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

20 downloads 1082 Views 16MB Size Report

This content was uploaded by our users and we assume good faith they have the permission to share this book. If you own the copyright to this book and it is wrongfully on our website, we offer a simple DMCA procedure to remove your content from our site. Start by pressing the button below!
Report copyright / DMCA form

DOWNLOAD PDF

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 . In a somewhat later paper, the electron impact induced fragmentation characteristics of these compounds were described . Other early studies focussed on the thione-thiol tautomerism of 3-arylindoline-2-thiones . The keto-enol/enolate interconversions of indoline-2-thiones and their oxa- or selena-analogues in aqueous media have also been investigated recently . Indoline-2-thiones have been prepared via lithiation of certain 2-substituted anilines followed by reaction with CS2 , or thiomethylation of 2-chloro-1methylindole-3-carbonyl amides, followed by demethylation . Preparation of the parent indoline-2-thione (1) has also been accomplished by treatment of a 2-1ithiated indole with elemental sulfur . A modified method, involving a combination of P4S10 and NazCO3 in THF, has been developed to effect the thionation of oxindoles to indoline-2thiones , 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 . It has also been demonstrated that indoline-2-thiones can serve as precursors for the preparation of 2aminoindoles . The access to a wide variety of indoline-2-thiones permitted preparation of various disulfides with the general structure 5 for biological assessment . A related 2,2'-bisindolylsulfide possessing N,N'dimethylaminoethyl groups has also been previously evaluated as a serotonin antagonist . An early review on the chemistry of indoline-2-1hiones is also available .

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 , and in [2+2] n photocycloadditions with alkenes producing alkylindoles . 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 . Reduction of indoline-2-thiones with Raney-nickel, LiA1H4, or DIBAL has been shown to give indoles and/or indolines . 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 . Both papers include mechanistic and conformational studies. An X-ray study of the phosphine derivative 8 has also been reported . 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 . A synthesis of the interesting thione 9 from N-methylisatin and diethylcarbamoyl chloride in the presence of AIC13 has been described . Interestingly, the related compound 10 has been reported to easily produce indigo via a 2,2"-coupling accompanied by extrusion of sulfur . In a recent application, indoline-2-thiones have been utilized for the synthesis of various indole and indolenine derivatives . 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 . 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 . 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 , has also been synthesized previously by a bio-mimetic approach again starting from indoline-2-thione (1) , utilising the observation that 12 is formed from 14, a metabolite of cyclobrassinin (15) . 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) . This had previously been demonstrated to undergo biotransformation by the blackleg fungus Leptosphaeria maculans in a detoxification pathway leading to several related metabolites . Cyclobrassinin (15) has also been included in a synthetic study aiming at the preparation of related compounds via 3-aminomethylindole derivatives . 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 . The biosynthesis of brassicanal A (16) has been proposed to involve the intermediate 19, which could be trapped successfully with aniline . 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 . Feeding experiments with tetradeuterated derivatives of brassinin (20) and cyclobrassinin (15) demonstrated that both these compounds are biosynthetic precursors to brassilexin (12) . 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) . 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 , and a similar strategy was also employed for the preparation of various analogues of 21 . A comprehensive review covering many different aspects concerning sulfur-containing phytoalexins from cruciferous plants has also appeared recently .

~~_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 , and their diselena-analogues . 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 , and also the ester 23, or the aldehyde 24 . A similar reaction has been reported in the case o f 6-nitro- 1-methoxyindole . 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 . 2-Alkylthioindoles have also been encountered during studies on the behaviour of some hydroxynitrilium ions , or on treatment of 4-(o-aminophenyl)-l,2,3-thiadiazole with tert-BuOK . Moreover, 2-arylthioindoles or 2-alkylthioindoles have also been derived from isonitrile alkyne species using free-radical mediated cascade processes . 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 . 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 . 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 . 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 . 2-(Toluenesulfonyl)indoles have also been used as substrates in radical induced preparation of [1,2-a]indoles , while 1,2bis(phenylsulfonyl)-indole (28) has been reported to participate in a conjugate addition with lithium dimethylcuprate to give 2-phenylsulfonyl-3-methylindole . A 2-methanesulfonylindole derivative has also been included in a quantitative structure-activity relationship (QSAR) study on indole based melatonin receptor ligands . 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 . The thieno[2,3b]indole 30 produced by a Streptomyces strain has been identified as a plant growth regulator . 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 . 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 . In connection with studies on thionation of bisindoles, the interesting thienoindole 33 was isolated and the structure was confirmed by X-ray crystallography . 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 . 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 . 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 . 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 . 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 . The interesting bisindole 46 was obtained as a side product during the preparation of the phytoalexin brassilexin (12) .

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 . Access to compounds such as 48, incorporating a large ring, has been gained by employing a new annelation based on the sulfoxide precursors 49 . 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 . Interestingly, the parent compound 50 had probably been obtained already in 1938 from the melt of indole with sulfur , the correct structure of 50 was however proposed later when the same reaction was performed in DMF, thus providing a useful preparative route . 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 ; 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 . Compound 50 has also been demonstrated to display considerable antifungal properties, in particular against dermatophytes and the fungus BotIytis cinerea .

-"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 was reported to furnish 52, as was the reaction of N-methylindoline-2-thione (2) with p-toluenesulfonyl azide ; an experiment which was previously incorrectly claimed to produce the isoindigo derivative 54 . Compound 54 has also been claimed as the product of the thionation of N,N'-dimethylisoindigo (55) with Lawesson's reagent ; 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 , 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 . 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 , the structure of which was later analysed by X-ray crystallography .

~ 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 . 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 . 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 . Other developments in this area include a ferrocenesulfonation of indole , sulfenylation of e.g. N-methylindole, 2,2'-biindolyl or 2-phenylindole using the complex of trifluoromethanesulfonic anhydride and dimethysulfide , or the synthesis of various 3-alkylthioindoles by treatment of 2-methylindole with thiourea, and subsequent S-alkylation . 3-Arylsulfonylindoles have been obtained by oxidation of the corresponding 3-arylthioindoles, and were further transformed into 3cyanoindoles . 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 . 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 . 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 , 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 . 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 . The construction of hexasubstituted benzenes, e.g. 59 containing the 3-mercaptoindole moiety, as preorganized ligands containing three , or six 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 .

/~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 , preparation of indole-3dithiocarbamates , and an investigation of the chemical and physical properties of indole-3-sulfonium ylides and related structures . 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 , whereas a number of differently substituted derivatives, among others the tricyclic system 61 have been prepared using a modified Gassmann oxindole synthesis . The sulfone of compound 60 was also isolated from a rhodium catalyzed cyclization of a diazoamide precursor . 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 , or in the development of new indole containing dopaminergic agents . 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 . A protocol for non-reductive desulfenylation of 3-(alkylthio)oxindoles employing a combination of p-toluenesulfonic acid and triphenylphosphine has been described as a complement to the reductive method employing metal hydrides . Further studies involving related 3-thioindoles encompass a reexamination of some reactions of 5-hydroxysulfoxides , and the development of a method for the generation of bicyclic o-quinodimethanes . The interesting molecule 63 has been reported as a product from the reaction of the gem-dichloride 64 with potassium ethyl xanthate . The 3,3-bis(phenylthio)oxindole 65 has been identified as one of the products from a nitrosation experiment performed on N-methyl-3phenylthioindole . A highly regioselective monofluorination of substituted 3-(phenylthio)oxindoles has been reported recently, producing the corresponding 3-fluoro-3(phenylthio)oxindoles .

~~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 , and from reactions of sulfanyl radicals with azidoalkynes . The interaction of a 3phenylthioindole derivative with calf thymus DNA has been investigated, including an X-ray crystallographic study . The structurally interesting brominated natural product echinosulfone A 66 was isolated from the southern Australian marine sponge Echinodictyum . 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 .

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 , whereas some closely related structures

10


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

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 . 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 . An indole-3-sulfide belonging to this class has also been subjected to metabolism studies in rhesus monkeys or rat liver microsomes . 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 . Some related 3-indolylsulfones have also been evaluated as potential platelet-activating factor antagonists .

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 . 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 . 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 . Related fluorinated compounds having a six-membered sulfur containing spiro ring have also been synthesized .


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 , and has as well been included in studies aiming at understanding the photophysics of various trans-stilbene analogues , whereas two mechanistic studies have focussed on the electrochemical oligomerization of 76 . Other related studies in this area encompass an investigation on the influence of relative humidity on the electrical properties of polymerised 76 , and the preparation of a co-polymer from 76 and dithienopyrrole . Polymeric 76 has also been probed for electronic and ionic conductivity , and has also been used for the construction of a solid state battery which also contained gold and magnesium . The pentacyclic molecule 77 has been reported as a product from a Fischer indolization reaction . Tetrahydrothiopyranoindoles such as 78 have been prepared by cyclization of imine precursors using the base system NaNH2-tert-BuONa , and were also demonstrated to undergo a ring opening process giving 2-alkylindoles under the influence of A1C13 and benzylthiol . 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 . 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 . 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 , which was recently applied on 2,2'-biindolyls for an alternative generation of 81 and 82 .

12


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 . A thermal process leading to the indole alkaloid arcyriaflavin A, possibly involving the in situ formation of the dithiin 87 has also been described . 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 . 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 . 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


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 . 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 .

~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 . Further studies on the rearrangement of compounds of type 95 have later demonstrated that a complex intermolecular mechanism is in operation . 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 , which could later be isolated when the second sulfenylation was performed in the presence of a base . 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 . 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 . 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 . The dielectrophile 1,2-ethanedisulfenyl chloride has been employed for the synthesis various dithioethylene substituted aromatics, to provide among others, the indole derivative 98 . A more complex system containing the core of 98 was obtained from the reaction of the spirooxindole 99 with POC13 and DMF . The optically active brominated alkaloids itomanindoles A (100) and B (101) have been isolated from the red alga Laurencia brongniartii, wherewith the structure

14


of 100 was determined using X-ray crystallography . Additional related natural products, for instance 102, were later derived from the same alga species . Some 3-alkylthioindoline-2-thiones have been generated and used for the preparation of a sulfur analogue of the leukotriene synthesis inhibitor MK886 . 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 . Compound 103 has previously been isolated in low yield from the thionation of isatin with P4S10 in refluxing pyridine . 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 . Some additional fused systems, having the general structure 106 have also been prepared and studied . 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.


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.


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 is that 5-endo-trig processes are particularly disfavoured . 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 .

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 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 . 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 . 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 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 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 or bis(sym-collidine)iodine(l) perchlorate 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 . 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 . 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 . 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


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 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 . 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 . 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 . 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) . 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'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 . 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 (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 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 . 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 . 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 , 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 . 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 , 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) which, understandably was significantly more convenient than radical-based methods using a tin hydride, and deprotection then gave


33

the diol 114, identical in all respects to an established precursor to L-(+)-muscarine [cf 89] . 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 . 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 , 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 . Subsequent hydrogenation in the presence of Boc anhydride 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 to give acetate 124 in moderate yield; the use of potassium superoxide and 18-crown-6 also in DMF gave marginally better yields of the corresponding alcohol, typically 60-70% at most. A viable alternative to this 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 . 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 . 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 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 . 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 . 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 . 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 . 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 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 ; 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 . 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 . 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.


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 . 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 . 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 .

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 . 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 . 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 and the persulfate 164 . 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 . In contrast, phenyl- or methylsulfenyl chlorides produce only the alkene addition product 167 . 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 . 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 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 . 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 . 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 . In contrast, the amino alcohol derivative 183 is converted very efficiently into the iodopyrrolidine 184 . 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 .

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


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 . 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 . 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 .

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 . 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 . Stereocontrol is good in more highly substituted examples .

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~ . 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 . Such cyclizations can also be carried out asymmetrically using thioether 162b . 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 . 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 . 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 . 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 . 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 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 . 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 . 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 . 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 .


45

Exposure of these to iodine in acetonitrile or dichloromethane containing sodium hydrogen carbonate then delivered excellent yields of the [3-iodofurans 232 . 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 . 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 . However, it is known that the related allenic alkoxides 238 do undergo iodocyclization leading to the iodofurans 240, via the 2,5-dihydrofurans 239 . This may in reality be an example of 5-exo-trig cyclization following participation of the methoxyl group (see above).

R1

..... OH 235

R2

/~~ 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 .

/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 .

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 .

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 . A similar rearrangement (83 --) 84) has been shown to occur using bismuth triflate, which has the advantages of low toxicity and moisture tolerance . 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 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'"
. 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 . Enamides (e.g., 147) can be

Three-Membered Ring Systems

69

converted to corresponding aziridinylamides 148 with excellent enantioselectivity using the chiral diaziridine 146 . 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 . 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 . 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 . 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 .

70


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 .

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


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 . 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 . 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 .

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 . 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 .

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


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 , the formation of pyrrolines 180 in the presence of acrylonitrile and solid sodium hydroxide , and thermal ring-opening to a 1,3-dipole followed by capture with electron-rich alkenes to provide substituted pyrrolidines 183 . Some radical variants include the intramolecular 5-endo cyclization of 3-(2-methyleneaziridin-l-yl)propyl radicals 185 to methylenepiperidine derivatives 186 , 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 . 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


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 .

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 . 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 .

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 .

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 .

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 .

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 . 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 . 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 . Stereochemical inversion occurs on benzylic bromination of 15 (R ~ - Ar, R 2 = H) with NBS to give 15 (R ~ - Br, R 2 = At). . 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 . 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 .

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 and the stereoselective synthesis of oxetanones are available . 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 . 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 .

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 . 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 .

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 , and the Lewis acid promoted reactions of 2methoxy-2-siloxyoxetane with allylsilane . 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 .

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 . 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 . 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 .

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) .

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 . 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 . The dithiete 37 is one of three products obtained after chromatography when diadamantylacetylene reacts with S2Cl 2 . The cycloaddition reaction of the ynamine 38 with an aryl isothiocyanate affords the 2Hthietamine 39 in high yield when the ynamine is stable . Thietanylureas are available from thietanyl 3-isocyanate .

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 .

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 . 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 . 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 .

~---p

"'"~R

p

L f~

.-"

-l 45

R

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

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 . 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 , the utility of 4-formyl-13-1actams as synthons in stereocontrolled syntheses and the use of [3-1actams in the synthesis of complex nucleoside antibiotics and macrocyclic peptides . 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 . 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 .

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 . Staudinger reactions have been used to obtain [3-1actams as substituents on quinones (e.g. 55) and as spiro compounds (e.g. 56) . 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 .

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 .

% 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 or the

83 action of propane phosphonic acid anhydride on glycine 'Dane salt' (the condensation product of glycine sodium salt with methyl acetoacetate).. 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 and a mixture of triethylamine, 2,2'-dipyridyl sulfide and triphenyl phosphine (Ohno's reagent) . 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 , by use of the Mitsunobu reaction conditions , 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 . 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 .

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 . 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 .

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 .

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 . 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 . 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 .

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 . 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 . Photochemical cyclisation of N-methylacryloylthiobenzanilide 81 in the solid state gave 82 .

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 . Thioesters 84 have been cyclised by triethyl phosphite to carbapenems with heteroarylthio substituents . A novel carbapenem 85 shows broad spectrum activity against gram-positive organisms (including MRSA type) . 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 . Further investigations and evaluation of the azomethine ylide strategy for bicyclic 13-1actamsynthesis have been reported . 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 . 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 . 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 . 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 . 2,7-Dialkylidenecephalosporin sulfones 92 are reported to be potent class C lactamase inhibitors and other cephalosporin sulfones show human elastase inhibiting abilities . Many novel cephalosporins have been reported as a

86 result of the search for antibiotics active against MRSA bacteria . _

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 . 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 .

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 . Several methods have been employed to obtain tficyclic lactams including the [2+2] cyc]oaddition of indene and an isocyanate , the Wittig cyclJsation of suitably ],4-disubstJtuted 13-lactams , base induced intramolecular reaction of the 13-lactam nitrogen atom at an activated carbon atom to yield, for instance, 97 , and the [2+4] cycloaddition of dimethyl acetylenedicarboxylate with bicyclJc 13-lactam dienes (e.g. 98) to give (e.g. 99) . 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 , and the radical cyclisation of 1-substituted-4-methylenecyclopropyl-[3-1actams to afford 102 .

