derivatives were obtained <0lAG(E) 1286>.

5.3.3

SYNTHESIS

5.3.3.1 Furans

Reaction of the imine derived from 7-oxabicyclo[2,2,1]hept-5-en-2-one with PhSCI or mCPBA both provided the same 2-substituted furan in high yields via two different reaction pathways as depicted below <01HCA3667>.

~

PhSC,P h S ~

PhS~.~ N.',.Bn

N~Bn

C,-PhS~

N-~Bn

o A o.oI1\ o; H"N-Bn ~<~O-.'~..J~.A r

NHBn

H20

0

N~Bn o /

"J o

ArCO2-

Bn

Cyclization of phosphorylated allenic glycols under a basic condition afforded 3-hydroxy2,3-dihydrofurans, which were converted to 2-substituted furans upon treatment with a catalytic amount of TsOH <01S 1539>.

.h

===,

(EtO)2(O)P

H

Et3N

.0%

72~176 "~

TsOH

..P(O)(OEt)289~176~ 0 ~ P(O)(OEt)2 Ph Ph

Magnesium bromide catalyzed reaction of 2,5-dimethoxy-2,5-dihydrofuran with vinyl ether derivatives afforded the corresponding functionalized 2-alkylfurans in a good yield. The reaction might proceed through the concerted mechanism, in which the MgBr2-activated dihydrofuran reacted with the vinyl ether via a cyclic intermediate <01TL2023>. 2'- and 3'-Furyl sugars were prepared conveniently from the corresponding hydroxyl aldehydes derivatives by a fluoride-induced deprotection-cyclization reactions or acidcatalyzed cyclization reaction <01EJO2955>. Asymmetric carbonyl-ene reactions of benzaldehyde and 3-methylene-2,3-dihydrofurans catalyzed by Ti(O-i-Pr)4-(S)-binol afforded 3-substituted furans with high enantioselectivity. The furan product served as the key intermediate in the synthesis of (S)-fluoxetine hydrochloride, a potent and commercially important serotonin-uptake inhibitor <01T9925>. Reaction of 2-alkynal acetals with divalent titanium reagents and aldehydes provided, after acid work up, 2,3-disubstituted furans in good to excellent yields <01TL5501>.

154

X.-L. Hou, Z. Yang and H.N.C. Wong

1. Ti(OPrJ)2,2 iprMgBr 2. tBuCHO _

Ph

.

83%

tBu

The Michael addition-aldol condensation reactions of ml3-unsaturated enones with an organocopper reagent and (tetrahydropyranyloxy)acetaldehyde was followed by treatment of the products with TsOH to afford 2,3-disubstituted furans in moderate to good yields <00OL4095>. Thermal rearrangement of the cyclopropylketone below gave an air-sensitive dihydrofuran, which on reaction with DDQ furnished the furodiazepinedione in a high yield <00OLA249>.

R R~ < 5X10-5 mbar O~~.,.N~,O 200oc, 30min ~ N y O 91% - O-~ ,2 L) -/~-NHR ( = /~--NH 4-methoxybenzyl) O

RI

DDQ o~N~ "O CHCl3 ~ reflux /~-- NH 91% O

Reaction of ml3-acetylenic ketones with Cr(II) in the presence of aldehydes, trimethylsilyl chloride and water afforded 2,5-disubstituted furans in good to excellent yields. The reaction presumably went through the one-electron reduction of acetylenic ketones with Cr(II) via the Baylis-Hillman type intermediate <01SL1614>. Tandem dimerization followed by cyclization of alkynones catalyzed by PdCIz(PPh3)2 provided 3,3'-bifurans, while under a similar condition 2,5-disubstituted furans were obtained if the catalyst was Pd(PPh3)4 or Pd(OAc)2. The formation of bifurans was attributed to the involvement of hydridopalladium halide in the PdCI2(PPh3)2 catalyzed reaction <01JOC6014>. The "furan last" strategy was successfully employed to the synthesis of furanocembranolide as illustrated below. The 2,3,5trisubstituted furan containing a macrocyclic ring was obtained in high yield when the cyclic ynone was treated with silica gel <01JOC8037>. CO2Bu t

O ~cO2gut Silica gel .e

DPSO

O DPSO"

Reactions of 2-trialkylsilyl- and trialkylstannyl-substituted furans with benzhydryl cations provided 2,5-disubstituted furans and ipso-substituted furans. Kinetic investigations of the reactions revealed that the monosubstituted product was produced from the protonolysis of the 2,5-disubstituted furylstannane, while the 2,5-disubstituted furan was derived from an electrophilic substitution of the mono-substituted furan. Introduction of a trialkylsilyl and a trialkylstannyl group to the 2-position of furan hardly affected the reactivity of this position towards carbenium ions (ipso attack), while the 5-position is somewhat activated <01OL1629, 01OL1633>. A general protocol was developed towards a mild and regioselective arylation of 2furaldehyde using functionalized aryl halides in the presence of a catalytic amount of PdCI2PCy 3. The slow addition of aryl halides to the reaction mixture avoided the homo-coupling efficiently <01OL1677>. A one-pot Suzuki coupling of aryl halides with in situ generated 5(diethoxymethyl)-2-furylboronic acid catalyzed by palladium also provided 5-aryl-2-

155

Five-Membered Ring Systems: Furans and Benzofurans

furaldehydes in high yields <01S1681>. Palladium-catalyzed coupling reaction of 2(alkyltelluro)furan with terminal alkynes also gave acetylenic furan derivatives in good yield <01TL8927>. The synthesis of [22]metacyclophanes with furan bridges afforded another example. The reaction of bromobenzodihydropyrene with NaNH~ and a catalytic amount of tBuOK in an excess of furan gave the adduct, which underwent Diels-Alder reaction once more followed by a retro-Diels-Alder reaction to lead to the desired furan product <01H(54)249>. The Diels-Alder reaction is still a useful strategy for the preparation of complex molecules. As an example involving the introduction of three carbon substituents, the reaction of an oxazole with a propargyl ketone in a cycloaddition and retro-Diels-Alder process constituted a highly regioselective construction of 2,3,4-trisubstituted furans <01JA4492>. A two-step, one-pot synthetic entry into functionalized furans with benzyl or allyl substituent at the 3-position was reported. Thus, 1,4-addition of a propargylic alkoxide to a conjugate acceptor provided the enolate, which underwent a palladium-mediated cyclization involving an unsaturated halides or triflates as a coupling partner to give 4-benzylidene tetrahydrofurans. A subsequent treatment of the benzylidenetetrahydrofuran with potassium tert-butoxide yielded substituted furans through a decarboxylative elimination reaction <01JOC4069>.

EtO2C".,tf/CO2Et

+ LiO

5 mol)/oPdCl2(PPh3)2 ~ o / \ O E t B#o o

-

,8%

A two-step one-pot synthesis of 2,3,5-trisubstituted furans from epoxyalkynyl esters was reported, in which a facile SmI2-mediated reduction was used for the generation of the 2,3,4trien-l-ols, and the reduction was followed by a Pd(II)-catalyzed cycloisomerization <01JOC564>. An attractive variant of this reaction was extended to the preparation of tetrasubstituted furans. Thus, when electrophilic Pd(II) complexes were generated in situ by an oxidative addition of aryl halides or triflates to Pd(0), the oxypalladation process was followed by a reductive elimination and tetrasubstituted furans were formed <01 TL3839>.

OAc BnO.._y O

PdX2L 2. BzOH, Pd(OAc)2(PPh3)2 / \ ~ .PdL2X

0xypalladati~ |/ -HX,+L - [ B n O ' ' ' ' ~ 0 % Ph

nO

h v

69----~/o BnO

~ Ph

The indirect 3-alkylation of 2,5-dimethylfuran was achieved via a tandem Michael addition of a nitroalkane and elimination of nitrous acid starting from cis-3-hexene-2,5-dione, a ring opening product of 2,5-dimethylfuran. Hydrogenation of the carbon-carbon double bond and a subsequent Paal-Knorr reaction provided 3-substituted-2,5-dimethylfurans <01S2003>. Selective ring bromination of methyl 2-methyl-3-furoate with NBS was realized when DMF, an aprotic polar solvent, was used. If the same reaction was carried out in CCI,,

156

X.-L. Hou, Z Yang and H.N.C. Wong

bromination took place at the side chain together with a minor amount (ca. 5%) of the 5bromo derivative <01TL2643>. Furans functioned as 1,4-dicarbonyl compounds in acidic media and underwent the recyclization reaction to provide new heterocycles <01JOC8685>. Ceric ammonium nitrate-promoted oxidative addition of 13-ketophosphonates to vinyl acetates followed by a mild acid-catalyzed Paal-Knorr cyclization produced 3-furylphosphonates in a regioselective manner <01 SL703>. Rhodium(II)-catalyzed reactions between diazosulfones and aldehydes yielded an entry to carbonyl ylides, which underwent inter- and intra-molecular cyclization reactions with dipolarophiles, such as alkynes and alkenes, to afford tetrasubstituted furans in modest to good yields <01SL646>. The rhodium(II) acetate catalyzed reaction of 3-diazobenzopyran2,4(3H)-dione with terminal alkynes provided a mixture of 2-substituted furo[3,2-c]coumarin and furo[2,3-b]coumarin, presumably through a formal [3+2] cycloaddition reaction <01S735>. Furo[3,2-c]coumarins were also produced from 4-hydroxycoumarins and ahaloketones via a tandem O-alkylation-cyclization procedure <01TL3503> The condensation of dimethyl diglycolate and aryl glyoxylates in the presence of potassium tert-butoxide as base provided a series of 4-arylfuran-3-ols bearing one tert-butyl ester and one methyl ester. As such, this furandicarboxylate allowed an easy differentiation of the two esters for selective chemical modifications <01TL6429>.

O

O

Ph~O

KOtBu,tBuOH Ph OH CsHsMe,70 ~ . ~ MeO"J~o~J~OMe + 0 / "OMe 72% " tBuO2C CO2Me Iodocyclization of 3-alkyne-l,2-diols via 5-endo-dig mode followed by dehydration led to the generation of 13-iodofurans in excellent yields <01TL5945>.

5.3.3.2 Di- and Tetrahydrofurans Several syntheses of 2,3-dihydrofuran skeletons were recorded in 2001. Thus, dehydroisoo~-lapachone, a naturally occurring dihydrofuranonaphthoquinone and dehydroiso-13lapachone were synthesized in yields of 3.5% and 3.2% respectively in a single step conversion from lapachol <01IJC(B)89>. Manganese(III) acetate also mediated radical reactions from which araliopsine and other related quinoline alkaloids were obtained <01T4719>. These reactions were also performed in an ionic liquid 1-butyl-3methylimidazolium tetrafluoroborate <01CC1350>. Silver carbonate mediated oxidative addition of 1,3-diketones to fulvenes was found to provide cyclopenta[b]chromenes <01TL935>. A facile synthesis of naphthofurandiones via cerium(IV) ammonium nitrate mediated oxidative addition of 2-hydronaphthoquinone to dienes was also reported <01 T7705 >. The key step in Mori's synthesis of (S)-(-)-nocardione A involved a Mitsunobu-type ring closure of a diol, which gave the dihydrobenzofuran in low yield (19%). Consecutive oxidation and deprotection of this dihydrobenzofuran intermediate yielded (S)-(-)-nocardione A <01EJO4313>. Cyclopropanes substituted with a donor and an acceptor group underwent ring opening to form 2,3-dihydrofurans. For example, the (t-butyldiphenylsilyl)cyclopropane dicarboxylate depicted below was converted to the 2,3-dihydrofuran in 96% yield <01OL2717>.

Five-Membered Ring Systems: Furans and Benzofurans

MeO2C.~

+ /TiCI4 , ,.~O% OMe

7,OI4 ....

MeO/~o/T--iCI 4 MeO2C-~J .

'vl~:~'~'J 2~"~

SiR3 (SIR3= SiPh2Bu') ~

~OMe " ~'''''~ 96% H3~ R3Si

SiR3

157

.CO2Me

Intramolecular enolate addition to an o-fluoroacrylate was a key step in the synthesis of a heteroyohimbine indole alkaloid containing a 2,3-dihydrofuran moiety <01SL1125>. An endo ring closure at the sp-hybridized carbon center of an allenyl unit to form a 2,3dihydrofuran as shown below was observed when the allenyl sulfoxide containing a primary 5-hydroxy group was allowed to react with potassium tert-butoxide <01 OL3385>.

[ ~ . SOPh

HO

i

KOBut

O~

100%

SOPh Me

In one of his synthetic studies of 5-alkynylacylsilanes, Narasaka discovered that only bis(diphenylphosphino)butane (dppb) was able to assist the palladium catalyzed formation of the 2,3-dihydrofuran as depicted below <01CL 1210>.

O ' ~ S iMe2Ph " ~ Ph

Pd(OAc)2 dppb 27%

Ph~SiMe2Ph

Rh~(OAc)4 catalyzed reaction between a vinyldiazo compound and benzaldehydes gave mixtures of two 2,3-dihydrofurans by cyclization of intermediate carbonyl ylides <01JOC5395>. Fluoroalkyl substituted 2,3-dihydrofurans were also prepared by rhodium(II) catalyzed addition of trifluoroacetyldiazoacetates to vinyl ethers <01T3383>. 2,3Dihydrofurans were synthesized in a highly enantioselective manner from allenylsilanes and ethyl glyoxylate. The reactions were catalyzed by a chiral bis(oxazolinyl)pyridine-scandium triflate complex <01JA12095>. A synthesis of 2,3-dihydrofurans was also achieved from samarium diiodide promoted reactions of diaryl ketones and chalcones <01S 1004>. Tri- and tetrasubstituted 2,5-dihydrofurans were synthesized with complete axis to center chirality transfer via gold(III) chloride catalyzed conversions of functionalized ~hydroxyallenes and an example is depicted below <01OL2537>. A Mitsunobu reaction was employed in the synthesis of spiro-linked 2,5-dihydrofuran that is a precursor towards the individual C3 epimer of an NK-1 receptor antagonist <01OL667>. A double ring closing metathesis reaction was also employed in another enantioselective synthesis of NK-1 receptor antagonists <01OL671>.

tBu,,' ~ o ~ . ~ H CO2Et nBu OH

AuCI3 100%

tBuh~/--~,',H nBu~ "0 / %CO2Et

A novel and stereoselective synthesis of trans-2,5-disubstituted 2,5-dihydrofurans was reported recently <01T9335>. As can be seen below, a nucleophilic attack of phenyllithium

158

X.-L. Hou, Z Yang and H.N.C. Wong

provided a 85:15 mixture of two chromatographically separable alcohols, one of which was reduced and heated to form a 2,5-dihydrofuran.

H nBu -" O

PhLi 86%

H nBu Ph (major isomer)

NaBH3CN 67%

H nBu h

Heat 82%

nBu Ph

Another way in which 2,5-dihydrofurans could be made was by an intramolecular radical cyclization of a vinyl iodide with an cql3-unsaturated ester as depicted below. Griseolic acid B was synthesized utilizing this cyclization as the key step <01OL3583>.

~O,~

n'Bu3SnH' AIBN

",,O

EtO2 E t O 2 C . ~ ~ H~'"~O/~

33%

O~.,,.,,O EtO2C z ,~ = O ICO2Et

In a three component reaction, the zwitterionic intermediate resulted from the addition of a dimethoxy carbene to dimethyl acetylenedicarboxylate was trapped by an aldehyde to provide 2,5-dihydrofurans in good yields <01TL2043>. Ring closing metathesis reactions are useful for the construction of 2,5-dihydrofurans. Hoveyda and Schrock have reviewed the use of Schrock's molybdenum catalysts in the synthesis of dihydrofurans as well as other compounds <01CEJ945>. Grubbs recorded the application of his ruthenium catalysts in an enantioselective construction of 2,5dihydrofurans <01OL3225> <01JAIl312>. A domino metathesis of an alkynyl substituted cycloalkene displayed below led to the disubstituted 2,5-dihydrofuran in an acceptable yield <01TL5245>. 2,5-Dihydrofurans were also obtained via olefin metathesis in supercritical CO 2 <01JA9000>.

PCY3 ~~/

i~cY3Ph ' .

.

.

.

.

.

.

67% A new three-component organoruthenium catalyst system consisting of [RuCl~(pcymene)] 2, 1,3-bis(mesityl)inidazolium chloride and cesium carbonate was recently utilized in intramolecular metathesis reactions of enynes, from some of which 2,5-dihydrofurans were produced <01SL397>. The same type of precursor also underwent cobalt-mediated cycloisomerization reactions to form 2,5-dihydrofurans, as illustrated <01OL4161>. nBu

SiMe3 C02(CO)8,t-BuOOH O~

57%

nBu Ht,,

H

SiMe3

159

Five-Membered Ring Systems: Furans and Benzofurans

The synthesis of tetrahydrofurans continues to be one of the active areas in organic synthetic methodology and progress in this area has been reviewed <01JCS(P1)2303>. Stereoselective constructions of the tetrahydrofuran nucleus by alkoxyl radical cyclizations have also been reviewed <01EJO619>. Another review deals with the rearrangement and cycloaddition of ylides generated from diazo compounds, in which the formation of some interesting tetrahydrofuran molecules has been recorded <01CSR50>. Williamson cycloetherification has always been a method of choice. For example, the racemic epoxide shown below was biotransformed to a chloroalcohol which then underwent a spontaneous dehydrochlorination to yield the tetrahydrofuran in 79% chemical yield as well as in 86% ee <01TA41, 01EJO4537>. Enzyme-initiated reactions of this type have been reviewed <01CSR332>. In his route to the ring A segment of gambieric acid, Yamamoto also observed a cycloetherification reaction after deprotection of the triethylsilyl group of the mesylate compound illustrated below <01TL3645>. In a similar manner, tetrahydrofuran derivatives were obtained by Chakraborty <01JOC4091>, Martfn <01OL3289>, Ward <01T2057>, de Groot <01T5657>, LaLonde <01JMC180> and Brown <01TL473> via Williamson-type cycloetherification reactions <01JMC180>. 2,5-Disubstituted tetrahydrofurans were also synthesized through a palladium(0)-catalyzed stereoselective cyclization of hydroxy-allyl acetates <01H(54)419, 01OL1953>. 0

Rhodococcus

c J ~ B u F"~O

L

o

~

~

sp.~ CI. ~ . - ~

OH

SM~788

O

_

-

P

OSiEt3

OMs v

Bu

,

OH . Bu4NF 84'/o

-~

F " O ~

t,.~6

OH

~ -Hc, ' ....~

i H

Bu

O P v A

Intramolecular epoxide opening reactions have also been applied to the preparation of tetrahydrofuran derivatives. Recent examples from natural product synthesis are described in the total synthesis of (-)-isolaurallene by Crimmins et al. <01JA1533>, in synthetic studies towards the C5-C20 segment of the azaspiracids <01OL975>, in Urones's synthesis of prehispanolone analogs <01SL153> and in Martin's synthesis of marine natural products <01JOC1420>. The regiochemical control in these intramolecular cyclizations was also studied by Borhan <01OL2489>. Haloetherification is also a popular strategy for tetrahydrofuran formation. In Tanaka's total synthesis of mosin B, a pivotal step involved the treatment of the allyl alcohol with I(co11)2C10,. A highly stereoselective iodoetherification reaction was believed to proceed, leading to the formation of the tetrahydrofuran epoxide as a single isomer after subsequent base treatment <01OL429>. The same strategy was also employed by Cossy in the preparation of monocyclic as well as bicyclic tetrahydrofuran derivatives <01TL251> and by Guindon in the synthesis of 2,3,5-trisubstituted tetrahydrofurans <01JOC8992>. As illustrated in the following scheme, a stereospecific synthesis of substituted tetrahydrofuran derivatives was reported by Warren, employing the opening of episulfonium ion intermediates via a mechanism similar to that of the haloetherification <01JCS(P1)138>. Thomas reported the total synthesis of pamamycin-607, a crucial step of which involved the addition of phenylselenenyl electrophiles to an alkene, followed by a stereospecific ring-opening of the generated episelenenium ion <01TIA969>. Two total syntheses of pamamycin-607 were also recorded more recently <01JA10131> <01TL7801>. Sugihara reported his procedures for the realization of tetrahydrofurans via cyclization reactions involving alkoxymercuration routes <01H(54)629>.

160

X.-L. Hou, Z Yang and H.N.C. Wong

Me+

MeS,,,,.~

OH p-TsOH= ~

99% = C

Tetrahydrofurans were also synthesized through consecutive epoxidation and cyclization reactions of 1,5-dienes with RuO 4 <01EJO997>, RezO7 <01T5255>, KMnO, <01TL7741> and OsO, <01TL971> <01TL7741>. An asymmetric permanganate-promoted oxidative cyclization of 1,5-dienes was also recorded <0lAG(E)4496>. Bishomoallylic alcohols were converted in good yields and in high diastereoselectivity into tetrahydrofurans by a Cp2TiCI2 - t-butyl hydroperoxide- 4/~ molecular sieves system <01SL 1479>. Radical cyclizations also represent an important method for the synthesis of tetrahydrofurans. A 5-exo-trig radical cyclization of an oxygen cetered radical was used as a route to 2-methyl-4-phenyltetrahydrofurans <01CC799>. When a 1-(2-chloroethoxy)-l-ostyrylcyclopropane was treated with an excess of lithium powder at -10~ a spirotetrahydrofuran was unexpectedly isolated, apparently by radical cyclization. A similar result was obtained when a tetrahydrofuran solution of lithium-naphthalene was used <01CEJ4723>. Triethylborane-induced radical cyclization has also been used to furnish tetrahydrofurans <01JA3137>. Another investigation involving a radical cyclization mechanism was the preparation of tetrahydrofurans from hydrophobic substrates in a combination of water-soluble radical initiator 2,2'-azobis[2-(2-imidazolin-2-yl)propane] (VA061), water-soluble chain carrier 1-ethylpiperidine hypophosphite (EPHP), and surfactant cetyltrimethylammonium bromide (CTAB) <01OLl157>. Nitrate radicals <01H(55)377> and phosphonyl radicals <01TL3137> were also used to induce an oxidative and selfterminating cyclization, from which substituted tetrahydrofurans were obtained. A short and stereoselective total synthesis of (+)-dihydrosesamin and (+)-acuminatin methyl ether by radical cyclization of epoxides using a Ti(III) reagent as a radical initiator was also recorded <01SL1249>. A thorough investigation of the influence of Lewis acids on the radical cyclization of 13-allyloxyalkyl phenyl selenides to tetrahydrofurans has been reported <01OL3459>. Nair reported a CAN-mediated oxidative cyclization of cinnamyl ethers, which resulted in the formation of trans-3,4-disubstituted tetrahydrofurans as shown below <01CC1682>. Toluene-p-sulfonyl mediated radical cyclization of bis(allenes) utilizing pTsBr or p-TsSePh also led to trans-3,4-disubstituted tetrahydrofurans <01CC 1306>.

P'~~L ?Ar O/

CAN,02, Ph H Ar _ dry56~176 MeOH = O~.....l<.OMe \O/

(Ar=3,4,5-trimethoxyphenyl)

Moeller synthesized tetrahydrofuran natural products (+)-linalool oxide <01OL2685> and (+)-nemorensic acid <01TL7163> by employing intramolecular coupling reactions of enol ether radical cations as well as ketene dithioacetal radical cations with oxygen nucleophiles.

161

Five-Membered Ring Systems: Furans and Benzofurans

H•OMe Me OH

Me/q'Me

OH

RVCanode MeO 2F/mole, Et4NOTs,8 mA ~"JMOMe 2,6-1utidine e MeOH-THF L..../O + -, = ~.. Me 80o/0 M~'OH

MeO ~,,IMOMe e L...v,O MemOMe H

The synthesis of a tetrahydrofuran compound corresponding to the C11--C26 segment of pectenotoxin II was accomplished by Roush. In his synthesis, Roush made use of a SnCI 4promoted [3+2] annulation of an allylsilane and methyl pyruvate, leading to a tetrasubstituted tetrahydrofuran in 66-75% yield and in >20:1 diastereoselectivity <01OL1949>. Another Lewis acid promoted [3+2] cycloaddition of epoxides with alkynyltungstens also led to the formation of tetrahydrofurans in an enantiospecific manner <01JA7427> An enantiospecific oxidative ring contraction of a 6-deoxy-D-gulal was employed by Gin in the preparation of a tetrasubstituted tetrahydrofuran for the total synthesis of (+)-pyrenolide D <01AG(E)1128>. 3-Vinyltetrahydrofurans were successfully synthesized via a palladium(0)-catalyzed cycloaddition of electron-deficient alkenes with allylic carbonates, as illustrated below <01JOC7142>. Another Pd(II)-catalyzed cyclization of allylsilanes led to the formation of 2vinyltetrahydrofurans <01 CEJ4097>. t B u ~ CN CN

Pd2(dba)3-CHCl3 s dppe N + H o ~ O ' , ~ OP 'F o

looo/o

'Bo~"o "~

trans : cis = 73 : 27

O HO

~

SiMe3

Li2[PdCl4]cuCi2 H O ~ 4 86%

~

A regio- and enantioselective reaction was developed by Trost, in which 2-methyl-2vinyloxirane and ethyl acetoacetate underwent a palladium(0) catalyzed reaction in the presence of a chiral phosphine ligand to form a tetrahydrofuran in good yield and ee. It was also discovered that tetrabutylammonium triphenyldifluorosilicate increased the rate of interconversion of diastereomeric n-allylpalladium complexes, thereby enhancing both regioselectivity and enantioselectivity <01JA12907>. The first total synthesis of (_)epimagnolin A was achieved utilizing an intramolecular rhodium catalyzed C-H insertion reaction of a diazo compound <01TLA73>. (_)-Asarinin and (_+)-fargesin were synthesized in a similar manner <01JOC6719>. The intermolecular Lewis acid catalyzed reaction of protected 13-hydroxycarbonyls with benzyl diazoacetates <01TL1819> or ptolylsulfonyldiazomethane <01T5227> also provided tetrahydrofurans in good stereoselectivities. Total syntheses of the cytotoxic diterpenoids (-)-sclerophytin A and its diastereomers were reported by Paquette <01JA9021>, whose approaches involved multistep conversions of the optically active y-lactones into a tetrahydrofurans. A similar strategy was employed to the stereoselective synthesis of the potent 5-1ipoxygenase inhibitor CMI-977 <01IJC(B)1043>. Synthesis of 3-acyltetrahydrofurans was achieved by acid-promoted rearrangements of acetals derived from anti-allylic diols <010L 1225>. This strategy was also employed in the total synthesis of sclerophytin A <01JA9033>.

X.-L. Hou, Z Yang and H.N.C. Wong

162

/Pr

OH

TfOH

O

H..O

98o~ Me~"-\O/"ipr

The synthesis of an aesthetical "oxa bowl" called pentaoxa[5]peristylane was reported by Mehta recently employing as a pivotal step an intramolecular cascade acetalizaion. In the solid state pentaoxa[5]peristylane showed C3 symmetry which is attributable to a multicolumnar framework with maximal C-HoooO hydrogen bonding interactions mediated by the less acidic cyclopentanoid hydrogens and the oxygen atoms <01JOC6905>.

OHC.

1.03 39%

[ OHC..

9

. IOH

I~ L

-]

CHO

/

"1'6H0 I clio j

2-Dibromoalkylidenetetrahydrofurans were synthesized by dibromoolefination of ylactones utilizing bromomethylenetriphenylphosphorane <01TL7265>. Other methods by which 2-alkylidenetetrahydrofurans can be realized were the reactions between 1,3dicarbonyl dianions and epibromohydrin derivatives <01CEJ565>, between 1,3-dicarbonyl dianions and 1,4-dibromo-2-butene <01CEJ1056> or 1-bromo-2-chloroethane <01JOC6057>, and between 1,3-bis(trimethylsiloxy)-l,3-butadienes and c~-chloroacetyl chlorides <01CEJ1720>. An intramolecular version of these reactions was recently employed in synthetic studies on the sarcodictyins <01T8531>. A review on these transformations has also appeared recently <01 CEJ3858>. An improved synthesis of (E)-cyclic-13-alkoxyacrylates was reported by Kato and Akita, who used an oxidative cyclization-methoxycarbonylation route for cyclic and acyclic 4-yn-l-ols in the presence of palladium(II) and p-benzoquinone <01TIA203>.

QH :~'C

~ 02Me

Pd(MeCN)2Cl2 H p-benzoquinone /-..~.,,,O CO, MeOH , ~ , ~ ....,,/~.kCO2Me 95%

C02Me

3-Alkylidenetetrahydrofurans were most conveniently prepared through cyclization reactions involving radicals generated by irradiation of alkyl halides in the presence of Et3N and this method was employed to the synthesis of (_)-bisabolangelone <01T5173>. A series of spirocyclic ethers containing 3-alkylidenetetrahydrofuran skeletons was prepared by radical cyclization of epoxides through a Ti(III) radical initiator <01IJC(B)925> <01S2500>. Loh found that In(OTf)3 promoted the reactions between homoallylic alcohols and 1 equivalent of aldehydes to afford 3-alkylidenetetrahydrofurans as the major product <01JA2450>. In the presence of 0.1 equivalent of an aldehyde, the same condition only led to the corresponding tetrahydrofuran. In another study, polysubstituted tetrahydrofurans and 3alkylidenetetrahydrofurans were produced via In(OTf)3 promoted reactions <01OL2669>. A novel palladium--catalyzed [3+2] cycloaddition of alkylidenecyclopropanes with aldehydes was also found to provide 3-alkylidenetetrahydrofurans <01AG(E)1298>. It was proposed

163

Five-Membered Ring Systems: Furans and Benzofurans

that alkylidenecyclopropanes played the role of trimethylenemethanes that reacted with aldehydes in a [3+2] manner.

Bu~===~ + Bu" "

pd(pph3)4 , Bu3PO CHO 75%

Bu~

Palladium(0) also catalyzed the 3-component reaction between unsaturated halides or triflates, propargyl alcohols and the Michael acceptors alkylidenemalonates, leading to the formation of 3-alkylidenetetrahydrofurans <01JOC 175>. Highly enantioselective formation of 2-alkylidenetetrahydrofurans was also realized by palladium-catalyzed ene-type cyclizations of 1,6-enynes <01AG(E)249, 01 T5137> and 1,2-dien-7-ynes <01JA8416>.

CO2Me L:~OI[.. Pd(OCOC (R)NAP>99% -B I F3)2 = 1 ~C o 2 M e '

Pd(PhCN)2CI2 II SnPh3 ~'~'-h'~.~1'~tBuM P(C6 o2S Fs)372% i-SnPha ....tBuMe2SPi-'h''"O/: -/J~'.~

94%ee

P

O

Novel tetracyclic dienone systems containing 3-alkylidenetetrahydrofuran frameworks could be prepared by a dicobalt octacarbonyl catalyzed [2+2+2] carbonylative cycloaddition reaction of triynes as illustrated below <01OL1065>. [2+2+2] Annulation of 1,6-diynes was mediated by tetramethallylchromate prepared from CrCI3 and methallylmagnesium chloride, giving bicyclo[4.3.0]nonadiene derivatives in good yields <01JA4629> O Co2(CO)8

siipr3

CO 75%

_-- ipr3Si

O~ O n O

5.3.3.3 Benzo[b]furans and Related Compounds Substituted difuranonaphthalenes were used as a two-photon photosensitizer with a focused laser beam to generate singlet oxygen. Their syntheses are straightforward; for example, in the presence of I~CO 3, 1,5-dihydroxynaphthalene coupled with 1-phenyl-2bromodecanone to give 1,5-bis(1-phenyl- 1-nonanon-2-yloxy)naphthalene, which with methanesulfonic acid gave 3,8-diphenyl-2,7-dioctyldifurano[2,3-a:2',3'-f]naphthalene <01JA1215>. An acid catalyzed cationic cyclization of electron-rich ~-benzoyldiphenylmethanols was utilized to construct 2,3-disubstituted benzo[b]furans. <01S 1487>. From a theoretical study on the physical properties of heterobuckybowl molecules, the results indicated that of two approaches to make the target molecule, Approach 1 was more favored than Approach 2 because 6E for Approach 1 was negative but for Approach 2 it was positive <01JOC6523>.

164

X.-L. Hou, Z Yang and H.N, C. Wong

o~

o~

OH

___1. . . .

O

~.__2__._

OH

Pterocarpans, an important class of naturally occurring isoflavanoids used as potent antisnake venom antidotes, were effectively synthesized by a radical mediated 5-endo-trig cyclization of substituted 4-(2-bromophenoxy)-2H-chromene <01EJO3461>.

n-Bu~SnH AIBN -

BrO.~~

9~\H

=__

88%

CI

A different approach for the synthesis of racemic trans-pterocarpans was also developed. A trans-fused 2-3-disubstituted dihydrobenzofuran was produced by AgBF4-promoted intramolecular cyclization, and after reduction of an ester function the six-membered oxygen ring was formed by Mitsunobu cyclization <01 T7113>.

1 A BF4(47 ,

2. LiAIH4 (93 %) HO BnS

"'--

~

pph3

DEAD

OH

58%

H"~)/~~

An efficient approach to two types of 2,3-disubstituted benzo[b]furans was reported by Flynn. In typical examples, the starting iodophenol was allowed to react with a phenylacetylene and an iodobenzene in the present of Pd(PPh3)2C12 and MeMgC1 with or without CO to lead to the 3-aroylbenzofuran (as shown) in the presence of CO, or to the 3arylfuran in its absence <01CC 1594>.

p-MeOC6H4C-CH CO, MeMgCl Pd(PPh3)2CI2 ,,r,

64%

Ar =

MeO" v

u

O

------,

OMe

Synthesis of 3-substituted benzo[b]furans was realized from a combination of benzotriazole chloride mediated intramolecular cyclization and low-valent titanium promoted reduction. Thus, the sodium salt of 2-hydroxybenzophenone was first allowed to react with a 1-benzotriazol-l-ylalkyl chloride to give a ketone which was cyclized by LDA. Eventually, A titanium promoted elimination led to the desired 3-phenylbenzo[b]furan in good yield <01JOC5613>.

165

Five-Membered Ring Systems: Furans and Benzofurans H

ONaO ~Ph

H Bt"~O 0 Bt/L"C/ ~ " P h 97%

Bt //,~"~OH ~Ph LDA= ~ ph TiCI3-Li 97% 65%

Benzofuro[2,3-c]pyridines were synthesized by either an intramolecular Heck reaction or a radical reaction in good to moderate yields as shown below <01 TL6499>. Another palladium catalyzed cyclization procedure also led to dih ydrobenzo[b]furans <01JA 12202>.

c

EtaN,MeCN,THF 75% O2Et

/~k O'~N ~

AIBN 81%

\C02Et

C02Et

The synthesis of 2-(dialkylaminomethyl)benzo[b]furans was achieved by a reliable and rapid method which involved the use of a solvent-free mixture of cuprous iodide and alumina under microwave irradiation. This promoted the condensation of o-ethnylphenol, secondary amines and para-formaldehyde <01TL6049>.

Me

+ (CH20)n+H ~ N - - - ~ -~7 -,,,,u UFI

Cul,AI203 M e ~ Microwave= ~ d 64%

/---N Nk_~/N ~

An improved procedure for the synthesis of the core structure of (+_)-galanthamine was developed by employing an oxidative intramolecular cyclization in which the pivotal step involved the treatment of the starting material as depicted below with phenyliodine(l]I) bis(trifluoroacetate) (PIFA). The final target (_+)-galanthamine was obtained by further manipulation of this key intermediate <0lAG(E)3062>. Another efficient total synthesis of (_)-galanthamine was developed by employing a methylamine mediated rearrangement as a key step <0 lAG(E)4745>. o

HO ~N,CHO BnO~ BnO" "F"

OBnO

PIFA CF3CH2OH~ "~,,,~ ,.CHO 90% = u ~ N BnO" "~

OBn MeNH

"~

(+)-Galanthamine

Me~NH2THF ,1 0~ 0O % OMe

OMe

A related solid phase method, involving palladium mediated deprotection of a phenyl allyl ether and cyclization on to a dienone, has also been described <01JA6740>. In a synthesis of

166

X.-L. Hou, Z Yang and H.N.C. Wong

8-O-methylpopolohuanone E, the benzo[b]furan core structure was obtained by cyclization of a phenol on to a chlorocyclohexadienone unit with loss of HCI. In a concise total synthesis of frondosin B, the seven-membered ring based key intermediate 2,3-disubstituted benzo[b]furan was constructed by a classical Friedel-Crafts reaction. Through two different approaches, further manipulations of the resulting ketone led to the final target molecule frondosin B <01JA1878>. O H

o=<-

~. (coc0~

MeO

.,i ~J

o,y,...~

-78~ t~)-20~ MeO /"',~r"O

-Me

67%

~

-'0

Me

~~0 Me Frondosin B

A Baylis-Hillman reaction was used for the construction of novel arylfuran scaffolds. In a typical example, when phenanthrene-9,10-dione (1.0 raM) was treated with methyl vinyl ketone (3.0 raM) in the presence of titanium tetrachloride (1.0 raM) in dichloromethane at room temperature, 2-methylphenanthro[9,10-b]furan-3-carboxaldehyde was obtained. A mechanism for the formation of these compounds is discussed in the article <01TL 1147>. 0

0

i~Me

TiCl4

H Me

70%

In order to search for conformationally restricted 5-HT2A/2C receptor agonists, a useful method for the synthesis of an enantiomerically pure heterocyclic tetrahydrobenzo[1,2-b;4,5b']difuran based alkylamines was developed. The route to the core structure is illustrated below. Thus, when the chlorobromo compound was treated with Mg in the presence of EtMgBr, the tetrahydrobenzodifuran was obtained. This was further functionalized by reaction with a chiral acyl chloride and AICI 3, followed by reduction of the ketone carbonyl group with triethylsilane in trifluoroacetic acid <01JMC1003>. Clio

~ Br

Mg, EtMgBr THF o Br

CI~

0

79%

0

Aplysin and aplysinol, naturally occurring anti-tumor agents of marine origin with the scaffolds of substituted dihydrobenzo[b]furans, were synthesized from 2methylenedihydrobenzofurans by sulfur or tributyltin hydride/AIBN-mediated cyclization. <01T791>. An enantiospecific approach for the total synthesis of (-)-aplysin and (-)debromoaplysin was achieved employing a Claisen rearrangement as a key step. Synthetically, the chiral starting m-cresyl ether was allowed to undergo a thermal reaction in DMF in a sealed tube at 180~ for 72 h, leading to a mixture of cyclized products from both ortho and para Claisen rearrangements in a ratio of 5:1:2 (total yield 64%). Further

167

Five-Membered Ring Systems: Furans and Benzofurans

transformations of the major isomer afforded (-)-aplysin and (-)-debromoaplysin, respectively <01TL4913>.

./•O•//.__

180~ 72h 64%

(majorisomer)

(-)-Aplysin

The synthesis of a potentially chiral 7,8-dioxa[6]helicene 34 was achieved by NBS oxidation of its precursor 7a,14c-dihydro-7,8-dioxa[6]helicene <01JOC200>. Stereoselective bimolecular oxidative coupling of enantiopure phenylpropenoic amides was performed both enzymatically (HRP/I-I202) and chemically (Ag20). This method provided a diastereo- and enantioselective synthesis of dehydrodiconiferyl ferulate <01 T371>. O

R' O~---~.

34

[O1 =_HO 30-70% OMe O MeO ~ OH R' = HN_v ~ OEt N =

R'

OMe and diastereoisomer

02 An efficient, one pot method for the synthesis of benzo[b]fluoren-10-ones was achieved by Cs2CO3 promoted sequential deprotonation and cyclization. The benzofuran ring was generated by an intramolecular acylation of an enolate <01TL8429>.

~ MeO "~ "oHOMe+ Br F Br

iOMe

MeO

GS2003DMF65% -~

O OMe

~ ~~_~M

Br

O

.OMe e

A novel synthetic approach was established in which the Wilkinson's catalyst activated the C-H bond of aromatic imines to generate functionalized dihydrobenzofurans. The characteristic feature of this annulation procedure was the cross-coupling reaction proceeded selectively at the more hindered ortho site, providing functionalized bicyclic ring systems that would be otherwise difficult to access <01JA9692>.

BnN_.~..R1 ~Rc~~3

1. (PPh3)3RhCI, 12500or150~ 2. 1MHCI(aq)

O R ~" R~

R3

,,

50-65% A novel photocyclization of tosylstilbenes was employed to effectively generate a densely functionalized tricyclic compound. Thus, irradiation of the tosylstilbene illustrated below with a medium pressure mercury lamp in the presence of iodine and an excess of propylene

168

X.-L. Hou, Z Yang and H.N.C. Wong

oxide (PO) led to the product in 91% yield. The functions of PO was to trap the generated HI, and the tosyl substituent on the stilbene was expected to impart an electron deficiency that protected it against unwanted oxidations during the photochemical reaction <01OL1343>.

MeO2C EtO2C. Me

MeO2C

~O

hv TS

OAc

91%

EtO2C~ -

O Ts

Me Furoindol

OAc

An efficient synthetic methodology was developed in which the palladium-mediated intramolecular carbonylative annulation of o-alkynylphenols was employed to construct benzo[b]furo[3,4-d]furan-l-ones by a tandem reaction. Several densely functionalized alkynyl- phenols were cyclized into their respective substituted benzo[b]furo[3,4-d]furan-1ones in good yields under conditions of a combination of PdCI2(PPh3)2, dppp and CsOAc in acetonitrile at 55~ under a balloon pressure of CO. An example is depicted below <010L1387>.

F

F

o

TBSO~

F

CO

,,

H

CsOAc MeCN 55~ 75%

HO" "?"

~ = =

O

HO

In a typical application of aryldiazonium salts as illustrated in the following Scheme, diversified dihydrobenzo[b]furans were generated from the same precursor by its treatment with the corresponding reagents such as sodium iodide, copper(II) chloride, copper(II) bromide, or copper(I) cyanide. Importantly, all these compounds have the potential to be used as therapeutic agents for improved psoralen ultraviolet radiation therapy via reducing mutagenicity <01H(55)1081>.

~

Me

Me

Me N2+BF4 -

o" " o ' " t" "o 5 = Me

I

NBS

Nal-I2

92%

95% Me

Me

The first total synthesis of the dihydrobenzofuran (_+)-linderal A, a potent inhibitor in melanin biosynthesis of cultured B-16 melanoma cell, was achieved via a 20-step reaction sequence starting from 4,6-dimethoxysalicylaldehyde <010L 1359>. Rh~(S-DOSP)4-catalyzed asymmetric intramolecular C-H insertion has been used to generate substituted dihydrobenzo[b]furans. In this reaction, Rh2(S-DOSP),-catalyzed decomposition of substituted aryldiazoacetates a t - 5 0 ~ resulted in a very efficient C-H

Five-Membered Ring Systems: Furans and Benzofurans

169

insertion transformation, and both yields and enantioselectivities were over 90% in some specific cases <01OL1475>.

CO2Me ""

Me

Me

Rh2(S-DOSP)4 ......

~O2Me

~

Me

98% (94% ee)

A biomimetic route for the synthesis of dihydrobenzo[b]furan heterocycles was investigated via a reagent-based electrochemical transformation of 2-(2'-hydroxyethyl)quinine precursors. It was believed that a putative oxonium ion was generated by treatment of the quinone with PPTS, followed by reduction with dihydroquinone (DHQ) to generate a radical species which underwent either further reduction by DHQ to give the product or a direct dimerization <01JOC4965>.

O Ho~O

PPTS DHQ

F

o

R

o

R DHQ

R

OH

+

OH

o

A kinetic resolution of (_)-neolignans by lipase catalyzed acetylation in an organic solvent was investigated <01TA785>. A synthesis of eupomatenoid-15 from 2,3-5-tribromobenzofuran involved regioselective Negishi-type cross coupling at C-2 followed by the introduction of substituents at C-3 by lithiation and methylation and at C-5 by nickel catalyzed reaction with propenylmagnesium chloride <01SL1284>. Regioselective electrobromination of benzo[b]furan was achieved successfully by a selective choice of solvents and bromide salts. Thus, upon electrolysis of benzo[b]furan in a NH,Br solution of HOAc/H20 (100/1), substitution occurred at the C-5 position of benzo[b]furan, giving 5bromobenzo[b]furan. After passage of totally 4 F/mol of electricity in a similar medium, 5,7dibromobenzo[b]furan was obtained as the sole product. However, electrolysis of benzo[b]furan in CI-I~CI~O (1/1) and/or HOAc/H20 (10/1) in the presence of either NaBr or NH4Br gave 2,3-dihydro-2,3-dibromobenzo[b]furan <01H(54)825>. Upon thermolysis of the cycloproparene depicted below, a 2,3-disubstituted naphtho[b]furan was generated quantitatively <01T3529>.

o

NMe2 -CONMe2

,-,ea, ~ [C:::oOONMe21 hv ~

NMe2

=

CO,,,Me2

NMe2

Oxidative rearrangement of benzo[b]furan-2-carboximidamide mediated by (dicarboxy)iodobenzene provided N-acyl-N-(2-benzo[b]furyl)urea in 14% yield. <01JCS(P1)680>. A gas-phase cascade reaction was applied to the synthesis of 2,7bis(benzo[b]furan) from the phosphonium ylide illustrated below. A plausible reaction sequence, starting with a Claisen rearrangement, has been proposed <01 SL228>.

FVP 700-850~

170

X.-L. Hou, Z Yang and H.N.C. Wong

A short and convergent method for the synthesis of complex cyclopentatetrahydrobenzo[b]furans by annulation of a benzo[b]furan-3-one has been described <01TL8281>. In an elegant synthesis of the nominal (-)-diazonamide A the key intermediate 2,3,3trisubstituted chiral 2,3-dihydrobenzo[b]furan was constructed from a precursor aldehyde through a sequence of photolytic deprotection, cyclization and acetyl protection steps and a revised structure for (-)-diazonamide A was proposed <0lAG(E)4765, 0lAG(E)4770, 0lAG(E)4705>. In the total synthesis of heliquinomycinone, the polymethoxy-substituted naphthofuran was employed as a key subunit to build up the heliquinomycinone scaffold. <01AG(E)4709, 01AG(E)4713>. A highly enantioselective homochiral ligand for the addition of diethylzinc to aldehydes was synthesized from dibenzofuran. Synthetically, the dibenzofuran was allowed to undergo a regioselective lithiation, and was followed by addition of formaldehyde to afford the primary alcohol as shown below. Subsequent conversion of this alcohol into its corresponding bromide, and reaction with (S)-prolinol in the presence of I~CO 3 yielded the target chiral ligand <01CL 1108>.

1. NBS, Me2S ~ O H 2. (S)-Prolinol, v,,,.,i f....OH HO.....1 K2003 ~O.,,,~

1. BuLi, Et20, TMEDA 2. (CH20)n 81% (two steps)

-

82% (two steps)

(/

HO/""t,ri~ r

\~t--J/ \')

5.3.3.4 Benzo[c]furans and Related Compounds The most exciting results in the field of benzo[c]furans (isobenzofurans) in 2001 were obtained by Warrener, who prepared and characterized stable crystalline benzo[c]furans linked through the 1 and 3 positions and incorporated into alicyclophanes. Their synthesis was achieved by adding arynes to the furan precursor shown, followed by hydrogenation and thermal elimination of ethene. It was found that these compounds are excellent dienes <01CC1550>. Warrener also reported several syn facial oxygen bridged [n]polynorbornanes that belong to a new class of polarofacial frameworks composed of fused dihydrofurans or dihydroisobenzofurans <01T571 >.

R

R

1-Phenylisobenzofuran was employed as a building block in synthetic routes towards the oxa-bridged analogs RPR 225,370 and RPR 222,490 of farnesyltransferase inhibitor RPR 115,135 <01JOC3797>. A short synthesis of (_)-halenzquinone was reported by Rodrigo, in which 4,7-dimethoxyisobenzofuran was a main building block <01JOC3639>. Rodrigo also

171

Five-Membered Ring Systems: Furans and Benzofurans

prepared (_)-xestoquinone, (_)-9-methoxyxestoquinone and (_)-10-methoxyxestoquinone employing a similar strategy <01T309>. _CO2H N

H O

N

MeO RPR 115,135

RPR 225,370 endo RPR 222,490 exo

O Ph

MeO

1,3-Diphenylisobenzofuran was used as a reactive diene to trap a highly strained bicyclic alkyne <01JOC3806>. Phenanthro[2,3-c]furan has been isolated and found to be sufficiently stable for characterization in solution, but is nonetheless more reactive than isobenzofuran <01TL789>. LDA OMe O Enantiomerically pure 1,3-dihydrobenzo[c]furan derivatives were recently obtained from ophthaldehyde and 1,2-O-isopropylidene-a-D-xylofuranose <01TA4995>. An oxonium ion was proposed as an intermediate in the Amberlyst | 15E promoted reaction of the cyclic allylic lactol ether shown in the following scheme. A (2,5)oxonium-ene process was believed to be the subsequent route from which aldehydes were generated <01TL6859>. Amberlyst| 15E

c.o

+

55:45

Acknowledgements: HNCW wishes to thank the Areas of Excellence Scheme established under the University Grants Committee of the Hong Kong Special Administrative Region, China (Project No. AoEfP-10/01) and the Croucher Foundation (Hong Kong) for financial support. XLH acknowledges with thanks supports from the National Natural Science Foundation of China, National Outstanding Youth Fund, the Chinese Academy of Sciences, and Shanghai Committee of Science and Technology.

5.3.4 REFERENCES 01ACR595 01AHC1 0lAG(E)249

M. Harmata, Acc. Chem. Res. 2001, 34, 595. A. P. Sadimenko,Adv. Heterocycl. Chem. 2001, 78, 1. M. Hatano, M. Terada, K. Mikami, Angew. Chem. Int. Ed. 2001, 40, 249.

172 01AG(E)1128 0 lAG(E) 1286 01AG(E)1288 0lAG(E)3062 0lAG(E)3613 0lAG(E)4496 0lAG(E)4684 0lAG(E)4705 0lAG(E)4709 0lAG(E)4713 0lAG(E)4745 0lAG(E)4765 0lAG(E)4770 01CC695 01CC799 01CC1306 01CC1350 01CC1550 01CC1594 01CC1682 01CC2744 01CEJ565 01CEJ945 01CEJI056 0ICE J1720 01CEJ3858 01CEJ3890 3890. 01CEJ4097 01CEJ4723 01CHJC282 01CLII08 01CL1210 01CSR50 01CSR332 01EJO269 01EJO619 01EJO633 01EJO997 01EJO1669 01EJO 1845 01EJO2869 01 EJO2891 01EJO2955 01EJO3461 01EJO4313 01EJO4537 01EJO4543 01H(54)249 01H(54)419

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Five-Membered Ring Systems: Furans and Benzofurans 01JNP1301 01JNP1322 01JNP1365 01JNP1383 01JNP1398 01JNP1434 01JNPI460 01JNP1468 01JNP1471 01JNP1502 01JNP1521 01JNP1527 01JOC134 01JOC175 175. 01JOC200 01JOC564 01JOC1420 01JOC1716 01JOC2011 01JOC2400 01JOC3119 01JOC3639 01JOC3797 01JOC3806 01JOC4069 01JOC4091 01JOC4732 01JOC4965 01JOC5395 01JOC5613 01JOC6014 01JOC6057 01JOC6523 01 JOC6719 01JOC6905 01JOC6982 01JOC7067 01JOC7142 7142. 01JOC7240 01JOC7869 01JOC8037

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176 01JOC8070 01JOC8685 01JOC8992 00OL4095 00OL4249 01OL107 01OL161 01OL401 01OL429 01OL481 01OL667 01 OL671 01OL703 01OL811 01OL861 01OL929 01OL975 01OL1065 0lOLl 157 01OL1225 01OL1295 01OL1315 01OL1343 01OL1359 01OL1363 01OL1387 01OL1475 01OL1479 01OL1629 01OL1633 01OL1677 010L 1949

01OL1953 01OL2489 01OL2537 01OL2669 01 OL2681 01OL2685 01OL2701 01OL2717 01OL2891 01OL3225 01OL3289 01OL3385 01OL3459 01OL3583 01OL3663 01OL3769 01OL3899 01OL3935

X.-L. Hou, Z Yang and H.N.C. Wong G. Rassu, L. Auzzas, L. Pinna, V. Zambrano, L. Battistini, F. Zanardi, L. Marzocchi, D. Acquotti, G. Casiraghi, J. Org. Chem. 2001, 66, 8070. A. V. Gutnov, V. T. Abaev, A. V. Butin, A. S. Dmitriev, J. Org. Chem. 2001, 66, 8685. Y. Guindon, F. Soucy, C. Yoakim, W. W. Ogilvie, L. Plamondon, J. Org. Chem. 2001, 66, 8992. J. M6ndez-Andino, L. A. Paquette, Org. Lett. 2000, 2, 4095. C. Funke, M. Es-Sayed, A. de Meijere, Org. Lett. 2000, 2, 4249. O. Arjona, R. Menchaca, J. Plumet, Org. Lett. 2001, 3, 107. S. R. Gilbertson, Z. Fu, Org. Lett. 2001, 3, 161. M. H. Haukaas, G. A. O'Doherty, Org. Lett. 2001, 3, 401. N. Maezaki, N. Kojima, A. Sakamoto, C. Iwata, T. Tanaka, Org. Lett. 2001, 3, 429. K. W. Hunt, P. A. Grieco, Org. Len. 2001, 3, 481. J. J. Kulagowski, N. R. Curtis, C. J. Swain, B. J. Williams, Org. Lett. 2001, 3, 667. D. J. Wallace, J. M. Goodman, D. J. Kennedy, A. J. Davies, C. J. Cowden, M. S. Ashwood, I. F. Cottrell, U.-H. Dolling, P. J. Reider, Org. Lett. 2001, 3, 671. S. Liras, J. E. Davoren, J. Bordner, Org. Len. 2001, 3, 703. H.-T. Shih, H.-H. Shih, C.-H. Cheng, Org. Lett. 2001, 3, 811. T. J. Donohoe, A. Raoof, I. D. Linney, M. Helliwell, Org. Lett. 2001, 3, 861. A. Vakalopoulos, T. F. J. Lampe, H. M. R. Hoffmann, Org. Lett. 2001, 3, 929. A. B. Dounay, C. J. Forsyth, Org. Lett. 2001, 3, 975. S. U. Son, Y. A. Yoon, D. S. Choi, J. K. Park, B. M. Kim, Y. K. Chung, Org. Lett. 2001, 3, 1065. Y. Kita, H. Nambu, N. G. Ramesh, G. Anilkumar, M. Matsugi, Org. Lett. 2001, 3, 1157. F. Cohen, D. W. C. MacMillan, L. E. Overman, A. Romero, Org. Lett. 2001, 3, 1225. C.-C. Pai, R.-S. Liu, Org. Lett. 2001, 3, 1295. C. BOhm, O. Reiser, Org. Lett. 2001, 3, 1315. J. Enjo, L. Castedo, G. Tojo, Org. Lett. 2001, 1343. M. Yamashita, N. Ohta, I. Kawasaki, S. Ohta, Org. Lett. 2001, 3, 1359. T. Kubota, M. Tsuda, J. Kobayashi, Org. Lett. 2001, 3, 1363. Y.-H. Hu, Z. Yang, Org. Lett. 2001, 3, 1387. H. M. L. Davies, M. V. A. Grazini, E. Aouad, Org. Len. 2001, 3, 1475. R. Sakai, T. Koike, M. Sasaki, K. Shimamoto, C. Oiwa, A. Yano, K. Suzuki, K. Tachibana, H. Kamiya, Org. Lett. 2001, 3, 1479. M. Herrlich, N. Hampel, H. Mayr, Org. Lett. 2001, 3, 1629. M. Herrlich, H. Mayr, Org. Lett. 2001, 3, 1633. M. S. McClure, B. Glover, E. McSorley, A. Millar, M. H. Osterhout, F. Roschangar, Org. Lett. 2001, 3, 1677. G. C. Micalizio, W. R. Roush, Org. Lett. 2001, 3, 1949. S. D. Burke, L. Jiang, Org. Lett. 2001, 3, 1953. R. S. Narayan, M. Sivakumar, E. Bouhlel, B. Borhan, Org. Lett. 2001, 3, 2489. A. Hoffmann-Rtider, N. Krause, Org. Lett. 2001, 3, 2537. T.-P. Loh, Q.-Y. Hu, K.-T. Tan, H.-S. Cheng, Org. Lett. 2001, 3, 2669. J. R. McElhanon, D. R. Wheeler, Org. Lett. 2001, 3, 2681. S.-Q. Duan, K. D. Moeller, Org. Lett. 2001, 3, 2685. T. Katoh, M. Nakatani, S. Shikita, R. Sampe, A. Ishiwata, O. Ohmori, M. Nakamura, S. Terashima, Org. Lett. 2001, 3, 2701. V. K. Yadav, R. Balamurugan, Org. Lett. 2001, 3, 2717. S. Y. Cho, H. I. Lee, J. K. Cha, Org. Lett. 2001, 3,2891. T. J. Seiders, D. W. Ward, R. H. Grubbs, Org. Lett. 2001, 3, 3225. D. Dfaz, T. Martfn, V. S. Martfn, Org. Lett. 2001, 3, 3289. C. Mukai, H. Yamashita, M. Hanaoka, Org. Lett. 2001, 3, 3385. C. Ericsson, L. Engman, Org. Lett. 2001, 3, 3459. S. Knapp, M. R. Madduru, Z.-J. Lu, G. J. Morriello, T. J. Emge, G. A. Doss, Org. Lett. 2001, 3, 3583. M. Harmata, P. R. Schreiner, Org. Lett. 2001, 3, 3663. A. S. K. Hashmi, T. M. Frost, J. W. Bats, Org. Lett. 2001, 3, 3769. M. H. Haukaas, G. A. O'Doherty, Org. Lett. 2001, 3, 3899. L. J. Vald6s III, H.-M. Chang, D. C. Visger, M. Koreeda, Org. Lett. 2001, 3, 3935.

Five-Membered Ring Systems: Furans and Benzofurans 01OL4161 01P(56)611 01P(56)759 01P(56)769 01P(57)537 01P(57)579 01P(58)475 01S735 01S1004 01S1065 01S1487 01S1539 01S1681 01S2003 01S2500 01SL153 01SL228 01SL397 01SL646 01SL703 01SL753 01SLl123 01SLl125 01SL1249 01SL1284 01SL1479 01SL1614 01Tl19 01T297 01T309 01T371 01T571 01T791 01T2057 01T2711 01T2791 01T2981 01T3165 01T3221 01T3383 01T3529 01T4719 01T4849 01T5137 01T5161 01T5173 01T5227

177

A. Ajamian, J. L. Gieason, Org. Lett. 2001, 3, 4161. K. Franke, A. Porzel, M. Masaoud, G. Adam, J. Schmidt, Phytochemistry 2001, 56, 611. A. M. L. Seca, A. M. S. Silva, A. J. d. Silvestre, J. A. S. Cavaleiro, F. M. J. Domingues, C. Pascoal-Neto, Phytochemistry 2001, 56, 759. H. Tanaka, H. Etoh, N. Watanabe, H. Shimizu, M. Ahmad, g. H. Rizwani, Phytochemistry 2001, 56, 769. P. P. Mebe, Phytochemistry 2001, 57, 537. D. E. Pegnyemb, R. G. Tih, B. L. Sondengam, A. Blond, B. Bodo, Phytochemistry 2001, 57, 579. K. Y. Orabi, S. I. AI-Qasoumi, M. M. EI-Olemy, J. S. Mossa, I. Muhammad, Phytochernistry 2001, 58, 475. S. Tollari, G. Palmisano, S. Cenini, G. Cravotto, G. B. Giovenzana, A. Penoni,Synthesis 2001, 735. Y.-M. Ma, Y.-M. Zhang, J. Chen, Synthesis 2001, 1004. J. S. Yadav, B. V. S. Reddy, C. R. Madhuri, G. Sabitha, Synthesis 2001, 1065. N. Yoshida, T. Ohwada, Synthesis 2001, 1487. V. K. Brel, Synthesis 2001, 1539. M. S. McClure, F. Roschangar, S. J. Hodson, A. Millar, M. H. Osterhout, Synthesis 2001, 1681. R. Ballini, G. Bosica, D. Fiorini, G. Giarlo, Synthesis 2001, 2003. A. Gans~iuer, M. Pierobon, H. Bluhm, Synthesis 2001, 2500. P. Basabe, A. Estrella, I. S. Marcos, D. Dfez, A. M. Lithgow, A. J. P. White, D. J. Williams, J. G. Urones, Synlett 2001, 153. R. A. Aitken, A. N. Garnett, Svnlett 2001, 228. L. Ackermann, C. Bruneau, P. H. Dixneuf, Synlett 2001, 397. T. Johnson, D. R. Cheshire, M. J. Stocks, V. T. Thurston, Synlett 2001, 646. R. Ruzziconi, H. Couthon-Gourv6s, J.-P. Gourv6s, B. Corbel, Synlett 2001, 703. A. de la Hoz, A. Dfaz-Ortiz, J. M. Fraile, M. V. G6mez, J. A. Mayoral, A. Moreno, A. Saiz, E. V~izquez, Synlett 2001, 753. N. Toyooka, M. Nagaoka, H. Kakuda, H. Nemoto, Synlett 2001, 1123. A. Boumendjel, J.-M. Nuzillard, G. Massiot, Synlett 2001, 1125. K. K. Rana, C. Guin, S. C. Roy, Synlett 2001, 1249. T. Rach, M. Bartels, Synlett 2001, 1284. A. Lattanzi, G. D. Sala, M. Russo, A. Scettri, Synlen 2001, 1479. K. Takai, R. Morita, S. Sakamoto, Synlett 2001, 1614. S. A. M. Abdelgaleil, H. Okamura, T. Iwagawa, A. Sato, I. Miyahara, M. Doe, M. Nakatani, Tetrahedron 2001, 57, 119. S.-Y. Gao, S. Ko, Y.-L. Lin, R. K. Peddinti, C.-C. Liao, Tetrahedron 2001, 57, 297. H. S. Sutherland, K. C. Higgs, N. J. Taylor, R. Rodrigo, Tetrahedron 2001, 57, 309. M. Orlandi, B. Rindone, G. Molteni, P. Rummakko, G. Brunow, Tetrahedron 2001, 57, 371. R. N. Warrener, D. Margetic, P. J. Foley, D. N. Butler, A. Winling, K. A. Beales, R. A. Russell, Tetrahedron 2001, 57, 571. D. C. Harrowven, M. C. Lucas, P. D. Howes, Tetrahedron 2001, 57, 791. R. S. Ward, D. D. Hughes, Tetrahedron 2001, 57, 2057. K.-X. Yan, K. Terashima, Y. Takaya, M. Niwa, Tetrahedron 2001, 57, 2711. F. Castronovo, M. Clericuzio, L. Toma, G. Vidari, Tetrahedron 2001, 57, 2791. A. Ortega, P. E. Garcfa, J. C~denas, C. Mancera, S. Marquina, L. del C. Gardufio, E. Maldonado, Tetrahedron 2001, 57, 2981. R. Murali, H. S. P. Rao, H. W. Scheeren, Tetrahedron 2001, 57, 3165. S. K. Bur, S. F. Martin, Tetrahedron 2001, 57, 3221. Y.-L. Wang, S.-Z. Zhu, Tetrahedron 2001, 57, 3383. B. Halton, C. S. Jones, D. Margetic, Tetrahedron 2001, 57, 3529. G. Bar, A. F. Parsons, C. B. Thomas, Tetrahedron 2001, 57, 4719. H.-F. Luo, L.-P. Zhang, C.-Q Hu, Tetrahedron 2001, 57, 4849. J.-C. Galland, S. Dias, M. Savignac, J.-P. Gen6t, Tetrahedron 2001,57, 5137. J. M. Harris, G. A. O'Doherty, Tetrahedron 2001, 57, 5161. J. Cossy, V. Bellosta, J.-L. Ranaivosata, B. Gille, Tetrahedron 2001, 57, 5173. S. R. Angle, S. Z. Shaw, Tetrahedron 2001, 57, 5227.