CH2OEs ~N~M e O 100CO2Et

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

TBSO

87

102

R

4.8 R E F E R E N C E S R. Fernfindezw, A. Ferrette, J. M. Lassaletta, J. M. Llera, A. Monge, Angew. Chem., Int. Ed. Engl. 2000, 39, 2893. 00AHC221 J. Nakayama, A. Ishii, Adv. Heterocycl. Chem. 2000, 77, 221. 00BMC2781 M.Tsushima, K. Iwamatsu, E. Umemura, T. Kudo, Y. Sato, S. Shiokawa, H. Takizawa, Y. Kano, K. Kobayashi, T. Ida, A. Tamura, K. Atsumi, Bioorg. Med. Chem. 2000, 8, 2781. 00CC2327 L.V. Jackson, J. C. Walton, J. Chem. Soc., Chem. Commun. 2000, 2327. 00CHE1232 N. Grigan, G. Veinberg, I. Shestakova, I. Kanepe, E. Lukevics, Chem. Heterocycl. Comp. (Engl. Transl.) 2000, 36, 1232. 00CL1082 Y. Kabe, A. Sato, S. Kadoi, K. Chiba, W. Ando, Chem. Lett. 2000, 1082. 00CPB1577 T. Kambara, K. Tomioka, Chem. Pharm. Bull. 2000, 48, 1577. 00H2379 P. Davoli, F. Prati, Heterocycles 2000, 53, 2379. 00IJC(B)304 J. Azizian, Y. Sarrafi, M. Mehrdad, K. Jadidi, hzdian J. Chem., Sect. B: Org. Chem. hzc. Med. Chem. 2000, 39B, 304. 00JAN1045 T.W. Glinka, A. Cho, Z. J. Zhang, M. Ludwikow, G. Griffith, K. Huie, S. J. Hecker, M. N. Dudley, V. J. Lee, S. Chamberland, J. Antibiot. 2000.53, 1045. 00JCS(P1)2862 A. Mitchinson, A. Nadin, J. Chem. Soc., Perkin Trans. 1 2000, 2862 00JCS(P1)4373 N. K. Capps, G. M. Davies, D. Loakes, D. W. Young, J. Chem. Soc., Perkin Trans. 1 2000, 4373. 00JOC6780 E. Fernandez-Megia, M. A. Montaos, F. J. Sarica, J. Org. Chem. 2000, 65, 6780. 00JOC7248 R. Tennyson, D. Romo, J. Org. Chem. 2000, 65, 7248. 00JOC8372 W.-H. Ham, C.-Y. Oh, Y.-S. Lee, J.-H. Hyun, J. Org. Chem. 2000, 65, 8372. 00JOC8458 A. Arrieta, F. P. Cossio, B. Lecea, J. Org. Chem. 2000, 65, 8458. 00MI15 M. Mori, O. Kanno, Annu. Rep. S a n t o Res. Lab. 2000, 52, 15. 00MI 125 M. A. Hussein, A. A. Shorbagi, N. M. Omar, Z. S. Farghaly, Bull. Pharm. Sci., Assiut Univ. 2000, 23, 125. 00MI245 P. Wessig, U. Lindemann, O. Surygina, J. Inf. Rec. 2000, 25, 245. 00MI565 M. A. Allakhverdiev, R. K. Alekperov, A. N. Shirinova, N. A. Akperov, Russ. J. Org. Chem. 2000, 36, 565. 00MI651 M. Abe, E. Torii, M. Nojima, Main Group Met. Chem. 2000, 23, 651. 00OL2889 A. Ishiwata, L. P. Kotra, K. Miyashita, T. Nagase, S. Mobashery, Org. Lett. 2000, 2, 2889. 00OL3245 M. Mori, Y. Kozawa, M. Nishida, M. Kanamaru, K. Onozuka, M. Takimoto, Org. Lett. 2000, 2, 3245. 00PAC 1721 O. Dirat, C. Kouklovsky, M. Mauduit, Y. Langlois, Pure Appl. Chem. 2000, 72, 1721. 00PAC 1763 C. Paloma, J. M. Aizpurua, I. Ganbao, M. Oiarbide, Pure Appl. Chem. 2000, 72, 1763. 00RHA33 T. Kawabata, Rev. Heteroatom. Chem. 2000, 22, 33. 00SC3685 S. Mignani, D. Monysset, I. Le Roy, L. Stella, Synth. Commun. 2000, 30, 3685. 00SC3737 K. S. Crichfield, J. E. Hart, J. T. Lampert, R. K. Vaid, Synth. Commun. 2000, 30, 3737. 00SC4177 V. V. Govande, M. Arun, A. R. A. S. Deshmukh, B. M. Bhawal, Synth. Commun. 2000, 30, 4177. 00SL1699 T. Bach, Synlett 2000, 1699. 00T5571 E. Turos, M. I. Konaklieva, R. X.-F. Ren, H. Shi, J. Gonzalez, S. Dickey, D. Lim, Tetrahedron 2000, 56, 5571. 00T5631 M. I. Page, A. P. Laws, Tetrahedron 2000, 56, 5631. 00AG(E)2893

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 , and general reviews of heterocyclic chemistry and sulfur compounds 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 , 1,3-dithiole-fused terthiophenes , dithiophenes , alkoxythiophenes , biphenylthiophenes , and thieno[2,3-d]thiazoles . A novel sulfurbridged heterocycle, trithiapentalene 2, was prepared by thiolation of keto dienamine 1 with Lawesson's reagent or P4S,0 . 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) . The reaction between acrylic acids and thionyl chloride led to 3chlorobenzo[b]thiophene-2-carbonyl chlorides including a benzo[2,1-b:4,5b']dithiophene . 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 . Similar intramolecular condensation reactions were utilized to prepare thieno[2,3-blthiophenes , thieno[2,3-c]pyridines , 5-nitrobenzo[b]thiophenes , thiophene-3-carboxylates , benzo[b]thiophenequinones , and complex thiophene-2carboxamides . An improved synthesis of thiophene-3-carboxaldehyde involved the condensation of thioacetaldehyde dimer with acrolein followed by aromatization with sulfuryl chloride . 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 . 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 . 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 ""

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 , human cytochrome P450 inhibitor (ticlopidine) , nitric oxide synthase inhibitors (thieno[2,3-c]pyridines) , ohD receptor antagonists (thieno[2,3-d]pyrimidine2,4-diones) , E-selective and ICAM-1 expression inhibitors (thieno[2,3d]pyrimidines and thieno[2,3-c]pyridines ), HMG-CoA reductase inhibitors (thieno[2,3-b]pyridines) , and anti-HIV agents (benzo[2,1-b:4,5-b']dithiophenes). The preparation of additional ring systems that have been reported include pyrido[2',3':4,5]thieno[2,3-c]pyridazines , thieno[2,3-b][1,4]thiazines , and many other complex thiophene-containing

103

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

heterocycles including those previously mentioned in this review. The preparation of thienoquinoxalines has been reviewed . Analogues of biologically active natural products have been prepared including thiophene derivatives of podophyllotoxin and prodigiosin . 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 , antitumor agent 145 , tubulin binding agents , avl33antagonist 146 , anti-HIV agents , 5-HTIA receptor antagonists , P38 kinase inhibitors , urokinase inhibitors , Raf kinase inhibitors , PAL1 inhibitors , ~ adrenoceptor agonists , topoisomerase II inhibitors , subnanomolar inhibitors of human carbonic anhydrase II , endolethin antagonists , novel phototoxic agents , trypanocidal agents , and antibacterial agents . Finally, the synthesis and/or evaluation of various tetrahydrothiophenes have been reported including antibiotics , glycosidase inhibitors , and anti-HIV agents . 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) , pyrrolethiophenes , and pyrrole-imidazoles . Ferrocene moities (e.g., 148) have also been investigated as moderate electron donors in donor-thiopheneacceptor complexes . A novel class of bimetallic complexes (e.g., 149) containing both iron and chromium has been synthesized . 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 . Finally, the preparation of thiophenes conjugated to fullerenes (e.g., 127 and 37 ) has been reported in association with self-assembled monolayers and photoinduced charge transfer . 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 (!), trithiahexaphyrins , dithiasapphyrins , dithiaporphyrins , Schiff-base macrocycles (e.g., 150) , N-confused thiaporphyrins , tetrathiafulvenesubstituted [22]annulenes , thiophene-containing calix[n]pyrroles , and dithiophene-substituted phthalocyanines . Additional types of novel thiophene-containing macrocycles and annulenes that have been prepared and/or evaluated include thiophene cage complex 151 , dithiophene-containing porphyrin cage complex (fluoride anion recognition) , macrocyclic Mannich bases (e.g., 152) , thiophene-containing calixarenes , dithiophene-substituted calixarenes , thiophene-containing crown thioether 153 , thiophene-containing cyclophanes (e.g., 80) , trithiophene-diacetylene macrocycles , and tubular sexithiophene 73 . Thiohelicenes, helical shaped aromatic macrocycles containing fused thiophene tings, have been prepared and/or evaluated including helicene 106 , [5]thiahelicenes (chiral recognition) , [7]thiahelicenes (photochromism) , and [n]thiahelicenes (n=5,7,9,11) . A theoretical study concerning the feasibility of thiophene-containing heterobuckybowls appeared .

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 , violene/cyanine hybrids , carboxamide-based molecular recognition templates , novel fluorophores , dithiothiophene nickel and gold complexes (conductors), and star-shaped molecules (liquid crystals) 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 , pentathiophenes , sexithiophene 76 ), llmers , and 48-mer (!) 154 . The preparation of long monodisperse

105

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

oligothiophenes has also been reviewed . A solid-phase approach to well defined tetrathiophenes has been reported . The preparation of oligothiophenes with novel substitution patterns has been reported including those with chiral side chains , amine groups , thiols groups , alkylthiol groups , phosphines (platinum complexes) , fused adamantyl groups , and fused silole groups . A detailed study of the acidcatalyzed oligomerization of 2-hydroxymethylthiophenes has appeared . Oligothiophenes have been prepared with different groups located on one or both ends including those conjugated to cyclophanes , porphyrins , polybenzyl ether dendrons , ferrocenes , chromene groups , Ru(II) complexes , perfluoroalkyl groups , tris(thiol) groups (self-assembled monolayers) , fluorenes , isothiocyanates (fluorescent markers) , diarylamines (glasses) , and fullerenes . Mixed thiophene cooligomers have been prepared and/or evaluated including those containing chiral binaphthyl groups , naphthyl groups , 1,4-phenyl groups , fluorene groups , spirofluorenyl groups , phosphole groups , thiazole groups , and tungsten-capped calixarenes .

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 and polythiophene-transition metal hybrids . Polythiophenes have been evaluated as novel materials in a variety of fields including for novel electronic devices , optical devices , DNA molecular recognition , biosensors , organic films , stereoselective synthesis , and chemical lithography . New approaches to the synthesis of polythiophenes have been reported . Finally, the functionalization of polythiophenes on an electrode surface has been reported . 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 . 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 . The synthesis and chemistry of the novel bicyclic ring system selenabicyclo[3.1.0]hexene 157 has been explored . Polymer systems containing selenophene units have been prepared

106

E.T. Pelkey

and characterized . Finally, the preparation of porphyrin-related macrocycles containing selenophene rings 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

Griineberg, S .; Wendt, B.; Klebe, G. Angew. Chem. ha. Ed. 2001, 40, 389. tlopf, tt.Angew. Chem. htt. Ed. 2001, 40,705. Wiirthner, F.Angew. Chem. h~t. Ed. 2001, 40, 1037. Murguly, E.; Norsten, T. B.; Branda, N. R.Angew. Chem. Int. Ed. 2001,40, 1752. Noack, A.; Schr6der, A.; Hartmann, It.Angew. Chem. hzt. Ed. 2001, 40, 3008. Takeuchi, M.; Shioya, T.; Swager, T. M. Angew. Chem. h~t. Ed. 2001, 40, 3372. Pacholska, E.; Latos-Grazynski, L.; Ciunik, Z. Angew. Chem. hzt. Ed. 2001, 40, 4466. Briehn, C. A.; Schiedel, M.-S.; Bonsen, E. M.; Schuhmann, W.; B~iucrle, P. Angew. Chem. ha. Ed. 2001, 40, 4680. Guyard, L.; An, M. N. D.; Audebert, P.Adv. Mater. 2001, 13,133. Mena-Osteri~, E.; B~iuerle, P. Adv. Mater. 2001, 13,243. Wolf, M. O.Adv. Mater. 2001, 13,545. Besbes, M.; Tripp6, G.; Lcvillain, E.; Mazari, M.; Le Deft, F.; Perepichka, I. F.; Derdour, A.; Gorgues, A.; Sail6, M.; Roncali, J. Adv. Mater. 2001, 13, 1249. Kros, A.; van t{6vell, W. F. M.; Sommerdijk, N. A. J. M.; Nolte, R. J. M. Adv. Mater. 2001, 13, 1555. Tovar, J. D.; Swager, T. M. Adv. Mater. 2001, 13, 1775. Zhang, F.; Svensson, M.; Andersson, M. R.; Maggini, M.; Bucclla, S.; Menna, E.; Ingan~is, O. Adv. Mater. 2001, 13, 1871. Ha-Duong, N.-T.; Dijols, S.; Macherey, A.-C.; Goldstein, J. A.; Dansette, P. M.; Mansuy, D. Biochemistly 2001, 40, 12112. Higuchi, tI.; Ishikura, T.; Mori, K.; Takayama, Y.; Yamamoto, K.;Tani, K.; Miyabayashi, K.; Miyake, M. Bull. Chem. Soc. Jign. 2001, 74,889. Sumi, N.; Nakanishi, H.; Ueno, S.; Takimiya, K.; Aso, Y.; Otsubo, T. Bull. Chem. Soc. Jpn. 2001, 74, 979. Sato, M.-a.; Sakamoto, M.-a.; Kashiwagi, S.-i.; Suzuki, T.; Itoroi, M. Bull. Chern. Soc. Jpn. 2001, 74, 1737. Otsubo, T.; Aso, Y.; Takimiya, K. Bldl. Chem. Soc.,lpn. 2001, 74, 1789. Morimoto, tt.; Fukushima, C.; Yamauchi, R.; Hosino, T.; Kikkawa, K.; Yasuda, K.; Yamada, K. Bioorg. Med. Chem. 2001, 9,255. Martinez-Merino, V.; Cerecetto, H. Bioorg. Med. Chem. 2001, 9, 1025. Stephens, C. E.; Felder, T. M.; Sowell, J. W.; Andrei, G.; Balzarini, J.; Snoeck, R.; De Clercq, E.Bioorg. Med. Chem. 2001, 9, 1123. Redman, A. M.; Johnson, J. S.; Dally, R.; Swartz, S.; Wild, tt.; Paulsen, II.; Caringal, Y.; Gunn, D.; Renick, J.; Osterhout, M.; Wilhelm, S. M.; Housley, T. J.; Bhargava, A.; Ranges, G. E.; Shrikhande, A.; Young, D.; Bombara, M.; Scott, W. J. Bioorg. Med. Chem. Lett. 2001, 11, 9. Kim, It. O.; Kim, Y. H.; Suh, tt.; Jeong, L. S. Bioorg. Med. Chem. Lett. 2001, ]1,599. Wilson, K. J.; Illig, C. R.; Subasinghe, N.; tloffman, J. B.; Rudolph, M. J.; Soll, R.; Molloy, C. J.; Bone, R.; Green, D.; Randall, T.; Zhang, M.; Lewandowski, F. A.; Zhou, Z.; Sharp, C.; Maguire, D.; Grasberger, B.; DesJarlais, R. L.; Spurlino, J.Bioorg. Med. Chem. Lett. 2001, 11.915.

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

Beaton, H.; Boughton-Smith, N.; ltamley, P.; Ghelani, A.; Nicholls, D. J.; Tinker, A. C.; Wallace, A. V.Bioorg. Med. Client. Lett. 2001, 11, 1027. Wirsching, J.; Voss, J.; Adiwidjaja, G.; Balzarini, J.; De Clercq, E.Bioorg. Med. Chem. Lett. 2001,11, 1049. Carroll, W. A.; Sippy, K. B.; Esbenshade, T. A.; Buckncr, S. A.; Hancock, A. A.; Meyer, M. D. Bioorg. Med. Chem. Lett. 2001,11,1119. Yuasa, H.; Takada, J.; Itashimoto, II.Bioorg. Med. Chem. Lett. 2001, 11, 1137. Suzuki, M.; lwasaki, H.; Fujikawa, Y.; Sakashita, M.; Kitahara, M.; Sakoda, R. Bioorg. Med. Chem. Lett. 2001, 11, 1285. Subasinghe, N. L.; Illig, C.; Itoffman, J.; Rudolph, M. J.; Wilson, K. J.; Soil, R.; Randle, T.; Green, D.; Lewandowski, F.; 7Jaang, M.; Bone, R.; Spurlino, J.; DesJarlais, R.; Deckman, I.; Molloy, C. J.; Manthey, C.; Zhou, Z.; Sharp, C.; Maguire, D.; Crysler, C.; Grasberger, B. Bioorg. Med. Chem. Lett. 2001,11, 1379. Shrader, W. D.; Young, W. B.; Sprengeler, P. A.; Sangalang, J. C.; Elrod, K.; Carr, G Bioorg. Med. Chem. Lett. 2001, 11, 1801. Peyman, A.; Scheunemann, IC-H.; Will, D. W.; Knolle, J.; Wehner, V.; Breipohl, G.; Stilz, tt. U.; Carniato, D.; Ruxer, J.-M.; Gourvest, J.-F.; Aubcrval, M.; Doucet, B.; Baron, R.; Gaillard, M.; Gadek, T. R.; Bodary, S, Bioorg. Med. Chem. Lett. 2001,11,2011. Heerding, D. A.; Chan, G.; DeWolf, W. E.; Fosbcrry, A. P.; Janson, C. A.; Jaworski, D. D.; McManus, E.; Miller, W. H.; Moore, T. D.; Payne, D. J.; Qiu, X.; Rittenhouse, S. F.; SlaterRadosti, C.; Smith, W.; Takata, D. T.; Vaidya, K. S.; Yuan, C. C. K.; Huffman, W. FBioorg. Med. Chem. Lett. 2001, 11,2061. Lisowski, V.; Enguehard, C.; Lancelot, J.-C.; Caignard, D.-H.; Atassi, G.; Renard, P.; Rault, S . Bioorg. Med. Chem. Lett. 2001, 11, 2205. Fujiwara, T.; Kimoto, M.; Sugiyama, tI.; ltirao, I.; Yokoyama, S. Bioorg. Med. Chem. Lett. 2001,1i, 2221. Hynn, B. L.; Hynn, G. P.; Ilamel, E.; Jung, M. K.Bioorg. Med. Chem. Lett. 2001, l l , 2341. Folkes, A.; Roe, M. B.; Sohal, S.; Golec, J.; Faint, R.; Brooks, T.; Charlton, P.Bioorg. Med. Chem. Lett. 2001, 11,2589. Shailendra; Bharti, M.; Garza, M. T. G.; Cruz-Vega, 13. E.; Garza, J. C.; Saleem, K.; Naqvi, F.; Azam, A. Bioorg. Med. Chem. Lett. 2001, 11,2675. Smith, R. A.; Barbosa, J.; Blum, C. L.; Bobko, M. A.; Caringal, Y. V.; Dally, R.; Johnson, J. S.; Katz, M. E.; Kennure, N.; Kingery-Wood, J.; Lee, W.; Lowinger, T. B.; Lyons, J.; Marsh, V.; Rogers, D. H.; Swartz, S .; Wallhlg, T.; Wild, II. Bioorg. Med. Chem. Lett. 2001, 11,2775. Bromidge, S. M.; Grfffith, K.; tteightman, T. D.; Jennings, A.; King, F. D.; Mo~, S. F.; Newman, H.; Riley, G.; Routledge, C.; Serafinowska, H. T.; Thomas, D. R.Bioorg. Med. Chem. Lett. 2001, 11,2843. Weatherman, R. V.; Carroll, D. C.; Scanlan, T. S. Bioorg. Med. Client. Lett. 2001, 31,3129. F(irstner, A.; Grabowski, J.; Lehmann, C. W.: Kataoka, T.; Nagai, K.ChemBioChem 2001, 2, 60. Bilik, P.; Tanious, F.; Kumar, A.; Wilson, W. D.: Boykin, D. W.; Colson, P.; Houssier, C.; Facompr6, M.; Tardy, C.; Bailly, C. ChemBioChem 2001, 2,559. Malaun, M.; Reeves, Z. R.; Paul, R. L.; JeffcH, J. C.; McCleverty, J. A.; Ward, M. D.; Asselberghs, I.; Clays, K.; Persoons, A. Chem. Commltn. 2001, 49. Finikova, O.; Cheprakov, A.; Bcletskaya, I.; Vinogradov, S. Chem. Commun. 2001, 261. Feuerstein, M.; Laurenti, D.; Bougeant, C.; Doucct, H.; Santelli, M. Chem. Commlm. 2001, 325. Matsuda, K.; Takayama, K.; Irie, M. Client. Commltn. 2001, 363. Kurata, H.; Nakaminami, H.; Matsumoto, K.; Kawase, T.; Oda, M.Chem. Commun. 2001, 529. Kawai, T.; Sasaki, T.; Irie, M. Chem. Commltn. 2001, 711. Lucas, L. N.; van F~ch, J.; Kellogg, R. M.; Fcringa, B. L. Chem. Commun. 2001, 759. Kean, C. L.; Pickup, P. G. Chem. Commttn. 2001, 815. Liu, S.-G.; Martineau, C.; Rahnundo, J.-M.; Roncali, J.; Echegoyen, L. Chem. Commun. 2001, 913. Rajca, A.; Wang, H.; Pawitranon, V.; Brett, T. J.; Stezowski, J. J. Chem. Commltn. 2001, 1060.

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

Charas, A.; Morgado, J.; Martinho, J. M. G.; Alc~icer, L.; Cacialli, F. Chem. Commun. 2001, 1216. Yu, J.; Holdcroft, S. Chem. Comrnun. 2001, 1274. Wong, K.-T.; Hung, T. It.; Kao, S. C.; Chou, C. H.; Su, Y. O. Chem. Cornmun. 2001, 1628. Pan, G.-L.; Fan, M. G.; Fan, P.; Wang, It. Z.;Wei, Z. C. Chern. Comrnun. 2001, 1744. Zhu, L.; Tang, H.; tlarima, Y.; Yamashita, K.; ttirayama, D.;Aso, Y.; Otsubo, T. Chem. Commun. 2001, 1830. Nakagawa, H.; Kobori, Y.; Yoshida, M.; Yamada, K.-i. Chem. Cornmun. 2001, 2692. Belo, D.; Alves, I1.; Lopes, E. B.; Duarte, M. T.; Gama, V.; Rovira, C.; Veciana, J. Chem. Eur..1. 2001, 7, 511. Giannetto, M.; Mori, G.; Notti, A.; Pappalardo, S.; Parisi, M. F. Chem. Eur. J. 2001, 7, 3354. Matsuda, K.; Irie, M. Chem. Eur..1. 2001, 7, 3466. Hay, C.; Hissler, M.; Fischmeister, C.; Rault-Berthelot, J.; Toupet, L.; Nyulfiszi, L.; R6au, R. Chem. Eur. J. 2001, 7, 4222. Sprutta, N.; Latos-Grazynski, L. Chem. Eur. J. 2001, 7, 5099. Nakagawa, H.; Kobori, Y.; Yamada, K.-I. Chirality 2001,13,722. Uchida, K.; Fujita, M.; Aoi, Y.; Saito, M.; Irie, M. Chem. Lett. 2001, 366. Matsuda, K.; Matsuo, M.; Irie, M. Chem. Lett. 2001, 436. Kiln, M.-S .; Kawai, T.; Irie, M. Chem. Lett. 2001, 702. Nakayama, J.; Takayama, Y.; Sugihara, Y.; Ishii, A. Chem. Lett. 2001, 758. Kloc, K.; Osajda, M.; Mlochowski, J. Chem. Lett. 2001, 826. Yamada, T.; Azurni, R.; Tachibana, H.; Sakai, ti4 Abe, M.; BSuerle, P.; Matsurnoto, M. Chem. Lett. 2001, 1022. Yu, J.; Offino, F. P.; Holdcroft, S. Chem. Mater. 2001,13, 526. Naudin, E.; El Mehdi, N.; Soucy, C.; Breau, L.; B61anger, D. Chem. Mater. 2001,13,634. Benincori, T.; Consonni, V.; Gramatica, P.; Pilati, P.; Rizzo, S.; Sannincol6, F.; Todeschini, R.; Zotti, G. Chem. Mater. 2001,13, 1665. Lee, Y. S .; Sadki, S .; Tsuie, B .; Reynolds, J. R. Chem. Mater. 2001, 13, 2234. Caronna, T.; Catellani, M.; Luzzati, S.; Malpezzi, L.; Meille, S. V.; Mele, A.; Richter, C.; Sinisi, R. Chem. Mater. 2001, 13, 3906. Barbarella, G.; Favaretto, L.; Sotgiu, G.; Antolini, L.; Gigli, G.; Cingolani, R.; Bongini, A. Chem. Mater. 2001,13, 4112. Hong, X. M.; Katz, H. E.; Lovinger, A. J.; Wang, B.-C.; Raghavachari, K. Chem. Mater. 2001,13, 4868. Landrnan, M.; G6rls, H.; Lotz, S. Eur. J. b~org. Chem.2001, 233. Goldoni, F.; Antolini, L.; Pourtois, G.; Schenning, A. P. H. J.; Janssen, R. A. J.;Lazzaroni, R.; Br6das, J.-L.; Meijer, E. W.Eur. J. bzorg. Chem. 2001, 821. Belo, D.; Alves, H.; Rabaca, S.; Pereira, L. C.; Duarte, M. T.;Gama, V.; tlenriques, R. T.; Almeida, M.; Ribera, E.; Rovira, C.; Veciana, J.Eur. J. htorg. Chem. 2001, 3127. L6re-Porte, J.-P.; Moreau, J. J. E.;Torreilles, C. Eur. J. Org. Chem. 2001, 1249. Hiinig, S.; Langels, A.; Schmittel, M.; Wenner, H.; Perepichka, I. F.; Peters, K. Eur. J. Org. Chem. 2001, 1393. Moore, T. D.; Chesney, A.; Bryce, M. R.; Batsanov, A. S.; Kelly, J. F.; Howard, J. A. K.; Perepichka, I. F.; Perepichka, D. F.; Meshulam, G.; Berkovic, G.; Kotler, Z.; Mazor, R.; Khodorkovsky, V. Eur. J. Org. Chem. 2001, 2671. Greve, D. R.; Apperloo, J. J.; Janssen, R. A. J.Eur. J. Org. Chem. 2001, 3437. Mamouni, A.; Daich, A.; Marchalin, S .; Decroix, I3. Heterocycles 2001, 54,275. Sensfuss, U.; Habicher, W.-D. Heterocycles 2001, 55, 171. Erker, T.; Krainz, E. Heterocycles2001, 55,255. Honda, E.; Watanabe, S .-i.; Iwamura, T.; Kataoka, T. Iteterocycles 2001, 55,465. Hirota, T.; Tomita, K.-i.; Sasaki, K.; Okuda, K.; Yoshida, M.;Kashino, S. Heterocycles 2001, 55, 741. Liska, R. Heterocycles 2001, 55, 1475. Raposo, M. M. M.; Kitsch, G. Heterocycles2001, 55, 1487. Lee, J. Y.; Baek, N. J.; Lee, S. J.; Park, H. J.; Lee, Y. S. lteterocycles 2001, 55, 1519. Racan6, L.; Tralic-Kulenovic, V.; Fiser-Jakic, L.; Boykin, D. W.; Karminski-Zamola, G. Heterocycles 2001, 55, 2085.

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

Kumar, P. N.; Prasanna, B.; Chandramouli, G. V. P.Heterocycl. Cornrnun. 2001, 7, 271. Gulevskaya, V. I.; Kuvshinov, A. M.; Shevelev, S. A. Heterocycl. Comrnun. 2001, 7, 283. Pitsinos, E. N.; Lehn, J.-M.; De Cian, A. Helv. Chim. Acta 2001, 84, 22. M~irkl,v. G.; Bruns, D.; Dietl, H.; Kreitmeier, P. ttelv. Chim. Acta 2001,84, 2220. Miyasaka, H.; Murakami, M.; Itaya, A.; Guillaumont, D.; Nakamura, S.; Irie, M.J. Ant. Chem. Soc. 2001,123,753. Norsten, T. B.; Branda, N. R. J. Am. Chem. Soc. 2001, 123, 1784. Weinberger, D. A.; Higgins, T. B.; Mirkin, C. A.; Stern, C. L.; Liable-Sands, L. M.; Rheingold, A. L. J. Ant. Chem. Soc. 2001, I23, 2503. Sakamoto, Y.; Komatsu, S .; Suzuki, T.J. Ant. Chem. Soc. 2001, 123, 4643. Ewen, J. A.; Elder, M. J.; Jones, R. L.;Rheingold, A. L.; Liable-Sands, L. M.; Sommer, R. D. J. Ant. Chem. Soc. 2001,123, 4763. Apperloo, J. J.; Janssen, R. A. J.; Malenfant, P. R. L.; Fr6chet, J. M. JJ. Am. Chem. Soc. 2001,123, 6916. Norsten, T. B.; Peters, A.; McDonald, R.; Wang, M.; Branda, N. R.I. Am. Chem. Soc. 2001, 123, 7447. Deng, X.; Liebeskind, L. S. J. Ant. Chem. Soc. 2001, 123, 7703. Vigalok, A.; Zhu, Z.; Swager, T. M.J. Ant. Chem. Soc. 2001,123, 7917. Anand, V. G.; Pushpan, S. K.; Venkatraman, S.; Dey, A.; Chandrashekar, T. K.; Joshi, B. S.; Roy, R.; Teng, W.; Senge, K. R. J. Am. Chem. Soc.2001, 123, 8620. Meng, H.; Bao, Z.; Lovinger, A. J.; Wang, B.-C.; Mujsce, A. M J. Ant. Chem. Soc. 2001, 123, 9214. Matsuda, K.; Irie, M.J. Ant. Chem. Soc. 2001,123, 9896. Clot, O.; Wolf, M. O.; Patrick, B. O.J. Ant. Chem. Soc. 2001,123, 9963. Barbarella, G.; Zambianchi, M.; Pudova, O.; Paladini, V.; Ventola, A.; Cipriani, F.; Gigli, G.; Cingolani, R.; Citro, G.J. Am. Chem. Soc. 2001, 123, 11600. Phillips, K. E. S.; Katz, T. J.; Jockusch, S.; Lovinger, A. J.; Turro, N. jd. Ant. Chem. Soc. 2001,123, ] 1899. Del Valle, M. A.; Moreno, J.; Diaz, F. R.; Tagle, L. H.; Bern6de, J. C., Tregoiiet, YJ. Appl. Polym. Sci. 2001, 81,2019. Brugier, D.; Outurquin, F.; Paulmier, C.J. Chem. Soc., Perkin Trans. 1 2001, 37. Hawksley, D.; Griffin, D. A.; Leeper, F. JJ. Chem. Soc, Perkin Trans. I 2001, 144. Armengol, M.; Joule, J. A..I. Chem. Soc., Perkin Trans. I 2001, 154. Procter, D. J.J. Chem. Soc., Perkin Trans. 12001, 335. Shilai, M.; Kondo, Y.; Sakamoto, T.J. Chem. Soc., Perkin Trans. 1 2001, 442. Mitschke, U.; B~iuerle, P.J. Chem. Soc., Perkin Trans. 1 2001, 740. Kumar, S.J. Chem. Soc, Perkin Trans. 12001, 1018. Boyd, D. R.; Sharma, N. D.; Harrison, J. S.; Kennedy, M. A.; Allen, C. C. R.; Gibson, D. TJ. Chem. Soc, Perkin Trans. 1 2001, 1264. Chaffin, J. D. E.; Barker, J. M.; tluddleston, P. R.I. Chem. Soc., Perkin Trans. 1 2001, 1398. Kumaresan, D.; Agarwal, N.; Ravikanth, M.J. Chem. Soc., Perkin Trans. 1 2001, 1644. Kim, B. t1.; Jeon, I.; Han, T. H.; Park, II. J.; Jun, Y. MJ. Chem. Soc., Perkin Trans. 12001, 2035. Jackson, Y. A.; Itepburn, S. A.; Reynolds, W. F.J. Chem. Soc., Perkin Trans. 1 2001, 2237. Katritzky, A. R.; Vvedensky, V. Y.; Tymoshenko, D. Od. Chem. Soc., Perkin Trans. 1 2001, 2483. Gilchrist, T. L.J. Chem. Soc., Perkin Trans. 12001, 2491. Halfpenny, J.; Rooney, P. B.; Sloman, Z. S d. Chem. Soc., Perkin Trans. 1 2001, 2595. Lee, J. S.; Lee, D. J.; Kim, B. S.; Kim, K.J. Chem. Soc., Perkin Trans. 1 2001, 2774. Bowman, W. R.; Cloonan, M. O.; Krintel, S. L.J. Chem. Soc., Perkin Trans. 1 2001, 2885. Field, J. S.; Haines, R. J.; Lakoba, E. I.; Sosabowski, M. H.J. Chem. Soc, Perkin Trans. 1 2001, 3352. Pigeon, P.; Othman, M.; Decroix, B.J. Heterocycl. Chem. 2001, 38, 35. Luo, J.-K.; Cabal, M.-P.; Federspiel, R. F.; Castle, R. N.J. tteterocycl. Chem. 2001, 38, 137. Ito, K.; Ohba, T.; Tamura, T.; Ogata, T.; Watanabe, H.; Suzuki, Y.; Hara, T.;Morisawa, Y.; Sone, T.J. Heterocycl. Chem. 2001, 38,293.

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 . There also appeared a review of simple indole alkaloids and those with a nonrearranged monoterpenoid unit .

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 . 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 . 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 . 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 . Additionally, this reaction process was employed in the first synthesis of a conformationally restricted 2,2'-bipyrrole , a class of compounds that can represent highly luminescent materials . 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 . 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 . 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 reported an improvement on the Cushman pyrrole synthesis 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 . 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 , 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 .

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 .

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~ . /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 . 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 . 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 . Gore described a somewhat similar intramolecular approach involving the anionic cyclization of ~-allenylhydrazines affording 3-pyrrolines . 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 . 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 . 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 . 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 . 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 , 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 . 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 . 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 . 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 . 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 .

[~~

.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 . 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 .

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 . 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 .

+ 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 . 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 .

+

~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 .

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


amine hydrochlorides 69 to produce monoalkylation products 70 in aqueous media .

+

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 . 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 .

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 . 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 . 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 . 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) . 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 .

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 . 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 . Additionally, the pyrrole D-A reaction was utilized as a key step in the synthesis of epibatidine derivatives displaying antinociceptive effects , while the reactions of masked o-benzoquinones with pyrroles were also examined .

+

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 . 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 . This one-pot reaction consists of three steps: a) hydroamination of the alkyne triple bond; b) hydrogen migration of the resulting

122


amino alcohol to an aminoketone (Bischler-type intermediate), and; c) cyclization to the indoles 90 . 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 . These authors now provide full details for this procedure and propose a reaction pathway involving alkanol group transfer from alkanolamines to anilines . The use of an "environmentally safer" solvent, namely chloroaluminate ionic liquids (1butylpyridinium chloride-A1Cl3), was reported as being effective for the Fischer indole synthesis . The Buchwald-Hartwig Fischer indole synthesis involving Pd-catalyzed preparation of N-arylbenzophenone hydrazones was utilized by Gmeiner for the synthesis of indoloparacyclophanes . 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 . 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 . '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 . 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 . 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 .

[ ~ ' ~ '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 . 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 . 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 and P.A. Evans 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


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 . 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 . 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 . In one variant, after cyclization of iodo alkene 113 and subsequent carbon monoxide insertion, termination of this queuing process with hydride reagents, organostannes , or as illustrated below with NaBPh4, yields the termolecular adduct 114 .

[~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 . A similar approach was employed for the synthesis of spiro- and fused heterocycles .

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 . Schultz employed this traceless sulfonamide linker strategy in a cleverly designed combinatorial synthesis of 2,3,5-trisubstituted indoles . 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 . 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 .

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 . 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 . 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 . 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 . 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 . 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 or using the Pd(OAc)2/P(t-Bu)3 system . 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 . 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 . Additionally, upon treatment with excess butyllithium, 2-iodoindole (141) undergoes both deprotonation at nitrogen and lithium-halogen exchange to generate 1,2-dilithioindole (142) . 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 .

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 . 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~ . 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 . 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 . • 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 . 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 . 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 .

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 . 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 .

~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 .

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 . 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 .

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 . 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 . 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 . 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 . 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 . 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 . 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 . Meanwhile, Chakrabaty published a review on the synthesis and biological activity of diindolylalkanes . 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 . 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 . 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 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 . Meanwhile, Mancini and Piettre 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 . 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


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 . 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 . 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 . 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 . Additionally, this same author devised a new, indirect route to 5methoxyindoles via Diels-Alder reactions of quinone imine ketals .

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 . 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 .

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 . 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 . 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 .

N" 201

-HC(OMe)3 "

Fmoc-Cl~ 202 " ~

pyr.

~'J

203

oc

134


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 . 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 . In another structureproving synthesis, Mort ascertained the absolute configuration of (-)-axinellamine A, a metabolite of the marine sponge Axinella sp. . Liebscher reported the synthesis of the marine natural product phorbazole C possessing a chlorinated pyrrole-, an oxazole- and a phenol ring . Kock described the isolation of novel bromopyrrole alkaloids from the Caribbean sponge Stylissa caribica and Agelas sventres , while four new bioactive bromopyrrole-derived alkaloids were isolated from the marine sponge Axinella brevistyla collected in western Japan . 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 . 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 . Finally, although not formally a pyrrole, an enantioselective synthesis of epibatidine employing a highly selective asymmetric hereto Diels-Alder reaction was reported by Evans . 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 , leading to his proposing revised structures for both . As regards these target molecules, Magnus utilized a photo-Fries rearrangement for the synthesis of the diazonamide macrocycle , while Nicolaou employed a Suzuki coupling of a 4-bromoindole derivative for construction of the aromatic core of this target . At present then, the most architecturally challenging indole alkaloid remains nodulisporic acid (209), towards which Smith reported construction of western hemisphere and eastern hemisphere subtargets . While on the topic of challenging targets, Danishefsky published an interesting retrospective commentary on his work on the himastatin problem . 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 . 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 . Pearson meanwhile reported the total synthesis of the Kopsia lapidilecta alkaloid lapidilectine B . Employing chiral auxiliaries for secodine-type intramolccular Diels-Alder reactions, Kuehne reported enantioselectivc syntheses of coronaridine and 18methoxycoronaridine . Cook reported an enantiospecific total synthesis of the sarpagine/macroline indole alkaloid trinervine and utilized an oxy-anion Cope rearrangement in syntheses of alkaloid G and ajmaline . The asymmetric synthesis and stereochemical assignment of the marine indole alkaloid chelonin B was reported . 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 . Bringmann reported the first total synthesis of the Murraya alkaloid murrastifoline-F, an unsymmetric, N,C-bonded heterobiarylic biscarbazole . 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 . Meanwhile, Hart dcscribed the synthesis of the spirocyclic oxindole entalantrypinone, the enantiomer of a natural product produced by the fungus Penicillium thymicola . 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 as well as a Wackcr-type catalytic system using atmospheric oxygen as the stoichiometric oxidant . Meanwhile, Brana described the synthesis and antiproliferative effects of a novel class of bisindolylmaleimides .