178 01T5255 01T5657 0IT6003 01T7113 01T7303 01T7337 01T7705 01T8531 01T9335 01T9597 01T9925 01T10203 01T10281 01TA41 01TA785 01 TA2309 01TA4935 00TA4995 01TL61 01TL149 01TL251 01TL473 01TL789 01TL935 01TL971 01TL975 01TL1147 01TL1657 01TL1819 01TL2023 01TL2043 01TL2333 01TL2643 01TL2801 01TL2817 01TL3137 01TL3171 01TL3351 01TL3503 01TL3645 01TL3839 01TL4203 01TL4577 01 TL4969 01TL4913 01 TL5245 01TL5501 01TL5841 01TL5945 01TL6019 01TL6049

X.-L. Hou, Z. Yang and H.N.C. Wong

L. J. D'Souza, S. C. Sinha, S.-F. Lu, E. Keinan, S. C. Sinha, Tetrahedron 2001, 57, 5255. M. G. Bolster, B. J. M. Jansen, A. de Groot, Tetrahedron 2001, 57, 5657. S. Onitsuka, H. Nishino, K. Kurosawa Tetrahedron 2001, 57, 6003. T. G. van Aardt, H. van Rensburg, D. Ferreira, Tetrahedron 2001, 57, 7113. P. C. Shieh, C. W. Ong, Tetrahedron 2001, 57, 7303. Y. Wang, S. Zhu, G. Zhu, Q. Huang, Tetrahedron 2001, 57, 7337. V. Nair, P. M. Treesa, D. Maliakal, N. P. Rath, Tetrahedron 2001, 57, 7705. S. M. Ceccarelli, U. Piarulli, C. Gennari, Tetrahedron 2001, 57, 8531. H.-X. Shi, H.-Z. Liu, R. Bloch, G. Mandville, Tetrahedron 2001, 57, 9335. E. Redero, C. Sandoval, F. Bermejo, Tetrahedron 2001, 57, 9597. W. H. Miles, E. J. Fialcowitz, E. S. Halstead, Tetrahedron 2001, 57, 9925. G. Desimoni, G. Faita, S. Filippone, M. Mella, M. Grazia, M. Zema, Tetrahedron 2001, 57, 10203. B. S. Siddiqui, F. Afshan, S. Faizi, Tetrahedron 2001, 57, 10281. S. F. Mayer, A. Steinreiber, R. V. A. Orru, K. Faber, Tetrahedron: Asymmetry 2001, 12, 41. S. M. O. van Dyck, G. L. F. Lemi6re, T. H. M. Jonckers, R. Dommisse, L. Pieters, V. Buss, Tetrahedron: Asymmetry 2001, 12, 785. A. S. Demir, O. Sesenoglu, Z. Gerqek-Arkin, Tetrahedron." Asymmetry 2001, 12, 2309. A. G. Cs~k~, P. Vogel, Tetrahedron: Asymmetry 2001, 11, 4935. D. F. Ewing, C. Len, G. Mackenzie, G. Ronco, P. Villa, Tetrahedron: Asymmetry 2000, 11, 4995. Y. Takaya, H. Kikuchi, Y. Terui, J. Komiya, Y. Maeda, A. Ito, Y. Oshima, Tetrahedron Lett. 2001, 42, 61. M. Harmata, G. Bohnert, C. L. Barnes, Tetrahedron Lett. 2001, 42, 149. J. Cossy, L. Tresnard, D. Belotti, D. G. Pardo, Tetrahedron Lett. 2001, 42, 251. R. C. D. Brown, C, J. R. Bataille, J. D. Hinks, Tetrahedron Lett. 2001, 42,473. M. E. Thibault, L. A. Pacarynuk, T. L. L. Closson, P. W. Dibble, Tetrahedron Lett. 2001, 42, 789. B.-C. Hong, I-C. Shen, J.-H. Liao, Tetrahedron Lett. 2001, 42, 935. T. J. Donohoe, J. J. G. Winter, M. Helliwell, G. Stemp, Tetrahedron Lett. 2001, 42, 971. H. Oh, D. C. Swenson, J. B. Gloer, C. A. Shearer, Tetrahedron Lett. 2001, 42, 975. D. Basavaiah, B. Sreenivasulu, J. S. Rao, Tetrahedron Lett. 2001, 42, 1147. K. Burger, A. Fuchs, L. Hennig, B. Helmreich, Tetrahedron Lett. 2001, 42, 1657. S. R. Angle, K. Chann, Tetrahedron Lett. 2001, 42, 1819. C. Malanga, S. Mannucci, Tetrahedron Lett. 2001, 42, 2023. V. Nair, S. Bindu, L. Balagopal, Tetrahedron Lett. 2001, 42, 2043. G.-H. Wang, J.-H. Sheu, M. Y. Chiang, T.-J. Lee, Tetrahedron Lett. 2001, 42, 2333. H. Khatuya, Tetrahedron Lett 2001, 42, 2643. X. Franck, M. E. V. Araujo, J.-C. Jullian, R. Hocquemiller, B. Figad~re, Tetrahedron Lett. 2001, 42, 2801. Y. Kobayashi, H. P. Acharya, Tetrahedron Lett. 2001, 42, 2817. J. M. Barks, B. C. Gilbert, A. F. Parsons, B. Upeandran, Tetrahedron Lett. 2001, 42, 3137. J. Blanchet, M. Bonin, L. Micouin, H.-P. Husson, Tetrahedron Lett. 2001, 42, 3171. S. Kajikawa, H. Nishino, K. Kurosawa, Tetrahedron Lett. 2001, 42, 3351. F. Risitano, G. Grassi, F. Foti, C. Bilardo, Tetrahedron Lett. 2001, 42, 3503. I. Kadota, N. Oguro, Y. Yamamoto, Tetrahedron Lett. 2001, 42, 3645. J. M. Aurrecoechea, E. P6rez, Tetrahedron Lett. 2001, 42, 3839. K. Kato, A. Nishimura, Y. Yamamoto, H. Akita, Tetrahedron Lett. 2001, 42, 4203. A. Massa, L. Palombi, A. Scettri, Tetrahedron Lett. 2001, 42, 4577. O. Germay, N. Kumar, E. J. Thomas, Tetrahedron Lett. 2001, 42, 4969. A. Srikrishna, N. C. Bahu, Tetrahedron Lett. 2001, 42, 4913. A. RiJckert, D. Eisele, S. Blechert, Tetrahedron Lett. 2001, 42, 5245. X. Teng, T. Wada, S. Okamoto, F. Sata, Tetrahedron Lett. 2001, 42, 5501. T. J. Donohoe, J.-B. Guillermin, A. A. Calabrese, D. S. Walter, Tetrahedron Lett. 2001, 42, 5841. G. M. M. EI-Taeb, A. B. Evans, S. Jones, D. W. Knight, Tetrahedron Lett. 2001, 42, 5945. K. Lee, J. K. Cha, Tetrahedron Lett. 2001, 42, 6019. G. W. Kakalka, L. Wang, R. M. Pagni, Tetrahedron Lett. 2001, 42, 6049.

Five-Membered Ring Systems: Furans and Benzofurans

01TL6381 01TL6429 01TL6499 01TL6577 01TL6859 01TL6995 01TL7163 01TL7265 01TL7379 01TL7401 01TL7741 01TL7801 01TL7935 01TL8281 01TL8429 01 TL8927 01TL9089

179

J. S. Yadav, B. V. S. Reddy, C. Madhuri, G. Sabitha, B. Jagannadh, S. K. Kumar, A. C. Kunwar, Tetrahedron Lett. 2001, 42, 6381. B. Tse, A. B. Jones, Tetrahedron Lett. 2001, 42, 6429. C. Morice, M. Domostoj, K. Briner, A. Mann, J. Suffert, C.-G. Wermuth, Tetrahedron Lett. 2001, 42, 6499. G. Gopalakrishnan, N. D. P. Singh, V. Kasinath, M. S. R. Krishnan, R. Malathi, S. S. Rajan, Tetrahedron Lett. 2001, 42, 6577. H. Ohmura, K. Mikami, Tetrahedron Lett. 2001, 42, 6859. M. da Concei~:ao, F. de Oliveira, L. S. Santos, R. A. Pilli, Tetrahedron Lett. 2001, 42, 6995. B. Liu, K. D. Moeller, Tetrahedron Lett. 2001, 42, 7163. Y. Lakhrissi, C. Taillefumier, F. Chr6tien, Y. Chapleur, Tetrahedron Lett. 2001, 42, 7265. W. W. Harding, D. S. Simpson, H. Jacobs, S. McLean, W. F. Reynolds, Tetrahedron Lett. 2001, 42, 7379. M. Saeed, T. Ilg, M. Schick, M. Abbas, W. Voelter, Tetrahedron Letr 2001, 42, 7401. B. Travis, B. Borhan, Tetrahedron Lett. 2001, 42,7741. Y. Wang, H. Bernsmann, M. Gruner, P. Metz, Tetrahedron Lett. 2001, 42, 7801. R. A. Batey, D. A. Powell, A. Acton, A. J. Lough, Tetrahedron Lett. 2001, 42, 7935. M. R. Dobler, I. Bruce, F. Cederbaum, N. G. Cooke, L. J. Diorazio, R. G. Hall, E. Irving, Tetrahedron Lett. 2001, 42,8281. M. D. Collini, C. P. Miller, Tetrahedron Lett. 2001, 42, 8429. G. Zeni, D. S. L0dtke, C. W. Nogueira, R. B. Panatieri, A. L. Braga, C. C. Silverira, H. A. Stefani, J. B. T. Rocha, Tetrahedron Lett. 2001, 42, 8927. J. S. Yadav, B. V. S. Reddy, S. K. Pandey, R. Srihari, I. Prathap, Tetrahedron Lett. 2001, 42, 9089.

180

Chapter 5.4 Five Membered Ring Systems: With More than One N Atom

Larry Yet Albany Molecular Research, Inc., Albany, NY USA larryy @albmolecular, com

5.4.1

INTRODUCTION

Advancements in the chemistry of pyrazoles, imidazoles, triazoles, tetrazoles, and related fused heterocyclic derivatives continued in 2001. Solid-phase combinatorial chemistry of pyrazoles and benzimidazoles has been particularly active. Synthetic routes to all areas continue to be pursued vigorously with improvements and applications. Applications of imidazole- and 1,2,3-benzotriazole-containing reagents to a wide array of synthetic operations remained a constant theme.

5.4.2

PYRAZOLES AND RING-FUSED DERIVATIVES

Flash vacuum pyrolysis reactions of 1H-pyrazole, 3,5-dimethylpyrazole, and 3,5diphenylpyrazole were carried out over ZCOY-7, NH4-Y, and Na-Y zeolites <01JOC2943>. A complete model for the prediction of 1H and ~3C-NMR chemical shifts and torsional angles in phenyl-substituted pyrazoles has been published <01T4179>. Diphenylpyrazole was treated with triethylaluminum to afford a pyrazolate-bridged dialuminum complex <01CC353>. Spectroscopic studies have revealed 3-(2-pyridyl)-2-pyrazoline derivatives to be novel fluorescent probes for Zn(II) ions <01TL9199>. The synthesis of the pyrazole core structure in 2001 has been approached from many angles. The classical method involves the reaction of 1,3-difunctional species with hydrazine derivatives. [3-Chlorovinylaldehydes 1 and 3 were converted to pyrazolo[3,4-b]quinolines 2 and pyrazolo[3,4-c]pyrazoles 4, respectively, in the presence of hydrazine hydrate and ptoluenesulfonic acid under microwave irradiation <01TL3827>. ~-Methoxyvinyl trifluoromethyl ketones 5 underwent regiospecific cyclization with aminoguanidine to give trifluoromethyl alcohols 6, which were dehydrated to give trifluoromethylated 2-[1H-pyrazol1-yl]pyrimidines 7 <01S1505>. Microwave assisted condensation of aromatic acyl compounds with N,N-dimethylformamide diethyl acetal yielded 1-aryl-3-dimethylarninoprop-2-enones, which in the presence of hydrazine afforded the corresponding 3-arylpyrazoles <01S55>. Photochemical reactions of perfluoroalkyl iodide 8 and ct-chlorostyrenes 9 in the presence of hydrazine-acetic acid complex afforded 5-aryl-3-perfluoroalkylpyrazoles 10 <01TL33>.

181

Five-Membered Ring Systems." With More than One N Atom

Reactions of r with hydrazines afforded various substituted-pyrazoles <01JHC109>. Treatment of c~-benzotriazolyl-cx,13-unsaturated ketones with monosubstituted hydrazines followed by alkylation at the 4-position of the pyrazoline ring afforded unsymmetrical 1,3,5-triaryl-4-alkylpyrazolines and -pyrazoles <01JOC6787>. Cyclocondensations of diacetylenic ketones with hydrazines afforded alkynyl substituted pyrazoles <01JCS(PI)2906>. Me v

"N

-~Microwave

"CI

~1

1

CHO

RNHNH2

CI

Microwave

i~h

2

Me

3

4

R O R F3C " J[ ' ~ ' ~ OM e

NH2NHC(NH)NH 2 EtOIq, reflux =

R

F3C

H2SO4 CH2CI2-'-

N.~... N

F3C N~ N

I

5

R

Ph

R . / [ ' - ~ . ~ C F3

R-~~CF3

6

7

(CF2)n-ICF3 CF3(CF2)nl

A'N~._-CI/---

+

1. (gu3Sn)2, hv, 0 2, Phil 2. NH2NH2"HOAc, EtOH

-~

H lO

Acid- and base-promoted methods have been popular for the syntheses of pyrazoles. r Aminohydrazones 11 underwent base-promoted heterocyclization reactions at room temperature to produce 1-aminocarbonyl-lH-pyrazol-5(2/4~-ones 12, which under thermal solvolytic cleavage to afford 1H-pyrazol-5(2l/)-ones 13 <01T2031>. (3E)-4-Phenyl-3-buten2-one hydrazones (14) were treated with excess lithium diisopropylamide and condensed with several aromatic esters followed by acid-cyclization to afford 3-(2-phenylethenyl)-lHpyrazoles 15 <01SC539>. Base-mediated synthesis of 1,4-dihydrobenzopyranopyrazoles 19 was achieved with bromovinyl hydrazones 16 via [2+3] intramolecular cycloaddition of diazo intermediate 17 <01TL6599>. Dilithiated C(ot),N-phenylhydrazones were condensed with either ethyl oxanilate, ethyl 4'-chloroxanilate or ethyl oxamate, followed by acid-catalyzed cyclizations to afford 1H-pyrazole-5-carboxamides <01JHC691>. Polylithiated 2'phenylacetohydrazides were condensed with aromatic esters followed by acid-catalyzed cyclizations to yield 1,2-dihydro-3H-pyrazol-3-ones <01JHC695>.

O

Me

R O

R3 R4 k_--lq

H

N"N , NHR2 R-N'R4~3

O

O

H

THF

O

12

Me H

heat

O~..NHR 2 11

R3 R4 ~1~

Me

H

13

182

L. Yet 1. LDA (xs)

Me

ph..~.~-

R2

2. R2CO2Me . 3. H30(~, heat

N -NHR 14

~~~~N~N..R Ph 15

Br

Br NNHTs

"

Nail

~Br N ~-; "N '~

=

16

=_

[./.

17

R

o,

' ~ H H 18

R

19

Palladium-catalyzed cyclization reactions with aryl bromides have been used to synthesize pyrazole derivatives. N-Aryl-N'-(o-bromobenzyl)hydrazines 20 or [N-Aryl-N'-(obromobenzyl)hydrazinato-N']-triphenylphosphonium bromides 21 participated in palladiumcatalyzed intramolecular amination reactions to give 1-aryl-lH-indazoles 22 <01TL2937>. Thermal extrusion of sulfur dioxide or carbon dioxide from their respective heterocyclic precursors 23 or 24 generated 1,2-diaza-l,3-butadienes 25, which underwent palladium(0)catalyzed carbonylation to yield 2,3-pyrazol-l(5H)-ones 26 <01OL3651> or [4 + 2] DielsAlder reactions with N-phenyldiazamaleimide to afford cycloadducts 27 <01OL3647>. C~ R.~/~.%..~~ ~,, NH I~h

NaOt-Bu, PhMe 90 ~

20

R

NaOt-Bu, dioxane 90 ~

"Ph

22

R

Ar

NH Ph

21

Ar i

N ---N,, R1 ~

-~

0 23

R2

100 ~ PhMe

RL.~N.N.Ar R 2 / \ y . . .~~ . x

(5)

~_

Ar l N~N R"~

24

R

R1

~

O N ..j'~ I~

2 ~

.

~

N-Ph

R2 26

Ar ,

0

A2 0 27

Efficient syntheses of 4-fluoro-5-(perfluoroalkyl)pyrazoles were conducted using organofluorosilicon building blocks <01EJO187>. Selenium-induced cyclizations of homoallylhydrazines afforded pyrazolidine, 1-pyrazoline, and 2-pyrazoline derivatives <01T10259>. Synthesis of indazole-N-oxides via the 1,7-electrocyclization of azomethine ylides has been reported <01TL5081 >. Aqueous potassium dichloroiodate has been found to be a general iodinating agent for pyrazole (28) to 3-iodopyrazole (29) <01TL2089>. Grignard addition to 4-(N-pyrazolyl)-4oxoalkanoic esters 30 afforded various 7-keto esters 31 <01H(54)309>. The acylimine mediated N-N bond cleavage of pyrazolidinediones and its subsequent conversion to

183

Five-Membered Ring Systems: With More than One N Atom

dihydropyrimidinediones and malonamides has been reported <01TLI>. Tris(pyrazolyl)methane ligands (Tpm) were equilibrated with various substituted pyrazoles to form new 'mixed' tris(pyrazolyl)methanes <01TL5>. 1-Hydroxypyrazole (32)was selectively N-alkylated to provide the corresponding 2-alkyl-pyrazole-l-oxides 33, which were subsequently deoxygenated and halogenated into 1-alkyl-5-halopyrazoles 34 <01S1053>. Hydroxybenzyl pyrazoles 35 and 37 were converted to 4-substituted pyrazolo[4,3-c]quinolines 36 and 9-substituted pyrazolo[3,4-c]quinolines 38, respectively, via novel anionic annelation procedures <01JOC4214>. Several pyrazoloquinolines and pyrazoloisoquinolines were halogenated, and the utility of these prepared halides was demonstrated by a series of palladium-catalyzed cross-coupling reactions <01JCS(P1)861>. N,N-Bis(pyrazole-l-ylmethyl) alkylamines were prepared in one step by condensation of two equivalents of 1(hydroxymethyl)-3,5-disubstituted pyrazoles with primary amines under microwave irradiation <01SC1315>. A homodimer of 1-hydroxypyrazole has been synthesized as a new potential ligand for asymmetric synthesis <01JCS(P1)1566>. 3-Arylated 1-hydroxypyrazoles were synthesized from 3-metalated pyrazole-l-oxides <01JOC8654>. Silicon or tin 4-metalated pyrazoles were prepared from silyl- or stannylcupration from 4-halopyrazoles <01S1949>. 1Methyl-, 4-nitro-, 4-amino- and 4-iodopyrazole-3-ones were prepared from pyrazole-3-ones <01JHC1065>. Me

~N "NH

I KlCl2'H20 ~ ~~N ,NH

28

M e a n "N

R~~OR2 o

O

29

32

-

33

%N.N.OBn 36

R3

- ~ r . ~i~1 ~

O

6 R q2

31

-

POX3'CHCI3= ~ N ,N X h 34

1. n-BuLi, -78 ~ 2. RCN,-78 ~

O

30

~NN-OH RBr'CHCl3=~ ~ N QN - Q O 80-100~ ' h

35

R3MgX -

%N.N.OBn 37

2. LDA, -78 oc 3. DDQ

__

R

,%N.N_OBn 38

The regioselective synthesis, mechanism, and structural analysis of 4,7,8,9-tetrahydro-2ttpyrazolol[3,4-b]quinolin-5(6H)-ones were investigated <01T6947>. 5-Alkyl-4-amino-2(trifluoromethyl)pyridines were transformed to trifluoromcthylated 1H-pyrazolo[4,3c]pyridines <01T2051>. Tris(pyrazolyl)- 1.3,5-triazincs werc prcparcd by cyclotrimerization of pyrazolyl nitriles in solvent-free conditions <01T4397>. An expeditious solvent-free synthesis of pyrazolino/iminopyrimidino/thioxopyrimidino imidazoline derivatives from readily accessible oxazolones on solid support using microwave irradiation has been described <01S1509>. Claisen condensation of 4-acctyl-5-hydroxypyrazoles with various esters followed by acid-catalyzed ring closures afforded 1H-pyrano[2,3-c]pyrazol-4-ones <01JHC193>. Reactions of 5-aminopyrazoles with paraformaldehyde in formic or

184

L. Yet

trifluoroacetic acids gave pyrazolo[3,4-c]isoquinolines conveniently in an one-pot synthesis <01JHC523>. Quinoxaline-2-aldoximes and-ketoximes reacted with hydrazines under acidic conditions to afford 1H-pyrazolo[3,4-b]quinoxalines <01JHC829>. Enantiopure pyrrolo[3,4c]pyrazole derivatives were synthesized from intramolecular cycloaddition of homochiral nitrilimines <01SC3799>. Several new pyrazolo[1,5-a]pyrimidines were prepared from condensation of 3-amino-l,5-dihydro-l-fp-tosyl)pyrazole with bifunctional reagents <01SC3547>. Polymer-bound 1,2-diaza-l,3-butadienes have been employed in the solid-phase syntheses of 4-triphenylphosphoranylidene-4,5-dihydropyrazol-5-ones and 4-methoxy-lH-pyrazol-5(2H)-ones <01T5855>. Solid-phase synthesis of substituted pyrazolones 40 from polymerbound 13-keto esters 39 have been published <01EJO1631>. Solid phase cycloaddition of nitrile imines to resin-bound enamines afforded 1,4-diarylpyrazoles after acidic cleavage <01JCS(P1)2817>. O

R1

O 2. TFA, CH3CN

39 5.4.3

R2

O

40

I M I D A Z O L E S AND RING-FUSED D E R I V A T I V E S

The EPR and density functional studies of light-induced radical pairs in a single crystal of a hexaarylbiimidazolyl derivative were investigated <0lAG(E)580>. A theoretical study of the intermolecular hydrogen transfers in 2,3-dihydroimidazol-2-ylidene and 2,3-dihydrothiazol-2ylidene has been published <01TL3897>. Substituted imidazoles and 1.~;-dialkylimidazolium salts were fully deuteriated on the heterocyclic ring using deuterium oxide over heterogeneous palladium catalysts <01CC367>. IH NMR spectra of a series of 1,2- and 1,3diarylimidazolidines were analyzed and correlated with their conformational features <01JHC849>. A multinuclear NMR study of the restricted rotation in a bis(imidazole) nucleoside was performed <01JCS(P1)1216>. Several new chiral imidazolylidine ligands were synthesized and were found to be useful in giving high enantioselectivities in asymmetric hydrogenation of aryl alkenes <01JACS8878>. Reaction of [60]fullerene with 2-diazo-4,5dicyanoimidazole afforded a new compound which contains an electron poor aromatic heterocycle attached to the fullerene sphere <01TL6823>. General procedures for the synthesis of the imidazole core have been published in 2001. Treatment of haloanilines 41 in the presence of bis(trimethylsilyl)amide with carbonylimidazole 42 afforded amides 43, which reacted with potassium carbonate in N,Ndimethylacetamide to yield imidazo[1,5-a]quinoxalin-4(5H)-ones 44 <01TL4297>. An alternative method for preparing imidazo[ 1,5-a]quinoxalin-4(5H)-ones from quinoxalin-2-ones with tosylmethyl isocyanide has also been reported <01TL4293>. 13-Ketoamides 45 underwent regiospecific cyclization in the presence of ammonium acetate under microwave irradiation to yield 2,4-disubstituted imidazoles 46 <01SL218>. 2,5-Dihydro-2,5-dimethoxy furylamine 47 was converted to trichloroacetamidine 48, followed by intramolecular cyclization with trifluoroacetic acid at ethanolic reflux to afford ethyl 3-(2-ethoxycarbonyl-lH-imidazol-4yl)propenoate 49 <01SL135>. A two-step solution-phase synthesis of benzimidazoles was performed using a UDC (Ugi/de-Boc/cyclize) strategy <01TL4959>. Carbodiimides 50 reacted with primary amines to yield 2-alkylamino-4tt-imidazolin-4-ones 51 <01SC1053>. Syntheses of substituted imidazoles and dimerization products using cells and lactase from Trametes versicolor has been reported <01T7693>. Substituted

185

Five-Membered Ring Systems." With More than One N Atom

aminocarbonyldiazenecarboxylates 52 reacted with 1,3-diketones or 13-ketoesters under mild conditions in the presence of zirconium(IV) chloride to give highly functionalized imidazolin2-ones 53 <01SL1237>. Chalcones 54 participated in a rhodium-catalyzed electrophilic diamination reaction with N,N-dichloro-p-toluenesulfonamide in the presence of acetonitrile to afford imidazolines 55 <0lAG(E)4277>. 1H-lmidazole derivatives 57 were synthesized in a one-pot procedure by cyclocondensation of ketones 56 with [hydroxy(tosyloxy)iodo]benzene and amidines <01S2075>. Reductive cyclization of 4-alkyl-2-nitroacetanilides with baker's yeast afforded 6-alkylbenzimidazolcs and 1-hydroxy-2-methyl-6-alkylbenzimidazoles <01JCS(P1)2754>. Aryl-(Z)-N-[2-amino-l,2-dicyanovinyI]formamidine cyclizes in the presence of base to give 1,5-diamino-4-cyanoimidazole or 1,5-diamino-4(cyanoformimidoyl)imidazole, depending on the rcaction conditions or the nature of the base used <01SC3225>. The syntheses of a number of 1-substituted-5-aminoimidazole-4carbaldehydes from reduction of the corresponding 5-amino-4-cyanoimidazolc derivatives has been reported <01S2393>.

0

X

R--~

11

0

NH2

42

R--~

NaHMDS,THF

X

HN'~'N .~/

K2C03'DMA

N~O

R ~

N H

41 X = F, CI

N H

43

•••'•/N•1/R2

NH4OAc, DMF Microwave

O

Iql

44

45

~/L" R2 N~ 11

R

H 46 --/

~OMe MeO....\ O / ~ _ N H 2

Cl3CCN,THF

~~..OMe = MeO" "0" ~--NH

47

48

'~--NH

50

CHCI2

0 R1" ~ ' ~ 54

R2

0 R1NH~N=NCO2R2 52

TsNCI2, CH3CN ~"N Ts O ~ [Rh(C3F7C02)212~ ~ N R1, ~ v ,-R2 PPh3 R~ ~COR2 56 55

HNyN C02Et

CI3C'

O

C02Et Ph"'~~. h/~ RNH2 N~ ' N-R P N=C-NAr CH2CI2 \ NHAr

1. TFA 2. EtOH, 80 ~

CHO

49

0 0 R3~CH2~R4 ZrCI4, 0H2012,0 ~

0 R1--N'~N--NHC02 R2 R3~C_R 4 s3

6 R2

1. PhI(OH)OTs, CH3CN NH R3"~'NH2, CHCI3

57

L. Yet

186

1,2-Diamines have been useful precursors for the syntheses of benzimidazoles. Treatment of o-phenylenediamines 58 with hexachloroacetone under sonication provided substituted bisbenzimidazoles 59 in good yields <01SC607>. Successive Buchwald-Hartwig amination of 1,2-dibromobenzene (60) to 1,2-diaminobenzene 61, followed by ring closure in the presence of acid afforded benzimidazolium salts 62 <01OL2673>. Condensation of ophenylenediamine with cinnamic acids in refluxing ethylene glycol afforded 2-styryl benzimidazole derivatives <01SC3439>. o

~

R

NH2

Cl3C,~-...CCl3 , ethylene glycol

NH2

sonication 50 ~

..~"-...~N

....

H ~/.. N

L:,.jL_

'

R

58

fly

R

H 59

R1

9,

Br 60

2. Pd(O), R2NH2

(MeO)3CR 3

-~

NHR 2 61

R 3 X C)

HCI 62

R2

The imidazole core structure itself has been utilized for several synthetic operations. Several 4-vinylimidazoles, prepared from Stille cross-coupling reactions of protected 4iodoimidazoles with tributylvinylstannane, were found to be effective diene partners in DielsAlder reactions <01OL1319>. 1-Trityl-4-vinyl-lH-imidazole was used as a new building block for the preparation of 13-fluoro- and 13,13-difluorohistamine <01JOC4687>. Treatment of 1-benzylimidazole (63) with diisopropylcarbamyl chloride and base afforded imidazolium salt 64, which was trapped with various carbonyl electrophiles to give 2-substituted-1benzylimidazoles 66 <01OL157>. Rhodium-catalyzed C-H carbocyclization of benzimidazoles 67 afforded tricyclic imidazoles 68 <01JACS2685>. An efficient stereocontrolled synthesis of 2-benzimidazolyl-C-nucleosides has been disclosed <01TL647>. Palladium-catalyzed oxidation of imidazolidines afforded the monoamide of the corresponding diamine <01JCS(P1)949>. Substituted imidazolcs and 13-dialkylimidazolium salts can be fully deuteriated on the heterocyclic ring using deuterium oxide over heterogenous palladium catalysts <01CC367>. (4S,5S)- and (4R,5R)-4,5-Dimethoxy-2-imidazolidinones were utilized as versatile synthons for 1,2-diamines <01TL6353>. Sterically congested trans-4,5-di-tertbutyl-2-imidazolidinone and trans-4,5-di-(1-adamantyl)-2-imidazolidinone underwent unusual N-acylation reactions with acyl chlorides in the presence of organic amines to give 3-oxoacyl derivatives <01TL6565>. Reactions of 2-aminobenzimidazole with triphenylphosphine and dialkyl acetylenedicarboxylates afforded stable heterocyclic phosphorus ylides in excellent yields <01SC2639>. A catalytic asymmetric synthesis of ot,13-epoxy esters, aldehydes, amides, and X,5-epoxy [3-keto esters from ~,13-unsaturated carboxylic acid imidazoles with a lanthanide-BINOL catalyst and tert-butyl hydroperoxide has been reported <01JACS9474>. Imidazolidine 69 was subjected to asymmetric lithiation, electrophilic substitution, and hydrolysis to afford chiral, substituted ethylenediamines 70 <01OL3799>. Synthesis of 4- and 5-substituted 1-hydroxyimidazoles through directed lithiation and metal-halogen exchange has been reported <01JOC8344>. Aqueous potassium dichloroiodate has been found to be a general iodinating agent for imidazoles 71 to diiodoimidazoles 72 <01TL2089>. Arylboronic acids 73 reacted efficiently with imidazoles in the presence of a novel diamine-copper complex

] 87

Five-Membered Ring Systems." With More than One N Atom

to give a variety of N-arylimidazoles 74 in aqueous medium <01JOC1528>. This same reaction was also studied in the presence of nitrogen chelating bidentate ligands <01JOC7892>.

I~: \> CICON(i i-Pr2NEt -Pr)2 13n R'R2CO

CON(i-Pr)2-1 CON(i-Pr)2 ~:\~)(::~) / ' R'R2co =- U --N\~--~-~, K'I~O ~R1 ~R2 Bn

63

J

~- L~ ~...-"N N\~____~ ROCON(i R2 -Pr)21

13n

64

Bn 65

66

160 ~ THF

N

67n=0,1,2

68

1. sec-BuLi, (-)-sparteine ') 2. RX N 3. TFA, CH2CI2 13oc 69

"~ R

I

R KlCl2' H20~_ ~ ~ \ ~ - R

NH2 70

~B(OH)2 73

I

H 71

H 72

[Cu(OH)'TMEDA]2CI2 H20' O2'25~ ~ ~ _ _ N"'~N HN~N

~-IR-_/2

74

Imidazole-containing reagents have found useful applications in a variety of organic transformations. A second generation of ruthenium-based olefin metathesis catalysts coordinated with 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene ligand 75 has been utilized in the highly selective cross-metathesis reaction with phenyl vinyl sulfone <01TL6425> and in the (E)-selective cross metathesis of fluorinated olefins with various functionalized alkenes in good to excellent yields <01CC1692>.

Mes--N .N-Mes CI...... R~u_/Ph I

CId " PCY3 75

Bulky imidazolium salts 76 and 77 were found to greatly accelerate the amination of aryl chlorides using nickel catalysts <01TL5689> and palladium catalysts <01JOC7729>, to be useful ligands in the palladium-catalyzed ot-arylation of esters and protected amino acids <01JACS8410>, to be catalytic, environmentally benign solvents for the cyanide displacement

188

L. Yet

on benzyl chloride <01CC887>, and were found to be effective catalysts for the ring-opening alkylation of m e s o epoxides by an alkylaluminum complex <01OL2229>. Aryldiazonium tetrafluoroborate substrates effectively cross-coupled with aryl, vinyl, and alkyl boronates in the presence of catalytic bulky imidazolium salt 76 and palladium(II) acetate <01OL3761>. Bulky imidazolium salt 78 was an effective phosphine ligand for highly efficient Heck reactions of aryl bromides with n-butyl acrylate <0lOLl511>. N-Heteroaryl-7azabicyclo[2.2.1]heptane derivatives were prepared by palladium-catalyzed amination reactions with bisimidazolium salt 79 <01OL1371>.

XQ

r/~~N~pph2 Br Q

76 77

X = cI X = BF4

78

_/~.N-Mes Me, / - - - N ~ ~'k/---Me 2CIQ ~

.Mes

79

Ionic liquids have been a popular topic of interest in 2001. A review on catalytic reactions in ionic liquids has been published <01CC2399>. An improved preparation and use of room temperature ionic liquids in lipase-catalyzed enantio- and regioselective acylations have been reported <01JOC8395>. Facile preparation of 1-alkyl(arylalkyl)-3-methyl(ethyl)imidazolium bromides and chlorides have been reported <01JHC265>. The ionic liquid 1-butyl-3methylimidazolium tetrafluoroborate (80, [bmim][BF4]) has been employed in Stille crosscoupling reactions <01OL233>, in manganese(Ill) acetate-mediated radical reactions <01CC1350>, in the first biphasic oligomerization of ethane to higher ot-olefins with cationic nickel complexes <01CCl186>, and for the manganese dioxide oxidation of codeine methyl ether to thebaine <01TL6831>. A novel method for the synthesis of dihydropyrimidinones by three-component Biginelli condensations of aldehydes with t3-dicarbonyl compounds and urea using room temperature ionic liquid 80 as catalyst under solvent-free and neutral conditions has been developed <01TL5917>. Newly grafted soluble liquid phase derived from imidazolium ionic liquids was utilized in Knoevenagel and 1,3-dipolar cycloaddition reactions <01TL6097>. Alcohols were efficiently converted to alkyl halides using 1-n-butyl-3methylimidazolium halides in the presence of Bronsted acids at room temperature <01OL3727>. The ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphorate (81, [bmim][PF6]) has been utilized in heterogeneous Pd/C catalyzed Heck reactions <01TL4349> and lipase-catalyzed transesterifications of secondary alcohols <01OL1507>. Ionic liquids such as 80 and 81 have been employed as solvents in the lipase catalyzed kinetic resolution of 1-phenylethanol with improved enantioselectivity <01CC425>, as recyclable reaction media for the tetrahydropyranylation of alcohols <01T4405> and for the Baylis-Hillman reaction <01T4189>. An expeditious solvent-frce route to ionic liquids using microwaves was published <01CC643>. Base-promoted reactions using ionic liquid 81 have been employed in some Knoevenagel and Robinson annulation reactions <01TL6053>. The catalyst reactivity and reusability for the lanthanide triflate-catalyzed three component synthesis of or-amino phosphonates have been examined in room temperature ionic liquid 81 <01CC1698> and also in the scandium triflate catalyzed Diels-Alder reactions <01JSC(CC)1122>. Immobilized baker's yeast reduction of ketones and j3-ketoesters in a 10:1 ionic liquid 81/water mixture gave good enantioselectivities of alcohols and 13-hydroxy esters, respectively <01TL7517>.

Five-Membered Ring Systems." With More than One N Atom

189

Solid-support-bound 1-aminoimidazolium chlorochromate 82 proved to be a selective oxidant for benzylic and cinnamylic alcohols <01S382>. Imidazolyl-Ndifluoromethyltrimethylsilanes 83 are versatile sources of heteroaryl-N-difluoromethyl anions in reactions with carbonyl compounds <01SL374>.

Pyrrolo[1,2,3-de]quinoxalines were unexpected products from 1,3-dipolar cycloaddition of dihydroimidazolium ylides with unsaturated ct-bromoketones <01TL3951>. A rapid synthesis of substituted imidazo[2,1-blthiazoles under microwave conditions has been published <01SC1257>. Inverse electron demand cycloadditions of 2-substituted imidazoles with dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate produced imidazo[4,5-d]pyridazines in good yields <01T5497>. Several solid-phase combinatorial approaches to the benzimidazole core have been developed in 2001. Solid-supported 1,2-benzenediamines have been useful precursors for many of these reactions. For example, aryldiamines 84 were cyclized on resin with excess cyanogen bromide followed by acidic cleavage to afford 2-aminobenzimidazoles 85 <01TL2635>. Solid-supported thioureas 86 were cyclized to 2-aminobenzimidazoles 87 after acidic cleavage <01TL1627>. A series of 1,2-disubstituted benzimidazoles 89 were prepared in several steps from solid-supported thiol 1,2-benzenediamines 88 <01OL83>. A silicon traceless solid-phase synthesis of 5-benzoylbenzimidazoles has been developed <01CJC1556>.

190

L. Yet

Other methods for the preparation of imidazoles on solid-supports have been reported. Solid-supported 1-hydroxyimidazole 90 underwent anionic, transmetallation, cross-coupling, and cleavage reactions to afford 2-aryl/heteroaryl substituted 1-hydroxyimidazoles 91 <01S909>. Tile solid-phase synthesis of [3,5,7]-lH-imidazo[1,5-a]imidazol-2(3tt)-ones 93 from acylated dipeptides 92 was accomplished using B ischler-Napieralski conditions <01TL623>. Resin-bound guanidines 94 were cleaved under acidic conditions to give trisubstituted 2-aminoimidazolones 95 <01TL1455>. A traceless synthesis of 3-acylamino imidazo[1,2-a]pyridines 97 were accomplished using universal Rink-isonitrile resin 96 with aldehydes and 2-aminopyridine <01TL2269>. The multi-component synthesis of imidazo[1,2a] annulated heterocycles was performed on ot-isocyano resin esters <01SL1263>. The solidphase synthesis of substituted imidazoline-tethered 2,3-diketopiperazines, cyclic ureas, and cyclic thioureas have been reported <01JCO612>. Resin-bound thioureas 98 reacted with amines in the presence of mercuric chloride to give intermediate resin-bound guanidines, which underwent intramolecular cyclization and simultaneous cleavage from the resin in the presence of acid to provide 2,3,5-trisubstituted 4tI-imidazolones 99 <01JCO521>.

Five-Membered Ring Systems." With More than One N Atom

5.4.4

191

1,2,3-TRIAZOLES AND RING-FUSED DERIVATIVES

X-Ray crystallographic evidence for a vinylogous anomeric effect in benzotriazolesubstituted heterocycles has been reported <01T3309>. 13C NMR was utilized as a useful tool for the unambiguous identification of ring substituted N]~2)~3)-alkylbenzotriazole isomers <01H(55)1133>. The experimental and theoretical study of the basicity of N-H- and N-methyl1,2,3-triazoles in the gas phase, in solution, and in the solid state have been reported <01EJO3031>. A JH and 13C NMR conformational study of 2-(benzotriazol-l-yl)-substituted tetrahydrofurans has been investigated <01CJC 1655>. Benzotriazole-based methodologies continued to be dominant in 2001. An account exploiting the use of benzotriazole methodology in the preparation of mono-, 1,1-di-, trans-l,2di- and trisubstituted ethylenes has been published <01 SL458>. N-(~aminoalkyl)benzotriazoles underwent Lewis acid-catalyzed isonitrile insertion followed by thiol additions to afford novel o~-amino-N-substituted thioacetimidates <01JOC2865>. Imidoylbenzotriazoles reacted with oxa(thia)zolines in the presence of alkyllithium to yield masked N-substituted [3-enamino acid derivatives <01JOC4041>. N-Functionalized benzotriazole-l-carboximidoyl chlorides acted as synthetic equivalents for isocyanide dichlorides, which could be condensed with amines, aryl thiols, and potassium thiocyanate to afford entries to polysubstituted guanidines, S-aryl isothioureas, and 2-aminoquinazoline-4thiones <01JOC2854>. Allyl benzotriazoles and isothiocyanates were condensed and cyclized to furnish electron-rich 3-functionalized-2-aminothiophenes and 1,3-disubstituted-2methylthiopyrroles <01JOC2850>. 1-[Amido(2-pyridinyl)methyl]benzotriazoles were condensed with cyanides to yield 1-amido-3-aryl- and-alkylimidazo[1,5-a]pyridines <01JOC2862>. A method for the addition of a benzotriazole moiety to the 5'-terminus of an oligonucleotide via phosphoramidite chemistry has been developed <01TL2197>. Free-radical cyclizations onto differently substituted 1,2,3-triazoles installed in sugar templates have been reported <01JOC3717>. The conversions by dimethyldioxirane of 1-alkylbenzotriazoles to their N-oxides and 2-alkylbenzotriazoles to their 2-alkyl-trans-4,5,6,7-diepoxy-4,5,6,7tetrahydrobenzotriazoles have been published <01JOC5585>. 1,4-Benzothiazepines and 1,4benzoxazepines were prepared from cyclizations of 1-[2-arylthio(oxy)ethyl]-5-benzotriazolyl2-pyrrolidinones and 3-benzotriazolyl-2- [2-arylthio(oxy)ethyl]- 1-isoindolinones <01JOC5590>. o~-(Benzotriazolyl)methyl thioethers were reacted with styrenes under Lewis acid catalysis to give novel polysubstituted thiochromans <01JOC5595>. Acetanilides were reacted with 1,1 '-sulfinylbis(benzotriazole) and trimethylchlorosilane at 45-65 ~ to afford 1,2di(benzotriazol-l-ly)-2-arylimino-l-ethanethiones while heating the same reagents at 110 ~ yielded dibenzo[b,h][1,4,7]thiadiazonines <01JOC5601>. The preparation of 2,3-disubstituted benzofurans by reactions of o-hydroxyphenyl ketones or o-(1-hydroxy-2,2dimethy]propyl)phenol with 1-benzotriazol-l-ylalkyl chlorides in two or three steps were reported <01JOC5613>. Cyclization of N-benzotriazolylmethyl-N-phenethylamines in the presence of aluminum chloride followed by addition of sodium borohydride or nucleophiles

192

L. Yet

afforded N-methyl- 1,2,3,4-tetrah ydroisoquinolines and N-substituted- 1,2,3,4tetrahydroisoquinolines, respectively <01 TA2427>. o~-Benzotriazolylalkyl ketone tosylhydrazones 100 were used to prepare 1,2,3-thiadiazoles <01JOC4045>. N-Boc-N-(benzotriazol-l-ylmethyl)benzylamine (101) acted as a 1,1-dipole equivalent to synthesize various trans-4,5-disubstituted imidazolidinones <01JOC2858>. S(1H-1,2,3-benzotriazol-l-ylmethyl)-O-ethylcarbonodithioate (102) was used to generate the benzotriazolylmethyl radical which was trapped by a variety of olefins <1H(54)301>. Acylbenzotriazoles 103 were synthesized by palladium-catalyzed carbonylation of benzotriazole and hypervalent iodonium salts <01SC1633> and have been used in conjunction with aryl isocyanates to prepare amidines <01JOC 1043>. 1(Trimethylsilylmethyl)benzotriazole (104) was utilized as a one-carbon synthon for the conversion of alkyl and aryl carboxylic acids into their corresponding homologated acids or esters <01JOC5606>. A 1-amino-lH-benzotriazole substrate has been employed in the first efficient method for intermediate benzyne intramolecular trapping of phenols in a new approach to xanthene syntheses <01JCS(P1) 1771>. N-Acyl-lH-benzotriazole-1carboximidamides 105 were employed in the synthesis of substituted 4(6)-amino-l,3,5-triazon2-ones and -1,3,5-triazin-2-thiones <01JOC6797>. N,N-Di-tert-butoxycarbonyl-lHbenzotriazole-l-carboxamidine derivatives 106 have been found to be highly efficient reagents for the conversion of primary and secondary amines in solution and in solid phase to diprotected guanidines <01OL3859>. N-(l'-Benzotriazolylmethyl)-5-phenylmorpholin-2-one has been found to be a stable crystalline chiral azomethine ylide precursor <01SL1841>.

N

N

100

N S

,,_,,,Boo

,,_{ NNHTs R

101

'Bn

11)2

k---S

N

k-.-.TMS

105

11)3

/~,==O

R

N.

1R1RN- N

104

N

o,=t

BocHN 106 X = H,

5-CI, 6-NO2

A one-pot sequential and cascade sequence involving the formation of allylic azides, from aryl/heteroaryl/vinyl halides, allene and sodium azide, by palladium catalyzed anion capture, and cyclization-anion capture, followed by 1,3-dipolar cycloaddition provided a variety of 1,2,3-triazoles in good yields <01T7729>. Reaction of ot,13-acetylenic aldehydes 107 with sodium azide in dimethylsulfoxide followed by hydrolysis afforded 5-substituted-4carbaldehyde- 1,2,3-triazole derivatives 108 <01TL9117>.

107

H

1. NAN3, DMSO, 25 -~ 2. Hydrolysis

R c.o N.

N N" H 108

Five-Membered Ring Systems." With More than One N Atom

193

Polymer-supported benzotriazoles were employed as catalysts in the synthesis of tetrahydroquinolines by condensation of aldehydes with aromatic amines <01JCO341> and as synthetic auxiliaries and traceless linkers for the combinatorial synthesis of unsymmetrical ureas <01JCO354>. The solid-phase development of a 1-hydroxybenzotriazole linker for heterocyclic synthesis using analytical constructs has bcen described <01JCO387>. Three new examples of polymer-supported triazole and benzotriazole leaving groups have been published <01JCO167>. Reactions of [1,2,3]triazolo[1,5-c]pyrimidine with some electrophiles and nucleophiles were investigated <01T10111>.

5.4.5

1,2,4-TRIAZOLES AND RING-FUSED DERIVATIVES

Gas-phase pyrolysis of 4-amino-3-allylthio-l,2,4-triazoles provided a new route to [1,3]thiazolo[3,2-b][1,2,4]triazoles <01JCS(P1)424>. The kinetics of the thermal rearrangement of 4-ethyl-3,5-diphenyl-4H- 1,2,4-triazolcs have been investigated <01JHC955>. The counteranion-dependent symmetry of Cu(II)-4-amino-l,2,4-triazole polymeric chains was investigated <01 CC1254>. Acyl 1H-benzotriazol-l-carboximidamides 109 and hydrazines were employed in a general synthesis of N,N-disubstituted 3-amino-l,2,4-triazoles 110 <01S897>. A2-1,2,4-Triazolin-5 ones 112 were prepared from 1-aryl/alkyl-6-phenyl-2-thiobioureas 111 in the presence of benzyl chloride and aqueous ethanol <01SC1599, 01T2003>. Reaction of N-[2(heteroarylhydrazono)ethyl]benzamides 113 with lead tetraacetate or (diacetoxyiodo)benzene afforded benzoylaminomethyl substituted 1,2,4-triazoles 114 <01SC1511>. An ionic complex, obtained from N204 and 18-crown-6, has been utilized for the efficient oxidation of urazoles to 1,2,4-triazol-3,5-diones <01T1627>. Urazoles 115 were converted to their corresponding triazololinediones 116 in the presence of silica gel and sodium nitrite <01T8381>. Similarly, a combination of potassium monopersulfate and sodium nitrite in the presence of wet silica was used as an effective oxidizing agent for the oxidation of urazoles and bis-urazoles to 4-substituted-l,2,4-triazole-3,5-diones <01SCl149>. Cyclization of 1,2,4triazenes 117 with oxidizing agents such as NaC10, Ca(C10)2, Dess-Martin periodinane and TPAP/NMO afforded 1,3,5-trisubstituted-l,2,4-triazoles 118 <01TL9677>. N-amination of 2,6-diamino-4-bromopyridine (119) with O-mesitylenesulfonylhydroxylamine (120) and subsequent reaction with aldehydes afforded, upon oxidative ring-closure, 5-bromo-l,2,4triazolopyridines 121, useful precursors for combinatorial or parallel Suzuki cross-coupling reactions <01SL1917>.

N NH2NHR 4 .~ -------N CHCI3 1R2RN /~R3 109

0

H i ' ~ N--N

/N

IlL,-NHCOPh

113

0 H BnCI N~___R3 N-_N PhHN "JL'N'N~"NHR aq. EtOH H S ~4 111 11o Pb(OAc)4 or " P-hl(OAc)2' CH2C12~

x"•N,N /N"~___NHCOPh 114

0 R'Nff~\

.L NH

BnS/-~N 112

194

L. Yet

HN-NH

o-Z.N~O

SiO2

N-N

NaNO2~- oJ-.N3~ o

115

116

Ph NaCIO or Ca(CIO)2 or N-N'H Dess-Martin Periodinane ph--~/ or TPAP/NMO NH R__/ 117

~

BF H2N'~NH

02 ~-ONH 2

119

118

gr

(120)

2. RCHO 3.1N KOH 4. air

2

N..N ,,Ph

Ph--~N~,.., R

H2N.~~ 121

N R

Reaction of N-alkyl-l,2,4-triazoles 122 with an alkyl radical generated from the corresponding carboxylic acid afforded the triazole ring 123 alkylated selectively in the 5position <01TL7353>.

a2 RI~-N/~'N

~1= j 122

,,r

R2CO2H, AgNO3 (NH4)2S208,TFA, H20

h-__/ 123

Novel 3-arylazo- 1,7-disubstituted[ 1,2,4}triazolo[4,3-a ]pyrimidinone-5(1H)-ones were prepared from the reaction of 2-thiouracil derivatives with either 3-chloro- or 3-nitro-l,5diarylformazans <01SC731>. Spiro[3tt-indole-3,5'(4'H)-[1,2,4]triazoline]-2-ones were obtained thermally and under microwave irradiation by reaction of the corresponding isatin imines with nitrilimines <01SC1069>. Heating dialkyl acetylenedicarboxylates in DMF condensed [1,2,4]-triazolo[4,3,-b]pyridazine-6-(5t/)-thiones underwent unprecedented ring transformations yielding novel tetracyclic 1,3-diazepines and thiazolotriazole derivatives depending on the applied reaction temperatures <01T7191>. Condensation of 3-aryl-4-amino5-mercapto-l,2,4-triazoles with different L-amino acids in the presence of phosphorus oxychloride afforded various chiral fused heterocyclic 1,2,4-triazoles <01JHC355>. Novel 1,2,4-triazolyl-isoquinolinium zwitterions have been synthesized and confirmed by X-ray diffraction analysis <01JHC403>. 3-Aryl-6,7-dihydro-s-triazolo[3,4-b][1,3]thiazines and 3aryl-5,6-dihydrothiazolo[2,3-c]-s-triazoles were synthesized by nucleophilic substitution of 3aryl-5-mercapto-l,2,4-triazoles with 1,3-dibromopropane and 1,2-dichloroethane <01SC2841>. A novel synthesis of 1,2,4-triazolo[4,3-a]pyrimidin-5-one derivatives has been published <01T10133>. The first example of the novel ring system, 1,2,4-triazolo[1,2-a]benzotriazoles, has been reported <01TL9109>. A solid-phase route to 5-aryl-3-arylthiomethyl-l,2,4-triazoles has been developed that permits the incorporation of two elements of diversity with a novel 4-benzyloxy-2methoxybenzylamine resin <01OL3341>.

F i v e - M e m b e r e d Ring Systems." I.~Tth More than One N Atom

5.4.6

195

TETRAZOLES AND RING-FUSED DERIVATIVES

The synthesis, spectral characteristics, and the reactions of electrophiles with 1H- and (mesoionic) 2H-pyrrolotetrazoles were studied <01JCS(P1)720, 729>. The synthesis and crystal structure of a ot-keto tetrazole-based dipeptide mimics has been reported <01TL5641>. Novel tetrazol-5-yl-isoquinolinium zwitterions have been synthesized and confirmed by X-ray diffraction analysis <01JHC199>. Application of natural bond orbital analysis to delocalization and aromaticity in C-substituted tetrazoles has been investigated <01JOC8737>. Reactions of nitriles 124 with sodium azide and catalytic zinc bromide proceeded readily in refluxing water to give 5-substituted 1H-tetrazoles 125 in good yields <01JOC7945>. Fused 5heterotetrazole ring systems 127 were synthesized from thermal [2+3] intramolecular cycloadditions of azido nitriles 126 <01 OL4091 >.

.NAN3,ZnBr2 = N%N, R-CN H20,100 ~ ,,~ R N'NH 124

125

NCZ N3 ~n

140 ~ [2+3]

N---N "N Z"~N L~

n = 0,1; z = O , S , N 127

126

Reactions of 2-(tetrazol-5-yl)alkyl ketones and 2-(tetrazol-5-yl)alkanoic acid derivatives 128 with lead tetraacetate afforded alk-2-ynyl ketones and alk-2-ynoic acid derivatives 129 <01JCS(P1)ll31>.

0 X'~

5.4.7

R

N:N H Pb(OAc)4 ~ L ~ N(~ "N dioxane X 128

129

R

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Five-Membered Ring Systems." With More than One N Atom

01JOC2854 01JOC2858 01JOC2862 01JOC2865 01JOC2943 01JOC3717 01JOC4041 01JOC4045 01JOC4214 01JOC4687 01JOC5585 01JOC5590 01JOC5595 01JOC5601 01JOC5606 01JOC5613 01JOC6787 01JOC6797 01JOC7729 01JOC7892 01JOC7945 01JOC8344 01JOC8395 01JOC8654 01JOC8737 01OL83 01OL157 01OL233 01OL1319 01OL1371 01OL1507 01OL1511 01OL2229 01OL2673 01OL3341 01OL3647 01OL3651 01OL3727 01OL3761 01OL3799 01OL3859 01OL4091 01S55 01S382 01S897 01S909 01S1053 01S1505 01S1509 01S1949 01S2075 01S2393

] 97

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198

01SC539 01SC607 01SC731 01SC1053 01SC1069 01SCl149 01SC1257 01SC1315 01SC1511 01SC1599 01SC1633 01SC2639 01SC2841 01SC3225 01SC3439 01SC3547 01SC3799 01SL135 01SL218 01SL374 01SL458 01SL1237 01SL1263 01SL1841 01SL1917 01T1627 01T2003 01T2031 01T2051 01T3309 01T4179 01T4189 01T4397 01T4405 01T5497 01T5855 01T6947 01T7191 01T7693 01T7729 01T8384 01T10111 01T10133

L. Yet

S.J. Pastine, W. Kelly, Jr., J.N. Templeton, III, C.F. Beam,Synth. Commun. 2001, 31, 539. M.C. Rezende, E.L. Dall'Oglio, C. Zucco, Synth. Cornmutz. 2(}01,31,607. A.S, Shawali, A.tt. Elghandour, A.R. Sayed, Synth. Cornmun. 2001, 31,731. M.-W. Ding, Z.-F. Xu, Z.-J. Liu, T.-J. Wu, Synth. Commun. 2001, 31, 1053. J. Azizian, S. Soozangarzadeh, K. Jadidi, Synth. Commun. 2001,31, 1069. M.A. Zoffigol, M. Baghe~adeh, G. Chehardoli, S.E. Mallakpour, Synth. Commun. 2001, 31, 1149. A. Gellis, Y. Njoya, M.P. Crozet, P. Vanelle, Synth. Cornmun. 2001, 31, 1257. R. Touzani, A. Ramdani, T. Ben-Hadda, S.E. Kadiri, O. Maury, It. LeBozec, P.H. Dixneuf, Synth. Contrnun. 2001,31, 1315. I. Music, B. Vercek, Synth. Commun. 2001,31, 1511. M.M. Suni, V.A. Nair, C.P. Joshua, Synth. Corttrtttttt. 2001, 31, 1599. L. Wang, Z.-C. Chen, Synth. Commun. 2001, 31, 1633. A. Shaabani, H.R. Safaei, II.R. Bijanzadeh, Synth. Commun. 2001, 31, 2639. Z. Wang, H. Shi, tl. Shi, Synth. Commun. 2001,31,2841. A. Yahya-Zadeh, B.L. Booth, Synth. Commun. 2001,31, 3225. P.K. Dubey, R. Kumar, C.R. Kumar, J.S.Gro~crt, D.I~. I tooper, Synth. Contmun. 2001, 31,3439. H.H. Abdel-Razik, A.A. Fadda, Synth. Commun. 2001, 31,3547. G. Broggini, G. Molteni, T. Pilati, G. 7~cchi, Synth. Cornrnun. 2001, 31,3799. M. Vuilhorgne, J. Bouquerel, J.-C. tlardy, S. Mignani, Synlett 2001, 135. P.M. Fresneda, P. Molina, M.A. Sanz, Synlett 2001, 218. G. Bissky, V.I. Staninets, A.A. Kolomeitsev, G.-V. R6schenthaler, Synlett 2001, 374. A.R. Katritzky, D. Toader, Synlett 2001, 458. S. Bombek, R. Lenarsic, M. Kocevar, S. Polanc, Synlett 2001, 1237. J.J. Chen, A. Golebiowski, S .R. Klopfenstein, J. McClenaghan, S.X.Peng, D.E. Portlock, L. West, Synlett 2001, 1263. D.J. Aldous, E.M.-N. Hamelin, L.M. Harwood, S. Thurairatnam, Synlett 2001, 1841. M. Nettekoven, Synlett 2001, 1917. M.A. Zolfigol, M.H. Zebarjadian, G. Chehardoli, S.E. Mallakpour, M. Shamsipur Tetrahedron 2001, 57, 1627. M.M. Suni, V.A. Nair, C.P. Joshua, Tetrahedron 2001, 57, 2003. G. Abbiati, A. Arcadi, O.A. Attanasi, L. De Crescentini, E. Rossi, Tetrahedron 2001, 57, 2031. V.I. Tyvorskii, D.N. Bobrov, O.G. Kulinkovich, K.A. Tehrani, N. De Kimpe, Tetrahedron 2001, 57, 2051. A.R. Katritzky, P.J. Steel, S .N. Denisenko, Tetrahedron 2001,57, 3309. J.R. Carrillo, F.P. Cossio, A. Diaz-Ortfz, M.J. G6mez-Escalonilla, A. de la Hoz, B. Lecea, A. Moreno, P. Prieto, Tetrahedron 2001, 57, 4179. J.N. Rosa, C.A.M. Afonso, A.G. Santos, Tetrahedron 2001, 57, 4189. A. de la Hoz, A. Diaz-Ortiz, J. Elguero, L.J. Martinez, A. Moreno, A. S~inchez-Migall6n, Tetrahedron 2001, 57, 4397. L.C. Branco, C.A.M. Afonso, Tetrahedron 2001, 57, 4405. Z.-K. Wan, G.H.C. Woo, J.K. Snyder, Tetrahedron 2001,57, 5497. O.A. Attanasi, L. De Crescentini, P. Filippone, F. Mantellini, L.F. Tietze, Tetrahedron 2001, 57, 5855. J. Quiroga, D. Mejia, B. lnsuasty, R. Abonia, M. Nogueras, A. S~nchez, J. Cobo, J.N. Low, Tetrahedron 2001,57, 6947. M. Simo, A. Csampai, V. tlarmat, O. Barabas, G. Magyarfalvy, Tetrahedron 2001, 57, 7191. A. Schafer, M. Specht, A. Iletzheim, W. Francke, F. Schauer, Tetrahedron 2001, 57, 7693. M. Gardiner, R. Grigg, M. Kordes, V.Sridharan, N. Vicker, Tetrahedron 2001, 57, 7729. M.A. Zolfigol, M. Torabi, S .E. Mallakpour, Tetrahedron 2001, 57, 8384. B. Abarca, R. Ballesteros, M. Chadlaoui, J. Miralles, J.V. Murillo, D. Colonna, Tetrahedron 2001, 57, 10111. H.M. Hassaneen, H.A. Abdelhadi, T.A. Abdallah,Tetrahedron 2001, 57, 10133.

F i v e - M e m b e r e d Ring Systems." With More than One N Atom

199

01T10259 01TA2427 01TL1 01TL5 01TL33

M. Ternon, F. Outurquin, C. Paulmier, Tetrahedron 2001, 57, 10259. A.R. Katritzky, I t.-Y. He, R. Jiang, Q. Long, Tetrahedron: Asymmetry 2001, 12, 2427. Y. Gong, M.J. Bausch, L. Wang, Tetrahedron Lett. 2001,42, 1. M.S. Goodman, M.A. Bateman, Tetrahedron Lett. 2001, 42, 5. M. Ohkoshi, M. Yoshida, II. Matsuyama, M. Iyoda, Tetrahedron Lett. 2001, 42, 33.

01TL623

Y. Yu, tt.M. El Abdellaoui, J.M. Ostresh, R.A. Houghten, Tetrahedron Lett. 2001, 42, 623. D. Guianvarc'h, R. Benhida, J.-L. Fourrey, Tetrahedron Lett. 2001, 42,647. M. Li, L.J. Wilson, Tetrahedron Lett. 2001, 42, 1455. V. Krchfi~ik, J. Smith, J. V~igner, Tetrahedron Lett. 2001, 42, 1627. S.J. Garden, J.C. Torres, S.C. de Souza Melo, A.S. Lima, AC. Pinto, E.L.S. Lima, Tetrahedron Lett. 2001, 42, 2089. R. Brown, W.E. Smith, D. Graham, Tetrahedron Lett. 2001, 42, 2197. J.J. Chen, A. Golebiowski, J. McClenaghan, S.R. Klopfenstein. L. West, Tetrahedron Lett. 2001, 42, 2269. J. Lee, A. Doucette, N.S. Wilson, J. Lord, Tetrahedron Lett. 2001, 42, 2635. J.J. Song, N.K. Lee, Tetrahedron Lett. 2001,42, 2937. S. Paul, M. Gupta, R. Gupta, A. Loupy, Tetrahedron Lett. 2001,42, 3827. M.-J. Cheng, C.-H. ttu, Tetrahedron Lett. 2001, 42, 3897. R.C.F. Jones, J.N. Iley, P.M.J. Lory, S.C. Coles, M.E. Light, M.B. tlursthouse, Tetrahedron Lett. 2001, 42, 3951. P. Chen, J.C. Barrish, E. Iwanowicz, J. Lin, M. S. Bedna~, B.-C. Chen, Tetrahedrotd.ett. 2001, 42, 4293. D. Norris, P. Chen, J.C. Barrish, J. Das, R. Moquin, B.-C. Chen, P. Guo, Tetrahedron Lett. 2001, 42, 4297. tt. Hagiwara, Y. Shimizu, T. Hoshi, T. Suzuki, M. Ando, K. Ohkubo, C. Yokoyama, Tetrahedron Lett. 2001, 42, 4349. P. Tempest, V. Ma, S. Thomas, Z.tlua, M.G. Kelly, C. tlulme, Tetrahedron Lett. 2001, 42, 4959. M. Nyerges, I. Fejes, A. Vir~inyi, P.W. Groundwater, L. T6ke, Tetrahedron Lett. 2001, 42, 5081. B.C.H. May, A.D. Abell, Tetrahedron Lett. 2001, 42, 5641. B. Gradel, E. Brenner, R. Schneider, Y. Fort, Tetrahedron Lett. 2001, 42, 5689. J. Peng, Y. Deng, Tetrahedron Lett. 2001, 42, 5917. D.W. Morrison, D.C. Forbes, J.tt. Davis, Jr., Tetrahedron Lett. 2001, 42, 6053. J. Fraga-Dubreuil, J.P. Bazureau, Tetrahedron Lett. 2001, 42, 6097. R. Seo, T. Ishizuka, A.A.-M. Abdel-Aziz, T. Kunieda, Tetrahedron Lett. 2001, 42, 6353. K. Grela, M. Bieniek, Tetrahedron Lett. 2001, 42, 6425. A.A.-M. Abdel-Aziz, tt. Matsunaga, T. Kunieda, Tetrahedron Lett. 2001, 42, 6565. S. Chandrasekhar, G. Rajaiah, P. Srihari, Tetrahedron Lett. 2001, 42, 6599. P.G. Rasmussen, T.S. Fabre, P.A. Beck, M.J. Eissa, J. Escobcdo, R.M. Strongin, Tetrahedron Lett. 2001, 42, 6823. R.D. Singer, P.J. Scammells, Tetrahedron Left. 2001,42, 6831. K.B. Hansen, S.A. Springfield, R. Desmond, P.N. Devine, E.J.J. Grabowski, PJ.Reider, Tetrahedron Lett. 2001, 42, 7353. J. Howarth, P. James, J. Dai, Tetrahedron Lett. 2001, 42, 7517. A.R. Katritzky, T.-B. ttuang, PJ. Steel, Tetrahedron Lett. 2001, 42, 9109. M. Journet, D. Cai, J.J. Kowal, R.D. Larsen, Tetrahedron Lett. 2001, 42, 9117. P. Wang, N. Onozawa-Komatsuzaki, Y. Himeda, H. Sugihara, H. Arakawa, K. Kasuga, Tetrahedron Lett. 2001,42, 9199. K. Paulvannan, R. Itale, D. Sedehi, T. Chen,Tetrahedron Lett. 2001, 42, 9677.

01TL647 01TL1455 01TL1627 01TL2089 01TL2197 01TL2269 01TL2635 01TL2937 01TL3827 01TL3897 01TL3951 01TL4293 01TIA297 01TL4349 01TL4959 01TL5081 01TL~641 01TL5689 01TL5917 01TL6053 01TL6097 01TL6353 01TL6425 01TL6565 01TL6599 01TL6823 01TL6831 01TL7353 01TL7517 01TL9109 01TL9117 01TL9199 01TL9677

200

Chapter 5.5

Five-Membered Ring Systems" With N & S (Se) Atoms

David J. Wilkins

Key Organics Ltd., Highfield Industrial Estate, Camelford, Cornwall PL32 9QZ, UK. davidw @keyo rganics, ltd. uk Paul A. Bradley

Pfizer Global Research & Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. paul a bradley@ sandwich.pfizer.com

5.5.1

ISOTHIAZOLES

Reaction of the 5-unsubstituted isothiazole 1,1-dioxide (2; R = H) with a vast excess of triethylphosphite (TEP) at 100 ~ gave the phosphonate 3 as the sole product in 50% yield; compound 3 being formed through nucleophilic attack of TEP at C-5. When the reaction was performed on the corresponding 5-bromo derivative (2; R = Br) in toluene, using an equimolar amount of TEP, the phosphonate 1 was obtained via an addition-elimination process. Subsequent treatment of 2 with a vast excess of TEP at 100 ~ gave the bisphosphonate 4 in 63% yield. The same product could also be obtained directly, by heating 1 in TEP at 110 ~ for 4h <01T5455>.

201

Five-Membered Ring Systems." With N & S (Se) Atoms

O .O

(EtO)2(O)P ~ ~ / N Ar

NEt2 1

53%

O /O

P(OEt)3 / PhMe Reflux / 90% P (OEt)3 10 ~

Ar

NEt2

P(OEt)3

H OsO

(EtO)2(O)P,,~/N

100 ~ / 50%

Ar~'-- \ H NEt2

2

100 ~ /

P(OEt)3

A,. Meo j H Qs -0 (EtO)2(O) P"z~ "N (EtO)2(O)P

NEt2

The isothiazolylphosphonate 1 underwent 1,3-dipolar cycloaddition reactions with diazomethane and with nitrile oxides. Firstly, treatment of 1 with ethereal diazomethane gave a mixture of the 2-tautomeric pyrazolines 5 and 6. Subsequent dissolution of the mixture in chloroform resulted in complete conversion into the more stable 2-pyrazoline 6. The cycloaddition of 1 with both 4-chlorobenzonitrile oxide and 4-methoxybenzonitrile oxide afforded isothiazolo[5,4-d]isoxazoles 8 in good yield with a very high degree of regioselectivity. Both compounds 6 and 8 were stable at room temperature but underwent decomposition when heated with bases. 6 underwent a base catalysed elimination of SO2 and diethylcyanamide with cleavage of the isothiazole ring, giving the pyrazolylphosphonate 7 when treated with DBU or KOH / EtOH. Reaction of 8 with an excess of ethanolic KOH gave the isoxazole 10 which was produced via the intermediate 9. The isothiazole 9 could be isolated from 8 using 1 equivalent of ethanolic KOH <01T5455>.

202

D.J. Wilkins and P.A. Bradley

0

O\ 0 (EtO)2(O)P- S HN--N(/" \N

0

'\

(EtO)e(O)NP~S~,N

CI--12N2/,4 / 85% 0 ,0 (EtO)z(O)P.~ ~ N Ar

NEt2

Ar NEt2

/

Ar

H N--N //~

DBU or

NEt2

KOH / EtOH

6

P(O)(OEt)2

Ar 7

ICNO (EtO)2(O)P, O)s,,O A r ~ \N

A r //\~

l eq. KOH/etOH

N//\ /~r~ 0 ,~,r 'NEt2

80%

U O~"0 \N 0,~, r ,NEt2

/

9

k/ 10 eq. KOH / EtOH Ar~.

SO2NH2

Ar. Ar~= 4-MeO-Phand 4-CI-Ph o

Ar

10 Thiazyl chloride, NSC1 (generated in situ from ethyl carbamate, SOC12 and pyridine) has been shown to convert 2,5- and 2,3,5-substituted furans 11 into 5acylisothiazoles 12 in boiling benzene or toluene. Even fully substituted 3bromofurans 13 gave isothiazoles 12 with displacement of the bromine atom, under more vigorous conditions <01JCS(P1)1304>.

R Ph

Ph

,

11

(NSCI) >

~ Ph

0

Ph

(NSCI) ~

12

Br.~R Ph

Ph 13

Reaction of NSCI with deactivated furans 14 (with electron-withdrawing groups such as ester, cyano, benzoyl and phenylsulfonyl in the 2-position) afforded 5acylisothiazoles 15 with the electron-withdrawing group in the 3-position. These transformations required more forcing reaction conditions giving only moderate yields (24-60%) of isothiazole product <01JCS(P1) 1304>.

203

Five-Membered Ring Systems." With N & S (Se) Atoms

X

(NSCl)

Ph

X 0 14

15

X = CO2Et, CN, CH=NOMe and SQ2Ph

Pedras and Zaharia reported the first synthesis of the antifungal Sinalexin 17. This involved regioselective formylation of 1-methoxyindoline-2-thione (16; R = OMe) under standard Vilsmeier conditions, followed by an unprecedented ammonia workup. A similar formylation of indoline-2-thione (16; R --- H) yielded Brassilexin 18 in 70% yield <010L 12 ] 3>.

R = OMe

OMe

17 60%

~N

S

R=H

R 70%

16

H 18

Reaction conditions: (a) POCI3 / DMF; (b) 12 / Py

Irradiation of a series of 3-mono and 3,3-disubstituted 2,3dihydro[1,2]benzisothiazole 1,1-dioxides 19 at 254 nm in MeOH resulted in facile rearrangement to the corresponding benzisothiazole 1,1-dioxide derivatives 20. The authors describe a plausible mechanism for the transformation which involves initial S-N homolysis, followed by N-O cyclisation and subsequent rearrangement. Similar transformations were also reported for various annulated benzisothiazole 1,1-dioxides <01S 1228>.

n' d ~.S'.

N-X

R' d UV light / MeOH

,~

~ s N

O" "0 19

-OX '(3

20

R1 = H, Me, Ph; R2 = H, Me, Ph; X = CH2OMe, CH2OPr~

204

D.J. Wilkins and P.A. Bradley

Flash Vacuum Pyrolysis (FVP) of a series of oxime ethers 21 (10-2-10 .3 Torr) gave products derived from the corresponding iminyl radicals 22. Benzo[d]isothiazoles 23 were formed as the major products in all cases via an Siii mechanism <01JCS(P1)1079>. FVP

~

N

\OMe R

R

21

22

R

R 23

Yield of 23 (%)

H Me Ph

48 45 48

Leardini et al. also reported the formation of the same benzo[d]isothiazole 23, but in lower yield (18-25%), by thermal decomposition of the corresponding tert-butyl ortho-(phenylsulfonyl)phenyliminoxy peracetates <01JCS(P1)1072>. Benzo[d]isothiazoles could also be produced by FVP of the sulfides 24 <01JCS(P1)1079>.

S~ph N.Ar R 24

R = H, Me, Ph Ar = Ph, p-tolyl

205

Five-Membered Ring Systems." With N & S (Se) Atoms

5.5.2

THIAZOLES

The synthesis of optically active thiazolo[3,2-a]pyridinones has been described. Chiral thiazolines 27, prepared from the condensation of imino ethers 25 with (R)cysteine methyl ester 26, undergo a ketene-imine cycloaddition reaction with Meldrum's acid derivatives 28 to givc thiazolo[3,2-a]pyridinones 29 in good yields <01JOC6756>.

R'.., ~OEt

HS....j,CO2Me

NH.HCI

R~~. S -

NH2.HCI

CO2Me

27

26

25

o

d

O"~OH \

28

O

CO2Me 29

A novel method for the synthesis of 2-mercaptothiazoles 33 has been described. The cyclocondensation of alkynyl(phenyl)iodonium salts 30 with ammonium dithiocarbamate affords 2-mercaptothiazoles in moderate to good yields. The proposed mechanism involves an initial addition reaction to give 31, which undergoes a polyhetero Claisen rearrangement to generate the carbene 32. The carbene then undergoes cycloaromatisation to give 2-mercaptothiazoles 33 <01 $358>.

III

Ph

Ph

/1\ TsO Ph

NH2 +

S- ~ S

NH2 s/~s/l\ph

+ NH 4

31

30

H S

C; 32

Ph

Ph

HS 33

206

D.J. Wilkins and P.A. Bradley

The synthesis of novel trisubstituted thiazoles has been reported. The reaction of otdiazo-13-ketoesters 34 with aromatic thioamides 36 mediated by copper (I) catalysis affords thiazole-5-carboxylate derivatives 38 in good yield. The mechanism involves the initial formation of a carbenoid 35, which reacts with the thiocarbonyl group to give the adduct 37 which undergoes cyclocondensation to give thiazoles 38. The use of other metal catalysts such as Rh2(OAc)4, led to complex reaction mixtures. An aromatic ring adjacent to the thiocarbonyl group is also essential as aliphatic thioamides or thioureas do not react and only products resulting from decomposition of the diazo compounds are observed <01S2021>. Ar

0

0

R

0 OEt

~

R

0 C.

/3=:=S OEt

3 ~

N2 35

34

0 NH

/'/"-R 0 37

R Ar~\s/~CO2Et

38

An efficient route to thiazoline-4-carboxylates with a cyclopropyl substituent at the 5-position has been described. Under basic conditions, thiocarboxamides 39 or N,Nthioureas undergo Michael addition to 2-chloro-2-cyclopropylideneacetates 40, reacting via the sulfur atom, to give the adduct 41, subsequent cyclisation of 41 then gives the thiazoline-4-carboxylate 42 in moderate to good yields. Acid hydrolysis of 42 gives the cyclopropyl analogue of penicillamines 43. Under acidic conditions the Michael adducts can be isolated as hydrochloride salts in almost quantitative yield. Cyclisation of these salts under basic conditions gives 42, except in the presence of Ti(Oipr)4 when spirocyclopropyl annelatcd thiazinones 44 are obtained <01EJO3025>.

207

Five-Membered Ring Systems." With N & S (Se) Atoms

S R

R~~.NH

CI

R"~~C

NH2 39

C02Me 41

40

0

C02H 43

42

I

44

A new facile synthesis of 2-aminothiazole-5-carboxylates has been developed which does not involve the preparation and isolation of ot-formyl-ot-haloacetates. The reaction of ethyl 13-ethoxyacrylate 45 with N-bromosuccinimide afforded the otbromo-ot-formylacetate hemiacetal 46. In situ cyclisation of this intermediate with thioureas gives 2-aminothiazole-5-carboxylates 47 in good to excellent yields <01TL2101 >.

EtO./'~/C02 Et

OH

NBS

EtO~ / C o 2 E t Br 46

45

S R,, . ~

HN

NH2

R

N

N~ \ S/ ~C02Et H

. . ,

47

The oxidation of thiazolidincs can follow a number of different pathways; oxidation can occur to give 2 or 3-thiazolines with further oxidation to thiazoles, or oxidation at the N or S atoms can occur. The regioselective oxidation of thiazolidine4-carboxylates to 3-thiazoline-4-carboxylates has been reported. In a typical reaction, treatment of the thiazolidine 48 with an excess of MnO2 at 50 ~ for 5 h gave the 3thiazoline 49 in good yield and the thiazole 50 in 20% yield <01TL1519>.

208

D.J. Wilkins and P.A. Bradley

~N ~ Me02C.... H

iPr

48

Mn02 ~-- MeO2C~N~'~'~iPr 4-Me02C~N-N/~-~iPr ~/ S 50

49

A variety of heterocyclic thioamides 51 were treated with dimethyl acetylenedicarboxylate (DMAD) to give novel conjugated bisheterocycles incorporating a thiazolinone ring 52. Isoxazolyl, imidazolyl, 1,2,3-triazolyl and 1,2,3thiadiazolyl thiazolines have been prepared. It is interesting to note that the thioamide group reacts in preference to the amino group in these reactions <01T2179>.

0 s

/N~NH2 Y\X,,2"-NH2 51

CO2Me Y\X/2-----NH2 52

X=NH, S Y=CH, N The fluorination of thiazolidines is not possible using fluorinating agents such as N-fluoropyridinium salts. Anodic fluorination of N-benzoyl, N-acetyl and Nformylthiazolidines such as 53 derived from L-cysteine has been carried out in DME and acetonitrile containing various supporting fluoride salts using an undivided cell. 5-Fluorothiazolidine derivatives such as 54 were obtained in good yields with moderate to high diastereoselectivity. The diastereoselectivity is greatly influenced by the size of the substituent on the nitrogen atom. Surprisingly, under similar conditions, the thiazolidine containing a 4-carboxylic acid substituent 55 underwent fluorination and decarboxylation to give the 4-hydroxy-5-fluoro derivative 56 <01JOC7020>.

209

Five-Membered Ring Systems: With N & S (Se) Atoms

.$7

/_.~CO2Me S~N -

'

F-'z~,CO2Me .' ~ Et3N.4HF, DME Pt anode

O

/

N "

'

O

54, 95% de

53

-2e, -H§

.~CO2H

F

-. ~ Et D3anode M N'4HF' Ept

S~N

O ~

S~N

55

56

The preparation of 2 and 5-arylsubstituted thiazoles via a palladium catalysed Negishi cross coupling has been described. 2-Aryl substituted thiazoles 58 were prepared by oxidative insertion of zinc into 2-bromothiazole 57 to give the thiazolezinc bromide, followed by palladium (0) catalysed Negishi cross coupling with either an aryl bromide or heteroaryl bromide. 5-Aryl substituted thiazoles 60 were prepared by regioselective C-5 lithiation of 2-(trimethylsilyl)thiazole 59, followed by transmetallation with zinc chloride to give 5-thiazolezinc chloride and cross coupling with either an aryl bromide or heteroaryl bromide. A range of substituents on the aryl halide were tolerated under these reaction conditions. The synthetic sequences have also been combined to give 2,5-diaryl substituted thiazoles via stepwise C-2 and C-5 arylation and vice versa <01S 128>.

1. Zn dust

=

/~S,,~

2. Pd(PPh3)4, ArX 58

57

/~__,~ S

1. nBuLi, ZnCl,. Si(CH3)3

59

Ar

~

2. Pd(PPh3)4, ArX

3. H§

..~--S ~ Ar

60

A new methodology for the preparation of phenyliminothiazolidinones has been described. The reaction of maleic anhydride (61) with the thiourea 62 gave the 2imino-l,3-thiazolidin-4-one 63. If maleimides are treated under similar conditions,

210

D.J. Wilkins and P.A. Bradley

1,3-thiazolidin-4-one acetamides are formed. The proposed mechanism involves initial nucleophilic attack by the sulfur atom on the thiourea onto the maleic anhydride to give the intermediate 64, this intermediate can then cyclise via the more nucleophilic N-methyl nitrogen by two different pathways. Path (a) would give the thiazolidinone 63, whereas path (b) leads to the thiazinone 65, which is not observed. The structures were confirmed by X-ray data <01H(55)1283>.

o

§

\ 61

62

63

O

HoL_s b

o~~N~ 0 a N~~] b 64

J

,X

J 65

a

63

The 1,3-dipolar cycloaddition reaction of azomethine ylides with thioketones has been used to prepare 1,3-thiazolidines. The metallated azomethine ylides 67 were generated in situ by treating c~-amino acid ester imines 66 with lithium bromide and DBU. The ylides were then treated with highly reactive thioketones such as thiobenzophenone or fluorene-9-thione, to afford 1,3-thiazolidine derivatives 68 (main isomer) and 69 (minor isomer) in good yield and in diastereoisomeric ratios of between 2:1 and 4:1 <01H(55)691>.

211

Five-Membered Ring Systems." With N & S (Se) Atoms

AN

R'

H LiBr, DBU H CQeMe " ~ Ar

Ar

R' §

/OMe

R~ R

M"~--- 0

66

67

R2

R2

4-3-s Ar"

H

R'

4

C02Me

H

s R' ~

C02Me

69

68

A general procedure for the solution phase synthesis of amino-l,3-thiazoles has been described. It is based on the condensation of amidines 70 or thiouronium salts 71, with isothiocyanates 72, affording amidinothioureas 73 and thiouriedothioureas 74. Subsequent treatment with ot-bromoketones 75 led to the S-alkylated intermediates 76 and 77 which yielded 1,3-thiazoles of types 78 and 79 via a base catalysed ring closure. This reaction sequence could conveniently be performed in one pot without isolation of the intermediates, allowing for the efficient generation of combinatorial libraries <01T153>.

NH~_ CI-

DMF DBU

NH~

0 R~/[~B

S

a

70; R ~ = Aryl 71' R1 = ArCH2S_

-

H

72

H

73; R 1 = Aryl 74: R 1 = ArCH2S3

R

0

H 76; R~ = Aryl 77" R' = ArCH2S-

'"

75

r

212

D.J. Wilkins and P.A. Bradley 3

R

3

+

0

~

H 76; R1=Aryl 77: R1=ArCH2S-

R'=

Ar-

N

N-4

H

H

78

" ~ = ArCH2S1

~.

H2N~ i

N=N_4 H

79

The first palladium catalysed ring expansion reactions of 2-vinylthiiranes with carbodiimides or ketenimines to give thiazolidine derivatives has been described. Treatment of the 2-vinylthiirane (80) with the carbodiimide 81 using 5 tool% Pd2(dba)3.CHC13 and 10 mol% dppp afforded the lhiazoline 82 in 97% yield. Reaction with ketenimines 83 under similar conditions gave the thiazolidine 84. When this method was repeated using (R)-BINAP instead of dppp, thiazolidines were prepared in optically active form with enantiomeric excesses of up to 78% <01JOC3502>. C!

CI----~N~N~Cl

S 80

81

N

~

83

82

~C02Et CI

C02Et 84

The mechanism is thought to involve initial formation of a n-allyl palladium complex 85 generated by oxidative addition of 2-vinylthiiranes to palladium (0) species; further reaction of this complex with the carbodiimide gives 86. Nucleophilic addition to the n-allyl moiety gives the product <01JOC3502>.

Five-Membered Ring Systems." With N & S (Se) Atoms

213

2

R-~..~N/R

3

86

85

3

R--N~Nx 2

,,R

,

R

The synthesis of natural products incorporating a thiazole ring, e.g., Epothilones continues to attract a lot of interest. The synthesis of 15-aza Epothilones has been described <01JOC4369>. A total synthesis of Epithilone A <01EJO1701> and Epithilone B <01MI2261> have also been reported.

5.5.3

THIADIAZOLES

5.5.3.1 1,2,3-Thiadiazoles The most common, convenient and versatile preparation of the 1,2,3-thiadiazole ring system is undoubtedly the Hurd-Mori reaction. This was again widely reported in the literature during 2001 e.g., <01MI173, 01JOC4045 and 01SL557>. A versatile synthesis of a series of novel 4-substituted 1,2,3-thiadiazoles 88 not easily obtained by other methods was described by Filippone et al. The final step in the preparation of 88 involved Hurd-Mori cyclisation of or-substituted hydrazones 87 using thionyl chloride at room temperature. Compounds of type 88 were attractive targets due to their potential use in medicinal and agricultural chemistry <01SL557>.

214

D.,I. Wilkms and P.A. Bradley

2 4 R R |

H

0 0./~-~0 R1

0 , , ~ 0 R1

0

SOCL~ / a

R 3 0 ~

R"4

H/~L-S .N

0

88

87

R~ = Me, Et; R2= H, Ph, Me, iPr, CO 2Et; 1=13= Me, Et, Bn R4= CO2Me , co2gn, CO2Et, CO2tBU

Treatment of the 4-benzotriazol-1-yl-5-substituted 1,2,3-thiadiazole system 89 with a series of O- and S-nucleophiles gave novel 5-substituted 1,2,3-thiadiazoles 91 in variable yields (11-76%). The reactions were proposed to proceed via a diazoethanethione intermediate 90 which thcn underwent nucleophilic displacement of the benzotriazole moiety, followed by ring closure <01JOC4045>. H

R N\S"P"'Bt 89

R

R'

"-

S 90

Nail'--

1

N\S/~"'X 91

X=OorS

5.5.3.2

1,2,4-Thiadiazoles

Searching the 2001 literature revealed very fcw interesting references for the 1,2,4thiadiazole ring system. The authors considered that none of the work described within these references warranted inclusion in this chapter.

5.5.3.3

1,2,5-Thiadiazoles

Trithiazyl trichloride (92) has proved to be a very versatile reagent for the preparation of the 1,2,5-thiadiazole ring system. One-pot reaction of 92 converts primary and secondary enamines, enamides and 1,2,3-triazoles into 1,2,5-thiadiazoles in good to moderate yields <01JCS(P1)662>. 92 reacts as a 1,2-bis-electrophile, adding an N-S unit across C=C-N. Firstly, rcaction of 92 with a series of stable primary enamines 93 gave moderate yields (28-62%) of the 1,2,5-thiadiazole 94 with electron-withdrawing groups in the 3-position <01JCS(P1)662>.

215

Five-Membered Ring Systems." With N & S (Se) Atoms

CI I

N.-S..N

Me

H

CI S"N~S'cI

H2N

X

92

rt/16 h

Me ~

N'-s-'N

93

94

X = CN, C02Me, C02Et,-C02CH2C6H4NO2(P) The optimum yield of the chloropropyl 1,2,5-thiadiazole 97 was produced by treatment of the enamino-ester 95 with trithiazyl trichloride (92) in boiling CC14. It was postulated that the reaction proceeded via the thiadiazolium salt 96 which could be then 'dealkylated' by chloride ion to give 97 <01JCS(P1)662>. ^

H

CO2Et

CO2Et

_.1)

S/

CI-

95

..

CO2Et

CI

96

97

Reaction of trithiazyl trichloride (92) with enamidcs 98 provided a new route to aryl-l,2,5-thiadiazoles 100. Thc reaction prcsumably proceed via the Nacylthiadiazolium salts 99 which were too scnsitive to be isolated <01JCS(P1)662>. R H

NHAc

._

CO2Et N.

-

98

"S/N\NHAc

99

CI ~

R ~

CO2Et N

\S

/N

1 O0

R = H (53%); Ph (38%) Finally, condensation of trithiazyl trichloride (92) with 1,2,3-triazoles 101 with electron-withdrawing substitucnts gave 1,2,5-thiadiazolcs 102. Although the scope of this reaction is limited, it does provide an attractive route to thiadiazoles with electron-withdrawing substituents <01JCS(P1)662>.

R~__/X N.>N/NH 101

R.~~X

92

~

N\ /N S 102

X = electron withdrawing group

216

D.J. Wilkins and P.A. Bradley

K i m et al. reported a preparation of a series of 3-aryl-l,2,5-thiadiazole-4carboxamides 104 by reaction of 5-amino-3-arylisoxazoles 103 with tetrasulfur tetranitride antimony(V)chloride (S4N4.SbCIs) in toluene at 100 ~ Yields were moderate (27-57%) and allowed access to novel thiadiazole analogues <01H(55)75>.

O

. ~ o , N Ar H2N

103

_

S4N4.SbCIs

PhMe. 100~

=

H2N--~_ j A r II il N,, ,,N S 104

A new and practical method for the reduction of 2,1,3-benzothiadiazole to 1,2benzenediamines with magnesium and MeOH was described. The method is unique in that it only worked with MeOH. No reduction was observed when EtOH was used as solvent. Sensitive functional groups such as bromo, chloro, cyano and ester were well tolerated under these conditions, giving excellent yields (75-97%) of the 1,2benzenediamine <01TL2277>.

5.5.3.4 1,3,4-Thiadiazoles Reaction of 5-substituted 2-acylamino-l,3,4-thiadiazoles 105 with 1.5 equivalents of base and more than 4 equivalents of alkyl bromide gave 3-alkylated products 106 regiospecifically and in excellent yield. No 2-position amide-nitrogen (exo products) alkylated products were observed <01H(55)579>. 3

N--N

O

,.Zs N.z

R3Br/ Base

105

N--N

,,R

O

106

Yields 72-99% The bis[1,2]dithiolo[1,4]thiazine ketothione 107 has been shown to react with a series of N-arylbenzohydrazonoyl chlorides 108 in the presence of Et3N to give 1,3,4thiadiazoles 109. The authors suggested a rational mechanism for the formation of 109, which involved both a cycloaddition and sulfur extrusion process <01JOC5766>.

217

Five-Membered Ring Systems." With N & S (Se) Atoms

O S

""1

S

S.j~,.S.J~S, 9

S

Ar I~.CI +

107

O

N

[,,/ ArN--

S

1_

,, NH t Ar

S~-'S

108

109

Yields: 35-95%

The spiro-l,3,4-thiadiazoline 110 loses N2 at -45 ~ to give the short-lived adamantanethione S-methylide dipole 111. Interception of 111 by various acidic reagents has led to further fuctionalisation of the adamantane ring system, giving thio derivatives <01T145>. H

H

•

-N2

H

H

H 110

111

Perhaps the most useful characteristic of these thiocarbonyl ylides is their ability to participate in 1,3-cycloaddition reactions. Huisgen et al. reported that the diphenyl1,3,4-thiadiazole 112 underwent loss of N2 at -45 ~ to give the ylide 113. The nucleophilic dipole of 113 was then shown to undergo cycloadditions with electrophilic carbon-carbon double and triple bonds <01HCA981>.

N=N Ph

S 112

-45 ~,.. -N2

S+ Ph 113 I DMAD

MeO2~CO2Me

D--E

Ph

D----E

p

S

218

D.J. Wilkins and P.A. Bradley

In a subsequent communication, Huisgen also described the preparation of the thiocarbonyl ylides (114" R = H and Me) and their cycloaddition reactions with tetracyanoethylene (TCNE) <01HCA1805>.

-Ws

R= H, Me

R 114

5.5.4

SELENAZOLES AND SELENADIAZOLES

The preparation of selenazoles by the cyclocondensation of primary selenoamides and alkynyl(phenyl)iodonium salts has been reported. The reaction was found to be general and applicable to alkylethnyl(phenyl)iodonium salts and phenylethynyl(phenyl)iodonium salts. Several arylselenoamides containing various substituents such as chloro, methyl, methoxy and dimethylamino groups underwent successful conversion to the corresponding selenazole. The proposed mechanism involves an initial addition reaction to give the adduct 115 which undergoes an unusual polyhetero Claisen rearrangement to give 116. 116 then eliminates iodobenzene to generate the carbene 117 which then cycloaromatises to the selenazole 118 <01JHC503>.

I

R NH2

TsO

/! X

Ar/~Se

NH Ar

H N

Ar

R

I

Se'~ \ Ph

I\ Ph

Ph 115

R Ar

Se 118

H N

H Se

C: 117

Se

R C~ + I\

Ph

116

Selenopenams have been synthesized via free radical homolytic substitution of aryl or alkyl radicals at the selenium atom. Refluxing the Barton ester 119; R = Me in benzene gave the selenocycle 120; R = Me in low yield. Alternatively, if 119, R = H, is irradiated (250W, tungsten lamp) the selenopenam 120; R = H is produced in moderate yield.

Five-Membered Ring System,v: With N & S (Se) Atoms

R

] 0

.

C02Et 0

.

.

.

'n

0

S

219

~.

C02Et

120

119

A second approach to this type of compound starts from the benzylselenoamide 121 which was cyclised to the chloroazctidinone 122 using potassium hydride. Treatment of 122 with sodium iodide did not give the expected iodo derivative but the ring closed selenopenem 123 in moderate yield <01TL4737>.

CI 0

CI o~N~/~Ph

~ Se~...Ph

122

121

Nal

0

Se

123

Selenazolone derivatives 126 have been prepared by the reaction of primary aromatic selenoamides 124 with haloacyl halides 125.1,3-Selenazol-4-ones were the only products obtained, the isomeric 1,3-seleno-5-ones were not observed as determined by 77Se-13C coupling constants. The formation of 126 is explained by initial amide bond formation followed by ring closure. When aliphatic selenoamides were used as substrates only decomposition products were obtained <01S731>.

0 Se R~..NH2 + 124

0 Ci/~....~jCl 125

--

NS~ e' R-~ 126

The reaction of 1,2-diaza-l,3-butadienes with selenoureas and selenobenzamides to give selenazoline derivatives has been reported. An interesting difference between the regioselectivity in the reaction of selenobenzamides and selenoureas is observed. Selenoureas 128, after initial addition to the terminal carbon of the heterodiene moiety 127 to give the intermediate 129, then ring closes onto the carboxylate group to give

220

D.J. Wilkins and P.A. Bradley

the selenazolinone 130. Selenobenzamides 131 undergo a similar addition to give the intermediate 132 but then ring closes onto the hydrazone moiety to give the selenazoline 133 <01SL144>.

~0

Se

2

H2N.~N R /~1R2 8

N/'Jq~R' 127

Se

~

O

H2N'~Ph131 O

HN-'/'::~Se ~N,, ~ R R

H

Se'.~~NH Ph 132

129

\ N,~Se 2~N

R

"R~

130

0 /

H \

N.~Se Ph 133

Five-Membered Ring Systems." With N & S (Se) Atoms

5.5.5

221

REFERENCES

B. Zhu and J. S. Panek, Eur. J. Org. Chem., 2001, 1701. M. W. Notzel, T. Labahn, M. Es-Sayed and A. de Meijere, Eur. J. Org. Chem., 2001, 3025. Y. C. Kong, K. Kim and Y. J. Park, Heterocycles, 2001, 55, 75. 01H(55)75 N. S. Cho, H. Y. Hwang, J. G. Kim and II-H-Suh, Heterocycles, 2001, 55, 579. 01H(55)579 A. Gebert, A. Linden and H. Heimgartner, Heterocycles, 2001, 55, 691. 01H(55)691 H-G. Hahn, K. D. Nam and H. Mah, Heterocycles, 2001, 55, 1283. 01H(55)1283 R. Huisgen, X. Li, H. Giera and E. Langhals, Heir. Chim. Acta, 2001, 84, 981. 01HCA981 R. Huisgen, G. Mloston and E. Langhals, Helv. Chim. Acta, 2001, 84, 1805. 01HCA 1805 C. W. Rees and T. Y. Yue, J. Chem. Soc., Perkin Trans 1, 2001, 662. 01JCS(P1)662 01JCS(P 1) 1072 R. Leardini, H. McNab, M. Minozzi and D. Nanni, J. Chem. Soc., Perkm Trans 1, 2001, 1072. 01JCS(P1)1079 T. Creed, R. Leardini, H. McNab, D. Nanni, I. S. Nicoison and D. Reed, J. Chem. Soc., Perkin Trans 1, 2001, 1079. 01JCS(P1)I304 J. Guillard, C. Lamazzi, O. Meth-Cohn, C. W. Rees, A. P. White and D. J. Williams, J. Chem. Soc., Perkin Trans. 1, 2001, 1304. P-F. Zhang and Z-C. Chen, J. Heterocvcl. Chem., 2001, 38, 503. 01JHC503 C. Larksarp, O. Sellier and H. Alper, ,L Org. Chem., 2001, 3502. 01JOC3502 A. R. Katritzky, D. O. Tymoshenko and G. N. Nikonov, J. Org. Chem., 2001, 66, 01JOC4045 4045. S. J. Stachel, C. B. Lee, M. Spassova, M. D. Chappell, W. G. Bornmann, S. J. 01JOC4369 Danishefsky, T-C. Chou and Y. Guan, J. Org. Chem., 2001, 66, 4369. C. W. Rees, T. Torroba, S. Barriga, P. Fuertes, C. F. Marcos, D. Miguel and O. A. 01JOC5766 Rakitin, J. Org. Chem., 2001, 66, 5766. H. Emtenas, L. Alderin and F. Aimqvist, J. Org. Chem., 2001, 66, 6756. 01JOC6756 D. Baba, H. Ishii, S. Higashiya, K. Fujisawa and T. Fuchigami, J. Org. Chem., 2001, 01JOC7020 66, 7020. Y. Y. Morzherin, T. V. Giukhareva, V. S. Mokrushin, A. V. Tkachev and V. A. 01MI173 Bakulev, Heterocyclic Commun., 2001, 7, 173. H. J. Martin, P. Pojarliev, H. Kahlig and J. Mulzer, Chem. Eur. J., 2001, 7, 2261. 01MI2261 M. Soledad. C. Pedras and I. L. Zaharia, Org. Lett., 2001, 3, 1213. 01OL1213 J. Jensen, N. Skaerbaek and P. Vedso, Synthesis, 2001, 128. 01S128 P-F. Zhang and Z-C. Chen, Synthesis, 2001, 358. 01S358 M. Koketsu, Y. Takenaka and H. Ishihara, Synthesis, 2001, 731. 01S731 D. Dopp, P. Lauterfield, M. Schneider, G. Henkel, Y. Abed el Sayed, Issac, I. 01S1228 Elghamry, Synthesis, 2001, 1228. X. Fontrodona, S. Diaz, A. Linden and J. M. Villalgordo, Synthesis, 2001, 2021. 01S2021 O. A. Attanasi, P. Filippone, B. Guidi, F. R. Perrulli and S. Santeusanio, Synlett, 01SL144 2001, 144. O. A. Attanasi, L. De. Crescentini, P. Filippone and F. Mantellini, Synlett, 2001, 557. 01SL557 G. Mloston and R. Huisgen, Tetrahedron, 2001, 57, 145. 01T145 T. Masquelin and D. Obrecht, Tetrahedron, 2001, 57, 153. 01T153 V. S. Berseneva, Y. Y. Morzherin, W. Dehaen, I. Luyten and V. A. Bakulev, 01T2179 Tetrahedron, 2001, 57, 2179. F. Clerici, M. L. Gelmi, E. Pini and M. Valle, Tetrahedron, 2001, 57, 5455. 01T5455 X. Fernandez, R. Fellous, L. Lizzani-Cuvelier, M. Loiseau and E. Dunach, 01TL1519 Tetrahedron Lett., 2001, 42, 1519. R. Zhao, S. Gove, J. E. Sundeen and B-C. Chen, Tetrahedron Lett., 2001, 42, 2101. 01TL2101 M. Prashad, Y. Liu and O. Repic, Tetrahedron Lett., 2001, 42, 2277. 01TL2277 M. W. Carland, R. L. Martin and C. H. Schiesser, Tetrahedron Lett., 2001, 42, 4737. 01TL4737 01EJO1701 01EJO3025

222

Chapter 5.6 Five-Membered Ring Systems: With O & S (Se, Te) Atoms

R. Alan Aitken* and Stephen J. Costello

University of St. Andrews, UK [email protected]

5.6.1

1,3-DIOXOLES AND DIOXOLANES

Reaction of epoxides 1 with CO2 to give dioxolanones 2 may be catalysed either by mixed alkali metal/manganese halides <00USP6160130> or alkali metal/lead/indium halides <00USP6156909> and the use of ionic liquids for this reaction has also been described <01NJC639>. Methods for the preparation of dioxolanes 3 <01JAP151768, 01JAP158782> and 4 <01JAP199977> have been patented and an improved method for the synthesis of vinylene carbonate 5 has been described <01EUP1101762>. Methylenedioxolanones such as 6 may be prepared from 3-chlorolactic acid <01JOU704> and transfer hydrogenation of :Jtosyloxyacetophenone 7 using a chiral ruthenium catalyst and formic acid as hydrogen source unexpectedly gives 8 in 94% e.e. <01TA1801>. Full details of a study of anodic fluorination of dioxolanones 9 which is solvent dependent giving mainly 10 in DME but mainly 11 in CH2C12 have appeared <01T9067> and the further fluorination of compound 11 has also been studied <00JAP344763>. The use of the enzyme oxynitrilase to catalyse synthesis of cyanohydrins such as 12 has been examined <01T2213>.

R2"~O

"T%o XO--J,x.,/OCORR" XO--~ R2/~O

1

2

R" ~O~

o Ph~'/'OTs

6

7

3

4

= ph-~ O

MeMe~

8

0

( 5

O "TIOH CN

12

O==~oOLsAr = O:=~~~:~SAr+O==~oO~F 9

10

11

Photochemical addition of dioxolanyl radicals to _,~-unsamrated ketones gives the monoprotected 1,4-dione derivatives 13 <01T10319> and the platinum catalysed domino

223

Five-Membered Ring Systems: With 0 & S (Se, Te) Atoms

reaction of 14 with phenols to give the dioxolanone 15 involves the unusual elimination and re-incorporation of CO2 <0lAG(E)616>. Treatment of 1,2-diols with 1,2di(phenylsulfonyl)ethene gives the dioxolanes 16 thus providing a new protecting group for carbohydrate chemistry <01S286>. Cycloreversion of the anions derived from trans fused dioxolanes such as 17 with loss of PhCO2- has been examined as a method of generating Ecycloalkenes <00S 1756>. 0

0

O'~OMe ArOH . =-

O[,, [I 3 ~ RO~ 1,.><,,.,.,.......~/R

O-"[l'-o

OAr

R~ O 13

14

PhSO2

O~"R

16

15

ph---~O"]'F~'S O"~.....~

ph__~O--~__OH MEITO"~OSiMe3 O

17

18

19

New methods for hydrolysis of 2,2-dimethyl-l,3-dioxolanes include ceric ammonium nitrate and oxalic acid in acetonitrile <01SL535> and a polymer-supported dicyanoketene acetal <01SL1311>. Oxidative cleavage of 2-phenyl-l,3-dioxolane using O2 and an Nhydroxyphthalimide / Co(OAc)2 catalyst gives the hydroxyester 18 <01TLA955> while treatment of 2,2-diethyl-1,3-dioxolane with Et2N-SiMe3 and MeI gives the silyloxyethyl enol ether 19 <01 CL740>. Asymmetric Lewis acid mediated enantioselective ring opening of m e s o 1,3-dioxolanes has been examined as a method for desymmetrisation of m e s o 1,2-diols <01SL61 > and MeLi and MezCuLi are reported to give opposite stereoselectivity in their conjugate addition to 20 <00TA3849>. A bornanol derived chiral auxiliary has been evaluated in the alkylation of 21 but d.e.s are poor <01SC805>. The chiral dioxolanone alcohols 22 have proved to be useful synthetic intermediates <01TA1015> and Wittig reaction of dioxolane 23 is the key step in a synthesis of the butyrolactone 24 <01TL531>. Reaction of terpenoid Grignard reagents with dioxolane 25 provides a route to enantiomerically pure terpene triols <01H(54)585> and nitrone 26 has been used for asymmetric 1,3-dipolar cycloaddition <00JOC7000>. Me

Me Me

Me~M~~Me

0

0

p 20

But....J 22

C02Et

.--R

OH

21

R

_Ph ~

0 24 -0

0

.Ph

Me , +_..~Me

H O~/~.,,e I~ v' Me Me 25

26

The application of TADDOLs 27 in asymmetric synthesis has been the subject of a major review <0lAG(E)92> and developments in this area have continued with reports of catalysis

224

R.A. Aitken and SJ. Costello

using polymer supported TADDOLs <01OL2551> and TADDOL crown ethers <01S647>. Synthesis of the related unsymmetrical diols 28 has also been described <01MI489>. Dioxolane-containing ligands have also been effective in transition metal catalysed reactions and examples include the diphosphite 29 <01MIP21580> and a sugar acetonide-derived phosphite which has been used for rhodium catalysed hydrosilylation of ketones in up to 50% e.e. <01TA633>. The mechanism of the rhodium catalysed reaction of 30 to give 31 has been examined using deuterium labelling <01TL6187> and rhodium catalysed reaction of 32 with aromatic aldehydes and Me3SiC1 gives unexpected products which can be explained by the interrnediacy of the bicyclic oxonium ylide 33 <01CC1086>.

R O''-A~/'~ArO H Me o~A~AroH R~O'~I~.'AO H M e ~ o ' ~ O H 27

~

-.4/ ~

28

CO2Me ~..O ~ o.P(OAr)2 Ar =

29

O"P(OAr)2 -CO2Me

o/--~o .o. 30

Me Me

31

32

33

New applications of compounds in this section include the use of simple 1,3-dioxolan-4ones as electrolyte solvents for batteries <01MIP38319>, use of ketals of pyruvic acid 34 as "dietary supplements" <01USP6177576>, evaluation of the four diastereomers of 35 as muscarinic acetylcholine antagonists <01BMCL247> and use of dioxolanone-containing compounds such as 36, which act as squalene and cholesterol synthetase inhibitors, for treatment of hypercholesterolaemia <01JAP187789>. o

o

Me Me

34

X = OH, O-M +, OR', NR'2 Ph" ~C)H.~NMe 2 Me 35

o

MeSO2..N..~O ~----0 H 36

225

Five-Membered Ring Systems." With 0 & S (Se, Te) Atoms

5.6.2

1,3-DITHIOLES AND DITHIOLANES

The preparation and cleavage of 1,3-dithiolanes has been reviewed <00RCR947>. New catalysts for the reaction of aldehydes and ketones with ethane-l,2-dithiol to form dithiolanes include iodine in THF <01TL4425> and iodine supported on neutral alumina <01 CL794> while selective reaction of aldehydes in the presence of ketones is possible using either indium trichloride <01TL359> or "trichloroisocyanuric acid" (1,3,5trichlorohexahydro-1,3,5-triazine-2,4,6-trione) <01SL1641 >. An improved synthesis of 2-trimethylsilyl-l,3-dithiolane has been reported <01TIA557> and reaction of the disodium salt 37 with cithcr PhCHC12 or CH2CI 2 has been used to obtain the corresponding benzoditelluroles 38 <00MIl127>. Preparation of dithiolethiones 39 has been reported <01OL1941> and the two step conversion of alkynes R~C-CR 2 into either dithiolones 40 or dithiolethiones 41 is possible by palladium catalysed addition of Pr%Si-S-S-SiPr~3 followed by treatment with F- and either PhSCOC1 or CSC12 <01T5739>. A method for synthesis of 2-amino-l,3-dithiolium salts has been described <01SC1271> and treatment of vinylthiiranes 42 with X=C=S and a palladium catalyst affords the dithiolanes 43 <01JOC3502>. The cyclobutenedione dithioacctals 44 have been prepared and are found to undergo ready electrocyclic ring-opening <01S1076>. Reaction of alkenyldithiolanes 45 with Bu2CuLi or BuLl and an electrophile E + followed by nickcl catalysed reaction with R3MgI gives alkene products 46 <01SL977>. Both 1,3-dithiolane-2-thione and 1,3-dithiole2-thione react with N-phenyltriazolinedione with loss of sulfur to give the zwitterionic adducts 47 <01H(55)155>. Treatment of the diol 48 with perchloric acid results in a novel rearrangement to give the aldehyde 49 <01CC369>. A polymeric dithiole 50 has been used to prepare stabilised gold nanoparticles <01 CC613>. R1

e-Na +

"S

37

38

"S 42

O

47

R2

43

"0

48

Ar

41X=S

45

OH 49

S

40 X = O

R1/~"~"~ ~'S R2

44

-

R

39

E

RI,,~~

R2

46

O

? 50

A major review covering recent developments in tetrathiafulvalene (TTF) chemistry has appeared <01AG(E)1373>. The application of time-dependent density-function theory explains the electronic spectra of TTF and derivatives better than previous semi-empirical methods <01T7883>. It has been found that, contrary to previous assumptions, the radical cation of tetrakis(methylthio)TTF does not undergo dimerisation at room temperature but exists as a paramagnetic monomer <01CC2736>. The first wholly q-TF charge transfer complex 51 has been prepared and its X-ray structure determined <01CC2722>. The preparation of 52 and 53 has been described <01MI51> and theoretical methods have been used to account for the selective deprotection of only the left hand cyanoethyl group in 54

226

R.A. Aitken and SJ. Costello

<01NJC769>. Copper complexes of the type (55)2"CUCI4 have been prepared <01JMAC385>. Other new simple TTF compounds include the TTF pyridinium salts 56 <01EJO73> and 57 <01TL1571> and TI'F-bound acetylacetones such as 58 <01TL3189>. The effect of different factors on the rearrangement of 1,4-dithiins to give TITs and alkylidenedithioles has been discussed <01TL875>.

HO2C

RS~s

,-c S

S--/SR

,Ls

SI-~CO2H

RS.

S

51

0

2 0

MeSaS

Me@Me

S-"-'~S

Me'~s~

$

Me/-"S

- - N U+ e ~ ~

St%Me I r,~-.~NMe

55

Me'~s~s ~'~s Me/ ~S

S '~

.S-

54

52 R = Me

53R=Et

S

56

MeS~fs

S--~~

MeSIS~SJ 57

S~\Me 58

-I-

The wide range of new ring-fused TTF type donors prepared and studied includes 59 <00CR(C)387>, 60 <00NJC1418>, 61 <00AM983>, 62 <01CL86>, 63 <00JMAC2063> and the four compounds 64 <01JMAC1026>. Other new selenium-containing donors include 65 <01S1614>, five compounds of type 66 <01H(54)225>, and 67 which forms a superconducting complex with Aul 2- <01AG(E)1122>.

59

60

62 X : O , S

Se 65

61

63

64 •

Se

Y=S, Se

Se-~se 66 X, Y, Z = S, Se

67

Several chiral TTF analogues and examples bearing functional groups have been described including 68 <01SL1476>, 69 and 70 <01JCS(P1)407>, 71 <01MIP32645>, 72 <01T5015> and the cis and trans isomers of 73 <01TL5729>. A series of butylthioTTF oligomers have been prepared <01EJO2983> and 74 forms a 1:1 charge transfer salt with tetrafluoroTCNQ <01NJC834>. The well known donor BEDT-TTF 75 forms an unusual conducting salt of formula (75)2+ FsS-CHF-CF2SO~- <01JMAC2008> and a ternary complex of 75, chromium oxalate and 18-crown-6 is the first charge transfer complex found to contain proton channels <01CC1462>.

227

Five-Membered Ring Systems." With 0 & S (Se, Te) A toms

"eTsTs)~sT~

Me,'"~S/ -"S

S"- ~ 0 /

HO--~/fS'~S ~o~

,S--z'S"~/--OH ~_sAS>~S~s_J~-o.

68

69

Me " ~ S T S~=~sTS~x,/~ OH PhT S T s ~ = = = ~ s T S ~ --OH Me~XS/ -'S S~S...-/ ~--OH ~-S/-"S S~s._../ ~--OH 70

MeO S/T- -,S MEOW. ~,,"'-- s

71

,S...,/S..>.....~OMe E t ' / S ~ j s S-- ~S S~/ S/h=~S~sI~OMe EtL S ~ S ~ S ~ S ~ S L 72

s) s

73

There has also been continuing interest in extended T]"F analogues and examples of this type include 76 <01TL4191>, the azulene systems 77 <01H(54)377>, redox-active dendralenes such as 78 <00CEJ1955> and the heterocycle linked compounds 79 and 80 <01ZN(B)297>, 81 <01CL514> and 82 <01JAP48881>.

F

S

S 74

S

svs

,._s

,,

75

R

N

79

Se_~ S e

=s ~ ~; ~ s~_~ ~o Y

.l

s=

~oJ

More complex extended derivatives include acetylenic compounds such as 83 <01CC1848> and a variety of systems based on the anthracene structure 84 <01CEJ973, 01EJO749, 00JOC9092, 01T725>. The [4+1] cycloaddition of diisocyanides with otthionothioamides has also been used to construct extended T I T derivatives <01EJO655>. A variety of new donor-acceptor systems have been examined including 85 <01JMAC374>, fulvene compounds such as 86 <01OL2329>, compound 87 <01JMAC1772> and compounds with a TTF covalently .joined to a trinitrofluorene <01OL1431>, a p-nitrostyryl group <01EJO1927> or a tetracyanoanthraquinodimethane <01JOC4517>. TI'F compounds have again played a prominent role in the development of supramolecular chemistry with reports on 'l'TF-containing rotaxanes <01T947>, host-guest complexes <01JOC3559>, "molecular shuttles" <01TL4223>, cyclophanes <01TLl143>, macrocycles <01JOC713, 01JOC3313>, crown ethers <00CEJ1947, 01CEJ447, 00JOC8269, 01EJO933>, porphyrins <00AG(E)2497> and dendrimers containing up to 96 TTF units <00S1695, 0lAG(E)224>.

228

R.A. Aitken and SJ. Costello

Further studies on compounds with TTF attached to C60 in various ways have also appeared <01TL3447, 01TL3717>.

R S ~ _

C02Me I ~ CO2Me R S

eO C' 'S Me02(~

83

R CN MeOWs

S ~S~%

NO2

)-=(

84

I.~S.,.]

MeO/~c N S"~I"S /

85

R SR

R=H, ---SIR3,-~---~---C6H4-N(C12H25)2

I

S

i, s 02N

NO2 NO2 NO2

86