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 . 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 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 . 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 . 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 . Two more new labdane diterpenes, cacofurans A and B were isolated from a sponge Cacospongia sp. .

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 . From the same source khayanone, 2-hydroxyseneganolide and 1-O-acetylkhayanolide A were also obtained . The CHCI3 extract of the bark of Aphanamixis polystachya yielded another new limonoid 3 . Two new tetranortriterpenoids 7isovaleroylcycloseverinolide and 7-isovaleroylcyclopiatalantin were obtained from the root bark of Severinia buxifolia collected in Hainan, China . 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 Five new sesquiterpenes 4-8 were provided from the crude extract of fresh and undamaged fruiting bodies of Collybia maculata . 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 . 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) . 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 . Salvinorin C, a new neoclerodane diterpene, was isolated from the bioactive fraction of the hallucinogenic Mexican mint Salvia divinorum . Two new limonoids polygonumin A and B 12 were obtained for the first time from the whole plant of Polygonum orientale L . Deoxyobacunone, a new limonoid, was obtained from the root bark of Harrisonia abyssinica collected in Nigeria . 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 .

,~"-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 . 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 . 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 . 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 . 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 . Another naturally occurring 2,3,4-trisubstituted furan radulifolin C was

142


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

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 . 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 . Tetrahydrofuran skeletons are also abundant in naturally occurring molecules. For example, furoplocamioids A-C, three novel polyhalogenated furanoid monoterpenes were obtained from Plocamium cartilagineum . Tetillapyrone and nortetillapyrone were isolated and characterized from the extract of the marine sponge Tetilla japonica from the Bay of Thailand . Two new cytotoxic annonaceous acetogenin, namely annomolin and annocherimolin were found from an EtOH extract of the seeds of Annona cherimolia . 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 . 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 . Recently, a new squalene-derived epoxy tri-tetrahydrofuran diol 18 was isolated from the endemic Jamaican plant Spathelia glabrescens . 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 . From the bark and seeds of Colophospermum mopane was also obtained two new grindelic acid derivative, namely dihydrogrindelic acid and dihydrogrindelaldehyde . 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 . 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 . A spirodienone structure was observed by NMR spectroscopy as one of the important structures present in spruce and aspen lignins .

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 . Massarilactone A was obtained from cultures of the freshwater aquatic fungus Massarina tunicata and its absolute configuration was determined . A new dihydrogarofuran alkaloid 23 was yielded from the antimicrobially active EtOH extracts of Maytenus heterophylla . 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 . 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 . A reinvestigation of Euphorbia decipiens with a modified extraction method yielded the new myrsinane-type diterpene ester 24 . From the petroleum-ether extract of the dried aerial parts of Hypericum papuanum was isolated furonewuinone A .

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 . 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 . Furanodictine A and B, two amino sugar analogs produced by cellular slime mold Dictyostelium discoideum were isolated and found to exhibit neuronal differentiation activities . 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 . The same research team also reported the absolute stereochemistry of amphidinolide C . Two new quinoid diterpenes with nor-abietane skeleton, namely ll3-hydroxycryptotanshinone andloxocryptotanshinone were isolated from roots of the Iranian medicinal plant Perovskia abrotanoides . A bioassay-guided fractionation of Machaerium multiflorum gave a novel (+)-trans-hexahydrodibenzopyran named machaeriol B . Dehydroxymethylailanthoidol was isolated from the leaves of Litsea acutivena . From the stems of Derris malaccensis a new rotenoi 12a-hydroxyelliptone was isolated and its structure was substantiated by spectroscopic and chemical methods . 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) . 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 . 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 .

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 . Two new quinoline alkaloids, 2-acetylevolitrine and 2-acetylpteleine were identified from the root bark of Melicope semecarpifolia by means of spectroscopic analyses . Two novel biflavonoids, isolophirone C and dihydrolophirone C were obtained from the stem bark of the Cameroonian medicinal plant Ochna afzelii . From the core of Hibiscus cannabinus were isolated two phenolic constituents whose structures were proved to be boehmenan H and boehmenan K . The structures of three isoflavonoids from Erythrina suberosa var. glabrescences called erysubins C-E were elucidated on the basis of spectroscopic analyses . Two other new isoflavonoids eryvarins D and E were obtained from the roots of Erythrina variegata (Leguminosae) . The EtOH extract of the whole plant of Justicia neesii gave tiruneesiin after chromatography . 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 . The novel resveratrol trimer caraphenol A was obtained from the roots of Caragana sinica and its structure and stereochemistry were elucidated by spectroscopic data . An oligostilbene called (+)-viniferol A was also isolated from the stem of Vitis vinifera "Kyohou" cultivated in the Wakayama Prefecture in Japan . Another four new stilbene oligomeric glucosides named gnemonoside A, B, C and C were isolated from the stem of Gnetum gnemonoides (BRONGN) . 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 . 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 . Rocagloic acid, a cytotoxic compound, was isolated from the leaves of Aglaia elliptifolia . A structurally related compound 33 was also obtained from the twigs of Aglaia oligophylla collected in Vietnam . Two unusual diarylheptanoid derivatives, neocalyxins A and B were identified from the EtOH extract of the seeds of Alpinia blepharocalyx .

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 . A new ellagitannin, phyllanemblinin A, was obtained from Phyllanthus emblica .

5.3.2

REACTIONS

146


5.3.2.1 Furans The intramolecular [4+3] cycloaddition reaction towards seven-membered rings involving furans and allylic cations have been reviewed . A review on the use of 2siloxyfurans as butenolide precursors has appeared . Organometallic compounds of furans and their benzoannulated derivatives have also been summarized . 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 . The Diels-Alder adduct of furan with acrylic acid was also used to construct the all diastereomeric stereotetrads (polypropionate fragments) . 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 . Reaction of 2-glycosylfuran with benzyne followed by an acidcatalyzed rearrangement of the product provided the aromatic part of C-aryl glycosides . Benzyl aryl ether dendrons and dendrimers containing thermally reversible furan-maleimide Diels-Alder adducts were prepared up to the third generation . 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 . When silica-supported Lewis acids were used in the absence of microwave irradiation, normal Diels-Alder adducts were obtained instead . 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 .

/

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 .

~

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


ring was generated. The reaction was controlled not only by the size of the amide appendage but also by the electronegativity of the amide . 3-Methylthiofuran reacted with a variety of 2-substituted cycloalkenones to afford the corresponding Diels-Alder adducts with high regio- and stereoselectivities . 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 .

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 . 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 .

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 . 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

. 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 . 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 . An intramolecular [4+3] cycloaddition of trimethylsilylmethyl substituted furan derivatives gave rise to the adducts with a high level of diastereoselectivity . 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 . 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 . 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 . 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 . Singlet oxygen oxidation of 5-methoxyfurans also provided endoperoxides, which were converted to isolable functionalized 2-oxetanyl hydroperoxides as illustrated below . 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 . 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 . 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 . It was discovered that reaction of 5methyl-2-silyloxyfuran with arylacetaldehydes took place at the 3- and/or 5-positions . The reaction of 5-silyloxyfuran with a chiral aldehyde gave a vinylogous aldol product with different stereoselectivity and high stereoselectivity . The intermolecular vinylogous Mannich reaction of 2-methyl-5-


149

silyloxyfuran with cyclic iminium ions of differing ring size was carried out . 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 . 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 . 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 . 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 . 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 .

_~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 . 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 . 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 .

150


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 .

/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 . 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 .

=- 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 . 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 . 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 . 2-Acylfurans reacted with ammonia at 150 ~ in a sealed vessel provided 3-hydroxypyridines in moderate yields . Microwave- and ultrasound-assisted oxidation of 3substituted furans by employing NBS to furnish a-substituted-ml3-unsaturated butyrolactones was also reported . Metal catalyzed cyclopropanation reaction of methyl 2furoate was used in the preparation of trisubstituted butyrolactones . 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 .

MeO

PhCOCHN2 Rh2(OAc)479% -"-

MeO

O

~~O


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 . The temperature and viscosity dependence of the spin-directed stereoselectivity of the Patern6--Btichi photocycloaddition reactions between 2,3-dihydrofuran and benzaldehyde were studied .

~

~+ 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 as well as BOC-protected trans-4-hydroxy-L-proline . Palladium catalyzed addition of secondary amines to 2,3-dihydrofuran was also accomplished from which c~-aminotetrahydrofurans were obtained as shown below . Stereoselective formation of 2-substituted tetrahydrofurans was also realized from Lewis acid-promoted reactions between wlactols and silyl enol ethers . 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 . Mechanistic and computational studies were carried out on intermolecular asymmetric Heck reactions . 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 . A LiBF4-catalyzed imino Diels-Alder reaction was also performed on 2,3-dihydrofuran in Yadav's synthesis of furanoquinolines . 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 . 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 . 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 . 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 . 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 .

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 . Medium ring heterocycles can also be realized through an oxidative cleavage of the double bond of a 2,5-dihydrofuran as depicted .

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 . Enantiomers of tricyclic furan products were prepared accordingly via pivotal Diels-Alder reactions of the optically active 2,5-dihydrofurans as exemplified below .

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 .

.•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


hydrosilylative dimerization with subsequent elimination of HOSiC13 and water . 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 .

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 .

~

PhSC,P h S ~

PhS~.~ N.',.Bn

N~Bn

C,-PhS~

N-~Bn

o A o.oI1\ o; H"N-Bn ~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 . [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 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 . An acid catalyzed cationic cyclization of electron-rich ~-benzoyldiphenylmethanols was utilized to construct 2,3-disubstituted benzo[b]furans. . 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 .

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 .

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 .

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 .

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 .

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 . Another palladium catalyzed cyclization procedure also led to dih ydrobenzo[b]furans .

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 .

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 . Another efficient total synthesis of (_)-galanthamine was developed by employing a methylamine mediated rearrangement as a key step . 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 . In a synthesis of

166


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 . O H

o=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 .

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 .

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 . 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 .

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 . 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 .

N=N Ph

S 112

-45 ~,.. -N2

S+ Ph 113 I DMAD

MeO2~CO2Me

D--E

Ph

D----E

p

S

218


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) .

-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 .

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 .

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 .

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


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 .

~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 or alkali metal/lead/indium halides and the use of ionic liquids for this reaction has also been described . Methods for the preparation of dioxolanes 3 and 4 have been patented and an improved method for the synthesis of vinylene carbonate 5 has been described . Methylenedioxolanones such as 6 may be prepared from 3-chlorolactic acid and transfer hydrogenation of :Jtosyloxyacetophenone 7 using a chiral ruthenium catalyst and formic acid as hydrogen source unexpectedly gives 8 in 94% e.e. . 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 and the further fluorination of compound 11 has also been studied . The use of the enzyme oxynitrilase to catalyse synthesis of cyanohydrins such as 12 has been examined .

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 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 . Treatment of 1,2-diols with 1,2di(phenylsulfonyl)ethene gives the dioxolanes 16 thus providing a new protecting group for carbohydrate chemistry . 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 . 0

0

O'~OMe ArOH . =-

O[,, [I 3 ~ RO~ 1,.> 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 . 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 . 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 . Oxazolinyloxiranes 171, obtained by a Darzens reaction of compound 165 (R = C1) with tolualdehyde, could be deprotonated and alkylated stereospecifically . Uncatalysed reaction of stannylated oxazoline 174 with 2-bromonaphthoquinone 173 afforded, with a remarkable regioselectivity, compound 175, which was then reduced to naphthol 176 . Several new oxazolinyl ligands were synthesised and applied in asymmetric synthesis. Paracyclophane ligand 177 was applied to the enantioselective alkylation of aldehydes with diethylzinc . Simple phosphinite 178 afforded high enantiomeric excess in Pd-catalysed alkylation of allylic acetates , and enantioselective hydrogenation of alkenes .

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 . Oxazolylphenols 180 were prepared from the corresponding aromatic derivatives (carboxylic acids or nitriles) and 13-aminoalcohols . Through an analogous reaction, ligands of general formula 181 were synthesised and used to produce Rh-complexes , as well as tridentate ligand 182 . Several immobilized oxazolidinyl ligands have been proposed and used for producing Cu complexes as catalysts for asymmetric Diels-Aldcr reactions , for cyclopropanation of olcfins , or for the enantioselective Mukaiyama reaction and Pd-catalysed allylic substitution . 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 , [2+2] cycloaddition , Heck reaction , radical-mediated coniugate addition , oxidative coupling of titanium enolate , cyclopropanation in ionic liquids , Mukaiyama-Michael reactions ,

250

S. Cicchi, F.M. Cordero and D. Giomi

addition of allenylsilane , 1,3-DC cycloaddition , phenyl transfer from organozinc to aldehydes . Finally, tripodal ligands 183 and 184, based on oxazolinyl nuclei, were used as catalysts for enantioselective Michael addition and for sugar molecular recognition .

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%) . 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 .

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 " 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 . Titanium tetrachloride and (-)-sparteine with N-acyloxazolidinones and oxazolidinethiones were used in asymmetric aldol additions . 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 . 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 . 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 . 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 . 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 . A very mild method for the alcoholysis of benzyloxycarbonyl-5-oxazolidinones, using alcohols and hydrogen carbonate, was reported . N-protected 5-oxazolidinones 223 reacted with chloromethylithium to afford intermediates 224 which were hydrolysed to o~-aminoalkyl ot'-chloromethyl ketones 225 . 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 .

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 . 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 . 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 . The synthesis and the electroluminescence applications of Tb(III)-complexes with oxadiazole-functionalised I]-diketonate ligands 233 were reported .

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


REFERENCES

0lAG(E)598 01AG(E)1875 0lAG(E)2082 0lAG(E)2519 0lAG(E)4445 0lAG(E)4705

C.G. Espino, J. Du Bois,Angew. Chem. Int. Ed. Eng. 2001, 40,598. T. Bosanac, J.M. Yang, C.S. Wilcox,Angew. Chem. h~t. Ed. Eng. 2001, 40, 1875. J.W. Bode, N. Fraefel, D. Muri, E.M. Carreira,Angew. Chern. hzt. Ed. Eng. 2001, 40, 2082. S. Orlandi, A. Mandoli, D. Pini, P. Salvadori, Angew. Chem. htt. Ed. Eng. 2001, 40, 2519. J. Blankenstein, A. Pfal~,Angew. Chem. h~t. Ed. Eng. 2001,40, 4445. K.C. Nicolaou, X. Huang, N. Giuseppone, P.B. Rao, M. Bella, M.V. Reddy, S .A. Snyder, Angew. Chem. htt. Ed. Eng. 2001, 40, 4705. 0lAG(E)4765 J. Li, S. Jeong, L. Esser, P.G. Harran,Angew. Chern. ha. Ed. Eng. 2001, 40, 4765. 01AG(E)4770 J. Li, A.W.G. Burgett, L. Esser, C. Amezcua, P.G. ttarran, Angew. Chem. htt. Ed. Eng. 2001, 40, 4770. 0lAG(E)4906 J. Li, A.W.G. Burgett, L. Esser, C. Amezcua, P.G. tIarran,Angew. Ckem. hit. Ed. Eng. 2001, 40, 4906. 01BMCL2593 A.J. Duplantier, G.E. Beckius, R.J. Chambers, L.S. Chupak, T.II. Jenkinson, A.S. Klein, K.G. Kraus, E.M. Kudlacz, M.W. McKechney, M. Pettersson, C.A. Whitney, A.J. Milici~ioorg. Med. Chem. Lett. 2001, 11,2593. 01CC915 P. Gebarowski, W. Sas, Ckem. Commun. 2001, 915. 01CC1304 P. Boutillier, S.Z. Zard, Chem. Commun. 2001, 1304. 01CC1558 M.W. Davies, R.A.J. Wybrow, C.N. Johnson, J.P.A. Ilarrity, Ckem. Commun. 2001, 1558. 01CC1590 F.M. Cordero, S. Valenza, F. Machetti, A. Brandi, Chem. Cornmun. 2001, 1590. 01CC1684 E. Gonzfilez-Zamora, A. Fayol, M. Bois-Choussy, A. Chiaroni, J. 7~u, Chem. Contmun. 2001, 1684. 01CC1894 S. Huppe, H. Rezaei, S.Z. Zard, Chem. Cornmlut. 2001, 1894. 01CC1936 RJ. Clarke, I.J. Shannon, Chem. Commun. 2001, 1936. 01CEJ1845 C.H. Tan, A.B. ttolmes, Chem. Eur..L 2001, 7, 1845. 01CEJ5318 J. Barluenga, F. Aznar, M.A. Palomero, Chem. Eur. J. 2001, 7, 5318. 01EJO759 M. Lalk, H. Reinke, K. Peseke,Eur..1. Org. Chem. 2001, 759. 01EJO1033 L. Raimondi, M. Benaglia, Eur..1. Org. Chem. 2001, 1033. 01EJO1893 U. Chiacchio, A. Corsaro, D. Iannazzo, A. Piperno, A. Procopio, A. Rescifina, G. Romeo, R. Romeo,Eur. J. Org. Chem. 2001, 1893. 01EJO2257 P. Langer, J. Wuckelt, M. D6ring, P.R. Schreiner, H. G6rls, Eur..1. Org. Chem. 2001, 2257. 01EJO2425 K. Schierle-Amdt, D. Kolter, K. Daniehneier, E. Steckhan, Eur. J. Org. Chem. 2001,2425. 01EJO2965 P. ten Holte, B.CJ. Van Esseveldt, L. Thijs, B. Zwanenburg, Eur..1. Org. Chem. 2001, 2965. 01EJO2999 F. Cardona, A. Goti, A. Brandi, Eur. J. Org. Client. 2001, 2999. 01EJO3067 A. Scheurer, P. Mosset, W. Bauer, R.W. Saalfrank,Eur. J. Org. Chem. 2001, 3067. 01EJO3789 A. de Meijere, M. yon Seebach, S.I. Kozhushkov, R. Boese, D. Blaser, S. Cicchi, T. Dimoulas, A. Brandi, Eur. J. Org. Chem. 2001, 3789. 01H(55)823 M. Ohba, R. Izuta, Heterocycles, 2001,55,823. 01JA2907 M.A. Arai, M. Kuraishi, T. Arai, tt. SasaiJ. Ant. Chem. Soc. 2001, 123, 2907. 01JA3243 J.C. Lee, J.K. Cha.,J. Ant. Chem. Soc. 2001,123, 3243. 01JA3611 J.W. Bode, E.M. Carreira, J. Am. Chem. Soc 2001, 123, 3611. 01JA4480 D.A. Evans, K.A. Scheidt, J.N. Johnston, M. C. Willis, J. Am. Chem. Soc. 2001, 123, 4480. 01JA5602 C. Palomo, M. Oiarbide, F. Dias, A. Ortiz, A. Linden,L Ant. Chem. Soc. 2001, 123, 5602. 01JA5818 M. Gerisch, J.R. Krumper, R.G. Bergman, T. Don Tilley,J. Am. Chem. Soc. 2001, 123, 5818. 01JA6179 J. Wang, R. Wang, J. Yang, Z. Zheng, M.D. Carducci, T. Cayou, N. Peyghambarian, G.E. Jabbour, J. Am. Chem. Soc. 2001, 123, 6179. 01JA6700 G. Zhao, X. Sun, H. Bienaym6, J. Zhu, J. Ant. Chem. Soc 2001, 123, 6700. 01JA7228 W. Adam, K. Peters, E.-M. Peters, S.B. Schambonyd. Ant. Chem. Soc. 2001, 123, 7228. 01JA9461 K. Benakli, C. Zha, R.J. Kerns,J. Am. Soc. 2001, 123, 9461. 01JA10425 M. Clark, R.C. Schoenfeld, B. Ganem,J. Ant. Chern. Soc. 2001,123, 10425. 01JA10942 A.B. Smith III, K.P. Minbiole, P.R. Verhoest, M. Schelhaas, J. Am. Chem. Soc. 2001,123, 10942. 01JA11075 J.A. Pesti, J.G. Yin, L.H. Zhang, L. Anzalone,L Ant. Chem. Soc. 2001,123, 110751. 01JA12095 D.A. Evans, Z.K. Sweeney, T. Rovis, J.S. Tedrowd. Ant. Chem. Soc. 2001, 123, 12095. 01JCR(S)436 K.A. Kumar, K.M.L. Rai, K.B. Umesha,J. Chem. Res. (S) 2001, 436. 01JCS(P1)949 A. Alexakis, I. Aujard, J. Pytkowicz, S. Roland, P. Mangeney, J. Chem. Soc. Perkin Trans. I 2001, 949. 01JCS(P1)1168 C.J. Easton, G.A. Heath, C.M.M. tlughes, C.K.Y. Lee, G.P. Savage, G.W. Simpson, E.R.T. Tiekink, G.J. Vuckovic, R.D. Webster,./. Chem. Soc., Perkin Trans. 1 2001, 1168.