87 Finally in this section, salts of compound 88 lacking the fully unsaturated qq'F structure have been reported to be organic superconductors <01JA4174> and their magnetic properties have been described <01CC2538>.

5.6.3

1,3-OXATHIOLES AND OXATHIOLANES

The use of LiBF4 in acetonitrile as a catalyst allows selective reaction of aldehydes with 2-mercaptoethanol to form 1,3-oxathiolanes while acyclic ketones remain unreacted <01SL238> and breakdown of 1,3-oxathiolanes to the corresponding carbonyl compounds may be achieved using Amberlyst 15 and glyoxylic acid under solvent-free conditions <01SL1251>. Reaction of 2-styryl-l,3-oxathiolanes 89 with TIC14 and a styrene derivative ArC(RX)=CHR 2 followed by KOH affords the dihydrothiins 90 <01CC2284>. The stereoselectivity of the reaction of the 2-anion of benzoxathiole S-oxide 91 with various electrophiles has been examined <01T10365>.

/---S

S-~JS S---~ 88

Me O~ 89

MeS . ~ Ph

9O

r 91

O

229

Five-Membered Ring Systems." With 0 & S (Se, Te) A toms

5.6.4

1,2-DIOXOLANES

A review of recent advances in the chemistry of cyclic peroxides contains a good deal of information on 1,2-dioxolanes <01MI601 >.

5.6.5

1,2-DITHIOLES AND D I T H I O L A N E S

The bicylic compounds 92 may be prepared by treating either the ylide Ph3P=CAr 2 or the thione Ar2C=S with sulfur in boiling xylene in the presence of maleic anhydride to trap the intermediate thioketone S-sulfide <00H(53)2753>. Treatment of malonates 93 with P2S5 and sulfur in xylene in the presence of catalytic 2-mercaptobenzothiazole and ZnO affords the 1,2-dithiole-3-thiones 94 <00S1749>. Further advances in the chemistry of the bis(1,2dithiolo)thiazine systems 95 include formation of the N-unsubstituted compounds (R = H, X = O/S) by deprotection of (R = CH2CH2COzH) with sulfuric acid <00JCS(P1)3421> and synthesis of the sulfonylimines (R = Et, X = NSO2Ar) <01JCS(P1)2409>. Decomposition of the bicyclic dithiolodithioles 96 to give a variety of heterocumulenes has been examined using both flash vacuum pyrolysis and EI mass spectrometric conditions <01JCS(P2)356>. Treatment of 1,5-dithiocane with triflic anhydride gives the bicyclic salt 97 and upon reaction of this with aqueous sodium bicarbonate the monosulfoxide of the starting compound is produced <00MI1415>. A review of such transannular interactions between chalcogens also includes information on systems such as 98 and 99 <00JOM(611)l16>. Reaction of 1,2-dithiole-3-thione 100 with N-phenyltriazolinedione gives the stable zwitterionic product 101 <01H(55)155>.

s, o Ar" ,~,r

O

x

)fs

b 93

92

x

s

S

S

94

95

X s ArN

+ S s

+

X_R 1

20Tr

~

97 Me

lO0

-R 2

~.~Z.R~

98 99 X, Y, Z = S and/or Se and/or Te

96 X = S, NAt Me

101

0

1

Me Me

ph/ "CI 102

230

5.6.6

R.A. Aitken and SJ. Costello

1,2-OXATHIOLES

2,1-Benzoxaselenoles such as 102 have been prepared in a multi-step sequence starting from o-phenylselenobenzaldehyde <01HAC317>.

5.6.7

T H R E E OR FOUR H E T E R O A T O M S

The competition between dehydrogenation and formation of 1,2,4-trioxolanes upon ozonolysis of 1,4-cyclohexadienes and their mono epoxides has been examined <01EJO1899>. The first 1,2,4-trithiolium dication 104 has been formed by treatment of the trithietane salt 103 with liquid SO2 and characterised by NMR and an X-ray structure <01CC1370>. Flash vacuum pyrolysis of 1,2,4-trithiolane coupled with matrix isolation allows the generation and detection of thioformaldehyde S-sulfide, CH2=S+-S -, which is found to be in equilibrium with dithiirane <0lAG(E)393>. The synthesis, structure and oneelectron redox reactions of a variety of mixed benzo-l,2,3-trichalcogenoles 105 have been reported <00JOM(611)136>. Oxidation of the tetrathiolane 106 with dimethyldioxirane proceeds by way of the disulfoxide 107 and extrusion of $20 to afford the dithiirane S-oxide 108 <00JOM(611)127>. Compound 107 may be considered the first genuine 1,2-disulfoxide and its X-ray structure is presented. +

* S\

Ph-Xs~S

"

X

2 SbF 6-

SbF 6-

103

R

104

Ss

106

U

s-s+

"S

105 X, Y, Z = S/Se

S.s ,s 107

O

108

0

Five-Membered Ring Systems: With 0 & S (Se, Te) Atoms

5.6.8

REFERENCES

00AM983 00CEJ1947 00CEJ1955 00CR(C)387 00H(53)2753 00JAP344763 00JCS(P1)3421 00JMAC2063 00JOC7000 00JOC8269 00JOC9092 00JOM(611)116 00JOM(611)127 00JOM(611)136 00MI1127 00MI1415 00NJC1418 00RCR947 00S1695 00S1749 00S1756 00TA3849 00USP6156909 00USP6160130 0lAG(E)92 0lAG(E)224 0lAG(E)393 0lAG(E)616 01AG(E) 1122 01AG(E)1373 0lAG(E)2497 01BMCL247 01CC369 01CC613 01CC1086 01CC1370

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R.A. Aitken and S.I. Costello

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Five-Membered Ring Systems." With 0 & S (Se, Te) A toms 01MI489 01MI601 01MIP21580 01MIP32645 01MIP38319 01NJC639 01NJC769 01NJC834 01OL1431 01OL1941 01OL2329 01OL2551 01S286 01S647 01S1076 01S1614 01SC805 01SC1271 01SL61 01SL238 01SL535 01SL977 01SL1251 01SL1311 01SL1476 01SL1641 01T725 01T947 01T2213 01T5015 01T5739 01T7883 01T9067 01T10319 01T10365 01TA633 01TA1015 01TA1801 01TL359 01TL531 01TL875 01TLl143 01TL1571 01TL3189 01TL3447 01TL3717 01TL4191 01TL4223 01TL4425 01TL4557

233

M. X. Li, Y.-M. Wang and R. R. Chen,Chin. Chem. Lett. 2001, 12,489 [Chem. Abstr. 2001,

135,242166]. K. J. McCullough and M. Nojima, Current Org. Chem. 2001, 6, 601 [Chem. Abstr. 2001, 135, 180714]. K. A. Kreutzer, W. Tam, J. M. Garner and J. R.Boyles, PCT h~t. Appl. WO 21,580 (2001) [Chem. Abstr. 2001,134, 252470]. T. Ozturk, F. Turksoy, J. D. Wallis and T. Uxnit, PCT hit. Appl. WO 32,645 (2001) [Chem. Abstr. 2001,134, 340527]. O. Boese, M. Rieland, D. Seffer and W. Kalbreyer, PCTbzt.Appl. WO 38,319 (2001) [Chem. Abstr. 2001,134, 366866]. J. Peng and Y. Deng, New. J. Chem. 2001, 25,639. S. B. Nielsen and M. B. Nielsen, New. J. Chem. 2(101, 25,769. O. J. Dautel and M. Founnigu6, New. J. Chem. 2001,25,834. D. F. Perepichka, M. R. Bryce, E. J. L. Mclnnes and J. P. Zhao, Org. Lett. 2001,3, 1431. C. Jia, D. Zhang, W. Xu and D. Zhu, Org. Lett. 2001,3, 1941. E. Aqad, P. Leriche, G. Mabon, A. Gorgues and V. Khodorkovsky, Org. Lett. 2001,3, 2329. S. Degni, C.-E. Wil6n and R. Leino, Org. Lett. 2001, 3, 2551. F. Ch6ry, P. Rollin, O. De Lucchi and S. (;o~su, Synthesis 201)1,286. J. Irurre, M. Riera and M. A. Cintora, Synthesis 201)1,647. W. Regenhardt, E. Schaumann and H. W. Moore, Synthesis, 2001 1076. M. Kodani, K. Takimiya, Y. Aso, T. Otsubo, T. Nakayashiki and Y. Misaki, Synthesis 2001, 1614. M. D. Evans and P. T. Kaye, Synth. Conlrnlln. 2001,31,805. M. L. Birsa, Synth. Commun. 2001, 31, 1271. T. Harada, H. Yamanaka and A. Oku, Synlett 2001, 61. J. S. Yadav, B. V. S. Reddv and S. K. Pandcy, S),nlett 2001,238. X. Xiao and D. Bai, Synlet't 2001, 535. C.-C. Chiang and T.-Y. Lah, Synlett 2001, 977. S. P. Chavan, P. Soni and S. K. Kamat, Synlett 2001, 1251. Y. Masaki, T. Yamada and N. Tanaka, Synlett 2001, 1311. T. Konoike, K. Namba, T. Shinada, K. Sakaguchi, G. C. Papavassiliou, K. Murata and Y. Ohfune, Synlett 2001, 1476. H. Firouzabadi, N. Iranpoor and H. H~arkhani, Synlett 2001, 1641. M. A. Herranz, S. Gonz~ilez, I. P6rez and N. Martin, Tetrahedron 2001,57, 725. P. R. Ashton, J. Becher, M. C. T. Fvfe, M. B. Nielsen, J. F.Stoddart, A. J. P. White and D. J. Williams, Tetrahedron 2001,57, 947. P. Bianchi, G. Roda, S. Riva, B. Danieli, A. Zabelinskaja-Mackova and H. Griengl, Tetrahedron 2001, 57, 2213. N. Saygili, R. J. Brown, P. Day, R. Hoelzl, P. Kathi~amanathan, E. R. Mageean, T. Ozturk, M. Pilkington, M. M. B. Qayyum, S. S. Turner, L. Vorwerg and J. D. Wallis, Tetrahedron 2001, 57, 5015. Y. Gareau, M. Tremblay, D. Gauvrcau and I I. Juteau, Tetrahedron 2001, 57, 5739. R. Andreu, J. Garin and J. Orduna, Tetrahedron 2001, 57, 7883. H. Ishii, N. Yamada and T. Fuchigami, Tetrahedron 2001, 57, 9067. R. Mosca, M. Fagnoni, M. Mella and A. Albini, Tetrahedron 2001, 57, 10319. S. Cabiddu, E. Cadoni, S. Melis, G. Gelli, M. G. Cabiddu, C. Faltuoni, S. De Montis and S. lanelli, Tetrahedron 2001, 57, 10365. A. Su~irez, A. Pizzano, I. Fern,'indez and N. Khiar, Tetrahedron AsymmeOy 2001, 12,633. A. Battaglia, G. Barbaro, P. Giorgianni, A. Guerrini and A. Pepe, Tetrahedron Asymmeoy 2001, 12, 1015. D. J. Cross, J. A. Kenny, I. Itouston, L. Campbell, T.Walsgrove and M. Wills, Tetrahedron Asymmeoy 2001, 12, 1801. S. Muthusamy, S. A. Babu and C. Gunanathan, Tetrahedron Lett. 2001, 42,359. G. V. Reddy, V. Sreevani and D. S. Iyengar, Tetrahedron Lett. 2001, 42,531. R. Andreu, J. Garin, J. Orduna and J. M. Royo, Tetrahedron Left. 2001, 42,875. M. R. Bryce, G. Cooke, F. M. A. Duclairoir and V. M. Rotello, Tetrahedron Lett. 2001, 42, 1143. O. P.-T. Levi, J. Y. Becker, A.Ellern and V. Khodorkovsky, Tetrahedron Lett. 2001, 42, 1571. N. Bellec and D. Lorcy, Tetrahedron Lett. 2001, 42, 3189. D. Kreher, S.-G. Liu, M. Cariou, P. Hudhomme, A. Gorgues, M. Mas, J. Veciana and C. Rovira, Tetrahedron Lett. 2001, 42, 3447. S.-G. Liu, D. Kreher, P. t tudhomme, E. Levillain, M. Cariou, J. Delaunay, A. Gorgues, J. Vidal-Garcedo, J. Veciana and C. Rovira, Tetrahedron Lett. 2001, 42, 3717. Y. Yamashita, M. Tomura and K. hnaeda, Tetrahedron Lett. 2001, 42, 4191. M. R. Bryce, G. Cooke, W. Dcvonport, F. M. A. Duclairoir and V. M. Rotello, Tetrahedron Lett. 2001, 42, 4223. S. Samajdar, M. K. Basu, F. F. Becker and B. K. Banik, Tetrahedron Lett. 2001, 42, 4425. A. Degl'Innocenti, A. Capperucci and T. Nocentini, Tetrahedron Lett. 2001, 42, 4557.

234 01TL4955 01TL5729 01TL6187 01USP6177576 01ZN(B)297

R.A. Aitken and S.1. Costello Y. Chen and P. G. Wang, Tetrahedron Lett. 2001, 42, 4955. S. Kimura, S. Hanazato, H. Kurai, T. Mori, Y. Misaki and K. Tanaka, Tetrahedron Lett2001, 42, 5729. J. S. Clark, Y.-S. Wong and R. J. Townsend, Tetrahedron Lett. 2001, 42, 6187. M. J. Arnold, US Pat. 6,177,576 (2001) [Chem. Abstr. 2001, 134, 100876]. G. C. Papavassiliou, Y. Misaki, K. Takahashi, J. Yamada, G. A aMousdis, T. Sharahata and T. Ise, Z. Natulforsch. Teil B 2001, 56,297.

235

Chapter 5.7

Five-Membered Ring Systems: With 0 & N Atoms

Stefano Cicchi, Franca M. Cordero, Donatella Giomi Universitgt di Firenze, Italy donatella, giomi @unifi, it

5.7.1

ISOXAZOLES

The wide range of biological activities (insecticidal, antibacterial, antibiotic, antitumour, antifungal, anti-HIV, etc.) of isoxazoles and isoxazolines has made them popular synthetic targets. Numerous syntheses of isoxazoles and isoxazolines involve [3+2] cycloadditions of nitrile oxides with alkynes and alkenes. 1,3-Dipolar cycloadditions (1,3-DC) of ~cyanocinnamate esters and aryl nitrile oxides, generated in situ by oxidative dehydrogenation of aldoximes, afforded ethyl 3,5-diarylisoxazole-4-carboxylates in 48-71% yields after HCN elimination <01JCR(S)436>. Analogously, dimethyl 3-(9'-anthracenyl)-isoxazole-4,5dicarboxylate was obtained in good yield from anthracene-9-carbonitrile oxide, derived from the corresponding aldoxime, and dimethyl acetylenedicarboxylate (DMAD) <01JHC415>.

Boc N"OH HNv,J~ -~r + 1

|

~.z,~ 1) NaOCI,TEA, CH2CI2(29%) HCI _ O OMe ~.)aq. H(~l,dioxane,r.t. (99%~ H2N'- ~ ~ ' f " " ~ O M e 2

~..

N-O

N

N ,

0

3

0 N

H

N-O

o

Treatment of the aldoxime 1 with sodium hypochlorite and NEt3 in the presence of the terminal alkyne 2 gave rise, after deprotection, to the isoxazole derivative 3, converted to 4 by EDCI coupling with the suitable carboxylic acid. Employing different terminal alkynes and carboxylic acids a novel series of isoxazolylpropionic acid derivatives, proved potent antagonists of the c~413~integrin, was synthesised <01BMC2593>. An efficient two-step protocol for the regioselective assembly of a range of highly substituted isoxazoles arose from 1,3-DC of alkynylboronates 6 with nitrile oxides 5:

236

S. Cicchi, F.M. Cordero and D. Giomi

isoxazoleboronic esters 7 were isolated in satisfactory yields and with excellent levels of regiocontrol (a single regioisomer was obtained when R 2 ~: H). These potentially valuable synthetic intermediates have been shown to give rise efficiently to Suzuki coupling reactions with bromobenzene and allyl bromide affording, respectively, compounds 8 and 9 in excellent yields <01CC1558>. Mes Ph 0

-

R1 5

CI-

10

R2 ~ B

--

/0- / \ L" [ - - -

Ergo,,e,ux R 1 --

R1

0"~ ~ B-O/ ~

PhBr 7

R2 = Me,/

"'OF'R _

dioxane,

Mes,Ph,tBu R2= Me,Bu,Ph 7

N "OH

N-O TEA = THF 12 (90%)

N-O

85 ~

\

m2 r-,-~

N.O~

,

r~ =r'n \ Mes ~"~'/'~ Br

/___.~

N..O.~.L... ph

~

R = Ph, vinyl, 2-thienyl, .. -TMS 13 (80-94%)

Structurally diverse 5-substituted isoxazoles 13 were obtained from a similar two-step procedure involving 1,3-DC of iodoacetylene 11 with 2-pyridyl nitrile oxide, coming from 10, followed by Pd-catalysed reaction of 5-iodoisoxazolylpyridine 12 with an organometallic reagent <01OL4185>. 3-Ethoxy-4-iodo-5-methylisoxazole was also exploited in palladiumcatalysed coupling reactions to afford in good yields the corresponding 4-substituted derivatives <01T2195>, while silyl- or stannylcupration of 4-haloisoxazoles gave rise to silicon or tin 4-metalated derivatives as useful intermediates for further transformations <01S1949>. 5-Perfluoroalkylsubstituted isoxazoles were prepared in satisfactory yields from nitrile oxides and ethyl 3-perfluoroalkyl-3-pyrrolidino acrylates <01T5781>.

Solid-phase synthesis of 3-hydroxymethyl isoxazoles 17 was accomplished in acceptable yields and purity through 1,3-DC of different alkynes 15 to resin bound nitrile oxides, generated from nitro compounds 14 under Mukaiyama conditions. This method is robust enough to be carried out by an automated synthesiser <01TL4951>. A complementary solid-phase 1,3-DC methodology allowed the regioselective preparation

237

Five-Membered Ring Systems: With 0 & N Atoms

of a library of isoxazoles and isoxazole-based amino acids: by anchoring acetylenic compounds I8 on trityl chloride resin and generating the nitrile oxides in situ from suitable carbonyl derivatives 20, structurally different isoxazoles 22 were obtained in satisfactory yields and purity <01JOC6823>. Cyclocondensations of hydroxylamine with 13-diketone equivalent three carbon 1,3difunctionalized units continue to be an important route for the synthesis of isoxazoles. A regioselective method affording directly 3-phenyl-5-substituted isoxazoles 26 employed as starting material ~-benzotriazolyl-ot,13-unsaturated ketones 24, stereoselectively generated in good yields from benzotriazolylacetophenone 23, and the corresponding aldehyde in the presence of piperidine <01JOC6787>.

Bt~~h R'CHO~R'/~----'~ oBt Ph HONH2 ITHF__ I R'Bt~o.~h 23

24

(55-71%)

' -- R'~O"~h

25

26(55-81%)

0 27

TsOH-H20, c6m6

E=C02Et 28(97%) 2) Electrophile29(65-95%)

30

A clean, efficient and economical procedure arose from coupling microwave with solventfree technique: reactions of aromatic aldehydes with phenylnitromethane under microwave irradiation, on basic alumina, afforded excellent yields (90-96%) of 3,5-diphenyl-4arylisoxazoles within 2-3 minutes <01OPP381>. An improved procedure for the lateral lithiation of ethyl 4-acetyl-5-methyl-3-isoxazolyl carboxylate (27) was performed by protecting the acetyl substituent with a 5,5-dimethyl-l,3dioxanyl group. Treatment of 28 with LDA followed by quenching with a variety of electrophiles such as alkyl halides, aldehydes, TMSCI and Me3SnC1 produced 5functionalised 3-isoxazolyl carboxylic acid derivatives 29, as prodrugs for the AMPA glutamate neurotransmitters <01T8039>. Starting from 27, a novel synthesis of the potent glutamate neurotransmitter agonist ( R S ) - A C P A (30) was also described <01TL8415>. Rh2(S-DOSP)4-catalysed decomposition of heteroaryldiazoacetates in the presence of styrene or 1,1-diphenylethylene was easily achieved allowing highly diastereo- and enantioselective cyclopropanation reactions. Isoxazolyldiazoacetate 31 was a very reactive system leading to cyclopropanes 32 in high yields and stereoselectivities <01JOC6595>. Isoxazoles substituted with electron-withdrawing groups at the 4-position undergo electrochemical and yeast-catalysed N-O bond cleavage releasing the enolised dicarbonylimine functionality <01JCS(P l ) 1168>. A new and efficient anionic domino process of 3-aminoisoxazoles with oxaldiimidoyl dichlorides, involving cleavage of the isoxazole ring besides cyclisation reactions, provided a regioselective access to 2,4-dihydro- 1H-imidazo[45-b]quinoxalines 33 <01 EJO2257>. Two-step highly diastereoselective pericyclic homodomino processes, involving hetero Diels-Alder reactions of ethyl vinyl ether on the nitroalkene moiety of 4-nitroisoxazoles 34 and 1,3-DC of the same reagent on the nitronates 35, allowed the direct synthesis of spiro

238

S. Cicchi, F.M. Cordero and D. Giomi

tricyclic nitroso acetals 36 and 37 <01 T4237>. R N-O @ . ~ E 31

N2

Ph

N=O

/ N'-,.~. N

phi,.= R 32 R = H (84%, 93%de, 86%ee) R = Ph (91%, 95%ee) EtO

~_.~___/0Et Ph Oi //~ / N . 0 -

-

~/

CH2CI2 N ' O ~ o E t 40-~C Iq

34

5.7.2

.~

R2

hexane, r.t.

E=CO2Me

o+

,t,r Ar

Ph/~ N-O Rh2(S-DOSP)4 ~ , , , E

33

EtQ

OEt Ph, ~ 0 ~ "- N.O - N ~

Ph / " " O

OEt

% N. 0

+

N ~ O E R 36 (85%) R = C02Me37 (5%) (60%) R = COPh (12%) Iq

35

t

ISOXAZOLINES

Discrimination of diastereotopic groups and faces in intramolecular 1,3-DC of nitrile oxides and N-benzyl nitrones were studied. For example nitrile oxides 38 afforded isoxazolines 39 with complete diastereotopic group selection (dr >99:1) and a high degree of rt-face discrimination (dr from 10:1 to 26:1) <01JOC3834>. Isoxazoline 41 was obtained from racemic thioesters 40 in yields up to 89% and >90% ee by means of a dynamic kinetic resolution catalysed by lipase PS-30 in the presence of phosphate buffer (pH = 9.2), an amine, and a surfactant <01JAl1075>. 0

RO

-~ Wn "OR

O X Y ~ O R

+

X Y"'~~n

38 39a 39b n=I'X=allyl;Y=OR'R=TBS 13 '1 (77%) n = I " X = O R ; Y = a l i y l ; R , R = C M e 2 10"1 (59%) n=O;X=OR;Y=allyl;R,R=CMe 2 26 '1 (59%)

RS

lipase PS-30 ~ / C 0 2 H Triton X-1 O0 J .

OR Ar

(S/R)-40

TEA, H20 ~ buffer, 40 ~

R = Et, n-Pr, n-Bu

Ar (R)-41 >90% ee

The new approach to product isolation by means of 'precipiton-functional protecting group' was applied to the synthesis of some 5-methoxycarbonylisoxazolines. For instance, the soluble A-lsoxazohne 2. 43 was prepared in Et20. The Xz precipiton auxiliary was then isomerised to the (E) form to obtain 44 that showed a very low solubility in hexanes, Et20 and MeOH. All by-products were easily washed away and after methanolysis the isoxazoline 45 was isolated in good yield and high purity <01AG(E)1875>.

239

Five-Membered Ring Systems." With 0 & N Atoms

touc oo o.

tBu

0

Et20

42 XZ =

(88%)

OXz

THF, reflux

43

P-Ph-C6H4~_~__~C6H4CH2

tBu

(84%)

tBu i) washing O / r ~ XEOH ~ N ii) MeOH, TEA ~ "O"1~ THF OMe 45 (90%) /

+

OXE 44

//---C6H4CH2 XE=p_Ph_C6H4___v

A new gram-scale one-pot preparation of enantiomerically pure isoxazoline 2-oxides 47 starting from 2,3-epoxy alcohols 46 was developed. The selectivity of the process was low (dr from 56:44 to 72:28) but the diastereomeric products could be separated by column chromatography. The bis-tert-butyldimethylsilyl N-oxide derivatives could be deoxygenated in very good yields by exposure to hot trimethyl phosphite to obtain the corresponding isoxazolines 48 <01OL727>. OI O

-R3 OH i) BAIB, cat. TEMPO

R2. . . . 46

ii) 02N~co2Et imidazole (62-97%)

-, R~' \).__C02Et OH OH 47

i) TBDMSC!

30--N

RI,,,

ii) P(OMe)3 R2'~;~ "OTBDMS 100 ~ OTBDMS 48

1,3-DC reactions of mesitonitrile oxide and C,N-diphenyl nitrone with the resin-bound chiral N-crotonyl-oxazolidinone 49 in the presence of different amounts of Mg(II) cation were reported. The study showed that the isoxazoline and isoxazolidine adducts can be obtained on solid-phase, but with lower selectivity and yield than the corresponding product synthesised in solution <01T8313>. O

,....~N ~ O

49

Me? ~CO2Et NOH

Et02C,, .0.. Me? "'~__~N

p-i~s 81

Me~

/OCONH2 [.OH

s2

Intramolecular 1,3-DC of the highly functionalised nitrile oxide coming from 50 was used for the construction of the eight-membered ring in the enantioselective synthesis of FR900482 analogue 52. The ethoxycarbonyl group was introduced on the terminus of the olefin in order to control both the regio- and slereochemistry of the cycloaddition reaction <01OL2575>. Analogously the synthetic approach to illudin C, based on the intramolecular nitrile oxide-olefin cycloaddition to afford intermediate 54, proved to be a very effective method to assemble the sesquiterpene tricyclic ring system <0 l OL2611 >. Natural polyketide macrolides epothilones A and B were synthesized via a diastereoselective hydroxyl directed nitrile oxide cycloaddition and a new chemoselective protocol for isoxazoline reduction <01JOC6410, 01JA3611>. In particular, Mg(II) directed 1,3-DC of nitrile oxides with chiral allylic alcohols 56 could be used to generate isoxazolines 57 in a high selective fashion <0lAG(E)2082>, and conjugate A2-isoxazolines, such as 58,

240

S. Cicchi, F.M. Cordero and D. Giomi

were selectively reduced to the corresponding unsaturated 13-hydroxy ketones 59, by sequential treatment with SmI2 and B(OH)3 <01OL1587>.

HO,

N

O-N

"% I

0

chloramine T

MeOH/H20 (72%)

"EtOH, 40 ~ (99%)

2) MsCI, TEA DBU (73%)

53

"

54

illudin C

HO... R2 z,,. .R 4 PrOH N-O ,-,4 ~+ "['YY-------~R'~rl R' CI,.JI,,,R1 R3 OH cMgcBI~ R3" "'R2 OH 55 56 57

N-O R.

i) Sml 2 0 OH THF _ U .I. R3 - ' - - - - ~ R ' / ~ V'Ra ii) B(OH)3 R2

H20

58

59

4-Unsubstituted isoxazolinones 60 were chlorinated and then converted into 1chloroalkynes 61 upon treatment with NaNO2 and FeSO4 in AcOH/H20 <01CC1894>. The nitrous acid mediated cleavage of isoxazolidinones and the intermolecular radical addition of xanthates were used as key steps in the synthesis of alkynes 64 which correspond to the formal adducts of an alkynyl radical to the alkene 62 <01CC1304>.

N-O RJ~"'~O 60

1) TMSCI, Bu4NBr DMSO, THF R-~ CI 61 2)NAN02, Fe2SO 4 (33-50%) H20, AcOH R"

R1 65 M=Cr, W

68

R5

,OMe

Ph

M(CO)5

4 R3

(81-97%)

P

~/ 62

R' ~

M(CO)5

XO I, 66 R"

N~,~R R

63

~

R2 (72-94%)

'

NAN02

~ R

Fe2S04 (20-80%)R

4 R3

'

64

OMe

R2 "O~",~" ~-

67 R1

R/'O '''~ 69 (59%)

Ph 70 (9%)

"" R 71 R = H, Me, Et,/-Pr

A series of stable chromium and tungsten Fischer dienyl carbenes 66 were prepared by 1,3DC of alkenylethynyl carbene complexes 65 with nitrones. Treatment of isoxazolines with isocyanides afforded highly functionalised 2,3-dihydro-1,2-benzisoxazoles 67 in a completely selective fashion and with high yields <01CEJ5318>. 4-Butadienyl-4-isoxazolines, such as 68, underwent thermolysis to afford mainly a dihydroazepine derivative through the formation of an intermediate azomethine ylide <01T4349>. Spiro bis(isoxazoline) ligands 71 were used in the catalytic asymmetric Wackertype cyclisation of alkenyl alcohols <01JA2907>.

241

Five-Membered Ring Systems." With 0 & N Atoms

5.7.3

ISOXAZOLIDINES

Several enantiomerically pure isoxazolidines have been achieved by intra- or intermolecular 1,3-DC reactions of chiral nitrones and used as key intermediates in the syntheses of a variety of natural compounds and their analogues. For example the ethyl ester of the non-proteinogenic amino acid 4-oxopipecolic acid 75 was achieved via 1,3-DC of the chiral nitrone 72 with butenol followed by intramolecular cyclisation and non-reductive opening of the isoxazolidine ring of 73 induced by DABCO in refluxing acetonitrile. The cycloaddition step, that was performed in multigram scale, was not diastereoselective, but the diastereomeric piperidones 74 could be easily separated and transformed into enantiomerically pure amino esters by removal of the chiral auxiliary <01T4995>. The enantioselective synthesis of antimalarial (+)-febrifugine and (+)-isofebrifugine alkaloids was achieved through the 1,3-DC of (S)-5-alkoxy-2,3,4,5-tetrahydropyridine-1oxide 76 with allyl alcohol followed by hydrogenolytic N-O bond fission and suitable elaboration of the product <01OL953>.

CHCO2Et 1)

OH J

A

+

R,~- ---0., 72 2) MsCI, py R*= (R)CH(CH3)Ph O

O

O

DABCO ~ - ~ H2 ~~NI ~ C02E t MeCN Pd(OH)2 t ' ~ "N" "C02Et ------~" R* MsO reflux R* H 73 74 75

C02Et

Ho _ _

i +

O76

HO-.../

~N-o/

....

78

....

o

77

(+)-febrifugine

o

(+)-isofebrifugine

o

_~

180 ~

(70%)

79

1)H2/Pd(OH)2 HO~ H f - O H (56%) C02Me 2) Red-AI - (xx11~l..~ ....OH (85%) (-)-rosrnarinecine

(-)-Rosmarinecine was prepared from L-malic derived pyrrolo[1,2-b]isoxazolidine 78 through a cycloreversion-intramolecular nitrone cycloaddition process followed in sequence by isoxazolidine reductive ring opening and reduction of the lactone and lactam moieties <01OL1367>. Another pyrrolizidine alkaloid, (+)-l-epiaustraline, was synthesized through a tandem intermolecular [4 + 2]/intramolecular [3 + 2] nitroalkene cycloaddition of 80 and the chiral vinyl ether 81. In this process the configuration of four of the five final stereocenters was established with high stereocontrol. A suitable elaboration of the primary adduct 82 gave the nitroso acetal 83, which was transformed into the polyhydroxy-pyrrolizidine under hydrogenolytic conditions <01JOC4276>. A new synthesis of the indolizidine alkaloid (+)-allopumiliotoxin 323B' was achieved through intramolecular 1,3-DC of the (Z)-N-alkenylnitrone 84. The major cycloadduct 85,

242

S. Cicchi, F.M. Cordero and D. Giomi

which showed the correct absolute configuration at C-4 and C-8 stereocenters, arose from the regiochemical preference for incorporation of the newly formed C-C bond in a six-membered ring which places the OTBDMS group in an axial orientation <01CEJ 1845>. R*O~ 81

~.,.~'-si~O~No2 /-Pr" "/-Pr 80

MAPh toluene (49%)

OH 1) RaNi/H2 HO.... 2) HF "

(55%)

Hd

OR' 84

R* = [ ~ r r r , "

~

N

X

88

H(~ I:t OH 83

,,Ph

MAPh = methylaluminum bis(2,6-diphenylphenoxide)

OR'

OR'

OH ~

d,C

85 R = (CH2)3OBz; R'= TBDMS

"OH

TBSO~/

H bH

(+)-all

~wH. , HOH ~ ~ HQ-,I/ -,~ -.,,I,,OH 1) 5% HCI aq. --v

,-, O- .,OR* ,u"N "

TsO

&H: /-Pr-Si-O 82 /.er/

(+)- 1-epiaust ral ine

R -O..

,-, O- .,OR* ,,\ , U - N " ~

:

iliotoxi 323

1)5~176 2) NalO4

.,H O

2) Raney-Ni, H2, 10 bar (70%)

oOu.m

,'OH

HO,~..~ "

3) Raney-Ni, H2, 10 bar (55%)

87

H ....

OH

89

Intramolecular 1,3-DC of sugar-derived nitrones followed by reductive cleavage of the isoxazolidine N-O bond have been used in the synthesis of aminocyclopentitols and anellated carbasugar derivatives <01TL4925, 01TL5769, 01EJO759>. In all the reported examples the polycyclic isoxazolidines were obtained with high or complete diasteroselectivity. New polyhydroxylated quinolizidine and indolizidine derivatives (azasugars) were synthesised by intramolecular cycloaddition of O~-D-glucose derived N-(3-alkenyl)nitrones. The cycloadduct 87 was obtained as a unique diastereoisomer and transformed into 88 and 89 in two- and three-step sequence, respectively <01 CC915>.

O N.,<

Z

Z

i

....

H

N

91 toluene reflux, 36 h (92%)

2) HCI Z ~ C O 2 3) LiOH

=

(-)-90 O~+

H2NOC~..

1) Sml2 =

92

OH

(78%)

H

NH2

-

I

OBn

z: % ~

93

.002 R

CO2R

CO2R ....

H20, 60 ~ 94

(79%)

AcOH, M e O H

95

(98%)

~""J"'~"

O 96

O 97

RR-GPTM

243

Five-Membered Ring Systems." With 0 & N Atoms

Several C-glycosylated amino acids were obtained by 1,3-DC of (-)-menthone-derived chiral nitrone (-)-90 and allyl- or vinyl glycosidcs. For instance the cycloaddition of (-)-90 and 91 occurred with complete diastereo- and regioselectivity to afford the isoxazolidine 92 in 92% yield. The a-amino acid moiety was then obtained by Sm(II) mediated cleavage of the N-O bond followed by N,N-acetal and amide hydrolysis <01OL1375>. The new Gly-Pro turn mimetic (GPTM) 97 and its enantiomer were synthesised by elaboration of the pyrrolo[ 1,2-b]isoxazolidine 95 <01 CC1590>. Some target molecules containing the isoxazolidine ring have been prcparcd for different purposes. For example two different syntheses of racemic cyclopent[c]isoxazolidine 98 demonstrated that 98 is not the corrcct structure of alkaloid pyrinodemin A isolatcd from the marine sponge Aml)himedon sp. <01OLl145, 01TL1639>. New nucleosidc analogs, where the ribose moiety has been replaced by an isoxazolidine ring, such as 99,100 and 101, have been synthesised in order to test their activity as new potential drugs <01TL1777, 01EJO1893, 01T8551>.

H........

H

"-R

"0" 102

~

98

H

W3

o 10 -~" mbar

J~-,~ HO

V/9

~

H3C

HO

99

1 O0 B = Ty, Ad

-R 103

H3C

101 B' = Cytosine, 5-Methylcytosine

ii) NaBH3CN 104

H3 C

AcQH or

NaBH 4, EtOH

105

0

L-'-

Spirofused isoxazolidines were used as precursors of azepine derivatives. In particular, 1,3-DC of cyclic and acyclic nitrones with cyclobutylidenccyclopropane resulted in the regioselective formation of adducts 102 (47-85% yield) which underwent thermal rearrangement with opening of the four member ring to afford spirocyclopropane azepinones 103 (19-32% yield) <01EJO3789>. Spiroisoxazolidincs 104 were transformed into hydroxylated azepanes 105 through a two-step sequcnce (27-98% yicld) <01TL7497>. The intramolecular 1,3-DC of norbornadiene-tcthcred nitrones occurred in moderate to good yields for a variety of substrates and were found to bc highly rcgio- and stereoselective. For example each of the polycyclic isoxazolidines 107 was obtained as a single isomer (1971% yield) <01JOC5113>. Chiral Lewis acid catalysis has been used in the synthesis of optically active isoxazolidines 108 and 5-isoxazolidinones 109 via 13-DC of nitrones with 3alkenoyl-oxazolidin-2-ones <01TL6715> and conjugate addition of N-benzylhydroxylamine to 2-alkenoyl-pyrazolidin-3-ones <01OL4181>, respectively. The asymmetric endo cyclisation reactions of various substituted O-allyl oximes 110, promoted by the enantiomerically pure sclcnyl trit-latc 111, afforded optically active isoxazolidines 112 in high yields (58-93%) and with good diastereoselectivity (up to 93:7). The organoselenium moiety could be then removed by treatment with Ph3SnH in the presence of a catalytic amount of AIBN <01TA3053>.

244

S. Cicchi, F.M. Cordero and D. Giomi

Stereoselection in 1,3-DC reactions of chiral allyl ethers <01EJO1033> and kinetic resolution by means of cycloaddition reaction, including 1,3-DC of nitrones <01EJO2999>, have been reviewed.

iN. 106

O

107

X = OH2, (CH2)2, O, OCH2, CH20

+ ~'EF~RRR1 [ ~ ~ S e

SMe OTf

110 111 R1= H, Me, Et, Ph

R 109 (83-96% ee) R = Me, Ar = p-MeOC6H4 R = Ar = Ph

108 (94-99% ee)

R = H, Me; Ar = Ph, p-MeC6H4, p_MeOC6H4 SMe 1) PhCH2Br _ ~ TEA (65%) ~ is b o.NF H ~ (58-93%) " 2) Ph3SnH (~...,./L.. R1 AIBN (85%) ~ ' ~ H 112 R1 = Ph 113

Ph

5.7.40XAZOLES Multicomponent reactions (MCR) combining three or more reactants together in a single order event offer great possibility for molecular diversity and are becoming a cornerstone of combinatorial chemistry. In this context, a novel three-component reaction of an aldehyde 114, an amine 115, and a suitably functionalised isocyanoacetamide 116 provided a polysubstituted 5-aminooxazole 117 which could be used as chemical platform to generate new scaffolds; reactions with ct,13-unsaturated acyl chlorides afforded pyrrolopyridines 119 through intramolecular Diels-Alder (IMDA) cycloaddition of 118 <01OL877>. Starting from o-amino methyl cinnamate as amine component the domino 3CR/IMDA process gave rise to oxa-bridged tetracyclic tetrahydroquinolines as mixtures of two separable diastereomers where 120 was the predominant one <01CC1684>. A careful choice of starting materials also allowed the synthesis of 5-aminooxazoles 121, easily converted into macrocyclodepsipeptides 122 under acidic conditions <01JA6700>.

0 RICHO + R2NH2 + CN R3 114

CI~%/R4

115 2

MeOH (60-96 ~/o)

NR2 117

R3

4

O~ "-

R "N ~ R 4 . J_ . , , , .

A toluene '

R"

R,R = (CH2)20(CH2)2

NR2

116 IOI

NHR2

"r~, I~~NR2 R3 118

NR2 Me02C~

-NHR2 R 2 - - N O ~ O ~ " RI~"-'~N f'~ R3 119 (55-68%)

"N" "R 1 H 120 (40-94%)

R3

245

Five-Membered Ring Systems." With 0 & N Atoms

Methods for the synthesis of oxazole-containing cyclic peptides have been developed and the total synthesis of the hexapeptide dendroamidc A 124 has been accomplished in satisfactory yield employing D-Ala-oxazole 123 as key intermediate <01JOC3459>. Oxazole amino acids were also employed to synthesise new backbone-modified analogues of the insect neuropeptide proctolin containing oxazole rings as amide bonds replacements <01OL3427>.

O

a2"a~Oa

5

llL~)# a1 a2a~)~--~- 0 OR tOluen# " ~ O O O~ or MeCN H~ ~N,,J...R5

N[]@NR4

,

121

O,

~ 125

osN

....

HN--o

0

122 (40-88%) O=(

/--NHCbz

NH2.HOAc ~ . ~ 0

Cbz-Gly

~"~/'-'N H

_=

IBCF = ~"<.i--N NMM, DMF H (66%)

126

N ~ ...... Boc Ph Ph~oNo~

CbzHNo~ N

N

1. PPh3, TEA C2Cl6 2. CICO2Et,TEA DMAP (53%)

127

CO2Et

128

CO2Et

CbzHN~ ~ J

Ph

0 ~.~ /NHBoc N

0" x~N .L_~-/

__+

"~N o.

N ..CI &

0

(78%) 129

C02Et

130

C02Et

131

1. PBu3, DMF Ph TEA 2. Ph(CH2)2CH% LHMDS ~N~N_~ O AgNCO R ~ N . ~ 0 Tf2O R~N_~ 3. Bu3SnCHCH2 R/I~" X CH2N2~ THF = -78 ~ r.t. ".,,'~T* Pd(PPh3)4,DMF R = CH2CI 135 (75%) 132 133 134 (48-90%) Reactions of acyl cyanides with aldchydcs and HCI afforded 4-chlorooxazole derivatives, potential building blocks for natural product synthesis <01S745>. A new modification of the Chan rearrangement proved to bc the basis of a versatile and direct strategy for iterative polyoxazole synthesis suitably exploited for the preparation of the indole-bisoxazole fragment of the complex natural product diazonamide A. Indolyloxazole

246

S. Cicchi, F.M. Cordero and D. Giomi

127, coming from amino ketone 125 through cyclodehydration of the amide 126 according to Wipf's procedure, was converted to the imide 128; the key LDA-mediated Chan reaction afforded amino ketone 129 which was transformed into the indole-bisoxazole 130 in > 90% enantiomeric purity <01OL1261>. Syntheses of the macrocyclic aromatic core of diazonamide A were also reported via a Dieckmann-type cyclisation <01OL2451> or a novel Sm(II)-based hetero pinacol rnacrocyclisation cascade reaction <0lAG(E)4705>; nevertheless the total synthesis of nominal diazonamides performed by Harran and coworkers established a different revised structure 131 for natural (-)-diazonamide A <0 lAG(E)4765, 0 lAG(E)4770, 01AG(E)4906>. A facile assembly of 2,4-orthogonally-functionalised oxazoles as useful bidirectional linchpins was achieved by treatment with diazomethane of acyl isocyanates, generated in situ from acyl halides 132: oxazolones 133 were converted to the oxazole triflates 134, useful intermediates for further synthetic elaborations as highlighted by the synthesis of 135 via Wittig and Stille reactions <01SL1739>. This linchpin tactic was used in the stereocontrolled total synthesis of the potent cytostatic agent (+)-phorboxazole A <01JA 10942>. A synthetic procedure based on the aza-Wittig reaction of o~-azidoacetyl ferrocene 136 with diacyl chlorides and triphenylphosphine was developed to prepare new oxazoloferrocene ligands 137-140 containing two oxazole rings in the conjugation chain. Studying the complexation properties of such compounds, the new heterotrimetallic system 141 was obtained in excellent yield by treatment of 140 with Pd2(dba)3 and DMAD <01T6765>.

RFe-~~

RFe

0 i i 138 (50%) ~ , ~ ~ ~ , , , , , , / N ~ Fe

RF

RF 137 (45%)

RFe

RFe

139(51%)

o. o

136

140(79~176 ~ 141 (98%)

E ~ E <~ E

E

E=CO2Me

Reactions of aromatic or heteroaromatic aldehydes 144 with a ROMPgel Tosmic reagent 143, available from the ring opening metathesis of 142, allowed the preparation of a small library of oxazoles 145 in high yields and with minimal purification <01OL271>. The application of the Moody's procedure to the solid-phase synthesis involved as key step the rhodium-catalysed decomposition of resin-bound o~-diazo-13-ketoesters 146 in the presence of primary amides to afford N-H insertion products 147; cyclodehydration gave 148, further elaborated during cleavage from the resin towards substituted oxazoles 149 <01OL2173>. Thermal IMDA reaction of acetylene-tethered oxazoles was a key step in the synthesis of tropoloisoquinoline alkaloids <01JA3242>, while the analogous conversion of suitable oxazole-olefins to cyclopenta[c]pyridines was promoted by catalytic amounts of Cu(II) triflate <01H(55)823>. DA cycloadditions of methyleneoxazolones 150 with dienes afforded spirooxazolones 151 which were regio- and diastereoselectively converted to carbocyclic

247

Five-Membered Ring Systems: With 0 & N Atoms

serine analogues 152 <01T6429>; moreover, 1,3-DC with phenyldiazomethane and HPLC resolution of a racemic precursor provided, after ring-opening of the primary spiro adduct, enantiomerically pure aminodiphenylcyclopropanecarboxylic acids 153 on a multigram scale <01T6019>.

o,:o

.....

CHO

.....

HN.c o

O'N

70o

142

143

o~S--~NC

145 (68-90%)

v

O

O

i~O

R1CONH2

O

O

Rh2Oct4= (~'-O 146

N2

toluene60 ~

O.~,NH 147 R1

R2 = CH2OH'CO2R'CONR2

O CI2"PPh3 ~)--O

R

TEA 0H2012

~ R1

---~0 ~'-R 1

148

149 (23-57%)

Ph

PhCHN2 O O ~ R~,,. O .~N//~.~ P h EtAICI2 = Ph NHBoc R1 CH2CI2 ~''OCO2Et 153 R1= Ph 150 R1= OCO2Et R = H,Me 151 (35-47%)

5.7.5

/'~N

R~'J'""~*CO2H , ' " " ~ .... OH 152

OXAZOLINES

Some new methods have been developed to synthesise oxazolines. Using the chiral nitridomanganese complex 154 (stoichiometric) in the presence of acyl chlorides, it was possible to obtain oxazolines from alkenes. The reaction afforded enantioenriched oxazolines in good yield and selectivity mainly using (E) olefins <01TL9019>.

H

'H

O

R'N-N~ ~

E,OJt, N

155

I 0104

157

159 (38%)

156

+ 0104-

158

OH

"

160 (61%)

Proazaphosphatrane (155), a strong nonionic base, catalysed the reaction of ethyl isocyanoacetate with aromatic and aliphatic aldehydes to afford trans-oxazoline 156 with

248

S. Cicchi, F.M. Cordero and D. Giomi

high selectivity <01TL6263>. Irradiation of perchlorate salts of N-methylpyridinium (157) and pyrylium (158) in wet acetonitrile afforded oxazolines 159 and 160 in good yields <01JA10425>. O

.OBn O O HN" NH2OBn ~N/[~'N ~ . . ~

O

161

AIMe2CI

BF3"Et20"

O~H ~ ~N)IXN N .....j 0

TEA (60~176 4 t ~ P h

163

r

~Ph

162 (> 95%, 80%de)

1) BzCI 2) BF3.Et20

O/~,~,1011

3) TEA, MeOH, (82%)

Me

164

Ph

An asymmetric synthesis of 5-isopropyloxazoline-4-carboxylic acid methyl ester (164) was performed through the ring expansion on N-acylaziridine (163). The synthesis started from 4-methylpentenoyl imidate 161 that underwent 1,4-addition of O-benzylhydroxylamine. Ring closure, activation of the aziridine and final ring expansion catalysed by BF3.EtzO afforded the desired compound <01TA563>. A highly stereoselective synthesis of ~[3-unsaturated oxazolines was described. The lithiated oxazolines 165 (R = H, C1) afforded (E) or (Z) olefines, depending on the R group, through nucleophilic addition to nitrone 166 <0 ITA9183>. a |

165 Cu(CN)Li2 R1 \

-OR//2 169

~166 NO2

R2 THF, -78 gC

167 RI,,R /NO2

-~ 170 (67-96%)

The same reagent 165 (R = H, Me) was used to produce oxazoline cyanocuprate 169 with CuCN.2LiC1. This cyanocuprate gave 1,4-addition to a large number of nitroalkenes in good yields <01TL7375>. Oxazolinyloxiranes 171, obtained by a Darzens reaction of compound 165 (R = C1) with tolualdehyde, could be deprotonated and alkylated stereospecifically <01JOC3049>. Uncatalysed reaction of stannylated oxazoline 174 with 2-bromonaphthoquinone 173 afforded, with a remarkable regioselectivity, compound 175, which was then reduced to naphthol 176 <01JOC7530>. Several new oxazolinyl ligands were synthesised and applied in asymmetric synthesis. Paracyclophane ligand 177 was applied to the enantioselective alkylation of aldehydes with diethylzinc <01 TA529>. Simple phosphinite 178 afforded high enantiomeric excess in Pd-catalysed alkylation of allylic acetates <01TL5553>, and enantioselective hydrogenation of alkenes <01AG(E)4445 >.

249

Five-Membered Ring Systems: With 0 & NAtoms

171

~ ~

1~ 173

a

~/I~N

(30-43%)

~ ' R ,,R2 '

.~,,~"~""j~. ~p Ph f"

.

R~

R'

172

~ 175

~i 0/~___ R " -"N

,,I

(57-64'~)

~ _ :/~__.R

R1.~'" 178 0.. PPh2

177

~

PPh2 179

I~'

OH 176

R=tBu; CPh3; anthracen-9-yl; 2-ethoxy-naphthalen-1-yl; 3,4,5-trialkyl-pheny; ada mantan-1-yl-

Phosphine oxazoline ligands 179 were synthesiscd through three different methodologies and employed in Pd-catalysed allylic substitution reactions <01JOC206>. Oxazolylphenols 180 were prepared from the corresponding aromatic derivatives (carboxylic acids or nitriles) and 13-aminoalcohols <01EJO3067>. Through an analogous reaction, ligands of general formula 181 were synthesised and used to produce Rh-complexes <01JA5818>, as well as tridentate ligand 182 <01OM4144>. Several immobilized oxazolidinyl ligands have been proposed and used for producing Cu complexes as catalysts for asymmetric Diels-Aldcr reactions <01TA2931, 01OL2493, 01SL709>, for cyclopropanation of olcfins <01CC1936, 01JOC8893>, or for the enantioselective Mukaiyama reaction <0lAG(E)2519> and Pd-catalysed allylic substitution <01TA1475>. R ~. t0u

2

R

180

N/'R1

181

I_3..

R2 N~ ~ )n R. ~ _R

0

N

O" "N R ~J~R R2

1::{2 -L.R1

R=H 184n= 1 R= Me

183n=0

Many examples of known ligands or ligands modified without affecting the oxazoline moiety were used to afford complexes for catalysis in Diels-Alder reaction <01TL7617, 01TL6231>, [2+2] cycloaddition <01OL2125>, Heck reaction <01TL365>, radical-mediated coniugate addition <01OL299>, oxidative coupling of titanium enolate <01OL2993>, cyclopropanation in ionic liquids <01TL1891>, Mukaiyama-Michael reactions <01JA4480>,

250

S. Cicchi, F.M. Cordero and D. Giomi

addition of allenylsilane <01JA2095>, 1,3-DC cycloaddition <01TL6715>, phenyl transfer from organozinc to aldehydes <01JOM157>. Finally, tripodal ligands 183 and 184, based on oxazolinyl nuclei, were used as catalysts for enantioselective Michael addition <01TIA175> and for sugar molecular recognition <01 TL5049>.

5.7.6

OXAZOLIDINES

New syntheses and new reactivity were described both for oxazolidines and oxazolidinones. Diaryl substituted 1,3-oxazolidines were synthesised by copper catalysed addition of acetone and ethyl diazoacetate to imines. The reaction, tested on a large number of examples, afforded oxazolidines 187 (cis/trans mixtures) along with variable amounts of aminoalcohols 188 (5-19%) <01TL3487>. Reductive lithiation of a diastereoisomeric mixture (dr 92: 8) of the bicyclic 2-phenyl-l,3oxazolidine 189 followed by alkylation allowed the highly diastereoselective synthesis of N(o~-alkyl-substituted)benzyl-2-hydroxymethylpiperidines 190 and 191 <01TL 129>.

H

'~-N'

Ar2 N2CHCO2Et E t O 2 C ~ Arl 186

Ar1

185

- Cu cat. = acetone,r.t.

N

Ph Li LiO~_.NL THF

~.y )

"---"

. ooc 4h

iPh

189

.L

O',,~.N'-Ar2 / \ 187 (93-53%)

Et O 2 C ~ Arl HO HN-..Ar2 188(5-19%) R

RX

190/191

HO~vN.~ h~O~~_jN R - A Ph C6H13 >95 " <5 PhCH2 93 "7 C4H9 >95" <5

Ph::OHR2 190

P0,C

N/ -~C6H12 OHCi 80 oC 194 24h (72%)

+

192

\

Me0H = 65 ~ 24h (75%)

191

N/

OH(~

193

R1

,,, 195

yield

50% 74% 56%

R3

O

Ph

Ar 196

An oxidative ring opening of oxazolidine 192, catalysed by PdlC, afforded two different formamides, 193 and 194, depending on the solvent <01JCS(P1)949>. Chiral oxazolidine-substituted alkenes 195, beating a urea functionality, were shown to be suitable substrates for highly stereoselective epoxidation and singlet-oxygen ene reactions <01JA7228, 01OL79>. The presence of an oxazolidine ring, derived from ephedrine, at the ortho position of a N,N-dimethylbenzamide 196 induced atropisomerism and allowed the synthesis of a new amido-phosphine ligand <01TA695>. Several interesting syntheses of oxazolidinones have been published. The most outstanding is a Rh-catalysed C-H insertion reaction for the oxidative conversion of carbamates to oxazolidinones <0lAG(E)598>. The reaction allowed the synthesis (generally 74-85% yield) of structurally diversified oxazolidinones (e.g. 198) starting from easily available carbamates (e.g. 197). The reaction is stereoselective (retention of configuration)

251

F i v e - M e m b e r e d Ring Systems." With 0 & N Atoms

supporting the hypothesis of direct insertion of a nitrene or nitrenoid intermediate into methine or methylene centre.

0 197

Phl(OAc)2- ,,~198-3 MgO

0

CONH2 OH 199 n=1,2

H ~0 0

MeCN, H20 (96-100%)

O0

Complementary to this synthetic method is the synthesis of 2-oxazolidinones via Hofmann rearrangement mediated by bis(trifluoroacetoxy)iodobenzene. This procedure afforded, starting from 13-hydroxyamides 199, oxazolidinones 200 in almost quantitative yield <01TL1449>. Palladium catalysed carbonylation of 13-aminoalcohols is a well known procedure for the synthesis of oxazolidinones but the existing method presents several drawbacks, especially for primary amines. The electrochemical carbonylation of amino alcohols catalysed by Pd(II) resulted a mild and efficient methodology <01TL3451>. A onepot reaction, in water, of benzoylhydrazines 202, chloroacetaldehyde (201), tetraallyltin (203) and catalytic Sc(OTf)3 afforded N-amido-4-allyloxazolin-2-ones 204 in good yield <01SLl140>. A solid-phase synthesis of oxazolidinones 206 has been performed in which the final ring closure reaction also detaches the desired compound from the resin. The carbamate 205 is especially susceptible to base-promoted cycloelimination <01 EJO2965>.

0 + Cl'v"~ H 201

O~..r.

1) Sc(OTf)3 Q H~ R NH + (....~.~4S n H20/THF(1/9) / ~ N - N % , O ~ NH2 2) NaHCO3

202

R1 s~CI 1)HO.v~OH 07 "0

2) R2NCO

203

~

(63-75 %)

204

R1 0 t [ ~ o / / S ~ ) . . v ~ 0/[~...N..R2 205

H

R1 = Me, Et, t-Bu, CH2N3; R2 = Ts, Ph, p-Ac-Ph, p-Br-Ph, p-NO2-Ph

O

DBN

o/L[..N.. R2 R1

206 (6-43%)

Enantiopure 4,5-dialkoxy-2-oxazolidinones 207 and 208, obtained by resolution of the racemate, are a new class of synthons for use in the preparation of optically pure c~-amino aldehydes and s-amino acids <01OL897>. Similar chemistry was performed with 2oxazolidinones 209 and 210 <01EJO2425>. Simple reflux of chiral 5-iodomethyl-2-oxazolidinones 211 in methanol with indium metal (2 equivalents) afforded chiral allylic amines 212 in excellent yields (80-96%) <01TL6385>. The use of Pd(dba)3 with posphine ligands as DPPF or Xantphos catalysed the N-arylation of 2-oxazolidinones 213 <01OL2539, 01TL3681>. Treatment of N-enoyl oxazolidine-2-thiones 215 with Lewis acids induced a sulfur migration with high asymmetric induction to afford 13-mercapto imides 216 <01JA5602>.

252

S. Cicchi, F.M. Cordero and D. Giomi

ROk/___ .,0 Me

X..~{OMe

O,~.NH

R1

O\ /NH

0

0

207R=Me 208R=Bn

209 R = C I 210 R = H

R2

HN,,[1'/O

ArBr

R~

~ base, toluene (45-95%)

213 0

0

R2

R 2 / ~ N"~,s In ~-}--~ ~=,-- I MeOH R 211 S

0

214 0

R

212

0

LIJ

ArtN~I]'O

R2~NH R~.~ / H

2) H20 (56-95%)

215

0

SH

LIJ R

R1 = H, PhCH2, i-PrCH2, Me' R2 = H, Me

216

50->96 d.e.

The chemistry of 4-isopropyl-3-(methylthiomethyl)-5,5-diphenyloxazolidin-2-one 217 was developed for the synthesis of 1,2-diols, 2-aminoalcohols, 2-hydroxy esters, butenolides and 4-hydroxy-2-alkenoate <01JOC3059>. Titanium tetrachloride and (-)-sparteine with N-acyloxazolidinones and oxazolidinethiones were used in asymmetric aldol additions <01JOC894>. Oxazolidinone protected 2-amino-2-deoxy-D-glucose derivative 218 was a versatile intermediate for stereoselective oligosaccharide synthesis and the formation of a-linked glycosides. The oxazolidine moiety was an effective 'non participating' group for the stereoselective synthesis of or-linked glycosides and can be produced on a large scale <01JA9461>. The oxazolidinyl ring was used as a scaffold for ring closing metathesis reactions to afford perhydroazepines, tropanes, aminocyclitol, as 219, or oxazolidinyl azacycles 220, useful for the synthesis of hydroxypyrrolizidines <01JOC1413, 01TIA633, 01TL4079>. Ketone 221 catalysed the asymmetric epoxydation of substituted olefines with high yields and enantioselectivity. The oxazolidinone ring altered the electronic properties of the carbon atom at the ot position of the carbonyl group and increased the stability of 221 against an undesired Bayer-Villiger reaction <01OL715>. The oligomer 222 of enantiopure 4-carboxybenzyl-5methyl oxazolidin-2-one folded into ordered structure. The monomer can be considered a member of a new class of pseudoprolines <01JOC727>. 0

OAc

S. j

oA.J

Ac

HO SPh

o

0 219

0 /!

Bu~ N

221

BnQ Ph

OH

218

0

OH

0 .....

IL N

0 ....

JL N

222

0 ....

JL N

220

0 ....

JL-oBn

253

Five-Membered Ring Systems: With 0 & N Atoms

R

0 Y RI..N-~

0

"~--0

BrCH2CI BuLi --

R1,,N .

223 ~n

Li

0 H§ R 1 H N , , v , ' ~ CI ~ :

224 Bn

-

~n225

0

226 C02 a

A new procedure for the synthesis of oxazolidin-5-ones under basic conditions used CH212 and K2CO3 in acetonitrile <01SL1326>. A very mild method for the alcoholysis of benzyloxycarbonyl-5-oxazolidinones, using alcohols and hydrogen carbonate, was reported <01TL5319>. N-protected 5-oxazolidinones 223 reacted with chloromethylithium to afford intermediates 224 which were hydrolysed to o~-aminoalkyl ot'-chloromethyl ketones 225 <01TL5883>. Gallagher and co-workers published a detailed study on the behaviour of [3-1actam derivatives 226 as precursor for N-acylazomethine ylides. The behaviour of this class of compounds were different from the previously known N-aikyl azomethine ylides <01JCS (P 1) 1897>.

5.7.7

OXADIAZOLES

1,2,4-Oxadiazoles were described as good bioisosters of ester or amide in a variety of biological models. In general, these compounds were obtained via cyclocondensation processes of O-acyl-oxyamidines. In particular, TBAF was found to be a mild and efficient catalyst for the straightforward synthesis of 3,5-disubstituted-1,2,4-oxadiazoles 229 from acyl derivatives 228. A variety of acylators (acyl chlorides, anhydrides) and nitriles were used to expand the scope of substituents around the oxadiazole ring <01TL1441>. A library of 24 1,2,4-oxadiazoles 229 was synthesised with good yields and purities employing carboxylic acids for the conversion of oxyamidines 227 to acyl derivatives 228 in the presence of TBTU as activating agent <01TL1495>. 2,2-Dimethoxy-l,3,4-oxadiazoline 230 was exploited as source of dimethoxycarbene: its thermolysis at 110 ~ in benzene in the presence of adamantanethione (231) afforded the thiirane 232 in 92% yield <01OL2455>. The synthesis and the electroluminescence applications of Tb(III)-complexes with oxadiazole-functionalised I]-diketonate ligands 233 were reported <01JA6179>.

HO-N R2OOX

H2N I~R I

227

~

O " H2NI ~ R 1 (50-98%)

228

R2

229

S

R

Meo OMe

N/~O 230'

31

co o.,,oo-c

O 232

233

R):=O

254

5.7.8

S. Cicchi, F.M. Cordero and D. Giomi

REFERENCES

0lAG(E)598 01AG(E)1875 0lAG(E)2082 0lAG(E)2519 0lAG(E)4445 0lAG(E)4705

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Five-Membered Ring Systems." With 0 & N Atoms

255

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256 01T4349 01T4995 01T5781 01T6019 01T6429 01T6765 01T8313 01T8551 01TA529 01TA563 01TA695 01TA1475 01TA2931 01TA3053 01TA9183 01TL129 01TL365 01TL1441 01TL1449 01TL1495 01TL1639 01TL1777 01TL1891 01TL3451 01TL3487 01TL3681 01TL4079 01TL4175 01TL4633 01TIA925 01TL4951 01TL5049 01TL5319 01TL5553 01TL5769 01TL5883 01TL6231 01TL6263 01TI~385 01TI~715 01TL7375 01TL7497 01TL7617 01TL8039 01TL8415 01TL9019

S. Cicchi, F.M. Cordero and D. Giomi

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257

Chapter 6.1 Six-Membered Ring Systems: Pyridines and Benzo Derivatives

D. Scott Coffey, Stanley P. Kolis and Scott A. May

Lilly Research Laboratories, Indianapolis, IN, USA coffey_scott@ lilly.com, kolis_stanley@ lilly.corn and may_scott_a@ lilly.com

6.1.1 INTRODUCTION Pyridines and their benzo-derivatives have played an important role in the synthesis of biologically active synthetic and natural substances. As a result, the construction of this molecular architecture has attracted the attention of a diverse array of synthetic methodologies. Notably, transition metal catalysis, radical reactions and cycloaddition chemistry-based methods have been developed for the construction of this important ring system. Detailed herein is a summary of the methods developed for the synthesis of pyridines, quinolines, isoquinolines and piperidines that were disclosed in the literature in 2001. Rather than survey all existing methods for the construction of these compound classes, this review will serve as a supplement and update to the review published last year in this volume. 6.1.2 PYRIDINES

6.1.2.1 Preparation of Pyridines The synthesis of pyridines and pyridine derivatives has been an active area of research over the past year. One main emphasis in the area of pyridine synthesis in 2001 has been the application of cycloaddition strategies. Itoh and co-workers report two related Ru-mediated [2+2+2] cycloaddition reactions to afford annulated pyridines (Scheme 1). For example, treatment of substituted 1,6-heptadiyne 1 with an isocyanate (2) in the presence of catalytic

MeO2CJ ~ MeO2C" \

+

1

MeO2C~/ ~ MeO2C" \ 1

i'" ~

Cp*Ru(cod)CI(5 mol%) CICH2CH2CI,83~ (93%)

2

+

CO2Etl Cp*Ru(cod)Cl(2 mol%) III CICH2CH2CI160"~ N (83%) 4

Scheme 1

MeO2C" k,..---~-~./%O

258

D.S. Coffey, S.P. Kolis and S.A. May

Cp*Ru(cod)C1 affords pyridone 3 in excellent yield <01OL2117>. The authors have also shown that the same strategy can be applied with 1,6-heptadiynes and electron-deficient nitriles (J.+4--->5) <01CCl102>. Other metal-mediated processes include the formation of pyridines through the palladium-catalyzed cyclization of olefinic ketone O-pentafluorobenzoyloximes <01CL526>. Annulated pyridines have also been synthesized via a [4+2] cycloaddition strategy involving oxazole 6, which is made via a multicomponent coupling reaction in a single step <01OL877>. Acylation of 6 with a ot,13-unsaturated acyl chloride is the first step in a domino reaction where an intramolecular Diels-Alder reaction is followed by a retro-Michael reaction (7--~8). n-C6aj

..~QR--H n-C6H'3

o

toluene, reflux

JI - ./~.... N ~ N/~-~Ok.___/C,....~.jCO2Et Bn

0

R1

Yield

.OMe ~_/---~OMe ~-'/-~ i

3

N

R1 N'

0

Bn

t 7

n_C6H13 .R1

65%

N Bn

58%

I

.~ OH

0 2Et

Cycloaddition reactions involving 1- and 2-azadienes represent a powerful approach to pyridine scaffolds. Ishar and co-workers have reported a facile route to Hantzch-type 1,4dihydropyridines (11) though the [4+2] cycloaddition of 1-azadiene 9 and an assortment of allenic esters including 10 <01OL2133>. In similar fashion, Palacios has reported the [4+2] cycloaddition reaction between 2-azadienes and enamines to afford substituted 2,3dihydropyridines in modest to good yields <01EJOC2115>. Oxidation methods for conversion of Hantszch 1,4-dihydropyridines into pyridines is also well known. Recently, Lu reported a mild iron-mediated process to accomplish this transformation in good yield <01SC2625>.

Ph~N

-Ph 9

\C02Et 10

Benzene reflux 96%

Ph ~~.C02Et I

Ph 11

Amination of dienals and dienones followed by 6n-azaelectrocyclization is a well known method for construction of substituted pyridines. Scientists at Dow AgroSciences published a

259

Six-Membered Rings." Pyridines and Benzo derivatives

practical synthesis of 2-alkyl-4-aminopyridines via the amination of acetylenic ketones (12-->14) <01TL1847>. Using a similar condensation-electrocyclization strategy, Beccalli and co-workers report an approach to pyrido[2,3-b]indoles <01T4787>. Notably, Katsumura has recently reported on the rate acceleration of 6~-azaelectrocyclization based on substitution of 1-azatrienes at the C4 and C6 positions <01JOC3099>.

/~ ~ OMe 12

~O

NH3,100 psi 100~

NH~

14h

(86%) 14

13 Furo- or thieno[2,3-b]pyridine derivatives have been synthesized via Smiles rearrangement followed by cyclization <01H741>. Under basic conditions, a facile rearrangement takes place (15-->16) which then leads to cyclization to form the pyridine ring portion of the desired compound 17 in modest yield.

N~~

/S CN

KOtBU

CN

(52%)

15

16

"

NH2 17

Other notable methods for pyridine formation include microwave-mediated addition of malononitrile to bisarylidinecycloalkanones <01JCR(M)268>. 2,3-Disubstituted pyridines have also been synthesized via 3-halo-l-azaallylic anions in good yields <01JOC53>.

6.1.2.2 Reactions of Pyridines The use of substituted pyridines in organic synthesis has broad application. The pyridine functionality has been associated with many biologically active agents <01JA9908>, but has also served as a handle to perform other chemistry via chelation to the nitrogen <01OL941>. One area of keen interest this past year has been the use of the pyridyl nitrogen as a directing influence on chemical reactions (Scheme 2). Yoshida and co-workers have reported the use of 2-trimethylsilylpyridine (18) as a hydroxymethylating equivalent <01JOC3970>. Simple deprotonation of 18 followed by the addition of an electrophile affords intermediate 20 in excellent yields. Tamao-Fleming oxidation of silicon reveals the latent hydroxy functionality (20-->21). On the heels of this work, Yoshida reported a conceptually similar reaction employing vinylsilanes which serve as acceptors for Grignards (22-->24) <01AC(E)2337>. The resulting anionic intermediate can then be trapped by an appropriate electrophile. The 2silylpyridine directing group is then removed oxidatively.

260

D.S. Coffey, S.P. Kolis and S.A. May

tBuLi I -~~/S f"~ N- -Li I Ph(CH2)3Br ~ "

S

iJ

18

(84%)

19

••1/sN .... Li

22

h

[o] (98%)

HO-C(~2 HO/

i

Si~ Me2

/Si 20

18

ii

~p

21

1.nBuMgBr ~ 2. AllylBr = (93%)

L Si Me2

/

[o]

(89%)

. jJ

HO

23

24

Scheme 2 Levacher and co-workers have reported the deracemization of alkyl diarylmethanes with (-)-sparteine or a chiral proton source (25--~26) <01TL4515>. Spivey has also applied ortho metallation techniques to synthesize pyridine analogs for use as phase transfer catalysts <01JCS(P1)1785>.

A. (-)-SparteinethenH§ B. RLithenchiralH§donor 25

Upto 36%ee via A Upto 84%eevia B

26

Pyridines have also been constructed as essential portion of ligands used for transition metal catalysis. Chan and co-workers report the synthesis of dipyridylphosphines as ligands for the Ru-catalyzed asymmetric hydrogenation of 13-ketoesters <01SL1050>. Failer and coworkers report on the synthesis and use of a Ruthenium (R)-QUINAP catalyst for use in enantioselective Diels-Alder reactions <01OM2454>. The use of pyridines in cross coupling reactions was widespread in 2001. While this concept is not new, the number of examples clearly represents the importance of the pyridine group in organic synthesis. For example, pyridines participated as cross-coupling partners for the Pd-catalyzed Negishi reaction <01JA2719>, the Suzuki reaction <01TL2093>, Sonogashira coupling <01JOC4165>, carbonylative cross-coupling reactions <01TL3689>, Pd-mediated pyridine-N coupling reactions <01OL1351, 01TL6815> and a notable zirconocene coupling <01AC(I)2142>. For example, polyfunctional pyridines have been synthesized through the cross-coupling between halopyridines and aryl grignards (27--~28) <01TL5717>.

261

Six-Membered Rings." Pyridines and Benzo derivatives

PhMgBr, THF, -40 ~

/C02Et

~

tBu3P (10 mol%) Pd(dba)2 (10 mol%)

X

zCO2Et

Ph

27

28 X=Br, 95% X=CI, 92%

The copper-catalyzed amination of bromopyridine 29 was reported by workers at Merck on route to the synthesis of muscarinic (M3) antagonist 31 <01TL3251>. Interestingly, an uncatalyzed amination of 3-nitropyridines has also been reported <01JCS(P1)376>. Other metal mediated processes have been used to access pyridines with important biological activity as well <01JOC605><01TL6811>.

.•N.••N

1 Br C u 2 0 , NH3, 100 ~

AcHN

N

~N

NH2

Ethylene glycol 91%

29

ao

0

11

N

NH2

1

Pyridines have also been used in cyclization reactions. Two noteworthy examples are shown in scheme 3. The reaction of substituted pyridine 32 with a nitrile affords imidazo[1,5a]pyridine 33 in excellent yield <01JOC2862>. Oku and co-workers have reported the use of tetrahydroquinolizinium ylides in a 1,3-dipolar cycloaddition reaction (34--~35) <01JOC1638>. Sieburth has also published an account of the [4+4] photocyclization reaction of pyridones on route to fusicoccin <01Sl185>. o

~

N._N 0 ~ N

TiCI4, 60 ~ 91%

---C5Hll 33

32

~

0 C02tBu ,34

N

~ C02Me DMSO,80 ~ 60% Scheme 3

~ c ~ N~ ~ 0 MeO

35

0

262

D.S. Coffey, S.P. Kolis and S.A. May

6.1.2.3 Pyridine N-Oxides and Pyridinium The synthesis and utilization of pyridinium and pyridine N-oxides has also been a topic of interest in 2001. While pyridine N-oxides are normally synthesized via the pyridine <01T7501, 01T5009>, the direct construction of these systems was reported by cyclization of vinamidinium salts in a [3+2+1] annulation reaction <01OL209>. Accordingly, vinamidinium salt 37 is treated with the enolate of methyl acetoacetate (36) then with hydroxylamine to afford substituted pyridine N-oxide 38 in good yield.

0

\1~" ('~)" "0

tBuOK, THF, 45 min .NMe2

36

then AcOH, TFA then hydroxylamine 78%

I0

37

38

The synthesis of 1-azatyrosine relied on the formation of an N-oxide to achieve acceptable results in an asymmetric hydrogenation (40-->41). All attempts to conduct the same hydrogenation reaction with pyridine 39 met with failure. Presumably, the N-oxide prevents non-productive metal-substrate complex during the reaction <01OL3157>. Pyridine N-oxides have also been utilized by Katritzky as an effective way to activate the 2-position to nucleophilic attack <01H 1703>.

Bn O ~ ~ NHCBz ~.%i~C02Me 0

-

40

Bn O \ ~ MeOH Catalyst 80%

[0] Bn O . ~ ~ . I~ . . j.]..NHCBz

v

~C02Me "/-N0 41 83% ee >96% ee after cryst.

/.V~-BnO"~]L..

--a" '"~ "COeMe

._~HCBz

N.HOBz

"a" v

39

"C02Ue 42

Catalyst = (R,R)-[Rh(Et-DUPHOS)COD)]BF4 Generation of pyridinium salts has long been an effective method to activate the pyridine ring toward reduction. Ganem has reported a route to 1-azasugars (45) through a selective Fowler reduction (43-->44) <01OL201>. Similarly Bates has reported a synthesis of (_-_+)tashiromine which features the reduction of a pyridinium salt <01JCS(P1)654>.

~ 43

C02Me

NaBH4,MeOH PhOCOCI, -78 ~

~/C02Me

OH

HO~~CH20H

C02Ph

I

H

44

45

The use of pyridinium salts is also an effective method to activate pyridine rings toward nucleophilic substitution. Bennasar has reported the addition of cuprates into the 2-position of

263

Six-Membered Rings." PyrMines and Benzo derivatives

pyridinium salts <01TL585>. Similarly Comins efficiently adds the lithiated ethyl propiolate (46-447) to the 2-position on route to a synthesis of (+)-allopumilotoxin (48) <01OL469>. Finally, the addition of triflic anhydride has been used by Katritzky to activate pyridine and allow for the reaction of ketones to the 4-position <01OL2807>. OMe TIPS..

0 R*OCOCI

i C02R*

46

70%, >96% de

"

H

C02Et

47

48

R*=( +)-trans- 2-(ot-cum yl)cycloh exyl

6.1.3

QUINOLINES

6.1.3.1 Preparation of Quinolines The utilization of organometallic reagents in the construction of quinolines and quinoline intermediates continues to be an area of great interest. Catalytic Rh(I) complexes were used to catalyze the cyclization of N-aryl trifluoracetimidoyl chlorides with internal and terminal alkynes. This method afforded 3,4-substituted-2-trifluoromethyl quinolines with high levels of regiocontrol of the substituents at the 3- and 4- positions <0lOLl 109>. A useful method to prepare 3-carboxymethoxymethyl-2,3-dihyd ro-4-quinolines via a palladium-mediated carbonylation was also developed. Subjection of 49 to the carbonylating conditions shown below afforded products such as quinolone 50 in good yields <01JOC2175>. A palladium catalyzed, intramolecular cyclization of 2-haloanilines and ketone enolates was also utilized to prepare quinoline derivatives such as 2,6-methano-l-benzazocine derivatives <01ASC439>. Reactions catalyzed by ruthenium were also examined. In a modified version of the Friedlaender quinoline synthesis, 2-aminobenzyl alcohol was oxidatively cyclized with a variety of ketones in the presence of several Ru catalysts to afford 2-substituted quinolines in good yield <01CC2576>. Ring-closing olefin metathesis technology utilizing Ru catalysis was also used to prepare 1,2-dihydroquinolines <01TL8029>. Additionally, 2-arylquinolines were prepared by a Sm/TiC14 induced reductive cyclization of 2-nitro-l,3-diphenyl-2-propen-l-ones <01JCR(S)108>. Anionic annelation reactions were showcased in the preparation of 4substituted pyrazolo[4,3-c]quinolines and 9-substituted pyrazolo[4,3-c]quinolines <01JOC4214>. PdCl2(PPh3)2 '

R R = H or Cbz 49

PhH:MeCN CO

0

R R = H or Cbz 50

Cycloaddition reactions also provide a very straightforward means for the preparation of the quinoline scaffold. Hexahydropyrrolo[3,2-c]quinolines, the core structure of the Martinella alkaloids, were prepared through an intramolecular [3 + 2] azomethine ylide-alkene cycloaddition. Condensation of an aldehyde such as 51 and N-alkyl amino acids followed by decarboxylation and cycloaddition afforded quinoline derivatives such as 52 <01T4095>. The

264

D.S. Coffey, S.P. Kolis and S.A. May

preparation of 4-arylhexahydropyrroloquinolines was also accomplished through a [4 + 2] cycloaddition of cyclic enamides and imines derived from aromatic amines <01T5615>. In a complementary fashion, hexahydrofuro[3,2-c]quinolines were constructed via a dysprosium (III) catalyzed coupling reaction between anilines (1.0 equiv.) and dihydrofurans (2.0 equiv.). The aniline reacts with 1 equivalent of dihydrofuran to form a 2-azadiene which undergoes a formal Diels-Alder reaction with another equivalent of dihydrofuran <01TL7935>. An enantioselective route to tetrahydroquinolines utilizing an aza-Diels-Alder reaction between an imine prepared from anilines and glyoxylate derivatives containing chiral auxiliaries and cyclopentadiene was also reported <01T6399>. Imino Diels-Alder reactions of N-aryl aldimines with 3,4-dihydro-2H-pyran were effectively catalyzed with lithium perchlorate in diethylether to afford the corresponding tetrahydroquinoline derivatives <01SL240>. Furthermore, tetrahydroquinolines were also prepared in asymmetric fashion via an inverse electron demand Diels-Alder reaction using a chiral Ti(IV) catalyst <01OL1973>. O

Br~~N

R

~

RNHCH2CO2H B r \ ~ . ~ Et3N, DMF,

Ts

51

52

Ts

Functionalized 3-substituted tetrahydroquinolines were prepared in highly enantioselective fashion from o-nitrocinnamyl intermediates prepared from 53 (Scheme 4). Rhodium catalyzed asymmetric hydrogenation of 54 afforded intermediate 55 (-98% ee) which was converted to tetrahydroquinoline 56. Similarly, Sharpless epoxidation of 57 afforded intermediate 58 (---90% ee) which was converted to tetrahydroquinoline 59 <01OL2053>. Trans- and cis-3hydroxy-4-phenyl-l,2,3,4-tetrahydroquinolines were prepared from the corresponding aniline and (2R*, I'R*)- or (2R*, l'S*)-2-(~-bromobenzyl)oxirane with good selectivity. These tetrahydroquinoline derivatives can be converted to 4-phenylquinolines <01H1249>.

C02Me

?

~ I

/ tN02

C02Me

NHAc Rh+[L][CODISbF6 o2 H2, THF

NHAc NO2

(98% y, 98% ee)

OMe 54

OMe

-

=

R

OMe

OMe

55

56

CH20 H

CH20H

Sharpless asym. epoxidation NO2 (60% y, ~90% ee)

53

_NHAc

OMe

"NO2 OMe

57

58

OH R OMe 59

Scheme 4

Various other cyclization protocols for the synthesis of quinoline derivatives were reported in 2001. Functionalized 3-formylquinolines were prepared by condensation of functionalized anilines such as 60 and vinamidinium salt 61. Subsequent cyclization and hydrolysis afforded

265

Six-Membered Rings." Pyridines and Benzo derivatives

3-formylquinoline derivatives 62 <01S1351>. Treatment of Baylis-Hillman acetates of ohalobenzaldehydes with sulfonamides followed by nucleophilic aromatic substitution affordcd 3-alkoxycarbonylquinolines <01BKCS799>. Additionally, 1,4-dihydroquinolines can be prepared by treatment of Baylis-Hillman acetates of o-halobenzaldehydes with benzyl amine or cyclohexylamine followed by nucleophilic aromatic substitution and isomerization <01TL8341>. The reaction of o-aminobenzoic acid and ot-arylketene dithioacetals was reported to provide quinoline and quinolonc derivativcs <01TL2553>. Lewis acid promotion of the reactions of o-aminobenzaldehyde with a dithioacetal was shown to afford 2ethylthioquinoline <01JOC3924>. There were several reports that utilized anilines as precursors to quinoline derivatives. Two such examples include the acid mediated cyclization of 3-(N-aryl-N-sulfonylamino)propionaldchydes derived from the corresponding aniline <01H105> and a Vilsmeier cyclization of 2'-aminochalcones <01T3465>. A three component stereoselective synthesis of tetrahydroquinolincs catalyzed by clay/water mixtures was also reported <01EJOC2513>.

1)

I

J ~N-~ @ 2) H+

~NH2

2BE4

Q

| 61

X ~ / C H O

60

62

The use of microwave technology in synthesis continues to gain popularity. A microwaveenhanced synthesis of 3-aryl-4-hydroxyquinolin-2(1/0-ones by cyclization of a malonodianilide under solvent free conditions was reported <01TL1367>. Microwave irradiation was also used to prepare quinolones from anthranilic acid and ketones <01SC3647>. A microwave promoted, intramolecular cyclization of an isocyanate in the ortho position of a stilbene derivative to afford a quinolone derivative was also reported <01T6197>. 6.1.3.2 Reactions of Quinolines One routine method for the functionalization of quinolines is the addition of substituents to the 2-position. Further advances in the catalytic, enantioselective Reissert-type reaction were reported. Quinoline 63 was treated with 2-furoyl chloride and TMSCN in the presence of Lewis acid-Lewis base bifunctional catalyst 64 followed by reduction of the corresponding enamine to afford quinoline 65 in 93% ee. Quinoline 65 was subsequently converted to (-)-L689,560, a potent NMDA receptor antagonist <01JA6801>. Additions of allysilanes to quinolines acylated with chloroformate esters and catalyzed by various triflate salts were reported <01T109>. 1) 64 (1 tool%)

Z

CI . I-CI

63 Z = P(O)(o-tol)2

_.

64

TMSCN N(allyl)2 2-furoyl chloride

2) NaBH3CN, AcOH MeOH

CI

N.(allyl)2

~ ~ ....

CN ~

65 (91% y, 93% ee)

L-689,560

266

D.S. Coffey, S.P. Kolis and S.A. May

Cycloaddition reactions are not only used to construct quinoline derivatives, but also used to elaborate them. Phenanthridone derivatives were prepared by Diels-Alder reactions with 2(1H)-quinolones and butadiene derivatives <01CPB407>. The synthesis of pyranoquinolines via a formal [3 + 3] cycloaddition was also reported. For example, aldehyde 66 was treated with piperidine and acetic anhydride to afford the corresponding iminum ion which undergoes a [3 + 3] cycloaddition with 4-hydroxyquinolone (67) to give pyranoquinoline 68. Intermediates such as pyranoquinoline 68 were used in the total syntheses of simulenoline and huajiaosimuline <01JOC 1049>. O R"~

piperidine, Ac20, toluene then,

O

I

I

O

~ ~ , ~ /

R

~176

R = (CHe)2OTBS or

(CH2)2COCH(CH3)2

HO" Y / ' h , 67

Quinoline derivatives can also be further elaborated by various oxidation or reduction methods. Oxidation of 2- and 3-haloquinolines with either ozone and hydrogen peroxide or catalytic ruthenium tetroxide afforded the corresponding 5- and 6-halopyridine-2,3-carboxylic acids, which can serve as important synthetic building blocks <01S2495>. The use of polymer-supported rhodium (I)-l,3-bis(diphenylphosphino)propane moieties for the heterogeneous hydrogenation of quinoline was also reported <01 OM2660>. A molecular O2/2methylpropanal system was used to prepare the N-oxide of 8-hydroxyquinoline <01SC167>. Conditions were also developed to oxidize 5,8-dimethoxy-2-methylquinoline to 2methylquinoline-5,8-dione using NBS and H2SO4 without bromination <010LA45>. Microwave irradiation also proved beneficial in the elaboration of quinolines. Various 2ketomethylquinolines were prepared by heating 2-methylquinolines with acyl chlorides and silica gel in a conventional microwave oven <01TL4363>. The microwave assisted, solventfree synthesis of pyrazolo[3,4-b]quinolines from 2-chloro-3-formylquinolines and hydrazines was also reported <01TL3827>. Additionally, intramolecular radical additions to quinolines were also studied <01TL2907>. 6.1.4

ISOQUINOLINES

6.1.4.1 Preparation of Isoquinolines Isoquinoline derivatives and sub-units are found in many natural products, pharmaceutically interesting compounds, etc. making their preparation a topic of much research. Methods utilizing palladium catalysis continue to be popular. An in depth study of the palladium catalyzed annulation of internal acetylenes with the tert-butylimines of oiodobenzaldehyde and 3-halo-2-alkenals to prepare isoquinoline and pyridine derivatives was reported <01JOC8042>. In a complementary fashion the cross-coupling of a alkynylbenzaldimines with organic halides was also reported. Treatment of an o-(1alkynyl)benzylaldimine such as 69 and a corresponding organic halide (70) in the presence of a palladium (0) catalyst afforded isoquinoline derivatives (71) <01OLA035> (Scheme 5). Similarly, isoquinolines such as 73 were prepared by treating iminoalkynes (72) with an electrophile such as I2 which resulted in subsequent ring closure <01OL2973>. Additionally, the intramolecular palladium catalyzed coupling between aryl halides and amide enolates to

267

Six-Membered Rings: Pyridines and Benzo derivatives

afford 4-aryl-3-isoquinolone derivatives was reported. The isoquinolone derivatives were subsequently converted to 4-arylisoquinolines <01 OL631 >.

~ N

lt-Bu

v

~-~,..R1

+

R2X 70

cat. Pd (0), base

2

69

71

/t-Bu

electrophlie

Ph 72

R1

X

Ph

73

X = H, I, PhS, P-O2NC6H4S,PhSe Scheme 5

The stereoselective syntheses of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives and other 3-substituted-tetrahydroisoquinolines rcmain a topic of great interest. One approach utilized phase transfer catalysis of C2-symmetric chiral quaternary ammonium bromides. For example, treatment of imine 74 with dibromide 75 and 50% KOH in the presence of 1 tool% of (S,S)-3,4,5-F3-Ph-NAS-Br followcd by hydrolysis of the imine and treatment with sodium bicarbonate afforded the t-butyl ester of tetrahydroisoquinoline-3carboxylic acid derivative 76 in 98% ee <01S1716>. An intramolecular Pictet-Spengler reaction of an oxazolindino ester was reported to provide quaternary tetrahydroisoquinoline-3carboxylic acid derivatives in a highly asymmetric fashion <01TL2111>. An AIC13 promoted cyclization of N-benzotriazolylmethyl-N-phenethylamines also proved useful in the preparation of optically active tetrahydroisoquinoline-3-carboxylic acid derivatives <01TA2427>. Additionally, the enantioselective synthesis of 3-substituted tetrahydroquinolin-l-ones by a (-)sparteine-mediated lateral metalation of o-alkylated benzamides followed by imine addition was reported <01JOC1992>. Arylglycines were also used as templates in the synthesis of 3aryl- 1,2,3,4-tetrahydroquinolin-4-ols <01 EJOC4343 >.

ph .___Nv~O + [~~Br pff OtBu 74 75

1) (S,S)-3,4,5-F3-Ph-NAS-Br

Br

toluene-50%KOH 2) 1.0 N HCI 3) NaHCO3

0 ~NH"JJ'OtBu 76 82% y, 98% ee

The asymmetric synthesis of 1-substituted-l,2,3,4-tetrahydroisoquinolines received much attention as well. The Pictet-Spengler reaction of N-sulfinyl amines such as 77 afforded 1substituted-l,2,3,4-tetrahydroisoquinolines (78) with diastereomeric ratios as high as 96:4. The chiral auxiliary can be removed with HC1 in EtOH <01TL8885>. A similar method was used O

M e O ~ MeO~ - ~ . ~ 77

R~... H HN-.=(~stP-T~ BF~80oEt2 %

M e O ~ M e O ~ 78

I~",~S/p-Tel R

oG

268

D.S. Coffey, S.P. Kolis and S.A. May

to transfer chirality from amino acids in the diastereoselective synthesis of 1benzyltetrahydroisoquinoline derivatives <01OL997>. On a related note, a study on the regioselectivity of the Pictet-Spengler reaction in the preparation of halotetrahydroisoquinolines was also reported <01TL6251>. Another method for the preparation of enantiopure 1-substituted tetrahydroisoquinolines involved diasteroselective intramolecular ring opening of the N,O-acetal moiety of perhydrobenzoxazine 79 via an arylmetal affording 80 as a single diastereomer. Removal of the auxiliary afforded enantiopure tetrahydroisoquinolines 81 <01JOC243, 01JA 1817>. Similar perhydrobenzoxazines were used to prepare enantiopure 4-substituted tetrahydroisoquinolines as well via 6-exo radical cyclizations <01T4005>. Methodology was also developed for the stereodivergent syntheses of 1,20b-cis- and 1,10b-trans-thiazo[4,3-a]isoquinoline derivatives utilizing an intramolecular cyclization of aryllithiums and N-acyliminium ions <01EJOC1267>. A stereoselective synthesis of the tetrahydroisoquinoline moiety of the antitumor antibiotic tetrazomine was also reported <01JOC3133>.

R

R

1) t-BuLi Et20,-90 ~ Br 2) Et2AICI

~OH

F,,",.,,T~~ R 1) NaOAc PCC, \_....,..~k]N~ II I R 2) KOH

NR.• ~R

H

R

1

79

81

80

Tetrahydroisoquinolines were also prepared by an electrophilic aromatic substitution reaction of 2-amidoacroleins. Exposure of N-aryl-substituted 3-amido-1,3-dioxins 82 to Lewis acids results in retrocycloadditions to afford 2-amidoacroleins 83 and concomitant electrophilic aromatic substitution to afford tetrahydroisoquinolines 84 <01OL3349>. The synthesis of isoquinoline derivatives via cyclization reactions received attention as well. Some examples include the preparation of isoquinolines by a photocyclization of 1-methoxy-2-azabuta-l,3dienes <01TL3575>. The photochemically induced preparation of 1-methyl-l,2,3,4tetrahydronaphtho[2,1-f]isoquinolines was also reported <01T 1981 >.

O

R2

r 82

R1

R2

[ 83

R1

0

84

R1

6.1.4.2 Reactions of Isoquinolines Elaboration of isoquinoline derivatives in asymmetric fashion was examined as well in 2001. In a manner similar to that described in section 6.1.3.2, an enantioselective Reissert-type reaction was utilized to construct a chiral, quaternary center at the C 1 position of isoquinoline derivatives. For example, treatment of isoquinoline 85 with vinyl chloroformate and TMSCN in the presence of bifunctional catalyst 86 afforded isoquinoline derivatives such as 87 in up to 95% ee. The effect of the R group at the 1-position and the catalyst counterion were detailed.

269

Six-Membered Rings: Pyridines and Benzo derivatives

A synthesis of MK801, a potent, noncompetitive antagonist of NMDA receptors, was accomplished using this methodology <01JA10784>. Another report detailed the use of a gulonic acid derivative as a chiral auxiliary. Tetrahydroisoquinolines were coupled with 2,3,4,5,6-di-O-isopropylidene-2-keto-L-gulonic acid to afford the corresponding gulonic amide. Alkylation of these amides with various organic halides afforded 1-substituted tetrahydroisoquinolines with up to 84% diastereoselectivity <01JOC8744>. Addition of nucleophiles such as silyl enol ethers and allyltributyltin in the presence of the acid chloride of (S)-alanine afforded 1-substituted tetrahydroisoquinolines with diastereoselectivitites as high as 95% <01T8827>. Additionally, racemic isoquinoline alcohols were resolved using lipases in up to >99% ee <01TA1185>.

Br

z

R1 R'~ N

Z = P(O)Ph2 86

85

catalyst86 (2.5mol%) TMSCN

R

R 1 --CH2=cHococ/ R1~ ~ . _ b N O ~ R "CNO 87

upto 95%ee

A useful N-arylation of tetrahydroisoquinoline using aryl halides and Pd (II)-BINAP was reported <01SC987>. Additionally, benzo[a]quinolizine-4-thiones such as 89 were prepared by ring annulation of isoquinoline 88 with several acyclic and cyclic [3-oxodithioesters <01OL229>. The reaction of 2-alkyl-l-methylthioisoquinolinium salts with active methylene compounds in the presence of sodium hydride was reported to provide 2-alkyl-l-(substituted methylene)isoquinolines in good yield <01H435>. Furthermore, a synthesis of tetrahydroisoquinolin-l-ones by an autooxidative approach was published. Treatment of Nbenzyltetrahydroisoquinoline-l-carboxylate with Nail in DMF gave the corresponding Nbenzyltetrahydroisoquinolin-1-one in quantitative yield <01 TL3427>.

MeO~ MeO-~'~'~ N 88 Me

6.1.5

Et3N/C6H6/A MeO~,~-,,,.~ O S MeO,~-~/S RI"~R2 SMe 89 R~I R2

PIPERIDINES

6.1.5.1 Preparation of Piperidines The ring closing metathesis reaction continues to be a valuable tool for the production of piperidines in racemic and optically active form <01TL9373, 01T5393>. Osipov, Dixneuf and co-workers synthesized 4-substituted piperidines 92 and 93 via a combination of ring opening and ring closing metathesis <01SL621>. The metathesis substrates 90 and 91 were constructed via an ene reaction.

270

D.S. Coffey, S.P. Kolis and S.A. May

OF3 ,,__Nz "CO2Me

----/-- 'PG

(CY3P)2Ru=CHPhCi2 . ~ ~ 4 ~ . / ~ f ~ < - C F3 ...... H I - . CO2Me CH2CI2, rt '<.,,,/i~i,,pG

90 n=0, PG = SO2Ph 91 n = l , PG = BOC

92 n=0, PG = SO2Ph, 85% 9;3 n = l , PG = BOG, 8 6 %

The RCM reaction has also been used in the asymmetric synthesis of a variety of piperidine containing natural products including fagomine and its congeners <01TA817>, pipermethysine <01OL3381>, coniine <01TA2269, 01JOM359>, solenopsin A <01TA2269>, (-)pipecoline <01JOM359>, and piperidine alkaloids derived from tobacco <01JOC6305>. The process group at Merck also made use of a double RCM for the synthesis of NK-1 receptor antagonists <01OL671>. In contrast to the ring closing metathesis reaction, ring expansion reactions continue to find use as methodology for the synthesis of piperidines <01OL2383>. In particular, access to enantiomerically pure piperidines is readily available by using pyroglutamic acid derivatives as a source of naturally occurring chirality <01SL1575, 01TL5705>. The process group at Merck also used a ring expansion reaction to prepare a key intermediate (94) used in the preparation of the above mentioned NK-1 receptor antagonists <01TL6223>. The source of asymmetry in this case was a Jacobsen epoxidation on an acyclic precursor. Shipman and coworkers also reported on a novel, one-pot 4-step synthesis of piperidines that involves ring expansion of a 2-methylene aziridine 95. This led to a short synthesis of (S)-coniine 96 <01CC1784>.