Five-Membered Ring Systems." With 0 & N Atoms

255

O1JCS(P1)1897 G.A. Brown, K.M. Anderson, J.M. Large, D. Planchenault, D. Urban, N.J. Hales, T. Gallagher,.l. Chem. Soc. Perkm Trans. 12001, 1897 and references cited therein. 01JHC415 X.C. Han, N.R. Natale,J. tteterocycl. Chem. 2001,38,415. 01JOC206 D.-R. Hou, J.H. Reibenspies, K. Burgess,J. Org. Chem. 2001, 66,206. 01JOC727 S. Lucarini, C. Tomasini, J. Org. Chem. 2001, 66,727. M.T. Crimmins, B.W. King, E.A. Tabet, K. Chaudhary, J. Org. Chem. 2001, 66,894. 01JOC894 01JOC1413 A.I. Meyers, S.V. Downing, MJ. Weiser,.l. Org. Chem. 2001, 66, 1413. A. Abbotto, V. Capriati, L. Degennaro, S. Florio, R. Luisi, M. Pierrot, A. Salomone, .1. Org. 01JOC3049 Chem. 2001, 66, 3049. C. Gaul, K. Sch~irer, D. Seebach,.l. Org. Chem. 2001, 66, 3059 01JOC3059 01JOC3459 Z. Xia, C.D. Smith, J. Org. Chem. 2001,66, 3459. T. lshikawa, K. Shimizu, H. Ishii, S. Ikeda, S. Saito,.l. Org. Chem. 2001, 66, 3834. 01JOC3834 01JOC4276 S. Denmark, J.J. Cottell,J. Org. Chem. 2001, 66, 4276. 01JOC5113 G.K. Tranmer, W. Tam,J. Org. Chem. 2001, 66 5113. 01JOC6410 J.W. Bode, E.M. Carreira,.l. Org. Chem.2001, 66, 6410. 01JOC6595 tt.M.L. Davies, RJ. Townscnd,.l. Org. Chem. 2001, 66, 6595. A.R. Katri~ky, M. Wang, S. Zhang, M.W. Voronkov,.l. Org. Chem. 2001, 66, 6787. 01JOC6787 L. De Luca, G. Giacomelli, A. Riu,.l. Org. Chem. 2001, 66, 6823. 01JOC6823 K.W. Stagliano, H.C. Malinakova, J.S. llarwood,J. Org. Chem. 2001, 66, 7530. 01JOC7530 M.I. Burguete, J.M. Fraile, J.I. Garcia, E. Garcia-Verdugo, C.I. l Ierrerias, S.V. Luis, J.A. 01JOC8893 Mayoral,J. Org. Chem. 2001, 66, 8893. C. Bolm, N. Hermanns, M. Kesselgruber, J.P. ttildebrand,l. Organomet. Chem. 2001, 624, O1JOM157 157. 01OL79 W. Adam, S. B. Schambony, Org. Lett. 2001,3, 79. A.G.M. Barrett, S.M. Cramp, A J. Henncssy, P.A. Procopiou, R.S. Robcrts, Org. Lett. 2001,3, 01OL271 271. 01OL299 M. Murakata, H. Tsutsui, O. Hoshino, Org. Lett. 2001,3, 299. 01OL715 H. Tian, X. She, Y. Shi, Org. Lett. 2001,3, 715. E. Marotta, L.M. Micheloni, N. Scardovi, P. Righi, Org. Lett. 2001, 3,727. 01OL727 X. Sun, P. Janvier, G. Zhao, H. Bienaym6, J. 7Jm, Org. Lett. 2001,3,877. 01OL877 T. Morita, Y. Nagasawa, S. Yahiro, H. Matsunaga, T. Kunieda, Org. Lett. 2001, 3,897. 01OL897 H. Ooi, A. Urushibara, T. Esumi, Y. lwabuchi, S. tlatakeyama, Org. Lett. 2001, 3,953. 01OL953 J.E. Baldwin, S.P. Romeril, V. Lee, T.D.W. Claridge, Org. Lett. 2001, 3, 1145. 01OLl145 01OL1261 P. Wipf, J.-L. Methot, Org. Lett. 2001,3, 1261. A. Goti, M. Cacciarini, F. Cardona, F.M. Cordero, A. Brandi, Org. Lett. 2001,3, 1367. 01OL1367 B. Westermann, A. Walter, U. FIorke, H.J. Altenbach, Org. Lett. 2001,3, 1375. 01OL1375 J.W. Bode, E.M. Carreira, Org. Lett. 21)01,3, 1587. 01OL1587 01OL2125 D.A. Evans, J.M. Janey, Org. Lett. 2001, 3, 2125. B. Clapham, C. Spanka, K.D. Janda, Org. Lett. 2001, 3, 2173. 01OL2173 E. Vedejs, M.A. Zajac,Org. Lett. 2001,3, 2451. 01OL2451 M. Dawid, G. Mlostofi, J. Warkentin, Org. Lett. 2001,3, 2455. 01OL2455 D. Rechavi, M. Lemaire,Org. Lett. 2001, 3, 2493. 01OL2493 S. Cacchi, G. Fabrizi, A. Goggiamani, G. Zappia, Org. Lett. 2001,3, 2539. 01OL2539 M. Kambe, E. Arai, M. Suzuki, II. Tokuyama, T. Fukuyama, Org. Lett. 2001,3, 2575. 01OL2575 R.A. Aungst, C. Chan, R.L. Funk, Org. Lett. 2001, 3, 2611. 01OL2611 P.Q. Nguyen, H.J. Schafer, Org. Lett. 2001,3, 2993. 01OL2993 A. Plant, F. Stieber, J. Scherkenbeck, P. Losel, ! t. Dyker, Org. Lett. 2001, 3, 3427. 01OL3427 M.P. Sibi, M. Liu, Org. Lett. 2001,3, 4181. 01OL4181 Y.-Y. Ku, T. Grieme, P. Shanna, Y.-M. Pu, P. Raje, It. Morton, S. King, Org. Lett. 2001, 3, 01OL4185 4185. C. Mazet, L.H. Gade, Organometallics 2001, 20, 4144. 01OM4144 M. Kidwai, P. Sapra, Org. Prep. Proced. Int. 2001,33, 381. 01OPP381 01S745 A. Radspieler, J. Liebscher, Synthesis 2001, 745. M. Calle, P. Cuadrado, A.M. Gonz~lez-Nogal, R. Valcro, Synthesis 2001, 1949. 01S1949 S.-I. Fukuzawa, tt. Matsuzawa, K. Metoki, Synlett 2001, 709. 01SL709 S. Kobayashi, T. Hamada, K. Manabe, Synlett 2001, 1140. 01SLl140 S. Karmakar, D.K. Mohapatra, Synlett 2001, 1326. 01SL1326 A.B. Smith III, K.P. Minbiole, S. Freeze, Synlett 2001, 1739. 01SL1739 It. Kromann, F.A. SIoK, T.N. Johansen, P. Krogsgaard-Larsen, Tetrahedron 20t)1, 57, 2195. 01T2195 D. Giomi, S. Turchi, A. Danesi, C. Faggi, Tetrahedron 2001, 57, 4237. 01T4237

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


W. Friebolin, W. Eberbach, Tetrahedron 2001,57, 4349. F. Machetti, F.M. Cordero, F. De Sarlo, A. Brandi Tetrahedron 2001,57, 4995. P. Weimin, Z. Shizheng, J. Guifang, Tetrahedron 2001,57, 5781. A.I. Jim6nez, P. L6pez, L. Oliveros, C. Cativiela, Tetrahedron 2001, 57, 6019. F. Clerici, M.L. Gelmi, A. Gambini, D. Nava, Tetrahedron 2001, 57, 6429. A. T~irraga, P. Molina, D. Curiel, M.D. Velasco, Tetrahedron 2001, 57, 6765. G. Faita, A. Paio, P. Quadreili, F. Rancati, P. Seneci, Tetrahedron 2001, 57, 8313. E. Colacino, A. Converso, A. Liguori, A. Napoli, C. Siciliano, G. Sindona Tetrahedron 2001, 57, 8551. X.-W. Wu, X.-L. Hou, I~.-X. Dai, J. Tao, B.-X. Cao, J. Sun, l'ctrahedron: Asymmetry 2001, 12,529. G. Cardillo, L. Gentilucci, M. Gianotti, A. "Folomelli, Tetrahedron: Asymrneoy 2001,12,563. J. Clayden, L.W. Lai, M. llelliwell, Tetrahedron: Asymmeoy 2001, 12,695. K. Hallman, C. Moberg, Tetrahedron: Asymmeoy 2001,12, 1475. J.K. Park, S.-W. Kim, T. Ityeon, B.M. Kim,Tetrahedron: Asymmetpy 2001, 12, 2931. M. Tiecco, I.,. Testaferri, F. Marini, S. Sternativo, C. Santi, L. Bagnoli, A. Temperini, Tetrahedron: Asymmetly 2001, 12, 3053. V. Capriati, L. Degennaro, S. Florio, R. I,uisi, Tetrahedron Lett. 2001, 42, 9183. U. Azzena, L. Pilo, E. Piras, Tetrahedron Lett. 2001, 42,129. S.R. Gilbertson, Z. Fu, D. Xie, Tetrahedron Lett. 2001, 42,365. A.R. Gangloff, J. Litvak, EJ. Shelton, D. Sperandio, V.R. Wang, K.D. Rice, Tetrahedron Lett 2001, 42, 1441, C. Yu, Y. Jiang, B. Liu, I,. Itu,Tetrahedron Lett. 2001, 42, 1449. R.F. Poulain, A.L. Tartar, B.P. D6prez, Tetrahedron Lett. 2001, 42, 1495. B.B. Snider, B. Shi, Tetrahedron Lett. 2001, 42, 1639. U. Chiacchio, A. Corsaro, D. lannazzo, A. Piperno, A. Procopio, A. Rcscifina, G. Romeo, R. Romeo, Tetrahedron Lett. 2001, 42, 1777. J.M. Fraile, J.I. Garcia, C.I. tlerrerias, J.A. Mayoral, D. Carrie, M. Vaultier, Tetrahedron: AsyrnmeOy 2001,12, 1891. I. Chierotto, M, Feroci, Tetrahedron Lett. 2001, 42, 3451. S.-H. Lee, J. Yang, T.D. Han, Tetrahedron Lett. 2001, 42, 3487. D.J. Madar, H. Kopecka, D. Pireh, J. Pease, M. Pliuschev, R.J. Sciotti, P.E. Wiedeman, S.W. Djuric, Tetrahedron Lett. 2001,42, 3681. T. Subramanian, C.-C. Lin, C.-C. Lin,Tetrahedron Lett. 2001, 42, 4079 S.-G. Kim, K.H. Alan, Tetrahedron Lett. 2001, 42, 4175. C. Agami, F. Couty, N. Rabazo, Tetrahedron Lett. 2001, 42, 4633. S.M. Jachak, N.P. Karche, D.D. Dhavale, Tetrahedron Lett. 2001, 42, 4925. E. Cereda, A. Ezhaya, M. Quai, W. Barbaglia, Tetrahedron Lett. 2001, 42, 4951. H.-J. Kim, Y.-[t. Kim J.-I Ilong, Tetrahedron Lett. 2001, 42, 5049. P. Allevi, G. Cighetti, M. Anastasia, Tetrahedron Lett. 2001, 42, 5319. G. Jones, C.J. Richards, Tetrahedron Lett. 2(~H, 42, 5553. J.K. Gallos, K.C. Damianou, C.C. Dellios, Tetrahedron Lett. 2001, 42, 5769. T. Onishi, N. Hirose, T. Nakano, M. Nakazawa, K. Izawa, Tetrahedron Lett. 2001, 42, 5883. A.K. Ghosh, M. Shirai, Tetrahedron Lett. 2001, 6231. P. Kisanga, P. Ilankumaran, J.G. Verkade, Tetrahedron Lett. 2001, 42, 6263. J.S. Yadav, A. Bandyopadhyay, B.V.S. Reddy, Tetrahedron Lett. 2001, 42, 6385. S. Iwasa, S. Tsushhna, T. Shimada, II. Nishiyama, Tetrahedron Lett. 2001, 42, 6715. F. Simonelli, G.C. Clososki, A.A. Dos Santos, A.R.M. De Oliveira, F. De A. Marques, P.H.G. Zarbin, Tetrahedron Lctt. 2001,42, 7375. J.K. Gallos, S .C. Demeroudi, C.C. Stathopoulou, C.C. Dcllios, Tetrahedron Lett. 2001,42, 7497. K. Hiri6, K. Watanabe. I. Abe, M. Koseki, Tetrahedron Lett. 2001, 42, 7617. D.J. Burkhart, P. Zhou, A. Blumenfeld, B. Twamley, N.R. Natale, Tetrahedron Lett. 2001, 42, 8039. D.J. Burkhart, B. Twamley, N.R. Natale, Tetrahedron Lett. 2001, 42, 8415. S. Minakata, M. Nishimura, q'. Takahashi, Y. Oderaotoshi, M. Komatsu, Tetrahedron Lett. 2001, 42, 9019.

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 . The authors have also shown that the same strategy can be applied with 1,6-heptadiynes and electron-deficient nitriles (J.+4--->5) . Other metal-mediated processes include the formation of pyridines through the palladium-catalyzed cyclization of olefinic ketone O-pentafluorobenzoyloximes . 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 . 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 . 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 . 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 .

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) . Using a similar condensation-electrocyclization strategy, Beccalli and co-workers report an approach to pyrido[2,3-b]indoles . Notably, Katsumura has recently reported on the rate acceleration of 6~-azaelectrocyclization based on substitution of 1-azatrienes at the C4 and C6 positions .

/~ ~ 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 . 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 . 2,3-Disubstituted pyridines have also been synthesized via 3-halo-l-azaallylic anions in good yields .

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 , but has also served as a handle to perform other chemistry via chelation to the nitrogen . 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 . 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) . The resulting anionic intermediate can then be trapped by an appropriate electrophile. The 2silylpyridine directing group is then removed oxidatively.

260


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) . Spivey has also applied ortho metallation techniques to synthesize pyridine analogs for use as phase transfer catalysts .

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 . Failer and coworkers report on the synthesis and use of a Ruthenium (R)-QUINAP catalyst for use in enantioselective Diels-Alder reactions . 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 , the Suzuki reaction , Sonogashira coupling , carbonylative cross-coupling reactions , Pd-mediated pyridine-N coupling reactions and a notable zirconocene coupling . For example, polyfunctional pyridines have been synthesized through the cross-coupling between halopyridines and aryl grignards (27--~28) .

261


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 . Interestingly, an uncatalyzed amination of 3-nitropyridines has also been reported . Other metal mediated processes have been used to access pyridines with important biological activity as well .

.•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 . Oku and co-workers have reported the use of tetrahydroquinolizinium ylides in a 1,3-dipolar cycloaddition reaction (34--~35) . Sieburth has also published an account of the [4+4] photocyclization reaction of pyridones on route to fusicoccin . 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


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 , the direct construction of these systems was reported by cyclization of vinamidinium salts in a [3+2+1] annulation reaction . 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 . Pyridine N-oxides have also been utilized by Katritzky as an effective way to activate the 2-position to nucleophilic attack .

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) . Similarly Bates has reported a synthesis of (_-_+)tashiromine which features the reduction of a pyridinium salt .

~ 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 . Similarly Comins efficiently adds the lithiated ethyl propiolate (46-447) to the 2-position on route to a synthesis of (+)-allopumilotoxin (48) . 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 . 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 . 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 . 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 . 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 . Ring-closing olefin metathesis technology utilizing Ru catalysis was also used to prepare 1,2-dihydroquinolines . Additionally, 2-arylquinolines were prepared by a Sm/TiC14 induced reductive cyclization of 2-nitro-l,3-diphenyl-2-propen-l-ones . Anionic annelation reactions were showcased in the preparation of 4substituted pyrazolo[4,3-c]quinolines and 9-substituted pyrazolo[4,3-c]quinolines . 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 . The

264


preparation of 4-arylhexahydropyrroloquinolines was also accomplished through a [4 + 2] cycloaddition of cyclic enamides and imines derived from aromatic amines . 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 . 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 . 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 . Furthermore, tetrahydroquinolines were also prepared in asymmetric fashion via an inverse electron demand Diels-Alder reaction using a chiral Ti(IV) catalyst . 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 . 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 .