~~~..~OD I-'n H #n /."H

MsCI; Et3N

Cl (-~),,.~R~n '~/HPh

nBU4NOAc 85%m 99% ee

~.,kOAc "N" "'/Ph Bn 94

Me~.-- Ph N

1) R~MgCI,Cul 2) ICH2CH2CH21 3) NaBH(OAo)3 42%

95

V ~ R1 Phi-H Me 96

Dearomatization of pyridine is an excellent method for synthesizing piperidines, and a variety of applications using these readily available feedstocks have appeared. Pyridine has been reductively dearomatized via hydrogenation <01TL93, 01JOC5264, 01BMCL2337>, hydride addition <01CPB721, 01JCS(P1)2389, 01OL3217> and dissolving metal reduction <01JCS(P1)1435>. Addition of alkylmetal reagents to activated pyridines is another effective method for dearomatization and piperidine synthesis. Charette and co-workers have developed the addition of alkyl Grignard reagents and alkyl cuprates to pyridines activated as amidines (97) <01JAl1829>. By synthesizing a chiral amidine, they were able to achieve a short total synthesis of (-)-coniine (98) from pyridine.

271

Six-Membered Rings." Pyridines attd Benzo derivatives

0 ph/JJ"-NH ~l .....%OMe

,~MgBr

0

Tf20 pyridine

..~ -OTf AuxN Ph 97

1) H2,Pd(OH)2 2) Boc20,NaOH AuxN'~Ph

Boc

npr

98

In a similar manner, Kunz and co-workers reported a diastereoselective alkylation of 2trimethylsiloxypyridine with a variety of Grignard reagents. The auxiliary used in this case was a galactosyl-based auxiliary substituted on the pyridine nitrogen <01SL1569>. Comins and co-workers also continued their development of this method for the total synthesis of (-)deoxoprosopinine <01JOC6829> and the core of spirolucidine <01OL3217>. A novel strategy for piperidine synthesis has been developed by Harrity and co-workers <01SL1596>. A variety of piperidines were synthesized in yields ranging from 63-82% by employing a [3+3] cycloaddition reaction between enantiomerically pure aziridines 100 (generated from amino acids) and palladium Irimethylenemethane complexes (99). The efficiency of the methodology was demonstrated through a 4-step synthesis of (-)pseudoconhydrine (101).

(~ Q ---~/-- pdLn 99

THF + .~ NPMBS reflux np~ 63% 1 O0

~ npr,,,.

PMBS

~OH npr,,,. H 101

The hetero Diels-Alder reaction <01H1591, 01TL5693> and dipolar cycloadditions continue to constitute important approaches to piperidines. Kibayashi and co-workers used an intramolecular acylnitroso Diels-Alder reaction to synthesize (-)-lepadins A,B, and C from an acyclic precursor <01JOC3338>. An intramolecular nitrone cycloaddition was used by Machetti and co-workers to produce both enantiomers of 4-oxopipecolic acid <01T4995>. Their synthesis proceeds from a nitrone bearing an ot-methylbenzylamine chiral auxiliary. Noteworthy in this report is the presence of large-scale experimental procedures: the nitrone formation and cycloaddition reactions were performed on 285 mmol and 226 mmol scales, respectively. Finally, heteroatom based-cyclizations of acyclic precursors continue to be the most popular method for piperidine synthesis. In addition to procedures employing reductive amination of acyclic precursors <01JA12510, 01OL759, 01OL2985, 01OL3169, 01SL1329, 01Tl169, 01TL3431> and lactam formation <01T8193, 01TL3831, 01TL8483>, other procedures have also appeared.

272

D.S. Coffey, S.P. Kolis and S.A. May

6.1.5.2 Reactions of Piperidines A variety of methods are awdlable for functionalization at the 2-position of piperidines. Syntheses of (+/-)-securinine, <01OL703>, (-)-cpipinidinol and (-)-pinidinol <01TL4609> wcre achieved by functionalization of a preexisting piperidine core. In addition, Murat and coworkers reported a novel Ru3(CO)12 catalyzed coupling reaction of unfunctionalized piperidines with olefins <01JA10935>. Not unlike the popular directed metalation reaction, this procedure makes use of an N-(2-pyridyl) substituent to direct the chemistry. Reactivity of 2,3-unsaturated piperidines provides intcrcsting and efficient chemistry for the synthesis of more complex piperidines <01OL769>. Construction of 2-spirocyclic piperidines 104 and 105 was achieved via the semipinacol rearrangement of cyclobutyl (102) and cyclopentyl (103) substituted precursors <01OL2109>. The products contain the structural features of natural products such as histrionicotoxin, halichlorinc and fasicularin.

n=l, R=RI=H CSA, CHCl3 45 ~

TBSO~.r....-~ O Ns.~ ~L~ ~ ,c~D ,

R1 TBSO~...h.--" ,,0

n=2, R=TMS,R' =OH DMDO"TiCI4

)n

I -"~n -]-s

102 (n=l) 103 (n=2)

104 (n=l) 105 (n=2)

4-Substituted piperidines are typically best synthesized through derivatization of 4pyridones. Access to substituted pipcridine derivatives may occur through rcductive amination <01JMC3343>, oxidation of the carbonyl to an ot-hydroxy kctal <01TL5713>, or Grignard addition <01BMC371>. Access to 4 - a m i n o piperidine derivatives was also achieved through Grignard addition to 4-imino piperidincs <01JHC837> and Curtius rearrangement on piperidine 4-carboxamide <01NNNI067>. The latter approach was used for the parallel synthesis of a library of cdK2 inhibitors. Tv,,o different approaches to 4-piperidinyl glycine

0

CBzHN ..C02Me tetramethyl ~ [(R,R)-Me-BPE-Rh-COD]OTf

O~.P(OEt)2 CBzHN/J,,,,,CO2Me +

guanidine 106

k..NJ

H2, 100%yield; 94% ee

107

CBzHN ~ C 02Me

+ C CI-N~ H3 02H ....

0~... 108

OR

"N" ClI-!' "H 109

109 were also presented <01JMC2499>, one in enantiomerically enriched form <01TA2421>. Shieh and co-workers at Novartis used an enantioselective, rhodium-catalyzed hydrogenation to produce CBz-protected 4-piperidiny.l melhyl glycinalc (108) in 94% ee. An increase in

273

Six-Membered Rings: Pyridines and Benzo derivatives

enantiomeric excess (to 98% ee) was observed upon removal of the CBz group and hydrolysis of the ester to the acid (108 --)109). The asymmetric hydrogenation step (107 ") 108) was scaled to >150 g of substrate. Transition metal catalysis presents itself as a very useful tool for the construction of substituted piperidines. The ready availability of vinyl triflates such as 110 from carbonyl compounds allows 4-piperidones to be elaborated to 4-substituted piperidines (e.g. 111) via the Suzuki Coupling <01OL2317>,<01OL3483>. The resulting 3,4-unsaturated piperidines themselves can be further elaborated by taking advantage of the reactivity of the trisubstituted olefin <01OL2625>. Liras and co-workers at Pfizer used this strategy combined with Ring Closing Metathesis to synthesize a variety of tetrahydroisoquinolines that were of interest as novel opiates (112).

OTf

[~OMe

R

110

~~[.,OMe

R

111

/OMe

"~,~,.~J

(Cy3P)2Ru=CHPhCI 2

OMe ~~/' '

R

R 112

The 3,4-olefin of unsaturated piperidines can also be derivatized by electrophilic aromatic substitution in superacid media <01T15821>. Lee and co-workers elaborated a simple 3,4unsaturated piperidine into a key intermediate employed in the construction of the potent gastrointestinal stimulant cisapride <01SC1081>. Conjugate additions to unsaturated piperidinones constitute an important method for the stereoselective generation of piperidines <01OL611>. Hayashi and co-workers have

~0 Bn 113 F

Bn 114

+

F.-~

Rh(acac)(C2H4)2 (R)-BINAP B(OH)2 dioxane,97%ee F

O

Bn

\N/

274

D.S. Coffey, S.P. Kolis and S.A. May

developed an asymmetric Rh-catalyzed addition of arylboronic acids to dihydropyridinones such as 113 <01JOC6852>. The resulting enantiomerically pure 4-aryl-2-piperidinones 114 are key intermediates for the synthesis of biologically active compounds. In particular, a key intermediate for the synthesis of (-)-paroxetine was synthesized. Finally, the use of stoichiometric amounts of transition metal complexes can play an important role in the synthesis of functionalized piperidines. <01H1439> Liebeskind and coworkers have developed a chiral transition metal complex and have used it in the synthesis of (-)-indolizidine 209B <01JA12477>. A lipase mediated allylic alcohol resolution provides access to both antipodes of enantiomerically pure allyl acetates (115) which can be used to form an q3-allyl molybdenum complex (116). Hydride abstraction followed by methoxide quench yields a reactive species 117 which may be further functionalized through reactions with Grignard reagents. The eventual products 119 arc 2,3,6-trisubstituted piperidines in enantiomerically pure form.

TpMo(CO)2 AcO

1) Mo(DMF)3(CO)3

;Bz

|

~Bz

115

116

TpMo(CO)2

TpMo(CO)2 1) HBF4

MeO~''"

(~Bz 117

Me

2) R1M

MEOW,,'

1

2) R2M

CBz 118

TpMo(CO)2

dBz

d;Bz 119

6.1.6

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Six-Membered Rings." Pyridines and Benzo derivatives 01Tl169 01T1981 01T3465 01T4005 01T4095 01T4787 01T4995 01T5009 01T5393 01T5615 01T6197 01T6399 01T7501 01T8193 01T8827 01TA817 01TAl185 01TA2269 01TA2421 01 TA2427 01TL93 01TL585 01TL1367 01TL1847 01TL2093 01TL2111 01TL2553 01TL2907 01TL3251 01TL3427 01TL3431 01TL3575 01TL3689 01TL3827 01TL3831 01TL4363 01TL4373 01TL4515 01TL5693 01TL5705 01TL5713 01TL5717 01TL5821 01TL6087 01TL6223 01TL6251 01TL6811 01TL6815

277

A. Datta, J. S. Ravi Kumar, S. Roy Tetrahedron 2001,57, 1169. E. Martinez, J.C. Estevez, R.J.Estevez, L. Castedo Tetrahedron 2001, 57, 1981. S. Akila, S. Selvi, K. Balasubramanian Tetrahedron 2001, 57, 3465. R. Pedrosa, C. Andres, J.M. Iglesias, M.A. Obeso Tetrahedron 2001, 57, 4005. H. Mahmud, C.J. Lovely, H.V. RasikaDias Tetrahedron 2001, 57, 4095. E. M. Beccalli, F. Clerici, A. Marchesini Tetrahedron 2001, 57, 4787. F. Machetti, F.M. Cordero, F. De Sarlo, A. Brandi Tetrahedron 2001,57, 4995. K. Wojciechowski, S. Kosinski Tetrahedron 2001, 57, 5009. C. Agami, F. Couty, N. Rabasso Tetrahedron 2001, 57, 5393. M. Hadden, M. Nieuwenhuyzen, D. Potts, P. J. Stevenson, N. Thompson Tetrahedron 2001, 57, 5615. P.M. Fresneda, P. Molina, S. Delgado Tetrahedron 21~1, 57, 6197. S.K. Bertilsson, J.K. Ekegren, S.A. Modin, P.G. Andersson Tetrahedron 2001, 57, 6399. H. Mizfufune, H. Irie, S. Katsube, T. Okada, Y. Mizuno, M. Arita, Tetrahedron 2001, 57, 7501. G. Allan, A.J. Carnell, M.L.E. Hernandez, A. Pettman Tetrahedron 2001, 57, 8193. T. Itoh, K. Nagata, M. Miyazaki, K. Kameoka, A. Ohsawa Tetrahedron 2001, 57, 8827. Y. Banba, C. Abe, H. Nemoto, A. Kato, I. Adachi, tl. Takahata Tetrahedron." Asymmeoy 2001,12,817. G. Guanti, R. Riva Tetrahedron." Asymmeoy 2001, 12, 1185. R. Kumareswaran, A. Hassner Tetrahedron: Asymmetly 2001,12, 2269. W.-C. Shieh, S. Xue, N. Reel, R. Wu, J. Fitt, O. Repic Tetrahedron: Asymmetry 2001, 12, 2421. A.R. Katritzky, H.-Y. tte, R. Jiang, Q. Long Tetrahedron: Asymmeoy 2001, 12, 2427. H. Tanaka, H. Sakagami, K. Ogasawara Tetrahedron Lett. 2001, 43, 93. M . - L . Bennasar, C. Juan, J. Bosch, TetrahedronLett. 2001, 43,585. J.H.M. Lange, P.C. Verveer, S.J.M. Osnabrug, G.M. Visser Tetrahedron Lett. 2001, 42, 1367. V. B. Hegde, J. M. Renga, J. M. Owcn, Tetrahedron Lett., 2001, 42, 1847. G. A. Morris, S. T. Nguyen, Tetrahedron Lett. 2001, 42, 2093. V. Alezra, M. Bonin, L. Micouin, tI-.P. Husson Tetrahedron Lett., 2001,42,2111. M.X. Wang, Y. Liu, Z.T. Huang Tetrahedron Lett. 2001, 42, 2553. D.C. Harrowven, B J. Sutton, S. Coulton Tetrahedron Lett. 2001, 42, 2907. F. Lang, D. Zewge, I.N. Houpis, R.P. Volante Tetrahedron Lett. 2001, 42, 3251. M. Bois-Choussy, M. De Paolis, J. Zhu Tetrahedron Lett. 2001, 42, 3427. A. Jourdant, J. Zhu Tetrahedron Lett. 2001, 42,3431. P.J. Campos, M. Caro, M.A. Rodriguez Tetrahedron Lett. 2001, 42, 3575. S. Couve-Bonnaire, J. -F. Carpentier, A. Mortreux, Y. Castanet, Tetrahedron Lett. 2001, 42, 3689. S. Paul, M. Gupta, R. Gupta, A. Loupy TetrahedronLett. 2001, 42, 3827. C. Grison, S. Geneve, P. Coutrot Tetrahedron Lett. 2001, 42, 3831. H. Loghmani-Khouzani, M.M. Sadeghi, J. Safari, A. Minaeifar Tetrahedron Lett. 2001, 42, 4363. B.C. Maity, V.M. Swamy, A. Sarkar Tetrahedron Lett. 2001, 42, 4373. L. Prat, G. Dupas, J. Duflos, G. Queguiner, J. Bourguignon, V. Levacher Tetrahedron Lett. 2001, 42, 4515. W.M. De Borggraeve, F.J.R. Rombouts, E.V. Van der Eycken, S.M. Toppet, G.J. ttoornaert Tetrahedron Lett. 2001, 42, 5693. J. Cossy, O. Mirguet, D.G. Pardo, J.-R. Desmurs Tetrahedron Lett. 2001, 42, 5705. J. Cossy, J.L. Molina, J.-R. Desmurs Tetrahedron Lett. 2001, 42, 5713. V. Bonnet, F. Mongin, F. Tr6court, G. Qu6guiner, P. Knochel, Tetrahedron Lett. 2001, 42, 5717. D.A. Klumpp, P.S. Beauchamp, G.V. Sanchcz, Jr., S. Aguirre, S. deLeon Tetrahedron Lett. 2001, 42, 5821. I. Ungureanu, P. Klotz, A. Schoenfelder, A. Mann Tetrahedron Lett. 2001, 42, 6087. J. Lee, T. Hoang, S. Lewis, S.A.Weissman, D.Askin, R.P. Volante, P.J. Reider Tetrahedron Lett. 2001, 42, 6223. S.D. Cho, S.Y. Song, E.J. Ilur, M. Chen, W.H. Joo, J.R. Falck, Y.J. Yoon, D.S. Shin Tetrahedron Lett. 2001, 42,6251. M. Palucki, D. L. Hughes, N. Yasuda, C. Yang, P. J.Reider, Tetrahedron Lett. 2001, 42, 6811. L. S. Frey, K. Marcantonio, D. E. Frantz, J. A. Murry, R. D. Tillyer, E. J. J. Grabowski, P. J. Reider, Tetrahedron Lett. 2001, 42, 6815.

278 01TL7935 01TL8029 01TL8341 01TL8483 01TL8885

D.S. Coffey, S.P. Kolis and S.A. May R.A. Batey, D.A. Powell, A. Acton, A.J.Lough Tetrahedron Lett. 2001, 42, 7935. M. Arisawa, C. Theeraladanon, A. Nishida, M. Nakagawa Tetrahedron Lett. 2001, 42, 8029. J.N. Kim, H.S. Kim, J. H. Gong, Y. M. Chung Tetrahedron Lett. 2001, 42, 8341. C. Flamant-Robin, Q. Wang, N. A. Sasaki Tetrahedron Lett. 2001, 42, 8483. C. Gremmen, M.J. Wanner, G.-J. Koomen Tetrahedron Lett. 2001, 42, 8885.

279

Chapter 6.2

Six-Membered Ring Systems" Diazines and Benzo Derivatives Grace H. C. Woo and John K. Snyder Boston University, Boston, MA, USA gwoo@ chem.bu.edu and jsnyder@ chem.bu.edu

Zhao-Kui Wan Wyeth Research, 87 Cambridge Park Drive, Cambridge, MA 02140, USA zwan @wyeth, corn

6.2.1

INTRODUCTION

Diazines and their derivatives are extremely important to the field of chemistry as well as the general population due to their invaluable biological activities. In 2001 alone, there were hundreds of publications on their syntheses as well as the reactions of these heterocycles. This review is comprised of the most significant of these reports.