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


3-formylquinoline derivatives 62 . Treatment of Baylis-Hillman acetates of ohalobenzaldehydes with sulfonamides followed by nucleophilic aromatic substitution affordcd 3-alkoxycarbonylquinolines . 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 . The reaction of o-aminobenzoic acid and ot-arylketene dithioacetals was reported to provide quinoline and quinolonc derivativcs . Lewis acid promotion of the reactions of o-aminobenzaldehyde with a dithioacetal was shown to afford 2ethylthioquinoline . 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 and a Vilsmeier cyclization of 2'-aminochalcones . A three component stereoselective synthesis of tetrahydroquinolincs catalyzed by clay/water mixtures was also reported .

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 . Microwave irradiation was also used to prepare quinolones from anthranilic acid and ketones . A microwave promoted, intramolecular cyclization of an isocyanate in the ortho position of a stilbene derivative to afford a quinolone derivative was also reported . 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 . Additions of allysilanes to quinolines acylated with chloroformate esters and catalyzed by various triflate salts were reported . 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


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 . 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 . 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 . The use of polymer-supported rhodium (I)-l,3-bis(diphenylphosphino)propane moieties for the heterogeneous hydrogenation of quinoline was also reported . A molecular O2/2methylpropanal system was used to prepare the N-oxide of 8-hydroxyquinoline . Conditions were also developed to oxidize 5,8-dimethoxy-2-methylquinoline to 2methylquinoline-5,8-dione using NBS and H2SO4 without bromination . 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 . The microwave assisted, solventfree synthesis of pyrazolo[3,4-b]quinolines from 2-chloro-3-formylquinolines and hydrazines was also reported . Additionally, intramolecular radical additions to quinolines were also studied . 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 . 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) (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 . 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 .

~ 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 . An intramolecular Pictet-Spengler reaction of an oxazolindino ester was reported to provide quaternary tetrahydroisoquinoline-3carboxylic acid derivatives in a highly asymmetric fashion . An AIC13 promoted cyclization of N-benzotriazolylmethyl-N-phenethylamines also proved useful in the preparation of optically active tetrahydroisoquinoline-3-carboxylic acid derivatives . 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 . Arylglycines were also used as templates in the synthesis of 3aryl- 1,2,3,4-tetrahydroquinolin-4-ols .

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 . 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


to transfer chirality from amino acids in the diastereoselective synthesis of 1benzyltetrahydroisoquinoline derivatives . On a related note, a study on the regioselectivity of the Pictet-Spengler reaction in the preparation of halotetrahydroisoquinolines was also reported . 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 . Similar perhydrobenzoxazines were used to prepare enantiopure 4-substituted tetrahydroisoquinolines as well via 6-exo radical cyclizations . 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 . A stereoselective synthesis of the tetrahydroisoquinoline moiety of the antitumor antibiotic tetrazomine was also reported .

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 . 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 . The photochemically induced preparation of 1-methyl-l,2,3,4tetrahydronaphtho[2,1-f]isoquinolines was also reported .

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 . 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 . 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% . Additionally, racemic isoquinoline alcohols were resolved using lipases in up to >99% ee .

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 . Additionally, benzo[a]quinolizine-4-thiones such as 89 were prepared by ring annulation of isoquinoline 88 with several acyclic and cyclic [3-oxodithioesters . 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 . 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 .

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 . Osipov, Dixneuf and co-workers synthesized 4-substituted piperidines 92 and 93 via a combination of ring opening and ring closing metathesis . The metathesis substrates 90 and 91 were constructed via an ene reaction.

270


OF3 ,,__Nz "CO2Me

----/-- 'PG

(CY3P)2Ru=CHPhCi2 . ~ ~ 4 ~ . / ~ f ~ < - C F3 ...... H I - . CO2Me CH2CI2, rt '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 ,. The resulting 3,4-unsaturated piperidines themselves can be further elaborated by taking advantage of the reactivity of the trisubstituted olefin . 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 . Lee and co-workers elaborated a simple 3,4unsaturated piperidine into a key intermediate employed in the construction of the potent gastrointestinal stimulant cisapride . Conjugate additions to unsaturated piperidinones constitute an important method for the stereoselective generation of piperidines . 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


developed an asymmetric Rh-catalyzed addition of arylboronic acids to dihydropyridinones such as 113 . 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. Liebeskind and coworkers have developed a chiral transition metal complex and have used it in the synthesis of (-)-indolizidine 209B . 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

REFERENCES

01AC(E)2337 01AC(I)2142 01ASC439 01BKCS799

K. Itami, K. Mitsudo, J.-i. YoshidaA,gew. Chem., h~t. Ed. 2001, 40, 2337. J.R. Nitschke, T.D. Tilley Angew. Chem., ha. Ed. 2001, 40, 2142. D. Sole, L. Vallverdu, J. Bonjoch Adv. Synth. Catal. 2001,343,439. Y.M. Chung, tI.J. Lee, S.S. Hwang, J.N. KimBulletin of the Korean Chemical Society 2001, 22,799.

O1BMC371 01BMCL2337 01CC1102 01CC1784 01CC2576 01CL526 01CPB407 01CPB721 01EJOC1267

H. Annoura, K. Nakanishi, M. Uesugi, A. Fukunaga, S. Imajo, A. Miyajima, Y. TamuraHorikawa, S. Tamura Bioorg. Med. Chem. 2001,10,371. A.K. Durra, M.C. Davis, M.E.A. Reith Bioorg. Med. Chem. Lett. 2001,11, 2337. Y. Yamamoto, S. Okuda, K. Itoh Chem. Commun. 2001, 1102. J. F. Hayes, M. Shipman, It. Twin Chem. Commun. 2001, 1784. C.S. Cho, B.T. Kim, T.-J. Khn, S.C. Shim Chern. Commun, 2001, 2576. H. Tsutsui, K. Narasaka Chem. Lett. 2001, 526. R. Fujita, K. Watanabe, T. Yoshisuji, I1. Matsuzaki, Y. tlarigaya, tI. Hongo Chem. Pharrn. Bull. 2001, 49,407. Y. Takeuchi, M. Koike, K. Azuma, II. Nishioka, ti. Abe, tt.-Y. Kim, Y. Wataya, T. Harayama Chem. Pharm. Bull. 2001,49, 721. I. Osante. M.I. Collado. E.l~ete. N. SotomavorEur. J. Ore.. Chem. 2001, 1267.

Six-Membered Rings: Pyridines and Benzo derivatives 01EJOC2115 01EJOC2513 01EJOC4343 01H105 01H741 01H1249 01H435 01H1439 01H1591 01H1703 01JA1817 01JA2719 01JA6801 01JA9908 01JA10784 01JA10935 01JA11829 01JA12477 01JA12510 01JCR(S) 108 01JCR(S)268 01JCS(P1)376 01JCS(P1)654 01JCS(P1)1435 01JCS(P 1) 1785 01JCS(P 1)2389 01JHC837 01JMC2499

01JMC3343

01JOC53 01JOC243 01JOC605 01JOC1049 01JOC1638 01JOC1992 01JOC2175 01JOC2862 01JOC3099 01JOC3133 01JOC3338 01 JOC3924 01JOC3970 01JOC4165 01JOC4214 01JOC5264 01JOC6305 01JOC6829 01JOC6852 01JOC8042 01JOC8744 01JOM359

275

F. Palacios, C. Alonso, G. Rubiales, J. M. Ezpeleta, Eur. J. Org. Chem. 2001, 2115. G. Sartori, F. Bigi, R. Maggi, A. Mazzacani, G. Oppici Eur. J. Org. Chem. 2001, 2513. E. Anakabe, J.L. Vicario, D. Badia, L. Carrillo, V. Yoldi Eur. J. Org. Chem. 2001, 4343. H. Tokuyama, M. Sato, T. Ueda, T. Fukuyama Heterocycles 2001, 54, 105. T. Hirota, K.-I. Tomita, K. Sasaki, K. Okuda, M. Yoshida, S. Kashino Heterocycles 2001, 55, 741. M. Karikomi, H. Tsukada, T. Toda Heterocycles 2001, 55, 1249. R. Fujita, N. Watanabe, H. Tomisawa Heterocycles 2001, 55, 435. M. Ishizaki, Y. Kasama, M. Zyo, Y. Nimi, O. Hoshino Heterocycles 2001, 55, 1439. K. Ishimaru, T. Kojima Heterocycles 2001, 55, 1591. A.R. Katritzky, T. Kurz, S. Zhang, M. Voronkov, P.J. Steel Heterocycles 2001, 55, 1703. R. Pedrosa, C. Andres, J.M. Iglesias, A. Perez-Encabo J. Am. Chem. Soc. 2001, 123, 1817. C. Dai, G.C. Fu J. Am. Chem. Soc. 2001, 123, 2719. M. Takamura, K. Funabashi, M. Kanai J. Am. Chem. Soc. 2001, 123, 6801. K. Yabu, S. Masumoto, S. Yamasaki, Y. Hamashima, M. Kanai, W. Du, D.P. Curran, M. Shibasaki J. Am. Chem. Soc. 2001, 123, 9908. K. Funabashi, H. Ratni, M. Kanai, M. Shibasaki J. Am. Chem. Soc. 2001, 123, 10784. N. Chatani, T. Asaumi, S. Yorimitsu, T. Ikdea, F. Kakiuchi, S. Murai J. Am. Chem. Soc. 2001, 123, 10935. A.B. Charette, M. Grenon, A. Lemire, M. Pourashraf, J. Martel J. Am. Chem. Soc. 2001, 123, 11829. C. Shu, A. Alcudia, J. Yin, L.S. Liebeskind J. Ant. Chem. Soc. 2001, 123, 12477. M. Sugiura, H. Hagio, R. Hirabayashi, S. Kobayashi J. Am. Chem. Soc. 2001, 123, 12510. Y. Ma, Y. Zhang J. Chem. Res. Synopses 2001, 108. J.-F. Zhou, S.-J. Tu, J.-C. Feng J. Chem. Res. Synopses 2001, 268. J.M. Bakke, H. Svensen, R. Trevisan J. Chem. Soc., Perkin 1 2001, 376. R.W. Bates, J. Boonsombat J. Chem. Soc., Perkin Trans. 1 2001, 654. T.J. Donohoe, A.J. McRiner, M. Helliwell, P. Sheldrake J. Chem. Soc., Perkin 1 2001, 1435. A.C. Spivey, A. Maddaford, D.P. Leese, A.J. Redgrave J.. Chem. Soc., Perkin 1 2001, 1785. J. R. Hanrahan, K.N. Mewett, M. Chebib, P.M. Burden, G.A.R. Johnston J. Chem. Soc., Perkin 1 2001, 2389. Alirio Paima R., S. Salas, V. Kouznetsov, E. Stashenko, Gisela Montenegro N., Angel Fontela G. J. Heterocyclic Chem. 2001, 38, 837. S. Pikul, N.E. Ohler, G. Ciszewski, N.C. Laufersweiler, N.G. Almstead, B. De., M.G. Natchus, L.C. Hsieh, M.J. Janusz, S.X. Peng, T.M. Branch, S.L. King, Y.O. Taiwo, G.E. Mieling J. Med. Chem. 2001, 44, 2499. J.R. Tagat, R.W. Steensma, S.W. McCombie, D.V. Nazareno, S.-I. Liu, B.R. Neustadt, K. Cox, S. Xu, L. Wojick, M.G. Murray, N. Vantuno, B.M. Baroudy, J.M. Strizki J. Med. Chem. 2001, 44, 3343. W. Aelterman, N. D. Kimpe, V. Tyvorskii, O. Kulinkovich J. Org. Chem. 2001, 66, 243. R. Pedrosa, C. Andres, J.M. Iglesias J. Org. Chem. 2001, 66,243. J.J. Song, N.K. Yee J. Org. Chem. 2001, 66, 605. M.J. McLaughlin, R.P. Hsung J. Org. Chem .2001, 66, 1049. E. I. Kostik, A. Abiko, A. Oku, J. Org. Chem. 2001, 66, 1638. V. Derdau, V. Snieckus J. Org. Chem. 2001, 66, 1992. J.A. Nieman, M.D. Ennis J. Org. Chem., 2001, 66, 2175. A.R. Katritzky, G. Qiu J. Org. Chem. 2001, 66, 2862. K. Tanaka, H. Mori, M. Yamamoto, S. Katsumura J. Org. Chem. 2001, 66, 3099. P. Wipf, C.R. Hopkins J. Org. Chem. 2001, 66, 3133. T. Ozawa, S. Aoyagi, C. Kibayashi J. Org. Chem.2001, 66, 3338. T. Okauchi, T. Tanaka, T. Minami J. Org. Chem. 2001, 66, 3924. K. Itami, T. Kamei, K. Mitsudo, T. Nokami, J. Yoshida, J. Org. Chem. 2001, 66, 3970. M. Erdelyi, A. Gogoll J. Org. Chem. 2001, 66, 4165. J. Pawlas, P. Vedso, P. Jakobsen, P.O. Huusfeldt, M. Begtrup J. Org. Chem. 2001, 66, 4214. B. Zacharie, M. Moreau, C. Dockendorff J. Org. Chem. 2001, 66, 5264. F.-X. Felpin, S. Girard, G. Vo-Thanh, R.J. Robins, J. Villieras, J. Lebreton J. Org. Chem. 2001, 66, 6305. D.L. Comins, M.J. Sandelier, T.A. Grillo J. Org. Chem. 2001, 66, 6829. T. Senda, M. Ogasawara, T. Hayashi J. Org. Chem. 2001, 66, 6852. K.R. Roesch, H. Zhang, R.C. Larock J. Org. Chem. 2001, 66, 8042-8051. S. Adam, X. Pannecoucke, J.-C. Combret, J.-C. Quirion J. Org. Chem. 2001, 66, 8744-8750. K. Pachamuthu, Y.D. Vankar J. Organomet. Chem. 2001, 624, 359-363.

276 01NNN1067

01OL201 01OL209 01OL229 01OL445 01OL469 01OL611 01OL631 01OL671 010L759 010L769 010L877 010L941 010L997 01OLl109 01OL1351 01OL1973 01OL2053 01OL2109 01OL2117 01OL2133 01OL2317 01OL2383 01OL2625 01OL2807 01OL2973 01OL2985 01OL3157 01OL3169 01OL3217 01OL3349 01OL3381 01OL3483 01OL4035 01OM2454 01OM2660 01Sl185 01S1351 01S1716 01S2495 01SC167 01SC987

D.S. Coffey, S.P. Kolis and S.A. May P.W. Shum, N.P. Peet, P.M. Weintraub, T.B. Le, Z. Zhao, F. Barbone, B. Cashman, J. Tsay, S. Dwyer, P.C. Loos, E.A. Powers, K. Kropp, P.S. Wright, A. Bitonti, J. Dumont, D.R. Borcherding Nucleotides, Nucleosides and Nucleic Acids 2001,20, 1067-1078. G. Zhao, U. C. Deo, B. Ganem, Org. Lett, 2001, 3,201. I. W. Davies, J. -F. Marcoux, P. J. Reider, Org.Lett, 2001, 3,209. A. Roy, S. Nandi, H. lla, J. Junjappa Org. Lett, 2001, 3,226-232. D.W. Kim,,ll.Y. Choi, K-.L. Lee, D.Y. Chi Org. Lett., 2001, 3,445-447. D.L. Comins, S. Huang, C.L. McArdle, C.L. Ingalls Org. Lett. 2001, 3,469. M. amat, M. Perez, N. Lior, J. Bosch, E. Lago, E. Molins Org. Lett. 2001,3,611. T. Honda, H. Namika, F. Satoh Org. Lett., 2001, 3, 631. 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. F. A. Davis, H. Zhang, S .H. Lee Org. Lett. 2001, 3,759. D.L. Comins, A.-C. Hiebel, S. Huang Org. Lett. 2001, 3,769. X. S. Sun, P. Janvier, G. Zhao, tI. Bienaymr, J. Zhu Org. Lett. 2001, 3,877. T. Rispens, J. B. F. N. Engberts, Org.Lett. 2001,3,941. A. Zawadzka, A. Leniewski, J.K. Maurin, K. Wojtasiewicz, Z. Czarnocki Org. Lett., 2001, 3, 997. H. Amii, Y. Kishikawa, K. Uneyama Org. Lett. 2001, 3, 1109. J. A. Arterburn, K. V. Rao, R. Ramdas, B. R. Dible, Org. Lett. 2001, 3, 1351. G. Sundararajan, N. Prabagaran, B. Varghese Org. Lett. 2001, 3, 1973. I. Gallou-Dagommer, P. Gastaud, T.V. RajanBabu Org. Lett. 2001, 3, 2053. M.D.B. Fenster, B.O. Patrick, G.R. Dake Org. Lett. 2001, 3, 2109. Y. Yamamoto, H. Takagishi, K. Itoh Org. Lett. 2001, 3, 2117. M.P.S. Ishar, K. Kumar, S. Kaur, S. Kumar, N. K. Girdhar, S. Sachar, A. Marwaha, A. Kapoor, Org. Lett. 2001, 3, 2133. M. G. Bursavich, C.W. West, D.tI. Rich Org. Lett. 2001, 3, 2317. N. Prevost, M. Shipman Org. Lett. 2001, 3, 2383. M.G. Bursavich, D.H. Rich Org. Lett. 2001,3, 2625. A. R. Katritzky, S. Zhang, T. Kurz, M. Wang, Org.Lett. 2001, 3, 2807. Q. Huang, J.A. Hunter, R.C. Larock Org. Lett. 2001,3, 2973. G. Kim, S.-d. Jung, W.-j. Kim Org. Lett. 2001,3, 2985. M. Adamczyk, S .R. Akireddy, R.E. Reddy Org. Lett. 2001, 3, 3157. F. A. Davis, B. Chao, A. Rao Org. Lett. 2001, 3, 3169. D.L. Comins, A.L. Williams Org. Lett. 2001, 3, 3217. J.R. Fuchs, R.L. Funk Org. Lett. 2001, 3, 3349. R.G. Arrayas, A. Alcudia, L.S .Liebeskind Org. Lett. 2001, 3, 3381. S. Liras, M.P. Allen, J.F. Blake Org. Left. 2001,3, 3483. G. Dai, R.C. Larock Org. Lett. 2001, 3, 4035. J.W. Failer, B.J. Grimmond Organometallics 2001,20, 2454. C. Bianchini, M. Frediani, G. Mantovani, F. Vizza Organometallics 2001, 20, 2660. K.F. McGee, Jr., T.H. Al-'I'el, S.M.Sieburth Synthesis 2001, 1185. N.J. Tom, E.M. Ruel Synthesis 2001, 1351. T. Ooi, M. Takeuchi, K. Maruoka Synthesis 2001, 1716. M.-D. Le Bas, C. Gueret, C. Perrio, M.-C. Lasne, L. Barre Synthesis 2001, 2495. R.S. Dongre, T.V. Rao, B.K. Sharma, B. Sain, V.K. Bhatia Synth. Commun. 2001, 31,167. J. Meneyrol, P. [Ielissey, C. Tratrat, S. Giorgi-Renault, It.-P. Husson Synth. Commun. 2001,

31,987. 01SC1081 01SC2625 01SC3647 01SL240 01SL621 01SL1050 01SL1329 01SL1569 01SL1575 01SL1596 01T109

B.J. Kim, D.K. Pyun, H.J. Jung, H.J.Kwak, J.t-I. Kim, E.J. Kim, W.J.Jeong, C.H. Lee Synth. Commun. 2001,31, 1081. J. Lu, Y. Bai, Z. Wang, B. Yang, W. Li Synth. Cortzrnttn. 2001, 31, 2625. M.S. Khajavi, A.A. Mohammadi, S .S .S. Hosseini Synth. Commun. 2001, 31,3647. J.S. Yadav, B.V.S. Reddy, R. Srinivas, C. Madhuri, T. Ramalingam Synlett 2001, 240-242. S.N. Osipov, N.M. Kobelikova, G.T. Shchetnikov, A.F., Kolomiets, C. Bruneau, P.H.Dixneuf Synlett 2001, 621. J. Wu, H. Chen, Z.-Y. Zhou, C.H. Yeung, A.S.C. Chan Synlett 2001, 1050. J. Desire, P.J. Dransfield, P.M. Gore, M.Shipman Synlett 2001, 1329. M. Follman, A. Rosch, E. Klegraf, tt. Kunz Synlett 2001, 1569. J. Cossy, O. Mirguet, D.G. Pardo Synlett 2001, 1575. S.J. Hedley, W.J. Moran, A.H.G.P. Prenzel, D.A. Price, J.P.A. Harrity Synlett 2001, 1596. R. Yamaguchi, T. Nakayasu, B. Ilatano, T. Nagura, S. Kozima, K.-I. Fujita Tetrahedron 2001, 57, 109.