6.2.2 PYRIMIDINES 6.2.2.1 Preparations of Pyrimidines A common method for the preparation of the fully aromatized pyrimidine skeleton is the condensation of amidine-containing substrates with suitable carbonyl compounds. Among these protocols, o~,[3-unsaturated carbon yl and 1,3-dicarbonyl compounds are often used. For example, in the search for COX-2-selective inhibitors, Almansa and co-workers synthesized a variety of pyrazolo[1,5-a]pyrimidines 4 by condensing 3-aminopyrazoles 3 with an array of enones 1 or with 1,3-dicarbonyl derivatives 2 <01JMC350>. F

~~~~~i~-R3 O 1 or

o.yR 1 R2-~ 2

R3

o

"N""~ 11 - 70% from 1 H ~,,.~,,. 53 - 54% from 2 v .SO2Me 3

SO2Me

R2/~R3 4

280

G.H.C. Woo, J.K. Snyder and Z-K. Wan

In the same report, imidazo[1,2-a]pyrimidines 7 were also prepared through the condensation of 2-amino-4-methylpyrimidine 5 with o~-bromo ketone 6 under thermal conditions. No yield was given in this latter reaction. F F

Me

0

+

5

i eMF,60oC D ~ Me SO M

6

N

S02M e 7

Fomum and co-workers reported a novel synthesis of biologically active pyrimido[1,2a]benzimidazoles 10 from aminobenzimidazoles 8 and allenic nitriles 9 in good yields. Some of these heterocycles showed modest antibiotic and antiarrhythmic properties <01JCS(P1)457>. 2 R~

H ~/).__

NH2 +

R~

R'\

/C--C--CHCN R

--

R1~

N/k~ _ N H

2

R---~

10

R'

A new and efficient approach to the synthesis of 6-amidino-2-oxopurines 15 was reported by Proenca and co-workers <01JCS(P1)1241>. The reaction between 5-amino-4-cyanoformimidoylimidazoles 11 and tosyl isocyanate occurred under mild conditions to provide 15 in nearly quantitative yields. In the proposed mechanism, cyclization of intermediate 12 by closure of the urea nitrogen onto the adjacent cyano group gives 13. Ring opening of 13 then produces a reactive isocyanate intermediate 14, which undergoes cyclization and tautomerization to give 15. Purinones 15 rearrange to pyrimido[5,4-d]pyridimidin-2-ones 16 in the presence of acetic acid in DMF in quantitative yield.

(\ I]

.~.<_j .o

O--(~=N--Ts

. /NW"-~~ /

L C~~""Tsj

11

12

RHN. > N...~.O

N "NTs H 16

HOAc, DMF

R .N-...~N ~ 0

cyclization

.

r

/L 13H~~~ Ts _J 1

.~&=c-

~,J~(',. "-tautomerization <, r.5 ~ H2N "NTs 15

H2N "Nls 14

281

Six-Membered Ring Systems." Diazines and Benzo Derivatives

Eynde and co-workers reported a microwave-mediated regioselective synthesis of pyrimido[1,2-a]pyrimidines <01T1785>. It was noted that three-component reactions of ketone 17, aldehyde 18, and guanidine 19 provided 1,4-dihydropyrimidines 20 in good to excellent yields. Subsequent reactions of 20 with 3-formylchromone 21 under microwave irradiation generated one of the two possible regioisomers 22, which exists as an equilibrium mixture of two tautomers 22a and 22b. These rcactions using microwave irradiation were shown to be better than the more conventional thermal conditions.

Et02C'~_... Ph" "0

+

17

0

,~rCHO + 18

~"

> 95%

0

N'~NH2 H2N 19

20, microwave

21

Ar H C~NI~ NaHC03, DMF. E t O 2./[L.., 75 - 85%

Ph

N H

NH2

20

H•O

Ar H H Et02C - . ~ N

Ar H [ ~ O H OH E t O 2 C ' ~ N ~ O

p h./[~.N//J-,..N//L-.H

p hH~ N//J'--.N//J"..H

22a (4H)

22b (2H)

In the synthesis of lipoprotein-associated phospholipase A~ inhibitors reported by Smith and coworkers, the pyrimidone rings of 24 originated from the condensation of amines with acylisothiocyanate 23 <01BMCL701>. No yields were reported in these transformations. Using similar chemistry, it was also reported that vinylogous carbamate 25 cyclized to fused pyrimidones 26 upon reaction with an isocyanate, isothiocyanate, or dithioketal <01H115>.

SCN

0

o

MeO"

N

23

a) R1-NH2,DMF; then NaOEt = "N" "OMe b) R2CI/Br,i-Pr2NEt, DCM

Bn..N/--....,/C 02 Me ~NH 25

2

SCN~C02Et or N~CO2Et MeS/J~'SMe 69 - 82%

N

~..1

R2S/\N / i~1

Bn . . N . ~ ~ t

0

N

\N-" "OMe

24

N/~CO2Et

L - v ~ N//I'-..SR 26

Nucleophilic addition to a nitrile instead of a carbonyl group can provide aminopyrimidines. Condensation of thiourea with a variety of pyridylnitriles 27 produced aminopyrimidines 28 in good yields as reported by Kumar and co-workers <01 HC52>.

282

G.tt.C. Woo, J.K. Snyder and Z-K. Wan

R1

S

R2

NH2

R1

67 75%

R2

-

27

NH2

H

S

28

6.2.2.2 Reactions of Pyrimidines Aromatic nucleophilic substitution reactions (SNAr) are commonly applied in the transformations of pyrimidines. With appropriate leaving groups, C-N, C-O, C-S and C-C bond formations on pyrimidines are possible. For C-N bond formation, chloride as a leaving group represents the majority of such operations. For example, the synthesis of pyrimido[1,4]diazepine N-oxide 32 began with a SNAr reaction between 29 and amine 30 with chloride as the leaving group to produce 31. Subsequent treatment of 31 with hydroxylamine in presence of pyridine in methanol led to intramolecular coniugate additions following oxime formation to furnish the target pyrimidodiazepine 32 along with pyrimidine by-products 33 and 34 <01JCS(P1)622>.

OMe Me N ~ D

%'%,MeO

OMe Me .4[...~-...

30 BnHN/-.,,.,~-~CO2Me Et3N, CHCI3

29

. ~~N }N~ N

Me~

/

0 n

NH2OH/py -'--

Me02C" 31 (82%)

MeO Me

HON

O-

OMe Me

02Me

H Bn/

+

HON

+

MeO2C._j/~ J

32 ( 4 9 % )

OMe Me

33

Me02C ~/~___ /

(25%)

34 (24%)

In this same work, it was also reported that the pyrimidoazepinone 35 was formed when 31 was heated in MeOH. Presumably 35 arose via Michael addition of the enol of 31 onto the internal double bond <01JCS(P1)622>.

OMe 0 MeO

N

N Bn 31

MeO C02M e

74%

MeO

0

Bn

02Me

35

In the search for inhibitors of cell adhesion molecule expression in human endothelial cells, thieno[2,3-d]pyrimidin-4-one 36 was first subjected to a Krapcho decarboethoxylation. The resultant pyrimidone was then converted to 4-chlorothieno[2,3-d]pyrimidine 37. With chloride as a leaving group, new C-S and C-N bond formations were easily achieved by SNAr displacements to produce 38 <01JMC988>. Yields were not given for all compounds

283

Six-Membered Ring Systems: Diazines and Benzo Derivatives

made. A similar example using chloride as a leaving group was reported by J~ischke in the synthesis of multifunctional dinucleotide analogues for application in the preparation of RNA conjugates <01T1261>. O

HN/E.,.~.~ 1)LiCI,DMSO,150 ~ CIN ~.~N. E t O ~ N I~S~2--Et - 2)Poc, 3, reflux '~ 0

36

37

RXH Et-

X ~ E,

~ 38: X = S,

NH

Triazoles are also often used as leaving groups in C-N bond forming SNAr reactions, particularly when the corresponding chloride fails. For example, pyrimidones 39 were first converted to triazoles 40, with subsequent reactions with amines leading to the formation of the desired aminopyrimidones 41. This strategy was utilized in Leumann's synthesis of (5'S)5'-C-alkyl-2'-deoxynucleosides 41a <01HCA87>, Saigo's synthesis of 5-formylcytidines 41b <01TL1061>, An's synthesis of 5-methylcytidine derivative 41e <01JOC2789>, as well as Pedroso's synthesis of modified oligonucIeotides containing 4-guanidino-2-pyrimidinone nucleobases 41d <01T179>.

R JLNH N Sugar*

triazole

R

N"

N

POCI3, TEA

Sugar* Sugar* 40

.39

41a: R = H, R'= H, PhCO 41b: R = C H O , R ' = H 41c: R = M e , R' = H 41d: R = Me, R'= C(NH)NHR"

Other leaving groups, such as sulfonate, have also been reported. Giordano and coworkers first converted 2'-deoxyguanosine (R = NHCOPr i) and 2'-deoxyinosine (R = H) derivatives 42 to the O-sulfonylated derivatives 43 by reactions with 2,4,6triisopropylbenzenesulfonyl chloride (TPS-CI). Subsequent reactions of 43 with tempamine in boiling CH2C12 furnished the C-O to C-N bond transformation to give 44 for use in the synthesis of EPR active oligonucleotides <01S565>. Similar chemistry also produced the spin-labeled 2'-deoxycytidine analogues as well.

OH

N N....~,/..~ i .... p Sugar 42

TPS-C!

"" t e m p a m i n e NH~NN/~." N CH2CI2,reflux N~<..N//j....R 54 - 69% N N Sugar R 43 Sugar 44

OTPS

While aminations of pyrimidines typically exploit SyAr substitutions, direct lithiation of pyrmidine derivatives 45 with LDA or see-BuLl, and in situ quenching with the nitroso electrophile MNP led to the formation of the new C-N bond in the products 46 <01JOC3513>. These hydroxyl amines were subsequently oxidized to aminoxyl radical spin labels. Analogous chemistry on purine nucleosides was also reported.

284

G.H.C. Woo, J.K. Snyder and Z-K. Wan

O

O

H ~N~ 0

i) LDAorsec-BuU,THF

,

Sugar

ii)

NO

H/~N~I .~ 0 N

(MNP)

Su~lar OH

45 - 59%

45

46

Glycosidations are also important reactions of pyrimidines and their derivatives. Voss and co-workers treated 1,4-dithiofuranoside 47 with 2,4-bis-O-trimethylsilyluracils 48 in the presence of NIS to yield the desired products 49 as anomeric mixtures <01EJOC1077>. OTMS B n O J I~Bn

R

N

22

75%

-'-

47

0 "0 mn

OTMS

OBn

48

0 49

A similar glycosidation strategy was reported by Kumar and co-workers <01HC52>. Reactions of the trimethylsilyl derivatives of pyrido[2,3-d]pyrimidines 50 with 13-Dribofuranose 51 in the presence of SnCI4 led to the formation of the desired coupled products 52 in good yields. R, 1

BzO--~OAc

~ N1 / / L ,NH2 ,,. Rn

SnCl 4

+

BzO

STMS

50

NH 2

OBz

63 - 72%

51

52

The selective hydrolysis of 2,4-diaminopyrimidines 53 to 4-aminopyrimid-2-ones 54 under acidic conditions was also reported. Treatment of 53 with 6M HC1 led to the formation of pyrimidone 54, which contrasts with the regioslectivity usually observed with 2,4diaminopyrimidines <01JOC192>. O-

H -N

N,.~ NH 2

F{~

Nil 2

6M HCI

R1

O--N

H

H N-.0

R1

53

R 1 = CH 3, R2 = H" 55% 54

Palladium-catalyzed cross-coupling reactions were also reported. In Smith's synthesis of the lipoprotein-associated phospholipase A2 inhibitor discussed in Section 6.2.2.1, the cyclization precursor 23 was prepared by a Heck coupling between bromopyrimidine 55 and ethyl acrylate to give 56, which was then converted to 23 following conventional procedures <01BMCL701>. Yields were not reported.

285

Six-Membered Ring Systems." Diazines and Benzo Derivatives

O

Br~

N

~"-C02Et,

H

Pd(OAc)2, P(o-Tol)3, Et3N 9

Et02C~ - / ~ ~ - N II....N-I //..,.. OMe

_~_

SS

6.2.3

56

/

S C N ~ N MeO~j

LN//I'-OM e 23

QUINAZOLINES

6.2.3.1 Preparations of Quinazolines Quinazolines, the benzo derivatives of pyrimidines, were prepared in a variety of ways from methods analogous to those used to synthesize pyrimidines to vastly different condensation schemes. In the solid-phase synthesis of quinazolin-2,4-diones reported by Makino and co-workers, SNAr reactions were first accomplished on aryl fluoride 59 which was derived from aniline 57 by coupling with 2-fluoro-5-nitrobenzoic acid (58). Employing an array of amines, substitution on the solid support led to the formation of products 60 <01SL333>. Carbonylation of 60 with carbonyl diimidazole (CDI) followed by acid promoted cleavage from the solid support provided quinazolin-2,4-diones 61 (X = O). Thiocarbonylation of 60 with thiocarbonyldiimidazole (TCDI), followed by acid cleavage, provided the thio analogues 62 (X = S) in excellent yields <01TL1749>.

Extending this chemistry by repeated cycles of nitro group reduction with SnC12, acylation of the resultant anilines with 58, and SNAr reactions with primary amines gave 63. Finally, carbonylation of 63 with subsequent cleavage from the support gave the oligomer 64 with four quinazolin-2,4-dione units in 22% yield <01SL333>.

286

G.IL C. Woo, J.K. Snyder and Z-K. Wan

Anthranilic acids and derivatives are often used as starting materials for the preparation of quinazolinones. For example, Drizin and co-workers applied this strategy to build a library of quinazolinones in the search for selective OhA subtype antagonists. Anthranilate esters 65 reacted with isocyanates to generate quinazolin-2,4-diones 66 <01JMC1971>. Similarly, quinazolin-4-ones 69 were synthesized by first converting 67 to 68 followed by cyclization with an isocyanate under acidic conditions. 0

0 R3

MeO

R1HN / ".....~ \ R 2

R4_N=C=O

R \N

,,.

toluene, reflux

O//"~'N~~R

6.5

2

66

0

0

0

R (Me)2NCH(OMe)2 H2N"

R

~

"R 67

R = OMe

R --(Me)2N"

N .Jl

~

-R 68

R4_N=C=O R4.~ H+

R 69

In a similar fashion, quinazolin-4-ones 72 were synthesized by reactions of 70 with anthranilate 71 in presence of molecular sieves as reported by Tatibouet and co-workers <01TL2977>. Ring cleavage took place under either basic or acidic conditions to give quinazolin-2,4-diones 73.

287

Six-Membered Ring Systems." Diazines and Benzo Derivatives

oR, N~SBn 0 +

MeO 0

io "79% MS 4AO R~ up

H

OBn OBn 70

OH- ~ 0 ~ ' / N H" 1 ] ~ or H' sugartN..r]~..~ O 73

N

BnO OBn 72

71

In the synthesis of 2-alkylthio-3-quinazolin-4-ones 76 reported by Powers, treatment of isatoic anhydride (74), derived from anthranilic acid, with aminoacetonitrile followed by reaction with thiophosgene provided the quinazolinone 75 <01JHC419>. Alkylation of 75 led to the thioethers 76 in good to excellent yields. A very similar compound, quinazolin-2,4dione 78, was synthesized from 77 and aminoacetonitrile bisulfate <01JOC4723>. 0

~N.~

0

0

1) H2NCH2CN(64~176G-~-.~N~CN RX ~ N ~ C N S 62 - 92%" I[~~N//J""SR H 0 2)CSCI2(81;o) t[Lv~"N~ H

74

75

0 ~N_SSO2Me

0 H3NCH2CNHS04 ~ N ~ C N PY ~ N ~ O

O

76

81~

H

77

78

Analogously, anthranilonitrile 79 was also used as starting material for the preparation of quinazolinones. Chowdhury and co-workers reported the synthesis of ring fused thioquinazolinone 82 by condensing anthranilonitrile 79 with N-methylsulfanylthiocarbonylglycine ester 81 <01H1747>. In comparison, reaction of 81 with anthranilate ester 80 led to 83. O

R

0

NH2 CN) 80 (R= C02Et) 79 (R =

o

H

DMF

r~~N~CO2Et

S 81

82

(41%from79)

83 (47%from80)

Anthranilonitrile derived isothiocyanate 84 was also used to construct quinazolinones. Nanni and co-workers reported a dimerization of 84 in the presence of Mn(OAc)3 in HOAc to give fused quinazoline 86 in excellent yield <01T7221>. In contrast, dimerization of the anthranilate ester 85 gave quinazoline 87 as the major product, though in only 30% yield. It was assumed that a thiourea intermediate was initially formed which then cyclized through an ionic and/or radical mechanism. However, when thiourea 88 was treated under the same conditions, 89 was the major product along with minor products 90, 91, 92 and 93.

288

o#

G.H.C. Woo, J.K. Snyder and Z-K. Wan

R [ ~

Mn(OAc)3 AcOH, 60 ~

NCS

~

~N,~S H

N-- N---~XN

=/"s"

CN) 85 (R = C02Me)

84 (R =

86 (87% from 84) NH

~ C

Mn(OAc)3

NS .N~..N..Ph H H

87 (30% from 85) NHPh

H 89 (47%)

AcOH,60 ~

C02Me

90

0

H 91 (8~

(14%) CN

0

88

92 (6%)

93 (8%)

Wang and co-workers reported the intramolecular cyclocondensation of 2-anilino-3aroylquinolines to quino[2,1-b]quinazolines <01TL2553>. Under basic conditions, compounds 94 cyclized to quinazolines 95 in excellent yields.

OH O

I]4 O.. Ar Ar

~

,

NaOH/EtOH, reflux

~

N

O

89 - 99% C02R

94

95

The condensation of appropriately substituted o-ketoanilines with cyanate also has been used to prepare quinazolinones. For example, in the synthesis of novel reverse transcriptase inhibitors, 3-trifluoromethylquinazoline derivative 98 was synthesized by Corbett and coworkers <01BMCL211>. Treatment of trifluoromethyl ketone 96 with potassium cyanate yielded aminol 97, which was subsequently dehydrated in refluxing xylenes to give the quinazolinone 98.

CI

OMe "~

COCF3

NHP 96

KOCN

CI\

OMe OH NH

HOAc/H20

N P 97

0

xylenes

CI

OMe .CF3 N

M.S.4A

P 98

0

289

Six-Membered Ring Systems." Diazines attd Benzo Derivatives

6.2.3.2 Reactions of Quinazolines Quinazolines undergo many of the same reactions as pyrimidines, such as SNAr reactions, using a chloride as the leaving group. For example, Chenard and co-workers chemoselectively converted quinazolinethione 99 to chloride intermediate 100. Subsequent SNAr displacement of the chloride with amines led to the formation of aminoquinazolinones 101 <01JMC1710>.

oCl'-[-~ F ~ N 99

oC"-U

oCl-..~~

~-'q'~ POOl3 F ~ N

-N-L---s o,s"

~

F

N ~

R..2

R

lOl

1 O0

In work previously cited <01BMCL2I 1>, Corbett and co-workers reported an annulation onto the quinazolinone ring system. Treatment of 102 with 3-pyridyl acetylide generated in situ led to formation of adduct 103, which was then hcated in POC13 to provide a mixture of imidoyl chlorides 104. Heating the crude chlorides in a solution of thiourea in ethanol gave a 5-exo-dig cyclized product 105.

OF: AF

F.

CF3 N

F~

,r;'N~ Br [/~'J~~Br

,F~

n-BuLi,THF

F\

NH

then add acetylideto 102

I

PMB

N H

102

103 -

Ar

Ar

S H2N~" NH2

POCI3

EtOH

s

,d

_ / -~/CF 3 F ~ N H H

104

105

In the same report <01BMCL211>, similar acetylide adducts 106 were formed in the same manner. After demethylation, the resultant phenol cyclized onto the alkynes using either NaOMe or DBU as the base promoter. All of the cyclization processes afforded exclusively the 6-endo-dig products 107. R R

CI\

N

II

.

BF3.OEt2

CI

NH CI J~ 2) NaOMe N O or DBU H

H 98

106

NH N H 107

An additional cyclization was reported by Powers to prepare imidazolo- and pyrroloquinazolinones. Treatment of quinazolinone 76 with thiols in presence of t-BuOK led

290

G.H.C. Woo, J.K. Snyder amt Z-K. Wan

to the tricyclic products 108 <01JOC4723>. In contrast, direct treatment of 76 with Nail in DMF led to dimerization products 109 <01JHC419>.

O

O

0 R-SH ~ N / ~ C N t-BuOK [ ~ ~ N/~-...SR

H 108

CN

Nail DMF

76

Reduction of the pyrimidone ring in quinazolinone systems can be easily achieved. For example, hydrogenation of 110 under conventional conditions gave the hydroquinazolinone 111 as reported by Drizin and co-workers <01JMC1971>.

OMe

OMe O N ~

OMe e

110

H2, Pd 40%

O ~ N ~ O M e

L...NI.,.-~~OM e H 111

6.2.4 PYRIDAZINES 6.2.4.1 Preparations of Pyridazines A long-established method to prepare pyridazines is the condensation of 1,4-dicarbonyl compounds with hydrazine. For example, Lam and Lee used a solid-phase procedure to synthesize various substituted pyridazines <01CL274>. Sodium benzenesulfinate resin 112 was treated with (~-bromoketones to produce resin-bound sulfones 113 in excellent yields. Further treatment with a second portion of ct-bromoketone in base gave the immobilized diketones 114. Finally, a library of substituted pyridazines was prepared by condensation of these diketones with hydrazine to obtain the substituted pyridazines 115 which are released from the resin by elimination driven by aromatization.

291

Six-Membered Ring Systems." Diazines and Benzo Derivatives

A similar condensation was used by Ohta and co-workers in the synthesis of pyridazinefused isopropylidenenorbornadiene 119 <01JCS(P1)1372>. Compound 118 was prepared by the cycloaddition of 116 and dimethylfulvene 117. Hydrolysis of acetal 118 with formic acid followed by condensation with hydrazine hydrate gave 119.

I

c.o

Ill

CH(OEt)2

tol, reflux -__

+

CHO

I

1. formic acid

H

7

2. NH2NH2=H20 CH(OEt)2

116

119 H

118

117

overall yield -- 40%

Another very popular and efficient method to synthesize pyridazines remains the inverse electron demand Diels-Alder reactions of 1,2,4,5-tetrazines with electron rich dienophiles. Wan and Snyder reported the [4 + 2]-cycloaddition of the readily available tetrazine 121 with N-protected 2-aminoimidazole 120 to obtain pyridazine 122 (86%). Subsequent deprotection and decarboxylation gave 123, the structure originally assigned to zarzissine, a cytotoxic marine natural product <01T5497>. Zarzissine was thcn reassigned as the imidazole[4,5b]pyrazine 124. C02M e Me2N/~N

+ H

2. aq. KOH 99%

N I~1

THF

~ C02M e

120 1. HOAo/HCI

N I~

C02Me Me2N/~N

86%

C02Me

121 "

122

H2N--
N

123

H 124

corrected Zarzissin e structu re

Similarly, [4 + 2]-cycloadditions were used to construct the pyridazino[4,5-b]indole 126 during the synthesis of the staurosporinone analogue 132 in excellent yield <01TL7929>. Under Weinreb conditions, compound 126 was regiospecifically transformed into tethered alkynylamide 130 in good yield with amine 129. The alkynylamine 129 was successfully prepared by coupling 127 and 128 under Sonogashira conditions. Pyrrolo[3,4-c]carbazoles 131, obtained after the intramolecular [4 + 2]-cycloaddition were subsequently converted to the staurosporinone analogue 132.

292

G.H.C. Woo, J.K. Snyder and Z-K. Wan .C02Me ii

+ N

I

i

N R = CI, Br, H

C02Me

125

CH2CI21

PdCI2(PPh3)2

127

121

Cul, NHEt 2 75-86%

95% ~ C02M e

/

C02Me 129

126

I

AIMe3 71-76%

\

0

R

H

I C02Et 132

diglyme BHT upto 90%

C02Me

130

6.2.4.2

H

/"

N

N" ~

"o-C6H4R

C02Me 131

Reactions of Pyridazines

New developments in the explosive field of palladium-catalyzed cross coupling reactions have included pyridazines as coupling partners. Rival and co-workers introduced a Suzuki cross-coupling during an one-step synthesis of 3-amino-6-arylpyridazines 135 <01TL2115>. This is claimed to be the first use of an unprotected aminopyridazine (133) in Suzuki crosscouplings as the electron deficient aryl halide. Electron donating substituents on the phenylboronic acid 134, such as a methyl group, provided optimal yields. N-N CI~__~NH2 133

~

R"

B(OH)2 134

pd(PPh3) 4 Na2C03 35 - 60%

R 1

35

NH2

Aldous and co-workers also reported extensive results on palladium-catalyzed coupling reactions. They introduced the utility of electron-deficient pyridazinyl triflate 136 in Stille and Suzuki biaryl cross-couplings with electron rich aryl stannanes and aryl boronates 137 <01SL150>. Electron deficient aryl stannanes resulted in more sluggish reactions and poor yields. In general, Suzuki reactions were found to be better than the corresponding Stille couplings.

293

Sbc-Membered Ring Systems." Diaz.ines and Benzo Derivatives

N-N Me---~ \X/.~O. /0 S-O

+

CF3

Pd(PPh3)4 ~

X--Ar

N-N Me~Ar

137

136

138

Yield%

Ar-X

Yield%

Ar-X

Yield%

77

N~-~Sn (Me)3

<~~--B~(~~

84

•••-Sn(Me)3

not isolated

22

~B(OH)2

84

~B(Et)2

15

~ ~ - - S n (n-Bu)3

6

~B(OH)2

54

Ar-X

Recently, QuEguiner and co-workers reviewed the directed metallation of azines and diazines <01T4489>. The metallations of diazines such as pyridazines 139 and 142 are more challenging than pyridines due to the lower level of their LUMOs which makes them prone to nucleophilic additions and electron transfer. Due to their nucleophilicity, alkyllithium reagents are less efficient metallating reagents than LDA and LTMP. The metallations of numerous substituted pyridazines were reported followed by quenching with electrophiles to yield higher substituted pyridazines such as 141 and 143, albeit often in modest yield.

OMe N~

1. LTMP 2. TsN3

R 139

OMe N ~ N3 R

Fe, NH4C, 43 - 83%

OMe NN~H 2 , , N R 141

140

0~ O M e

142

1. LTMP 3. hydrolysis 12 - 26%

MeO~o

OH

N 143

A novel method of pyrrole ring annulation onto a pyridazine based on a tandem SNH-S~I4 amination process using enamines as difunctional nucleophiles, was reported <01TL5981>. Thus, enamine 144 reacted with 145 in the presence of AgPy2MnO4 to afford 146 in one pot in modest yields. A mechanism was also presented.

294

G.H.C. Woo, J.K. Snyder and Z-K. Wan

O ~ N R

O ~ N R

-----"

I

ioj

I

145 R1

-H20

H

O~

N/J~NCa

I

R1

o

R1

\

N--

I

~N

I

146

I

11 - 4 4 %

Tricyclic compounds containing the pyridazine moiety were prepared during the synthesis of nevirapine derivatives, a potent HIV-1 reverse transcriptase inhibitor <01JHC125>. Pyridazine 147 under goes nucleophilic substitution with appropriate amines to afford 148, which can be isolated. Subsequent cyclization completes the construction of tricyclic cores 149 and 150 as neviraspine analogues. 0

0

R

R

amines N, N/.~L...Cl CI...--~..N-. N

N-.N//L-.NH CI~&-N~N

28 - 87%

I

R

148

147

Na2C03 38 - 64% 0

0 NH

0

NR

C I ~

N~~N

CI

+

CI

~

Nevirapine

"N

R

R 149

R

150

149:150

R=C2H 5 1:2.1

J~ 1 '2.8

C3H7 1'1.2

As mentioned earlier in Section 6.2.4.1, pyridazines also react readily with electron-rich dienophiles to undergo inverse electron demand Diels-Alder reaction <01TL7929>. 6.2.5

CINNOLINES

6.2.5.1 Preparations of Cinnolines

Cinnolines, one of the two benzo derivatives of pyridazines, received considerable attention due to the pharmacological activities exhibited by these heterocycles. Hydrazones 152, prepared by coupling aryl diazonium salts with the enaminones 151 <01T1609>, were

I

295

Six-Membered Ring Systems." Diazines and Benzo Derivatives

cyclized in concentrated H2SO4 to afford cinnolines 153. The mechanism presumably involves an intramolecular electrophilic addition to the aromatic ring by the protonated formyl group, followed by elimination of water. O o

Ar/

""~

"NMe2

RC6H4N2C I

Ar

N.

65 - 78%

151

H

N"

H

R~

152

H2SO 4, 1O0~

R

5 - 60%

Ar

153

In another novel condensation, 3-diethylamino-5-ethynyl-l,4-naphthoquinones 154 reacted with an excess of hydrazine hydratc in boiling pyridine to provide cinnolines 155 in acceptable yields <01RCB 1668>. R

,N. . NN,.~ .~[ -CH2R Et2N

NH2NH 2

9H20

E t 2 N ~

pyridine 0 154

20 - 60%

0

R = Ph, P-C6H4-OMe, P-C6H4-N02

155

6.2.5.2 Reactions of Cinnolines

Chlorocinnolines 156 and 158 were metallated with LTMP or LDA by deprotonation followed by quenching with various electrophiles to introduce substituents at C3 and C4 in moderate to good yields, 157 and 159 <01T4489>. In general these yields were better than those reported earlier for pyridazine deprotonation <Sec.6.2.4.2>. CI

1. LTMP, THF

~

E I

C

2. E +

156

3. hydrolysis 60 - 88%

CI

157 E = CH(OH)Me, CH(OH)Ph CI

1. LTMP, THF 2. E + 158

3. hydrolysis 35 - 89%

159 E = CH(OH)Me, CH(OH)Ph CH(OH)(4-(OMe)Ph), Me, I, C02H

Al-Awadi and co-workers investigated unique routes to polynuclear aromatic compounds using flash vacuum pyrolysis (FVP) of 3-arylcinnolines <01T7377>. The FVP of 160 at

296

G.H.C. Woo, J.K. Snyder and Z-K. Wan

900~ and 0.02 Torr gave low yields of phenanthrenes 166 and phenylacetylenes 162 as the major products and anthracenes 168 and diarylacetylenes 164 as the minor products. The ratio of these four products depended on the R-substituent on the phenyl ring in 160. The mechanistic pathways for the products are also illustrated in the same scheme. These pyrolytic conversions presumably took place via N2 elimination followed by formation of diradical intermediates. o

o N2

R

__

O

H-shift H

161

160

R = H, CI, OMe, NO 2

R__~

.A,co

= R

~ H'shift

162

:CO ~ C O ~/]""~

cyclization

R H

a~ - I 0

15 - 46%

-'a~ ' l

O

-- = ~ 168

3- 15% 6.2.6

PHTHALAZINES

6.2.6.1

Preparations of Phthalazines

Phthalazines, the other benzopyridazines, were also prepared most frequently through condensation of hydrazine with 1,4-dicarbonyl compounds. This was illustrated by Napoletano and co-workers who employed the condensation of lactone 169 with hydrazine to obtain 170 <01BMCL33>. After the POC13 chlorination, chlorophthalazine 171 was produced. Treating 171 under a variety of conditions, including SNAr displacements and Sonogashira couplings, resulting in a series of new PDE4 inhibitors 172 in good yields.

297

Six-Membered Ring Systems." Diazmes and Benzo Derivatives

O

O

169

CI

NH2NH2 / O ~ N H CH3CO2H 99% 17o

Ci ~ / ~ , N

POCl3

/ O ~

N

11 "1 R

variousreagents 172

cl~

N

Similarly, Searcey and Tsoungas prepared phthalazine 174 by condensation of dialdehyde 173 with hydrazine in excellent yield during their investigation of potential precursors to DNA intercalators <01TL6589>.

H 3 C O " ~ CHO v

NH2NH2

"CHO

H3CO~N

82%

'/t~-"t"'~N 174

173

Stajer and co-workers reported a new series of tricyclic heterocycles 178 containing the phthalazine moiety <01JCS(P1)558>. This pyrimido[2,1-a]phthalazine was synthesized by first treating acyl hydrazide 175 with 2-aroylbenzoic acids 176 to give 177. Then, 177 was converted into 178 upon refluxing in toluene by a retro Diels-Alder reaction eliminating cyclopentadiene.

+

, , oo2. ~

Ar

0 175

176

0

EtOH refl----ux Tol,r e ~

~ 0 N. ,, M NN ~Ar 1,,

,,~ N,.N~ Ar

Joule and co-workers accomplished their synthesis of phthalazines utilizing Robev's method <81TL345>. First, 2-bromobenzaldehyde 179 was treated with hydrazine to give 180, which was transformed into phthalazine 181 after the elimination of one of the aryl residues <81TL345> promoted with either AIC13 or A1Br3, though only in 13% yield <01H2139>. Phthalazine 181 efficiently coupled with phenylethyne under palladium catalyzed conditions to give alkyne 182 which was brominated to afford dibromoalkene 183.

298

G.H.C. Woo, J.K. Snyder and Z-K. Wan

In the presence of disodium trithiocarbonate, compound 183 cyclized to afford novel tricyclic compound 184 in acceptable yield.

[ ~Br CHO

N2H4/H2SO4 aq. 83% NH3 '~ ~ Br

179

AICI313% ~ AIBr3

~ BrN

180

Ph

CI2Pd(PPh3)2,= Cul, Et3N 76%

N"NB ~

N

,~.N

Br2 -__ CH2CI2

Ph

182

59%

181

.~.~ Br

Ph

N

183

aq. Na2CS3 = MeOH 50%

~N Ph 184

6.2.6.2 Reactions of Phthalazines

As seen with pyridazines, palladium catalyzed coupling reactions were also frequently applied in the phthalazine field. For example, commercially available 1,4dichlorophthalazine 185 was aminated to give 186 in good yield by aromatic nucleophilic substitution with N-methylpiperazine <01S699>. Then, 186 was coupled with various substituted arylboronic acids to obtain 187 by Suzuki-type cross-coupling reactions. Best results were obtained with electron-donating substituents on the arylboronic acid.

c,

N

H N

C! 185

I N

I N

~ ~ ,n- uOH

N

N

TEA

70%

N

CI

I [~N~

B(OH)2

@_

N

R

,N

Pd-souree

10 - 70%

18

R

186

Unstable N-ylide 188 underwent a 1,3-dipolar cycloaddition with dimethyl acetylenedicarboxylate (DMAD) to afford novel nitrogen heterocycle 189 in over 90% yield <01TL8379>. The cycloaddition was stereospecific and only cis-cycloadducts 189 were observed. Cycloadduct 189 underwent allylic rearrangement upon temperature increase (i.e. 0~ to rt) followed by aromatization upon refluxing in acetic acid to afford 191.

299

Six-Membered Ring Systems: Diazines and Benzo Derivatives

Bz

H Bz

I~N"N"~'

Et3N

Q-H"',

/ ,,,:x/ ---~,

E

E

heat

=

E

syn-188

E I'1 "T 190

cis-189

E = CO2Me

Bz

,~~AcOH,

heat >90%

E

191

6.2.7

PYRAZINES

6.2.7.1 Preparations of Pyrazines The most common way to construct the pyrazine ring is the condensation of 1,2-diamines with 1,2-dicarbonyl compounds followed by the aromatization. Pritchard and co-workers developed an efficient procedure to prepare pyrazines, quinoxalines and 1,2,4-triazines by such condensations <01JCS(P1)668>. Dicarbonyl component 193, prepared by coupling amino acid 192 with (tert-butoxycarbonylmethylene)triphenylphosphine using DCC-DMAP, underwent ozonolysis to give 194. Then, 194 was treated with 1,2-ethylenediamine followed by aromatization with Pd-C to give pyrazine 195 in good yield. O

N_HBoc

O

O

DCC, DMAP 63%

192

O 03 ~.

O

_NHBoc

PPh 3

O

193

O

BuO t

1. H2N

79% co2tBu 194

O

NH 2

2. 10% Pd-c 62%

.....

!.

N'~" BuO

i,c

)2 '"NHBoc 195

Similarly, the pyrazine moiety of pyrazine-fused-isopropylideneorbornadiene 198 was prepared by condensation of 1,2-diketone compound 196 and ethylenediamine, followed by dehydrogenation of 197 in presence of nickel peroxide (overall yield 41%) <01JCS(P1)1372>. Then, compound 198 was treated with electrophilic reagents such mCPBA, NBS, and 4-phenyl-l,2,4-triazole-3,4(4H)-dione (PTAD) to measure the effect of the pyrazine ring on the 7t-facial selectivity in these electrophilic reactions.

300

G.H.C. Woo, J.K. Snyder and Z-K. Wan

I

I

H2N NH2 p-TsOH

I

NiO2

Y

-

0 196

----N

Overall yield = 41%

197

198

Recently, Kamitori reported a new procedure to synthesize fluorine-containing heterocycles including pyrazines and imidazoles <01JHC773>. Aldehyde-derived dialkylhydrazones 199 were treated with trifluoroacetic anhydride to give 200, which was then hydrolyzed with H2SO4 to afford 201. ot-Diketohydrates 201 reacted readily with diamines such as diamino succinonitrile to afford pyrazines 202, or with 1,2phenylenediamine to yield quinoxalines 203 in good yields. R\ Me/N-N~'~ R1

-

TFAA 2,6-1utidine

R\

,.

Me/N-N==~R1

O R I ~

H OH OF3 201

H2S04

200

199

NC

.COCF3

N~

NC"~NH2 .~

OF3

o 76%

"I

52 - 93% N~

202

OF3

203

A large number of heterocycles exhibiting antitumor activity contain pyrazino[2,3b]indoles such as B-220 (204), an ellipticine analogue <01H925>. M~rour and co-workers developed a straightforward syntheses of pyrazino[2,3-b]indoles 207 by the reaction of ethylenediamine and 206 to give 207 and 208 in 10% and 72% yields, respectively. Unaromatized product 208 spontaneously aromatized to 207 upon contact with air after stirring in ethyl acetate and methanol for 6 days. 0 O H2N NH2 ~ N Br2 Br --96% 82% N Ac H Ac Final yield = 68% 206 207 + 205 EtOAc/MeOH L

~"

.~N

..N ~ , / - ~ . ~ Me N'~N ~ M e B-220

NMe2

204 H

208

H

301

Six-Membered Ring Systems: Diazines and Benzo Derivatives

Zhang and co-workers accomplished a regioselective synthesis of thieno[2,3-b]pyrazines 213 by condensation of 209 with 210 <01SC725>. Selectivity for 211 over 212 was enhanced using excess trifluoroacetic acid (TFA). Increasing the amount of TFA from 2 to 17 equivalents improved the selectivity from 3.6:1 to 15.5:1, 211:212, respectively. The reason for this selectivity was thought to be due to initial imine formation from the 2-amino group of 209 with the ketone carbonyl at 210 during the condensation and subsequent cyclization giving 211.

H2NvCN L TsOH H2N

+

O R ' ~ "OR~

SP

TFA

R.~N~CN

OR1

209

N

210

II ~

~N~ON

SPh

R

N

211

SPh

212

NH2 213 In an interesting approach, Chandrasekhar and Gopalaiah used a Beckmann rearrangement to construct fully substituted pyrazines <01TL8123>. One advantage of using this rearrangement was that no additional reagent was needed. The oxime hydrochloride 214 was thermally dehydrated to the corresponding N-alkylnitrilium ion 215 followed by deprotonation to the nitrile ylide 216, which dimerized to form dihydropyrazine 217. Dihydropyrazine 217 oxidized upon exposure to air into pyrazine 218 during work-up.

N,OH Bn,,~B n HCI

110~

=-

G [ Bn--N-C-Bn }

214

Ph ~ C ,C~p Bn

H ('H+) ~_ [ Ph-C-N-C-Bn @ (~)

215

~N~

216

Ph .N~ Bn h

Bn

N 217

]

[o]

Ph.. N_

Bn

Ph 218 67%

6.2.7.2 Reactions of Pyrazines As seen with pyridazines and benzopyridazines, directed metallation methodology of pyrazines and their benzo derivatives was also reported <01T4489>. Metallation of chloropyrazines 219 and quenching with protected ribonic lactone 220 yielded pyrazine Cribosides 221.

302

G.II. C. Woo, J.K. Snyder and Z-K. Wan R N

1 . R

N

Cl

2.

BnO BnO~.

219

~o--~o ]

R=H, CI

OBn

3. H20

[

0

OBn

220

OBn

--N

OBn

221 65 - 72%

Sato and Narita accomplished the acylation of pyrazines by Stille reactions of bromopyrazines 222 with 1-ethoxyvinylstannanes 223 using copper co-catalysts <01S1551>. They found that the copper additive increased the yields from 31% to 93%. The Cu-induced acceleration was most prominent for electron-deficient pyrazines, which are more reactive in the Pd-catalyzed reactions. R3 R

0

+

N~ N

R1

222

EtO~__~___fRs Bu3Sn /

1. Pd-cat, CuX 2. aq. HCI

223

R5 = H, Me

77 - 96% X = I, Br, CI

R4 R

N~-'~"R1 224 R 4 = Me, Et

6.2.8 PHENAZINES 6.2.8.1 Preparations of Phenazines

Naturally occurring phenazines have attracted considerable attention because of their interesting biological activities <96TL9227>. Phenazines are also widely employed in metalbinding ligands in all aspects of coordination chemistry, and in modern applications to areas such as supramolecular chemistry and bioinorganic chemistry <84JPC5709>. As with pyrazines (Section 6.2.7.1), phenazines, the dibenzo derivatives of pyrazine, can also be prepared from the reaction of diamines and dicarbonyl compounds. Chattopadhyaya and co-workers utilized this method to build phenazine systems in the synthesis of [Ru(phen)2dppz] 2+ 228, which were used for structure elucidation of nucleic acids without radioactive probes <01JACS3551>. The phenazine component of [Ru(phen)2dppz] 2§ was prepared by condensation of 226 and 3,4-diaminobenzoic acid. Diketone complex 226 was prepared by two consecutive ligand displacements from RuCI3.

Six-Mernbered Ring Systems." Diazines and Benzo Derivatives

-1 1,10-phenanth roline

RuCI 3

303

2+

CI

1,10-phenanthroline-5,6-dione

24 2+

--7

225

227

226

2+

~

phen 228

dppz'

Giorgi-Renault and co-workers introduced a new method to prepare phenazine bis-Noxides <01SC2329>. Oxidation of 229 with excess NaC10 in presence of KOH gave 230 in excellent yield, followed by esterification to afford 231. Then, compound 233 was prepared by condensation of 231 and enamine 232. 5,10-Dioxyphenazine-2-carboxylic acid 236 was prepared by a two-step aromatization of precursor 233. First 233 was dibrominated in presence of NBS and a catalytic amount of benzoyl peroxide, then subsequent dehydrobromination 234 by KOBu t afforded aromatized product 235. Finally, saponification of 235 gave the final product 236 in good yield.

304

G.tt.C. Woo, J.K. Snyder and Z-K. Wan

229

~ N

0 1. NaCIO, KOH H 0 2 C ~ ~ 2. HCI N0 94% 230

~

MeOH

0 MeO2C'-~~N~ ,(:::)

H2S04

~

90%

231

232

MeO2C'~~NN ~

DMF 58%

NBS, (C6H5C02,2 M e O 2 C ~ N

(~ 233

t-BuOK MeO2C 80%

v

-~N'

~

~

Br

86% 234

.

.aO._.

!'N~"'~

H2O, MeOH

v

!-N~'~

93% 235

236

6.2.8.2 Reactions of Phenazines

A simple synthesis of bisintercalant 240, a bisphenazine, was reported <01TL5701>. First, 2-(bromomethyl)phenazine 237 underwent an SN2 displacement with 4,4'-bipyridine 238 to afford 239 in refluxing acctonitrilc in 30% yield. Another displacement reaction with 237 in refluxing acetonitrile then gave target 240 in 57% yield. N

Br

N 237

1. CH3CN

+

2. NH4PF6 " ~

N/~ ~~@/N

4hr

30%

QN ~ ~] pF6(~ ~N~

239

1. CH3CN,240

(~N

2. NH4PF6 3days

57%

(:~ 2PF6

240

@l'~ N.,~ N

6.2.9

QUINOXALINES

6.2.9.1 Preparations of Quinoxalines

Quinoxaline derivatives attract many chemists due to their wide range of biological activities including antifungal, anticancer and antiinflammatory activities <88H2481>.

305

Six-Membered Ring Systems." Diazines and Benzo Derivatives

Furthermore, several of these quinoxaline derivatives exhibit antidiabetic, antiallergic, and angiotensin II receptor antagonistic properties <94JMC2846>. The most well known method to construct quinoxalines remains the condensation between 1,2-phenylenediamine and a 1,2-dicarbonyl compound as seen in the preparation of pyrazines (Section 6.2.7.1). For example, the reaction of 1,2-phenylenediamine (242) and dicarbonyl compound 241 gave quinoxalines 243 in good yields <01SL1953>.

R'

R2HN

RaN~L..s~O

H2N~'~ H2N" ~

241

R,

EtOH 58 - 63%

R3N

N

242

243

Peters and Peters applied similar chemistry to synthesize linear dibenzo heterocycles terminating in a quinoxaline system <01JHC1055>. Fused quinoxalines 245 were prepared from the condensation of 1,2-phenylenediamine 242 with 1,2-dicarbonyl compounds 244.

~

H2N

0

I

ph--N-.R 244

X=CH2, (CH2)2, SCH2 R=Ph, Me

H2N

EtoH

H+ 21 - 60%

X

N~.

t ph~N'R

242 245

Filippone and co-workers reported a resin-bound synthesis of quinoxalines <01HCA2379> using both Wang and Merrifield resins. Polymer-bound 3-diazenylbut-2enoates 246 reacted readily with substituted 1,2-phenylenediamines 247 to afford polymerbound quinoxalines 250 through intermediates 248 and 249. Final products were cleaved by treatment with MeONa in MeOH/THF to afford 251.

306

G.II. C. Woo, J.K. Snyder and Z-K. Wart

Sarodnick and Linker developed an one-pot synthesis of quinoxaline 254 from 1,2phenylenediamine (242) and 2,3-butanedione monoxime 252 via oxime intermediate 253 < 01JHC829>. Yields were only moderate.

-OH 242

6.2.9.2

30%

N

252

55%

253

254

Reactions of Quinoxalines

Directed ortho-metallations were also applied to quinoxalines. 2-Methoxyquinoxaline 255 was metallated and then trapped with numerous electrophiles <01T4489>. However, the yields of desired products 256 were low due to substantial dimerization which limited the efficiency of the electrophilic trapping reaction.

1. OMe 255

2. E+ 3. H20

,tHE

Z ~

E = D, CH(OH)Me, CH(OH)Ph, CH(OH)(2-(OMe)Ph), I, C(OH)Ph2

"N 256

+

Dimer

OMe 9 - 53%

Quinoxalines are useful intermediates for the syntheses of many bioactive natural products. Kato and co-workers illustrated a simple and facile bromination of heteroarenes using quinoxaline 257. The hydroxy group on 257 was replaced with a bromine by treatment with P2Os and Bu4NBr in toluene to afford 258. This method provided precursors for many important reactions such as Pd-catalyzed cross couplings <01TL4849>.

307

Six-Membered Ring Systems." Diazmes attd Benzo Derivatives

[ ~ a?, ~j,/oa

P205,au4aar

N

•

[ ~ N~j,TBr

Tol, 100~

257

N

79%

258

Joule and Armengol also employed Pd-catalyzed couplings of 2-haloquinoxalines 259 in the syntheses of thieno[2,3-b]quinoxalines 262 <01JCS(P1)978>. The 2-haloquinoxalines were cross-coupled with an alkyne catalyzed by Pd(0) (Sonagashira coupling) to give alkyne 260, which was dibrominated with 1 equivalent of bromine to afford 1,2-dibromoalkene 261. 1,2-Dibromoalkenes 261 readily reacted with Na2CS3 to give a thieno[2,3-b]quinoxaline 262 with the loss of the bromine and cyclization.

R2

NTHal

R'-fi-

~R

N

2

1 equiv Br 92 59%

Pd(O) 82%

259

N..:

Br

R'~N~~Br

R2

260

Na2CS3 53%

261

R, f f ' ~ ~.~

N~~.~R 2 N//~'S" 262

Charushin and co-workers prepared the first example of fluorine-containing quinoxaline derivatives, pyrimido[4,5-b]quinoxalines 265, in two steps <01MC54>. First, orthoaminonitriles 263 were converted into carboxamides 264 upon treatment with concentrated sulfuric acid, followed by cyclization of the ortho-aminocarboxamides 264 with triethyl orthoformate to give 265 in excellent yield.

F ~ N.--/ ~ F -N< CN NH2

H2SO4 _~ F . ~ N 92% F

263

0 .:~CONH2 HC(OEt)387% FJ~..~N//J-..N//jF~N~@NH N NH2 264

265

In presence of indium metal in aqueous ethanol, the pyrazine moieties of quinoxalines 266 were easily and selectively reduced to the tetrahydro derivatives 267 in excellent yields .

H N~ 266

aq NH40H 9 71 - 9 7 %

N H 267

308

G.H.C. Woo, J.K. Snyder and Z-K. Wan

6.2.10 R E F E R E N C E S 81TL345 84JPC5709 88H2481 94JMC2846 96TL9227 01BMCL33 01BMCL211

01BMCL701

01CL274 01EJOC1077 01Hl15 01H925 01H1747 01H2139 01HA52 01HCA87 01HCA2379 01JACS3551 01JCS(P1)457 01JCS(P1)558 01JCS(P1)622 01JCS(P1)668 01JCS(P1)955 01JCS(P1)978 01JCS(P1)1241 01JCS(P1)1372 01JHC125 01JHC419 01JHC773 01JHC829 01JHC1055 01JMC350 01JMC988

01JMC1710 01JMC1971

S. K. Robev, Tetrahedron Lett. 1981, 22,345. A. Yamagishi,J. Phys. Chern. 1984, 88, 5709. G. Sakata, K. Makino, Y. Kurasawa,Heterocycles 1988, 27, 2481. D. Catarzi, L. Cecchi, V. Colotta, F. Melani, G. Filacchioni, C. Martini, L. Giusti, A. Lucacchini, J. Med. Chem. 1994, 37, 2846. Y. Hosoya, H. Adachi, H. Nakamura, Y. Nishimura, H. Naganawa, Y. Okami and T. Takeuchi, Tetrahedron Lett. 1996, 37, 9227. M. Napoletano, G. Norcini, F. Pellacini, F. Marchini, G. Morazzoni, P. Ferlenga, L. Pradella, Bioorg. Med. Chem. Left. 2001, 11,33 J. W. Corbett, S. Pan, J. A. Markwalder, B. C. Cordova, R. M. Klabe, S. Garber, J. D. Rodgers, S. K. Erickson-Viitanen, Bioorg. Med. Chem. Lett. 2001, 11,211.

It. F. Boyd, B. Hammond, D. M. B. Hickey, R. J. Ire, C. A. Leach, V. A. Lewis, C. H. Macphee, K. J. Milliner, I. L. Pinto, S. A. Smith, I. G. Stansfield, C. J. Theobald, C. M. Whittaker, Bioorg. Med. Chem. Lett. 2001, 11,701. Y. Chen, Y. Lain, S.-Y. Lee, Chem.Lett. 2001, 3,274. J. Wirsching, J. Voss, G. Adiwidjaja, A. Giesler, J. Kopf, Eur. J. Org. Chem. 2001, 1077. A. Z. M. S. Chowdhury, Y. Shibata, lteterocyles2001, 55,115. F.-A. Alphonse, S. Routier, G. Caudert, J.-Y. Mdrour,Heterocycles 2001,55,925. A. Z. M. S. Chowdhury, Y. Shibata, M. Morita, K. Kaya, T. Sano, Heterocyles 2001, 55, 1747. A. K. Karim, M. Annengol, J. A. Joule,Heterocycles 2001, 55, 2139. N. Kumar, G. Singh, A. K. Yadav, tteteroatom Chem. 2001,12, 52. H. Trafelet, E. Stulz, C. Leumann, Helv. Chim. Acta 2001, 84, 87. O. A. Attanasi, L. De Crescentini, P. Filippone, F. Mantellini, S. Santeusanio,Helv. Chim. Acta 2001, 84, 2379. D. Ossipov, P. I. Pradeepkumar, M. I tolmer, J. Chattopadhyaya,J. Am. Chem. Soc.2001, 123, 3551. P. F. Asobo, H. Wahe, J. T. Mbafor, A. E. Nkengfack, Z. T. Fomum, E. F. Sopbue, D. D6pp, J. Chem. Soc., Perkin Trans. 1 2001, 457. P. Soh~ir, F. Mikl6s, A. Csfimpai, G.St,'ijer,J. Chem. Soc., Perkin i 2001, 558. F. Heaney, C. Burke, D. Cunningham, P. McArdle, J. Chem. Soc., Perkin Trans. 1 2001, 622. R. M. Adlington, J. E. Baldwin, D. Catterick, G. J. Pritchard, J. Chem. Soc. Perkin Trans. I 2001, 668. M. R. Pitts, J. R. Harrison, C. J. Moody, J. Chem. Soc. Perkin 1 2001, 955. M. Armengol, J. A. Joule,J. Chem. Soc. Perkin 1 2001, 978. B. L. Booth, I. M. Cabral, A. M. Dias, A. P. Freitas, A. M. Matos Beja, M. F. Proenca, M. R. Silva, J. Chem. Soc., Perkin Trans. 12001, 1241. T. Kobayashi, K. Miki, B. Nikaeen, A. Ohta,J. Chem. Soc., Perkin 1 2001, 1372. G. Iteinisch, B. Matuszczak, E. Spielmann, M.Witvrouw, C. Pannecouque, E. De Clereq, J. Heterocyclic Chern. 2001,38, 125. M. GiJtschow, J. C. Powers, J. Heterocyclic Chem. 2001 38,419. Y. Kamitori, J. Heterocyclic Chem. 2001, 38,773. G. Sarodnick, T. Linker, J. Ileterocyclic Chem. 2001, 38,829. G. Kollenz, R. Theuer, K. Peters, E.-M. Peters, J. Heterocyclic Chem. 2001, 38, 1055. C. Almansa, A. F. de Arriba, F. L. Cavalcanti, L. A. G6mez, A. Miralles, M. Merlos, J. Garcia-Rafanell, J. Forn,J. Med. Chem. 2001, 44,350. A. O. Stewart, P. A. Bhatia, C. M. McCar~, M. V. Patel, M. A. Staeger, D. L. Arendsen, I. W. Gunawardana, L. M. Melcher, G.-D. Zhu, S. A. Boyd, D. G. Fry, B. L. Cool, L. Kifle, K. Lartey, K. C. Marsh, A. J. Kempf-Grote, P. Kilgannon, W. Wisdom, J. Meyer, W. M. Gallatin, G. F. Okasinski, J. Med. Chem. 2001, 44,988. B. L. Chenard, W. M. Welch, J. F. Blake, T. W. Butler, A. Reinhold, F. E. Ewing, F. S. Menniti, M. J. Pagnozzi,J. Med. Chem. 2001, 44, 1710. M. D. Meyer, R. J. Altenbach, ti. Bai, F. Z. Basha, W. A. Carroll, J. F. Kerwin, Jr., S. A. Lebold, E. Lee, J. K. Pratt, K. B.Sippy, K. Tietje, M. D. Wendt, M. E. Brune, S. A.

Six-Membered Ring Systems. Diazines and Benzo Derivatives

01JOC192 01JOC2789 01JOC3513 01JOC4723 01MC54 01RCB1668 01S565 01S699 01S1551 01SC2329 01SC725 01SL150 01SL333 01SL1953 01T179 01T1261 01T1609 01T1785 01T4489 01T5497 01T7221 01T7377 01TL1061 01TL1749 01TL2115 01TL2553 01TL2977 01TL4849 01TL5701 01TL5981 01TL6589 01TL7929 01TL8123 01TL8379

309

Buckner, A. A. Hancock, I. Drizin, J. Med. Chem. 2001, 44, 1971. J. Teixid6, J. I. Borrell, C. Colominas, X. Deupi, J. L. Matallana, J. L. Falc6, B. MartinezTeipel,J. Org. Chem. 2001, 66,192. H. An, T. Wang, A. Maier, M. Manoharan, B. S. Ross, P. D. Cook, J. Org. Chem. 2001, 66, 2789. M. Aso, T. Ikeno, K. Norihisa, M. Tanaka, N. Koga, II. Suemune, J. Org. Chem. 2001, 66, 3513. M. Giitschow, J. C. Powers, J. Org. Chem. 2001, 66, 4723. V. N. Charushin, S. K. Kotovskaya, N. M. Perova, O. N. Chupakhin, Mendeleev Commun. 2001, 54. I. D. Ivanchikova, R. N. Myasnikova, M. S. Shvartsberg, Russ. Chem. Bull., h~t. Ed. 2001, 50, 1668. C. Giordano, F. Fratini, D. Attanasi, I~. Cellai, Synthesis 2001,565. S. Guery, I. Parrot, Y. Rival, C. G. Wermuth, Synthesis 2001, 699. N. Sato, N. Narita, Synthesis 2001, 1551. M. Haroun, P. I Ielissey, S. Giorgi-Renault, Synth. Commun. 2001, 31,2329. W. Zhang, A. R. tlaight, K. L. Ford, S. I. Parekh, Synth. Cummun 2001, 31,725. D. J. Aldous, S. Bower, N. Moorcroft, M. Todd, Synlett 2001, 150. S. Makino, N. Suzuki, E. Nakanishi, T. Tsuji, Synlett 2001, 333. B. Zaleska, D. Ciez, J.Lech, Synlett 2001, 1953. J. Robles, A. Grandas, E. Pedroso, Tetrahedron 2001, 57, 179. F. Hausch, A. J~ischke, Tetrahedron 2001, 57, 1261. N. A. A1-Awadi, M. tI. Elnagdi, Y. A. Ibrahim, K. Kaul, A. Kumar,Tetrahedron 2001, 57, 1609. J. J. V. Eynde, N. tlecq, O. Kataeva, C. O. Kappe, Tetrahedron 2001, 57, 1785. A. Turck, N. PI6, F. Mongin, G. Qu6guiner, Tetrahedron 2001, 57, 4489. Z.-K. Wan, G. H. C. Woo, J. K Snyder, Tetrahedron 2001, 57, 5497. G. Calestani, L. CapeIla, R. Leardini, M. Minozzi, D. Nanni, R. Papa, G. Zanardi, Tetrahedron 2001, 57, 7221. Y.A. Ibrahim, N. A. AI-Awadi, K. Kaul, Tetrahedron 2001, 57, 7377. A. A.-H. A. Rahman, T. Wada, K. Saigo, TetrahedronLett. 2001, 42, 1061. S. Makino, E. Nakaishi, T. Tsuji, Tetrahedron Lett. 2001, 42, 1749. S. Guery, I. Parrot, Y. Rival, C. G. Wermuth, Tetrahedron Lett. 2001, 42, 2115. M.-X. Wang, Y. Liu, Z.-T. Huang, Tetrahedron Lett. 2001, 42, 2553. J. Girniene, D. Gueyrard, A. Tatibou6t, A. Sackus, P. Rollin, Tetrahedron Lett. 2001, 42, 2997. Y. Kato, S. Okada, K.Tomimoto, T. Mase, Tetrahedron Lett. 2001,42, 4849. M.-J., Fem~indez, K. B. Grant, F. Herraiz, X. Yang, A. Lorente,Tetrahedron Lett. 2001, 42, 5701. A. V. Gulevskaya, D. V. Besedin, A. F. Pozharskii, Z. A. Starikova,Tetrahedron Lett. 2001, 42, 5981. P. G. Tsoungas, M. Searcey, Tetrahedron Lett. 2001,42, 6589. R. Nomak, J. K. Snyder, Tetrahedron Lett. 2001, 42, 7929. S. Chandrasekhar, K. Gopalaiah, TetrahedpvnLett. 2001, 42, 8123. F. Dumitrascu, C. I. Mitan, C. Draghici, M. T. Caproiu, D. Raileanu, Tetrahedron Lett. 2001, 42, 8379.

310

Chapter 6.3

Six-Membered Ring Systems: Triazines, Tetrazines and Fused Ring Polyaza Systems*

Carmen Ochoa and Pilar Goya Instituto de Qu(mica Mddica (CSIC), Madrid, Spain. carmela@ iqm.csic.es and iqmg310@ iqm.csic.es

6.3.1. TRIAZINES Metal complexes of some divalent and trivalent metal ions with the Schiff base 3-(c~benzoylbenzylidenehydrazino)-5,6-diphenyl-l,2,4-triazine (HBZDT) have been investigated <01SRI205>. The synthesis and spectral characterization of organotin(IV) 1,3,5-triazine2,4,6-trithiolato complexes have been reported <01JOM(627)6>. Transition metal complexes of 2,4,6-trimercapto-l,3,5-triazine (TMT) as potential precursors to nanoparticulate metal sulfides have been described <01JOM(623)185>. A family of receptors for flavins based on 6aryl-2,4-acyldiamino-l,3,5-triazines has been synthesized <01TL7357>. Thermodynamic stabilities of linear and crinkled tapes and cyclic rosettes in melamine-cyanurate assemblies have been studied <01JA7518>. An in-situ fluorescent labelling probe of highly volatile methylamine with 8-(4,6-dichloro- 1,3,5-tri azinoxy)quinoline has been designed <01NJC872>. 2,4,6-Tris(2-fluoroanilino)-l,3,5-triazine successively undergoes one- two- three-fold deprotonation in the presence of (BuLi)-Li-n. The dilithiated triazenate exists as the dimeric complex (thf)(6)Li-4[(RN)(2)(RNH)C3N3](2) in the solid state (R = 2-F-C6H4) featuring bidentate N-endo-C-N-exo chelation sites <01CC2104>. Spontaneous formation of complementary hydrogen-bond pairs and their hierarchical self-assembly into chiral supramolecular membranes are achieved in water by mixing amphiphilic pairs of glutamate derived melamine and ammonium derivatized azobenzene cyanuric acid <01JA6792>. IH-, and '3C-NMR investigations of sigma-adduct formation of 1,2,4-triazine 4-oxides and 3chloro-6-phenyl-l,2,4-triazine with liquid ammonia and alkylamines have been carried out <01H(55) 127>.

6.3.1.1 Synthesis The solid phase synthesis of 1-substituted 4,5-dihydro-l,2,4-triazin-6-ones from imidate esters and substituted hydrazines has been reported <01TL6455>. The first reported solid phase synthesis of 3-amino-l,2,4-triazin-5(4H)-ones has been described. Reaction of polymerbound isothiourea with 2,3-diaza-3-pentenedioic anhydride afforded the title compounds in *Dedicated to Professor Wolfgang Pfleiderer on his 75th birthday

311

Six-Membered Ring Systems.'Triazines, Tetrazines and Fused Ring Polyaza Systems

good yields and high purity <01TL4433>. An efficient and enantioselective synthesis of 1,2,4-triazine substituted c~-amino acids from vicinal tricarbonyls has been reported <01JCS(P1)668>. Ring closure reactions of thiosemicarbazide derivatives and aryl, alkylketones yielded 2,5-substituted 3-thiol-l,2,4-triazines <0IIJC(B)500>. The synthesis of 3,3"bis(5,6-dibromomethyl-l,2,4-triazine) 1, a new polyfunctional bipyridine analogue for constructing supramolecular structures, has been synthesized from 2,3-butanedione and oxylhydrazidine, by two routes, in moderate to high yields <01SC1221>. O Br

Br O

NH2 NH2 N

+

NH2 NH2

Br.

N=N

EtOH ~'~

~-N

N-N N~

Br

"Br

Br

Reaction of imidazolone 2, used as building block, with hydrazines yielded 1,2,4-triazin-6one derivatives 3 <00MI229>. O ~ N - - c H 2 - - - ~ ~

,N- \-o

O

N

RNHNH2

Me

~

H2N-/"~ ~" ~r~ R N.. N

HO

O

~--"

Me

3 The reaction of bis(mercaptothioformyihydrazido)phthalate 4 with cyanamide yielded the bis-l,2,4-triazin-6-yl derivative 5 <01PS65>.

CI CI

+ NH "SH l~lH2

O

~- ~I [ ~ ~ O

=

SH

~HN.N

H

H2N~N~

S~J"-SH

4

S

5

New analogues of the antimalarial 2,5-diamino-3-phenoxypropoxy-l,3,5-triazine have been prepared and shown to maintain the activity against resistant P. falciparum strains <01JMC3925>. Cyclodesulfurization of N,N,N'-trisubstituted glycosyl thioureas 6 with silver cyanate gave 1-glycosyl-5-azauracil derivatives 7, as nucleoside analogues in good yields <01MI459>. S R2 ~ .,~O II R2 AgOCN/MeCN N R1--NH~C~ 5 h, 50 ~ RI~N-..tl~NH II

6

O

7 R1 = 2,3,4,6-tetra-O-acetyl-13-D-glucopyranosyl;2,3,5-tri-O-acetyl-13-D-ribofuranosyl R2 = NEt2, pyrrolidinyl-1,piperidino

312

C. Ochoa and P. Goya

The synthesis of diaryl-l,3,5-triazines 10, a new class of potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) has been reported. The requisite amidines 8 were readily prepared from the corresponding phenylacetonitriles, while the isourea partners 9 were obtained in modest yields by the reaction of diphenyl cyanocarbonimidate with the appropriate aniline <01BMCL2229>. H

Ar'"~ "NH2 PhOI"~N"Ar2DMF NH + N NC" 70-80~ 8

H H 21 A r ' " ~ l N~-]/NH~Ar2 Arl-'~FI~NyN\Ar NH2 lO

9

Reaction of oxoniobocene complex 11 with excess phenyl isocyanate gave a mixture of heterocycle 12 and triphenylisocyanurate 13 in a 3:2 ratio. In contrast, the reaction of [(CsMes)2Nb(=O)OMe] with phenyl isocyanate in molar ratios from 1:3 to 1:100 yielded pure triazine 13 <01JOM(634)47>. O

ph~ N-.-C....O

(CsMe5)2Nb(=O)H O,~N.Ph Ph--N,~N ,'Ph 11 + THE p#% O/~"N% Ph 12

13

Synthesis of 4(6)-amino-l,3,5-triazine-2-ones and 2-thiones starting from benzotriazole derivatives has been reported <01JOC6797>. The first template photochemical synthesis of a 1,3,5-triazine derivative as a receptor capable of differentiating between thymine and uracil has been described <01CC1446>. A new solid phase synthesis of trisubstituted 6amino(substituted)-2,4-dioxo-3,4-dihydro- 1,3,5-triazines from a resin-bound amine component has been reported <01JCO278>. The synthesis of thirteen tris(azol-l-yl)-l,3,5triazines, as a new class of multidentate ligands, has been described <01H(55)905>. Tris(pyrazolyl-l,3,5-triazines) 14 have been prepared by cyclotrimerization of aromatic nitriles, in piperidine and in solvent-free conditions <01T4397>.

~N-N...Ph CN C~. N~/-./~ I Ph

(CF3SO3)3Y Piperidine 200 ~ h

~-~' N . ~N, , ~ F.~.m?~ .-... ] N N Ph" N" N/') ~ N "Ph

The synthesis of high-loading resins functionalized with 1,3,5-triazine dendrimers to be used as scavenger resins for combinatorial chemistry has been reported <01TL493>. Triazapentadienium iodides are efficient intermediates in heterocyclic synthesis. They react with aryl isocyanates or isothiocyanates to give oxo and thioxo-triazine derivatives <01JHC93>. The synthesis and characterization of a new class of liquid crystalline, highly luminiscent molecules containing a 2,4,6-triphenyl-l,3,5-triazine unit have been reported

Six-Membered Ring Systems: Triazines, Tetrazines and Fused Ring Polyaza Systems

313

<01TL3993>. By reaction of dialkyl aminomalonates with formaldehyde, 1,3,5tris(dialkoxycarbonylmethyl)hexahydro-l,3,5-triazines have been prepared. These compounds on nitration under mild conditions yielded the corresponding nitromethyl derivatives <01MI194>. Carbodiimide 15 is an unstable compound that on long storage at room temperature or on heating in glyme solutions was converted into trimer 16. Trimer 16 was hydrolyzed by atmospheric moisture into triazinetrione 17, which has been identified by Xray diffraction analysis <01EJO 1225>.

F

F

F

CF3SO2N~c..N ..c~NSO2CF3

O..~C..N.c//O

N=C=NSO2CF3 -----

N.c..N

F

---~

N SO20F3

15

F

N..C.. N F

F

16

17

An unexpected transformation of 2,4,6-trisubstituted 1,2,3,5-oxathiadiazine 2-oxide derivative 18 on alumina, yielding 1,2,4,5-thiatriazine 1,1-dioxide derivatives 19, has been reported <00MI 1229>.

(3,, ,,N-CO-CBr3 N"S~'o

(3,. ,,O N"S"NH

Alumina

CH C,

18, R = CCI3,CBr3

19

6.3.1.2 Reactions

A short, high yield synthesis of polysubstituted 1-azafluorenones from 1,2,4-triazines 20 via 22 and 23 using metallation and intramolecular inverse Diels-Alder reaction has been

described <0 IS 1800>.

Br 0 RL .N . ~ ~J 2 2 6 6-Tetramethylpipeddine ' ~ "~1~1 ,-.,,

20

21

R1,- _N 22 +

!.

~lMe3

Cul/PdCl2(Ph3P);

Ra

Me3Si\ ~

R1""~ N~''-,,~,

~ 23

22 ,xY----R2

~.~R 3

314

C. Ochoa and P. Goya

The addition of dimethyl acetylenedicarboxylate (DMAD) to 6-methyl-l,2,4-triazine3(2H)thione-5(4H)-one afforded 2-methoxylcarboxy-7-methyl-l,3-thiazino[3,2-b][1,2,4]triazine-4,8-dione <00PS(165)285>. A new synthetic approach to condensed 1,2,4-triazines based on using the tandem A(N)-S-N(ipso) and S-N(H)-S-N(ipso) reactions has been developed. 5-Methoxy-3-phenyl-l,2,4-triazine and its N 1-methyl quaternary salts reacted with C,N-, C,O- and NAP-bifunctional nucleophiles to give triazacarbazoles, benzofuro[2,3e] [1,2,4]-triazines and 6-azapurine derivatives <01JHC901>. The synthesis of some novel 3,7-dimethyl-4H-pyrazolo[5, l-c] [ 1,2,4] triazine-4-ones from 4-amino-3-mercapto-1,2,4triazine-5-one derivatives has been reported <01JHC71I>. Some new fused heterobicyclic nitrogen systems such as 1,2,4-triazino[3,4-b][1,3,4]thiadiazolones 26 have been synthesized, as anti-HIV and anticancer drugs, from treatment of 4-amino-3-mercapto-6-substituted-l,2,4triazine-5-ones 24 with benzoic acid derivatives 25 <01PHA376>.

OH I ~.N..NH

.-~s

+

R

~

0

OH

POCI 3

.~ ~ i ~ OH N"N

!

NH2 24

26, R = Cl, Br, NO2 Ikl~R

25

1,2,4-Triazino[3,4-b]thiadiazine derivatives 29 and 30 have been prepared by cyclization of 4-amino-3-phenylacylmercapto-l,2,4-triazine-5-one 28, obtained from triazinone 27, in acid medium, via an unusual pathway <01PS(170)205>. Cyclocondensation of 6-methyl-4amino-l,2,4-triazin-3-one -5-thione, an isomer of 27, with propargyl bromide provided a novel 1,2,4-triazino[4,5-b ]thiadiazine system <01PS(170) 193>.

Ph S.~N-s~ HN'N 27

+ e

PhCOOH2Br =

Ph

S.,~N. 0 --H+ N.N2Me 28

Ph

S,,.~ I'' i~1~; + S....~I~....~O N. N 29

e

N" N~'~x"Me 30

A novel synthesis of 2-acylpiperidines via inverse electron demand Diels-Alder reaction of 5-acyl-l,2,4-triazines has been reported <01OPP501>. Substituted 1,3,5-triazines and pyrimidines have been prepared from 1,3,5-triazine and lithium amidinate, alkyl- or 1-azaallyllithium <01JCS(P1)ll03>. 2-Amino-4,5-dichloro1,3,5-triazines have been used as starting material to obtain a melamine-barbituric acid dye assembly <01CC2260> and macrocyclic triazine-based receptor molecules <01EJO2825>. Starting from 2,6-diamino-4-chloro-l,3,5-triazine, several 1,3,5-triazine substituted polyamines, as potential new antitrypanosomal drugs, have been synthesized and tested <01JMC3440>. 2,4,6-Trichloro-l,3,5-triazine has been used as starting material to obtain new cyclic peptidomimetics <01JOC507>, chiral building blocks for a bifunctional system <01EJO3523>, dendrimers based on melamine <01JA8914>, and aromatic polyesters

315

Six-Membered Ring Systems." Triazines, Tetrazines and Fused Ring Polyaza Systems

containing 1,3,5-triazine rings . The transformation of 1,3,5-triazine derivatives 31 into a new class of NNRTs 32 has been achieved by two pathways, as is shown in the scheme. Nucleophilic displacement in 32 (Z = C1) yielded triazines 33 <01BMCL2229>. H

H Arl -- X --~ N~r.-" N'--~

N..~N z

Ny.N Z

31,Z=Cl, H

ii

CN

//~/,/

,i

=N~[~N z \

for Z = CI Nucleophile

"~ ill

"CN

"

32, z = c,, H

X = NH, S, 0

~

Ar11 X-..~ N~/"CI

N..~N Z

N..~N

K.....~CN

Y 33, Y -- NH2, NHMe NMe2, F, NHPr, N-morpholino, NHOH

i; 4-Aminobenzonitrile, DIEA, 1,4-dioxane, 25 ~ or reflux; ii; Ar 1NH2, DIEA or ArlOH, Nail; iii; 1,4-Dioxane, 25 ~ or reflux