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 . 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 . 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 . 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]

.~.. 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 . 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 .

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 . 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 . 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 . The synthesis and spectral characterization of organotin(IV) 1,3,5-triazine2,4,6-trithiolato complexes have been reported . Transition metal complexes of 2,4,6-trimercapto-l,3,5-triazine (TMT) as potential precursors to nanoparticulate metal sulfides have been described . A family of receptors for flavins based on 6aryl-2,4-acyldiamino-l,3,5-triazines has been synthesized . Thermodynamic stabilities of linear and crinkled tapes and cyclic rosettes in melamine-cyanurate assemblies have been studied . An in-situ fluorescent labelling probe of highly volatile methylamine with 8-(4,6-dichloro- 1,3,5-tri azinoxy)quinoline has been designed . 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 . 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 . 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 .

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 . 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 . An efficient and enantioselective synthesis of 1,2,4-triazine substituted c~-amino acids from vicinal tricarbonyls has been reported . Ring closure reactions of thiosemicarbazide derivatives and aryl, alkylketones yielded 2,5-substituted 3-thiol-l,2,4-triazines . 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 . 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 . 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 .

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 . 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 . 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 . 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 . 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 . 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 . 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 . The synthesis of thirteen tris(azol-l-yl)-l,3,5triazines, as a new class of multidentate ligands, has been described . Tris(pyrazolyl-l,3,5-triazines) 14 have been prepared by cyclotrimerization of aromatic nitriles, in piperidine and in solvent-free conditions .

~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 . Triazapentadienium iodides are efficient intermediates in heterocyclic synthesis. They react with aryl isocyanates or isothiocyanates to give oxo and thioxo-triazine derivatives . 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

. 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 . 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 .

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 .

(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 .

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


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 . 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 . 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 . 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 .

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 . 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 .

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 . Substituted 1,3,5-triazines and pyrimidines have been prepared from 1,3,5-triazine and lithium amidinate, alkyl- or 1-azaallyllithium . 2-Amino-4,5-dichloro1,3,5-triazines have been used as starting material to obtain a melamine-barbituric acid dye assembly and macrocyclic triazine-based receptor molecules . 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 . 2,4,6-Trichloro-l,3,5-triazine has been used as starting material to obtain new cyclic peptidomimetics , chiral building blocks for a bifunctional system , dendrimers based on melamine , 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 . 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 . 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 . Reactions of perhydro-l,3,5-triazin2,4,6-triones to give several 1,2-mercaptoalkyl substituted derivatives have been described . Some reactions from hexachlorocyclophosphazanes to give crown-ethers bearing chlorocyclophosphazane subunits , , hexasubstituted cyclotri-phosphazanes, under microwave assisted methods , and nickel(II) complexes as antifungal agents , 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 .

316

Me-

M


+

~--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 .

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 . 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 . The X-ray crystal structure of 3,6-bis(2-pyridinio-l,2,4,5-tetrazine diperchlorate has been published . Dicopper (I) complexes with reduced states of 3,6-bis(2'-pyrimidyl)-l,2,4,5tetrazine have been described . 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 . A comparative density functional study in tetrazines and tetraphosphorins and related compounds has been carried out . Electrochemical vs photo-induced electron transfer has been studied in tetrazine bridged osmium dimers . 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 .

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 . 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 . 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 . 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) . 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 . 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 . 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 . The second paper documents the synthesis of spiro(2,6-diphenylpiperidine-thiazolo[3,2-b]l,2,4,5-tetrazines) .

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 . 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 . 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 . 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 . 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 . In the second, (N-l, NH 2, '5N-2) and (N-I, N-3, NH 2, 15N-3) labelled adenines have been reported .

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 and 3-aroyl-pyrazolo[5, l-c][ 1,2,4]triazines have been prepared . 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 . 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 . 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 . 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 .

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 .

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 . 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 .

320


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 . 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 . The synthesis and biological evaluation of purine containing butenolides have been reported . New substituted purines, obtained from 4,5-diaminopyrimidines and 1,3-diketones have been described . A facile synthesis of 6-cyano-9-substituted-9H-purines and their ring expansion to pyrimidino[5,4-d]pyrimidines have been described . 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 . 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 . 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 .

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 . 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 .

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 . 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 , with an N-acylamido group at the 5'-position of the phenyl ring , and monagra, a chiral 5-(2methyl-2,3-dihydro-7-benzofuryl)pyrazolo-pyrimidone . 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 . A facile one pot synthesis of this system has also been reported . 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 . 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 . 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


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 . 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 . In a report dealing with corticotropin-releasing hormone receptor agonists, 2,7-dimethylthiazolo[4,5-d]pyridazine-4-(5H)-thione has been described . 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 . A series of 1,3,4-oxathiadiazol-2-yldihydrothiazolo[4,5-d]pyrimidine-5(H)thiones has been synthesized . 6.3.3.2 Reactions

A Mannich reaction of imidazo[4,5-d][1,2,3]triazine aminomethyl derivative 72 . 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 , and alkylation of some purine derivatives using microwaveassisted methods have been reported . 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 . A novel solid-phase preparation of 2,6,9-trisubstituted purines for combinatorial library generation has been reported . A concise and traceless linker strategy towards combinatorial libraries of 2,6,9-substituted purines has been reported . 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 . 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 , and to study the use of different palladium reagents in attempts to prepare 2-alkynyl substituted purines . 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 . 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 . 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 . 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 . 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 . Further reports concerning rcactivity of purines included a new Sandmeyer iodination of 2-aminopurines in non-aqueous conditions . 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 . 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 . 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 . 6-Amidino-2-oxopurines underwent a rearrangement in the presence of acetic acid and DMF to give pyrimido[5,4-d]pyrimidin-2-ones . Reaction of 8-chlorotheophylline and hydrazone derivatives, in a simple one pot synthesis, afforded novel 1,2,4-triazolo[3,4-d]purines . Condensation of 8-hydrazinotheophylline with appropriate glyoxylic acids yielded 3-substituted-l,2,4triazino-[ 3,4-f]purine-4,6,8-trione derivatives .

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 . Identification of (6R)-5,6,7,8-tetrahydro-D-monapterin as the native pteridine in Tetrahymena pyriformis has been reported . A novel modified pterin has been isolated from

324


the Eustidoma species ascidian . 7,8-Dihydropterin-6-carboxylic acid has been identified as the light emitter of the luminous milliped, Luminodesmus sequoiae .

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 .

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 .

/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 . Cyclization of 4,4-dimethylhydropyridazine-3,6-dione 3-hydrazones with esters of keto dicarboxylic acids yielded tetrahydropyridazinotriazinones . The synthesis of some new biologically active triazinothiadiazinones has been reported . The synthesis and biological study of 6-polyhydroxyalkylpteridines have been described . The synthesis of bicyclic pyrimidine derivatives as ATP analogues, among them tetrahydropteridines and pyrimidopiperazines, has been reported . Several reports dealing with the preparation of pyrido[2,3-d]pyrimidine derivatives have been published , , , using microwaves under solvent free conditions , , as analogues of antifolates , and as a orally active non-nucleoside adenosine kinase inhibitors . A facile one pot synthesis of pyrimido[4,5-d]pyrimidines and pyrido[2,3-d]pyrimidines has been reported . 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 . 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 . 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 . 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 . The synthesis of phosphoramidate building blocks of isoxanthopterin N-8-(2'-deoxy-[3-D-ribonucleosides) has been reported . 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 . 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 . 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 .

326


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 and selective A, adenosine receptor antagonists , have been reported. 2-Cyanoethanethioamide has been used in heterocyclic synthesis to obtain pyridopyrazolo[1,2,4]triazine derivatives . Polycyclic derivatives containing naphthalenotriazolotriazinum salts have been synthesized as inhibitors of reverse transcriptase and of the efflux pump . The syntheses of bis(1,3,4thiadiazolo)-l,3,5-triazinium halides , bis(isoquinolo)-l,3,5-triazinium iodide derivatives, bis(benzothiazolo)-l,3,5-triazinium iodide derivatives, and bis(pyrido)-l,3,5triazinium iodide derivatives 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 .

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 . The synthesis of new heterocondensed pteridines has been reported .

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 .

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

A. Mc Cluskey, M. Finn, M. Bowman, R. Smith, P.A. Keller, Aust. J. Chem. 2000, 53, 905. S.A. Nassar, J. Chem. Soc. Pakistan, 2000, 22, 229. G.L. Rusinov, R.I. Ishmetova, I.S. Selezneva, T.A. Kalugina, Russ. J. Org. Chem. 2000, 36, 873. E.N. Utkina, A.A. Michurin, A.V. Shishulina, Russ. J. Org. Chem. 2000, 36, 1229. M.M. Heravi, Y.S. Beneshtiha, R.H. Shoar, N.Nami, Phosphorus Sulfur Silicon 2000, 165, 205. B.A. Nadkarni, V.R. Kamat, B.G. Khadse, Ar~eim.-Forsch. 2001, 51,569. D. Sharpies, G. Hajos, Z. Rield, D. Csanyi, J. Molnar, D. Szabo, Arch. Pharm. (Weinheim, Ger.) 2001, 334, 269. H. Liu, D. Miao, X.H. Bu, Acta Crystallogr. Sect. E 2001, 127. A.K. Terami, A. Mishra, Bioorg. Med. Chem. 2001, 9, 715. T. Kumagai, T. Okubo, H. Kataoka-Okubo, S. Chaki, S. Okuyama, A. Nakazato, Bioorg. Med. Chem. 2001, 9, 1357. D.-K. Kim, N. Lee, J.Y. Lee, D.H. Ryu, J.-S. Kim, S.-H. Lee, J.-Y. Choi, K. Chang, Y.-W. Kim, G.-J. Im, W.-S, Choi, T.-K. Kim, J.-H. Ryu, N.-H Kim, K. Lee, Bioorg. Med. Chem. 2001, 9, 1609. D.-K. Kim, D.H. Ryu, N. Lee, J.Y. Lee, J.-S. Kim, S. Lee, J.-Y. Choi, J.-H. Ryu, N.-H Kim, G.-J. Im, W.-S, Choi, T.-K. Kim, Bioorg. Med. Chem. 2001, 9, 1895. M. Kuse, A. Kanakubo, S. Suwan, K. Koga, M. Isobe, O. Shimomura, Bioorg. Med. Chem. Lett. 2001, 11, 1073. D.W. Ludovici, R.W. Kavash, M.J. Kukla, C.Y. Ho, H. Ye, B.L. De Corte, K. Andries, M.-P. de B6thune, H. Azijn, R. Pauwels, H.E.L. Moereels, J. Heeres, L.M.H. Koymans, M.R. de Jonge, K. J.A. Van Aken, F.F.D. Daeyaert, P.J. Lewi, K. Das, E. Arnold, P.A. Janssen, Bioorg. Med. Chem. Lett. 2001, 11, 2229. B. Bradshaw, D. Collison, C.D. Garner, J.A. Joule, J. Chem. Soc., Chem. Commun. 2001, 123. G. Love, C. Carr, R. Quarrell, Chem. Commun. 2001, 737. D.M. Bassani, X. Sallenave, V. Darcos, J.P. Desvergne, Chem. Commun. 2001, 1446. L.S. Shimizu, M.D. Smith, A. D. Hughes, K.D. Shimizu, Chem. Cornmun. 2001, 1592. F. Rivals, A. Steiner, Chem. Commun. 2001, 2104. E.C. Constable, C. Edwin, C. E. Housecroft, B.M. Kariuki, M. Benson, N. Kelly, C.B. Smith, Chem. Commun. 2001, 2134. F. Wurthner, S. Yao, B. Heise, C. Tschierske, Chem. Commun. 2001, 2260. K. Kim, B.B. Wang, Chem. Commun. 2001, 2268. M. Saeed, R.J. Abdeljalil, W. Voelter, M.M. Elabedelah, Chem. Lett. 2001, 660. J.M. Quintela, C. Peinador, M.J. Moreire, A. Alfonso, L.M. Botana, R. Riguera, Eur. J. Med. Chem. 2001, 36, 321. J. Sauer, G.R. Pabst, U. Holland, H. S. Kim, S. Loebbecke, Eur. J. Org. Chem. 2001, 697. L.M. Yagupolskii, V. Svetlana, V. Shelyazhenko, I.I. Maletina, V.N. Petrik, E.B. Rusanov, A.N. Chernega, Eur. J. Org. Chem. 2001, 1225. J. Sauer, P. Bauerlein, W. Ebenbeck, C Gouseties, H. Sichert, T. Troll, F. Utz, U. Wallfahrer, Eur. J. Org. Chem. 2001, 2629. J. Sauer, P. Bauerlein, W. Ebenbeck, R. Dyllickbrenzinger, C Gouseties, H. Sichert, T. Troll, U. Wallfahrer, Eur. J. Org. Chem. 2001, 2639. D.W.P.M. Lowik, C. R. Love, Eur. J. Org. Chem. 2001, 2825. A. Iuliano, E. Attolino, P. Salvadori, Eur. J. Org. Chem. 2001, 3523. T. Sugimoto, K. Ikemoto, S. Murata, M. Tazawa, T. Nomura, Y. Hagino. H. Ichinose, T. Nagatsu, A. Wada, Heterocycles 2001, 54, 283.

328 01H(54)291 01H(54)461 01H(55)127 01H(55)905 01H(55) 1679 01H(55)1789 01HCA918 01HCA2330 01IC2256 01IC2263 01IJC(A)893 01IJC(B)191

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

H. Rodrfguez, R. P6rez, M. Su~irez, A. Lam, N. Cabrales, A. Loupy, Heterocycles 2001, 54, 291. N. Ozeki, N, Shimomura, H. Harada, Heterocycles, 2001, 54, 461. A. Rykowski, O.N. Chupakin, D.N. Kozhevnikov, V.L. Rusinov, H.C. Van der Plas, Heterocycles 2001, 55, 127. V. Milata, R.M. Claramunt, P. Cabildo, M.D. Santa Maria, P. Cornago, L. Infantes, F.H. Cano, J. Elguero, Heterocycles 2001, 55, 905. F. Schonfeld, R. Troschutz, Heterocycles, 2001, 55, 1679. N.R. Albojuk, M.M. Elabadelah, S.S. Sabri, A. Michel, W. Voelter, C.M. Mossmer, Y. Alabed, Heterocycles 2001, 55, 1789. T. Sugimoto, K. Ikemoto, S. Murata, M. Tazawa, T. Nomura, Y. Hagino. H. Ichinose, T. Nagatsu, Helv. Chim. Acta 2001, 84, 918. J. Lehbauer, W. Pfleiderer, Heir. Chim. Acta 2001, 84, 2330. M. Gloeckle, K.W. Markus, A. Klein, E. Roduner, G. Huebner, S. Zalis, J. van Slageren, F. Renz, P. Guetlich, Inorg. Chem. 2001, 40, 2256. M. Gloeckle, K. Huebler, H.-J. Kuemmerer, G. Denninger, W. Kaim, Inorg. Chem. 2001, 40, 2263. B.P. Baranwal, S.S. Das, U. Farva, Indian J. Chem. (A) 2001, 40, 893. K. Srinivas, P.S. Rao, B. Narsaiah, J.M. Rao, Indian J. Chem. (B) 2001, 40, 191. J. Hazarika, J.C.S. Kataky, Indian J. Chem. (B) 2001, 40, 255. J. Mohan, Anupama, Indian J. Chem. (B) 2001, 40, 368. B.S. Holla, R. Gosalves, B.K. Sarojini, S. Shenoy, Indian J. Chem. (B) 2001, 40, 475. P. Upadhyay, H. Joshi, J. Upadhyay, A.J. Baxi, A.R. Parikh, Indian J. Chem. (B) 2001, 40, 500. J. Mohan, Indian J. Chem. (B), 2001, 40, 584. J.B. Shah, P.M. Patel, S.K. Patel, K.C. Patel, Indian J. Chem. (B) 2001, 40, 729. T. Kawasaki, M. Tokuhiro, N. Kimizuka, T. Kunitake, J. Am. Chem. Soc 2001, 123, 6792. A.G. Bielejewska, C.E. Marjo, L.J. Prins, P. Timmerman, F. Dejong, D.N. Reinhoudt, J. Am. Chem. Soc 2001, 123, 7518. D.L. Boger, J.Y. Hong, J. Am. Chem. Soc 2001, 123, 8515. W. Zhang, D.T. Nowland, L.M. Thomson, W.M. Lackowski, E.E. Simanek, J. Am Chem. Soc 2001, 123, 8914. A. Gopalsarny, H. Yang, J. Comb. Chem. 2001, 3, 278. E.S.H. Elashry, N. Rashed, L.F. Awad, A.A.H. Abdelrahman, H.A. Rashed J. Chem. Res. (S) 2001, 129. A.K. Singh, J. Sooriyakumar, M. Kadarkaraisamy, J.E. Drake, M.B. Hursthouse, M.E. Light, R.J. Butcher, J. Chem. Res. (S) 2001, 339. Y.A. Allam, R.H. Swellem, G.A.M. Nawwar, J. Chem. Res. (S) 2001, 342. S.M. Agarny, J. Chem. Res. (S) 2001, 349. T. Nagamatsu, H. Yamasaki, J. Chem. Soc., Perkin Trans. 1 2001, 130. R.M. Adlington, J.E. Baldwin, D. Catterick, G.J. Pritchard, J. Chem. Soc., Perkin Trans. 1 2001, 668. W.M. Boesveld, P.B. Hitchcock, M.F. Lappert, J. Chem. Soc., Perkin Trans. 1 2001, 1103. , B.L. Booth, I.M. Cabral, A.M. Dias, A.P. Freitas, A.M.M. Beja, M.F. Proenca, M.R. Silva, J. Chem. Soc., Perkin Trans. 1 2001, 1241. G. Andresen, A. B. Eriksen, B. Dalhus, L.L. Gundersen, F. Rise, J. Chem. Soc., Perkin Trans. 1 2001, 1662. A. Alazmi, B.L. Booth, R.A. Carpenter, A. Carvalho, E. Marrelec, R.G. Pritchard, M.F.J.R.P. Proenca, J. Chem. Soc., Perkin Trans. 1 2001, 2532 J. Arrowsmith, S.A. Jennings, D.A.F. Langnel, R.T. Wheelhouse, M.F.G. Stevens, J. Chem. Soc., Perkin Trans. 1 2001, 4432. V.N. Charushin, E.V. Nosova, G.N. Lipunova, M.I. Kodess, J. Fluorine Chem. 2001, 110, 25. C. Landreau, D. Deniaud, A. Reliquet, F. Reliquet, J.C. Meslin, J. Heterocycl. Chem. 2001, 38, 93. T. Ueda, N. Yatsuzuka, S. Nagai, K. Okada, E. Takeichi, H. Segi, J. Sakakibara J. Heterocycl. Chem. 2001, 38, 141. M. Legraverend, O. Ludwig, S. Leclerc, L. Meijer, J. Heterocycl. Chem. 2001, 38, 299. C.G. Dave, K.J. Patel, J. Heterocycl. Chem. 2001, 38, 457. P.J. Bhuyan, H.N. Borah, K.C. Lekhok, J. S. Sandhu, J. Heterocycl. Chem. 2001, 38, 491. F. Dasettimo, A.M. Marini, G. Pardi, G. Primofiore, S. Salerno, F. Simorini, J. Heterocycl. Chem. 2001, 38, 607.