The high yielding synthesis of 6-aryl-2,4-diamino-l,3,5-triazines via palladium catalyzed Suzuki cross-coupling reaction of 6-chloro-2,4-diaminotriazine and arylboronic acids has been described <01T2787>. Chiral 5,6-diaryl-5,6-dihydro-2,4-diamino-l,3,5-triazines undergo facile racemization by a reversible thermal electrolytic reaction mechanism. The transient intermediate can lead, after tautomerization, to rearranged racemic 6-aryl-5,6dihydro-2-amino-4-anilino-l,3,5-triazines <01CC737>. Reactions of perhydro-l,3,5-triazin2,4,6-triones to give several 1,2-mercaptoalkyl substituted derivatives have been described <01MI956>. Some reactions from hexachlorocyclophosphazanes to give crown-ethers bearing chlorocyclophosphazane subunits <01JOC5701>, <01NJC1078>, hexasubstituted cyclotri-phosphazanes, under microwave assisted methods <01OPP376>, and nickel(II) complexes as antifungal agents <01IJC(A)893>, have been reported. A bis(urea) macrocycle 36 has been synthesized from perhydro-l,3,5-triazin-2-one derivative 34 through macrocycle 35 as shown in the scheme <01CC1592>.

316

Me-

M

C. Ochoa and P. Goya

+

~--NH

BrH2c

.0.

NaH CH2Br THF

Me /---N /N---~ Me Me--~--N ~=::O O==fk N--~-Me Me/ k----N N--/ Me

34 35

{.oc.~/~N.

-~

MeOH/A

HN-~~NH o=(

~=o

HN~~~NH

36 A tandem decarboxylation/Diels-Alder reaction of 5-amino- 1-phenyl-4pyrazolecarboxylic acid with 1,3.5-triazines has been reported <01TL8419>.

6.3.2 TETRAZINES A polymeric sodium complex of 3,6-bis(2-pyridyl)-l,2,4,5-tetrazine with an unusual coordination geometry about the sodium has been reported <01CC2134>. The structure and spectroelectrochemistry of an acceptor-bridged heterodinuclear complex containing 3,6-bis(2pyridyl)-l,2,4,5-tetrazine, Rh and Re have been established <01OM1437>. The X-ray crystal structure of 3,6-bis(2-pyridinio-l,2,4,5-tetrazine diperchlorate has been published <01AX(E)127>. Dicopper (I) complexes with reduced states of 3,6-bis(2'-pyrimidyl)-l,2,4,5tetrazine have been described <01IC2263>. The conceptually simple mixed-valent diiron compound [(NC)sFe(~t-tz)Fe(CN)5] with the 1,2,4,5-tetrazine (tz) bridging ligand has been obtained as a stable material and its characteristics studied <01IC2256>. A comparative density functional study in tetrazines and tetraphosphorins and related compounds has been carried out <01JST59>. Electrochemical vs photo-induced electron transfer has been studied in tetrazine bridged osmium dimers <01JPC(B)8829>. 6.32.1 Synthesis The reaction of bis(mercaptothioformylhydrazido)phthalate 37 with dimethylformamide yielded the bis-l,2,4,5-tetrazin-3-yl derivative 38 <01PS(175)65>.

0 H [ ~ ~ I - L NH/N,~S ~~.~O HN.NH

S/~SH 37

SH

H

H + ph~N'NH2

DMF EtOH

Ph'N'N~S

~N.NH

-

N.NH

ph~N'N'~S H 38

Six-Membered Ring Systems."Triazines, Tetrazinesattd Fused Ring Polyaza Systems

317

Treatment of imidoyl chloride 39 with sodium azide was accompanied by evolution of dinitrogen, which started at 48-50 eC and was completed within a few hours and the intermediate product transformed into dihydrotetrazinc 40. The structure of 40 has been established by X-ray diffraction analysis <01EJO1225>. S02Ph Ph_C=NSO2Ph Cl

-

NaN3 50 ~

39

I

s

~ IPh-C--N--S-Ph/ / I + JJ

L

o

] /

j

_N2 -

Ph--'(\

N-N

\~---Ph

a-,,

40 S02Ph

6.32.2 Reactions Quantum mechanical calculations have shown that N,N cycloaddition of alkenes and alkynes to 1,2,4,5-tetrazines is possible as an alternative to the well-known C,C cycloaddition (Carboni-Lindsey reaction). Formation of 1,2,4-triazole dcrivatives (formal product of N,N cycloaddition) along with the pyrazole (formal product of C,C cycloaddition) corroborated this theoretical prediction <01OL1725>. The cycloaddition elimination sequence between 3,6-disubstituted 1,2,4,5-tetrazines 41 and cyclopropenes 42 provided 3,4-diazanorcaradienes 43. Compounds 43 can still act as 13-dienes with cyclopropenes producing tetracyclic azo compounds 44 <01EJO2629>. Azo compounds 44 are versatile starting compounds and in photolysis reactions, with accompanying loss of nitrogen, afforded homotropylidenes (bicyclo[5,2]octa-2,5-dienes) <01EJO2639>. R~

,

R~

..,"

R

R "t

R'

41

43

? R'.,J"N

44

R1 : C02Me , C02H R2 = H, Me

The role of 7-substituents in governing the facial selectivity for the DA (Diels-Alder) reaction of benzonorbornadienes with 3,6-bis(2-pyridyl)-l,2,4,5-tetrazine has been studied <01MI353>. The inverse electron demand cycloadditions of 2-substituted imidazoles with dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate produced imidazo[4,5-d]pyridazines in good yields. This reaction has been used to revise the structure of zarzissine, a cytotoxic marine alkaloid <01T5497>. Two papers have dealt with thiazolo[3,2-b][1,2,4,5]tetrazines and fused derivatives. Starting from 6,6-diethyl-perhydro-l,2,4,5-tetrazin-3-thione 45, fused thiazolo[3,2b][1,2,4,5]-tetrazines, such as 46, and trans-dihydropyrazolo[3',4'/4,5]thiazolo[3,2b][1,2,4,5]tetrazine, such as 47, have been obtained <01IJC(B)584>. The second paper documents the synthesis of spiro(2,6-diphenylpiperidine-thiazolo[3,2-b]l,2,4,5-tetrazines) <01MI219>.

318

C. Ochoa and P. Goya Et. Et HN~V~'NH I

I

Et. Et HN-~.NH

HN'lfNHs 45

I

Et.

Et

HN~.NH

I

i

i

N'~N~N

NO2

47 ~

46

~.~,..,~"N02

CI An asymmetric total synthesis of ent-(-) roseophilin has been reported involving an inverse electron demand DA reaction of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate <01JA8515>. The electron deficient character of the diazadiene system of 1,2,4,5-tetrazines has been used to obtain epibatidine analogs (7-azabicyclo[2,2,1 ]heptane derivatives) through an inverse type DA reaction <01JMC47>. 3,6-Bis(2H-tetrazol-5-yl)-l,2,4,5-tetrazine (BTT) has been reported to be a bifunctional compound capable of [4 + 2] cycloadditions through its tetrazine unit (compounds 48) and of acylating ring-opening reactions through its tetrazole ring (compounds 49 and 50). Thus, linear oligoheterocycles with 1,2,4,5-tetrazine, pyridazine, 1,3,4-oxadiazole, thiophene, furan and pyrrole units, in sequences not easily available by other synthetic methods, can be obtained <01EJO697>. X x +

~'-r

MeCN =

HN" ~., . N=N

. . . .

N-N

"NH J, N=I'd

48 X = OH2, (CH2)4

HN'N, I ~/"~\ N=N

//"--'~ p,, N-N N~'''j

RCOCI

N N" ,~

N=N

N , ~N

49

BTT PhNCO

PhHN,,'u---O

N-N 50

O ~ N H Ph

6.3.3 FUSED [6]+[5] POLYAZA SYSTEMS A new N-methylpurine, mucronatine, has been isolated from a marine sponge and its structure assigned <01TL7257>. Two reports have dealt with labelled adenine derivatives. In the first, fully labelled adenine was obtained in four steps, in good yield, and its tautomerism studied by ~SN-NMR and theoretical calculations <01JOC5463>. In the second, (N-l, NH 2, '5N-2) and (N-I, N-3, NH 2, 15N-3) labelled adenines have been reported <01JOC6472>.

Six-Membered Ring Systems:Triazines, Tetrazines and Fused Ring Polyaza Systems

319

6.3.3.1 Synthesis Several derivatives of 1,2,4-triazine fused to different heterocycles have been reported. Thus, pyrazolo[ 1,5-c][ 1,2,4]triazines <01 SC3547> and 3-aroyl-pyrazolo[5, l-c][ 1,2,4]triazines have been prepared <01JCR(S)349>. A general method for the incorporation of the ISN label into position 1 of 6-nitro-l,2,4-triazolo[5,1-c][1,2,4]triazine-7-one by using K'sNO3 has been reported <01SC2351>. 1,4-Dipolar and 1,3-dipolar reactions of ~x-alkoxycarbonylcycloimmonium N-amidines with dipolarophiles yielded new imidazo[2,1-f][ 1,2,4]triazinium inner salts <01JOC8528>. Reactions of chlorocarbonyl isocyanate with 5-aminopyrazoles and active methylene nitriles are a novel pathway to obtain pyrazolo[1,5-a][1,3,5]triazines and barbiturates <01SC3459>. A novel synthesis of 4-methylthiopyrazolo[1,5-a][1,3,5]triazines 53 via reaction of dimethyl N-cyanodithioiminocarbonate 52 with 5-aminopyrazoles 51 has been published <01SC3453>.

a1 ~/ N/CN N + HN MeS~"SMe NH2 51

~ ~N. ~NH2 EtOH _- I q ' ~ ~ "T piperidine '" N-N~" M~N SMe

52

53

The synthesis and unusual chemical reactivity of certain novel 4,5-disubstituted 7-benzylpyrazolo[2,3-d][1,2,3]triazines 55 have been described. This unusual fused system, only two previous derivatives of which were known, has been obtained starting from diethyl 2-nitropyrrole-3,4-dicarboxylate 54 via an alkylation, ammonolysis, reduction and an intramolecular diazo coupling sequence <01JOC4776>.

NO2 1) BnBr H2NOC'-,~ NH -~ ~.~/N-Bn EtO2C~ 2) NH3 H2NOC./~/ 54

EtO2C" ~

NO2

H 2 N O C ' ~ H2 .J.~/N-Bn H2NOC~

HCl " NaNO2

NH2 HCI H2NOC.,.~ ~/N-Bn Fe(m)H2NOC~

HN~O" J ~ CONH2 N~N.,~..N, Bn 55

Bis(imidazotetrazines) related to the antitumor agents mitozolomide and temozolomide have been prepared <01JCS(P1)4432>. The preparation and thermolysis of new stable heterocyclic precursors 56 of 1,2-diaza-l,3-butadienes 57 have been described and the resulting reactive diazadienes have been trapped in situ with N-phenyltriazolinedione affording triazolotetrazine 58 <01 OL3647>.

320

C. Ochoa and P. Goya

Ph I NII.N

Ph i O

N~.N

R~

O

o

P.,

o

N"N "N~'J~ 1 I !~1 N-Ph

2

56

57

58

R 1 = R 2 = AIk, Ar, OAr, SAr Solvent = PhCH3, C6H4(CH3)2, or PhCI

The synthesis of new purine derivatives characterized by the presence of a 2-hydroxymethylpyrrolidine substituent at C-2, designed to inhibit cyclin-dependant kinases (CDK's) has been reported <01JHC299>. In another report, dealing also with CDK inhibitors, several 2,6,9-trisubstituted purine derivatives have been synthesized and the crystal structure solved, for one of them, in complex with human CDK 2 <01JMC524>. The synthesis and biological evaluation of purine containing butenolides have been reported <01JMC1749>. New substituted purines, obtained from 4,5-diaminopyrimidines and 1,3-diketones have been described <01IJC191>. A facile synthesis of 6-cyano-9-substituted-9H-purines and their ring expansion to pyrimidino[5,4-d]pyrimidines have been described <01JCS(P1)2532>. Novel adenosine receptor antagonists, 2-alkynyl-8-aryl-9-methyl-adenines, have been synthesized and their SAR toward hepatic glucose production induced via agonism of the A2B receptor studied <01JMC170>. A reinvestigation of the reaction of urea derivatives of diaminomaleonitriles with aldehydes or ketones in the presence of triethylamine has established that the products of these reactions are not pyrimidino[5,4-c]pyrimidines, as previously reported, but 8-oxo-6-carboxamido-l,2-dihydropurines <01JOC8436>. The reaction of 5-amino-4-cyano-formimidoylimidazoles 59 with tosyl isocyanate 60 is a mild and efficient method for the synthesis of the corresponding 6-amidino-2-oxopurines 61 <01JCS(P1)1241>.

NH2 R'r+i=NH

+

Me---(~SO2NCO

N 59

MeCN =-

R ~N~NH~N"r~N"~ 0 TsN" NH 2

60

R = (CH2)2OH, C6H4OMe-4 , C6H4CN-4, C6H4Me.4 (CH2)2OCONHTs

New alkylated theophyllines have been synthesized by chemical modification of diphylline <01JCR(S)129>. A series of aryl-l,2,3,6-tetrahydropyridino-purine 63,-3H-1,2,3triazolo [4,5-d]pyrimidine 64,-purin-8-one 65 and-7H-pyrrolo[2,3-d]pyrimidine 66 derivatives have been synthesized and the affinity for the CRF1 (corticotropin-releasing factor) receptor studied. The synthetic sequence involved the coupling of the aryltetrahydropyridine with previously described chloro derivatives 62 <01BMC1357>.

Six-Membered Ring Systems.'Triazines, Tetrazines and Fused Ring Polyaza Systems

321

CI N~"h----y ~

Ar

62 OH Ar-.~

Boc

Ar

..'X-

'

N ~ y ~

iii

"~N

I'~N/+2

H

Boc

63, yl_y2 = N=C(H) 64, yl_y2 = N(Me)=C(O): 65, yl_y2 = N=N; 66, yl_y2 = C(Me)=C(H, Me)

i; ArMg-Br, THF;ii' TFA-CH2CI2 or conc. HCI" iii; isoPr2NEt, EtOH

An expeditious solvent-free synthesis of pyrazolino-/ iminopyrimidino-/ thioxopyrimidino-imidazolines from readily accessible oxazolones on a solid support using microwaves has been described <01S1509>. Three papers have appeared dealing with sildenafil (Viagra) analogues. These concern pyrazolo[4,3-d]pyrimidine derivatives containing an ether ring fused into the phenyl moiety <01BMC1609>, with an N-acylamido group at the 5'-position of the phenyl ring <01BMC1895>, and monagra, a chiral 5-(2methyl-2,3-dihydro-7-benzofuryl)pyrazolo-pyrimidone <01H(55)1789>. A series of pyrazolo[3,4-d]pyrimidines substituted at position 1 and 6 has been synthesized, and their effect on histamine release from rat peritoneal mast cells measured <01EJM321>. A facile one pot synthesis of this system has also been reported <01JHC491>. A novel one pot synthesis of 3-arylazo-l,2,4-triazolo[4,3-a]pyrimidin-5(lt/)-ones via reaction of 2-thiouracil derivatives with 3-chloro- or 3-nitro-l,5-diarylformazans has been described <01SC713>. The synthesis and anti-inflammatory activities of N-4,N-5-disubstituted-3-methyl-lHpyrazolo[3,4-c]pyridazines have been reported. Thus, reaction of pyrazole 67 with oxalic acid in sodium acetate afforded the 2-oxoethanehydrazonic acid 68 which was cyclized with SnC14 to give pyrazolo[3,4-c]pyridazine 69; this was thcn used to prepare other derivatives such as 70 <01BMC715>. O Me

(HOOC)2= H

N-NH2

EtO-~;

Me

~ ~.OH N"N~"~N I "N II H

67

68

I PhNO2 SnCl4

OH

NHR

M N ~ ~ N ~ N NH

1) POCI3 2) RNH2

H 70

H

69

C. Ochoa and P. Goya

322

Several reports have dealt with fused [6+5] derivatives containing sulfur atoms. Thus, the synthesis and evaluation of the antibacterial and antifungal activity of s-triazolo [3,4-b ][ 1,3,4]thiadiazoles, s-triazolo[3,4-b ][ 1,3,4]thiadiazines and s-triazolo[3 ',4'/2,3][ 1,3,4]thiadiazino-[5,6-b]quinoxaline have been reported <01IJC(B)368>. A series of 3,6substituted-7H-s-triazolo[3,4-b][1,3,4]thiadiazines has been prepared through condensation of suitable 3-substituted-4-amino-5-mercapto-l,2,4-triazoles with phenacyl bromides and their anthelmintic activity tested <01AF569>. In a report dealing with corticotropin-releasing hormone receptor agonists, 2,7-dimethylthiazolo[4,5-d]pyridazine-4-(5H)-thione has been described <00AJC905>. An efficient one pot synthesis of s-triazolo[3,4-b][1,3,5]thiadiazines containing a chiral side chain by a double Mannich type reaction has been reported <01JHC929>. A series of 1,3,4-oxathiadiazol-2-yldihydrothiazolo[4,5-d]pyrimidine-5(H)thiones has been synthesized <01IJC(B)255>. 6.3.3.2 Reactions

A Mannich reaction of imidazo[4,5-d][1,2,3]triazine aminomethyl derivative 72 <00MI873>. O

71

derivative

71

afforded

its

O

H

H

H2C N~ 72 ~.0, ~

Transformations of 7-methylpurines with alkoxy and chloro substituents under the action of methyl iodide <01PJC1327>, and alkylation of some purine derivatives using microwaveassisted methods have been reported <01H(54)291>. 2,6,8-Trisubstituted purines have been synthesized from 2,6-dichloropurine bound to polystyrene-based Rink resin at the N-9 position. Selective successive displacements of the chlorine atoms in the 2 and 6 positions followed by bromination of C-8 and Stille coupling concluded the synthesis <01TL6515>. A novel solid-phase preparation of 2,6,9-trisubstituted purines for combinatorial library generation has been reported <01TL2771>. A concise and traceless linker strategy towards combinatorial libraries of 2,6,9-substituted purines has been reported <01JOC8273>. In relation to cyclin-dependent kinase (CDK) inhibitors, extensive work has been carried out to develop a general strategy for the construction of 2,6,9-trisubstituted purine libraries in which the purine scaffold is connected to the resin via a carbon-sulfur bond <01TL8161,01TL8165, 01TL8169>. For example, 6-thiopurines 73 or 6-chloropurines 74-76 reacted with MerrifieldC or -SH resins to afford purine bound resins 77-79. S-oxidation of resin 79 and reaction of the desired sulfone with 4-methoxybenzylamine proved effective for the release of the purine from the resin and simultaneous C-substitution affording compound 80.

Six-Membered Ring Systems." Triazines, Tetrazines attd Fused Ring Pob,aza Systems

323

The 2-iodopurine containing resin 79 has becn subsequently used to introduce amino substituents at C-2 <01TL8165>, and to study the use of different palladium reagents in attempts to prepare 2-alkynyl substituted purines <01TL8169>. Starting from 2-fluoro-4chloropurine, a synthetic method to prepare a novel polymer-supported 2(diphenylmethylsilyl) ethoxymethyl chloridc (DSEM-CI) linker and its applications have been described <01CC2268>. Another report has dealt with the synthesis of aryl, N-aryl and O-aryl substituted purine libraries by the palladium-mediated coupling of boronic acids, anilines or phenols at the C-2 position, and copper(II)-mediated N-arylation with boronic acids at the N-9 position <01TL8751>. The synthcsis of 2- and 6-substituted purines has been accomplished using protic and Pd-mediated coupling reactions. Boronic acids and amines have been successfully coupled under thc same conditions <01SL1097>. The Suzuki-Miyaura cross-coupling reactions of 2-halo-, 6-halo- or 8-halopurines with boronic acids leading to 2aryl-, 6-aryl- or 8-aryl- and alkenylpurine derivatives have been reported <01S1704>. Bromination of purines has been reported. Diaminopurines, immobilized on a polymeric support have been treated with a charge transfer complex of bromine and lutidine to afford 8brominated derivatives <01TL6279>. Further reports concerning rcactivity of purines included a new Sandmeyer iodination of 2-aminopurines in non-aqueous conditions <01H(54)461>. Tetrahydrodiazepinopurine and/or tetrahahydropyrimidopurine systems have been obtained from substituted 4-iminopurines in an attempt to prepare asmarine analogs, which contain the unique tetrahydro- 1,4-diazepino[ 1,2,3-g,h ]purine system <01 TL5941 >. Starting from guanine, a 9-vinylguanine derivative has been obtained, for the first time, and fully characterized by X-ray analysis. It can be used to obtain aza analogues of 2',3'dideoxy nucleosides through cycloaddition processes <01T4035>. Completely regioselective addition of Grignard reagents to an N-protccted purin-2-one followed by rearomatization and deprotection afforded 6-substituted purin-2-ones which were prepared as analogues of cytokinins <01JCS(P1)1662>. 6-Amidino-2-oxopurines underwent a rearrangement in the presence of acetic acid and DMF to give pyrimido[5,4-d]pyrimidin-2-ones <01JCS(P1)1241>. Reaction of 8-chlorotheophylline and hydrazone derivatives, in a simple one pot synthesis, afforded novel 1,2,4-triazolo[3,4-d]purines <01JOC4055>. Condensation of 8-hydrazinotheophylline with appropriate glyoxylic acids yielded 3-substituted-l,2,4triazino-[ 3,4-f]purine-4,6,8-trione derivatives <01JHC607>.

6.3.4 FUSED [6]+[6] POLYAZA SYSTEMS Application of fluorescence-detected circular dichroism (FDCD) to the determination of the major pterin (L-monapterin) from Escherichia coli has been published <01H(54)283>. Identification of (6R)-5,6,7,8-tetrahydro-D-monapterin as the native pteridine in Tetrahymena pyriformis has been reported <01HCA918>. A novel modified pterin has been isolated from

324

C. Ochoa and P. Goya

the Eustidoma species ascidian <01JNP1100>. 7,8-Dihydropterin-6-carboxylic acid has been identified as the light emitter of the luminous milliped, Luminodesmus sequoiae <01BMCL1073>.

6.3.4.1 Synthesis Reaction of 6-cyanoimino-5-diazo-l,3-dimethylpyrimidine-2,4-dione 81 with propanethiol afforded 3-amino-5,7-dimethylpyrimido[4,5-e][1,2,4]triazine-6,8-dione 82 in quantitative yield <01JHC141>.

o Me"N.~N2 I

PrSH

o Me"N"~N'N

--.c.

I

Me

Me

81

82

The Mannich condensation reaction of phenylglyoxal monophenylhydrazone 83 and aminal 84 gave rise to product 85 which was cyclized to the morpholinotriazine derivative 86 <01ZN(B)533>.

/N ..\3 Ph 83

O 84

NH "Ph

85

Hg(m) Ph

/--N

O 'Ph

86

An easy and high yielding one pot synthesis of enantiomerically pure 1,4,5,6-tetrahydro1,2,4-triazines fused to a carbohydrate skeleton, starting from benzyl-4-amino-2,3-dihydro-4deoxy-13-L-lyxopyranoside and N-arylhydrazone derivatives has been reported <01CL660>. Cyclization of 4,4-dimethylhydropyridazine-3,6-dione 3-hydrazones with esters of keto dicarboxylic acids yielded tetrahydropyridazinotriazinones <01JHC877>. The synthesis of some new biologically active triazinothiadiazinones has been reported <01IJC(B)475>. The synthesis and biological study of 6-polyhydroxyalkylpteridines have been described <01JHC727>. The synthesis of bicyclic pyrimidine derivatives as ATP analogues, among them tetrahydropteridines and pyrimidopiperazines, has been reported <01JOC5783>. Several reports dealing with the preparation of pyrido[2,3-d]pyrimidine derivatives have been published <01JCR(S)342>, <01JCR(S)339>, <01JHC457>, using microwaves under solvent free conditions <01TL5625>, <01T1785>, as analogues of antifolates <01H(55)1679>, and as a orally active non-nucleoside adenosine kinase inhibitors <01JMC2133>. A facile one pot synthesis of pyrimido[4,5-d]pyrimidines and pyrido[2,3-d]pyrimidines has been reported <01SL1299>. 6.3.4.2 Reactions Regioselective alkylation of pyridotriazine derivatives related to reumycin derivatives has been studied in order to obtain 1-alkyltoxoflavin and 8-alkylfervenulin derivatives of biological significance <01JCS(P1)130>. Mercapto-l,2,4-benzotriazine 87 has been

325

Six-Membered Ring Systems."Triazines, Tetrazinesand Fused Ring Polyaza Systems

condensed with propiolic acid to afford S-acrylic derivative 88 and this regioselectively cyclized to 1,3-thiazino [2,3-c] [ 1,2,4]benzotriazin-4-one 89 <01PS(170) 187>. H N. N

-

-

-

H N- N

CO2H

NI~sH H

=

H

...

N I/L..S....~/.CO2H - H

N I/L.S O ~

88

87

89

Coupling of unprotected phosphinate phosphapeptides with two acyl azides derived from folic acid and methotrexate led to the corresponding pteroylphosphapeptides which are of interest as potent inhibitors of folylpoly-gamma-glutamate synthetase <01JOC5146>. Synthetic methods to conjugate folic acid to oligodeoxynucleotides have been described. These conjugates are capable of enhancing cytotoxicity towards 5-fluorouracil resistant human colorectal tumor cells <01JOC5655>. The synthesis of phosphoramidate building blocks of isoxanthopterin N-8-(2'-deoxy-[3-D-ribonucleosides) has been reported <01HCA2330>. Reaction of 6,8-dimethylpyrimido[4,5-c]pyridazine-5,7-dione 90 with some secondary amines in the presence of an oxidant produced 6,8dimethylpyrrolo[2',3':3,4]pyridazino[6,5-d]-pyrimidine-7,9-dione derivatives 91. The reaction represents a new method of pyrrole ring annulation to an azine nucleus <01TL5981>. a 1

o

(E)-R1CH=CHNHR2 Ag(PY)2Mn04 I

Me 90

Me~N.~~N--

R2

i

Me

91 R1 =H, Me, Et; R2--Et,Pr,Bu

6.3.5 MISCELLANEOUS FUSED RING POLYAZA SYSTEMS Several reports have dealt with structures that could be included under this heading, but only those including triazine, tetrazine and pteridine systems will be highlighted. 6.3 .5.1 Synthesis A cyameluric high polymer melon (a linear form of the <01MI19>. New derivatives of structures 93 and 94, have been

92 has been synthesized by two step solid-polymerization of decamer of 2,5,8-triamino-tris-s-triazine) at about 700 eC fused fluoroquinolones bearing five aromatic rings, including synthesized <01JFC(110)25>.

326

C. Ochoa and P. Goya

I

NH N~'~N N~J',,.NI~N NH~N~N I~NH

i

~ ~ t

0

ICO2Et

N.Me

--

92

0

i~~1

ICO2H

~ ~ N'TN

93

94

The preparation of new 1,2,4-triazino[4,3-a]benzimidazole derivatives, as selective aldose reductase inhibitors <01JMC4359> and selective A, adenosine receptor antagonists <01JMC316>, have been reported. 2-Cyanoethanethioamide has been used in heterocyclic synthesis to obtain pyridopyrazolo[1,2,4]triazine derivatives <01PS(175)15>. Polycyclic derivatives containing naphthalenotriazolotriazinum salts have been synthesized as inhibitors of reverse transcriptase and of the efflux pump <01AP(334)269>. The syntheses of bis(1,3,4thiadiazolo)-l,3,5-triazinium halides <01S1327>, bis(isoquinolo)-l,3,5-triazinium iodide derivatives, bis(benzothiazolo)-l,3,5-triazinium iodide derivatives, and bis(pyrido)-l,3,5triazinium iodide derivatives <01JOC1310> have been carried out. The reaction of 3-amino-2-thioxo-4(1H)-quinazolinone or its methylthio derivative 96 with hydrazonoyl halides 95, in the presence of ethanol and triethylamine afforded 6H-1,2,4,5tetrazino[3,2-b]quinazolin-6-ones 97 <01M959>.

CI H R.,,~N,.N-.Ar

O ~N~L.

O S

= ~

I

N/_..~.N.N I

Me 95

R=CONHPh,Ph,CO2Et,Ac

H Ar

96

97

Stable pyrano[2,3-g]pteridines related to molybdopterin have been synthesized <01CC123>. The synthesis of new heterocondensed pteridines has been reported <01JHC1173>.

6.3.5.2 Reactions

5-Alkyl-l,5-dihydro-l,2,3,4,5,6-hexaazaaceanthrylenes 1 0 0 , derivatives of a new tetracyclic ring system, have been synthesized through diazo compound 99 by diazotization of 4-alkylamino-3-amino- 1H-pyrazolo[4,3-c]quinolines 98 <01SC 1971 >.

HN'-N v

"N- "NHR

N=N

HN"N R

H2SO4/H20

I

N

R 98

99

100 R = Pr, tBu, Bu

Six-Membered Ring Systems:Triazines, Tetrazines and Fused Ring Polyaza Systems

327

Ring closure reactions of a 4-hydrazino[1]benzofuro[2,3-d]pyridazine, derived from naturally occurring rotenone, yielded [1]benzofuro[2,3-d]pyridazines fused with 1,2,4triazole, 1,2,4-triazine, and 1,2,4-triazepine derivatives < 0 1 J H C 1097>.

6.3.4 REFERENCES 00AJC905 00MI229 00MI873 00MI1229 00PS(165)285 01AF569 01AP(334)269 01AX(E)127 01BMC715 01BMC1357 01BMC1609

01BMC1895 01BMCL1073 01BMCL2229

01CC123 01CC737 01CC1446 01CC1592 01CC2104 01CC2134 01CC2260 01CC2268 01CL660 01EJM321 01EJO697 01EJO1225 01EJO2629 01EJO2639 01EJO2825 01EJO3523 01H(54)283

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01IJC(B)255 01IJC(B)368 01IJC(B)475 01IJC(B)500 01IJC(B)584 01IJC(B)729 01JA6792 01JA7518 01JA8515 01JA8914 01JCO278 01JCR(S)I29 01JCR(S)339 01JCR(S)342 01JCR(S)349 01JCS(P1)130 01JCS(P1)668 01JCS(P1)1103 01JCS(P1)1241 01JCS(P1)1662 01JCS(P1)2532 01JCS(P1)4432 01JFC(110)25 01JHC93 01JHC141 01JHC299 01JHC457 01JHC491 01JHC607

C. O c h o a a n d P. G o y a

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330 01MI956 01NJC872 01NJC1078 01OL1725 01 OL3647 01OM1437 01OPP376 01OPP501 01PHA376 01PJC1327 01PS(170)187 01PS(170)193 01PS(170)205 01PS(175)15 01PS(175)65 01S1327 01S1509 01S1704 01S1800 01SC713 01SC1221 01SC1971 01SC2351 01SC3453 01SC3459 01SC3547 01SL1097 01SL1299 01SRI205 01T1785 01T2787 01T4035 01T4397 01T5497 01TL493 01TL2771 01TL3993 01TL4433 01TL5625 01TL5941 01TL5981 01TL6279 01TL6455 01TL6515 01TL7257 01TL7357 01TL8161

C. Ochoa and P. Goya S.G. Fattakhov, M.M. Shulaeva, V.S. Reznik, Russ. J. Gen. Chem. 2001, 71,956. H.M. Ma, U. Jarzak, W. Thiemann, New J. Chem. 2001, 25, 872. A. Maia, D. Landini, M. Penso, K. Brandt, M. Siwy, G. Schroeder, B. Gierczyk, New J. Chem. 2001, 25, 1078. X. Zhou, G. Efim, J. T. Klug, V. Khodorkovsky, Org. Lett. 2001, 3, 1725. R.K. Boeckman, P. Ge, J.E. Reed, Org. Lett. 2001, 3, 3647. T. Scheiring, J. Fiedler, W. Kaim, Organometallics 2001, 20, 1437. C.F. Ye, W.M. Liu, Y.X. Chen, Z.W. Ou, Org. Prep. Proced. Int. 2001, 33, 376. A. Rykowski, E. Olendes, D. Branowska, H. C. Van Derplas, Org. Prep. Proced. Int., 2001, 33, 501. Z. El Gendy, J.M. Morsy, H.A. Allimony, W.R.A.M. Ali, R.M. Abdelrahman, Pharmazie 2001, 56, 376. A. Kowalska, A. Maslankiewicz, Pol. J. Chem. 2001, 75, 1327. M.M. Heravi, N. Montazeri, M. Rahimizadeh, M. Bakavoli, M. Ghassemzadeh, Phosphorus Sulfur Silicon 2001, 170, 187. M.M. Heravi, G. Rajabzadeh, M. Rahimizadeh, M. Bakavoli, M. Ghassemzadeh, Phosphorus Sulfur Silicon 2001, 170, 193. M.M. Heravi, G. Rajabzadeh, M. Rahimizadeh, M. Bakavoli, M. Ghassemzadeh, Phosphorus Sulfur Silicon 2001, 170, 205. M.A.A. El Neairy, A.M. Abdelfattah, Phosphorus Sulfur Silicon 2001, 175, 15. H.A. Saad, Phosphorus Sulfur Silicon 2001, 175, 65 M. Walther, K. Wermann, H. Gorls, E. Anders, Synthesis 2001, 1327. M. Kidwai, P. Sapra, K.R. Bhushan, P. Misra, Synthesis 2001, 1509. M. Havelkova, D. Dvorak, M. Hocek, Synthesis 2001, 1700. T. Hundsdorf, H. Neunhoeffer, Synthesis 2001, 1800. A.S. Shawali, A.H. Elghandour, A.R. Sayed, Syn. Commun. 2001, 31,713. C. Yang, Y.D. Ciu, Syn. Commun. 2001, 31,1221. R.A. Mekheimer, Syn. Commun. 2001, 31, 1971. O.N. Chupakhin, E.N. Ulomsky, S.L. Deev, V.L. Rusinov, Syn. Commun. 2001, 31,2351. G.H. Elgemeie, S.R. Elezbawy, H.A. Elaziz, Syn. Commun. 2001, 31, 3453. G.H. Elgemeie, S.R. Elezbawy, H.A. Ali, Syn. Commun. 2001, 31, 3459. H.H. Abdelrazik, A.A. Fadda, Syn. Commun. 2001, 31, 3547. W.K.D. Brill, C. Rivatoniolo, S. Muller, Synlett 2001, 1097. A.J. Thakur, P. Saikia, D. Prajapati, J.S. Sandhu, Synlett 2001, 1299. Y.S. Xie, Q.L. Liu, X.L. Xu, J. Yu, R. Lin, Syn. React. Inorg. Metal-Org. Chem. 2001, 31,205. J.J.V. Eynde, N. Hecq, O. Kataeva, C.O. Kappe, Tetrahedron 2001, 57, 1785. G. Cooke, H.A. Decremiers, V.M. Rotello, B. Tarbit, P.E. Van Desrtraeten, Tetrahedron 2001, 57, 2787. R. Dalpozzo, A. Denino, L. Maiuolo, A. Procopio, G. Demunno, G. Sindona, Tetrahedron 2001, 57, 4035. A de la Hoz, A. Dfaz Ortiz, J. Elguero, L.J. Martfnez, A. Moreno, A. S~inchez Mingall6n, Tetrahedron 2001, 57,4397. Z.K. Wan, G.H.C. Woo, J.K. Snyder, Tetrahedron 2001, 57, 5497. A. Marsh, J. Carlisle, S.C. Smith, Tetrahedron Lett. 2001, 42,493. P.H. Dorff, R.S. Garipati, Tetrahedron Lett. 2001, 42,2771. C.H. Lee, T. Yamamoto, Tetrahedron Lett. 2001, 42, 3993. R.Y. Yang, A.P. Kaplan, Tetrahedron Lett. 2001, 42, 4433. J. Quiroga, C. Cisneros, B. Insuasty, R. Abonia, M. Nogueras, A. S~inchez, Tetrahedron Lett. 2001, 42, 5625. D. Pappo, A. Rudi, Y. Kashman, Tetrahedron Lett. 2001, 42,5941. A.W. Gulevskaya, D.V. Besedin, A.F. Pozharskii, Z.A. Starikova, Tetrahedron Lett. 2001, 42, 5981. W.K.D. Brill, C. Rivatoniolo, Tetrahedron Lett. 2001, 42, 6279. B. Martfnez Teipel, E. Michelotti, M.J. Kelly, D.G. Weaver, F. Acholla, K. Beshah, J. Teixido, Tetrahedron Lett. 2001, 42, 6455. W.K.D. Brill, C. Rivatoniolo, Tetrahedron Lett. 2001, 42, 6515. M.L. Bourguet Kondracki, M.T. Martin, J. Vacelet, M. Guyot, Tetrahedron Lett. 2001, 42, 7257. E. Jeoung, H.A. Decremiers, R. Deans, G. Cooke, S.L. Heath, P.E. Vanderstraeten, V.M. Rotello, Tetrahedron Lett. 2001, 42, 7357. V. Brun, M. Lagraverend, D.S. Grierson, Tetrahedron Lett. 2001, 42, 8161.

Six-Membered Ring Systems: Triazines, Tetrazines and Fused Ring Polyaza Systems 01TL8165 0 ITL8169 01TL8419 01 TL8751 01ZN(B)533

V. Brun, M. Lagraverend, D.S. Grierson, Tetrahedron Lett. 2001, 42, 8165. V. Brun, M. Lagraverend, D.S. Grierson, Tetrahedron Lett. 2001, 42, 8169. Q. Dang, Y. Liu, Z. Sun, Tetrahedron Lett. 2001, 42, 8419. S. Ding, N.S. Gray, Q. Ding, P.G. Schult, Tetrahedron Lett. 2001, 42,8751. H. Mohrle, G. Keller, Z Naturforsch. (B) 2001, 56, 533.

331

332

Chapter 6.4 Six-Membered Ring Systems" With O and/or S Atoms John D. Hepworth James Robinson Ltd., Huddersfield, UK j. d. hepw o rth @tinyw o rld. co. uk B. Mark Heron

Department of Colour Chemistry University of Leeds, Leeds, UK ccdbmh @leeds.ac, uk

6.4.1

INTRODUCTION

Reviews of saturated oxygen heterocycles <01JCS(P1)2303> and anthocyanins and other flavonoids <01NPR310> have been published. The stereoselective synthesis of axially chiral natural products using biaryl lactones <01ACR615> and applications of the pyrolysis of 2,2-dimethyl-l,3-dioxan-4,6-dione (Meldrum's acid) in synthesis <01S2059> have been discussed. A review of the 13-alkyl Suzuki-Miyaura cross-coupling reaction contains examples of pyran ring formation <0lAG(E)4545>. Diphosphine ligands with a xanthene backbone for use in transition metal catalysts <01ACR895> and molecular switches and motors based on thiopyran-l'-ylidene-9H-thioxanthones <01ACR504> have been reviewed. Total syntheses of several macrolides have been reported, including (+)-phorbazole A <01JA10942> and (+)-zampanolide <01JA12426>, both of which construct the cis-2,6disubstituted tetrahydropyran using a Petasis-Ferrier rearrangement. Three total syntheses <0lAG(E)3842>, <01JOC8973>, <01OL3149> and a partial synthesis <01TL797> of the microtubule-stabilising anticancer agent (-)-laulimalide have been disclosed. Apoptolidin, a macrolide which induces apoptosis of rat glia cells, has been synthesised <0 lAG(E)3849>, as has its aglycon, apoptolidinone <0 lAG(E)2063>. Total syntheses of the spiroketal macrolide spongistatin 1, using boron-mediated aldol reactions to define the stereochemistry, <0lAG(E)4055> and spongistatin 2 and various fragments <01AG(E)191>, <01AG(E)196>, <01OL949> have been achieved, as have those of rutamycin B and oligomycin C <01JOC2747>. Syntheses of tetracyclic units of azaspiracid, a marine toxin, <01AG(E)1262>, <0lAG(E)4068>, <01TL6035> and of the tricyclic spiroketal portion of the lituarines <01OL3979> have been reported. Two total syntheses of the polyketide ratjadone have been published <01JOC1885>, <01OL1383>. Various fragments of the marine polyethers, ciguatoxin <01AG(E)1090>, <01CC381>, <01H(54)93>, <01H(54)789>, <01TL2821>, <01TL6219> and gambierol <01JA6702>, <01OL2749>, <01OL3549>, <01T3019>, <01TL3645>, <01TL3649>, <01TIA729>, <01TL6195> <01TL6199> have been synthesised. Stereoselective oxonium ylide [2,3]-sigmatropic rearrangements are the basis of an efficient iterative route to polycyclic

333

Six-Membered Ring Systems: With 0 and~or S Atoms

ethers <01JA5144>. An approach to the CD-ring portion of hemibrevetoxin B involves no protecting groups and controls the relative stereochemistry with only achiral reagents. The key feature, used for the first time in natural product synthesis, is the desymmetrisation of a centrosymmetric molecule <01AG(E)4082>.

6.4.2

H E T E R O C Y C L E S CONTAINING ONE OXYGEN ATOM

6.4.2.1 Pyrans Cyclopentenes 1 and acyclic trienes 2 are converted into 2,2-disubstituted 3,6-dihydro-2Hpyrans in high yield and with very good enantioselectivity in a Mo-catalysed ring closing metathesis (RCM) (Scheme 1) <01JA3139>. A double RCM has been used to synthesise the bisdihydropyran 3 <01S2007> and hexaallyl ethers furnish the tris(cyclic ether) 4 through a triple Ru-catalysed RCM (Scheme 2) <01OL1989>. This methodology has been used in combination with hydroformylation to synthesise spirocyclic lactones <01JOC7658>. O ~ P h v ~ O ~

5 examples ~ 73 - 95% yield 74 - 96 % ee

(i) .

~ (ii)...

//

1

2

3 examples 90 - 93% yield 74 - >98 % ee

\\

Reagents: (i) 5 reel % Me catalyst, Phil, 50 ~ (ii) 5 mol % Me Catalyst, PhMe, heat. Scheme 1

83 % O x O

~ 0

0.,.,,~

'"; oCo o 4

65 %

Reagents: (i) Grubbs' catalyst, Phil, RT, 2 h. Scheme 2 The 2-ethynyldihydropyran 6 results from the asymmetric Cr-catalysed hetero Diels-Alder (hDA) reaction of 1-benzyloxybuta-l,3-diene with alkynal 5 and subsequent desilylation (Scheme 3) <0lAG(E)3667>. A triflate-catalysed enantioselective construction of a dihydropyran from a chiral crotylsilane and an alkynal features in a synthesis of the C19-C28 fragment of the phorboxazole system <010L 1693>. ( 3 +H

(i) ~ " TIPS

(i.i), (iii) BnOX""~O/"'"'~'~"~ 90 % yield

89 % ee

65 % yield % ee -,,,._.>99

~ BnO TIPS

6

Reagents: (i) 3 mol % Cr catalyst, RT, 36 h; (ii) TBAF, THF; (iii) 4-TsOH Scheme 3 The endo-selective reaction of a resin-bound heterodiene with a chiral vinyl ether catalysed by Eu(fod)3 occurs with excellent facial selectivity; the catalyst can be recycled <01TL8849>.

334

J.D. Hepworth and B.M. Heron

Epoxides tethered to a propargyltungsten complex undergo an intramolecular B F3catalysed [3+3] cycloaddition with high diastereoselectivity. The products are bicyclic pyranyltungsten complexes from which the fused dihydropyrans can be obtained by an oxidative demetallation (Scheme 4) <01JOC8106>. Chiral cycloalkylidene e,13-unsaturated iminium salts 7, derived from the 0t,13-unsaturated aldehyde by reaction with piperidine, react with 6-methyl-4-hydroxypyran-2-one in a tandem Knoevenagel condensation and electrocyclisation to give spiroheterocycles 8, though with only poor diastereoselectivity. Formation of the dihydropyran ring is the result of a formal [3+31 cycloaddition (Scheme 5) <01TL609>. Stereoselective cis- and trans- dihydroxylations of the double bond in these fused dihydropyrans have been described <010L2141 >.

74%(i)

w.(Cp)(CO)a .~ O ~

CpW(CO)3 ~

C02Bn (ii)

9O%

Reagents: (i) 25 mol % BFs.OEt2, CIt2C12,-40 ~ (ii) BnOH, 12, CII2C12,-40 ~ Scheme 4 o

0

0

OH H

I

R

7

EtOAc ~ R 0O - " l J " - . . f f / ~ 85 ~ 24 h "/1"~-~0"~

15 examples 20 - 78 %

Scheme 5

The reaction of epoxides with homoallylic alcohols when catalysed by InC13 provides an efficient synthesis of substituted tetrahydropyrans (Scheme 6) <01TL793> and 2,6-disubstituted tetrahydropyran-4-ols are formed with high diastereoslectivity in the montmorillonite-catalysed reaction between homoallylic alcohols and aldehydes <01TL89>. 0

Tol.~-.]

+ ~ O H

InCI3, CHCI3 RT, 5 h

~

CI

~..0/~

9 examples T ol 73 - 96 %

Scheme 6 Substituted 4-methylenetetrahydropyrans are formed stereoselectively by a Bi(III)promoted intramolecular Sakurai cyclisation (Scheme 7) <01TL8685> and Sn(II) catalyses the reaction of acetals with the allylsilane 9 which also yields the 4-methylene compounds (Scheme 8) <01BCJ569>.

O ~ T R1 MS OCON(iPr)2

R2CHO'Bi(OTf)3"H20 CH2CI2, -78 - 0 oC

f~OCON(iPr)2 R2f~O/~R1

Scheme 7

7 examples 28 - 98 %

335

Six-Membered Ring Systems: With 0 and~or S Atoms

TMSv~/~'OTMS

+ R1R2C(OMe)2

9

Sn(OTf)2 = " CH2CI2 R 1 R ~

6 examples 21 - 87 %

Scheme 8 The intramolecular asymmetric oxyselenenylation of a dihydropyran offers a new approach to both enantiomers of 1,7-dioxaspiro[5.5]undecane <01TL1931> and the substituted derivatives of this spiroketal system which form part of the didemnaketals have been prepared in a stereocontrolled manner from pulegone <01OL847>. 6.4.2.2 [1]Benzopyrans (Chromenes) Application of directed ortho metallation methodology (DoM) to aryl O-carbamates offers a route to 2H-[1]benzopyrans that complements those using Friedel-Crafts chemistry. Furthermore, the directing effect controls the regiochemistry of the reaction (Scheme 9) <01S140>. An anionic cyclisation also features in the synthesis of chromeno[4,3-c]pyrazoles <01JOC4214>, a fused heterocyclic system which has also been constructed from bromvinylhydrazones by way of a [3+2] cycloaddition <01TL6599>. R

[ ~

(i) tBuLi,/THF,~C -78 ~ OCONEt2

(ii) ~

R

[ ~ . ~

9 examples

22- 58 %

HO

(iii) AcOH, 0 ~ Scheme 9 Vinylquinones 10, accessible from bromoquinones by a Stille coupling reaction, are enolised to quinone methides and so give 2H-chromenes on heating in a polar aprotic solvent (Scheme 10) <01OL3875>.

+

Bu3Sn/~'~

r

"
"CO2Me

O

"
"CO2MeJ

1

86 %

-,,
Reaction of benzo[b]furan with Li in the presence of 4,4'-ditert.butylbiphenyl (DTBB) leads to the dilithio species 11. Subsequent reaction with carbonyl compounds affords the 2-propenylphenol derivatives 12 which readily cyclise to the benzopyran (Scheme 11) <01EJO2809>.

336

J.D. Hepworth and B.M. lteron OH i

"

R'

=0-97%

11 12 Reagents: (i) Li, 5 mol % DTBB, TIIF, 0 ~ (ii) R1R2C=O, -78 ~ then H20; (iii) 85 %, H3PO4, PhMe, heat. Scheme 11

2-Amino-4H-[1]benzopyrans are produced in good yields under aqueous conditions in a one-pot reaction of an aldehyde, malononitrile and a phenol catalysed by cetyltrimethylammonium chloride (CTAC) (Scheme 12) <01T1395>.

R~

+ OH

CN

a 1

CTAC, H20 ./~-~~/CN 110~ 6h ~ R 2 - - ~ ' . . . J L

+ R1CHO

NH2

11 examples 74-94%

Scheme 12

Alkylidene carbenes 14 undergo a 1,6-C-H insertion at the peri-position of naphthols 13 to yield dibenzo[bc]pyrans (Scheme 13) <01TL6031>.

[~/ OH

CI

nBuLi ..

CI

~-

/CI

IPhOTf

=_

CI

13

~

CI

14

5 examples 28 - 47 %

47 %

Scheme 13

Dibenzo[bd]pyrans are formed when o-(bromomethyl)phenyllead triacetates are heated with phenols (Scheme 14) <01TL5875>. Fused dibenzo -pyrans and-thiopyrans result from the cycloaromatisation of the non-conjugated tetraynes 15 (Scheme 15) <01H(54)887>.

+

(AcO)3Pb~ B r ~ l

3 eq. DMAP, 3 eq. E t 3 N II

RT, 1 h

..d.........~...~J R ftU...j

6 examples 13-65%

Scheme 14

TMS

HO

TMS ~--~///

Phil 25 ~

72 h

ax--/ 15

Scheme 15

OH

/~/ X=0,51% X=S, 19%

337

Six-Membered Ring Systems." With 0 and~or S Atoms

6.4.2.3 Dihydro[1 ]benzopyrans (Chromans) The reaction between 2',4'-dihydroxyacetophenone and vinyl ketones catalysed by CaC12/KOH in aqueous conditions yields the Michael product 16, which is readily cyclised to the chroman. However, when a,13-unsaturated aldehydes are used, a chroman or chromene is formed directly depending upon the substitution pattern of the aldehyde (Scheme 16) <01H(55)2051>.

OH

R1 R2~O

Ac

4-TsOH, (MeO)3CH 'MeOH

o

CaCI2, KOH"H20, MeOH

Ac

16

o

72%

Ac 8 0 % OH R2 n2

R2

= ~

CaCl2, KOH H20, MeOH

e

OH R1 or A

c

~

R1

~ "O" "OH Ac R1 = Me, R2 = H

R1 = H, R2 = Me

52 %

10%

Scheme 16

~I"~'~O~R2R2

Schiff bases containing a tethered alkene react with difluorocarbene to yield cis-fused benzopyrano[3,4-b]pyrrolidines. An intramolecular 1,3-dipolar cycloaddition is involved. Tethered alkynes give the corresponding pyrroles <01TL533>. The reaction of 2-allyloxybenzaldehyde with N-benzylglycine also gives this tricyclic system <01TL2455>. The BF3-promoted reaction of benzaldehyde with silylketene dithioacetal results in the deoxygenative formation of an allylic cation. This S-stabilised intermediate can be captured by an o-hydroxy substituent leading to the chroman 17 (Scheme 17) <01JOC3924>.

••.CHO "~

"OH

SEt

+

./__~'3Et TMS

BF3.OEt2

SEt

CH2CI2

~

h 1"/

SEt 58 %

SEt Et

Scheme 17

Both E- and Z- substituted 4-methylenechromans can be prepared by the Pd-catalysed intramolecular cyclisation of iodophenyl alkynyl ethers (Scheme 18) <01TL2657>.

ff..CH2OH Pd(OAc)2' PPh3 L.,. LL J --O~ 79 %

=HCO2Na,DMF, Bu4NCI R = CH2OH

{~o

I ~

Scheme 18

R Pd(PPh3)4,CO Et3N, AgOAc

'"'=v2"'-i]

MeOH, DMF,H20 R=H 79 %

338

J.D. Hepworth and B.M. Heron

The anodic oxidation of substituted bromophenols yields spirodienones e.g. 18. These undergo a Lewis acid catalysed rearrangement to chromans, the regiochemistry of which is dependent on the substituents present in the spiro compound (Scheme 19) <01T5533>. Br

Br

HO

..OH I

[O1 ..

Br

O

BF3.OEt2 HO

=_

0H2012 -20 ~

+

18

Br

33 %

55 %

Scheme 19 Sequential [5+2]- and [4+2]- cycloadditions feature in a one-pot synthesis of fused chromans 20. Initial Rh-catalysed reaction between a conjugated enyne and the vinylcyclopropane 19 gives a diene that is trapped by a dienophile. Aromatisation of the product is facile (Scheme 20) <0lAG(E)3895>. 0 (ii)

=

0

0

19 0

20

Reagents: (i) 2 mol % [{Rh(CO)2CI}2],TCE, H+; (ii) 1,4-naphthoquinone,air

Scheme 20 6.4.2.4 [2]Benzopyrans and dihydro[2]benzopyrans (Isochromenes and isochromans) An intramolecular nucleophilic substitution reaction occurs when the difluorostyrenes 21 are treated with Nail; good yields of 3-fluoroisochromenes result. A similar approach using the analogous phenylmethanethiols leads to 3-fluoro-lH-[2]benzothiopyrans (Scheme 21) <01BCJ971>. R1 ~ O H

R1

"I~0

DMF, RT " R3

21

R1

R2

R

8 examples 50- 94 %

R2

Scheme 21

An intramolecular Friedel-Crafts alkylation of propargyl silyl ethers 22 gives 4-allenylisochromans presumably via an allenyl cation (Scheme 22) <01JOC4635>.

339

Six-Membered Ring Systems: With 0 and~or S Atoms

R1 ...~

~

R2 /L--OTMS 'Ph

MeOA'~,/~'-/O 22

R2~]],/Ph .... TMSOTf _ 9 4 examples R1 8 0 - 9 8 % 78 Oc, CH2012~ ~ / 3 L ~ MeOAL.~...~...../O Scheme 22

Amide-directed metallation-transmetallation enables allylation to be achieved in the 3-position of the naphthalene derivative 23, cyclisation of which yields the naphtho[2,3-c]pyran-l-one (Scheme 23). Application of similar methodology to benzothiophene afforded the [1]benzothieno[2,3-c]pyran system <01TL5955>. Directed ortho metallation also features in a synthesis of 4-arylisochroman-3-ols <01 TL9293>.

OCONEt2 ~CONEt2

OCONEt2 ~3(i)' 8 (ii) ~

t -2

MeO

O

)i i 61%" i(

OMe OMe OMe 23 Reagents:(i) 2.5eq.sBuLi,TMEDA,THF,-78~ (ii) CuBr-M~S,allylbromide; (iii) 6NHCI,heat,36h Scheme 23

Various 1,3-disubstituted benzo[c]pyran-5,8-diones are accessible by rearrangement of the transient Diels-Alder adducts from styrene and 2-substituted 1,4-benzoquinones <01 T8653>. There is appreciable interest in naphtho[2,3-c]pyran-5,10-diones because of their biological activity. A one-pot synthesis of the system involves the conjugate addition of enamines to 2-(1-hydroxyalkyl)-l,4-benzoquinones and the subsequent cyclisation (Scheme 24). The amine function may be lost or retained. Several natural products have been synthesised using this protocol <01JCS(P 1)2977>.

O ~ ~ O

~ R. ~

O

R2

~+ ~R~/''N/'~ / ' (i) P / hMeA '~R r' T R = 3 O HII R3 (ii) air, SiO2 ~ O

I,

O

R'

1

Scheme 24

6 examples 48 - 8 3 %

6.4.2.5 Pyrylium Salts The photolysis of pyrylium perchlorates in AcOH/Ac20 leads to cyclopentenes via ring opening of the initially formed epoxide by the solvent. When wet CH3CN is used as solvent, the sole product is the bicyclic oxazoline 24 (Scheme 25) <01JA10425>.

AcO

AcO

AcO'"' AcO

+ AcO'"' AcO 5:2 ratio,60 %

OH hv hv -AcOH, AC20 CIO? " MeCN,H2O= Scheme 25

N~ " 24

1%

340

J.D. Hepworth and B.M. Heron

6.4.2.6 Pyranones The Pd-catalysed annulation of 13-chloroacrylates with alkynes affords good yields of trisubstituted 2H-pyran-2-ones (Scheme 26) <01NJC179>.

//•v,,•."**"'•.

~ C O 2 M e CI

+

~"

PdCI2(PPh3)2 = Et3N, 120 ~ 20 h

Scheme 26

9 examples

J .02.04-z4~176

Hetero-fused pyran-2-ones result from coupling the Fischer carbene complex 25 with the 3-alkynyl derivatives of furan and thiophene 2-carboxaldehydes (Scheme 27) <01TL777>.

.C.r(CO)5 X~C

Ph3P

HO X=O, S

F

OMe

=

/ 7

0) 4

L XI"CHO

OMe -

"

O

J

Scheme 27 A variety of 5,6-fused dihydropyran-2-ones can be obtained from an enyne tandem RCM. Initial formation of the cyclopentene ring from 26 in a Ru-catalysed enyne metathesis is followed by cyclisation involving the a,13-unsaturated ketone and formation of the pyranone ring (Scheme 28). The method enables 6,5,6- and 6,6,6- tricyclic systems to be synthesised <01 CC2648>. (9

Q

26

Ru

Reagents: (i) 5 mol % Ru catalyst, CH2C!2, 40 ~ 6 - 12 h

95 %

6 examples 72 - 100 %

Scheme 28 Application of RCM to acrylates derived from terpene aldehydes containing a remote double bond yielded the 6-substituted dihydropyran-2-ones <01TL6069> and oxabicyclo[3.2.1]octane undergoes an efficient ring-opening cross-metathesis with electron-rich alkenes to give unsymmetrically 2,6-disubstituted tetrahydropyran-4-ones <01 OL4275>. The reaction of aromatic aldehydes with the silyl dienolate 27 under Binap catalysis yields 5,6-disubstituted dihydropyran-2-ones with excellent dia- and enantio- stereoselectivities (Scheme 29). Aliphatic aldehydes show similar stereoselectivity but a linear aldol product is also formed <01 OL3807>. O O

~ O T M ? OMe

PhCHO

CuF.(S)-tolBinap o - Q " R-T = Ph~

27

:

Scheme 29

anti/syn>98:2

87 %ee, 85%

H O " ~ ~ ~,,~ BnO

28

~.

~'~-O

Six-Membered Ring Systems: With 0 and~or S Atoms

341

An enolate conjugate addition to a 13-bromomethacrylate offers a good route to the protected E-ring fragment of (S)-camptothecin, a 6-oxodihydropyran-3-carboxylic acid 28 <01JCS(P1)2903>. Pyranones have appreciable value in synthesis, especially through ring transformation reactions, and it is therefore useful to have access to a variety of substituted derivatives. 6-Substituted 5-iodopyran-2-ones, prepared from 2-en-4-ynoic acids, readily insert Zn into the C w I bond. The organozinc derivatives provide access to 6-substituted and 5,6-disubstituted pyran-2-ones (Scheme 30) <01TL2859>.

III

(i)

(ii)

R1

R1

R1/~O-"~O

(iii) .

3 3 - 79 %

R1/~O...--~O

Reagents: (i) 3 eq. 12, 3 eq. NaHCO 3, MeCN, 1.5 h; (ii) 3 eq. Zn dust THF, RT, 3 h; (iii) R2I or R2Br, Pd2(dba)3,Ph3P, THF 15 - 39 h Scheme 30 2-Oxopyrancarboxylic acids undergo a Hunsdiecker reaction offering an attractive route to bromopyranones <01TL1065>. 3,5-Dibromopyran-2-one yields tricyclic lactones in a facile Diels-Alder reaction with sterically hindered cycloalkenyl silyl ethers. Manipulation of the products leads to naphthalene derivatives <01TL8193>. Oxepan-4-ones are formed in a SnCln-promoted three-component reaction between cyclopropapyranones, silyl enolates and glyoxylates (Scheme 31) <01H(55)855, 01TL1095>.

.•C•R

5

R1

VR2G3., R4 i

(i), (ii), (iii)

. ~0

~O

(iv) or ( v )

R1

R1

i

7 examples

0 R4

OTMS R2"~R4 R3 29

11 examples

26 - 66 %

37 - 85 %

Reagents (i) 29, SnC14,4A mol. sieve, CH2CI2, -78 ~ (ii) SnCI4, H(CO)CO2RS;(iii) MsCI, Et3N, CH2CI2, then DBU; (iv) 29, BF3.OEt2, -78 ~ CH2C12;(v) 29, TMSOTf, -40 ~ MeCN Scheme 31

6.4.2.7 Coumarins The long-established Pechmann synthesis of coumarins has been revisited. The reaction of phenols with ethyl acetoacetate (EAA) occurs in better yield at lower temperatures and milder conditions in ionic liquids which act as both solvent and Lewis acid catalyst <01TL9285> and in solvent free reactions catalysed by 4-TsOH <01CLll0>. Microwave irradiation of aminophenols and EAA on a solid support of graphite and montmorillonite K10 rapidly gives good yields of 4-substituted 7-aminocoumarins <01TL2791 >. K10 is also effective in the synthesis of coumarins from phloroglucinol and 3-arylpropynoyl chlorides and of 3,4-dihydrocoumarins using cinnamoyl chlorides. At high

342

J.D. Hepworth and B.M. lleron

temperatures, chromones may be produced through Fries rearrangement of the ester <01S2247>. A three-component tandem Knoevenagel - hDA reaction has been used to variety of pyranocoumarins <01EJO3711, 01JHC965, 01S49, 01TA707>. 4-hydroxycoumarin with paraformaldehyde generates a quinone methide that is substituted fulvenes to afford the tetracyclic adducts (Scheme 32) <01T5807>.

OH

0

/ ~ R 0

intermediate synthesise a Reaction of trapped with

~1 10 examples

O

O

5o - 85 % a 1

Reagents: (i) (CH20)n' ~ ~ [~-('R2 ~

,

anhyd. 1,4-dioxane, 100 ~ Ar, 5 h

Scheme 32

4-Tosylcoumarins undergo Pd-catalysed cross coupling reactions with terminal alkynes and with RZnBr to give a variety of 4-substituted coumarins <01JOC3642> and the vinyl phosphates 30 react with organozinc reagents under Ni catalysis (Scheme 33) <01JOC7875>. Ni-catalysis is also involved in the synthesis of benzocoumarins from the reaction between 7-oxabenzonorbornadiene and alkyl propiolates (Scheme 34). Substituted 7oxanorbornadiene yields tetrahydrocoumarins with complete regio- and stereo-selectivity <0lAG(E)1286>.

OPO(OR1)2

R2

0 O)

(i)

+

30

14 examples 32 - 91%

Reagents- (i) 1 mol % NiCl2(dppe), R2ZnX, Phil, 25 ~ Scheme 33

~ R2

R2 15 examples, 56 - 89 %

Reagents: (i) NiBr2(dppe), Zn, MeCN, 80 ~ Scheme 34

The isocoumarin fragment of the rubromycins has been obtained through a Heck coupling of the substituted terephthalic acid with the enol ether of methyl pyruvate followed by acid catalysed cyclisation (Scheme 35) <01TL3567>.

OMe MeO~CO2M

e

(i)

OMe M e O ~ ~ ] / C O ~ Me

(ii) e

Reagents: (i)

OMe ==~

C02Me

OMe 0 MeO~]..~ O "0

e

Pd(PPh3)4,K2CO3,71%; (ii) 5 % tlCI, MeOH, 83 % Scheme 35

Some naturally occurring 3,4-dihydroisocoumarins have been obtained by the A1C13catalysed rearrangement of 3-benzylphthalides <01JCS(P1)3017>.

343

Six-Membered Ring Systems: With 0 and~or S Atoms

6.4.2.8 Chromones Polymer supported synthetic equivalents of chromones and 3-formylchromones have been obtained from 2'-hydroxyacetophenones <01TL5331>. 3-Formylchromones react with aminobenzoic acids to yield either 3-(arylaminomethylene)-2-hydroxychroman-4-ones or 3-(aryliminomethyl)chromones according to the conditions used <01T3455>. Flavones are halogenated selectively in the 3-position on treatment with PhI(OAc)2 and a TMS halide <01SC2101>. The reaction of 3-halogeneochromones with amines is known to be complex; the products are dependent on conditions, type of amine and the halogen. It is now reported that secondary amines react with the three 3-halogenochromones 31 in the presence of K2CO3 in DMF to give exclusively 2-aminomethylene-3(2H)-benzofuranones (Scheme 36) <01H(55)881>. O O

~

R2RaNH'K2CO3~ DMF, RT

X

R1

31 X = CI, Br, I

R~-~~~N

17 examples R2R3 72 - 96 %

Scheme 36

The reaction of 2-trifluoromethylchromones with ethyl mercaptoacetate yields dihydrothieno[2,3-c]coumarins; diethyl 3,4-dithiaadipate is a by-product indicating a redox process (Scheme 37) <01TL5117>.

R~~,~

0

CF3

3 HSCH2CO2Et, Et3N, 80 - ~= R..] ~ ~ O ~ ~ -EtOH, -H20 OF3 -(SCH2CO2Et)2 -

5examples 75 - 85 %

Scheme 37 The anodic fluorination of 3-benzylidenechroman-4-ones and of 3-(4-chlorobenzyl)chromone occurs exclusively at the 2-position. The fluorine atom is activated to nucleophilic displacement <01JOC7691>. Flavanones undergo a Baeyer-Villiger rearrangement to dihydro-1,5-benzodioxepin-2-ones on treatment with H202 and methyltrioxorhenium <01TL5401>. The synthesis of benzoxazepines from chromanones forms part of a review of the 7-membered ring compounds <01JHC 1011 >. In the presence of aldehydes, the SnCl4-catalysed ring opening of methanochromanones leads to trans-fused tetrahydrofuro[2,3-b][ 1]benzopyranones, which can be isomerised to the cis-fused compound (Scheme 38)<01H(55)135>.

O "O"

~1 H_ CO2Me CO2Me

10 mol % SnCI4 0H2CI2

~k~'J~"O---H Scheme 38

,O, H CO2Me CH2CI2 Rt, 6 h

~~.,~O..,~d____-'R H

344

J.D. Hepworth and B.M. Heron

Synthesis of both enantiomers of the pyrano[3,2-c]benzopyran-4-one, neuchromenin, 32 has been accomplished from 6,7-dihydroxychroman-4-one and the enantiomers of ethyl 3-hydroxybutanoate <01EJO1963>. The benzopyranone unit can be incorporated into a polycyclic system by the Mn(III)-catalysed oxidative cyclisation of the substituted chroman4-one 33. The sequence generates the tetracycle with the same relative stereochemistry found in the sponge-derived puupehenols (Scheme 39) <01JCS(P1)206>.

O H HO"

"~

33 Reagents: (i) Mn(OAc)3, Cu(OAc)2.H20, AcOH, 58 ~ 5 h, 25 %; (ii) Mn(OAc)3, AcOH, 80 ~ 12 h, 58 %

"(3"

32

Scheme 39

Lithiation of the iodobenzyl keto ester 34 using mesityllithium induces an intramolecular addition and leads to the isochromanone <01OL13>. The direct hydroxylation of isochromanones involves enolisation and reaction with t-BuOOH or N-methylmorpholine N-oxide in the presence of CuI <01H(55)2157>. MesLi, THF

0

34

-78 ~

1h

0

-'-

70 %

0

OMe

35

6.4.2.9 Xanthones and xanthenes

1-Bromoxanthones have been used to construct the novel heterocyclic system, [ 1]benzopyrano[2,3,4-i,j]isoquinoline 35 <01TL5219>. Cyclisation of 2-aryloxybenzonitrile derivatives in CF3SO3H affords xanthone-iminium triflates 36. Vigorous hydrolysis leads to xanthones. The method has been applied to the synthesis of polynuclear dixanthones and a polyxanthone <01 OL2337>. O

(i)

(ii)

36

Reagents: (i) CF3SO3H, RT, 120 h; (ii) 75 % H2SO4, 140 ~ 24 h Xanthenes are obtained in good yield when a phenolic group intramolecularly traps benzynes generated from 1-amino-lH-benzotriazoles. The reaction conditions are such that iodine is incorporated into the product (Scheme 40) <01JCS(P1)1771>.

Six-Membered Ring Systems: With 0 and~or S Atoms

[~ OMe

OH

"N

"N

NHBoc (i) CF3CO2H (ii) NIS

NH2

345

I

81% ..OMe

OMe Scheme40

OMe

The 9-xanthenylmethyl unit is a photocleavable protecting group for amines <01TL6645> and xanthen-9-ylidenes are protecting groups in glycerol chemistry <01JCS(P1)1807>.

6.4.3

H E T E R O C Y C L E S CONTAINING ONE SULFUR ATOM

6.4.3.1 Thiopyrans and analogues The conjugated thioesters 37 derived from the reaction of 1,l-bis(ethylsulfanyl)perfluorobut-l-ene with magnesium halides behave as dienophiles. Reaction with dienes occurs selectively at the thiocarbonyl group to give high yields of fluorinated 3,6-dihydro-2Hthiopyrans <01TL2133>. A hDA reaction also features in a synthesis of a phosphonothiashikimic acid derivative, employing a phosphonodithioformate as the heterodienophile <01 CC611 >.

F~_~set C2F5 SEt

MgBr2 = F3C~ heat,74 % Br

s

~

F SEt

80 %

37

.._ ~

F,

C

SEt

F3

r

Aliphatic homoallyl mercaptans and aldehydes yield trisubstituted tetrahydrothiopyrans with good diastereoselectivity through an InC13-mediated Prins reaction. Similar selectivity is observed with 1-phenyl-3-butene-l-thiol and benzaldehyde; scrambling is noted with substituted benzaldehydes (Scheme 41) <01JOC739>. CI _C~

SH ph./J"-....,"~.

PhCHO,InC,3 = CH2Cl2

~

Ph

Scheme 41

+

h~,~

Ph P 8:1 97%

Ph

1,5-Cyclooctadiene is readily converted into 2,6-dichloro-9-thiabicyclo[3.3.1]nonane by treatment with either SCI2 or $2C12 followed by SO2C12. Reaction with chloramine T and related compounds occurs at S and provides a reliable route to N-sulfonylsulfilimines <01JOC594>. Both halogen atoms can be replaced by a wide variety of nucleophiles and in some cases the reaction is reversible. Reaction with brucine gives a 7:1 diastereoisomeric mixture, and the enantiomeric excess is retained on further reaction with NaN3 (Scheme 42) <01JOC4386>.

346

J.D. Hepworth and B.M. lteron

=

~ ....

CI

26 examples Nu 71 -98%

CI

Reagents: (i) SCI 2 or $2C12 then SO2C12, CH2CI2, 95 - 100 %; (ii) nucleophile (Nu), NaHCO3 or KzCO3 or Ag20 , MeCN or tt20 Scheme 42

An efficient synthesis of thiopyrylium fluoroborate involves the quantitative dehydrogenation of 2H-thiopyran, which is prepared from ethyl vinyl sulfide. A single crystal X-ray study showed the cation to be planar <01EJO2477>. 3-Substituted 2H-[1]benzothiopyrans result from a Baylis-Hillman reaction between 2,2'-dithiodibenzaldehyde, behaving as a masked 2-mercaptobenzaldehyde, and electrondeficient alkenes (Scheme 43) <01S2389>. [ ~

S"S

DBU

8 examples 40 - 67 %

CHCI3, RT

OHC

Scheme 43 On treatment with a Lewis acid, ct-(benzotriazolyl)methyl thioethers generate 0t-thionium ions which can be trapped by styrenes in a [4 + + 2] cationic cycloaddition to produce thiochromans 38. The reaction proceeds in high yield and allows good variation in substitution pattern. The stereoselectivity is variable, though often only one isomer is obtained and seldom more than two <01JOC5595>. R2 S

r

Bt = benzotriazol-l-yl

R3

1.5 - 2.0 eq. Lewis acid, 25 ~ - reflux

R4 R3 CH2CI 2

r

R'

18 examples 40 -99 %

38

The base-catalysed reaction of 6-aryl-3-carbomethoxy-4-methylthio-2tt-pyran-2-one 39 with tetrahydrothiopyran-4-one affords the isothiochroman 40. Similarly, reaction with thiochroman-4-one gives a benzo[c]thiochromene. The carbanion derived from the thiopyranone attacks the pyranone at the electrophilic 6-position with concomitant ring cleavage and loss of CO2. Cyclisation involves nucleophilic attack at the 4-carbonyl function (Scheme 44) <01JOC5333>.

Ar"

SMe

O

.~CO2Me

~. ~

CO2Me KOH, DMF RT, 15h

"O" "O

39

MeS

7examples S 50-73% Ar

Scheme 44

40

Thiosalicylic acid is the precursor of thiochromones in a synthesis in which the key step is an intramolecular Wittig reaction (Scheme 45) <01T9755>.

347

Six-Membered Ring Systems." With 0 and~or S Atoms

v

"SH

~

O

"SCOR

Lv

"SCOR

O

1

10 examples

Reagents: (i) RCOC1 or (RCO)20, aq. KOH, 0 ~ - RT, 0.5 h, 75 - 80 %; (ii) TBDMS-CI, 1.5 eq. imidazole, CH2CI2, 0 ~ - RT, 7 - 8 h, 65 - 70 %" (iii) Ph3P=CHSiMe3, THF, heat, 16 - 38 h, 58 - 90 %

Scheme 45

Isothiochroman-4-one oxime 41 results from quenching the dication generated in a solution of 1-(benzylthio)-l-(methylthio)-2-nitroethene in trifluoromethanesulfonic acid with methanol (Scheme 46) <01EJO1525>.

I

~..,.~,~s

(~.OH 1

HON

L~

MeOH,CH2CI2 L~....,~L..../S -10 ~ 40 min

~" 41

-sR2 examples 70 - 83 %

Scheme 46

6.4.4

HETEROCYCLES

CONTAINING TWO OR MORE OXYGEN ATOMS

6.4.4.1 Dioxins 6-Carbomethoxymethyl-3-methoxy-l,2-dioxane, a feature of some marine sponges, has been synthesised by hemiketalisation of a keto ester followed by an intramolecular Michael addition (Scheme 47) <01TL7281>.

MeO2C+

MeO.~ ,,, H202.H2NCONH2 HOO.., 1 Et2NH,(CF3)2CHOH 4-TsOH, MeOH MeO2CA~.J 72 % MeO2C 72 %

O_O O Me ,,_._z -

Scheme 47 2-(Acyloxy)benzoyl chlorides undergo a base-catalysed cyclisation to 2-alkylidenebenzo[1,3]dioxin-4-ones. Although acetylsalicylic acid is formed on treatment of 42 (R ~ = R 2 = H) with water and hence behaves as a prodrug for aspirin, reaction with alcohols and carboxylic acids results in addition to the methylene function (Scheme 48) <01TL5231>. O

~.~COCI -,
Et3N, PhMe -~ [ ~ O . . ~ O C 6 examples 110 ~ 15 h 27 - 67 % R1R2 Scheme 48

42

The reaction of 1-naphthyl acrylate with an excess of an aldehyde in CH3CN and in the presence of D A B C O leads to 5-methylene-l,3-dioxan-4-ones (Scheme 49) <01CC1612>.

348

J.D. Hepworth and B.M. Heron

O~ONp

RCHO,MeCN

O.~O.,.]/R

30 mol % DABC~) ~ . . . O Np = 1-naphthyl R Scheme 49

3 examples 75-91%

(Z)-2-Acyl-2-enals are readily prepared by retrocycloaddition of 5-acyl-4-alkyl-4H-1,3dioxins <01JA9455> and cis-fused decalins are accessible by reduction of the intramolecular photo-product from 2-cycloalkenyl- 1,3-dioxin-4-ones <01H(54)765>. Both fused 1,4-dioxanes and substituted naphthalenes can be obtained from the pentacyclic acetals derived from 1,4-dioxene. A sequence of nucleophilic substitution, annulation and an intramolecular Friedel-Crafts reaction is involved (Scheme 50) <01TL231>.

OMe

OMe

,,v,

MeO

,v,

Reagents: (i) tBuLi; (ii) 3-acetylanisole,THF, -70 - 0 ~ (iii) cat. TMSOTf, L..~O'I'MS MeCN, -40 to -10 ~ (iv) Et3SiH, TiC14,CH2C12,-70 ~ (v) HCIO4, MeCN, heat Scheme 50 The Pd(0)-catalysed heteroannulation of 1,2-dihydroxybenzenes with propargyl carbonates leads to 2,3-dihydro-2-ylidene-l,4-benzodioxins generally in good yield and with good regioselectivity. The stereochemistry of the double bond depends on the substitution pattern of the alkyne (Scheme 51) <01JOC6634>. Rz

+ R1

OCO2Me

O " ~["~"~O + THF, RT O 20 examples, 47 - 99 % Scheme 51

R2

6.4.4.2 Trioxanes The trioxane ring system has been synthesised from allylic alcohols through reaction with molecular oxygen and triethylsilane in the presence of a Co catalyst. The product peroxy alcohol reacts readily with carbonyl compounds to form the trioxane (Scheme 52) <01TL4569>. Water-soluble 3-aryl-l,2,4-trioxanes 43 have been prepared from cyclohexanone; the peroxide unit is introduced photochemically from air and the benzoic acid group is derived from styrene <01JMC3054>.

349

Six-Membered Ring Systems." Witlz 0 and~orS Atoms

HO kj

. .. (I), (ii)

1 RI

~

. 11 examples

Reagents: (i) Co(acac)2, Et~SiH, RT, O-~; (ii) R1R2C=O,cat. 4-TsOH "

_ H /~_

HO2CI"~J -

Scheme 52

H

0

u--~

H CO2Me

OMe 43

44

Interest continues in the artemisinins. The 6-oxo artemisinin analogue 44 has been described <01H(54)607>. C-10 deoxo carba analogues of artemisinin 45 are readily accessible from the 10-benzoate of dihydroartemisinin (DHA) through a ZnC12-catalysed reaction with aromatic allylsilanes. The new artemisinins are more potent than artemisinin itself <01JCS(P1)2682>. The C-10 phenoxylation of DHA, catalysed by a combination of TMSOTf and AgC104, occurs with excellent stereoselectivity. The products exhibit potent antimalarial activity <01JMC58>. The 10-DHA acetate and difluoroenoxysilanes yield 10difluoromethylene ketones in a Lewis acid-catalysed reaction (Scheme 53); epimerisation of C-9 occurs and the stereochemistry at C-10 varies with the silane used <01JOC7858>. ~H"-

H~

" ~

H':O_~~

OTMS '",H

/

F ~ F

H :

Ar

Lewis-78acid'~

O-7(~ 2

H 8examples k~. , 30- 83 %

H OOF--~'" COAr F

C)COMe Scheme 53

The stereochemistry of the addition of Br2 to dehydroDHA is opposite to that of I2 enabling the synthesis of isomers of the ring-contracted aldehyde to be achieved (Scheme 54) <01TL2125>. H ~

(i)

H :

,,,H 9 ~ CliO

H "

(ii) ~

H ~D~_f/

Reagents: (i) Br2, CCI4 then H20 then Et3N, 92 'T~; (ii) I2, phosphate buffer, H20 , tBuOtI, 57 % Scheme 54

"

H " .,,,H "CliO

H ~._.~/

-

O 4G

Artemisitene 46 undergoes Michael additions with benzimidazole and triazoles <01TL2843> and with organolithium and Grignard reagents <01JMC4688>. (+)-Deoxoartemisitene has been synthesised from artemisinic acid and converted into a range of C-11 derivatives via initial oxidation of the alkene function. These derivatives lack the problematic acetal unit at C-12 <01TL3997>. Artemisitene is a source of 6,7-dehydroartemismic acid <01JCS(,P1)2421>. The degradation of artemisinin <01HCA928>, <01JMC3150> and the mechanism of its antimalarial activity <01JCS(P1)605> have been studied further.

350 6.4.5

J.D. Hepworth and B.M. Heron

H E T E R O C Y C L E S CONTAINING TWO OR MORE SULFUR ATOMS

6.4.5.1 Dithianes and trithianes

Oxetanes are sufficiently activated towards nucleophilic attack by the Lewis acidity of the Ti complex 47 such that CS2 converts them into 1,3-dithiane-2-thiones 48 in high yield. Under the same conditions, thietane does not react <01 T7149>.

~_O

CS2

+

Ti catalyst 47 120 ~ 48 h

=

S S"~S Lv-J

48

OiPr -O -i~O ,O31" i ~-~-NJ

4 examples 9~ 1~176 ~176

47

In the presence of montmorillonite K10, 13,1Y-dichlorosulfides, prepared by the addition of SC12 to alkenes, yield 1,4-dithianes on treatment with H2S <01S2397>. Calculations have established the axial preference of a 2-(dimethylphosphinoyl) group in 1,3,5-trithiane and in 1,3-dithiane tetroxide and suggest that hydrogen bonding contributes to the stability of the axial conformer <01JOC2925>. The peri-fused 1,2,3-trithiane 2-oxide 50, which is conveniently prepared from disulfide 49, is an efficient sulfur monoxide transfer reagent. Dienes are converted into cyclic sulfoxides, from which thiophenes can be obtained under Pummerer conditions, and the disulfide is regenerated <01 OL3565>. o

S~S ,,,

49 6.4.6

(i) LiAIH4, Et20, h e a t (ii) SOCI2, py, Et20 65 %

~

~ stS"[~

/

PhCI, heat

50

~ O

+ 49 7examples 38 - 100 %

H E T E R O C Y C L E S CONTAINING BOTH OXYGEN AND SULFUR IN THE SAME RING

6.4.6.10xathianes

502 undergoes a hDA reaction with the (E)- and (Z)- 4-(fluoromethylidene)-3-methylene2,3-dihydronaphthalene to yield the tricyclic 1,2-oxathiine 2-oxides. This first solid sultine exists in a sofa conformation (Scheme 55) <01CC1214>.

(i)= ~

~,. O.s.,,o

F,,~O.s.,,o J . -40~ . ~ =(ii)

Reagents: (i) SO 2, CD2CI 2, -80 ~ (ii) 502, -40 ~ Scheme 55 2-Vinyl derivatives of 1,3-benzoxathiin-4-ones 51 can be synthesised from methyl thiosalicylate involving an initial propargylation followed by a Sonogashira cross-coupling

351

Six-Membered Ring Systems: With 0 and~orS Atoms

reaction with aryl iodides. A Cu-catalysed cyclisation occurs after ester hydrolysis (Scheme 56) <01JCS(P1)1649>. O

~~

.CO2Me

(i), (ii)

"SH

[ / ~ ~ CO2Me

= ~S~'~Ar

(iii)-

(v)

(~"~O

8 exampies

-" ~ ~ ' S ~ ~ " " A r 51

Reagents: (i) propargyl bromide, K2CO3, Me2CO, heat, 16 h; (ii) ArI, 3.5 mol % (PPh3)2PdCI2, 6 mol % CuI, Et3N, RT, 24 h; (iii) KOH, MeOH, RT, 2 h; (iv) HCI; (v) 20 mol % CuI, Et3N, THF, heat, 24 h Scheme 56 o-Thioquinones act as the diene in cycloaddition reactions with acyclic dienes <01JCS(P1)3020> and with carbocyclic and heterocyclic dienes <01T8349> to give a variety of 1,4-benzoxathiins. However, with furan the o-thioquinone behaves as the dienophile. Inverse electron demanding Diels-Alder reactions with styrenes and manipulation of the resulting adducts allows the synthesis of 4-thiaflavans <01 CC551>. NMR and X-ray studies of some spiro-l,3-oxathianes, prepared from cyclohexanones and 3-mercapto-l-propanols, indicate that the heterocyclic ring exists in the chair conformation. The system can exhibit flexible, semi-flexible and anancomeric behaviour according to the substituents present <01T8751>.

6.4.7

REFERENCES

01ACR504 01ACR615 01ACR895 01AG(E)191

01AG(E)I96 0 lAG(E) 1090 01AG(E)1262 01AG(E) 1286 0lAG(E)2063 0lAG(E)3667 0lAG(E)3842 0lAG(E)3849 0lAG(E)3895 0lAG(E)4055

01AG(E)4068

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352 0lAG(E)4082 0lAG(E)4545

J.D. Hepworth and B.M. Heron

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Six-Membered Ring Systems: With 0 and~or S Atoms 01JCS(P1)2682 01JCS(P1)2903 01JCS(P1)2977 01JCS(P1)3017 01JCS(P1)3020 01JHC965 01JHC1011 01JMC58

01JMC3054 01JMC3150 01JMC4688 01JOC594 01JOC739 01JOC1885 01JOC2747 01JOC2925 01JOC3642 01JOC3924 01JOC4214 01JOC4386 01JOC4635 01JOC5333 01JOC5595 01JOC6634 01JOC7658 01JOC7691 01JOC7858 01JOC7875 01JOC8106 01JOC8973 01NJC179 01NPR310 0lOLl3 01OL847 01OL949 01OL1383 01OL1693 01OL1989

353

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354 01OL2141 01OL2337 01OL2749 01OL3149 01OL3549 01OL3565 01OL3807 01OL3875 01OL3979 01OL4275 01SC2101 01S49 01S140 01 $2007 01S2059 01S2247 01S2389 01S2397 01T1395 01T3019 01T3455 01T5533 01T5807 01T7149 01T8349 01T8653 01T8751 01T9755 01TA707 01TL89 01TL231 01TL533 01TL609 01TL777 01TL793 01TL797 01TL1065 01TL 1095 01TL1931 01TL2125 01TL2133 01TL2455 01TL2657

J.D. Hepworth and B.M. Heron L.R. Zehnder, L.-L. Wei, R.P. Hsung, K.P. Cole, M.J. McLaughlin, H.C. Shen, H.M. Sklenicka, J. Wang, C.A. Zificsak, Org. Lett. 2001, 3, 2141. H.M. Colquhoun, D.F. Lewis, D.J. Williams, Org. Lett. 2001, 3, 2337. Y. Sakamoto, G. Matsuo, H. Matsukura, T. Nakata, Org. Lett. 2001, 3, 2749. I. Paterson, C. De Savi, M. Tudge, Org. Lett. 2001, 3, 3149. H. Fuwa, M. Sasaki, K. Tachibana, Org. Lett. 2001, 3, 3549. R. S. Grainger, A. Procopio, J. W. Steed, Org. Lett. 2001, 3, 3565. G. Bluet, B. Baz~in-Tejeda, J.-M. Campagne, Org. Lett. 2001, 3, 3807. K.A. Parker, T.L. Mindt, Org. Lett. 2001, 3, 3875. A.B. Smith III, M. Frohn, Org. Lett. 2001, 3, 3979. D.L. Wright, L.C. Usher, M. Estrelle-Jiminez, Org. Lett. 2001, 3, 4275. H.S. Rho, B.-S. Ko, Y.-S. Ju, Synth. Commun. 2001, 31, 2101. G. Cravotto, G.M. Nano, S. Tagliapietra, Synthesis 2001, 49. B.A. Chauder, A.V. Kalinin, V. Snieckus, Synthesis 2001, 140. A. Ahmed, E. Ohler, J. Mulzer, Synthesis 2001, 2007. A.E.-A.M. Gaber, H. McNab, Synthesis 2001, 2059. J.-M. Lee, T.-H. Tseng,Y.-J. Lee, Synthesis 2001, 2247. P.T. Kaye, X.W. Nocanda, Synthesis 2001, 2389. E. Roversi, R. Scopelliti, E. Solari, R. Estoppey, P. Vogel, P. Brana, B. Menrndez, J.A. Sordo, Synthesis 2001, 2397. R. Ballini, G. Bosica, M. L. Conforti, R. Maggi, A. Mazzacani, P. Righi, G. Sartori, Tetrahedron 2001, 57, 1395. H. Fuwa, M. Sasaki, K. Tachibana, Tetrahedron 2001, 57, 3019. H. Stankovirov~i, M. L~icov~i, A. G~iplovsk3~, J. ChovancovL N. PrrnayovL Tetrahedron 2001, 57, 3455. K. Moil, S. Yamamura, S. Nishiyama, Tetrahedron 2001, 57, 5533. V. Nair, C.N. Jayan, K.V. Radhakrishnan, G. Anilkumar, N.P. Rath, Tetrahedron 2001, 57, 5807. S. Motokucho, D. Takeuchi, F. Sanda, T. Endo, Tetrahedron 2001, 57, 7149. V. Nair, B. Mathew, N.P. Rath, M. Vairamani, S. Prabhakar, Tetrahedron 2001, 57, 8349. J. A. Valderrama, D. Pessoa-Mahana, R. A. Tapia, A. Rojas de Arias, H. Nakayama, S. Torres, J. Miret, M. E. Ferreira, Tetrahedron 2001, 57, 8653. A. Terec, I. Grosu, L. Muntean, L. Toupet, G. PIr, C. Socaci, S. Mager Tetrahedron 2001, 57, 8751. P. Kumar, M.S. Bodas, Tetrahedron 2001, 57, 9755. G. Cravotto, G.M. Nano. G. Palmisano, S. Tagliapietra, Tetrahedron Asymmetry 2001, 12,707. J.S. Yadav, B.V. Subba Reddy, G. Mahesh Kumar, Ch.V.S.R. Murthy Tetrahedron Lett. 2001, 42, 89. I. Hanna, V. Michaut, L. Ricard, Tetrahedron Lett. 2001, 42, 231. M.S. Novikov, A.F. Khlebnikov, O.V. Besedina, R. R. Kostikov, Tetrahedron Lett. 2001, 42, 533. M.J. McLaughlin, H.C. Shen, R.P. Hsung, Tetrahedron Lett. 2001, 42,609. Y. Zhang, J.W. Herndon, Tetrahedron Lett. 2001, 42,777. J. Li, C.-J. Li, Tetrahedron Lett. 2001, 42, 793. G.T. Nadolski, B.S. Davidson, Tetrahedron Lett. 2001, 42, 797. C.-G. Cho, J.-S. Park, I.-H. Jung, H. Lee, Tetrahedron Lett. 2001, 42, 1065. Y. Sugita, C. Kimura, H. Hosoya, S. Yamadoi, I. Yokoe, Tetrahedron Lett. 2001, 42, 1095. M. Uchiyama, M. Oka, S. Harai, A. Ohta, Tetrahedron Lett. 2001, 42, 1931. F. Grellepois, D. Bonnet-Delpon, J.-P. Brgur, Tetrahedron Lett. 2001, 42, 2125. J.-P. Bouillon, Y. G. Shermolovich, C. Portella, Tetrahedron Lett. 2001, 42, 2133. B.B. Snider, S.M. O'Hare, Tetrahedron Lett. 2001, 42, 2455. O. Barberan, M. Alami, J.-D. Brion, Tetrahedron Lett. 2001, 42, 2657.

Six-Membered Ring Systems: With 0 and/or S Atoms

01 TL2791 01 TL2821 01TL2843 01TL2859 01TL3567 01 TL3645 01 TL3649 01TL3997 01TL4569 01TL4729 01TL5117 01TL5219 01TL5231 01TL5331 01TL5401 01TL5875 01TL5955 01TL6031 01TL6035 01 TL6069 01TL6195 01TL6199 01TL6219 01TL6599 01TL6645 01TL7281 01TL8193 01TL8685 01TL8849 01TL9285 01TL9293

355

S. Fr~re, V. Thi6ry, T. Besson, Tetrahedron Lett. 2001, 42, 2791. K. Kira, M. Isobe, Tetrahedron Lett. 2001, 42, 2821. X.-B. Liao, J.-Y. Han, Y. Li, Tetrahedron Lett. 2001, 42, 2843. F. Bellina, M. Biagetti, A. Carpita, R. Rossi, Tetrahedron Lett. 2001, 42, 2859. S.P. Waters, M.C. Kozlowski, Tetrahedron Lett. 2001, 42, 3567. I. Kadota, N. Oguro, Y. Yamamoto, Tetrahedron Lett. 2001, 42, 3645. I. Kadota, H. Takamura, Y. Yamamoto, Tetrahedron Lett. 2001, 42, 3649. M. Jung, K. Lee, H. Jung, Tetrahedron Lett. 2001, 42, 3997. P.M. O'Neill, M. Pugh, J. Davies, S.A. Ward, B.K. Park, Tetrahedron Lett. 2001, 42, 4569. I. Kadota, H. Takamura, K. Sato, Y. Yamamoto, Tetrahedron Len. 2001, 42, 4729. V.Y. Sosnovskikh, B.I. Usachev, D.V. Sevenard, E. Lork, G.-V. R6schenthaler, Tetrahedron Lett. 2001, 42, 5117. A. Garcfa, D. Domfnguez, Tetrahedron Lett. 2001, 42, 5219. P.Babin, B. Bennetau, Tetrahedron Lett. 2001, 42, 5231. J.I. Borrell, J. Teixid6, E. Schuler, E. Michelotti, Tetrahedron Lett. 2001, 42, 5331. R. Bernini, E. Mincione, M. Cortese, G. Aliotta, A. Oliva, R. Saladino, Tetrahedron Lett. 2001, 42, 5401. A.Y. Federov, F. Carrara, J.-P. Finet, Tetrahedron Lett. 2001, 42, 5875. S. Kamila, C. Mukherjee, A. De, Tetrahedron Lett. 2001, 42, 5955. K.S. Feldman, A.L. Perkins, Tetrahedron Lett. 2001, 42,6031. R.G. Carter, D.E. Graves, Tetrahedron Lett. 2001, 42, 6035. Y. Du, D.F. Wiemer, Tetrahedron Lett. 2001, 42, 6069. I. Kadota, C.-H. Park, K. Sato, Y. Yamamoto, Tetrahedron Lett. 2001, 42, 6195. I. Kadota, C. Kadowaki, H. Takamura, Y. Yamamoto, Tetrahedron Lett. 2001, 42, 6199. H. Imai, H. Uehara, M. Inoue, H. Oguri, T. Oishi, M. Hirama, Tetrahedron Lett. 2001, 42, 6219. S. Chandrasekhar, G. Rajaiah, P. Srihari, Tetrahedron Lett. 2001, 42, 6599. H. Du, M.K. Boyd, Tetrahedron Lett. 2001, 42, 6645. N. Murakami, M. Kawanishi, S. Itagaki, T. Horii, M. Kobayashi, Tetrahedron Lett. 2001, 42, 7281. C.-G. Cho, Y.-W. Kim, W.-K. Kim, Tetrahedron Lett. 2001, 42, 8193. B. Leroy, I.E. Mark6, Tetrahedron Lett. 2001, 42, 8685. G. Dujardin, S. Leconte, L. Coutable, E. Brown, Tetrahedron Lett. 2001, 42, 8849. M.K. Potdar, S.S. Mohile, M.M. Salunkhe, Tetrahedron Lett. 2001, 42, 9285. A. Bieniek, J. Epsztajn, J. A. Kowalska, Z. Malinowski, Tetrahedron Lett. 2001, 42, 9293.

356

Chapter 7 Eight-Membered and Larger Rings George R. Newkome Departments of Polymer Science and Chemistry, The University of Akron, Akron, OH, USA newkome @uakron.edu

7.1

INTRODUCTION

Since the creation of crown ethers in the mid 1960s, the field has blossomed into a diverse landscape of macromolecules possessing novel combinations of heteroatoms, ring sizes, and (multiple) interlocking tings, that are, in essence, fascinating structures possessing artistic beauty. Most recently, the expansion into crystal engineering, has added a focus on the intermolecular interactions within the nanoscale r6gime. Numerous reviews, concepts, highlights, accounts, and perspectives have appeared throughout the past year that are of interest: for example, to molecular containers: hemicarcerands <01ACR95>, porous and robust metal-organic carboxylate frameworks (modular chemistry) <01ACR319>, or metal-mediated self-assembly <01 CEJ3637>; molecular machines based on transition metals <01ACR488, 01ACR477>, rotaxanes <01ACR445, 01RCR28, 00PAC2233, 01ACR465>, catenanes, <01ACR433> or cyclodextrins <01ACR456>; the molecular design of artificial molecular and ion recognition systems <01ACR865>; intramolecular edge-to-edge aromatic interactions <01ACR885>; sapphyrins <01ACR989>; calixarenes <01CCR3, 01SEIE839, 01H181>; planar chirality in macroheterocycles <01EJOC 1801 >; calixpyrroles <01 CCR57>; infrared luminescence of lanthanide macrocyclic complexes <01RIC299>; molecular recognition of neutral and anionic guests <01RIO207>; pendant-arm azamacrocycles <01RIC165>; macrocyclic corrosion inhibitors <01COR273>; supramolecular recognition <01YH557>; nanocomposites, based on macrocycles <01RIC125>; mixed macrocyclic coordination compounds <01RICI>; interconversion of monomers, polymers and/or polymers <01RFP15>; oligopyrrole macrocycles <01CCCC693>; coordination polymers containing gold centers <01CCR313>; metal systems incorporating linked synthetic macrocycles <01CCR249>; macrocyclic receptors for amines <01JIPMCI>; phthalocyanines <01MRC68>; oxophlorins <01CCR349>; macrocyclic glycopeptide chiral stationary phases <01CST25>; chiral separations using macrocyclic antibiotics <01JCA73>; photochromic crown ethers <00MI01>; spectral properties of precursors and derivatives of porphyrins <01RCR656>; and theoretical research on porphyrins <01JPP01>. Because of space limitations, only meso- and macrocycles possessing heteroatoms and/or subheterocyclic rings are reviewed; in general, lactones, lactams, and cyclic imides have been excluded. In view of the delayed availability of some articles appearing in previous years, several have been incorporated.

Eight-Membered and Larger Rings 7.2

357

C A R B O N - O X Y G E N RINGS

C,O-Macrocycles come in all sizes and shapes and there continues to be new aspects to crown ethers, which were reported over 35 years ago. 24-Membered macrocycles with chalcone subunits and isobutenyl linkages have been formed through a mixed aldol condensation <00OL3829>. Polycondensation of a trifunctional, ketone-activated fluoroarene with bis- or tris-phenoxides under pseudo-high dilution conditions gave rise to a series of very large macropolycyclic aromatic ethereal ketones (1), reduction of the carbonyl moieties afforded the ethereal parent; as therein suggested "this approach to large, closed-network molecules is not restricted to the aromatic polyethereal ketone systems ...but should be applicable to any type of branching polycondensation..." <01CC2574>. The novel direct reactions between trioxanes and ethylene oxide have been reported from which three cyclic formals were isolated <01TL271>. A cobalt-mediated macrocyclization via formation of a pyridine moiety has been demonstrated for the generation of large ethereal fused macrocycles from bis-alkynes and nitriles or alkyne-nitriles and alkynes in synthetically viable yields <01JA3157>. Potassium cations facilitated the acceleration of the Aldol reaction through the fast, reversible formation of a 1:1:1 sandwich complex between the formylbenzo- and acetylbenzo-15-crown-5 as well as metal cation <01OL353>. Novel dithiane-spiro-crown ethers, prepared from 5,5di(hydroxymethyl)-l,3-dithiane, were used as building blocks to assemble photolabile biscrown ethers via addition to dicarbonyl-containing ethers <01OL2633>. Optically active artificial hosts, based on a phenolphthalein skeleton, have been formed for the visual enantiomeric recognition of alanine derivatives <010L4071>.

~CF3

~

~(~F3

'----"

Calix[n]arenes continue to play an important role in supramolecular chemistry, since they possess a convenient platform for the assembly of convergent loci. Photo-switchable calixarene crown ethers possessing the stilbene subunit were prepared via the McMurry coupling of the corresponding bisbenzaldehyde-calix[4]arene derivatives; unlike the diazobenzene relatives, these stilbene crowns did not undergo thermal isomerization <01TL5291>. The stepwise synthesis of cone and partial cone 1,3-bridged n-propoxy calix[4]crown ethers possessing an electro-polymerizable 2,2'-dithiophen-3-yl-hexylene functionality on the lower rim has been described; the appended heterosubunit did not affect the size-selectivity of the calix[4]crown unit <01CEJ3354>. The synthesis of nitro derivatives of 1,3-calix-[4]arene biscrown-6 has appeared and has been shown to have a role in the complexation of the cesium cation <01TL8285>. A biscalix[4]arene has been demonstrated to possess remarkably

G.R. Newkome

358

enhanced inclusion ability for the N-methylpyridinium ion caused by the increasing 7t-basicities of the aryl rings <01TL7465>. Reductive homocoupling of 4-substituted-2,6-diformylphenols with Et3SiH in the presence of Me3SiOTf or the heterocoupling reaction with the tris(trimethylsilyl) ether of 4-substituted2,6-bis(hydroxymethyl)phenols afforded a series of homooxacalix[n]arenes <01TL1733>. During the stepwise preparation of hexahomotrioxacalix[3]arenes, an irregular heptahomotetraoxacalix[3]arene (2) was formed, shown to possess a pseudo-C2-symmetry, and demonstrated to be very substituent dependent <01JOC4083>. New homooxacalixarenes have been prepared in the simple thermal dehydration of the bis(hydroxymethyl)phenols <01JOC1497>. The first synthesis of C3-symmetrical and unsymmetrical hexahomotrioxacalix[3]naphthalenes has been reported <01JOC1473>. Treatment of the 1,5-bridged calix[8]arenes with alkali metal carbonates induced the folding of the large skeleton into a 90 cone conformation possessing triads of contiguous directed OH-bearing rings <01 OL1605>. Two new C2v cavitands, based on resorcin[4]arene, were reported and their binding Iq 2

0~0

3

properties with nine small guests were evaluated <01TL1927>. Treatment of an acrylate bearing a secondary ammonium salt and terminal di-tert-butylphenyl moiety with dibenzo-24crown-8 afforded the pseudorotaxanes monomer; this free monomer, DB24C8, was heated at 60 ~ for 20h in the presence of AIBN to give the side-chain-type polyrotaxane <01M5449>. Two complementary "Daisy Chain" monomers, possessing a secondary ammonium ioncontaining sidearm, were grafted onto a macrocycle with either a [24]- or [25]crown-8 composition; in either the solid or gas phase, these monomers formed dimeric superstructures <01JOC6857>. The synthesis and characterization of nanosized, molecular containers, which are hybrids of self-folding cavitands and metalloporphyrins, have been reported <01JA4659>. An alternative to SO2 expulsion is via the intermediate tetrathiacyclophane, generated by oxidative cyclization of a tetrathiol, which upon desulfurization afforded the dithiacyclophane <01JA4704>. Subsequent methylation with (MeO)2CHBF4, followed by the Stevens rearrangement gave the ring-contracted, bis-thiomethyl ether that was S-methylated and subjected to a Hofmann elimination affording 3, which is in a 1:20 equilibrium with 4.

7.3

CARBON-NITROGEN RINGS

Polyamines, which have imbedded diverse subunits such as: aryl <01TI_A983, 01IC7065, 01JOC2722, 01OL3499, 01JOC2769>, pyridine <01JOC2722>, bipyridine <01JOC4170, 01IC6172, 01IC2968>, terpyridine <01TL6275>, pyrazole <01JA10560>, 1,2,4-trazoles

359

Eight-Membered and Larger Rings

<01JOC2281>, and benzotriazole <01CC2710> continue to challenge the ingenuity of the synthetic and physical chemist. The porosity and acidity of A1-MCM-41 molecular sieve have been shown to play a critical role in the formation of calix[4]arene from pyrrole and cyclohexanone; 70.3 % of the cyclic tetramer and 12.3 % of the linear dimer were reported <01CC2226>. The Clezy formylation of the a-free tripyrrane, obtained from pyrrole and acetone, was used to prepare the dialdehyde derivative, then acid condensation of the two components produced the three-dimensional bicyclo[3,3,3]nonapyrrole 5 <01JA9716>. The preparation of the 20 membered E,E,E,E-1,6,11,16-tetra(arylsulfonyl)-1,6,11,16tetraazacycloicosa-3,8,13,18-tetraene has appeared <01TL9001>. A novel highly symmetrical cube-shaped trication [C36H7sN16]3+ (6) with 16-nitrogen donors was self-assembled from tris(2-ethylamino)amine and formalin and in which two water molecules were clathrated within the cavity <01CC2652>. 2,6,10,14,18,22-Hexaazaspiro[11.ll]tricosane (7) was prepared in a seven step procedure from pentaerythritoI; the novel aspect is the hydrolysis of spiro bis(hexahydro-lH,4H,7tt-3a,6a,9a-triazaphenalene) in the last step to generate the two 12-membered rings <01TL2735>. The cyclam-like tetraamine 8 was prepared by coupling bispidine and its bis(a-chloroacetamide) derivative, followed by reduction; this is proposed as a new type of proton sponge <01TL3097>.

N

i N N

/

.N

N.

.N

'l.

N

,'

if-N i

" .N .

/r--\

.

.

.

N

N

_

,

/--NH "; #,, NH "'/ HN HN- / X---NH

,

HN-,

.

/

'\ _ _ 1 /

' , .

7

8 R = II, Y = H-,

The first stopperless tetrathiafulvalene-based [2]pseudorotaxanes molecular shuttle has appeared <01TL4223>, but there has recently appeared a corrigendum, in which "the interconversion between occupied and unoccupied stations probably occurs principally via an intermolecular rather than an intramolecular route, the term shuttle is inappropriate" <02TL537>. Three hetero[3]rotaxanes, which incorporate one linear, one neutral, and one tetracationic components, have been assembled using intermolecular H-bonding and donoraccepter interactions <01JOC7035>. The reversible light-driven dethreading-rethreading of a

G.R. Newkome

360

pseudorotaxanes was reported by exploiting the E-Z photoisomerization of azobenzene <01CC 1860>. The unnatural porphyrin family still fascinates the imagination from aryl substitutions, confused or unnatural pyrrole substitution, and their inclusion in complex structures. 6,11,16,21-Tetraphenylbenziporphyrin, in which one pyrrole is replaced by a benzene ring, is formed in good yields by the condensation of the appropriate precursor with pyrrole and benzaldehyde <01CEJ5113>. The 8,19-dimethyl-9,13,14,18-tetraethyloxybenziporphyrin coordinates Pd(II) to form a four-coordinate anionic complex; NMR data demonstrate the retention of macrocyclic aromaticity and coordination via a carbon ~-donor <01IC6892>. The total electronic energy and nucleus-independent chemical shift of 95 isomers of N-confused porphyrins have been calculated by the density functional theory; the stability decreases by increasing the number of confused pyrrole rings <01JOC8563>. Cyclic hexameric arrays possessing multiple porphyrin subunits have been synthesized and shown to possess wheel-like arrays with diameters of ca. 35 ,~" bridging spoke-like guests have also been incorporated <01JOC7402>. Care must be exercised, since condensation of phenyldipyrromethane with bisnaphthaldehyde leads to an unexpected formation of a scrambled 5,10-bridged porphyrin; an alternative scrambling mechanism to dipyrromethane acidolysis may be operative <01TL355>. 7.4

CARBON--SULFUR RINGS

Cyclization of mercaptomethyl materials and halomethyl derivatives using CsOH under high dilution conditions afforded (57 - 75 %) the corresponding dithiafluorenophanes, which after oxidation generated the respective sulfones, that are then pyrolyzed at 500 ~ under reduced pressure to give (25 -40 %) the desired fluorenophanes <01JOC9023>. This procedure continues to be an excellent route to crowded cyclophanes. During the study of the Pummerer reaction, in which p-bis(methylthio)aromatic S-oxides with (CF3CO)20 has afforded the proposed cyclic bis(dithia dication) 9, the p-bis(benzylthio)benzene S-oxide was treated with (CF3SO2)20 at low temperatures affording the cyclic tetrakis(disulfide) tetramer (10) that was

) 9

+

S\S~S/s 10

isolated in 81% yield <01JOC2085>. A convenient and rapid preparation of symmetrical disulfides from alkyl or aryl halides using sulfurated borohydride exchange resin under anhydrous condition has appeared <01 TL6741>. The recently reported <00EJOC2479> tetrathiacyclodiynes were converted to the corresponding tetrathiacyclopropenonophanes <01JOC3416> by treatment with excess sodium salt of trichloroacetic acid at 60 ~ in DME, then hydrolysis of the gem-dichlorocyclopropene intermediates.

361

Eight-Membered and Larger Rings 7.5

CARBON-SELENIUM RINGS

The first complex of a polydentate selenoether with a nonmetallic element, e.g., As(Ill), has been reported <01JA11801>; the {AsC13)4([24]aneSe6) } was obtained in high yield and proven by single crystal X-ray analysis, in which a bridging facial arrangement (Se2AsCI2AsSe2) was demonstrated, whereas the remaining As moieties are located at the remaining Se sites. 7.6

C A R B O N - B O R O N RINGS

Treatment of 1-boraadamantane-THF with dimethylsulfoxonium methylide gave a monohomologated product; however, polyhomologation afforded a giant "tube-like" species, 11, which upon oxidative cleavage gave star-like polymethylene polymers <01 OL3063>. B

11 7.7

CARBON-OXYGEN/CARBON-NITROGEN-(OXYGEN) RINGS

Silver ion movement through the core of 1,3-alternate calix[4]crown-5-azacrown-5 a n d bis-aza-crown-5 (12) has been evaluated; only 12 has been demonstrated to undergo this intramolecular metal ion tunneling through the 7t-basic calixtube <01TL8047>. The first synthesis of free-base analogues of 13 involving 18-crown-6, 24-crown-8 and 30-crownbridges has been reported <01JOC4419>; complexation of the 24-crown-8 bis-porphyrin with (C6HsCH2)2NH2PF6 was also shown. 7.8

CARBON-NITROGEN-OXYGEN RINGS

Azacrown ethers have a unique advantage in that N-attachment is generally easy and permits a method to control the character of the N-electron contribution to complexation. Thus, different N-substituents have instilled different utilitarian properties, for example: Ntriphenylimidazole (chemiluminescence) <01TL7453>, Malachite Green leuconitrile (photochromic) <01M2262>, tetraalkyl-p-phenylenediamine (chemosensor) <01TL3541, 01TL3533, 01TL3537>, a N-anthryl-aza crown ether (chemosensor) <01OL1467>, and an azo dye (chemosensor) <01TLA725>.

G.R. Newkome

362

o

o

k_ M 12

13 m = 1,2,3 The incorporation of diazacrown ethers into a polymeric polyimide backbone has been reported and shown to complex barium(II) <01CM4635>. The two diazacrowns have had attached two terpyridine units and one phenanthroline creating a new polytopic receptor for modular construction in order to incorporate different supramolecular inorganic architectures <01IC6901>. The complexation of 1,9-diaza-18-crown-8 with lanthanum nitrate has been analyzed by three independent methods: NMR, X-ray analysis, and simulations <01OL325>. Insight into Na + and K + cation - n-interactions has been experimentally probed using diaza-18crown-6 lariat ethers having ethylene side arms attached to different aromatic n-donors <01JA3092>. The bridged ligand 14-oxa-1,4,8,11-tetraazabicyclo[9.5.3]nonadecane has been formed by the high dilution cyclization of 1-oxa-4,8-diazacyclododecane with 1,3-bis(ot-chloroacetamido)propane, followed by reduction <01IC2737>. The one-pot construction of 14 was realized from 2,6-bis(bromomethyl)pyridine with a phosphonate-modified bisphenol A in a dipolar aprotic solvent with mild base; after monodealkylation, the tetralithium salt was shown to bind basic amino acid esters in water <01OL1597>. A diphenylglycoluril-based receptor with N~-BOC-L-lysine arms, prepared from diphenylglycouril tetrachloride, was shown to selfassemble to form well-defined tubules in CHCI~ and vesicles in water <01TL2751, 01JOC1538>. A series of 21-oxoporphyrin building blocks with alkyne moieties was created so that boron-dipyrrin units could be attached <01TL8547>. Novel intramolecular N-strapped porphyrins have been reduced regio- and stereoselectively to N-alkylphlorins <01TL419>. The urealeno crown ethers (15) have been shown to bind two equivalents of lithium ion both cooperatively and selectively over the other alkali metal ions <01OL3999>.

Eight-Membered and Larger Rings

EtDp=o

[~

363

0=-p~,OEt o

|

EIO#'P-'-O

-o

o~N]J

O=-P,~oEt

lS

14

7.9

C A R B O N - S U L F U R - O X Y G E N RINGS

Several S,O-bridged 13- to 30-membered cyclic di- and tetraalkynes were prepared from dihydroxybenzene and 1,2-bis(bromomethyl)benzene; during Na2S/alumina induced cyclization, an unexpected formation of 2,6-divinyl-l,4-dithane was observed <01TL7485>. A series of redox active ligands prepared from a tetrathiafulvalene core with polyether subunits of varying lengths has appeared <01CEJ447>. A strained, 5-ring, macrocycle (16) possessing both ethereal and sulfone components was synthesized by means of a nickel-catalyzed intramolecular coupling of a bis-chlorophenylene-terminated precursor, then shown to undergo F-promoted ring-expansion to give a series of higher oligomers, including cyclic counterparts <01OL4031>. Access to a new chiral C,S,O-macrocycle was possible by treatment of a spiroindane bisphenol with 2,2'-bis(4-fluoro-3-trifluoromethylphenyl)-bithiophene <01CEJ3000>. 7.10 C A R B O N - N I T R O G E N - S U L F U R RINGS Synthetic routes to monoazathiacrown ethers were reported, from which monoaza-trithia12-crown-4,-tetrathia-15-crown-5, and-pentathia-18-crown-6 were obtained by reaction of bis(2-chloroethyl)amine with the appropriate dithiol in the presence of lithium hydroxide in THF <01JOC7008>. The synthesis and complexation of two heteroditopic lariat azathiaether macrocycles possessing acylurea functionalized pendant arms were reported <01CC2678>. Similarly, a series of diazatrithia-15-crown-5 and diazatrithia-16-crown-5 ligands possessing two 8-hydroxyquinoline sidearms has appeared; selected members could be chemical sensors for Zn +2 <01JOC4752>. The 5,10,15,20-tetra(p-tolyl)-21,23-dithiaporphyrin with an inverted pyrrole ring, 5,10,15,20-tetra(p-tolyl)-2-aza-21-carba-22,24-dithiaporphyrin and 5,10,15,20-tetra(p-tolyl)25,27-dithiasaporphyrin have been synthesized by the condensation of 2,5-bis[(ptolyl)hydroxymethyl]thiophene and pyrrole <01OL1933>; whereas, their acid condensation yield the novel heteroporphyrins: 5,10,15,20,25,30,35,40-octa(p-tolyl)-41,43,45,47-tetrathia[36]octaporphyrin(1.1.1.1.1.1.1.1) and 5,10,15,20,5,30,35,40-octa(p-tolyl)-dihydro41,43,45,47-tetrathia[38 ] octaporphyrin( 1.1.1.1.1.1.1.1 ) <01 CEJ5099>. 7.11 C A R B O N - P H O S P H O R U S - S I L I C O N - O X Y G E N RINGS Treatment of 4,6-bis(tert-butyl)-l,3,2-diazaphosphinine with dimethylsiloxy)ethane afforded the open-bisazaphosphine, which

1,2-bis(phenylethynylunder high

dilution

364

G.R. Newkome

conditions with added reagent gave the desired macrocycle (17) <00JOC1054>. Other members of the series were prepared in the same manner; X-ray crystal data and reduction information

0/5.0

\

Ph., "Si--X, .//.

Ph

ph~r--~'Si--X P ~ , ~ f "Si N Ph 17 X = OCH2CH20 X = OCH2C(Me)2CH20

16

were obtained on a related member in this family <01JA6654>. 7.12 C A R B O N - N I T R O G E N - P H O S P H O R U S - O X Y G E N RINGS

Comparative naphtholysis of crown-bearing tetrachlorocyclotriphosphazene, prepared by the treatment of hexachlorocyclotriphosphazatriene with the disodium salt of the tetraethylene glycol, and its acyclic analog revealed a significant macrocyclic effect of the substituent on both the kinetics and regiochemistry of chlorine substitution in the N3P3 ring <01JOC5701>. 7.13 CARBON-NITROGEN-METAL RINGS The self-assembled molecular barrel 18 was quantitatively formed from the cobalt-mediated -

18

[2+2] dimerization of bis(3-pyridinyl)acetylene intermediate by treatment with enPd(NO3)2 in MeOH-H20 <01JA3818>. The formation of metallo[2]catenanes and caged structures has been successfully achieved by mixing of the appropriate ratios of extended and directed bispyridines with Pd(II) or Pt(II) salts <01CC1652, 01CEJ4142, 01JA9634, 01CC1554, 01CC2676, 01OL3141, 0lOLl601, 01JA980, 01JOC1002> <01JA3872, 01JA5424, 01JA10545>, Ru(arene) complexes <01CEJ3197>, and Re(CO)3Br complexes <01IC3154>. Although pyridine is by far the ligand of choice, another popular directed bonding pair is derived from the nitrile moiety; a series of cavitands-based coordination cages has appeared that exemplify this connectivity <01JA7539>. The main factors controlling the cage's self-assembly are: the

Eight-Membered and Larger Rings

365

ligand-metal-ligand bond angle of ca. 90 ~ Pd or Pt as the metal, a weakly coordinated counterion, and preorganization of the tetradentate cavitands ligand. Although numerous supramolecular, coordination-based assemblies featuring well-defined cavities have appeared, only a small number have been used as building blocks for microporous materials. A short overview of their construction and importance has appeared <01CM3113>. 7.14 C A R B O N - P H O S P H O R U S - M E T A L RINGS The synthesis and characterization of new metallacyclic materials with Re(I) and Os(II) centers of the type [{Re(CO)3CI(C2nP2)}2 or 4], e.g., 19, as well as mixed-metal relatives <01CEJ2425>. [M2L3] coordination cages of the rigid bridging diphosphines bis(diphenylphosphino)acetylene and trans-l,2-bis(diphenylphosphino)ethylene with silver(I) salts have been created and studied <01 CEJ2644>. Treatment of fac-[(CO)3Re(Br)(PPhz(CH2)6CH=CH2)2] with Grubbs' catalyst afforded (80 % of) the seventeen-membered macrocyclic chelating diphosphine complex, whose reduction with Pd/C at 1 atm afforded the saturated analogue in 98 %; other macroheterocycles were prepared in a similar manner <01CEJ3931>. Ph2P-' CI(OC)3Re \ Ph2P -

--(--)l~Ph2 rn

--

(~-)m

Re(CO)3Cl / PPh2

19

7.15 C A R B O N - P H O S P H O R U S - S U L F U R - M E T A L RINGS Treatment of the dipotassium salt of 1,3,4-thiadiazole-2,5-dithiol with difunctional ligands, e.g., 1,6-bis(diphenylphosphino)hexane, ct,cs and l,l'bis(diphenylphosphino)ferrocene, in a 1:1 ratio gave the desired cyclic (45-65 %), as well as oligomeric, dinuclear materials <01IC6266>. 7.16 C A R B O N - N I T R O G E N - O X Y G E N - M E T A L RINGS The 1,1'-(OCH2CH2OTs)2-ferrocene derivative was treated with various diaza-[n]-crown-m ethers to give ferrocene cryptands, in which subsequent complexation with Group 1 and 2 metal ions affords large shifts in the redox potentials and consequently to a drastic decrease in the binding strength (up to l08) <01CEJ4438>. 7.17 C A R B O N - N I T R O G E N - P H O S P H O R U S - M E T A L RINGS A method that utilizes the "weak-link synthetic approach" and hemilabile ligands, e.g., derived from to prepare a new class of flexible, redox-active binuclear macrocycles <01IC2940>.

N,N'-dimethyl-N,N'-bis[2-(diphenylphosphino)ethyl]-l,4-phenylenediamine, N,N,N'N'-tetramethyl-l,4-phenylenediamine (Wurster's reagent), was used

366

G.R. Newkome

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Eight-Membered and Larger Rings 01CEJ4142 01CEJ4438 01CEJ5099 01CM3113 01CM4635 01COR273 01CST25 01EJOC1801 01H181 01IC2737 01IC2940 01IC2968 01IC3154 01IC6172 01IC6266 01IC6892 01IC6901 01IC7065 01JA980 01JA3092 01JA3157 01JA3818 01JA3872 01JA4659 01JA4704 01JA5424 01JA6654 01JA7539 01JA9634 01JA9716 01JA10545 01JA10560 01JAIl801 01JIPMC1 01JOC1002 01JOC1054 01JOC1473 01JOC1497 01JOC1538

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368 01JOC2085 01 JOC2281 01JOC2722 01JOC2769 01JOC3416 01JOC4083 01JOC4170 01JOC4419 01JOC4752 01JOC5701 01JOC6857 01JOC7008 01JOC7035 01JOC7402 01JOC8563 01JOC9023 01JPP01 01M2262 01M5449 01MRC68 01OL325 01OL353 01OL1467 01OL1597 01OL1601 01OL1605 01OL1933 01OL2633 01OL3063 01OL3141 01OL3499 01OL3999 0101A031 01 OL4071

01RCR28 01RCR656 01RFP15 01RIC1 01RIC125 01RIC165 01RIC299 01RIO207 01SEIE839 01TL271

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Eight-Membered and Larger Rings

01TL355 01TIA19 01TL1733 01TL1927 01TL2735 01TL2751 01TL3097 01TL3541 01TL3533 01TL3537 01TIA223 01TL4725 01TL4983 01TL5291 01TL6275 01TL6741 01TL7453 01TL7465 01TL7485 01TL8047 01TL8285 01TL8547 01TL9001 01YH557 02TL537

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370

INDEX

Acetylbenzo- 15-crown-5,357 Achmatowicz reaction, 149 (_+)-Acuminatin, 160 Adenine, 318 N-Alkylphlorins, 362 3-{Alkylthio)oxindoles, 9 2-Alkylthioindoles, 3, 4, 13 3-Alkylthioindoles, 7, 13 2-Aminothiophenes, 91, 92 Analgesic agents, 10 ct2 Adrenoceptor agonists, 103 Angiotensin II receptor antagonistic, 305 [22] Annulenes, 104 Antiallergic compounds, 305 Antibiotics, 10,103 Anticancer agents, 304 Antidiabeticagents, 305 Antifungal activity, 6, 10,304 Anti-HIV agents, 102, 103 Antiinflanunatory agents, 304 Antinociceptive effects, 121 Antitumor antibiotic, 9 Aplasmomycin, 32 Aplysin, 166 Apoptolidin, 332 Arcyriaflavin A, 12 Artemisinins, 348 Artificial nucleosides, 103 Arylboronic acids, 186 2-Arylthioindoles, 4 3-Arylthioindoles, 7, 8, 9 Arynes, 344 (_+)-Asarinin, 161 Asymmetric dihydroxylation, 56 Asymmetric epoxidation, 53, 55, 57, 58 Asymmetric hydrogenation, 184,260,262,272, 273 Asymmetric lithiation, 186 Asymmetric synthesis, 66,183 2-Azabicyclo[2.2.0]hexanes, 76 Azamacrocycles, 356 1-Azasugars, 262 Azauracils, 311 Azepines, 243Azetidines, 75 Azetidinones, 42, 46, 81,253 Aziridines, 65-74, 76,248 Azomethine ylide cycloaddition, 135 Azomethine ylides, 209,, 240,253,263 Baeyer-Villiger reaction, 55 Baker's yeast reduction, 188 Barton ester, 218 Barton-Zard synthesis, 117 Baylis-Hillman reaction, 86,154,166,188,265, 346 Beak deprotonation, 116

Beckmann rearrangement, 301 Benzimidazoles, 186 Benzisoxazoles, 240 Benzocoumarins, 153,342 1,3-Benzoditelluroles, 225 Benzodithiaselenoles, 229 Benzo[ 1,4]dithiino[2,3-b]indole, 14 Benzo[2,1 -b :4,5-b ']dithiophcnes, 90,102 Benzo[b]fluorcn- 10-ones, 167 Benzo[b]furans, 144,163-70,335 Benzo[c]furans, 170-1 Benzofilro[2,3-c]pyridines, 165 Benzo[d]isothiazoles, 203 Benzopyrans, 335-6 Benzothiadiselenoles, 229 Benzo[f]thieno[2,3-c ]azepine, 98 Benzothieno[4,5,6-ij][2,7]naphthyridine-7-ones, 99 Benzolhieno[2,3-c]pyrans, 339 Bcnzo[b]thieno[2,3-a ]pyrrolo[3,4-c]carbazole, 97 Benzo[c]thiochromenes, 346 Benzo[b]thiophenequinones, 91 Benzo[b]thiophenes, 92-105,339 Bcnzo[c]thiophenes, 101 Benzothiopyrans, 346 1,2,4-Benzotriazines, 324 Benzotriazoles, 191-3,237,344,346 Benzotriselenoles, 229 Benzotrithioles, 229 2,1-Benzoxaselenoles, 230 1,3-Benzoxathiole 3-oxides, 229 Bicyclo[3.3.3 ]nonapyrrole, 359 2,2'-Biindolyls, 11 3,3 '-Biindolyls, 6 Biosensors, 105 Biosynthesis, 3 Birch reaction, 149 (_+)-Bisabolangelone, 162 Bis(alkynes), 357 p-Bis(benzylthio)benzene S-oxide, 360 2,6-Bis(bromomethyl)py ridine, 362 4,6-Bis(tert-butyl)-1,3,2-diazaphosphinine, 364 Bischler indole synthesis, 121 Bischler-Napieralski conditions, 190 trans- l ,2-B is(diphenylphosphino)ethylene, 365 Bis(hydroxymethyl)phenols, 358 Bismuth triflate catalyst, 64 Bis(naphthaldehyde), 360 Bisphenol A Bis(thiophene), 94, 96 Boraadamantane, 361 Brassicanal A, 3 Brassilexin, 3, 5,202 Brassinin, 3 1,3-Bridged n-propoxy calix[4]crown, 357 3-B rolnofu tans, 201

Index Bryostatins, 152 Buchwald-Hartwig amination, 123, 186 Butenolides, 149,150 C60, 93,101 Calcium entry blockers, 10 Calculations, 53 Calixarenes, 104, 105,356,357 Calix[n ]pyrroles, 104 Calixtube, 361 Carbapenems, 84 Carbazoles, 131 Carbenes, 60, 95,204 Carbonyl ylides, 157 Catenanes, 356 Cavitands, 358,365 CC-1065, 9 Cephalosporins, 85 Chan rearrangement, 245 Chemical lithography, 105 Chemiluminescence, 361 Chemosensor, 361 Chiral auxiliaries, 66 Chiral recognition, 104 Chiral salen catalysts, 52, 61 Chiral separations, 356 Chiral transition metal complex, 274 Chromans, 337-8 2It-Chromenes, 164,335-6 Chromium complexes, 53 Chromium hexacarbonyl, 95 Chromones, 342 Ciguatoxin, 332 Cinnolines, 294-6 Claisen condensation, 183 Claisen rearrangement, 166,169,204,217 Clerodanes, 140 Clezy fonnylation, 359 Combinatorial chemistry, 126,189,210 Combretastatin A-4, 93,102 Confused porphyrins, 360 Coordination-based assemblies, 365 Cope rearrangement, 148 Copper-assisted cycloisomerization, 117 Copper (I) catalysis, 205 Copper-catalyzed anfination, 261 Corey-Chaykovsky reaction, 66 Coumarins, 145,341 COX-2 inhibitors, 279 Crown ethers, 356 Crystal Violet dyes, 92 Curtius rearrangement, 272 Cushman pyrrole synthesis, 115 3-Cyanoindoles, 8 Cyclizations, 4-exo, 27 Cyclizations, 5-endo, 19, 44 Cyclizations, 6-exo, 24 Cycloaddition chemistry, 101 [3+2] Cycloadditions, 72, 99,161,235,335 [3+3] Cycloadditions, 271,334

371 [4+2] Cycloadditions, 338 [4+3] Cycloadditions, 146 [5+21 Cycloadditions, 338 Cvclobra~sinin, 3 Cyclodcxtrins, 356 [4+2] Cyclodimerization, 2 [4+41 Cyclodhnerization, 101 Cyclopenta[c]pyridincs, 246 "Daisy Chain" monomers, 358 Dcndralcncs, 100 Densitv functional studies, 184 Deraccmization, 260 Dcss-Martin oxidation, 62, 193 Desuffurization, 6,358 Diazacrown ethcrs, 362 Diazacvclododecanc, 362 Diazatrithia- 15-crown-5,363 Diazatrithia- 16-crown-5,363 Diazepines, 154 1,3-Diazepincs, 194 (-)-Diazonamidc A, 170,245 Dibenzo[bd]pyrans, 336 Dibcnzo-24-crown-8,358 Dibcnzofu tans, 145 Dibenzothiophenc, 94 Dichlorocyclopropcnc, 361 Didemnakctals, 335 Diels-Alder reactions, 99,101,121,131,132,134, 146,182,186,188,258,260,264,266,271,291, 294,297 Dihydrobenzofu rans, 167 2,3-Dihydrofurans, 47, 151,156 2,5-Dihydrofurans, 47, 150,157 Dihydropyrans, 333-5 1,_9-Dihvd r i dropv i n.c s ~ ,76 (+_)-Dihydrosesamin, 160 Dihydrothienocoumarin, 91 Dihydrothieno[2,3-b]naphtho-4,9-dione, 93 4,5-Dihydrothiophcncs, 46 Dihydroxybenzcne, 363 5,6-Dihydroxyindolc, 10 5,5-Di(hydroxymethyl)- 1,3-dithiane, 357 6,7-Dihydroxyoxindolc, 8 1.2-Dilithioindole, 126 [2+2lDunerization, 364 1,2-Dioxanes, 347 1,3-Dioxancs, 24 1.3-Dioxan-4-oncs, 347 1.4,2-Dioxazines, 41 I)ioxins, 347 1,2-Dioxolanes, 228 1,3-Dioxolanes, 222-4 1,3-Dioxolan-2-ones, 222 1,3-Dioxolan-4-oncs, 222--4 1,3-Dioxol-2-oncs, 222,223 Dipeptide mhnics, 195 Diphosphines, 365 1,3-Dipolar cycloaddition rcactions, 188,189,192, 201,209,216,235,238,239,261,271,298,337

372 1,5-Dipolar cylization, 157 Dipyrromethane, 360 Directed ortho metallation, 95 1,3-Diselenoles, 227 Dithiacyclophane, 358 Dithiadiselenafidvalenes, 226 Dithiafluorenophanes, 360 3,3-Dithiaindolenine, 13 Dithianes, 22, 349 Dithiaporphyrins, 104 Dithiasapphyrins, 104 1,2-Dithietanes, 79 1,2-Dithietes, 79 Dithiin, 12 Dithioindigo, 11 1,2-Dithiolanes, 228 1,3-Dithiolanes, 224,225 1,3-Dithiolane-2-thiones, 225 1,3-Dithioles, 100,224,227,228 1,3-Dithiole-2-thiones, 225 1,2-Dithiole-3-thiones, 228,229 1,3-Dithiolium salts, 225 1,3-Dithiol-2-ones, 225 1,2-Dithiol-3-ones, 228 Dithiophenes, 90,102,103 2,6-Divinyl- 1,4-dithane, 363 DNA interactive agents, 114 DNA intercalators, 297 DNA molecular recognition, 105 Dopamine transporters, 121 Dopaminergic agents, 8 Echinosulfone, 9 Electrochromic properties, 11 1,7-Electrocyclization, 182 Electronic devices, 105 Ellipticine, 102 Ellipticine analogue, 300 5-Endo-cyclization, 72 6-Endo-dig cyclization, 289 5-Endo-dig cyclizations, 156 6-Endo radical cyclization, 100 Endothelin antagonists, 9 5-Endo-trig cyclization, 128 Epibatidine, 317 Epibatidine derivatives, 121 (-,-)-Epimagnolin A, 161 Epothilones, 212,239 Epoxides, 52--65 Estrogen receptor modulation, 102 5-Exo-dig cyclization, 289 5-Exo-trig cyclizations, 160 (+_)-Fargesin, 161 Ferrocene cryptands, 365 Ferrocenes, 246 Fischer carbenes, 240 Fischer indole synthesis, 7, 11,122 Flash vacuum pyrolysis, 93,180,203,296 Flavanones, 343 Flavones, 343

bzdex Huorenophanes, 360 Fluorescent probes, 180 Fluoride anion recognition, 104 Fluorination, 207 Fluorophores, 104 Fluorous medium, 54 Fowler reduction, 262 F-Promoted ring expansion, 363 Free-radical cascade, 4 Free-radical cyclizations, 191 Friedel-Crafts acylation, 92, 94,124,129 Fricdl~inder quinoline synthesis, 263 Frondosin B, 166 Fukuyama indole synthesis, 125 Fullerenes, 101,103,105,184 Furanoditerpenes, 141 Fu ranosesquiterpenes, 139 Furans, 25, 39, 44, 47, 139-79 Furo[2,3-b]coumarins, 156 Fu ro[3,2-c]coumarins, 156 Furofurans, 142 Fu ro[2,3-b]pyridine, 259 Furo[3,2-c]quinolines, 264 Fuscd porphyrins, 101 (+_)-Galanthamine, 165 Gambierol, 332 Gassman oxindole synthesis, 8 Gewald reaction, 91 Glycosidase inhibitors, 103 Gold complexes, 104 Goldberg reaction, 126 Grignard reagents, 182,259,270,271,272,274 Grindelic acid, 142 Griseolic acid B, 158 Grubbs' catalyst, 365 Guanine, 322 Halogen-metal exchange, 95, 96 llantzsch synthesis, 258 Heck reactions, 120,123,124,151,165,188,284, 342 Iteliquinomycinone, 170 Hemibrevetoxin B, 333 ! Ieptahomotetraoxacalix[3]arene, 358 t teterobuckybowls, 104 ! Ietero Diels-Aldcr reaction, 271 Hetero[3 ]rotaxanes, 360 ttexaazaspiro[ 11.11 ]tricosane, 359 Hexachlorocyclotriphosphazatriene, 364 I Iexahomotrioxacalix[3]arenes, 358 ttigh throughput screening, 5 HIV-1 reverse transcriptase inhibitors, 10,294 HMG-CoA reductase inhibitors, 102 Hoffmann-Shechter rearrangement, 150 t Iomooxacalix[n ]arenes, 35~ I Iurd-Mori reaction, 212 N-Hydroxyindoles, 9 Illudin C, 239 Imidazoles, 184-91,320 Imidazo[ 1,2-a ]pyridines, 190

bMex Imidazo[ 1,2-a ]pyrhnidines, 280 Imidazo[2,1-b]thiazoles, 189 Iminium salts, 55, 56 Iminyl radicals, 203 Indigo, 13 Indirubin, 5 Indium trichloride, 64 Indole-3-dithiocarbamates, 8 Indole-N-nucleosides, 2 Indoles, 1-14, 47,121-34 Indole-2-stannane, 97 Indole-3-sulfonimn ylides, 8 Indoline-2-thiones, 1, 2, 3 Indolizidines, 241,242 Indolocarbazoles, 97,102 3-Indolylsulfones, 10 Insecticidal activities, 10 Intramolecular coupling, 363 [2+3]Intramolecular cycloadditions, 181,195 Iodocyclization, 93 Iodolactonization, 19 Ion recognition, 356 Irradiation, 203,218 Isatin, 5, 6, 13 Isobenzofurans, 170-1 Isochromans, 338-9 Isochromenes, 338-9 Isocoumarins, 342 Isoindigo, 7 (-)-Isolaurallene, 159 Isoquinolines, 266-9 Isothiazoles, 150,200-4 Isothiazolo[5,4-d]isoxazoles, 201 Isoxazoles, 235-8 Isoxazolidines, 41, 42,241-4 Isoxazolines, 47,238-40 Itomanindoles A, 13 Jacobsen epoxidation, 270 Jacobsen's catalyst, 52 Katsuki trajectory, 53 Kinetic resolution, 61 Knoevenagel reaction, 188 Kuanoniamine A, 99 Lactase, 185 Lanthanide catalysts, 58,119,186,188 Laulimalide, 332 Lawesson's reagent, 7, 90 Leukotriene synthesis inhibitors, 9, 14 Lewis acid carbocycl~ations, 62 Lewis acid catalysts, 62, 64, 92, 98,101,191 Lewis acid catalyzed [3+3]-cycloaddition, 63 Lewis acids, 71, 119 (+)-Linalool oxide, 160 (-,-)-Linderal A, 168 Lipase catalyzed kinetic resolution, 188 5-Lipoxygenase activation protein (FLAP) inhibitors, 9 Liquid crystals, 104 Lithiated indoles, 1, 4, 14

373 Lituarines, 332 Macrocyclization, 357 Mannich bases, 104 Mannich reaction, 94, 119,134 McMurry coupling, 357 Melatonin receptor, 4 Meldrum's acid, 204 Merrifield resins, 305 [2:]Metacyciophanes, 155 ot-Metalation, 95 o-Metalation, 132 Metallo[2]catenanes, 364 Metalloporphyrins, 358 Mctathesis reactions, 118,132, 158,187,252,263, 269,273 333 Methanochromanones, 343 Mcthyltrioxorhenium, 54 Michael addition, 130,205,282 Microelectronics, 105 Microwave irradiation, 67, 71,90,114,115,119, 122,130,180,183,189,194,265,266,281 Mitsunobu reactions, 38, 56, 83,157 Modular chemistry., 356 Molecular devices, 100,103,356 Molecular recognition templates, 104 Montmorillonite, 114 Mosin B, 159 Mucronatine, 318 Mukaiyama reaction, 249 Muscarine, 28, 32 Nanocomposites, 356 Naphtho[b]furans, 169 Naphtho[2,1-f]isoquinolines, 268 Naphtho[2,3-c]pyran-5,10-diones, 339 Naphtho[ 2 ',1 ':4,5 ]th ieno [2,3-c ]naphtho [2,1 ]]quinoline, 98 Naphtho[ 1,2-b]thiophenes, 92 Naphtho[2,1-b]thiophenes, 92 Negishi reactions, 93,169,208,260 (+)-Nemorensic acid, 160 Neuchromcnin, 343 Nickel catalysts, 187 Nitric oxide synthase inhibitors, 102 Nitrile oxides, 235,238,239 Nitrone cycloaddition, 271 Nitrones, 238,243 NMDA-glycine antagonists, 132,265 (S)-(-)-Nocardione A. 156 Nonactic acid, 37 Oligothiophenes optics materials, 120 Oligosalen catalyst, 96,104,105 Organic dyes, 103 Organic films, 105 Organic scmiconductor, 96 Organometallic cross-coupling, 96, 97 1,3,4-Oxadiazines, 41 1,2,4-Oxadiazoles, 253 1,3,4-Oxadiazolines, 253 1,2,3,5-Oxathiadiazines, 313

374 Oxathianes, 350 1,3-Oxathiolanes, 227 1,2-Oxathioles, 228 Oxazoles, 244-7 Oxazolidines, 250-3 Oxazolidinones, 250 Oxazo!ines, 247-50 Oxepanones, 341 Oxetanes, 27, 77, 148,349 Oxetanones, 77 Oxiranes, 52-65 Oxonium ylides, 332 Oxophlorins, 356,362 Oxy-anion Cope rearrangement, 134 P38 kinase inhibitors, 103 Paal-Knorr reaction, 155,156 Palladium-catalyzed amination, 188 Palladium-catalyzed cyclization, 123,124,258 Palladium-catalyzed reactions, 65, 96, 97, 116, 118,127, 128,131,132, 182,183,186, 187, 192, 208,266,284,292,297,298,306 Palladium catalyzed ring expansion, 211 Palladium-mediated carbonylation, 263 Palladium/ruthenium-catalyzed three-component process, 118 Pamamycin 607, 37 Pamamycin-607,159 Paraherquamide A, 8 Paterno-Biichi reaction, 77 Payne rearrangement, 62 PDE4 inhibitors, 296 Pechmann synthesis, 341 Penicillins, 85 Pentaerythritol, 359 Pentaoxa[5]peristylane, 162 Pentathiepino[6,7-b]indoles, 6, 13, 14,126 Pentathiepins, 6 Pentathiophenes, 104 Peptides, 248 Petasis reaction, 130 Petasis-Ferrier rearrangement, 332 Phallotoxins, 5 Phase transfer catalysts, 69,260 Phenanthro[3,2-b][ 1]benzothiophene, 102 Phenan thro [2,3-c ]fu ran, 171 Phenazines, 302-4 Phenolphthalein, 357 Phenyldipyrromethane, 360 3-Phenylthioindole, 11 Phorbazole, 332 (+)-Phorbol, 148 (+)-Phorboxazole A, 246 Phorboxazole, 333 Phosphapeptides, 325 Phosphetanes, 79 Phosphole, 105 Phospholipase A 2 inhibitors, 281,284 Photochromism, 100, 104,361

Index

Photocyclization reactions, 2, 94, 98,100,162, 261,268 Photo-Fries rearrangement, 134 Photoinduced charge transfcr, 103 I'tlotoisomerization, 360 Photolabile systems, 100 Photooxygenation, 148 Photoloxic agents, 103 Phthalazincs, 296-9 Phthalocyanines, 104,356 Phytoalcxins, 2, 3, 5, 9 Pictet-Spengler reaction, 133,267,268 Pipecolic acid, 241 Piperidines, 149,250,269-74, 314 Piperidones, 241 Plasminogen activator inhibitor, 94 Plalclct-activating factor antagonists, 10 Podophyllotoxin, 103 Polycondensation, 357 Polymer-supported, 193 Polythiophenes, 105 Polytopic receptor, 362 Porphyrins, 356 Proctolin, 248 Prodigiosin, 103 Prolein tyrosine phosphatase inhibitors, 5 Protomycinolide IV, 21 Proton sponge, 359 Pseudo-high dilution, 357 Pseudorotaxanes, 358,360 Psoralens, 168 Ptcrins, 323 Pterocarpans, 164 Pudovik reaction, 125 Pumiliotoxins, 241 Pummerer reactions, 93,360 Purines, 318-23 Puupchcnols, 343 Pyranocoumarins, 341 Pyranones, 339--41 Pyrano[2,3-c ]py razol-4-ones, 183 Pyrans, 333-5 Pyrazincs, 299-302 Pyrazino[2,3-b]indoles, 300 Pyrazolcs, 180-4,316 Pyrazolincs, 41 Pyrazolo[3,4-clisoquinolines, 183 Pyrazolo[3,4-c ]pyrazolcs, 180 Pyrazolo[3,4-c]pyridazines, 321 Pyrazolo[ 1,5-a ]pyrimidincs, 184,279 Pyrazolo[3,4-dlpyrimidines, 320 Py razolo [4,3-d ]py rimidincs, 320 Pyrazolo[4,3-c]pyridines, 183 Pyrazolo[3,4-b]quinolines, 180,266 Pyrazolo[4,3-c]quinolines, 263,325 Pyridazines, 290-4 Pyridazino[4,5-b]indolc, 291 Pyridincs, 257-62 Pyrido[2,3-b]indoles, 259

Index Pyrido[2,3-d]pyrimidines, 284,324 Pyrido[2',3':4,5]thieno[2,3-c ]pyridazines, 102 Pyrimidines, 279-85 Pyrimido[ 1,2-a ]benzimidazoles, 280 Pyrimido[ 1,4]diazepine, 282 Pyrimido[2,1-a ]phthalazine, 297 Fyrimido[4,5-c ]pyridazines, 324 Pyrimido[ 1,2-a ]pyrimidines, 281 Py rimido[4,5-d]pyrimidines, 324 Pyrimido[5,4-d]pyrimidines, 319,323 Pyrimido[5,4-d]py ridimidin-2-ones, 280 Pyrimido[ 4 ,5-b ]quinoxalines, 307 Pyrimido[4,5-e 1[1,2,4 ]triazines, 323 Pyrinodemin A, 243 l:'yrroles, 45,114-21,337 Pyrrolidines, 151 Fyrrolidines. 38, 15I Pyrrolizidines, 147 Pyrrolo[3,4-c ]carbazoles, 291 Fyrrolo[3,2-e ]indole, 8 Fyrrolo[ 1,2-b]isoxazolidines, 243 Pyrrolo[3,2-c ]quinolines, 263 Pyrrolo[ 1,2,3-de]quinoxalines, 189 Pyrylium salts, 339 QSAR study, 4 Quinazolines, 285-90 o-Quinodimethanes, 9,100,101,147 Quinolines, 263---6 Quinolizidines, 242 Quinone methides, 335,341 Quino[2,1-b]quinazolines, 288 Quinoxalines, 238,304-7 Radical cyclization, 100 Raf kinase inhibitors, 103 Reissert reaction, 265,268 Retro-Diels-Alder reaction, 155 Retro-Michael reaction, 258 Reverse transcriptase inhibitors, 288 Rhenium-catalyzed reactions, 54 Rhodium carbenoids, 60, 66 Rhodium catalyzed asymmetric hydrogenation, 264 Rhodium catalyzed cyclkation, 8 Rhodium-catalyzed reactions, 115,121,185,186, 205,274 Ring closing metathesis reactions, 118,132,263, 269,273 Ring expansion reactions, 270 Ring-opening reactions, 70 Rink resin, 190 RNA conjugates, 283 Robinson annulation reactions, 188 Roseophilin, 45, 317 (-)-Rosmarinecine, 241 Rotaxanes, 356 Rubromycins, 342 Ruthenium catalysts, 187,260 Ruthenium-catalyzed reactions, 122,257 Sakurai cyclisation, 334 Samarium catalyzed processes, 65,115

375 Sarcodictyins, 162 Scaffolds, 100,101,102 (-)-Sclerophytin A, 161 Selenabicyclo[3.1.0]hexene, 105 Sclenadiazoles, 218 Selenazoles, 218 Selenocyclization, 30, 35 Sclcnophencs, 105 Semivioxanthin, 95 Serine protease inhibitor, 102 Serotonin antagonist, 2 Serotonin transporters, 121 Sexithiophene, 96,104 Shapiro reaction, 128 Sharpless epoxidation, 264 [2,3]-Sigmatropic rearrangement, 332 [3,3]-Sigmatropic rearrangement, 122 Silacyclobutanes, 79 Silacyclobutenes, 79 Sinalbins, 3 Sinalexin, 202 Smiles rearrangement, 259 SO2 expulsion, 358 Solid state batte~, 11 Solid-phase synthesis, 9, 91, 96, 104, 117,124, 125,133,180,184,189,190, 192,193,194,288, 290 Sonogashira coupling, 44, 97,122,124,260,296, 306 Sparteine-mediated metalation, 267 Spectroscopic probes, 103 Spin labels, 284 Spirooxindole, 13 Spongistatins, 332 2-Stannylindole, 4 Star-shaped molecules, 104 Staudinger reaction, 81 Stevens rearrangement, 358 Stilbenc crowns, 357 Stille coupling, 44, 45, 97,132, 186, 188,246, 292, 302,322,335 Sulfur ylides, 58, 59, 66, 91 Superbasic system, 127 Supercritical CO2,119 Supramolecular assemblies, 120 Suzuki coupling, 97, 124, 125,134,154, 193,260, 273,292,298,315,322,332 Tamao-Iqeming oxidation, 259 Taxol, 82 Tellurophenes, 105 Terthiophenes, 90 Tetrachlorocyclotriphosphazene, 364 Tetraethyloxybenziporphyrin, 360 Tetrahydrofurans, 158 Tetrahydrofurans, 20, 151 Tetrahydropyrans, 334 Tetrahydroquinolines, 247 Tetrahydrothiophenes, 42 Tetraphenylbenziporphyrin, 360

376 Tetraselenafulvalenes, 226 Tetrathiacyclodiynes, 361 Tetrathiacyclophane, 358 Tetrathiacyclopropenonophanes, 361 Tetrathiafulvalenes, 224-8 Tetrathiaoctaphyrin, 104 Tetrathiocine, 12 Tetrathiolanes, 229 Tetrathiophenes, 105 1,2,4,5-Tetrazines, 316-8 Tetrazoles, 195 Theophyllines, 320 1,2,3-Thiadiazoles, 213 1,2,5-Thiadiazoles, 214 1,3,4-Thiadiazoles, 216 1,3,4-Thiadiazole-2,5-dithiol, 365 Thiaflavans, 351 Thiazoles, 205-13

Thiazolo[ 5 ,4-b ]indole, 5 Thiazolo[4,3-a ]isoquinoline, 268 Thiazolo[4,5-d]pyridazines, 321 Thiazolo[3,2-a ]pyridinones, 204 Thiazolo[4,5-d]pyrimidines, 321 Thiazolotriazole, 194 Thieno[2,3-b]benzothiophene, 92 Thieno[3,2-b]carbazole, 102 Thieno[3,2-c ]dithiin, 100 Thieno [2,3-b ]indole, 5 Thieno[2,3-b]indol-3-one, 5 Thieno[2,3-b]pyrazines, 301 Thieno[2,3-b]pyridines, 102,259 Thieno[2,3-c]pyridines, 91,102 Thieno[3,4-c ]pyridines, 101 Thieno [2,3 -d ]pyrimid ine-2,4-dio nes, 102 Thieno[2,3-d]pyrimidines, 102 Thieno[2,3-d]pyrimidin-4-one, 282 Thieno[ 2,3-b ]pyrroles, 92 Thieno[3,4-c ]pyrroles, 101 Thienoquinoxalines, 102 Thieno[2,3-b]quinoxalines, 90,306 Thieno[2,3-b][ 1,4]thiazines, 102 Thieno[ 2,3-d]thiazoles, 90 Thieno[2,3-b]thiophenes, 91, 92 Thiiranes, 46 Thiocarbonyl ylides, 93,217 Thiochromones, 346 Thiohelicenes, 104 Thioindigo, 6, 13 3-Thioindoles, 8, 9 Thiophene oligomers, 104 Thiophene-2-borates, 96 Thiophene-3-borates, 96 Thiophene-l,l-dioxides, 94, 99 Thiophene- 1-imides, 94 Thiophene-2-iodonium, 96 Thiophene-2-1ead, 96 Thiophene-l-oxides, 94 Thiophenes, 90-105 Thiophene-2-stannanes, 96

bzdex Thiophene-2-zincates, 96 Thiopyrano[2,3-b]indoles, 2 Thiopyrans, 336,345 Thiopyrylium salts, 345 Thrombin receptor antagonists, 125 Ticlopidine, 102 Topoisomerase II inhibitors, 103 Tosmic, 246 1,2,4-Triazines, 310-6 1,3,5-Triazines, 310-6 1,2,4-Triazino[4,3-a ]benzimidazoles, 325 1,2,3-Triazoles, 191-3 1,2,4-Triazoles, 193,316 Triazolo [3,4-b][ 1,3,4]thiadiazoles, 321 1,2,4-Triazolo[ 1,2-a ]benzotriazoles, 194 Triazolo[3,4-hi[ 1,3,4 ]thiadiazines, 321 1,2,4-Trioxanes, 348 Trioxanes, 357 1,2,4-Trioxolanes, 229 Triphase catalyst, 53 Trithiahexaphyrins, 104 Trithiancs, 349 Trithiapentalcnc, 90 1,2,4-Trithiolium dications, 229 Tropoloisoquinolines, 246 Tubulin binding agents, 102,103 Tyrosine kinase inhibitors, 4 Ugi/de-Boc/cyclize strategy, 184 Unnatural porphyrin, 360 Urokinase inhibitors, 103 Valcrolactones, 19 Vilsmeier cyclization, 265 Vilsmeier reaction, 202 Vilsmeier-Arnold-I Iaack formylation, 3 Vinamidinium salts, 262 Wang resins, 305 Weak-link synthetic approach, 365 Williamson cycloetherification, 159 Wittig reactions, 8, 98 Wittig rearrangement, 84 Wurster's rcagent, 366 Xanthenes, 344 Xanthones, 344 X-ray crystallography, 2, 5, 7, 9, 12, 13,191,194, 195 Ylidcs, 216 Ytterbium complex, 57 Zampanolide, 332 Zeolites, 68,180 Zileuton, 98 Zirconoccne coupling, 260

A critical review of the 1999 literature preceded by three chapters on current heterocyclic topics

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Progress in Heterocyclic Chemistry, Volume 20 (Progress in Heterocyclic Chemistry)

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Progress in Heterocyclic Chemistry, Volume 19 (Progress in Heterocyclic Chemistry)

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Progress in Heterocyclic Chemistry, Volume 9 (Progress in Heterocyclic Chemistry)

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Aromaticity in Heterocyclic Compounds (Topics in Heterocyclic Chemistry)

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Heterocyclic Scaffolds I: ß-Lactams (Topics in Heterocyclic Chemistry)

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Heterocyclic Scaffolds I: ß-Lactams (Topics in Heterocyclic Chemistry)

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Heterocyclic chemistry

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Progress In Heterocyclic Chemistry, Vol. 19

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Progress in Heterocyclic Chemistry. Volume 12

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Progress in Heterocyclic Chemistry, Volume 19

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Topics in current chemistry, 216, Stereoselective Heterocyclic Synthesis III

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Progress in Heterocyclic Chemistry. Volume 7

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Progress in Heterocyclic Chemistry, Volume 8

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Progress in Heterocyclic Chemistry, Volume 17

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Progress in Heterocyclic Chemistry. Volume 13

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Progress in Heterocyclic Chemistry, Volume 20

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Progress in Heterocyclic Chemistry. Volume 15

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Progress in Heterocyclic Chemistry. Volume 16

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Progress in Heterocyclic Chemistry, Volume 16

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