Six-Membered Ring Systems:Triazines, Tetrazines and Fused Ring Polyaza Systems 01JHC711 01JHC727

329

A.A. El Barbary, M.A. El Badawi, Y.M. Loksha, J. Heterocycl. Chem. 2001, 38, 711. M.D. L6pez, M.L. Quijano, A. S~inchesz, M. Nogueras, J. N. Low, J. Heterocycl. Chem. 2001, 38, 727. 01JHC877 K. Wejroch, J. Lange, J. Karolakwojciechowska, J. Sosnicki, T. Jagodzinski, A. Kielak, J. Heterocycl. Chem. 2001, 38, 877. 01JHC901 O.N. Chupakin, G.L. Rusinov, D.G. Beresnev, V.N. Charushin, H. Neunhoeffer, J. Heterocycl. Chem. 2001, 38, 901. 01JHC929 H.J. Shi, H.X. Shi, Z.Y. Wang, J. Heterocycl. Chem. 2001, 38, 929. 01JHC1097 S. Nagai, S. Takemoto, T. Ueda, K. Mizutani, Y. Ouzumi, H. Tokuda, J. Heterocycl. Chem. 2001, 38, 1097. 01JHCll73 A.Z.M.S. Chowdhury, Y. Shibata, M. Morita, K, Kaya, K. Hiratani, J. Heterocycl. Chem. 2001, 38, 1173. 01JMC47 D. Che, T. Wegge, M.T. Stubbs, G. Seitz, H. Meier, C. Methfessel, J. Med. Chem. 2001, 44, 47. 01JMC170 H. Harada, O. Asano, Y. Hoshino, S. Yosihikawa, M. Matsukura, Y. Kabasawa, J. Niijima, Y. Kotake, N. Watanabe, T. Kawata, T. Inoue, T. Horizoe, N. Yasuda, H, Minami, K. Nagata, M. Murakami, J. Nagaoka, S. Kobayashi, I. Tanaka, S. Abe, J. Med. Chem. 2001, 44, 170. 01JMC316 F. Da Settimo, G. Primifiore; S. Taliani, A.M. Marini, C. La Motta, E. Novellino, G. Greco, A. Lavecchia, L. Trincavelli, C. Martini, J. Med. Chem. 2001, 44, 316. 01JMC524 M.K. Dreyer, D.R. Borcherding, J.A. Dumont, N.P. Peet, J.T. Tsay, P.S. Wright, A.J. Bitonti, J. Shen, S.H. Kim, J. Med. Chem. 2001, 44, 524. 01JMC1749 G.H. Hakimelahi, N.W. Mei, A.A. Moosavimovahedi, H. Davari, S. Hakimelahi, K.Y. King, J.R. Hwu, Y.S. Wen, J. Med. Chem. 2001, 44, 1749. 01JMC2133 C.H. Lee, M.Q. Jiang, M. Cowart, G. Gfesser, R. Perner, K.H. Kim, Y.G. Gu, M. Williams, M.F. Jarvis, E.A. Kowaluk, A.O. Stewart, S.S. Bhagwat J. Med. Chem. 2001, 44, 2133. 01JMC3440 B. Klenke, M. Stewart, M.P. Barret, R. Brun, I.H. Gilbert, J. Med. Chem. 2001, 44, 3440. 01JMC3925 N.P. Jensen, A.L. Ager, R.A. Bliss, C. J. Canfield, B.M. Kotecka, K.H. Rieckmann, J. Terpinski, D.P. Jacobus, J. Med. Chem. 2001, 44, 3925. 01JMC4359 F. Da Settimo, G. Primifiore; A. Da Settimo, C. La Motta, S. Taliani, F. Simorini, E. Novellino, G. Greco, A. Lavecchia, E. Boldrini, J. Med. Chem. 2001, 44, 4359. 01JNPI1100 R.M. Vanwagoner, J. Jompa, A. Tahir, C.M. Ireland, J. Nat. Prod. 2001, 64, 1100. 01JOC507 D. Scharn, L. Germeroth, J. Schneider Mergener, H, Wenschuh, J. Org. Chem. 2001, 66, 507. 01JOC1310 K.S. Huang, M.J. Haddadin, M.M. Olmstead, M.J. Kurth, J. Org. Chem. 2001, 66, 1310. 01JOC4055 A.S. Shawali, M.A.N. Mosselhi, N.M. Tawfik J. Org. Chem. 2001, 66, 4055. 01JOC4776 M.T. Migawa, L.B. Townsend, J. Org. Chem. 2001, 66, 4776. 01JOC5146 N. Valiaeva, D. Bartley, T. Konno, J.K. Coward, J. Org. Chem. 2001, 66, 5146. 01JOC5463 A. Laxer, D.T. Major, H.E. Gottlieb, B. Fischer, J. Org. Chem. 2001, 66, 5463. 01JOC5655 J.Q. Liu, C. Kolar, T.A. Lawson, W.H. Gmeiner, J. Org. Chem. 2001, 66, 5655 01JOC5701 K. Brandt, M. Siwy, I.P. Czomperlik, J. Silberring, J. Org. Chem. 2001, 66, 5701. 01JOC5783 G.M. Makara, W. Ewing, Y. Ma, E. Witner, J. Org. Chem. 2001, 66, 5783. 01JOC6472 M.L. Jain, Y.P. Tsao, N.L. Ho, J.W. Cheng, J. Org. Chem. 2001, 66, 6472. 01JOC6797 A.R. Katritzky, B.V. Rogovoy, V.Y. Vedensky, N. Herbert, B. Forood, J. Org. Chem. 2001, 66, 6797. 01JOC8273 S. Ding, N.S. Gray, Q. Ding, P.G. Schultz, J. Org. Chem. 2001, 66, 8273. 01JOC8436 B.L. Booth, A.M. Dias, M.F. Proenka, M.E.A. Zaki, J. Org. Chem. 2001, 66, 8436. 01JOC8528 J. Valenciano, E. S~inchez Pav6n, A.M. Cuadro, J.J.Vaquero, J. Alvarez Builla, J. Org. Chem. 2001, 66, 8528. 01JOM(623)185 J.R. Bailey, M.J. Hatfield, K.R. Henke, M.K. Krepps, J.L. Morris, T. Otieno, K.D. Simonetti, E. A. Wall, D.A. Atwood, J. Organomet. Chem. 2001, 623,185. 01JOM(627)6 I. Hiaduc, M.F. Mahon, K.C. Maloy, M.M. Venter, J. Organomet. Chem. 2001, 627, 6. 01JOM(634)47 O. Blacque, H. Brunner, M.M. Kubicki, J.C. Leblanc, W. Meier, C. Moise, Y. Mugnier, A. Sadorge, J. Wachter, M. Zabel, J. Organomet. Chem. 2001, 634, 47. 01JPC(B)8829 R.J. Forster, T.E. Keyes, J. Phys. Chem. (B) 2001, 105, 8829. 01JST(567)59 A. Skancke, J.F. Liebman, J. Mol. Struct. 2001, 567-568, 59. 131M959 M.A. Abdallah, Monatsh Chem. 2001, 132,959. 01MI19 T. Komatsu, Macromol. Chem. Phys. 2001, 202, 19. 01MI194 M.A. Ischenko, V.D. Nikolaev, A.A. Sokolov, S.V. Nikolaeva, Russ. J. Org. Chem. 2001, 37, 194. 01MI219 V.R. Venkataraman, K.S. Ali, Indian J. Heterocycl. Chem. 2001, I0, 219. 01MI353 R.N. Warrener, P.A. Harrison, Molecules, 2001, 6, 353. 01MI459 Y. Gama, I. Shibuya, M. Shimizu, M. Goto, J. Carbohydr. Chem. 2001, 20, 459.

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 and anthocyanins and other flavonoids have been published. The stereoselective synthesis of axially chiral natural products using biaryl lactones and applications of the pyrolysis of 2,2-dimethyl-l,3-dioxan-4,6-dione (Meldrum's acid) in synthesis have been discussed. A review of the 13-alkyl Suzuki-Miyaura cross-coupling reaction contains examples of pyran ring formation . Diphosphine ligands with a xanthene backbone for use in transition metal catalysts and molecular switches and motors based on thiopyran-l'-ylidene-9H-thioxanthones have been reviewed. Total syntheses of several macrolides have been reported, including (+)-phorbazole A and (+)-zampanolide , both of which construct the cis-2,6disubstituted tetrahydropyran using a Petasis-Ferrier rearrangement. Three total syntheses , , and a partial synthesis of the microtubule-stabilising anticancer agent (-)-laulimalide have been disclosed. Apoptolidin, a macrolide which induces apoptosis of rat glia cells, has been synthesised , as has its aglycon, apoptolidinone . Total syntheses of the spiroketal macrolide spongistatin 1, using boron-mediated aldol reactions to define the stereochemistry, and spongistatin 2 and various fragments , , have been achieved, as have those of rutamycin B and oligomycin C . Syntheses of tetracyclic units of azaspiracid, a marine toxin, , , and of the tricyclic spiroketal portion of the lituarines have been reported. Two total syntheses of the polyketide ratjadone have been published , . Various fragments of the marine polyethers, ciguatoxin , , , , , and gambierol , , , , , , , 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 . 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 .

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) . A double RCM has been used to synthesise the bisdihydropyran 3 and hexaallyl ethers furnish the tris(cyclic ether) 4 through a triple Ru-catalysed RCM (Scheme 2) . This methodology has been used in combination with hydroformylation to synthesise spirocyclic lactones . 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) . 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 . ( 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 .

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) . 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) . Stereoselective cis- and trans- dihydroxylations of the double bond in these fused dihydropyrans have been described .

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) and 2,6-disubstituted tetrahydropyran-4-ols are formed with high diastereoslectivity in the montmorillonite-catalysed reaction between homoallylic alcohols and aldehydes . 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) and Sn(II) catalyses the reaction of acetals with the allylsilane 9 which also yields the 4-methylene compounds (Scheme 8) .

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 and the substituted derivatives of this spiroketal system which form part of the didemnaketals have been prepared in a stereocontrolled manner from pulegone . 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) . An anionic cyclisation also features in the synthesis of chromeno[4,3-c]pyrazoles , a fused heterocyclic system which has also been constructed from bromvinylhydrazones by way of a [3+2] cycloaddition . 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) .

+

Bu3Sn/~'~

r

"

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

A critical review of the 1999 literature preceded by three chapters on current heterocyclic topics

Progress in Heterocyclic Chemistry, Volume 14: A critical review of the 2001 literature preceded by two chapters on current heterocyclic topics

Progress in Heterocyclic Chemistry, Volume 9: A critical review of the 1996 literature preceded by two chapters on current heterocyclic topics

Progress in Heterocyclic Chemistry, Volume 13, Volume 13: A critical review of the 2000 literature preceded by two chapters on current heterocyclic topics

Progress in Heterocyclic Chemistry, Volume 9, Volume 9: A critical review of the 1996 literature preceded by two chapters on current heterocyclic topics

Progress in Heterocyclic Chemistry, Volume 9: A critical review of the 1996 literature preceded by two chapters on current heterocyclic topics

Progress in Heterocyclic Chemistry, Volume 11: A critical review of the 1998 literature preceded by two chapters on current heterocyclic topics

Progress in Heterocyclic Chemistry, Volume 12, Volume 12: A critical review of the 1999 literature preceded by three chapters on current heterocyclic topics

Progress in Heterocyclic Chemistry, Volume 18 (Progress in Heterocyclic Chemistry) (Progress in Heterocyclic Chemistry)

Progress in Heterocyclic Chemistry, Vol. 17 (Progress in Heterocyclic Chemistry) (Progress in Heterocyclic Chemistry)

Progress in Heterocyclic Chemistry, Volume 13 (Progress in Heterocyclic Chemistry)

Progress in Heterocyclic Chemistry, Volume 20 (Progress in Heterocyclic Chemistry)

Progress in Heterocyclic Chemistry, Volume 19 (Progress in Heterocyclic Chemistry)

Progress in Heterocyclic Chemistry, Volume 9 (Progress in Heterocyclic Chemistry)

Aromaticity in Heterocyclic Compounds (Topics in Heterocyclic Chemistry)

Heterocyclic Scaffolds I: ß-Lactams (Topics in Heterocyclic Chemistry)

Heterocyclic Scaffolds I: ß-Lactams (Topics in Heterocyclic Chemistry)

Heterocyclic chemistry

Progress In Heterocyclic Chemistry, Vol. 19

Progress in Heterocyclic Chemistry. Volume 12

Progress in Heterocyclic Chemistry, Volume 19

Topics in current chemistry, 216, Stereoselective Heterocyclic Synthesis III

Progress in Heterocyclic Chemistry. Volume 7

Progress in Heterocyclic Chemistry, Volume 8

Progress in Heterocyclic Chemistry, Volume 17

Progress in Heterocyclic Chemistry. Volume 13

Progress in Heterocyclic Chemistry, Volume 20

Progress in Heterocyclic Chemistry. Volume 15

Progress in Heterocyclic Chemistry. Volume 16

Progress in Heterocyclic Chemistry, Volume 16

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

A critical review of the 1999 literature preceded by three chapters on current heterocyclic topics

Progress in Heterocyclic Chemistry, Volume 14: A critical review of the 2001 literature preceded by two chapters on current heterocyclic topics

Progress in Heterocyclic Chemistry, Volume 9: A critical review of the 1996 literature preceded by two chapters on current heterocyclic topics

Progress in Heterocyclic Chemistry, Volume 13, Volume 13: A critical review of the 2000 literature preceded by two chapters on current heterocyclic topics

Progress in Heterocyclic Chemistry, Volume 9, Volume 9: A critical review of the 1996 literature preceded by two chapters on current heterocyclic topics

Progress in Heterocyclic Chemistry, Volume 9: A critical review of the 1996 literature preceded by two chapters on current heterocyclic topics

Progress in Heterocyclic Chemistry, Volume 11: A critical review of the 1998 literature preceded by two chapters on current heterocyclic topics

Progress in Heterocyclic Chemistry, Volume 12, Volume 12: A critical review of the 1999 literature preceded by three chapters on current heterocyclic topics

Progress in Heterocyclic Chemistry, Volume 18 (Progress in Heterocyclic Chemistry) (Progress in Heterocyclic Chemistry)

Progress in Heterocyclic Chemistry, Vol. 17 (Progress in Heterocyclic Chemistry) (Progress in Heterocyclic Chemistry)

Progress in Heterocyclic Chemistry, Volume 13 (Progress in Heterocyclic Chemistry)

Progress in Heterocyclic Chemistry, Volume 20 (Progress in Heterocyclic Chemistry)

Progress in Heterocyclic Chemistry, Volume 19 (Progress in Heterocyclic Chemistry)

Progress in Heterocyclic Chemistry, Volume 9 (Progress in Heterocyclic Chemistry)

Aromaticity in Heterocyclic Compounds (Topics in Heterocyclic Chemistry)

Heterocyclic Scaffolds I: ß-Lactams (Topics in Heterocyclic Chemistry)

Heterocyclic Scaffolds I: ß-Lactams (Topics in Heterocyclic Chemistry)

Heterocyclic chemistry

Progress In Heterocyclic Chemistry, Vol. 19

Progress in Heterocyclic Chemistry. Volume 12

Progress in Heterocyclic Chemistry, Volume 19

Topics in current chemistry, 216, Stereoselective Heterocyclic Synthesis III

Progress in Heterocyclic Chemistry. Volume 7

Progress in Heterocyclic Chemistry, Volume 8

Progress in Heterocyclic Chemistry, Volume 17

Progress in Heterocyclic Chemistry. Volume 13

Progress in Heterocyclic Chemistry, Volume 20

Progress in Heterocyclic Chemistry. Volume 15

Progress in Heterocyclic Chemistry. Volume 16

Progress in Heterocyclic Chemistry, Volume 16

Recommend Documents